FR2822468A1 - New arylamino-substituted triazine or diazine derivatives, used as telomerase inhibiting anticancer agents, by fixing the G-quadruplex structure of DNA or RNA - Google Patents

Abstract

New compounds (I) for fixing the G-quadruplex structure of DNA or RNA comprise a triazine or diazine spacer group bonded via amino groups to (i) a nitrogen-containing aromatic ring and (ii) an aromatic ring. New compounds for fixing the G-quadruplex structure of DNA or RNA comprise nitrogen-containing aromatic compounds of formula Het-N(R3)-Sp-N(R'3)-Ar (I) or their salts, in any possible isomeric form (racemic, enantiomeric or diastereomeric). Het = nitrogen-containing ring selected from quinoline or isoquinoline (both optionally substituted (os) by at least one of NRaRb, R and/or OR); quinoline or isoquinoline containing a quaternized N atom; benzamidine; or pyridine; Ar = aromatic ring selected from nitrogen-containing rings as defined for Het; phenyl (os by halo, OR, CONH2, CONHR, CON(R)2, guanyl, SR, NH2, NHR, N(R)2, 3-8C alkyleneimino, NO2, 1-4C aminoalkyl or 2-4C aminoalkenyl); or mono-, di- or tricyclic heterocycle (containing 0-2 heteroatoms in each ring, provided that at least one heteroatom is present; and os by one or more of R, 1-4C alkylene or 1-4C alkenylene); Ra, Rb, R3, R'3 = H or 1-4C alkyl; R = 1-4C alkyl; Sp = spacer selected from triazine groups (os by Ar or A); or diazine (specifically pyrimidine or quinazoline) group (os as for the triazine groups); A = NR1R2, R1,R2-substituted 1-6C alkyl, OR1 or SR1; R1, R2 = H; optionally mono- or polysubstituted 1-8C alkyl; Ar; quinuclidinyl; pyrrolidinyl (os by R or phenyl-(1-4C) alkyl); piperazinyl or homopiperazinyl (both os by alkyl, cycloalkyl or phenylalkyl); morpholinyl; pyridnyl, piperidinyl or piperidyl (all os by one or more R or phenyl-(1-4C) alkyl); indazolyl; naphthyl; benzotriazolyl; benzimidazolyl; pyrimidinyl (os by one or more R); acenaphthene residue; or amino (os by 1 or 2 of alkyl, phenylakyl, alkylaminoalkyl and/or dialkylaminoalkyl); or, in NR1R2 or R1,R2-substituted 1-6C alkyl, R1 and R2 may together complete an os, saturated or unsaturated, 3-6 membered monocyclic or 8-10 membered ring system, optionally containing 1 or 2 of N, O and/or S as heteroatom(s); Provided that NR1R2 is other than NH2, NHR or N(R)2 with identical R groups.

Description

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CHEMICAL DERIVATIVES AND THEIR APPLICATION AS ANTITELOMERASE AGENT
The present invention relates to cancer therapy and relates to novel anticancer agents having a very particular mechanism of action. It also concerns new chemical compounds as well as their therapeutic application in humans.

 The present invention relates to the use of novel non-nucleotide chemical compounds that interact with specific structures of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). These new compounds consist of a distribution agent linked to two aminoaromatic groups. These new 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 telomerase inhibition via the stabilization of these G-quadruplexes is the arrest of cell mitosis and the death of rapidly dividing cells such as cancer cells and possibly the induction of cell senescence. cancerous.

 The compounds of the present invention have the therapeutic advantage of blocking telomerase. From a biological point of view, telomerase allows the addition of T-GG G-type repeats of DNA sequences, called telomeric sequences, at the end of the telomere, during cell division. By this action telomerase makes the cell immortal. Indeed, in the absence of this enzymatic activity, the cell loses at each division 100 to 150 bases, which

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la rend rapidement senescente. Lors de l'apparition de cellules cancéreuses à division rapide, il est apparu que ces cellules présentaient des télomères maintenus à une longueur stable au cours de la division cellulaire. Dans ces cellules cancéreuses il est apparu que la télomérase était fortement activée et qu'elle permettait l'addition de motifs répétés de séquences télomériques à la fin du télomère et permettait donc la conservation de la longueur du télomère dans les cellules cancéreuses. Il est apparu depuis quelques temps que plus de 85 % des cellules cancéreuses présentaient des tests positifs à la présence de télomérase alors que les cellules somatiques ne présentent pas cette caractéristique.

makes it quickly senescente. During the appearance of rapidly dividing cancer cells, it appeared that these cells had telomeres maintained at a stable length during cell division. In these cancerous cells it was found that telomerase was highly activated and that it allowed the addition of repeated motifs of telomeric sequences at the end of the telomere and thus allowed the preservation of telomere length in cancer cells. It has been known for some time that more than 85% of cancer cells have tests positive for the presence of telomerase while somatic cells do not have this characteristic.

 Thus telomerase is a very coveted target for treating cancer cells. The first obvious approach to block telomerase has been 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 are diaminoanthraquinones (Sun et al., J. Med Chem 40 (14), 2113-6) or diethyloxadicarbocyanines (Wheelhouse R.

T. et al. J. Am. Chem. Soc. 1998 (120) 3261-2).

 WO 99/40087 discloses the use of compounds which interact with Gquadruplex structures which are perylenic compounds and carbocyanines containing at least seven rings including two heterocycles.

 It was quite surprising that simple structures made it possible to obtain at least equivalent results with structures that were much less complicated from a chemical point of view.

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Les composés de la présente invention qui répondent à l'objectif visé c'est-à-dire qui fixent la structure G-quadruplex d'ADN ou d'ARN et notamment la structure G-quadruplex des télomères et par ce fait présentent une activité inhibitrice des télomérases répondent à la formule générale suivante : cycle aromatique azoté-NR3-répartiteur-NR'3- cycle aromatique dans laquelle le cycle aromatique azoté, représente :
0 une quinoléine éventuellement substituée par au moins un groupe N (Ra) (Rb) dans lequel Ra et Rb, identiques ou différents représentent l'hydrogène ou un radical alkyle en C1-C4, (ou) un groupe alkoxy ou alkyle à chaîne courte en cl-c4 ou
0 une quinoléine possédant un atome d'azote sous forme quaternaire ou
0 une benzamidine ou
0 une pyridine le cycle aromatique représente
0 une quinoléine éventuellement substituée par au moins un groupe N (Ra) (Rb) dans lequel Ra et Rb, identiques ou différents représentent l'hydrogène ou un radical alkyle en C1-C4, (ou) un groupe alkoxy ou alkyle à chaîne courte en
C1-C4 ou
0 une quinoléine possédant un atome d'azote sous forme quaternaire ou
0 une benzamidine ou

The compounds of the present invention which serve the intended purpose, that is to say which bind the G-quadruplex structure of DNA or RNA and in particular the G-quadruplex structure of the telomeres and thereby exhibit an activity. inhibitors of telomerases have the following general formula: aromatic ring nitrogen-NR3-distribution-NR'3-aromatic ring in which the aromatic ring nitrogen, represents:
A quinoline optionally substituted with at least one N (Ra) (Rb) group in which Ra and Rb, which may be identical or different, represent hydrogen or a C1-C4 alkyl radical, (or) an alkoxy or short-chain alkyl group; in cl-c4 or
A quinoline having a nitrogen atom in quaternary form or
0 a benzamidine or
A pyridine the aromatic ring represents
A quinoline optionally substituted with at least one N (Ra) (Rb) group in which Ra and Rb, which may be identical or different, represent hydrogen or a C1-C4 alkyl radical, (or) an alkoxy or short-chain alkyl group; in
C1-C4 or
A quinoline having a nitrogen atom in quaternary form or
0 a benzamidine or

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0 une pyridine ou 0 un noyau phényle éventuellement substitué par un groupement halogène ; alkoxy en Cl-C4 ; cyano ; carbonylamino éventuellement substitué par un ou plusieurs groupes alkyle en C1-C4 ; guanyl ; alkylthio en C1-C4 ; amino, alkylamino en C1-C4, dialkylamino en C1-
C4 pour chaque groupe alkyle et dont les parties alkyles peuvent ensemble former un cycle en C3-C8, nitro ; alkylèneamino en C1-C4 ; alkénylèneamino en C2-C4,
0 un noyau hétérocyclique mono ou bi ou tricyclique comportant 0 à 2 hétéroatome par cycle à la condition qu'au moins un hétéroatome soit présent dans au moins un cycle éventuellement substitué par un ou plusieurs groupes alkyle en Cl-C4 ou par des groupes alkylène en C1-C4 ou alkénylène en C2-C4 R3 et R'3, identiques ou différents, représentent indépendamment l'un de l'autre l'hydrogène ou un radical alkyle en Ci-C4 le répartiteur représente : un groupe triazine éventuellement substitué par un radical XR1 (R2) dans lequel X représente un atome d'azote N pour former NR1R2, un radical alkyle linéaire ou ramifié en C1-C6 pour former alkR1R2, un atome d'oxygène 0 pour former OR1 ou un atome de soufre S pour former SR1,

A pyridine or a phenyl ring optionally substituted by a halogen group; C1-C4 alkoxy; cyano; carbonylamino optionally substituted by one or more C1-C4 alkyl groups; guanyl; C1-C4 alkylthio; amino, C1-C4 alkylamino, C1-C4 dialkylamino
C4 for each alkyl group and the alkyl portions of which may together form a C3-C8 nitro ring; C1-C4 alkyleneamino; C 2 -C 4 alkenyleneamino,
A mono or bi or tricyclic heterocyclic ring having 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 alkylene groups thereof; C1-C4 or C2-C4 alkenylene R3 and R'3, which may be identical or different, represent, independently of one another, hydrogen or a C1-C4 alkyl radical, the distribution block represents: a triazine group optionally substituted with a radical XR1 (R2) in which X represents a nitrogen atom N to form NR1R2, a linear or branched C1-C6 alkyl radical to form alkR1R2, an oxygen atom O to form OR1 or a sulfur atom S to form SR1,

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avec Rl et R2 identiques ou différents sont choisis parmi l'atome d'hydrogène ; alkyle Cl-C8 éventuellement substitué par un radical amino, alkylamino, dialkylamino, (phényl) (alkyl) amino, (alkylphényl) (alkyl) amino, alcoxy en C1-
C4, thioalcoxy en C1-C4, trifluorométhyle, pyrrolidinyle, pipéridyle, pipérazinyle, morpholinyle, pyridyle ou phényle ; un cycle aromatique tel que défini ci-dessus ; un radical quinuclidine, un radical pyrrolidinyle, pipérazinyle, morpholinyle, pyridyle ou un radical pipéridyle éventuellement substitué par alkyle Cl-C4 étant entendu que Rl et R2 identiques ne représentent pas tous deux hydrogène ou alkyle Cl-C4 non substitué et R1 et R2 différents ne représentent pas l'un hydrogène et l'autre alkyle CI-C4 non substitué ou bien lorsque X représente N ou alkyle, Rl et R2 forment ensemble avec X auquel ils sont liés un radical monocyclique de 3 à 6 chaînons ou bicyclique de 8 à 10 chaînons saturé ou insaturé renfermant éventuellement un ou deux hétéroatomes identiques ou différents choisis parmi N, 0 ou S, un groupe diazine éventuellement substitué par les mêmes groupes que la triazine ou un de ses sels,

with R1 and R2 identical or different are selected from the hydrogen atom; C1-C8 alkyl optionally substituted with amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1-C6 alkoxy
C4, C1-C4thioalkoxy, trifluoromethyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, pyridyl or phenyl; an aromatic ring as defined above; a quinuclidine radical, a pyrrolidinyl, piperazinyl, morpholinyl, pyridyl radical or a piperidyl radical optionally substituted with C1-C4 alkyl, it being understood that R1 and R2 are identical and do not represent hydrogen or unsubstituted C1-C4 alkyl and R1 and R2 are not one hydrogen and the other unsubstituted C1-C4 alkyl, or when X is N or alkyl, R1 and R2 together with X to which they are attached form a 3- to 6-membered monocyclic or a bicyclic radical of 8 to 10 saturated or unsaturated chain members optionally containing one or two identical or different heteroatoms chosen from N, O or S, a diazine group optionally substituted by the same groups as triazine or a salt thereof,

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ces composés étant sous toutes les formes isomères possibles racémiques, énantiomères et diastéréo- isomères.

these compounds being in all possible isomeric forms racemic, enantiomers and diastereoisomers.

