Patent Grant
8884062
This invention relates to a compound having an inhibitory activity against production of amyloid β protein and useful for treating diseases induced by production, secretion and/or deposition of amyloid β protein.
In the brain of Alzheimer's patient many insoluble spots (senile plaque) are found, which is formed by extraneuronal accumulation of a peptide called amyloid β protein comprised of about 40 amino acids. Neuronal death caused by the senile plaque is considered to develop Alzheimer's Disease and an enhancer of amyloid β protein decomposition or vaccine of amyloid β protein etc. are extensively studied as a remedy for Alzheimer's Disease.
Secretase is an enzyme producing amyloid β protein by intracellular cleavage of a protein called amyloid β protein precursor (APP). An enzyme playing a role for producing an N-terminal of the amyloid β protein is called BACE1 (beta-site APP-cleaving enzyme) and an inhibitor of the BACE1, which will reduce production of amyloid β protein, could be a remedy for treating Alzheimers disease.
Patent literature 1 discloses a compound with a chemical structure similar to that of the compound of the present invention, having an inhibitory activity of NO synthetase and effective for treating dementia.
Patent literature 2-5 and non-patent literature 1-2 disclose compounds with a chemical structure similar to those of the compound of the present invention, and describe that each compound is useful as an anti-hypotensive agent, morphine-like analgesic or tranquilizer, intermediate of a therapeutic agent. NPYY5 antagonist, analgesic and the like.
Patent literatures 6-14 disclose BACE-1 inhibitors having a chemical structure different from that of the compound of the present invention. Also, patent literature 15 discloses a BACE-1 inhibitor,
This invention provides with a compound having an inhibitory activity against BACE-1 and useful for treating diseases induced by production, secretion and/or deposition of amyloid β protein.
The present invention provides with
1) a compound of the formula (I):
wherein the ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,
R1 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,
R2a and R2b are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl,
R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted carbocyclyl lower alkyl, optionally substituted heterocyclyl lower alkyl, optionally substituted carbocyclyl lower alkoxy, optionally substituted heterocyclyl lower alkoxy, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkyloxy, optionally substituted heteroaralkyloxy, optionally substituted lower alkylthio, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, or R3a and R3b or R3c and R3d may form a carbocyclic ring together with a linked carbon atom or may form oxo,
provided the following compounds i) and ii) are excluded;
i) a compound in which R2a is hydrogen, R2b is hydrogen, acetyl or phenyl, R1 is methyl, and the ring A is phenyl or 4-methoxyphenyl;
ii) a compound in which R2a is hydrogen, R2b is hydrogen, acetyl or phenyl, R1 is ethyl and the ring A is 3,4-dimethoxyphenyl,
a pharmaceutically acceptable salt or solvate thereof;
1′) a compound of the formula (I):
wherein the ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,
R1 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,
R2a and R2b are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl,
R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbarnoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, or
R3a and R3b or R3c and R3d may form a carbocyclic ring together with a linked carbon atom, provided the following compounds i) and ii) are excluded:
i) a compound in which R2a is hydrogen, R2b is hydrogen, acetyl or phenyl, R1 is methyl, and the ring A is phenyl or 4-methoxyphenyl;
ii) a compound in which R2a is hydrogen, R2b is hydrogen, acetyl or phenyl, R1 is ethyl and the ring A is 3,4-dimethoxyphenyl,
a pharmaceutically acceptable salt or solvate thereof;
2) the compound of I) or 1′) described above,
wherein the ring A is
wherein the ring A′ is a carbocyclic group or a heterocyclic group,
G is
wherein R5 is hydrogen, lower alkyl or acyl,
R6 is optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl,
W1 is O or S,
W2 is O, S or NR5,
Ak is optionally substituted lower alkylene, optionally substituted lower alkenylene or optionally substituted lower alkynylene,
the ring B is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group and each le may be independent:
R4 is halogen, hydroxyl, mercapto, halogeno lower alkyl, lower alkoxy, amino, lower alkylamino, acylamino or lower alkylthio and each R4 may be independent;
A pharmaceutically acceptable salt or solvate thereof;
2′) the compound of 1) or 1′) described above
wherein the ring A is
wherein the ring A′ is a carbocyclic group or a heterocyclic group,
G is
wherein R5 is hydrogen, lower alkyl or acyl,
R6 is optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl,
W1 is O or S,
W2 is O, S or NR5,
Ak is optionally substituted lower alkylene, optionally substituted lower alkenylene or optionally substituted lower alkynylene,
the ring B is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group and each R5 may be independent:
R4 is halogen, hydroxyl, mercapto, halogeno lower alkyl, lower alkyl, lower alkoxy, amino, lower alkylamino, acylamino or lower alkylthio and each R4 may be independent;
A pharmaceutically acceptable salt or solvate thereof;
3) the compound of 2) or 2′) described above wherein the ring A′ is phenyl or a nitrogen-containing aromatic heterocyclic group, a pharmaceutically acceptable salt or solvate thereof;
3′) the compound of 2) or 2′) described above wherein the ring A′ is phenyl, a pharmaceutically acceptable salt or solvate thereof;
3″) the compound of 2) or 2′) described above wherein the ring A′ is a nitrogen-containing aromatic monocyclic heterocyclic group, a pharmaceutically acceptable salt or solvate thereof;
3′″) the compound of 2) or 2′) described above wherein the ring A′ is pyridyl, a pharmaceutically acceptable salt or solvate thereof;
4) the compound of 1)-3), 1′), 2′), 3″), 3″) or 3′″) described above wherein R1 is C1-C3 alkyl, a pharmaceutically acceptable salt or solvate thereof;
4′) the compound of 1)-3), 1′), 2′), 3′), 3″) or 3′″) described above wherein R1 is optionally substituted lower alkynyl, a pharmaceutically acceptable salt or solvate thereof;
5) the compound of 1)-4), 1′), 2′), 3′), 3″), 3′″), 4′) described above wherein R2a and R2b are both hydrogen, a pharmaceutically acceptable salt or solvate thereof;
6) the compound of 1)-5), 1′), 2′), 3′), 3″), 3′″) or 4′) described above wherein all of R3a, R3b, R3c and R3d are hydrogen, a pharmaceutically acceptable salt or solvate thereof;
6′) the compound of 1)-5), 1′), 2′), 3′), 3″), 3′″) or 4′) described above wherein R3a and R3b are the same substituent selected from halogen and optionally substituted lower alkyl, a pharmaceutically acceptable salt or solvate thereof;
6″) the compound of 1)-5), 1′), 2′), 3′), 3″), 3′″) or 4′) described above wherein R3c and R3d are the same substituent selected from halogen and optionally substituted lower alkyl, a pharmaceutically acceptable salt or solvate thereof;
6′″) the compound of 1)-5), 1′), 2′), 3′), 3″), 3′″) or 4′) described above wherein R3a and R3b or R3c and R3d form a carbocyclic ring together with a linked carbon atom a pharmaceutically acceptable salt or solvate thereof;
7) the compound of 1)-5), 1′), 2′), 3′), 3″), 3′″) or 4′) described above wherein R3c or R3d is optionally substituted carbocyclic ring lower alkoxy or optionally substituted heterocyclyl lower alkoxy, a pharmaceutically acceptable salt or solvate thereof;
7′) the compound of 1)-5), 1′), 2′), 3′), 3″), 3′″) or 4′) described above wherein R3c and R3d form oxo together with a linked carbon atom, a pharmaceutically acceptable salt or solvate thereof;
8) a pharmaceutical composition comprising a compound of 1) 7), 1′), 2′), 3′), 3′), 3′″), 4′) 6′), 6″), 6′″) or 7′) described above, a pharmaceutically acceptable salt or solvate thereof as an active ingredient; and
9) a pharmaceutical composition having a BACE 1 inhibitory activity comprising a compound of 1) 7), 1′), 2′), 3′), 3″), 3′″), 4′) 6′), 6′″) or 7′) described above, a pharmaceutically acceptable salt or solvate thereof as an active ingredient;
The present invention also provides with
10) the pharmaceutical composition having a BACE 1 inhibitory activity of 9) described above, which is a composition having inhibitory activity of amyloid β protein production;
11) the pharmaceutical composition having a BACE 1 inhibitory activity of 9) described above, which is a medicine for treating diseases induced by production, secretion and/or deposition of amyloid 0 protein;
12) the pharmaceutical composition having a BACE 1 inhibitory activity of 9) described above, which is a medicine for treating Alzheimer's disease;
13) a method for treating diseases induced by production, secretion and/or deposition of amyloid β protein, characterized in administering a compound of the formula (I) described in 1) above, a pharmaceutically acceptable salt or solvate thereof;
14) use of a compound of the formula (I) described in 1) above, a pharmaceutically acceptable salt or solvate thereof described in 1) above, in manufacturing a medicine for treating diseases induced by production, secretion and/or deposition of amyloid 3 protein;
15) a method for treating diseases induced by BACE 1 characterized in administering a compound of the formula (I) described in 1) above, a pharmaceutically acceptable salt or solvate thereof;
16) use of a compound of the formula (I) described in 1) above, a pharmaceutically acceptable salt or solvate thereof, in manufacturing a medicine for treating diseases induced by BACE 1;
17) a method for treating Alzheimer's disease characterized in administering a compound of the formula (I) described in 1) above, a pharmaceutically acceptable salt or solvate thereof; and
18) use of a compound of the formula (I) described in 1) above, a pharmaceutically acceptable salt or solvate thereof in manufacturing a medicine for treating Alzheimer's disease.
A compound of the present invention is useful for treating diseases induced by production, secretion and/or deposition of amyloid β protein (Alzheimer's disease etc.).
In this description, “halogen” includes fluorine, chlorine, bromine and iodine.
A moiety of halogen in “halogeno lower alkyl” and “halogen lower alkoxycarbonyl” is the same as “halogen” above.
“Lower alkyl” includes C1-C15, preferably C1-C10, more preferably C1-C6 and further more preferably C1-C3 straight or branched alkyl, and for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl are exemplified.
A moiety of alkyl in “lower alkoxy”, “halogeno lower alkyl”, “hydroxyl lower alkyl”, “hydroxyl lower alkoxy”, “lower alkoxycarbonyl”, “halogeno lower alkoxycarbonyl”, “lower alkoxycarbortyl lower alkyl”, “lower alkylamino”, “lower alkoxy lower alkyl”, “hydroxyimino lower alkyl”, “lower alkoxyitnino lower alkyl”, “amino lower alkyl” “lower alkoxy lower alkoxy”, “lower alkoxy lower alkenyl”, “lower alkoxycarbonyl lower alkenyl”, “lower alkoxy lower alkynyl”, “lower alkoxycarbonyl lower alkynyl”, “lower alkyl carbamoyl”, “lower alkyl carbamoyl”, “lower alkoxyimino”, “lower alkylthio”, “lower alkylsulfonyl”, “lower alkylsulfonyloxy”, “lower alkyl sulfamoyl”, “lower alkyl sulfinyl”, “carbocyclyl lower alkyl”, “carbocyclyl lower alkyl”, “carbocyclyl lower alkoxy”, “carbocyclyl lower alkoxycarbonyl”, “carbocyclyl lower alkylamino”, “carbocyclyl lower alkyl carbamoyl”, “cycloalkyl lower alkyl”, “cycloalkyl lower alkoxy”, “cycloalkyl lower alkylamino”, “cycloalkyl lower alkoxycarbonyl”, “cycloalkyl lower alkylcarbamoyl”, “aryl lower alkyl”, “aryl lower alkoxy”, “aryl lower alkylamino”, “lower alkoxycarbonyl”, “aryl lower alkoxycarbarnoyl”, “heterocyclyl lower alkyl”, “heterocyclyl lower alkoxy”, “heterocyclyl lower alkylamino”, “heterocyclyl lower alkoxycarbonyl” and “heterocyclyl lower alkylcarbamoyl” is the same as “alkyl” above.
“Optionally substituted lower alkyl” may be substituted with one or more of substituent(s) selected from a substituent group α.
Group α is a group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, imino, hydroxyimino, lower alkoxyimino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbarnoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfonyl, cyano, nitro, a carbocyclic group and a heterocyclic group.
One or more of substituent(s) selected from the substituent group α is exemplified as a substituent of “optionally substituted lower alkoxy”, “optionally substituted lower alkoxycarbonyl” and “optionally substituted lower alkylthio”
“Lower alkylidene” includes a divalent group derived from the “lower alkyl” above, and methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene and hexylidene etc. are exemplified.
“Lower alkenyl” includes C2-C15, preferably C2-C10, more preferably C2-C6 and further more preferably C2-C4 straight or branched alkenyl having one or more double bond(s) at any position thereof. Examples of lower alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and the like.
“Lower alkynyl” includes C2-C10, preferably C2-C8, more preferably C3-C6 straight or branched alkynyl haying one or more triple bond(s) at any position thereof. Examples of lower alkynyl include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. Lower alkynyl may additionally have a double bond at any position thereof.
One or more of subsistent(s) selected from the substituent group α is exemplified as a substituent of “optionally substituted lower alkenyl” and “optionally substituted lower alkynyl”.
A moiety of lower alkenyl in “hydroxyl lower alkenyl”, “lower alkoxy lower alkenyl”, “lower alkoxycarbonyl lower alkenyl”, “carbocyclyl lower alkenyl”, “lower alkenyloxy”, “lower alkenylthio” and “lower alkenylamino” is the same as that of “lower alkenyl”.
A moiety of lower alkynyl in “hydroxyl lower alkynyl”, “lower alkoxy lower alkynyl”, “lower alkoxycarbonyl lower alkynyl”, “carbocyclyl lower alkynyl”, “lower alkynyloxy”, “lower alkenylamino” and “lower alkynylamino” is the same as that of “lower alkynyl” above
One or more substituents selected from lower alkyl, acyl, hydroxyl, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group etc. is exemplified as a substituent of “optionally substituted amino” and “optionally substituted carbamoyl”.
“Acyl” includes C1-C10 aliphatic acyl, carbocyclyl carbonyl and heterocyclic carbonyl, and examples of acyl include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, benzoyl, cyclohexanecarbonyl, pyridinecarbonyl, furancarbonyl, thiopheriecarbonyl, benzothiazolecarbonyl, pyrazinecarbonyl, piperidinecarbonyl, thiomorpholino and the like.
A moiety of acyl in “acylamino” and “acyloxy” is the some as described above.
One or more substituents selected from the substituent group α is exemplified as a substituent in “optionally substituted acyl” and a moiety of the ring in carbocyclyl carbonyl and heterocyclylcarbonyl is optionally substituted with one or more substituent(s) selected from lower alkyl, the substituent group α and lower alkyl substituted with one or more substituent(s) selected from the substituent group α.
“A carbocyclic group” includes cycloalkyl, cycloalkenyl, aryl, and non-aromatic fused carbocyclic group etc.
“Cycloalkyl” includes C3-C10, preferably C3-C8 and more preferably C4-C8 carbocyclic group and examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
A moiety of cycloalkyl in “cycloalkyl lower alkyl”, “cycloalkyloxy”, “cycloalkyl lower alkoxy”, “cycloalkylthio”, “cycloalkylamio”, “cycloalky lower alkylamino”, “cycloalkylsulfamoyl”, “cycloalkylsulfonyl”, “cycloalkylcaxbamoyl”, “cycloalkyl lower alkylcarbamoyl”, “cycloalkyl lower alkoxycarbonyl” and “cycloalkylcarbonyl” is the same as “cycloalkyl” described above
“Cycloalkenyl” includes the above cycloalkyl having one or more double bond(s) at any position on the ring, and examples of the cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl, and cyclohexadienyl etc.
Examples of “aryl” include phenyl, naphthyl, anthryl and phenanthryl etc, and especially phenyl is preferable.
“Non-aromatic fused carbocyclic group” includes a group in which two or more cyclic groups selected from “cycloalkyl”, “cycloalkenyl” and “aryl” described above fused, and examples of “Non-aromatic fused carbocyclic group” include indanyl, indenyl, tetrahydronaphthyl and fluorenyl etc.
“Forming a carbocyclic ring together with a linked carbon atom” means that two substituents jointly form “cycloalkyl” above.
A moiety of the carbocyclic ring in “carbocyclyloxy”, “carbocyclyl lower alkyl”, “carbocyclyl lower alkenyl”, “carbocyclyl lower alkynyl”, “carbocyclyl lower alkoxy”, “carbocyclyl lower alkoxycarbonyl”, “carbocyclylthio”, “carbocyclyl amino”, “carbocyclyl lower alkylamino”, “carbocyclylcarbonyl”, “carbocyclylsulfamoyl”, “carbocyclysulfonyl”, “carbocyclylcarbamoyl”, “carbocyclyl lower alkyl carbamoyl”, “carbocyclyloxycarbonyl” is the same as the “carbocyclic group”.
A moiety of aryl in “aryl lower alkyl”, “aryloxy”, “aryloxycarbonyl”, “aryloxycarbonyloxy”, “aryl lower alkoxycarbonyl”, “arylthio”, “arylamino”, “aryl lower alkoxy”, “aryl lower alkylamino”, “arylsulfonyl”, “arylsulfonyloxy”, “arylsulfinyl”, “arylsulfamoyl”, “arylcarbamoyl” and “aryl lower alkylcarbamoyl” is the same as the “aryl” above,
“Heterocyclic group” includes a heterocyclic group containing one or more heteroatom(s) each independently selected from O, S and N, and examples of “heterocyclic group” include 5- or 6-membered heteroaryl such as pyrrolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl etc.; a non-aromatic heterocyclic group such as dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, pyrazolidinyl, pirazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl and tetrahydropyridazinyl etc.;
a fused bicyclic heterocyclic group such as indolyl, isoindolyl, indazolyl, indolidinyl, quinolyl, isoquinolyl, cinnolinyl, phthaladinyl, quinazolinyl, naphthilidinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, thienopyridyl, thienopyrrolyl, thienopyrazolyl thienopyrazinyl, furopyrrolyl, thienothienyl, imidazopyridyl, pyrazolopyridyl, thiazolopyridyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyridazolopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, dthydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl, dihydrobenzjmidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl, benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl, dihydrobenzodioxinyl, dihydrobenzooxedinyl, ditiydrobenzooxepinyl and dihydrothienodioxinyl etc.; and a fused tricyclic heterocyclic group such as carbazolyl, xanthenyl, phenothiazinyl, phenoxathiinyl, pherioxaclinyl, dibenzofuryl, imidazoquinolyl and tetrahydrocarbazolyl etc.; and preferably includes 5- or 6-membered heteroaryl and a non-aromatic heterocyclic group.
A moiety of the heterocyclic group “heterocyclyl lower alkyl”, “heterocyclyloxy”, “heterocyclylthio”, “heterocyclylcarbonyl”, “heterocyclyl lower alkoxy”, “heterocyclyl amino”, “heterocyclyl carbonylamino”, “heterocyclyl sulfamoyl”, “heterocyclylsulfonyl”, “heterocyclylcarbamoyl”, “heterocyclyloxycarbonyl”, “heterocyclyl lower alkylamino”, “heterocyclyl lower alkoxycarbonyl” and “heterocyclyl lower alkylcarbarnoyl” is the same as the “heterocyclic group” above.
“A nitrogen-containing aromatic heterocyclic group” means a group of the “heterocyclic group” above containing at least one nitrogen atom, and examples of the “nitrogen-containing aromatic heterocyclic group” include 5- or 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl etc.;
a fused bicyclic heterocyclo group such as indolyl, isoindolyl, indazolyl, indolidinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthaladinyl, quinazolinyl, naphthilidinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridyl, pyrazolopyridine, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthylidinyl, dihydrobenzofuryl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzoxazine etc.; and
a fused tricyclic heterocyclo group such as carbazolyl, acridinyl, xanthenyl and imidazoquinolyl etc.; and pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropiridyl, dihydrobenzimidazolyl, tetrahydropyridyl, tetrahydrothiazolyl and tetrahydroisothiazolyl etc.
“The heterocyclic group” or “nitrogen-containing aromatic heterocyclic group” above may be linked to other group at any position on the ring,
“Nitrogen-containing aromatic monocyclic heterocyclic group” means a monocyclic group in the “nitrogen-containing aromatic heterocyclic group” and examples of the “Nitrogen-containing aromatic monocyclic heterocyclic group” include 5- or 6-membered heteroaryl such as pyrrolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl etc.
“The nitrogen-containing aromatic monocyclic heterocyclic group” above may be linked to other group at any carbon atom on the ring.
Examples of a substituent in the “optionally substituted carbocyclic group” and “optionally substituted heterocyclic group” of the ring A and B include the substituent group α (preferably halogen, hydroxyl, acyl, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, cyano, lower alkylamino, lower alkylthio etc.); lower alkyl optionally substituted with one or more substituent(s) selected from the substituent group α, hydroxyimino and lower alkoxyimino, wherein examples of preferable substituents include halogen, hydroxyl, lower alkoxy, lower alkoxycarbonyl etc.; amino lower alkyl substituted with one or more substituent(s) selected from the substituent group α, wherein examples of preferable substituents include acyl, lower alkyl and/or lower alkoxy etc.;
hydroxyimino lower alkyl, lower alkoxyimino lower alkyl;
lower alkenyl optionally substituted with one or more substituent(s) selected from the substituent group α, wherein examples of preferable substituents include lower alkoxycarbonyl, halogen and/or halogeno lower alkoxycarbonyl;
lower alkynyl optionally substituted with one or more substituent(s) selected from the substituent group α, wherein examples of preferable substituents include lower alkoxycarbonyl etc;
lower alkoxy optionally substituted with one or more substituent(s) selected from the substituent group α, wherein examples of preferable substituents include halogenocarbamoyl, oxetane, lower alkylcarbarnoyl, hydroxyl lower alkylcarbamoyl;
lower alkoxy lower alkoxy optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkenyloxy optionally substituted with one or more substituent(s) selected from the substitute group α wherein examples of preferable substituents include halogen, hydroxyl, amino, lower alkyl etc.;
lower alkoxy lower alkenyloxy optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkynyloxy optionally substituted with one or more substituent(s) selected from the substituent group α, wherein examples of preferable substituents include halogen, hydroxyl etc.;
lower alkoxy lower alkynyloxy optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkylthio optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkenylthio optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkynylthio optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkynylthio substituted with one or more substituent(s) selected from the substituent group α;
lower alkenylamino substituted with one or more substituent(s) selected from the substituent group α;
lower alkynylamino substituted with one or more substituent(s) selected from the substituent group α;
aminooxy optionally substituted with one or more substituent(s) selected from lower alkylidene and the substituent group α;
acyl substituted with one or more substituent(s) selected from the substituent group α;
lower alkylsulfonyl optionally substituted with one or more substituent(s) selected from the substituent group α;
lower alkylsulfinyl optionally substituted with one or more substituent(s) selected from the substituent group α;
sulfamoyl;
lower alkylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α;
a carbocyclic group (preferably cycloalkyl, aryl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
a heterocyclic group optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclyl lower alkyl (preferably cycloalkyl lower alkyl, aryl lower alkyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyl lower alkyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclyloxy (preferably cycloalkyloxy, aryloxy etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyloxy optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclyl lower alkoxy (preferably cycloalkyl lower alkoxy, aryl lower alkoxy, etc) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyl lower alkoxy (preferably cycloalkyl lower alkoxycarbonyl, aryl lower alkoxycarbonyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl,
carbocyclyl lower alkoxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyl lower alkoxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclylthio (preferably cycloalkylthio, arylthio etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclylthio optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclyl amino (preferably cycloalkylamino, arylamino etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclylamino optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclyl lower alkylamino (preferably cycloalkyl lower alkylamino, aryl lower alkylamino etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyl lower alkylamino optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
lower alkylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α;
carbocyclylsulfamoyl (preferably cycloalkyl sulfamoyl, arylsulfamoyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclylsulfonyl (preferably cycloalkyl sulfonyl, arylsulfonyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclylsulfonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclylcarbamoyl (preferably cycloalkyl carbamoyl, aryl carbamoyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyl carbamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
carbocyclyl lower alkylcarbamoyl (preferably cycloalkyl lower alkylcarbamoyl, aryl lower alkylcarbamoyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyl lower alkylcarbamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl, carbocyclyloxycarbonyl (preferably cycloalkyloxycarbonyl, aryloxycarbonyl etc.) optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
heterocyclyloxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group et, azide, lower alkyl and halogeno lower alkyl;
lower alkylenedioxy optionally substituted with halogen;
oxo, azide and the like.
