Patent Application
20110166343
The present invention relates to thienopyrazole derivatives, pharmaceutically acceptable salts and solvates thereof, having selective PDE 7 (phosphodiesterase VII) inhibiting effect. Further, the present invention relates to an intermediate compounds for preparing said theinopyrazole derivatives and a process for producing them. These compounds are effective compounds for treating various kinds of diseases such as allergic diseases, inflammatory diseases and immunological diseases.
Cyclic AMP (cAMP) or cyclic GMP (cGMP), which is an intracellular second messenger substance, is decomposed and inactivated by phosphodiesterases (PDE 1 to PDE 11). The PDE 7 selectively decomposes cAMP, and is characterized as an enzyme which is not inhibited by rolipram. Rolipram is a selective inhibitor of PDE 4, which decomposes cAMP similarly.
It is suggested that PDE 7 plays an important role for activating T cells (Beavo, et al., Science, 283, 848 (1999)), and is well known that activation of T-cell is concerned with the exacerbation of allergic diseases, inflammatory diseases or immunological diseases. These diseases are for example bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, sepsis, Crohn's disease, rejection reaction in transplantation, graft versus host disease (GVH disease), and restenosis after angioplasty [J. Allergy Clin. Immunol., 2000 November; 106(5 Suppl.): S221-6; Am. J. Respir. Crit. Care Med., 1996 February; 153(2): 629-32; Am. J. Respir. Crit. Care Med., 1999 November; 160(5 Pt 2): S33-7; Clin. Exp. Allergy, 2000 Feb.; 30(2): 242-54; Hosp. Med., 1998 July; 59(7): 530-3; Int. Arch. Allergy Immunol., 1998 March; 115(3): 179-90; J. Immunol., 1991 Feb.; 15; 146(4): 1169-74; Osteoarthritis Cartilage, 1999 Jul.; 7(4): 401-2; Rheum. Dis. Clin. North Am., 2001 May; 27(2): 317-34; J. Autoimmun., 2001 May; 16(3): 187-92; Curr. Rheumatol. Rep., 2000 Feb.; 2(1): 24-31; Trends Immunol., 2001 Jan.; 22(1): 21-6; Curr. Opin. Immunol., 2000 Aug.; 12(4): 403-8; Diabetes Care, 2001 Sep.; 24(9): 1661-7; J. Neuroimmunol., 2000 Nov.; 1; 111(1-2): 224-8; Curr. Opin. Immunol., 1997 Dec.; 9(6): 793-9; JAMA, 1999 Sep. 15; 282(11):1076-82; Semin. Cancer Biol., 1996 Apr.; 7(2): 57-64; J. Interferon Cytokine Res., 2001 Apr.; 21(4): 219-21].
Therefore, it is considered that a compound having PDE 7 inhibiting effect is useful for treating various kinds of diseases such as allergic diseases, inflammatory diseases or immunological diseases concerned with T cells.
There has been proposed that many compounds selectively inhibit PDE 7. There can be mentioned the examples such as imidazopyridine derivatives (Patent Document 1), dihydropurine derivatives (Patent Document 2), pyrrole derivatives (Patent Document 3), benzothiopyranoimidazolone derivatives (Patent Document 4), heterocyclic compounds (Patent Document 5; Patent Document 6), quinazoline and pyridopyrimidine derivatives (Patent Document 7), spiro tricyclic compounds (Patent Document 8), thiazole and oxathiazole derivatives (Patent Document 9), sulfonamide derivatives (Patent Document 10), heterobiarylsulfonamide derivatives (Patent Document 11), dihydroisoquinoline derivatives (Patent Document 12), guanine derivatives (Non-Patent Document 1), benzothiadiazine derivatives and benzothienothiadiazine derivatives (Non-Patent Document 2, and Non-Patent Document 3). However, no curative medicines having PDE 7 inhibiting effect as main pharmacological mechanism have developed up to now.
Though some compounds having thienopyrazole skeleton have been known (Patent Documents 13-24; Non-Patent Documents 4-8), there is no suggestion that these compounds have PDE 7 inhibiting effect. Further, the method for producing the thienopyrazole derivatives of the present invention has been reported (Non-Patent Documents 9-11); however, the substituents on the thienopyrazole skeleton are different from those of the present invention.
Patent Document 17: U.S. Pat. No. 6,022,307
Patent Document 24: U.S. Pat. No. 3,649,641
Non-Patent Document 1: Bioorg. Med. Chem. Lett., 11 (2001), 1081
Non-Patent Document 2: J. Med. Chem., 43 (2000), 683
Non-Patent Document 3: Eur. J. Med. Chem., 36 (2001), 333
Non-Patent Document 4: Russ. J. Org. Chem., 39 (2003), 893
Non-Patent Document 5: Aknos Consulting and Solutions GmbH Co., Catalog: Akos samples
Non-Patent Document 6: Phosphorus, sulfur and silicon and related Elements, 157 (2000), 107
Non-Patent Document 9: Phosphorus, sulfur and silicon and related Elements, 157 (2000), 107
The purpose of the present invention is to provide novel compounds having PDE 7 inhibiting activity, and PDE 7 inhibitors containing said inhibitors as an active ingredient. Further, the present invention provides useful intermediate compounds for manufacturing the above-mentioned novel compounds.
The compounds of the present invention inhibit PDE 7 selectively, and therefore, enhance cellular cAMP level. Consequently, the compounds of the present invention are useful for treating various kinds of diseases such as allergic diseases, inflammatory diseases or immunological diseases by inhibiting the activation of T-cells.
For example, the compounds of the present invention are useful for treating or preventing the diseases such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, sepsis, Crohn's disease, rejection reaction in transplantation, GVH disease, restenosis after angioplasty.
Through extensive investigations of researching compounds having the capabilities of inhibiting PDE 7, the present inventors discovered that the compounds having thienopyrazole skeleton in the molecule represented by the formula (I) mentioned below possess potent and selective PDE 7 inhibiting effect, and thus, completed the present invention.
Accordingly, as one aspect of the present invention, it is provided thienopyrazole compounds represented by the following formula (I):
wherein:
R1 is substituted or unsubstituted C3-C8 alkyl group, substituted or unsubstituted cycloalkyl group or substituted or unsubstituted heterocycloalkyl group;
R2 is a hydrogen atom or substituted or unsubstituted C1-C3 alkyl group;
R3 is a hydrogen atom, substituted or unsubstituted C1-C3 alkyl group, or a halogen atom;
R4 is substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group —CONR5R6 or —CO2R7;
R5 and R6 are, same or different from each other, a hydrogen atom; C1-C6 alkyl group which may be substituted by a halogen atom, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted cycloalkyl group, a group-NR7COR8, —COR8, —NR9R10; substituted or unsubstituted cycloalkyl group; substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted aryl group; substituted or unsubstituted heteroaryl group; or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom binding R5 and R6;
R7 is a hydrogen atom, or substituted or unsubstituted C1-C3 alkyl group;
R8 is substituted or unsubstituted heterocycloalkyl group, or a a group —OH, —OR7 or —NR9R10;
R9 and R10 are, same or different from each other, a hydrogen atom, substituted or unsubstituted C1-C3 alkyl group, substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted acyl group; a group —SO2R7, or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom binding R5 and R6;
or pharmaceutically acceptable salts or solvates thereof.
Another aspect of the present invention, it is provided PDE 7 inhibiting composition containing the thienopyrazole compounds mentioned above, or pharmaceutically acceptable salts or solvates thereof as an active ingredient.
Still another aspect of the present invention, it is provided a method for preparing the thienopyrazole compounds represented by the formula (I).
In particular, the method is comprised by chlorination of pyrazole-5-one derivative represented by the formula (VI):
wherein, R1 and R2 have the same meanings as defined above; and then, by an electrophilic substitution reaction of the resulting compound without separation to give the pyrazole derivative of the formula (IV):
wherein, R1, R2 and R3 have the same meanings as defined above; then, by reacting the resulting pyrazole derivative of formula (IV) with the compound of the formula (III) in the presence of base:
wherein, R4 has the same meanings as defined above; to give the compound of the formula (II):
wherein, R1, R2, R3 and R4 have the same meanings as defined above; and then, by treating the resulting compound of formula (II) with base to give thienopyrazole compound of the formula (I):
wherein, R1, R2, R3 and R4 have the same meanings as defined above.
Additionally, the intermediate compound of the formula (IV) can be obtained by electrophilic substitution reaction of chloropyrazole compound of the formula (V):
wherein, R1 and R2 have the same meanings as defined above.
Furthermore, the compound of the formula (I) can be obtained by one pot synthesis from the compound of the formula (IV) without separation of the intermediate compound of the formula (II). In particularly, it is provided the manufacturing method for the compound of the formula (I), in which R3 is a hydrogen atom.
The compounds of the present invention inhibit PDE 7 selectively, and therefore, the compounds of the present invention are useful for treating or preventing the diseases such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, septicemia sepsis, Crohn's disease, rejection reaction of transplantation, GVH disease, restenosis after angioplasty.
Further, the compounds of the formula (II) and (IV) are important intermediate compounds for synthesis of the present compound of formula (I), and therefore, by using these intermediates, the compounds of the present invention represented by the formula (I) can be obtained by simple and easy way.
The present invention will now be explained more specifically as following.
The term “Cn-Cm alkyl group” of the present invention includes a straight or a branched-chained alkyl group having n to m carbon atoms. The term “cycloalkyl group” means cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The term “heterocycloalkyl group” may be 3 to 7 membered monocyclic or polycyclic heterocyclic group containing the same or different 1 to 4 hetero atom(s) such as oxygen, nitrogen or sulfur atom(s), and examples may include piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, azetidinyl, imidazolidinyl, oxazolidinyl, hexahydropyrrolidinyl, octahydroindolidinyl, octahydroquinolidinyl, octahydroindolyl, and oxo-derivatives thereof.
The “halogen atom” includes chlorine, fluorine, bromine and iodine. The term “aryl group” may be aromatic hydrocarbon group, which consists of mono-benzene ring, or binding or condensed benzene ring, such as phenyl, naphthyl, biphenyl and the like; and dicyclic or tricyclic group, which consists of benzene ring condensed with cycloalkyl or heterocyclic ring, such as 1,2,3,4-tetrahydronaphthalene, 2,3-dihydroindene, indoline, coumarone and the like.
The term “heteroaryl group” may be 5 to 7 membered monocyclic heteroaryl group or polycyclic heteroaryl group, and having 2 to 8 carbon atoms with 1 to 4 hetero atom(s) such as oxygen, nitrogen, sulfur atom(s), in which the polycyclic heteroaryl group has condensed ring system by the same or different nomocyclic heteroaryl or benzene ring each other; or polycyclic group which is consisted of heteroaryl group condensed with cycloalkyl or heterocycloalkyl ring.
The examples include pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzothiophenyl, isoxazolyl, indazolyl, benzoimidazolyl, phthalazinyl, triazolyl, benzooxazolyl, benzothiazolyl, dihydrocyclopentapyridinyl, dihydro-pyrropyridinyl and the like.
Examples of suitable substituent of the present invention may include straight, branched-chained or cyclic C1-C8 alkyl group, which may be substituted by one or more methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, cyclohexyl, cycloheptyl, methoxymethyl, hydroxymethyl, trifluoromethyl, C1-C3 alkoxy group, halogen atom, and hydroxyl group; hydroxyl group; cyano group; substituted or unsubstituted alkoxy group such as methoxy, ethoxy group; amino group which may be substituted by C1-C6 alkyl group or acyl group such as amino, methylamino, ethylamino, dimethylamino, acylamino and the like; carboxylic group; substituted or unsubstituted ester group; phosphate group; sulfonic group; substituted or unsubstituted aryl group; substituted or unsubstituted heteroaryl group; saturated or unsaturated heterocycloalkyl group which may be substituted; substituted or unsubstituted carbamoyl group; substituted or unsubstituted amide group; substituted or unsubstituted thioamide group; halogen atom; nitro group; substituted or unsubstituted sulfone group; substituted or unsubstituted sulfonylamide group; oxo group; substituted or unsubstituted urea group; straight, branched-chained or cyclic alkenyl group such as ethenyl, propenyl, cyclohexenyl and the like.
Examples of suitable substituent of “C3-C8 alkyl group which may be substituted” in the group of R1 may include hydroxyl group, halogen atom, alkoxy group and the like, and examples of suitable substituent of “cycloalkyl group which may be sunstituted” in the group of R1 include hydroxyl group, alkoxy group, oxo group, C1-C3 alkyl group such as methyl group. Examples of suitable substituent of “heterocyclo alkyl group which may be substituted” in the group of R1 may include C1-C3 alkyl group such as methyl group.
Examples of suitable substituent of “C1-C3 alkyl group which may be substituted” in the group R2 may include hydroxyl group, alkoxy group, halogen atom such as fluorine atom. Further, examples of suitable substituent of C1-C3 alkyl group which may be substituted” in the group R3 include hydroxyl group, alkoxy group, halogen atom such as fluorine atom.
Examples of suitable substituent of “aryl group which may be substituted” and “heteroaryl group which may be substituted” in the group R4 may include hydroxyl group, halogen atom, heterocycloalkyl group which may be substituted by C1-C6 alkyl group.
Examples of suitable substituent of “cycloalkyl group which may be substituted” in the groups R5 and R6 may include hydroxyl group; oxo group; carboxyl group; carboxyl ester group; cyano group; C1-C6 alkyl group {in which said C1-C6 alkyl group may be substituted by C1-C3 alkoxyl group, hydroxyl group, amino group which may be substituted by C1-C6 alkyl group, arylsulfonyloxy group, heterocycloalkyl group (in which said heterocycloalkyl group may be substituted by hydroxyl group, C1-C6 alkyl group, oxo group or acetyl group)}; amide group (in which said amide group may be substituted by cycloalkyl group or C1-C6 alkyl group which may be substituted by hydroxyl group); heterocycloalkylamide group which may be substituted by C1-C6 alkyl group; heterocycloalkylamide group which may be substituted by hydroxyl group; amino group (in which said amino group may be substituted by C1-C6 alkyl group which may be substituted by C1-C3 alkoxy group and acyl group); heterocycloalkyl group {in which said heterocycloalkyl group may be substituted by C1-C6 alkyl group (in which said alkyl group may be substituted by hydroxyl group), oxo group, acyl group, hydroxyl group, amino group which may be substituted by C1-C6 alkyl group, amino group which may be substituted by acyl group, C1-C3 alkoxy group, alkoxycarbonyl group, carboxyl group, aminocarbonyl group which may be substituted by C1-C6 alkyl group, or sulfonyl group which may be substituted by C1-C6 alkyl group}.
Examples of suitable substituent of “heterocycloalkyl group which may be substituted” may include benzyl group; acyl group; oxo group; heterocycloalkyl group (in which said heterocycloalkyl group may be substituted by C1-C6 alkyl group, acyl group, sulfonyl group which may be substituted by C1-C6 alkyl group or alkoxycarbonyl group); C1-C6 alkyl group which may be substituted by carboxyl group or carboxylic ester group; amido group which may be substituted by C1-C6 alkyl group; heterocycloalkylamide group which may be substituted by C1-C6 alkyl group; sulfonyl group which may be substituted by C1-C6 alkyl group; sulfonamide group which may be substituted by C1-C6 alkyl group; cycloalkyl group which may be substituted by oxo or hydroxyl group; alkoxycarbonyl group, and the like.
Further, examples of suitable substituent of “aryl group which may be substituted” in the group of R5 and R6 may include halogen atom; nitro group; cyano group; acyl group; amino group which may be substituted by acyl group; amide group (in which said amide group may be substituted by C1-C6 alkyl group which may be substituted by C1-C3 alkoxy group or C1-C6 alkyl group which may be substitute by hydroxyl group); alkoxycarbonylamino group; alkoxycarbonyl group; alkoxy group (in which said alkoxy group may be substituted by carboxyl group, carboxylic ester group, or amide group); carbonyl group; carboxyl group; carboxylic ester group; carbamoyl group; sulfonic group; sulfonamide group; aminosulfonyl group; C1-C6 alkyl group (in which said alkyl group may be substituted by C1-C3 alkoxy group, hydroxyl group or hetrocycloalkyl group which may be substituted by C1-C6 alkyl group); heterocycloalkylamide group which may be substituted by C1-C6 alkyl group; heterocycloalkyl group which may be substituted by hydroxyl group; acetic acid group; acetic acid amide group; or heterocycloalkyl group (in which said heterocycloalkyl group may be substituted by hydroxyl group, oxo group, acyl group, C1-C6 alkyl group, amino group which may be substituted by C1-C6 alkyl group, amino group which may be substituted by acyl group, C1-C3 alkoxy group, alkoxycarbonyl group, and the like).
Examples of suitable substituent of “heteroaryl group which may be substituted” in the group of R5 and R6 may include halogen atom; acyl group; amide group {in which said amide group may be substituted by C1-C6 alkyl group (in which said alkyl group may be further substituted by amino group which may be substituted by C1-C6 alkyl group or hydroxyl group)}; cycloalkyl group which may be substituted by hydroxyl group; cycloheteroalkyl group which may be substituted by C1-C6 alkyl group or acyl group; heterocycloalkylamide group which may be substituted by C1-C6 alkyl group; heterocycloalkylamide group which may be substituted by hydroxyl group; oxo group; acylamino group; C1-C6 alkyl group (in which said alkyl group may be substituted by cycloheteroalkyl group which may be substituted by hydroxyl group, acyl group or cycloheteroalkyl group which may be substituted hydroxyl group); carboxyl group; carboxylic ester group; sulfonyl group; heterocycloalkyl group (in which said heterocycloalkyl group may be substituted by hydroxyl group, oxo group, acyl group, C1-C6 alkyl group, amino group which may be substituted by C1-C6 alkyl group, amino group which may be substituted by acyl group, C1-C3 alkoxy group, alkoxycarbonyl group, and the like).
Examples of suitable substituent of “substituted or unsubstituted heterocycloalkyl group which is formed said ring system together with nitrogen atom which they are bonded” may include acyl group; amide group; C1-C6 alkyl group or C1-C3 alkoxy group; carbonyl group; carboxyl group; carboxylic ester group; hydroxyl group; carbamoyl group; sulfonamide group; aminosulfonic group; oxo group; and the like.
Examples of suitable substituent of “C1-C3 alkyl group which may be substituted” in the group R7 may include hydroxyl group, alkoxy group, halogen atom such as fluorine atom, and the like.
Examples of suitable substituent of “heterocycloalkyl group which may be substituted” in the group R8 may include hydroxyl group, alkoxy group, oxo group, acyl group, C1-C6alkyl group, C1-C3alkoxy group, carboxyl group, amide group, and the like.
In the groups R9 and R10, examples of suitable substituent of “C1-C3 alkyl group which may be substituted” may include hydroxyl group, alkoxy group and the like. Further, examples of suitable substituent of “heterocycloalkyl group which may be substituted” may include C1-C6 alkyl group, hydroxyl group, alkoxy group, oxo group, acyl group and the like, and examples of suitable substituent of “acyl group which may be substituted” may include C1-C6 alkyl group, hydroxyl group, alkoxy group and the like.
Examples of suitable substituent of “substituted or unsubstituted heterocycloalkyl group which is formed said ring system together with nitrogen atom which they are bonded” include acyl group, amide group, C1-C6 alkyl group, C1-C3 alkoxy group, carbonyl group, carboxyl group, carboxylic ester group, hydroxyl group, carbamoyl group, sulfonamide group, aminosulfonic group, and the like.
Preferable compounds of the formula (I) of the present invention may include the compounds wherein R1 is cyclohexyl group, cycloheptyl group or tetrahydropyranyl group; R2 is methyl group; R3 is a hydrogen atom; and R4 is the group —NR5R6 (in which one of these R5 and R6 is a hydrogen atom).
It is understood that when the compounds of the formula (I) of the present invention exist in the tautomeric mixtures, each tautomeric isomers per se, as well as the mixture thereof. Furthermore, the radiolabelled compound of the formula (I) shall be included within the scope of the compounds of the present invention.
The compounds of the present invention may contain one or more asymmetric carbon atom and therefore, the compounds of the present invention may exist as optically isomer of (R)-form or (S)-form, racemic forms, as well as diastereomers. Further, the compounds of the present invention may exist as geometrical isomer such as (Z)-form or (E)-form due to the double bond in the substituent. Therefore, the compounds of the present invention should include these isomers per se as well as the isomeric mixtures thereof.
The compounds of the present invention may form acid additional salt thereof with various acids. Examples of the acid additional salt include the salts with inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; salts with organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, picric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, trichloroacetic acid, trifluoroacetic acid, asparaginic acid, glutamic acid and the like.
The compounds of the present invention may form pharmaceutically acceptable salts by treating with various kinds of metal, especially alkali metal or alkali earth metal. These salts may include sodium salt, potassium salt, calcium salt and the like. Further, the compounds of the present invention may include hydrate thereof or solvate with ethanol or isopropanol thereof, and polymorphisms thereof.
The following compounds are preferable thienopyrazole compounds of the formula (I) of the present invention.
The compounds represented by the formula (I) of the present invention may be prepared by the following methods.