 For the purposes of the above formula, the term "nitrogenous aromatic ring" means a heterocycle comprising at least one nitrogen atom or an aromatic group which does not contain a heteroatom in the ring but which contains at least one nitrogen atom in a hydrocarbon-based chain linked to the cycle such as a guanidino or guanyl chain.

 The aromatic ring represents in particular a radical quinaldine, quinoleine, benzamidine, pyridine and phenyl as defined above and optionally substituted as indicated above.

As the C3-C8 ring which can form the alkyl portions of the dialkylamino radicals defined above, there may be mentioned for example the aziriridine, azetidine, pyrrolidine, oxazolidine, thiazolidine, piperidine, piperazine, morpholine, thiomorpholine or azepine rings.

The subject of the present invention is the compounds which fix the G-quadruplex structure of telomeres, characterized in that they correspond to the general formula as defined above.

The subject of the present invention is in particular the compounds as defined above, characterized in that the tundish represents: a triazine group optionally substituted with an XR1 radical (R2) in which X represents a nitrogen atom N to form NR1R2, a oxygen atom 0

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pour former OR1 ou un atome de soufre S pour former SR1, avec R1 et R2 identiques ou différents sont choisis parmi l'atome d'hydrogène ; alkyle Cl-C8 éventuellement substitué par un radical amino, alkylamino, dialkylamino, (phényl) (alkyl) amino, (alkylphényl) (alkyl) amino, alcoxy en Cl-
C4, par un radical pyrrolidinyle, pyridyle ou par un radical phényle ; un cycle aromatique tel que défini ci- dessus ; un radical quinuclidine, un radical pyrrolidinyle ou un radical pipéridyle éventuellement substitué par alkyle C1-C4 étant entendu que Rl et R2 identiques ne représentent pas tous deux hydrogène ou alkyle Cl-C4 non substitué et R1 et R2 différents ne représentent pas l'un hydrogène et l'autre alkyle C1-C4 non substitué, ou bien lorsque X représente N, Rl et R2 forment ensemble avec X auquel ils sont liés un radical pipérazinyle, pipéridyle, pyrrolidinyle, morpholinyle ou thiomorpholinyle, un groupe diazine éventuellement substitué par les mêmes groupes que la triazine ou un de ses sels,

to form OR1 or a sulfur atom S to form SR1, with R1 and R2 identical or different are selected from hydrogen atom; C1-C8alkyl optionally substituted by amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1-4alkoxy,
C4, with a pyrrolidinyl, pyridyl or phenyl radical; an aromatic ring as defined above; a quinuclidine radical, a pyrrolidinyl radical or a piperidyl radical optionally substituted by C1-C4 alkyl, it being understood that both R1 and R2 are identical and do not represent hydrogen or unsubstituted C1-C4 alkyl and different R1 and R2 do not represent hydrogen. and the other unsubstituted C1-C4 alkyl, or when X is N, R1 and R2 together with X to which they are attached a piperazinyl, piperidyl, pyrrolidinyl, morpholinyl or thiomorpholinyl radical, a diazine group optionally substituted by the same groups that triazine or one of its salts,

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 these compounds being in all possible isomeric forms racemic, enantiomers and diastereoisomers.

The present invention particularly relates to compounds as defined above characterized in that the diazine groups are pyrimidines or quinazolines.

dans laquelle :
A représente un radical XR1 (R2) dans lequel X représente un atome d'azote, d'oxygène, de soufre ou un radical alkyle en C1-C6 pour former l'un des radicaux suivants : The present invention more particularly relates to the compounds as defined above characterized in that XR1 (R2) is such that when X represents N, one of R1 and R2 represents the hydrogen atom and the Another one of R 1 and R 2 is chosen from the values defined for R 1 and R 2, ie R 1 and R 2 together with the nitrogen atom to which they are attached form a piperazinyl, pyrrolidinyl, piperidyl or morpholino radical. The present invention particularly relates to the compounds defined herein. above fixing the Gquadruplex structure of telomeres characterized in that they correspond to formula (I) below:

in which :
A represents a radical XR1 (R2) in which X represents a nitrogen, oxygen, sulfur or a C1-C6 alkyl radical to form one of the following radicals:

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NR1R2 avec R1 et R2 identiques ou différents sont choisis parmi l'atome d'hydrogène ; alkyle C1-C8 éventuellement substitué par un radical amino, alkylamino, dialkylamino, (phényl) (alkyl) amino, (alkylphényl) (alkyl) amino, alcoxy en Cl-
C4, thioalcoxy en C1-C4, trifluorométhyle, pyrrolidinyle, pipéridyle, pipérazinyle, morpholinyle, pyridyle ou phényle ; un cycle aromatique tel que défini ci-dessus ; un radical quinuclidine, un radical pyrrolidinyle, pipérazinyle, morpholinyle, pyridyle ou un radical pipéridyle éventuellement substitué par alkyle C1-C4 étant entendu que R1 et R2 identiques ne représentent pas tous deux hydrogène ou alkyle C1-C4 non substitué et R1 et R2 différents ne représentent pas l'un hydrogène et l'autre alkyle C1-C4 non substitué ou bien lorsque X représente N ou alkyle, R1 et R2 forment ensemble avec X auquel ils sont liés un radical monocyclique de 3 à 6 chaînons ou bicyclique de 8 à 10 chaînons saturé ou insaturé renfermant éventuellement un ou deux hétéroatomes identiques ou différents choisis parmi N, 0 ou S, e un groupe OR1 ou SR1 dans lequel R1 a la même signification que précédemment étant entendu que R1 ne représente pas hydrogène ou alkyle C1-C4 non substitué, ou

NR1R2 with R1 and R2 identical or different are selected from the hydrogen atom; C1-C8 alkyl optionally substituted with amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1-4alkoxy
C4, C1-C4thioalkoxy, trifluoromethyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, pyridyl or phenyl; an aromatic ring as defined above; a quinuclidine radical, a pyrrolidinyl, piperazinyl, morpholinyl, pyridyl radical or a piperidyl radical optionally substituted with C1-C4 alkyl, it being understood that both R1 and R2 are identical and do not represent hydrogen or unsubstituted C1-C4 alkyl and different R1 and R2 do not are not one hydrogen and the other unsubstituted C1-C4 alkyl or when X is N or alkyl, R1 and R2 together with X to which they are bonded a 3 to 6-membered monocyclic or 8 to 10-membered bicyclic radical saturated or unsaturated chain members optionally containing one or two identical or different heteroatoms chosen from N, O or S; e is a group OR1 or SR1 in which R1 has the same meaning as above, provided that R1 does not represent hydrogen or C1-C4 alkyl not substituted, or

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a un groupe alkyle contenant 1 à 6 atomes de carbone substitué par RI R2 tels que définis ci-dessus
R3 et R'3, identiques ou différents, représentent indépendamment l'un de l'autre l'hydrogène ou un groupe alkyle en C1-C4 Ari et Ar2 identiques ou différents représentent
1. quand Ar, et Ar2 sont identiques : 'un motif quinoléine éventuellement substitué par au moins un groupe
N (Ra) (Rb) dans lequel Ra et Rb identiques ou différents représentent l'hydrogène ou un radical alkyle en C1-
C4, (ou) un groupe alkoxy ou alkyle à chaîne courte contenant 1 à 4 atome de carbone ou # une quinoléine possédant un atome d'azote sous forme quaternaire ou # une benzamidine ou # une pyridine attachée en position-4 ou fusionnée avec un groupe aryle ou hétéroaryle éventuellement substituée

par un groupe alkyle en C1-C4 2. quand Ar, et Ar2 sont différents * Ar, et Ar2 représentent tous les deux l'une des possibilités évoquées ci- dessus pour Ar, et Ar2 ou Ar1 représente l'une des possibilités ci- dessus et Ar2 représente

has an alkyl group containing 1 to 6 carbon atoms substituted by RI R2 as defined above
R3 and R'3, which may be identical or different, represent, independently of each other, hydrogen or a C1-C4 alkyl group. Ar and Ar2, which may be identical or different, represent
1. when Ar 1 and Ar 2 are identical: a quinoline moiety optionally substituted by at least one group
N (Ra) (Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a C1-C4 alkyl radical;
C4, (or) an alkoxy or short chain alkyl group containing 1 to 4 carbon atoms or # a quinoline having a nitrogen atom in quaternary form or # a benzamidine or # a pyridine attached at the 4-position or fused with a optionally substituted aryl or heteroaryl group

by a C1-C4 alkyl group, when Ar1 and Ar2 are different * Ar1 and Ar2 both represent one of the possibilities mentioned above for Ar, and Ar2 or Ar1 represents one of the possibilities mentioned above. above and Ar2 represents

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* un noyau phényle éventuellement substitué par un groupement halogène, alkoxy en C1-C4, cyano, carbonylamino éventuellement substitué par un ou plusieurs groupes alkyle en C1-C4, guanyl, alkylthio en C1-C4, amino, alkylamino en C1-C4, dialkylamino en
C1-C4 pour chaque groupe alkyle, nitro, alkylèneamino en C1-C4, (ou) alkénylèneamino en C2-C4, ou un radical pipérazinyle éventuellement substitué par un radical alkyle C1-C4, * un noyau hétérocyclique mono ou bi ou tricyclique comportant 0 à 2 hétéroatome par cycle à la condition qu'au moins un hétéroatome soit présent dans au moins un cycle éventuellement substitué par un ou plusieurs groupes alkyle en C1-C4 ou par des groupes alkylène en C1-C4 ou alkénylène en C2-C4 ou un de ses sels, ces composés de formule (I) étant sous toutes les formes isomères possibles racémiques, énantiomères et diastéréo-isomères.

a phenyl ring optionally substituted by a halogen, C 1 -C 4 alkoxy, cyano or carbonylamino group optionally substituted with one or more C 1 -C 4 alkyl, guanyl, C 1 -C 4 alkylthio, amino, C 1 -C 4 alkylamino or dialkylamino groups; in
C1-C4 for each alkyl group, nitro, C1-C4 alkyleneamino, (or) alkenyleneamino C2-C4, or a piperazinyl radical optionally substituted by a C1-C4 alkyl radical, * a mono or bi or tricyclic heterocyclic ring containing 0 to 2 hetero atoms per ring provided that at least one heteroatom is present in at least one ring optionally substituted with one or more C 1 -C 4 alkyl groups or C 1 -C 4 alkylene or C 2 -C 4 alkenylene groups or of its salts, these compounds of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers.

