RU2190613C2 - Camptothecin analogs, methods of their synthesis and pharmaceutical composition based on thereof - Google Patents

Abstract

FIELD: organic chemistry, biochemistry, pharmacy. SUBSTANCE: invention relates to novel analogs of camptothecin of the formula (I)

where R₁ means alkyl, alkylene, alkynyl; R₂, R₃, R₄ mean H, halogen atom, halogenalkyl, alkyl, alkenyl, -(CH₂)_mOR₆, unsubstituted or substituted phenyl or phenylalkyl; or R₃ and R₄ form in common a chain with 3-4 members that can comprise CH, CH₂, O, N or NR₉; R₃ means H, halogen atom, halogenalkyl, alkyl, alkoxy-group, substituted or unsubstituted phenyl or phenylalkyl; R₆ means H; R₉ means H, alkyl; R₁₈ and R₁₉ mean H, halogen atom, alkyl, alkoxy-group, hydroxy-group; R₂₀ means H, halogen atom; R_p means H, -C(O)-A-NR₂₂R₂₃ where A means alkylene radical; R₂₂ and R₂₃ mean H, alkyl; n = 0-6; if R_p means H then R₃ and R₄ in common form a chain with 3 or 4 members. These compounds show an inhibitory activity with respect to monoisomerase (1) and therefore they can be used as an active component in pharmaceutical composition and for its preparing. Also, the invention relates to methods of synthesis of compound of the formula (I) by interaction of compound of the formula (D)

with a primary amine and by acylation of compound of the formula (D) or (Ia)

with derivatives of C(O)-A-NR₂₂R₂₃. EFFECT: improved methods of synthesis, valuable biochemical properties. 13 cl, 1 tbl, 26 ex

Description

Камптотецин и его аналоги обладают антипролиферативной активностью на нескольких раковых клеточных линиях, включая клеточные линии рака толстой кишки, легкого и молочной железы у человека (Suffness M. et al., The Alkaloids Chemistry and Pharmacology (Химия и фармакология алкалоидов), Bross A. , ed. Vol. 25, p.73 (Academic Press, 1985)). Предполагается, что антипролиферативная активность камптотецина связана с его ингибирующим действием в отношении ДНК топо-изомеразы I.Camptothecin is a naturally occurring compound that was first isolated from the leaves and bark of a Chinese plant called Camptotheca acuminata (see Wall et al., J. Amer. Chem. Soc. 88: 3888 (1966). Camptothecin is a pentacyclic compound formed indolisino [1,2-b] quinoline fragment (rings A, B, C and D) condensed with six-membered α-hydroxylactone (ring E). The carbon at position 20, bearing the α-hydroxyl group, is asymmetric and gives the molecule rotational energy The natural form of camptothecin and has the absolute configuration "S" of carbon 20 and corresponds to the following formula:

Camptothecin and its analogues have antiproliferative activity on several cancer cell lines, including human colon, lung and breast cancer cell lines (Suffness M. et al., The Alkaloids Chemistry and Pharmacology, Chemistry and Pharmacology of Alkaloids), Bross A., ed. Vol. 25, p. 73 (Academic Press, 1985)). It is assumed that the antiproliferative activity of camptothecin is associated with its inhibitory effect against DNA topoisomerase I.

 Moreover, camptothecin and some of its analogues are not soluble in water, which makes them difficult to administer parenterally. Water-soluble derivatives of camptothecin were obtained when rings A and B had substituents capable of forming salts (cf., for example, US patent 4981968, US patent 5049668, European patent 540099). However, these products showed lower antitumor activity than water-insoluble derivatives. Other water-soluble camptothecin derivatives have also been obtained where the hydroxyl group at the 20 position has been esterified with an acid having a salt capable of forming a radical, such as, for example, glycine (cf. US Pat. No. 4,943,579 and PCT WO 96/02546). These derivatives are designated by a specialist in this field under the name "prodrug form", since, being biologically inactive, they become such only in the process of metabolism after administration to the patient. Prodrug forms of camptothecin α-hydroxylactone analogues showed good antitumor efficacy in animals and in clinical trials, but were accompanied by side effects, such as severe diarrhea, which could endanger the patient's life. Therefore, it is necessary to develop water-soluble camptothecin analogs that are more effective and more well tolerated.