(wherein, R1, R2, R3 and R4 have same meanings mentioned above; L is C1-C3 lower alkyl group)
First, the compound (VI) obtained from the compound (VIII) by reacting with R1NHNH2 (VII) in accordance with the known method (e.g., International Patent Publication WO 03/053,975). Namely, the compound (VIII) is reacted with 1 to 2 equivalents, preferably about 1 equivalent of the compound (VII) in the solvent or absent of the solvent at room temperature to 120° C. The solvent to be used in the reaction is inorganic acid aqueous solution such as hydrochloric acid or sulfuric acid; aromatic carbon hydrate such as benzene or toluene; organic acid such as acetic acid; ethers such as 1,4-dioxane or tetrahydrofuran; halogenated hydrocarbons such as dichloromethane; alcohols such as methanol or ethanol; or the mixture solvent there of.
After the reaction is completed, the reaction mixture is neutralized and the mixture is extracted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (VI) can be obtained by removal of the solvent. This compound (VI) can be purified by recrystallization, if necessary.
The starting compounds (VII) and (VIII) to be used in this reaction can be commercially available or can be known compounds (e.g., J. Org. Chem., 1981, 46, 5414-5415). Further, the compounds (VII) can be used as salt with acidic compounds, such as hydrochloric acid salt or acetic acid salt.
Then, the resulting compound (VI) is converted to the compound (V) in accordance with the common method. Namely, the reaction can be conducted by reacting the compound (VI) with 1 to 6 equivalents of halogenating reagent such as phosphorous oxychloride or thionyl chloride in aromatic hydrocarbon solvent such as benzene or toluene, or the absence of the solvent, at room temperature to refluxing temperature of the solvent for 1 to 12 hours. After the reaction is completed, the compound (V) can be obtained by removal of the solvent.
The obtained compound (V) is converted, without further purification, to the compound (IV) by an electrophilic substitution reaction. For example, the compound, (V) in which R3 is a hydrogen atom, can be obtained by Vilsmeier reaction with the reaction reagent prepared from 1 to 5 equivalents of phosphorus oxychloride, in the amide solvent such as N,N-dimethylformamide. The reaction is carried out at room temperature to 120° C. for 1 to 12 hours.
After the reaction is completed, inorganic base aqueous solution such as sodium hydroxide aqueous solution is added to the reaction mixture and the mixture is extracted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (IV) can be obtained by removal of the solvent. This compound (IV) can be purified by column chromatography or recrystallization, if necessary.
Further, the compound (IV) can be converted directly from the compound (IV) by Vilsmeier reaction in single process, or one-pot synthesis reaction without separation of the intermediate compound (V). Namely, the compound (VI) is treated with 2 to 5 equivalents of phosphorous oxychloride without using the reaction solvent at room temperature to 120° C. to obtain the compound (V) in the reaction mixture. Then, to this reaction mixture containing the resulting compound (V) is added formamide solvents such as N,N-dimethylformamide at 0° C. to 120° C., and the Vilsmeier reaction is carried out at room temperature to 120° C. for 1 to 24 hours.
After the reaction is completed, inorganic base aqueous solution such as sodium hydroxide aqueous solution is added to the reaction mixture and the mixture is extracted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (IV) can be obtained by removal of the solvent. This compound (IV) can be purified by column chromatography or recrystallization, if necessary.
Then, the obtained compound (IV) is converted to the compound (II). The reaction is carried out by treating the compound (IV) with 1 to 1.5 equivalents of the compound (III), in the solvent at room temperature to 80° C. for 0.5 to 8 hours. The solvent to be used in this reaction is polar solvent such as acetonitrile or N,N-dimethylformamide; ethers such as 1,4-dioxane or tetrahydrofuran; halogenated hydrocarbons such as dichloromethane; alcohols such as methanol or ethanol; or the mixture solvent thereof. In this reaction, the compound (III) is previously treated with base such as potassium carbonate, sodium hydride, potassium tert-butoxide, sodium methylate or sodium hydroxide.
After the reaction is completed, water is added to the reaction mixture and the mixture is extracted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (II) can be obtained by removal of the solvent. This compound (II) can be purified by column chromatography or recrystallization, if necessary.
Then, the obtained compound (II) is converted to the compound (I) of the present invention by ring formation reaction.
The reaction condition of this ring formation may vary depending on the variety of the group R4. When the group R4 is the group: —CO2R7, the compound (I) can be obtained from the compound (II) by treating with 1 to 1.5 equivalents of the base such as potassium carbonate, sodium hydride, sodium methylate or sodium hydroxide in the solvent at 0° C. to 80° C. for 0.5 to 24 hours. The solvent to be used in this reaction is polar solvent such as acetonitrile or N,N-dimethylformamide; ethers such as 1,4-dioxane or tetrahydrofuran; halogenated hydrocarbons such as dichloromethane; alcohols such as methanol or ethanol; or the mixture solvent there of.
After the reaction is completed, water is added to the reaction mixture and the mixture is extracted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (I) can be obtained by removal of the solvent. This compound (I) can be purified by column chromatography, if necessary.
Further, when the group R4 is the group: —CO2R7, the compound (I) can be obtained from the compound (IV), without the separation of the compound (II) in the corresponding stepwise reaction.
When the group R4 is an aryl group which may be substituted or a heteroaryl group which may be substituted, the compound (I) can be obtained from the compound (II) by treating with 1 to 3 equivalents of the strong base such as lithium diisopropylamide or lithium bis(trimethylsilyl) amide in the ethers such as diethylether or tetrahydrofuran.
After the reaction is completed, water is added to the reaction mixture and the mixture is extracted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution, then, the organic solvent is removed off. The resulting residue is dissolved in alcohols such as methanol or ethanol, and the acid such as hydrochloric acid is added to the mixture, and then, the mixture is stirred at room temperature to 60° C. to obtain the compound (I).
After the reaction is completed, water is added to the reaction mixture and the mixture is extracted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (I) can be obtained by removal of the solvent. This compound (I) can be purified by column chromatography or recrystallization, if necessary.
In the case of the group R4 is the group: —CONR5R6, first, the compound (I) in which the group R4 is —CO2R7 obtained by the method described above, is converted to the compound (I) in which the group R4 is —CO2H. This convertion reaction is the hydrolysis reaction of ester compound, and can be carried out in the several manners. For example, the hydrolysis reaction can be carried out in the presence of the base such as sodium hydroxide, in the solvent at room temperature to refluxing temperature of the solvent. The solvent to be used in the reaction may be alcohols such as methanol or ethanol; water; or the mixture solvent thereof. After the reaction is completed, the reaction mixture is condensed, and the mixture is neutralized by adding hydrochloric acid to obtain the compound (I) in which the group R4 is —CO2H.
Then, the resulting compound (I) in which the group R4 is —CO2H is converted to the compound in which the group R4 is —CONR5R6 by amidation reaction in accordance with the several known methods. For example, the compound (I) in which the group R4 is —CO2H is converted to the corresponding acid chloride by treating with the halogenating reagent such as phosphorous oxychloride or thionyl chloride. Then, the obtained acid chloride is treated with the amine compound HNR5R6 in the presence of base catalyst such as triethylamine in solvent at OOC to room temperature. The solvent to be used in the reaction may be halogenated hydrocarbons such as dichloromethane; aromoatic hydrocarbons such as toluene or benzene; ethers such as diethylether or tetrahydrofurane; or the mixture solvent thereof.
After the reaction is completed, the reaction mixture is diluted with the organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (I) in which the group R4 is —CONR5R6 can be obtained by removal of the solvent. This compound can be purified by column chromatography or recrystallization, if necessary.
All reaction mentioned above are well known, and the reagents to be used or the reaction conditions to be applied can be easily established in accordance with the standard text book and the examples mentioned later. Further, the other methods or modified methods for obtaining the compound (I) of the present invention can be easily selected by the person skilled in this field.
The present invention is illustrated in more detail by way of the following Biological Test, Examples, and Manufacturing Examples.
The synthesis of the compounds of the present invention and intermediate compounds to be used in the synthesis are illustrated in the Examples and Manufacturing Examples mentioned later. Further, the physicochemical data and chemical structure of the compounds and intermediate compounds obtained by the Examples and Manufacturing Examples are summarized in the Tables mentions later.
The compound numbers in the Examples are identical to those in the Tables.
It is to be noted that the present invention is not limited by those Examples in any way.
The PDE 7 (phosphodiesterase VII) inhibiting effect of the compounds of the present invention was performed by the following method, which was modified assay method described in Biochemical. Pharmacol. 48(6), 1219-1223 (1994).
(1) The active fraction of PDE 7 (phosphodiesterase VII) was obtained. That is, MOLT-4 (obtainable from ATCC as ATCC No. CRL-1582), which was cell line of human acute lymphoblastic lymphoma T cells, was incubated in RPMI1640 culture medium containing 10% fetal bovine serum to obtain 5×108 MOLT-4 cells. The cells were collected by centrifugation and suspended with 10 mL of buffer solution A [25 mM of tris-HCl, 5 mM of 2-mercaptoethnol, 2 mM of benzamidine, 2 mM of EDTA, 0.1 mM of 4-(2-aminoethyl)benzensulfonyl hydrochloride; pH 7.5], then homogenized by Polytron® homogenizer. The homogenate were centrifuged under 25,000×G for 10 minutes at 4° C. The supernatant was separated and thus obtained supernatant was further centrifuged under 100,000×G for 60 minutes at 4° C., and then filtrated with 0.2 μm filter to obtain the soluble fraction.
(2) The obtained soluble fraction was filled in equilibrium HiTrap Q column (5 mL×2) with buffer solution A, and phosphodiesterase fractions were eluted by 300 mL of buffer solution A with linear gradient from 0 to 0.8 M NaCl concentration. 5 mL each of 60 eluents were collected, and each eluents were examined for cyclic AMP metabolic activities of phosphodiesterase. The fraction eluting with about 350 mM NaCl concentration parts, where metabolic activities were not inactivated by 10 μM of rolipram (selective inhibitor for phosphodiesterase IV) and 10 μM of milrinone (selective inhibitor for phosphodiesterase III), were collected as storage solution for using to test PDE 7 inhibiting effect.
(3) The tested compound having desired concentration was reacted in the solution of 20 mM tris-HCl (pH7.5), 1 mM of MgCl2, 100 μM of EDTA, 330 μg/mL of bovine serum albumin, 4 μg/mL of 5′-nucleotidase, 0.1 μCi of 3H-CAMP (0.064 μM of cAMP), 10 μM of rolipram in storage solution of PDE 7 for 2 hours at 25° C. After the reaction, suspension of Sephadex®-QAE in 10 mM of HEPES-Na (pH 7.0) was added to the reaction mixture, and the mixture was left at rest for 5 minutes. Further, Sephadex®-QAE was added to the obtained supernatant and the mixture was left at rest for 5 minutes, then, the radioactivity of the solution was measured.
(4) IC50 was calculated as 50% inhibiting concentration of the metabolic activities of phosphodiesterase VII of the tested compound.
The compounds of the present invention selectively inhibit PDE 7 and their selectivities are more than 10 times compared to other phosphodiesterase. Therefore, it is expected that the side effect of the compounds of the present invention caused by other isozyme to be less.
For example, the selectivity against PDE 4 (phosphodiesterase IV) of the compounds of the present invention was affirmed by means of the following Biological Test.
The PDE 4 (phosphodiesterase IV) inhibiting effect of the compounds of the present invention was performed by the following method, which was modified assay method described in Biochemical. Pharmacol. 48(6), 1219-1223 (1994).
(1) The active fraction of PDE 4 (phosphodiesterase IV) was obtained. That is, the livers obtained from three Balb/c mice (male, 12 weeks: obtainable from CLEA Japan, Inc.) were suspended with 30 mL of buffer solution B [20 mM of bis-tris, 5 mM of 2-mercaptoethnol, 2 mM of benzamidine, 2 mM of EDTA, 0.1 mM of 4-(2-aminoethyl)benzensulfonyl hydrochloride, 50 mM of sodium acetate; pH 6.5], then homogenized by Polytron® homogenizer. The homogenate were centrifuged under 25,000×G for 10 minutes at 4° C. The supernatant was separated and thus obtained supernatant was further centrifuged under 100,000×G for 60 minutes at 4° C., and then filtrated with 0.2 μm filter to obtain the soluble fraction.
(2) The obtained soluble fraction was filled in equilibrium DEAE sepharose column (1×10 cm) with buffer solution B, and phosphodiesterase fractions were eluted by 120 mL of buffer solution B with linear gradient from 0.05 to 1M sodium acetate concentration. 5 mL each of 24 eluents were collected, and each eluents were examined for cyclic AMP metabolic activities of phosphodiesterase. The fraction eluting with about 620 mM of sodium acetate concentration parts, where metabolic activities were inactivated by 3 μM of rolipram (selective inhibitor for phosphodiesterase IV), were collected as storage solution to test PDE 4 inhibiting effect.
(3) The tested compound having desired concentration was reacted in the solution of 20 mM tris-HCl (pH 7.5), 1 mM of MgCl2, 100 μM of EDTA, 330 μg/mL of bovine serum albumin, 4 μg/mL of 5′-nucleotidase, 0.1 μCi of 3H-cAMP (0.064 μM of cAMP), and storage solution of PDE 4 for 2 hours at 25° C. After the reaction, suspension of Sephadex®-QAE in 10 mM of HEPES-Na (pH 7.0) was added to the reaction mixture, and the mixture was left at rest for 5 minutes. Further, Sephadex®-QAE was added to the obtained supernatant and the mixture was left at rest for 5 minutes, then, the radioactivity of the solution was measured.
(4) IC50 was calculated as 50% inhibiting concentration of the metabolic activities of phosphodiesterase IV of the tested compound.
As the results of the mentioned above Biological Test 2, the IC50 of the compounds of PDE 4 inhibiting effect of the present invention was more than 10 times weaker than that of PDE 7 inhibiting effect.
In the following Tables 1 to 4, the IC50 values of PDE 7 inhibiting activities and PDE 4 inhibiting activities were summarized.
The compounds of the present invention inhibit PDE 7 selectively, and therefore, enhance cellular cAMP level. Consequently, the compounds of the present invention are useful for treating various kinds of diseases such as allergic diseases, inflammatory diseases or immunological diseases. For example, the compounds of the present invention are useful for treating or preventing the diseases such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, sepsis, Crohn's disease, rejection for organ transplantation, GVH disease, and restenosis after angioplasty.
The compounds of the present invention can be used for preparation of the pharmaceutical composition or PDE 7 inhibitor. As an active ingredient, one or more compounds may be administered in the appropriated formulation. The formulation for oral administration may include for example, capsules, granules, fine granules, syrups, dry syrups or the like; the formulation for parenteral administration may include, for example injectable solution, suppository formulation such as rectal suppository or vaginal suppository, nasal administration such as sprays, or percutaneous absorption formulation such as ointment and tapes, and the like.
The administration dose may vary depending on the various kinds of factors. These factors may be the condition of the patients, the severity of the diseases, ages, existence of a complication, as well as formulation. A usual recommended daily dose for oral administration is within the range of 0.1-1,000 mg/day/adult, preferably 0.1-500 mg/day/adult, and more preferably 1-100 mg/day/adult. In the case of parenteral administration, a usual recommended daily dose is within the range of 1/10 to ½ based on dose of oral administration. These doses can be adjusted depending on age, as well as the patient's condition.
The toxicological properties of the compounds of the present invention is low, therefore, the compounds of the present invention is expected to have high safety margin.
The compounds of the present invention and intermediate compounds used for the synthesis of the compounds of the present invention are illustrated in the following Manufacturing Examples and Examples. The physicochemical data and chemical structure of the compounds are summarized in the Tables mentions later. The compound numbers in the Examples and Manufacturing Examples are identical to those in the Tables.
To a solution of 500 mg (3.05 mmol) of 5-nitroindoline in 10 mL of anhydrous dichloromethane was added 798 mg (3.65 mmol) of di-tert-butyl dicarbonate under ice cooling, and the mixture was stirred for 1.5 hours. Then, to this mixture was added catalytic amount of 4-dimethylamiopyridine and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=6/1) to give 800 mg (99%) of the title compound.
80 mg of 10% palladium-carbon was added to a solution of 760 mg (2.88 mmol) of the compound obtained in the Manufacturing Example 1 in 60 mL of methanol, and the reaction atmosphere was exchanged to hydrogen gas atmosphere. Then, the mixture was stirred for 30 minutes at room temperature and filtrated by Celite®. The filtrate was removed under reduced pressure to give 670 mg (99%) of the title compound.
To a solution of 300 mg (1.28 mmol) of the compound obtained in the Manufacturing Example 2 in 10 mL of anhydrous dichloromethane were added 191 μL (2.69 mmol) of acetyl chloride and 375 μL (2.69 mmol) of triethylamine, and the mixture was stirred for 1 hour at room temperature. Then, water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate and removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1 to 1/2) to give 370 mg (quantitative) of the title compound.
A mixture solution of 330 mg (1.19 mmol) of the compound obtained in the Manufacturing Example 3 in 15 mL of 4M-HCl/dioxane was stirred for 1.5 hours at room temperature. Then, diethylether was added to the reaction mixture and the resulting precipitates were collected to give 173 mg (68%) of the title compound.
To a solution of 300 mg (2.17 mmol) of 6-aminonicotinic acid in 50 mL of chloroform were added 370 μL (4.34 mmol) of isopropylamine, 4 mL of anhydrous propanephosphonic acid (25 wt % solution in ethyl acetate) and 1.4 mL (10 mmol) of triethylamin, and the mixture was stirred for 6 hours at room temperature. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1 to 5/1) to give 30 mg (8%) of the title compound.
To a solution of 300 mg (1.83 mmol) of 5-nitroindoline in 20 mL of dichloromethane were added 141 μL (2.74 mmol) of methanesulfonyl chloride and 382 μL (2.74 mmol) of triethylamine, and the mixture was stirred for 2 hours at room temperature. 141 μL (2.74 mmol) of methanesulfonyl chloride and 255 μL (1.83 mmol) of triethylamine were further added to the reaction mixture, and the mixture was stirred for 2 hours at room temperature. Then, water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with diethyl ether, then, the precipitates were collected by filtration to give 410 mg (92%) of the title compound.
The title compound 150 mg (58%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 6, instead of the compound obtained in the Manufacturing Example 1.
To a solution of 415 μL (3.38 mmol) of 1-piperazineethanol in 20 mL of dichloromethane were added 500 mg (2.26 mmol) of 4-nitrobenzenesulfonyl chloride and 472 μL (3.38 mmol) of triethylamine under ice cooling, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was diluted with dichloromethane and the organic layer was washed with water, saturated sodium bicarbonate aqueous solution and saturated saline solution and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=30/1) to give 670 mg (94%) of the title compound.
The title compound 175 mg (77%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Manufacturing Example 8, instead of the compound obtained in the Manufacturing Example 2.
The title compound 130 mg (95%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 9, instead of the compound obtained in the Manufacturing Example 1.
The title compound 130 mg (68%) was obtained in a manner similar to the Manufacturing Example 3 by use of tert-butyl trans-4-amino-cyclohexylcarbamate, instead of the compound obtained in the Manufacturing Example 2.
To a solution of 220 mg (0.86 mmol) of the compound obtained in the Manufacturing Example 11 in 8 mL Of dichloromethane was added 8 mL of trifluoroacetic acid at room temperature, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was condensed and the residue was treated with diethylether. The resulting precipitates were collected by filtration to give 194 mg (84%) of the title compound.
To a mixture solution of 384 μL (5.0 mmol) of methoxyacetic acid and 691 mg (5.0 mmol) of p-nitroaniline in 10 mL of dichloromethane were added 1.53 mg (5.5 mmol) of 2-chloro-1,3-dimethylimidazoliumhexafluorophosphate and 1.53 mL (111.0 mmol) of triethylamine, and the mixture was refluxed for 7 hours. Then, the reaction mixture was extracted with ethyl acetate, the extract was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=2/1) to give 750 mg (71%) of the title compound.
The title compound 604 mg (86%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 13, instead of the compound obtained in the Manufacturing Example 1.
The title compound 536 mg (quantitative) was obtained in a manner similar to the Manufacturing Example 2 by use of 1-methyl-4-(5-nitro-2-pyridinyl)piperazine, instead of the compound obtained in the Manufacturing Example 1.
To a solution of 500 mg (2.26 mmol) of 3-nitrobenzenesulfonyl chloride in 30 mL of dichloromethane were added 275 μL (2.48 mmol) of N-methylpiperazine and 786 μL (5.64 mmol) of triethylamine, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with dichloromethane and the organic layer was washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with diethyl ether to give 510 mg (79%) of the title compound.
The title compound 350 mg (98%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 16, instead of the compound obtained in the Manufacturing Example 1.
To a solution of 554 μL (5.0 mmol) of 3,4-difluoronitrobenzene in 10 mL of dimethyl sulfoxide were added 1.38 mg (10.0 mmol) of potassium carbonate and 803 μL (10.0 mmol) of 2-methylaminoetanol, and the mixture was stirred for 1.5 hours at 100° C. The reaction mixture was cooled to room temperature and extracted with ethyl acetate, then, the extract was washed with water and saturated saline solution. After dried over with anhydrous sodium sulfate, the solvent was removed under reduced pressure ant the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1) to give 1.06 g (99%) of the title compound.
The title compound 900 mg (quantitative) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 18, instead of the compound obtained in the Manufacturing Example 1.
