Title of Invention	"CAMPTOTHECIN DERIVATIVES AND ITS COMPOSITION THEREOF"
Abstract	Camptothecin is a natural compound first isolated from the leaves and the bark of the Chinese plant known as camptotheca acuminata (see Wall et al., J. Amer. Chem. Soc. 88:3888 (1966)). Camptothecin is a pentacyclic compound consisting of a quinoline indolizine [1,2-b] fragment merged with a 6-chain α-hydroxylactone. The carbon atom in position 20, which carries the α-hydroxy group, is asymmetrical and gives the molecule a rotatory capability. The natural form of camptothecin has the absolute "S" configuration at carbon atom 20 and has the following formula:

Title of Invention

"CAMPTOTHECIN DERIVATIVES AND ITS COMPOSITION THEREOF"

Abstract

Camptothecin is a natural compound first isolated from the leaves and the bark of the Chinese plant known as camptotheca acuminata (see Wall et al., J. Amer. Chem. Soc. 88:3888 (1966)). Camptothecin is a pentacyclic compound consisting of a quinoline indolizine [1,2-b] fragment merged with a 6-chain α-hydroxylactone. The carbon atom in position 20, which carries the α-hydroxy group, is asymmetrical and gives the molecule a rotatory capability. The natural form of camptothecin has the absolute "S" configuration at carbon atom 20 and has the following formula:

