Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-30
2001-11-27
Trinh, Ba K. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S309000, C514S320000, C514S323000, C546S148000, C546S200000, C546S201000, C546S205000, C546S214000, C546S216000
Reexamination Certificate
active
06323217
ABSTRACT:
BACKGROUND OF THE INVENTION
The compounds of the present invention are useful in the treatment of diseases or pathological conditions in which endothelial dysfunction is known to be a pathogenic and/or aggravating mechanism. Such pathologies are : atherosclerosis, the existence of vascular risk factors (dyslipidaemia, diabetes, systemic arterial hypertension), the various clinical forms of myocardial or peripheral ischaemia, cardiac insufficiency and the various forms of pulmonary arterial hypertension. Such compounds are also useful in the treatment of patients undergoing heart transplantation or vascular repermeabilisation such as a bypass, thrombolysis or arterial dilatation with or without a stent.
A reduction in the vascular availability of nitrogen monoxide (NO) constitutes the major mechanism of endothelial dysfunction observed in the diseases and pathological conditions mentioned above and explains its pathogenic role (
Cardiovasc. Res
., 1999, 43, 572
; Coronary. Art. Dis
. 1999, 10, 277
; Coronary. Art. Dis
., 1999, 10, 301
; Coronary. Art. Dis
., 1999, 10, 287
; Coronary. Art. Dis
., 1999, 10 295).
In those pathological conditions, the endothelial dysfunction may in fact result from two main mechanisms: 1) inadequate production of NO associated with inhibition of endothelial NO synthase by endogenous inhibitors such as ADMA (asymmetric dimethyl-arginine), the plasma concentration of which increases in patients exhibiting cardiovascular risk factors (
Cardiovasc. Res
., 1999, 43 542
; Hypertension
, 1997, 29, 242
; Circulation
, 1997, 95, 2068), 2) inactivation of NO by the superoxide anion (O
2
−
), the production of which is increased in pathological conditions (
Cardiovasc. Res
., 1999, 43, 562
; Eur. J. Biochem
. 1997, 245, 541
; J. Clin. Invest
., 1993, 91 2546).
Under normal conditions, NO produces major effects such as: 1) regulation of arterial vasomotricity by means of its vasodilator effect (
N Engl. J. Med
., 1993, 329, 2002
; Nature
, 1980, 288, 373), 2) limitation of platelet adhesion and aggregation (Trends
Pharmacol. Sci
, 1991, 12, 87), 3) control of the adhesion of leukocytes and monocytes to endothelial cells (
Proc. Natl Acad Sci. USA
, 1991, 88, 4651), 4) inhibition of the proliferation of vascular smooth muscle cells (
Cardiovasc. Res
., 1999, 43, 580
, Circulation
, 1993, 87 V51), which explains why the deficiency of NO in the arterial wall is favourable to pathological phenomena such as vasoconstriction, thrombosis, lipid accumulation and proliferation of vascular smooth muscle cells.
In vitro experiments have enabled it to be shown that the compounds of the present invention enable limitation of the endothelial dysfunction and of the reduced vascular availability of NO induced by tests involving the two physiopathological mechanisms already mentioned: inhibition of endothelial NO synthase and oxidative stress due to production of O
2
−
.
Thus, in addition to the fact that they are new, by virtue of their specific pharmacological activity, which is capable of limiting the development of endothelial dysfunction, the compounds of the present invention are useful in preventing the development, extension and complications of atherosclerotic lesions, especially in patients exhibiting a vascular risk factor (dyslipidaemia, diabetes, arterial hypertension), and in treating the various clinical forms of myocardial or peripheral ischaemia, cardiac insufficiency and the various forms of pulmonary arterial hypertension. The compounds are also used for preventing vascular complications (spasm, thrombosis, restenosis, accelerated atherosclerosis) in patients undergoing a bypass, vascular dilatation with or without a stent or other forms of vascular repermeabilisation and also heart transplantation.