To a solution of 4.84 g (30 mmol) of 4-phenylpiperidine in 30 mL of conc. sulfuric acid was added gradually a solution of 1.26 mL of fuming nitric acid in 5 mL of conc. sulfuric acid under ice cooling, and after addition, the reaction mixture was warmed up to room temperature. Then, the reaction mixture was poured into 200 g of ice and sodium hydroxide aqueous solution was added slowly until the mixture to be alkalified. The mixture was extracted with chloroform and the organic layer was dried over with anhydrous sodium sulfate. The solvent removed under reduced pressure. Then, 2.18 g (10 mmol) of di-tert-butyl dicarbonate was added to a solution of the resulting residue in 20 mL of dichloromethane, and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 0.78 g (8%) of the title compound.
The title compound 392 mg (57%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 20, instead of the compound obtained in the Manufacturing Example 1.
The title compound 2.33 g (92%) was obtained in a manner similar to the Manufacturing Example 18 by use of N-ethylpiperazine instead of 2-methylaminoethanol.
The title compound 2.21 g (87%) was obtained in a manner similar to the Manufacturing Example 18 by use of N-methylhomopiperazine, instead of 2-methylaminoethanol.
The title compound 1.85 g (94%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 22, instead of the compound obtained in the Manufacturing Example 1.
To a solution of 3.9 mL (35 mmol) of 3,4-difluoronitrobenzene in 60 mL of dimethyl sulfoxide were added 9.7 mL (87.5 mmol) of N-methylpiperazine and 12.1 g (87.5 mmol) of potassium carbonate, and the mixture was refluxed for 5 hours at 100° C. The reaction mixture was cooled to room temperature and poured into 500 mL of ice water, and the resulting precipitates were collected. The collected precipitates were dissolved in 2M-HCl aqueous solution and washed with ether. The aqueous layer was neutralized with 4M-NaOH aqueous solution to give the precipitates. The precipitates were collected to give 5.71 g (68%) of the title compound.
The title compound 2.76 g (quantitative) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 25, instead of the compound obtained in the Manufacturing Example 1.
The title compound 2.82 g (quantitative) was obtained in a manner similar to the Manufacturing Example 25 by use of 1,4-dioxa-8-azaspiro[4.5]decane, instead of N-methylpiperazine.
To a solution of 2.0 g (7.09 mmol) of the compound obtained in the Manufacturing Example 27 in 30 mL of methanol was added 200 mg of platinum on sulfide carbon, and the reaction atmosphere was changed to hydrogen gas atmosphere. Then, the mixture was stirred for 5 hours at normal pressures and temperature. The reaction mixture was filtrated by Celite®, and the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=3/1 to 1/1) to give 1.71 g (96%) of the title compound.
The title compound 3.05 g (quantitative) was obtained in a manner similar to the Manufacturing Example 25 by use of 3,4-dichloronitrobenzene and 1,4-dioxa-8-azaspiro[4.5]decane, instead of 3,4-difluoronitorobenzene and N-methylpiperazine, respectively.
The title compound 1.84 g (85%) was obtained in a manner similar to the Manufacturing Example 28 by use of the compound obtained in the Manufacturing Example 29, instead of the compound obtained in the Manufacturing Example 27.
The title compound 1.85 g (94%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 23, instead of the compound obtained in the Manufacturing Example 1.
The title compound 2.17 g (quantitative) was obtained in a manner similar to the Manufacturing Example 2 by use of 4-[2-(4-morpholinyl)-ethyl]nitrobenzene, instead of the compound obtained in the Manufacturing Example 1.
To a mixture solution of 685 mg (6.0 mmol) of 1-methylhydantoin in 10 mL of N,N-dimethylformamide and 10 mL of tetrahydrofuran was added 240 mg (6.9 mmol) of sodiumhydride (60% oily) at room temperature, and the mixture was stirred for 30 minutes at the same temperature. Then, 1.08 g (5.0 mmol) of p-nitrobenzyl bromide was added to the reaction mixture, and the mixture was stirred for over night at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 1.38 g (quantitative) of the title compound.
To a mixture solution of 1.33 g (5.34 mmol) of the compound obtained in the Manufacturing Example 33 in 12 mL of ethanol and 6 mL of conc. hydrochloric acid was added 5.41 g (24.01 mmol) of tin chloride (II) dehydrate at room temperature, and the mixture was stirred for 2 hours at 75° C. The reaction mixture was cooled to room temperature, alkalized by adding of 4N-sodium hydroxide aqueous solution and treated with chloroform. The mixture was filtered with Celite®, and chloroform layer was separated and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1.148 g (98%) of the title compound.
To a solution of 765 mg (4.99 mmol) of trans-4-cyanocyclohexane carboxylic acid in 10 mL of tert-butanol was added 766 μL (5.49 mmol) of triethylamine and 1.13 mL (5.24 mmol) of diphenylphosphorylazide at room temperature, and the mixture was refluxed for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added to this mixture and the organic layer was washed with saturated sodium bicarbonate aqueous solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=2/1) to give 608 mg (54%) of the title compound.
The title compound 361 mg (90%) was obtained in a manner similar to the Manufacturing Example 4 by use of the compound obtained in the Manufacturing Example 35, instead of the compound obtained in the Manufacturing Example 3.
To a solution of 3.60 g (11.95 mmol) of 2-[2-(4-methyl-2,3-dioxo-1-piperazinyl)ethyl]phthalimide in 30 mL of ethanol was added 695 μL (14.34 mmol) of hydrazine monohydrate and the mixture was stirred at 40° C. for over night. The reaction mixture was cooled to room temperature, then, 25 mL of water and 6 mL of 6N—HCl were added to this mixture and the mixture was stirred for 5 hours at room temperature. After removed off the insoluble substances by filtration, the filtrate was concentrated and the residue was re-crystallized by 2% water-ethanol solution to give 2.12 g (85%) of the title compound.
To a solution of 500 mg (2.50 mmol) of tert-butyl 4-piperidinyl-carbamate in 20 mL of dichloromethane was added 522 μL (3.74 mmol) of triethylamine and 276 μL (3.00 mmol) of dimethylaminocarbonyl chloride and the mixture was stirred for 2 hours at room temperature. Then, the mixture was treated with ethyl acetate and the organic layer was washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 636 mg (94%) of the title compound.
The title compound 571 mg (quantitative) was obtained in a manner similar to the Manufacturing Example 4 by use of the compound obtained in the Manufacturing Example 38, instead of the compound obtained in the Manufacturing Example 3.
To a solution of 412 mg (2.06 mmol) of tert-butyl 4-piperidinyl-carbamate in 20 mL of dichloromethane were added 430 μL (3.09 mmol) of triethylamine and 265 μL (2.47 mmol) of dimethylsulfamoyl chloride and the mixture was stirred for 2 hours at room temperature. Then, the mixture was treated with ethyl acetate and the organic layer was washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 536 mg (85%) of the title compound.
The title compound 0.42 g (quantitative) was obtained in a manner similar to the Manufacturing Example 4 by use of the compound obtained in the Manufacturing Example 40, instead of the compound obtained in the Manufacturing Example 3.
The title compound 4.70 g (96%) was obtained in a manner similar to the Manufacturing Example 2 by using methyl (2S,4S)-1-benzyloxycarbonyl-4-tert-butoxycarbonylaminopyrrolidine-2-carboxylate, instead of the compound obtained in the Manufacturing Example 1.
To a solution of 4.60 g (18.83 mmol) of the compound obtained in the Manufacturing Example 42 in 80 mL of dioxane and 80 mL of water were added 2.29 g (28.55 mmol) of potassium isocyanate and 3.23 mL (56.49 mmol) of acetic acid, and the mixture was stirred for 17 hour at room temperature. Then, the mixture was treated with ethyl acetate and the organic layer was washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1) to give 2.32 g (43%) of the title compound.
To a solution of 2.21 g (7.69 mmol) of the compound obtained in the Manufacturing Example 43 in 150 mL of methanol was added gradually 615 mg (15.38 mmol) of sodium hydride (60% oily) and the mixture was stirred for 30 minutes at room temperature. After condensed the reaction mixture, ethyl acetate and diluted hydrochloric acid were added to this mixture. The organic layer was separated and dried over with anhydrous sodium sulfate, and the solvent removed under reduced pressure to give 1.8 g (92%) of the title compound.
The title compound 1.18 g (91%) was obtained in a manner similar to the Manufacturing Example 4 by use of the compound obtained in the Manufacturing Example 44, instead of the compound obtained in the Manufacturing Example 3.
The title compound 730 mg (quantitative) was obtained in a manner similar to the Manufacturing Example 2 by use of 1-(5-nitro-2-pyridinyl)-2-imidazolidinone, instead of the compound obtained in the Manufacturing Example 1.
The title compound 179 mg (69%) was obtained in a manner similar to the Manufacturing Example 2 by use of 3-(4-nitrophenyl)-2,4-imidazolidinedione, instead of the compound obtained in the Manufacturing Example 1.
The title compound 413 mg (95%) was obtained in a manner similar to the Manufacturing Example 2 by use of 3-(4-nitrophenyl)-1-methyl-2,4-imidazolidinedione, instead of the compound obtained in the Manufacturing Example 1.
The title compound 1.98 g (quantitative) was obtained in a manner similar to the Manufacturing Example 2 by use of (3R)-1-(4-nitrophenyl)-3-pyrrolidinol, instead of the compound obtained in the Manufacturing Example 1.
The title compound 2.19 g (65%) was obtained in a manner similar to the Manufacturing Example 18 by use of (R)-3-pyrrolidinol, instead of 2-methylaminoethanol.
The title compound 1.81 g (99%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 50, instead of the compound obtained in the Manufacturing Example 1.
The title compound 1.91 g (49%) was obtained in a manner similar to the Manufacturing Example 16 by use of 4-hydroxypiperidine, instead of N-methylpiperazine.
The title compound 1.56 g (52%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 52, instead of the compound obtained in the Manufacturing Example 1.
The title compound 1.91 g (49%) was obtained in a manner similar to the Manufacturing Example 8 by use of 4-hydroxypiperidine, instead of 1-piperazineethanol.
To a solution of 1.5 g (5.24 mmol) of the compound obtained in the Manufacturing Example 54 in 60 mL of dichloromethane was added 1.32 mL (5.76 mmol) of tert-butyldimethylsilyl trifluorate at 0° C., and the mixture was stirred overnight at room temperature. After the reaction, the reaction mixture was washed with water and the organic layer was dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=5/1) to give 2.04 g (97%) of the title compound.
The title compound 1.67 g (98%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 55, instead of the compound obtained in the Manufacturing Example 1.
The title compound 2.28 g (82%) was obtained in a manner similar to the Manufacturing Example 25 by use of 2-fluoro-5-nitrobenzotrifluoride, instead of 3,4-difluoronitrobenzene.
The title compound 1.96 g (99%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 57, instead of the compound obtained in the Manufacturing Example 1.
To a solution of 686 mg (5.04 mmol) of 2-methyl-1,2,5-thiadiazolidine 1,1-dioxide in 10 mL of N,N-dimethylformamide was added 212 mg (5.30 mmol) of sodium hydride (60% oily) at room temperature, and the mixture was stirred for 1 hour at the same temperature. Then, 1.41 g (5.54 mmol) of N-(2-bromoethyl)phthalimide was added to the reaction mixture, and the mixture was stirred for 1.5 hours at 75° C. After the reaction, water was addedtothereactionmixtureandsolventwasremovedunderreducedpressure. The resulting residue was treated with water and extracted with dichloromethane and the organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/5), and solidified by treating with ethyl acetate/ether to give 526 mg (34%) of the title compound.
To a suspension of 500 mg (1.62 mmol) of the compound obtained in the Manufacturing Example 59 in 5 mL of ethanol was added 94 μL (1.94 mmol) of hydrazine monohydrate, and the mixture was stirred for 6 hours at 70° C. Then, insoluble substances were removed off by filtration and the filtrate was removed under reduced pressure, and 5 mL of water and 1.5 mL of 6M-HCl aqueous solution were added to the residue. Then, the mixture was stirred for 6 hours at room temperature and insoluble substances were removed off by filtration and the filtrate was removed under reduced pressure. The resulting residue was recrystallized from ethanol to give 287 mg (82%) of the title compound.
To a solution of 4.77 g (30.0 mmol) of 3,4-difluoronitrobenzene in 100 mL of N,N-dimethylformamide were added 5.33 g (40.0 mmol) of potassium carbonate and 3.03 g (30.0 mmol) of 4-hydroxypiperidine and the mixture was stirred for 1 hour at 120° C. After the reaction mixture was cooled to room temperature, the reaction mixture was diluted with chloroform and insoluble substances were removed off by filtration. The filtrate was condensed and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1.5/1) to give 3.1 g (43%) of the title compound.
To a solution of 2.95 g (12.28 mmol) of the compound obtained in the Manufacturing Example 61 in 100 mL of ethanol was added 600 mg of 5%-palladium carbon, and the atmosphere was exchanged to hydrogen atmosphere. The mixture was stirred for 2 hours at room temperature and filtered. The filtrate was removed under reduced pressure to give 2.48 g (96%) of the title compound.
To a solution of 21.43 g (0.1 mol) of tert-butyl N-(trans-4-aminocyclohexyl) carbamate in 250 mL of N,N-dimethylformamide were added 16.76 mL (0.12 mol) of bis (2-bromoethyl)ether and 34.85 mL (0.25 mol) of triethylamine, and the mixture was stirred for 6 hours at 70° C. Then solvent was removed under reduced pressure and the residue was treated with ethyl acetate. The organic layer was washed with sodium carbonate aqueous solution and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:chloroform alone to chloroform/methanol=30/1) to give 19.92 g (70%) of the title compound.
To a solution of 18.53 g (65.16 mmol) of the compound obtained in the Manufacturing Example 63 in 65 mL of chloroform was added 130 mL of 4N—HCl/ethyl acetate solution, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was treated with 200 mL of diethyl ether and separated precipitates were collected to give 16.22 g (97%) of the title compound.
To a solution of 1.275 g (9.04 mmol) of 4-fluoronitrobenzene in 30 mL of N,N-dimethylformamide were added 1.87 g (13.56 mmol) of potassium carbonate and 905 mg (9.04 mmol) of piperazine-2-one, and the mixture was stirred for 1 hour at 130° C. and for 1 hour at 140° C. The reaction mixture was cooled to room temperature and diluted with chloroform, then, insoluble substances were removed off by filtration. The filtrate was condensed under reduced pressure and the resulting solid was washed with ethanol to give 859 mg (43%) of the title compound.
The title compound 640 mg (89%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 65, instead of the compound obtained in the Manufacturing Example 1.
The title compound 2.55 g (99%) was obtained in a manner similar to the Manufacturing Example 2 by use of N,N-dimethyl-3-nitrobenzene-sulfonamide, instead of the compound obtained in the Manufacturing Example 1.
To a solution of 955 mg (4.13 mmol) of 3-[(2-hydroxyethyl) sulfonyl]-nitrobenzene in 30 mL of dichloromethane were added 747 mg (4.96 mmol) of tert-butyldimethylsilyl chloride and 10 mg of 4-dimethylaminopyridine, and the mixture was stirred for over night at room temperature. Then, the reaction mixture was diluted with dichloromethane and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=4/1 to 2/1) to give 1.27 g (89%) of the title compound.
The title compound 856 mg (94%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 68, instead of the compound obtained in the Manufacturing Example 1.
To a suspension of 2.946 g (13.73 mmol) of 2-chloro-N-(4-nitrophenyl)acetamide in 30 mL of ethanol was added 3.31 mL (41.18 mmol) of 2-(methylamino)ethanol and the mixture was refluxed for 4 hours. After the reaction mixture was cooled to room temperature and condensed, then, the residue was treated with ethyl acetate. The organic layer was washed with water and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 2.05 g (59%) of the title compound.
To a solution of 1.48 g (5.84 mmol) of the compound obtained in the Manufacturing Example 70 in 50 mL of tetrahydrofuran were added 1.75 mL (7.01 mmol) of tri-n-butylphosphine and 1.21 g (7.01 mmol) of 1,1′-azobis-(N,N-dimethylformamide), and the mixture was stirred for 4 hours at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give 738 mg (54%) of the title compound.
The title compound 545 mg (quantitative) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 71, instead of the compound obtained in the Manufacturing Example 1.
To a suspension of 11.0 g (6.3 mmol) of 2-chloro-5-nitropyridine in 20 mL of n-propanol was added 1.9 g (18.9 mmol) of 4-hydroxypiperidine, and the mixture was stirred for 1.5 hours at 100° C. After cooling the reaction mixture, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=50/1) to give 1.37 g (97%) of the title compound.
To a suspension of 1.35 g (6.04 mmol) of the compound obtained in the Manufacturing Example 73 in 18 mL of ethanol and 3 mL of water were added 1.3 g of reduced iron and 0.25 mL of conc. hydrochloric acid, and the mixture was stirred for 2 hours at 90° C. After cooling the reaction mixture, the mixture was filtrated by Celite® and filtrate was condensed under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1) to give 601 mg (51%) of the title compound.
To a solution of 1.72 mL (15 mmol) of 2,3,4-trifluorobenzene in N,N-dimethylformamide were added 1.01 g (10 mmol) of 4-hydroxypiperidine and 2.3 mL (20 mmol) of 2,6-lutidine, and the mixture was stirred for 24 hours at room temperature. The solvent was removed under reduced pressure, and saturated sodium bicarbonate aqueous solution was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=2/1 to ethyl acetate alone) to give 1.82 g (70%) of the title compound.
The title compound 1.23 g (78%) was obtained in a manner similar to the Manufacturing Example 74 by use of the compound obtained in the Manufacturing Example 75, instead of the compound obtained in the Manufacturing Example 73.
To a solution of 1.55 g (10 mmol) of 2-fluoro-5-nitrotoluene in 35 mL of N,N-dimethylformamide were added 1.01 g (10 mmol) of 4-hydroxypiperidine and 1.8 g (13 mmol) of potassium carbonate, and the mixture was stirred for 2 hours at 120° C. The reaction mixture was poured into ice and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1) to give 1.5 g (63%) of the title compound.
The title compound 1.2 g (quantitative) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 77, instead of the compound obtained in the Manufacturing Example 1.
The title compound 2.0 g (81%) was obtained in a manner similar to the Manufacturing Example 77 by use of 2-fluoro-5-nitrobenzonitrile, instead of 2-fluoro-5-nitrotoluene.
To a suspension of 11.0 g (4.04 mmol) of the compound obtained in the Manufacturing Example 79 in 10 mL of water were added 790 mg (14.14 mmol) of iron and 130 mg (2.42 mmol) of ammonium chloride, and the mixture was refluxed for 3 hours. After the reaction mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1 to 1/4) to give 327 mg (37%) of the title compound.
The title compound 2.30 g (98%) was obtained in a manner similar to the Manufacturing Example 77 by use of methyl 2-fluoro-5-nitrobenzoate, instead of 2-fluoro-5-nitrotoluene.
The title compound 1.83 g (91%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 81, instead of the compound obtained in the Manufacturing Example 1.
To a suspension of 9.5 g (184 mmol) of tert-butyl piperidin-4-yl carbamate in 200 mL of 1,2-dichloroethane were added 4.4 mL (47.4 mmol) of tetrahydro-4H-pyran-4-one and 1.0 mL of acetic acid, and the mixture was stirred for 30 minute. The reaction mixture was cooled to 0° C., and to this mixture was added 15 g (71.1 mmol) of sodium triacetoxyborohydride and the mixture was stirred for 4 hours at room temperature, then, 5.0 g (23.6 mmol) of sodium triacetoxyborohydride was further added to the mixture and the mixture was stirred for 64 hours at room temperature. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=2/1) to give 11.54 g (86%) of the title compound.
The title compound 10.8 g (quantitative) was obtained in a manner similar to the Manufacturing Example 4 by use of the compound obtained in the Manufacturing Example 83, instead of the compound obtained in the Manufacturing Example 3.
The title compound 4.0 g (96%) was obtained in a manner similar to the Manufacturing Example 83 by use of benzyl 4-oxocyclohexylcarbamate and tert-butyl 1-piperazinecarbamate, instead of tetrahydro-4H-pyran-4-one and tert-butyl piperidin-4-ylcarbamate, respectively.
The title compound 2.6 g (quantitative) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 85, instead of the compound obtained in the Manufacturing Example 1.
The title compound 686 mg (78%) was obtained in a manner similar to the Manufacturing Example 4 by use of tert-butyl 6-(hydroxylmethyl)pyridin-3-ylcarbamate, instead of the compound obtained in the Manufacturing Example 3.
The title compound 604 mg (89%) was obtained in a manner similar to the Manufacturing Example 3 by use of tert-butyl trans-4-aminocyclohexylcarbamate and chloroacetyl chloride, instead of the compound obtained in the Manufacturing Example 2 and acetyl chloride, respectively.
To a suspension of 560 mg (1.93 mml) of the compound obtained in the Manufacturing Example 88 in 5 mL of ethanol was added 464 μL (5.78 mmol) of 2-(methylamino) ethanol and the mixture was refluxed for 1 hour. After cooling, the solvent was removed under reduced pressure and water was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by recrystallization (isopropanol) to give 391 mg (61%) of the title compound.
