Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-28
2003-11-11
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S197000, C544S198000, C544S208000, C544S209000
Reexamination Certificate
active
06645964
ABSTRACT:
The present invention relates to cancer therapy and to novel anticancer agents having a mechanism of action which is quite specific. It also relates to novel chemical compounds as well as their therapeutic application in humans.
The present invention relates to the use of novel non-nucleotide chemical compounds which interact with specific structures of deoxyribonucleic acid (DNA). These novel compounds consist of a distribution agent linked to two aminoaromatic groups. These novel compounds are useful in the treatment of cancers and act in particular as telomerase-inhibiting agents. They are particularly useful for stabilizing DNA in G-quadruplex structure (guanine tetrads). The therapeutic application of the inhibition of telomerase via the stabilization of these G-quadruplexes is the termination of cellular mitosis and the death of rapidly dividing cells such as cancer cells and possibly the induction of the senescence of cancer cells.
The compounds of the present invention have the advantage, from the therapeutic point of view, of blocking telomerase. From a biological point of view, telomerase allows the addition of repetitive DNA sequences of the TTAGGG type, termed telomeric sequences, at the end of the telomer, during cell division. Through this action, telomerase renders the cell immortal. Indeed, in the absence of this enzymatic activity, the cell loses, at each division, 100 to 150 bases, which rapidly renders it senescent. During the appearance of rapidly dividing cancer cells, it appeared that these cells possessed telomers which were maintained at a stable length during cell division. In these cancer cells, it appeared that telomerase was highly activated and that it allowed the addition of repetitive motifs of telomeric sequences at the end of the telomer and therefore allowed conservation of the length of the telomer in the cancer cells. It appeared for some time that more than 85% of cancer cells showed positive tests for the presence of telomerase whereas somatic cells do not show this characteristic.
Thus, telomerase is a highly coveted target for treating cancer cells. The first obvious approach for blocking telomerase was the use of nucleotide structures (Chen et al., Proc. Natl. Acad. Sci. USA 93(7), 2635-2639). Among the non-nucleotide compounds which have been used in the prior art, there may be mentioned the diaminoanthraquinones (Sun et al., J. Med. Chem. 40(14), 2113-6) or the diethyloxadicarbocyanins (Wheelhouse R. T. et al., J. Am. Chem. Soc. 1998(120), 3261-2).
Patent WO 99/40087 describes the use of compounds which interact with the G-quadruplex structures which are perylene compounds and carbocyanins containing at least seven rings including two heterocycles.
It appeared, quite surprisingly, that simple structures made it possible to obtain a result which is at least equivalent with structures which are a lot less complicated from a chemical point of view. The compounds of the present invention which meet the intended objective, that is to say which bind the G-quadruplex structure and thereby exhibit a telomerase-inhibiting activity, correspond to the following general formula:
nitrogen-containing aromatic ring—NR
3
—distribution agent—NR′
3
—aromatic ring
in which
the nitrogen-containing aromatic ring represents:
a quinoline optionally substituted with at least one group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a short-chain C1-C4 alkyl and/or alkoxy radical and/or
a quinoline possessing a nitrogen atom in quaternary form or
a benzamidine or
a pyridine
the aromatic ring represents
a quinoline optionally substituted with at least one group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a short-chain C1-C4 alkyl and/or alkoxy radical and/or
a quinoline possessing a nitrogen atom in quaternary form or
a benzamidine or
a pyridine or
a phenyl ring optionally substituted at the meta or para position with a halogen group, C1-C4 alkoxy group, cyano group, carbonylamino group optionally substituted with one or more C1-C4 alkyl groups, guanyl groups, C1-C4 alkylthio groups, amino groups, C1-C4 alkylamino groups, C1-C4 dialkylamino groups for each alkyl group, nitro group, alkylene-amino group or alkenyleneamino group or
a mono- or bi- or tricyclic hetero-cyclic ring comprising 0 to 2 heteroatoms per ring provided that at least one heteroatom is present in at least one ring optionally substituted with one or more C1-C4 alkyl groups or with alkylene or alkenylene groups
R3 and R′3, which are identical or different, represent independently of one another hydrogen or a C1-C4 alkyl radical
the distribution agent represents:
a triazine group optionally substituted with an alkyl radical having 1 to 4 carbon atoms, a thio, oxy or amino radical which are themselves optionally substituted with one or more short-chain alkyl chains containing 1 to 4 carbon atoms or a halogen atom or
a carbonyl group or
a group C(═NH)—NH—C(═NH) or
an alkyldiyl group containing 3 to 7 carbon atoms or
a diazine group optionally substituted with the same groups as the triazine
or one of its salts.
For the purposes of the above formula, nitrogen-containing aromatic ring is understood to mean a heterocycle comprising at least one nitrogen atom or an aromatic group containing no heteroatom in the ring but containing at least one nitrogen atom in a hydrocarbon chain attached to the ring, such as for example a guanidino or guanyl chain.
Among all the compounds included above, the use of those comprising, as distribution agent, a triazine or diazine group is preferred. Among the diazine groups, the use of pyrimidines is preferred. Among the triazines, those preferred are the compounds corresponding to formula (I) below:
in which:
A represents
an amino group of formula NR1R2 in which R1 and R2, which are identical or different, represent hydrogen or a straight or branched alkyl group containing 1 to 4 carbon atoms or
a group OR1 or SR1 in which R1 has the same meaning as above or
an alkyl group containing 1 to 4 carbon atoms or a trifluoromethyl group or
a hydrogen atom or
a halogen atom chosen from fluorine, chlorine, bromine or iodine
R3 and R′3, which are identical or different, represent independently of one another hydrogen or a C1-C4 alkyl radical
Ar
1
and Ar
2
, which are identical or different, represent
1. when Ar, and Ar
2
are identical:
a quinoline motif optionally substituted with at least one group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a short-chain alkyl and/or alkoxy radical containing 1 to 4 carbon atoms or
a quinoline possessing a nitrogen atom in quaternary form or
a benzamidine or
a pyridine attached at the 4-position or fused with an aryl or heteroaryl group optionally substituted with a C1-C4 alkyl group
2. when Ar
1
and Ar
2
are different
Ar
1
and Ar
2
both represent one of the possibilities mentioned above for Ar
1
and Ar
2
or
Ar
1
represents one of the above possibilities and Ar
2
represents
a phenyl ring optionally substituted at the meta or para position with a halogen group, C1-C4 alkoxy group, cyano group, carbonylamino group optionally substituted with one or more C1-C4 alkyl groups, guanyl groups, C1-C4 alkylthio groups, amino groups, C1-C4 alkylamino groups, C1-C4 dialkylamino groups for each alkyl group, nitro group, alkyleneamino group or alkenyleneamino group
a mono- or bi- or tricyclic hetero-cyclic ring comprising 0 to 2 heteroatoms per ring provided that at least one heteroatom is present in at least one ring optionally substituted with one or more C1-C4 alkyl groups or with alkylene or alkenylene groups
or one of its salts.
It is evident that the quinoline motifs may be substituted by any other group not involved in the intended application; thus, acridine or isoquinoline or quinazoline or quinoxaline or phthalazine or benzothiazine or benzoxazine or phenoxazine or phenothiazine groups are included in the definition of the quinoline groups.
Among the above compounds of formula (I), there
Laoui Abdelazize
Lavelle François
Mailliet Patrick
Mergny Jean-Louis
Petitgenet Odile
Aventis Pharma S.A.
Finnegan Henderson Farabow Garrett & Dunner LLP
Raymond Richard L.
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