JPH05148251A - Novel thiazole derivative - Google Patents

Abstract

(57) [Summary] (Modified) [Objective] To provide a novel thiazole derivative having excellent immune disease therapeutic action or inflammatory disease therapeutic action and having few side effects. [Structure] A novel thiazole derivative typified by a compound having the following structural formula. [Chemical 1]

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel thiazole derivative useful as a therapeutic or preventive agent for autoimmune diseases and inflammatory diseases.

[0002]

2. Description of the Related Art Conventionally, acidic nonsteroidal anti-inflammatory agents, gold preparations, steroids, etc. have been used as therapeutic agents for autoimmune diseases such as rheumatoid arthritis. Its use is limited. As the mechanism of development of autoimmune diseases has been elucidated, levamisole and D-penicillamine are used as immunomodulators that are said to have no effect on the normally functioning immune system and normalize the function causing the disorder. Has been attracting attention as a causative agent, but it is not always in a satisfactory state due to side effects.

[0003]

[Problems to be Solved by the Invention] As a therapeutic agent for autoimmune diseases, it is necessary to improve the immune action exhibiting abnormal reactivity. As a therapeutic agent for rheumatoid arthritis, which is one of the autoimmune diseases, it is desirable that it has not only a clear effect on chronic inflammation but also an improving effect on the underlying immune abnormality. In addition, since therapeutic agents for these diseases often require long-term administration, it is required to have few side effects. On the other hand, thiazole derivatives having various physiological activities have been reported (for example,
JP-A-63-152368 and JP-A-3-6856
No. 7, etc.) have further excellent immune abnormality-improving action and chronic inflammation-improving action, and development of a therapeutic agent with fewer side effects is desired.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found compounds that show strong effects on both immunoabnormality-improving action and chronic inflammation-improving action and have few side effects. Heading out, the present invention has been completed. That is, the present invention has the general formula [1]

[Chemical 2] [In the formula, A represents a single bond, a linear or branched lower alkylene group, or a linear or branched lower alkenylene group, and B represents a single bond or -CO-. R1 is a carboxy group or -CONR7 OR8 (R7, R8
Each independently represent a hydrogen atom or a lower alkyl group), R2 represents a lower alkyl group, R3 and R4 each independently represent a hydrogen atom, a lower alkyl group, or a lower alkoxycarbonyl group, and R5 represents R6 represents a hydrogen atom or a halogen atom, and R6 represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a thiol group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a nitro group, an amino group. ,
It represents a substituted amino group, a cyano group, a carboxy group, or an acyl group. ] It is related with the novel thiazole derivative represented by these, or its pharmaceutically acceptable salt.

The compound of the present invention will be described in detail below.

In the definition of the above-mentioned general formula [I], the linear or branched lower alkylene group has, for example, 1 to 1 carbon atoms.
And four alkylene groups, specifically methylene,
Examples thereof include ethylene, methylmethylene, trimethylene, 2-methylethylene, tetramethylene, ethylethylene and the like.

Examples of the straight-chain or branched lower alkenylene group include alkenylene groups having 2 to 4 carbon atoms, specifically vinylene, 2-methylvinylene, propenylene, 2-methylpropenylene, Or butenylene and the like can be mentioned.

The lower alkoxycarbonyl group includes, for example, a carbonyl group substituted by an alkoxy group having 1 to 4 carbon atoms, specifically, methoxycarbonyl,
Examples thereof include ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, butoxycarbonyl, 2-butoxycarbonyl, 2-methylpropoxycarbonyl, and 1,1-dimethylethoxycarbonyl.

Examples of the lower alkyl group include an alkyl group having 1 to 4 carbon atoms, specifically, methyl,
Examples thereof include ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, and 1,1-dimethylethyl.

Examples of the halogen atom include fluorine, chlorine, bromine and iodine.

Examples of the lower alkoxy group include linear or branched C1-C4 methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1,1-dimethylethoxy and the like.

Examples of the lower alkylthio group include linear or branched ones having 1 to 4 carbon atoms such as methylthio, ethylthio, propylthio, 2-methylethylthio and butylthio.

The lower alkylsulfinyl group is a linear or branched one having 1 to 4 carbon atoms, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl,
2-Methylethylsulfinyl, butylsulfinyl and the like can be mentioned.

Examples of the lower alkylsulfonyl group include linear or branched ones having 1 to 4 carbon atoms such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, 2-methylethylsulfonyl and butylsulfonyl.

Examples of the substituted amino group include monomethylamino, dimethylamino, monoethylamino, diethylamino, dipropylamino, 1-methylethylamino and the like.

Examples of the acyl group include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group and a pivaloyl group. The position at which the R6 -Ph-B group (Ph represents phenylene) is substituted with the phenyl group includes, for example, the 3 or 4 position.

In the present invention, preferred compounds include
General formula [2]

[Chemical 3] [In the formula, A, R2, R3, R4, R5, and R6 have the same meanings as described above. ] The compound represented by these, or its pharmaceutically acceptable salt is mentioned.

Furthermore, as a more preferred compound, a compound represented by the general formula [3]

[Chemical 4] [In the formula, R3 'represents lower alkyl, R6' represents a hydrogen atom,
Alternatively, it represents a halogen atom, and R2 and R5 have the same meanings as described above. ] The compound represented by these, or its pharmaceutically acceptable salt is mentioned.

