Antagonists of the vanilloid receptor subtype 1 (vr1) and use thereof

Abstract

The present invention is directed to compounds of formula (I) wherein variables W, X, Y, D, A, n, R 1 , R 2 and R 9 are as defined in the description.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, amide, ester, prodrug, or salt of a prodrug thereof, wherein
 A is O or —N(R 3 ); 
 D is —N(R 4 ), O or S; 
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, alkyl, —C(O)alkyl, and —S(O) 2 (alkyl); 
 R 1  and R 2  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, cyano, nitro, halogen, —OR 5 , —OC(O)R 5 , —SR 5 , —S(O) 2 R 5 , —S(O) 2 OR 5 , —S(O) 2 N(R 5 )(R 6 ), —N(R 5 )(R 6 ), —N(R 6 )C(O)R 5 , —N(R 6 )C(O)N(R 5 )(R 6 ), —N(R 6 )S(O) 2 N(R 5 )(R 6 ), —C(O)R 5 , —C(O)OR 5 , —C(O)N(R 5 )(R 6 ), haloalkyl, -alkylenyl-OR 5 , -alkylenyl-OC(O)R 5 , -alkylenyl-SR 5 , -alkylenyl-S(O) 2 R 5 , -alkylenyl-S(O) 2 OR 5 , -alkylenyl-S(O) 2 N(R 5 )(R 6 ), -alkylenyl-N(R 5 )(R 6 ), -alkylenyl-N(R 6 )C(O)R 5 , -alkylenyl-N(R 6 )C(O)N(R 5 )(R 6 ), -alkylenyl-N(R 6 )S(O) 2 N(R 5 )(R 6 ), -alkylenyl-C(O)R 5 , -alkylenyl-C(O)OR 5 , -alkylenyl-C(O)N(R 5 )(R 6 ), —R 7 , and -alkylenyl-R 7 ; provided that when one of R 1  and 
 R 2  is hydrogen, the other is not hydrogen; 
 R 5  at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl and benzyl; 
 R 6  at each occurrence is independently selected from the group consisting of hydrogen and alkyl; 
 R 7  at each occurrence is independently selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl; wherein each R 7  is independently substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy, —S(alkyl), —S(O) 2 (alkyl), —N(H) 2 , —N(H)(alkyl), —N(alkyl) 2 , —N(H)C(O)alkyl, —C(O)OH, —C(O)Oalkyl, —C(O)NH 2 , —C(O)N(H)alkyl, —C(O)N(alkyl) 2 , —R 8 , cyanoalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylenyl-S(alkyl), -alkylenyl-S(O) 2 (alkyl), -alkylenyl-N(H) 2 , -alkylenyl-N(H)(alkyl), -alkylenyl-N(alkyl) 2 , -alkylenyl-N(H)C(O)alkyl, -alkylenyl-C(O)OH, -alkylenyl-C(O)Oalkyl, -alkylenyl-C(O)NH 2 , -alkylenyl-C(O)N(H)alkyl, -alkylenyl-C(O)N(alkyl) 2 , and -alkylenyl-R 8 ; 
 R 8  at each occurrence is independently selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl; wherein each R 8  is independently substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy, —S(alkyl), —S(O) 2 (alkyl), —N(H) 2 , —N(H)(alkyl), —N(alkyl) 2 , —N(H)C(O)alkyl, —C(O)OH, —C(O)Oalkyl, —C(O)NH 2 , —C(O)N(H)alkyl, —C(O)N(alkyl) 2 , cyanoalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylenyl-S(alkyl), -alkylenyl-S(O) 2 (alkyl), -alkylenyl-N(H) 2 , -alkylenyl-N(H)(alkyl), -alkylenyl-N(alkyl) 2 , -alkylenyl-N(H)C(O)alkyl, -alkylenyl-C(O)OH, -alkylenyl-C(O)Oalkyl, -alkylenyl-C(O)NH 2 , -alkylenyl-C(O)N(H)alkyl, and -alkylenyl-C(O)N(alkyl) 2 ; 
 W and Y are each independently selected from the group consisting of —C(R x )(R y )— and —N(R z )—; provided that when one of W and Y is —N(R z )—, then the other is —C(R x )(R y )—; 
 X is selected from the group consisting of —C(O)—, —C(R x )(R y )—, —N(R z ), —C(R x )(R y )—C(R x )(R y )—, —C(O)—C(R x )(R y )—, —C(R x )(R y )—C(O)—, —C(R x )(R y )—N(R z )— and —N(R z )—C(R x )(R y )—; provide that when one of W and Y is —N(R z )—, then X is selected from the group consisting of —C(R x )(R y )— and —C(R x )(R 37 )—C(R x )(R y )—; 
 R x  and R y  at each occurrence are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, —OR a , —OC(O)R a , —SR a , —S(O) 2 R a , —S(O) 2 N(R a )(R b ), —S(O) 2 OR a , —N(R a )(R b ), —N(R b )C(O)R a , —N(R b )C(O)N(R a )(R b ), —N(R b )S(O) 2 N(R a )(R b ), —C(O)OR a , —C(O)R a , —C(O)N(R a )(R b ), -alkylenyl-OR a , -alkylenyl-OC(O)R a , -alkylenyl-SR a , -alkylenyl-S(O) 2 R a , -alkylenyl-S(O) 2 N(R a )(R b ), -alkylenyl-S(O) 2 OR a , -alkylenyl-N(R a )(R b ), -alkylenyl-N(R b )C(O)R a , -alkylenyl-N(R b )C(O)N(R a )(R b ), -alkylenyl-N(R b )S(O) 2 N(R a )(R b ), -alkylenyl-C(O)OR a , -alkylenyl-C(O)R a , -alkylenyl-C(O)N(R a )(R b ), —R 8  and -alkylenyl-R 8 ; 
 R a  at each occurrence is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, —R 8  and -alkylenyl-R 8 ; 
 R b  at each occurrence is independently selected from the group consisting of hydrogen, alkyl and haloalkyl; 
 alternatively, R a  and R b  together with the nitrogen atom to which they are attached form a heterocycle ring substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, alkyl and haloalkyl; 
 R z  at each occurrence is independently selected from the group consisting of hydrogen, alkyl, —C(O)alkyl, and —S(O) 2 (alkyl); 
 R 9  at each occurrence is independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl and haloalkoxyalkyl; and 
 n is 0, 1, 2, or 3. 
 
