Patent Application
20090156612
The present invention relates to a substituted imidazole compound and the like, which has a superior renin inhibitory activity and is useful as an agent for the prophylaxis or treatment of hypertension, various organ damages attributable to hypertension, and the like.
Hypertension is one of representative lifestyle-related diseases. Hypertension which is left untreated for long time lays a heavy burden on the cardiovascular system and results in arteriosclerosis to progress, thus causing various disorders in important organs, such as cerebral hemorrhage, cerebral infarction, cardiac failure, angina pectoris, myocardial infarction, renal failure and the like. Accordingly, the purpose of treating hypertension lies not only in lowering the blood pressure, but also in improving and/or preventing disorders in important organs including brain, heart and kidney, by controlling the blood pressure. As a method of treating hypertension, there are available fundamental treatments based on improvement in the lifestyle, such as dietetic therapy, exercise therapy and the like, as well as an attempt to control the blood pressure by positive pharmaceutical intervention.
The renin-angiotensin (RA) system is a system of biosynthesis of angiotensin II (AII), which is a major vasopressor factor, and takes an important role in the control of the blood pressure and the amount of body fluid. AII exhibits a strong vasoconstrictive effect brought by the intervention of AII receptors on the cellular membrane, thus raising the blood pressure, and also promotes cellular propagation or production of extracellular matrix by directly acting on the AII receptors in the cardiac cells or renal cells. Therefore, drugs inhibiting increase in the activity of the RA system can be expected to have a blood pressure lowering action as well as a powerful organ protecting action, and thus active researches on such drugs have been conducted so far.
The method of inhibiting the AII action is broadly classified into methods of inhibiting the biosynthesis of AII and methods of inhibiting the binding of AII to AII receptors. For the drugs inhibiting the biosynthesis of AII, angiotensin converting enzyme (ACE) inhibitory drugs have been already put to practical use and are being confirmed to have a blood pressure lowering action as well as an effect for protecting various organs. However, since ACE is an enzyme identical to kininase II, which is a bradykinin degrading enzyme, ACE inhibitory drug inhibits the biosynthesis of AII as well as the degradation of bradykinin. As a result, ACE inhibitory drugs are believed to induce side effects such as dry cough, angioedema and the like, which are considered to be caused by accumulation of bradykinin.
As the drugs inhibiting the binding of AII to AII receptors, AII type 1 receptor blockers (ARB) have been developed. ARB has a merit in that it can inhibit, at the receptor level, the action of AII that is biosynthesized by not only ACE but also an enzyme other than ACE, such as chymase and the like. It is known that administration of ACE inhibitors and ARB increases the plasma renin activity (PRA) as a compensatory feedback effect, since these drugs act on a more peripheral region of the RA system.
Renin is an enzyme occupying a position at the uppermost stream of the RA system, and converts angiotensinogen to angiotensin I. A renin inhibitory drug inhibits the RA system by inhibiting the biosynthesis of AII in the same manner as the ACE inhibitory drugs do, and thus can be expected to have a blood pressure lowering action or an effect of protecting various organs. Since the renin inhibitory drug does not have influence on the metabolism of bradykinin, it is believed to have no risk of side effects such as dry cough and the like, that are observed with the ACE inhibitory drugs. Furthermore, while the ACE inhibitory drugs or ARB increase the PRA level, the renin inhibitory drugs are the only drugs that can reduce PRA.
As renin inhibitors, orally administrable Aliskiren has been reported (Chem. Biol., 2000, vol. 7, pages 493-504; Hypertension, 2003, vol. 42, pages 1137-1143; J. Hypertens., 2005, vol. 23, pages 417-426 etc.). In addition, low molecular weight renin inhibitory drugs are disclosed in WO 2004/002957, WO 2004/089915 and the like.
Imidazole compounds have been reported as orexin receptor antagonists (e.g., WO 2003/002559, WO 2003/002561, WO 2003/032991, WO 2003/041711, WO 2003/051368, WO 2003/051871, WO 2003/051873, WO 2004/026866, WO 2004/041791 etc.).
There is a demand on the development of a novel compound having a superior renin inhibitory activity, which is useful as a pharmaceutical agent (e.g., hypertension, agent for the prophylaxis or treatment of various organ damages attributable to hypertension and the like, and the like).
The present inventors have conducted various studies, and as a result, first succeeded in the creation of a novel compound represented by the following formula (I) and a salt thereof, and found that the compound and a salt thereof unexpectedly have a superior renin inhibitory activity, and are useful as pharmaceutical agents, which resulted in the completion of the present invention.
Accordingly, the present invention relates to the following:
[1] a compound represented by the formula:
wherein
R1 is a substituent,
R2 is a cyclic group optionally having substituent(s), C1-10 alkyl optionally having substituent(s), C2-10 alkenyl optionally having substituent(s) or C2-10 alkynyl optionally having substituent(s),
R3 is a hydrogen atom, a halogen atom, C1-6 alkyl or C1-6 alkoxy,
X is bond or spacer having 1 to 6 atoms in the main chain,
ring A is C5-7 cycloalkane optionally having substituent(s), and
ring B is piperazine optionally further having substituent(s) besides R1,
or a salt thereof [hereinafter to be sometimes abbreviated as compound (I)];
[2] the compound of the aforementioned [1], wherein R1 is a hydrocarbon group optionally having substituent(s);
[3] the compound of the aforementioned [1], wherein R2 is C6-14 aryl optionally having substituent(s) or C3-10 cycloalkyl optionally having substituent(s);
[4] the compound of the aforementioned [1], wherein R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy;
[5] the compound of the aforementioned [1], wherein X is bond or C1-6 alkylene optionally having substituent(s);
[6] the compound of the aforementioned [1], wherein ring A is C5-7 cycloalkane optionally having substituent(s) selected from a halogen atom, a hydrocarbon group optionally having substituent(s), hydroxy optionally having a substituent and amino optionally having substituent(s);
[7] the compound of the aforementioned [1], wherein ring B is a ring represented by the formula:
wherein R1 is as defined above;
[8] a compound represented by the formula:
wherein
R1 is
(a) C1-6 alkyl substituted by hydroxy optionally having a substituent,
(b) C1-6 alkyl substituted by phenylamino optionally having substituent(s), or
(c) C7-13 aralkyl optionally having substituent(s);
R2 is optionally halogenated C6-10 aryl;
R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy;
X is bond or C1-6 alkylene optionally having substituent(s); and
ring A is
(a) C5-7 cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C1-3 alkyl optionally having substituent(s), or
(b) C5-7 cycloalkane substituted by amino optionally having substituent(s);
[9] (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol or a salt thereof;
[10] Methyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate or a salt thereof;
[11] (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol or a salt thereof;
[12] (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(2-methoxy-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol or a salt thereof;
[13] Ethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate or a salt thereof;
[14] (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol or a salt thereof;
[15] (1S,2R)-2-[4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol or a salt thereof;
[16] Methyl [(1S,2S)-2-(4-{[(2R)-2-(2-anilinoethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate or a salt thereof;
[17] (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(2-morpholinobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol or a salt thereof;
[18] (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-methylcyclohexanol or a salt thereof;
[19] (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol or a salt thereof;
[20] (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-{[4-(1H-pyrazol-1-yl)phenyl]amino}ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol or a salt thereof;
[21] (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(5-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol or a salt thereof;
[22] (1S,2R)-2-{4-[((2R)-2-{2-[(2-Ethyl-1,3-benzoxazol-5-yl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol or a salt thereof;
[23] 1-[(4-{[(2R)-2-(2-Anilinoethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)methyl]cyclohexanol or a salt thereof;
[24] a prodrug of the compound of the aforementioned [1];
[25] a pharmaceutical agent comprising the compound of the aforementioned [1] or a prodrug thereof;
[26] the pharmaceutical agent of the aforementioned [25], which is a renin inhibitor;
[27] the pharmaceutical agent of the aforementioned [25], which is an agent for the prophylaxis or treatment of hypertension;
[28] the pharmaceutical agent of the aforementioned [25], which is an agent for the prophylaxis or treatment of various organ damages attributable to hypertension;
[29] a method for the prophylaxis or treatment of hypertension in a mammal, which comprises administering an effective amount of the compound of the aforementioned [1] or a prodrug thereof to the mammal;
[30] use of the compound of the aforementioned [1] or a prodrug thereof for the production of an agent for the prophylaxis or treatment of hypertension; and the like.
Compound (I) has a superior renin inhibitory activity, and thus it is useful as an agent for the prophylaxis or treatment of hypertension, various organ damages attributable to hypertension, and the like.
Examples of the “halogen atom” in the present specification include fluorine, chlorine, bromine and iodine.
Examples of the “C1-4 alkylenedioxy” in the present specification include methylenedioxy, ethylenedioxy, trimethylenedioxy and the like.
Examples of the “C1-6 alkyl” in the present specification include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
Examples of the “C1-6 alkoxy” in the present specification include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
Examples of the “C1-6 alkoxy-carbonyl” in the present specification include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.
Examples of the “C1-6 alkyl-carbonyl” in the present specification include acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanoyl and the like.
The “optionally halogenated” in the present specification means being optionally substituted by 1 to 5, preferably 1 to 3, halogen atoms.
Examples of the “hydrocarbon group” of the “hydrocarbon group optionally having substituent(s)” in the present specification include C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-3 alkylidene, C3-10 cycloalkyl, C3-10 cycloalkenyl, C4-10 cycloalkadienyl, C6-14 aryl, C7-13 aralkyl, C8-13 arylalkenyl, C3-10 cycloalkyl-C1-6 alkyl and the like. The above-mentioned C3-10 cycloalkyl, C3-10 cycloalkenyl and C4-10 cycloalkadienyl are each optionally condensed with a benzene ring.
Examples of the “C1-10 alkyl” in the present specification include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like. Among these, C1-6 alkyl is preferable.
Examples of the “C2-10 alkenyl” in the present specification include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like. Among these, C2-6 alkenyl is preferable.
Examples of the “C2-10 alkynyl” in the present specification include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Among these, C2-6 alkynyl is preferable.
Examples of the “C1-3 alkylidene” in the present specification include methylene, ethylidene, propylidene, isopropylidene and the like.
Examples of the “C3-10 cycloalkyl” in the present specification include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl, adamantyl and the like. Among these, C3-6 cycloalkyl is preferable. The above-mentioned C3-10 cycloalkyl is optionally condensed with a benzene ring. Examples of the condensed group include indanyl, tetrahydronaphthyl, fluorenyl and the like.
Examples of the “C3-10 cycloalkenyl” in the present specification include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. The above-mentioned C3-10 cycloalkenyl is optionally condensed with a benzene ring. Examples of the condensed group include indenyl and the like.
Examples of the “C4-10 cycloalkadienyl” in the present specification include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like. The above-mentioned C4-10 cycloalkadienyl is optionally condensed with a benzene ring.
Examples of the “C6-14 aryl” in the present specification include phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like. Among these, C6-10 aryl is preferable, and phenyl is more preferable. The above-mentioned C6-14 aryl is optionally condensed with C3-10 cycloalkane (examples of the C3-10 cycloalkane include rings corresponding to the above-mentioned C3-10 cycloalkyl). Examples of the condensed group include tetrahydronaphthyl and the like.
Examples of the “C7-13 aralkyl” in the present specification include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like.
Examples of the “C8-13 arylalkenyl” in the present specification include styryl and the like.
Examples of the “C3-10 cycloalkyl-C1-6 alkyl” in the present specification include cyclopropylmethyl, cyclohexylmethyl and the like.
The “hydrocarbon group” of the “hydrocarbon group optionally having substituent(s)” optionally have substituent(s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position(s). When the number of the substituents is not less than 2, respective substituents may be the same or different.
Examples of the “substituent” of the “hydrocarbon group optionally having substituent(s)” include the following substituents.
(1) a halogen atom;
(2) C3-10 cycloalkyl (e.g., cyclopropyl, cyclohexyl);
(3) C6-14 aryl (e.g., phenyl, naphthyl) optionally having 1 to 3 substituents selected from
Examples of the “cyclic group” of the “cyclic group optionally having substituent(s)” in the present specification include an aromatic group, a non-aromatic cyclic group and the like.
Examples of the “aromatic group” include an aromatic hydrocarbon group and an aromatic heterocyclic group.
Examples of the “aromatic hydrocarbon group” include C6-14 aryl and the like.
Examples of the “aromatic heterocyclic group” include a 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a fused aromatic heterocyclic group. Examples of the fused aromatic heterocyclic group include a group derived from a fused ring wherein a ring corresponding to such 4- to 7-membered monocyclic aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms, a 5-membered aromatic heterocycle containing one sulfur atom and a benzene ring are condensed, and the like.
Examples of the “aromatic heterocyclic group” include 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic groups such as furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5-yl), triazinyl (e.g., 1,3,5-triazin-2-yl, 1,3,5-triazin-4-yl, 1,2,3-triazin-4-yl, 1,2,4-triazin-3-yl) and the like;
fused aromatic heterocyclic groups such as quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), quinazolyl (e.g., 2-quinazolyl, 4-quinazolyl), quinoxalyl (e.g., 2-quinoxalyl, 6-quinoxalyl), benzofuranyl (e.g., 2-benzofuranyl, 3-benzofuranyl), benzothienyl (e.g., 2-benzothienyl, 3-benzothienyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzisoxazolyl (e.g., 7-benzisoxazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (e.g., 1H-indazol-3-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, 2H-imidazo[1,2-a]pyridin-3-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-2-yl), pyrazolopyridyl (e.g., 1H-pyrazolo[4,3-c]pyridin-3-yl), pyrazolothienyl (e.g., 2H-pyrazolo[3,4-b]thiophen-2-yl), pyrazolotriazinyl (e.g., pyrazolo[5,1-c][1,2,4]triazin-3-yl) and the like; and the like.
Examples of the “non-aromatic cyclic group” include a non-aromatic cyclic hydrocarbon group and a non-aromatic heterocyclic group.
Examples of the “non-aromatic cyclic hydrocarbon group” include C3-10 cycloalkyl, C3-10 cycloalkenyl and C4-10 cycloalkadienyl, each of which is optionally condensed with a benzene ring, and the like.
Examples of the “non-aromatic heterocyclic group” include a 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a fused non-aromatic heterocyclic group. Examples of the fused non-aromatic heterocyclic group include a group derived from a fused ring wherein a ring corresponding to such 4- to 7-membered monocyclic non-aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered heterocycle containing 1 or 2 nitrogen atoms, a 5-membered heterocycle containing one sulfur atom and a benzene ring are condensed, and the like.
Examples of the “non-aromatic heterocyclic group” include 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic groups such as pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (e.g., piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), morpholinyl (e.g., morpholino), thiomorpholinyl (e.g., thiomorpholino), piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), hexamethyleniminyl (e.g., hexamethylenimin-1-yl), oxazolidinyl (e.g., oxazolidin-2-yl), thiazolidinyl (e.g., thiazolidin-2-yl), imidazolidinyl (e.g., imidazolidin-2-yl, imidazolidin-3-yl), oxazolinyl (e.g., oxazolin-2-yl), thiazolinyl (e.g., thiazolin-2-yl), imidazolinyl (e.g., imidazolin-2-yl, imidazolin-3-yl), dioxolyl (e.g., 1,3-dioxol-4-yl), dioxolanyl (e.g., 1,3-dioxolan-4-yl), dihydrooxadiazolyl (e.g., 4,5-dihydro-1,2,4-oxadiazol-3-yl), 2-thioxo-1,3-oxazolidin-5-yl, pyranyl (e.g., 4-pyranyl), tetrahydropyranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), thiopyranyl (e.g., 4-thiopyranyl), tetrahydrothiopyranyl (e.g., 2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl), 1-oxidotetrahydrothiopyranyl (e.g., 1-oxidotetrahydrothiopyran-4-yl), 1,1-dioxidotetrahydrothiopyranyl (e.g., 1,1-dioxidotetrahydrothiopyran-4-yl), tetrahydrofuryl (e.g., tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), pyrazolidinyl (e.g., pyrazolidin-1-yl, pyrazolidin-3-yl), pyrazolinyl (e.g., pyrazolin-1-yl), tetrahydropyrimidinyl (e.g., tetrahydropyrimidin-1-yl), dihydrotriazolyl (e.g., 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (e.g., 2,3,4,5-tetrahydro-1H-1,2,3-triazol-1-yl) and the like; fused non-aromatic heterocyclic groups such as dihydroindolyl (e.g., 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (e.g., 1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl (e.g., 2,3-dihydrobenzofuran-5-yl), dihydrobenzodioxinyl (e.g., 2,3-dihydro-1,4-benzodioxinyl), dihydrobenzodioxepinyl (e.g., 3,4-dihydro-2H-1,5-benzodioxepinyl), tetrahydrobenzofuranyl (e.g., 4,5,6,7-tetrahydrobenzofuran-3-yl), chromenyl (e.g., 4H-chromen-2-yl, 2H-chromen-3-yl), dihydroquinolinyl (e.g., 1,2-dihydroquinolin-4-yl), tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (e.g., 1,2-dihydroisoquinolin-4-yl), tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydroisoquinolin-4-yl), dihydrophthalazinyl (e.g., 1,4-dihydrophthalazin-4-yl) and the like; and the like.
The “cyclic group” optionally has substituent(s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position(s). When the number of the substituents is not less than 2, respective substituents may be the same or different. Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like.
Examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent(s)” in the present specification include an aromatic heterocyclic group and a non-aromatic heterocyclic group.
Examples of the “aromatic heterocyclic group” and “non-aromatic heterocyclic group” include those similar to the “aromatic heterocyclic group” and “non-aromatic heterocyclic group” which are exemplified as the “cyclic group” of the “cyclic group optionally having substituent(s)”.
The above-mentioned “heterocyclic group” optionally has substituent(s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position(s). When the number of the substituents is not less than 2, respective substituents may be the same or different. Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like.
Examples of the “hydroxy optionally having a substituent” in the present specification include (1) hydroxy, (2) hydroxy having, instead of a hydrogen atom of hydroxy, for example, a substituent selected from the aforementioned “hydrocarbon group optionally having substituent(s)”, the aforementioned “heterocyclic group optionally having substituent(s)”, the groups exemplified as the substituents which the aforementioned “hydrocarbon group optionally having substituent(s)” optionally has, and the like, and the like.
Specific examples of the “hydroxy optionally having a substituent” include (1) hydroxy, (2) hydroxy optionally having a substituent selected from C1-10 alkyl optionally having substituent(s), C2-10 alkenyl optionally having substituent(s), C3-10 cycloalkyl optionally having substituent(s), C3-10 cycloalkenyl optionally having substituent(s), C6-14 aryl optionally having substituent(s), C7-13 aralkyl optionally having substituent(s), C8-13 arylalkenyl optionally having substituent(s), a heterocyclic group optionally having substituent(s), acyl and the like, and the like.
The aforementioned C1-10 alkyl, C2-10 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C6-14 aryl, C7-13 aralkyl and C8-13 arylalkenyl optionally have substituent(s) (preferably 1 to 3 substituents) at substitutable position(s). Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different.
Examples of the “amino optionally having substituent(s)” in the present specification include (1) amino, (2) amino having, instead of hydrogen atom(s) of amino, for example, 1 or 2 substituents selected from the aforementioned “hydrocarbon group optionally having substituent(s)”, the aforementioned “heterocyclic group optionally having substituent(s)”, the groups exemplified as the substituents which the aforementioned “hydrocarbon group optionally having substituent(s)” optionally has, and the like, and the like.
Specific examples of the “amino optionally having substituent(s)” include (1) amino, (2) amino optionally having 1 or 2 substituents selected from C1-10 alkyl optionally having substituent(s), C2-10 alkenyl optionally having substituent(s), C3-10 cycloalkyl optionally having substituent(s), C3-10 cycloalkenyl optionally having substituent(s), C6-14 aryl optionally having substituent(s), C7-13 aralkyl optionally having substituent(s), C8-13 arylalkenyl optionally having substituent(s), a heterocyclic group optionally having substituent(s), acyl and the like, and the like.
The aforementioned C1-10 alkyl, C2-10 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C6-14 aryl, C7-13 aralkyl and C8-13 arylalkenyl optionally have substituent(s) (preferably 1 to 3 substituents) at substitutable position(s). Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different.
Examples of the “mercapto optionally having a substituent” in the present specification include (1) mercapto, (2) mercapto having, instead of a hydrogen atom of mercapto, for example, a substituent selected from the aforementioned “hydrocarbon group optionally having substituent(s)”, the aforementioned “heterocyclic group optionally having substituent(s)”, the groups exemplified as the substituents which the aforementioned “hydrocarbon group optionally having substituent(s)” optionally has, and the like, and the like.
Specific examples of the “mercapto optionally having a substituent” include (1) mercapto, (2) mercapto optionally having a substituent selected from C1-10 alkyl optionally having substituent(s), C2-10 alkenyl optionally having substituent(s), C3-10 cycloalkyl optionally having substituent(s), C3-10 cycloalkenyl optionally having substituent(s), C6-14 aryl optionally having substituent(s), C7-13 aralkyl optionally having substituent(s), C8-13 arylalkenyl optionally having substituent(s), a heterocyclic group optionally having substituent(s), acyl and the like, and the like.
The aforementioned C1-10 alkyl, C2-10 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C6-14 aryl, C7-13 aralkyl and CB-13 arylalkenyl optionally have substituent(s) (preferably 1 to 3 substituents) at substitutable position(s). Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different.
Examples of the “acyl” in the present specification include a group represented by the formula: —CORA, —CO—ORA, —SO2RA, —SORA, —CO—NRA′RB′ or —CS—NRA′RB′ [wherein RA is a hydrogen atom, a hydrocarbon group optionally having substituent(s) or a heterocyclic group optionally having substituent(s), and RA′ and RB′ are the same or different and each is a hydrogen atom, a hydrocarbon group optionally having substituent(s) or a heterocyclic group optionally having substituent(s), or RA′ and RB′ optionally form, together with the adjacent nitrogen atom, a nitrogen-containing heterocycle optionally having substituent(s)] and the like.
Examples of the “nitrogen-containing heterocycle” of the “nitrogen-containing heterocycle optionally having substituent(s)” formed by RA′ and RB′ together with the adjacent nitrogen atom include a 5- to 7-membered nitrogen-containing heterocycle containing, as a ring-constituting atom besides carbon atoms, at least one nitrogen atom and optionally further containing one or two heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Specific examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like.
The nitrogen-containing heterocycle optionally has substituent(s) (preferably 1 to 3, more preferably 1 or 2 substituents) at substitutable position(s). Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different.
Preferable examples of the “acyl” include
(1) formyl;
(2) carboxy;
(3) carbamoyl;
(4) C1-6 alkyl-carbonyl;
(5) C1-6 alkoxy-carbonyl optionally having 1 to 3 substituents selected from carboxy, carbamoyl, thiocarbamoyl, C1-6 alkoxy-carbonyl and C1-6 alkyl-carbonyloxy (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl; carboxymethoxycarbonyl, carboxyethoxycarbonyl, carboxybutoxycarbonyl; carbamoylmethoxycarbonyl; thiocarbamoylmethoxycarbonyl; ethoxycarbonylmethoxycarbonyl, ethoxycarbonylethoxycarbonyl, methoxycarbonylbutoxycarbonyl, ethoxycarbonylbutoxycarbonyl; tert-butylcarbonyloxymethoxycarbonyl);
(6) C3-10 cycloalkyl-carbonyl (e.g., cyclopentylcarbonyl, cyclohexylcarbonyl);
(7) C6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl) optionally having 1 to 3 substituents selected from a halogen atom, cyano, C1-6 alkyl optionally substituted by 1 to 3 halogen atoms, C1-6 alkoxy, carboxy, C1-6 alkoxy-carbonyl, an aromatic heterocyclic group (e.g., tetrazolyl, oxadiazolyl), a non-aromatic heterocyclic group (e.g., oxooxadiazolyl) and carbamoyl;
(8) C6-14 aryloxy-carbonyl (e.g., phenyloxycarbonyl, naphthyloxycarbonyl) optionally having 1 to 3 substituents selected from carboxy, C1-6 alkoxy-carbonyl and carbamoyl;
(9) C7-13 aralkyloxy-carbonyl optionally having 1 to 3 substituents selected from carboxy, carbamoyl, thiocarbamoyl, C1-6 alkoxy-carbonyl, a halogen atom, cyano, nitro, C1-6 alkoxy, C1-6 alkylsulfonyl and C1-6 alkyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl; carboxybenzyloxycarbonyl; methoxycarbonylbenzyloxycarbonyl; biphenylylmethoxycarbonyl);
(10) carbamoyl mono- or di-substituted by C1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, trifluoroethylcarbamoyl, N-methoxyethyl-N-methylcarbamoyl);
(11) C1-6 alkylsulfonyl optionally having 1 to 3 substituents selected from carboxy, carbamoyl and C1-6 alkoxy-carbonyl (e.g., methylsulfonyl, carboxymethylsulfonyl);
(12) C1-6 alkylsulfinyl (e.g., methylsulfinyl);
(13) thiocarbamoyl;
(14) C7-13 aralkyl-carbonyl (e.g., benzylcarbonyl, phenethylcarbonyl);
(15) aromatic heterocyclyl (e.g., furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, benzofuryl, benzothienyl, quinoxalinyl)-carbonyl (e.g., furylcarbonyl, thienylcarbonyl, thiazolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, pyrazinylcarbonyl, benzofurylcarbonyl, benzothienylcarbonyl, quinoxalinylcarbonyl) optionally having 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl, C7-13 aralkyl, C1-6 alkoxy, carboxy, C1-6 alkoxy-carbonyl and carbamoyl; and the like.
Each symbol in the formula (I) is described in detail in the following.
R1 is a substituent.
Examples of the “substituent” for R1 include a halogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), hydroxy optionally having a substituent, amino optionally having substituent(s), acyl and the like.
R1 is preferably a halogen atom, a hydrocarbon group optionally having substituent(s), hydroxy optionally having a substituent, amino optionally having substituent(s) or the like, more preferably a hydrocarbon group optionally having substituent(s), further more preferably C1-6 alkyl optionally having substituent(s), C7-13 aralkyl optionally having substituent(s) or the like, particularly preferably
(a) C1-6 alkyl substituted by hydroxy optionally having a substituent (e.g., a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), heterocyclylcarbonyl optionally having substituent(s)),
(b) C1-6 alkyl substituted by a heterocyclic group optionally having substituent(s) or amino optionally having substituent(s),
(c) C7-13 aralkyl optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), cyano, hydroxy, C1-6 alkoxy optionally having substituent(s), a heterocyclic group optionally having substituent(s)), or the like.
More preferably, R1 is
(a) C1-6 alkyl substituted by hydroxy optionally having a substituent (e.g., a fused aromatic heterocyclic group such as benzofuranyl (e.g., 5-benzofuranyl, 6-benzofuranyl), benzothienyl (e.g., 5-benzothienyl, 6-benzothienyl), benzoxazolyl (e.g., 5-benzoxazolyl, 6-benzoxazolyl), benzisoxazolyl (e.g., 5-benzisoxazolyl, 6-benzisoxazolyl), benzothiazolyl (e.g., 5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-5-yl, indol-6-yl), indazolyl (e.g., 1H-indazol-5-yl, 1H-indazol-6-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-c]pyridin-5-yl, 2H-imidazo[1,2-a]pyridin-5-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-5-yl), pyrazolopyridyl (e.g., 1H-pyrazolo[4,3-c]pyridin-5-yl), pyrazolothienyl (e.g., 2H-pyrazolo[3,4-b]thiophen-2-yl) and the like),
(b) C1-6 alkyl substituted by phenylamino optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s)),
(c) C7-13 aralkyl optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s), a monocyclic aromatic heterocyclic group optionally having substituent(s)), or the like.
Preferable embodiments of R1 include
(1) C7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl) optionally having 1 to 3 substituents selected from
Other preferable embodiments of R1 include
(1) C7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from
Still other preferable embodiments of R1 include
(1) C7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from
R2 is a cyclic group optionally having substituent(s), C1-10 alkyl optionally having substituent(s), C2-10 alkenyl optionally having substituent(s) or C2-10 alkynyl optionally having substituent(s).
The aforementioned C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl optionally have substituent(s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position(s). Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different.
R2 is preferably C6-14 aryl optionally having substituent(s), C3-10 cycloalkyl optionally having substituent(s) or the like.
R2 is more preferably optionally halogenated C6-10 aryl (e.g., phenyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl) or the like.
R2 is particularly preferably optionally halogenated C6-10 aryl (e.g., phenyl) or the like.
R3 is a hydrogen atom, a halogen atom, C1-6 alkyl or C1-6 alkoxy.
R3 is preferably a hydrogen atom, a halogen atom, C1-3 alkyl (e.g., methyl, ethyl, propyl, isopropyl), C1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy) or the like, more preferably a hydrogen atom or the like.
X is bond or spacer having 1 to 6 atoms in the main chain.
The “main chain” of the “spacer having 1 to 6 atoms in the main chain” for X is a straight chain connecting ring A and imidazole, and the atom number of the main chain is counted such that the number of atoms in the main chain will be minimum. The “main chain” consists of 1 to 6 atoms selected from a carbon atom and a hetero atom (e.g., O, S, N etc.), and may be saturated or unsaturated. In addition, S may be oxidized.
Examples of the “spacer having 1 to 6 atoms in the main chain” include straight chain C1-6 alkylene, —X1—NH—X2—, —X1—O—X2— and —X1—S—X2— [wherein X1 and X2 are the same or different and each is bond or straight chain C1-5 alkylene, when X1 and X2 are both straight chain C1-5 alkylene, then the total carbon number of straight chain C1-5 alkylene for X1 and straight chain C1-5 alkylene for X2 is 5 or less, and S is optionally oxidized] and the like.
Examples of the “straight chain C1-6 alkylene” include —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2— and —CH2CH2CH2CH2CH2CH2—.
Examples of the “straight chain C1-5 alkylene” for X1 or X2 include —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2— and —CH2CH2CH2CH2CH2—.
The “spacer having 1 to 6 atoms in the main chain” optionally has substituent(s) (preferably 1 to 3 substituents) at substitutable position(s) (optionally at the carbon atom and nitrogen atom constituting the main chain). Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different.
X is preferably bond, C1-6 alkylene optionally having substituent(s) or the like.
X is more preferably
(1) bond,
(2) C1-6 alkylene optionally having substituent(s) selected from C1-6 alkyl and C6-10 aryl (e.g., phenyl) or the like.
Ring A is C5-7 cycloalkane optionally having substituent(s).
Examples of the “C5-7 cycloalkane” of the “C5-7 cycloalkane optionally having substituent(s)” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane and the like.
The “C5-7 cycloalkane” of the “C5-7 cycloalkane optionally having substituent(s)” optionally has substituent(s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position(s). When the number of the substituents is not less than 2, respective substituents may be the same or different, and may be substituted at the same carbon of ring A. In addition, two substituents may be bonded each other to form, with C5-7 cycloalkane, an optionally substituted ring (a fused ring or spiro ring).
Examples of the fused ring or spiro ring include a fused ring or spiro ring consisting of C5-7 cycloalkane and C3-10 cycloalkane, C3-10 cycloalkene, C4-10 cycloalkadiene or a heterocycle. Examples of the “C3-10 cycloalkane”, “C3-10 cycloalkene”, “C4-10 cycloalkadiene” and “heterocycle” include rings corresponding to the aforementioned C3-10 cycloalkyl, C3-10 cycloalkenyl, C4-10 cycloalkadienyl and heterocyclic group.
Examples of the “substituent” of the “C5-7 cycloalkane optionally having substituent(s)” include a halogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), hydroxy optionally having a substituent, amino optionally having substituent(s), mercapto optionally having substituent(s), cyano, acyl and the like. Preferable example thereof include a halogen atom, a hydrocarbon group optionally having substituent(s), hydroxy optionally having a substituent, amino optionally having substituent(s) and the like. More preferable Example thereof include a halogen atom, a hydrocarbon group optionally having substituent(s), hydroxy optionally having a substituent and the like.
Ring A is preferably C5-7 cycloalkane optionally having substituent(s) selected from a halogen atom, a hydrocarbon group optionally having substituent(s), hydroxy optionally having a substituent and amino optionally having substituent(s).
More preferably, ring A is
(a) C5-7 cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent(s) (e.g., a halogen atom, a hydrocarbon group optionally having substituent(s) etc.), or
(b) C5-7 cycloalkane substituted by amino optionally having substituent(s) (e.g., a hydrocarbon group optionally having substituent(s), acyl etc.).
Further more preferably, ring A is
(a) C5-7 cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent(s) (e.g., C1-3 alkyl optionally having substituent(s) etc.), or
(b) C5-7 cycloalkane substituted by amino optionally having substituent(s) (e.g., C1-6 alkoxy-carbonyl etc.).
Still more preferably, ring A is
(a) C5-7 cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C1-3 alkyl optionally having substituent(s), or
(b) C5-7 cycloalkane substituted by amino optionally having substituent(s) (e.g., C1-6 alkoxy-carbonyl etc.).
Still more preferably, ring A is
(a) C5-7 cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent(s) (e.g., cyclopropylmethyl, methyl, methoxymethyl, ethoxymethyl etc.), or
(b) C5-7 cycloalkane substituted by amino optionally having substituent(s) (e.g., methoxycarbonyl, ethoxycarbonyl etc.).
Preferable embodiments of ring A is the following [A] and [B] and the like.
[A]: C5-7 cycloalkane optionally having 1 to 5 substituents selected from
(1) a halogen atom;
(2) C1-6 alkyl optionally having 1 to 5 substituents selected from
More preferable embodiments of ring A is the following [A] and [B] and the like.
[A]: C5-7 cycloalkane optionally having 1 to 5 substituents selected from
(1) a halogen atom;
(2) C1-6 alkyl optionally having 1 to 5 substituents selected from
Ring B is piperazine optionally further having substituent(s) besides R1.
Examples of the “substituent” which ring B optionally further has include groups exemplified as the “substituent” for R1 optionally has, and the like. Specific examples of the “substituent” include optionally substituted C1-6 alkyl, for example, C1-6 alkyl optionally having a 5- or 6-membered non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C1-6 alkyl and oxo, and the like.
Ring B is preferably a ring represented by the formula:
wherein R1 is as defined above. The piperazine ring optionally has 1 to 3 C1-6 alkyl at the ring-constituting carbon atom.
Preferable examples of compound (I) include the following compounds.
Compound (I) wherein
R1 is a hydrocarbon group optionally having substituent(s);
R2 is C6-14 aryl optionally having substituent(s) or C3-10 cycloalkyl optionally having substituent(s);
R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy;
X is bond or C1-6 alkylene optionally having substituent(s); and
ring A is C5-7 cycloalkane optionally having substituent(s) selected from a halogen atom, a hydrocarbon group optionally having substituent(s), hydroxy optionally having a substituent and amino optionally having substituent(s).
A compound represented by the formula:
wherein
R1 is
(a) C1-6 alkyl substituted by hydroxy optionally having a substituent (e.g., a fused aromatic heterocyclic group such as benzofuranyl (e.g., 5-benzofuranyl, 6-benzofuranyl), benzothienyl (e.g., 5-benzothienyl, 6-benzothienyl), benzoxazolyl (e.g., 5-benzoxazolyl, 6-benzoxazolyl), benzisoxazolyl (e.g., 5-benzisoxazolyl, 6-benzisoxazolyl), benzothiazolyl (e.g., 5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-5-yl, indol-6-yl), indazolyl (e.g., 1H-indazol-5-yl, 1H-indazol-6-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-c]pyridin-5-yl, 2H-imidazo[1,2-a]pyridin-5-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-5-yl), pyrazolopyridyl (e.g., 1H-pyrazolo[4,3-c]pyridin-5-yl), pyrazolothienyl (e.g., 2H-pyrazolo[3,4-b]thiophen-2-yl) and the like),
(b) C1-6 alkyl substituted by phenylamino optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s)), or
(c) C7-13 aralkyl optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s), a monocyclic aromatic heterocyclic group optionally having substituent(s));
R2 is optionally halogenated C6-10 aryl (e.g., phenyl), or C3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl);
R3 is a hydrogen atom;
X is
(1) bond, or
(2) C1-6 alkylene optionally having substituent(s) selected from C1-6 alkyl and C6-10 aryl (e.g., phenyl); and
ring A is
(a) C5-7 cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent(s) (e.g., C1-3 alkyl optionally having substituent(s) etc.), or
(b) C5-7 cycloalkane substituted by amino optionally having substituent(s) (e.g., C1-6 alkoxy-carbonyl etc.).
A compound represented by the formula:
wherein
R1 is
(a) C1-6 alkyl substituted by hydroxy optionally having a substituent (e.g., a fused aromatic heterocyclic group such as benzofuranyl (e.g., 5-benzofuranyl, 6-benzofuranyl), benzothienyl (e.g., 5-benzothienyl, 6-benzothienyl), benzoxazolyl (e.g., 5-benzoxazolyl, 6-benzoxazolyl), benzisoxazolyl (e.g., 5-benzisoxazolyl, 6-benzisoxazolyl), benzothiazolyl (e.g., 5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-5-yl, indol-6-yl), indazolyl (e.g., 1H-indazol-5-yl, 1H-indazol-6-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-c]pyridin-5-yl, 2H-imidazo[1,2-a]pyridin-5-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-5-yl), pyrazolopyridyl (e.g., 1H-pyrazolo[4,3-c]pyridin-5-yl), pyrazolothienyl (e.g., 2H-pyrazolo[3,4-b]thiophen-2-yl) and the like),
(b) C1-6 alkyl substituted by phenylamino optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s)), or
(c) C7-13 aralkyl optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s), a monocyclic aromatic heterocyclic group optionally having substituent(s));
R2 is optionally halogenated C6-10 aryl (e.g., phenyl);
R3 is a hydrogen atom, a halogen atom, C1-3 alkyl (e.g., methyl, ethyl, propyl, isopropyl) or C1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy);
X is
(1) bond, or
(2) C1-6 alkylene optionally having substituent(s) (e.g., C1-6 alkyl, C6-10 aryl (e.g., phenyl), etc.); and
ring A is
(a) C5-7 cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C1-3 alkyl optionally having substituent(s), or
(b) C5-7 cycloalkane substituted by amino optionally having substituent(s) (e.g., C1-6 alkoxy-carbonyl etc.).
Compound B′ wherein R1 is C1-6 alkyl substituted by hydroxy optionally having a substituent (e.g., a fused aromatic heterocyclic group such as benzofuranyl (e.g., 5-benzofuranyl, 6-benzofuranyl), benzothienyl (e.g., 5-benzothienyl, 6-benzothienyl), benzoxazolyl (e.g., 5-benzoxazolyl, 6-benzoxazolyl), benzisoxazolyl (e.g., 5-benzisoxazolyl, 6-benzisoxazolyl), benzothiazolyl (e.g., 5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-5-yl, indol-6-yl), indazolyl (e.g., 1H-indazol-5-yl, 1H-indazol-6-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-c]pyridin-5-yl, 2H-imidazo[1,2-a]pyridin-5-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-5-yl), pyrazolopyridyl (e.g., 1H-pyrazolo[4,3-c]pyridin-5-yl), pyrazolothienyl (e.g., 2H-pyrazolo[3,4-b]thiophen-2-yl) and the like).
Compound B′ wherein R1 is C1-6 alkyl substituted by phenylamino optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s)).
Compound B′ wherein R1 is C7-13 aralkyl optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s), a monocyclic aromatic heterocyclic group optionally having substituent(s)).
Compound B′ wherein ring A is C5-7 cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C1-3 alkyl optionally having substituent(s).
Compound B′ wherein ring A is C5-7 cycloalkane substituted by amino optionally having substituent(s) (e.g., C1-6 alkoxy-carbonyl etc.).
A compound represented by the formula:
wherein
R1 is
(1) C7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl) optionally having 1 to 3 substituents selected from
R2 is optionally halogenated C6-10 aryl (e.g., phenyl), or C3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl);
R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy;
X is
(1) bond, or
(2) C1-6 alkylene optionally having substituent(s) selected from C1-6 alkyl and C6-10 aryl (e.g., phenyl); and
ring A is
[A] C5-7 cycloalkane optionally having 1 to 5 substituents selected from the following (1) to (8), or [B] C5-7 cycloalkane forming, together with a 5- or 6-membered non-aromatic heterocycle, a spiro ring (e.g., 1-oxa-3-azaspiro[4.5]decyl) optionally having 1 or 2 oxo:
(1) a halogen atom;
(2) C1-6 alkyl optionally having 1 to 5 substituents selected from
Compound (I) wherein
R1 is
(1) C7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from
R2 is optionally halogenated C6-10 aryl (e.g., phenyl), or C3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl);
R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy;
X is
(1) bond, or
(2) C1-6 alkylene optionally having substituent(s) selected from C1-6 alkyl and C6-10 aryl (e.g., phenyl);
ring A is
[A] C5-7 cycloalkane optionally having 1 to 5 substituents selected from the following (1) to (8), or [B] C5-7 cycloalkane forming, together with a 5- or 6-membered non-aromatic heterocycle, a spiro ring (e.g., 1-oxa-3-azaspiro[4.5]decyl) optionally having 1 or 2 oxo:
(1) a halogen atom;
(2) C1-6 alkyl optionally having 1 to 5 substituents selected from
ring B is piperazine optionally further having, besides R1, C1-6 alkyl optionally having a 5- or 6-membered non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C1-6 alkyl and oxo.
Compound (I) wherein
R1 is
(1) C7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from
R2 is optionally halogenated C6-10 aryl (e.g., phenyl), or C3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl);
R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy;
X is
(1) bond, or
(2) C1-6 alkylene optionally having substituent(s) selected from C1-6 alkyl and C6-10 aryl (e.g., phenyl);
ring A is
[A] C5-7 cycloalkane optionally having 1 to 5 substituents selected from the following (1) to (8), or [B] C5-7 cycloalkane forming, together with a 5- or 6-membered non-aromatic heterocycle, a spiro ring (e.g., 1-oxa-3-azaspiro[4.5]decyl) optionally having 1 or 2 oxo:
(1) a halogen atom;
(2) C1-6 alkyl optionally having 1 to 5 substituents selected from
ring B is piperazine optionally further having, besides R1, C1-6 alkyl optionally having a 5- or 6-membered non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C1-6 alkyl and oxo.
Specific examples of compound (I) include
Another specific examples of compound (I) include
Examples of the salt of compound (I) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
Preferable examples of the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like.
Preferable examples of the salt with organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine or the like.
Preferable examples of the salt with inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or the like.
Preferable examples of the salt with organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like.
Preferable examples of the salt with basic amino acid include a salt with arginine, lysine, ornithine or the like.
Preferable examples of the salt with acidic amino acid include a salt with aspartic acid, glutamic acid or the like.
Of these, a pharmaceutically acceptable salt is preferable. When the compound has an acidic functional group, examples thereof include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.) and the like, ammonium salts, and the like. When the compound has a basic functional group, examples thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
The production methods of compound (I) are shown in the following.
Compound (I) is obtained by, for example, a method shown in the following reaction scheme or a method analogous thereto, or the like.
Each of compounds (II)-(VIII) shown in the reaction scheme may form a salt. Examples of the salt include salts similar to the salts of compound (I).
The compound obtained in each step can also be used for the next reaction directly as the reaction mixture or as a crude product. In addition, it can also be isolated from the reaction mixture according to a conventional method, and can be isolated and purified by a known method such as phase transfer, concentration, solvent extraction, fractional distillation, pH conversion, crystallization, recrystallization, chromatography and the like.
The schematic drawings of the reaction scheme are shown in the following.
R is C1-4 alkyl, Y is a hydrogen atom or an alkali metal atom, PG is an N-protecting group (e.g., benzyl, tert-butoxycarbonyl, benzyloxycarbonyl etc.), and the other symbols are as defined above.
This method is used for the production of compound (IV) wherein R3 is a hydrogen atom.
Compound (II) may be commercially available, or can be produced according to a method known per se, for example, the method described in Tetrahedron: Asymmetry, 1997, vol. 8, pages 3153-3159, or the like, or a method analogous thereto.
The production of compound (III), and the production of compound (IV) by the reaction of compound (II) with compound (III) are performed, for example, according to the method described in Journal of Organic Chemistry, 1994, vol. 59, pages 7635-7642, or the like, or a method analogous thereto.
Compound (IV) wherein R3 is a halogen atom, C1-6 alkyl or C1-6 alkoxy can be produced according to a method known per se, for example, the method described in Journal of Organic Chemistry, 2004, vol. 69, pages 8829-8835, or the like, or a method analogous thereto.
Compound (IV) can be modified by further carrying out one or more of known acylation reaction, alkylation reaction, amination reaction, oxidation-reduction reaction, cyclization reaction, carbon chain extension reaction, substituent exchange reaction and the like, as desired.
Compound (V) can be produced by subjecting compound (IV) to known hydrolysis, for example, alkali-hydrolysis or acid-hydrolysis.
