MXPA99005768A - Pro-drugs and counterparts of camptothecin, their application as medicines - Google Patents

Abstract

The invention concerns novel counterparts of camptothecin and in particular products complying with the following formulae:8-ethyl-8,9-dihydro-8-hydroxy-1-benzyl-2H,10H,12H-[1,3]oxazino[5, 6-f]oxepino[3',4':6,7]indolizino[1,2-b]quinolein-10,13(15H)-dione;5-ethyl-9,10-difluoro-4, 5-dihydro-5-(2-amino-1-oxoethoxy)-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinolein-3,15(4H, 13H)-dione;5-ethyl-9,10-difluoro-4,5-dihydro-5-(2-amino-1-oxopropoxy)-1H-oxepino[3',4':6, 7]indolizino[1,2-b]quinolein-3,15(4H,13H)-dione. The invention also concerns their method of preparation, their application as medicines, the pharmaceutical compositions containing them and their use in producing tumoricidal, antiviral and parasiticide medicines.

Description

PROFACTIC AND ANALOGUE FORMS OF CAMPOTOTECINE, AND ITS APPLICATION AS MEDICINES Description of the invention Camptothecin is a natural compound that has been isolated for the first time from the leaves and bark of the Chinese plant called camptotheca a cumina ta (see Wall et al., J. Amer. Chem. Soc. 88: 3888 (1996)) Camptothecin is a pentacyclic compound consisting of a fragment of indolizine [1,2-b] quinoline (cycles A, B, C and D) fused with a six-membered a-hydroxylactone (cycle E). The carbon in position 20, which has the a-hydroxyl group, is asymmetric and gives the molecule a rotating power. The natural form of camptothecin has the absolute configuration "S" in carbon 20 and responds to the following formula: REF .: 303.2-9 Camptothecin and its analogues have an antiproliferative activity in several cancer cell lines, which comprise the cell lines of human tumors of the colon, lung and breast (Suffnes, M. et al .: The Alkaloids Chemistry and Pharmacology , Bross, A., ed., Vol 25, p 73 (Academic Press, 1985)). It is suggested that the antiproliferative activity of camptothecin is related to its inhibitory activity on DNA topoisomerase. On the other hand, camptothecin and some of its analogues are not water-soluble, which makes its administration by parenteral route difficult. This has been prepared from the water-soluble derivatives of camptothecin where cycles A and B have salivable substituents (see, for example, U.S. Patent Nos. 4,981,968, 5,049,668 and European Patent No. 540,099). But these products have shown a reduced anti-tumor activity in relation to that of the non-water-soluble derivatives. It has also been prepared from other water-soluble derivatives of camptothecins where the hydroxyl group at position 20 is esterified by an acid having a salifiable radical, such as for example glycine (see US Pat. No. 4,943,579 and PCT No. WO). 96/02546). These derivatives are designated by the person skilled in the art by the name of "prodrug forms" since they are not biologically active as such, but only after a first stage of metabolization once administered to the patient. The prodrug forms of the α-hydroxylactone analogs of camptothecin have shown good antitumor efficacy in animals and in the clinic, but accompanied by adverse side effects, such as the appearance of severe diarrhea that may endanger the life of the patient. It is therefore necessary to develop water-soluble analogs of camptothecin that are more effective and better tolerated. On the other hand, it has been indicated that a-hydroxylactone has an absolute requirement both for the activity in vi ve and in vi tro of the camptothecins (Camptothecins: New Anticancer Agents, Putmesil, M., and collaborators, ed. ., p.27 (CRC Press, 1995); Wall, M. et al., Cancer Res. 55: 753 (nineteen ninety five); Hertzberg et al., J. Med. Chem. 32: 715 (1982) and Crow et al., J. Med. Chem. : 4160 (1992)). However, the Applicant has discovered that the 7-member ß-hydroxylactones have a biological activity comparable or superior to that of the α-hydroxylactones (unpublished PCT application No. FR 96/00980). The present invention relates to the novel derivatives of this class of camptothecin analogs, in which a seven-member β-hydroxylactone replaces the natural a-hydroxylactone of camptothecin. By β-hydroxylactone is meant a lactone which includes a carbon atom supplementary between the carbon of the carboxyl and the carbon a that carries the hydroxyl in the α-hydroxylactone. Two solutions have been chosen in order to increase the water solubility of the camptothecin analogues. The first consists in grafting an oxazine on the A cycle of the molecule, and the second in conceiving pro-drug forms by acetylating the hydroxyl functional group of the β-hydroxylactone. More precisely, among this novel class of camptothecin analogs, the compounds according to the present invention are either analogues modified by attachment of an oxazine cycle on the carbons 10 and 11, or pro-drug forms in which a β-hydroxylactone replaces the natural a-hydroxylactone from camptothecin. The compounds of the present invention are thus analogous β-hydroxylactones of camptothecin on which an oxazine cycle or the water-soluble prodrugs have been grafted, and have a powerful biological activity which is unexpected with respect to the prior art. The subject of the invention is more particularly the compounds of the formula (I) or (II): under the racemic form, of enantiomer or all combinations of these forms, in which: Ri represents a lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, (lower alkoxy) (lower alkyl) or (lower alkylthio) (lower alkyl ); R2, R3 and R. independently represent hydrogen halo, lower haloalkyl, lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, (CH) mNR6R7, (CH2) mOR6, (CH2) mSR6, (CH2) mC02R6, (CH2) ", NR6C (0) Rβ, (CH2) mC (0) R8, (CH2) mOC (0) R8, O (CH2) raNR6R7, OC (0) NR6R7, OC (O) (CH2) mC02R6, or (CH2) n [N «X], OC (0) [N * X], (CH2) m0C (O) [N * X] (wherein [N «X], in this invention, represents a heterocyclic group of 4 to 7 members with the Nitrogen atom N which is a member of the heterocyclic group, and X represents the remaining members, necessary to complete the heterocyclic group, selected from the group consisting of O, S, CH2, CH, N, NR9 and CH1), aryl or arylalkyl substituted (i.e., one to four times on the aryl or heterocycle group) or unsubstituted, in which the substituent is a lower alkyl, halo, Nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or (lower alkoxy) (lower alkyl), or R2 and R or R3 and R together form a chain of 3 or 4 members, in which the elements of the chain are selected from the group consisting of CH, CH2, O, S, N or NR9; represents hydrogen, halo, lower haloalkyl, lower alkyl, lower alkoxy, (lower alkoxy) (lower alkyl), (lower alkylthio) (lower alkyl), cycloalkyl, cycloalkylalkyl lower, cyano, cyanoalkyl, (lower alkyl) (sulfonylalkyl), Lower hydroxyalkyl, nitro, (CH2) mC (O) R8, (CH2) mNR6C (O) Rβ, (CH2) mNR6R7, CH2) mN (CH3) (CH2) ONR6R7, (CH2) mOC. { O) R8, (CH?) M0C (0) NRfiR7, (CH?) MS (0) qR .., (CH2) mP (0) R? 2Ri3, (CH2) 2P (S) Ra2Ri3, or (CH2) n [N «X], OC (0) [N« X], (CH2) mOC (0) [N «X], aryl or substituted lower arylalkyl, (i.e., one to four times on the aryl or heteroaryl group) or unsubstituted, in which the substituent is an alkyl Lower, halo, nitro, amino, (lower alkyl) (amino), lower haloalkyl, lower hydroxyalkyl, lower alkoxy or (lower alkoxy) (lower alkyl); Re and R7 independently represent hydrogen, a lower alkyl, lower hydroxyalkyl, (lower alkyl) (lower aminoalkyl), lower aminoalkyl, cycloalkyl, lower cycloalkylalkyl, lower alkenyl, (lower alkoxy) (lower alkyl), lower haloalkyl, or substituted aryl or arylalkyl (i.e. one to four times on the aryl group) or unsubstituted, in which the substituent is a lower alkyl, halo, Nitro, amino, (lower alkyl) (amino), lower haloalkyl, lower hydroxyalkyl, lower alkoxy or (lower alkoxy) (lower alkyl); R_ represents hydrogen, a lower alkyl, hydroxyalkyl, amino, (lower alkyl) (amino), (lower alkyl) (lower aminoalkyl), lower aminoalkyl, cycloalkyl, cycloalkylalkyl lower, lower alkenyl, alkoxy Lower, (lower alkoxy) (lower alkyl), lower haloalkyl, or substituted aryl or arylalkyl (ie, one to four times over the aryl group, or unsubstituted, in which the substituent is a lower alkyl, halo, nitro, amino, (lower alkyl) (amino), lower haloalkyl, lower hydroxyalkyl, lower alkoxy or (lower alkoxy) (lower alkyl); Rc represents hydrogen, a lower alkyl, lower haloalkyl, aryl or aryl substituted with one or more groups selected from the lower alkyl, halo, nitro, amino, (lower alkyl) (amino), lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or (lower alkoxy) (lower alkyl); R 1 represents hydrogen, a lower alkyl, lower haloalkyl, lower alkoxy, aryl, or substituted aryl (i.e. having one to four substitutions on the aryl group) by one or more groups selected from the lower alkyl, lower haloalkyl, hydroxyalkyl radical lower, or (lower alkoxy) (lower alkyl); Ri: represents a lower alkyl, aryl, (CH2) mORi4, (CH2) mSRi4, (CH2) 2NR14Ri5 or (CH2) ra [N «X]; R12 and R13 independently represent a lower alkyl, aryl, lower alkoxy, aryloxy or amino; R 14 and 15 independently represent hydrogen, a lower alkyl or aryl; Ri6 represents hydrogen or 0R2 ?; Ri? represents ORs or NR6R7; Ris Y 19 independently represent hydrogen, halo, lower alkyl, lower alkoxy or hydroxyl; R2o represents hydrogen or halo; R21 represents hydrogen, a lower alkyl, CHO or C (O) (CH2) mCH3; R p represents hydrogen or an easily cleavable group selected from among the groups corresponding to the formula -C (O) -A-NR 22 R 23, in which A represents a linear or branched alkylene radical and optionally substituted with a radical chosen from the radicals free hydroxyl, esterified or salified, halogen, free, esterified or salified carboxyl, amino, mono- or dialkylamino, while R22 and R23 independently represent hydrogen, lower alkyl, hydroxy-lower alkyl, (lower alkyl) (lower aminoalkyl), lower aminoalkyl, cycloalkyl, cycloalkylalkyl lower, lower alkenyl, (lower alkoxy) (lower alkyl), lower haloalkyl, or aryl or arylalkyl substituted (i.e., one to four times over the aryl group) or unsubstituted, in which the substituent is a lower alkyl radical, halo, nitro, amino, (lower alkyl) (amino), lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or (lower alkoxy) (lower alkyl); m is an integer between 0 and 6; n is l or 2; and q represents a number from 0 to 2; and [N «X] represents a heterocyclic group of 4 to 7 members, X representing the chain necessary to complete said heterocyclic group and selected from the group consisting of O, S, CH2, CH, N, NR9 and CORio," it being understood that when R p is a hydrogen atom, R 3 and R together form a 3 or 4 membered chain; or a pharmaceutically acceptable salt of the latter. As used herein, the term "lower" with reference to the alkyl, alkylthio and alkoxy groups designates saturated, linear or branched aliphatic hydrocarbon groups, including from 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 lower term designates the groups which include from 2 to 6 carbon atoms and one or more double or triple bonds, such as, for example, the vinyl, allyl, isopropenyl, pentenyl, hexanyl, propenyl groups. ethynyl, propynyl and butynyl. 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 ring, each ring containing at most 7 members, such as, for example, phenyl, naphthyl, anthracyl, biphenyl or indenyl. The term "halo" means chlorine, bromine, iodine or fluoro. The radicals corresponding to the terms lower haloalkyl, lower cyanoalkyl, lower nitroalkyl, lower amidoalkyl, lower hydrazinoalkyl, lower azidoalkyl, arylalkyl, lower hydroxyalkyl, (lower alkoxy) (lower alkyl), (lower alkylthio) (lower alkyl), and ( lower alkyl) (lower sulfonylalkyl) are substituted, respectively, by one to three halo, cyano, nitro, amido, hydrazino, azido, aryl, hydroxyl, lower alkoxy, lower alkylthio or lower sulfonyl groups. The radical (lower alkyl) (amino) may contain one of two lower alkyl groups, and represent, for example, NHCH 3, NHCH 2 CH 3, N (CH 3) 2, or N (CH 3) (CH 2 CH 3). The term "free, esterified, etherified or salified hydroxyl" refers to the OH, OCOR26, R27 groups and the alcoholate salt. The compounds according to the present invention have two possible enantiomeric forms, that is to say under the "R" and "S" configurations. The present invention includes the two enantiomeric forms and all combinations of these forms, the "RS" racemic mixtures comprising. In an effort of simplicity, when no specific configuration is indicated in the structural formulas, it should be understood that the two enantiomeric forms and their mixtures are represented.

