Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
2000-05-05
2004-06-08
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C514S018700, C514S019300
Reexamination Certificate
active
06747127
ABSTRACT:
BACKGROUND OF THE INVENTION
Thrombin is an important serine protease in hemostasis and thrombosis. One of the key actions of thrombin is receptor activation. A functional human thrombin receptor (TR), 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 SEQ. ID. No. 1) N-terminus acting as a tethered ligand to recognize a site on the receptor, can trigger activation and signal transduction leading to platelet aggregation. Peptide analogues based on this hexapeptide have also shown good agonist activity leading to platelet aggregation. Since 1991, two other protease-activated receptors with extensive homology to the thrombin receptor, “PAR-2” and “PAR-3,” were cloned, and found to be activated by similar N-terminal hexapeptide sequences. Hence, agonists/antagonists of the thrombin receptor, such as those included in this invention, may be useful in activating/antagonizing these protease-activated receptors as well.
Activation of the thrombin receptor by agonist compounds of this invention may mimic thrombins role in tissue repair. Thrombin can initiate effects related to wound healing, such as: increasing vascular permeability to allow entry of cells and fluid into injured tissue (A. B. Malik,
Semin. Thromb. Haemostasis
1986, 184); increasing the synthesis of PDGF by endothelial cells (J. M. Harlan,
J. Cell Biol.
1986, 103, 1129); and increasing the adhesion of platelets, monocytes, and neutrophils to endothelial cells (M. P. Bevilacqua,
Science
1989, 243, 1160). Tissue repair in rats following surgical incision is accelerated by the use of thrombin (D. H. Carney,
J. Clin. Invest.
1992, 89, 1469). Thus, agonists at the thrombin receptor may be useful as wound healing agents or in tissue repair.
The peptide-based antagonists of the thrombin receptor in this present invention may show efficacy against myocardial infarction, stroke, restenosis, angina, atherosclerosis, and ischemic attacks by virtue of their ability to prevent platelet aggregation. The thrombin receptor has also been identified on other cell types: endothelial, fibroblast, osteosarcoma, smooth muscle, 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 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, restenosis, cancer, osteoporosis, and neurodegenerative disorders.
SUMMARY OF THE INVENTION
The present invention is directed to compounds represented by the following general formula (I):
wherein A
1
, A
2
, A
3
, X, Y, and Z are defined later.
These compounds are thrombin receptor modulators and may be useful either as agonists in wound healing and tissue repair or as antagonists in myocardial infarction, stroke, restenosis, angina, atherosclerosis, ischemic attacks, inflammation, cancer, osteoporosis, or neurodegenerative disorders.
DETAILED DESCRIPTION OF THE INVENTION
More particularly, the present invention is directed to compounds of the following formula (I):
wherein
A
1
is an alkyl amino acid residue selected from Cha, Leu and Ile, an amino alkyl amino acid residue selected from Arg and Lys, or an aryl amino acid residue selected from Phe, substituted Phe, Tyr, or Trp;
A
2
is an amino alkyl amino acid residue selected from Lys, Orn, Arg, and homo Arg;
A
3
is an aryl amino acid residue selected from Phe, substituted Phe, Tyr, Trp, phenyl-Gly, 2-thienyl-Ala and 3-thienyl-Ala, an alkyl amino acid residue selected from Cha, Leu and Ile, an amido alkyl amino acid selected from Asn and Gln, or an amino alkyl amino acid residue selected from Arg, homo Arg, Orn and Lys;
X is selected from CO, CS, or SO
2
;
Y is selected from aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylethylenyl, substituted heteroarylethylenyl, arylacrylamidoheteroaryl, substituted arylacrylamidoheteroaryl, heteroarylacrylamidoheteroaryl and substituted heteroarylacrylamidoheteroaryl, preferably, Y is not pyrrolidinyl, substituted pyrrolidinyl, phenyl or 2-aminophenyl; most preferably, Y is selected from heteroaryl, substituted heteroaryl, arylacrylamidoheteroaryl, and substituted arylacrylamidoheteroaryl;
Z is selected from NH
2
, NH-alkyl, NH-aralkyl, or an amino alkyl amino acid residue selected from Arg-NH
2
; and
wherein all amino acids are of the L configuration;
and the pharmaceutically acceptable salts thereof.
In the compounds of formula (I), the amino acid residues comprising the A
1
, A
2
, and A
3
substituents are attached to the adjacent moiety according to standard nomenclature so that the amino-terminus (N-terminus) of the amino acid is drawn on the left and the carboxy-terminus of the amino acid is drawn on the right. So, for example, in Compound 1, where A
1
is Cha, A
2
is Arg and A
3
is Phe, the N-terminus of the Cha (A
1
) is attached to the X substituent and the carboxy-terminus of the Cha (A
1
) is attached to the N-terminus of the A
2
substituent (Arg), similarly, the the N-terminus of the Arg (A
2
) is attached to the carboxy-terminus of the A
1
substituent and the carboxy-terminus of the Arg (A
2
) is attached to the N-terminus of the A
3
substituent (Phe), similarly, the N-terminus of the Phe (A
3
) is attached to the carboxy-terminus of the A
2
substituent and the carboxy-terminus of the Phe (A
3
) is attached to the Z substituent.
When a particular group is “substituted” (e.g., Phe, heterocycloalkyl, heteroaryl, acrylamidoheteroaryl), that group may have from 1 to 4 substituents independently selected from: halo (I, Br, Cl, F), C
1
-C
8
alkyl, C
1
-C
8
alkoxy, amino, amido, carboxyl, cyano, nitro, fluorinated C
1
-C
8
alkyl, fluorinated C
1
-C
8
alkoxy, or aryl (preferably, phenyl or substituted phenyl).
The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, unless otherwise noted alkyl and alkoxy whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, or any number within this range. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. Cycloalkyl groups contain 3 to 8 ring carbons and preferably 5 to 7 carbons. Similarly, alkenyl and alkynyl groups include straight and branched chain alkenes and alkynes having 1 to 8 carbon atoms, or any number within this range.
The term “aryl” as used herein, alone or in combination with other terms, represents an aromatic hydrocarbon group. Examples of aryl groups include, but are not limited to,
Hawkins Michael J.
Maryanoff Bruce E.
McComsey David F.
Low Christopher S. F.
Lukton David
Ortho-McNeil Pharmaceutical , Inc.
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