The reaction is advantageously carried out under alkali conditions. Preferable examples of the alkali to be used for this step include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. The amount of the alkali to be used is about 1 mol to large excess, preferably 1 to 5 mol, per 1 mol of compound (IV).
The reaction is advantageously carried out in an inert solvent. While the solvent is not particularly limited as long as the reaction proceeds, preferable examples of the solvent include alcohols such as methanol, ethanol, propanol and the like; hydrocarbons such as benzene, toluene, cyclohexane, hexane and the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like, a mixed solvent thereof, and the like.
While the reaction time varies depending on the reagent or solvent to be used, it is generally 30 min to 24 hr, preferably 30 min to 8 hr.
The reaction temperature is generally 0 to 150° C., preferably 20 to 80° C.
After the reaction, compound (V) (wherein Y is a hydrogen atom) is obtained as a free form by neutralizing the reaction mixture with a mineral acid (e.g., hydrochloric acid, sulfuric acid etc.), an organic acid (e.g., acetic acid etc.) or an ion exchange resin. Alternatively, compound (V) (wherein Y is an alkali metal atom such as lithium, sodium, potassium and the like) is obtained as an alkali metal salt of the carboxylic acid by directly concentrating the reaction mixture.
Compound (VII) can be produced by a condensation reaction of compound (V) with compound (VI).
Compound (VI) may be commercially available, or can be produced according to a method known per se, for example, the method described in WO 2003/000181 or the like, or a method analogous thereto.
When Y is a hydrogen atom, the condensation reaction is carried out according to a conventional peptide synthesis technique, for example, an acid chloride method, an acid anhydride method, a mixed anhydride method, a method of using N,N′-dicyclohexylcarbodiimide (DCC), an active ester method, a method of using N,N′-carbonyldiimidazole (CDI), a method of using diethyl cyanophosphate (DEPC), a method of using N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl) and 1-hydroxybenzotriazole (HOBt), or the like. Compound (VI) is used in an amount of about 1 to 2 mol, preferably about 1.0 to 1.1 mol, per 1 mol of compound (V). The reagent for the aforementioned methods is used in an amount of about 1 to 2 mol, preferably about 1.1 to 1.3 mol, per 1 mol of compound (V). The reaction temperature is generally −10 to 80° C., preferably 0 to 30° C.
When Y is an alkali metal atom, the condensation reaction is advantageously carried out according to a method using WSC HCl and HOBt. Compound (VI) is used in an amount of about 1 to 2 mol, preferably about 1.0 to 1.1 mol, per 1 mol of compound (V). WSC.HCl is used in an amount of about 1 to 4 mol, preferably about 1.5 to 2.5 mol, per 1 mol of compound (V). HOBt is used in an amount of about 1 to 8 mol, preferably about 2.5 to 5.0 mol, per 1 mol of compound (V). The reaction temperature is generally −10 to 100° C., preferably 40 to 70° C.
In any case, the condensation reaction is preferably carried out in a solvent. Examples of the solvent to be used include the above-mentioned halogenated hydrocarbons; the above-mentioned ethers; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; dimethyl sulfoxide, pyridine, acetonitrile and a mixed solvent thereof.
While the reaction time varies depending on the reagent or solvent to be used, it is generally 30 min to 3 days, preferably 30 min to 15 hr.
Compound (VII) can also be produced by further carrying out one or more of known hydrolysis reaction, acylation reaction, alkylation reaction, amination reaction, oxidation-reduction reaction, cyclization reaction, carbon chain extension reaction, substituent exchange reaction and the like, as desired.
Compound (I) can be produced by removing the N-protecting group PG of compound (VII). In addition, in each of the aforementioned reactions, when the starting compound has an amino group, a carboxyl group or a hydroxy group as a substituent, a protecting group generally used in peptide chemistry and the like may be introduced into these groups. By removing the protecting group as necessary after the reaction, the objective compound can be obtained. Introduction or removal of these protective groups may be carried out according to a method known per se, for example, the method disclosed in Theodora W. Greene and Peter G. M. Wuts, “Protective Groups in Organic Synthesis, 3rd Ed.”, Wiley-Interscience (1999), or the like.
As the amino-protecting group, for example, formyl group; C1-6 alkyl-carbonyl group, phenylcarbonyl group, C1-6 alkoxy-carbonyl group, allyloxycarbonyl (Alloc) group, phenyloxycarbonyl group, fluorenylmethyloxycarbonyl (Fmoc) group, C7-10 aralkyl-carbonyl group (e.g., benzylcarbonyl and the like), C7-10 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl (Cbz) and the like), C7-10 aralkyl group (e.g., benzyl and the like), trityl group, phthaloyl group, dithiasuccinoyl group, N,N-dimethylaminomethylene group, each optionally having substituent(s), and the like can be mentioned. As the substituent(s), for example, phenyl group, a halogen atom, C1-6 alkyl-carbonyl group, C1-6 alkoxy group optionally substituted by halogen atom(s) (e.g., methoxy, ethoxy, trifluoromethoxy and the like), nitro group and the like can be used. The number of the substituent(s) is 1 to 3.
As the carboxyl-protecting group, for example, C1-6 alkyl group, allyl group, benzyl group, phenyl group, trityl group, trialkylsilyl group, each optionally having substituent(s), and the like can be mentioned. As the substituent(s), for example, a halogen atom, formyl group, C1-6 alkyl-carbonyl group, C1-6 alkoxy group optionally substituted by halogen atom(s) (e.g., methoxy, ethoxy, trifluoromethoxy and the like), nitro group and the like can be used. The number of the substituent(s) is 1 to 3.
As the hydroxy-protecting group, for example, C1-6 alkyl group, C7-20 aralkyl group (e.g., benzyl, trityl and the like), formyl group, C1-6 alkyl-carbonyl group, benzoyl group, C7-10 aralkyl-carbonyl group (e.g., benzylcarbonyl and the like), 2-tetrahydropyranyl group, tetrahydrofuranyl group, trialkylsilyl group (e.g., trimethylsilyl, tert-butyldimethylsilyl, diisopropylethylsilyl and the like), each optionally having substituent(s), and the like can be mentioned. As the substituent(s), for example, a halogen atom, C1-6 alkyl group, phenyl group, C7-10 aralkyl group (e.g., benzyl and the like), C1-6 alkoxy group, nitro group and the like can be used. The number of the substituent(s) is 1 to 4.
When compound (I) is obtained as a free compound, it can be converted to the object salt according to a method known per se or a method analogous thereto, and when it is obtained as a salt, it can be converted to a free compound or the object salt according to a method known per se or a method analogous thereto.
Compound (I) may be used as a prodrug. A prodrug of compound (I) means a compound which is converted to compound (I) with a reaction due to an enzyme, an gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to compound (I) with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound which is converted to compound (I) by hydrolysis etc. due to gastric acid, etc.
Examples of a prodrug of compound (I) include a compound wherein an amino group of compound (I) is acylated, alkylated or phosphorylated (e.g., compound wherein amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated, and the like); a compound wherein a hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., a compound wherein a hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated, and the like); a compound wherein a carboxyl group of compound (I) is esterified or amidated (e.g., a compound wherein a carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified or methylamidated, and the like) and the like. These compounds can be produced from compound (I) by a method known per se.
A prodrug of compound (I) may also be one which is converted into compound (I) under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).
When compound (I) has an isomer such as optical isomer, steric isomer, positional isomer, rotational isomer and the like, any isomers and a mixture thereof are encompassed in compound (I). For example, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I). Such isomer can be obtained as a single product by a synthesis method, a separation method (e.g., concentration, solvent extraction, column chromatography, recrystallization etc.), optical resolution method (e.g., fractional recrystallization, chiral column method, diastereomer method etc.) and the like known per se.
Compound (I) may be a crystal, and both a single crystal and crystal mixtures are encompassed in compound (I). Crystals can be produced by crystallization according to crystallization methods known per se.
Compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate (e.g., non-hydrate etc.), both of which are encompassed in compound (I).
A compound labeled with an isotope (e.g., 3H, 14C, 35S, 125I and the like) and the like is also encompassed in compound (I).
Deuterium-converted compound wherein 1H has been converted to 2H(D) are also encompassed in the compound (I).
Compound (I) or its prodrug, or salts thereof (hereinafter, sometimes to be abbreviated to as a compound of the present invention) exhibit superior renin inhibitory activity. They have low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiac toxicity, drug interaction, carcinogenicity, etc.) and high water-solubility, and are excellent in the aspects of stability, pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.) and efficacy, thus being useful as medicine.
The compound of the present invention acts as a renin inhibitory drug in mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, cattle, sheep, monkey, human, etc.), and is useful as a drug inhibiting the RA system by inhibiting the biosynthesis of AII, and is useful as an agent for the prophylaxis or treatment of various diseases caused by the RA system.
Examples of such diseases include hypertension (e.g., essential hypertension, renal vascular hypertension, renoparenchymal hypertension, primary aldosteronism, Cushing's syndrome etc.), blood pressure circadian rhythm abnormality, heart diseases (e.g., cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, failure of expansion, cardiac myopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, cardiac infraction etc.), cerebrovascular disorders (e.g., asymptomatic cerebrovascular disorder, transient cerebral ischemia, apoplexy, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction etc.), cerebral edema, cerebral circulatory disorder, recurrence and sequela of cerebrovascular disorders (e.g., neurotic symptom, psychic symptom, subjective symptom, disorder in daily living activities etc.), ischemic peripheral circulation disorder, myocardial ischemia, venous insufficiency, progression of cardiac insufficiency after cardiac infarction, renal diseases (e.g., nephritis, glomerulonephritis, glomerulosclerosis, renal failure, nephrotic syndrome, thrombotic vasculopathy, complication of dialysis, organ damage including nephropathy by radiation irradiation etc.), arteriosclerosis including atherosclerosis (e.g., aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis etc.), vascular hypertrophy, vascular hypertrophy or obliteration and organ damages after intervention (e.g., percutaneous transluminal coronary angioplasty, stenting, coronary angioscopy, intravascular ultrasound, dounce thrombolytic therapy etc.), vascular re-obliteration and restenosis after bypass, polycythemia, hypertension, organ damage and vascular hypertrophy after transplantation, rejection after transplantation, ocular diseases (e.g., glaucoma, ocular hypertension etc.), thrombosis, multiple organ disorder, endothelial dysfunction, hypertensive tinnitus, other cardiovascular diseases (e.g., deep vein thrombosis, obstructive peripheral circulatory disorder, arteriosclerosis obliterans, obstructive thromboangiitis, ischemic cerebral circulatory disorder, Raynaud's disease, Berger disease etc.), metabolic and/or nutritional disorders (e.g., diabetes, impaired glucose tolerance, insulin resistance, hyperinsulinemia, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, obesity, hyperlipidemia, hypercholesterolemia, hyperuricacidemia, hyperkalemia, hypernatremia etc.), metabolic syndrome, nerve degeneration diseases (e.g., Alzheimer's disease, Parkinson's syndrome, Creutzfeldt-Jakob disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS encephalopathy etc.), central nervous system disorders (e.g., damages such as cerebral hemorrhage and cerebral infarction, and sequela and complication thereof, head injury, spinal injury, cerebral edema, sensory malfunction, sensory functional disorder, autonomic nervous system disorder, autonomic nervous system malfunction etc.), dementia, migraine, defects of memory, disorder of consciousness, amnesia, anxiety symptom, catatonic symptom, discomfort mental state, sleep disorder, agrypnia, sychopathies (e.g., depression, epilepsy, alcoholism etc.), inflammatory diseases (e.g., arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitis etc.; inflammation after operation or injury; remission of swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory intestinal diseases such as Crohn's disease, ulcerative colitis etc.; meningitis; inflammatory ocular disease; inflammatory pulmonary disease such as pneumonia, pulmonary silicosis, pulmonary sarcoidosis, pulmonary tuberculosis etc.), allergic diseases (e.g., allergic rhinitis, conjunctivitis, gastrointestinal allergy, pollinosis, anaphylaxis etc.), chronic obstructive pulmonary disease, interstitial pneumonia, pneumocytis carinni pneumonia, collagen diseases (e.g., systemic lupus erythematodes, scleroderma, polyarteritis etc.), hepatic diseases (e.g., hepatitis including chronic hepatitis, hepatic cirrhosis etc.), portal hypertension, digestive system disorders (e.g., gastritis, gastric ulcer, gastric cancer, gastric disorder after operation, dyspepsia, esophageal ulcer, pancreatitis, colon polyp, cholelithiasis, hemorrhoidal disease, varices ruptures of esophagus and stomach etc.), blood and/or myelopoietic diseases (e.g., erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple myelopathy etc.), bone diseases (e.g., fracture, refracture, osteoporosis, osteomalacia, bone Paget's disease, sclerosing myelitis, rheumatoid arthritis, joint tissue dysfunction and the like caused by osteoarthritis of the knee and diseases similar to these), solid tumor, tumors (e.g., malignant melanoma, malignant lymphoma, cancer of digestive organs (e.g., stomach, intestine etc.) etc.), cancer and cachexia following cancer, metastasis cancer, endocrinopathy (e.g., Addison's disease, pheochromocytoma etc.), urinary organ and/or male genital diseases (e.g., cystitis, prostatic hypertrophy, prostatic cancer, sex infectious disease etc.), female disorders (e.g., climacteric disorder, gestosis, endometriosis, hysteromyoma, ovarian disease, breast disease, sex infectious disease etc.), disease relating to environment and occupational factors (e.g., radiation hazard, hazard by ultraviolet, infrared or laser beam, altitude sickness etc.), respiratory diseases (e.g., cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis and pulmonary embolism etc.), infectious diseases (e.g., viral infectious diseases with cytomegalovirus, influenza virus, herpes virus etc., rickettsiosis, bacterial infectious disease etc.), toxemias (e.g., sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome etc.), otorhinolaryngological diseases (e.g., Meniere's syndrome, tinnitus, dysgeusia, vertigo, disequilibrium, dysphagia etc.), skin diseases (e.g., keloid, hemangioma, psoriasis etc.), intradialytic hypotension, myasthenia gravis, systemic diseases such as chronic fatigue syndrome and the like.
The compound of the present invention can be used in combination with an existing hypertension therapeutic drug such as an ACE inhibitor (captopril, enalapril maleate, alacepril, delapril hydrochloride, imidapril hydrochloride, quinapril hydrochloride, cilazapril, temocapril hydrochloride, trandolapril, benazepril hydrochloride, perindopril, lisinopril, etc.), ARB (losartan potassium, candesartan cilexetil, valsartan, TAK-536, TAK-491, irbesartan, telmisartan, eprosartan, olmesartan medoxomil, etc.), an aldosterone receptor antagonist (spironolactone, eplerenone, etc.), a Ca-ion channel inhibitor (verapamil hydrochloride, diltiazem hydrochloride, nifedipine, amlodipine hydrochloride, azelnidipine, aranidipine, efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, barnidipine hydrochloride, felodipine, benidipine hydrochloride, manidipine hydrochloride, etc.), diuretic (trichlormethiazide, hydrochlorothiazide, benzylhydrochlorothiazide, indapamide, tripamide, meticrane, mefruside, furosemide, triamterene, chlorthalidon etc.), a β-blocker (propranolol hydrochloride, atenolol, metoprolol tartrate, bisoprolol fumarate, etc.), an α,β-blocker (carvedilol, etc.), and the like.
Moreover, the compound of the present invention can be also used in combination with an antithrombotic drug such as heparin sodium, heparin calcium, warfarin calcium (Warfarin), a blood coagulation factor Xa inhibitor, drug having a function of balance correction in the coagulation-fibrinolysis system, an oral thrombin inhibitor, a thrombolytic drug (tPA, urokinase, etc.), an antiplatelet drug [aspirin, sulfinpyrazone (Anturane), dipyridamol (Persantine), ticlopidine hydrochloride (Panaldine), clopidogrel, cilostazol (Pletal), GPIIb/IIIa antagonist (ReoPro, etc.)], and the like. Also, the compound can be used in combination with a lipid lowering drug or a cholesterol lowering drug. Examples thereof include a squalene synthase inhibitor (lapaquistat acetate etc.), fibrates (clofibrate, benzafibrate, gemfibrozil, etc.), nicotinic acid, its derivatives and analogs (acipimox, probucol, etc.), a bile acid binding resin (cholestyramine, colestipol, etc.), an omega-3 polyunsaturated fatty acid (EPA (eicosapentaenoic acid), DHA (docosahexaenoic acid), or a mixture thereof etc.), a compound inhibiting cholesterol absorption (sitosterol, neomycin, etc.), and a squalene epoxidase inhibitor (NB-598 and its analogs, etc.). Furthermore, other possible combination components are an oxidosqualene-lanosterol cyclase, for example, a decalin derivative, an azadecalin derivative, an indane derivative and the like. Combination with a HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) inhibitor (atorvastatin calcium hydrate, pravastatin sodium, simvastatin, itavastatin, lovastatin, fluvastatin, etc.) is also possible.
The compound of the present invention can also be used in combination with a therapeutic drug for diabetes or a therapeutic drug for diabetic complications. For example, the compound of the present invention can be used in combination with an insulin preparation, an insulin sensitivity improving drug [pioglitazone hydrochloride, rosiglitazone, etc.], an α-glucosidase inhibitor [voglibose, acarbose, miglitol, emiglitate etc.], biguanide [phenformin, metformin, buformine etc.], insulin secretagogue [tolbutamide, glibenclamide, gliclazide, nateglinide, mitiglinide, glimepiride etc.], a dipeptidylpeptidase IV inhibitor [Alogliptin benzoate, Vidagliptin (LAF237), P32/98, Saxagliptin (BMS-477118) etc.], Kinedak, Penfill, Humulin, Euglucon, Glimicron, Daonil, Novolin, Monotard, Glucobay, Dimelin, Rastinon, Bacilcon, Deamelin S, Iszilin family, or the like.
In addition, the compound can be also used together with other pharmaceutical components, including a bone disease medicine, a myocardial protective drug, a coronary artery disease medicine, a chronic cardiac failure medicine, a hypothyroidism medicine, a nephrotic syndrome medicine, a chronic renal failure medicine, a gynecological disease medicine, an infection medicine, or the like.
The administration mode may be exemplified by (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the combination drug, (2) simultaneous administration through the same administration route of two preparations obtained by separately formulating the compound of the present invention and the combination drug, (3) administration with a time interval through the same administration route of two preparations obtained by separately formulating the compound of the present invention and the combination drug, (4) simultaneous administration through different administration routes of two preparations obtained by separately formulating the compound of the present invention and the combination drug, (5) administration with a time interval through different administration routes of two preparations obtained by separately formulating the compound of the present invention and the combination drug (for example, administration in order of the compound of the present invention and then the combination drug, or administration in the reverse order), or the like. The amount of the combination drug to be administered can be appropriately selected with reference to the clinically used dosage. The mixing ratio of the compound of the present invention and the combination drug can be appropriately selected in accordance with the subject of administration, administration route, disease to be treated, symptoms, combination, and the like.
The compound of the present invention can be also used in combination with, for example, gene therapy involving VEGF, TNFα or the like, or therapeutic methods involving various antibody medicines or the like.
The compound of the present invention can be safely administered individually, or according to ordinary methods (for example, methods described in the Japanese Pharmacopeia, etc.), as a pharmaceutical composition mixed with pharmaceutically acceptable carriers, for example, a tablet (including a sugar-coated tablet and a film-coated tablet), a film, a powder, a granule, a capsule, a liquid, an emulsion, a suspension, an injectable preparation, a suppository, a sustained release preparation, a patch and the like, either orally or parenterally (e.g., topical, rectal, intravenous administration, etc.).
The dosage form of the aforementioned pharmaceutical preparation may be exemplified by oral preparations such as a tablet (including a sublingual tablet and a buccal disintegration tablet), a film (including a buccal disintegration film), a capsule (including a soft capsule and a microcapsule), a granule, a powder, a troche, a syrup, an emulsion, a suspension and the like; and parenteral preparations such as an injectable preparation (e.g., a subcutaneous injectable preparation, an intravenous injectable preparation, intramuscular injectable preparation, intraperitoneal injectable preparation, a drip infusion), external preparation (e.g., a percutaneous preparation, an ointment), a suppository (e.g., a rectal suppository, a vaginal suppository), a pellet, a transnasal preparation, a transpulmonary preparation (inhalant), an eye drop and the like.
These preparations may be controlled release preparations such as a rapid release preparation, a sustained release preparation and the like (e.g., a sustained release microcapsule).
The content of the compound of the present invention in the pharmaceutical composition is about 0.01 to 100% by weight of the entire composition.
The amount of administration of the compound of the present invention may vary depending on the subject of administration, administration route, subject disease or the like; however, in the case of administering orally to an adult as a hypertension medicine, the amount of administration is about 0.0005 to 2 mg/kg of body weight, preferably about 0.001 to 1 mg/kg of body weight, and more preferably about 0.001 to 0.5 mg/kg of body weight, in terms of compound (I), the active ingredient, possibly once to several times a day.
The aforementioned pharmaceutically acceptable carrier may be exemplified by various organic or inorganic carrier materials that are conventionally used as preparation materials, for example, excipient, gliding agent, binding agent and disintegrant for solid preparations; or solvent, solution aid, suspending agent, isotonic agent, buffering agent, soothing agent and the like for liquid preparations. Further, if necessary, additives such as preservative, antioxidant, colorant, sweetening agent, adsorbing agent, wetting agent and the like can be also used.
Examples of the excipient include lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light silicic anhydride and the like.
Examples of the gliding agent include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binding agent include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like.
Examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, L-hydroxypropylcellulose and the like.
Examples of the solvent include water for injection, alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive oil and the like.
Examples of the dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; and the like.
Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates, citrates and the like.
Examples of the soothing agent include benzyl alcohol and the like.
Examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of the antioxidant include sulfites, ascorbic acid, α-tocopherol and the like.
Examples of the colorant include water-soluble Food coal tar dyes (e.g., Food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2, and the like), water-insoluble lake dyes (e.g., aluminum salts of the aforementioned water-soluble Food coal tar dyes), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide) and the like.
Examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
The present invention is explained in detail in the following by referring to Reference Examples, Examples, Preparation Examples and Experimental Examples, which are not to be construed as limitative. Of the synthesis starting materials used in Reference Examples and Examples, synthetic methods of known compounds are omitted.
“Room temperature” in the following Reference Examples and Examples represents a temperature of about 10° C. to about 35° C., and “%” represents weight % unless otherwise stated. Provided that, yield represents mol/mol %.
1H-NMR spectra were measured with a Varian MERCURY 300 (300 MHz) spectrometer or a BRUKER ADVANCE 300 spectrometer (300 MHz) using tetramethylsilane as an internal standard. All of the δ values are represented in ppm.
LC/MS spectra were measured under the following conditions.
Equipment: Agilent 1100 HPLC (Gilson 215 autosampler)/Waters ZQ, or Waters 2795/ZQ
Column: CapcellPak C18UG120 (1.5 mmID×35 mL, S-3 μm), manufactured by Shiseido Co., Ltd.
Solvent: Solution A (0.05% trifluoroacetic acid-containing water), Solution B (0.04% trifluoroacetic acid-containing water)
Gradient cycle: 0.00 min (A/B=90/10), 2.00 min (A/B=5/95), 2.75 min (A/B=5/95), 2.76 min (A/B=90/10), 3.45 min (A/B=90/10)
Flow rate: 0.5 ml/min
Mass spectrum: electrospray ionization (ESI)
Reverse-phase HPLC analysis was carried out on an YMC CombiPrep ODS-A (20 mmID×50 mL, S-5 μm) Column using a Gilson UniPoint system, and eluted with 0.1% trifluoroacetic acid-containing acetonitrile/water (10:90-100:0) at a flow rate of 25 ml/min.
The microwave reactor used was Discover of CEM.
Other symbols used in the present text indicate the following meanings.
s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt: double triplet, td: triple doublet, dq: double quartet, tq: triple quartet, ddd: double double doublet, m: multiplet, br: broad.
Me: methyl, Et: ethyl, nPr: n-propyl, iPr: isopropyl, nBu: n-butyl, iBu: isobutyl, tBu: tert-butyl, Boc: tert-butoxycarbonyl, Cbz: benzyloxycarbonyl, Tr: trityl.
DMA: N,N-dimethylacetamide, DME: 1,2-dimethoxyethane, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, THF: tetrahydrofuran.
ADDP: 1,1′-(azodicarbonyl)dipiperidine,
9-BBN: 9-borabicyclo[3.3.1]nonane,
BEMP: 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin,
BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,
DAST: (diethylamino)sulfur trifluoride,
DBU: 1,8-diazabicyclo[5.4.0]-7-undecene,
DCC: dicyclohexylcarbodiimide,
DEAD: diethyl azodicarboxylate,
DMAP: 4-(dimethylamino)pyridine,
dppf: 1,1′-bis(diphenylphosphino)ferrocene,
DTBAD: di-tert-butyl azodicarboxylate,
HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,
HOBt: 1-hydroxybenzotriazole,
mCPBA: m-chloroperbenzoic acid,
Pd2 (dba) 3: tris(dibenzylideneacetone)dipalladium(0),
TBAF: tetra-n-butylammonium fluoride,
TFA: trifluoroacetic acid,
WSC.HCl: 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride.
Sodium hydride (60% in oil) (11.62 g) was suspended in THF (270 ml), and, while stirring the suspension, a solution of benzaldehyde (28.27 g) and ethyl isocyanoacetate (27.39 g) in THF (55 ml) was added dropwise over 20 min at room temperature. The mixture was stirred at room temperature for 2.5 hr, and ice-cooled. Acetic acid (45 ml) was added dropwise, and the mixture was stirred for 10 min, poured into ice water, and extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2-2:1) was concentrated under reduced pressure to give the object compound (40.27 g) as an oil.
1H-NMR (CDCl3) δ 0.98-1.40 (3H, m), 4.06-4.38 (2H, m), 7.06-7.68 (7H, m), 8.21-8.47 (1H, m)
Ethyl 2-(formylamino)-3-phenylacrylate (40.27 g) was dissolved in carbon tetrachloride-chloroform (3:1, 440 ml), the solution was ice-cooled, and NBS (34.33 g) was added. The mixture was stirred at 0° C. for 1.5 hr, and then at room temperature for 3 hr, and ice-cooled again. Triethylamine (19.52 g) was added, and the mixture was stirred at 0° C. for 20 min, and then at room temperature for 40 min. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3-1:2) was concentrated under reduced pressure to give the object compound (44.88 g) as an oil.
1H-NMR (CDCl3) δ 0.89-1.45 (3H, m), 3.97-4.46 (2H, m), 6.91 (1H, br s), 7.28-7.46 (5H, m), 7.95-8.28 (1H, m)
Ethyl 3-bromo-2-(formylamino)-3-phenylacrylate (16.33 g) and triethylamine (13.86 g) were dissolved in dichloromethane (150 ml), and the solution was ice-cooled. Phosphoryl chloride (9.24 g) was added, and the mixture was stirred at 0° C. for 2 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was vigorously stirred at room temperature for 1 hr, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:6) was concentrated under reduced pressure at 30° C. or below to give the object compound (14.82 g) as an oil.
1H-NMR (CDCl3) δ 1.03-1.42 (3H, m), 4.04-4.42 (2H, m), 7.25-7.56 (5H, m)
Cyclohexylamine (0.21 ml) and triethylamine (0.26 ml) were dissolved in DMF (5 ml), and the solution was ice-cooled. Methyl 3-bromo-2-isocyano-3-phenylacrylate (500 mg) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (240 mg).
MS (ESI+, m/e) 285 (M+1)
(1S,2S)-2-(Benzyloxy)cyclohexylamine (848 mg) and triethylamine (1.06 ml) were dissolved in DMF (10 ml), and the solution was ice-cooled. Methyl 3-bromo-2-isocyano-3-phenylacrylate (1.0 g) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (1.26 g).
1H-NMR (CDCl3) δ 1.05-1.38 (3H, m), 1.56-1.84 (3H, m), 1.91-2.01 (1H, m), 2.17-2.30 (1H, m), 3.44-3.59 (1H, m), 3.68-3.78 (1H, m), 3.79 (3H, s), 4.25 (1H, d), 4.43 (1H, d), 6.99-7.09 (2H, m), 7.22-7.33 (3H, m), 7.33-7.48 (5H, m), 7.57 (1H, s)
In the same manner as in Reference Example 5, the following compounds (Reference Examples 6-14) were obtained.
1H-NMR (CDCl3) δ 1.05-1.38 (3H, m), 1.56-1.84 (3H, m), 1.91-2.01 (1H, m), 2.17-2.30 (1H, m), 3.44-3.59 (1H, m), 3.68-3.78 (1H, m), 3.79 (3H, s), 4.25 (1H, d), 4.43 (1H, d), 6.99-7.09 (2H, m), 7.22-7.33 (3H, m), 7.33-7.48 (5H, m), 7.57 (1H, s)
1H-NMR (CDCl3) δ 1.17-1.36 (2H, m), 1.68-1.87 (2H, m), 1.96-2.09 (4H, m), 3.65-3.79 (5H, m), 7.28-7.37 (2H, m), 7.45-7.55 (3H, m), 7.64 (1H, s)
1H-NMR (CDCl3) δ 1.53-1.70 (2H, m), 1.75-1.91 (4H, m), 1.96-2.15 (2H, m), 3.77 (3H, s), 4.18-4.29 (1H, m), 7.29-7.39 (2H, m), 7.43-7.52 (2H, m), 7.65 (1H, s)
1H-NMR (CDCl3) δ 1.26-1.40 (2H, m), 1.49-1.63 (4H, m), 1.64-1.82 (2H, m), 1.83-1.93 (2H, m), 1.95-2.05 (2H, m), 3.77 (3H, s), 3.81-3.93 (1H, m), 7.32 (2H, s), 7.43-7.53 (3H, m), 7.66 (1H, s)
1H-NMR (CDCl3) δ 1.52-1.71 (2H, m), 1.73-1.86 (3H, m), 2.04-2.22 (2H, m), 2.62 (1H, br s), 3.75 (3H, s), 4.10 (1H, s), 7.34-7.42 (2H, m), 7.44-7.52 (3H, m), 7.61 (1H, s)
1H-NMR (CDCl3) δ 1.67-1.87 (4H, m), 1.95-2.09 (2H, m), 2.13-2.21 (1H, m), 3.78 (3H, s), 4.03-4.09 (1H, m), 4.22-4.37 (2H, m), 7.12-7.15 (2H, m), 7.26-7.47 (7H, m), 7.57 (1H, s)
MS (ESI+, m/e) 377 (M+1)
1H-NMR (CDCl3) δ 1.04-1.09 (2H, m), 1.36-1.74 (5H, m), 1.83-1.93 (1H, m), 2.41-2.49 (2H, m), 3.76 (3H, s), 3.76-3.82 (1H, m), 7.32-7.35 (2H, m), 7.46-7.49 (3H, m), 7.69 (1H, s)
MS (ESI+, m/e) 297 (M+1)
1H-NMR (CDCl3) δ 1.31-1.45 (4H, m), 1.51-1.57 (1H, m), 1.63-1.72 (1H, m), 1.99-2.13 (2H, m), 2.33-2.36 (1H, m), 3.76 (3H, s), 4.24-4.31 (1H, m), 7.31-7.35 (2H, m), 7.45-7.48 (2H, m), 7.67 (1H, s)
MS (ESI+, m/e) 297 (M+1)
1H-NMR (CDCl3) δ 1.37-1.51 (2H, m), 1.51-1.65 (2H, m), 1.65-1.79 (3H, m), 1.86 (2H, dd), 3.44 (1H, d), 3.57 (1H, s), 3.75 (3H, s), 4.14-4.24 (2H, m), 7.32-7.41 (2H, m), 7.41-7.54 (3H, m), 7.71 (1H, s)
(1R,2S)-2-Aminocyclohexanol hydrochloride (5.3 g) and triethylamine (15.1 ml) were dissolved in DMF (100 ml), and the solution was ice-cooled. Ethyl 3-bromo-2-isocyano-3-phenylacrylate (9.8 g) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (6.13 g).
1H-NMR (CDCl3) δ 1.10 (3H, t), 1.21-1.37 (2H, m), 1.38-1.52 (1H, m), 1.60-1.79 (2H, m), 1.80-1.97 (2H, m), 2.22-2.37 (2H, m), 3.76 (1H, dt), 4.04 (1H, br s), 4.13 (2H, q), 7.20-7.31 (2H, m), 7.39-7.51 (3H, m), 7.86 (1H, s)
In the same manner as in Reference Example 15, the following compounds (Reference Examples 16-20) were obtained.
MS (ESI+, m/e) 315 (M+1)
1H-NMR (CDCl3) δ 1.10 (3H, t), 1.21-1.37 (2H, m), 1.38-1.52 (1H, m), 1.60-1.79 (2H, m), 1.80-1.97 (2H, m), 2.22-2.37 (2H, m), 3.76 (1H, dt), 4.04 (1H, br s), 4.13 (2H, q), 7.20-7.31 (2H, m), 7.39-7.51 (3H, m), 7.86 (1H, s)
1H-NMR (CDCl3) δ 0.99-1.14 (3H, m), 1.17-1.26 (3H, m), 1.29-1.37 (2H, m), 1.43-1.58 (5H, m), 1.61-1.68 (5H, m), 3.81 (1H, q), 4.22 (2H, dq), 7.47 (3H, td), 7.96 (1H, s)
1H-NMR (CDCl3) δ 1.19 (3H, t), 1.33-1.47 (3H, m), 1.49-1.65 (7H, m), 4.19 (2H, dd), 4.64 (1H, s), 7.10-7.24 (3H, m), 7.31-7.40 (4H, m), 7.46 (3H, s), 8.57 (1H, s)
1H-NMR (CDCl3) δ 1.20 (3H, t), 1.35-1.47 (3H, m), 1.49-1.60 (3H, m), 1.68 (4H, d), 4.19 (2H, dq), 4.64 (1H, s), 7.21 (3H, dd), 7.31-7.36 (4H, m), 7.40-7.49 (3H, m), 8.57 (1H, s)
A mixture of ethyl 3-bromo-2-isocyano-3-phenylacrylate (1.50 g), trans-2-aminocycloheptanol (1.05 g), triethylamine (4.50 ml) and DMF (20 ml) was stirred at room temperature for 2 days, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (860 mg).
1H-NMR (CDCl3) δ 1.21 (3H, t), 1.27-1.41 (1H, m), 1.51-1.61 (3H, m), 1.63-1.72 (3H, m), 1.77-1.84 (2H, m), 1.88-2.01 (1H, m), 3.74-3.86 (1H, m), 3.93-4.04 (1H, m), 4.19 (2H, q), 7.36-7.49 (5H, m), 7.61 (1H, s)
MS (ESI+, m/e) 329 (M+1)
A mixture of ethyl 3-bromo-2-isocyano-3-phenylacrylate (500 mg), 1-(aminomethyl)cyclohexanol (440 mg), N,N-diisopropylethylamine (1.9 ml) and DMF (7 ml) was stirred at room temperature for 12 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object compound (447 mg).
1H-NMR (CDCl3) δ 1.02-1.17 (3H, m), 1.23 (3H, t), 1.28-1.37 (4H, m), 1.44-1.47 (1H, m), 1.63 (3H, br s), 3.80 (2H, s), 4.19 (2H, q), 7.28-7.37 (2H, m), 7.39-7.50 (3H, m), 7.79 (1H, s)
MS (ESI+, m/e) 329 (M+1)
tert-Butyl [(1S,2S)-2-aminocyclohexyl]carbamate (1.29 g) and ethyl 3-bromo-2-isocyano-3-phenylacrylate (1.4 g) were dissolved in DMF (15 ml). N,N-Diisopropylethylamine (1.29 g) was added, and the mixture was stirred at room temperature for 40 hr. DBU (761 mg) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. Saturated brine was added to the reaction mixture, and the liberated oil was extracted with ethyl acetate. The extract was washed successively with 6% aqueous sodium bicarbonate, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (1.24 g).
1H-NMR (CDCl3) δ 1.05-1.41 (6H, m), 1.34 (9H, s), 1.75-1.85 (3H, m), 2.06 (2H, t), 3.44-3.51 (1H, m), 3.73-3.79 (1H, m), 4.05 (1H, s), 4.22 (2H, q), 7.32-7.34 (2H, m), 7.48-7.52 (3H, m), 7.72 (1H, s)
(1S,2S)-Cyclohexane-1,2-diamine (1.37 g) and ethyl 3-bromo-2-isocyano-3-phenylacrylate (1.12 g) were dissolved in DMF (5 ml), and the mixture was stirred at room temperature for 15 hr. Saturated brine was added to the reaction mixture, and the liberated oil was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (860 mg) as an oil.
1H-NMR (CDCl3) δ 1.02-1.44 (6H, m), 1.21 (3H, t), 1.59-1.81 (3H, m), 1.95-2.00 (2H, m), 3.02 (1H, dt), 3.43 (1H, dt), 4.22 (2H, q), 7.36-7.38 (2H, m), 7.46-7.49 (3H, m), 7.69 (1H, s)
In the same manner as in Reference Example 24, the following compounds (Reference Examples 25-26) were obtained.
1H-NMR (CDCl3) δ 1.03-1.39 (3H, m), 1.22 (3H, t), 1.45 (2H, br s), 1.59-1.82 (3H, t), 1.96-2.01 (2H, m), 3.02 (1H, dt), 3.44 (1H, dt), 4.22 (2H, q), 7.36-7.38 (2H, m), 7.44-7.50 (3H, m), 7.69 (1H, s)
1H-NMR (CDCl3) δ 1.19-1.85 (12H, m), 2.17-2.31 (1H, m), 3.03 (1H, br s), 3.84-3.90 (1H, m), 4.22 (2H, q), 7.30-7.33 (2H, m), 7.44-7.48 (3H, m), 7.84 (1H, s)
4-(1,4-Dioxaspiro[4.5]dec-8-yl)morpholin-3-one (1.24 g) was dissolved in acetic acid-THF-water (4:2:1, 40 ml), and the solution was stirred at 65° C. for 17 hr. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (700 mg) as an oil.
1H-NMR (CDCl3) δ 1.67-2.09 (4H, m), 2.43-2.63 (4H, m), 3.30 (2H, t), 3.85-3.92 (2H, m), 4.22 (2H, s), 4.93-5.04 (1H, m)
Trimethylsulfoxonium iodide (5.4 g) was dissolved in DMSO (40 ml). Sodium hydride (60% in oil, 972 mg) was added, and the mixture was stirred at room temperature for 30 min. A solution of 4-(4-oxocyclohexyl)morpholin-3-one (4.0 g) in DMSO (80 ml) was added thereto, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was poured into ice water, and extracted with ethyl acetate-THF (1:1). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (2.0 g) as an oil.
1H-NMR (CDCl3) δ 1.30-1.38 (2H, m), 1.69-1.89 (4H, m), 2.05-2.16 (2H, m), 2.69 (2H, s), 3.32-3.35 (2H, m), 3.87-3.90 (2H, m), 4.20 (2H, s), 4.59-4.69 (1H, m)
4-(1-Oxaspiro[2.5]oct-6-yl)morpholin-3-one (2.0 g) and benzylamine (3.0 g) were dissolved in ethanol (20 ml), and the solution was stirred at 80° C. for 12 hr. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure. This was dissolved in methanol (20 ml), 20% palladium hydroxide-carbon (50% containing water, 200 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the suspension was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (1.5 g) as an oil.
1H-NMR (CDCl3) δ 1.30-1.46 (2H, m), 1.48-1.59 (2H, m), 1.64-1.73 (2H, m), 1.77-2.02 (4H, m), 2.53-2.63 (2H, m), 2.62 (1H, s), 3.29-3.39 (2H, m), 3.80-3.91 (2H, m), 4.18-4.19 (2H, m), 4.39-4.55 (1H, m)
A solution of methyl 3-bromo-2-isocyano-3-phenylacrylate (1.23 g), 4-[4-(aminomethyl)-4-hydroxycyclohexyl]morpholin-3-one (1.5 g) and triethylamine (1.85 ml) in DMF (15 ml) was stirred at room temperature for 12 hr in an argon stream, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-20:0:1) was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (700 mg).
1H-NMR (CDCl3) δ 1.02-2.08 (11H, m), 2.35 (2H, s), 3.20-3.37 (3H, m), 3.75-3.91 (4H, m), 4.07-4.51 (4H, m), 7.09-7.56 (5H, m), 7.88 (1H, s)
Sodium hydride (60% in oil, 10.1 g) was suspended in THF (200 ml), and the suspension was ice-cooled. A solution of methyl isocyanoacetate (21.8 g) and 3-fluorobenzenecarbaldehyde (23.3 g) in THF (50 ml) was added dropwise thereto. After the completion of the dropwise addition, the mixture was stirred at room temperature for 3 hr. The reaction mixture was ice-cooled, acetic acid (40 ml) was gradually added thereto, and the mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (7:3) was concentrated under reduced pressure to give ethyl 3-(3-fluorophenyl)-2-(formylamino)acrylate (34.5 g) as a solid.
The total amount thereof was dissolved in carbon tetrachloride-chloroform (1:1, 400 ml), and the solution was ice-cooled. NBS (27.1 g) was added thereto, and the mixture was stirred at 0° C. for 1.5 hr, and then at room temperature for 3 hr. The reaction mixture was ice-cooled again, triethylamine (21.2 ml) was added, and the mixture was stirred at 0° C. for 20 min, and then at room temperature for 40 min. The reaction mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give ethyl 3-bromo-3-(3-fluorophenyl)-2-(formylamino)acrylate (39.2 g) as an oil.
The total amount thereof and triethylamine (45.3 ml) were dissolved in diethyl ether (300 ml), and the solution was ice-cooled. A solution of phosphorus oxychloride (21.0 ml) in diethyl ether (100 ml) was added dropwise, and the mixture was stirred at 0° C. for 3 hr. The reaction mixture was ice-cooled, poured into 10% potassium carbonate aqueous solution (400 ml), and the mixture was vigorously stirred at room temperature for 2 hr. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:17) was concentrated under reduced pressure to give ethyl 3-bromo-3-(3-fluorophenyl)-2-(isocyano)acrylate (19.76 g) as an oil.
The total amount thereof was dissolved in DMF (50 ml), the solution was added to a solution of (1S,2S)-2-aminocyclohexanol (9.6 g) and triethylamine (21.0 ml) in DMF (150 ml) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (9.15 g) as an amorphous solid.
1H-NMR (CDCl3) δ 1.12 (3H, t), 1.20-1.44 (4H, m), 1.55-1.82 (3H, m), 1.84-1.96 (1H, m), 2.04-2.17 (1H, m), 3.49-3.63 (1H, m), 3.79-3.93 (1H, m), 4.06-4.17 (2H, m), 7.07-7.17 (2H, m), 7.35-7.49 (2H, m), 7.63 (1H, s)
MS (ESI+, m/e) 333 (M+1)
In the same manner as in Reference Example 31, the following compounds (Reference Examples 32-38) were obtained.
1H-NMR (CDCl3) δ 1.07-1.45 (6H, m), 1.60-1.83 (3H, m), 1.93-2.03 (2H, m), 3.05 (1H, dt), 3.43 (1H, dt), 3.78 (3H, s), 7.23-7.27 (2H, m), 7.44-7.50 (1H, m), 7.69 (1H, s)
1H-NMR (CDCl3) δ 1.15-1.55 (6H, m), 1.56-2.15 (14H, m), 3.25 (1H, br s), 3.88 (3H, s), 3.93-4.05 (1H, m), 7.46 (1H, s)
1H-NMR (CDCl3) δ 0.74-0.85 (2H, m), 1.06-1.18 (2H, m), 1.19-1.34 (2H, m), 1.37-1.52 (2H, m), 1.55-1.86 (5H, m), 1.95 (2H, s), 2.08 (2H, s), 3.88 (3H, s), 4.28 (1H, tt), 7.48 (1H, s)
MS (ESI+, m/e) 333 (M+1)
1H-NMR (CDCl3) δ 1.10 (3H, t), 1.19-1.77 (6H, m), 1.83-2.02 (2H, m), 2.30 (1H, qd), 3.64-3.76 (1H, m), 4.08-4.20 (3H, m), 6.77-6.85 (2H, m), 6.92 (1H, tt), 7.84 (1H, s)
1H-NMR (CDCl3) δ 1.13-1.43 (5H, m), 1.53-1.86 (4H, m), 1.98-2.22 (2H, m), 2.65-2.90 (1H, m), 3.51 (1H, dd), 3.75-3.86 (1H, m), 4.12-4.30 (2H, m), 7.15-7.22 (1H, m), 7.24-7.35 (2H, m), 7.72-7.75 (1H, m)
1H-NMR (CDCl3) δ 1.14 (3H, t), 1.23-1.37 (2H, m), 1.62-1.69 (1H, m), 1.70-1.83 (2H, m), 1.89-2.03 (1H, m), 2.07-2.17 (1H, m), 3.52-3.66 (1H, m), 3.79-3.93 (1H, m), 4.15 (2H, q), 7.11-7.27 (3H, m), 7.33-7.46 (1H, m), 7.66 (1H, s)
Ethyl 1-[(1S,2S)-2-aminocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (850 mg) and triethylamine (378 mg) were dissolved in dichloromethane (10 ml), and the solution was ice-cooled. Ethyl chloroformate (322 mg) was added, and the mixture was stirred at 0° C. for 2 hr. The mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (450 mg).
