Benzo[b]pyrano[3,2-h]acridin-7-one...

Details Benzo[b]pyrano[3,2-h]acridin-7-one... Benzo[b]pyrano[3,2-h]acridin-7-one...

2002-07-25

2003-11-04

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S279000, C514S232800, C514S211090, C514S230800, C546S041000, C546S047000, C544S125000

Reexamination Certificate

active

06642248

ABSTRACT:

The present invention relates to new benzo[b]pyrano[3,2-h]acridin-7-one compounds.
FIELD OF THE INVENTION
The compounds of the invention are derivatives of acronycine, an alkaloid which has anti-tumour properties that have been demonstrated in experimental models (
J. Pharm. Sci.,
1966, 55 (8), 758-768). However, despite having quite a broad spectrum of activity, acronycine is of low potency and moderate activity. The solubility of the compound is, moreover, low, which limits its bioavailability, as well as its use in pharmaceutical compositions for administration by the intravenous route.
Various modifications have been made to the molecule, for example those described in
J. Med. Chem.,
1996, 39, 4762-4766 or EP 1 042 326, allowing a significant improvement in the potency, anti-tumour efficacy and solubility of the products. Nevertheless, anti-cancer therapeutic requirements call for the constant development of new anti-tumour agents with the aim of obtaining medicaments that are simultaneously more active and better tolerated. More specifically, solid tumours constitute a major problem for anti-cancer chemotherapy because of their intrinsic and/or acquired resistance to existing compounds. Moreover, certain compounds which are shown to be highly active with respect to certain cell lines are found to be inactive with respect to other cell lines or indeed toxic. It is therefore of prime importance to have access to the widest range of compounds exhibiting powerful cytotoxic activity in order to have available the most effective treatments for the totality of tumour disorders, together with limited secondary effects and the longest desirable action over time.
Besides the fact that the compounds of the invention are new, they have surprising in vitro and in vivo activity which is greater than that observed hitherto. The compounds discovered by the Applicant accordingly have anti-tumour properties that make them especially useful in the treatment of cancers and, especially, of solid tumours.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to compounds of formula (I):
wherein:
X and Y, which may be the same or different, represent, independently of one another, a group selected from:
hydrogen and halogen atoms,
mercapto, cyano, nitro, linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)-trihaloalkyl and linear or branched trihalo-(C
1
-C
6
)alkyl-carbonylamino groups,
groups of formulae —ORa, —NRaRb, —NRa—C(O)-T
1
, —O—C(O)-T
1
, —O-T
2
-NRaRb, —O-T
2
-ORa, —NRa-T
2
-NRaRb, —NRa-T
2
-ORa and —NRa-T
2
-CO
2
Ra wherein:
Ra represents a group selected from a hydrogen atom and a linear or branched (C
1
-C
6
)alkyl group, an aryl group and an aryl-(C
1
-C
6
)alkyl group wherein the alkyl moiety is linear or branched,
Rb represents a group selected from a hydrogen atom and a linear or branched (C
1
-C
6
)alkyl group, an aryl group and an aryl-(C
1
-C
6
)alkyl group wherein the alkyl moiety is linear or branched, or
 Ra+Rb, together with the nitrogen atom carrying them, form a monocyclic 5- or 6-membered heterocycle optionally containing in the cyclic system a second hetero atom selected from oxygen and nitrogen,
T
1
represents a group selected from linear or branched (C
1
-C
6
)alkyl, linear or branched (C
2
-C
6
)alkenyl, aryl, aryl-(C
1
-C
6
)alkyl (wherein 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 and —NRaRb wherein Ra and Rb are as defined hereinbefore,
T
2
represents a linear or branched (C
1
-C
6
)alkylene chain,
or X and Y, when they are in adjacent positions, together form a methylenedioxy group or an ethylenedioxy group,
it being understood that the substituents X and Y may be present on either of the two adjacent benzene rings,
R
1
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
R
2
represents a group selected from a hydrogen atom and linear or branched (C
1
-C
6
)alkyl, —ORa, —NRaRb, —NRa—C(O)-T
1
, —O—C(O)-T
1