Examples of the pharmaceutically acceptable salt of the novel thiazole derivative represented by the general formula [1] include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, formic acid and acetic acid. , Salts with organic carboxylic acids such as fumaric acid, maleic acid, malic acid, tartaric acid, aspartic acid, or glutamic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxybenzenesulfonic acid, or dihydroxybenzenesulfonic acid Salts with sulfonic acids, such as salts with alkali metals such as sodium or potassium, salts with alkaline earth metals such as calcium or magnesium, trimethylamine,
Examples thereof include salts with organic bases such as triethylamine or pyridine, and ammonium salts. The compounds of the present invention include stereoisomers, optically active forms and tautomers, and further include all hydrates and crystal forms.

The novel thiazole derivative represented by the general formula [I] can be produced, for example, by the following methods. Method A

[Chemical 5] (In the formula, B, R2, R3, R4, R5 and R6 have the same meanings as described above.) The compound of the present invention represented by the general formula [5] is represented by the general formula [4]
Compounds of potassium permanganate, chromic acid, silver oxide,
Alternatively, it can be obtained by treating with an oxidizing agent such as nitric acid. As a preferred solvent, water or an acid such as acetic acid or sulfuric acid is used in some cases. It can be produced by reacting under these solvents at an appropriate temperature from under ice cooling to the reflux temperature of the solvent used.

Method B

[Chemical 6] (In the formula, R9 represents a lower alkyl group, A, B, R2,
R3, R4, R5 and R6 have the same meanings as described above. The compound of the present invention represented by the general formula [7] has the general formula [6]
It can be produced by alkaline hydrolysis of the compound (1). Examples of the base used here include inorganic bases (for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.), organic bases (triethylamine, imidazole, etc.), metal alkoxides (sodium methoxide, potassium t-butoxide, etc.). ) Is mentioned. Examples of the solvent include water, methanol, ethanol, dimethylsulfoxide, and the like, and if necessary, these can be mixed and used. The reaction temperature is appropriately selected from room temperature to the reflux temperature of the solvent.

Method C

[Chemical 7] (In the formula, R10 and R11 each independently represent a hydrogen atom or lower alkyl, and A, B, R2, R3, R4, R5
, And R6 have the same meaning as described above. ) General formula

The compound of the present invention represented by [9] is obtained, for example, from Journal of Medicinal Chemistry (J. Me.
d. Chem. ), 30, p. 574, 1987, according to the method described in the general formula [7]. That is, after treating the compound of formula [7] with oxalyl chloride in the presence of a halogenated hydrocarbon solvent such as dimethylformamide and methylene chloride, the reaction solution is represented by the general formula [8] It can be produced by dropping it into a solution of the compound to be reacted at an appropriate temperature from ice temperature to the reflux temperature of the solvent.

Method D

[Chemical 8] (In the formula, R12 and R13 each independently represent a lower alkyl group or a lower alkoxycarbonyl group, and B, R2, R
3, R4, R5, and R6 have the same meanings as described above. The compound represented by the general formula [4] is obtained by converting the compound of the general formula [10] into Vilsmeier Reagent (Vilsmeier Re
agent; a reagent for formylation with N, N-dimethylformamide or methylformamide in the presence of phosphorus oxychloride, oxalyl chloride or thionyl chloride). R12 of the general formula [10]
When one or both of R 13 and R 13 are an alkoxycarbonyl group, an alkoxycarbonyl group free from the alkoxycarbonyl group is obtained depending on the conditions. Preferred solvents include halogenated hydrocarbon solvents such as methylene chloride, chloroform, and 1,2-dichloroethane. Alternatively, N, N-dimethylformamide can also serve as the solvent. It can be produced by reacting under these solvents at an appropriate temperature from room temperature to the reflux temperature of the solvent used.

Method E

[Chemical 9] (In the formula, R9 represents lower alkyl, B, R2, R3,
R4, R5, and R6 have the same meaning as described above. The compound represented by the general formula [13] is obtained by halogenating the compound represented by the general formula [11] by a conventional method (for example, bromine is added dropwise in an ether solution) to halogenate methylene at the α-position, It can be produced by treating with a thiourea derivative represented by the general formula [12] in an alcohol solvent. The reaction temperature is preferably room temperature to the reflux temperature of the solvent.

Method F

[Chemical 10] (In the formula, R9 represents lower alkyl, B, R2, R5,
And R6 have the same meaning as described above. The compound represented by the general formula [11] can be produced by heating the compound represented by the general formula [14] in the presence of an acid such as acetic acid or sulfuric acid. Preferred solvents include, for example, dimethylformamide, dimethylsulfoxide, or tetrahydrofuran, ether solvents such as 1,4-dioxane, or methanol, ethanol,
Examples thereof include alcohol solvents such as butanol and isopropanol, which can be produced by reacting under an appropriate temperature from 50 ° C. to the reflux temperature of the solvent used.

Method G

[Chemical 11] (In the formula, R9 represents lower alkyl, X represents a halogen atom, and B, R2, R5, and R6 have the same meanings as described above.) The compound represented by the general formula [14] is represented by the general formula [14]. The compound represented by [15] can be produced by reacting the compound represented by the general formula [16] in the presence of a base such as sodium hydride. Preferred solvents include, for example, ether solvents such as dimethylformamide, dimethylsulfoxide, or tetrahydrofuran, 1,4-dioxane, etc., and the reaction is conducted under these solvents at a suitable temperature from room temperature to the reflux temperature of the solvent used. It can be manufactured by

Method H

[Chemical 12] (In the formula, R12 represents a hydrogen atom or a lower alkyl group,
R13 represents a lower alkoxycarbonyl group, B, R2,
R3, R4, R5 and R6 have the same meanings as described above. The compound represented by the general formula [18] is obtained by reacting the compound of the general formula [17] with palladium carbon (Pd / Pd / Pd / Pd / Alcohol-based solvent such as 2-propanol).
It can be produced by hydrogenating using a catalyst such as C) at room temperature and atmospheric pressure.

