Thiazolo naphthyl acids

Abstract

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

1 . A 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, C 3 -C 8  cycloalkyl, halogen, or C 1 -C 3  perfluoroalkoxy; 
 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, 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; with the proviso that when b is from 1 to 6, Ar is phenyl, furanyl, thienyl, pyrazolyl, oxazolyl, or fluorenyl. 
     
   
   
       2 . The compound of  claim 1  wherein Ar is phenyl, furanyl, thienyl, pyrazolyl, oxazolyl, or fluorenyl. 
   
   
       3 . The compound of  claim 1  wherein said C 1-12  alkyl is unsubstituted or optionally substituted with halogen and said C 1-6  alkoxy is unsubstituted or optionally substituted with halogen. 
   
   
       4 . The compound of  claim 3  wherein said C 1-12  alkyl is unsubstituted C 1-12  alkyl or C 1-3  perfluoroalkyl and said C 1-6  alkoxy is unsubstituted C 1-6  alkoxy or C 1-3  perfluoroalkoxy. 
   
   
       5 . The compound of  claim 1  wherein Ar is phenyl, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, oxazolyl, or fluorenyl. 
   
   
       6 . The compound of  claim 1  wherein
 Ar is phenyl, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, oxazolyl, or fluorenyl;   R 1  is hydrogen, halogen, C 1 -C 6  alkyl or —(CH 2 ) p -phenyl;   R 2  and R 3  are independently hydrogen, C 1 -C 6  alkyl, phenyl-(CH 2 ) p —, or halogen;   R 4  is —CHR 5 CO 2 H, —CH 2 -tetrazole, —CH(R 5 )C 6 H 4 CO 2 H or an acid mimic;   R 5  is hydrogen or benzyl; and   p is from 0 to 3   
     or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof. 
   
   
       7 . The compound of  claim 6  wherein said C 1 -C 6  alkyl is unsubstituted C 1 -C 6  alkyl or C 1 -C 3  perfluoroalkyl and the ring of said benzyl group is unsubstituted or 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. 
   
   
       8 . The compound of  claim 6  having formula 2: 
     
       
         
         
             
             
         
       
     
     or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof. 
   
   
       9 . The compound of  claim 8  wherein R 4  is —CHR 5 CO 2 H, —CH 2 -tetrazole, or CH(R 5 )C 6 H 4 CO 2 H. 
   
   
       10 . The compound of  claim 6  having formula 3: 
     
       
         
         
             
             
         
       
     
     or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof. 
   
   
       11 . The compound of  claim 10  wherein R 4  is —CHR 5 CO 2 H, —CH 2 -tetrazole, or CH(R 5 )C 6 H 4 CO 2 H. 
   
   
       12 . The compound of  claim 6  having 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 3 -C 6  cycloalkyl, —(CH 2 ) p —C 3 -C 6  cycloalkyl, halogen, —(CH 2 ) p -phenyl, or —O(CH 2 ) p -phenyl. 
   
   
       13 . The compound of  claim 12  wherein said C 1 -C 6  alkyl is unsubstituted C 1 -C 6  alkyl or C 1 -C 3  perfluoroalkyl and C 1 -C 6  alkoxy is unsubstituted C 1 -C 6  alkoxy or C 1 -C 3  perfluoroalkoxy. 
   
   
       14 . The compound of  claim 12  wherein R 4  is —CHR 5 CO 2 H, —CH 2 -tetrazole, or CH(R 5 )C 6 H 4 CO 2 H. 
   
   
       15 . The compound of  claim 12  wherein R 1  is hydrogen. 
   
   
       16 . The compound of  claim 6  having formula 6: 
     
       
         
         
             
             
         
       
     
     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 3 -C 6  cycloalkyl, —(CH 2 ) p —C 3 -C 6  cycloalkyl, halogen, —(CH 2 ) p -phenyl, or —O(CH 2 ) p -phenyl. 
   
   
       17 . The compound of  claim 16  wherein said C 1 -C 6  alkyl is unsubstituted C 1 -C 6  alkyl or C 1 -C 3  perfluoroalkyl and C 1 -C 6  alkoxy is unsubstituted C 1 -C 6  alkoxy or C 1 -C 3  perfluoroalkoxy. 
   
