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    • 专利摘要:
    The present invention provides a substituted isoxazolylthiophene compound represented by the formula (I) or a salt thereof. <Formula I> Wherein R 1 and R 2 each represent an alkyl group having 1 to 5 carbon atoms, R 3 represents a cyano group or CONR 5 R 6 (wherein R 5 and R 6 each represent a hydrogen atom or 1 to 10 carbon atoms). An alkyl group), R 4 represents an alkyl group having 1 to 5 carbon atoms or a phenyl group, and n represents an integer of 0 to 2. The compounds of the present invention are useful for the treatment or prevention of various bone diseases or neurological diseases by specifically enhancing the action of cell differentiation inducing factors present in vivo.
    公开号:KR20010075447A
    申请号:KR1020017004000
    申请日:1999-09-29
    公开日:2001-08-09
    发明作者:마사히로 하라다；준꼬 다께다；도시오 나까무라；시우지 사이또
    申请人:우에하라 아끼라；다이쇼 세이야꾸 가부시끼가이샤；
    IPC主号:
    专利说明:

    Substituted Isoxazolylthiophene Compounds
    [2] Conventionally, condensation tee described in WO98 / 09958 specification as a compound which generates a therapeutic or prophylactic effect of a bone disease or a neurological disease by enhancing the action of a cell differentiation inducing factor present in vivo or a cell differentiation inducing factor administered in vivo. Offen derivatives and the like have been reported, but the compounds of the present invention have not been reported.
    [3] Disclosure of the Invention
    [4] As a result of various studies, the present inventors have found that certain kinds of substituted isoxazolylthiophene compounds are effective compounds for the treatment or prevention of bone diseases or neurological diseases, and have completed the invention.
    [5] That is, this invention is a substituted isoxazolylthiophene compound represented by general formula (I), or its salt.
    [6]
    [7] Wherein R 1 and R 2 each represent an alkyl group having 1 to 5 carbon atoms, R 3 represents a cyano group or CONR 5 R 6 (wherein R 5 and R 6 each represent a hydrogen atom or 1 to 10 carbon atoms). An alkyl group), R 4 represents an alkyl group having 1 to 5 carbon atoms or a phenyl group, and n represents an integer of 0 to 2.
    [8] In the present invention, the alkyl group having 1 to 5 carbon atoms is a linear or branched alkyl group, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-pen Til group etc. are mentioned.
    [9] In the present invention, an alkyl group having 1 to 10 carbon atoms is a linear or branched alkyl group, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-pen A methyl group, n-hexyl group, n-octyl group, etc. are mentioned.
    [10] In the present invention, salts include hydrates in addition to salts with pharmaceutically usable acids (hydrochloric acid, sulfuric acid, nitric acid, tartaric acid, citric acid, maleic acid, fumaric acid, and the like).
    [11] The present invention also includes a compound which is metabolized in vivo after administration to produce a compound of the present invention or a compound which is metabolized in vivo to produce the same compound as the active body compound produced by being metabolized.
    [12] Compound (I) of this invention can be manufactured by the method shown below, for example.
    [13] 1) A compound in which R 3 of the compound (I) of the present invention is a cyano group and n is O can be produced by the method shown in Scheme 1 or the like.
    [14]
    [15] In Scheme 1, R 1 and R 2 have the same meanings as described above, and R 7 is a group represented by COCH 3 , COCH 2 R 4, or CH 2 COR 4 (R 4 means the same as above).
    [16] The detailed description of Scheme 1 is shown below.
    [17] 1) - (1) of (Ia) and (Ib) a compound of the present invention can obtain a diketone compound (Ⅱ) is represented by R 7 COCH 3 as the starting material.
    [18]
    [19] That is, after condensation of diketone compound (II) and carbon disulfide (CS 2 ) in which R 7 is a group represented by COCH 3 in the presence of a base, one sulfur atom derived from carbon disulfide of the resulting condensate is chloroacetonitrile or bromine. Haloacetonitriles such as moacetonitrile and the remaining sulfur atoms are R 2 -X 1 (wherein R 2 is the same as described above, X 1 is a halogen atom such as a chlorine atom or a bromine atom, methylsulfoxy group, or the like). Thioether compound (III), which is a group in which R 7 is represented by COCH 3 by an intramolecular cyclization reaction.
    [20] Bases used in this reaction include alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (lithium carbonate, sodium carbonate, potassium carbonate, etc.), alkali metal carbonates (sodium carbonate, hydrogen carbonate). Potassium, etc.), alkali metal hydrides (sodium hydride, potassium hydride, etc.), inorganic bases (metal sodium, metal potassium, sodium amide, etc.), alkali metal alkoxides (sodium methoxide, sodium ethoxide, t-butoxy potassium Etc.), organic base (triethylamine, diisopropylethylamine, tri-n-butylamine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4. 0] -7-undecene, pyridine, N, N-dimethylaminopyridine, etc., organometallic compounds (n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, sodium bis (trimethylsilyl Amide) and the like.
    [21] This reaction can be performed in a solvent-free or solvent. Solvents used include methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, diethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, Chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, water and the like.
