ANTAGONISTS OF THE VANILLOID RECEPTOR SUBTYPE 1 (VR1) AND USE THEREOF
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.