Full Text	New analogues of camptothecin, their medical application and the pharmaceutical substances that contain them Camptothecin is a natural compound first isolated from the leaves and the bark of the Chinese plant known as camptotheca acuminata (see Wall et al., J. Amer. Chem. Soc. 88:3888 (1966)). Camptothecin is a pentacyclic compound consisting of a quinoline indolizine [1,2-b] fragment merged with a 6-chain α-hydroxylactone. The carbon atom in position 20, which carries the a-hydroxy group, is asymmetrical and gives the molecule a rotatory capability. The natural form of camptothecin has the absolute "S" configuration at carbon atom 20 and has the following formula: (Formula Removed) Camptothecin has an inhibiting effect on the growth of many strains of cancer cells including those in human tumours of the colon, the lung and the breast (Suffness, M. et al.: The Alkaloids Chemistry and Pharmacology, Bross, A., ed., Vol. 25, p. 73 (Academic Press, 1985)). It is suggested that the growth-inhibiting action of camptothecin is related to its inhibition of topoisomerase I in DNA. It has been shown that the a-hydroxylactone is an absolute requirement for the activity of camptothecin both in vivo and in vitro (Camptothecins: New Anticancer Agents, Putmesil, M., and his colleagues, ed., p. 27 (CRC Press, 1995); Wall, M. and his colleagues, Cancer Res. 55:753 (1995); Hertzberg et al., J. Med. Chem. 32:715 (1982) and Crow et al., J. Med. Chem. 35:4160 (1992)). The present invention concerns a new class of analogues of camptothecin, wherein the natural α-hydroxylactone in camptothecin is replaced by a ß-hydroxylactone. The compounds according to the present invention show a powerful biological action that is unexpected in view of prior art. The subject of the invention is therefore new analogues of camptothecin which differ from any known derivatives of camptothecin in that they contain a ß-hydroxylactone (or its open hydroxycarboxylic form) in the place of an a-hydroxylactone (or its open hydroxycarboxylic form); or a pharmaceutically acceptable salt of the latter. The term derivative of camptothecin is taken to mean a compound having the same structure as camptothecin (in other words a quinoline indolizine [1,2-b] fragment which is merged with a 6-chain α-hydroxylactone), with or without other chemical substitutions on the structure. Different derivatives of camptothecin are well known to specialists, as described below. The term ß-hydroxylactone is taken to mean a lactone that comprises an additional carbon atom between the carbon of the carboxyl group and the a-carbon carrying the hydroxy group in the a-hydroxylactone. An analogue of camptothecin according to the invention may therefore comprise substitutions on the quinoline indolizine [1,2-5] fragment (for example to improve the solubility of the compound) or on the open or closed ß-hydroxylactone (for example in order to improve the stability of the compound). Typical substitutions on the closed ß-hydroxylactone comprise an alkyl substitution (for example ethyl) on the ¸ß-carbon. Typical substitutions on the open ß-hydroxylactone comprise alkyl substitutions on the ß-carbon, substitutions (for example, amidation) on the resulting carboxylic acid, and substitutions (for example, esterification) or eliminations of the resulting hydroxyl group. The subject of the invention is more particularly the compounds of the formula (I) and (II) (Formula Removed) in racemic or enantiomeric form or any combinations of these forms, wherein R1 represents an inferior alkyl, an inferior alkenyl, an inferior alkynyl, an inferior haloalkyl, an inferior alkoxy inferior alkyl or an inferior alkylthio inferior alkyl; R.2, R3 and R4 independently represent H, halo, inferior haloalkyl, inferior alkyl, inferior alkenyl, cyano, inferior cyanoalkyl, nitro, inferior nitroalkyl, amido, inferior amidoalkyl, hydrazine inferior hydrazinoalkyl, azido, inferior azidoalkyl, (CH2)mNR6R7, (CH2)mOR6, (CH2)mSR6, (CH2)mC02R6, (CH2)mNR6C(0)R8, (CH2)mC(0)R8, (CH2)m0C(0)R8, 0(CH2)mNR6R7, OC(0)NR6R7, OC(0)(CH2)mC02R6, or (CH2)n[N«X]f OC(0)[N«X], (CH2)mOC(0)[N=X] (wherein [N=X], in this invention, represents a heterocyclic group of 4 to 7 links 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 COR10), aryl or substituted inferior arylalkyl (that is, substituted between I and 4 times oft the aryl group or the heterocycle) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro, amino, inferior aminoalkyl, inferior haloalkyl, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy inferior alkyl or R2 and R3 together form a chain with 3 or 4 links, wherein the elements of the chain are selected from the group consisting of CH, CH2, O, S, N or NR9; R5 represents H, halo, inferier haloalkyl, inferior alkyl, inferior alkoxy, inferior alkoxy inferior alkyl, inferior alkylthio inferior alkyl, cycloalkyl, cycloalkyl inferior alkyl, cyano, cyanoalkyl, inferior alkyl inferior sulphonylalkyl, inferior hydroxyalkyl, nitro, (CH2)mC(0)Rg, (CH2)mNR6C(0)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOC(0)R8, (Cg2)mOC(0)NR6R7, (CH2)mS(0)qRn, (CH2)mP(0)R12R13, (CH2)2P(S)Ri2R13, or (CH2)n[N~X], OC(0)[N«X], (CH2)mOC\|0)[N=X], aryl or substituted inferior arylalkyl (that is, one to four times on the aryl or hetero aryl group) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro, amino, inferior alkyl amino, haloinferior alkyl, inferior hydroxyalkyl, inferior alkoxy or inferior alkoxy inferior alkyl; R6 and R7 independently represent H, an inferior alkyl, inferior hydroxyalkyl, inferior alkyl inferior aminoalkyl, inferior aminoalkyl, cycloalkyl, cycloalkyl inferior alkyl, inferior alkenyl, inferior alkoxy inferior alkyl, inferior haloalkyl, or aryl or substituted inferior arylalkyl (that is, one to four times on the aryl group) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro, amino, inferior alkylamino, inferior haloalkyl, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy inferior alkyl; R8 represents H, an inferior alkyl, inferior hydroxyalkyl, amino, inferior alkylamino, inferior alkyl inferior aminoalkyl, inferior aminoalkyl, cycloalkyl, cycloalkyl inferior alkyl , inferior alkenyl, inferior alkoxy, inferior alkoxy inferior alkyl, inferior haloalkyl, or aryl or substituted inferior arylalkyl (that is, one to four times on the aryl group) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro, amino, inferior alkylamino, inferior haloalkyl, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy inferior alkyl; R9 represents H, an inferior alkyl, inferior haloalkyl, aryl, or aryl substituted by one or more groups chosen from the inferior alkyl radical, halo, nitro, amino, inferior alkylamino, inferior haloalkyl, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy inferior alkyl; R10 represents H, art inferior alkyl, inferior haloalkyl, inferior alkoxy, aryl, or substituted aryl (that is, with one to four substituting agents on the aryl group) by one or more gsoups chosen from the inferior alkyl radical, inferior haloalkyl, inferior hydroxyalkyl, or inferior alkoxy inferior alkyl; Rll represents an inferior alkyl, aryl, (CH2)mOR14, (CH2)mSR14, (CH2)2NR14R15 or (CH2[N=X]; Rl2 and R13 independently represent artinferior alkyl, aryl, inferior alkoxy, aryloxy or amino; Rl4 and R15 independently represent H, an inferior alkyl or aryl; Rl 6 represents H or OR21; Rl7 represents OR6 or NR6R7; Rl8 and R19 independently represent H, halo, inferior alkyl, inferior alkoxy or hydroxy; R20 represents H or halo; R2l represents H, an inferior alkyl, CHO or C(0)(CH2)mCH3; m is a whole number between 0 and 6; n is 1 or 2; and q represents a whole number from 0 to 2; and [N=X] represents a heterocyclic group with 4 to 7 links, X representing the link necessary to complete the said heterocyclic group and selected from the group consisting of O, S, CH2, CM, N, NR9 and COR10; or a pharmaceutical^ acceptable salt of the latter. Theinvention particularly relates to compounds of formulae I and II as defined above wherein R] represents an inferior alkyl, inferior alkenyl, inferior haloalkyl, inferior alkoxy inferior alkyl, or inferior alkylthio inferior alkyl; R5 represents H, halo, inferior haloalkyl, inferior alkyl, inferior alkoxy, inferior alkoxy inferior alkyl, inferior alkylthio inferior alkyl, cycloalkyl, cycloalkyl inferior alkyl, oyano, cyanoalkyl, inferior hydroxyalkyl, nitro, (CH2)mC(0)R8, (CH2)mNR6C(0)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOC(0)R8, (CH2)mOC(0)NR6R7, or (CH2)„[N«X], OC(0)[N=X], (CH2)mOC[N«X], aryl or inferior arylalkyl, substituted or not; R12 and R13 independently represent an inferior alkyl; R16 represents OR21; and Rl8. Rl9 and R20 represent H. More preferably, R2 represents H or halo, and preferably H, chloro or fluoro; and R3 represents H, an inferior alkyl, halo, or OR6 wherein R6 represents H, an inferior alkyl or an inferior arylalkyl, and preferably H, fluoro, chloro, methyl or methoxy. More preferably again, R2 and R3 together form acaethylenedioxy or an ethylenedioxy. Theinvention more particularly relates to compounds of formulae I and II wherein R2 represents an atom of hydrogen or halogen, R3 represents a halogen atom, an inferior alkyl or an inferior alkoxy, R4 and R16 represent atoms of hydrogen and R18, R19 and R20 represent hydrogen atoms; or a pharmaceutically acceptable salt of the latter. Preferably, an aminoalkyl radical will be chosen for R5. More particularly, the subject of the invention is the products described below in the examples, satisfying the following formulae: - 5-ethyl-9,10-difluoro-4,5~dihydro-5-hydroxy-12-(l,2,5,6-tetrahydropyridinomethyl-lH- oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione hydrochloride - 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperidinomethyl)-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-hydroxy-12-pyrrolidinomethyl-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperazinomethyl)-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-hydroxy-12-piperidinomethyl-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-dimethylaminomethyl-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-morpholinomethyl-lH-oxepino[3',4' :6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-dimethyl-12-(4-methylpiperazinomethyl)-lH-oxepino[3' ,4' :6,7] indolizino[ 1,2-b] quinoline-3,15(4H,13H)-dione - 12-benzylmethylaminomethyl-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-lH-oxepino[3' ,4' :6,7] indolizinof 1,2-b] quinoline-3,15(4H, 13H)-dione - 12-(4-benzylpiperazinomethyl) -9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl- 1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-piperidinomethyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 12-(4-benzylpiperazinomethyl)-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-lH-oxepino[3' ,4' :6,7] indolizino[ 1,2-b] quinoline-3 J 5(4H, 13H)-dione - 12-(4-benzylpiperazinomethyl)-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-lH- oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-dimethylaminomethyl-1H- oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione 5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-lH- oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 5-ethyl-9-fluoro-4,5-dihydro-5-hydr«xy-10-methyl-12-pyrrolidinomethyl-lH- oxepinof [3,4,6,7,]indolizino[1,2-b]quinoliue-3,15-(4H,13H)-dione 5-ethyl-9-fluoro~4,5-dihydro-5-hydroxy-10-methyl-12-(l,2,5,6-tetrahydropyridinomethyl)-lH-oxepino\|3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 12-diisobutylaminomethyl-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-lH- oxepino[3' ,4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-l0-methoxy-12-(4-methylpiperazinomethyl)-lH- oxepino[3',4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H- oxepino[3',4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy 10-methoxy-12-dimethylaminomethyl-lH- oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-lH- oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione hydrochloride - 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-( 1,2,5,6-tetrahydropiperidinomethyl)- 1H- oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperidinomethyl)-lH-oxepino[3',4' :6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione - 5-ethyl-4,5-dihydro-5-hydroxy-10-metfaoxy-12-(4-methylpiperazinomethyl)-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy- 12-pyrrolidinomethyl-1 H-oxepino[3',4' :6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione - 12-(4-benzylpiperazinomethyl)-5-ethy4-4,5-dihydro-5-hydroxy-10-methoxy-lH- oxepino[3',4' :6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-l0-methyl-12-(4-methylpiperidinomethyl)-lH- oxepino[3',4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione - 10-benzyloxy-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7] indolizinof 1,2-b] quinoline-3,15(4H, 13H)-dione - 5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy~lH-oxepino[3,4':6,7] indolizino[l,2-b] quinoline-3,15(4H, 13H)-dione or a pharmaceutically acceptable salt of one of these. The invention more particularly relates to compounds of formula II as defined above, wherein R1 represents the ethyl group; R2 and R3 independently represent H, an inferior alkyl, halo, inferior haloalkyl or (CH2)mOR6, or R2 and R3 together form a methylenedioxy or an ethylenedioxy; R4 and R5 independently represent H, an inferior alkyl, (CH2)mNR6R7, or (CH2)n[N=X] not substituted or substituted by an inferior alkyl; R.20 represents H and R17 represents OR6, where R6 represents H or an inferior alkyl, or NR6R7 wherein R6 and R7 independently represent H, an inferior alkyl, aryl or inferior arylalkyl. Preferably, R4 represents H or (CH2)mNR6R7, wherein R6 and R7 independently represent H or an inferior alkyl; R5 represents H, an inferior alkyl or (CH2)n[N=X] not substituted or substituted by an inferior alkyl; R17 represents OR6, where R6 represents H or an inferior alkyl; or a fharmaceutically acceptable salt of the latter. Typical examples of [N=X] substituted or not substituted are the radicals piperidyl, morpholinyl, piperazinyl, imidazolyl and 4-methyl piperazinyl. More preferably, R2 represents H or halo and preferably H, chloro or fluoro; R3 represents H, an inferior alkyl, halo or OR6 where R6 represents H, an inferior alkyl or an inferior alkyl aryl and preferably H, fluoro, chloro, methyl or methoxy. More preferably again, R2 and R3 together form a dioxymethylene or a dioxyethylene. More particularly, the invention relates to the products described below in the examples that satisfy the following formulae: - 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperidinomethyl)-lH-oxepino[3',4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione; - 5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-lH-oxepino[3',4' :6,7] indolizinof 1,2-b] quinoline-3,15(4H, 13H)-dione; - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-l€-methyl-12-(4-methylpiperidinomethyl)-1H- oxepino[3' ,4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione; - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-pyrrolidinomethyl-lH-oxepino[3' ,4': 6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione; - 9-chloro-5-ethy1-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3',4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione; - 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperidinomethyl-lH-oxepino[3',4' :6,7] indolizino[ 1,2-b] quinoline-3,15(4H,13H)-dione; - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-1H- oxepino [3',4':6,7] indolizino[1,2-b] quinoline-3,15(4H,13H)-dione; or a pharmaceutically acceptable salt of one of these. As used here with reference to the alkyl, alkeylthio and alkoxy groups, the term "inferior" designates saturated, linear or ramified aliphatic hydrocarbon groups comprising from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methylthio, ethylthio, methoxy and ethoxy. In referring to the alkenyl or alkynyl groups, the term "inferior" designates groups comprising 2 to 6 carbon atoms and one or more double or triple bonds, for example the following groups : vinyl, allyl, isopropenyl, pentenyl, hexanyl, ethynyl propenyl. propynyl and butynyl. The term "cycloalkyl" designates a cycle of 3 to 7 carbon atoms, for example the following groups : cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term aryl designates a mono-, di- or tricyclic hydrocarbon compound with at least one aromatic ring, each ring containing a maximum of 7 links, for example phenyl, naphthyl, anthracyl, biphenyl or indenyl. The term halo signifies chloro, bromo, iodo or fluoro. The radicals corresponding to the expressions inferior haloalkyl, inferior cyanoalkyl, inferior nitroalkyl, inferior amidoalkyl, inferior hydrazinoalkyl, inferior azidoalkyl, inferior arylalkyl, inferior hydroxyalkyl, inferior alkoxy inferior alkyl, inferior alkylthio inferior alkyl, and inferior alkyl inferior sulphonylalkyl are substituted respectively by between one and three halo, cyano, nitro, amido, hydrazino, azido, aryl, hydroxy, inferior alkoxy, inferior alkylthio or inferior sulphonyl groups. The amino inferior alkyl radical may contain one or two inferior alkyl groups, and represent for example NHCH3, NHCH2CH3, N(CH3)2, ou N(CH3)(CH2CH3). Examples of [N=X] include the piperidinyl, morpholinyl, piperizinyl and imidazolyl groups. As is observed for camptothecin, the carbon atom carrying the hydroxyl function in ß-hydroxylactone or the P-hydroxycarboxylate group in compounds according to the present invention is asymmetrical. Consequently the compounds according to the present invention have two possible enantiomeric forms, that is, the "R" and "S" configurations. The present invention encompasses the two enantiomeric forms and all combinations of these forms, including the racemic "RS" mixtures. With a view to simplicity, when no specific configuration is shown in the structural formulae, it should be understood that the two enantiomeric forms and their mixtures are represented. Other objects of the invention are the processes for preparing compounds of general formula I and II, either from camptothecin or substituted camptothecins, or by total chemical synthesis. The invention therefore concerns a process for preparing compounds of formulae I and II according to the invention, and in particular the products whose formulae are shown above, starting from camptothecin or from substituted camptothecins, characterised in that - the α-hydroxylactone in camptothecin of general formula (Formula Removed) wherein R1, R2, R3, R4, R5 and R20 have the meaning given above, is reduced, in order to obtain the a-hydroxylactol of general formula A (Formula Removed) wherein R1, R2, R3, R4, R5 and R20 have the meaning indicated above, - in the compound A thus formed, the carbon-carbon bond linking the neighbouring carbinols is cut by treatment with a suitable oxidising agent so as to give a compound of general formula B wherein R\, R2, R3, R4, R5 and R20 have the meanings indicated above. - this is then treated by a functionalised alkylating agent and the formyl function of the compound of general formula B is cut to give a $-hydroxyester of general formula C (Formula Removed) wherein R1, R2, R3, R4, R5, R18 Rl9 and R20 have the meanings indicated above and R17 represents OR6 and R6 represents an inferior alkyl, cycloalkyl, cycloalkyl inferior alkyl, inferior alkenyl, inferior alkoxy inferior alkyl, or aryl or inferior arylalkyl; - the said compound of general formula C is cycled to give the ß-hydroxylactonic compound of general formula D (Formula Removed) wherein R1, R2, R3, R4, R5, R18, Rl9 and R20 have the meanings indicated above, - the lactone of general(Formula Removed) formula D is openedjto gave the compound of formula E wherein R1, R2, R3, R4, R5 R17, Rl8, R19 and R20 have the meaning indicated above; R16 represents OR21 wherein R21 represents H or an inferior alkyl; and R17 represents OR6 or NHR6 and R6 represents an inferior alkyl, cycloalkyl, cycloalkyl inferior alkyl, inferior alkenyl, inferior alkoxy inferior alkyl, or aryl or inferior arylalkyl. Certain compounds of formula E can also be obtained by hydrolysing the ester function in compounds of the corresponding formula- D. The compounds of general formula E wherein R16 and/or R17 independently represent the hydroxy radical, can be esterified or amidified in conventional conditions familiar to the specialist in order to produce the corresponding esters or amides of formula E. In the above process, the groups R1, R2, R3 and R4 can be protected if necessary using the conventional protection methods (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)). In this process, reduction is effected using a reducing agent in an appropriate solvent, for example sodium borohydride in methanol. The stage corresponding to the formation of compound B from compound A is effected in oxidising conditions, for example using lead tetraacetate, periodic acid or sodium metaperiodate in an appropriate solvent, for example acetic acid. Treatment using a functionalised alkylating agent can be effected using a metal derivative, for example of lithium or zinc, a carboxylic ester in an anhydrous aprotic solvent such as tetrahydrofurane. The lactonisation stage whereby compound D is obtained from compound C usually takes place in acidic conditions environment and can be effected, for example, by treatment by trifluoroacetic acid or hydrogen chloride dissolved in an anhydrous solvent such as dichloromethane or dioxane. The lactonic cycle of compound D can be opened to produce compound E for example by hydrolysis in alkaline conditions, followed by neutralisation. Examples of substituted camptothecins, used as starting substances, can be found in American patents Nos. 4 473 692, 4 604 463,4 894 956, 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, patent applications PCT 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. Accordingly the invention also concerns a process for preparing compounds of formulae I and II, characterised in that - a compound of general formula M (Formula Removed) wherein R1, R18 and R19 have the meanings indicated above and R20 represents hydrogen or a halogen atom, is coupled with a 2-halo-3-quinoline-methanol of general formula N (Formula Removed) wherein R2, R3, R4, and R5 have the meanings indicated above and X represents a halogen atom, to give thecompound of formula O (Formula Removed) wherein R1, R2, R3, R4, R5, R18, R19. R20 aud X have the meanings indicated above; - then the compound of general formula O is cyclised to obtain the compound of general formula D as defined above. In the above process, the groups R, R2, R3,and R4 can be protected if necessary using the conventional methods of protection (Greene, T,M Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)). The compound O is formed from the compounds of general formulae M and N by a process known to the professional as Mitsunobu's reaction (see Mitsunobu, O. et al., Synthesis, p. 1 (1981)). This involves displacing the hydroxyl function of the compound N by a nucleophile such as the compound M, or a deprotonated derivative of the latter, by a treatment with a phosphine, for example triphenylphosphine, and an azodicarboxylate derivative, for example diethyl azodicarboxylate, in an aprotic solvent, for example tetrahydrofurane or N,N-dimethylformamide. The compound O is cyclised preferably in the presence of a catalyst containing palladium (for example palladium diacetate) in basic conditions (provided for example by an alkaline acetate possibly combined with a phase transfer agent, for example tetrabutylammonium bromide), in an aprotic solvent such as acetonitrile or N,N-dimethylformamide, at a temperature between 50 °C and 120 °C (R. Grigg et al., Tetrahedron 46, page 4003 (1990)). The compounds of general formula M are new. They can be prepared according to a process characterised in that - the carbonyl of a pyridine of general formula (Formula Removed) wherein R1 and R20 have the meanings indicated above and R22 represents a halogen atom or an inferior alkoxy, is protected by an acetal function, to give the compound of general formula F (Formula Removed) wherein R\, R20 and R22 have the meanings indicated above the groups Z and Z' independently represent an inferior alkyl or form together a saturated hydrocarbon chain of 2 to 4 carbon atoms; - a hydroxymethyl function is inl reduced in\|o the compound of general formula F in order to produce a compound of general formula G (Formula Removed) wherein R1, R20, R22 Z and Z' have the meanings indicated above, - then the alcohol function of the compound of general formula G is protected to give a compound of general formula H (Formula Removed) wherein R1, R20, R22, Z and Z' have the meanings indicated above and R23 represents a protective group for the alcohol function, - the acetal function in the compound of general formula H is removed to give the compound of general formula F (Formula Removed) wherein R1, R20, R22, and R23 have the meanings indicated above, - the compound of formula F is treated by a fanctionalised alkylating agent to give a fl- hydroxyester of general formula J (Formula Removed) wherein R\, R2Q, R22» and R23 have the meanings indicated above and R17, Ris and R19 are as defined in general formula II - the protective group R23 is removed from* the, compound of general formula J to give a compound of general formula K (Formula Removed) wherein Ri, R18, R19, R20 and R22 have thm meanings indicated above and R17 represents OR6 or NHR6 and R6 represents H, an inferior alkyl, cycloalkyl, cycloalkyl inferior alkyl, inferior alkenyl, inferior alkoxy inferior alkyl, or aryl or inferior arylalkyl, - the compound of general formula K is cyofsed into a compound of general formula L (Formula Removed) wherein R1, R18, R19, R20, and R22 have the meanings indicated above, and finally - the radical R22 in compound L is converted into a carbonyl, to produce the compound of general formula M (Formula Removed) wherein Ri, Ris, R19, and R20 have the meanings indicated above. The carbonyl function of a 4-acyl-2-halopyridine (obtained for example according to Lamattina, J.L. J. Heterocyclic Chem. 20, p. 553 (1983)) is protected preferably by an acetal function, preferably a cyclic acetal, in the conventional conditions familiar to the professional (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)). The intermediate product obtained in this way is treated by an alcoholate of sodium or potassium in an aprotic solvent (for example acetonitrile), or in the alcohol from which the alcoholate is derived, at a temperature between 0 °C and 100 °C to give the compound of general formula F. The said compound can be lithiated in position 3 by treatment by an aryl-lithium or alkyl-lithiura (for example mesityl-lithium) in an etherated solvent such as tetrahydrofurane at a temperature between -100 °C and 0 °C. To the intermediate lithiated product obtained in this way, a formylating electrophile such as N,N-dimethylformamide is added, and the aldehyde thus obtained, after hydrolysis, is treated by a reducing agent such as sodium borohydride to give the compound of general formula G. The alcohol function in the compound G is protected in a conventional manner familiar to the professional, to give a compound of general formula H. Examples of protective groups for the alcohol function comprise those that form ethers [that is, methyl, methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, benzyloxymethyl, t-butyl, and benzyl (whether substituted or not)], and esters (that is, formate, acetate and isobutyrate). For other examples of protective groups for primary hydroxyls, reference may be made to Greene, T., Protective Groups in Organic Synthesis, 10-86 (John Wiley & Sons, 1981). Removal of the protection from the compound of general formula H to give the compound of general formula F is carried out in selective conditions that maintain the integrity of the radical R23, for example by treatment in acidic conditions (for example using trifluoroacetic acid). The selective conditions for protecting and deprotecting functional groups are familiar to the professional (Greene, T., Protective Groups in Organic Synthesis, 10-86 (John Wiley & Sons, 1981)). Treatment of the compound I' by a functionalised alkylating agent to give a p-hydroxy ester of general formula J can be performed using a lithium enolate or a zinc derivative of a carboxylic ester in anhydrous aprotic solvent, for example tetrahydrofurane. The protection group R23 on the compound of general formula J is removed to give a compound of general formula K, in conditions of protection removal familiar to the professional. For example, when R23 is a benzyl group, an alcoholic solution of the compound of general formula J together with a catalyst containing palladium can be exposed to an atmosphere of hydrogen at a pressure of 0.5 to 10 bar. The compound of general formula K obtained in this way can be cyclised in acidic conditions (for example by treatment with trifluoroacetic acid, or hydrochloric gas dissolved in an anhydrous solvent such as diehloromethane or dioxane) to give a 7-chain (3-hydroxylactonic cycle such as the compound of general formula L. The compounds of general formula L can be converted into pysidones of general formula M, for example by treatment with hot hydrochloric acid, or witth trimethylsilyl iodide. The 2-halo-3-quinoline-methanols of general formula N can be obtained from acetanilides of general formula P (Formula Removed) wherein R2, R3 and R4 have the meanings indicated in the general formulae for compounds I and II. In the following processes, the groups R2, R3 and R4 can be protected if necessary by conventional methods of protection (Greene, T., Protective Groups in Organic Synthesis, 10-86 (John Wiley & Sons, 1981)). The compounds of formula N can therefore be obtained using the following process : the said anilines of formula P are N-acetylated by treatment with an acetylating agent, for example acetic anhydride. The acetanilides thus obtained are treated at a temperature between 50°C and 100°C, for preference 75°C by a reagent known to the professional as Vilsmeyer's reagent (obtained by the action of phosphoryl oxychloride on N,N-dimethyl formamide at a temperature between 0°C and 10°C) to give the corresponding 2-chloro-3-quinoline carbaldehyde (see for example 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 atom in position 2 of the 2-chloro-3-quinoline carbaldehydes can be substituted by iodine or bromine by heating the product in an inert solvent such as acetonitrile in the presence of a salt of iodine or bromine (for example sodium iodide or tetrabutylammonium bromide). A trace of acid such as concentrated hydrochloric acid may be necessary to catalyse this conversion. The 2-halo-3-quinoline carbaldehydes are easily reduced into the corresponding 2-halo-3-quinoline methanols of general formula N, in conventional conditions known to the professional such as treatment in an alcoholic solvent (for example, methanol) with sodium borohydride at a temperature between 0 °C and 40 °C. The compounds of formula N can also be obtained using the following process : the anilines of general formula P as defined above are acetylated by reaction with a nitrile (such as chloroacetonitrile or propionitrile) in the presence of boron trichloride and 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 (see Sugasawa, T, et al, J. Am. Chem. Soc. 100, p. 4842 (1978)). The intermediate product thus obtained is then treated by ethyl malonyl chloride in an aprotic solvent such as acetonitrile in the presence of a base such as triethylamine, then treated by an alkaline alcoholate, for example sodium methylate in methanol, to give an ethyl 2-hydroxy-3-quinoline carboxylate substituted in position 4. The latter is converted into ethyl 2-chloro-3-quinoline carboxylate by treating with phosphoryl oxychloride. When position 4 of the quinoline carries a chloromethyl group, a nucleophilic substitution can be made by treating with a secondary amine such as dimethylamine, N-methylpiperazine, morpholine or piperidine. The ethyl 2-chloro-3-quinoline carboxylate is then reduced by diisobutylaluminium hydride in an aprotic solvent such as dichloromethane to give the 2-chloro-3-quinoline methanol of general formula N. Analogues of the intermediate compounds (N) have been described in the literature and in particular in patent application PCT 95/05427. Another object of the invention, concerns, as new industrial products and particularly as new industrial products intended for preparing products of formula I or II, the products of formulae F and M as described above. Certain compounds of the invention can be prepared in the form of pharmaceutically acceptable salts using the usual methods. Acceptable salts comprise, as examples and in a non-limiting manner, addition salts of inorganic acids such as chlorhydrate, sulphate, phosphate, diphosphate, bromohydrate and nitrate, or of organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methane sulfonate, p-toluene sulfonate, pamoate, salicylate, oxalate and stearate. Salts formed from bases such as sodium or potassium hydroxide also fall within the field of application of the present invention, when they are useable. Other examples of pharmaceutically acceptable salts can be found in "Pharmaceutical Salts", J. Pharm. Sci. 66:1 (19771). The compounds of the present invention possess interesting pharmacological properties. Thus the compounds of the present invention have an inhibiting action on topoisomerase I and/or II and an anti-tumoral action. The state of the art suggests that the compounds of the invention have an anti-parasitic and/or anti-virus action. Accordingly the compounds of the present invention can be used for different therapeutic applications. Illustrations of the pharmacological qualities of the compounds of the invention are given hereunder in the experimental section. The compounds can inhibit topoisomerase, for example of type I and/or II in a patient, for example a mammal such as man, when a therapeutically effective quantity of a compound of formula (I) or formula (II) is administered to titiis patient. The compounds of the invention also possess an anti-tumoral activity. They can be used for treating tumours, for examples tumours expressing a topoisomerase, in a patient by administering a therapeutically effective amount of a compound of formula (I) or formula (II). Typical tumours or cancers comprise cancers of the oesophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, breast, cervix uteri, corpus endometrium, ovaries, prostate, testicles, bladder, kidneys, liver, pancreas, bones, conjunctive tissue of the skin, eyes, brain and the central nervous system, as well as cancer of the thyroid, leukaemia, Hodgkin's disease, lymphomas other than those of Hodgkin, multiple myelomas and others. They can also be utilised for treating parasitic infections by inhibiting haemoflagellates (for example in trypanosomiasis or infections caused by Leishmania) or by inhibiting Plasmodia (as for example in malaria), but also for the treatment of viral infections or diseases. These properties render the products of formulae (I) and (II) suitable for pharmaceutical use. Another subject of the present application is, as medicines, the products of formula (I) and (II) as defined above, together with the addition salts with the pharmaceutically acceptable inorganic or organic acids of the said products of formulae I and II, and the pharmaceutical compositions containing, as active principle, at least one of the medicines defined above. The invention thus concerns pharmaceutical compositions containing a compound of the invention or an addition salt of a pharmaceutically acceptable acid of such a compound, in association with a pharmaceutically acceptable medium depending on the method of administration chosen (for example oral, intravenous, intraperitoneal, intramuscular, transdermic or subcutaneous). The pharmaeeutical composition (for example, therapeutic) may be in the form of a solid, of a liquid, of liposomes or lipidic micellae. The pharmaceutical composition may be in solid form, as for example powders, pills, granules, tablets, liposomes, capsules or suppositories. The pill, tablet or capsule may 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 long enough period to allow this composition to pass undigested into the small intestine of the said patient. The compound can be administered locally, for example at the very location of the tumour. The compound may also be administered using the prolonged release process (for example a prolonged release composition or with an infusion pump). Suitable solid media may for example be calcium phosphate, magnesium stearate, magnesium carbonate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxy methyl cellulose, polyvinyl pyrrolidine and wax. The pharmaceutical compositions containing a compound of the invention can also be presented in liquid form, as for example solutions, emulsions, suspensions or as a prolonged release formulation. Suitable liquid media can for example be water, organic solvents such as glycerol or glycols such as polyethylene glycol, as well as mixtures of the above in different proportions in water. Another object of the invention is also the use of products of formula (I) or (II) as defined above, for the preparation of drugs intended to inhibit topoisomerase, and more particularly topoisomerase of type I or II, of drugs intended for treating tumours, of drugs intended for treating parasitic infections, as well as drugs intended for treating viral infections or diseases. The dose of a compound according to the present invention, appropriate for treating the diseases or infections mentioned above, vary according to the method of administration, the patient's age and body weight, and the patient's condition, and the definitive decision will be taken by the treating clinician or veterinarian. Such a quantity determined by the treating clinician or veterinarian is here denoted the "therapeutically effective quantity". Illustrations of the pharmacological properties of the compounds of the invention are given hereunder in the experimenlal section. The compounds can inhibit topoisomerase, for example of type I and/or II, in a patient, for example a mammal such as man, when a therapeutically effective quantity of a compound of formula (I) or formula (II) is administered to this patient. All the technical and scienlific terms used here, unless otherwise defined, 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, all the patents and all other references mentioned here are incorporated by reference. The following examples are given to illustrate the above procedures and should in no circumstances be regarded as limiting the scepe of the invention. EXPERIMENTAL SECTION Example 1 : tert-butyl ß-ethyl-ß-hydroxy--(8-hydroxymethyl-9-oxo (11H)- indolizino-[l,2-b] quinoline-7-yl)-propionate l.a. 4-ethyl-3,4-dihydroxy-lH-pyrano [3',4':6,7] indolizino [1,2-b] quinoline- 14(4H,12H)-one Sodium borohydride (14 g, 370 mmol) is added in portions to a suspension of (S)-(+)-camptothecin (14 g, 40 mmol), that may be obtained using different commercial sources such as Aldrich Chemical Co. (Milwaukee, WI), in methanol (750 ml) and the resulting mixture is heated slowly to 55 ° C so as to obtain a limpid solution that is then agitated for 16 hours at ambient temperature. The solvent is then evaporated under reduced pressure, the residue is recovered in water (250 ml), neutralized by the addition of acetic acid (21 ml) and left at rest for 2 hours at 4° C. The resulting suspension is filtered and washed successively with cold water, acetoae and diethyl ether, which, after drying under reduced pressure, permits obtaining the sought compound in the form of a white solid (m.p. 280 °C). l.b. 8-formyloxymethyl-7-propionylindolizino [1,2-b] quinoline-9 (11H)-one A solution of sodium metaperiodate (14 g, 65 mmol) is added dropwise in water (140 ml) to a suspension of 4-ethyl-3,4-dihydroxy-lH-pyrano [3',4':6,7] indolizino [1,2b] quinoline-14(4H,12H)-one (13,4 g; 38 mmol) in glacial acetic acid (720 ml) and the resulting solution is agitated for one hour at ambient temperature. The reaction mixture is then poured into a mixture of ice/water (650 ml)#and the resulting suspension is agitated for one half-hour then filtered and washed successively with water, isopropyl alcohol, and diethyl ether, which, after drying under reduced pressure, produces the sought compound (11.5 g) in the form of a pale yellow solid m.p. > 20 °C (d). I.e. tert-buty ß-ethyl-ß-hydroxy-(8-droxymethyl-9-oxo(llH)-indolizino- [1,2-b] quinoline-7-yl)-propionate A zinc suspension (6.5g, 100 mmol) agitated with a magnetic agitator in anhydrous diethylether (50 ml) under argon, is activated, by dropwise addition of chlorotrimethylsilane (0.75 ml, 5.7 mmel). The reaction medium is agitated again 15 minutes at ambient temperature and then heated to reflux. The heating bath is then removed and tert-buiy\ bromoacetate (15 ml, 100 mmol) is added dropwise at a rate assuring the maintenance of reflux. The external heating is replaced and pursued again for one hour. The ethereal solution resulting flom the Reformatsky reagent is left to cool to ambient temperature then transferred, by means of a formula, into a suspension of 8-formyloxymethyl-7-propionylindolizino [l,2b] quinoline-9-(11H)-one (1.6g, 4.7 mmol) in anhydrous tetrahydrofuran (40 ml) under asgon. The reaction mixture is agitated at reflux for one hour, then left to cool to ambient temperature, and the reaction is stopped by adding saturated ammonium chloride (100 ml) and is extracted with chloroform (3 x 100 ml). The combined chloroformic extracts are dried on sodium sulphate, evaporated, and the residue is purified by gel chromatography on silica gel (1-2% MeOH/CH2Cl2), which makes possible obtaining 0.64 g of the sought-after compound (31 %) in the form of a pale yellow solid (m.p. 146-149 °C). RMN-lH (CDC13): 0.93 (t, 3H); 1.37 (s, 9H); 1.99 (m, 2H); 2.97 (dd, 2H); 3.5 (se, 1H); 5.10 (s, 2H); 5,.4 (s, 2H); 7.40 (s,lH); 7.59 (t> 1H); 7.83 (t, 1H); 7.90 (d, 1H); 8.20 (d, 1H); 8.34 (s, 1H). RMN-13C (CDCI3): 8.18 ; 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. Example ethyl ß-ethyl-ß-hydroxy--(8-hydroxymethyl-9-oxo (llH)-indolizino-[l,2b] quinoline-7-yl)-propionate A suspension of zinc (500 mg, 7.64 mmol) and of 8-formyloxymethyl-7-propionylindolizino [1,2-b] quinoline-9 (llH)-one (400 mg, 1.15 mmol) in anhydrous tetrahydrofuran (20 ml) containing 10 mg oihydroquinone is heated to reflux under argon. The heating bath is removed and the exothermic reaction initiated by the addition of a drop of ethyl bromoacetate and a small crystal of iodine. Reflux is maintained by the dropwise addition of ethyl bromoacetate (500 µ1, 4MB mmol) then the reaction mixture is again heated at reflux for one hour. After cooling to ambient temperature, the reaction is stopped by adding saturated ammonium chloride (40 ml) and methanol (30 ml). The resultant mixture is agitated for 5 minutes then filtered and evaporated. The residue is dissolved in dichloromethane (30 ml), washed with water and dried on sodium sulfate. This is followed by the elimination of the solvent and a purification by column chromatography (Si02, CH2Cl2/MeOH 98/2) resulting in 230 mg (49 %) of the sought compound in the form of a yellow solid (m.p. 157-161 ° C). RMN^H (CDC13): 0.93 (t, 3H); 1.20 (t, 3»); 2.02 (m, 2H); 3.07 (dd, 2H); 4.11 (q, 2H); 4.9 (se, 1H); 5.08 (s, 2H); 5.23 (s, 2H); 7.45 (s,lH); 7.62 (t, 1H); 7.80 (t,lH); 7.90 (d, 1H); 8.22 (d, 1H); 8.36 (s, IH). RMN-l3c (CDCI3): 8.09 ; 14.01 ; 34.67 ; 44.85 ; 49.94 ; 58.31 ; 61.09 ; 77.21 ; 100.78 ; 127.78 ; 127.96 ; 128.11 ; 128.72 ; 129.16 ; 129.65 ; 130.60 ; 131.32 ; 142.76 ; 148.28 ; 152.55 ; 155.09 ; 162.22 ; 172.59. IR (KBr): 766 ; 1009 ; 1184 ; 1582 ; 1647 ; 1750. Example 3 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino- [l,2-b]quinoline-3,15 (4H, 13H)-dione tert-butyl ß-ethyl-ß-hydroxy--(8-hydroXymethyl-9-oxo (1 lH)-indolizino-[l,2-b] quinoline-7-yl)-propionate (1.45 g, 3.32 mmol) is dissolved in anhydrous dichloromethane (25 ml) and treated with a saturated solution of hydrogen chloride in dichloromethane (100 ml). The resultant mixture is maintained at -20 °C for 16 hours. The precipitate is filtered, washed with methanol and dried under reduced pressure, which leads to 662 mg (55 %) of the sought after compound in the fibrin of a yellow solid (m.p. >300 °C). RMN-1H (DMSO): 0.90 (t, 3H); 1.20 (q, 2H); 3.27 (dd, 2H); 5.29 (s, 2H); 5.49 (dd, 2H); 7.42 (s, IH); 7.73 (t, IH); 7.90 (t, IH) ; 8.16 (t, 2H); 8.71 (s, IH). RMN-13C (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. Example 4: ß--ethyl-ß-hydroxy-)-8-hydroxymethyl-9-oxo(llH)-indolizino- [1,2-b] quinoline-7-yl)-propionic acid An aqueous solution of potassium hydroxyde (0.1N, 30 ml) is added to 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15(4H,13H)- dione (500 mg, 1.38 mmol) and the resultant suspension is agitated at ambient temperature for 16 hours, which results in an almost clear liquid that is filtered. The filtrate is acidified to pH 3.5 with IN hydrochloric acid, and the yellow precipitate is recovered by filtration, washed with water and acetone, then dried under reduced pressure. 415 mg (79 %) of the sought compound is obtained in the form of a monohydrate (m.p. 165-167 °C). RMN-!H (DMSO): 0.82 (t, 3H); 2.10 (m, 2H); 2.83 (d, 2H); 3.12 (d, 2H); 3.25 (se, 1H); 4.81 (s, 2H); 5.26 (s, 2H); 5.76 (se, JH) ; 7.38 (s, 1H); 7.71 (t, 1H); 7.84 (t, 1H); 8.10 (d, 1H); 8.18 (d, 1H); 8.34 (s, 1H); 12.15 (se, 1H). RMN-13C (DMSO): 8.16 ; 34.80 ; 46.71 ; 50.36 ; 55.73 ; 76.53 ; 100.17 ; 127.50; 128.00 ; 128.26 ; 128.69 ; 129.06 ; 130.01; 130.45 ; 131.63 ; 142.57 ; 148.09 ; 153.19 ; 156.07 ; 161.22 ; 172.27. IR (KBr): 1020 ; 1188 ; 1413 ; 1586 ; 1651; 1694. E x a m p I raethTgl ß--ethyl-ß-hydroxy--(8-hydroxymethyl-9-oxo (11H)-indolizino-[l,2-b] quinoline-7-yl)-propionate 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15(4H,13H)-dione (180 mg, 0,5 mmol), in suspension in methanol (50 ml) is treated with 6N dry hydrogen chloride in methanol (0,5 ml) and maintained at reflux until completely dissolved (4 hours). The volatile compounds are evaporated and the residue is dissolved in dichloromethane (50 ml), washed with diluted sodium hydroxyde (0.05 N, 15 ml) and brine (15 ml). The organic phaseus dried over sodium sulphate and evaporated. The residual solid is purified by silica gel column chromatography (MeOH at 3% / CH2CI2) and the purified product is taken up in diethyl ether, filtered and dried, which gives 120 mg (58 %) of the sought after compound in the form of a pale yellow solid (m.p. 163-166 °C). RMN-!H (CDCI3): 0.93 (t, 3H); 2.2 (m, 2H); 3.05 (dd, 2H); 3.49 (s, 3H); 3.62 (s, 3H); 4.93 (s, 2H); 5.22 (d, 2H); 5.52 (s, 1H); 7.21 (s, 1H); 7.62 (t, 1H); 7.81 (t, 1H); 7.91 (d, 1H); 8.22 (d, 1H); 8.36 (s, 1H). RMN-13C (CDCI3): 7.74 ; 35.54 ; 46.82 ; 50.15 ; 51.67 ; 58.10 ; 65.33 ; 78.03 ; 100.17 ; 125.57 ; 127.70 ; 128.04 ; 128.10 ; 128.35 ; 129.53 ; 130.39 ; 130.94 ; 143.87 ; 148.75 ; 152.94 ; 157.83 ; 161.74 ; 171.35. IR (KBr): 1207 ; 1595 ; 2655 ; 1709. Example 6 ethyl ß-ethyl-α,-difluoro-ß-hydroxy--(8-hydroxymethyl- 9-oxo (11H)-indolizino-[l,2-b] quino!ine-7-yl)-propionate About one half of the total quantity of ethyl bromodifluorocetate (1.8 ml, 14 mmol), 8-formyloxymethyl-7-propionylindolizino [l,2-b]quinoline-9 (11H)-one (2.0 g, 5.75 mmol, such as is obtained in example Lb) in suspension with anhydrous THF (10 ml), is added dropwise under argon to a suspension of zinc (1.25 g, 17.2 mmol) in anhydrous THF (40 ml) at reflux, then the remaining g)art of the ethyl bromodifluorocetate is added. The reaction mixture is maintained at reflux for another half-hour. After cooling to ambient temperature, the reaction is stopped by adding saturated aqueous ammonium chloride (20 ml) and the reaction mixture is extracted with dichloromethane (3 x 20 ml). The combined organic extracts are dried and concentrated. The residue is taken up in diethyl ether (10 ml), filtered and purified by column chromatography (SiC«2, CH2Cl2MeOH 98/2), resulting in 664 mg (26 %) of the sought compound in the form of a yellow solid (m.p. 208-209 °C). RMN-1H (CDC13) : 0.91 (t, 3H) ; 1.38 (t, 3H) ; 2.32 (m, 2H) ; 4.8 (se, 1H) ; 4.38 (q, 2H) ; 5.09 (d, 2H); 5.13 (dd, 2H); 7.42 (s,lH); 7.55 (t, 1H) ; 7.72 (t, 1H); 7.79 (d, 1H); 8.08 (d, 1H); 8.22 (s, 1H) RMN-13C (CDCI3): 6.97 ; 13.93 ; 28.63 ; 50.18 ; 56.27 ; 63.15 ; 77.20 ; 81.96 (t); 101.27 ; 116.40 (t); 127.67 ; 127.77 ; 127.97 ; 128.31 ; 129.26 ; 130.33 ; 130.94 ; 131.23 ; 143.16 ; 148.34 ; 150.20 ; 151.91; 161.21; 163.21 (t). IR (KBr): 1124 ; 1308 ; 1591; 1647 ; 1748. Example ethyl ß-7thyl-ß-hydroxv--(8-hydroxymethyl-9-oxo (11H)-indolizino-[l,2-b]quinoline-7-yl)-propionate A suspension of zinc (1.25 g, 19.1 mmol), 8-methyl-7-propionylindolizino [l,2-b]quinoline-9 (11H)-one (500 mg, 1.43 mmol, such as is obtained by Kinsburry, W.D., Tetrahedron Lett. 29: 6847 (1988)) and silver acetate (250 mg, 1.50 mmol) in anhydrous tetrahydrofuran (10 ml) is agitated at ambient temperature in an argon atmosphere. At the end of 10 minutes, the reaction mixture is activated by the dropwise addition of a molar solution of chlorodiethylaluminium (10 ml, 10 mmol), then ethyl bromoacetate (1.25 ml, 11.3 mmol) is added1 dropwise and the resultant mixture and left to react for another 5 hours. The reaction is stopped by the successive addition of ethyl alcohol (10 ml) and a saturated solution of potassium and sodium tartrate (10 ml). The resultant mixture is agitated again for one hour, filtered and concentrated under reduced pressure. The residue is taken up in dichloromethane (30 ml), washed with water, dried and concentrated. Column chromatography (SiO2, CH2Cl2/MeOH 98/2) allows to obtain 93 mg (15%) of the sought product in the form of a pale yellow solid (m.p. 185-188 °C). RMN-lH (CDCI3): 0.91 (t, 3H); 1.17 (t, 3H); 1.99 (m, 2H); 2.49 (s, 3H); 3.10 (dd, 2H); 4.11 (q, 2H); 4.6 (se, 1H); 5.25 (s, 2H); 7.65 (t, 1H); 7.67 (s,lH); 7.80 (t, 1H); 7.90 (d, 1H); 8.22 (d, 1H); 8.34 (s, 1H). RMN-13C (CDCI3): 8.02 ; 13.99 ; 14.72 ; 33.14 ; 43.97 ; 50.02 ; 61.0 ; 76.54 ; 101.90 ; 127.65 ; 127.84 ; 128.08 ; 128.81 ; 128.88 ; 130.74 ; 131.59 ; 131.65 ; 140.33 ; 147.64 ; 152.96; 153.61; 162.11; 172.91. IR (KBr): 762 ; 1192 ; 1576 ; 1653 ; 1740. Example 8 tert-butyl ß-ethyl ß-hydroxy--(8-hydroxymethyI-9-oxo (11H)-indolizino-[l,2-b] quinoline-7-yl)-puopionate Acetic anhydride (70 µl, 0.7 mmol) is added dropwise to a solution of tert-butyl ß-ethyl-ß-hydroxy--(8-hydroxymethyl-9-oxo (1 lH) indolizino- [l,2-b]quinoline-7-yl)-propionate (200 mg, 0.46 mmol) and triethylamine (140 µl), 1 mmol) in dichloromethane (5 ml) and the resultant mixture is agitated at ambient temperature for 21 hours. The volatile compounds are evaporated and the residue is purified by a silica gel column chromatography (1-2 % MeOH / CH2CI2), Resulting in 152 mg of the sought compound in the form of a yellow solid (m.p. 195-196 °C). RMN-lH (CDCI3): 0.88 (t, 3H); 1.32 (s, 9M) ; 1.93 (m, 2H); 2.07 (s, 3H); 2.97 (dd, 2H); 4.8 (se, 1H); 5.28 (s, 2H); 5.59 (dd, 2H); 7.9 (s, 1H); 7.63 (t, 1H); 7.80 (t, 1H); 7.90 (d, 1H) ; 8.23 (d, 1H); 8.34 (s, 1H). RMN-13C (CDCI3): 8.02 ; 21.06 ; 27.91 ; 35.05 ; 45.58 ; 50.16 ; 59.23 ; 77.52 ; 82.26; 100.59 ; 124.21 ; 127.91 ; 128.10 ; 128.14 ; 128.97 ; 129.18 ; 130.68 ; 131.46 ; 142.85 ; 148.29 ; 152.43 ; 158.49 ; 161.83 ; 171.13 ; 171.90. Example 9: 5,12-diethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3\4': 6,7]-indolizino [1,2-b] quinoline-3,15 (4H,13H)-dione This compound is prepared in a manner analogous to example 1, except that in stage l.a. the 7-ethyl camptothecin (Sawada et al. Chem. Pharm. Bull. 39:2574 (1991)) is used in place of the camptothecin. The sought compound is obtained in the form of a bright yellow solid (m.p. > 270 °C). RMN-!H (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, 1H); 7.76 (t, 1H); 7.89 (t, 1H) ; 8.18 (d, lH);8.32(d, 1H). RMN-13C (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. Example 10 : ß--ethyl-)-(12-ethyl-8-hydroxymethyl-9-oxo (HH)-indoIizino- [1,2-b] quinoline-7-yl)-ß-hydroxy-propionic acid This compound is prepared in a manner analogous to example 4, except that 5,12-diethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4': 6\|7]-indolizino [1,2-b] quinoline-3,15 (4H,13H)-dione is used in place of 5-ethyl-4,5-dihydro)-5-hydroxy-lH-oxepino [3',4': 6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione. It is obtained in the form of a sightly off-white solid (m.p. 238-239 °C). RMN-1H (DMSO): 0.82 (t, 3H); 1.35 (t, 3H); 2.01 (m, 2H); 2.85 (d, 2H); 3.18 (d, 2H); 3.22 (q, 2H) ; 4.81 (s, 2H); 5.00 (se, 1H); 5.24 (s, 2H); 5.78 (se, 1H) ; 7.38 (s, 1H); 7.77 (t, 1H); 7.86 (t, 1H); 8.18 (d, 1H); 8.28 (d, 1H); 12.10 (se, 1H). RMN-13C (DMSO): 8.12 ; 14.15 ; 22.41 ; 34.78 ; 46.74 ; 49.65 ; 55.71 ; 76.51 ; 100.04 ; 124.22 ; 126.63 ; 127.48 ; 128.12 ; 128.21 ; 129.94 ; 130.02 ; 143.10 ; 145.59 ; 148.69 ; 152.62 ; 156.03 ; 161.22 ; 172.22. Example 11: 8-ethyl-2,3,8,9-tetrahydro-8-hydroxy-10H,12H-[l,4]dioxino [2,3-g] oxepino [3.4.6.7.]indolizino [l,2-b[quinoline-10,13 (15H)-dione 11 JL 2-ethyl-2-(2-methoxy-4-pyridyl) l,3 dioxolane (F) Azeotropic water is distilled for one entiffe night with a Dean Stark apparatus from a mixture of 2-chloro-4-propionylpyridine (10 g, 59 mmol) obtained as in Lamattina, J.L. /. Heterocyclic Chem. 20, p. 553 (1983)), ethylene glycol (20 ml) and p-toluenesulfonic acid (250 mg) in toluene (150 ml). The solvent is then eliminated under reduced pressure, the acid is neutralized with a saturated aqueous solution of sodium bicarbonate (100 ml) and the product is extracted using ether. The combined ethereal extracts are washed with brine, dried on sodium sulphate and evaporated, which produces 13.3 g (96 %) of the crude product protected by the caxbonyl 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 ; Si02, tert-butyl methyl 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 brine, dried on sodium sulphate and evaporated, resulting in a product (F) is recovered in the form of a clear liquid. ll.b. 2-ethyl-2-(3-hydroxymethyl-2-methoxy-4-pyridyl)-l,3 dioxolane (G) Tert-butyllithium (1.7 M in pentane, 100 ml, 170 mmol) is added dropwise using a cannula, to a solution of bromomesitylene (13 mg, 85 mmol) in anhydrous tetrahydrofurane (300 ml) at -78° C under ai-gon. The resultant white precipitate is agitated at -78 °C for one hour then 2-ethyl-2-C2-methoxy-4-pyridyl)-l,3-dioxolane (10 g, 44,8 mmol) is added and the reaction mixture is agitated 15 minutes at -78 °C, one hour ar 0 °C and one hour at ambient temperature. After another cooling to -78 °C, anhydrous N,N-dimethylformamide (100 mmol) is added and the reaction mixture is left to reheat to ambient temperature then is agitated for 16 hours, after which an analysis by thin layer chromatography (SiC>2, TBMO/HX 50/50) shows the complete consumption of the starting compound. 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 on sodium sulphate and evaporated, resulting in a yellow oil which is purified by column chromatography (SiO2, TBMO/HX : 0/100 to 5/95 in order to elute the mesytylene derivatives then 20/80 to 50/50 to elute the product), and the intermediary aldehyde (7 g) is recovered. The aldehyde is dissolved in methanol (100 ml) and treated with sodium borohydride (5 g, 132 mmol). The resultant mixture is agitated until complete consumption of the intermediary aldehyde (about 1 hour; follow-up by thin layer chromatography). The solvent is then evaporated, the residue is reoovered in ether, washed with water and brine, dried, and the solvent is evaporated. The column chromatography (SiO2, TBMO/HX 10/90 to 50/50) of the residue yields 7 g (global yield 62 %) of product (G) in the form of a yellow oil. ll.c. 2-(3-benzyloxymethyI-2-methoxy-4ipyridyl)-2-ethyl-l,3-dioxolane(H) A solution of 2-ethyl-2-(3-hydroxymethyl-2-methoxy-4-pyridyl)-l,3-dioxolane (7 g, 30 mmol) and of benzyl chloride (5 ml, 45 mmo!) in anhydrous tetrahydrofuran (50 ml) is added dropwise to a suspension of sodium hydride (80 % in mineral oil, 1.85 g, 61 mmol) in anhydrous tetrahydrofuran (100 ml) and tie reaction mixture is maintained at reflux for 16 hours. The reaction mixture is then left to c©ol to ambient temperature, the reaction is stopped with water (50 ml) and the reaction mixture is concentrated under reduced pressure. The residue is dissolved in diethyl ether (150 ml) and washed with water and brne, dried and evaporated. A purification by column chromatography (Si02, TBMO/HX; 5/95 to 20/80) yields the product protected by benzyl (H) (9 g,.87 %) in the form of a clear oil. 11. d. l-(3-benzyloxymethyl-2-methosxy-4-pyridyl)-propane-l-one (I') 2-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-2-ethyl-l,3-dioxolane (9 g, 27 mmol) is treated with trifluoracetic acid (10 ml) and water (5 ml) for 3 hours with a bath temperature of 120 °C. The reaction mixture is concentrated under reduced pressure and the residual traces of the acids are neutralized by the addition of saturated aqueous sodium bicarbonate. An ether extraction is followed by column chromatography (Si02, TBMO/HX 10/90), yielding 5.5 g (70 %) of product (I). 11. e. tert-butyl ß-ethyl-ß-hydroxy--(3-benzyloxymethyl-2-methoxy-4-pyridyl)-propionate (J) tert-butyl bromoacetate (13 ml, 80 mmol) isadded dropwise to a suspension of zinc (5,3 g, 80 mmol, activated by treatment with 6N HO for 10 seconds, then washed successively with water until neutral pH, acetone and diethyl ether) in anhydrous tetrahydrofuran (60 ml) to reflux. The reaction medium is maintained at reflux for another 10 minutes after the addition is finished. A solution of l-(3-benz0oxymethyl-2-methoxy-4-pyridyl)-propane-l-one (5.8 g, 20 mmol) in tetrahydrofuran anhydride (20 ml) is added, and the reaction mixture is agitated under reflux for one more hour. The reaction is stopped at 0 °C with saturated aqueous ammonium chloride (100 ml) and the reaction mixture extracted with diethyl ether. The combined extracts are dried on sodium sulphate and evaporated, yielding a yellow oil which is purified by column chromatography (SiC>2, TBMO/HX; 5/95 to 10/90) to obtain the tert-butyl ester (J) (7 g, 95 %) in the form of a clear oil. 11. tert-butyl ß-ethyl-ß-hydroxy -(3-hydroxymethyl-2-methoxy-4-pyridyl)- propionate (K) tert-butyl P-ethyl-P-hydroxy-Y-(3-benzyloxyanethyl-2-methoxy-4-pyridyl)-propionate (1 g, 2;5 mmol) is hydrogenolised at atmospheric pressure and ambient temperature by using 5 % of palladium on charcoal as a catalyst (50 mg) and absolute ethanol as solvent (10 ml). Once the reaction is finished (6 hours), the catalyst is separated by filtration and the solvent is evaporated, which yields 0.7 g (90 %> of product (K) of a sufficient purity for a subsequent synthetic use. 11. g 5-ethyl-l,5-dihydro-5-hydroxy-$-methoxy-oxepino [3,4-c] pyridine -3 (4H)-one (L) tert-butyl P-ethyl-P-hydroxy-Y-(3-hydroxymethyl-2-methoxy-4-pyridyl)-propionate (8.8 g, 28 mmol) is treated with trifluoroacetic acid (30 ml) for 3 hours at ambient temperature. The volatile components are evaporated and the residue is purified by column chromatography (Si02 CH2Cl2/MeOH; 100?0 to 98/2), which results in a clear oil, which, after treatment with toluene, yields 5;9 g of product (L) (89 %) in the form of white crystals (m.p. 97-98 °C). ll.h 5-ethyl-l,5-dihydro-5-hydroxycoxepino [3,4-c] pyridine 3,9(4H,8H)-dione (M) 5-ethyl-l,5-dihydro-5-hydroxy-9-methoxy oxepino [3,4-c] pyridine-3-(4H)-one (0,5 g, 2.1 mmol) in hydrochloric acid IN (20 ml) is heated to reflux for 9 hours. The reaction mixture is concentrated under reduced pressure and the residue is dried again by the addition and evaporation of toluene, two times, then left overnight under reduced pressure in the presence of phosphorous pentoxide. The resultant oil is dissolved in acetonitrile anhydride (5 ml) and agitated under argon? for 24 hours. The precipitate is filtered and dried, which yields 0.23g (49 %) of a white solid (M) (m.p. 118-119 °C). 11. i. 6,7-ethylenedioxy -2-iodo-3-quinoline-methanoI (N) The procedures described by Meth-Cohn et al., Chem. Soc. Perkin Trans. I, p. 1520 (1981), Meth-Cohn, J. Chem. Soc. Perkin Trans. I, p. 2509 (1981), and Nakasimhan et al, J. Am. Chem. Soc. 112, p. 4431 (1990), are used. 3,4-ethylenedioxyacetanilide (22 g, 113 mmol) is added to the Vilsmeyer reagent obtained by the dropwise addition of phosphoryl oxychloride (71 ml, 0.77 mol) to dimethylformamide anhydride (23 ml, 0.28 mmol), chilled in an ice-water bath and agitated for another 0.5 hour in an argon atmosphere. The resultant mixture is heated to 75° C for 16 hours. After cooling to ambient temperature, the reaction mixture is added to a mixture of ice and water (300 ml) and extracted with dichloromethane (5 x 200 ml). The combined organic extracts are dried on sodium sulphate, filtered and concentrated. The solid residue is placed into suspension in dichloromethane (20 ml), filtered and dried under reduced pressure, which yields 10 g (35 %) of 2-chloro-6,7-ethylenedioxyquinoline-3-carbaldehyde in the form of a yellow solid (m.p. 222-224 °C). This intermediate is treated with sodium iodide (30 g, 0.2 mol) and concentrated hydrochloric acid (1.5 mlMn acetonitrile to reflux (150 ml) for 24 hours. After cooling to ambient temperature, the solvent is eliminated under reduced pressure and the residue is taken up in 50 % aqueous tefrahydrofuran (200 ml), filtered, washed with tetrahydrofuran and dried under reduced presure, which yields 12 g of 6,7-ethylenedioxy-2-iodoquinoline-3-carbaldehyde in the form of a yellow solid (m.p. 155-157 °C). This intermediate is treated with sodium boroh^dride (2 g, 52 mmol) in methanol at ambient temperature for 0.5 hour. The solvent is eliminated under reduced pressure and the residue is taken up in water and filtered. The resulting Solid is dried under reduced pressure in the presence of phosphorous pentoxide, which yields 11 g of (6,7-ethylenedioxy-2-iodoquinoline-3-yl)-methanol in the form of a yellow solid (m.p. 178-180 °C). ll.j. 5-ethyl-8-(6,7-ethylenediox-2-iodo-3-quinolinemethyl)-l,5-dihydro- 5-hydroxy-oxepino [3,4-c] pyridine 3,9 (4H-8H)-dione (O) Over 5 minutes, diethyl azodicarboxylate (570 µl, 3.6 mmol) is added dropwise to a solution of 5-ethyl-l,5-dihydro-5-hydroxy-oxepino [3,4-c] pyridine 3,9(4H,8H)-dione (400 mg, 1.79 mmol), of the compound (N) obtained in the preceding stage 11. (770 mg, 2.23 mmol), and of triphenylphosphine (934 mg, 3.58 mmol) in a mixture of anhydrous THF/DMSO (8/1 v/v, 45 ml). The resultant mixture is agitated under argon at ambient temperature for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in chloroform (100 ml). The resultant solution is washed with brine (4 x 50 ml), dried on sodium sulphate and evaporated. The residue is purified by column chromatography (Si02, CH2Cl2/MeOH; 99/1 to 98/2), yielding 650 mg (66%) of product (O) in the form of a white solid (m.p. 165-167 °C). 11 .k. 8-ethyl-2,3,8,9-tetrahydro-8>hydroxy-10H,12H- [l,4]dioxino[2,3-g]oxepino[3',4':6,7]indoliMno [l,2-b]quinoline-10,13(15H)-dione 5-ethyl-8-(6,7-ethylenedioxy-2-iodoquinoline-3'yl)methyl-4,5-dihydro-5-hydroxy-(lH,3H)oxepino [3,4-c] pyridine-3-dione (600 mg, 1.1 mmol), tetrabutylammonium bromide (352 mg, 1.1 mmol), sodium acetate (369 mg, 4.4 mmol) and palladium II acetate (98 mg, 0.43 mmol) are dissolved in anhydrous acetonitrile (40 ml) and heated to 90 °C under argon for 16 hours. After cooling to ambient temperature, a white precipitate is separated from the reddish solution. This precipitate is filtered and dried under reduced pressure. The crude product is put into suspension in water, filtered and dried under reduced pressure in the presence of phosphorous pentoxide, yielding 250 mg of die sought compound in the form of a clear yellow solid (m,p. > 250° C). RMN-lH (DMSO): 0.91 (t, 3H); 1.87 (m, 2H); 3.08 (d, 1H); 3.51 (d, 1H); 4.45 (s, 4H); 5.19 (s, 2H); 5.47 (dd, 2H); 6.02 (se, 1H\|>; 7.33 (s, 1H); 7.54 (s,lH); 7.55 (s, 1H); 8.43 (s, 1H). RMN-13C (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. Example 12: 10-benzyloxy-5-ethy[4,5\|-dihydro-5-hydroxy-lH-oxepino [3\4':6,7] indolizino [l,2-b]quinoline-3,15#4H,13H)-dione 12.a. (6-benzyloxy-2 -iodoquinoline-3yl)-methanol This compound is prepared in a method analogous to that outlined in stage ll.i. of example 11, but using 4-benzyloxyacetanili€e in place of 3,4-ethylenedioxyacetanilide. A purification by column chromatography on silica gel (using dichloromethane as eluant) is necessery to isolate (8% yield) to a sufficient purity the intermediary 6-benzyloxy-2-chloroquinoline-3-carbaldehyde (m.p. 180-182 °C). Next, the halogen exchange yields 6-benzyloxy-2-iodoquinoline-3-carbaldehyde (m.p. 155-157 °C) and the subsequent reduction with sodium borohydride yields \|6-benzyloxy-2-iodoquinoline-3-yl)-methanol (m.p. 147-149 °C). 12.b. 8-(6-benzyloxy-2-iodo-3-quinollnemethyl)-l,5-dihydroxy-5-ethyl-5-hydroxy-oxepino [3,4-c] pyridine-3,9(4H,8H)-dione This compound is prepared in a method analogous to that outlined in stage ll.j. of example 11, but using (6-benzyloxy-2-iodoquinoline-3-yl)-methanol in place of (6,7-ethylenedioxy-2-iodoquinoline-3-yl)-methanol. This compound appears in the form of a white solid (m.p. 197-199 °C). 12.c 10-benzyloxy-5-ethyl-4,5-dihydisp-5-hydroxy-lH-oxepino [3',4':6,7] indolizino [l,2-b]quinoline-3,15(4H,13H)-dione This compound is prepared in a method analagous to the one indicated in stage ll.k. of example 11, but using 8-(6-benzyloxy-2-iodo-3-quinolinemethyl)-l,5-dihydroxy-5-ethyl-5-hydroxy-oxepino [3,4-c] pyridine-3%9(4H,8H)-dione in place of 5-ethyl-8-(6,7-ethylenedioxy-2-iodoquinoline-3-yl)methyl-4,5-dihydro-5-hydroxy(lH,3H)oxepino [3,4-c] pyridine-3-dione. The sought compound appears in the form of a clear yellow solid (m.p. > 250 °C). RMN-!H (DMSO): 0.90 (t, 3H); 1.85 (m, W) ; 3.08 (d, 1H); 3.50 (d, 1H); 5.25 (s, 2H); 5.30 (s, 2H); 5.50 (dd, 2H) ; 6.05 (s, 1H); 7.30-7.70 (m, 8H) ; 8.10 (d, 1H) ; 8.55 (s, 1H). RMN-13C (DMSO): 8.43 ; 36.48 ; 38.28 ; 50.65 ; 61.42 ; 70.00 ; 73.32 ; 99.05 ; 107.71 ; 122.05 ; 123.42 ; 128.18 ; 128.26 ; 128.70; 129.40 ; 130.19 ; 130.48 ; 130.63 ; 136.65 ; 144.18 ; 144.90; 150.53 ; 155.91 ; 157.31 ; 159.24; 172.06. Example 13 -(12-benzyIoxy-8-hydroxymethyl-9-oxo (11H)-indolizino [1,2-b] quinoline-7-yl)-ß-ethyl-ß-hydroxy-propionic acid (E) This compound is prepared in a manner analagous to the one explained in example 4, but using 10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7] indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione in place of 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione. It appears in the form of a yellow solid (m.p. 171-173 °C). RMN-!H (DMSO): 0.80 (t, 3H); 2.00 (m, 2H) ; 2.85 (d, 1H); 3.15 (d, 1H); 4.80 (s, 2H); 5.25 (s, 2H); 5.30 (s, 2H); 5.75 (se, 1H) ; 7.30 (s, 1H); 7.35-7.70 (m, 7H) ; 8.10 (d, 1H) ; 8.55 (s, 1H). RMN-13C (DMSO): 8.11 ; 34.75 ; 46.68 ; 50.35 ; 55.70 ; 69.97 ; 76.51; 99.45 ; 107.78 ; 123.28 ; 127.64 ; 128.18 (2C); 128.26 ; 128.70 (2C); 129.33 ; 130.17 ; 130.47 ; 130.57 ; 136.69 ; 142.79 ; 144.17 ; 150.93 ; 156.03 ; 157.19 ; 161.20. Example 14: 5-ethyl-4,5-dihydro-5,10-dihydroxy-lH-oxepino [3',4':6,7]-indolizino [l,2-bquinoline-3,15 (4H,13H)-dione 10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7] indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione (370 mg, 0.79 mmol) is treated with hydrogen at atmospheric pressure and at ambient temperature using 10 % palladium on charcoal as catalyst (60 mg) and trifluoroacetic acid as solvent (15 ml). Once the reaction is terminated (16 hours), dichloromethane (50 ml) and methanol (50 ml) are added to the reaction mixture, the catalyst is filtered and the volatile components are evaporated under reduced pressure, which permits obtaining the crude form of the sought after compound containing traces of trifluoroacetic acid. These traces are eliminated by codistillation with 1,4 dioxane. The product obtained is in the form of an orange solid (m.p. 150° C (d)), with a purity sufficient for further synthetic use. RMN-lH (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 3.02 (d, 1H); 3.45 (d, 1H); 5.19 (s, 2H); 5.37 (d, 1H) ; 5.50 (d, 1H) ; 5.98 (se, 1H) ; 7.26 (s 1H) ; 7.31 (s, 1H) ; 7.40 (d, 1H) ; 8.00 (d, 1H) ; 8.42 (s, 1H) ; 10.32 (s, 1H). RMN-13C (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. Example 15: ll-(dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy- lH-oxepino [3',4':6,7]-indolizino [l,2-b]quiiioline-3,15 (4H,13H)-dione chlorhydrate 15.a. H-(dimethyIamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-lH-oxepino [3',4':6,7]-indoIizino [l,2-b]quinoline-3,15 (4H,13H)-dione A suspension of 10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7] indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione (260 mg, 0.69 mmol) in acetic acid (15 ml) is treated with 37 % aqueous formaldehyde (500 µ1) and 40 % aqueous dimethylamine (500 µl). The resultant mixture is agitated at ambient temperature for 16 hours. The reaction mixture is concentrated to dryness and the residue is purified by column chromatography (Si02, CH2Cl2/MeOH; 100/0 to 90/10) followed by crystallization with acetonitrile, yielding 102 mg of the sought compound. 15. b. ll-(dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-lH-oxepino [3',,4':6,7]indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione chlorhydrate Diluted hydrochloric acid (IN) is added dropwise to a suspension of ll-(dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-lH-oxepino [3',4':6,7]-indo]izino [l,2-b]quinoline-3,15 (4H, 13H)-dione (102 mg) in water, until completely dissolved. The water is evaporated under reduced pressure and the residue is put into suspension in acetonitrile (5 ml) and filtered, yielding 103 mg of the sought salt (m.p. 248 °C (d)). RMN-1H (DMSO): 0.88 (t, 3H); 1.85 (m, 2H) ; 2.84 (s, 6H); 3.08 (d, 1H); 3.5 (d, 1H) ; 4.73 (s, 2H) ; 5.25 (s, 2H) ; 5.47 (dd, 2H); 7.33 (s, 1H) ; 7.38 (s,lH) ; 7.72 (d, 1H); 8.19 (d, 1H); 8.99 (s, 1H); 9.92 (se, 1H); 11.45 (s, 1H). RMN-^C (DMSO): 8.46 ; 34.36 ; 42.44 (3C); 50.61 (2C); 61.42 ; 73.35 ; 99.19 ; 108.63 ; 122.21 ; 122.36 ; 126.86 ; 129.13 ; 130.61 ; 133.09 ; 143.53 ; 144.70 ; 149.76 ; 155.98 ; 157.17 ; 159.27 ; 172.06. Example 16: 5-ethyl-9-fluoro-4,5-dinydro-5-hydroxy-10-methoxy-lH-oxepino [3,4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione This compound is obtained from 3-fluoro-4-methoxyaniline according to the method illustrated by the stages 1 Li, 1 l.j. and 1 l.k. of example 11. Yellow solid (m.p. > 250 °C). RMNMH (DMSO): 0.89 (t, 3H) ; 1.85 (q,2H) ; 3.08 (d, 1H); 3.49 (d, 1H); 4.00 (s, 3H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d,lH); 6.00 (s, 1H); 7.32 (s, 1H); 7.72 (d, 1H); 7.91 (d, 1H); 8.58 (s, 1H). RMN-13C (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. Example 17: 9-chIoro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyI-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione This compound is obtained from 3-chloro-4-methoxyaniline according to the method illustrated by the stages ll.i., ll.j. and ll.k. of example 11. Yellow solid (m.p. > 250 ° C). RMN-1!! (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 2.55 (s, 3H); 3.07 (d, 1H); 3.45 (d, 1H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 1H) ; 8.60 (s, 1H). RMN-13C (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. Example 18: 5-ethyl-9,10-difluoro- 4,5-dihydro-5-hydroxy-lH-oxepino [3',,4':6,7]indolizino [l,2-b\|quinoline-3,15 C4H43H)-dione This compound is obtained from 3,4-difluoroanIine according to the method illustrated by the stages ll.i., ll.j. and ll.k. of example 11. Yellow solid (m.p. > 250 ° C). RMN-!H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.47 (d, 1H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H) ; 7.39 (s, 1H); 8.15 (q, 1H) ; 8.25 (q, 1H); 8.68 (s, 1H). RMN-13C (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. Example 19: 7-ethyl-7,8-dihydro-7-hydroxy-9H,llH- [l,3]dioxolo[4,5-g] oxepino[3',4':6,7]-indolizino [l,2-b]quinolme-9,12 (14H)-dione chlorhydrate This compound is obtained from 3,4-methylenedioxyaniline according to the method illustrated by the stages ll.i., ll.j. and ll.k. of example 11. Beige solid (m.p. > 250 °C). RMN-!H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 5.20 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.00 (s, 1H); 6.30 (s, 2H) ; 7.30 (s, 1H) ; 7.49 (d, 2H) ; 8.45 (s, 1H). RMN-13C (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. Example 20: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-lH-oxepino [3',4':6,7]-mdolizino [l,2-b]quinoline-3,15 (4H,13H)-dione This compound is obtained from 3-chloro-4-methoxyaniline according to the method illustrated by stages 1 l.i., 1 l.j. and 1 l.k. of example 11. White solid (m.p. > 250 °C). RMN-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H) ; 3.07 (d, 1H); 3.45 (d, 1H); 4.01 (s, 3H); 5.22 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.02 (s, 1H); 7.31 (s, 1H); 7.68 (s, 1H); 8.20 (s, 1H); 8.55 (s, 1H). RMN-13C (DMSO): 8.22 ; 36.27 ; 42.30 ; 50.48 ; 56.69 ; 61.23 ; 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. Example 21: 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-lH-oxepino [3',,4':6,7]indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione This compound is obtained from 4-methoxyaniline according to the method illustrated by the stages 1 l.i., 1 l.j. and 1 l.k. of example 11. Yellow solid (m.p. > 250 °C) RMN-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 3.95 (s, 3H); 5.28 (s, 2H); 5.40 (d, 1H); 5.51 (d, 1H); 6.00 (s, 1H); 7.38 (s, 1H); 7.51 (d, 2H); 8.07 (d, 1H); 8.55 (s, 1H). RMN-13C (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. Example 22: 9,ll-dichloro-5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indoIizino [l,2-b]quinoline-3,15 (4H,13H)-dione This compound is obtained from 3,5-dichloroaniline according to the method illustrated by the stages 1 l.i., 1 l.j. and 1 l.k. of example 11. Yellow solid (m.p. > 250 °C). RMN-lH (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 5.30 (s, 2H); 5.41 (d, 1H); 5.55 (d, 1H); 6.08 (s, 1H); 7.41 (s, 1H); 8.05 (s, 1H); 8.21 (s, 1H); 8.91 (s, 1H). RMN-13C (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. Example 23: 5-ethyl-9-fluoro-4,5-dhydro-5-hydroxy-10-methyl-lH-oxepino [3',4* :6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione This compound is obtained from 3-fluoro-4-methylaniline according to the method illustrated by the stages ll.i, ll.j. and ll.k. of example 11. Yellow solid (m.p. > 250 °C). RMN-1H (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 2.49 (s, 3H); 3.08 (d, 1H); 3.49 (d, 1H); 5.21 (s, 2H); 5.39 (d, 1H); 5.51 (d,lH); 6M (s, 1H) ; 7.39 (s, 1H); 7.87 (d, 1H); 8.05 (d, 1H); 8.61 (s, 1H). RMN-^C (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. Example 24: 5-ethyl-10-fluoro-4,5-dinydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino[l,2-b]quinolme-3,15 (4H,13H)-dione This compound is obtained from 4-fluoroaniline according to the method illustrated by the stages 1 l.i., 1 l.j. and 1 l.k. of example 11. White solid (m.p. > 250 °C). RMN-lH (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 5.29 (s, 2H); 5.39 (d, 1H); 5.55 (d, 1H); 6.30 (s, 1H); 7.9 (s, 1H); 7.80 (q, 1H); 7.99 (q, 1H); 8.23 (q, 1H) ;8.68 (s, 1H). RMN-13C (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. Example 25: 10-chloro-5-ethyl-4-5-dihydro-5-hydroxy-lH-oxepino [3\4' :6,7]-indolizino [l,2-b]quinoline-3,15H(4H,13H)-dione This compound is obtained from 4-chloroaniline according to the method illustrated by the stages ll.i., ll.j. and ll.k. of example 11. Yellow solid (m.p. > 250 °C). RMN-lH (DMSO): 0.85 (t, 3H); 1.85 (q, 2H) ; 3.07 (d, 1H); 3.47 (d, 1H); 5.25 (s, 2H) ; 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H); 7.39 (s, 1H); 7.89 (d, 1H); 8.19 (d, 1H); 8.29 (s, 1H); 8.67 (s, 1H). RMN-13C (DMSO): 8.40 ; 36.46 ; 42.47 ; 50.70 ; 61.42 ; 73.31 ; 100.00 ; 122.96 ; 127.31 ; 127.42 ; 128.87 ; 131.11 ; 132.12; 144.34 ; 146.53 ; 153.38 ; 155.88 ; 159.20; 172.04. IR (KBr): 1069 ;1483 ; 1606 ; 1741. Example 26: 10-chloro-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino[l,2-b]quinoline-3,15(4H,13H)-dione This compound is obtained from 4-chloo-3-fluoroaniline according to the method illustrated by the stages 11.1., 11 .j. and 11 .k. of example 11. Yellow solid (m.p. > 250 °C). RMN-1H (DMSO): 0.85 (t, 3H) ; 1.85 (q, 2H) ; 3.07 (d, 1H); 3.45 (d, 1H); 5.25 (s, 2H); 5.39 (d, 1H) ; 5.51 (d, 1H); 6.05 (s, 1H) ; 7.40 (s, 1H) ; 8.20 (d, 1H) ; 8.40 (d, 1H) ; 8.68 (s, 1H). RMN-13C (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. Example 27: 5,12-diethyl-4,5-dihydro-5,10-dihydroxy-ll-morpholinomethyl- lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione This compound is obtained from morpholine according to the method illustrated by the stages ILL, ll.j. and ll.k. of example 11. White solid (m.p. > 250 °C). RMN-lH (DMSO): 0.85 (t, 3H); 1.87 (q, 2H); 2.53 (s, 4H); 3.03 (d, 1H); 3.45 (d, 1H); 3.57 (s, 4H); 4.02 (s, 2H) ; 5.01 (s, 2H); 5.38 (d, 1H); 5;52 (d, 1H); 6.0 (se, 1H); 7.30 (s, 1H); 7.42 (d, 1H); 7.95 (d, 1H); 8.82 (s, 1H). RMN-13C (DMSO): 8.45 ; 3.49 ; 42.58 ; 53.04 ; 61.44 ; 66.33 ; 73.33 ; 98.81 ; 113.78 ; 121.81 ; 122.74 ; 126.80 ; 129.05 ; 129.91 ; 143.72 ; 145.07 ; 149.24 ; 155.06 ; 156.92 ; 159.28 ; 172.08. IR (KBr): 1515 ; 1595 ; 1654 ; 1736. Example 28: 5,12-diethyI-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-lH- oxepino [3',,4':6,7]indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione 28.a. 5-fluoro-4-methoxy-2-propionylaniline (This product is obtained according Sugasawa T ; Toyoda T ; Adachi M ; Saskura K, J. Am Chem Soc, 100 (1978) p. 4842-4852). A solution of 3-fluoro-4-methoxy-aniline (20 g, 142 mmol) in anhydrous dichloromethane (200 ml), under an argon atmosphere and at 0° C, is added dropwise to boron trichloride (1 M in heptane, 156 ml, 156 mmol). The pink suspension thus obtained is maintained under agitation 5 min. Then propionitrile (33 ml, 420 mmol) followed by aluminium trichloride (20.9 g, 156 mmol) is added dropwise in small portions. The reaction medium is heated to reflux for 3 hours, chilled at 0° C, hydrolyzed by adding, carefully, 2N hydrochloric acid (100 ml), then brought to reflux for 45 min. After chilling to 0 °C, a precipitate is obtained which is then filtered, washed with dichloromethane, then taken up in water (300 ml). The aqueous phase is basified to an alkaline pH, extracted with dichloromethane, then with ethyl acetate. The organic phase is dried (MgSO,4) then evaporated, yielding a crude product which is purified by column chromatography (Si02, AcOEt/Hpt: 1/99 to 20/80). 