    [22] The use and kind of the base and the solvent described above are appropriately selected depending on the substrate used for the reaction and the reaction conditions.
    [23] Then, R 7 is R 7 and R 4 -COOH of the resulting thiophene compound (Ⅲ) represented by COCH 3 (R 4 has the same meaning) alkyl, such as a carboxylic acid compound of the methyl ester, ethyl ester represented by Compounds of the invention by condensation with activated derivatives such as esters or acid halides or acid anhydrides, followed by R 7 to groups represented by COCH 2 COR 4 , followed by condensation cyclization reactions using hydroxylamine and its derivatives (Ia) or (Ib) can be obtained.
    [24] It is preferable to perform this condensation reaction in presence of a base, As a base, Alkali metal hydroxide (lithium hydroxide, sodium hydroxide, potassium hydroxide etc.), Alkali metal carbonate (lithium carbonate, sodium carbonate, potassium carbonate etc.), alkali metal hydrogencarbonate (Sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydrides (sodium hydride, potassium hydride, etc.), inorganic bases (metal sodium, metal potassium, sodium amide, etc.), alkali metal alkoxides (sodium methoxide, sodium ethoxide) Seeds, t-butoxy potassium and the like), organic bases (triethylamine, diisopropylethylamine, tri-n-butylamine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8 -Diazabicyclo [5.4.0] -7-undecene, pyridine, N, N-dimethylaminopyridine, etc., organometallic compounds (n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropyl Amide, sodium bis (trimethylsilyl) amide, and the like).
    [25] This reaction can be carried out in a solvent or a solvent. Solvents used include methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, diethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, Chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, water and the like.
    [26] In addition, the hydroxylamine used for condensation cyclization reaction may use a salt with hydrochloric acid, sulfuric acid, etc., and it is preferable to perform reaction in presence of a base. Bases include alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (lithium carbonate, sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonates (sodium bicarbonate, potassium hydrogen carbonate, etc.), alkali metals. Hydrides (sodium hydride, potassium hydride, etc.), inorganic bases (metal sodium, metal potassium, sodium amide, etc.), alkali metal acetates (such as sodium acetate), alkali metal alkoxides (sodium methoxide, sodium ethoxide, t -Butoxy potassium and the like), organic base (triethylamine, diisopropylethylamine, tri-n-butylamine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabi Cyclo [5.4.0] -7-undecene, pyridine, N, N-dimethylaminopyridine, etc., organometallic compounds (n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, sodium Bis (trimethylsilyl) amide, etc.) etc. are mentioned.
    [27] This reaction can be carried out in a solvent or a solvent. Solvents used include methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, diethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, Chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, water and the like.
    [28] The use and type of reagents and solvents used in both of the above reactions are appropriately selected depending on the substrate used in the reaction and the reaction conditions.
    [29] 1)-(2) The compounds (Ic to If) of the present invention can obtain diketone compound (II) as a starting material in which R 7 is represented by COCH 2 R 4 or CH 2 COR 4 in Scheme 1.
    [30]
    [31] That is, R 7 is COCH 2 R 4 or CH 2 COR 4 using the resulting diketone compound (Ⅱ) represented by, and 1) in accordance with the recipe shown in (1) R 7 is COCH 2 R 4 or CH 2 The thiophene compound (III) which is group represented by COR <4> can be obtained.
    [32] Then, R 7 is COCH 2 R 4 or CH 2 then the R 7 of the resulting thiophene compound (Ⅲ) represented by COR 4 formylation, halo methylene Chemistry, alkoxy methylene screen or aminomethylene Chemistry, hydroxylamine and its By the condensation cyclization reaction using a derivative, the compounds (Ic to If) of the present invention can be obtained.
    [33] The formylation reaction is a method of condensing formic acid esters such as methyl formate and ethyl formate and carbon monoxide in the presence of a base, or making the carbonyl group of R 7 an enamine with a secondary amine such as dimethylamine, pyrrolidine, morpholine, N, N-dimethylformamide derivatives such as N, N-dimethylformamide or N, N-dimethylformamide dimethylacetal, t-butoxy (dimethylamino) methane, and the like, such as phosgene, phosphorus oxychloride and oxalyl chloride It can carry out by the method etc. which make it act in presence.
    [34] The aminomethyleneation reaction can be performed using N, N- dimethylformamide derivatives, such as N, N- dimethylformamide dimethyl acetal and t-butoxy (dimethylamino) methane.
    [35] The halomethylenelation reaction can be carried out by making the carbonyl group of R 7 an enamine with secondary amines such as dimethylamine, pyrrolidine, and morpholine, and then reacting haloforms such as chloroform in the presence of a base.
    [36] The alkoxy methyleneation reaction can be performed by heating in presence of alkyl ortho formate, such as methyl ortho formate and ethyl ortho formate, and acetic anhydride.
    [37] The aminomethyleneation reaction can be performed by making N, N- dimethylformamide derivatives, such as N, N- dimethylformamide dimethyl acetal and t-butoxy (dimethylamino) methane, act.