Method I

[Chemical 13] (In the formula, R12 represents a hydrogen atom or a lower alkyl group,
R13 represents a lower alkoxycarbonyl group, R14 represents a lower alkyl group, and B, R2, R3, R4, R5, and R6 have the same meanings as described above. The compound represented by the general formula [18] is obtained by reacting the compound of the general formula [4] with the compound of the general formula [19] in the presence of a base such as sodium hydride or sodium methoxide. Preferred solvents include, for example, N, N
An amide solvent such as dimethylformamide or dimethylacetamide, an ether solvent such as dimethylsulfoxide, or tetrahydrofuran or 1,4-dioxane, and the like, and a suitable temperature from room temperature to the reflux temperature of the solvent used under these solvents. It can be produced by reacting at various temperatures. When B is -CO-, it is preferable to carry out the reaction after protecting with acetal or the like (the conditions for acetalization and deacetalization are 14 V, pages 2518 and 2519 of the New Experimental Chemistry Course, The Chemical Society of Japan). Ed., 3rd edition issued April 15, 1983).

Method J

[Chemical 14] (In the formula, R15 represents a lower alkyl group, X represents a halogen atom, and B, R2, R3, R4, R5, and R6 have the same meanings as described above.) A compound represented by the general formula [21]. Can be produced by reacting the compound of general formula [20] with the compound of general formula [12] in an alcohol solvent such as methanol or ethanol at an appropriate temperature from room temperature to the reflux temperature of the solvent. it can.

K method

[Chemical 15] (In the formula, R16, R17 and R18 each represent lower alkyl, X represents a halogen atom, B, R2, R5 and R
6 has the same meaning as above. The compound represented by the general formula [24] is a compound represented by the general formula [22] in a mixed solution of an inert solvent such as benzene and toluene and a 50% aqueous sodium hydroxide solution in tetra-
It can be produced by treating with a compound represented by the general formula [23] in the presence of a phase transfer catalyst such as n-butylammonium hydrogensulfate.

The general formulas [8], [10], [12], [15], [16], which are the raw material compounds in the above production method,
The compounds represented by [19], [20], and [23] are known compounds per se, or compounds that can be synthesized by a known synthesis method. For example, the general formula [10]
And the compounds represented by [15] are disclosed in JP-A-63-15
It can be manufactured by the method described in Japanese Patent No. 2368. The compound represented by the general formula [19] is, for example, Chemische Berich.
te), 92, 2499, 1959, or Journal of the American Chemical Society (J. Am. Chem. Soc.), 83, 17
It can be produced by the method described on page 33, 1961. In addition, the compound represented by the general formula [20] is a compound of Journal of the Organic Chemistry (J. Or.
g. Chem. ), 43, 2087, 1978 and 42, 1389, 1977.

The compound of the present invention represented by the above general formula [1] and a pharmaceutically acceptable salt thereof can be administered orally or parenterally when it is used as a drug. That is, it can be orally administered in the form of commonly used dosage forms, such as tablets, capsules, syrups, or suspensions, or a solution thereof,
A liquid formulation such as an emulsion or a suspension may be parenterally administered by injection. Furthermore, it can also be administered rectally in the form of suppositories.

The above-mentioned suitable dosage forms can be prepared by incorporating the active compound into an acceptable conventional carrier, excipient, binder, stabilizer and the like. When used in an injection form, acceptable buffers, solubilizers, isotonic agents and the like can be added. The dose and frequency of administration vary depending on the symptoms, age, body weight, and administration form, but usually about 1 to 200 for an adult orally per day.
In the case of injection, 0 mg, preferably 5 to 1000 mg, and 0.05 to 200 mg can be administered once or in several divided doses.

[0034]

INDUSTRIAL APPLICABILITY The compound of the present invention and a pharmaceutically acceptable salt thereof are used for autoimmune diseases (for example, rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma, Sjogren's syndrome, Hashimoto's disease, myasthenia gravis). , Basedow's disease, Addison's disease, juvenile diabetes (Type I diabetes), autoimmune blood diseases (eg, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia, etc.), ulcerative colitis, chronic active hepatitis , Glomerulonephritis, interstitial lung fibrosis, etc.), or inflammatory diseases (eg, osteoarthritis, gout, atopic dermatitis, psoriasis, etc.), etc.

That is, the compounds of the present invention showed remarkable effects in test systems including animal models of chronic inflammation (rat adjuvant arthritis etc.) and animal models of immune abnormality (mouse type III allergic reaction etc.). Therefore, the compound of the present invention is characterized by acting not only on the obvious effect on chronic inflammation but also on the underlying immune disorder.
Such an action suggests the efficacy of the compound of the present invention for autoimmune diseases such as rheumatoid arthritis and inflammatory diseases.

Furthermore, it is considered that the compound of the present invention has improved pharmacokinetics by introducing a polar functional group into the thiazole ring, has less side effects, and can be sufficiently administered for a long period of time.

[0037]

The present invention will be described below with reference to examples and reference examples, but the present invention is not limited to these examples. Example 1

[Chemical 16] 5-Formyl-4- (1- (2-fluoro-4-biphenylyl) ethyl) -2-methylaminothiazole (1.00 g, 2.9 mmol) in acetone (20 ml)
And a Jones reagent (a reagent in which chromic acid (VI) was dissolved in concentrated sulfuric acid and water; 2 ml) was added dropwise under ice cooling, and the mixture was stirred for 1 hour. Further, Jones reagent (2 ml) was added dropwise and stirred for 1 hour. 2-Propyl alcohol was added to the reaction solution in a small amount, extracted with ether, washed with water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and recrystallized from ethyl acetate to give the desired product, 4- (1- (2-fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylic acid (205 mg). , 0.58 mmol, yield 20%) was obtained as white crystals. Melting point 133-134 ° C

Example 2

[Chemical 17] Ethyl 4- (1- (2,4′-difluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylate (1.00 g, 2.48 mmol) was dissolved in methanol (20 ml), Potassium hydroxide (420
mg, 7.49 mmol) in water (4 ml),
The mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was diluted with water, and washed with ether. The aqueous layer was acidified with 1M hydrochloric acid (about pH 4) and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue obtained was recrystallized from methanol to give the desired product, 4-
(1- (2,4'-difluoro-4-biphenylyl))
Ethyl) -2-methylamino-5-thiazolecarboxylic acid (599 mg, 1.60 mmol, yield 65%) was obtained as white crystals. Melting point 195-195.5 ° C

Example 3

[Chemical 18] In the same manner as in Example 2, 4- (1- (2-fluoro-
4-biphenylyl) ethyl) -2-dimethylamino-
From ethyl 5-thiazolecarboxylate, the desired 4- (1-
(2-Fluoro-4-biphenylyl) ethyl) -2-
Dimethylamino-5-thiazolecarboxylic acid was obtained. Melting point 166.5-167 ° C

Example 4

[Chemical 19] In the same manner as in Example 2, 4- (1- (2-fluoro-
4- (1- (2-Fluoro-4-biphenylyl) ethyl) -2-amino-from ethyl 4-biphenylyl) ethyl) -2-amino-5-thiazolecarboxylate
5-thiazolecarboxylic acid was obtained. Melting point 155-158 ° C

Example 5

[Chemical 20] In the same manner as in Example 2, 4- (1- (2-fluoro-
4'-methoxy-4-biphenylyl) ethyl) -2-
From ethyl methylamino-5-thiazolecarboxylate, the desired 4- (1- (2-fluoro-4′-methoxy-4-
Biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylic acid was obtained. Melting point 167.5-168 ° C (decomposition)

Example 6

[Chemical 21] 4- (1- (4'-acetyl-2-fluoro-4-biphenylyl) ethyl) -2- in the same manner as in Example 2
From ethyl methylamino-5-thiazolecarboxylate, the desired 4- (1- (4'-acetyl-2-fluoro-4-
Biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylic acid was obtained. Melting point 158-159 ° C (decomposition)

Example 7

[Chemical formula 22] In the same manner as in Example 2, 4- (1- (2-fluoro-
4'-Nitro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylate ethyl 4- (1- (2-fluoro-4'-nitro-4-biphenylyl) ethyl)- 2-Methylamino-5-thiazolecarboxylic acid was obtained. Melting point 158-160 ° C

Example 8

[Chemical formula 23] In the same manner as in Example 2, the target 4- (1- (3-benzoylphenyl) ethyl) was obtained from ethyl 4- (1- (3-benzoylphenyl) ethyl) -2-methylamino-5-thiazolecarboxylate. 2-Methylamino-5-thiazolecarboxylic acid was obtained. Melting point 154-157 ° C (decomposition)

Example 9

[Chemical formula 24] In the same manner as in Example 2, the target 2- (4- was obtained from ethyl 2- (4- (1- (2-fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolyl) acetate.
(1- (2-fluoro-4-biphenylyl) ethyl)
2-Methylamino-5-thiazolyl) acetic acid was obtained. Melting point 102-105 ° C

Example 10

[Chemical 25] The target compound was obtained from methyl 3- (4- (1- (2-fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolyl) propionate in the same manner as in Example 2.
-(4- (1- (2-fluoro-4-biphenylyl))
Ethyl) -2-methylamino-5-thiazolyl) propionic acid was obtained. Melting point 179-180 ° C Example 11

[Chemical formula 26] In the same manner as in Example 2, the desired 4-(-(1- (4′-ethoxycarbonyl-2-fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylate was obtained from the desired 4- ( 1- (4'-Carboxy-2-fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylic acid was obtained. Melting point 172-175 ° C (decomposition)

Example 12

[Chemical 27] Of 4- (1- (2-fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylic acid (5.00 g, 14.0 mmol) and dimethylformamide (1.03 g, 14.1 mmol) Oxalyl chloride (3.93 g, 31.0 mmol) was added dropwise to a methylene chloride (200 ml) solution while stirring with ice cooling, and 4
Stir for 0 minutes. Separately, a solution of hydroxylamine hydrochloride (3.91 g, 56.3 mmol) in water (5 ml) and triethylamine (8.55 g, 84.5 mmo).
l) was added to tetrahydrofuran (100 ml) to prepare a solution, and the above thiazolecarboxylic acid reaction solution was added dropwise to the solution under ice-cooling stirring, followed by stirring for 30 minutes. The reaction solution was acidified with 1M hydrochloric acid (pH 4) and extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The obtained residue is purified by a silica gel column and the desired 4- (1-
(2-Fluoro-4-biphenylyl) ethyl) -2-
Methylamino-5-thiazolecarbohydroxamic acid (2.50 g, 6.73 mmol, 48%) was obtained as a pale brown amorphous. Melting point 118 ° C

Example 13

[Chemical 28] In the same manner as in Example 11, the target N-methyl-4 was obtained from 4- (1- (2-fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylic acid.
-(1- (2-Fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarbohydroxamic acid was obtained. Melting point 82-84 ° C

Example 14

[Chemical 29] In the same manner as in Example 11, the target N-methoxy- was obtained from 4- (1- (2-fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylic acid.
4- (1- (2-Fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolylamide dihydrochloride was obtained. Melting point 66-68 ° C

Reference Example 1

[Chemical 30] 1,2-Dichloroethane (110 ml) was added to dimethylformamide (33.3 g), and phosphorus oxychloride (10.5 g, 68.5 mmol) was added to 1,2-dichloroethane (10.5 g) under ice-cooling stirring.
-Dichloroethane (40 ml) solution was added dropwise, and after completion of the addition, the mixture was stirred at room temperature for 15 minutes. Ice-cool again, 2- (N-
t-butoxycarbonyl-N-methyl) amino-4-
(1- (2-fluoro-4-biphenylyl) ethyl)
Thiazole (18.9 g, 45.8 mmol) 1,2
-Add dichloroethane (300 ml) solution dropwise to the reaction mixture,
After completion of the dropping, the mixture was stirred at room temperature for 1 hour and then refluxed for 4 hours. The solvent of the reaction solution was evaporated under reduced pressure, 10% aqueous sodium hydroxide solution (36 ml) was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is purified by silica gel column chromatography, and 5-formyl-4- (1- (2-
Fluoro-4-biphenylyl) ethyl) -2-methylaminothiazole (6.99 g, 20.5 mmol, yield 45%) was obtained as pale yellow crystals. Melting point 126-128 ° C

Reference Example 2

[Chemical 31] 4- (2,4'-difluoro-4-biphenylyl)-
Ethyl 3-oxopentanoate (1.00 g, 3.01 m
mol) and methanol (97 mg, 3.03 mmo
l) was dissolved in methylene chloride (3.0 ml) and cooled under ice,
A solution of sulfuryl chloride (427 mg, 3.16 mmol) in methylene chloride (1 ml) was added dropwise, and the mixture was stirred for 1 hour.
The solvent was distilled off at a low temperature, and the residue was methanol (10 ml).
Dissolved in N-methylthiourea (326 mg,
3.62 mmol) was added and the mixture was stirred at 50 ° C. for 1 hour. Further, N-methylthiourea (100 mg) was added, and the mixture was stirred for 1 hour and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by a silica gel column and the objective ethyl 4- (1- (2,4'-fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylate (1.06 g) was obtained. , 2.62 mmo
l, yield 87%) was obtained as a white amorphous. 1H-NMR (CDCl3) δ ppm: 1.35 (3
H, t), 1.61 (3H, d), 2.97 (3H,
d), 4.23-4.33 (2H, m), 5.21 (1
H, q), 5.52 (1H, br), 7.07-7.5.
0 (7H, m).

Reference Example 3

[Chemical 32] 4- (2-Fluoro-4'- by the same method as in Reference Example 2
From ethyl methoxy-4-biphenylyl) -3-oxopentanoate, ethyl 4- (1- (2-fluoro-4′-methoxy-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylate was obtained. Obtained. 1H-NMR (CDCl3) δ ppm: 1.35 (3
H, t), 1.62 (3H, d), 2.95 (3H,
d), 3.84 (3H, s), 4.23-4.33 (2
H, m), 5.20 (1H, q), 5.62 (1H, b
r), 6.93-7.47 (7H, m).

Reference Example 4

[Chemical 33] In the same manner as in Reference Example 4, 4- (4'-acetyl-2-
From ethyl fluoro-4-biphenylyl) -3-oxopentanoate, ethyl 4- (1- (4'-acetyl-2-fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylate was obtained. Obtained. 1H-NMR (CDCl3) δ ppm: 1.34 (3
H, t), 1.63 (3H, d), 2.62 (3H,
s), 2.90 (3H, d), 4.28 (2H, m),
5.25 (1H, q), 6.27 (1H, br), 7.
24-7.38 (7H, m).

Reference Example 5

[Chemical 34] 4- (2-Fluoro-4'- by the same method as in Reference Example 2
From ethyl nitro-4-biphenylyl) -3-oxopentanoate, 4- (1- (2-fluoro-4′-nitro-
4-biphenylyl) ethyl) -2-methylamino-5
-Ethyl thiazolecarboxylate was obtained. 1H-NMR (CDCl3) δ ppm: 1.34 (3
H, t), 1.63 (3H, d), 2.91 (3H,
d), 4.29 (2H, m), 5.26 (1H, q),
6.32 (1H, m), 7.31-7.34 (3H,
m), 7.65 (2H, dd), 8.24 (2H,
d).

Reference Example 6

[Chemical 35] In the same manner as in Reference Example 2, 4- (1- (3) was obtained from ethyl 4- (3-benzoylphenyl) -3-oxopentanoate.
-Benzoylphenyl) ethyl) -2-methylamino-
Obtained ethyl 5-thiazolecarboxylate. Melting point 176-177 ° C

Reference Example 7

[Chemical 36] By using thiourea instead of N-methylthiourea of Reference Example 2 in the same manner, from ethyl 4- (2-fluoro-4-biphenylyl) -3-oxopentanoate, 4-
(1- (2-fluoro-4-biphenylyl) ethyl)
Obtained ethyl-2-amino-5-thiazolecarboxylate. Melting point 147-148 ° C

Reference Example 8

[Chemical 37] In the same manner as in Reference Example 4, 4- (2-fluoro-4-biphenylyl) -3-oxopentanoate was used to give 4-
(1- (2-fluoro-4-biphenylyl) ethyl)
Ethyl 2-methylamino-5-thiazolecarboxylate was obtained. Melting point 108-109 ° C

Reference Example 9

[Chemical 38] Ethyl 4- (1- (2-fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolecarboxylate (3.55 g, 9.23 mmol), methyl iodide (2.81 g, 18.8 mmol). ) To benzene (70m
It was dissolved in 1), 50% aqueous sodium hydroxide solution (35 ml) and tetra-n-butylammonium hydrogensulfate (3.13 g, 9.22 mmol) were added thereto, and the mixture was stirred at room temperature for 5 hours and a half. Dilute the reaction mixture with water, pH with hydrochloric acid
After adjusting to 6, the mixture was extracted with ethyl acetate. Wash the organic layer with water,
The residue obtained by concentrating under reduced pressure after drying with sodium sulfate was purified with a silica gel column and the desired 4- (1- (2-fluoro-4)
-Biphenylyl) ethyl) -2-dimethylamino-5
-Ethyl thiazolecarboxylate (3.68 g, 9.23
(mmol, quantitative) colorless oil was obtained. 1H-NMR (CDCl3) δ ppm: 1.34 (3
H, t), 1.64 (3H, d), 3.14 (6H,
s), 4.27 (2H, m), 5.18 (1H, q

Reference Example 10

[Chemical Formula 39] 2- (2,4'-Difluoro-4-biphenylyl) propionic acid (1.20 g, 4.58 mmol) was suspended in toluene (10 ml), and dimethylformamide (2
Drop) and thionyl chloride (1.09g, 9.16mmo)
1) was added, and the mixture was stirred at 80 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and then toluene was further added and concentrated under reduced pressure to remove excess thionyl chloride to obtain an acid chloride. Meldrum's acid (1.32g, 9.16mmo
1) and pyridine (1.45 g, 18.3 mmol) were dissolved in 1,2-dichloroethane (15 ml), and while maintaining the temperature of the reaction system at 0 to 2 ° C., 1, 2 of the above acid chloride was dissolved.
A solution of 2-dichloroethane (5 ml) was added dropwise. After stirring at the same temperature for 1 hour, ethanol (1.06 g, 23.0
mmol) was added dropwise. After stirring at the same temperature for 20 minutes, 2
Reflux for hours. 5% Hydrochloric acid (10 ml) was added dropwise to the reaction solution to separate the organic layer. The organic layer was washed with water and 5% aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by a silica gel column, and ethyl 4- (2,4′-difluoro-4-biphenylyl) -3-oxopentanoate (1.02 g, 3.07 mmol, yield 67%) was obtained. Was obtained as a pale yellow oil. 1 H-NMR (CDCl3) δ ppm: 1.25 (3
H, t), 1.46 (3H, d), 3.43 (2H,
q), 4.96 (1H, q), 4.12-4.21 (2
H, m), 7.01-7.53 (7H, m).

Reference Example 11

[Chemical 40] 2- (2-fluoro-4 'by the same method as in Reference Example 10
4 from -methoxy-4-biphenylyl) propionic acid
Obtained ethyl-(2-fluoro-4'-methoxy-4-biphenylyl) -3-oxopentanoate. 1H-NMR (CDCl3) δ ppm: 1.24 (3
H, t), 1.52 (2H, d), 3.73 (1H,
q), 3.85 (3H, s), 4.09-4.22 (2
H, m), 6.96-7.50 (7H, m).

Reference Example 12

[Chemical 41] 2- (4′-acetyl-2) was prepared in the same manner as in Reference Example 10.
4-fluoro-4-biphenylyl) propionic acid
Obtained ethyl-(4'-acetyl-2-fluoro-4-biphenylyl) -3-oxopentanoate. 1 H-NMR (CDCl3) δ ppm: 1.25 (3
H, t), 1.47 (3H, d), 2.64 (3H,
s), 3.35-3.65 (2H, m), 3.99 (1
H, q), 4.76 (2H, q), 7.05-8.07.
(7H, m).

Reference Example 13

[Chemical 42] 2- (2-fluoro-4 'by the same method as in Reference Example 10
4-nitro-4-biphenylyl) propionic acid
(2-fluoro-4'-nitro-4-biphenylyl)
Ethyl-3-oxopentanoate was obtained. 1 H-NMR (CDCl3) δ ppm: 1.25 (3
H, t), 1.48 (3H, d), 3.45 (2H,
m), 4.02 (1H, q), 4.17 (2H, m),
7.09-7.18 (2H, m), 7.46 (1H,
t), 7.70-7.73 (2H, m), 8.27-
8.33 (2H, m).

