Chemical derivatives and their application as antitelomerase agents

Abstract

The present invention relates to cancer therapy and to novel anticancer agents having a mechanism of action which is quite specific. It also relates to novel chemical compounds as well as their therapeutic application in humans.

1 . A compound which binds a G-quadruplex structure of DNA or RNA, wherein the compound corresponds to the following formula:
   nitrogen-containing aromatic ring-NR 3 -distribution agent-NR′ 3 -aromatic ring   in which:
 the nitrogen-containing aromatic ring represents:
 a quinolinyl or isoquinolinyl radical optionally substituted with one or more radicals chosen from among:
 N(Ra)(Rb), wherein Ra and Rb are identical or different and represent hydrogen or C1-C4 alkyl radical, and 
 a short-chain C1-C4 alkoxy or alkyl group, 
 
 a quinolinyl or isoquinolinyl radical possessing a nitrogen atom in quaternary form, 
 or 
 a pyridinyl radical; 
 or wherein the nitrogen-containing aromatic ring is replaced by a benzimidinyl radical; 
 
 the aromatic ring represents:
 a quinolinyl radical optionally substituted with one or more radicals chosen from among:
 N(Ra)(Rb), wherein Ra and Rb are identical or different and represent hydrogen or C1-C4 alkyl radical, and 
 a short-chain C1-C4 alkoxy or alkyl group, 
 
 a quinolinyl radical possessing a nitrogen atom in quaternary form, 
 a benzamidinyl radical, 
 a pyridinyl radical, 
 a phenyl ring optionally substituted with a halogen group, C1-C4 alkoxy group, cyano group, carbonylamino group optionally substituted with one or more C1-C4 alkyl groups, guanyl group, C1-C4 alkylthio group, amino group, C1-C4 alkylamino group, C1-C4 dialkylamino group for each alkyl, C1-C4 dialkylamino group for each alkyl in which the alkyl portions together form a C3-C8 ring, nitro group, C1-C4 alkyleneamino group, or C2-C4 alkenyleneamino group, 
 or 
 a mono- or bi- or tricyclic heterocyclic ring comprising 0 to 2 heteroatoms per ring wherein at least one heteroatom is present in at least one ring that is optionally substituted with one or more C1-C4 alkyl groups, C1-C4 alkylene groups, or C2-C4 alkenylene groups; 
 
 R3 and R′3 are identical or different and represent, independently of one another, hydrogen or C1-C4 alkyl radical; 
 the distribution agent represents: i) a triazine group, wherein the triazine group is optionally substituted with:
 an aromatic ring as defined above, or 
 a radical XR1(R2), where X represents a nitrogen to form NR1R2, a linear or branched C1-C6 alkyl radical to form alkR1R2, an oxygen to form OR1, or a sulfur to form SR1,
 wherein R1 and R2, which are identical or different, are chosen from among hydrogen; a C1-C8 alkyl radical optionally substituted with one or more radicals which are identical or different; an aromatic ring as defined above; a quinuclidine radical; a pyrrolidinyl radical which is optionally substituted with an alkyl or phenylalkyl radical where alkyl is C1-C4 alkyl; a piperazinyl radical which is optionally substituted with an alkyl, cycloalkyl or phenylalkyl radical; a morpholinyl radical; a pyridyl radical or a piperidyl radical which are optionally substituted with one or more alkyl or phenylalkyl radicals where alkyl is C1-C4 alkyl; an indazolyl radical; a naphthyl radical; a benzotriazole radical; a pyrimidinyl radical optionally substituted with one or more C1-C4 alkyls; and an acenaphthene radical; or 
 a radical where X represents N or alkyl, R1 and R2 are as defined above, and R1, R2 and X form a saturated or unsaturated 3- to 6-membered monocyclic or 8- to 10-membered bicyclic radical optionally containing one or two identical or different heteroatoms chosen from N, O or S; 
 
 with the provisos that if X represents a nitrogen and R1 and R2 are identical, then R1 and R2 do not both represent hydrogen or unsubstituted C1-C4 alkyl, and if X represents a nitrogen and R1 and R2 are different, then one does not represent hydrogen and the other an unsubstituted C1-C4 alkyl; or 
 
 ii) a diazine group
 wherein the diazine group is optionally substituted with any of the groups defined above for the triazine group; 
 
   or any salts, isomeric forms, racemates, enantiomers and diastereoisomers thereof.   
   
