Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-08
2004-05-04
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S245000, C514S252010, C514S252020, C514S252030, C514S252050, C544S182000, C544S212000, C544S238000
Reexamination Certificate
active
06730672
ABSTRACT:
The invention relates to a group of aminoheterocyclic derivatives, or pharmaceutically-acceptable salts thereof, which possess antithrombotic and anticoagulant properties and are accordingly useful in methods of treatment of the human or animal body. The invention also relates to processes for the preparation of said aminoheterocyclic derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect.
The antithrombotic and anticoagulant effect produced by the compounds of the invention is believed to be attributable to their strong inhibitory effect against the activated coagulation protease known as Factor Xa. Factor Xa is one of a cascade of proteases involved in the complex process of blood coagulation. The protease known as thrombin is the final protease in the cascade and Factor Xa is the preceding protease which cleaves prothrombin to generate thrombin.
Certain compounds are known to possess Factor Xa inhibitory properties and the field has been reviewed by R. B. Wallis,
Current Opinion in Therapeutic Patents,
1993, 1173-1179. Thus it is known that two proteins, one known as antistatin and the other known as tick anticoagulant protein (TAP), are specific Factor Xa inhibitors which possess antithrombotic properties in various animal models of thrombotic disease.
It is also known that certain non-peptidic compounds possess Factor Xa inhibitory properties. Of the low molecular weight inhibitors mentioned in the review by R. B. Wallis, all possessed a strongly basic group such as an amidinophenyl or amidinonaphthyl group.
It is the object of the present invention to provide a new class of agent which lacks the amidino group previously believed to be an essential feature for a Factor Xa inhibitor.
We have now found that certain amino-substituted heterocyclic derivatives possess Factor Xa inhibitory activity. Many of the compounds of the present invention also possess the advantage of being selective Factor Xa inhibitors, that is the enzyme Factor Xa is inhibited strongly at concentrations of test compound which do not inhibit or which inhibit to a lesser extent the enzyme thrombin which is also a member of the blood coagulation enzymatic cascade.
The compounds of the present invention possess activity in the treatment or prevention of a variety of medical disorders where anticoagulant therapy is indicated, for example in the treatment or prevention of thrombotic conditions such as coronary artery and cerebro-vascular disease. Further examples of such medical disorders include various cardiovascular and cerebrovascular conditions such as myocardial infarction, the formation of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes, vascular injury including reocclusion and restenosis following angioplasty and coronary artery bypass surgery, thrombus formation after the application of blood vessel operative techniques, the introduction of artificial heart valves or on the recirculation of blood, cerebral infarction, cerebral thrombosis, stroke, cerebral embolism, pulmonary embolism, ischaemia and angina (including unstable angina).
The compounds of the invention are also useful as inhibitors of blood coagulation in an ex-vivo situation such as, for example, the storage of whole blood or other biological samples suspected to contain Factor Xa and in which coagulation is detrimental.
According to one aspect of the invention there is provided an aminoheterocyclic derivative of the formula I (set out hereinafter) wherein G
1
is CH or N;
G
2
is CH or N;
G
3
is CH or N;
m is 1 or 2;
R
1
is hydrogen, amino, halogeno, cyano, (1-4C)alkyl or (1-4C)alkoxy;
M
1
is a group of the formula
NR
2
—L
1
—T
1
R
3
in which R
2
and R
3
together form a (1-4C)alkylene group,
L
1
is (1-4C)alkylene, and
T
1
is CH or N,
and wherein 1 or 2 methylene groups within L
1
and the ring formed when R
2
and R
3
are linked optionally bears a (1-4C)alkyl substituent;
A is a direct link to the carbonyl group, or A is (1-4C)alkylene;
M
2
is a group of the formula
(T
2
R
4
)
r
—L
2
—T
3
R
5
in which r is 0 or 1,
T
2
is CH or N,
T
3
is CH or N,
R
4
is hydrogen or (1-4C)alkyl, R
5
is hydrogen or (1-4C)alkyl, or R
4
and R
5
together form a (1-4C)alkylene, methylenecarbonyl or carbonylmethylene group, or R
4
is a (2-3C)alkylene group which is linked to a methylene group within L
2
forming a 5- or 6-membered ring involving R
4
and T
2
, or R
5
is a (2-3C)alkylene group which is linked to a methylene group within L
2
forming a 5- or 6-membered ring involving R
5
and T
3
,
L
2
is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl, (1-3C)alkylene-carbonyl or phenylene, and, when r is 1, L
2
may also be carbonyl-(1-3C)alkylene, and wherein 1 or 2 methylene groups within L
2
and the rings formed when R
4
and R
5
, R
4
and L
2
or R
5
and L
2
are linked optionally bears a substituent selected from the group consisting of oxo, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl N-(1-4C)alkyl-N-phenylcarbamoyl, N-[phenyl-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[phenyl-(1-3C)alkyl]carbamoyl, N-[hydroxy-(2-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[hydroxy-(2-3C)alkyl]carbamoyl, N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[carboxy-(1-3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]-N-[hydroxy-(2-3C)alkyl]carbamoyl, N-[carboxy-(1-3C)alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl, N-(1-4C)alkyl-N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]carbamoyl, N-[(1-4C)alkoxycarbonyl-(1-3C)alkyl]-N-[hydroxy-(2-3C) alkyl]carbamoyl, N-[(1-4C)alkoxycarbonyl-(1-3C) alkyl]-N-[(1-4C)alkoxy-(2-3C)alkyl]carbamoyl, (1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl, N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl, pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidinocarbonyl-(1-4C)alkyl, morpholinocarbonyl-(1-4C)alkyl, piperazin-1-ylcarbonyl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl-(1-4C)alkyl, N-phenylcarbamoyl-(1-4C)alkyl, N-[phenyl-(1-3C)alkyl]carbamoyl-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl and phenyl-(1-4C)alkyl,
and wherein any heterocyclic group in said substituent optionally bears 1 or 2 substituents selected from the group consisting of (1-4C)alkyl, (1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl,
and wherein any phenyl or phenylene group in M
2
optionally bears 1 or 2 substituents selected from the group consisting of halogeno, trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy;
M
3
is a direct link to X, or M
3
is a group of the formula
L
3
—(NR
6
)
s
in which s is 0 or 1,
R
6
is hydrogen or (1-4C)alkyl, or R
5
and R
6
together form a (1-4C)alkylene, methylenecarbonyl or carbonylmethylene group, or R
6
is a (2-3C)alkylene group which is linked to a methylene group within L
3
forming a 5- or 6-membered ring involving NR
6
,
L
3
is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl, carbonyl-(1-3C)alkylene or phenylene, and, when s is 1, L
3
may also be (1-3C)alkylene-carbonyl,
and wherein 1 or 2 methylene groups within L
3
and the rings formed when R
5
and R
6
or R
6
and L
3
are linked optionally bears a substituent selected from the group consisting of oxo, carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl, N-phenylcarbamoyl, N-(1-4C)alkyl-N-phenylcarbamoyl, N-[phen
Faull Alan Wellington
Mayo Colette Marie
Preston John
Stocker Andrew
McKenzie Thomas
Morgan & Lewis & Bockius, LLP
Shah Mukund J.
Zeneca Limited
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