These may be substituted with one or more substituents selected from these groups.
Also the ring A may be substituted with one or more group(s) selected from
Preferable examples of (i) to (xixi) above include
wherein Ak is optionally substituted lower alkylene, optionally substituted lower alkenylene or optionally substituted lower alkynylene, and the other symbols are the same as described above.
In other cases of “an optionally substituted carbocyclic group” and “an optionally substituted heterocyclic group”, one or more substituent(s) selected from a group of lower alkyl and the substituent group α may be exemplified as a substituent of “an optionally substituted carbocyclic group” and “an optionally substituted heterocyclic group”
“Heteroaryl” includes an aromatic cyclic group among the “heterocyclic group” above.
“Lower alkylene” includes C1-C10, preferably C1-C6, more preferably C1-C3 straight or branched divalent carbon chain, and for example, methylene, climethylene, trimethylene, tetramethylene and methyl trimethylene are exemplified.
A moiety of lower alkylene in “lower alkylenedioxy” is the same as the “lower alkylene” described above,
“Lower alkenylene” includes C2-C10, preferably C2-C6, more preferably C2-C4 straight or branched divalent carbon chain having a double bond at any arbitrary position thereof, and vinylene, propenylene, butenylene, butadienylene, methyl propenylene, pentenylene and hexenylene are exemplified.
“Lower alkynylene” includes C2-C10, preferably C2-C6, more preferably C2-C4 straight or branched divalent carbon chain having a triple bond and also a double bond at any arbitrary position thereof, and for example, ethynylene, propynylene, butynylene, pentynylene and hexynylene are exemplified.
Examples of a substituent in “optionally substituted lower alkylene”, “optionally substituted lower alkenylene” and “optionally substituted lower alkynylene” include the substituent group α, and preferably halogen and hydroxyl etc. are exemplified.
Examples of a substituent in “optionally substituted carbocyclyl lower alkyl”, “optionally substituted heterocyclyl lower alkyl”, “optionally substituted carbocyclyl lower alkoxy”, and “optionally substituted heterocyclyl lower alkoxy” include one or more substituent(s) selected from lower alkyl and the substituent group α.
In this specification, “solvate” includes a solvate with an organic solvent and a hydrate etc. and hydrate may be coordinated with optional number of water molecule.
The compound (1) includes pharmaceutical acceptable salt thereof. Examples of the pharmaceutical acceptable salt include a salt with an alkali metal such as lithium, sodium and potassium etc., an alkali earth metal such as magnesium, calcium etc., ammonium, an organic base and an amino acid; a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid or hydroiodic acid etc., and an organic acid such as acetic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzensulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc. Especially hydrochloric acid, phosphoric acid, tartaric acid or methane sulfonic acid is preferable. These salts can be prepared by a method usually carried out.
The compound (I) is not construed to be limited to a specific isomer but to include all possible isomers such as a keto-enol isomer, an imine-enamine isomer, a diastereoisomer, an optical isomer and a rotational isomer etc. For example, a compound (I) in which R2a is hydrogen includes a tautomer as follows;
The compound (I) of the present invention can be prepared, for example, according to the non-patent literature 1 or a method described below; Preparation of an aminodihydrothiazine ring (1-1) or (1-2):
(In the scheme above, at least one of R2b and R2c is hydrogen, R3b and R3d are each independently hydrogen, halogen, hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group, and the other symbols are the same as described above.)
The 1st step: A Grignard reagent having a corresponding substituent of the objective compound such as vinyl magnesium chloride, vinyl magnesium bromide and propenyl magnesium bromide etc. is added to a compound a, which is commercially available or can be prepared by a known method, in a solvent such as ether, tetrahydrofuran etc. or a mixed solvent of ether-tetrahydrofuran etc., at −100° C. to 50° C., preferably −80° C. to 0° C. and the mixture is stirred for 0.2 to 24 hours, preferably 0.2 to 5 hours to give a compound b.
The 2nd step: To a compound b in an acid such as acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid etc. or a mixture thereof under the presence of a solvent such as toluene etc. or without a solvent, is added a substituted thiourea having a corresponding substituent of the objective compound such as thiourea, N-methylthiourea, N,N′-dimethylthiourea etc., and the mixture is stirred at −20° C. to 100° C., preferably 0° C. to 80° C., for 0.5 hours to 120 hours, preferably 1 hour to 72 hours to give a compound c,
The 3rd step: To a compound c in a solvent such as toluene etc. or without a solvent, is added an acid such as trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid etc. or a mixture thereof and reacted at −20° C. to 100° C., preferably 0° C. to 50° C., for 0.5 hours to 120 hours, preferably 1 hour to 72 hours to give a compound (I-2) when R2b is hydrogen or a compound (I-1) when R2c is hydrogen.
(In the scheme above, L is a leaving group such as halogen or lower alkylsulfonyl etc. and the other symbols are the same as described above.)
The 1st step: Thiocyanate such as sodium thiocyanate or ammonium thiocyanate etc. is reacted with a compound d, which is commercially available or can be prepared by a known method, in a solvent such as toluene, chloroform, tetrahydrofuran etc. under the presence of water and an acid such as hydrochloric acid or sulfuric acid etc. at 0° C. to 150° C., preferably at 20° C. to 100° C. for 0.5 to 24 hours, preferably 1 to 12 hours to give a compound e.
The 2nd step: A reducing agent such as sodium borohydride etc. is added to and reacted with a compound e in a solvent such as tetrahydrofuran, methanol, ethanol, water etc. or a mixture of ethanol-water etc. under the presence of buffering agent such as sodium dihydrogen phosphate at −80° C. to 50° C., preferably at −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours to give a compound f.
The 3rd step: A compound f is reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride, carbon tetrachloride-triphenylphosphine etc, in a solvent such as toluene, dichloromethane etc. or without a solvent at −80° C. to 50° C., preferably at −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours; or it is reacted with a sulfonating agent such as methanesulfonyl chloride, p-toluenesulfonyl chloride etc. in a solvent such as toluene, dichloromethane etc. under the presence of a base such as triethylamine etc. at −80° C. to 50° C., preferably at −20° C. to 20° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours to give a compound g.
The 4th step: A compound g is reacted with ammonia or a primary amine such as methylamine etc. in a solvent such as methanol, ethanol, water etc. or a mixture of methanol-water etc. at −20° C. to 80° C., preferably at 0° C. to 40° C. for 0.5 to 48 hours, preferably 1 to 24 hours to give the compound (I-3).
(In the scheme above, at least one of R2b and R2c is hydrogen and the other symbols are the same as described above.)
The step: Thiourea or a substituted thiourea corresponding to the objective compound such as N-methyl thiourea, N,N-dimethylthiouers, N,N′-dimethylthiouera etc. is reacted with a compound o, which is commercially available or can be prepared by a known method, in a solvent such as ethanol, methanol, tetrahydrofuran, toluene etc. at −20° C. to 200° C., preferably at 0° C. to 150° C. for 0.5 to 200 hours, preferably 1 to 120 hours to give a compound p,
The 2nd step: A Grignard reagent corresponding to the objective compound such as methyl magnesium chloride, ethyl magnesium bromide and benzyl magnesium bromide etc, is added to a compound p in a solvent such as ether, tetrahydrofuran etc. or a mixed solvent thereof at −100° C. to 50° C., preferably −80° C. to 30° C. and the mixture is stirred for 0.2 to 24 hours, preferably 0.5 to 5 hours to give a compound q.
The step: To a compound q in a solvent such as toluene etc. or without a solvent, is added an acid such as trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid etc. or a mixture thereof and reacted at −20° C. to 100° C., preferably 0° C. to 50° C. for 0.5 hours to 200 hours, preferably 1 hour to 150 hours to give a compound (I-6) (R2c═H) or a compound (I-7) (R2b═H).
Preparation of an Aminodihydrothiazine Ring (I-8)
(In the scheme, each symbol is the same as described above)
The 1st step: Ammonium chloride is added to a compound r which can be prepared by a known method in a solvent such as acetic acid etc. at 0° C. to 200° C., preferably 10° C. to 100° C. for 0.1 hours to 100 hours, preferably 0.5 hour to 24 hours to give a compound.
The 2nd step: A reducing agent such as lithium aluminium hydride; diisobutyl aluminium hydride etc. is reacted with a compound s in a solvent such as tetrahydrofuran, diethyl ether etc. at −80° C. to 150° C., preferably 0° C. to 100° C. for 0.1 hours to 24 hours, preferably 0.5 hour to 12 hours to give a compound t.
The 3rd step: Isothiocyanate corresponding to the objective compound such as 4-methoxybenzyl isothiocyanate, t-butyl isothiocyanate etc, or carbamoyl halide corresponding to the objective compound such as N,N-dimethyl thiocarbamoyl chloride, N,N-diethyl thiocarbamoyl chloride etc. is reacted with a compound t in a solvent such as toluene, chloroform, tetrahydrofuran etc. under the presence of a base such as diisopropylethylamine, triethylamine, pyridine, sodium hydroxide etc. or without a base at 0° C. to 150° C., preferably 20° C. to 100° C. for 0.5 hours to 120 hours, preferably 1 hour to 72 hours to give a compound u.
The 4th step: A halogenating agent such as thionyl chloride, phosphoryl oxychloride, carbon tetrachloride-triphenyl phosphine etc. is reacted with a compound u in a solvent such as acetonitrile, toluene, dichloromethane etc. at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 hours to 24 hours, preferably 0.5 hour to 12 hours, or a sulfonylating agent such as methanesulfonyl chloride, p-toluenesulfonyl chloride is reacted with a compound u in a solvent such as toluene, dichloromethane etc. under the presence of a base such as triethylamine at −80° C. to 50° C., preferably −20° C. to 20° C. for 0.1 hours to 24 hours, preferably 0.5 hour to 12 hours. The resulting halogenated compound or sulfonate ester derivative is reacted with a base such as diisopropylethylamine, potassium carbonate, sodium bicarbonate, sodium hydride, sodium hydroxide etc. at 0° C. to 150° C., preferably 20° C. to 100° C. for 0.5 hours to 120 hours, preferably 1 hour to 72 hours to give a compound (I-8).
(In the scheme, R17 is optionally substituted lower alkyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group and other symbols are the same as described above)
An acylating agent corresponding to the objective compound such as benzoyl chloride, 2-furoyl chloride, acetic anhydride etc, is reacted with a compound (I-12) in which R2b is hydrogen under the presence a solvent such as tetrahydrofuran, dichloromethane etc. or without a solvent and under the presence of a base such as pyridine or triethylamine etc. or without a solvent at −80° C. to 100° C. preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours, or a compound (I-12) is reacted with a carboxylic acid having a substituent corresponding to the objective compound such as amino acid or glycolic acid etc. in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane etc. under the presence of a condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole etc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to give a compound (I-13) and/or (I-14)(when R2a is hydrogen).
(In the scheme above, CONR18R19 is optionally substituted carbamoyl and the other symbols are the same as described above)
A compound (I-16) having a carboxyl group as a substituent on the ring A is reacted with a primary or secondary amine having a substituent corresponding to the objective compound (e.g., aniline, 2-aminopyridine, dimethylamine etc.) in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane etc. under the presence of a condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole etc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to give a compound (I-17).
(In the scheme, NHR20 is optionally substituted amino, NR20COR21 is optionally substituted acylamino, optionally substituted ureido or carboxyamino having a substituent on the oxygen atom and the other symbols are the same as described above.)
A compound (I-18) having an optionally substituted amino group on the ring A is reacted with a reagent having a substituent corresponding to the objective compound such as acid chlorides, acid anhydrides, chlorocarbonate esters, isocyanates etc. under the presence of a solvent such as tetrahydrofuran, dichloromethane etc. or without a solvent under the presence of a base such as pyridine, triethylamine etc. or without a base at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours, or a compound (I-18) is reacted with a carboxylic acid having a substituent corresponding to the objective compound such as benzoic acid, 2-pyridinecarboxylic acid etc. in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane etc. under the presence of a condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazote etc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to give a compound (I-19).
(In the scheme, NHR20 is optionally substituted amino and R22 is lower alkyl.)
A compound (I-18) having an amino group on the ring A is reacted with an aldehyde having a substituent corresponding to the objective compound such as benzaldehyde, pyridine-2-carboaldehyde etc. and a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride etc. in a solvent such as dichloromethane, tetrahydrofuran etc. under the presence of an acid such as acetic add etc. or without an acid at −80° C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 150 hours, preferably 1 hour to 24 hours to give a compound (I-20),
(In the scheme above, R23 is optionally substituted lower alkyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group and the other symbols are the same as described above.)
A compound (I-21) having a hydroxy group on the ring A is reacted with an alkylating agent having a substituent corresponding to the objective compound such as benzyl chloride, methyl iodide etc. in a solvent such as dimethylformamide, tetrahydrofuran etc. under the presence of a base such as potassium carbonate, sodium hydroxide, sodium hydride etc. at −80° C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 150 hours, preferably 1 hour to 24 hours, or a compound (I-18) is reacted with an alcohol such as 2-aminoethanol etc. in a solvent such as dimethylformamide, tetrahydrofuran etc. under the presence of a Mitsunobu reagent such as triphenylphosphine-azodicarboxylic acid diethyl ester etc. at −80° C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 72 hours, preferably 1 hour to 24 hours to Rive a compound (I-22).
(In the scheme above, Hal is halogen, G is optionally substituted lower alkenyl, optionally substituted alkynyl, optionally substituted alkoxycarbonyl, an optionally substituted carbocyclic, group or an optionally substituted heterocyclic group etc. and the other symbols are the same as described above)
A compound (I-23) having halogen as a substituent on the ring A is reacted with a compound having substituent corresponding to the objective compound (e.g., styrene, propargyl alcohol, aryl boronic acid, carbon monoxide etc.) in a solvent such as tetrahydrofuran, dimethylformamide, 1,2-dimethoxyethane, methanol etc. under the presence of a base such as triethylamine, sodium carbonate etc., a palladium catalyst such as palladium acetate, palladium chloride etc. and a ligand such as triphenylphosphine etc. and under irradiation of microwave or without the irradiation, at −80° C. to 150° C., preferably 0° C. to 100° C. for 0.5 hours to 72 hours, preferably 1 hour to 24 hours to give a compound (I-24).
(In the scheme above. R24 is hydrogen, optionally substituted lower alkyl etc., R25 is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group etc., and the other symbols are the same as described above.)
A compound (I-25) having an acyl group as a substituent of the ring A is reacted with a hydroxylamine having a substituent corresponding to the objective compound such as hydroxylamine, methoxylamine, O-benzylhydroxylamine etc. or a salt thereof in a solvent such as methanol, ethanol etc. under the presence of an additive such as potassium acetate etc. or without an additive at −80° C. to 100° C., preferably 0° C. to 40° C. for 0.5 hours to 150 hours, preferably 1 hour to 72 hours to give a compound (I-26).
Coupling Reaction
(In the scheme above. R26 is a substituent corresponding to each objective compound)
The 1st step:
A compound v is reacted with a reagent having a substituent corresponding to the objective compound such as acyl halide, acid anhydride, chlorocarbonate ester, isocyanate etc. (e.g., benzoyl chloride, 2-furoyl chloride, acetic anhydride, benzyl chloroformate, di-ten-butyl dicarbonate, phenyl isocyanate etc.) in a solvent such as tetrahydrofuran, dichloromethane, dimethylformamide etc. or without a solvent under the presence of a base such as pyridine, triethylamine etc. or without a base at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours, or a compound A is reacted with a carboxylic acid having a substituent corresponding to the objective compound such as benzoic acid, 2-pyridinecarboxylic acid etc. in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane, methanol etc. under the presence of a condensation agent such as dicyclohexylcarbodiimide, carbonyl diimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate etc. at −80° C. to 100° C., preferably −20° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours to give a compound w.
When the substituent R has a functional group which disturb the said reaction, it can be carried out by protecting the functional group with a suitable protecting group and then deprotecting it at a subsequent appropriate step.
The 2nd Step:
A compound w is reacted in a solvent such as methanol, ethanol, ether, tetrahydro furan, 1,4-dioxane, dichloromethane, ethyl acetate etc. containing trifluoroacetic acid etc. or in neat, or in neat trifluoroacetic acid at −30° C. to 100° C., preferably 0° C. to 90° C. for 0.5 to 12 hours to give a compound (I-27). Alternatively, the objective compound can be synthesized according to the method described in Protective Groups Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.
Preparation of an Optically Active Isomer
1) Preparation of an Optically Active Isomer ae
For example, an optically active isomer ae, one embodiment of the compounds of the present invention, can be prepared according to the following scheme:
(In the scheme above, R1 is optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl; R27 is a chiral sulfoxide having optionally substituted lower alkyl, optionally substituted lower alkenyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, or a chiral auxiliary group such as α-methyl benzyl etc.; R3a, R3b, R3c, and R3d are each independently hydrogen, halogen, hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; R28 is optionally substituted lower alkyl or optionally substituted lower alkenyl; R2a and R2b are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl; and the other symbols are the same as described above.)
The compounds y and z above can be prepared by a method described in
Alternatively, these compounds can be prepared by optical resolution of each intermediate or the final product, or according to methods described below. Examples of the optical resolution method include a separation of optical isomers using an optically active column, kinetic resolution by an enzyme reaction etc., crystallization of diastereomers by salt formulation using a chiral acid or chiral base, and a preferential crystallization etc,
The 1st step: Compound y can be obtained by reacting Compound x, which is commercially available or can be prepared by a known method, with a chiral reagent having a substituent corresponding to the objective compound such as α-methylbenzylamine, para-toluene, tert-butylsulfine amide etc, at 60° C. to 120° C., preferably 80° C. to 100° C. in a solvent such as ether, tetrahydrofuran, toluene, benzene etc. or a mixed solvent such as ether-tetrahydrofuran etc. for 0.5 to 24 hours, preferably 0.5 to 5 hours, in the presence of molecular sieves or magnesium sulfate etc., under continuous evaporation by Dean-Stark apparatus, or according to the method described in the above literatures.
The 2nd step: A compound z can be diastereo-selectively obtained by reacting an enolate of lithium, aluminium, zinc, titan etc, prepared Gonna reagent having a substituent corresponding to the objective compound such as acetate ester etc., which is commercially available or can be prepared by a known method, or ketenesilyl acetate prepared from a reagent having a substituent corresponding to the objective compound such as ethyl acetate etc. with a compound a in a solvent such as ether, tetrahydrofuran toluene, dichloromethane etc. or a mixed solvent such as ether-tetrahydrofuran etc. under the presence of a Lewis acid such as titanium tetrachloride, ether-trifluoroborane complex etc. or without a Lewis acid at −100° C. to 50° C., preferably −80° C. to −30° C. for 0.5 to 24 hours, preferably 0.5 to 5 hours. Alternatively, the compound z can be diastereo-selectively prepared by the method described in the literature (1) or (3).
The 3rd step: A compound z is reacted with a compound c in a solvent such as methanol, ethanol, ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, ethyl acetate etc. containing hydrogen chloride, trifluoroacetic acid etc. or in neat trifluoroacetic acid at −30° C. to 100° C., preferably −10° C. to 90° C. for 0.5 to 12 hours, preferably 0.5 to 5 hours to give a compound aa.
The 4th step: A reducing agent such as borane-tetrahydrofuran complex, borane-dimethyl sulfoxide complex, borane-triethylamine complex, borane-pyridine complex etc. or ether- or tetrahydrofuran-solution thereof is reacted with a compound aa in a solvent such as ether, tetrahydrofuran, toluene etc. or a mixed solvent such as ether-tetrahydrofuran etc. at −30° C. to 30° C., preferably −10° C. to 20° C. for 0.5 to 12 hours, preferably 0.5 to 5 hours to give a compound ab.
The 5th step: Calcium carbonate or potassium carbonate etc. is added to a compound ab in a solvent such as dichloromethane, toluene etc. or a mixed solvent such as dichloromethane-water etc. and thiophosgene is added at −30° C. to 50° C., preferably −10° C. to 25° C. and the mixture is reacted for 0.5 to 12 hours, preferably 0.5 to 5 hours to give a compound ac.
The 6th step: Oxalyl chloride or thionyl chloride etc, and a catalytic amount of N,N-dimethylformamide are added to a compound ac in a solvent such as dichloromethane, tetrahydrofuran, toluene etc. at −30° C. to 50° C., preferably −10° C. to 20° C. and the mixture is reacted at 0° C. to 100° C., preferably 20° C. to 90° C. for 0.5 to 12 hours, preferably 0.5 to 5 hours to give a compound ad. Alternatively, it is obtained by a method described in Comprehensive Organic Transformations, Richard C Larock (Mcgraw-Hill).
The 7th step: 15% to 30% Ammonia water or a reagent having a substituent corresponding to the objective compound such as tert-butylamine etc. is added to a compound ad in a solvent such as ethyl acetate, dichloromethane, tetrahydrofuran, toluene etc. at −30° C. to 50° C., preferably −10° C. to 30° C. and the mixture is reacted at −10″C to 30° C., preferably 0° C. to 30° C. for 0.5 to 72 hours to give a compound ae-i or a compound ae-ii.
When R2a and/or R2b is hydrogen in the resulting compound ae-i or ae-ii, a substituent of the objective compound, R2a and/or R2b, may be further introduced by a conventional method if it is necessary.
1′) Method for Preparing an Optically Active Isomer Method B
An optically active compound ah of the present invention can be also prepared by a method below:
(In the scheme, the symbols are the same as described above.)
The 1st step to the 4th step: the same as described in 1) above.
The 5th step: Isothiocyanate having a protecting group which is commercially available or can be prepared by a known method is added to a compound ab in a solvent such as dichloromethane, toluene, acetone etc, or a mixed solvent at −30° C. to 50° C., preferably −10° C. to 2.5° C. and the mixture is reacted for 0.5 to 12 hours, preferably 0.5 to 5 hours to give a compound ag.
The 6th step: Oxalyl chloride or thionyl chloride etc. and a catalytic amount of N,N-dimethylformamide are added to a compound ag in a solvent such as dichloromethane, tetrahydrofuran, toluene etc. at −30° C. to 50° C., preferably −10° C. to 25° C., or 1-chloro-N,N-2-trimethyl-1-propenenylamine is added to a compound ag, and reacted at 0° C. to 100° C., preferably 20° C. to 90° C. for 0.5 to 72 hours to give a compound ah-i or ah-ii.
2) Introduction of R3a and R3b
An optically active compound ae-iii or ae-iv of the present invention can be also prepared by introducing R3a and R3b as shown below:
(In the scheme above, each symbol is the same as described above)
When preparing a compound ae-iii ae-iv in which R3a and R3b are substituted on the carbon atom next to S atom, a compound z is processed through the 3rd and 4th steps in place of the 3rd and 4th steps of 1) described above, and R3a and R3b are introduced in advance.
The 3rd step: A Grignard reagent having a substituent corresponding to the objective compound such as methyl magnesium chloride, ethyl magnesium bromide etc. is added to a compound z in a solvent such as ether, tetrahydrofuran etc. or a mixed solvent such as ether-tetrahydrofuran etc. at −100° C. to 50° C., preferably −80° C. to 30° C., or a compound z is convened to Weinreb Amide and reacted with a Grignard reagent having a substituent corresponding to the objective compound such as R3aMgBr, R3bMgBr. The reaction mixture is reacted for 0.2 to 24 hours, preferably 0.2 to 5 hours to give a compound aa′.
The 4th Step: A compound aa′ is reacted in a solvent such as methanol, ethanol, ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, ethyl acetate etc. containing hydrogen chloride, trifluoroacetic acid etc. or n neat trifluoroacetic acid at −30° C. to 100° C., preferably −10° C. to 90° C. for 0.5 to 12 hours, preferably 0.5 to 5 hours to give a compound ab′.
