Therapeutic agent for renal failure

Abstract

The present invention relates to a therapeutic agent for renal failure comprising, as an active ingredient, a 4,8-inter-m-phenylene prostaglandin I 2 derivative, and also relates to a method of treatment of renal failure using the same.

1 . A therapeutic agent for renal failure comprising, as an active ingredient, a 4,8-inter-m-phenylene prostaglandin I 2  derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  represents: 
 (A) COOR 2  
 wherein R 2  represents: 
 1) hydrogen or a pharmacologically acceptable positive ion;  
 2) a straight-chain C 1-12  alkyl group or a branched C 3-14  alkyl group;  
 3) -Z-R 3  
 wherein Z represents a valence bond or a straight-chain or branched alkylene group represented by C t H 2t  where t represents an integer from 1 to 6; and R 3  represents a C 3-12  cycloalkyl group unsubstituted or substituted by 1 to 3 substituents of R 4  where R 4  is hydrogen or a C 1-5  alkyl group;  
 
 
 4) —(CH 2 CH 2 O) n CH 3  
 wherein n represents an integer from 1 to 5;  
 
 5) -Z-Ar 1  
 wherein Z has the same meaning as defined above; and Ar 1  represents phenyl, α-naphthyl, β-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, α-furyl, β-furyl, α-thienyl, β-thienyl or substituted phenyl (wherein the substituted phenyl contains at least one substituent of chlorine, bromine, fluorine, iodine, trifluoromethyl, a C 1-4  alkyl group, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidobenzamide, —CH═N—NH—C(═O)—NH 2 , —NH—C(═O)-Ph, —NH—C(═O)—CH 3  or —NH—C(═O)—NH 2 );  
 
 6) —C t H 2t COOR 4  
 wherein each of C t H 2t  and R 4  has the same meaning as defined above;  
 
 7) —C t H 2t N(R 4 ) 2  
 wherein each of C t H 2t  and R 4  has the same meaning as defined above;  
 
 8) —CH(R 5 )—C(═O)—R 6 , 
 wherein R 5  represents hydrogen or benzoyl; and R 6  represents phenyl, p-bromophenyl, p-chlorophenyl, p-biphenyl, p-nitrophenyl, p-benzamidophenyl or 2-naphthyl;  
 
 9) —C p H 2p —W—R 7  
 wherein W represents —CH═CH—, —CH═CR 7 — or —C≡C—; R 7  represents hydrogen or a straight-chain or branched C 1-30  alkyl or aralkyl group; and p represents an integer from 1 to 5; or  
 
 10) —CH(CH 2 OR 8 ) 2  
 wherein R 8  represents a C 1-30  alkyl or acyl group;  
 
 
 
 (B) —CH 2 OH;  
 (C) —C(═O)N(R 9 ) 2  
 wherein R 9  represents hydrogen or a straight-chain C 1-12  alkyl group, a branched C 3-12  alkyl group, a C 3-12  cycloalkyl group, a C 4-13  cycloalkylalkylene group, a phenyl group, a substituted phenyl group (wherein the substitute or substituents are the same radicals as defined for (A)-5) described above), a C 7-12  aralkyl group, or —SO 2 R 10  where R 10  represents a C 1-10  alkyl group, a C 3-12  cycloalkyl group, a phenyl group, a substituted phenyl group (wherein the substitute or substituents are the same radicals as defined for (A)-5) described above) or a C 7-12  aralkyl group; provided that the two R 9  radicals are the same as or different from each other, but when one represents —SO 2 R 10 , then the other does not represent —SO 2 R 10 ; or  
 
