Benzimidazolone peptidometics as thrombin receptor antagonist

Details Benzimidazolone peptidometics as thrombin receptor antagonist Benzimidazolone peptidometics as thrombin receptor antagonist

2000-06-22

2003-10-07

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S385000, C514S386000, C514S387000, C514S393000, C514S394000, C548S300100, C548S305700, C546S273400

Reexamination Certificate

active

06630451

ABSTRACT:

FIELD OF THE INVENTION
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 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 benzimidazolone peptidomimetics represented by the general formula (I) below.
SUMMARY OF THE INVENTION
The present invention is directed to structurally novel compounds represented by the following general formula (I):
wherein
A
1
and A
2
are each independently a D- or L-amino acid selected from the group consisting of alanine, &bgr;-alanine, arginine, homoarginine, cyclohexylalanine, citrulline, cysteine (optionally substituted with C
1
-C
4
alkyl, aryl, or arC
1
-C
4
alkyl), 2,4-diaminobutyric acid (optionally substituted with acyl, C
1
-C
4
alkyl, aroyl, amidino, or MeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl, C
1
-C
4
alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine, indanylglycine, lysine (optionally substituted with acyl, C
1
-C
4
alkyl, aroyl, MeC(NH)—), valine, methionine, proline, serine (optionally substituted with C
1
-C
4
alkyl, aryl, or arC
1
-C
4
alkyl), homoserine (optionally substituted with C
1
-C
4
alkyl, aryl, or arC
1
-C
4
alkyl), tetrahydroisoquinoline-3-COOH, threonine (optionally substituted with C
1
-C
4
alkyl, aryl, or arC
1
-C
4
alkyl), ornithine (optionally substituted with acyl, C
1
-C
4
alkyl, aroyl, MeC(NH)—), and an unsubstituted or substituted aromatic amino acid selected from the group consisting of phenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine, histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine, aryl-&bgr;-alanine, and heteroaryl-&bgr;-alanine wherein the substituents on the aromatic amino acid are independently selected from one or more of halogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, hydroxy, C
1
-C
4
alkoxycarbonyl, amino, amidino, guanidino, fluorinated C
1
-C
4
alkyl, fluorinated C
1
-C
4
alkoxy, C
1
-C
4
alkylsulfonyl, C
1
-C
4
alkylcarbonyl, cyano, aryl, heteroaryl, arC
1
-C
4
alkyl, C
2
-C
4
alkenyl, alkynyl, or nitro;
Preferably, A
1
and A
2
are each independently an L-amino acid selected from the group consisting of alanine, &bgr;-alanine, arginine, homoarginine, cyclohexylalanine, citrulline, cysteine (optionally substituted with C
1
-C
4
alkyl, aryl, or arC
1
-C
4
alkyl), 2,4-diaminobutyric acid (optionally substituted with acyl, C
1
-C
4
alkyl, aroyl, amidino, or MeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl, C
1
-C
4
alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine, indanylglycine, lysine (optionally substituted with acyl, C
1
-C
4
alkyl, aroyl, MeC(NH)—), valine, methionine, proline, serine (optionally substituted with C
1
-C
4
alkyl, aryl, or arC
1
-C
4
alkyl), homoserine (optionally substituted with C
1
-C
4
alkyl, aryl, or arC
1
-C
4
alkyl), tetrahydroisoquinoline-3-COOH, threonine (optionally substituted with C
1
-C
4
alkyl, aryl, or arC
1
-C
4
alkyl), ornithine (optionally substituted with acyl, C
1
-C
4
alkyl, aroyl, MeC(NH)—), and an unsubstituted or substituted aromatic amino acid selected from the group consisting of phenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine, histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine, aryl-&bgr;-alanine, and heteroaryl-&bgr;-alanine wherein the substituents on the aromatic amino acid are independently selected from one or more of halogen, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, hydroxy, C
1
-C
4
alkoxycarbonyl, amino, amidino, guanidino, fluorinated C
1
-C
4
alkyl, fluorinated C
1
-C
4
alkoxy, C
1
-C
4
alkylsulfonyl, C
1
-C
4
alkylcarbonyl, cyano, aryl, heteroaryl, arC
1
-C
4
alkyl, C
2
-C
4
alkenyl, alkynyl, or nitro;
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
dialkylaminoC
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
alkoxyC
1
-C
8
alkyl, C
1
-C
8
alkylamino or C
1
-C
8
dialkylamino;
Preferably, R
1
is selected from amino, C
1
-C
6
alkylamino, C
1
-C
6
dialkylamino, arylamino, arC
1
-C
6
alkylamino, heteroalkylC
1
-C
6
alkylamino, —N(C
1
-C
6
alkyl)—C
1
-C
6
alkyl-N(C
1
-C
6
alkyl)
2
, heteroalkyl or substituted heteroalkyl wherein the substituent on the heteroalkyl is selected from oxo, amino, C
1
-C
6
alkoxyC
1
-C
6
alkyl, C
1
-C
6
alkylamino or C
1
-C
6
dialkylamino;
R
2
and R
3
are each independently selected from hydrogen, C
1
-C
8
alkyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkylC
1
-C
8
alkyl, aryl, heteroalkyl, substituted heteroalkyl (wherein the substituent on the heteroalkyl is one or more substituents independently selected from C
1
-C
8
alkoxycarbonyl, C
1
-C
8
alkyl, or C
1
-C
4
alkylcarbonyl), heteroalkylC
1
-C
8
alkyl, indanyl, acetamidinoC
1
-C
8
alkyl, aminoC
1
-C
8
alkyl, C
1
-C
8
alkylaminoC
1
-C
8
alkyl, C
1
-C
8
, dialkylaminoC
1
-C
8
alkyl, unsubstituted or substituted heteroarylC
1
-C
8
alkyl or unsubstituted or substituted arC
1
-C
8
alkyl, wherein the substituent on the aralkyl or heteroarylalkyl group is one or more substituents independently selected from halogen, nitro, amino, C
1
-C
8
alkyl, C
1
-C
8
alkoxy, hydroxy, cyano, C
1
-C
4
alkylcarbonyl, C
1
-C
8
alkoxycarbonyl, hydroxyC
1
-C
8
alkyl or aminosulfonyl; or
R
2
and R
3
together with the nitrogen to which

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