Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-26
2002-04-02
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S275700, C546S277100, C548S362500, C548S468000
Reexamination Certificate
active
06365617
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to certain novel thrombin receptor antagonists, their synthesis and their use for the treatment of diseases associated with thrombosis, restenosis, hypertension, heart failure, arrhythmia, inflammation, angina, stroke, atherosclerosis, ischemic conditions, Angiogenesis related disorders, cancer, and neurodegenerative disorders.
BACKGROUND OF THE INVENTION
Thrombin is an important serine protease in hemostasis and thrombosis. One of the key actions of thrombin is cellular modulation via receptor activation. A functional human thrombin receptor (PAR-1), cloned by Coughlin in 1991 (T.-K. Vu,
Cell
1991, 64, 1057), was found to be a member of the G-protein coupled receptor (GPCR) superfamily. The receptor activation putatively occurs by N-terminal recognition and proteolytic cleavage at the Arg-41/Ser-42 peptide bond to reveal a truncated N-terminus. This new receptor sequence, which has an SFLLRN (Ser-Phe-Leu-Leu-Arg-Asn) N-terminus acting as a tethered ligand to recognize a site on the receptor, can trigger activation and signal transduction leading to platelet aggregation. Since 1991, three other protease-activated receptors with extensive homology to the thrombin receptor, “PAR-2” (S. Nystedt,
Proc. Natl. Acad. Sci USA
1994, 91, 9208), “PAR-3” (H. Ishihara,
Nature
1997, 386, 502), and “PAR-4” (W.-F. Xu,
Proc. Natl. Acad. Sci USA
1998, 95, 6642), have been cloned. Thrombin receptor (PAR-1) specific antibody-induced blockade of the platelet thrombin receptor has shown efficacy against arterial thrombosis in vivo (J. J. Cook
Circulation
1995, 91, 2961). Hence, antagonists of the thrombin receptor (PAR-1) are useful to block these protease-activated receptors and, as such, may be used to treat platelet mediated thrombotic disorders such as myocardial infarction, stroke, restenosis, angina, atherosclerosis, and ischemic conditions.
The thrombin receptor (PAR-1) has also been identified on other cell types: endothelial, fibroblast, renal, osteosarcoma, smooth muscle, myocytes, tumor, and neuronal/glia. Thrombin activation of endothelial cells upregulates P-selectin to induce polymorphonuclear leukocyte adhesion—an inflammatory response of the vessel wall (Y. Sugama,
J. Cell Biol
. 1992, 119, 935). In fibroblasts, thrombin receptor (PAR-1) activation induces proliferation and transmission of mitogenic signals (D. T. Hung,
J. Cell Biol
. 1992, 116, 827). Thrombin has been implicated in osteoblast proliferation through its activation of osteoblast cells (D. N. Tatakis,
Biochem. Biophys. Res. Commun
. 1991, 174, 181). Thrombin has been implicated in the regulation and retraction of neurons (K. Jalink,
J. Cell. Biol
. 1992, 118, 411). Therefore, in this context, the antagonist compounds of this invention may also be useful against inflammation, osteoporosis, Angiogenesis related disorders, cancer, neurodegenerative disorders, hypertension, heart failure, arrhythmia, glomerulonephritis.
The compounds of the present invention are a structurally novel class of indole and indazole urea-peptoids represented by the general formula (I) below.
SUMMARY OF THE INVENTION
The present invention is directed to structurally novel compounds reresented by the following general formula (I):
wherein:
R
1
is selected from amino, C
1
-C
8
alkylamino, C
1
-C
8
dialkylamino, arylamino, arC
1
-C
8
alkylamino, C
3
-C
8
cycloalkylamino, heteroalkylC
1
-C
8
alkylamino, heteroalkylC
1
-C
8
alkyl-N-methylamino, C
1
-C
8
dialkylamino C
1
-C
8
alkylamino, —N(C
1
-C
8
alkyl)—C
1
-C
8
alkyl-N(C
1
-C
8
alkyl)
2
, —N(C
1
-C
8
alkyl)(C
1
-C
8
alkenyl), —N(C
1
-C
8
alkyl)(C
3
-C
8
cycloalkyl), heteroalkyl or substituted heteroalkyl, wherein the substituent on the heteroalkyl is selected from oxo, amino, C
1
-C
8
alkoxy, C
1
-C
8
alkyl, C
1
-C
8
alkylamino or C
1
-C
8
dialkylamino;
R
2
is selected from unsubstituted or substituted aryl, arC
1
-C
8
alkyl, C
3
-C
8
