Superoxide radical inhibitor

Abstract

A superoxide radical inhibitor containing, as an effective ingredient, an azole derivative represented by the general formula (1),[wherein R1 represents a phenyl group which may have 1-3 lower alkoxy groups as substituent(s) on the phenyl ring, a phenyl group having a lower alkylenedioxy group, or the like; R2 represents a hydrogen atom, a phenyl group, a halogen atom, a lower alkoxycarbonyl group, a lower alkyl group, an amino-lower alkyl group which may have a lower alkyl group as a substituent, a dihydrocarbostyril group, or the like; R3 represents a group of the formula,(R4B represents a hydroxyl group, a carboxy group, a lower alkenyl group or a lower alkyl group, m represents 0, 1 or 2); X represents a sulfur atom or an oxygen atom] or a salt thereof.

We claim:  
     
       1. A thiazole derivative of the general formula,                    
       wherein: 
       R 1  represents a phenyl group which may have ,substituents on the phenyl ring, 1-5 groups selected from the group consisting of an alkoxy group, a tri-lower alkyl group substituted silyloxy group, a lower alkyl group, a hydroxyl group, a lower alkenyloxy group, a lower alkylthio group, a phenyl group which may have a group selected from the group consisting of a thiazole group having, as a substituent on the thiazolyl ring, a phenyl group which may have a lower alkoxy group on the phenyl ring, a carboxyl group and a hydroxyl group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a halogen atom, a nitro group, a group of the formula.                    
       (wherein A represents a lower alkylene group or a group                    
       l represents 0 or 1; and R 8  and R 9 , which may be the same or different, each represent a hydrogen atom, a lower alkyl group, a lower alkanoyl group, an amino-lower alkyl group which may have a lower alkyl group as a substituent, or a piperidinyl-lower alkyl group; further R 8  and R 9  as well as the adjacent nitrogen atom being bonded thereto, together with or without another nitrogen atom or oxygen atom may form a five- to six-membered saturated or unsaturated heterocyclic group; said five- to six-membered heterocyclic group may have a lower alkanoyl group or a lower alkyl group as a substituent), a lower alkanoyl group, a lower alkanoyloxy group, a lower alkoxycarbonyl group, a cyano group, a tetrahydropyranyloxy group which may have 1-4 substitutents, selected from the group consisting of a hydroxyl group, a lower alkoxycarbonyl group, a phenyl-lower alkoxy group, a hydroxyl group or a lower alkanoyloxy group-substituted lower alkyl group and a lower alkanoyloxy group, and amidino group, a hydroxysulfonyloxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a mercapto group, a lower alkoxy-substituted lower alkoxy group, a lower alkyl group having hydroxyl groups, a lower alkenyl group, an aminothiocarbonyloxy group which may have a lower alkyl group as a substituent an aminocarbonylthio group which may have a lower alkyl group as a substituent, a lower alkanoyl-substituted lower alkyl group, a carboxy group, a group of the formula,                    
       (wherein R 21  and R 22 , which may be the same or different each represent a hydrogen atom or a lower alkyl group), a phenyl-lower alkoxycarbonyl group, a lower alkynyl group, a lower alkoxycarbonyl-substituted lower alkyl group, a carboxy-substituted lower alkyl group, a lower alkoxycarbonyl-substituted alkenyl group, a carboxy-substituted lower alkenyl group, a lower alkyl-sulfonyloxy group, which may have a halogen atom, a lower alkoxy-substituted lower alkoxycarbonyl group, a lower alkenyl group having halogen atoms and a phenyl-lower alkoxy group; and a phenyl group having a lower alkylenedioxy group from  1  to  3  lower alkoxy groups as substituents; 
       R 2E  represents a hydrogen atom; and  
       R 3E  represents a 5 to 15 membered monocyclic, bicyclic or tricyclic heterocyclic residual group having 1 to 2 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and said heterocyclic residual group pyridyl group which may have 1 to 3 substituents selected from the group consisting of an oxo group, an  alkyl group, a benzoyl group, a lower alkanoyl group, a hydroxy hydroxy group, a carboxy group, a lower alkoxycarbonyl group, a lower alkylthio group, a group of the formula.                    
       (wherein A is lower alkylene group or a group                    
       and; R 23  and R 24 , which may be the same or different, each represent a hydrogen atom or a lower alkyl group; further R 23  and R 24  as well as the adjacent nitrogen atom being bonded thereto, together with or without another nitrogen atom or oxygen atom may form a five- to six-membered saturated heterocyclic group; and said five- to six-membered heterocyclic group may have a lower alkyl group as a substituent), a cyano group, a lower alkyl group having hydroxy groups, a phenylaminothiocarboyl group and an amino-lower alkoxycarbonyl group which may have a lower alkyl group as a substituent or a furyl group which has  1  to  3  substituents selected from the group consisting of an alkyl group, a benzoyl group, a lower alkanoyl group, a hydroxy group, a carboxy group, a lower alkoxycarbonyl group, a lower alkylthio group, a group of the formula:                   
       (wherein A is a lower alkylene group or a group                   
       and R 23    and R   24   , which may be the same or different, each represent a hydrogen atom or a lower alkyl group; further R   23    and R   24    as well as the adjacent nitrogen atom being bonded thereto, together with or without another nitrogen atom or oxygen atom may form a five -  to six - membered saturated heterocyclic group; and said five -  to six - membered heterocyclic group may have a lower alkyl group as a substituent), a cyano group, a lower alkyl group having hydroxy groups, a phenylaminothiocarbonyl group and an amino - lower alkoxycarbonyl group which may have a lower alkyl group as a substituent,  or a salt thereof; 
       provided that R 3E  is not a unstubstituted pyrazinyl group;  
       provided further that R 3  is not a 3-hydroxy-2,5-dioxo-3-pyrrolinyl group;  
       provided further that when R 3E  is a julolidine or tetrahydroquinoline group, which may have a C 1 -C 6  alkyl group, then R 1  is not a group of the formula:                    
       (wherein R CC  is a hydroxyl group, mono- or di- C 1 -C 6  alkylated amino group; and each of R AA  and R BB , which may be the same or different, is a hydrogen atom a C 1 -C 6  alkoxy group which may be substituted by a carboxyl group, or a C 1 -C 6  alkyl group which may be substituted by a carboxyl group); and 
       provided further that R 3E  is not a substituted or unsubstituted cumarinyl group or a substituted or unsubstituted 5,6-benzocumarinyl group ; provided that when R 3E    is a pyridyl group which may have  1  to  3  hydroxy groups as substituents, then the pyridyl group is not substituted at the  2   - position with a hydroxy group.   
     
