NO316749B1 - New camptothecin analogs, their preparation methods, their use as pharmaceuticals and pharmaceutical compositions containing said analogs - Google Patents

Abstract

Camptothecin analogues where the camptothecin hydroxy lactone is: (i) a beta -hydroxy lactone; or (ii) the corresp. beta -hydroxy acid resulting from ring-opening of the aforementioned lactone; or a (iii) deriv. of the beta -hydroxy acid in (ii) or its one of its salts. Also claimed are new industrial prods. of formula (M) and (A). R1 = lower alkyl, lower alkenyl, lower alkynyl, halo(lower alkyl), lower alkoxy(lower alkyl) or lower alkylthio(lower alkyl); R20 = H or halo; R22 = F, Cl, or lower alkoxy; R23 = prim. hydroxy-protecting gp.; and R18, R19 = H, halo, lower alkyl, lower alkoxy or OH.

Description

The present invention relates to new camptothecin analogues, production methods for these, use thereof as medicines and pharmaceutical mixtures containing said analogues.

Camptothecin is a natural compound first isolated from the leaves and bark of the Chinese plant camptotheca acuminata (see Wall et al., J. Amer. Chem. Soc. 88: 3888 (1996)). Camptothecin is a pentacyclic compound consisting of an indolizino[1,2-]quinoline fragment condensed with a six-membered α-hydroxylactone. The carbon atom in position 20, which carries the α-hydroxy group, is asymmetric and gives the molecule rotational properties. The natural form of camptothecin has absolute S configuration at carbon 120

and has the following formula:

Camptothecin has anti-proliferative activity for several cancerous cell lines, including the cell lines of human colon, lung and breast tumors (Suffness, M. et al.: The Alkaloids Chemistry and Pharmacology, Bross, A., ed., Vol. 25, p. 73 (Academic Press, 1985)). It has been suggested that the anti-proliferative activity of camptothecin is related to its inhibitory activity on DNA topoisomerase I.

It has been indicated that the α-hydroxylactone was an absolute condition for both the in vivo and in vitro activity of camptothecin (Camptothecins: New Anticancer Agents, Putmesil, M., et al., ed., p. 27 (CRC Press , 1995); Wall, M. et al.

Cancer Res. 55:753 (1995); Hertzberg et al., J. Med. Chem. 32:715 (1982) and Crow et al., J. Med. Chem. 35:4160 (1992)). The present invention relates to a new class of camptothecin compounds, where p-hydroxylactone replaces the natural a-hydroxylactone in camptothecin. The compounds according to the present invention have strong biological activity which is unexpected in relation to known technology.

The invention thus relates to new camptothecin compounds which differ from all known camptothecin compounds in that they contain a β-hydroxylactone (or its open hydroxycarboxyl form) instead of an α-hydroxylactone (or the open hydroxycarboxyl form); or a pharmaceutically acceptable salt thereof. The camptothecin compound is to be understood as a compound having the same structural skeleton as camptothecin (i.e. an indolizino[1,2-b] quinoline fragment condensed to a six-membered α-hydroxylactone), with or without other chemical substitutions on the skeletal structure (e.g. camptothecin compounds). Various camptothecin compounds are well known to those skilled in the art, as described below. By p-hydroxylactone is meant a lactone which comprises an additional carbon atom between the carbon in the carboxyl group and the a-carbon atom which carries the hydroxy group in the a-hydroxylactone. The p-hydroxylactone can be a cyclic group with seven members, where the ester bond between the carbonyl group and the neighboring oxygen atom is hydrolysed, resulting in the formation of a carboxylic acid group and a hydroxyl group, which groups can be substituted or unsubstituted.

A camptothecin compound according to the invention may comprise substitutions on the indolizino[1,2-5]-quinoline fragment (e.g. to improve the solubility of the compound) or on the open or closed p-hydroxylactone (e.g. to improve the stability of the connection). Examples of substitutions on closed p-hydroxylactone include alkyl substitution (eg ethyl) on the p-carbon atom. Examples of substitution on the open p-hydroxylactone include alkyl substitution on the p-carbon atom, substitutions (eg amidation) on the resulting carboxylic acid and substitutions (eg esterification) or exclusions on the resulting hydroxyl group.

The invention relates more particularly to compounds of formula (I) and formula (II),

in racemic or enantiomeric form or any combination of these forms, where

R 1 represents a lower-alkyl, a lower-alkenyl, a lower-haloalkyl, or a lower-alkyl-lower-alkyl;

R2. R 3 and R 4 independently represent H, halogen, lower-haloalkyl,

lower-alkyl, nitro, amido, lower-amidoalkyl, hydrazino, lower-hydrazinoalkyl, azido, lower-azidoalkyl, (CH2)mNR6R7, (CH2)mOR6, (CH2)mSR6, (CH2)mC(0)R8, OC( 0)NR6R7, (CH2)n[N=X] or (CH2)mOC(0)[N=X] unsubstituted or substituted, wherein the substituent is a lower-alkyl, halogen, nitro, amino, lower-alkylamino, lower -halogenoalkyl, lower-hydroxyalkyl, lower-alkyl or lower-alkyl-lower-alkyl or OC(0)[N=X], or R2 and R3 together form a chain with 3 or 4 links where the mentioned links in the chain are chosen from the existing group

of CH, CH2, O, S, N or NR9;

R5 represents H, halogen, lower-halogenoalkyl, lower-alkyl, lower-alkoxy, lower-alkoxy lower-alkyl, lower-alkylthio lower-alkyl, lower-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, (CH2)n[N=X] or OC(0)[N=X] unsubstituted or substituted, wherein the substituent is a lower-alkyl, halogen, nitro, amino, lower-alkylamino, lower-halogenoalkyl, lower-hydroxyalkyl, lower-alkyl, or lower-alkyllower- alkyl; or (CH2)mOC(0)[N=X];

R6 and R7 independently represent H, a lower-alkyl, lower-hydroxyalkyl,

lower-alkylamino-lower-alkyl, lower-aminoalkyl, cycloalkyl, lower-cycloalkyl-alkyl, lower-alkoxy-lower-alkyl, aryl, lower-arylalkyl or lower-haloalkyl;

R 8 represents H, a lower-alkyl, lower-hydroxyalkyl, lower-alkylamino, lower-alkylamino lower-alkyl, lower-aminoalkyl, cycloalkyl, lower-cycloalkyl-alkyl, lower-alkenyl, lower-alkoxy, lower-alkoxy lower-alkyl , lower-haloalkyl, aryl or lower-arylalkyl;

R 8 represents H, a lower alkyl or lower haloalkyl;

R 10 represents H, a lower alkyl, lower haloalkyl or lower alkoxy;

Ri 6 represents OR21;

R 1 7 represents OR 6 or NR 6 R 7 ;

R18. R 19 and R 20 represent H;

R 21 represents H, a lower alkyl.CHO or C(O)(CH 2 )mCH 3 ;

m is an integer) from 0 to 6;

n is 1 or 2; and

q represents an integer from 0 to 2; and

[N=X] represents a 4 to 7 membered heterocyclic group and X

represents the chain necessary to complete said heterocyclic group and is selected from the group consisting of O, S, CH 2 , CH, N, NR 1 and COR 10 ; or a pharmaceutically acceptable salt thereof;

it being understood that "lower" when it denotes alkyl, alkenyl, alkynyl, alkoxy or alkylthio means up to 6 carbon atoms.

The invention further particularly relates to compounds of formula I as defined, in which Ri represents ethyl; R2 and R3 independently represent H, lower alkyl, halogen, halogen-lower alkyl or (CH2)mOR6. or R2 and R3 together form methylenedioxy or ethylenedioxy; and R4 and R5 independently represent H, lower alkyl, {CH2)mNR6R7 or (CH2)n[N=X] unsubstituted or substituted with lower alkyl, as well as pharmaceutically acceptable salts thereof. Preferably, R4 represents H or (CH2)mNR6R7 where R6 and R7 independently represent H or lower alkyl, and R5 represents H, lower alkyl or (CH2)n[N=X] substituted or unsubstituted with lower alkyl; as examples of [N=X] which is substituted or unsubstituted, piperidyl, morpholinyl, piperazinyl, imidazolyl and 4-methylpiperazinyl can be given.

More preferably, R 2 represents H or halogen, and preferably H, chlorine or fluorine; and R 3 represents H, lower alkyl, halogen, or OR 6 where R 6 represents H, lower alkyl or aryl-lower alkyl, and preferably H, fluorine, chlorine, methyl or methoxy. Correspondingly preferably, R2 and R3 together form methylenedioxy or ethylenedioxy.

More particularly, the invention concerns the products described below in the examples, especially the products corresponding to the following formulas: - 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino [3',4':6,7]-indolizine [ 1,2-6] quinoline-3,15(4H,13H)-dione - 5,12-diethyl-4,5-dihydro-5-hydroxy-1H-oxepino [3',4':6,7]- indolizino [1,2-b]quinoline-3,15(4H,13H)-dione - 8-ethyl-2,3,8,9-tetrahydro-8-hydroxy-10H,12H-[1,4]dioxino [ 2,3-g] oxepino [3\4':6,7] indolizino [1,2-b] quinoline-10,13 (15H)-dione - 10-benzyloxy-5-ethyl-4,5-dihydro- 5-hydroxy-1H-oxepino[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione - 5-ethyl-4,5-dihydro- 5,10,-dihydroxy-1H-oxepino [3',4':6,7]-indolizino [1,2-b]quinoline-3,15 (4H,13H)-dione -11-(dimethylamino)methyl- 5-Ethyph^,5-dihydro-5,10-di<y>drox<y>-1 H -oxepino [3\4':6,7]-indolizino [1,2-6] quinoline-3,15 (4H,13H)-dione - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino[3',4':6,7]indolizino[1,2 -b]quinoline-3,15(4H,13H)-dione , - 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-1 /-/-o xepino[3',4':6,7]indolizino [1,2-b]quinoline-3,15(4H,13H)-dione - 5-ethyl-9,10-difluoro-4,5-dihydro-5 -hydroxy-1H-oxepino[3',4,:6)7]indolizino[1l2-b] quinoline-3,15(4H,13H)-dione - 7-ethyl-7,8-dihydro-7-hydroxy- 9W,11H-[1,3]dioxolo[4,5-g]oxepino[3',4':6,7]indolizino[1,2-b]quinoline-9,12[14H]-dione - 9- chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-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-1H-oxepino [3',4':6,7] indolizino [1, 2-b] quinoline-3 ,15{4H, 13H)-dione - 9,11-dichloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino[3',4':6,7]indolizino[1,2- b]quinoline-3,15(4H,13H)-di ion - 5-ethyl-9-flouro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3',4':6 ,7] indolizino [1,2-b]quinoline-3,15(4H,13H)-dione - 5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-1 H -oxepino [3', 4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione - 10-chloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino [3',4':6,7]indolizino[1,2-b]quinoline-3,15{4H,13H)-dione - 10-chloro-5-ethyl-9-f luoro-4,5-dihydro-5-hydroxy-1 H -oxepino [3',4':6,7]indolizino [1, 2- b ]quinoline-3,15(4H,13H)-dione - 5, 12-diethyl-4,5-dihydro-5,10-dihydroxy-11-morpholino methyl-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15 ( 4H,13H)-dione - 5,12-diethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino[3,,4':6,7]indolizino[1,2 -b]quinoline-3,15{4H,13H)-dione - 5-ethyl-4,5-dihydro-5-hydroxy-12-methyl-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-(4-methyl piperazinomethyl)

-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-morpholinomethyl H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline- 3,15(4H,13H)-dione - 5-ethyl-4,5-dihydro-5-hydroxy-12-(4-methyl piperazinomethyl)-1H-oxepino[3',4':6,7]indolizino [1,2-b]quinoline-3,15(4H,13H)-dione - 5-ethyl-4,5-dihydro-5-hydroxy-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-12-morpholinomethyl-1H-oxepinol[3',4 ':6,7]indolizino [1,2-b]quinoline-3,15(4H,13H)-dione - 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 - 5-ethyl-10-fluoro-4,5- dihydro-5-hydroxy-12-morpholinomethyl-1H-oxepino[3,,4':6,7]tndolizino[1,2-b]quinoline-3,15(4H,13H)-dione - 5-ethyl- 9-Fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-{4-methylpiperazinomethyl)-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-morpholinomethyl-1H-oxepino[3',4':6,7 ]indole izino[1,2-b]quinoline-3,15(4H,13H)-dione - 5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-12-piperidinomethyl-1 H- oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione - 8-ethyl-2,3,8,9-tetrahydro-8-hydroxy -16-(4-methyl piperazinomethyl)-10H,12H-[1,4] dioxino [2,3-g] oxepino [3',4':6,7] indolizino [1,2-b] quinoline-10 ,13[15H]-dione - 9-chloro-5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-12-morpholinomethyl-1H-oxepino[3,,4':6,7]indolizino [1,2-b]quinoltene-3,15(4H,13H)-dione

or a pharmaceutically acceptable salt thereof.

Particularly preferred is the compound -5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-1H-oxepino[3,,4,:6I7]indolizino[1,2-b] quinoline-3,15 (4H,13H)-dione; or a pharmaceutically acceptable salt thereof.

The invention relates more particularly to compounds of formula II as defined above, in which F?2 and R3 independently represent H, lower alkyl, halogen, halogen-lower alkyl or (CH2)mOR6, or R2 and R3 together form methylenedioxy or ethylenedioxy; R4 and R5 independently represent H, lower alkyl, (CH2)mNR6R7, or (CH2)n[N=X] unsubstituted or substituted with lower alkyl; R 20 represents H and R 17 represents OR 6 , where R 6 represents H or lower alkyl, or NR 6 R 7 where R 6 and R 7 , independently, represent H, lower alkyl, aryl or aryl-lower alkyl, as well as pharmaceutically acceptable salts thereof. Preferably, R4 represents H or (CH2)mNR6R7. wherein R 6 and R 7 independently represent H or lower alkyl; R 5 represents H, lower alkyl or (CH 2 ) n [N=X] unsubstituted or substituted with lower alkyl; and R 17 represents OR 6 where R 6 represents H or lower alkyl; or a pharmaceutically acceptable salt thereof. Examples of [N=X] substituted or unsubstituted are the residues piperidyl, morpholinyl, piperazinyl, imidazolyl and 4-methylpiperazinyl.

More preferably R 2 represents H or halogen and preferably H, chlorine or fluorine; R 3 represents H, lower alkyl, halogen or OR 6 where R 6 represents H, lower alkyl or aryl-lower alkyl and preferably H, fluorine, chlorine, methyl or methoxy. More preferably, R2 and R3 together also form methylenedioxy or ethylenedioxy.

