Compounds useful for preparation of Beta-3 adrenoreceptor agonist

Abstract

This invention related to novel sulfonamide substituted chroman derivatives which are useful in the treatment of beta-3 receptor mediated conditions.

What is claimed as new and useful is:  
     
         1 . A compound of the formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 R is hydrogen, hydroxy, oxo, halo, C 1 -C 10 haloalkyl, C 1 -C 10 alkyl, cyano, nitro, NR 1 R 1 , S R 1 , OR 1 , SO 2 R 2 , OCOR 2 , NR 1 COR 2 , COR 2 , NR 1 SO 2 R 2 , NR 1 CO 2 R 1 , pyrrole, or Ar 2 , optionally substituted with hydroxy, halogen, cyano, NR 1 R 1 , SR 1 , trifluoromethyl, OR 1 , C 3 -C 8  cycloaklyl, phenyl, NR 1  COR 2 , COR 2  SO 2 R 2 , OCOR 2 , NR 1  SO 2 R 2 , or NR 1  CO 2 R 1 ;  
 R 1  is hydrogen, C 1 -C 10  alkyl optionally substituted with 1 to 4 substituents selected from hydroxy, halogen, CO 2 H, CO 2 C 1 -C 10  alkyl, SO 2 C 1 -C 10 alkyl, C 1 -C 10  alkoxy; or C 3 -C 8  cycloalkyl, phenyl or naphthyl, each optionally substituted with 1 to 4 substituents selected from halogen, nitro, oxo, C 1 -C 10  alkyl, C 1 -C 10  alkoxy, and C 1 -C 10  alkylthio;  
 R 2  is R 1  or NR 1  R 1 ;  
 R 3  is hydrogen, C 1 -C 10  alkyl or  
                     
 Ar 1  is Ar 1 —O—CH 2 , phenyl, or a 5 or 6 membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and N, each moiety being optionally fused to a 5 membered heterocyclic ring containing from 1 to 4 hetero atoms selected from O, S, and N, the fused heterocyclic ring being optionally fused to a phenyl ring or substituted with oxo;  
 m is 1, 2 or 3;  
 (CH 2 ) m  may be optionally replaced with C—O—(CH 2 ) m ;  
 X is SO 2 -piperizinyl, NR 3 —SO 2 , or SO 2 —NR 3 ;  
 n is 0, 1, 2, 3, or 4;  
 Ar 2  is phenyl, or a 5 or 6 membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and N, each moiety being optionally substituted with halogen, C 1 -C 10  alkyl, C 1 -C 10  alkoxy, and OR, or being fused to a 5 membered heterocyclic ring containing from 1 to 4 hetero atoms selected from O, S, and N, the fused heterocyclic ring being optionally fused to a phenyl ring or optionally substituted with oxo;  
 Y is O—Y, NR 1 , NR 1  CO, C 3 -C 8  cycloalkyl or a 5 or 6 membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and N, each of which is optionally substituted with oxo;  
 p is 0 or 1;  
 R 4 is hydrogen, R 1 , R 2 , oxo, C 1 -C 10  heteroalkyl, C 1 -C 10  alkyl, C 1 -C 10  haloalkyl, each being optionally substituted with C 3 -C 8  cycloalkyl, phenyl, naphthyl, benzofuran, carbazole, dibenzothiofuran, or a 5 or 6 membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S, and N, each ring structure being optionally substituted with halo and C 1 -C 10  alkyl,  
 and pharmaceutically acceptable salts and esters thereof.  
 
     
     
         2 . A compound of  claim 1  wherein Ar 1  is optionally substituted phenyl or pyridyl, X is NR 3 —SO 2  or SO 2 -NR 3 , Ar 2  is phenyl, pyridyl pyrimidinyl or pyrrolyl, Y is optionally substituted pyridyl, pyrrolyl, pyrimidinyl, quinolinyl, imadazolyl, and dihydrohenzofuranyl, and R 4  is R 1  or optionally substituted C 1 -C 10  alkyl.  
     
     
         3 . A compound of  claim 2  wherein m is one and n is zero or one.  
     
     
         4 . A compound of  claim 3  wherein R 3  is hydrogen and R 4 is C 1 -C 10  alkyl optionally substituted with optionally substituted C 3 -C 8  cycloalkyl, phenyl, or pyridyl.  
     
     
         5 . A compound of  claim 4  wherein R is hydrogen, halo, C 1 -C 10  alkyl, nitro or NR 1 R 1 , n is zero, X is attached to the chroman moiety in the 6 position, n is zero, Ar 2  is phenyl or pyridyl, and Y is optionally substituted pyridyl or pyrrolyl.  
     
     
         6 . A compound of  claim 1  wherein the —OH group of the compound of Formula 1 is in the R configuration.  
     