   
       2 . The compound of  claim 1 , wherein one or both of R1 and R2 represents a C1-C8 alkyl radical optionally substituted with one or more radicals which are identical or different, chosen from among:
 an amino radical which is optionally substituted with one or two radicals which are identical or different, chosen from alkyl, hydroxyalkyl, alkoxyalkyl, phenylalkyl, carboxyalkyl, hydroxycarboxyalkyl, acyl, naphthyl, phenyl and alkylphenyl radicals;   a trialkylammonium radical;   a hydroxyl radical;   a C1-C4 alkoxy radical;   a thioalkoxy radical;   a trifluoromethyl radical;   a free, salified, esterified or amidated carboxyl radical;   a pyrrolidinyl radical optionally substituted with C1-C4 alkyl;   a piperidyl radical;   a piperazinyl radical optionally substituted with alkyl or phenylalkyl where alkyl is C1-C4 alkyl;   a morpholinyl radical;   a pyridyl radical; and   a naphthyl radical or phenyl radical optionally substituted with one or more radicals chosen from C1-C4 alkoxy radicals, halogen or an amino radical optionally substituted as defined above.   
   
   
       3 . The compound of  claim 1 , wherein the distribution agent represents
 a triazine group optionally substituted with:
 an aromatic ring as defined in  claim 1 , or 
 a radical XR1(R2), where X represents a nitrogen to form NR1R2, a linear or branched C1-C6 alkyl radical to form alkR1R2, an oxygen to form OR1, or a sulfur to form SR1, 
 wherein R1 and R2, which are identical or different, are chosen from:
 hydrogen; 
 a C1-C8 alkyl radical optionally substituted with one or more radicals chosen from the radicals amino, alkylamino, dialkylamino, dialkoxyalkylamino, dihydroxyalkylamino, alkoxyalkylamino, hydroxyalkylamino, hydroxycarboxy-alkylamino, trialkylamino, naphthylamino, phenylamino, acylamino, (alkyl)(phenylalkyl)amino, (phenyl)(alkyl)amino, (alkylphenyl)(alkyl)amino, hydroxyl, C1-C4 alkoxy, C1-C4 thioalkoxy, trifluoromethyl, free, salified, esterified or amidated carboxyl, pyrrolidinyl optionally substituted with C1-C4 alkyl, piperidyl, piperazinyl optionally substituted with alkyl or phenylalkyl with alkyl as C1-C4, morpholinyl, pyridyl, naphthyl or phenyl optionally substituted with one or more radicals chosen from the radicals C1-C4 alkoxy, halogen, amino, alkylamino and dialkylamino; 
 an aromatic ring as defined in  claim 1 ; 
 a quinuclidine radical; 
 a pyrrolidinyl radical which is optionally substituted with an alkyl or phenylalkyl radical where alkyl is C1-C4 alkyl; 
 a piperazinyl radical which is optionally substituted with an alkyl, cycloalkyl or phenylalkyl radical; 
 a morpholinyl radical; 
 a pyridyl radical or a piperidyl radical which are optionally substituted with one or more alkyl or phenylalkyl radicals where alkyl is C1-C4 alkyl; 
 an indazolyl radical; 
 a naphthyl radical; 
 a benzotriazole radical; 
 a pyrimidinyl radical optionally substituted with one or more C1-C4 alkyls; and 
 an acenaphthene radical; or 
 a radical where X represents N or alkyl, R1 and R2 are as defined above, and R1, R2 and X form a radical chosen from the following radicals: piperazinyl optionally substituted with one or more radicals which are identical or different; pyrrolidinyl optionally substituted with C1-C4 alkyl or alkoxy, hydroxyl, acylamino, pyrrolidinylalkyl and pyridyl; 1,2,3,4-tetrahydroisoquinolinyl; diazepine optionally substituted with alkyl or pyrrolidinylalkyl; piperidyl optionally substituted with alkyl, alkoxy or alkoxyalkyl, hydroxyl and cycloalkylalkyl; morpholinyl; imidazolinyl optionally substituted with alkyl, 
 
 with the provisos that if X represents a nitrogen and R1 and R2 are identical, then R1 and R2 do not both represent hydrogen or unsubstituted C1-C4 alkyl, and if X represents a nitrogen and R1 and R2 are different, then one does not represent hydrogen and the other an unsubstituted C1-C4 alkyl; or 
   a diazine group,
 wherein the diazine group is optionally substituted with any of the groups defined above for the triazine group; 
   or any salts, isomeric forms, racemates, enantiomers and diastereoisomers thereof.   
   