More particularly, the invention concerns the products described below in the examples, especially the products with the following formulas: - tert-butyl-p-ethyl-p-hydroxy-y-(8-hydroxymethyl-9-oxo (11H)-indolizino-[1, 2 - b] quinolin-7-yl)-propionate - ethyl-p-ethyl-p-hydroxy-y-(8-hydroxymethyl-9-oxo (11 H)-indolizino-[1,2-6]quinoltn-7- yl)-propionate - p-ethyl-p-hydroxy-γ-(8-hydroxymethyl-9-oxo (11H)-indolizino-[1,2-6] quinolin-7-yl)-propionic acid - methyl-p-ethyl -p-hydroxy-γ-{8-hydroxymethyl-9-oxo (11 H )-indolizino-[1,2-6] quinolin-7-yl)-propionate - ethyl-p-ethyl-α,α-difluoro- p-hydroxy-y-(8-hydroxymethyl-9-oxo (11H)-indolizino-[1,2-6] quinolin-7-yl)-propionate - ethyl p-ethyl-p-hydroxy-y-(8 -hydroxymethyl-9-oxo (11 H)-indolizino-[1,2-6]quinolin-7-yl)-propionate - tert-butyl-p-ethyl-p-hydroxy-y-(8-hydroxymethyl-9- oxo (11H)-indolizino-[1,2-6]quinolin-7-yl)-propionate - p-ethyl-y-(12-ethyl-8-hydroxymethyl-9-oxo (11H)-indolizino-[1, 2-6] quinolin-7-yl)-p-hydroxy-propionic acid - y-(12-benzyloxy-8-hydroxymethyl-9-ozo (11H) -indolizino[1,2-6]quinolin-7-yl)-P-ethyl-p-hydroxy-propionic acid (E)

or a pharmaceutically acceptable salt thereof.

As used herein, as previously mentioned, lower in connection with alkyl, alkylthio and alkoxy means saturated, aliphatic hydrocarbon groups, linear or branched, having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methylthio, ethylthio, methoxy and ethoxy. In the case of alkenyl or alkynyl, these denote lower groups having 2 to 6 carbon atoms and one or more double or triple bonds, such as vinyl, allyl, isopropenyl, pentenyl, hexanyl, propenyl, ethynyl, propynyl and butynyl. The term cycloalkyl means a cyclic group with 3 to 7 carbon atoms, such as the groups cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term aryl means a hydrocarbon compound which is mono-, di- or tricyclic with at least one aromatic ring, each ring containing a maximum of 7 members, such as phenyl, naphthyl, anthracyl, biphenyl or indenyl. The term halogen means chlorine, bromine, iodine or fluorine. The residues corresponding to the expressions halogen-lower alkyl, cyano-lower alkyl, nitro-lower alkyl, amido-lower alkyl, hydrazino-lower alkyl, azido-lower alkyl, aryl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, and lower alkyl-sulfonyl-lower alkyl are respectively substituted with one to three of the groups halogen, cyano, nitro, amido, hydrazino, azido, aryl, hydroxy, lower alkoxy, lower alkylthio or lower sulfonyl. The remainder lower alkylamino may contain one or two lower alkyl groups, and represents, for example, NHCH3, NHCH2CH3, N(CH3)2 or N(CH3)(CH2CH3). Examples of [N=X] include the groups piperidinyl, morpholinyl, piperizinyl and imidazolyl.

In camptothecin, the carbon atom with the hydroxy function on the 3-hydroxyactone or the B-hydroxycarboxylate group of the compounds according to the present invention is asymmetric. Accordingly, the compounds according to the present invention have two possible enantiomeric configurations, i.e. R and S configurations. The present invention encompasses the two enantiomer configurations and all combinations of these configurations, also RS-racemic mixtures. For the sake of simplicity, it should be understood that when no particular configuration is indicated in the structural formulas, both the two enantiomer configurations and mixtures thereof are represented.

The invention further comprises methods for the preparation of the compounds of the general formulas I and II, either by starting from camptothecin or substituted camptothecin, or by total chemical synthesis.

The invention thus relates to a method for producing compounds with formulas I and II according to the invention from camptothecin or substituted camptothecin, characterized in that

- the ct-hydroxylactone of camptothecin of the general formula

in which R 1 , R 2 , R 3 , R 4 , R 5 and R 20 have the meanings given above, is reduced to give an α-hydroxylactol of the general formula A

in which R 1 , R 2 , R 3 , R 4 , R 5 and R 20 have the meanings given above,

- in the thus formed compound A, the carbon-carbon bond that binds the neighboring carbinols is broken by treatment with a suitable oxidizing agent, which gives a compound of formula B

in which R 1 , R 2 , R 3 , R 4 , R 5 and R 20 have the meanings given above

- which is then treated with a functional alkylating agent, and the functional formyl group in formula B is broken, giving the B-hydroxy ester of the general formula C

in which R 1 , R 2 , R 3 , R 4 , R 5 , R 18 . R 19 and R 20 have the meanings given above and R 17 represents OR 6 and R 6 represents lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, or aryl or aryl-lower alkyl; - the compound of the general formula C is cyclized, giving the p-hydroxylactone compound of the general formula D in which Ri, R2, R3, R4, R5, R18. R19 and R20 have the meanings given above, - the lactone of general formula D is opened, giving the compound of formula E

in which R 1 , R 2 , R 3 , R 4 , R 5 , R 17 , R 18 , R 19 and R 20 have the meanings given above; R 16 represents OR 21 where R 21 represents H or lower alkyl; and R 17 represents OR 6 or NHR 6 and R 6 represents H, lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, or aryl or aryl-lower alkyl.

Certain compounds of formula E can also be obtained by hydrolyzing the ester function of the corresponding compounds of formula C. Compounds of the general formula E where R16 and/or R„ independently represent a hydroxy residue can be esterified or amidated under classical conditions known by those skilled in the art, giving esters or amides of formula E.

In the above process, the groups R 1 , R 2 , R 3 and R 4 can, if necessary, be protected according to known protection methods (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)). During this method, the reduction takes place using a reducing agent in a suitable solvent such as e.g. sodium borohydride in methanol. The step corresponding to the formation of compound B from compound A is carried out under oxidizing conditions, such as e.g. with lead tetraacetate, periodic acid or sodium periodate in a suitable solvent such as e.g. acetic acid. The treatment with a functionalized alkylating agent can be carried out using a metal derivative, e.g. lithium or zinc, or with a carboxylic acid ester in an anhydrous, aprotic solvent such as e.g. tetrahydrofuran. The lactonization step to obtain compound D from compound C is generally carried out under acidic conditions, e.g. by treatment with trifluoroacetic acid or hydrochloride gas dissolved in an anhydrous solvent such as dichloromethane or dioxane. The opening of the lactone ring in compound D to obtain compound E can e.g. is carried out by hydrolysis under alkaline conditions, followed by neutralization.

Examples of substituted campothecins that can be used as starting materials can be found in US Patent 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, PCT Applications Nos. US91/08028, US94/06451, US90/05172, US92/04611, US93/10987, US91/09598, EP94/03058 and EP95/00393 and European patent applications no. 325 247, 495 432, 321 122 and 540 099.

The invention also relates to a method for producing the compounds with formulas I and II, characterized in that

- a compound of the general formula M

in which R 1 , R 18 and R 19 have the meanings given above and R 20 represents hydrogen or halogen, is coupled with a 2-halo-3-quinoline-methanol of the general formula N in which R 2 , R 3 , R 4 and R 5 have the meanings given above and X represents halogen, giving a compound of formula O in which R-|, R 2 , R 3 , R 4 , R 5 , R 18 . R19. R 20 and X have the meanings given above; - the compound of the general formula O is then cyclized, giving the compound of the general formula D as indicated above.

In the above process, the groups R 1 , R 2 , R 3 and R 4 can, if necessary, be protected according to known protection methods (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)). The formation of compound O from the compounds of the general formulas M and N is carried out by a process known to those skilled in the art, termed the Mitsunobu reaction (see Mitsunobu, O. and coil. Synthesis, p.1 (1981)). It consists in replacing the hydroxyl function in compound N with a nucleophile such as compound M, or a deprotonated derivative thereof, by treatment with a phosphine, e.g. triphenylphosphine, and an azodicarboxylate derivative, e.g. diethyl azodicarboxylate, in an aprotic solvent such as tetrahydrofuran or N,M-dimethylformamide. Cyclization of compound O preferably takes place in the presence of a palladium catalyst (e.g. palladium diacetate) under basic conditions (e.g. provided by alkaline acetate optionally combined with a phase transfer agent such as 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 the general formula M are new. They can be produced according to a method characterized by

- the carbonyl group in the pyridine with the general formula

in which R 1 and R 20 have the meanings given above and R 22 represents halogen or lower alkoxy, is protected by an acetal function, giving a compound of the general formula F in which R 1 , R 20 and R 22 have the meanings given above and the groups Z and Z' independently represents lower alkyl or together form a saturated hydrocarbon chain of 2 to 4 carbon atoms; - a hydroxymethyl function is introduced into the compound of the general formula F, which gives a compound of the general formula G

in which Ri, R20. R 22 > 2 and Z' have the meanings given above,

- then the alcohol function in the compound with the general formula G is protected, which gives a compound with the general formula H

in which Ri, R20. R22 > 2 and Z' have the meanings given above and R23 represents a protecting group for the alcohol group, - the acetal of the compound of the general formula H is deprotected, giving the compound of the general formula I'

in which Ri, R20. R22 and R23 have the meanings given above,

- the compound of formula I' is treated with a functionalized alkylating agent, which gives a p-hydroxy ester of the general formula J

in which Ri, R20. R 22 and R 23 have the meanings given above, Ri 8 and Ri 9 are as defined in the general formula II and R 17 is OR 6 where R 1 is lower alkyl, cycloalkyl, lower cycloalkylalkyl, lower alkenyl, lower alkoxy-lower alkyl or aryl or lower arylalkyl; - the protective group R23 is cleaved from the compound of the general formula J, which gives a compound of the general formula K in which Ri, R18. R19. R20 and R22 have the meanings given above and R17 represents OR6 and R6 represents lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, lower alkenyl, lower alkoxy-lower alkyl, or aryl or aryl-lower alkyl, - the compound of the general formula K is cyclized, giving a compound of the general formula L in which R-], R18, R19, R20 and R22 have the meanings given above, and finally - the residue R22 in the compound L is converted to carbonyl, giving a compound of the general formula M

in which R 1 , R 18 , R 19 and R 20 have the meanings given above.

The carbonyl function of a 4-acyl-2-halopyridine (obtained for example according to Lamattina, J.L. J. Heterocydic Chem. 20, p. 553 (1983)) is preferably protected with an acetal group, preferably a cyclic acetal, according to classical conditions known to those skilled in the art (Green, T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)). When R22 is chlorine or fluorine, the intermediates thus obtained are treated with a sodium alcoholate or potassium alcoholate in an aprotic solvent (e.g. acetonitrile) or in the alcohol from which the alcoholate is derived, at a temperature between 0° and 100°C, giving a compound of formula F. The latter can be lithiated in the 3-position by treatment with aryl- or alkyl-lithium (e.g. mesityl-lithium) in an etherified solvent such as tetrahydrofuran at a temperature between -100°C and 0° C. A formylating electrophile such as N,N-dimethylformamide is added to the lithiated intermediate thus obtained, and the resulting aldehyde is treated, after hydrolysis, with a reducing agent such as sodium borohydride to give the compound of general formula G. The protection of the alcohol function in compound G is carried out according to classical methods known to those skilled in the art, giving a compound of the general formula H. Examples of protecting groups for the alcohol o includes those that form ethers [e.g. methyl, methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, benzyloxymethyl, t-butyl and benzyl (optionally substituted) and esters (eg formate, acetate and isobutyrate). For other examples of other primary hydroxyl protecting groups, see Greene, T., Protective Groups in Organic Synthesis, 10-86 (John Wiley & Sons, 1981). The deprotection of the compounds of general formula H to give the compound of general formula I1 is carried out under selective conditions which maintain the integrity of the R23 residue, e.g. by treatment under acidic conditions (e.g. with trifluoroacetic acid). The selective conditions for protection and deprotection of the functional groups are well known to those skilled in the art (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)). The treatment of the compound I' with a functional alkylating agent resulting in the p-hydroxy ester of the general formula J can be carried out by means of a lithium enolate or a zinc derivative of a carboxylic acid ester in an aprotic, anhydrous solvent, e.g. tetrahydrofuran. The protecting group F?23 in the compound of the general formula J is cleaved, giving the compound of the general formula K, under cleaving conditions known to those skilled in the art. When e.g. R23 is a benzyl group, an alcoholic solution of the compound of the general formula J plus a palladium catalyst can be subjected to a hydrogen atmosphere of 0.5 to 10 bar. The cyclization of the thus obtained compound of the general formula K can be subjected to acidic conditions (e.g. treatment with trifluoroacetic acid or hydrochloride gas dissolved in an anhydrous solvent such as dichloromethane or dioxane), giving a B-hydroxylactone ring with 7 joint as in the compound with the general formula L. Compounds with the general formula L can be converted to the pyridones with the general formula M by e.g. hot hydrochloric acid treatment or with a trimethylsilyl iodide.

2-Halo-3-quinoline-methanol of the general formula N can be obtained from the acetanilides of the general formula P

in which R 2 , R 3 and R 4 have the meanings given in the compounds of the general formulas I and II. In the procedures below, the groups R 2 , R 3 and R 4 may be protected, if necessary, according to classical protection methods (Greene, T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)).

The compounds of formula N can be obtained according to the following methods: the anilines of formula P are N-acetylated by treatment with an acetylating agent such as e.g. acetic anhydride. The acetanilides thus obtained are treated at a temperature between 50° C and 100° C, preferably 75° C, with a reagent known to those skilled in the art under the name Vilsmeyer reagent (obtained by the action of phosphoryloxychloride on N.N-dimethylformamide at a temperature between 0 °C and 10°C), giving the corresponding 2-chloro-3-quinolinecarbaldehyde (see for example Meth-Cohn, et al., J. Chem. Soc, Perkin Trans, /p.1520 (1981); Meth-Cohn , et al. J. Chem. Soc, Perkin Trans. I p. 2509 (1981); and Nakasimhan et al. J. Am. Chem. Soc, 112, p. 4431 (1990)). The chlorine in position 2 in 2-chloro-3-quinoline carbaldehydes can be replaced by iodine or bromine by heating the product in an inert solvent such as acetonitrile in the presence of an iodine or bromine salt (e.g. sodium iodide or tetrabutylammonium bromide) . Trace amounts of acid such as concentrated hydrochloric acid may be necessary to catalyze this conversion. The 2-halo-3-quinolinecarbaldehydes are readily reduced to the corresponding 2-halo-3-quinolinemethanols of the general formula N, under classical conditions known to those skilled in the art, such as treatment in an alcoholic solvent (e.g. methanol) with sodium borohydride at a temperature between 0° C and 40° C.

The compounds of formula N can then be obtained according to the following method: the anilines of formula P are acylated by reaction with a nitrile (such as chloroacetonitrile or propionitrile) in the presence of boron trichloride and another Lewis acid such as aluminum trichloride, titanium tetrachloride or diethyl aluminum chloride in an aprotic solvent or a mixture of aprotic solvents, followed by hydrolysis (cf. Sugasawa, T, et al. J. Am. Chem. Soc. 100, p. 4842

(1978)). The intermediate thus obtained is then treated with ethylmalonyl chloride in an aprotic solvent such as acetonitrile in the presence of a base such as triethylamine, and then treated with an alkaline alcoholate, e.g. sodium methylate in methanol, which gives an ethyl 2-hydroxy-3-quinoline carboxylate substituted in position 4. The latter is converted to an ethyl 2-chloro-3-quinoline carboxylate by treatment with a phosphoryloxychloride. When position 4 in the quinoline carries a chloromethyl group, a nucleophilic substitution can be carried out by treatment with a secondary amine such as e.g. dimethylamine, N-methylpiperazine, morpholine or piperidine. The ethyl 2-chloro-3-quinoline carboxylate is then reduced with diisobutylaluminum hydride in an aprotic solvent such as dichloromethane, yielding 2-chloro-3-quinoline methanol of the general formula N. The analogues of the intermediate (N) compounds are described in the literature and in particular in PCT application 95/05427.

The invention further relates to new industrial products and in particular new industrial products for the production of products of formula I and II, specifically the products M as described above.

Certain compounds according to the invention can be prepared in the form of pharmaceutically acceptable salts according to usual methods. The acceptable salts include, by way of example and not limitation, the addition salts with inorganic acids such as chlorohydrate, sulfate, phosphate, diphosphate, bromohydrate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p -toluenesulfonate, pamoate, salicylate, oxalate and stearate. Salts formed with bases such as sodium or potassium hydroxide are also covered by the present invention where they can be used. For other examples of pharmaceutically acceptable salts, see "Pharmaceutical Salts", J. Pharm. Pollock. 66:1 (1977).

The compounds according to the present invention have interesting pharmacological properties. This is because the compounds according to the present invention have an inhibitory effect on topoisomerase I and/or II and anti-tumor activity. Current technology indicates that the compounds according to the invention have an antiparasitic and/or antiviral activity. The compounds according to the invention can thus be used for various therapeutic applications.

The compounds can inhibit topoisomerase, for example type I and/or II, in a patient, e.g. a mammal such as a human, by administering to the patient a therapeutically effective amount of a compound of formula (I) or formula (II).

The compounds according to the invention also have anti-tumor activity. They can be used for the treatment of tumours, e.g. tumors expressing topoisomerase, in a patient by administering a therapeutically effective amount of a compound of formula (I) or formula (II). Some examples of tumors or cancers include cancer of the esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lungs, colon, breast, cervix, endometrium, ovaries, prostate, testes, bladder, kidneys, liver, pancreas -gland, bone, connective tissue, skin, eye, brain and central nervous system, as well as thyroid cancer, leukaemia, Hodgkin's disease, non-Hodgkin's lymphomas, multiple melanomas and others.

They can also be used to treat parasitic infections by inhibiting

f

hemoflagellates {eg in trypanosoma or leishmania infections) or by inhibiting plasmodium (such as in malaria), but also for the treatment of viral infections or diseases.

These properties make the products of formula I and II suitable for pharmaceutical use. The present invention also includes the products of formula I and II as defined above, as well as pharmaceutically acceptable addition salts with organic acids or mineral acids of the products of formula I and II, as drugs, as well as pharmaceutical preparations containing as an active ingredient one of the drugs defined above .

The invention thus relates to pharmaceutical preparations comprising a compound according to the invention or an addition salt thereof with a pharmaceutically acceptable acid, together with a pharmaceutically acceptable carrier selected according to the method of administration (e.g. oral, intravenous, intraperitoneal, intramuscular, transdermal or subcutaneous). The pharmaceutical preparation (eg therapeutic) can be in the form of a solid, a liquid, liposome or lipid micelle.

The pharmaceutical preparation can be in the form of a solid substance, e.g. powders, pills, granules, tablets, liposomes, capsules or suppositories. A pill, tablet or capsule can be coated with a substance that can protect the preparation from the action of the stomach acid or enzymes in the stomach of an individual for a sufficient time for the preparation to pass undigested to the small intestine. The connection can thus be administered locally, e.g. when placed next to the tumor. The compound can also be administered by delayed release (eg, a delayed release formulation or an infusion pump). A suitable solid carrier can e.g. be calcium phosphate, magnesium stearate, magnesium carbonate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose,

sodium carboxymethylcellulose, polyvinylpyrrolidine and wax. The pharmaceutical preparation containing a compound according to the invention can also

t

is presented in the form of a liquid, e.g. solutions, emulsions, suspensions or one with extended release. Suitable liquid carriers can e.g. be water, organic solvent media such as glycerol or glycols such as polyethylene glycol, as well as mixtures thereof in various proportions, in water.

The invention also includes the use of the products of formula I and II as defined above, for the preparation of a drug for inhibiting topoisomerase, and more particularly type I and type II isomerase, a drug for the treatment of tumors, a drug for the treatment of parasitic infections and a drug for the treatment of viral infections or diseases.

The dose of a compound of the present invention for the treatment of the diseases or disorders indicated above varies according to the method of administration, the age and body weight of the individual being treated and the condition thereof, and is ultimately determined by the attending physician or veterinarian, and is herein designated " therapeutically effective amount".

In the following experimental part, an illustration of the pharmacological properties of the compounds is given.

When the technical and scientific terms used here are not specifically defined, they have the same meaning as is normally understood by an ordinary specialist in the area covered by the invention. All publications, patent applications, patents and other literature listed here are hereby incorporated by reference.

The following examples are given to illustrate the above methods and should not be considered limiting of the scope of the present invention.

EXPERIMENTAL SECTION:

Example 1: tert-Butyl-p-ethyl-p-hydroxy-y-(8-hydroxymethyl-9-oxo- (11H)-indolizino-[1,2-b]quinolin-7-yl)-propionate

1. a. 4-ethyl-3,4-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14 (4H,12H)-one

Sodium borohydride (14 g, 370 mmol) is added portionwise to a suspension of (S)-(+}-camptothecin (14 g, 40 mmol, which can be obtained from various commercial sources such as Aldrich Chemical Co. (Milwaukee, Wl)) , in methanol (750 mL) and the resulting mixture is slowly heated to 55° C. to obtain a clear solution which is then stirred for 16 hours at ambient temperature. The solvent is then evaporated under reduced pressure, the residue is taken up in water (250 mL). , neutralized by the addition of acetic acid (21 ml) and allowed to rest for 2 hours at 4° C. The resulting suspension is filtered and washed successively with cold water, acetone and diethyl ether, which, after drying under reduced pressure, gives the desired the compound in the form of a white solid,

sm.p. 280°C.

1.b. 8-formyloxymethyl-7-propionylindolizino[1,2-b]quinolin-9(11H)-one

A solution of sodium periodate (14 g, 65 mmol) in water (140 mL) is added dropwise to a suspension of 4-ethyl-3,4-dihydroxy-1H-pyrano[3',4':6,7]- indolizino[1,2-b]quinolin-14(4H,12H)-one (13.4 g, 38 mmol) in glacial acetic acid (720 mL) and the resulting solution is stirred for one hour at ambient temperature. The reaction mixture is then poured into an ice/water mixture (650 ml) and the resulting suspension is stirred for half an hour and then filtered and washed successively with water, isopropyl alcohol and diethyl ether, which, after drying under reduced pressure, gives the desired compound (11.5 g) in the form of a pale yellow solid, m.p. > 200°C (d).

1x. tert-Butyl l-p-ethyl l-p-hydroxy-γ-(8-hydroxy methyl-9-oxo(11 H)-indolizino-[1,2-b]quinolin-7-yl)-propionate

A suspension of zinc (6.5 g, 100 mmol) stirred with a magnetic stirrer in anhydrous diethyl ether (50 mL) under argon is activated by dropwise addition of chlorotrimethylsilane (0.75 mL, 5.7 mmol). The mixture is stirred for a further 15 minutes at ambient temperature and heated to reflux. The heating bath is then removed and tert-butyl bromoacetate (15 mL, 100 mmol) is added dropwise at a rate that ensures maintenance of reflux. The external heating is again applied and continued for another hour. The etherified solution resulting from the Reformatsky reagent is allowed to cool to ambient temperature and is then transferred by cannula to a suspension of 8-formyloxymethyl-7-propionylindolizino[1,2-b]quinolin-9(11H)-one (1.6 g, 4.7 mmol) in anhydrous tetrahydrofuran (40 mL) under argon. The reaction mixture is stirred under reflux for one hour, then allowed to cool to ambient temperature, the reaction is quenched by the addition of saturated ammonium chloride (100 mL) and the mixture is extracted with chloroform (3 x 100 mL). The combined chloroform extracts are dried over sodium sulfate, evaporated, and the residue is purified by column chromatography on silica gel (1-2% MeOH/CH2Cl2) to give 0.64 g of the desired compound (31%) as a pale yellow, solid, m.p. 146-149°C.

NMR-<1>H (CDCl 3 ): 0.93 (t, 3H); 1.37 (s, 9H); 1.99 (m, 2H); 2.97 (dd, 2H);

3.5 (see, 1H); 5.10 (s, 2H); 5.24 (s, 2H); 7.40 (s, 1H); 7.59 (t, 1H); 7.83 (t, 1H); 7.90 (d, 1H); 8.20 (d, 1H); 8.34 (p, 1H).

NMR-C<13> (CDCl3): 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 2: Ethyl-B-et<y>l-p-h<y>drox<y>-y-(8-h<y>drox<y>methyl-9-oxo(11H)-indolizino-[1,2-b ]quinolin-7-yl)-propionate

A suspension of zinc (500 mg, 7.64 mmol) and 8-formyloxymethyl-7-propionylindolizino[1,2-b]quinolin-9(11H)-one (400 mg, 1.15 mmol) in anhydrous tetrahydrofuran (20 ml) containing 10 mg of hydroquinone is heated to reflux under argon. The heat bath is removed, and an exothermic reaction started by adding a drop of ethyl bromoacetate and a small crystal of iodine. Reflux is maintained by dropwise addition of ethyl bromoacetate (500 µl, 4.48 mmol) and the reaction mixture is again heated under reflux for one hour. After cooling to ambient temperature, the reaction is stopped by the addition of saturated ammonium chloride (10 ml) and methanol (30 ml). The resulting mixture is stirred for 5 minutes and then filtered and evaporated. The residue is dissolved in dichloromethane (30 ml), washed with water and dried over sodium sulfate. This is followed by removal of the solvent and purification by column chromatography (SiO 2 , CH 2 Cl 2 /MeOH 98/2), which gives 230 mg (49%) of the desired compound as a yellow solid, m.p. 157-161°C.

NMR-<1>H (CDCl3 ): 0.93 (t, 3H); 1.20 (t, 3H); 2.02 (rn, 2H); 3.07 (dd, 2H);

4.11 (q, 2H); 4.9 (see, 1H); 5.08 (s, 2H); 5.23 (s, 2H); 7.45 (s, 1H); 7.62 (t, 1H); 7.80 <t.1H); 7.90 (d, 1H); 8.22 (d, 1H); 8.36 (p.1H).

NMR-C<13> (CDCl3): 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-1H-oxepino[3',4':6,7]-indolizine[1,2-b]quinoline-3,15 (4H,13H) -dion

Tert-butyl-p-ethyl-p-hydroxy-γ-(8-hydroxymethyl-9-oxo(11H)-indolizino-[1,2-b]quinolin-7-yl)propionate (1.45 g, 3 .32 mmol) is dissolved in anhydrous dichloromethane (25 ml) and treated with a solution saturated with hydrogen chloride in dichloromethane (100 ml). The resulting mixture is kept at -20°C for 16 hours. The precipitate is filtered, washed with methanol and dried under reduced pressure to give 662 mg (55%) of the desired compound as a yellow solid, m.p. > 300° C.

NMR-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, 1H); 7.73 (t, 1H); 7.90 (t, 1H); 8.16 (t, 2H); 8.71 (p, 1H). NMR-C<1>3 (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: p-ethyl-p-hydroxy-γ-(8-hydroxymethyl-9-oxo (11H)-indolizino-[1,2-b]quinolin-7-yl)-propionic acid

An aqueous solution of potassium hydroxide (0.1 N, 30 mL) is added to 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino[3',4':6,7]-indolizino[1, 2-b]quinoline-

3,15(4H,13H)-dione (500 mg, 1.38 mmol) and the resulting suspension is stirred at ambient temperature for 16 h, yielding a nearly clear solution which is filtered. The filtrate is acidified to pH 3.5 with 1 N hydrochloric acid, and the precipitated yellow substance is recovered by filtration, washed with water and acetone and then dried under reduced pressure. 415 mg (79%) of the desired compound is obtained in the form of the monohydrate, m.p. 165-167°C.

NMR-1 H (DMSO): 0.82 (t, 3H); 2.10 (rn, 2H); 2.83 (d, 2H); 3.12 (d, 2H);

3.25 (see, 1H); 4.81 (s, 2H); 5.26 (s, 2H); 5.76 (see, 1H); 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 (see, 1H).

NMR-C<13> (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.

Example 5: Methyl-B-ethyl-B-hydroxy-{8-hydroxymethyl-9-oxo (11H)-indolizino-[1,2-b] quinothin-7-yl)-propionate

S-ethylM.S-dihydro-S-hydroxy-IH-oxepino^^^ejJ-indolizinoII^-bJquinoline-S.IS (4H,13H)-dione (180 mg, 0.5 mmol), in suspension in methanol ( 50 ml) is treated with dry 6N hydrogen chloride in methanol (0.5 ml) and kept under reflux until dissolution is complete (4 hours). The volatile compounds are evaporated and the residue is dissolved in dichloromethane (50 mL), washed with dilute sodium hydroxide (0.05 N, 15 mL) and brine (15 mL). The organic fraction is dried over sodium sulfate and evaporated. The remaining solid is purified by column chromatography on silica gel (MeOH in 3% / CH 2 Cl 2 ) and the purified product is recovered from diethyl ether, filtered and dried to give 120 mg (58%) of the desired compound as a pale yellow, solid, m.p. 163-166°C.

NMR-<1>H (CDCl3 ): 0.93 (t, 3H); 2.2 (rn, 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 (p, 1H).

NMR-C 3 (CDCl 3 ): 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-6-ethyl-α,α-difluoro-B-hydroxy[8-hydroxymethyl-9-oxo (11H)-indolizino-[1,2-b]quinolin-7-yl)-propionate

To a suspension of zinc (1.25 g, 17.2 mmol) in anhydrous refluxing THF (40 mL) is added approximately half of the total amount of ethyl bromodifluoroacetate (1.8 mL, 14 mmol), 8-formyloxymethyl -7-propionylindolizino[1,2-b]quinolin-9 (11H)-one (2.0 g, 5.75 mmol, as obtained in Example 1.b.) in suspension in anhydrous THF (10 ml), and then the remaining portion of the ethyl bromodifluoroacetate. The reaction mixture is kept under reflux for another half hour. After cooling to ambient temperature, the reaction is quenched by the addition of 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 (SiO2, CH2CI2 / MeOH:98/2), giving 664 mg (26%) of the product as a yellow solid, m.p. . 208-209°C.

