Substituted Heteroarylalkanoic Acids

Abstract

Disclosed are substituted heteroarylalkanoic acids of the following formula D-A-C(O)R′, where D, A, and R′ are defined herein. These compounds are useful in the treatment of chronic complications arising from diabetes mellitus. Also disclosed are pharmaceutical compositions containing the compounds and methods of treatment employing the compounds, as well as methods for their synthesis.

1 . A compound of the formula
   D-A-C(O)R′   
     or a pharmaceutically acceptable salt thereof wherein
 D is a heteroaryl group selected from the group consisting of 
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         where 
         Y is -Z-Ar where
 Z is a bond, O, S, C(O)NH, or C 1 -C 6  alkylene optionally substituted with C 1 -C 2  alkyl; and 
 Ar represents 
 an aryl or aryl(C 1 -C 6 )alkyl group, where the aryl portion is optionally substituted with up to 5 groups independently selected from
 (1) halogen, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7  and N(R 7 ) 2  wherein each R 7  is independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 1 -C 6  haloalkoxy; and 
 (2) phenyl, pyridyl, furyl, and thienyl, each of which is optionally substituted with one, two, or three groups independently selected from halogen, (C 1 -C 6 )alkyl, hydroxy, halogen, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 17 , SR 17 , S(O)R 17 , S(O) 2 R 17  and N(R 17 ) 2  wherein each R 17  is independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 1 -C 6  haloalkoxy; 
 
 a heteroaryl or heteroaryl(C 1 -C 6 )alkyl group, where the heteroaryl portion is optionally substituted by one, two or three groups independently selected from
 (1) halogen, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 27 , SR 27 , S(O)R 27 , S(O) 2 R 27  and N(R 27 ) 2  wherein each R 27  is independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 1 -C 6  haloalkoxy; and 
 (2) phenyl, pyridyl, furyl, and thienyl, each of which is optionally substituted with one, two, or three groups independently selected from halogen, (C 1 -C 6 )alkyl, hydroxy, halogen, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 37 , SR 37 , S(O)R 37 , S(O) 2 R 37  and N(R 37 ) 2  wherein each R 37  is independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 1 -C 6  haloalkoxy; 
 
 
         R 3  is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, aryl, —SR 15  or —OR 15 , where R 15  is (C 1 -C 6 )alkyl, aryl, or aryl(C 1 -C 6 )alkyl where each aryl is optionally mono-, di-, or trisubstituted with halogen, (C 1 -C 6 )alkyl, hydroxy, halogen, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7  and N(R 7 ) 2 , 
         R 4  is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, or benzoyl where the phenyl portion is optionally mono-, di-, or trisubstituted with halogen, (C 1 -C 6 )alkyl, hydroxy, halogen, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7  and N(R 7 ) 2 ; 
         R 5  is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 ) alkyl, halo(C 1 -C 6 )alkyl, hydroxy, amino, mono- or di(C 1 -C 6 )alkylamino, or aryl where aryl is optionally substituted with up to three groups independently selected from halogen, (C 1 -C 6 )alkyl, hydroxy, halogen, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7  and N(R 7 ) 2 ; 
         R 6  is hydrogen, (C 1 -C 6 )alkyl, oxo, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl or aryl(C 1 -C 6 )alkyl where the aryl portion is optionally mono-, di-, or trisubstituted with halogen, (C 1 -C 6 )alkyl, hydroxy, halogen, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7  and N(R 7 ) 2 ; 
       
       A is a C 1 -C 4  alkylene group optionally substituted with C 1 -C 2  alkyl or mono- or disubstituted with halogen; and 
       R′ is hydroxy, benzyloxy, di(C 1 -C 6 )alkylaminoethyloxy, acetoxymethyl, pivaloyloxymethyl, phthalidoyl, ethoxycarbonyloxyethyl, 5-methyl-2-oxo-1,3-dioxol-4-yl methyl, or (C 1 -C 6 )alkoxy optionally substituted by N-morpholino or di(C 1 -C 6 )alkylamino. 
     
