Benzothiophene, benzofuran and indole compounds

Details Benzothiophene, benzofuran and indole compounds Benzothiophene, benzofuran and indole compounds

2000-10-13

2001-10-16

Huang, Evelyn Mei (Department: 1625)

Textiles: spinning, twisting, and twining

57, 57, 57, 57, 57, 57, C546S174000, C546S256000, C546S275100, C546S281100, C546S277700, C546S284100, C549S054000, C549S406000, C548S483000, C548S484000

Reexamination Certificate

active

06302837

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new benzothiophene, benzofuran and indole compounds, and to pharmaceutical compositions containing them. These new compounds are useful for their therapeutic activity in the field of fibrinolysis and thrombosis, by virtue of their property of inhibiting the activity of PAI-1.
PAI-1 is a powerful inhibitor of plasminogen activators (tissue plasminogen activator and urokinase). In vitro and in vivo, it causes inhibition of the breakdown of the fibrinous clots, formed by the action of thrombin on fibrinogen. A number of epidemiological studies have shown that, in man, high levels of PAI-1 are associated with more frequent occurrence of thromboembolic disorders. Moreover, in experimental models of thrombosis and thrombolysis, inhibition of the activity of PAI-1 by anti-PAI-1 monoclonal antibodies reduces the incidence of thromboses or reocclusions. The therapeutic value of molecules having the property of inhibiting the activity of PAI-1 in the fibrinous clot that has been formed or that is in the process of being formed is thus to enable it to be broken down at an early stage before it is complexed with Factor XIIIa and thus to reduce the incidence of thromboembolic accidents in patients having high levels of PAI-1. Such compounds are therapeutically valuable in all pathologies for which the origin is thrombosis (such as myocardial infarction, angina, intermittent claudication, cerebral vascular accidents, deep vein thrombosis, or pulmonary embolism) and in pathologies in which thrombotic risks are increased (such as hypertension, hypercholesterolaemia, diabetes, obesity, genetic coagulation anomalies (Factor V Leiden, deficit in proteins C and S) or acquired coagulation anomalies).
The compounds of the present invention, in addition to being new, have proved to be more powerful PAI-1 inhibitors than those described in the literature, which thus makes them potentially useful in the treatment of thrombosis, pathologies the origin of which is thrombosis and pathologies causing an increase in thrombotic risks.
PRIOR ART OF THE INVENTION
A number of antithrombotics have been described in the literature. This is the case, more, especially, of the compounds described in Patent Specifications WO 97/45424, WO 94/08962, EP 540 051 and GB 2225012.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to compounds of formula (I):
wherein:
X represents an oxygen atom, a sulphur atom, or an NR
3
group wherein R
3
represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, a linear or branched (C
1
-C
6
)acyl group, an aryl group, an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, or a heteroaryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched,
Y represents an oxygen atom, a sulphur atom or an NR
3
group, the R
3
group being as defined above, or may represent a single bond when X represents an NR′
3
group wherein R′
3
represents a heteroaryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched,
T represents a nitrogen atom when the bond that links it to the adjacent carbon atom is single (—), or a carbon atom or a CH group depending on whether the bond that links it to the adjacent carbon atom is single (—) or double (
),
A represents a single bond or a group selected from (C
1
-C
6
)alkylene (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups, aryl groups, aryl-(C
1
-C
6
)alkyl groups in which the alkyl moiety is linear or branched, cycloalkyl groups, heterocycloalkyl groups or heteroaryl groups), arylene, cycloalkylene, heterocycloalkylene, heteroarylene and an —SO
2
—R
4
— group (the SO
2
moiety being linked to T) wherein R
4
represents a group selected from linear or branched (C
1
-C
6
)alkylene, arylene, aryl-(C
1
-C
6
)alkylene in which the alkylene moiety is linear or branched, cycloalkylene, heterocycloalkylene and heteroarylene,
W represents a group selected from hydroxy, linear or branched (C
1
-C
6
)alkoxy, aryloxy, aryl-(C
1
-C
6
)alkoxy in which the alkoxy moiety is linear or branched, cycloalkyloxy, heterocycloalkyloxy, heteroaryloxy, amino (which may itself be substituted by one or two identical or different groups each independently of the other selected from linear or branched (C
1
-C
6
)alkyl, aryl, aryl-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched, and cycloalkyl) and hydroxyamino,
U
1
represents an oxygen atom, a sulphur atom or a linear or branched (C
1
-C
6
)alkylene chain wherein one or more of the carbon atoms may optionally be replaced by one or more hetero atoms selected from oxygen, nitrogen and sulphur, the said alkylene chain being optionally substituted by one or more identical or different groups selected from halogen, hydroxy, linear or branched (C
1
-C
6
)alkyl and linear or branched (C
1
-C
6
)alkoxy,
V
1
represents an arylene, heteroarylene or heterocycloalkylene group,
U
2
represents a single bond, an oxygen, nitrogen or sulphur atom or a linear or branched (C
1
-C
6
)alkylene chain wherein one or more carbon atoms may optionally be replaced by one or more identical or different groups selected from oxygen, sulphur and nitrogen atoms (a nitrogen atom being substituted by a group selected from hydrogen and linear or branched (C
1
-C
6
)alkyl) and an SO
2
group,
V
2
represents an aryl, heteroaryl or heterocycloalkyl group,
Ra, Rb and Rc, which may be identical or different, each independently of the others represents a group selected from:
hydrogen, halogen,
hydroxy, cyano, nitro,
linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)acyl, carboxy, linear or branched (C
1
-C
6
)alkoxycarbonyl, linear or branched (C
1
-C
6
)trihaloalkyl,
amino (optionally substituted by one or two groups, which may be identical or different, each independently of the other selected from linear or branched (C
1
-C
6
)alkyl, aryl and aryl-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched),
aryloxy, aryl-(C
1
-C
6
)alkoxy in which the alkoxy moiety is linear or branched, heteroaryloxy, heteroaryl-(C
1
-C
6
)alkoxy in which the alkoxy moiety is linear or branched,
and a group of formula —U
1
—V
1
—U
2
—V
2
wherein U
1
, U
2
, V
1
and V
2
are as defined hereinbefore,
or two of them together form a methylenedioxy or ethylenedioxy group (each of those groups being optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups, aryl groups or aryl-(C
1
-C
6
)alkyl groups in which the alkyl moiety is linear or branched),
R
1
represents:
an aryl group substituted by from one to five identical or different substituents each independently of the others selected from halogen, hydroxy, cyano, nitro, carboxy, linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)acyl, linear or branched (C
1
-C
6
)alkoxycarbonyl, linear or branched (C
1
-C
6
)trihaloalkyl (optionally substituted by a hydroxy group), linear or branched (C
1
-C
6
)trihaloalkoxy, amino (optionally substituted by one or two linear or branched (C
1
-C
6
)alkyl groups, one of which alkyl groups may be optionally substituted by a group selected from amino, linear or branched (C
1
-C
6
)alkylamino and di-(C
1
-C
6
)alkylamino in which the alkyl moieties are each linear or branched), amino-(C
1
-C
6
)alkoxy (in which the alkoxy moiety is linear or branched and the amino moiety is optionally substituted by one or two, identical or different, linear or branched (C
1
-C
6
)alkyl groups), (C
1
-C
6
)alkoxycarbonyl(C
1
-C
6
)alkyl in which the alkoxy and alkyl moieties are each linear or branched, linear or branched (C
1
-C
6
)-alkylcarbonylamino, aryl-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched, aryloxy, aryl-(C
1
-C
6
)alkoxy in which the alkoxy moiety is linear or branched, arylamino, aryl-(C
1
-C
6
)alkylamino in which the alkyl moiety is linear or branched, arylsulphanyl, aryl-(C
1
-C
6
)alkylsulphanyl in which the alkyl moiety is lin

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