589 mg (5.25 mmol) of potassium t-butoxide was added to a suspension solution of 560 mg (1.7 mmol) of the compound obtained in the Manufacturing Example 89 in 10 mL of tetrahydrofuran, and a solution of 499 mg (2.62 mmol) of p-toluenesulfonyl chloride in 5 mL of tetrahydrofuran was added to this mixture, then, the mixture was stirred for 2 hours at 0° C. 499 mg (2.62 mmol) of p-toluenesulfonyl chloride and 589 mg (5.25 mmol) of potassium t-butoxide were further added to the reaction mixture, and the mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1) to give 398 mg (75%) of the title compound.
The title compound 349 mg (quantitative) was obtained in a manner similar to the Manufacturing Example 4 by use of the compound obtained in the Manufacturing Example 90, instead of the compound obtained in the Manufacturing Example 3.
The title compound 2.6 g (67%) was obtained in a manner similar to the Manufacturing Example 83 by use of benzyl 4-oxocyclohexylcarbamate and ethyl isonipecocotinate, instead of tetrahydro-4H-pyran-4-one and tert-butyl piperidin-4-ylcarbamate, respectively.
The title compound 1.58 g (quantitative) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Manufacturing Example 92, instead the compound obtained in the Manufacturing Example 1.
To a solution of 14.1 g (0.10 mol) of 4-fluoronitrobenzene in 200 mL of N,N-dimethylformamide were added 20.73 (0.15 mol) of potassium carbonate and 10.1 g (0.10 mol) of 4-hydroxypiperidine and the mixture was stirred for 1 hour at 140° C. The reaction mixture was cooled to room temperature and the mixture was treated with chloroform, then insoluble substances were removed off by filtration. The filtrate was condensed and the residue was recrystallized from ethanol to give 17.27 g (78%) of the title compound.
To a solution of 17.09 g (76.95 mmol) of the compound obtained in the Manufacturing Example 94 in 300 mL of methanol was added 2.0 g of 5%-palladium-carbon, and the atmosphere was exchanged to hydrogen atmosphere. The mixture was stirred for over night at room temperature and the mixture was filtrated. The filtrate was removed under reduced pressure to give 13.04 g (88%) of the title compound.
A mixture solution of 39.88 g (0.265 mol) of cyclohexylhydazine HCl salt in 28.57 mL (0.265 mol) of methyl acetoacetate was heated for 1 hour at 120° C. After the reaction mixture was cooled to room temperature, dichloromethane was added to this mixture and the mixture was neutralized by 2N-NaOH aqueous solution. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was treated with hexane to give crystalline and the crystalline was collected by filtration to give 33.84 g (71%) of the title compound.
A mixture of 13.5 g (74.9 mmol) of the compound obtained in the Example 1 and 13.5 mL of phosphorus oxychloride was heated for 2 hours at 110° C. Then, the reaction mixture was cooled to room temperature and condensed under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with saturated sodium bicarbonate aqueous solution and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent removed under reduced pressure to give 9.84 g (66%) of the title compound.
To a solution of 9.84 g (49.52 mmol) of the compound obtained in the Example 2 in 50 mL of N,N-dimethylformamide was added 11.5 mL (123.8 mmol) of phosphorous oxychloride under ice cooling, and the mixture was stirred for 30 minutes at room temperature and for 1 hour at 80° C. Then, the reaction mixture was cooled to room temperature and condensed under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with saturated sodium bicarbonate aqueous solution and saturates saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=10/1) to give 8.73 g (76%) of the title compound.
A mixture of 10 g (0.61 mol) of the compound obtained in the Example 1 and 216 mL (2.32 mol) of phosphorus oxychloride was heated and stirred for 2 hours at 110° C. Then, the reaction mixture was cooled to room temperature and added gradually to 630 mL of cooled N,N-dimethylformamide. After adding, the mixture was stirred for 30 minutes at room temperature and for 5 hours at 80° C. The reaction mixture was cooled to room temperature, and the mixture was poured slowly into ice. Chloroform was added to this mixture and pH of the mixture was adjusted to about 4 by 4N-NaOH aqueous solution (about 2.3 L). The organic layer was separated and water layer was extracted with chloroform. The combined organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/10 to 1/7) to give 100.8 g (73%) of the title compound.
To a solution of 8.0 g (35.3 mmol) of the compound obtained in the Example 3 in 100 mL of acetonitrile were added 4.84 mL (44.1 mmol) of ethyl thioglycolate and 7.32 g (52.93 mmol) of potassium carbonate, and the mixture was refluxed for 4 hours. Then, 1.93 mL (17.64 mmol) of ethyl thioglycolate and 2.43 g (17.64 mmol) of potassium carbonate were further added to the reaction mixture and the mixture was refluxed for 2 hours. After the reaction mixture was cooled to room temperature and condensed under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=4/1) to give 8.09 g (74%) of the title compound.
To a solution of 7.95 g (25.61 mmol) of the compound obtained in the Example 4 in 100 mL of N,N-dimethylformamide were added 5.31 g (38.42 mmol) of potassium carbonate and 677 mg (2.56 mmol) of 18-crown-6, and the mixture was heated for 2 hours at 120° C. to 130° C. After cooling the reaction mixture to room temperature, the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/acetone=15/1) to give 2.2 g (29%) of the title compound.
To a solution of 63.4 mL (0.578 mmol) of ethyl thioglycolate in 1 L of tetrahydrofuran was added gradually 23 g (0.578 mol) of sodium hydride (60% oily) under ice cooling, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was cooled with ice water, and a solution of 100.8 g (0.444 mol) of the compound obtained in the Example 3 in 400 mL of tetrahydrofuran was added gradually to this reaction mixture during 45 minutes, and the mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was cooled with ice water, and 23 g (0.578 mol) of sodium hydride (60% oily) was added gradually to this reaction mixture, and the mixture was stirred for 30 minutes at 0° C. After the reaction, the reaction mixture was poured slowly into ice/ethyl acetate solution, and the organic layer was separated. The water layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated saline solution, then dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/8 to 1/5) to give 104.7 g (81%) of the title compound.
To a solution of 11.89 g (40.66 mmol) of the compound obtained in the Example 5 in 100 mL of ethanol was added 44.7 mL (44.7 mmol) of 1N sodium hydroxide solution, and the mixture was heated for 1 hour at 60° C. Then, the reaction mixture was cooled to room temperature and condensed under reduced pressure. Water and diethyl ether were added to the residue and the water layer was separated. 23 mL of 2N—HCl aqueous solution was added to the water layer, and the resulting precipitates were collected to give 10.38 g (97%) of the title compound.
To a suspension of 60 mg (0.23 mmol) of the compound obtained in the Example 6 in 2 mL of dichloromethane was added 33 μL (0.45 mmol) of thionyl chloride, and the mixture was stirred for 8 hours at 80° C. Then, the solvent was removed under reduced pressure to give the corresponding acid chloride intermediate compound.
Next, 27 μL (0.25 mmol) of benzylamine and 79 μL of triethylamine were added to the solution of the above acid chloride intermediate compound in 2 mL of anhydrous dichloromethane under ice-cooling, and the mixture was stirred for 1.5 hours at room temperature. Then, water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate and removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=4/1 to 3/1) to give 75 mg (94%) of the title compound.
The title compound 65 mg (84%) was obtained in a manner similar to the Example 7 by use of aniline, instead of benzylamine.
The title compound 89 mg (82%) was obtained in a manner similar to the Example 7 by use of N-(4-aminophenyl)-N-methylacetamide, instead of benzylamine.
The title compound 73 mg (65%) was obtained in a manner similar to the Example 7 by use of N-(4-amino-3-methoxyphenyl)acetamide, instead of benzylamine.
The title compound 30 mg (27%) was obtained in a manner similar to the Example 7 by use of 1-acetyl-2,3-dihydro-1H-indol-5-ylamine, instead of benzylamine.
The title compound 101 mg (89%) was obtained in a manner similar to the Example 7 by use of ethyl 4-aminophenylcarbamate, instead of benzylamine.
The title compound 133 mg (92%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 2, instead of benzylamine.
The title compound 68 mg (99%) was obtained in a manner similar to the Manufacturing Example 4 by use of the compound obtained in the Example 13, instead of the compound obtained in the Manufacturing Example 3.
The title compound 95 mg (95%) was obtained in a manner similar to the Example 7 by use of 5-aminoindole, instead of benzylamine.
The title compound 85 mg (89%) was obtained in a manner similar to the Example 7 by use of 4-(4-morpholinyl) aniline, instead of benzylamine.
The title compound 175 mg (60%) was obtained in a manner similar to the Example 7 by use of 3-nitroaniline, instead of benzylamine.
The title compound 142 mg (quantitative) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Example 17, instead of the compound obtained in the Manufacturing Example 1.
To a solution of 60 mg (0.17 mmol) of the compound obtained in the Example 18 in 4 mL of anhydrous tetrahydrofuran were added 25 μL (0.35 mmol) of acetyl chloride and 50 μL (0.35 mmol) of triethylamine under ice cooling, and the mixture was stirred for 2 hour at room temperature. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over with anhydrous sodium sulfate and removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=2/1 to 1/2) to give 15 mg (22%) of the title compound.
The title compound 37 mg (41%) was obtained in a manner similar to the Example 7 by use of 4-amino-N-methylbenzamide, instead of benzylamine.
The title compound 47 mg (75%) was obtained in a manner similar to the Example 19 by use of the compound obtained in the Example 14 and propionyl chloride, instead of using the compound obtained in the Example 18 and acetyl chloride, respectively.
The title compound 62 mg (82%) was obtained in a manner similar to the Example 19 by use of the compound obtained in the Example 14 and ethyl chlorocarbonate, instead of the compound obtained in the Example 18 and acetyl chloride, respectively.
The title compound 68 mg (89%) was obtained in a manner similar to the Example 19 by use of the compound obtained in the Example 14 and isobutyryl chloride, instead of the compound obtained in the Example 18 and acetyl chloride, respectively.
The title compound 66 mg (87%) was obtained in a manner similar to the Example 19 by use of the compound obtained in the Example 14 and n-butyryl chloride, instead of the compound obtained in the Example 18 and acetyl chloride, respectively.
The title compound 59 mg (76%) was obtained in a manner similar to the Example 19 by use of the compound obtained in the Example 14 and propanoyl chloride, instead of the compound obtained in the Example 18 and acetyl chloride, respectively.
The title compound 60 mg (58%) was obtained in a manner similar to the Example 7 by use of 5-amino-1,3-dihydro-2H-indol-2-one, instead of benzylamine.
The title compound 28 mg (43%) was obtained in a manner similar to the Example 7 by use of N-(4-amino-2-chlorophenyl)acetamide, instead of benzylamine.
The title compound 30 mg (32%) was obtained in a manner similar to the Example 7 by use of 4-amino-N-ethylbenzamide, instead of benzylamine.
The title compound 62 mg (70%) was obtained in a manner similar to the Example 7 by use of 4-(methoxymethyl) aniline, instead of benzylamine.
The title compound 65 mg (76%) was obtained in a manner similar to the Example 7 by use of (4-aminophenyl)methanol, instead of benzylamine.
The title compound 88 mg (90%) was obtained in a manner similar to the Example 7 by use of 4-(4-morpholinylcarbonyl)aniline, instead of benzylamine.
The title compound 57 mg (53%) was obtained in a manner similar to the Example 7 by use of 4-[(4-methyl-1-piperazinyl)carbonyl]aniline, instead of benzylamine.
The title compound 33 mg (33%) was obtained in a manner similar to the Example 7 by use of N-(4-aminophenyl)methanesulfonamide, instead of benzylamine.
The title compound 22 mg (22%) was obtained in a manner similar to the Example 7 by use of 4-amino-N-methylbenzenesulfonamide, instead of benzylamine.
The title compound 76 mg (80%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 4, instead of benzylamine.
The title compound 36 mg (32%) was obtained in a manner similar to the Example 7 by use of 4-[(4-methyl-1-piperazinyl)sulfonyl]aniline, instead of benzylamine.
The title compound 50 mg (50%) was obtained in a manner similar to the Example 7 by use of 4-amino-N-(2-methoxyethyl)benzamide, instead of benzylamine.
The title compound 54 mg (62%) was obtained in a manner similar to the Example 7 by use of p-aminoacetophenone, instead of benzylamine.
The title compound 86 mg (92%) was obtained in a manner similar to the Example 7 by use of 4-amino-N,N-dimethylbenzamide, instead of benzylamine.
The title compound 80 mg (51%) was obtained in a manner similar to the Example 7 by use of ethyl 4-aminobenzoate, instead of benzylamine.
To a solution of 55 mg (0.13 mmol) of the compound obtained in the Example 40 in 8 mL of ethanol was added 134 μL of 1M sodium hydroxide solution, and the mixture was stirred for 1 hour at room temperature. Then, 20 mL of water was added to the reaction mixture and the water layer was washed with ethyl acetate. The water layer was neutralized by adding of 1M-HCl solution, and the resulting precipitates were collected to give 33 mg (65%) of the title compound.
The title compound 73 mg (31%) was obtained in a manner similar to the Example 7 by use of 2-methoxy-4-nitroaniline, instead of benzylamine.
The title compound 22 mg (37%) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Example 42, instead of the compound obtained in the Manufacturing Example 1.
The title compound 27 mg (49%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 43, instead of the compound obtained in the Manufacturing Example 2.
The title compound 47 mg (49%) was obtained in a manner similar to the Example 7 by use of 4-amino-N-isopropylbenzamide, instead of benzylamine.
The title compound 93 mg (72%) was obtained in a manner similar to the Example 7 by use of 4-amino-N-(2-hydroxyethyl)benzamide, instead of benzylamine.
The title compound 33 mg (37%) was obtained in a manner similar to the Example 7 by use of N-(5-amino-2-pyridinyl)acetamide, instead of benzylamine.
The title compound 81 mg (96%) was obtained in a manner similar to the Example 7 by use of p-anisidine, instead of benzylamine.
The title compound 65 mg (85%) was obtained in a manner similar to the Example 7 by use of cyclopentylamine, instead of benzylamine.
The title compound 82 mg (quantitative) was obtained in a manner similar to the Example 7 by use of cyclohexylamine, instead of benzylamine.
The title compound 89 mg (89%) was obtained in a manner similar to the Example 7 by use of 4-amino-N-(tert-butyl)benzamide, instead of benzylamine.
The title compound 13 mg (20%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 5, instead of benzylamine.
The title compound 11 mg (19%) was obtained in a manner similar to the Example 7 by use of 4-aminophenylformamide, instead of benzylamine.
The title compound 71 mg (32%) was obtained in a manner similar to the Example 7 by use of tert-butyl 4-[(4-aminophenyl)sulfonyl]-1-piperazinecarboxylate, instead of benzylamine.
The title compound 30 mg (61%) was obtained in a manner similar to the Manufacturing Example 4 by use of the compound obtained in the Example 54, instead of the compound obtained in the Manufacturing Example 3.
The title compound 14 mg (12%) was obtained in a manner similar to the Example 7 by use of 4-(4-morpholinylsulfonyl)aniline, instead of benzylamine.
The title compound 41 mg (43%) was obtained in a manner similar to the Example 7 by use of 4-(methylsulfonyl) aniline, instead of benzylamine.
The title compound 42 mg (49%) was obtained in a manner similar to the Example 19 by use of the compound obtained in the Example 14 and cyclopropanecarbonyl chloride, instead of the compound obtained in the Example 18 and acetyl chloride, respectively.
The title compound 106 mg (quantitative) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 7, instead of benzylamine.
The title compound 94 mg (97%) was obtained in a manner similar to the Example 7 by use of 1-acetyl-1H-indole-5-amine, instead of benzylamine.
The title compound 67 mg (96%) was obtained in a manner similar to the Example 7 by use of cyclopropylamine, instead of benzylamine.
The title compound 200 mg (81%) was obtained in a manner similar to the Example 7 by use of 1-benzyl-4-piperidinylamine, instead of benzylamine.
To a solution of 180 mg (0.42 mol) of the compound obtained in the Example 62 in 4 mL of 1,2-dichloroethane was added 50 μL of 1-chloroethyl chloroformate, and the mixture was refluxed for 2 hours. Then, the reaction mixture was cooled to room temperature and condensed under reduced pressure. The residue was dissolved in 6 mL of methanol and the mixture was refluxed for 3 hours. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The residue was washed with ethyl acetate and the resulting precipitates were collected to give 109 mg (69%) of the title compound.
The title compound 40 mg (78%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 63, instead of the compound obtained in the Manufacturing Example 2.
The title compound 320 mg (96%) was obtained in a manner similar to the Example 7 by use of ethyl (4-aminophenoxy)acetate, instead of benzylamine.
The title compound 268 mg (95%) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 65, instead of the compound obtained in the Example 40.
The title compound 24 mg (39%) was obtained in a manner similar to the Manufacturing Example 5 by use of the compound obtained in the Example 66 and methylamine (30%-methanol solution), instead of 6-aminonicotic acid and isopropylamine, respectively.
The title compound 223 mg (93%) was obtained in a manner similar to the Example 7 by use of ethyl(4-aminophenyl)acetate, instead of benzylamine.
The title compound 157 mg (84%) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 68, instead of the compound obtained in the Example 40.
The title compound 31 mg (50%) was obtained in a manner similar to the Manufacturing Example 5 by use of the compound obtained in the Example 69 and methylamine (30%-methanol solution), instead of 6-aminonicotic acid and isopropylamine, respectively.
The title compound 158 mg (quantitative) was obtained in a manner similar to the Example 7 by use of tert-buty 4-(4-aminophenyl)-1-piperazine-carboxylate, instead of benzylamine.
The title compound 108 mg (88%) was obtained in a manner similar to the Manufacturing Example 4 by use of the compound obtained in the Example 71, instead of the compound obtained in the Manufacturing Example 3.
The title compound 32 mg (63%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 72, instead of the compound obtained in the Manufacturing Example 2.
The title compound 82 mg (quantitative) was obtained in a manner similar to the Example 7 by use of trans-4-aminocyclohexanol, instead of benzylamine.
To a solution of 4.0 g (11.1 mmol) of the compound obtained in the Example 74 in 200 mL of dichloromethane was added 5.0 g (13.3 mmol) of pyridinium dichromate, and the mixture was stirred for 6 hours at room temperature. Then, 5.0 g (13.3 mmol) of pyridinium dichromate was further added to the reaction mixture and the mixture was stirred for 18 hours. The reaction mixture was filtrated with Celite® and the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give the 2.6 g (65%) of the title compound.
The title compound 65 mg (90%) was obtained in a manner similar to the Manufacturing Example 5 by use of the compound obtained in the Example 66 and N-methylpiperazine, instead of 6-aminonicotic acid and isopropylamine, respectively.
The title compound 43 mg (67%) was obtained in a manner similar to the Manufacturing Example 5 by use of the compound obtained in the Example 66 and dimethylamine HCl salt, instead of 6-aminonicotic acid and isopropylamine, respectively.
The title compound 60 mg (28%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 10, instead of benzylamine.
To a solution of 45 mg (0.08 mmol) of the compound obtained in the Example 78 in 41 mL of ethanol was added 86 μL of 1M sodium hydroxide aqueous solution, and the mixture was stirred for 1 hour at room temperature. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1) to give 31 mg (74%) of the title compound.
The title compound 28 mg (30%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 12, instead of benzylamine.
The title compound 58 mg (92%) was obtained in a manner similar to the Example 7 by use of methylamine HCl salt, instead of benzylamine.
The title compound 9.70 g (80%) was obtained in a manner similar to the Example 1 by use of cyclopentylhydrazine HCl salt, instead of cyclohexylhydrazine HCl salt.
The title compound 4.5 g (81%) was obtained in a manner similar to the Example 2 by use of the compound obtained in the Example 82, instead of the compound obtained in the Example 1.
The title compound 4.0 g (79%) was obtained in a manner similar to the Example 3-1 by use of the compound obtained in the Example 83, instead of the compound obtained in the Example 2.
The title compound 1.9 g (36%) was obtained in a manner similar to the Example 4 by use of the compound obtained in the Example 84, instead of the compound obtained in the Example 3.
The title compound 1.47 g (87%) was obtained in a manner similar to the Example 5-1 by use of the compound obtained in the Example 85, instead of the compound obtained in the Example 4.
The title compound 0.49 g (68%) was obtained in a manner similar to the Example 6 by use of the compound obtained in the Example 86, instead of the compound obtained in the Example 5.
The title compound 88 mg (72%) was obtained in a manner similar to the Example 7 by use of N-(4-aminophenyl)acetamide and the compound obtained in the Example 87, instead of benzylamine and the compound obtained in the Example 6 respectively.
The title compound 16.27 g (52%) was obtained in a manner similar to the Example 1 by use of cycloheptylhydrazine HCl salt, instead of using cyclohexylhydrazine HCl salt.
The title compound 6.92 g (79%) was obtained in a manner similar to the Example 2 by use of the compound obtained in the Example 89, instead of the compound obtained in the Example 1.
The title compound 6.47 g (84%) was obtained in a manner similar to the Example 3-1 by use of the compound obtained in the Example 90, instead of the compound obtained in the Example 2.
To a solution of 6.4 g (26.6 mmol) of the compound obtained in the Example 91 in 100 mL of acetonitrile were added 3.06 mL (27.9 mmol) of ethyl thioglycolate and 7.72 g (55.88 mmol) of potassium carbonate, and the mixture was refluxed for 23 hours. Then, 3.06 mL (27.9 mmol) of ethyl thioglycolate was further added ant the mixture was refluxed for 3 hours. After cooling the reaction mixture to room temperature, the mixture was condensed and the residue was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane/acetone=20/1) to give 2.46 g (30%) of the title compound.
The title compound 1.40 g (67%) was obtained in a manner similar to the Example 6 by use of the compound obtained in the Example 92, instead of the compound obtained in the Example 5.
The title compound 71 mg (60%) was obtained in a manner similar to the Example 7 by use of N-(4-aminophenyl)acetamide and the compound obtained in the Example 93, instead of benzylamine and the compound obtained in the Example 6, respectively.
The title compound 103 mg (96%) was obtained in a manner similar to the Example 7 by use of N-methylaniline, instead of benzylamine.
The title compound 80 mg (96%) was obtained in a manner similar to the Example 7 by use of 4-aminopyridine, instead of benzylamine.
The title compound 48 mg (57%) was obtained in a manner similar to the Example 7 by use of 3-aminopyridine, instead of benzylamine.
To a suspension of 170 mg (0.643 mmol) of the compound obtained in the Example 6 in 3 mL of 1,2-dichloroethane was added 94 μL (1.29 mmol) of thionyl chloride, and the mixture was stirred for 1.5 hours at 90° C. After cooling the reaction mixture to room temperature, and the solvent was removed under the reduced pressure to give the corresponding acid chloride intermediate compound.
Then, to a solution of 170 mg (0.643 mmol) of 4-nitroaniline in 4 mL of tetrahydrofuran was added 77 mg (60% oily; 1.93 mmol) of sodium borohydride, and the mixture was stirred for 10 minutes at room temperature. Next, a solution of the above acid chloride in 3 mL of tetrahydrofuran was added to this mixture, and the mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting solid was washed with methanol to give 150 mg (61%) of the title compound.
The title compound 142 mg (quantitative) was obtained in a manner similar to the Manufacturing Example 2 by use of the compound obtained in the Example 98, instead of the compound obtained in the Manufacturing Example 1.
The title compound 10 mg (24%) was obtained in a manner similar to the Example 19 by use of the compound obtained in the Example 99, instead of the compound obtained in the Example 18.
The title compound 92 mg (88%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 14, instead of benzylamine.
The title compound 98 mg (43%) was obtained in a manner similar to the Example 7 by use of methyl 5-amino-2-pyridinecarboxylate, instead of benzylamine.
The title compound 160 mg (87%) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 102, instead of the compound obtained in the Example 40.
The title compound 44 mg (77%) was obtained in a manner similar to the Manufacturing Example 5 by use of the compound obtained in the Example 103 and methylamine (30%-methanol solution), instead of 6-aminonicotic acid and isopropylamine, respectively.
The title compound 50 mg (85%) was obtained in a manner similar to the Manufacturing Example 5 by use of the compound obtained in the Example 103 and dimethylamine HCl salt, instead of 6-aminonicotic acid and isopropylamine, respectively.
The title compound 76 mg (77%) was obtained in a manner similar to the Example 7 by use of 4-(4-methyl-1-piperazinyl)aniline, instead of benzylamine.
To a suspension of 563 mg (1.287 mmol) of the compound obtained in the Example 106 in 5.6 mL of methanol was added 85.6 μL (1.319 mmol) of methanesulfonic acid at 50° C., and the mixture was refluxed. Then, the reaction mixture was gradually cooled to 0° C. and the resulting precipitates were collected to give 452 mg (66%) of the title compound.
The title compound 300 mg (quantitative) was obtained in a manner similar to the Example 7 by use of 4-cyanoaniline, instead of benzylamine.
1-Cyclohexyl-3-methyl-N-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide 235 mg (79%) was obtained in a manner similar to the Example 7 by use of 4-cyanoaniline, instead of benzylamine. Next, to a solution of 132 mg (0.301 mmol) of the above free base compound in 2 mL of methanol was added 166 μL of 4N—HCl/dioxane, and the mixture was diluted with diethyl ether. The resulting precipitates were collected to give 140 mg (91%) of the title compound.
1-Cyclohexyl-3-methyl-N-{3-[(4-methyl-1-piperazinyl)sulfonyl]-phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide 133 mg (87%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 17, instead of benzylamine. Next, to a solution of 133 mg (0.265 mmol) of the above free base compound in 3 mL of methanol was added 80 μL of 4N—HCl/dioxane, and the mixture was diluted with diethyl ether. The resulting precipitates were collected to give 138 mg (97%) of the title compound.
The title compound 45 mg (34%) was obtained in a manner similar to the Example 7 by use of 3-amino-N-methylbenzenesulfonamide, instead of benzylamine.
The title compound 89 mg (78%) was obtained in a manner similar to the Example 106 by use of the compound obtained in the Example 93, instead of the compound obtained in the Example 6.
The title compound 106 mg (80%) was obtained in a manner similar to the Example 7 by use of 3-(4-methyl-1-piperazinyl)aniline, instead of benzylamine.
To a suspension of 4.1 g (15.51 mmol) of the compound obtained in the Example 6 in 50 mL of 1,2-dichloroethane was added 2.26 mL (31.02 mmol) of thionyl chloride, and the mixture was refluxed for 1.5 hours. After cooling of the reaction and the solvent was removed under reduced pressure to give the corresponding acid chloride intermediate compound.
Then, 3.04 g (15.82 mmol) of the compound obtained in the Manufacturing Example 95 and 4.32 mL (31.02 mmol) of triethylamine were added to a solution of the above acid chloride intermediate compound in 150 mL of anhydrous dichloromethane under ice cooling, and the mixture was stirred for 20 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1 to 30/1) to give 7.5 g (83%) of the title compound.
The title compound 160 mg (59%) was obtained in a manner similar to the Example 10 by use of the compound obtained in the Example 93, instead of the compound obtained in the Example 6.
The title compound 342 mg (88%) was obtained in a manner similar to the Example 98 by use of 4-amino-3,5-dichloropyridine, instead of 4-nitoraniline.
To a solution of 1.2 g (5.29 mmol) of the compound obtained in the Example 3 in 21 mL of ethanol were added 2.07 g (6.35 mmol) of S-(4-bromobenzyl) isothiourea hydrobromic acid salt and 10.6 mL of 2N-sodium hydroxide solution, and the mixture was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, the mixture was condensed and the residue was diluted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=7/1) to give 1.723 g (82%) of the title compound.
To a solution of 1.623 g (4.13 mmol) of the compound obtained in the Example 117 in 30 mL of tetrahydrofuran was added gradually a solution of 10.3 mL (10.3 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran at −78° C., and the mixture was stirred for 30 minutes at the same temperature. Then, the reaction mixture was warmed slowly to 0° C. during 1 hour, and water was added to the reaction mixture. The mixture was extracted with dichloromethane and the organic layer was dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and 15 mL of ethanol and 10 mL of 4N—HCl/dioxane were added to the residue and the mixture was stirred for 30 minutes at room temperature and for 30 minutes at 60° C. Then, the reaction mixture was cooled to room temperature and condensed under reduced pressure. The residue was diluted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate aqueous solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=8/1) to give 717 mg (46%) of the title compound.
To a solution of 175 mg (0.466 mmol) of the compound obtained in the Example 118 in 30 mL of toluene were added 115 μL (1.40 mmol) of N-methylpiperazine, 89.6 mg (0.933 mmol) of sodium tert-butoxide, 5.2 mg (0.023 mmol) of palladium acetate (II) and 9.4 mg (0.0466 mmol) of tri-tert-butyl-phosphine, and the mixture was refluxed for 5 hours. After the mixture was cooled to room temperature, ethyl acetate was added to the mixture and the organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 158 mg (86%) of the title compound.
The title compound 143 mg (94%) was obtained in a manner similar to the Example 107 by use of the compound obtained in the Example 119, instead of the compound obtained in the Example 106.
The title compound 124 mg (65%) was obtained in a manner similar to the Example 119 by use of N-methylhomopiperazine, instead of N-methylpiperazine.
The title compound 82 mg (78%) was obtained in a manner similar to the Example 7 by use of 2-aminoethanol, instead of benzylamine.
The title compound 103 mg (94%) was obtained in a manner similar to the Example 7 by use of 3-amino-1-propanol, instead of benzylamine.
The title compound 99 mg (68%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 19, instead of benzylamine.
To a solution of 91 mg (0.211 mmol) of the compound obtained in the Example 124 in 2 mL of diethyl ether and 1 mL of ethyl acetate was added 63 μL (0.25 mmol) of 4N—HCl/1,4-dioxane, and 3 mL of diethyl ether was further added to the mixture. The resulting precipitates were collected to give 86 mg (87%) of the title compound.
The title compound 365 mg (92%) was obtained in a manner similar to the Example 7 by use of ethyl cis-4-aminocyclohexanecarboxylate, instead of benzylamine.
cis-4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}cyclohenxanecarboxylic acid
The title compound 123 mg (88%) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 126, instead of the compound obtained in the Example 40.
To a solution of 185 mg (0.433 mmol) of the compound obtained in the Example 126 in 6 mL of tetrahydrofuran were added 56 mg (1.33 mmol) of lithium chloride and 50 mg (1.33 mmol) of sodium borohydride, and the mixture was stirred for 14 hours at room temperature. Then, ethyl acetate was added to the mixture and the organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/3) to give 110 mg (66%) of the title compound.
The title compound 605 mg (96%) was obtained in a manner similar to the Example 7 by use of ethyl trans-4-aminocyclohexanecarboxylate hydrochloric acid salt, instead of benzylamine.
The title compound 150 mg (80%) was obtained in a manner similar to the Example 128 by use of the compound obtained in the Example 129, instead of the compound obtained in the Example 126.
The title compound 90 mg (quantitative) was obtained in a manner similar to the Example 7 by use of tert-butyl trans-4-aminocyclohexyl-carbamate, instead of benzylamine.
To a solution of 890 mg (1.93 mmol) of the compound obtained in the Example 131 in 5 mL of N,N-dimethylformamide was added 9.66 mL of 4N—HCl/dioxane, and the mixture was stirred for 3 hours at room temperature. Then, the mixture was diluted with dichloromethane and 50 mL of 1N-sodium hydroxide solution was added to the mixture. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by alkaline silica gel column chromatography (eluent:chloroform/methanol=60/1) to give 495 mg (71%) of the title compound.
To a solution of 120 mg (0.333 mmol) of the compound obtained in the Example 132 in 8 mL of N,N-dimethylformamide were added 46.8 μL (0.333 mmol) of bis(2-chloroethyl)ether, 116 μL (0.832 mmol) of triethylamine, 50 mg (0.333 mmol) of sodium iodide, and 6.5 μL (0.333 mmol) of 15-crown-5, and the mixture was stirred for 24 hours at 100° C. After the reaction mixture was cooled to room temperature, the mixture was extracted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:chloroform/methanol=20/1) to give 22 mg (15%) of the title compound.
Saturated sodium bicarbonate solution and ethyl acetate were added to the compound obtained in the Example 63, and the organic layer was dried over with anhydrous sodium sulfate. The solvent was removed and the residue was purified by alkaline silica gel column chromatography (eluent:chloroform/methanol=60/1) to give 411 mg (60%) of the title compound.
To a solution of 150 mg (0.433 mmol) of the compound obtained in the Example 134 in 8 mL of dichloromethane were added 44 μL (0.476 mmol) of tetrahydro-4-pyranone and 128 mg (0.606 mmol) of sodium triacetoxyborohydride, and the mixture was stirred for 24 hours at room temperature. Then, saturated sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1) to give 70 mg (38%) of the title compound.
The title compound 180 mg (92%) was obtained in a manner similar to the Example 135 by use of 1,4-cyclohexanedione monoethyleneketal, instead of tetrahydro-4-pyranone.
To a solution of 153 mg (0.314 mmol) of the compound obtained in the Example 136 in 3 mL of acetone and 1 mL of water was added 71.8 mg (0.377 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 2 days. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate and removed under reduced pressure to give 120 mg (86%) of the title compound.
To a solution of 109 mg (0.246 mmol) of the compound obtained in the Example 137 in 8 mL of ethanol was added 14.0 mg (0.369 mmol) of sodium borohydride, and the mixture was stirred for 1 hour at 0° C. Then, dichloromethane was added to the reaction mixture and the organic layer was washed with water, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1) to give 67 mg (61%) of the title compound.
The title compound 649 mg (quantitative) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 21, instead of benzylamine.
To a solution of 584 mg (1.12 mmol) of the compound obtained in the Example 139 in 3 mL of dichloromethane was added 0.86 mL (11.2 mmol) of trifluoroacetic acid at room temperature, and the mixture was stirred for 1.5 hours at the same temperature. Then, the mixture was extracted with dichloromethane and the organic layer was washed with 2N sodium hydroxide solution and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=100/1) to give 437 mg (92%) of the title compound.
The title compound 94 mg (86%) was obtained in a manner similar to the Example 125 by use of the compound obtained in the Example 140, instead of the compound obtained in the Example 124.
To a solution of 174 mg (0.4412 mmol) of the compound obtained in the Example 140 in 5 mL of chloroform were added 31 μL (0.494 mmol) of methyl iodide and 86 μL (0.618 mmol) of triethylamine, and the mixture was stirred for 2 hours at room temperature. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate and removed under reduced pressure. The residue was purified by alkaline silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 46 mg (26%) of the title compound.
The title compound 90 mg (42%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 24, instead of benzylamine.
The title compound 161 mg (76%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 31, instead of benzylamine.
The title compound 401 mg (80%) was obtained in a manner similar to the Example 7 by use of ethyl 4-amino-2-methoxybenzoate, instead of benzylamine.
The title compound 242 mg (59%) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 145, instead of the compound obtained in the Example 40.
To a solution of 200 mg (0.48 mmol) of the compound obtained in the Example 146 in 3 mL of anhydrous dichloromethane were added 64 μL (0.58 mmol) of N-methylpiperazine and 111 mg (0.58 mmol) of 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide HCl salt, and the mixture was stirred for 3 hours at room temperature. Then, saturated sodium bicarbonate aqueous solution was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1 to 10/1). The obtained crude crystalline was dissolved in 4M-HCl/dioxane and the solvent was removed under reduced pressure. The obtained solid was collected to give 124 mg (49%) of the title compound.
The title compound 76 mg (79%) was obtained in a manner similar to the Example 147 by use of morpholine, instead of N-methylpiperazine.
The title compound 68 mg (69%) was obtained in a manner similar to the Example 147 by use of 4-hydroxypiperidine, instead of N-methylpiperazine.
The title compound 53 mg (58%) was obtained in a manner similar to the Example 147 by use of 2-aminoethanol, instead of N-methylpiperazine.
The title compound 73 mg (78%) was obtained in a manner similar to the Example 147 by use of 2-methoxyethylamine, instead of N-methylpiperazine.
The title compound 31 mg (36%) was obtained in a manner similar to the Example 147 by use of methylamine HCl salt, instead of N-methylpiperazine.
The title compound 70 mg (80%) was obtained in a manner similar to the Example 147 by use of dimethylamine HCl salt, instead of N-methyl-piperazine.
The title compound 136 mg (79%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 26, instead of benzylamine.
A suspension of 100 mg (0.22 mmol) of the compound obtained in the Example 154 in 2 mL of methanol was heated at 50° C., and to this suspension was added 14 mL (0.22 mmol) of methanesulfonic acid, then, the mixture was refluxed for 10 minutes. The reaction mixture was cooled gradually and the appeared precipitates were collected to give 68 mg (56%) of the title compound.
The title compound 169 mg (95%) was obtained in a manner similar to the Example 7 by use of 3-chloro-4-(4-methyl-1-piperazinyl)aniline, instead of benzylamine.
The title compound 546 mg (96%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 28, instead of benzylamine.
To a solution of 500 mg (1.00 mmol) of the compound obtained in the Example 157 in a mixture solution of 20 mL of toluene and 2 mL of water was added 229 mg (1.20 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed for 8 hours. Then, the reaction mixture was cooled to room temperature and condensed under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 460 mg (quantitative) of the title compound.
To a suspension of 150 mg (0.33 mmol) of the compound obtained in the Example 158 in anhydrous methanol was added 15 mg (0.39 mmol) of sodium borohydride under ice cooling, and the mixture was stirred for 3 hours at the same temperature and for 2 hours at room temperature. Then, acetone was added to the reaction mixture and the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and the organic layer was washed with water and saturated saline solution. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/2 t 0/1) to give 114 mg (76%) of the title compound.
To a suspension of 900 mg (3.40 mmol) of the compound obtained in 15 mL of 1,2-dichloroethane was added 497 μL (6.81 mmol) of thionyl chloride, and the mixture was refluxed for 1.5 hours. After cooling the reaction mixture, the solvent removed under reduced pressure to give acid chloride intermediate compound.
Then, 752 mg (3.57 mmol) of the compound obtained in the Manufacturing Example 62 and 949 μL (6.81 mmol) of triethylamine were added to a solution of acid chloride intermediate compound obtained above in 40 mL of anhydrous dichloromethane, and the mixture was stirred for 6 hours at room temperature. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was recrystallized from ethanol to give 0.86 g (55%) of the title compound.
The title compound 565 mg (96%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 30, instead of benzylamine.
The title compound 282 mg (61%) was obtained in a manner similar to the Example 158 by use of the compound obtained in the Example 160, instead of the compound obtained in the Example 157.
The title compound 90 mg (90%) was obtained in a manner similar to the Example 159-1 by use of the compound obtained in the Example 161, instead of the compound obtained in the Example 158.
To a suspension of 150 mg (0.33 mmol) of the compound obtained in the Example 158 in 3 mL of 1,2-dichloroethane were added 68 μL (0.66 mmol) of trimethylamine (30%-ethanol solution), 20 μL of acetic acid and 105 mg (0.50 mmol) of sodium triacetoxyborohydride, and the mixture was stirred for 18 hours at room temperature. Then, saturated sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by alkaline silica gel column chromatography (eluent:dichloromethane/methanol=20/1) to give 148 mg (97%) of the title compound.
To a suspension of 200 mg (0.43 mmol) of the compound obtained in the Example 161 in 3 mL of 1,2-dichloroethane were added 88 μL (0.85 mmol) of trimethylamine (30%-ethanol solution), 15 μL of acetic acid and 135 mg (0.64 mmol) of sodium triacetoxyborohydride, and the mixture was stirred for 4 hours at room temperature. Then, saturated sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, the dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in 4 mL of dichloromethane. To this mixture were added 186 mg (0.85 mmol) of tert-butyldicarbonate and 0.14 mL (1.02 mmol) of triethylamine, and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1) to give 236 mg (95%) of the title compound.
To a solution of 211 mg (0.36 mmol) of the compound obtained in the Example 164 in 3 mL of dichloromethane was added 1.5 mL of trifluoroacetic acid, and the mixture was stirred for 1.5 hours at room temperature. After removal of the solvent under reduced pressure, water was added to the residue and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by alkaline silica gel column chromatography (eluent=dichloromethane/methanol=40/1) to give 116 mg (66%) of the title compound.
To a solution of 150 mg (0.42 mmol) of the compound obtained in the Example 75 in 3 mL of dichloromethane were added 93 μL (0.84 mmol) of N-methylpiperazine, 15 μL of acetic acid and 133 mg (0.63 mmol) of sodium triacetoxyborohydride, and the mixture was stirred for 3 hours at room temperature. Then, saturated sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by alkaline silica gel column chromatography (eluent:ethyl acetate) to give 103 mg (56%) of the title compound.
The title compound 101 mg (53%) was obtained in a manner similar to the Example 166 by use of N-methylhomopiperazine, instead of N-methylpiperazine.
The title compound 30 mg (20%) was obtained in a manner similar to the Example 166 by use of 4-methoxypiperidine p-toluenesulfonic acid salt, instead of N-methylpiperazine.
The title compound 252 mg (78%) was obtained in a manner similar to the Example 166 by use of benzyl 1-homopiperazinecarboxylate, instead of N-methylpiperazine.
A mixture solution of 219 mg (0.38 mmol) of the compound obtained in the Example 169 in 3 mL of 30%-HBr/acetic acid was stirred for 3 hours at room temperature. Then, the reaction mixture was neutralized by 4M-sodium hydroxide aqueous solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by alkaline silica gel column chromatography (eluent:dichloromethane/methanol=30/1) to give 126 mg (75%) of the title compound.
The title compound 96 mg (99%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 170 and acetic anhydride, instead of the compound obtained in the Manufacturing Example 2 and acetyl chloride, respectively.
The title compound 131 mg (73%) was obtained in a manner similar to the Example 166 by use of N-(2-methoxylethyl)methylamine, instead of N-methylpiperazine.
The title compound 34 mg (19%) was obtained as by-product in the Example 172.
The title compound 664 mg (98%) was obtained in a manner similar to the Example 166 by use of 1,4-dioxa-8-azaspiro[4.5]decane, instead of N-methylpiperazine.
A mixture of 384 mg (0.79 mmol) of the compound obtained in the Example 174 in 6 mL of 6M-HCl aqueous solution was stirred for 9 days at room temperature. Then, the reaction mixture was neutralized by saturated sodium bicarbonate aqueous solution and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 317 mg (91%) of the title compound.
The title compound 102 mg (quantitative) was obtained in a manner similar to the Example 159 by use of the compound obtained in the Example 175, instead of the compound obtained in the Example 158.