The compound ab′ is processed in the same reactions as the 5th to 7th steps of 1) above to give the objective compound ae-iii or ae-iv.
When the substituent L of a compound ad′ is eliminated to give a compound ad″ shown below, the objective compound ae′-iii or ae′-iv is obtained by processing the compound ad″ it through the 7th step in place of the 7th step described in 1) above.
The 7th step: A compound ad″ is dissolved in conc. sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid etc. and reacted at −30° C. to 100° C., preferably −10° C. to 40° C. for 0.1 to 12 hours, preferably 0.5 to 5 hours to give a compound ae′.
3) Conversion of a Substituent (1)
A preparation of a compound af-1 by conversion of the substituent is illustrated below:
(In the scheme, R8a and R8b are an amino-protecting group, and the other symbols are the same as described above.)
Trisdibenzylideneacetonedipalladium, palladium acetate, palladium(0) prepared in situ etc. and a phosphine ligand such as tri-tert-butylphosphine, dicyclohexylbiphenylphosphine etc. are added to a compound ae-1 in a solvent such as tetrahydrofuran, toluene, xylene etc. and further a reagent having a substituent corresponding to the objective compound such as lithium hexamethylenedisilazide, benzophenonimine etc. is added thereto at −10° C. to 30° C., then the reaction mixture is reacted at 30° C. to 120° C., preferably 50° C. to 100° C. for 0.5 to 48 hours, preferably 3 to 20 hours to give a compound af-1.
Any amino-protecting group which is deprotected by a method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. can be used and examples of the protecting group include lower alkoxycarbonyl, lower alkenyloxycarbonyl, acyl, methane-sulfonyl), trifluoromethanesulfonyl and toluenesulfonyl etc.
4) Conversion of a Substituent (2)
A preparation of a compound af-2 by conversion of the substituent is illustrated below:
(In the scheme, each symbol is the same as described above.)
A catalyst of catalytic reduction such as 10% palladium-carbon etc, is added to a compound ae-2 in a solvent such as tetrahydrofuran, ethyl acetate, methanol etc. and it is reacted under the pressure of normal to 5 atom, preferably normal to 2 atom of hydrogen atmosphere at 30° C. to 120° C., preferably 50° C. to 80° C. for 0.5 to 48 hours, preferably 6 to 20 hours to give a compound af-2. Alternatively, the compound af-2 is obtained by a method described in Comprehensive Organic Transformations, Richard C Larock (Mcgraw-Hill).
5) Conversion of a Substituent (3)
A preparation of a compound af-3 by conversion of the substituent is illustrated below:
(In the scheme, R9 is hydroxyl, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, optionally substituted lower alkyl amino, optionally substituted aromatic carbocyclyloxy, optionally substituted heterocyclyloxy, optionally substituted aromatic carbocyclylthio, optionally substituted heterocyclylthio, optionally substituted carbocyclylamino, optionally substituted heterocyclylamino, cyano azide, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, optionally substituted carbamoyl etc, and the other symbols are the same as described above.)
A reagent having a substituent corresponding to the objective compound such as ethanol, methanthiol, dimethylamine etc. is added to a compound ae-3 in a solvent such as tetrahydrofuran, ethanol etc, under the presence of a base such as sodium methoxide, potassium tert-butoxide, sodium hydroxide, sodium hydride etc. or without a base at −10° C. to 50° C. and it is reacted for 0.5 to 12 hours, preferably 1 to 8 hours to give a compound af-3. If necessary, a coupling reaction may be carried out in the same manner as the method for preparing a compound (I-19) described above.
In every step described above, f a starting compound has a functional group which disturb the reaction (e.g., hydroxyl, mercapto, amino, formyl, carbonyl, carboxyl etc.), it is recommended to protect the functional group and deprotect it at a subsequent appropriate step with a method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.
Further the order of steps may be changed and each reaction intermediate may be isolated and used in the subsequent step.
Examples of a preferable compound in the present invention include the followings:
In a formula (I′)
1) a compound in which the ring A′ is phenyl or a nitrogen-containing aromatic heterocyclic group (hereinafter called a compound in which the ring A′ is A′1),
a compound in which the ring A′ is benzene, pyridine, indole, benzisoxazole, benzopyrazole, benzofuran, benzothiophene, benzodioxole, or dihydrobenzodioxolane (hereinafter called a compound in which the ring A′ is A′2),
a compound in which the ring A′ is benzene (hereinafter called a compound in which the ring A′ is A′3),
a compound in which the ring A′ is pyridine (hereinafter called a compound in which the ring A′ is A′4)
2) a compound in which R1 is optionally substituted lower alkyl (hereinafter called a compound in which R1 is R1-1),
a compound in which R1 is methyl (hereinafter called a compound in which R1 is R1-2),
3) a compound in which R2a and R2-b are each independently hydrogen, lower alkyl or acyl(hereinafter called a compound in which R2a and R2b are R2-1),
a compound in which both of R2a and R2b are hydrogens (hereinafter called a compound in which R2a and R2b are R2-2),
4) a compound in which R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxyl, lower alkyl or amino (hereinafter called a compound in which R3a, R3b, R3c and R3d are R3-1),
a compound in which R3a and R3b, or R3c and R3d taken together foil cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl together (hereinafter called a compound in R3a, R3b, R3c and R3d are R3-2)
a compound in which R3a and R3b, or R3c and R3d are the same substituent selected compound in which R3a, R3b, R3c and R3d from halogen and lower alkyl (hereinafter called a compound in which R3a, R3b, R3c and R3d are R3-3),
a compound in which all of R3a, R3b, R3c and R3d are hydrogens (hereinafter called a compound in which R3a, R3b, R3c and R3d are R3-4),
5) a compound in which n is 0 to 2, R4 is each independently halogen, lower alkoxy, lower alkylamino, lower alkylthio, oxo or lower alkylenedioxy (hereinafter called a compound in which R4 is R4-1),
a compound in which n is 0 to 2, R4 is each independently halogen (hereinafter called a compound in which R4 is R4-2),
6) a compound in which G is (ii), (iv), (v), (x), (xiii) or (xiv) above (hereinafter called a compound in which G is G1),
a compound in which G is (ii′), (ii″), (iv′), (v′), (x′), (xiii′ (xiv′) above (hereinafter called a compound in which G is G2),
a compound in which G is (ii′), (ii′), (iv′), (v′), (x′), (xiii′) or (xiv′) above, and the ring B is optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted thiazolyl, optionally substituted isoxazolyl, optionally substituted benzothiazolyl, optionally substituted thiazolopyridyl, optionally substituted quinolyl, optionally substituted isoquinolyl or optionally substituted naphthylidinyl, optionally substituted quinazolinyl, or optionally substituted pyridopyrimidinyl (hereinafter called a compound in which G is G3),
a compound in which G is (ii′) above (hereinafter called a compound in which G is G4),
a compound in which a combination of the ring A′, R1, R2a and R2b, R3a, and R3d, n and R4, and G is as follows;
(A′1, R1-1, R2-1, R3-1, R4-1, G1), (A′1, R1-1, R2-1, R3-1, R4-1, G2), (A′1, R1-1, R2-1, R3-1, R4-1, G3), (A′1, R-1, R2-1, R3-1, R4-1, G4), (A′1, R1-1, R2-1, R3-1, R4-2, G1), (A′1, R1-1, R2-1, R3-1, R 4-2, G2), (A′1, R1-1, R2-1, R3-1, R4-2, G3), (A′1, R1-1, R2-1, R3-1, R4-2, G4), (A′1, R1-1, R2-1, R3-2, R4-1, G1), (A′1, R1-1, R2-1, R3-2, R4-1, G2), (A′1, R1-1, R2-1, R3-2, R4-1, G3), (A′1, R1-1, R2-1, R3-2, R4-1, G4), (A′1, R1-1, R2-1, R3-2, R4-2, G1), (A′1, R1-1, R2-1, R3-2, R4-2, G2), (A′1, R1-1, R 2-1, R3-2, R4-2, G3), (A′1, R1-1, R2-1, R3-2, R4-2, G4), (A′1, R1-1, R2-1, R3-3, R4-1, G1), (A′1, R1-1, R2-1, R3-3, R4-1, G2), (A′1, R1-1, R2-1, R3-3, R4-1, G3), (A′1, R1-1, R2-1, R3-3, R4-1, G4), (A′1, R1-1, R2-1, R3-3, R4-2, G1), (A′1, R1-1, R2-1, R3-3, R4-2, G2), (A′1, R1-1, R2-1, R3-3, R4-2, G3), (A′1, R1-1, R2-1, R3-3, R4-2, G4), (A′1, R1-1, R2-1, R3-4, R4-1, G1), (A′1, R1-1, R2-1, R3-4, R4-1, G 2), (A′1, R1-1, R2-1, R3-4, R4-1, G3), (A′1, R1-1, R2-1, R3-4, R4-1, G4), (A′1, R1-1, R2-1, R3-4, R4-2, G1), (A′1, R1-1, R2-1, R3-4, R4-2, G2), (A′1, R1-1, R2-1, R3-4, R4-2, G3), (A′1, R1-1, R2-1, R3-4, R4-2, G4), (A′1, R1-1, R2-2, R3-1, R4-1, G1), (A′1, R1-1, R2-2, R3-1, R4-1, G2), (A′1, R1-1, R2-2, R 3-1, R4-1, G3), (A′1, R1-1, R2-2, R3-1, R4-1, G4), (A′1, R1-1, R2-2, R3-1, R4-2, G1), (A′1, R1-1, R2-2, R3-1, R4-2, G2), (A′1, R1-1, R2-2, R3-1, R4-2, G3), (A′1, R1-1, R2-2, R3-1, R4-2, G4), (A′1, R1-1, R2-2, R3-2, R4-1, G1), (A′1, R1-1, R2-2, R3-2, R4-1, G2), (A′1, R1-1, R2-2, R3-2, R4-1, G3), (A′1, R 1-1, R2-2, R3-2, R4-1, G4), (A′1, R1-1, R2-2, R3-2, R4-2, G1), (A′1, R1-1, R2-2, R3-2, R4-2, G2), (A′1, R1-1, R2-2, R3-2, R4-2, G3), (A′1, R1-1, R2-2, R3-2, R4-2, G4), (A′1, R1-1, R2-2, R3-3, R4-1, G1), (A′1, R1-1, R2-2, R3-3, R4-1, G2), (A′1, R1-1, R2-2, R3-3, R4-1, G3), (A′1, R1-1, R2-2, R3-3, R4-1, G4), (A′1, R1-1, R2-2, R3-3, R4-2, G1), (A′1, R1-1, R2-2, R3-3, R4-2, G2), (A′1, R1-1, R2-2, R3-3, R4-2, G3), (A′1, R1-1, R2-2, R3-3, R4-2, G4), (A′1, R1-1, R2-2, R3-4, R4-1, G1), (A′1, R1-1, R2-2, R3-4, R4-1, G2), (A′1, R1-1, R2-2, R3-4, R4-1, G3), (A′1, R1-1, R2-2, R3-4, R4-1, G4), (A′1, R1-1, R2-2, R3-4, R4-2, G1), (A′1, R1-1, R2-2, R3-4, R4-2, G2), (A′1, R1-1, R2-2, R3-4, R4-2, G3), (A′1, R1-1, R 2-2, R3-4, R4-2, G4), (A′1, R1-2, R2-1, R3-1, R4-1, G1), (A′1, R1-2, R2-1, R3-1, R4-1, G2), (A′1, R1-2, R2-1, R3-1, R4-1, G3), (A′1, R1-2, R2-1, R3-1, R4-1, G4), (A′1, R1-2, R2-1, R3-1, R4-2, G1), (A′1, R1-2, R2-1, R3-1, R4-2, G2), (A′1, R1-2, R2-1, R3-1, R4-2, G3), (A′1, R1-2, R2-1, R3-1, R4-2, G4), (A′1, R1-2, R2-11R3-2, R4-1, G1), (A′1, R1-2, R2-1, R3-2, R4-1, G2), (A′1, R1-2, R2-1, R3-2, R4-1, G3), (A′1, R1-2, R2-1, R3-2, R4-1, G4), (A′1, R1-2, R2-1, R3-2, R4-2, G1), (A′1, R1-2, R2-1, R3-2, R4-2, G2), (A′1, R1-2, R2-1, R3-2, R4-2, G3), (A′1, R1-2, R2-1, R3-2, R4-2, G4), (A′1, R1-2, R2-1, R3-3, R4-1, G1), (A′1, R1-2, R2-1, R3-3, R4-1, G2), (A′1, R1-2, R2-1, R3-3, R4-1, G3), (A′1, R1-2, R2-1, R 3-3, R4-1, G4), (A′1, R1-2, R2-1, R3-3, R4-2, G1), (A′1, R1-2, R2-1, R3-3, R4-2, G2), (A′1, R1-2, R2-1, R3-3, R4-2, G3), (A′1, R1-2, R2-1, R3-3, R4-2, G4), (A′1, R1-2, R2-1, R3-4, R4-1, G1), (A′1, R1-2, R2-1, R3-4, R4-1, G2), (A′1, R1-2, R2-1, R3-4, R4-1, G3), (A′1, R1-2, R2-1, R3-4, R4-1, G4), (A′1, R 1-2, R2-1, R3-4, R4-2, G1), (A′1, R1-2, R2-1, R3-4, R4-2, G2), (A′1, R1-2, R2-1, R3-4, R4-2, G3), (A′1, R1-2, R2-1, R3-4, R4-2, G4), (A′1, R1-2, R2-2, R3-1, R4-1, G1), (A′1, R1-2, R2-2, R3-1, R4-1, G2), (A′1, R1-2, R2-2, R3-1, R4-1, G3), (A′1, R1-2, R2-2, R3-1, R4-1, G4), (A′1, R1-2, R2-2, R3-1, R4-2, G1), (A′1, R1-2, R2-2, R3-1, R4-2, G2), (A′1, R1-2, R2-2, R3-1, R4-2, G3), (A′1, R1-2, R2-2, R3-1, R 4-2, G4), (A′1, R1-2, R2-2, R3-2, R4-1, G1), (A′1, R1-2, R2-2, R3-2, R4-1, G2), (A′1, R1-2, R2-2, R3-2, R4-1, G3), (A′1, R1-2, R2-2, R3-2, R4-1, G4), (A′1, R1-2, R2-2, R3-2, R4-2, G1), (A′1, R1-2, R2-2, R3-2, R4-2, G2), (A′1, R1-2, R2-2, R3-2, R4-2, G3), (A′1, R1-2, R2-2, R3-2, R4-2, G4), (A′1, R1-2, R2-2, R3-3, R4-1, G1), (A′1, R1-2, R2-2, R3-3, R4-1, G2), (A′1, R1-2, R2-2, R3-3, R4-1, G3), (A′1, R1-2, R2-2, R3-3, R4-1, G4), (A′1, R1-2, R2-2, R3-3, R4-2, G1), (A′1, R1-2, R2-2, R3-3, R4-2, G2), (A′1, R1-2, R2-2, R3-3, R4-2, G3), (A′1, R1-2, R2-2, R3-3, R4-2, G4), (A′1, R1-2, R2-2, R3-4, R4-1, G1), (A′1, R1-2, R2-2, R3-4, R4-1, G2), (A′1, R1-2, R2-2, R3-4, R4-1, G3), (A′1, R1-2, R2-2, R3-4, R4-1, G4), (A′1, R1-2, R2-2, R3-4, R4-2, G1), (A′1, R1-2, R2-2, R3-4, R4-2, G2), (A′1, R1-2, R2-2, R3-4, R4-2, G3), (A′1, R1-2, R2-2, R3-4, R4-2, G4),
(A′2, R1-1, R2-1, R3-1, R4-1, G1), (A′2, R1-1, R2-1, R3-1, R4-1, G2), (A′2, R1-1, R2-1, R3-1, R4-1, G3), (A′2, R1-1, R2-1, R3-1, R4-1, G4), (A′2, R1-1, R2-1, R3-1, R4-2, G1), (A′2, R1-1R2-1, R3-1, R 4-2, G2), (A′2, R1-1, R2-1, R3-1, R4-2, G3), (A′2, R1-1, R2-1, R3-1, R4-2, G4), (A′2, R1-1, R2-1, R3-2, R4-1, G11), (A′2, R1-1, R2-1, R3-2, R4-1, G2), (A′2, R1-1, R2-1, R3-2, R4-1, G3), (A′2, R1-1, R2-1, R3-2, R4-1, G4), (A′2, R1-1, R2-1, R3-2, R4-2, G1), (A′2, R1-1, R2-1, R3-2, R4-2, G2), (A′2, R1-1, R 2-1, R3-2, R4-2, G3), (A′2, R1-1, R2-1, R3-2, R4-2, G4), (A′2, R1-1, R2-1, R3-3, R4-1, G1), (A′2, R1-1, R2-1, R3-3, R4-1, G2), (A′2, R1-1, R2-1, R3-3, R4-1, G3), (A2, R1-1, R2-11, R3-3, R4-1, G4), (A′2, R1-1, R2-1, R3-3, R4-2, G1), (A′2, R1-1, R2-1, R3-3, R4-2, G2), (A′2, R1-1, R2-1, R3-3, R4-2, G3), (A′2, R1-1, R1-1, R3-3, R4-2, G4), (A′2, R1-1, R2-1, R3-4, R4-1, G11), (A′2, R1-1, R2-1, R3-4, R4-1, G 2), (A′2, R1-1, R2-1, R3-4, R4-1, G3), (A′2, R1-1, R2-1, R3-4, R4-1, G4), (A′2, R1-1, R2-1, R3-4, R4-2, G1), (A′2, R1-1, R2-1, R3-4, R4-2, G2), (A′2, R1-1, R2-1, R3-4, R4-2, G3), (A′2, R-1, R2-1, R3-4, R4-2, G4), (A′2, R1-1, R2-2, R3-1, R4-1, G1), (A′2, R1-1, R2-2, R3-1, R4-1, G2), (A′2, R1-1, R2-2, R3-1, R4-1 G3), (A′2, R1-1, R2-2, R3-1, R4-1, G4), (A′2, R1-1, R2-2, R3-1, R4-2, G1), (A′2, R1-1, R2-2, R3-1, R4-2, G2), (A′2, R1-1, R2-2, R3-1, R4-2, G3), (A′2, R1-1, R2-2, R3-1, R4-2, G4), (A′2, R1-1, R2-2, R3-2, R4-1, G 1), (A′2, R1-1, R2-2, R3-2, R4-1, G2), (A′2, R1-1, R2-2, R3-2, R4-1, G3), (A′2, R 1-1, R2-2, R3-2, R4-1, G4), (A′2, R1-1, R2-2, R3-2, R4-2, G1), (A′2, R1-1, R2-2, R3-2, R4-2, G2), (A′2, R1-1, R2-2, R3-2, R4-2, G3), (A′2, R1-1, R2-2, R3-2, R4-2, G4), (A′2, R1-1, R2-2, R3-3, R4-1, G1), (A′2, R1-1, R2-2, R3-3, R4-1, G2), (A′2, R1-1, R2-2, R3-3, R4-1, G3), (A′2, R1-1, R2-2, R3-3, R4-1, G4), (A′2, R1-1, R2-2, R3-3, R4-2, G1), (A′2, R1-1, R2-2, R3-3, R4-2, G2), (A′2, R1-1, R2-2, R3-3, R 4-2, G3), (A′2, R1-1, R2-2, R3-3, R4-2, G4)(A′2, R1-1, R2-2, R3-4, R4-1, G1), (A′2, R1-1, R2-2, R3-4, R4-1, G2), (A′2, R1-1, R2-2, R3-4, R4-1, G3), (A2, R1-1, R2-2, R3-4, R4-1, G4), (A′2, R1-1, R2-2, R3-4, R4-2, G1), (A′2, R1-1, R2-2, R3-4, R4-2, G2), (A′2, R1-1, R2-2, R3-4, R4-2, G3), (A2, R1-1, R 2-2, R3-4, R4-2, G4), (A′2, R1-2, R2-1, R3-1, R4-1, G1), (A′2, R1-2, R2-1, R3-1, R4-1, G2), (A′2, R1-2, R2-1, R3-1, R4-1, G3), (A′2, R1-2, R2-1, R3-1, R4-1, G4), (A′2, R1-2, R2-1, R3-1, R4-2, G1), (A′2, R1-2, R2-1, R3-1, R4-2, G2), (A′2, R1-2, R2-1, R3-1, R4-2, G3), (A′2, R1-2, R2-1, R3-1, R4-2, G4), (A′2, R1-2, R2-1, R3-2, R4-1, G1), (A′2, R1-2, R2-1, R3-2, R4-1, G2), (A′2, R1-2, R2-1, R3-2, R4-1, G3), (A′2, R1-2, R2-1, R3-2, R4-1, G4), (A′2, R1-2, R2-1, R3-2, R4-2, G1), (A′2, R1-2, R2-1, R3-2, R4-2, G2), (A′2, R1-2, R2-1, R3-2, R4-2, G3), (A′2, R1-2, R2-1, R3-2, R4-2, G4), (A′2, R1-2, R2-1, R3-3, R-4-1, G1), (A′2, R1-2, R2-1, R3-3, R4-1, G2), (A′2, R1-2, R2-1, R3-3, R4-1, G3), (A′2, R1-2, R2-1, R 3-3, R4-1, G4), (A′2, R1-2, R2-1, R3-3, R4-2, G1), (A′2, R1-2, R2-1, R3-3, R4-2, G2), (A′2, R1-2, R2-1, R3-3, R4-2, G3), (A′2, R1-2, R2-1, R3-3, R4-2, G4), (A′2, R1-2, R2-1, R3-4, R4-1, G1), (A′2, R1-2, R2-1, R3-4, R4-1, G2), (A′2, R1-2, R2-1, R3-1, R4-1, G3), (A′2, R1-2, R2-1, R3-4, R4-1, G4), (A′2, R 1-2, R2-1, R3-4, R4-2, G1), (A′2, R1-2, R2-1, R3-4, R4-2, G2), (A′2, R1-2, R2-1, R3-4, R4-2, G3), (A′2, R1-2, R2-1, R3-4, R4-2, G4), (A′2, R1-2, R2-2, R3-1, R4-1, G1), (A′2, R1-2, R2-2, R3-1, R4-1, G2), (A′2, R1-2, R2-2, R3-1, R4-1, G3), (A′2, R1-2, R2-2, R3-1, R4-1, G4), (A′2, R1-2, R2-2, R3-1, R4-2, G1), (A′2, R1-2, R2-2, R3-1, R4-2, G2), (A′2, R1-2, R2-2, R3-1, R4-2, G3), (A′2, R1-2, R2-2, R3-1, R 4-2, G4), (A′2, R1-2, R2-2, R3-2, R4-1, G1), (A′2, R1-2, R2-2, R3-2, R4-1, G2), (A′2, R1-2, R2-2, R3-2, R4-1, G3), (A′2, R1-2, R2-2, R3-2, R4-1, G4), (A′2, R1-2, R2-2, R3-2, R4-2, G1), (A′2, R1-2, R2-2, R3-2, R4-2, G2), (A′2, R1-2, R2-2, R3-2, R4-2, G3), (A′2, R1-2, R2-2, R3-2, R4-2, G4), (A′2, R1-2, R 2-2, R3-3, R4-1, G1), (A′2, R1-2, R2-2, R3-3, R4-1, G2), (A′2, R1-2, R2-2, R3-3, R4-1, G3), (A′2, R1-2, R2-2, R3-3, R4-1, G4), (A′2, R1-2, R2-2, R3-3, R4-2, G1), (A′2, R1-2, R2-2, R3-3, R4-2, G2), (A′2, R1-2, R2-2, R3-3, R4-2, G3), (A′2, R1-2, R2-2, R3-3, R4-2, G4), (A2, R1-2, R2-2, R3-4, R4-1, G1), (A′2, R1-2, R2-2, R3-4, R4-1, G2), (A′2, R1-2, R2-2, R3-4, R4-1, G3), (A′2, R1-2, R2-2, R3-4, R4-1, G 4), (A′2, R1-2, R2-2, R3-4, R4-2, G1), (A2, R1-2, R2-2, R3-4, R4-2, G2), (A′2, R1-2, R2-2, R3-4, R4-2, G3), (A′2, R1-2, R2-2, R3-4, R4-2, G4),
