Lipase inhibitors

Abstract

The invention provides a compound of formula (I) as defined herein that is useful in the treatment and prevention of a disorder such as cachexia, stroke, atherosclerosis, coronary artery disease, or diabetes and disorders and conditions associated therewith. The invention also provides a method of screening for lipase inhibitors using a compound of formula (I) and determining its lipase inhibitory activity. activity.

What is claimed is: 
     
         1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 L 1  is a bond, C 1-10  alkylene, C 2-10  alkenylene, or C 2-10  alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from —C 1-4  alkyl, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl), and further wherein one or more —CH 2 — units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C 1-4  alkyl)-, —CO—, —CO—NH—, —NH—CO—, —S—, —SO—, or —SO 2 —, 
 R 1  is independently selected from C 1-4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl), a 5 to 7-membered, saturated or unsaturated carbon ring structure wherein optionally one to three of the carbon atoms are replaced by N, O, or S, said ring structure being optionally substituted with C 1-4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl), or a aryl or heteroaryl optionally substituted with C 1-4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-41  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl), 
 R 2  is optionally substituted aryl or optionally substituted heteroaryl but not pyrazolyl, wherein said aryl or said heteroaryl may be substituted with one or more groups independently selected from C 1-4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl), or R 2  is pyrazolyl optionally substituted with one or more groups independently selected from C 1-4  alkyl, halogen, —CF 3 , —CN, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl); 
 R 3  is C 1-10  alkylene, C 2-10  alkenylene, or C 2-10  alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from halogen, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl), and further wherein one or more —CH 2 — units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C 1-4  alkyl)-, —CO—, —CO—NH—, —NH—CO—, —S—, —SO—, or —SO 2 —; 
 m is an integer of 0 to 8; and 
 each R 4  is independently selected from C 1-4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl); 
 R 5  is aryl or heteroaryl; 
 
       or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
     
     
         2 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 L 1  is a bond, C 1-10  alkylene, C 2-10  alkenylene, or C 2-10  alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from —C 1-4  alkyl, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl), and further wherein one or more —CH 2 — units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C 1-4  alkyl)-, —CO—, —CO—NH—, —NH—CO—, —S—, —SO—, or —SO 2 —; 
 R 1  is independently selected from C 1-4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl), a 5 to 7-membered, saturated or unsaturated carbon ring structure wherein optionally one to three of the carbon atoms are replaced by N, O, or S, said ring structure being optionally substituted with C 1-4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl), or a aryl or heteroaryl optionally substituted with C 1-4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl); 
 R 2  is optionally substituted aryl or optionally substituted heteroaryl but not pyrazolyl, wherein said aryl or said heteroaryl may be substituted with one or more groups independently selected from C 1-4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl); or R 2  is pyrazolyl optionally substituted with one or more groups independently selected from C 1-4  alkyl, halogen, —CF 3 , —CN, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl) 
 R 3  is C 1-10  alkylene, C 2-10  alkenylene, or C 2-10  alkynylene, wherein said alkylene, said alkenylene or said alkynylene is optionally substituted with one or more groups independently selected from halogen, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl), and further wherein one or more —CH 2 — units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C 1-4  alkyl)-, —CO—, —CO—NH—, —NH—CO—, —S—, —SO—, or —SO 2 —; 
 m is an integer of 0 to 8; 
 each R 4  is independently selected from C 1-4  alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4  alkyl), —NH 2 , —NH(C 1-4  alkyl), or —N(C 1-4  alkyl)(C 1-4  alkyl); 
 R 5  is aryl or heteroaryl optionally substituted as shown in formula (I), selected from phenyl, benzyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazinyl, tetrazolyl, thiophenyl (thienyl), thiazolyl, furanyl (furyl), furazanyl, oxazolyl, isoxazolyl, benzthienyl, benzfuryl, benzimidazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, indolyl indazolyl, chinolinyl, naphthyl, anthracenyl; 
 
       or a pharmaceutically acceptable salt, solvate or prodrug thereof. 
     
     
         3 . A compound of  claim 1  wherein R 5  is thiophenyl, piperidinyl, indolyl or methylindolyl. 
     
     
         4 . A compound of  claim 1  wherein R 2  is selected from phenyl, benzyl, pyridyl, furanyl, thiophenyl, pyrrolyl. 
     
     
         5 . A compound of  claim 1  wherein R 2  is selected from pyrrazolyl, pyridinyl, thienyl, and furanyl. 
     
     
         6 . A compound of  claim 1  wherein R 2  is selected from among 
       
         
           
           
               
               
           
         
       
       wherein R signifies the point of attachment to the structure of formula (I) 
     
     
         7 . A compound of  claim 1  wherein R 2  is phenyl. 
     
     
         8 . A compound of  claim 7  having an IC 50  for lipase activity of less than 40 uM. 
     
     
         9 . A compound of  claim 8  wherein the lipase is ATGL. 
     
     
         10 . A compound of  claim 1 , for use in the treatment or prevention of a disorder. 
     
     
         11 . A compound of  claim 10 , for use in the treatment or prevention of diabetes type II, stroke, atherosclerosis, coronary artery disease, high triglyceride levels, cachexia, or its associated or related disorders or conditions, including weight loss, muscle atrophy or wasting, fat loss, reduced WAT. 
     
     
         12 . A method of inhibiting the activity of a lipase in vitro, by contacting said lipase with a compound of formula (I) as per  claim 1 . 
     
     
         13 . A method of  claim 12  wherein the lipase is ATGL. 
     
     
         14 . A pharmaceutical composition comprising the compound of formula (I) as per  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         15 . A method for treating or preventing diabetes type II, coronary artery disease, atherosclerosis, stroke, cachexia, or its associated or related disorders or conditions, including weight loss, muscle atrophy or wasting, fat loss, and/or reduced WAT, the method comprising the administration of the compound of formula (I) as per  claim 1 , optionally in a pharmaceutical composition that includes a pharmaceutically acceptable excipient, to a subject in need of such a treatment or prevention. 
     
     
         16 . A method for identifying a compound that inhibits the activity of a lipase, comprising:
 (a) contacting a compound with a cell expressing lipase polypeptide; and   (b) measuring the activity of said lipase in the presence or absence of said compound,   
       wherein a compound that blocks or reduces the activity of said lipase is identified as a compound that inhibits the activity of the lipase, and 
       wherein said compound of step (a) is a compound of formula (I) as per  claim 1 . 
     
     
         17 . The method of  claim 16  wherein said lipase is ATGL. 
     
     
         18 . A method for identifying a compound useful in the prevention, amelioration, inhibition or treatment of cachexia, atherosclerosis, stroke, coronary artery disease, type II diabetes, and/or disorders and/or conditions associated or related thereto, comprising:
 a. contacting a compound with a cell expressing ATGL polypeptide; and   b. measuring the expression and/or activity of ATGL in the presence or absence of said compound,   
       wherein a compound that blocks or reduces the activity of ATGL is identified as a compound useful in the prevention, amelioration, inhibition or treatment of said disorders, diseases or the disorders or conditions associated thereto, and wherein the compound of step (a) is a compound of formula (I) as per  claim 1 . 
     
     
         19 . The method of  claim 18  wherein the compound is one that is able to reduce blood FFA levels. 
     
     
         20 . The method of  claim 18  wherein the compound is one that does not lead to reduced blood glucose levels. 
     
     
         21 . The method of  claim 18  wherein the compound is substantially non-toxic. 
     
     
         22 . A method for identifying a compound that prevents, ameliorates and/or inhibits cachexia, stroke, type II diabetes, atherosclerosis, or coronary artery disease, and/or the disorders or conditions associated or related thereto, comprising:
 a) contacting a compound with an ATGL polypeptide or fragments thereof; and   b) measuring a compound-polypeptide property.