 (D) —CH 2 OTHP (wherein THP represents a tetrahydropyranyl group);  
 A represents: 
 1) —(CH 2 ) m —;  
 2) —CH═CH—CH 2 —;  
 3) —CH 2 —CH═CH—;  
 4) —CH 2 —O—CH 2 —;  
 5) —CH═CH—;  
 6) —O—CH 2 —; or  
 7) —C≡C— 
 wherein m represents an integer from 1 to 3; Y represents hydrogen, a C 1-4  alkyl group, chlorine, bromine, fluorine, formyl, methoxy or nitro group; B represents —X—C(R 11 )(R 12 )OR 13    
 wherein: 
 R 11  represents hydrogen or a C 1-4  alkyl group;  
 R 13  represents hydrogen, a C 1-14  acyl group, a C 6-15  aroyl group, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl or t-butyl;  
 X represents: 
 1) —CH 2 —CH 2 —;  
 2) —CH═CH—; or  
 3) —C≡C—; and  
 
 
 R 12  represents: 
 1) a straight-chain C 1-12  alkyl group or a branched C 3-14  alkyl group;  
 2) -Z-Ar 2 ; 
 wherein Z has the same meaning as defined above; and Ar 2  represents phenyl, α-naphthyl, β-naphthyl, or at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, a C 1-4  alkyl group, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, or  
 
 3) —C t H 2t OR 14 ; 
 wherein C t H 2t  has the same meaning as defined above; and R 14  represents a straight-chain C 1-6  alkyl group, a branched C 3-6  alkyl, phenyl, or at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, an C 1-4  alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, cyclopentyl, cyclohexyl, or a cyclopentyl or cyclohexyl substituted by 1 to 4 straight-chain C 1-4  alkyl groups;  
 
 4) -Z-R 3  
 wherein each of Z and R 3  has the same meaning as defined above;  
 
 5) —C t H 2t —CH═C(R 15 )R 16  
 wherein C t H 2t  has the same meaning as defined above; and R 15  and R 16  independently represent hydrogen, methyl, ethyl, propyl or butyl group; or  
 
 6) —C u H 2u —C≡C—R 17  
 wherein u represents an integer from 1 to 7; C u H 2u  represents a straight-chain or branched alkylene group; and R 17  represents a straight-chain C 1-6  alkyl group; and E represents hydrogen or —OR 18    
 
 
 
 wherein R 18  represents a C 1-12  acyl group, a C 7-15  aroyl group or R 2  (wherein R 2  has the same meaning as defined above); and the formula is in the isomeric d-form, l-form or dl-form.  
 
     
     
         2 . A therapeutic agent for renal failure comprising, as an active agent, a 4,8-inter-m-phenylene prostaglandin I 2  derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  represents COOR 2  wherein R 2  represents hydrogen or a pharmacologically acceptable positive ion;  
 A represents: 
 1) —(CH 2 ) m —; or  
 2) —CH 2 —CH═CH—
 wherein m represents an integer from 1 to 3;  
 
 
 Y represents hydrogen;  
 B represents —X—C(R 11 )(R 12 )OR 13  
 wherein each of R 11  and R 13  represent hydrogen;  
 X represents: 
 1) —CH═CH—; or  
 2) —C≡C—; and  
 
 
 R 12  represents: 
 1) -Z-Ar 2 ;  
 2) -Z-R 3 ; or  
 3) —C u H 2u —C≡C—R 17  
 wherein Z represents a valence bond or a straight-chain or branched alkylene group represented by C t H 2t  where t represents an integer from 1 to 6; Ar 2  represents phenyl, α-naphthyl, β-naphthyl, or at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, a C 1-4  alkyl group, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl; R 3  represents a C 3-12  cycloalkyl group; u represents an integer from 1 to 7; C u H 2u  represents a straight-chain or branched alkylene group; and R 17  represents a straight-chain C 1-6  alkyl group;  
 
 
 E represents —OH; and  
 the formula is in the isomeric d-form, l-form or dl-form.  
 
     
     
         3 . The therapeutic agent for renal failure according to  claim 1 , wherein the 4,8-inter-m-phenylene prostaglandin I 2  derivative is beraprost or a salt thereof.  
     
     
         4 . The therapeutic agent according to any one of  claims 1  to  3 , wherein the renal failure is chronic renal failure.  
     