The title compound 126 mg (66%) was obtained in a manner similar to the Example 166 by use of cis-2,6-dimethylmorpholine, instead of N-methylpiperazine.
The title compound 50 mg (26%) was obtained as by-product in the Example 177.
The title compound 182 mg (89%) was obtained in a manner similar to the Example 166 by use of the compound obtained in the Example 175 and methylamine (30% ethanol solution), instead of the compound obtained in the Example 75 and N-methylpiperazine, respectively.
The title compound 35 mg (72%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 179 and acetic anhydride, instead of the compound obtained in the Manufacturing Example 2 and acetyl chloride, respectively.
To a mixture solution of 70 mg (0.15 mmol) of the compound obtained in the Example 179 in 2 mL of ethanol and 2 mL of water were added 30 mg of paraformaldehyde and 1 mL of formic acid, and the mixture was refluxed for 6 hours. Further 30 mg of paraformaldehyde and 1 mL of formic acid were added to the reaction mixture, and the mixture was refluxed for 18 hours. Then, the reaction mixture was cooled to room temperature and neutralized with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from ethyl acetate to give 32 mg (44%) of the title compound.
The title compound 176 mg (58%) was obtained in a manner similar to the Example 166 by use of tert-butyl 4-piperidinecarbamate, instead of N-methylpiperazine.
The title compound 94 mg (31%) was obtained as by-product in the Example 182.
The title compound 82 mg (60%) was obtained in a manner similar to the Example 165 by use of the compound obtained in the Example 182, instead of the compound obtained in the Example 164.
The title compound 63 mg (95%) was obtained in a manner similar to the Example 165 by use of the compound obtained in the Example 183, instead of the compound obtained in the Example 164.
The title compound 218 mg (74%) was obtained in a manner similar to the Example 166 by use of tert-butyl 1-piperazinecarboxylate, instead of N-methylpiperazine.
The title compound 72 mg (14%) was obtained as by-product in the Example 186.
The title compound 146 mg (86%) was obtained in a manner similar to the Example 165 by use of the compound obtained in the Example 186, instead of the compound obtained in the Example 164.
The title compound 51 mg (97%) was obtained in a manner similar to the Example 165 by use of the compound obtained in the Example 187, instead of the compound obtained in the Example 164.
The title compound 81 mg (95%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 188, instead of the compound obtained in the Manufacturing Example 2.
To a solution of 143 mg (0.305 mmol) of the compound obtained in the Example 144 in 2 mL of ethanol was added 38.9 mg (0.335 mmol) of fumaric acid, and the resulting precipitates were collected to give 139 mg (86%) of the title compound.
The title compound 6.93 g (58%) was obtained in a manner similar to the Example 1 by use of 4-tetrahydropyranylhydrazine, instead of cyclohexylhydrazine HCl salt.
A mixture solution of 6.87 g (3.77 mmol) of the compound obtained in the Example 192 and 14.1 mL (150.8 mmol) of phosphorous oxychloride was stirred for 1 hour at 110° C. After the reaction mixture was cooled to room temperature, this mixture was added gradually to ice-cooled 40 mL of N,N-dimethylformamide, and the mixture was stirred for 1 hour at room temperature and for 3 hours at 90° C. Then, the reaction mixture was cooled with ice and diluted with ethyl acetate, and pH of the reaction mixture was adjusted to 4 by adding 2N-NaOH aqueous solution. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated saline solution and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=2/1) to give 4.64 g (54%) of the title compound.
To a solution of 16.54 mL (0.151 mol) of ethyl thioglycolate in 300 mL of tetrahydrofuran was added 6.03 g (0.151 mol) of sodium hydride (60% oily) in small portions, and the mixture was stirred for 3 minutes. Then, 31.36 g (0.137 mol) of the compound obtained in the Example 193 was added to this mixture at once, and the mixture was stirred for 1 hour. Further, 6.03 g (0.151 mol) of sodium hydride (60% oily) was added to this mixture in small portions at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=3/1 to 2/1) to give 30.1 g (76%) of the title compound.
The title compound 4.26 g (99%) was obtained in a manner similar to the Example 6 by use of the compound obtained in the Example 194, instead of the compound obtained in the Example 5.
The title compound 166 mg (84%) was obtained in a manner similar to the Example 7 by use of 4-(4-methyl-1-piperazinyl)aniline and the compound obtained in Example 194, instead of benzylamine and the compound obtained in the Example 6, respectively.
The title compound 214 mg (83%) was obtained in a manner similar to the Example 7 by use of [3-fluoro-4-(4-methyl-1-piperazinyl)]aniline and the compound obtained in Example 195, instead of benzylamine and the compound obtained in the Example 6, respectively.
The title compound 173 mg (87%) was obtained in a manner similar to the Example 7 by use of 4-(4-morpholinylmethyl)aniline, instead of benzylamine.
41.7 mg (0.59 mmol) of fumaric acid was added to a mixture of 150 mg (0.432 mmol) of the compound obtained in the Example 198 in 1 mL of ethanol, and 2 mL of diethyl ether was further added to the mixture. Then, the mixture was stirred for over night and appeared precipitates were collected by filtration to give 112 mg (59%) of the title compound.
The title compound 83 mg (75%) was obtained in a manner similar to the Example 7 by use of 4-[(2-dimethylamino)ethyl]aniline, instead of benzylamine.
The title compound 140 mg (68%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Example 32, instead of benzylamine.
The title compound 185 mg (88%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Example 34, instead of benzylamine.
The title compound 116 mg (57%) was obtained in a manner similar to the Example 7 by use of 4-(3-methyl-2,5-dioxo-1-imidazolidinyl) aniline, instead of benzylamine.
The title compound 2.18 g (95%) was obtained in a manner similar to the Example 7 by use of methyl trans-4-aminocyclohexanecarboxylate, instead of benzylamine.
The title compound 1.48 g (quantitative) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 204, instead of the compound obtained in the Example 40.
To a solution of 200 mg (0.496 mmol) of the compound obtained in the Example 204 in 5 mL of tetrahydrofuran was added 43 mg (1.98 mmol) of lithium borohydride, and the mixture was stirred for 1.5 hours under heating at 70° C. The reaction mixture was cooled to room temperature and water was added to the mixture and mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was recrystallized from isopropanol/hexane (1/1) to give 76 mg (41%) of the title compound.
To a solution of 200 mg (0.513 mmol) of the compound obtained in the Example 205 in 5 mL of dichloromethane and 1 mL of N,N-dimethylformamide were added 51.3 μL (0.462 mmol) of N-methylpiperazine and 750 mg of PS carbodiimide (Argonaut Co.), and the mixture was stirred for over night at room temperature. The reagent removed off by filtration and the filtrate was condensed to give 36 mg (15%) of the title compound.
The title compound 18 mg (8%) was obtained in a manner similar to the Example 207 by use of 2M-dimethylamine in tetrahydrofuran, instead of N-methylpiperazine.
The title compound 189 mg (84%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Example 36, instead of benzylamine.
The title compound 1.89 g (99%) was obtained in a manner similar to the Example 7 by use of [2-(N-Boc-N-methyl)amino]ethylamine, instead of benzylamine.
The title compound 1.71 g (quantitative) was obtained in a manner similar to the Manufacturing Example 4 by use of the compound obtained in the Example 210, instead of the compound obtained in the Manufacturing Example 3.
To a solution of 150 mg (0.381 mmol) of the compound obtained in the Example 211 in 5 mL of dichloromethane were added 54 μL (0.572 mmol) of acetic anhydride and 123 μL (1.53 mmol) of pyridine, and the mixture was stirred for 1 hour at room temperature. Then, 54 μL (0.572 mmol) of acetic anhydride and 123 μL (1.53 mmol) of pyridine were further added to the reaction mixture, and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture and the mixture was extracted with dichloromethane, and the organic layer was dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=30/1) to give 120 mg (87%) of the title compound.
To a solution of 150 mg (0.381 mmol) of the compound obtained in the Example 211 in 5 mL of dichloromethane were added 44 μL (0.572 mmol) of methanesulfonyl chloride and 212 μL (1.53 mmol) of triethylamine, and the mixture was stirred for 1 hour at room temperature. After the reaction, water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1), and the eluate was treated with 4N—HCl/dioxane to give 128 mg (77%) of the title compound.
To a solution of 250 mg (0.722 mol) of the compound obtained in the Example 134 in 6 mL of dichloromethane were added 88 μL (0.794 mmol) of ethyl bromoacetate and 151 μL (1.082 mmol) of triethylamine, and the mixture was stirred for 3 days at room temperature. Then, water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 237 mg (76%) of the title compound.
The title compound 176 mg (86%) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 214, instead of the compound obtained in the Example 40.
To a solution of 252 mg (0.727 mmol) of the compound obtained in the Example 134 in 5 mL of N,N-dimethylformamide were added 128 μL (0.873 mmol) of ethyl 2-bromoisobutyrate and 152 μL (1.09 mmol) of triethylamine, and the mixture was stirred for over night at 70° C. Then, water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 115 mg (34%) of the title compound.
The title compound 65 mg (69%) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 216, instead of the compound obtained in the Example 40.
The title compound 198 mg (90%) was obtained in a manner similar to the Example 7 by use of 1-(4-aminophenyl)-4-piperidinol and the compound obtained in the Example 195, instead of benzylamine and the compound obtained in the Example 6, respectively.
To a solution of 150 mg (0.488 mol) of the compound obtained in the Example 122 in 5 mL of tetrahydrofuran were added 75.6 mg (0.586 mmol) of 5,5-dimethyloxazolidine-dione, 154 mg (0.586 mmol) of triphenylphsophine and 267 μL (0.586 mmol) of diethyl azodicarboxylate (40% toluene solution), and the mixture was stirred for 2 hours at room temperature. After the reaction, water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydroussodiumsulfateandthesolventwasremovedunderreducedpressure. The resulting residue was purified by silica gel column chromatography (eluent:dichloromethane/acetone=2/1 for first trial, and hexane/ethyl acetate=2/1 for second trial) to give 133 mg (65%) of the title compound.
The title compound 164 mg (99%) was obtained in a manner similar to the Example 214 by use of the compound obtained in the Example 211 and 4-morpholinylcarbonyl chloride, instead of the compound obtained in the Example 134 and ethyl bromoacetate, respectively.
The title compound 119 mg (80%) was obtained in a manner similar to the Example 214 by use of the compound obtained in the Example 211 and dimethylaminocarbonyl chloride, instead of the compound obtained in the Example 134 and ethyl bromoacetate, respectively.
To a solution of 150 mg (0.381 mmol) of the compound obtained in the Example 211 in 5 mL of dichloromethane and 5 mL of water were added 158 mg (1.14 mmol) of potassium carbonate and 44 μL (0.572 mmol) of ethyl chlorocarbonate, and the mixture was stirred for over night at room temperature. Then, water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 120 mg (83%) of the title compound.
The title compound 124 mg (83%) was obtained in a manner similar to the Example 214 by use of the compound obtained in the Example 211 and methoxyacetyl chloride, instead of the compound obtained in the Example 134 and ethyl bromoacetate, respectively.
To a solution of 150 mg (0.381 mmol) of the compound obtained in the Example 211 in 6 mL of dichloromethane were added 34.8 mg (0.458 mmol) of hydroxyacetic acid, 186 μL (1.335 mmol) of triethylamine, 61.8 mg (0.458 mmol) of N-hydroxybenzotriazole and 80.4 mg (0.419 mmol) of 1-ethyl-3-(3′-di-methylaminopropyl)carbodiimide, and the mixture was stirred for 3 hours at room temperature. Then, water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 87 mg (60%) of the title compound.
The title compound 128 mg (74%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 205 and 2-N-methylaminoethanol, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 565 mg (97%) was obtained in a manner similar to the Example 7 by use of methyl (1S,3S)-3-aminocyclopentanecarboxylate, instead of benzylamine.
The title compound 542 mg (quantitative) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 226, instead of the compound obtained in the Example 40.
The title compound 88 mg (35%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Example 37, instead of benzylamine.
The title compound 176 mg (91%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 227 and 2M-dimethylamine tetrahydrofuran solution, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 137 mg (84%) was obtained in a manner similar to the Example 125 by using the compound obtained in the Example 229, instead of the compound obtained in the Example 124.
The title compound 772 mg (99%) was obtained in a manner similar to the Example 7 by use of methyl (1R,3R)-3-aminocyclopentanecarboxylate, instead of benzylamine.
The title compound 822 mg (quantitative) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 231, instead of the compound obtained in the Example 40.
The title compound 153 mg (79%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 232 and 2M-dimethylamine tetrahydrofuran solution, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 80 mg (54%) was obtained in a manner similar to the Example 125 by use of the compound obtained in the Example 233, instead of the compound obtained in the Example 124.
The title compound 241 mg (95%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 39, instead of benzylamine.
The title compound 236 mg (96%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 205 and morpholine, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 122 mg (79%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 205 and methylamine (30% ethanol solution), instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 115 mg (64%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 205 and cyclopropylamine, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 157 mg (86%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 205 and 4-hydroxypiperidine, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 257 mg (99%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 41, instead of benzylamine.
The title compound 2.57 g (98%) was obtained in a manner similar to the Example 7 by use of 4-amino-1-Boc-piperidine, instead of benzylamine.
The title compound 2.29 g (97%) was obtained in a manner similar to the Manufacturing Example 4 by using the compound obtained in the Example 241, instead of the compound obtained in the Manufacturing Example 3.
The title compound 2.32 g (97%) was obtained in a manner similar to the Example 7 by use of (3S)-1-benzyl-3-aminopyrrolidine, instead of benzylamine.
To a solution of 2.26 g (5.35 mmol) of the compound obtained in the Example 243 in 50 mL of 1,2-dichloroethane was added 721 μL (6.68 mmol) of 1-chloroethyl chloroformate, and the mixture was refluxed for 2 hours. Then, 289 μL (2.67 mmol) of 1-chloroethyl chloroformate was further added to this mixture and the mixture was refluxed for 1 hour under stirring. The solvent was removed under reduced pressure and 50 mL of methanol was added to the residue, and the mixture was refluxed for 30 minutes. The solvent was removed under reduced pressure and the residue was treated with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane. The organic layer was dried over with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1) to give 0.83 g (47%) of the title compound.
The title compound 155 mg (85%) was obtained in a manner similar to the Example 214 by use of the compound obtained in the Example 244 and dimethylaminocarbonyl chloride, instead of the compound obtained in the Example 134 and ethyl bromoacetate, respectively.
The title compound 155 mg (85%) was obtained in a manner similar to the Example 125 by use of the compound obtained in the Example 245, instead of the compound obtained in the Example 124.
To a solution of 136 mg (0.362 mmol) of the compound obtained in the Example 206 in 10 mL of tetrahydrofuran were added 72 mg (0.724 mmol) of hydantoin, 135 μL (0.543 mmol) of tri-n-butylphosphine and 1,1′-azobis (N,N-dimethylformamide), and the mixture was stirred for 3 hours at 60° C. The reaction mixture was cooled to room temperature, treated with water, and extracted with ethyl acetate. The organic layer was dried over with anhydrous sodium sulfate and removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent:ethyl acetate) to give 96 mg (58%) of the title compound.
The title compound 2.73 g (98%) was obtained in a manner similar to the Example 7 by using ethyl isonipecotic acid, instead of benzylamine.
The title compound 1.1 g (99%) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 248, instead of the compound obtained in the Example 40.
The title compound 195 mg (94%) was obtained in a manner similar to the Example 224 by use of methylamine (30% ethanol solution) and the compound obtained in the Example 249, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 2.29 g (quantitative) was obtained in a manner similar to the Example 7 by use of ethyl (R)-nipecotic acid, instead of benzylamine.
The title compound 595 mg (74%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 45, instead of benzylamine.
To a solution of 150 mg (0.374 mmol) of the compound obtained in the Example 252 in 10 mL of tetrahydrofuran were added 30 μL (0.747 mmol) of methanol, 122 mg (0.476 mmol) of triphenylphosophine and 213 μL (0.467 mmol) of diethylazodicarboxylate (40% toluene solution), and the mixture was stirred for 1 hour at room temperature. Then, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/acetone=2/1 for first trial; dichloromethane/ethyl acetate=1/1 for second trial), and obtained product was converted to the HCl salt by treating with 100 μL of 4N—HCl/dioxane solution and recrystallized from methanol-ethanol (1/1) to give 23 mg (15%) of the title compound.
The title compound 595 mg (74%) was obtained in a manner similar to the Example 7 by use of (±)-3-hydroxymethylpiperidine, instead of benzylamine.
The title compound 123 mg (80%) was obtained in a manner similar to the Example 7 by use of 4-(dimethylaminocarbonyl)aniline, instead of benzylamine.
The title compound 199 mg (83%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 46, instead of benzylamine.
The title compound 462 mg (quantitative) was obtained in a manner similar to the Example 206 by use of the compound obtained in the Example 226, instead of the compound obtained in the Example 204.
The title compound 74 mg (40%) was obtained in a manner similar to the Example 247 by use of the compound obtained in the Example 257, instead of the compound obtained in the Example 206.
The title compound 54 mg (27%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 47, instead of benzylamine.
The title compound 104 mg (61%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 48 and the compound obtained in the Example 195, instead of benzylamine and the compound obtained in the Example 6, respectively.
The title compound 101 mg (63%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 46 and the compound obtained in the Example 195, instead of benzylamine and the compound obtained in the Example 6, respectively.
The title compound 308 mg (64%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 49, instead of benzylamine.
The title compound 397 mg (79%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 51, instead of benzylamine.
The title compound 80 mg (35%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 53, instead of benzylamine.
The title compound 243 mg (69%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 56, instead of benzylamine.
To a solution of 231 mg (0.374 mmol) of the compound obtained in the Example 265 in 5 mL of tetrahydrofuran was added 562 μL (0.562 mmol) of tetrabutylammoniumfluoride (1M-tetrahydrofuran solution), and the mixture was stirred for over night at room temperature. Then, the reaction mixture was treated with ethyl acetate, and the organic layer was washed with water, saturated saline solution and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/2) to give 176 mg (94%) of the title compound.
The title compound 139 mg (64%) was obtained in a manner similar to the Example 7 by use of 4-aminophenethylalcohol, instead of benzylamine.
The title compound 161 mg (96%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 62 and the compound obtained in the Example 195, instead of benzylamine and the compound obtained in the Example 6, respectively.
The title compound 229 mg (80%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 58, instead of benzylamine.
To a suspension of 150 mg (0.416 mmol) of the compound obtained in the Example 132 in 2.5 mL of tetrahydrofuran were added 52 μL (0.50 mmol) of 2-chloroethyl chloroformate and 87 μL (0.624 mmol) of triethylamine, and the mixture was stirred for 3 hours at room temperature. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give urethane intermediate compound.
Next, to a mixture solution of the urethane intermediate compound obtained above in 2 mL of ethanol and 4 mL of tetrahydrofuran was added 2 mL of 4M-NaOH aqueous solution, and the mixture was stirred for 40 hours at room temperature. The solvent was removed under reduced pressure and the residue was treated with water, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:chloroform/methanol=10/1) to give 180 mg (quantitative) of the title compound.
To a suspension of 150 mg (0.416 mmol) of the compound obtained in the Example 132 in 4 mL of tetrahydrofuran was added 71 μL (0.832 mmol) of 2-chloroethylsocyanate, and the mixture was stirred for 3.5 hours at room temperature. 2 mL of 1M-NaOH aqueous solution was added to the reaction mixture, and the mixture was stirred. Then, further 5 mL of 4M-NaOH aqueous solution and 15 mL of tetrahydrofuran were added to the mixture, and the mixture was stirred for 2 hours. Next, 5 μL of 15-crown-5 was added to the reaction mixture and the mixture was further stirred for 43 hours at room temperature, then, 5 mL of ethanol was added to the reaction mixture and stirred for 6 hours at 80° C. The solvent was removed under reduced pressure and the residue was treated with water. The mixture was extracted with chloroform and the organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:chloroform/methanol=10/1) to give 106 mg (55%) of the title compound.
To a suspension of 150 mg (0.416 mmol) of the compound obtained in the Example 132 in 5 mL of xylene was added 62 mg (0.624 mmol) of succinic anhydride, and the mixture was refluxed for 5 hours. The solvent was removed under reduced pressure and the residue was treated with ether. The appeared precipitates were collected to give 178 mg (93%) of the title compound.
A mixture of 141 mg (0.306 mmol) of the compound obtained in the Example 272, 2 mL of acetic anhydride and 33 mg of sodium acetate was stirred for 3 hours at 60° C. and for 14 hours at 80° C., then, 2 mL of acetic anhydride was further added to the reaction mixture, and the mixture was stirred for 6 hours at 100° C. After the reaction, ice water was added to the reaction mixture and the mixture was neutralized by adding saturates sodium bicarbonate aqueous solution, and extracted with chloroform. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with ethanol to give 59 mg (49%) of the title compound.
To a solution of 150 mg (0.416 mmol) of the compound obtained in the Example 132 in 10 mL of dichloromethane were added 87 μL (0.624 mmol) of triethylamine and 61 μL (0.50 mmol) of 3-chloropropanesulfonyl chloride, and the mixture was stirred for 1.5 hours at room temperature. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give sulfonamide intermediate compound.