     
       2. The thiazole derivative of  claim 1 , wherein R 1  phenyl group which may have from 1-3 substituents selected the group consisting of an alkoxy group and a hydroxyl group, or a salt thereof. 
     
     
       3. The thiazole derivative of  claim 2 , wherein R 1  i phenyl group which may have from 1-3 lower alkoxy groups as substituents, or a salt thereof. 
     
     
       4. The thiazole deriative of  claim 3 , wherein the heterocyclic residual group of R 3E  is pyrrolidinyl, piperidinyl, piperazinyl, morpholin, pyridyl, 1,2,5-6-tetrahydropyridyl, thienyl, quinolyl, 1-4-dihydroquinolyl, benzothiazolyl, pyr, pyrimidyl, pyridazylthienyl, pyrrolyl, carbostyryl, 3-4-dih carbostyryl, 1,2,3,4-tetrahydroquinolyl, indolyl, isoindoly, indolinyl, benzoimidazolyl, benzooxazolyl, imidazolidnyl, isoquinolyl, quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, carbazolyl, acrydinyl, chromanyl, isoindoliny isochromanyl, pyrazolyl, imidazolyl, pyrazolidinyl, phenothiazinyl, benzofuryl, 2,3-dihydrobenzo(b) furyl, benzothienyl, phenoxthiinyl, phenoxazinyl, 4H-chromenyl, 1H-indazolyl, phenazinyl, xanthenyl, thianthrenyl, isoindolinyl, imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, pyranyl, pyrazolidinyl, 2-pyrazoli quinclidinyl, 1-4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl, 1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithiadihydronaphthalenyl, phenanthridinyl, 1,4-dithianaphthalenyl, dibenzo(b,e)azepine or 6,11-dihydro-5H-dibenzo(b,e)azepine, or a salt thereof. 
     
     
       5. The thiazole derivative of  claim 4 , wherein the heterocyclic residual group is a pyridyl group, or a salt thereof. 
     
     
       6. The thiazole derivative according to  claim 1 , wherein R 1  is a phenyl group which may have 1 to 3 lower alkoxy groups as substituents; R 3E  is a pyridyl or furyl heterocyclic residual group which may have 1 to 3 substituents selected from the group consisting of an oxo group, an alkyl group, a benzoyl group, a lower alkanoyl group, a hydroxyl group, a carboxy group, a lower alkoxycarbonyl group, a lower alkylthio group, a group of the formula:                    
       (wherein A is the same as defined above; R 23  and R 24  which may be the same or different, each represents a hydrogen atom or a lower alkyl group; further R 23  and R 24 , as well as the adjacent nitrogen atom being bonded thereto, together with or without another nitrogen atom or oxygen atom may form a five- to six-membered saturated heterocyclic group which may have a lower aklyl group as a substituent), a cyano group, a lower alkyl group having hydroxyl groups, a phenylaminothiocarbonyl group and an amino-lower alkoxycarbonyl group which may have a lower alkyl group as a substituent; or a salt thereof. 
     
     
       7. The thiazole derivative according to claim  6   1 wherein R 3E  is a pyridyl or furyl heterocyclic residual  group which may have 1 to 3 substituents selected from the group consisting of a carboxy group, a hydroxyl  hydroxy group, a lower alkoxycarbonyl group and a lower alkyl group having hydroxyl  hydroxy groups; or a salt thereof. 
     
     
       8. The thiazole derivative according to  claim 7 , wherein R 3E  is a pyridyl group which may have 1 to 3 substituents selected from the group consisiting of a carboxy group, a hydroxyl group,  and a lower alkoxycarbonyl group  and a lower alkyl group having hydroxyl groups ; or a salt thereof. 
     
     
       9. 2-(3,4-Diethoxyphenyl)-4-(2-carboxy-σ-pyridyl)-thiazole. 
     
     
       10. A superoxide radical inhibitor comprising as the active ingredient a thiazole derivative or a salt thereof of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       11. A superoxide radical inhibitor comprising as the active ingredient 2-(3,4-diethoxyphenyl)-4-(2-carboxy-6-pyridyl) thiazole and a pharmaceutically acceptable carrier. 
     
     
       12. The thiazole derivative according to  claim 1 , wherein R 3E    is a furyl group which has  1  to  3  substituents selected from the group consisting of a carboxy group, a hydroxy group, a lower alkoxycarbonyl group and a lower alkyl group having hydroxy groups; or a salt thereof.