     
         7 . A compound useful in the preparation of compounds of Formula 1 of the formula  
       
         
           
           
               
               
           
         
       
       wherein, 
 R is hydrogen, hydroxy, oxo, halo, C 1 -C 10 haloalkyl, C 1 -C 10  alkyl, cyano, nitro, NR 1 R 1 , S R 1 , OR 1 , SO 2 R 2 , OCOR 2 , NR 1 COR 2 , COR 2 , NR 1  SO 2 R 2 , NR 1 CO 2 R 1 , pyrrole, or Ar 2 , optionally substituted with hydroxy, halogen, cyano, NR 1 R 1 , SR 1 , trifluoromethyl, OR 1 , C 3 -C 8  cycloaklyl, phenyl, NR 1 COR 2 , COR 2 , SO 2 R 2 , OCOR 2 , NR 1  SO 2 R, or NR 1  CO 2 R 1 ;  
 R 1  is hydrogen, C 1 -C 10  alkyl optionally substituted with 1 to 4 substituents selected from hydroxy, halogen, CO 2 H, CO 2 C 1 -C 10  alkyl, SO 2 C 1 -C 10 alkyl, C 1 -C 10  alkoxy; or C 3 -C 8  cycloalkyl, phenyl or naphthyl, each optionally substituted with 1 to 4 substituents selected from halogen, nitro, oxo, C 1 -C 1  alkyl, C 1 -C 10  alkoxy, and C 1 -C 10  alkylthio;  
 R 2  is R 1  or NR 1 R 1 ;  
 R 3  is hydrogen, C 1 -C 10  alkyl or  
                     
 m is 1, 2 or 3;  
 (CH 2 ) m  may be optionally replaced with C—O—(CH 2 ) m ;  
 X is SO 2 -piperizinyl, NR 3 —SO 2 , or SO 2 —NR 3 ;  
 n is 0, 1, 2, 3, or 4;  
 Ar 2  is phenyl, or a 5 or 6 membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and N, each moiety being optionally substituted with halogen, C 1 -C 10  alkyl, C 1 -C 10  alkoxy, and OR, or being fused to a 5 membered heterocyclic ring containing from 1 to 4 hetero atoms selected from O, S, and N, the fused heterocyclic ring being optionally used to a phenyl ring or optionally substituted with oxo;  
 Y is O—Y, NR 1 , NR 1 CO, C 3 -C 8  cycloalkyl or a 5 or 6 membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and N, each of which is optionally substituted with oxo;  
 p is 0 or 1;  
 R 4  is hydrogen, R 1 , R 2 , oxo, C 1 -C 10  heteroalkyl, C 1 -C 10  alkyl, C 1 -C 10  haloalkyl, each being optionally substituted with C 3 -C 8  cycloalkyl, phenyl, naphthyl, benzofuran, carbazole, dibenzothiofuran, or a 5 or 6 membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S, and N, each ring structure being optionally substituted with halo and C 1 -C 10  alkyl,  
 
     
     
         8 . A compound of  claim 7  wherein X is NR 3 —SO 2  or SO 2 —NR 3 , Ar 2  is phenyl, pyridyl pyrimidinyl or pyrrolyl, Y is optionally substituted pyridyl, pyrrolyl, pyrimidinyl, quinolinyl, imadazolyl, and dihydrohenzofuranyl, and R 4  is R 1  or optionally substituted C 1 -C 10  alkyl.  
     
     
         9 . A compound of  claim 8  wherein m is one and n is zero or one.  
     
     
         10 . A compound of  claim 9  wherein R 3  is hydrogen and R 4  is C 1 -C 10  alkyl optionally substituted with optionally substituted C 3 -C 8  cycloalkyl, phenyl, or pyridyl.  
     
     
         11 . A compound of  claim 10  wherein n is zero, X is attached to the chroman moiety in the 6 position, n is zero, Ar 2  is phenyl or pyridyl, and Y is optionally substituted pyridyl or pyrrolyl.  
     
     
         12 . A compound useful in the preparation of compounds of Formula 1 of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R is hydrogen, hydroxy, oxo, halo, C 1 -C 10 haloalkyl, C 1 -C 10  alkyl, cyano, nitro, NR 1 R 1 , S R 1 , OR 1 , SO 2 R 2 , OCOR 2 , NR 1 COR 2 , COR 2 , NR 1 SO 2 R 2 , NR 1 CO 2 R 1 , pyrrole, or Ar 2 , optionally substituted with hydroxy, halogen, cyano, NR 1 R 1 , SR 1 , trifluoromethyl, OR 1 , C 3 -C 8  cycloaklyl, phenyl, NR 1 COR 2 , COR 2 , SO 2 R 2 , OCOR 2 , NR 1 SO 2 R 2 , or NR 1 CO 2 R 1 ;  
 R 1  is hydrogen, C 1 -C 10  alkyl optionally substituted with 1 to 4 substituents selected from hydroxy, halogen, CO 2 H, CO 2 C 1 -C 10  alkyl, SO 2 C 1 -C 10 alkyl, C 1 -C 10  alkoxy; or C 3 -C 8  cycloalkyl, phenyl or naphthyl, each optionally substituted with 1 to 4 substituents selected from halogen, nitro, oxo, C 1 -C 10  alkyl, C 1 -C 10  alkoxy, and C 1 -C 10  alkylthio;  
 R 2  is R 1  or NR 1 R 1 ;  
 R 3  is hydrogen, C 1 -C 10  alkyl or  
                     
