Bicyclic amino-pyrazinone compounds

Details Bicyclic amino-pyrazinone compounds Bicyclic amino-pyrazinone compounds

2001-12-14

2004-02-03

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S183000, C514S357000, C514S358000, C514S413000, C514S423000, C544S349000, C544S350000, C546S112000, C546S113000, C546S121000, C546S290000, C546S304000, C548S416000, C548S452000, C548S453000, C548S465000, C548S570000

Reexamination Certificate

active

06686358

ABSTRACT:

BACKGROUND 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 venous and arterial thrombosis pathology in view, in particular, of its marked ability to cause autoamplification of the coagulation cascade (F. Toti et al., Sang, Thrombose, Vaisseaux 1992, 4, 483-494 and T. M. Reilly et al., Blood Coagulation and Fibrinolysis 1992, 3, 513-517).
The specific and direct inhibition of thrombin is more efficient and presents fewer risks of haemorrhage than treatment with heparin. Direct inhibitors of thrombin do currently exist, but the drawback of such peptide substances is that they are not active when administered by the oral route.
DESCRIPTION OF THE PRIOR ART
Peptidomimetic compounds having an oral antithrombotic activity have previously been described in the literature. These include, in particular, the boronic acid compounds described in the patent specifications EP 293 881, EP 471 651, EP 615 978 and EP 792 883 and the compounds described in the patent specifications WO 94 29336 and WO 95 23609.
The synthesis of new serine protease inhibitors for the purpose of increasing the potency and selectivity of the compounds previously described in the literature has therefore been of particular interest.
The activity of the new compounds is demonstrated by the increase of various coagulation times.
Furthermore, the compounds are active when administered by the oral route.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates more specifically to the 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 groups selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl,
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, S and —NR
3
groups, wherein R
3
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
n represents an integer such that 1≦n≦6,
R
2
represents any one of the following groups:
X represents a CH group or a nitrogen atom,
R
4
represents a hydrogen or halogen atom,
R
5
represents any one of the groups:
R
a
NHCOHN— wherein R
a
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
R
b
SO
2
NHCO(NH)
p
—, wherein R
b
represents a linear or branched (C
1
-C
6
)-alkyl group and p represents 0 or 1,
HON═C(NH
2
)—, HN═C(NHOH)—,
R
c
—(CH
2
)
m
—Y— wherein:
Y represents CH
2
, O, S or R
a
N,
m represents a integer such that 0≦m≦3,
R
c
represents a saturated or unsaturated heterocycle having 5 or 7 ring members containing from 1 to 4 hetero atoms selected from oxygen, nitrogen and sulphur, the said heterocycle optionally containing one or more carbonyl functions and optionally being substituted by one or more identical or different substituents selected from halogen atoms, linear or branched (C
1
-C
6
)alkyl groups, linear or branched (C
1
-C
6
)alkoxy groups, and amino groups (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups), or c: a bicyclic system of formula
wherein:
X is as defined hereinbefore and B, together with the carbon atoms to which it is attached, forms an aryl or a saturated or unsaturated heterocycle having 5 or 7 ring members containing from 1 to 4 hetero atoms selected from oxygen, nitrogen and sulphur, the said heterocycle optionally containing at least one carbonyl function and optionally being substituted by one or more identical or different substituents selected from halogen atoms, linear or branched (C
1
-C
6
)alkyl groups, linear or branched (C
1
-C
6
)alkoxy groups, and amino groups (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups),
to their isomers, to their N-oxides and to pharmaceutically acceptable addition salts thereof with an acid or a base.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, 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, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
An aryl group is to be understood as meaning phenyl, biphenylyl or naphthyl, each of those groups optionally being substituted by one or more identical or different groups selected from halogen, linear or branched (C
1
-C
6
)alkyl (optionally substituted by a hydroxy group, a carboxy group, an amino group (itself optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups) or 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, linear or branched (C
1
-C
6
)trihaloalkyl, linear or branched (C
1
-C
6
)trihaloalkoxy, amino (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups), linear or branched (C
1
-C
6
)alkylcarbonyloxy, carboxymethoxy and carbamoylmethoxy (optionally N-substituted by one or two linear or branched (C
1
-C
6
)alkyl groups).
A heteroaryl group is to be understood as meaning an aromatic mono- or bi-cyclic group having from 5 to 12 ring members containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, wherein the heteroaryl may optionally be substituted by one or more identical or different groups selected from halogen, linear or branched (C
1
-C
6
)alkyl (optionally substituted by a hydroxy group, a carboxy group, an amino group (itself optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups) or 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, linear or branched (C
1
-C
6
)trihaloalkyl, 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). Of the heteroaryl groups, the following may be mentioned without implying any limitation: thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl.
A cycloalkyl group is to be understood as meaning a saturated or unsaturated, mono- or bi-cyclic hydrocarbon group having from 3 to 12 ring members, wherein the ring may optionally be substituted by one or more identical or different groups selected from halogen, linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, hydroxy, linear or branched (C
1
-C
6
)trihaloalkyl, amino (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups) and aryl.
Of the cycloalkyl groups, the following may be mentioned without implying any limitation: cyclopentyl, cyclohexyl, indanyl, tetrahydronaphthyl.
A heterocycloalkyl group is to be understood as meaning a saturated or unsaturated, mono- or bi-cyclic group having from 4 to 12 ring members containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, wherein the heterocycle may optionally be substituted by one or more identical or different groups selected from halogen, linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, hydroxy, linear or branched (C
1
-C
6
)trihaloalkyl, amino (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups), aryl and diarylmethyl. Of the heterocycloalkyl groups, the following groups may

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