 In addition, it is indicated that α-hydroxylactone is absolutely necessary for both in vivo and in vitro activity of camptothecins (Camptothecins: New Anticancer Agents (Camptothecins: new anti-cancer 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)). However, the applicant has shown that 7-membered β-hydroxylactones have biological activity comparable to or superior to the activity of α-hydroxylactones (unpublished PCT application of France 96/00980). The present invention relates to new derivatives of this class of camptothecin analogs in which the 7-membered β-hydroxylactone replaces the natural α-hydroxylactone camptothecin. By β-hydroxylactone is meant a lactone comprising an additional carbon atom between a carboxyl carbon and an α-carbon containing hydroxyl in α-hydroxylactone.

 To increase the water solubility, two solutions of camptothecin analogs were chosen: the first was the introduction of oxazine into ring A of the molecule, and the second was the creation of prodrug forms by acetylation of the hydroxyl function of β-hydroxylactone.

 More specifically, among the new class of camptothecin analogs, the compounds of the present invention are either analogues modified by fixing the oxazine ring at carbons 10 and 11, or prodrug forms in which the natural α-hydroxylactone camptothecin is replaced with β-hydroxylactone. Thus, the compounds in this invention are β-hydroxylactone analogues of camptothecin into which the oxazine ring has been introduced, or are water-soluble proliferative forms and have high biological activity, which is unexpected in light of the development of the prior art in this field.

в рацемической или энантиомерной формах или в виде сочетания этих форм, где:
R₁ представляет низший алкил, низший алкенил, низший алкинил,
R₂, R₃ и R₄ представляют, независимо, Н, галоген, низший галогеналкил, низший алкил, низший алкенил, -(СН₂)_mОR₆, фенил или фенилалкил, замещенный (т. е. замещенный одним до четырех заместителей в фенильной группе) или незамещенный, где заместитель представляет собой низший алкил, галоген или R₃ и R₄ образуют вместе цепь с 3-4 членами, в которой элементы цепи выбраны из группы, состоящей из СН, СН₂, О, N или NR₉;
R₅ представляет Н, галоген, низший галогеналкил, низший алкил, низший алкокси, замещенный или незамещенный фенил или алкилфенил (т.е. замещенный от одного до четырех заместителей в фенильной группе), где заместитель представляет собой низший алкил, галоген;
R₆ представляет Н, низший алкил,
R₉ представляет Н, низший алкил,
R₁₈ и R₁₉ представляют, независимо, Н, галоген, низший алкил, низший алкокси или гидрокси;
R₂₀ представляет Н или галоген;
R_p представляет Н или легко отщепляемую группу, предпочтительно выбранную из групп, соответствующих формуле -С(О)-А-NR₂₂R₂₃, где А представляет линейный или разветвленный алкиленовый радикал, тогда как R₂₂ и R₂₃ представляют, независимо, Н, низший алкил;
m = 0 - 6, целое число;
понимается, что когда R_p представляет атом водорода, R₃ и R₄ вместе образуют цепь с 3 или 4 членами;
или фармацевтически приемлемая соль последних.More specifically, the subject of the invention are compounds of formula (I)

