Rhodanine derivatives and pharmaceutical compositions

Abstract: Disclosed is a rhodanine derivative of formula (I). A rhodanine derivative of formula (I) wherein R¹ is hydrogen, C₁-C₈ alkyl, carboxyl(C₁-C₄)alkyl or (C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl; R² is -CH₂-CH₂-R³, (CH=CH) R³ (m is 0 or 1), - =CH-R⁴ (R is C₁-C₃ alkyl) or (CH₂) CONHR⁴ (n is 0 or 1-­ 4); R³ is a thienyl or furyl group which may be substituted by C₁-C₃ alkyl or halogen; a pyrrolyl group which may be substituted by carboxy(C₁-C₃)alkyl on the nitrogen atom; or a phenyl group which may be substituted by one or more substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-­ C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; and R⁴ is a phenyl group which may be substituted by one or more of the same substituents as defined above, or a pharmaceutically acceptable salt thereof. The derivatives are of an inhibitory activity against aldose reductase and useful for the prevention or treatment of complications of diabetes.

Description: FIELD OF THE INVENTION This invention relates to rhodanine derivatives of formula (I) following below, processes for preparing the same and their use for the preparation of and in pharmaceutical compositions having an inhibitory activity against aldose reductase which comprise said derivatives as an active ingredient. BACKGROUND OF THE INVENTION An aldose reductase is an enzyme which catalyzes the conversion of aldose in vivo, e.g. glucose or galactose into its corresponding polyol, e.g. sorbitol or galactitol, respectively. It is known that the sorbitol and galactitol produced by the action of this enzyme are accumulated in the lenses, the peripheral nerves, the kidney, etc., of diabetics and galactosemiacs, thus causing complications of diabetes, e.g. retinopathy, diabetic cataract, neuropathy and nephropathy. Thus the inhibition of the enzyme aldose reductase permits the prevention or treatment of the above-described complications. EP-A- 0 047 109 and EP-A- 0 143 461 disclose certain rhodanine derivatives which possess an inhibitory activity against aldose reductase. However, the compounds disclosed therein are structurally different from the compounds (I) of the present invention in respect to the nitrogen atom on the rhodanine ring being substituted. JP-A-64-52765 discloses further compounds wherein the nitrogen atom on the rhodanine ring is not substituted and which also possess an inhibitory activity against aldose reductase. However those compounds are also structurally different from the compounds (I) of the present invention with respect of the substituents attached to the 5-position through a double bond. This also applies to the rhodanine derivatives disclosed in JP-A-01-52 765 which are also known as aldose reductase inhibitors. However, these compounds are also structurally different from the compounds (I) of the present invention in respect to the substituent R³ at the 5-position of the rhodanine moiety. In "Chem. Abstr.", 111 (18), No. 163 902 v (October 1989), and in EP-A-0 316 790 rhodanine derivatives are disclosed which are structurally closely related to the compounds (I) of the present invention. However, in the former document the rhodanine derivatives disclosed therein are used as optical materials and in the latter document the rhodaninde derivatives disclosed therein have an inhibitory activity against chemical mediators including leucotrienes for treatment of asthma. Furthermore, both documents teach that it is essential to have a carboxymethyl or (carboxylate)methyl group at the 3-position of the rhodanine moiety. In so far they are also structurally different from compounds (I) of the present invention. The object of the present invention is to find rhodanine derivatives having an improved inhibitory activity against aldose reductase which causes severe complications of diabetes. Surprisingly, it has been found that the above object can be achieved according to the present invention by rhodanine derivatives having the following general formula (I). DISCLOSURE OF THE INVENTION According to a first aspect the present invention relates to the use of rhodanine derivatives of formula (I) wherein R¹ is hydrogen, C₁-C₈ alkyl, carboxyl(C₁-C₄)alkyl or (C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl; R² is -CH₂-CH₂-R³, (m is 0 or 1), (R is C₁-C₃ alkyl) or (n is 0 or 1-4); R³ is a thienyl or furyl group which may be substituted by C₁-C₃ alkyl or halogen; a pyrrolyl group which may be substituted by carboxy(C₁-C₃)alkyl on the nitrogen atom; or a phenyl group which may be substituted by one or more substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; and R⁴ is a phenyl group which may be substituted by one or more of the same substituents as defined above, or of pharmaceutical acceptable salts thereof for the preparation of medicaments for the prevention or treatment of complications of diabetes. Preferred compounds of formula (I) are those wherein R¹ is hydrogen, C₁-C₆ alkyl, carboxy(C₁-C₄)alkyl or (C₁-C₃)alkoxycarbonyl(C₁-C₄)alkyl as well as compounds of formula (I), wherein R² is -CH₂-CH₂-R³ and R³ is a phenyl group which is substituted by one or two substituents selected from the group consisting of C₁-C₃ alkoxy, carboxy(C₁-C₃)alkoxy und (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy. Particularly preferred is the use of compounds of formula (I) wherein R² is -CH=CH-R³ and R³ is a thienyl or furyl group which may be substituted by C₁-C₃ alkyl or halogen; a pyrrolyl group which may be substituted by carboxy(C₁-C₃)alkyl on the nitrogen atom; or a phenyl group which may be substituted by one or more substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; wherein R² is a phenyl group substituted by 2H-tetrazolyl-(C₁-C₄)alkoxy; wherein R² is -CONHR⁴ and R⁴ is a phenyl group substituted by carboxyl or (C₁-C₃)alkoxycarbonyl; wherein R² is n is 1 to 3 and R⁴ is a phenyl group substituted by carboxyl or (C₁-C₃)alkoxycarbonyl; wherein R² is and R⁴ is a phenyl group substituted by C₁-C₃ alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy or carboxy(C₁-C₃)alkoxy; wherein R² is and R⁴ is a phenyl group substituted by C₁-C₃ alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy or carboxy(C₁-C₃)alkoxy. According to a second aspect the present invention relates to the use of rhodanine compounds of formula (I) as defined above or of pharmaceutically acceptable salts thereof for the preparation of medicaments for the inhibition of aldose reductase. According to a third aspect the present invention relates to new rhodanine derivatives of the formula (I) wherein if R¹ is hydrogen: R² is -CH₂-CH₂-R³¹, -R³², -CH=CH-R³², and -(CH₂) n CONHR⁴, wherein R is C₁-C₃ alkyl, n is 0 - 4, R³¹ is a thienyl or furyl group which may be substituted by C₁-C₃ alkyl or halogen; a pyrrolyl group which may be substituted by carboxy(C₁-C₃)alkyl on the nitrogen atom; or a phenyl group which may be substituted by one or more substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; R³² is a pyrrolyl group substituted by carboxy(C₁-C₃)alkyl on the nitrogen atom, a thienyl group which may be substituted by C₁-C₃ alkyl or halogen, a furyl group substituted by C₁-C₃ alkyl or halogen or a phenyl group which may be substituted by one or more substitutents selected from the group consisting of C₁-C₃ alkyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; and R⁴ is a phenyl group which may be substituted by one or more substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; and if R¹ is C₁-C₈ alkyl, carboxyl(C₁-C₄)alkyl or (C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl: R² is R³¹ as defined above, -CH₂-CH₂-R³³ , -CH=CH-R³³, and -(CH₂) n -CONHR⁴ wherein R is C₁-C₃ alkyl; n is 0 - 4, R³³ is a furyl group which may be substituted by C₁-C₃ alkyl or halogen; and R⁴ is as defined above. According to a fourth aspect the present invention relates to pharmaceutical compositions which comprise as an active ingredient at least one compound of the formula (I) wherein if R¹ is hydrogen R² is -CH₂-CH₂-R³, (m is 0 or 1), (R is C₁-C₃ alkyl) or (n is 0 or 1-4); R³ is a thienyl or furyl group which may be substituted by C₁-C₃ alkyl or halogen; a pyrrolyl group which may be substituted by carboxy(C₁-C₃)alkyl on the nitrogen atom; or a phenyl group which may be substituted by one or more substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; and R⁴ is a phenyl group which may be substituted by one or more of the same substituents as defined above, and if R¹ is C₁-C₈ alkyl, carboxyl(C₁-C₄)alkyl or (C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl: R² is R³¹ as defined above, -CH₂-CH₂-R³³ , -CH=CH-R³³, and -(CH₂) n -CONHR⁴ wherein R is C₁-C₃ alkyl; n is 0 - 4, R³³ is a furyl group which may be substituted by C₁-C₃ alkyl or halogen; and R⁴ is as defined above or of at least one pharmaceutically acceptable salt thereof, associated with one or more pharmaceutically acceptable additives thereof. The compounds of the present invention, in the case of having an acid radical therein, can form their salts with pharmaceutically acceptable inorganic or organic bases and the salts are also included in the scope of the present invention. The compounds of the present invention contain an asymmetric carbon atom or a double bond in the substituent at the 5-position of the rhodanine ring and there are therefore an optical isomer based on the asymmetric carbon atom or cis, trans isomers based on the double bond. Thus these isomers and the mixtures thereof are also included in the scope of the present invention. The groups included in the definition of formula (I) are further illustrated below. C₁-C₈ alkyl in the definition of R¹ includes straight or branched chain alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-amyl, n-hexyl, n-heptyl and n-octyl. Carboxy(C₁-C₄)alkyl in the definition of R¹ includes e.g. -CH₂COOH, -(CH₂)₂COOH, -(CH₂)₃COOH or -(CH₂)₄COOH, (C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl includes e.g. -CH₂COOCH₃, -CH₂COOC₂H₅, -CH₂COOC₃H₇, -CH₂COOC₄H₉, -(CH₂)₂COOCH₃, -(CH₂)₂COOC₂H₅, -(CH₂)₂COOC₃H₇, and -(CH₂)₂COOC₄H₉. Of the substituents on the phenyl group in the definition of R³, (C₁-C₃)alkoxycarbonyl includes e.g. -COOCH₃, -COOC₂H₅, and -COOC₃H₇; carboxy(C₁-C₃)alkoxy includes e.g. -OCH₂COOH, -O(CH₂)₂COOH, and -O(CH₂)₃COOH.; and (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy includes e.g. -OCH₂COOCH₃, -OCH₂COOC₂H₅, and -OCH₂COO(CH₂)₃CH₃. Representative example of benzyloxycarbonyl(C₁-C₃)alkoxy is that of piperidinylcarbonyl(C₁-C₃)alkoxy is and that of 2H-tetrazolyl(C₁-C₄)alkoxy is Representative example of carboxy(C₂-C₄)alkenyl is -CH=CH-COOH.; and that of (C₁-C₃) alkoxycarbonyl(C₂-C₄)alkenyl is -CH=CH-COOCH₃, and -CH=CH-COOC₂H₅. Representative example of carboxy(C₁-C₃)alkyl includes -CH₂COOH, -(CH₂)₂COOH, and -(CH₂)₃COOH. and that of (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl includes -(CH₂)₂COOCH₃, and -(CH₂)₂COOC₂H₅. Representative examples of substituted thienyl, furyl and pyrrolyl groups in the definition of R³ include 3-methyl-2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl, 4-chloro-2-thienyl, 5-chloro-2-thienyl, 3-methyl-2-furyl, 4-methyl-2-furyl, 5-methyl-2-furyl, 4-chloro-2-furyl, 2-(N-carboxymethyl)-pyrrolyl, and 2-(N-carboxyethyl)-pyrrolyl. Representative examples of substituted phenyl groups in the definition of R³ and R⁴ include 2-, 3- or 4-tolyl, 3- or 4-ethylphenyl, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 3-hydroxy-4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-isopropoxy-3-methoxyphenyl, 3,4,5-trimethoxyphenyl, 3-tert-butyl-4-hydroxyphenyl, 4-hydroxy-3,5-diisopropylphenyl, 3,5-di-tert-butyl-4-hydroxyphenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 3,4-dichlorophenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-carboxyphenyl, 3- or 4-cyanophenyl, 4-aminophenyl, 4-(N,N-dimethyl)aminophenyl, 2-, 3- or 4-methoxycarbonylphenyl, 4-carboxymethoxyphenyl, 4-methoxy-4-carboxymethoxyphenyl, 4-methoxycarbonylmethoxyphenyl, 4-ethoxycarbonylmethoxyphenyl, 2- or 3-carboxymethoxyphenyl, 2- or 3-methoxycarbonylmethoxyphenyl, 2-, 3- or 4-ethoxycarbonylmethoxyphenyl, 4-carboxyvinylphenyl, 4-ethoxycarbonylvinylphenyl, 4-carboxyethylphenyl, 4-ethoxycarbonylethylphenyl, 4-(2H-tetrazolyl)-methoxyphenyl, 4-(2H-tetrazolyl)-phenyl, 4-(2H-tetrazolyl)-butyleneoxyphenyl, 4-ethoxycarbonylmethoxy-3-methoxyphenyl, 4-methoxycarbonylmethoxy-3-methoxyphenyl, 3-ethoxy-4-methoxycarbonylmethoxyphenyl, 3-methoxycarbonylmethoxy-2-methoxyphenyl, 3-methoxycarbonylmethoxy-4-methoxyphenyl, 2-methoxycarbonylmethoxy-4-methoxyphenyl, 3,4-dimethoxycarbonylmethoxyphenyl, 4-carboxymethoxy-3-ethoxyphenyl, 3-carboxymethoxy-4-methoxyphenyl, 3-carboxymethoxy-4-methoxyphenyl, 2-carboxymethoxy-4-methoxyphenyl, 3,4-dicarboxymethoxyphenyl, 5-isopropyl-2-methoxycarbonylmethoxyphenyl, 5-chloro-2-methoxycarbonylmethoxyphenyl, 2-benzyloxycarbonylmethoxy-5-chlorophenyl, 5-chloro-2-piperidynilcarbonylmethoxyphenyl, 5-bromo-2-methoxycarbonylmethoxyphenyl, 3,5-dichloro-2-methoxycarbonylmethoxyphenyl, 2-carboxymethoxy-5-isopropylphenyl, 2-carboxymethoxy-5-chlorophenyl, 5-bromo-2-methoxycarbonylmethoxyphenyl, 5-carboxymethoxy-3,5-dichlorophenyl, 3,5-dibromo-2-methoxycarbonylmethoxyphenyl, 2-methoxycarbonylmethoxy-5-trifluoromethylphenyl, 3,5-dimethoxy-4-methoxycarbonylmethoxyphenyl, 3,5-dimethyl-4-methoxycarbonylmethoxyphenyl, 4-ethoxycarbonylmethoxy-3,5-diisopropylphenyl, 3,5-dibromo-2-carboxymethoxyphenyl, 2-carboxymethoxy-5-trifluoromethylphenyl, 4-carboxymethoxy-3,5-dimethoxyphenyl, 4-carboxymethoxy-3,5-dimethylphenyl and 4-carboxymethoxy-3,5-diisopropylphenyl. The compounds of formula (I) can be prepared by reacting rhodanine of formula (II) with an aldehyde or ketone of formula (III) wherein R¹ and R² have the same meanings as defined above. In this reaction, the aldehyde or ketone of formula (III) may be employed in the range of 0.5 to 10 moles per mole of rhodanine of formula (II), but both may be usually employed in equimolar amounts. The aldehyde or ketone is preferably used in a slightly excess amount relative to rhodanine, e.g. 1.1 to 1.5 moles per mole of rhodanine of formula (II). The reaction may be carried out without any solvents or preferably in the presence of an organic solvent. The organic solvents used include hydrocarbons such as n-hexane, ligroin, benzene, and toluene.; lower alcohols such as methanol, ethanol, and isopropanol.; ether solvents such as ether, tetrahydrofuran, and dioxane.; esters such as ethyl acetate, and butyl acetate.; chlorinated hydrocarbons such as ethylene dichloride, chloroform, trichloroethylene, and carbon tetrachloride.; aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, diethylformamide, and dimethylacetamide,; and protic polar solvents such as formic acid, and acetic acid.; and such solvents may be employed alone or in combination with two or more thereof. The reaction may be carried out at any temperature and preferably under heating. Generally, the reaction may be carried out at a temperature of 50 to 150°C, depending upon the solvents to be employed. Further, the reaction is preferably conducted at a temperature in the neighborhood of the boiling point of the solvent employed, which is easily controllable for the reaction temperature. Preferably, a catalyst may be added for promoting the reaction. The catalysts used include ammonia; secondary amines such as piperidine, and diethylamine.; salts of organic acids such as ammonium acetate, sodium acetate, etc. Such catalysts may be employed alone or in combination with two or more thereof. These catalysts may be used in the range of 0.2 to 5 moles per mole of rhodanine of formula (II), with the range of 1.0 to 1.5 moles being preferred. The reaction will be completed in 1 to 12 hours, depending upon the reactivity of reactants employed and such conditions as reaction temperatures. The reaction product may be separated from the reaction mixture obtained as above according to any conventional means in the art. For instance, the reaction product can be isolated by such means as concentration of the reaction mixture followed by separation by recrystallization or chromatography. If necessary, the compounds of formula (I) can be converted into the pharmaceutically acceptable salts in a conventional manner by using pharmaceutically