1H-NMR (CDCl3) δ 1.05-1.23 (8H, m), 1.32-1.45 (1H, m), 1.79 (3H, t), 2.05-2.08 (2H, m), 3.52 (1H, br t), 3.85 (1H, br s), 3.79-4.05 (2H, m), 4.15-4.25 (3H, m), 7.30-7.32 (2H, m), 7.48-7.51 (3H, m), 7.72 (1H, s)
In the same manner as in Reference Example 39, the following compounds (Reference Examples 40-44) were obtained.
1H-NMR (CDCl3) δ 1.17-1.23 (5H, m), 1.32-1.45 (1H, m), 1.74-1.83 (3H, m), 2.05-2.07 (2H, m), 3.55 (4H, s), 3.85 (1H, br s), 4.15-4.24 (2H, m), 4.42 (1H, br s), 7.11-7.48 (5H, m), 7.72 (1H, s)
1H-NMR (CDCl3) δ 1.11-1.26 (8H, m), 1.31-1.46 (1H, m), 1.74-1.82 (3H, m), 2.05-2.08 (2H, m), 3.53 (1H, t), 3.86 (1H, br s), 3.97-4.05 (2H, m), 4.15-4.25 (3H, m), 7.30-7.32 (2H, m), 7.47-7.49 (3H, m), 7.72 (1H, s)
1H-NMR (CDCl3) δ 1.14-1.44 (9H, m), 1.57-1.60 (1H, m), 1.71-1.74 (1H, m), 1.87-1.91 (3H, m), 3.89-4.02 (4H, m), 4.14-4.22 (2H, m), 4.93 (1H, br d), 7.43-7.47 (5H, m), 7.57 (1H, s)
1H-NMR (CDCl3) δ 1.15-1.46 (4H, m), 1.77-1.85 (3H, m), 2.05-2.06 (2H, m), 3.55 (3H, br s), 3.75 (3H, s), 3.84 (1H, br s), 7.02-7.10 (2H, m), 7.19 (1H, dt), 7.43-7.51 (1H, m), 7.72 (1H, s)
1H-NMR (CDCl3) δ 1.15-1.27 (5H, m), 1.33-1.46 (1H, m), 1.71-1.85 (3H, m), 2.05-2.09 (2H, m), 3.56 (1H, dt), 3.74 (3H, s), 3.85 (1H, br s), 3.96-4.04 (2H, m), 4.47 (1H, br d), 7.03-7.11 (2H, m), 7.15-7.21 (1H, m), 7.43-7.50 (1H, m), 7.74 (1H, s)
Ethyl 1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (3.14 g) was dissolved in pyridine (50 ml), and the solution was ice-cooled. Methanesulfonyl chloride (1.49 g) was added dropwise over 1 min, and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 ml). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (3.35 g) as an amorphous solid.
1H-NMR (CDCl3) δ 1.20 (3H, t), 1.35-1.56 (2H, m), 1.77-1.87 (3H, m), 2.09-2.14 (1H, m), 2.34-2.40 (1H, m), 2.61 (3H, s), 3.80-3.89 (1H, m), 4.17-4.26 (2H, m), 4.74-4.82 (1H, m), 7.33-7.35 (2H, m), 7.49-7.52 (3H, m), 7.77 (1H, s)
A solution of ethyl 1-{(1S,2S)-2-[(methylsulfonyl)oxy]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (3.0 g) and sodium azide (3.9 g) in DMSO (30 ml) was stirred at 80° C. for 15 hr. The reaction mixture was poured into ice water, and the liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (2.1 g).
1H-NMR (CDCl3) δ 1.22 (3H, t), 1.28-1.44 (2H, m), 1.50-1.60 (2H, m), 1.78-2.03 (3H, m), 2.10-2.24 (1H, m), 3.69-3.70 (1H, m), 3.83-3.89 (1H, m), 4.22 (2H, q), 7.30-7.33 (2H, m), 7.46-7.51 (3H, m), 7.79 (1H, s)
A solution of ethyl 1-{(1S,2S)-2-[(methylsulfonyl)oxy]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (785 mg) and TBAF (1.40 g) in acetonitrile (10 ml) was heated under reflux for 20 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (430 mg).
1H-NMR (CDCl3) δ 1.22 (3H, t), 1.25-1.34 (1H, m), 1.42-1.67 (3H, m), 1.81-1.91 (2H, m), 2.04-2.24 (2H, m), 3.71-3.86 (1H, m), 4.23 (2H, q), 4.70 (1H, d), 7.28-7.32 (2H, m), 7.47-7.49 (3H, m), 7.82 (1H, d)
Ethyl 1-[(1S,2R)-2-azidocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (2.00 g) was dissolved in methanol (15 ml), 10% palladium-carbon (50% containing water, 500 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (1.84 g).
1H-NMR (CDCl3) δ 0.98 (2H, br s), 1.20-1.88 (10H, m), 2.18-2.31 (1H, m), 3.03 (1H, br s), 3.84-3.90 (1H, m), 4.22 (2H, q), 7.30-7.33 (2H, m), 7.44-7.51 (3H, m), 7.84 (1H, s)
Ethyl 1-[(1S,2R)-2-aminocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.80 g) was dissolved in THF (10 ml), and the solution was ice-cooled. Triethylamine (865 mg) and benzyl chloroformate (1.18 g) were added. The mixture was stirred at 0° C. for 1 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with 6% aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (1.61 g).
1H-NMR (CDCl3) δ 1.18 (3H, t), 1.23-1.44 (3H, m), 1.56-1.60 (1H, m), 1.68-1.75 (1H, m), 1.87-1.90 (3H, m), 3.91-4.04 (1H, m), 4.20 (2H, q), 4.92-5.07 (3H, m), 7.34-7.47 (10H, m), 7.58 (1H, s)
Ethyl 1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (5.5 g) and triethylamine (5.3 g) were dissolved in DMSO (55 ml), and the solution was cooled to 15° C.
A solution of pyridine-sulfur trioxide complex (8.4 g) in DMSO (20 ml) was added dropwise over 5 min. The mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice water, and the liberated oil was extracted with ethyl acetate. The extract was washed successively with 6% aqueous sodium bicarbonate, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (5.4 g).
1H-NMR (CDCl3) δ 1.21 (3H, t), 1.70-1.76 (2H, m), 2.03-2.30 (4H, m), 2.39-2.45 (1H, m), 2.54-2.60 (1H, m), 4.22 (2H, q), 4.46 (1H, dd), 7.24-7.27 (2H, m), 7.42-7.46 (3H, m), 7.58 (1H, s)
In the same manner as in Reference Example 50, the following compound (Reference Example 51) was obtained.
MS (ESI+, m/e) 331 (M+1)
Trimethylsulfoxonium iodide (17.96 g) was dissolved in DMSO (300 ml), and sodium hydride (60% in oil, 3.26 g) was added at room temperature. After stirring for 30 min, the mixture was cooled to 15 to 20° C. A solution of ethyl 1-(2-oxocyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate (21.24 g) in DMSO (75 ml) was added dropwise thereto over 20 min, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ice water, and the liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give a racemic mixture (18.54 g) of ethyl 1-[(3R,4S)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate and ethyl 1-[(3S,4R)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate.
1H-NMR (CDCl3) δ 1.23 (3H, t), 1.35-1.44 (2H, m), 1.65-2.17 (8H, m), 1.51 (1H, d), 4.11 (1H, dd), 4.22 (2H, q), 7.26-7.30 (2H, m), 7.46-7.50 (3H, m), 7.71 (1H, s)
The obtained racemate was optically resolved by normal phase chiral HPLC under the following conditions.
column: CHIRALPAK AD 50 mm ID×500 mL
mobile phase: hexane-ethanol (9:1)
flow rate: 80 ml/min
temperature: 30° C.
detection: UV (254 nm)
injection volume-concentration: 10 mg/ml, 47 ml (load: 470 mg)
In the same manner as in Reference Example 52, the following compound (Reference Example 53) was obtained.
MS (ESI+, m/e) 344 (M+1)
MS (ESI+, m/e) 344 (M+1)
Ethyl 1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazole-4-carboxylate (680 mg) and benzylamine (430 mg) were dissolved in acetonitrile (10 ml). Lithium perchlorate (426 mg) was added, and the mixture was heated under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-7:3) was concentrated under reduced pressure to give the object compound (785 mg) as an amorphous solid.
1H-NMR (CDCl3) δ 1.01 (1H, dt), 1.15-1.25 (1H, m), 1.21 (3H, t), 1.48-1.52 (1H, m), 1.65-1.86 (5H, m), 2.11 (2H, s), 2.26 (2H, dq), 3.52 (1H, dd), 3.67 (2H, s), 4.21 (2H, dq), 7.10-7.18 (4H, m), 7.28-7.46 (6H, m), 7.06 (1H, s)
Ethyl 1-{2-[(benzylamino)methyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (770 mg) was dissolved in methanol (8 ml), 20% palladium hydroxide-carbon (50% containing water, 200 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl 1-[2-(aminomethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (590 mg).
1H-NMR (CDCl3) δ 1.02 (1H, dt), 1.17 (3H, t), 1.22-1.28 (1H, m), 1.51-1.54 (1H, m), 1.66-1.88 (4H, m), 2.20-2.33 (3H, m), 2.56 (3H, br s), 3.58 (1H, dd), 4.13-4.24 (2H, m), 7.29 (2H, br s), 7.45-7.49 (3H, m), 8.08 (1H, s)
The above-mentioned ethyl 1-[2-(aminomethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (584 mg) and triethylamine (258 mg) were dissolved in dichloromethane (10 ml), and the solution was ice-cooled. Ethyl chloroformate (203 mg) was added, and the mixture was stirred at 0° C. for 2 hr, and concentrated under reduced pressure. To the residue was added ethyl acetate. The mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (615 mg) as an amorphous solid.
1H-NMR (CDCl3) δ 1.07-1.22 (8H, m), 1.51-1.83 (6H, m), 2.22 (1H, dq), 2.73-2.84 (2H, m), 3.63 (1H, dd), 3.91 (1H, br s), 4.05 (2H, dq), 4.20 (2H, q), 5.47 (1H, br t), 7.30 (2H, br s), 7.48-7.51 (3H, m), 8.05 (1H, s)
Sodium hydride (60% in oil, 88 mg) was suspended in DMF (3 ml), 3-(methylthio)propan-1-ol (267 μl) was added thereto, and the mixture was stirred at room temperature for 30 min. To this was added ethyl 1-[(3R,4S)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate (240 mg), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (318 mg).
MS (ESI+, m/e) 433 (M+1)
Ethyl 1-(2-oxocyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate (6.5 g) and methyltriphenylphosphonium bromide (11.15 g) were dissolved in THF (100 ml), and potassium tert-butoxide (3.5 g) was added at 15 to 17° C. After stirring at room temperature for 2 hr, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate. The mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-3:2) was concentrated under reduced pressure to give the object compound (6.0 g) as an amorphous solid.
1H-NMR (CDCl3) δ 1.24 (3H, t), 1.37-1.46 (2H, m), 1.81-2.01 (4H, m), 2.09-2.13 (1H, m), 2.46 (1H, d), 4.19-4.28 (4H, m), 4.85 (1H, s), 7.34-7.36 (2H, m), 7.43-7.45 (3H, m), 7.66 (1H, s)
A mixture of ethyl 1-(2-methylenecyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate (4.66 g), ethyl {[(4-nitrophenyl)sulfonyl]oxy}carbamate (8.7 g), calcium oxide (1.68 g) and dichloromethane (100 ml) was stirred at room temperature for 15 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-3:2) was concentrated under reduced pressure to give a mixture (ratio 3:2, 2.16 g) as an amorphous solid of ethyl 4-[4-(ethoxycarbonyl)-5-phenyl-1H-imidazol-1-yl]-1-azaspiro[2.5]octane-1-carboxylate and the starting material. This was dissolved in ethanol (15 ml), and boron trifluoride diethyl etherate (425 mg) was added. The mixture was stirred at 70° C. for 26 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (276 mg) as an amorphous solid.
1H-NMR (CDCl3) δ 0.94 (3H, t), 1.24 (6H, t), 1.44-1.53 (2H, m), 1.53-1.67 (2H, m), 1.80-1.84 (2H, m), 2.00-2.11 (2H, m), 2.64-2.74 (1H, m), 3.00-3.17 (2H, m), 3.64-3.71 (1H, m), 4.05-4.16 (2H, m), 4.18-4.28 (3H, m), 4.55 (1H, br s), 7.34-7.48 (5H, m), 7.67 (1H, s)
A mixture of cyclohexylurea (755 mg), ethyl 2-diazo-3-oxo-3-phenylpropionate (1.00 g), rhodium (II) acetate dimmer (30 mg), toluene (10 ml) and 1,2-dichloroethane (10 ml) was stirred at 80° C. for 1 hr, and cooled to room temperature. TFA (1.0 ml) was added, and the reaction mixture was stirred at room temperature for 2 days, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-4:1) was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (1.01 g).
1H-NMR (CDCl3) δ 1.10 (6H, t), 1.71 (3H, t), 1.69 (2H, br s), 2.27 (2H, d), 3.44-3.57 (1H, m), 4.10 (2H, q), 7.26-7.37 (2H, m), 7.47 (2H, d), 7.42-7.51 (1H, m), 8.87 (1H, br s)
MS (ESI+, m/e) 315 (M+1)
Ethyl 1-cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (500 mg) was dissolved in dichloromethane (10 ml), and the solution was ice-cooled. Triethyloxonium tetrafluoroborate (1M dichloromethane solution, 5.0 ml) was added dropwise, and the reaction mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-4:1) was concentrated under reduced pressure to give the object compound (319 mg).
1H-NMR (CDCl3) δ 1.11 (6H, q), 1.45 (3H, t), 1.58 (1H, d), 1.74 (2H, d), 1.65-1.80 (2H, m), 2.05 (1H, dd), 1.97-2.12 (1H, m), 3.51 (1H, t), 4.15 (2H, q), 4.56 (2H, q), 7.26-7.33 (1H, m), 7.29 (1H, dd), 7.40-7.46 (1H, m), 7.43 (2H, d)
MS (ESI+, m/e) 343 (M+1)
A mixture of ethyl 1-cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (10.0 g) and phosphoryl chloride (70 ml) was stirred at 100° C. for 31 hr, and cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-7:3) was concentrated under reduced pressure to give the object compound (4.69 g).
1H-NMR (CDCl3) δ 1.08-1.21 (6H, m), 1.53-1.68 (2H, m), 1.71-1.85 (5H, m), 3.85 (1H, br s), 4.09-4.23 (2H, m), 7.25-7.34 (2H, m), 7.42-7.51 (3H, m)
MS (ESI+, m/e) 333 (M+1)
A mixture of ethyl 3-iodo-2-nitro-3-phenylacrylate (7.00 g), trans-2-aminocyclohexanol hydrochloride (4.59 g), triethylamine (12.5 ml) and acetonitrile (60 ml) was stirred at room temperature for 12 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-4:1) was concentrated under reduced pressure to give the object compound (5.28 g).
1H-NMR (CDCl3) δ 0.88-1.01 (3H, m), 1.23-1.30 (2H, m), 1.38-1.48 (1H, m), 1.57-1.71 (4H, m), 1.78-1.89 (1H, m), 1.94-2.06 (1H, m), 2.18 (1H, br s), 2.94-3.07 (1H, m), 3.50-3.62 (1H, m), 3.90 (2H, br s), 7.24-7.35 (2H, m), 7.40-7.51 (3H, m)
MS (ESI+, m/e) 335 (M+1)
A mixture of ethyl 3-[(trans-2-hydroxycyclohexyl)amino]-2-nitro-3-phenylacrylate (4.49 g), 10% palladium-carbon (50% containing water, 500 mg) and trimethyl orthoacetate (150 ml) was subjected to catalytic reduction at 80° C. for 11 hr under hydrogen pressure (5 kgf/cm2). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (360 mg).
1H-NMR (CDCl3) δ 0.83-0.97 (1H, m), 1.12-1.26 (4H, m), 1.63-1.73 (2H, m), 1.76-1.83 (1H, m), 1.97-2.08 (2H, m), 2.13-2.29 (3H, m), 2.45 (1H, br s), 3.06-3.21 (1H, m), 3.61-3.77 (1H, m), 4.05-4.21 (3H, m), 7.24-7.36 (4H, m), 7.44 (1H, br s)
MS (ESI+, m/e) 329 (M+1)
Methyl 1-[(1S,2S)-2-(benzyloxy)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.25 g) was dissolved in methanol-THF (1:1, 20 ml). 8N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and partitioned between ethyl acetate and 10% aqueous citric acid solution. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (1.11 g) as an amorphous solid.
1H-NMR (CDCl3) δ 1.14-1.29 (3H, m), 1.59-1.87 (3H, m), 1.92-2.06 (1H, m), 2.20-2.36 (1H, m), 3.55 (1H, td), 3.75-3.87 (1H, m), 4.23 (1H, d), 4.48 (1H, d), 7.01 (2H, s), 7.19-7.32 (4H, m), 7.39-7.47 (5H, m), 7.91 (1H, br s)
In the same manner as in Reference Example 64, the following compound (Reference Example 65) was obtained.
1H-NMR (CDCl3) δ 1.14-1.29 (3H, m), 1.59-1.87 (3H, m), 1.92-2.06 (1H, m), 2.20-2.36 (1H, m), 3.55 (1H, td), 3.75-3.87 (1H, m), 4.23 (1H, d), 4.48 (1H, d), 7.01 (2H, s), 7.19-7.32 (4H, m), 7.39-7.47 (5H, m), 7.91 (1H, br s)
A mixture of methyl 1-[(1R,2R)-2-(benzyloxy)cyclopentyl]-5-phenyl-1H-imidazole-4-carboxylate (680 mg), lithium hydroxide monohydrate (400 mg), THF (4 ml), methanol (4 ml) and water (6 ml) was stirred at 70° C. for 12 hr, and concentrated under reduced pressure. The residual aqueous solution was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (468 mg).
MS (ESI+, m/e) 363 (M+1)
In the same manner as in Reference Example 66, the following compounds (Reference Examples 67-70) were obtained.
MS (ESI+, m/e) 283 (M+1)
MS (ESI+, m/e) 283 (M+1)
1H-NMR (CDCl3) δ 1.12 (3H, br s), 1.46 (3H, t), 1.61 (1H, br s), 1.67-1.83 (2H, m), 1.76 (2H, d), 2.05 (1H, s), 2.07 (1H, d), 3.58 (1H, dd), 4.50 (2H, q), 7.25-7.37 (2H, m), 7.38-7.49 (1H, m), 7.44 (2H, d)
MS (ESI+, m/e) 315 (M+1)
1H-NMR (DMSO-d6) δ 0.96-1.11 (3H, m), 1.53 (1H, br s), 1.68-1.83 (4H, m), 1.87-2.03 (2H, m), 3.62-3.77 (1H, m), 7.34-7.42 (2H, m), 7.44-7.53 (3H, m)
MS (ESI+, m/e) 305 (M+1)
A solution of ethyl 1-[(1S,2R)-2-azidocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (2.30 g) and potassium hydroxide (1.15 g) in ethanol (20 ml) was heated under reflux for 1.5 hr. The solvent was evaporated under reduced pressure, and the residue was acidified with 1N hydrochloric acid. The precipitated crystals were collected by filtration, and dried to give the object compound (1.86 g).
1H-NMR (DMSO-d6) δ 1.22-1.40 (4H, m), 1.74-1.84 (3H, m), 2.06-2.19 (1H, m), 3.81-3.90 (2H, m), 7.37-7.52 (5H, m), 7.90 (1H, s), 11.90 (1H, br s)
In the same manner as in Reference Example 71, the following compounds (Reference Examples 72-75) were obtained.
1H-NMR (DMSO-d6) δ 0.93-0.98 (1H, m), 1.28-1.34 (2H, m), 1.60-1.79 (5H, m), 3.44 (3H, s), 3.55-3.61 (1H, m), 3.90-3.93 (1H, m), 7.09-7.12 (1H, m), 7.31-7.49 (5H, m), 7.89 (1H, s), 11.74 (1H, br s)
1H-NMR (DMSO-d6) δ 0.94-0.98 (1H, m), 1.08 (3H, t), 1.25-1.33 (2H, m), 1.60-1.79 (5H, m), 3.54-3.60 (1H, m), 3.85-3.91 (3H, m), 7.06-7.09 (1H, m), 7.32-7.49 (5H, m), 7.96 (1H, s), 11.80 (1H, br s)
1H-NMR (DMSO-d6) δ 1.09 (3H, s), 1.20-1.34 (2H, m), 1.53-1.57 (2H, m), 1.73-1.84 (2H, m), 3.38 (2H, q), 3.69 (1H, br s), 3.88-4.00 (3H, m), 7.44-7.58 (5H, m), 8.81 (1H, s), 13.00 (1H, br s)
1H-NMR (DMSO-d6) δ 1.24-1.44 (4H, m), 1.74-1.82 (2H, m), 1.83-1.95 (1H, m), 2.08-2.20 (1H, m), 3.71-3.87 (1H, m), 4.73 (1H, d), 7.36-7.48 (5H, m), 7.91 (1H, d), 11.96 (1H, br s)
Ethyl 1-[(1S,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (6.1 g) was dissolved in ethanol-THF (1:1, 200 ml). 8N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with 1N hydrochloric acid, subjected to DIAION HP-20 (manufactured by Mitsubishi Chemical), and washed with water. The fraction eluted with acetone was concentrated under reduced pressure to give the object compound (4.52 g) as an amorphous solid.
MS (ESI+, m/e) 287 (M+1)
Methyl 5-(3-fluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylate (1.05 g) was dissolved in methanol-THF (1:1, 20 ml). 8N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with 1N hydrochloric acid, subjected to DIAION HP-20 (manufactured by Mitsubishi Chemical), and washed with water. The fraction eluted with acetone was concentrated under reduced pressure to give the object compound (981 mg) as an amorphous solid.
1H-NMR (DMSO-d6) δ 0.71-1.41 (5H, m), 1.41-1.99 (5H, m), 2.89-3.94 (2H, m), 6.88-7.67 (4H, m), 7.84 (1H, br s)
In the same manner as in Reference Example 77, the following compounds (Reference Examples 78-83) were obtained.
1H-NMR (DMSO-d6) δ 1.11-2.14 (20H, m), 3.10-3.33 (1H, m), 4.04-4.23 (1H, m), 8.08 (1H, s)
1H-NMR (DMSO-d6) δ 0.61 (2H, br s), 0.87 (2H, d), 1.07-2.02 (11H, m), 4.08 (1H, br s), 4.90 (1H, br s), 7.33 (1H, br s)
MS (ESI+, m/e) 305 (M+1)
MS (ESI+, m/e) 323 (M+1)
MS (ESI+, m/e) 323 (M+1)
MS (ESI+, m/e) 305 (M+1)
Ethyl 1-[(3S,4R)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate (7.83 g) was dissolved in methanol (120 ml). Sodium methoxide (28% methanol solution, 23.1 ml) was added at room temperature, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added water (24 ml), and the mixture was further stirred at 60° C. for 6 hr. After cooling to room temperature, the mixture was neutralized (pH 7) with hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was dissolved in water, subjected to DIAION HP-20 (manufactured by Mitsubishi Chemical), and washed with water, and the fraction eluted with acetone was concentrated under reduced pressure to give the object compound (7.92 g) as an amorphous solid.
1H-NMR (DMSO-d6) δ 1.03 (1H, t), 1.26-1.44 (2H, m), 1.44-1.79 (4H, m), 1.96-2.14 (1H, m), 2.58-2.65 (1H, m), 2.68-2.77 (1H, m), 2.90-3.00 (3H, m), 3.62-3.73 (1H, m), 5.08 (1H, br s), 7.21-7.47 (5H, m), 7.95 (1H, s), 11.74 (1H, br s)
In the same manner as in Reference Example 84, the following compound (Reference Example 85) was obtained.
MS (ESI+, m/e) 349 (M+1)
A solution of N-(tert-butoxycarbonyl)-2-fluoro-D-phenylalanine (999 mg), ethyl N-benzylglycinate (716 mg), WSC HCl (811 mg) and HOBt (524 mg) in DMF (18 ml) was stirred at room temperature for 15 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (1.62 g) as an amorphous solid.
MS (ESI+, m/e) 359 (M+1-“Boc”)
In the same manner as in Reference Example 86, the following compounds (Reference Examples 87-101) were obtained.
MS (ESI+, m/e) 359 (M+1-“Boc”)
MS (ESI+, m/e) 359 (M+1-“Boc”)
MS (ESI+, m/e) 377 (M+1-“Boc”)
MS (ESI+, m/e) 377 (M+1-“Boc”)
MS (ESI+, m/e) 395 (M+1-“Boc”)
MS (ESI+, m/e) 409 (M+1-“Boc”)
MS (ESI+, m/e) 409 (M+1-“Boc”)
MS (ESI+, m/e) 409 (M+1-“Boc”)
MS (ESI+, m/e) 371 (M+1-“Boc”)
MS (ESI+, m/e) 519 (M+1)
MS (ESI+, m/e) 367 (M+1-“Boc”)
MS (ESI+, m/e) 421 (M+1)
MS (ESI+, m/e) 307 (M+1-“Boc”)
1H-NMR (CDCl3) δ 0.74-1.88 (25H, m), 3.70-3.89 (1H, m), 4.09-4.29 (2H, m), 4.42-4.61 (2H, m), 4.74-4.92 (2H, m), 5.10-5.18 (1H, m), 7.18-7.38 (5H, m)
1H-NMR (CDCl3) δ 1.11-1.52 (12H, m), 3.66-4.26 (5H, m), 4.36-4.78 (3H, m), 4.83-5.13 (1H, m), 5.22-5.37 (1H, m), 5.65 (1H, br s), 6.61-7.49 (10H, m)
A solution of N-(tert-butoxycarbonyl)-3-(pyridin-3-yl)-D-alanine (5.00 g), ethyl N-benzylglycinate (3.81 g), WSC.HCl (4.32 g) and HOBt (2.79 g) in DMF (85 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (8.28 g) as an oil (it was allowed to crystallization at low temperature).
MS (ESI+, m/e) 442 (M+1)
In the same manner as in Reference Example 102, the following compounds (Reference Examples 103-106) were obtained.
MS (ESI+, m/e) 442 (M+1)
MS (ESI+, m/e) 442 (M+1)
MS (ESI+, m/e) 480 (M+1)
MS (ESI+, m/e) 431 (M+1)
A mixture of N-(tert-butoxycarbonyl)-2,4-dichloro-D-phenylalanine (5.00 g), glycine ethyl ester hydrochloride (2.19 g), WSC.HCl (3.44 g), HOBt (2.22 g), triethylamine (1.82 g) and DMF (70 ml) was stirred at room temperature for 15 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give the object compound (5.69 g).
1H-NMR (CDCl3) δ 1.28 (3H, t), 1.36 (9H, s), 3.00-3.07 (1H, m), 3.31 (1H, dd), 3.95 (1H, dd), 4.05 (1H, dd), 4.21 (2H, q), 4.48-4.50 (1H, m), 5.05-5.07 (1H, m), 6.52 (1H, br s), 7.15-7.21 (2H, m), 7.38 (1H, s)
MS (ESI+, m/e) 319 (M+1-“Boc”)
In the same manner as in Reference Example 107, the following compound (Reference Example 108) was obtained.
MS (ESI+, m/e) 358 (M+1)
To a solution of ethyl N-(tert-butoxycarbonyl)-2-fluoro-D-phenylalanyl-N-benzylglycinate (1.58 g) in dichloromethane (0.9 ml) was added TFA (9 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with toluene. The mixture was again concentrated under reduced pressure to remove TFA. The residue was dissolved in dichloromethane (15 ml), triethylamine (3 ml) was added, and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate-THF (4:1, 100 ml). The solution was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give the object compound (950 mg).
1H-NMR (CDCl3) δ 3.14 (1H, dd), 3.22 (1H, d), 3.38 (1H, dd), 3.63 (1H, d), 4.33-4.37 (1H, m), 4.49 (1H, d), 4.56 (1H, d), 6.18 (1H, s), 6.93-7.06 (2H, m), 7.14 (1H, dt), 7.20-7.28 (3H, m), 7.31-7.36 (3H, m)
MS (ESI+, m/e) 313 (M+1)
In the same manner as in Reference Example 109, the following compounds (Reference Examples 110-124) were obtained.
1H-NMR (CDCl3) δ 3.12-3.24 (3H, m), 3.61 (1H, d), 4.33-4.37 (1H, m), 4.49 (1H, d), 4.56 (1H, d), 6.51 (1H, s), 6.92-6.99 (3H, m), 7.19-7.24 (3H, m), 7.30-7.37 (3H, m)
MS (ESI+, m/e) 313 (M+1)
1H-NMR (CDCl3) δ 3.02 (1H, d), 3.08 (1H, dd), 3.21 (1H, dd), 3.55 (1H, d), 4.32-4.36 (1H, m), 4.39 (1H, d), 4.55 (1H, d), 6.68 (1H, s), 6.84-6.91 (2H, m), 7.07-7.18 (4H, m), 7.30-7.33 (3H, m)
MS (ESI+, m/e) 313 (M+1)
1H-NMR (CDCl3) δ 3.09 (1H, dd), 3.20 (1H, dd), 3.23 (1H, d), 3.63 (1H, d), 4.32-4.37 (1H, m), 4.41 (1H, d), 4.62 (1H, d), 6.85 (1H, s), 6.87-6.89 (1H, m), 6.94-7.06 (2H, m), 7.16-7.19 (2H, m), 7.31-7.36 (3H, m)
MS (ESI+, m/e) 331 (M+1)
1H-NMR (CDCl3) δ 3.11-3.23 (2H, m), 3.38 (1H, d), 3.68 (1H, d), δ 4.33-4.37 (1H, m), 4.48 (1H, d), 4.61 (1H, d), 6.67-6.79 (4H, m), 7.17-7.20 (2H, m), 7.28-7.37 (3H, m)
MS (ESI+, m/e) 331 (M+1)
1H-NMR (CDCl3) δ 3.14 (1H, dd), 3.27 (1H, dd), 3.42 (1H, d), 3.70 (1H, d), 4.36-4.39 (1H, m), 4.44 (1H, d), 4.65 (1H, d), 6.55 (1H, s), 6.85-6.93 (1H, m), 7.01-7.10 (1H, m), 7.17-7.20 (2H, m), 7.30-7.35 (3H, m)
MS (ESI+, m/e) 349 (M+1)
MS (ESI+, m/e) 363 (M+1)
1H-NMR (CDCl3) δ 3.13 (1H, d), 3.21-3.31 (2H, m), 3.60 (1H, d), 4.37 (1H, d), 4.37-4.41 (1H, m), 4.62 (1H, d), 6.66 (1H, s), 7.15-7.20 (2H, m), 7.28-7.39 (5H, m), 7.50-7.56 (2H, m)
MS (ESI+, m/e) 363 (M+1)
1H-NMR (CDCl3) δ 3.07 (1H, d), 3.18 (1H, dd), 3.28 (1H, dd), 3.58 (1H, d), 4.29 (1H, d), 4.37-4.41 (1H, m), 4.68 (1H, d), 6.50 (1H, s), 7.16-7.19 (2H, m), 7.24-7.27 (2H, m), 7.32-7.35 (3H, m), 7.43 (2H, d)
MS (ESI+, m/e) 363 (M+1)
1H-NMR (CDCl3) δ 2.97 (1H, d), 3.06 (1H, dd), 3.15 (1H, dd), 3.51 (1H, d), 3.75 (3H, s), 4.28-4.32 (1H, m), 4.43 (1H, d), 4.51 (1H, d), 6.43 (1H, s), 6.72 (2H, d), 7.04 (2H, d), 7.16-7.20 (2H, m), 7.29-7.34 (3H, m)
MS (ESI+, m/e) 325 (M+1)
1H-NMR (CDCl3) δ 3.06 (1H, dd), 3.07 (1H, d), 3.18 (1H, dd), 3.56 (1H, d), 4.32-4.36 (1H, m), 4.35 (1H, d), 4.60 (1H, d), 6.63 (1H, s), 7.00 (2H, d), 7.14-7.17 (2H, m), 7.27-7.36 (5H, m)
MS (ESI+, m/e) 373 (M+1)
1H-NMR (CDCl3) δ 2.76 (1H, dd), 2.88-3.16 (4H, m), 3.78 (1H, d), 3.88 (1H, d), 4.15 (1H, dd), 4.48 (1H, d), 4.75 (1H, d), 6.87 (1H, s), 7.10-7.20 (4H, m), 7.25-7.40 (5H, m)
MS (ESI+, m/e) 321 (M+1)
1H-NMR (CDCl3) δ 1.01 (9H, s), 1.55 (1H, dd), 2.11 (1H, dd), 3.79 (1H, d), 3.87 (1H, dd), 4.06 (1H, dt), 4.54 (1H, d), 4.63 (1H, d), 6.32 (1H, br s), 7.23-7.26 (2H, m), 7.30-7.38 (3H, m)
MS (ESI+, m/e) 275 (M+1)
MS (ESI+, m/e) 261 (M+1)
1H-NMR (CDCl3) δ 0.93-1.05 (2H, m), 1.12-1.29 (3H, m), 1.40-1.46 (1H, m), 1.57-1.89 (8H, m), 3.76-3.89 (2H, m), 4.06-4.12 (1H, m), 4.59 (2H, dd), 6.98 (1H, s), 7.24-7.38 (5H, m)
1H-NMR (DMSO-d6) δ 2.70-2.82 (1H, m), 2.99-3.11 (1H, m), 3.32-3.43 (2H, m), 4.14-4.26 (2H, m), 4.55 (1H, d), 6.52 (2H, d), 6.83 (2H, d), 7.11 (2H, m), 7.23-7.39 (3H, m), 8.23-8.31 (1H, m), 9.26 (1H, s)
To a solution of ethyl N-(tert-butoxycarbonyl)-3-(pyridin-3-yl)-D-alanyl-N-benzylglycinate (8.27 g) in dichloromethane (5 ml) was added TFA (50 ml), and the mixture was stirred at room temperature for 50 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with toluene. The mixture was again concentrated under reduced pressure to remove TFA. The residue was dissolved in dichloromethane (75 ml), triethylamine (15 ml) was added thereto, the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure, and the residue was dissolved in chloroform (about 200 ml). The solution was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give the object compound (4.14 g).
1H-NMR (CDCl3) δ 3.14 (1H, dd), 3.16 (1H, d), 3.26 (1H, dd), 3.60 (1H, d), 4.37-4.41 (1H, m), 4.50 (2H, s), 7.12-7.19 (3H, m), 7.24 (1H, s), 7.28-7.33 (3H, m), 7.50 (1H, dt), 8.48-8.50 (2H, m)
MS (ESI+, m/e) 296 (M+1)
In the same manner as in Reference Example 125, the following compounds (Reference Examples 126-129) were obtained.
MS (ESI+, m/e) 296 (M+1)
1H-NMR (CDCl3) δ 3.14 (1H, dd), 3.22 (1H, dd), 3.26 (1H, d), 3.64 (1H, d), 4.38-4.43 (1H, m), 4.40 (1H, d), 4.61 (1H, d), 6.91 (1H, s), 7.10 (2H, d), 7.16-7.21 (2H, m), 7.31-7.39 (3H, m), 8.44 (2H, d)
MS (ESI+, m/e) 296 (M+1)
1H-NMR (CDCl3) δ 3.02 (1H, d), 3.36 (2H, d), 3.50 (1H, d), 4.12 (1H, d), 4.35-4.39 (1H, m), 4.59 (1H, d), 6.31 (1H, s), 6.98 (1H, d), 7.02-7.05 (2H, m), 7.13-7.27 (5H, m), 7.37 (1H, d), 7.64 (1H, d), 8.21 (1H, s)
MS (ESI+, m/e) 334 (M+1)
1H-NMR (CDCl3) δ 3.18 (1H, dd), 3.30 (1H, dd), 3.42 (1H, d), 3.70 (1H, d), 4.34-4.37 (1H, m), 4.50 (1H, d), 4.59 (1H, d), 6.83 (1H, s), 7.18-7.22 (2H, m), 7.28-7.36 (4H, m), 7.63 (1H, s), 8.11 (1H, s)
MS (ESI+, m/e) 285 (M+1)
Ethyl N-(tert-butoxycarbonyl)-2,4-dichloro-D-phenylalanylglycinate (5.68 g) was suspended in dichloromethane (4 ml). TFA (40 ml) was added, and the mixture was stirred at room temperature for 50 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with toluene. The mixture was again concentrated under reduced pressure to remove TFA. The residue was dissolved in ethanol (60 ml), triethylamine (12 ml) was added, and the mixture was heated under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, and the crystals were collected by filtration to give the object compound (3.40 g).
1H-NMR (DMSO-d6) δ 3.06 (1H, dd), 3.17 (1H, dd), 3.53 (1H, dd), 3.64 (1H, d), 3.94-3.98 (1H, m), 7.32 (1H, d), 7.39 (1H, dd), 7.58 (1H, d), 8.07 (2H, s)
MS (ESI+, m/e) 273 (M+1)
Ethyl N-(tert-butoxycarbonyl)-3-(1,3-thiazol-4-yl)-D-alanylglycinate (5.6 g) was dissolved in dichloromethane (5 ml). TFA (15 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with toluene. The mixture was again concentrated under reduced pressure to remove TFA. The residue was dissolved in methanol (40 ml), triethylamine (8 ml) was added thereto, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate-THF (4:1, 250 ml). The solution was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give the object compound (2.4 g) as an amorphous solid.
MS (ESI+, m/e) 212 (M+1)
A solution of (2R)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid (50 g), ethyl N-benzylglycinate (28.6 g), WSC.HCl (34 g) and HOBt (25 g) in DMF (300 ml) was stirred at room temperature for 12 hr, and poured into aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform (150 ml), TFA (15 ml) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with toluene. The mixture was again concentrated under reduced pressure. The residue was dissolved in chloroform (400 ml), triethylamine (70 ml) was added thereto, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was washed successively with water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate-hexane (1:1), and the precipitated crystals were collected by filtration to give the object compound (57 g).
MS (ESI+, m/e) 367 (M+1)
A mixture of (3R)-1-benzyl-3-(2-fluorobenzyl)piperazine-2,5-dione (942 mg) and THF (25 ml) was ice-cooled, and lithium aluminum hydride (458 mg) was added by small portions. The mixture was stirred at room temperature for 30 min, and then at 60° C. for 1.5 hr. The mixture was cooled to −78° C., and ethanol-ethyl acetate (1:1, 3 ml) and 1N aqueous sodium hydroxide solution (6 ml) were successively added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 40 min. The insoluble material was filtered, and washed with ethyl acetate. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-10:1) was concentrated under reduced pressure to give the object compound (595 mg) as an oil.
1H-NMR (CDCl3) δ 1.57 (1H, br s), 1.90 (1H, t), 2.06 (1H, dt), 2.61 (1H, dd), 2.68-2.85 (4H, m), 2.92 (1H, dt), 3.00-3.06 (1H, m), 3.44 (1H, d), 3.55 (1H, d), 6.98-7.07 (2H, m), 7.15-7.32 (7H, m)
MS (ESI+, m/e) 285 (M+1)
In the same manner as in Reference Example 133, the following compounds (Reference Examples 134-146) were obtained.
1H-NMR (CDCl3) δ 1.65 (1H, br s), 1.88 (1H, dd), 2.08 (1H, dt), 2.54 (1H, dd), 2.66-3.03 (6H, m), 3.46 (1H, d), 3.53 (1H, d), 6.87-6.97 (3H, m), 7.20-7.32 (6H, m)
MS (ESI+, m/e) 285 (M+1)
1H-NMR (CDCl3) δ 1.62 (1H, br s), 1.86 (1H, t), 2.03-2.11 (1H, m), 2.51 (1H, dd), 2.64-2.99 (6H, m), 3.46 (1H, d), 3.53 (1H, d), 6.49-7.00 (2H, m), 7.12-7.18 (2H, m), 7.21-7.32 (5H, m)
MS (ESI+, m/e) 285 (M+1)
1H-NMR (CDCl3) δ 1.61 (1H, br s), 1.85 (1H, t), 2.07 (1H, dt), 2.50 (1H, dd), 2.65 (1H, dd), 2.71-2.84 (3H, m), 2.89-2.99 (2H, m), 3.46 (1H, d), 3.53 (1H, d), 6.86-6.90 (1H, m), 6.95-7.10 (2H, m), 7.22-7.32 (5H, m)
MS (ESI+, m/e) 303 (M+1)
MS (ESI+, m/e) 321 (M+1)
MS (ESI+, m/e) 335 (M+1)
1H-NMR (CDCl3) δ 1.61 (1H, br s), 1.88 (1H, t), 2.08 (1H, dt), 2.61 (1H, dd), 2.73-2.85 (4H, m), 2.92 (1H, dt), 2.97-3.06 (1H, m), 3.47 (1H, d), 3.53 (1H, d), 7.21-7.48 (9H, m)
MS (ESI+, m/e) 335 (M+1)
1H-NMR (CDCl3) δ 1.59 (1H, br s), 1.89 (1H, t), 2.08 (1H, dt), 2.61 (1H, dd), 2.71-2.84 (4H, m), 2.91 (1H, dt), 2.97-3.06 (1H, m), 3.47 (1H, d), 3.53 (1H, d), 7.21-7.31 (8H, m), 7.54 (1H, d)
MS (ESI+, m/e) 335 (M+1)
1H-NMR (CDCl3) δ 1.64 (1H, br s), 1.87 (1H, t), 2.07 (1H, dt), 2.47 (1H, dd), 2.65 (1H, dd), 2.71-2.95 (5H, m), 3.46 (1H, d), 3.54 (1H, d), 3.79 (3H, s), 6.83 (2H, d), 7.11 (2H, d), 7.23-7.32 (5H, m)
MS (ESI+, m/e) 297 (M+1)
1H-NMR (CDCl3) δ 1.53 (1H, br s), 1.86 (1H, t), 2.05 (1H, dt), 2.33-2.45 (1H, m), 2.62-3.10 (9H, m), 3.46 (1H, d), 3.58 (1H, d), 7.08-7.32 (9H, m)
MS (ESI+, m/e) 293 (M+1)
1H-NMR (CDCl3) δ 0.91 (9H, s), 1.18-1.20 (2H, m), 1.62 (1H, br s), 1.75 (1H, t), 1.94-2.02 (1H, m), 2.70-2.92 (5H, m), 3.44 (1H, d), 3.53 (1H, d), 7.22-7.31 (5H, m)
MS (ESI+, m/e) 247 (M+1)
MS (ESI+, m/e) 233 (M+1)
MS (ESI+, m/e) 273 (M+1)
1H-NMR (DMSO-d6) δ 1.52-2.88 (8H, m), 3.08-3.73 (4H, m), 6.64 (2H, d), 6.94 (2H, d), 7.16-7.35 (5H, m), 9.17 (1H, br s)
MS (ESI+, m/e) 283 (M+1)
(3R)-1-Benzyl-3-(3,5-difluorobenzyl)piperazine-2,5-dione (4.36 g) was dissolved in THF (55 ml), and borane-THF (1.0M THF solution, 105.6 ml) was added dropwise at room temperature over 15 min. The mixture was stirred at room temperature for 1 hr, and then at 60° C. for 15 hr. The reaction mixture was ice-cooled, and water (6 ml) was added dropwise over 5 min. The mixture was stirred at room temperature for 10 min, and the reaction mixture was concentrated under reduced pressure. To the residue was added 2N hydrochloric acid (60 ml), and the mixture was stirred at 50° C. for 30 min. The reaction mixture was ice-cooled again, basified with 8N aqueous sodium hydroxide solution to weak basic (pH 8-9), and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-20:0:1) was concentrated under reduced pressure to give the object compound (1.81 g) as an oil (it was allowed to crystallization at low temperature).
1H-NMR (CDCl3) δ 1.64 (1H, br s), 1.86 (1H, t), 2.08 (1H, dt), 2.54 (1H, dd), 2.64-3.01 (6H, m), 3.47 (1H, d), 3.53 (1H, d), 6.61-6.74 (3H, m), 7.24-7.32 (5H, m)
MS (ESI+, m/e) 303 (M+1)
In the same manner as in Reference Example 147, the following compounds (Reference Examples 148-152) were obtained.
1H-NMR (CDCl3) δ 2.14-2.28 (3H, m), 2.78-2.93 (5H, m), 3.19-3.32 (1H, m), 3.50 (1H, d), 3.67 (1H, d), 3.81 (1H, s), 7.04-7.19 (2H, m), 7.22-7.37 (5H, m), 7.58 (1H, td), 8.53 (1H, dd).
