WO1996002529A1

WO1996002529A1 - Thiopheneacetic acid derivative

Info

Publication number: WO1996002529A1
Application number: PCT/JP1995/001393
Authority: WO
Inventors: Kazuyuki Tomisawa; Masahiro Hasegawa; Morihiro Mitsukuchi; Katsuo Hatayama
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 1994-07-13
Filing date: 1995-07-12
Publication date: 1996-02-01
Also published as: AU2936295A

Abstract

A thiopheneacetic acid derivative represented by general formula (I) and a salt thereof, each having an inflammatory cytokine production inhibitor effect and an antiphlogistic and analgesic effect and being efficacious in treating autoimmune diseases such as rheumatoid arthritis, wherein X represents hydrogen, halogen, lower alkyl, C5-C7 cycloalkyl or lower alkoxy; and R represents hydrogen or lower alkyl.

Description

Description Thiophene acetic acid derivative Technical field

The present invention relates to a novel thiopheneacetic acid derivative, and more particularly to a thiopheneacetic acid derivative effective for treating autoimmune diseases such as rheumatoid arthritis.

Background art

Therapeutic agents for rheumatoid arthritis include anti-inflammatory drugs (diclophanac, piroxicam, etc.) used symptomatically to suppress inflammation, and immunomodulators (auranofin, D —Penicillamine, oral benzalite, etc.).

Rheumatoid arthritis is a progressive inflammatory disease, and the main site of the lesion is the joint synovium.In recent years, cytodynamics has been attracting attention as a molecule that causes synovial lesions and synovial proliferation. . Of these, interleukin-1, 1, 6 and 8 are overproduced at the lesion site, and the amount of production is well correlated with the degree of synovial tissue inflammation and the degree of joint bone fracture.

Therefore, drugs that suppress these cytokines are expected to have effects on cartilage destruction, abnormal synovial cell proliferation, and immune abnormalities that are difficult to treat with existing drugs.

On the other hand, rheumatism has been used in combination with immunomodulators and non-steroid anti-inflammatory drugs, but the frequency of side effects on patients due to the administration of both drugs has been a major issue.

Accordingly, an object of the present invention is to provide a novel thiopheneacetic acid derivative having an inflammatory cytokine production inhibitory action and an anti-inflammatory analgesic action, which is useful for treating autoimmune diseases such as rheumatoid arthritis.

Disclosure of the invention

As a result of intensive studies, the present inventors have found that a certain thiopheneacetic acid derivative can achieve the above-mentioned object, and further conducted research based on the findings. Ming completed.

That is, an object of the present invention is to provide a compound of the formula (I)

(In the formula, X represents a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group having 5 to 7 carbon atoms, or a lower alkoxy group, and R represents a hydrogen atom or a lower alkyl group.) A thiopheneacetic acid derivative represented by the formula:

It is another object of the present invention to provide thiophaninacetic acid derivatives of formula (I) and salts thereof for use as an active ingredient in a pharmaceutical composition.

Still another object of the present invention is to provide a pharmaceutical composition containing a thiopheneacetic acid derivative of the formula (I) or a salt thereof as an active ingredient.

Still another object of the present invention is to provide use of a thiopheneacetic acid derivative of the formula (I) and a salt thereof for producing a pharmaceutical composition for treating an autoimmune disease. Still another object of the present invention is to provide a method for treating an autoimmune disease, which comprises administering to a human an effective amount of a thiopheneacetic acid derivative of the formula (I) or a salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, a halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and a lower alkyl group is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, etc. It is an alkyl group having 1 to 4 carbon atoms. Cycloalkyl groups having 5 to 5 carbon atoms include cyclopentyl, cyclohexyl, and cyclobutyl groups, and lower alkoxy groups include carbon atoms such as methoxy, ethoxy, propoquine, and isopropoxy groups. 1 to 4 lower alkoxy groups

Examples of the salt of the thiopheneacetic acid derivative of the formula (I) include an alkali metal salt and an alkaline earth metal salt of the thiophenic acid derivative of the formula (I) when R in the formula (I) represents a hydrogen atom. Metal salts or amine salts may be mentioned.