   
       18 . The compound of  claim 16  wherein R 4  is —CHR 5 CO 2 , —CH 2 -tetrazole, or CH(R 5 )C 6 H 4 CO 2 H. 
   
   
       19 . The compound of  claim 1  that is 3-phenyl-2-{[6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}propanoic acid or a pharmaceutically acceptable salt or ester form thereof, 2-{[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid or a pharmaceutically acceptable salt or ester form thereof, {[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}acetic acid or a pharmaceutically acceptable salt or ester form thereof; 5-({[6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole or a pharmaceutically acceptable salt or ester form thereof; or 5-({[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}methyl)-1H-tetraazole or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       20 . The compound of  claim 1  that is 2-{[1-bromo-6-(5-bromo-2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}-3-phenylpropanoic acid or a pharmaceutically acceptable salt or ester form thereof; ({6-[2-(2,6-dichlorobenzyl)-1,3-thiazol-4-yl]-2-naphthyl}oxy)acetic acid or a pharmaceutically acceptable salt or ester form thereof; 4-({[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}methyl)benzoic acid or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       21 . A method comprising administering a compound of  claim 1  to a subject. 
   
   
       22 . The method of  claim 21  further comprising determining a level of PAI-1 activity in a subject. 
   
   
       23 . The method of  claim 22  wherein said determination is made before administration of said compound. 
   
   
       24 . The method of  claim 22  wherein said determination is made after administration of said compound. 
   
   
       25 . A method of modulating PAI-1 activity comprising identifying a subject in need of PAI-1 modulation and administering to the subject an effective amount of a compound of the 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, C 3 -C 8  cycloalkyl, halogen, or C 1 -C 3  perfluoroalkoxy; 
 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. 
     
   
   
       26 . The method of  claim 25  wherein Ar is phenyl, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, oxazolyl or fluorenyl. 
   
   
       27 . The method of  claim 25  wherein said C 1-12  alkyl is unsubstituted or optionally substituted with halogen and said C 1-6  alkoxy is unsubstituted or optionally substituted with halogen. 
   
   
       28 . The method of  claim 25  wherein Ar is unsubstituted phenyl or phenyl substituted with from 1 to 3 groups selected from 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, or —O(CH 2 ) p -phenyl. 
   
   
       29 . The method of  claim 25  wherein the effective amount is from about 25 mg/kg to about 200 mg/kg. 
   
   
       30 . The method of  claim 25  wherein
 Ar is phenyl, naphthyl, furanyl, thienyl, benzofuranyl, benzothienyl, indolyl, pyrazolyl, oxazolyl, or fluorenyl;   R 1  is hydrogen, halogen, C 1 -C 6  alkyl or —(CH 2 ) p -phenyl;   R 2  and R 3  are independently hydrogen, C 1 -C 6  alkyl, phenyl-(CH 2 ) p —, or halogen;   R 4  is —CHR 5 CO 2 H, —CH 2 -tetrazole, —CH(R 5 )C 6 H 4 CO 2 H or an acid mimic;   R 5  is hydrogen or benzyl; and   p is from 0 to 3   
     or a solvate, hydrate or pharmaceutically acceptable salt or ester form thereof. 
   
   
       31 . The method of  claim 30  wherein said C 1 -C 6  alkyl is unsubstituted C 1 -C 6  alkyl or C 1 -C 3  perfluoroalkyl. 
   
   
       32 . A method for treating impairment of the fibrinolytic system, thrombosis, atrial fibrillation, pulmonary fibrosis, myocardial ischemia, stroke, thromboembolic complication of surgery, cardiovascular disease, atherosclerotic plaque formation, chronic obstructive pulmonary disease, renal fibrosis, Alzheimer's disease, cancer, diabetes, or polycystic ovary syndrome comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1 as defined in  claim 25 . 
   
   
       33 . The method of  claim 32  wherein the thrombosis is selected from the group consisting of venous thrombosis, arterial thrombosis, cerebral thrombosis, and deep vein thrombosis. 
   
   
       34 . The method of  claim 32  wherein the cardiovascular disease is caused by noninsulin dependent diabetes mellitus in a subject. 
   
   
       35 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof, and a pharmaceutically acceptable excipient or carrier.