     
     
         2 . The compound of formula (I) according to  claim 1 , wherein D is —N(R 4 ). 
     
     
         3 . The compound according to  claim 2 , wherein A is O. 
     
     
         4 . The compound according to  claim 2 , wherein A is —N(R 3 ). 
     
     
         5 . The compound of formula (I) according to  claim 1 , wherein D is S. 
     
     
         6 . The compound according to  claim 5 , wherein A is O. 
     
     
         7 . The compound according to  claim 5 , wherein A is —N(R 3 ). 
     
     
         8 . The compound of formula (I) according to  claim 1 , wherein D is O. 
     
     
         9 . The compound of formula (I) according to  claim 8 , wherein A is O. 
     
     
         10 . The compound according to  claim 8 , wherein A is —N(R 3 ). 
     
     
         11 . The compound according to  claim 10 , wherein R 3  is hydrogen. 
     
     
         12 . The compound according to  claim 11 , wherein R 2  is —R 7  and R 1  is hydrogen. 
     
     
         13 . The compound according to  claim 12 , wherein —R 7  is aryl. 
     
     
         14 . The compound according to  claim 13 , wherein —R 7  is phenyl. 
     
     
         15 . The compound according to  claim 14 , wherein
 W is —C(R x )(R y );   Y is —C(R x )(R y ); and   X is —C(O)—C(R x )(R y )—.   
     
     
         16 . The compound according to  claim 15 , wherein R x  and R y  are hydrogen. 
     
     
         17 . The compound according to  claim 16 , wherein the compound is selected from the group consisting of:
 8-({5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-3,4-dihydronaphthalen-2(1H)-one;   8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one;   8-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one;   8-{[5-(4-bromophenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one;   8-{[5-(4-methoxyphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one;   8-[(5-phenyl-1,3-oxazol-2-yl)-amino]-3,4-dihydronaphthalen-2(1H)-one;   8-{[5-(2-methylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one; and   8-{[5-(3-methylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one.   
     
     
         18 . The compound according to  claim 14 , wherein
 W is —C(R x )(R y );   Y is —C(R x )(R y ); and   X is —C(R x )(R y )—C(R x )(R y )—.   
     
     
         19 . The compound according to  claim 18  wherein R x  is —N(R a )(R b ), and R a  and R b  are hydrogen. 
     
     
         20 . The compound according to  claim 19 , wherein the compound is selected from the group consisting of:
 N 1 -(5-p-methylphenyloxazol-2-O-5,6,7,8-tetrahydronaphthalene-1,7-diamine;   N 1 -[5-(4-Trifluoromethylphenyl)oxazol-2-yl]-5,6,7,8-tetrahydronaphthalene-1,7-diamine; and   N 1 -[5-(2-Fluoro-4-trifluoromethylphenyl)oxazol-2-yl]-5,6,7,8-tetrahydro-naphthalene-1,7-diamine.   
     
     
         21 . The compound according to  claim 18 , wherein R x  is selected from the group consisting of hydrogen and —O(R a ), wherein R y  is hydrogen, and wherein R a  is hydrogen. 
     
     
         22 . The compound according to  claim 21 , wherein the compound is selected from the group consisting of:
 8-({5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;   8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;   (2S)-8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;   (2R)-8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;   8-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;   8-{[5-(4-pyrrolidin-1-ylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;   8-{[5-(4-bromophenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;   8-{[5-(4-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;   8-{[5-(4-methoxyphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;   8-[(5-phenyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol;   8-{[5-(2-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol; and   8-{[5-(3-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol.   
     
     
         23 . The compound according to  claim 18 , wherein R x  is —N(R a )(R b ), R a  is —S(O) 2 (alkyl), and R b  is hydrogen. 
     
     
         24 . The compound of  claim 23  that is
 N-[8-(5-p-methylphenyloxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]methanesulfonamide. 
 
     
     
         25 . The compound according to  claim 12 , wherein —R 7  is cycloalkyl. 
     
     
         26 . The compound according to  claim 25 , wherein
 W is —C(R x )(R y );   Y is —C(R x )(R y ); and   X is —C(O)—C(R x )(R y )—.   
     
     
         27 . The compound according to  claim 26 , wherein R x  and R y  are hydrogen. 
     
     
         28 . The compound according to  claim 27 , that is 8-{[5-(1-adamantyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one. 
     
     
         29 . The compound according to  claim 25 , wherein
 W is —C(R x )(R y );   Y is —C(R x )(R y ); and   X is —C(R x )(R y )—C(R x )(R y )—.   
     
     
         30 . The compound according to  claim 29 , wherein R x  is selected from the group consisting of hydrogen and —O(R a ), wherein R a  is hydrogen, and wherein R y  is hydrogen. 
     
     
         31 . The compound according to  claim 30 , that is
 8-{[5-(1-adamantyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol.   
     
     
         32 . The compound according to  claim 11 , wherein R 2  is alkyl and R 1  is hydrogen. 
     
     
         33 . The compound according to  claim 32 , wherein
 W is —C(R x )(R y );   Y is —C(R x )(R y ); and   X is —C(O)—C(R x )(R y )—;   and wherein R x  and R y  are hydrogen.   
     
     
         34 . The compound according to  claim 33 , wherein the compound is selected form the group consisting of:
 8-[(5-methyl-1,3-oxazol-2-yl)-amino]-3,4-dihydronaphthalen-2 (1H)-one; and   8-[(5-tert-butyl-1,3-oxazol-2-yl)-amino]-3,4-dihydronaphthalen-2(1H)-one.   
     
     
         35 . The compound according to  claim 32 , wherein
 W is —C(R x )(R y );   Y is —C(R x )(R y ); and   X is —C(R x )(R y )—C(R x )(R y )—;   wherein R x  is selected from the group consisting of hydrogen and —O(R a ),   wherein R a  is hydrogen and wherein R y  is hydrogen.   
     
     
         36 . The compound according to  claim 35 , that is 8-[(5-methyl-1,3-oxazol-2-yl)-amino]-1,2,3,4-tetrahydronaphthalen-2-ol; and
 8-[(5-tert-butyl-1,3-oxazol-2-yl)-amino]-1,2,3,4-tetrahydronaphthalen-2-ol.   
     
     
         37 . The compound according to  claim 11 , wherein R 2  is -alkyl-R 7  and R 1  is hydrogen. 
     
     
         38 . The compound according to  claim 37 , wherein R 7  is phenyl. 
     
     
         39 . The compound according to  claim 38 , wherein
 W is —C(R x )(R y );   Y is —C(R x )(R y );   X is —C(O)—C(R x )(R y )—; and wherein R x  and R y  are hydrogen.   
     
     
         40 . The compound of  claim 39  that is 8-[(5-benzyl-1,3-oxazol-2-yl)amino]-3,4-dihydronaphthalen-2(1H)-one. 
     
     
         41 . The compound according to  claim 38 , wherein
 W is —C(R x )(R y );   Y is —C(R x )(R y );   X is —C(R x )(R y )—C(R x )(R y )—;   wherein R x  is selected from the group consisting of hydrogen and —O(R a ),   wherein R a  is hydrogen and wherein R y  is hydrogen.   
     
     
         42 . The compound according to  claim 41 , wherein the compound is 8-[(5-benzyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol. 
     
     
         43 . The compound according to  claim 10 , wherein
 R 3  is alkyl;   W is —C(R x )(R y );   Y is —C(R x )(R y );   X is —C(R x )(R y )—C(R x )(R y )—;   R x  is selected from the group consisting of hydrogen and —O(R a ), wherein R a  is hydrogen and wherein R y  is hydrogen.   
     
     
         44 . The compound according to  claim 43 , wherein the compound is
 8-(methyl {5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol.   
     
     
         45 . The compound according to  claim 10 , wherein
 R 3  is alkyl;   W is —C(R x )(R y );   Y is —C(R x )(R y ); and   X is —C(O)—C(R x )(R y )—.   
     
     
         46 . The compound according to  claim 10 , wherein
 R 3  is —C(O)alkyl;   W is —C(R x )(R y );   Y is —C(R x )(R y );   X is —C(R x )(R y )—C(R x )(R y )—;
 R x  is selected from the group consisting of hydrogen and —O(R a ), wherein R a  is hydrogen and wherein R y  is hydrogen. 
   
     
     
         47 . The compound according to  claim 46 , wherein the compound is
 N-[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.   
     
     
         48 . The compound according to  claim 10 , wherein
 R 3  is —C(O)alkyl;   W is —C(R x )(R y );   Y is —C(R x )(R y ); and   X is —C(O)—C(R x )(R y )—.   
     
     
         49 . The compound according to  claim 7 , wherein
 R 1  is hydrogen;   R 2  is —R 7 ,   R 3  is hydrogen;   R 7  is phenyl;   W is —C(R x )(R y );   Y is —C(R x )(R y );   X is —C(R x )(R y )—C(R x )(R y )—;   R x  is —O(R a ), and R y  is hydrogen.   
     
     
         50 . The compound according to  claim 49 , wherein the compound is:
 8-(5-Phenylthiazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol.   
     
     
         51 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. 
     
     
         52 . A method of treating a disorder wherein the disorder is ameliorated by inhibiting vanilloid receptor subtype 1 (VR1) in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         53 . The method of  claim 52 , wherein the disorder is selected from the group of pain, neuropathic pain, allodynia, pain associated with inflammation, inflammatory hyperalgesia, bladder overactivity, and urinary incontinence. 
     
     
         54 . A method of treating bladder overactivity in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         55 . A method of treating urinary incontinence in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         56 . A method of treating pain in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         57 . A method of treating thermal hyperalgesia in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof.