Camptothecin is a natural compound which was isolated for the first time from the leaves and bark of the Chinese plant called camptotheca acuminata (seer Wall et al., J. Amer. Chem. Soc. 88:3888 (1966)). Camptothecin is a pentacyclic compound, constituted by a an indolizino[1,2-b]quinoline fragment fused with an xcex1-hydroxylactone with six links, and corresponding to the following formula: 
Camptothecin has an anti-proliferative activity in several cancerous cell lines, including the cell lines of human colon, lung and breast tumours (Suffness, M. et al.: The Alkaloids Chemistry and Pharmacology, Bross, A., ed., Vol. 25, p. 73 (Academic Press, 1985)). It has been established that the anti-proliferative activity of camptothecin is related to its inhibitor activity on DNA topoisomerase I.
It had been indicated that xcex1-hydroxylactone was an absolute requirement both for in vivo and in vitro activity of camptothecin (Camptothecins: New Anticancer Agents, Putmesil, M., et al., ed., p. 27 (CRC Press, 1995); Wall, M. et al., Cancer Res. 55:753 (1995); Hertzberg et al., J. Med. Chem. 32:715 (1982) and Crow et al., J. Med. Chem. 35:4160 (1992)). Unexpectedly, the Applicant had discovered that xcex2-hydroxylactones with 7 links have a biological activity which is comparable to or greater than that of xcex1-hydroxylactones (PCT Application No. FR 96/00980). Now, the Applicant has just discovered unexpectedly that certain camptothecin analogues comprising neither xcex1-hydroxylactone nor xcex2-hydroxylactone also present an inhibitory activity on topoisomerases. The present invention therefore relates to a new class of tetracyclic analogues of camptothecin, in which the natural xcex1-hydroxylactone of camptothecin or the xcex2-hydroxylactone of the analogues previously described by the Applicant is absent. The compounds according to the present invention have a powerful biological activity inhibiting topoisomerase I and/or topoisomerase II, which is unexpected with respect to the prior state of the art.
A subject of the invention is therefore compounds of formula (I), 
in racemic or enantiomeric form or any combination of these forms, in which
R1 represents a lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, lower alkoxyalkyl or lower alkylthioalkyl radical;
R2, R3 and R4 represent, independently, an H, hydroxy, lower alkoxy, arylalkoxy, halo, lower haloalkyl, lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, (CH2)mNR6R7, (CH2)mOR6, (CH2)mSR6, (CH2)mCO2R6, (CH2)mNR6C(O)R8, (CH2)mC(O)R8, (CH2)mOC(O)R8, O(CH2)mNR6R7, OC(O)NR6R7, OC(O)(CH2)mCO2R6, aryl or lower arylalkyl radical substituted (i.e., substituted one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl) or R2 and R3, or R3 and R4, or R4 and R5, independently form together a chain with 3 or 4 links, in which the elements of the chain are selected from the group consituted by CH, CH2, O, S, N or NR9;
R5 represents an H, halo, lower haloalkyl, lower alkyl, lower alkoxy, lower alkoxyalkyl, lower alkylthioalkyl, cycloalkyl, lower cycloalkylalkyl, cyano, cyanoalkyl, lower alkanesulphonylalkyl, lower hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOC(O)R8, (CH2)mOC(O)NR6R7, aryl or lower arylalkyl radical substituted (i.e. one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxyalkyl;
R6 and R7 represent, independently, H, a lower alkyl, lower hydroxyalkyl, lower alkylaminoalkyl, lower aminoalkyl, cycloalkyl, lower cycloalkylalkyl, lower alkenyl, lower alkoxyalkyl, lower haloalkyl, or aryl or lower arylalkyl radical substituted (i.e., one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl, or, when the chains R6 and R7 are attached to the same nitrogen atom, R6 and R7 optionally together form an aromatic or non-aromatic heterocycle, for example a heterocycle of morpholine, piperazine or piperidine type, said heterocycle being optionally substituted by one or more groups chosen from the lower alkyl, substituted or non-substituted aryl, substituted or non-substituted arylalkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxyalkyl radicals;
R8 represents an H, lower alkyl, lower hydroxyalkyl, amino, lower alkylamino, lower alkylaminoalkyl, lower aminoalkyl, cycloalkyl, lower cycloalkylalkyl, lower alkenyl, lower alkoxy, lower alkoxyalkyl, lower haloalkyl, or aryl or lower arylalkyl radical substituted (i.e., one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl radical;
R9 represents an H, lower alkyl, lower haloalkyl, aryl or arylalkyl radical, the aryl or arylalkyl group optionally being able to be substituted on the aromatic cycle by one or more groups chosen from the lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl radicals;
R10 represents a cyano, C(O)OR11, 1H-1,2,3,4-tÈtrazo-5-yl or 1-alkyl-1,2,3,4-tÈtrazo-5-yl radical;
R11 represents an H, lower alkyl, lower haloalkyl, lower hydroxyalkyl, alkylcarbonyloxyalkyl, (CH2)pNR6R7, aryl, arylalkyl or aryl radical, the aryl or arylalkyl group optionally being able to be substituted on the aromatic cycle by one or more groups chosen from the lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl radical;
or a pharmaceutically acceptable salt of the latter.