The present invention also relates to novel compounds characterized in that they correspond to formula (I) below:

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dans laquelle : A représente un radical XR1 (R2) dans lequel X représente un atome d'azote, d'oxygène, de soufre ou un radical alkyle en C1-C6 pour former l'un des radicaux suivants : * NR1R2 avec R1 et R2 identiques ou différents sont choisis parmi l'atome d'hydrogène ; alkyle C1-C8 éventuellement substitué par un radical amino, alkylamino, dialkylamino, (phényl) (alkyl) amino, (alkylphényl) (alkyl) amino, alcoxy en C1-C4, thioalcoxy en C1-C4, trifluorométhyle, pyrrolidinyle, pipéridyle, pipérazinyle, morpholinyle, pyridyle ou phényle ; un cycle aromatique tel que défini ci-dessus ; un radical quinuclidine, un radical pyrrolidinyle, pipérazinyle, morpholinyle, pyridyle ou un radical pipéridyle éventuellement substitué par alkyle C1-C4 étant entendu que R1 et R2 identiques ne représentent pas tous deux hydrogène ou alkyle
C1-C4 non substitué et R1 et R2 différents ne représentent pas l'un hydrogène et l'autre alkyle C1-C4 non substitué ou bien lorsque X représente N ou alkyle, R1 et
R2 forment ensemble avec X auquel ils sont liés un radical monocyclique de 3 à 6 chaînons ou bicyclique de 8 à 10 chaînons saturé ou insaturé renfermant éventuellement un ou deux hétéroatomes identiques ou différents choisis parmi N, 0 ou S,

in which: A represents a radical XR1 (R2) in which X represents a nitrogen, oxygen, sulfur or a C1-C6 alkyl radical to form one of the following radicals: * NR1R2 with R1 and R2 identical or different are chosen from the hydrogen atom; C1-C8alkyl optionally substituted with amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1-C4alkoxy, C1-C4thioalkoxy, trifluoromethyl, pyrrolidinyl, piperidyl, piperazinyl morpholinyl, pyridyl or phenyl; an aromatic ring as defined above; a quinuclidine radical, a pyrrolidinyl, piperazinyl, morpholinyl, pyridyl radical or a piperidyl radical optionally substituted with C1-C4 alkyl, it being understood that R1 and R2 are identical and do not both represent hydrogen or alkyl
Unsubstituted C1-C4 and different R1 and R2 do not represent one hydrogen and the other unsubstituted C1-C4 alkyl or when X is N or alkyl, R1 and
R2 together with X to which they are bound a 3- to 6-membered monocyclic or bicyclic radical of 8 to 10 membered saturated or unsaturated optionally containing one or two identical or different heteroatoms selected from N, O or S,

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un groupe OR1 ou SR1 dans lequel R1 a la même signification que précédemment étant entendu que R1 ne représente pas hydrogène ou alkyle C1-C4 non substitué, ou * un groupe alkyle contenant 1 à 6 atomes de carbone substitué par R1 R2 tels que définis ci-dessus R3 et R'3, identiques ou différents, représentent indépendamment l'un de l'autre l'hydrogène ou un groupe alkyle en C1-C4 Ari et Ar2 identiques ou différents représentent * quand Ar, et Ar2 sont identiques : * un motif quinoléine éventuellement substitué par au moins un groupe
N (Ra) (Rb) dans lequel Ra et Rb identiques ou différents représentent l'hydrogène ou un radical alkyle en C1-
C4, (ou) un groupe alkoxy ou alkyle à chaîne courte contenant 1 à 4 atome de carbone ou * une quinoléine possédant un atome d'azote sous forme quaternaire ou * une benzamidine ou * une pyridine attachée en position-4 ou fusionnée avec un groupe aryle ou hétéroaryle éventuellement substituée par un groupe alkyle en C1-C4 * quand Ar, et Ar2 sont différents

a group OR1 or SR1 in which R1 has the same meaning as above, it being understood that R1 does not represent hydrogen or unsubstituted C1-C4 alkyl, or * an alkyl group containing 1 to 6 carbon atoms substituted by R1 R2 as defined herein. R3 and R'3, which may be identical or different, represent, independently of one another, hydrogen or a C1-C4 alkyl group. Ar and Ar2, which are identical or different, represent * when Ar and Ar2 are identical: quinoline moiety optionally substituted by at least one group
N (Ra) (Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a C1-C4 alkyl radical;
C4, (or) alkoxy or short chain alkyl containing 1 to 4 carbon atoms or quinoline having a nitrogen atom in quaternary form or benzamidine or pyridine attached at the 4-position or fused with a aryl or heteroaryl group optionally substituted with a C1-C4 alkyl group when Ar1 and Ar2 are different

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* Ar, et Ar2 représentent tous les deux l'une des possibilités évoquées ci- dessus pour Ar, et Ar2 ou . Arl représente l'une des possibilités ci- dessus et Ar2 représente * un noyau phényle éventuellement substitué par un groupement halogène, alkoxy en C1-C4, cyano, carbonylamino éventuellement substitué par un ou plusieurs groupes alkyle en C1-C4, guanyl, alkylthio en C1-C4, amino, alkylamino en C1-C4, dialkylamino en
C1-C4 pour chaque groupe alkyle, nitro, alkylèneamino en C1-C4, (ou) alkénylèneamino en C2-C4, ou un radicla pipérazinyle éventuellement substitué par un radical alkyle C1-C4, * un noyau hétérocyclique mono ou bi ou tricyclique comportant 0 à 2 hétéroatome par cycle à la condition qu'au moins un hétéroatome soit présent dans au moins un cycle éventuellement substitué par un ou plusieurs groupes alkyle en C1-C4 ou par des groupes alkylène en C1-C4 ou alkénylène en C2-C4 ou un de ses sels, ces composés de formule (I) étant sous toutes les formes isomères possibles racémiques, énantiomères et diastéréo-isomères.

* Ar, and Ar2 both represent one of the possibilities mentioned above for Ar, and Ar2 or. Ar 1 represents one of the above possibilities and Ar 2 represents a phenyl ring optionally substituted by a halogen, C 1 -C 4 alkoxy, cyano or carbonylamino group optionally substituted by one or more C 1 -C 4 alkyl, guanyl or alkylthio groups. C1-C4, amino, C1-C4 alkylamino, dialkylamino
C1-C4 for each alkyl group, nitro, C1-C4 alkyleneamino, (or) alkenyleneamino C2-C4, or a piperazinyl radicla optionally substituted by a C1-C4 alkyl radical, * a mono or bi or tricyclic heterocyclic ring containing 0 to 2 hetero atoms per ring provided that at least one heteroatom is present in at least one ring optionally substituted with one or more C 1 -C 4 alkyl groups or C 1 -C 4 alkylene or C 2 -C 4 alkenylene groups or of its salts, these compounds of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers.

 The present invention relates in particular to the compounds of formula (I) as defined above in which A represents a radical XR1 (R2) in

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lequel X représente un atome d'azote N pour former NR1R2, un atome d'oxygène 0 pour former OR1 ou un atome de soufre S pour former SR1 comme suit : 'NR1R2 avec R1 et R2 identiques ou différents sont choisis parmi l'atome d'hydrogène ; alkyle C1-C8 éventuellement substitué par un radical amino, alkylamino, dialkylamino, (phényl) (alkyl) amino, (alkylphényl) (alkyl) amino, alcoxy en C1-C4, par un radical pyrrolidinyle, pyridyle ou par un radical phényle ; un cycle aromatique tel que défini ci-dessus ; un radical quinuclidine, un radical pyrrolidinyle ou un radical pipéridyle éventuellement substitué par alkyle C1-C4 étant entendu que R1 et R2 identiques ne représentent pas tous deux hydrogène ou alkyle
C1-C4 non substitué et R1 et R2 différents ne représentent pas l'un hydrogène et l'autre alkyle C1-C4 non substitué, ou bien lorsque X représente N, R1 et R2 forment ensemble avec X auquel ils sont liés un radical pipérazinyle, pipéridyle, pyrrolidinyle, morpholinyle ou thiomorpholinyle, * ou un groupe OR1 ou SR1 dans lequel R1 a la même signification que précédemment étant entendu que R1 ne représente pas hydrogène ou alkyle C1-C4 non substitué.

wherein X represents a nitrogen atom N to form NR1R2, an oxygen atom O to form OR1 or a sulfur atom S to form SR1 as follows: NR1R2 with R1 and R2 identical or different are selected from the atom of hydrogen; C1-C8 alkyl optionally substituted by amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1-C4 alkoxy, by pyrrolidinyl, pyridyl or phenyl; an aromatic ring as defined above; a quinuclidine radical, a pyrrolidinyl radical or a piperidyl radical optionally substituted by C1-C4 alkyl, it being understood that R1 and R2, which are identical, do not both represent hydrogen or alkyl
Unsubstituted C1-C4 and different R1 and R2 are not hydrogen and the other unsubstituted C1-C4 alkyl, or when X is N, R1 and R2 together with X to which they are attached a piperazinyl radical, piperidyl, pyrrolidinyl, morpholinyl or thiomorpholinyl; or a group OR1 or SR1 in which R1 has the same meaning as above with the proviso that R1 does not represent hydrogen or unsubstituted C1-C4 alkyl.

The present invention more specifically relates to the compounds of formula (I) as defined above in which when A represents NR1R2 is one of R1 and R2 represents the hydrogen atom and the other of R1 and R2 is chosen among the values defined for R1

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 and R2 is R1 and R2 together with the nitrogen atom to which they are attached a piperazinyl, pyrrolidinyl, piperidyl or morpholinyl radical.

parmi les groupes suivants : 4-amino-ou 4-méthylaminoou 4-diméthylamino-quinolyl ou quinolinium dont le noyau quinolinium est éventuellement substitué par un groupe méthyle ; pyridyle ; phényle éventuellement substitué par un ou plusieurs atomes d'halogène ou par un radical pipérazinyle ou alkylpipérazinyle ; alkyle en C1-C4 substitué par un radical amino, alkylamino ou dialkylamino, (phényl) (alkyl) amino, (alkylphényl) (alkyl) amino, alcoxy en C2-C4, par un radical pyrrolidinyle ou par un radical phényle, radicaux dans lesquels les groupes alkyle possèdent 1 à 4 atomes de carbone ; un radical pyrrolidinyle ; un radical pipéridyle éventuellement substitué par un radical alkyle en C1-C4 ; ou un radical quinuclidine soit un radical pyrrolidinyle, un radical morpholino ou un radical pipérazinyle éventuellement substitué par un radical alkyl C1-C4 soit un radical 0-phényle, 0-pyridyle, ou 0-alkyle substitué par un radical amino, alkylamino ou dialkylamino
Parmi les composés définis ci-dessus, on cite particulièrement les composés caractérisés en ce que

Ar, et Ar2 représentent un groupe choisi parmi les groupes suivants : 4-amino-ou 4-méthylamino-ou 4diméthylamino-quinolyl ou quinolinium dont le noyau The present invention relates more precisely to the compounds of formula (I) as defined above in which group A represents: either an amino radical substituted by a chosen radical

among the following groups: 4-amino-or 4-methylamino or 4-dimethylamino-quinolyl or quinolinium whose quinolinium ring is optionally substituted by a methyl group; pyridyl; phenyl optionally substituted with one or more halogen atoms or with a piperazinyl or alkylpiperazinyl radical; C 1 -C 4 alkyl substituted with amino, alkylamino or dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C 2 -C 4 alkoxy, by pyrrolidinyl or phenyl, radicals in which the alkyl groups have 1 to 4 carbon atoms; a pyrrolidinyl radical; a piperidyl radical optionally substituted with a C1-C4 alkyl radical; or a quinuclidine radical is a pyrrolidinyl radical, a morpholino radical or a piperazinyl radical optionally substituted by a C1-C4 alkyl radical is a 0-phenyl, 0-pyridyl or 0-alkyl radical substituted by an amino, alkylamino or dialkylamino radical;
Among the compounds defined above, the compounds characterized in that

Ar 1 and Ar 2 represent a group chosen from the following groups: 4-amino-or 4-methylamino or 4-dimethylamino-quinolyl or quinolinium whose nucleus

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quinolinium est éventuellement substitué par un groupe méthyle ; ou phényle éventuellement substitué par un ou plusieurs atomes d'halogène.

quinolinium is optionally substituted with a methyl group; or phenyl optionally substituted with one or more halogen atoms.

parmi les groupes suivants : 4-amino-ou 4-méthylaminoou 4-diméthylamino-quinolyl ou quinolinium dont le noyau quinolinium est éventuellement substitué par un groupe méthyle ; pyridyle ; phényle éventuellement substitué par un ou plusieurs atomes d'halogène ou par un radical pipérazinyle ou alkylpipérazinyle ; alkyle en C1-C4 substitué par un radical amino, alkylamino ou dialkylamino, (phényl) (alkyl) amino, (alkylphényl) (alkyl) amino, alcoxy en C2-C4, par un radical pyrrolidinyle ou par un radical phényle, radicaux dans lesquels les groupes alkyle possèdent 1 à 4 atomes de carbone ; un radical pyrrolidinyle ; un radical pipéridyle éventuellement substitué par un radical alkyle en C1-C4 ; ou un radical quinuclidine soit un radical pyrrolidinyle, un radical morpholino ou un radical pipérazinyle éventuellement substitué par un radical alkyl C1-C4 soit un radical 0-phényle, 0-pyridyle, ou 0-alkyle substitué par un radical amino, alkylamino ou dialkylamino. Among the compounds defined above, there are also particularly mentioned compounds characterized in that the group A represents: an amino radical substituted by a chosen radical

among the following groups: 4-amino-or 4-methylamino or 4-dimethylamino-quinolyl or quinolinium whose quinolinium ring is optionally substituted by a methyl group; pyridyl; phenyl optionally substituted with one or more halogen atoms or with a piperazinyl or alkylpiperazinyl radical; C 1 -C 4 alkyl substituted with amino, alkylamino or dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C 2 -C 4 alkoxy, by pyrrolidinyl or phenyl, radicals in which the alkyl groups have 1 to 4 carbon atoms; a pyrrolidinyl radical; a piperidyl radical optionally substituted with a C1-C4 alkyl radical; or a quinuclidine radical is a pyrrolidinyl radical, a morpholino radical or a piperazinyl radical optionally substituted by a C1-C4 alkyl radical is a 0-phenyl, 0-pyridyl or 0-alkyl radical substituted by an amino, alkylamino or dialkylamino radical.

