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 for treatment of renal failure using the same.

1 - 10 . (canceled)  
   
   
       11 . A method for treatment of chronic renal failure comprising administering a therapeutically 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 unsubstittued 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-uryl, 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 araalkyl 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, a 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 1-2  acyl group, a C 7-15  aroyl group or R 2  (wherein R 2  has the same meaning as defined above); and the formula (I) is in the isomeric d-form, l-form or dl-form.  
 
 
 
     
   
   
       12 . The method for treatment of chronic renal failure according to  claim 11 , 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 (I) is in the isomeric d-form, l-form or dl-form.  
 
   
   
       13 . The method according to  claim 11 , wherein the 4,8-inter-m-phenylene prostaglandin I 2  derivative is beraprost or a salt thereof.  
   
   
       14 . The method according to  claim 11 , wherein the causal disease of the chronic renal failure is glomerulonephritis, nephrosclerosis or diabetic nephropathy.  
   
   
       15 . The method according to  claim 11 , wherein said chronic renal failure is defined by raise of serum creatinine level and/or blood urea nitrogen level.  
   
   
       16 . The method according to  claim 11 , wherein said chronic renal failure is progressive chronic renal failure in which serum creatinine level and/or blood urea nitrogen level raise(s) with time.  
   
   
       17 . The method according to  claim 11 , wherein increase in serum creatinine level and/or blood nitrogen level is(are) reduced, or t5he serum creatinine level and/or blood urea nitrogen level is(are) decreased.