Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-19
2001-09-11
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...
C514S230800, C514S232800, C514S211090, C514S280000, C544S099000, C544S125000, C540S455000, C540S521000, C546S041000, C546S047000
Reexamination Certificate
active
06288073
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new acronycine compounds and to pharmaceutical compositions containing them.
Acronycine is an alkaloid having anti-tumour properties which have been demonstrated in experimental models (
J. Pharmacol. Sci.
1966, 55 (8), 758-768). However, despite a broad spectrum of activity, the poor solubility of acronycine limits its bioavailability and does not allow for the possibility of its use in an injectable form of administration.
Various chemical modifications have been carried out on that molecule, such as those described in the article
J. Med. Chem.
1996, 39 4762-4766, and have allowed the problem of the solubility of the compounds to be solved to some extent.
The compounds of the invention, as well as being new, have valuable solubilisation properties which are suited to administration of the compounds in liquid form and, surprisingly, they also exhibit an activity in vitro and in vivo which is far superior to that observed hitherto. Accordingly, the new analogues, discovered by the Applicants, have anti-tumour properties which render them especially suitable for use in the treatment of cancers and, especially, of solid tumours.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates more particularly to compounds of formula (I):
in which:
X and Y, which may be identical or different, each independently of the other represents 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 linear or branched (C
1
-C
6
)trihaloalkyl group, an amino group (optionally substituted by one or two identical or different linear or branched (C
1
-C
6
)alkyl groups which are themselves optionally substituted by a linear or branched (C
1
-C
6
)alkoxy group or by a group of the 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 or a linear or branched (C
1
-C
6
)alkyl group), or X and Y together form a methylenedioxy group or an ethylenedioxy group,
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 which is optionally substituted:
by a group of the 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 or a linear or branched (C
1
-C
6
) hydroxyalkyl group,
or by a saturated or unsaturated, monocyclic or bicyclic heterocycle having from 5 to 7 ring members and 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 which is optionally substituted:
by one or two identical or different linear or branched (C
1
-C
6
)alkyl groups,
by a linear or branched (C
1
-C
6
)alkylcarbonyl group which is eventually substituted by a group of the formula NR
7
R
8
wherein R
7
and R
8
are as defined above,
by a group of the formula —R
9
—NR
7
R
8
wherein R
9
represents a linear or branched (C
1
-C
6
)alkylene group and 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 or a linear or branched (C
1
-C
6
)hydroxyalkyl group,
by a linear or branched (C
1
-C
6
)alkylene group which is substituted by a saturated or unsaturated, monocyclic or bicyclic heterocycle having from 5 to 7 ring members and containing one or two hetero atoms selected from oxygen, nitrogen and sulphur,
or by a group of the formula
wherein R
9
is as defined above and R
10
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,
A represents a —CH═CH— group or an ethylene group of the formula —CH(R
5
)—CH(R
6
) wherein R
5
and R
6
, which may be identical or different, each independently of the other represents:
a hydrogen atom,
a hydroxy group,
a linear or branched (C
1
-C
6
)alkoxy group,
a linear or branched (C
1
-C
6
)alkylcarbonylexy group,
an arylcarbonyloxy group,
an amino group optionally substituted by one or two identical or different linear or branched (C
1
-C
6
)alkyl groups or by a linear or branched (C
1
-C
6
)acyl group,
a mercapto group, a linear or branched (C
1
-C
6
)alkylthio group or an arylthio group,
or R
5
and R
6
together form:
wherein Z represents an oxygen atom or a sulphur atom,
a —O—(CH
2
)
n
—O— group wherein n is an integer from 1 to 4 inclusive,
or a
group wherein B′ represents a single bond, a linear or branched (C
1
-C
6
)alkylene group or a linear or branched (C
1
-C
6
)alkenylene group,
or R
5
and R
6
form together with the carbon atoms carrying them an oxirane group or an aziridine group, optionally substituted on the nitrogen atom by a linear or branched (C
1
-C
6
)alkyl group,
wherein the term “aryl” denotes a phenyl or naphthyl group optionally containing one or more identical or different substituents selected from hydroxy, halogen, carboxy, nitro, amino, linear or branched (C
1
-C
6
)alkylamino, linear or branched di-(C
1
-C
6
)alkylamino, 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,
their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base.
Of the pharmaceutically acceptable acids there may be mentioned by way of non-limiting examples 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, etc.
Of the pharmaceutically acceptable bases there may be mentioned by way of non-limiting examples sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred substituents R
3
and R
4
according to the invention are linear or branched (C
1
-C
6
)alkyl groups, with R
3
and R
4
being identical or different.
The preferred substituents R
2
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 above, and advantageously amino groups substituted by a group of the formula —R
9
—NR
7
R
8
wherein R
9
is as defined above, and R
7
and R
8
, which may be identical or different, represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group.
Advantageously, the preferred compounds of the invention are those of formula (I) in which A represents a —CH═CH— group or a group of the formula —CH(R
5
)—CH(R
6
)— wherein R
5
and R
6
represent a hydroxy group or a linear or branched (C
1
-C
6
)alkylcarbonyloxy or R
5
and R
6
together form a
group.
Especially advantageously, the preferred compounds of the invention are the compounds of formula (I) which are:
-(±)cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]-acridin-7-one,
-cis-7-methoxy-4,4,15-trimethyl-3a,8,15,15c-tetrahydro-4H-benzo[b][1,3]dioxolo[4′,5′:4,5]pyrano[3,2-h]acridine-2,8-dione,
-6-methoxy-3,3,14-trimethyl-7,14-dihydro-3H-benzo[b]pyrano[3,2-h]acridin-7-one,
-6-(diethylaminopropylamino)-3,3,14-trimethyl-7,14-dihydro-3H-benzo[b]pyrano[3,2-h]acridin-7-one,
-(±)-cis-diacetoxy-6-(diethylaminopropylamino)-3,3,14-trimethyl-2,3,7,14-tetrahydro-1H-benzo[b]pyrano[3,2-h]acridin-7-one.
The isomers, N-oxides and, where appropriate, the addition salts with a pharmaceutically acceptable acid or base of the preferred compo
Atassi Ghanem
Koch Michel
Michel Sylvie
Pfeiffer Bruno
Pierre Alain
Adir et Compagnie
Huang Evelyn Mei
Sage G. Patrick
The Firm of Hueschen and Sage
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