Among the compounds defined above, the compounds characterized in that, when Ar 1 and Ar 2 are identical, Ar 1 and Ar 2 represent a group chosen from 4-amino or 4-methylamino or 4-dimethylamino groups, are furthermore particularly cited. -quinolyl

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 or quinolinium whose quinolinium ring is optionally substituted by a methyl group.

Among the compounds defined above, mention is made particularly of the compounds characterized in that when Ar 1 and Ar 2 are different
1. Ar, represents: * a quinoline unit substituted by at least one N (Ra) (Rb) group in which Ra and Rb, which are identical or different, represent hydrogen or a C1-C4 alkyl radical or an alkoxy or alkyl group; short chain containing 1 to 4 carbon atoms or quinoline having a quaternary nitrogen atom or benzamidine except where A is diethylamine, hydrogen or an amine group or pyridine attached in position -4 or fused with an aryl or heteroaryl group
2. Ar 2 represents a ring as defined above but different or a phenyl ring optionally substituted by a halogen, methoxy, cyano, carbonylamino, guanyl, methylthio, amino, methylamino, dimethylamino, morpholine or C 1 -C 4 alkyleneamino group. or C 2 -C 4 alkenyleneamino

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* un noyau quinoline, benzimidazole, indole, benzothiophène, benzofurane, benzothiazole, benzoxazole, carbazole, quinazoline, quinoxaline éventuellement substitué par un ou plusieurs groupes alkyle en C1-C4 ou par des groupes alkylène en C1-C4 ou alkénylène en C2-C4 Parmi les composés définis ci-dessus, on cite plus particulièrement les composés caractérisés en ce que A représente un radical amino substitué par un radical choisi parmi les groupes suivants : les radicaux 4- amino-ou 4-méthylamino-ou 4-diméthylamino-quinolyl ou quinolinium dont le noyau quinolinium est éventuellement substitué par un groupe méthyle ; les radicaux alkyle en C1-C4 substitués par un radical amino, alkylamino, dialkylamino, (phényl) (alkyl) amino, (alkylphényl) (alkyl) amino, pyrrolidinyle ou pyridyle ; ou le radical quinuclidine Parmi les composés définis ci-dessus, on cite également les composés caractérisés en ce que A représente soit un radical amino substitué par un radical pyridyle ; phényle éventuellement substitué par un radical pipérazinyle ou alkylpipérazinyle ; un radical pipéridyle éventuellement substitué par un radical alkyle en C1-C4 soit un radical pipérazinyle éventuellement substitué par un radical alkyl C1-C4
Parmi les composés définis ci-dessus, on cite encore les composés caractérisés en ce que A représente un radical 0-phényle, 0-pyridyle, ou 0-alkyle substitué par un radical amino, alkylamino ou dialkylamino
Parmi les produits préférés tels que définis cidessus, on peut citer les produits des exemples 1, 2,

a quinoline, benzimidazole, indole, benzothiophene, benzofuran, benzothiazole, benzoxazole, carbazole, quinazoline or quinoxaline ring optionally substituted by one or more C1-C4 alkyl groups or by C1-C4 alkylene or C2-C4 alkenylene groups; the compounds defined above, there are mentioned more particularly the compounds characterized in that A represents an amino radical substituted by a radical chosen from the following groups: 4-amino-or 4-methylamino or 4-dimethylamino-quinolyl radicals or quinolinium whose quinolinium nucleus is optionally substituted by a methyl group; C1-C4 alkyl radicals substituted with an amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, pyrrolidinyl or pyridyl radical; or the quinuclidine radical Among the compounds defined above, mention is also made of the compounds characterized in that A represents either an amino radical substituted with a pyridyl radical; phenyl optionally substituted with a piperazinyl or alkylpiperazinyl radical; a piperidyl radical optionally substituted by a C1-C4 alkyl radical is a piperazinyl radical optionally substituted by a C1-C4 alkyl radical;
Among the compounds defined above, the compounds characterized in that A represents an O-phenyl, O-pyridyl or O-alkyl radical substituted by an amino, alkylamino or dialkylamino radical are also mentioned.
Among the preferred products as defined above, mention may be made of the products of Examples 1, 2,

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11, 17, 19, 20, 27, 29, 31, 32 et 33 du tableau 1 cidessous qui portent respectivement les noms suivants : 2, 4-bis- (4-diméthylamino-2-méthyl-quinolin-6-yl) amino- 6- (3-diméthylamino-propyl) amino- [l, 3, triazine (exemple 1) 2, 4, 6-tris- (4-amino-2-méthyl-quinolin-6-yl) amino- [l, 3, triazine (exemple 2) 2, 4-bis- (4-amino-2-méthyl-quinolin-6-yl) amino-6- (4diméthylamino-2-méthyl-quinolin-6-yl) amino- [1, 3, triazine (exemple 11) 2, 4-bis- (4-amino-2-méthyl-quinolin-6-yl) amino-6- (quinuclidin-3-yl) amino- [l, 3, triazine (exemple 17) 2, 4-bis- (4-diméthylamino-2-méthyl-quinolin-6-yl) amino- 6- (l-méthyl-pipéridin-4-yl)- [l, 3, triazine (exemple 19) 2, 4-bis- (4-diméthylamino-2-méthyl-quinolin-6-yl) amino- 6- (l-méthyl-pipérazin-4-yl)- [l, 3, triazine (exemple 20) 2, 4-bis- (4-diméthylamino-2-méthyl-quinolin-6-yl) amino- 6- (pyridin-4-yl) méthylamino- [l, 3, triazine (exemple 27) 2, 4-bis- (4-amino-2-méthyl-quinolin-6-yl) amino-6phénoxy-[1, 3, triazine (exemple 29) 2, 4-bis- (4-amino-2-méthyl-quinolin-6-yl) amino-6- (3diméthylamino-propyl) oxy- [1, 3, triazine (exemple 31) 2, 4-bis- (4-amino-2-méthyl-quinolin-6-yl) amino-6- (pyridin-4-yl) oxy- [l, 3, triazine (exemple 32)

11, 17, 19, 20, 27, 29, 31, 32 and 33 of Table 1 below which respectively bear the following names: 2,4-bis (4-dimethylamino-2-methyl-quinolin-6-yl) amino 6- (3-dimethylamino-propyl) amino- [1,3-triazine (Example 1) 2,4,6-tris- (4-amino-2-methyl-quinolin-6-yl) amino- [1]; 3, triazine (Example 2) 2,4-bis- (4-amino-2-methyl-quinolin-6-yl) amino-6- (4-dimethylamino-2-methyl-quinolin-6-yl) amino-1, 3, triazine (Example 11) 2,4-bis- (4-amino-2-methyl-quinolin-6-yl) amino-6- (quinuclidin-3-yl) amino- [1,3-triazine (Example 17 2, 4-bis (4-dimethylamino-2-methyl-quinolin-6-yl) amino-6- (1-methyl-piperidin-4-yl) - [1,3-triazine (Example 19) 2, 4-bis- (4-dimethylamino-2-methyl-quinolin-6-yl) amino-6- (1-methyl-piperazin-4-yl) - [1,3-triazine (Example 20) 2, 4-bis (4-Dimethylamino-2-methyl-quinolin-6-yl) amino-6- (pyridin-4-yl) methylamino- [1,3] triazine (Example 27) 2, 4-bis- (4-amino) -2- 2-methyl-quinolin-6-yl) amino-6-phenoxy- [1,3] triazine (Example 29) 2,4-bis- (4-amino-2-methyl-quinolin-6-yl) amino-6- (3-methylamino-propyl) oxy- [1,3-triazine (Example 31) 2, 4-bis- (4-Amino-2-methyl-quinolin-6-yl) amino-6- (pyridin-4-yl) oxy- [1,3-triazine (Example 32)

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2, 4-bis- (4-amino-2-méthyl-quinolin-6-yl) amino-6- (phénylméthyl) oxy- [l, 3, triazine (exemple 33).

2,4-bis- (4-amino-2-methyl-quinolin-6-yl) amino-6- (phenylmethyl) oxy- [1,3] triazine (Example 33).

 It is obvious that the quinoline units may be substituted by any other group not involved in the intended application, so acridine or isoquinoline groups or quinazoline or quinoxaline or phthalazine or benzothiazine or benzoxazine or phenoxazine or phenothiazine are included in the definition of quinoline groups.

 Among the compounds of formula (I) above, those which contain two heterocycles chosen from 4-aminoquinolyl, 4-aminoquinolinium or quinolinium groups whose quinolinium nucleus is optionally substituted by a methyl group are preferred.

 Another object of the present invention relates to the use of the compounds of formula (I) as a pharmaceutical product for human use.

sont décrits ci-après. The processes for preparing the compounds of formula (I):

are described below.

General method 1
According to a first process for the preparation of the compounds of general formula (I) in which Ar, and

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Ar2 d'une part et R3 et R'3 d'autre part sont identiques et définis tels que précédemment et R représente un atome d'halogène tel que chlore ou fluor, une fonction amino, alkylamino ou dialkylamino dont les parties alkyles droites ou ramifiées contiennent de 1 à 4 atomes de carbone, alkyloxy ou alkylthio dont les parties alkyles droites ou ramifiées contiennent de 1 à 4 atomes de carbone, peuvent être obtenus par amination d'une dihalogénotriazine, très généralement une dichloro-s-triazine, de formule générale (B) dans laquelle A est défini comme ci-dessus par une amine aromatique ou hétéroaromatique de formule générale (C) dans laquelle Ar est défini comme précédemment en opérant selon le schéma 1 :

Ar2 on the one hand and R3 and R'3 on the other hand are identical and defined as above and R represents a halogen atom such as chlorine or fluorine, an amino, alkylamino or dialkylamino function whose straight or branched alkyl parts contain from 1 to 4 carbon atoms, alkyloxy or alkylthio whose straight or branched alkyl parts contain from 1 to 4 carbon atoms, can be obtained by amination of a dihalotriazine, very generally a dichloro-s-triazine, of general formula (B) wherein A is defined as above by an aromatic or heteroaromatic amine of general formula (C) wherein Ar is defined as above by operating according to Scheme 1:

Diagram 1
In the case where A represents a halogen atom, it is useful to react the corresponding 2,4,6-trihalo-striazine of general formula (B) with the aromatic or heteroaromatic amine ArNHR3 of general formula (C).

 The procedure is generally to condense one mole of dihalo-s-triazine, or trihalo-s-triazine, with 2 moles of aromatic or heteroaromatic amine. The reaction takes place in an inert medium under the conditions of

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la réaction. On peut citer parmi les solvants inertes l'acétone éventuellement aqueux ou un alcool éventuellement aqueux comme l'éthanol, ou un solvant halogéné tel que le dichlorométhane, ou un éther tel que l'oxyde de diéthyle ou le dioxane, ou un solvant aprotique polaire tel que le DMF le DMSO ou la NMP. On opère de préférence à une température comprise entre 20 C et le reflux, en présence notamment d'une base organique, telle que la triéthylamine, ou minérale, telle que la soude ou le carbonate de sodium ou de potassium. Il est également possible de ne pas utiliser de base lors de la réaction d'amination, et d'isoler un chlorhydrate du produit de formule générale (A), dont la base peut ensuite être libérée.

the reaction. Among the inert solvents, there may be mentioned acetone, which may be aqueous, or an optionally aqueous alcohol such as ethanol, or a halogenated solvent such as dichloromethane, or an ether such as diethyl ether or dioxane, or a polar aprotic solvent. such as DMF, DMSO or NMP. The reaction is preferably carried out at a temperature of between 20 ° C. and reflux, in the presence in particular of an organic base, such as triethylamine, or mineral, such as sodium hydroxide or sodium or potassium carbonate. It is also possible not to use a base during the amination reaction, and isolate a hydrochloride of the product of general formula (A), the base can then be released.

 The dihalo or trihalo-s-triazines of general formula (B) are either commercial or known, and can be obtained under the conditions described in the literature.