(A′3, R1-1, R2-1, R3-1, R4-1, G 1), (A′3, R1-1, R2-1, R3-1, R4-1, G2), (A′3, R1-1, R2-1, R3-1, R4-1, G3), (A′3, R1-1, R2-1, R3-1, R4-1, G4), (A′3, R1-1, R2-1, R3-1, R4-2, G1), (A′3, R1-1, R2-1, R3-1, R 4-2, G2), (A′3, R1-1, R2-1, R3-1, R4-2, G3), (A′3, R1-1, R2-1, R3-1, R4-2, G4), (A′3, R1-1, R2-1, R3-2, R4-1, G1), (A′3, R1-1R2-1, R3-2, R4-1, G2), (A′3, R1-1, R2-1, R3-2, R4-1, G3), (A′3, R1-1, R2-1, R3-2, R4-1, G4), (A′3, R1-1, R2-1, R3-2, R4-2, G1), (A′3, R1-1, R2-1, R3-2, R4-2, G2), (A′3, R1-1, R 2-1, R3-2, R4-2, G3), (A′3, R1-1, R2-1, R3-2, R4-2, G4)(A′3, R1-1, R2-1, R3-3, R4-1, G1), (A′3, R1-1, R2-1, R3-3, R4-1, G2), (A′3, R1-1, R2-1, R3-3, R4-1, G3), (A′3, R1-1, R2-1, R3-3, R4-1, G4), (A′3, R1-1, R2-1, R3-3, R4-2, G1), (A′3, R1-1, R2-1, R3-3, R4-2, G2), (A′3, R1-1, R2-1, R3-3, R4-2, G3), (A′3, R1-1, R2-1, R3-3, R4-2, G4), (A′3, R1-1, R2-1, R3-4, R4-1, G1)(A′3, R1-1, R2-1, R3-4, R4-1, G 2), (A′3, R1-1, R2-1, R3-4, R4-1, G3), (A′3, R1-1, R2-1, R3-4, R4-1, G4), (A′3, R1-1, R2-1, R3-4, R4-2, G1), (A′3, R1-1, R2-1, R3-4, R4-2, G2), (A′3, R1-1, R2-1, R3-4, R4-2, G3), (A′3, R1-1, R2-1, R3-4, R4-2, G4), (A′3, R1-1, R2-2, R3-1, R4-1, G1), (A′3, R1-1, R2-2, R3-1, R4-1, G2), (A′3, R1-1, R2-2, R 3-1, R4-1, G3), (A′3, R1-1, R2-2, R3-1, R4-1, G4), (A′3, R1-1, R2-2, R3-1, R4-2, G1), (A′3, R1-1, R2-2, R3-1, R4-2, G2), (A′3, R1-1, R2-2, R3-1, R4-2, G3), (A′3, R1-1, R2-2, R3-1, R4-2, G4), (A′3, R1-1, R2-2, R3-2, R4-1, G1), (A′3, R1-1, R2-2, R3-2, R4-1, G2), (A′3, R1-1, R2-2, R3-2, R4-1, G3), (A′3, R 1-1, R2-2, R3-2, R4-1, G4), (A′3, R1-1, R2-2, R3-2, R4-2, G1), (A′3, R1-1, R2-2, R3-2, R4-2, G2), (A′3, R1-1, R2-2, R3-2, R4-2, G3), (A′3, R1-1, R2-2, R3-2, R4-2, G4), (A′3, R1-1, R2-2, R3-3, R4-1, G1), (A′3, R1-1, R2-2, R3-3, R4-1, G2), (A′3, R1-1, R2-2, R3-3, R4-1, G3), (A′3, R1-1, R2-2, R3-3, R4-1, G4), (A′3, R1-1, R2-2, R3-3, R4-2, G1), (A′3, R1-1, R2-2, R3-3, R4-2, G2), (A′3, R1-1, R2-2, R3-3, R 4-2, G3), (A′3, R1-1, R2-2, R3-3, R4-2, G4), (A′3, R1-1, R2-2, R3-4, R4-1, G1), (A′3, R1-1, R2-2, R3-4, R4-1, G2), (A′3, R1-1, R2-2, R3-4, R4-1, G3), (A′3, R1-1, R2-2, R3-4, R4-1, G4), (A′3, R1-1, R2-2, R3-4, R4-2, G1), (A′3, R1-1, R2-2, R3-4, R4-2, G2), (A′3, R1-1, R2-2, R3-4, R4-2, G3)(A′3, R1-1, R 2-2, R3-4, R4-2, G4), (A′3, R1-2, R2-1, R3-1, R4-1, G1), (A′3, R1-2, R2-1, R3-1, R4-1, G2), (A′3, R1-2, R2-1, R3-1, R4-1, G3), (A′3, R1-2, R2-1, R3-1, R4-1, G4), (A′3, R1-2, R2-1, R3-1, R4-2, G1), (A′3, R1-2, R2-1, R3-1, R4-2, G2), (A′3, R1-2, R2-1, R3-1, R4-2, G3), (A′3, R1-2, R2-1, R3-1, R4-2, G4), (A′3, R1-2, R2-1, R3-2, R4-1, G1), (A′3, R1-2, R2-1, R3-2, R4-1, G2), (A′3, R1-2, R2-1, R3-2, R4-1, G 3), (A′3, R1-2, R2-1, R3-2, R4-1, G4), (A′3, R1-2, R2-1, R3-2, R4-2, G1), (A′3, R1-2, R2-1R3-2, R4-2, G2), (A′3, R1-2, R2-1, R3-2, R4-2, G3), (A′3, R1-2, R2-1, R3-2, R4-2, G4), (A′3, R1-2, R2-1, R3-3, R4-1, G1), (A′3, R1-2, R2-1, R3-3, R4-1, G2), (A′3, R1-2, R2-1, R3-3, R4-1, G3), (A′3, R1-2, R2-1, R 3-3, R4-1, G4), (A′3, R1-2, R2-1, R3-3, R4-2, G1), (A′3, R1-2, R2-1, R3-3, R4-2G2), (A′3, R1-2, R2-1, R3-3, R4-2, G3), (A′3, R1-2, R2-1, R3-3, R4-2, G4), (A′3, R1-2, R2-1, R3-4, R4-1, G1), (A′3, R1-2, R2-1, R3-4, R4-1, G2), (A′3, R1-2, R2-1, R3-4, R4-1, G3), (A′3, R1-2, R2-1, R3-4, R4-1, G4), (A′3, R 1-2, R2-1, R3-4, R4-2, G1), (A′3, R1-2, R2-1, R3-4, R4-2, G2), (A′3, R1-2, R2-1, R3-4, R4-2, G3), (A′3, R1-2, R2-1, R3-4, R4-2, G4), (A′3, R1-2, R2-2, R3-1, R4-1, G1), (A′3, R1-2, R2-2, R3-1, R4-1, G2), (A′3, R1-2, R2-2, R3-1, R4-1, G3), (A′3, R1-2, R2-2, R3-1, R4-1, G4), (A′3, R1-2, R2-2, R3-1, R4-2, G1), (A′3, R1-2, R2-2, R3-1, R4-2, G2), (A′3, R1-2, R2-2, R3-1, R4-2, G3), (A′3, R1-2, R2-2, R3-1, R 4-2, G4), (A′3, R1-2, R2-2, R3-2, R4-G1)(A′3, R1-2, R2-2, R3-2, R4-1, G2), (A′3, R1-2, R2-2, R3-2, R4-1, G3), (A′3, R1-2, R2-2, R3-2, R4-1, G4), (A′3, R1-2, R2-2, R3-2, R4-2, G1), (A′3, R1-2, R2-2, R3-2, R4-2, G2), (A′3, R1-2, R2-2, R3-2, R4-2, G3), (A′3, R1-2, R2-2, R3-2, R4-2, G4), (A′3, R1-2, R 2-2, R3-3, R4-1, G1), (A′3, R1-2, R2-2, R3-3, R4-1, G2), (A′3, R1-2, R2-2, R3-3, R4-1 G3), (A′3, R1-2, R2-2, R3-3, R4-1, G4), (A′3, R1-2, R2-2, R3-3, R4-2, G1), (A′3, R1-2, R2-2, R3-3, R4-2, G2), (A3, R1-2, R2-2, R3-3, R4-2, G3), (A′3, R1-2, R2-2, R3-3, R4-2, G4), (A′3, R1-2, R2-2, R3-4, R4-1, G1), (A′3, R1-2, R2-2, R3-4, R4-1, G2), (A′3, R1-2, R2-2, R3-4, R4-1, G3), (A′3, R1-2, R2-2, R3-4, R4-1, G4), (A′3, R1-2, R2-2, R3-4, R4-2, G1), (A′3, R1-2, R2-2, R3-4, R4-2, G2), (A′3, R1-2, R2-2, R3-4, R4-2, G3), (A′3, R1-2, R2-2, R3-4, R4-2, G4),
(A′4, R1-1, R2-1, R3-1, R4-1, G1), (A′4, R1-1, R2-1, R3-1, R4-1, G2), (A′4, R1-1, R2-1, R3-1, R4-1, G3), (A′4, R1-1, R2-1, R3-1, R4-1, G4), (A′4, R1-1, R2-1, R3-1, R4-2, G1), (A′4, R1-1, R2-1, R3-1, R 4-2, G2), (A′4, R1-1, R2-1, R3-1, R4-2, G3), (A′4, R1-1, R2-1, R3-1, R4-2, G4), (A′4, R1-1, R2-1, R3-2, R4-1, G1), (A′4, R1-1, R2-1, R3-2, R4-1, G2), (A′4, R1-1, R2-1, R3-2, R4-1, G3), (A′4, R1-1, R2-1, R3-2, R4-1, G4), (A′4, R1-1, R2-1, R3-2, R4-2, G1), (A′4, R1-1, R2-1, R3-2, R4-2, G2), (A′4, R1-1, R 2-1, R3-2, R4-2, G3), (A′4, R1-1, R2-1, R3-2, R4-2, G4), (A′4, R1-1, R2-1, R3-3, R4-1, G1), (A′4, R1-1, R2-1, R3-3, R4-1, G2), (A′4, R1-1, R2-1, R3-3, R4-1, G3), (A′4, R1-1, R2-1, R3-3, R4-1, G4), (A′4, R1-1, R2-1, R3-3, R4-2, G1), (A′4, R1-1, R2-1, R3-3, R4-2, G2), (A′4, R1-1, R2-1, R3-3, R4-2, G3), (A′4, R1-1, R2-1, R3-3, R4-2, G4), (A′4, R1-1, R2-1, R3-4, R4-1, G1), (A′4, R1-1, R2-1, R3-4, R4-1, G 2), (A′4, R1-1, R2-1, R3-4, R4-1, G3), (A′4, R1-1, R2-1, R3-4, R4-1, G4), (A′4, R1-1, R2-1, R3-4, R4-2, G1), (A′4, R1-1, R2-1, R3-4, R4-2, G2), (A′4, R1-1, R2-1, R3-4, R4-2, G3), (A′4, R1-1, R2-1, R3-4, R4-2, G4), (A′4, R1-1, R2-2, R3-1, R4-1, G1), (A′4, R1-1, R2-2, R3-1, R4-1, G2), (A4, R1-1, R2-2, R 3-1, R4-1, G3), (A′4, R1-1, R2-2, R3-1, R4-1, G4), (A′4, R1-1, R2-2, R3-1, R4-2, G1), (A′4, R1-1, R2-2, R3-1, R4-2, G2), (A′4, R1-1, R2-2, R3-1, R4-2, G3), (A′4, R1-1, R2-2, R3-1, R4-2, G4), (A′4, R1-1. R2-2, R3-2, R4-1, G1), (A′4, R1-1, R2-2, R3-2, R4-11 G2), (A′4, R1-1, R2-2, R3-2, R4-1, G3), (A′4, R 1-1, R2-2, R3-2, R4-1, G4), (A′4, R1-1, R2-2, R3-2, R4-2, G1), (A′4, R1-1, R2-2, R3-2, R4-2, G2), (A′4, R1-1, R2-2, R3-2, R4-2, G3), (A′4, R1-1, R2-2, R3-2, R4-2, G4), (A′4, R1-1, R2-2, R3-3, R4-1, G1), (A′4, R1-1, R2-2, R3-3, R4-1, G2), (A′4, R1-1, R2-2, R3-3, R4-1, G3), (A′4, R1-1, R2-2, R3-3, R4-1, G4), (A′4, R1-1, R2-2, R3-3, R4-2, G1), (A′4, R1-1, R2-2, R3-3, R4-2, G2), (A′4, R1-1, R2-2, R3-3, R 4-2, G3), (A′4, R1-1, R2-2, R3-3, R4-2, G4), (A′4, R1-1, R2-2, R3-4, R4-1, G1), (A′4, R1-1, R2-2, R3-4, R4-1, G2), (A′4, R1-1, R2-2, R3-4, R4-1, G3), (A′4, R1-1, R2-2, R3-4, R4-1, G4), (A′4, R1-1, R2-2, R3-4, R4-2, G1), (A′4, R1-1, R2-2, R3-4, R4-2, G2), (A′4, R1-1, R2-2, R3-4, R4-2, G3), (A′4, R1-1, R 2-2, R3-4, R4-2, G4), (A′4, R1-2, R2-1, R3-1, R4-1, G1), (A′4, R1-2, R2-1, R3-1, R4-1, G2), (A′4, R1-2, R2-1, R3-1, R4-1, G3), (A′4, R1-2, R2-1, R3-1, R4-1, G4), (A′4, R1-2, R2-1, R3-1, R4-2, G1), (A′4, R1-2, R2-1, R3-1, R4-2, G2), (A′4, R1-2, R2-1, R3-1, R4-2, G3), (A′4, R1-2, R2-1, R3-1, R4-2, G4), (A′4, R1-2, R2-1, R3-2, R4-1, G1), (A′4, R1-2, R2-1, R3-2, R4-1, G2), (A′4, R1-2, R2-1, R3-2, R4-1, G 3), (A′4, R1-2, R2-1, R3-2, R4-1, G4), (A′4, R1-2, R2-1, R3-2, R4-2, G1), (A′4, R1-2, R2-1, R3-2, R4-2, G2), (A′4, R1-2, R2-1, R3-2, R4-2, G3), (A′4, R1-2, R2-1, R3-2, R4-2, G4), (A′4, R1-2, R2-1, R3-3, R4-1, G1), (A′4, R1-2, R2-1, R3-3, R4-1, G2), (A′4, R1-2, R2-1, R3-3, R4-1, G3), (A′4, R1-2, R2-1, R 3-3, R4-1, G4), (A′4, R1-2, R2-1, R3-3, R4-2, G1), (A′4, R1-2, R2-1, R3-3, R4-2, G2), (A′4, R1-2, R2-1, R3-3, R4-2, G3), (A′4, R1-2, R2-1, R3-3, R4-2, G4), (A′4, R1-2, R2-1, R3-4, R4-1, G1), (A′4, R1-2, R2-1, R3-4, R4-1, G2), (A′4, R1-2, R2-1, R3-4, R4-1, G3), (A′4, R1-2, R2-1, R3-4, R4-1, G4), (A′4, R 1-2, R2-1, R3-4, R4-2, G1), (A′4, R1-2, R2-1, R3-4, R4-2, G2), (A′4, R1-2, R2-1, R3-4, R4-2, G3), (A′4, R1-2, R2-1, R3-4, R4-2, G4), (A′4, R1-2, R2-2, R3-1, R4-1, G1), (A′4, R1-2, R2-2, R3-1, R4-1, G2), (A′4, R1-2, R2-2, R3-1, R4-1, G3), (A′4, R1-2, R2-2, R3-1, R4-1, G4), (A′4, R1-2, R2-2, R3-1, R4-2, G1), (A′4, R1-2, R2-2, R3-1, R4-2, G2), (A′4, R1-2, R2-2, R3-1, R4-2, G3), (A′4, R1-2, R2-2, R3-1, R4-2, G4), (A′4, R1-2, R2-2, R3-2, R4-1, G1), (A′4, R1-2, R2-2, R3-2, R4-1, G2), (A′4, R1-2, R2-2, R3-2, R4-1, G3), (A′4, R1-2, R2-2, R3-2, R4-1, G4), (A′4, R1-2, R2-2, R3-2, R4-2, G1), (A′4, R1-2, R2-2, R3-2, R4-2, G2), (A′4, R1-2, R2-2, R3-2, R4-2, G3), (A′4, R1-2, R2-2, R3-2, R4-2, G4), (A′4, R1-2, R 2-2, R3-3, R4-1, G1), (A′4, R1-2, R2-2, R3-3, R4-1, G2), (A′4, R1-2, R2-2, R3-3, R4-1, G3), (A′4, R1-2, R2-2, R3-3, R4-1, G4), (A′4, R1-2, R2-2, R3-3, R4-2, G1), (A′4, R1-2, R2-2, R3-3, R4-2, G2), (A′4, R1-2, R2-2, R3-3, R4-2, G3), (A′4, R1-2, R2-2, R3-3, R4-2, G4), (A′4, R1-2, R2-2, R3-4, R4-1, G1), (A′4, R1-2, R2-2, R3-4, R4-1, G2), (A′4, R1-2, R2-2, R3-4, R4-1, G3), (A′4, R1-2, R2-2, R3-4, R4-1, G 4), (A′4, R1-2, R2-2, R3-4, R4-2, G1), (A′4, R1-2, R2-2, R3-4, R4-2, G2), (A′4, R1-2, R2-2, R3-4, R4-2, G3) or (A′4, R1-2, R2-2, R3-4, R4-2, G4).
Compounds of the present invention are useful for treating diseases induced by production, secretion or deposition of amyloid β protein, and effective for the treatment and/or prophylaxis, or improvement of conditions for Alzheimer's dementia (Alzheimer's disease, senile dementia of Alzheimer type etc.), Down's disease, disturbance of memory, prion disease (Creutzfeldt-Jakob disease etc.), mild cognitive impairment (MCI), Dutch-type hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, other degenerated dementia, vascular degenerated mixed dementia, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear paralysis, dementia associated with corticobasal degeneration, diffuse Lewy Bodies Alzheimer's disease, age-related macular degeneration, Parkinson's disease, or amyloid angiopathy etc.
Since compounds of the present invention have several efficacies such as having a potent inhibitory activity against BACE-1 having a high selectivity against other enzymes etc., they can be a drug with less side effects. Moreover they can be a drug having a wide margin of safety by choosing an optically active isomer of appropriate stereochemistry. Further they have a lot of merits such as good metabolic stability, high solubility, high absorbability of oral administration, high bioavailability, good clearance and high transitivity to brain, long half-life, high ratio of non protein binding, lower inhibition of hERG channel and CYP, and/or negative result of Ames Test, and, therefore, they can be superior drugs.
A compound of the present invention may be administrated together with other agent (e.g., other agent for treating Alzheimer's disease such as acetylcholine esterase etc.). The compound can be given in combination with an antidementia drug such as donepezil hydrochloride, tacrine, galantamine, rivastigmine, zanapezil, memantine or vinpocetine, for example.
A compound of the present invention may be orally administrated as powder, granule, tablet, capsule, pill or liquid formulation, or parentally administrated as injection, suppository, formulation of transdermal absorption or inhalation. Also, an effective amount of the compound may be formulated together with medicinal additives suitable for the formulation such as an excipient, binder, moistening agent, disintegrant and/or lubricant etc.
Dose of a compounds of the present invention depends on condition of diseases, route of administration, age and body weight of a patient, but in the case of oral administration to an adult, the dose range is usually 0.1 μg to 1 g/day, preferably 0.01 to 200 mg/day and in the case of parenteral administration the dose range is usually 1 μg to 10 g/day, preferably 0.1 to 2 g/day.
The present invention is illustrated in details by examples and test examples but the present invention is not limited to these examples.
In EXAMPLES, each abbreviation has the following meaning:
Me: methyl
Et: ethyl
iPr, Pri isopropyl
tBu: t-butyl
Ph: phenyl
Bn: benzyl
Boc: tert-butoxycarbonyl
TFA: trifluoroacetic acid
THF: tetrahydrofuran
DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate
DMF: N,N-dimethylformamide
The 1st step: Compound (1) (101.5 g) was cooled to −18° C. and conc. sulfuric acid (400 ml) was added dropwise in 65 minutes while the inner temperature was kept at −15° C. or below. Separately fuming nitric acid (60 ml) was added to conc. sulfuric acid (180 ml) chilled to 4° C. in 45 minutes while the temperature was kept at 10° C. or below and the resulted mixed acid was added dropwise to the solution of (1) prepared before in an hour while the temperature was kept at −30° C. or below. The mixture was stirred at −20° C. or below for 1.5 hours, poured into 2.5 kg of ice-water and stirred for an hour. The precipitated crystals were filtered to give compound (2) (121.5 g).
1H-NMR (CDCl3): 2.71 (3H, d, J=5.1 Hz), 7.35 (1H, dd, J=9.3, 9.0 Hz), 8.41 (1H, ddd, J=9.0, 3.9, 3.0 Hz), 8.78 (1H, dd, J=6.3, 3.0 Hz).
The 2nd step: Compound (2) (20 g) was dissolved in ethanol (400 ml), Pd—C (10% dry)(2.0 g) was added thereto and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 hours. Then Pd—C (10% dry) (1.0 g) was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 1.5 hours, and further Pd—C (10% (dry) (1.0 g) was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 15 minutes. Pd—C was filtered off, the solvent was evaporated under reduced pressure and the residue of compound (3) (15.9 g) was obtained.
1H-NMR (DMSO-d6): 2.50 (3H, d, J=4.8 Hz), 5.21 (2H, brs, 1H), 6.78 (1H, ddd, J=8.7, 4.2, 3.0 Hz), 6.94 (1H, dd, J=6.3, 3.0 Hz), 6.99 (1H, dd, J=1.4, 8.7 Hz).
The 3rd step: Compound (3) (15.8 g) was dissolved in THF (79 ml), anhydrous trifluoroacetic acid (16.1 ml) and triethylamine (20.2 ml) were added under ice cooling and the mixture was stirred for 20 minutes. After the addition of water (30 ml), it was stirred under ice cooling for 20 minutes and the precipitated crystals were filtered. The filtrate was extracted with ethyl acetate (80 ml) and 50 ml, the organic layer was washed with water (60 ml), saturated brine. The crystals filtered previously were dissolved in the organic layer and dried over sodium sulfate. Sodium sulfate was filtered, the filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate under warming. After the addition of hexane (50 ml) and stirring under ice cooling for 20 minutes, the precipitated crystals were filtered. The mother liquid was concentrated again under reduced pressure, crystallized by the addition of ethyl acetate (8 ml) and hexane (12 ml) and compound (4) (totally 20.4 g) was obtained.
1H-NMR (CDCl3): 2.70 (3H, d, J=5.1 Hz), 7.24 (1H, dd, J=10.5, 9.3 Hz), 8.00 (1H, dd, J=6.2, 2.9 Hz), 8.21 (1H, m), 8.78 (1H, brs).
The 4th step: 1.6 M Vinyl magnesium chloride-THF solution (122 mil) was dissolved in THF (161 ml), cooled to −40° C. in a nitrogen atmosphere and a THF (81 ml) solution of compound (4) (16.1 g) was added dropwise thereto. The reaction solution was stirred at −40° C. for 20 minutes, 1.6 M vinyl magnesium chloride-THF solution (20 mil) was further added and the mixture was stirred at −40° C. for 15 minutes. The reaction solution was poured into a mixture of chilled ethyl acetate (480 ml), a saturated aqueous solution of ammonium chloride (80 ml) and water (80 ml) with stirring, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (200 ml), the organic layers were combined, washed with water (80 ml), and saturated brine successively, and dried over sodium sulfate. Sodium sulfate was filtered, the filtrate was concentrated under reduced pressure and the residue of compound (5) (22.4 g) was obtained.