   
       4 . The compound of  claim 1 , wherein the diazine group is a pyrimidine. 
   
   
       5 . The compound of  claim 1 , wherein X in XR1(R2) is nitrogen, and one of R1 and R2 is as defined in  claim 1  and the other of R1 and R2 represents hydrogen or C1-C4 alkyl radical optionally substituted with an amino, alkylamino, dialkylamino or phenyl radical; or
 R1, R2, and the nitrogen atom to which they are attached, form a piperazinyl radical optionally substituted with one or more radicals chosen from alkyl; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; phenylalkyl; alkoxyalkyl; hydroxyalkyl; hydroxyalkoxyalkyl; alkoxy; pyrrolidinylalkyl; C3-C8 cycloalkyl; pyrazinyl; pyrimidinyl; pyridyl; furylcarbonyl; furfurylcarbonyl; quinolyl; pyrrolidinyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, acylamino, pyrrolidinylalkyl, or pyridyl; 1,2,3,4-tetrahydroisoquinolinyl; diazepine optionally substituted with alkyl or pyrrolidinylalkyl; piperidyl optionally substituted with alkyl, alkoxy or alkoxyalkyl; hydroxyl; cycloalkylalkyl; morpholinyl; and imidazolinyl optionally substituted with alkyl.   
   
   
       6 . The compound of  claim 1 , wherein the compound corresponds to the following formula:
   nitrogen-containing aromatic ring-NR 3 -distribution agent-NR′ 3 -aromatic ring   in which   the nitrogen-containing aromatic ring represents:
 a quinolinyl or isoquinolinyl radical optionally substituted with one or more radicals chosen from among:
 N(Ra)(Rb), wherein Ra and Rb are identical or different and represent hydrogen or C1-C4 alkyl radical, and 
 a short-chain C1-C4 alkoxy or alkyl group, 
 
 a quinolinyl radical possessing a nitrogen atom in quaternary form, 
 or 
 a pyridinyl radical; 
 or wherein the nitrogen-containing ring is replaced by a benzimidinyl radical; 
   the aromatic ring represents:
 a quinolinyl radical optionally substituted with one or more radicals chosen from among:
 N(Ra)(Rb), wherein Ra and Rb are identical or different and represent hydrogen or C1-C4 alkyl radical, and 
 a short-chain C1-C4 alkoxy or alkyl group, 
 
 a quinolinyl radical possessing a nitrogen atom in quaternary form, 
 a benzamidinyl radical, 
 a pyridinyl radical, 
 a phenyl ring optionally substituted with a halogen group, C1-C4 alkoxy group, cyano group, carbonylamino group optionally substituted with one or more C1-C4 alkyl groups, guanyl group, C1-C4 alkylthio group, amino group, C1-C4 alkylamino group, C1-C4 dialkylamino group, C1-C4 dialkylamino group in which the alkyl portions together form a C3-C8 ring, nitro group, C1-C4 alkyleneamino group, or C2-C4 alkenyleneamino group, or 
 a mono- or bi- or tricyclic heterocyclic ring comprising 0 to 2 heteroatoms per ring wherein at least one heteroatom is present in at least one ring that is optionally substituted with one or more C1-C4 alkyl groups, C1-C4 alkylene, or C2-C4 alkenylene groups; 
   R3 and R′3 are identical or different and represent, independently of one another, hydrogen or C1-C4 alkyl radical;   
     the distribution agent represents:
 i) a triazine group,
 wherein the triazine group is optionally substituted with:
 a radical XR1(R2), where X represents a nitrogen to form NR1R2, a linear or branched C1-C6 alkyl radical to form alkR1R2, an oxygen to form OR1, or a sulfur to form SR1, 
 wherein R1 and R2, which are identical or different, are chosen from among hydrogen; C1-C8 alkyl optionally substituted with a radical chosen from amino, alkylamino, dialkylamino, (phenyl)(alkyl)amino, (alkylphenyl)(alkyl)-amino, C1-C4 alkoxy, C1-C4 thioalkoxy, trifluoromethyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, pyridyl and phenyl; an aromatic ring as defined in  claim 1 , a quinuclidine radical; a pyrrolidinyl, piperazinyl, morpholinyl, pyridyl or a piperidyl radical optionally substituted with C1-C4 alkyl; or 
 a radical where X represents N or alkyl, R1 and R2 are as defined above, and R1, R2 and X form a saturated or unsaturated 3- to 6-membered monocyclic or 8- to 10-membered bicyclic radical optionally containing one or two identical or different heteroatoms chosen from N, O or S; 
 