 Ar 1  is Ar 1 —O—CH 2 , phenyl, or a 5 or 6 membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and N, each moiety being optionally fused to a 5 membered heterocyclic ring containing from 1 to 4 hetero atoms selected from O, S, and N, the fused heterocyclic ring being optionally fused to a phenyl ring or substituted with oxo;  
 m is 1, 2 or 3;  
 (CH 2 ) m  may be optionally replaced with C—O—(CH 2 ) m ;  
 X is SO 2 -piperizinyl, NR 3 —SO 2 , or SO 2 —NR 3 ;  
 n is 0, 1, 2, 3, or 4;  
 Ar 2  is phenyl, or a 5 or 6 membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and N, each moiety being optionally substituted with halogen, C 1 -C 10  alkyl, C 1 -C 10  alkoxy, and OR, or being fused to a 5 membered heterocyclic ring containing from 1 to 4 hetero atoms selected from O, S, and N, the fused heterocyclic ring being optionally fused to a phenyl ring or optionally substituted with oxo;  
 Y is O—Y, NR 1  NR 1 CO, C 3 -C 8  cycloalkyl or a 5 or 6 membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S and N, each of which is optionally substituted with oxo;  
 p is 0 or 1;  
 R 4  is hydrogen, R 1 , R 2 , oxo, C 1 -C 10  heteroalkyl, C 1 -C 10  alkyl, C 1 -C 10  haloalkyl, each being optionally substituted with C 3 -C 8  cycloalkyl, phenyl, naphthyl, benzofuran, carbazole, dibenzothiofuran, or a 5 or 6 membered heterocyclic ring with from 1 to 4 heteroatoms selected from O, S, and N, each ring structure being optionally substituted with halo and C 1 -C 10  alkyl.  
 
     
     
         13 . A compound of  claim 12  wherein Ar 1  is optionally substituted phenyl or pyridyl, X is NR 3 —SO 2  or SO 2 —NR 3 , Ar 2  is phenyl, pyridyl pyrimidinyl or pyrrolyl, Y is optionally substituted pyridyl, pyrrolyl, pyrimidinyl, quinolinyl, imadazolyl, and dihydrohenzofuranyl, and R 4  is R 1  or optionally substituted C 1 -C 10  alkyl.  
     
     
         14 . A compound of  claim 13  wherein m is one and n is zero or one.  
     
     
         15 . A compound of  claim 14  wherein R 3  is hydrogen and R 4  is C 1 -C 10  alkyl optionally substituted with optionally substituted C 3 -C 8  cycloalkyl, phenyl, or pyridyl.  
     
     
         16 . A compound of  claim 15  wherein R is hydrogen, halo, C 1 -C 10  alkyl, nitro or NR 1 R 1 , n is zero, X is attached to the chroman moiety in the 6 position, n is zero, Ar 2  is phenyl or pyridyl, and Y is optionally substituted pyridyl or pyrrolyl.  
     
     
         17 . A method of treating a beta-3 adrenergic receptor mediated condition which comprises administering to a patient in need thereof a pharmaceutically effective amount of a compound of Formula 1, or a salt or ester thereof.  
     
     
         18 . A method of treating a beta-3 adrenergic receptor mediated condition which comprises administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 9 , or a salt or ester thereof.  
     
     
         19 . A method of treating obesity in mammals which comprises administering to a patient in need thereof a pharmaceutically effective amount of a compound of Formula 1, or a salt or ester thereof.  
     
     
         20 . A method of treating obesity in mannals which comprises administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 9 , or a salt or ester thereof.  
     
     
         21 . A method of treating diabetes in mammals which comprises administering to a patient in need thereof a pharmaceutically effective amount of a compound of Formula 1, or a salt or ester thereof.  
     
     
         22 . A method of treating diabetes in mammals which comprises administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 9 , or a salt or ester thereof.  
     
     
         23 . A pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.  
     
     
         24 . A composition comprising an effective amount of a compound of Formula I, or a salt hereof, in combination with an inert carrier.