When it is used without further precision, the term alkyl refers to a lower alkyl radical. As used in this text, the term lower with reference to the alkyl, alkylthio and alkoxy groups designates saturated aliphatic hydrocarbon groups, linear or branched, comprising 1 to 6 carbon atoms, such as for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methylthio, ethylthio, methoxy and ethoxy. With reference to the alkenyl or alkynyl groups, the term lower designates groups comprising 2 to 6 carbon atoms and one or more double or triple bonds, such as for example the vinyl, allyl, isopropenyl, pentenyl, hexanyl, propenyl ethynyl, propynyl and butynyl groups. The term cycloalkyl designates a cycle of 3 to 7 carbons, such as for example the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. The term aryl designates a mono-, di- or tricyclic hydrocarbon compound with at least one aromatic cycle, each cycle containing at most 7 links, such as for example phenyl, naphthyl, anthracyl, biphenyl or indenyl. The term halo means chloro, bromo, iodo or fluoro. The radicals corresponding to the expressions lower haloalkyl, lower cyanoalkyl, lower nitroalkyl, lower amidoalkyl, lower hydrazinoalkyl, lower azidoalkyl, lower arylalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkylthioalkyl, and lower alkanesulphonylalkyl are substituted, respectively, by one to three halo, cyano, nitro, amido, hydrazino, azido, aryl, hydroxy, lower alkoxy, lower alkylthio or lower sulphonyl groups. The lower alkylamino radical can contain one or two lower alkyl groups, and represent for example NHCH3, NHCH2CH3, N(CH3)2, or N(CH3)(CH2CH3).
The compounds according to the present invention carry an asymetric carbon. As a result, the compounds according to the present invention have two possible enantiomeric forms, i.e. in the xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d configurations. The present invention includes the two enantiomeric forms and all combinations of these forms, including the xe2x80x9cRSxe2x80x9d racemic mixtures. For the sake of simplicity, when no specific configuration is indicated in the structural formulae, it should be understood that the two enantiomeric forms and their mixtures are represented.
Preferably, a subject of the invention is the compounds of formula (I) as defined above in which R1 represents a lower alkyl radical, R2 represents a hydrogen or halogen atom, R3 represents a hydrogen or halogen atom, a lower alkyl or lower alkoxy radical, R4 represents a hydrogen atom, R5 represents a hydrogen atom or a lower alkyl radical, R10 represents a cyano, C(O)OR11 or 1H-1,2,3,4-tetrazo-5-yl radical, and finally R11 represents an H, lower alkyl, lower haloalkyl, lower hydroxyalkyl, alkylcarbonyloxyalkyl, (CH2)pNR6R7, aryl, arylalkyl or aryl radical, the aryl or arylalkyl group being optionally able to be substituted one the aromatic cycle by one or more groups chosen from the lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl radical; or a pharmaceutically acceptable salt of these compounds.
According to another preferred variant of the invention, R1 represents an ethyl group, R2 represents a hydrogen, chlorine or fluorine atom, R3 represents H, a lower alkyl, halo, or OR6 radical in which R6 represents H, a lower alkyl or lower arylalkyl radical, and preferably H, fluoro, chloro, methyl, methoxy or benzyloxy, R4 represents a hydrogen atom, R5 represents a hydrogen atom or a lower alkyl radical, R10 represents a cyano, C(O)OR11 or 1H-1,2,3,4-tetrazo-5-yl radical, and finally R11 represents an H, lower alkyl, lower haloalkyl, lower hydroxyalkyl, alkylcarbonyloxyalkyl, (CH2)pNR6R7, aryl, arylalkyl or aryl radical, the aryl or arylalkyl group optionally being able to be substituted on the aromatic cycle by one or more groups chosen from the lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl radical.
