Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-29
2004-05-25
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S019300, C544S250000
Reexamination Certificate
active
06740657
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to certain novel compounds, their synthesis and their use for the treatment of thrombin receptor mediated diseases. More particularly, this invention relates to aminomethyl-pyrroloquinazoline compounds and pharmaceutical compositions thereof useful as thrombin receptor antagonists, methods for production thereof and methods for treating thrombin receptor mediated 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. Nat. 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. The thrombin 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 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 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, 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, thrombin receptor antagonist compounds, particularly PAR-1 antagonists, may also be useful against inflammation, osteoporosis, cancer, neurodegenerative disorders, hypertension, heart failure, arrhythmia or glomerulonephritis.
The structure activity relationships of pyrroloquinazoline compounds as small molecule inhibitors of the intramolecular ligand of the thrombin receptor have been reported (D. A. Burnett, et al.,
Bioorg. Med. Chem. Lett.,
1999, 2073-2077), disclosing pyrroloquinazoline compounds of the general formula:
wherein R is selected from 4-(i-Pr)benzyl, 4-(t-Bu)benzyl, 6-(Me)naphthalen-2-ylmethyl, 4-(OEt)benzyl, 4-(Et)benzyl, 4-(SMe)benzyl, 4-(ethenyl)benzyl; NR
1
R
2
is selected from methylamino, dimethylamino, ethylamino, ethanolamino, N-cyclopropylamino, N-methyl-N-cyclopropylamino, 1-piperidinyl, 2-1,2,3,4-tetrahydro-isoquinoline or 1-piperazinyl; and, NR
3
R
4
is selected from amino, methylamino or dimethylamino.
U.S. Pat. No. 4,118,561 to Ledig discloses 7-(substituted) and 7,8-disubstituted pyrrolo[3,2-f]quinazoline-1,3-diamines having anti-bacterial activity of the general formula:
wherein
(a) X is hydrogen and Y is —CH
2
R or —R
1
wherein R is hydrogen; methyl; ethyl; n-propyl; i-propyl; n-butyl; i-butyl; n-pentyl; n-hexyl; 2-methyl-1-propenyl; cyclobutyl; cyclopentyl; cyclohexyl; 2-phenylethyl; 2-phenylvinyl; phenyl; phenyl monosubstituted in the 2-, 3-, or 4-position by chlorine, bromine, iodine, fluorine, trifluoromethyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, trifluoromethoxy, cyano, methylsulfonyl, acetyl, propionyl, methylthio, ethylthio, carbethoxy, carboxyl, sodium carboxy, or potassium carboxy; phenyl monosubstituted in the 3-position by amino or nitro; phenyl disubstituted in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-positions by methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy, chlorine, bromine, iodine or fluorine; phenyl trisubstituted in the 2,4,6- or 3,4,5-positions by methyl, ethyl, methoxy, or ethoxy; 2,3,5,6-tetramethylphenyl; 3,4-(methylenedioxy)phenyl; 1-naphthalenyl; 2-naphthalenyl, 2-methyl-1-naphthalentyl; 1-bromo-2-naphthalentyl; 2-pyrindinyl; 3-pyrindinyl; 4-pyrindinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl; 3-thienyl; 4-thiazolyl, 3,5-dimethyl-4-isoxazolyl; tetrahydro-2-furanyl; or benzo[b]thien-3-yl; and R
1
is hydrogen; phenyl monosubstituted in the 2- or 4-position by amino, nitro, cyano, acetyl, propionyl, methylsulfonyl, trifluoromethyl or carbethoxy; 2,4-dinitrophenyl; 2,4-diaminophenyl; 2-cyano-4-nitrophenyl; 2-cyano-4-aminophenyl; 3-methyl-4-nitrophenyl; 3-methyl-4-aminophenyl; 2-trifluoromethyl-4-nitrophenyl; 2-trifluoromethyl-4-aminophenyl; 2-thiazolyl; 2-pyrindinyl; 5-nitro-2-pyrindinyl; 2-pyrimidinyl; 2-pyrazinyl; 2-quinolinyl; 4-quinolinyl; 4-methyl-2-quinolinyl; 7-chloro-4-quinolinyl; 7-trifluoromethyl-4-quinolinyl; 2-methyl-4-quinolinyl; 3-methyl-2-quinoxalinyl; 2-phenyl-4-quinolinyl; or benzothiazolyl; 5-amino-2-pyrindinyl; and (b) X is methyl, phenyl, or chlorine, and Y is hydrogen, methyl, benzyl, 3-cyanobenzyl, 4-cyanobenzyl, or 2,5-dimethylbenzyl; provided that when X is phenyl, Y may only be hydrogen or methyl, and when X is chlorine, Y may only be benzyl.
The aminomethyl-pyrroloquinazoline compounds of the present invention have not been heretofore disclosed as thrombin receptor antagonists. Accordingly, it is an object of the present invention to provide aminomethyl-pyrroloquinazoline compounds useful as thrombin receptor antagonists, particularly as PAR-1 antagonists. It is another object of the invention to provide methods for producing the instant aminomethyl-pyrroloquinazoline compounds. It is a further object of the invention to provide methods for treating thrombin receptor mediated disorders, particularly PAR-1 mediated disorders including, but not limited to, inflammation, osteoporosis, hypertension, angina, atherosclerosis, thrombosis, restenosis, arrhythmia, myocardial infarction, heart failure, stroke, ischemic conditions, glomerulonephritis, cancer and neurodegenerative disorders.
SUMMARY OF THE INVENTION
The present invention is directed to structurally novel aminomethyl-pyrroloquinazoline compounds of Formula (I):
wherein:
R
1
is selected from the group consisting of aryl, heteroaryl and C
3
-C
8
cycloalkyl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C
1
-C
4
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, C
1
-C
4
alkoxy, aryl, heteroaryl, amino, amido, amidino, guanidino, hydroxy, nitro and cyano;
R
2
and R
3
are independently selected from the group consisting of hydrogen, C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, C
3
-C
8
cycloalkyl and aryl(C
1
-C
8
)alkyl; alternatively, when independently selected from the group consisting of C
1
-C
8
alkyl and C
2
-C
8
alkenyl, R
2
and R
3
may, together with the nitrogen to which they are attached, form a saturated or partially saturated 4 to 6 membered heterocyclyl ring;
n is an integer selected from 0, 1, 2 or 3;
X is selected from the group consisting of hydrogen, —OR
4
, —NH
2
, —NHR
4
and —NR
4
R
5
;
R
4
and R
5
are independently selected from the group consisting of C
1
-C
8
alkyl, C
3
-C
8
cycloalkyl and aryl(C
1
-C
8
)alkyl;
Y is selected from the group consisting of haloge
Maryanoff Bruce E.
McComsey David F.
Zhang Han-Cheng
Ortho-McNeil Pharmaceutical , Inc.
Raymond Richard L.
Truong Tamthom N.
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