Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-20
2002-05-28
Solola, T. A (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S235800, C514S252020, C514S252050, C514S252140, C514S254050, C514S256000, C514S326000, C544S056000, C544S121000, C544S238000, C544S295000, C544S335000, C544S370000, C546S245000
Reexamination Certificate
active
06395731
ABSTRACT:
This application is a 371 of PCT/GB99/01312 filed Apr. 27, 1999.
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 formula (I)
wherein:
A is a 5- or 6-membered monocyclic aromatic ring containing 1 or 2 nitrogen ring heteroatoms optionally substituted by one, two or three atoms or groups selected from halo (for example fluoro, chloro or bromo), oxo, carboxy, trifluoromethyl, cyano, amino, hydroxy, nitro, C
1-4
alkyl (for example methyl or ethyl), C
1-4
alkoxy (for example methoxy or ethoxy), C
1-4
alkoxycarbonyl, C
1-4
alkylamino (for example methylamino or ethylamino), di-C
1-4
alklylamino (for example dimethylamino or diethylamino) or aminoC
1-4
alkyl (for example aminomethyl or aminoethyl);
the 1,4-phenylene ring of the compound of formula I is unsubstituted or is substituted by one or two substituents selected from halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, C
1-4
alkyl, C
2-4
alkenyl and C
2-4
alkynyl, from the substituent —(CH
2
)
n
Y
1
wherein n is 0-4 and Y
1
is selected from hydroxy, amino, carboxy, C
1-4
alkoxy, C
2-4
alkenyloxy, C
2-4
alkynyloxy, C
1-4
alkylamino, di-C
1-4
alkylamino, pyrrolid-1-yl, piperidino, morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, piperazin-1-yl, 4-C
1-4
alkylpiperazin-1-yl, C
1-4
alkylthio, C
1-4
alkylsulphinyl, C
1-4
alkylsulphonyl, C
2-4
alkanoylamino, benzamido, C
1-4
alkylsulphonamido and phenylsulphonamido, from the substituent —(CH
2
)
n
Y
2
wherein n is 0-4 and Y
2
is selected from carboxy, carbamoyl, C
1-4
alkoxycarbonyl, N—C
1-4
alkylcarbamoyl, N,N-di-C
1-4
alkylcarbamoyl, pyrrolid-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, 1-oxothiomorpholinocarbonyl, 1,1-dioxothiomorpholinocarbonyl, piperazin-1-ylcarbonyl, 4-C
1-4
alkylpiperazin-1-ylcarbonyl, C
1-4
alkylsulphonamidocarbonyl, phenylsulphonamidocarbonyl and benzylsulphonamidocarbonyl, from a substituent of the formula —X
3
—L
2
—Y
2
wherein X
3
is a group of the formula CON(R
5
), CON(L
2
—Y
2
), C(R
5
)
2
O, O, N(R
5
) or N(L
2
—Y
2
), L
2
is C
1-4
alkylene, Y
2
has any of the meanings defined immediately hereinbefore and each R
5
is independently hydrogen or C
1-4
alkyl, and from a substituent of the formula —X
3
—L
3
—Y
1
wherein X
3
is a group of the formula CON(R
5
), CON(L
3
—Y
1
), C(R
5
)
2
O, O, N(R
5
) or N(L
3
—Y
1
), L
3
is C
2-4
alkylene, Y
1
has any of the meanings defined immediately hereinbefore and each R
5
is independently hydrogen or C
1-4
allyl, and wherein any heterocyclic group in a substituent of the 1,4-phenylene ring of compounds of formula I optionally bears 1 or 2 substituents selected from carboxy, carbamoyl, C
1-4
alkyl, C
1-4
alkoxycarbonyl, N—C
1-4
alkylcarbamoyl and NN-di-C
1-4
alkylcarbamoyl, and wherein any phenyl group in a substituent of the 1,4-phenylene ring of compounds of formula I optionally bears 1 or 2 substituents selected from halo, trifluoromethyl, cyano, C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, C
2-4
alkenyloxy and C
2-4
alkynyloxy;
B is CH or N;
the heterocyclic ring containing B is unsubstituted or is substituted by one or two substituents selected from hydroxy, oxo, carboxy and C
1-4
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 0, 1 or 2, preferably n is 1 or 2;
R and R
1
are independently selected from hydrogen, C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, hydroxyC
1-4
alkyl, carboxyC
1-4
alkyl and C
1-4
alkoxycarbonylC
1-4
alkyl or where possible R and R
1
may together form a 5- or 6-membered optionally substituted saturated or partially unsaturated (preferably saturated) heterocyclic ring which may include in addition to the nitrogen to which R and R
1
are attached 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulphur;
E is fluoro, chloro or bromo;
D and D
1
are independently selected from hydrogen, C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, oxo and hydroxy;
provided that when E is bromo and B is N then A is not 2-pyridyl, 4-pyridyl, 4-pyrimidinyl or 4-pyridazinyl, and when E is chloro and B is N then A is not 3-pyridyl, 4-pyridyl or 4-pyrimidinyl;
and pharmaceutically acceptable salts thereof.
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 further to be understood that, insofar as certain of the compounds of formula (I) 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 acti
Preston John
Rayner John W
Smithers Michael J
Stocker Andrew
Thorsten Nowak
Astrazeneca AB
Morgan & Lewis & Bockius, LLP
Solola T. A
Wright Sonya
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