More particularly, a subject of the invention is the products described below in the examples, and corresponding to the following formulae:
tert-butyl 3-(9-benzyloxy-10-fluoro-4-oxo-4,6-dihydroindolizino [1,2-b]quinoline-2-yl)-3-hydroxypentanoate;
tert-butyl 3-(10-fluoro-9-methoxy-4-oxo-4,6-dihydroindolizino[1,2-b]quinoline-2-yl)-3-hydroxypentanoate;
tert-butyl 3-hydroxy-3-(7-methyl-4-oxo-4,6-dihydroindolizino[1,2-b]quinoline-2-yl)pentanoate;
3-hydroxy-3-(4-oxo-4,6-dihydroindolizino[1,2-b]quinoline-2-yl)pentanitrile;
tert-butyl 3-hydroxy-3-(4-oxo-4,6-dihydroindolizino[1,2-b]quinoline-2-yl)pentanoate;
3-hydroxy-3-(4-oxo-4,6-dihydroindolizino[1,2-b]quinoline-2-yl)pentanoic acid;
3-(9-benzyloxy-10-fluoro-4-oxo-4,6-dihydroindolizino[1,2-b]quinoline-2-yl)-3-hydroxypentanoic acid;
3-(10-fluoro-9-methoxy-4-oxo-4,6-dihydro-indolizino[1,2-b]quinoline-2-yl)-3-hydroxypentanoic acid;
3-hydroxy-3-(7-methyl-4-oxo-4,6-dihydroindolizino[1,2-b]quinoline-2-yl)pentanoic acid;
3-(9-benzyloxy-4-oxo4,6-dihydroindolizino[1,2-b]quinoline-2-yl)-3-hydroxypentanoic acid;
3-(10-chloro-9-methyl-4-oxo-4,6-dihydro-indolizino[1,2-b]quinoline-2-yl)-3-hydroxypentanoic acid;
methyl 3-hydroxy-3-(4-oxo-4,6-dihydroindolizino[1,2-b]quinoline-2-yl)pentanoate;
tert-butylcarbonyloxy-methyl 3-hydroxy-3-(4-oxo-4,6-dihydroindolizino[1,2-b]quinoline-2-yl)pentanoate;
2-[1-hydroxy-1-(1H-1,2,3,4-tetrazo-5-ylmethyl)propyl]-4,6-dihydroindolizino[1,2-b]quinoline-4-one;
or a pharmaceutically acceptable salt of the latter.
For the invention there will be quite particularly preferred 3-hydroxy-3-(4-oxo-4,6-dihydroindolizino[1,2-b]quinoline-2-yl)pentanoic acid or a pharmaceutically acceptable salt of the latter.
A subject of the invention is also a process for the preparation of the compounds of general formula (I) characterized in that a pyridinone of general formula A 
in which R1 has the meaning indicated above and the Z1 group represents a lower alkyl radical, is N-alkylated with a quinoline of general formula B 
in whiche R2, R3, R4 and R5 have the meaning indicated above, X represents a chlorine, bromine or iodine atom and Y represents either a bromine atom, or a hydroxyl radical, in order to produce the compound of general formula C 
in which R1, R2, R3, R4, R5, X1 and Z1 have the meaning indicated above,
then the compound of general formula C is cyclized in order to obtain the compound of general formula (I) in which R1, R2, R3, R4 and R5 have the meaning indicated above, and R10 represents a carbalkoxy radical.
