WO1996002529A1 - Derive de l'acide thiophene acetique - Google Patents

Derive de l'acide thiophene acetique Download PDF

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Publication number
WO1996002529A1
WO1996002529A1 PCT/JP1995/001393 JP9501393W WO9602529A1 WO 1996002529 A1 WO1996002529 A1 WO 1996002529A1 JP 9501393 W JP9501393 W JP 9501393W WO 9602529 A1 WO9602529 A1 WO 9602529A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
acid derivative
acid
salt
Prior art date
Application number
PCT/JP1995/001393
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English (en)
Japanese (ja)
Inventor
Kazuyuki Tomisawa
Masahiro Hasegawa
Morihiro Mitsukuchi
Katsuo Hatayama
Original Assignee
Taisho Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to AU29362/95A priority Critical patent/AU2936295A/en
Publication of WO1996002529A1 publication Critical patent/WO1996002529A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • 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.
  • 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.
  • cytodynamics has been attracting attention as a molecule that causes synovial lesions and synovial proliferation.
  • 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.
  • 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.
  • 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.
  • an object of the present invention is to provide a compound of the formula (I)
  • 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
  • R represents a hydrogen atom or a lower alkyl group.
  • 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.
  • a halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • a reduction reaction using a reducing agent such as lithium aluminum hydride, sodium borohydride, or sodium metal
  • 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.
  • ordinary reaction conditions for halogenating a hydroxyl group can be applied.
  • compound (VI) can be added to an organic solvent (eg, tetrahydrofuran, benzene, carbon tetrachloride, N, N-dimethylformamide, dimethylsulfonate).
  • organic solvent eg, tetrahydrofuran, benzene, carbon tetrachloride, N, N-dimethylformamide, dimethylsulfonate.
  • Halogenating agents for example, thionyl chloride, phosphorus pentachloride, thionyl bromide, phosphorus tribromide, etc.
  • 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.
  • a conventional cyanating agent for example, sodium cyanide, potassium cyanide, copper cyanide, etc.
  • 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.
  • 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.
  • a metallic hydroxide such as sodium hydroxide, lithium hydroxide, or lithium hydroxide can be used.
  • 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:
  • 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. .
  • R -OH (Wherein, R 2 has the same meaning as described above.).
  • the organic solvent is acetone, N, N-dimethylformamide, dimethyl sulfoxide and the like
  • 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.
  • 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.
  • 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, ⁇ -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 ' ⁇ type (actisol), starch, crystalline cellulose, hydroquine Propyl starch, partially alpha starch And the like.
  • binders include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethylcellulose, polyvinyl alcohol, pullulan, alpha starch, agar, tarragand, sodium alginate And propylene glycol alginate.
  • lubricant examples 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.
  • antioxidants examples include dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxydisole (BHA), ⁇ -tocopherol, and citric acid.
  • the coating agent examples 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.
  • 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.
  • plasticizer include triethyl citrate, triacetin, and cetanol.
  • 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.
  • Test Example 1 Effect on adjuvant arthritis (a rheumatoid arthritis disease state model) 1) Test animals
  • mice Seventeen-week-old Sprague-Dawley rats (body weight: 160-190 g) were subjected to the test in groups of 10 animals.
  • 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.
  • 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 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.
  • 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.

Abstract

L'invention concerne un dérivé de l'acide thiophène acétique représenté par la formule générale (I) et un sel de celui-ci, ayant des propriétés inhibitrices sur la production de cytokines inflammatoires, des propriétés antiphlogistiques et analgésiques et efficace pour traiter les maladies auto-immunes telles que la polyarthrite rhumatoïde. Dans la formule (I), X représente un hydrogène, un halogène, un alkyle inférieur, un C5-C7 cycloalkyle ou un alcoxy inférieur et R représente un hydrogène ou un alkyle inférieur.
PCT/JP1995/001393 1994-07-13 1995-07-12 Derive de l'acide thiophene acetique WO1996002529A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29362/95A AU2936295A (en) 1994-07-13 1995-07-12 Thiopheneacetic acid derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP6/161212 1994-07-13
JP16121294 1994-07-13

Publications (1)

Publication Number Publication Date
WO1996002529A1 true WO1996002529A1 (fr) 1996-02-01

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WO (1) WO1996002529A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7521473B2 (en) 2004-02-25 2009-04-21 Wyeth Inhibitors of protein tyrosine phosphatase 1B
US7662995B2 (en) * 2003-02-21 2010-02-16 Chiesi Farmaceutici S.P.A. 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4826755A (fr) * 1971-08-06 1973-04-09
JPS4913789B1 (fr) * 1968-04-16 1974-04-03

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4913789B1 (fr) * 1968-04-16 1974-04-03
JPS4826755A (fr) * 1971-08-06 1973-04-09

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7662995B2 (en) * 2003-02-21 2010-02-16 Chiesi Farmaceutici S.P.A. 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases
US8022250B2 (en) 2003-02-21 2011-09-20 Chiesi Farmaceutici S.P.A. 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases
US20110288175A1 (en) * 2003-02-21 2011-11-24 Chiesi Farmaceutici S.P.A. 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases
US8314268B2 (en) * 2003-02-21 2012-11-20 Chiesi Farmaceutici S.P.A. 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases
US7521473B2 (en) 2004-02-25 2009-04-21 Wyeth Inhibitors of protein tyrosine phosphatase 1B

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