Compounds for the treatment of metabolic disorders

Abstract

Compounds useful for the treatment of various metabolic disorders, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis, are disclosed.

1 . A method for treating a mammalian subject with a condition selected from the group consisting of insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis comprising administering to the subject an amount of a biologically active agent effective to treat the condition, wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 m is 0 or 1;  
 q is 0 or 1;  
 t is 0 or 1;  
 R 5  is alkyl having from 1 to 3 carbon atoms;  
 R 9  is hydrogen, halo, or alkoxy having from 1 to 3 carbon atoms;  
 A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or 
 cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or  
 a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and 0 and the heteroaromatic ring is covalently bound to the remainder of the compound of formula I′ by a ring carbon; and  
 
 X is —CH 2 —, Q is —OR 1  and R 1  is ethyl; or X is —CH 2 CR 12 R 13 — or —CH 2 CH(NHAc)— wherein each of R 12  and R 13  is independently hydrogen or methyl, Q is OR 1  and R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms; or X is —CH 2 CH 2 — and Q is NR 10 R 11  wherein one of R 10  and R 11  is hydrogen, alkyl having from 1 to 3 carbon atoms or hydroxy, and the other is hydrogen or alkyl having from 1 to 3 carbon atoms;  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
   
   
       2 . The method of  claim 1 , wherein the agent is administered orally.  
   
   
       3 . The method of  claim 1 , wherein the subject is a human.  
   
   
       4 . The method of  claim 3 , wherein the agent is administered in an amount from one milligram to four hundred milligrams per day.  
   
   
       5 . The method of  claim 1 , wherein the condition is insulin resistance syndrome or Type II Diabetes.  
   
   
       6 . The method of  claim 1 , wherein the condition is Type 1 Diabetes.  
   
   
       7 . The method of  claim 1 , wherein the treatment reduces a symptom of diabetes or the chances of developing a symptom of diabetes, wherein the symptom is selected from the group consisting of: atherosclerosis, obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, retinopathy, foot ulceration and cataracts, associated with diabetes.  
   
   
       8 . The method of  claim 1 , further comprising administering to the subject an effective amount of a therapeutic agent selected from the group consisting of: metformin; glyburide; GLUCOVANCE (combined formulation of metformin and glyburide); atorvastatin; lovastatin; pravastatin; simvastatin; clofibrate; gemfibrozil, rosiglitazone; pioglitazone; acarbose; and repaglinide.  
   
   
       9 . The method of  claim 1 , wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 m is 0 or 1;  
 q is 0 or 1;  
 t is 0 or 1;  
 R 5  is alkyl having from 1 to 3 carbon atoms;  
 A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or 
 cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or  
 a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula I by a ring carbon; and  
 
 X is —CH 2 — and R 1  is ethyl; or X is —CH 2 CH 2 — or —CH 2 CH(NHAc)— and R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms;  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
   
   
       10 . The method of  claim 9 , wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 m is 0 or 1;  
 q is 0 or 1;  
 t is 0 or 1;  
 R 2  and R 3  are each independently selected from hydrogen, halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy;  
 R 5  is alkyl having from 1 to 3 carbon atoms; and  
 X is —CH 2 — and R 1  is ethyl; or X is —CH 2 CH 2 — or —CH 2 CH(NHAc)— and R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms;  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
   
   
       11 . The method of  claim 10 , wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 m is 0 or 1;  
 p is 1 and R 1  is ethyl; or p is 2 and R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms;  
 R 2  and R 3  are each independently selected from hydrogen, halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy;  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
   
   
       12 . The method of  claim 11 , wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 m is 0;  
 R 1  is H or alkyl having from 1 to 7 carbon atoms;  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
   
   
       13 . The method of  claim 9 , wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms,  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
   
   
       14 . The biologically active agent of  claim 9 , wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms; and  
 Het is a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula IC by a ring carbon.  
 
   
   
       15 . A method for treating a mammalian subject with a condition selected from the group consisting of insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis comprising administering to the subject an amount of a biologically active agent effective to treat the condition, wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 t is 0 or 1;  
 m is 0 and r is 1, or mis 1 and r is 0;  
 A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or 
 cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are mono-substituted by methyl or ethyl; or  
 a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula II by a ring carbon;  
 
 z is  
                     
 R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms;  
 R 4  is hydrogen; —NHCOOC(CH 3 ) 3 ; —NHCH 3 ; or —NHCH 2 CH 3 ;  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
   
   
       16 . The method of  claim 15 , wherein the agent is administered orally.  
   
