Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-12
2003-07-08
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S254090, C514S321000, C514S323000, C544S368000, C544S373000, C546S198000, C546S201000
Reexamination Certificate
active
06589956
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention relates to new benzenesulphonamide compounds, and to pharmaceutical compositions containing them.
The compounds of the present invention have a novel structure giving them a TXA
2
receptor antagonist and 5HT
2
serotoninergic receptor antagonist character.
1. Description of the Prior Art
Compounds having a benzenesulphonamide chain have been described in Application EP 864 561 in relation to their NO-yielding character and their thromboxane A
2
(TXA
2
) receptor antagonist character, as well as in Application EP 648 741 solely in relation to their TXA
2
receptor antagonist properties or WO 95 06046 as antagonists of receptors of TXA
2
and precursors thereof, prostaglandin H
2
(PGH
2
).
2. Background of the Invention
Platelet aggregation and vasospasms play an essential role in the aetiology and development of atherothrombotic cardiovascular diseases. TXA
2
, an arachidonic acid metabolite, and serotonin (5HT), a neurotransmitter, are both powerful vasoconstrictor agents, and are able to induce or reinforce platelet activation, resulting in the aggregation thereof. The vasoconstrictor and pro-aggregation actions of TXA
2
are effected through the intermediary of membrane receptors called TP receptors (Medicinal Research Reviews, 1991, 11, 5, p. 503) while those of serotonin are effected through the intermediary of 5HT
1
or 5HT
2
receptors (T.I.P.S., 1991, 121, p. 223). Research strategies pursued with the aim of finding agents that block the production and/or activation of TXA
2
have led to the development of selective TP receptor antagonists, of TXA
2
-synthase inhibitors, or of mixed agents that exhibit both properties (Medicinal Research Reviews, ibid., T.I.P.S., 1991, 121, 158). Like TXA
2
, serotonin acts by stimulating platelets and vascular constriction and its activity is found to be increased in atherothrombotic diseases.
The idea of compounds that oppose both the process that causes thromboxane to become active and the process that causes serotonin to become active is extremely useful for the clinician. Such products have the advantage of offering more complete protection both against the activation of platelets and against vasospasms. It will thus be possible for such products to be used in the treatment of pathologies associated with increased activity of TXA
2
and 5-HT especially in the treatment of atherothrombotic cardiovascular diseases, such as myocardial infarction, angina pectoris, cerebral vascular accidents, Raynaud's disease, and also asthma and bronchospasms, as well as migraine and venous diseases.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula (I):
wherein:
R
a
represents a hydroxy, alkoxy, optionally substituted aryloxy or optionally substituted arylalkyloxy, amino, alkylamino, dialkylamino, optionally substituted arylamino or optionally substituted arylalkylamino group,
A represents:
either a CH group, in which case R
1
represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted arylcarbonyl, optionally substituted arylcarbonylalkyl, optionally substituted aryloxy, optionally substituted aryloxyalkyl, optionally substituted arylthio, optionally substituted arylthioalkyl, optionally substituted arylamino, optionally substituted arylalkylamino, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylcarbonylalkyl, optionally substituted heteroaryloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylthio, optionally substituted heteroarylthioalkyl, optionally substituted heteroarylamino or optionally substituted heteroarylalkylamino group,
or a nitrogen atom, in which case R
1
represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted arylcarbonyl, optionally substituted arylcarbonylalkyl, optionally substituted arylsulphonyl, optionally substituted aryloxyalkyl, optionally substituted arylthioalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylcarbonyl, optionally substituted heteroarylcarbonylalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylsulphonyl or optionally substituted heteroarylthioalkyl group,
or R
1
—A together represent an oxygen atom or a group
wherein R
3
and R
4
, which may be identical or different, each represents a hydrogen atom, an optionally substituted aryl group, an alkyl group or an optionally substituted heteroaryl group,
R
2
being a hydrogen atom or an alkyl group,
R
b
and R
c
, which may be identical or different, each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a hydroxy group or a trihaloalkyl group,
n is an integer of from 2 to 6 inclusive,
m and p are identical or different integers of from 0 to 6 inclusive,
to their enantiomers and diastereoisomers, and also to addition salts thereof with a pharmaceutically acceptable acid or base,
wherein:
the term “alkyl” denotes a linear or branched chain having from 1 to 6 carbon atoms,
the term “alkoxy” denotes a linear or branched alkyl-oxy group having from 1 to 6 carbon atoms,
the term “trihaloalkyl” denotes a carbon chain having from 1 to 3 carbon atoms and from 1 to 3 identical or different halogen atoms,
the term “cycloalkyl” denotes a saturated cyclic group having from 3 to 8 carbon atoms,
the term “aryl” denotes a phenyl or naphthyl group,
the term “heteroaryl” denotes an aromatic monocyclic group, or a bicyclic group in which at least one of the rings is aromatic, having from 5 to 11 ring members and from 1 to 5 hetero atoms selected from nitrogen, oxygen and sulphur,
the term “substituted” relating to aryl, arylcarbonyl, arylcarbonylalkyl, aryloxy, aryloxyalkyl, arylthio, arylthioalkyl, arylamino, arylalkylamino, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heteroaryloxy, heteroaryloxyalkyl, heteroarylthio, heteroarylthioalkyl, heteroarylamino, and heteroarylalkylamino, arylsulphonyl, arylsulphonylalkyl, heteroarylsulphonyl and heteroarylsulphonylalkyl, denotes that the groups in question are substituted in the aromatic moiety by one or two identical or different substituents selected from halogen atoms and alkyl groups, alkoxy groups, hydroxy groups, cyano groups, nitro groups, amino groups (optionally substituted by one or two alkyl groups) and groups C(O)R
d
, R
d
representing a group selected from hydroxy, alkoxy and amino, wherein the heteroaryl and heteroarylalkyl groups may also be substituted by an oxo group in the non-aromatic moiety of the heteroaryl.
Preferred compounds of the invention are those wherein, taken together or separately, the value of the substituent m is 2, the value of n is 2, the value of p is 2, the substituent R
a
represents a hydroxy group and the substituent R
2
represents a hydrogen atom or a methyl group.
An especially advantageous embodiment of the invention relates to compounds of formula (I) wherein m, n and p are each 2, R
a
represents a hydroxy group, R
2
represents a hydrogen atom or a methyl group, R
b
represents a halogen atom, R
c
represents a hydrogen atom, and A represents a nitrogen atom in which case R
1
represents a hydrogen atom or an alkyl, cycloalkyl, optionally substituted aryl, optionally substituted arylcarbonyl or optionally substituted heteroaryl group, or A represents a CH group in which case R
1
represents a hydrogen atom or an alkyl, cycloalkyl, optionally substituted aryl, optionally substituted arylcarbonyl or optionally substituted heteroaryl group, or R
1
—A together represent an oxygen atom or a group R
3
R
4
C═C wherein R
3
and R
4
represent an optionally substituted aryl group.
More especially, preferred compounds of formula (I) are those wherein m, n and p are each 2, R
a
represents a hydroxy group, R
2
represents a hydrogen atom or a methyl group, R
b
represents a halogen at
Cimetiere Bernard
Lavielle Gilbert
Simonet Serge
Vayssettes-Courchay Christine
Verbeuren Tony
Les Laboratoires Servier
The Firm of Hueschen and Sage
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