MS (ESI+, m/e) 268 (M+1)
1H-NMR (CDCl3) δ 1.60 (1H, br s), 1.88 (1H, t), 2.09 (1H, dt), 2.56 (1H, dd), 2.66-3.07 (6H, m), 3.47 (1H, d), 3.53 (1H, d), 7.12 (2H, d), 7.24-7.35 (5H, m), 8.51 (2H, d)
MS (ESI+, m/e) 268 (M+1)
MS (ESI+, m/e) 306 (M+1)
1H-NMR (CDCl3) δ 1.83 (1H, t), 2.06 (1H, dt), 2.56 (1H, dd), 2.64-3.07 (7H, m), 3.48 (2H, s), 6.76 (1H, s), 7.21-7.33 (6H, m), 7.44 (1H, s)
MS (ESI+, m/e) 257 (M+1)
1H-NMR (CDCl3) δ 1.62 (1H, br s), 1.87 (1H, t), 2.07 (1H, dt), 2.50 (1H, dd), 2.66 (1H, dd), 2.71-2.99 (5H, m), 3.46 (1H, d), 3.53 (1H, d), 7.07 (2H, d), 7.21-7.32 (5H, m), 7.41 (2H, d)
MS (ESI+, m/e) 345 (M+1)
(3R)-1-Benzyl-3-(pyridin-3-ylmethyl)piperazine-2,5-dione (4.13 g) was dissolved in THF (60 ml), and borane-THF (1.0M THF solution, 111.9 ml) was added dropwise at room temperature over 15 min. The mixture was stirred at room temperature for 1 hr, and then at 60° C. for 15 hr. The reaction mixture was ice-cooled, water (6.5 ml) was added dropwise over 5 min, and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, to the residue was added 2N hydrochloric acid (65 ml), and the mixture was stirred at 50° C. for 30 min. The reaction mixture was ice-cooled again, basified with 8N aqueous sodium hydroxide solution to weak basic (pH 8-9), and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol-triethylamine (1:0:0-100:5:2) was concentrated under reduced pressure to give the object compound (1.98 g) as an oil.
1H-NMR (CDCl3) δ 1.76 (1H, br s), 1.88 (1H, t), 2.08 (1H, dt), 2.57 (1H, dd), 2.67-3.04 (6H, m), 3.46 (1H, d), 3.53 (1H, d), 7.19-7.34 (6H, m), 7.50 (1H, dt), 8.45-8.47 (2H, m)
MS (ESI+, m/e) 268 (M+1)
(3R)-3-(2,4-Dichlorobenzyl)piperazine-2,5-dione (3.39 g) was dissolved in THF (55 ml), and borane-THF (1.0M THF solution, 99.3 ml) was added dropwise at room temperature over 15 min. The mixture was stirred at room temperature for 1 hr, and then at 60° C. for 6 hr, and the reaction mixture was ice-cooled. Water (6 ml) was added dropwise over 5 min, and the mixture was stirred at room temperature for 10 min, and concentrated under reduced pressure. To the residue was added 2N hydrochloric acid (60 ml), and the mixture was stirred at 50° C. for 30 min. The reaction mixture was ice-cooled again, basified with 8N aqueous sodium hydroxide solution to weak basic (pH 8-9), and extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give the object compound (1.09 g).
MS (ESI+, m/e) 245 (M+1)
A mixture of (2R)-2-(2,4-dichlorobenzyl)piperazine (1.08 g), tert-butanol (20 ml), water (15 ml) and 1N aqueous sodium hydroxide solution (4.63 ml) was ice-cooled, and di-tert-butyl bicarbonate (1.01 g) was added thereto. The mixture was stirred at room temperature for 6 hr, and concentrated under reduced pressure to about half-volume. The residue was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:8:0-20:0:1) was concentrated under reduced pressure to give the object compound (154 mg) as an oil.
1H-NMR (CDCl3) δ 1.45 (9H, s), 2.62-2.71 (3H, m), 2.81-2.95 (5H, m), 3.87-3.91 (2H, m), 7.15-7.21 (2H, m), 7.38 (1H, s)
MS (ESI+, m/e) 345 (M+1)
A mixture of (3R)-3-(1,3-thiazol-4-ylmethyl)piperazine-2,5-dione (1.0 g) and THF (30 ml) was ice-cooled, and lithium aluminum hydride (0.9 g) was added by small portions. The mixture was stirred at room temperature for 30 min, and then at 50° C. for 2 hr, and cooled to −78° C. Sodium sulfate hydrate and 1N aqueous sodium hydroxide solution (0.5 ml) were successively added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1 hr. The insoluble material was filtered, and washed with ethyl acetate. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure. The residue was dissolved in tert-butanol (5 ml), 2.5N aqueous sodium hydroxide solution (5 ml) and di-tert-butyl bicarbonate (2.18 g) were successively added, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (50 ml). The solution was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (100 mg) as an oil.
MS (ESI+, m/e) 284 (M+1)
(3R)-1-Benzyl-3-(4-bromobenzyl)piperazine (2.64 g) was dissolved in THF (20 ml), and di-tert-butyl bicarbonate (1.75 g) was added. The mixture was stirred at room temperature for 3 hr, and the reaction mixture was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (2.87 g).
1H-NMR (CDCl3) δ 1.38 (9H, s), 1.95 (1H, dd), 2.08 (1H, dt), 2.58 (1H, d), 2.82-2.98 (3H, m), 3.17 (1H, dt), 3.31 (1H, d), 3.55 (1H, d), 3.91-4.08 (2H, m), 6.87 (2H, d), 7.24-7.34 (7H, m)
MS (ESI+, m/e) 445 (M+1)
A mixture of tert-butyl (2R)-4-benzyl-2-(4-bromobenzyl)piperazine-1-carboxylate (1.00 g), morpholine (215 mg), BINAP (140 mg), sodium tert-butoxide (324 mg), Pd2(dba)3 (82 mg) and toluene (20 ml) was stirred at 90° C. for 15 hr in an argon stream, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:5-1:2) was concentrated under reduced pressure to give the object compound (986 mg) as an oil (it was allowed to crystallization at low temperature).
1H-NMR (CDCl3) δ 1.39 (9H, s), 1.95 (1H, dd), 2.04 (1H, dt), 2.63 (1H, d), 2.72-2.84 (2H, m), 2.96-3.04 (1H, m), 3.07 (4H, dd), 3.18 (1H, dt), 3.36 (1H, d), 3.51 (1H, d), 3.84 (4H, dd), 3.85-4.15 (2H, m), 6.72 (2H, d), 6.95 (2H, d), 7.27-7.34 (5H, m)
MS (ESI+, m/e) 452 (M+1)
tert-Butyl (2R)-4-benzyl-2-(4-morpholinobenzyl)piperazine-1-carboxylate (937 mg) was dissolved in dichloromethane (2 ml). TFA (5 ml) was added, and the mixture was stirred at room temperature for 50 min. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions, and the mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2-1:0) was concentrated under reduced pressure to give the object compound (728 mg) as an oil.
1H-NMR (CDCl3) δ 1.63 (1H, br s), 1.87 (1H, t), 2.07 (1H, dt), 2.45 (1H, dd), 2.63 (1H, dd), 2.71-2.97 (5H, m), 3.13 (4H, dd), 3.46 (1H, d), 3.53 (1H, d), 3.84 (4H, dd), 6.84 (2H, d), 7.09 (2H, d), 7.21-7.31 (5H, m)
MS (ESI+, m/e) 352 (M+1)
4-{[(2R)-4-Benzylpiperazin-2-yl]methyl}phenol (12 g) was dissolved in methanol (240 ml), 20% palladium hydroxide-carbon (50% containing water, 3.0 g) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the suspension was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in a mixed solvent of tert-butanol (100 ml) and water (100 ml), and 2.5N sodium hydroxide (40 ml) and di-tert-butyl bicarbonate (17.6 g) were added under ice-cooling. After stirring for 12 hr, the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (10.7 g) as an amorphous solid.
MS (ESI+, m/e) 393 (M+1)
Di-tert-butyl (2R)-2-(4-hydroxybenzyl)piperazine-1,4-dicarboxylate (10.7 g), 4-nitrophenyl trifluoromethanesulfonate (8.1 g) and potassium carbonate (7.6 g) were suspended in DMF (170 ml), and the suspension was stirred at room temperature for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (11.2 g) as an amorphous solid.
MS (ESI+, m/e) 525 (M+1)
A solution of di-tert-butyl (2R)-2-(4-{[(trifluoromethyl)sulfonyl]oxy}benzyl)piperazine-1,4-dicarboxylate (1.05 g), zinc cyanide (282 mg) and tetrakis(triphenylphosphine)palladium(0) (231 mg) in DMF (10 ml) was stirred at 80° C. for 15 hr. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-3:7) was concentrated under reduced pressure to give di-tert-butyl (2R)-2-(4-cyanobenzyl)piperazine-1,4-dicarboxylate (570 mg) as crystals.
The total amount thereof was dissolved in dichloromethane (1 ml), and TFA (3 ml) was added thereto. The mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. To the residue was 6% aqueous sodium bicarbonate was added by small portions to neutralize the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4-[(2R)-piperazin-2-ylmethyl]benzonitrile (600 mg) as an oil.
The total amount thereof and aqueous sodium hydroxide solution (100 mg/10 ml) were dissolved in tert-butanol (10 ml), and the solution was ice-cooled. Di-tert-butyl bicarbonate (546 mg) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-4:1) was concentrated under reduced pressure to give the object compound (145 mg) as an amorphous solid.
MS (ESI+, m/e) 302 (M+1)
tert-Butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (15.1 g), benzaldehyde (7.4 g) and acetic acid (4.2 g) were dissolved in 1,2-dichloroethane (200 ml), and the solution was ice-cooled. Sodium triacetoxyborohydride (19.3 g) was added, and the mixture was stirred at room temperature for 15 hr, and neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced pressure to give the object compound (16.1 g) as crystals.
MS (ESI+, m/e) 307 (M+1)
[(2S)-4-Benzylpiperazin-2-yl]methanol (25.84 g) was dissolved in THF (250 ml). Di-tert-butyl bicarbonate (27.34 g) was added by small portions, and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1.5:1) was concentrated under reduced pressure to give the object compound (38.34 g) as an oil.
1H-NMR (CDCl3) δ 1.45 (9H, s), 2.09 (1H, dt), 2.31 (1H, dd), 2.83 (1H, d), 2.97 (1H, d), 3.36-3.53 (3H, m), 3.83-3.99 (5H, m), 7.25-7.33 (5H, m)
MS (ESI+, m/e) 307 (M+1)
In the same manner as in Reference Example 164, the following compound (Reference Example 165) was obtained.
1H-NMR (CDCl3) δ 1.46 (9H, s), 2.01 (1H, dt), 2.20-2.24 (1H, m), 2.25 (1H, dd), 2.68-2.72 (2H, m), 3.01 (1H, dt), 3.37-3.60 (4H, m), 3.85-3.98 (3H, m), 4.26-4.30 (1H, m), 7.25-7.34 (5H, m)
MS (ESI+, m/e) 321 (M+1)
Benzyl 3-[(2R)-4-benzyl-3,6-dioxopiperazin-2-yl]propionate (25 g) was dissolved in THF (350 ml), and the solution was cooled to −20° C. Lithium aluminum hydride (13 g) was added over 30 min, and the mixture was stirred at room temperature for 30 min, and then at 50° C. for 12 hr. The mixture was cooled to −78° C., and sodium sulfate hydrate and 1N aqueous sodium hydroxide solution (5 ml) were successively added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1 hr. The insoluble material was filtered, and washed with ethyl acetate. The filtrate was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (150 ml), di-tert-butyl bicarbonate (13.4 g) was added, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give the object compound (8.2 g) as an oil.
MS (ESI+, m/e) 335 (M+1)
tert-Butyl (2S)-4-benzyl-2-(hydroxymethyl)piperazine-1-carboxylate (12.26 g) was dissolved in dichloromethane (130 ml), and a solution of pyridine-sulfur trioxide complex (19.10 g) in DMSO (130 ml) and triethylamine (12.14 g) were added at 0° C. The reaction mixture was stirred at 0° C. for 2 hr, and poured into ice-cooled saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (6.28 g) as an oil.
1H-NMR (CDCl3) δ 1.43-1.48 (9H, m), 2.12 (1H, dt), 2.27 (1H, dd), 2.69-2.73 (1H, m), 3.06-3.15 (1H, m), 3.30 (1H, d), 3.44 (1H, d), 3.56 (1H, d), 3.78 (0.5H, d), 3.90 (0.5H, d), 4.38 (0.5H, s), 4.58 (0.5H, s), 7.22-7.34 (5H, m), 9.49 (1H, s)
MS (ESI+, m/e) 305 (M+1)
In the same manner as in Reference Example 167, the following compound (Reference Example 168) was obtained.
1H-NMR (CDCl3) δ 1.44 (9H, s), 2.04 (1H, dt), 2.20 (1H, dd), 2.66-2.84 (4H, m), 3.01-3.09 (1H, m), 3.42 (1H, d), 3.51 (1H, d), 3.84-3.88 (1H, m), 4.60-4.64 (1H, m), 7.25-7.28 (5H, m), 9.73 (1H, s)
MS (ESI+, m/e) 319 (M+1)
Triphenylphosphine (9.4 g) and carbon tetrabromide (11.9 g) were suspended in diethyl ether (200 ml), tert-butyl (3S)-4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (9.2 g) was added over 5 min by small portions, and the mixture was stirred at room temperature for 15 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-3:7) was concentrated under reduced pressure to give the object compound (8.5 g) as an oil.
MS (ESI+, m/e) 370 (M+1)
tert-Butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (3.69 g) was dissolved in DMF (35 ml). Sodium benzenethiolate (1.98 g) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added 6% aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-3:7) was concentrated under reduced pressure to give tert-butyl (3S)-4-benzyl-3-[(phenylthio)methyl]piperazine-1-carboxylate (3.77 g) as an oil. 3.67 g therefrom was dissolved in 1,2-dichloroethane (30 ml), and 1-chloroethyl chloroformate (1.58 g) was added. The mixture was heated under reflux for 5 hr, and concentrated under reduced pressure. To the residue was added methanol (30 ml), and the mixture was further heated under reflux for 4 hr, and concentrated under reduced pressure. The residue was neutralized with 6% aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (1.44 g) as an oil.
MS (ESI+, m/e) 309 (M+1)
tert-Butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (912 mg) and trimethyl(trifluoromethyl)silane (853 mg) were dissolved in THF (20 ml). TBAF (several mg) was added, and the mixture was stirred at room temperature for 4 hr, and concentrated under reduced pressure to give the object compound (1.34 g) as an oil.
MS (ESI+, m/e) 447 (M+1)
tert-Butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (2.5 g) was dissolved in THF (25 ml), and the mixture was cooled to −30° C. Cyclopropylmagnesium bromide (0.5M THF solution, 40 ml) was added thereto, and the mixture was stirred at −20° C. for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (2.2 g) as an amorphous solid.
MS (ESI+, m/e) 347 (M+1)
In the same manner as in Reference Example 172 and by the reaction of known methyl (1,4-dibenzylpiperazin-2-yl)acetate with methylmagnesium bromide, the following compound (Reference Example 173) was obtained.
MS (ESI+, m/e) 339 (M+1)
tert-Butyl (2S)-4-benzyl-2-{2,2,2-trifluoro-1-[(trimethylsilyl)oxy]ethyl}piperazine-1-carboxylate (1.34 g) was dissolved in chloroform (2 ml). TFA (2 ml) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions, and the mixture was basified with small amount of potassium carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (772 mg) as an oil.
MS (ESI+, m/e) 275 (M+1)
In the same manner as in Reference Example 174, the following compound (Reference Example 175) was obtained.
MS (ESI+, m/e) 247 (M+1)
1-(1,4-Dibenzylpiperazin-2-yl)-2-methylpropan-2-ol (1.0 g) was dissolved in methanol (30 ml), 20% palladium hydroxide-carbon (50% containing water, 200 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 17 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue and potassium carbonate (300 mg) were dissolved in THF (15 ml) and water (30 ml), and the mixture was cooled to 0° C. (2Z)-{[(tert-Butoxycarbonyl)oxy]imino}(phenyl)acetonitrile (726 mg) was added thereto, and the mixture was stirred at the same temperature for 1 hr, and then at room temperature for 3 hr. To the reaction mixture was added 30% aqueous citric acid solution, and the mixture was washed with diethyl ether twice. The aqueous layer was saturated with potassium carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (500 mg) as an oil.
MS (ESI+, m/e) 259 (M+1)
A solution of tert-butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (6.27 g), isopropylamine (2.44 g), acetic acid (2.47 g) and dichloromethane (80 ml) in DMF (40 ml) was stirred at room temperature for 40 min, sodium triacetoxyborohydride (8.73 g) was added, and the mixture was further stirred at room temperature for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was stirred at room temperature for 15 min. After stirring, the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (6.37 g) as an oil.
1H-NMR (CDCl3) δ 0.98 (3H, d), 1.00 (3H, d), 1.46 (9H, s), 1.99-2.08 (2H, m), 2.73-2.96 (6H, m), 3.07 (1H, dt), 3.38 (1H, d), 3.54 (1H, d), 3.85-3.89 (1H, m), 4.07 (1H, br s), 7.30-7.32 (5H, m)
MS (ESI+, m/e) 348 (M+1)
In the same manner as in Reference Example 177, the following compounds (Reference Examples 178-179) were obtained.
1H-NMR (CDCl3) δ 1.45 (9H, s), 2.02-2.11 (2H, m), 2.80-2.84 (2H, m), 3.12 (1H, dt), 3.39-4.28 (7H, m), 6.54 (2H, d), 6.62-6.67 (1H, m), 7.10-7.15 (2H, m), 7.27-7.34 (5H, m)
MS (ESI+, m/e) 382 (M+1)
1H-NMR (CDCl3) δ 1.44 (9H, s), 1.59 (1H, br s), 1.97 (1H, dd), 2.00 (1H, dd), 2.09 (1H, dd), 2.71 (1H, d), 2.85-3.03 (4H, m), 3.46 (2H, s), 3.71 (2H, s), 3.77 (3H, s), 3.80 (3H, s), 3.80-3.86 (1H, m), 6.40-6.46 (2H, m), 7.12 (1H, d), 7.20-7.33 (5H, m)
MS (ESI+, m/e) 456 (M+1)
tert-Butyl (2R)-2-(anilinomethyl)-4-benzylpiperazine-1-carboxylate (2.75 g) and triethylamine (1.46 g) were dissolved in THF (60 ml), ethylsuccinyl chloride (2.37 g) was added, and the mixture was stirred at room temperature for 3 hr. The mixture was poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-chloroform-hexane (1:1:4) was concentrated under reduced pressure to give the object compound (3.56 g) as an oil.
MS (ESI+, m/e) 510 (M+1)
tert-Butyl (2R)-4-benzyl-2-{[(2,4-dimethoxybenzyl)amino]methyl}piperazine-1-carboxylate (1.91 g) and triethylamine (850 mg) were dissolved in THF (35 ml), and 2-methoxybenzoyl chloride (1.43 g) was added. The mixture was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2-1:1) was concentrated under reduced pressure to give the object compound (1.90 g) as an amorphous solid.
MS (ESI+, m/e) 590 (M+1)
In the same manner as in Reference Example 181, the following compounds (Reference Examples 182-184) were obtained.
MS (ESI+, m/e) 560 (M+1)
MS (ESI+, m/e) 596 (M+1)
MS (ESI+, m/e) 566 (M+1)
5-Methoxy-4,4-dimethyl-5-oxovaleric acid (4.46 g) was dissolved in THF (100 ml), and oxalyl chloride (3.90 g) and DMF (50 μl) were added. The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in THF (10 ml), and the solution was added to a solution of tert-butyl (2R)-4-benzyl-2-[(isopropylamino)methyl]piperazine-1-carboxylate (4.24 g) and triethylamine (2.59 g) in THF (90 ml). The mixture was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3-1:1) was concentrated under reduced pressure to give the object compound (5.91 g) as an oil.
MS (ESI+, m/e) 504 (M+1)
In the same manner as in Reference Example 185, the following compound (Reference Example 186) was obtained.
MS (ESI+, m/e) 538 (M+1)
tert-Butyl (2S)-4-benzyl-2-{[(4-ethoxy-4-oxobutanoyl)(phenyl)amino]methyl}piperazine-1-carboxylate (3.55 g) was dissolved in ethanol (115 ml), and 2N aqueous lithium hydroxide solution (75 ml) was added. The mixture was stirred at room temperature for 1 hr, and poured into ice water. While vigorously stirring the mixture, 6N hydrochloric acid was added by small portions to neutralize the mixture. The mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (3.21 g) as an amorphous solid.
MS (ESI+, m/e) 482 (M+1)
A mixture of 4-[{[(2S)-4-benzyl-1-(tert-butoxycarbonyl)piperazin-2-yl]methyl}(phenyl)amino]-4-oxobutyric acid (3.20 g), HOBt ammonium salt (1.21 g), WSC.HCl (1.53 g) and DMF (45 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (3.00 g) as an amorphous solid.
MS (ESI+, m/e) 481 (M+1)
tert-Butyl (2S)-4-benzyl-2-{[(isopropyl)(5-methoxy-4,4-dimethyl-5-oxopentanoyl)amino]methyl}piperazine-1-carboxylate (3.03 g) was dissolved in dichloromethane (7.5 ml), TFA (15 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions, and potassium carbonate was added by small portions to basify the mixture. The mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (2.41 g) as an oil.
MS (ESI+, m/e) 404 (M+1)
In the same manner as in Reference Example 189, the following compounds (Reference Examples 190-191) were obtained.
MS (ESI+, m/e) 438 (M+1)
MS (ESI+, m/e) 381 (M+1)
tert-Butyl (2S)-4-benzyl-2-{[(2,4-dimethoxybenzyl)(2-methoxybenzoyl)amino]methyl}piperazine-1-carboxylate (1.89 g) was dissolved in dichloromethane (3 ml), TFA (12 ml) was added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions. To the mixture was added potassium carbonate by small portions to basify the mixture, and the mixture was extracted with ethyl acetate (along with which the insoluble material was filtered off). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to about 50 ml. The insoluble material was filtered off again. The filtrate was concentrated under reduced pressure, and the crystals were collected by filtration to give the object compound (1.09 g).
1H-NMR (CDCl3) δ 2.01 (1H, t), 2.22 (1H, dt), 2.78 (1H, d), 2.88 (1H, d), 2.96 (1H, dt), 3.12 (1H, dt), 3.19-3.27 (1H, m), 3.44-3.57 (4H, m), 3.85-3.96 (4H, m), 6.94 (1H, d), 7.05 (1H, dt), 7.22-7.32 (5H, m), 7.43 (1H, ddd), 8.13 (1H, dd), 8.18 (1H, t)
MS (ESI+, m/e) 340 (M+1)
In the same manner as in Reference Example 192, the following compounds (Reference Examples 193-194) were obtained.
1H-NMR (CDCl3) δ 2.18 (1H, t), 2.30 (1H, t), 2.74 (1H, d), 2.88 (1H, d), 2.95 (1H, t), 3.14 (1H, d), 3.32-3.34 (1H, m), 3.47 (1H, d), 3.54 (1H, d), 3.60 (1H, d), 3.61 (1H, d), 5.47 (1H, br s), 7.26-7.49 (8H, m), 7.58 (1H, t), 7.80-7.82 (2H, m)
MS (ESI+, m/e) 310 (M+1)
1H-NMR (CDCl3) δ 2.17 (1H, dd), 2.30 (1H, dt), 2.76 (1H, d), 2.86 (1H, d), 2.98 (1H, dt), 3.16 (1H, dt), 3.27-3.31 (1H, m), 3.47-3.59 (4H, m), 4.96 (1H, br s), 6.88-6.95 (1H, m), 7.24-7.34 (7H, m), 7.45 (1H, br t)
MS (ESI+, m/e) 346 (M+1)
tert-Butyl (2S)-4-benzyl-2-{[(cyclohexylcarbonyl)(2,4-dimethoxybenzyl)amino]methyl}piperazine-1-carboxylate (2.26 g) was dissolved in dichloromethane (3.5 ml), TFA (15 ml) was added thereto, and the mixture was stirred at room temperature for 1.5 hr, and then at 70° C. for 10 min. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions. To the mixture was added potassium carbonate by small portions to basify the mixture, and the mixture was extracted with ethyl acetate (along with which the insoluble material was filtered off). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to about 50 ml. The insoluble material was filtered off again. The filtrate was concentrated under reduced pressure, and the crystals were collected by filtration to give the object compound (473 mg).
1H-NMR (CDCl3) δ 1.17-1.85 (12H, m), 2.01-2.09 (2H, m), 2.68-2.74 (2H, m), 2.82-3.01 (3H, m), 3.16 (1H, ddd), 3.28 (1H, dt), 3.48 (2H, s), 5.88 (1H, br s), 7.23-7.34 (5H, m)
MS (ESI+, m/e) 316 (M+1)
Diethyl benzylphosphonate (473 mg) was dissolved in THF (9 ml), the solution was ice-cooled, and sodium hydride (60% in oil) (113 mg) was added. The mixture was stirred at room temperature for 30 min, and ice-cooled again, and a solution of tert-butyl (2R)-4-benzyl-2-(2-oxoethyl)piperazine-1-carboxylate (600 mg) in THF (3 ml) was added. The mixture was further stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9) was concentrated under reduced pressure to give the object compound (428 mg) as an oil.
1H-NMR (CDCl3) δ 1.40 (9H, s), 2.02-2.11 (2H, m), 2.61 (2H, t), 2.74 (1H, d), 2.80 (1H, d), 3.12 (1H, dt), 3.36 (1H, d), 3.57 (1H, d), 3.83-3.87 (1H, m), 4.09-4.13 (1H, m), 6.00-6.11 (1H, m), 6.32 (1H, d), 7.13-7.36 (10H, m)
MS (ESI+, m/e) 393 (M+1)
(Cyclopropylmethyl)(triphenyl)phosphonium bromide (385 mg) was dissolved in THF (10 ml), and the mixture was cooled to −78° C. N-Butyllithium (1.6M hexane solution, 1.25 ml) was added thereto, and the mixture was stirred at −20° C. for 20 min. A solution of tert-butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (608 mg) in THF (5 ml) was added thereto, and the mixture was further stirred at −20° C. for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (700 mg) as an oil.
MS (ESI+, m/e) 343 (M+1)
1-(Bromomethyl)-2-(trifluoromethoxy)benzene (1.37 g) and triethyl phosphite (1.2 ml) were dissolved in toluene (2.4 ml), and the mixture was heated under reflux for 15 hr. The reaction mixture was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (1.77 g) as an oil.
1H-NMR (CDCl3) δ 1.25 (6H, t), 3.21 (1H, s), 3.28 (1H, s), 3.97-4.22 (4H, m), 7.19-7.34 (3H, m), 7.46-7.55 (1H, m)
In the same manner as in Reference Example 198, the following compounds (Reference Examples 199-200) were obtained.
1H-NMR (CDCl3) δ 1.25 (6H, t), 3.12 (1H, s), 3.19 (1H, s), 3.97-4.18 (4H, m), 7.04-7.40 (4H, m)
1H-NMR (CDCl3) δ 1.25 (6H, t), 3.11 (1H, s), 3.18 (1H, s), 3.95-4.19 (4H, m), 7.12-7.21 (2H, m), 7.29-7.37 (2H, m)
Diethyl (2-fluorobenzyl)phosphonate (500 mg) was dissolved in THF (10 ml), and the solution was ice-cooled. Sodium hydride (60% in oil) (112 mg) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was ice-cooled again, a solution of tert-butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (562 mg) in THF (5 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (943 mg) as an oil.
MS (ESI+, m/e) 397 (M+1)
In the same manner as in Reference Example 201, the following compounds (Reference Examples 202-209) shown in Table 1 were obtained.
tert-Butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (500 mg) was dissolved in THF (5 ml), and the solution was cooled to 0° C. Triphenyl (pyridin-2-ylmethyl)phosphonium chloride-potassium hydride (1:1) (1059 mg) was added thereto, and the mixture was stirred at room temperature for 17 hr. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (590 mg) as an oil.
MS (ESI+, m/e) 380 (M+1)
tert-Butyl (2R)-4-benzyl-2-[(2E)-3-phenyl-2-propen-1-yl]piperazine-1-carboxylate (424 mg) was dissolved in dichloromethane (1.5 ml), TFA (3 ml) was added thereto, and the mixture was stirred at room temperature for 40 min. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions. To the mixture was added potassium carbonate by small portions to basify the mixture, and the mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (315 mg) as an oil.
1H-NMR (CDCl3) δ 2.05 (1H, t), 2.21 (1H, dt), 2.40 (2H, t), 2.72 (1H, d), 2.85-3.09 (4H, m), 3.47 (1H, d), 3.56 (1H, d), 4.54 (1H, br s), 6.11 (1H, dt), 6.43 (1H, d), 7.16-7.33 (10H, m)
MS (ESI+, m/e) 293 (M+1)
In the same manner as in Reference Example 211, the following compound (Reference Example 212) was obtained.
MS (ESI+, m/e) 243 (M+1)
In the same manner as in Reference Example 211, the following compounds (Reference Examples 213-221) shown in Table 2 were obtained.
To tert-butyl (2R)-4-benzyl-2-[(E)-2-(pyridin-2-yl)vinyl]piperazine-1-carboxylate (280 mg) was added 4N hydrogen chloride-ethyl acetate solution (10 ml), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (260 mg).
MS (ESI+, m/e) 280 (M+1)
tert-Butyl (2R)-4-benzyl-2-(2-oxoethyl)piperazine-1-carboxylate (1.42 g) and 2-methyl-2-butene (4.6 ml) were dissolved in dioxane (17 ml), and a solution of sodium chlorite (2.22 g) and sodium dihydrogen phosphate (3.06 g) in water (11.5 ml) was added thereto. After stirring at room temperature for 1.5 hr, sodium chlorite (0.55 g) and sodium dihydrogen phosphate (0.55 g) were added thereto, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was poured into saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-2:1) was concentrated under reduced pressure to give the object compound (882 mg) as an amorphous solid.
1H-NMR (CDCl3) δ 1.44 (9H, s), 2.16 (1H, dt), 2.38 (1H, dd), 2.65 (1H, dd), 2.86-2.99 (3H, m), 3.17-3.21 (2H, m), 3.57 (1H, d), 3.65 (1H, d), 3.88-3.92 (1H, m), 4.44 (1H, br s), 7.26-7.36 (5H, m)
MS (ESI+, m/e) 335 (M+1)
A mixture of [(2R)-4-benzyl-1-(tert-butoxycarbonyl)piperazin-2-yl]acetic acid (300 mg), 5-phenyl-1H-tetrazole (144 mg), DCC (204 mg) and toluene (6 ml) was stirred at 100° C. for 4 hr, and cooled to room temperature. The insoluble material was filtered, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure, and the crystals were collected by filtration to give the object compound (332 mg).
1H-NMR (CDCl3) δ 1.27 (9H, s), 2.09 (1H, t), 2.25 (1H, dd), 2.78-2.82 (2H, m), 3.22-3.26 (2H, m), 3.47 (1H, d), 3.56 (1H, d), 3.53-3.58 (1H, m), 4.04-4.10 (1H, m), 4.55-4.59 (1H, m), 7.22-7.34 (5H, m), 7.43-7.50 (3H, m), 7.96-7.99 (2H, m)
MS (ESI+, m/e) 435 (M+1)
tert-Butyl (2R)-4-benzyl-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazine-1-carboxylate (332 mg) was dissolved in dichloromethane (1.5 ml), TFA (3 ml) was added thereto, and the mixture was stirred at room temperature for 50 min. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions. To the mixture was added potassium carbonate by small portions to basify the mixture, and the mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (254 mg) as an oil.
1H-NMR (CDCl3) δ 2.02 (1H, t), 2.13-2.21 (3H, m), 2.74 (1H, d), 2.86 (1H, d), 2.90-3.07 (3H, m), 3.32-3.41 (1H, m), 3.53 (2H, s), 7.22-7.32 (5H, m), 7.45-7.55 (3H, m), 7.98-8.01 (2H, m)
MS (ESI+, m/e) 335 (M+1)
A solution of [(2R)-4-benzyl-1-(tert-butoxycarbonyl)piperazin-2-yl]acetic acid (576 mg), o-phenylenediamine (931 mg), WSC.HCl (660 mg) and HOBt (466 mg) in DMF (18 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate-THF (4:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic acid (25 ml), and the solution was stirred at 65° C. for 3 hr, and concentrated under reduced pressure. TFA (5 ml) was added to the residue, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions. To the mixture was added potassium carbonate by small portions to basify the mixture, and the mixture was saturated with sodium chloride, and extracted with ethyl acetate-THF (4:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-10:0:1) was concentrated under reduced pressure to give the object compound (290 mg) as an amorphous solid.
1H-NMR (CDCl3) δ 1.89 (1H, t), 2.10 (1H, dt), 2.73-2.83 (2H, m), 2.87-3.11 (4H, m), 3.24-3.32 (1H, m), 3.47 (2H, s), 7.17-7.33 (9H, m), 7.53 (2H, br s)
MS (ESI+, m/e) 307 (M+1)
Di-tert-butyl (2R)-2-(4-{([(trifluoromethyl)sulfonyl]oxy}benzyl)piperazine-1,4-dicarboxylate (6.0 g), triethylamine (11 ml), palladium(II) acetate (510 mg) and dppf (1.26 g) were suspended in ethanol (65 ml), and the suspension was stirred at 80° C. for 12 hr under a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and the insoluble material was filtered through celite. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure, and the crystals were collected by filtration to give the object compound (4.1 g).
MS (ESI+, m/e) 449 (M+1)
Di-tert-butyl (2R)-2-[4-(ethoxycarbonyl)benzyl]piperazine-1,4-dicarboxylate (1.79 g) was dissolved in ethanol (15 ml), pulverized potassium hydroxide (673 mg) was added, and the mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (5 ml). The mixture was weakly acidified (pH 3-4) with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-{[(2R)-1,4-bis(tert-butoxycarbonyl)piperazin-2-yl]methyl}benzoic acid (1.67 g) as crystals. 1.65 g therefrom was dissolved in THF (15 ml), the solution was ice-cooled, N-methylmorpholine (435 mg) and ethyl chloroformate (467 mg) were successively added. The mixture was stirred at 0-5° C. for 1 hr, and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (30 ml). The solution was washed successively with 6% aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-3:7) was concentrated under reduced pressure to give di-tert-butyl (2R)-2-(4-{([(ethoxycarbonyl)oxy]carbonyl}benzyl)piperazine-1,4-dicarboxylate (1.48 g) as an oil.
The total amount thereof was dissolved in THF (15 ml), and the solution was ice-cooled. Sodium borohydride (379 mg) was added, and then methanol (3 ml) was added dropwise over 5 min. The mixture was stirred at the same temperature for 30 min, and saturated aqueous ammonium chloride solution (5 ml) was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give di-tert-butyl (2R)-2-[4-(hydroxymethyl)benzyl]piperazine-1,4-dicarboxylate (1.11 g) as an amorphous solid. 1.10 g therefrom was dissolved in dichloromethane (20 ml), manganese dioxide (2.35 g) was added thereto, and the mixture was stirred at room temperature for 15 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give di-tert-butyl (2R)-2-(4-formylbenzyl)piperazine-1,4-dicarboxylate (1.01 g) as an oil. 1.00 g therefrom and trimethyl(trifluoromethyl)silane (702 mg) were dissolved in THF (10 ml), and TBAF (several mg) was added thereto. The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure to give di-tert-butyl (2R)-2-[4-(2,2,2-trifluoro-1-hydroxyethyl)benzyl]piperazine-1,4-dicarboxylate (1.35 g) as an oil.
To the total amount thereof was added TFA (3 ml), and the mixture was stirred at room temperature for 30 min, and concentrated under reduced pressure. The residue was dissolved in THF (15 ml), and the solution was ice-cooled. N,N-Diisopropylethylamine (1.28 g) and di-tert-butyl bicarbonate (539 mg) were successively added, and the mixture was stirred at room temperature for 15 hr, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1-7:3) was concentrated under reduced pressure to give the object compound (0.9 g) as an amorphous solid.
MS (ESI+, m/e) 375 (M+1)
A mixture of tert-butyl (3S)-4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (3.00 g), sodium hydride (60% in oil) (500 mg) and THF (50 ml) was stirred at room temperature for 1 hr, and ice-cooled, and methyl 6-chloronicotinate (1.68 g) was added. The reaction mixture was further stirred at room temperature for 2 hr, and poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:19-3:2) was concentrated under reduced pressure to give the object compound (2.83 g).
1H-NMR (CDCl3) δ 1.43 (9H, s), 2.31 (1H, br s), 2.75 (1H, dd), 2.91 (1H, br s), 3.45 (3H, br s), 3.58 (2H, br s), 3.91 (3H, s), 3.97-4.09 (1H, m), 4.50 (1H, d), 4.63 (1H, br s), 6.78 (1H, d), 7.21-7.36 (5H, m), 8.15 (1H, dd), 8.80 (1H, d)
MS (ESI+, m/e) 442 (M+1)
tert-Butyl (3S)-4-benzyl-3-({[5-(methoxycarbonyl)pyridin-2-yl]oxy}methyl)piperazine-1-carboxylate (1.00 g) was dissolved in methanol (30 ml), 20% palladium hydroxide-carbon (50% containing water, 150 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 1 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (747 mg).
1H-NMR (CDCl3) δ 1.47 (9H, s), 1.91 (1H, br s), 2.81 (1H, dd), 3.08 (2H, td), 2.96-3.12 (1H, m), 3.73 (2H, s), 3.91 (4H, s), 4.30 (1H, d), 4.36 (1H, d), 6.78 (1H, d), 8.16 (1H, dd), 8.80 (1H, d)
MS (ESI+, m/e) 352 (M+1)
A mixture of tert-butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (1.85 g), 2-cyanophenol (471 mg), potassium carbonate (1.04 mg) and DMF (5 ml) was stirred at 60° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:2) was concentrated under reduced pressure to give tert-butyl (3S)-4-benzyl-3-[(2-cyanophenoxy)methyl]piperazine-1-carboxylate (2.00 g) as an oil.
The total amount thereof was dissolved in 1,2-dichloromethane (50 ml), and the solution was ice-cooled. 1-Chloroethyl chloroformate (830 μl) was added thereto, and the mixture was stirred at 80° C. for 2 hr. After stirring, the solvent was evaporated under reduced pressure. Methanol (3 ml) was added to the residue, and the mixture was heated under reflux for 1 hr. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was suspended in THF (20 ml), N,N-diisopropylethylamine (3.4 ml) and di-tert-butyl bicarbonate (1.07 g) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (19:1) was concentrated under reduced pressure to give the object compound (805 mg) as an amorphous solid.
MS (ESI+, m/e) 218 (M+1-“Boc”)
tert-Butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (1.2 g) and 3,5-difluorophenol (509 mg) were dissolved in acetonitrile (30 ml), potassium carbonate (663 mg) was added thereto, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give tert-butyl (3S)-4-benzyl-3-[(3,5-difluorophenoxy)methyl]piperazine-1-carboxylate (1.09 g) as an amorphous solid. The total amount thereof was dissolved in methanol (20 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (906 mg) as an amorphous solid.
MS (ESI+, m/e) 273 (M+1-“Boc”)
In the same manner as in Reference Example 232, the following compounds (Reference Examples 233-234) were obtained.
MS (ESI+, m/e) 293 (M+1)
MS (ESI+, m/e) 329 (M+1)
A solution of tert-butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (370 mg) and 4-methylpyrazole (99 mg) in DMF (5 ml) was ice-cooled, and sodium hydride (60% in oil, 60 mg) was added thereto. The mixture was stirred at 0° C. for 15 min, and then at room temperature for 1 hr, and poured into ice-cooled saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 70 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 2 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (90 mg) as an oil.
MS (ESI+, m/e) 281 (M+1)
In the same manner as in Reference Example 235, the following compounds (Reference Examples 236-239) were obtained.
MS (ESI+, m/e) 268 (M+1)
MS (ESI+, m/e) 267 (M+1)
MS (ESI+, m/e) 317 (M+1)
MS (ESI+, m/e) 318 (M+1)
A solution of tert-butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (600 mg) and imidazole (150 mg) in DMF (10 ml) was ice-cooled, and sodium hydride (60% in oil, 84 mg) was added thereto. The mixture was stirred at 0° C. for 15 min, and then at 60° C. for 1 hr, and poured into ice-cooled saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 2 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (210 mg) as an oil.
MS (ESI+, m/e) 267 (M+1)
In the same manner as in Reference Example 240, the following compound (Reference Example 241) was obtained.
MS (ESI+, m/e) 295 (M+1)
To a solution of tert-butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (370 mg) and 3-trifluoromethylpyrazole (272 mg) in DMF (3 ml) was added BEMP (600 mg). The mixture was stirred at room temperature for 2 hr, and poured into ice-cooled saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (4:1) was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 2 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (261 mg) as an oil.
MS (ESI+, m/e) 335 (M+1)
A mixture of tert-butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (370 mg), 1H-benzimidazole (236 mg), potassium carbonate (690 mg) and DMF (5 ml) was stirred at 60° C. for 12 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (160 mg) as an oil.
MS (ESI+, m/e) 317 (M+1)
Potassium tert-butoxide (1.58 g) was dissolved in tert-butanol (60 ml), tert-butyl (3S)-4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (3.06 g) and 2-bromopyridine (1.74 g) were added, and the mixture was stirred at 80° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give tert-butyl (3S)-4-benzyl-3-[(pyridin-2-yloxy)methyl]piperazine-1-carboxylate (1.67 g) as an amorphous solid. The total amount thereof was dissolved in methanol (50 ml), 20% palladium hydroxide-carbon (50% containing water, 200 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (990 mg) as an amorphous solid.
MS (ESI+, m/e) 294 (M+1)
tert-Butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (1.00 g) was dissolved in THF (10 ml), and the solution was ice-cooled. 3-Methoxyphenylmagnesium bromide (1M THF solution, 4.0 ml) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give tert-butyl (2S)-4-benzyl-2-[(hydroxy) (3-methoxyphenyl)methyl]piperazine-1-carboxylate (1.26 g) as an amorphous solid.
The total amount thereof and lithium chloride (1.26 g) were suspended in 1,2-dichloroethane (15 ml), and the suspension was ice-cooled. Methanesulfonyl chloride (280 μl) and triethylamine (970 μl) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:2) was concentrated under reduced pressure to give (8aS)-7-benzyl-1-(3-methoxyphenyl)hexahydro[1,3]oxazolo[3,4-a]pyrazin-3-one (942 mg) as an amorphous solid. 900 mg therefrom was dissolved in ethanol-THF (1:1, 30 ml), 8N aqueous sodium hydroxide solution (5 ml) was added thereto, and the mixture was stirred at 50° C. for 24 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (10 ml) and THF (10 ml). Benzyl chloroformate (420 μl) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:2) was concentrated under reduced pressure to give benzyl (2S)-4-benzyl-2-[(hydroxy)(3-methoxyphenyl)methyl]piperazine-1-carboxylate (469 mg) as an amorphous solid.
460 mg therefrom was dissolved in dichloromethane (10 ml), DAST (240 μl) was added thereto at −78° C., and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:2) was concentrated under reduced pressure to give benzyl (2S)-4-benzyl-2-[(fluoro)(3-methoxyphenyl)methyl]piperazine-1-carboxylate (449 mg) as an amorphous solid.
300 mg therefrom was dissolved in ethanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give (2R)-2-(3-methoxybenzyl)piperazine as an amorphous solid. The total amount thereof was dissolved in tert-butanol (5 ml) and water (4 ml), 8N aqueous sodium hydroxide solution (670 μl) and di-tert-butyl bicarbonate (146 mg) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (17:3) was concentrated under reduced pressure to give the object compound (55 mg) as an oil.
MS (ESI+, m/e) 307 (M+1)
tert-Butyl (2R)-4-benzyl-2-(2-hydroxyethyl)piperazine-1-carboxylate (320 mg) was dissolved in DMF (5 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 48 mg) was added thereto, and the mixture was stirred at 0° C. for 10 min. After stirring, (bromomethyl)cyclopropane (120 μl) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give tert-butyl (2R)-4-benzyl-2-[2-(cyclopropylmethoxy)ethyl]piperazine-1-carboxylate (150 mg) as an amorphous solid. To 140 mg therefrom was added 4N hydrogen chloride-ethyl acetate solution (5 ml), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure to give the object compound (141 mg) as an amorphous solid.