, —O-T
2
-NRaRb, —O-T
2
-ORa, —NRa-T
2
-NRaRb, —NRa-T
2
-ORa and —NRa-T
2
-CO
2
Ra groups, wherein Ra, Rb, T
1
and T
2
are as defined hereinbefore,
R
3
, R
4
, which may be the same or different, represent, independently of one another, a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
W represents a group of formula —CH(R
5
)—CH(R
6
)—, —CH═C(R
7
)—, —C(R
7
)═CH— or —C(O)—CH(R
d 8
)— wherein:
R
5
and/or R
6
, represent(s) a group selected from —W
1
—C(W
2
)—W
3
-T
1
, —W
4
—C(W
2
)-T′
1
, —W
1
—S(O)
n
—W
3
-T
1
and —W
1
—S(O)
n
—T
1
wherein:
W
1
represents an oxygen or sulphur atom or a nitrogen atom substituted by a hydrogen atom or by a linear or branched (C
1
-C
6
)alkyl group, an aryl group or an aryl-(C
1
-C
6
)alkyl group wherein the alkyl moiety is linear or branched,
W
2
represents an oxygen atom or a sulphur atom,
W
3
represents an oxygen or sulphur atom or a nitrogen atom substituted by a hydrogen atom or by a linear or branched C
1
-C
6
) alkyl group, an aryl group or an aryl-(C
1
-C
6
)alkyl group wherein the alkyl moiety is linear or branched, a bond when T
1
represents a linear or branched (C
2
-C
6
) alkenyl group,
W
4
represents a sulphur atom or a nitrogen atom substituted by a hydrogen atom or by a linear or branched (C
1
-C
6
)alkyl group, an aryl group or an aryl-(C
1
-C
6
)alkyl group wherein the alkyl moiety is linear or branched,
T
1
is as defined hereinbefore,
T′
1
represents a group selected from linear or branched (C
2
-C
6
)alkenyl, aryl, aryl-(C
1
-C
6
)alkyl (wherein the alkyl moiety is linear or branched), a linear or branched (C
1
-C
6
)alkylene chain substituted by a group selected from —ORa and —NRaRb wherein Ra and Rb are as defined hereinbefore,
n represents an integer selected from 1 and 2,
 and in the case where only one of the two groups R
5
and R
6
represents a group as defined hereinbefore then the other of the said groups R
5
or R
6
represents a group selected from a hydrogen atom, hydroxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)alkyl-carbonyloxy, arylcarbonyloxy, aryl-(C
1
-C
6
)alkyl-carbonyloxy (wherein the alkyl moiety is linear or branched), and amino optionally substituted by one or two, identical or different, linear or branched (C
1
-C
6
)alkyl groups,
R
7
represents a group selected from hydroxy, linear or branched (C
1
-C
6
)alkoxy, —C(W
2
)-T
1
, —W
1
—C(W
2
)—W
3
-T
1
, —W
1
—C(W
2
)-T
1
, —W
1
—S(O)
n
—W
3
-T
1
and —W
1
—S(O)
n
—T
1
wherein W
1
, W
2
, W
3
, T
1
and n are as defined hereinbefore, or R
7
may have the additional meaning of a hydrogen atom when R
2
represents a group —O-T
2
-ORa and/or when X represents a hydrogen atom and Y, located in the 13-position of the naphthyl system of the pentacyclic skeleton, represents an amino group optionally substituted by one or two identical or different groups selected independently of one another from linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)acyl and linear or branched trihalo-(C
1
-C
6
)alkyl-carbonyl,
R
8
represents a linear or branched (C
1
-C
6
)alkoxy or linear or branched (C
1
-C
6
)alkyl-carbonyloxy group, or may have the additional meaning of hydroxy when R
2
represents a group —O-T
2
-ORa as defined hereinbefore,
to their enantiomers, diastereoisomers and N-oxides, and to addition salts thereof with a pharmaceutically acceptable acid or base.
Aryl is understood to mean a phenyl or naphthyl group optionally containing one or more, identical or different, substitutents selected from hydroxy, halogen, carboxy, nitro, amino, linear or branched (C
1
-C
6
)alkylamino, di(C
1
-C
6
)alkylamino wherein each alkyl moiety may be linear or branched, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)acyl and linear or branched (C
1
-C
6
)alkyl-carbonyloxy.
Isomers are understood to comprise optical isomers, that is to say enantiomers and diastereoisomers.
Among the pharmaceutically acceptable acids there may be mentioned, with

Affiliated with

Also associated with

Rating

Benzo[b]pyrano[3,2-h]acridin-7-one... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Benzo[b]pyrano[3,2-h]acridin-7-one..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzo[b]pyrano[3,2-h]acridin-7-one... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3129178