NMR-<1>H (CDCl3 ): 0.91 (t, 3H); 1.38 (t, 3H); 2.32 (m, 2H); 4.8 (see, 1H); 4.38 (q, 2H); 5.09 (d, 2H); 5.13 (dd, 2H); 7.42 (s, 1H); 7.55 (t, 1H); 7.72 (t, 1H); 7.79 (d, 1H); 8.08 (d, 1H); 8.22 (p, 1H)

NMR-C<13 > (CDCl3 ): 6.97; 13.93; 28.63; 50.18; 56.27; 63.15; 77.20; 81.96 (h); 101.27; 116.40 (h); 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 (h).

IR (KBr): 1124; 1308; 1591; 1647; 1748.

Example 7: Ethyl-B-ethyl-B-hydroxy^-{8-hydroxymethylN9-oxo{11tf)-indolizino-[1,2-b]quinolin-7-yl)-propionate

A suspension of zinc (1.25 g, 19.1 mmol), 8-methyl-7-propionylindolizino[1,2-b]quinolin-9-(11H)-one (500 mg, 1.43 mmol, as obtained according to Kingsburry, W. D., Tetrahedron Lett. 29:6847 (1988)) and silver acetate (250 mg, 1.50 mmol) in anhydrous tetrahydrofuran (10 mL) are stirred at ambient temperature under an atmosphere of argon. After 10 minutes, the reaction mixture is activated by the dropwise addition of a molar solution of chlorodiethyl aluminum (10 mL, 10 mmol), and then ethyl bromoacetate (1.25 mL, 11.3 mmol) is added dropwise and the resulting mixture is left to react for another 5 hours. The reaction is stopped by the successive addition of ethyl alcohol (10 ml) and a solution saturated with potassium and sodium tartrate (10 ml). The resulting mixture is stirred for an additional hour, filtered and concentrated under reduced pressure. The residue is taken up in dichloromethane (30 ml), washed with water, dried, concentrated and purified by column chromatography (SiO 2 , CH 2 Cl 2 / MeOH:98/2), which gives 93 mg (15%) of the desired product in the form of a pale yellow solid, m.p. 185-188°C.

NMR-<1>H (CDCl3 ): 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 (see, 1H); 5.25 (s, 2H); 7.65 (t, 1H); 7.67 (s, 1H); 7.80 (t, 1H); 7.90 (d, 1H); 8.22 (d, 1H); 8.34 (p, 1H).

NMR-C<13> (CDCl3): 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-p-ethyl-p-hydroxy-γ-(8-hydroxymethyl-9-oxo-(11H)-indolizino-[1,2-/]quinolin-7-yl)-propionate

Acetic anhydride (70 µl, 0.7 mmol) is added dropwise to a solution of tert-butyl-/?-ethyl-B-hydroxy-γ-{8-hydroxymethyl-9-oxo(11 H )-indolizino-[1, 2-b]-quinolin-7-yl)-propionate (200 mg, 0.46 mmol) and triethylamine (140 µl, 1 mmol) in dichloromethane (5 mL), and the resulting mixture is stirred at ambient temperature for 21 h. The volatile components are evaporated, and the residue is purified by column chromatography on silica gel

(1-2% MeOH / CH2CI2), giving 152 mg of the desired compound as a yellow solid, m.p. 195-196°C.

NMR-<1>H (CDCl 3 ): 0.88 (t, 3H); 1.32 (s, 9H); 1.93 (m, 2H); 2.07 (s, 3H);

2.97 (dd, 2H); 4.8 (see, 1H); 5.28 (s, 2H); 5.59 (dd, 2H); 7.39 (s, 1H); 7.63 (t, 1H); 7.80 (t, 1H); 7.90 (d, 1H); 8.23 (d, 1H); 8.34 (p, 1H).

NMR-C<13> (CDCl3): 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-diethyl5-dihydro-5-hydroxy-1H-oxepino[3',4,:6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

This compound is prepared analogously to example 1, except that i

step 1.a. 7-ethyl-camptothecin (Sawada et al., Chem. Pharm. Bull. 39:2574 (1991)) is used instead of camptothecin. The desired compound is obtained in the form of a clear yellow solid, m.p. > 270°C.

NMR-<1>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, 1H); 8.32 (d, 1H).

NMR-C<1>3 (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: p-ethyl-γ-{12-ethyl-8-hydroxymethyl-9-oxo(11H)-indolizino-[1,2-b]quinolin-7-yl)-p-hydroxy-propionic acid

This compound is prepared analogously to Example 4, except that 5,12-diethyl-4,5-dihydro-5-hydroxy-1H-oxepino[3',4,:6,7]-indolizino[1,2-b ]-quinoline-3,15 (4H,13W)-dione is used instead of 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino[3',4':6,7]-indolizino[1, 2-b]quinoline-3,15(4H,13W)-dione. It is obtained in the form of a slightly grey-white solid, m.p. 238-239°C.

NMR-<1>H (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 (see, 1H); 5.24 (s, 2H); 5.78 (see, 1H);

7.38 (s, 1H); 7.77 (t, 1H); 7.86 (t, 1H); 8.18 (d, 1H); 8.28 (d, 1H); 12.10 (see, 1H). NMR-C<1>3 (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-[1,4]dioxino-[2I3-g]oxepino[3',4':6,7]indoli2ino [1,2-b]quinoline-10,13-(15tf)-dione

11.a. 2-ethyl-2-(2-methoxy-4-pyridyl)-1,3-dioxolane (F)

Water is azeotropically distilled (overnight) with a Dean Stark apparatus from a mixture of 2-chloro-4-propionylpyridine (10 g, 59 mmol) obtained as in Lamattina, J.L. J. Heterocytic Chem. 20, p. 553 (1983)), ethylene glycol (20 ml) and p-toluenesulfonic acid (250 mg) in toluene (150 ml). The solvent is then removed under reduced pressure, the acid is neutralized with saturated aqueous sodium bicarbonate (100 mL), and the product is extracted with ether. The combined ether extracts are washed with brine, dried over sodium sulfate and evaporated to give 13.3 g (96%) of the crude product protected with the carbonyl group, which is refluxed with 3 equivalents of sodium methoxide in acetonitrile until the reaction was complete (checked by thin layer chromatography: SiO 2 , tert-butyl methoxide/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 over sodium sulfate and evaporated to give a brown oil which is distilled (70-75° C, 0.04 mbar); 10.7 g (total recovery 81%) of product (F) is obtained in the form of a clear liquid.

11.b. 2-ethyl-2-(3-hydroxymethyl-2-methoxy-4-pyridyl)-1,3-dioxolane (G)

Tert-butyllithium (1.7 M in pentane, 100 mL, 170 mmol) is added dropwise, using a cannula, to a solution of the bromomesitylene (13 mL, 85 mmol) in anhydrous tetrahydrofuran (300 mL) at -78°C. under argon. The resulting white precipitate is stirred at -78°C for one hour and then 2-ethyl-2-(2-methoxy-4-pyridyl)-1,3-dioxolane (10 g, 44.8 mmol) is added and the reaction mixture is stirred for 15 minutes at -78° C., one hour at 0° C. and one hour at ambient temperature. After further cooling to -78° C, anhydrous N,N-dimethylformamide (100 mmol) is added, and the reaction mixture is again allowed to warm to ambient temperature and is then stirred for 16 hours, after which analysis by thin-layer chromatography (SiO 2 , TBMO/HX:50/ 50) shows that the output connection is completely exhausted. The reaction is quenched with saturated ammonium chloride and the reaction mixture is extracted with diethyl ether (200 mL, 50 mL, 50 mL). The combined extracts are dried over sodium sulfate and evaporated to give a yellow oil which is purified by column chromatography (SiO 2 , TBMO/HX: 0/100 to 5/95 to elute the mesitylene derivatives and then 20/80 to 50/50 to to elute the product) to give the aldehyde intermediate (7 g). The aldehyde is dissolved in methanol (100 mL) and treated with sodium borohydride (5 g, 132 mmol), and the resulting mixture is stirred until the aldehyde intermediate was completely consumed (about 1 hour) as determined analytically by thin layer chromatography. The solvent is then evaporated, the residue is taken up in ether, washed with water and brine, dried, and the solvent is evaporated. Column chromatography (SiO 2 , TBMO/HX: 10/90 to 50/50) of the residue gives 7 g (total 62%) of product (G) as a yellow oil.

11 times. 2-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-2-ethyl-

1,3-dioxolane (H)

A solution of 2-ethyl-2-(3-hydroxymethyl-2-methoxy-4-pyridyl)-1,3-dioxolane (7 g, 30 mmol) and benzyl chloride (5 mL, 45 mmol) 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 the reaction mixture is refluxed for 16 h. The reaction mixture is then allowed to cool to ambient temperature, the reaction is quenched 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 brine, dried and evaporated. Purification by column chromatography (SiO 2 , TBMO/HX: 5/95 to 20/80) gives the product protected with benzyl (H), 9 g, (87%) as a clear oil.

11.d. 1-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-propan-1-one (I')

2-(3-Benzyloxymethyl-2-methoxy-4-pyridyl)-2-ethyl-1,3-dioxolane (9 g, 27 mmol) is treated with trifluoroacetic acid (10 mL) and water (5 mL) at a bath temperature of 120° C for 3 hours. The reaction mixture is concentrated under reduced pressure and remaining traces of the acids are neutralized by the addition of saturated, aqueous sodium carbonate. Extraction with ether followed by column chromatography (SiO 2 , TBMO/HX: 10/90) gives 5.5 g (70 %) of product (I)..

11 .e. tert-Butyl-[3-ethyl-(3-hydroxy-γ-(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 HCl for 10 seconds, then washed successively with water until the pH is neutral, acetone and diethyl ether) in anhydrous tetrahydrofuran (60 mL) under reflux. The reaction medium is kept under reflux for a further 10 minutes after the addition is finished. Then a solution of 1-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-propan-1-one (5.8 g, 20 mmol) in anhydrous tetrahydrofuran (20 mL) is added and the reaction mixture is stirred under reflux for another hour. The reaction is quenched at 0°C with saturated aqueous ammonium chloride (100 mL) and the reaction mixture is extracted with diethyl ether. The combined extracts are dried over sodium sulfate and evaporated to give a yellow oil which is purified by column chromatography (SiO 2 , TBMO/HX: 5/95 to 10/90) to give the tert-butyl ester (J) (7 g, 95%) in the form of a clear oil.

11 .f. tert-Butyl l-B-ethyl l-B-hydroxy -γ-(3-hydroxymethyl-2-methoxy-4-pyridyl) propionate (K)

tert-Butyl-B-ethyl-p-hydroxy-γ-(3-benzyloxymethyl-2-methoxy-4-pyridyl)-propionate (1 g, 2.5 mmol) is hydrolyzed at atmospheric pressure and at ambient temperature using 5% palladium on carbon which

catalyst (50 mg) and absolute ethanol as solvent (10 ml). When the reaction is complete (6 h), the catalyst is separated by filtration and the solvent is evaporated, yielding 0.7 g (90%) of product (K) which is sufficiently pure for subsequent synthetic use.,

in

11.g. 5-ethyl-1,5-dihydro-5-hydroxy-9-methoxy-oxepino[3,4-c]pyridin-3(4H)-one (L)

Tert-butyl-p-ethyl-B-hydroxy-γ-(3-hydroxymethyl-2-methoxy-4-pyridyl) propionate (8.8 g, 28 mmol) is treated with trifluoroacetic acid (30 mL) for 3 h at ambient temperature . The volatiles are evaporated and the residue is purified by column chromatography (SiO 2 , CH 2 Cl 2 /MeOH: 100/0 to 98/2), giving a clear oil which, after treatment with toluene, gives 5.9 g of product (L) (89 %) in the form of white crystals, m.p. 97-98°C.

11, h. 5-ethy 1-1,5-dihydro-5-hydroxy-oxepino[3,4-c]pyridine-3,9(4H,8H)-dione (M)

5-Ethyl-1,5-dihydro-5-hydroxy-9-methoxy-oxepino[3,4-c]pyridin-3(4H)-one (0.5 g, 2.1 mmol) in 1N hydrochloric acid (20 ml) is heated under reflux for 9 hours. The reaction mixture is concentrated under reduced pressure, and the residue is again dried by adding and evaporating toluene, twice, and is then allowed to stand overnight under reduced pressure in the presence of phosphorus pentoxide. The resulting oil is dissolved in anhydrous acetonitrile (5 mL) and stirred under argon for 24 hours. The precipitate is filtered and dried to give 0.23 g (49%) of a white solid (M), m.p. 118-119°C.

11.i. 6,7-ethylenedioxy-2-iodo-3-quinoline-methanol (N)

The methods described by Meth-Cohn et al., J. Chem. Soc. Perkin Trans. I, p. 1520 (1981); Meth-Cohn, J. Chem. Soc. Perkin Trans I,

pp. 2509 (1981); and Nakasimhan et al., J. Am. Chem. Soc. 112,

p. 4431 (1990), is applied. 3,4-ethylenedioxyacetanilide (22 g, 113 mmol) becomes

added to the Vilsmeyer reagent obtained by dropwise addition of phosphoryl oxychloride (71 mL, 0.77 mol) to anhydrous dimethylformamide (23 mL, 0.28 mol), cooled in an ice-water bath, and stirred for an additional 0.5 hour under an atmosphere of argon. The resulting 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 over sodium sulphate, filtered and concentrated. The solid residue is suspended in dichloromethane (20 mL), filtered and dried under reduced pressure to give 10 g (35%) of 2-chloro-6,7-ethylenedioxyquinoline-3-carbaldehyde as a yellow solid, sm .p. 222-224° C. This intermediate is treated with sodium iodide (30 g, 0.2 mol) and concentrated hydrochloric acid (1.5 mL) in refluxing acetonitrile (150 mL) for 24 hours. After cooling to ambient temperature, the solvent is removed under reduced pressure and the residue is taken up in 50% aqueous tetrahydrofuran (200 mL), filtered, washed with tetrahydrofuran and dried under reduced pressure to give 12 g of 6,7-ethylenedioxy-2-iodoquinoline- 3-carbaldehyde in the form of a yellow solid, m.p. 155-157° C. The above intermediate is treated with sodium borohydride (2 g, 52 mmol) in methanol (200 mL) at ambient temperature for 0.5 h. The solvent is removed 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 phosphorus pentoxide to give 11 g of (6,7-ethylenedioxy-2-iodoquinolin-3-yl)-rethanol as a yellow solid,

sm.p. 178-180°C.

11.j. 5-Ethyl-8-(6,7-ethylenedioxy-2-iodo-3-quinolinemethyl)-1,5-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-ethylN,5-dihydro-5-hydroxy-oxepino[3,4-c]-pyridine-3,9 (4H,8H)-dione (400 mg, 1.79 mmol), the compound obtained during previous step 11.i. (770 mg, 2.23 mmol) and triphenylphosphine (934 mg, 3.58 mmol) in a mixture of anhydrous THF/DMSO (8/1 v/v, 45 mL) and the resulting mixture stirred 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 resulting solution is washed with brine (4 x 50 mL), dried over sodium sulfate, and evaporated. The residue is purified by column chromatography (SiO 2 , CH 2 Cl 2 /MeOH: 99/1 to 98/2), giving 650 mg (66%) of product (0) as a white solid, m.p. 165-167°C.