   
   
       2 . A compound according to  claim 1 , wherein Ar is
 (A) phenyl or phenyl(C 1 -C 6 )alkyl, where the phenyl portion of each is optionally substituted with up to 3 groups independently selected from halogen, (C 1 -C 6 )alkyl, hydroxy, halogen, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7  and N(R 7 ) 2  wherein each R 7  is independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy; or   (B) a heterocyclic 5-membered ring having one nitrogen, oxygen or sulfur, two nitrogens one of which may be replaced by oxygen or sulfur, or three nitrogens one of which may be replaced by oxygen or sulfur, said heterocyclic 5-membered ring substituted by one or two fluoro, chloro, (C 1 -C 6 )alkyl or phenyl, or condensed with benzo, or substituted by one of pyridyl, furyl or thienyl,
 the phenyl and benzo rings 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, preferably, two fluoro and one trifluoromethyl, or three fluoro, said pyridyl, furyl or thienyl optionally substituted in the 3-position by fluoro, chloro, bromo, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy; 
   (C) a heterocyclic 6-membered ring having one to three nitrogen atoms, or one or two nitrogen atoms and one oxygen or sulfur, said heterocyclic 6-membered ring substituted by one or two (C 1 -C 6 )alkyl or phenyl, or condensed with benzo, or substituted by one of pyridyl, furyl or thienyl, said phenyl or benzo 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;
 said benzo-condensed heterocyclic 5-membered or 6-membered rings optionally substituted in the heterocyclic 5-membered or 6-membered ring by one of fluoro, chloro, bromo, methoxy, or trifluoromethyl; 
   (D) oxazole or thiazole condensed with a 6-membered aromatic group containing one or two nitrogen atoms, with thiophene or with furane, each optionally substituted by one of fluoro, chloro, bromo, trifluoromethyl, methylthio or methylsulfinyl;   (E) imidazolopyridine or triazolopyridine optionally substituted by one of trifluoromethyl, trifluoromethylthio, bromo, or (C 1 -C 6 )alkoxy, or two of fluoro or chloro;   (F) thienothiophene or thienofuran optionally substituted by one of fluoro, chloro or trifluoromethyl;   (G) thienotriazole optionally substituted by one of chloro or trifluoromethyl;   (H) naphthothiazole; naphthoxazole; or thienoisothiazole.   
   
   
       3 . A compound according to  claim 1 , wherein Z is (C 1 -C 6 )alkylene and Ar is a substituted phenyl of Formula II or a substituted benzothiazole of Formula III 
     
       
         
         
             
             
         
       
     
     wherein R 8 , R 8 ′, R 9 , R 9 ′, R 10 , R 11 , R 12 , R 13  and R 14  are independently hydrogen, halogen, (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )haloacetyl, cyano, nitro, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )haloalkylthio, OR 7 , SR 7 , S(O)R 7 , S(O) 2 R 7  or N(R 7 ) 2  wherein each R 7  is independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 1 -C 6  haloalkoxy. 
   
   
       4 . A compound according to  claim 3 , wherein R 8 , R 8 ′, R 9 , R 9 ′, R 10 , R 11 , R 12 , R 13  and R 14  are independently hydrogen, hydroxy, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )haloalkyl, cyano, nitro, or N(R 7 ) 2  wherein each R 7  is independently hydrogen or C 1 -C 6  alkyl. 
   
   
       5 . (canceled) 
   
   
       6 . A compound according to  claim 4 , wherein Z is (C 1 -C 3 )alkylene and Ar is 
     
       
         
         
             
             
         
       
     
     and R 11 , R 12 , R 13  and R 14  are independently hydrogen, hydroxy, (C 1 -C 6 )alkoxy, halogen, (C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )haloalkyl, cyano, nitro, or N(R 7 ) 2  wherein each R 7  is independently hydrogen or C 1 -C 6  alkyl. 
   
   
       7 - 11 . (canceled) 
   
   
       12 . A compound according to  claim 6 , wherein D is 
     
       
         
         
             
             
         
       
     
     where
 E, G, and K represent sulfur or C—R 3 , provided that one and only one of E, G, and K is sulfur; and 
 R 3  represents hydrogen, C 1 -C 6  alkyl, or phenyl(C 1 -C 6 )alkyl. 
 
   
   
       13 - 14 . (canceled) 
   
   
       15 . A compound according to  claim 6 , wherein D is 
     
       
         
         
             
             
         
       
       E and G represent sulfur or C—R 3 , provided that one and only one of E and G is sulfur; and 
       each R 3  independently represents hydrogen, C 1 -C 6  alkyl, or phenyl(C 1 -C 6 )alkyl. 
     
