Thrombin receptor antagonists

Details Thrombin receptor antagonists Thrombin receptor antagonists

2000-04-07

2001-12-04

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S357000, C546S178000, C546S337000

Reexamination Certificate

active

06326380

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to substituted tricyclic thrombin receptor antagonists, pharmaceutical compositions containing them and their use in the treatment of diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, cerebral ischemia and cancer.
Thrombin is known to have a variety of activities in different cell types and thrombin receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts. It is therefore expected that thrombin receptor antagonists will be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role.
Thrombin receptor antagonists peptides have been identified based on structure-activity studies involving substututions of amino acids on thrombin receptors. In Bernatowicz et al,
J. Med. Chem
., 39 (1996), p. 4879-4887, tetra- and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH
2
and N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NH
2
. Peptide thrombin receptor anatgonists are also disclosed in WO 94/03479, published Feb. 17, 1994.
Himbacine, a piperidine alkaloid of the formula
has been identified as a muscarinic receptor antagonist. The total synthesis of (+)-himbacine is disclosed in Chackalamannil et al,
J. Am.Chem Soc
., 118 (1996), p. 9812-9813.
SUMMARY OF THE INVENTION
The present invention relates to thrombin receptor antagonists represented by the formula I
or a pharmaceutically acceptable salt thereof, wherein:
the single dotted line represents an optional double bond;
the double dotted line represents an optional single bond;
n is 0-2;
Q is
 wherein
n
1
and n
2
are independently 0-2; or when the double bond is not present, Q is also fused R-substituted aryl or R-substituted heteroaryl;
R is 1 to 3 substituents independently selected from the group consisting of H, C
1
-C
6
alkyl, halogen, hydroxy, amino, (C
1
-C
6
)alkylamino, (C
1
-C
6
)dialkylamino, (C
1
-C
6
)alkoxy, —COR
16
, —COOR
17
, —SOR
16
, —SO
2
R
16
, —NR
16
COR
16a
, —NR
16
COOR
16a
, —NR
16
CONR
4
R
5
, fluoro-(C
1
-C
6
)alkyl, difluoro(C
1
-C
6
)alkyl, trifluoro(C
1
-C
6
)alkyl, C
3
-C
6
cycloalkyl, C
2
-C
6
alkenyl, aryl(C
1
-C
6
)alkyl, aryl(C
2
-C
6
)alkenyl, heteroaryl(C
1
-C
6
)alkyl, heteroaryl(C
2
-C
6
)alkenyl, hydroxy(C
1
-C
6
)alkyl, amino(C
1
-C
6
)alkyl, aryl and thio(C
1
-C
6
)alkyl;
R
1
and R
2
are independently selected from the group consisting of H, C
1
-C
6
alkyl, fluoro(C
1
-C
6
)alkyl, difluoro(C
1
-C
6
)alkyl, trifluoro-(C
1
-C
6
)alkyl, C
3
-C
6
cycloalkyl, C
2
-C
6
alkenyl, aryl(C
1
-C
6
)alkyl, aryl(C
2
-C
6
)alkenyl, heteroaryl(C
1
-C
6
)alkyl, heteroaryl(C
2
-C
6
)alkenyl, hydroxy(C
1
-C
6
)alkyl, amino(C
1
-C
6
)alkyl, aryl and thio(C
1
-C
6
)alkyl; or R
1
and R
2
together form a ═O group;
R
3
is H, hydroxy, C
1
-C
6
alkoxy, —SOR
16
, —SO
2
R
17
, —C(O)OR
17
, —C(O)NR
18
R
19
, C
1
-C
6
alkyl, halogen, fluoro(C
1
-C
6
)alkyl, difluoro(C
1
-C
6
)alkyl, trifluoro(C
1
-C
6
)alkyl, C
3
-C
6
cycloalkyl, C
2
-C
6
alkenyl, aryl(C
1
-C
6
)alkyl, aryl(C
2
-C
6
)alkenyl, heteroaryl(C
1
-C
6
)alkyl, heteroaryl(C
2
-C
6
)alkenyl, hydroxy(C
1
-C
6
)alkyl, amino(C
1
-C
6
)alkyl, aryl or thio(C
1
-C
6
)alkyl;
Het is a mono-, bi- or tricyclic heteroaromatic group of 5 to 14 atoms comprised of 1 to 13 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein a ring nitrogen can form an N-oxide or a quaternary group with a C
1
-C
4
alkyl group, wherein Het is attached to B by a carbon atom ring member, and wherein the Het group is substituted by 1 to 4 substituents, W, independently selected from the group consisting of H; C
1
-C
6
alkyl; fluoro(C
1
-C
6
)alkyl; difluoro(C
1
-C
6
)alkyl; trifluoro-(C
1
-C
6
)-alkyl; C
3
-C
6
cycloalkyl; heterocycloalkyl; heterocycloalkyl substituted by C
1
-C