Reference Example 14

[Chemical 43] By a method similar to that in Reference Example 10, ethyl 4- (3-benzoylphenyl) -3-oxopentanoate was obtained from 2- (3-benzoylphenyl) propionic acid. 1H-NM
R (CDCl3) δ ppm: 1.23 (3H, t),
1.47 (3H, d), 3.40 (2H, q), 4.0
1 (1H, q), 4.09-4.20 (2H, m),
7.45-7.82 (9H, m).

Reference Example 15

[Chemical 44] In the same manner as in Reference Example 10, 2- (2-fluoro-4-)
Biphenylyl) propionic acid (flurbiprofen)
4- (2-fluoro-4-biphenylyl) -3-
Obtained ethyl oxopentanoate. 1 H-NMR (CDCl3) δ ppm: 1.25 (3
H, t), 1.47 (3H, d), 3.43 (2H,
q), 3.97 (1H, q), 4.15 (2H, q),
7.06-7.55 (8H, m).

Reference Example 16

[Chemical 45] 5- (2-Fluoro-4-biphenylyl) -4-oxohexanoic acid (500 mg, 1.52 mmol) was dissolved in diethyl ether (10 ml), and bromine (243 mg, 1.52 mmol) was added thereto under ice cooling. The mixture was added dropwise and stirred at room temperature for 3 hours and a half. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in methanol, and N-methylthiourea (16
4 mg, 1.82 mmol) was added and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by medium pressure silica gel column chromatography to obtain the desired 2- (4- (1
-(2-Fluoro-4-biphenylyl) ethyl) -2
-Methylamino-5-thiazolyl) ethyl acetate (209
mg, 0.524 mmol, yield 35%) was obtained as a yellow oil. 1 H-NMR (CDCl3) δ ppm:
1.23 (3H, t), 1.62 (3H, d), 2.9
1 (3H, d), 3.57-3.71 (3H, m),
5.08 (1H, br), 7.12-7.53 (8H,
m).

Reference Example 17

[Chemical 46] 2- (3- (2-fluoro-4-biphenylyl) -2
-Oxobutyl) diethyl malonate (5.00 g, 1
2.5 mmol) was dissolved in acetic acid (100 ml) and 30% sulfuric acid (100 ml) and refluxed for 4 hours. After allowing to cool, the reaction solution was extracted with ether, the organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained is treated with ethanol (100
ml), concentrated sulfuric acid (1.0 g) was added, and the mixture was heated at 50 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with ether. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate and water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by medium pressure silica gel column chromatography,
Objective 5- (2-fluoro-4-biphenylyl) -4
-Oxohexanoic acid (2.21 g, 6.71 mmol,
Yield 54%) was obtained as a pale yellow oil. 1H-NMR (CDCl3) δ ppm: 1.23 (3
H, t), 1.45 (3H, d), 2.45-2.77.
(4H, m), 3.84 (1H, q), 4.10 (2
H, q), 7.02-7.56 (8H, m).

Reference Example 18

[Chemical 47] 60% sodium hydride (1.88 g, 47.0 mmo
l) was washed with hexane to remove the oil, dimethylformamide (DMF, 23 ml) was added thereto, and diethyl malonate (7.52 g, 47.
0 mmol) in DMF (5 ml) was added dropwise at 50 ° C.
After the temperature was raised to 1-chloro-3- (2-fluoro-4-biphenylyl) butan-2-one (10.0 g, 36.1
DMF (40 ml) solution of (mmol) was added dropwise, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured into ice water and extracted with diethyl ether. The organic layer was washed with 1M hydrochloric acid, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by medium pressure silica gel column chromatography to obtain the desired 2-
Diethyl (3- (2-fluoro-4-biphenylyl) -2-oxobutyl) malonate (8.98 g, 22.4)
mmol, yield 62%) was obtained as a pale yellow oil. 1H-NMR (CDCl3) δ ppm: 1.20-
1.31 (6H, m), 1.45 (3H, d), 2.9
3-3.13 (2H, m), 3.82-3.87 (2
H, m), 4.11-4.25 (4H, m), 7.01
-7.56 (8H, m).

Reference Example 19

[Chemical 48] 3- (4- (1- (2-fluoro-4-biphenylyl) ethyl) -2- (Nt-butoxycarbonyl-N
Methyl -methyl) amino-5-thiazolyl) propionate (1.00 g, 2.01 mmol) was dissolved in concentrated hydrochloric acid / acetic acid (1:11, 20 ml), and the mixture was stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 1 with 1M aqueous sodium hydroxide solution.
It was adjusted to 0 and extracted with chloroform. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by a silica gel column to obtain the desired 3- (4- (1- (2
Methyl -fluoro-4-biphenylyl) ethyl) -2-methylamino-5-thiazolyl) propionate (47
8 mg, 1.20 mmol, yield 60%) was obtained. 1H-NMR (CDCl3) δ ppm: 1.62 (3
H, d), 2.52 (2H, t), 2.89 (3H,
d), 2.90-3.11 (2H, m), 3.66 (3
H, s), 4.12 (1H, q), 5.06 (1H, b
r), 7.13-7.53 (8H, m).

