Antidiabetic agents

Abstract

A compound of the formula wherein R 1 is: R 5 is: and n, m, Z, R 8 , R 9 , R 10 and R 11 are as defined herein, useful in the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly, myocardial ischemia.

1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salt thereof; wherein 
 n is 0, 1, 2, 3 or 4;  
 m is 0, 1, 2, 3 or 4;  
 Z is oxygen or sulfur;  
 R 1  is  
                     
 wherein the dashed lines represent optional double bonds;  
 a is 1, 2 or 3;  
 each R 2  is independently hydrogen, halo, hydroxy, amino, nitro, (C 1 -C 6 )alkoxy, cyano, C(O)H or (C 1 -C 6 )alkyl optionally substituted by one to three fluoro atoms;  
 R 3  is hydrogen, halo, cyano, (C 1 -C 6 )alkyl or (C 1 -C 3 )alkynyl;  
 R 4  is hydrogen, halo, cyano or (C 1 -C 6 )alkyl;  
 R 5  is  
                     
 wherein the dashed lines represent optional double bonds;  
 A, B and E are each independently nitrogen or CR 15 ;  
 X and Y are each independently CH 2 , oxygen, S(O) d  wherein d is 0, 1 or 2; nitrogen or NR 16 ;  
 R 8 , R 9 , R 10  and R 11  are each independently hydrogen or (C 1 -C 6 )alkyl;  
 R 12  is hydrogen, HC(O)(C 0 -C 6 )alkyl, carboxy(C 0 -C 3 )alkyl, R 17 R 18 N—C(O)—(C 0 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, R 17 (C 1 -C 3 )alkyl, R 17 R 18 N(C 0 -C 3 )alkyl, (C 1 -C 6 )alkyl-C(O)—NH, (C 6 -C 10 )aryl-C(O)—NH, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl-C(O)—NH, (C 2 -C 9 )heteroaryl(C 1 -C 5 )alkyl-C(O)—NH, (C 1 -C 6 )alkylaminocarbonylamino, (C 6 -C 10 )arylaminocarbonylamino, (C 6 -C 10 )aryl(C 1 -C 6 )alkylaminocarbonylamino, (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkylaminocarbonylamino, (C 1 -C 6 )alkylsulfonylamino, (C 6 -C 10 )aryl(C 1 -C 6 )alkylsulfonylamino, (C 2 -C 9 )heteroarylsulfonylamino, (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkylsulfonylamino, (C 1 -C 6 )alkylsulfonyl N((C 1 -C 6 )alkyl), (C 6 -C 10 )aryl(C 1 -C 6 )alkylsulfonyl N((C 1 -C 6 )alkyl), (C 2 -C 9 )heteroarylsulfonyl N((C 1 -C 6 )alkyl), (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkylsulfonyl N((C 1 -C 6 )akyl), (C 3 -C 7 )cycloalkylamino, ((C 3 -C 7 )cycloalkyl) 2 amino, (C 3 -C 7 )cycloalkylcarbonylamino, (C 6 -C 10 )aryl(C 3 -C 7 )cycloalkylcarbonylamino, (C 2 -C 9 )heteroaryl(C 3 -C 7 )cycloalkylcarbonylamino, (C 3 -C 7 )cycloalkylaminocarbonylamino, (C 6 -C 10 )aryl(C 3 -C 7 )cycloalkylaminocarbonylamino, (C 2 -C 9 )heteroaryl(C 3 -C 7 )cycloalkylaminocarbonylamino, (C 3 -C 7 )cycloalkylsulfonylamino, (C 6 -C 10 )aryl(C 3 -C 7 )cycloalkylsulfonylamino, (C 2 -C 9 )heteroaryl(C 3 -C 7 )cycloalkylsulfonylamino, (C 3 -C 7 )cycloalkylsulfonyl N((C 3 -C 7 )cycloalkyl), (C 6 -C 10 )aryl(C 3 -C 7 )cycloalkylsulfonyl N((C 3 -C 7 )cycloalkyl, (C 2 -C 9 )heteroarylsulfonyl N((C 3 -C 7 )cycloalkyl), (C 2 -C 9 )heteroaryl(C 3 -C 7 )cycloalkylsulfonyl N((C 3 -C 7 )cycloalkyl), (C 1 -C 6 )alkyl S(O) c , (C 3 -C 7 )cycloalkyl S(O) c , (C 6 -C 10 )aryl(C 1 -C 6 )alkyl S(O) c , (C 6 -C 10 )aryl S(O) c , (C 1 -C 6 )alkylamino S(O) c , (C 1 -C 6 )arylamino S(O) c , (C 6 -C 10 )arylC 1 -C 6 )alkylamino S(O) c  wherein c is 0, 1 or 2;  
 R 13  is hydrogen or (C 1 -C 6 )alkyl;  
 R 14  is hydrogen, hydroxy, (C 1 -C 6 )alkoxy, (C 6 -C 10 )aryloxy or NR 17 R 18 ;  
 R 15  is hydrogen, (C 1 -C 6 )alkylcarbonylcarboxy, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl piperazinylcarbonyl or piperidinylcarbonyl;  
 R 16  is hydrogen, HCO, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, carboxy(C 1 -C 6 )alkyl, piperidinyl(C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )acyl; piperidinyl carbonyl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkylcarbonyl or morpholinyl(C 1 -C 6 )alkylcarbonyl;  
 R 17  and R 18  are each independently hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl and (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl.  
 
     
     
         2 . A compound of  claim 1 , wherein R 2  is  
       
         
           
           
               
               
           
         
       
       wherein a is 1 or 2; and each R 2  is independently halo, amino or (C 1 -C 6 )alkyl optionally substituted by one to three fluoro atoms.  
     
     
         3 . A compound of  claim 1 , wherein n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and Z is oxygen.  
     
     
         4 . A compound according to  claim 1 , wherein R 5  is  
       
         
           
           
               
               
           
         
       
       wherein A, B and E are CR 15 ; 
 X is oxygen or nitrogen;  
 Y is oxygen or NR 16 ;  
 R 12  is hydrogen, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 3 )alkyl or carboxy;  
 R 15  is hydrogen, (C 1 -C 6 )alkylcarbonylcarboxy, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl piperazinylcarbonyl or piperidinylcarbonyl;  
 R 16  is HCO, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, carboxy(C 1 -C 6 )alkyl, piperidinyl(C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )acyl; piperidinyl carbonyl(C 1 -C 6 )alkyl, hydroxy((C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkylcarbonyl or morpholinyl(C 1 -C 6 )alkylcarbonyl.  
 
     
     
         5 . A compound of  claim 1 , wherein R 5  is  
       
         
           
           
               
               
           
         
       
       wherein A is CR 15 ; 
 B and E are each independently CR 15  or nitrogen; and  
 X and Y are each independently nitrogen or CH 2 .  
 
     
     
         6 . A compound of  claim 1 , wherein R 5  is  
       
         
           
           
               
               
           
         
       
       wherein A is CR 15 ; 
 B and E are each independently CR 15  or nitrogen; and  
 X and Y are each independently nitrogen or CH 2 .  
 
     
     
         7 . A compound of  claim 1 , wherein R 1  is  
       
         
           
           
               
               
           
         
       
       wherein a is 1 or 2; and each R 2  is independently halo, amino or (C 1 -C 6 )alkyl optionally substituted by one to three fluoro atoms; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; Z is oxygen and R 5  is  
       
         
           
           
               
               
           
         
       
       wherein A, B and E are CR 15 ; 
 X is oxygen or nitrogen;  
 Y is oxygen or NR 16 ;  
 R 12  is H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl or carboxy;  
 R 15  is hydrogen, (C 1 -C 6 )alkylcarbonylcarboxy, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl piperazinylcarbonyl or piperidinylcarbonyl;  
 R 16  is HCO, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, carboxy(C 1 -C 6 )alkyl, piperidinyl(C 1 -C 6 )alkylcarbonyl; (C 1 -C 6 )acyl; piperidinyl carbonyl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkylcarbonyl or morpholinyl(C 1 -C 6 )alkylcarbony.  
 
     
     
         8 . A compound of  claim 1 , wherein R 1  is  
       
         
           
           
               
               
           
         
       
       wherein a is 1 or 2; and each R 2  is independently halo, amino or (C 1 -C 6 )alkyl optionally substituted by one to three fluoro atoms; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; Z is oxygen and R 5  is  
       
         
           
           
               
               
           
         
       
       wherein A is CR 15 ; 
 B and E are each independently CR 15  or nitrogen; and  
 X and Y are each independently nitrogen or CH 2 .  
 
     
     
         9 . A compound of  claim 1 , wherein R 1  is  
       
         
           
           
               
               
           
         
       
       wherein a is 1 or 2; and each R 2  is independently halo, amino or (C 1 -C 6 )alkyl optionally substituted by one to three fluoro atoms; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; Z is oxygen and R 5  is  
       
         
           
           
               
               
           
         
       
       wherein A is CR 15 ; 
 B and E are each independently CR 15  or nitrogen; and  
 X and Y are each independently nitrogen or CH 2 .  
 
     
     
         10 . A compound of  claim 1 , wherein said compound is selected from the group consisting of: 
 5-Chloro-1H-indole-2-carboxylic acid (4-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;    5-Chloro-1H-indole-2-carboxylic acid (9-methanesulfonylamino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;    5-Chloro-1H-indole-2-carboxylic acid (9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;    {8-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylamino}-acetic acid ethyl ester;    {2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-4-hydroxymethyl-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-acetic acid:    5-Chloro-1H-indole-2-carboxylic acid (9-amino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;    5-Chloro-1H-indole-2-carboxylic acid [9-(2-hydroxy-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;    {2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-acetic acid;    5-Methyl-1H-indole-2-carboxylic acid (9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;    5-Chloro-1H-indole-2-carboxylic acid {9-[2-(3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl-]6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide;    5-Chloro-1H-indole-2-carboxylic acid [4-(piperidine-1-carbonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;    5-Chloro-1H-indole-2-carboxylic acid (3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-amide;    5-Fluoro-1H-indole-2-carboxylic acid (6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;    5-Chloro-1H-indole-2-carboxylic acid [9-(2-hydroxy-ethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide;    5-Chloro-1H-indole-2-carboxylic acid (6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;    5-Chloro-1H-indole-2-carboxylic acid (9-methyl-6,7,8,9-tetrahydro-5-oxa-9-aza -benzocyclohepten-2-yl)-amide;    2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylic acid;    5-Chloro-1H-indole-2-carboxylic acid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl) -amide;    5-Methyl-1H-indole-2-carboxylic acid (6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;    5-Chloro-1H-indole-2-carboxylic acid (9-dimethylcarbamoyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;    5-Chloro-1H-indole-2-carboxylic acid [9-(2-oxo-2-pyrrolidin-1-yl-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;    5-Bromo-1H-indole-2-carboxylic acid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;    5-Methyl-1H-indole-2-carboxylic acid (2,3,4,5-tetrahydro-benzo[b]dioxocin-8-yl)-amide;    8-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid:    5-Methyl-1H-indole-2-carboxylic acid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;    5-Chloro-1H-indole-2-carboxylic acid [9-(3,4-dihydroxy-pyrrolidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide;    5-Chloro-1H-indole-2-carboxylic acid [4-(4-methyl-piperazine-1-carbonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;    1H-Indole-2-carboxylic acid (9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;    1H -Indole-2-carboxylic acid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;    5-Chloro-1H-indole-2-carboxylic acid -[9-(4-methyl-piperazine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide;    5-Fluoro-1H-indole-2-carboxylic acid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;    5-Chloro-1H-indole-2-carboxylic acid {9-[(2-hydroxy-ethylcarbamoyl)-methyl]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide;    2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylic acid methyl ester;    5-Chloro-1H-indole-2-carboxylic acid [9-(2-hydroxy-ethyl)-4-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;    1H-Indole-2-carboxylic acid (2,3,4,5-tetrahydro-benzo[b]dioxocin-8-yl)-amide; and    5-Fluoro-1H-indole-2-carboxylic acid (2,3,4,5-tetrahydro-benzo[b]dioxocin-8-yl)-amide.    
     
     
         11 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.  
     
     
         12 . A method of treating atherosclerosis, diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hyperglycemia, hypertension, tissue ischemia or myocardial ischemia in a mammal, the method comprising administering to said mammal suffering from atherosclerosis, diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hyperglycemia, hypertension, tissue ischemia or myocardial ischemia a compound of  claim 1 , a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said compound of  claim 1 .  
     
     
         13 . A method of inhibiting glycogen phosphorylase in a mammal, the method comprising administering to said mammal in need of glycogen phosphorylase ihibition a compound of  claim 1 , a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said compound of  claim 1 .  
     
     
         14 . A method of treating diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia, the method comprising the step of administering to a patient suffering from diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia a compound of  claim 1  or a pharmaceutically acceptable salt thereof in combination with at least one additional compound useful for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia.