Pyrrolo-naphthyl acids and methods for using them

Abstract

The present invention relates to pyrrolo-naphthyl compounds of the formula and methods of using them to modulate PAI-1 expression and to treat PAI-1 related disorders.

1 . A method for treating impairment of the fibrinolytic system, cardiovascular disease, atherosclerotic plaque formation, chronic obstructive pulmonary disease, polycystic ovary syndrome, diabetes, Alzheimer's disease, or cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Formula 1:  
     
       
         
         
             
             
         
       
     
     or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof; wherein: 
 Ar is aryl or heteroaryl;  
 R 1  is hydrogen, C 1 -C 12  alkyl, C 6-14  aryl, C 6-14 ar(C 1-6 )alkyl, —(CH 2 ) p -heteroaryl, —(CH 2 ) p —CO-aryl, —(CH 2 ) p —CO-heteroaryl, —(CH 2 ) p —CO—(C 1 -C 6 )alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, or C 3 -C 8  cycloalkyl.  
 R 2  and R 3  are independently hydrogen, C 1 -C 12  alkyl, C 6-14  aryl, C 6-14 ar(C 1-6 )alkyl, —(CH 2 ) p -heteroaryl, halogen, C 1 -C 6  alkoxy, aralkyl, alkoxyaryl, nitro, carboxy(C 1 -C 6  alkyl), carbamide, carbamate, or C 3 -C 8  cycloalkyl;  
 R 4  is —CH(R 6 )(CH 2 ) n R 5 , —C(CH 3 ) 2 R 6 , —CH(R 5 )(CH 2 ) n R 6 , —CH(R 5 )C 6 H 4 R 6 , —CH(R 5 )C 6 H 3 (CO 2 H) 2 , CH(R 5 )C 6 H 2 (CO 2 H) 3 , or an acid mimic;  
 R 5  is hydrogen, C 1 -C 6  alkyl, C 6 -C 12  aryl, aralkyl, C 3 -C 8  cycloalkyl, or —(CH 2 ) n (R 7 );  
 R 6  is CO 2 H, tetrazole, or PO 3 H;  
 R 7  is  
                     
 n is from 0 to 6;  
 p is from 0 to 3;  
 b is from 0 to 6; and  
 a is from 0 to 6.  
 
   
   
       2 . The method of  claim 1  wherein C 1-12  alkyl is unsubstituted C 1-12  alkyl or C 1-3  perfluoroalkyl; C 1-6  alkoxy is unsubstituted C 1-6  alkoxy or C 1-3  perfluoroalkoxy; and said aralkyl group is unsubstituted benzyl or benzyl substituted with from 1 to 3 groups selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, C 3 -C 6  cycloalkyl, —(CH 2 ) p —C 3 -C 6  cycloalkyl, halogen, C 1 -C 3  perfluoroalkyl, C 1 -C 3  perfluoroalkoxy, —(CH 2 ) p -phenyl, and —O(CH 2 ) p -phenyl.  
   
   
       3 . The method of  claim 1  wherein the compound is of Formula 2 
     
       
         
         
             
             
         
       
     
     or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof.  
   
   
       4 . The method of  claim 1  wherein the compound is of Formula 3:  
     
       
         
         
             
             
         
       
     
     or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof.  
   
   
       5 . The method of  claim 1  wherein the compound is of Formula 4:  
     
       
         
         
             
             
         
       
     
     or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof.  
   
   
       6 . The method of  claim 1  wherein the compound is of Formula 5:  
     
       
         
         
             
             
         
       
     
     or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof wherein R 8 , R 9 , R 10 , R 11  and R 12  are independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, C 6-14 ar(C 1-6 )alkyl, C 3 -C 6  cycloalkyl, —(CH 2 ) p —C 3 -C 6  cycloalkyl, halogen, —(CH 2 ) p -phenyl, or —O(CH 2 ) p -phenyl.  
   
   
       7 . The method of  claim 6  wherein C 1-6  alkyl is unsubstituted C 1-6  alkyl or C 1-3  perfluoroalkyl and C 1-6  alkoxy is unsubstituted C 1-6  alkoxy or C 1-3  perfluoroalkoxy.  
   
   
       8 . The method of  claim 1 , wherein: 
 Ar is aryl or heteroaryl;    R 1  is hydrogen, C 1 -C 6  alkyl or —(CH 2 ) p -phenyl;    R 2  and R 3  are independently hydrogen, unsubstituted C 1 -C 6  alkyl, phenyl-(CH 2 ) p —, halogen or C 1 -C 3  perfluoroalkyl;    R 4  is —CHR 5 CO 2 H, —CHR 5 C 6 H 4 CO 2 H, —CHR 5 C 6 H 3 (CO 2 H) 2 , —CH 2 -tetrazole or an acid mimic;    R 5  is hydrogen, phenyl, or benzyl, and    p is from 0 to 3.    
   
   
       9 . The method of  claim 1  wherein Ar is phenyl, naphthyl, furanyl, thiophenyl, benzofuranyl, benzothiophenyl, indolyl, pyrazolyl, oxazolyl or fluorenyl.  
   
   
       10 . The method of  claim 1  wherein R 4  is —CHR 5 CO 2 H.  
   
   
       11 . The method of  claim 1  wherein R 4  is —(CH 2 )-tetrazole.  
   
   
       12 . The method of  claim 1  wherein R 4  is —CH(R 5 )C 6 H 4 CO 2 H.  
   
   
       13 . The method of  claim 1  wherein the compound is: 
 3-phenyl-2-{[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}propanoic acid or a pharmaceutically acceptable salt or ester form thereof;    2-{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid or a pharmaceutically acceptable salt or ester form thereof;    {[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid or a pharmaceutically acceptable salt or ester form thereof;    2-{[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid or a pharmaceutically acceptable salt or ester form thereof; or    3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoic acid or a pharmaceutically acceptable salt or ester form thereof.    
   
   
       14 . The method of  claim 1  wherein the compound is: 
 [(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetic acid or a pharmaceutically acceptable salt or ester form thereof;    {[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}acetic acid or a pharmaceutically acceptable salt or ester form thereof;    2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid or a pharmaceutically acceptable salt or ester form thereof;    5-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole or a pharmaceutically acceptable salt or ester form thereof; or    5-({[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole or a pharmaceutically acceptable salt or ester form thereof.    
   
   
       15 . The method of  claim 1  wherein the compound is: 
 5-({[6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole or a pharmaceutically acceptable salt or ester form thereof;    5-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}-1H-tetraazole or a pharmaceutically acceptable salt or ester form thereof;    5-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole or a pharmaceutically acceptable salt or ester form thereof;    4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}benzoic acid or a pharmaceutically acceptable salt or ester form thereof; or    4-({[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)benzoic acid or a pharmaceutically acceptable salt or ester form thereof.    
   
   
       16 . The method of  claim 1  wherein the compound is: 
 4-{[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]methyl}isophthalic acid or a pharmaceutically acceptable salt or ester form thereof or    4-({[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}methyl)isophthalic acid or a pharmaceutically acceptable salt or ester form thereof.    
   
   
       17 . The method of  claim 1  wherein the therapeutically effective amount is from about 25 mg/kg to about 200 mg/kg.  
   
   
       18 . The method of  claim 1  wherein the cardiovascular disease is caused by noninsulin dependent diabetes mellitus in a subject.  
   
   
       19 . The method of  claim 1  wherein the cancer is breast or ovarian cancer.  
   
   
       20 . The method of  claim 1  for the treatment of diabetes.