1H-NMR (CDCl3): 1.74 (3H, d, J=1.2 Hz), 5.16 (1H, dd, J=10.5, 0.9 Hz), 5.27 (1H, d, J=17.3, Hz), 6.26 (1H, ddd, J=17.3, 10.5, 1.7 Hz), 7.07 (1H, dd, J=11.1, 9.6 Hz), 7.64-7.69 (2H, m), 7.94 (1H, brs).
The 5th step: The residue of compound (5) (22.3 g) and thiourea (5.17 g) were dissolved in acetic acid (112 ml), 1 M HCl-ethyl acetate (97 ml) was added thereto and the mixture was stirred at 40° C. for 18 hours. The solvent was evaporated under reduced pressure, toluene (150 ml) was added and again concentrated under reduced pressure. After repeating the same procedure, crystals were precipitated. Ethyl acetate (100 ml) was added to the crystalline residue, the mixture was stirred under ice cooling for an hour and the crystals were filtered to give compound (6) (15.1 g).
1H-NMR (DMSO-d6): 2.08 (3H, s), 4.10 (2H, d, J=7.8 Hz), 5.72 (1H, t, J=7.8 Hz), 7.23-7.32 (1H, m), 7.60-7.69 (2H, m), 9.25 (3H, brs), 11.39 (1H, brs).
The 6th step: Compound (6) (10.0 g) was dissolved in THF (50 ml), conc. sulfuric acid (5.74 ml) was added thereto and stirred at 60° C. for 2 hours. After evaporation of TFA under reduced pressure, ice-water (100 ml) was added. The mixture was stirred under ice-cooling for an hour, and the precipitated crystals were filtered to give compound (7) (11.2 g).
1H-NMR (CDCl3): 1.72 (3H, s), 2.02-2.18 (1H, m), 2.54-2.76 (2H, m), 3.14-3.28 (1H, m), 7.37 (1H, dd, J=1.9, 8.8 Hz), 7.62 (1H, dd, J=7.5, 3.0 Hz), 7.80 (1H, ddd, J=8.8, 3.9, 3.0 Hz), 8.77 (1H, brs), 9.38 (H, brs), 10.66 (1H, brs), 11.50 (1H, brs).
The 7th step: MeOH (28 ml), THF (35 ml) and 5 N NaOH (10.9 ml) were added to compound (7) (7.00 g) and stirred at 50° C. for 4 hours. Toluene (50 ml) was added and extracted, and the aqueous layer was further extracted with toluene (50 ml) and ethyl acetate (60 ml). All the organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The solvent was concentrated under reduced pressure, the resulted crystalline residue was washed with hexane (20 ml) to give compound (8) (3.45 g).
1H-NMR (CDCl3): 1.60 (3H, d, J=1.5 Hz), 1.76-1.87 (1H, m), 2.44-2.54 (1H, m), 2.66-2.76 (1H, m), 2.86-2.94 (1H, m), 6.50 (1H, ddd, J=8.7, 3.6, 3.0 Hz), 6.66 (1H, dd, J=7.1, 3.0 Hz), 6.81 (1H, dd, J=12.0, 8.7 Hz).
The 1st step: Compound (3) (15.6 g) was dissolved in ethyl acetate (78 ml), acetic anhydride (10.6 ml) and pyridine (9.07 ml) were added under ice cooling, and the mixture was stirred for 15 minutes. Ethyl acetate (100 ml) and water (50 ml) were added, extracted, and the aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with 2 M HCl (50 ml), a saturated solution of sodium bicarbonate (50 ml) and saturated brine, dried over sodium sulfate. Sodium sulfate was filtered, the filtrate was concentrated under reduced pressure, and ethyl acetate (50 ml) and hexane (50 mil) were added to the residue. The mixture was stirred under ice cooling for 30 minutes and the precipitated crystals were filtered to give compound (9) (total 14.9 g).
1H-NMR (CDCl3): 2.20 (3H, s), 2.66 (3H, d, J=5.1 Hz), 7.13 (H, dd, J=10.5, 9.0 Hz), 7.70 (1H, dd, J=6.3, 3.0 Hz), 7.79 (1H, brs), 8.11 (1H, ddd, J=9.0, 4.1, 3.0 Hz).
The 2nd step: Compound (9) (10.0 g) was dissolved in THF (50 ml), cooled in ice and sodium hydride (2.25 g) was added in a nitrogen atmosphere. After stirring for 15 minutes, the resulted mixture was added dropwise to a solution of 1.6 M vinyl magnesium chloride (86 ml)/THF (70 ml) cooled to −40° C. After stirring at −40° C. for 15 minutes and then 0° C. for 20 minutes, a saturated aqueous solution of ammonium chloride (50 ml)/water (50 ml) was chilled and added. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). Organic layers were combined, washed with water and saturated brine, dried over sodium sulfate. Sodium sulfate was filtered, the filtrate was concentrated under reduced pressure to give a residue of compound (10) (13.7 g).
1H-NMR (CDCl3): 1.69 (3H, s), 2.16 (3H, s), 5.12 (1H, d, J=10.5 Hz), 5.24 (1H, d, J=17.4 Hz), 6.26 (1H, ddd, J=17.4, 10.5, 1.5 Hz), 6.98 (1H, dd, J=11.1, 8.7 Hz), 7.33 (1H, brs), 7.50-7.59 (2H, m).
The 3rd step: The residue of compound (10) (6.56 g) and thiourea (1.88 g) were dissolved in acetic acid (33 ml), 1 M HCl-acetic acid (37 ml) was added and stirred at 40° C. for 7 hours. The solvent was evaporated under reduced pressure, toluene (50 ml) was added and concentrated again under reduced pressure. The same procedure was repeated again, ethyl acetate (30 ml) was added to the residue and stirred at room temperature overnight. The precipitate was filtered to give compound (11) (5.77 g).
1H-NMR (DMSO-d6): 2.03 (3H, s), 2.06 (3H, s), 4.09 (2H, d, J=7.5 Hz), 5.67 (1H, t, J=7.5 Hz), 7.12 (1H, dd, J=10.7, 8.9 Hz), 7.46-7.59 (2H, m), 9.24 (4H, brs), 10.11 (1H, s).
The 4th step: compound (11) (5.16 g) was dissolved in conc. sulfuric acid (15.5 ml) and stirred at room temperature for an hour. It was poured into ice-water (100 ml), adjusted to pH 10 by the addition of an aqueous solution of potassium hydroxide and extracted with ethyl acetate (200 ml) and a little amount of MeOH. The organic layer was washed with water and saturated brine, dried over sodium sulfate. Sodium sulfate was filtered, the filtrate was concentrated under reduced pressure, ethyl acetate (20 ml) and hexane (15 ml) were added to the residue and the precipitate was filtered. The filtrate was concentrated, ethyl acetate (5 ml) and hexane (5 ml) were added and the precipitate was filtered to give compound (12) (total 3.16 g).
1H-NMR (CDCl3): 1.62 (3H, d, J=0.9 Hz), 1.80-1.91 (1H, m), 2.16 (3H, s), 2.47-2.58 (1H, m), 2.62-2.73 (1H, m), 2.87-2.98 (1H, m), 4.36 (2H, brs), 6.99 (1H, dd, J=11.7, 8.7 Hz), 7.14 (1H, dd, J=7.1, 3.0 Hz), 7.80 (1H, ddd, J=8.7, 4.2, 3.0 Hz), 7.97 (1H, brs),
The 5th step: Compound (12) (2.50 g) was suspended in ethanol (25 ml), 6 M HCl (10.2 ml) was added and the mixture was stirred at 90° C. for 3 hours. 2 M NaOH (35 ml) was added, the organic solvent was evaporated and the residue was extracted with ethyl acetate (70 ml). The aqueous layer was further extracted with ethyl acetate (30 ml), organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate.
Sodium sulfate was filtered, the filtrate was concentrated under reduced pressure, and the crystalline residue was washed with ethyl acetate (3 ml) and hexane (10 ml). The crystals were filtered to give compound (8) (total 1.22 g).
The 1st step: A ethanol solution of 20% sodium ethoxide (5.12 ml, 16.2 mmol, 40 eq.) was added to compound (13) (150 mg, 406 μmol) and stirred at room temperature for 6 hours. The reaction solvent was evaporated under reduced pressure, 2 M hydrochloric acid (8.12 ml, 16.2 mmol, 40 eq.) was added to the resulted residue and extracted with chloroform. The extracting solution was washed with water and dried over anhydrous sodium sulfate. The crude product (189 mg) was obtained by evaporation of the solvent under reduced pressure, to which 4 M HCl-ethyl acetate solution (1.89 ml) was added and the mixture was stirred at room temperature for 14 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (14) (90.8 mg, 76% yield) as a yellow powder.
1H NMR (CDCl3) δ1.52 (3H, t, J=6.8 Hz), 1.67 (3H, s), 1.93-2.00 (1H, m), 2.60-2.67 (2H, m), 2.94-3.00 (1H, m), 4.19 (2H, q, J=6.8 Hz), 6.93 (1H, d, J=9.3 Hz), 8.14 (1H, dd, J=8.7, 2.4 Hz), 8.31 (1H, d, J=2.5 Hz).
The 2nd step: A powder of 10% palladium-carbon (45.4 mg) was added to a methanol (908 μl) solution of compound (14) (90.8 mg, 307 mmol) and the mixture was stirred in a hydrogen atmosphere for 22 hours. The reaction mixture was filtered through a Celite pad and the filtrate was evaporated under reduced pressure. The residue was washed with ethyl acetate to give compound (15) (65.8 mg, 81% yield) as an yellow powder.
1H NMR (DMSO-d6) δ 1.29 (3H, t, J=6.9 Hz), 1.45 (3H, s), 1.51-1.58 (1H, m), 2.46-2.48 (1H, m), 2.61-2.64 (1H, m), 2.80-2.83 (1H, m), 3.85-3.91 (2H, m), 6.38 (1H, dd, J=8.3, 2.5 Hz), 6.52 (1H, d, J=2.4 Hz), 6.67 (1H, d, J=8.6 Hz)
The 1st step: 3′-Bromoacetophenone (15.0 g) and compound (16) (9.13 g) were dissolved in tetrahydrofuran (250 ml), and tetraethoxytitanium (39.5 ml) was added thereto at room temperature with stirring. Then the reaction mixture was stirred at 75° C. for 5 hours, and saturated brine was added after disappearance of compound (1) was confirmed. Titanium oxide formed in the reaction was filtered off, the filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified with a column chromatography to give compound (17) (20.1 g).
1H-NMR (CDCl3): 1.33 (9H, s), 2.75 (3H, s), 7.30 (1H, t. J=7.8) 7.59-7.63 (1H, m), 7.79 (1H, d, J=7.8) 8.0 (1H, s)
The 2nd step: A 2.64 M hexane solution of n-butyllithium (79.5 ml) is added dropwise to a tetrahydrofuran (100 ml) solution of diisopropylamine (42.1 ml) in a nitrogen atmosphere at −78° C. After stirring at 0° C. for 30 minutes, the reaction solution was again cooled to −78° C. and tert-butyl acetate (26.9 ml) dissolved in tetrahydrofuran (100 ml) is added dropwise. After stirring at −78° C. for 30 minutes, chlorotriisopropoxytitanium dissolved in tetrahydrofuran (150 ml) is added dropwise. After stirring at the same temperature for 70 minutes, compound (2) (20.1 g) dissolved in tetrahydrofuran (100 ml) was added dropwise. After then, the reaction solution was stirred at −78° C. for 3 hours, and an aqueous solution of ammonium chloride was added after disappearance of compound (2) was confirmed. Titanium oxide formed in the reaction was filtered off, the filtrate was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of compound (18) (26.4 g).
The 3rd step: The crude product of compound (18) (26.4 g) was dissolved in toluene (80 ml), the solution was added dropwise to a 1 M solution of aluminium diisobutyl hydride in toluene (253 ml) with stirring at 0° C. The reaction solution was stirred at room temperature for 1.5 hours and 1 N hydrochloric acid solution was added after disappearance of compound (3) was confirmed. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by crystallization to give compound (19) (18.1 g).
1H-NMR (CDCl3): 1.28 (9H, s), 1.71 (3H, s), 2.19-2.24 (2H, m), 3.27-3.32 (1H, m), 3.54-3.66 (1H, m), 3.87-3.97 (1H, m), 5.10-5.11 (1H, m), 7.22 (1H, t. J=8.1) 7.32-7.41 (2H, m), 7.56-7.58 (1H, m)
The 4th step: Compound (19) (18. g) was dissolved in methanol (30 ml), and 10% hydrochloric acid in methanol (130 ml) was added dropwise therein at room temperature. The reaction solution was stirred at room temperature for 4 hours and 1 N hydrochloric acid was added after disappearance of compound (4) was confirmed. The mixture was extracted with ethyl acetate, the aqueous layer was neutralized with a 2 N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give a crude product of compound (20) (14.1 g).
The 5th step: The crude product of compound (20) (32.8 g) and potassium carbonate (37.1 g) were dissolved in a mixed solvent of toluene (450 nm) and water (225 ml) and thiopbosgene (15.3 ml) was added dropwise cooled at 0° C. with stirring. After then, the reaction solution was stirred at 0° C. for an hour and water was added when disappearance of compound (5) was confirmed. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of compound (21) (38.4 g).
The 6st step: The crude product of (21) (38.4 g) was dissolved in toluene (384 ml), and thionyl chloride (29.4 ml) and N,N-dimethylformamide (1.04 ml) were added dropwise at 0° C. with stirring. After then, the reaction solution was stirred at 80° C. for 5 hours, and after disappearance of compound (6) was confirmed, the reaction solution was evaporated under reduced pressure to give a crude product of compound (22) (40.9 g).
The 7th step: The crude product of compound (22) (40.9 g) was dissolved in tetrahydrofuran (250 ml) and 25% ammonia-water (250 ml) was added with stirring at 0° C. After then the reaction solution was stirred at room temperature for 16 hours, and a saturated aqueous solution of sodium bicarbonate was added after disappearance of compound (21) was confirmed. The organic layer was separated and the aqueous solution was extracted with dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a crude product of compound (23) (38.3 g).
The 8th step: The crude product of compound (23) (38.3 g) is dissolved in tetrahydrofuran (383 ml), di-tert-butyl dicarbonate (61.5 g) and N,N-dimethylaminopyridine (1.64 g) are added and the mixture was stirred at room temperature for 72 hours. After disappearance of compound (23) was confirmed, the solvent was evaporated under reduced pressure. The residue was purified with a silicagel column chromatography to give compound (24) (45.3 g)
1H-NMR (CDCl3): 1.54 (9H, s), 1.57 (3H, s), 1.96 (2H, t, J=6.0), 2.80-2.92 (1H, m), 3.00-3.13 (1H, m), 7.21 (1H, J=8.1) 7.28-7.41 (2H, m), 7.52-7.55 (1H, m)
The 9th step: In a nitrogen atmosphere, compound (24) (12.1 g), trisdibenzylideneacetonedipalladium (1.14 g) and dicyclohexylbiphenylpbosphine (0.88 g) were dissolved in toluene (125 ml), and a 1.6 M solution of lithium hexamethyldisilazide in tetrahydrofuran (46.9 ml) was added with stirring at room temperature. The reaction solution was warmed up to 80° C. and stirred for 16 hours. After disappearance of compound (21) was confirmed, the reaction solution was cooled at 0° C. and diethyl ether and 1 N hydrochloric acid were added. After stirring at 0° C. for 10 minutes, the solution was neutralized with a saturated aqueous solution of sodium carbonate. It was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (25) (6.84 g).
1H-NMR (CDCl3): 1.51 (9H, s), 1.69 (3H, s), 2.01-2.12 (1H, m), 2.40-2.51 (1H, m), 2.67-2.76 (2H, m), 6.55-6.67 (3H, m), 7.15 (1H, t. J=8.1).
The 1st step: After the addition of compound (1) (70.00 g) to conc. sulfuric acid (279 ml) cooled in an acetonitrile/dry ice bath with stirring, a mixture of fuming nitric acid (42 ml) and conc. sulfuric acid (98 ml) were added dropwise. After stirring for 16 minutes, the mixture was gradually poured into ice, the precipitated crystals were filtered and dried to give compound (2) (77.79 g).
1H-NMR (CDCl3) δ: 2.71 (3H, d, J=4.9 Hz), 7.34 (1H, t, J=9.3 Hz), 8.40 (H, ddd, J=9.3, 6.2, 3.0 Hz), 8.78 (1H, dd, J=6.2, 3.0 Hz).
The 2nd step: A solution of compound (2) (73.94 g), (R)-(+)-2-methyl-2-propanesulfinamide (53.82 g) and tetraethyl orthotitanate (230.20 g) in tetrahydrofuran (500 ml) were reacted for 2.5 hours under heating to reflux, and then the reaction mixture was gradually poured into ice and the resulted insoluble materials were filtered. It was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give compound (26) (85.44 g).
1H-NMR (CDCl3) δ: 1.34 (9H, s), 2.81 (3H, d, J=3.5 Hz), 7.29 (1H, t, J=8.9 Hz), 8.31 (1H, dt, J=8.9, 2.9 Hz), 8.55 (1H, dd, J=6.3, 2.9 Hz).
The 3rd step: A solution of tert-butyl acetate (6.08 g) in tetrahydrofuran (10 ml) was added dropwise to a 2 M solution of lithium diisopropylamide/tetrahydrofuran/n-heptane/ethylbenzene (27.9 ml) cooled in an acetone/dry ice bath with stirring. After stirring for 20 minutes, a solution of chlorotitanium isopropoxide (17.5 ml) in tetrahydrofuran (30 ml) was added dropwise, the mixture was stirred for an hour and a solution of compound (26) (5.00 g) in tetrahydrofuran (10 ml) was added dropwise. After reacting for an hour, the reaction solution was gradually poured into an aqueous solution of ammonium chloride cooled in ice with stirring and the resulted insoluble materials were filtered. It was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (27) (5.49 g).
1H-NMR (CDCl3) δ: 1.30 (9H, s), 1.35 (9H, s), 1.86 (3H, s), 3.11 (1H, dd, J=16.2, 2.1 Hz), 3.26 (1H, dd, J=16.2, 2.1 Hz), 5.55 (1H, s), 7.18 (1H, dd, J=11.1, 8.9 Hz), 8.18 (1H, ddd, J=8.9, 4.0, 2.9 Hz), 8.53 (1H, dd, J=7.0, 2.9 Hz).
Ratio of diastereomers (3S:3R=97:3) HPLC Column: CHIRALPAK AS-RH, Detection: 254 nm: Column temp.: 25° C., Mobile phase: 40% MeCNaq., Flow rate: 0.5 ml/min.
Note: As to the stereochemistry of compound (27) obtained above, it is known that 3S-isomer is preferentially prepared as written in the literature A etc. and it is also possible to prepare each diastereomer selectively by choosing appropriate metal species and/or a reaction condition.
Literature A: (I) T. Fujisawa et al., Terahedron Lett., 37, 3881-3884 (1996), (2) D. H. Hua et al, Sulfur Reports, vol. 21, pp. 211-239 (1999), (3) Y. Koriyama et al., Tetrahedron, 58, 9621-9628 (2002), (4) Yong Qin et al., J. Org. Chem., 71, 1588-1591 (2006).
The 4th step: A solution of 4 M HCl/1,4-dioxane (50 ml) was added to compound (27) (12.74 g) and the mixture was stirred at 80° C. for an hour, diethyl ether (50 ml) was added, the precipitated crystals were filtered and dried to give compound (28) (7.67 g).
1H-NMR (DMSO-d6) δ: 1.76 (3H, s), 3.25 (2H, s), 7.62 (1H, dd, J=119., 4 Hz), 8.33-8.48 (2H, m).
The 5th step: A solution of 1 M tetrahydrofuran-borane in tetrahydrofuan (2029 mil) was added dropwise to a solution of compound (28) (141.32 g) in tetrahydrofuran (707 ml) cooled in ice with stirring and it was reacted for 3 hours and 6 minutes. The reaction mixture was poured into a mixture of sodium bicarbonate (511 g), ice (1500 g) and ethyl acetate (3000 ml) stirred at room temperature, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (29) (115.46 g) as a crude product.
The 6th step: Toluene (25 ml) and water (12.5 ml) were added to the compound (29) (3.76 g) obtained in the 5th step and stirred under ice cooling. After the addition of potassium carbonate (7.97 g), thiophosgene (2.85 g) was added dropwise. After reacting for 3 hours, water was added, extracted with toluene and the organic layer was dried over anhydrous magnesium sulfate. A part of the solvent was evaporated under reduced pressure to give compound (30) as a crude product.
The 7th step: Compound (30) obtained in the 6th step was dissolved in toluene (17.4 ml) and thionyl chloride (6.67 g) and N,N-dimethylformamide (0.128 ml) were added with stirring at room temperature. The mixture was stirred at 80° C. for 2 hours, water was added, extracted with toluene and concentrated under reduced pressure to give compound (31) (4.03 g) as a crude product.
The 8 step: Compound (31) (4.03 g) obtained in the 7th step was dissolved in tetrahydrofuran (23.8 ml) and 28% ammonia-water (23.8 ml) was added under ice cooling with stirring. The mixture was stirred at room temperature for 3 days, the reaction solution was concentrated under reduced pressure and ethyl acetate was added therein. Conc. hydrochloric acid (6 ml) was added under ice cooling with stirring, the precipitated crystals were washed with ethyl acetate and water and dried to give compound (32) (2.14 g).
1H-NMR (DMSO-d6) δ: 1.76 (3H, s), 2.13-2.24 (1H, m), 2.68-2.74 (2H, m), 3.19-3.25 (1H, m), 7.63 (1H, dd, J=11.4, 8.9 Hz), 8.07 (1H, dd, J=7.0, 3.5 Hz), 8.36 (1H, dt, J=8.9, 3.5 Hz), 11.22 (1H, s).
The 9th step: Compound (32) (100 mg) was dissolved in methanol (2 ml), 10% palladium-carbon powder (50 mg) was added, and the mixture was stirred in a hydrogen atmosphere at room temperature for 18 hours. Insoluble materials were filtered off, the filtrate was evaporated under reduced pressure, sodium carbonate and water were added therein and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give compound (33) (68 mg).
1H-NMR (CDCl3) δ: 1.59 (3H, s), 1.81 (1H, ddd, J=14.1, 10.9, 3.5 Hz), 2.47 (1H, ddd, J=14.1, 5.9, 3.5 Hz), 2.71 (1H, td, J=10.9, 3.5 Hz), 2.89 (1H, ddd, J=10.9, 5.9, 3.5 Hz), 3.57 (2H, br s), 6.49 (1H, dt, J=8.5, 3.3 Hz), 6.67 (1H, dd, J=6.9, 3.3 Hz), 6.80 (1H, dd, J=11.8, 8.5 Hz).
The 1st step: A solution of compound (38) (5.00 g), (R)-(+)-2-methyl-2-propanesulfinamide (3.33 g) and tetraethyl orthotitanate (17.11 g) in tetrahydrofuran (50 ml) was reacted under beating to reflux for 7 hours, and then, it was poured portionwise into saturated brine and the resulted insoluble materials were filtered off. It was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with a silicagel column chromatography to give compound (39) (6.37 g).
1H-NMR (CDCl3) δ: 1.34 (9H, s), 2.79 (3H, s), 8.26 (1H, t, J=2.3 Hz), 8.76 (1H, d, J=2.3 Hz), 8.96 (1H, d, J=23 Hz).
The 2nd Step: A solution of 2.66 M n-butyllithium/n-hexane (32.4 ml) was added dropwise to a solution of diisopropylamine (9.36 g) in tetrahydrofuran (39 ml) cooled in an acetone/dry ice bath with stirring and the mixture was stirred under ice cooling for 30 minutes. The reaction solution was stirred again in an acetone/dry ice bath and a solution of tert-butyl acetate (4.88 g) in tetrahydrofuran (8 ml) was added dropwise. After stirring for 40 minutes, a solution of chlorotitanium triisopropoxide (23.00 g) in tetrahydrofuran (88 ml) was added dropwise. After stirring for 10 minutes, a solution of compound (39) (6.37 g) in tetrahydrofuran (65 ml) was added dropwise. After reacting for 30 minutes, the reaction solution was poured portionwise into an aqueous solution of ammonium chloride and the resulted insoluble materials were filtered off. It was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (40) (8.03 g) as a crude product.
