EP1373252A1 - Derives chimiques et leur application comme agents antitelomerase - Google Patents

Derives chimiques et leur application comme agents antitelomerase

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Publication number
EP1373252A1
EP1373252A1 EP02720068A EP02720068A EP1373252A1 EP 1373252 A1 EP1373252 A1 EP 1373252A1 EP 02720068 A EP02720068 A EP 02720068A EP 02720068 A EP02720068 A EP 02720068A EP 1373252 A1 EP1373252 A1 EP 1373252A1
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EP
European Patent Office
Prior art keywords
alkyl
radical
optionally substituted
amino
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02720068A
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German (de)
English (en)
French (fr)
Inventor
Patrick Mailliet
Abdelazize Laoui
Jean-François RIOU
Gilles Doerflinger
Jean-Louis Mergny
François HAMY
Thomas Caulfield
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Aventis Pharma SA
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Filing date
Publication date
Priority claimed from FR0103916A external-priority patent/FR2822468B1/fr
Application filed by Aventis Pharma SA filed Critical Aventis Pharma SA
Publication of EP1373252A1 publication Critical patent/EP1373252A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention relates to cancer therapy and relates to new anticancer agents having a very specific mechanism of action. It also relates to new chemical compounds as well as their therapeutic application in humans.
  • the present invention relates to the use of new non-nucleotide chemical compounds that interact with ' "specific structures of deoxyribonucleic acid (DNA) or ribonucleic acid
  • RNA RNA
  • RNA RNA
  • RNA RNA
  • RNA RNA
  • telomerase inhibiting agents a distributing agent linked to two aminoaromatic groups.
  • telomerase inhibiting agents a distributing agent linked to two aminoaromatic groups.
  • They are particularly useful for stabilizing DNA in a 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.
  • telomerase makes it possible to add repeated DNA sequences of the TTAGGG type, called telomeric sequences, at the end of the telomer, during cell division.
  • telomerase makes the cell immortal.
  • the cell loses 100 to 150 bases each division, which makes it rapidly sinking.
  • telomeres maintained at a stable length during cell division.
  • telomerase was highly activated and that it allowed the addition of repeating motifs of telomeric sequences at the end of the telomer and therefore allowed the conservation of the length of the telomer in cancer cells. It has been shown for some time that more than 85% of cancer cells have positive tests for the presence of telomerase while somatic cells do not have this characteristic.
  • telomerase is a highly renowned target for treating cancer cells.
  • the first obvious approach to blocking telomerase was the use of nucleotide structures (Chen et al., Proc. Natl. Acad. Sci. USA 93 (7), 2635-2639).
  • nucleotide structures Chon et al., Proc. Natl. Acad. Sci. USA 93 (7), 2635-2639.
  • G-quadruplexes which are perylenic compounds and carbocyanines containing at least seven rings including two heterocycles.
  • the compounds of the present invention which meet the objective that is to say, securing the G-quadruplex structure of DNA or RNA and in particular the G-quadruplex structure of telomers and thereby 'have a activity inhibitor of ' telomerases correspond to the following general formula: nitrogen aromatic cycle - NR 3 - distributor - NR' 3 - aromatic cycle in which
  • a quinoline or isoquinoline optionally substituted by at least one radical chosen from a group N (Ra) (Rb) in which Ra and Rb, identical or different, represent hydrogen or a C1-C4 alkyl radical, and one or more group (s) C1-C4 alkoxy or short chain alkyl linked to a carbon or nitrogen atom of the quinoline or isoquinoline ring or a quinoline or isoquinoline having a nitrogen atom in quaternary form or
  • the aromatic ring represents 0 a quinoline or isoquinoline optionally substituted by at least one radical chosen from a group N (Ra) (Rb) in which Ra and Rb, identical or different represent hydrogen or a C1-C4 alkyl radical, and one or more alkoxy or short chain C1-C4 alkyl group (s) linked to a carbon or nitrogen atom of the quinoline or isoquinoline ring or
  • C1-C4 amino, C1-C4 alkylamino, C1-C4 dialkylamino for each alkyl group and the alkyl parts of which can together form a C3-C8, nitro ring; C1-C4 alkyleneeamino; alkenylene ino in C2-C4;
  • the distributor represents: a triazine group optionally substituted by an aromatic ring as defined above or by a radical XR1 (R2) in which X represents a nitrogen atom N to form NR1R2, a linear or branched alkyl radical in C1 -C6 to form alkRlR2, an oxygen atom 0 to form
  • OR1 or a sulfur atom S to form SRI, with RI and R2 - identical or different are chosen from the hydrogen atom; a C1-C8 alkyl radical optionally substituted by one or more identical or different radicals; an aromatic ring as defined above optionally substituted; a quinuclidine radical; a pyrrolidinyl radical itself optionally substituted by an alkyl or phenylalkyl radical with alkyl C1-C4; a piperazinyl radical or
  • Homopiperazinyl itself optionally substituted by an alkyl, cycloalkyl or phenylalkyl radical; a morpholinyl radical; a pyridyl, piperidinyl radical or a piperidyl radical
  • alkyl or phenylalkyl radicals with C1-C4 alkyl; an indazolyl radical; a naphthyl radical; a benzotriazole radical; a radical
  • Benzoimidazolyl a pyrimidinyl radical optionally substituted by one or more alkyl with C1-C4 alkyl; an acenaphthene radical; an amino radical itself optionally substituted by a
  • RI and R2 do not represent one hydrogen and the other unsubstituted C1-C4 alkyl or when X represents N or alkyl, RI and R2 form, together with X to which they are linked, a monocyclic radical of 3 to 6 members or bicyclic of 8 to 10 members saturated or unsaturated optionally containing one or two identical or different hetero atoms chosen from N, 0 or S, this radical being optionally substituted, - a diazine group optionally substituted by the same groups as triazine or one of its salts, these compounds being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms.
  • the subject of the present invention is the compounds as defined above, characterized in that they correspond to the following general formula: nitrogen aromatic cycle - NR 3 - distributor - NR ' 3 - aromatic cycle in which
  • a quinoline or isoquinoline optionally substituted by at least one radical chosen from a group N (Ra) (Rb) in which Ra and
  • Rb identical or different, represent hydrogen or a C1-C4 alkyl radical, and a C1-C4 short chain alkoxy or alkyl group or 0 a quinoline or isoquinoline having a nitrogen atom in quaternary form or 0 a benzamidine or
  • quinoline optionally substituted by at least one radical chosen from a group
  • Ra and Rb which are identical or different, represent hydrogen or a C1-C4 alkyl radical, and an alkoxy or short-chain C1-C4 alkyl group or 0 a quinoline having a d atom '' nitrogen in quaternary form or
  • C4 cyano; carbonylamino optionally substituted with one or more C1-C4 alkyl groups; guanyl; C1-C4 alkylthio; a ino, C1-C4 alkylamino, C1-C4 dialkylamino for each alkyl group and the alkyl parts of which can together form a C3-C8 ring, nitro; C1-C4 alkyleneeamino; C2-C4 alkenyleneamino; 0 a heterocyclic mono or bi or tricyclic ring comprising 0 to 2 heteroatoms per cycle provided that at least one heteroatom is present in at least one ring optionally substituted by one or more C1-C4 alkyl groups or by alkylene groups C1-C4 or C2-C4 alkenylene • R3 and R'3, identical or different, independently of one another represent hydrogen or a C1-C4 alkyl radical
  • the distributor represents: - a triazine group optionally substituted by an aromatic ring as defined above or by an XR1 (R2) radical in which X represents a nitrogen atom N to form NR1R2, a linear or branched alkyl radical in C1-C6 to form alkRlR2, an oxygen atom 0 to form OR1 or a sulfur atom S to form SRI, with Ri and R2 identical or different are chosen from the hydrogen atom; a C1-C8 alkyl radical optionally substituted by one or more identical or different radicals; an aromatic cycle as defined above; a quinuclidine radical; a pyrrolidinyl radical itself optionally substituted by an alkyl or phenylalkyl radical with C1-C4 alkyl; a piperazinyl radical itself optionally substituted by an alkyl, cycloalkyl or phenylalkyl radical; a morpholinyl radical; a pyridyl radical or a
  • RI and R2 identical do not both represent hydrogen or C1-C4 unsubstituted alkyl and Ri and R2 different do not represent one hydrogen and the other C1-C4 alkyl unsubstituted or when X represents N or alkyl ,
  • RI and R2 together with X to which they are linked form 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 chosen from N, 0 or S, an optionally diazine group substituted by the same groups as triazine or one of its salts, these compounds being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms.
