Heterocyclic derivatives as inhibitors of factor Xa

Details Heterocyclic derivatives as inhibitors of factor Xa Heterocyclic derivatives as inhibitors of factor Xa

2001-11-15

2004-04-20

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S364000

Reexamination Certificate

active

06723723

ABSTRACT:

The invention relates to heterocyclic derivatives, or pharmaceutically-acceptable salts thereof, which possess antithrombotic and anticoagulant properties and are accordingly useful in methods of treatment of humans or animals. The invention also relates to processes for the preparation of the heterocyclic 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.
We have now found that certain 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 or after general surgery such as hip replacement surgery 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.
Accordingly in one aspect the present invention provides compounds of the formula
wherein:
A is an optionally substituted 5- or 6-membered monocyclic aromatic ring containing 1, 2 or 3 ring heteroatoms selected from oxygen, nifrogen and sulphur atoms;
B
1
, B
2
, B
3
and B
4
are independently CH or a nitrogen atom, wherein the ring formed from B
1
, B
2
, B
3
and B
4
may optionally be substituted; with the proviso that at least one of B
1
, B
2
, B
3
and B
4
is nitrogen;
T
1
is CH or N;
T
2
is CH or N; with the proviso that at least one of T
1
and T
2
is N;
X
1
is SO, SO
2
, C(R
4
)
2
or CO when T
1
is CH or N; or in addition X
1
is O or S when T
1
is CH;
and wherein each R
4
is independently hydrogen or (1-4C)alkyl;
L
1
is (1-4C)alkylene or (1-3 C)alkylenecarbonyl;
R
2
is hydrogen or (1-4C)alkyl;
R
3
is hydrogen or (1-4C)alkyl;
or R
2
and R
3
are joined to form a (1-4C)alkylene or —CH
2
CO— group; wherein the ring formed by T
1
, R
2
, R
3
, T
2
and L
1
is optionally substituted;
X
2
is S(O)
y
wherein y is one or two, C(R
5
)
2
or CO; and each R
5
is independently hydrogen or (1-4C)alkyl;
Y is selected from hydrogen, halo, trifluromethyl, trifluoromethoxy, cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkoxycarbonyl,
N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl, (2-4C)alkanoyl, (2-4C)alkanoylamino, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C)alkyl, carbamoyl-(1-4C)alkyl, N-(1-4C)alkylcarbamoyl-(1-4C)alkyl and N,N-di-(1-4C)alkylcarbamoyl-(1-4C)alkyl;
n is 1 or 2; and
B
5
and B
6
is selected from N or CH; with the proviso that at least one of B
5
and B
6
is N;
and pharmaceutically acceptable salts thereof.
In this specification the term “alkyl” includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only. An analogous convention applies to other generic terms.
It is to be understood that certain heterocyclic derivatives of the present invention can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess Factor Xa inhibitory activity.
It is fuirther to be understood that, insofar as certain of the compounds of the formula defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention encompasses any such optically active or racemic form which possesses Factor Xa inhibitory activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
Preferably A is a pyridyl, pyrimidinyl or pyridazinyl ring for example 4-pyridyl, 2-pyridyl, 4-pyridazinyl, 3-pyrimidinyl, 4-pyrimidinyl or 3-pyridyl. Of these 4-pyrimidinyl, 4-pyradaziiiyl and 4-pyridyl are preferred, with 4-pyrimidinyl and 4-pyridyl most preferred.
In one aspect A is unsubstituted. In another aspect A is substituted by one, two or three atoms or groups selected from halo (for example fluoro, chloro or bromo), trifluoromethyl, cyano, amino, oxo, hydroxy, nitro, (1-4C)alkyl (for example methyl or ethyl), (1-4C)alkoxy (for example methoxy or ethoxy), (1-4C)alkylamino (for example methylamino or ethylamino) or di-(1-4C)alkylamino (for example dimethylamino or diethylamino). For the avoidance of doubt substituents may also be on any heteroatom.
Preferably the ring formed by B
1
, B
2
, B
3
and B
4
is a pyridinediyl, wherein B
1
, or B
3
is a nitrogen atom, pyrimidinediyl, wherein B
1
and B
2
or B
3
and B
4
are nitrogen atoms, pyridazinediyl, wherein B
1
, B
3
and B
4
or B
1
, B
2
and B
3
are nitrogen atoms. Of these pyridinediyl and pyrimidinediyl are preferred, and pyridinediyl is most preferred.
In one aspect the ring containing B
1
, B
2
, B
3
and B
4
is unsubstituted. In another aspect the ring containing B
1
, B
2
, B
3
and B
4
is substituted by one or two substituents selected from hydroxy, carboxy, (1-4C)alkoxycarbonyl or one of the following;
—(CH
2
)
n
—R, —(CH
2
)
n
—NRR
1
, —CO—R, —CO—NRR
1
, —(CH
2
)
n
—CO—R and —(CH
2
)
n
—CO—NRR
1
;
wherein n is 1 or 2;
R and R
1
are independently selected from hydrogen, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, hydroxy(1-4C)alkyl, carboxy(1-4C)alkyl and (1-4C)alkoxycarbonyl-(1-4C)alkyl or where possible R and R
1
may together form a 5- or 6-membered optionally substituted heterocyc

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