 The aromatic or heteroaromatic amines of general formula (C) are either known or can be easily prepared by known methods for the synthesis of aromatic or heteroaromatic amines.

 In the case where Ar1 and Ar2 are different, the triazine of general formula (A) can be obtained by sequential displacement of halogen atoms, very generally chlorine atoms, products of general formula (B) by amines AriNHR3 then Ar2NHR'3 of general formula (C) according to scheme 2:

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Schéma 2 Généralement on opère avec 1 mole de dihalogénos-triazine, ou trihalogéno-s-triazine, et 1 mole d'amine ArlNHR3. On préfère opérer dans un solvant inerte tel que l'acétone éventuellement aqueux ou un alcool éventuellement aqueux, comme l'éthanol, ou un solvant halogéné, tel que le dichlorométhane, ou un éther tel que l'oxyde de diéthyle ou le dioxane, ou un solvant aprotique polaire tel que le DMF le DMSO ou la NMP. Selon une meilleure manière de mettre en oeuvre l'invention on opère à une température comprise entre 20 C et 50oC. Ensuite on ajoute 1 mole d'amine Ar2NHR'3 au produit de formule générale (D), qui peut être éventuellement isolé. On opère notamment à une température comprise entre 50 C et le reflux.

Scheme 2 Generally one operates with 1 mole of dihalogénos-triazine, or trihalogéno-s-triazine, and 1 mole of amine ArlNHR3. It is preferred to operate in an inert solvent such as optionally aqueous acetone or an optionally aqueous alcohol, such as ethanol, or a halogenated solvent, such as dichloromethane, or an ether such as diethyl ether or dioxane, or a polar aprotic solvent such as DMF, DMSO or NMP. According to a better way of implementing the invention, the reaction is carried out at a temperature of between 20 ° C. and 50 ° C. Then 1 mole of amine Ar2NHR'3 is added to the product of general formula (D), which can optionally be isolated. It operates in particular at a temperature between 50 C and reflux.

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Advantageously, it is possible to operate under the conditions described in J. Fluor. Chem., 1988, 39 (1), 117-123.

General method 2
According to a second method, the products of general formula (A) in which ArlNHR3 and Ar2NHR'3 are defined as previously and R represents a group NR1R2 or OR1 or SR1 or alkR1R2 can also be prepared by nucleophilic displacement of a halogen atom. , generally a chlorine atom, of a product of general formula (A) in which R represents a halogen atom according to scheme 3:

R = 0 (ou F ou Br ou 1) R= NR, ou OR1 ou SR1 ou Ralk Schéma 3 On opère généralement en condensant 1 mole de produit de formule générale (A) dans lequel R représente un atome d'halogène, préférentiellement un atome de chlore, avec 1 mole d'amine R1R2NH ou d'alcoolate R10- ou de thioalcoolate RIS ou d'organométallique RlR2alkM, M pouvant représenter par exemple le magnésium ou le lithium ou le zinc. La réaction a lieu en milieu inerte dans les conditions de

R = 0 (or F or Br or 1) R = NR, or OR1 or SR1 or Ralk Scheme 3 The procedure is generally carried out by condensing 1 mole of product of general formula (A) in which R represents a halogen atom, preferentially a chlorine atom, with 1 mole of R1R2NH amine or R10- alcoholate or RIS thioalcoholate or RlR2alkM organometallic, M may represent for example magnesium or lithium or zinc. The reaction takes place in an inert medium under the conditions of

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la réaction. On peut citer parmi les solvants inertes l'acétone éventuellement aqueux ou un alcool éventuellement aqueux comme l'éthanol,, ou un solvant halogéné tel que le dichlorométhane, ou un éther tel que l'oxyde de diéthyle ou le dioxane ou le tétrahydrofurane, étant entendu que ces éthers sont les solvants utilisables lorsqu'on utilise un organométallique RlR2alkM, ou un solvant aprotique polaire tel que le DMF le DMSO ou la NMP. Lorsque le groupe entrant représente un groupe R1R2NH, on opère de préférence à une température comprise entre 200C et le reflux, en présence notamment d'une base organique, telle que la triéthylamine, ou minérale, telle que la soude ou le carbonate de sodium ou de potassium. Il est également possible de ne pas utiliser de base lors de la réaction d'amination, et d'isoler un chlorhydrate du produit de formule générale (A), dont la base peut ensuite être libérée. Lorsque le groupe entrant représente un groupe RIO'ou RIS'on opère préférentiellement avec un alcoolate ou un thioalcoolate alcalin ou alcalinoterreux, tel qu'un sel de sodium ou de potassium ou de lithium ou d'ammonium ou de césium ou de baryum, dans un solvant aprotique polaire tel que le DMF ou le DMSO ou la NMP, à une température comprise entre 50 Oc et le reflux. Lorsque le groupe entrant représente un groupe RlR2alk on opère très préférentiellement dans un éther comme l'oxyde de diéthyle ou le dioxane ou le tétrahydrofurane à une température comprise entre-70 0 et le reflux du milieu réactionnel.

the reaction. Among the inert solvents, there may be mentioned acetone, which may be aqueous, or an optionally aqueous alcohol such as ethanol, or a halogenated solvent such as dichloromethane, or an ether such as diethyl ether or dioxane or tetrahydrofuran, being It is understood that these ethers are the solvents that can be used when using an organometallic R1R2alkM, or a polar aprotic solvent such as DMF, DMSO or NMP. When the input group represents a R 1 R 2 NH group, the reaction is preferably carried out at a temperature of between 200 ° C. and reflux, in the presence in particular of an organic base, such as triethylamine, or mineral, such as sodium hydroxide or sodium carbonate or of potassium. It is also possible not to use a base during the amination reaction, and isolate a hydrochloride of the product of general formula (A), the base can then be released. When the input group represents a RIO'or RIS'on group, it is preferably carried out with an alkali or alkaline earth alcoholate or thioalcoholate, such as a sodium or potassium or lithium or ammonium or cesium or barium salt, in a polar aprotic solvent such as DMF or DMSO or NMP, at a temperature of between 50 ° C. and reflux. When the input group represents an R 1 R 2alk group, it is most preferably carried out in an ether such as diethyl ether or dioxane or tetrahydrofuran at a temperature of between -70 ° C. and the reflux of the reaction medium.

 It is understood that s-triazines of general formula can be obtained in the form of libraries, by applying the methods described in Schemes 1,2, or 3 in parallel chemistry and / or

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combinatoire en phase liquide ou en phase solide, étant entendu que, lorsqu'on travaille en phase solide, l'un quelconque des réactifs est préalablement fixé sur un support solide, choisi en fonction de la réaction chimique mise en jeu, et que ladite réaction chimique est suivie d'une opération de clivage du produit de la réaction du support solide.

combinatorial in the liquid phase or in the solid phase, it being understood that, when working in the solid phase, any one of the reagents is previously fixed on a solid support, chosen according to the chemical reaction involved, and that said reaction chemical is followed by a cleavage operation of the reaction product of the solid support.

 The present invention also relates to therapeutic compositions containing a compound according to the invention, in combination with a pharmaceutically acceptable carrier according to the chosen mode of administration. The pharmaceutical composition may be in solid, liquid or liposome form.

 Among the solid compositions include powders, capsules, tablets. Oral forms may also include solid forms protected from the acidic environment of the stomach. The supports used for the solid forms consist in particular of mineral supports such as phosphates, carbonates or organic supports such as lactose, celluloses, starch or polymers. The liquid forms consist of solutions of suspensions or dispersions. They contain as dispersive carrier either water, or an organic solvent (ethanol, NMP or others) or mixtures of surfactants and solvents or complexing agents and solvents.

 The administered dose of the compounds of the invention will be adapted by the practitioner according to the route of administration of the patient and the state of the latter.

 The compounds of the present invention may be administered alone or in admixture with other

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anticancéreux. Parmi les associations possibles on peut citer . les agents alkylants et notamment le cyclophosphamide, le melphalan, l'ifosfamide, le chlorambucil, le busulfan, le thiotepa, la prednimustine, la carmustine, la lomustine, la semustine, la steptozotocine, la decarbazine, la témozolomide, la procarbazine et l'hexaméthylmélamine * les dérivés du platine comme notamment le cisplatine, le carboplatine ou l'oxaliplatine

'les agents antibiotiques comme notamment la bléomycine, la mitomycine, la dactinomycine, . les agents antimicrotubules comme notamment la vinblastine, la vincristine, la vindésine, la vinorelbine, les taxoides (paclitaxel et docétaxel) * les anthracyclines comme notamment la doxorubicine, la daunorubicine, l'idarubicine, l'épirubicine, la mitoxantrone, la losoxantrone * les topoisomérases des groupes I et II telles. que l'étoposide, le teniposide, l'amsacrine, l'irinotecan, le topotecan et le tomudex, 'les fluoropyrimidines telles que le 5fluorouracile, l'UFT, la floxuridine,

'les analogues de cytidine telles que la 5-azacytidine, la cytarabine, la gemcitabine, la 6-mercaptomurine, la 6-thioguanine

cancer. Among the possible associations we can mention. alkylating agents and especially cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednimustine, carmustine, lomustine, semustine, steptozotocine, decarbazine, temozolomide, procarbazine and hexamethylmelamine * platinum derivatives such as cisplatin, carboplatin or oxaliplatin

antibiotic agents such as bleomycin, mitomycin, dactinomycin, etc. antimicrotubules such as vinblastine, vincristine, vindesine, vinorelbine, taxoids (paclitaxel and docetaxel) * anthracyclines such as doxorubicin, daunorubicine, idarubicin, epirubicin, mitoxantrone, losoxantrone * topoisomerases of groups I and II such. etoposide, teniposide, amsacrine, irinotecan, topotecan and tomudex, fluoropyrimidines such as fluorouracil, UFT, floxuridine,

cytidine analogues such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomurine, 6-thioguanine

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les analogues d'adénosine telles que la pentostatine, la cytarabine ou le phosphate de fludarabine * le méthotrexate et l'acide folinique 'les enzymes et composés divers tels que la L-asparaginase, l'hydroxyurée, l'acide transrétinoique, la suramine, la dexrazoxane, l'amifostine, l'herceptin ainsi que les hormones oetrogéniques, androgéniques

. les agents antivasculaires tels que les dérivés de la combretastatine ou de la colchicine et leur prodrug.

adenosine analogs such as pentostatin, cytarabine or fludarabine phosphate; methotrexate and folinic acid; various enzymes and compounds such as L-asparaginase, hydroxyurea, transretinic acid, suramin, dexrazoxane, amifostine, herceptin as well as androgenic, androgenic hormones

. antivascular agents such as derivatives of combretastatin or colchicine and their prodrug.

 It is also possible to associate the compounds of the present invention with radiation treatment. These treatments can be administered simultaneously, separately, sequentially. The treatment will be adapted to the patient to be treated by the practitioner.

 The stabilization activity of G-quadruplexes can be determined by a method using the formation of a complex with fluorescein, the experimental protocol of which is described below.

oligonucleotides
All olignucleotides, modified or unmodified, were synthesized by Eurogentec SA, Seraing, Belgium. The oligonucleotide FAM + DABCYL carries the reference catalog, OL-0371-0802. It has the sequence: GGGTTAGGGTTAGGGTTAGGG corresponding to 3.5 repetitions of the human telomeric motif (strand rich in G). Fluorescein is attached to the 5 'end, DABCYL at the 3' end, by the chemical arms described by Eurogentec. The concentration of the samples is

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vérifiée par spectrophotométrie, en enregistrant le spectre d'absorbance entre 220 et 700 nm et en utilisant le coefficient d'extinction molaire fourni par le fournisseur.

verified by spectrophotometry, recording the absorbance spectrum between 220 and 700 nm and using the molar extinction coefficient provided by the supplier.

fluorescent est ajouté à la concentration finale de 0. 2 uM. tampons
All experiments were performed in 10 mM sodium cacodylate pH 7.6 buffer containing 0.1 M Lithium Chloride (or Sodium Chloride). The absence of fluorescent contamination in the buffer was previously verified. The oligonucleotide

fluorescent is added to the final concentration of 0.2 μM.

Fluorescence Study All fluorescence measurements were performed on a Spex Fluorolog DM1B apparatus, using an excitation line width of 1.8 nm and an emission bandwidth of 4.5 nm. The samples are placed in a 0.2 x 1 cm micro quartz dish. The temperature of the sample is controlled by an external water bath.