MS (ESI+, m/e) 275 (M+1)
tert-Butyl (3S)-4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (1.00 g) was dissolved in DMF (15 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 156 mg) was added thereto, and the mixture was stirred at 0° C. for 10 min. After stirring, 2-bromo-6-(trifluoromethyl)pyridine (884 mg) was added thereto, and the mixture was stirred at room temperature for 4 hr. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (2:3) was concentrated under reduced pressure to give tert-butyl (3S)-4-benzyl-3-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)piperazine-1-carboxylate (1.44 g) as an amorphous solid. 1.41 g therefrom was dissolved in ethanol (50 ml), 20% palladium hydroxide-carbon (50% containing water, 300 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (937 mg) as an oil.
MS (ESI+, m/e) 362 (M+1)
In the same manner as in Reference Example 247, the following compound (Reference Example 248) was obtained.
MS (ESI+, m/e) 362 (M+1)
(2R)-1,4-Dibenzyl-2-vinylpiperazine (1.10 g) was dissolved in THF (10 ml), 9-BBN (0.5M THF solution, 30 ml) was added, and the mixture was stirred at room temperature for 12 hr. To the reaction mixture were added triphenylphosphine (168 mg), 1-iodo-4-(trifluoromethyl)benzene (1.53 g), tetrakis(triphenylphosphine)palladium(0) (92 mg) and 3N aqueous sodium hydroxide solution (3.1 ml), and the mixture was stirred at 70° C. for 24 hr. The solvent was evaporated under reduced pressure, 2N aqueous sodium hydroxide solution (80 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with diethyl ether, and the organic layer was back-extracted with 1N hydrochloric acid. The acidic aqueous layer was separated, basified with 8N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give (2R)-1,4-dibenzyl-2-{2-[4-(trifluoromethyl)phenyl]ethyl}piperazine (751 mg) as an amorphous solid.
The total amount thereof was dissolved in ethanol (20 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give (2R)-2-{2-[4-(trifluoromethyl)phenyl]ethyl}piperazine as an amorphous solid. The total amount thereof was dissolved in tert-butanol (10 ml) and water (8 ml), 1N aqueous sodium hydroxide solution (1.71 ml) and di-tert-butyl bicarbonate (373 mg) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (17:3) was concentrated under reduced pressure to give the object compound (455 mg) as an oil.
MS (ESI+, m/e) 359 (M+1)
tert-Butyl (2R)-4-benzyl-2-(2-hydroxyethyl)piperazine-1-carboxylate (13.33 g) was dissolved in methanol (135 ml), 20% palladium hydroxide-carbon (50% containing water, 4.0 g) was added thereto, and the mixture was subjected to catalytic reduction at room temperature for 4 hr under moderate-pressure (5.0 kgf/cm2). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (9.44 g) as an oil.
1H-NMR (CDCl3) δ 1.47 (9H, s), 1.68 (1H, br s), 2.07-2.11 (1H, m), 2.36-2.40 (3H, m), 2.64-2.75 (1H, m), 2.85-2.96 (3H, m), 3.38-3.42 (1H, m), 3.66 (1H, dt), 3.82-3.86 (1H, m), 4.24 (1H, br s)
MS (ESI+, m/e) 231 (M+1)
tert-Butyl (2R)-2-(2-hydroxyethyl)piperazine-1-carboxylate (9.44 g) was dissolved in dioxane (90 ml), and the solution was ice-cooled. A solution of sodium carbonate (4.78 g) in water (45 ml) and benzyl chloroformate (7.34 g) were added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-2:1) was concentrated under reduced pressure to give the object compound (14.17 g) as an oil.
MS (ESI+, m/e) 265 (M+1-“Boc”)
Triphenylphosphine (1.29 g) and carbon tetrabromide (1.63 g) were suspended in diethyl ether (20 ml), a solution of 1-tert-butyl 4-benzyl (2R)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate (1.50 g) in diethyl ether (10 ml) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added THF (30 ml), triphenylphosphine (1.29 g) and carbon tetrabromide (1.63 g) were added thereto, and the mixture was further stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (60 ml). Triphenylphosphine (1.29 g) and carbon tetrabromide (1.63 g) were further added thereto, and the mixture was stirred at room temperature for 3 days. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:19-3:7) was concentrated under reduced pressure to give the object compound (697 mg) as an oil.
MS (ESI+, m/e) 427 (M+1)
A mixture of 1-tert-butyl 4-benzyl (2R)-2-(2-bromoethyl)piperazine-1,4-dicarboxylate (320 mg), 4-methyl-1H-pyrazole (123 mg), potassium carbonate (415 mg) and DMF (5 ml) was stirred at 50° C. for 10 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:1) was concentrated under reduced pressure to give the object compound (330 mg) as an oil.
MS (ESI+, m/e) 429 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate (14.17 g) and triethylamine (5.90 g) were dissolved in THF (80 ml), and the solution was ice-cooled. Methanesulfonyl chloride (5.57 g) was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crystals were collected by filtration to give the object compound (15.54 g).
1H-NMR (CDCl3) δ 1.47 (9H, s), 1.88-2.04 (2H, m), 2.93-2.98 (5H, m), 3.95-4.33 (7H, m), 5.10 (1H, d), 5.17 (1H, d), 7.30-7.39 (5H, m)
MS (ESI+, m/e) 343 (M+1-“Boc”)
A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (708 mg), phenol (188 mg), potassium carbonate (332 mg), potassium iodide (133 mg) and DMF (16 ml) was stirred at 65° C. for 15 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (591 mg) as an oil.
MS (ESI+, m/e) 441 (M+1)
In the same manner as in Reference Example 255, the following compounds (Reference Examples 256-320) shown in Table 3-1-Table 3-7 were obtained. In the column of “MS (ESI+)” in the Tables, “*” means that a mass value of “M+1-“Boc”” was obtained, and “**” means that a mass value of “M+1-“tBu”” was obtained (a mass value of M+1 was obtained for other compounds).
A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (221 mg), 2-fluorophenol (84 mg), potassium carbonate (138 mg), potassium iodide (83 mg) and DMF (5 ml) was stirred at 65° C. for 15 hr. Saturated brine was added to the reaction mixture, and the liberated oil was extracted with ethyl acetate. The extract was washed successively with 6% aqueous sodium bicarbonate, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-3:7) was concentrated under reduced pressure to give the object compound (210 mg) as an oil.
MS (ESI+, m/e) 459 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (1.11 g) was dissolved in DMF (10 ml), methyl 4-hydroxybenzoate (681 mg), potassium carbonate (1.38 g) and potassium iodide (415 mg) were added, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (452 mg) as an oil.
MS (ESI+, m/e) 499 (M+1)
A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (708 mg), methyl 3-hydroxypyridine-2-carboxylate (490 mg), potassium carbonate (332 mg), potassium iodide (266 mg) and DMF (16 ml) was stirred at 65° C. for 15 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was ice-cooled, and washed successively with 0.5N aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (658 mg) as an oil.
MS (ESI+, m/e) 500 (M+1)
In the same manner as in Reference Example 323, the following compounds (Reference Examples 324-335) shown in Table 4-1-Table 4-2 were obtained. In the column of “MS (ESI+)” in the Tables, “*” means that a mass value of “M+1-“Boc”” was obtained (a mass value of M+1 was obtained for other compounds).
Methyl 3-fluoro-4-hydroxybenzoate (1.0 g) was dissolved in ethanol (10 ml), hydrazine monohydrate (2.9 g) was added thereto, and the mixture was heated under reflux for 12 hr. The solvent was evaporated under reduced pressure, triethyl orthoformate (10 ml) was added thereto, and the mixture was heated under reflux for 12 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in diisopropyl ether, and the precipitated crystals were collected by filtration to give the object compound (755 mg).
1H-NMR (DMSO-d6) δ 2.11 (3H, s), 6.61-6:75 (2H, m), 7.73 (1H, t), 10.54 (1H, br s)
MS (ESI+, m/e) 195 (M+1)
In the same manner as in Reference Example 336, the following compounds (Reference Examples 337-340) were obtained.
1H-NMR (DMSO-d6) δ 2.55 (3H, s), 7.13 (1H, t), 7.56-7.75 (2H, m), 10.79 (1H, br s)
MS (ESI+, m/e) 195 (M+1)
1H-NMR (DMSO-d6) δ 2.59 (3H, s), 6.95-7.07 (1H, m), 7.22-7.38 (2H, m), 9.92 (1H, br s)
MS (ESI+, m/e) 195 (M+1)
1H-NMR (DMSO-d6) δ 2.55 (3H, s), 3.86 (3H, s), 6.94 (1H, d), 7.37-7.44 (2H, m), 9.88 (1H, s)
MS (ESI+, m/e) 207 (M+1)
1H-NMR (DMSO-d6) δ 2.54 (3H, s), 3.84 (3H, s), 7.09 (1H, d), 7.35-7.51 (2H, m), 9.59 (1H, br s)
MS (ESI+, m/e) 207 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (442 mg) was dissolved in DMA (10 ml), and methyl 3-hydroxy-4-methoxybenzoate (273 mg) and cesium carbonate (652 mg) were added thereto. The mixture was stirred at 60° C. for 15 hr, and the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (7:3) was concentrated under reduced pressure to give the object compound (482 mg) as a colorless amorphous solid.
MS (ESI+, m/e) 429 (M+1-“Boc”)
In the same manner as in Reference Example 341, the following compounds (Reference Examples 342-346) were obtained.
MS (ESI+, m/e) 541 (M+1)
MS (ESI+, m/e) 541 (M+1)
MS (ESI+, m/e) 541 (M+1)
MS (ESI+, m/e) 553 (M+1)
MS (ESI+, m/e) 553 (M+1)
A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (619 mg), 1H-benzimidazole (331 mg), potassium carbonate (1.20 g) and DMF (7 ml) was stirred at 50° C. for 10 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced pressure to give the object compound (510 mg) as an oil.
MS (ESI+, m/e) 465 (M+1)
3,5-Di-tert-butyl-1H-pyrazole (204 mg) was dissolved in DMF (7 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 46 mg) was added thereto, and the mixture was stirred at 0° C. for 15 min. After stirring, 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (250 mg) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (220 mg) as an oil.
MS (ESI+, m/e) 527 (M+1)
In the same manner as in Reference Example 347 or Reference Example 348, the following compounds (Reference Examples 349-363) shown in Table 5-1-Table 5-2 were obtained. In the column of “Base” in the Tables, the compounds described as “K2CO3” were synthesized according to the method of Reference Example 347 and the compounds described as “NaH” were synthesized according to the method of Reference Example 348. In addition, in the column of “MS (ESI+)” in the Tables, “*” means that a mass value of “M+1-“Boc”” was obtained, and “**” means that a mass value of “M+1-“tBu”” was obtained (a mass value of M+1 was obtained for other compounds).
A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (700 mg), 1,2-dihydro-3H-indazol-3-one (212 mg), potassium carbonate (450 mg) and DMF (6 ml) was stirred at 80° C. for 3 hr, the insoluble material was filtered off using silica gel, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object compound (423 mg).
1H-NMR (CDCl3) δ 1.36 (9H, s), 2.05 (1H, s), 2.19 (1H, br s), 2.89 (1H, br s), 3.08 (2H, br s), 4.05-4.16 (1H, m), 4.12 (1H, d), 4.41 (2H, br s), 5.14 (2H, s), 7.07 (1H, td), 7.25-7.39 (9H, m), 7.65 (1H, br s)
MS (ESI+, m/e) 481 (M+1)
In the same manner as in Reference Example 364, the following compounds (Reference Examples 365-371) were obtained.
1H-NMR (CDCl3) δ 1.35 (9H, br s), 1.98 (4H, br s), 2.90 (1H, br s), 3.04 (2H, br s), 3.84 (1H, br s), 3.96 (1H, br s), 4.14 (2H, br s), 5.14 (2H, br s), 7.03 (3H, br s), 7.29 (6H, br s), 9.17 (1H, br s)
MS (ESI+, m/e) 481 (M+1)
1H-NMR (CDCl3) δ 1.38 (9H, s), 1.95 (2H, br s), 3.03 (2H, br s), 3.81 (2H, br s), 3.95 (1H, br s), 4.04-4.19 (1H, m), 4.12 (2H, d), 5.14 (2H, q), 7.05 (1H, s), 7.17 (3H, ddd), 7.11-7.22 (1H, m), 7.25-7.35 (5H, m)
MS (ESI+, m/e) 482 (M+1)
1H-NMR (CDCl3) δ 1.44 (9H, br s), 1.88 (2H, br s), 2.90 (1H, br s), 3.05 (2H, br s), 3.82 (2H, br s), 4.09 (4H, br s), 4.60 (2H, br s), 5.14 (2H, br s), 6.96 (4H, br s), 7.31 (5H, br s)
MS (ESI+, m/e) 496 (M+1)
1H-NMR (CDCl3) δ 1.36 (9H, br s), 1.89 (1H, d), 2.08 (1H, qd), 1.98-2.13 (3H, m), 2.56 (2H, td), 2.81-2.97 (3H, m), 3.00 (1H, d), 3.09 (2H, br s), 3.83 (1H, d), 3.94 (1H, br s), 4.21 (2H, br s), 5.13 (2H, q), 5.92 (1H, t), 6.91 (1H, br s), 7.03-7.12 (2H, m), 7.13-7.20 (1H, m), 7.22-7.36 (4H, m), 7.28 (1H, d)
MS (ESI+, m/e) 547 (M+1)
1H-NMR (CDCl3) δ 1.38 (9H, br s), 1.69-1.79 (2H, m), 1.80-1.93 (3H, m), 2.25-2.41 (4H, m), 2.28 (3H, d), 2.89 (1H, br s), 3.04 (2H, br s), 3.84 (1H, d), 3.94 (1H, br s), 4.11 (2H, br s), 5.13 (2H, q), 5.91 (1H, br s), 6.95-7.09 (4H, m), 7.22-7.37 (5H, m)
MS (ESI+, m/e) 561 (M+1)
MS (ESI+, m/e) 488 (M+1)
MS (ESI+, m/e) 488 (M+1)
A mixture of 1-tert-butyl 4-benzyl (2R)-2-[2-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]piperazine-1,4-dicarboxylate (515 mg), methyl iodide (100 μl), cesium carbonate (1.00 g) and DMA (5 ml) was stirred at room temperature for 3 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object compound (473 mg).
1H-NMR (CDCl3) δ 1.30 (9H, br s), 1.85-2.01 (2H, m), 2.93 (1H, d), 3.01 (2H, br s), 3.34-3.45 (3H, m), 3.81 (2H, br s), 3.94 (1H, br s), 4.04-4.20 (1H, m), 4.12 (2H, q), 5.05-5.20 (2H, m), 6.87-7.02 (2H, m), 7.03-7.14 (1H, m), 7.03-7.14 (1H, m), 7.22-7.36 (5H, m)
MS (ESI+, m/e) 495 (M+1)
A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (3.00 g), sodium azide (2.50 g) and DMF (20 ml) was stirred at 80° C. for 12 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:19-4:1) was concentrated under reduced pressure to give the object compound (2.19 g).
1H-NMR (CDCl3) δ 1.47 (9H, s), 1.69 (1H, br s), 1.84 (1H, t), 1.84 (1H, d), 2.93 (1H, d), 2.92 (1H, d), 3.01 (1H, br s), 3.25 (2H, br s), 4.00 (2H, br s), 4.27 (1H, br s), 5.14 (2H, d), 7.30-7.40 (5H, m)
MS (ESI+, m/e) 390 (M+1)
A mixture of 1-tert-butyl 4-benzyl (2R)-2-(2-azidoethyl)piperazine-1,4-dicarboxylate (500 mg), propargyl alcohol (360 mg) and toluene (7 ml) was stirred at 130° C. for 12 hr in a sealed stainless tube, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:19-4:1) was concentrated under reduced pressure to give the object compound (510 mg).
1H-NMR (CDCl3) δ 1.46 (9H, d), 1.77-1.94 (1H, m), 2.04 (1H, br s), 2.18 (1H, d), 2.95 (2H, br s), 3.26 (1H, br s), 3.86 (1H, br s), 4.02 (2H, br s), 4.13 (1H, br s), 4.27 (2H, br s), 4.64 (1H, br s), 4.78 (1H, s), 5.14 (2H, d), 7.09-7.21 (1H, m), 7.23-7.38 (5H, m)
MS (ESI+, m/e) 446 (M+1)
In the same manner as in Reference Example 374, the following compounds (Reference Examples 375-378) were obtained.
1H-NMR (CDCl3) δ 1.45 (9H, br s), 1.79-1.95 (1H, m), 2.03-2.19 (2H, m), 2.34 (1H, br s), 2.50 (1H, br s), 2.90 (4H, br s), 3.27 (1H, br s), 3.74 (1H, br s), 3.85 (1H, br s), 3.95 (2H, br s), 4.06 (1H, br s), 4.28 (1H, br s), 5.14 (2H, br s), 7.16 (1H, br s), 7.26 (1H, br s), 7.35 (4H, br s)
MS (ESI+, m/e) 460 (M+1)
1H-NMR (CDCl3) δ 0.67 (1H, br s), 0.84 (2H, dd), 0.89-1.04 (1H, m), 0.94 (2H, td), 1.43 (9H, d), 1.94 (1H, dt), 2.14 (1H, br s), 2.35 (1H, s), 2.87 (1H, br s), 3.03 (1H, br s), 4.12 (2H, d), 4.08 (1H, br s), 4.25 (2H, br s), 5.13 (2H, d), 7.15-7.19 (1H, m), 7.22-7.37 (5H, m)
MS (ESI+, m/e) 456 (M+1)
MS (ESI+, m/e) 488 (M+1)
1H-NMR (CDCl3) δ 1.44 (9H, s), 1.98-2.08 (1H, m), 2.25 (1H, d), 2.69 (3H, s), 2.92 (2H, d), 3.03 (1H, br s), 3.94 (1H, br s), 3.98-4.21 (3H, m), 4.38 (2H, br s), 5.06-5.21 (1H, m), 5.14 (1H, d), 7.34 (5H, s), 8.15 (1H, s)
MS (ESI+, m/e) 458 (M+1)
A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]ethyl}piperazine-1,4-dicarboxylate (360 mg), acetic anhydride (1.0 ml) and pyridine (1.0 ml) was stirred at room temperature for 12 hr, and concentrated under reduced pressure to give the object compound (390 mg).
1H-NMR (CDCl3) δ 1.44 (9H, s), 2.03-2.16 (4H, m), 2.23 (3H, s), 2.89 (1H, br s), 2.96 (1H, br s), 3.04 (1H, br s), 4.15 (1H, br s), 4.21-4.36 (3H, m), 5.07-5.22 (4H, m), 7.30-7.40 (5H, m), 7.55-7.72 (1H, m)
MS (ESI+, m/e) 488 (M+1)
A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (620 mg), 1H-indazole (331 mg), potassium carbonate (1.2 g) and DMF (7 ml) was stirred at 50° C. for 10 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate-hexane (1:1) were concentrated under reduced pressure, respectively. The residue of the less polar fraction was vacuum-dried to give 1-tert-butyl 4-benzyl (2R)-2-[2-(1H-indazol-1-yl)ethyl]piperazine-1,4-dicarboxylate (380 mg), and the residue of the more polar fraction was vacuum-dried to give 1-tert-butyl 4-benzyl (2R)-2-[2-(2H-indazol-2-yl)ethyl]piperazine-1,4-dicarboxylate (170 mg), as an amorphous solid, respectively.
MS (ESI+, m/e) 465 (M+1)
MS (ESI+, m/e) 465 (M+1)
A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (800 mg), ethyl 5-methyl-1H-pyrazole-3-carboxylate (560 mg), potassium carbonate (1.1 g) and DMF (20 ml) was stirred at 50° C. for 10 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate-hexane (1:1) were concentrated under reduced pressure, respectively. The residue of the less polar fraction was vacuum-dried to give 1-tert-butyl 4-benzyl (2R)-2-{2-[3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl]ethyl}piperazine-1,4-dicarboxylate (470 mg), and the residue of the more polar fraction was vacuum-dried to give 1-tert-butyl 4-benzyl (2R)-2-{2-[5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl]ethyl}piperazine-1,4-dicarboxylate (390 mg), as an amorphous solid, respectively.
MS (ESI+, m/e) 501 (M+1)
MS (ESI+, m/e) 501 (M+1)
In the same manner as in Reference Example 381, the following compound (Reference Example 382) was obtained.
MS (ESI+, m/e) 523 (M+1)
MS (ESI+, m/e) 523 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-(2-phenoxyethyl)piperazine-1,4-dicarboxylate (585 mg) was dissolved in dichloromethane (2 ml), TFA (4 ml) was added thereto, and the mixture was stirred at room temperature for 50 min. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate-saturated brine (1:1) by small portions. To the mixture was added potassium carbonate by small portions to basify the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (435 mg) as an oil.
MS (ESI+, m/e) 341 (M+1)
In the same manner as in Reference Example 383, the following compounds (Reference Examples 384-422) shown in Table 6-1-Table 6-5 were obtained.
1-tert-Butyl 4-benzyl (2R)-2-[2-(1H-indazol-1-yl)ethyl]piperazine-1,4-dicarboxylate (380 mg) was dissolved in chloroform (5 ml), TFA (5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with toluene (10 ml), and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (300 mg) as an oil.
MS (ESI+, m/e) 365 (M+1)
In the same manner as in Reference Example 423, the following compound (Reference Example 424) was obtained.
MS (ESI+, m/e) 365 (M+1)
A mixture of 1-tert-butyl 4-benzyl (2R)-2-[2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)ethyl]piperazine-1,4-dicarboxylate (415 mg) and 2N hydrogen chloride-ethyl acetate solution was stirred at room temperature for 4 hr, and concentrated under reduced pressure to give the object compound (325 mg).
MS (ESI+, m/e) 381 (M+1)
In the same manner as in Reference Example 425, the following compounds (Reference Examples 426-502) shown in Table 7-1-Table 7-8 were obtained.
tert-Butyl (2R)-4-benzyl-2-(3-hydroxypropyl)piperazine-1-carboxylate (8.0 g) was dissolved in methanol (100 ml), 20% palladium hydroxide-carbon (50% containing water, 4.0 g) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (70 ml), and the solution was ice-cooled. Benzyl chloroformate (4.1 g), sodium carbonate (2.8 g) and water (35 ml) were added, and the mixture was stirred at 0° C. for 15 min, and then at room temperature for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give the object compound (8.1 g) as an oil.
MS (ESI+, m/e) 379 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-(3-hydroxypropyl)piperazine-1,4-dicarboxylate (2.0 g) was dissolved in THF (10 ml), and the solution was ice-cooled. Triethylamine (1.1 ml) and methanesulfonyl chloride (510 μl) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (2.1 g) as an amorphous solid.
MS (ESI+, m/e) 457 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-(3-hydroxypropyl)piperazine-1,4-dicarboxylate (250 mg) was dissolved in chloroform (2 ml), TFA (2 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (200 mg) as an oil.
MS (ESI+, m/e) 279 (M+1)
In the same manner as in Reference Example 255, the following compound (Reference Example 506) was obtained.
MS (ESI+, m/e) 455 (M+1)
In the same manner as in Reference Example 380, the following compound (Reference Example 507) was obtained.
MS (ESI+, m/e) 479 (M+1)
MS (ESI+, m/e) 479 (M+1)
In the same manner as in Reference Example 383, the following compounds (Reference Examples 508-510) were obtained.
MS (ESI+, m/e) 355 (M+1)
MS (ESI+, m/e) 379 (M+1)
MS (ESI+, m/e) 379 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-(3-hydroxypropyl)piperazine-1,4-dicarboxylate (500 mg), ethyl 5-methyl-1H-pyrazole-3-carboxylate (550 mg) and tri-tert-butylphosphine (267 mg) were dissolved in toluene (20 ml), ADDP (420 mg) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and the solvent was evaporated under reduced pressure to give the object compound (140 mg) as an oil.
MS (ESI+, m/e) 415 (M+1)
(2R)-2-Benzyl-2-methylpiperazine (1.10 g) and triethylamine (1.61 ml) was dissolved in THF (50 ml), and the solution was ice-cooled. A solution of di-tert-butyl bicarbonate (1.61 ml) in THF (10 ml) was added over 30 min, and the mixture was stirred at 0° C. for 3 hr. The solvent was evaporated under reduced pressure, to the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (4:1) was concentrated under reduced pressure to give the object compound (1.06 g).
MS (ESI+, m/e) 291 (M+1)
1-[(1S,2S)-2-(Benzyloxy)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (376 mg) was suspended in DMF (10 ml), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (332 mg), WSC.HCl (288 mg) and HOBt (184 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (762 mg) as an amorphous solid.
MS (ESI+, m/e) 635 (M+1)
In the same manner as in Reference Example 513, the following compounds (Reference Examples 514-515) were obtained.
MS (ESI+, m/e) 635 (M+1)
MS (ESI+, m/e) 570 (M+1)
To a solution of 5-(3-fluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylic acid (304 mg) in DMF (8 ml) were added tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (332 mg), WSC.HCl (288 mg) and HOBt (184 mg), and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (19:1) was concentrated under reduced pressure to give the object compound (380 mg) as an amorphous solid.
MS (ESI+, m/e) 563 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (3.30 g), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (3.32 g), WSC.HCl (2.88 g) and HOBt (2.30 g) in DMF (100 ml) was stirred at 60° C. for 5 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (5.45 g) as an amorphous solid.
MS (ESI+, m/e) 589 (M+1)
1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (330 mg) was suspended in DMF (5 ml), 2-[(2R)-4-benzylpiperazin-2-yl]ethanol (264 mg), WSC.HCl (230 mg) and HOBt (168 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (355 mg) as an amorphous solid.
MS (ESI+, m/e) 533 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-[2-(2-fluorophenoxy)ethyl]piperazine-1,4-dicarboxylate (210 mg) was dissolved in ethyl acetate (1 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in toluene (1 ml). The suspension was concentrated again, and the residue was vacuum-dried. This was suspended in DMF (2 ml), 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (135 mg), WSC.HCl (118 mg), HOBt (94 mg) and triethylamine (83 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (205 mg) as an amorphous solid.
MS (ESI+, m/e) 671 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1,4-dicarboxylate (409 mg) was dissolved in methanol (2 ml), 4N hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was suspended in DMF (5 ml), 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (271 mg), WSC.HCl (236 mg), HOBt (151 mg) and triethylamine (229 μl) were added, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (486 mg) as an amorphous solid.
MS (ESI+, m/e) 711 (M+1)
In the same manner as in Reference Example 520, the following compounds (Reference Examples 521-525) were obtained.
MS (ESI+, m/e) 711 (M+1)
MS (ESI+, m/e) 711 (M+1)
MS (ESI+, m/e) 669 (M+1)
MS (ESI+, m/e) 779 (M+1)
MS (ESI+, m/e) 708 (M+1)
1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (110 mg) was suspended in DMF (5 ml), benzyl (3R)-3-[2-(1H-indazol-1-yl)ethyl]piperazine-1-carboxylate (121 mg), WSC.HCl (126 mg) and HOBt (202 mg) were added, and the mixture was stirred at 60° C. for 10 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (140 mg) as an amorphous solid.
MS (ESI+, m/e) 677 (M+1)
In the same manner as in Reference Example 526, the following compound (Reference Example 527) was obtained.
MS (ESI+, m/e) 677 (M+1)
A solution of 1-[(1S,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (144 mg), (3R)-1-benzyl-3-[(E)-2-cyclopropylvinyl]piperazine (125 mg), WSC.HCl (125 mg), HOBt (23 mg), N,N-diisopropylethylamine (181 μl) and DMAP (12 mg) in DMF (2 ml) was stirred at room temperature for 12 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-4:0:1) was concentrated under reduced pressure to give the object compound (110 mg) as an amorphous solid.
MS (ESI+, m/e) 511 (M+1)
Methyl 1-cyclohexyl-5-phenyl-1H-imidazole-4-carboxylate (240 mg) was dissolved in ethanol-THF (1:1, 10 ml), lithium hydroxide monohydrate (30 mg) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethanol, and the suspension was again concentrated under reduced pressure. This was suspended in DMF (15 ml), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (240 mg), WSC.HCl (178 mg) and HOBt (142 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (321 mg) as an amorphous solid.
MS (ESI+, m/e) 529 (M+1)
In the same manner as in Reference Example 529, the following compounds (Reference Examples 530-536) were obtained.
MS (ESI+, m/e) 531 (M+1)
MS (ESI+, m/e) 545 (M+1)
MS (ESI+, m/e) 485 (M+1)
MS (ESI+, m/e) 487 (M+1)
MS (ESI+, m/e) 636 (M+1)
MS (ESI+, m/e) 609 (M+1)
MS (ESI+, m/e) 559 (M+1)
A mixture of ethyl 1-(trans-2-hydroxycycloheptyl)-5-phenyl-1H-imidazole-4-carboxylate (860 mg), lithium hydroxide monohydrate (165 mg), ethanol (10 ml) and water (6 ml) was stirred at 65° C. for 3 hr, and concentrated under reduced pressure. The residue was mixed with tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (868 mg), WSC.HCl (1.00 g), HOBt (1.60 g) and DMF (15 ml), and the mixture was stirred at 50° C. for 12 hr, and poured into water. The obtained crystals were collected by filtration, and washed successively with water and ethyl acetate to give the object compound (421 mg). The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (754 mg). The yield of the obtained object compound was 1.17 g in total.
MS (ESI+, m/e) 559 (M+1)
Ethyl 1-{(1S,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (400 mg) was dissolved in methanol-water (2:1, 6 ml), lithium hydroxide monohydrate (63 mg) was added, and the mixture was stirred at 65° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethanol. The suspension was concentrated again, and the residue was vacuum-dried. This was suspended in DMF (8 ml), (3R)-1,3-dibenzylpiperazine (320 mg), WSC.HCl (383 mg) and HOBt (613 g) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give tert-butyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (550 mg) as an amorphous solid. 539 mg therefrom was dissolved in dichloromethane (2 ml), TFA (1 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate. The liberated oil was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (450 mg) as an amorphous solid.
MS (ESI+, m/e) 534 (M+1)
Ethyl 1-{(1S,2S)-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (424 mg) was dissolved in ethanol-water (2:1, 6 ml), lithium hydroxide monohydrate (69 mg) was added, and the mixture was stirred at 65° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethanol. The suspension was concentrated again, and the residue was vacuum-dried. This was suspended in DMF (5 ml), (3R)-1-benzyl-3-(3,5-difluorobenzyl)piperazine (333 mg), WSC.HCl (422 mg) and HOBt (674 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (530 mg) as an amorphous solid.
MS (ESI+, m/e) 642 (M+1)
Ethyl 1-(2-{[(ethoxycarbonyl)amino]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate (300 mg) was dissolved in ethanol-water (2:1, 6 ml), lithium hydroxide monohydrate (45 mg) was added, and the mixture was stirred at 65° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethanol. The suspension was concentrated again, and the residue was vacuum-dried. This was suspended in DMF (8 ml), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (240 mg), WSC.HCl (277 mg) and HOBt (442 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (300 mg) as an amorphous solid.
MS (ESI+, m/e) 600 (M+1)
Ethyl 1-{(1S,2S)-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (540 mg) was dissolved in ethanol-water (2:1, 9 ml), lithium hydroxide monohydrate (88 mg) was added, and the mixture was stirred at 65° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethanol. The suspension was concentrated again, and the residue was vacuum-dried. This was suspended in DMF (10 ml), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (464 mg), WSC.HCl (537 mg) and HOBt (858 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (385 mg) as an amorphous solid.
MS (ESI+, m/e) 616 (M+1)
Ethyl 1-[(3R,4S)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate (1.31 g) was dissolved in methanol-THF (1:4, 25 ml), lithium hydroxide monohydrate (505 mg) and water (10 ml) were added, and the mixture was stirred at 50° C. for 15 hr. The mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was suspended in DMF (10 ml), tert-butyl 3-benzylpiperazine-1-carboxylate (817 mg), WSC.HCl (1.13 g) and HOBt (1.36 g) were added, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (914 mg) as an amorphous solid.
MS (ESI+, m/e) 593 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-(benzyloxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (500 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (264 mg) as an amorphous solid.
MS (ESI+, m/e) 545 (M+1)
In the same manner as in Reference Example 543, the following compound (Reference Example 544) was obtained.
MS (ESI+, m/e) 545 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (272 mg) was dissolved in THF (10 ml), acetic acid (20 μl), WSC.HCl (144 mg) and DMAP (6 mg) were added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (19:1) was concentrated under reduced pressure to give the object compound (268 mg) as an amorphous solid.
MS (ESI+, m/e) 587 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (250 mg) and 4-nitrobenzoic acid were dissolved in THF (20 ml), DTBAD (424 mg) and PS-triphenylphosphine resin (manufactured by Argonaut Technologies, 2.15 mmol/g, 856 mg) were added, and the mixture was stirred at room temperature for 15 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (207 mg) as an amorphous solid.
MS (ESI+, m/e) 694 (M+1)
tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2R)-2-[(4-nitrobenzoyl)oxy]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (205 mg) was dissolved in methanol-THF (1:1, 10 ml), 8N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (19:1) was concentrated under reduced pressure to give the object compound (117 mg) as an amorphous solid.
MS (ESI+, m/e) 545 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (163 mg) was dissolved in THF (2 ml), sodium hydride (60% in oil, 60 mg) was added thereto, and the mixture was stirred at room temperature for 30 min. After stirring, 1-bromo-3-methoxypropane (115 mg) was added thereto. The reaction mixture was heated under reflux for 15 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (66 mg) as an amorphous solid.
MS (ESI+, m/e) 617 (M+1)
In the same manner as in Reference Example 548, the following compounds (Reference Examples 549-552) were obtained.
MS (ESI+, m/e) 585 (M+1)
MS (ESI+, m/e) 587 (M+1)
MS (ESI+, m/e) 603 (M+1)
MS (ESI+, m/e) 631 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (191 mg) was dissolved in DMF (2 ml), sodium hydride (60% in oil, 70 mg) was added, and the mixture was stirred at room temperature for 30 min. After stirring, 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine (245 mg) was added thereto. The mixture was stirred at 80° C. for 15 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give tert-butyl (3R)-4-({1-[(1S,2S)-2-(3-aminopropoxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (160 mg) as an amorphous solid. This was mixed with triethylamine (40 mg) and dichloromethane (2 ml), and the mixture was ice-cooled. Acetyl chloride (25 mg) was added thereto, and the mixture was stirred at 0° C. for 30 min. After stirring, the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (120 mg) as an amorphous solid.
MS (ESI+, m/e) 644 (M+1)
A mixture of tert-butyl (3R)-3-benzyl-4-{[1-(trans-2-hydroxycycloheptyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (280 mg), 4-nitrobenzoic acid (335 mg), PS-triphenylphosphine resin (manufactured by Argonaut Technologies, 1.99 mmol/g) (930 mg), DTBAD (460 mg) and THF (20 ml) was stirred at room temperature for 3 days, and the insoluble material was filtered off. The filtrate was diluted with ethyl acetate, and washed successively with 0.5N aqueous sodium hydroxide solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:0) was concentrated under reduced pressure to give the object compound (224 mg).
MS (ESI+, m/e) 708 (M+1)
A mixture of tert-butyl (3R)-3-benzyl-4-[(1-{cis-2-[(4-nitrobenzoyl)oxy]cycloheptyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (220 mg), 1N aqueous sodium hydroxide solution (1.5 ml) and ethanol (6 ml) was stirred at room temperature for 13 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (171 mg).
MS (ESI+, m/e) 559 (M+1)
A mixture of tert-butyl (3R)-3-benzyl-4-({1-[trans-2-hydroxycycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (105 mg), sodium hydride (60% in oil, 15 mg) and THF (5 ml) was stirred at room temperature for 1 hr, and ice-cooled. To the reaction mixture was added 1-bromo-3-methoxypropane (45 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hr, and then at 65° C. for 12 hr. The mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:0) was concentrated under reduced pressure to give the object compound (40 mg).
MS (ESI+, m/e) 631 (M+1)
In the same manner as in Reference Example 556, the following compound (Reference Example 557) was obtained.
MS (ESI+, m/e) 617 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (163 mg) and DMAP (220 mg) were dissolved in THF (5 ml), and the solution was ice-cooled. 4-Nitrophenyl chloroformate (182 mg) was added, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added ethylamine (1M THF solution, 2 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (190 mg) as an amorphous solid.
MS (ESI+, m/e) 616 (M+1)
In the same manner as in Reference Example 558, the following compounds (Reference Examples 559-560) were obtained.
MS (ESI+, m/e) 630 (M+1)
MS (ESI+, m/e) 708 (M+1)
A mixture of tert-butyl (3R)-3-benzyl-4-({1-[trans-2-hydroxycycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (137 mg), 4-nitrophenyl chloroformate (75 mg), DMAP (100 mg) and THF (3 ml) was stirred at room temperature for 1 hr, and furfurylamine (110 mg) was added thereto. The reaction mixture was further stirred at room temperature for 3 days, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with aqueous citric acid solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (2:3-1:0) was concentrated under reduced pressure to give the object compound (115 mg).
MS (ESI+, m/e) 682 (M+1)
tert-Butyl (3R)-4-({1-[(1S,2R)-2-azidocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (2.5 g) was dissolved in methanol (25 ml), 10% palladium-carbon (50% containing water, 800 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (2.26 g) as an amorphous solid.
MS (ESI+, m/e) 544 (M+1)
tert-Butyl (3R)-4-({1-[(1S,2R)-2-aminocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (217 mg) and cyclopropanecarbaldehyde (28 mg) were dissolved in dichloroethane (2 ml), and acetic acid (24 mg) and sodium triacetoxyborohydride (110 mg) were added. The mixture was stirred at room temperature for 5 hr, and neutralized with 6% aqueous sodium bicarbonate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (150 mg) as an amorphous solid.
MS (ESI+, m/e) 598 (M+1)
In the same manner as in Reference Example 563, the following compound (Reference Example 564) was obtained.
MS (ESI+, m/e) 652 (M+1)
tert-Butyl (3R)-4-({1-[(1S,2R)-2-aminocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (217 mg) and triethylamine (60 mg) were dissolved in dichloromethane (3 ml), the solution was ice-cooled, and cyclopropanecarbonyl chloride (52 mg) was added. The mixture was stirred at 0° C. for 30 min, and neutralized with 6% aqueous sodium bicarbonate (2 ml). The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (203 mg) as an amorphous solid.
MS (ESI+, m/e) 612 (M+1)
In the same manner as in Reference Example 565, the following compounds (Reference Examples 566-567) were obtained.
MS (ESI+, m/e) 648 (M+1)
MS (ESI+, m/e) 614 (M+1)
To a solution of tert-butyl (3R)-4-({1-[(1S,2R)-2-aminocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (217 mg) in dichloromethane (3 ml) were added ethyl isocyanate (36 mg) and triethylamine (1 drop) at room temperature. The mixture was stirred at room temperature for 2 hr, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (175 mg) as an amorphous solid.
MS (ESI+, m/e) 615 (M+1)
(1S,2S)-2-(4-{[(2R)-2,4-Dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine (160 mg) and triethylamine (36 mg) were dissolved in dichloromethane (2 ml), and the solution was ice-cooled. Methyl chloroformate (28 mg) was added thereto, and the mixture was stirred at 0° C. for 2 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (100 mg) as an amorphous solid.
MS (ESI+, m/e) 592 (M+1)
(1S,2S)-2-(4-{[(2R)-2,4-Dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine (300 mg) and triethylamine (85 mg) were dissolved in dichloromethane (5 ml), and the solution was ice-cooled. Ethyl chloroformate (73 mg) was added thereto, and the mixture was stirred at 0° C. for 2 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (260 mg) as an amorphous solid.
MS (ESI+, m/e) 606 (M+1)
In the same manner as in Reference Example 570, the following compounds (Reference Examples 571-574) were obtained.
MS (ESI+, m/e) 620 (M+1)
MS (ESI+, m/e) 634 (M+1)
MS (ESI+, m/e) 636 (M+1)
MS (ESI+, m/e) 641 (M+1)
2-Chloroethyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (192 mg) was dissolved in THF (3 ml), sodium hydride (60% in oil, 14 mg) was added thereto, and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (120 mg) as an amorphous solid.
MS (ESI+, m/e) 604 (M+1)
tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2S)-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (185 mg) was dissolved in DMF (2 ml), sodium hydride (60% in oil, 24 mg) was added thereto, and the mixture was stirred at room temperature for 30 min. After stirring, methyl iodide (85 mg) was added thereto, and the mixture was further stirred at room temperature for 15 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (145 mg) as an amorphous solid.
MS (ESI+, m/e) 630 (M+1)
In the same manner as in Reference Example 576, the following compound (Reference Example 577) was obtained.
MS (ESI+, m/e) 688 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (4.2 g) was dissolved in dichloromethane (60 ml). A solution of Dess-Martin reagent (3.9 g) in dichloromethane (60 ml) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with chloroform. The extract was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate-THF. 10% Aqueous sodium thiosulfate solution was added thereto, and the mixture was stirred at room temperature for 30 min. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate, and the precipitated crystals were collected by filtration to give the object compound (2.35 g). The second crystals (1.37 g) of the object compound were obtained from the mother liquor. The yield of the obtained object compound was 3.72 g in total.
MS (ESI+, m/e) 543 (M+1)
In the same manner as in Reference Example 578, the following compounds (Reference Examples 579-580) were obtained.
MS (ESI+, m/e) 543 (M+1)
MS (ESI+, m/e) 543 (M+1)
tert-Butyl (3R)-3-benzyl-4-{[1-(2-oxocyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (150 mg) was dissolved in THF (5 ml), and the solution was cooled to −78° C. n-Butylmagnesium chloride (2M THF solution, 560 μl) was added thereto, and the mixture was stirred at −78° C. for 1.5 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (36 mg) as an amorphous solid.
MS (ESI+, m/e) 601 (M+1)
tert-Butyl (3R)-3-benzyl-4-{[1-(2-oxocyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (163 mg) was dissolved in THF (2 ml), and the solution was ice-cooled. Methylmagnesium bromide (3M diethyl ether solution, 300 μl) was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (110 mg) as an amorphous solid.
MS (ESI+, m/e) 559 (M+1)
tert-Butyl (3R)-3-benzyl-4-{[1-(2-oxocyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (150 mg) and trimethyl(trifluoromethyl)silane (79 mg) were dissolved in THF (2 ml), TBAF (several mg) was added, and the mixture was stirred at room temperature for 15 hr, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (38 mg) as an amorphous solid.
MS (ESI+, m/e) 613 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-oxocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (150 mg) was dissolved in THF (5 ml), bromo(2-ethoxy-2-oxoethyl)zinc (0.5M THF solution, 4 ml) was added thereto at room temperature, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (140 mg) as an amorphous solid.
MS (ESI+, m/e) 631 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-(2-ethoxy-2-oxoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (300 mg) was dissolved in ethanol (2 ml), and 1N aqueous sodium hydroxide solution (4 ml) was added. The mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residual aqueous solution was washed with ethyl acetate, and neutralized with 10% aqueous citric acid solution. This was extracted with ethyl acetate, the extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (280 mg).
MS (ESI+, m/e) 603 (M+1)
A solution of [(2S)-2-(4-{[(2R)-2-benzyl-4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]acetic acid (100 mg), methylamine (2M THF solution, 91 μl), WSC.HCl (41 mg) and HOBt (30 mg) in DMF (2 ml) was stirred at room temperature for 12 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (70 mg) as an amorphous solid.
MS (ESI+, m/e) 616 (M+1)
In the same manner as in Reference Example 586, the following compounds (Reference Examples 587-588) were obtained.
MS (ESI+, m/e) 630 (M+1)
MS (ESI+, m/e) 682 (M+1)
Sodium borohydride (862 mg) was suspended in ethanol (9 ml), and the suspension was ice-cooled. Calcium chloride (1.23 g) was added over 10 min, and the mixture was stirred at 0° C. for 30 min. A solution of tert-butyl (3R)-3-benzyl-4-({1-[(1S)-2-(2-ethoxy-2-oxoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (900 mg) in THF (9 ml) was added thereto over 20 min, and the mixture was stirred at 0° C. for 2 hr, and then at room temperature for 2 hr. Water (20 ml) was slowly added. This was extracted with ethyl acetate, the extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (830 mg) as an amorphous solid.
MS (ESI+, m/e) 589 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-hydroxy-2-(2-hydroxyethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (530 mg) was dissolved in dichloromethane (7 ml). A solution of Dess-Martin reagent (460 mg) in dichloromethane (5 ml) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform (30 ml), 10% aqueous sodium thiosulfate solution was added, and the mixture was stirred for 30 min. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (517 mg).
MS (ESI+, m/e) 586 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-hydroxy-2-(2-oxoethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (300 mg) was dissolved in DMF-dichloromethane (1:2, 3 ml), benzylamine (134 μl) and acetic acid (2 drops) were added, and the mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (163 mg) was added thereto, and the mixture was further stirred at room temperature for 12 hr. To the reaction mixture was added ethyl acetate (3 ml) over 15 min, and the mixture was poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform-methanol (9:1) was concentrated under reduced pressure to give the object compound (85 mg) as an amorphous solid.
