Tetrazole derivatives and aldose reductase inhibition therewith

Abstract

The present invention relates to an aldose reductase inhibitor having the following formula: <IMAGE> R1 is a hydrogen atom or -A-COOR5 (A is an alkylene group having 1 to 4 carbon atoms and R5 is a hydrogen atom or a lower alkyl group), and R2, R3 and R4 are the same as or different from each other and selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen atom, a carboxyl group, an alkyl group, an amide group, an amino group, an alkoxy group, an aryl group, an aryloxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a nitro group, -NHCOCOOR6 (R6 is a hydrogen atom or a lower alkyl group), a mono- or dialkylaminosulfonyl group, and a residual group having the following formula: <IMAGE> (A and R5 are the same as in the above). The compounds defined in the above are excellent in aldose reductase inhibitory activity and low in toxicity. Therefore, those compounds are useful as a preventive agent and/or a remedy for diabetic complications such as neuropathy, retinopathy, nephropathy, cataracts and keratopathy.

What is claimed is: 
     
       1. A compound having the following formula (I): ##STR15## .[.wherein R 1  is --A--COOR 5 , and where A is an alkylene group having 1 to 4 carbon atoms and R 5  is a hydrogen atom or a lower alkyl group; and.]. .Iadd.wherein .Iaddend.   R 2 , R 3 , and R 4  are selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen group, a carboxyl group, an alkyl group, an amide group, an amino group, an alkoxy group, an aryl group, an aryloxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a nitro group, --NHCOCOOR 6  where R 6  is a hydrogen atom or lower alkyl group, a mono- or dialkylaminosulfonyl group, and a residual group having the following formula (II): ##STR16## .[.and where A and R 5  are the same as above; with the proviso that the compound of formula (I) does not include the following combination of substituents:   wherein A is an ethylidene group or isopropylidene group, R 5  is a hydrogen atom or ethyl group, and R 2 , R3, and R 4  are hydrogen atoms;   wherein A is a methylene group, R 5  is a hydrogen atom, a methyl group or an ethyl group, and R 2 , R 3  and R 4  are hydrogen atoms;   wherein A is a trimethylene group or tetramethylene group, R 5  is a hydrogen atom or a methyl group, and R 2 , R 3  and R 4  are hydrogen atoms; and   wherein A is a methylene group, R 5  is a hydrogen atom or an ethyl group, R 2  and R 3  are hydrogen atoms, and R 4  is a 3- or 4-bromine atom, a 3- or 4-chlorine atom, a 3- or 4-nitro group, a 3- or 4-methyl group or a 3-trifluoromethyl group.]. .Iadd.with the proviso that R 2 , R 3 , and R 4  are not all hydrogen atoms, and with the further proviso that when R 2  and R 3  are hydrogen atoms, R 4  is not a 3- or 4-bromine atom, a 3- or 4- chlorine atom, a 3- or 4-nitro group, a 3- or 4-methyl group or a 3-trifluoromethyl group. .Iaddend. .[.   
     
     
       2.  A composition comprising an effective amount of a compound in combination with a physiologically acceptable additive, said compound having the following formula (I): ##STR17## wherein R 1  is --A--COOR 3 , and where A is an alkylene group having 1 to 4 carbon atoms and R 5  is a hydrogen atom or a lower alkyl group; and R 2 , R 3  and R 4  are selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen atom, a carboxyl group, an alkyl group, an amide group, an amino group, an alkoxy group, an aryl group, an aryloxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a nitro group, --NHCOCOOR 6  where R6 is a hydrogen atom or a lower alkyl group, a mono-or dialkylaminosulfonyl group, and a residual group having the following formula (II): ##STR18##  and where A and R 5  are the same as above: with the proviso that the compound of formula (I) does not include the following combination of substituents:   wherein A is an ethylidene group or isopropylidene group, R 5  is a hydrogen atom or an ethyl group, and R 2 , R 3  and R 4  are hydrogen atoms;   wherein A is a methylene group, R 5  is a hydrogen atom, a methyl group or an ethyl group, R 2 , R 3  and R 4  are hydrogen atoms;   wherein A is a trimethylene group or a tetramethylene group, R 5  is a hydrogen atom or a methyl group, and R 2 , R 3  and R 4  are hydrogen atoms; and   wherein A is a methylene group, R 5  is a hydrogen atom or an ethyl group, R 2  and R 3  are hydrogen atoms, and R 4  is a 3- or 4-bromine atom, a 3- or 4-chlorine atom, a 3-or 4-nitro group, a 3-or 4-methyl group or a 3-trifluoromethyl group..].   
     
     
       3. A method for alleviating diabetic complications in an animal comprising administering to the animal an effective amount of a compound having the following formula (I): ##STR19## wherein R 1  is a hydrogen atom or --A--COOR 5 , and where A is an alkylene group having 1 to 4 carbon atoms and R 5  is a hydrogen atom or a lower alkyl group; and R 2 , R 3  and R 4  are selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen atom, a carboxyl group, an alkyl group, an amide group, an amino group, an alkoxy group, an aryl group, an aryloxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a nitro group, --NHCOCOOR 6  where R 6  is a hydrogen atom or a lower alkyl group, a mono-or dialkylaminosulfonyl group, and a residual group having the following formula (II): ##STR20##  and where A and R 5  are the same as above.   
     
     
       4. The method of claim 3 wherein the compound is administered to the animal in an amount ranging from 1 to 1000 mg per adult animal. 
     
     
       5. The method of claim 4 wherein the administration is made by oral administration, intravenous injection, subcutaneous injection, intramuscular injection or local medication. 
     
     
       6. The method of claim 3 wherein the compound is admixed with a physiologically acceptable additive prior to administration. 
     
     
       7. A method of inhibiting aldose reductase in an animal comprising administering to the animal an effective amount of a compound having the following formula (I): ##STR21## wherein R 1  is a hydrogen atom or --A--COOR 5 , and where A is an alkylene group having 1 to 4 carbon atoms and R 5  is a hydrogen atom or a lower alkyl group; and R 2 , R 3  and R 4  are selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen atom, a carboxyl group, an alkyl group, an amide group, an amino group, an alkoxy group, an aryl group, an arytoxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, a nitro group --NHCOCOOR 6 , where R 6 , is a hydrogen atom or a lower alkyl group, a mono- or dialkylaminosulfonyl group, and a residual group having the following formula (II): ##STR22## and where A and R 5  are the same as above.   
     
     
       8. The method of claim 7 wherein said compound is administered to the animal in an amount ranging from 1 to 1000 mg per adult animal. 
     
     
       9. The method of claim 7 wherein the administration is made by oral administration, intravenous injection, subcutaneous injection, intramuscular injection or local medication. 
     
     
       10. The method of claim 7 wherein the compound is admixed with a physiologically acceptable additive prior to administration. .Iadd. 
     
     
       11.  A composition comprising an effective amount of a compound of claim 1 in combination with a physiologically acceptable additive. .Iaddend.