Hydroisoindoline tachykinin receptor antagonists
View Patent ↗The present invention is directed to certain hydroisoindoline compounds which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, depression, and anxiety.
1. A compound of the formula I:
wherein:
R 1 is selected from the group consisting of:
(1) hydrogen,
(2) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
(3) cyclopentenone, which is unsubstituted or substituted with hydroxyl or methyl,
(4) —(CO)—C 1-6 alkyl,
(5) —(CO)—NH 2 ,
(6) —(CO)—NHC 1-6 alkyl, and
(7) —(CO)—N(C 1-6 alkyl)(C 1-6 alkyl);
X is independently selected from the group consisting of:
(1) hydrogen,
(2) fluorine, and
(3) methyl;
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
2. The compound of claim 1 of the formula Ia:
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
3. The compound of claim 1 of the formula Ib:
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
4. The compound of claim 1 wherein R 1 is selected from the group consisting of:
(1) hydrogen,
(2) methyl,
(3) 2-phenylethyl,
(4) 2-hydroxyethyl,
(5) cyclopent-2-en-1-one,
(6) 5-hydroxycyclopent-2-en-1-one,
(7) 4-hydroxycyclopent-2-en-1-one,
(8) 2-methylcyclopent-2-en-1-one,
(9) acetyl,
(10) NH 2 —C(O)—,
(11) NH(CH 3 )—C(O)—, and
(12) NH(CH 3 ) 2 —C(O)—.
5. The compound of claim 1 wherein X is hydrogen.
6. The compound of claim 1 wherein X is fluorine.
7. A compound which is selected from the group consisting of:
8. A compound of Formula A
Wherein R 1 and X are defined as follows:
Ex. #
R 1
X
5
4-F
6
H
7
2-Me
8
4-F
9
2-Me
10
2-Me
11
4-F
12
2-Me
13
2-Me
14
4-F
15
2-Me, 4-F
16
2-Me, 4-F
17
2-Me, 4-F
18
2-Me, 4-F
19
2-Me, 4-F
20
4-F
21
2-Me
22
2-Me, 4-F
23
4-F
24
2-Me
25
2-Me, 4-F
26
4-F
27
2-Me
28
2-Me, 4-F
29
4-F
30
2-Me
31
2-Me, 4-F
32
4-F
33
2-Me
34
2-Me, 4-F
35
4-F
36
2-Me
37
2-Me, 4-F
38
2-Me
39
2-Me, 4-F
40
4-F
41
2-Me
42
2-Me, 4-F
43
4-F
44
2-Me
45
2-Me, 4-F
or a pharmaceutically acceptable salt thereof;
B
Ex. #
R 1
X
46
4-F
47
H
48
2-Me
49
4-F
50
2-Me
51
2-Me
52
4-F
53
2-Me
54
2-Me
g 55
4-F
56
2-Me, 4-F
57
2-Me, 4-F
58
2-Me, 4-F
59
2-Me, 4-F
60
4-F
61
2-Me, 4-F
62
4-F
63
2-Me
64
2-Me, 4-F
65
4-F
66
2-Me
67
2-Me, 4-F
68
4-F
69
2-Me
70
2-Me, 4-F
71
4-F
72
2-Me
73
2-Me, 4-F
74
4-F
75
2-Me
76
2-Me, 4-F
77
4-F
78
2-Me
79
2-Me, 4-F
80
2-Me
81
2-Me, 4-F
82
4-F
83
2-Me
84
2-Me, 4-F
85
4-F
86
2-Me
87
2-Me, 4-F
or a pharmaceutically acceptable salts thereof.
9. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.