MS (ESI+, m/e) 678 (M+1)
tert-Butyl (3R)-3-benzyl-4-[(1-{(1S)-2-[2-(benzylamino)ethyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (100 mg) was dissolved in methanol (3 ml), 20% palladium hydroxide-carbon (50% containing water, 30 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give the object compound (25 mg) as an amorphous solid.
MS (ESI+, m/e) 588 (M+1)
tert-Butyl (3R)-4-({1-[(1S)-2-(2-aminoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (150 mg) and triethylamine (13 mg) were dissolved in dichloromethane (3.5 ml), acetyl chloride (8 mg) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give the object compound (41 mg) as an amorphous solid.
MS (ESI+, m/e) 630 (M+1)
A mixture of tert-butyl (3R)-3-benzyl-4-({1-[(1S)-2-hydroxy-2-(2-hydroxyethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (100 mg), silver oxide (44 mg), methyl iodide (0.150 ml) and dichloromethane (2 ml) was heated under reflux for 12 hr. The reaction mixture was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (60 mg) as an amorphous solid.
MS (ESI+, m/e) 617 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-hydroxy-2-(2-hydroxyethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (110 mg) was dissolved in DMF (2 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 18 mg) was added thereto, and the mixture was stirred at 0° C. for 30 min. Methyl iodide (14 μl) was added thereto, and the mixture was further stirred at 0° C. for 1 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (70 mg) as an amorphous solid.
MS (ESI+, m/e) 603 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-oxocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (500 mg) and ethyl (diethoxyphosphoryl)acetate (227 mg) were dissolved in THF (5 ml), and the solution was ice-cooled. Sodium hydride (60% in oil) (55 mg) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (440 mg) as an amorphous solid.
MS (ESI+, m/e) 613 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2E)-2-(2-ethoxy-2-oxoethylidene)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (230 mg) was dissolved in ethanol (2 ml), 2N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at room temperature for 1 hr, and neutralized with 10% aqueous citric acid solution. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate-THF. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (220 mg).
MS (ESI+, m/e) 585 (M+1)
A solution of (2E)-[(2S)-2-(4-{[(2R)-2-benzyl-4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexylidene]acetic acid (120 mg), propylamine (25 μl), WSC.HCl (59 mg) and HOBt (38 mg) in DMF (2 ml) was stirred at room temperature for 12 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (180 mg) as an oil.
MS (ESI+, m/e) 626 (M+1)
Trimethylsulfoxonium iodide (106 mg) was dissolved in DMSO (5 ml), sodium hydride (60% in oil, 19 mg) was added thereto, and the mixture was stirred at room temperature for 30 min. A solution of tert-butyl (3R)-3-benzyl-4-{[1-(2-oxocyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (400 mg) in DMSO (10 ml) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (221 mg) as an amorphous solid.
MS (ESI+, m/e) 557 (M+1)
Sodium hydride (60% in oil) (60 mg) was suspended in DMF (3 ml), 1-propanol (135 μl) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (167 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (160 mg) as an amorphous solid.
MS (ESI+, m/e) 617 (M+1)
In the same manner as in Reference Example 600, the following compounds (Reference Examples 601-619) shown in Table 8-1-Table 8-3 were obtained.
tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (240 mg) and ethylamine (2M THF solution, 650 μl) were dissolved in acetonitrile (3 ml), lithium perchlorate (92 mg) was added, and the mixture was reacted at 100° C. for 5 min using microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (220 mg) as an amorphous solid.
MS (ESI+, m/e) 602 (M+1)
In the same manner as in Reference Example 620, the following compounds (Reference Examples 621-622) were obtained.
MS (ESI+, m/e) 616 (M+1)
MS (ESI+, m/e) 654 (M+1)
tert-Butyl (3R)-3-benzyl-4-[(1-{2-[(ethylamino)methyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (120 mg) was dissolved in pyridine (2 ml), and the solution was ice-cooled. Acetic anhydride (19 μl) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (105 mg) as an amorphous solid.
MS (ESI+, m/e) 644 (M+1)
Copper iodide (160 mg) was suspended in THF (5 ml), and the suspension was ice-cooled. Methylmagnesium bromide (1M THF solution, 1.6 ml) was added, and the mixture was stirred at 0° C. for 30 min. A solution of tert-butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (111 mg) in THF (5 ml) was added thereto, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (73 mg) as an amorphous solid.
MS (ESI+, m/e) 573 (M+1)
In the same manner as in Reference Example 624, the following compound (Reference Example 625) was obtained.
MS (ESI+, m/e) 587 (M+1)
Copper iodide (144 mg) was suspended in THF (5 ml), and the suspension was ice-cooled. Cyclopropylmagnesium bromide (0.5M THF solution, 2.9 ml) was added, and the mixture was stirred at 0° C. for 30 min. A solution of tert-butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (200 mg) in THF (5 ml) was added thereto, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate-methanol (4:1) were concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[(1R,2R)-2-(cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (49 mg) as an amorphous solid, and tert-butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-(cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (214 mg) as an amorphous solid.
MS (ESI+, m/e) 599 (M+1)
MS (ESI+, m/e) 599 (M+1)
In the same manner as in Reference Example 626, the following compound (Reference Example 627) was obtained.
MS (ESI+, m/e) 601 (M+1)
MS (ESI+, m/e) 601 (M+1)
Sodium hydride (60% in oil) (100 mg) was suspended in DMF (3 ml), 2-(methylthio)ethanol (280 mg) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (280 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-{[1-(2-hydroxy-2-{[2-(methylthio)ethoxy]methyl}cyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (270 mg) as an amorphous solid. 145 mg therefrom was dissolved in dichloromethane (3 ml), and the solution was ice-cooled. mCPBA (119 mg) was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (7:3) was concentrated under reduced pressure to give the object compound (119 mg) as an amorphous solid.
MS (ESI+, m/e) 681 (M+1)
In the same manner as in Reference Example 628, the following compounds (Reference Examples 629-631) were obtained.
MS (ESI+, m/e) 695 (M+1)
MS (ESI+, m/e) 707 (M+1)
MS (ESI+, m/e) 721 (M+1)
Sodium hydride (60% in oil) (24 mg) was suspended in DMF (3 ml), 1,3-thiazol-2-ylmethanol (81 mg) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2R)-2-(chloromethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (119 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (96 mg) as an amorphous solid.
MS (ESI+, m/e) 672 (M+1)
In the same manner as in Reference Example 632, the following compounds (Reference Examples 633-637) were obtained.
MS (ESI+, m/e) 663 (M+1)
MS (ESI+, m/e) 660 (M+1)
MS (ESI+, m/e) 666 (M+1)
MS (ESI+, m/e) 705 (M+1)
MS (ESI+, m/e) 691 (M+1)
Lithium bis(trimethylsilyl)amide (1.1M THF solution, 3.6 ml) was dissolved in THF (5 ml), and the solution was cooled to −10° C. A solution of acetonitrile (221 μl) in THF (3 ml) was added over 3 min, and the mixture was stirred at −10° C. for 30 min. A solution of tert-butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (557 mg) in THF (5 ml) was added thereto, and the mixture was stirred at −10° C. for 1 hr, and then at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (370 mg) as an oil.
MS (ESI+, m/e) 598 (M+1)
tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (334 mg) was dissolved in DMF (5 ml), sodium ethanethiolate (80%) (315 mg) was added, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (324 mg) as an amorphous solid.
MS (ESI+, m/e) 619 (M+1)
tert-Butyl (3R)-3-benzyl-4-[(1-{2-[(ethylthio)methyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (105 mg) was dissolved in dichloromethane (5 ml), and the solution was ice-cooled, m-chloroperbenzoic acid (95 mg) was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (7:3) was concentrated under reduced pressure to give the object compound (52 mg) as an amorphous solid.
MS (ESI+, m/e) 651 (M+1)
Sodium hydride (60% in oil) (40 mg) was suspended in DMF (3 ml), (3-methyloxetan-3-yl)methanol (120 mg) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (110 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (100 mg) as an amorphous solid.
MS (ESI+, m/e) 659 (M+1)
tert-Butyl (3R)-3-benzyl-4-({5-(3-fluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (825 mg) was dissolved in 1,2-dichloroethane (30 ml), Dess-Martin reagent (929 mg) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with chloroform. The extract was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate-THF. 10% Aqueous sodium thiosulfate solution was added thereto, and the mixture was stirred for 30 min. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate, and the precipitated crystals were collected by filtration to give tert-butyl (3R)-3-benzyl-4-{[5-(3-fluorophenyl)-1-(2-oxocyclohexyl)-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (650 mg).
Trimethylsulfoxonium iodide (376 mg) was dissolved in DMSO (10 ml), sodium hydride (60% in oil, 55 mg) was added thereto, and the mixture was stirred at room temperature for 30 min. A solution of the oxo form obtained in the above in DMSO (20 ml) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (401 mg) as an amorphous solid.
MS (ESI+, m/e) 575 (M+1)
tert-Butyl (3R)-3-benzyl-4-{[5-(3-fluorophenyl)-1-(cis-1-oxaspiro[2.5]oct-4-yl)-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (390 mg) was dissolved in methanol (5 ml), sodium methoxide (28% methanol solution, 650 μl) was added, and the mixture was stirred at 50° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (337 mg) as an amorphous solid.
MS (ESI+, m/e) 607 (M+1)
(1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (3.39 g) was dissolved in methanol (200 ml), 20% palladium hydroxide-carbon (50% containing water, 500 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (50 ml), and the solution was ice-cooled. Di-tert-butyl bicarbonate (1.66 g) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (3.52 g) as an amorphous solid.
MS (ESI+, m/e) 543 (M+1)
tert-Butyl (3R)-3-(2-hydroxyethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (108 mg) and DMAP (73 mg) were dissolved in THF (5 ml), 4-nitrophenyl chloroformate (60 mg) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added pyrrolidine (142 mg), and the mixture was further stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (90 mg) as an amorphous solid.
MS (ESI+, m/e) 640 (M+1)
tert-Butyl (3R)-3-(2-hydroxyethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (560 mg) was dissolved in 1,2-dichloroethane (10 ml), Dess-Martin reagent (657 mg) was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with chloroform. The extract was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate-THF. 10% Aqueous sodium thiosulfate solution was added thereto, and the mixture was stirred at room temperature for 30 min. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (17:3) was concentrated under reduced pressure to give the object compound (411 mg) as an amorphous solid.
MS (ESI+, m/e) 541 (M+1-“Boc”).
2-Bromo-6-(trifluoromethyl)pyridine (375 mg) was dissolved in diethyl ether (10 ml), and the solution was cooled to −78° C. Butyllithium (1.6M hexane solution, 0.95 ml) was added, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added a solution of tert-butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-oxoethyl)piperazine-1-carboxylate (250 mg) in diethyl ether (10 ml) at −78° C., and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fractions eluted with ethyl acetate-methanol (19:1) were concentrated under reduced pressure to give tert-butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{(2R)-2-hydroxy-2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}piperazine-1-carboxylate (65 mg) as an amorphous solid, and tert-butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{(2S)-2-hydroxy-2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}piperazine-1-carboxylate (73 mg) as an amorphous solid.
MS (ESI+, m/e) 688 (M+1)
MS (ESI+, m/e) 688 (M+1)
tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-oxoethyl)piperazine-1-carboxylate (150 mg) was dissolved in THF (10 ml), and the solution was ice-cooled. Phenylmagnesium bromide (1.08M THF solution, 0.85 ml) was added, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fractions eluted with ethyl acetate-methanol (19:1) were concentrated under reduced pressure to give tert-butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(2R)-2-hydroxy-2-phenylethyl]piperazine-1-carboxylate (45 mg) as an amorphous solid, and tert-butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(2S)-2-hydroxy-2-phenylethyl]piperazine-1-carboxylate (73 mg) as an amorphous solid.
MS (ESI+, m/e) 619 (M+1)
MS (ESI+, m/e) 619 (M+1)
(1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (242 mg), phenol (64 mg) and triphenylphosphine (239 mg) were dissolved in THF (15 ml), DEAD (40% toluene solution, 396 μl) was added, and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (20 ml). The mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the object fraction was concentrated under reduced pressure to give the object compound (32 mg) as an amorphous solid.
MS (ESI+, m/e) 609 (M+1)
tert-Butyl (3R)-3-(2-hydroxyethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (109 mg) was dissolved in DMF (3 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 18 mg) was added thereto, and the mixture was stirred at 0° C. for 10 min. After stirring, 2-bromopyridine (29 μl) was added thereto at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (19:1) was concentrated under reduced pressure to give the object compound (16 mg) as an oil.
MS (ESI+, m/e) 620 (M+1)
In the same manner as in Reference Example 650, the following compounds (Reference Examples 651-656) were obtained.
MS (ESI+, m/e) 688 (M+1)
MS (ESI+, m/e) 621 (M+1)
MS (ESI+, m/e) 688 (M+1)
MS (ESI+, m/e) 688 (M+1)
MS (ESI+, m/e) 645 (M+1)
MS (ESI+, m/e) 688 (M+1)
Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1-carboxylate (940 mg) was dissolved in methanol (50 ml), 1N aqueous sodium hydroxide solution (26.4 ml) was added, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the solvent was concentrated under reduced pressure. The residue was diluted with ethyl acetate-THF (3:1), and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (896 mg).
MS (ESI+, m/e) 697 (M+1)
4-{2-[(2R)-4-[(Benzyloxy)carbonyl]-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzoic acid (139 mg) was suspended in DMF (3 ml), cyclopropylamine (23 mg), WSC.HCl (58 mg) and HOBt (37 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (98 mg) as an amorphous solid.
MS (ESI+, m/e) 736 (M+1)
In the same manner as in Reference Example 658, the following compounds (Reference Examples 659-661) were obtained.
MS (ESI+, m/e) 724 (M+1)
MS (ESI+, m/e) 736 (M+1)
MS (ESI+, m/e) 778 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate (2.0 g) and triethylamine (2.3 ml) were dissolved in DMSO (20 ml), a solution of pyridine-sulfur trioxide complex (2.6 g) in DMSO (10 ml) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (9:1) was concentrated under reduced pressure to give the object compound (1.9 g) as an oil.
1H-NMR (CDCl3) δ 1.45 (9H, s), 2.48-2.74 (2H, m), 2.82-3.18 (3H, m), 3.77-4.20 (3H, m), 4.54-4.84 (1H, m), 5.02-5.25 (2H, m), 7.21-7.51 (5H, m), 9.53-9.84 (1H, m)
1-tert-Butyl 4-benzyl (2R)-2-(2-oxoethyl)piperazine-1,4-dicarboxylate (1.5 g) and aniline (1.1 g) were dissolved in dichloromethane-DMF (2:1, 30 ml), acetic acid (0.5 ml) was added, and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (2.6 g) was added thereto, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (1.8 g) as an oil.
MS (ESI+, m/e) 440 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-(2-oxoethyl)piperazine-1,4-dicarboxylate (400 mg) and N-methylaniline (237 mg) were dissolved in dichloromethane-DMF (2:1, 8 ml), acetic acid (0.29 ml) was added, and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (466 mg) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced pressure to give the object compound (370 mg) as an oil.
MS (ESI+, m/e) 454 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-(2-anilinoethyl)piperazine-1,4-dicarboxylate (380 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate solution (5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (670 mg) as an oil.
MS (ESI+, m/e) 340 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-{2-[methyl(phenyl)amino]ethyl}piperazine-1,4-dicarboxylate (380 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate solution (5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (260 mg) as an oil.
MS (ESI+, m/e) 354 (M+1)
Copper iodide (4.57 g) was suspended in THF (100 ml), and the suspension was ice-cooled. Methylmagnesium bromide (1M THF solution, 45 ml) was added, and the mixture was stirred at 0° C. for 30 min. A solution of ethyl 1-[(3S,4R)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate (4.90 g) in THF (50 ml) was added thereto, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (4.61 g) as an amorphous solid.
1H-NMR (CDCl3) δ 0.61 (3H, t), 0.90-1.32 (7H, m), 1.44-1.95 (7H, m), 2.12-2.33 (1H, m), 3.62 (1H, dd), 4.16-4.28 (1H, m), 7.19-7.37 (2H, m), 7.38-7.54 (3H, m), 8.04 (1H, s)
MS (ESI+, m/e) 389 (M+1)
In the same manner as in Reference Example 667, the following compound (Reference Example 668) was obtained.
1H-NMR (CDCl3) δ −0.18-0.06 (2H, m), 0.25-0.50 (2H, m), 0.63-0.80 (1H, m), 1.07-1.33 (5H, m), 1.45-2.00 (8H, m), 2.24 (1H, dd), 3.45-3.71 (1H, m), 4.08-4.31 (2H, m), 7.12-7.36 (3H, m), 7.36-7.55 (2H, m), 8.03 (1H, s)
MS (ESI+, m/e) 369 (M+1)
Ethyl 1-[(3S,4R)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate (1.0 g) was dissolved in ethanol (30 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (972 mg) as an amorphous solid.
1H-NMR (CDCl3) δ 0.84 (3H, s), 1.22 (5H, t), 1.42-1.93 (6H, m), 2.19 (1H, dd), 3.56 (1H, dd), 4.12-4.29 (2H, m), 7.17-7.40 (2H, m), 7.41-7.53 (3H, m), 8.04 (1H, s)
MS (ESI+, m/e) 329 (M+1)
Ethyl 1-[(1R,2S)-2-ethyl-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (3.85 g) was dissolved in ethanol (30 ml), 4N aqueous sodium hydroxide solution (14 ml) was added thereto, and the mixture was stirred at 60° C. for 15 hr. After cooling to room temperature, the mixture was neutralized (pH 7) with diluted hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was suspended in THF (100 ml), and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object compound (4.30 g) as a powder mixed with an inorganic salt thereof.
1H-NMR (DMSO-d6) δ 0.52 (3H, t), 0.60-1.22 (6H, m), 1.23-1.47 (1H, m), 1.50-1.90 (4H, m), 1.95-2.32 (1H, m), 7.35 (6H, m)
MS (ESI+, m/e) 315 (M+1)
In the same manner as in Reference Example 670, the following compounds (Reference Examples 671-672) were obtained.
1H-NMR (CDCl3) δ −0.16 (2H, br s), 0.08-0.39 (3H, m), 0.66-1.05 (2H, m), 1.05-1.34 (2H, m), 1.43 (1H, s), 1.53-1.97 (4H, m), 2.03-2.30 (1H, m), 3.48-3.67 (1H, m), 3.68-3.84 (1H, m), 7.10-7.44 (5H, m), 7.95 (1H, s)
MS (ESI+, m/e) 341 (M+1)
1H-NMR (DMSO-d6) δ 0.66 (3H, s), 0.97-1.23 (2H, m), 1.28-1.43 (1H, m), 1.49-1.88 (4H, m), 2.16 (1H, tq), 3.39-3.56 (1H, m), 3.55-3.68 (1H, m), 7.30-7.44 (2H, m), 7.46-7.58 (3H, m), 8.34-8.52 (1H, m)
MS (ESI+, m/e) 301 (M+1)
Ethyl 1-[(3S,4R)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate (1.96 g) was dissolved in ethanol (30 ml), sodium ethoxide (20% ethanol solution, 11.8 ml) was added thereto at room temperature, and the mixture was stirred at 60° C. for 3 hr. 1N Aqueous sodium hydroxide solution (6 ml) was added thereto, and the mixture was further stirred at 60° C. for 3 hr. After cooling to room temperature, the mixture was neutralized (pH 7) with diluted hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was suspended in ethanol (100 ml), and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object compound (2.28 g) as a powder mixed with an inorganic salt thereof.
1H-NMR (CDCl3) δ 1.00 (3H, t), 1.12-1.29 (2H, m), 1.41-1.54 (1H, m), 1.59-1.71 (1H, m), 1.71-1.83 (3H, m), 2.11-2.27 (1H, m), 2.80 (2H, s), 3.26 (2H, q), 3.66-3.82 (1H, m), 4.29 (1H, br s), 7.23-7.36 (2H, m), 7.38-7.46 (3H, m), 8.12 (1H, s)
MS (ESI+, m/e) 345 (M+1)
In the same manner as in Reference Example 86, the following compounds (Reference Examples 674-676) were obtained.
1H-NMR (CDCl3) δ 1.19-1.72 (12H, m), 2.50-3.31 (2H, m), 3.64-3.90 (3H, m), 4.00-4.27 (3H, m), 4.48-5.46 (3H, m), 6.75-6.92 (2H, m), 7.01-7.42 (7H, m)
MS (ESI+, m/e) 417 (M+1-“Boc”)
MS (ESI+, m/e) 519 (M+1)
In the same manner as in Reference Example 109, the following compounds (Reference Examples 677-679) were obtained.
1H-NMR (DMSO-d6) δ 2.90-3.00 (1H, m), 3.04-3.19 (2H, m), 3.47 (1H, d), 3.74 (3H, s), 4.08-4.15 (1H, m), 4.43 (2H, s), 6.64-6.76 (4H, m), 6.96 (2H, dd), 8.09 (1H, br s)
1H-NMR (CDCl3) δ 3.06 (1H, d), 3.21 (2H, d), 3.54 (1H, d), 4.35-4.40 (1H, m), 4.43 (1H, d), 4.55 (1H, d), 6.49 (1H, s), 7.16-7.53 (14H, m)
MS (ESI+, m/e) 371 (M+1)
MS (ESI+, m/e) 373 (M+1)
In the same manner as in Reference Example 133, the following compounds (Reference Examples 680-681) were obtained.
1H-NMR (CDCl3) δ 2.51-3.10 (9H, m), 3.40-3.61 (2H, m), 3.66-3.74 (1H, m), 3.80 (3H, s), 6.80-6.93 (4H, m), 7.09-7.36 (5H, m)
MS (ESI+, m/e) 297 (M+1)
1H-NMR (CDCl3) δ 1.64 (1H, br s), 1.92 (1H, t), 2.10 (1H, dt), 2.57 (1H, dd), 2.72-2.94 (5H, m), 2.98-3.07 (1H, m), 3.48 (1H, d), 3.55 (1H, d), 7.21-7.58 (14H, m)
MS (ESI+, m/e) 343 (M+1)
In the same manner as in Reference Example 147, the following compound (Reference Example 682) was obtained.
MS (ESI+, m/e) 345 (M+1)
tert-Butyl [(1R)-1-benzyl-2-oxopropyl]carbamate (3.42 g) was dissolved in 1,2-dichloroethane (50 ml), benzylamine (1.39 g) and acetic acid (780 mg) were added, and the mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (3.6 g) was added thereto, and the mixture was further stirred at room temperature for 15 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (4.40 g) as an oil.
MS (ESI+, m/e) 355 (M+1)
A mixture of tert-butyl [(1R)-1-benzyl-2-(benzylamino)propyl]carbamate (1.06 g), potassium carbonate (498 mg), ethyl bromoacetate (501 mg) and ethanol (10 ml) was stirred at 50° C. for 5 hr, and the solvent was evaporated under reduced pressure. The residue was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (430 mg) as an oil.
MS (ESI+, m/e) 441 (M+1)
Ethyl N-benzyl-N-{(2R)-2-[(tert-butoxycarbonyl)amino]-1-methyl-3-phenylpropyl}glycinate (419 mg) was dissolved in dichloromethane (1 ml), TFA (2 ml) was added thereto, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (5 ml). Triethylamine (1 ml) was added thereto at room temperature, and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (270 mg) as an oil.
MS (ESI+, m/e) 295 (M+1)
A mixture of (6R)-4,6-dibenzyl-5-methylpiperazin-2-one (265 mg) and THF (6 ml) was ice-cooled, and lithium aluminum hydride (68 mg) was added by small portions. The mixture was stirred at room temperature for 30 min, and then at 60° C. for 3 hr. The mixture was cooled to −78° C., and ethanol-ethyl acetate (1:1, 2 ml) and 1N aqueous sodium hydroxide solution (2 ml) were successively added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 40 min. The insoluble material was filtered, and washed with ethyl acetate. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (240 mg) as an oil.
MS (ESI+, m/e) 281 (M+1)
In the same manner as in Reference Example 157, the following compound (Reference Example 687) was obtained.
MS (ESI+, m/e) 445 (M+1)
In the same manner as in Reference Example 158, the following compound (Reference Example 688) was obtained.
MS (ESI+, m/e) 452 (M+1)
tert-Butyl (2R)-4-benzyl-2-(2-bromobenzyl)piperazine-1-carboxylate (445 mg), (2-methoxypyridin-3-yl)boronic acid (184 mg), tetrakis(triphenylphosphine)palladium(0) (58 mg) and sodium carbonate (254 mg) were suspended in 1,2-dimethoxyethane-water (2:1, 9 ml), and the suspension was stirred at 100° C. for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give the object compound (145 mg) as an oil.
MS (ESI+, m/e) 473 (M+1)
A mixture of tert-butyl (2R)-4-benzyl-2-(2-bromobenzyl)piperazine-1-carboxylate (445 mg), 2-chloro-6-(tributylstannyl)pyridine (426 mg), tetrakis(triphenylphosphine)palladium(0) (58 mg) and toluene (5 ml) was stirred at 100° C. for 15 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give the object compound (140 mg) as an oil.
MS (ESI+, m/e) 478 (M+1)
tert-Butyl (2R)-4-benzyl-2-(2-bromobenzyl)piperazine-1-carboxylate (890 mg), bis(pinacolato)diboron (584 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (65 mg) and potassium acetate (590 mg) were dissolved in DMF (10 ml), and the solution was stirred at 120° C. for 20 hr. Ethyl acetate-water (2:1) was added to the reaction mixture, and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (500 mg) as an oil.
MS (ESI+, m/e) 4.93 (M+1)
tert-Butyl (2R)-4-benzyl-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazine-1-carboxylate (420 mg) was dissolved in acetone (4 ml), and a solution of potassium peroxymonosulfate (524 mg) in water (4 ml) was added at room temperature. The mixture was stirred at room temperature for 10 min, saturated aqueous sodium thiosulfate solution (4 ml) was added, and the liberated oil was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give the object compound (300 mg) as an oil.
MS (ESI+, m/e) 383 (M+1)
tert-Butyl (2R)-4-benzyl-2-(2-hydroxybenzyl)piperazine-1-carboxylate (300 mg), phenylboronic acid (95 mg), copper(II) acetate (283 mg), pyridine (308 mg), triethylamine (395 mg) and pulverized molecular sieves 4 A (600 mg) were suspended in dichloromethane, and the suspension was stirred at room temperature for 20 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give the object compound (150 mg) as an oil.
MS (ESI+, m/e) 459 (M+1)
A mixture of tert-butyl (2R)-4-benzyl-2-(2-bromobenzyl)piperazine-1-carboxylate (445 mg), 1-methyl-5-(tributylstannyl)-1H-pyrazole (426 mg), tetrakis(triphenylphosphine)palladium(0) (58 mg) and toluene (5 ml) was stirred at 100° C. for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give the object compound (240 mg) as an oil.
MS (ESI+, m/e) 447 (M+1)
In the same manner as in Reference Example 243, the following compounds (Reference Examples 695-696) were obtained.
MS (ESI+, m/e) 343 (M+1)
MS (ESI+, m/e) 343 (M+1)
A mixture of (3R)-1-benzyl-3-(2-bromobenzyl)piperazine-2,5-dione (500 mg), phenylboronic acid (250 mg), tetrakis(triphenylphosphine)palladium(0) (231 mg), sodium carbonate (355 mg), DME(7 ml) and water (3.5 ml) was heated under reflux for 12 hr, and concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the suspension was washed with 10% aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:0) was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (290 mg) (The racemization proceeded in the course of the reaction.)
MS (ESI+, m/e) 371 (M+1)
In the same manner as in Reference Example 133, the following compound (Reference Example 698) was obtained.
MS (ESI+, m/e) 343 (M+1)
Benzyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (8.36 g) and triethylamine (9.3 ml) were dissolved in DMF (50 ml), and the solution was ice-cooled. Trityl chloride (9.78 g) was added, and the mixture was stirred at 0° C. for 1 hr, and then at room temperature for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (8.54 g) as an amorphous solid.
MS (ESI+, m/e) 493 (M+1)
Benzyl (3S)-3-(hydroxymethyl)-4-tritylpiperazine-1-carboxylate (985 mg), 3-fluorothiophenol (308 mg) and tri-tert-butylphosphine (486 mg) were dissolved in toluene (40 ml), ADDP (757 mg) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (600 mg) as an amorphous solid.
MS (ESI+, m/e) 361 (M+1-“Tr”)
Benzyl (3S)-3-{[(3-fluorophenyl)thio]methyl}-4-tritylpiperazine-1-carboxylate (600 mg) was dissolved in dichloromethane (10 ml), and the solution was ice-cooled. mCPBA (542 mg) was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give benzyl (3S)-3-{[(3-fluorophenyl)sulfonyl]methyl}-4-tritylpiperazine-1-carboxylate (624 mg) as an amorphous solid. The total amount thereof was dissolved in ethyl acetate (5 ml), 4N hydrogen chloride-ethyl acetate solution (5 ml) was added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (250 mg) as an oil.
MS (ESI+, m/e) 393 (M+1)
Benzyl (3S)-3-(hydroxymethyl)-4-tritylpiperazine-1-carboxylate (985 mg) and triethylamine (836 μl) were dissolved in DMSO (10 ml), a solution of sulfur trioxide pyridine complex (955 mg) in DMSO (5 ml) was added while cooling in water bath, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (591 mg).
1H-NMR (CDCl3) δ 2.94-3.38 (4H, m), 3.71-4.06 (2H, m), 4.24-4.38 (1H, m), 5.03 (2H, s), 7.12-7.37 (14H, m), 7.39-7.64 (6H, m), 8.51 (1H, br s)
Benzyl (3S)-3-formyl-4-tritylpiperazine-1-carboxylate (295 mg) and 2-ethyl-1,3-benzoxazole-5-amine (97 mg) were dissolved in 1,2-dichloroethane (5 ml), acetic acid (0.25 ml) and sodium triacetoxyborohydride (191 mg) were added, and the mixture was stirred at room temperature for 15 hr. 4N Hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (128 mg) as an oil.
MS (ESI+, m/e) 395 (M+1)
A mixture of 1-(benzyloxy)-4-bromo-2-methoxybenzene (1.47 g), morpholine (479 mg), BINAP (311 mg), sodium tert-butoxide (721 mg), Pd2(dba)3 (183 mg) and toluene (45 ml) was stirred at 90° C. for 15 hr in an argon stream, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate-THF (3:1) (along with which the insoluble material was filtered off). The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:6-1:2) was concentrated under reduced pressure, and the crystals were collected by filtration to give the object compound (1.13 g).
1H-NMR (CDCl3) δ 3.05-3.08 (4H, m), 3.83-3.86 (4H, m), 3.87 (3H, s), 5.08 (2H, s), 6.37 (1H, dd), 6.55 (1H, d), 6.80 (1H, d), 7.28-7.44 (5H, m)
MS (ESI+, m/e) 300 (M+1)
In the same manner as in Reference Example 704, the following compound (Reference Example 705) was obtained.
1H-NMR (CDCl3) δ 2.13 (3H, s), 3.02-3.08 (4H, m), 3.61 (2H, t), 3.76 (2H, t), 3.88 (3H, s), 5.09 (2H, s), 6.38 (1H, dd), 6.57 (1H, d), 6.80 (1H, d), 7.28-7.44 (5H, m)
MS (ESI+, m/e) 341 (M+1)
4-[4-(Benzyloxy)-3-methoxyphenyl]morpholine (1.12 g) was dissolved in methanol-THF (3:1, 40 ml), 20% palladium hydroxide-carbon (50% containing water, 560 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give the object compound (684 mg).
1H-NMR (CDCl3) δ 3.04-3.07 (4H, m), 3.85-3.87 (4H, m), 3.87 (3H, s), 5.30 (1H, br s), 6.44 (1H, dd), 6.54 (1H, s), 6.83 (1H, d)
MS (ESI+, m/e) 210 (M+1)
In the same manner as in Reference Example 706, the following compound (Reference Example 707) was obtained.
1H-NMR (CDCl3) δ 2.14 (3H, s), 3.00-3.06 (4H, m), 3.61 (2H, t), 3.77 (2H, t), 3.87 (3H, s), 5.41 (1H, br s), 6.44 (1H, dd), 6.54 (1H, d), 6.83 (1H, d)
MS (ESI+, m/e) 251 (M+1)
4-Bromo-2-fluorophenol (26.8 g) and 3-chloro-2-methyl-1-propene (13.7 ml) were dissolved in acetone (420 ml), potassium carbonate (29.0 g) was added thereto, and the mixture was heated under reflux for 15 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (29.9 g).
1H-NMR (CDCl3) δ 1.83 (3H, s), 4.48 (2H, s), 5.04 (2H, d), 6.84 (1H, t), 7.13 (2H, m)
A mixture of 4-bromo-2-fluoro-1-[(2-methyl-2-propen-1-yl)oxy]benzene (29.9 g) and N,N-diethylaniline (30 ml) was stirred at 190° C. for 5 hr. The mixture was cooled to room temperature, and diisopropyl ether was added thereto. The mixture was washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in toluene (240 ml), boron trifluoride diethyl ether complex (30 ml) was added thereto, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (18.9 g).
1H-NMR (CDCl3) δ 1.51 (6H, s), 3.04 (2H, s), 6.97-7.24 (2H, m)
5-Bromo-7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran (18.9 g) was dissolved in THF (250 ml), and the solution was cooled to −78° C. n-Butyllithium (1.6M hexane solution, 53 ml) was added, and the mixture was stirred at −78° C. for 1 hr. Triisopropyl borate (21 ml) was added thereto at −78° C., and the mixture was stirred at room temperature for 12 hr. To the reaction mixture was added 1N hydrochloric acid (150 ml), and the mixture was stirred at room temperature for 3 hr, and extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (6.54 g).
1H-NMR (DMSO-d6) δ 1.16-1.35 (2H, m), 1.45 (6H, s), 7.26-7.50 (2H, m), 7.90 (2H, br s)
(7-Fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (1.2 g) was dissolved in acetone (20 ml), a solution of OXONE (3.7 g) in water (20 ml) was added dropwise at room temperature, and the mixture was stirred for 10 min. To the reaction mixture was added 10% aqueous sodium thiosulfate solution (100 ml), and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, and the aqueous layer was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give the object compound (600 mg).
1H-NMR (DMSO-d6) δ 1.50 (2H, m), 3.00 (6H, s), 4.86 (1H, br s), 6.41-6.50 (2H, m)
In the same manner as in Reference Example 255, the following compounds (Reference Examples 712-719) shown in Table 9 were obtained. In the column of “MS (ESI+)” in the Table, “*” means that a mass value of “M+1-“Boc”” was obtained (a mass value of M+1 was obtained for other compounds).
In the same manner as in Reference Example 341, the following compounds (Reference Examples 720-734) shown in Table 10-1-Table 10-2 were obtained.
1-tert-Butyl 4-benzyl (2R)-2-[2-(phenylthio)ethyl]piperazine-1,4-dicarboxylate (0.8 g) was dissolved in dichloromethane (10 ml), and the solution was ice-cooled. mCPBA (0.3 g) was added thereto, and the mixture was stirred at 0° C. for 1 hr. mCPBA (0.2 g) was further added under ice-cooling, and the mixture was stirred at 0° C. for 3 hr. The reaction mixture was poured into aqueous sodium hydrogensulfite solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (0.78 g) as an amorphous solid.
MS (ESI+, m/e) 473 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-[2-(phenylthio)ethyl]piperazine-1,4-dicarboxylate (0.8 g) was dissolved in dichloromethane (10 ml), and the solution was ice-cooled. mCPBA (0.6 g) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into aqueous sodium hydrogensulfite solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (0.85 g) as an amorphous solid.
MS (ESI+, m/e) 489 (M+1)
In the same manner as in Reference Example 663, the following compounds (Reference Examples 737-756) shown in Table 11-1-Table 11-2 were obtained.
In the same manner as in Reference Example 383 or Reference Example 665, the following compounds (Reference Examples 757-783) shown in Table 12-1-Table 12-3 were obtained. In the column of “Acid” in the Tables, the compounds described as “TFA” were synthesized according to the method of Reference Example 383 and the compounds described as “HCl” were synthesized according to the method of Reference Example 665.
In the same manner as in Reference Example 425, the following compounds (Reference Examples 784-803) shown in Table 13-1-Table 13-2 were obtained.
4-Acetylaniline (540 mg) was dissolved in DMF (20 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 160 mg) was added thereto, and the mixture was stirred at 0° C. for 15 min. After stirring, 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (885 mg) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give 1-tert-butyl 4-benzyl (2R)-2-{2-[(4-acetylphenyl)amino]ethyl}piperazine-1,4-dicarboxylate (740 mg) as an oil. The total amount thereof was dissolved in ethyl acetate (5 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (650 mg).
MS (ESI+, m/e) 382 (M+1)
Benzyl [(2R)-4-benzyl-3,6-dioxopiperazin-2-yl]acetate (2.00 g) was dissolved in methanol (40 ml), 20% palladium hydroxide-carbon (50% containing water, 500 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 17 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (1.41 g).
1H-NMR (DMSO-d6) δ 2.68 (1H, dd), 2.85 (1H, dd), 3.78 (2H, q), 4.24 (1H, s), 4.36 (1H, d), 4.69 (1H, d), 7.27-7.36 (5H, m), 8.22 (1H, s), 12.50 (1H, br s)
MS (ESI+, m/e) 263 (M+1)
[(2R)-4-Benzyl-3,6-dioxopiperazin-2-yl]acetic acid (262 mg), aniline (102 mg) and HATU (570 mg) were dissolved in pyridine (5 ml), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid (40 ml), and the precipitated crystals were collected by filtration, washed with water, and vacuum-dried to give the object compound (320 mg).
MS (ESI+, m/e) 338 (M+1)
In the same manner as in Reference Example 806, the following compounds (Reference Examples 807-826) shown in Table 14-1-Table 14-2 were obtained.
A mixture of 2-[(2R)-4-benzyl-3,6-dioxopiperazin-2-yl]-N-phenylacetamide (320 mg) and THF (10 ml) was ice-cooled, and lithium aluminum hydride (216 mg) was added by small portions. The mixture was stirred at room temperature for 30 min, and then at 60° C. for 15 hr, and cooled to −78° C. Ethanol-ethyl acetate (1:1, 1 ml) and 1N aqueous sodium hydroxide solution (2 ml) were successively added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 40 min. The insoluble material was filtered, and washed with ethyl acetate. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (145 mg) as an oil.
MS (ESI+, m/e) 296 (M+1)
In the same manner as in Reference Example 827, the following compounds (Reference Examples 828-847) shown in Table 15-1-Table 15-2 were obtained.
[(2R)-4-Benzyl-3,6-dioxopiperazin-2-yl]acetic acid (262 mg) and 4-(difluoromethoxy)aniline (159 mg) were dissolved in pyridine (5 ml), HATU (570 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with heptane, and the mixture was again concentrated under reduced pressure to remove pyridine. The residue was dissolved in ethyl acetate, and the solution was washed successively with saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crystals were collected by filtration to give 2-[(2R)-4-benzyl-3,6-dioxopiperazin-2-yl]-N-[4-(difluoromethoxy)phenyl]acetamide (370 mg). The total amount thereof was suspended in THF (10 ml), and the suspension was ice-cooled. Lithium aluminum hydride (200 mg) was added by small portions, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 3 hr, and was cooled to −78° C. Water (0.2 ml), 4N aqueous sodium hydroxide solution (0.2 ml) and water (0.6 ml) were successively added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 40 min. The insoluble material was filtered, and washed with THF. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-10:1) was concentrated under reduced pressure to give the object compound (330 mg) as an oil.
MS (ESI+, m/e) 362 (M+1)
In the same manner as in Reference Example 848, the following compounds (Reference Examples 849-854) shown in Table 16 were obtained.
[(2R)-4-Benzyl-1-(tert-butoxycarbonyl)piperazin-2-yl]acetic acid (200 mg) and aniline (55 mg) were dissolved in pyridine (5 ml), HATU (340 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with heptane, and the mixture was again concentrated under reduced pressure to remove pyridine. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give tert-butyl (2R)-2-(2-anilino-2-oxoethyl)-4-benzylpiperazine-1-carboxylate (120 mg) as an amorphous solid. This was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate solution (5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the suspension was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (110 mg).
MS (ESI+, m/e) 310 (M+1)
In the same manner as in Reference Example 855, the following compound (Reference Example 856) was obtained.
MS (ESI+, m/e) 324 (M+1)
3-Methoxyaniline (1.2 g) and triethylamine (2 ml) were dissolved in THF (20 ml), and the solution was ice-cooled. 2-Nitrobenzenesulfonyl chloride (2.65 g) was added thereto, and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (3.2 g).
1H-NMR (CDCl3) δ 3.77 (3H, s), 6.68-6.78 (2H, m), 6.82 (1H, t), 7.16 (1H, t), 7.55-7.76 (2H, m), 7.83-7.91 (2H, m)
In the same manner as in Reference Example 857, the following compounds (Reference Examples 858-862) were obtained.
1H-NMR (CDCl3) δ 2.57 (3H, s), 7.36-7.54 (3H, m), 7.54-7.66 (1H, m), 7.68-7.79 (3H, m), 7.83-7.90 (2H, m)
1H-NMR (CDCl3) δ 7.05-7.39 (4H, m), 7.53-8.00 (4H, m)
1H-NMR (DMSO-d6) δ 6.47-6.58 (1H, m), 7.23 (2H, d), 7.67-8.09 (5H, m), 8.39 (1H, d), 10.81 (1H, s)
1H-NMR (DMSO-d6) δ 2.75 (3H, s), 3.58 (1H, br s), 7.18 (1H, dd), 7.60 (1H, d), 7.73-8.04 (5H, m), 10.88 (4H, s)
1H-NMR (CDCl3) δ 2.82 (3H, s), 7.20 (1H, dd), 7.46 (1H, br s), 7.50-7.58 (1H, m), 7.64-7.73 (1H, m), 7.75-7.83 (3H, m), 7.87 (1H, dd)
1-tert-Butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (885 mg) was dissolved in DMF (20 ml), N-(3-acetylphenyl)-2-nitrobenzenesulfonamide (1.3 g) and cesium carbonate (1.3 g) were added thereto. The mixture was stirred at 60° C. for 12 hr, and the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (700 mg) as an amorphous solid.
MS (ESI+, m/e) 555 (M+1)
2-Nitro-N-[4-(trifluoromethoxy)phenyl]benzenesulfonamide (652 mg), 1-tert-butyl 4-benzyl (2R)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate (550 mg) and triphenylphosphine (472 mg) were dissolved in toluene (20 ml), DEAD (40% toluene solution, 1 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (740 mg) as an amorphous solid.
MS (ESI+, m/e) 709 (M+1)
In the same manner as in Reference Example 864, the following compounds (Reference Examples 865-867) were obtained.
MS (ESI+, m/e) 691 (M+1)
MS (ESI+, m/e) 696 (M+1)
MS (ESI+, m/e) 696 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-(2-{(3-acetylphenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1,4-dicarboxylate (700 mg) and mercaptoacetic acid (0.22 ml) were dissolved in DMF (5 ml), lithium hydroxide monohydrate (264 mg) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and poured into saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give 1-tert-butyl 4-benzyl (2R)-2-{2-[(3-acetylphenyl)amino]ethyl}piperazine-1,4-dicarboxylate (190 mg) as an amorphous solid. The total amount thereof was dissolved in ethyl acetate (5 ml), 4N hydrogen chloride-ethyl acetate solution (10 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the suspension was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (120 mg).
MS (ESI+, m/e) 382 (M+1)
In the same manner as in Reference Example 868, the following compounds (Reference Examples 869-870) were obtained.
MS (ESI+, m/e) 424 (M+1)
MS (ESI+, m/e) 406 (M+1)
A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (530 mg), N-(2-methoxyphenyl)-2-nitrobenzenesulfonamide (490 mg), potassium carbonate (415 mg) and DMF (10 ml) was stirred at 50° C. for 12 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced pressure to give 1-tert-butyl 4-benzyl (2R)-2-(2-{(2-methoxyphenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1,4-dicarboxylate (650 mg) as an oil. This was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the suspension was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (490 mg).
MS (ESI+, m/e) 555 (M+1)
In the same manner as in Reference Example 871, the following compound (Reference Example 872) was obtained.
MS (ESI+, m/e) 555 (M+1)
1-tert-Butyl 4-benzyl (2R)-2-(2-{(2-methyl-1,3-benzothiazol-5-yl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1,4-dicarboxylate (420 mg) was dissolved in ethyl acetate (5 ml), 4N hydrogen chloride-ethyl acetate solution (10 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the suspension was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (310 mg).
MS (ESI+, m/e) 596 (M+1)
In the same manner as in Reference Example 873, the following compound (Reference Example 874) was obtained.
MS (ESI+, m/e) 596 (M+1)
In the same manner as in Reference Example 529, the following compounds (Reference Examples 875-877) were obtained.