Examples of the alkali metal salt include a salt with an alkali metal such as sodium, potassium, and lithium. Examples of the alkaline earth metal salt include a salt with an alkaline earth metal such as calcium. Examples of the amine salt include alkylamines such as methylamine, ethylamine, and propylamine; dialkylamines such as dimethylamine, getylamine, and di-n-propylamine; trialkylamines such as triethylamine; and piperidine, morpholine, piperazine, and pyrrolidine. Salts with a heterocyclic amine compound and the like can be mentioned.

The thiophenin acetic acid derivative represented by the formula (I) (hereinafter abbreviated as compound (I)) is prepared, for example, by a method shown in the following reaction scheme 1 or reaction scheme 2 to give a 5-phenylphenyl acetic acid derivative represented by the formula (IV) The compound can be produced by obtaining an olefin-3-acetonitrile derivative (IV), followed by hydrolysis and further esterification by the method shown in Reaction Scheme 3.

Reaction Scheme 1

(IV)

Wherein X is as defined above. Reaction scheme 2

CO, R ¹ H, OH

Halogenation

(V) (VI)

(VII) (IV)

(In the formula, Y represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom. X has the same meaning as described above, and R ¹ represents a hydrogen atom or a lower alkyl group.) Reaction Scheme 3

Hydrolysis

(IV)

(la) (lb)

(Wherein, X is as defined above, and R ² represents a lower alkyl group)

(1) Preparation of 5-phenylthiophene-3-acetonitrile derivative (IV) i) As shown in Reaction Scheme 1, first, the method of AR Surrey et al. [Journal of American Chemical Society, Vol. 33 (1944)] or a method analogous thereto can be used to convert the 2-phenylthiolane-14one derivative (Π) represented by the formula (11), which can be easily produced from a cinnamic acid ester derivative, with cyanoacetic acid. Condensation ¾carbonate To give a compound of formula (Π Π). Subsequently, the obtained compound (III) is dehydrogenated with a suitable dehydrogenating agent to obtain a 5-fluorothiophene-3-aceto-2-tril derivative (IV).

In the above condensation decarboxylation reaction, it is possible to apply general Knoevenagel reaction conditions, for example, heating for 1 to 24 hours in benzene or toluene using ammonium acetate or piperidine monoacetic acid as a catalyst. By refluxing, the desired product (111) is obtained. In the dehydrogenation reaction of the compound (III), examples of the dehydrating agent include 2,3-dichloro-5,6-dicyanor1.4-benzoquinone (hereinafter, referred to as DDQ) and chloranil. The reaction solvent can be benzene, toluene, dioxane, tetrahydrofuran, or the like, and is reacted at room temperature to the reflux temperature of the solvent for 0.5 to 24 hours to obtain the desired product (IV).

i i) Compound (IV) can also be produced by the method shown in Reaction Scheme 2.

That is, a thiophenecarboxylic acid derivative (V) represented by the formula (V), which is disclosed in JP-A-2-193990 and is known, is reduced to give 5-phenylthiophene. 13-Methanol derivative (VI). Next, the hydroxyl group of compound (VI) is converted to halogen by a halogenating agent to obtain a methyl halide (VII). Compound (IV) can be obtained by reacting compound (VI I) with a cyanating agent. In this production method, the reduction reaction of compound (V) is carried out by the usual reduction of carboxylic acid or ester to alcohol. Reaction conditions can be used. For example, a reduction reaction using a reducing agent such as lithium aluminum hydride, sodium borohydride, or sodium metal can be mentioned. The reducing agent is generally used at 1 to 5 molar equivalents relative to compound (V). The solvent used in this reaction may be arbitrarily selected depending on the reducing agent, and generally, getyl ether, tetrahydrofuran, methanol, ethanol, toluene and the like can be used. The reaction temperature is from 0 ° C to the reflux temperature of the solvent, preferably from 0 ° C to room temperature, and the reaction time is usually from 1 to 2 hours. For the halogenation reaction of compound (VI), ordinary reaction conditions for halogenating a hydroxyl group can be applied. For example, compound (VI) can be added to an organic solvent (eg, tetrahydrofuran, benzene, carbon tetrachloride, N, N-dimethylformamide, dimethylsulfonate). Halogenating agents (for example, thionyl chloride, phosphorus pentachloride, thionyl bromide, phosphorus tribromide, etc.) are added to compound (VI) in 55 molar equivalents are added and the mixture is stirred at 0 ° C. to the reflux temperature of the solvent for 1 to 5 hours.