cycoalkyl or heteroaryl, wherein the substituents on the aryl, aralkyl, cycloalkyl or heteroaryl group are independently selected from one or more of halogen, nitro, amino, cyano, hydroxyalkyl, C
1
-C
8
alkyl, C
1
-C
8
alkoxy, C
1
-C
8
alkoxycarbonyl, acetyl, fluorinated C
1
-C
4
alkyl, fluorinated C
1
-C
4
alkoxy or C
1
-C
4
alkylsulfonyl;
R
3
is selected from H or C
1
-C
8
alkyl;
R
4
and R
5
are each selected from H, C
1
-C
8
alkyl, amino C
1
-C
8
alkyl, amidino C
1
-C
8
alkyl, guanidino C
1
-C
8
alkyl, aryl, aryl C
1
-C
8
alkyl, substituted aryl, substituted arylC
1
-C
8
alkyl, heteroaryl, heteroaryl C
1
-C
8
alkyl, substituted heteroaryl, substituted heteroaryl C
1
-C
8
alkyl, cyclo C
3
-C
6
alkyl or substituted cycloC
3
-C
6
alkyl, wherein the substituents on the aryl, aralkyl, cycloalkyl or heteroaryl group are independently selected from one or more of halogen, nitro, amino, amidino, guanidino, cyano, hydroxyalkyl, C
1
-C
8
alkyl, C
1
-C
8
alkoxy, C
1
-C
8
alkoxycarbonyl, acetyl, fluorinated C
1
-C
4
alkyl, fluorinated C
1
-C
4
alkoxy or C
1
-C
4
alkylsulfonyl;
R
6
and R
7
are each selected from H, C
1
-C
8
alkyl, amino-C
1
-C
8
alkyl, amino-C
3
-C
8
cycloalkyl, amidino C
1
-C
8
alkyl, guanidino C
1
-C
8
alkyl, aryl, substituted aryl, aryl C
1
-C
8
alkyl, substituted aryl C
1
-C
8
alkyl, heteroaryl C
1
-C
8
alkyl or substituted heteroaryl C
1
-C
8
alkyl, wherein the substituents on the aryl, aralkyl, cycloalkyl or heteroaryl group are independently selected from one or more of halogen, nitro, amino, amidino, guanidino, cyano, hydroxyalkyl, C
1
-C
8
alkyl, C
1
-C
8
alkoxy, C
1
-C
8
alkoxycarbonyl, acetyl, fluorinated C
1
-C
4
alkyl, luorinated C
1
-C
4
alkoxy or C
1
-C
4
alkylsulfonyl;
Either R
5
or R
7
must be H when m is 1; in addition, when R
5
is H, then R
4
cannot be H; and, when R
7
is H, then R
6
cannot be H;
R
8
is selected from H, C
1
-C
8
alkyl, amino C
1
-C
0
alkyl, allyl, C
3
-C
8
cycloalkyl, substituted C
3
-C
8
cycloalkyl, aryl, substituted aryl, ar C
1
-C
8
alkyl, substituted ar C
1
-C
8
alkyl, heteroaryl, substituted heteroaryl, heteroaryl C
1
-C
8
alkyl or substituted heteroaryl C
1
-C
8
alkyl, wherein the substituents on the aryl, aralkyl, cycloalkyl or heteroaryl group are independently selected from one or more of halogen, nitro, amino, amidino, guanidino, cyano, hydroxyalkyl, C
1
-C
8
alkyl, C
1
-C
8
alkoxy, C
1
-C
8
alkoxycarbonyl, acetyl, fluorinated C
1
-C
4
alkyl, fluorinated C
1
-C
4
alkoxy or C
1
-C
4
alkylsulfonyl;
X is CH or N;
n is an integer selected from 0, 1, 2 or 3;
m is an integer selected from 0 or 1;
p is an integer selected from 1 or 2; and,
pharmaceutically acceptable salts thereof.
In one embodiment of the invention is the compound of formula (I) wherein
R
1
is selected from dimethylamino, diethylamino, di-(n-propyl)amino,
R
2
is selected from unsubstituted or substituted aryl, arC
1
-C
6
alkyl, C
3
-C
6
cycloalkyl or heteroaryl, where the substituents on the aryl, aralkyl, cycloalkyl or heteroaryl group are independently selected from one to three substituents selected from halogen, cyano, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, C
1
-C
4
alkoxycarbonyl, fluorinated C
1
-C
4
alkyl, fluorinated C
1
-C
4
alkoxy or C
1
-C
4
alkylsulfonyl; preferably, R
2
is unsubstituted or substituted phenyl wherein the substituent is one or two substituents selected from fluorine, chlorine, iodine, methyl, cyano or trifluoromethyl;
R
3
is selected from H or C
1
-C
4
alkyl; preferably, R
3
is H;
R
4
and R
5
are each independently selected from H, C
1
-C
4
alkyl, aminoC
1
-C
6
alkyl, amidinoC
1
-C
6
alkyl, guanidinoC
1
-C
6
alkyl, aryl, arC
1
-C
8
alkyl, substituted aryl, or substituted arC
1
-C
8
alkyl, wherein the substituents on the aryl or aralkyl are independently selected from one or two of halogen, nitro, amino, amidino, guanidino, cyano, hydroxyalkyl, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkoxycarbonyl, acetyl, fluorinated C
1
-C
4
alkyl, fluorinated C
1
-C
4
alkoxy or C
1
-C
4
alkylsulfonyl;
R
6
and R
7
are each independently selected from H, C
1
-C
4
alkyl, aminoC
1
Hoekstra William J.
Maryanoff Bruce E.
McComsey David F.
Zhang Han-Cheng
Ortho-McNeil Pharmaceutical , Inc.
Ramsuer Robert W.
Woodrow Hal B.
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