MS (ESI+, m/e) 617 (M+1)
MS (ESI+, m/e) 626 (M+1)
MS (ESI+, m/e) 626 (M+1)
tert-Butyl (2R)-4-benzyl-2-(2-bromobenzyl)piperazine-1-carboxylate (1.78 g) was dissolved in methanol (5 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DMF (30 ml). 1-{(1S,2S)-2-[(Methoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylic acid (1.37 g), WSC.HCl (1.15 g), HOBt (757 mg) and N,N-diisopropylethylamine (3.56 ml) were added, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (2.31 g) as an amorphous solid.
MS (ESI+, m/e) 670 (M+1)
1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (330 mg) and [(2S)-4-benzylpiperazin-2-yl]methanol (206 mg) were suspended in DMF (10 ml), WSC.HCl (288 mg) and HOBt (189 mg) were added thereto, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, the residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (410 mg) as an amorphous solid.
MS (ESI+, m/e) 519 (M+1)
In the same manner as in Reference Example 879, the following compounds (Reference Examples 880-881) were obtained.
MS (ESI+, m/e) 657 (M+1)
MS (ESI+, m/e) 621 (M+1)
tert-Butyl (3S)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(phenylthio)methyl]piperazine-1-carboxylate (310 mg) was dissolved in dichloromethane (5 ml), and the solution was ice-cooled. mCPBA (123 mg) was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (312 mg) as an amorphous solid.
MS (ESI+, m/e) 637 (M+1)
tert-Butyl (3S)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(phenylthio)methyl]piperazine-1-carboxylate (310 mg) was dissolved in dichloromethane (5 ml), and the solution was ice-cooled. mCPBA (247 mg) was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (317 mg) as an amorphous solid.
MS (ESI+, m/e) 653 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (200 mg), 1-benzyl-3-(biphenyl-2-ylmethyl)piperazine (240 mg), WSC.HCl (173 mg) and HOBt (110 mg) in DMF (7 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate-methanol (4:1) were concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-4-benzyl-2-(biphenyl-2-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (180 mg) as an amorphous solid, and (1S,2R)-2-(4-{[(2S)-4-benzyl-2-(biphenyl-2-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (130 mg) as an amorphous solid.
MS (ESI+, m/e) 655 (M+1)
MS (ESI+, m/e) 655 (M+1)
In the same manner as in Reference Example 884, the following compound (Reference Example 885) was obtained.
MS (ESI+, m/e) 609 (M+1)
MS (ESI+, m/e) 609 (M+1)
In the same manner as in Reference Example 519, the following compounds (Reference Examples 886-890) were obtained.
MS (ESI+, m/e) 664 (M+1)
MS (ESI+, m/e) 686 (M+1)
MS (ESI+, m/e) 671 (M+1)
MS (ESI+, m/e) 659 (M+1)
MS (ESI+, m/e) 710 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (490 mg), benzyl (3R)-3-(2-{(2-methoxyphenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1-carboxylate (290 mg), WSC.HCl (253 mg) and HOBt (175 mg) in DMF (10 ml) was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (600 mg) as an amorphous solid.
MS (ESI+, m/e) 867 (M+1)
In the same manner as in Reference Example 891, the following compounds (Reference Examples 892-894) were obtained.
MS (ESI+, m/e) 867 (M+1)
MS (ESI+, m/e) 908 (M+1)
MS (ESI+, m/e) 908 (M+1)
Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-{(2-methoxyphenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1-carboxylate (300 mg) and mercaptoacetic acid (92 mg) were dissolved in DMF (5 ml), lithium hydroxide monohydrate (84 mg) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and poured into saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (190 mg) as an amorphous solid.
MS (ESI+, m/e) 682 (M+1)
In the same manner as in Reference Example 895, the following compounds (Reference Examples 896-898) were obtained.
MS (ESI+, m/e) 682 (M+1)
MS (ESI+, m/e) 723 (M+1)
MS (ESI+, m/e) 723 (M+1)
In the same manner as in Reference Example 645, the following compounds (Reference Examples 899-901) were obtained.
MS (ESI+, m/e) 654 (M+1)
MS (ESI+, m/e) 662 (M+1)
MS (ESI+, m/e) 638 (M+1)
Benzyl (3R)-3-(2-anilinoethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate obtained in the course of the below-mentioned Example 428 (150 mg) and triethylamine (0.048 ml) were dissolved in dichloromethane (5 ml), and the solution was ice-cooled. Acetyl chloride (59 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:2) was concentrated under reduced pressure to give the object compound (90 mg) as an amorphous solid.
MS (ESI+, m/e) 694 (M+1)
In the same manner as in Reference Example 902, the following compound (Reference Example 903) was obtained.
MS (ESI+, m/e) 720 (M+1)
(1S,2R)-2-[4-({(2R)-2-[2-(4-Bromo-2-fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol (the compound of the below-mentioned Example 257) (220 mg) was dissolved in THF (10 ml), di-tert-butyl bicarbonate (94 mg) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (270 mg) as an amorphous solid.
MS (ESI+, m/e) 715 (M+1)
tert-Butyl (3R)-3-[2-(4-bromo-2-fluorophenoxy)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (220 mg), potassium carbonate (85 mg), copper iodide (I) (19 mg) and pyrazole (42 mg) were suspended in DMF (5 ml), and the suspension was reacted at 160° C. for 5 min using microwave reactor. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (30 mg) as an amorphous solid.
MS (ESI+, m/e) 703 (M+1)
tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-oxoethyl)piperazine-1-carboxylate (200 mg) and isoindoline (132 mg) were dissolved in dichloromethane-DMF (2:1, 3 ml), acetic acid (67 μl) was added, and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (235 mg) was added thereto, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (110 mg) as an oil.
MS (ESI+, m/e) 644 (M+1)
In the same manner as in Reference Example 906, the following compounds (Reference Examples 907-909) were obtained.
MS (ESI+, m/e) 658 (M+1)
MS (ESI+, m/e) 658 (M+1)
MS (ESI+, m/e) 619 (M+1)
In the same manner as in Reference Example 341, the following compounds (Reference Examples 910-912) were obtained.
MS (ESI+, m/e) 483 (M+1)
MS (ESI+, m/e) 496 (M+1)
MS (ESI+, m/e) 492 (M+1)
In the same manner as in Reference Example 425, the following compounds (Reference Examples 913-915) were obtained.
MS (ESI+, m/e) 383 (M+1)
MS (ESI+, m/e) 396 (M+1)
MS (ESI+, m/e) 392 (M+1)
In the same manner as in Reference Example 879, the following compound (Reference Example 916) was obtained.
MS (ESI+, m/e) 631 (M+1)
In the same manner as in Reference Example 883, the following compound (Reference Example 917) was obtained.
MS (ESI+, m/e) 663 (M+1)
To an ice-cooled solution of diisopropylamine (1.5 ml) in THF (6 ml) was added dropwise n-butyllithium (5 ml, 2.5M hexane solution), and the mixture was stirred for 30 min. The mixture was added dropwise to a solution of 5-bromo-2-methyl-1,3-benzothiazole (1.14 g) in THF (6 ml) which was cooled to −78° C., and the mixture was stirred at the same temperature for 30 min. Methyl iodide (1.6 ml) was added, and the mixture was further stirred for 1 hr. To the reaction mixture was added ethyl acetate (50 ml), and the mixture was allowed to warm to room temperature, and washed successively with 1N hydrochloric acid (10 ml) and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure. The residue, bis(pinacolato)diboron (1.5 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (200 g) and potassium acetate (4 g) were dissolved in THF (40 ml), and the solution was stirred at refluxing temperature for 20 hr. To the reaction mixture was added ethyl acetate-water (2:1), and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure. The residue was dissolved in acetone (20 ml), and a solution of potassium peroxymonosulfate (3.0 g) in water (20 ml) was added at room temperature. The mixture was stirred at room temperature for 10 min, aqueous saturated thiosodium sulfate solution (20 ml) was added, and the liberated oil was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 2-ethyl-1,3-benzothiazol-5-ol (324 mg) and 2-isopropyl-1,3-benzothiazol-5-ol (245 mg) as an amorphous solid, respectively.
1H-NMR (CDCl3) δ 1.48 (3H, t), 3.21 (2H, q), 6.77 (1H, br s), 6.99 (1H, dd), 7.47-7.72 (2H, m)
1H-NMR (CDCl3) δ 1.50 (6H, d), 3.54 (1H, dt), 5.46 (1H, br s), 6.98 (1H, dd), 7.53 (1H, d), 7.63 (1H, d).
A solution of 1-tert-butyl 4-benzyl (2R)-2-{2-[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}piperazine-1,4-dicarboxylate (152 mg) in DMF (5 ml) was ice-cooled, sodium hydride (60% in oil) (12 mg) was added, and the mixture was stirred at room temperature for 30 min. 1-Bromo-3-methoxypropane (46 mg) was added, and the mixture was stirred for 2 hr, and poured into ice-cooled saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (220 mg) as an oil.
MS (ESI+, m/e) 582 (M+1)
In the same manner as in Reference Example 919, the following compound (Reference Example 920) was obtained.
MS (ESI+, m/e) 568 (M+1)
In the same manner as in Reference Example 341, the following compounds (Reference Examples 921-948) were obtained.
MS (ESI+, m/e) 401 (M+1-“Boc”)
MS (ESI+, m/e) 385 (M+1-“Boc”)
MS (ESI+, m/e) 473 (M+1)
MS (ESI+, m/e) 489 (M+1)
MS (ESI+, m/e) 393 (M+1-“Boc”)
MS (ESI+, m/e) 409 (M+1-“Boc”)
MS (ESI+, m/e) 489 (M+1)
MS (ESI+, m/e) 529 (M+1)
MS (ESI+, m/e) 515 (M+1)
MS (ESI+, m/e) 483 (M+1)
MS (ESI+, m/e) 485 (M+1)
MS (ESI+, m/e) 490 (M+1)
MS (ESI+, m/e) 506 (M+1)
MS (ESI+, m/e) 506 (M+1)
MS (ESI+, m/e) 522 (M+1)
MS (ESI+, m/e) 510 (M+1)
MS (ESI+, m/e) 496 (M+1)
MS (ESI+, m/e) 510 (M+1)
MS (ESI+, m/e) 524 (M+1)
MS (ESI+, m/e) 510 (M+1)
MS (ESI+, m/e) 496 (M+1)
MS (ESI+, m/e) 577 (M+1)
MS (ESI+, m/e) 527 (M+1)
MS (ESI+, m/e) 427 (M+1)
MS (ESI+, m/e) 555 (M+1)
MS (ESI+, m/e) 497 (M+1)
MS (ESI+, m/e) 469 (M+1)
MS (ESI+, m/e) 483 (M+1)
In the same manner as in Reference Example 663, the following compounds (Reference Examples 949-951) were obtained.
MS (ESI+, m/e) 488 (M+1)
MS (ESI+, m/e) 488 (M+1)
MS (ESI+, m/e) 483 (M+1)
In the same manner as in Reference Example 383, the following compounds (Reference Examples 952-981) were obtained.
MS (ESI+, m/e) 482 (M+1)
MS (ESI+, m/e) 468 (M+1)
MS (ESI+, m/e) 401 (M+1)
MS (ESI+, m/e) 385 (M+1)
MS (ESI+, m/e) 373 (M+1)
MS (ESI+, m/e) 389 (M+1)
MS (ESI+, m/e) 393 (M+1)
MS (ESI+, m/e) 409 (M+1)
MS (ESI+, m/e) 389 (M+1)
MS (ESI+, m/e) 429 (M+1)
MS (ESI+, m/e) 415 (M+1)
MS (ESI+, m/e) 383 (M+1)
MS (ESI+, m/e) 385 (M+1)
MS (ESI+, m/e) 390 (M+1)
MS (ESI+, m/e) 406 (M+1)
MS (ESI+, m/e) 406 (M+1)
MS (ESI+, m/e) 422 (M+1)
MS (ESI+, m/e) 410 (M+1)
MS (ESI+, m/e) 396 (M+1)
MS (ESI+, m/e) 410 (M+1)
MS (ESI+, m/e) 424 (M+1)
MS (ESI+, m/e) 410 (M+1)
MS (ESI+, m/e) 396 (M+1)
MS (ESI+, m/e) 477 (M+1)
MS (ESI+, m/e) 427 (M+1)
MS (ESI+, m/e) 327 (M+1)
MS (ESI+, m/e) 455 (M+1)
MS (ESI+, m/e) 397 (M+1)
MS (ESI+, m/e) 369 (M+1)
MS (ESI+, m/e) 383 (M+1)
MS (ESI+, m/e) 388 (M+1)
MS (ESI+, m/e) 388 (M+1)
MS (ESI+, m/e) 383 (M+1)
In the same manner as in Reference Example 243, the following compound (Reference Example 985) was obtained.
MS (ESI+, m/e) 345 (M+1)
In the same manner as in Reference Example 806, the following compounds (Reference Examples 986-988) were obtained.
MS (ESI+, m/e) 366 (M+1)
MS (ESI+, m/e) 370 (M+1)
MS (ESI+, m/e) 386 (M+1)
In the same manner as in Reference Example 827, the following compounds (Reference Examples 989-991) were obtained.
MS (ESI+, m/e) 324 (M+1)
MS (ESI+, m/e) 328 (M+1)
MS (ESI+, m/e) 344 (M+1)
In the same manner as in Reference Example 255, the following compounds (Reference Examples 992-995) were obtained.
MS (ESI+, m/e) 377 (M+1-Boc)
MS (ESI+, m/e) 391 (M+1-Boc)
MS (ESI+, m/e) 355 (M+1-Boc)
MS (ESI+, m/e) 385 (M+1-Boc)
In the same manner as in Reference Example 383, the following compounds (Reference Examples 996-999) were obtained.
MS (ESI+, m/e) 377 (M+1)
MS (ESI+, m/e) 391 (M+1)
MS (ESI+, m/e) 385 (M+1)
MS (ESI+, m/e) 385 (M+1)
2,3-Dihydro-1H-inden-2-ol (161 mg) was dissolved in DMF (5 ml), sodium hydride (60% in oil) (60 mg) was added, and the mixture was stirred at room temperature for 1 hr. 1-tert-Butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (443 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was poured into aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (6:4) was concentrated under reduced pressure to give 1-tert-butyl 4-benzyl (2R)-2-[2-(2,3-dihydro-1H-inden-2-yloxy)ethyl]piperazine-1,4-dicarboxylate (252 mg) as an oil. The obtained 1-tert-butyl 4-benzyl (2R)-2-[2-(2,3-dihydro-1H-inden-2-yloxy)ethyl]piperazine-1,4-dicarboxylate (252 mg) was dissolved in methanol (5 ml), 4N hydrogen chloride-ethyl acetate solution was added. The mixture was stirred at room temperature for 5 hr, and concentrated to give the object compound (157 mg).
MS (ESI+, m/e) 381 (M+1)
In the same manner as in Reference Example 529, the following compound (Reference Example 1001) was obtained.
MS (ESI+, m/e) 670 (M+1)
tert-Butyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (5.04 g) was dissolved in methanol (10 ml), 4N hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature for 5 hr, and concentrated. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give the object compound (4.02 g).
MS (ESI+, m/e) 570 (M+1)
Ethyl 1-[(1S,2S)-2-aminocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.57 g) and DMAP (916 mg) were dissolved in THF (50 ml), and the solution was ice-cooled. 4-Nitrophenyl chloroformate (1.21 g) was added, and the mixture was stirred at 0° C. for 1 hr, and then at room temperature for 2 hr. To the reaction mixture was added cyclobutanol (0.77 ml), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give ethyl 1-[(1S,2S)-2-{[(cyclobutyloxy)carbonyl]amino}cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.22 g) as an amorphous solid. The obtained ethyl 1-[(1S,2S)-2-{[(cyclobutyloxy)carbonyl]amino}cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.22 g) was dissolved in ethanol (30 ml), 2N aqueous sodium hydroxide solution (14.8 ml) was added, and the mixture was stirred at 60° C. for 15 hr. After cooling to room temperature, the mixture was neutralized (pH 7) with diluted hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was suspended in ethanol (100 ml), and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object compound (1.20 g) as a powder mixed with an inorganic salt thereof.
NMR (DMSO-d6) δ: 0.84-1.13 (1H, m), 1.36 (3H, br. s.), 1.42-2.01 (8H, m), 2.04-2.26 (2H, m), 3.11-3.24 (1H, m), 3.70-3.97 (1H, m), 4.67 (1H, t, J=7.5), 7.12 (1H, d, J=9.0), 7.29-7.40 (2H, m), 7.39-7.59 (3H, m), 8.31 (1H, s), 12.23 (1H, br. s.).
Ethyl 1-[(1S,2S)-2-aminocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (940 mg) and triethylamine (0.836 ml) were dissolved in THF (50 ml), 2-methoxyethyl chlorocarbonate (499 mg) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give ethyl 1-[(1S,2S)-2-{[(2-methoxyethoxy)carbonyl]amino}cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.20 g). The obtained ethyl 1-[(1S,2S)-2-{[(2-methoxyethoxy)carbonyl]amino}cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.20 g) was dissolved in methoxyethanol (30 ml), 2N aqueous sodium hydroxide solution (14.5 ml) was added, and the mixture was stirred at 60° C. for 15 hr. After cooling to room temperature, the mixture was neutralized (pH 7) with diluted hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was suspended in ethanol (100 ml), and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object compound (1.23 g) as a powder mixed with an inorganic salt thereof.
NMR (CDCl3) δ: 0.93-1.48 (4H, m), 1.48-2.08 (4H, m), 2.08-2.56 (2H, m), 2.94-4.10 (8H, m), 6.76-7.89 (6H, m).
In the same manner as in Reference Example 1004, the following compound (Reference Example 1005) was obtained.
NMR (DMSO-d6) δ: 0.86-1.07 (1H, m), 1.14-1.46 (1H, m), 1.62 (3H, d, J=9.8), 1.70-1.91 (2H, m), 2.56 (3H, s), 2.96-3.63 (2H, m), 3.63-3.86 (1H, m), 7.10 (1H, d, J=9.1), 7.27-7.39 (2H, m), 7.38-7.47 (3H, m), 7.98 (1H, s).
In the same manner as in Reference Example 39, the following compound (Reference Example 1006) was obtained.
1H-NMR (CDCl3) 6: ppm 1.12-1.23 (11H, m), 1.34-1.46 (1H, m), 1.73-1.86 (3H, m), 2.02-2.10 (2H, m), 3.46-3.53 (1H, m), 3.85 (1H, brs), 4.09-4.13 (1H, m), 4.20 (2H, q), 4.72-4.80 (1H, m), 7.30-7.32 (2H, m), 7.48-7.51 (3H, m), 7.73 (1H, s).
In the same manner as in Reference Example 66, the following compound (Reference Example 1007) was obtained.
1H-NMR (DMSO-d6) 6: ppm 1.08 (6H, dd), 1.07-1.09 (1H, m), 1.24-1.35 (2H, m), 1.63-1.78 (3H, m), 1.94-2.07 (2H, m), 3.49-3.58 (1H, m), 3.86-3.88 (1H, m), 4.53-4.61 (1H, m), 7.15 (1H, d), 7.39-7.41 (2H, m), 7.54-7.57 (3H, m), 9.40 (1H, brs), 11.99 (1H, brs).
A solution of 1-[(1S,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (129 mg), (3R)-1-benzyl-3-(3,5-difluorobenzyl)piperazine (142 mg), WSC.HCl (104 mg) and HOBt (73 mg) in DMF (3 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give (1R,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol (205 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (6 ml), 20% palladium hydroxide-carbon (50% containing water, 105 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (50:1-10:1) was concentrated under reduced pressure. The residue was diluted with diethyl ether (2 ml), 4N hydrogen chloride-ethyl acetate solution (99 μl) was added, and the precipitated crystals were collected by filtration to give the object compound (89 mg).
MS (ESI+, m/e) 481 (M+1)
A solution of 1-[(1R,2R)-2-(benzyloxy)cyclopentyl]-5-phenyl-1H-imidazole-4-carboxylic acid (460 mg), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (368 mg), WSC.HCl (292 mg) and HOBt (206 mg) in DMF (8 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[(1R,2R)-2-(benzyloxy)cyclopentyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (401 mg) as an amorphous solid. 200 mg therefrom was dissolved in dichloromethane (1 ml), TFA (1 ml) was added thereto, and the mixture was stirred at room temperature for 30 min. After stirring, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (152 mg).
MS (ESI+, m/e) 521 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (132 mg), tert-butyl (3R)-3-(2,4-dichlorobenzyl)piperazine-1-carboxylate (145 mg), WSC.HCl (92 mg) and HOBt (65 mg) in DMF (3.5 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give tert-butyl (3R)-3-(2,4-dichlorobenzyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (194 mg) as an amorphous solid. The total amount thereof was dissolved in ethyl acetate (1 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with diethyl ether (8 ml), and the precipitated crystals were collected by filtration to give the object compound (93 mg).
MS (ESI+, m/e) 557 (M+1)
A mixture of ethyl 1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazole-4-carboxylate (440 mg), lithium hydroxide monohydrate (100 mg), ethanol (3 ml) and water (3 ml) was stirred at 60° C. for 10 hr, and concentrated under reduced pressure. The residue was mixed with tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (440 mg), WSC.HCl (640 mg), HOBt (1.00 g) and DMF (7 ml). The mixture was stirred at 50° C. for 3 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:0) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (510 mg) as an amorphous solid. 200 mg therefrom was dissolved in dichloromethane (2 ml), and TFA (2 ml) was added thereto. The mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (116 mg).
MS (ESI+, m/e) 459 (M+1)
Ethyl 1-[(1S)-1-(1-hydroxycyclohexyl)ethyl]-5-phenyl-1H-imidazole-4-carboxylate (900 mg) and lithium hydroxide monohydrate (220 mg) were dissolved in a mixed solvent of methanol (10 ml) and water (2 ml). The solution was heated under reflux for 15 hr, and concentrated under reduced pressure. The residue was mixed with tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (730 mg), WSC.HCl (610 mg), HOBt (1.21 g) and DMF (10 ml). The mixture was stirred at 60° C. for 3 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the object fraction was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[(1S)-1-(1-hydroxycyclohexyl)ethyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate. The total amount thereof was dissolved in ethyl acetate (2.5 ml), and 4N hydrogen chloride-ethyl acetate solution (2.5 ml) was added thereto. The mixture was stirred for 30 min, and concentrated under reduced pressure to give the object compound (696 mg).
MS (ESI+, m/e) 473 (M+1)
Methyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (100 mg) was dissolved in methanol (2 ml), 20% palladium hydroxide-carbon (50% containing water, 30 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (78 mg) as an amorphous solid.
MS (ESI+, m/e) 502 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[trans-2-hydroxycycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (250 mg) was dissolved in dichloromethane (2 ml), TFA (2 ml) was added, and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (199 mg).
MS (ESI+, m/e) 459 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[cis-2-hydroxycycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (165 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 2 hr. Diethyl ether (10 ml) was added, and the crystals were collected by filtration, and washed with diethyl ether to give the object compound (146 mg).
MS (ESI+, m/e) 459 (M+1).
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (165 mg), benzyl (3R)-3-{2-[(2,6-dimethylpyridin-3-yl)oxy]ethyl}piperazine-1-carboxylate (194 mg), WSC.HCl (115 mg) and HOBt (81 mg) in DMF (3.5 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-20:0:1) was concentrated under reduced pressure to give benzyl (3R)-3-{2-[(2,6-dimethylpyridin-3-yl)oxy]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (268 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (7.5 ml), 20% palladium hydroxide-carbon (50% containing water, 135 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (25:1-10:1) was concentrated under reduced pressure. The residue was diluted with diethyl ether (5 ml), 4N hydrogen chloride-ethyl acetate solution (216 μl) was added thereto, and the precipitated crystals were collected by filtration to give the object compound (184 mg).
MS (ESI+, m/e) 548 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (165 mg), benzyl (3R)-3-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazine-1-carboxylate (216 mg), WSC.HCl (115 mg) and HOBt (81 mg) in DMF (3.5 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-20:0:1) was concentrated under reduced pressure to give benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazine-1-carboxylate (290 mg) as an amorphous solid. The total amount thereof was dissolved in 25% hydrogen bromide-acetic acid solution (2 ml), and the solution was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was washed with diethyl ether. Potassium carbonate was added by small portions to the aqueous layer to basify the layer, and the mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (25:1-10:1) was concentrated under reduced pressure. The residue was diluted with diethyl ether (3 ml), 4N hydrogen chloride-ethyl acetate solution (110 μl) was added thereto, and the precipitated crystals were collected by filtration to give the object compound (68 mg).
MS (ESI+, m/e) 590 (M+1)
A mixture of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (165 mg), benzyl (3R)-3-[2-(2-chlorophenoxy)ethyl]piperazine-1-carboxylate hydrochloride (208 mg), WSC.HCl (144 mg), HOBt (115 mg), triethylamine (101 mg) and DMF (2 ml) was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give benzyl (3R)-3-[2-(2-chlorophenoxy)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (200 mg) as an amorphous solid. The total amount thereof was dissolved in ethanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at 65° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (95 mg) as an amorphous solid.
MS (ESI+, m/e) 554 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (100 mg), benzyl (3R)-3-[2-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]piperazine-1-carboxylate hydrochloride (125 mg), WSC.HCl (115 mg), HOBt (45 mg) and triethylamine (150 μl) in DMF (4 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-17:3) was concentrated under reduced pressure to give benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]piperazine-1-carboxylate (124 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (3 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 10 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was treated with 2N hydrogen chloride-ethyl acetate solution to give the object compound (55 mg).
MS (ESI+, m/e) 559 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (100 mg), benzyl (3R)-3-[2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)ethyl]piperazine-1-carboxylate hydrochloride (125 mg), WSC HCl (115 mg), HOBt (45 mg) and triethylamine (150 μl) in DMF (4 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-17:3) was concentrated under reduced pressure to give benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)ethyl]piperazine-1-carboxylate (49 mg) as an amorphous solid. The total amount thereof was dissolved in ethanol (3 ml), 4N aqueous sodium hydroxide solution (1 ml) was added thereto, and the mixture was stirred at 70° C. for 10 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with 2N hydrogen chloride-ethyl acetate solution to give the object compound (16 mg).
MS (ESI+, m/e) 559 (M+1)
A mixture of ethyl 1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazole-4-carboxylate (100 mg), lithium hydroxide monohydrate (20 mg), ethanol (3 ml) and water (1 ml) was stirred at 80° C. for 3 hr, and concentrated under reduced pressure. The residue was mixed with benzyl (3R)-3-[2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)ethyl]piperazine-1-carboxylate hydrochloride (134 mg), WSC.HCl (115 mg), HOBt (230 mg), triethylamine (150 μl) and DMF (4 ml). The mixture was stirred at 50° C. for 5 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:9:0-17:0:3) was concentrated under reduced pressure to give benzyl (3R)-4-({1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)ethyl]piperazine-1-carboxylate (43 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (4 ml), 20% palladium hydroxide-carbon (50% containing water, 20 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was treated with 2N hydrogen chloride-ethyl acetate solution to give the object compound (37 mg).
MS (ESI+, m/e) 529 (M+1)
Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1-carboxylate (216 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the suspension was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (115 mg) as an amorphous solid.
MS (ESI+, m/e) 577 (M+1)
In the same manner as in the above-mentioned Example 1 (Method A)-Example 15 (Method O), the following compounds (Examples 16-343) shown in Table 17-1-Table 17-3, Table 18-1-Table 18-10, Table 19-1-Table 19-2, Table 20-1-Table 20-2, Table 21-1-Table 21-4 and Table 22-1-Table 22-12 were obtained. Where necessary, each compound was isolated and purified by a known means such as phase transfer, liquid conversion, solvent extraction, silica gel column chromatography, reversed-phase preparative HPLC and the like. The final products were isolated as a hydrochloride by a treatment with 4N hydrogen chloride-ethyl acetate solution, as in Method A and the like, or isolated as crystals or an amorphous solid in a free from, as in Method B and the like. In the column of “Salt” in the Tables, the compounds described as “-” were isolated as a free form.
The chemical names of the compounds (Examples 16-343) shown in Table 17-1-Table 17-3, Table 18-1-Table 18-10, Table 19-1-Table 19-2, Table 20-1-Table 20-2, Table 21-1-Table 21-4 and Table 22-1-Table 22-12 are as follows.
In the same manner as in Example 2 (Method B), the following compounds (Examples 344-347) were obtained.
MS (ESI+, m/e) 435 (M+1)
MS (ESI+, m/e) 393 (M+1)
MS (ESI+, m/e) 473 (M+1)
MS (ESI+, m/e) 465 (M+1)
In the same manner as in Example 6 (Method F) except that the final product was isolated as a hydrochloride by treating with 4N hydrogen chloride-ethyl acetate solution, the following compound (Example 348) was obtained.
MS (ESI+, m/e) 546 (M+1)
To tert-butyl (3R)-3-benzyl-4-[(1-cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (300 mg) was added TFA (3 ml), and the mixture was stirred at room temperature for 5 min, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, and the extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (232 mg).
MS (ESI+, m/e) 429 (M+1)
To tert-butyl (3R)-3-benzyl-4-{[1-(trans-2-hydroxycyclopentyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (1.15 g) was added TFA (10 ml), and the mixture was stirred at room temperature for 5 min, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give (1R,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol (96 mg) and (1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol (72 mg), as an amorphous solid, respectively.
MS (ESI+, m/e) 431 (M+1)
MS (ESI+, m/e) 431 (M+1)
trans-2-(4-{[(2R)-4-Benzyl-2-isobutylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol (270 mg) was dissolved in methanol (8 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fractions were neutralized with saturated aqueous sodium hydrogen carbonate, and the mixtures were extracted with chloroform, respectively. The extracts were dried over anhydrous sodium sulfate, and the solvents were evaporated under reduced pressure, respectively. The residue of the less polar fraction was vacuum-dried to give (1S,2S)-2-(4-{[(2R)-2-isobutylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol (60 mg), and the residue of the more polar fraction was vacuum-dried to give (1R,2R)-2-(4-{[(2R)-2-isobutylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol (50 mg), as an amorphous solid, respectively.
MS (ESI+, m/e) 397 (M+1)
MS (ESI+, m/e) 397 (M+1)
To tert-butyl (3R)-3-benzyl-4-({1-[(1S,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (110 mg) was added TFA (3 ml), and the mixture was stirred at room temperature for 5 min, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, and the extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (92 mg).
MS (ESI+, m/e) 445 (M+1)
To tert-butyl (3R)-3-benzyl-4-{[1-(cis-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (260 mg) was added TFA (3 ml), and the mixture was stirred at room temperature for 5 min, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (89 mg).
MS (ESI+, m/e) 445 (M+1) (The other diastereomer obtained by this method is the same as the compound of the above-mentioned Example 352.)
Methyl 1-[cis-2-(hydroxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (containing a trace of ethyl acetate) (600 mg) and lithium hydroxide (120 mg) were dissolved in a mixed solvent of methanol (10 ml) and water (2 ml), and the solution was heated under reflux for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (530 mg), WSC.HCl (440 mg), HOBt (2.90 g) and DMF (10 ml). The mixture was stirred at 60° C. for 3 hr, poured into aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in TFA (5 ml). The solution was stirred for 30 min, and poured into aqueous potassium carbonate solution, and the mixture was extracted with dichloroethane. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fractions were diluted with aqueous potassium carbonate solution, and the mixtures were extracted with ethyl acetate, respectively. The extracts were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compounds as an amorphous solid, respectively.
tert-Butyl (3R)-3-benzyl-4-({1-[trans-2-hydroxycyclohexyl]-2-methyl-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (55 mg) was dissolved in 1,2-dichloroethane (2 ml), TFA (2 ml) was added, and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was washed with diethyl ether to give the object compound (46 mg) as a TFA salt.
MS (ESI+, m/e) 459 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-(2-ethoxy-2-oxoethylidene)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (100 mg) was dissolved in acetic acid-water (2:1, 1.5 ml), and the solution was stirred at 80° C. for 12 hr. The reaction mixture was poured into water, and the mixture was neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate-THF (1:1). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and 4N hydrogen chloride-ethyl acetate solution was added thereto. The solvent was evaporated under reduced pressure to give the object compound (70 mg) as an amorphous solid.
MS (ESI+, m/e) 513 (M+1)
Ethyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (500 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (420 mg) as an amorphous solid.
MS (ESI+, m/e) 516 (M+1)
Ethyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (530 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 200 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (415 mg) as an amorphous solid.
MS (ESI+, m/e) 552 (M+1)
Ethyl 1-{cis-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (501 mg) was dissolved in ethanol-water (2:1, 6 ml), lithium hydroxide monohydrate (69 mg) was added, and the mixture was stirred at 65° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethanol. The suspension was again concentrated under reduced pressure, and the residue was vacuum-dried. This was suspended in DMF (5 ml), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (360 mg), WSC.HCl (498 mg) and HOBt (796 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-[(1-{cis-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (560 mg) as an amorphous solid. 500 mg therefrom was dissolved in dichloromethane (1 ml), TFA (1 ml) was added at room temperature, and the mixture was stirred for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with 6% aqueous sodium bicarbonate. The liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object less polar fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (55 mg) as an amorphous solid.
MS (ESI+, m/e) 516 (M+1)
tert-Butyl (3R)-3-benzyl-4-{[1-(2-butyl-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (36 mg) was dissolved in ethyl acetate (0.5 ml), 4N hydrogen chloride-ethyl acetate solution (0.5 ml) was added, and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure to give the object compound (30 mg).
MS (ESI+, m/e) 501 (M+1)
tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (170 mg) was dissolved in DMF (3 ml), sodium ethoxide (61 mg) was added, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[2-(ethoxymethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (70 mg) as an amorphous solid. The total amount thereof was dissolved in ethanol (2 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (30 mg) as an amorphous solid.
MS (ESI+, m/e) 503 (M+1)
In the same manner as in Example 361 except that the object compound was isolated as a hydrochloride, the following compound (Example 362) was obtained.
MS (ESI+, m/e) 489 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[(1R,2R)-2-(cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (49 mg) was dissolved in methanol (2 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. To the residue was toluene (5 ml) was added, and the mixture was further concentrated under reduced pressure to give the object compound (15 mg) as an amorphous solid.
MS (ESI+, m/e) 499 (M+1)
In the same manner as in Example 363, the following compound (Example 364) was obtained.
MS (ESI+, m/e) 499 (M+1)
tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (221 mg) and 2-(methylsulfonyl)ethanamine (99 mg) were dissolved in acetonitrile (5 ml), lithium perchlorate (85 mg) was added, and the mixture was reacted at 100° C. for 5 min using microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[2-hydroxy-2-({[2-(methylsulfonyl)ethyl]amino}methyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (235 mg) as an amorphous solid. To the total amount thereof was added 4N hydrogen chloride-ethyl acetate solution (2 ml), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fractions were neutralized with saturated aqueous sodium hydrogen carbonate, and the mixtures were extracted with ethyl acetate, respectively. The extracts were dried over anhydrous sodium sulfate, and the solvents were evaporated under reduced pressure to give (1R,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-({[2-(methylsulfonyl)ethyl]amino}methyl)cyclohexanol (26 mg) as an amorphous solid, and (1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-({[2-(methylsulfonyl)ethyl]amino}methyl)cyclohexanol (15 mg) as an amorphous solid.
MS (ESI+, m/e) 580 (M+1)
MS (ESI+, m/e) 580 (M+1)
2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride (70 mg) was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fractions were collected, and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, respectively. The organic layers were dried over anhydrous sodium sulfate, and the solvents were evaporated under reduced pressure, respectively. 4N Hydrogen chloride-ethyl acetate solutions (1 ml) were added to the residues, and the mixtures were concentrated under reduced pressure, respectively. Toluene (5 ml) was added to the residues, and the mixtures were again concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride (HPLC retention time: short, Example 366a, 24 mg) as an amorphous solid, and (1R,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride (HPLC retention time: long, Example 366b, 17 mg) as an amorphous solid.
MS (ESI+, m/e) 489 (M+1)
MS (ESI+, m/e) 489 (M+1)
(the alternative synthetic method of the above-mentioned Example 366a; The object compound was isolated as a dihydrochloride.)
tert-Butyl (3R)-3-benzyl-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (5.45 g) was dissolved in methanol (10 ml), 4N hydrogen chloride-ethyl acetate solution (10 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (4.47 g). 2.73 g therefrom was dissolved in ethanol (10 ml), 4N hydrogen chloride-ethyl acetate solution (3.07 ml) was added, and the mixture was heated with stirring to 70° C. Ethanol (5 ml) was added at the same temperature, and the mixture was cooled to room temperature while stirring. The precipitated crystals were collected by filtration to give the object compound (2.57 g).
MS (ESI+, m/e) 489 (M+1)
(1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol obtained in the course of the above-mentioned Example 367 (1.00 g) was dissolved in ethyl acetate (20 ml), a solution of fumaric acid (238 mg) in ethanol (5 ml) was added, and the mixture was heated at 70° C. to give a homogeneous solution. Ethyl acetate (10 ml) was added at the same temperature, the mixture was left to stand at room temperature for 15 hr, and the precipitated crystals were collected by filtration to give the object compound (1.13 g).
MS (ESI+, m/e) 489 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[2-(2-cyanoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (150 mg) was dissolved in toluene (5 ml), and trimethylsilylazide (33 μl) and dibutyl(oxo)tin (6 mg) were added. The mixture was heated under reflux for 12 hr, and the solvent was evaporated under reduced pressure. To the residue was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-[(1-{2-hydroxy-2-[2-(1H-tetrazol-5-yl)ethyl]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (27 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (1 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fraction was concentrated under reduced pressure to give (1R,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[2-(1H-tetrazol-5-yl)ethyl]cyclohexanol trifluoroacetate (6 mg) as an amorphous solid, and (1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[2-(1H-tetrazol-5-yl)ethyl]cyclohexanol trifluoroacetate (9 mg) as an amorphous solid.
MS (ESI+, m/e) 541 (M+1)
MS (ESI+, m/e) 541 (M+1)
tert-Butyl (3R)-3-benzyl-4-({1-[2-(2-cyanoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (150 mg) was dissolved in 1M ammonia-ethanol solution (15 ml), Raney cobalt (30 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl (3R)-4-({1-[2-(3-aminopropyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (200 mg) as an oil. The total amount thereof was dissolved in pyridine (2 ml), and the solution was ice-cooled. Acetic anhydride (24 μl) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give tert-butyl (3R)-4-[(1-{2-[3-(acetylamino)propyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]-3-benzylpiperazine-1-carboxylate (32 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (1 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fraction was concentrated under reduced pressure to give N-{3-[(1R,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]propyl}acetamide trifluoroacetate (11 mg) as an amorphous solid, and N-{3-[(1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]propyl}acetamide trifluoroacetate (10 mg) as an amorphous solid.
MS (ESI+, m/e) 544 (M+1)
MS (ESI+, m/e) 544 (M+1)
60% Sodium hydride (40 mg) was suspended in DMF (3 ml), N-(2-hydroxyethyl)acetamide (124 mg) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (111 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give tert-butyl (3R)-4-{[1-(2-{[2-(acetylamino)ethoxy]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}-3-benzylpiperazine-1-carboxylate (79 mg) as an amorphous solid. To the total amount thereof was added 4N hydrogen chloride-ethyl acetate solution (2 ml), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fraction was concentrated under reduced pressure to give N-(2-{[(1R,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]methoxy}ethyl)acetamide trifluoroacetate (32 mg) as an amorphous solid, and N-(2-{[(1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]methoxy}ethyl)acetamide trifluoroacetate (37 mg) as an amorphous solid.
MS (ESI+, m/e) 560 (M+1)
MS (ESI+, m/e) 560 (M+1)
In the same manner as in Example 371, the following compound (Example 372) was obtained.
MS (ESI+, m/e) 572 (M+1)
MS (ESI+, m/e) 572 (M+1)
tert-Butyl (3R)-3-benzyl-4-{[1-(2-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (74 mg) was dissolved in methanol (1 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fractions were collected, saturated aqueous sodium hydrogen carbonates were added, and the mixtures were extracted with ethyl acetate, respectively. The extracts were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]methyl}cyclohexanol (31 mg) as an amorphous solid, and (1R,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]methyl}cyclohexanol (30 mg) as an amorphous solid.
MS (ESI+, m/e) 607 (M+1)
MS (ESI+, m/e) 607 (M+1)
1-(1,3-Thiazol-2-yl)ethanol (230 mg) was dissolved in DMF (10 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 70 mg) was added thereto, and then tert-butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (200 mg) was added, and the mixture was stirred at 50° C. for 15 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (2.5 ml), 4N hydrogen chloride-ethyl acetate solution (2.5 ml) was added, and the mixture was stirred for 30 min, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fractions were collected, and diluted with aqueous potassium carbonate solution, and the mixtures were extracted with ethyl acetate, respectively. The extracts were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, respectively. The residues were treated with 4N hydrogen chloride-ethyl acetate solution to give the object compound, respectively.
In the same manner as in Example 374, the following compound (Example 375) was obtained.
MS (ESI+, m/e) 600 (M+1)
MS (ESI+, m/e) 600 (M+1)
tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (111 mg) was dissolved in DMF (3 ml), lithium hydroxide monohydrate (84 mg) was added, and the mixture was stirred at 100° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[2-hydroxy-2-(hydroxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (70 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (1 ml), 5% hydrogen chloride-methanol solution (1 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added toluene, and the mixture was again concentrated under reduced pressure to give the object compound (60 mg) as an amorphous solid.
MS (ESI+, m/e) 475 (M+1)
Sodium hydride (60% in oil) (40 mg) was suspended in DMF (3 ml), propane-1,3-diol (91 mg) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (110 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-[(1-{2-hydroxy-2-[(3-hydroxypropoxy)methyl]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (91 mg) as an amorphous solid. The total amount thereof was dissolved in ethanol (2 ml), 5% hydrogen chloride-methanol solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. To the residue was added toluene (5 ml), and the mixture was again concentrated under reduced pressure to give the object compound (100 mg) as an amorphous solid.
MS (ESI+, m/e) 533 (M+1)
Ethyl 1-((1S,2R)-2-hydroxy-2-{[3-(methylthio)propoxy]methyl}cyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate (318 mg) was dissolved in ethanol-THF (1:1, 4 ml), lithium hydroxide monohydrate (23 mg) and water (1 ml) were added thereto, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethanol. The suspension was again concentrated under reduced pressure, and the residue was vacuum-dried. The half amount of the residue was suspended in DMF (5 ml), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (153 mg), WSC.HCl (142 mg) and HOBt (113 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-{[1-((1S,2R)-2-hydroxy-2-{[3-(methylthio)propoxy]methyl}cyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (94 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (2 ml), and 4N hydrogen chloride-ethyl acetate solution (2 ml) was added thereto. The mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fraction was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (60 mg) as an amorphous solid.
MS (ESI+, m/e) 563 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (569 mg), (3R)-1-benzyl-3-(3,5-difluorobenzyl)piperazine (496 mg), WSC.HCl (377 mg) and HOBt (266 mg) in DMF (9 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1.5:1-2:1) was concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (546 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (15 ml), 20% palladium hydroxide-carbon (50% containing water, 275 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-chloroform-methanol (1:1:0-10:10:1) was concentrated under reduced pressure. The residue was diluted with diethyl ether (6 ml), and 4N hydrogen chloride-ethyl acetate solution (244 μl) was added thereto. The precipitated crystals were collected by filtration to give the object compound (366 mg).
MS (ESI+, m/e) 525 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (132 mg), (3R)-1-benzyl-3-(pyridin-3-ylmethyl)piperazine (112 mg), WSC.HCl (92 mg) and HOBt (65 mg) in DMF (2.5 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-20:1) was concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-4-benzyl-2-(pyridin-3-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (202 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (5.5 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fractions were collected, and diluted with saturated aqueous sodium hydrogen carbonate-saturated brine (1:1), and the mixture was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was diluted with diethyl ether (6 ml), and 4N hydrogen chloride-ethyl acetate solution (192 μl) was added thereto. The precipitated crystals were collected by filtration to give the object compound (103 mg).
MS (ESI+, m/e) 490 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (132 mg), (3R)-1-benzyl-3-(1H-imidazol-4-ylmethyl)piperazine (108 mg), WSC.HCl (92 mg) and HOBt (65 mg) in DMF (2.5 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-10:1) was concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-4-benzyl-2-(1H-imidazol-4-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (140 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 140 mg) was added thereto, and the mixture was subjected to catalytic reduction at 60° C. for 10 hr under moderate-pressure (5 kgf/cm2). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was diluted with saturated aqueous sodium hydrogen carbonate-saturated brine (1:1), and the mixture was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was diluted with diethyl ether (2 ml), and 4N hydrogen chloride-ethyl acetate solution (68 μl) was added thereto. The precipitated crystals were collected by filtration to give the object compound (37 mg).