  • R1 and R2 represents (s) a C1-C8 alkyl radical optionally substituted by one or several identical or different radicals
  • these radicals are chosen from the following radicals: the amino radical itself optionally substituted by one or two identical or different radicals chosen from the alkyl, hydroxyalkyl, alkoxyalkyl, alkylphenylalkyl radicals, phenylalkyl, carboxyalkyl, hydroxycarboxyalkyl, acyl naphthyl, phenyl and alkylphenyl; the trialkylammonio radical; hydroxy radicals; C1-C4 alkoxy; thioalkoxy; trifluoromethyl; acyl; free, salified, esterified or amidified carboxy; imidazolyl; pyrrolidinyl optionally substituted with C1-C4 alkyl; piperidyl and piperaz
  • the distributor represents: a triazine group optionally substituted by an aromatic ring as defined above or by 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 alkRlR2, an oxygen atom 0 to form 0R1 or a sulfur atom S to form ' SRI, with Ri and R2 identical or different are chosen from l 'hydrogen atom; C1-C8 alkyl optionally substituted by one or more radicals chosen from amino, alkyla ino, dialkyla ino, alkoxyalkylamino, dialcoxyalkylamino, hydroxyalkylamino, dihydroxyalkylamino, hydroxycarboxyalkylamino, trial ylamino +, naphtyla ino, phenyla ino radicals, acylamino (alkyl) (phenylalkyl) amino, (phenyl) (alkyl) amino,
  • alkylphenyl (alkyl) (alkyl) amino, hydroxy, C1-C4 alkoxy, C1-C4 thioalkoxy, trifluoromethyl, acyl, free, salified, esterified or amidated carboxy, imidazolyl, pyrrolidinyl optionally substituted by C1-C4 alkyl, piperidyl, piperazinyl and possible homopiperazinyl-
  • Morpholinyl a pyridyl radical or a piperidyl radical optionally substituted by one or more alkyl or phenylalkyl radicals with C1-C4 alkyl; an indazolyl radical; a radical
  • Naphthyl a benzotriazole radical; a pyrimidinyl radical optionally substituted by one or more alkyl with C1-C4 alkyl; an acenaphthene radical, it being understood that when XR1R2 represents 35 NR1R2, then RI and R2 identical do not not both represent hydrogen or C1-C4 unsubstituted alkyl and RI and R2 different do not represent one hydrogen and the other C1-C4 alkyl unsubstituted or else when X represents N or alkyl, RI and R2 form together with X to which they are linked a radical chosen from the following radicals: piperazinyl or homopiperazinyl optionally substituted by one or more identical or different radicals / pyrrolidinyl optionally substituted by C1-C4 alkyl or alkoxy, hydroxy, acylamino, pyrrolidinylalkyl, pyridinyl and pyridyl
  • XR1 is such that when X represents N, either one of RI and R2 represents the hydrogen atom or a C1-C4 alkyl radical optionally substituted by amino, alkylamino, dialkylamino or phenyl, and the other of RI and R2 is chosen from the values defined for RI and R2 in any one of claims 1 to 5, either RI and R2 together with the nitrogen atom to which they are linked a cyclic radical chosen from the following radicals: a piperazinyl or homopiperazinyl is optionally substituted by one or more radicals selected from alkyl, aminoalkyl, alkylaminoalkyl, dialkyla inoalkyle, phenylalkyl, alkoxyalkyl , hydroxyal
  • RI and R2 represents (s) a C1-C8 alkyl radical optionally substituted by one or more identical or different radicals, these radicals are chosen from the amino radical itself optionally substituted by one or two identical or different radicals chosen from the alkyl, hydroxyalkyl, alkoxyalkyl, phenylalkyl, carboxyalkyl, hydroxycarboxyalkyl, acyl, naphthyl, phenyl and alkylphenyl radicals; the trialkylam onio radical; hydroxy radicals; C1-C4 alkoxy; thioalkoxy; trifluoromethyl; free, salified, esterified or amidified carboxy; pyrrolidinyl optionally substituted with C1-C4 alkyl; piperidyl; piperazinyl optionally substituted by alkyl or phenylalkyl with C1-C4 alkyl;
  • the distributor represents: a triazine group optionally substituted by an aromatic ring such as - defined above or by 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 alkRlR2, an oxygen atom O to form ORl or a sulfur atom S to form SRI, with RI and R2 identical or different are chosen from the hydrogen atom;
  • C1-C8 alkyl optionally substituted by one or more radicals chosen from amino, alkylamino, dialkylamino, dialkoxyalkylamino, dihydroxyalkylamino, alkoxyalkylamino, hydroxyalkylamino,
  • alkylamino and dialkylamino an aromatic cycle as defined above; a quinuclidine radical; a pyrrolidinyl radical itself optionally substituted by an alkyl radical or
  • RI and R2 form, together with X to which they are linked, a radical chosen from the following radicals: piperazinyl optionally substituted by one or
  • pyrrolidinyl optionally substituted with C1-C4 alkyl or alkoxy, hydroxy, acylamino, pyrrolidinylalkyl and pyridyl; 1, 2, 3, 4-tetrahydroiso-
  • Alkyl Alkyl; morpholinyl; imidazolinyl optionally substituted with alkyl, or a diazine group optionally substituted with the same groups as triazine or a salt thereof, these compounds being in all the possible racemic, enantiomeric and diastereoisomeric isomeric forms.
  • XR1 is such that when X represents N, either one of RI and R2 represents the hydrogen atom or an alkyl radical in C1 -C4 optionally substituted with an amino, alkylamino, dialkylamino or phenyl radical and the other of RI and R2 is chosen from the values defined for RI and R2 in any one of claims 1 to 8, either Ri and R2 form together with l nitrogen atom to which they are linked a piperazinyl radical optionally substituted by one or more radicals chosen from alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylalkyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxyalkyl with C3-C8 cycloalkyl, pyrazinyl , pyrimidinyl, pyridyl, furylcarbonyl, furfurycarbonyl
  • the subject of the present invention is the compounds fixing the G-quadruplex structure of telomeres characterized in that they correspond to the general formula as defined above.
  • the present invention thus relates to compounds as defined above, characterized in that they correspond to the following general formula: nitrogen aromatic cycle - NR 3 - distributor - NR ' 3 - aromatic cycle in which
  • a quinoline optionally 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 in C1-C4 or
  • Rb 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 having a nitrogen atom in quaternary form or
  • C4 cyano; carbonyla ino possibly substituted with one or more C1-C4 alkyl groups; guanyl; C1-C4 alkylthio; amino, C1-C4 alkylamino, C1-C4 dialkylamino for each alkyl group and the alkyl parts of which can together form a C3-C8, nitro ring; C1-C4 alkyleneeamino; C2-C4 alkenyleneamino,
  • heterocyclic ring mono or bi or tricyclic, comprising 0 to 2 heteroatoms per cycle, provided that at least one heteroatom is present in at least one ring optionally substituted by one or more C1-C4 alkyl groups or by alkylene groups C1-C4 or C2-C4 alkenylene
  • R3 and R'3, identical or different, independently of one another represent hydrogen or a C1-C4 alkyl radical
  • the distributor represents: a triazine group optionally substituted by an XR1 (R2) radical in which X represents a nitrogen atom N to form NR1R2, a linear or branched C1-C6 alkyl radical to form alkRlR2, an oxygen atom O to form ORl or a sulfur atom S to form SRI, with RI and R2 identical or different are chosen from the hydrogen atom;
  • C1-C8 alkyl optionally substituted by an amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1- alkoxy radical C4, C1-C4 thioalkoxy, trifluoromethyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, pyridyl or pheny
  • RI and R2 together with X to which they are linked form 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 chosen from N, 0 or S, an optionally diazine group substituted by the same groups as triazine or one of its salts, these compounds being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms.
  • nitrogen aromatic cycle means a heterocycle comprising at least one nitrogen atom or an aromatic group not comprising a heteroatom in the cycle but containing at least one nitrogen atom in a hydrocarbon chain linked to the ring such as for example a guanidino or guanyl chain.
  • the aromatic ring represents in particular a quinaldine, quinoline, benzamidine, pyridine and phenyl radical as defined above and optionally substituted as indicated above.
  • C3-C8 ring which the alkyl parts of the dialkylamino radicals defined above can form mention may, for example, be made of them.
  • alkyl radical designates linear or branched radicals in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and decyl radicals as well as their linear or branched position isomers
  • radical - alkoxy designates linear or branched radicals in particular - methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, pentoxy or hexoxy radicals as well as their linear position isomers or branched
  • radical - alkoxy designates linear or branched radicals in particular - methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, pentoxy or hexoxy radicals as well
  • halogen atom designates the chlorine, fluorine, bromine or iodine atoms, and in particular chlorine and fluorine atoms
  • cycloalkyl radical designates the cyclohexyl, cyclopropyl, cyclobutyl radicals and also the cycloheptyl and cyclooctyl radicals
  • alkylphenyl denotes a phenyl radical substituted by one or more alkyl radicals as defined above linear or branched preferably containing at most 4 carbon atoms
  • NH (alk) and N (alk) (alk) denote a radical amino substituted respectively by one or two alkyl radicals, such alkyl radicals being linear or branched and preferably containing at most 4 carbon atoms
  • acylamino designates the radicals -C (0) -NH2, -C (0) -NH ( alk) and -C (O) -N (alk) (alk)
  • acyl denotes a radical RC (O) - in which R represents a radical chosen from the hydrogen atom, linear or branched alkyl radicals containing at most 8 carbon atoms or a saturated or unsaturated carbocyclic or heterocyclic radical, chosen for example from the aromatic or non-aromatic rings defined above: the term acyl thus denotes for example the formyl, acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, benzoyl, pyrrolidinylcarbonyl, pyrazinylcarbonyl, piperazinylcarbonyl, furylcarbonyl or furfurylcarbonyl radicals.
  • the carboxy radical (s) of the products of formula (I) can be salified or esterified by various groups known to those skilled in the art, among which there may be mentioned, for example:
  • mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethan ⁇ lamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N- methylglucamine
  • the alkyl radicals to form alkoxy carbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals being able to be substituted by radicals chosen for example from atoms of halogen, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, such as, for example, in chloromethyl, hydroxypropyl, methoxymethyl, propionyloxy ethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups.
  • the addition salts with mineral or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic acids, benzoic, maleic, fu aric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulfonic acids such as for example methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid such as for example methanedisulfonic acid, alpha acid, beta-ethane disulfonic acid, arylmonosulfonic acids such as benzenesulfonic acid and aryldisulfonic acids.
  • salts of acceptable products of formula (I) are in particular usable, non-toxic salts: such salts of products of formula (I) as defined above can be obtained by the ordinary methods known to a person skilled in the art, for example by combining a compound of formula (I) with an organic or inorganic acid or a base in a solvent or a dispersant or from another salt by cation or anion exchange.
  • stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in an axial or equatorial position, and the different possible rotational conformations of the ethane derivatives.
  • stereoisomerism due to the different spatial arrangements of substituents attached, either on double bonds or on rings, which is often called geometric isomerism or cis-trans isomerism.
  • stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.
  • the subject of the present invention is in particular the compounds as defined above, characterized in that the distributor represents: - a triazine group optionally substituted by 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 SRI, with Ri and R2 identical or different are chosen from the hydrogen atom; C1-C8 alkyl optionally substituted by an amino radical, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1-C4 alkoxy, by a pyrrolidinyl, pyridyl radical or by a phenyl radical; an aromatic ring as defined above 7 a quinuclidine radical, a pyrrolidinyl radical or a piperidyl radical optionally substituted with C1-C4 alkyl, it being understood that identical Ri and
  • the present invention particularly relates to the compounds as defined above, characterized in that the diazine groups are pyrimidines or quinazolines.
  • a more particular subject of the present invention is the compounds as defined above, characterized in that XR1 (R2) is such that when X represents N, that is one of Ri and R2 represents the hydrogen atom and the other of Ri and R2 is chosen from the values defined for RI and R2, that is to say RI and R2 form, together with the nitrogen atom to which they are linked, a piperazinyl, pyrrolidinyl, piperidyl or morpholino radical.
  • the present invention particularly relates to compounds as defined above, characterized in that they correspond to formula (I) below:
  • A represents a radical XR1 (R2) in which X represents a nitrogen, oxygen or sulfur atom or a C1-C6 alkyl radical to form one of the following radicals:
  • NR1R2 with RI and R2 identical or different are chosen from the hydrogen atom; a C1-C8 alkyl radical optionally substituted by one or more identical or different radicals; an aromatic cycle as defined above; a quinuclidine radical; a pyrrolidinyl radical itself optionally substituted by an alkyl or phenylalkyl radical with C1-C4 alkyl; a piperazinyl or homopiperazinyl radical itself optionally substituted by an alkyl, cycloalkyl or phenylalkyl radical; a radical morpholinyl; a pyridyl, piperidinyl or a piperidyl radical optionally substituted by one or more alkyl or phenylalkyl radicals with C1-C4 alkyl; an indazolyl radical; a naphthyl radical; a benzotriazole radical; a benzimidazolyl radical; a pyrimidinyl radical optional
  • R3 and R'3 identical or different, independently of one another represent hydrogen or a C1-C4 alkyl group
  • a quinoline or isoquinoline motif optionally substituted by at least one radical chosen from a group N (Ra) (Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a C1-C4 alkyl radical, and one or more C1-C4 alkoxy or short chain alkyl group (s) linked to a carbon or nitrogen atom of the quinoline or isoquinoline ring or
  • • Ari and Ar 2 both represent one of the possibilities mentioned above for • Ari represents one of the possibilities above and Ar 2 represents * 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, dialkylamino in C1-C4 for each alkyl, nitro, C1-C4 alkyleneamino, (or) alkenylene-amino in C2-C4, or a piperazinyl radical optionally substituted by a C1-C4 alkyl radical,
  • RI and R2 represents (s) a C1-C8 alkyl radical optionally substituted by a or more identical or different radicals, these radicals are chosen from the amino radical itself optionally substituted by one or two identical or different radicals chosen from the alkyl, hydroxyalkyl, alkoxyalkyl, phenylalkyl, carboxyalkyl, hydroxycarboxyalkyl, acyl, naphthyl, phenyl and alkylphenyl; the trialkylammonio radical; hydroxy radicals; alkoxy; thioalkoxy; trifluoromethyl; acyl; free, salified, esterified or identified carboxy; ' imidazolyle; pyrrolidinyl optionally substituted with C1-C4 alkyl; piperidyl and piperazinyl optionally substituted by alkyl or phenylalky
  • XR1 is such that when X represents N, that is one of RI and R2 represents the atom of hydrogen and the other of RI and R2 is chosen from the values defined above for RI and R2, ie RI and R2 form, together with the nitrogen atom to which they are linked, a piperazinyl, homopiperazinyl, pyrrolidinyl, piperidyl radical , pyridinyl, morpholinyl, thiomorpholinyl, imidazolinyl, diazepine, 1, 2, 3, 4-tetrahydroquinoline or 1, 2, 3, 4-tetrahydroisoquinoline, all these radicals being optionally substituted by one or more radicals as defined above.
  • A represents an aromatic ring as defined above or a radical XR1 (R2) in which X represents an atom d nitrogen N to form NR1R2, a linear or branched alkyl radical C1-C6 for forming alkRlR2 a dpf oxygen O to form ENT or S sulfur atom to form SRI with RI and the same or different R 2 are selected from the hydrogen atom;
  • C1-C8 alkyl optionally substituted by one or more radicals chosen from amino, alkylamino, dialkylamino, dialkoxyalkylamino, dihydroxyalkylamino, alkoxyalkylamino, hydroxyalkylamino, hydroxycarboxyalkylamino, trialkylammonium, naphthylamino, phenylamino, acylamino) alkyl (phenylalkyl) radicals ) amino, alkylamino, dialkylamino, dialkoxyalkylamino, dihydroxyalky
  • XR1 is such that when X represents N, either one of RI and R2 represents the atom d hydrogen or a C1-C4 alkyl radical optionally substituted by an amino, alkylamino, dialkylamino or phenyl radical and the other of RI and R2 is chosen from the values defined for RI and R2 in any one of Claims 1 to 8 either Ri and R2 form, together with the nitrogen atom to which they are linked, a piperazinyl or homopiperazinyl radical optionally substituted by one or more radicals chosen from alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylalkyl, alkoxyalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl with C1-C6 alkoxy, imidazolyl-aminoalkyl, imi
  • the present invention particularly relates to compounds of formula (I) as defined above, characterized in that they correspond to the following formula:
  • A represents a radical XR1 (R2) in which X represents a nitrogen, oxygen or sulfur atom or a C1-C6 alkyl radical to form one of the following radicals:
  • NR1R2 with RI and R2 identical or different are chosen from the hydrogen atom; C1-C8 alkyl optionally substituted by one or more identical or different radicals; an aromatic cycle as defined above; a quinuclidine radical; a pyrrolidinyl radical itself optionally substituted by an alkyl or phenylalkyl radical with C1-C4 alkyl; a piperazinyl radical itself optionally substituted by an alkyl, cycloalkyl or phenylalkyl radical; a morpholinyl radical; a pyridyl radical or a piperidyl radical optionally substituted by one or more alkyl or phenylalkyl radicals with C1-C4 alkyl; an indazolyl radical; a naphthyl radical; a benzotriazole radical; a pyrimidinyl radical optionally substituted by one or more alkyl with C1-C4 alkyl; an acenap
  • RI and R2 do not both represent hydrogen or unsubstituted C1-C4 alkyl and different RI and R2 do not represent one hydrogen and the other unsubstituted C1-C4 alkyl or when X represents N or alkyl,
  • Ri and R2 form, together with X to which they are linked, 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 chosen from N, O or S,
  • Ri has the same meaning as above, it being understood that RI does not represent hydrogen or unsubstituted C1-C4 alkyl, or • an alkyl group containing 1 to 6 carbon atoms substituted by Ri R2 as defined above
  • R3 and R'3 identical or different, independently of one another represent hydrogen or a C1-C4 alkyl group
  • a quinoline unit optionally 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) 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 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, dialkylamino in C1-C4 for each alkyl, nitro, C1-C4 alkyleneamino, (or) C2-C4 alkenyleneamino, or a piperazinyl radical optionally substituted by a C1-C4 alkyl radical,
  • the present invention relates in particular to the compounds as defined above, characterized in that when one or both of R1 and R2 represents (s) a C1-C8 alkyl radical optionally substituted by one or more identical or different radicals, these radicals are chosen from the amino radical itself optionally substituted by one or two identical or different radicals chosen from the alkyl, hydroxyalkyl, alkoxyalkyl, phenylalkyl, carboxyalkyl, hydroxycarboxyalkyl, acyl, naphthyl, phenyl and alkylphenyl radicals; the trialkyla monio radical; hydroxy radicals; alkoxy; thioalkoxy; trifluoromethyl; free, salified, esterified or amidified carboxy; pyrrolidinyl optionally substituted with C1-C4 alkyl; piperidyl; piperazinyl optionally substituted by alkyl or phenylalkyl with C1-C4 alkyl; morpholinyl
  • the present invention thus relates to the compounds as defined above, characterized in that XR1 (R2) is such that when X represents N, either one of Ri and R2 represents the hydrogen atom and the other of Ri and R2 is chosen from the values defined for RI and R2, ie Ri and R2 form, together with the nitrogen atom to which they are linked, a piperazinyl, pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, i idazolinyl, diazepine or 1,2 radical, 3, 4-tetrahydro-isoquinoline, all these radicals being optionally substituted by one or more radicals.
  • A represents an aromatic ring as defined above or 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 alkRlR2, an oxygen atom O to form OR1 or a sulfur atom S to form SRI, with RI and R2 identical or different are chosen from the hydrogen atom;
  • C1-C8 alkyl optionally substituted by one or more radicals chosen from amino, alkylamino, dialkylamino, dialkoxyalkylamino, dihydroxyalkylamino, alkoxyalkylamino, hydroxyalkylamino, hydroxycarboxy-alkylamino, trialkylammonio, naphthylamino, phenylamino, alkyl) amino radicals , (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino radicals , (phenyl) (alkyl) amino
  • XR1 is such that when X represents N, either one of RI and R2 represents the hydrogen atom or an alkyl radical in C1 -C4 optionally substituted with an amino, alkylamino, dialkylamino or phenyl radical and the other of RI and R2 is chosen from the values defined for RI and R2 in any one of claims 1 to 8, either RI and R2 form together with l nitrogen atom to which they are linked a piperazinyl radical optionally substituted by one or more radicals chosen from alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylalkyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxyalkyl with alkoxy, pyrrolidinylalkyl, cycloalkyl C3-C8, pyrazinyl, pyrimidinyl, pyridyl
  • the present invention thus relates to the compounds defined above fixing the G-quadruplex structure of telomeres characterized in that they correspond to formula (I) below:
  • A represents a radical XR1 (R2) in which X represents a nitrogen, oxygen or sulfur atom or a C1-C6 alkyl radical to form one of the following radicals:
  • NR1R2 with RI and R2 identical or different are chosen from the hydrogen atom; C1-C8 alkyl optionally substituted by an amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino radical, C1-C4 alkoxy, C1-C4 thioalkoxy, 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 identical RI and R2 do not both represent hydrogen or unsubstituted C1-C4 alkyl and RI and R2 are different do not represent
  • R3 and R'3 identical or different, independently represent one of the other 1 'hydrogen and a C1-C4 alkyl group
  • a quinoline motif optionally substituted by at least one N (Ra) (Rb) group in which Ra and Rb 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
  • the present invention also relates to the new compounds characterized in that they correspond to formula (I) below:
  • A represents a radical XR1 (R2) in which X represents a nitrogen, oxygen or sulfur atom or a C1-C6 alkyl radical to form one of the following radicals:
  • NR1R2 with RI and R2 identical or different are chosen from the hydrogen atom; C1-C8 alkyl optionally substituted by amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1-C4 alkoxy, C1-C4 thioalkoxy, 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 by C1-C4 alkyl it being understood that identical RI and R2 do not both represent hydrogen or unsubstituted C1-C4 alkyl and different RI and R2 do not represent one hydrogen and
  • R3 and R'3 identical or different, independently of one another represent hydrogen or a C1-C4 alkyl group
  • a quinoline unit optionally 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) a short-chain alkoxy or alkyl group containing 1 to 4 carbon atoms or
  • A represents a radical XRl (R2) in which X represents a nitrogen atom N to form NR1R2, an oxygen atom O for form OR1 or a sulfur atom S to form SRI as follows: • NR1R2 with RI and R2 identical or different are chosen from the hydrogen atom; C1-C8 alkyl optionally substituted by an amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C1-C4 alkoxy radical, by a pyrrolidinyl, pyridyl radical or by 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 identical RI and R2 do not
  • R1 and R2 can form, together with the nitrogen atom to which they are linked, a piperazinyl, homopiperazinyl, pyrrolidinyl, piperidyl or morpholinyl radical which may be substituted, for example by alkyl or piperidyl.
  • the present invention relates more precisely to the compounds of formula (I) as defined above in which when A represents NR1R2 either one of RI and R2 represents the hydrogen atom and the other of RI and R2 is chosen among the values defined for RI and R2, that is to say RI and R2 form together with the nitrogen atom to which they are linked a piperazinyl, pyrrolidinyl, piperidyl or morpholinyl radical.
  • a subject of the present invention is also the compounds defined above, characterized in that Ari and Ar 2 represent a group chosen from the following groups: 4-amino- or 4-methylamino- or 4-dimethylamino-quinolyl, -isoquinolyl, quinolinium or isoquinolinium in which the quinolyl, isoquinolyl, quinolinium or isoquinolinium nucleus is optionally substituted by one or more methyl group (s) linked to a carbon or nitrogen atom in the ring; or phenyl optionally substituted by one or more halogen atoms.
  • Ari and Ar 2 represent a group chosen from the following groups: 4-amino- or 4-methylamino- or 4-dimethylamino-quinolyl, -isoquinolyl, quinolinium or isoquinolinium in which the quinolyl, isoquinolyl, quinolinium or isoquinolinium nucleus is optionally substituted by one or more methyl group (s) linked to
  • the present invention thus relates to the compounds defined above, characterized in that the group A represents: either an amino radical substituted by a radical chosen from the following groups: 4-amino- or 4-methylamino- or 4-dimethylamino- quinolyl, -isoquinolyl, quinolinium or isoquinolinium in which the quinolyl, isoquinolyl, quinolinium or isoquinolinium nucleus is optionally substituted by one or more methyl group (s) linked to a carbon or nitrogen atom in the ring; pyridyle; phenyl optionally substituted by one or more halogen atoms or by a piperazinyl or alkylpiperazinyl radical; C1-C4 alkyl substituted by an amino, alkylamino or dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C2-alkoxy, alkoxy radical by an alkylpiperaziny
  • a pyrrolidinyl radical either a morpholino radical or a piperazinyl radical optionally substituted by a C1-C4 alkyl or piperidyl radical, or an 0-phenyl, O-pyridyl, or O-alkyl radical substituted by an amino, alkylamino or dialkylamino radical
  • a subject of the present invention is thus the compounds defined above, characterized in that when Ari and Ar 2 are identical, Ari and Ar 2 represent a group chosen from the groups 4-amino- or 4-methylamino- or 4-dimethylamino-quinolyl , -isoquinolyl, quinolinium or isoquinolinium in which the quinolyl, isoquinolyl, quinolinium or isoquinolinium nucleus is optionally substituted by one or more methyl group (s) linked to a carbon or nitrogen atom in the ring.
  • the present invention relates even more precisely to the compounds of formula (I) as defined above in which the group A represents: or an amino radical substituted by a radical chosen from the following groups: 4-amino- or 4-methylamino- or 4-dimethylamino-quinolyl or quinolinium in which the quinolinium ring is optionally substituted by a methyl group; pyridyle; phenyl optionally substituted by one or more halogen atoms or by a piperazinyl or alkylpiperazinyl radical; C1-C4 alkyl substituted by an amino, alkylamino or dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C2-C4 alkoxy radical, by a pyrrolidinyl radical or by a phenyl radical, radicals in which alkyl groups have 1 to 4 carbon atoms; a pyrrolidinyl radical; a piperidyl
  • ri and Ar 2 represent a group chosen from the following groups: 4-amino- or 4-methylamino- or 4-dimethylamino-quinolyl or quinolinium whose nucleus quinolinium is optionally substituted with a methyl group; or phenyl optionally substituted by one or more halogen atoms.
  • group A represents: or an amino radical substituted by a radical chosen from the following groups: 4-amino- or 4-methylamino- or 4-dimethylamino-quinolyl or quinolinium in which the quinolinium ring is optionally substituted by a methyl group; pyridyle; phenyl optionally substituted by one or more halogen atoms or by a piperazinyl or alkylpiperazinyl radical; C1-C4 alkyl substituted by an amino, alkylamino or dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, C2-C4 alkoxy radical, by a pyrrolidinyl radical or by a phenyl radical, radicals in which alkyl groups have 1 to 4 carbon atoms; a pyrrolidinyl radical; a piperidyl radical optionally substitute
  • Ari and Ar 2 represent a group chosen from the groups 4-amino- or 4-methylamino- or 4-dimethylamino - quinolyl or quinolinium, the quinolinium nucleus of which is optionally substituted by a methyl group.
  • Ari 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 a short-chain alkoxy or alkyl group containing 1 to 4 carbon atom or
  • a phenyl nucleus optionally substituted by a halogen, methoxy, cyano, carbonylamino, guanyl, methylthio, amino, methylamino, dimethylamino, morpholine, C1-C4 alkyleneamino or C2-C4 alkenyleneamino group
  • A represents an amino radical substituted by a radical chosen from the following groups: 4-amino- or 4-methylamino- or 4-dimethylamino-quinolyl or quinolinium radicals in which the quinolinium ring is optionally substituted by a methyl group; C1-C4 alkyl radicals substituted by an amino, alkylamino, dialkylamino, (phenyl) (alkyl) amino, (alkylphenyl) (alkyl) amino, pyrrolidinyl or pyridyl radical; or the quinuclidine radical.
  • A represents either an amino radical substituted by one or more radicals as defined above or a piperazinyl, homopiperazinyl, piperidinyl or pyrrolidinyl radical optionally substituted (s) by one or more radicals as defined above.
  • A represents either an amino radical substituted by a pyridyl radical; phenyl optionally substituted with a piperazinyl or alkylpiperazinyl radical; a piperidyl radical optionally substituted by a C1-C4 alkyl radical or a piperazinyl radical optionally substituted by a C1-C4 alkyl radical.
  • A represents an O (or S) - aromatic ring radical or an O (or S) -alkyl radical with optionally substituted alkyl.
  • A represents an O-phenyl, O-pyridyl, O-pyrimidinyl or O-alkyl radical substituted by an amino, alkylamino or dialkylamino or else an S-phenyl, S-pyridyl, S-pyrimidyl or S-quinoleinyl radical.
  • A represents an O-phenyl, O-pyridyl or O-alkyl radical substituted by an amino, alkylamino or dialkylamino radical.
  • quinoline units can be substituted by any other group which does not intervene in the intended application, thus groups acridines or isoquinolines or quinazolines or quinoxalines or phthalazines or benzothiazines or benzoxazines or phenoxazines or phenothiazines are included in the definition of quinoline groups.
  • Preferred among the compounds of formula (I) above are those which comprise two heterocycles chosen from the 4-aminoquinolyl, 4-aminoquinolinium or quinolinium groups in which the quinolinium nucleus is optionally substituted by a methyl group.
  • Another object of the present invention relates to the use of the compounds of formula (I) as a pharmaceutical product for human use.
  • the present invention relates very particularly to pharmaceutical compositions comprising, by way of active ingredient a product of formula (I) as defined above.
  • the present invention relates very particularly to pharmaceutical compositions comprising, as active principle, a product of formula (I) in Table 1 below.
  • the present invention relates very particularly to pharmaceutical compositions comprising, as active ingredient, a product of formula (I) chosen from those whose names are cited above.
  • the invention therefore extends to pharmaceutical compositions containing as active principle at least one of the medicaments as defined above.
  • compositions can be administered by the oral route, by the parenteral route or by the local route as a topical application to the skin and the mucous membranes or by injection by the intravenous or intramuscular route.
  • compositions can be solid or liquid and can be presented in all the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, pills, tablets, capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods.
  • the active ingredient can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various agents wetting, dispersing or emulsifying, preservatives.
  • the reaction takes place in an inert medium under the reaction conditions. Mention may be made, among the inert solvents, of 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.
  • the operation is preferably carried out at a temperature of between 20 ° C.
  • 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.
  • the triazine of general formula (A) can be obtained by sequential displacement of the halogen atoms, very generally chlorine atoms, of the products of general formula (B) by the amines Ar ⁇ NHR 3 then Ar 2 NHR ' 3 of general formula (C) according to scheme 2:
  • 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.
  • the operation is carried out at a temperature between 20 ° C and 50 ° C.
  • 1 mole of amine Ar 2 NHR ' 3 is added to the product of general formula (D), which can be optionally isolated.
  • the products of general formula (A) in which Ar ⁇ NHR 3 and Ar 2 NHR ' 3 are defined as above and R represents a group NR1R2 or ORl or SRI or alkRlR2 can also be prepared by nucleophilic displacement of an atom of halogen, generally a chlorine atom, of a product of general formula (A) in which R represents a halogen atom according to scheme 3:
  • R Cl (or F or Br or 1)
  • R NR., R 2 or OR., Or SR n or R., R 2 alk
  • the operation is preferably carried out at a temperature between 20 ° C. and reflux, in the presence in particular of an organic base, such as triethylamine, or an inorganic base, such as sodium hydroxide or carbonate. sodium or potassium.
  • an organic base such as triethylamine
  • an inorganic base such as sodium hydroxide or carbonate. sodium or potassium.
  • the incoming group represents an RIO “ or RIS " group
  • an alkali or alkaline earth alcoholate or thioalcoholate such as a sodium or potassium or lithium or ammonium or cesium or barium salt
  • a polar aprotic solvent such as DMF or DMSO or NMP
  • the operation is very preferably in an ether such as diethyl ether or. dioxane or tetrahydrofuran at a temperature between -70 ° C and the reflux of the reaction medium.
  • the s-triazines of general formula can be obtained in the form of libraries, by applying the methods described in diagrams 1, 2, or 3 in parallel and / or combinatorial chemistry in the liquid phase or in the solid phase, it being understood that, when working in the solid phase, any of the reactants is previously fixed on a solid support, chosen as a function of the chemical reaction involved, and that said chemical reaction 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 mode of administration chosen.
  • the pharmaceutical composition can be in solid, liquid or liposome form.
  • solid compositions mention may be made of powders, capsules, tablets.
  • oral forms it is also possible to include the solid forms protected from the acid 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.
  • Liquid forms are made up of solutions of suspensions or dispersions. They contain as dispersive support 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 can be administered alone or in admixture with other anticancer agents.
  • anticancer agents include anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents
  • alkylating agents and in particular cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednimustine, carmustine, lomustine, semustine, steptozotocin, decarbazine, temozolomide, procarbazine and hexamethylmelamine
  • platinum derivatives such as cisplatin, carboplatin or oxaliplatin
  • antibiotic agents such as bleomycin, mitomycin, dactinomycin
  • antimicrotubule agents such as vinblastine, vincristine, vindesine, vinorelbine, taxoides (paclitaxel and docetaxel)
  • anthracyclines such as doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, losoxantrone • topoisomerases of groups I and II such. as etoposide, teniposide, amsacrine, irinotecan, topotecan and tomudex,
  • fluoropyrimidines such as 5-fluorouracil, UFT, floxuridine,
  • cytidine analogues such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomurine, 6-thioguanine
  • adenosine analogs such as pentostatin, cytarabine or fludarabine phosphate
  • enzymes and various compounds such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramin, dexrazoxane, amifostine, herceptin as well as the oestrogenic and androgenic hormones • anti-vascular agents such as combretastatin or colchicine derivatives and their pro-drugs.
  • the stabilization activity of the 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 not, have been synthesized by Eurogentec SA, Seraing, Belgium.
  • the oligonucleotide FAM + DABCYL carries the catalog reference, 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 to the 3' end, by the chemical arms described by Eurogentec. The concentration of the samples is verified by spectrophotometry, recording the absorbance spectrum between 220 and 700 nm and using the molar extinction coefficient provided by the supplier.
  • the absence of fluorescent contamination in the buffer has been previously checked.
  • the fluorescent oligonucleotide is added to the final concentration of 0.2 ⁇ M.
  • oligonucleotide stock solution with a strand concentration of 0.2 ⁇ M in a 0.1 M LiCl 10 mM cacodylate buffer pH 7.6 is previously prepared, briefly heated to 90 ° C and slowly cooled to 20 ° C, then distributed in aliquots of 600 ⁇ l in fluorescence cells. 3 ⁇ l of water (for control) or 3 ⁇ l of the product to be tested (stock at 200 ⁇ M, final concentration 1 ⁇ M) are then added and mixed. The samples are then left 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.
  • the Tm of the reference sample without addition of product is 44 ° C. in a Lithium Chloride buffer. This temperature is brought to more than 55 ° C. in a sodium chloride buffer.
  • the addition of a G-quadruplex stabilizing compound induces an increase in Tm. This increase is considered significant if it is greater than 3 °.
  • the biological activity, antitelomerase is determined by the following experimental protocol:
  • the HL60 leukemia line is obtained from the ATCC (Americam Type Culture Collection, Rockville USA). Cells are grown in suspension in medium RPMI 1640 containing, 2 mM L-Glutamine, Penicillin 200 U / ml, streptomycin 200 ⁇ g / ml, gentamycin 50 ⁇ g / ml and supplemented with 10% fetal calf serum inactivated by heat. An aliquot of 10 5 cells is centrifuged at 3000xG and the supernatant discarded.
  • the cell pellet is resuspended by several successive pipetting in 200 ⁇ l of lysis buffer containing 0.5% CHAPS, Tris-HCl pH 7.5 10 mM, MgCl 2 ImM, EGTA 1 mM, ⁇ -mercaptoethanol 5 mM, PMSF 0.1 mM and glycerol 10% and is kept in ice for 30 minutes.
  • the lysate is centrifuged at 16 OOOOxG for 20 minutes at 4 ° C and 160 ⁇ l of the supernatant is recovered.
  • the determination of the proteins of the extract is carried out by the Bradford method.
  • the extract is stored at -80 ° C.
  • telomerase activity is determined by a protocol for extending the oligonucleotide TS ( 5 'AATCGTTCGAGCAGAGTTTT ' ), in the presence of a cellular extract enriched in telomerase activity and of compounds which are added at different concentrations ( 10, 1, 0.1 and 0.01 ⁇ M).
  • the extension reaction is followed by PCR amplification of the extension products using the oligonucleotides TS and CXext ( 5 'GTGCCCTTACCCTTACCCTTACCCTAA 3' ).
  • the reaction medium is prepared according to the following composition:
  • Bovine albumin serum 0.1 mg / ml
  • the oligonucleotides are obtained from Eurogentec (Belgium) and are stored at -20 ° C at a stock concentration of 1 mg / ml in distilled water.
  • reaction samples are assembled in 0.2 ml PCR tubes and a drop of paraffin oil is placed on each of the reactions of the experiment before the tubes are closed.
  • the reaction samples are then incubated in a Cetus 4800 type PCR apparatus under the following temperature conditions:
  • the samples are then analyzed by 12% acrylamide gel electrophoresis in TBE IX buffer for 1 hour at a voltage of 200 volts, using a Novex electrophoresis system.
  • the acrylamide gels are then dried on a sheet of Whatmann 3 mm paper at 80 ° C. for 1 hour.
  • the analysis and quantification of the reaction products are carried out using an Instantlmager device (Pacard).
  • Compound value - blank value / Enzyme control value - blank value x 100.
  • concentration of compound inducing a 50% inhibition of the telomerase reaction (IC50) is determined using a semi logarithmic graphical representation of the d values 'inhibition obtained as a function of' each of the concentrations of compound tested.
  • a compound is considered to be active as an antelomerase agent when the amount inhibiting 50% telomerase reaction is notably less than 5 ⁇ M.
  • 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 (American Type Culture Collection, Rockville USA).
  • the A549 cells are cultured in a layer in a culture flask in RPMI 1640 medium, L-Glutamine at 2 mM, Penicillin 200 U / ml, streptomycin 200 ⁇ g / ml and supplemented with 10% fetal calf serum inactivated by heat.
  • KB cells are cultured in a culture flask layer in Dulbelco's medium containing, 2 mM L-Glutamine, Penicillin 200 U / ml, streptomycin 200 ⁇ g / ml and supplemented with 10% fetal calf serum inactivated by heat .
  • the cells in the exponential growth phase are trypsinized, washed in PBS IX and are seeded in 96-well microplates (Costar) at a rate of 4 ⁇ 10 4 cells / ml for A549 and 1.5 ⁇ 10 4 cells / ml
  • the concentration of compound inducing a 50% inhibition of growth is determined using a semi logarithmic graphical representation of the inhibition values obtained as a function of each of the concentrations of compound tested.
  • a compound is considered to be active as a cytotoxic agent if the inhibitory concentration of 50% of the growth of the tumor cells tested is notably less than 10 ⁇ M.
  • the following nonlimiting examples are given to illustrate the invention.
  • Table 1 gives the chemical structures as well as the G-quartet, antitelomerase and cytotoxic activities of 202 products which constitute, in chronological order as this table lists them, Examples 1 to 202 of the present invention which illustrate the present invention without however limiting it.
  • Table 1 gives the chemical structures as well as the G-quartet, antitelomerase and cytotoxic activities of 202 products which constitute, in chronological order as this table lists them, Examples 1 to 202 of the present invention which illustrate the present invention without however limiting it.
  • Examples 1 to 28 described in Table 1 can be prepared by parallel synthesis in liquid medium:
  • a magnetic heating reactor with Zy ark condenser of the STEM RS2050 type containing 25 wells in parallel provided with a 50 ml glass tube, 50 mg of a product corresponding to the following formula is introduced:
  • Example 20 4-bis- (4-dimethylamino-2-methyl-quinolin-6-yl) amino-6- (4-methyl-piperazin-1-yl) - [1, 3, 5] triazine , can also be advantageously prepared as follows:
  • Examples 29 to 33 Examples 29 to 33 described in Table 1 can be prepared by parallel synthesis in liquid medium:
  • Examples 34 to 108 can be obtained by operating as described above for Examples 1 to 28.
  • Examples 103 to 115 and Example 196 can be obtained by operating as described above for Examples 29 to 33.
  • Examples 116 to 133, 177 and 183 can be obtained by operating as described above for Examples 29 to 33, but by replacing RIOH with R1SH.
  • the example can be obtained by operating as follows •: 1 g of 2, -dichloro-6-phenyl- [1, 3, 5] -triazine which can be obtained by operating according to Tetrahedron 2000, 56, 9705, is dissolved in 100 ml of dioxane in 100 ml of dioxane -9711. Then 0.9 of 4-dimethylamino-2-methyl-quinoline-6-amine and 1.2 g of potassium carbonate are added, then the reaction medium is heated at 80 ° C. for 18 hours. After cooling, the solvent is evaporated under reduced pressure and the residue is taken up in 100 L of water. The precipitate formed is drained, washed with water and dried under reduced pressure.
  • Example 178 can be obtained by operating as in Example 134 but starting with 2,4-dichloro-6-phenylmethyl- [1, 3, 5] -triazine which can be obtained by operating according to Tetrahedron 2000, 56, 9705-9711.
  • Examples 135 to 176, 178 to 182, 184, 187 to 195 and 197 to 202 can be obtained by operating as described above for Examples 1 to 28, except that the volume of DMF is reduced from 5 to 2 mL and the heating temperature is increased from 80 to 108-110 ° C.
  • Example 186 2, 4-bis- ((4-dimethylamino-2-methyl-quinolin-6-yl) amino) -6- (4-cyclopentyl-piperazin-1-yl) - [1, 3, 5 ] triazine, can advantageously be prepared as follows:
  • - B represents an Ar ⁇ NR 3 radical, a radical chosen from the radicals:
  • C ' represents - an Ar 2 NR 3 radical chosen from the radicals:
  • Amines, alcohols or phenols and thiols or thiophenols, necessary for the introduction of radicals of type B, C or A of the products of general formula (Ib), are:
  • amines are introduced into a 24-well, stirred, pressurizable, stainless steel reactor: 0.094 g of isopropylamine 0.173 g of diethylamine hydrochloride 0.120 g of 2-methoxyethylamine 0.091 g of azetidine 0.114 g of pyrrolidine
  • Step 2 Reduction in parallel of 6-nitroquinolines
  • the products described above are each distributed in 4 wells. Their reduction is carried out in the apparatus described above, by introducing into each well 0.050 g of 10% palladium on carbon and 1.5 ml of a methanol / dichloromethane solution (80/20 by volume). After obturation and inerting, the mixture is stirred for 6 hours at 20 ° C. under 6 bars of hydrogen.
  • the solutions of the wells of the same composition are combined, the catalyst is filtered and then rinsed with 5 ml of methanol. The filtrate is then concentrated under reduced pressure.
  • the products are purified by LCMS under the conditions described in step 1. This gives the following:
  • o 2,4-bis (dimethylamino) -quinoline-6-amine (A4 / B4 / C4) can be prepared by operating as follows:
  • 2,4-bis (dimethylamino) -6-nitro-quinoline can be prepared as follows: 300 mg of 2,4-dichloro-6-nitro-quinoline is dissolved in 12 ml of DMF in the presence of 853 mg of potassium carbonate and 1 g of dimethylammonium hydrochloride. The reaction mixture is stirred at 100 ° C for 3 hours. After returning to room temperature, the insoluble material is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is hydrolyzed by adding water and the precipitate obtained is recovered by filtration and then dried under reduced pressure. 180 mg of 2,4-bis (dimethylamino) -6-nitro-quinoline are thus obtained in the form of a yellow powder, the mass spectrum of which is as follows:
  • 2,4-dichloro-6-nitro-quinoline can be prepared as follows: A solution of 500 mg of 6-nitro-quinoline-2,4-diol in 10 ml of P0C1 3 is brought to reflux for 3 hours . After returning to ambient temperature, the reaction mixture is concentrated under reduced pressure and then taken up with water. The pH of the aqueous phase is brought to 8 by adding a 28% aqueous ammonia solution and the aqueous phase is extracted with dichloromethane. The organic phase is then dried over magnesium sulfate and then concentrated under reduced pressure.
  • 4-Dimethylamino-2-methylamino-6-nitro-quinoline can be prepared as follows: 188 mg of 4-chloro-2-methylamino-6-nitro-quinoline is dissolved in 8 L of DMF in the presence of 546 mg of potassium carbonate and 645 mg of dimethylammonium hydrochloride. The reaction mixture is stirred at 100 ° C for 10 hours. After returning to ambient temperature, it is hydrolyzed by adding water and the aqueous phase thus obtained is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. 150 mg of 4-dimethylamino-2-methylamino-6-nitro-quinoline are thus obtained in the form of a yellow powder, the mass spectrum of which is as follows:
  • 4-chloro-2-methylamino-6-nitro-quinoline can be prepared as follows: 600 mg of 2,4-dichloro-6-nitro-quinoline is dissolved in 10 mL of THF in the presence of 2.15 mL of a 2M solution of dimethylamine in THF. The reaction mixture is stirred at 90 ° C for 3 hours. After returning to ambient temperature, the reaction medium is concentrated under reduced pressure. A fraction of the residue obtained is purified by HPLC on a Chromasil column (C18, 5 ⁇ M, 100x20mm) with a water-acetonitrile mixture containing 0.07% TFA (gradient 95/5 to 60/40 by volume in 20 minutes at a flow rate of 20 L / min) as eluent. 188 mg of (4-chloro-2-methylamino-6-nitroquinoline) are obtained in the form of a yellow powder, the mass spectrum of which is as follows:
  • 2,4-dichloro-6-nitro-quinoline can be prepared as described in the previous example.
  • 4-dimethylamino-2-methyl-quinoline-7-amine (A6 / B6 / C6) can be prepared by operating as follows:
  • N7-benzhydrylidene-4-dimethylamino-2-methyl-quinoline-7-amino can be prepared in the following way: 100 mg of 7-chloro-4-dimethylamino-2-methyl-quinoline in mixture with 5-chloro- 4-dimethylamino-2-methyl-quinoline in proportions 70/30 (in mole), in solution in 2 ml of 1, 2-dimethoxyethane is added to a mixture of 41.2 mg of tris (dibenzylideneacetone) dipalladium, 35.4 mg of 2 -cyclohexylphosphino-2 '(N, N-dimethylamino) -biphenyl and 221.2 mg of cesium carbonate under argon.
  • 7-chloro-4-dimethylamino-2-methyl-quinoline can be prepared as follows: 500 mg of 4, 7-dichloro-2-methyl-quinoline mixed with 4, 5-dichloro-2-methyl-quinoline in the proportions 70/30 (in mole), is dissolved in 12 ml of DMF in the presence of 1.63 g of potassium carbonate and 1.96 g of dimethylammonium hydrochloride. The reaction mixture is stirred at 100 ° C for 3 hours. After returning to ambient temperature, the insoluble material is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is hydrolyzed by adding water and the aqueous phase thus obtained is extracted with dicholoromethane.
  • 7-dichloro-2-methyl-quinoline can be prepared as follows: A 500 mg solution of 7-chloro-2-methyl-quinolin-4-ol, mixed with 5-chloro-2- methyl-quinolin-4-ol in proportions 70/30 (in mole), in 7.6 mL of P0C1 3 is brought to reflux for 3 hours. After returning to ambient temperature, the reaction mixture is concentrated under reduced pressure and then taken up with water. The pH of the aqueous phase is brought to 8 by adding a saturated aqueous solution of sodium hydrogencarbonate and the precipitate thus obtained is recovered by filtration, washed with water and then dried under reduced pressure.
  • o 6-dimethylamino-phenanthridin-2-amine (Cl4) can be prepared by operating as follows:
  • 6-chloro-2-nitro-phenanthridine can be prepared as follows: A solution of 200 mg of
  • o • l-Dimethylamino-isoquinoline-7-amine (C15) can be prepared by operating as follows:
  • L-dimethylamino-7-nitro-isoquinoline can be prepared as follows: 375 mg of l-chloro-7-nitro-isoquinoline in mixture with l-chloro-5-nitro-isoquinoline in proportions 40/60 ( in moles) is dissolved in 6 ml of DMF in the presence of 1.24 g of potassium carbonate and 1.46 g of dimethylammonium hydrochloride. The reaction mixture is stirred at 100 ° C for 3 hours. After returning to ambient temperature, it is hydrolyzed by adding water and the aqueous phase thus obtained is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure.
  • L-chloro-7-nitro-isoquinoline can be prepared as follows: A solution of 580 mg of 7-nitro-isoquinolin-1-ol, mixed with 5-nitro-isoquinolin-1-ol in proportions 40/60 (in moles), in 6 mL of POCI 3 is brought to reflux for 3 hours. After returning to room temperature, the reaction mixture is added with cyclohexane until a precipitate is obtained which is recovered by filtration and then taken up with water. The pH of the aqueous phase thus obtained is brought to 8 - by adding an aqueous solution of 28% ammonia and the resulting precipitate is recovered by filtration, washed with water and then dried under reduced pressure.
  • 7-nitro-isoquinolin-1-ol can be prepared as follows: 500 mg of 1-isoquinolinol are placed in solution in 5 ml of concentrated sulfuric acid at 0 ° C. 348 mg of potassium nitrate is then added and the reaction mixture is stirred at 0 ° C for 1 hour and then overnight at room temperature. It is then thrown into a water-ice mixture and the pH of the aqueous solution thus obtained is brought to pH 8 by addition of a 28% aqueous ammonia solution. The precipitate obtained is recovered by filtration, washed with water and then dried under reduced pressure.
  • 4-dimethylamino-2-methyl-quinoline-6-N-methyl-acetamide can be prepared as follows: 250 mg of 4-dimethylamino-2-methyl-quinoline-6-acetamide in solution in 2 mL of DMF at 0 ° C., 45 mg of 60% sodium hydride in oil are added. After 20 minutes of stirring at room temperature, the reaction medium is again cooled to 0 ° C. and 77 ⁇ L of methyl iodide are added. After 2 hours of stirring at room temperature, water is added and the aqueous phase is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure.
  • 4-Dimethylamino-2-methyl-quinoline-6-acetamide can be prepared as follows: at 300 mg of
  • 4-Dimethylamino-2-methyl-quinoline-6-amine can be prepared as described in patent WO 0140218. o 4-dimethylamino-2-phenyl-quinoline-6-amine (C17) can be prepared by operating as follows:
  • the ' 4-dimethylamino-2-phenyl-quinoline-6-acetamide can be prepared as follows: 400 mg of 4-chloro-2-phenyl-quinoline-6-acetamide is dissolved in 15 ml of DMF in the presence 1.86 g of potassium carbonate and '1.10 g of dimethylammonium hydrochloride. The reaction mixture is stirred at 150 ° C for 6 hours. After returning to ambient temperature, it is hydrolyzed by adding water and the aqueous phase thus obtained is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. 360 mg of 4-dimethylamino-2-phenyl-quinoline-6-acetamide are thus obtained in the form of a brown oil, the mass spectrum of which is as follows:
  • the 4-chloro-2-phenyl-quinoline-6-acetamide can be prepared as follows: A solution of 380 mg of 4-hydroxy-2-phenyl-quinoline-6-acetamide in 2 ml of P0C1 3 is brought to the reflux for 3 hours. After returning to room temperature, the reaction mixture is added with cyclohexane until a precipitate is obtained which is recovered by filtration and then taken up with water. The pH of the aqueous phase thus obtained is brought to 8 by adding a 28% aqueous ammonia solution and the resulting precipitate is recovered by filtration, washed with water and then dried under reduced pressure. 400 mg of 4-chloro-2-phenyl-quinoline-6-acetamide are thus obtained in the form of a yellow powder, the mass spectrum of which is as follows:
  • the 4-hydroxy-2-phenyl-quinoline-6-acetamide can be prepared as follows: 1 g of ethyl 3- (4-acetylamino-phenylamino) -3-phenyl-acrylate is poured into 20 ml of dowtherm Has reflux. After 45 minutes, it returns to ambient temperature and the reaction medium is supplemented with cyclohexane until formation of a precipitate which is recovered by filtration, washed with cyclohexane and then dried under reduced pressure. 688 mg of 4-hydroxy-2-phenyl-quinoline-6-acetamide are thus obtained in the form of an ocher powder, the mass spectrum of which is as follows:
  • Ethyl 3- (4-acetylamino-phenylamino) -3-phenyl-acrylate can be prepared as follows:
  • 4-dimethylamino-2-isopropyl-6-nitro-quinoline can be prepared as follows: 450 mg of 4-chloro-2-isopropyl-6-nitro-quinoline mixed with 4-chloro-2-isopropyl- 8-nitro-quinoline in proportions 8.5 / 1.5 is dissolved in 12 mL of DMF in the presence of 1.2 g of potassium carbonate and 1.47 g of dimethylammonium hydrochloride. The reaction mixture is stirred at 100 ° C for 3 hours. After returning to ambient temperature, it is hydrolyzed by adding water and the aqueous phase thus obtained is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure.
  • 4-chloro-2-isopropyl-6-nitro-quinoline can be prepared as follows: A solution of 475 mg of 2-isopropyl-6-nitro-quinolin-4-ol, mixed with 2-isopropyl- 8-nitro-quinolin-4-ol in proportions 8.5 / 1.5 (in moles), in 4 mL of P0C1 3 is brought to reflux for 3 hours. After returning to ambient temperature, the reaction mixture is added with water and cyclohexane and the pH of the aqueous phase is brought to 8. addition of an aqueous solution of 28% monique. A precipitate is formed which is recovered by filtration and the aqueous phase is extracted with dichloromethane.
  • 2-isopropyl-6-nitro-quinolin-4-ol can be prepared as follows: 450 mg of 2-isopropyl-1H-quinolin-4-one are placed in solution in 5 ml of acid concentrated sulfuric at 0 ° C. 243 mg of potassium nitrate is then added and the reaction mixture is stirred at 0 ° C for 1 hour and then overnight at room temperature. It is then thrown into a water-ice mixture and the pH of the aqueous solution thus obtained is brought to pH 8 by addition of a 28% aqueous ammonia solution. A precipitate forms which is collected by filtration and dried under reduced pressure.
  • 2-isopropyl-1H-quinolin-4-one can be prepared as follows: 4.09g of benzyl 2-isopropyl-4-triisopr ⁇ ylsilanyloxy-2H-quinoline-1-carboxylate in solution in 115 ml of methanol is placed under hydrogen atmosphere (5 bar) in the presence of 400 mg of 10% palladium on carbon for 12 hours. After filtration on celite, the filtrate is concentrated under reduced pressure.
  • Benzyl 4-oxo-4H-quinoline-1-carboxylate can be prepared as follows: to 179 mg of 4-hydroxyquinoline in 3 ml of tert-butanol at 30 ° C. are added 179 mg of sodium hydride to 60% in oil then the reaction mixture is heated to 50 ° C until the end of gas evolution. It then returns to room temperature and 673 ⁇ L of benzyl chloroformate is added dropwise then the mixture is stirred for 3 hours. The reaction medium is then hydrolyzed with 10 ml of water and the pH is brought to 4 by addition of a 0.5 M aqueous solution of hydrochloric acid.
  • the 2,7-dimethyl-4-dimethylamino-6-nitro-quinoline-6-amine can be prepared as follows: 500 mg of 4-chloro-2, 7-dimethyl-6-nitro-quinoline in mixture with the 4-chloro-2, 7-dimethyl-8-nitro-quinoline in proportions 35/65 (in moles) is dissolved in 8 ml of DMF in the presence of 1.46 g of potassium carbonate and 1.72 g of hydrochloride dimethyl. The reaction mixture is stirred at 100 ° C for 3 hours. After returning to ambient temperature, it is hydrolyzed by adding water and the aqueous phase thus obtained is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure.
  • 4-chloro-2, 7-dimethyl-6-nitro-quinoline can be prepared as follows: A solution of 660 mg of 2, 7-dimethyl-6-nitro-quinolin-4-ol, mixed with 2, 7-dimethyl-8-nitro-quinolin-4-ol in proportions 35/65 (in moles), in 5 ml of P0C1 3 is brought to reflux for 3 hours. After returning to ambient temperature, the reaction mixture is added with cyclohexane until a precipitate is obtained which is recovered by filtration and then taken up with water. The pH of the aqueous phase thus obtained is brought to 8 by adding a 28% aqueous ammonia solution and the resulting precipitate is recovered by filtration, washed with water and then dried under reduced pressure.
  • 2, 7-dimethyl-6-nitro-quinolin-4-ol can be prepared as follows: 625 mg of 2, 7-dimethyl-quinolin-4-ol are placed in solution in 6 mL of concentrated sulfuric acid at 0 ° C. 365 mg of potassium nitrate is then added and the reaction mixture is stirred at 0 ° C for 1 hour and then overnight at room temperature. It is then thrown into a water-ice mixture and the pH of the aqueous solution thus obtained is brought to pH 7 by adding a 28% aqueous ammonia solution. The precipitate obtained is recovered by filtration, washed with water and then dried under reduced pressure.
  • the 2, 7-dimethyl-quinolin-4-ol can be prepared in the following way: 3.54 g of ethyl 3-m-tolylamino-but-2-enoate is thrown into 30 ml of dowtherm A at reflux. After 45 minutes, it returns to ambient temperature and the reaction medium is supplemented with cyclohexane until a precipitate is formed which is recovered by filtration, washed with cyclohexane and then dried under reduced pressure.
  • 3-m-tolylamino-but-2-enoic acid ethyl ester can be prepared as follows: 2 mL of m-toluidine in 8 mL of absolute ethanol are added 2.59 ml of ethyl acetoacetate, '24 drops of acetic acid and 6.29 g of drierite. The reaction mixture is brought to reflux for 48 hours. After returning to ambient temperature, the insoluble material is removed by filtration and the filtrate is concentrated under reduced pressure. 3.54 g of ethyl 3-m-tolylamino-but-2-enoate are thus obtained in the form of a colorless oil, the mass spectrum of which is as follows:
  • 2-dimethylamino-5-nitro-1H-benzoimidazole can be prepared as follows: 500 mg of 2-chloro-5-nitro-1H-benzoimidazole in solution in 4 ml of DMF in the presence of 825 mg of dimethylmmonium hydrochloride and 395 mg of p-toluene sulfonic acid is heated at 100 ° C for 20 hours. After return to temperature ambient, water is added and the aqueous phase is extracted with dichloromethane. The organic phase is washed with an aqueous IN sodium hydroxide solution, dried over magnesium sulphate and concentrated under reduced pressure. 239 mg of 2-dimethylamino-5-nitro-1H-benzoimidazole is thus obtained in the form of a brown solid, the mass spectrum of which is as follows:
  • 2-chloro-5-nitro-1H-benzoimidazole can be prepared as described in the literature (Jung, F.; Delvare, C.; Boucherot, D.; Ha on, A. ' J. Med. Chem. 1991, 34 (3), 1110-1116
  • o 2-dimethylamino-3-methyl-3H-benzoimidazol-5-amine (C22) can be prepared by operating as follows: 314 mg of 2-dimethylamino-5-nitro-1H-benzoimidazole is added to a solution of 122 mg of 60% sodium hydride in oil in 6 mL of DMF. After the addition of 110 ⁇ L of iodomethane, the reaction mixture is stirred at ambient temperature for 3 hours then added with a saturated aqueous solution of ammonium chloride. The aqueous phase is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure.
  • 2-Dimethylamino-5-nitro-1H-benzoimidazole can be prepared as described in the previous example.
  • o L-dimethylamino-3-methyl-isoquinoline-7-amine (C24) can be prepared by operating as follows:
  • L-dimethylamino-3-methyl-7-nitro-isoquinoline can be prepared as follows: 810 mg of 2- (l-acetyl-2-oxo-propyl) -5-nitro-benzonitrile is heated to 40 ° C for 16 hours in 10 mL of a 40% aqueous dimethylamine solution. After returning to ambient temperature, 30 ml of a 2.5N aqueous hydrochloric acid solution are added and then the aqueous phase is washed with ethyl acetate. The aqueous phase is brought back to pH 9 by addition of a 5N aqueous sodium hydroxide solution and the resulting precipitate is recovered by filtration and dried under reduced pressure.
  • the 9-phenoxy-acridin-2-amine can be prepared as follows: 494 mg of 9-phenoxy-acridin-2-trifluoroacetamide in solution in 50 ml of methanol is added with 3 ml of water and 940 mg of potassium carbonate. The reaction medium is brought to reflux for 5 hours. After returning to ambient temperature and concentration under reduced pressure, water is added and the aqueous phase is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. 385 mg of 9-phenoxy-acridin-2-amine are thus obtained in the form of an orange mouse, the mass spectrum of which is as follows:
  • the 9-phenoxy-acridin-2-trifluoroacetamide can be prepared as follows: 770 mg of 9-chloro-acridin-2-trifluoroacetamide is heated at 100 ° C. for 15 hours in 2.23 g of phenol. ambient, dichloromethane is added and the organic phase is washed successively with an aqueous solution of IN sodium hydroxide and water, then is dried over magnesium sulphate and concentrated under reduced pressure. 594 mg of 9-phenoxy-acridin-2-trifluoroacetamide are thus obtained in the form of a red powder, the mass spectrum of which is as follows:
  • 9-chloro-acridin-2-trifluoroacetamide can be prepared as follows: A solution of 725 mg of 2-trifluoroacetamido-acridone in 7 ml of P0C1 3 is brought to reflux for 30 minutes. After returning to ambient temperature and concentration under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate is added and the resulting precipitate is recovered by filtration, washed with water and then dried under reduced pressure. 770 mg 9-chloro-acridin-2- is thus obtained trifluoroacetamide in the form of a yellow powder with a mass spectrum as follows:
  • 2-trifluoroacetamido-acridone can be prepared as follows: to 400 mg of 2-aminoacridone in solution in 6.5 mL of dichloromethane at 0 ° C, are added 535 ⁇ L of triethylamine, 405 ⁇ L of trifluoroacetic anhydride and 13 mg of DMAP. The reaction mixture is stirred at room temperature for 15 hours. After concentration under reduced pressure, water is added and the resulting precipitate is recovered by filtration and then dried under reduced pressure.
  • o L-dimethyiamino-3-methyl-isoquinoline-7-amine (C24) can be prepared by operating as follows:
  • L-dimethylamino-3-methyl-7-nitro-isoquinoline can be prepared as follows: 810 mg of 2- (l-acetyl-2-oxo-propyl) -5-nitro-benzonitrile is heated to 40 ° C for 16 hours in 10 mL of a 40% aqueous dimethylamine solution. After returning to ambient temperature, 30 ml of a 2.5N aqueous hydrochloric acid solution are added and then the aqueous phase is washed with ethyl acetate. The aqueous phase is brought back to pH 9 by addition of a 5N aqueous sodium hydroxide solution and the resulting precipitate is recovered by filtration and dried under reduced pressure. 190 mg of l-dimethylamino-3-methyl-7-nitro-isoquinoline are thus obtained in the form of an orange powder, the mass spectrum of which is as follows:
  • the 5-nitro-1- (2-tert-butyldimethylsilyloxy-ethyl) - indole can be prepared as follows: To a suspension of 1.1 mmol of sodium hydride in 2 ml of DMF under argon is added 1 mmol of 5 -nitroindole. The reaction mixture is stirred at ambient temperature until the evolution of gas has ended and then 1.2 mmol of
  • reaction mixture Upon completion of the reaction, the reaction mixture is hydrolyzed with a saturated aqueous solution of ammonium chloride.
  • the aqueous phase thus obtained is extracted with dichloromethane and the organic phase is dried over magnesium sulfate and then concentrated under reduced pressure.
  • 5-nitro-1- (2-tert-butyldimethylsilyloxyethyl) -indole is thus obtained after purification on silica.
  • amines necessary for the introduction of type A radicals of general formula (lb) are • either commercial: o 1- (2-pyrrolidinoethyl) piperazine (A14) o 1- (2-morpholinoethyl) piperazine (A25) o 1- (3-morpholinopropy) piperazine (A27)
  • the G-quartet, antitelomerase and cytotoxic activities of the various compounds exemplified 1 to 176, given in Table 1 are determined according to the operating protocols described above.

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IL158056A0 (en) 2004-03-28
IL158056A (en) 2010-02-17
JP2004524349A (ja) 2004-08-12
AU2002251140B2 (en) 2007-03-15
AR034297A1 (es) 2004-02-18
MY130957A (en) 2007-07-31
MXPA03008269A (es) 2004-10-15
PE20020959A1 (es) 2002-12-17
CA2442012A1 (fr) 2002-10-03
CO5380035A1 (es) 2004-03-31
WO2002076975A1 (fr) 2002-10-03

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