Methods of Reducing Serum Glucose and Triglyceride Levels and for Inhibiting Angiogenesis Using Substituted Indolealkanoic Acids

Abstract

Disclosed are methods of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis, the methods comprising administration of substituted indolealkanoic acids to patients in need of such treatment. Also disclosed are such compounds useful in the treatment of angiogenesis, hyperglycemia, hyperlipidemia and chronic complications arising from diabetes mellitus. Also disclosed are pharmaceutical compositions containing the compounds.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         A is C 1 -C 4  alkyl; 
         Z is a bond; 
         R 1  is hydrogen, halogen, or alkyl having 1-6 carbon atoms; 
         R 3  is hydrogen, alkyl group of 1-6 carbon atoms, or halogen; 
         R 2 , R 4  and R 5  are independently hydrogen or halogen; 
         R 6  is hydroxy; 
         R a  is hydrogen; 
         and Ar represents 
         a heterocyclic 5-membered ring having one nitrogen, two nitrogens one of which may be replaced by sulfur, said heterocyclic 5-membered ring optionally being condensed with benzo, said benzo being optionally substituted by one of iodo, cyano, nitro, perfluoroethyl, trifluoroacetyl, or (C 1 -C 6 )alkanoyl, one or two of fluoro, chloro, bromo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, trifluoromethoxy, trifluoromethylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl or trifluoromethyl, or two fluoro or two trifluoromethyl with one hydroxy or one (C 1 -C 6 )alkoxy, or one or two fluoro and one trifluoromethyl, or three flour; or 
         a heterocyclic 6-membered ring having one to two nitrogen atoms, or one nitrogen atom and sulfur, said heterocyclic 6-membered ring optionally being condensed with benzo, said benzo being optionally substituted by one of iodo or trifluoromethylthio, or one or two of fluoro, chloro, bromo, (C 1 -C 6 ) alkyl, (C 1 -C 6 )alkoxy. (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl, or trifluoromethyl, and said pyridyl, furyl or thienyl optionally substituted in the 3-position by fluoro, chloro, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy. 
       
     
     
         2 . A compound according to  claim 1 , wherein Ar represents
 benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalyl, or thiazolyl, each of which is optionally substituted with one of iodo, cyano, nitro, perfluoroethyl, trifluoroacetyl, or (C 1 -C 6 )alkanoyl, one or two of fluoro, chloro, bromo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy. (C 1 -C 6 )alkylthio, trifluoromethoxy, trifluoromethylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl or trifluoromethyl, or two fluoro or two trifluoromethyl with one hydroxy or one (C 1 -C 6 )alkoxy, or one or, preferably, two fluoro and one trifluoromethyl, or three fluoro; or   phenyl group optionally substituted with up to 5 groups independently selected from halogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens), nitro, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7  or N(R 7 ) 2  wherein R 7  is hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino.   
     
     
         3 . A compound according to  claim 2 , wherein Ar is benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalyl, or thiazolyl, each of which is optionally substituted with one trifluoromethyl or up to three fluoro groups. 
     
     
         4 . A compound according to  claim 1  wherein at least one of R 1  and R 3  is not hydrogen; 
     
     
         5 . A compound according to  claim 1  wherein R 2 , R 4  and R 5  are all hydrogen. 
     
     
         6 . A compound according to  claim 1  wherein R 1  is hydrogen or alkyl having 1-6 carbon atoms. 
     
     
         7 . A compound according to  claim 5 , wherein R 1  is hydrogen or methyl. 
     
     
         8 . A compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         A is methylene; 
         Z is a bond; 
         R 1  is hydrogen or alkyl having 1-6 carbon atoms; 
         R 3  is hydrogen or halogen; 
         provided that at least one of R 1  and R 3  is not hydrogen; 
         R 2 , R 4  and R 5  are all hydrogen; 
         R 6  is hydroxy; 
         R a  is hydrogen; 
         and Ar represents
 benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalyl, or thiazolyl, each of which is optionally substituted with one of iodo, cyano, nitro, perfluoroethyl, trifluoroacetyl, or (C 1 -C 6 )alkanoyl, one or two of fluoro, chloro, bromo, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, trifluoromethoxy, trifluoromethylthio, (C 1 -C 6 )alkylsulfinyl, (C 1 -C 6 )alkylsulfonyl or trifluoromethyl, or two fluoro or two trifluoromethyl with one hydroxy or one (C 1 -C 6 )alkoxy, or one or, preferably, two fluoro and one trifluoromethyl, or three fluoro; or 
 phenyl group optionally substituted with up to 5 groups independently selected from halogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens), nitro, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7  or N(R 7 ) 2  wherein R 7  is hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, and mono- or di(C 1 -C 6 )alkylamino. 
 
       
     
     
         9 . A compound according to  claim 6 , where R 1  is hydrogen or methyl. 
     
     
         10 . A compound according to  claim 8 , wherein Ar is benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalyl, or thiazolyl, each of which is optionally substituted with one trifluoromethyl or up to three fluoro groups. 
     
     
         11 . A compound according to  claim 8 , wherein Ar is phenyl substituted with one group. 
     
     
         12 . A compound according to  claim 8 , wherein Ar is phenyl substituted with SO 2 R 7 . 
     
     
         13 . A compound according to  claim 1 , which is:
 2-methyl-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid;   5-chloro-3-(4,5,7-Trifluorobenzothiazol-2-yl)methyl-indole-N-acetic Acid; 5-fluoro-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid;   3-(3-nitrophenyl)methyl-indole-N-acetic acid;   5-Methyl-3-(5-Trifluoromethylbenzothiazol-2-yl)methyl-indole-N-acetic acid or   5-Bromo-3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid.   
     
     
         14 . A compound of general formula (I): 
       
         
           
           
               
               
           
         
         wherein R 6 , R 3  and R 4  are hydrogen; 
         R 2  is halo; 
         R 5  and R 6  are hydrogen; 
         R 7  is C 1 -C 6 alkyl; 
         R 8  is a phenyl, naphthalenyl, thiazole, biphenyl, quinolinyl or quinoxalinyl group, any of which may be substituted with one or more halo, C 1 -C 6  alkyl, —O(C 1 -C 6 )alkyl, —SO 2 R 11 , or —OH groups;
 wherein R 11  is independently hydrogen or C 1 -C 6  alkyl; 
 
         R 9  is hydrogen; or a pharmaceutically acceptable salt thereof. 
       
     
     
         15 . The compound of  claim 14 , wherein, R 2  is fluoro; and R 7  methyl. 
     
     
         16 . A pharmaceutical composition comprising a compound of  claim 14  together with a pharmaceutical excipient or carrier. 
     
     
         17 . A pharmaceutical composition, comprising a compound of  claim 15  together with a pharmaceutical excipient or carrier.