The 3rd step: Lithium aluminium hydride (2.85 g) was added portionwise to a solution of the compound (40) (8.03 g) obtained in the 2nd step in tetrahydrofuran (100 ml) cooled in ice with stirring and the mixture was stirred for 2 hours. Acetone, water, and a 1N aqueous solution of sodium hydroxide were added portionwise and the mixture was stirred at room temperature for 30 minutes. The insoluble materials were filtered off and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give compound (41) (5.83 g) as a crude product
The 4st step: A solution of 10% HCl/methanol (60 ml) was added to a solution of the compound (41) (5.83 g) obtained in the 3rd step in methanol (60 ml) cooled in ice with stirring and stirred at room temperature for 16 hours. The reaction solution was made alkaline by the addition of water and potassium carbonate, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound (42) (5.07 g) as a crude product.
The 5th step: Imidazole (2.24 g) and t-butyldimethylsilyl chloride (3.77 g) were added to a solution of the compound (42) (5.07 g) obtained in the 4th step in N,N-dimethylformamide (26 ml) with stirring at room temperature and the mixture was stirred for 1 hour and 40 minutes. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (43) (3.82 g).
1H-NMR (CDCl3) δ: −0.04 (3H, s), −0.01 (3H, s), 0.85 (9H, s), 1.51 (3H, s), 1.98 (2H, t J=6.0 Hz), 3.49-3.54 (1H, m), 3.65 (1H, dt, J11.1, 6.0 Hz), 8.02 (1H, t, J=2.2 Hz), 8.53 (1H, d, J=2.2 Hz), 8.63 (1H, d, J=2.2 Hz).
The 6th step: Toluene (25 ml) and water (13 ml) were added to compound (43) (3.82 g) and stirred under ice cooling. After the addition of potassium carbonate (5.14 g), thiophosgene (1.83 g) was added dropwise. After reacting for 2 hours, water was added, extracted with chloroform and the organic layer was dried over anhydrous magnesium sulfate. A part of the solvent was evaporated under reduced pressure to give compound (44) as a crude product.
The 7th step: Thionyl chloride (4.43 g) and N,N-dimethylformamide (0.08 ml) were added to a solution of the compound (7) obtained in the 6th step in toluene (25 ml) with stirring at room temperature. The mixture was stirred at 80° C. for 5 hours, concentrated under reduced pressure to give compound (45) (5.03 g) as a crude product.
The 8th step: 28% Ammonia water (60 ml) was added to a solution of the compound (45) (5.03 g) obtained in the 7th step in tetrahydrofuran (60 ml) stirred under ice cooling and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to give compound (46) (4.92 g) as a crude product.
The 9th step: A mixture of the compound (46) (4.92 g) obtained in the 8th step, di-t-butyl dicarbonate (9.28 g), triethylamine (3.23 g), 4-dimethylaminopyridine (0.13 g) and tetrahydrofuran (106 ml) was stirred at room temperature for 3 days. The insoluble materials were filtered off, water was added to the filtrate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound (47) (8.31 g) as a crude product.
The 10th step: A mixture of the compound (47) (8.31 g) obtained in the 9th step, di-t-butyl dicarbonate (6.96 g), triethylamine (3.23 g), 4-dimethylaminopyridine (0.13 g) and tetrahydrofuran (50 ml) was stirred at room temperature for an hour. After the addition of water, it was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (48) (1.23 g).
1H-NMR (CDCl3) δ: 1.53 (18H, s), 1.60 (3H, s), 1.93 (1H, ddd, J=13.8, 9.4, 3.9 Hz), 2.06 (1H, ddd, J=13.8, 3.9, 1.9 Hz), 2.91 (1H, ddd, J=12.9, 3.9, 1.9 Hz), 3.15 (1H, ddd, J=12.9, 9.4, 3.9 Hz), 7.89 (1H, t, J=2.1 Hz), 8.55-8.57 (2H, m).
The 11th step: Compound (48) (190 mg), trisdibenzylideneacelonedipalladium (54 mg), dicyclohexylbiphenylphosphine (41 mg) were dissolved in toluene (5 ml), stirred at room temperaturea, and 1.6 M solution of lithium hexamethyldisilazide in tetrahydrofuran (0.73 ml) was added therein. The reaction solution was warmed up to 85° C. and stirred for 9 hours, then, it was cooled in ice and diethyl ether and a 1 N solution of hydrochloric acid were added. After stirring for 10 minutes, it was neutralized by the addition of a saturated aqueous solution of sodium carbonate and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (49) (27 mg).
1H-NMR (CDCl3) δ: 1.51 (9H, s), 1.68 (3H, s), 2.12 (1H, ddd, J=14.8, 11.0, 3.0 Hz), 2.38-2.47 (1H, m), 2.64-2.70 (1H, m), 2.78-2.82 (1H, m), 3.80 (2H, br s), 6.90 (1H, t, J=2.4 Hz), 7.98 (1H, dd, J=10.4, 2.4 Hz).
The 1st step: A solution of compound (50) (38.93 g), (R)-(+)-2-methyl-2-propanesulfinamide (13.20 g) and tetraethyl orthotitanate (67.76 g) in tetrahydrofuran (389 ml) was reacted under heating to reflux for 4 hours. A saturated aqueous solution of ammonium chloride was added portionwise therein and the resulted insoluble materials were filtered off. The filtrate was concentrated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound (51) (30.52 g) as a crude product.
1H-NMR (CDCl3) δ: 1.32 (9H, s), 2.83 (3H, s), 7.55-7.65 (2H, m), 8.06 (1H, d, J=8.5 Hz).
The 2nd step: A solution of tert-butyl acetate (22.99 g) in tetrahydrofuran (148 ml) was added dropwise to a 2.0 M solution of lithium diisoprorylamide/n-heptane/ethylbenzene/tetrahydrofuran (202.5 ml) cooled in an acetone/dry ice bath with stirring. After stirring for 45 minutes, a solution of chlorotitanium triisopropoxide (108.36 g) in tetrahydrofuran (342 ml) was added dropwise and stirred for 40 minutes. A solution of the compound (51) (30.52 g) in tetrahydrofuran (342 ml) was added dropwise and reacted for an hour. The reaction solution was poured portionwise into an aqueous solution of ammonium chloride with stirring under ice cooling and the resulted insoluble materials were filtered off. It was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (52) (27.40 g).
1H-NMR (CDCl3) δ: 1.30 (9H, s), 1.35 (9H, s), 1.65 (3H, s), 3.01 (1H, d, J=16.5 Hz), 3.38 (1H, d, J=16.5 Hz), 5.60 (1H, s), 7.31 (1H, dd, J=5.9, 2.7 Hz), 7.48-7.50 (2H, m).
The 3rd step: Lithium aluminium hydride (5.67 g) was added porionwise to a solution of the compound (52) (22.40 g) in tetrahydrofuran (336 ml) stirred in an ice salt bath and stirred for 7 hours. After the addition of acetone, water and a 1 N aqueous solution of sodium hydroxide, the insoluble materials were filtered off and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound (53) (18.75 g) as a crude product.
The 4th step: A solution of 10% HCl/methanol (94 ml) was added to a solution of the compound (53) (18.75 g) obtained in the 3rd step in methanol (94 ml) stirred under ice cooling and stirred at room temperature for 1.5 hours. The reaction solution was made alkaline by the addition of water and potassium carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound (54) (21.03 g) as a crude product.
The 5th step: Imidazole (5.49 g) and tert-butyldimethylsilyl chloride (10.53 g) were added to a solution of the compound (54) (21.03 g) in N,N-dimethylformamide (210 ml) stirred at room temperature and the mixture was stirred for an hour. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (55) (20.12 g).
1H-NMR (CDCl3) δ: −0.04 (3H, s), −0.02 (3H, s), 0.84 (9H, s), 1.47 (3H, s), 1.95-2.15 (2H, m), 3.54-3.63 (2H, m), 7.29 (1H, dd, J=6.1, 2.6 Hz), 7.45-7.48 (2H, m).
The 6th step: Toluene (66 ml) and water (33 ml) were added to compound (55) (10.06 g) and stirred under ice cooling. After the addition of potassium carbonate (11.13 g), thiophosgene (2.86 ml) was added dropwise. After reacting for an hours, water was added, extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (56) (9.43 g).
1H-NMR (CDCl3) δ: −0.03 (6H, s), 0.82 (9H, s), 1.80 (3H, s), 2.21-2.24 (1H, m), 2.44-2.48 (1H, m), 3.57 (1H, ddd, J=12.0, 5.8, 4.8 Hz), 3.71 (1H, ddd, J=12.0, 5.8, 4.8 Hz), 7.37 (1H, dd, J=7.5, 1.2 Hz), 7.48-7.58 (2H, m).
The 7th step: 28% Ammonia water (47 ml) was added to compound (56) 9.43 g) dissolved in tetrahydrofuran (94 ml) stirred at room temperature. After stining for 16 hours, water was added, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (57) (6.35 g) as a crude product.
The 8th step: Acetic acid (1.09 g) and a 1.0 M solution of tetrabutylammonium fluoride/tetrahydrofuran (18.20 mil) were added to a solution of the compound (57) (6.35 g) obtained in the 7th step in tetrahydrofuran (127 ml) stirred under ice cooling. After stirring at room temperature for 3 hours, water and potassium carbonate were added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (58) (4.47 g).
1H-NMR (CDCl3) δ: 1.85 (3H, s), 2.27-2.31 (2H, br m), 3.73-3.83 (2H, m), 5.86 (2H, br s), 7.43 (1H, d, J=7.8 Hz), 7.52 (11H, d, J=7.8 Hz), 7.61 (1H, t, J=7.8 Hz), 7.81 (1H, br s).
The 9th step: 1-Chloro-N,N,2-trimethyl-1-propenylamine (2.16 g) was added to compound (58) (4.47 g) dissolved in dichloromethane (89 ml) stirred under ice cooling. After stirring at room temperature for 1.5 hours, water was added and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (59) (2.91 g).
1H-NMR (CDCl3) δ: 1.53 (3H, s), 1.88 (1H, ddd, J=13.9, 10.1, 3.8 Hz), 2.40 (1H, ddd, J=13.9, 6.6, 3.8 Hz), 2.71 (1H, ddd, J=13.9, 10.1, 3.8 Hz), 2.95 (1H, tt, J=6.6, 3.8 Hz), 4.33 (2H, br s), 7.29 (1H, dd, J=7.5, 1.2 Hz), 7.41-7.50 (1H, m).
The 10th step: A mixture of compound (59) (2.91 g), di-tert-butyl dicarbonate (5.52 g), 4-dimethylaminopyridine (0.12 g) and tetrahydrofuran (29 ml) was stirred at room temperature for 2.5 hours. The reaction solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (60) (1.23 g).
1H-NMR (CDCl3) δ: 1.53 (23H, s), 1.60 (3H, s), 1.93 (1H, ddd, J=13.8, 9.4, 3.9 Hz), 2.06 (1H, ddd, J=13.8, 3.7, 1.8 Hz), 2.91 (1H, ddd, J=12.7, 3.7, 1.9 Hz), 3.15 (1H, ddd, J=12.9, 9.2, 3.7 Hz), 7.89 (1H, t, J=2.1 Hz), 8.55-8.57 (2H, m).
The 11th step: Compound (60) (3.30 g), trisdibenzylideneacetonedipalladium (0.93 g), dicyclohexylbiphenylphosphine (0.73 g) were dissolved in toluene (66 ml), stirred at room temperature, and a 1.6 M solution of lithium hexamethyldisilazide in tetrahydrofuran (12.7 ml) was added therein. The reaction solution was warmed up to 80° C. and stirred for 8 hours, then, it was cooled in ice and diethyl ether and a 1 N solution of hydrochloric acid were added. After stirring for 5 minutes, it was neutralized by the addition of a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (61) (1.55 g).
1H-NMR (CDCl3) δ: 1.61 (3H, s), 1.74-1.80 (1H, m), 1.96-2.11 (1H, m), 2.64-2.82 (2H, m), 4.41 (2H, br s), 6.39 (1H, dd, J=8.1, 0.6 Hz), 6.71 (1H, dd, J=8.1, 0.6 Hz), 7.42 (1H, t, J=8.1 Hz).
The 1st step: Compound (63) (3.31 g) prepared in the same manner as Reference Example 6 and 7 described above was dissolved in dichloromethane (16.5 ml), bis(2,4-dimethoxybenzyl)amine (4.45 g) was added and the solvent was evaporated under reduced pressure after stirring at room temperature for an hour and standing for 15 hours. The residue was purified with silicagel chromatography to give compound (63) (5.77 g).
1H-NMR (CDCl3): −0.10 (3H, s), −0.07 (3H, s), 0.77 (9H, s), 1.93 (3H, s), 2.08-2.27 (1H, m), 3.06-3.28 (1H, m), 3.38 (1H, ddd, J=10.8, 6.8, 6.8 Hz), 3.55 (1H, ddd, J=10.8, 6.8, 6.8 Hz), 3.78 (6H, s), 3.79 (6H, s), 4.81-5.05 (1H, br), 6.43-6.50 (4H, m), 7.07 (1H, d, J=1.9 Hz), 7.17 (2H, d, J=7.3; H-z), 8.05-8.16 (2H, m).
The 2nd step: Compound (63) (5.77 g) was dissolved in tetrahydrofuran (60 ml) and acetic acid (1.01 g) and 1 M tetrabutylammonium fluoride/tetrahydrofuran-solution (15 ml) were added and the mixture was stirred at room temperature for 150 minutes. Water was added, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel chromatography to give compound (64) (3.94 g).
1H-NMR (CDCl3): 1.99 (3H, s), 1.91-2.02 (1H, m), 3.10 (1H, ddd, J=14.6, 6.6, 5.2), 3.36-3.51 (2H, m), 3.78 (6H, s), 3.80 (6H, s), 4.58 (2H, d, J=15.8 Hz), 4.72 (2H, d, J=15.8 Hz), 6.43-6.51 (4H, m), 7.12 (1H, dd, J=5.3, 2.0 Hz), 7.18-7.29 (3H, m), 8.20 (1H, dd, J=5.3, 0.6 Hz), 8.28-8.31 (1H, br).
The 3rd step: Compound (64) (3.94 g) was dissolved in dichloromethane (20 ml) and 1-chloro-N,N′,2-trimethyl-1-propenylamine (1.86 mil) was added under ice cooling with stirring. After stirring at room temperature for 2 hours, water was added, extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (65) (3.41 g).
1H-NMR (CDCl3): 1.49 (3H, s), 1.99 (1H, ddd, J=13.3, 7.6, 3.2 Hz), 2.31 (1H, ddd, J=13.3, 8.6, 3.7), 2.78 (1H, ddd, J=12.2, 8.6, 3.2 Hz), 3.04 (1H, ddd, J=12.2, 7.6, 3.7 Hz), 3.77 (6H, s), 3.79 (6H, s), 4.60 (2H, d, J=15.8 Hz), 4.76 (2H, d, J=15.8 Hz), 6.45-6.52 (4H, m), 7.08 (1H, dd, J=5.3, 2.1 Hz), 7.17-7.27 (3H, m), 8.40 (1H, dd, J=5.3, 0.5 Hz).
The 1st step: Compound (66) (4.72 g) derived by a conventional method from an intermediate prepared in the same manner as the compound (27) described above was dissolved in tetrahydrofuran (150 ml) and a diethylether solution of methyl magnesium bromide (3M, 37 ml) was added dropwise with stirring under ice cooling in a nitrogen stream for 12 minutes. After stirring 3 hours, a saturated aqueous solution of ammonium chloride (190 ml) was added dropwise, extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (67) (2.11 g).
1H-NMR (DMSO-d6): 0.75 (3H, s), 1.09 (3H, s), 1.21 (9H, s), 1.79 (3H, s), 2.06 (1H, m), 2.29 (1H, m), 4.97 (1H, s), 6.57 (1H, s), 7.17 (1H, dd, J=8.7, 12.0 Hz), 7.48-7.53 (1H, m), 7.99-8.03 (1H, m), 11.26 (1H, bs).
The 2nd step: Compound (67) (2.11 g) was dissolved in methanol (7.8 ml) and hydrochloric acid-methanol solution (5-10%)(15.6 ml) was added with stirring at room temperature, and the mixture was stirred for 1.5 hours. Then the reaction solution was poured into ice water and ethyl acetate (100 ml), a saturated aqueous solution of sodium bicarbonate (50 ml) was added and extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate (50 ml), organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from n-hexane to give compound (68) (1.42 g).
1H-NMR (DMSO-d): 0.65 (3H, s), 1.10 (3H, s), 1.43 (3H, s), 1.85 (1H, d, J=14.4 Hz), 2.17 (1H, dd, J=1.5, 14.4 Hz), 7.12 (1H, dd, J2.7, 12.0 Hz), 7.60-7.64 (1H, m), 7.90 (1H, dd, J=2.7, 7.5 Hz), 11.35 (1H, bs).
The 3rd step: Toluene (9.6 ml) and water (4.8 ml) were added to compound (68) (1.42 g) and suspended, potassium carbonate (2.13 g) was added with stirring under ice cooling and 2 minutes later thiophosgene (0.51 ml) was added at once and the stirring was continued.
The temperature was back to room temperature 40 minutes later, toluene (40 ml) and water were added and extracted an hour later. The aqueous layer was further extracted with toluene, organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude product (69) (2.02 g).
The 4th step: Tetrahydrofuran (17 ml) was added to triphenylphosphine (1.735 g) and N-chlorosuccinimide (833 mg), suspended in a nitrogen stream and stirred at room temperature for 10 minutes. A tetrahydrofuran (21 ml) solution of the crude product (69) (2.02 g) was added dropwise using a dropping funnel for 2 minutes. After stirring for 6 hours, the mixture was left stand at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (70) (828 mg).
1H-NMR (DMSO-d6): 1.54 (3H, s), 1.86 (3H, s), 2.81 (1H, d, J=13.8 Hz), 2.92 (1H, d, J=3.8 Hz), 4.73 (1H, s), 4.85 (11H, m), 7.28-7.35 (1H, m), 7.77-7.82 (2H, m), 11.39 (H, bs).
The 5th step: Compound (70) (828 mg) was dissolved in tetrahydrofuran (4 ml), conc. ammonia water (28%) (4 ml) was added with stirring under ice cooling and the temperature was back to room temperature after stirring for 5 minutes. After 25 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate (50 ml). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel chromatography to give a compound (71) (260 mg).
1H-NMR (DMSO-d6): 1.47 (3H, bs), 1.66 (3H, bs), 2.58 (1H, d, J=12.3 Hz), 4.71 (1H, s), 4.87 (3H, bs), 6.42 (1H, bs), 6.51 (1H, dd, J=2.7, 7.2 Hz), 6.75 (2H, bs), 7.54 (1H, bs).
The 6th step: Compound (71) (245 mg) was dissolved in chilled conc. sulfuric acid (4.9 ml) and stirred under ice cooling for 2 hours. The reaction solution was poured into ice water with stirring and pH was adjusted to 2-3 by the addition of a 5N aqueous solution of sodium hydroxide. Ethyl acetate (100 ml) and an aqueous solution of potassium carbonate were added and extracted under alkaline condition. The alkaline layer was further extracted with ethyl acetate (50 ml). Organic layers were combined, washed with saturated brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (72) (101 mg) as a crystal.
1H-NMR (DMSO-d6): 0.83 (3H, s), 1.27 (3H, s), 1.44 (3H, s), 1.54 (1H, d, J=14.1 Hz), 2.45 (1H, d, J=14.1 Hz), 4.79 (2H, s), 5.89 (2H, bs), 6.32-6.37 (1H, m), 6.58 (1H, dd, J=2.7, 7.2 Hz), 6.72 (1H, dd, J=8.7, 12.3 Hz).
The 1st step: Ethyl bromodifluoroacetate (0.77 ml) was added to a suspension of zinc dust (392 mg) in tetrahydrofuran (4 ml) with stirring in a nitrogen stream at room temperature, stirred for 15 minutes, ethyl bromodifluoroacetate (0.29 ml) was added, stirred for 30 minutes to prepare a solution of ethyl bromozincdifluoroacetate. This solution was added to a solution of compound (73) in tetrahydrofuran (3 ml) in a nitrogen stream and stirred for 8 hours. 3% Ammonia water was added to the reaction mixture with stirring under ice cooling, extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (74) (696 mg).
1H-NMR (DMSO-d6) δ: 1.17 (3H, t, J=7.2 Hz), 1.18 (9H, s), 2.00 (3H, brs), 4.24 (2H, q, J=7.2 Hz), 5.56 (1H, brs), 7.56 (dd, J=9.0, 11.7 Hz), 8.36 (1H, m), 8.49 (1H, dd, J=3.0, 6.6 Hz).
The 2nd step: Compound (74) (670 mg) was dissolved in tetrahydrofuran (6.7 ml) and lithium borohydride (71 mg) was added in a nitrogen stream with stirring under ice cooling. After stirring for 30 minutes, acetic acid (198 mg) and ice water were added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (75) (401 mg).
1H-NMR (DMSO-d6) δ: 1.20 (9H, s), 2.00 (3H, d, J=3.6 Hz), 3.80 (1H, m), 4.00 (1H, m), 5.99 (1H, s), 6.34 (1H, 1, J=5.7 Hz), 7.53 (1H, dd, J=9.0, 12.0 Hz), 831 (1H, m), 8.50 (1H, dd, J=2.7, 6.6 Hz).
The 3rd step: Compound (75) (394 mg) was dissolved in methanol (3 ml), and 4N—HCl/1,4-dioxane (1.35 ml) was added with stirring under ice cooling. After stirring for 30 minutes, the mixture was stirred at room temperature for 1.5 hours. Ice water was added to the reaction solution and washed with ethyl acetate. The aqueous layer was made alkaline by the addition of a 2M aqueous solution of potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give compound (76) (293 mg).
1H-NMR (DMSO-d6) δ: 1.62 (3H, d, J=2.7 Hz), 2.62 (2H, brs), 3.65-3.83 (2H, m), 5.31 (1H, brt), 7.44 (1H, dd, J=9.0, 11.4 Hz), 8.23 (1H, m), 8.59 (1H, dd, J=3.0, 6.9 Hz).
The 4th step: Compound (76) (266 mg) was dissolved in acetone (3 ml) and benzoyl isothiocyanate (164 mg) was added in a nitrogen stream with stirring under ice cooling. After stirring for an hour, the mixture was stirred at room temperature for an hour. The reaction solution was concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (77) (353 mg).
1H-NMR (DMSO-d6) δ: 2.30 (3H, brs), 3.65-3.96 (2H, m), 5.90 (1H, brt), 7.42-7.68 (4H, m), 7.93-7.96 (2H, m), 8.17-8.33 (2H, m), 11.42 (1H, brs), 12.31 (1H, brs).
The 5th step: Compound (77) (348 mg) was dissolved in dichloromethane (4 ml) and 1-chloro-N,N-2-trimethyl-1-propenylamine (131 mg) was added in a nitrogen stream with stirring under ice cooling. After stirring for 15 hours at room temperature, ice water was added and neutralized by the addition of potassium carbonate. It was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (78) (308 mg).
1H-NMR (CDCl3) δ: 1.89 (3H, d, J=3.0 Hz), 3.17 (1H, ddd, J=8.4, 10.2, 13.2 Hz), 3.51 (1H, ddd, J=6.0, 13.2, 19.2 Hz), 7.23 (1H, dd, J9.0, 10.8 Hz), 7.49-7.64 (3H, m), 7.91 (2H, d, J=7.2 Hz), 8.24 (1H, m), 8.43 (1H, dd, J=3.0, 6.6 Hz), 8.57 (1H, br).
