Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-15
2001-10-16
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S212060, C514S253040, C514S383000, C540S518000, C544S362000, C544S366000, C546S120000, C548S262400
Reexamination Certificate
active
06303625
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to certain novel compounds, their synthesis and their use for the treatment of thrombosis disorders. More particularly, the compounds are fibrinogen receptor antagonists which inhibit platelet aggregation and are useful in treating thrombotic disorders.
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, re-occlusion 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 RGDbased 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).
Accordingly, it is an object of the invention to identify compounds which are antagonists of GPIIb/IIIa. It is another object of the invention to identify compounds which inhibit platelet aggregation by inhibiting the binding of fibrinogen to GPIIb/IIIa. Another object of this invention is to identify compounds which are useful for treating thrombotic disorders. Still another object of the invention is to identify methods for treating thrombosis disorders using the compounds of the present invention.
We now describe a series of triazolopyridine compounds which act as antagonists of GPIIb/IIIa and are useful for treating thrombotic disorders.
SUMMARY OF THE INVENTION
The present invention is directed to compounds represented by the following general formula (I) or (II):
wherein M is (CH
2
)
m
, CH═CH, CH═CF, CF═CH, or C≡C;
n is can integer selected from 0, 1 or 2;
A is selected from 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 hydrogen, C
1
-C
8
alkyl, CH═(NH), CMe═(NH), C
2
-C
6
acyl, C
1
-C
8
alkoxycarbonyl or ar(C
1
-C
8
alkoxy)carbonyl, preferably, R
9
is hydrogen;
R
2
is selected from hydrogen, C
1
-C
8
alkyl or C
2
-C
6
acyl, preferably, R
2
is hydrogen;
R
10
is selected from hydrogen or C(O)N(R
1
)YZ, wherein R
1
is selected from hydrogen, C
1
-C
8
alkyl or C
3
-C
8
cycloalkyl, preferably R
10
is hydrogen;
Y is selected from (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;
R
3
is selected from C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, aryl, ar(C
1
-C
8
)alkyl or heteroaryl;
R
4
is selected from hydrogen, C
1
-C
8
alkyl or C
3
-C
8
cycloalkyl, preferably, is hydrogen;
p is an integer selected from 2 or 3;
q is an integer selected from 1, 2, or 3, preferably, q is 1;
Z is CO
2
R
8
;
R
5
is selected from hydrogen or C(O)NHQ(CHW)
r
CO
2
R
8
, preferably R
5
is 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-(C
1
-C
8
)alkyl, preferably, Q is CH
2
, CH-substituted-heteroaryl or CH-heteroaryl;
W is selected from hydrogen or N(R
6
)T-R
7
, preferably W is hydrogen when Q is CH-aryl or CH-heteroaryl, and W is N(R
6
)T-R
7
when Q is CH
2
;
R
6
is selected from hydrogen, C
1
-C
8
alkyl or C
2
-C
6
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 C
1
-C
8
alkyl, aryl, ar(C
1
-C
8
)alkyl, ar(C
1
-C
8
)alkoxy, C
1
-C
8
alkoxy, (C
1
-C
8
)alkylamino or unsubstituted or substituted heteroaryl(C
0
-C
8
)alkyl; and
R
8
is hydrogen, C
1
-C
8
alkyl, or CH
2
C(O)NR
11
R
12
, preferably, R
8
is hydrogen or CH
2
C(O)NR
11
R
12
; wherein
R
11
and R
12
are each independently selected from hydrogen, C
1
-C
8
alkyl, or C
3
-C
8
cycloalkyl, preferably, R
11
and R
12
are C
1
-C
8
alkyl;
m is an integer selected from 1, 2, or 3, preferably, m is 1 or 2;
r is an integer selected from 0 or 1; and
R
15
is selected from hydrogen or C
1
-C
8
alkyl preferably, R
15
is hydrogen; and pharmaceutically acceptable salts thereof.
