Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-29
2001-02-20
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S318000, C514S326000, C514S255030, C544S360000, C544S365000, C546S189000, C546S193000, C546S200000
Reexamination Certificate
active
06191145
ABSTRACT:
BACKGROUND OF THE INVENTION
Platelet aggregation constitutes the initial hemostatic response to curtail bleeding induced by vascular injury. However, pathological extension of this normal hemostatic process can lead to thrombus formation. The final, common pathway in platelet aggregation is the binding of fibrinogen to activated, exposed platelet glycoprotein IIb/IIIa (GPIIb/IIIa). Agents which interrupt binding of fibrinogen to GPIIb/IIIa, therefore, inhibit platelet aggregation. These agents are, therefore, useful in treating platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, unstable angina, reocclusion following thrombolytic therapy and angioplasty, inflammation, and a variety of vaso-occlusive disorders. The fibrinogen receptor (GPIIb/IIIa) is activated by stimuli such as ADP, collagen, and thrombin exposing binding domains to two different peptide regions of fibrinogen: alpha-chain Arg-Gly-Asp (RGD) and gamma-chain His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val (HHLGGAKQAGDV, &ggr;400-411). Since these peptide fragments themselves have been shown to inhibit fibrinogen binding to GPIIb/IIIa, a mimetic of these fragments would also serve as an antagonist. In fact, prior to this invention, potent RGD-based antagonists have been revealed which inhibit both fibrinogen binding to GPIIb/IIIa and platelet aggregation e.g., Ro-438857 (L. Alig,
J. Med. Chem.
1992, 35, 4393) has an IC
50
of 0.094 &mgr;M against in vitro thrombin-induced platelet aggregation. Some of these agents have also shown in vivo efficacy as antithrombotic agents and, in some cases, have been used in conjunction with fibrinolytic therapy e.g., t-PA or streptokinase, as well (J. A. Zablocki,
Current Pharmaceutical Design
1995, 1, 533).
The glycolamide ester compounds of the present invention are orally-active GPIIb/IIIa antagonists which exhibit improved oral absorption and in vivo activity over their carboxylic acid congeners. As demonstrated by the results of the pharmacological studies described hereinafter, the compounds show the ability to block fibrinogen binding to isolated GPIIb/IIa (IC
50
's of ca. 0.0005-0.01 &mgr;M), inhibit platelet aggregation in vitro in the presence of a variety of platelet stimuli (IC
50
's of ca. 0.1-1.0 &mgr;M vs. thrombin), and furthermore, inhibit ex vivo platelet aggregation in animal models. Additionally, these agents exhibit efficacy in animal thrombosis models as their progenitors had shown (“Nipecotic Acid Derivatives As Antithrombotic Compounds,” application Ser. No. 08-213772, filed Mar. 16, 1994 and “Carboxamide Derivatives of Pyrrolidine, Piperidine, and Hexahydroazepine for the Treatment of Thrombosis Disorders,” application Ser. No. 60-016675, filed May 1, 1996). The compounds of the present invention are carboxylic acid glycolamide esters which show efficacy as antithrombotic agents by virtue of their ability to prevent platelet aggregation. Additionally, because the compounds of this invention inhibit integrin-mediated cell-cell or cell-matrix adhesion, they may be useful against inflammation, bone resorption, tumor cell metastasis, etc. (D. Cox,
Drug News
&
Perspectives
1995, 8, 197).
