Cycloalkylmethoxy-substituted acetic acid derivatives, processes for their preparation and their use as pharmaceuticals

Abstract

Provided herein are methods for the treatment of metabolic diseases such as disorders of fatty acid metabolism and glucose utilization as well as disorders in which insulin resistance is involved, in a patient. comprising the administration of novel compounds of formula I below: in which the substituents are defined herein including their physiologically acceptable salts,

1 . A method for treating or preventing a disorder of fatty acid metabolism or glucose utilization in a patient, comprising administering to said patient a therapeutically effective amount of a compound having the formula I:  
       
         
           
           
               
               
           
         
       
       in which: 
 Ring A is a (C 3 -C 8 )-cycloalkanediyl ring or a (C 3 -C 8 )-cycloalkenediyl ring, wherein one or more carbon atoms of the (C 3 -C 8 )-cycloalkanediyl ring or the (C 3 -C 8 )-cycloalkenediyl ring are optionally replaced by oxygen atoms;  
 R1 and R2 are:  
 (a) independently of one another H, F, Cl, Br, CF 3 , OCF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, SCF 3 , SF 5 , OCF 2 —CHF 2 , (C 6 -C 10 )-aryl, (C 6 -C 10 )-aryloxy, OH, or NO 2 ; or  
 (b) together with the phenyl, pyridine, 1H-pyrrole, thiophene or furan ring form fused, partially or unsaturated bicyclic (C 6 -C 10 )-aryl or (C 5 -C 11 )-heteroaryl;  
 R3 is:  
 H, (C 1 -C 6 )-alkyl, (C 3 -C 8 )-cycloalkyl, (C 1 -C 3 )-alkyl-(C 3 -C 8 )-cycloalkyl, phenyl, (C 1 -C 3 )-alkyl-phenyl, (C 5 -C 6 )-heteroaryl, (C 1 -C 3 )-alkyl-(C 5 -C 6 )-heteroaryl, or (C 1 -C 3 )-alkyl fully or partially substituted by F;  
 W is:  
 (a) is CH or N if o=1, or  
 (b) is O, S or NR10 if o=0;  
 X is (C 1 -C 6 )-alkanediyl, wherein one or more carbon atoms of the (C 1 -C 6 ) alkanediyl may be replaced by oxygen atoms;  
 Y1 is (CR13R14) p , wherein p is 1 or 2;  
 Y2 is CH2, O, S, SO, SO 2  or NR9;  
 n is 0-2;  
 R4 is H, (C 1 -C 6 )-alkyl, NR9, or F if Y2 is not O;  
 R5 is H, (C 1 -C 6 )-alkyl, NR9, or F if Y2 is not O;  
 R6 is H, (C 1 -C 6 )-alkyl; or F if n is not O;  
 R7 is: 
 H, F (if n is not 0), (C 1 -C 6 )-alkoxy, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 8 )-cycloalkyl, (C 1 -C 6 )-alkyl that may be unsubstituted or substituted by one or more radicals selected from the group consisting of: 
 hydroxyl, phenyl, (C 5 -C 11 )-heteroaryl, (C 1 -C 6 )-alkoxy and NR11R12, or  
 
 phenyl that may be unsubstituted or substituted by one or more radicals from the group consisting of hydroxy, (C 1 -C 6 )-alkoxy, F and CF 3 ,  
 
 with the proviso that R7 is not NR11R12 or (C 1 -C 6 )-alkoxy if R6=F;  
 R6 and R7 are together with the carbon atom that carries them (C 3 -C 8 )-cycloalkyl;  
 R8 is H or (C 1 -C 6 )-alkyl;  
 R9 is:  
 H, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, aryl-(C 1 -C 4 )-alkyl, CO—(C 1 -C 6 )-alkyl, CO—(C 6 -C 10 )-aryl, CO—(C 1 -C 6 )-alkyl-(C 6 -C 10 )-aryl, CO—(C 5 -C 11 )-heteroaryl, C(O)—O—(C 1 -C 6 )-alkyl, C(O)—O—(C 1 -C 6 )-alkyl-(C 6 -C 10 )-aryl, C(O)—O—(C 6 -C 10 )-aryl, C(O)—O—(C 5 -C 11 )-heteroaryl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )-alkyl-(C 6 -C 10 )-aryl, SO 2 —(C 1 -C 6 )-alkyl-SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(C 6 -C 10 )-aryl, SO 2 —(C 5 -C 11 )-heteroaryl, wherein aryl or heteroaryl, or both may be unsubstituted or substituted by (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, F, Cl, CO—(C 1 -C 6 )-alkyl;  
 R10 is H, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl-phenyl;  
 R11 is H, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl-phenyl;  
 R12 is H, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl-phenyl;  
 R13 is H or (C 1 -C 6 )-alkyl; and  
 R14 is H or (C 1 -C 6 )-alkyl; or  
 a physiologically acceptable salt of the compound;  
 a solvate of the compound; or  
 a physiologically active derivative of the compound.  
 
     
     
         2 . The method of  claim 1  for treating or preventing a disorder involving insulin resistance in a patient, comprising the administration of a therapeutically effective amount of the compound of formula I of  claim 1  to the patient.  
     
     
         3 . The method of  claim 1  for treating or preventing diabetes mellitus and its sequelae in a patient, comprising the administration of a therapeutically effective amount of the compound of formula I of  claim 1  to the patient.  
     
     
         4 . The method of  claim 1  for treating or preventing dysipidemias and their sequelae in a patient, comprising the administration of a therapeutically effective amount of the compound of formula I of  claim 1  to the patient.  
     
     
         5 . The method of  claim 1  for treating or preventing a physiological state associated with a metabolic syndrome in a patient, comprising the administration of a therapeutically effective amount of the compound formula I of  claim 1  to the patient.  
     
     
         6 . The method of  claim 1 , further comprising the administration of a therapeutically effective amount of a second active compound for treating or preventing disorders of the fatty acid metabolism and glucose utilization disorders to the patient.  
     
     
         7 . The method of  claim 2 , further comprising administering to the patient a therapeutically effective amount of a second compound for treating or preventing a disorder in which insulin resistance is involved.  
     
     
         8 . A method for treating or preventing a disorder of fatty acid metabolism or glucose utilization in a patient, comprising the administration of a therapeutically effective amount of a compound comprised of formula I to the patient:  
       
         
           
           
               
               
           
         
       
       in which: 
 ring A is a (C 3 -C 8 )-cycloalkanediyl or a (C 3 -C 8 )-cycloalkenediyl, wherein one or more carbon atoms of the (C 3 -C 8 )-cycloalkanediyl or the (C 3 -C 8 )-cycloalkenediyl may be replaced by oxygen atoms;  
 R1 and R2 are:  
 (a) independently of one another H, F, Cl, Br, CF 3 , OCF 3 , (C 1 -C 6 )-alkyl, O-(C 1 -C 6 )-alkyl, SCF 3 , SF 5 , OCF 2 —CHF 2 , (C 6 -C 10 )-aryl, (C 6 -C 10 )-aryloxy, OH, or NO 2 ; or  
 (b) together with the phenyl, pyridine, 1H-pyrrole, thiophene or furan ring form fused, partially or unsaturated bicyclic (C 6 -C 10 )aryl, or (C 5 -C 11 )-heteroaryl;  
 R3 is:  
 H, (C 1 -C 6 )-alkyl, (C 3 -C 8 )-cycloalkyl, (C 1 -C 3 )-alkyl-(C 3 -C 8 )-cycloalkyl, phenyl, (C 1 -C 3 )-alkyl-phenyl, (C 5 -C 6 )-heteroaryl, (C 1 -C 3 )-alkyl-(C 5 -C 6 )-heteroaryl, or (C 1 -C 3 )-alkyl fully or partially substituted by F;  
 W is:  
 (a) is CH or N if o=1, or  
 (b) is O, S or NR10 if o=0;  
 X is (C 1 -C 6 )-alkanediyl, wherein the C 1  or C 2  carbon atom to Ring A may be replaced by an oxygen atom;  
 Y1 is (CR13R14) p , wherein p is 1 or 2;  
 Y2 is CH2, O, S, SO, SO2 or NR9;  
 n is 0-2;  
 R4 is H, (C1-C6)-alkyl, NR9, or F if Y2 is not O;  
 R5 is H, (C 1 -C 6 )-alkyl, NR9, or F if Y2 is not O;  
 R6 is H, (C 1 -C 6 )-alkyl; or F if n is not 0;  
 R7 is: 
 H, F (if n is not 0), (C 1 -C 6 )-alkoxy, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 8 )-cycloalkyl, (C 1 -C 6 )-alkyl that may be unsubstituted or substituted by one or more radicals selected from the group consisting of: 
 hydroxyl, phenyl, (C 5 -C 11 )-heteroaryl, (C 1 -C 6 )-alkoxy and NR11R12, or  
 
 phenyl that may be unsubstituted or substituted by one or more radicals from the group consisting of hydroxy, (C 1 -C 6 )-alkoxy, F and CF 3 ,  
 
 with the proviso that R7 is not NR11R12 or (C 1 -C 6 )-alkoxy if R6=F;  
 R6 and R7 are together with the carbon atom that carries them (C 3 -C 8 )-cycloalkyl;  
 R8 is H or (C 1 -C 6 )-alkyl;  
 R9 is:  
 H, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, aryl-(C 1 -C 4 )-alkyl, CO—(C 1 -C 6 )-alkyl, CO—(C 6 -C 10 )-aryl, CO—(C 1 -C 6 )-alkyl-(C 6 -C 10 )-aryl, CO—(C 5 -C 11 )-heteroaryl, C(O)—O—(C 1 -C 6 )-alkyl, C(O)—O—(C 1 -C 6 )-alkyl-(C 6 -C 10 )-aryl, C(O)—O—(C 6 -C 10 )-aryl, C(O)—O—(C 5 -C 11 )-heteroaryl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )-alkyl-(C 6 -C 10 )-aryl, SO 2 —(C 1 -C 6 )-alkyl-SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(C 6 -C 10 )-aryl, SO 2 —(C 5 -C 11 )-heteroaryl, wherein aryl or heteroaryl, or both may be unsubstituted or substituted by (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, F, Cl, CO—(C 1 -C 6 )-alkyl;  
 R10 is H, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl-phenyl;  
 R11 is H, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl-phenyl;  
 R12 is H, (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl-phenyl;  
 R13 is H or (C 1 -C 6 )-alkyl; and  
 R14 is H or (C 1 -C 6 )-alkyl; or  
 a physiologically acceptable salt of the compound;  
 a solvate of the compound; or  
 a physiologically active derivative of the compound.  
 
     
     
         9 . The method of  claim 8  for treating or preventing a disorder of fatty acid metabolism or glucose utilization in a patient, comprising the administration of a therapeutically effective amount of the compound of formula I of  claim 8  to the patient.  
     
     
         10 . The method of  claim 8  for treating or preventing a disorder involving insulin resistance in a patient, comprising the administration of a therapeutically effective amount of the compound of formula I of  claim 8  to the patient.  
     
     
         11 . The method of  claim 8  for treating or preventing diabetes mellitus and its sequelae in a patient, comprising the administration of a therapeutically effective amount of the compound of formula I of  claim 8  to the patient.  
     
     
         12 . The method of  claim 8  for treating or preventing dyslpidemias and their sequelae in a patient, comprising the administration of a therapeutically effective amount of the compound of  claim 2  to the patient.  
     
     
         13 . A method for treating or preventing a physiological state associated with a metabolic syndrome in a patient, comprising administering a therapeutically effective amount of the compound of  claim 2  to the patient.  
     
     
         14 . The method of  claim 8 , further comprising administering the patient a therapeutically effective amount of a second active compound for treating and/or preventing disorders of the fatty acid metabolism and glucose utilization disorders.  
     
     
         15 . The method of  claim 8 , further comprising administering to the patient a therapeutically effective amount of a second compound for treating and/or preventing a disorder in which insulin resistance is involved.