Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-15
2001-08-21
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S349000, C544S350000
Reexamination Certificate
active
06277851
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new bicyclic amino-pyrazinone compounds, to pharmaceutical compositions containing them, and to their use as inhibitors of trypsin-related serine proteases.
One of those serine proteases, thrombin, is the key enzyme for coagulation and plays a central role in the pathology of venous and arterial thromboses, especially in view of its marked ability to cause auto-amplification of the coagulation cascade (F. Toti et al., Sang, Thrombose, Vaisseaux [Blood, Thrombosis, Vessels] 1992, 4, 483-494 and T. M. Reilly et al., Blood Coagulation and Fibrinolysis 1992, 3, 513-517).
The direct and specific inhibition of thrombin is more efficient and poses fewer risks of haemorrage than treatment with heparin. Direct inhibitors of thrombin currently exist but the disadvantage of those peptide substances is that they are not active when administered by the oral route.
Peptidomimetic compounds having an oral antithrombotic activity have already been described in the literature. They include, for example, the boronic acid compounds described in Patent Specifications EP 293 881, EP 471 651, EP 615 978 and EP 792 883 and the compounds described in Patent Specifications WO 94 29336 and WO 95 23609.
It has therefore been of particular interest to synthesise new serine protease inhibitors in order to increase the effectiveness and selectivity of compounds already described in the literature.
The activity of those new compounds is demonstrated by the increase in various coagulation times.
The compounds are, moreover, active when administered by the oral route.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to compounds of formula (I):
wherein:
R
1
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group (optionally substituted by one or more identical or different substituents selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, carboxy, linear or branched (C
1
-C
6
)-alkoxycarbonyl, and carbamoyl groups), a hydroxy group, a cycloalkyl group, a heterocycloalkyl group or a group of formula (G):
wherein A
1
represents a single bond, a —CH
2
—, —CH
2
—CH
2
— or —N(CH
3
)— group or an oxygen or sulphur atom, and X
1
and X
2
, which may be identical or different, each represent a carbon or nitrogen atom,
R represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
represents a saturated ring having from 4 to 7 ring members that may contain in addition to the nitrogen atom one or two hetero atoms selected from O and S, or —N(R
2
) groups,
R
2
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
n represents an integer wherein 1≦n≦6,
Ar represents an aryl or heteroaryl group, its isomers, N-oxydes and pharmaceutically-acceptable acid or base addition salts thereof.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid, camphoric acid, etc..
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
“Aryl group” is understood to mean phenyl, biphenylyl or naphthyl, each of those groups being optionally substituted by one or more halogen atoms and/or by one or more identical or different groups selected from linear or branched (C
1
-C
6
)alkyl (optionally substituted by a hydroxy or carboxy group or by a carbamoyl group (itself optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups)), linear or branched (C
1
-C
6
)alkoxy, hydroxy, trihalo-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched, trihalogenoalkoxy in which the alkyl moiety is linear or branched, amino (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups), linear or branched alkylcarbonyloxy group, carboxymethoxy and carbamoylmethoxy (optionally N-substituted by one or two linear or branched (C
1
-C
6
)alkyl groups).
“Heteroaryl group” is understood to mean a mono- or bi-cyclic aromatic group having from 5 to 12 ring members and containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heteroaryl may be optionally substituted by one or more halogen atoms and/or by one or more identical or different groups selected from linear or branched (C
1
-C
6
)alkyl (optionally substituted by a hydroxy or carboxy group or by a carbamoyl group (itself optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups)), hydroxy, linear or branched (C
1
-C
6
)alkoxy, trihalo-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched, phenyl, amino (optionally N-substituted by one or more linear or branched (C
1
-C
6
)alkyl groups), carboxymethoxy and carbamoylmethoxy (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups).
Among the heteroaryl groups there may be mentioned by way of non-limiting example the thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidinyl, pyrazinyl and pyridazinyl groups.
“Cycloalkyl group” is understood to mean a saturated or unsaturated mono- or bi-cyclic hydrocarbon group having from 3 to 12 ring members, it being understood that the ring system may be optionally substituted by one or more halogen atoms and/or by one or more identical or different groups selected from linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, hydroxy, trihalo-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched, amino (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups) and aryl.
Among the cycloalkyl groups there may be mentioned by way of non-limiting example the cyclopentyl, cyclohexyl, indanyl and tetrahydronaphthyl groups.
“Heterocycloalkyl group” is understood to mean a saturated or unsaturated, mono- or bi-cyclic group having from 4 to 12 ring members and containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heterocycle may be optionally substituted by one or more halogen atoms and/or by one or more identical or different groups selected from linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, hydroxy, trihalo-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched, amino (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups), aryl and diarylmethyl.
Among the heterocycloalkyl groups there may be mentioned by way of non-limiting example the azetidinyl, pyrrolidinyl, piperidyl and dihydrocyclopenta[b]pyridyl groups.
The preferred compounds of formula (I) are those wherein n is 1.
The ring
as defined for formula (I) is preferably a pyrrolidinyl group.
The group Ar as defined for formula (I) is preferably a phenyl or pyridyl group, each of those groups being optionally substituted by one or more halogen atoms and/or by one or more identical or different groups selected from linear or branched (C
1
-C
6
)alkyl (optionally substituted by a hydroxy or carboxy group or by a carbamoyl group (itself optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups)), linear or branched (C
1
-C
6
)alkoxy, hydroxy, trihalo-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched, amino (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups), carboxymethoxy and carbamoylmethoxy (optionally N-substituted by one or two linear or branched (C
1
-C
6
)alkyl groups).
The invention relates also to a process for the preparation of compounds of formula (I), characterised in that a compound of formula (II):
wherein A is as defined for formula (I), P
1
represents an amino-function-
De Nanteuil Guillaume
Gloanec Philippe
Rupin Alain
Vallez Marie-Odile
Verbeuren Tony
Adir et Compagnie
Sage G. Patrick
Shah Mukund J.
The Firm of Hueschen and Sage
Truong Tamthom N.
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