    [38] Bases used in the formylation reaction and halomethylene reaction include alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (lithium carbonate, sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonates ( Sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydrides (sodium hydride, potassium hydride, etc.), inorganic bases (metal sodium, metal potassium, sodium amide, etc.), alkali metal acetates (such as sodium acetate), alkali metal alkoxy De (sodium methoxide, sodium ethoxide, t-butoxy potassium, etc.), organic base (triethylamine, diisopropylethylamine, tri-n-butylamine, 1,5-diazabicyclo [4.3.0 ] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine, N, N-dimethylaminopyridine and the like), organometallic compounds (n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, sodium bis ( Li and the like can be mentioned methylsilyl) amide, etc.).
    [39] In addition, a formylation reaction, a halomethylene-ized reaction, an alkoxymethylene-ized reaction, and an aminomethylene-ized reaction can be performed in a solventless or solvent. Solvents used include methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, diethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, Chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, water and the like.
    [40] The use, type, and the like of the reagents and solvents used in both of the above reactions can be appropriately selected depending on the substrate and reaction conditions used in the reaction.
    [41] 2) Compound (Ig) in which R 3 of compound (I) of the present invention is a group represented by CONR 5 R 6 (wherein R 5 and R 6 are the same as above) and n is O is It can be obtained by hydrolyzing the cyano group of the compounds (Ia to If) under acidic or basic conditions.
    [42]
    [43] Hydrolysis reaction in this reaction can be performed by the normal reaction which hydrolyzes a nitrile group. For example, acidic hydrolysis, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate using a single or arbitrary combination of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, polyphosphoric acid, etc. And alkali hydrolysis using ammonia and the like.
    [44] This reaction can be carried out in a solvent or a solvent. Solvents used include methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, diethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, Chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, water and the like.
    [45] The use, type, and the like of the reagents and solvents used in the above reactions are appropriately selected depending on the substrate used in the reaction and the reaction conditions.
    [46] In addition, the compound (Ig) of this invention can be obtained by the following method.
    [47] That is, chloroacetonitrile used to thioether one sulfur atom derived from carbon disulfide in the process for preparing thiophene compound (III), which is represented as intermediate for preparation of compounds (Ia to If) of the present invention in 1)-(1). A thiophene compound (III) having an alkoxycarbonyl group in place of the cyano group can be obtained by using halogenated acetate esters such as methyl bromoacetate and bromoacetate instead of haloacetonitrile such as bromoacetonitrile.
    [48] Subsequently, the alkoxycarbonyl group of the thiophene compound (III) which has an alkoxycarbonyl group instead of a cyano group is hydrolyzed by a carboxyl group in acidic or basic conditions, and then, by condensation cyclization reaction using hydroxylamine, the compound of 1) of this invention. A compound having a carboxyl group can be obtained instead of the cyano group of (Ia to If).
    [49] The said hydrolysis reaction can be performed by the normal reaction which hydrolyzes ester. For example, acidic hydrolysis, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate using a single or arbitrary combination of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, polyphosphoric acid, etc. And alkali hydrolysis using ammonia and the like.
    [50] This reaction can be carried out in a solvent or a solvent. Solvents used include methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, diethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, Chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, water and the like.
    [51] The use, type, and the like of the reagents and solvents used in the above reactions are appropriately selected depending on the substrate used in the reaction and the reaction conditions.
    [52] Finally, the compound (Ig) of the present invention can be obtained by amidating a carboxyl group with an amino compound represented by HNR 5 R 6 (wherein R 5 and R 6 have the same meaning as above).
    [53] As an amidation reaction, the exchange reaction of the ester by an amine, the condensation reaction of the carboxylic acid and amine obtained by hydrolyzing ester, etc. are mentioned. As a condensing agent, For example, acid halogenating agents, such as thionyl chloride, alkyl chlorocarbonates, such as ethyl chlorocarbonate, dicyclohexyl carbodiimide, 1-ethyl-3- (3-dimethylamino) propyl carbodiimide, etc. Sulfonyl chloride compounds such as carbodiimide compounds, methanesulfonyl chloride, phosphorus compounds such as diphenyl phosphite and diphenylphosphoryl chloride, triphenylphosphine-diethyl azadicarboxylate, N, N '-Carbodiimidazole and the like.
    [54] This reaction can be carried out in a solvent or a solvent. Solvents used include methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, diethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, Chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, water and the like.
    [55] The use, type, and the like of the reagents and solvents used in the above reactions are appropriately selected depending on the substrate used in the reaction and the reaction conditions.
    [56] 3) Compounds of the present invention (I) in which n is 1 or 2 are conventional oxidations in which the sulfur atom of the alkylthio group (-SR 2 ) of the compound (Ia to Ig) of the present invention is oxidized to sulfoxide or sulfone. It can be obtained by using a reaction. Examples of the oxidizing agent used in the oxidation reaction include hydrogen peroxide, t-butylhydroperoxide, metachloroperbenzoic acid, peracetic acid, sodium metaperiodate, sodium abromite, sodium hypochlorite, periodic benzene and the like.
    [57] This reaction can be carried out in a solvent or a solvent. Solvents used include methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, diethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, Chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, water and the like.