 with the provisos that if X represents a nitrogen and R1 and R2 are identical, then R1 and R2 do not both represent hydrogen or unsubstituted C1-C4 alkyl, and if X represents a nitrogen and R1 and R2 are different, then one does not represent hydrogen and the other an unsubstituted C1-C4 alkyl; or 
 
 ii) a diazine group
 wherein the diazine group is optionally substituted with any of the groups defined above for the triazine group; 
 
 
     or any salts, isomeric forms, racemates, enantiomers and diastereoisomers thereof. 
   
   
       7 . The compound of  claim 1 , wherein the distribution agent represents:
 i) a triazine group optionally substituted with a radical XR1(R2) where X represents a nitrogen to form NR1R2, an oxygen to form OR1, or a sulfur to form SR1,   wherein R1 and R2, which are identical or different, are chosen from among:
 hydrogen, 
 C1-C8 alkyl optionally substituted with a radical chosen from amino, alkylamino, dialkylamino, (phenyl)(alkyl)amino, (alkylphenyl)(alkyl)-amino, C1-C4 alkoxy, pyrrolidinyl, pyridyl, and phenyl, 
 an aromatic ring as defined in  claim 1 ; 
 a quinuclidine radical; 
 a pyrrolidinyl radical; and 
 a piperidyl radical optionally substituted with C1-C4 alkyl, or 
   a radical where X represents N, R1 and R2 are as defined above, and R1, R2, and X form a piperazinyl, piperidyl, pyrrolidinyl, morpholinyl or thiomorpholinyl radical,
 with the provisos that if X represents a nitrogen and R1 and R2 are identical, then R1 and R2 do not both represent hydrogen or unsubstituted C1-C4 alkyl, and if X represents a nitrogen and R1 and R2 are different, then one does not represent hydrogen and the other an unsubstituted C1-C4 alkyl; or 
   ii) a diazine group   wherein the diazine group is optionally substituted with any of the groups defined above for the triazine group; or any salts, isomeric forms, racemates, enantiomers and diastereoisomers thereof.   
   
   
       8 . The compound of  claim 1 , wherein X in XR1(R2) represents N, one of R1 and R2 represents a hydrogen atom and the other of R1 and R2 is as defined in  claim 1 ; or
 R1 and R2, together with the nitrogen atom to which they are attached, form a piperazinyl, pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, imidazolinyl, diazepine, or 1,2,3,4-tetrahydroisoquinoline radical, all these radicals being optionally substituted with one or more radicals.   
   
   
       9 . A pharmaceutical composition comprising, as active ingredient, one or more compounds according to  claim 1 ; and a pharmaceutically acceptable excipient. 
   
   
       10 . A pharmaceutical composition comprising, as active ingredient, one or more compounds according to  claim 2 ; and a pharmaceutically acceptable excipient. 
   
   
       11 . A pharmaceutical composition comprising, as active ingredient, one or more compounds according to  claim 4 ; and a pharmaceutically acceptable excipient. 
   
   
       12 . A pharmaceutical composition comprising, as active ingredient, one or more compounds according to  claim 7 ; and a pharmaceutically acceptable excipient. 
   
   
       13 . A method of inhibiting the activity of a telomerase comprising contacting one or more compounds of  claim 1  with a telomerase. 
   
   
       14 . A method of treating cancer comprising administering one or more compounds of  claim 1  to a patient in need of said treatment. 
   
   
       15 . The method according to  claim 14 , wherein the one or more compounds is administered in combination with a second anticancer agent. 
   
   
       16 . The method according to  claim 15 , wherein the second anticancer compound is chosen from alkylating agents, platinum derivatives, antibiotic agents, antimicrotubule agents, anthracyclines, group I and II topoisomerases, fluoropyrimidines, cytidine analogues, adenosine analogues, L-asparaginase, hydroxyurea, trans-retinoic acid, suramine, irinotecan, topotecan, dexrazoxane, amifostine, herceptin, estrogenic and androgenic hormones, and antivascular agents. 
   
   
       17 . The method according to  claim 14 , wherein the one or more compounds is administered in combination with radiation. 
   
   
       18 . The method according to  claim 18 , wherein the compound and radiation are administered simultaneously, separately or sequentially.