11.k. 8-ethyl-2,3,8,9-tetrahydro-8-hydroxy-10H,12H-[1,4]dioxino[2,3-g]-oxepino[3',4':6,7]indolizino[ 1,2-Jb]quinoline-10,13(15H)-dione

5-ethyl-8-(6,7-ethylenedioxy-2-iodoquinolin-3-yl)methyl-4,5-dihydro-5-hydroxy-(1H, 3H)oxepino[3,4-c]pyridin-3- dione (600 mg, 1.1 mmol),

tetrabutylammonium bromide (352 mg, 1.1 mmol), sodium acetate (359 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 h. After cooling to ambient temperature, a white precipitate separates from the reddish solution. This precipitated substance is filtered and dried under reduced pressure. The crude product is suspended in water, filtered and dried under reduced pressure over phosphorus pentoxide, yielding 250 mg of the desired compound as a clear yellow solid, m.p. > 250°C.

NMR-<1>H (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 (see, 1H); 7.33 (s, 1H); 7.54 (s, 1H); 7.55 (s, 1H); 8.43 (p, 1H).

NMR-C 3 (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-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino-[3',4':6,7]-indolizino [1,2-fc]quinoline-3,15 (4H,13H)-dione

12.a. (6-Benzyloxy-2-iodo-3-quinoline)-methanol

This compound is prepared analogously to the method indicated in step 11.i. in Example 11, but using 4-benzyloxyacetanilide instead of 3,4-ethylenedioxyacetanilide. Purification by silica gel column chromatography and the use of dichloromethane as eluent is necessary to isolate (8% recovery) with sufficient purity, the intermediate 6-benzyloxy-2-chloroquinoline-3-carbaldehyde, m.p. 180-182° C. Then exchange of halogen gives 6-benzyloxy-2-iodoquinoline-3-carbaldehyde, m.p. 155-157° C and subsequent reduction to sodium borohydride gives (6-benzyloxy-2-iodoquinolin-3-yl)-methanol, m.p. 147-149°C.

12.b. 8-(6-Benzyloxy-2-iodo-3-quinolinemethyl)-1,5-dihydroxy-5-ethyl-5-hydroxy-oxepino[3,4-c]pyridine-3,9(4H,8H)-dione

This compound is prepared analogously to the method indicated in step 11 .j. in Example 11, but using (6-benzyloxy-2-iodoquinolin-3-yl)-methanol instead of (6,7-ethylenedioxy-2-iodoquinolin-3-yl)-methanol. This compound is obtained as a white solid, m.p. 197-199°C.

12.C. 10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino-[3',4':6,7]-indolizino[1,2-b]quinoline-3,15(4H, 13N)-dione

This compound is prepared analogously to the method indicated in step 11.k. in Example 11, but using 8-(6-benzyloxy-2-iodo-3-quinolinemethyl)-1,5-dihydroxy-5-ethyl-5-hydroxy-oxepino[3,4-c]pyridine-3,9( 4W, 8H)-dione instead of 5-ethyl-8-(6,7-ethylenedioxy-2-iodoquinolin-3-yl)methyl-4,5-dihydro-5-hydroxy-(1H, 3H)oxepino[3,4 -c]pyridine-3-dione. The desired compound is obtained as a clear yellow solid, m.p. > 250°C.

NMR-<1>H (DMSO): 0.90 (t, 3H); 1.85 (m, 2H); 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).

NMR-C 13 (DMSO): 8.43; 36.48; 38.28; 50.65; 61.42; f 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: γ-(12-benzyloxy-8-hydroxymethyl-9-oxo(11H)-indolizino-[1,2-b]quinolin-7-yl)-p-ethyl-B-hydroxy-propionic acid (E)

This compound is prepared by a method analogous to that described in Example 4, but using 10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino[3',4': 6,7]-indolizino [1,2-b]quinoline-3,15-(4H,13tf)-dione instead of 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino[3',4 ':6,7]-indolizino[1,2-b]quinoline-3,15(4H,13H)-dione. It is obtained as a yellow solid, m.p. 171-173°C.

NMR-<1>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 (see, 1H); 7.30 (s, 1H); 7.35-7.70 (m, 7H); 8.10 (d, 1H); 8.55 (p, 1H).

NMR-C<1>3 (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-1H-oxepino[3',4':6,7]-indolizino[1,2-b]quinoline-3,15-( 4H,13H)-dione

10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino[3',4':6,7]-indolizino-[1,2-£>]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 carbon as catalyst (60 mg) and trifluoroacetic acid as solvent (15 mL). When the reaction is finished (16 hours),

dichloromethane (50 mL) and methanol (50 mL) are added to the reaction mixture, the catalyst is filtered off, and the volatiles are evaporated under reduced pressure to give the desired crude compound containing traces of trifluoroacetic acid. These traces are eliminated by co-distillation with 1,4-dioxane. The product is obtained in the form of an orange solid, m.p. 150° C (d), with sufficient purity for further synthetic application.

NMR-<1>H (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 (see, 1H); 7.26 (p 1H); 7.31 (s, 1H); 7.40 (d, 1H); 8.00 (d, 1H); 8.42 (s, 1H); 10.32 (p, 1H).

NMR-C<1>3 (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: 11-(dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepino[3\4':6,7]-indolizino[1,2-b]quinoline -

3,15 (4H,13H)-dione

15. a. 11-(Dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepino [3\4':6,7]-indolizino [1,2-b]quinoline-3,15 (4H,13H)-dione

A suspension of 10-benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino-[3\4':6,7]-indolizino[1,2-b]quinoline-3,15 ( 4H,13H)-dione (260 mg, 0.69 mmol) in acetic acid (15 mL) is treated with 37% aqueous formaldehyde (500 µl) and 40% aqueous dimethylamine (500 µl) and the resulting mixture is stirred at ambient temperature for 16 hours. The reaction mixture is concentrated to dryness and the residue is purified by column chromatography (SiO 2 , CH 2 Cl 2 /MeOH: 100/0 to 90/10) followed by crystallization with acetonitrile to give 102 mg of the desired compound.

15.b. 11 -(dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-1 H -oxepino[3',4':6,7]-indolizino[1,2-/>] quinoline- 3,15{4H,13H)-dione chlorohydrate

Dilute hydrochloric acid (1 N) is added dropwise to a suspension of 11 -(dimethylaminoJmethyl-S-ethyl^.S-dihydro-S.10-dihydroxy-1H-oxepino-[y^Æ.Tl-indolizinoII^-b] quinoline -3,15(4H,13H)-dione (102 mg) in water, until dissolution is complete. Water is evaporated under reduced pressure, and the residue is suspended in acetonitrile (5 mL) and filtered, yielding 103 mg of the desired salt, mp 248° C (d).

NMR-<1>H (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, 1H); 7.72 (d, 1H); 8.19 (d, 1H); 8.99 (p, 1H); 9.92 (see, 1H); 11.45 (p, 1H).

NMR-C<13> (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-dihydro-5-hydroxy-10-methoxy-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3 ,15(4H,13H)-dione

This compound is obtained from 3-fluoro-4-methoxyaniline according to the method illustrated in steps 11i, 11j and 11k of Example 11. Yellow solid, m.p. > 250°C.

NMR-<1>H (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 3.08 (d, 1H); 3.49 (d, 1H); 4.00 (p, 3H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.00 (p, 1H); 7.32 (s, 1H); 7.72 (d, 1H); 7.91 (d, 1H); 8.58 (p, 1H).

NMR-C<13> (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-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino[3,>4':6,7]indolizino[1,2-b]quinoline-3 ,15(4H,13H)-dione

This compound is obtained from 3-chloro-4-methoxyaniline according to the method illustrated in steps 11 i, 11 j and 11 k of Example 11. Yellow solid; sm.p. > 250°C.

NMR-<1>H (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 (s, 1H); 7.39 (s, 1H); 8.10 (s, 1H); 8.20 (s, 1H); 8.60 (p, 1H).

NMR-C<13> (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-1H-oxepino[3',4,:6,7]indolizino[1,2-b] ki noi in-3 ,15(4H,13H)-dione

This compound is obtained from 3,4-difluoroaniline according to the method illustrated in steps 11i, 11j and 11k of Example 11. Yellow solid; sm.p. > 250°C.

NMR-<1>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 (p, 1H).

NMR-C<1>3 (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,11H-[1,3]dioxolo [4,5-g]

oxepino [3\4':6,7] indolizino [1,2-b] quinoline-9,12[14H]-dione

This compound is obtained from 3,4-methylenedioxyaniline according to the method illustrated in steps 11 i, 11] and 11 k of Example 11. Cream solid; sm.p. >250°C.

NMR-<1>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 (p, 1H); 6.30 (s, 2H); 7.30 <s, 1H); 7.49 (d, 2H); 8.45 (p.1H).

NMR-C<13> (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-1H-oxepino [3\4':6,7] indolizino [1,2-b] quinoline-3, 15(4H,13H)-dione

This compound is obtained from 3-chloro-4-methoxyaniline according to the method illustrated in steps 11 i, 11 j and 11 k of Example 11. White solid; sm.p. > 250°C.

NMR-<1>H (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 (p, 1H).

NMR-C<13> (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-1H-oxepino

[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

This compound is obtained from 4-methoxyaniline according to the method illustrated in steps 11 .i., 11 j. and 11.k. in Example 11. Yellow solid;

sm.p. > 250°C.

NMR-<1>H (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 (p, 1H); 7.38 (s, 1H); 7.51 (d, 2H); 8.07 (d, 1H); 8.55 (p, 1H).

NMR-C<13> (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: 9,11-dichloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino[3',4,:6,7]indolizino[1,2-b]quinoline-3,15 (4H,13H)-dione

This compound is obtained from 3,5-dichloroaniline according to the method illustrated in steps 11 .i., 11 .j. and 11.k. in Example 11. Yellow solid;

sm.p. > 250°C.

NMR-<1>H (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 (p, 1H).

NMR-C<13> (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-dihydro-5-hydroxy-10-methyl 1-1H-oxepino

[3\4':6,7] indolizino [1,2-Jb]quinoline-3,15(4H,13H)-dione

This compound is obtained from 3-fluoro-4-methylaniline according to the method illustrated in steps 11 .i., 11 .j. and 11.k. in Example 11. Yellow solid; sm.p. > 250°C.

NMR-<1>H (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, 1H); 6.05 (s, 1H); 7.39 (s, 1H); 7.87 (d, 1H); 8.05 (d, 1H); 8.61 (p, 1H).

NMR-C<13> (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-dihydro-5-hydroxy-1H-oxepino-[3',4':6,7]indolizino[1,2-b]quinoline-3,15( 4H,13H)-dione

This compound is obtained from 4-fluoroaniline according to the method illustrated in steps 11 .i., 11 .j. and 11.k. in Example 11. White solid; sm.p. > 250°C.

NMR-<1>H (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); 7.39 (s, 1H); 7.80 (q, 1H); 7.99 (q, 1H); 8.23 (q, 1H); 8.68 (s, 1H).

NMR-C<1>3 (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-1H-oxepino-[3',4':6[7]indoli2ino[1,2-b]quinoline-3,15( 4H,13H)-dione

This compound is obtained from 4-chloroaniline according to the method illustrated in steps 11.i., 11.j. and 11.k. in Example 11. Yellow solid. sm.p. > 250°C.

NMR-<1>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); 7.89 (d, 1H); 8.19 (d, 1H); 8.29 (s, 1H); 8.67 (p, 1H).

NMR-C<13> (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-1H-oxepino-[3',4':6,7]indolizino[1,2-b]quinoline- 3,15(4H,13H)-dione

This compound is obtained from 4-chloro-3-fluoroaniline according to the method illustrated in steps 11.i., 11.j. and 11.k. in Example 11. Yellow solid. sm.p.

> 250°C.

NMR-<1>H (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 (p, 1H).

NMR-C<13> (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: 5l12-diethyl-4,5-dihydro-5,10-dihydroxy-11-morpholino-methyl-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3 ,15-(4H.13H)-dione

This compound is obtained from morpholine according to the method illustrated in Example 15.a. White solid, m.p. > 250°C.

NMR-<1>H (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 (see, 1H); 7.30 (s, 1H); 7.42 (d, 1H); 7.95 (d, 1H); 8.82 (p, 1H).

NMR-C 13 (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-diethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino[3',4':6,7]indolizino[1,2-b] quinoline -3,15(4H,13H)-dione 28.a. 5-fluoro-4-methoxy-2-propionylaniline

(This product is obtained according to Sugasawa T; Toyoda T; Adachi M; Sasakura K, J. Am. Chem. Soc, 100 (1978), pp.4842-4852). Boron trichloride (1M in heptane, 156 ml , 156 mmol). The pink suspension thus obtained is kept under stirring for 5 minutes, and then propionitrile (33 ml, 420 mmol) is added dropwise followed by aluminum trichloride (20.8 g, 156 mmol) in small portions. The reaction mixture is heated under reflux for 3 hours, cooled again to 0° C., hydrolyzed by the careful addition of 2N hydrochloric acid (100 ml), and then refluxed for 45 minutes. After further cooling to 0° C, a precipitate is obtained which is filtered, washed with dichloromethane, and then taken up again in water (300 ml). The aqueous phase is basified to alkaline pH, and extracted with dichloromethane and then ethyl acetate. The organic phase is dried (MgSO4) and

then evaporated, to give a crude product which is purified by column chromatography (SiC-2, AcOEt/Hpt: 1/99 to 20/80). 15.3 g of a yellow solid is obtained.

NMR-<1>H (CDCl 3 ): 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, a solution of ethyl malonyl chloride (12.9 ml, 100 mmol) in anhydrous acetonitrile (30 ml) is added dropwise. The reaction medium is allowed to return to ambient temperature, a solution of sodium ethylate (obtained with 1.8 g, 78 mmol sodium in 80 ml ethanol) is added dropwise via a cannula, and the mixture is then allowed to stir for 12 h at ambient temperature. The reaction mixture is poured into ice-water (100 ml) and stirred for 2 hours, then the precipitated substance is filtered and washed with water, ethanol and ether. 19.4 g of a white, solid substance is obtained.

NMR-<1>H (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); 11.93 (p, 1H).

IR (KBr): 786; 1083; 1410; 1521; 1644; 1725.

28.c. Ethyl 2-ctor-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 refluxed for 6 hours. The phosphoryl chloride is distilled. The reaction mixture is poured into ice-water. It is taken up in dichloromethane for dissolution. The organic phase is washed with water, and then with a solution of saturated sodium chloride. The organic phase is dried with magnesium sulfate and the solvent is evaporated. The residue is suspended in ether and the unconverted starting material (4 g) is filtered off. The filtrate is evaporated, and the residue is purified by column chromatography (SiO 2 , AcOEt/Hpt: 5/95 to 20/80). 10.9 g of a white, solid substance is obtained.