in racemic or enantiomeric forms or in the form of a combination of these forms, where:
R ₁ represents lower alkyl, lower alkenyl, lower alkynyl,
R ₂ , R ₃ and R ₄ are independently H, halogen, lower haloalkyl, lower alkyl, lower alkenyl, - (CH ₂ ) _m OR ₆ , phenyl or phenylalkyl substituted (i.e., substituted with one to four substituents in phenyl group) or unsubstituted, where the substituent is lower alkyl, halogen, or R ₃ and R ₄ form together a chain with 3-4 members, in which the chain elements are selected from the group consisting of CH, CH ₂ , O, N or NR ₉ ;
R ₅ represents H, halogen, lower haloalkyl, lower alkyl, lower alkoxy, substituted or unsubstituted phenyl or alkyl phenyl (i.e., substituted from one to four substituents in the phenyl group), where the substituent is lower alkyl, halogen;
R ₆ represents H, lower alkyl,
R ₉ represents H, lower alkyl,
R ₁₈ and R ₁₉ are independently H, halogen, lower alkyl, lower alkoxy or hydroxy;
R ₂₀ represents H or halogen;
R _p represents H or an easily cleavable group, preferably selected from groups corresponding to the formula —C (O) —A — NR ₂₂ R ₂₃ , where A represents a linear or branched alkylene radical, while R ₂₂ and R ₂₃ represent independently H lower alkyl;
m = 0 - 6, an integer;
it is understood that when R _p represents a hydrogen atom, R ₃ and R ₄ together form a chain with 3 or 4 members;
or a pharmaceutically acceptable salt thereof.

As used here, the term "lower", used in relation to alkyl, alkylthio or alkoxy groups, means linear or branched saturated aliphatic hydrocarbon groups containing from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl , butyl, tert-butyl, methylthio, ethylthio, methoxy and ethoxy. As for alkenyl or alkynyl groups, the term “lower” means groups containing from 2 to 6 carbon atoms and one or more double or triple bonds, such as, for example, vinyl, allyl, isopropenyl, pentenyl, hexanyl, ethynyl, propenyl, propynyl and butynyl groups. The term "cycloalkyl" means a ring of 3-7 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. The term “aryl” means a mono-, di- or tricyclic hydrocarbon compound with at least one aromatic ring, each ring containing alkyl, lower alkenyl, lower alkoxy, lower alkoxy lower alkyl, lower haloalkyl, or substituted or unsubstituted aryl or lower arylalkyl (i.e., substituted one to four times in the aryl group), wherein the substituent is lower alkyl, halogen, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxy lower alkyl;
R ₉ represents H, lower alkyl, lower haloalkyl, aryl or aryl substituted with one or more groups selected from the following radicals: lower alkyl, halogen, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
R ₁₀ represents H, lower alkyl, lower haloalkyl, lower alkoxy, aryl or aryl substituted (i.e., having one to four substituents in the aryl group) with one or more groups selected from the following radicals: lower alkyl, lower haloalkyl, lower hydroxyalkyl or lower alkoxy lower alkyl;
R ₁₁ represents lower alkyl, aryl, (CH ₂ ) _m OR ₁₄ , (CH ₂ ) _m —SR ₁₄ , (CH ₂ ) ₂ NR ₁₄ R ₁₅ or (CH ₂ ) _m [N = X];
R ₁₂ and R ₁₃ are independently lower alkyl, aryl, lower alkoxy, aryloxy or amino;
R ₁₄ and R ₁₅ are independently H, lower alkyl or aryl;
R ₁₆ represents H or OR ₂₁ ;
R ₁₇ represents OR ₆ or NR ₆ R ₇ ;
R ₁₈ and R ₁₉ are independently H, halogen, lower alkyl, lower alkoxy or hydroxy;
R ₂₀ represents H or halogen;
R ₂₁ represents H, lower alkyl, CHO or C (O) (CH ₂ ) _m CH ₃ ;
R _p represents H or an easily cleavable group, preferably selected from groups corresponding to the formula —C (O) —A — NR ₂₂ R ₂₃ , wherein A is a linear or branched alkylene radical optionally substituted with a radical selected from free, esterified or hydroxy salt halogen, free, etherified or salt carboxy, amino, mono- or dialkylamino radicals, while R ₂₂ and R ₂₃ are independently H, lower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, icloalkyl lower alkyl, lower alkenyl, lower alkoxy lower alkyl, lower halogenated or substituted or unsubstituted aryl or lower arylalkyl (i.e., substituted one to four times in the aryl group), where the substituent is lower alkyl, halogen, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;
m = 0 - 6, an integer;
n is 1 or 2; and
q = 0, 1, up to 2; and
[N = X] represents a heterocyclic group with 4-7 members, X represents a chain necessary to complete said heterocyclic group and is selected from the group consisting of O, S, CH ₂ , CH, N, NR ₉ and COR ₁₀ ;
it is understood that when R _p represents a hydrogen atom, R ₃ and R ₄ together form a chain with 3 or 4 members;
or a pharmaceutically acceptable salt thereof.