The 6th step: Compound (78) (297 mg) was dissolved in ethanol (4 ml), water (1.5 ml) and conc. hydrochloric acid (1.5 ml) were added and the mixture was stirred at 90° C. for 2.5 hours. Water was added to the reaction solution, washed with ethyl acetate and the aqueous layer was made alkaline by the addition of a 2M aqueous solution of potassium carbonate. It was extracted with ethyl acetate, washed with brine and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (79) (89 mg).
1H-NMR (CDCl3) δ: 1.85 (3H, d, J=3.6 Hz), 3.15 (1H, ddd, J=8.7, 10.5, 12.9 Hz), 3.50 (1H, ddd, J=5.4, 12.9, 18.3 Hz), 4.51 (2H, brs), 7.19 (1H, dd, J=9.0, 11.1 Hz), 8.20 (1H, ddd, J=3.0, 6.9, 9.0 Hz), 8.54 (1H, dd, J=3.0, 6.9 Hz).
The 7th step: Compound (79) (82 mg) was dissolved in dichloromethane (1 ml), di-tert-butyldicarbonate (176 mg) and 4-dimethylaminopyridine (4 mg) were added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (80) (101 mg).
1H-NMR (CDCl3) δ: 1.56 (18H, S), 1.90 (3H, d, J=3.6 Hz), 3.27 (1H, ddd, J=6.6, 9.3, 12.9 Hz), 3.69 (1H, ddd, J=4.2, 12.9, 17.4 Hz), 7.23 (1H, dd, J=9.0, 12.0 Hz), 8.24 (1H, ddd, J=3.0, 9.0, 12.0 Hz), 8.41 (1H, ddd, J=2.4, 3.0, 6.0 Hz).
The 8th step: Compound (80) (4.76 g) was dissolved in methanol (70 ml), 10% Pd—C(containing 50% water) (238 g) was added and the mixture was stirred in a hydrogen atmosphere for 20 hours. The catalyst was filtered off, the solvent was evaporated under reduced pressure to give compound (81) (4.43 g)
1H-NMR (CDCl3) δ: 1.54 (18H, S), 1.85 (3H, d, J=2.4 Hz), 3.24 (1H, m), 3.44 (1H, m), 3.53 (2H, brs), 6.61 (1H, m), 6.82-6.89 (2H, m).
The 1st step: A solution of 2.0M lithium diisopropylamide/n-heptane/ethyl benzene (182 ml) in tetrahydrofuan (150 ml) was cooled in a dry ice-acetone bath, and a solution of methyl isobutyrate (27.17 g) in tetrahydrofuran (90 ml) was added dropwise with stirring. After stirring for 40 minutes, a solution of chlorotitanium triisopropoxide (97.07 g) in tetrahydrofuran (300 ml) was added dropwise. After stirring for 15 minutes, a solution of compound (86) (25.39 g) in tetrahydrofuran (150 ml) was added dropwise. After the reaction for 2.5 hours, the reaction mixture was poured portionwise into an aqueous solution of ammonium chloride stirred under ice cooling and the formed insoluble materials were filtered. It was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (87) (23.98 g).
1H-NMR (CDCl3) δ: 1.12 (3H, s), 1.22 (3H, s), 1.35 (9H, s), 1.99 (3H, d, J=5.8 Hz), 3.75 (3H, s), 5.65 (1H, s), 7.20 (OH, dd, J=11.5, 8.9 Hz), 8.18-8.21 (1H, m), 8.45 (1H, dd, J=6.9, 2.9 Hz).
The 2nd step: Compound (87) (391 mg) was dissolved in tetrahydrofuran (4 ml) and lithium borohydride (44 mg) was added in 3 minutes in a nitrogen stream with stirring at room temperature. After stirring for 2 hours, lithium borohydride (22 mg) was further added and the stirring was continued. After stirring for 2 hours, a saturated aqueous solution of ammonium chloride was slowly added to the reaction solution with stirring under ice cooling, extracted with ethyl acetate 5 minutes later, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (88) (175 mg).
1H-NMR (DMSO-d6) δ: 0.65 (3H, d, J=1.8 Hz), 0.93 (3H, s), 1.22 (9H, s), 1.93 (3H, d, J=6.6 Hz), 3.24 (1H, d, J=8.4 Hz), 3.74 (1H, d, J=8.4 Hz), 5.96 (1H, bs), 6.75 (1H, s), 7.47 (1 μl, dd, J=9.0, 12.0 Hz), 8.23 (1H, ddd, J=3.0, 3.0, 9.0 Hz), 8.39 (1H, dd, J=3.0, 6.9 Hz).
The 3rd step: Compound (88) (331 mg) was dissolved in methanol (1.5 ml), and a hydrogen chloride-methanol solution (5-10%) (3 ml) was added with stirring at room temperature. After stirring for 1.5 hours, the reaction solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate-methanol (9:1), poured into ice water, and a saturated aqueous solution of sodium bicarbonate (4 ml) was added, extracted, washed with saturated brine and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the powder obtained by the addition of n-hexane to the solid was filtered to give a compound (89) (207 mg).
1H-NMR (DMSO-d6) δ: 0.80 (6H, s), 1.59 (3H, d, J=4.5 Hz), 3.16 (1H, d, J=10.8 Hz), 7.38 (1H, dd, J=9.0, 12.0 Hz), 8.17 (1H, ddd, J=3.0, 3.0, 9.0 Hz), 8.64 (1H, dd, J=3.0, 6.9 Hz)
The 4th step: Compound (89) (150 mg) was dissolved in acetone (3 ml) and benzoyl isothiocyanate (0.079 ml) was added in a nitrogen stream with stirring under ice cooling. After stirring for 2 hours, the reaction solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (90) (236 mg).
LCMS: 420 m/z [M+H]+
The 5th step: Compound (90) (233 mg) was dissolved in dichloromethane (4 ml) and chloropropenylamine (0.081 ml) was added at once in a nitrogen stream with stirring at room temperature. After stirring for 23 hours, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (91) (128 mg).
1H-NMR (DMSO-d6) δ: 0.83 (3H, s), 1.12 (3H, s), 1.72 (3H, s), 2.69 (1H, d, J=13.2 Hz), 2.90-3.10 (1H, m), 7.44-7.58 (4H, m), 8.00 (2H, d, J=7.5 Hz), 8.23-8.35 (2H, m), 10.75 (1H, bs).
The 6th step: Compound (91) (20 mg) was suspended in 99.5% ethanol (0.4 ml), 6N hydrochloric acid (0.2 ml) was added and the mixture was stirred in a oil bath beated to 90° C.
After stirring for 17 hours, the reaction solution was poured into water, and extracted with ethyl acetate. The aqueous layer was made alkaline by the addition of a saturated aqueous solution of potassium carbonate (pH=11), extracted with ethyl acetate, washed with saturated brine and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (92) (14 mg).
1H-NMR (DMSO-d6) δ: 0.72 (3H, s), 1.00 (3H, d, J=3.6 Hz), 1.54 (3H, d, J=4.8 Hz), 2.61 (1H, d, J=12.3 Hz), 3.09 (H, d J=12.3 Hz), 5.98 (2H, s), 7.41 (1H, dd, J=9.0, 11.7 Hz), 8.16-8.21 (1H, m), 8.42 (1H, dd, J=3.0, 6.9 Hz).
The 7th step: Compound (92) (12 mg) was dissolved in dichloromethane (0.1 ml) and a di-tert-butyldicarbonate-dichloromethane solution (0.0966M, 1.2 ml) was added with stirring at room temperature. After stirring for 2 hours, the reaction solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (93) (15 mg).
1H-NMR (DMSO-d6) δ: 0.70 (3H, s), 1.02 (3H, s), 1.43 (9H, s), 1.56 (3H, bs), 2.61 (1H, d, J=2.9 Hz), 3.16 (1H, m), 7.45 (1H, dd, J=9.0, 11.4 Hz), 8.20-8.24 (1H, m), 8.35 (1H, m), 9.87 (1H, bs).
The 8th step: Methanol (4.1 ml) was added to compound (93) (823 mg), suspended, and 10% Pd—C (50% wet) (412 mg) was added. A catalytic reduction was carried out at normal pressure, and methanol (8.2 ml) was added when a solid was precipitated and the reduction was further continued. After 23 hours, the catalyst was filtered through a Celite pad, washed with warm methanol, and the washings were combined. The solvent was evaporated under reduced pressure and the powder precipitated by the addition of diisopropylether to the residue was filtered to give compound (94) (638 mg).
1H-NMR (DMSO-d6) δ: 0.87 (3H, bs), 1.06 (3H, bs), 1.39 (9H, s), 1.57 (3H, bs), 2.66-2.72 (2H, m), 4.97 (2H, bs), 6.45-6.47 (2H, m), 6.78 (1H, m), 9.65 (1H, bs).
The 1st step: 3-(Trifluoromethyl)-1H-pyrazole (591 mg) was dissolved in dimethylformamide (7 ml), potassium carbonate (601 mg) and compound (104) (500 mg) were added thereto and stirred at room temperature overnight. The reaction was quenched by an addition of water. The insoluble materials were filtered and washed with diisopropylether. The resulted solid was dried under reduced pressure to give compound (105) (644 mg).
1H-NMR (CDCl3) δ: 4.08 (3H, s), 6.81 (1H, d, J=2.5 Hz), 8.65 (1H, s), 9.14 (1H, s), 9.45 (1H, s).
The 2nd step: Compound (105) (640 mg) was added to a mixed solvent of water-methanol (6 ml, 1:1), lithium hydroxide (84 mg) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was acidified by the addition of 2N hydrochloric acid, the insoluble materials were filtered off and washed with diisopropylether.
The resulted solid was dried under reduced pressure to give compound (106) (343 mg).
1H-NMR (DMSO-d6) δ: 7.20 (1H, d, J=2.5 Hz), 8.93 (1H, s), 9.12 (1H, s), 9.33 (1H, s).
The 1st step: A mixture of compound (107) (1000 mg), dioxane (2 ml), and 28% ammonia water (2 ml) was stirred at 50° C. for 19 hours. The reaction solution was concentrated under reduced pressure. Water was added to the residue, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give a compound (108) (476 mg).
1H-NMR (CDCl3) δ: 1.63 (9H, s), 5.04 (2H, br s), 8.03 (1H, s), 8.69 (1H, s).
The 2nd step: 3-Bromo-2-oxopropanoic acid ethyl ester (1582 mg) was added to compound (108) (475 mg) in dimethoxyethane (4 ml) and the mixture was stirred at 75° C. for 2.5 hours. The reaction solution was diluted with diisopropylether, the insoluble materials were filtered, washed with diisopropylether and hexane, and dried under reduced pressure. The residue was stirred in tert-butyl alcohol (7.5 ml) at 95° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (109) (709 mg).
1H-NMR (CDCl3) δ: 1.46 (3H, t, J=7.1 Hz), 1.66 (9H, s), 4.50 (2H, q, J=7.1 Hz), 8.35 (1H, s), 8.89 (1H, s), 9.24 (1H, s).
The 3rd step: A mixture of compound (09) (270 mg), dioxane (3 ml) and 28% ammonia water (2.5 ml) was stirred in a pressure bottle at 50° C. for 6 hours. The reaction solution was concentrated under reduced pressure to give a crude product of compound (110) (249 mg).
1H-NMR of the crude product (CDCl3) δ: 1.67 (9H, s), 5.79 (1H, br s), 8.35 (1H, s), 8.90 (1H, s), 9.15 (1H, s).
The 4th step: 2,2,2-Trichloroacetyl chloride (253 mg) was added at 0° C. to a mixture of compound (10) (146 mg), triethylamine (282 mg) and dimethylaminopyridine (6.8 mg) in tetrahydrofuran (9 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and the reaction was quenched by the addition of a saturated aqueous solution of sodium bicarbonate. It was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give compound (111) (99 mg) as a crude product.
The 5th step: Compound (111) (95 mg) was dissolved in chloroform (3 ml), trifluoroacetic acid (1330 mg) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give a crude product. The residue was suspended with ethyl acetate and diisopropylether and the insoluble materials were filtered and washed with diisopropylether. The residue was dried under reduced pressure to give a composition including compound (112).
The 1st step: A 2.6M n-butyl lithium/hexane solution (9.38 ml) was added dropwise for 10 minutes to diisopropylamine (2.75 g) dissolved in tetrahydrofuran (25 ml) under stirring in a dry ice/acetone bath. After stirring in a ice bath for 10 minutes and in a dry ice/acetone bath for 10 minutes, tert-butyl α-benzyloxyacetate (5.21 g) dissolved in tetrahydrofuran (25 ml) was added dropwise for 30 minutes. After stirring for 40 minutes, chlorotitaniumtriisopropoxide (6.60 g) dissolved in tetrahydrofuran (50 ml) was added dropwise. After stirring for 30 minutes, compound (73) (2.68 g) dissolved in tetrahydrofuran (50 ml) was added dropwise for 10 minutes and stirred for 90 minutes. A suspension of ammonium chloride (7.52 g) in tetrahydrofuran-water (1:1, 40 ml) was stirred at room temperature, and the reaction mixture was added thereto at once and the precipitated insoluble materials were filtered. The filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (4.49 g).
1H-NMR (CDCl3) δ: 1.14 (3.6H, s), 1.22 (3.6H, s), 1.27 (5.4H, s), 1.39 (5.4H, s), 1.96 (1.2H, s), 1.99 (1.8H, s), 4.31 (0.4H, s), 4.34 (0.6H, d, J=1.6 Hz), 4.41 (0.4H, d, J=11.6 Hz), 4.45 (0.6H, s), 4.56 (0.4H, s), 4.68 (0.6H, d, J=11.6 Hz), 4.81 (0.4H, d, J=11.6 Hz), 5.01 (0.6H, s), 7.06-7.38 (6H, m), 8.18 (0.6H, d, J=8.8 Hz), 8.24 (0.4H, d, J=9.1 Hz), 8.42-8.47 (1H, m).
The 2nd step: Compound (113) (4.49 g) was dissolved in trifluoroacetic acid (44 ml), stirred at room temperature for an hour and the solvent was evaporated under reduced pressure. The resulted residue was dissolved in 10% hydrochloric acid-methanol (44 ml), stirred at room temperature overnight and the reaction solution was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (22 ml) and a solution of 1 M-borane-tetrahydrofuran complex in tetrahydrofuran (44.1 mJ) was added dropwise for 15 minutes under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. Water (50 ml) was added therein with stirring under ice cooling, stirred for 15 minutes and ethyl acetate (50 ml) and potassium carbonate (16 g) were added. It was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained compound (114) (3.27 g) was used in the next step without purification.
The 3rd step: Benzoyl isothiocyanate (1.41 ml) was added to compound (114) (3.27 g) in methylenechloride (16.5 ml), stirred at room temperature for an hour and the solvent was evaporated under reduced pressure. The residue was purified with a silicagel column chromatography to give compound (115) (3.14 g).
1H-NMR (CDCl3) δ: 2.14 (1.35H, s), 2.21 (1.65H, s), 3.73-4.07 (3H, m), 4.43 (0.55H, d, J=11.5 Hz), 4.63 (0.55H, d, J=11.5 Hz), 4.74 (0.45H, d. J=11.5 Hz), 4.78 (0.45H, d, J=11.5 Hz), 7.20-7.38 (4H, m), 7.43-7.51 (2H, m), 7.56-7.63 (1H, m), 7.75-7.86 (2H, m), 8.08-8.17 (1H, m), 8.24-8.34 (1H, m), 8.91-9.01 (1H, m), 11.81 (0.55H, s), 11.90 (0.45H, s).
The 4th step: α-Chlorotetramethylenamine (1.67 ml) was added to compound (115) (3.14 g) in methylenechloride (15.5 ml), stirred at room temperature for 30 minutes and pH was adjusted to over 11 by the addition of water (15 ml) and potassium carbonate. It was extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (116) (2.66 g).
1H-NMR (CDCl3) δ: 1.58 (3 bH, s), 1.81 (3 aH, s), 2.76 (bH, dd, J=13.4, 1.8 Hz), 3.09 (bH, dd, J=13.4, 6.1 Hz), 3.16 (aH, dd, J=13.8, 3.9 Hz), 3.35 (aH, dd, J=13.8, 1.8 Hz), 4.21-4.25 (aH, m), 4.28 (aH, d, J=12.4 Hz), 4.33-4.38 (bH, m), 4.49-4.56 (a+bH, m), 4.73 (bH, d, J=11.9 Hz), 6.83-7.60 (10H, m), 7.91-8.23 (3H, m), 8.25-8.30 (bH, m), 8.74 (aH, m).
The 5th step: Hydrazine monohydrate (0.73 ml) was added to compound (116) (1.44 g) in ethanol (7.2 ml) and stirred at room temperature for 2 hours. Water was added, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained compound (117) (1.14 g) was used in the next step without purification.
The 6th step: A solution of di-tert-butyl dicarbonate (1.65 g) in methylenechloride (5.5 ml) and 4-dimethylaminopyridine (37 mg) were added to compound (117) (1.14 g) in methylenechloride (5.5 ml) and stirred at room temperature for an hour. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (118) (1.52 g).
1H-NMR (CDCl3) δ: 1.47 (8.1H, s), 1.51 (9.9H, s), 1.53 (1.35H, s), 1.75 (1.65H, s), 3.01-3.49 (2H, m), 3.81-3.86 (0.55H, m), 4.07-4.09 (0.45H, m), 4.17 (0.45H, d, J=12.1 Hz), 4.25 (0.55H, d, J=1.16 Hz), 4.41 (0.45H, d, J=12.1 Hz), 4.49 (0.55H, d, J=11.6 Hz), 6.73-6.78 (1H, m), 6.94-7.23 (5H, m). 8.11-8.18 (1H, m), 8.22-8.27 (0.55H, m), 8.51-8.55 (0.45H, m).
The 7th step: 20 w/w % Palladium hydroxide supported by carbon (40 mg) was added to a solution of compound (118) (211.3 mg) in ethanol (2 ml), stirred in a hydrogen atmosphere of 1 atom at room temperature for 22 hours and filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (119) (149.1 mg).
1H-NMR (CDCl3) δ: 1.46 (8.1H, s), 1.51 (9.9H, s), 1.54 (1.35H, s), 1.74 (1.65H, s), 2.91 (0.55H, d, J=12.9 Hz), 3.02 (0.55H, dd, J=12.9, 6.3 Hz), 3.15 (0.45H, dd, J=13.3, 3.0 Hz), 3.37-3.73 (2H, br), 3.43 (0.45H, d, J=13.3 Hz), 4.13-4.18 (1H, m), 4.22 (0.45H, d, J=11.9 Hz), 4.34 (0.45H, d, J=11.9 Hz), 4.49 (0.55H, d, J=11.6 Hz), 4.59 (0.55H, d, J=11.6 Hz), 6.45-6.61 (1H, m), 6.71-7.39 (7H, m).
Compound (34) (125 mg) and DMT-MM (162 mg) were suspended in methanol (1.2 ml), stirred at room temperature for 30 minutes and compound (33) (117 mg) was added therein. After stirring for 5 hours, the product was isolated by a silicagel thin-layer chromatography to give the objective compound (46) (13.5 mg).
1H-NMR (DMSO-d6) δ: 1.47 (3H, s), 1.81 (1H, d, J=11.6 Hz), 2.12 (1H, bs), 2.54-2.59 (1H, m), 2.97 (1H, bs), 3.28 (2H, d, 6.4 Hz), 3.52 (2H, d, 6.5 Hz), 3.88 (3H, s), 5.69 (2H, s), 7.09 (1H, dd, J=11.8, 6.8 Hz), 7.50 (1H, s), 7.60 (1H, d, J=7.8 Hz), 7.67 (1H, s), 10.06 (1H, s).
The 1st step: Sodium hydride (302 mg) is added to DMF (3.0 ml) and 3-butene alcohol (3.0 ml) under ice cooling in a nitrogen atmosphere. After stirring at room temperature for 1.0 hour, compound (35) (300 mg) was added and stirred under heating at 65° C. After 7 hours, the reaction solution was neutralized by the addition of 2M hydrochloric acid and concentrated under reduced pressure. Water was added to the resulted residue and filtered to give compound (36) (87 mg, 23.7%).
The 2nd step: Compound (36) (65.8 mg) and compound (37) (50 mg) were dissolved in methanol (2.0 ml), DMT-MM (93.7 mg) was added and the mixture was stirred at room temperature. After 6 hours, the solvent was evaporated under reduced pressure and the residue was purified with a column chromatography using chloroform/methanol to give compound (86) (40 mg, 44.5%).
1H-NMR (DMSO-d6) δ: 1.65 (3H, s), 2.03-2.09 (1H, m), 2.34-2.38 (1H, m), 2.51-2.61 (2H, m), 3.10-3.13 (1H, m), 3.57 (2H, t, J=4.4 Hz), 4.45 (2H, t, J=6.4 Hz), 5.13 (21, dd, J=29.1, 13.9 Hz), 5.83-5.92 (1H, m), 7.08 (1H, d, J=7.8 Hz), 7.40 (1H, t, J=8.0 Hz), 7.84 (1H, s), 7.91 (1H, d, J=8.1 Hz), 8.36 (1H, s), 8.87 (1H, s), 10.56 (1H, s).
A carboxylic acid, R—COOH corresponding to the objective compound (0.115 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.106 mmol) were dissolved in methanol (0.4 ml) and stirred by shaking at room temperature for 1.5 hours. A solution of compound A (0.0884 mmol) in methanol (0.4 ml) was added and the mixture was stirred for 8 hours. The reaction solvent was concentrated, dissolved in ethyl acetate (1 ml) and dimethylsulfoxide (0.5 ml), a 2N aqueous solution of sodium hydroxide (1 ml) was added and stirred by shaking for 2 hours. The organic layer was separated and concentrated to give a crude product of compound B. Trifluoroacetic acid (0.3 ml) was added and stirred by shaking at room temperature for 14 hours, dimethylsulfoxide (0.4 ml) was added and the product was purified with preparative LC/MS to give the objective compound C.
The 1st step: Compound (82) (506 mg) was dissolved in chloroform (30.0 m), an aqueous solution (10.0 ml) of sodium bicarbonate (851 mg) and thiophosgene (0.111 ml) were added and stirred under ice cooling for 40 minutes. The organic layer was separated from the reaction solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (83) (457 mg).
1H-NMR (DMSO-d6) δ: 1.44 (9H, s), 1.51 (3H, s), 1.60 (1H, s), 2.17 (1H, s), 2.68 (1H, s), 3.05 (1H, s), 7.30 (1H, t, J=10.1 Hz), 7.42 (1H, s), 7.58 (1H, s).
The 2nd step: Compound (83) (240 mg) was dissolved in methylelechloride (3.60 ml), pyridine-2-ylmethanamine (74.8 mg) and triethylamine (0.192 ml) were added and the mixture was stirred at room temperature for 40 minutes. The reaction solution was washed with distilled water, the separated organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (84) (210 mg).
1H-NMR (DMSO-d6) δ: 1.46 (9H, s), 1.65 (3H, s), 2.05 (2H, s), 2.57 (1H, s), 2.97 (1H, s), 4.86 (2H, s), 7.29 (3H, m), 7.40 (1H, d, J=7.3 Hz), 7.66 (1H, s), 7.84 (1H, s), 8.27 (1H, s), 8.58 (1H, s), 9.96 (1H, s).
The 3rd step: Compound (84) (95.1 ml) was dissolved in toluene (1.50 ml), dicyclohexylcarbodiimide (40.1 mg) was added and the mixture was stirred under irradiation of microwave at 100° C. for 20 minutes. The reaction solution was concentrated under reduced pressure and the residue was purified with a column chromatography to give compound (85) (38.0 mg).
1H-NMR (DMSO-d6) δ: 1.40 (9H, s), 1.61 (3H, s), 1.94 (2H, s), 2.57 (1H, s), 2.88 (1H, s), 6.55 (1H, d, J=6.3 Hz), 6.59 (1H, d, J=8.6 Hz), 7.07 (1H, d, 8.6 Hz), 7.13 (2H, s), 7.29 (1H, s), 7.41 (1H, s, J=9.3; H), 7.96 (1H, d, J=6.8 Hz), 8.85 (1H, s).