     
         5 . The therapeutic agent according to any one of  claims 1  to  3 , wherein the causal disease of the renal failure is glomerulonephritis or diabetic nephropathy.  
     
     
         6 . A method for treatment of renal failure comprising administering an effective amount of a 4,8-inter-m-phenylene prostaglandin I 2  derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  represents: 
 (A) COOR 2  
 wherein R 2  represents: 
 1) hydrogen or a pharmacologically acceptable positive ion;  
 2) a straight-chain C 1-12  alkyl group or a branched C 3-14  alkyl group;  
 3) -Z-R 3  
 wherein Z represents a valence bond or a straight-chain or branched alkylene group represented by C t H 2t  where t represents an integer from 1 to 6; and R 3  represents a C 3-12  cycloalkyl group unsubstituted or substituted by 1 to 3 substituents of R 4  where R 4  is hydrogen or a C 1-5  alkyl group;  
 
 
 4) —(CH 2 CH 2 O) n CH 3  
 wherein n represents an integer from 1 to 5;  
 
 5) -Z-Ar 1  
 wherein Z has the same meaning as defined above; and Ar 1  represents phenyl, α-naphthyl, β-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, α-furyl, β-furyl, α-thienyl, β-thienyl or substituted phenyl (wherein the substituted phenyl contains at least one substituent of chlorine, bromine, fluorine, iodine, trifluoromethyl, a C 1-4  alkyl group, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidobenzamide, —CH═N—NH—C(═O)—NH 2 , —NH—C(═O)-Ph, —NH—C(═O)—CH 3  or —NH—C(═O)—NH 2 );  
 
 6) —C t H 2t COOR 4  
 wherein each of C t H 2t  and R 4  has the same meaning as defined above;  
 
 7) —C t H 2t N(R 4 ) 2  
 wherein each of C t H 2t  and R 4  has the same meaning as defined above;  
 
 8) —CH(R 5 )—C(═O)—R 6 , 
 wherein R 5  represents hydrogen or benzoyl; and R 6  represents phenyl, p-bromophenyl, p-chlorophenyl, p-biphenyl, p-nitrophenyl, p-benzamidophenyl or 2-naphthyl;  
 
 9) —C p H 2p —W—R 7  
 wherein W represents —CH═CH—, —CH═CR 7 — or —C≡C—; R 7  represents hydrogen or a straight-chain or branched C 1-30  alkyl or aralkyl group; and p represents an integer from 1 to 5; or  
 
 10) —CH(CH 2 OR 8 ) 2  
 wherein R 3  represents a C 1-30  alkyl or acyl group;  
 
 
 
 (B) —CH 2 OH;  
 (C) —C(═O)N(R 9 ) 2  
 wherein R 9  represents hydrogen or a straight-chain C 1-12  alkyl group, a branched C 3-12  alkyl group, a C 3-12  cycloalkyl group, a C 4-13  cycloalkylalkylene group, a phenyl group, a substituted phenyl group (wherein the substitute or substituents are the same radicals as defined for (A)-5) described above), a C 7-12  aralkyl group, or —SO 2 R 10  where R 10  represents a C 1-10  alkyl group, a C 3-12  cycloalkyl group, a phenyl group, a substituted phenyl group (wherein the substitute or substituents are the same radicals as defined for (A)-5) described above) or a C 7-12  aralkyl group; provided that the two R 9  radicals are the same as or different from each other, but when one represents —SO 2 R 10 , then the other does not represent —SO 2 R 10 ; or  
 
 (D) —CH 2 OTHP (wherein THP represents a tetrahydropyranyl group);  
 A represents: 
 1) —(CH 2 ) m —;  
 2) —CH═CH—CH 2 —;  
 3) —CH 2 —CH═CH—;  
 4) —CH 2 —O—CH 2 —;  
 5) —CH═CH—;  
 6) —O—CH 2 —; or  
 7) —C≡C— 
 wherein m represents an integer from 1 to 3; Y represents hydrogen, a C 1-4  alkyl group, chlorine, bromine, fluorine, formyl, methoxy or nitro group; B represents —X—C(R 11 )(R 12 )OR 13    
 wherein: 
 R 11  represents hydrogen or a C 1-4  alkyl group;  
 R 13  represents hydrogen, a C 1-14  acyl group, a C 6-15  aroyl group, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl or t-butyl;  
 X represents: 
 1) —CH 2 —CH 2 —;  
 2) —CH═CH—; or  
 3) —C≡C—; and  
 