   
       17 . The method of  claim 15 , wherein the subject is a human.  
   
   
       18 . The method of  claim 17 , wherein the agent is administered in an amount from one milligram to four hundred milligrams per day.  
   
   
       19 . The method of  claim 15 , wherein the condition is insulin resistance syndrome or Type II Diabetes.  
   
   
       20 . The method of  claim 15 , wherein the condition is Type 1 Diabetes.  
   
   
       21 . The method of  claim 15 , wherein the treatment reduces a symptom of diabetes or the chances of developing a symptom of diabetes, wherein the symptom is selected from the group consisting of: atherosclerosis, obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, retinopathy, foot ulceration and cataracts, associated with diabetes.  
   
   
       22 . The method of  claim 15 , wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 m is 0 or 1;  
 r is 0 or 1;  
 z is  
                     
 R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms;  
 R 4  is hydrogen; —NHCOOC(CH 3 ) 3 ; —NHCH 3 ; or —NHCH 2 CH 3 ;  
 R 3  is hydrogen or halo;  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
   
   
       23 . A method for treating a mammalian subject with a condition selected from the group consisting of insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis comprising administering to the subject an amount of a biologically active agent effective to treat the condition, wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or 
 cycloalkyl having from 3 to 6 ring carbon atoms wherein one or both ring carbons are independently mono-substituted by methyl or ethyl; or  
 a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula III by a ring carbon.  
 
 
   
   
       24 . The method of  claim 23 , wherein the agent is administered orally.  
   
   
       25 . The method of  claim 23 , wherein the subject is a human.  
   
   
       26 . The method of  claim 25 , wherein the agent is administered in an amount from one milligram to four hundred milligrams per day.  
   
   
       27 . The method of  claim 23 , wherein the condition is insulin resistance syndrome or Type II Diabetes.  
   
   
       28 . The method of  claim 23 , wherein the condition is Type 1 Diabetes.  
   
   
       29 . The method of  claim 23 , wherein the treatment reduces a symptom of diabetes or the chances of developing a symptom of diabetes, wherein the symptom is selected from the group consisting of: atherosclerosis, obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, retinopathy, foot ulceration and cataracts, associated with diabetes.  
   
   
       30 . A method for treating a mammalian subject with a condition selected from the group consisting of insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis comprising administering to the subject an amount of a biologically active agent effective to treat the condition, wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms;  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
   
   
       31 . The method of  claim 30 , wherein the agent is administered orally.  
   
   
       32 . The method of  claim 30 , wherein the subject is a human.  
   
   
       33 . The method of  claim 32 , wherein the agent is administered in an amount from one milligram to four hundred milligrams per day.  
   
   
       34 . The method of  claim 30 , wherein the condition is insulin resistance syndrome or Type II Diabetes.  
   
   
       35 . The method of  claim 30 , wherein the condition is Type 1 Diabetes.  
   
   
       36 . The method of  claim 30 , wherein the treatment reduces a symptom of diabetes or the chances of developing a symptom of diabetes, wherein the symptom is selected from the group consisting of: atherosclerosis, obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, retinopathy, foot ulceration and cataracts, associated with diabetes.  
   
   
       37 . A method for treating a mammalian subject with a condition selected from the group consisting of insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis comprising administering to the subject an amount of a biologically active agent effective to treat the condition, wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms;  
 R14 is hydroxy or hydrogen; and  
 A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or 
 cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or  
 a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula V′ by a ring carbon;  
 or a pharmaceutically acceptable salt of the compound.  
 
 
   
   
       38 . The method of  claim 37 , wherein the agent is administered orally.  
   
   
       39 . The method of  claim 37 , wherein the subject is a human.  
   
   
       40 . The method of  claim 39 , wherein the agent is administered in an amount from one milligram to four hundred milligrams per day.  
   
   
       41 . The method of  claim 37 , wherein the condition is insulin resistance syndrome or Type II Diabetes.  
   
   
       42 . The method of  claim 37 , wherein the condition is Type 1 Diabetes.  
   
   
       43 . The method of  claim 37 , wherein the treatment reduces a symptom of diabetes or the chances of developing a symptom of diabetes, wherein the symptom is selected from the group consisting of: atherosclerosis, obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, retinopathy, foot ulceration and cataracts, associated with diabetes.  
   