MS (ESI+, m/e) 479 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (198 mg), (3R)-1-benzyl-3-[(2E)-3-phenyl-2-propen-1-yl]piperazine (184 mg), WSC.HCl (138 mg) and HOBt (97 mg) in DMF (4 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-20:0:1) was concentrated under reduced pressure to give (1S,2R)-2-[4-({(2R)-4-benzyl-2-[(2E)-3-phenyl-2-propen-1-yl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol (301 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (8.5 ml), 20% palladium hydroxide-carbon (50% containing water, 150 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (25:1) was concentrated under reduced pressure. The residue was diluted with diethyl ether (3 ml), and 4N hydrogen chloride-ethyl acetate solution (137 μl) was added thereto. The precipitated crystals were collected by filtration to give the object compound (175 mg).
MS (ESI+, m/e) 517 (M+1)
To tert-butyl (3R)-3-benzyl-4-({5-(3-fluorophenyl)-1-[cis-2-hydroxy-2-(methoxymethyl)cyclohexyl]-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (330 mg) was added TFA (3 ml), and the mixture was stirred at room temperature for 5 min, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fractions were collected, and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (103 mg).
MS (ESI+, m/e) 507 (M+1)
The fractions containing the other diastereomer obtained by the reversed-phase preparative HPLC in the above-mentioned Example 383 were collected, and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (109 mg).
MS (ESI+, m/e) 507 (M+1)
2-[4-({(2S)-4-Benzyl-2-[(benzyloxy)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol (530 mg) was dissolved in ethanol (15 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fractions were collected, and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, respectively. The organic layers were dried over anhydrous magnesium sulfate, and the solvents were evaporated under reduced pressure to give 2-[4-({(2S)-2-[(benzyloxy)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol (244 mg) and 2-(4-{[(2S)-2-(hydroxymethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (9 mg).
MS (ESI+, m/e) 519 (M+1)
MS (ESI+, m/e) 429 (M+1)
(1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(2-phenoxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (32 mg) was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 10 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (23 mg) as an amorphous solid.
MS (ESI+, m/e) 519 (M+1)
(the alternative synthetic method of the above-mentioned Example 386; The object compound was isolated as a dihydrochloride.)
1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (330 mg) was suspended in DMF (10 ml), benzyl (3R)-3-(2-phenoxyethyl)piperazine-1-carboxylate hydrochloride (377 mg), WSC.HCl (288 mg), HOBt (184 mg) and triethylamine (0.279 ml) were added thereto, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-phenoxyethyl)piperazine-1-carboxylate (452 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (50 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol, the solution was acidified with 4N hydrogen chloride-ethyl acetate solution, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to give the object compound (334 mg).
MS (ESI+, m/e) 519 (M+1)
Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[(1-oxidopyridin-3-yl)oxy]ethyl}piperazine-1-carboxylate (80 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the suspension was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (43 mg) as an amorphous solid.
MS (ESI+, m/e) 520 (M+1)
Benzyl (3R)-3-[2-(2-fluorophenoxy)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (205 mg) was dissolved in methanol (2 ml), 20% palladium hydroxide-carbon (50% containing water, 200 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 1 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (145 mg) as an amorphous solid.
MS (ESI+, m/e) 537 (M+1)
Benzyl (3R)-3-(2-{4-[(cyclopropylamino)carbonyl]phenoxy}ethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (98 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 20 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the suspension was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (60 mg) as an amorphous solid.
Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(1H-indazol-1-yl)ethyl]piperazine-1-carboxylate (140 mg) was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 70 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (71 mg) as an amorphous solid.
MS (ESI+, m/e) 543 (M+1)
In the same manner as in Example 391, the following compound (Example 392) was obtained.
MS (ESI+, m/e) 543 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (150 mg), benzyl (3R)-3-{2-[3-(cyclopent-1-en-1-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]ethyl}piperazine-1-carboxylate hydrochloride (230 mg), WSC.HCl (180 mg), HOBt (70 mg) and triethylamine (220 μl) in DMF (7 ml) was stirred at 50° C. for 4 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-9:0:1) was concentrated under reduced pressure to give benzyl (3R)-3-{2-[3-(cyclopent-1-en-1-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (122 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (4 ml), 20% palladium hydroxide-carbon (50% containing water, 20 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 16 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was diluted with saturated aqueous sodium hydrogen carbonate-saturated brine (1:1), and the mixture was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with 2N hydrogen chloride-ethyl acetate solution to give the object compound (44 mg).
MS (ESI+, m/e) 627 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (150 mg), benzyl (3R)-3-{2-[3-(cyclohex-1-en-1-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]ethyl}piperazine-1-carboxylate hydrochloride (237 mg), WSC.HCl (180 mg), HOBt (70 mg) and triethylamine (220 μl) in DMF (7 ml) was stirred at 50° C. for 4 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-9:0:1) was concentrated under reduced pressure to give benzyl (3R)-3-{2-[3-(cyclohex-1-en-1-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (146 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (4 ml), 20% palladium hydroxide-carbon (50% containing water, 20 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 16 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was diluted with saturated aqueous sodium hydrogen carbonate-saturated brine (1:1), and the mixture was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with 2N hydrogen chloride-ethyl acetate solution to give the object compound (60 mg).
MS (ESI+, m/e) 641 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (409 mg), benzyl (3R)-3-[2-(4-acetyl-1H-1,2,3-triazol-1-yl)ethyl]piperazine-1-carboxylate hydrochloride (512 mg), WSC HCl (475 mg), HOBt (190 mg) and triethylamine (520 μl) in DMF (8 ml) was stirred at room temperature for 14 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:9:0-17:0:3) was concentrated under reduced pressure to give benzyl (3R)-3-[2-(4-acetyl-1H-1,2,3-triazol-1-yl)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (616 mg) as an amorphous solid. The total amount thereof was dissolved in ethanol (6 ml), 4N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at 70° C. for 14 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-4:1) was concentrated under reduced pressure to give the object compound (16 mg).
MS (ESI+, m/e) 494 (M+1)
A solution of 1-[(1S,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (144 mg), (3R)-1-benzyl-3-[(E)-2-(2-fluorophenyl)vinyl]piperazine (158 mg), WSC.HCl (125 mg), HOBt (20 mg), N,N-diisopropylethylamine (181 μl) and DMAP (12 mg) in DMF (2 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give (1R,2S)-2-[4-({(2R)-4-benzyl-2-[(E)-2-(2-fluorophenyl)vinyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol (184 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (67 mg). (During the catalytic reduction, the racemization of the piperazine side chain proceeded together with the removal of the benzyl protecting group and the reduction of the unsaturated bond.)
MS (ESI+, m/e) 477 (M+1)
In the same manner as in Example 396, the following compounds (Examples 397-404) shown in Table 23 were obtained. (Each compound was isolated as a diastereomer mixture.)
In the same manner as in Example 396, the following compounds (Examples 405-412) shown in Table 24 were obtained. Each compound was isolated as a diastereomer by subjecting the diastereomer mixture to optical resolution by reversed-phase preparative HPLC (the purification conditions are described above). The final products were isolated as crystals or an amorphous solid in a free form or a hydrochloride by a known means such as phase transfer, liquid conversion, solvent extraction and the like. In the column of “Salt” in the Table, the compounds described as “-” were isolated as a free form.
A mixture of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (165 mg), (3R)-1-benzyl-3-[(E)-2-(pyridin-2-yl)vinyl]piperazine dihydrochloride (261 mg), WSC.HCl (192 mg), HOBt (306 mg), triethylamine (670 μl) and DMF (10 ml) was stirred at 60° C. for 5 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-7:0:3) was concentrated under reduced pressure to give (1S,2R)-2-[4-({4-benzyl-2-[(E)-2-(pyridin-2-yl)vinyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol (208 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (6 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (120 mg). (During the catalytic reduction, the racemization of the piperazine side chain and the reduction of the pyridine ring proceeded together with the removal of the benzyl protecting group and the reduction of the unsaturated bond.)
MS (ESI+, m/e) 510 (M+1)
(1R,2S)-2-[4-({(2R)-4-Benzyl-2-[(E)-2-cyclopropylvinyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol (100 mg) was dissolved in methanol (3 ml), 20% palladium hydroxide-carbon (50% containing water, 30 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, the suspension was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure. The residue was vacuum-dried to give the object compound (25 mg) as an amorphous solid. (During the catalytic reduction, the ring-opening of the cyclopropyl group and the racemization of the piperazine side chain proceeded together with the removal of the benzyl protecting group and the reduction of the unsaturated bond.)
MS (ESI+, m/e) 425 (M+1)
(1S,2R)-2-{4-[((2R)-2-{(2RS)-2-Hydroxy-2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol trihydrochloride (1:1 mixture of the compounds of Example 199 and 200, 104 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was treated with 4N hydrogen chloride-ethyl acetate solution to give the object compound (103 mg). (The hydroxyl group was not removed, and the reduction of the pyridine ring alone proceeded.)
MS (ESI+, m/e) 593 (M+1)
Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1-carboxylate (486 mg) was dissolved in ethanol (8 ml), 4N aqueous sodium hydroxide solution (4 ml) was added, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, the residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fraction was concentrated under reduced pressure to give the object compound (237 mg).
MS (ESI+, m/e) 563 (M+1)
In the same manner as in Example 416, the following compounds (Examples 417-418) were obtained.
MS (ESI+, m/e) 563 (M+1)
MS (ESI+, m/e) 563 (M+1)
In the same manner as in Example 416 except that the final product was isolated as a dihydrochloride by a known operation such as phase transfer, liquid conversion, solvent extraction and the like, the following compound (Example 419) was obtained.
MS (ESI+, m/e) 536 (M+1)
A mixture of methyl 6-{[(2S)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methoxy}nicotinate trihydrochloride (the compound of Example 198, 220 mg), lithium hydroxide monohydrate (140 mg), methanol (3 ml) and water (3 ml) was stirred at room temperature for 3 days, and methanol was evaporated under reduced pressure. The residual aqueous solution was adjusted with 1N hydrochloric acid to pH 6-8. The solution was subjected to DIAION HP-20 (manufactured by Mitsubishi Chemical), and washed with water. The fraction eluted with acetone was concentrated under reduced pressure to about ⅓ volume, and the resulting crystals were collected by filtration to give the object compound (147 mg).
MS (ESI+, m/e) 550 (M+1)
Methyl (4-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)acetate (the compound of Example 261) (125 mg) was dissolved in methanol (3 ml), potassium hydroxide (36 mg) was added, and the mixture was stirred at 65° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with 1N hydrochloric acid. The mixture was again concentrated under reduced pressure, and the residue was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (62 mg) as an amorphous solid.
MS (ESI+, m/e) 577 (M+1)
Benzyl (3R)-3-{2-[4-(4-acetylpiperazin-1-yl)phenoxy]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (120 mg) was dissolved in ethanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred 65° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, and the liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-10:0:1) was concentrated under reduced pressure to give the object compound (80 mg) as an amorphous solid.
MS (ESI+, m/e) 603 (M+1)
Benzyl (3R)-3-[2-(4-cyano-2-methoxyphenoxy)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (25 mg) was dissolved in ethanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added thereto, and the mixture was stirred at 65° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was treated with 4N hydrogen chloride-ethyl acetate solution to give the object compound (3 mg).
MS (ESI+, m/e) 592 (M+1)
1-(2-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)ethanone (the compound of Example 240, 105 mg) was dissolved in methanol (5 ml), and the solution was ice-cooled. Sodium borohydride (11 mg) was added, and the mixture was stirred at 0° C. for 5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (63 mg).
MS (ESI+, m/e) 563 (M+1)
1-(3-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)ethanone (the compound of Example 233) (50 mg) was dissolved in methanol (10 ml), and the solution was ice-cooled. Sodium borohydride (4 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the object fraction was concentrated under reduced pressure to give the object compound (14 mg) as an amorphous solid.
MS (ESI+, m/e) 563 (M+1)
1-(4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)ethanone (the compound of Example 231) (50 mg) was dissolved in methanol (10 ml), and the solution was ice-cooled. Sodium borohydride (4 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the object fraction was concentrated under reduced pressure to give the object compound (13 mg) as an amorphous solid.
MS (ESI+, m/e) 563 (M+1)
In the same manner as in Example 3 (Method C), the following compound (Example 427) was obtained.
MS (ESI+, m/e) 503 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (650 mg), benzyl (3R)-3-(2-anilinoethyl)piperazine-1-carboxylate (800 mg), WSC.HCl (566 mg) and HOBt (360 mg) in DMF (10 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give benzyl (3R)-3-(2-anilinoethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (850 mg) as an amorphous solid. 120 mg therefrom was dissolved in methanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added thereto, and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water, and the suspension was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:2) was concentrated under reduced pressure to give the object compound (50 mg) as an amorphous solid.
MS (ESI+, m/e) 518 (M+1)
A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (165 mg), benzyl (3R)-3-{2-[methyl(phenyl)amino]ethyl}piperazine-1-carboxylate (195 mg), WSC.HCl (144 mg) and HOBt (92 mg) in DMF (10 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[methyl(phenyl)amino]ethyl}piperazine-1-carboxylate (180 mg) as an amorphous solid. 160 mg therefrom was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 80 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 1 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:2) was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was acidified with 4N hydrogen chloride-ethyl acetate solution, and concentrated under reduced pressure to give the object compound (130 mg) as an amorphous solid.
MS (ESI+, m/e) 532 (M+1)
In the same manner as in the above-mentioned Example 1 (Method A)-Example 15 (Method O), the following compounds (Examples 430-567) shown in Table 25-1-Table 25-2, Table 26, Table 27-1-Table 27-2 and Table 28-1-Table 28-8 were obtained. Where necessary, each compound was isolated and purified by a known means such as phase transfer, liquid conversion, solvent extraction, silica gel column chromatography, reversed-phase preparative HPLC and the like. The final products were isolated as a hydrochloride by a treatment with 4N hydrogen chloride-ethyl acetate solution, as in Method A and the like, or isolated as crystals or an amorphous solid in a free from, as in Method B and the like. In the column of “Salt” in the Tables, the compounds described as “-” were isolated as a free form.
The chemical names of the compounds (Examples 430-567) shown in Table 25-1-Table 25-2, Table 26, Table 27-1-Table 27-2 and Table 28-1-Table 28-8 are as follows.
In the same manner as in Example 1 (Method A) except that the treatment of the final product with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compound (Example 568) was obtained as a free amorphous solid.
MS (ESI+, m/e) 503 (M+1)
In the same manner as in Example 6 (Method F), the following compounds (Examples 569-572) were obtained. The compound of Example 572 was isolated as a 2 TFA salt by subjecting the final product to reversed-phase preparative HPLC (the purification conditions are described above), and directly concentrating the object fraction under reduced pressure.
MS (ESI+, m/e) 527 (M+1)
MS (ESI+, m/e) 536 (M+1)
MS (ESI+, m/e) 536 (M+1)
MS (ESI+, m/e) 581 (M+1)
A mixture of ethyl 1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazole-4-carboxylate (100 mg), lithium hydroxide monohydrate (20 mg), ethanol (3 ml) and water (1 ml) was stirred at 80° C. for 3 hr, and concentrated under reduced pressure. The residue was mixed with benzyl (3R)-3-(2-anilinoethyl)piperazine-1-carboxylate (109 mg), WSC.HCl (115 mg), HOBt (230 mg) and DMF (4 ml). The mixture was stirred at 50° C. for 5 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:9:0-17:0:3) was concentrated under reduced pressure to give benzyl (3R)-3-(2-anilinoethyl)-4-({1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (116 mg) as an amorphous solid. The total amount thereof was dissolved in ethanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at 65° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (55 mg) as an amorphous solid.
MS (ESI+, m/e) 488 (M+1)
Methyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(2-bromobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (671 mg) was dissolved in 1,2-dichloroethane (15 ml), 1-chloroethyl chloroformate (715 mg) was added, and the mixture was heated under reflux for 8 hr, and concentrated under reduced pressure. To the residue was added methanol (15 ml), and the mixture was further heated under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, to the residue saturated was added aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (204 mg) as an amorphous solid.
MS (ESI+, m/e) 580 (M+1)
In the same manner as in Example 574, the following compound (Example 575) was obtained.
MS (ESI+, m/e) 567 (M+1)
In the same manner as in Example 382 except that the treatment of the final product with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compound (Example 576) was obtained as an amorphous solid.
MS (ESI+, m/e) 530 (M+1)
Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[methyl(phenyl)amino]ethyl}piperazine-1-carboxylate obtained in the course of Example 429 (150 mg) was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 70 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:2) was concentrated under reduced pressure to give the object compound (75 mg) as an amorphous solid.
MS (ESI+, m/e) 538 (M+1)
In the same manner as in Example 416, the following compounds (Examples 578-580) were obtained. The compounds of Examples 579-580 were isolated as free amorphous solids by extracting the final product with ethyl acetate and subjecting the extract to basic silica gel column chromatography.
MS (ESI+, m/e) 562 (M+1)
MS (ESI+, m/e) 589 (M+1)
MS (ESI+, m/e) 589 (M+1)
tert-Butyl (2R)-4-benzyl-2-(2-(pyridin-2-yl)benzyl)piperazine-1-carboxylate (140 mg) was dissolved in ethyl acetate (1 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in toluene (1 ml), and the suspension was again concentrated under reduced pressure. The residue was suspended in DMF (2 ml), 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (96 mg), WSC.HCl (83 mg), HOBt (67 mg), triethylamine (187 mg) were added, and the suspension was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give (1S,2R)-2-[4-({(2R)-4-benzyl-2-[2-(6-chloropyridin-2-yl)benzyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol (115 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (3 ml), 20% palladium hydroxide-carbon (50% containing water, 60 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 6 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (67 mg). (During the catalytic reduction, the removal of the chlorine atom proceeded together with the removal of the benzyl protecting group.)
MS (ESI+, m/e) 566 (M+1)
Benzyl (3R)-3-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazine-1-carboxylate (200 mg) was dissolved in DMF (30 ml), 1-{(1S,2S)-2-[(methoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylic acid (168 mg), WSC.HCl (142 mg), HOBt (93 mg) and N,N-diisopropylethylamine (253 μl) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give benzyl (3R)-4-[(1-{(1S,2S)-2-[(methoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]-3-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazine-1-carboxylate (100 mg) as an amorphous solid. The total amount thereof was dissolved in 25% hydrogen bromide-acetic acid solution (2 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the mixture was washed with ethyl acetate. To the aqueous layer was added potassium carbonate by small portions to basify the layer, and the mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (11 mg) as an amorphous solid.
MS (ESI+, m/e) 545 (M+1)
(1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol obtained in the course of Example 367 (489 mg) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (149 mg) were dissolved in DMF (5 ml), potassium hydrogen carbonate (150 mg) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (7:3) was concentrated under reduced pressure to give the object compound (28 mg) as an amorphous solid.
MS (ESI+, m/e) 601 (M+1)
1-(4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)pyrrolidin-2-one (the compound of Example 294) (105 mg) and potassium hydrogen carbonate were suspended in DMF (3 ml). A solution of 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (37 mg) in DMF (2 ml) which was cooled to 0° C. was added dropwise thereto, and the mixture was stirred at 0° C. for 1 hr, and then at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (7:3) was concentrated under reduced pressure to give the object compound (71 mg) as an amorphous solid.
MS (ESI+, m/e) 714 (M+1)
In the same manner as in Example 1 (Method A) except that the treatment of the final product with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compounds (Examples 585-588) were obtained as a free amorphous solid.
MS (ESI+, m/e) 532 (M+1)
MS (ESI+, m/e) 532 (M+1)
MS (ESI+, m/e) 575 (M+1)
MS (ESI+, m/e) 575 (M+1)
In the same manner as in Example 9 (Method I) except that the treatment of the final product (excluding Example 595) with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compounds (Examples 589-594) were obtained as a free amorphous solid.
MS (ESI+, m/e) 561 (M+1)
MS (ESI+, m/e) 536 (M+1)
MS (ESI+, m/e) 579 (M+1)
MS (ESI+, m/e) 574 (M+1)
MS (ESI+, m/e) 584 (M+1)
MS (ESI+, m/e) 536 (M+1)
In the same manner as in Example 8 (Method H), the following compound (Example 595) was obtained.
MS (ESI+, m/e) 563 (M+1)
In the same manner as in Example 10 (Method J) except that the treatment of the final product with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compound (Examples 596) was obtained as a free amorphous solid.
After the reaction by Method J, the residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (100:0-80:20) was concentrated under reduced pressure to give [2-({2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}thio)-1,3-thiazol-4-yl]methyl acetate (113 mg, MS (ESI+, m/e) 614 (M+1)) as a component having a short retention time, and (1S,2R)-2-(4-{[(2R)-2-(2-{[4-(hydroxymethyl)-1,3-thiazol-2-yl]thio}ethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (20 mg, MS (ESI+, m/e) 570 (M+1)) as a component having a long retention time.
The following compounds of Examples 597-644 can be synthesized according to the above-mentioned methods.
(1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol fumarate (50 mg) was dissolved in methanol (1.5 ml) at 60° C., ethyl acetate (15 ml) was added, and the mixture was cooled to 0° C. The precipitated crystals were collected by filtration to give the object compound (41 mg).
(1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-{2-[(5-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol (3.75 g) and fumaric acid (736 mg) were dissolved in ethanol (100 ml) while heating (60° C.), and the solvent (about 50 ml) was evaporated under reduced pressure. To the residue was added acetonitrile (150 ml), and the solvent (about 100 ml) was evaporated under reduced pressure. The residue was left to stand at room temperature for 1 hr, and the crystals were collected by filtration, washed with a small amount of acetonitrile, and dried under reduced pressure to give the object compound (3.5 g) as crystals.
melting point: 157-158° C.
Methyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (900 mg) and succinic acid (197 mg) were dissolved in ethanol (20 ml) while heating (60° C.), and the solvent was evaporated under reduced pressure. To the residue were added acetonitrile (20 ml) and ethyl acetate (30 ml), and the mixture was stirred at room temperature for 12 hr. The crystals were collected by filtration, washed with a small amount of acetonitrile, and dried under reduced pressure to give the object compound (800 mg) as crystals.
melting point: 157-176° C.
Ethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (36 g) and malonic acid (6.45 g) were dissolved in ethanol (500 ml) while heating (80° C.), and the solvent was evaporated under reduced pressure. To the residue were added ethanol (300 ml) and water (30 ml), and the mixture was heated (80° C.). Ethyl acetate (300 ml) was added, and the mixture was stirred at room temperature for 12 hr. The crystals were collected by filtration, washed with a small amount of ethyl acetate, and dried under reduced pressure to give the object compound as crystals (25.2 g).
melting point: 166-167° C.
(1S,2S)-2-(4-{[(2R)-4-Benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine (171 mg) and DMAP (44 mg) were dissolved in THF (3 ml), propyl chlorocarbonate (39 mg) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give propyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (182 mg). The obtained propyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (182 mg) was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water) (20 mg) was added, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (94 mg).
MS (ESI+, m/e) 566 (M+1)
In the same manner as in Example 649, the following compounds (Examples 650-654) were obtained.
MS (ESI+, m/e) 551 (M+1)
MS (ESI+, m/e) 536 (M+1)
MS (ESI+, m/e) 582 (M+1)
MS (ESI+, m/e) 580 (M+1)
MS (ESI+, m/e) 566 (M+1)
(1S,2S)-2-(4-{[(2R)-4-Benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine (171 mg) and triethylamine (0.209 ml) were dissolved in THF (3 ml), 2-fluoroethyl chlorocarbonate (0.057 ml) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give 2-fluoroethyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (113 mg). The obtained 2-fluoroethyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (113 mg) was dissolved in THF (5 ml), 20% palladium hydroxide-carbon (50% containing water) (20 mg) was added, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (91 mg).
MS (ESI+, m/e) 570 (M+1)
In the same manner as in Example 655, the following compounds (Examples 656-659) were obtained.
MS (ESI+, m/e) 558 (M+1)
MS (ESI+, m/e) 587 (M+1)
MS (ESI+, m/e) 586 (M+1)
MS (ESI+, m/e) 572 (M+1)
(1S,2S)-2-(4-{[(2R)-4-Benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine (171 mg) and DMAP (110 mg) were dissolved in THF (5 ml), and the solution was ice-cooled. 4-Nitrophenyl chloroformate (91 mg) was added, and the mixture was stirred at 0° C. for 1 hr, and then at room temperature for 2 hr. To the reaction mixture was added cyclopropylmethanol (0.791 ml), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give cyclopropylmethyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (130 mg) as an amorphous solid. The obtained cyclopropylmethyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (130 mg) was dissolved in THF (5 ml), 20% palladium hydroxide-carbon (50% containing water) (20 mg) was added, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (88 mg).
MS (ESI+, m/e) 578 (M+1)
In the same manner as in Example 660, the following compounds (Examples 661-663) were obtained.
MS (ESI+, m/e) 579 (M+1)
MS (ESI+, m/e) 588 (M+1)
MS (ESI+, m/e) 578 (M+1)
In the same manner as in Example 1 (Method A) except that the treatment of the final compound with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compounds (Examples 664-676) were obtained by isolating as a free amorphous solid.
MS (ESI+, m/e) 576 (M+1)
MS (ESI+, m/e) 576 (M+1)
MS (ESI+, m/e) 615 (M+1)
MS (ESI+, m/e) 615 (M+1)
MS (ESI+, m/e) 603 (M+1)
MS (ESI+, m/e) 603 (M+1)
MS (ESI+, m/e) 589 (M+1)
MS (ESI+, m/e) 589 (M+1)
MS (ESI+, m/e) 575 (M+1)
MS (ESI+, m/e) 532 (M+1)
MS (ESI+, m/e) 529 (M+1)
MS (ESI+, m/e) 607 (M+1)
MS (ESI+, m/e) 619 (M+1)
In the same manner as in Example 3 (Method C) except that the treatment of the final compound with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compounds (Examples 677-682) were obtained by isolating as a free amorphous solid.
MS (ESI+, m/e) 524 (M+1)
MS (ESI+, m/e) 567 (M+1)
MS (ESI+, m/e) 565 (M+1)
MS (ESI+, m/e) 539 (M+1)
MS (ESI+, m/e) 539 (M+1)
MS (ESI+, m/e) 503 (M+1)
In the same manner as in Example 6 (Method F), the following compound (Example 683) was obtained.
MS (ESI+, m/e) 580 (M+1)
In the same manner as in Example 11 (Method K), the following compounds (Examples 684-692) were obtained.
MS (ESI+, m/e) 593 (M+1)
MS (ESI+, m/e) 566 (M+1)
MS (ESI+, m/e) 594 (M+1)
MS (ESI+, m/e) 598 (M+1)
MS (ESI+, m/e) 614 (M+1)
MS (ESI+, m/e) 580 (M+1)
MS (ESI+, m/e) 588 (M+1)
MS (ESI+, m/e) 618 (M+1)
MS (ESI+, m/e) 604 (M+1)
In the same manner as in Example 9 (Method I), the following compounds (Examples 693-762) were obtained.
MS (ESI+, m/e) 607 (M+1)
MS (ESI+, m/e) 593 (M+1)
MS (ESI+, m/e) 588 (M+1)
MS (ESI+, m/e) 588 (M+1)
MS (ESI+, m/e) 590 (M+1)
MS (ESI+, m/e) 576 (M+1)
MS (ESI+, m/e) 595 (M+1)
MS (ESI+, m/e) 611 (M+1)
MS (ESI+, m/e) 611 (M+1)
MS (ESI+, m/e) 600 (M+1)
MS (ESI+, m/e) 627 (M+1)
MS (ESI+, m/e) 615 (M+1)
MS (ESI+, m/e) 601 (M+1)
MS (ESI+, m/e) 615 (M+1)
MS (ESI+, m/e) 601 (M+1)
MS (ESI+, m/e) 587 (M+1)
MS (ESI+, m/e) 588 (M+1)
MS (ESI+, m/e) 588 (M+1)
MS (ESI+, m/e) 574 (M+1)
MS (ESI+, m/e) 688 (M+1)
MS (ESI+, m/e) 618 (M+1)
MS (ESI+, m/e) 568 (M+1)
MS (ESI+, m/e) 646 (M+1)
MS (ESI+, m/e) 588 (M+1)
MS (ESI+, m/e) 560 (M+1)
MS (ESI+, m/e) 574 (M+1)
MS (ESI+, m/e) 602 (M+1)
MS (ESI+, m/e) 588 (M+1)
MS (ESI+, m/e) 544 (M+1)
MS (ESI+, m/e) 601 (M+1)
MS (ESI+, m/e) 580 (M+1)
MS (ESI+, m/e) 602 (M+1)
MS (ESI+, m/e) 566 (M+1)
MS (ESI+, m/e) 626 (M+1)
MS (ESI+, m/e) 590 (M+1)
MS (ESI+, m/e) 571 (M+1)
MS (ESI+, m/e) 542 (M+1)
MS (ESI+, m/e) 563 (M+1)
MS (ESI+, m/e) 576 (M+1)
MS (ESI+, m/e) 590 (M+1)
MS (ESI+, m/e) 560 (M+1)
MS (ESI+, m/e) 596 (M+1)
MS (ESI+, m/e) 546 (M+1)
MS (ESI+, m/e) 582 (M+1)
MS (ESI+, m/e) 572 (M+1)
MS (ESI+, m/e) 559 (M+1)
MS (ESI+, m/e) 568 (M+1)
MS (ESI+, m/e) 555 (M+1)
MS (ESI+, m/e) 660 (M+1)
MS (ESI+, m/e) 655 (M+1)
MS (ESI+, m/e) 670 (M+1)
MS (ESI+, m/e) 600 (M+1)
MS (ESI+, m/e) 540 (M+1)
MS (ESI+, m/e) 554 (M+1)
MS (ESI+, m/e) 597 (M+1)
MS (ESI+, m/e) 553 (M+1)
MS (ESI+, m/e) 579 (M+1)
MS (ESI+, m/e) 586 (M+1)
MS (ESI+, m/e) 598 (M+1)
MS (ESI+, m/e) 598 (M+1)
MS (ESI+, m/e) 546 (M+1)
MS (ESI+, m/e) 550 (M+1)
MS (ESI+, m/e) 598 (M+1)
MS (ESI+, m/e) 590 (M+1)
MS (ESI+, m/e) 578 (M+1)
MS (ESI+, m/e) 586 (M+1)
MS (ESI+, m/e) 571 (M+1)
MS (ESI+, m/e) 580 (M+1)
MS (ESI+, m/e) 579 (M+1)
MS (ESI+, m/e) 597 (M+1)
In the same manner as in Example 9 (Method I) except that the treatment of the final compound with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compounds (Examples 763-766) were obtained by isolating as a free amorphous solid.
MS (ESI+, m/e) 588 (M+1)
MS (ESI+, m/e) 600 (M+1)
MS (ESI+, m/e) 588 (M+1)
MS (ESI+, m/e) 588 (M+1)
10.0 g of the compound of Example 1 and 3.0 g of magnesium stearate are granulated with 70 ml of an aqueous solution of soluble starch (7.0 g as soluble starch), then and the mixture is dried and mixed with 70.0 g of lactose and 50.0 g of corn starch (any of lactose, corn starch, soluble starch and magnesium stearate is products in conformity to the 14th revision of the Japanese Pharmacopoeia). The mixture is compressed to give tablets.
Human renin was obtained by expressing preprorenin (1-406) in an animal cell, treating the prorenin (24-406) contained in the culture supernatant with trypsin, and taking the active type (67-406).
A plasmid DNA to express human renin in HEK293 cells was prepared as follows. PCR was carried out using human renal cDNA (Clontech Laboratories, Inc., Marathon Ready cDNA) as the template and using two synthetic DNAs (5′-AAGCTTATGGATGGATGGAGA-3′; SEQ ID No.1, and 5′-GGATCCTCAGCGGGCCAAGGC-3′; SEQ ID No.2), and the obtained fragments were cloned using a TOPO TA Cloning Kit (Invitrogen Corp.). The obtained fragments were subcloned into pcDNA3.1(+) that had been cleaved by HindIII and BamHI, thus to obtain a plasmid DNA for human preprorenin expression (pcDNA3.1(+)/hREN).
A plasmid DNA to express human angiotensinogen in HEK293 cells was prepared as follows. PCR was carried out using human liver cDNA (Clontech Laboratories, Inc., Marathon Ready cDNA) as the template and using two synthetic DNAs (5′-AAGCTTATGCGGAAGCGAGCACCCCAGTCT-3′; SEQ ID No.3, and 5′-GGATCCTCACTTGTCATCGTCGTCCTTGTAGTCTGCTGTGCTCAGCGGGTTGGCCACGC-3′; SEQ ID No.4), and the obtained fragments were cloned using a TOPO TA Cloning Kit (Invitrogen Corp.). The obtained fragments were subcloned into pcDNA3.1(+) that had been cleaved by HindIII and BamHI, thereby to give a plasmid DNA for expression of human angiotensinogen having a FLAGtag on the C-terminal (pcDNA3.1(+)/hAngiotensinogen-FLAG). Then, PCR was carried out using the pcDNA3.1(+)/hAngiotensinogen-FLAG as the template and using two synthetic DNAs (5′-CCTTAAGCTTCCACCATGCGGAAGCGAGCACCCCAGTCT-3′; SEQ ID No.5, and 5′-TTGGATCCTCATGCTGTGCTCAGCGGGTTGGCCACGCGG-3′; SEQ ID No.6), and the obtained fragments were cloned using a TOPO TA Cloning Kit (Invitrogen Corp.). The obtained fragments were subcloned into pcDNA3.1(+) that had been cleaved by HindIII and BamHI, thus to obtain a plasmid DNA for human angiotensinogen expression (pcDNA3.1(+)/hAngiotensinogen).
Expression of human preprorenin was conducted using FreeStyle 293 Expression System (Invitrogen Corp.). According to the manual accompanying the FreeStyle 293 Expression System, the plasmid DNA for human preprorenin expression (pcDNA3.1(+)/hREN) constructed in the above-mentioned (1) was used to conduct transient expression by FreeStyle 293-F cells. After transfection of the plasmid DNA, the cells were subjected to shaking culture under the conditions of 37° C., 8% CO2 and 125 rpm for 3 days. A 600-ml aliquot of the culture solution was centrifuged at 2,000 rpm for 10 min to recover the culture supernatant containing prorenin (24-406). The culture supernatant was concentrated by ultrafiltration using a PM10 membrane (Millipore, Inc.) to a volume of about 50 ml, and then was dialyzed against 20 mM Tris-hydrochloric acid (pH 8.0). The dialyzate was fed to a 6-ml RESOURCE Q column (GE Healthcare) equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) at a flow rate of 3 ml/min to adsorb the prorenin (24-406). After washing the column with the buffer solution used in the equilibration, elution was carried out by means of a linear concentration gradient of sodium chloride from 0 M to 0.4 M. The fraction containing prorenin (24-406) was collected and concentrated using Vivaspin 20 (molecular weight cut off 10,000; Vivascience, Inc.) to a volume of about 2 ml.
The concentrated liquid was subjected to gel filtration chromatography using HiLoad 16/60 Superdex 200 pg (GE Healthcare) equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) containing 0.15 M sodium chloride, at a flow rate of 1.4 ml/min, thus to obtain 3.6 mg of purified prorenin (24-406).
To 3.6 mg of prorenin (24-406) dissolved in 5.2 ml of 0.1 M Tris-hydrochloric acid (pH 8.0), 12 μg of trypsin (Roche Diagnostics Corp.) was added, and the mixture was allowed to react at 28° C. for 55 min to carry out activation of renin. After the reaction, 0.4 ml of immobilized trypsin inhibitor (Pierce Biotechnology, Inc.) was added to remove the trypsin used in the activation by adsorption. The reaction liquid containing the active type renin was concentrated using Vivaspin 20 (molecular weight cut off 10,000, Vivascience, Inc.), and was diluted with 20 mM Tris-hydrochloric acid (pH 8.0). The diluted liquid was fed to a TSKgel DEAE-5PW column (7.5 mm I.D.×75 mm, Tosoh Corp.) equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) at a flow rate of 1 ml/min to adsorb the active type renin (67-406). The column was washed with the buffer solution used for the equilibration, and then elution was carried out by means of a sodium chloride linear concentration gradient from 0 M to 0.3 M, thus to obtain 1.5 mg of a purified product of active type renin (67-406).
Expression of human angiotensinogen was conducted using FreeStyle 293 Expression System (Invitrogen Corp.). According to the manual accompanying the FreeStyle 293 Expression System, the plasmid DNA for human angiotensinogen expression (pcDNA3.1(+)/hAngiotensinogen) constructed in the above-mentioned (2) was used to conduct transient expression by FreeStyle 293-F cells. After transfection of the plasmid DNA, the cells were subjected to shaking culture under the conditions of 37° C., 8% CO2 and 125 rpm for 3 days. A 600-ml aliquot of the culture solution was centrifuged at 2,000 rpm for 10 min to recover the culture supernatant containing angiotensinogen. To the culture supernatant was added ammonium sulfate (30% saturated concentration), and the mixture was thoroughly stirred and centrifuged at 8,000 rpm for 20 min. The obtained supernatant was added to TOYO Pearl butyl 650M (2×5 cm, Tosoh Corporation) equilibrated with 50 mM tris-hydrochloric acid (pH 8.0) containing 30% saturated ammonium sulfate, at a flow rate of 25 ml/min to allow adsorption. After washing with equilibration buffer, angiotensinogen was eluted by linear concentration gradient from the buffer used for equilibration to 20 mM tris-hydrochloric acid (pH 8.0). The eluate containing angiotensinogen was applied to repeated concentration and dilution using Vivaspin 20 (molecular weight cut off 10,000, Vivascience, Inc.), and the buffer was changed to 20 mM tris-hydrochloric acid (pH 8.0). The eluate was fed to a 6-ml RESOURCE Q column (Amersham Biosciences, Inc.) equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) containing 50 mM sodium chloride at a flow rate of 6 ml/min to adsorb the angiotensinogen. After washing the column with the buffer solution used in the equilibration, elution was carried out by means of a linear concentration gradient of sodium chloride from 50 mM to 400 mM. The fractions containing angiotensinogen were collected and concentrated using Vivaspin 20 (molecular weight cut off 10,000, Vivascience, Inc.) to a volume of about 2 ml. The concentrated liquid was subjected to gel filtration chromatography using HiLoad 26/60 Superdex 200 pg (GE Healthcare) equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) containing 0.15 M sodium chloride, at a flow rate of 2.0 ml/min, thus to obtain 7.0 mg of purified angiotensinogen.
As a substrate for renin activity measurement, a substrate peptide (FITC-Acp-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Gln-Arg-NH2; SEQ ID No.8) wherein the N-terminal of a peptide prepared in reference to a partial sequence (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn-Glu-NH2; SEQ ID No.7) of human angiotensinogen was bound with epsilon aminocaproic acid (Acp) as a linker and labeled with a fluorescence reagent Fluorescein isothiocyanate (FITC). 2 μl each of the test compound (containing 100% DMSO) was added to each well of a 384-well black plate (Nalge Nunc International Co., Ltd.). Renin was diluted with a buffer solution for reaction (20 mM citric acid-sodium citrate (pH 6.0)) to a concentration of 4.7 nM, and 30 μl each of the dilution was added to each well. The dilution was left to stand at 37° C. for 10 min, and then 8 μl of each of a 25 μM solution of substrate peptide was added to each well to initiate the reaction. The reaction mixture was left to stand at 37° C. for 30 min, and then 40 μl each of a reaction terminating solution [200 mM Tris-hydrochloric acid (pH 8.0), 0.04% Triton-X 100, 0.4% Coating 3 reagent (Caliper Life Sciences Corp.) and 1 μM CGP-29287 (Bachem Holding AG)] was added to each well to terminate the reaction.
The substrate peptide and the product peptide were separated by a microchip type capillary electrophoresis system 250HTS (Caliper Life Sciences Co., Ltd.), and the rate of reaction [(peak height of product)/(peak height of product+peak height of substrate)×100(%)] was calculated from the ratio of the respective peak height of the peptides obtained by fluorimetric detection (excitation wavelength 457 nm, measurement wavelength 530 nm), and was used as an index of the renin activity.
While the reaction rate of the well where 100% DMSO only was added was taken as 0% inhibition rate, and the reaction rate of the well where 10 μM of CGP-29287 was added was taken as 100% inhibition rate, the renin inhibitory activity of the wells where the test compound (containing 100% DMSO) was added was calculated.
The results are presented in Table 29.
It can be seen from the results of Table 29 that compound (I) of the present invention has a superior renin inhibitory activity as evidenced by an IC50 value of 1 μM or less.
As a substrate for renin activity measurement, the angiotensinogen mentioned in (5) above was used. 1 μl each of the test compound (containing 100% DMSO) was added to each well of a 384-well plate (ABgene). Renin was diluted with a buffer solution for reaction (20 mM sodium phosphate (pH 7.4)) to a concentration of 57 pM, and 14 μl each of the dilution was added to each well. The dilution was left to stand at 37° C. for 10 min, and then 5 μl of each of a 6 μM solution of substrate angiotensinogen was added to each well to initiate the reaction. The reaction mixture was left to stand at 37° C. for 30 min, and then 20 μl each of a reaction terminating solution [20 mM Tris-hydrochloric acid (pH 7.4), 150 mM sodium chloride, 0.1% BSA, 0.05% Tween 20 and 1 μM CGP-29287] was added to each well to terminate the reaction, thus an enzyme reaction solution was obtained. The amount of angiotensin I produced by an enzyme reaction was quantified by Enzyme Immuno Assay (EIA) described below.
Anti-angiotensin I antibody (Peninsula Laboratories Inc.) diluted 5,000-fold with PBS was added to each well of a 384 well black plate (Nalge Nunc International Co., Ltd.) by 25 μl, and left standing overnight at 4° C. to immobilize the antibody in the plate. The antibody solution was removed, PBS solution (100 μl) containing 1% BSA was added to each well, and the mixture was left standing at room temperature for 2 hr for blocking. The blocking solution was removed, and each well was washed 5 times with 100 μl of 0.05% Tween20-PBS. An angiotensin I standard solution (Wako Pure Chemical Industries, Ltd.) prepared to 0.156-10 nM with an enzyme reaction solution or buffer [20 mM tris-hydrochloric acid (pH 7.4), 150 mM sodium chloride, 0.1% BSA, 0.05% Tween20] was dispensed to each well by 10 μl. Then, a biotinated angiotensin I solution (AnaSpec, 15 μl) prepared to 1.6 nM with a buffer [20 mM tris-hydrochloric acid (pH 7.4), 150 mM sodium chloride, 0.01% BSA, 0.05% Tween20] was added to each well, mixed with a plate mixer and left standing at room temperature for 1 hr. The solutions were removed from each well, and each well was washed 5 times with 100 μl of 0.05% Tween20-PBS. Horseradish peroxydase Streptavidin (PIERCE Biotechnology inc., 25 μl) diluted to 100 ng/ml with a buffer [20 mM tris-hydrochloric acid (pH 7.4), 150 mM sodium chloride, 0.1% BSA, 0.05% Tween 20] was added to each well and the mixture was left standing at room temperature for 30 min. The solutions were removed from each well, and each well was washed 5 times with 100 μl of 0.05% Tween20-PBS. SuperSignal ELISA femto Maximum Sensitivity Substrate (PIERCE Biotechnology Inc.) was added by 25 μl and luminescence intensity was measured by EnVision (Perkin Elmer Inc.). An analytical curve was drawn from the luminescence intensity of a well containing an angiotensin I standard solution, and the amount of angiotensin I produced by an enzyme reaction was calculated and used as an index of renin activity.
While the reaction rate of the well where 100% DMSO only was added was taken as 0% inhibition rate, and the reaction rate of the well where angiotensin I was not contained was taken as 100% inhibition rate, the renin inhibitory activity of the wells where the test compound (containing 100% DMSO) was added was calculated.
Example compounds 1-367, 369-429 were measured by the method of the above-mentioned (6) or (7). As a result, all compounds showed a renin inhibitory activity of 30% or above at a concentration of 1 μM.
Example compounds 430-596, 645-766 were measured by the method of the above-mentioned (7). As a result, all compounds showed a renin inhibitory activity of 25% or above at a concentration of 0.1 μM.
It is clear therefrom that compound (I) of the present invention has a superior renin inhibitory activity.
Sequence listing free text
[SEQ ID NO: 1] primer
[SEQ ID NO: 2] primer
[SEQ ID NO: 3] primer
[SEQ ID NO: 4] primer
[SEQ ID NO: 5] primer
[SEQ ID NO: 6] primer
[SEQ ID NO: 7] partial sequence of human angiotensinogen
[SEQ ID NO: 8] substrate peptide of renin
Compound (I) has superior renin inhibitory activity and thus is useful as an agent for the prophylaxis or treatment of hypertension, various organ damages attributable to hypertension, and the like.
This application is based on patent application Nos. 120292/2007 and 207271/2007 filed in Japan, the contents of which are hereby incorporated by reference.
| Number | Date | Country | Kind |
|---|---|---|---|
| 120292/2007 | Apr 2007 | JP | national |
| 207271/2007 | Aug 2007 | JP | national |