The cyanation reaction of the compound (VII) is carried out by using a conventional cyanating agent (for example, sodium cyanide, potassium cyanide, copper cyanide, etc.) in an amount of 1 to 5 mol equivalent to the compound (VII), and using a reaction solvent (for example, It proceeds by stirring in dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, etc. at room temperature to 60 ° C for 2 to 5 hours.

(2) Production of compound (I)

i) The compound (IV) thus obtained is hydrolyzed as shown in Reaction Scheme 3 to produce a carboxylic acid type compound (la) in which R in compound (I) is a hydrogen atom.

In this reaction, ordinary reaction conditions for hydrolyzing nitril to form a carboxylic acid can be applied. That is, for example, in the case of alkaline hydrolysis, a metallic hydroxide such as sodium hydroxide, lithium hydroxide, or lithium hydroxide can be used. For acid hydrolysis, mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, organic acids such as formic acid, acetic acid, and p-toluenesulfonic acid, and mixtures thereof can be used.

The carboxylic acid type compound (Ia) thus obtained can be converted to the above-mentioned salt with an alkali metal, an alkaline earth metal or an amine by performing a reaction known per se:

Iii) As shown in Reaction Scheme 3, compound (Ia) can be converted to an ester-type compound (lb) in which R is a lower alkyl group in compound (I) by a usual esterification reaction. .

There are various esterification reactions. For example, a method in which a corresponding alkylating agent is allowed to act on a carboxylic acid compound (Ia) in an organic solvent in the presence of a base, or a carboxylic acid compound (la) in the presence of an acid catalyst, Equivalent expression

R ^: -OH (Wherein, R ² has the same meaning as described above.).

Here, the organic solvent is acetone, N, N-dimethylformamide, dimethyl sulfoxide and the like, and the base is sodium carbonate, potassium carbonate and the like. Alkylating agents include alkyl halides such as methyl iodide and isopropyl bromide, and dialkyl sulfates such as dimethyl sulfate and getyl sulfate. Acid catalysts include mineral acids such as sulfuric acid and hydrochloric acid, and organic acids such as p-toluenesulfonic acid.

The compound of the present invention has an excellent effect on adjuvant arthritis in rats, an inhibitory effect on production of interleukin 1 which is one of inflammatory cytokines, and an anti-inflammatory analgesic effect. It is effective in treating autoimmune diseases such as rheumatism, systemic lupus erythematosus, and systemic sclerosis.

The compound of the present invention is usually orally or parenterally administered to a human. When administered orally, the thiopheneacetic acid derivative of the present invention is combined with a vehicle, a disintegrant, a binder, a lubricant, an antioxidant, a coating, a coloring agent, a flavoring agent, a surfactant, a plasticizer, and the like. They can be mixed and administered as granules, powders, capsules and tablets. For parenteral administration, they can be administered as injections, infusions and suppositories.

In formulating the above preparations, the usual preparation methods can be used.

Excipients include, for example, mannitol, xylitol, sorbitol, budo-sugar, sucrose, lactose, crystalline cellulose, crystalline cellulose 'carboxymethylcellulose sodium, calcium hydrogen phosphate, wheat starch, rice starch, corn starch , Potato starch, sodium carboxymethyl starch, dextrin, α-cyclodextrin, / 3-cyclodextrin, carboxyvinyl polymer, light gay anhydride, titanium oxide, magnesium metasilicate aluminate, polyethylene glycol, medium-chain triglyceride And the like. Disintegrants include low-substituted hydroxyquinepropylcellulose, carboquine methylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium 'Α type (actisol), starch, crystalline cellulose, hydroquine Propyl starch, partially alpha starch And the like.