In the above process, the formation of compound C from the compounds of general formula A and B is carried out, when Y represents a hydroxyl function, by a treatment known to a person skilled in the art as Mitsunobu""s reaction (see Mitsunobu, O. et al., Synthesis, p.1 (1981)). It is necessary for the hydroxyl function of compound B to be displaced by a nucleophile such as compound A, or a deprotonated derivative of the latter, by treatment with a phosphine, for example triphenylphosphine, and an azodicarboxylate derivative, for example diethyl azodicarboxylate, in an aprotic solvent such as, for example, N,N-dimethylformamide or dioxane at a temperature preferably comprised between 0xc2x0 C. and 60xc2x0 C. such as, for example, ambient temperature. The formation of compound C from the compounds of general formula A and B, when Y represents a bromine atom, is carried out by treatment of the compound of general formula B by a deprotonated compound of general formula A in an aprotic solvent such as, for example, tetrahydrofuran, dioxane or N,N-dimethylformamide, at a temperature preferably comprised between 0xc2x0 C. and 30xc2x0 C. The deprotonation of the compound of general formula A is carried out by treatment with an alkaline alkoxide, an alkaline amide or an alkaline hydride, such as, for example, sodium hydride, in an aprotic solvent such as, for example, tetrahydrofuran, at a temperature preferably comprised between 0xc2x0 C. and 30xc2x0 C. Cyclization of compound C is preferably carried out in the presence of a palladium catalyst (for example palladium diacetate) under basic conditions (provided for example by an alkaline acetate optionally combined with a phase transfer agent such as for example tetrabutylammonium bromide), in a solvent such as acetonitrile or amyl alcohol, at a temperature preferably comprised between 50xc2x0 C. and 120xc2x0 C. (R. Grigg and coll., Tetrahedron 46, page 4003 (1990)).
A subject of the invention is also a process for the preparation of compounds of general formula (I) characterized in that a pyridinone of general formula D 
in which R1 has the meaning indicated above and the Z2 and Z3 groups represent, independently, a lower alkyl radical or Z2 and Z3 form together a saturated hydrocarbon chain with 2 to 4 carbons, is N-alkylated with a quinoline of general formula B as defined above in order to produce the compound of general formula E 
in which R1, R2, R3, R4, R5, X, Z2 and Z3 have the meaning indicated above,
then the compound of general formula E is cyclined in order to obtain the compound of general formula F 
in which R1, R2, R3, R4, R5, Z2 and Z3 have the meaning indicated above,
then the protected carbonyl function of the compounds of general formula F is released in order to produce the compound of general formula G 
in which R1, R2, R3, R4, and R5 have the meaning indicated above,
then the carbonyl function of the compound of general formula G is treated by an epoxidizing agent in order to produce the compound of general formula H 
in which R1, R2, R3, R4, and R5 have the meaning indicated above,
then the epoxide of the compound of general formula H is treated with a nitrilating agent in order to produce the compound of general formula (I), in which R1, R2, R3, R4, and R5 have the meaning indicated above, and R10 represents a cyano radical.
In the above process, the formation of the compound E from compounds of general formula B and D is carried out, when Y represents a hydroxyl function, by a treatment known to a person skilled in the art under the name of Mitsunobu""s reaction (refer to Mitsunobu, O. et al., Synthesis, p.1 (1981)). It is necessary for the hydroxyl function of compound B to be displaced by a nucleophile such as compound D, or a deprotonated derivative of the latter, by treatment with a phosphine, for example triphenylphosphine, and an azodicarboxylate derivative, for example diethyl azodicarboxylate, in an aprotic solvent such as, for example, tetrahydrofuran, at a temperature preferably comprised between 0xc2x0 C. and 60xc2x0 C., for example at ambient temperature. The formation of compound E from compounds of general formula B and D, when Y represents a bromine atom, is carried out by treatment of the compound of general formula B by a deprotonated compound of general formula D in an aprotic solvent such as, for example, tetrahydrofuran, dioxane or N,N-dimethylformamide, at a temperature preferably comprised between 0xc2x0 C. and 30xc2x0 C. The deprotonation of the compound of general formula D is carried out by treatment with an alkaline alkoxide, an alkaline amide or an alkaline hydride, such as, for example, sodium hydride, in an aprotic solvent such as, for example, tetrahydrofuran, at a temperature preferably comprised between 0xc2x0 C. and 30xc2x0 C. Cyclization of compound E is preferably carried out in the presence of a palladium catalyst (for example palladium diacetate) under basic conditions (provided for example by an alkaline acetate optionally combined with a phase transfer agent such as for example tetrabutylammonium bromide), in a solvent such as acetonitrile or amyl alcohol, at a temperature preferably comprised between 50xc2x0 C. and 120xc2x0 C. (R. Grigg et al., Tetrahedron 46, page 4003 (1990)). The release of the protected carbonyl function of the compound of general formula F in order to produce the compound of general formula G is carried out by treatment in acid conditions such as those supplied, for example, by trifluoroacetic acid. The epoxidization producing the compound of general formula H is carried out treating the compound of general formula G with a sulphur ylide, obtained by deprotonation of a trialkylsulphonium salt such as, for example, trimethylsulphonium iodide, by an alkaline alkoxide such as, for example, potassium tert-butylate, in an aprotic polar solvent such as, for example, dimethylsulphoxide, at a temperature preferably comprised between 0xc2x0 C. and 30xc2x0 C. The opening of the epoxide of the compound of general formula H in order to produce the compound of general formula (I) in which R10 represents a cyano radical is obtained by treatment of the compound of general formula H with a nitrilating agent such as, for example, trimethylsilyl cyanide, in the presence of a Lewis acid such as, for example, diethylaluminium chloride, in an aprotic solvent such as, for example, dichloromethane, at a temperature preferably comprised between 0xc2x0 C. and 30xc2x0 C.