    [58] The use, type, and the like of the reagents and solvents used in the above reactions are appropriately selected depending on the substrate used in the reaction and the reaction conditions.
    [59] Since the compound of this invention has strong bone formation promoting activity, it can be used individually or in mixture with a carrier for bone reconstruction as a bone formation promoter at the time of repair and transplantation of bone or alveolar bone.
    [60] When used as a bone formation accelerator, it can be administered orally and parenterally in the form of tablets, powders, solutions, injections, suppositories, and the like, and can also be administered by a method such as direct application to surgically extracted bone. The dosage may be appropriately administered in consideration of age, sex, weight, and the like.
    [61] When mixed and used for a bone reconstruction carrier, the method of attaching or containing the compound of this invention to an artificial bone etc. which consist of a metal, a ceramic, or a polymer is mentioned. The artificial bone is preferably made porous in the surface so that the osteoblast differentiation promoter of the present invention can be released from the living tissue when it is implanted in the bone defect.
    [1] The present invention relates to a novel substituted isoxazolylthiophene compound and a pharmaceutical composition useful for enhancing cell differentiation inducing factor action using the same as an active ingredient.
    [62] Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
    [63] Example 1
    [64] 3,4'-dimethyl-4- (isoxazol-5-yl) -5- (methylthio) thiophene-2-carboxamide
    [65] a) ethyl 3-methyl-5-methylthio-4-propionylthiophene-2-carboxylic acid
    [66] A water (8 mL) solution containing 85% potassium hydroxide (13.6 g, 175.2 mmol) under ice cooling in a dimethyl sulfoxide (88 mL) solution containing 2,4-hexanedione (10.0 g, 87.6 mmol), carbon disulfide (7.3 g, 96.4 mmol) was added dropwise successively, followed by stirring at the same temperature for 30 minutes. Subsequently, a dimethylsulfoxide (8 ml) solution containing ethyl bromoacetate (13.2 g, 78.8 mmol) was added dropwise under ice cooling, and stirred for 30 minutes at the same temperature, followed by methyl iodide (12.4 g, 87.6 mmol). Was added and stirred again for 20 minutes. The reaction solution was extracted with ethyl acetate, and the organic layer was washed (in order of water, saturated brine), dried (magnesium sulfate anhydride), filtered and concentrated under reduced pressure.
    [67] The residue thus obtained was dissolved in N, N-dimethylformamide (80 ml), anhydrous potassium carbonate (12.1 g, 87.6 mmol) was added, and the mixture was stirred at room temperature for 10 hours. Water was added to the reaction mixture, and the precipitate was filtered, washed (water), dried and then recrystallized from ethyl acetate-n-hexane to thereby give the colorless crystals 3-methyl-5-methylthio-4-propionylthiophen-2-carbine. Ethyl acid (7.3 g, 31%) was obtained.
    [68] Melting point: 114.0 to 115.0 ° C
    [69] b) 3,4'-dimethyl-4- (isoxazol-5-yl) -5- (methylthio) thiophene-2-carboxylic acid
    [70] Ethyl formate (22 mL), 3-methyl-5-methylthio-4-propionylthiophene-2 in 6.0% sodium hydride (2.14 g, 53.6 mmol) washed three times with n-hexane (5 mL) at room temperature. A tetrahydrofuran (54 mL) solution containing ethyl carboxylate (7.0 g, 25.7 mmol) was added sequentially, followed by heating and stirring at 80 ° C for 1 hour. The reaction solution was returned to room temperature, made acidic by addition of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layer was washed with water, dried (magnesium sulfate anhydride) and concentrated under reduced pressure.
    [71] Ethanol (22 mL) and 6N sodium hydroxide aqueous solution (7.3 mL) were added to the obtained residue, and the mixture was heated and stirred at 60 ° C for 1 hour. The reaction solution was returned to room temperature, acidified by addition of tribasic hydrochloric acid, followed by extraction with ethyl acetate, and the organic layer was washed with water, dried (magnesium sulfate anhydride) and concentrated under reduced pressure.
    [72] Pyridine (11 mL) and hydroxylamine hydrochloride (1.83 g, 26.4 mmol) were added to the obtained residue, and the mixture was heated and stirred at 80 ° C for 1 hour. The reaction solution was cooled, diluted with water, acidified by addition of 12N hydrochloric acid, and extracted with ethyl acetate. The crude crystals obtained by washing the organic layer in the order of water (saturated saline solution), drying (magnesium sulfate anhydride) and concentration under reduced pressure were recrystallized with ethyl acetate-n-hexane to give 3,4'-dimethyl-4- ( Isoxazol-5-yl) -5- (methylthio) thiophene-2-carboxylic acid (5.56 g, 80%) was obtained.