Next, to a mixture solution of the sulfonamide intermediate compound obtained above in 5 mL of ethanol was added 2 mL of 4M-NaOH aqueous solution, and the mixture was stirred for 1.5 hours at room temperature and for 3 hours at 80° C. The reaction mixture was cooled and treated with water, and then, extracted with chloroform. The organic layer was washed with water and saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from ethanol to give 112 mg (58%) of the title compound.
To a solution of 200 mg (0.555 mmol) of the compound obtained in the Example 132 in 4 mL of tetrahydrofuran were added 66 mg (0.22 mmol) of tri-phosgene and 232 μL (1.66 mmol) of triethylamine, and the mixture was stirred for 1 hour at room temperature. Then, 195 mg (0.55 mmol) of p-toluene sulfonic acid sarcosine benzyl ester and 77 μL (0.555 mmol) of triethylamine were added to the reaction mixture, and the mixture was stirred for 5 hours at room temperature. Water was added to the reaction mixture and the mixture was extracted with chloroform, and the organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:chloroform/methanol=15/1) to give 227 mg (72%) of the title compound.
To a solution of 207 mg (0.366 mmol) of the compound obtained in the Example 275 in 5 mL of ethanol was added 0.5 mL of 6M-HCl aqueous solution and the mixture was refluxed for 4 hours. After the reaction, the mixture was neutralized by adding saturated sodium bicarbonate aqueous solution, and extracted with chloroform. The organic layer was washed with water and saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:chloroform/methanol=15/1) to give 169 mg (quantitative) of the title compound.
To a solution of 150 mg (0.487 mmol) of the compound obtained in the Example 122 and 55.6 mg (0.487 mmol) of 1-methylhydantoin 4 mL of tetrahydrofuran were added 12 μL (0.487 mmol) of n-butylphosphine and 83.8 mg (0.487 mmol) of 1,1′-azobis(N,N-dimethylformamide), and the mixture was stirred for 5 hours at room temperature. The reaction mixture was treated with water and extracted with chloroform. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:ethyl acetate) to give 113 mg (58%) of the title compound.
The title compound 147 mg (75%) was obtained in a manner similar to the Example 277 by use of the compound obtained in the Example 123, instead of the compound obtained in the Example 122.
To a suspension of 200 mg (0.555 mmol) of the compound obtained in the Example 132 in 4 mL of tetrahydrofuran were added 66 mg (0.22 mmol) of triphosgene and 232 μL (1.66 mmol) of triethylamine and the mixture was stirred for 1 hour at room temperature. Then, 54 μL (0.66 mmol) of 2-(methylamino) ethanol was added to the reaction mixture and the mixture was stirred for 3 hours at room temperature. The reaction mixture was treated with water and extracted with chloroform, washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:chloroform/methanol=15/1) to give 190 mg (74%) of the title compound.
To a suspension of 187 mg (0.519 mmol) of the compound obtained in the Example 279 in 6 mL of tetrahydrofuran was added 140 mg (1.25 mmol) of potassium tert-butoxide and the mixture was cooled to 0° C. Then, a solution of 119 mg (0.623 mmol) of p-toluenesulfonyl chloride in 2 mL of tetrahydrofuran was added gradually to the reaction mixture and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was treated with water and extracted with chloroform. The organic layer was washed with water and saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:chloroform/methanol=20/1) to give 115 mg (64%) of the title compound.
The title compound 716 mg (98%) was obtained in a manner similar to the Example 7 by use of β-alanine ethyl ester HCl salt, instead of benzylamine.
The title compound 620 mg (99%) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 281, instead of the compound obtained in the Example 40.
The title compound 663 mg (88%) was obtained in a manner similar to the Example 7 by use of glycine tert-butyl ester HCl salt, instead of benzylamine.
A mixture solution of 637 mg (1.68 mmol) of the compound obtained in the Example 283 and 5 mL of 4M-HCl/dioxane was stirred for 5 hours at room temperature, and after the reaction, the solvent was removed under reduced pressure. The residue was treated with water and extracted with chloroform, and the organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 556 mg (quantitative) of the title compound.
A suspension solution of 85 mg (0.253 mmol) of the compound obtained in the Example 282, 246 mg (0.337 mmol) of PS-carbodiimide (Argonaut Co.), and 39 mg (0.287 mmol) of 1-hydroxybenzotriazole in 4 mL of dichloromethane was stirred for 10 minutes at room temperature. To the reaction mixture was added 20 μL (0.228 mmol) of morpholine, and the mixture was stirred for 20 hours at room temperature. Then, 267 mng (0.861 mmol) of MP-carbonate (Argonaut Co.) was added to the reaction mixture and the mixture was stirred for 3 hours at room temperature. The reaction mixture was filtrated and the filtrate was condensed under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give 80 mg (78%) of the title compound.
The title compound 2.23 g (97%) was obtained in a manner similar to the Example 7 by use of N-(2-aminomethyl) carbamic acid tert-butyl ester, instead of benzylamine.
To a solution of 2.18 g (5.36 mmol) of the compound obtained in the Example 286 in 20 mL of dichloromethane was added 5 mL of 4M-HCl/dioxane, and the mixture was stirred for 18 hours at room temperature. After reaction, the solvent was removed under reduced pressure and the residue was neutralized with saturated sodium bicarbonate aqueous solution, and extracted with chloroform. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with ethanol to give 670 mg (41%) of the title compound.
The title compound 52 mg (57%) was obtained in a manner similar to the Example 285 by use of 2.0M-dimethylamine/tetrahydrofuran, instead of morpholine.
The title compound 79 mg (70%) was obtained in a manner similar to the Example 285 by use of 1-methyl-4-(methylamino)piperidine, instead of morpholine.
The title compound 74 mg (70%) was obtained in a manner similar to the Example 285 by use of 4-hydroxypiperidine, instead of morpholine.
The title compound 62 mg (63%) was obtained in a manner similar to the Example 285 by use of the compound obtained in the Example 284, instead of the compound obtained in the Example 282.
The title compound 63 mg (71%) was obtained in a manner similar to the Example 285 by use of the compound obtained in the Example 284 and 2.0M-dimethylamine/tetrahydrofuran, instead of the compound obtained in the Example 282 and morpholine, respectively.
The title compound 68 mg (67%) was obtained in a manner similar to the Example 285 by use of the compound obtained in the Example 284 and N-methylpiperazine, instead of the compound obtained in the Example 282 and morpholine, respectively.
The title compound 75 mg (73%) was obtained in a manner similar to the Example 285 by use of the compound obtained in the Example 284 and 4-hydroxypiperidine, instead of the compound obtained in the Example 282 and morpholine, respectively.
The title compound 84 mg (80%) was obtained in a manner similar to the Example 285 by use of N-methylpiperazine, instead of morpholine.
The title compound 41 mg (41%) was obtained in a manner similar to the Example 191 by use of the compound obtained in the Example 295, instead of the compound obtained in the Example 144.
The title compound 81 mg (74%) was obtained in a manner similar to the Example 285 by use of the compound obtained in the Example 284 and 1-methyl-4-(methylamino) piperidine, instead of the compound obtained in the Example 282 and morpholine, respectively.
The title compound 74 mg (79%) was obtained in a manner similar to the Example 191 by use of the compound obtained in the Example 297, instead of the compound obtained in the Example 144.
To a suspension of 150 mg (0.490 mmol) of the compound obtained in the Example 287 in 3 mL of tetrahydrofuran were added 102 μL (0.735 mmol) of triethylamine and 61 μL (0.590 mmol) of 2-chloroethyl chloroformate, and the mixture was stirred for 2 hours at room temperature. Then, 210 mg (1.08 mmol) of 28%-sodium methoxide/methanol solution was added to the reaction mixture and the mixture was stirred for 2 hours at room temperature, and further 130 mg (0.674 mmol) of 28%-sodium methoxide/methanol solution was added to the reaction mixture and the resulting mixture was stirred for 15 hours at room temperature. Then, the reaction mixture was treated with water and extracted with chloroform. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from ethyl acetate to give 107 mf (58%) of the title compound.
The title compound 125 mg (62%) was obtained in a manner similar to the Example 274 by use of the compound obtained in the Example 287, instead of the compound obtained in the Example 132.
The title compound 160 mg (60%) was obtained in a manner similar to the Example 279 by use of the compound obtained in the Example 287, instead of the compound obtained in the Example 132.
The title compound 110 mg (80%) was obtained in a manner similar to the Example 280 by use of the compound obtained in the Example 301, instead of the compound obtained in the Example 279.
The title compound 763 mg (67%) was obtained in a manner similar to the Example 7 by use of ethyl 4-aminobutyrate HCl salt, instead of benzylamine.
The title compound 690 mg (quantitative) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 303, instead of the compound obtained in the Example 40.
The title compound 98 mg (67%) was obtained in a manner similar to the Example 7 by use of 3-(2-aminoethyl)-2,4-imidazolidinedione, instead of benzylamine.
The title compound 101 mg (85%) was obtained in a manner similar to the Example 285 by use of the compound obtained in the Example 304 and 2.0M-dimethylamine/tetrahydrofuran solution, instead of the compound obtained in the Example 282 and morpholine, respectively.
To a solution of 150 mg (0.487 mmol) of the compound obtained in the Example 122 in 5 mL of tetrahydrofuran were added 90 mg (0.634 mmol) of 1,5,5-trimethylhydantoin, 166 mg (0.634 mmol) of triphenylphosphine and 289 μL (0.634 mmol) of 40%-diethyl azodicarboxylate/toluene solution, and the mixture was stirred for 30 minutes at room temperature. After the reaction, the reaction mixture was treated with water and extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/2) to give 146 mg (69%) of the title compound.
The title compound 106 mg (53%) was obtained in a manner similar to the Example 307 by use of 2,4-thiazolidinedione, instead of 1,5,5-trimethylhydantoin.
The title compound 766 mg (93%) was obtained in a manner similar to the Example 7 by use of (1-aminocyclopropyl)methanol, instead of benzylamine.
The title compound 111 mg (58%) was obtained in a manner similar to the Example 307 by use of the compound obtained in the Example 309 and 1-methylhydantoin, instead of the compound obtained in the Example 122 and 1,5,5-trimethylhydantoin, respectively.
To a solution of 170 mg (0.555 mmol) of the compound obtained in the Example 287 in 5 mL of acetonitrile were added 52.5 μL (0.555 mmol) of methyl bromoacetate and 153 mg (1.11 mmol) of potassium carbonate, and the mixture was refluxed for 3 hours. The reaction mixture was cooled and filtrated. The filtrate was treated with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1 to 10/1) to give 93 mg (44%) of the title compound.
To a solution of 78.8 mg (0.208 mmol) of the compound obtained in the Example 311 in 1.5 mL of dioxane and 1.5 mL of water were added 25.3 mg (0.312 mmol) of potassium cyanate and 36 μL of acetic acid, and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was treated with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:ethyl acetate/methanol=20/1 to 10/1) to give 73 mg (84%) of the title compound.
To a solution of 68 mg (0.161 mmol) of the compound obtained in the Example 312 in 6 mL of methanol was added 13 mg (60% oily; 0.323 mmol) of sodiumhydride, and the mixture was stirred for 1.5 hour at room temperature. The solvent was removed and the residue was treated with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from ethanol to give 20 mg (32%) of the title compound.
The title compound 195 mg (96%) was obtained in a manner similar to the Example 307 by use of 5,5-dimethylhydantoin, instead of 1,5,5-trimethylhydantoin.
The title compound 227 mg (94%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 60, instead of benzylamine.
The title compound 84 mg (65%) was obtained in a manner similar to the Example 307 by use of the compound obtained in the Example 313 and ethanol, instead of 1,5,5-trimethylhydantoin and the compound obtained in the Example 122, respectively.
The title compound 82 mg (66%) was obtained in a manner similar to the Example 307 by use of the compound obtained in the Example 313 and methanol, instead of 1,5,5-trimethylhydantoin and the compound obtained in the Example 122, respectively.
The title compound 170 mg (56%) was obtained in a manner similar to the Example 7 by use of (S)-(+)-2-amino-1-propanol, instead of benzylamine.
The title compound 46 mg (24%) was obtained in a manner similar to the Example 307 by use of the compound obtained in the Example 318 and hydantoin, instead of the compound obtained in the Example 122 and 1,5,5-trimethylhydantoin, respectively.
The title compound 2.32 g (97%) was obtained in a manner similar to the Example 7 by use of (3R)-(−)-1-benzyl-3-aminopyrrolidine, instead of benzylamine.
To a solution of 2.28 g (5.40 mmol) of the compound obtained in the Example 320 in 15 mL of dichloromethane was added gradually 1.16 mL (10.8 mmol) of 1-chloroethyl formate at 0° C., and the mixture was stirred for 1 hour at the same temperature and for 2 hours at room temperature. The solvent was removed under reduced pressure and 25 mL of ethanol was added to the residue, then, the mixture was refluxed for 2.5 hours. After cooling, the solvent was removed under reduced pressure, and the residue was treated with 6M-HCl aqueous solution. Water layer was washed with ether, and neutralized by 4M-NaOH aqueous solution, and extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by alkaline silica gel column chromatography (eluent:dichloromethane/methanol=50/1 to 30/1) to give 1.06 g (59%) of the title compound.
To a solution of 150 mg (0.451 mmol) of the compound obtained in the Example 321 in 5 mL of dichloromethane were added 50 μL (0.541 mmol) of N,N-dimethylcarbamoyl chloride and 94 μL of (0.677 mmol) of triethylamine, and the mixture was stirred for 4 hours at room temperature. The reaction mixture was treated with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by alkaline silica gel column chromatography (eluent:dichloromethane/methanol=30/1 to 10/1) to give 177 mg (97%) of the title compound.
0.11 mL (0.44 mmol) of 4M-HCl/ethyl acetate was added to a solution of 150 mg (0.372 mmol) of the title compound in 1 mL of ethyl acetate, and the mixture was treated with ether, then, stirred for 2 hours. The precipitates were collected to give 152 mg (93%) of the title compound.
The title compound 357 mg (98%) was obtained in a manner similar to the Example 7 by use of (R)-(−)-2-amino-1-propanol, instead of benzylamine.
The title compound 67 mg (18%) was obtained in a manner similar to the Example 307 by use of the compound obtained in the Example 324 and hydantoin, instead of the compound obtained in the Example 122 and 1,5,5-trimethylhydantoin, respectively.
The title compound 343 mg (94%) was obtained in a manner similar to the Example 7 by use of (S)-(−)-1-amino-2-propanol, instead of benzylamine.
The title compound 57 mg (15%) was obtained in a manner similar to the Example 307 by use of the compound obtained in the Example 326 and hydantoin, instead of the compound obtained in the Example 122 and 1,5,5-trimethylhydantoin, respectively.
The title compound 338 mg (93%) was obtained in a manner similar to the Example 7 by use of (R)-(+)-1-amino-2-propanol, instead of benzylamine.
The title compound 42 mg (11%) was obtained in a manner similar to the Example 307 by use of the compound obtained in the Example 328 and hydantoin, instead of the compound obtained in the Example 122 and 1,5,5-trimethylhydantoin, respectively.
The title compound 355 mg (94%) was obtained in a manner similar to the Example 7 by use of (R)-(−)-2-mino-1-butanol, instead of benzylamine.
The title compound 66 mg (18%) was obtained in a manner similar to the Example 307 by use of the compound obtained in the Example 330 and hydantoin, instead of the compound obtained in the Example 122 and 1,5,5-trimethylhydantoin, respectively.
The title compound 392 mg (99%) was obtained in a manner similar to the Example 7 by use of D-valinol, instead of benzylamine.
The title compound 97 mg (22%) was obtained in a manner similar to the Example 307 by use of the compound obtained in the Example 332 and hydantoin, instead of the compound obtained in the Example 122 and 1,5,5-trimethylhydantoin, respectively.
The title compound 493 mg (quantitative) was obtained in a manner similar to the Example 7 by use of tert-butyl 2-amino-2-methylpropyl-carbamate, instead of benzylamine.
A mixture solution of 470 mg (1.08 mmol) of the compound obtained in the Example 334 in 2 mL of 4M-HCl/dioxane was stirred for 3 hours at room temperature. Then, the solvent was removed under reduced pressure and the residue was treated with ether and the resultant precipitates were collected. The collected precipitates were dissolved in water and the mixture was neutralized with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane. The organic layer was washed with water and saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 344 mg (92%) of the title compound.
To a solution of 304 mg (0.882 mmol) of the compound obtained in the Example 335 in 5 mL of ethanol was added gradually a solution of 114 mg (0.882 mmol) of ethyl isocyanatoacetate in 5 mL of ethanol, and the mixture was stirred for 3 hours at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in 5 mL of ethanol, then, 5 mL of 6M-HCl aqueous solution was added to the mixture. The mixture was refluxed for 3 hours, and the solvent was removed under reduced pressure. The residue was neutralized with saturated sodium bicarbonate aqueous solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:ethyl acetate) to give 336 mg (91%) of the title compound.
The title compound 227 mg (70%) was obtained in a manner similar to the Example 323 by use of the compound obtained in the Example 336, instead of the compound obtained in the Example 322.
The title compound 162 mg (41%) was obtained in a manner similar to the Example 7 by use of 2,2-dimethyl-1,3-propanediamine, instead of benzylamine.
The title compound 123 mg (72%) was obtained in a manner similar to the Example 336 by use of the compound obtained in the Example 338, instead of the compound obtained in the Example 335.
The title compound 280 mg (42%) was obtained in a manner similar to the Example 7 by use of (±)-trans-(2-aminocyclopropyl)methanol, instead of benzylamine.
The title compound 215 mg (87%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 66, instead of benzylamine.
The title compound 152 mg (77%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 66 and the compound obtained in the Example 195, instead of benzylamine and the compound obtained in the Example 6, respectively.
The title compound 1.78 g (95%) was obtained in a manner similar to the Example 7 by use of methyl m-aminobenzoate, instead of benzylamine.
The title compound 1.67 g (quantitative) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 343, instead of the compound obtained in the Example 40.
The title compound 145 mg (90%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 344 and 2M-dimethylamine/tetrahydrofuran solution, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 167 mg (94%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 344 and morpholine, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 605 mg (99%) was obtained in a manner similar to the Example 7 by use of methyl trans-4-aminocyclohexanecarboxylate HCl salt and the compound obtained in the Example 195, instead of benzylamine and the compound obtained in the Example 6, respectively.
The title compound 540 mg (98%) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 347, instead of the compound obtained in the Example 40.
The title compound 117 mg (91%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 348 and 2M-dimethylamine/tetrahydrofuran solution, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 132 mg (93%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 348 and morpholine, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 137 mg (94%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 348 and 4-hydroxypiperidine, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 97 mg (76%) was obtained in a manner similar to the Example 224 by use of the compound obtained in the Example 348 and 1-methylpiperazine, instead of the compound obtained in the Example 211 and hydroxyacetic acid, respectively.
The title compound 199 mg (90%) was obtained in a manner similar to the Example 7 by use of N-(3-aminopropyl)morpholine, instead of benzylamine.
The title compound 174 mg (82%) was obtained in a manner similar to the Example 7 by use of N-(2-aminoethyl)morpholine, instead of benzylamine.
The title compound 148 mg (70%) was obtained in a manner similar to the Example 7 by use of N-(2-aminoethyl)piperidine, instead of benzylamine.
The title compound 628 mg (96%) was obtained in a manner similar to the Example 206 by use of the compound obtained in the Example 347, instead of the compound obtained in the Example 204.
To a suspension solution of 510 mg (1.35 mmol) of the compound obtained in the Example 356 in 20 mL of dichloromethane and 20 mL of chloroform were added 270 mg (1.42 mmol) of p-toluenesulfonyl chloride and 131 μL (1.62 mmol) of pyridine, and the mixture was stirred for over night at room temperature. Then, further 270 mg (1.42 mmol) of p-toluenesulfonyl chloride and 131 μL (1.62 mmol) of pyridine were added twice to the reaction mixture at 50° C., and the mixture was stirred for over night. Further, 270 mg (1.42 mmol) of p-toluenesulfonyl chloride, 131 μL (1.62 mmol) of pyridine and 226 μL (1.62 mmol) of triethylamine were added twice to the reaction mixture, and the mixture was stirred for over night. Then, the reaction mixture was washed with water and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1 to ethyl acetate only) to give 402 mg (56%) of the title compound.
To a solution of 120 mg (0.226 mmol) of the compound obtained in the Example 357 in 5 mL of N,N-dimethylformamide was added 79 μL (0.903 mmol) of morpholine, and the mixture was stirred for 12 hours at 100° C. Then, the reaction mixture was cooled to room temperature, and treated with 20 mL of ethylacetate. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=40/1) to give 52 mg (52%) of the title compound.
The title compound 92 mg (quantitative) was obtained in a manner similar to the Example 358 by use of 2M-dimethylamine/tetrahydrofuran solution, instead of morpholine.
The title compound 82 mg (87%) was obtained in a manner similar to the Example 358 by use of 1-acetylpiperazine, instead of morpholine.
The title compound 133 mg (66%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 67 and the compound obtained in the Example 195, instead of benzylamine and the compound obtained in the Example 6, respectively.
The title compound 74 mg (39%) was obtained in a manner similar to the Example 7 by use of 3-methylsulfonylaniline HCl salt and the compound obtained in the Example 195, instead of benzylamine and the compound obtained in the Example 6, respectively.