A subject of the invention is also a process for the preparation of compounds of general formula (I) characterized in that the carbonyl function of a compound of general formula G as defined above is treated with an appropriate alkylating agent in order to produce the corresponding compound of general formula (I). Said alkylating agent can be provided using reaction conditions known to a person skilled in the art as Reformatsky""s reaction. It is necessary to treat a haloacetic ester such as, for example, tert-butyl bromoacetate, or a haloacetonitrile such as, for example, chloroacetonitrile, with a transition metal such as, for example, zinc, in an aprotic solvent such as, for example, tetrahydrofuran at a temperature preferably comprised between 0xc2x0 C. and 60xc2x0 C. Said alkylating agent can also be provided by a lithium enolate of an acetic ester such as, for example, tert-butyl acetate treated by lithium diisopropylamidide in an aprotic solvent such as, for example, tetrahydrofuran, at a temperature preferably comprised between xe2x88x9278xc2x0 C. and ambient temperature.
A subject of the invention is also a process for the preparation of compounds of general formula (I) characterized in that the ester function of a compound of general formula (I) in which R10 represents a carbalkoxy radical is hydrolyzed in order to produce a compound of general formula (I) in which R10 represents a carboxy radical. This conversion is generally obtained under alkaline conditions provided by an alkaline base such as, for example, lithium hydroxide, in an aqueous polar solvent such as, for example, aqueous methanol or also a tetrahydrofuran/methanol/water mixture. When the ester function of the compound of general formula (I) to be treated is derived from a tertiary alcohol such as, for example, tert-butyl alcohol, saponification can be obtained under acid conditions provided, for example by an aqueous mineral acid such as, for example, hydrochloric acid or sulphuric acid, or also a strong organic acid such as, for example, trifluoroacetic acid.
A subject of the invention is also a process for the preparation of compounds of general formula (I) characterized in that the acid function of a compound of general formula (I) in which R10 represents a c y radical is esterified in order to produce a compound of general formula (I) in which R10 represents a carbalkoxy radical. Such a conversion is obtained in particular by treatment of the initial carboxylic acid with an appropriate alcohol such as, for example, ethanol, in the presence of an acid catalyst such as, for example, concentrated sulphuric acid or concentrated hydrochloric acid at a temperature preferably comprised between 40xc2x0 C. and the boiling point of the alcohol in question. The carboxylic acid activated by an agent such as, for example, carbonyldiimidazole or thionyl chloride or dicyclohexylcarbodiimide can also be treated with an alcohol. Finally, there is also included in this esterification process the treatment of the carboxylic group by a base such as, for example, soda or potassium carbonate, in a polar solvent such as, for example, dimethylsulphoxide or N,N-dimethylformamide, followed by an alkylating electrophile such as, for example, methyl iodide or chloromethyl pivaloate.
A further subject of the invention is a process for the preparation of compounds of general formula (I) characterized in that the ester function of a compound of general formula (I) in which R10 represents a carbalkoxy radical is transesterified in order to produce a compound of general formula (I) in which R10 represents another carbalkoxy radical. Transesterification can be obtained by treatment in the alcohol from which the desired ester is derived, in the presence of acid catalysis provided, for example, by concentrated sulphuric acid or titanium isopropoxide, at a temperature preferably comprised between 40xc2x0 C. and the reflux temperature of the alcohol in question.