acceptable inorganic or organic bases. Examples of the bases include hydroxides or carbonates of alkali metals such as sodium, potassium, etc. or alkaline earth metals such as magnesium, and calcium.; aluminum hydroxide; ammonia; ammonium carbonate; primary amines such as methylamine, and ethylamine,.; secondary amines such as diethylamine, and morpholine,.; and tertiary amines such as triethylamine, and pyridine. The rhodanine derivatives of formula (I) and the pharmaceutically acceptable salts thereof have an inhibitory activity against aldose reductase which catalyzes the conversion of an aldose into the corresponding polyol, thus inhibiting an abnormal increase in sorbitol content in cells of diabetic patients. Thus the compounds of formula (I) and their salts of the present invention are useful for the prevention and treatment of diabetic complications, e.g. retinopathy, diabetic cataract, neuropathy and nephropathy. The compounds of the present invention exhibited a significant inhibitory activity against aldose reductase at 10⁻⁵ to 10⁻⁶ molar concentrations, for example according to experiments in a laboratory conducted in accordance with the modification (Biochemical Pharmacology, 25 , 2505 (1976)) of the method described in J. Biol. Chem., 240 , 877 (1965) using an aldose reductase obtained from rat lenses. Thus the present invention provides pharmaceutical compositions which comprise as an active ingredient the rhodanine derivatives of formula (I) or the pharmaceutically acceptable salts thereof. The pharmaceutical compositions can be formulated into solid, semi-solid or liquid preparations in a usual manner using conventional pharmaceutically acceptable carriers. The pharmaceutical preparations may be administered orally or parenterally. Such preparations may include tablets, capsules, suppositories, troches, syrups, creams, ointments, plasters, cataplasms granules, powders, injections, suspensions, inhalations, and aerosols. They may be formed into double layer tablets or multilayer tablets with other drugs. Further, tablets may be formed, if necessary, into tablets having usual coated films, e.g. sugar-coated tablets, enteric-coated tablets, film-coated tablets. Examples of the carriers include e.g. excipients, binders, diluents and lubricants, typical examples of which are lactose, starch, sugar, microcrystalline cellulose, magnesium stearate, silicon dioxide, talc, physiological salt solution and sterilized water. The pharmaceutical preparations may contain 0.1 to 100% by weight of the active ingredient and suitably 1 to 50% by weight for oral administration and 0.1 to 10% by weight for injection. The active compounds are effective over a wide dosage range. For example, dosages per day will normally fall within the range of 0.001 to 1000 mg/kg-body weight, but the amount of the compound actually administered will be determined by a physician in the light of the relevant circumstances including the condition to be treated, the route of administration, age, sex, severity of the patient's symptoms, etc. EXAMPLE 1 Ethyl 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate A mixture of 1.33 g (0.01 mol) of rhodanine, 2.48 g (0.01 mol) of ethyl 4-(3-oxo-1-butenyl)phenoxycetate, 0.77 g (0.01 mol) of ammonium acetate and 20 ml of toluene was heated under reflux for 3 hours. After cooling, 100 ml of water were added to the reaction mixture which was extracted with ethyl acetate (3 x 100 ml). The ethyl acetate layer was washed twice with water and once with a saturated saline solution, dried and concentrated under reduced pressure to give orange crystals. The crystals were purified by silica gel column chromatography (eluent, chloroform : ethyl acetate) to obtained 0.28 g (7.7% yield) of Isomer A of ethyl 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate from the first eluate and 0.48 g (13.2% yield) of Isomer B from the subsequent eluate. Isomer A Yellow crystals, m.p. 209-213°C (dec.) Mass spectrum (m/e); 363 (M⁺) NMR(DMSO-d₆) δ: 1.22(t, 3H), 2.50(s, 3H), 4.17(q, 2H), 4.80(s, 2H), 6.65(d, 1H, J=16Hz), 6.95 (d, 2H), 7.32(d, 1H, J=16Hz), 7.68(d, 2H), 13.40(br, s, 1H) IR(KBr) cm⁻¹: 1740, 1680, 1603, 970, 959 Isomer B Yellow crystals, m.p. 220-223°C (dec.) Mass spectrum (m/e); 363 (M⁺) NMR(DMSO-d₆) δ: 1.22(t, 3H), 2.16(s, 3H), 4.20(q, 2H), 4.80(s, 2H), 7.00(d, 2H), 7.28(d, 1H, J=16Hz), 7.54(d, 2H), 8.45(d, 1H, J=16Hz), 13.45(br, s, 1H) IR(KBr) cm⁻¹: 1772, 1689, 1604, 981, 926 In accordance with similar procedure as mentioned in Example 1, the compounds shown in the following Examples 2 to 20 were obtained from the corresponding aldehydes or ketones. EXAMPLE 2 Ethyl 6-(3,4-dimethoxyphenyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoate Yield 7% NMR(CDCl₃) δ: 1.30(t, 3H), 2.50-2.65(m, 2H), 2.75-290(m, 2H), 3.92(s, 3H), 3.95(s, 3H), 4.18(q, 2H), 6.80-7.20(m, 4H), 8.47(d, 1H, J=16Hz), 9.75(br, s, 1H) IR(KBr) cm⁻¹: 1730, 1671, 1540, 979 EXAMPLE 3 4-[3-(4-Oxo-2-thioxo-5-thiazolidinylidene)-1-hexenyl]benzoic acid Isomer A Yield 6% Yellow crystals, m.p. 278-280°C (dec.) Mass spectrum (m/e); 333 (M⁺) NMR(DMSO-d₆) δ: 1.00(t, 3H), 1.45-1.70(m, 2H), 7.40(d, 1H, J=16Hz), 7.70(d, 2H, J=8Hz), 7.95(d, 2H, J=8Hz), 8.58(d, 1H, J=16Hz), 3.00(br, s, 1H), 3.60(br, s, 1H) IR(KBr) cm⁻¹: 1695, 1680, 1605, 980 Isomer B Yield 6% Yellow crystals, m.p. 257-261°C (dec.) Mass spectrum (m/e); 333 (M⁺) IR(KBr) cm⁻¹: 1690, 1605, 1540, 945 EXAMPLE 4 5-[α-Hexyl-4-(1H-tetrazol-5-yl)methoxycinnamilidene-4-oxo-2-thioxothiazolidine Yield 9% Brown crystals, m.p. above 300°C NMR(DMSO-d₆) δ: 0.80-1.00(m, 3H), 1.20-1.60(m, 8H), 2.35-2.50(m, 2H), 5.24(s, 2H), 7.05-7.20(m, 3H), 7.50(d, 2H), 8.50(d, 1H, J=16Hz) IR(KBr) cm⁻¹: 3400, 1675, 1600, 1573, 970 EXAMPLE 5 Ethyl 6-(2-fluorophenyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoate Isomer A Yield 13.5%, m.p. 159-161°C (dec.) NMR(CDCl₃) δ: 1.29(t, 3H), 2.60(q, 2H), 2.86(q, 2H), 4.19(q, 2H), 7.00-7.40(m, 3H), 7.32(d, 1H, J=16.6Hz), 7.72(t x d, 1H), 8.59(d, 1H, J=16.6Hz), 8.33(bs, 1H) IR(KBr) cm⁻¹: 3158, 1728, 1680, 1608, 1547, 1485, 1074, 1027, 963, 761 Isomer B Yield 4.3%, m.p. 163-164.5°C (dec.) NMR(CDCl₃) δ: 1.27(t, 3H), 2.58(t, 2H), 3.43(t, 2H), 4.15(q, 2H), 6.75(d, 1H, J=15.6Hz), 7.05-7.45(m, 4H), 7.56(t x d, 1H), 9.34(bs, 1H) IR(KBr) cm⁻¹: 3402, 1715, 1694, 1602, 1544, 1067, 966, 764 EXAMPLE 6 Ethyl 6-(4-trifluoromethylphenyl)-4-(4-oxo-2-thioxo-5- thiazolidinylidene)-5-hexenoate Isomer A Yield 10%, m.p. 172-174°C (dec.) NMR(CDCl₃) δ: 1.29(t, 3H), 2.60(t, 2H), 2.86(t, 2H), 4.19(q, 2H), 7.12(d, 1H, J=16.6Hz), 7.62(d, 2H), 7.69(d, 2H), 8.64(d, 1H, J=16.6Hz), 9.50(bs, 1H) IR(KBr) cm⁻¹: 3418, 1724, 1679, 1617, 1550, 1330, 1199, 1122, 1069, 990, 827 Isomer B Yield 2%, m.p. 171-174°C (dec.) NMR(CDCl₃) δ: 1.27(t, 3H), 2.58(t, 2H), 3.43(t, 2H), 4.15(q, 2H), 6.71(d, 1H, J=15.6Hz), 7.27(d, 1H, J=15.6Hz), 7.57-7.64(m, 4H), 9.23(bs, 1H) IR(KBr) cm⁻¹: 3414, 1734, 1711, 1618, 1554, 1439, 1329, 1201, 1070 EXAMPLE 7 Ethyl 6-(4-cyanophenyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoate Yield 17.8%, m.p. 196-200°C (dec.) NMR(CDCl₃) δ: 1.28(t, 3H), 2.58(t, 2H), 2.85(t, 2H), 4.18(q, 2H), 7.08(d, 1H, J=16.6Hz), 7.66(s, 4H), 8.65(d, 1H, J=16.6Hz), 9.46(bs, 1H) IR(KBr) cm⁻¹: 3416, 2222, 1720, 1678, 1544, 1211, 1074, 824 EXAMPLE 8 Ethyl 6-(3-hydroxyphenyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoate Isomer A Yield 6%, m.p. 200-205°C (dec.) NMR(CDCl₃+DMSO-d₆) δ: 1.26(t, 3H), 2.55(t, 2H), 3.38(t, 2H), 4.13(q, 2H), 6.60(d, 1H, J=16Hz), 6.80-7.30(m, 5H), 8.99(s, 1H), 12.80(bs, 1H) IR(KBr) cm⁻¹: 3588, 3514, 1712, 1702, 1611, 1580, 1552, 1494, 1456, 1264, 1068, 959 Isomer B Yield 11.8%, m.p. 197-199°C (dec.) NMR(CDCl₃+DMSO-d₆) δ: 1.28(t, 3H), 2.50-2.90(m, 4H), 4.17(q, 2H), 6.75-7.30(m, 5H), 8.55(q, 1H, J=16Hz), 8.92(s, 1H), 12.80(bs, 1H) EXAMPLE 9 Methyl 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene-1-nonenyl]benzoate Isomer A Yield 5%, m.p. 175-176°C Mass spectrum (m/e); 389 (M⁺) NMR(CDCl₃) δ: 0.85-1.00(m, 3H), 1.20-1.70(m, 8H), 3.10(t, 2H), 3.94(s, 3H), 6.74(d, 1H, J=15.6Hz), 7.18(d, 1H, J=15.6Hz), 7.58(d, 2H), 8.07(d, 2H), 9.45(bs, 1H) IR(KBr) cm⁻¹: 3412, 3148, 1721, 1684, 1610, 1545, 1283, 1222, 1111, 1075, 