Examples of binders include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethylcellulose, polyvinyl alcohol, pullulan, alpha starch, agar, tarragand, sodium alginate And propylene glycol alginate.

Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, tanolek, hydrogenated oil, sucrose fatty acid ester, dimethyl polysiloxane, microcrystalline wax, beeswax, and beeswax. No.

Examples of antioxidants include dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxydisole (BHA), α-tocopherol, and citric acid.

Examples of the coating agent include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and phthalate acetate. Cellulose acid, Polyvinyl acetate methyl acetyl acetate, Aminoalkyl methacrylate copolymer, Hydroxypropyl methylcellulose acetate succinate, Methacrylic acid copolymer, Cellulose acetate trimellitate (CAT), Polyvinyl acetate phthalate, Shellac And so on. Coloring agents include, for example, tar dyes and titanium oxide. Flavoring odorants include cunic acid, adipic acid, ascorbic acid, menthol and the like.

Examples of surfactants include polyoxyethylene hydrogenated castor oil, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polyoxyethylene boropropyl propylene block copolymers, polysorbates, sodium lauryl sulfate, Examples include macrogol and sucrose fatty acid ester. Examples of the plasticizer include triethyl citrate, triacetin, and cetanol.

Hereinafter, the present invention will be described in more detail with reference examples, examples, and test examples.

The structural formulas of the compounds of the present invention described in the following Examples and Test Examples are summarized in Table 1 below.

Table 1: Compounds of Examples and Test Examples

Compound XR of the present invention

Compound No. 1 H H

Compound No. 2 CH: H

Compound No. 3 OCH _: H

Compound No. 4 F H

Compound o. 5 C 1 H

Compound No. 6 Br H Compound No. 7 〇 H Compound No. 8 H CHa

Compound No. 9 CH: CH ₃

Compound No.10 F CH ₃

Compound No.11 C 1 CH ₃

Compound No.12 Br CH ₃

Compound No. 13 C 1 C ₂ H

Compound o.14 C 1 iC ₃ H Reference example Production of 5-phenylthiophene-3-acetonitrile

2-phenyl-2-alanone 4-one 2.23 g, cyanoacetic acid 2.0 g benzene 2 ml of 5 Om acetic acid and 1 ml of piperidine were added, and the mixture was heated and flown for 6 hours. The reaction solution was washed with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate and water in that order, dried (magnesium sulfate), and the solvent was distilled off. The residue was dissolved in 30 ml of toluene, DDQ 3.2 was added, and the mixture was stirred at room temperature for 1 hour. The solution was washed with aqueous sodium bicarbonate and then with water, dried (magnesium sulfate), and the residue obtained by evaporating the solvent was purified by silica gel chromatography and recrystallized from hexane-monoether to give the desired product (colorless crystals) 1.65 g I got

m. p. 7 2 7 ° C.

Example 1 Production of 5-fluorothiophene-3-acetic acid (Compound No. 1)

1) 5-phenylthiophene 1-3-methanol

To a suspension of 1.8 g of lithium aluminum hydride in tetrahydrofuran at room temperature was added 15.0 g of 5-monophenylthiophene-3-methyl methyl ribonate in small portions, followed by stirring at room temperature for 1.5 hours. . The reaction solution was cooled, decomposed with water and diluted hydrochloric acid, and extracted with ethyl acetate. The extract is washed with sodium hydrogen carbonate and water in that order, dried (magnesium sulfate), and the solvent is distilled off to give crude 5-phenylthiophene-3-methanol (colorless crystals). 5 g were obtained.

m. p. 92-94. C.