The 4h step: Compound (85) (38.0 mg) was dissolved in chloroform (0.50 ml), trifluoroacetic acid (1.00 ml) was added and stirred at room temperature for 2 hours. The reaction solution was extracted with a mixture of chloroform/methanol and washed with an aqueous solution of potassium carbonate and distilled water. The separated organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. Diisopropylether was added to the residue and the precipitated powder was filtered to give compound (668) (9.39 mg).
1H-NMR (DMSO-d6) δ: 1.58 (3H, s), 1.90 (1H, s), 2.44 (1H, s), 2.62 (1H, t, J=9.7 Hz), 3.06 (1H, s), 6.57 (2H, td, J−15.0, 6.3 Hz), 7.05 (1H, dd, J=12.1, 10.6 Hz), 7.15 (1H, s), 7.24 (1H, d, J=5.3 Hz), 7.31 (1H, dd, J=7.7, 3.7 Hz), 7.42 (1H, d, J-8.8 Hz), 7.99 (1H, d, J=6.8 Hz), 8.85 (1H, s).
The 1st step: A solution of 20M lithium diisopropylde/n-hepetane/ethylbenzene (172 ml) in tetrahydrofuran (280 m) was cooled in a dry ice/acetone bath and a solution of with stirring. After stirring for an hour, a solution of chlorotitanium triisopropoxide (92) compound (73) (24.56 g) in tetrahydrofuran (120 ml) was added dropwise. After reaction for 2 hours, the reaction solution was added portionwise to an aqueous solution of ammonium chloride with stirring under ice cooling and the precipitated insoluble materials were filtered. It was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (95) (15.49 g).
1H-NMR (CDCl3) δ: 1.16-1.19 (2H, m), 1.24 (9H, s), 1.28-1.32 (2H, m), 1.36 (9H, s), 1.46 (3H, s), 1.50-1.55 (2H, m), 1.64-1.72 (2H, m), 5.45 (1H, s), 7.11-7.16 (1H, m), 8.11-8.16 (1H, m), 8.67 (1H, dd, J=6.9, 2.9 Hz).
The 2nd step: 2.0 M Hydrochloric acid/ethyl acetate (30 ml) was added to compound (95) (2.48 g) and stirred at 65° C. for 5.5 hours. Diisopropylether was added and the precipitated solid was filtered to give a crude product of compound (96) (1.66 g).
The 3rd step: A solution of compound (96) (1.66 g) in tetrahydrofuran (8.3 ml) was stirred under ice cooling and a solution of 1M borane/tetrahydrofuran (21.8 ml) was added and the mixture was stirred at room temperature for 2 hours and 45 minutes. Ice and sodium bicarbonate were added, extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of compound (97) (1.36 g).
The 4th step: A solution of compound (97) (1.36 g) in acetone (20 ml) was stirred under ice cooling, a solution of benzoyl isothiocyanate (0.92 g) in acetone (6 ml) was added and the mixture was stirred for 40 minutes. After the addition of water, the reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (98×) (1.68 g).
1H-NMR (CDCl3) δ: 0.67-0.73 (3H, m), 0.84-0.88 (1H, m), 1.73 (1H, t, J=5.6 Hz), 2.29 (3H, d, J=2.0 Hz), 3.44 (1H, dd, J=12.2, 5.1 Hz), 3.82 (1H, dd, J=12.2, 5.1 Hz), 7.14 (1H, dd, J=11.0, 9.0 Hz), 7.52 (2H, t, J=7.6 Hz), 7.63 (1H, t, J=7.6 Hz), 7.87 (2H, d, J=7.6 Hz), 8.17 (1H, ddd, J=9.0, 3.9, 2.9 Hz), 8.27 (1H, dd, J=6.8, 2.9 Hz), 8.82 (1H, s), 11.75 (1H, s).
The 5th step: Compound (98) (1.68 g) was dissolved in dichloromethane (17 ml), stirred under ice cooling and 1-chloro-N,N,2-trimethyl-1-propenylamine (0.60 g) was added. After stirring at room temperature for an hour, water was added, the reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (99) (1.34 g).
1H-NMR (CDCl3) δ: 0.77-0.82 (1H, m), 0.95-1.07 (2H, m), 1.38-1.40 (1H, m), 1.52 (3H, d, J=1.1 Hz), 2.25 (1H, d. J=13.0 Hz), 3.05 (1H, d, J=13.0 Hz), 7.27 (1H, dd, J=10.8, 8.9 Hz), 7.40-7.54 (3H, m), 8.18-8.27 (3H, m), 8.36 (1H, dd, J=6.7, 2.7 Hz).
The 6th step: Hydrazine monohydrate (038 g) was added to a solution of compound (99×) (1.00 g) in ethanol (10 ml) under stirring at room temperature. After stirring for 4 hours, it was stirred under heating at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound (100) (0.69 g) as a crude product.
The 7th step: A mixture of compound (100) (0.91 g), di-tert-butyldicarbonate (1.55 g), 4-dimethylaminopyridine (0.04 g) and tetrahydrofuran (9.1 ml) was stirred at room temperature for 1 hour and 15 minutes. Water was added, the reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (101) (1.28 g).
1H-NMR (CDCl3) δ: 0.37-0.41 (1H, m), 0.50-0.54 (1H, m), 0.68 (2H, t, J=7.7 Hz), 1.56 (18H, s), 1.78 (3H, d, J=4.0 Hz), 2.35 (1H, d, J=12.7 Hz), 3.57 (1H, dd, J=12.7, 1.8 Hz), 7.12-7.21 (1H, m), 8.15 (1H, ddd, J=8.9, 3.9, 3.0 Hz), 8.39 (1H, dd, J=6.7, 3.0 Hz).
The 8th step: Compound (101) (1.28 g) was dissolved in ethyl acetate (13 ml), 10% Pd—C (0.64 g) was added and the mixture was stirred at room temperature for 13 hours and 30 minutes. The insoluble materials were filtered, the filtrate was concentrated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (102) (1.07 g).
1H-NMR (CDCl3) δ: 0.51-0.58 (2H, m), 0.81-0.86 (2H, m), 1.54 (18H, s), 1.64 (3H, d, J=3.0 Hz), 2.60 (1H, d, J=12.4 Hz), 3.08 (1H, d, J=12.4 Hz), 3.50 (2H, s), 6.51 (1H, ddd, J=8.6, 3.7, 3.0 Hz), 6.78-6.84 (2H, m), 7.18-7.21 (1H, m).
The 9th step: A solution of 5-methylpyrazine-2-carboxylic acid (59 mg) in N,N-dimethylformamide (1.5 ml) was stirred under ice cooling, and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo(4,5-b)pyridinium-3-oxide hexafluorophosphate (196 mg) and triethylamine (61 mg) were added and the mixture was stirred for 10 minutes. A solution of compound (102) (200 mg) in N,N-dimethylformamide (3 ml) was added and the mixture was stirred at room temperature for 4 hours. Water was added, extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (103) (170 mg).
The 10th step: Compound (103) (170 mg) was dissolved in dichloromethane (0.75 ml), stirred under ice cooling, trifluoroacetic acid (0.75 ml) was added and the mixture was stirred at room temperature for 3 hours. After concentration of the reaction solution under reduced pressure, ice water was added, potassium carbonate was added with stirring under ice cooling and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and ether/hexane was added to the residue. The precipitated solid was filtered to give compound (674) (104 mg)
1H-NMR (CDCl3) δ: 0.53-0.59 (1H, m), 0.65-0.72 (1H, m), 0.85-0.91 (1H, m), 1.14-1.17 (1H, m), 1.47 (3H, d, J=2.0 Hz), 2.46 (1H, d, J=12.1 Hz), 2.69 (3H, s), 2.89 (1H, dd, J 12.1, 1.3 Hz), 7.06 (1H, dd, J=11.5, 8.8 Hz), 7.45 (1H, dd, J=6.8, 2.8 Hz), 7.94 (1H, ddd, J=8.8, 4.0, 2.8 Hz), 8.44 (1H, d, J=1.3 Hz), 9.36 (1H, d, J=1.3 Hz), 9.60 (1H, s).
The 1st step: Dichloromethane-trifluoroacetic acid (1:1, 1 ml) was added to compound (120) (49 mg) and stirred at room temperature for an hour. The reaction solution was concentrated under reduced pressure, dimethyl sulfoxide-acetic anhydride (1:1, 1 ml) was added to the residue, stirred at 50° C. for 1.5 hours and the solvent was evaporated under reduced pressure. Hydrochloric acid (1M, 0.5 ml) was added to the residue and stirred at 50° C. for 1 hours. A saturated aqueous solution of sodium bicarbonate was added, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography. A mixture of chloroform-diethyl ether/ethyl acetate was added and the precipitated slid was filtered to give compound 687 (17 mg)
1H-NMR (CDCl3) δ: 1.78 (3H, s), 3.52 (1H, d, J=15.1 Hz), 3.73 (1H, d, 15.1 Hz), 7.06 (1H, dd, J=10.4, 8.6 Hz), 7.73 (1H, dd, J=6.6, 1.3 Hz), 7.82-7.86 (1H, m), 7.90 (1H, d, J=1.3 Hz), 8.48 (1H, d, J=1.3 Hz), 9.79 (1H, s).
The 1st step: In a nitrogen atmosphere, diisopropylamine (20.3 ml) and tetrahydrofuran (83.5 ml) were added and cooled to −60° C. in an acetone/dry ice bath and a solution of 1.63M n-butyl lithium/n-hexane was added dropwise while stirring was continued until the temperature rose to 0° C. After stirring for 30 minutes, the reaction solution was cooled to −60° C. in an acetone/dry ice bath and a solution of tert-butyl acetate (16.8 ml) in tetrahydrofuran (22.2 ml) was added dropwise with stirring. After stirring for 45 minutes, a solution of compound (121) (11.1 g) in tetrahydrofuran (22.2 ml) was added dropwise. After 2.5 hours, a saturated aqueous solution of ammonium chloride (100 ml) was stirred under ice cooling and the reaction solution was poured portionwise therein, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (122) (8.83 g).
1H-NMR (CDCl3) δ: 1.32 (17H, s), 1.93 (3H, s), 3.15 (1H, d, J=16.4 Hz), 3.66 (1H, d, J=16.2 Hz), 5.50 (1H, s), 8.12 (1H, s), 8.36 (1H, s).
The 2nd step: Lithium aluminium hydride (0.76 g) and tetrahydrofuran (5 ml) were cooled in an ice-salt bath in a nitrogen atmosphere and a solution of compound (122) (3.03 g) in tetrahydrofuran (10 ml) was added dropwise with stirring. After stirring for 15 minutes, acetone (4 ml) was added, insoluble materials were filtered, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound (123) (2.30 g) as a crude product.
MS: 385 m/z [M+H]+
The 3rd step: 10% Hydrochloric acid/methanol solution (30 ml) was added to compound (123) (2.2 g) and stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, the residue was basified with a 2.0M aqueous solution of potassium carbonate and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. Toluene (30 ml) and water (15 ml) were added to the resulted crude product (2.25 g), cooled in a ice bath and potassium carbonate (1.58 g) and thiophosgene (0.656 ml) were added with stirring. After stirring at room temperature for 30 minutes, the reaction solution was extracted with toluene, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, toluene (30 ml), thionyl chloride (1.25 ml) and N,N-dimethylformamide (0.044 ml) were added to the resulted residue and the mixture was stirred under heating at 80° C. for 1.5 hours. The solvent was evaporated under reduced pressure, ice water was added, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (124) (1.26 g).
1H-NMR (CDCl3) δ: 1.56 (3H, s), 2.54-2.64 (1H, m), 3.07-3.17 (1H, m), 3.29-3.38 (1H, m), 3.50-3.57 (11H, m), 8.13 (1H, d, J=2.4 Hz), 8.44 (1H, d, J=2.4 Hz).
The 4th step: Tetrahydrofuran (12.6 ml) and 28% ammonia water (6.3 ml) were added to compound (124) (1.26 g) and stirred at room temperature for 1.5 hours. The reaction solution was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give compound (125) (1.13 g) as a crude product.
1H-NMR (CDCl3) δ: 1.70 (3H, s), 2.15-2.21 (1H, m), 2.52-2.58 (1H, m), 2.70-2.77 (1H, m), 3.05-3.11 (1H, m), 4.44 (2H, br s), 8.12 (1H, s), 8.34 (1H, s).
The 5th step: Tetrahydrofuran (11.3 ml) and di-tert-butyldicarbonate (0.89 ml) were added to compound (125) (1.13 g) and stirred at room temperature for an hour.
Di-tert-butyldicarbonate (1.13 ml) and 4-dimethylaminopyridine (0.086 g) were added and further stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (126) (1.59 g).
1H-NMR (CDCl3) δ: 1.53 (18H, s), 1.73 (3H, s), 1.90-1.97 (1H, m), 2.63-2.69 (1H, m), 2.93-2.99 (1H, m), 3.21-3.28 (1H, m), 8.24 (1H, d, J=2.3 Hz), 8.36 (1H, d, J=2.3 Hz).
The 6th step: N,N-Dimethylformmamide (40 ml) was added to compound (126) (2.00 g) in a nitrogen stream, cooled in an ice bath with stirring and sodium methoxide (2.074 g) was added therein. After stirring at room temperature for 1.5 hours, the reaction solution was warmed up to 60° C. and stirred for 2 hours. It was cooled in a ice bath, neutralized by the addition of 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 2M aqueous solution of potassium carbonate and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (127) (1.69 g).
1H-NMR (CDCl3) δ: 1.52 (9H, s), 1.70 (3H, s), 1.96-2.03 (1H, m), 2.54-2.61 (1H, m), 2.80-2.85 (1H, m), 2.97-3.00 (1H, m), 3.97 (3H, s), 7.62 (1H, d, J=1.5 Hz), 8.15 (1H, d, J=1.5 Hz).
The 7th step: Compound (127) (1.571 g), trisdibenzylideneacetonedipalladium (0.414 g) and butynyl-1-adamantylphosphine (0.324 g) were dissolved in toluene under a nitrogen stream, and a solution of 1.6M lithium hexamethyldisilazide/tetrahydrofuran (5.66 ml) was added at room temperature with stirring. The reaction solution was warmed up to 80° C. and stirred for 3 hours. Then diethyl ether and 1 N hydrochloric acid were added with stirring under ice cooling. After stirring for 5 minutes, it was neutralized by the addition of a saturated aqueous solution of sodium carbonate, extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (128) (1.55 g).
1H-NMR (CDCl3) δ: 1.52 (9H, s), 1.72 (3H, s), 1.86-1.93 (1H, m), 2.02 (2H, s), 2.52-2.59 (1H, m), 2.74-2.79 (1H, m), 3.13-3.18 (1H, m), 3.90 (3H, s), 6.96 (1H, d, J=2.3 Hz), 7.59 (1H, d, J=1.8 Hz).
The 8th step: Compound (128) (0.20 g), 5-methylpyridine-2-carboxylic acid (0.10 g) and O-(7-azabenzotriazole-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU)(0.28 g) were dissolved in N,N-dimethylformamide (2 ml), triethylamine (0.119 ml) was added and the mixture was stirred at room temperature for 1.0 hours. A 2M aqueous solution of potassium carbonate was added, extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulted residue was dissolved in chloroform (4.0 ml), trifluoroacetic acid (1.0 ml) was added and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, the residue was made basic by the addition of a 2.0M aqueous solution of potassium carbonate, extracted with ethyl acetate and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (680) (0.096 g).
1H-NMR (DMSO-d6) δ: 1.47 (3H, s), 1.77-1.83 (1H, m), 2.34-2.39 (1H, m), 2.48-2.53 (1H, m), 2.63 (3H, s), 2.89-2.96 (1H, m), 3.90 (3H, s), 5.86 (2H, br s), 8.10 (1H, d, J=2.3 Hz), 8.47 (1H, d, J=2.5 Hz), 8.69 (1H, s), 9.14 (1H, s), 10.69 (1H, s).
The 9th step: Compound (680) (0.096 g) and sodium iodide (0.193 g) were dissolved in acetonitrile (5.0 ml), trimethylsilylchloride (0.164 ml) was added and the mixture was stirred at room temperature for 2.5 hours. Sodium iodide (0.193 g) and trimethyl silylchloride (0.164 ml) were added and stirring was continued at room temperature for 12 hours. A 2.0M aqueous solution of potassium carbonate, extracted with ethyl acetate and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give compound (681) (0.073 g) as a crude product.
1H-NMR (DMSO-d6) δ: 1.52 (3H, s), 1.80-1.85 (1H, m), 2.62 (3H, s), 2.64-2.69 (2H, m), 2.96-3.01 (1H, m), 7.77 (1H, d, J=2.5 Hz). 7.96 (1H, d, J=2.3 Hz), 8.67 (1H, s), 9.10 (1H, s), 10.58 (1H, s).
The 10th step: Compound (681) (0.031 g) was dissolved in tetrahydrofuran (2.0 ml), di-tert-butyldicarbonate (0.030 ml) was added and the mixture was stirred at room temperature for 1.5 hours. Di-tert-butyldicarbonate (0.030 ml) was further added and the stirring was continued at room temperature for 2.0 hours. The reaction solution was concentrated under reduced pressure, the resulted residue was dissolved in N, N-dimethylformamide (0.5 ml) and potassium carbonate (23.9 mg) was added. A solution of methyl iodide (12.2 mg) in N,N-dimethylformamide (0.5 ml) was added with stirring at room temperature. After stirring at room temperature for 3 hours, methyl iodide (11.05 mg) was added and the mixture was stirred at room temperature for 2 hours. Brine was added, extracted with ethyl acetate and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the resulted residue was dissolved in chloroform (2.0 ml), trifluoroacetic acid (0.5 ml) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the resulted residue was made alkaline by the addition of a 2.0M aqueous solution of potassium carbonate, extracted with ethyl acetate and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with a silicagel column chromatography to give compound (682) (4.2 mg).
1H-NMR (DMSO-d6) δ: 1.46 (3H, s), 1.95-2.01 (1H, m), 2.33-2.39 (1H, m), 2.62 (3H, s), 2.64-2.69 (1H, m), 2.74 (3H, s), 2.92-2.98 (1H, m), 7.90 (1H, d, J=2.5 Hz), 7.94-7.95 (1H, m), 8.67 (1H, s), 9.09 (1H, s), 10.57 (1H, s).
The other compounds are prepared in the same manner. Chemical structures and physical constants are shown below.
1H-NMR (DMSO-d6) δ: 1.47 (3H, s), 1.77-1.83 (1H, m), 2.34-2.39 (1H, m), 2.48-2.53 (1H, m), 2.63 (3H, s), 2.89-2.96 (1H, m), 3.90 (3H, s), 5.86 (2H, br s), 8.10 (1H, d, J= 2.3 Hz), 8.47 (1H, d, J = 2.5 Hz), 8.69 (1H, s), 9.14 (1H, s), 10.69 (1H, s).
1H-MMR (DMSO-d6) δ: 1.52 (3H, s), 1.80-1.85 (1H, m), 2.62 (3H, s), 2.64-2.69 (2H, m), 2.96-3.01 (1H, m), 7.77 (1H, d, J = 2.5 Hz), 7.96 (1H, d, J = 2.3 Hz), 8.67 (1H, s), 9.10 (1H, s), 10.58 (1H, s).
1H-NMR (DMSO-d6) δ: 1.46 (3H, s), 1.95-2.01 (1H, m), 2.33-2.39 (1H, m), 2 62 (3H, s), 2 64-2.69 (1H, m), 2.74 (3H, s), 2.92-2.98 (1H, m), 7.90 (1H, d, J = 2.5 Hz), 7.94-7.95 (1H, m), 8.67 (1H, s), 9.09 (1H, s), 10.57 (1H, s).
Forty eight point five μL of substrate peptide solution (Biotin-XSEVNLDAEFRHDSGC-Eu: X-ε-amino-n-capronic acid, Eu=Europium cryptate) was added to each well of 96-hole half-area plate (a black plate: Corning Incorporated), and after addition of 0.5 μl of the test sample (dissolved in N,N′-dimethylformaldehyde) and 1 μl of Recombinant human BACE-1 (R&D Systems), the reaction mixture was incubated at 30° C. for 3 hours. The substrate peptide was synthesized by reacting Cryptate TBPCOOH mono SMP (CIS bio international) with Biotin-XSEVNLDAEFRHDSGC (Peptide Institute, Inc.). The final concentrations of the substrate peptide and Recombinant human BACE-1 were adjusted to 18 nM and 7.4 nM respectively, and the reaction was performed in sodium acetate buffer (50 mM sodium acetate, pH 5.0, 0.008% Triton X-10).
After the incubation for reaction, 50 μl of 8.0 μg/ml Streptavidin-XL665 (CIS bio international) dissolved in phosphate buffer (150 mM K2HPO4—KH2PO4, pH 7.0, 0.008% Triton X-100, 0.8 M KF) was added to each well and left stand at 30° C. for an hour. After then, fluorescence intensity was measured (excitation wavelength: 320 nm, measuring wavelength: 620 nm and 665 nm) using Wallac 1420 multilabel counter (Perkin Elmer life sciences). Enzymatic activity was determined from counting ratio of each wavelength (10,000×Count 665/Count 620) and 50% inhibitory concentration against the enzymatic activity was calculated. IC50 values of the test compounds are indicated in Table 139.
The following compounds have shown IC50 values equal to or under 1 μM in the same assay; same assay;
Also, compounds 462, 463, 465, 467, 469, 470, 471, 472, 479, 482, 483, 486, 489, 490, 492, 501, 503, 507, 508, 509, 510, 511, 512, 516, 518, 519, 523, 527, 528, 531, 532, 533, 536, 538, 539, 540, 542, 545, 546, 547, 548, 549, 552, 553, 554, 555, 556, 557, 558, 560, 561, 562, 564, 565, 567, 568, 569, 570, 571, 572, 573, 574, 575, 578, 581, 582, 583, 584, 586, 587, 590, 595, 596, 600, 601, 602, 603, 604, 605, 606, 609, 612, 613, 637, 644, 646, 461, 468, 478, 491, 502, 505, 508, 517, 530, 537, 542, 544, 559, 563, 566, 576, 577, 597, 598, 599 and 645 showed IC50 values equal to or under 1 μM in the same assay.
The following compounds also showed IC50 values equal to or under 1 μM in the same assay;
compounds 647, 648, 649, 650, 651, 654, 656, 657, 658, 659, 661, 666, 670, 671, 672, 673, 675, 676, 677, 678, 679, 683, 684, 685, 686, 687, 688, 690, 691, 692, 693, 694, 695, 696 and 697, 652, 655, 660, 662, 664, 665, 667, 669, 674 and 689.
Compound of the formula (I) and lactose are put through a sieve of No. 60 mesh. Corn starch is put through a sieve of No. 120 mesh and these are mixed with V-shaped mixer.
An aqueous solution of HPC-L (Hydroxypropyl cellulose of Low viscosity) is added to the mixed powder, kneaded, granulated (extusion granulation; pore diameter 0.5-1 mm) and put into a drying process. The resulted dried granule is sieved with vibrating screen (12/60 mesh) to give a granular formulation.
Compound of the formula (I) and lactose are put through a sieve of No. 60 mesh. Corn starch is put through a sieve of No. 120 mesh and these are mixed. An aqueous solution of HPC-L is added to the mixed powder, kneaded, granulated and dried. Particle size of the resulted dried granule is regulated and each of 150 mg is filled in No. 5 hard-gelatin capsule.
Compound of the formula (I), lactose, microcrystalline cellulose and CMC-Na (sodium salt of carboxymethylcellulose) are put through a sieve of No. 60 mesh and mixed. Magnesium stearate is mixed with the mixed granule above to give a mixed powder for tablet, which is compressed by a tabletting machine to give a tablet of 150 mg.
A compound of the present invention can be a useful drug for treating diseases induced by production, secretion and/or deposition of amyloid β protein.
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| Number | Date | Country | |
|---|---|---|---|
| 20140073815 A1 | Mar 2014 | US |
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| Parent | 12596796 | US | |
| Child | 13417786 | US |
| Number | Date | Country | |
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| Parent | 13417786 | Mar 2012 | US |
| Child | 13887745 | US |