NMR-<1>H (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-ethyl-7-fluoro-6-methoxy-3-quinolinemethanol

A solution of ethyl 2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinoline carboxylate

(10.8 g, 35 mmol) in anhydrous dichloromethane (200 mL) is treated dropwise at ambient temperature under an inert atmosphere with diisobutylaluminum hydride (1M in dichloromethane, 65 mL, 65 mmol), and then heated to 40° C. for 4 h. The mixture is cooled to 0°C, and a 20% aqueous solution of Rochelle salt (105 mL) and dichloromethane (200 mL) is carefully added, and stirring is continued for 1 hour. The mixture is decanted, washed three times with water, and the organic phase is dried over magnesium sulfate and the solvent is evaporated. The residue is purified by column chromatography (SiO 2 , AcOEt/Hpt: 5/95 to 50/50). You get 6 g of a white, solid substance.

NMR-<1>H (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-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3, 15(4H,13H)-dione

2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinemethanol is coupled with compound (M) as described in step 11.j. in Example 11. The resulting coupling product is cyclized according to the method of step 11 .k. A yellow solid is obtained,

sm.p. > 275°C.

NMR-<1>H (CF 3 COOD): 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 (rn, 1H); 8.16 (m, 1H); 8.31 (p, 1H).

NMR-C<13> (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-1H-oxepino

[3,,4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione

2-acetylaniline is used in the method described in examples 28.b., 28.c. and the 28th giving 2-chloro-4-methyl-3-quinolinemethanol. The latter is connected with compound (M) as described in step 11 .j. in Example 11. The resulting coupling product is cyclized according to the procedure in step 11 .k. A yellow solid is obtained, m.p. > 260°C.

NMR <1>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, 1H).

NMR-C<13> (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-methyl-piperazinomethyl)-1H-oxepino[3',4':6,7]indolizino -[1,2-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), pp. 4842-4852). To a solution of 3-chloro-4-methoxyaniline (23.6 g, 150 mmol) under an inert atmosphere at 0° C is successively added dropwise a molar solution of boron trichloride in hexane (164 ml, 164 mmol), chloroacetonitrile (11.4 mL, 180 mmol), and a molar solution of diethylaluminum chloride in hexane (164 mL, 164 mmol). The reaction medium is heated under reflux for 1 hour, cooled to 0° C., hydrolyzed by careful addition of 2N hydrochloric acid (90 mL), and then refluxed for 1 hour. It is cooled again and a concentrated solution of sodium bicarbonate is added to pH 14. The solution is extracted with ethyl acetate and the organic phase is washed with water and then brine. It is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is recovered in isopentane, decanted, and insoluble material is taken up in a minimal amount of isopropyl ether, and isopentane is added to precipitate the product. This is filtered off and dried under vacuum. 17.26 g of a brown solid is obtained.

NMR-<1>H (CDCl 3 ): 3.82 (s, 3H); 4.60 (s, 2H); 6.11 (s, 2H); 6.78 (s, 1H); 7,11 (p, 1H).

30.b. Ethyl 7-chloro-4-chloromethyl-2-hydroxy-6-methoxy-3-quinoline carboxylate

To a solution of 5-chloro-2-chloroacetyl-4-methoxyaniline (17 g, 73 mmol) and triethylamine (18.5 mL, 131 mmol) in anhydrous acetonitrile (310 mL), under argon and at 0° C., a solution of ethylmalonyl chloride (17 ml, 131 mmol) was added dropwise. It is stirred for 2 hours at ambient temperature, and then a solution of sodium ethanolate in ethanolate (obtained with 1.88 g, 80 mmol of sodium in 90 ml of ethanol) is added dropwise at 0° C. It is stirred for 12 hours at ambient temperature. 300 ml of water is added and it is stirred again for 20 minutes. The precipitated substance is filtered and washed with water, ethanol and ethyl ether. After drying in a vacuum, 16.7 g of a yellowish solid substance is obtained.

in

NMR-<1>H (DMSO): 1.31 (t, 3H); 3.95 (s, 3H); 4.36 (q, 2H); 4.95 (s, 2H); 7.46 (s, 1H); 7.49 (p.1H).

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-quinolinecarboxylate (116.7 g, 50 mmol) in phosphoryl chloride (100 mL) is refluxed for 6 h. The phosphoryl chloride is distilled off. The residue is taken up in water and stirred for 30 min. The precipitated substance is filtered off and washed with water for neutralization. The precipitated substance is taken up in dichloromethane and with a saturated solution of sodium chloride. It is filtered through a pad of celite and the filtrate is decanted. The organic phase is washed again with a saturated solution of sodium chloride. It is dried over magnesium sulfate and filtered and evaporated under reduced pressure. You get 15.88 g of a brown oil.

NMR-<1>H (CDCl3 ): 1.47 (t, 3H); 4.08 (t, 3H); 4.55 (q, 2H); 4.87 (s, 2H); 7.35 (s, 1H); 8.09 (p, 1H).

30.d. Ethyl 2,7-dichloro-6-methoxy-4-(4-methylpiperazinomethyl)-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) are heated to 60° C. for 30 min. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase is decanted and washed with water. It is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is taken up in water, stirred for 15 minutes, filtered, washed with water and dried under

vacuum. The residue is purified by column chromatography (SiO 2 , MeOH/CH 2 Cl 2 : 5/95 to 8/92). You get 6.7 g of a beige, solid product.

NMR-<1>H (CDCl 3 ): 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 (p, 1H).

30.e. 2,7-dichloro-6-methoxy-4-(4-methylpiperazinomethyl)-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 slowly added. It is stirred for one hour at ambient temperature. The reaction mixture is poured slowly into 300 ml of a solution of a 20% Rochelle salt solution. It is stirred for one hour; filtered on celite; is decanted, and the organic phase is washed with a saturated solution of sodium chloride. It is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The solid is taken up in isopropyl ether, filtered and dried in vacuo. 4.3 g of the desired product (80%) are obtained in the form of a yellow solid.

NMR-<1>H (CDCl 3 ): 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 (p, 1H).

30.f. 9-chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-12-(4-methyl-piperazinomethyl)-1H-oxepino[3',4':6)7]indolizino[1, 2-b]quinoline-3,15(4W,13H)-dione

2,7-dichloro-6-methoxy-4-(4-methylpiperazinomethyl)-3-quinoline-methanol is coupled with compound (M) as described in step 11.j. in example 11. The resulting coupling product is cyclized according to the method described in step 11 .k. A yellow solid is obtained, m.p. > 250°C.

NMR-<1>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, 1H); 8.16 (p, 1H).

NMR-C<13> (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-12-morpholinomethyl-1H-oc$epino[3',4':6,7]indolizino[1, 2-b]quinoline-3,15(4W,13H)-dione

3-chloro-4-methoxyaniline is used in the method described in examples 30.a., 30.b. and 30.c. which gives ethyl 2,7-dichloro-4-chloromethyl-6-methoxy-3-quinoline carboxylate which is treated according to the procedure in example 30.d., using morpholine instead of N-methylpiperazine, and the solution is reduced according to to the procedure in example 30.e. to the corresponding quinoline methanol. The latter is coupled to the compound (M) as described in step 11 in example 11. The resulting coupling product is cyclized according to the procedure in step 11.k. A beige solid is obtained, m.p. > 250°C.

NMR-<1>H (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 (p, 1H).

NMR-C<13> (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-b]quinoline- 3,15(4H,13H)-dione

Aniline is used in the method described in examples 30.a., 30.b. and 30.c. which gives ethyl 2-chloro-4-chloromethyl-3-quinolinecarboxylate which is treated according to the method in example 30.d. with N-methylpiperazine, and then reduced according to the method in example 30.e. to the corresponding quinoline methanol. The latter is connected to the connection (M) as described in step 11.j. in example 11. The resulting coupling product is cyclized according to the procedure in step 1 .k. A yellow solid is obtained, m.p. > 260°C.

NMR-<1>H (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 (see, 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,-.6,7]indolizino[1,2-b]quinoline-3,15( 4H,13H)-dione

Aniline is used in the method described in examples 30.a., 30.b. and 30.c. which gives ethyl 2-chloro-4-chloromethyl-3-quinoline carboxylate which is treated according to the method in example 30.d., using piperidine instead of N-methylpiperazine, and then reduces according to the method in example 30.e. to the corresponding quinoline methanol. The latter is connected with the compound (M) as described in step 11 .j. in example 11. The resulting coupling product is cyclized according to the procedure in step 1 .k. A yellow solid is obtained, m.p. > 260°C.

NMR-<1>H (DMSO): 0.86 (t, 3H); 1.40 {see, 2H); 1.48 (see, 4H); 1.87 (q, 2H); 2.50 (p, 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 (see, 1H); 7.75 (t, 1H); 7.85 (t, 1H); 8.15 (d, 1H); 8.45 (d, 1H). NMR-C<1>3 (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-4,5-dihydro-5-hydroxy-12-morpholinomethyl-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H ,13H)-dione

Aniline is used in the method described in examples 30.a., 30.b. and 30.c. which gives ethyl 2-chloro-4-chloromethyl-3-quinoline carboxylate which is treated according to the procedure in example 30.d, using morpholine instead of N-methylpiperazine, and then reduces according to the procedure in example 30.e. to the corresponding quinoline methanol. The latter is connected with compound (M) as described in step 11 j. in example 11. The resulting coupling product is cyclized according to the procedure in step 1.k. A yellow solid is obtained, m.p. > 260°C.

NMR-<1>H (DMSO): 0.86 (t, 3H); 1.87 (q, 2H); 3.05 (d, 1H); 3.30 (s, 4H); 3.49 (d, 1H); 3.55 (see, 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).

NMR-C<1>3 (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

4-fluoroaniline is used in the method described in examples 30.a., 30.b. and 30.c. which gives ethyl 2-chloro-4-chloromethyl-6-fluoro-3-quinoltenecarboxylate which is treated according to the method in example 30.d. with N-methylpiperazine, and then reduces according to the procedure in example 30.e. to the corresponding quinoline methanol. This last is connected with compound (M) as described in step 11.]. in example 11. The resulting coupling product is cyclized according to the procedure in step 1 .k. A yellow solid is obtained, m.p. > 275°C.

NMR-<1>H (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).

NMR-C<13> (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-4,5-dihydro-5-hydroxy-12-morpholinomethyl-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3 ,15(4H,13H)-dione

4-fluoroaniline is used in the method described in examples 30.a., 30.b. and 30.c. which gives ethyl 2-chloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treated according to the method in example 30.d., using morpholine instead of N-methylpiperazine, and then reduces according to the method in example 30.e. to the corresponding quinoline methanol. The latter is connected with the compound (M) as described in step 11 .j. in example 11. The resulting coupling product is cyclized according to the procedure in step 1 .k. A beige solid is obtained, m.p. > 250°C.

NMR-<1>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).

NMR-C<13> (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[ 1,2-b] quinoline-3,15(4H,13H)-dione

3-Fluoro-4-methylaniline is used in the method described in examples 30.a., 30.b. and 30.c. which gives ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinoltnecarboxylate which is treated according to the method in example 30.d. with N-methylpiperazine, and then reduces according to the procedure in example 30.e. to the corresponding quinoline methanol. The latter is connected with the compound (M) as described in step 11 .j. in example 11. The resulting coupling product is cyclized according to the procedure in step 1 .k. A yellow solid is obtained, m.p. > 260°C.

NMR-<1>H (CDCl3 ): 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-1H-oxepino[3',4':6,7]indolizino[1,2-b ]quinoline-3,15(4H,13H)-dione

3-Fluoro-4-methylaniline is used in the method described in examples 30.a., 30.b. and 30.c. which gives ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to the procedure in Example 30.d., using morpholine instead of N-methylpiperazine, and then reduces according to the procedure in example 30.e. to the corresponding quinoline methanol. The latter is connected with the compound (M) as described in step 11 .j. in example 11. The resulting coupling product is cyclized according to the procedure in step 1 .k. A yellow solid is obtained, m.p. > 260°C.

NMR-<1>H (DMSO + CDCl 3 ): 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).

NMR-C<13> (CF 3 CO 2 D): 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-1H-oxepino[3',4':6,7]indolizino[1,2-b ]-quinoline-3,15(4H,13W)-dione

3-Fluoro-4-methylaniline is used in the method described in examples 30.a., 30.b. and 30.c. which gives ethyl 2-chloro-4-chloromethyl-7-fluoro-6-methyl-3-quinolinecarboxylate which is treated according to the procedure in Example 30.d., using piperidine instead of N-methylpiperazine, and then reduces according to the procedure in example 30.e. to the corresponding quinoline methanol. The latter is connected with the compound (M) as described in step 11.j. in example 11. The resulting coupling product is cyclized according to the procedure in step 1 .k. A yellow solid is obtained, m.p. > 260°C.

NMR-<1>H (CF 3 CO 2 D): 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 (see, 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 (p, 1H).

NMR-C<13> (CF 3 CO 2 D): 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-methyl-piperazinomethyl)-10H,12H-[1,4]dioxino[2,3-g]oxepino- [3',4':6,7]indolizino[1,2-D]quinoline-10,13[15H]-dione

3,4-ethylenedioxyaniline is used in the method described in examples 30.a., 30.b. and 30.c. which gives ethyl 2-chloro-4-chloromethyl-6,7-ethylenedioxy-3-quinolinecarboxylate which is treated according to the method in example 30.d. with N-methylpiperazine, and then reduces according to the procedure in example 30.e. to the corresponding quinoline methanol. The latter is connected with the compound (M) as described in step 11 .j. in example 11. The resulting coupling product is cyclized according to the procedure in step 1.k. A yellow solid is obtained, m.p. > 260°C.

NMR-<1>H (DMSO): 0.92 (t, 3H); 1.89 (q, 2H); 2.16 (s, 3H); 2.50 (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 (p, 1H).

NMR-C<1>3 (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-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-12-morpholinomethyl-1H-oxepino[3',4':6,7]indolizino[1,2-b ]-quinoline-3,15(4H,13H)-dione

3-chloro-4-fluoroaniline is used in the method described in examples 30.a., 30.b. and 30.c. which gives ethyl 2,7-dichloro-4-chloromethyl-6-fluoro-3-quinolinecarboxylate which is treated according to the procedure in Example 30.d., using morpholine instead of N-methylpiperazine, and then reduces according to the procedure in example 30.e. to the corresponding quinoline methanol. The latter is connected with the compound (M) as described in step 11 .j. in example 11. The resulting coupling product is cyclized according to the procedure in step 1 .k. A beige solid is obtained, m.p. > 250°C.

NMR-1 H (CF 3 COOD): 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).