    [73] Melting point: 190.0 to 191.5 ° C
    [74] c) 3,4'-dimethyl-4- (isoxazol-5-yl) -5- (methylthio) thiophene-2-carboxamide
    [75] To tetrahydrofuran (15 mL) containing 3,4'-dimethyl-4- (isoxazol-5-yl) -5- (methylthio) thiophene-2-carboxylic acid (4.13 g, 15.3 mmol) At room temperature, N, N-dimethylformamide (0.5 mL) and thionyl chloride (2.0 g, 16.9 mmol) were added and stirred for 20 minutes, followed by 25% ammonia water (10 mL). The reaction solution was extracted with ethyl acetate, and then the organic layer was washed (in order of water, saturated brine), dried (magnesium sulphate anhydride), and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate). 1: 1), and recrystallized with diethyl ether-n-hexane to give 3,4'-dimethyl-4- (isoxazol-5-yl) -5- (methylthio) thiophen-2- as colorless crystals. Carboxamide (2.19 g, 53%) was obtained.
    [76] Melting Point: 140.0-141.0 ° C
    [77] Example 2
    [78] 3-ethyl-4- (4-methylisoxazol-5-yl) -5- (methylthio) thiophene-2-carbonitrile
    [79] a) 3-ethyl-5-methylthio-4-propionylthiophene-2-carbonitrile
    [80] To a dimethyl sulfoxide (100 mL) solution containing 2,4-heptanedione (10.0 g, 78.0 mmol), a water (10 mL) solution containing 85% potassium hydroxide (10.3 g, 156.0 mmol) under ice cooling, disulfide Carbon (5.9 g, 78.0 mmol) was added dropwise sequentially and then stirred for 30 minutes at the same temperature. Subsequently, a dimethyl sulfoxide (10 mL) solution containing chloroacetonitrile (5.3 g, 70.2 mmol) under ice-cooling was added dropwise over 5 minutes, stirred at the same temperature for 20 minutes, and then potassium carbonate (10.8 g, 78.0 mmol) and methyl iodide (12.2 g, 85.8 mmol) were added and stirred for another 30 minutes. The reaction solution was extracted with ethyl acetate, and the organic layer was washed (in order of water, saturated brine), dried (magnesium sulfate anhydride), filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 10: 1), and then the obtained crystal was washed with n-hexane to give 3-ethyl-5-methylthio-4- as a colorless prism crystal. Propionylthiophene-2-carbonitrile (14.8 g, 88%) was obtained.
    [81] Melting point: 66.0 ~ 67.0 ° C
    [82] b) 3-ethyl-4- (4-methylisoxazol-5-yl) -5- (methylthio) thiophene-2-carbonitrile
    [83] Ethyl formate (1.48 g, 20.0 mmol), 3-ethyl-5-methylthio-4-propionylthiophene-2- in a benzene (20 mL) suspension containing sodium methoxide (1.08 g, 20.0 mmol) at room temperature A benzene (20 mL) solution containing ethyl carboxylate (2.39 g, 10.0 mmol) was added sequentially, followed by stirring at room temperature for 30 minutes, followed by tetrahydrofuran containing ethyl formate (1.48 g, 20.0 mmol). (20 mL) solution was added and stirred for another 16 hours. The reaction solution was washed (in the order of 3N hydrochloric acid, water, saturated brine), dried (magnesium sulfate anhydride) and concentrated under reduced pressure.
    [84] Pyridine (20 mL) and hydroxylamine hydrochloride (0.76 g, 11.0 mmol) were added to the obtained residue, and the mixture was heated and stirred at 80 ° C. for 45 minutes. The reaction solution was returned to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed (in order of water, saturated brine), dried (magnesium sulfate anhydride), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 4: 1 to 3: 1). By purification, 3-ethyl-4- (4-methylisoxazol-5-yl) -5- (methylthio) thiophen-2-carbonitrile (O.87 g, 33%) as a yellow oily substance was obtained. .
    [85] NMR (200 MHz, CDCl 3 ) δ: 1.08 (t, 3H, J = 7.5 Hz), 2.01 (s, 3H), 2.55 (s, 3H), 2.66 (q, 2H, J = 7.5 Hz), 8.22 ( s, 1H)
    [86] Example 3
    [87] 3-ethyl-4- (4-methylisoxazol-5-yl) -5- (methylthio) thiophene-2-carboxamide
    [88] To 3-ethyl-4- (4-methylisoxazol-5-yl) -5- (methylthio) thiophene-2-carbonitrile (0.87 g, 3.3 mmol) was added 60 mL of concentrated sulfuric acid (11 mL). After heating at 占 폚 for 1.5 hours, the reaction solution was returned to room temperature, ice was added, and the mixture was extracted with ethyl acetate. The organic layer was washed (in order of water, saturated aqueous sodium hydrogen carbonate solution, saturated brine), dried (magnesium sulfate anhydride) and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / ethyl acetate = 1: 0 to 3: 1), and then recrystallized from diethyl ether to thereby give 3-ethyl-4- (4-methylisomeric as colorless crystals. Sazol-5-yl) -5- (methylthio) thiophene-2-carboxamide (0.39 g, 42%) was obtained.
    [89] Melting Point 93.5-94.5 ° C
    [90] Example 4
    [91] 4- (4-methylisoxazol-5-yl) -5-methylthio-3- (1-propyl) thiophene-2-carboxamide
    [92] Instead of 2,4-hexanedione used in the production method of Example 1, 3,5-octanedione was used as a starting material, and produced in accordance with the production method of Example 1 to obtain a compound of the present invention as a colorless oily substance.