15.3 g of a yellow solid is obtained. RMN-lH (CDCI3): 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. 28.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 anhydrous acetonitrile (110 ml), under argon and at 0 °C, is added dropwise a solution of ethylmalonyl chloride (12.9 ml, 100 mmol) in anhydrous acetronitrile (30 ml). The reaction medium is left to return to ambient temperature. A solution of sodium ethylate (obtained with 1.8 g, 78 mmol, of sodium in 80 ml of ethanol) is cannulated dropwise into the reaction medium, which is then left to agitate for 12 hours at ambient temperature. The reaction mixture is poured into ice water (100 ml) and agitated for 2 hours, then the precipitate is filtered and washed with water, ethanol and ether. 19.4 g of a white solid is obtained. RMN-lH (DMSO): 1.25 (m, 6H); 2.78 (q, 2H) ; 3.92 (s, 3H); 4.30 (q, 2H); 7.15 (d, 2H); 7.40 (d,2H);l 1.93 (s,lH). IR (KBr): 786 ; 1083 ; 1410 ; 1521 ; 1644; 1725. 28. 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-quinolinecarboxylate (19.4 g, 0.066 mol) in phosphoryl chloride (243 ml) is brought to reflux for 6 hours. The phosphoryl chloride is distilled. The reaction mixture is poured into ice water and taken up in dichloromethane to make soluble. The organic phase is washed with water, then with a saturated solution of sodium chloride. The organic phase is dried on magnesium sulphate and the solvent is evaporated. The residue is suspended in ether and the non-converted starting product (4 g) is filtered. The filtrate is evaporated and the residue is purified by column chromatography (Si02, AcOEt/Hpt: 5/95 to 20/80). 10.9 g of a white solid is obtained. RMN-lH (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. 28.d. 2-chloro-4-ethyi-7-fluoro-6-methoxy-3-quinolinemethanol 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 ambient temperature under inert atmosphere .with diisobutylaluminum hydride (1 M in dichloromethane, 65 ml, 65 mmol), then heated to 40 °C for 4 hours. The reaction medium is chilled to 0 °C, a 20 % aqueous solution of Rochelle salt and dichloromethane (200 ml) are added carefully and the agitation is maintained for 1 hour. The mixture is decanted, the organic phase is washed three times with water and dried on magnesium sulfate. The solvent is then evaporated. The residue is purified by column chromatography (SiC>2, AcOEt/Hpt: 5/95 to 50/50). 6 g of a white solid is obtained. RMN-1H (DMSO): 1.28 (t, 3H); 3.25 (q, 2H); 4.04 (s, 3H); 4.77 (d, 2H); 5.27 (t, 1H); 7.55 (d, 2H); 7.73 (d, 2H). IR (KBr): 840 ; 864 ; 1023 ; 1232 ; 1267 ; 1317 ; 1444 ; 1511 ; 1569. 28.e. 5,12-diethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione 2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinemethanol is coupled to compound (M) as described in stage ll.j. of example 11. The resultant coupling product is cyclized according to the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 275 °C). RMN-lH (CF3COOD): 1.07 (m, 3H); 1.62 (m, 3H); 2.27 (m,2H); 3.44 (d, 1H); 3.54 (m, 2H); 3.91 (d, 1H); 4.25 (s, 3H) ; 5.60 (d, 1H) ; 5.74 (s, 2H); 5.98 (d, 1H); 7.85 (m, 1H); 8.16 (m,lH); 8.31 (s,lH). RMN-13C (CF3COOD): 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. Example 29 : 5-ethyl-4,5-dihydro-5-hydroxy-12-methyl-lH-oxepino [3',4' :6,7]-indolizino [l,2-b]quinoline-3,15(4H,13H)-dione The procedures described in stages 28.b., 28.c. and 28.d. of example 28 are applied to 2-acetylaniline, yielding 2-chloro-4-methyl-3-quinolinemethanol. The latter is coupled to compound (M) as described in stage 11. j. of example 11. The resultant coupling product is cyclized according to the procedure of stage 11. k. A yellow solid is obtained (m.p. > 260 °C). RMN !H (DMSO): 0.87 (t, 3H); 1.87 (q, 2H); 2.78 (s, 3H); 2.80 (d, 1H); 3.55 (d, 1H); 5.27 (s, 2H); 5.42 (d, 1H) ; 5.52 (d, 1H); 6.04 (s, 1H) ; 7.39 (s, 1H); 7.75 (t, 1H); 7.88 (t, 1H); 8.13 (d, 1H); 8.25 (d,lH). RMN-13C (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. Example 30: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy- 12-(4-methylpiperazinomethyl)-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione 30.a. 5-chloro-2-chloroacetyl-4-methoxyaniline (This product is obtained according to Sugasawa T., Toyoda T., Adachi M., Sasakura K., J. Am.. Chem.. Soc, 100 (1978), p 4842-4852), A molar solution of boron trichloride in hexane (164 ml, 164 mmol), chloroacetonitmle (11.4 ml, 180 mmol), and a molar solution of diethylaluminum chloride in hexane (164 ml, 164 mmol) are added dropwise in succession to a solution of 3-chloro-4-methoxyaniline (23.6 g, 150 mmol) in an inert atmosphere at 0 °C. The reaction medium is heated to reflux for 1 hour then cooled to 0 °C, hydrolized by adding carefully 2N hydrochloric acid (90 ml), then maintained at reflux for 1 hour. It is chilled again and a concentrated solution of sodium bicarbonate is added to reach pH 14. The reaction mixture is extracted with ethyl acetate, the organic phase is washed with water, then with salt water. The organic phase is dried on magnesium sulfate, filtered and evaporated under reduced pressure. The residue is taken up in isopentane, decanted, then what is insoluble is taken up in the minimum (amount) of isopropyl ether, and isopentane is added to precipitate the product. After filtration and drying under vacuum, 17.6 g of a brown solid are obtained. RMN-1H (CDCI3): 3.82 (s, 3H); 4.60 (s, 2H) ; 6.11 (s, 2H); 6.78 (s, 1H); 7.11 (s, 1H). 30. b. Ethyl 7-chIoro~4-chloromethyl-2-hydroxy-6-methoxy-3-quinoline-carboxylate Ethylmalonyl chloride (17 ml, 131 mmol) is added dropwise to a solution of 5-chloro-2-chloroacetyl-4-methoxyaniline (17 g, 73 mmol) and of triethylamine (18.5 ml, 131 mmol) in anhydrous acetonitrile (310 ml) under argon and at 0 °C. The reaction mixture is agitated for 2 hours at ambient temperature, then a solution of sodium ethylate in ethanol (obtained by 1.88 g, 80 mmol, of sodium in 90 ml of ethanol) is added dropwise at 0 °C . The reaction mixture is then agitated for 12 hours at ambient temperature. 300 ml of water are added, and agitation is maintained for another 20 minutes. The precipitate is filtered, washed with water, ethanol, and ethyl ether. After drying in vacuum, 16.7 g of yellowish solid are obtained. RMN-!H (DMSO) : 1.31 (t, 3H) ; 3.95 (s, 3H) ; 4.36 (q, 2H) ; 4.95 (s, 2H) ; 7.46 (s, 1H) ; 7.49 (s,lH). 30. c. Ethyl 2,7-dichloro-4-chloromethyl-6-methoxy-3-quinoline-carboxylate A suspension of ethyl 7-chloro-4-chloromethyl-2-hydroxy-6-methoxy-3-quinoline-carboxylate (116.7 g, 50 mmol) in phosphoryl chloride (100 ml) is brought to reflux for 6 hours. The phosphoryl chloride is distilled. The residue is taken up in water and agitated for 30 min. The precipitate is filtered and washed with water until neutralization. The precipitate is taken up in dichloromethane together with a saturated solution of sodium chloride. After filtraation on a bed of celite and decantation of the filtrate, the organic phase is washed again with a saturated solution of sodium chloride. After drying on magnesium sulfate, filtration and evaporation under reduced pressure, 15.88 g of a brown oil are obtained. RMN-!H (CDCI3): 1.47 (t, 3H); 4.08 (t, 3H) ; 4.55 (q, 2H); 4.87 (s, 2H); 7.35 (s, 1H) ; 8.09 (s, 1H). 30. d. Ethyl 2,7-dichioro-6-methoxy-4-(4-methylpiperazinomethyI)-3-quinoline-carboxylate A mixture of ethyl 2,7-dichloro-4-chloromethyl-6-methoxy-3-quinoline-carboxylate (6.9 g, 20 mmol) and N-methylpiperazine (9 ml, 80 mmol) is heated to 60 °C for 30 min. The reaction mass is diluted in water and extracted with ethyl acetate. The organic phase is decanted and washed with water. After drying on magnesium sulfate, filtration and evaporation under reduced pressure,, the residue is taken up in water, agitated 15 minutes, filtered, washed with water and dried in vacuum. The residue is purified by column chromatography (Si02, MeOH/CH2Cl2; 5/95 to 8/92). 6.7 g of a beige solid are obtained. RMN-!H (CDC13): 1.45 (t, 3H); 2.28 (s, 3H); 2.35-2,70 (m, 8H); 3.86 (s, 2H); 4.04 (s, 3H); 4.48 (q, 2H); 7.77 (s, 1H) ; 8.05 (s, 1H). 30.e. 2,7-dichloro-6-methoxy-4-(4-methyIpiperazinomethyl)-3-quinoline-methanol Ethyl 2,7-dichloro-6-methoxy-4-(4-methylpiperazinomethyl)-3-quinoline-carboxylate (6 g, 14.5 mmol) is dissolved in methylene chloride (120 ml). A molar solution of diisobutyl aluminum hydride in methylene chloride (60 ml, 60 mmol) is added slowly. The reaction mixture is agitated for one hour at ambient temperature. The reaction mixture is poured slowly into 300 ml of 20 % Rochelle salt solution. The resulting mixture is agitated for one hour, filtered on celite and decanted. The organic phase is washed with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and evaporated under reduced pressure. The solid is taken up in isopropyl ether, filtered and dried in vacuum. 4.3 g (80 %) of sought compound is obtained in the form of a yellow solid. RMN-JH (CDCI3): 2.27 (s, 3H); 2.30-2.80 (m, 8H); 4.03 (s, 3H); 4.08 (s, 2H); 4.96 (s, 2H); 5.95 (s, 1H); 7.37 (s, 1H); 8.05 (s, 1H). 30. f. 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methyI-piperazinomethyl)-lH-oxepino [3,4,6,7,]-indalizino [l,2-b]quinoline-3,15 (4H,13H)-dione 2,7-dichloro-6-methoxy-4-(4-methylpiperazinomethyl)-3-quinoline-methanol is coupled to compound (M) as described in stages 11. j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in stage 11. k. A yellow solid is obtained (m.p. > 250 °C). RMN-^H (DMSO): 0.87 (t, 3H); 1.84 (q, 2H); 2.53 (s, 4H); 3.08 (d, 1H); 3.47 (d, 1H); 3.58 (s, 4H); 4.06 (s, 5H); 5.30 (s, 2H); 5.42 (q, 2H); 6.03 (s, 1H); 7.31 (s, 1H); 7.91 (s, lH);8.16(s, 1H). RMN-13C (DMSO) : 8.42 ; 36.53 ; 50.65 ; 53.30 ; 56.67 ; 62.00 ; 66.50 ; 73.32 ; 99.31; 104.86 ; 122.32 ; 126.94 ; 127.70 ; 129.83 ; 130.44 ; 138.89 ; 144.22 ; 144.85 ; 151.05 ; 153.17; 155.92; 159.19; 172.06. IR (KBr): 862 ; 1063 ; 1116 ; 1248 ; 1595 ; 1655 ; 1744 ; 3449. Example 31: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy- ll-morpholinomethyl-lH-oxepmo [3,4,6,7,]indolizino[1,2-b-blquinoline-3,15 (4H,13H)-dione The procedure described in the examples 30.a., 30. b. and 30. c. is applied to 3-chloro-4-methoxyaniline resulting in ethyl 2,7-dichloro-4-chloromethyl-6-methoxy-3-quinoline-carboxylate which is treated according to the procedure in example 30. d., using morpholine in place of N-methylpiperazine, then reduced according to the method in example 30. e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in ll.k. A beige solid is obtained (m.p. > 250 °C). RMISMH (DMSO): 0.87 (t, 3H); 1.84 (q, 2H) ; 2.15 (s, 3H); 2.32 (s, 4H); 2.50 (s, 4H); 3.08 (d, 1H) ; 3.47 (d, 1H); 4.06 (s, 5H) ; 5.29 (s, 2H) ; 5.46 (q, 2H); 6.06 (s, 1H); 7.31 (s, 1H) ; 7.92 (s, 1H); 8.17 (s, 1H). RMN-13C (DMSO): 8.42 ; 36.51 ; 42.57 ; 45.93 ; 50.66 ; 52.83 ; 55.05 ; 56.09 ; 56.72; 61.44 ; 73.29 ; 99.30 ; 104.89 ; 122.32 ; 126.89 ; 127.63 ; 129.85 ; 130.16 ; 138.78 ; 144.18 ; 144.81 ; 151.03 ; 153.10 ; 155.10; 159.17 ; 172.07. IR (KBr): 1055 ; 1252 ; 1596 ; 1655 ; 1747 ; 3449. Example 32: 5-ethyl-4,5-dihydro-5-hydroxy-12-(4-methyl piperazinomethyl)- 1H-oxepino[3',4':6,7] indolizino [1,2-] quinoline -3,15(4H,13H)-dione The procedure described in the examples 30.a., 30. b. and 30. c. is applied to aniline resulting in ethyl 2-chloro-4-chloromethyl-3~quinolinecarboxylate which is treated according to the procedure in example 30. d. using N-methylpiperazine, then reduced according to the method in example 30. e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 11 .k. A yellow solid is obtained (m.p. > 260 °C). RMN-lH (DMSO): 0.86 (t, 3H); 1.87 (q, 2H)2.14 (s, 3H); 2.32-2,60 (m, 8H); 3.05 (d, 1H); 3.48 (d, 1H); 4.09 (q, 2H); 5.42 (d, 1H); 5;52 (d, 1H); 6.03 (se, 1H); 7.40 (s, 1H); 7.72 (t, 1H); 7.85 (t, 1H); 8.16 (d, 1H); 8.45 (d, 1H). IR(KBr): 1652 ; 1735 ; 3424. Example 33: 5-ethyl-4,5-dihydro-5-hydroxy-12-piperidinomethyl-1H-oxepino [3,,4':6,73indolizino[l,2-^]quinoline-3,15(4Jfir,13H)-dione The procedure described in the examples 30.a., 30. b. and 30. c. is applied to aniline resulting in ethyl 2-chloro-4-chlorometh^l-3-quinolinecarboxylate which is treated according to the procedure in example 30. d., using piperidine in place of N-methylpiperazine, then reduced according to the method in example 30. e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A yellow solid is obtained (m.p. > 260 °C). RMN-1H (DMSO): 0.86 (t, 3H); 1.40 (se, 2H); 1.48 (se, 4H) ; 1.87 (q, 2H); 2.50 (s, 4H); 3.05 (d, 1H); 3.48 (d, 1H); 4.04 (q, 2H); 5.33 (s, 2H); 5.42 (d, 1H); 5.51 (d, 1H); 6.07 (se, 1H); 7.75 (t, 1H); 7.85 (t, 1H); 8.15 (d, 1H); 8.45 (d, 1H). RMN-13C (DMSO): 8.47 ; 23.50 ; 25.82 ; 36.50 ; 42.50 ; 50.68 ; 54.47 ; 58.00 ; 61.42; 73.35 ; 99.55 ; 122.61 ; 125.31 ; 127.58 ; 129.54 ; 129.55 ; 129.56 ; 129.57 ; 140.49 ; 144.95 ; 148.63 ; 152.41 ; 155.90 ; 159.23 ; 172.07. IR (KBr): 1659 ; 1727 ; 3408. Example 34: 5-ethyl-4,S-dihydro-S-hy:droxy-12-morpholinomethyl-lH- oxepino[3,,4,:6,7]indolizino[l,2-6]quinoline-3,15(4H,13H)-dione The procedure described in the examples 30.a., 30. b. and 30. c. is applied to aniline resulting in ethyl 2-chloro-4-chloromethyl-3~quinolinecarboxylate which is treated according to the procedure in example 30. d., using morpholine in place of N-methylpiperazine, then reduced according to the method in example 30. e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A. yellow solid is obtained (m.p. > 260 °C). RMN-!H (DMSO): 0.86 (t, 3H); 1.87 (q, 2H); 3.05 (d, 1H); 3.30 (s, 4H); 3.49 (d, 1H); 3.55 (se, 4H); 4.10 (q, 2H); 5.35 (s, 2H) ; 5.40 (d, 1H); 5.54 (d, 1H); 6.04 (s, 1H); 7.72 (t, 1H); 7.85 (t, 1H); 8.16 (d, 1H); 8.47 (d, 1H). RMN-13C (DMSO) : 8.42 ; 36.51 ; 42.57 ; 50.68 ; 53.51 ; 56.06 ; 61.42 ; 66.41 ; 73.34 ; 99.56 ; 122.64 ; 125.25 ; 127.56 ; 129.81 ; 139.55 ; 144.92 ; 148.62 ; 152.39 ; 155.89 ; 159.21 ; 172.05. IR (KBr): 1657 ; 1729 ; 3347. Example 35: 5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy- 12-(4-methylpiperazinomethyl)-1H-oxepino[3',4' :6,7]indolizino [1,2-b] quinoline-3,15(4H,13H)-dione The procedure described in the examples 30a., 30.b. and 30.c. is applied to 4-fluoroaniline resulting in ethyl 2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treated according to the procedure in example 30.d. using N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in ll.k. A yellow solid is obtained (m.p. > 275 °C). RMN-1H (DMSO) : 0.87 (t, 3H); 1.85 (q, 2H) ; 2.15 (s, 3H); 2.31 (m, 4H) ; 2.50 (m, 4H); 3.07 (d, 1H); 3.48 (d, 1H); 4.04 (m, 2H) ; 5.31 (s, 2H); 5.40 (d, 1H); 5.53 (d, 1H) ; 6.05 (s, 1H); 7.38 (s, 1H); 7.77 (m, 1H); 8.19 (m, 2H). RMN-13C (DMSO): 8.43 ; 36.51 ; 42.54 ; 45.89 ; 50.67 ; 52.92 ; 54.93 ; 55.92 ; 73.32 ; 99.56; 122.69; 130.43; 132.40; 139.69; 144.70; 145.84; 152.19; 155.90; 159.17; 172.05. IR (KBr): 836 ; 1051 ; 1217 ; 1291 ; 1612 ; 1662 ; 1726. Example 36: 5-ethyl-10-fluoro-4,5ldihydro-5-hydroxy-12-morpholinomethyl- lH-oxepino[3,,4,:6,7]indoIizino[l,2-b]quinoline-3,15(4H,13H)-dione The procedure described in the examples 30.a., 30.b. and 30.c. is applied to 4-fluoroaniline resulting in ethyl 2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treated according to the procedure in example 30.d., using morpholine in place of N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A beige solid is Obtained (m.p. > 250 °C). RMN-!H (DMSO) : 0.87 (m, 3H); 1.85 (m, 2H); 2.51 (m,4H) ; 3.06 (d, 1H) ; 3.48 (d, 1H); 3.56 (m, 4H); 4.05 (m, 2H); 5.34 (s, 2H) ; 5.40 (d, 1H); 5.53 (d, 1H); 6.04 (s, 1H); 7.38 (s, 1H) ; 7.77 (m, 1H); 8.21 (m, 2H). RMN-13C (DMSO) : 8.40 ; 36.47 ; 42.52 ; 50.59 ; 53.40 ; 56.14 ; 61.44 ; 66.41 ; 73.29 ; 99.58 ; 109.05 ; 109.28 ; 120.11 ; 120.37 ; 122.68 ; 128.53 ; 130.53 ; 132.43 ; 139.13 ; 144.62 ; 145.79 ; 152.07 ; 155.94 ; 159.14 ; 161.59 ; 172.04. IR (KBr): 834 ; 860 ; 1061 ; 1118 ; 1215 ; 1286 ; 1516 ; 1609 ; 1658 ; 1734. Example 37: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl- 12-(4-methylpiperazinomethyl)-1H-oxepino[3',4':6,7]indolizino[l,2-b] quinoline-3,15(4H,13H)-dione The procedure described in the examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline, resulting in ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to the procedure in example 30.d. using N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A yellow solid is obtained (m.p. > 260 °C). RMN-1H (CDC13): 1.00 (t, 3H); 2.00 (q, 2H); 2.35 (s, 3H); 2.50 (s, 3H); 2.61 (m, 8H); 3.33 (d, 1H); 3.39 (d, 1H); 3.97 (d, 1H) ; 4.07 (d, 1H); 5.17 (d, 1H); 5.38 (d, 1H); 5.52 (d, 1H); 5.63 (d, 1H); 7.13 (d, 1H); 7.28 (s, 1H); 7.99 (d, 1H). IR (KBr): 1652 ; 1747 ; 3430. Example 38: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl- 12-morpholinomethyl-lH-oxepino[3,4':6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)- dione The procedure described in the examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline, resulting in ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to the procedure in example 30.d., using morpholine in place of N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A yellow solid is obtained (m.p. > 260 °C). RMN-lH (DMSO + CDC13): 1.00 (t, 3H) ; 2.02 (q, 2H); 2.57 (s, 3H); 2.60 (s, 4H); 3.23 (d, 1H) ; 3.45 (d, 1H); 3.75 (s, 4H) ; 4.11 (s, 2H); 5.44 (s, 2H); 5.47 (d, 1H); 5.65 (d, 1H) ; 7.62 (s, 1H) ; 7.73 (d, 1H); 8.24 (d, 1H). RMN-13C (CF3CO2D): 8.35 ; 13.93 ; 16.01 ; 22,24 ; 25.29 ; 38.18 ; 43.42 ; 54.19 ; 56.04 ; 56.74 ; 64.16 ; 65.09 ; 77.48 ; 108.29 ; 108.57 ; 128.07 ; 128.70 ; 129.90 ; 135.64 ; 138.03 ; 139.86 ; 141.10 ; 141.56 ; 147.78 ; 158.30 ; 161.87 ; 178.72. IR (KBr): 117 ; 1609 ; 1654 ; 1750 ; 3437. Example 39: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl- 12-piperidinomethyl-lH-oxepino [3',4':6,7] indolizino [1,2-b] quinoline-3,15(4H,13H)-dione The procedure described in the examples 30.a,, 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline, resulting in ethyl 2-ehloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to the procedure in example 30.d., using piperidine in place of N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A yellow solid is obtained (m.p. > 260 °C). RMN-1H (CF3CO2D): 1.09 (s, 3H); 1.70 (t, 1H); 2.03 (m, 5H); 2.25 (s, 2H); 2.70 (s, 3H); 3.54 (d, 3H); 3.88 (d, 1H); 4.01 (se, 2H); 5.30 (q, 2H); 5.65 (d, 1H); 5.96 (d, 1H); 6.10 (s, 2H); 8.16 (d, 1H); 8.35 (s, 1H); 8.61 (s, 1H). RMN-13C (CF3CO2D): 8.47 ; 16.07 ; 20.93 ; 22.18 ; 24.76 ; 38.28 ; 43.53 ; 54.30 ; 56.12 ; 58.33; 64.24; 77.56; 108.37; 111.30; 128.20; 129.02; 129.98; 135.60; 138.29; 139.90 ; 141.60 ; 142.26 ; 147.57 ; 158.28 ; 161.90; 167.63 ; 170.31; 178.82. IR (KBr): 1605 ; 1657 ; 1728 ; 3399. Example 40: 8-ethyl-2,3,8,9-tetrahydro-8-hydroxy- 16-(4-methylpiperazinomethyl)-10H,12H-[l,4] dioxino [2,3-g] oxepino [3'4':6,7]indolizino [1,2-b] quinoline-10,13[15H]-dione The procedure described in the examples 30.a., 30.b. and 30.c. is applied to 3,4-ethylenedioxyaniline, resulting in ethyl 2~chloro-4-chloromethyl-6,7-ethylenedioxy-3-quinolinecarboxylate which is treated according to the procedure in example 30.d. using N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A yellow solid is obtained (m.p. > 260 °C). RMN-1H (DMSO) : 0.92 (t, 3H) ; 1.89 (q, 2H); 2.16 (s, 3H) ; 2,.0 (m, 8H) ; 3.12 (d, 1H) ; 3.50 (d, 1H) ; 3.95 (s, 2H); 4.47 (s, 4H); 5.19 (q, 2H); 5.43 (d, 1H); 5. 56 (d, 1H); 7.35 (s, 1H) ; 7.54 (s, 1H); 7.76 (s, 1H). RMN-13C (DMSO): 8.45 ; 24.80 ; 36.51; 42.48 ; 45.90 ; 50.45 ; 52.98 ; 54.91 ; 56.10 ; 61.44 ; 64.43 ; 73.30 ; 99.03 ; 109.46 ; 113.51 ; 121.95 ; 123.51 ; 127.76 ; 137.99 ; 145.00; 145.14 ; 145.27 ; 147.24 ; 150.53 ; 155.99 ; 159.18 ; 172.27 ; 177.00. IR (KBr): 1656 ; 1743 ; 3422. Example 41: 9-chloro-5-ethyH0-fluoro-4,5-dihydro-5-hydroxy- 12-morpholinomethyl-lH-oxepino[3,4,:6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)- dione The procedure described in the examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-fluoroaniline, resulting in ethyl 2,7-dichloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treated according to the procedure in example 30.d., using morpholine in place of N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A beige solid is obtained (m.p. > 250 °C). RMN-H (CF3COOD): 1.09 (t, 3H); 2.30 (m, 2H); 3.50 (d, 1H); 3.90 (d, 1H); 3.98 (d, 4H); 4.36 (s, 4H); 5.38 (q, 2H); 5.64 (d, 1H); 5.96 (d, 1H); 6.23 (q, 2H); 8.57 (d, 1H); 8.60 (s, 1H); 8.85 (d, 1H). RMN-13C (CF3COOD): 8.10 ; 37.80 ; 43.11 ; 54.31 ; 55.78 ; 63.75 ; 65.11 ; 77.06 ; 128.28 ; 129.55 ; 130.33 ; 136.26 ; 137.11; 138.40 ; 139.67 ; 139.85 ; 148.58 ; 157.54; 159.74; 161.31; 178.00. IR (KBr): 848 ; 1042 ; 1230 ; 1609 ; 1658 ; 1750; 3310 ; 3387. Example 42 : resolution of 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino [1,2-b] quinoline-3,15 (4H,13H)-dione A mixture of P-ethyl-P-hydroxy-(8-hydroxymethylindolizino[l,2-b]quinoline-9-(llH)-one-7-yl)-propionic acid (19.5 g, 52mmol) and L-(-)-α-methylbenzylamine (12.12 g, 100 mmol) in absolute ethanol (11) is carried to boiling, hot filtered and allowed to rest 68 hours. The precipitate is filtered and washed with ethanol and ether, yielding 9.8 g of a white solid. An analysis by high pressure affinity chromatography on the chiral phase ("HPLC chiral" on a Chiral-AGP column (Chromtech, Stockholm, Sweden) 100 x 4mm, 2 % acetonitrile eluant in a 10 mM at pH 6.9 phosphate buffer, eluant peaks at 4.5 and 7.5 min) reveals two peaks integrating respectively for 24 % and 76 % of the total surface of the two peaks. The solid is taken up in 93 % ethanol (350 ml) at reflux, then allowed to rest 48 hours. The precipitate is filtered, then washed with ethanol and ether to obtain 4.8 g of a white solid, giving two integrating peaks respectively for 9 % and 91 % of the total surface of the two peaks by chiral HPLC. The solid is taken up in 50 % ethanol (48 ml) at reflux then allow to rest for 48 hours. The precipitate is filtered, then washed with ethanol and ether resulting in 2.7 g of a white solid giving two integrating peaks respectively for 1 % and 99 % of the total surface of the two peaks by chiral HPLC. The resultant salt, diastereoisomerically enriched, is taken up in distilled water (20 ml) and treated with acetic acid (0.35 ml, 6.4 mmol) for 15 min. The obtained precipitate is filtered, washed with water, acetone and ether then dried in a vacuum at 80 °C resulting in 1.1 g of a white solid. The latter is taken up in absolute ethanol (55 ml) with concentrated hydrochloric acid added (11.5 N, 11 ml) resulting in a yellow solution which is agitated at ambient temperature for 68 h. The precipitate thus obtained is filtered and washed with water, ethanol and ether, then dried in vacuum at 80 °C resulting in 770 mg of enantiomerically enriched 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione. An analysis by chiral HPLC (Chiral-AGP column, eluted by a 2 to 5 % gradient of acetonitrile in a l0mM ar pH 6.9 phosphate buffer, eluant peaks at 15 and 20 min) reveals an enantiomeric excess of 98 %. The procedure described above can be repeated replacing the L-(-)-α-methylbenzylamine by D-(+)-α-methylbenzylamine. The other enantiomer of 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3\4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione is thus obtained. Example 43: 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(l,2,5,6- tetrahydropiridinomethyl-1H-oxepinot[3,4,6,7,]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione hydrochloride The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3,4-difluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d„ using 1,2,5,6-tetrahydropyridine instead of N-methylpiperazine, and then reduced irj the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage ll.k. The free base thus obtained is suspended in absolute ethanol (50 ml/mmol) and treated with hydrogen chloride in ethanol (2.5 N; 5 eq.). At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The light orange solid obtained is washed with ether (m.p. 264 °C). RMISMH (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 2.26-2.30 (m, 1H) ; 2.50 (m, 1H); 3.09 (d, 1H); 3.40 (m, 2H); 3.48 (d, 1H); 3.87 (m, 2H); 5.05 (m, 2H); 5.48 (q, 2H); 5.65 (m, 2H); 5.89 (m, 1H); 7.42 (s, 1H); 8.24-8.30 (m, 1H); 8.76-8.82 (m, 1H); 10.86 (s, 1H). RMN-13C (DMSO): 8.44 ; 22.36 ; 36.5 ; 42.7 ; 48.71 ; 50.30 ; 51.49 ; 61.42 ; 73.23 ; 100.16 ; 112.64 ; 112.83 ; 116.05 ; 120.26 ; 123.31 ; 125.29 ; 125.40 ; 131.17 ; 133.97 ; 144.15 ; 146.26 ; 146.37 ; 148.74 ; 150.52 ; 151.23 ; 153.20 ; 153.53 ; 155.99 ; 159.04 ; 172.02. IR (KBr): 662 ; 1064 ; 1268 ; 1452 ; 1523 ; 1598 ; 1652 ; 1743 ; 2936 ; 3027 ; 3418. Example 44: 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methyl piperidinomethyl)-lH-oxepino[3,,4':6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)- dione The procedure described in examples 30.a., 30.b, and 30.c. is applied to 3,4-difluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using 4-methylpiperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A beige solid is obtained (m.p. > 250 °C). RMN-lH (DMSO): 0.9 (m, 6H); 1.1 (m, 2H); 1.4 (m, 1H); 1.55 (d, 2H); 1.85 (q, 2H); 2.1 (t, 2H); 2.85 (m, 2H) ; 3.25 (dd, 2H) ; 4 (s, 2H) ; 5.3 (s, 2H) ; 5.45 (dd, 2H) ; 6.05 (s, 1H); 7.35 (s, 1H); 8.15 (dd, 1H); 8.45 (dd, 1H), IR (KBr): 1454 ; 1518 ; 1608 ; 1658 ; 1733 ; 2804 ; 2926 ; 3311. Suspending in absolute ethanol (50 ml/mmol) the free base obtained as described above and subsequent treating with hydrogen chloride in ethanol (2,5 N; 5 eq.) yields the corresponding hydrochloride. At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The strong yellow solid obtained is washed with ether (m.p. > 250 °C). RMN-1H (DMSO): 0.85 (m, 6H); 1.7 (m, 5H); 1.85 (q, 2H); 3.15 (s, 1H); 3.25 (dd, 2H) ; 3.3 (m, 2H) ; 4.9 (s, 2H) ; 5.45 (dd, 2H) ; 5.6 (s, 2H) ; 6.1 (s, 1H) ; 7.4 (s, 1H) ; 8.25 (dd, 1H); 8.75 (dd, 1H); 10.35 (s, 1H). IR (KBr): 1270 ; 1455 ; 1523 ; 1606 ; 1653 ; 1742 ; 2943 ; 3419. Example 45: 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy- 12-pyrrolidinomethyl-1H-oxepino[3,,4':6,7]indolizino[l,2-6]quinoline-3,15(4H,13H)- dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3,4-difluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using pyrrolidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A beige solid is obtained (m.p. > 250 °C). RMN-lH (DMSO): 0.85 (1, 3H); 1.7 (s, 4H); 1.85 (q, 2H); 2.55 (s, 4H); 3.25 (dd, 2H); 4.15 (d, 2H); 5.35 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.35 (s, 1H); 8.15 (dd, 1H) ; 8.45 (dd, 1H). IR (KBr): 1455 ; 1518 ; 1605 ; 1657 ; 1731 ; 2801 ; 2970 ; 3422. Suspending in absolute etbanol (50 ml/mmol) the free base obtained as described above and subsequent treating with hydrogen chloride in ethanol (2.5 N; 5 eq.) yields the corresponding hydrochloride. At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The light orange solid obtained is washed with ether (m.p. > 250 °C). RMN-lH (DMSO): 0.85 (t, 3H); 1.9 (m, 4H); 2.1 (s, 2H); 3.25 (dd, 2H); 3.3 (m, 2H); 3.55 (m, 2H) ; 5.05 (s, 2H); 5.45 (dd, 2H); 5.6 (s, 2H); 6.1 (s, 1H); 7.4 (s, 1H); 8.3 (dd, 1H); 8.75 (dd, 1H); 10.75 (s, 1H). IR (KBr): 1454 ; 1522 ; 1603 ; 1653 ; 1743 ; 2970 ; 3394. Example 46: 5-ethyl-9,10-difluoro«4,5»dihydro-5-hydroxy-12-(4-methyl piperazmomethyl-liy-oxepino[3,,4,:6,7]indoli2ino[l,2-ft]quinolme-3,15(41?,13iar)- dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3,4-difluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d. and reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C). RMN-!H (CDC13 + CD3OD): 0.99 (t, 3H) ; 2.00 (q, 2H); 2.32 (s, 3H); 3.24 (d, 1H) ; 3.37 (s, 1H); 3.42 (d, 1H); 4.04 (s, 2H); 5.37 (s, 2H); 5.43 (d, 1H); 5.64 (d, 1H); 7.56 (s, 1H); 7.84 (dd, 1H); 8.22 (dd, 1H). RMN-13C (CDCI3 + CD3OD): 7.87 ; 36.11; 42.16 ; 45.33 ; 52.67 ; 54.52 ; 56.47 ; 61.97; 73.26 ; 101.17 ; 110.81 ; 115.49 ; 122.93 ; 128.63 ; 139.83 ; 144.28 ; 146.40 ; 149.27 ; 151.27 ; 151.64 ; 152.31 ; 153.82 ; 156.50; 159.71 ; 172.56. IR (KBr): 1607 ; 1656 ; 1732 ; 2795 ; 3411. Example 47: 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy- 12-piperidmomethyl-lH-oxepino[3',4':6,7Iindolizino[l,2-b]qumoline-3,15(4H,13H)- dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3,4-difluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using piperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light green solid is obtained (m.p. 266-268 °C). RMN-!H (DMSO): 0.86 (t, 3H); 1.42-1.49 (m, 6H); 1.85 (q, 2H); 2.47 (m, 4H); 3.06 (d, 1H); 3.48 (d, 1H); 4.00 (q, 2H); 5.31 (s, 2H); 5.46 (dd, 2H); 6.04 (s, 1H); 7.37 (s, 1H); 8.14 (m, 1H); 8.46 (m, 1H). RMN-13C (DMSO): 8.43 ; 24.01 ; 25.8 ; 36.52 ; 42.56 ; 50.60 ; 54.29 ; 56.91 ; 61.41 ; 73.30; 99.81 ; 111.86; 115.67; 122.94; 130,10; 140.66; 144.49; 146.12; 153.18; 155.86 ; 159.14 ; 172.03. IR (KBr): 1258 ; 1452 ; 1517 ; 1607 ; 1661 ; 1731 ; 2950 ; 3480. Example 48: 5-ethyl-9,10-difluoro-4,S-dihydro-5-hydroxy-12-dimethyIamino- methyl-1H-oxepino[3,4,6,7,]indolizino[1,2-b]quinoline-3,15(4H,13H)dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3,4-difluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using dimethylamine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light beige solid is obtained (m.p. > 270 °C). RMN-lH (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.25 (s, 6H); 3.08 (d, 1H); 3.47 (d, 1H); 3.95 (q, 2H); 5.28 (s, 2H); 5.46 (dd, 2H); 6.06 (s, 1H); 7.37 (s, 1H); 8.14 (s, 1H); 8.42 (s, 1H). RMN-13C (DMSO): 8.42 ; 14.06 ; 33.36 ; 45.44 ; 50.57 ; 61.40 ; 65.14 ; 72.05 ; 72.93 ; 73.30 ; 99.82 ; 99.95 ; 115.78 ; 115.85 ; 122.96 ; 125.01 ; 130.08 ; 140.56 ; 144.54 ; 146.16 ; 155.86 ; 159.19 ; 172.03. IR (KBr): 1516 ; 1613 ; 1654 ; 1731; 3450. Example 49: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl- 12-morpholino methyl- lH-oxepino[3',4':6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-methylaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using morpholine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. oiexample 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 300 °C). RMN-lH (DMSO): 0.87 (t, 3H); 1.84 (q, 2H); 2.50 (s, 4H); 2.58 (s, 3H); 3.07 (d, 1H); 3.46 (d, 1H); 3.57 (s, 4H); 4.08 (dd, 2H); 5.30 (s, 2H); 5.51 (dd, 2H); 6.06 (s, 1H); 7.35 (s, 1H); 8.15 (s, 1H); 8.41 (s, 1H). RMN-13C (DMSO): 8.42 ; 20.57 ; 36.51; 42.55; 50.76 ; 53.46 ; 55.86 ; 61.42 ; 66.42 ; 73.29 ; 99.73 ; 122.78 ; 128.40 ; 130.10; 135.31 ; 136.26 ; 139.36 ; 144.61 ; 147.79 ; 152.81 ; 155.86; 159.16; 172.04. IR (KBr) : 1613 ; 1657 ; 1736 ; 3432. Example 50: 9-chloro-5-ethyl-4,5-Hihydro-5-hydroxy-10-methyl- 12-(4-methylpiperazinomethyl)lJ^-oxepino[3',4,:6,7]indoIizino [l,2-6]quinoline-3,15(4H,13H)-dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-methylaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d. and reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage ll.k. A yellow solid is obtained (m.p. 262-268 °C). RMN-1!! (DMSO): 0.87 (t, 3H); 1.86 (q, 2H); 2.15 (s, 3H); 2.20-260 (m, 8H); 2.60 (s, 3H); 3.05 (d, 1H); 3.49 (d, 1H); 4.09 (dd, 2H) ; 5.32 (s, 2H); 5.50 (dd, 2H); 6.05 (s, 1H); 7.37 (s, 1H); 8.21 (s, LH); 8.43 (s, 1H). RMN-13C (DMSO): 8.42 ; 20.56 ; 36.50; 42.55 ; 45.91 ; 50.81 ; 53.00 ; 54.94 ; 55.65 ; 61.43 ; 73.29 ; 79.36 ; 99.69 ; 122.75 ; 126.32 ; 128.37 ; 129.84 ; 135.25 ; 136.23 ; 139.87 ; 144.57 ; 147.75 ; 152.76 ; 155.87 ; 159.15 ; 172.04. IR (KBr): 1607 ; 1658 ; 1733 ; 3424. Example 51: 12-benzylmethylaminomethyl-9-chloro-5-ethyl-4,5-dihydro- 5-hydroxy-10-methyl-lH-oxepmo[3,,4:6,7imdolizino[l,2-b]quinoline-3,15(4H,13H)- dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-methylaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using N-methylbenzylamine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. 275-278 °C). RMN-1H (DMSO): 0.88 (t,3H); 1.85 (m, 2H); 2.13 (s, 3H); 2.55 (s, 3H); 3.10 (d, 1H); 3.50 (d, 1H); 3.67 (s, 2H); 4.05 (dd, 2H); 5.30 (s, 2H); 5.39-5.57 (dd, 2H); 6.05 (s, 1H); 7.36 (m, 6H); 8.15 (s, 1H) ; 8.31 (s, 1H). RMN-13C (DMSO): 9.10 ; 21.15 ; 37.20 ; 42.86 ; 43.23 ; 51.32 ; 55.78 ; 62.10 ; 62.88 ; 73.99; 80.05; 100.44; 123.47; 126.99; 127.32; 128.09; 129.17; 129.96; 130.86; 135.75 ; 136.84 ; 139.51 ; 140.67 ; 145.38 ; 148.54 ; 153.50 ; 156.54 ; 159.85 ; 172.73. IR (KBr): 1609 ; 1655 ; 1729 ; 3395. Example 52: 12-(4-benzylpiperazinomethyl)-9-chloro-5-ethyl-4,5-dihydro- 5-hydroxy-10-methyl-lH-oxepino[3,,4,:6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)- dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-methylaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using N-benzylpiperazine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A beige solid is obtained (m.p. 244=249 °C: RMN-lH (DMSO): 0.86 (t, 3H); 1.83 (m, 2H); 2.38-2.60 (m, 8H); 2.57 (s, 3H); 3.08 (d. 1H); 3.46 (s ,2H); 4.08 (m, 2H); 5.30 (s, 2H); 5.51 (dd, 2H); 6.05 (s, 1H); 7.30 (m, 6H); 8.16 (s, 1H); 8.40 (s,lH). RMN-13C (DMSO): 9.10 ; 21.23 ; 37.19 ; 43.21 ; 51.48 ; 53.54 ; 53.80 ; 56.35 ; 62.09 ; 62.84 ; 73.97 ; 97.67 ; 100.39 ; 123.45 ; 127.05 ; 127.75 ; 129.02 ; 129.63 ; 130.61 ; 135.95 ; 136.93 ; 139.14 ; 140.52 ; 145.27 ; 148.45 ; 153.47 ; 156.52 ; 159.83 ; 172.72. IR (KBr): 1567 ; 1587 ; 1652 ; 1748 ; 3422. Example 53 : 9-chloro-5~ethyl-4,5-dihydro-5-hydroxy-10-methyl- 12-piperidinomethyl-1H-oxepino[3',4,:6,7]Indolizino[l,2-B]quinoline-3,15(4H,13H)- dione The procedure described in examples 30,a., 30.b. and 30.c. is applied to 3-chloro-4-methylaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using piperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. 255 °C). RMN-lH (DMSO): 0.86 (t, 3H); 1.50 (m, 6H); 1.84 (m, 2H); 2.50 (m, 4H); 2.58 (s, 3H); 3.05 (d, 1H); 3.45 (d, 1H); 4.04 (m, 2H); 5.32 (s, 2H); 5.51 (dd, 2H); 6.10 (s, 1H); 7.37 (s, 1H); 8.20 (s, 1H); 8.42 (s, 1H). RMN-^C (DMSO): 9.11 ; 21.24 ; 24.70; 26.50; 37.20; 43.23 ; 51.43 ; 55.10 ; 57.21 ; 62.09; 73.99; 98.05; 100.38; 123.44; 127.10; 129.12; 130.59; 135.89; 136.91; 140.99 ; 145.31 ; 148.50 ; 153.52 ; 156.51; 159.85 ; 172.73. IR (KBr): 1601 ; 1654 ; 1728 ; 3436. Example 54: 12-(4-benzylpiperazlnomethyl)-5-ethyl-9-fluoro-4,5-dihydro- 5-hydroxy-lH-oxepino[3',4,:6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 4-fluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using N-benzylpiperazine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A white solid is obtained (m.p. 262 °C). RMN-JH (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 2.37 (s, 4H); 2,.7 (s, 4H); 3.07 (d, 1H); 3.5 (s, 2H) ; 3.47 (d, 1H) ; 4.08 (q, 2H); 5.32 (s, 2H); 5.46 (dd, 2H); 6.03 (s, 1H); 7.35 (m, 5H); 7.38 (s, 1H); 7.77 (m, 1H); 8.20 (m, 2H). RMN-13C (DMSO): 8.41 ; 36.49 ; 42.53 ; 50.65 ; 52.82 ; 53.03 ; 55.95 ; 61.41 ; 62.14; 72.3 ; 99.55 ; 109.31 ; 120.14 ; 120.40 ; 122.70 ; 127.05 ; 128.32 ; 128.55 ; 128.96 ; 130.40 ; 138.42 ; 139.65 ; 144.66 ; 145.83 ; 152.15 ; 155.89 ; 159.15 ; 161.57 ; 172.02. IR (KBr): 740 ; 834 ; 1071 ; 1193 ; 1220 ; 1288 ; 1360 ; 1451 ; 1516 ; 1592 ; 1655 ; 1749 ; 2813 ; 2950 ; 3434. Example 55 : 12-(4-benzyIpiperazinomethyl)-5-ethyl-9-£luoro-4,5-dihydro- 5-hydroxy-10-methyl-lH-oxepino[3,,4,:6,7]idolizino[l,2-b]quinoline-3,15(4H,13H)-dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using N-benzylpiperazine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light beige solid is obtained (m.p. 259 °C). RMNMH (DMSO): 0.86 (t, 3H) ; 1.85 (q, 2H); 2.38 (m, 4H); 2.50 (s, 4H); 3.06 (d, 1H) ; 3.36 (s, 3H); 3.46 (s, 2H) ; 3.47 (d, 1H) ; 4.07 (q, 2H); 5.29 (s, 2H); 5.46 (dd, 2H) ; 6.02 (s, 1H); 7.23-7,35 (m, 6H); 7.8 (d, 1H); 8.35 (d, 1H). RMN-13C (DMSO): 8.40 ; 15.45 ; 36.47 ; 42.54 ; 50.7 ; 52.84 ; 53.13 ; 55.81 ; 61.4; 62.14 ; 73.29 ; 99.57 ; 112.45 ; 122.61 ; 124.73 ; 127.05 ; 128.32 ; 128.96 ; 138.45 ; 139.81 ; 1444.68 ; 152.63 ; 155.85 ; 159.15 ; 172.02. IR (KBr): 1013 ; 1069 ; 1169 ; 1241 ; 1266; 1475 ; 1577 ; 1594 ; 1655 ; 1744. Example 56: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl- ll-dimethylaminomethyl-1H-oxepino[3,4,6,7,]lindolizino[1,2,b] quinoline-3,15(4H,13H)-dione The procedure described in examples 30,a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using dimethylamine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 11 .j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light beige solid is obtained (m.p. 184-190 °C). RMN-1H (DMSO) : 0.86 (t, 3H) ; 1.85 (q, 2H) ; 2.26 (s, 6H) ; 2.5 (s, 3H) ; 3.05 (d, 1H); 3.48 (d, 1H) ; 3.98 (q, 2H); 5.28 (s, 2H); 5.46 (dd, 2H); 6.06 (s, 1H); 7.37 (s, 1H); 7.84 (d, 1H) ; 8.35 (d, 1H). RMN-13C (DMSO): 8.45 ; 15.50 ; 36.52 ; 45.59 ; 50.62 ; 57.36 ; 61.43 ; 73.33 ; 99.66 ; 112.29 ; 112.50 ; 122.67 ; 124.71 ; 126.99 ; 127.20 ; 127.44 ; 129.08 ; 140.16 ; 144.80; 148.82 ; 152.71 ; 155.89 ; 159.22 ; 160.75 ; 172.07. IR (KBr): 1448 ; 1595 ; 1653 ; 1749 ; 2950; 3438. Example 57: 5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy- 10-methyl-lH-oxepino[3',4,:6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using diethylamine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light beige solid is obtained (m.p. > 270 °C). RMN-1H (DMSO): 0.87 (t, 3H); 1.04 (t, 6H) ; 1.86 (q, 2H); 2.50 (q, 2H); 2.54 (s, 3H) ; 2.56 (q, 2H) ; 3.08 (d, 1H); 3.48 (d, 1H) ; 4.11 (q, 2H); 5.25 (s, 2H) ; 5.46 (dd, 2H) ; 6.05 (s, 1H); 7.35 (s, 1H); 7.80 (d, 1H); 8.36 (d, 1H). RMN-^C (DMSO): 8.45 ; 11.68 ; 11.78 ; 15.43 ; 15.57 ; 36.5 ; 42.5 ; 46.68 ; 46.83 ; 46.99 ; 50.77 ; 51.85 ; 52.08 ; 61.44 ; 73.30 ; 99.60 ; 112.18 ; 112.36 ; 122.6 ; 124.6 ; 126.9 ; 127.1 ; 128.8 ; 141.45 ; 144.6 ; 148.6 ; 148.7 ; 152.65 ; 155.9 ; 159.1 ; 160.7 ; 163.2; 172.1. IR (KBr): 1217 ; 1295 ; 1448 ; 1463 ; 1507 ; 1609 ; 1660 ; 1725 ; 2971 ; 3559. Suspending in absolute ethanol (50 ml/mmol) the free base obtained as described above and subsequent treating with hydrogen chloride in ethanol (2,5 N; 5 eq.) yields the corresponding hydrochloride. At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The strong yellow solid obtained is washed with ether (m.p. 269-272 °C). RMN-lH (DMSO): 0.87 (t, 3H); 1.34 (m, 1H) ; 1.86 (q, 2H); 2.56 (s, 3H); 3.07 (d, 1H); 3.19 (m, 2H); 3.39 (m, 2H); 3.49 (d, 1H) ; 4.97 (m, 2H); 5.41 (d, 1H); 5.54 (d, 1H); 5.58 (s, 2H); 6.08 (s, 1H); 7.42 (s, 1H) ; 7.96 (d, 1H); 8.43 (d, 1H); 10.38 (s, 1H). IR (KBr): 1039 ; 1070 ; 1226 ; 1282 ; 1509 ; 1654; 1724 ; 1744 ; 2921 ; 3409 ; 3489. Example 58: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methyl piperidinomethyl)-lH-oxepino[3,4,6,7,]indolizino[1,2,-b] quinoline-3,15(4H,13H)-dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using 4-methylpiperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C). RMN-!H (DMSO) : 1.00-0,80 (complex, 6H) ; 1.12 (q, 1H) ; 1.37 (s, 1H) ; 1.57 (d, 3H) ; 1.85 (q, 2H) ; 2.13 (t, 2H); 2.82 (s, 1H) ; 2.85 (s» 1H); 3.05 (d, 1H) ; 3.25 (s, 3H) ; 3.48 (d, 1H); 4.04 (q, 2H); 5.28 (s, 2H); 5.39 (d, 1H); 5.52 (d, 1H); 6.03 (s, 1H) ; 7.36 (s, 1H); 7.82 (d, 1H); 8.40 (d, 1H). RMN-13C (DMSO): 0.29 ; 8.43 ; 13.68 ; 15.48 ; 19.40 ; 21.93 ; 23.23 ; 30.39 ; 34.20 ; 36.52 ; 42.55 ; 50.67 ; 53.84 ; 56.29 ; 57.67 ; 61.40 ; 73.32 ; 99.59 ; 112.49 ; 122.62 ; 124.80 ; 127.18 ; 129.10 ; 140.31 ; 144.58 ; 148.64 ; 152.69 ; 155.84 ; 159.19 ; 172.05. IR (KBr): 1597 ; 1653 ; 1747 ; 3446. Example 59 : 5-ethyI-9-fluoro-4,5-dihydro-5-hydroxy-10-methyI- ll-pyrrolidinomethyl-lH-oxepino[3,4,3,7]indolizino[1,2,b]quinoline-3,15(4H,13H). dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using pyrrolidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C). RMN-!H (DMSO): 0.86 (t, 3H); 1.72 (s, 4H) ; 1.85 (q, 2H); 2.57 (s, 4H); 3.05 (d, 1H) ; 3.28 (s, 3H); 3.48 (d, 1H); 4.18 (q, 2H); 5,28 (s, 2H); 5.39 (d, 1H); 5.52 (d, 1H); 6.03 (s, 1H); 7.36 (s, 1H); 7.82 (d, 1H); 8.35 (d, 1H). RMN-13C (DMSO) : 0.37 ; 8.47 ; 15.57 ; 23.48 ; 36.53 ; 42.61 ; 50.61 ; 53.45 ; 54.09 ; 61.42 ; 73.33 ; 99.59 ; 112.37 ; 122.64 ; 124.51 ; 127.00 ; 127.25 ; 128.63 ; 140.65 ; 144.77 ; 148.65 ; 152.73 ; 155.87 ; 159.20 ; 162.00 ; 167.00 ; 172.07. IR (KBr): 1608 ; 1656 ; 1729 ; 3400. Example 60 : 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl- 12-(1,2,5,6,-tetrahydropiridinomethy)-lH-oxepino[3,4,6,7,]indolizino [l,2-b]quinoline-3,15(4H,13H)-dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using 1,2,5,6-tetrahydropyridine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C). RMN-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.08 (s, 2H); 2.64 (t, 2H); 3.03 (s, 2H); 3.05 (d, 1H) ; 3.28 (s, 3H); 3.48 (d, 1H); 4.12 (d, 1H); 4.17 (d, 1H); 5.28 (s, 2H); 5.39 (d, 1H) ; 5.52 (d, 1H); 5.64 (d, 1H); 5.72 (d, 1H); 6.03 (s, 1H) ; 7.36 (s, 1H); 7.83 (d, 1H); 8.36 (d, 1H). RMN-13C (DMSO): 8.45 ; 15.54 ; 25.84 ; 36.54 ; 42.55 ; 49.78 ; 50.68 ; 52.52 ; 55.81 ; 61.42; 73.33; 99.62; 112.53; 122.66; 124.78; 125.03; 127.09; 127.19; 131.73; 139.98 ; 144.76 ; 148.79 ; 152.73 : 155.86 ; 159.19 ; 160.76 ; 163.25 ; 172.07. IR (KBr): 1605 ; 1656 ; 1733 ; 3451. Example 61: 12-diisobutylaminomethyl-5-ethyl-9-fluoro-4,5-dihydro- 5-hydroxy-10-methyl-lH-oxepino[3,4,3,7,]indolizino[1,2,b] quinoline-3,15,(4H,13H)- dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using diisobutylamine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C). RMN-1H (DMSO): 0.75 (d, 12H); 0.87 (t, 3H); 1.83 (m, 4H); 2.15 (d, 1H) ; 2.48 (s, 3H); 3.06 (d, 1H); 3.47 (d, 1H); 4.01 (q, 2H); 5.28 (s, 2H); 5.39 (d, 1H); 5.53 (d, 1H); 6.03 (s, 1H); 7.37 (s, 1H); 7.83 (d, 1H); 8.49 (d, 1H). RMN-^C (DMSO): 9.09 ; 16.14 ; 21.73 ; 26.57 ; 26.70 ; 37.15 ; 43.14 ; 51.05 ; 55.49 ; 62.08; 64.74; 73.98; 100.42; 113.03; 123.38; 125.58; 127.12; 127.32; 128.59; 130.27 ; 141.32 ; 145.51; 149.38 ; 149.51 ; 153.20 ; 156.62 ; 159.86 ; 161.31 ; 163.79 ; 172.72. IR (KBr) : 1599 ; 1656 ; 1747 ; 2796 ; 3448. Example 62: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy- 12-(4-methyl piperazinomethyl)-lH-oxepino[3,4,6,7]indolizino [1,2-b] quinoline-3,15(4H,13H)-dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30. d., using 1,2,5,6-tetrahydropyridine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light yellow solid is obtained (m.p. 274 °C). RMN-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.15 (s, 3H); 2.31 (m, 4H); 2.47 (m, 4H) ; 3.06 (d, 1H); 3.47 (d, 1H); 4.05 (m, 2H) ; 4.05 (s, 3H); 5.28 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.35 (s, 1H); 7.87 (d, 1H) ; 7.94 (d, 1H). RMN-13C (DMSO) : 8.44 ; 36.53 ; 45.58 ; 45.95 ; 50.68 ; 52.86 ; 55.07 ; 56.20 ; 56.47 ; 61.45; 73.32; 99.19; 105.90; 113.74; 113.91; 122.22; 125.60; 129.46; 138.83; 144.51; 144.62 ; 144.94 ; 147.85 ; 147.98 ; 150.96 ; 152.82 ; 155.34 ; 155.96 ; 159.19 ; 172.09. IR (KBr): 1270 ; 1515 ; 1594 ; 1648 ; 1747 ; 2950 ; 3438. Example 63: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy- 12-piperidinomethyl-lH-oxepino[3',4,:6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)- dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using piperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light green solid is obtained (m.p. > 275 °C). RMN-!H (DMSO): 0,86 (t, 3H); 1.42-1,50 (m, 6H); 1.84 (q, 2H); 2.50 (m, 4H); 3.05 (d, 1H); 3.48 (d, 1H); 4.03 (s, 2H); 4.05 (s, 3H); 5.30 (s, 2H); 5.45 (dd, 2H) ; 6.02 (s, 1H) ; 7.5 (s, 1H); 7.9 (d, 1H); 7.99 (d, 1H). RMN-13C (DMSO) : 8.44 ; 24.07 ; 25.9 ; 36.54 ; 42.57 ; 50.60 ; 54.26 ; 56.40 ; 57.11 ; 61.42 ; 73.33 ; 99.17 ; 105.97 ; 113.75 ; 113.92 ; 122.21 ; 125.66 ; 129.46 ; 139.23 ; 144.54 ; 144.98 ; 147.94 ; 151.0 ; 152.82 ; 155.34 ; 155.89 ; 159.20 ; 172.07. IR (KBr): 860 ; 1057 ; 1270 ; 1514 ; 1656 ; 1748 ; 2857 ; 2932 ; 3397. Suspending in absolute ethanol (50 ml/mmol) the free base obtained as described above and subsequent treating with hydrogen chloride in ethanol (2,5 N; 5 eq.) yields the corresponding hydrochloride. At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The light yellow solid obtained is washed with ether (m.p. 264 °C). RMN-»H (DMSO) : 0.86 (t, 3H); 1.42 (m, 1H) ; 1.70-1.85 (m, 7H) ; 3.06 (d, 1H); 3.33 (m, 4H); 3.47 (m, 1H); 4.19 (s, 3H); 5.00 (s, 2H); 5.40 (d, 1H); 5.54 (d, 1H); 5.61 (s, 2H); 6.02 (s, 1H); 7.37 (s, 1H); 7.95-8.04 (m, 2H); 10.46 (s, 1H). RMN-13C (DMSO): 9.12 ; 22.11 ; 22.91 ; 37.63 ; 43.20 ; 52.27 ; 53.20 ; 54.00 ; 54.75 ; 57.91 ; 58.15 ; 62.12 ; 62.78 ; 73.97 ; 100.06 ; 106.96 ; 107.14 ; 114.80 ; 123.20 ; 126.58 ; 130.48 ; 134.14 ; 145.33 ; 145.48 ; 149.49 ; 149.62 ; 151.76 ; 153.84 ; 156.36 ; 156.69 ; 159.76; 172.73. IR (KBr): 1010 ; 1072 ; 1240 ; 1271 ; 1469 ; 1511; 1574 ; 1598 ; 1648 ; 1734 ; 2525 ; 2944 ; 3430 ; 3507. Example 64: 9-chIoro-5-ethyI-4,5-dibydro-5-hydroxy-10-methoxy- 12-dimethylaminomethyl-lH-oxepino[3',4,6,7]indolizino[l,2-b]quinoline- 3,15(4H,13H)-dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-methoxyaniline to produce ethyl 2,7,-dichloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using dimethylamine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C). RMNMH (DMSO): 0.86 (t, 3H); 1.84 (q, 2H) ; 2.29 (s, 6H); 3.06 (d, 1H); 3.42 (d, 1H); 3.98 (q, 2H); 4.05 (s, 3H); 5.27 (s, 2H); 5.45 (s, 2H); 5.95 (s, 1H); 7.32 (s, 1H); 7.82 (s, lH);8.19(s, 1H). RMN-13C (DMSO): 8.41 ; 36.50 ; 42.55 ; 45.58 ; 50.62 ; 56.70 ; 57.42 ; 61.42 ; 73.29 ; 99.28 ; 104.66 ; 122.34 ; 126.92 ; 127.55 ; 129.89 ; 130.04 ; 139.19 ; 144.20 ; 144.81 ; 151.08 ; 153.15 ; 155.91 ; 159.18 ; 172.04. IR (KBr): 1048 ; 1242 ; 1482 ; 1611 ; 1659 ; 1730 ; 3301 ; 3417. Example 65: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy- 12-piperidinomethyl-1H-oxepino[3,,4':6,7]indblizino[l,2-b]quinoleine-3,15(4H,13H)-dione hydrochloride The procedure described in examples 30,a., 30.b. and 30.c. is applied to 3-chloro-4-methoxyaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated aceording to procedure of example 30.d., using piperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage ll.k. The obtained free base is suspended in absolute ethanol (50 ml/mmol) and subsequently treated with hydrogen chloride in ethanol (2,5 N; 5 eq.). At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The orange solid obtained is washed with ether (m.p. > 250 °C). RMN-!H (DMSO): 0.86 (t, 3H); 1.43 (q, 1H) ; 1.70 (d, 1H); 1.76 (m, 2H); 1.86 (m, 4H); 3.07 (d, 1H) ; 3.28 (m, 2H) ; 3.47 (m, 3H) ; 4.20 (s, 3H); 5.00 (q, 2H); 5.41 (d, 1H); 5.54 (d, 1H); 5.62 (s, 1H); 6.10 (s, 1H); 7.36 (s, 1H); 7.88 (s, 1H); 8.31 (s, 1H). RMN-13C (CF3COOD): 8.44; 22.11 ; 24.79; 38.27 ; 43.51 ; 54.28 ; 56.01 ; 58.51 ; 58. 75 ; 64.23 ; 77.59 ; 104.22 ; 110.49; 124.68; 129.44; 131.91 ; 136.61 ; 140.01 ; 141.33 ; 144.72 ; 158.25 ; 161.10 ; 161.89 ; 178.85. IR (KBr): 1079 ; 1288 ; 1488 ; 1562 ; 1578 ; 1648 ; 1747 ; 2936 ; 3406. Example 66: 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy- 12-(l,2,5,6-tetrahydropyridinomethyl)-lH-oxepino[3',4':6,7]indolizino [l,2-b]quinoline-3,15(4H,13H)-dione hydrochloride The procedure described in examples 30.a., 30.b. and 30.c. is applied to 4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d„ using 1,2,5,6-tetrahydropyridine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage ll.k. The obtained free base is suspended in absolute ethanol (50 ml/mmol) and subsequently treated with hydrogen chloride in ethanol (2,5 N; 5 eq.). At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The yellow solid obtained is washed with ether (m.p. > 250 °C). RMN-lH (DMSO): 0.86 (t, 3H); 1.87 (q, 2H); 2.32 (m, 1H); 3.07 (d, 1H) ; 3.48 (m, 3H); 3.89 (m, 8H); 4.06 (s, 3H); 5.08 (m, 2H); 5.40 (d, 1H); 5.54 (d, 1H); 5.63 (q, 2H); 5.67 (d, 2H) ; 5.93 (d, 2H); 7.37 (s, 1H) ; 7.59 (q, 1H); 7.79 (d, 1H) ; 8.14 (d, 1H); 10.80 (s, 1H). RMN-13C (DMSO): 8.47 ; 25.97 ; 36.40 ; 42.55 ; 49.75 ; 50.25 ; 50.61 ; 52.36 ; 56.05 ; 61.44; 73.36; 98.95; 103.74; 121.99; 122.29; 124.98; 125.50; 128.84; 129.84; 131.18 ; 138.47 ; 144.63 ; 145.18 ; 150.01 ; 155.93 ; 159.24; 172.10. IR (KBr): 827 ; 1065 ; 1228 ; 1289 ; 1592; 1653 ; 1746 ; 2363 ; 3373. Example 67: 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methyl piperidinomethyl)-lH-oxepino[3',4,:6,7]indolizino[l,2-3]quinoline-3,15(4H,13H)- dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using 4-methylpiperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C). RMN-lH (CF3COOD): 1.17 (m, 6H); 1.62 (m, 2H); 1.89 (s, 1H); 2.07 (q, 2H); 2.25 (m, 2H); 3.54 (m, 3H); 3.89 (d, 1H); 4.02 (s, 2H); 4.19 (s, 3H); 7.94 (s, 1H); 8.10 (m, 1H); 8.29 (s, 1H); 8.50 (m, 1H). RMN-13C (CF3COOD): 8.43 ; 13.79 ; 17.43 ; 20.89 ; 30.01 ; 32.85 ; 38.26 ; 43.50 ; 54.13 ; 56.09 ; 57.87 ; 58.27 ; 64.22 ; 77.57 ; 107.37 ; 110.56 ; 125.75 ; 129.36 ; 129.42 ; 132.78 ; 136.04 ; 136.65 ; 139.91 ; 140.38 ; 144.31 ; 158.30 ; 161.94 ; 164.90 ; 178.84. IR (KBr): 825 ; 1056 ; 1230 ; 1260 ; 1516 ; 1641 ; 1655 ; 1736 ; 2921; 3395. Example 68: 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methyl piperazinomethyl)-lH-oxepino[3,4,:6,7]indollzino[l,2-b]quinolme-3,15(4H,13H)- dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d. and reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. 215-219 °C). RMN-lH (DMSO): 0.85 (t, 3H); 1.85 (m, 2H); 2.15 (s, 3H); 2.35 (m, 4H); 2.5 (m, 4H); 3.25 (dd, 2H); 3.95 (s, 3H); 4.05 (s, 2H); 5.3 (s, 2H); 5.45 (dd, 2H); 6 (s, 1H); 7;3 (s, 1H); 7.5 (d, 1H); 7.7 (s, 1H); 8.05 (d, 1H). RMN-13C (DMSO): 9.12 ; 14.36 ; 20.08 ; 23.93 ; 46.61 ; 51.35 ; 53.58 ; 55.71 ; 56.34 ; 56.73 ; 58.37 ; 62.11 ; 74.03 ; 99.62 ; 104.49 ; 122.66 ; 123.11 ; 129.54 ; 130.53 ; 131.82 ; 139.05 ; 145.3 ; 145.86 ; 150.67 ; 156.62; 158.71 ; 159.91 ; 172.77. IR (KBr): 1590 ; 1624 ; 1655 ; 1744 ; 2801 ; 2935 ; 3423. Example 69 : 5-ethyI-4,5-dihydro-5-hydroxy-10-methoxy- 12-pyrrolidinomethyl-lH-oxepino[3',4,:6,7]indolizino[l,2-b]qumoline-3,15(4H,13H)- dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using pyrrolidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C). RMN-lH (DMSO): 0.85 (t, 3H); 1,7 (s, 4H); 1.85 (q, 2H); 2.55 (s, 4H); 3.25 (dd, 2H); 3.9 (s, 3H); 4.15 (s, 2H); 5.25 (s, 2H); 5.45 (dd, 2H); 6 (s, 1H); 7.35 (s, 1H); 7.5 (d, 1H); 7.7 (s, 1H); 8.05 (d, 1H). RMN-13C (DMSO): 9.68 ; 24.74 ; 51.8 ; 54.71 ; 55.25 ; 56.3 ; 56.87 ; 62.3 ; 62.64 ; 74.5 ; 100.14; 104.8; 104.92; 123.19; 123.45; 129.79; 130.49; 132.32; 132.50; 140.5; 145.83 ; 146.4 ; 151.27 ; 157.15 ; 159.25 ; 160.45 ; 173.3. IR (KBr): 1255 ; 1516 ; 1535 ; 1613 ; 1655 ; 1735 ; 3438 ; 3762 ; 3830. Example 70: 12-(4-benzylpiperazinomethyl)-5-ethyl-4,5-dihydro-5-hydroxy- 10-methoxy-lH-oxepino[3,,4':6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using N-benzylpiperazine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A beige solid is obtained (m.p. > 250 °C). RMN-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.45 (s, 2H); 2.4 (m, 4H); 2.55 (m, 4H); 3.25 (dd, 2H); 3.45 (s, 2H); 3.95 (s, 3H); 4.05 (s, 2H); 5.3 (s, 2H); 5.45 (dd, 2H) ; 6 (s, 1H); 7.3 (m, 6H); 7.5 (d, 1H); 7.75 (s, 1H); 8 (d, 1H). RMN-13C (DMSO) : 7.38 ; 49.56 ; 51.89 ; 54.46 ; 54.82 ; 54.98 ; 55.1 ; 60.1 ; 60.35 ; 61.11 ; 72.26 ; 97.86 ; 102.6 ; 102.76 ; 120.9 ; 121 ; 121.2 ; 121.4 ; 126 ; 127.25 ; 127.77 ; 127.88 ; 128.76 ; 130.13 ; 130.2 ; 137.25 ; 137.36 ; 143.53 ; 144.08 ; 148.86 ; 156.86 ; 156.95 ; 158.15 ; 171.02. IR (KBr): 1235 ; 1259 ; 1517 ; 1586 ; 1614 ; 1654 ; 1747 ; 2927 ; 3450 ; 3762 ; 3848. Suspending in absolute ethanol (50 ml/mmol) the free base obtained as described above and subsequent treating with hydrogen chloride in ethanol (2,5 N; 5 eq.) yields the corresponding hydrochloride. At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The yellow solid obtained is washed with ether (m.p. > 250 °C). RMISMH (DMSO): 0.85 (t, 3H); 1.85 (q, 2H>; 2.5 (s, 2H); 2.65 (m, 2H); 3 (m, 2H) ; 3.2 (m, 2H); 3.35 (dd, 2H); 3.35 (s, 2H); 3.95 (s, 3H); 4.15 (s, 2H); 4.3 (s, 2H); 5.3 (s, 2H); 5.45 (dd, 2H); 7.3 (s, 1H); 7.4 (s, 2H); 7.55 (m, 2H); 7.7 (s, 1H); 8.05 (d, 1H); 10.45 (s, 1H). IR (KBr): 1207 ; 1233 ; 1439 ; 1449 ; 1458 ; 1508 ; 1610 ; 1620 ; 1655 ; 1727 ; 3398. Example 71: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl- 12-(4-methyIpiperidinomethyl)-lH-oxepino [3',4':6,7] indolizino [l,2-b] quinoline-3,15(4H,13H)-dione The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-methylaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using piperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 275 °C). RMN -1H (DMSO): 0.86 (m, 6H); 1.15 (m, 2H); 1.37 (m, 1H); 1.60 (m, 2H); 1.80 (m, 2H); 2.10 (m, 2H); 2.60 (s, 3H); 2.80 (m, 2H); 3.05 (d, 1H); 3.48 (d, 1H); 4.02 (s, 2H); 5.30 (s, 2H); 5.45 (dd, 2H); 6.02 (s, 1H); 7.40 (s, 1H); 8.20 (s, 1H); 8.40 (s, 1H). RMN-13C (DMSO): 9.10 ; 21.28 ; 22.61; 31.07 ; 34.89 ; 37.18 ; 43.22 ; 54.53 ; 56.83 ; 62.10 ; 73.94 ; 80.06 ; 100.43 ; 123.41 ; 127.08 ; 129.11 ; 130.58 ; 135.88 ; 136.89 ; 141.00; 145.28 ; 148.49 ; 153.51 ; 156.60 ; 159.85 ; 172.77 ; 174.05. IR (KBr): 1605 ; 1657 ; 1734 ; 3342. Example 72: 10-benzyloxy-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-lH- oxepino [3',4':6,7] indolizino [1,2-6] quinoline-3,15(4H,13H)-dione The procedure described in examples 30.a.t 30.b. and 30.c. is applied to 3-fluoro-4-methoxyacetanilide to yield 2-chloro-7-fluoro-6-methoxyquinoline-3-carbaldehyde which is treated with an excess of boron tribromide in dichloromethane at room temperature during 24 hours. The obtained 2-chloro-7-fluoro-6-hydroxy-quinoline-3-carbaldehyde is O-benzylated in dimethylformamide in the presence of benzyl bromide and potassium carbonate to yield 6-benzyloxy-2-chloro-7-fluoro-quinoline-3-carbaldehyde, the latter being reduced in the corresponding quinolinemethanol using sodium borohydride in methanol. The obtained quinolinemethanol is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 275 °C). RMN-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H) ; 3.05 (d, 1H); 5.25 (s, 2H); 5.37 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.4-7.6 (m, 5H); 7.88 (d, 1H); 7.95 (d, 1H); 8.56 (s, 1H). Example 73: 5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy-lH-oxepino [3,4':6,7] indolizino [1,2-b] quinoline -13,15-(4H-13H)-dione The hydrogenolysis procedure of example 14 is applied to compound of example 72. A yellow solid is obtained (m.p. > 275 °C). RMN-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H) ; 3.05 (d, 1H); 5.25 (s, 2H) ; 5.37 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H) ; 7.8 (d, 1H) ; 7.90 (d, 1H) ; 8.56 (s, 1H). PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION 1. Test on DNA relaxation induced by topoisomerase 1 All the reactions were performed in a 20 µl reaction buffer consisting of 50 mM of Tris-HC1 (pH 7.5), 50 mM of KC1, 0.5 mm of dithiothreitol, 10 mM of MgCl2, 0.1 mM of ethylenediamine tetraacetic acid (EDTA), 30µg/ml of bovine serum albumen and 300 ng of coiled pUC19 (Pharmacia Biotech, Orsay, France) with or without compounds to be tested at specific concentrations. All the compounds to be tested were initially dissolved in dimethylsulphoxide (DMSO) at 50 mM, the other dilutions being made using distilled water. The final concentration of DMSO did not exceed 1% (by volume). The reaction was initiated by adding one unit of topoisomerase 1 of purified calf thymus DNA (Gibco-BRL, Paisley, United Kingdom) and was carried out for 15 minutes at 37°C. The reactions were stopped by adding 3 µl of a mixture containing sodium dodecylsulphate at 1%, 20 mM of EDTA and 500 µg/ml of proteinase K (Boehringer Mannheim, Meylan, France). After a further 30 minutes of incubation at 37°C, 2 µl of a buffer containing 10 mM of Na2HP04, 0.3% bromophenol blue and 16% Ficoll were added to the specimens which were subjected to electrophoresis in 1.2% agar gels at 1 V/cm for 20 hours in a buffer containing 36 mM of Tris-HCl pH 7.8, 30 mM of Na2HP04, 1 mM of EDTA and 2 µg/ml of chloroquine. The gels were stained with 2 µg/ml of ethidium bromide, photographed in UV light at 312 nm with a camera and the fluorescent intensity measured with a bioProfil camera (Vilber Lourmat, Lyon, France) in order to determine the percentage of relaxed DNA. Each experiment was performed at least three times and duplicated. In each experiment, the coiled plasmid DNA was incubated alone or with topoisomerase 1. The reaction was complete within 15 minutes. For each compound to be tested, or control, the coiled plasmid DNA was incubated in the presence of 500 µM of the compound to be tested with or without enzymes, plus the compound to be tested, at concentrations of 10 µM, 100 µM, 200 µM and 500 µM. As shown in table I, examples 2, 3, 4, 9, 10 and 11 inhibit the relaxation activity encouraged by the topoisomerase 1 in a manner that depends on dose. (Table Removed) TABLE I 2. Tests on cell growth a. Eight strains of tumour cells were used in this study: L1210 (mouse lymphocytic leukaemia), HCT15 and LOVO (strains of human colon adenocarcinoma cells), A549 (human lung carcinoma), A172, U373 and U87 (human glioblastomas). All these strains were obtained from the American type culture collection (ATCC), Rockville, Md, United States. Cultures of L1210 cells in suspension were cultivated in a Dulbecco modified eagle medium (DMEM) (BioWhitaker, Verviers, Belgium) completed with 10% of foetal calf serum inactivated by heating, 2 mM of glutamine, 50 U/ml of penicillin and 50 fig/ml of streptomycin. HT29 cells were cultivated in single-layer cultures in a McCoy 5a medium (Gibco, Paisley, United Kingdom) completed with 10% foetal calf serum inactivated by heating plus 2 mM of glutamine and 50 µg/ml of gentamycin. The other cells were cultivated in an essential modified Earle medium (EMEM; Gibco, Paisley, United Kingdom) completed with 5% foetal calf serum inactivated by heat, 2 mM of glutamine, 50 U/ml of penicillin and 50 µg/ml of streptomycin. All these cell strains were cultivated at 37°C in a moistened atmosphere containing 95% air and 5% CO2. Inhibition of the growth of the strains of tumour cells was determined using an MTT test. 1500 L1210 cells in a culture medium (according to the cell medium requirements) were seeded in a well of a microplaque (tissue culture level: 96 wells, flat bottom) 24 hours before treatment with the compounds to be tested. For these dose-response investigations, the cells were incubated with each of the compounds to be tested or their corresponding solvent (controls) for 48 hours with a final concentration range of 1.10" to 1.10" . All the compounds were dissolved just before use in dimethylsulphoxide (DMSO) at a concentration of 50 mM. Other drug dilutions were performed in the culture medium. The final concentration of DMSO never exceeded 0.2% (by volume). As controls, the solutions of drugs were replaced by the solvent that was diluted successively in the same way as the compounds under test. After the incubation period, the MTT marking reagent (3-[4,5-dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide; Thiazol blue, Sigma M 565, Sigma, St Louis, MO, United States) was added at a final concentration of 0.3 mg/ml to each well. The cells were incubated for 4 hours at 37°C in a moistened atmosphere. This stage allows the mitochondrial dehydrogenase in the living cells to convert the MTT yellow tetrazolium salt into crystals of purple formazan. The supernatant part was eliminated and the crystals of formazan formed were dissolved in DMSO. The resulting coloured solution was quantified by absorption at 570 nm using a scanning multi-chamber spectrophotometer. The growth data were expressed as a percentage of living cells in the wells treated, divided by the living cells in the controls. Each point represents the mean of three independent experiments, each experiment representing six determinations. For the other cell strains (HCT15, LOVO, A549, A172, U373, and U87), 1000 to 2000 cells were seeded in a well of a plate of microwells 24 hours before the drug treatment. They were incubated with each of the compounds to be tested or their corresponding solvent (controls) for 72 hours for a final concentration range of 1.10" to 1.10" M. The results were expressed as percentages of growth calculated by the optical density (OD) of the cells treated with a drug divided by the OD of the control cells (cells treated with DMSO). As shown on table II, the compounds to be tested inhibited the growth of the cells in a manner that depended on dose. (Table Removed) TABLE II b. Nine strains of tumour cells were used in this investigation: PC3, DU145 (human prostate cells), MCF7 and MCF7-ADR (mammary cells, the symbol "ADR" was used to indicate that the cells have been made resistant to adriamycin), A427 (human lung adenocarcinoma), HT29 (human colon adenocarcinoma cells), T24s, T24r (human bladder cells, the T24r were resistant to adriamycin, amongst other things). The PC3, DU145 and A427 cells were obtained from the American type culture collection (ATCC, Rockville, Md, United States). The MCF7 and MCF7-ADR cells were provided gratis by Dr Jacques Soudon (Pharmacell, Paris, France). The T24s and T24r cells were given gratis by Dr Robert Kiss (Free University of Brussels, Belgium). HT29 cells were cultivated in single-layer cultures in a 4.5 g/1 DMEM medium (Gibco, Paisley, United Kingdom) completed with 10% of foetal calf serum inactivated by heat plus 2 mM of glutamine and 50 µg/ml of gentamycin (Gibco, Paisley, United Kingdom). The other cells were cultivated in an essential modified Earle medium EMEM at 4,5 g/1 (Gibco, Paisley, United Kingdom) completed with 10% of foetal calf serum inactivated by heat, 2 mM of glutamine (Gibco, Paisley, United Kingdom), 50 U/ml of penicillin and 50 u,g/ml of streptomycin (BioWhitaker, Verviers, Belgium). All the cell strains were cultivated at 37°C in a moistened atmosphere containing 95% air and 5% CO2. Inhibition of the growth of the strains of tumour cells was determined using a WST1 colorimetry test. Between 500 and 4000 cells in a culture medium (according to the cell medium requirements) were seeded in a well of a microplaque (96 wells, flat bottom) 24 hours before treatment with the compounds to be tested. For these concentration-response studies, the cells were incubated with each of the compounds to be tested or their -13 corresponding solvent (controls) for 72 hours in a final concentration range from 1x10 to 1 x 10" M. All the compounds were dissolved in dimethylsulphoxide (DMSO) or in water for the water soluble compounds. The following dilutions of the compounds of the present invention were made in the culture medium such that the final concentration of DMSO, where the latter enters into the composition of the vector, was still 0.1% (by volume). As controls, the solutions of compounds were replaced by the solvent that was diluted successively in the same way as the compounds under test. After incubation, the WST1 marking reagent (4-[3-(4-iodophenyi)-2-(4-nitrophenyl)-2h-5-tetrazolio]-l,3-benzene disulphonate) (Boehringer Mannheim, Germany) was added to a final concentration of 9% in each well. The cells were incubated for between 2 and 4 hours at 37 °C in a moistened atmosphere. This stage allows the mitochondrial dehydrogenase of the living cells to convert the WST1 orange tetrazolium salt into crystals of purple formazan. The resulting coloured solution was quantified by a double-beam reading (450 and 690 nm) using a scanning multi-chamber spectrophotometer. The results are expressed in the form of a window of concentrations, expressed as mol/litre, including the inhibiting concentration at 50% (IC50). They are shown on tables IIIA) and IIIB). The examples where the number is followed by an "s" correspond to the salts of the compounds. The abbreviations Cpt, Adr and Tpt represent camptothecin, adriamycin and topotecan respectively. (Table Removed) TABLE IIIA) (Table Removed) TABLE III B) We claim; 1. A camptothecin compound characterized in that it corresponds to formula (I) (Formula Removed) m racemic or enantiomeric form or any combinations of these forms, wherein Rl represents an inferior alkyl, an inferior alkenyl, an inferior alkynyl, an inferior haloalkyl, an inferior alkoxy inferior alkyl or an inferior alkylthio inferior alkyl; R2, R3 and R4 independently represent H, halo, inferior haloallqrl, inferior alkyl, inferior alkenyl, cyano, inferior cyanoalkyl, nitro, inferior nitroalkyl, amido, inferior amidoalkyl, hydrazino, inferior hydrazinoalkyl. azido, inferior azidoalkyl, (CH2)mNR6R7. (CH2)mOR6, (CH2)n,SR6, (CH2)mCO2R6, (CH2)mNR6C(O)R8. (CH2)n,C(O)R8, (CH2)mOC(O)R8, O(CH2)mNR6R7, OC(O)NR6R7, OC(O)(CH2)mCO2R6. or (CH2)n[N=X], OC(O)[N=X], (CH2)mOC(O)[N=X] (wherein [N=X]. in this invention, represents a heterocyclic group of 4 to 7 links 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 COR10), aryl or substituted inferior arylalkyl (that is, substituted between 1 and 4 times on the aryl group or the heterocycle) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro, amino, inferior aminoalkyl, inferior haloalkyl, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy inferior alkyl or R2 and R3 together form a chain with 3 or 4 links, wherein the elements of the chain are selected from the group consisting of CH, CH2,0, S, N or NR9; R.5 represents H, balo, inferior haloalkyl, inferior alkyl, inferior alkoxy, inferior alkoxy inferior alkyl, inferior alkylthio inferior alkyl, cycloalkyl, cycloalkyl inferior alkyl, cyano, cyanoalkyl, inferior alkyl inferior sulphonylalkyl, inferior hydroxyalkyl, nitro, (CH2)mC(O)R8, (CH2)mNR6C(O)R8, (CH2)MNR6R7. (CH2)mN(CH3)(CH2)„NR6R7 (CH2)mOC(O)R8. (CH2)mOC(O)NR6R7, (CH2)mS(O)qRn. (CH2)mP(O)R12Rl3, (CH2)2P(S)R12Rl3, or (CH2)n[N=X], OC(O)[N=X], (CH2)mOC(O)[N=X], aryl or substituted inferior arylalkyl (that is, one to four times on the aryl or hetero aryl group) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro, amino, inferior alkyl amino, haloinferior alkyl, inferior hydroxyalkyl, inferior alkoxy or inferior alkoxy inferior alkyl; R6 and R7 independently represent H, an inferior alkyl, inferior hydroxyalkyl, inferior alkyl inferior aminoalkyl, inferior aminoalkyl, cycloalkyl, cycloalkyl inferior alkyl, inferior alkenyl, inferior alkoxy inferior alkyl, inferior haloalkyi, or aryl or substituted inferior arylalkyl (that is, one to four times on the aryl group) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro, amino, inferior alkylamino, inferior haloalkyi, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy inferior alkyl; R8 represents H, an inferior alkyl, inferior hydroxyalkyl, amino, inferior alkylamino, inferior alkyl inferior aminoalkyl. inferior aminoalkyi, cycloalkyl, cycloalkyl inferior alkyl , inferior alkenyl, inferior alkoxy, inferior alkoxy inferior alkyl, inferior haloalkyi, or aryl or substituted inferior arylalkyl (that is, one to four times on the aryl group) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro. amino, inferior alkylamino, inferior haloalkyi, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy inferior alkyl; R9 represents H, an inferior alkyl, inferior haloalkyi, aryl, or aryl substituted by one or more groups chosen from the inferior alkyl radical, halo, nitro, amino, inferior alkylamino, inferior haloalkyi, inferior hydroxyalkyl, inferior alkoxy,or inferior alkoxy inferior alkyl; R10 represents H, an inferior alkyl, inferior haloalkyl, inferior alkoxy, aryl, or substituted aryl (that is, with one to four substituting agents on the aryl group) by one or more groups chosen from the inferior alkyl radical, inferior haloalkyi, inferior hydroxyalkyl, or inferior alkoxy inferior alkyl; Rll represents an inferior alkyl, aryl, (CH2)mOR14, (CH2)inSR14, (CH2)2NR14Rl5 or (CH2)m[N=X]; Rl2 and R13 independently represent an inferior alkyl, aryl, inferior alkoxy, aryloxy or amino; Rl4 and R15 independently represent H, an inferior alkyl or aryl; R18 and R19 independently represent H, halo, inferior alkyl, inferior alkoxy or hydroxy; R20 represents H or halo; R21 represents H, an inferior alkyl, CHO or C(O)(CH2)mCH3; m is a whole number between 0 and 6; n is 1 or 2; and q represents a whole number from 0 to 2; and [N=X] represents a heterocyclic group with 4 to 7 links, X representing the link necessary to complete the said heterocyclic group and selected from the group consisting of O, S, CH2, CH, N, NR9 and COR10; or a pharmaceutically acceptable salt thereof, wherein 'inferior' means upto 6 carbon atoms. 2. A compound as claimed in claim 1, wherein R2 represents an atom of hydrogen or halogen; R3 represents an halogen atom, an inferior alkyl or an inferior alkoxy; R4 represents an hydrogen atom; R18. Rl9 et R20 represent an hydrogen atom; or a pharmaceutically acceptable salt thereof. 3. A compound as claimed in claim 2, wherein R5 is an aminoalkyl or a pharmaceutically acceptable salt thereof. 4. A compound as claimed in claimed in claim 1, wherein the said compound is selected from among: - 5-ethyI-9.10-difluoro-4,5-dihydro-5-hydroxy-12-(l,2,5,6-tetrahydropyridinomethyl-lH- oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione hydrochloride - 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-inethylpiperidinoniethyl)-lH- oxepino[3,4:6,7] indolizino[l,2-b] quinoIine-3,15(4H,13H)-dione 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-pyrrolidinoinethyl-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperazinomethyl)-lH- oxcpino[3'.4 :6,7] indolizino[1;2-b] qumolme-3,15(4H,13H)-dionc -5-ethyI-910-difluoro-4,5-dihydro-5-hydroxy-12-piperidinomethyl-lH-oxepino[3',4':6,7] indolizino[l^-b] qumoline-3,15(4H, 13H)-dione - 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-dimethylaminomcthyl-lH-oxepino[3,,4':6,7] mdoIizino[l,2-b3 qainoline-3,I5(4H,13H)-dione - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-merhyi-12-inorpholinoinethyl-lH-oxqjino[3'.4':6,7] indolizmo[l,2-b] quinolinc-3.15(4H,13H)-dione - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-dimethyl-12-(4-inethylpipcrazinoinethyl)-lH-oxepino[3',4':6,7] mdoli2dno[l,2-b] quinoline-3,15(4H,13H)-dione - 12-benzyhnethylaminomethyl-9-chloro-5-ethy I-4,5-dihy dro-5-hydroxy-10-methyl-1H-oxepino[3%4':6,7] mdoli2ino[l,2-b] quinoline-3,15(4H.13H)-dione - 12-(4-benzylpiperazmomethyl)-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy- 10-m IH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-piperidinomethyl-lH-oxepino[3',4':6,7] mdolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 12-(4-benzylpiperazinomethyl)-5-cthyl-9-fluoro-4,5-dihydro-5-hydroxy-lH-oxepmo[3,4':6,7] mdoIizino[l,2-b] qainoline-3,15(4H,13H)Hiione - 12-(4-benzylpiperazinomethyl)-5-ethyl-9-fluon)-4,5-dihydro-5-hydroxy-10-methyl-lH- oxepino[3,4':6,73 indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-dimethylamiDomethyl-lH- oxepino[3.4:6,7] mdoJyLzino[l,2'-b] quinolme-3.15(4H,13H)-dione 5-ethyl-12-dicthylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3,4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 5-ethyl-9-fluoio-4,5-dihydro-5-hydroxy'10-methyI-12-(4-methylpiperidinomethyl)-lH- oxepinor3',4':6,7] indolizmo [1,2-b] quinoline-3,15(4H.13H)-dione - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-pyrrolidinomethyl-lH- oxepino[3',4':6,7] indolizino[1,2-b] quinoline-3,15(4H,13H)-dione 5-ethy1-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(1,2,5,6-tetrahydropyridinomethyl)-1H-oxepino[3',4':6,7] indolizino(1,2-b] quinoline-3,15(4H,13H)-dione - 12-diisobutylaininomethyl-5-ethyl-9-fIuoro-4,5-dihydro-5-hydroxy-10-methyl-lH-oxepino[3',4*:6,7] indolizano[l,2-b] quinoline-3,15(4H,13H)-dione -5-etfayl-9-fluon)-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-xnethylpiperazinomethyl)-lH-oxepinoI3',4':6,73 indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy- 10-methoxy- 12-piperidlnomethyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] qiiinoIine-3,15(4H,I3H)-dione - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-dimcthylaminomethyI-1H-oxepino[3%4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoIine-3,15(4H,13H)-dione hydrochloride -5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(l,2,5,6-tetrahydropiperidinomethyl)-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperidinomethyl)-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15C4H,13H)-dione - 5-ethyI-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperazinomethyl)-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinolme-3,15(4H,13H)-dione - 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-pyrrolidinomethyl-1 H-oxepino[3' ,4':6,7] indolizino[ 1,2-b] quinoIine-3,15(4H, 13H)-dione - 12-(4-benzylpiperazinomethyl)-5-ethyl-4,5-dihydro-5-hydroxy-l 0-methoxy-IH- oxepino[3',4':6,7] indolizinotl,2-b] quinoline-3,15(4H,13H)-dione - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-1H- oxepmo[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione - 10-benzyloxy-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-1 H-oxepino [3',4':6,7] indolizino [ 1,2-b] quinoline-3,15(4H, 13H)-dione - 5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy-lH-oxepinoi:3',4':6,7] indolizino[l,2-b] qiiinoline-3,15(4H, 13H)-dione or a pharmaceutically acceptable salt of one of these. 5. A compound as claimed in claim 4, wherein the said compound is selected from among: - 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperidinomethyl)-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione; - 5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione; - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-lH- oxepino[3',4':6,7] indoIizino[l,2-b] quinoline-3,15(4H,13H)-dione; - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-pyrrolidinomethyl-lH-oxepino[3',4':6,7] indolizino[l,2-b] qviinoline-3,15(4H,13H)-dione; - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15C4H,13H)-dione; - 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methyIpiperidinomethyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione; - 9-chIoro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-1H- oxepino [3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione; or a pharmaceutically acceptable salt of one of these. 6. A compound as claimed in any of claims 1 to 5 or a pharmaceutically acceptable salt thereof for use as a medicine. 7. The compounds as claimed in any of claims 1 to 5 as and when used for preparation of a pharmaceutical compsition 8. A compound substantially as herein described with reference to the foregoing examples. 9. Pharmaceutical composition substantially as herein described with reference to the foregoing examples.