The oligonucleotide alone was analyzed at 20.30, 40.50, 60.70 and 800C. The emission spectra are recorded using an excitation wavelength of 470 nm. Excitation spectra are recorded using either 515 nm or 588 nm as the emission wavelength. The spectra are corrected for the response of the instrument by reference curves. A significant extinction (80-90%) of fluorescein fluorescence at room temperature is observed, in agreement with an intramolecular fold of the oligonucleotide at 20 C in the form of a Gquadruplex, which induces a juxtaposition of its

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extrémités 5'et 3', respectivement liées à la fluoresceine et au DABCYL. Cette juxtaposition entraîne un phénomène déjà décrit d'extinction de fluorescence, utilisé pour les"Molecular Beacons".

5 'and 3' ends respectively bound to fluorescein and DABCYL. This juxtaposition results in a previously described phenomenon of fluorescence quenching, used for "Molecular Beacons".

concentration en brin de 0. 2 pM dans un tampon 0. 1 M LiCl 10 mM cacodylate pH 7. 6 est préalablement préparée, chauffée brièvement à 90 C et refroidie lentement à 20 C, puis distribuée par aliquots de 600 pl dans les cuves de fluorescence. 3 pl d'eau (pour le contrôle) ou 3 pl du produit à tester (stock à 200 pM, concentration finale 1 pM) sont alors ajoutés et mélangés. Les échantillons sont alors laissés à incuber pendant au moins 1 heure à 20 Oc avant chaque mesure. Tm in fluorescence
A stock solution of oligonucleotide at

strand concentration of 0. 2 μM in a buffer 0. 1 M LiCl 10 mM cacodylate pH 7. 6 is prepared beforehand, heated briefly to 90 ° C and cooled slowly to 20 ° C., then distributed in aliquots of 600 μl in the vats of fluorescence. 3 μl of water (for control) or 3 μl of the product to be tested (stock at 200 μM, final concentration 1 μM) are then added and mixed. The samples are then allowed to incubate for at least 1 hour at 20 ° C before each measurement.

The use of longer incubation times (up to 24 hours) has no influence on the result obtained.

température initiale de 20 C, porté à 800C en 38 minutes, laissé 5 minutes à 80 C, puis refroidi à 20 C en 62 minutes. Durant ce temps, la fluorescence est mesurée simultanément à deux longueurs d'onde d'émission (515 nm et 588 nm) en utilisant 470 nm comme longueur d'onde d'excitation. Une mesure est effectuée toutes les 30 secondes. La température du bain-marie est enregistrée en parallèle, et le profil de fluorescence en fonction de la température est reconstitué à partir de ces valeurs. Les profils de

fluorescence sont ensuite normalisés entre 20 C et 80 C, et la température pour laquelle l'intensité d'émission à 515 nm est la moyenne de celles à haute et basse température est appelée Tm. Dans ces conditions, Each experiment only allows the measurement of a single sample. This one is first incubated at a

initial temperature of 20 C, heated to 800C in 38 minutes, left for 5 minutes at 80 C, then cooled to 20 C in 62 minutes. During this time, the fluorescence is measured simultaneously at two emission wavelengths (515 nm and 588 nm) using 470 nm as the excitation wavelength. A measurement is performed every 30 seconds. The temperature of the water bath is recorded in parallel, and the fluorescence profile as a function of temperature is reconstituted from these values. Profiles of

The fluorescence is then normalized between 20 C and 80 C, and the temperature at which the emission intensity at 515 nm is the average of those at high and low temperature is called Tm.

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le Tm de l'échantillon de référence sans addition de produit est de 44 C dans un tampon Chlorure de Lithium. Cette température est portée à plus de 55 Oc dans un tampon Chlorure de Sodium. L'addition d'un composé stabilisant le G-quadruplex induit une augmentation du Tm. Cette augmentation est jugée significative si elle est supérieure à 3 .

the Tm of the reference sample without product addition is 44 C in Lithium Chloride buffer. This temperature is increased to over 55 ° C in a Sodium Chloride buffer. The addition of a G-quadruplex stabilizing compound induces an increase in Tm. This increase is judged significant if it is greater than 3.

The biological activity antitélomerase is determined by the following experimental protocol:
Preparation of the extract enriched in human telomerase activity
The leukemia line HL60 is obtained from the ATCC (Americam Type Culture Collection, Rockville USA). The cells are cultured in suspension in RPMI 1640 medium containing 2 mM L-Glutamine, 200 U / ml Penicillin, 200 μg / ml Streptomycin, 50 μg / ml Gentamycin and 10% inactivated fetal calf serum supplemented with heat.

proteines de l'extrait est effectué par la méthode de Bradford. L'extrait est conservé à-80 C. An aliquot of 105 cells is centrifuged at 3000xG and the supernatant discarded. The cell pellet is resuspended by several successive pipettings into 200 μl of lysis buffer containing CHAPS 0. 5%, TrisHCl pH 7.5 10 mM, 1 mM MgCl 2, 1 mM EGTA, 5 mM ss-mercaptoethanol, 0.1 mM PMSF and glycerol. 10% and is kept in ice for 30 minutes. The lysate is centrifuged at 16,000xg for 20 minutes at 4 ° C. and 160 μl of the supernatant is recovered. The dosage of

Proteins from the extract is made by the Bradford method. The extract is stored at -80 C.

Assay of telomerase activity
Inhibition of telomerase activity is determined by an extension protocol of

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l'oligonucléotide TS (5'AATCGTTCGAGCAGAGTT3'), en présence d'un extrait cellulaire enrichi en activité télomérase et des composés qui sont ajoutés à différentes concentrations (10,1, 0.1 et 0,01 pM). La réaction d'extension est suivie d'une amplification PCR des produits d'extension à l'aide des oligonucléotides TS et CXext (5'GTGCCCTTACCCTTACCCTTACCCTAA3').

the oligonucleotide TS (5'AATCGTTCGAGCAGAGTT3 '), in the presence of a cell extract enriched in telomerase activity and compounds which are added at different concentrations (10.1, 0.1 and 0.01 μM). The extension reaction is followed by PCR amplification of the extension products using the oligonucleotides TS and CXext (5'GTGCCCTTACCCTTACCCTTACCCTAA3 ').

Produit à tester ou solvant sous un volume de 5 ul Eau bi-distillée QS 50 pl The reaction medium is prepared according to the following composition:
Tris HCl pH 8.3 20 mM
1.5 mM MgCl2
Tween 20 0, 005% (W / V)
EGTA 1 mM dATP 50 μM dGTP 50 μM dCTP 50 μM dTTP 50 μM
Oligonucleotide TS 2 μg / ml
Oligonucleotide CXext 2 pg / ml
Serum Albumin bovine 0.1 mg / ml
Taq DNA polymerase 1 U / ml alpha 32P dCTP (3000 Ci / mmol) 0.5 l
Telomerase Extract 200 ng under a volume of 10 pl

Test product or solvent in a volume of 5 μl Bi-distilled water QS 50 μl

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Les oligonucléotides sont obtenus auprès d'Eurogentec (Belgique) et sont conservés à-20 C à une concentration stock de 1 mg/ml dans de l'eau distillée.

The oligonucleotides are obtained from Eurogentec (Belgium) and are stored at -20 ° C. at a stock concentration of 1 mg / ml in distilled water.

 The reaction samples are assembled in 0.2 ml PCR tubes and a drop of paraffin oil is deposited on each of the reactions of the experiment before the closure of the tubes.

The reaction samples are then incubated in a Cetus 4800 PCR apparatus according to the following temperature conditions:
15 minutes at 300C,
1 minute at 90 C, followed by 30 cycles of,
30 seconds at 94OC,
30 seconds at 50 C, and 1 minute 30 seconds at 72OC, followed by a final cycle of 2 minutes at 72OC.

For each of the samples, a 10 μl aliquot is pipetted under the oil layer and mixed with 5 μl of a depot buffer containing:
TBE 3X glycerol 32 (w / v)
Bromophenol blue 0. 03%
Xylene cyanol 0. 03%
The samples are then analyzed by electrophoresis in 12% acrylamide gel in 1 × TBE buffer for 1 hour at a voltage of 200 volts, using a Novex electrophoresis system.

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The acrylamide gels are then dried on a Whatmann paper sheet 3 mm at 800C for 1 hour.

InstantImager (Pacard). The analysis and the quantification of the products of the reaction are carried out using a device

InstantImager (Pacard).

 For each concentration of test compound, the results are expressed as percent inhibition of the reaction and calculated from the untreated enzymatic control and the sample without enzyme (white) according to the following formula: (Compound value-white value / Enzyme control value - white value) x 100.

 The concentration of compound inducing a 50% inhibition of the telomerase reaction (IC50) is determined using a semi-log plot of the inhibition values obtained as a function of each of the concentrations of test compound.

% de la réaction télomérase est notamment inférieure à 5 uM. It is considered that a compound is active as an antituherase agent when the inhibiting amount

% of the telomerase reaction is in particular less than 5 μM.

The cytotoxic biological activity on human tumor lines is determined according to the following experimental protocol:
The A549 human cell lines originate from the ATCC (Americam Type Culture Collection, Rockville USA). A549 cells are cultured in a culture flask in RPMI 1640 medium, 2 mM L-Glutamine, 200 U / ml Penicillin,

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streptomycine 200 ug/ml et additionné de 10 % de sérum foetal de veau inactivé par la chaleur. Les cellules KB sont cultivées en couche en flacon de culture dans du milieu de Dulbelco's contenant, L-Glutamine à 2 mM, Pénicilline 200 U/ml, streptomycine 200 ug/ml et additionné de 10 % de sérum foetal de veau inactivé par la chaleur.

streptomycin 200 μg / ml and supplemented with 10% heat-inactivated fetal calf serum. The KB cells are cultured in a culture flask in Dulbelco's medium containing 2 mM L-Glutamine, 200 U / ml Penicillin, 200 μg / ml streptomycin and 10% heat-inactivated fetal calf serum supplemented with heat-inactivated calf serum. .

 The cells in the exponential phase of growth are trypsinized, washed in IX PBS and are seeded in 96-well microplates (Costar) at a rate of 4x104 cells / ml for A549 and 1.5 × 10 4 cells / ml (0.2 ml / well) and then incubated for 96 hours. hours in the presence of varying concentrations of product to be studied (10.1, 0.1 and 0.01 μM, each point in quadruplicate). 16 hours before the end of incubation, 0.02% neutral red is added to each well. At the end of the incubation, the cells are washed with 1X PBS and lysed with 1% sodium lauryl sulfate. Cellular incorporation of the dye, which reflects cell growth, is evaluated spectrophotometrically at a wavelength of 540 nm for each sample using a Dynatech MR5000 reading device.

For each concentration of test compound, the results are expressed as a percentage of cell growth inhibition and calculated from the untreated control and cell-free culture medium (blank) according to the following formula: (Compound value-white value / Value cell-value white control) x 100
The compound concentration inducing a 50% inhibition of growth (IC50) is determined using a semi-graphical representation.

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logarithmique des valeurs d'inhibition obtenues en fonction de chacune des concentrations de composé testée.

logarithmic inhibition values obtained as a function of each of the concentrations of test compound.

It is considered that a compound is active as a cytotoxic agent if the inhibitory concentration of 50% of the growth of the tumor cells tested is in particular less than 10 .mu.M.

The following nonlimiting examples are given to illustrate the invention.

Example 1 Preparation of N, N-bis- (4-dimethylamino-2-methyl-quinolin-6-yl) -N "- (3-dimethylamino-propyl) - [1,3,5] triazine In a 250-mL flask containing 50 ml of DMF, with stirring, 0.5 g (0. 0036 mol) of potassium carbonate, 1 g (0. 00189 mol) of N6- [4- (2methyl-4-dimethylamino-quinolin-6) are successively charged. ylamino) -6-chloro- [1, 3, 5] triazin-2-yl] -4-dimethylamino-2-methylquinoline-6-amine prepared according to patent W0001561 and 1 mL (0. 0078 mol) of N, N -dimethyl-1,3-propanediamine, then heated for 15 hours at 1000 C. The reaction medium is concentrated and taken up in 100 ml of water The precipitate formed is filtered off, washed with 2x50 ml of 1N NaOH and then dried.