NMR-C<13> (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: Cleavage of 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino-[3\4':6,7]-indolizine[1,2-b quinoline-3,15 (4H,13H )-dione

A mixture of p-ethyl-(3-hydroxy-γ-(8-hydroxymethylindolizino-[1,2-b]quinolin-9-(11/-/)-on-7-yl)-propionic acid (19.5 g , 51 mmol) and L-(-)-α-methylbenzylamine (12.12 g, 100 mmol) in absolute ethanol (1 L), is heated to boiling, hot filtered and allowed to stand for 68 h. The precipitate is filtered off and washed with ethanol and ether to give 9.8 g of a white solid Analysis by high pressure liquid chromatography on stationary chiral phase ("HPLC chiral" on a Chiral-AGP column (Chromtech, Stockholm, Sweden) 100 x 4 mm, 2% acetonitrile eluent in 10 mM phosphate buffer pH 6.9, eluting peaks at 4.5 and 7.5 min) show peaks integrating 24% and 76% of the total surface of the two peaks, respectively. The solid is taken up in 93% ethanol (350 mL) under reflux and then allowed to rest for 48 hours.The precipitate is then washed with ethanol and ether to give 4.8 g of a white solid which gives two integrated peaks for 9% and 91% of the total surface a v the peaks by chiral HPLC. The solid is taken up again in 50% ethanol (48 ml) under reflux and allowed to rest for 48 hours. The precipitate is then washed with ethanol and ether to give 2.7 g of a white solid which gives two integrating peaks for 3% and 97% respectively of the total area of the two peaks by chiral HPLC. The solid is taken up in 50% ethanol (22 ml) under reflux and then allowed to rest for 48 hours. The precipitate is then filtered and washed with ethanol and ether to give 1.6 g of a white solid which gives two integrating peaks for 1% and 99% of the total area of the two peaks respectively by chiral HPLC. The resulting salt, diastereoisomerically enriched, taken up in distilled water (20 mL), is treated with acetic acid (0.35 mL, 6.4 mmol) for 15 min. The resulting precipitate is filtered, washed with water, acetone and ether and then dried in vacuo at 80° C., giving 1.1 g of a white solid. The latter is taken up in absolute ethanol (55 ml) to which concentrated hydrochloric acid (11.5 N, 11 ml) has been added, giving a yellow solution which is stirred at ambient temperature for 68 hours. The thus obtained precipitate is filtered and washed with water, ethanol and ether, and then dried under vacuum at 80° C., which gives 770 mg of 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino[3 ',4':6,7]-indolizine [1,2-b]-quinoline-3,15(4W,13H)-dione which is enantiomerically enriched. Analysis by chiral HPLC (Chiral-AGP column, eluted with a gradient of 2 to 5% acetonitrile in 10 mM phosphate buffer at pH 6.9, eluting peaks after 15 and 20 min) shows an enantiomeric excess of 98%. The method described above is repeated, but the L-(-)-α-methylbenzylamine is replaced by D-(+)-α-methylbenzylamine. The second enantiomer of 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino-[3\4':6,7]-indolizine[1,2-b]quinoline-3,15 ( 4H,13H)-dione.

By using the methods indicated above, the following compounds can also be prepared, and are also part of the invention and constitute preferred compounds: 10-benzyloxy-5,12-diethyl-4,5-dihydro-5-hydroxy-1 H-oxepino [ 3',4':6,7]-indolizino[1,2-b]quinoline-3,15 ( A H , 13 H )-dione; S,^-diethyM,S-dihydro-S,10-dihydroxy-1H-oxepinop1, 4':6,7]indolizino[1,2-b]-quinoline3,15(4H,13H)-dione;

5,12-diethyl-4,5-dihydro-5,10-dihydroxy-11-dimethylaminomethyl-1H-oxepino-[3',4':6,7]indolizino[1,2-b]quinoline-3, 15 (AH, 13H)-dione;

5-ethyl-4,5-dihydro-5-hydroxy-9,10-dimethoxy-1H-oxepino[3,,4':6,7]indolizino-[1,2-b]quinoline-3,15(4H , 13H)-dione;

10- bromo-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino[3',4,:6,7]indolizino[1,2-b]-quinoline-3,15(4H,13H )-dione;

11- bromo-5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino[3',4':6,7]-indolizino[1,2-b]quinoline-3,15 (4H, 13H)-dione;

5-ethyl-12-diethylaminomethyl-4,5-dihydro-5-hydroxy-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15 ( AH, 13H )-dione;

IN

5-ethyl-4,5-dihydro-5-hydroxy-1H,3H-cyclopenta[g]oxepino[3',4':6,7]-indolizino[1,2-b]quinoline-3,16 [ 14H]-dione;

7- ethyl-7,8-dihydro-7-hydroxy-16-(4-methylpiperazino methyl)-9H, 11H-[1,3]-dioxolo[4,5-g]oxepino[3',4':6 ,7]indolizino[1,2-b]quinoline-9,12 [14 H]-dione;

5-ethyl-4,5-dihydro-5-hydroxy-12-(1-imidazylmethyl)-1H-oxepino[3',4':6,7]-indolizino[1,2-b]quinoline-3,15 [4H, 13H]-dione;

8- ethyl-8,9-dihydro-8-hydroxy-10H,12H-oxepino[3,,4':6,7]indolizino[1,2-b]-pyrido[2,3-g]quinoline-10 ,13 [15H]-dione;

5-ethyl-4,5,9,10,11,12-hexahydro-5-hydroxy-1H,3H-benzo[g]oxepino-p^e.TlindolizinoIl ,2-b]quinoline-3,17 [15H] -dione;

8-Ethyl-8,9-dihydro-8-hydroxy-14H, 10H, 12H-[1,3]dioxino[4,5-g]oxepino-p^e^indolizinotl^-bJquinoline-10.IS [15H] -dione;

7-ethyl-7,8-dihydro-7-hydroxy-1H,9H,11H-oxepino[3',4':6,7]indolizino[1,2-b]-pyrrolo[2,3-g]quinoline -9,12 [14H]-dione;

7-Ethyl-7,8-dihydro-7-hydroxy-1H,9H,11H-imidazo[4,5-g]oxepino[3',4':6,7]-indolizino[1,2-b]quinoline -9,12 [14H]-dione;

7-Ethyl-7,8-dihydro-7-hydroxy-1H,9H,11H-oxepino[3',4':6,7]indolizino[1,2-b]-1,2,3-triazolo[4 ,5- g ]quinoline-9,12 [ 14 H]-dione;

7-ethyl-7,8-dihydro-7-hydroxy-9H,11H-oxepino[3',4':6,7]indolizino[1,2-b]-thiazolo[4,5-g]quinoline- 9,12 [14H]-dione; and

7-ethyl-7,8-dihydro-7-hydroxy-9H,11H-oxazolo[4,5-g]oxepino[3',4':6,7]-indolizino[1,2-b]quinolin- 9,12 [14H]-dione.

Pharmacological examination of the products according to the invention

1. Test on the relaxation activity of DNA induced with topoisomerase 1. All reactions are carried out in a reaction buffer of 20 µl consisting of 50 mM tris-HCl (pH 7.5), 50 mM KCl, 0.5 mM dithiothritol, 10 mM MgCl 2 , 0.1 mM ethyldiaminetetraacetic acid (EDTA), 30 µl/ml bovine albumin serum and 300 ng coiled pUC19 (Pharmacia Biotech, Orsay, France) with or without the compounds to be tested at different concentrations. All the compounds to be tested are first dissolved in 50 mM dimethylsulfoxide (DMSO), the other dilutions being made with distilled water. The final concentration 1 DMSO does not exceed 1% (vol/vol). The reaction is initiated by the addition of one unit of topoisomerase 1 from purified calf thymus DNA (Gibco-BRL. Paisley, UK) and carried out for 15 minutes at 37°C. The reaction is stopped by the addition of 3 µl of a mixture containing 1% sodium dodecyl sulfate, 20 mM EDTA and 500 µg/ml proteinase K (Boehringer, Mannheim, Melan, France). After a further incubation period of 30 min at 37°C, 2 µl of loading buffer containing 10 mM Na 2 HPO 4 , 0.3% bromophenol blue and 16% Ficoll is added to samples subjected to 1.2% to 1 V/cm agar gel electrophoresis for 20 h in a buffer containing 36 mM pH 7.8 Tris-HCl, 30 mM Na 2 PO 4 , 1 mM EDTA and 2 µg/ml chloroquine. The gels are stained with 2 µg/ml ethidium bromide, photographed in 312 nm UV light with photographic equipment and the fluorescence intensity is measured with a bioProfil camera (Vilber Lourmat, Lyon, France) to determine the percentage of relaxed DNA. Each experiment is performed at least three times in duplicate.

In each experiment, the coiled DNA plasmid is incubated alone or with topoisomerase 1. The reaction is completed within 15 minutes. For each test compound or control, the coiled DNA plasmid is incubated in the presence of 500 µM of the compound to be tested with or without enzyme plus the compound, at concentrations of 10 µM, 100 µM, 200 µM and 500 µM. As indicated in Table 1, examples 2, 3, 4, 9, 10 and 11 inhibit the relaxation activity promoted by topoisomerase 1 in a dose-dependent manner.

2. Test of cell proliferation

Eight tumor cell lines are used in this investigation: L1210 (lymphocytic leukemia in mice), HCT15 and LOVO (adenocarcinoma cell lines from human colon), A549 (lung carcinoma in humans), A172, U373 and U87 (glioblastomas in humans). All these lines were obtained from the American Type Collection Cultures (ATCC), Rockville, Md. The cultures of the L1210 cells in suspension are grown in Dulbecco's modified Eagle's medium (DMEM) (BioWhitaker, Verviers, Belgium) with 10% fetal calf serum inactivated

upon heating, 2 mM glutamine, 50 U/ml penicillin and 50 µg/ml streptomycin. HT29 cells are grown in monolayer culturers in a 5aMcCoy medium (Gibco, Paisley, UK) with 10% heat-inactivated fetal calf serum and then supplemented with 2 mM glutamine and 50 µg/ml gentamycin. The other cells are grown in Earles modified essential medium (EMEM); Gibco, Paisley, UK) with 5% heat-inactivated fetal calf serum, 2 mM glutamine, 50 U/ml penicillin and 50 µg/m streptomycin. All cell lines are grown at 37°C in a humidified atmosphere containing 95% air and 5% CO 2 .

Inhibition of proliferation of tumor cell lines is determined by means of an MTT test, where 1500 L1210 cells in a culture medium (according to the need of the cell medium) are cultured in a well of microdish plates (level of tissue culture: 96 wells, flat-bottomed) 24 hours before treatment with the compounds to be investigated. For these dose-response experiments, the cells are incubated with each of the compounds to be investigated or their solvent (control) for 48 hours at a final concentration of 1.10'° to 1.10"4 M. All compounds are dissolved immediately before use in dimethyl sulfoxide ( DMSO) at a concentration of 50 mM. Other dilutions of the drugs are carried out in the culture medium. The final concentration of DMSO never exceeds 0.2% (vol/vol). As a control, the drug solutions are replaced with the solvent which is successively diluted in the same manner as the compounds to be examined.

After the incubation period, the marker reagent MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; Thiazol blue, Sigma M 565, Sigma, St Louis, MO) is added to a final concentration of 0.3 mg/ml to each well. The cells are incubated for 4 hours at 37°C for 4 hours in a humid atmosphere. This step allows the mitochondrial dehydrogenase of the living cells to convert the yellow tetrazolium salt MTT into blue-red formazan crystals. The supernatant is removed and the formazan crystals formed are solubilized with DMSO. The resulting colored solution is quantified by absorbance at 570 nm using a multi-dish scanning spectrophotometer. Data regarding proliferation are expressed as percentage of live cells in the treated wells, divided by live cells in the controls. Each point represents the mean of three independent experiments, each experiment representing six determinations.

For the other cell lines (HCT15, LOVO, A549, A172, U373, U87), 1000 to 2000 cells are seeded in a well of a microwell plate 24 hours before the medical treatment. They are incubated with each of the compounds to be tested or the corresponding solvent (control) for 72 hours at a final concentration of 1.10-<10> to 1.10-6 M.

The results are expressed as percent proliferation calculated by the optical density of the cells treated with a drug divided by the optical density of the control cells (the cells treated with DMSO). As indicated in Table II, the compounds investigated inhibited proliferation of the cells in a dose-dependent manner.

3. Test of development in vivo

The compounds according to the invention are examined in vivo using lymphoblastic leukemia L1210 cell lines from mice. The tumor cells are given by a series of i.p. administrations in mice DBA/2 (Lafacedu, Lyon, France). In the experiment, 106 cells/0.2 ml are injected i.p. in female B6D2F1 mice. Treatment begins on day 1 after inoculation with leukemia and continues until day 4 or often day 8. The compounds to be tested are injected i.p. or i.v. in different concentrations, and the volume injected is regulated to 0.1 ml/10 g body weight. The untreated mice die between day 9 and day 14 after injection of lymphoblastic leukemia L1210 cells and survival of the treated mice is observed for a period of up to 60 days.

The experiment is carried out with 5-ethyl-4,5-dihydro-5-hydroxy-1/7-oxepino[3',4':6,7]-indolizine[1,2-b] quinoline-3,15(4H ,13H)-dione. This compound extended the life of the mice by 50% at concentrations between 0.32 and 2.5 mg/kg administered i.p. for 4 days and at concentrations between 0.32 and 5.0 mg/kg administered i.v. for 8 days.

Claims (27)

1. Compound, characterized in that said compound has formula (I) or formula (II), in racemic or enantiomeric form or any combination of these forms, where Ri represents a lower-alkyl, a lower-alkenyl, a lower- haloalkyl or a lower-alkyl-lower-alkyl; R2. R 3 and R 4 independently represent H, halogen, lower-haloalkyl, lower-alkyl, nitro, amido, lower-amidoalkyl, hydrazino, lower-hydrazinoalkyl, azido, lower-azidoalkyl, (CH2)mNR6R7, (CH2)mOR6, (CH2)mSR6, (CH2)mC(0)R8, OC( 0)NR6R7, (CH2)n[N=X] or (CH2)mOC(0)[N=X] unsubstituted or substituted, wherein the substituent is a lower-alkyl, halogen, nitro, amino, lower-alkylamino, lower -halogenoalkyl, lower-hydroxyalkyl, lower-alkyl or lower-alkyl-lower-alkyl or OC(0)[N=X], or R2 and R3 together form a chain with 3 or 4 links where the mentioned links in the chain are chosen from the group consisting of CH, CH2, O, S, N or NRg; R5 represents H, halogen, lower-haloalkyl, lower-alkyl, lower- Alkoxy, Lower-Alkoxy Lower-Alkyl, Lower-Alkylthio Lower-Alkyl, Lower-Hydroxyalkyl, Nitro, (CH2)mC(0)R8, (CH2)mNR6C(0)R8, (CH2)mNR6R7, (CH2)mN( CH3)(CH2)nNR6R7, (CH2)mOC(O)R8, (CH2)mOC(0)NR6R7. (CH2)n[N=X] or OC(0)[N=X] unsubstituted or substituted, wherein the substituent is a lower-alkyl, halogen, nitro, amino, lower-alkylamino, lower-haloalkyl, lower-hydroxyalkyl, lower-alkoxy or lower-alkoxy lower-alkyl; or (CH2)mOC{0)[N=X]; R6 and R7 independently represent H, a lower-alkyl, lower-hydroxyalkyl, lower-alkylamino-lower-alkyl, lower-aminoalkyl, cycloalkyl, lower-cycloalkyl-alkyl, lower-alkoxy-lower-alkyl, aryl, lower-arylalkyl or lower-haloalkyl; R8 represents H, a lower-alkyl, lower-hydroxyalkyl, lower- alkylamino, lower-alkylamino lower-alkyl, lower-aminoalkyl, cycloalkyl, lower-cycloalkyl-alkyl, lower-alkenyl, lower-alkoxy, lower-alkoxy lower-alkyl, lower-haloalkyl, aryl or lower-aryl-alkyl; R 9 represents H, a lower alkyl or lower haloalkyl; R 10 represents H, a lower-alkyl, lower-haloalkyl or lower- alkoxy; R 1 e represents OR 21 ; R 1 7 represents OR 6 or NR 6 R 7 ; R18. R 19 and R 20 represent H; R 21 represents H, a lower alkyl.CHO or C(O)(CH 2 )mCH 3 ; m is an integer from 0 to 6; n is 1 or 2; and q represents an integer from 0 to 2; and [N=X] represents a 4 to 7 membered heterocyclic group and X represents the chain necessary to complete said heterocyclic group and is selected from the group consisting of O, S, CH2, CH, N, NR9 and COR10; or a pharmaceutically acceptable salt thereof; it being understood that "lower" when it denotes alkyl, alkenyl, alkynyl, alkoxy or alkylthio means up to 6 carbon atoms. 2. Compound according to claim 1, characterized in that Ri represents the ethyl group; or a pharmaceutically acceptable salt thereof. 3. Compound according to claim 2, characterized in that said compound has formula (I); or a pharmaceutically acceptable salt thereof. 4. Compound according to claim 2, characterized in that said compound has formula (II); or a pharmaceutically acceptable salt thereof. 5. Compound according to claim 3, characterized in that R2 and R3 independently represent H, a lower alkyl, halogen, lower haloalkyl or (CH2)mOR6, or R2 and R3, together form a methylenedioxy or an ethylenedioxy; and R4 and R5 independently represent H, a lower alkyl, (CH2)mNR6R7 or (CH2)n[N=X] unsubstituted or substituted by a lower alkyl; or a pharmaceutically acceptable salt thereof. 6. Compound according to claim 5, characterized in that R4 represents H or (CH2)mNR6R7 where R6 and R7 independently represent H or a lower alkyl and R5 represents H, a lower alkyl or (CH2)n[N=X] substituted or unsubstituted, and [N=X] represents the piperazinyl or morpholinyl group, and said substituent is a lower alkyl; or a pharmaceutically acceptable salt thereof. 7. Compound according to claim 6, characterized in that R 2 represents H or a halogen; and R 3 represents H, a lower alkyl, halogen or OR 6 where R 6 represents H, a lower alkyl or lower arylalkyl; or a pharmaceutically acceptable salt thereof. 8. Compound according to claim 7, characterized in that R 2 represents H, chlorine or fluorine; and R 3 represents H, fluoro, chloro, methyl or methoxy; or a pharmaceutically acceptable salt thereof. 9. Compound according to claim 6, characterized in that R2 and R3 together form methylenedioxy or ethylenedioxy; or a pharmaceutically acceptable salt thereof. 10. Compound according to claim 3, characterized in that said compound is selected from the products corresponding to the following formulas: - 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino [3',4':6, 7]-indolizine [1, 2-b) quinoline-3,15 (4H,13H)-dione - 5,12-diethyl-4,5-dihydro-5-hydroxy-1H-oxepino [3',4' :6,7]-indolizino [1,2-b]quinoline-3,15(4H,13H)-dione-8-ethyl-2,3,8,9-tetrahydro-8-hydroxy-10H,12H-[ 1,4] dioxino [2,3-fif] oxepino [3',4':6,7] indolizino [1,2-b] quinoline-10,13 (15H)-dione -10-benzyloxy-5-ethyl -4,5-dihydro-5-hydroxy-1 H -oxepino [3',4':6,7]-indolizino [1,2-b] quinoline-3,15 (4H,13H)-dione - 5- ethyl-4,5-dihydro-5,10,-dihydroxy-1H-oxepino[3',4':6,7]-indolizino[1,2-b]quinoline-3,15 (4H,13H)- dione - 11-(dimethylamino)methyl-5-ethyl-4,5-dihydro-5,10-dihydroxy-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-methoxy-1H-oxepino[3',4':6,7]indolizino [1,2-b]quinoline-3,15(4H,13H)-dione -<g>-chloro-S-ethyM.S-dihydro-S-hydroxy-10-methyl-IH -oxepino^^^e^lindolizino [1,2-b]quinoline-3,15(4H,13H)-dione - 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-1H- oxepino[3',4':6,7]indolizino[1,2-b] quinoline-3,15(4H,13H)-dione - 7-ethyl-7,8-dihydro-7-hydroxy-9H,11H -[1,3] dioxolo [ 4, 5- g] oxepino [3\4':6,7] indolizino [1,2-b] quinoline-9,12[14H]-dione - 9-chloro-5- ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1 H -oxepino [3',4':6,7] indolizino [1,2-b] quinoline-3,15(4H, 13H)- dione - 5-ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1 H -oxepino [3',4':6,7] indolizino [1,2-b] quinoline-3,15(4H ,13H)-dione - 9,11-dichloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline- 3,15(4H,13H)-dione - 5-ethyl-9-flouro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino [3',4':6,7] indolizino [ 1,2-b]quinoline-3,15(4H, 13H)-dione - 5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-1H-oxepino [ 3' A' :§, 7 ] indolizino[1,2-b]quinoline-3,15(4H,13H)-dione -10-chloro-5-ethyl-4,5-dihydro-5-hydroxy-1 H -oxepino [3',4' :6,7]indolizino[1,2-b]quinoline-3,15(4H,13H}-dione - 10-chloro-5-ethyl-9-fl uor-4,5-dihydro-5-hydroxy-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione - 5, 12-diethyl-4,5-dihydro-5,10-dihydroxy-11-morpholino methyl-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15 ( 4H,13H)-dione - 5,12-diethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepinoI^.^ej] indolizino[1,2-b]quinoline- 3,15(4H, 13H)-dione - 5-ethyl-4,5-dihydro-5-hydroxy-12-methyl-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-(4-methyl piperazinomethyl)-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-morpholinomethyl-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione - 5-ethyl-4,5 -dihydro-5-hydroxy-12-(4-methyl piperazinomethyl)-1 H-oxepino [3',4':6,7] indolizino [1,2-b] quinoline-3,15(4H,13H)- dione - 5-ethyl-4,5-dihydro-5-hydroxy-12-piperidinomethyl-1H-oxepino [3',4':6,7]indolizino [1,2-b]quinoline-3,15(4H ,13H)-dione - S-ethyM.S-dihy dro-S-hydroxy-^-morpholinomethyl-1H-oxepinoip'^'^,?] indolizino [1,2-b]quinoline-3,15(4H, 13H)-dione - 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 - 5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-12-morpholinomethyl-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-hydroxy-10-methyl-12-(4-methylpiperazinomethyl)-1H-oxepino[3',4 ':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione - 5-ethyl-9-fluoroM,5-dihydro-5-hydroxy-10-methyl-12-morpholinomethyl -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-piperidinomethyl-1H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione - 8- ethyl-2,3,8,9-tetrahydro-8-hydroxy-16-(4-methyl piperazinomethyl)-1 OH, 12H-[1,4] dioxino [2,3-g] oxepino [3',4' :6,7]indolizino[1,2-b]quinoline-10,13[15H]-dione - 9-chloro-5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-12-morpholinomate yl-1 H- oxepino[3,,4':6,7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione or a pharmaceutically acceptable salt thereof. 11. Compound according to claim 3, characterized in that said compound has the following formula: - 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-1H-oxeptno[3',4':6, 7]indolizino[1,2-b]quinoline-3,15(4H,13H)-dione; or a pharmaceutically acceptable salt thereof. 12. Compound according to claim 4, characterized in that R2 and R3 independently represent H, a lower alkyl, halogen, lower haloalkyl or (CH2)mOR6 or R2 and R3 together form methylenedioxy or ethylenedioxy; R 4 and R 5 independently represent H, lower alkyl, (CH 2 ) mNR 6 R 7 or (CH 2 ) n [N=X] unsubstituted or substituted with lower alkyl; R 20 represents H; R17 represents OR6, where R6 represents H or lower- alkyl or NR 6 R 7 wherein R 6 and R 7 independently represent H, lower alkyl, aryl or lower arylalkyl; or a pharmaceutically acceptable salt thereof. 13. Compound according to claim 12, characterized in that R4 represents H or (CH2)mNR6R7 where R6 and R7 independently represent H or a lower alkyl, R5 represents H, lower alkyl or (CH2)n[N=X] unsubstituted or substituted with lower alkyl and [N=X] is the piperizinyl or morpholinyl group; and R 17 represents OR 6 , where Re represents H or lower alkyl; or a pharmaceutically acceptable salt thereof. 14. Compound according to claim 12, characterized in that R 2 represents H or halogen; R 3 represents H, lower alkyl, halogen or represents OR 6 , where R 6 represents H, lower alkyl or lower arylalkyl; or a pharmaceutically acceptable salt thereof. 15. Compound according to claim 14, characterized in that R 2 represents H, chlorine or fluorine; and R 3 represents H, fluoro, chloro, methyl or methoxy; or a pharmaceutically acceptable salt thereof. 16. Compound according to claim 13, characterized in that R2 and R3 together form dioxymethylene or dioxyethylene; or a pharmaceutically acceptable salt thereof. 17. Compound according to claim 4, characterized in that said compound is selected from the products corresponding to the following formula: - t-butyl-p-ethyl-B-hydroxy-y-(8-hydroxymethyl-9-oxo (11H) -indolizino-[1,2-b]quinolin-7-yl)-propionate - ethyl-p-ethyl-B-hydroxy-7-(8-hydroxymethyl-9-oxo (11H)-indolizino-[1,2- b] quinolin-7-yl)-propionate - p-ethyl-p-hydroxy-γ-(8-hydroxymethyl-9-oxo (11H)-indolizino-[1,2-b] quinolin-7-yl)-propionic acid - methyl-p-ethyl-p-hydroxy-y-(8-hydroxymethyl-9-oxo (11H)-indolizino-[1,2-b] kinotin-7-yl)-propionate - ethyl-p-ethyl-a ,α-difluoro-p-hydroxy-γ-(8-hydroxymethyl-9-oxo (11 H )-indolizino-[1,2-b] quinolin-7-yl)-propionate - ethyl-p-ethyl-p- hydroxy-y-(8-hydroxymethyl-9-oxo (11 H )-indolizino-[1,2-b] quinolin-7-yl)-propionate - tert -butyl-p-ethyl-p-hydroxy-y- (8-Hydroxymethyl-9-oxo (11 H )-indolizino-[1,2-b]quinolin-7-yl)-propionate - p -ethyl-y-(12-ethyl-8-hydroxymethyl-9-oxo ( 11H)-indolizino-[1,2-b]quinolin-7-yl)-p-hydroxy-propionic acid -y-(12-benzyloxy-8-hydroxymethyl-9-ozo (11H)-indolizino[1,2-b]quinolin-7-yl)- p-ethyl-p-hydroxy-propionic acid (E) or a pharmaceutically acceptable salt thereof. 18. Production method for the compounds with formulas I and II according to any one of claims 1 to 17, characterized in that: - α-hydroxylactone of camptothecin with the general formula where R-|, R2, R3, R4, R5 and R20 have the meaning given above, is reduced to the α-hydroxylactol of the general formula A where Ri, R2, R3. R4, R5 and R20 have the meanings given above, - in compound A thus formed the carbon-carbon bond connecting the neighboring carbinols is cut off by treatment with a suitable oxidizing agent which gives the corresponding carbonyls to obtain a compound of the formula B where R 1 , R 2 , R 3 , R 4 . R5 and R20 have the meaning stated above, - treatment is then carried out with a functionalized alkylating agent and the formyl group in the compound of formula B thus formed is cut off to form a B-hydroxyester of the general formula C where Ri, R2, R3. R4. R5, R18. R 19 and R 20 have the meanings given above and R 17 represents OR 6 and R 6 represents lower-alkyl, cycloalkyl, lower-cycloalkyl alkyl, lower-alkenyl, lower-alkoxy-lower-alkyl or aryl or lower-arylalkyl; - said compound with the general formula C is cyclized to form the p-hydroxylactone compound with the general formula D where R-|, R2, R3, R4, R5, R18. R19 and R20 have the meanings given above, - the lactone of general formula D is opened to form the compound of formula E where R 1 , R 2 , R 3 , R 4 , R 5 , R 18 . R19°9 R20 have the meanings given above; R 16 represents OR 21 where R 21 represents H or a lower alkyl; and R 17 represents OR 6 or NHR 6 and R 6 represents H, a lower-alkyl, cycloalkyl, lower-cycloalkyl-alkyl, lower-alkenyl, lower-alkoxy-lower-alkyl or aryl or lower-arylalkyl. 19. Production method for the compounds with the formulas I and II according to any one of claims 1 to 17, characterized in that: - a compound with the general formula M where R-j, R18 and R19 have the meanings given above and R20 represents hydrogen or a halogen atom, is coupled with a 2-halo-3-quinoline-methanol of the general formula N where R 1 , R 2 , R 3 , R 4 and R 5 have the meanings given above and X represents a halogen atom, forming the compound of formula O where Ri t R2, R3, R4, R5, R18, R19, R20 and X have the meanings given above; - then the compound with the general formula O is cyclized to form the compound with the general formula D as defined above. 20. As new industrial products, the compounds of formula M wherein R 1 is a lower-alkyl, lower-alkenyl, lower-alkynyl, lower-haloalkyl, lower-alkoxy-lower-alkyl or lower-alkylthio-lower-alkyl; R 18 and R 19 independently represent H, halogen, lower alkyl, lower alkoxy or hydroxy; and R 20 represents H or halogen it being understood that "lower" when referring to alkyl, alkenyl, alkynyl, alkoxy or alkylthio means up to 6 carbon atoms. 21. Compounds according to claim 20, characterized in that Ri represents ethyl and R18, R19 and R20 represent H. 22. As medicaments the products of formula (I) or (II) as defined in claims 1 to 17, as well as their addition salts with pharmaceutically acceptable mineral-enes organic acids of said products of formula (I) or (II). 23. Pharmaceutical preparations containing the compounds of formula (I) or (II) as defined in claims 1 to 17, as well as their addition salts with pharmaceutically acceptable mineral or organic acids of said products of formula (I) or (II). 24. Use of the products of formula (I) and (II) as defined in any of claims 1 to 17 for the manufacture of medicaments for inhibiting topoisomerase. 25. Use of the products of formula (I) and (II) as defined in any of claims 1 to 17 for the preparation of anti-tumoral drugs. 26. Use of the products of formula (I) and (II) as defined in any of claims 1 to 17 for the manufacture of anti-viral drugs. 27. Use of the products of formula (I) and (II) as defined in any of claims 1 to 17 for the manufacture of anti-parasitic drugs.