    [93] NMR (200 MHz, CDCl 3 ) δ: 0.84 (t, 3H, J = 7.8 Hz), 1.49 (dq, 2H, J = 7.8 Hz, 7.8 Hz), 1.99 (s, 3H), 2.51 (s, 3H) , 2.71 (t, 2H, 7.8 Hz), 5.85 (br.s, 2H), 8.23 (s, 1H)
    [94] Example 4 '
    [95] 3-isopropyl-4- (4-methylisoxazol-5-yl) -5- (methylthio) thiophene-2-carboxamide
    [96] Instead of 2,4-hexanedione used in the preparation method of Example 1, 2-methyl-3,5-heptanedone was used as a starting material, prepared in accordance with the preparation method of Example 1, and recrystallized from diethyl ether-n hexane. The compound of this invention was obtained by this.
    [97] Melting point: 105.0 ℃
    [98] Example 5
    [99] 3,4'-dimethyl-5-ethylthio-4- (isoxazol-5-yl) thiophene-2-carboxamide
    [100] Ethyl bromide was used in place of the methyl iodide used in the production method of Example 2 and prepared in accordance with the production methods of Examples 2 and 3 to obtain a compound of the present invention as colorless acicular crystals.
    [101] Melting point: 120.0 to 121.0 ° C. (recrystallization solvent: ethyl acetate-n hexane)
    [102] Example 6
    [103] 3,4'-dimethyl-5- (isopropylthio) -4- (isoxazol-5-yl) thiophene-2-carboxamide
    [104] Instead of methyl iodide used in the preparation method of Example 2, isopropyl iodide was used and prepared in accordance with the preparation methods of Examples 2 and 3 to obtain a compound of the present invention as colorless crystals.
    [105] Melting point: 108.0 to 109.0 ° C. (recrystallization solvent: diethyl ether-n hexane)
    [106] Example 7
    [107] 3-ethyl-4- (4-methylisoxazol-5-yl) -5- (methylthio) thiophene-2-carboxamide
    [108] Instead of 2,4-hexanedione used in the preparation method of Example 1, 2,4-heptanedione was used as a starting material, and it manufactured according to the manufacturing method of Example 1, and obtained the compound of this invention of colorless crystals.
    [109] Melting point: 136.5 to 138.0 ° C. (Recrystallization solvent: diethyl ether)
    [110] Example 8
    [111] 4- {4- (1-butyl) isoxazol-5-yl} -3-methyl-5- (methylthio) thiophene-2-carboxamide
    [112] Instead of 2,4-hexanedione used in the preparation method of Example 1, 2,4-nonanedione was used as a starting material, and it manufactured according to the manufacturing method of Example 1, and obtained the colorless oily compound of this invention.
    [113] NMR (200 MHz, CDCl 3 ) δ: 0.87 (t, 3H, J = 6.2 Hz), 1.20-1.61 (m, 4H), 2.28-2.65 (m, 2H), 2.30 (s, 3H), 2.51 (s , 3H), 5.61 (br.s, 2H), 8.25 (s, 1H)
    [114] Example 9
    [115] 4- {4- (isopropyl) isoxazol-5-yl} -3-methyl-5- (methylthio) thiophene-2-carboxamide
    [116] Instead of 2,4-hexanedione used in the preparation method of Example 1, 6-methyl-2,4-heptanedione was used as a starting material, and produced in accordance with the preparation method of Example 1 to prepare a compound of the present invention as colorless crystals Got it.
    [117] Melting point: 111.5 to 112.5 ° C. (recrystallization solvent: diethyl ether)
    [118] Example 10
    [119] 4- (4-phenylisoxazol-5-yl) -5-methylthio-3- (1-propyl) thiophene-2-carboxamide
    [120] Instead of 2,4-hexanedione used in the preparation method of Example 1, 1-phenyl-2,4-pentanedione was used as a starting material, and it prepared according to the manufacturing method of Example 1, and obtained the compound of this invention of colorless crystals. .
    [121] Melting Point: 140.0-141.0 DEG C (Recrystallization Solvent: Diethyl Ether)
    [122] Example 11
    [123] 3,3'-dimethyl-4- (isoxazol-5-yl) -5- (methylthio) thiophene-2-carboxamide
    [124] a) 4-acetyl-3-methyl-5- (methylthio) thiophene-2-carboxylic acid ethyl
    [125] Instead of 2,4-hexanedione used in the preparation method of Example 1, 2,4-pentanedione was used as a starting material, and produced in accordance with the preparation method of Example 1-a) to yield 4-acetyl-3- as colorless crystals. Ethyl methyl-5- (methylthio) thiophene-2-carboxylic acid was obtained.