A subject of the invention is also a process for the preparation of compounds of general formula (I) characterized in that the nitrile function of a compound of general formula (I) in which R10 represents a cyano radical undergoes a dipolar addition with a nitride in order to produce a compound of general formula (I) in which R10 represents a 1,2,3,4-tetrazole-5-yl radical. The latter conversion is obtained by treatment of the cyano compound by a nitride such as, for example, trimethylsilyl nitride, in the presence of a catalyst such as, for example, dibutyltin oxide, in an aprotic solvent such as, for example, toluene, at a temperature preferably comprised between 50xc2x0 C. and 110xc2x0 C., for example the reflux temperature of toluene.
In all the processes of the invention described above, the functions carried by the R2, R3, R4 and R5 groups can be protected and deprotected if necessary according to standard protection-deprotection methods known to a person skilled in the art (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)). An illustration of this concept of protection-deprotection is given by Example 1 below: the starting product is an aniline of general formula L where R3 is a methoxy radical and the final product corresponds to a compound of general formula (I) where R3 is a benzyloxy radical.
The pyridinones of general formula A are new. They can be prepared according to a process characterized in that a 2-alkoxypyridine of general formula J 
in which R1, Z1, Z2 and Z3 have the meaning indicated above is deprotected in order to produce the pyridinone of general formula K 
in which R1 has the meaning indicated above;
then the compound of general formula K is treated with a functionalized alkylating agent in order to obtain a compound of general formula A in which R1 and Z1 have the meaning indicated above.
The 2-alkoxypyridines of general formula J can be obtained, for example, according to a process described in Application PCT/FR96/00980. The deprotection of the compounds of general formula J can be obtained either by treatment with a dilute mineral acid such as, for example, normal hydrochloric acid, at a temperature preferably comprised between 60xc2x0 C. and 120xc2x0 C. such as, for example, reflux temperature. The deprotection of the compounds of general formula J can also be carried out by treatment with a dealkylating agent such as, for example, boron tribromide or trimethylsilyl iodide (optionally generated in situ), in an aprotic solvent such as, for example, dichloromethane or acetonitrile, at a temperature preferably chosen between 40xc2x0 C. and 90xc2x0 C. or, for example, the reflux temperature of the solvent. Treatment of the compound of general formula K with a functionalized alkylating agent can be carried out under reaction conditions known to a person skilled in the art as Reformatsky""s reaction. It is necessary to treat a haloacetic ester such as, for example, tert-butyl bromoacetate, or a haloacetonitrile such as, for example, chloroacetonitrile, with a transition metal such as, for example, zinc, in an aprotic solvent such as, for example, tetrahydrofuran at a temperature preferably comprised between 0xc2x0 C. and 60xc2x0 C. An appropriate alkylating agent can also be provided by a lithium enolate of an acetic ester such as, for example, tert-butyl acetate treated with lithium diisopropylamidide in an aprotic solvent such as, for example, tetrahydrofuran, at a temperature preferably comprised between xe2x88x9278xc2x0 C. and ambient temperature.
The pyridinones of general formula D are new. They can be obtained according to a process characterized in that the ketonic function is protected in the compound of general formula K in order to obtain a compound of general formula D in which R1, Z2 and Z3 have the meaning indicated above. Such a protection obtained under standard reaction conditions and known to a person skilled in the art as acetalization (Greene, T., protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)).
The quinolines of general formula B can be obtained from anilines of general formula L 
in which R2, R3 and R4 have the meaning indicated in the general formulae of compounds (I), or also are precursors of the latter in the context of the use of protection-deprotection techniques. In this way, in the processes below, the R2, R3 and R4 groups can be protected if necessary according to standard protection methods (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley and Sons 1981)). An illustration of this concept of protection-deprotection is given by Example 1 below: the starting product is an aniline of formula L where R3 is a methoxy radical and the final product corresponds to a compound of formula (I) where R3 is a benzyloxy radical.
