Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-02
2001-09-11
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S412000, C514S414000, C546S112000, C548S452000, C548S465000
Reexamination Certificate
active
06288077
ABSTRACT:
The present invention relates to new 2,3-methano-amino acid compounds.
BACKGROUND OF THE INVENTION
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 already 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 effectiveness and selectivity of the compounds already described in the literature has therefore been of particular interest.
In addition, the new compounds increase various coagulation times and are active when administered by the oral route.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to compounds of formula (I):
wherein:
n represents 2 or 3,
R
1
represents a (C
3
-C
8
)cycloalkyl group, an optionally substituted phenyl group or a linear or branched (C
1
-C
6
)alkyl group optionally substituted by one or more identical or different groups selected from halogen, (C
3
-C
8
)cycloalkyl and optionally substituted phenyl,
R
2
represents
an amino group,
an amidino group optionally substituted by one or more identical or different groups selected from linear or branched (C
1
-C
6
)alkyl and hydroxy,
a guanidino group optionally substituted by a linear or branched (C
1
-C
6
)alkyl group, or
an isothioureido group optionally substituted by a linear or branched (C
1
-C
6
)alkyl group,
Ar represents an aryl group or a monocyclic nitrogen-containing heteroaryl group,
X
1
represents a hydroxy group , an amino group or an —NHR
3
group,
R
3
represents a propargyl group, an iminomethyl group, a linear or branched (C
1
-C
6
)alkylsulphonyl group, a linear or branched aryl(C
1
-C
6
)alkylsulphonyl group, a —CONR′
3
R″
3
group or a linear or branched (C
1
-C
6
)alkyl group optionally substituted by:
a —CO
2
R′
3
group,
a —CONR′
3
R″
3
group,
a heterocyclic group,
an aminosulphonyl group,
an aryl group, or
a heteroaryl group,
R′
3
and R″
3
, which may be identical or different, each represents a hydrogen atom, or a linear or branched (C
1
-C
6
)alkylsulphonyl group, an aryl group, a linear or branched (C
1
-C
6
)alkyl group (optionally substituted by a carboxy group, a linear or branched (C
1
-C
6
)alkoxycarbonyl group or a carbamoyl
group) or form, with the nitrogen atom carrying them, a heterocyclic group, to their isomers, and also to addition salts thereof with a pharmaceutically acceptable acid or 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 optionally substituted phenyl group is to be understood as being substituted by one or more identical of 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 trihalo-(C
1
-C
6
)alkyl and amino (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups).
A heterocyclic group is to be understood as meaning a saturated or unsaturated, 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, it being understood that the heterocycle may be optionally 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, oxo, hydroxy, linear or branched trihalo-(C
1
-C
6
)alkyl groups and amino (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups). Preferred heterocyclic groups are the groups morpholinyl, piperazinyl, piperidyl, dihydrotriazolyl and imidazolinyl.
An aryl group is to be understood as meaning phenyl, biphenylyl or naphthyl, each of those groups being optionally 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 trihalo-(C
1
-C
6
)alkyl, amino (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups) and carboxy.
A heteroaryl group is to be understood as meaning an aromatic mono- or bicyclic group having from 5 to 12 ring members containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that heteroaryl may be optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, trihalomethyl and amino (optionally substituted by one or more 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, pyrazolyl and quinolyl. Preferred heteroaryl groups are optionally substituted pyridyl and optionally substituted quinolyl groups.
The preferred relative configuration of the 2,3-methano-amino acid group of the compounds of formula (I) is cis ((2R,3S) or (2S,3R)). The preferred absolute configuration of the 2,3-methano-amino acid group of the compounds of formula (1) is (2S,3R).
Preferred R
1
groups of formula (I) are cycloalkyl and optionally substituted alkyl groups.
Preferred R
2
groups of formula (I) are amino and amidino groups.
The term “aryl” in relation to the group Ar as defined for formula (I) is preferably an optionally substituted phenyl group.
The term “monocyclic nitrogen-containing heteroaryl” in relation to the group Ar as defined for fornula (y) is preferably an optionally substituted pyridyl group.
Preferred X
1
groups of formula (I) are amino and —NHR
3
groups, wherein R
3
represents a linear or branched aryl(C
1
-C
6
)alkylsulphonyl group or an optionally substituted, linear or branched (C
1
-C
6
)alkyl group.
The invention relates also to a process for the preparation of compounds of formula (I) which is characterized in that a compound of formula (II):
wherein n is as defined for formula (I) and Bn represents a benzyl group, is reacted with
a compound of formula (III):
wherein R
1
is as defined for formula (I), X
2
represents an oxygen atom or —NH—, and P
1
represents an amino function-protecting or hydroxy function-protecting group, in the presence of a peptide coupling agent,
to yield a compound of formula (IV):
wherein n, R
1
, X
2
, Bn and P
1
are as defined hereinbefore, which compound of formula (IV) is then converted, by catalytic hydrogenation or by hydrolysis, into a compound of formula (V):
wherein n, R
1
, X
2
and P
1
are as defined hereinbefore,
which compound of formula (V) is then reacted with a compound of formula (VI):
wherein A
De Nanteuil Guillaume
Gloanec Philippe
Rupin Alain
Verbeuren Tony
Adir et Compagnie
Chang Ceila
Sage G. Patrick
The Firm of Hueschen and Sage
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