Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-14
2003-04-08
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S374000, C514S378000, C514S385000, C514S403000, C548S215000, C548S240000, C548S300100, C548S356100, C548S569000
Reexamination Certificate
active
06545037
ABSTRACT:
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.
The compounds of the present invention have a novel structure giving them a TXA
2
receptor antagonist and 5HT
2
serotonergic receptor antagonist character.
BACKGROUND OF THE INVENTION
Platelet aggregation and vasospasms play an essential role in the etiology and development of atherothrombotic cardiovascular disorders. 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 via 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 contractions and its activity is found to be increased in atherothrombotic disorders.
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 disorders, such as myocardial infarction, angina pectoris, cerebral vascular accidents, Raynaud's disease, and also asthma and bronchospasms, as well as migraine and venous disorders.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the compounds of formula (I):
wherein:
n is an integer of from 1 to 3 inclusive,
m is an integer of from 0 to 6 inclusive,
R
a
represents a hydroxy, linear or branched (C
1
-C
6
)alkoxy, aryloxy or arylalkyloxy group,
R
1
and R
2
represent independently a hydrogen atom, a halogen atom, an alkyl group, a linear or branched (C
1
-C
6
)alkoxy group, a hydroxy group or a linear or branched (C
1
-C
6
)perhaloalkyl group,
R
3
represents a hydrogen atom or an alkyl, arylalkyl, cycloalkylalkyl, aryl or cycloalkyl group,
T
1
represents an alkylene, O-alkylene, alkylene—O—or (C
1
-C
3
)alkylene-O-(C
1
-C
3
)-alkylene group,
G represents a G
1
- or G
1
-T
2
-A- group wherein:
A represents an aryl group,
T
2
represents a bond or an alkylene, —O-alkylene, alkylene-O- or (C
1
-C
3
)alkylene-O —(C
1
-C
3
)alkylene group,
G
1
represents a —NR
4
R
5
group wherein R
4
and R
5
represent independently a hydrogen atom, or an alkyl, cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, cycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group,
or G
1
represents a heterocycloalkyl group of formula
having from
5 to 7 ring members, wherein Y represents a nitrogen atom, an oxygen atom or a CH or CH
2
group and R
6
represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylcarbonyl, optionally substituted arylcarbonylalkyl, optionally substituted diarylalkyl, optionally substituted diarylalkenyl, optionally substituted (aryl)(hydroxy)alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylcarbonyl or optionally substituted heteroarylcarbonylalkyl group,
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 “alkenyl” denotes a chain having from 2 to 6 carbon atoms and containing from 1 to 3 double bonds,
the term “alkylene” denotes a linear or branched divalent group containing from 1 to 6 carbon atoms, unless specified otherwise,
the term “cycloalkyl” denotes a saturated cyclic group containing from 3 to 8 carbon atoms,
the term “aryl” denotes a phenyl or naphthyl group,
the term “heteroaryl” denotes a mono- or bi-cyclic group having from 4 to 11 ring members that is unsaturated or partially saturated and contains from 1 to 5 hetero atoms selected from nitrogen, oxygen and sulphur,
the terms “diarylalkyl” and “diarylalkenyl” denote, respectively, alkyl and alkenyl groups as defined hereinbefore, substituted by two identical or different aryl groups as defined hereinbefore,
the term “substituted” relating to aryl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, diarylalkyl, diarylalkenyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl and heteroarylcarbonylalkyl denotes that the groups in question are substituted in the aromatic moiety by one or more halogen atoms, alkyl groups, linear or branched (C
1
-C
6
)alkoxy groups, hydroxy groups, cyano groups, nitro groups or amino groups (optionally substituted by one or two alkyl groups), wherein the heteroaryl and heteroarylalkyl groups may also be substituted by an oxo group.
Amongst the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic, camphoric acid, etc . . .
Amongst the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc . . .
Preferred compounds of the invention are those wherein n is 2.
Other preferred compounds of the invention are those wherein m is 2.
An advantageous embodiment of the invention relates to compounds of formula (I) wherein R
3
represents a hydrogen atom.
Another advantageous embodiment of the invention relates to compounds of formula (I) wherein R
a
represents a hydroxy group.
In the compounds of formula (I), G
1
preferably represents a heterocycloalkyl group of formula
There may be mentioned, for example, without implying any limitation, the groups piperidine, pyrrole, piperazine . . .
Advantageously, in the groups G
1
, R
6
represents a group selected from alkyl (for example methyl), arylcarbonyl (for example benzoyl), arylcarbonylalkyl (for example benzoyl-methyl), diarylalkenyl (for example bisphenylmethylene), (aryl)(hydroxy)alkyl (for example (phenyl)(hydroxy)methyl), aryl (for example phenyl), and heteroaryl, each of those groups being optionally substituted in their aromatic moiety where such a moiety is present. Advantageously, the substituent chosen will be a halogen atom or an alkoxy group.
Amongst the preferred heteroaryl groups there may be mentioned more especially the groups 1,2-benzisoxazole, 1,2-benzisothiazole, . . .
An especially advantageous embodiment of the invention relates to compounds of formula (I) wherein n and m are each 2, R
a
represents a hydroxy group, R
2
and R
3
each represents a hydrogen atom, R
1
represents a halogen atom, and G
1
represents a heterocycloalkyl group of formula
wherein Y represents a
nitrogen atom or a —CH or CH
2
group, and R
6
is selected from the groups alky, arylcarbonyl, arylcarbonylalkyl, diarylalkenyl, (aryl)(hydroxy)alkyl, aryl and heteroaryl.
Amongst the preferred compounds of the invention there may be mentioned more especially 3-(6-&lc
Cimetiere Bernard
Descombes Jean-Jacques
Lavielle Gilbert
Simonet Serge
Verbeuren Tony
Les Laboratoires Servier
Rao Deepak
Styles C.
The Firm of Hueschen and Sage
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