1017, 950, 768 Isomer B Yield 17%, m.p. 148-150°C Mass spectrum (m/e); 389 (M⁺) NMR(CDCl₃) δ: 0.85-1.00(m, 3H), 1.25-1.70(m, 8H), 2.50(t, 2H), 3.93(s, 3H), 7.08(d, 1H, J=16.6Hz), 7.65(d, 2H), 8.05(d, 2H), 8.68(d, 1H, J=16.6Hz), 9.80(bs, 1H) IR(KBr) cm⁻¹: 3166, 1706, 1609, 1552, 1441, 1281, 1195, 1111, 1065, 970, 879, 769 EXAMPLE 10 Ethyl 2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)hexyl]- phenoxyacetate Isomer A Yield 50%, m.p. 109-110.3°C (CH₂Cl₂-IPE) NMR(CDCl₃) δ: 1.00(t, 3H), 1.30(t, 3H), 1.55(m, 2H), 2.52(m, 2H), 2.80-2.95(m, 4H), 4.27(q, 2H),4.69(s, 2H), 6.72(d, 1H), 6.92(t, 1H), 7.07-7.25(2H), 9.02(bs, 1H) IR(KBr) cm⁻¹: 3380, 3120, 1710, 1605, 1445, 1195, 760 Isomer B Yield 25%, m.p. 121.6-122.5°C (CHCl₃-IPE) NMR(CDCl₃) δ: 0.98(t, 3H), 1.30(t, 3H), 1.60(m, 2H), 2.19(m, 2H), 2.90(m, 2H), 3.11(m, 2H), 4.26(q, 2H), 4.63(s, 2H), 6.72(d, 1H), 6.94(t, 1H), 7.10-7.30(2H), 9.22(bs, 1H) IR(KBr) cm⁻¹: 3450, 3060, 1758, 1695, 1600, 1460, 1215, 755, 675 Example 11 Ethyl 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-nonenyl]cinnamate Isomer A Yield 2.4%, m.p. 187.5-189.0°C (CH₂Cl₂-IPE) NMR(CDCl₃) δ: 0.90(t, 3H), 1.34(t,3H), 1.25-1.60(8H), 3.10(t, 2H), 4.28(q, 2H), 6.49(d, 1H), 6.70(d, 1H), 7.14(d, 1H), 7.56(s, 4H), 7.67(d, 1H), 9.03(bs, 1H) IR(KBr) cm⁻¹: 3430, 3130, 3020, 1710, 1680, 1635, 1540, 1305, 1210, 680 Isomer B Yield 6.5%, m.p. 199.5-200.2°C (CH₂Cl₂-IPE) NMR(CDCl₃) δ: 0.91(t, 3H), 1.36(t, 3H), 1.25-1.67(8H), 2.50(t, 2H), 4.28(q, 2H), 6.48(d, 1H), 7.08(d, 1H), 7.58(q, 4H), 7.69(d, 1H), 8.63(d, 1H), 9.30(bs, 1H) IR(KBr) cm⁻¹: 3450, 3110, 1700, 1635, 1550, 1315, 1200, 975, 820, 685 EXAMPLE 12 Ethyl 6-(4-methoxycarbonylphenyl)-4-(4-oxo-2-thioxo-5- thiazolidinylidene)-5-hexenoate Yield 5%, m.p. 173.5-176.7°C NMR(CDCl₃) δ: 9.34(br, s, 1H), 8.64(d, 1H), 8.05(d, 2H), 7.64(d, 2H), 7.12(d, 1H), 4.18(q, 4H), 3.93(s, 3H), 2.84(t, 2H), 2.60(t, 2H), 1.59(s, 3H), 1.28(t, 3H) IR(KBr) cm⁻¹: 3214, 2980, 1720, 1705, 1611, 1554 EXAMPLE 13 Ethyl 6-(2-thienyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoate Isomer A Yield 5%, m.p. 157.9-160.1°C NMR(CDCl₃) δ: 7.43-7.06(m, 4H), 6.43(d, 1H), 4.16(q, 2H), 3.37(t, 2H), 2.57(t, 2H), 1.27(t, 3H) IR(KBr) cm⁻¹: 3134, 3034, 2980, 2866, 1730, 1679, 1589, 1546 Isomer B Yield 4.5%, m.p. 151.4-153.0°C NMR(CDCl₃) δ: 8.38(d, 1H), 7.40-7.03(m, 4H), 4.18(q, 2H), 2.70(t, 2H), 2.63(t, 2H), 1.28(t, 3H) IR(KBr) cm⁻¹: 3150, 3054, 2924, 2862, 1733, 1680, 1589, 1549 EXAMPLE 14 Ethyl 6-(3-methyl-2-thienyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoate Isomer A Yield 4% NMR(CDCl₃) δ: 7.46(d, 1H), 7.32(d, 1H), 6.89(d, 1H), 6.35(d, 1H), 4.14(q, 2H), 3.40(t,2H), 2.57(t, 2H), 2.36(s, 3H), 1.26(t, 3H) Isomer B Yield 3% NMR(CDCl₃) δ: 8.22(d, 1H), 7.29(d, 1H), 7.31(d, 1H), 6.87(d, 1H), 4.18(q, 2H), 2.82(t, 2H), 2.58(t, 2H), 2.35(s, 3H), 1.28(t, 3H) EXAMPLE 15 Ethyl 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]-2-methoxyphenoxyacetate Yield 50% NMR(DMSO-d₆) δ: 1.23(t, 3H), 2.16(s, 3H), 3.83(s, 3H), 4.18(q, 2H), 4.81(s, 2H), 6.93(d, 1H, J=8.3Hz), 7.15(d, 1H, J=8.3Hz), 7.17(s, 1H), 7.28(d, 1H, J=16Hz), 8.44(d, 1H, J=16Hz), 13.45(bs, 1H) EXAMPLE 16 Ethyl 3-{4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)nonanyl]phenyl}propionate Isomer A Yield 11%, m.p. 45.5-47.7°C NMR(CDCl₃) δ: 0.90(t, 3H), 1.23(t, 3H), 1.2-1.6(8H), 2.43(dd, 2H), 2.59(t, 2H), 2.7-2.85(m, 4H), 2.93(t, 2H), 4.12(q, 2H), 7.12(q, 4H), 9.03(bs, 1H) IR(KBr) cm⁻¹: 3430, 3160, 3070, 1730, 1700, 1610, 1450, 1220, 670 Isomer B Yield 14%, m.p. 84.7-87.3°C NMR(CDCl₃) δ: 0.90(t, 3H), 1.23(t, 3H), 1.2-1.45(6H), 1.45-1.6(2H), 2.15(dd, 2H), 2.60(t, 2H), 2.75(dd, 2H), 2.92(t, 2H), 3.06(dd, 2H), 4.12(q, 2H), 7.17(q, 4H), 9.22(bs, 1H) IR(KBr) cm⁻¹: 3430, 3160, 3050, 1730, 1695, 1605, 1450, 1220, 1080, 675 EXAMPLE 17 5-[α-Methyl-4-(1H-tetrazol-5-yl)cinnamylidene]-4-oxo-2-thioxothiazolidine Yield 10%, m.p. above 300°C Mass spectrum (m/e); 329 (M⁺) IR(KBr) cm⁻¹; 3400, 3036, 1684, 1616, 1550, 1437, 1204, 1075, 829 EXAMPLE 18 Methyl N-[2-(4-oxo-2-thioxo-5-thiazolidinylidene)propionyl]-anthranilate Yield 33%, m.p. 242°C (dec.) Mass spectrum (m/e); 336 (M⁺) NMR(CDCl₃ + DMSO-d₆) δ: 2.80(s, 3H), 3.98(s, 3H), 7.21(t, 1H), 7.62(t, 1H), 8.11(d, 1H), 8.78(d, 1H), 12.16(s, 1H), 13.28(bs, 1H) IR(KBr) cm⁻¹: 3460, 3174, 1691, 1659, 1607, 1592, 1541, 1440, 1301, 1281, 1092, 987, 929, 759 EXAMPLE 19 Methyl N-[5-(4-oxo-2-thioxo-5-thiazolidinylidene)hexanoyl]anthranilate Yield 53%, m.p. 174-178°C (dec.) Mass spectrum (m/e); 378 (M⁺) NMR(CDCl₃) δ: 1.90-2.10(m, 2H), 2.01(s, 3H), 2.54(t, 2H), 2.99(t, 2H), 3.92(s, 3H), 7.07(t, 1H), 7.54(t, 1H), 8.02(d, 1H), 8.71(d, 1H), 9.55(bs, 1H), 11.09(bs, 1H) IR(KBr) cm⁻¹: 3260, 3116, 1701, 1670, 1648, 1611, 1591, 1540, 1454, 1379, 1268, 1252, 1211, 1090, 1069, 759 EXAMPLE 20 5-{4-[4-(1H-Tetrazol-5-yl)butyloxy]benzylidene}-4-oxo-2-thioxothiazolidine Yield 39%, m.p. 225-227°C (dec.) NMR(DMSO-d₆) δ: 1.70-2.00(m, 4H), 2.85-3.05(m, 2H), 4.00-4.20(m, 2H), 7.10(d, 2H), 7.56(d, 2H), 7.70(s, 1H), 13.80(bs, 1H), 15.90(bs, 1H) IR(KBr) cm⁻¹: 2858, 1690, 1570, 1513, 1451, 1339, 1331, 1298, 944, 826 EXAMPLE 21 4-[3-(4-Oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxy-acetic acid A mixture of 0.12 g of Isomer A of ethyl 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate, 5 ml of water and 1 ml of 5% sodium hydroxide solution was stirred at room temperature for one hour. 10% hydrochloric acid was added to the mixture and the precipitated crystals were collected by filtration and washed with methanol to give Isomer A (54% yield) of 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid. In the same manner, Isomer B of 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid was obtained in 47% yield from Isomer B of ethyl 4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate. Isomer A Brown crystals, m.p. 260-263°C (dec.) Mass spectrum (m/e); 335 (M⁺) NMR(DMSO-d₆) δ: 2.50(s, 3H), 4.70(s, 2H), 6.65(d, 1H, J=16Hz), 6.95(d, 2H), 7.30(d, 1H, J=16Hz), 7.65(d, 2H), 13.30(br, s, 1H) IR(KBr) cm⁻¹: 753, 1674, 1599, 958 Isomer B Brown crystals, m.p. 261-263°C (dec.) Mass spectrum (m/e); 335 (M⁺) NMR(DMSO-d₆) δ: 2.15(s, 3H), 4.70(s, 2H), 7.00(d, 2H), 7.28(d, 1H, J=16Hz), 7.54(d, 2H), 8.45(d, 1H, J=16Hz), 13.40(br, s, 1H) IR(KBr) cm⁻¹: 1740, 1699, 1603, 973 The ester products obtained in the above examples were subjected to hydrolysis by a similar procedure as in Example 21 to obtain the compounds shown in the following Examples 22 to 37. EXAMPLE 22 6-(2-Fluorophenyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoic acid (from Isomer A of Example 5) Yield 33%, m.p. 224-227°C (dec.) NMR(CDCl₃ + DMSO) δ: 2.45-2.60,(m, 2H), 2.82(t, 2H), 7.00-7.40(m, 4H), 7.70(t, 1H), 8.63(d, 1H, J=16.6Hz), 13.20(bs, 1H) IR(KBr) cm⁻¹: 3414, 1712, 1662, 1607, 1555, 1485, 1454, 1286, 1240, 1210, 1194, 969, 762 EXAMPLE 23 6-(4-Trifluoromethylphenyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoic acid (from Isomer A of Example 6) Yield 31%, m.p. 182-188°C (dec.) IR(KBr) cm⁻¹: 3412, 1716, 1690, 1674, 1617, 1554, 1329, 1200, 1133, 1069, 977, 827 EXAMPLE 24 6-(4-Cyanophenyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoic acid (from the product of Example 7) Yield 76% (cis-trans mixture) m.p. 248-251°C (dec.) IR(KBr) cm⁻¹: 3406, 2232, 1735, 1674, 1548, 1436, 1293, 1212, 1134, 1070, 825 EXAMPLE 25 6-(3-Hydroxyphenyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoic acid (from Isomer A of Example 8) Yield 80%, m.p. 248-250°C (dec.) NMR(DMSO-d₆) δ: 2.20-2.70(m, 4H), 6.50-7.20(m, 5H), 8.72(d, 1H, J=16Hz), 9.50(bs, 1H) IR(KBr) cm⁻¹: 3336, 1681, 1608, 1547, 1450, 1204, 953 EXAMPLE 26 4-[3-(4-Oxo-2-thioxo-5-thiazolidinylidene)-1-nonenyl]benzoic acid (from Isomers A and B of Example 9) Isomer A (from Isomer A of Example 9) Yield 80%, m.p. 228-230°C (dec.) Mass spectrum (m/e); 375 (M⁺) NMR(CDCl₃-DMSO-d₆) δ: 0.80-1.00(m, 3H), 1.20-1.70(m, 8H), 3.00-3.20(m, 2H), 6.74(d, 1H, J=15.6Hz), 7.18(d, 1H, J=15.6Hz), 7.60(d, 2H), 8.04(d, 2H), 13.09(bs, 1H) IR(KBr) cm⁻¹: 1693, 1611, 1547, 1420, 1204, 1073, 948, 767 Isomer B (from Isomer B of Example 9) Yield 40%, m.p. 240-243°C (dec.) Mass spectrum (m/e); 375 (M⁺) NMR (CDCl₃ - DMSO-d₆) δ: 0.80-1.00(m, 3H), 1.20-1.70(m, 8H), 