   
       44 . The method of  claim 37 , wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms;  
 A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or 
 cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or  
 a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula V by a ring carbon;  
 or a pharmaceutically acceptable salt of the compound.  
 
 
   
   
       45 . The biologically active agent of  claim 44 , wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms;  
 R 2  and R 3  are each independently selected from hydrogen, halo, alkyl having 1 or 2 carbon 
 atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy;  
 or a pharmaceutically acceptable salt of the compound.  
 
 
   
   
       46 . A method for treating a mammalian subject with a condition selected from the group consisting of insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis comprising administering to the subject an amount of a biologically active agent effective to treat the condition, wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 R 1  is hydrogen or alkyl having from 1 to 3 carbon atoms; and  
 A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or 
 cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or  
 a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula XCI by a ring carbon;  
 or a pharmaceutically acceptable salt of the compound.  
 
 
   
   
       47 . The method of  claim 46 , wherein the agent is administered orally.  
   
   
       48 . The method of  claim 46 , wherein the subject is a human.  
   
   
       49 . The method of  claim 48 , wherein the agent is administered in an amount from one milligram to four hundred milligrams per day.  
   
   
       50 . The method of  claim 46 , wherein the condition is insulin resistance syndrome or Type II Diabetes.  
   
   
       51 . The method of  claim 46 , wherein the condition is Type 1 Diabetes.  
   
   
       52 . The method of  claim 46 , wherein the treatment reduces a symptom of diabetes or the chances of developing a symptom of diabetes, wherein the symptom is selected from the group consisting of: atherosclerosis, obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, retinopathy, foot ulceration and cataracts, associated with diabetes.  
   
   
       53 . A method for treating a mammalian subject with a condition selected from the group consisting of insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis comprising administering to the subject an amount of a biologically active agent effective to treat the condition, wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 n is 1 or 2;  
 R 1  is hydrogen or alkyl having from 1 to 3 carbon atoms; and  
 A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or 
 cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or  
 a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula CXVI by a ring carbon;  
 or a pharmaceutically acceptable salt of the compound.  
 
 
   
   
       54 . The method of  claim 53 , wherein the agent is administered orally.  
   
   
       55 . The method of  claim 53 , wherein the subject is a human.  
   
   
       56 . The method of  claim 55 , wherein the agent is administered in an amount from one milligram to four hundred milligrams per day.  
   
   
       57 . The method of  claim 53 , wherein the condition is insulin resistance syndrome or Type II Diabetes.  
   
   
       58 . The method of  claim 53 , wherein the condition is Type 1 Diabetes.  
   
   
       59 . The method of  claim 53 , wherein the treatment reduces a symptom of diabetes or the chances of developing a symptom of diabetes, wherein the symptom is selected from the group consisting of: atherosclerosis, obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, retinopathy, foot ulceration and cataracts, associated with diabetes.  
   
   
       60 . A method for treating a mammalian subject with a condition selected from the group consisting of insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis comprising administering to the subject an amount of a biologically active agent effective to treat the condition, wherein the agent is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein
 n is 0, 1 or 2;  
 R 1  is hydrogen or alkyl having from 1 to 3 carbon atoms;  
 R 15  is hydrogen or alkyl having from 1 to 3 carbon atoms;  
 R 9  is hydrogen, halo, hydroxy, or alkoxy having from 1 to 3 carbon atoms;  
 A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; or 
 cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently mono-substituted by methyl or ethyl; or  
 a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of formula CXVII by a ring carbon;  
 or a pharmaceutically acceptable salt of the compound.  
 
 
   
   
       61 . The method of  claim 60 , wherein the agent is administered orally.  
   
   
       62 . The method of  claim 60 , wherein the subject is a human.  
   
   
       63 . The method of  claim 62 , wherein the agent is administered in an amount from one milligram to four hundred milligrams per day.  
   
   
       64 . The method of  claim 60 , wherein the condition is insulin resistance syndrome or Type II Diabetes.  
   
   
       65 . The method of  claim 60 , wherein the condition is Type 1 Diabetes.  
   
   
       66 . The method of  claim 60 , wherein the treatment reduces a symptom of diabetes or the chances of developing a symptom of diabetes, wherein the symptom is selected from the group consisting of: atherosclerosis, obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, retinopathy, foot ulceration and cataracts, associated with diabetes.