DISCLOSURE OF THE INVENTION
The present invention is directed to compounds represented by the following general formula (I):
wherein A, X, M, R
5
, R
10
, and n are as hereinafter defined. The glycolamide ester compounds of the present invention are orally-active GPIIb/IIIa antagonists which exhibit improved oral absorption and in vivo activity over their carboxylic acid congeners. These platelet aggregation inhibitors are useful in treating platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, reocclusion following thrombolytic therapy and angioplasty, inflammation, unstable angina, and a variety of vaso-occlusive disorders. These compounds are also useful as antithrombotics used in conjunction with fibrinolytic therapy (e.g., t-PA or streptokinase). Pharmaceutical compositions containing such compounds are also part of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
More particularly, the present invention is directed to compounds of the following formula (I):
wherein M is (CH
2
)
m
, CH═CH or C≡C;
A is selected from any of piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, NHR
2
or
wherein R
9
is selected from any of H, alkyl, CH(NH), CMe(NH) or acyl, preferably R
9
is hydrogen;
R
10
is H or C(O)N(R
1
)YZ,
wherein R
1
is selected from H or cycloalkyl;
R
2
is selected from any of H, alkyl or acyl, preferably R
2
is hydrogen;
R
5
is H or C(O)NHQ(CHW)
r
CO
2
R
8
; wherein Q is selected from CH
2
, CH-aryl, CH-heteroaryl, CH-substituted-heteroaryl or CH-alkyl; preferably Q is CH
2
, CH-substituted-heteroaryl or CH-heteroaryl; W is selected from H or N(R
6
)T—R
7
, preferably W is H when Q is CH, and N(R
6
)—T—R
7
when Q is CH
2
; wherein R
6
is selected from any of H, alkyl or acyl, preferably R
6
is hydrogen; T is selected from C(O), C(N—CN) or SO
2
, preferably T is C(O); R
7
is selected from any of alkyl, aryl, aralkyl, alkoxy, or aminoalkyl; and R
8
is H or CH
2
C(O)NR
11
R
12
, preferably R
8
is CH
2
C(O)NR
11
R
12
, most preferably R
8
is CH
2
C(O)NEt
2
; R
11
and R
12
are selected from H, alkyl, or cycloalkyl, preferably R
11
and R
12
are alkyl;
m is the integer 1, 2, or 3, preferably m is 1 or 2;
X is selected from any of C(O), C(O)O, C(O)NH, CH
2
, or SO
2
;
n is the integer 1, 2, or 3;
r is 0 or 1;
Y is selected from any of (CH
2
)
p
, CH(R
3
)(CH
2
)
q
, (CH
2
)
q
CH(R
3
), (CH(CO
2
R
4
)CH
2
)
q
, (CH
2
)
q
CHOH or piperidine-3-carboxylic acid; with the proviso that when Y is (CH
2
)
p
and p is 2, X is other than C(O) or when X is C(O) then either R
1
is other than H or R
2
is other than H, and with the proviso that when Y is (CH(CO
2
R
4
)CH
2
)
q
X is other than C(O) or CH
2
;
p is 2 or 3;
q is 1, 2, or 3, preferably, q is 1;
R
3
is alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, aryl, aralkyl or heteroaryl;
R
4
is H or alkyl or cycloalkyl, preferably R
4
is hydrogen;
Z is CO
2
CH
2
C(O)NR
11
R
12
; provided that at least one of R
5
and R
10
is hydrogen and R
5
and R
10
are not hydrogen at the same time;
provided that when R
5
is C(O)NHQ(CHW)
r
CO
2
R
8
, and Q is CH-heteroaryl or CH-substituted-heteroaryl, and R
8
is H, then M is CH═CH;
or the enantiomer or the pharmaceutically acceptable salt thereof.
Preferably, the group C(O)N(R
1
)YZ is attached to the ring carbon of the central azacycle at the 3- or 4-position (4-position when larger than a five-membered ring), and most preferably the 3-position.
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 1-8 carbons. 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 5-8 ring carbons and preferably 6-7 carbons.
The term “aryl”, “heteroaryl” or “substituted heteroaryl” as used herein alone or in combination with other terms indicates aromatic or heteroaromatic groups such as phenyl, naphthyl, pyridyl, thienyl, furanyl, or quinolinyl wherein the substituent is an alkyl group. The term “aralkyl” means an alkyl group substituted with an aryl group.
The term “acyl” as used herein means an organic radical having 2-6 carbon atoms derived from an organic acid by removal of the hydroxyl group.
The compounds of the present invention may also be present in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt generally takes a form in which the nitrogen on the 1-piperidine (pyrrolidine, piperazine) substituent is protonated with an inorganic or organic acid. Representat
Appollina Mary
Lambkin Deborah C.
Ortho-McNeil Pharmaceutical , Inc.
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