NK1 antagonists
View Patent ↗A compound having the general structure shown in Formula I: or pharmaceutically acceptable salts and/or solvates thereof are useful in treating diseases or conditions mediated by NK 1 receptors, for example various physiological disorders, symptoms or diseases, including emesis, depression, anxiety and cough.
1. A compound of formula I:
or pharmaceutically acceptable salts thereof, wherein;
R 1 and R 2 are selected from the group consisting of alkyl, haloalkyl, alkyl substituted with one or more hydroxyl groups, —CN, alkynyl, —N(R 6 ) 2 , —N(R 6 )—S(O 2 )-alkyl, N(R 6 )C(O)—N(R 9 ) 2 , -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, —C(O)-alkyl, —C(═N—OR 5 )-alkyl, [—(C(O)—N(R 9 ) 2 ], —C(O)—O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)—O-alkyl, -alkylene-C(O)—N(R 9 ) 2 ,
with the proviso that at least one of R 1 and R 2 is —CN,
W is ═C(R 8 )— or ═N—;
X is —C(O)— or —S(O 2 )—;
Y is selected from the group consisting of —CH 2 —, —O—, and —N(R 6 )—C(O)—, with the proviso that:
(a) The nitrogen atom of —N(R 6 )—C(O)— is bonded to X, and
(b) If R 1 and/or R 2 is
and Y is —O—, X is not —S(O 2 )—;
Z is —C(R 7 ) 2 , —N(R 6 )—, or —O—;
R 3 is selected from the group consisting of H, and unsubstituted alkyl;
R 4 is H;
R 5 is H or alkyl;
R 8 is selected from the group consisting of H, alkyl, cycloalkyl, and aryl;
each R 7 is independently H or alkyl; or
each R 7 , together with the ring carbon to which they are shown attached, form a cycloalkylene ring;
R 8 is selected from the group consisting of H, alkyl, alkyl substituted with one or more hydroxyl groups, —N(R 6 ) 2 , —N(R 6 )—S(O 2 )-alkyl, —N(R 6 )—S(O 2 )-aryl, —N(R 6 )—C(O)-alkyl, —N(R 6 )—C(O)-aryl, alkylene-O-alkyl, and —CN;
R 9 is selected from the group consisting of H, alkyl, and aryl, or each R 9 , together with the nitrogen to which they are shown attached, form a heterocycloalkyl ring;
Ar 1 is unsubstituted phenyl;
Ar 2 is phenyl substituted with 0-3 substituents selected from the group consisting of haloalkyl;
n is 0, 1, or 2; and
m is 1, 2 or 3.
2. The compound according to claim 1 , wherein the compound of formula I has the following structure:
and pharmaceutically acceptable salts thereof.
3. The compound according to claim 1 , wherein:
R 3 is unsubstituted alkyl;
Ar 2 is substituted phenyl; and
n is 1,
and pharmaceutically acceptable salts thereof.
4. The compound according to claim 2 , wherein:
R 3 is unsubstituted alkyl;
Ar 2 is substituted phenyl; and
n is 1,
and pharmaceutically acceptable salts thereof.
5. The compound according to claim 4 , wherein:
Ar 2 is 3,5-bis(trifluoromethyl)phenyl,
and pharmaceutically acceptable salts thereof.
6. The compound according to claim 5 , wherein:
R 3 is —CH 3 ,
and pharmaceutically acceptable salts thereof.
7. The compound according to claim 6 , wherein:
one of R 1 or R 2 is
and pharmaceutically acceptable salts thereof.
8. The compound according to claim 6 , wherein:
one of R 1 or R 2 is
wherein W is ═C(R 8 )—
and pharmaceutically acceptable salts thereof.
9. The compound according to claim 6 , wherein:
one of R 1 and R 2 is
and pharmaceutically acceptable salts thereof.
10. The compound according to claim 6 , wherein:
one of R 1 or R 2 is —CN,
and pharmaceutically acceptable salts thereof.
11. The compound according to claim 7 , wherein:
X is —S(O 2 )—;
Y is —CH 2 —; and
m is 2,
and pharmaceutically acceptable salts thereof.
12. The compound according to claim 7 , wherein:
X is C(O)—;
Y is —CH 2 —; and
m is 2,
and pharmaceutically acceptable salts thereof.
13. The compound according to claim 7 , wherein:
X is —C(O)—;
Y is —CH 2 —; and
m is 3,
and pharmaceutically acceptable salts thereof.
14. The compound according to claim 7 , wherein:
X is —C(O)—;
Y is —O—; and
m is 2,
and pharmaceutically acceptable salts thereof.
15. The compound according to claim 7 , wherein:
X is —C(O)—;
Y is —CH 2 —; and
m is 1,
and pharmaceutically acceptable salts thereof.
16. The compound according to claim 7 , wherein:
X is —C(O)—;
Y is —NH—C(O)—;
m is 1,
and pharmaceutically acceptable salts thereof.
17. The compound according to claim 8 , wherein:
Z is —NH—; and
R 8 is H,
and pharmaceutically acceptable salts thereof.
18. The compound according to claim 8 , wherein:
Z is —NH—; and
R 8 is —NH—S(O 2 )—CH 3 ,
and pharmaceutically acceptable salts thereof.
19. The compound according to claim 8 , wherein:
Z is —NH—;
R 8 is —CH 2 —OH,
and pharmaceutically acceptable salts thereof.
20. The compound according to claim 8 , wherein:
Z is —NH—;
R 8 is —CH 2 —O—CH 3 ,
and pharmaceutically acceptable salts thereof.
21. The compound according to claim 8 , wherein:
Z is —NH—;
R 8 is —NH 2 ,
and pharmaceutically acceptable salts thereof.
22. The compound according to claim 8 , wherein:
Z is
and
R 8 is H,
and pharmaceutically acceptable salts thereof.
23. The compound according to claim 8 , wherein:
Z is —C(CH 3 ) 2 —; and
R 8 is H,
and pharmaceutically acceptable salts thereof.
24. The compound according to claim 1 , having the Formula IB
wherein R 1 and R 3 are selected from the group consisting of:
Compound
R 1
R 2
1
—CN
2
—CN
5
—CH 2 CN
6
—CH 3
7
—CN
8
—C(O)—O—CH 3
9
—CN
12
—CH 2 OH
13
—CH 2 OCH 3
14
—CH 2 OCH 3
32
—CN
33
—CN
34
—CN
35
—CN
36
—NH—S(O 2 )—CH 3
—CN
37
—CN
—NH—S(O 2 )—CH 3
38
—CH 2 CN
39
—CN
—NH 2
40
—NH 2
—CN
41
—NH—C(O)—NH 2
—CN
42
—CN.
25. A compound represented by the following formula:
and pharmaceutically acceptable salts thereof.
26. A compound represented by the following formula:
and pharmaceutically acceptable salts thereof.
27. A compound represented by the following formula:
and pharmaceutically acceptable salts thereof.
28. A pharmaceutical composition comprising:
at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, at least one serotonin reuptake inhibitor, and at least one compound of claim 1 .
30. A purified compound according to claim 1 or a purified pharmaceutically acceptable salt thereof.