Classifications

• • 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
  • C07D333/26—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D333/38—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 3-acetoxy- thiophene-2-carboxylic acid, which will hereinafter be named MR-2058, of formula
• the invention also relates to a process for the preparation of compound MR-2058, to pharmaceutical compositions containing them and to the use thereof in the preparation of medicaments useful in the treatment of arteriosclerosis.
• the compound of the invention is characterized by the presence of a carboxy group; therefore the present invention also relates to all the possible salts of the acid with non toxic, pharmaceutically acceptable organic and inorganic bases.
• said salts are the sodium, potassium, calcium, iron, zinc salts; as well as those with diethylethanolamine, morpholine, piperidine, triethylamine.
• SMC smooth muscle cells
• MR-2058 has a surprising activity inhibiting proliferation of SMC of the arterial wall, and it also has other interesting physiological properties.
• MR-2058 proved to have a marked ability to inhibit the proliferation of SMC from rat aorta, in the test carried out according to the procedure described by Bernini et al. (Pharm. Res. 1 , 27-35, 1990).
• MR-2058 was found to have an anti-platelet aggregation activity comparable to that of acetylsalicylic acid.
• Ethyl propiolate (II) is condensed with ethyl thioglycolate (III) in an equimolar ratio.
• the resulting compound (IV) is cyclized to ethyl 3-hydroxythiophene-2-carboxylate (V); the subsequent hydrolysis of the ester and the acetylation of the hydroxy group at the 3-position give MR-2058 (I).
• reaction of (II) and (III) is carried out in a medium consisting of an aqueous-organic homogeneous phase, comprising an organic solvent mixed with water in various ratios; solvents such as methanol, ethanol, acetone, dioxane can be used, a 1/1 (v/v) ethanol-water mixture being preferred.
• solvents such as methanol, ethanol, acetone, dioxane can be used, a 1/1 (v/v) ethanol-water mixture being preferred.
• an acid-binding agent such as trimethylamine, triethylamine, pyridine.
• Compound (III) is present in the two isomeric cis-trans forms; however the isomeric mixture is directly used in the subsequent step.
• Cyclization of (IV) occurs via the carbanion, and it is carried out with conventional methods in which such an intermediate is formed, i.e. in the presence of a strong base, such as an alkali alkoxide, for example sodium methoxide, in anhydrous solvents, such as benzene, toluene, xylene.
• a strong base such as an alkali alkoxide, for example sodium methoxide
• anhydrous solvents such as benzene, toluene, xylene.
• NMR analysis evidences the presence of the two cis/trans isomers in a 77/23 ratio.
• the product is directly used for the subsequent step.
• Salification of the carboxy group of (I) can be carried out with conventional techniques.
• the corresponding sodium, potassium, ethanolamine salts were prepared.
• the present invention also relates to pharmaceutical compositions containing compound MR-2058 as the active ingredient, alone or in admixture with conventional carriers and excipients, according to the techniques described, for example, in "Remington's Pharmaceutical Sciences Handbook” Mack. Pub. Co., N.Y. U.S.A.
• compositions are soft and hard gelatin capsules, tablets, optionally in gastro-resistant or slow-release forms, powders, solutions and suspensions for the oral and parenteral administrations, suppositories, sustained-release forms.
• the pharmaceutical carriers can be excipients for solid forms, such as lactose, talc, PVP; granulating agents, such as magnesium stearate; suspending agents, such as methyl cellulose; and/or surfactants, such as polyoxyethylene stearate; preservatives, such as hydroxybenzoates; flavoring and sweetening agents.
• compositions of the invention are formulated preferably in unitary dosage forms, containing a therapeutically effective amount of MR-2058.
• the daily dosage will depend on the severity of the disease to treat, as well as on the patient's conditions.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

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ID=11359782

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Cited By (2)

Families Citing this family (3)

Citations (1)

• 1991
  • 1991-04-24 IT ITMI911146A patent/IT1247527B/it active IP Right Grant
• 1992
  • 1992-03-31 AU AU14534/92A patent/AU1453492A/en not_active Abandoned
  • 1992-03-31 WO PCT/EP1992/000713 patent/WO1992019612A1/en active Application Filing

Patent Citations (1)

Non-Patent Citations (2)

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