2.49(t, 2H), 7.06(d, 1H, J=16.6Hz), 7.62(d, 2H), 8.04(d, 2H), 8.71(d, 1H, J=16.6Hz), 12.65(bs, 1H) IR(KBr) cm⁻¹: 3430, 1696, 1610, 1546, 1441, 1420, 1267, 1203, 1075 EXAMPLE 27 2-[3-(4-Oxo-2-thioxo-5-thiazolidinylidene)hexyl]phenoxyacetic acid (from Isomers A and B of Example 10) Isomer A (from Isomer A of Example 10) Yield 95%, m.p. 181.5-184.5°C NMR(CDCl₃ + CD₃OD) δ: 1.00(t, 3H), 1.57(m, 2H), 2.52(m, 2H), 2.75-2.95(m, 4H), 4.67(s, 2H), 6.73(d, 1H), 6.93(t, 1H), 7.05-7.27(2H) IR(KBr) cm⁻¹: 3440, 3150, 3060, 1745, 1650, 1595, 1497, 1235, 755 Isomer B (from Isomer B of Example 10) Yield 95%, m.p. 219.5-222.5°C NMR(CDCl₃ + CD₃OD) δ: 0.97(t, 3H), 1.60(m, 2H), 2.19(m, 2H), 2.88(m, 2H), 3.09(m, 2H), 4.64(s, 2H), 6.76(d, 1H), 6.94(t, 1H), 7.10-7.27(2H) IR(KBr) cm⁻¹: 3430, 3160, 3060, 1740, 1690, 1595, 1500, 1440, 1220, 750, 675 EXAMPLE 28 4-[3-(4-Oxo-2-thioxo-5-thiazolidinylidene)-1-nonenyl]-cinnamic acid (from Isomer A of Example 11) Yield 90%, m.p. 230-243°C IR(KBr) cm⁻¹: 3450, 1690, 1630, 1550, 1430, 1200, 980 EXAMPLE 29 6-(4-Carboxyphenyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoic acid (from the product of Example 12) Yield 70%, m.p. 263°C (dec.) IR(KBr) cm⁻¹: 3400, 3075, 2850, 1695, 1611, 1545 EXAMPLE 30 6-(2-Thienyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoic acid (from the product of Example 13) Yield 90%, m.p. 175°C (dec.) IR(KBr) cm⁻¹: 3412, 2850, 1682, 1591, 1549 EXAMPLE 31 6-(3-Methyl-2-thienyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoic acid (from the product of Example 14) Yield 80%, m.p. 207°C (dec.) IR(KBr) cm⁻¹: 3430, 2850, 1700, 1585, 1551 EXAMPLE 32 4-[3-(4-Oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]-2-methoxyphenoxyacetic acid (from the product of Example 15) Yield 68%, m.p. 264-266°C (dec.) NMR(DMSO-d₆) δ: 2.15(s, 3H), 3.83(s, 3H), 4.71(s, 2H), 6.91(d, 1H), 7.10-7.20(m, 2H), 7.26(d, 1H, J=16.6Hz), 8.44(d, 1H, J=16.6Hz), 13.30(bs, 2H) IR(KBr) cm⁻¹: 3500, 1744, 1667, 1599, 1582, 1549, 1517, 1312, 1146, 1075, 1031, 966, 825, 676 EXAMPLE 33 3-{4-[3-(4-Oxo-2-thioxo-5-thiazolidinylidene)nonanyl]pheny}propionic acid (from Isomers A and B of Example 16) Isomer A (from Isomer A of Example 16) Yield 90%, m.p. 96.4-100.5°C NMR(CDCl₃) δ: 0.90(t, 3H), 1.2-1.6(8H), 2.45(dd, 2H), 2.66(t, 2H), 2.7-2.9(m, 4H), 2.94(t, 2H), 7.12(q, 4H), 9.78(bs, 1H) IR(KBr) cm⁻¹: 3430, 3140, 3050, 1715, 1665, 1605, 1450, 1325, 1225, 830, 680 Isomer B (from Isomer B of Example 16) Yield 95%, m.p. 153.5-157.0°C NMR(CDCl₃) δ: 0.90(t, 3H), 1.2-1.4(6H), 1.4-1.6(2H), 2.17(dd, 2H), 2.6-2.8(m, 4H), 2.95(t, 2H), 3.06(dd, 2H), 7.18(q, 4H), 9.98(bs, 1H) IR(KBr)cm⁻¹: 3430, 3175, 3075, 1710, 1690, 1600, 1440, 1300, 1220, 1080, 670 EXAMPLE 34 3-{2-[3-(4-Oxo-2-thioxo-5-thiazolidinylidene)pentyl]pyrrol-1-yl}propionic acid (from butyl 3-{2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)pentyl]pyrrol-1-yl}propionate) Yield 82%, m.p. 176.5°C IR(KBr)cm⁻¹: 3430, 3075, 1720, 1695, 1610, 1450, 1215, 1085, 730, 660 EXAMPLE 35 6-(2-Furyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoic acid (from ethyl 6-(2-furyl)-4-(4-oxo-2-thioxo-5-thiazolidinylidene)-5-hexenoate) Yield 80%, m.p. above 310°C IR(KBr) cm⁻¹: 3410, 2970, 2850, 1660, 1640, 1600, 1550 EXAMPLE 36 N-[2-(4-Oxo-2-thioxo-5-thiazolidinylidene)propionyl]anthranilic acid (from the product of Example 18) Yield 34%, m.p. 257°C (dec.) Mass spectrum (m/e); 322 (M⁺) NMR(CDCl₃ + DMSO-d₆) δ: 2.77(s, 3H), 7.19(t, 1H), 7.59(t, 1H), 8.13(d, 1H), 8.77(d, 1H), 12.55(s, 1H), 13.28(bs, 1H) IR(KBr) cm⁻¹: 3158, 1691, 1659, 1605, 1592, 1540, 1456, 1302, 1251, 1172, 987, 931, 758 EXAMPLE 37 N-[5-(4-Oxo-2-thioxo-5-thiazolidinylidene)hexanoyl]anthranilic acid (from the product of Example 19) Yield 80%, m.p. 206-212°C (dec.) Mass spectrum (m/e); 346 (M⁺) IR(KBr) cm⁻¹: 3074, 1713, 1664, 1608, 1586, 1533, 1449, 1411, 1294, 1261, 1203, 1164, 1151, 1079, 755 EXAMPLE 38 7-(3,4-Dimethoxyphenyl)-5-(4-oxo-2-thioxo-5-thiazolidinylidene)-6-heptenoic acid A mixture of 1.60 g (0.012 mol) of rhodanine, 3.06 g (0.01 mol) of ethyl 7-(3,4-dimethoxyphenyl)-5-oxo-6-heptenoate, 0.77 g (0.01 mol) of ammonium acetate and 20 ml of toluene was heated under reflux for 8 hours. After cooling, 100 ml of water were added to the reaction mixture which was extracted with ethyl acetate (3 x 100 ml). The ethyl acetate layer was washed three times with water and once with a saturated saline solution, dried over magnesium sulfate, filtered and the filtrate was concentratred under reduced pressure to afford a reddish brown oily substance. The oily substance was purified by silica gel column chromatography (eluent, chloroform) to obtain 0.5 g of ethyl 7-(3,4-dimethoxyphenyl)-5-(4-oxo-2-thioxo-5-thiazolidinylidene)-6-heptenoate. To 0.21 g of this compound was added 5 ml of water and 1 ml of 5% sodium hydroxide solution and the mixture was stirred at room temperature for 3 hours. This mixture was acidified with 10% hydrochloric acid, 100 ml of water was added to the acidified mixture which was extracted with ethyl acetate (3 x 120 ml). The ethyl acetate layer was washed three times with water and once with saturated saline solution, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, chloroform : methanol = 10:1) to obtain 0.12 g of Isomer A of 7-(3,4-dimethoxyphenyl)-5-(4-oxo-2-thioxo-5-thiazolidinylidene)-6-heptenoic acid from the first eluate and 0.03 g of Isomer B from the subsequent eluate. Ethyl ester Reddish brown crystals, m.p. 146-148°C (dec.) Mass spectrum (m/e); 421 (M⁺) IR(KBr) cm⁻¹: 1714, 1671, 1596, 1577, 971 Isomer A Reddish brown crystals, m.p. 223-225°C (dec.) Mass spectrum (m/e); 393 (M⁺) NMR(DMSO-d₆) δ: 1.80-2.00(m, 2H), 2.40-2.50(m, 2H), 2.52-2.70(m, 2H), 3.91(s, 3H), 3.93(s, 3H), 6.89(d, 1H), 7.10-7.20(m, 3H), 8.01(d, 1H, J=16Hz), 13.00(br, s, 1H) IR (KBr) cm⁻¹: 1697, 1596, 1541, 972 Isomer B Reddish brown crystals, m.p. 178-180°C (dec.) Mass spectrum (m/e); 393 (M⁺) NMR(DMSO-d₆) δ: 1.80-2.00(m, 2H), 2.35-2.50(m, 2H), 3.05-3.25(m, 2H), 3.91(s, 3H), 3.93(s, 3H), 6.50(d, 1H, J=16Hz), 6.80-6.95(m, 1H), 7.00-7.20(m, 2H), 7.28(d, 1H, J=16Hz), 12.30(br, s, 1H) IR(KBr) cm⁻¹: 1704, 1595, 1540, 954 EXAMPLE 39 Ethyl 2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate A mixture of 1.33 g (0.01 mol) of rhodanine, 2.48 g (0.01 mol) of ethyl 2-(3-oxo-1-butenyl)phenoxyacetate, 0.77 g (0.01 mol) of ammonium acetate and 20 ml of toluene was heated under reflux for 3 hours. After cooling, 100 ml of water were added to the reaction mixture which was extracted with ethyl acetate (3 x 100 ml). The ethyl acetate layer was washed twice with water and once with a saturated saline solution, dried and concentrated under reduced pressure to give orange crystals. The crystals were purified by silica gel column chromatography (eluent, chloroform : ethyl acetate) to obtain ethyl 2-[3-(4-oxo-2-thioxo-5-thiazolinylidene)-1-butenyl]phenoxyacetate (35.8% yield) from the first eluate. In accordance with similar procedure as mentioned in Example 39, the compounds shown in the following Examples 40 to 66 were obtained from the corresponding aldehydes or ketones. EXAMPLE 40 Methyl 2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 27.0% Reddish brown crystals, m.p. 213-215°C (dec.) IR(KBr) cm⁻¹: 1749, 1662, 1433, 1205 NMR(DMSO-d₆) δ: 2.16(s, 3H), 3.71(s, 3H), 4.90(s, 2H), 6.98(d, 1H), 7.08(d, 1H), 7.34(t, 1H), 7.52-7.62(3H), 8.57(d, 1H), 13,49(br, s, 1H) EXAMPLE 41 Methyl 2-[2-methyl-3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-propenyl]phenoxyacetate Yield 50.0% Orange crystals, m.p. 164-166°C (dec.) IR(KBr) cm⁻¹: 1748, 1696, 1568, 1446, 1308, 1240, 1213 NMR(CDCl₃) δ: 2.17(s, 3H), 3.82(s, 3H), 4.70(s, 2H), 6.79(d, 1H), 7.03(t, 1H), 7.27-7.34(3H), 7.52(s, 1H), 10.08(br, s, 1H) EXAMPLE 42 Methyl 2-methoxy-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 37.9% Orange crystals, m.p. 232-234°C (dec.) IR(KBr) cm⁻¹: 1733, 1663, 1511, 1214, 677 NMR(DMSO-d₆) δ: 2.16(s, 3H), 3.71(s, 3H), 3.83(s, 3H), 4.83(s, 2H), 6.94(d, 1H), 7.12-7.32(3H), 8.44(d, 1H), 13.45(br, s, 1H) EXAMPLE 43 Ethyl 2-methoxy-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)butyl]phenoxyacetate Yield 23.3% Pale yellow needles, m.p. 123-126°C IR(KBr) cm⁻¹: 1773, 1688, 