The title compound 135 mg (53%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 68 and the compound obtained in the Example 195, instead of benzylamine and the compound obtained in the Example 6, respectively.
The title compound 61 mg (60%) was obtained in a manner similar to the Example 266 by use of the compound obtained in the Example 363, instead of the compound obtained in the Example 265.
A mixture solution of 456.5 mg (1.00 mmol) of the compound obtained in the Example 159 and 142.8 μL (2.20 mmol) of methanesulfonic acid in 4 mL of ethanol was condensed under reduced pressure. The residue was treated with 5 mL of ethanol and the residue was solved in the solution by heating and refluxing. Then, 2 mL of isopropyl ether was added and the mixture was cooled gradually to room temperature. The resulting precipitates were collected by filtration to give 383 mg (59%) of the title compound.
To a solution of 228.3 mg (0.50 mmol) of the compound obtained in the Example 159 in 2 mL of ethanol was added 104.6 mg (0.55 mmol) of p-toluenesulfonic acid monohydrate at 50° C., and the mixture was condensed under reduced pressure. Then, 1.5 mL of isopropanol was added to the residue and the residue was solved in the mixture by heating at 70° C., and the mixture was cooled gradually to room temperature. The resulting precipitates were collected by filtration to give 281 mg (89%) of the title compound.
To a solution of 438.6 mg (1.00 mmol) of the compound obtained in the Example 114 in 4 mL of ethanol was added 71.4 μL (1.10 mmol) of methanesulfonic acid, and further 0.8 mL of ethyl acetate was added to the mixture. After refluxing the mixture, then, the mixture was cooled gradually to room temperature. The resulting precipitates were collected by filtration to give 424 mg (79%) of the title compound.
To a suspension of 219.3 mg (0.50 mmol) of the compound obtained in the Example 114 in 3 mL of ethanol was added 104.6 mg (0.55 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was refluxed. Then, the separated precipitates were dissolved by adding 0.6 mL of water and the mixture was cooled gradually to 0° C. The resulting precipitates were collected by filtration to give 244 mg (80%) of the title compound.
To a suspension of 120 mg (0.45 mmol) of the compound obtained in the Example 195 in 2 mL of 1,2-dichloroethane was added 66 μL (0.90 mmol) of thionyl chloride and the mixture was refluxed for 2 hours. After cooling the reaction mixture and the solvent removed under reduced pressure to give acid chloride intermediate compound.
314 μL (2.25 mmol) of triethylamine and 139 mg (0.54 mmol) of the compound obtained in the Manufacturing Example 64 were added to the solution of the acid chloride intermediate compound in 5 mL of anhydrous dichloromethane, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was treated with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1 to 10/1) to give 172 mg (88%) of the title compound.
The title compound 216 mg (quantitative) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 74, instead of benzylamine.
The title compound 177 mg (82%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 76, instead of benzylamine.
The title compound 189 mg (92%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 78, instead of benzylamine.
The title compound 209 mg (99%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 80, instead of benzylamine.
The title compound 224 mg (99%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 82, instead of benzylamine.
The title compound 167 mg (81%) was obtained in a manner similar to the Example 41 by use of the compound obtained in the Example 374, instead of the compound obtained in the Example 40.
The title compound 202 mg (quantitative) was obtained in a manner similar to the Example 369 by use of the compound obtained in the Manufacturing Example 74, instead of the compound obtained in the Manufacturing Example 64.
The title compound 187 mg (96%) was obtained in a manner similar to the Example 369 by use of the compound obtained in the Manufacturing Example 84, instead of the compound obtained in the Manufacturing Example 64.
To a suspension of 100 mg (0.26 mmol) of the compound obtained in the Example 103 in 5 mL of anhydrous dichloromethane were added 39.4 mg (0.39 mmol) of 4-hydroxypiperidine, 53 mg (0.39 mmol) of 1-hydroxy-benzotriazole, 74.8 mg (0.39 mmol) of 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide HCl salt and 72.5 μL (0.52 mmol) of triethylamine, and the mixture was stirred for 17 hours at room temperature. The reaction mixture was treated with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1) to give 102 mg (84%) of the title compound.
The title compound 76 mg (68%) was obtained in a manner similar to the Example 378 by use of 2-aminoethanol, instead of 4-hydroxypiperidine.
The title compound 87 mg (72%) was obtained in a manner similar to the Example 378 by use of N-methylpiperazine, instead of 4-hydroxypiperidine.
The title compound 71 mg (60%) was obtained in a manner similar to the Example 378 by use of N,N-dimethylethylenediamine, instead of 4-hydroxypiperidine.
The title compound 50 mg (39%) was obtained in a manner similar to the Example 378 by use of trans-4-aminocyclohexanaol, instead of 4-hydroxypiperidine.
The title compound 105 mg (84%) was obtained in a manner similar to the Example 378 by use of N-methylhomopiperazine, instead of 4-hydroxypiperidine.
The title compound 1.86 g (92%) was obtained in a manner similar to the Example 369 by use of 4-amino-1-Boc-piperidine, instead of the compound obtained in the Manufacturing Example 64.
A mixture solution of 1.81 g (4.03 mmol) of the compound obtained in the Example 384 in 10 mL of 4M-HCl/dioxane was stirred for 30 minutes at room temperature and for 2 hours at 60° C. After cooling the reaction mixture, the solvent was removed under reduced pressure and the residue was treated with saturated sodium bicarbonate aqueous solution, then, the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline solution and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1.22 g (87%) of the title compound.
The title compound 132 mg (91%) was obtained in a manner similar to the Example 322 by use of the compound obtained in the Example 385, instead of the compound obtained in the Example 321.
To a suspension of 220 mg (0.63 mmol) of the compound obtained in the Example 385 in 5 mL of 1,2-dichloroethane were added 15 μL of acetic acid and 151 mg (0.757 mmol) of 1-Boc-4-piperidone, and the mixture was stirred for 30 minutes at room temperature. Then, 200 mg (0.95 mmol) of sodium triacetoxyborohydride was added to the reaction mixture, and the mixture was stirred for 6 hours at room temperature. The reaction mixture was treated with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1) to give 230 mg (69%) of the title compound.
The title compound 165 mg (98%) was obtained in a manner similar to the Example 385 by use of the compound obtained in the Example 387, instead of the compound obtained in the Example 384.
The title compound 51 mg (62%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 388, instead of the compound obtained in the Manufacturing Example 2.
The title compound 68 mg (77%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 388 and methanesulfonyl chloride, instead of the compound obtained in the Manufacturing Example 2 and acetyl chloride, respectively.
The title compound 456 mg (46%) was obtained in a manner similar to the Example 369 by use of the compound obtained in the Manufacturing Example 86, instead of the compound obtained in the Manufacturing Example 64.
523 mg (52%) of the title compound was obtained as by-product in the Example 391.
A mixture of 419 mg (0.817 mmol) of the compound obtained in the Example 391 in 3 mL of 4M-HCl/dioxane and 1 mL of methanol was stirred for 5 hours at room temperature. The solvent was removed under reduced pressure and the residue was treated with ethanol. The resulting precipitates were collected by filtration to give 343 mg (83%) of the title compound.
The title compound 234 mg (51%) was obtained in a manner similar to the Example 393 by use of the compound obtained in the Example 392, instead of the compound obtained in the Example 391.
The title compound 100 mg (70%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 388 and acetic anhydride, instead of the compound obtained in the Manufacturing Example 2 and acetyl chloride, respectively.
The title compound 109 mg (71%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 393 and methanesulfonyl chloride, instead of the compound obtained in the Manufacturing Example 2 and acetyl chloride, respectively.
The title compound 113 mg (66%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 394 and acetic anhydride, instead of the compound obtained in the Manufacturing Example 2 and acetyl chloride, respectively.
The title compound 109 mg (69%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 385 and 4-morpholinyl chloride, instead of the compound obtained in the Manufacturing Example 2 and acetyl chloride, respectively.
The title compound 92 mg (56%) was obtained in a manner similar to the Manufacturing Example 3 by use of the compound obtained in the Example 385 and 4-methyl-1-piperazinecarbonyl chloride HCl salt, instead of the compound obtained in the Manufacturing Example 2 and acetyl chloride, respectively.
The title compound 843 mg (52%) was obtained in a manner similar to the Example 396 by use of trans-4-aminocyclohexanol, instead of the compound obtained in the Manufacturing Example 64.
To a solution of 828 mg (2.28 mmol) of the compound obtained in the Example 400 in 30 mL of dichloromethane were added 983 mg (4.56 mmol) of pyridinium chlorocromate and 2 g of Molecular sieves 4A, and the mixture was stirred for 4 hours at room temperature. The reaction mixture was filtrated by Celite®, and the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent:dichloromethane/ethyl acetate) and further purified by silica gel column chromatography (eluent:ethyl acetate) to give 668 mg (81%) of the title compound.
To a solution of 150 mg (0.415 mmol) of the compound obtained in the Example 401 in 3 mL of 1,2-dichloroethane were added 103 μL (0.83 mmol) of cis-2,6-dimethylmorpholine and 15 μL of acetic acid, and the mixture was stirred for 30 minutes at room temperature. Then, 132 mg (0.623 mmol) of sodium triacetoxyborohydride was added to the reaction mixture and the mixture was stirred for 4 hours at room temperature. The reaction mixture was treated with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The organic layer was removed under reduced pressure and the residue was purified by alkaline silica gel column chromatography (eluent:ethyl acetate/hexane=1/1) to give 132 mg (69%) of the title compound.
The title compound 46 mg (24%) was obtained in the Example 402 as by-product.
The title compound 215 mg (58%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 87, instead of benzylamine.
To a suspension of 700 mg (2.63 mmol) of the compound obtained in the Example 195 in 6 mL of 1,2-dichloroethane was added 384 μL (5.26 mmol) of thionyl chloride, and the mixture was refluxed for 2 hours. After reaction mixture was cooled, the solvent was removed under reduced pressure to give acid chloride intermediate compound.
Then, to a solution of the acid chloride intermediate compound obtained above in 8 mL of pyridine was added 400 mg (2.63 mmol) of methyl 5-amino-2-pyridinecarboxylate, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was treated with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:ethyl acetate) to give 956 mg (91%) of the title compound.
To a solution of 923 mg (2.30 mmol) of the compound obtained in the Example 405 in 5 mL of methanol was added 5 mL of 1M-NaOH aqueous solution, and the mixture was stirred for 1.5 hours at 60° C. After cooling the reaction mixture, the solvent was removed under reduced pressure and the residue was neutralized by adding 2.5 mL of 2M-HCl aqueous solution. The resulting precipitates were collected to give 870 mg (98%) of the title compound.
The title compound 118 mg (94%) was obtained in a manner similar to the Example 378 by use of the compound obtained in the Example 406 and trans-4-aminocyclohexanol, instead of the compound obtained in the Example 103 and 4-hydroxypiperidine, respectively.
The title compound 108 mg (91%) was obtained in a manner similar to the Example 378 by use of the compound obtained in the Example 406 and N,N-dimethylethylenediamine, instead of the compound obtained in the Example 103 and 4-hydroxypiperidine, respectively.
The title compound 35.6 mg (36%) was obtained in a manner similar to the Example 378 by use of the compound obtained in the Example 406 and 4-amino-1-methylpiperidine, instead of the compound obtained in the Example 103 and 4-hydroxypiperidine, respectively.
The title compound 109 mg (82%) was obtained in a manner similar to the Example 378 by use of the compound obtained in the Example 406 and 4-amino-1-acetylpiperidine, instead of the compound obtained in the Example 103 and 4-hydroxypiperidine, respectively.
To a suspension of 120 mg (0.324 mmol) of the compound obtained in the Example 404 in 3 mL of ethyl acetate were added 90 μL (0.648 mmol) of triethylamine and 38 μL (0.486 mmol) of methanesulfonyl chloride, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was treated with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution, water and saturated saline solution, respectively, then, dried over with anhydrous sodium sulfate. Sodium sulfate was removed off by filtration, and the filtrate was treated with 1 mL of 4M-HCl/dioxane, and the solvent was removed to give (5-{(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-yl)carbonyl]amino}-2-pyridinyl)methyl methanesulfonate HCl salt as the intermediate compound.
To a suspension of the intermediate compound obtained above in 3 mL of acetonitrile were added 162 mg (1.17 mmol) of potassium carbonate, 28.8 μL (0.33 mmol) of morpholine and 5.8 mg (0.035 mmol) of potassium iodide, and then, the mixture was stirred for 2 hours at 70° C. and for 15 hours at room temperature. Then, the reaction mixture was treated with water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1) to give 114 mg (80%) of the title compound.
To a solution of 100 mg (0.227 mmol) of the compound obtained in the Example 411 in 2 mL of ethanol was added 14.8 μL of methanesulfonic acid and the solvent was removed. The residue was recrystallized from isopropanol to give 77 mg (63%) of the title compound.
The title compound 104 mg (71%) was obtained in a manner similar to the Example 411 by use of 4-hydroxypiperidine, instead of morpholine.
The title compound 102 mg (66%) was obtained in a manner similar to the Example 411 by use of 1-acetylpiperazine, instead of morpholine.
The title compound 124 mg (72%) was obtained in a manner similar to the Example 369 by use of the compound obtained in the Manufacturing Example 91, instead of the compound obtained in the Manufacturing Example 64.
The title compound 130 mg (75%) was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 91, instead of benzylamine.
The title compound 115 mg (62%) was obtained in a manner similar to the Example 402 by use of 2-piperazine, instead of cis-2,6-dimethyl-morpholine.
The title compound 43 mg (23%) was obtained in the Example 471, as by-product.
To a suspension of 150 mg (0.415 mmol) of the compound obtained in the Example 401 in 3 mL of 1,2-dichloroethane were added 125 mg (0.83 mmol) of 1-methyl-2-piperazinone HCl salt, 15 μL of acetic acid, and 82 mg (1.0 mmol) of sodium acetate, and the mixture was stirred for 30 minutes at room temperature. Then, 132 mg (0.623 mmol) of sodium triacetoxyborohydride was added to the reaction mixture, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted by saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=10/1) to give 131 mg (69%) of the title compound.
The title compound 21 ng (11%) was obtained in the Example 419, as by-product.
The title compound 690 mg (37%) was obtained in a manner similar to the Example 369 by use of the compound obtained in the manufacturing Example 93, instead of the compound obtained in the Manufacturing Example 64.
The title compound 10.10 g (58%) was obtained in the Example 421, as by-product.
The title compound 59 mg (54%) was obtained in a manner similar to the Example 206 by use of the compound obtained in the Example 421, instead of the compound obtained in the Example 204.
The title compound 61 mg (55%) was obtained in a manner similar to the Example 206 by use of the compound obtained in the Example 422, instead of the compound obtained in the Example 204.
The title compound 76 mg (42%) was obtained in a manner similar to the Example 402 by use of 4-hydroxypiperidine, instead of cis-2,6-di-methylmorpholine.
A mixture solution of 400 mg (0.795 mmol) of the compound obtained in the Example 422 in 8 mL of 6M-HCl aqueous solution was refluxed for 2.5 hours. After cooling the reaction mixture, the solvent was removed under reduced pressure to give 1-(cis-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinecarboxylic acid HCl salt as intermediate compound.
Then, to a suspension of the intermediate compound obtained above in dichloromethane were added 0.60 mL (1.2 mmol) of 2M-dimethylamine/tetrahydrofuran, 229 mg (1.19 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl salt, 746 μL (5.35 mmol) of triethylamine and 182 mg (1.19 mmol) of 1-hydroxybenzotriazole, and the mixture was stirred for 95 hours at room temperature. The saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by alkaline silica gel column chromatography (eluent:ethyl acetate) to give 196 mg (49%) of the title compound.
A mixture solution of 400 mg (0.795 mmol) of the compound obtained in the Example 421 in 6M-HCl aqueous solution was stirred for 2 hours at 70° C. The solvent was removed to give 465 mg (quantitative) of the title compound.
The title compound 195 mg (78%) was obtained in a manner similar to the Example 378 by use of the compound obtained in the Example 427 and 2M-dimethylamine/tetrahydrofuran, instead of the compound obtained in the Example 103 and 4-hydroxypiperidine, respectively.
To a solution of 3.48 g (34.1 mmol) of tetrahydro-2H-pyran-3-ol in 350 mL of dichloromethane were added 11.1 g (51.2 mmol) of pyridinium chlorochromate, 3.16 g (38.5 mmol) of sodium acetate, and 30 g of molecular sieve 4A, and the mixture was stirred for 4 hours at room temperature. Then, the reaction mixture was filtrated by Celite® and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=2/1) to give dihydro-2H-pyran-3(4H)-one as intermediate compound.
A mixture solution of the intermediate compound obtained above and 4.6 g (34.1 mmol) of benzoylhydrazine in 20 mL of methanol was stirred for 4 hours at 60° C. After cooling the reaction mixture, the solvent was removed and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=30/1) to give 1.75 g (24%) of the title compound.
To a solution of 1.64 g (7.51 mmol) of the compound obtained in the Example 429 in methanol was added 257 mg (6.76 mmol) of sodium borohydride at 0° C., and the mixture was stirred for 3 hours at the same temperature. The solvent was removed and the residue was treated with water and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=30/1) to give 1.46 g (88%) of the title compound.
To a solution of 1.44 g (6.53 mmol) of the compound obtained in the Example 430 in 10 mL of water was added 20 mL of conc. HCl, and the mixture was stirred for 24 hours at 100° C. After cooling the reaction mixture, the insoluble substances were removed off by filtration, and the filtrate was condensed to give 1-(tetrahydro-2H-pyran-3-yl)hydrazine HCl salt as intermediate compound.
A mixture of the intermediate compound obtained above and 705 μL (6.53 mmol) of methyl acetoacetate was stirred for 2 hours at 110° C. The reaction mixture was cooled and diluted with water and ethyl acetate, then, neutralized by 1M-NaOH aqueous solution. The solvent was removed and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1) to give 793 mg (67%) of the title compound.
The title compound 452 mg (47%) was obtained in a manner similar to the Example 193 by use of the compound obtained in the Example 431, instead of the compound obtained in the Example 192.
To a solution of 259 μL (2.36 mmol) of ethyl thioglycolate in 4 mL of tetrahydrofuran was added 94 mg (2.36 mmol) of sodium borohydride (60% oily) at 0° C., and the mixture was stirred for 30 minutes at room temperature. Then, the reaction mixture was cooled to 0° C. and 415 mg (1.81 mmol) of the compound obtained in the Example 432 in 4 mL of tetrahydrofuran was added gradually to this mixture, and the mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was cooled to 0° C. and 94 mg (2.36 mmol) of sodium borohydride (60% oily) was added to this mixture, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was treated with ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl aceteta=3/1) to give 413 mg (78%) of the title compound.
The title compound 320 mg (89%) was obtained in a manner similar to the Example 6 by use of the compound obtained in the Example 433, instead of the compound obtained in the Example 5.
The title compound 185 mg (95%) was obtained in a manner similar to the Example 369 by use of the compound obtained in the Example 434, instead of the compound obtained in the Example 195.
The title compound 140 mg (71%) was obtained in a manner similar to the Example 419 by use of 1-ethyl-2-piperazinone HCl salt, instead of 1-methyl-2-piperazinone HCl salt.
The title compound 41 mg (21%) was obtained in the Example 436, as by-product.
To a solution of 150 mg (0.282 mmol) of the compound obtained in the Example 357 in 3 mL of N,N-dimethylformamide were added 93 mg (0.564 mmol) of 1-ethyl-2-piperazinone HCl salt, and 236 μL (1.7 mmol) of triethylamine, and the mixture was stirred for 5 hours at 100° C. Then, 43 mg (0.282 mmol) of sodium iodide was added to the reaction mixture and the mixture was stirred for 40 hours at 100° C. Further, 100 mg (0.61 mmol) of 1-ethyl-2-piperazinone HCl salt and 50 mg (0.33 mmol) of sodium iodide were added to the reaction mixture, and the mixture was stirred for 15 minutes at 120° C. using microwave. After the reaction, water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent:dichloromethane/methanol=20/1 to 15/1), and further alkaline silica gel column chromatography (eluent:ethyl acetate) to give 63 mg (46%) of the title compound.
The title compound 24 mg (18%) was obtained in a manner similar to the Example 438 by use of 1-methyl-2-piperazinone HCl salt, instead of 1-ethyl-2-piperazinone HCl salt.
The free base of the title compound was obtained in a manner similar to the Example 7 by use of the compound obtained in the Manufacturing Example 72 and the compound obtained in the Example 195, instead of benzylamine and the compound obtained in the Example 6, respectively. Then, 30.7 μL (0.473 mmol) of methanesulfonic acid was added to a solution of the free base of the compound obtained above in 2.5 mL of isopropanol, and the mixture was refluxed. The reaction mixture was cooled to room temperature and the resultant precipitates were collected to give 206 mg (83%) of the title compound.
Chemical structure and physicochemical data of the compounds obtained by the above-mentioned Manufacturing Examples and Examples are summarized in the following Tables.
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
1H-NMR
The present invention provides thienopyrazole derivatives having selective PDE 7 (phosphodiesterase VII) inhibiting effect. These compounds are effective compounds for treating various kinds of diseases such as allergic diseases, inflammatory diseases and immunologic diseases.