   
   
       16 . A compound according to  claim 6 , where D is 
     
       
         
         
             
             
         
       
     
   
   
       17 . A compound according to  claim 6 , where D is 
     
       
         
         
             
             
         
       
     
     and each R 3  is independently hydrogen, (C 1 -C 6 )alkyl or phenyl(C 1 -C 6 )alkyl. 
   
   
       18 . A compound according to  claim 6 , where D is 
     
       
         
         
             
             
         
       
     
     and each R 3  is independently hydrogen or (C 1 -C 6 )alkyl. 
   
   
       19 - 44 . (canceled) 
   
   
       45 . A compound according to  claim 1 , which is 
     [5-(4,5,7-Trifluoro-benzothiazol-2-ylmethyl)-thiophen-2-yl]-acetic acid; 
     [3-Methyl-4-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiophen-2-yl]-acetic acid; 
     [4-(4,5,7-Trifluoro-benzothiazol-2-ylmethyl)-thiophen-2-yl]-acetic acid; 
     [2-(4,5,7-Trifluoro-benzothiazol-2-ylmethyl)-thiophen-3-yl]-acetic acid; 
     [4-Methyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiophen-3-yl]-acetic acid; 
     [5-(4,5,7-Trifluoro-benzothiazol-2-ylmethyl)-thiophen-3-yl]-acetic acid; or 
     [2,5-Dimethyl-4-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiophen-3-yl]-acetic acid. 
   
   
       46 - 51 . (canceled) 
   
   
       52 . A compound according to  claim 1 , which is 
     [2-(4,5,7-Trifluoro-benzothiazol-2-ylmethyl)-thiazol-4-yl]-acetic acid. 
   
   
       53 . A method of preventing or alleviating chronic complications arising from diabetes mellitus, which comprises administering to a mammal in need of such treatment an effective amount of a compound according to  claim 1 . 
   
   
       54 . A method according to  claim 53  wherein the complications are selected from the group consisting of diabetic cataracts, retinopathy, nephropathy and neuropathy. 
   
   
       55 . A method for reducing serum uric acid levels, which method comprises administering to a mammal in need of such treatment an effective amount of a compound of  claim 1 . 
   
   
       56 . A method for treating or preventing gout, which method comprises administering to a mammal an effective amount of a compound of  claim 1 . 
   
   
       57 . A pharmaceutical composition which comprises a compound of  claim 1  and an ACE inhibitor, together with a pharmaceutically acceptable carrier and/or diluent. 
   
   
       58 - 77 . (canceled) 
   
   
       78 . A compound according to  claim 1  which is 
     [6-methyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]-acetic acid (m)ethyl ester; 
     [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]-acetic acid (m)ethyl ester; 
     2,6-Dimethyl-5-(4,5,7-trifluoro-benzothiazole-2-ylmethyl)-pyridin-3-yl-acetic acid hydrochloride (m)ethyl ester; 
     [2,6-Diethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]acetic acid methyl ester; 
     [2,6-Diphenyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]acetic acid (m)ethyl ester; [2,6-Dipropyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl]acetic acid methyl ester; 
     5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl-acetic acid (m)ethyl ester; 
     2,4,6-trimethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl-acetic acid (m)ethyl ester; 
     2,6-dimethyl-4-ethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl-acetic acid (m)ethyl ester; 
     2-Ethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl-acetic acid (m)ethyl ester; 
     2-benzyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl-acetic acid (m)ethyl ester; 
     2-phenyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl-acetic acid (m)ethyl ester; 
     6-Phenyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl-acetic acid (m)ethyl ester; 
     6-Benzyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl-acetic acid methyl ester; 
     2-phenoxy-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl)-acetic acid methyl ester; 
     [2,5-dimethyl-4-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiophen-3-yl]-acetic acid (m)ethyl ester; 
     [5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiophen-2-yl]-acetic acid; 
     [4-(4,5,7-Trifluoro-benzothiazol-2-ylmethyl)-thiophen-2-yl]-acetic acid methyl ester; 
     [4-(5-trifluoromethybenzothiazol-2-ylmethyl)-thiophen-2-yl]-acetic acid (m)ethyl ester; 
     [2-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiophen-3-yl]-acetic acid (m)ethyl ester; 
     [4-methyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiophen-3-yl]-acetic acid methyl ester; or 
     a pharmaceutically acceptable salt thereof.