DESCRIPTION OF THE PRIOR ART
Compounds of similar structure have been described in the literature, that being the case, more especially, for Patent Application WO 94/13659, which claims especially piperidine-benzofurane compounds. Such compounds are useful in the treatment and/or prophylaxis of arrhythmia. They are distinguished clearly from the compounds of the present invention by their chemical structure and especially by the absence of the sulphonamide function, and by their pharmacological properties.
Patent Specification EP 0 526 342 describes new (isoquinolin-5-yl)sulphonamides and claims those compounds for their usefulness in the treatment and prevention of disorders resulting from tissue pain phenomena.
DETAILED DESCRIPTION OF THE INVENTION
More especially, 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,
R
2a
and R
2b
, which may be identical or different, each independently of the other represents a group selected from a hydrogen atom, a halogen atom, a linear or branched (C
1
-C
6
)alkyl group, a hydroxy group, a linear or branched (C
1
-C
6
)alkoxy group, a linear or branched (C
1
-C
6
)trihaloalkyl group, a cyano group, a nitro group, an amino group, a linear or branched (C
1
-C
6
)alkylamino group, and a di-(C
1
-C
6
)-alkylamino group in which each alkyl moiety is linear or branched,
R
3
represents a hydrogen atom or a hydroxy group,
X represents an oxygen atom or a methylene group,
V represents a linear or branched (C
1
-C
6
)alkylene chain optionally containing one or more unsaturations and being optionally substituted by one or more identical or different groups selected from halogen atoms, hydroxy groups and linear or branched (C
1
-C
6
)alkoxy groups,
U represents a bond or a linear or branched (C
1
-C
6
)alkylene chain,
W represents a group selected from aryl and heteroaryl, each of those groups being optionally substituted by one or more identical or different groups selected from halogen atoms, linear or branched (C
1
-C
6
)alkyl groups, hydroxy groups, linear or branched (C
1
-C
6
)alkoxy groups, linear or branched (C
1
-C
6
)trihaloalkyl groups, oxo groups, cyano groups, nitro groups, amino groups, linear or branched (C
1
-C
6
)-alkylamino groups, di-(C
1
-C
6
)alkylamino groups in which each alkyl moiety is linear or branched, pyridyl groups, linear or branched (C
1
-C
6
)alkylcarbonyl groups, aminocarbonyl groups (the amino moiety being optionally substituted by one or two identical or different linear or branched (C
1
C
6
)alkyl groups), linear or branched (C
1
-C
6
)alkoxycarbonyl groups, linear or branched (C
1
-C
6
)trihaloalkylcarbonyl groups, linear or branched (C
1
-C
6
)alkylsulphonyl groups, and linear or branched (C
1
-C
6
)-trihaloalkylsulphonyl groups,
their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid or base,
it being understood that:
“aryl group” is understood to mean a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl and indenyl,
“heteroaryl group” is understood to mean a monocyclic aromatic or bicyclic system having from 5 to 12 ring members and containing from 1 to 3 identical or different hetero atoms selected from oxygen, nitrogen and sulphur, and in the case of a bicyclic system one of the rings has an aromatic character, it being possible for the other ring to be aromatic or partially hydrogenated.
Among the heteroaryl groups there may be mentioned by way of non-limiting example the groups pyridyl, pyrazolyl, isoxazolyl, dihydroisoxazolyl, quinolyl, isoquinolyl, tetrahydroisoquinolyl, benzofurazanyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, 2,1,3-benzoxodiazolyl, 2,1,3-benzothiadiazolyl, thieno[2,3-c]pyridyl, furo[2,3-c] pyridyl, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
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, glutamic ac
Bourguignon Marie-Pierre
Dessinges Aimee
Peglion Jean-Louis
Poitevin Christophe
Thollon Catherine
Adir et Compagnie
Sage G. Patrick
The Firm of Hueschen and Sage
Trinh Ba K.
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