Reference Example 20

[Chemical 49] 3- (4- (1- (2-fluoro-4-biphenylyl) ethyl) -2- (Nt-butoxycarbonyl-N
Methyl -methyl) amino-5-thiazolyl acrylate (1.80 g, 3.62 mmol) was added to ethanol (20
0 ml), 10% palladium carbon (2.7 g) was added thereto, and hydrogenated at room temperature. When the consumption of hydrogen was stopped, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure. The resulting residue is purified by medium pressure silica gel column chromatography to obtain the desired 3-
Methyl (4- (1- (2-fluoro-4-biphenylyl) ethyl) -2- (Nt-butoxycarbonyl-N-methyl) amino-5-thiazolyl) propionate (1.10 g, 2.21 mmol) , Yield 60%) was obtained. In addition, 500 mg (1.00 mmol, 2
8%) recovered. 1H-NMR (CDCl3) δ ppm: 1.56 (9
H, s), 1.64 (3H, d), 2.55 (2H,
t), 2.93-3.11 (2H, m), 3.53 (3
H, s), 3.66 (3H, s), 4.16 (1H,
q), 7.15-7.54 (8H, m).

Reference Example 21

[Chemical 50] 60% sodium hydride (904 mg, 22.6 mmo
l) was suspended in dimethyl sulfoxide (25 ml), and methyldiethylphosphonoacetate (4.7
5 g, 22.6 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. To this was added 5-formyl-4- (1- (2-fluoro-4-biphenylyl) ethyl) -2- (Nt-butoxycarbonyl-N-methyl) aminothiazole (5.0 g, 11.3 mmol). A dimethylformamide (5.0 ml) solution was added dropwise, and the mixture was heated with stirring at 80 ° C. for 10 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by a silica gel column to obtain the desired 3- (4
Methyl-(1- (2-fluoro-4-biphenylyl) ethyl) -2- (Nt-butoxycarbonyl-N-methyl) amino-5-thiazolyl) acrylate (E,
Z mixture, 1.90 g, 3.83 mmol, yield 34
%) Was obtained. 1 H-NMR (CDCl3) δ ppm: 1.58 (9
H, s), 1.65 (3H, d), 3.11 & 3.55
(Total 3H, each), 3.77 (3
H, d), 4.32 & 4.42 (total 1H, e
achs), 5.70 & 6.05 (total 1
H, each d), 7.17-7.53 (8H,
m), 7.89 & 8.10 (total 1H, eac
h s).

Reference Example 22

[Chemical 51] Dimethylformamide (188.5g, 2.58mo
l) with 1,2-dichloroethane (EDC, 623 ml)
Dissolved in water and stirred under ice-cooling with phosphorus oxychloride (59.
A solution of 4 g) of EDC (226 ml) was slowly added dropwise, and the mixture was stirred at room temperature for 15 minutes. Cool it again with ice, 4- (1
-(2-Fluoro-4-biphenylyl) ethyl) -2
EDC (1 of-(Nt-butoxycarbonyl-N-methyl) aminothiazole (107 g, 259 mmol)
132 ml) solution was added dropwise over 40 minutes and then at room temperature for 1
Stir for hours. After refluxing for another 3 hours, the mixture was concentrated under reduced pressure. A solution of sodium hydroxide (193 g) in water (1930 ml) was slowly added to the obtained residue while cooling with ice,
It was extracted with chloroform. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by medium pressure silica gel column chromatography to give the desired 5-formyl-4-
(1- (2-fluoro-4-biphenylyl) ethyl)
2- (Nt-butoxycarbonyl-N-methyl) aminothiazole (31.7 g, 72.0 mmol, yield 28%) was obtained. 1 H-NMR (CDCl3) δ ppm: 1.58 (9
H, s), 1.78 (3H, d), 3.61 (3H,
s), 4.73 (1H, q), 7.06-7.55 (8)
H, m), 10.12 (1H, s).

Reference Example 23

[Chemical 52] 4- (1- (2-fluoro-4-biphenylyl) ethyl) -2-methylaminothiazole (100 g, 320
mmol) and di-t-butyl dicarbonate (175 g, 80
2 mmol) in tetrahydrofuran (THF, 750 m
1) and dissolved in 1,8-diazabicyclo [5.4.0] -7-undecene (DBU, 60) under ice-cooling stirring.
g, 394 mmol) in THF (90 ml) was added dropwise, and the mixture was heated at 50 ° C. for 13 hours. The residue obtained by concentrating the reaction solution under reduced pressure was diluted with chloroform and washed with water, 1M hydrochloric acid (three times), and water in this order. After drying the organic layer with sodium sulfate,
The residue obtained by concentration under reduced pressure was purified by medium pressure silica gel column chromatography, and the obtained crystals were washed with methanol to give the desired 4- (1- (2-fluoro-4-biphenylyl) ethyl). -2- (Nt-butoxycarbonyl-N-methyl) aminothiazole (109 g, 2
(63 mmol, yield 82%) was obtained as white crystals. Melting point 98-98.5 ° C

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location A61K 31/425 ABG ACD (72) Inventor Yoshihiko Kimura 3-1, 98 Kasuga, Konohana-ku, Osaka No. Sumitomo Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. A general formula [1]: [In the formula, A represents a single bond, a linear or branched lower alkylene group, or a linear or branched lower alkenylene group, and B represents a single bond or -CO-. R1 is a carboxy group or -CONR7 OR8 (R7, R8
Each independently represent a hydrogen atom or a lower alkyl group), R2 represents a lower alkyl group, R3 and R4 each independently represent a hydrogen atom, a lower alkyl group, or a lower alkoxycarbonyl group, and R5 represents R6 represents a hydrogen atom or a halogen atom, and R6 represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a thiol group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a nitro group, an amino group. ,
It represents a substituted amino group, a cyano group, a carboxy group, or an acyl group. ] The novel thiazole derivative represented by these, or its pharmaceutically acceptable salt.