Amide derivatives as trpv1 antagonists

Abstract

The present invention relates to compounds of formula (I), or pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof, wherein R 1 , R 2 , and R 3 , are defined in the specification. Compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.

1 . A compound of formula (I) essentially free of its (3R) enantiomer, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein
 R 1  represents formula (i), (ii), (iii), or (iv) 
 
       
         
           
           
               
               
           
         
         R 2  represents formula (v), (vi), (vii), (viii), (ix), (x), (xi), or (xii) 
       
       
         
           
           
               
               
           
         
         R 3  is C 1-6  alkyl; 
         R 4  represents optional substituents of R 1 , and is, at each occurrence, independently alkyl, alkenyl, alkynyl, —CN, halogen, —OR a , —NO 2 , —N(R a )(R b ), —N(R b )C(O)R a , —N(R b )S(O) 2 R a , —N(R b )C(O)OR a , —N(R b )C(O)N(R a )(R b ), —N(R b )S(O) 2 N(R a )(R b ), —C(O)R a , —C(O)OR a , —C(O)N(R a )(R b ), —S(O) 2 R a , —S(O) 2 OR a , —S(O) 2 N(R a )(R b ), —(CR d R e ) q —CN, haloalkyl, —(CR d R e ) q —OR a , —(CR d R e ) q —NO 2 , —(CR d R e ) q —N(R a )(R b ), —(CR d R e ) q —N(R b )C(O)R a , —(CR d R e ) q —N(R b )S(O) 2 R a , —(CR d R e ) q —N(R b )C(O)OR a , —(CR d R e ) q —N(R b )C(O)N(R a )(R b ), —(CR d R e ) q —N(R b )S(O) 2 N(R a )(R b ), —(CR d R e ) q —C(O)R a , —(CR d R e ) q —C(O)OR a , —(CR d R e ) q —C(O)N(R a )(R b ), —(CR d R e ) q —S(O) 2 R a , —(CR d R e ) q —S(O) 2 OR a , or —(CR d R e ) q —S(O) 2 N(R a )(R b ); 
         R 5  and R 6  are optional substituents of R 2 , and each of which at each occurrence is independently alkyl, alkenyl, alkynyl, halogen, —CN, halogen, —OR a , —NO 2 , —N(R a )(R b ), or haloalkyl; 
         R a  and R b , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl; 
         R d  and R e , at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; 
         X 1  is O or S; 
         m is 0, 1, 2, 3, 4, or 5; 
         n is 0, 1, 2, 3, or 4; 
         p is 0, 1, or 2; 
         q is 1, 2, 3, or 4; and 
         s is 0 or 1. 
       
     
     
         2 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 2  represents formula (vi) 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2  or a pharmaceutically acceptable salt thereof, wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3  or a pharmaceutically acceptable salt thereof, wherein R 3  is methyl. 
     
     
         5 . The compound of  claim 2  or a pharmaceutically acceptable salt thereof, wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 5  or a pharmaceutically acceptable salt thereof, wherein R 3  is methyl. 
     
     
         7 . The compound of  claim 1  having formula (II) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 , and R 5  are as defined in  claim 1 . 
     
     
         8 . The compound of  claim 7  or a pharmaceutically acceptable salt thereof wherein R 3  is methyl. 
     
     
         9 . The compound of  claim 1  selected from the group consisting of
 (3S)-3′-chloro-3-methyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide; 
 (3S)-3′-chloro-3-methyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide; 
 (3S)-3,3′-dimethyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide; 
 (3S)-3-methyl-3′-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide; 
 (3S)-3,3′-dimethyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide; 
 (3S)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-N-(4-(trifluoromethylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamide; 
 (3S)—N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide; 
 (3S)—N-(4-tert-butylphenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide; 
 (3S)—N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide; and 
 (3S)-3-methyl-1-(3-methylpyridin-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         10 . A pharmaceutical composition comprising a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. 
     
     
         11 . The pharmaceutical composition according to  claim 10  further comprising acetaminophen or one or more nonsteroidal anti-inflammatory drug, or a combination thereof. 
     
     
         12 . A method of treating pain, wherein pain comprises chronic pain, neuropathic pain, inflammatory pain, post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns, back pain, visceral pain, cancer pain, dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, post stroke pain, pelvic hypersensitivity, pelvic pain, menstrual pain, comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 
     
     
         13 . The method according to  claim 12  further comprising the step of co-administering with acetaminophen or with one or more nonsteroidal anti-inflammatory drug, or combination thereof. 
     
     
         14 . The method according to  claim 13  wherein the nonsteroidal anti-inflammatory drug is ibuprofen. 
     
     
         15 . A method of treating incontinence, micturition disorder, renal colic, cystitis, stroke, acute cerebral ischemia, post stroke pain, cerebrovascular ischemia, multiple sclerosis, asthma, cough, chronic obstructive pulmonary disease (COPD), broncho-constriction, gastroesophageal reflux disease (GERD), dysphagia, ulcer, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis, Crohn's disease, cancer chemotherapy-induced emesis, or obesity, comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 
     
     
         16 . The method according to  claim 15  further comprising the step of co-administering with acetaminophen or with one or more nonsteroidal anti-inflammatory drug, or a combination thereof. 
     
     
         17 . The method according to  claim 16  wherein the nonsteroidal anti-inflammatory drug is ibuprofen. 
     
     
         18 . A method of treating inflammatory states, comprising burns, rheumatoid arthritis and osteoarthritis comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 
     
     
         19 . The method according to  claim 18  further comprising the step of co-administering with acetaminophen or with one or more nonsteroidal anti-inflammatory drug, or a combination thereof. 
     
     
         20 . The method according to  claim 19  wherein the nonsteroidal anti-inflammatory drug is ibuprofen.