1607, 1517, 1436, 1238, 1195, 806 NMR(CDCl₃) δ: 1.29(t, 3H), 1.95(s, 3H), 2.76(t, 2H), 3.14(t, 2H), 3.88(s, 3H), 4.26(q, 2H), 4.66(s, 2H), 6.75(s, 2H), 6.81(s, 1H), 9.89(br, s, 1H) EXAMPLE 44 Methyl 2-ethoxy-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 31.3% Orange crystals, m.p. 213.5°C IR(KBr) cm⁻¹: 1740, 1675, 1550, 1207, 968 NMR(DMSO-d₆) δ: 1.36(t, 3H), 2.17(s, 3H), 3.70(s, 3H), 4.10(q, 2H), 4.83(s, 2H), 6.93(d, 1H), 7.14(d, 1H), 7.17(s, 1H), 7.25(d, 1H), 8.43(d, 1H), 13.30(br, s, 1H) EXAMPLE 45 Methyl 2-ethoxy-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-butyl]phenoxyacetate Yield 76.0% Yellow crystals, m.p. 107°C IR(KBr) cm⁻¹: 1738, 1700, 1602, 1522, 1457, 1223 EXAMPLE 46 Methyl 2-methoxy-6-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 38.2% Orange crystals, m.p. 227°C (dec.) IR(KBr) cm⁻¹: 1740, 1662, 1553, 1280, 1207 EXAMPLE 47 Methyl 2-methoxy-6-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-butyl]phenoxyacetate Yield 40.0% Yellow crystals, m.p. 150-167°C IR(KBr) cm⁻¹: 1782, 1740, 1698, 1602, 1215, 663 EXAMPLE 48 Methyl 2,6-dimethoxy-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 2.0% Orange crystals, m.p. 222°C IR(KBr) cm⁻¹: 3460, 1675, 1583, 1455, 1215, 1135 EXAMPLE 49 Methyl 4-chloro-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 19.6% Orange crystals, m.p. 225-226°C IR(KBr) cm⁻¹: 1760, 1678, 1553, 1440, 1214 NMR(DMSO-d₆) δ: 2.15(s, 3H), 3.70(s, 3H), 4.92(s, 2H), 7.02(d, 1H), 7.30-7.58(m, 3H), 8.58(d, 1H), 13.49(br, s, 1H) EXAMPLE 50 Benzyl 4-chloro-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1 butenyl]phenoxyacetate Yield 12.5% Orange crystals, m.p. 130-140°C IR(KBr) cm⁻¹: 1748, 1677, 1554, 1444, 1203 EXAMPLE 51 Butyl 4-chloro-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Isomer A Yield 5.8% Orange crystals, m.p. 189-190°C IR(KBr) cm⁻¹: 3440, 1750, 1685, 1555, 1210 NMR(CDCl₃) δ: 0.92(t, 3H), 1.30-1.49(m, 2H), 1.58-1.74(m, 2H), 2.60(s, 3H), 4.25(t, 2H), 4.71(s, 2H), 6.73(d, 1H), 6.82(d, 1H), 7.30(m, 1H), 7.50(s, 1H), 7.55(d, 1H), 9.42(br, s, 1H) Isomer B Yield 6.8% Orange crystals, m.p. 149-150°C IR(KBr) cm⁻¹: 3440, 1748, 1680, 1550, 1205 NMR(CDCl₃) δ: 0.93(t, 3H), 1.28-1.48(m, 2H), 1.56-1.74(m, 2H), 2.21(s, 3H), 4.22(t, 2H), 4.70(s, 2H), 6.70(d, 1H), 7.25(m, 1H), 7.50-7.70(2H), 8.60(d, 1H), 9.42(br, s, 1H) EXAMPLE 52 1-{4-Chloro-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetyl}piperidine Yield 11.5% Orange cyrstals, m.p. 275°C IR(KBr) cm⁻¹: 2950, 2860, 1705, 1650, 1490, 1450, 1230, 1195 NMR(DMSO-d₆) δ: 1.40-1.70(m, 6H), 2.17(s, 3H), 3.30-3.50(m, 4H), 4.97(s, 2H), 7.00(d, 1H), 7.30-7.45(2H) 7.52(s, 1H), 8.57(d, 1H), 13.50(br, s, 1H) EXAMPLE 53 Ethyl 2-methoxy-4-[2-methyl-3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-propenyl]phenoxyacetate Yield 24.7% Brown crystals, m.p. 179-181°C (dec.) IR(KBr) cm⁻¹: 1757, 1688, 1553, 1516, 1445, 1265, 1193, 1147 NMR(DMSO-d₆) δ: 1.22(t, 3H), 2.19(s, 3H), 3.82(s, 3H), 4.18(q, 2H), 4.81(s, 2H), 6.90-7.19(m, 4H), 7.35(s, 1H), 13.68(br, s, 1H) EXAMPLE 54 Ethyl 2,6-diisopropyl-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 11.6% Yellow crystals, m.p. 239-241°C (dec.) IR(KBr) cm⁻¹: 1754, 1674, 1455, 1215, 1201 NMR(CDCl₃) δ: 1.27(d, 12H), 1.35(t, 3H), 2.20(s, 3H), 3.28-3.42(m, 2H), 4.32(q, 2H), 4.39(s, 2H), 7.11(d, 1H), 7.33(s, 2H), 8.58(d, 1H), 9.79(br, s, 1H) EXAMPLE 55 Ethyl 2-methoxy-4-[3-(3-methyl-4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Isomer A Yield 9.1% Yellow crystals, m.p. 183-187°C IR(KBr) cm⁻¹: 1731, 1695, 1562, 1517, 1303, 1280, 1250, 1143, 1122 NMR(CDCl₃) δ: 1.30(t, 3H), 2.64(s, 3H), 3.48(s, 3H), 3.95(s, 3H), 4.28(q, 2H), 4.73(s, 2H), 6.65(d, 1H), 6.80(d, 1H), 7.05-7.17(3H) Isomer B Yield 9.5% Orange crystals, m.p. 172-174°C (dec.) IR(KBr) cm⁻¹: 1739, 1511, 1279, 1127, 803 NMR(CDCl₃) δ: 1.29(t, 3H), 2.21(s, 3H), 3.48(s, 3H), 3.96(s, 3H), 4.27(q, 2H), 4.72(s, 2H), 6.79(d, 1H), 7.03-7.11(3H), 8.62(d, 1H) EXAMPLE 56 Methyl 4-bromo-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 20.8% Orange crystals, m.p. 235°C IR(KBr) cm⁻¹: 1763, 1678, 1442, 1215, 680 NMR(DMSO-d₆) δ: 2.17(s, 3H), 3.74(s, 3H), 4.90(s, 2H), 6.95(d, 1H), 7.40-7.70(3H), 8.58(d, 1H), 13.46(br, s, 1H) EXAMPLE 57 Methyl 2,4-dichloro-6-[3-(4-oxo-2-thioxo-5-thizolidinylidene)-1-butenyl]phenoxyacetate Yield 40.7% Yellow crystals, m.p. 252°C IR(KBr) cm⁻¹: 1765, 1450, 1205, 1175, 1050 NMR(DMSO-d₆) δ: 2.20(s, 3H), 3.75(s, 3H), 4.72(s, 2H), 7.57(q, 2H), 7.64(d, 1H), 8.55(d, 1H), 13.50(br, s, 1H) EXAMPLE 58 Methyl 2,4-dibromo-6-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 46.3% Yellow crystals, m.p. 249°C IR(KBr) cm⁻¹: 1765, 1710, 1560, 1448, 1202 NMR(DMSO-d₆) δ: 2.18(s, 3H), 3.75(s, 3H), 4.67(s, 2H), 7.50(d, 1H), 7.77(dd, 2H), 8.55(d, 1H), 13.50(br, s, 1H) EXAMPLE 59 Methyl 2-methoxy-5-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 37.8% Red powders, m.p. 225-229°C (dec.) IR(KBr) cm⁻¹: 1745, 1675, 1546, 1514, 1266, 1218, 677 NMR(DMSO-d₆) δ: 2.52(s, 3H), 3.73(s, 3H), 3.83(s, 3H), 4.88(s, 2H), 6.63(d, 1H), 7.02(d, 1H), 7.26-7.33(3H), 13.39(br, s, 1H) EXAMPLE 60 Methyl 2-methoxycarbonylmethoxy-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Isomer A Yield 10.4% Orange crystals, m.p. 190-196°C IR(KBr) cm⁻¹: 1750, 1682, 1550, 1517, 1440, 1218, 685 NMR(DMSO-d₆) δ: 2.54(s, 3H), 3.75(s, 3H), 3.77(s, 3H), 4.85(s, 2H), 4.90(s, 2H), 6.64(d, 1H), 6.95(d, 1H), 7.10-7.30(m, 3H), 13.30(br, s, 1H) Isomer B Yield 17.8% Red crystals, m.p. 182-186°C IR(KBr) cm⁻¹: 1765, 1670, 1545, 1517, 1435, 1220, 677 NMR(DMSO-d₆) δ: 2.17(s, 3H), 3.75(s, 3H), 3.77(s, 3H), 4.83(s, 2H), 4.85(s, 2H), 6.95(d, 1H), 7.10-7.30(m, 3H), 8.45(d, 1H), 13.50(br, s, 1H) EXAMPLE 61 Methyl 2-[2-propyl-3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-propenyl]phenoxyacetate Isomer A Yield 13.5% Yellow crystals, m.p. 147-149°C (dec.) IR(KBr) cm⁻¹: 1743, 1699, 1580, 1432, 1227, 749 NMR(CDCl₃) δ: 1.03(t, 3H), 1.50-1.68(m, 2H), 2.44(t, 2H), 3.80(s, 3H), 4.68(s, 2H), 6.78(d, 1H), 7.01(t, 1H), 7.15-7.34(3H), 7.63(s, 1H), 9.88(br, s, 1H) Isomer B Yield 17.5% Brown crystals, m.p. 142-144°C (dec.) IR(KBr) cm⁻¹: 1772, 1687, 1557, 1437, 1215, 1187 NMR(CDCl₃) δ: 0.99(t, 3H), 1.15-1.62(m, 2H), 2.40-2.48(m, 2H), 3.81(s, 3H), 4.71(s, 2H), 6.79(d, 1H), 7.03(t, 1H), 7.27-7.38(m, 2H), 7.47(s, 1H), 10.12(br, s, 1H) EXAMPLE 62 Methyl 4-isopropyl-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Isomer A Yield 24.6% Orange crystals, m.p. 200-202°C IR(KBr) cm⁻¹: 1760, 1673, 1204, 676 NMR(CDCl₃) δ: 1.26(d, 6H), 2.22(s, 3H), 2.85-2.99(m, 1H), 3.81(s, 3H), 4.72(s, 2H), 6.70(d, 1H), 7.15(dd, 1H), 7.56-7.70(3H), 8.65(d, 1H), 10.63(br, s, 1H). Isomer B Yield 9.6% Orange powders, m.p. 192-196°C (dec.) IR(KBr) cm⁻¹: 1759, 1679, 1547, 1210, 678 NMR(CDCl₃) δ: 1.25(d, 6H), 2.62(s, 3H), 2.82-2.96(m, 1H), 3.84(s, 3H), 4.73(s, 2H), 6.72(d, 1H), 6.89(d, 1H), 7.18(dd, 1H), 7.35(1H), 7.59(d, 1H), 9.65(br, s, 1H) EXAMPLE 63 Methyl 2-[2-methyl-3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-propenyl]phenoxyacetate Yield 41.5% Yellowish brown powders, m.p. 160-162°C (dec.) IR(KBr) cm⁻¹: 1763, 1732, 1691, 1564, 1437, 1205, 1190, 679 NMR(DMSO-d₆) δ: 2.15(s, 3H), 3.72(s, 3H), 4.82(s, 2H), 6.91-7.38(6H), 13.73(br, s, 1H) EXAMPLE 64 Methyl 2,6-dimethyl-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 41.0% Yellow crystals, m.p. 211-214°C (dec.) IR(KBr) cm⁻¹: 1760, 1717, 1557, 1440, 1218, 1206, 1153 EXAMPLE 65 Methyl 4-methoxy-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 45.7% Red crystals, m.p. 244-247°C (dec.) IR(KBr) cm⁻¹: 1746, 1497, 1216, 1200 NMR(DMSO-d₆) δ: 2.16(s, 3H), 3.70(s, 3H), 3.76(s, 3H), 4.83(s, 2H), 6.88-7.08(3H), 7.52(d, 1H), 8.54(d, 1H), 13.48(br, s, 1H) EXAMPLE 66 Methyl 4-trifluoromethyl-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate Yield 38.3% m.p. 240-241°C (dec.) IR(KBr) cm⁻¹: 3272, 1734, 1429, 1221, 1190, 1131, 1107 NMR(DMSO-d₆) δ: 2.17(s, 3H), 3.73(s, 3H), 5.05(s, 2H), 7.21(d, 1H), 7.49(d, 1H), 7.67(d, 1H), 7.83(s, 1H), 8.65(d, 1H), 13.56(br, s, 1H) EXAMPLE 67 2-[3-(4-Oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid A mixture of 0.85 g of ethyl 2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetate, 5 ml of water and 1 ml of 5% sodium hydroxide solution was stirred at room temperature for one hour. 10% hydrochloric acid was added to the mixture and the precipitated crystals were collected by filtration and washed with methanol to give 2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid in the yield of 76%. Yellowish brown crystals, m.p. 235-238°C (dec.) IR(KBr) cm⁻¹: 3398, 1738, 1672, 1549, 1438, 1244, 1217, 751, 670 NMR(DMSO-d₆) δ: 2.20(s, 3H), 4.69(s, 2H), 6.82(d, 1H), 7.03(t, 1H), 7.29(t, 1H), 7.56-7.71(m, 2H), 8.64(d, 1H), 13.05(br, s, 1H) The ester products obtained in the above examples were subjected to hydrolysis by a similar procedure as in Example 67 to obtain the compounds shown in the following Examples 68 to 89. EXAMPLE 68 2-[2-Methyl-3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-propenyl]phenoxyacetic acid (from the product of Example 41) Yield 21.0% Orange crystals, m.p. 218-220°C (dec.) IR(KBr) cm⁻¹: 3432, 1719, 1595, 1568, 1455, 1236, 1194, 743 NMR(DMSO-d₆) δ: 2.08(s, 3H), 4.70(s, 2H), 6.95(d, 1H), 6.98(d, 1H), 7.13(s, 1H), 7.15(s, 1H), 7.25-7.34(2H) EXAMPLE 69 2-Methoxy-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)butyl]phenoxyacetic acid (from the product of Example 43) Yield 32.7% Yellow powders, m.p. 166-170°C (dec.) IR(KBr) cm⁻¹: 1724, 1690, 1608, 1517, 1240, 1206, 816 EXAMPLE 70 2-Ethoxy-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butyl]phenoxyacetic acid (from the product of Example 44) Yield 99.8% Red crystals, m.p. 249-250°C IR(KBr) cm⁻¹: 3460, 1739, 1675, 1555, 1523, 1218 NMR(DMSO-d₆) δ: 1.40(t, 3H), 2.16(s, 3H), 4.10(q, 2H), 4.72(s, 2H), 6.88(d, 1H), 7.10-7.30(m, 3H), 8.45(d, 1H) EXAMPLE 71 2-Ethoxy-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)butyl]phenoxyacetic acid (from the product of Example 45) Yield 81.5% Yellow crystals, m.p. 199-200°C IR(KBr) cm⁻¹: 3410, 1715, 1610, 1520, 1215 EXAMPLE 72 2-Methoxy-6-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 46) Yield 83.0% Yellowish brown crystals, m.p. 210°C (dec.) IR(KBr) cm⁻¹: 3425, 1690, 1608, 1580, 1274, 1210 EXAMPLE 73 2-Methoxy-6-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)butyl]phenoxyacetic acid (from the product of Example 47) Yield 95% Yellow crystals, m.p. 209-229°C IR(KBr) cm⁻¹: 3450, 1698, 1610, 1485, 1220 EXAMPLE 74 2,6-Dimethoxy-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 48) Yield 83.0% Light brown crystals, m.p. 227-237°C IR(KBr) cm⁻¹: 3450, 1680, 1585, 1425, 1215, 1122 EXAMPLE 75 4-Chloro-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 49) Yield 95.5% Red crystals, m.p. 244-247°C IR(KBr) cm⁻¹: 3460, 1685, 1601, 1545, 1200 EXAMPLE 76 2-Methoxy-4-[2-methyl-3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-propenyl]phenoxyacetic acid (from the product of Example 53) Yield 15.7% Brown crystals, m.p. 229-231°C (dec.) IR(KBr) cm⁻¹: 3390, 1737, 1569, 1511, 1276, 1233, 1194, 686 NMR(DMSO-d₆) δ: 2.20(s, 3H), 3.81(s, 3H), 4.72(s, 2H), 6.88-7.18(4H), 7.35(s, 1H), 13.00(br, s, 1H), 13.68(br, s, 1H) EXAMPLE 77 2,6-Diisopropyl-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 54) Yield 32.9% Yellow crystals, m.p. 279-282°C IR(KBr) cm⁻¹: 3410, 2964, 1673, 1219 NMR(DMSO-d₆) δ: 1.21(d, 12H), 2.17(s, 3H), 3.24-3.34(m, 2H), 4.35(s, 2H), 7.32(d, 1H), 7.37(s, 2H), 8.50(d, 1H), 13.47(br, s, 1H) EXAMPLE 78 2-Methoxy-4-[3-(3-methyl-4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 55) Yield 94.0% Brown crystals, m.p. 241-245°C (dec.) IR(KBr) cm⁻¹: 3412, 1748, 1513, 1279, 1253, 1143, 1126 NMR(DMSO-d₆) δ: 2.21(s, 3H), 3.36(s, 3H), 3.84(s, 3H), 4.73(s, 2H), 6.92(d, 1H), 7.15-7.19(2H), 7.34(d, 1H), 8.50(d, 1H), 13.04(br, s, 1H) EXAMPLE 79 4-Bromo-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 56) Yield 99.5% Orange crystals, m.p. 245°C IR(KBr) cm⁻¹: 3450, 1685, 1548, 1440, 1200, 680 NMR(DMSO-d₆) δ: 2.13(s, 3H), 4.74(s, 2H), 6.90(d, 1H), 7.35-7.84(3H), 8.63(d, 1H) EXAMPLE 80 2,4-Dichloro-6-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 57) Yield 97.4% Light brown crystals, m.p. 263°C IR(KBr) cm⁻¹: 3450, 1685, 1568, 1453, 1210, 1050 NMR(DMSO-d₆) δ: 2.17(s, 3H), 4.58(s, 2H), 7.53(s, 2H), 7.74(d, 1H), 8.54(d, 1H), 13.40(br, s, 1H) EXAMPLE 81 2,4-Dibromo-6-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 58) Yield 96.4% Reddish brown crystals, m.p. 260-270°C IR(KBr) cm⁻¹: 3450, 1685, 1557, 1445, 1200 NMR(DMSO-d₄) δ: 2.15(s, 3H), 4.55(s, 2H), 7.62-7.80(3H), 8.50(d, 1H), 13.00(br, s, 1H) EXAMPLE 82 2-Methoxy-5-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 59) Yield 34.0% Reddish brown powders, m.p. 244-246°C (dec.) IR(KBr) cm⁻¹: 3412, 1736, 1599, 1545, 1513, 1263, 1231, 1195, 680 EXAMPLE 83 2-Methoxycarbonylmethoxy-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid Isomer A (from Isomer A of Example 60) Yield 99.0% Red crystals, m.p. 299°C (dec.) IR(KBr) cm⁻¹: 3430, 1695, 1605, 1515, 1420, 1203, 675 Isomer B (from Isomer B of Example 60) Yield 91.7% Red crystals, m.p. 314°C (dec.) IR(KBr) cm⁻¹: 3450, 1693, 1600, 1550, 1515, 1430, 1230, 1200, 678 NMR(DMSO-d₆) δ: 2.20(s, 3H), 4.72(s, 4H), 6.93(d, 1H), 7.10-7.30(m, 3H), 8.45(d, 1H) EXAMPLE 84 2-[2-Propyl-3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-propenyl]phenoxyacetic acid (from the product of Example 61) Yield 24.2% Orange powders, m.p. 234-238°C (dec.) IR(KBr) cm⁻¹: 3430, 1702, 1597, 1563, 1224 EXAMPLE 85 4-Isopropyl-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 62) Yield 84.0% Yellowish brown crystals, m.p. 264-268°C (dec.) IR(KBr) cm⁻¹: 3422, 1718, 1670, 1442, 1210, 676 NMR(DMSO-d₆) δ: 1.21(d, 6H), 6H), 2.17(s, 3H), 2.81-2.91(m, 1H), 4.75(s, 2H), 6.88(d, 1H), 7.17(d, 1H), 7.24-7.60(2H), 8.59(d, 1H), 13, 18(br, s, 1H) EXAMPLE 86 2-[2-Methyl-3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-propenyl]phenoxyacetic acid (from the product of Example 63) Yield 54.3% Yellow powders, m.p. 224-228°C (dec.) IR(KBr) cm⁻¹: 3398, 3222, 1730, 1713, 1575, 1438, 1220, 1188 NMR(DMSO-d₆) δ: 2.16(s, 3H), 4.71(s, 2H), 6.90-7.40(6H), 12.88(br, s, 1H), 13.74(br, s, 1H) EXAMPLE 87 2,6-Dimethyl-4-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 64) Yield 70.0% Yellow crystals, m.p. 269-273°C (dec.) IR(KBr) cm⁻¹: 3424, 1722, 1703, 1555, 1440, 1218, 1152 EXAMPLE 88 4-Methoxy-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 65) Yield 84.9% Brown crystals, m.p. 261-263°C (dec.) IR(KBr) cm⁻¹: 3414, 1731, 1713, 1497, 1449, 1214 NMR(DMSO-d₆) δ: 2.16(s, 3H), 3.76(s, 3H), 4.72(s, 2H), 6.93(s, 2H), 7.10(s, 1H), 7.55(d, 1H), 8.55(d, 1H), 13.05(br, s, 1H), 13.50(br, s, 1H) EXAMPLE 89 4-Trifluoromethyl-2-[3-(4-oxo-2-thioxo-5-thiazolidinylidene)-1-butenyl]phenoxyacetic acid (from the product of Example 66) Yield 75.4% Orange crystals, m.p. 267-269°C (dec.) IR(KBr) cm⁻¹: 3426, 1705, 1342, 1265, 1201, 1132 NMR(DMSO-d₆): 2.17(s, 3H), 4.93(s, 2H), 7.17(d, 1H), 7.49(d, 1H), 7.67(d, 1H), 7.82(s, 1H), 8.65(d, 1H), 13.25(br, s, 1H), 13.55(br, s, 1H) Pharmaceutical Example 1 Tablets (one tablet) N-[2-(4-oxo-2-thioxo-5-thiazolidinylidene)propionyl]anthranilic acid (active ingredient) 10 mg Lactose 67 mg Crystalline cellulose 15 mg Cornstarch 7 mg Magnesium stearate 1 mg 100 mg The above components were uniformly blended to form a powder for direct tabletting. The powder was compressed on a rotary tablet machine to yield tablets each weighing 100 mg and having a diameter of 6 mm. Pharmaceutical Example 2 Granules (one divided form) N-[2-(4-oxo-2-thioxo-5-thiazolidinylidene)propionyl]anthranilic acid (active ingredient) 10 mg Lactose 90 mg Cornstarch 50 mg Crystalline cellulose 50 mg Hydroxypropylcellulose 10 mg Ethanol 90 mg The active ingredient, lactose, cornstarch and cellulose were uniformly blended and a solution of hydroxypropylcellulose in ethanol was added. The resulting mixture was kneaded and granulated according to extrusion granulation method and the granules were dried in a dryer at 50°C. The dried granules were sieved out to a grain size of 297 µm - 1460 µm to form granules. One divided form contains 200 mg. Pharmaceutical Example 3 Injectable solutions N-[2-(4-oxo-2-thioxo-5-thiazolidinylidene)propionyl]anthranilic acid (active ingredient) 1 mg Sodium chloride 10 mg Distilled water ad lib. Total 1.0 ml Sodium chloride and the active ingredient were