The quinolines of formula B can be obtained according to the following process: the anilines of general formula L as defined above are N-acetylated by treatment with an acetylating agent such as, for example, acetic anhydride. The acetanilides obtained in this way are treated at a temperature preferably comprised between 50xc2x0 C. and 100xc2x0 C., more preferentially at 75xc2x0 C., with a reagent known to a person skilled in the art as Vilsmeyer""s reagent (obtained by the action of phosphoryl oxychloride on N,N-dimethylformamide at a temperature preferably comprised between 0xc2x0 C. and 10xc2x0 C.) in order to produce the corresponding 2-chloro-3-quinolinecarbaldehyde (refer, for example, to Meth-Cohn, et al. J. Chem. Soc., Perkin Trans. I p.1520 (1981); Meth-Cohn, et al. J. Chem. Soc., Perkin Trans. I p.2509 (1981); and Nakasimhan et al. J. Am. Chem. Soc., 112, p.4431 (1990)). The chlorine in position 2 of the 2-chloro-3-quinolinecarbaldehydes can be substituted by iodine or bromine by heating the product in an inert solvent such as, for example, acetonitrile in the presence of an iodine or bromine salt (for example sodium iodide or tetrabutylammonium bromide). A trace of acid such as concentrated hydrochloric acid may be necessary in order to catalyze this conversion. The 2-halo-3-quinolinecarbaldehydes are easily reduced to the corresponding 2-halo-3-quinolinemethanols of general formula B where Y represents a hydroxyl function, under standard conditions known to a person skilled in the art such as treatment in an alcoholic solvent (for example methanol) with sodium borohydride at a temperature preferably comprised between 0xc2x0 C. and 4xc2x0 C. The 2-halo-3-quinolinemethanols of general formula B where Y represents a hydroxyl function can be converted into 3-bromomethyl-2-haloquinolines of general formula B where Y represents a bromine atom by treatment with tetrabromomethane in the presence of a phosphine such as, for example, triphenylphosphine, in a chlorinated aprotic solvent such as, for example, dichloromethane or 1,2-dichloroethane at ambient temperature.
The quinolines of formula B can also be obtained according to the following process: the anilines of general formula L as defined above are acylated by reaction with a nitrile (such as chloroacetonitrile or propionitrile) in the presence of boron trichloride and of another Lewis acid such as aluminium trichloride, titanium tetrachloride or diethylaluminium chloride in an aprotic solvent or a mixture of aprotic solvents, followed by hydrolysis (cf Sugasawa, T, et al. J Am. Chem. Soc. 100, p. 4842 (1978)). The intermediate obtained in this way is then treated with ethylmalonyl chloride in an aprotic solvent such as acetonitrile in the presence of a base such as triethylamine, then treated with an alkaline alcoholate, for example sodium ethylate in ethanol, in order to produce ethyl 2-hydroxy-3-quinolinecarboxylate substituted in position 4. The latter is converted into ethyl 2-chloro-3-quinolinecarboxylate by treatment with phosphoryl oxychloride. When position 4 of the quinoline carries a chloromethyl group, a nucleophilic substitution can be carried out by treatment with a secondary amine such as for example dimethylamine, N-methylpiperazine, morpholine or piperidine. The ethyl 2-chloro-3-quinolinecarboxylate is then reduced by diisobutylaluminium hydride in an aprotic solvent such as dichloromethane in order to produce 2-chloro-3-quinolinemethanol of general formula B. Analogues of the intermediate quinolines B have been described in the literature and in particular in PCT Application No. 95/05427.
A subject of the invention is also, as new industrial products, and in particular as new industrial products intended for the preparation of the products of general formula (I), the products of formulae A, D and K as described above.
Certain compounds of the invention can be prepared in the form of pharmaceutically acceptable salts according to the usual methodes. Acceptable salts include, as a non-limitative example, the addition salts of inorganic acids such as hydrochloride, sulphate, phosphate, diphosphate, hydrobromide and nitrate or those of inorganic acids such as acetate, maleate, fumarate, tartarate, succinate, citrate, lactate, methane sulphonate, p-toluenesulphonate, pamoate, salicylate, oxalate and stearate. The salts formed from bases such as sodium or potassium hydroxide also fall within the field of application of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference can be made to xe2x80x9cPharmaceutical Saltsxe2x80x9d, F. M. Berge, J. Pharm. Sci. 66:1 (1977).