2) 3-Chloromethyl-1-5-phenylthiophene

Crude 5-phenylthiophene 1-3-methanol 16.5 g to tetrahydrofuran

6 Dissolve in 20 ml of N-N, N-dimethylformamide, add 9.4 ml of thionyl chloride dropwise at room temperature, stir at room temperature for 1 hour, pour the reaction mixture into ice water, extract with ethyl acetate, and extract the organic layer. After washing with water and drying (magnesium sulfate), the solvent was distilled off to obtain 26.3 g of crude 3-chloromethyl-15-phenylthiophene.

m.p. 37-40 ° C.

3) 5-Phenylthiophene 3-acetonitrile

26.3 g of crude 3-chloromethyl-15-phenylthiophene was dissolved in 50πι1 of dimethylsulfoxide, 4.8 g of sodium cyanide was added, and the mixture was stirred at 50 for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate), the solvent was distilled off, the residue was purified by silica gel chromatography, and recrystallized from ethyl acetate-n-hexane to give 5-phenylthiophene-3-acetonitrile. 15.0 g were obtained.

m. p. 7 7 2. C.

4) 5-phenylthiophene-3-acetic acid

To 15.0 g of 5-phenylthiophene-13-acetonitrile were added 130 ml of ethanol and 130 ml of 1 N potassium hydroxide, and the mixture was heated and passed for 3 hours. After cooling, the reaction solution was poured into concentrated hydrochloric acid-ice and extracted with ethyl acetate. The extract was washed with water, dried (magnesium sulfate), and the solvent was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to obtain 10.8 g of the desired product.

m.p. 15 4 to 15 5 ° C

Example 2

The following compounds of the present invention (Ia) were obtained according to Example 1 using various compounds (V) (R ¹ = CH ₃ ) shown in the above Reaction Scheme 2.

5- (4-methylphenyl) thiophene-3-acetic acid (Compound No. 2)

m. p. 148-150. C

5- (4-methoxyphenyl) thiophene-3-acetic acid (Compound No. 3)

m.p. 1 48 to 150 ° C

5- (4-fluorophenyl) thiophene-3-acetic acid (Compound No. 4)

mp 1 5 3 to 1 5 5 ⁰ C

5- (4-Monochlorophenyl) thiophene-3-acetic acid (Compound No. 5)

m.p.150-152. C

5-(4-Promofenil) Thiophene-1-acetic acid (Compound No. 6)

m. p. 163-16-165. C

5- (4-cyclohexylphenyl) thiophene 3-acetic acid (Compound No. 7) m.p.156-158 ° C

Conducted: Production of 35-phenylthiophene-3-methyl acetate (Compound No. 8)

A solution of 3 ml of concentrated sulfuric acid in 30 ml of methanol was added to 6.0 g of 5-phenylthiophene-3-acetic acid, and the mixture was heated under reflux for 2 hours. After methanol was distilled off under reduced pressure, water was added and extracted with dityl acetate. The extract was washed with water, dried (magnesium sulfate), and then the solvent was distilled off. The residue was purified by silica gel chromatography to obtain 6.35 g of the desired product (colorless oil). NMR (CDC 13) 5 (p pm);

3.64 (2 H, S)

3.72 (3 H, S)

7.07 (1 H, m)

7.1 3 to 7.40 (4 H, m)

7.5 8 (2 H, d, J = 9 Hz)

Example 4

The following compound of the present invention (Ib) was obtained according to Example 3 using various compounds (Ia) shown in the above Reaction Scheme 3.

5- (4-Methylphenyl) thiophene-3-methyl acetate (Compound No. 9)

2. 3 6 (3 Η, S)

3.64 (2 Η, S)

3.73 (3 Η, S)

7. 04 (1 Η, m)

7.1 7 (3 Η, m)

7. 4 8 (2 Η, d, J = 9 Η ζ)

5-(4-Monofluorophenyl) thiophene-3-methyl acetate (Compound \ ο. 10)

3.65 (2 H, S)

3.75 (3 H, S)

7.00 to 7.1 3 (3 H, m)

7.18 (1 H, d, J = 1.5 Hz)

7.50 ~ 7.60 (2 H, m)

5- (4-chlorophenyl) thiophene-3-methyl acetate (Compound No. 11) m.p. 37-39. C

5 - (4-Puromofuweniru) Chiofuwen one 3- acetate (Compound No. 1 2) mp 5 8~ 6 0 0 C

5- (4-chlorophenyl) thiophene-3-ethyl acetate (Compound No. 13) mp 33 to 36. C

5- (4-chlorophenyl) thiophene-3-isopropyl acetate (Compound No. 14)

m. p. 46-48. C

Test Example 1 Effect on adjuvant arthritis (a rheumatoid arthritis disease state model) 1) Test animals

Seventeen-week-old Sprague-Dawley rats (body weight: 160-190 g) were subjected to the test in groups of 10 animals.

2) Test method

The suspension was sensitized by injecting 0.6 mg of the killed Mycobacterium tuberculosis (Pishi type) in 0.1 ml of liquid paraffin into the tail of each rat.

Compound (I) of the present invention as a test drug was suspended in a 5% arabia gum solution, and this was suspended in a group of 10 mg Zkg as compound (I) once a day from the day of sensitization for 16 consecutive days. Oral administration to rats.

In the control group, only 5% gum arabic was used and similarly administered orally to rats.

On the 17th day of sensitization, the volume of edema in the hind limbs was measured, and the edema inhibition rate of the drug administration group relative to the control group was calculated.

) Test results

The results are shown in Table 2.

Table 2: Effects on adjuvant arthritis

Test Example '2 IL-1 production inhibitory action Heparin-treated normal human peripheral blood is layered under aseptic conditions on Lymphoblep (Daiichi Pharmaceutical) to remove erythrocytes. The cells are then repopulated with fetal bovine serum 10%, penicillin 100 U / ml, streptomycin 1 The cells were suspended in RPMI-1640 medium (Gibco) supplemented with 00 Uzmase buffer solution (1 OmM and L-glutamine 2 mM) to prepare a cell number of 2 × 10 ⁶ cells ml.

Add 2501 of the prepared cell suspension, ConA (Sigma, 8.0 fig / ml solution) and the above-mentioned medium solution of the test compound (the compound of the present invention) to microplates (flat bottoms). Wells, manufactured by Iwaki Glass Co., Ltd.) and cultured in a 5% CO ₂ incubator for 48 hours. A medium solution of the test compound was prepared by dissolving the sample in ethanol, and then diluting with the above medium solution so that the final concentration of ethanol became 0.05%. After the culture, IL-1 (pg / ml) was measured in the cell supernatant using an ELISA kit (Amersham), and the 50% inhibition rate (IC _s . Value, wM) was calculated.

The results are shown in Table 3.

¾_3: I L-1 production inhibitory action

Industrial applicability

The thiopheneacetic acid derivative and its salt of the present invention show an excellent effect on rat adjuvant arthritis, an inhibitory effect on production of interleukin 1 which is one of inflammatory cytokines, and an anti-inflammatory analgesic effect. It is effective in treating autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis.

Claims

The scope of the claims

1. Formula (I)

(In the formula, X represents a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group having 5 to T carbon atoms, or a lower alkoxy group, and R represents a hydrogen atom or a lower alkyl group.) in represented by Chiofuwen acid derivatives and salts thereof ₌

2. A thiopheneacetic acid derivative of formula (I) and a salt thereof for use as an active ingredient in a pharmaceutical composition.

3. A pharmaceutical composition comprising a thiopheneacetic acid derivative of the formula (I) or a salt thereof as an active ingredient.

4. The pharmaceutical composition according to claim 3, for treating an autoimmune disease.

5. Use of a thiophene acetic acid derivative of the formula (I) and a salt thereof for producing a pharmaceutical composition for treating an autoimmune disease.

6. A method for treating an autoimmune disease, comprising administering to a human an effective amount of a thiopheneacetic acid derivative of the formula (I) or a salt thereof.