Preferably, the compounds of the present invention are of the formula
wherein M is (CH
2
)
m
, CH═CH, or C≡C; and all other variables are as defined above; and pharmaceutically acceptable salts thereof.
In one embodiment of the invention is the compound of formula (I) or (II), wherein:
wherein M is (CH
2
)
m
or CH═CH;
R
5
is C(O)NHQ(CHW)
r
CO
2
R
8
;
wherein Q is selected from CH
2
, CH-heteroaryl or CH-substituted-heteroaryl;
W is selected from hydrogen or N(R
6
)T-R
7
;
wherein R
6
is H; T is C(O);
R
7
is selected from C
1
-C
8
alkyl, aryl, ar(C
1
-C
8
)alkyl, ar(C
1
-C
8
)alkoxy, C
1
-C
8
alkoxy, or (C
1
-C
8
)alkylamino;
R
8
is hydrogen, C
1
-C
8
alkyl or CH
2
C(O)NR
11
R
12
; wherein R
11
and R
12
are each independently C
1
-C
8
alkyl;
R
10
is hydrogen;
R
15
is selected from hydrogen or C
1
-C
4
alkyl;
r is 1;
and all other variables are as defined above;
and pharmaceutically acceptable salts thereof.
In a class of the invention is the compound of formula (I) selected from:
wherein R
8
is hydrogen or CH
2
CONEt
2
;
R
13
is selected from hydrogen, 3-pyridyl or 3-quinolinyl;
R
14
is selected from hydrogen or NHCO
2
CH
2
Ph; and
R
15
is selected from hydrogen or methyl;
and pharmaceutically acceptable salts thereof.
Exemplifying the invention is the compound of formula (I) selected from:
&bgr;-[[[5,6,7,8-Tetrahydro-3-[2-(4-piperidinyl)ethyl]-1,2,4-triazolo[4,3-a]pyridin-8-yl]carbonyl]amino]-&bgr;S-3-pyridinepropanoic acid;
&bgr;-[[[5,6,7,8-Tetrahydro-3-[2-(4-piperidinyl)ethyl]-1,2,4-triazolo[4,3-a]pyridin-8-yl]carbonyl]amino]-&bgr;-propanoic acid;
&bgr;-[[[5,6,7,8-Tetrahydro-3-[2-(4piperidinyl)ethyl]-1,2,4-triazolo[4,3-a]pyridin-8-yl]carbonyl]amino]-&agr;S-benzyloxycarbonylamino-propanoic acid;
&bgr;-[[[5,6,7,8-Tetrahydro-3-[2-(4-piperidinyl)ethyl]-1,2,4-triazolo[4,3-a]pyridin-8-yl]carbonyl]amino]-&bgr;S-3-pyridinepropanoic acid 2-(Diethylamino)-2-oxoethyl ester;
&bgr;-[[[5,6,7,8-Tetrahydro-3-[2-(4-piperidinyl)ethenyl]-1,2,4-triazolo[4,3-a]pyridin-8-yl]carbonyl]amino]-&agr;S-benzyloxycarbonylamino-propanoic acid;
&bgr;-[[[5,6,7,8-Tetrahydro-3-[2-(4-piperidinyl)ethyl]-1,2,4-triazolo[4,3-a]pyridin-8-yl]carbonyl]amino]-&agr;S-benzyloxycarbonylamino-propanoic acid 2-(Diethylamino)-2-oxoethyl ester;
&bgr;-[[[5,6,7,8-Tetrahydro-3-[2-(4-piperidinyl)ethyl]-1,2,4-triazolo[4,3-a]pyridin-8-yl]carbonyl]amino]-&bgr;-3-thiophenepropanoic acid; or
&bgr;-[[&lsq
Hoekstra William J.
Lawson Edward C.
Maryanoff Bruce E.
Huang Evelyn Mei
Ortho-McNeil Pharmaceutical , Inc.
Woodrow Hal
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