JPH02193990A - Thiophenecarboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (X represents halogen, 5-7C cycloalkyl, lower alkyl or lower alkoxy; Y represents H or lower alkyl; R represents H, lower alkyl or benzyl; dotted line may represent double bond). EXAMPLE:2,3-Dihydro-5-(4-methylphenyl)thiophene-3-carboxylic acid. USE:A remedy for autoimmune disease such as rheumatoid arthritis and systemic lupus erythematosus without side effect. PREPARATION:For example, a compound expressed by formula II (R' represents lower alkyl or phenyl) is reacted with a base (example; sodium hydroxide or ammonia) or an acid (example; sulfuric acid or paratoluenesulfonic acid). The amount of the base used is 1-5mol equivalents based on the compound expressed by formula II and that of the acid is 1-10mol equivalents based on the compound expressed by formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel thiophenecarboxylic acid derivative, and more particularly to a thiophenecarboxylic acid derivative effective in treating autoimmune diseases such as rheumatoid arthritis.

There are several therapeutic agents for rheumatoid arthritis, which is one of the autoimmune diseases. and so on. Anti-inflammatory drugs are symptomatic treatments and cannot be used as fundamental therapeutic agents. On the other hand, therapeutic agents for immune diseases have recently been attracting attention as agents for treating the cause, but these agents are not always satisfactory in terms of efficacy, side effects, toxicity, etc.

Compounds having a structure similar to the compound of the present invention include those described in U.S. Pat.
Compounds described in Japanese Patent No. 575 and the like are known, but none are known as therapeutic agents for immune diseases.

SUMMARY OF THE INVENTION An object of the present invention is to provide a drug that is useful for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic erythematosus and has no side effects.

As a result of extensive research, the present inventors have discovered that certain thiophenecarboxylic acid derivatives have a strong effect on the immune system, and have also been found to be effective against adjuvant arthritis (rheumatoid arthritis, a typical autoimmune disease). The present invention has been completed based on the discovery that the present invention has an excellent effect on a pathological model (pathological model).

The present invention will be explained in detail below.

The present invention is based on the formula I (wherein, , a lower alkyl group or a benzyl group, and a dotted line indicates that the bond at that position may be a double bond.

) and immunological disease therapeutic agents containing these as active ingredients.

In the present invention, a halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and has 5 to 7 carbon atoms.
The cycloalkyl group is a cyclopentyl group, a cyclohexyl group or a cycloheptyl group. A lower alkyl group is an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a lower alkoxy group is an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group. group, isopropoxy group, etc.

The compound represented by formula (1) can be produced, for example, by the following method.

That is, the following formula (1), which is publicly known (described in JP-A No. 60-258160) (wherein, X, Y and R have the same meanings as above, and R' is a lower alkyl group or a phenyl group) By reacting the compound shown with a base or an acid, the compound of the present invention shown by the following formula (1) (wherein, X, Y and R have the same meanings as defined above) can be obtained. In this reaction, when a base is used, the base refers to sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide, lithium hydroxide, ammonia, methylamine, ethylamine,
It is an organic primary amine such as hydrazine, and is used in an amount of 1 to 5 molar equivalents relative to the compound of formula (1). The reaction solvent is methanol, ethanol, acetone, dioxane, tetrahydrofuran, dimethylformamide, or a mixed solvent of these and water. The reaction temperature is 0° C. to the reflux temperature of the solvent, and the reaction time is 1 to 24 hours. In addition, when an acid is used, the acid is a mineral acid such as sulfuric acid or hydrochloric acid, or an organic acid such as para-toluenesulfonic acid, and the reaction solvent used in an amount of 1 to 10 molar equivalents for the compound of formula I is water, methanol, etc. , ethanol, propatool, isopropanol, etc., and by selecting these solvents, R in (2) can be arbitrarily introduced. The reaction temperature is 20° C. to the reflux temperature of the solvent, and the reaction time is 1 to 24 hours.

Compound 2) can be reacted with a dehydrogenating agent to form the compound of the present invention represented by the following formula 2 (wherein, X, Y and R have the same meanings as defined above). The dehydrogenating agent used in this reaction may be any dehydrogenating agent used in similar reactions, such as 2,3-dichloro-5,6-dicya-to-1°4-benzoquinone (hereinafter referred to as DDQ), etc. Reaction solvents include benzene, toluene, xylene, tetrahydrofuran, dioxane, and acetone. The reaction temperature is 0°C to the reflux temperature of the solvent, and the reaction time is 0.5 to 24 hours.

The substituent R of the compound of the present invention represented by 2) can be converted from a hydrogen atom to an alkyl group or a benzyl group, or from an alkyl group or a benzyl group to a hydrogen atom. That is, when the substituent R of the compound of formula (1) is an alkyl group or a benzyl group, the compound of the present invention (2), in which R is a hydrogen atom, can be obtained by a normal ester hydrolysis reaction (alkaline hydrolysis). can. On the other hand, when the substituent R of the compound of formula (1) is a hydrogen atom, the present invention of formula (2) in which R is an alkyl group or a benzyl group is obtained by reacting with a corresponding alkylating agent or benzylating agent in the presence of a base. It can be a compound. Bases used in this reaction include sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogen carbonate, sodium hydride, and sodium hydroxide. Alkylating agents include alkyl halides such as methyl iodide, ethyl iodide, and propyl bromide, dialkyl sulfates such as dimethyl sulfate and diethyl sulfate, and benzylating agents include benzyl iodide, benzyl bromide, etc. It is. As the solvent, N,N-dimethylformamide, hexamethylphosphoric triamide, dimethyl sulfoxide, etc. are used.

The compound represented by the formula (1), which is the object of the present invention, has an excellent effect on adjuvant arthritis in rats, and also has an immunomodulatory effect on the blastogenesis of lymphocytes. Therefore, it is useful for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic erythematous lupus, as well as diseases based on immune dysfunction such as cancer, bacterial infections, and asthma.

For this purpose, the compounds of the present invention may be prepared in tablets, tablets, capsules, granules, etc., which can be prepared according to conventional formulation techniques.
It can be administered in dosage forms such as injections and liquids.

In each of the above formulations, conventional additives such as fillers, binders, disintegrants, pH adjusters, solubilizers and the like can be used.

The dosage of the compound of the present invention for a patient to be treated may vary depending on the patient's age, type of disease, condition, etc., but usually 10 to 1500 mg can be administered in one to several doses per day.

The usefulness of the compounds of the present invention will be shown below in test examples.

Test Example 1 [Effect on adjuvant arthritis (chronic rheumatoid arthritis pathology model)] 8 Appropriate-age Sprague-Dawley rats (body weight 160-1
(90g) 10 animals were used in the test as one group.

Rats in each group were sensitized by intradermally injecting a suspension of 0.6H of killed tuberculosis cells (bovine type) in O.Lml of liquid paraffin into the tails of each group. Various compounds of formula I were used as test drugs.
% gum arabic solution, and 100 mg/kg of the compound of formula (1) was orally administered to rats in separate groups once a day from the day of sensitization for 20 consecutive days. For the control group, only 5% gum arabic solution was used and was orally administered to rats in the same manner. The volume of edema in the hind limbs was measured over time from the day of sensitization, and the swelling suppression rate of the drug administration group relative to the control group was calculated. The results on the 21st day after sensitization are shown in Table 1.

(Note) A: 2.3-dihydro-5-(4-methylphenyl)thiophene-3-carboxylic acid B: 5-(4-methylphenyl)thiophene-3-carboxylic acid C: 5-(4-isopropyl) Phenylthiophene-3
-Carboxylic acid D: 5-(4-chlorophenyl)thiophene-3-carboxylic acid E: 5-(4-';/romphenyl)thiophene-3-
Carboxylic acid test example 2 [Acute toxicity test] 7-week-old Wistar male rats (body weight 149-160
g) Seven animals were used in the test as one group.

A suspension of 5-(4-methylphenylrubonic acid in a 5% gum arabic solution) was orally administered to the rats, and the progress was observed for 7 days after administration to determine the LD. value.

As a result, L D s. The value was over 1500 mg.

EXAMPLES Hereinafter, the method for producing the compound of the present invention will be explained in detail in Examples.

Example 1 2-Acetylthiomethyl-3-(4-methylbenzoyl)propionic acid 2.80 g of tetrahydrofuran (20
ml) solution, add 0.0% 80% hydrazine hydrate aqueous solution under stirring at room temperature. 8ynll was added dropwise, and the mixture was further stirred at the same temperature for 1 hour. Dilute hydrochloric acid was added to the reaction solution to make it weakly acidic, and the mixture was extracted with ether. The extract was washed with water, dried over magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography using hexane-dichloromethane-ether as a developing solvent, and then recrystallized from hexane-dichloromethane to obtain 2,3-dihydro-5-(4-methylphenyl)thiophene-3-carboxylic acid 1. .34g was obtained.

m. p. 112-114°C Example 2 2-Acetylthiomethyl-3-(4-brombenzoyl)propionic acid 3. A solution of concentrated sulfuric acid (1 ml) in methanol (20 ml) was added to 45 g, and after heating under reflux for 5 hours, methanol was distilled off. Dissolve the residue in ethyl acetate,
After washing with water, a saturated aqueous sodium bicarbonate solution, and water in this order, it was dried over magnesium sulfate. Ethyl acetate was distilled off, and the residue was diluted with hexane.
Recrystallized from ether to give 5-(4-bromphenyl)-
2.Methyl 3-dihydrothiophene-3-carboxylate 2
．． 42g was obtained.

m. p. 55-57°C Example 3 Same as Example 2, 2-acetylthiomethyl-3-(4
2.15 g of oily methyl 2.3-dihydro-5-(4-methylphenyl)thiophene-3-carboxylate was obtained from 2.80 g of -methylbenzoyl)propionic acid.

N M R (CDCI13) δ (ppm); 2,
34 (3H. 5) 3, 50 (IH. dd. J=11Hz. 9Hz
) 3, 72 (IH.dd.J=11Hz.7)1z)3
, 75 (3H. 9) 4, 15 (1) 1. m) 5,93 (LH, d, J=2Hz) 7,13 (IH, d, J=8Hz) 7,37<2H. d. J=8Hz> Example 4 Methyl 5-(4-bromphenyl)-2.3-dihydrothiophene-3-carboxylate 2. Dissolve 99 g in 20 ml of benzene, and add 2.50 g of DDQ to 3 ml under stirring at room temperature.
The mixture was added over a period of 0 minutes, and after stirring at the same temperature for an additional 30 minutes, insoluble materials were filtered off. The filtrate was washed with a saturated aqueous sodium bicarbonate solution, then with water, and dried over magnesium sulfate. After distilling off the benzene, the residue was recrystallized from hexane-ether to give 5-(
Methyl 4-bromphenyl)thiophene-3-carboxylate2. 61 g was obtained.

m. p. 90-92.5°C Example 5 Same as Example 4, methyl 2.3-dihydro-5-(4-methylphenyl)thiophene-3-carboxylate 2.
34 g to 5-(4-methylphenyl>thiophene-
2.09 g of methyl 3-carboxylate was obtained.

m. p. go ~ 82°C Example 6 (1) Same as Example 2, 2-acetylthiomethyl-3
-(4-chlorobenzoyl)propionic acid 3,01 g
2.55 g of crude methyl 5-(4-chlorophenyl)-2,3-dihydrothiophene-3-carboxylate from
I got it.

(2) This was treated in the same manner as in Example 4, and 2.2% of methyl 5-(4-chlorophenyl)thiophene-3-carboxylate was obtained.
0 g was obtained.

m, p, 68-70°C Using the corresponding starting materials, the following compounds were obtained according to Example 6.

Methyl 5-(4-ethylphenyl)thiophene-3-carboxylate m, p, 63-67°C Methyl 5-(4-isopropylphenyl)thiophene-3-carboxylate m, p, 33-34°C 5-( Methyl 4-methoxyphenyl)thiophene-3-carboxylate m, p, 100-101°C 3-(4-cyclohexylphenyl)thiophene-3-
Methyl carboxylate m, p, 94-95°C Example 7 (1) In Example 2, 20 ml of ethanol was used instead of methanol and treated in the same manner to obtain oily crude 5-(4
-bromphenyl)-2,3-dihydrothiophene-3
-3.10 g of ethyl carboxylate was obtained.

(2) This was treated in the same manner as in Example 4, and 1.7 ethyl 5-(4-fromophenyl)thiophene-3-carboxylate was obtained.
4 g was obtained.

m, p, 77-79°C Example 8 Same as Example 7, 2-acetylthiomethyl-3-(4
-methylbenzoyl)propionic acid 2.80 g to 5
-(4-methylphenyl)thiophene-3-carboxylic acid ethyl 1.45K was obtained.

m, p, 35-37°C Example 9 Same as Example 7, 2-acetylthiomethyl-3-(4
-chlorobenzoyl)propionic acid 3.01g to 5-
1.79 g of ethyl (4-chlorophenyl)thiophene-3-carboxylate was obtained.

m, p, 69-70°C Example 10 2.32 g of methyl 5-(4-methylphenyl)thiophene-3-carboxylate was dissolved in 20 mQ of tetrahydrofuran, and potassium hydroxide (2.0 g) in water was added with stirring at room temperature. - dropwise addition of methanol (1:5) (10 m) solution,
The mixture was further stirred at room temperature for 4 hours. After the reaction, methanol was distilled off, the residue was dissolved in water, washed with ether, made weakly acidic by adding diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from ethyl acetate to obtain 2.01 g of 5-(4-methylphenyl)thiophene-3-carboxylic acid.

m, p, 192-193°C Example 11 Corresponding compounds (R-C
H1) and the following compound (2) according to Example 10.
R-H) was obtained in the compound.