dissolved in distilled water to make up a total to 1.0 ml. Pharmaceutical Example 4 Suppositories N-[2-(4-oxo-2-thioxo-5-thiazolidinylidene)propionyl]anthranilic acid (active ingredient) 2 g Polyethylene glycol 4000 20 g Glycerol 78 g Total 100 g Glycerol was added to the active ingredient and then polyethylene glycol 4000 was added. The mixture was molten with heating and injected into a suppository dio and solidified by cooling to prepare suppositories, each weighing 1.5 g. Inhibitory Activity Against Aldose Reductase The compounds of the present invention were evaluated for the inhibitory activity against aldose reductase according to the following assay procedure. Assay Procedure Enzyme activity was assayed according to the modification [Biochemical Pharmacology, 25 , 2505 (1976)] of the method described in J. Biol. Chem., 240 , 877-882 (1965). SD strain male rats were sacrificed by decapitation, the lenses were excised and homogenized in cold distilled water. The homogenate was then centrifuged and the supernatant was used as the crude aldose reductase solution. Separately, a 0.1 M sodium phosphate buffer (pH 6.2) containing 0.4 M ammonium sulfate was prepared at 30°C. In this buffer were dissolved the present compound, the crude aldose reductase solution and nicotinamide-adenine dinucleotide phosphate, reduced form (NADPH). The mixture was preincubated at 30°C for 3 minutes and the reaction was initiated by addition of D,L-glyceraldehyde. In this case, the concentration of the present compound dissolved was 10⁻⁵ M and 10⁻⁶ M, respectively. The total amount of the assay mixture was 1.0 ml, containing 0.16 mM of NADPH, 10 mM of D,L-glyceraldehyde and 0.010-0.016 units of aldose reductase. The inhibitory activity of the present compounds against aldose reductase was measured using each 1.0 ml of the reaction mixture containing the present compound in the above concentration. In this measurement, the rate of NADPH oxidation was followed by recording the decrease in absorbance at 340 nm. The inhibitory activity of the present compounds against aldose reductase as measured was expressed in percentage of inhibition (%) as a relative activity based on a control value. The results are shown in the following table.

Claims: Use of compound of formula (I) wherein R¹ is hydrogen, C₁-C₈ alkyl, carboxyl(C₁-C₄)alkyl or (C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl; R² is -CH₂-CH₂-R³, (m is 0 or 1), (R is C₁-C₃ alkyl) or (n is 0 or 1-4); R³ is a thienyl or furyl group which may be substituted by C₁-C₃ alkyl or halogen; a pyrrolyl group which may be substituted by carboxy(C₁-C₃)alkyl on the nitrogen atom; or a phenyl group which may be substituted by one or more substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; and R⁴ is a phenyl group which may be substituted by one or more of the same substituents as defined above, or a pharmaceutically acceptable salt thereof for the preparation of medicaments for the prevention or treatment of complications of diabetes. The use of Claim 1 wherein R¹ is hydrogen, C₁-C₆ alkyl, carboxy(C₁-C₄)alkyl or (C₁-C₃)alkoxycarbonyl(C₁-C₄)alkyl. The use of Claim 1 wherein R² is -CH₂-CH₂-R³ and R³ is a phenyl group which is substituted by one or two substituents selected from the group consisting of C₁-C₃ alkoxy, carboxy(C₁-C₃)alkoxy and (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy. The use of Claim 1 wherein R² is -CH=CH-R³ and R³ is a thienyl or furyl group which may be substituted by C₁-C₃ alkyl or halogen; a pyrrolyl group which may be substituted by carboxy(C₁-C₃)alkyl on the nitrogen atom; or a phenyl group which may be substituted by one or more substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl. The use of Claim 1 wherein R² is a phenyl group substituted by 2H-tetrazolyl(C₁-C₄)alkoxy. The use of Claim 1 wherein R² is -CONHR⁴ and R⁴ is a phenyl group substituted by carboxyl or (C₁-C₃)alkoxycarbonyl. The use of Claim 1 wherein R² is n is 1 to 3 and R⁴ is a phenyl group substituted by carboxyl or (C₁-C₃)alkoxycarbonyl. The use of Claim 1 wherein R² is and R⁴ is a phenyl group substituted by C₁-C₃ alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy or carboxy(C₁-C₃)alkoxy. The use of Claim 1 wherein R² is and R⁴ is a phenyl group substituted by C₁-C₃ alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy or carboxy(C₁-C₃)alkoxy. Use of a compound of formula (I) wherein R¹ is hydrogen, C₁-C₈ alkyl, carboxyl(C₁-C₄)alkyl or (C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl; R² is -CH₂-CH₂-R³, (m is 0 or 1), (R is C₁-C₃ alkyl) or (n is 0 or 1-4); R³ is a thienyl or furyl group which may be substituted by C₁-C₃ alkyl or halogen; a pyrrolyl group which may be substituted by carboxy(C₁-C₃)alkyl on the nitrogen atom; or a phenyl group which may be substituted by one or more substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; and R⁴ is a phenyl group which may be substituted by one or more of the same substituents as defined above, or a pharmaceutically acceptable salt thereof for the preparation of medicaments for the inhibition of aldose reductase. A compound of the formula (I) wherein if R¹ is hydrogen: R² is -CH₂-CH₂-R³¹, -R³², -CH=CH-R³², and -(CH₂) n CONHR⁴, wherein R is C₁-C₃ alkyl, n is 0 - 4, R³¹ is a thienyl or furyl group which may be substituted by C₁-C₃ alkyl or halogen; a pyrrolyl group which may be substituted by carboxy(C₁-C₃)alkyl on the nitrogen atom; or a phenyl group which may be substituted by one or more substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; R³² is a pyrrolyl group substituted by carboxy(C₁-C₃)alkyl on the nitrogen atom, a thienyl group which may be substituted by C₁-C₃ alkyl or halogen, a furyl group substituted by C₁-C₃ alkyl or halogen or a phenyl group which may be substituted by one or more substitutents selected from the group consisting of C₁-C₃ alkyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; and R⁴ is a phenyl group which may be substituted by one or more substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; and if R¹ is C₁-C₈ alkyl, carboxyl(C₁-C₄)alkyl or (C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl: R² is R³¹ as defined above, -CH₂-CH₂-R³³ , -CH=CH-R³³, and -(CH₂) n -CONHR⁴ wherein R is C₁-C₃ alkyl; n is 0 - 4, R³³ is a furyl group which may be substituted by C₁-C₃ alkyl or halogen; and R⁴ is as defined above. A pharmaceutical composition which comprises as an active ingredient a compound of the formula (I) wherein if R¹ is hydrogen R² is -CH₂-CH₂-R³, (m is 0 or 1), (R is C₁-C₃ alkyl) or (n is 0 or 1-4); R³ is a thienyl or furyl group which may be substituted by C₁-C₃ alkyl or halogen; a pyrrolyl group which may be substituted by carboxy(C₁-C₃)alkyl on the nitrogen atom; or a phenyl group which may be substituted by one or more substituents selected from the group consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, halogen, trifluoromethyl, carboxyl, (C₁-C₃)alkoxycarbonyl, cyano, carboxy(C₁-C₃)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₃)alkoxy, benzyloxycarbonyl(C₁-C₃)alkoxy, piperidinylcarbonyl(C₁-C₃)alkoxy, 2H-tetrazolyl, 2H-tetrazolyl-(C₁-C₄)alkoxy, carboxy(C₂-C₄)alkenyl, (C₁-C₃)alkoxycarbonyl(C₂-C₄)alkenyl, carboxy(C₁-C₃)alkyl and (C₁-C₃)alkoxycarbonyl(C₁-C₃)alkyl; and R⁴ is a phenyl group which may be substituted by one or more of the same substituents as defined above, and if R¹ is C₁-C₈ alkyl, carboxyl(C₁-C₄)alkyl or (C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl: R² is R³¹ as defined above, -CH₂-CH₂-R³³ , -CH=CH-R³³, and -(CH₂) n -CONHR⁴ wherein R is C₁-C₃ alkyl; n is 0 - 4, R³³ is a furyl group which may be substituted by C₁-C₃ alkyl or halogen; and R⁴ is as defined above or a pharmaceutically acceptable salt thereof, associated with one or more pharmaceutically acceptable additives therefore.

Inventors: INOUE HITOSHI, KATO HIROKI, KINOSHITA NOBUHIRO, SUEDA NORIYOSHI, TAHARA YOSHIYUKI, INOUE, HITOSHI, KATO, HIROKI, KINOSHITA, NOBUHIRO, SUEDA, NORIYOSHI, TAHARA, YOSHIYUKI, INOUE, HITOSHI, MASUDA DAI-ICHI HEIGHTS 504
Applicants: NISSHIN FLOUR MILLING CO, NISSHIN FLOUR MILLING CO., LTD.
Application year: 1990
Main classification: C07D277
IPC codes: C07D277, C07D417