Compounds of...

Details Compounds of... Compounds of...

2000-06-15

2003-01-07

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S211090, C514S230800, C514S232800, C514S279000, C514S280000, C546S041000, C546S047000

Reexamination Certificate

active

06503919

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new compounds of 7-oxo-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin carboxylate and to pharmaceutical compositions containing them.
The compounds of the invention are derivatives of acronycine which is an alkaloid having anti-tumour properties that have been demonstrated in experimental models (
J. Pharm. Sci.
1966, 55 (8), 758-768). Despite a broad spectrum of activity, however, acronycine is sparingly soluble, which limits its bioavailability and its use in pharmaceutical compositions for administration by injection.
Various modifications have been made to this molecule, such as those described in
J. Med. Chem.,
1996, 39, 4762-4766, and have made it possible to resolve some of the difficulties associated with the problem of the solubility of these compounds. Nevertheless, anti-cancer therapy 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. In particular, solid tumours pose a major problem in anti-cancer chemotherapy owing to their intrinsic and/or acquired resistance to existing products.
In addition to the fact that the compounds of the invention are new, they have a surprising in vivo and in vitro activity that is superior to that observed hitherto. Moreover, the compounds have valuable properties in respect of solubility, making them suitable for administration of the compounds in liquid form. The compounds discovered by the Applicant thus have anti-tumour properties that make them especially useful in the treatment of cancer, especially of solid tumours.
DETAILED DESCRIPTION OF THE INVENTION
More especially, the present invention relates to compounds of formula (I):
wherein:
X and Y, 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 mercapto group, a cyano group, a nitro group, a linear or branched (C
1
-C
6
)alkyl group, a linear or branched (C
1
-C
6
)alkoxy group, a trihalo-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, and an amino group (optionally substituted by one or two identical or different linear or branched (C
1
-C
6
)alkyl groups which may themselves be substituted by a linear or branched (C
1
-C
6
)alkoxy group or by a group of formula —NR
7
R
8
wherein R
7
and R
8
, which may be identical or different, each independently of the other represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, an aryl group or an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched), or X and Y together form a methylenedioxy or ethylenedioxy group, it being understood that the substituents X and Y may be present on one or the other 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 hydrogen atom,
a hydroxy group,
a linear or branched (C
1
-C
6
)alkyl group,
a linear or branched (C
1
-C
6
)alkoxy group optionally substituted by a group selected from:
a group of formula NR
9
R
10
wherein R
9
and R
10
, which may be identical or different, each independently of the other represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, or a linear or branched (C
1
-C
6
)hydroxyalkyl group, and
a saturated or unsaturated monocyclic or bicyclic heterocycle having from 5 to 7 ring members containing one or two hetero atoms selected from oxygen, nitrogen and sulphur,
a linear or branched (C
1
-C
6
)alkylcarbonyloxy group, or
an amino group optionally substituted by:
one or two, identical or different, 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,
a linear or branched (C
1
-C
6
)alkylcarbonyl group optionally substituted by a group —NR
7
R
8
wherein R
7
and R
8
are as defined hereinbefore,
a group of formula —R
11
—NR
9
R
10
, wherein R
11
represents a linear or branched (C
1
-C
6
)alkylene group, and R
9
and R
10
, which may be identical or different, each independently of the other represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, or a linear or branched (C
1
-C
6
)hydroxyalkyl group,
a linear or branched (C
1
-C
6
)alkylene group, substituted by a saturated or unsaturated, monocyclic or bicyclic heterocycle having from 5 to 7 ring members containing one or two hetero atoms selected from oxygen, nitrogen and sulphur, or
by a group of formula —R
11
—CO—R
12
wherein R
11
, is as defined hereinbefore, and R
12
represents a hydroxy group or a linear or branched (C
1
-C
6
)alkoxy group,
R
3
and R
4
, which may be identical or different, each independently of the other represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
R
5
and/or R
6
represent(s) a group of formula —O—CO—U—V wherein:
U represents a linear or branched (C
1
-C
8
)alkylene chain, optionally substituted by one or more identical or different groups selected from aryl, hydroxy and linear or branched (C
1
-C
6
)alkoxy,
V represents a group selected from:
carboxy,
—CO
2
R
13
wherein R
13
represents a linear or branched (C
1
-C
6
)alkyl group (optionally substituted by one or more hydroxy groups), an aryl group or an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched,
hydroxy,
linear or branched (C
1
-C
6
)alkoxy,
—NR
7
R
8
wherein R
7
and R
8
, which may be identical or different, are as defined hereinbefore,
—NR
7
—CO
2
R
13
wherein R
7
and R
13
are as defined hereinbefore,
—NR
7
—COR
13
wherein R
7
and R
13
are as defined hereinbefore,
—COR
13
wherein R
13
is as defined hereinbefore, and
—CO—NR
7
R
8
wherein R
7
and R
8
, which may be identical or different, are as defined hereinbefore,
 and when only one of the two groups R
5
and R
6
represents a group of formula —O—CO—U—V, then the other of the said R
5
and R
6
groups represents a group Z selected from:
hydroxy,
linear or branched (C
1
-C
6
)alkoxy,
linear or branched (C
1
-C
6
)alkylcarbonyloxy,
arylcarbonyloxy,
aryl-(C
1
-C
6
)alkylcarbonyloxy in which 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,
their isomers, N-oxides, and 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 substituents selected from hydroxy, halogen, carboxy, nitro, amino, (C
1
-C
6
)alkylamino or di-(C
1
-C
6
)alkylamino in which the(each) alkyl moiety is 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
)alkylcarbonyloxy.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid, lysine, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred R
3
and R
4
substituents according to the invention are linear or branched (C
1
-C
6
)alkyl groups in which R
3
and R
4
may be identical or different. R
3
and R
4
are preferably identical and each represents a methyl group.
The preferred R
2
substituents according to the invention are linear or branched (C
1
-C
6
)alkoxy groups, or amino groups optionally substituted by one or two substituents as defined for formula (I).
According to an advantageous embodiment, the preferred compounds of the invention are those wherein R
5
represents a group of formula —O—CO—U—V wherein U and V are as defined for formula (I), and R
6
repre

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