5-(4-ethylphenyl)thiophene-3-carboxylic acid m, p, 196-197°C 5-(4-isopropylphenyl)thiophene-3-carboxylic acid ffi, p, 204-205°C 5-(4- Chlorphenyl)thiophene-3-carboxylic acid m, p, 204-206°C 5-(4-bromphenyl)thiophene-3-carboxylic acid m, p, 212-213°C 5-(4-methoxyphenyl)thiophene- 3-carboxylic acid ff1. p, 196-198°C 5-(4-cyclohexylphenyl)thiophene-3-
Carboxylic acid m, p, 247-249°C Example 12 2.83 g of 5-(4-bromphenyl)thiophene-3-carboxylic acid was dissolved in 30 m of N,N-dimethylformamide.
1, 4 Oml of isopropylbromide, and 2.7 g of potassium carbonate were added, and the mixture was heated and stirred at 60°C for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, the extract was washed with water, dried over magnesium sulfate, and then the solvent was distilled off. The residue was recrystallized from hexane to give 2.5 g of isopropyl 5-(4-bromphenyl)thiophene-3-carboxylate.
0 g was obtained.

m, p, 77-79°C Example 13 Benzyl bromide instead of isopropyl bromide 2.
5 g of benzyl 5-(4-bromphenyl)thiophene-3-carboxylate was prepared in the same manner as in Example 12.
．． 87 g was obtained.

m, p, 63-66°C Example 14 Same as Example 6, 2-acetylthiomethyl-3-(2
,5-dimethylbenzoyl)propionic acid 2.94 g
from 5-(2,5-dimethylphenyl)thiophene-3
-2.04 g of methyl carboxylate was obtained.

N M R (CDCR3) δ (ppm); 2, 34 (
3H, s) 2, 38 (3H, s) 3, 89 <31.9> 7, 08 (LH, d, J = 8 Hz) 7, 17 (IH, d, J = 8 Hz) 7, 20 (18, 8 > 7, 44 (LH, d, J = 2 Hz > s, 09 (IH, d, J = 2 Hz) Example 15 Similar to Example 4, 5-(2,5-dimethylphenyl)
2.46 g of methyl thiophene-3-carboxylate to 5-
2.09 g of (2,5-dimethylphenyl)thiophene-3-carboxylic acid was obtained.

m, p, 119-120°C Example 16 600 g of the compound obtained in Example 10, crystalline cellulose 12
0g and 126g of l-corn corn starch were mixed to make a uniform mixed powder, and 45g of hydroxypropylcellulose was mixed.
Granules were prepared by wet granulation using as a binder. After mixing 9 g of magnesium stearate with this, it was compressed into tablets.
3,000 tablets each having a diameter of 9 mm and a weight of 300 mg were obtained.

Example 17 600 g of the compound obtained in Example 10, crystalline cellulose 15
0 g, ) 140 g of corn corn starch and 10 g of magnesium stearate were uniformly mixed.

This mixed powder was filled into No. 1 hard capsules at a rate of 300 mg per capsule to obtain 3,000 capsules.

Example 18 200 g of the compound obtained in Example 10, 30 g of mannitol
0g, corn starch 450g, and magnesium stearate 10g to make a uniform mixed powder,
Granules were prepared by wet granulation using 50 g of hydroxypropyl cellulose as a binder to obtain granules i and ooog.

Example 19 A powder was prepared by uniformly mixing 200 g of the compound obtained in Example 10 and 800 g of lactose.
Each powder was divided into 1,000 packages to obtain 1,000 packages.

Claims (2)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X represents a halogen atom, a cycloalkyl group having 5 to 7 carbon atoms, a lower alkyl group, or a lower alkoxy group, and Y represents a hydrogen atom or a lower alkyl group. R represents a hydrogen atom, a lower alkyl group, or a benzyl group, and the dotted line indicates that the bond at that position may be a double bond. (2) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X represents a halogen atom, a cycloalkyl group having 5 to 7 carbon atoms, a lower alkyl group, or a lower alkoxy group, and Y represents a hydrogen atom or a lower alkyl group. R represents a hydrogen atom, a lower alkyl group, or a benzyl group, and the dotted line indicates that the bond at that position may be a double bond.) The active ingredient is a thiophenecarboxylic acid derivative represented by Immune disease treatment agent.