Artemisinin derivatives, method for the preparation thereof...

Details Artemisinin derivatives, method for the preparation thereof... Artemisinin derivatives, method for the preparation thereof...

2000-12-14

2001-10-23

Trinh, Ba K. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S354000, C514S450000

Reexamination Certificate

active

06307068

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new artemisinine compounds having valuable pharmacological properties as anti-tumour agents.
BACKGROUND OF THE INVENTION AND DESCRIPTION OF THE PRIOR ART
Artemisinine is an active ingredient isolated from Artemisia annual. L., well known for its action against malaria.
A number of artemisinine compounds are described for their properties against malaria (IN 173339), in the treatment of toxoplasmosis (U.S. Pat. No. 5,486,535), or for their anti-cancer action, such as, for example, the dimers of artemisinine described in Application WO 9701548.
The compounds of the present invention are, by their novel structure, new and have especially valuable pharmacological properties as anti-tumour agents.
DETAILED DESCRIPTION OF THE INVENTION
More especially, the present invention relates to compounds of formula (I):
R—O—A  (I)
wherein:
R represents the radical of formula (II):
A represents:
a group of formula (III):
 wherein—R
1
represents an aryl, substituted aryl, heteroaryl or substituted heteroaryl group,
—R
2
represents a hydrogen atom or a substituted or unsubstituted linear or branched (C
1
-C
6
)alkyl group,
or a group of formula (IV):
 wherein—Y represents a substituted or unsubstituted linear or branched (C
2
-C
14
)alkylene, substituted or unsubstituted linear or branched (C
2
-C
14
)alkenylene, substituted or unsubstituted linear or branched (C
2
-C
14
)alkynylene, phenylene, substituted phenylene, naphthylene or substituted naphthylene group,
—Z represents an oxygen or sulphur atom, or a group NR′
2
wherein R′
2
can have the same meanings as R
2
,
—R
3
represents a group of formula (III) as defined hereinabove,
it being understood that:
“aryl” is understood to mean a phenyl, naphthyl, phenanthryl, fluorenyl or anthryl group,
“heteroaryl” is understood to mean any mono- or bi-cyclic aromatic group containing from 5 to 10 atoms and which may contain from 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur,
the term “substituted” applied to the terms “aryl”, “heteroaryl”, “phenylene” and “naphthylene” means that those groups are substituted by one or more identical or different radicals selected from linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkoxycarbonyl, polyhalo-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched, aryloxy (unsubstituted or substituted by one or more identical or different groups selected from hydroxy, linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)-alkoxy, polyhalo-(C
1
-C
6
)alkyl in which the alkyl moiety is linear or branched and halogen atoms), nitro, amino, linear or branched (C
1
-C
6
)alkylamino, di-(C
1
-C
6
)alkylamino in which each alkyl moiety is linear or branched, alkylcarbonylamino, cyano and halogen atoms (fluorine, chlorine, bromine or iodine), or two adjacent carbon atoms may be substituted by an alkylenedioxy group,
the term “substituted” applied to the terms “alkyl”, “alkylene”, “alkenylene” and “alkynylene” means that those groups are substituted by one or more identical or different radicals selected from hydroxy, linear or branched (C
1
-C
6
)alkoxy, polyhaloalkyl, amino and halogen atoms (fluorine, chlorine, bromine or iodine),
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned, in non-limiting manner, the following acids: hydrochloric, hydrobromic, sulphuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulphonic, camphoric, etc.
Among the pharmaceutically acceptable bases there may be mentioned, in non-limiting manner, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred compounds of the invention are those in which:
A represents a group of formula (III),
A represents a group of formula (IV),
Z represents an oxygen atom,
Z represents a group NR′
2
,
Y represents a substituted or unsubstituted (C
2
-C
14
)-alkylene or -alkenylene chain,
Y represents phenylene or naphthylene, each substituted or unsubstituted,
R
1
represents an aryl or substituted aryl group.
Advantageously, the invention relates to compounds of formula (I) wherein A represents:
a group of formula (III) in which R
1
represents a substituted or unsubstituted phenyl group and R
2
represents a hydrogen atom or a methyl group,
or a group of formula (IV) in which Y represents a —(CH
2
)
n
— chain wherein n is such that 2≦n≦7, Z represents an oxygen atom or a group NR′
2
and R
3
represents a group of formula (III) wherein R
1
represents a phenyl or naphthyl group, each substituted or unsubstituted, and R
2
represents a hydrogen atom or a methyl group.
More especially still, the invention relates to compounds of formula (I) which are:
2-(4-bromophenyl)-2-dihydroartemisininyl-acetonitrile,
2-phenyl-2-dihydroartemisininyl-acetonitrile,
[(2-chlorophenyl)(cyano)methyl]dihydroartemisininyl 1,4-succinate,
dihydroartemisininyl 4-{[(4-bromophenyl)(cyano)methyl](methyl)amino}-4-oxobutanoate.
The enantiomers, diastereoisomers and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (V):
R
OH  (V)
wherein R is as defined hereinabove,
with which there is condensed
under conditions of acid catalysis, a compound of formula (VI):
 wherein R
1
and R
2
are as defined hereinabove,
to yield a compound of formula (I/a), a particular case of the compounds of formula (I):
wherein R, R
1
and R
2
are as defined hereinabove,
or a compound of formula (VII):
 wherein Y is as defined hereinabove, (or the corresponding acid chloride or anhydride), to yield a compound of formula (VIII):
wherein R and Y are as defined hereinabove,
with which there is reacted under conditions of acid catalysis, in the presence of a coupling agent, or after conversion to the corresponding acid chloride,
a compound of formula (VI) to obtain a compound of formula (I/b), a particular case of the compound of formula (I):
 wherein R, R
1
, R
2
and Y are as defined hereinabove,
a compound of formula (IX):
 wherein R, R
1
, R′
2
are as defined hereinabove,
to yield a compound of formula (I/c), a particular case of the compounds of formula (I):
wherein R, R
1
, R
2
, R′
2
are as defined hereinabove,
or a compound of formula (X):
 wherein R
1
and R
2
are as defined hereinabove,
to yield a compound of formula (I/d), a particular case of the compounds of formula (I):
wherein R, Y, R
1
and R
2
are as defined hereinabove,
which compounds (I/a) to (I/d) constitute the totality of the compounds of formula (I) and may be purified in accordance with a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and separated, where appropriate, into their optical or geometric isomers in accordance with conventional purification techniques.
The compound of formula (V) is readily accessible to the person skilled in the art by conventional reduction of (commercial) artemisinine. The compounds of formula (VI) are obtained by conventional condensaof a cyanide salt with the ketone of formula (XI):
wherein R
1
and R
2
are as defined hereinabove.
The compounds of formula (IX) are obtained by the action of an amine R′
2
NH
2
wherein R′
2
is as defined hereinabove on the compound of formula (VI).
The compounds of formula (X) are obtained by the action of H
2
S in the presence of a catalyst, such as Al
2
O
3
for example, on the compound of formula (VI).
Another advantageous process of the invention is the preparation of compounds of

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