6
alkyl or C
2
-C
6
alkenyl; C
2
-C
6
alkenyl; R
21
-aryl(C
1
-C
6
)alkyl; R
21
-aryl-(C
2
-C
6
)-alkenyl; heteroaryl(C
1
-C
6
)alkyl; heteroaryl(C
2
-C
6
)-alkenyl; hydroxy(C
1
-C
6
)alkyl; dihydroxy(C
1
-C
6
)alkyl; amino(C
1
-C
6
)alkyl; (C
1
-C
6
)alkylamino-(C
1
-C
6
)alkyl; di-((C
1
-C
6
)alkyl)-amino(C
1
-C
6
)alkyl; thio(C
1
-C
6
)alkyl; C
1
-C
6
alkoxy; C
2
-C
6
alkenyloxy; halogen; —NR
4
R
5
; —CN; —OH; —COOR
17
; —COR
16
; —OSO
2
CF
3
; —CH
2
OCH
2
CF
3
; (C
1
-C
6
)alkylthio; —C(O)NR
4
R
5
; —OCHR
6
-phenyl; phenoxy-(C
1
-C
6
)alkyl; —NHCOR
16
; —NHSO
2
R
16
; biphenyl; —OC(R
6
)
2
COOR
7
; —OC(R
6
)
2
C(O)NR
4
R
5
; (C
1
-C
6
)alkoxy; C
1
-C
6
alkoxy substituted by (C
1
-C
6
)alkyl, amino, —OH, COOR
17
, —NHCOOR
17
, —CONR
4
R
5
, aryl, aryl substituted by 1 to 3 substutuents independently selected from the group consisting of halogen, —CF
3
, C
1
-C
6
alkyl, C
1
-C
6
alkoxy and —COOR
17
, aryl wherein adjacent carbons form a ring with a methylenedioxy group, —C(O)NR
4
R
5
and heteroaryl;
R
21
-aryl; aryl wherein adjacent carbons form a ring with a methylenedioxy group;
heteroaryl; heteroaryl substituted by 1 to 4 substituents selected from the group consisting of halogen, C
1
-C
6
alkoxy, C
1
-C
6
alkyl, (C
1
-C
6
)alkylamino, di-((C
1
-C
6
)alkyl)amino, —OCF
3
, —NO
2
, hydroxy(C
1
-C
6
)alkyl, —CHO and phenyl; and heteroaryl wherein adjacent carbon atoms form a ring with a C
3
-C
5
alkylene group or a methylenedioxy group;
R
4
and R
5
are independently selected from the group consisting of H, C
1
-C
6
alkyl, phenyl, benzyl and C
3
-C
6
cycloalkyl, or R
4
and R
5
together are —(CH
2
)
4
—, —(CH
2
)
5
— or —(CH
2
)
2
NR
7
—(CH
2
)
2
— and form a ring with the nitrogen to which they are attached;
R
6
is independently selected from the group consisting of H, C
1
-C
6
alkyl or phenyl;
R
7
is H or (C
1
-C
6
)alkyl;
R
8
, R
10
and R
11
are independently selected from the group consisting of R
1
and —OR
1
, provided that when the optional double bond is present, R
10
is absent, and when ring Q is aromatic, R
10
and R
11
are absent;
R
9
is H, OH, C
1
-C
6
alkoxy, halogen or halo(C
1
-C
6
)alkyl;
B is —(CH
2
)
n3
—, —CH
2
—O—, —CH
2
S—, —CH
2
—NR
6
—, —C(O)NR
6
—. —NR
6
C(O)—,
 cis or trans —(CH
2
)
n4
CR
12
═CR
12a
(CH
2
))
n5
or —(CH
2
))
n4
C≡C(CH
2
)
n5
—, wherein n
3
is 0-5, n
4
and n
5
are independently 0-2, and R
12
and R
12a
are independently selected from the group consisting of H, C
1
-C
6
alkyl and halogen;
X is —O— or —NR
6
— when the double dotted line represents a single bond, or X is —OH or —NHR
20
when the bond is absent;
Y is═O, ═S, (H, H), (H, OH) or (H, C
1
-C
6
alkoxy) when the double dotted line represents a single bond, or when the bond is absent, Y is ═O, (H, H), (H, OH), (H, SH) or (H, C
1
-C
6
alkoxy);
R
15
is absent when the double dotted line represents a single bond and is H, C
1
-C
6
alkyl, —NR
18
R
19
, or —OR
17
when the bond is absent; or Y is
 or
 and R
15
is H or C
1
-C
6
alkyl;
R
16
and R
16a
are independently selected from the group consisting of C
1
-C
6
lower alkyl, phenyl or benzyl;
R
17
, R
18
and R
19
are independently selected from the group consisting of H, C
1
-C
6
alkyl, phenyl, benzyl;
R
20
is H, C
1
-C
6
alkyl, phenyl, benzyl, —C(O)R
6
or —SO
2
R
6
;
R
21
is 1 to 3 substutuents independently selected from the group consisting of —CF
3
, —OCF
3
, halogen, —NO
2
, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, (C
1
-C
6
)alkylamino, di-((C
1
-C
6
)alkyl)amino, amino(C
1
-C
6
)alkyl, (C
1
-C
6
)-alkylamino(C
1
-C
6
)alkyl, di-((C
1
-C
6
)alkyl)-amino(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, —COOR
17
, —COR
17
, —NHCOR
16
, —NHSO
2
R
16
and —NHSO
2
CH
2
CF
3
;
Z is —CH
2
—, —O—, —S(O)
0-2
—, —NR
22
—, —C(O)—, —C(═NOR
17
)— or —C(R
13
R
14
)—, wherein R
13
and R
14
, together with the carbon to which they are attached, form a spirocycloalkyl group of 3 to 6

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