Aryl carbonyl derivatives as therapeutic agents

Abstract

This invention relates to aryl carbonyl derivatives which are activators of glucokinase which may be useful for the management, treatment, control, or adjunct treatment of diseases, where increasing glucokinase activity is beneficial.

1 . A method of lowering blood glucose levels in a subject, the method comprising:
 administering to the subject a therapeutically effective amount of a liver-specific glucokinase activator, wherein the liver-specific glucokinase activator increases glucose utilization in the liver without inducing an increase in insulin secretion in response to glucose; thereby lowering blood glucose levels in the subject.   
     
     
         2 . The method of  claim 1 , wherein the subject has a disease selected from the group consisting of type II diabetes, impaired fasting glucose, hyperglycemia, impaired glucose tolerance, and Syndrome X. 
     
     
         3 . The method of  claim 2 , wherein the disease is type II diabetes. 
     
     
         4 . The method of  claim 1 , wherein the subject is at risk of experiencing hypoglycemia. 
     
     
         5 . The method of  claim 1 , wherein the subject is a human. 
     
     
         6 . The method of  claim 1 , wherein the liver-specific glucokinase activator is a compound of Formula (Ib) 
       
         
           
           
               
               
           
         
         wherein, 
         R 24  is selected from the group consisting of hydrogen, halogen, —C(O)OR 2 , —CN, —CF 3 , —OCF 3 , —NO 2 , —OR 2 , —NR 2 R 3 , C 1-6 -alkyl-Z-, cycloalkyl-Z-, heterocyclyl-Z-, aryl-Z-, heteroaryl-Z-, N(R 4 R 5 )—C 1-6 -alkylene-Z-, R 6 —W 1 —Z—, R 6 —W 1 —N(R 4 )—Z—, R 6 —N(R 4 )—Z—, and R 6 —W 1 —C 1-6 -alkylene-Z-;
 R 2  and R 3  independently of each other are selected from the group consisting of hydrogen, C 1-6 -alkyl, aryl-C 1-6 -alkylene-, heteroaryl-C 1-6 -alkylene-, C 1-6 -alkyl-arylene-, C 1-6 -alkyl-heteroarylene-, heteroaryl, and aryl; 
 Z is a direct bond, —O—, —NH— —NHCH 2 —, —S—, —SO 2 —, —C(O)NH—, —NHC(O)—, —N(H)CON(H)—, —N(CH 3 )CONH—, —N(H)SO 2 —, —SO 2 N(H)—, —C(O)—O—, —N(H)SO 2 N(H)—, or —O—C(O)—; 
 R 4 , R 5 , and R 6  independently of each other are selected from the group consisting of hydrogen, aryl, C 1-6 -alkyl, heteroaryl-C 1-6 -alkylene-, and aryl-C 1-6 -alkylene-; 
 W 1  is a direct bond, —O—, —C(O)—, —NH—, —S—, —SO 2 —, —C(O)NH—, —NHC(O)—, —N(H)CON(H)—, —N(H)SO 2 —, —SO 2 N(H)—, —C(O)—O—, —N(H)SO 2 N(H)—, or —O—C(O)—; 
 
         L 1  is a bond, -D-alkylene-E-, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —N(R 11 )—, or —C(═N—OR 12 );
 D is a direct bond or —O— and E is a direct bond or —O—; 
 R 11  is hydrogen or C 1-6 -alkyl; 
 R 12  is hydrogen or C 1-6 -alkyl; 
 
         G 1  is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-10 -cycloalkyl or C 3-10 -heterocyclyl, optionally substituted with one or more substituents selected from the group consisting of —CN, —CF 3 , —OCF 3 , —OR 18 , —NR 18 R 19 , C 3-10 -cycloalkyl and C 1-6 -alkyl;
 R 18  and R 19 , independently of each other, are hydrogen or C 1-6 -alkyl; 
 
         L 2  is a —N—(R 20 )—;
 R 20  is hydrogen; 
 
         L 3  is —C(O)—; 
         R 1  is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, or C 2-6 -alkynyl, optionally substituted with one or more substituents selected from the group consisting of R 33 , R 34 , and R 35 ;
 R 33 , R 34 , and R 35  independently of each other are selected from the group consisting of —CHF 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —OCF 2 CHF 2 , —S(O) 2 CF 3 , —SCF 3 , —OR 52 , —NR 52 R 53 , —SR 52 , —NR 52 S(O) 2 R 53 , —S(O) 2 NR 52 R 53 , —S(O)NR 52 R 53 , —S(O)R 52 , —S(O) 2 R 52 , —C(O)NR 52 R 53 , —OC(O)NR 52 R 53 , —NR 52 C(O)R 53 , —CH 2 C(O)NR 52 R 53 , —OCH 2 C(O)NR 52 R 53 , —CH 2 OR 52 , —CH 2 NR 52 R 53 , —OC(O)R 52 , —C(O)R 52  and —C(O)OR 52 ; 
 R 52  and R 53  independently of each other are selected from the group consisting of hydrogen, C 1-6 -alkyl, aryl-C 1-6 -alkylene-, heteroaryl-C 1-6 -alkylene, heteroaryl, and aryl; 
 or 
 R 52  and R 53 , when attached to the same nitrogen atom, together with the nitrogen atom to which they are attached, may form a 3- to 8-membered heterocyclic ring optionally containing one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and optionally containing one or two double bonds; 
 
         G 2  is 
       
       
         
           
           
               
               
           
         
         
           R 43  is —C 1-6 -alkylene-C(O)OR 54 ; and 
           R 54  is hydrogen, methy, or ethyl; 
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The method of  claim 6 , wherein the compound is {2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of  claim 6 , wherein the compound is {2-[3-(4-Methyl-2-[2-methylpropoxy]phenyl)-ureido]-thiazol-4-yl}-acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The method of  claim 6 , wherein the compound is {2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method of  claim 6 , wherein the compound is {2-[3-(4-Bromo-2-cyclopentanecarbonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method of  claim 6 , wherein the compound is {2-[3-(4-Bromo-2-cyclopentanecarbonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method of  claim 6 , wherein the compound is 3-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-propionic acid ethyl ester or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 6 , wherein the compound is 3-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-propionic acid or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The method of  claim 6 , wherein the compound is {2-[3-(2-Cyclohexanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 6 , wherein the compound is {2-[3-(4-Chloro-2-cyclopentanecarbonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid or a pharmaceutically acceptable salt thereof.