Antagonists of the vanilloid receptor subtype 1 (VR1) and use thereof

1. A method of treating a disorder selected from the group consisting of neuropathic pain, allodynia, inflammatory pain, inflammatory hyperalgesia, bladder overactivity, urinary incontinence, and thermal hyperalgesia, 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), or a pharmaceutically acceptable salt thereof, wherein formula (I) is

wherein,

A is O or —N(R 3 );

D is —N(R 4 ), O or S;

R 3 and R 1 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)C(O)N(R 5 , —N(R)S(O) 2 N(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)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—C(R x ), —C(R x ), —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 x )(R y )—;

provided 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 y )—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)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 b ), -alkylenyl-OR a , -alkylenyl-OC(O)R a , -alkylenyl-SR a , -alkylenyl-5(O) 2 R a , -alkylenyl-S(O) 2 N(R b ), -alkylenyl-S(O) 2 OR a , -alkylenyl-N(R 1 )(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)R 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 9 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, 1, 2, or 3.

2. The method of claim 1 , wherein the disorder is selected from the group of neuropathic pain, allodynia, inflammatory pain, inflammatory hyperalgesia, bladder overactivity, and urinary incontinence.

3. 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.

4. 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.

5. A method of treating inflammatory 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.

6. 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.