Full Text

New analogues of camptothecin, their medical application and the pharmaceutical substances that contain them
Camptothecin is a natural compound first isolated from the leaves and the bark of the Chinese plant known as camptotheca acuminata (see Wall et al., J. Amer. Chem. Soc. 88:3888 (1966)). Camptothecin is a pentacyclic compound consisting of a quinoline indolizine [1,2-b] fragment merged with a 6-chain α-hydroxylactone. The carbon atom in position 20, which carries the a-hydroxy group, is asymmetrical and gives the molecule a rotatory capability. The natural form of camptothecin has the absolute "S" configuration at carbon atom 20 and has the following formula:
(Formula Removed)
Camptothecin has an inhibiting effect on the growth of many strains of cancer cells including those in human tumours of the colon, the lung and the breast (Suffness, M. et al.: The Alkaloids Chemistry and Pharmacology, Bross, A., ed., Vol. 25, p. 73 (Academic Press, 1985)). It is suggested that the growth-inhibiting action of camptothecin is related to its inhibition of topoisomerase I in DNA.
It has been shown that the a-hydroxylactone is an absolute requirement for the activity of camptothecin both in vivo and in vitro (Camptothecins: New Anticancer Agents, Putmesil, M., and his colleagues, ed., p. 27 (CRC Press, 1995); Wall, M. and his colleagues, Cancer Res. 55:753 (1995); Hertzberg et al., J. Med. Chem. 32:715 (1982) and Crow et al., J. Med. Chem. 35:4160 (1992)). The present invention concerns a new class of analogues of camptothecin, wherein the natural α-hydroxylactone in camptothecin is replaced by a ß-hydroxylactone. The compounds according to the present invention show a powerful biological action that is unexpected in view of prior art.
The subject of the invention is therefore new analogues of camptothecin which differ from any known derivatives of camptothecin in that they contain a ß-hydroxylactone (or its open hydroxycarboxylic form) in the place of an a-hydroxylactone (or its open hydroxycarboxylic form); or a pharmaceutically acceptable salt of the latter. The term derivative of camptothecin is taken to mean a compound having the same structure as camptothecin (in other words a quinoline indolizine [1,2-b] fragment which is merged with
a 6-chain α-hydroxylactone), with or without other chemical substitutions on the structure. Different derivatives of camptothecin are well known to specialists, as described below. The term ß-hydroxylactone is taken to mean a lactone that comprises an additional carbon atom between the carbon of the carboxyl group and the a-carbon carrying the hydroxy group in the a-hydroxylactone.
An analogue of camptothecin according to the invention may therefore comprise substitutions on the quinoline indolizine [1,2-5] fragment (for example to improve the solubility of the compound) or on the open or closed ß-hydroxylactone (for example in order to improve the stability of the compound). Typical substitutions on the closed ß-hydroxylactone comprise an alkyl substitution (for example ethyl) on the ¸ß-carbon. Typical substitutions on the open ß-hydroxylactone comprise alkyl substitutions on the ß-carbon, substitutions (for example, amidation) on the resulting carboxylic acid, and substitutions (for example, esterification) or eliminations of the resulting hydroxyl group. The subject of the invention is more particularly the compounds of the formula (I) and (II)
(Formula Removed)
in racemic or enantiomeric form or any combinations of these forms, wherein
R1 represents an inferior alkyl, an inferior alkenyl, an inferior alkynyl, an
inferior haloalkyl, an inferior alkoxy inferior alkyl or an inferior alkylthio inferior alkyl; R.2, R3 and R4 independently represent H, halo, inferior haloalkyl, inferior alkyl, inferior alkenyl, cyano, inferior cyanoalkyl, nitro, inferior nitroalkyl, amido, inferior amidoalkyl, hydrazine inferior hydrazinoalkyl, azido, inferior azidoalkyl, (CH2)mNR6R7, (CH2)mOR6, (CH2)mSR6, (CH2)mC02R6, (CH2)mNR6C(0)R8, (CH2)mC(0)R8, (CH2)m0C(0)R8, 0(CH2)mNR6R7, OC(0)NR6R7, OC(0)(CH2)mC02R6, or (CH2)n[N«X]f OC(0)[N«X], (CH2)mOC(0)[N=X] (wherein [N=X], in this invention, represents a heterocyclic group of 4 to 7 links 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
COR10), aryl or substituted inferior arylalkyl (that is, substituted between I and 4 times oft the aryl group or the heterocycle) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro, amino, inferior aminoalkyl, inferior haloalkyl, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy inferior alkyl or R2 and R3 together form a chain with 3 or 4 links, wherein the elements of the chain are selected from the group consisting of CH, CH2, O, S, N or NR9;
R5 represents H, halo, inferier haloalkyl, inferior alkyl, inferior alkoxy,
inferior alkoxy inferior alkyl, inferior alkylthio inferior alkyl, cycloalkyl, cycloalkyl inferior alkyl, cyano, cyanoalkyl, inferior alkyl inferior sulphonylalkyl, inferior hydroxyalkyl, nitro, (CH2)mC(0)Rg, (CH2)mNR6C(0)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOC(0)R8, (Cg2)mOC(0)NR6R7, (CH2)mS(0)qRn, (CH2)mP(0)R12R13, (CH2)2P(S)Ri2R13, or (CH2)n[N~X], OC(0)[N«X], (CH2)mOC|0)[N=X], aryl or substituted inferior arylalkyl (that is, one to four times on the aryl or hetero aryl group) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro, amino, inferior alkyl amino, haloinferior alkyl, inferior hydroxyalkyl, inferior alkoxy or inferior alkoxy inferior alkyl;
R6 and R7 independently represent H, an inferior alkyl, inferior hydroxyalkyl, inferior alkyl inferior aminoalkyl, inferior aminoalkyl, cycloalkyl, cycloalkyl inferior alkyl, inferior alkenyl, inferior alkoxy inferior alkyl, inferior haloalkyl, or aryl or substituted inferior arylalkyl (that is, one to four times on the aryl group) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro, amino, inferior alkylamino, inferior haloalkyl, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy inferior alkyl;
R8 represents H, an inferior alkyl, inferior hydroxyalkyl, amino, inferior
alkylamino, inferior alkyl inferior aminoalkyl, inferior aminoalkyl, cycloalkyl, cycloalkyl inferior alkyl , inferior alkenyl, inferior alkoxy, inferior alkoxy inferior alkyl, inferior haloalkyl, or aryl or substituted inferior arylalkyl (that is, one to four times on the aryl group) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro, amino, inferior alkylamino, inferior haloalkyl, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy inferior alkyl;
R9 represents H, an inferior alkyl, inferior haloalkyl, aryl, or aryl substituted
by one or more groups chosen from the inferior alkyl radical, halo, nitro, amino, inferior alkylamino, inferior haloalkyl, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy inferior alkyl;
R10 represents H, art inferior alkyl, inferior haloalkyl, inferior alkoxy, aryl, or
substituted aryl (that is, with one to four substituting agents on the aryl group) by one or more gsoups chosen from the inferior alkyl radical, inferior haloalkyl, inferior hydroxyalkyl, or inferior alkoxy inferior alkyl;
Rll represents an inferior alkyl, aryl, (CH2)mOR14, (CH2)mSR14,
(CH2)2NR14R15 or (CH2[N=X];
Rl2 and R13 independently represent artinferior alkyl, aryl, inferior alkoxy, aryloxy or amino;
Rl4 and R15 independently represent H, an inferior alkyl or aryl;
Rl 6 represents H or OR21;
Rl7 represents OR6 or NR6R7;
Rl8 and R19 independently represent H, halo, inferior alkyl, inferior alkoxy or hydroxy;
R20 represents H or halo;
R2l represents H, an inferior alkyl, CHO or C(0)(CH2)mCH3;
m is a whole number between 0 and 6;
n is 1 or 2; and
q represents a whole number from 0 to 2; and [N=X] represents a
heterocyclic group with 4 to 7 links, X representing the link necessary to complete the said heterocyclic group and selected from the group consisting of O, S, CH2, CM, N, NR9 and COR10; or a pharmaceutical^ acceptable salt of the latter.
Theinvention particularly relates to compounds of formulae I and II as defined above wherein R] represents an inferior alkyl, inferior alkenyl, inferior haloalkyl, inferior alkoxy inferior alkyl, or inferior alkylthio inferior alkyl; R5 represents H, halo, inferior haloalkyl, inferior alkyl, inferior alkoxy, inferior alkoxy inferior alkyl, inferior alkylthio inferior alkyl, cycloalkyl, cycloalkyl inferior alkyl, oyano, cyanoalkyl, inferior hydroxyalkyl, nitro, (CH2)mC(0)R8, (CH2)mNR6C(0)R8, (CH2)mNR6R7, (CH2)mN(CH3)(CH2)nNR6R7, (CH2)mOC(0)R8, (CH2)mOC(0)NR6R7, or (CH2)„[N«X], OC(0)[N=X], (CH2)mOC[N«X], aryl or inferior arylalkyl, substituted or not; R12 and R13 independently represent an inferior alkyl; R16 represents OR21; and Rl8. Rl9 and R20 represent H.
More preferably, R2 represents H or halo, and preferably H, chloro or fluoro; and R3 represents H, an inferior alkyl, halo, or OR6 wherein R6 represents H, an inferior alkyl or an inferior arylalkyl, and preferably H, fluoro, chloro, methyl or methoxy. More preferably again, R2 and R3 together form acaethylenedioxy or an ethylenedioxy.
Theinvention more particularly relates to compounds of formulae I and II wherein R2 represents an atom of hydrogen or halogen, R3 represents a halogen atom, an inferior alkyl
or an inferior alkoxy, R4 and R16 represent atoms of hydrogen and R18, R19 and R20 represent hydrogen atoms; or a pharmaceutically acceptable salt of the latter. Preferably, an aminoalkyl radical will be chosen for R5.
More particularly, the subject of the invention is the products described below in the examples, satisfying the following formulae:
- 5-ethyl-9,10-difluoro-4,5~dihydro-5-hydroxy-12-(l,2,5,6-tetrahydropyridinomethyl-lH-
oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione hydrochloride
- 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperidinomethyl)-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-hydroxy-12-pyrrolidinomethyl-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperazinomethyl)-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-hydroxy-12-piperidinomethyl-lH-oxepino[3',4':6,7]
indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-dimethylaminomethyl-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-morpholinomethyl-lH-oxepino[3',4' :6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione

- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-dimethyl-12-(4-methylpiperazinomethyl)-lH-oxepino[3' ,4' :6,7] indolizino[ 1,2-b] quinoline-3,15(4H,13H)-dione
- 12-benzylmethylaminomethyl-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-lH-oxepino[3' ,4' :6,7] indolizinof 1,2-b] quinoline-3,15(4H, 13H)-dione
- 12-(4-benzylpiperazinomethyl) -9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl- 1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione

- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-piperidinomethyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 12-(4-benzylpiperazinomethyl)-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-lH-oxepino[3' ,4' :6,7] indolizino[ 1,2-b] quinoline-3 J 5(4H, 13H)-dione
- 12-(4-benzylpiperazinomethyl)-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-lH-
oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-dimethylaminomethyl-1H-
oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-lH-
oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 5-ethyl-9-fluoro-4,5-dihydro-5-hydr«xy-10-methyl-12-pyrrolidinomethyl-lH-
oxepinof [3,4,6,7,]indolizino[1,2-b]quinoliue-3,15-(4H,13H)-dione
5-ethyl-9-fluoro~4,5-dihydro-5-hydroxy-10-methyl-12-(l,2,5,6-tetrahydropyridinomethyl)-lH-oxepino|3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 12-diisobutylaminomethyl-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-lH-
oxepino[3' ,4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione
- 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-l0-methoxy-12-(4-methylpiperazinomethyl)-lH-
oxepino[3',4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione
- 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-
oxepino[3',4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione
- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy 10-methoxy-12-dimethylaminomethyl-lH-
oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-lH-
oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione hydrochloride
- 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-( 1,2,5,6-tetrahydropiperidinomethyl)- 1H-
oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperidinomethyl)-lH-oxepino[3',4' :6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione
- 5-ethyl-4,5-dihydro-5-hydroxy-10-metfaoxy-12-(4-methylpiperazinomethyl)-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy- 12-pyrrolidinomethyl-1 H-oxepino[3',4' :6,7]
indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione
- 12-(4-benzylpiperazinomethyl)-5-ethy4-4,5-dihydro-5-hydroxy-10-methoxy-lH-
oxepino[3',4' :6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione
- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-l0-methyl-12-(4-methylpiperidinomethyl)-lH-
oxepino[3',4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione
- 10-benzyloxy-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]
indolizinof 1,2-b] quinoline-3,15(4H, 13H)-dione
- 5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy~lH-oxepino[3,4':6,7] indolizino[l,2-b]
quinoline-3,15(4H, 13H)-dione
or a pharmaceutically acceptable salt of one of these.
The invention more particularly relates to compounds of formula II as defined above, wherein R1 represents the ethyl group; R2 and R3 independently represent H, an inferior alkyl, halo, inferior haloalkyl or (CH2)mOR6, or R2 and R3 together form a methylenedioxy or an ethylenedioxy; R4 and R5 independently represent H, an inferior alkyl, (CH2)mNR6R7, or (CH2)n[N=X] not substituted or substituted by an inferior alkyl;
R.20 represents H and R17 represents OR6, where R6 represents H or an inferior alkyl, or NR6R7 wherein R6 and R7 independently represent H, an inferior alkyl, aryl or inferior arylalkyl. Preferably, R4 represents H or (CH2)mNR6R7, wherein R6 and R7 independently represent H or an inferior alkyl; R5 represents H, an inferior alkyl or (CH2)n[N=X] not substituted or substituted by an inferior alkyl; R17 represents OR6, where R6 represents H or an inferior alkyl; or a fharmaceutically acceptable salt of the latter. Typical examples of [N=X] substituted or not substituted are the radicals piperidyl, morpholinyl, piperazinyl, imidazolyl and 4-methyl piperazinyl.
More preferably, R2 represents H or halo and preferably H, chloro or fluoro; R3 represents H, an inferior alkyl, halo or OR6 where R6 represents H, an inferior alkyl or an inferior alkyl aryl and preferably H, fluoro, chloro, methyl or methoxy. More preferably again, R2 and R3 together form a dioxymethylene or a dioxyethylene.
More particularly, the invention relates to the products described below in the examples that satisfy the following formulae:
- 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperidinomethyl)-lH-oxepino[3',4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione;
- 5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-lH-oxepino[3',4' :6,7] indolizinof 1,2-b] quinoline-3,15(4H, 13H)-dione;
- 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-l€-methyl-12-(4-methylpiperidinomethyl)-1H-
oxepino[3' ,4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione;
- 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-pyrrolidinomethyl-lH-oxepino[3' ,4': 6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione;
- 9-chloro-5-ethy1-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3',4':6,7] indolizino[ 1,2-b] quinoline-3,15(4H, 13H)-dione;
- 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperidinomethyl-lH-oxepino[3',4' :6,7] indolizino[ 1,2-b] quinoline-3,15(4H,13H)-dione;
- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-1H-
oxepino [3',4':6,7] indolizino[1,2-b] quinoline-3,15(4H,13H)-dione;
or a pharmaceutically acceptable salt of one of these.
As used here with reference to the alkyl, alkeylthio and alkoxy groups, the term "inferior" designates saturated, linear or ramified aliphatic hydrocarbon groups comprising from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methylthio, ethylthio, methoxy and ethoxy. In referring to the alkenyl or alkynyl groups, the term "inferior" designates groups comprising 2 to 6 carbon atoms and one or more double or triple bonds, for example the following groups : vinyl, allyl, isopropenyl, pentenyl,
hexanyl, ethynyl propenyl. propynyl and butynyl. The term "cycloalkyl" designates a cycle of 3 to 7 carbon atoms, for example the following groups : cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term aryl designates a mono-, di- or tricyclic hydrocarbon compound with at least one aromatic ring, each ring containing a maximum of 7 links, for example phenyl, naphthyl, anthracyl, biphenyl or indenyl. The term halo signifies chloro, bromo, iodo or fluoro. The radicals corresponding to the expressions inferior haloalkyl, inferior cyanoalkyl, inferior nitroalkyl, inferior amidoalkyl, inferior hydrazinoalkyl, inferior azidoalkyl, inferior arylalkyl, inferior hydroxyalkyl, inferior alkoxy inferior alkyl, inferior alkylthio inferior alkyl, and inferior alkyl inferior sulphonylalkyl are substituted respectively by between one and three halo, cyano, nitro, amido, hydrazino, azido, aryl, hydroxy, inferior alkoxy, inferior alkylthio or inferior sulphonyl groups. The amino inferior alkyl radical may contain one or two inferior alkyl groups, and represent for example NHCH3, NHCH2CH3, N(CH3)2, ou N(CH3)(CH2CH3). Examples of [N=X] include the piperidinyl, morpholinyl, piperizinyl and imidazolyl groups.
As is observed for camptothecin, the carbon atom carrying the hydroxyl function in ß-hydroxylactone or the P-hydroxycarboxylate group in compounds according to the present invention is asymmetrical. Consequently the compounds according to the present invention have two possible enantiomeric forms, that is, the "R" and "S" configurations. The present invention encompasses the two enantiomeric forms and all combinations of these forms, including the racemic "RS" mixtures. With a view to simplicity, when no specific configuration is shown in the structural formulae, it should be understood that the two enantiomeric forms and their mixtures are represented.
Other objects of the invention are the processes for preparing compounds of general formula I and II, either from camptothecin or substituted camptothecins, or by total chemical synthesis.
The invention therefore concerns a process for preparing compounds of formulae I and II according to the invention, and in particular the products whose formulae are shown above, starting from camptothecin or from substituted camptothecins, characterised in that
- the α-hydroxylactone in camptothecin of general formula
(Formula Removed)
wherein R1, R2, R3, R4, R5 and R20 have the meaning given above, is reduced, in order to obtain the a-hydroxylactol of general formula A
(Formula Removed)
wherein R1, R2, R3, R4, R5 and R20 have the meaning indicated above,
- in the compound A thus formed, the carbon-carbon bond linking the neighbouring
carbinols is cut by treatment with a suitable oxidising agent so as to give a compound of
general formula B
wherein R\, R2, R3, R4, R5 and R20 have the meanings indicated above.
- this is then treated by a functionalised alkylating agent and the formyl function of the
compound of general formula B is cut to give a $-hydroxyester of general formula C
(Formula Removed)
wherein R1, R2, R3, R4, R5, R18 Rl9 and R20 have the meanings indicated above and R17 represents OR6 and R6 represents an inferior alkyl, cycloalkyl, cycloalkyl inferior alkyl, inferior alkenyl, inferior alkoxy inferior alkyl, or aryl or inferior arylalkyl;
- the said compound of general formula C is cycled to give the ß-hydroxylactonic
compound of general formula D
(Formula Removed)
wherein R1, R2, R3, R4, R5, R18, Rl9 and R20 have the meanings indicated above,
- the lactone of general(Formula Removed)
formula D is openedjto gave the compound of formula E
wherein R1, R2, R3, R4, R5 R17, Rl8, R19 and R20 have the meaning indicated above; R16 represents OR21 wherein R21 represents H or an inferior alkyl; and R17 represents OR6 or NHR6 and R6 represents an inferior alkyl, cycloalkyl, cycloalkyl inferior alkyl, inferior alkenyl, inferior alkoxy inferior alkyl, or aryl or inferior arylalkyl.
Certain compounds of formula E can also be obtained by hydrolysing the ester function in compounds of the corresponding formula- D. The compounds of general formula E wherein R16 and/or R17 independently represent the hydroxy radical, can be esterified or amidified in conventional conditions familiar to the specialist in order to produce the corresponding esters or amides of formula E.
In the above process, the groups R1, R2, R3 and R4 can be protected if necessary using the conventional protection methods (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)). In this process, reduction is effected using a reducing agent in an appropriate solvent, for example sodium borohydride in methanol. The stage corresponding to the formation of compound B from compound A is effected in oxidising conditions, for example using lead tetraacetate, periodic acid or sodium metaperiodate in an appropriate solvent, for example acetic acid. Treatment using a functionalised
alkylating agent can be effected using a metal derivative, for example of lithium or zinc, a carboxylic ester in an anhydrous aprotic solvent such as tetrahydrofurane. The lactonisation stage whereby compound D is obtained from compound C usually takes place in acidic conditions environment and can be effected, for example, by treatment by trifluoroacetic acid or hydrogen chloride dissolved in an anhydrous solvent such as dichloromethane or dioxane. The lactonic cycle of compound D can be opened to produce compound E for example by hydrolysis in alkaline conditions, followed by neutralisation.
Examples of substituted camptothecins, used as starting substances, can be found in American patents Nos. 4 473 692, 4 604 463,4 894 956, 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, patent applications PCT 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.
Accordingly the invention also concerns a process for preparing compounds of formulae I and II, characterised in that
- a compound of general formula M
(Formula Removed)
wherein R1, R18 and R19 have the meanings indicated above and R20 represents hydrogen or a halogen atom, is coupled with a 2-halo-3-quinoline-methanol of general formula N
(Formula Removed)
wherein R2, R3, R4, and R5 have the meanings indicated above and X represents a halogen atom, to give thecompound of formula O
(Formula Removed)
wherein R1, R2, R3, R4, R5, R18, R19. R20 aud X have the meanings indicated above;
- then the compound of general formula O is cyclised to obtain the compound of general
formula D as defined above.
In the above process, the groups R, R2, R3,and R4 can be protected if necessary using the conventional methods of protection (Greene, T,M Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)). The compound O is formed from the compounds of general formulae M and N by a process known to the professional as Mitsunobu's reaction (see Mitsunobu, O. et al., Synthesis, p. 1 (1981)). This involves displacing the hydroxyl function of the compound N by a nucleophile such as the compound M, or a deprotonated derivative of the latter, by a treatment with a phosphine, for example triphenylphosphine, and an azodicarboxylate derivative, for example diethyl azodicarboxylate, in an aprotic solvent, for example tetrahydrofurane or N,N-dimethylformamide. The compound O is cyclised preferably in the presence of a catalyst containing palladium (for example palladium diacetate) in basic conditions (provided for example by an alkaline acetate possibly combined with a phase transfer agent, for example tetrabutylammonium bromide), in an aprotic solvent such as acetonitrile or N,N-dimethylformamide, at a temperature between 50 °C and 120 °C (R. Grigg et al., Tetrahedron 46, page 4003 (1990)).
The compounds of general formula M are new. They can be prepared according to a process characterised in that
- the carbonyl of a pyridine of general formula
(Formula Removed)
wherein R1 and R20 have the meanings indicated above and R22 represents a halogen atom or an inferior alkoxy, is protected by an acetal function, to give the compound of general formula F
(Formula Removed)
wherein R\, R20 and R22 have the meanings indicated above the groups Z and Z' independently represent an inferior alkyl or form together a saturated hydrocarbon chain of 2 to 4 carbon atoms;
- a hydroxymethyl function is inl reduced in|o the compound of general formula F in order
to produce a compound of general formula G
(Formula Removed)
wherein R1, R20, R22 Z and Z' have the meanings indicated above,
- then the alcohol function of the compound of general formula G is protected to give a
compound of general formula H
(Formula Removed)
wherein R1, R20, R22, Z and Z' have the meanings indicated above and R23 represents a protective group for the alcohol function,
- the acetal function in the compound of general formula H is removed to give the
compound of general formula F
(Formula Removed)
wherein R1, R20, R22, and R23 have the meanings indicated above,
- the compound of formula F is treated by a fanctionalised alkylating agent to give a fl-
hydroxyester of general formula J
(Formula Removed)
wherein R\, R2Q, R22» and R23 have the meanings indicated above and R17, Ris and R19 are as defined in general formula II
- the protective group R23 is removed from* the, compound of general formula J to give a
compound of general formula K
(Formula Removed)
wherein Ri, R18, R19, R20 and R22 have thm meanings indicated above and R17 represents OR6 or NHR6 and R6 represents H, an inferior alkyl, cycloalkyl, cycloalkyl inferior alkyl, inferior alkenyl, inferior alkoxy inferior alkyl, or aryl or inferior arylalkyl,
- the compound of general formula K is cyofsed into a compound of general formula L
(Formula Removed)
wherein R1, R18, R19, R20, and R22 have the meanings indicated above, and finally
- the radical R22 in compound L is converted into a carbonyl, to produce the compound of
general formula M
(Formula Removed)
wherein Ri, Ris, R19, and R20 have the meanings indicated above.
The carbonyl function of a 4-acyl-2-halopyridine (obtained for example according to Lamattina, J.L. J. Heterocyclic Chem. 20, p. 553 (1983)) is protected preferably by an acetal function, preferably a cyclic acetal, in the conventional conditions familiar to the professional (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)). The intermediate product obtained in this way is treated by an alcoholate of sodium or potassium in an aprotic solvent (for example acetonitrile), or in the alcohol from which the alcoholate is derived, at a temperature between 0 °C and 100 °C to give the compound of general formula F. The said compound can be lithiated in position 3 by treatment by an aryl-lithium or alkyl-lithiura (for example mesityl-lithium) in an etherated solvent such as tetrahydrofurane at a temperature between -100 °C and 0 °C. To the intermediate lithiated product obtained in this way, a formylating electrophile such as N,N-dimethylformamide is added, and the aldehyde thus obtained, after hydrolysis, is treated by a reducing agent such as sodium borohydride to give the compound of general formula G. The alcohol function in the compound G is protected in a conventional manner familiar to the professional, to give a compound of general formula H. Examples of protective groups
for the alcohol function comprise those that form ethers [that is, methyl, methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, benzyloxymethyl, t-butyl, and benzyl (whether substituted or not)], and esters (that is, formate, acetate and isobutyrate). For other examples of protective groups for primary hydroxyls, reference may be made to Greene, T., Protective Groups in Organic Synthesis, 10-86 (John Wiley & Sons, 1981). Removal of the protection from the compound of general formula H to give the compound of general formula F is carried out in selective conditions that maintain the integrity of the radical R23, for example by treatment in acidic conditions (for example using trifluoroacetic acid). The selective conditions for protecting and deprotecting functional groups are familiar to the professional (Greene, T., Protective Groups in Organic Synthesis, 10-86 (John Wiley & Sons, 1981)). Treatment of the compound I' by a functionalised alkylating agent to give a p-hydroxy ester of general formula J can be performed using a lithium enolate or a zinc derivative of a carboxylic ester in anhydrous aprotic solvent, for example tetrahydrofurane. The protection group R23 on the compound of general formula J is removed to give a compound of general formula K, in conditions of protection removal familiar to the professional. For example, when R23 is a benzyl group, an alcoholic solution of the compound of general formula J together with a catalyst containing palladium can be exposed to an atmosphere of hydrogen at a pressure of 0.5 to 10 bar. The compound of general formula K obtained in this way can be cyclised in acidic conditions (for example by treatment with trifluoroacetic acid, or hydrochloric gas dissolved in an anhydrous solvent such as diehloromethane or dioxane) to give a 7-chain (3-hydroxylactonic cycle such as the compound of general formula L. The compounds of general formula L can be converted into pysidones of general formula M, for example by treatment with hot hydrochloric acid, or witth trimethylsilyl iodide.
The 2-halo-3-quinoline-methanols of general formula N can be obtained from acetanilides of general formula P
(Formula Removed)
wherein R2, R3 and R4 have the meanings indicated in the general formulae for compounds I and II. In the following processes, the groups R2, R3 and R4 can be protected if necessary by conventional methods of protection (Greene, T., Protective Groups in Organic Synthesis, 10-86 (John Wiley & Sons, 1981)).
The compounds of formula N can therefore be obtained using the following process : the said anilines of formula P are N-acetylated by treatment with an acetylating agent, for example acetic anhydride. The acetanilides thus obtained are treated at a temperature between 50°C and 100°C, for preference 75°C by a reagent known to the professional as Vilsmeyer's reagent (obtained by the action of phosphoryl oxychloride on N,N-dimethyl formamide at a temperature between 0°C and 10°C) to give the corresponding 2-chloro-3-quinoline carbaldehyde (see for example 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 atom in position 2 of the 2-chloro-3-quinoline carbaldehydes can be substituted by iodine or bromine by heating the product in an inert solvent such as acetonitrile in the presence of a salt of iodine or bromine (for example sodium iodide or tetrabutylammonium bromide). A trace of acid such as concentrated hydrochloric acid may be necessary to catalyse this conversion. The 2-halo-3-quinoline carbaldehydes are easily reduced into the corresponding 2-halo-3-quinoline methanols of general formula N, in conventional conditions known to the professional such as treatment in an alcoholic solvent (for example, methanol) with sodium borohydride at a temperature between 0 °C and 40 °C.
The compounds of formula N can also be obtained using the following process : the anilines of general formula P as defined above are acetylated by reaction with a nitrile (such as chloroacetonitrile or propionitrile) in the presence of boron trichloride and 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 (see Sugasawa, T, et al, J. Am. Chem. Soc. 100, p. 4842 (1978)). The intermediate product thus obtained is then treated by ethyl malonyl chloride in an aprotic solvent such as acetonitrile in the presence of a base such as triethylamine, then treated by an alkaline alcoholate, for example sodium methylate in methanol, to give an ethyl 2-hydroxy-3-quinoline carboxylate substituted in position 4. The latter is converted into ethyl 2-chloro-3-quinoline carboxylate by treating with phosphoryl oxychloride. When position 4 of the quinoline carries a chloromethyl group, a nucleophilic substitution can be made by treating with a secondary amine such as dimethylamine, N-methylpiperazine, morpholine or piperidine. The ethyl 2-chloro-3-quinoline carboxylate is then reduced by diisobutylaluminium hydride in an aprotic solvent such as dichloromethane to give the 2-chloro-3-quinoline methanol of general formula N. Analogues of the intermediate compounds (N) have been described in the literature and in particular in patent application PCT 95/05427.
Another object of the invention, concerns, as new industrial products and particularly as new industrial products intended for preparing products of formula I or II, the products of formulae F and M as described above.
Certain compounds of the invention can be prepared in the form of pharmaceutically acceptable salts using the usual methods. Acceptable salts comprise, as examples and in a non-limiting manner, addition salts of inorganic acids such as chlorhydrate, sulphate, phosphate, diphosphate, bromohydrate and nitrate, or of organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methane sulfonate, p-toluene sulfonate, pamoate, salicylate, oxalate and stearate. Salts formed from bases such as sodium or potassium hydroxide also fall within the field of application of the present invention, when they are useable. Other examples of pharmaceutically acceptable salts can be found in "Pharmaceutical Salts", J. Pharm. Sci. 66:1 (19771).
The compounds of the present invention possess interesting pharmacological properties. Thus the compounds of the present invention have an inhibiting action on topoisomerase I and/or II and an anti-tumoral action. The state of the art suggests that the compounds of the invention have an anti-parasitic and/or anti-virus action. Accordingly the compounds of the present invention can be used for different therapeutic applications.
Illustrations of the pharmacological qualities of the compounds of the invention are given hereunder in the experimental section.
The compounds can inhibit topoisomerase, for example of type I and/or II in a patient, for example a mammal such as man, when a therapeutically effective quantity of a compound of formula (I) or formula (II) is administered to titiis patient.
The compounds of the invention also possess an anti-tumoral activity. They can be used for treating tumours, for examples tumours expressing a topoisomerase, in a patient by administering a therapeutically effective amount of a compound of formula (I) or formula (II). Typical tumours or cancers comprise cancers of the oesophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, breast, cervix uteri, corpus endometrium, ovaries, prostate, testicles, bladder, kidneys, liver, pancreas, bones, conjunctive tissue of the skin, eyes, brain and the central nervous system, as well as cancer of the thyroid, leukaemia, Hodgkin's disease, lymphomas other than those of Hodgkin, multiple myelomas and others.
They can also be utilised for treating parasitic infections by inhibiting haemoflagellates (for example in trypanosomiasis or infections caused by Leishmania) or by inhibiting Plasmodia (as for example in malaria), but also for the treatment of viral infections or diseases.
These properties render the products of formulae (I) and (II) suitable for pharmaceutical use. Another subject of the present application is, as medicines, the products of formula (I) and (II) as defined above, together with the addition salts with the pharmaceutically acceptable inorganic or organic acids of the said products of formulae I and II, and the pharmaceutical compositions containing, as active principle, at least one of the medicines defined above.
The invention thus concerns pharmaceutical compositions containing a compound of the invention or an addition salt of a pharmaceutically acceptable acid of such a compound, in association with a pharmaceutically acceptable medium depending on the method of administration chosen (for example oral, intravenous, intraperitoneal, intramuscular, transdermic or subcutaneous). The pharmaeeutical composition (for example, therapeutic) may be in the form of a solid, of a liquid, of liposomes or lipidic micellae.
The pharmaceutical composition may be in solid form, as for example powders, pills, granules, tablets, liposomes, capsules or suppositories. The pill, tablet or capsule may 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 long enough period to allow this composition to pass undigested into the small intestine of the said patient. The compound can be administered locally, for example at the very location of the tumour. The compound may also be administered using the prolonged release process (for example a prolonged release composition or with an infusion pump). Suitable solid media may for example be calcium phosphate, magnesium stearate, magnesium carbonate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxy methyl cellulose, polyvinyl pyrrolidine and wax. The pharmaceutical compositions containing a compound of the invention can also be presented in liquid form, as for example solutions, emulsions, suspensions or as a prolonged release formulation. Suitable liquid media can for example be water, organic solvents such as glycerol or glycols such as polyethylene glycol, as well as mixtures of the above in different proportions in water.
Another object of the invention is also the use of products of formula (I) or (II) as defined above, for the preparation of drugs intended to inhibit topoisomerase, and more particularly topoisomerase of type I or II, of drugs intended for treating tumours, of drugs intended for treating parasitic infections, as well as drugs intended for treating viral infections or diseases.
The dose of a compound according to the present invention, appropriate for treating the diseases or infections mentioned above, vary according to the method of administration, the patient's age and body weight, and the patient's condition, and the definitive decision
will be taken by the treating clinician or veterinarian. Such a quantity determined by the treating clinician or veterinarian is here denoted the "therapeutically effective quantity".
Illustrations of the pharmacological properties of the compounds of the invention are given hereunder in the experimenlal section.
The compounds can inhibit topoisomerase, for example of type I and/or II, in a patient, for example a mammal such as man, when a therapeutically effective quantity of a compound of formula (I) or formula (II) is administered to this patient.
All the technical and scienlific terms used here, unless otherwise defined, 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, all the patents and all other references mentioned here are incorporated by reference.
The following examples are given to illustrate the above procedures and should in no circumstances be regarded as limiting the scepe of the invention.
EXPERIMENTAL SECTION
Example 1 : tert-butyl ß-ethyl-ß-hydroxy--(8-hydroxymethyl-9-oxo (11H)-
indolizino-[l,2-b] quinoline-7-yl)-propionate
l.a. 4-ethyl-3,4-dihydroxy-lH-pyrano [3',4':6,7] indolizino [1,2-b] quinoline-
14(4H,12H)-one
Sodium borohydride (14 g, 370 mmol) is added in portions to a suspension of (S)-(+)-camptothecin (14 g, 40 mmol), that may be obtained using different commercial sources such as Aldrich Chemical Co. (Milwaukee, WI), in methanol (750 ml) and the resulting mixture is heated slowly to 55 ° C so as to obtain a limpid solution that is then agitated for 16 hours at ambient temperature. The solvent is then evaporated under reduced pressure, the residue is recovered in water (250 ml), neutralized by the addition of acetic acid (21 ml) and left at rest for 2 hours at 4° C. The resulting suspension is filtered and washed successively with cold water, acetoae and diethyl ether, which, after drying under reduced pressure, permits obtaining the sought compound in the form of a white solid (m.p. 280 °C).
l.b. 8-formyloxymethyl-7-propionylindolizino [1,2-b] quinoline-9 (11H)-one
A solution of sodium metaperiodate (14 g, 65 mmol) is added dropwise in water (140 ml) to a suspension of 4-ethyl-3,4-dihydroxy-lH-pyrano [3',4':6,7] indolizino [1,2b] quinoline-14(4H,12H)-one (13,4 g; 38 mmol) in glacial acetic acid (720 ml) and the resulting
solution is agitated for one hour at ambient temperature. The reaction mixture is then poured into a mixture of ice/water (650 ml)#and the resulting suspension is agitated for one half-hour then filtered and washed successively with water, isopropyl alcohol, and diethyl ether, which, after drying under reduced pressure, produces the sought compound (11.5 g) in the form of a pale yellow solid m.p. > 20 °C (d).
I.e. tert-buty ß-ethyl-ß-hydroxy-(8-droxymethyl-9-oxo(llH)-indolizino-
[1,2-b] quinoline-7-yl)-propionate
A zinc suspension (6.5g, 100 mmol) agitated with a magnetic agitator in anhydrous diethylether (50 ml) under argon, is activated, by dropwise addition of chlorotrimethylsilane (0.75 ml, 5.7 mmel). The reaction medium is agitated again 15 minutes at ambient temperature and then heated to reflux. The heating bath is then removed and tert-buiy\ bromoacetate (15 ml, 100 mmol) is added dropwise at a rate assuring the maintenance of reflux. The external heating is replaced and pursued again for one hour. The ethereal solution resulting flom the Reformatsky reagent is left to cool to ambient temperature then transferred, by means of a formula, into a suspension of 8-formyloxymethyl-7-propionylindolizino [l,2b] quinoline-9-(11H)-one (1.6g, 4.7 mmol) in anhydrous tetrahydrofuran (40 ml) under asgon. The reaction mixture is agitated at reflux for one hour, then left to cool to ambient temperature, and the reaction is stopped by adding saturated ammonium chloride (100 ml) and is extracted with chloroform (3 x 100 ml). The combined chloroformic extracts are dried on sodium sulphate, evaporated, and the residue is purified by gel chromatography on silica gel (1-2% MeOH/CH2Cl2), which makes possible obtaining 0.64 g of the sought-after compound (31 %) in the form of a pale yellow solid (m.p. 146-149 °C).
RMN-lH (CDC13): 0.93 (t, 3H); 1.37 (s, 9H); 1.99 (m, 2H); 2.97 (dd, 2H); 3.5 (se, 1H);
5.10 (s, 2H); 5,.4 (s, 2H); 7.40 (s,lH); 7.59 (t> 1H); 7.83 (t, 1H); 7.90 (d, 1H); 8.20 (d,
1H); 8.34 (s, 1H).
RMN-13C (CDCI3): 8.18 ; 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.
Example ethyl ß-ethyl-ß-hydroxy--(8-hydroxymethyl-9-oxo (llH)-indolizino-[l,2b] quinoline-7-yl)-propionate
A suspension of zinc (500 mg, 7.64 mmol) and of 8-formyloxymethyl-7-propionylindolizino [1,2-b] quinoline-9 (llH)-one (400 mg, 1.15 mmol) in anhydrous tetrahydrofuran (20 ml) containing 10 mg oihydroquinone is heated to reflux under argon.
The heating bath is removed and the exothermic reaction initiated by the addition of a drop of ethyl bromoacetate and a small crystal of iodine. Reflux is maintained by the dropwise addition of ethyl bromoacetate (500 µ1, 4MB mmol) then the reaction mixture is again heated at reflux for one hour. After cooling to ambient temperature, the reaction is stopped by adding saturated ammonium chloride (40 ml) and methanol (30 ml). The resultant mixture is agitated for 5 minutes then filtered and evaporated. The residue is dissolved in dichloromethane (30 ml), washed with water and dried on sodium sulfate. This is followed by the elimination of the solvent and a purification by column chromatography (Si02, CH2Cl2/MeOH 98/2) resulting in 230 mg (49 %) of the sought compound in the form of a yellow solid (m.p. 157-161 ° C).
RMN^H (CDC13): 0.93 (t, 3H); 1.20 (t, 3»); 2.02 (m, 2H); 3.07 (dd, 2H); 4.11 (q, 2H);
4.9 (se, 1H); 5.08 (s, 2H); 5.23 (s, 2H); 7.45 (s,lH); 7.62 (t, 1H); 7.80 (t,lH); 7.90 (d,
1H); 8.22 (d, 1H); 8.36 (s, IH).
RMN-l3c (CDCI3): 8.09 ; 14.01 ; 34.67 ; 44.85 ; 49.94 ; 58.31 ; 61.09 ; 77.21 ; 100.78 ;
127.78 ; 127.96 ; 128.11 ; 128.72 ; 129.16 ; 129.65 ; 130.60 ; 131.32 ; 142.76 ; 148.28 ;
152.55 ; 155.09 ; 162.22 ; 172.59.
IR (KBr): 766 ; 1009 ; 1184 ; 1582 ; 1647 ; 1750.
Example 3 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino-
[l,2-b]quinoline-3,15 (4H, 13H)-dione
tert-butyl ß-ethyl-ß-hydroxy--(8-hydroXymethyl-9-oxo (1 lH)-indolizino-[l,2-b] quinoline-7-yl)-propionate (1.45 g, 3.32 mmol) is dissolved in anhydrous dichloromethane (25 ml) and treated with a saturated solution of hydrogen chloride in dichloromethane (100 ml). The resultant mixture is maintained at -20 °C for 16 hours. The precipitate is filtered, washed with methanol and dried under reduced pressure, which leads to 662 mg (55 %) of the sought after compound in the fibrin of a yellow solid (m.p. >300 °C).
RMN-1H (DMSO): 0.90 (t, 3H); 1.20 (q, 2H); 3.27 (dd, 2H); 5.29 (s, 2H); 5.49 (dd,
2H); 7.42 (s, IH); 7.73 (t, IH); 7.90 (t, IH) ; 8.16 (t, 2H); 8.71 (s, IH).
RMN-13C (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.
Example 4: ß--ethyl-ß-hydroxy-)-8-hydroxymethyl-9-oxo(llH)-indolizino-
[1,2-b] quinoline-7-yl)-propionic acid
An aqueous solution of potassium hydroxyde (0.1N, 30 ml) is added to 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15(4H,13H)-
dione (500 mg, 1.38 mmol) and the resultant suspension is agitated at ambient temperature for 16 hours, which results in an almost clear liquid that is filtered. The filtrate is acidified to pH 3.5 with IN hydrochloric acid, and the yellow precipitate is recovered by filtration, washed with water and acetone, then dried under reduced pressure. 415 mg (79 %) of the sought compound is obtained in the form of a monohydrate (m.p. 165-167 °C).
RMN-!H (DMSO): 0.82 (t, 3H); 2.10 (m, 2H); 2.83 (d, 2H); 3.12 (d, 2H); 3.25 (se,
1H); 4.81 (s, 2H); 5.26 (s, 2H); 5.76 (se, JH) ; 7.38 (s, 1H); 7.71 (t, 1H); 7.84 (t, 1H);
8.10 (d, 1H); 8.18 (d, 1H); 8.34 (s, 1H); 12.15 (se, 1H).
RMN-13C (DMSO): 8.16 ; 34.80 ; 46.71 ; 50.36 ; 55.73 ; 76.53 ; 100.17 ; 127.50;
128.00 ; 128.26 ; 128.69 ; 129.06 ; 130.01; 130.45 ; 131.63 ; 142.57 ; 148.09 ; 153.19 ;
156.07 ; 161.22 ; 172.27.
IR (KBr): 1020 ; 1188 ; 1413 ; 1586 ; 1651; 1694.
E x a m p I raethTgl ß--ethyl-ß-hydroxy--(8-hydroxymethyl-9-oxo (11H)-indolizino-[l,2-b] quinoline-7-yl)-propionate
5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15(4H,13H)-dione (180 mg, 0,5 mmol), in suspension in methanol (50 ml) is treated with 6N dry hydrogen chloride in methanol (0,5 ml) and maintained at reflux until completely dissolved (4 hours). The volatile compounds are evaporated and the residue is dissolved in dichloromethane (50 ml), washed with diluted sodium hydroxyde (0.05 N, 15 ml) and brine (15 ml). The organic phaseus dried over sodium sulphate and evaporated. The residual solid is purified by silica gel column chromatography (MeOH at 3% / CH2CI2) and the purified product is taken up in diethyl ether, filtered and dried, which gives 120 mg (58 %) of the sought after compound in the form of a pale yellow solid (m.p. 163-166 °C).
RMN-!H (CDCI3): 0.93 (t, 3H); 2.2 (m, 2H); 3.05 (dd, 2H); 3.49 (s, 3H); 3.62 (s, 3H);
4.93 (s, 2H); 5.22 (d, 2H); 5.52 (s, 1H); 7.21 (s, 1H); 7.62 (t, 1H); 7.81 (t, 1H); 7.91 (d,
1H); 8.22 (d, 1H); 8.36 (s, 1H).
RMN-13C (CDCI3): 7.74 ; 35.54 ; 46.82 ; 50.15 ; 51.67 ; 58.10 ; 65.33 ; 78.03 ; 100.17 ;
125.57 ; 127.70 ; 128.04 ; 128.10 ; 128.35 ; 129.53 ; 130.39 ; 130.94 ; 143.87 ; 148.75 ;
152.94 ; 157.83 ; 161.74 ; 171.35.
IR (KBr): 1207 ; 1595 ; 2655 ; 1709.
Example 6 ethyl ß-ethyl-α,-difluoro-ß-hydroxy--(8-hydroxymethyl-
9-oxo (11H)-indolizino-[l,2-b] quino!ine-7-yl)-propionate
About one half of the total quantity of ethyl bromodifluorocetate (1.8 ml, 14 mmol), 8-formyloxymethyl-7-propionylindolizino [l,2-b]quinoline-9 (11H)-one (2.0 g,
5.75 mmol, such as is obtained in example Lb) in suspension with anhydrous THF (10 ml), is added dropwise under argon to a suspension of zinc (1.25 g, 17.2 mmol) in anhydrous THF (40 ml) at reflux, then the remaining g)art of the ethyl bromodifluorocetate is added. The reaction mixture is maintained at reflux for another half-hour. After cooling to ambient temperature, the reaction is stopped by adding saturated aqueous ammonium chloride (20 ml) and the reaction mixture is extracted with dichloromethane (3 x 20 ml). The combined organic extracts are dried and concentrated. The residue is taken up in diethyl ether (10 ml), filtered and purified by column chromatography (SiC«2, CH2Cl2MeOH 98/2), resulting in 664 mg (26 %) of the sought compound in the form of a yellow solid (m.p. 208-209 °C).
RMN-1H (CDC13) : 0.91 (t, 3H) ; 1.38 (t, 3H) ; 2.32 (m, 2H) ; 4.8 (se, 1H) ; 4.38 (q, 2H) ;
5.09 (d, 2H); 5.13 (dd, 2H); 7.42 (s,lH); 7.55 (t, 1H) ; 7.72 (t, 1H); 7.79 (d, 1H);
8.08 (d, 1H); 8.22 (s, 1H)
RMN-13C (CDCI3): 6.97 ; 13.93 ; 28.63 ; 50.18 ; 56.27 ; 63.15 ; 77.20 ; 81.96 (t);
101.27 ; 116.40 (t); 127.67 ; 127.77 ; 127.97 ; 128.31 ; 129.26 ; 130.33 ; 130.94 ; 131.23 ;
143.16 ; 148.34 ; 150.20 ; 151.91; 161.21; 163.21 (t).
IR (KBr): 1124 ; 1308 ; 1591; 1647 ; 1748.
Example ethyl ß-7thyl-ß-hydroxv--(8-hydroxymethyl-9-oxo (11H)-indolizino-[l,2-b]quinoline-7-yl)-propionate
A suspension of zinc (1.25 g, 19.1 mmol), 8-methyl-7-propionylindolizino [l,2-b]quinoline-9 (11H)-one (500 mg, 1.43 mmol, such as is obtained by Kinsburry, W.D., Tetrahedron Lett. 29: 6847 (1988)) and silver acetate (250 mg, 1.50 mmol) in anhydrous tetrahydrofuran (10 ml) is agitated at ambient temperature in an argon atmosphere. At the end of 10 minutes, the reaction mixture is activated by the dropwise addition of a molar solution of chlorodiethylaluminium (10 ml, 10 mmol), then ethyl bromoacetate (1.25 ml, 11.3 mmol) is added1 dropwise and the resultant mixture and left to react for another 5 hours. The reaction is stopped by the successive addition of ethyl alcohol (10 ml) and a saturated solution of potassium and sodium tartrate (10 ml). The resultant mixture is agitated again for one hour, filtered and concentrated under reduced pressure. The residue is taken up in dichloromethane (30 ml), washed with water, dried and concentrated. Column chromatography (SiO2, CH2Cl2/MeOH 98/2) allows to obtain 93 mg (15%) of the sought product in the form of a pale yellow solid (m.p. 185-188 °C).
RMN-lH (CDCI3): 0.91 (t, 3H); 1.17 (t, 3H); 1.99 (m, 2H); 2.49 (s, 3H); 3.10 (dd, 2H); 4.11 (q, 2H); 4.6 (se, 1H); 5.25 (s, 2H); 7.65 (t, 1H); 7.67 (s,lH); 7.80 (t, 1H); 7.90 (d, 1H); 8.22 (d, 1H); 8.34 (s, 1H).
RMN-13C (CDCI3): 8.02 ; 13.99 ; 14.72 ; 33.14 ; 43.97 ; 50.02 ; 61.0 ; 76.54 ; 101.90 ; 127.65 ; 127.84 ; 128.08 ; 128.81 ; 128.88 ; 130.74 ; 131.59 ; 131.65 ; 140.33 ; 147.64 ; 152.96; 153.61; 162.11; 172.91. IR (KBr): 762 ; 1192 ; 1576 ; 1653 ; 1740.
Example 8 tert-butyl ß-ethyl ß-hydroxy--(8-hydroxymethyI-9-oxo
(11H)-indolizino-[l,2-b] quinoline-7-yl)-puopionate
Acetic anhydride (70 µl, 0.7 mmol) is added dropwise to a solution of tert-butyl ß-ethyl-ß-hydroxy--(8-hydroxymethyl-9-oxo (1 lH) indolizino- [l,2-b]quinoline-7-yl)-propionate (200 mg, 0.46 mmol) and triethylamine (140 µl), 1 mmol) in dichloromethane (5 ml) and the resultant mixture is agitated at ambient temperature for 21 hours. The volatile compounds are evaporated and the residue is purified by a silica gel column chromatography (1-2 % MeOH / CH2CI2), Resulting in 152 mg of the sought compound in the form of a yellow solid (m.p. 195-196 °C).
RMN-lH (CDCI3): 0.88 (t, 3H); 1.32 (s, 9M) ; 1.93 (m, 2H); 2.07 (s, 3H); 2.97 (dd, 2H); 4.8 (se, 1H); 5.28 (s, 2H); 5.59 (dd, 2H); 7.9 (s, 1H); 7.63 (t, 1H); 7.80 (t, 1H); 7.90 (d, 1H) ; 8.23 (d, 1H); 8.34 (s, 1H).
RMN-13C (CDCI3): 8.02 ; 21.06 ; 27.91 ; 35.05 ; 45.58 ; 50.16 ; 59.23 ; 77.52 ; 82.26; 100.59 ; 124.21 ; 127.91 ; 128.10 ; 128.14 ; 128.97 ; 129.18 ; 130.68 ; 131.46 ; 142.85 ; 148.29 ; 152.43 ; 158.49 ; 161.83 ; 171.13 ; 171.90.
Example 9: 5,12-diethyl-4,5-dihydro-5-hydroxy-lH-oxepino
[3\4': 6,7]-indolizino [1,2-b] quinoline-3,15 (4H,13H)-dione
This compound is prepared in a manner analogous to example 1, except that in stage l.a. the 7-ethyl camptothecin (Sawada et al. Chem. Pharm. Bull. 39:2574 (1991)) is used in place of the camptothecin. The sought compound is obtained in the form of a bright yellow solid (m.p. > 270 °C).
RMN-!H (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, 1H); 7.76 (t, 1H); 7.89 (t, 1H) ; 8.18 (d, lH);8.32(d, 1H).
RMN-13C (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.
Example 10 : ß--ethyl-)-(12-ethyl-8-hydroxymethyl-9-oxo (HH)-indoIizino-
[1,2-b] quinoline-7-yl)-ß-hydroxy-propionic acid
This compound is prepared in a manner analogous to example 4, except that 5,12-diethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4': 6|7]-indolizino [1,2-b] quinoline-3,15 (4H,13H)-dione is used in place of 5-ethyl-4,5-dihydro)-5-hydroxy-lH-oxepino [3',4': 6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione. It is obtained in the form of a sightly off-white solid (m.p. 238-239 °C).
RMN-1H (DMSO): 0.82 (t, 3H); 1.35 (t, 3H); 2.01 (m, 2H); 2.85 (d, 2H); 3.18 (d, 2H); 3.22 (q, 2H) ; 4.81 (s, 2H); 5.00 (se, 1H); 5.24 (s, 2H); 5.78 (se, 1H) ; 7.38 (s, 1H); 7.77 (t, 1H); 7.86 (t, 1H); 8.18 (d, 1H); 8.28 (d, 1H); 12.10 (se, 1H). RMN-13C (DMSO): 8.12 ; 14.15 ; 22.41 ; 34.78 ; 46.74 ; 49.65 ; 55.71 ; 76.51 ; 100.04 ; 124.22 ; 126.63 ; 127.48 ; 128.12 ; 128.21 ; 129.94 ; 130.02 ; 143.10 ; 145.59 ; 148.69 ; 152.62 ; 156.03 ; 161.22 ; 172.22.
Example 11: 8-ethyl-2,3,8,9-tetrahydro-8-hydroxy-10H,12H-[l,4]dioxino
[2,3-g] oxepino [3.4.6.7.]indolizino [l,2-b[quinoline-10,13 (15H)-dione
11 JL 2-ethyl-2-(2-methoxy-4-pyridyl) l,3 dioxolane (F)
Azeotropic water is distilled for one entiffe night with a Dean Stark apparatus from a mixture of 2-chloro-4-propionylpyridine (10 g, 59 mmol) obtained as in Lamattina, J.L. /. Heterocyclic Chem. 20, p. 553 (1983)), ethylene glycol (20 ml) and p-toluenesulfonic acid (250 mg) in toluene (150 ml). The solvent is then eliminated under reduced pressure, the acid is neutralized with a saturated aqueous solution of sodium bicarbonate (100 ml) and the product is extracted using ether. The combined ethereal extracts are washed with brine, dried on sodium sulphate and evaporated, which produces 13.3 g (96 %) of the crude product protected by the caxbonyl 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 ; Si02, tert-butyl methyl 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 brine, dried on sodium sulphate and evaporated, resulting in a product (F) is recovered in the form of a clear liquid.
ll.b. 2-ethyl-2-(3-hydroxymethyl-2-methoxy-4-pyridyl)-l,3 dioxolane (G)
Tert-butyllithium (1.7 M in pentane, 100 ml, 170 mmol) is added dropwise using a cannula, to a solution of bromomesitylene (13 mg, 85 mmol) in anhydrous
tetrahydrofurane (300 ml) at -78° C under ai-gon. The resultant white precipitate is agitated at -78 °C for one hour then 2-ethyl-2-C2-methoxy-4-pyridyl)-l,3-dioxolane (10 g, 44,8 mmol) is added and the reaction mixture is agitated 15 minutes at -78 °C, one hour ar 0 °C and one hour at ambient temperature. After another cooling to -78 °C, anhydrous N,N-dimethylformamide (100 mmol) is added and the reaction mixture is left to reheat to ambient temperature then is agitated for 16 hours, after which an analysis by thin layer chromatography (SiC>2, TBMO/HX 50/50) shows the complete consumption of the starting compound. 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 on sodium sulphate and evaporated, resulting in a yellow oil which is purified by column chromatography (SiO2, TBMO/HX : 0/100 to 5/95 in order to elute the mesytylene derivatives then 20/80 to 50/50 to elute the product), and the intermediary aldehyde (7 g) is recovered. The aldehyde is dissolved in methanol (100 ml) and treated with sodium borohydride (5 g, 132 mmol). The resultant mixture is agitated until complete consumption of the intermediary aldehyde (about 1 hour; follow-up by thin layer chromatography). The solvent is then evaporated, the residue is reoovered in ether, washed with water and brine, dried, and the solvent is evaporated. The column chromatography (SiO2, TBMO/HX 10/90 to 50/50) of the residue yields 7 g (global yield 62 %) of product (G) in the form of a yellow oil.
ll.c. 2-(3-benzyloxymethyI-2-methoxy-4ipyridyl)-2-ethyl-l,3-dioxolane(H)
A solution of 2-ethyl-2-(3-hydroxymethyl-2-methoxy-4-pyridyl)-l,3-dioxolane (7 g, 30 mmol) and of benzyl chloride (5 ml, 45 mmo!) in anhydrous tetrahydrofuran (50 ml) is added dropwise to a suspension of sodium hydride (80 % in mineral oil, 1.85 g, 61 mmol) in anhydrous tetrahydrofuran (100 ml) and tie reaction mixture is maintained at reflux for 16 hours. The reaction mixture is then left to c©ol to ambient temperature, the reaction is stopped with water (50 ml) and the reaction mixture is concentrated under reduced pressure. The residue is dissolved in diethyl ether (150 ml) and washed with water and brne, dried and evaporated. A purification by column chromatography (Si02, TBMO/HX; 5/95 to 20/80) yields the product protected by benzyl (H) (9 g,.87 %) in the form of a clear oil.
11. d. l-(3-benzyloxymethyl-2-methosxy-4-pyridyl)-propane-l-one (I')
2-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-2-ethyl-l,3-dioxolane (9 g, 27 mmol) is treated with trifluoracetic acid (10 ml) and water (5 ml) for 3 hours with a bath temperature of 120 °C. The reaction mixture is concentrated under reduced pressure and the residual traces of the acids are neutralized by the addition of saturated aqueous sodium bicarbonate.
An ether extraction is followed by column chromatography (Si02, TBMO/HX 10/90), yielding 5.5 g (70 %) of product (I).
11. e. tert-butyl ß-ethyl-ß-hydroxy--(3-benzyloxymethyl-2-methoxy-4-pyridyl)-propionate (J)
tert-butyl bromoacetate (13 ml, 80 mmol) is*added dropwise to a suspension of zinc (5,3 g, 80 mmol, activated by treatment with 6N HO for 10 seconds, then washed successively with water until neutral pH, acetone and diethyl ether) in anhydrous tetrahydrofuran (60 ml) to reflux. The reaction medium is maintained at reflux for another 10 minutes after the addition is finished. A solution of l-(3-benz0oxymethyl-2-methoxy-4-pyridyl)-propane-l-one (5.8 g, 20 mmol) in tetrahydrofuran anhydride (20 ml) is added, and the reaction mixture is agitated under reflux for one more hour. The reaction is stopped at 0 °C with saturated aqueous ammonium chloride (100 ml) and the reaction mixture extracted with diethyl ether. The combined extracts are dried on sodium sulphate and evaporated, yielding a yellow oil which is purified by column chromatography (SiC>2, TBMO/HX; 5/95 to 10/90) to obtain the tert-butyl ester (J) (7 g, 95 %) in the form of a clear oil.
11. tert-butyl ß-ethyl-ß-hydroxy -(3-hydroxymethyl-2-methoxy-4-pyridyl)-
propionate (K)
tert-butyl P-ethyl-P-hydroxy-Y-(3-benzyloxyanethyl-2-methoxy-4-pyridyl)-propionate (1 g, 2;5 mmol) is hydrogenolised at atmospheric pressure and ambient temperature by using 5 % of palladium on charcoal as a catalyst (50 mg) and absolute ethanol as solvent (10 ml). Once the reaction is finished (6 hours), the catalyst is separated by filtration and the solvent is evaporated, which yields 0.7 g (90 %> of product (K) of a sufficient purity for a subsequent synthetic use.
11. g 5-ethyl-l,5-dihydro-5-hydroxy-$-methoxy-oxepino [3,4-c] pyridine -3 (4H)-one (L)
tert-butyl P-ethyl-P-hydroxy-Y-(3-hydroxymethyl-2-methoxy-4-pyridyl)-propionate (8.8 g, 28 mmol) is treated with trifluoroacetic acid (30 ml) for 3 hours at ambient temperature. The volatile components are evaporated and the residue is purified by column chromatography (Si02 CH2Cl2/MeOH; 100?0 to 98/2), which results in a clear oil, which, after treatment with toluene, yields 5;9 g of product (L) (89 %) in the form of white crystals (m.p. 97-98 °C).
ll.h 5-ethyl-l,5-dihydro-5-hydroxycoxepino [3,4-c] pyridine 3,9(4H,8H)-dione
(M)
5-ethyl-l,5-dihydro-5-hydroxy-9-methoxy oxepino [3,4-c] pyridine-3-(4H)-one (0,5 g, 2.1 mmol) in hydrochloric acid IN (20 ml) is heated to reflux for 9 hours. The reaction mixture is concentrated under reduced pressure and the residue is dried again by the addition and evaporation of toluene, two times, then left overnight under reduced pressure in the presence of phosphorous pentoxide. The resultant oil is dissolved in acetonitrile anhydride (5 ml) and agitated under argon? for 24 hours. The precipitate is filtered and dried, which yields 0.23g (49 %) of a white solid (M) (m.p. 118-119 °C).
11. i. 6,7-ethylenedioxy -2-iodo-3-quinoline-methanoI (N)
The procedures described by Meth-Cohn et al., Chem. Soc. Perkin Trans. I, p. 1520 (1981), Meth-Cohn, J. Chem. Soc. Perkin Trans. I, p. 2509 (1981), and Nakasimhan et al, J. Am. Chem. Soc. 112, p. 4431 (1990), are used. 3,4-ethylenedioxyacetanilide (22 g, 113 mmol) is added to the Vilsmeyer reagent obtained by the dropwise addition of phosphoryl oxychloride (71 ml, 0.77 mol) to dimethylformamide anhydride (23 ml, 0.28 mmol), chilled in an ice-water bath and agitated for another 0.5 hour in an argon atmosphere. The resultant mixture is heated to 75° C for 16 hours. After cooling to ambient temperature, the reaction mixture is added to a mixture of ice and water (300 ml) and extracted with dichloromethane (5 x 200 ml). The combined organic extracts are dried on sodium sulphate, filtered and concentrated. The solid residue is placed into suspension in dichloromethane (20 ml), filtered and dried under reduced pressure, which yields 10 g (35 %) of 2-chloro-6,7-ethylenedioxyquinoline-3-carbaldehyde in the form of a yellow solid (m.p. 222-224 °C). This intermediate is treated with sodium iodide (30 g, 0.2 mol) and concentrated hydrochloric acid (1.5 mlMn acetonitrile to reflux (150 ml) for 24 hours. After cooling to ambient temperature, the solvent is eliminated under reduced pressure and the residue is taken up in 50 % aqueous tefrahydrofuran (200 ml), filtered, washed with tetrahydrofuran and dried under reduced presure, which yields 12 g of 6,7-ethylenedioxy-2-iodoquinoline-3-carbaldehyde in the form of a yellow solid (m.p. 155-157 °C). This intermediate is treated with sodium boroh^dride (2 g, 52 mmol) in methanol at ambient temperature for 0.5 hour. The solvent is eliminated under reduced pressure and the residue is taken up in water and filtered. The resulting Solid is dried under reduced pressure in the presence of phosphorous pentoxide, which yields 11 g of (6,7-ethylenedioxy-2-iodoquinoline-3-yl)-methanol in the form of a yellow solid (m.p. 178-180 °C).
ll.j. 5-ethyl-8-(6,7-ethylenediox-2-iodo-3-quinolinemethyl)-l,5-dihydro-
5-hydroxy-oxepino [3,4-c] pyridine 3,9 (4H-8H)-dione (O)
Over 5 minutes, diethyl azodicarboxylate (570 µl, 3.6 mmol) is added dropwise to a solution of 5-ethyl-l,5-dihydro-5-hydroxy-oxepino [3,4-c] pyridine 3,9(4H,8H)-dione (400 mg, 1.79 mmol), of the compound (N) obtained in the preceding stage 11. (770 mg, 2.23 mmol), and of triphenylphosphine (934 mg, 3.58 mmol) in a mixture of anhydrous THF/DMSO (8/1 v/v, 45 ml). The resultant mixture is agitated under argon at ambient temperature for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in chloroform (100 ml). The resultant solution is washed with brine (4 x 50 ml), dried on sodium sulphate and evaporated. The residue is purified by column chromatography (Si02, CH2Cl2/MeOH; 99/1 to 98/2), yielding 650 mg (66%) of product (O) in the form of a white solid (m.p. 165-167 °C).
11 .k. 8-ethyl-2,3,8,9-tetrahydro-8>hydroxy-10H,12H-
[l,4]dioxino[2,3-g]oxepino[3',4':6,7]indoliMno [l,2-b]quinoline-10,13(15H)-dione
5-ethyl-8-(6,7-ethylenedioxy-2-iodoquinoline-3'yl)methyl-4,5-dihydro-5-hydroxy-(lH,3H)oxepino [3,4-c] pyridine-3-dione (600 mg, 1.1 mmol), tetrabutylammonium bromide (352 mg, 1.1 mmol), sodium acetate (369 mg, 4.4 mmol) and palladium II acetate (98 mg, 0.43 mmol) are dissolved in anhydrous acetonitrile (40 ml) and heated to 90 °C under argon for 16 hours. After cooling to ambient temperature, a white precipitate is separated from the reddish solution. This precipitate is filtered and dried under reduced pressure. The crude product is put into suspension in water, filtered and dried under reduced pressure in the presence of phosphorous pentoxide, yielding 250 mg of die sought compound in the form of a clear yellow solid (m,p. > 250° C).
RMN-lH (DMSO): 0.91 (t, 3H); 1.87 (m, 2H); 3.08 (d, 1H); 3.51 (d, 1H); 4.45 (s, 4H); 5.19 (s, 2H); 5.47 (dd, 2H); 6.02 (se, 1H|>; 7.33 (s, 1H); 7.54 (s,lH); 7.55 (s, 1H); 8.43 (s, 1H).
RMN-13C (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.
Example 12: 10-benzyloxy-5-ethy[4,5|-dihydro-5-hydroxy-lH-oxepino
[3\4':6,7] indolizino [l,2-b]quinoline-3,15#4H,13H)-dione
12.a. (6-benzyloxy-2 -iodoquinoline-3yl)-methanol
This compound is prepared in a method analogous to that outlined in stage ll.i. of example 11, but using 4-benzyloxyacetanili€e in place of 3,4-ethylenedioxyacetanilide. A purification by column chromatography on silica gel (using dichloromethane as eluant) is necessery to isolate (8% yield) to a sufficient purity the intermediary 6-benzyloxy-2-chloroquinoline-3-carbaldehyde (m.p. 180-182 °C). Next, the halogen exchange yields 6-benzyloxy-2-iodoquinoline-3-carbaldehyde (m.p. 155-157 °C) and the subsequent reduction with sodium borohydride yields |6-benzyloxy-2-iodoquinoline-3-yl)-methanol (m.p. 147-149 °C).
12.b. 8-(6-benzyloxy-2-iodo-3-quinollnemethyl)-l,5-dihydroxy-5-ethyl-5-hydroxy-oxepino [3,4-c] pyridine-3,9(4H,8H)-dione
This compound is prepared in a method analogous to that outlined in stage ll.j. of example 11, but using (6-benzyloxy-2-iodoquinoline-3-yl)-methanol in place of (6,7-ethylenedioxy-2-iodoquinoline-3-yl)-methanol. This compound appears in the form of a white solid (m.p. 197-199 °C).
12.c 10-benzyloxy-5-ethyl-4,5-dihydisp-5-hydroxy-lH-oxepino
[3',4':6,7] indolizino [l,2-b]quinoline-3,15(4H,13H)-dione
This compound is prepared in a method analagous to the one indicated in stage ll.k. of example 11, but using 8-(6-benzyloxy-2-iodo-3-quinolinemethyl)-l,5-dihydroxy-5-ethyl-5-hydroxy-oxepino [3,4-c] pyridine-3%9(4H,8H)-dione in place of 5-ethyl-8-(6,7-ethylenedioxy-2-iodoquinoline-3-yl)methyl-4,5-dihydro-5-hydroxy(lH,3H)oxepino [3,4-c] pyridine-3-dione. The sought compound appears in the form of a clear yellow solid (m.p. > 250 °C).
RMN-!H (DMSO): 0.90 (t, 3H); 1.85 (m, W) ; 3.08 (d, 1H); 3.50 (d, 1H); 5.25 (s, 2H); 5.30 (s, 2H); 5.50 (dd, 2H) ; 6.05 (s, 1H); 7.30-7.70 (m, 8H) ; 8.10 (d, 1H) ; 8.55 (s, 1H). RMN-13C (DMSO): 8.43 ; 36.48 ; 38.28 ; 50.65 ; 61.42 ; 70.00 ; 73.32 ; 99.05 ; 107.71 ; 122.05 ; 123.42 ; 128.18 ; 128.26 ; 128.70; 129.40 ; 130.19 ; 130.48 ; 130.63 ; 136.65 ; 144.18 ; 144.90; 150.53 ; 155.91 ; 157.31 ; 159.24; 172.06.
Example 13 -(12-benzyIoxy-8-hydroxymethyl-9-oxo (11H)-indolizino
[1,2-b] quinoline-7-yl)-ß-ethyl-ß-hydroxy-propionic acid (E)
This compound is prepared in a manner analagous to the one explained in example 4, but using 10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7] indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione in place of 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione. It appears in the form of a yellow solid (m.p. 171-173 °C).
RMN-!H (DMSO): 0.80 (t, 3H); 2.00 (m, 2H) ; 2.85 (d, 1H); 3.15 (d, 1H); 4.80 (s, 2H); 5.25 (s, 2H); 5.30 (s, 2H); 5.75 (se, 1H) ; 7.30 (s, 1H); 7.35-7.70 (m, 7H) ; 8.10 (d, 1H) ; 8.55 (s, 1H).
RMN-13C (DMSO): 8.11 ; 34.75 ; 46.68 ; 50.35 ; 55.70 ; 69.97 ; 76.51; 99.45 ; 107.78 ; 123.28 ; 127.64 ; 128.18 (2C); 128.26 ; 128.70 (2C); 129.33 ; 130.17 ; 130.47 ; 130.57 ; 136.69 ; 142.79 ; 144.17 ; 150.93 ; 156.03 ; 157.19 ; 161.20.
Example 14: 5-ethyl-4,5-dihydro-5,10-dihydroxy-lH-oxepino
[3',4':6,7]-indolizino [l,2-bquinoline-3,15 (4H,13H)-dione
10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7] indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione (370 mg, 0.79 mmol) is treated with hydrogen at atmospheric pressure and at ambient temperature using 10 % palladium on charcoal as catalyst (60 mg) and trifluoroacetic acid as solvent (15 ml). Once the reaction is terminated (16 hours), dichloromethane (50 ml) and methanol (50 ml) are added to the reaction mixture, the catalyst is filtered and the volatile components are evaporated under reduced pressure, which permits obtaining the crude form of the sought after compound containing traces of trifluoroacetic acid. These traces are eliminated by codistillation with 1,4 dioxane. The product obtained is in the form of an orange solid (m.p. 150° C (d)), with a purity sufficient for further synthetic use.
RMN-lH (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 3.02 (d, 1H); 3.45 (d, 1H); 5.19 (s, 2H); 5.37 (d, 1H) ; 5.50 (d, 1H) ; 5.98 (se, 1H) ; 7.26 (s 1H) ; 7.31 (s, 1H) ; 7.40 (d, 1H) ; 8.00 (d, 1H) ; 8.42 (s, 1H) ; 10.32 (s, 1H).
RMN-13C (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.
Example 15: ll-(dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-
lH-oxepino [3',4':6,7]-indolizino [l,2-b]quiiioline-3,15 (4H,13H)-dione chlorhydrate
15.a. H-(dimethyIamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-lH-oxepino [3',4':6,7]-indoIizino [l,2-b]quinoline-3,15 (4H,13H)-dione
A suspension of 10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7] indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione (260 mg, 0.69 mmol) in acetic acid (15 ml) is treated with 37 % aqueous formaldehyde (500 µ1) and 40 % aqueous dimethylamine (500 µl). The resultant mixture is agitated at ambient temperature for 16 hours. The reaction mixture is concentrated to dryness and the residue is purified by column chromatography (Si02, CH2Cl2/MeOH; 100/0 to 90/10) followed by crystallization with acetonitrile, yielding 102 mg of the sought compound.
15. b. ll-(dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-lH-oxepino [3',,4':6,7]indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione chlorhydrate
Diluted hydrochloric acid (IN) is added dropwise to a suspension of ll-(dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-lH-oxepino [3',4':6,7]-indo]izino [l,2-b]quinoline-3,15 (4H, 13H)-dione (102 mg) in water, until completely dissolved. The water is evaporated under reduced pressure and the residue is put into suspension in acetonitrile (5 ml) and filtered, yielding 103 mg of the sought salt (m.p. 248 °C (d)).
RMN-1H (DMSO): 0.88 (t, 3H); 1.85 (m, 2H) ; 2.84 (s, 6H); 3.08 (d, 1H); 3.5 (d, 1H) ; 4.73 (s, 2H) ; 5.25 (s, 2H) ; 5.47 (dd, 2H); 7.33 (s, 1H) ; 7.38 (s,lH) ; 7.72 (d, 1H); 8.19 (d, 1H); 8.99 (s, 1H); 9.92 (se, 1H); 11.45 (s, 1H).
RMN-^C (DMSO): 8.46 ; 34.36 ; 42.44 (3C); 50.61 (2C); 61.42 ; 73.35 ; 99.19 ; 108.63 ; 122.21 ; 122.36 ; 126.86 ; 129.13 ; 130.61 ; 133.09 ; 143.53 ; 144.70 ; 149.76 ; 155.98 ; 157.17 ; 159.27 ; 172.06.
Example 16: 5-ethyl-9-fluoro-4,5-dinydro-5-hydroxy-10-methoxy-lH-oxepino
[3*,4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione
This compound is obtained from 3-fluoro-4-methoxyaniline according to the method illustrated by the stages 1 Li, 1 l.j. and 1 l.k. of example 11. Yellow solid (m.p. > 250 °C).
RMNMH (DMSO): 0.89 (t, 3H) ; 1.85 (q,2H) ; 3.08 (d, 1H); 3.49 (d, 1H); 4.00 (s, 3H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d,lH); 6.00 (s, 1H); 7.32 (s, 1H); 7.72 (d, 1H); 7.91 (d, 1H); 8.58 (s, 1H).
RMN-13C (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.
Example 17: 9-chIoro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyI-lH-oxepino
[3',4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione
This compound is obtained from 3-chloro-4-methoxyaniline according to the method illustrated by the stages ll.i., ll.j. and ll.k. of example 11. Yellow solid (m.p. > 250 ° C).
RMN-1!! (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 2.55 (s, 3H); 3.07 (d, 1H); 3.45 (d, 1H);
5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 1H) ; 8.60 (s, 1H).
RMN-13C (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.
Example 18: 5-ethyl-9,10-difluoro- 4,5-dihydro-5-hydroxy-lH-oxepino
[3',,4':6,7]indolizino [l,2-b|quinoline-3,15 C4H43H)-dione
This compound is obtained from 3,4-difluoroanIine according to the method illustrated by the stages ll.i., ll.j. and ll.k. of example 11. Yellow solid (m.p. > 250 ° C).
RMN-!H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.47 (d, 1H); 5.25 (s, 2H);
5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H) ; 7.39 (s, 1H); 8.15 (q, 1H) ; 8.25 (q, 1H);
8.68 (s, 1H).
RMN-13C (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.
Example 19: 7-ethyl-7,8-dihydro-7-hydroxy-9H,llH-
[l,3]dioxolo[4,5-g] oxepino[3',4':6,7]-indolizino [l,2-b]quinolme-9,12 (14H)-dione
chlorhydrate
This compound is obtained from 3,4-methylenedioxyaniline according to the method illustrated by the stages ll.i., ll.j. and ll.k. of example 11. Beige solid (m.p. > 250 °C).
RMN-!H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 5.20 (s, 2H);
5.39 (d, 1H); 5.51 (d, 1H); 6.00 (s, 1H); 6.30 (s, 2H) ; 7.30 (s, 1H) ; 7.49 (d, 2H) ; 8.45
(s, 1H).
RMN-13C (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.
Example 20: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-lH-oxepino
[3',4':6,7]-mdolizino [l,2-b]quinoline-3,15 (4H,13H)-dione
This compound is obtained from 3-chloro-4-methoxyaniline according to the method illustrated by stages 1 l.i., 1 l.j. and 1 l.k. of example 11. White solid (m.p. > 250 °C).
RMN-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H) ; 3.07 (d, 1H); 3.45 (d, 1H); 4.01 (s, 3H);
5.22 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.02 (s, 1H); 7.31 (s, 1H); 7.68 (s, 1H); 8.20 (s,
1H); 8.55 (s, 1H).
RMN-13C (DMSO): 8.22 ; 36.27 ; 42.30 ; 50.48 ; 56.69 ; 61.23 ; 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.
Example 21: 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-lH-oxepino
[3',,4':6,7]indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione
This compound is obtained from 4-methoxyaniline according to the method illustrated by the stages 1 l.i., 1 l.j. and 1 l.k. of example 11. Yellow solid (m.p. > 250 °C)
RMN-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 3.95 (s, 3H);
5.28 (s, 2H); 5.40 (d, 1H); 5.51 (d, 1H); 6.00 (s, 1H); 7.38 (s, 1H); 7.51 (d, 2H); 8.07
(d, 1H); 8.55 (s, 1H).
RMN-13C (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.
Example 22: 9,ll-dichloro-5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino
[3',4':6,7]-indoIizino [l,2-b]quinoline-3,15 (4H,13H)-dione
This compound is obtained from 3,5-dichloroaniline according to the method illustrated by the stages 1 l.i., 1 l.j. and 1 l.k. of example 11. Yellow solid (m.p. > 250 °C).
RMN-lH (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 5.30 (s, 2H);
5.41 (d, 1H); 5.55 (d, 1H); 6.08 (s, 1H); 7.41 (s, 1H); 8.05 (s, 1H); 8.21 (s, 1H); 8.91 (s,
1H).
RMN-13C (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.
Example 23: 5-ethyl-9-fluoro-4,5-dhydro-5-hydroxy-10-methyl-lH-oxepino
[3',4* :6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione
This compound is obtained from 3-fluoro-4-methylaniline according to the method illustrated by the stages ll.i, ll.j. and ll.k. of example 11. Yellow solid (m.p. > 250 °C).
RMN-1H (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 2.49 (s, 3H); 3.08 (d, 1H); 3.49 (d, 1H);
5.21 (s, 2H); 5.39 (d, 1H); 5.51 (d,lH); 6M (s, 1H) ; 7.39 (s, 1H); 7.87 (d, 1H); 8.05 (d,
1H); 8.61 (s, 1H).
RMN-^C (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.
Example 24: 5-ethyl-10-fluoro-4,5-dinydro-5-hydroxy-lH-oxepino
[3',4':6,7]-indolizino[l,2-b]quinolme-3,15 (4H,13H)-dione
This compound is obtained from 4-fluoroaniline according to the method illustrated by the stages 1 l.i., 1 l.j. and 1 l.k. of example 11. White solid (m.p. > 250 °C).
RMN-lH (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 5.29 (s, 2H); 5.39 (d, 1H); 5.55 (d, 1H); 6.30 (s, 1H); 7.9 (s, 1H); 7.80 (q, 1H); 7.99 (q, 1H); 8.23 (q, 1H) ;8.68 (s, 1H).
RMN-13C (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.
Example 25: 10-chloro-5-ethyl-4-5-dihydro-5-hydroxy-lH-oxepino
[3\4' :6,7]-indolizino [l,2-b]quinoline-3,15H(4H,13H)-dione
This compound is obtained from 4-chloroaniline according to the method illustrated by the stages ll.i., ll.j. and ll.k. of example 11. Yellow solid (m.p. > 250 °C).
RMN-lH (DMSO): 0.85 (t, 3H); 1.85 (q, 2H) ; 3.07 (d, 1H); 3.47 (d, 1H); 5.25 (s, 2H) ;
5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H); 7.39 (s, 1H); 7.89 (d, 1H); 8.19 (d, 1H); 8.29
(s, 1H); 8.67 (s, 1H).
RMN-13C (DMSO): 8.40 ; 36.46 ; 42.47 ; 50.70 ; 61.42 ; 73.31 ; 100.00 ; 122.96 ;
127.31 ; 127.42 ; 128.87 ; 131.11 ; 132.12; 144.34 ; 146.53 ; 153.38 ; 155.88 ; 159.20;
172.04.
IR (KBr): 1069 ;1483 ; 1606 ; 1741.
Example 26: 10-chloro-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-lH-oxepino
[3',4':6,7]-indolizino[l,2-b]quinoline-3,15*(4H,13H)-dione
This compound is obtained from 4-chlo*o-3-fluoroaniline according to the method illustrated by the stages 11.1., 11 .j. and 11 .k. of example 11. Yellow solid (m.p. > 250 °C).
RMN-1H (DMSO): 0.85 (t, 3H) ; 1.85 (q, 2H) ; 3.07 (d, 1H); 3.45 (d, 1H); 5.25 (s, 2H);
5.39 (d, 1H) ; 5.51 (d, 1H); 6.05 (s, 1H) ; 7.40 (s, 1H) ; 8.20 (d, 1H) ; 8.40 (d, 1H) ; 8.68
(s, 1H).
RMN-13C (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.
Example 27: 5,12-diethyl-4,5-dihydro-5,10-dihydroxy-ll-morpholinomethyl-
lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione
This compound is obtained from morpholine according to the method illustrated by the stages ILL, ll.j. and ll.k. of example 11. White solid (m.p. > 250 °C).
RMN-lH (DMSO): 0.85 (t, 3H); 1.87 (q, 2H); 2.53 (s, 4H); 3.03 (d, 1H); 3.45 (d, 1H);
3.57 (s, 4H); 4.02 (s, 2H) ; 5.01 (s, 2H); 5.38 (d, 1H); 5;52 (d, 1H); 6.0 (se, 1H); 7.30 (s,
1H); 7.42 (d, 1H); 7.95 (d, 1H); 8.82 (s, 1H).
RMN-13C (DMSO): 8.45 ; 3.49 ; 42.58 ; 53.04 ; 61.44 ; 66.33 ; 73.33 ; 98.81 ; 113.78 ;
121.81 ; 122.74 ; 126.80 ; 129.05 ; 129.91 ; 143.72 ; 145.07 ; 149.24 ; 155.06 ; 156.92 ;
159.28 ; 172.08.
IR (KBr): 1515 ; 1595 ; 1654 ; 1736.
Example 28: 5,12-diethyI-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-lH-
oxepino [3',,4':6,7]indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione
28.a. 5-fluoro-4-methoxy-2-propionylaniline
(This product is obtained according Sugasawa T ; Toyoda T ; Adachi M ; Saskura K, J. Am Chem Soc, 100 (1978) p. 4842-4852). A solution of 3-fluoro-4-methoxy-aniline (20 g, 142 mmol) in anhydrous dichloromethane (200 ml), under an argon atmosphere and at 0° C, is added dropwise to boron trichloride (1 M in heptane, 156 ml, 156 mmol). The pink suspension thus obtained is maintained under agitation 5 min. Then propionitrile (33 ml, 420 mmol) followed by aluminium trichloride (20.9 g, 156 mmol) is added dropwise in small portions. The reaction medium is heated to reflux for 3 hours, chilled at 0° C, hydrolyzed by adding, carefully, 2N hydrochloric acid (100 ml), then brought to reflux for 45 min. After chilling to 0 °C, a precipitate is obtained which is then filtered, washed with dichloromethane, then taken up in water (300 ml). The aqueous phase is basified to an alkaline pH, extracted with dichloromethane, then with ethyl acetate. The organic phase is dried (MgSO,4) then evaporated, yielding a crude product which is purified by column chromatography (Si02, AcOEt/Hpt: 1/99 to 20/80). 15.3 g of a yellow solid is obtained.
RMN-lH (CDCI3): 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.
28.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 anhydrous acetonitrile (110 ml), under argon and at 0 °C, is added dropwise a solution of ethylmalonyl chloride (12.9 ml, 100 mmol) in anhydrous acetronitrile (30 ml). The reaction medium is left to return to ambient temperature. A solution of sodium ethylate (obtained with 1.8 g, 78 mmol, of sodium in 80 ml of ethanol) is cannulated dropwise into the reaction medium, which is then left to agitate for 12 hours at ambient temperature. The reaction mixture is poured into ice water (100 ml) and agitated for 2 hours, then the precipitate is filtered and washed with water, ethanol and ether. 19.4 g of a white solid is obtained.
RMN-lH (DMSO): 1.25 (m, 6H); 2.78 (q, 2H) ; 3.92 (s, 3H); 4.30 (q, 2H); 7.15 (d, 2H);
7.40 (d,2H);l 1.93 (s,lH).
IR (KBr): 786 ; 1083 ; 1410 ; 1521 ; 1644; 1725.
28. 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-quinolinecarboxylate (19.4 g, 0.066 mol) in phosphoryl chloride (243 ml) is brought to reflux for 6 hours. The phosphoryl chloride is distilled. The reaction mixture is poured into ice water and taken up in dichloromethane to make soluble. The organic phase is washed with water, then with a saturated solution of sodium chloride. The organic phase is dried on magnesium sulphate and the solvent is evaporated. The residue is suspended in ether and the non-converted starting product (4 g) is filtered. The filtrate is evaporated and the residue is purified by column chromatography (Si02, AcOEt/Hpt: 5/95 to 20/80). 10.9 g of a white solid is obtained.
RMN-lH (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.
28.d. 2-chloro-4-ethyi-7-fluoro-6-methoxy-3-quinolinemethanol
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 ambient temperature under inert atmosphere .with diisobutylaluminum hydride (1 M in dichloromethane, 65 ml, 65 mmol), then heated to 40 °C for 4 hours. The reaction medium is chilled to 0 °C, a 20 % aqueous solution of Rochelle salt and dichloromethane (200 ml) are added carefully and the agitation is maintained for 1 hour. The mixture is decanted, the organic phase is washed three times with water and dried on magnesium sulfate. The solvent is then evaporated. The residue is purified by column chromatography (SiC>2, AcOEt/Hpt: 5/95 to 50/50). 6 g of a white solid is obtained.
RMN-1H (DMSO): 1.28 (t, 3H); 3.25 (q, 2H); 4.04 (s, 3H); 4.77 (d, 2H); 5.27 (t, 1H);
7.55 (d, 2H); 7.73 (d, 2H).
IR (KBr): 840 ; 864 ; 1023 ; 1232 ; 1267 ; 1317 ; 1444 ; 1511 ; 1569.
28.e. 5,12-diethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione
2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinemethanol is coupled to compound (M) as described in stage ll.j. of example 11. The resultant coupling product is cyclized according to the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 275 °C).
RMN-lH (CF3COOD): 1.07 (m, 3H); 1.62 (m, 3H); 2.27 (m,2H); 3.44 (d, 1H); 3.54 (m,
2H); 3.91 (d, 1H); 4.25 (s, 3H) ; 5.60 (d, 1H) ; 5.74 (s, 2H); 5.98 (d, 1H); 7.85 (m, 1H);
8.16 (m,lH); 8.31 (s,lH).
RMN-13C (CF3COOD): 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.
Example 29 : 5-ethyl-4,5-dihydro-5-hydroxy-12-methyl-lH-oxepino
[3',4' :6,7]-indolizino [l,2-b]quinoline-3,15(4H,13H)-dione
The procedures described in stages 28.b., 28.c. and 28.d. of example 28 are applied to 2-acetylaniline, yielding 2-chloro-4-methyl-3-quinolinemethanol. The latter is coupled to compound (M) as described in stage 11. j. of example 11. The resultant coupling product is cyclized according to the procedure of stage 11. k. A yellow solid is obtained (m.p. > 260 °C).
RMN !H (DMSO): 0.87 (t, 3H); 1.87 (q, 2H); 2.78 (s, 3H); 2.80 (d, 1H); 3.55 (d, 1H);
5.27 (s, 2H); 5.42 (d, 1H) ; 5.52 (d, 1H); 6.04 (s, 1H) ; 7.39 (s, 1H); 7.75 (t, 1H); 7.88 (t,
1H); 8.13 (d, 1H); 8.25 (d,lH).
RMN-13C (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.
Example 30: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-
12-(4-methylpiperazinomethyl)-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione
30.a. 5-chloro-2-chloroacetyl-4-methoxyaniline
(This product is obtained according to Sugasawa T., Toyoda T., Adachi M., Sasakura K., J. Am.. Chem.. Soc, 100 (1978), p 4842-4852), A molar solution of boron trichloride in hexane (164 ml, 164 mmol), chloroacetonitmle (11.4 ml, 180 mmol), and a molar solution of diethylaluminum chloride in hexane (164 ml, 164 mmol) are added dropwise in succession to a solution of 3-chloro-4-methoxyaniline (23.6 g, 150 mmol) in an inert atmosphere at 0 °C. The reaction medium is heated to reflux for 1 hour then cooled to 0 °C, hydrolized by adding carefully 2N hydrochloric acid (90 ml), then maintained at reflux for 1 hour. It is chilled again and a concentrated solution of sodium bicarbonate is added to reach pH 14. The reaction mixture is extracted with ethyl acetate, the organic phase is
washed with water, then with salt water. The organic phase is dried on magnesium sulfate, filtered and evaporated under reduced pressure. The residue is taken up in isopentane, decanted, then what is insoluble is taken up in the minimum (amount) of isopropyl ether, and isopentane is added to precipitate the product. After filtration and drying under vacuum, 17.6 g of a brown solid are obtained.
RMN-1H (CDCI3): 3.82 (s, 3H); 4.60 (s, 2H) ; 6.11 (s, 2H); 6.78 (s, 1H); 7.11 (s, 1H).
30. b. Ethyl 7-chIoro~4-chloromethyl-2-hydroxy-6-methoxy-3-quinoline-carboxylate
Ethylmalonyl chloride (17 ml, 131 mmol) is added dropwise to a solution of 5-chloro-2-chloroacetyl-4-methoxyaniline (17 g, 73 mmol) and of triethylamine (18.5 ml, 131 mmol) in anhydrous acetonitrile (310 ml) under argon and at 0 °C. The reaction mixture is agitated for 2 hours at ambient temperature, then a solution of sodium ethylate in ethanol (obtained by 1.88 g, 80 mmol, of sodium in 90 ml of ethanol) is added dropwise at 0 °C . The reaction mixture is then agitated for 12 hours at ambient temperature. 300 ml of water are added, and agitation is maintained for another 20 minutes. The precipitate is filtered, washed with water, ethanol, and ethyl ether. After drying in vacuum, 16.7 g of yellowish solid are obtained.
RMN-!H (DMSO) : 1.31 (t, 3H) ; 3.95 (s, 3H) ; 4.36 (q, 2H) ; 4.95 (s, 2H) ; 7.46 (s, 1H) ; 7.49 (s,lH).
30. c. Ethyl 2,7-dichloro-4-chloromethyl-6-methoxy-3-quinoline-carboxylate
A suspension of ethyl 7-chloro-4-chloromethyl-2-hydroxy-6-methoxy-3-quinoline-carboxylate (116.7 g, 50 mmol) in phosphoryl chloride (100 ml) is brought to reflux for 6 hours. The phosphoryl chloride is distilled. The residue is taken up in water and agitated for 30 min. The precipitate is filtered and washed with water until neutralization. The precipitate is taken up in dichloromethane together with a saturated solution of sodium chloride. After filtraation on a bed of celite and decantation of the filtrate, the organic phase is washed again with a saturated solution of sodium chloride. After drying on magnesium sulfate, filtration and evaporation under reduced pressure, 15.88 g of a brown oil are obtained.
RMN-!H (CDCI3): 1.47 (t, 3H); 4.08 (t, 3H) ; 4.55 (q, 2H); 4.87 (s, 2H); 7.35 (s, 1H) ; 8.09 (s, 1H).
30. d. Ethyl 2,7-dichioro-6-methoxy-4-(4-methylpiperazinomethyI)-3-quinoline-carboxylate
A mixture of ethyl 2,7-dichloro-4-chloromethyl-6-methoxy-3-quinoline-carboxylate (6.9 g, 20 mmol) and N-methylpiperazine (9 ml, 80 mmol) is heated to 60 °C for 30 min. The reaction mass is diluted in water and extracted with ethyl acetate. The organic phase is decanted and washed with water. After drying on magnesium sulfate, filtration and evaporation under reduced pressure,, the residue is taken up in water, agitated 15 minutes, filtered, washed with water and dried in vacuum. The residue is purified by column chromatography (Si02, MeOH/CH2Cl2; 5/95 to 8/92). 6.7 g of a beige solid are obtained.
RMN-!H (CDC13): 1.45 (t, 3H); 2.28 (s, 3H); 2.35-2,70 (m, 8H); 3.86 (s, 2H); 4.04 (s, 3H); 4.48 (q, 2H); 7.77 (s, 1H) ; 8.05 (s, 1H).
30.e. 2,7-dichloro-6-methoxy-4-(4-methyIpiperazinomethyl)-3-quinoline-methanol
Ethyl 2,7-dichloro-6-methoxy-4-(4-methylpiperazinomethyl)-3-quinoline-carboxylate (6 g, 14.5 mmol) is dissolved in methylene chloride (120 ml). A molar solution of diisobutyl aluminum hydride in methylene chloride (60 ml, 60 mmol) is added slowly. The reaction mixture is agitated for one hour at ambient temperature. The reaction mixture is poured slowly into 300 ml of 20 % Rochelle salt solution. The resulting mixture is agitated for one hour, filtered on celite and decanted. The organic phase is washed with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and evaporated under reduced pressure. The solid is taken up in isopropyl ether, filtered and dried in vacuum. 4.3 g (80 %) of sought compound is obtained in the form of a yellow solid.
RMN-JH (CDCI3): 2.27 (s, 3H); 2.30-2.80 (m, 8H); 4.03 (s, 3H); 4.08 (s, 2H); 4.96 (s, 2H); 5.95 (s, 1H); 7.37 (s, 1H); 8.05 (s, 1H).
30. f. 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methyI-piperazinomethyl)-lH-oxepino [3,4,6,7,]-indalizino [l,2-b]quinoline-3,15 (4H,13H)-dione
2,7-dichloro-6-methoxy-4-(4-methylpiperazinomethyl)-3-quinoline-methanol is coupled to compound (M) as described in stages 11. j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in stage 11. k. A yellow solid is obtained (m.p. > 250 °C).
RMN-^H (DMSO): 0.87 (t, 3H); 1.84 (q, 2H); 2.53 (s, 4H); 3.08 (d, 1H); 3.47 (d, 1H);
3.58 (s, 4H); 4.06 (s, 5H); 5.30 (s, 2H); 5.42 (q, 2H); 6.03 (s, 1H); 7.31 (s, 1H); 7.91 (s,
lH);8.16(s, 1H).
RMN-13C (DMSO) : 8.42 ; 36.53 ; 50.65 ; 53.30 ; 56.67 ; 62.00 ; 66.50 ; 73.32 ; 99.31;
104.86 ; 122.32 ; 126.94 ; 127.70 ; 129.83 ; 130.44 ; 138.89 ; 144.22 ; 144.85 ; 151.05 ;
153.17; 155.92; 159.19; 172.06.
IR (KBr): 862 ; 1063 ; 1116 ; 1248 ; 1595 ; 1655 ; 1744 ; 3449.
Example 31: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-
ll-morpholinomethyl-lH-oxepmo [3,4,6,7,]indolizino[1,2-b-blquinoline-3,15 (4H,13H)-dione
The procedure described in the examples 30.a., 30. b. and 30. c. is applied to 3-chloro-4-methoxyaniline resulting in ethyl 2,7-dichloro-4-chloromethyl-6-methoxy-3-quinoline-carboxylate which is treated according to the procedure in example 30. d., using morpholine in place of N-methylpiperazine, then reduced according to the method in example 30. e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in ll.k. A beige solid is obtained (m.p. > 250 °C).
RMISMH (DMSO): 0.87 (t, 3H); 1.84 (q, 2H) ; 2.15 (s, 3H); 2.32 (s, 4H); 2.50 (s, 4H);
3.08 (d, 1H) ; 3.47 (d, 1H); 4.06 (s, 5H) ; 5.29 (s, 2H) ; 5.46 (q, 2H); 6.06 (s, 1H);
7.31 (s, 1H) ; 7.92 (s, 1H); 8.17 (s, 1H).
RMN-13C (DMSO): 8.42 ; 36.51 ; 42.57 ; 45.93 ; 50.66 ; 52.83 ; 55.05 ; 56.09 ; 56.72;
61.44 ; 73.29 ; 99.30 ; 104.89 ; 122.32 ; 126.89 ; 127.63 ; 129.85 ; 130.16 ; 138.78 ;
144.18 ; 144.81 ; 151.03 ; 153.10 ; 155.10; 159.17 ; 172.07.
IR (KBr): 1055 ; 1252 ; 1596 ; 1655 ; 1747 ; 3449.
Example 32: 5-ethyl-4,5-dihydro-5-hydroxy-12-(4-methyl piperazinomethyl)-
1H-oxepino[3',4':6,7] indolizino [1,2-*] quinoline -3,15(4H,13H)-dione
The procedure described in the examples 30.a., 30. b. and 30. c. is applied to aniline resulting in ethyl 2-chloro-4-chloromethyl-3~quinolinecarboxylate which is treated according to the procedure in example 30. d. using N-methylpiperazine, then reduced according to the method in example 30. e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 11 .k. A yellow solid is obtained (m.p. > 260 °C).
RMN-lH (DMSO): 0.86 (t, 3H); 1.87 (q, 2H)*2.14 (s, 3H); 2.32-2,60 (m, 8H); 3.05 (d, 1H); 3.48 (d, 1H); 4.09 (q, 2H); 5.42 (d, 1H); 5;52 (d, 1H); 6.03 (se, 1H); 7.40 (s, 1H); 7.72 (t, 1H); 7.85 (t, 1H); 8.16 (d, 1H); 8.45 (d, 1H). IR(KBr): 1652 ; 1735 ; 3424.
Example 33: 5-ethyl-4,5-dihydro-5-hydroxy-12-piperidinomethyl-1H-oxepino
[3,,4':6,73indolizino[l,2-^]quinoline-3,15(4Jfir,13H)-dione
The procedure described in the examples 30.a., 30. b. and 30. c. is applied to aniline resulting in ethyl 2-chloro-4-chlorometh^l-3-quinolinecarboxylate which is treated according to the procedure in example 30. d., using piperidine in place of N-methylpiperazine, then reduced according to the method in example 30. e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A yellow solid is obtained (m.p. > 260 °C).
RMN-1H (DMSO): 0.86 (t, 3H); 1.40 (se, 2H); 1.48 (se, 4H) ; 1.87 (q, 2H); 2.50 (s,
4H); 3.05 (d, 1H); 3.48 (d, 1H); 4.04 (q, 2H); 5.33 (s, 2H); 5.42 (d, 1H); 5.51 (d, 1H);
6.07 (se, 1H); 7.75 (t, 1H); 7.85 (t, 1H); 8.15 (d, 1H); 8.45 (d, 1H).
RMN-13C (DMSO): 8.47 ; 23.50 ; 25.82 ; 36.50 ; 42.50 ; 50.68 ; 54.47 ; 58.00 ; 61.42;
73.35 ; 99.55 ; 122.61 ; 125.31 ; 127.58 ; 129.54 ; 129.55 ; 129.56 ; 129.57 ; 140.49 ;
144.95 ; 148.63 ; 152.41 ; 155.90 ; 159.23 ; 172.07.
IR (KBr): 1659 ; 1727 ; 3408.
Example 34: 5-ethyl-4,S-dihydro-S-hy:droxy-12-morpholinomethyl-lH-
oxepino[3,,4,:6,7]indolizino[l,2-6]quinoline-3,15(4H,13H)-dione
The procedure described in the examples 30.a., 30. b. and 30. c. is applied to aniline resulting in ethyl 2-chloro-4-chloromethyl-3~quinolinecarboxylate which is treated according to the procedure in example 30. d., using morpholine in place of N-methylpiperazine, then reduced according to the method in example 30. e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A. yellow solid is obtained (m.p. > 260 °C).
RMN-!H (DMSO): 0.86 (t, 3H); 1.87 (q, 2H); 3.05 (d, 1H); 3.30 (s, 4H); 3.49 (d, 1H); 3.55 (se, 4H); 4.10 (q, 2H); 5.35 (s, 2H) ; 5.40 (d, 1H); 5.54 (d, 1H); 6.04 (s, 1H); 7.72 (t, 1H); 7.85 (t, 1H); 8.16 (d, 1H); 8.47 (d, 1H).
RMN-13C (DMSO) : 8.42 ; 36.51 ; 42.57 ; 50.68 ; 53.51 ; 56.06 ; 61.42 ; 66.41 ; 73.34 ; 99.56 ; 122.64 ; 125.25 ; 127.56 ; 129.81 ; 139.55 ; 144.92 ; 148.62 ; 152.39 ; 155.89 ; 159.21 ; 172.05.
IR (KBr): 1657 ; 1729 ; 3347.
Example 35: 5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-
12-(4-methylpiperazinomethyl)-1H-oxepino[3',4' :6,7]indolizino [1,2-b] quinoline-3,15(4H,13H)-dione
The procedure described in the examples 30a., 30.b. and 30.c. is applied to 4-fluoroaniline resulting in ethyl 2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treated according to the procedure in example 30.d. using N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in ll.k. A yellow solid is obtained (m.p. > 275 °C).
RMN-1H (DMSO) : 0.87 (t, 3H); 1.85 (q, 2H) ; 2.15 (s, 3H); 2.31 (m, 4H) ; 2.50 (m,
4H); 3.07 (d, 1H); 3.48 (d, 1H); 4.04 (m, 2H) ; 5.31 (s, 2H); 5.40 (d, 1H); 5.53 (d, 1H) ;
6.05 (s, 1H); 7.38 (s, 1H); 7.77 (m, 1H); 8.19 (m, 2H).
RMN-13C (DMSO): 8.43 ; 36.51 ; 42.54 ; 45.89 ; 50.67 ; 52.92 ; 54.93 ; 55.92 ; 73.32 ;
99.56; 122.69; 130.43; 132.40; 139.69; 144.70; 145.84; 152.19; 155.90; 159.17;
172.05.
IR (KBr): 836 ; 1051 ; 1217 ; 1291 ; 1612 ; 1662 ; 1726.
Example 36: 5-ethyl-10-fluoro-4,5ldihydro-5-hydroxy-12-morpholinomethyl-
lH-oxepino[3,,4,:6,7]indoIizino[l,2-b]quinoline-3,15(4H,13H)-dione
The procedure described in the examples 30.a., 30.b. and 30.c. is applied to 4-fluoroaniline resulting in ethyl 2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treated according to the procedure in example 30.d., using morpholine in place of N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A beige solid is Obtained (m.p. > 250 °C).
RMN-!H (DMSO) : 0.87 (m, 3H); 1.85 (m, 2H); 2.51 (m,4H) ; 3.06 (d, 1H) ; 3.48 (d,
1H); 3.56 (m, 4H); 4.05 (m, 2H); 5.34 (s, 2H) ; 5.40 (d, 1H); 5.53 (d, 1H); 6.04 (s, 1H);
7.38 (s, 1H) ; 7.77 (m, 1H); 8.21 (m, 2H).
RMN-13C (DMSO) : 8.40 ; 36.47 ; 42.52 ; 50.59 ; 53.40 ; 56.14 ; 61.44 ; 66.41 ; 73.29 ;
99.58 ; 109.05 ; 109.28 ; 120.11 ; 120.37 ; 122.68 ; 128.53 ; 130.53 ; 132.43 ; 139.13 ;
144.62 ; 145.79 ; 152.07 ; 155.94 ; 159.14 ; 161.59 ; 172.04.
IR (KBr): 834 ; 860 ; 1061 ; 1118 ; 1215 ; 1286 ; 1516 ; 1609 ; 1658 ; 1734.
Example 37: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-
12-(4-methylpiperazinomethyl)-1H-oxepino[3',4':6,7]indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
The procedure described in the examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline, resulting in ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to the procedure in example 30.d. using N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A yellow solid is obtained (m.p. > 260 °C).
RMN-1H (CDC13): 1.00 (t, 3H); 2.00 (q, 2H); 2.35 (s, 3H); 2.50 (s, 3H); 2.61 (m, 8H); 3.33 (d, 1H); 3.39 (d, 1H); 3.97 (d, 1H) ; 4.07 (d, 1H); 5.17 (d, 1H); 5.38 (d, 1H); 5.52 (d, 1H); 5.63 (d, 1H); 7.13 (d, 1H); 7.28 (s, 1H); 7.99 (d, 1H). IR (KBr): 1652 ; 1747 ; 3430.
Example 38: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-
12-morpholinomethyl-lH-oxepino[3,4':6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-
dione
The procedure described in the examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline, resulting in ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to the procedure in example 30.d., using morpholine in place of N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A yellow solid is obtained (m.p. > 260 °C).
RMN-lH (DMSO + CDC13): 1.00 (t, 3H) ; 2.02 (q, 2H); 2.57 (s, 3H); 2.60 (s, 4H);
3.23 (d, 1H) ; 3.45 (d, 1H); 3.75 (s, 4H) ; 4.11 (s, 2H); 5.44 (s, 2H); 5.47 (d, 1H);
5.65 (d, 1H) ; 7.62 (s, 1H) ; 7.73 (d, 1H); 8.24 (d, 1H).
RMN-13C (CF3CO2D): 8.35 ; 13.93 ; 16.01 ; 22,24 ; 25.29 ; 38.18 ; 43.42 ; 54.19 ; 56.04 ;
56.74 ; 64.16 ; 65.09 ; 77.48 ; 108.29 ; 108.57 ; 128.07 ; 128.70 ; 129.90 ; 135.64 ; 138.03 ;
139.86 ; 141.10 ; 141.56 ; 147.78 ; 158.30 ; 161.87 ; 178.72.
IR (KBr): 117 ; 1609 ; 1654 ; 1750 ; 3437.
Example 39: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-
12-piperidinomethyl-lH-oxepino [3',4':6,7] indolizino [1,2-b] quinoline-3,15(4H,13H)-dione
The procedure described in the examples 30.a,, 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline, resulting in ethyl 2-ehloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to the procedure in example 30.d., using piperidine in place of N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A yellow solid is obtained (m.p. > 260 °C).
RMN-1H (CF3CO2D): 1.09 (s, 3H); 1.70 (t, 1H); 2.03 (m, 5H); 2.25 (s, 2H); 2.70 (s,
3H); 3.54 (d, 3H); 3.88 (d, 1H); 4.01 (se, 2H); 5.30 (q, 2H); 5.65 (d, 1H); 5.96 (d, 1H);
6.10 (s, 2H); 8.16 (d, 1H); 8.35 (s, 1H); 8.61 (s, 1H).
RMN-13C (CF3CO2D): 8.47 ; 16.07 ; 20.93 ; 22.18 ; 24.76 ; 38.28 ; 43.53 ; 54.30 ; 56.12 ;
58.33; 64.24; 77.56; 108.37; 111.30; 128.20; 129.02; 129.98; 135.60; 138.29;
139.90 ; 141.60 ; 142.26 ; 147.57 ; 158.28 ; 161.90; 167.63 ; 170.31; 178.82.
IR (KBr): 1605 ; 1657 ; 1728 ; 3399.
Example 40: 8-ethyl-2,3,8,9-tetrahydro-8-hydroxy-
16-(4-methylpiperazinomethyl)-10H,12H-[l,4] dioxino [2,3-g] oxepino [3'4':6,7]indolizino [1,2-b] quinoline-10,13[15H]-dione
The procedure described in the examples 30.a., 30.b. and 30.c. is applied to 3,4-ethylenedioxyaniline, resulting in ethyl 2~chloro-4-chloromethyl-6,7-ethylenedioxy-3-quinolinecarboxylate which is treated according to the procedure in example 30.d. using N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A yellow solid is obtained (m.p. > 260 °C).
RMN-1H (DMSO) : 0.92 (t, 3H) ; 1.89 (q, 2H); 2.16 (s, 3H) ; 2,.0 (m, 8H) ; 3.12 (d, 1H) ;
3.50 (d, 1H) ; 3.95 (s, 2H); 4.47 (s, 4H); 5.19 (q, 2H); 5.43 (d, 1H); 5. 56 (d, 1H);
7.35 (s, 1H) ; 7.54 (s, 1H); 7.76 (s, 1H).
RMN-13C (DMSO): 8.45 ; 24.80 ; 36.51; 42.48 ; 45.90 ; 50.45 ; 52.98 ; 54.91 ; 56.10 ;
61.44 ; 64.43 ; 73.30 ; 99.03 ; 109.46 ; 113.51 ; 121.95 ; 123.51 ; 127.76 ; 137.99 ; 145.00;
145.14 ; 145.27 ; 147.24 ; 150.53 ; 155.99 ; 159.18 ; 172.27 ; 177.00.
IR (KBr): 1656 ; 1743 ; 3422.
Example 41: 9-chloro-5-ethyH0-fluoro-4,5-dihydro-5-hydroxy-
12-morpholinomethyl-lH-oxepino[3,4,:6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-
dione
The procedure described in the examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-fluoroaniline, resulting in ethyl 2,7-dichloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treated according to the procedure in example 30.d., using morpholine in place of N-methylpiperazine, then reduced according to the method in example 30.e. in the corresponding quinolinemethanol. The latter is coupled to compound (M) as described in step ll.j. of example 11. The resultant coupling product is cyclized according to the procedure outlined in 1 l.k. A beige solid is obtained (m.p. > 250 °C).
RMN-*H (CF3COOD): 1.09 (t, 3H); 2.30 (m, 2H); 3.50 (d, 1H); 3.90 (d, 1H); 3.98 (d,
4H); 4.36 (s, 4H); 5.38 (q, 2H); 5.64 (d, 1H); 5.96 (d, 1H); 6.23 (q, 2H); 8.57 (d, 1H);
8.60 (s, 1H); 8.85 (d, 1H).
RMN-13C (CF3COOD): 8.10 ; 37.80 ; 43.11 ; 54.31 ; 55.78 ; 63.75 ; 65.11 ; 77.06 ;
128.28 ; 129.55 ; 130.33 ; 136.26 ; 137.11; 138.40 ; 139.67 ; 139.85 ; 148.58 ; 157.54;
159.74; 161.31; 178.00.
IR (KBr): 848 ; 1042 ; 1230 ; 1609 ; 1658 ; 1750; 3310 ; 3387.
Example 42 : resolution of 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino
[3',4':6,7]-indolizino [1,2-b] quinoline-3,15 (4H,13H)-dione
A mixture of P-ethyl-P-hydroxy-(8-hydroxymethylindolizino[l,2-b]quinoline-9-(llH)-one-7-yl)-propionic acid (19.5 g, 52mmol) and L-(-)-α-methylbenzylamine (12.12 g, 100 mmol) in absolute ethanol (11) is carried to boiling, hot filtered and allowed to rest 68 hours. The precipitate is filtered and washed with ethanol and ether, yielding 9.8 g of a white solid. An analysis by high pressure affinity chromatography on the chiral phase ("HPLC chiral" on a Chiral-AGP column (Chromtech, Stockholm, Sweden) 100 x 4mm, 2 % acetonitrile eluant in a 10 mM at pH 6.9 phosphate buffer, eluant peaks at 4.5 and 7.5 min) reveals two peaks integrating respectively for 24 % and 76 % of the total surface of the two peaks. The solid is taken up in 93 % ethanol (350 ml) at reflux, then allowed to rest 48 hours. The precipitate is filtered, then washed with ethanol and ether to obtain 4.8 g of a white solid, giving two integrating peaks respectively for 9 % and 91 % of the total surface of the two peaks by chiral HPLC. The solid is taken up in 50 % ethanol (48 ml) at reflux then allow to rest for 48 hours. The precipitate is filtered, then washed with ethanol and ether resulting in 2.7 g of a white solid giving two integrating peaks respectively for 1 % and 99 % of the total surface of the two peaks by chiral HPLC. The resultant salt, diastereoisomerically enriched, is taken up in distilled water (20 ml) and treated with acetic acid (0.35 ml, 6.4 mmol) for 15 min. The obtained precipitate is filtered, washed with
water, acetone and ether then dried in a vacuum at 80 °C resulting in 1.1 g of a white solid. The latter is taken up in absolute ethanol (55 ml) with concentrated hydrochloric acid added (11.5 N, 11 ml) resulting in a yellow solution which is agitated at ambient temperature for 68 h. The precipitate thus obtained is filtered and washed with water, ethanol and ether, then dried in vacuum at 80 °C resulting in 770 mg of enantiomerically enriched 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3',4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione. An analysis by chiral HPLC (Chiral-AGP column, eluted by a 2 to 5 % gradient of acetonitrile in a l0mM ar pH 6.9 phosphate buffer, eluant peaks at 15 and 20 min) reveals an enantiomeric excess of 98 %. The procedure described above can be repeated replacing the L-(-)-α-methylbenzylamine by D-(+)-α-methylbenzylamine. The other enantiomer of 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3\4':6,7]-indolizino [l,2-b]quinoline-3,15 (4H,13H)-dione is thus obtained.
Example 43: 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(l,2,5,6-
tetrahydropiridinomethyl-1H-oxepinot[3,4,6,7,]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione hydrochloride
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3,4-difluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d„ using 1,2,5,6-tetrahydropyridine instead of N-methylpiperazine, and then reduced irj the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage ll.k. The free base thus obtained is suspended in absolute ethanol (50 ml/mmol) and treated with hydrogen chloride in ethanol (2.5 N; 5 eq.). At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The light orange solid obtained is washed with ether (m.p. 264 °C).
RMISMH (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 2.26-2.30 (m, 1H) ; 2.50 (m, 1H); 3.09 (d, 1H); 3.40 (m, 2H); 3.48 (d, 1H); 3.87 (m, 2H); 5.05 (m, 2H); 5.48 (q, 2H); 5.65 (m, 2H); 5.89 (m, 1H); 7.42 (s, 1H); 8.24-8.30 (m, 1H); 8.76-8.82 (m, 1H); 10.86 (s, 1H). RMN-13C (DMSO): 8.44 ; 22.36 ; 36.5 ; 42.7 ; 48.71 ; 50.30 ; 51.49 ; 61.42 ; 73.23 ; 100.16 ; 112.64 ; 112.83 ; 116.05 ; 120.26 ; 123.31 ; 125.29 ; 125.40 ; 131.17 ; 133.97 ; 144.15 ; 146.26 ; 146.37 ; 148.74 ; 150.52 ; 151.23 ; 153.20 ; 153.53 ; 155.99 ; 159.04 ; 172.02. IR (KBr): 662 ; 1064 ; 1268 ; 1452 ; 1523 ; 1598 ; 1652 ; 1743 ; 2936 ; 3027 ; 3418.
Example 44: 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methyl
piperidinomethyl)-lH-oxepino[3,,4':6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-
dione
The procedure described in examples 30.a., 30.b, and 30.c. is applied to 3,4-difluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using 4-methylpiperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A beige solid is obtained (m.p. > 250 °C).
RMN-lH (DMSO): 0.9 (m, 6H); 1.1 (m, 2H); 1.4 (m, 1H); 1.55 (d, 2H); 1.85 (q, 2H); 2.1 (t, 2H); 2.85 (m, 2H) ; 3.25 (dd, 2H) ; 4 (s, 2H) ; 5.3 (s, 2H) ; 5.45 (dd, 2H) ; 6.05 (s, 1H); 7.35 (s, 1H); 8.15 (dd, 1H); 8.45 (dd, 1H), IR (KBr): 1454 ; 1518 ; 1608 ; 1658 ; 1733 ; 2804 ; 2926 ; 3311.
Suspending in absolute ethanol (50 ml/mmol) the free base obtained as described above and subsequent treating with hydrogen chloride in ethanol (2,5 N; 5 eq.) yields the corresponding hydrochloride. At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The strong yellow solid obtained is washed with ether (m.p. > 250 °C).
RMN-1H (DMSO): 0.85 (m, 6H); 1.7 (m, 5H); 1.85 (q, 2H); 3.15 (s, 1H); 3.25 (dd, 2H) ; 3.3 (m, 2H) ; 4.9 (s, 2H) ; 5.45 (dd, 2H) ; 5.6 (s, 2H) ; 6.1 (s, 1H) ; 7.4 (s, 1H) ; 8.25 (dd, 1H); 8.75 (dd, 1H); 10.35 (s, 1H). IR (KBr): 1270 ; 1455 ; 1523 ; 1606 ; 1653 ; 1742 ; 2943 ; 3419.
Example 45: 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-
12-pyrrolidinomethyl-1H-oxepino[3,,4':6,7]indolizino[l,2-6]quinoline-3,15(4H,13H)-
dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3,4-difluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using pyrrolidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A beige solid is obtained (m.p. > 250 °C).
RMN-lH (DMSO): 0.85 (1, 3H); 1.7 (s, 4H); 1.85 (q, 2H); 2.55 (s, 4H); 3.25 (dd, 2H); 4.15 (d, 2H); 5.35 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.35 (s, 1H); 8.15 (dd, 1H) ; 8.45 (dd, 1H). IR (KBr): 1455 ; 1518 ; 1605 ; 1657 ; 1731 ; 2801 ; 2970 ; 3422.
Suspending in absolute etbanol (50 ml/mmol) the free base obtained as described above and subsequent treating with hydrogen chloride in ethanol (2.5 N; 5 eq.) yields the corresponding hydrochloride. At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The light orange solid obtained is washed with ether (m.p. > 250 °C).
RMN-lH (DMSO): 0.85 (t, 3H); 1.9 (m, 4H); 2.1 (s, 2H); 3.25 (dd, 2H); 3.3 (m, 2H);
3.55 (m, 2H) ; 5.05 (s, 2H); 5.45 (dd, 2H); 5.6 (s, 2H); 6.1 (s, 1H); 7.4 (s, 1H); 8.3 (dd,
1H); 8.75 (dd, 1H); 10.75 (s, 1H).
IR (KBr): 1454 ; 1522 ; 1603 ; 1653 ; 1743 ; 2970 ; 3394.
Example 46: 5-ethyl-9,10-difluoro«4,5»dihydro-5-hydroxy-12-(4-methyl
piperazmomethyl-liy-oxepino[3,,4,:6,7]indoli2ino[l,2-ft]quinolme-3,15(41?,13iar)-
dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3,4-difluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d. and reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C).
RMN-!H (CDC13 + CD3OD): 0.99 (t, 3H) ; 2.00 (q, 2H); 2.32 (s, 3H); 3.24 (d, 1H) ; 3.37 (s, 1H); 3.42 (d, 1H); 4.04 (s, 2H); 5.37 (s, 2H); 5.43 (d, 1H); 5.64 (d, 1H);
7.56 (s, 1H); 7.84 (dd, 1H); 8.22 (dd, 1H).
RMN-13C (CDCI3 + CD3OD): 7.87 ; 36.11; 42.16 ; 45.33 ; 52.67 ; 54.52 ; 56.47 ; 61.97; 73.26 ; 101.17 ; 110.81 ; 115.49 ; 122.93 ; 128.63 ; 139.83 ; 144.28 ; 146.40 ; 149.27 ; 151.27 ; 151.64 ; 152.31 ; 153.82 ; 156.50; 159.71 ; 172.56. IR (KBr): 1607 ; 1656 ; 1732 ; 2795 ; 3411.
Example 47: 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-
12-piperidmomethyl-lH-oxepino[3',4':6,7Iindolizino[l,2-b]qumoline-3,15(4H,13H)-
dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3,4-difluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which is
treated according to procedure of example 30.d., using piperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light green solid is obtained (m.p. 266-268 °C).
RMN-!H (DMSO): 0.86 (t, 3H); 1.42-1.49 (m, 6H); 1.85 (q, 2H); 2.47 (m, 4H); 3.06 (d,
1H); 3.48 (d, 1H); 4.00 (q, 2H); 5.31 (s, 2H); 5.46 (dd, 2H); 6.04 (s, 1H); 7.37 (s, 1H);
8.14 (m, 1H); 8.46 (m, 1H).
RMN-13C (DMSO): 8.43 ; 24.01 ; 25.8 ; 36.52 ; 42.56 ; 50.60 ; 54.29 ; 56.91 ; 61.41 ;
73.30; 99.81 ; 111.86; 115.67; 122.94; 130,10; 140.66; 144.49; 146.12; 153.18;
155.86 ; 159.14 ; 172.03.
IR (KBr): 1258 ; 1452 ; 1517 ; 1607 ; 1661 ; 1731 ; 2950 ; 3480.
Example 48: 5-ethyl-9,10-difluoro-4,S-dihydro-5-hydroxy-12-dimethyIamino-
methyl-1H-oxepino[3,4,6,7,]indolizino[1,2-b]quinoline-3,15(4H,13H)dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3,4-difluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6,7-difluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using dimethylamine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light beige solid is obtained (m.p. > 270 °C).
RMN-lH (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.25 (s, 6H); 3.08 (d, 1H); 3.47 (d, 1H);
3.95 (q, 2H); 5.28 (s, 2H); 5.46 (dd, 2H); 6.06 (s, 1H); 7.37 (s, 1H); 8.14 (s, 1H);
8.42 (s, 1H).
RMN-13C (DMSO): 8.42 ; 14.06 ; 33.36 ; 45.44 ; 50.57 ; 61.40 ; 65.14 ; 72.05 ; 72.93 ;
73.30 ; 99.82 ; 99.95 ; 115.78 ; 115.85 ; 122.96 ; 125.01 ; 130.08 ; 140.56 ; 144.54 ;
146.16 ; 155.86 ; 159.19 ; 172.03.
IR (KBr): 1516 ; 1613 ; 1654 ; 1731; 3450.
Example 49: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-
12-morpholino methyl- lH-oxepino[3',4':6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-methylaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using morpholine instead of N-methylpiperazine, and then reduced in the corresponding
quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. oiexample 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 300 °C).
RMN-lH (DMSO): 0.87 (t, 3H); 1.84 (q, 2H); 2.50 (s, 4H); 2.58 (s, 3H); 3.07 (d, 1H); 3.46 (d, 1H); 3.57 (s, 4H); 4.08 (dd, 2H); 5.30 (s, 2H); 5.51 (dd, 2H); 6.06 (s, 1H); 7.35 (s, 1H); 8.15 (s, 1H); 8.41 (s, 1H).
RMN-13C (DMSO): 8.42 ; 20.57 ; 36.51; 42.55; 50.76 ; 53.46 ; 55.86 ; 61.42 ; 66.42 ; 73.29 ; 99.73 ; 122.78 ; 128.40 ; 130.10; 135.31 ; 136.26 ; 139.36 ; 144.61 ; 147.79 ; 152.81 ; 155.86; 159.16; 172.04. IR (KBr) : 1613 ; 1657 ; 1736 ; 3432.
Example 50: 9-chloro-5-ethyl-4,5-Hihydro-5-hydroxy-10-methyl-
12-(4-methylpiperazinomethyl)lJ^-oxepino[3',4,:6,7]indoIizino [l,2-6]quinoline-3,15(4H,13H)-dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-methylaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d. and reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage ll.k. A yellow solid is obtained (m.p. 262-268 °C).
RMN-1!! (DMSO): 0.87 (t, 3H); 1.86 (q, 2H); 2.15 (s, 3H); 2.20-260 (m, 8H); 2.60 (s,
3H); 3.05 (d, 1H); 3.49 (d, 1H); 4.09 (dd, 2H) ; 5.32 (s, 2H); 5.50 (dd, 2H); 6.05 (s,
1H); 7.37 (s, 1H); 8.21 (s, LH); 8.43 (s, 1H).
RMN-13C (DMSO): 8.42 ; 20.56 ; 36.50; 42.55 ; 45.91 ; 50.81 ; 53.00 ; 54.94 ; 55.65 ;
61.43 ; 73.29 ; 79.36 ; 99.69 ; 122.75 ; 126.32 ; 128.37 ; 129.84 ; 135.25 ; 136.23 ; 139.87 ;
144.57 ; 147.75 ; 152.76 ; 155.87 ; 159.15 ; 172.04.
IR (KBr): 1607 ; 1658 ; 1733 ; 3424.
Example 51: 12-benzylmethylaminomethyl-9-chloro-5-ethyl-4,5-dihydro-
5-hydroxy-10-methyl-lH-oxepmo[3,,4*:6,7imdolizino[l,2-b]quinoline-3,15(4H,13H)-
dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-methylaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using N-methylbenzylamine instead of N-methylpiperazine, and then reduced in the
corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. 275-278 °C).
RMN-1H (DMSO): 0.88 (t,3H); 1.85 (m, 2H); 2.13 (s, 3H); 2.55 (s, 3H); 3.10 (d, 1H); 3.50 (d, 1H); 3.67 (s, 2H); 4.05 (dd, 2H); 5.30 (s, 2H); 5.39-5.57 (dd, 2H); 6.05 (s, 1H); 7.36 (m, 6H); 8.15 (s, 1H) ; 8.31 (s, 1H).
RMN-13C (DMSO): 9.10 ; 21.15 ; 37.20 ; 42.86 ; 43.23 ; 51.32 ; 55.78 ; 62.10 ; 62.88 ; 73.99; 80.05; 100.44; 123.47; 126.99; 127.32; 128.09; 129.17; 129.96; 130.86; 135.75 ; 136.84 ; 139.51 ; 140.67 ; 145.38 ; 148.54 ; 153.50 ; 156.54 ; 159.85 ; 172.73. IR (KBr): 1609 ; 1655 ; 1729 ; 3395.
Example 52: 12-(4-benzylpiperazinomethyl)-9-chloro-5-ethyl-4,5-dihydro-
5-hydroxy-10-methyl-lH-oxepino[3,,4,:6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-
dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-methylaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using N-benzylpiperazine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A beige solid is obtained (m.p. 244=249 °C:
RMN-lH (DMSO): 0.86 (t, 3H); 1.83 (m, 2H); 2.38-2.60 (m, 8H); 2.57 (s, 3H); 3.08 (d. 1H); 3.46 (s ,2H); 4.08 (m, 2H); 5.30 (s, 2H); 5.51 (dd, 2H); 6.05 (s, 1H); 7.30 (m, 6H); 8.16 (s, 1H); 8.40 (s,lH).
RMN-13C (DMSO): 9.10 ; 21.23 ; 37.19 ; 43.21 ; 51.48 ; 53.54 ; 53.80 ; 56.35 ; 62.09 ; 62.84 ; 73.97 ; 97.67 ; 100.39 ; 123.45 ; 127.05 ; 127.75 ; 129.02 ; 129.63 ; 130.61 ; 135.95 ; 136.93 ; 139.14 ; 140.52 ; 145.27 ; 148.45 ; 153.47 ; 156.52 ; 159.83 ; 172.72. IR (KBr): 1567 ; 1587 ; 1652 ; 1748 ; 3422.
Example 53 : 9-chloro-5~ethyl-4,5-dihydro-5-hydroxy-10-methyl-
12-piperidinomethyl-1H-oxepino[3',4,:6,7]Indolizino[l,2-B]quinoline-3,15(4H,13H)-
dione
The procedure described in examples 30,a., 30.b. and 30.c. is applied to 3-chloro-4-methylaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using piperidine instead of N-methylpiperazine, and then reduced in the corresponding
quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. 255 °C).
RMN-lH (DMSO): 0.86 (t, 3H); 1.50 (m, 6H); 1.84 (m, 2H); 2.50 (m, 4H); 2.58 (s,
3H); 3.05 (d, 1H); 3.45 (d, 1H); 4.04 (m, 2H); 5.32 (s, 2H); 5.51 (dd, 2H); 6.10 (s,
1H); 7.37 (s, 1H); 8.20 (s, 1H); 8.42 (s, 1H).
RMN-^C (DMSO): 9.11 ; 21.24 ; 24.70; 26.50; 37.20; 43.23 ; 51.43 ; 55.10 ; 57.21 ;
62.09; 73.99; 98.05; 100.38; 123.44; 127.10; 129.12; 130.59; 135.89; 136.91;
140.99 ; 145.31 ; 148.50 ; 153.52 ; 156.51; 159.85 ; 172.73.
IR (KBr): 1601 ; 1654 ; 1728 ; 3436.
Example 54: 12-(4-benzylpiperazlnomethyl)-5-ethyl-9-fluoro-4,5-dihydro-
5-hydroxy-lH-oxepino[3',4,:6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 4-fluoroaniline to produce ethyl 2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using N-benzylpiperazine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A white solid is obtained (m.p. 262 °C).
RMN-JH (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 2.37 (s, 4H); 2,.7 (s, 4H); 3.07 (d, 1H); 3.5 (s, 2H) ; 3.47 (d, 1H) ; 4.08 (q, 2H); 5.32 (s, 2H); 5.46 (dd, 2H); 6.03 (s, 1H); 7.35 (m, 5H); 7.38 (s, 1H); 7.77 (m, 1H); 8.20 (m, 2H).
RMN-13C (DMSO): 8.41 ; 36.49 ; 42.53 ; 50.65 ; 52.82 ; 53.03 ; 55.95 ; 61.41 ; 62.14; 72.3 ; 99.55 ; 109.31 ; 120.14 ; 120.40 ; 122.70 ; 127.05 ; 128.32 ; 128.55 ; 128.96 ; 130.40 ; 138.42 ; 139.65 ; 144.66 ; 145.83 ; 152.15 ; 155.89 ; 159.15 ; 161.57 ; 172.02. IR (KBr): 740 ; 834 ; 1071 ; 1193 ; 1220 ; 1288 ; 1360 ; 1451 ; 1516 ; 1592 ; 1655 ; 1749 ; 2813 ; 2950 ; 3434.
Example 55 : 12-(4-benzyIpiperazinomethyl)-5-ethyl-9-£luoro-4,5-dihydro-
5-hydroxy-10-methyl-lH-oxepino[3,,4,:6,7]idolizino[l,2-b]quinoline-3,15(4H,13H)-dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using N-benzylpiperazine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with
compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light beige solid is obtained (m.p. 259 °C).
RMNMH (DMSO): 0.86 (t, 3H) ; 1.85 (q, 2H); 2.38 (m, 4H); 2.50 (s, 4H); 3.06 (d, 1H) ; 3.36 (s, 3H); 3.46 (s, 2H) ; 3.47 (d, 1H) ; 4.07 (q, 2H); 5.29 (s, 2H); 5.46 (dd, 2H) ; 6.02 (s, 1H); 7.23-7,35 (m, 6H); 7.8 (d, 1H); 8.35 (d, 1H).
RMN-13C (DMSO): 8.40 ; 15.45 ; 36.47 ; 42.54 ; 50.7 ; 52.84 ; 53.13 ; 55.81 ; 61.4; 62.14 ; 73.29 ; 99.57 ; 112.45 ; 122.61 ; 124.73 ; 127.05 ; 128.32 ; 128.96 ; 138.45 ;
139.81 ; 1444.68 ; 152.63 ; 155.85 ; 159.15 ; 172.02.
IR (KBr): 1013 ; 1069 ; 1169 ; 1241 ; 1266; 1475 ; 1577 ; 1594 ; 1655 ; 1744.
Example 56: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-
ll-dimethylaminomethyl-1H-oxepino[3,4,6,7,]lindolizino[1,2,b] quinoline-3,15(4H,13H)-dione
The procedure described in examples 30,a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using dimethylamine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 11 .j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light beige solid is obtained (m.p. 184-190 °C).
RMN-1H (DMSO) : 0.86 (t, 3H) ; 1.85 (q, 2H) ; 2.26 (s, 6H) ; 2.5 (s, 3H) ; 3.05 (d, 1H); 3.48 (d, 1H) ; 3.98 (q, 2H); 5.28 (s, 2H); 5.46 (dd, 2H); 6.06 (s, 1H); 7.37 (s, 1H); 7.84 (d, 1H) ; 8.35 (d, 1H).
RMN-13C (DMSO): 8.45 ; 15.50 ; 36.52 ; 45.59 ; 50.62 ; 57.36 ; 61.43 ; 73.33 ; 99.66 ; 112.29 ; 112.50 ; 122.67 ; 124.71 ; 126.99 ; 127.20 ; 127.44 ; 129.08 ; 140.16 ; 144.80;
148.82 ; 152.71 ; 155.89 ; 159.22 ; 160.75 ; 172.07.
IR (KBr): 1448 ; 1595 ; 1653 ; 1749 ; 2950; 3438.
Example 57: 5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-
10-methyl-lH-oxepino[3',4,:6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using diethylamine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light beige solid is obtained (m.p. > 270 °C).
RMN-1H (DMSO): 0.87 (t, 3H); 1.04 (t, 6H) ; 1.86 (q, 2H); 2.50 (q, 2H); 2.54 (s, 3H) ;
2.56 (q, 2H) ; 3.08 (d, 1H); 3.48 (d, 1H) ; 4.11 (q, 2H); 5.25 (s, 2H) ; 5.46 (dd, 2H) ;
6.05 (s, 1H); 7.35 (s, 1H); 7.80 (d, 1H); 8.36 (d, 1H).
RMN-^C (DMSO): 8.45 ; 11.68 ; 11.78 ; 15.43 ; 15.57 ; 36.5 ; 42.5 ; 46.68 ; 46.83 ;
46.99 ; 50.77 ; 51.85 ; 52.08 ; 61.44 ; 73.30 ; 99.60 ; 112.18 ; 112.36 ; 122.6 ; 124.6 ;
126.9 ; 127.1 ; 128.8 ; 141.45 ; 144.6 ; 148.6 ; 148.7 ; 152.65 ; 155.9 ; 159.1 ; 160.7 ;
163.2; 172.1.
IR (KBr): 1217 ; 1295 ; 1448 ; 1463 ; 1507 ; 1609 ; 1660 ; 1725 ; 2971 ; 3559.
Suspending in absolute ethanol (50 ml/mmol) the free base obtained as described above and subsequent treating with hydrogen chloride in ethanol (2,5 N; 5 eq.) yields the corresponding hydrochloride. At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The strong yellow solid obtained is washed with ether (m.p. 269-272 °C).
RMN-lH (DMSO): 0.87 (t, 3H); 1.34 (m, 1H) ; 1.86 (q, 2H); 2.56 (s, 3H); 3.07 (d, 1H); 3.19 (m, 2H); 3.39 (m, 2H); 3.49 (d, 1H) ; 4.97 (m, 2H); 5.41 (d, 1H); 5.54 (d, 1H); 5.58 (s, 2H); 6.08 (s, 1H); 7.42 (s, 1H) ; 7.96 (d, 1H); 8.43 (d, 1H); 10.38 (s, 1H). IR (KBr): 1039 ; 1070 ; 1226 ; 1282 ; 1509 ; 1654; 1724 ; 1744 ; 2921 ; 3409 ; 3489.
Example 58: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methyl
piperidinomethyl)-lH-oxepino[3,4,6,7,]indolizino[1,2,-b] quinoline-3,15(4H,13H)-dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using 4-methylpiperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C).
RMN-!H (DMSO) : 1.00-0,80 (complex, 6H) ; 1.12 (q, 1H) ; 1.37 (s, 1H) ; 1.57 (d, 3H) ; 1.85 (q, 2H) ; 2.13 (t, 2H); 2.82 (s, 1H) ; 2.85 (s» 1H); 3.05 (d, 1H) ; 3.25 (s, 3H) ; 3.48 (d, 1H); 4.04 (q, 2H); 5.28 (s, 2H); 5.39 (d, 1H); 5.52 (d, 1H); 6.03 (s, 1H) ; 7.36 (s, 1H); 7.82 (d, 1H); 8.40 (d, 1H).
RMN-13C (DMSO): 0.29 ; 8.43 ; 13.68 ; 15.48 ; 19.40 ; 21.93 ; 23.23 ; 30.39 ; 34.20 ; 36.52 ; 42.55 ; 50.67 ; 53.84 ; 56.29 ; 57.67 ; 61.40 ; 73.32 ; 99.59 ; 112.49 ; 122.62 ; 124.80 ; 127.18 ; 129.10 ; 140.31 ; 144.58 ; 148.64 ; 152.69 ; 155.84 ; 159.19 ; 172.05. IR (KBr): 1597 ; 1653 ; 1747 ; 3446.
Example 59 : 5-ethyI-9-fluoro-4,5-dihydro-5-hydroxy-10-methyI-
ll-pyrrolidinomethyl-lH-oxepino[3,4,3,7]indolizino[1,2,b]quinoline-3,15(4H,13H).
dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using pyrrolidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C).
RMN-!H (DMSO): 0.86 (t, 3H); 1.72 (s, 4H) ; 1.85 (q, 2H); 2.57 (s, 4H); 3.05 (d, 1H) ;
3.28 (s, 3H); 3.48 (d, 1H); 4.18 (q, 2H); 5,28 (s, 2H); 5.39 (d, 1H); 5.52 (d, 1H);
6.03 (s, 1H); 7.36 (s, 1H); 7.82 (d, 1H); 8.35 (d, 1H).
RMN-13C (DMSO) : 0.37 ; 8.47 ; 15.57 ; 23.48 ; 36.53 ; 42.61 ; 50.61 ; 53.45 ; 54.09 ;
61.42 ; 73.33 ; 99.59 ; 112.37 ; 122.64 ; 124.51 ; 127.00 ; 127.25 ; 128.63 ; 140.65 ;
144.77 ; 148.65 ; 152.73 ; 155.87 ; 159.20 ; 162.00 ; 167.00 ; 172.07.
IR (KBr): 1608 ; 1656 ; 1729 ; 3400.
Example 60 : 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-
12-(1,2,5,6,-tetrahydropiridinomethy)-lH-oxepino[3,4,6,7,]indolizino
[l,2-b]quinoline-3,15(4H,13H)-dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using 1,2,5,6-tetrahydropyridine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C).
RMN-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.08 (s, 2H); 2.64 (t, 2H); 3.03 (s, 2H); 3.05 (d, 1H) ; 3.28 (s, 3H); 3.48 (d, 1H); 4.12 (d, 1H); 4.17 (d, 1H); 5.28 (s, 2H); 5.39 (d, 1H) ; 5.52 (d, 1H); 5.64 (d, 1H); 5.72 (d, 1H); 6.03 (s, 1H) ; 7.36 (s, 1H); 7.83 (d, 1H); 8.36 (d, 1H).
RMN-13C (DMSO): 8.45 ; 15.54 ; 25.84 ; 36.54 ; 42.55 ; 49.78 ; 50.68 ; 52.52 ; 55.81 ; 61.42; 73.33; 99.62; 112.53; 122.66; 124.78; 125.03; 127.09; 127.19; 131.73; 139.98 ; 144.76 ; 148.79 ; 152.73 : 155.86 ; 159.19 ; 160.76 ; 163.25 ; 172.07.
IR (KBr): 1605 ; 1656 ; 1733 ; 3451.
Example 61: 12-diisobutylaminomethyl-5-ethyl-9-fluoro-4,5-dihydro-
5-hydroxy-10-methyl-lH-oxepino[3,4,3,7,]indolizino[1,2,b] quinoline-3,15,(4H,13H)-
dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methylaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using diisobutylamine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C).
RMN-1H (DMSO): 0.75 (d, 12H); 0.87 (t, 3H); 1.83 (m, 4H); 2.15 (d, 1H) ; 2.48 (s,
3H); 3.06 (d, 1H); 3.47 (d, 1H); 4.01 (q, 2H); 5.28 (s, 2H); 5.39 (d, 1H); 5.53 (d, 1H);
6.03 (s, 1H); 7.37 (s, 1H); 7.83 (d, 1H); 8.49 (d, 1H).
RMN-^C (DMSO): 9.09 ; 16.14 ; 21.73 ; 26.57 ; 26.70 ; 37.15 ; 43.14 ; 51.05 ; 55.49 ;
62.08; 64.74; 73.98; 100.42; 113.03; 123.38; 125.58; 127.12; 127.32; 128.59;
130.27 ; 141.32 ; 145.51; 149.38 ; 149.51 ; 153.20 ; 156.62 ; 159.86 ; 161.31 ; 163.79 ;
172.72.
IR (KBr) : 1599 ; 1656 ; 1747 ; 2796 ; 3448.
Example 62: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-
12-(4-methyl piperazinomethyl)-lH-oxepino[3,4,6,7]indolizino [1,2-b] quinoline-3,15(4H,13H)-dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30. d., using 1,2,5,6-tetrahydropyridine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light yellow solid is obtained (m.p. 274 °C).
RMN-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H); 2.15 (s, 3H); 2.31 (m, 4H); 2.47 (m, 4H) ; 3.06 (d, 1H); 3.47 (d, 1H); 4.05 (m, 2H) ; 4.05 (s, 3H); 5.28 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.35 (s, 1H); 7.87 (d, 1H) ; 7.94 (d, 1H).
RMN-13C (DMSO) : 8.44 ; 36.53 ; 45.58 ; 45.95 ; 50.68 ; 52.86 ; 55.07 ; 56.20 ; 56.47 ; 61.45; 73.32; 99.19; 105.90; 113.74; 113.91; 122.22; 125.60; 129.46; 138.83;
144.51; 144.62 ; 144.94 ; 147.85 ; 147.98 ; 150.96 ; 152.82 ; 155.34 ; 155.96 ; 159.19 ;
172.09.
IR (KBr): 1270 ; 1515 ; 1594 ; 1648 ; 1747 ; 2950 ; 3438.
Example 63: 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-
12-piperidinomethyl-lH-oxepino[3',4,:6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-
dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-fluoro-4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using piperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage 1 l.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A light green solid is obtained (m.p. > 275 °C).
RMN-!H (DMSO): 0,86 (t, 3H); 1.42-1,50 (m, 6H); 1.84 (q, 2H); 2.50 (m, 4H); 3.05 (d,
1H); 3.48 (d, 1H); 4.03 (s, 2H); 4.05 (s, 3H); 5.30 (s, 2H); 5.45 (dd, 2H) ; 6.02 (s, 1H) ;
7.5 (s, 1H); 7.9 (d, 1H); 7.99 (d, 1H).
RMN-13C (DMSO) : 8.44 ; 24.07 ; 25.9 ; 36.54 ; 42.57 ; 50.60 ; 54.26 ; 56.40 ; 57.11 ;
61.42 ; 73.33 ; 99.17 ; 105.97 ; 113.75 ; 113.92 ; 122.21 ; 125.66 ; 129.46 ; 139.23 ;
144.54 ; 144.98 ; 147.94 ; 151.0 ; 152.82 ; 155.34 ; 155.89 ; 159.20 ; 172.07.
IR (KBr): 860 ; 1057 ; 1270 ; 1514 ; 1656 ; 1748 ; 2857 ; 2932 ; 3397.
Suspending in absolute ethanol (50 ml/mmol) the free base obtained as described above and subsequent treating with hydrogen chloride in ethanol (2,5 N; 5 eq.) yields the corresponding hydrochloride. At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The light yellow solid obtained is washed with ether (m.p. 264 °C).
RMN-»H (DMSO) : 0.86 (t, 3H); 1.42 (m, 1H) ; 1.70-1.85 (m, 7H) ; 3.06 (d, 1H);
3.33 (m, 4H); 3.47 (m, 1H); 4.19 (s, 3H); 5.00 (s, 2H); 5.40 (d, 1H); 5.54 (d, 1H);
5.61 (s, 2H); 6.02 (s, 1H); 7.37 (s, 1H); 7.95-8.04 (m, 2H); 10.46 (s, 1H).
RMN-13C (DMSO): 9.12 ; 22.11 ; 22.91 ; 37.63 ; 43.20 ; 52.27 ; 53.20 ; 54.00 ; 54.75 ;
57.91 ; 58.15 ; 62.12 ; 62.78 ; 73.97 ; 100.06 ; 106.96 ; 107.14 ; 114.80 ; 123.20 ; 126.58 ;
130.48 ; 134.14 ; 145.33 ; 145.48 ; 149.49 ; 149.62 ; 151.76 ; 153.84 ; 156.36 ; 156.69 ;
159.76; 172.73.
IR (KBr): 1010 ; 1072 ; 1240 ; 1271 ; 1469 ; 1511; 1574 ; 1598 ; 1648 ; 1734 ; 2525 ;
2944 ; 3430 ; 3507.
Example 64: 9-chIoro-5-ethyI-4,5-dibydro-5-hydroxy-10-methoxy-
12-dimethylaminomethyl-lH-oxepino[3',4,6,7]indolizino[l,2-b]quinoline-
3,15(4H,13H)-dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-methoxyaniline to produce ethyl 2,7,-dichloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using dimethylamine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C).
RMNMH (DMSO): 0.86 (t, 3H); 1.84 (q, 2H) ; 2.29 (s, 6H); 3.06 (d, 1H); 3.42 (d, 1H);
3.98 (q, 2H); 4.05 (s, 3H); 5.27 (s, 2H); 5.45 (s, 2H); 5.95 (s, 1H); 7.32 (s, 1H); 7.82 (s,
lH);8.19(s, 1H).
RMN-13C (DMSO): 8.41 ; 36.50 ; 42.55 ; 45.58 ; 50.62 ; 56.70 ; 57.42 ; 61.42 ; 73.29 ;
99.28 ; 104.66 ; 122.34 ; 126.92 ; 127.55 ; 129.89 ; 130.04 ; 139.19 ; 144.20 ; 144.81 ;
151.08 ; 153.15 ; 155.91 ; 159.18 ; 172.04.
IR (KBr): 1048 ; 1242 ; 1482 ; 1611 ; 1659 ; 1730 ; 3301 ; 3417.
Example 65: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-
12-piperidinomethyl-1H-oxepino[3,,4':6,7]indblizino[l,2-b]quinoleine-3,15(4H,13H)-dione hydrochloride
The procedure described in examples 30,a., 30.b. and 30.c. is applied to 3-chloro-4-methoxyaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated aceording to procedure of example 30.d., using piperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage ll.k. The obtained free base is suspended in absolute ethanol (50 ml/mmol) and subsequently treated with hydrogen chloride in ethanol (2,5 N; 5 eq.). At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The orange solid obtained is washed with ether (m.p. > 250 °C).
RMN-!H (DMSO): 0.86 (t, 3H); 1.43 (q, 1H) ; 1.70 (d, 1H); 1.76 (m, 2H); 1.86 (m, 4H); 3.07 (d, 1H) ; 3.28 (m, 2H) ; 3.47 (m, 3H) ; 4.20 (s, 3H); 5.00 (q, 2H); 5.41 (d, 1H); 5.54 (d, 1H); 5.62 (s, 1H); 6.10 (s, 1H); 7.36 (s, 1H); 7.88 (s, 1H); 8.31 (s, 1H).
RMN-13C (CF3COOD): 8.44; 22.11 ; 24.79; 38.27 ; 43.51 ; 54.28 ; 56.01 ; 58.51 ; 58. 75 ; 64.23 ; 77.59 ; 104.22 ; 110.49; 124.68; 129.44; 131.91 ; 136.61 ; 140.01 ; 141.33 ; 144.72 ; 158.25 ; 161.10 ; 161.89 ; 178.85. IR (KBr): 1079 ; 1288 ; 1488 ; 1562 ; 1578 ; 1648 ; 1747 ; 2936 ; 3406.
Example 66: 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-
12-(l,2,5,6-tetrahydropyridinomethyl)-lH-oxepino[3',4':6,7]indolizino [l,2-b]quinoline-3,15(4H,13H)-dione hydrochloride
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d„ using 1,2,5,6-tetrahydropyridine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage ll.k. The obtained free base is suspended in absolute ethanol (50 ml/mmol) and subsequently treated with hydrogen chloride in ethanol (2,5 N; 5 eq.). At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The yellow solid obtained is washed with ether (m.p. > 250 °C).
RMN-lH (DMSO): 0.86 (t, 3H); 1.87 (q, 2H); 2.32 (m, 1H); 3.07 (d, 1H) ; 3.48 (m, 3H); 3.89 (m, 8H); 4.06 (s, 3H); 5.08 (m, 2H); 5.40 (d, 1H); 5.54 (d, 1H); 5.63 (q, 2H); 5.67 (d, 2H) ; 5.93 (d, 2H); 7.37 (s, 1H) ; 7.59 (q, 1H); 7.79 (d, 1H) ; 8.14 (d, 1H); 10.80 (s, 1H).
RMN-13C (DMSO): 8.47 ; 25.97 ; 36.40 ; 42.55 ; 49.75 ; 50.25 ; 50.61 ; 52.36 ; 56.05 ; 61.44; 73.36; 98.95; 103.74; 121.99; 122.29; 124.98; 125.50; 128.84; 129.84; 131.18 ; 138.47 ; 144.63 ; 145.18 ; 150.01 ; 155.93 ; 159.24; 172.10. IR (KBr): 827 ; 1065 ; 1228 ; 1289 ; 1592; 1653 ; 1746 ; 2363 ; 3373.
Example 67: 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methyl
piperidinomethyl)-lH-oxepino[3',4,:6,7]indolizino[l,2-3]quinoline-3,15(4H,13H)-
dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using 4-methylpiperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in

stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C).
RMN-lH (CF3COOD): 1.17 (m, 6H); 1.62 (m, 2H); 1.89 (s, 1H); 2.07 (q, 2H); 2.25 (m, 2H); 3.54 (m, 3H); 3.89 (d, 1H); 4.02 (s, 2H); 4.19 (s, 3H); 7.94 (s, 1H); 8.10 (m, 1H); 8.29 (s, 1H); 8.50 (m, 1H).
RMN-13C (CF3COOD): 8.43 ; 13.79 ; 17.43 ; 20.89 ; 30.01 ; 32.85 ; 38.26 ; 43.50 ; 54.13 ; 56.09 ; 57.87 ; 58.27 ; 64.22 ; 77.57 ; 107.37 ; 110.56 ; 125.75 ; 129.36 ; 129.42 ; 132.78 ; 136.04 ; 136.65 ; 139.91 ; 140.38 ; 144.31 ; 158.30 ; 161.94 ; 164.90 ; 178.84. IR (KBr): 825 ; 1056 ; 1230 ; 1260 ; 1516 ; 1641 ; 1655 ; 1736 ; 2921; 3395.
Example 68: 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methyl
piperazinomethyl)-lH-oxepino[3,4,:6,7]indollzino[l,2-b]quinolme-3,15(4H,13H)-
dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d. and reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. 215-219 °C).
RMN-lH (DMSO): 0.85 (t, 3H); 1.85 (m, 2H); 2.15 (s, 3H); 2.35 (m, 4H); 2.5 (m, 4H);
3.25 (dd, 2H); 3.95 (s, 3H); 4.05 (s, 2H); 5.3 (s, 2H); 5.45 (dd, 2H); 6 (s, 1H); 7;3 (s,
1H); 7.5 (d, 1H); 7.7 (s, 1H); 8.05 (d, 1H).
RMN-13C (DMSO): 9.12 ; 14.36 ; 20.08 ; 23.93 ; 46.61 ; 51.35 ; 53.58 ; 55.71 ; 56.34 ;
56.73 ; 58.37 ; 62.11 ; 74.03 ; 99.62 ; 104.49 ; 122.66 ; 123.11 ; 129.54 ; 130.53 ; 131.82 ;
139.05 ; 145.3 ; 145.86 ; 150.67 ; 156.62; 158.71 ; 159.91 ; 172.77.
IR (KBr): 1590 ; 1624 ; 1655 ; 1744 ; 2801 ; 2935 ; 3423.
Example 69 : 5-ethyI-4,5-dihydro-5-hydroxy-10-methoxy-
12-pyrrolidinomethyl-lH-oxepino[3',4,:6,7]indolizino[l,2-b]qumoline-3,15(4H,13H)-
dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using pyrrolidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 250 °C).
RMN-lH (DMSO): 0.85 (t, 3H); 1,7 (s, 4H); 1.85 (q, 2H); 2.55 (s, 4H); 3.25 (dd, 2H);
3.9 (s, 3H); 4.15 (s, 2H); 5.25 (s, 2H); 5.45 (dd, 2H); 6 (s, 1H); 7.35 (s, 1H); 7.5 (d,
1H); 7.7 (s, 1H); 8.05 (d, 1H).
RMN-13C (DMSO): 9.68 ; 24.74 ; 51.8 ; 54.71 ; 55.25 ; 56.3 ; 56.87 ; 62.3 ; 62.64 ; 74.5 ;
100.14; 104.8; 104.92; 123.19; 123.45; 129.79; 130.49; 132.32; 132.50; 140.5;
145.83 ; 146.4 ; 151.27 ; 157.15 ; 159.25 ; 160.45 ; 173.3.
IR (KBr): 1255 ; 1516 ; 1535 ; 1613 ; 1655 ; 1735 ; 3438 ; 3762 ; 3830.
Example 70: 12-(4-benzylpiperazinomethyl)-5-ethyl-4,5-dihydro-5-hydroxy-
10-methoxy-lH-oxepino[3,,4':6,7]indolizino[l,2-b]quinoline-3,15(4H,13H)-dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 4-methoxyaniline to produce ethyl 2-chloro-4-chloromethyl-6-methoxy-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using N-benzylpiperazine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A beige solid is obtained (m.p. > 250 °C).
RMN-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.45 (s, 2H); 2.4 (m, 4H); 2.55 (m, 4H);
3.25 (dd, 2H); 3.45 (s, 2H); 3.95 (s, 3H); 4.05 (s, 2H); 5.3 (s, 2H); 5.45 (dd, 2H) ; 6 (s,
1H); 7.3 (m, 6H); 7.5 (d, 1H); 7.75 (s, 1H); 8 (d, 1H).
RMN-13C (DMSO) : 7.38 ; 49.56 ; 51.89 ; 54.46 ; 54.82 ; 54.98 ; 55.1 ; 60.1 ; 60.35 ;
61.11 ; 72.26 ; 97.86 ; 102.6 ; 102.76 ; 120.9 ; 121 ; 121.2 ; 121.4 ; 126 ; 127.25 ; 127.77 ;
127.88 ; 128.76 ; 130.13 ; 130.2 ; 137.25 ; 137.36 ; 143.53 ; 144.08 ; 148.86 ; 156.86 ;
156.95 ; 158.15 ; 171.02.
IR (KBr): 1235 ; 1259 ; 1517 ; 1586 ; 1614 ; 1654 ; 1747 ; 2927 ; 3450 ; 3762 ; 3848.
Suspending in absolute ethanol (50 ml/mmol) the free base obtained as described above and subsequent treating with hydrogen chloride in ethanol (2,5 N; 5 eq.) yields the corresponding hydrochloride. At first, a yellow solution is formed, then a precipitate which is recovered by filtration after concentration to 40% of the initial volume. The yellow solid obtained is washed with ether (m.p. > 250 °C).
RMISMH (DMSO): 0.85 (t, 3H); 1.85 (q, 2H>; 2.5 (s, 2H); 2.65 (m, 2H); 3 (m, 2H) ; 3.2 (m, 2H); 3.35 (dd, 2H); 3.35 (s, 2H); 3.95 (s, 3H); 4.15 (s, 2H); 4.3 (s, 2H); 5.3 (s, 2H); 5.45 (dd, 2H); 7.3 (s, 1H); 7.4 (s, 2H); 7.55 (m, 2H); 7.7 (s, 1H); 8.05 (d, 1H); 10.45 (s, 1H). IR (KBr): 1207 ; 1233 ; 1439 ; 1449 ; 1458 ; 1508 ; 1610 ; 1620 ; 1655 ; 1727 ; 3398.
Example 71: 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-
12-(4-methyIpiperidinomethyl)-lH-oxepino [3',4':6,7] indolizino [l,2-b] quinoline-3,15(4H,13H)-dione
The procedure described in examples 30.a., 30.b. and 30.c. is applied to 3-chloro-4-methylaniline to produce ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate which is treated according to procedure of example 30.d., using piperidine instead of N-methylpiperazine, and then reduced in the corresponding quinolinemethanol according to the method of example 30.e. The latter is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 275 °C).
RMN -1H (DMSO): 0.86 (m, 6H); 1.15 (m, 2H); 1.37 (m, 1H); 1.60 (m, 2H); 1.80 (m, 2H); 2.10 (m, 2H); 2.60 (s, 3H); 2.80 (m, 2H); 3.05 (d, 1H); 3.48 (d, 1H); 4.02 (s, 2H); 5.30 (s, 2H); 5.45 (dd, 2H); 6.02 (s, 1H); 7.40 (s, 1H); 8.20 (s, 1H); 8.40 (s, 1H). RMN-13C (DMSO): 9.10 ; 21.28 ; 22.61; 31.07 ; 34.89 ; 37.18 ; 43.22 ; 54.53 ; 56.83 ; 62.10 ; 73.94 ; 80.06 ; 100.43 ; 123.41 ; 127.08 ; 129.11 ; 130.58 ; 135.88 ; 136.89 ; 141.00; 145.28 ; 148.49 ; 153.51 ; 156.60 ; 159.85 ; 172.77 ; 174.05. IR (KBr): 1605 ; 1657 ; 1734 ; 3342.
Example 72: 10-benzyloxy-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-lH-
oxepino [3',4':6,7] indolizino [1,2-6] quinoline-3,15(4H,13H)-dione
The procedure described in examples 30.a.t 30.b. and 30.c. is applied to 3-fluoro-4-methoxyacetanilide to yield 2-chloro-7-fluoro-6-methoxyquinoline-3-carbaldehyde which is treated with an excess of boron tribromide in dichloromethane at room temperature during 24 hours. The obtained 2-chloro-7-fluoro-6-hydroxy-quinoline-3-carbaldehyde is O-benzylated in dimethylformamide in the presence of benzyl bromide and potassium carbonate to yield 6-benzyloxy-2-chloro-7-fluoro-quinoline-3-carbaldehyde, the latter being reduced in the corresponding quinolinemethanol using sodium borohydride in methanol. The obtained quinolinemethanol is coupled with compound (M) as described in stage ll.j. of example 11. The coupling product is cyclised following the procedure of stage 1 l.k. A yellow solid is obtained (m.p. > 275 °C).
RMN-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H) ; 3.05 (d, 1H); 5.25 (s, 2H); 5.37 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.4-7.6 (m, 5H); 7.88 (d, 1H); 7.95 (d, 1H); 8.56 (s, 1H).
Example 73: 5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy-lH-oxepino
[3,4':6,7] indolizino [1,2-b] quinoline -13,15-(4H-13H)-dione
The hydrogenolysis procedure of example 14 is applied to compound of example 72. A yellow solid is obtained (m.p. > 275 °C).
RMN-1H (DMSO): 0.86 (t, 3H); 1.85 (q, 2H) ; 3.05 (d, 1H); 5.25 (s, 2H) ; 5.37 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H) ; 7.8 (d, 1H) ; 7.90 (d, 1H) ; 8.56 (s, 1H).
PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION
1. Test on DNA relaxation induced by topoisomerase 1
All the reactions were performed in a 20 µl reaction buffer consisting of 50 mM of Tris-HC1 (pH 7.5), 50 mM of KC1, 0.5 mm of dithiothreitol, 10 mM of MgCl2, 0.1 mM of ethylenediamine tetraacetic acid (EDTA), 30µg/ml of bovine serum albumen and 300 ng of coiled pUC19 (Pharmacia Biotech, Orsay, France) with or without compounds to be tested at specific concentrations. All the compounds to be tested were initially dissolved in dimethylsulphoxide (DMSO) at 50 mM, the other dilutions being made using distilled water. The final concentration of DMSO did not exceed 1% (by volume). The reaction was initiated by adding one unit of topoisomerase 1 of purified calf thymus DNA (Gibco-BRL, Paisley, United Kingdom) and was carried out for 15 minutes at 37°C. The reactions were stopped by adding 3 µl of a mixture containing sodium dodecylsulphate at 1%, 20 mM of EDTA and 500 µg/ml of proteinase K (Boehringer Mannheim, Meylan, France). After a further 30 minutes of incubation at 37°C, 2 µl of a buffer containing 10 mM of Na2HP04, 0.3% bromophenol blue and 16% Ficoll were added to the specimens which were subjected to electrophoresis in 1.2% agar gels at 1 V/cm for 20 hours in a buffer containing 36 mM of Tris-HCl pH 7.8, 30 mM of Na2HP04, 1 mM of EDTA and 2 µg/ml of chloroquine. The gels were stained with 2 µg/ml of ethidium bromide, photographed in UV light at 312 nm with a camera and the fluorescent intensity measured with a bioProfil camera (Vilber Lourmat, Lyon, France) in order to determine the percentage of relaxed DNA. Each experiment was performed at least three times and duplicated.
In each experiment, the coiled plasmid DNA was incubated alone or with topoisomerase 1. The reaction was complete within 15 minutes. For each compound to be tested, or control, the coiled plasmid DNA was incubated in the presence of 500 µM of the compound to be tested with or without enzymes, plus the compound to be tested, at concentrations of 10 µM, 100 µM, 200 µM and 500 µM. As shown in table I, examples 2, 3, 4, 9, 10 and 11 inhibit the relaxation activity encouraged by the topoisomerase 1 in a manner that depends on dose.
(Table Removed) TABLE I
2. Tests on cell growth
a. Eight strains of tumour cells were used in this study: L1210 (mouse lymphocytic leukaemia), HCT15 and LOVO (strains of human colon adenocarcinoma cells), A549 (human lung carcinoma), A172, U373 and U87 (human glioblastomas). All these strains were obtained from the American type culture collection (ATCC), Rockville, Md, United States. Cultures of L1210 cells in suspension were cultivated in a Dulbecco modified eagle medium (DMEM) (BioWhitaker, Verviers, Belgium) completed with 10% of foetal calf serum inactivated by heating, 2 mM of glutamine, 50 U/ml of penicillin and 50 fig/ml of streptomycin. HT29 cells were cultivated in single-layer cultures in a McCoy 5a medium (Gibco, Paisley, United Kingdom) completed with 10% foetal calf serum inactivated by heating plus 2 mM of glutamine and 50 µg/ml of gentamycin. The other cells were cultivated in an essential modified Earle medium (EMEM; Gibco, Paisley, United Kingdom) completed with 5% foetal calf serum inactivated by heat, 2 mM of glutamine, 50 U/ml of penicillin and 50 µg/ml of streptomycin. All these cell strains were cultivated at 37°C in a moistened atmosphere containing 95% air and 5% CO2.
Inhibition of the growth of the strains of tumour cells was determined using an MTT test. 1500 L1210 cells in a culture medium (according to the cell medium requirements) were seeded in a well of a microplaque (tissue culture level: 96 wells, flat bottom) 24 hours
before treatment with the compounds to be tested. For these dose-response investigations, the cells were incubated with each of the compounds to be tested or their corresponding solvent (controls) for 48 hours with a final concentration range of 1.10" to 1.10" . All the compounds were dissolved just before use in dimethylsulphoxide (DMSO) at a concentration of 50 mM. Other drug dilutions were performed in the culture medium. The final concentration of DMSO never exceeded 0.2% (by volume). As controls, the solutions of drugs were replaced by the solvent that was diluted successively in the same way as the compounds under test.
After the incubation period, the MTT marking reagent (3-[4,5-dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide; Thiazol blue, Sigma M 565, Sigma, St Louis, MO, United States) was added at a final concentration of 0.3 mg/ml to each well. The cells were incubated for 4 hours at 37°C in a moistened atmosphere. This stage allows the mitochondrial dehydrogenase in the living cells to convert the MTT yellow tetrazolium salt into crystals of purple formazan. The supernatant part was eliminated and the crystals of formazan formed were dissolved in DMSO. The resulting coloured solution was quantified by absorption at 570 nm using a scanning multi-chamber spectrophotometer. The growth data were expressed as a percentage of living cells in the wells treated, divided by the living cells in the controls. Each point represents the mean of three independent experiments, each experiment representing six determinations.
For the other cell strains (HCT15, LOVO, A549, A172, U373, and U87), 1000 to 2000 cells were seeded in a well of a plate of microwells 24 hours before the drug treatment. They were incubated with each of the compounds to be tested or their corresponding solvent (controls) for 72 hours for a final concentration range of 1.10" to 1.10" M.
The results were expressed as percentages of growth calculated by the optical density (OD) of the cells treated with a drug divided by the OD of the control cells (cells treated with DMSO). As shown on table II, the compounds to be tested inhibited the growth of the cells in a manner that depended on dose.
(Table Removed) TABLE II
b. Nine strains of tumour cells were used in this investigation: PC3, DU145 (human prostate cells), MCF7 and MCF7-ADR (mammary cells, the symbol "ADR" was used to indicate that the cells have been made resistant to adriamycin), A427 (human lung adenocarcinoma), HT29 (human colon adenocarcinoma cells), T24s, T24r (human bladder cells, the T24r were resistant to adriamycin, amongst other things). The PC3, DU145 and A427 cells were obtained from the American type culture collection (ATCC, Rockville, Md, United States). The MCF7 and MCF7-ADR cells were provided gratis by Dr Jacques Soudon (Pharmacell, Paris, France). The T24s and T24r cells were given gratis by Dr Robert Kiss (Free University of Brussels, Belgium). HT29 cells were cultivated in single-layer cultures in a 4.5 g/1 DMEM medium (Gibco, Paisley, United Kingdom) completed with 10% of foetal calf serum inactivated by heat plus 2 mM of glutamine and 50 µg/ml of gentamycin (Gibco, Paisley, United Kingdom). The other cells were cultivated in an essential modified Earle medium EMEM at 4,5 g/1 (Gibco, Paisley, United Kingdom) completed with 10% of foetal calf serum inactivated by heat, 2 mM of glutamine (Gibco, Paisley, United Kingdom), 50 U/ml of penicillin and 50 u,g/ml of streptomycin (BioWhitaker, Verviers, Belgium). All the cell strains were cultivated at 37°C in a moistened atmosphere containing 95% air and 5% CO2.
Inhibition of the growth of the strains of tumour cells was determined using a WST1 colorimetry test. Between 500 and 4000 cells in a culture medium (according to the cell medium requirements) were seeded in a well of a microplaque (96 wells, flat bottom) 24 hours before treatment with the compounds to be tested. For these concentration-response
studies, the cells were incubated with each of the compounds to be tested or their
-13 corresponding solvent (controls) for 72 hours in a final concentration range from 1x10
to 1 x 10" M. All the compounds were dissolved in dimethylsulphoxide (DMSO) or in
water for the water soluble compounds. The following dilutions of the compounds of the
present invention were made in the culture medium such that the final concentration of
DMSO, where the latter enters into the composition of the vector, was still 0.1% (by
volume). As controls, the solutions of compounds were replaced by the solvent that was
diluted successively in the same way as the compounds under test.
After incubation, the WST1 marking reagent (4-[3-(4-iodophenyi)-2-(4-nitrophenyl)-2h-5-tetrazolio]-l,3-benzene disulphonate) (Boehringer Mannheim, Germany) was added to a final concentration of 9% in each well. The cells were incubated for between 2 and 4 hours at 37 °C in a moistened atmosphere. This stage allows the mitochondrial dehydrogenase of the living cells to convert the WST1 orange tetrazolium salt into crystals of purple formazan. The resulting coloured solution was quantified by a double-beam reading (450 and 690 nm) using a scanning multi-chamber spectrophotometer.
The results are expressed in the form of a window of concentrations, expressed as mol/litre, including the inhibiting concentration at 50% (IC50). They are shown on tables IIIA) and IIIB). The examples where the number is followed by an "s" correspond to the salts of the compounds. The abbreviations Cpt, Adr and Tpt represent camptothecin, adriamycin and topotecan respectively.
(Table Removed) TABLE IIIA) (Table Removed) TABLE III B)

We claim;

1. A camptothecin compound characterized in that it corresponds to formula (I)
(Formula Removed)
m racemic or enantiomeric form or any combinations of these forms, wherein
Rl represents an inferior alkyl, an inferior alkenyl, an inferior alkynyl, an
inferior haloalkyl, an inferior alkoxy inferior alkyl or an inferior alkylthio inferior alkyl; R2, R3 and R4 independently represent H, halo, inferior haloallqrl, inferior alkyl, inferior alkenyl, cyano, inferior cyanoalkyl, nitro, inferior nitroalkyl, amido, inferior amidoalkyl, hydrazino, inferior hydrazinoalkyl. azido, inferior azidoalkyl, (CH2)mNR6R7. (CH2)mOR6, (CH2)n,SR6, (CH2)mCO2R6, (CH2)mNR6C(O)R8. (CH2)n,C(O)R8, (CH2)mOC(O)R8,
O(CH2)mNR6R7, OC(O)NR6R7, OC(O)(CH2)mCO2R6. or (CH2)n[N=X], OC(O)[N=X], (CH2)mOC(O)[N=X] (wherein [N=X]. in
this invention, represents a heterocyclic group of 4 to 7 links 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 COR10), aryl or substituted inferior arylalkyl (that is, substituted between 1 and 4 times on the aryl group or the heterocycle) or not substituted, wherein the substituent is an inferior alkyl, halo, nitro, amino, inferior aminoalkyl, inferior haloalkyl, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy inferior alkyl or R2 and R3 together form a chain with 3 or 4 links, wherein the elements of the chain are selected from the group consisting of CH, CH2,0, S, N or NR9;

R.5 represents H, balo, inferior haloalkyl, inferior alkyl, inferior alkoxy,
inferior alkoxy inferior alkyl, inferior alkylthio inferior alkyl, cycloalkyl,
cycloalkyl inferior alkyl, cyano, cyanoalkyl, inferior alkyl inferior
sulphonylalkyl, inferior hydroxyalkyl, nitro, (CH2)mC(O)R8,
(CH2)mNR6C(O)R8, (CH2)MNR6R7. (CH2)mN(CH3)(CH2)„NR6R7
(CH2)mOC(O)R8. (CH2)mOC(O)NR6R7, (CH2)mS(O)qRn.
(CH2)mP(O)R12Rl3, (CH2)2P(S)R12Rl3, or (CH2)n[N=X],
OC(O)[N=X], (CH2)mOC(O)[N=X], aryl or substituted inferior arylalkyl
(that is, one to four times on the aryl or hetero aryl group) or not
substituted, wherein the substituent is an inferior alkyl, halo, nitro,
amino, inferior alkyl amino, haloinferior alkyl, inferior hydroxyalkyl,
inferior alkoxy or inferior alkoxy inferior alkyl;
R6 and R7 independently represent H, an inferior alkyl, inferior hydroxyalkyl,
inferior alkyl inferior aminoalkyl, inferior aminoalkyl, cycloalkyl,
cycloalkyl inferior alkyl, inferior alkenyl, inferior alkoxy inferior alkyl,
inferior haloalkyi, or aryl or substituted inferior arylalkyl (that is, one to
four times on the aryl group) or not substituted, wherein the substituent is
an inferior alkyl, halo, nitro, amino, inferior alkylamino, inferior
haloalkyi, inferior hydroxyalkyl, inferior alkoxy, or inferior alkoxy
inferior alkyl;
R8 represents H, an inferior alkyl, inferior hydroxyalkyl, amino, inferior
alkylamino, inferior alkyl inferior aminoalkyl. inferior aminoalkyi,
cycloalkyl, cycloalkyl inferior alkyl , inferior alkenyl, inferior alkoxy,
inferior alkoxy inferior alkyl, inferior haloalkyi, or aryl or substituted
inferior arylalkyl (that is, one to four times on the aryl group) or not
substituted, wherein the substituent is an inferior alkyl, halo, nitro.
amino, inferior alkylamino, inferior haloalkyi, inferior hydroxyalkyl,
inferior alkoxy, or inferior alkoxy inferior alkyl;
R9 represents H, an inferior alkyl, inferior haloalkyi, aryl, or aryl substituted
by one or more groups chosen from the inferior alkyl radical, halo, nitro,
amino, inferior alkylamino, inferior haloalkyi, inferior hydroxyalkyl,
inferior alkoxy,or inferior alkoxy inferior alkyl;
R10 represents H, an inferior alkyl, inferior haloalkyl, inferior alkoxy, aryl, or
substituted aryl (that is, with one to four substituting agents on the aryl
group) by one or more groups chosen from the inferior alkyl radical,
inferior haloalkyi, inferior hydroxyalkyl, or inferior alkoxy inferior alkyl;
Rll represents an inferior alkyl, aryl, (CH2)mOR14, (CH2)inSR14,
(CH2)2NR14Rl5 or (CH2)m[N=X];

Rl2 and R13 independently represent an inferior alkyl, aryl, inferior alkoxy, aryloxy or
amino; Rl4 and R15 independently represent H, an inferior alkyl or aryl;
R18 and R19 independently represent H, halo, inferior alkyl, inferior alkoxy or
hydroxy;
R20 represents H or halo;
R21 represents H, an inferior alkyl, CHO or C(O)(CH2)mCH3;
m is a whole number between 0 and 6;
n is 1 or 2; and
q represents a whole number from 0 to 2; and [N=X] represents a
heterocyclic group with 4 to 7 links, X representing the link necessary to
complete the said heterocyclic group and selected from the group
consisting of O, S, CH2, CH, N, NR9 and COR10;
or a pharmaceutically acceptable salt thereof, wherein 'inferior' means upto 6 carbon atoms.
2. A compound as claimed in claim 1, wherein
R2 represents an atom of hydrogen or halogen;
R3 represents an halogen atom, an inferior alkyl or an inferior alkoxy;
R4 represents an hydrogen atom;
R18. Rl9 et R20 represent an hydrogen atom;
or a pharmaceutically acceptable salt thereof.
3. A compound as claimed in claim 2, wherein R5 is an aminoalkyl or a pharmaceutically acceptable salt thereof.
4. A compound as claimed in claimed in claim 1, wherein the said compound is selected from among:
- 5-ethyI-9.10-difluoro-4,5-dihydro-5-hydroxy-12-(l,2,5,6-tetrahydropyridinomethyl-lH-
oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione hydrochloride
- 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-inethylpiperidinoniethyl)-lH-
oxepino[3*,4*:6,7] indolizino[l,2-b] quinoIine-3,15(4H,13H)-dione
5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-pyrrolidinoinethyl-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione

- 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperazinomethyl)-lH-
oxcpino[3'.4 :6,7] indolizino[1;2-b] qumolme-3,15(4H,13H)-dionc
-5-ethyI-910-difluoro-4,5-dihydro-5-hydroxy-12-piperidinomethyl-lH-oxepino[3',4':6,7] indolizino[l^-b] qumoline-3,15(4H, 13H)-dione
- 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-dimethylaminomcthyl-lH-oxepino[3,,4':6,7] mdoIizino[l,2-b3 qainoline-3,I5(4H,13H)-dione
- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-merhyi-12-inorpholinoinethyl-lH-oxqjino[3'.4':6,7] indolizmo[l,2-b] quinolinc-3.15(4H,13H)-dione

- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-dimethyl-12-(4-inethylpipcrazinoinethyl)-lH-oxepino[3',4':6,7] mdoli2dno[l,2-b] quinoline-3,15(4H,13H)-dione
- 12-benzyhnethylaminomethyl-9-chloro-5-ethy I-4,5-dihy dro-5-hydroxy-10-methyl-1H-oxepino[3%4':6,7] mdoli2ino[l,2-b] quinoline-3,15(4H.13H)-dione
- 12-(4-benzylpiperazmomethyl)-9-chloro-5-ethyl-4,5-dihydro-5-hydroxy- 10-m IH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione

- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-piperidinomethyl-lH-oxepino[3',4':6,7] mdolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 12-(4-benzylpiperazinomethyl)-5-cthyl-9-fluoro-4,5-dihydro-5-hydroxy-lH-oxepmo[3,4':6,7] mdoIizino[l,2-b] qainoline-3,15(4H,13H)Hiione
- 12-(4-benzylpiperazinomethyl)-5-ethyl-9-fluon)-4,5-dihydro-5-hydroxy-10-methyl-lH-
oxepino[3,4':6,73 indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-dimethylamiDomethyl-lH-
oxepino[3*.4*:6,7] mdoJyLzino[l,2'-b] quinolme-3.15(4H,13H)-dione
5-ethyl-12-dicthylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3,4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 5-ethyl-9-fluoio-4,5-dihydro-5-hydroxy'10-methyI-12-(4-methylpiperidinomethyl)-lH-
oxepinor3',4':6,7] indolizmo [1,2-b] quinoline-3,15(4H.13H)-dione
- 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-pyrrolidinomethyl-lH-
oxepino[3',4':6,7] indolizino[1,2-b] quinoline-3,15(4H,13H)-dione
5-ethy1-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(1,2,5,6-tetrahydropyridinomethyl)-1H-oxepino[3',4':6,7] indolizino(1,2-b] quinoline-3,15(4H,13H)-dione
- 12-diisobutylaininomethyl-5-ethyl-9-fIuoro-4,5-dihydro-5-hydroxy-10-methyl-lH-oxepino[3',4*:6,7] indolizano[l,2-b] quinoline-3,15(4H,13H)-dione -5-etfayl-9-fluon)-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-xnethylpiperazinomethyl)-lH-oxepinoI3',4':6,73 indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy- 10-methoxy- 12-piperidlnomethyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] qiiinoIine-3,15(4H,I3H)-dione
- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-dimcthylaminomethyI-1H-oxepino[3%4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione

- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoIine-3,15(4H,13H)-dione hydrochloride -5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(l,2,5,6-tetrahydropiperidinomethyl)-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperidinomethyl)-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15C4H,13H)-dione
- 5-ethyI-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methylpiperazinomethyl)-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinolme-3,15(4H,13H)-dione
- 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-pyrrolidinomethyl-1 H-oxepino[3' ,4':6,7]
indolizino[ 1,2-b] quinoIine-3,15(4H, 13H)-dione
- 12-(4-benzylpiperazinomethyl)-5-ethyl-4,5-dihydro-5-hydroxy-l 0-methoxy-IH-
oxepino[3',4':6,7] indolizinotl,2-b] quinoline-3,15(4H,13H)-dione
- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-1H-
oxepmo[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione
- 10-benzyloxy-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-1 H-oxepino [3',4':6,7]
indolizino [ 1,2-b] quinoline-3,15(4H, 13H)-dione
- 5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy-lH-oxepinoi:3',4':6,7] indolizino[l,2-b]
qiiinoline-3,15(4H, 13H)-dione
or a pharmaceutically acceptable salt of one of these.
5. A compound as claimed in claim 4, wherein the said compound is selected from among:
- 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-12-(4-methylpiperidinomethyl)-lH-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione;
- 5-ethyl-12-diethylaminomethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione;
- 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-lH-
oxepino[3',4':6,7] indoIizino[l,2-b] quinoline-3,15(4H,13H)-dione;
- 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-pyrrolidinomethyl-lH-oxepino[3',4':6,7] indolizino[l,2-b] qviinoline-3,15(4H,13H)-dione;
- 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-piperidinomethyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15C4H,13H)-dione;
- 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methyIpiperidinomethyl-1H-oxepino[3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione;
- 9-chIoro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-12-(4-methylpiperidinomethyl)-1H-
oxepino [3',4':6,7] indolizino[l,2-b] quinoline-3,15(4H,13H)-dione;
or a pharmaceutically acceptable salt of one of these.

6. A compound as claimed in any of claims 1 to 5 or a pharmaceutically acceptable salt thereof for use as a medicine.
7. The compounds as claimed in any of claims 1 to 5 as and when used for preparation of a pharmaceutical compsition
8. A compound substantially as herein described with reference to the foregoing examples.
9. Pharmaceutical composition substantially as herein described with reference to the
foregoing examples.

Documents:

3679-del-1997-abstract-(12-12-2008).pdf

3679-DEL-1997-Abstract-(30-10-2008).pdf

3679-del-1997-abstract.pdf

3679-del-1997-claims-(12-12-2008).pdf

3679-DEL-1997-Claims-(30-10-2008).pdf

3679-del-1997-claims.pdf

3679-del-1997-complete specification (granted).pdf

3679-DEL-1997-Correspondence-Others-(06-11-2008).pdf

3679-DEL-1997-Correspondence-Others-(30-10-2008).pdf

3679-del-1997-correspondence-others.pdf

3679-DEL-1997-Description (Complete)-(30-10-2008).pdf

3679-del-1997-description (complete).pdf

3679-DEL-1997-Form-1-(30-10-2008).pdf

3679-del-1997-form-1.pdf

3679-del-1997-form-13-(30-10-2008).pdf

3679-del-1997-form-18.pdf

3679-del-1997-form-2.pdf

3679-DEL-1997-Form-3-(30-10-2008).pdf

3679-del-1997-form-4.pdf

3679-del-1997-form-6.pdf

3679-DEL-1997-GPA-(30-10-2008).pdf

3679-DEL-1997-Petition-137-(30-10-2008).pdf

3679-DEL-1997-Petition-138-(30-10-2008).pdf

3679-del-1997-petition-138.pdf

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Patent Number

233423

Indian Patent Application Number

3679/DEL/1997

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

30-Mar-2009

Date of Filing

18-Dec-1997

Name of Patentee

SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES (S.C.R.A.S.)

Applicant Address

51/53 RUE DU DOCTEUR BLANCHE, 75016 PARIS, FRANCE.

Inventors:

#	Inventor's Name	Inventor's Address
1	BIGG DENNIS	8 RUE NEUVE 91190 GIF SUR YVETTE FRANCE.
2	LAVERGNE OLIVIER	6, RUE DES ANGLAIS 91300 MASSY FRANCE.
3	PLA RODAS FRANCESC	55 RUE CAMPRODON, 17430 SANTA COLOMA DE FARNERS, ESPAGNE.
4	POMMIER JACQUES	93/95 AVENUE HENRI BARBUSSE 92700 COLOMBES FRANCE.
5	ULIBARRI GERARD	20, RUE DU ROYAUME 91440 BURES SUR YVETTE RANCE.

PCT International Classification Number

C07D 491/22

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA