Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-05
2003-05-27
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S338000
Reexamination Certificate
active
06569858
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new 12,13-(pyranosyl)-indolo[2,3-a]pyrrolo[3,4-c]-carbazole and 12,13-(pyranosyl)-furo[3,4-c]indolo[2,3-a]carbazole compounds, and to pharmaceutical compositions containing them.
Anti-cancer therapeutic requirements call for the constant development of new cytotoxic agents, with the aim of obtaining medicaments that are both more active and better tolerated. The compounds of the present invention have, for example, anti-tumour properties, which makes them useful in the treatment of cancers.
PRIOR ART OF THE INVENTION
Various chemical modifications have been made to the rebeccamycin or staurosporine structure with a view to improving the anti-tumour potential. Mention may be made, for example, of Patent Specifications WO 98/07433, WO 99/02532 and EP 602 597 which claim rebeccamycin compounds comprising structural modifications to the oside moiety of the molecule and to the substituents present in the hexacyclic system. The article published in <<Bioorganic and Medicinal Chemistry 1998, 6, 1597-1604>> also describes such compounds having good cytotoxic activity.
In addition to the fact that the compounds of the invention are new, they have a surprising in vitro and in vivo activity that is superior to that observed hitherto. The compounds discovered by the Applicant accordingly have anti-tumour properties that make them particularly useful in the treatment of cancers.
DETAIL DESCRIPTION OF THE INVENTION
More especially, the present invention relates to compounds of formula (I)
wherein:
R
1
and R
2
which may be identical or different, each independently of the other represents a group of formula U-V wherein:
U represents a single bond or a linear or branched (C
1
-C
6
)alkylene chain, optionally substituted by one or more identical or different groups selected from halogen and hydroxy, and/or optionally containing one or more unsaturated bonds,
V represents a group selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, an azido group, a linear or branched (C
1
-C
6
)alkyl group, an aryl group, an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a hydroxy group, a linear or branched (C
1
-C
6
)alkoxy group, an aryloxy group, an aryl-(C
1
-C
6
)alkoxy group in which the alkoxy moiety is linear or branched, a formyl group, a carboxy group, an aminocarbonyl group, an NRaRb, —C(O)—T
1
, —C(O)—NRa—T
1
, —NRa—C(O)—T
1
, —O—C(O)—T
1
, —C(O)—O—T
1
, —O—T
2
—NRaRb, —O—T
2
—ORa, —O—T
2
—CO
2
Ra, —NRa—T
2
—NRaRb, —NRa—T
2
—ORa, —NRa—T
2
—CO
2
Ra and an —S(O)
n
—Ra group, wherein:
Ra and Rb, which may be identical or different, each represents a group selected from a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, an aryl group and an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, or
Ra+Rb form together with the nitrogen atom carrying them a monocyclic heterocycle having from 5 to 7 ring members, optionally containing within the ring system a second hetero atom selected from oxygen and nitrogen, and optionally being substituted by a group selected from linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, amino, linear or branched (C
1
-C
6
)alkylamino and di-(C
1
-C
6
)alkylamino in which each alkyl moiety is linear or branched,
T
1
represents a group 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 a linear or branched (C
1
-C
6
)alkylene chain substituted by a group selected from —ORa, —NRaRb, —CO
2
Ra, —C(O)Ra and —C(O)NRaRb wherein Ra and Rb are as defined hereinbefore,
T
2
represents a linear or branched (C
1
-C
6
)alkylene chain,
n represents an integer from 0 to 2 inclusive,
G represents an oxygen atom or an NR
3
group wherein R
3
represents a group selected from a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, an aryl group, an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a cycloalkyl group, a cycloalkyl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, an —ORa group, an —NRaRb group, an —O—T
2
—NRaRb group, an —NRa—T
2
—NRaRb group, a (C
1
-C
6
)hydroxyalkylamino group in which the alkyl moiety is linear or branched, a di((C
1
-C
6
)hydroxyalkyl)amino group in which each alkyl moiety is linear or branched, a —C(O)—Ra group, an —NH—C(O)—Ra group and a linear or branched (C
1
-C
6
)alkylene chain substituted by one or more identical or different groups selected from halogen atoms and the groups cyano, nitro, —ORa, —NRaRb, —CO
2
Ra, —C(O)Ra, (C
1
-C
6
)hydroxyalkylamino in which the alkyl moiety is linear or branched, di((C
1
-C
6
)hydroxyalkyl)amino in which each alkyl moiety is linear or branched, and —C(O)—NHRa, the groups Ra, Rb and T
2
being as defined hereinbefore,
X represents a group selected from a hydrogen atom, a hydroxy group, a linear or branched (C
1
-C
6
)alkoxy group, a mercapto group and a linear or branched (C
1
-C
6
)alkylthio group,
Y represents a hydrogen atom, or
X and Y together with the carbon atom carrying them form a carbonyl group,
X
1
represents a group selected from a hydrogen atom, a hydroxy group, a linear or branched (C
1
-C
6
)alkoxy group, a mercapto group and a linear or branched (C
1
-C
6
)alkylthio group.
Y
1
represents a hydrogen atom, or
X
1
and Y
1
together with the carbon atom carrying them form a carbonyl group,
R
4
and R
5
, which may be identical or different, each independently of the other represents a group selected from a hydrogen atom, a halogen atom, a hydroxy group, a linear or branched (C
1
-C
6
)alkoxy group, an aryloxy group, an aryl-(C
1
-C
6
)alkoxy group in which the alkoxy moiety is linear or branched, a linear or branched (C
1
-C
6
)alkyl group, an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, an aryl group, an amino group (itself being optionally substituted by one or two identical or different groups 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), an azido group, an —N═NRa group (wherein Ra is as defined hereinbefore), and an —O—C(O)—Rc group wherein Rc represents a linear or branched (C
1
-C
6
)alkyl group (optionally substituted by one or more groups selected from halogen, hydroxy, amino, linear or branched (C
1
-C
6
)alkylamino and di-(C
1
-C
6
)alkylamino in which each alkyl moiety is linear or branched), an aryl group, an aryl-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched, a cycloalkyl group and a heterocycloalkyl group.
R
6
represents a group of formula —U
1
-R
4
wherein U
1
represents a single bond or a methylene group, and R
4
is as defined hereinbefore,
or R
4
, R
5
and R
6
taken in pairs in adjacent or non-adjacent positions form with the carbon atoms carrying them a ring system having from 3 to 6 ring members, containing one or two oxygen atoms, with the remaining group R
4
, R
5
or R
6
that does not belong to the ring system having any one of the definitions of R
4
, R
5
or R
6
given hereinbefore,
their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base,
provided that the compounds of formula (I) are other than the following compounds:
1,11-dichloro-12,13-[1,2-(4—O-methyl-&bgr;-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione,
12,13-[1,2-(4—O-methyl-&bgr;-D-mannopyranosyl)-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]-pyrrolo[3,4-c]carbazole-5,7-dione,
12,13-[1,2-(4—O-methyl-&bgr;-D-mannopyranosyl)-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]-pyrrolo[3,4-c]carbazol-5-one, and
12,13-[1,2-(4—O-methyl-&bgr;-D-mannopyranosyl)-5,6,12,13-tetrahydro-(7H)-indolo[2,3-a]pyrrolo[3,4-c]-carbazol-7-one,
it also being understood that:
“cycloalkyl” is understood to mean a monocyclic or bicyclic group that is saturated
Anizon Fabrice
Atassi Ghanem
Marminon Christelle
Moreau Pascale
Pfeiffer Bruno
Ford John M.
Les Laboratoires Servier
The Firm of Hueschen and Sage
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