 
 R 12  represents: 
 1) a straight-chain C 1-12  alkyl group or a branched C 3-14  alkyl group;  
 2) -Z-Ar 2 ; 
 wherein Z has the same meaning as defined above; and Ar 2  represents phenyl, α-naphthyl, β-naphthyl, or at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, a C 1-4  alkyl group, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, or  
 
 3) —C t H 2t OR 14 ; 
 wherein C t H 2t  has the same meaning as defined above; and R 14  represents a straight-chain C 1-6  alkyl group, a branched C 3-6  alkyl, phenyl, or at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, an C 1-4  alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, cyclopentyl, cyclohexyl, or a cyclopentyl or cyclohexyl substituted by 1 to 4 straight-chain C 1-4  alkyl groups;  
 
 4) -Z-R 3  
 wherein each of Z and R 3  has the same meaning as defined above;  
 
 5) —C t H 2t —CH═C(R 15 )R 6  
 wherein C t H 2t  has the same meaning as defined above; and R 15  and R 16  independently represent hydrogen, methyl, ethyl, propyl or butyl group; or  
 
 6) —C u H 2u —C≡C—R 17  
 wherein u represents an integer from 1 to 7; C u H 2u  represents a straight-chain or branched alkylene group; and R 17  represents a straight-chain C 1-6  alkyl group; and  
 
 
 
 E represents hydrogen or —OR 18  
 wherein R 18  represents a C 1-12  acyl group, a C 7-15  aroyl group or R 2  (wherein R 2  has the same meaning as defined above); and the formula is in the isomeric d-form, l-form or dl-form.  
 
 
     
     
         7 . The method for treatment of renal failure according to  claim 6 , wherein the 4,8-inter-m-phenylene prostaglandin I 2  derivative is represented by the following formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  represents COOR 2  wherein R 2  represents hydrogen or a pharmacologically acceptable positive ion;  
 A represents: 
 1) —(CH 2 ) m —; or  
 2) —CH 2 —CH═CH—
 wherein m represents an integer from 1 to 3;  
 
 
 Y represents hydrogen;  
 B represents —X—C(R 11 )(R 12 )OR 13  
 wherein each of R 11  and R 13  represent hydrogen;  
 X represents: 
 1) —CH═CH—; or  
 2) —C≡C—; and  
 
 
 R 12  represents: 
 1) -Z-Ar 2 ;  
 2) -Z-R 3 ; or  
 3) —C u H 2u —C≡C—R 17  
 wherein Z represents a valence bond or a straight-chain or branched alkylene group represented by C t H 2t  where t represents an integer from 1 to 6; Ar 2  represents phenyl, α-naphthyl, β-naphthyl, or at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, a C 1-4  alkyl group, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl; R 3  represents a C 3-12  cycloalkyl group; u represents an integer from 1 to 7; C u H 2u  represents a straight-chain or branched alkylene group; and R 17  represents a straight-chain C 1-6  alkyl group;  
 
 
 E represents —OH; and  
 the formula is in the isomeric d-form, l-form or dl-form.  
 
     
     
         8 . The method for treatment of renal failure according to  claim 6 , wherein the 4,8-inter-m-phenylene prostaglandin I 2  derivative is beraprost or a salt thereof.  
     
     
         9 . The method for treatment of renal failure according to any one of  claims 6  to  8 , wherein the renal failure is chronic renal failure.  
     
     
         10 . The method for treatment of renal failure according to any one of  claims 6  to  8 , wherein the causal disease of the renal failure is glomerulonephritis or diabetic nephropathy.