1.2 g of N, N'-bis- (4-dimethylamino-2-methyl-quinolin-6-yl) -N- (3-dimethylamino-propyl) - [1,3,5] triazine are thus obtained. purified by flash chromatography on 30 g of silica (35-70hum) eluting with a mixture (85/10/5) of dichloromethane, methanol and triethylamine. 0.45 g (41%) of N, N'-bis (4-dimethylamino-2-methyl-quinolin-6-yl) -N "- (3-dimethylamino-propyl) are then obtained after drying under vacuum at 400 ° C. [1, 3, 5] triazine, in the form of a yellow powder whose characteristics are as follows:

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- analyse élémentaire : toc=64. 845 (cal=66. 3) ; % H=6. 855 (cal=7. 13) ; kan=25. 275 (cal=26. 58) ; - Spectre de R. M. N. li (300 MHz, (CD3) 2SO d6, Il en ppm) : 1, 73 (mt : 2H) ; 2, 17 (s : 6H) ; 2, 33 (t large, J = 7 Hz : 2H) ; 2, 53 (s large : 6H) ; 2, 92 (mf : 12H) ; 3, 43 (mt : 2H) ; 6, 51 et 6, 53 (2 s larges : 2H en totalité) ; 7, 06 (mf : 1H) ; 7, 51 (mt : 2H) ; de 8, 10 à 8, 30 (mt : 3H) ; 8,38 (mf : 1H) ; 9,24 (s large : 1H) ; 9,37 (s large : 1H).

- elemental analysis: toc = 64. 845 (cal = 66, 3); % H = 6. 855 (cal = 7, 13); kan = 25. 275 (cal = 26.58); 1 H NMR Spectrum (300 MHz, (CD3) 2SO d6, 11 ppm): 1.73 (mt: 2H); 2, 17 (s: 6H); 2.33 (broad t, J = 7 Hz: 2H); 2. 53 (bs: 6H); 2.92 (mp: 12H); 3.43 (mt: 2H); 6, 51 and 6, 53 (2s wide: 2H in total); 7.06 (mf: 1H); 7, 51 (mt: 2H); from 8, 10 to 8, 30 (mt: 3H); 8.38 (mf: 1H); 9.24 (brs: 1H); 9.37 (s wide: 1H).

Table 1 below gives the chemical structures as well as the G-quartet, antitelomerase and cytotoxic activities of 33 products which constitute, in the chronological order in which this table states them, Examples 1 to 33 of the present invention which illustrate the present invention without limiting it.

4 mole-équivalents de R1-NH-R2 et 30 mg de carbonate de potassium dans 5 mL de DMF. On chauffe à 800 pendant une nuit. Après refroidissement, on dilue avec 30 mL d'eau et on filtre le précipité obtenu. Le produit brut ainsi isolé est généralement propre (pureté LC/MS > Examples 1 to 28 described in Table 1 can be prepared by parallel synthesis in a liquid medium: In a magnetic heating reactor with Zymark condenser, of the STEM RS2050 type containing 25 wells in parallel provided with a 50 ml glass tube, introduced 50 mg of

4 mole-equivalents of R1-NH-R2 and 30 mg of potassium carbonate in 5 mL of DMF. Heat at 800 overnight. After cooling, it is diluted with 30 ml of water and the precipitate obtained is filtered off. The crude product thus isolated is generally clean (purity LC / MS>

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90%), il peut cependant être purifié par LC/MS en utilisant une colonne de silice C18 Waters Xterra 3. 5 uM, de diamètre 3 mm et de longueur 50 mm, en éluant par un gradient linéaire d'élution constitué au temps initial (to = 0 mn) par de l'eau additionnée de 0,05% de TFA et au temps final (tf = 4 mn) par de l'acétonitrile contenant 0,05% de TFA.

90%), it can however be purified by LC / MS using a C18 Waters Xterra 3. 5 μM silica column, with a diameter of 3 mm and a length of 50 mm, eluting with a linear elution gradient constituted at the initial time. (T = 0 min) with water containing 0.05% TFA and at the final time (tm = 4 min) with acetonitrile containing 0.05% TFA.

et on chauffe au reflux pendant une nuit. Après refroidissement, on dilue avec 30 mL d'eau et on filtre le précipité obtenu. Le produit brut ainsi isolé est purifié par LC/MS en utilisant une colonne de silice C18 Waters Xterra 3. 5 uM, de diamètre 3 mm et de longueur 50 mm, en éluant par un gradient linéaire d'élution constitué au temps initial (tO = 0 mn) par de l'eau additionnée de 0,05% de TFA et au temps final (tf = 4 mn) par de l'acétonitrile contenant 0,05% de TFA. Examples 29 to 33 described in Table 1 can be prepared by parallel synthesis in a liquid medium: In a magnetic heating reactor with Zymark condenser, of the STEM RS2050 type containing 25 wells in parallel equipped with a 50 ml glass tube, introduced 2 mole-equivalents of sodium hydride and 2 mole-equivalents of R10H in 5 mL of dioxane. It is brought to 400 for 30 minutes. Then 50 mg of

and refluxed overnight. After cooling, it is diluted with 30 ml of water and the precipitate obtained is filtered off. The crude product thus isolated is purified by LC / MS using a C18 Waters Xterra 3. 5 μM silica column, with a diameter of 3 mm and a length of 50 mm, eluting with a linear elution gradient constituted at the initial time (t0 = 0 min) with water containing 0.05% TFA and at the final time (tf = 4 min) with acetonitrile containing 0.05% TFA.

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By operating as for Examples 29 to 33, but replacing R10H by R1SH, the products of general formula (I) in which A represents SR1 with R1 as defined above can be obtained.

Example 34
The G-quartet, antitelomerase and cytotoxic activities of the various compounds exemplified 1 to 33, given in Table 1 are determined according to the operating procedures described above.

Claims (2)

A pyridine or a benzamidine or a quinoline having a nitrogen atom in quaternary form or Rb, which are identical or different, represent hydrogen or a C1-C4 alkyl radical, (or) an alkoxy or short-chain alkyl group; C1-C4 or 0 a quinoline optionally substituted by at least one N (Ra) (Rb) group in which Ra and 0 a pyridine, the aromatic ring represents 0 a benzamidine or a quinoline having a nitrogen atom in quaternary form or Rb, which are identical or different, represent hydrogen or a C1-C4 alkyl radical, (or) a C1-C4 short chain alkoxy or alkyl group or 0 a quinoline optionally substituted by at least one N (Ra) group (Rb in which Ra and Claims 1-Compounds fixing the G-quadruplex structure of DNA or RNA characterized in that they correspond to the following general formula: aromatic ring nitrogen-NF-distribution-NR'3-aromatic ring in which the aromatic nitrogen cycle Represents: <Desc / CLMS Page number 42> OR1 or a sulfur atom to form S SR1, where R1 and R2 are identical or different are selected from hydrogen; C1-C8 alkyl optionally substituted with a mono or bi or tricyclic heterocyclic ring having from 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-C6 alkyl groups; C4 or with C1-C4 alkylene or C2-C4 alkenylene groups R3 and R'3, which may be identical or different, represent, independently of one another, hydrogen or a C1-C4 alkyl radical, the distributor represents: a triazine group optionally substituted with a radical XR1 (R2) in which X represents a nitrogen atom N to form NR1R2, a linear or branched C1-C6 alkyl radical to form alkR1R2, an oxygen atom O to form C1- C4; amino, C1-C4 alkylamino, C1-C4 dialkylamino for each alkyl group and the alkyl portions of which may together form a C3-C8 ring, nitro; C1-C4 alkyleneamino; C 2 -C 4 alkenyleneamino; cyano; carbonylamino optionally substituted by one or more C1-C4 alkyl guanyl groups; alkylthio at a phenyl ring optionally substituted with a halogen group; C1-C6 alkoxy or a diazine group optionally substituted by the same groups as triazine or a salt thereof, these compounds being in any isomeric form possible racemic, enantiomeric and diastereoisomeric; . C4, C1-C4thioalkoxy, trifluoromethyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, pyridyl or phenyl; an aromatic ring as defined above; a quinuclidine radical, a pyrrolidinyl, piperazinyl, morpholinyl, pyridyl radical or a piperidyl radical optionally substituted with C1-C4 alkyl, it being understood that both R1 and R2 are identical and do not represent hydrogen or unsubstituted C1-C4 alkyl and different R1 and R2 are not one hydrogen and the other unsubstituted C1-C4 alkyl or when X is N or alkyl, R1 and R2 together with X to which they are bonded a 3 to 6-membered monocyclic or 8 to 10-membered bicyclic radical saturated or unsaturated chain members optionally containing one or two identical or different heteroatoms chosen from N, an amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C 1 -C 6 alkoxy radical; number 44> 2-Compounds fixing the G-quadruplex structure of telomeres characterized in that they correspond to the general formula as defined in claim 1. C4, by a pyrrolidine radical nyl, pyridyl or with a phenyl radical; an aromatic ring as defined in claim 1; a quinuclidine radical, a pyrrolidinyl radical or a piperidyl radical optionally substituted by C1-C4 alkyl, it being understood that R1 and R2 are identical and do not represent hydrogen or unsubstituted C1-C4 alkyl and different R1 and R2 do not represent hydrogen. and the other unsubstituted C1-C4 alkyl, or when X is N, R1 and R2 together with X to which they are attached are piperazinyl, piperidyl, 3-Compounds according to claim 1 or 2, characterized in that the dispatcher represents: a triazine group optionally substituted with a radical XR1 (R2) in which X represents a nitrogen atom N to form NR1R2, an oxygen atom O to form OR1 or a sulfur atom S to form SR1, with R1 and R2 identical or different are selected from the hydrogen atom; C1-C8 alkyl optionally substituted with amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1-C6 alkoxy, pyrrolidinyl, morpholinyl or thiomorpholinyl, or a diazine group optionally substituted by the same groups as triazine or a salt thereof, these compounds being in all the possible isomeric forms racemic, enantiomers and diastereoisomers. 4-Compounds according to any one of claims 1 to 3 characterized in that the diazine groups are pyrimidines and quinazolines. 5-Compounds according to any one of claims 1 to 4 characterized in that XR1 (R2) is such that when X represents N, one of R1 and R2 represents the hydrogen atom and the other of R1 and R2 is selected from the values defined for R1 and R2 is R1 and R2 together with the nitrogen atom to which they are attached a piperazinyl, pyrrolidinyl, piperidyl or morpholinyl radical. A represents a radical XR1 (R2) in which X represents a nitrogen, oxygen, sulfur atom or an alkyl radical in which: 6-Compounds according to claim 1 characterized in that they correspond to the formula (I ) below: C1-C6 to form one of the following radicals: NR1R2 with R1 and R2, the same or different, are selected from hydrogen; C1-C8alkyl optionally substituted with amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1-C4alkoxy, C1-C4thioalkoxy, trifluoromethyl, pyrrolidinyl, piperidyl, piperazinyl morpholinyl, pyridyl or phenyl; an aromatic ring as defined in claim 1; a quinuclidine radical, a pyrrolidinyl, piperazinyl, morpholinyl, pyridyl radical or a piperidyl radical optionally substituted with C1C4 alkyl, it being understood that R1 and R2 are identical and do not represent hydrogen or unsubstituted C1C4 alkyl and R1 and R2 different from each other do not represent hydrogen and the other unsubstituted C1-C4 alkyl or when X is N or alkyl, R1 and R2 together with X to which they are bonded a 3- to 6-membered monocyclic or 8 to 10-membered bicyclic radical saturated or unsaturated optionally containing one or two identical or different heteroatoms selected from N, O or S, e is a group OR1 or SR1 wherein R1 has the same meaning as above with the proviso that R1 does not represent hydrogen or unsubstituted C1-C4 alkyl, or Has an alkyl group containing 1 to 6 carbon atoms substituted by R1 R2 as defined above - R3 and R'3, identical or di The following are, independently of one another, hydrogen or an alkyl group C1-C4-Ar1 and Ar2 which are identical or different when Ar and Ar2 are identical: * a quinoline unit optionally substituted with at least one N group (Ra) (Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a C1-C4 alkyl radical, (or) a short-chain alkoxy or alkyl group containing 1 to 4 carbon atoms or a quinoline having a nitrogen atom in quaternary form or a benzamidine or pyridine attached at the 4-position or fused with an aryl or heteroaryl group optionally substituted with a C1-C4 alkyl group when Ar1 and Ar2 are different Ar1 and Ar2 both represent one of the possibilities mentioned above for Ar 1 and Ar 1 where Ar 1 represents one of the above possibilities and Ar 2 represents a phenyl ring optionally substituted with a halogen, alkoxy group or C1-C4, cyano, carbonylamino optionally substituted with one or more C4 for each C1-C4 alkyl, nitro, C1-C4 alkyleneamino, (or) alkenyleneamino group, or a piperazinyl radical optionally substituted with a C1-C4 alkyl radical, a mono or bi or tricyclic heterocyclic ring having 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; C4 or a C1-C4 alkylene or C2-C4 alkenylene group or a salt thereof, these compounds of formula (I) being in all possible isomeric forms racemic, enantiomeric and diastereoisomeric. a plurality of C1-C4 alkyl, guanyl, C1-C4 alkylthio, amino, C1-C4 alkylamino, C1-C4 dialkylamino groups represents a radical XR1 (R2) in which X represents a nitrogen atom, oxygen atom, sulfur or a C1-C6 alkyl radical to form one of the following radicals: in which: 7-Compounds characterized in that they correspond to the formula (I) below: <Desc / Clms Page number 49> NR1R2 with R1 and R2 identical or different are selected from the hydrogen atom; C1-C8alkyl optionally substituted with amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1-C4alkoxy, C1-C4thioalkoxy, trifluoromethyl, pyrrolidinyl, piperidyl, piperazinyl morpholinyl, pyridyl or phenyl; an aromatic ring as defined in claim 1; a quinuclidine radical, a pyrrolidinyl, piperazinyl, morpholinyl, pyridyl radical or a piperidyl radical optionally substituted with C1-C4 alkyl, it being understood that both R1 and R2 are identical and do not represent hydrogen or unsubstituted C1-C4 alkyl and different R1 and R2 do not are not one hydrogen and the other unsubstituted C1-C4 alkyl or when X is N or alkyl, R1 and R2 together with X to which they are bonded a 3 to 6-membered monocyclic or 8 to 10-membered bicyclic radical saturated or unsaturated chain members optionally containing one or two identical or different heteroatoms chosen from N, O or S; e is a group OR1 or SR1 in which R1 has the same meaning as above, provided that R1 does not represent hydrogen or C1-C4 alkyl not substituted, or e an alkyl group containing 1 to 6 carbon atoms substituted by R1 R2 as defined above </ a> quinoline motif evolved ntually substituted by at least one N (Ra) (Rb) group in which Ra and Rb, which are identical or different, represent hydrogen or a C1-C4 alkyl radical, (or) an alkoxy or short-chain alkyl group containing - R3 and R'3, which may be identical or different, represent, independently of one another, hydrogen or a C1-C4 alkyl group - Ar1 and Ar2, which are identical or different, represent * when Ar1 and Ar2 are identical: 1 to 4 carbon atoms or quinoline having a nitrogen atom in quaternary form or benzamidine or pyridine attached at the 4-position or fused with an aryl or heteroaryl group optionally substituted with a C1-C4 alkyl group * when Ar, and Ar2 are different. Ar 1 and Ar 2 both represent one of the possibilities mentioned above for Ar, and Ar 2 or Ar represents one of the above possibilities and Ar 2 represents a phenyl ring optionally substituted with a halogen, alkoxy group or C1-C4, cyano, carbonylamino optionally substituted by one or more C1-C4 alkyl, guanyl, C1-C4 alkylthio, amino, C1-C4 alkylamino, C1-C4 dialkylamino groups; <Desc / Clms Page number 51>  C4 for each alkyl group, nitro, C1-C4 alkyleneamino, (or) alkenyleneamino C2-C4, or a piperazinyl radical optionally substituted by a C1-C4 alkyl radical, * a mono or bi or tricyclic heterocyclic ring having 0 to 2 ring heteroatom with the proviso that at least one heteroatom is present in at least one ring optionally substituted by one or more C 1 -C 4 alkyl groups or C 1 -C 4 alkylene or C 2 -C 4 alkenylene groups or one of its salts, these compounds of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers.

8-Compounds according to claim 6 or 7, characterized in that A represents a radical XR1 (R2) in which X represents a nitrogen atom N to form NR1R2, an oxygen atom O to form OR1 or a sulfur atom S to form SR1 as follows: NR1R2 with R1 and R2 identical or different are selected from hydrogen; C1-C8 alkyl optionally substituted by amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1-C4 alkoxy, by pyrrolidinyl, pyridyl or phenyl; an aromatic ring as defined in claim 1; a quinuclidine radical, a pyrrolidinyl radical or a piperidyl radical optionally substituted with C1-C4 alkyl <Desc / Clms Page number 52> Unsubstituted C1-C4, or when X is N, R1 and R2 together with X to which they are attached a piperazinyl, piperidyl, pyrrolidinyl, morpholinyl or thiomorpholinyl radical, e or a group OR1 or SR1 in which R1 has the same meaning as previously being understood that R1 does not represent hydrogen or unsubstituted C1-C4 alkyl, or a salt thereof, these compounds being in all possible isomeric forms racemic, enantiomers and diastereoisomers. Unsubstituted C4 and different R1 and R2 do not represent one hydrogen and the other alkyl  it being understood that R1 and R2 are identical and do not both represent hydrogen or Cl-

9-Compounds according to any one of claims 6 to 8 characterized in that when A represents NR1R2 is one of R1 and R2 represents the hydrogen atom and the other of R1 and R2 is selected from the defined values for R1 and R2, R1 and R2 together with the nitrogen atom to which they are attached form a piperazinyl, pyrrolidinyl, piperidyl or morpholinyl radical.  group selected from the following groups: 4-amino or 4-methylamino or 4-dimethylamino-quinolyl or quinolinium whose quinolinium ring is optionally substituted by a methyl group; or phenyl optionally substituted with one or more halogen atoms.

10-Compounds according to any one of claims 1 to 8 characterized in that Ar, and Ar2 represent a 11-Compounds according to any one of claims 6 to 8 characterized in that the group A represents: <Desc / Clms Page number 53>  an amino radical substituted with a radical chosen from the following groups: 4-amino or 4-methylamino or 4-dimethylamino-quinolyl or quinolinium, the quinolinium ring of which is optionally substituted by a methyl group; pyridyl; phenyl optionally substituted with one or more halogen atoms or with a piperazinyl or alkylpiperazinyl radical; C 1 -C 4 alkyl substituted with amino, alkylamino or dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C 2 -C 4 alkoxy, by pyrrolidinyl or phenyl, radicals in which the alkyl groups have 1 to 4 carbon atoms; a pyrrolidinyl radical; a piperidyl radical optionally substituted with a C1-C4 alkyl radical; or a quinuclidine radical is a pyrrolidinyl radical, a morpholino radical or a piperazinyl radical optionally substituted by a C1-C4 alkyl radical is a 0-phenyl, 0-pyridyl or 0-alkyl radical substituted by an amino, alkylamino or dialkylamino radical 12 -Compounds according to any one of Claims 1 to 8, characterized in that when Ar and Ar2 are identical, Ar and Ar2 represent a group chosen from 4-amino-or 4-methylamino-or 4-dimethylamino-quinolyl groups or quinolinium whose quinolinium nucleus is optionally substituted by a methyl group.

13-Compounds according to any one of claims 1 to 8 characterized in that when Ar, and Ar2 are different Arl represents: a quinoline unit substituted by at least one N (Ra) (Rb) group in which Ra and Rb <Desc / Clms Page number 54> Ar 2 represents a ring as defined above but different or a phenyl ring optionally substituted by a halogen, methoxy, cyano, carbonylamino, guanyl, methylthio, amino, methylamino, dimethylamino, morpholine, C 1 -C 4 alkyleneamino or alkenyleneamino group; C2-C4 * a quinoline, benzimidazole, indole, benzothiophene, benzofuran, benzothiazole, benzoxazole, carbazole, quinazoline, quinoxaline optionally substituted by one or more C1-C4 alkyl groups or C1-C4 alkylene or alkenylene groups; C2-C4 14-Compounds according to any one of Claims 6 to 8, characterized in that A represents an amino radical substituted by a radical chosen from the following groups: 4-amino or 4-methylamino or 4-dimethylaminoquinolyl radicals or quinolinium whose nucleus  the same or different represent hydrogen or a C1-C4 alkyl radical or an alkoxy or short chain alkyl group containing 1 to 4 carbon atoms or a quinoline having a nitrogen atom in quaternary form or a benzamidine except in where A represents diethylamine, hydrogen or an amine group or pyridine attached at the 4-position or fused with an aryl or heteroaryl group

<Desc / Clms Page number 55>  2,4-bis- (4-amino-2-methyl-quinolin-6-yl) amino-6- (quinuclidin-3-yl) amino- [1,3] triazine (Example 17) 2, 4-bis- (4-dimethylamino-2-methyl-quinolin-6-yl) amino-6- (1-methyl-piperidin-4-yl) - [1,3,5] triazine (Example 19)

 2,4-bis- (4-dimethylamino-2-methyl-quinolin-6-yl) amino-6- (3-dimethylamino-propyl) amino- [1,3-triazine (Example 1) 2, 4, 6 tris- (4-amino-2-methyl-quinolin-6-yl) amino- [1,3-triazine (Example 2) 2,4-bis- (4-amino-2-methyl-quinolin-6-yl) amino-6- (4-dimethylamino-2-methyl-quinolin-6-yl) amino- [1,3] triazine (Example 11)

 quinolinium is optionally substituted with a methyl group; C1-C4 alkyl radicals substituted with an amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, pyrrolidinyl or pyridyl radical; or the quinuclidine radical 15-Compounds according to any one of claims 6 to 8, characterized in that A represents either an amino radical substituted with a pyridyl radical; phenyl optionally substituted with a piperazinyl or alkylpiperazinyl radical; a piperidyl radical optionally substituted by a C1-C4 alkyl radical is a piperazinyl radical optionally substituted by a C1-C4 alkyl radical; and 16-compounds according to any one of claims 6 to 8, characterized in that A represents a 0-phenyl radical, pyridyl, or 0-alkyl substituted with an amino, alkylamino or dialkylamino radical 17-Compounds according to any one of claims 1 and 2 corresponding to the following products:

<Desc / Clms Page number 56>  2,4-bis- (4-dimethylamino-2-methyl-quinolin-6-yl) amino-6- (1-methyl-piperazin-4-yl) - [1,3-triazine (Example 20) 2, 4 Bis (4-dimethylamino-2-methyl-quinolin-6-yl) amino-6- (pyridin-4-yl) methylamino- [1,3] triazine (Example 27) 2, 4-bis- (4- amino-2-methyl-quinolin-6-yl) amino-6-phenoxy-1,3,3-triazine (Example 29) 2,4-bis (4-amino-2-methyl-quinolin-6-yl) amino (3-Dimethylamino-propyl) oxy- [1,3-triazine (Example 31) 2,4-bis- (4-amino-2-methyl-quinolin-6-yl) amino-6- (pyridin-4- yl) oxy- [1,3-triazine (Example 32) 2,4-bis- (4-amino-2-methyl-quinolin-6-yl) amino-6- (phenylmethyl) oxy- [1,3] triazine (Example 33).

18. The use of the compounds of claim 1 for the preparation of a medicament having telomerase inhibitory activity. 19 - Use of the compounds according to any one of the preceding claims for the preparation of a medicament having anticancer activity. 20-Use of the compounds of claim 19 as a pharmaceutical product for human use. 21-Therapeutic associations consisting of a compound according to claim 1 and another anticancer compound. 22-Associations according to claim 21, characterized in that the anticancer compound is chosen from alkylating agents, platinum derivatives, antibiotic agents, antimicrotubule agents, anthracyclines, topoisomerases of groups I and II, fluoropyrimidines, the analogs. of cytidine, <Desc / Clms Page number 57>  adenosine analogues, various enzymes and compounds such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramin, irinotecan, topotecan, dexrazoxane, amifostine, herceptin and oetrogenic and androgenic hormones, antiviral agents.

23-therapeutic combination consisting of a compound according to claim 1 and radiation. 24-Associations according to any one of claims 21 to 23, characterized in that each of the compounds or radiations is administered simultaneously, separately or sequentially.