For that which concerns the prodrug forms of the invention (those for which R p is not a hydrogen atom, the products of the general formula I are preferred. Examples of substituted camptothecines, used as starting products, can be found in U.S. Patent Nos. 4,473,692, 4,604,463, 4,984,956, 5,162,532, 5,395,939, 5,315,007, 5,264,579, 5,258,516, 5,254,690, 5,212,317 and 5,341,745, PCT Patent Applications Nos. US91 / 08028, US94 / 06451, US90 / 05172, US92 / 04611, US93 / 10987, US91 / 09598, EP94 / 03058 and EP95 / 00393 and European patent applications Nos. 325 247, 495 432, 321 122 and 540 099. For compounds that include an oxazine cycle: - is treated with an amine primary, under the Mannich conditions, a ß-hydroxylactonic compound of the general formula D D wherein R3 is a hydroxyl radical, R4 is hydrogen, and Ri, R2, Rs, Ris, R19 and R20 have the meaning indicated above to obtain a β-hydroxylactonic compound of the general formula wherein Ri, R2, R5, R9, Ris, R19 and R20 have the meaning indicated above. This process consists of heating the starting material in the presence of a primary amine such as benzylamine, formaldehyde in an acidic solvent such as acid to a temperature of 30 ° to 80 ° C for a time ranging from 0.5 to 5 hours. acetic or propionic acid. It can alternatively be heated to a temperature of 30 ° C to 80 ° C for a time ranging from 0.5 to 5 hours, a suspension of the starting material in acetic acid by a hexahydrotriazine, tri-N-substituted as the. hexahydro-1,3,5,5-trimethyltriazine, 1,3,5-triethylhexahydrotriazine or 1,3,5-tribenylhexahydrotriazine. the lactone of the general formula la is optionally operated in an alkaline medium to give, after neutralization, the compound of the formula wherein Ri, R2, Rs, Rg, Ri7, Ris, Ris and R20 have the meaning indicated above; R? 6 represents OR21 in which R2? represents hydrogen or a lower alkyl; and Ri7 represents OR6 or NHR6 and R6 represents hydrogen, a lower alkyl, cycloalkyl, cycloalkylalkyl lower, lower alkenyl, (lower alkoxy) (lower alkyl), or aryl, or arylalkyl lower. the compound of the general formula D or the compound is preferably acylated, preferably with a derivative of the radical C (O) -AN-R22R23 as defined above, to give the β-hydroxylactonic compound of the general formula Ib, ie I with Rp different from hydrogen (pro-drug form of the invention). - in the same way that lactone la has been operated, lactone Ib can be operated to give the hydroxy acid Ilb.

In the previous process, groups R2, R3, R4 and R5 can be protected if necessary according to classical protection methods (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley &Sons 1981) ). If at least one of the groups R22 or R23 is hydrogen, or contains at least one functional group chemically incompatible with the acylation process, such as, for example, a primary or secondary amine, it is therefore necessary to have resorted to a resistant protective group to acylation conditions. A protective group commonly used for amines is tert-butyloxycarbonyl (BOC). The acylation reaction is then carried out as described above, then the protecting group is cleaved, for example by treatment with trifluoroacetic acid in the case of BOC, to give the compound of the general formula (I) or (II). The use of protecting groups is known to the person skilled in the art (for other examples, reference can be made to Greene, T., Protectives Groups in Organic Synthesis, John Wiley &Sons, 1981). The compounds of the formula D are prepared as follows: a compound of the general formula M is coupled wherein Ri, R? 8 and R? 9 have the meaning indicated above and R20 represents hydrogen or a halogen atom, with a 2-halo-3-quinoline-methanol of the general formula N wherein R2, R3, R4 and Rs have the meaning indicated above and X represents a halogen atom, to give the compound of the formula O wherein Rx, R2, R3, R4, Rs, Ris, R19, R2o and Y have the meaning indicated above; - then the compound of the formula O is cyclized to obtain the compound of the general formula D as defined above.

In the previous process, the Ri, R2, s, Y4 groups can be protected if necessary according to the classical methods of protection (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley &Sons 1981 )). The formation of the compound O from the compounds of the general formula M and N is effected by a treatment known to the person skilled in the art under the name Mitsunobu reaction (refer to Mitsunobu, O. et al., Synthesis, p. 1 (1981)). The object is to displace the hydroxyl functional group of compound N by a nucleophile such as compound M, or a deprotonated derivative thereof, by treatment with a phosphine, for example triphenylphosphine, and an azodicarboxylate derivative, for example azodicarboxylate diethyl, in an aprotic solvent such as, for example, tetrahydrofuran or N, N-dimethylformamide. The cyclization of compound O is preferably carried out in the presence of a palladium catalyst (for example palladium diacetate) under alkaline conditions (provided, for example, by an alkali metal acetate optionally combined with a phase transfer agent such as, for example, bromide of tetrabutylammonium), in an aprotic solvent such as acetonitrile or N, -dimethylformamide, at a temperature comprised between 50 ° C and 120 ° C (R. Grigg et al., Tetrahedron 46, page 4003 (1990)).

The compounds of the general formula M can be prepared according to a process characterized in that: - the carbonyl is protected from a pyridine of the general formula wherein Ri and R2o have the meaning indicated above and R24 represents a halogen atom or a lower alkoxy, by an acetal functional group, to give the compound of the general formula F wherein Ri, R2o and R24 have the meaning indicated above and groups Z and Z 'represent, independently, a lower alkyl group or together form a saturated hydrocarbon chain of 2 to 4 carbons; a hydroxymethyl functional group is introduced into the compound of the general formula F to obtain a compound of the general formula G in which Ri, R2o, R24, Z and Z 'have the meaning indicated above, - then the alcohol functional group of the compound of the general formula G is protected to give a compound of the general formula H H in which Ri, R2n, R24, Z and Z 'have the meaning indicated above and R25 represents a protective group of the alcohol functional group, the acetal of the compound of the general formula H is deprotected to give the compound of the general formula I ' in which Ri, R20, R24 and R25 have the meaning indicated above, The compound of the formula I 'is treated by a functionalized alkylating agent to give a β-hydroxy ester of the general formula J wherein Ri, R20, R24 and R25 have the meaning indicated above and Ri7, R_.8 and 19 are as defined in general formula II - the protective group R2s is broken in the compound of general formula J, give a compound of the general formula K, wherein Ri, R 8, Rig, R o and R 24 have the meaning indicated above and R 17 represents ORe or NHR 6, and R 6 represents hydrogen, a lower alkyl group, cycloalkyl, (cycloalkyl) (lower alkyl), lower alkenyl, ( lower alkoxy) (lower alsuyl), or aryl or arylalkyl, the compound of the general formula K is cyclized in the compound of the general formula L in which Ri, R? 3, ig, R20 and R24 have the meaning indicated above, and finally the radical R2 of compound L is converted to carbonyl, to obtain the compound of the general formula M wherein R_, Ris, R19 and R20 have the meaning indicated above. The carbonyl functional group of a 4-acyl-2-halopyridine (obtained for example according to Lamattina, JLJ Hétérocyclic Chem. 20, p 553 (1983) is preferably protected by an acetal functional group, preferably cyclic acetal, from according to the classical conditions known to the person skilled in the art (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley &Sons 1981)). The intermediary obtained in this way is treated with a sodium alcoholate or of potassium in an aprotic solvent (for example acetonitrile), or in alcohol where the alcoholate is derived, at a temperature comprised between 0 ° C and 100 ° C to give the compound of the general formula F. The latter can be lithiated in the position 3 by treatment with an aryl- or alkyl lithium (for example mesityl-thio) in an ether solvent such as tetrahydrofuran at a temperature comprised between -100 ° C and 0 ° C. The lithiated intermediate obtained in this way, an electrophile is stored Formulant such as N, N-dimethylformamide, and the aldehyde obtained in this way, after hydrolysis, is treated with a reducing agent such as sodium borohydride to give the compound of the general formula G. The protection of the functional group The alcohol of the compound G is made at the conventional conditions known to the person skilled in the art, to obtain a compound of the general formula H. Examples of protecting groups of the alcohol functional group include those forming the ethers [ie, methyl, methoxymethyl , tetrahydropyranyl, 2-methoxyethoxymethyl, benzyloxy ethyl, t-butyl and benzyl (substituted or not), and the esters (ie formate, acetate and isobutyrate). For other examples of primary hydroxyl protecting groups, reference may be made to Greene, T., Protectives Groups in Organic Synthesis, 10-86 (John Wiley &Sons, 1981). The deprotection of the compound of the general formula H to give the compound of the general formula I 'is carried out under the selective conditions while maintaining the integrity of the radical R2 =, for example, by treatment under acidic conditions (for example with trifluoroacetic acid). The selective conditions of protection and deprotection of the functional groups are known to the person skilled in the art (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley &Sons, 1981)). The treatment of the compound I 'by a functionalized alkylating agent, to give a β-hydroxy ester of the general formula J, can be carried out with the aid of a lithium enolate or a zinc derivative of a carboxylic ester in an anhydrous aprotic solvent , for example tetrahydrofuran. The protecting group R25 of the compound of the general formula J is cleaved to give a compound of the general formula K under the protection conditions known to those skilled in the art. For example, when R2s is a benzyl group, it can be subjected to an alcoholic solution of the compound of the general formula J added with a palladium catalyst, to an atmosphere of hydrogen under a pressure of 0.5 to 10 Barias. Cyclization of the compound of the general formula K obtained in this way can be carried out under acidic conditions (for example by treatment with trifluoroacetic acid, or the hydrochloric gas dissolved in an anhydrous solvent such as dichloromethane or dioxane) to give a β-cycle -7-membered hydroxylactone as in the compound of the general formula L. The compounds of the general formula L can be transformed into pyridones of the general formula M, for example, by treatment with hot hydrochloric acid, or by a treatment with tri-ethylsilyl iodide. The 2-halo-3-quinolein-methanol of the general formula N can be obtained from the acetanilides of the general formula P wherein R2, R3 and R4 have the meaning indicated in the general formulas of compounds I and II. In the following procedures, groups R2, R3 and R4 can be protected if necessary according to classical protection methods (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley &Sons 1981)). The compounds of the formula N can thus be obtained according to the following procedure: the anilines of the formula P 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 between 50 ° C and 100 ° C, preferably 75 ° C, by a reagent known to the person skilled in the art under the name Vilsmeyer reagent (obtained by the action of phosphoryl oxychloride on N, N-dimethylformamide at a temperature between 0 ° C and 10 ° C) to give the Corresponding 2-chloro-3-quinoleincarbaldehyde (reference is made, for example, to Meth-Cohn, et al., J. Chem. Soc, Perkin Trans. I, p. (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 with iodine or with bromine by heating the product in an inert solvent such as acetonitrile, in the presence of an iodine or bromine salt (for example iodide of sodium or tetrabutylammonium bromide). A trace of acid such as concentrated hydrochloric acid may be necessary to catalyze this transformation. The 2-halo-3-quinolinecarbaldehydes are easily reduced in corresponding 2-halo-3-quinoline-methanols of the general formula N, under the conventional conditions known to those skilled in the art, such as treatment in an alcohol solvent (for example methanol) ) with sodium borohydride at a temperature between 0 ° C and 40 ° C. The compounds of the formula N can also be obtained according to the following procedure: the anilines of the general formula P 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 aluminum trichloride, titanium tetrachloride or diethylaluorium chloride in an aprotic solvent or a mixture of aprotic solvents, followed by hydrolysis (see Sugasawa, T et al. J. Am. Chem. Soc. 100, p.4482 (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 alkali metal alcoholate, for example sodium methylate in methanol, to give an alkali metal. ethyl-3-hydroxy-3-quinolinecarboxylate substituted in the 4-position. The latter is converted to 2-chloro-3-quinolinecarboxylate by treatment with phosphoryl oxychloride. When position 4 of the quinoline possesses a chloromethyl group, a nucleophilic substitution can be effected 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 with diisobutylaluminum hydride in an aprotic solvent such as dichloromethane to give the 2-chloro-3-quinoline-methanol of the general formula N. The analogs of the intermediates (N) have have been described in the literature and in particular in PCT application 95/05427. Certain compounds of the invention can be prepared in the form of pharmaceutically acceptable salts according to the usual methods. Acceptable salts comprise, by way of example and not limitation, addition salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate , citrate, lactate, methanesulfonate, p-toluenesulfonate, pamoate, salicylate, oxalate and stearate. The salts formed from bases such as sodium or potassium hydroxide also fall within the scope of the present invention when these are usable. For other examples of pharmaceutically acceptable salts, reference can be made to "Pharmaceutical Salts", J. Pharm. Sci. 66: 1 (1977). The compounds of the present invention possess interesting pharmacological properties. It is in this way that the compounds of the present invention have an inhibitory activity of topoisomerase I and / or II and an antitumor activity.

The state of the art suggests that the compounds of the invention exhibit antiparasitic and / or antiviral activity. The compounds of the present invention can thus be used in different therapeutic applications. An illustration of the pharmacological properties of the compounds of the invention will be found later in the experimental part. The compounds can inhibit the topoisomerase, for example of type I and / or II, in a patient, for example a mammal such as man, by administering to this patient a therapeutically effective amount of a compound of the formula (I) or (II). The compounds of the invention also possess an anti-tumor activity. These can be used for the treatment of tumors, for example of tumors expressing a topoisomerase, in a patient by administering to the latter a therapeutically effective amount of a compound of the formula (I) or (II). Examples of tumors or cancers include cancers of the esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, breast, uterine cervix, body of the endometrium, ovaries, prostate, testes, bladder, kidneys, liver, pancreas, bones, connective tissues, skin, eyes, brain and central nervous system, as well as thyroid cancer, leukemia, Hodgkin's disease , lymphomas different from those of Hodgkin, multiple myelomas and others. These can also be used for the treatment of parasitic infections by inhibiting hemoflagellates (for example in trypanosomia or leishmanial infections) or by inhibition of plasmodium (such as malaria), but also for the treatment of infections or viral diseases. These properties make the products of the formula (I) or (II) suitable for pharmaceutical use. The present application also has the objective, in the form of medicaments, of the products of the formula (I) or (II) as defined above, as well as the addition salts with the pharmaceutically acceptable mineral or organic acids of the products of the formula (I) or (II) as well as the pharmaceutical compositions containing them, as an active principle, at least one of the medicaments as defined above. The invention also relates to pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier according to the chosen mode of administration (eg oral, intravenous, intraperitoneal) , intramuscular, transdermal or subcutaneous). The pharmaceutical composition (for example therapeutic) can be in the solid, liquid, liposome or lipid micelle form. The pharmaceutical composition may be in the solid form, for example, powders, pills, granules, tablets, liposomes, capsules or suppositories. The pill, the tablet or the capsule may be coated with a substance capable of protecting the composition against gastric action or enzymes in the subject's stomach, for a sufficient period of time to allow this composition to pass undigested into the small intestine from the last batch. The compound can also be administered locally, for example at the site of the tumor itself. The compound can also be administered according to the sustained release processes (e.g., a prolonged release composition or an infusion pump). Suitable solid supports can be, for example, calcium phosphate, magnesium stearate, magnesium carbonate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine and wax. Pharmaceutical compositions containing a compound of the invention can therefore also be presented in the liquid form, such as, for example, solutions, emulsions, suspensions or a prolonged release formulation. Suitable liquid supports 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.

The invention also aims to use the products of the general formula (I) or (II) as defined above, for the preparation of medicaments intended to inhibit the topoisomerase, and more particularly the topoisomerase of type I or of the type II, of drugs intended to treat tumors, drugs intended to treat parasitic infections, as well as drugs intended to treat infections or viral diseases. The dose of a compound according to the present invention, which is to be provided for the treatment of the aforementioned diseases or disorders, varies according to the mode of administration, the age and the body weight of the subject to be treated, as well as the state of the latter, and will be decided definitively by the doctor or veterinarian who attends. A certain amount such by the attending physician or veterinarian is referred to herein as "therapeutically effective amount". Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by an ordinary specialist of the domain to which this invention pertains. Likewise, all publications, patent applications, all patents and all other references mentioned herein are incorporated by reference. The following examples are presented to illustrate the above procedures and should not be considered in any way as limiting the scope of the invention.

EXPERIMENTAL PART Preparation 1 5-ethyl-4, 5-dihydro-5-hydroxy-1H-oxepino- [3 ', 4': 6, 7] indolizin- [1, 2-b] -quinoline-3, 15- (4H, 13H) -dione l.a 4-ethyl-3,4-dihydroxy, -lH-pyrano- [3 ', 4': 6, 7] indolizin- [1,2-b] quinolein-14- (4H, 12H) -one Sodium borohydride (14 g, 370 mmol) is added in portions to a suspension of (S) - (+) - camptothecin (14 g, 40 mmol, which can be obtained from different commercial sources such as Aldrich Chemical Company (Milwaukee, Wl)), in (750 ml) of methanol, and the resulting mixture is heated gently to 55 ° C, in order to obtain a clear solution which is then stirred for 16 hours at room temperature. The solvent is then evaporated under reduced pressure, the residue is taken up in (250 ml) of water, neutralized by the addition of (21 ml) of acetic acid and left to stand for 2 hours at 4 ° C. The resulting suspension is filtered and washed successively with cold water, with acetone and with diethyl ether, which makes it possible to obtain, after drying under reduced pressure, the desired compound in the form of a white solid, m.p. 280 ° C. 1. b. 8-for-yloxymethyl-7-propionyl indol i z ino- [1,2-b] -quin 1 ein-9 (11H) -one A solution of sodium metaperiodate (14 g, 65 mmol) in (140 ml) of water is added dropwise to a suspension of 4-ethyl-3,4-dihydroxy, -1H-pyrano- [3 ', 4' : 6, 7] -indolizine- [1,2-b] quinolein-14- (4H, 12H) -one (13.4 g, 38 mmol) in (720 ml) of glacial acetic acid and the resulting solution is stirred for a hour at room temperature. The reaction mixture is then poured into an ice / water mixture (650 ml) and the resulting suspension is stirred for half an hour and then filtered and washed successively with water, with isopropyl alcohol and with diethyl ether, which allows to obtain , after drying under reduced pressure, the compound sought (11.5 g) in the form of a pale yellow solid mp > 200 ° C (d). l.c. β-ethyl-β-hydroxy-β- (8-hydroxymethyl-9-oxo- (11H) -indol i z- [1,2-j] quinolin-7-yl) - tert-butyl propionate A suspension of zinc (6.5 g, 100 mmol) is stirred with a magnetic stirrer in anhydrous diethyl ether (50 ml) under an argon atmosphere, activated by the dropwise addition of chlorotrimethylsilane (0.75 ml, 5.7 mmol). It is stirred for 15 minutes at room temperature and then heated to reflux. The heating bath is then removed and tert-butyl bromoacetate (15 ml) is added, 100 mmol) drop by drop, at a rate that ensures maintenance of reflux. The external heating is stopped and continued for 1 more hours. The ethereal solution resulting from the Reformatsky reagent is allowed to cool to room temperature, and is then transferred via a cannula to a suspension of 8-formyloxymethyl-7-propionylindolizine- [1,2-b] -quinoline-9 (11H). ) -one (1.6 g, 4.7 mmol) in (40 ml) of anhydrous tetrahydrofuran under an argon atmosphere. The reaction mixture is stirred at reflux for 1 hour, after allowing to cool to room temperature, and the reaction is stopped by the addition of saturated ammonium chloride (100 ml) and extracted with chloroform (3 x 100 ml). The combined chloroform extracts are dried over sodium sulfate, evaporated, and the residue is purified by chromatography on a silica gel column (1-2% Methanol / Methylene Chloride), which allows 0.64 g of the desired compound to be obtained ( 31%) in the form of a pale yellow solid pf 146-149 ° C.

RMN-1 !! (CDC13): 0.93 (t, 3H); 1.37 (s, 9H); 1.99 (, 2H); 2.97 (dd, 2H); 3.5 (se, 1H); 5.10 (s, 2H); 5.24 (s, 2H); 7.40 (s, ÍH); 7.59 (t, ÍH); 7.83 (t, ÍH); 7.90 (d, ÍH); 8.20 (d, ÍH); 8.34 (s, ÍH). RMN-iJC (CDC13; 27.90; 34.59; 45.34 49.91 58. 55; 77.39; 82.42; 100.52; 127.67; 127.97; 128.10 128.64; 129.44; 129.79; 130.42; 130.99; 142.86 148.69; 152.75; 155.16; 162.38; 172.24. IR (KBr): 764; 1016; 1157; 1580; 1651; 1726 l.d. 5-ethyl-4, 5-dihydro-5-hydroxy-lH-oxepino- [3 ', 4': 6, 7] -indolizin [1,2-b] -quinoline-3, 15 (4H, 13H) - diona ß-Ethyl-β-hydroxy-β- (8-hydroxymethyl-9-oxo- (11H) -indole-1-butyl- [1,2-b] quinolin-7-yl) propionate tert -butyl (1.45 g, 3.32 mmol) is dissolved in anhydrous dichloromethane (25 ml) and treated with a saturated solution of hydrogen chloride in (100 ml) of dichloromethane. The resulting mixture is maintained at -20 ° C for 16 hours. The precipitate is filtered, washed with methanol and dried under reduced pressure, which makes it possible to obtain 662 mg (55%) of the desired compound, in the form of a yellow solid, m.p. > 300 ° C.

NMR-H (DMSO): 0.90 (t, 3H); 1.20 (q, 2H); 3.37 (dd, ÍH); 5.59 (s, 2H); 5.49 (dd, 2H); 7.42 (s, 1H); 7.73 (t, ÍH); 7.90 (t, ÍH); 8.16 (t, 2H); 8.71 (s, ÍH). 13 C NMR (DMSO): 8.45; 36.48; 42.54; 50.68; 61.44; 73.34; 99.78; 122.71; 127.83; 128.15; 128.75; 129.08; 130.07; 130.61; 131.81; 144.66; 148.04; 152.80; 155.91; 159.26; 172.08. IR (KBr): 761; 1127; 1204; 1285; 1580; 1653; 1757 Preparation 2: resolution of 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3 ', 4': 6, 7] - indolizine [1,2-b] -quinoline-3, 15- (4H, 13H) -dione A mixture of ß-ethyl-β-hydroxy (8-hydroxymethylindolizino [1,2-b] quinoline-9- (11H) -on-7-yl) propionic acid (19.5 g, 51 mmol) is heated to boiling. L- (-) -a-methylbenzylamine (12.12 g, 100 mmol) in (1 liter) of absolute ethanol is filtered hot and allowed to stand 68 hours. The precipitate is filtered and washed with ethanol and with ether to give 9.8 g of a white solid. An analysis by chiral high pressure liquid chromatography in chiral stationary phase ("chiral HPLC" on Chiral-AGP column (Chro tech, Stockholm, Sweden) of 100 x 4 mm, eluent: 2% acetonitrile in 10 mM phosphate buffer at pH 6.9, peaks eluting at 4.5 and 7.5 minutes) reveals two peaks that integrate respectively for 25% and 76% of the total area of two peaks. The solid is taken up in (350 ml) of 93% ethanol under reflux, then left to stand for 48 hours. The precipitate is filtered and then washed with ethanol and with ester to obtain 4.8 g of a white solid which gives two peaks of integration respectively for 9% and 91% of the total area of two peaks by chiral HPLC. The solid is taken up in 58% ethanol (48 ml) under reflux and then left to stand for 48 hours. The precipitate is filtered and then washed with ethanol and ether to give 2.7 g of a white solid which gives two peaks of integration respectively for 3% and 97% of the total area of two peaks by chiral HPLC. The solid is taken up in (22 ml) of 50% ethanol under reflux, then left to stand for 48 hours. The precipitate is filtered and then washed with ethanol and ether to obtain 1.6 g of a white solid which gives two peaks of integration respectively for 1% and 99% of the total area of two peaks by chiral HPLC. The resulting salt, diastereoisomerically enriched, collected in distilled water (20 ml), is treated with acetic acid (0.35 ml, 6.4 mmol) for 15 minutes. The precipitate obtained is filtered, washed with water, with acetone and with ether, and then dried under vacuum at 80 ° C to obtain 1.1 g of a white solid. The latter is taken up in (55 ml) of absolute ethanol added with concentrated hydrochloric acid (11.5 N, 11 ml) to obtain a yellow solution which is kept under stirring at room temperature for 68 hours. The precipitate obtained in this way is washed with water, with ethanol and with ether, then dried under vacuum at 80 ° C to obtain 770 mg of 5-ethyl-4., Enantiomerically enriched 5-dihydro-5-hydroxy-lH-oxepino- [3 ', 4': 6,7] -indolizin- [1,2-b] quinoline-3, 15 (4H, 13H) -dione. Analysis by chiral HPLC (Chiral-AGP column, eluted with a gradient of 2 to 5% acetonitrile in 10 mM phosphate buffer at pH 6.9, peaks eluting at 15 and 20 minutes) reveals an enantio-enric excess of 98% . The procedure described above is repeated by replacing the L- (-) -a-methylbenzylamine with the D - (+) -a-methylbenzylamine. The other enantiomer of 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino- [3 ', 4': 6, 7] -indol iz ino- [1, 2 -b is thus obtained ] quinoline-3,15- (4H, 13H) -dione.

Preparation 3: 5, 12-diethyl-4,5-dihydro-5-hydroxy-1H-oxepino- [3 ', 4': 6, 7] -indole iz ino [1,2-b] quinolein-3, 15 - (4H, 13H) -dione This compound is prepared in a manner analogous to preparation 1, except that in step l.a., 7-ethylcamptothecin (Sawada et al.

Chem. Pharm. Bull. 39: 2574 (1991) is used in place of camptothecin. The desired compound is obtained in the form of a bright yellow solid, m.p. > 270 ° C.

RMN-1.-. (DMSO): 0.92 (t, 3H); 1.39 (t, 3H); 1.93 (q, 2H); 3.08 (d, 2H); 3.25 (q, 2H); 3.51 (d, 2H); 5.32 (s, 2H); 5.52 (dd, 2H); 7.42 (s, ÍH); 7.76 (t, ÍH); 7.89 (t, ÍH); 8.18 (d, ÍH); 8.32 (d, ÍH). NMR-13 H (DMSO): 8.46; 14.15; 22.42; 36.50; 42.54; 49.95; 61.45; 73.35; 99.68; 122.61; 124.27; 126.76; 127.70; 128.27; 129.92; 130.18; 145.17; 145.82; 148.57; 152.15; 155.89; 159.26; 172.08.

Preparation 4: 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-1H-oxepino- [3 ', 4': 6,7] -indolizin [1,2-b] quinoline-3 , 15- (4H, 13H) -dione 4. to. 2-Ethyl-2- (2-methoxy-4-pyridyl) -1, 3-dioxolane Water is distilled azeotropically (overnight) with a Dean Stark apparatus from a 2-chloro-4-propionylpyridine mixture (10 g, 59 mmol) obtained as in Lamattina, J.L. J. Hé t érocycl i c Chem. 20, p. 553 (1983), (20 ml) of ethylene glycol and (250 mg) of p-toluenesulfonic acid in (150 ml) of toluene. The solvent is then removed under reduced pressure, the acid is neutralized with saturated aqueous sodium bicarbonate (100 ml) and the product is extracted with ether. The combined ether extracts are washed with brine, dried over sodium sulfate and evaporated, yielding 13.3 g (96%) of the crude product protected by the carbonyl group, which is brought to reflux with 3 equivalents of sodium methoxide in acetonitrile, until the end of the reaction (control by thin layer chromatography: SiO, tert-butylmethyl oxide / hexane (TBMO / HX) 50/50). The acetonitrile solution is then filtered and evaporated. The residue is taken up in ether, washed with water and with brine, dried over sodium sulfate and evaporated, which gives a brown oil that is distilled (70-75 ° C, 0.04 mbar); 10.7 g are recovered (overall yield 81%) of the product (F) in the form of a limpid oil. 4. b 2-ethyl-2- (3-hydroxymethi 1-2-methoxy-4-pyridyl) -1, 3-dioxolane It is added dropwise via a ther-but-il-li thio cannula (1.7 M in pentane, 100 ml, 170 mmol) to a solution of bromomesi filen (13 ml, 85 mmol) in anhydrous tetrahydrofuran (300 ml) at -78 ° C and under argon atmosphere. The resulting white precipitate is stirred at -78 ° C for 1 hour and then 2-ethyl-2- (2-methoxy-4-pyridyl) -1,3-dioxolane (10 g, 44.8 mmol) is added and the mixture of reaction is stirred for 15 minutes at 78 ° C, one hour at 0 ° C and one hour at room temperature. After further cooling to -78 ° C, the anhydrous N, N-di-ethylformamide (100 mmol) is added and the reaction mixture is allowed to warm to room temperature and is then stirred for 16 hours, after which a Thin layer chromatography analysis (YES02, TBMO / HX: 50/50) shows the complete consumption of the starting product. The reaction is stopped with saturated ammonium chloride and the reaction mixture is extracted with diethyl ether (200 ml, 50 ml, 50 ml). The combined extracts are dried over sodium sulfate and evaporated, which gives a yellow oil which is purified by column chromatography (Si02, TBMO / HX: 0/100 to 5/95 to elute the mesitylene derivatives and then 20 / 80 to 50/50 to elute the product) to obtain the intermediate aldehyde (7 g). The aldehyde is dissolved in (100 ml) of methanol, and treated with sodium borohydride (5 g, 132 mmol), and the resulting mixture is stirred until full consumption of the intermediate aldehyde (approximately 1 hour) with analytical control by chromatography on thin layer. The solvent is evaporated immediately, the residue is taken up in ether, washed with water and with brine, dried, and the solvent is evaporated. Column chromatography (Si02, TBMO / HX: 10/90 to 50/50) of the residue gives 7 g (62% overall yield) of the product (G) in the form of a yellow oil. 4. c 2- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -2- ethyl-1,3-dioxolane A solution of 2-ethyl-2- (3-hydroxymethyl-2-methoxy-4-pyridyl) -1,3-dioxolane (7 g, 30 mmol) and benzyl chloride (5 ml, 45 mmol) is added dropwise. ), in anhydrous tetrahydrofuran (50 ml), to a suspension of sodium hydride (80% in mineral oil, 1.85 g, 61 mmol) in anhydrous tetrahydrofuran (100 ml) and the reaction mixture was refluxed for 16 hours. hours. The reaction mixture is allowed to cool immediately to room temperature, the reaction is stopped with (50 ml) of water, and the reaction mixture is concentrated under reduced pressure. The residue is dissolved in (150 ml) of diethyl ether and washed with water and with brine, dried and evaporated. Purification by column chromatography (Si02, TBMO / HX: 5/95 to 20/80) gives the product protected by benzyl (H), 9 g (87%) in the form of a limpid oil. 4. d 1- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -propan-1-one Treat 2- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -2-ethyl-1,3-dioxolane (9 g, 27 mmol) with (10 mL) of trifluoroacetic acid and (5 mL) of water , at a bath temperature of 120 ° C for 3 hours. The reaction mixture is concentrated under reduced pressure and the residual traces of acids are neutralized by the addition of the saturated aqueous sodium bicarbonate. Extract with ether, followed by column chromatography (Si02, TBMO / HX: 10/90) gives 5.5 g (70%) of the product (I). 4. and. β-ethyl-β-hydroxy-β- (3-benzyloxymethyl-2-methoxy-4-pyridyl) tert-butyl propionate Excess drop tert-butyl bromoacetate (13 ml, 80 mmol) is added to a suspension of zinc (5.3 g, 80 mmol activated by treatment with 6 N HCl in 10 seconds, then washed successively with water to neutral pH, with acetone and with diethyl ether) in anhydrous tetrahydrofuran (60 ml) at reflux. The reaction mixture is refluxed for about 10 minutes after the addition is complete. Then, a solution of 1- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -propan-1-one (58 g, 20 mmol) in anhydrous tetrahydrofuran (20 ml) is added and the reaction mixture is stirred reflux for 1 additional hour. The reaction is stopped at 0 ° C with saturated aqueous ammonium chloride (100 ml) and the reaction mixture is extracted with diethyl ether. The combined extracts are dried over sodium sulfate and evaporated, which gives a yellow oil which is purified by column chromatography (SiO, TBMO / HX: 5/95 to 10/90) to obtain the tert-butyl ester ( J) (7 g, 95%) in the form of a limpid oil. 4. f. β-ethyl-β-hydroxy-β- (3-hydroxymethyl-2-methoxy-4-pyridyl) tert-butyl propionate The β-ethyl-β-hydroxy-β- (3-benzyloxymethyl-2-methoxy-4-pyridyl) tert-butyl propionate (1 g, 2.5 mmol) is hydrogenated at atmospheric pressure, and at room temperature using 5% palladium on carbon as catalyst (50 mg) and in absolute ethanol as solvent (10 ml). Once the reaction is complete (6 hours), the catalyst is separated by filtration and the solvent is evaporated, leaving 0.7 g (90%) of product (K) of sufficient purity for further synthetic use. 4. g. 5-ethyl-l, 5-dihydro-5-hydroxy-9-methoxy-oxepino [3,4-c] pyridin-3 (4H) -one The t-butyl β-ethyl-β-hydroxy-β- (3-hydroxymethyl-2-methoxy-4-pyridyl) propionate (8.8 g, 28 mmol) is treated with (30 ml) of trifluoroacetic acid for 3 hours at the room temperature. The volatiles are evaporated and the residue is purified by column chromatography (Si02, CH2CL2 / MeOH: 100/0 to 98/2), which gives a clear oil which, after treatment with toluene, gives 59 g of product ( L) (89%), in the form of white crystals, mp 97-98 ° C. 4. h. 5-ethyl-l, 5-dihydro-5-h.-hydroxy-oxepino [3,4-c] -pyridin-3, 9 (4H, 8H) -dione The mixture is refluxed for 9 hours in 1 N hydrochloric acid (20 ml), 5-ethyl-l, 5-dihydro-5-hydroxy-9-methoxy-oxepino [3,4-c] pyridine-3 (4H). -one (0.5 g, 2.1 mmol). The reaction mixture is concentrated under reduced pressure and the residue is still dried by addition and evaporation of toluene, twice, then left overnight under reduced pressure in the presence of phosphorus pentoxide. The resulting oil is dissolved in anhydrous acetonitrile (5 ml) and stirred under an argon atmosphere for 24 hours. The precipitate is filtered and dried, which gives 0.23 g (49%) of a white solid (M), m.p. 118-119 ° C. 4. i 2-chloro-6,7-difluoro-3-quinoline-methane1 The procedure described by Meth-Cohn et al., J. Chem. Soc. Perkin Trans. I, p. 1520 (1981); Meth-Cohn, J. Chem. Soc. Perkin Trans I, p. 2509 (1981). 3,4-Difluoroacetanilide (38 g, 22 mmol) is added to the Vilsmeyer reagent obtained by the dropwise addition of phosphoryl oxychloride (103 ml, 1.1 mol) to the anhydrous dimethylformamide (34 ml, 44 mmol), cooled with a water / ice bath and stir for 0.5 hours under an argon atmosphere. The resulting mixture is heated at 60 ° C for 16 hours. After cooling to room temperature, the reaction mixture is added to a mixture of ice and water (400 ml) which is kept under stirring for 2 hours, then it is filtered and washed successively with water, with ethanol and with ether. give 9 g of 2-chloro-6,7-difluoroquinoline-3-carbaldehyde in the form of a yellow solid pf 222-224 ° C. This intermediate is treated with sodium borohydride (2 g, 52 mmol) in (400 ml) of methanol at room temperature for 0.5 hour, and then the excess reagent is destroyed by the addition of (2 ml) of acetic acid. The solvent is removed under reduced pressure, the residue is placed in solution in ethyl acetate and washed successively with dilute sodium bicarbonate, with water and with a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and concentrated. The resulting solid is recrystallized from 1,2-dichloroethane to give 8 g of 2-chloro-6,7-difluoro-3-quinoline-methanol in the form of a beige solid. 4. j. 5-ethyl-8- (2-chloro-6,7-difluoro-3-quinoline-methyl) -1,5-dihydro-5-hydroxy-oxepino [3,4-c] pyridin-3,9) 4H, 8H) -diona Diethyl azodicarboxylate (570 μL, 3.6 mmol) is added dropwise over 5 minutes to a solution of 5-ethyl-l, 5-dihydro-5-hydroxy-oxepino [3,4-c] pyridin-3, 9 ( 4H, 8H) -dione (400 mg, 1.79 mmol), of the compound obtained in the preceding step 4. i. (770 mg, 2.23 mmol) and triphenylphosphine (934 mg, 3.58 mmol) in (45 ml) of anhydrous N, N-dimethylformamide, and the resulting mixture is stirred under argon atmosphere at room temperature for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in (100 ml) of ether. The resulting solution is washed with brine (4 x 50 ml), dried over sodium sulfate and evaporated. The residue is purified by column chromatography (SiO 2, CH 2 Cl / MeOH: 99/1 to 98/2), which gives 650 mg (66%) of the product (O) in the form of a white solid, m.p. 165-167 ° C. 4. k. 5-ethyl-9,10-difluoro-4, 5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6, 7] indolizino [1,2-b] -quinollein-3, 15 (4H , 13H) -dione. The 5-ethyl-8- (2-chloro-6,7-difluoro-3-quinoline-ethyl) -1,5-dihydro-5-hydroxy-oxepino is dissolved in (40 ml) of anhydrous acetonitrile. [3, 4-c] pyridin-3, 9 (4H, 8H) -dione (600 mg, 1.1 mmol), tetrabutylammonium bromide (352 mg, 1.1 mmol), sodium acetate (359 mg, 4.4 mmol) and acetate of palladium II (98 mg, 0.43 mmol), and heated at 90 ° C under an argon atmosphere for 16 hours. After cooling to room temperature, a white precipitate is separated from the reddish solution. This precipitate is filtered and dried under reduced pressure. The crude product is suspended in water, filtered and dried under reduced pressure over phosphorus pentoxide, which gives 250 mg of the desired compound in the form of a beige solid, m.p. > 250 ° C.

NMR-H (DMSO): 0.91 (t, 3H); 1.87 (m, 2H); 3.08 (d, ÍH); 3.51 (d, 1H); 4.45 (s, 4H); 5.19 (s, 2H), 5.47 (dd, 2H); 6.02 (se, ÍH); 7.33 s, ÍH); 7.54 (s, ÍH); 7.55 (s, ÍH); 8.43 (_3_- ÍH). 13 C NMR (DMSO): 8.43; 36.47; 42.54; 50.52; 61.43; 64. 43 (2C); 73.31; 99.07; 112.27; 113.14; 122.00; 124. 24; 128.18; 129.74; 144.59; 145.01; 145.33; 147.63; 150.88; 155.88; 159.23; 172.07.

Preparation 5: 5-ethyl-4,5-dihydro-5, 10-dihydroxy-1H-oxepino [3 ', 4': 6, 7] -indolizin- [1,2-b] quinoline-3, 15- ( 4H, 13H) -dione -benzyloxy-5-ethyl-4, 5-dihydro-5-hydroxy-lH-oxepino [3 ', 4': 6, 7] -indolizino [1,2-b] quinoline-3, 15- (4H, 13H) -dione (370 mg, 0.79 mmol) is treated with hydrogen at atmospheric pressure and at room temperature using 10% palladium on carbon as catalyst (60 mg) and (15 ml) of trifluoroacetic acid as solvent. Once the reaction is finished (16 hours), 50 ml of dichloromethane and 50 ml of methanol are added to the reaction mixture, the catalyst is filtered and the volatile components are evaporated under reduced pressure, which makes it possible to obtain the crude target compound It contains traces of trifluoroacetic acid. These traces are eliminated by codestylation with 1,4-dioxane. The product is obtained in the form of an orange solid, m.p. 150 ° C (d), of a sufficient purity for a subsequent synthetic use.

NMR-XH (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 3.02 (d, ÍH); 3.45 (d, ÍH); 5.19 (s, 2H); 5.37 (d, ÍH); 5.50 (d, ÍH); 5.98 (se, ÍH); 7.26 (s, ÍH); 7.31 (s, ÍH); 7.40 (d, ÍH); 8.00 (d, ÍH); 10.32 (s, 1H). 13 C NMR (DMSO): 8.47; 36.50; 42.61; 50.57; 61.46; 73.35; 98.84; 109.02; 121.83; 123.18; 129.50; 129.85; 130.12; 130.80; 143.39; 145.10; 149.69; 155.97; 156.82; 159.30; 172.11.

Preparation 6: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino [3 ', 4': 6, 7] indolizine [1,2-b] -quinoline- 3, 15 (4H, 13H) -dione This compound is obtained from 3-fluoro-4-methoxyaniline according to the method illustrated by steps 4. i., 4.j. and 4.k. of the preparation 4. Yellow solid, m.p. > 250 ° C.

NMR-2H (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 3.08 (d, ÍH); 3.49 (d, ÍH); 4.00 (s, 3H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, ÍH); 6.00 (s, ÍH); 7.32 (s, ÍH); 7.72 (d, ÍH); 7.91 (d, ÍH); 8.58 (s, ÍH). 13 C NMR (DMSO): 8.43; 36.48; 42.51; 50.68; 56.60; 61.42; 73.29; 99.25; 108.68; 113.52; 122.23; 126.33; 129.99; 130.30; 143.79; 144.70; 148.42; 151.18; 153.19; 155.81; 159.20; 172.06. IR (KBr): 1259: 1503; 1602; 1737 Preparation 7: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-1O-methyl-1H-oxepino- [3 ', 4': 6, 7] indolizine [1,2-b] - quinolein- 3, 15 (4H, 13H) -dione This compound is obtained from 3-chloro-4-methoxyaniline according to the method illustrated by steps 4. i., 4.j. and 4.k. of the preparation 4. Yellow solid; p.f. > 250 ° C.

NMR-XH (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 2.55 (s, 3H); 3.07 (d, ÍH); 3.45 (d, ÍH); 5.25 (s, 2H); 5.39 (d, ÍH); 5.51 (d, ÍH); 6.05 (s, ÍH); 7.39 (s, ÍH); 8.10 (s, 1H); 8.20 (s, ÍH); 8.60 (s, ÍH). 13 C NMR (DMSO): 8.43; 20.20; 36.47; 42.49; 50.67; 61.41; 73.28; 99.87; 122.82; 126.98; 127.99; 129.60; 130. 53; 131.08; 135.64; 136.56; 144.39; 147.11; 153. 10; 155.85; 159.18; 172.03. IR (KBr): 1208; 1479; 1606; 1656; 1724 Preparation 8: 8-ethyl-2, 3, 8, 9-tetrahydro-8-hydroxy-lOH, 12H- [1,4] dioxino- [2, 3-g] -oxepino-] 3 ', 4': 6 , 7] -indolizine- [1,2-b] quinolein-10, 13- (15H) -dione This compound is obtained from the 3, 4-ethylenedioxianiline according to the method illustrated by steps 4. i., 4.j. and 4.k. of the preparation 4. Yellow solid; p.f. > 250 ° C.

NMR-XH (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (s, ÍH); 3.47 (d, ÍH); 5.25 (s, 2H); 5.39 (d, ÍH); 5.51 (d, ÍH); 6.05 (s, ÍH); 7.39 (s, ÍH); 8.10 (q, ÍH); 8. 25 (s, ÍH); 8.68 (s, ÍH). 13 C NMR (DMSO): 8.41; 36.45; 42.48; 50.68; 61.40 73.25; 99.92; 114.44; 115.42; 115.58; 122.96; 125.52 130. 56; 131.46; 144.21; 145.25; 142.36; 153.41 155. 85; 159.15; 172.00. IR (KBr): 1266; 1512; 1581; 1618; 1751 Preparation 9: 7-ethyl-7,8-dihydro-7-hydroxy-9H, 11H- [1,3] dioxolo- [4, 5-gr] -oxepino [3 ', 4': 6, 7] -indolizin - [1,2- b] quinolein-9, 12- (14H) -dione This compound is obtained from the 3, 4-methylenedioxianiline according to the method illustrated by steps 4. i., 4.j. and 4.k. of the preparation 4. Solid in cream; p.f. > 250 ° C.

NMR - ^ - H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (s, 3H); 3.45 (d, ÍH); 5.20 (s, 2H); 5.39 (d, ÍH); 5.51 (d, ÍH); 6.00 (s, ÍH); 6.30 (s, 2H); 7.30 (s, ÍH); 7.49 (d, 2H); 8.45 (s, 1H). 13 C NMR (DMSO): 8.43; 36.49; 42.56; 50.58; 61.42; 73.31; 98.87; 102.75; 103.33; 104.92; 121.76; 125.74; 128.59; 130.33; 145.08; 146.69; 148.78; 150.19; 151.49; 155.90; 159.24; 172.08. IR (KBr): 1248; 1459; 1606; 1731 Preparation 10: 9-Chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino- [3 ', 4': 6, 7] indolizine [1,2-b] -quinoline - 3.15 (4H, 13H) -dione This compound is obtained from 3-chloro-4-methoxyaniline according to the method illustrated by steps 4. i., 4, j. and 4.k. of the preparation 4. White solid; p.f. > 250 ° C.

NMR-2H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, ÍH); 3.45 (d, ÍH); 4.01 (s, 3H); 5.22 (s, 2H); 5.39 (d, ÍH); 5.51 (d, ÍH); 6.02 (s, ÍH); 7.31 (s, ÍH); 7. 68 (s, ÍH); 8.20 (s, ÍH), 8.55 (s, ÍH), 13 C-NMR (DMSO): 8.22; 36.27; 42.30; 50.48; 56.69; 61. 2. 3; 73.08; 99.16; 107.44; 122.16; 127.12; 128.12; 129. 25; 130.02; 130.53; 143.29; 144.37; 151.12; 153. 29; 155.71; 158.98; 171.84. IR (KBr): 1056; 1256; 1483; 1592; 1657; 1747 Preparation 11_: 5-ethyl-4, 5-dihydro-5-hydroxy-10-methoxy-1H-oxepino [3 ', 4': 6, 7] -indolizine- [1,2-b] quinoline-3, 15 (4H, 13H) -dione This compound is obtained from 4-methoxyaniline according to the method illustrated by steps 4. i., 4.j. and 4.k. of the preparation 4. Yellow solid; p.f. > 250 ° C.

NMR ^ H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, ÍH); 3.45 (d, 1H); 3.95 (s, 3H); 5.28 (s, 2H); 5.40 (d, ÍH); 5.51 (d, ÍH); 6.00 (s, ÍH); 7.38 (s, ÍH); 7.51 (d, 2H); 8.07 (d, ÍH); 8.55 (s, ÍH). 13 C NMR (DMSO): 8.45; 36.48; 42.51; 50.64; 55.92; 61.42; 73.33; 99.01; 106.49; 122.02; 123.19; 129.59; 130.20; 130.43; 144.17; 144.94; 150.40; 155.92; 158.31; 159.26; 172.07. IR (KBr): 1251; 1604; 1655; 1735 Preparation 12: 9, ll-dichloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino- [3 ', 4': 6, 7] -indolizine- [1,2-b] quino1ein- 3, 15- (4H, 13H) -dione This compound is obtained from the 3, 5-dichloroaniline according to the method illustrated by steps 4. i., 4.j. and 4.k. of the preparation 4. Yellow solid; p.f. > 250 ° C.

NMR-XH (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, ÍH); 3.45 (d, ÍH); 5.30 (s, 2H); 5.41 (d, ÍH); 5.55 (d, ÍH); 6.08 (s, ÍH); 7.41 (s, ÍH); 8.05 (s, ÍH); 8. 21 (s, ÍH); 8.91 (s, ÍH). 13 C NMR (DMSO): 8.39; 36.45; 42.51; 51.03; 61.39; 73. 25; 100.62; 123.55; 124.63; 127.60; 128.08; 128. 56; 132.06; 132.19; 134.53; 143.77; 148.80; 154. 88; 155.82; 159.13; 171.98. IR (KBr): 1064; 1275; 1586; 1651; 1743 Preparation 13 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino- [3 ', 4': 6, 7] - indolizine- [1,2-b] - quino1ein-3, 15- (4H, 13H) -dione This compound is obtained from 3-fluoro-4-methylaniline according to the method illustrated by steps 4. i., 4.j. and 4.k. of the preparation 4. Yellow solid; p.f. > 250 ° C.

NMR-XH (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 2.49 (s, 3H); 3.08 (d, ÍH); 3.49 (d, ÍH); 5.21 (s, 2H); 5.39 (d, ÍH); 5.51 (d, 1H); 6.05 (s, ÍH); 7.39 (s, ÍH); 7.87 (d, ÍH); 8.05 (d, ÍH); 8.61 (s, ÍH). 13 C NMR (DMSO): 8.40; 15.14; 36.45; 42.52; 50.60; 61.41; 73.28; 99.71; 112.00; 122.66; 125.38; 127.66; 129.59; 130.28; 144.49; 147.88; 152.88; 155.85; 159.18; 162.25; 172.02. IR (KBr): 1054; 1580; 1651; 1760 Preparation 14 5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-1H-oxepino- [3 ', 4': 6,7] -indole and zino- [1,2-b] quinoline-3 , 15- (4H, 13H) -dione This compound is obtained from 4-fluoroaniline according to the method illustrated by steps 4. i., 4.j. and 4.k. of the preparation 4. White solid; p.f. > 250 ° C. <1> H-NMR (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, ÍH); 3.45 (d, ÍH); 5.29 (s, 2H); 5.39 (d, ÍH); 5.55 (d, ÍH); 6.30 (s, ÍH); 7.39 (s, ÍH); 7.80 (q, ÍH); 7. 99 (q, ÍH); 8.23 (q, ÍH); 8.68 (s, ÍH). 13 C NMR (DMSO): 8.40; 36.46; 42.48; 50.66; 61.41; 73. 31; 99.68; 111.83; 122.75; 128.93; 130.93; 131.22; 131. 93; 144.46; 145.27; 152.60; 155.89; 159.21; 172. 04. IR (KBr): 1209; 1589; 1659; 1739 Preparation 15: 10-chloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6, 7] indolizino [1,2-b] quinoline-3, 15 (4H , 13H) -dione This compound is obtained from 4-chloroaniline according to the method illustrated by steps 4. i., 4.j. and 4.k. of the preparation 4. Yellow solid; p.f. > 250 ° C.

RMN-1 !! (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, ÍH); 3.47 (d, ÍH); 5.25 (s, 2H); 5.39 (d, ÍH); 5.51 (d, ÍH); 6.05 (s, ÍH); 7.39 (s, ÍH); 7.89 (d, ÍH); 8. 19 (d, ÍH); 8.29 (s, ÍH); 8.67 (s, 1H). 13 C NMR (DMSO): 8.40; 36.46; 42.47; 50.70; 61.42 73.31; 100.00; 122.96; 127.31; 127.42; 128.87 131. eleven; 132.12; 144.34; 146.53; 153.38; 155.88 159. twenty; 172.04. IR (KBr): 1069; 1483; 1606; 1741 Preparation 16: 9-Chloro-5-ethyl-10-fluoro-4, 5-dihydro-5-hydroxy-1H-oxepino- [3 ', 4': 6, 7] indolizine [1,2- b] -quinoline - 3, 15 (4H, 13H) -dione This compound is obtained from 4-chloro-3-fluoroaniline according to the method illustrated by steps 4. i., 4.j. and 4.k. of the preparation 4. Yellow solid; p.f. > 250 ° C.

NMR-2H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, ÍH); 3.45 (d, ÍH); 5.25 (s, 2H); 5.39 (d, ÍH); 5.51 (d, ÍH); 6.05 (s, ÍH); 7.40 (s, ÍH); 8.20 (d, ÍH); 8. 40 (d, ÍH); 8.68 (s, ÍH). 13 C NMR (DMSO): 8.38; 36.47; 42.58; 50.71; 61.40; 73. 26; 99.99; 113.59; 123.09; 124.28; 127.74; 130.64; 131. 31; 144.13; 145.08; 153.57; 154.13; 155.84; 156. 61; 159.14; 172.00. IR (KBr): 1488; 1583; 1655; 1743 Preparation 17: 5, 12-diethyl-9-fluoro-4,5-dihydro-5-hydroxy-1O-methoxy-1H-oxepino [3 ', 4': 6, 7] indolizine [1,2-b] -quinoline- 3, 15 (4H, 13H) -dione 17. to 5-fluoro-4-methoxy-2-propionylaniline (This product is obtained according to Sugasawa T; Toyoda T; Adachi M; Sasakura K, J. Am. Chem. Soc, 100 (1978), pp. 4842-4852). To a solution of 3-fluoro-4-methoxyaniline (20 g, 142 mmol) in anhydrous dichloromethane (200 ml), under argon atmosphere and at 0 ° C, dropwise boron trichloride (IM in heptane, 156 ml) is added. , 156 mmol). The suspension obtained in this way is kept under stirring for 5 minutes and then propionitrile (33 ml, 420 mmol) followed by aluminum trichloride (20.8 g, 156 mmol) is added dropwise in small portions. The reaction medium is refluxed for 3 hours, cooled to 0 ° C, hydrolyzed by carefully adding 2N hydrochloric acid (100 ml), then refluxing for 45 minutes. After cooling to 0 ° C, a precipitate is obtained which is filtered, washed with dichloromethane, then taken up in (300 ml) of water. The aqueous phase is basified to alkaline pH, extracted with dichloromethane and then with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated to give a crude product which is purified by column chromatography (SiO2, AcOE / Hpt: 1/99 to 20/80). 15.3 g of a yellow solid are obtained.

NMR-XH (CDC13): 1.20 (t, 3H); 2.92 (q, 2H); 3.83 (s, 3H); 6.2 (s, 2H); 6.40 (d, 2H); 7.32 (d, 2H). ' IR (KBr): 857; 1148; 1240; 1561; 1583; 1662 17. b. Ethyl 4-ethyl-7-fluoro-2-hydroxy-6-methoxy-3-quinolinecarboxylate To a solution of 5-fluoro-4-methoxy-2-propionylaniline (15.3 g, 77.5 mmol) and triethylamine (13.9 ml, 100 mmol) in (110 ml) of anhydrous acetonitrile, under an argon atmosphere and at 0 ° C, a solution of ethylmalonyl chloride is added dropwise. (12.9 ml, 100 mmol) in anhydrous acetonitrile (30 ml). The reaction medium is allowed to reach room temperature, a solution of sodium ethylate (obtained by 1.8 g, 78 mmol, of sodium in 80 ml of ethanol) is heated dropwise and under an argon atmosphere, then left under stirring 12 hours at room temperature. The reaction mixture is poured into (100 ml) of ice water and stirred for 2 hours, then the precipitate is filtered and washed with water, with ethanol and with ether. 19.4 g of a white solid are obtained.

RMN-1 !! (DMSO): 1.25 (, 6H); 2.78 (q, 2H); 3.92 (s, 3H); 4.30 (q, 2H); 7.15 (d, 2H); 7.40 (d, 2H); 11.93 (s, ÍH). IR (KBr): 786; 1083; 1410; 1521; 1644; 1725 17. c. Ethyl 2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate A suspension of ethyl 4-ethyl-7-fluoro-2-hydroxy-6-methoxy-3-quinoline-3-quinolinecarboxylate (19.4 g, 0.066 mmol) in (243 ml) of phosphoryl chloride is heated at reflux for 6 hours. The phosphoryl chloride is distilled. The reaction mixture is transferred to ice water. Collect with dichloromethane to solubilize. The organic phase is washed with water, then with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and the solvent is evaporated. The residue is suspended in ether and the unconverted starting product (4 g) is filtered. The filtrate is evaporated and purified to the residue by column chromatography (SiO2, AcOEt / Hpt: 5/95 to 20/80). 10.9 g of a white solid are obtained.

NMR-aH (DMSO): 1.30 (t, 3H); 1.39 (t, 3H); 3.08 (q, 2H); 4.09 (s, 3H); 4.49 (q, 2H); 7.64 (d, 2H); 7.86 (d, 2H). IR (KBr): 865; 1016; 1082; 1190; 1224; 1253; 1272; 1508; 1571; 1732 17. d. 2-Chloro-4-ethyl-7-fluoro-6-methoxy-3-quinoline-methanol A solution of ethyl 2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate (10.8 g, 35 mmol) in anhydrous dichloromethane (200 ml) is treated dropwise at room temperature under an atmosphere. inert with diisobutylaluminum hydride (1 M in dichloromethane, 65 ml, 65 mmol), then heated at 40 ° C for 4 hours. After cooling to 0 ° C, an aqueous solution of Rochelle's 20% salt (105 ml) and (200 ml) of dichloromethane is added cautiously and kept under stirring for 1 hour. It is decanted, washed three times with water, the organic phase is dried over magnesium sulfate and the solvent is evaporated. The residue is purified by column chromatography (SiO2, AcOEt / Hpt: 5/95 to 50/50). 6 g of a white solid are obtained.

RMN-1 !! (DMSO): 1.28 (t, 3H); 3.25 (q, 2H); 4.04 (s, 3H); 4.77 (d, 2H); 5.27 (t, ÍH); 7.55 (d, 2H); 7.73 (d, 2H). IR (KBr): 840; 864; 1023; 1232; 1267; 1317; 1444; 1511; 1569 17. and. 5, 12-diethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino [3 ', 4'; 6,7] -indolizino [1,2-b] quinoline-3 15 (4H, 13H) -dione The 2-chloro-4-ethyl-1-7-fluoro-6-methoxy-3-quinoline-methanol is coupled to the compound (M) as described in example 4.j. of the preparation 4. The resulting coupling product is cyclized according to the procedure of step 4.k. A yellow solid is obtained, m.p. > 275 ° C.

RMN-1 !! (CF3C00D): 1.07 (m, 3H); 1.62 (m, 3H); 2.27 (m, 2H); 3.44 (d, ÍH); 3.54 (m, 2H); 3.91 (d, ÍH); 4.25 (s, 3H); 5.60 (d, ÍH); 5.74 (s, 2H); 5.98 (d, ÍH); 7.85 (m, ÍH); 8.16 (m, ÍH); 8.31 (s, ÍH). 13 C NMR (CF 3 COOD): 9.03; 14.20; 26.68; 38.77; 43.98 53.79; 58.27; 64.73; 77.93; 106.85; 109.24; 110.15 128.99; 129.20; 131.61; 137.32; 141.23; 144.13 154.79; 158.32; 160.25; 160.81; 179.30. IR (KBr): 1013; 1068; 1265; 1466; 1514; 1601; 1655; 1748 Preparation 18: 5-ethyl-4,5-dihydro-5-hydroxy-12-methyl-1H-oxepino- [3 ', 4': 6, 7] -indolizine- [1,2-b] quinoline-3, 15- (4H, 13H) -dione The procedure described by examples 17. b., 17. c. Is applied to 2-acetylaniline. and 17. d., to give 2-chloro-4-methyl-3-quinoline-methanol. The latter is coupled to the compound (M) as described in step 4.j. of the preparation 4. The resulting coupling product is cyclized according to the procedure of step 4.k. A yellow solid m.p. > 260 ° C.

RMN-1 !! (DMSO): 0.87 (t, 3H); 1.87 (q, 2H); 2.78 (s, 3H); 2.80 (d, ÍH); 3.55 (d, ÍH); 5.27 (s, 2H); 5.42 (d, ÍH); 5.52 (d, ÍH); 6.04 (s, 1H); 7.39 (s, ÍH); 7.75 (t, ÍH); 7.88 (t, ÍH); 8.13 (d, ÍH); 8.25 (d, 1H). 13 C NMR (DMSO): 8.23; 36.26; 42.36; 62.00; 73.11; 78.65; 79.13; 79.25; 99.52; 122.36; 124.30; 127.67; 129.54; 129.55; 129.56; 140.11; 145.06; 148.07; 152.00; 155.79; 159.09; 171.89. IR (KBr): 1649; 1751; 3404.

Preparation 19: 10-benzyloxy-5-ethyl-9-fluoro-4, 5-dihydro-5-hydroxy-1H-oxepino- [3 ', 4': 6, 7] - indolizine- [1,2-b] -quinoline- 3, 15 (4H, 13H) -dione The procedure exemplified in step 4. i. Is applied to 3-fluoro-4-methoxy-acetanilide to obtain 2-chloro-7-fluoro-6-methoxy-quinoline-3-carbaldehyde which is treated by an excess of boron tribromide in dichloromethane at room temperature for 24 hours. 2-Chloro-7-fluoro-6-hydroxy-quinoline-3-carbaldehyde is obtained, which is O-benzylated in dimethylformamide in. presence of benzyl bromide and potassium carbonate, to give the 6-benzyloxy-2-chloro-7-fluoro-quinoline-3-carbaldehyde which is reduced with sodium borohydride in methanol to give the corresponding quinoline-methanol. The latter is coupled to the compound (M) as described in step 4.j. of the preparation 4. The resulting coupling product is cyclized according to the procedure of step 4.k. A yellow solid is obtained, m.p. > 275 ° C.

RMN-1 !! (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 3.05 (d, ÍH); 5.25 (s, 2H); 5.37 (s, 2H); 5.45 (dd, 2H); 6.05 (s, ÍH); 7.4-7.6 (m, 5H); 7.88 (d, ÍH); 7.95 (d, ÍH); 8.56 (s, ÍH).

Preparation 20: 5-ethyl-9-fluoro-4, 5-dihydro-5, 10-dihydroxy-1H-oxepino- [3 ', 4': 6, 7] -indolizine- [1,2-b] -quinone - 3, 15- (4H, 13H) -dione Treat the compound of preparation 19 (0.79 mmol) dissolved in (15 ml) of trifluoroacetic acid, with hydrogen using palladium % on carbon (60 mg). A yellow solid m.p. > 275 ° C. 1 H NMR (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 3.05 (d, ÍH); 5.25 (s, 2H); 5.37 (s, 2H); 5.45 (dd, 2H); 6.05 (s, ÍH); 7.8 (d, ÍH); 7.90 (d, ÍH); 8.56 (s, ÍH).

The above preparations will serve as a basis for illustrating the invention by the following examples.

EXAMPLE 1: -ethyl-9, 10-difluoro-4,5-dihydro-5- (2-amino-1-oxoethoxy) -lH-oxepino [3 ', 4': 6, 7] indolizine [1,2-b] quinoline-3, 15 (4H, 13H) -dione to. 5-Ethyl-9,10-difluoro-4,5-dihydro-5- (2- (t-butyloxycarbonyl-amino) -1-oxoethoxy) -1H-oxepino hydrochloride [3 ', 4': 6, 7] indolizine [1,2-b] quinoline-3, 15 (4H, 13H) -dione A mixture of 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,1] indolizine [1,2-b] quinoline-3, 15 (4H, 13H) -dione (200 mg, 0.526 mmol, obtained according to preparation 4), of N-Boc-glycine (185 mg, 1051 mmol) and of a catalytic amount of 4-dimethylaminopyridine (20 mg) in Anhydrous pyridine (10 ml) is treated at 0 ° C and under an argon atmosphere with dicyclohexylcarbodiimide (239 mg, 1.16 mmol), then it is stirred at room temperature for 48 hours. Volatile materials are removed in vacuo and the residue is subjected to chromatography (SiO2, 1% methanol in chloroform) to give the desired intermediate (40 mg, 14%), as a yellow solid.

NMR-'H (CDC13): 1.20 (t, 3H); 1.38 (s, 9H); 1.40-1.70 (m, 2H); 3.10 (d, 1H); 4.00 (d, 2H); 4.30 (d, ÍH); 5.00 (t, ÍH); 5.20 (s, 2H); 5.30-5.90 (dd, 2H); 7.20 (s, ÍH); 7.50-8.10 (m, 2H); 8.30 (s, ÍH). b. 5-Ethyl-9,10-difluoro-4,5-dihydro-5- (2-amino-1-oxoethoxy) -lH-oxepino hydrochloride [3 ', 4': 6,7] -indolizine [1, 2] -b] -quinol ein-3, 15 (4H, 13H) -dione To the intermediate obtained above (40 mg, 0.072 mmol) in solution in (10 ml) of dichloromethane and kept at 0 ° C, saturated dioxane drop in hydrogen chloride (8 ml) is added dropwise. The yellow suspension formed in this way is kept under stirring for 2 hours, then the volatile materials are removed in vacuo. The residue, taken up from (5 ml) of water, is washed with (3 x 30 ml) of dichloromethane. The aqueous phase is frozen and lyophilized to give the expected salt, a yellow hygroscopic solid (20 mg, 50%).

NMR-2H (CDC13): 1.00 (t, 3H); 2.15 (m, ÍH); 2.30 (m, ÍH); 3.60 (d, ÍH); 3.90 (d, ÍH); 4.15 (s, 2H); 5.10 (s, 2H); 5.40 (d, 1H); 5.70 (d, 2H); 7.40 (s, ÍH); 7.80 (m, 2H); 8.50 (s, ÍH).

EXAMPLE 2: -ethyl-9, 10-difluoro-4,5-dihydro-5- (2-amino-1-oxo-propoxy) -IH-oxepino [3 r, 4 ': 6, 7] indolizine [1,2-b] -quinoline-3, 15 (4H, 13H) -dione The procedure of Example 1 is applied to 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,7] indolizine [1,2-b] ] quino1ein-3, 15- (4H, 13H) -dione using N-Boc-b-al anin instead of N-Bocillin, then the Boc protector of the intermediate obtained in this way is broken, by treatment with trifluoroacetic acid in dichloromethane. The volatile materials are evaporated in vacuo, the residue is taken up in dichloromethane. The resulting solution is washed with dilute bicarbonate, dried and evaporated. A yellow solid is obtained. Applying the method of examples 1 and 2 to other compounds, analogous results are obtained. There is thus access to any kind of camptothecin analogues in the form of "prodrug".

EXAMPLE 3: 1,8-diethyl-8,9-dihydro-8-hydroxy-2H, 10H, 12H- [1,3] oxazino [5,6-] oxepino [3 ', 4': 6,7] indolizine [1 , 2-b] quinoline-10, 13 (15H)) -dione A suspension of 5-ethyl-4,5-dihydro-5, 10-dihydroxy-1H-oxepino [3 ', 4': 6, 7] indolizine [1,2-b] quinoline-3, 15 (4H, 13H ) -dione (84 mg obtained according to preparation 5) in (2.5 ml) of acetic acid is treated with 1, 3, 5-triethylhexahydrotriazine (0.5 ml). The reaction mixture is stirred at 70 ° C for 30 minutes, then evaporated in vacuo. The residue is taken up in ethanol, filtered and washed with ether. A solid is obtained, m.p. > 275 ° C.

NMR-aH (DMSO): 0.87 (t, 3H); 1.50 (t, 3H); 1.85 (q, 2H); 2.77 (q, 2H); 3.05 (d, ÍH); 3.47 (d, ÍH); 4.37 (s, 2H); 5.00 (s, 2H); 5.22 (s, 2H); 5.45 (dd, 2H); 6.00 (s, ÍH); 7.34 (s, 1H); 7.36 (d, ÍH); 7.93 (d, ÍH); 8.53 (s, ÍH). 13 C NMR (DMSO): 8.46; 13.48; 36.46; 42.49; 45.49 46.44; 50.75; 61.43; 73.33; 82.06; 99.02; 112.90 122.00; 122.98; 125.42; 127.04; 129.04; 130.20 144.09; 144.97; 149.87; 152.92; 155.98; 172.07. IR (KBr): 1045; 1215; 1502; 1604; 1657; 1722 EXAMPLE 4: 8-ethyl-8, 9-dihydro-8-hydroxy-1-methyl-2H, 10H, 12H- [1, 3] oxazino [5, 6 /] oxepino [3 ', 4': 6, 7] indolizine [1,2-b] quinoline-10, 13 (15H) -dione A suspension of 5-ethyl-4,5-dihydro-5, 10-dihydroxy-1H-oxepino [3 ', 4': 6, 7] indolizino [1,2-b] quinoline-3, 15 (4H, 13H ) -dione (200 mg obtained according to preparation 5) in (5 ml) of acetic acid is treated with hexahydro-1,3,5-trimethyltriazine (110 mg). The reaction mixture is stirred at 70 ° C for 30 minutes, then evaporated in vacuo. The residue is taken up in ethanol, filtered and washed with ether. A solid is obtained, m.p. > 275 ° C.

RMN-1 !! (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 3.04 (d, ÍH); 3.48 (d, ÍH); 4.33 (s, 2H); 4.93 (s, 2H); 5.28 (s, 2H); 5.45 (dd, 2H); 6.01 (s, ÍH); 7.35 (s, 1H); 7.38 (d, ÍH); 7.94 (d, ÍH); 8.49 (s, 1H). 13 C NMR (DMSO): 8.46; 36.43; 37.85; 42.55; 48.68 50.79; 61.43; 73.35; 83.82; 99.04; 112.49; 122.04 123.00; 125.46; 127.14; 129.07; 130.27; 144.99 144.95; 152.46; 155.99; 172.09.

EXAMPLE 5: 8-ethyl-8, 9-dihydro-8-hydroxy-l-benzyl-2H, 10H, 12H- [1,3] oxazino [5,6-f] oxepino [3 ', 4': 6,7] indolizine [1,2-b] quinoline-10, 13 (15H) -dione: A suspension of 5-ethyl-4,5-dihydro-5, 10-dihydroxy-1H-oxepino [3 ',': 6, 7] indolizine [1,2-b] quinoline-3, 15 (4H, 13H ) -dione (200 mg obtained according to preparation 5) in (5 ml) of acetic acid, treated with 1,3,5-tribenylhexahydrotriazine (285 mg). The reaction mixture is stirred at 70 ° C for 30 minutes, then evaporated in vacuo. The residue is taken up in ethanol, filtered and washed with ether. A solid m.p. > 275 ° C.

RMN-1 !! (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.05 (d, ÍH); 3.47 (d, ÍH); 3.96 (s, 2H); 4.33 (s, 2H); 5.04 (s, 2H); 5.17 (s, 2H); 5.44 (dd, 2H); 6.01 (s, ÍH); 7.38 (m, 6H); 7.42 (d, ÍH); 7.97 (d, ÍH); 8.42 (s, ÍH). 13 C NMR (DMSO): 8.42; 19.96; 36.45; 42.51; 46.36; 50.78; 55.38; 61.39; 73.31; 99.00; 112.55; 122.01; 123.08; 125.38; 127.09; 127.47; 128.70; 129.14; 130.35; 128.40; 139.19; 144.18; 149.99; 152.84; 155.92; 159.24; 172.05 IR (KBr): 1056; 1205; 1225; 1248; 1504; 1535; 1599; 1655; 1726 EXAMPLE 6: 8-ethyl-8, 9-dihydro-4-fluoro-8-hydroxy-1-benzyl-2H, 10H, 12H- [1,3] oxazino [5,6- /] oxepino [3 ', 4': 6, 7] indolizine [1,2-b] quinoline-10, 13 (15H) -dione: A suspension of 5-ethyl-9-fluoro-4,5-dihydro-5, 10-dihydroxy-1H-oxepino [3 ', 4': 6, 7] indolizine [1,2-b] quinoline-3, 15 (4H, 13H) -dione (200 mg, obtained according to preparation 20) in (5 ml) of acetic acid, treated with 1,3,5-tribenylhexahydrotriazine (285 mg). The reaction mixture is stirred at 70 ° C for 30 minutes, then evaporated in vacuo. The residue is taken up in ethanol, filtered and washed with ether. A solid is obtained, m.p. > 250 ° C.

RMN-1 !! (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.05 (d, ÍH); 3.48 (d, ÍH); 3.95 (s, 2H); 4.45 (s, .2H); 5.20 (s, 4H); 5.45 (dd, 2H); 6.05 (s, ÍH); 7.40 (s, 7H); 7.90 (d, ÍH); 8.45 (s, 1H). IR (KBr): 1248; 1451; 15001; 1598; 1657; 1727 Pharmacological study of the products of the invention Test on DNA relaxation activity induced by topoisomerase 1.

All reactions are carried out in a reaction buffer of 20 μl consisting of 50 mM Tris-HCl (pH 7.5), 50 mM KCl, 0.5 mM dithiothreitol, 10 mM magnesium chloride, 0.1 mM ethylenediaminetetraacetic acid (EDTA) ), 30 μg / ml of bovine serum albumin and 300 ng of supercoiled pUC19 (Pharmacia Biotech, Orsay, France) with or without compounds to be tested at the defined concentrations. All the compounds to be tested are initially dissolved in dimethylsulfoxide (DMSO) or in water for water-soluble compounds, the other dilutions having been made in distilled water. The final DMSO concentration does not exceed 1% (v / v). The reaction is initiated by the addition of purified calf thymus DNA topoisomerase 1 (Life technologies / Gibco-BRL, Paisley, UK) such that the reaction is completed in 15 minutes at 37 ° C. The reactions are stopped by adding 3 μl of a mixture containing 1% sodium dodecyl sulfate, 20 mM EDTA and 500 μg / ml proteinase K (Boehringer Mannheim, Meylan, France). After an additional incubation period of 30 minutes at 37 ° C, 2 μl of a charge buffer containing 10 mM Na2HP04, 0.3% bromophenol blue and 16% Ficoll are added to the samples that are subjected to electrophoresis in 1.2% agarose gels at 1 V / cm for 20 hours, in a buffer containing 36 mM of Tris-HCl pH 7.8, 30 M of NaH2P04, 1 M of EDTA and 2 μg / ml of chloroquine. The gels are colored with 2 μg / ml of ethidium bromide, photographed under UV light at 312 nm with a camera with charge-coupled device (ccd) and the fluorescence intensity is measured with the help of a bioProfil image analyzer (Vilber Lourmat, Lyon, France) with a view to determining the percentage of relaxed DNA. In each experiment, the supercoiled plasmid DNA is incubated alone or with topoisomerase 1. The reaction is completed within 15 minutes. For each compound to be tested or control (the vehicle is called a control alone), the supercoiled plasmid DNA is incubated in the presence of the maximum concentration chosen for the experiment of the compound to be tested or the control, without enzyme or in the presence of the compound to be tested. , at concentrations ranging from 1 μM to 200 μM or from the control and in the presence of enzymes. As indicated in Table I, Examples 3 to 6 inhibit the relaxation activity favored by topoisomerase 1, in a concentration dependent manner.

TABLE I Micromolar concentration 10 50 100 200 Examples tmptothecin 88.7 62.4 52.9 46.9 3 79.7 46.9 33.5 23.2 4 86.2 32.7 35.1 32.1 5 56.2 30.4 28.0 24.2 6 55.6 39.9 38.9 30.0 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (16)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A camptothecin analogue for which the hydroxylactone of camptothecin is a β-hydroxylactone or the corresponding β-hydroxy acid resulting from the opening of this lactone, characterized in that said analog includes an optionally substituted cyclooxazine, grafted at positions 10 and 11 on cycle A.

2. An analogue of camptothecin, characterized in that the hydroxylactone of camptothecin is replaced by a β-hydroxylactone protected by an easily cleavable group or the corresponding β-hydroxy acid resulting from the opening of this lactone.

3. A compound, characterized in that the compound is of the formula (I) or the formula (II) under the racemic form, of enantiomer or all combinations of these forms, in which: Ri represents a lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, (lower alkoxy) (lower alkyl) or (lower alkylthio) (lower alkyl ); R2, R3 and R4 independently represent hydrogen halo, lower haloalkyl, lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, (CH2) mNR6R , (CH2) m0R6, (CH2) mSR6, (CH2) mC02R6, (CH2) mNR6C (0) R8, (CH2) mC (0) R8, (CH2) m0C (0) R8, O (CH2) mNR6R7, OC (0) NR6R7, OC (O) (CH2) mC02R6, or (CH2) n [N * X], OC (0) [N «X], (CH2) mOC (0) [N * X] (in the which [N «X], in this invention, represents a 4- to 7-membered heterocyclic group with the nitrogen atom N which is a member of the heterocyclic group, and X represents the remaining members, necessary to complete the heterocyclic group, selected from the group consisting of O, S, CH2, CH, N, NR9 and CH1), aryl or substituted arylalkyl (i.e. 10 one to four times on the aryl or heterocycle group) or unsubstituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, hydroxyalkyl Lower, lower alkoxy or lower alkoxy (lower alkyl), or R2 and R3 or R3 and R4 together form a 3- or 4-membered chain, in which the chain elements are selected from the group consisting of 20 consists of CH, CH2, O, S, N or NR9; R- represents hydrogen, halo, lower haloalkyl, lower alkyl, lower alkoxy, (lower alkoxy) (lower alkyl), (lower alkylthio) (lower alkyl), 25 cycloalkyl, cycloalkylalkyl, cyano, cyanoalkyl, (lower alkyl) (lower sulfonylalkyl), lower hydroxyalkyl, nitro, (CH2) mC (O) R8, (CH2) mNR6C (0) R8, (CH2) mNR6R7, CH2) mN (CH3) (CH2) nNR6R7, (CH2) m0C (O) R8, (CH2) mOC (0) NR6R7, CH2) mS (0) qRn, (CH2) mP (0) R12R? 3, (CH2) 2P ( S) R12Ri3, or (CH2) n [N «X], OC (0) [N * X], (CH2) mOC (O) [N« X], aryl or substituted arylalkyl, 10 (ie, one to four times on the aryl or heteroaryl group) or unsubstituted, in which the substituent is a lower alkyl, halo, nitro, amino, (lower alkyl) (amino), lower haloalkyl, Lower hydroxyalkyl, lower alkoxy or lower alkoxy (lower alkyl); Re and 7 independently represent hydrogen, a lower alkyl, lower hydroxyalkyl, (lower alkyl) (aminoalkyl Lower), lower aminoalkyl, cycloalkyl, lower cycloalkylalkyl, lower alkenyl, (lower alkoxy) (lower alkyl), lower haloalkyl, or substituted aryl or arylalkyl (is To say, one to four times over the aryl group) or unsubstituted, in which the substituent is a lower alkyl, halo, nitro, amino, (lower alkyl) (amino), lower haloalkyl, lower hydroxyalkyl, lower alkoxy or ( lower alkoxy) (lower alkyl); Re represents hydrogen, a lower alkyl, lower hydroxyalkyl, amino, (lower alkyl) (amino), (lower alkyl) 10 (lower aminoalkyl), lower aminoalkyl, cycloalkyl, cycloalkylalkyl lower, lower alkenyl, lower alkoxy, (lower alkoxy) (lower alkyl), lower haloalkyl, or aryl or Substituted arylalkyl (ie, one to four times on the aryl group, or unsubstituted, in which the substituent is a lower alkyl, halo, nitro, amino, (lower alkyl) (amino), haloalkyl Lower, lower hydroxyalkyl, lower alkoxy or (lower alkoxy) (lower alkyl); Rs represents hydrogen, a lower alkyl, lower haloalkyl, aryl or aryl Substituted with one or more groups selected from the group consisting of lower alkyl, halo, nitro, amino, (lower alkyl) (amino), lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or (lower alkoxy) (lower alkyl); R 10 represents hydrogen, a lower alkyl, lower haloalkyl, lower alkoxy, aryl, or substituted aryl (ie having one to four substitutions on the aryl group) by one or more groups selected from the lower alkyl, lower haloalkyl radical, lower hydroxyalkyl, or (lower alkoxy) (lower alkyl); R11 represents a lower alkyl, aryl, (CH2) mORi4, (CH2) mSRi4, (CH2) 2NR14R15 or (CH2) ra [N «X]; R 12 and R 3 represent, independently, a lower alkyl, aryl, lower alkoxy, aryloxy or amino; R14 and Ris independently represent hydrogen, a lower alkyl or aryl; Ri6 represents hydrogen or OR2 ?; R? 7 represents 0R6 or NR6R7; Rie and 19 independently represent hydrogen, halo, lower alkyl, lower alkoxy or hydroxyl; R20 represents hydrogen or halo; R2? represents hydrogen, a lower alkyl, CHO or C (0) (CH2) mCH3; R p represents hydrogen or an easily cleavable group selected from among the groups corresponding to the formula -C (O) -A-NR 22 R 23, in which A represents a linear or branched alkylene radical and optionally substituted with a radical chosen from the radicals free hydroxyl, esterified or salified, halogen, free, esterified or salified carboxyl, amino, mono- or dialkylamino, while R22 and R23 independently represent hydrogen, lower alkyl, hydroxy-lower alkyl, (lower alkyl) (lower aminoalkyl), lower aminoalkyl, cycloalkyl, cycloalkylalkyl lower, lower alkenyl, (lower alkoxy) (lower alkyl), lower haloalkyl, or aryl or arylalkyl substituted (i.e., one to four times over the aryl group) or unsubstituted, in which the substituent is a lower alkyl radical, halo, nitro, amino, (lower alkyl) (amino), lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or (lower alkoxy) (lower alkyl); m is an integer between 0 and 6; n is 1 or 2; and q represents a number from 0 to 2; and [N «X] represents a heterocyclic group of 4 to 7 members, X representing the chain necessary to complete said heterocyclic group and selected from the group consisting of O, S, CH2, CH, N, NR9 and CORio," it being understood that when Rp is a hydrogen atom, R3 and R4 together form a 3 or 4 member chain; or a pharmaceutically acceptable salt of the latter.

4. A compound according to claim 3, characterized in that Ri represents the ethyl group; or a pharmaceutically acceptable salt of the latter.

5. A compound according to claim 3, characterized in that R5 represents hydrogen, a lower alkyl or (CH2) mNR6R or (CH2) n [N «X] unsubstituted or substituted with a lower alkyl group; or a pharmaceutically acceptable salt of the latter.

6. A compound according to claim 3, characterized in that R3 and R4 form an optionally substituted cyclooxazine; or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 3, characterized in that Rp is an easily cleavable group; or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 7, characterized in that Rp represents the group C (O) - (Ai) -N-R22-R23 in which A12 represents CH2m or a branched lower alkylene radical, and m represents an integer between 0 and 6; or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 6, characterized in that this compound is chosen from among the compounds that respond to the following formulas: - 1, 8-diethyl-β, 9-dihydro-8-hydroxy-2H, 10H, 12H- [ 1, 3] oxazino [5,6-_f] oxepino [3 ', 4,': 6,7] indolizino [1,2-b] quinoline-10, 13 (15H) -dione-8-ethyl-8, 9-dihydro-8-hydroxy-2H, 10H, 12H- [1, 3] oxazino [5, 6-f] oxepino [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10 , 13 (15H) -dione-8-ethyl-8,9-dihydro-8-hydroxy-1-benzyl-2H, 10H, 12H- [1,3] oxazino [5, 6-f] oxepino [3 ', 4 ': 6, 7] indolizine [1,2-b] quinoline-10, 13 (15H) -dione-8-ethyl-8,9-dihydro-4-fluoro-8-hydroxy-1-benzyl-2H, 10H, 12H- [1, 3] oxazino [5, 6-f] oxepino [3 ', 4': 6, 1] indolizine [1,2-b] quinoline-10, 13 (15H) -dione or a salt pharmaceutically acceptable of the latter.

10. A compound according to claim 7, characterized in that the compound is chosen from the compounds that respond to the following formulas: 5-ethyl-9,10-difluoro-4,5-dihydro-5- (2-amino-1-1) oxoethoxy) -lH-oxepino [3 ', 4': 6, 7] indolizino [1,2-b] quinoline-3, 15 (4H, 13H) -dione; 5-ethyl-9, 10-difluoro-4,5-dihydro-5- (2-amino-1-oxopropoxy) -IH-oxepino [3 ', 4': 6,7] indolizine [1,2-b] quinoline-3, 15 (4H, 13H) -dione; or a pharmaceutically acceptable salt thereof.

11. As a medicament, a compound according to any of the preceding claims, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition, characterized in that it contains, as an active principle, at least one of the compounds according to any of claims 1 to 10.

13. The use of a compound according to any of claims 1 to 10, for the preparation of antitumor medicaments.

14. The process for preparing the compounds of the formula corresponding to the products of the formula I in which R3 and R4 form a cyclooxazine according to any of claims 1, 6 or 9, characterized in that: - it is treated with a primary amine, under the Mannich conditions, a ß-hydroxylactonic compound of the general formula D wherein R3 is a hydroxyl radical, R is hydrogen, and Ri, R2, Ris, R19 and R20 have the meaning indicated above, to obtain a β-hydrsylactonic compound of the general formula in which Ri, R, R5, Rg, Ris, 19 and R20 have the meaning indicated above.

15. The process for preparing the compounds of the formula Ib corresponding to the products of the formula I in which Rp is not a hydrogen atom, according to any of claims 2 to 10, characterized the process because: - acylated the compound of the general formula D wave preferably with a derivative of the radical (CO) -A-N-R22R23 as defined in claim 3, to give the β-hydroxylactonic compound of the general formula I with Rp other than hydrogen:

16. The process for preparing the compounds of formula II according to any of claims 1 to 10, characterized in that: - the lactone of general formula I is operated in basic medium, to give after neutralization the compound of the formula II wherein Ri, R2, R5, Rg, Ri7, Ris, R19 and R20 have the meaning indicated above; R? 6 represents OR21 in which R2? represents hydrogen or a lower alkyl group; and Ri7 represents OR6 or NHR6, and R6 represents hydrogen, a lower alkyl, cycloalkyl, (cycloalkyl) (lower alkyl), lower alkenyl, (lower alkoxy) (lower alkyl), or aryl (aryl) (lower alkyl) group.