    [126] Melting point: 76-77 ° C. (recrystallization solvent: diethyl ether-n hexane)
    [127] b) 3-methyl-5-methylthio-4- (3-oxobutyryl) thiophene-2-carboxylic acid ethyl
    [128] 4-acetyl-3-methyl-5- (methylthio) ti at room temperature in a tetrahydrofuran (5 mL) suspension containing 60% sodium hydride (0.64 g, 15.9 mmol) and ethyl acetate (8.16 g, 92.9 mmol) Tetrahydrofuran (10 mL) solution containing ethyl fen-2-carboxylic acid (2.0 g, 7.7 mmol) and ethanol (0.5 mL), tetrahydro containing dibenzo18-crown-6 ether (0.04 mg) The furan (5 mL) solution was added sequentially and then heated to reflux for 2 hours. The reaction solution was returned to room temperature, acidified by addition of 3N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed (in order of water, saturated brine), dried (magnesium sulfate anhydride) and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 20: 1) to give 3-methyl-5-methylthio-4- (3-oxobutyryl) thiophene as a yellow crystal. Ethyl 2-carboxylic acid (1.91 g, 82%) was obtained.
    [129] Melting point: 51-52 ° C.
    [130] c) 3,3'-dimethyl-4- (isoxazol-5-yl) -5- (methylthio) thiophene-2-carboxylic acid
    [131] Pyridine (11 mL) and hydroxylamine hydrochloride (0.29 g, 4.14) in 3-methyl-5-methylthio-4- (3-oxobutyryl) thiophene-2-carboxylic acid ethyl (1.13 g, 3.76 mmol) mmol) was added and stirred at 80 ° C. for 1 hour. The reaction solution was cooled, diluted with water, and extracted with diethyl ether. The organic layer was washed (water, tribasic hydrochloric acid, saturated brine in that order), dried (magnesium anhydride), and concentrated under reduced pressure. To a 1: 1 tetrahydrofuran-ethanol (7.4 mL) solution of the obtained residue, 20% aqueous sodium hydroxide solution (3.7 mL) was added at room temperature, and the mixture was heated and stirred at 80 ° C. for 1 hour. The reaction solution was returned to room temperature, acidified by addition of 3N hydrochloric acid, and the precipitate was filtered off and washed with water. The obtained crude crystal was dissolved in tetrahydrofuran (200 mL), dried (magnesium sulfate anhydride) and concentrated under reduced pressure, and then the obtained residue was recrystallized from diethyl ether -n-hexane to give 3,3'-dimethyl- as a yellow crystal. 4- (isoxazol-5-yl) -5- (methylthio) thiophene-2-carboxylic acid (0.90 g, 88%) was obtained.
    [132] Melting point: 248.0 to 249.0 ° C
    [133] d) 3,3'-dimethyl-4- (isoxazol-5-yl) -5- (methylthio) thiophene-2-carboxamide
    [134] By amidation according to the preparation method of Example 1-c), the compound of the present invention as pale yellow colorless acicular crystal was obtained.
    [135] Melting Point: 208.5 to 209.0 ° C. (Recrystallization Solvent: Tetrahydrofuran-nhexane)
    [136] Example 12
    [137] 4- (isoxazol-5-yl) -5-methylthio-3,3 ', N-trimethylthiophene-2-carboxamide
    [138] Instead of 25% aqueous ammonia used in the preparation method of Example 1-c), a 40% aqueous methylamine solution was used, and amidation was carried out according to the preparation method of Example 1-c) to obtain a compound of the present invention as colorless crystals.
    [139] Melting point: 98-99.5 degreeC (recrystallization solvent: diethyl ether)
    [140] Example 13
    [141] 3,4'-dimethyl-N- (1-hexyl) -4- (isoxazol-5-yl) -5- (methylthio) thiophene-2-carboxamide
    [142] N-hexylamine was used instead of 25% ammonia water used in the preparation method of Example 1-c) and amidated in accordance with the preparation method of Example 1-c) to obtain a colorless oily compound of the present invention.
    [143] NMR (200 MHz, CDCl 3 ) δ: 0.90 (t, 3H, J = 6.6 Hz), 1.21-1.65 (m, 8H), 1.99 (s, 3H), 2.30 (s, 3H), 2.49 (s, 3H ), 3.43 (dq, 2H, J = 6.6 Hz, 1.6 Hz), 5.75 (br.s, 1H), 8.23 (s, 1H)
    [144] Example 14
    [145] 4- (isoxazol-5-yl) -5-methylthio-3,3 ', N, N-tetramethylthiophen-2-carboxamide
    [146] Instead of 25% ammonia water used in the preparation method of Example 1-c), a 50% aqueous dimethylamine solution was used, followed by amidation according to the preparation method of Example 1-c) to obtain a compound of the present invention as a colorless oily substance.
    [147] NMR (200 MHz, CDCl 3 ) δ: 2.01 (s, 3H), 2.07 (s, 3H), 2.46 (s, 3H), 3.11 (s, 6H), 8.22 (s, 1H)
    [148] Example 15
    [149] 3,4'-dimethyl-4- (isoxazol-5-yl) -5- (methylsulfinyl) thiophene-2-carboxamide
    [150] 3,4'-dimethyl-4- (isoxazol-5-yl) -5- (methylthio) thiophene-2-carboxamide (0.10 g, 0.37) which is a compound of the present invention prepared by the preparation method of Example 1 m-chloroperbenzoic acid (0.07 g, O.41 mmol) was slowly added to a dichloromethane (3 mL) solution containing ice-cold and stirred at the same temperature for 30 minutes. The reaction solution was washed (saturated aqueous sodium hydrogen carbonate), dried (magnesium sulfate anhydride), concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) and recrystallized with ethyl acetate-n-hexane. Thus, 3,4'-dimethyl-4- (isoxazol-5-yl) -5- (methylsulfinyl) thiophene-2-carboxamide (0.064 g, 61%) as colorless crystals was obtained.
    [151] Melting Point: 152.0 ~ 153.0 ° C
    [152] Example 16
    [153] 3,4'-dimethyl-4- (isoxazol-5-yl) -5- (methylsulfonyl) thiophene-2-carboxamide
    [154] 3,4'-dimethyl-4- (isoxazol-5-yl) -5- (methylthio) thiophene-2-carboxamide (0.10 g, 0.37) which is a compound of the present invention prepared by the preparation method of Example 1 m-chloro perbenzoic acid (0.14 g, 0.81 mmol) was slowly added to a dichloromethane (3 mL) solution containing mmol) at room temperature, followed by further stirring for 4 hours. The reaction solution was washed (saturated aqueous sodium hydrogen carbonate), dried (magnesium sulphate anhydride) and concentrated under reduced pressure, and then the obtained residue was recrystallized from ethyl acetate-n-hexane to give 3,4'-dimethyl-4- as a colorless crystal. (Ixoxazol-5-yl) -5- (methylsulfonyl) thiophene-2-carboxamide (0.081 g, 73%) was obtained.
    [155] Melting Point: 182.0-183.0 ° C
    [156] Test Example 1
    [157] Alkaline phosphatase production-inducing promoting activity in rat fetal parietal bone-derived osteoblasts was measured for the compound of the present invention. In comparison with the test compound concentration of 2.5 μg / ml and no addition of the test compound, the ability to promote alkaline phosphatase production was 195% in Example 1, 155% in Example 3, 187% in Example 7, and Example 9 was 134%.
    [158] Test Example 2
    [159] The compound of the present invention was measured for its promoting activity against nodule induction in rat fetal parietal bone-derived osteoblasts. As a result, Example 1 was 342% at 1.0 µg / ml, Example 3 was 501% at 2.5 µg / ml, Example 7 was 576% at 2.5 µg / ml, and Example 9 was 550% at 2.5 µg / ml. It was.
    [160] The present invention specifically enhances the action of the cell differentiation inducing factor present in vivo, thereby making it possible to provide low molecular weight compounds useful for the treatment or prevention of various bone diseases or neurological diseases. Specifically, the present invention is useful as an agent for preventing or treating osteoporosis, or as an agent for promoting bone formation when restoring or transplanting bone or alveolar bone.
    权利要求:
    Claims (6)
    [1" claim-type="Currently amended] Substituted isoxazolylthiophene compounds represented by formula (I) or salts thereof.
    <Formula I>

    Wherein R 1 and R 2 each represent an alkyl group having 1 to 5 carbon atoms, R 3 represents a cyano group or CONR 5 R 6 (wherein R 5 and R 6 each represent a hydrogen atom or 1 to 10 carbon atoms). An alkyl group), R 4 represents an alkyl group having 1 to 5 carbon atoms or a phenyl group, and n represents an integer of 0 to 2.
    [2" claim-type="Currently amended] A compound which produces the same compound as the active body compound which is metabolized in vivo after administration to produce the compound according to claim 1 or metabolized in vivo to which the compound according to claim 1 is metabolized and produced.
    [3" claim-type="Currently amended] A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof as an active ingredient.
    [4" claim-type="Currently amended] A cell differentiation inducing factor agonist, comprising the compound according to claim 1 or a salt thereof as an active ingredient.
    [5" claim-type="Currently amended] Use of a compound according to claim 1 as a medicament.
    [6" claim-type="Currently amended] Use of a compound according to claim 1 for the preparation of a cell differentiation inducing factor agonist.
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    同族专利:
    公开号 | 公开日
    EP1120415A4|2002-01-23|
    DK1120415T3|2003-11-03|
    DE69909811T2|2004-01-29|
    EP1120415A1|2001-08-01|
    CN1117091C|2003-08-06|
    CN1321156A|2001-11-07|
    DE69909811D1|2003-08-28|
    EP1120415B1|2003-07-23|
    AU5997899A|2000-04-17|
    WO2000018765A1|2000-04-06|
    AT245643T|2003-08-15|
    PT1120415E|2003-12-31|
    CA2343194A1|2000-04-06|
    US6355663B1|2002-03-12|
    AU755425B2|2002-12-12|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-09-30|Priority to JP27628898
    1998-09-30|Priority to JP98-276288
    1999-09-29|Application filed by 우에하라 아끼라, 다이쇼 세이야꾸 가부시끼가이샤
    1999-09-29|Priority to PCT/JP1999/005315
    2001-08-09|Publication of KR20010075447A
    优先权:
    申请号 | 申请日 | 专利标题
    JP27628898|1998-09-30|
    JP98-276288|1998-09-30|
    PCT/JP1999/005315|WO2000018765A1|1998-09-30|1999-09-29|Substituted isoxazolylthiophene compounds|
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