Nor-seco himbacine derivatives useful as thrombin receptor...

Details Nor-seco himbacine derivatives useful as thrombin receptor... Nor-seco himbacine derivatives useful as thrombin receptor...

2001-06-13

2003-11-11

Desai, Rita (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S284100, C546S284700

Reexamination Certificate

active

06645987

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to nor-seco himbacine derivatives useful as thrombin receptor antagonists in the treatment of diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, cerebral ischemia, stroke, neurodegenerative diseases and cancer. Thrombin receptor antagonists are also known as protease activated receptor (PAR) antagonists. The compounds of the invention also bind to cannabinoid (CB2) receptors and are useful in the treatment of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis. The invention also relates to pharmaceutical compositions containing said compounds.
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 antagonist peptides have been identified based on structure-activity studies involving substitutions 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.
Cannabinoid receptors belong to the superfamily of G-protein coupled receptors. They are classified into the predominantly neuronal CB
1
receptors and the predominantly peripheral CB
2
receptors. These receptors exert their biological actions by modulating adenylate cyclase and Ca
+2
and K
+
currents. While the effects of CB
1
receptors are principally associated with the central nervous system, CB
2
receptors are believed to have peripheral effects related to bronchial constriction, immunomodulation and inflammation. As such, a selective CB
2
receptor binding agent is expected to have therapeutic utility in the control of diseases associated with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders of the lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis (R. G. Pertwee,
Curr. Med. Chem.
6(8), (1999), 635).
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.
Tricyclic himbacine-related compounds have been disclosed as thrombin receptor antagonists in U.S. Pat. No. 6,063,847.
SUMMARY OF THE INVENTION
The present invention relates to thrombin receptor antagonists represented by the formula I
or a pharmaceutically acceptable salt thereof, wherein:
Z is —(CH
2
)
n
—;
wherein R
10
is absent; or
wherein R
3
is absent;
the single dotted line represents an optional double bond;
the double dotted line represents an optional single bond;
n is 0-2;
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
7
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, (C
1
-C
6
)alkoxy(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, —NR
18
R
19
, —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
7
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, thio(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl or (C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl;
R
34
is (H, R
3
), (H, R
43
), ═O or ═NOR
17
when the optional double bond is absent; R
34
is R
44
when the double bond is present;
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
7
cycloalkyl; heterocycloalkyl; heterocycloalkyl substituted by C
1
-C
6
alkyl, C
2
-C
6
alkenyl, OH—(C
1
-C
6
)alkyl, or ═O; C
2
-C
6
alkenyl; R
21
-aryl(C
1
-C
6
)alkyl; R
21
-aryl-(C
2
-C
6
)-alkenyl; R
21
-aryloxy; R
21
-aryl-NH—; heteroaryl(C
1
-C
6
)alkyl; heteroaryl(C
2
-C
6
)-alkenyl; heteroaryloxy; heteroaryl-NH—; hydroxy(C
1
-C
6
)alkyl; dihydroxy(C
1
-C6)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(═NOR
17
)R
18
; 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
or heteroaryl;
R
21
-aryl; aryl wherein adjacent carbons form a ring with a methylenedioxy group;
R
41
-heteroaryl; 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
7
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, phenyl, (C
3
-C
7
)cycloalkyl, (C
3
-C
7
)cycloalkyl(Cl-C
6
)alkyl, (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl and amino(C
1
-C
6
)alkyl;
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;
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 H, —OH or —NHR
20
when the bond

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