The compounds of the present invention have useful pharmacological properties. In this way the compounds of the present invention have an inhibitory activity on topoisomerase I and/or an inhibitory activity on topoisomerase II. The state of the art suggests that the compounds of the invention have an anti-tumoral activity, an anti-parasitic activity and an anti-viral activity. The compounds of the present invention can in this way be used in different therapeutic applications.
There follows in the experimental part an illustration of the pharmacological properties of the compounds of the invention.
The compounds can inhibit the topoisomerases of type I and/or of type II, in a patient, for example a mammal such as man, by administration to this patient of a therapeutically effective quantity of a compound of general formula (I).
The compounds of the invention also have an anti-tumoral activity. They can be used for the treatment of tumours, for example of tumours expressing a topoisomerase, in a patient by administration to the latter of a therapeutically effective quantity of a compound of general formula (I). Examples of tumours or of cancers include cancers of the oesophagus, the stomach, the intestines, the rectum, the oral cavity, the pharynx, the larynx, the lung, the colon, the breast, the cervix uteri, the corpus endometrium, the ovaries, the prostate, the testes, the bladder, the kidneys, the liver, the pancreas, the bones, the conjunctive tissues, the skin, the eyes, the brain and the central nervous system, as well as cancer of the thyroid gland, leukaemia, Hodgkin""s disease, lymphomas other than Hodgkin""s, multiple myelomas and others.
They can also be used for the treatment of parasitic infections by inhibition of the hemoflagellates (for example in trypanosomiasis or infections of leishmania type) or by inhibition of plasmodia (such as for example in malaria), but also for the treatment of viral infections or diseases.
These properties make the products of general formula (I) suitable for pharmaceutical use. A subject of the present Application is therefore also, as medicaments, the compounds of general formula (I) as defined above, as well as the addition salts with pharmaceutically acceptable mineral or organic acids of products of general formula (I), as well as pharmaceutical compositions containing at least one of the compounds as defined above as active ingredient.
The invention thus relates to pharmaceutical compositions containing a compound of general formula (I) as defined previously or a pharmaceutically acceptable salt of the latter, combined with a pharmaceutically acceptable carrier chosen according to the administration mode (for example oral, intravenous, intraperitoneal, intramuscular, trans-dermic or sub-cutaneous administration). The pharmaceutical composition (for example therapeutic) can be in solid or liquid form, or in the form of liposomes or of lipidic micells.
The pharmaceutical composition can be in a solid form such as, for example, powders, pills, granules, tablets, liposomes, capsules or suppositories. The pill, tablet or capsule can be coated with a substance capable of protecting the composition from the action of gastric acid or enzymes in the subject""s stomach for a sufficient length of time to allow the composition to pass undigested into the subject""s small intestine. The compound can also be administered locally, for example at the very point where the tumour is located. The compound can also be administered according to the sustained release process (for example a sustained release composition or an infusion pump). The appropriate solid carriers can be, for example, calcium phosphate, magnesium stearate, magnesium carbonate, talc, sugars, lactose, dextrine, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax. The pharmaceutical compositions containing a compound of the invention can therefore also be presented in liquid form such as, for example, solutions, emulsions, suspensions or a sustained release formulation. The appropriate liquid carriers can be, for example, water, organic solvents such as glycerol or glycols such as polyethylene glycol, as well as their mixtures, in varying proportions, in water.
A subject of the invention is also the use of the products of formula (I) as defined above, for the preparation of medicaments intended to inhibit topoisomerases, and more particularly to inhibit the topoisomerases of type I, or the topoisomerases of type II, or, simultaneously, the two types of topoisomerase, for the preparation of medicaments intended to treat tumours, for the preparation of medicaments intended to treat parasitic infections, as well as for the preparation of medicaments intended to treat viral infections or diseases.
The dose of a compound according to the present invention, to be allowed for the treatment of the diseases or disorders mentioned above, varies according to the administration mode, the age and body weight of the subject to be treated as well as the subject""s state, and it will definitively be decided by the attending doctor or veterinary surgeon. Such a quantity determined by the attending doctor or veterinary surgeon is here called xe2x80x9ceffective therapeutic quantityxe2x80x9d.
Unless defined differently, all the technical and scientific terms used here have the same meaning as that normally understood by an ordinary specialist in the field to which this invention belongs. Similarly, all the publications, patent applications, patents and any other references mentioned here are included by way of reference.
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USPTO Backgrounds