As used here, the term "lower", used in relation to alkyl, alkylthio or alkoxy groups, means linear or branched saturated aliphatic hydrocarbon groups containing from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl , butyl, tert-butyl, methylthio, ethylthio, methoxy and ethoxy. As for alkenyl or alkynyl groups, the term “lower” means groups containing from 2 to 6 carbon atoms and one or more double or triple bonds, such as, for example, vinyl, allyl, isopropenyl, pentenyl, hexanyl, ethynyl, propenyl, propynyl and butynyl groups. The term "cycloalkyl" means a ring of 3-7 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. The term “aryl” means a mono-, di- or tricyclic hydrocarbon compound with at least one aromatic ring, each ring containing at least 7 members, such as, for example, phenyl, naphthyl, anthracyl, biphenyl or indenyl . The term "halogen" means chlorine, bromine, iodine or fluorine. The radicals corresponding to the expressions "lower haloalkyl", "lower cyanoalkyl", "lower nitroalkyl", "lower amidoalkyl", "lower hydrazinoalkyl", "lower azidoalkyl", "lower arylalkyl", "lower hydroxyalkyl", "lower alkoxy lower alkyl" , “lower alkylthio lower alkyl” and “lower alkyl lower sulfonylalkyl” are substituted with one to three halogens, respectively, cyano, nitro, amido, hydrazino, azido, aryl, hydroxy, lower alkoxy, lower alkylthio or lower sulfonylalkyl groups. The lower alkylamino radical may contain one or two alkyl groups and is, for example, NCH ₃ , NCH ₂ CH ₃ , N (CH ₃ ) ₂ or N (CH ₃ ) (CH ₂ CH ₃ ). The term “free esterified with an ester group,“ esterified with an ether group or hydroxy salt ”refers to OH, OCOR ₂₆ , OR ₂₇ groups and to an alcoholate salt.

 The compounds of the present invention have two possible enantiomeric forms, that is, with “R” and “S” configurations. The present invention includes two enantiomeric forms and any combination of these forms, including “RS” racemic mixtures. In order to simplify, where a specific configuration is not indicated in the structural formula, it should be understood that two enantiomeric forms and mixtures thereof are represented.

As for the prodrug forms of the invention (those for which R _{p is} not a hydrogen atom), products of general formula I are preferred.

 Examples of substituted camptothecins used as starting materials can be found in U.S. Pat. US90 / 05172, US92 / 04611, US93 / 10987, US91 / 09598, EP 94/03058 and EP 95/00393 and European Patent Applications 325247, 495432, 321122 and 540099.

где R₃ представляет собой гидроксильный радикал, R₄ представляет Н, и R₁, R₂, R₅, R₁₈, R₁₉ и R₂₀ имеют указанные выше значения,
обрабатывают первичным амином в условиях Манниха для получения β-гидроксилактонового соединения общей формулы Iа

где R₁, R₂, R₅, R₉, R₁₈, R₁₉ и R₂₀ имеют указанные выше значения.For compounds comprising an oxazine ring:
- β-hydroxylactone compound of the general formula D

where R ₃ represents a hydroxyl radical, R ₄ represents H, and R ₁ , R ₂ , R ₅ , R ₁₈ , R ₁₉ and R ₂₀ have the above meanings,
treated with primary amine under Mannich conditions to obtain a β-hydroxylactone compound of the general formula Ia

where R ₁ , R ₂ , R ₅ , R ₉ , R ₁₈ , R ₁₉ and R ₂₀ have the above meanings.

This method consists in heating the starting product in the presence of a primary amine, such as benzylamine, and formaldehyde in an acidic solvent, such as acetic acid or propionic acid, at a temperature of from 30 ^o to 80 ^o C for from 0.5 to 5 hours. Alternatively, a suspension of the starting material in acetic acid with tri-N-substituted hexahydrotriazine such as hexahydro-1,3,5-trimethyltriazine, 1,3,5-triethylhexahydrotriazine or 1,3,5-tribenzylhexahydrotriazine can be heated at a temperature of 30 ^o C to 80 ^o C for from 0.5 to 5 hours.

где R₁, R₂, R₅, R₉, R₁₇, R₁₈, R₁₉ и R₂₀ имеют указанные выше значения; R₁₆ представляет OR₂₁, где R₂₁ представляет Н или низший алкил; и R₁₇ представляет OR₆ или NHR₆, и R₆ представляет Н, низший алкил, циклоалкил, низший алкил циклоалкил, низший алкенил, низший алкил низший алкокси или арил, или низший алкиларил.- the lactone of general formula Ia is disclosed, optionally in an alkaline medium, to obtain, after neutralization, a compound of formula IIa

where R ₁ , R ₂ , R ₅ , R ₉ , R ₁₇ , R ₁₈ , R ₁₉ and R ₂₀ have the above meanings; R ₁₆ represents OR ₂₁ where R ₂₁ represents H or lower alkyl; and R ₁₇ is OR ₆ or NHR ₆ , and R ₆ is H, lower alkyl, cycloalkyl, lower alkyl cycloalkyl, lower alkenyl, lower alkyl, lower alkoxy or aryl, or lower alkylaryl.

- said compound of general formula D or Ia is optionally acylated, preferably with a derivative of the —C (O) -ANR ₂₂ R ₂₃ radical, as defined above to obtain a β-hydroxylactone compound of general formula Ib, i.e. I, in which R _p differs from H (prodrug form according to the invention).

In the above method, the groups R ₂ , R ₃ , R ₄ and R ₅ can be protected, if necessary, in accordance with conventional methods of protection (Greene T., Protective Groups in Organic Synthesis (Protective groups in organic synthesis) 10-86 (John Wiley & Sons 1981)). If at least one of the R ₂₂ or R ₂₃ groups is H or contains at least one function that is chemically incompatible with the acylation method, for example, such as a primary or secondary amine, then it is necessary to use a protective group that is resistant to acylation conditions . The protecting group commonly used for amines is tert-butoxycarbonyl (BOC). Then the acylation reaction is carried out as described above, then the protective group is cleaved, for example by treatment with trifluoroacetic acid in the case of BOC, to obtain a compound of general formula (I) or (II). The use of protective groups is known to the person skilled in the art (for other examples, refer to T. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons 1981).

где R₁, R₁₈ и R₁₉ имеют указанные выше значения, и R₂₀ представляет собой водород или атом галогена, приводят во взаимодействие с 2-галоген-3-хинолинметанолом общей формулы N

где R₂, R₃, R₄ и R₅ имеют указанные выше значения и Х представляет собой атом галогена, для получения соединения формулы О

где R₁, R₂, R₃, R₄, R₅, R₁₈, R₁₉, R₂₀ и X имеют указанные выше значения,
- затем соединение общей формулы О циклизуют для получения соединения общей формулы D, как определено выше.Compounds of formula D are prepared as follows:
- a compound of the general formula M

where R ₁ , R ₁₈ and R ₁₉ have the above meanings, and R ₂₀ represents hydrogen or a halogen atom, are reacted with 2-halogen-3-quinolinomethanol of the general formula N

where R ₂ , R ₃ , R ₄ and R ₅ have the above meanings and X represents a halogen atom, to obtain a compound of formula O

where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁₈ , R ₁₉ , R ₂₀ and X have the above meanings,
- then the compound of general formula O is cyclized to obtain the compound of general formula D as defined above.

In the above method, the groups R ₁ , R ₂ , R ₃ and R ₄ , if necessary, can be protected in accordance with standard methods of protection (Greene T., Protective Groups in Organic Synthesis (Protective groups in organic synthesis) 10-86 ( John Wiley & Sons 1981)). The formation of compound O, using compounds of the general formulas M and N, is carried out by processing known to the person skilled in the art under the name Mitsunobu reaction (see Mitsunobu O. et al., Synthesis, pl (1981)). The hydroxyl function of compound N is replaced by a nucleophile, such as compound M, or a deprotonated derivative of the latter, by treatment with phosphine, for example triphenylphosphine, and an azodicarboxylate derivative, for example diethyl azodicarboxylate, in an aprotic solvent such as tetrahydrofuran or N, N-dimethylformamide. Compound O is cyclized preferably in the presence of a palladium catalyst (e.g., palladium diacetate) under alkaline conditions (created, for example, by alkali metal acetate, optionally in combination with an interfacial transfer agent, such as, for example, tetrabutylammonium bromide) in an aprotic solvent, such as acetonitrile or N, N-dimethylformamide, at a temperature in the range of 50 ^{° C.} to 120 ^{° C.} (R. Grigg et al., Tetrahedron 46, page 4003 (1990)).

где R₁ и R₂₀ имеют значения, указанные выше, a R₂₄ представляет атом галогена или низший алкокси, защищают ацетальной функцией для получения соединения общей формулы F

где R₁, R₂₀ и R₂₄ имеют указанные выше значения, a Z и Z' группы представляют, независимо, низший алкил или образуют вместе насыщенную углеводородную цепь с 2-4 членами;
- в соединение общей формулы F вводят гидроксиметильную функцию для получения соединения общей формулы G

где R₁, R₂₀, R₂₄, Z и Z' имеют указанные выше значения,
- затем спиртовую функцию соединения общей формулы G защищают для получения соединения общей формулы Н

где R₁, R₂₀, R₂₄, Z и Z' имеют указанные выше значения и R₂₅ представляет собой защитную группу спиртовой функции,
- в ацетале соединения общей формулы Н снимают защиту для получения соединения общей формулы I'

где R₁, R₂₀, R₂₄ и R₂₅ имеют указанные выше значения,
- соединение формулы I' обрабатывают функционализированным алкилирующим агентом для получения β-гидрокси сложного эфира общей формулы J

где R₁, R₂₀, R₂₄ и R₂₅ имеют указанные выше значения, R₁₇, R₁₈ и R₁₉ являются такими, как определено в общей формуле II,
- расщепляют защитную группу R₂₅ в соединении общей формулы J для получения соединения общей формулы К

где R₁, R₁₈, R₁₉, R₂₀ и R₂₄ имеют указанные выше значения, и R₁₇ представляет OR₆ или NHR₆, и R₆ представляет Н, низший алкил, циклоалкил, низший алкил циклоалкил, низший алкенил, низший алкилалкокси или арил или низший алкиларил,
- соединение общей формулы К циклизуют в соединение общей формулы L

где R₁, R₁₈, R₁₉, R₂₀ и R₂₄ имеют указанные выше значения, и, наконец,
- радикал R₂₄ соединения L преобразовывают в карбонил для получения соединения общей формулы М

где R₁, R₁₈, R₁₉ и R₂₀ имеют указанные выше значения.Compounds of general formula M can be prepared according to a process, characterized in that
- carbonyl pyridine of the General formula

where R ₁ and R ₂₀ have the meanings given above, a R ₂₄ represents a halogen atom or lower alkoxy, protect with an acetal function to obtain a compound of General formula F

where R ₁ , R ₂₀ and R ₂₄ have the above meanings, and Z and Z 'groups independently represent lower alkyl or together form a saturated hydrocarbon chain with 2-4 members;
- a hydroxymethyl function is introduced into a compound of general formula F to obtain a compound of general formula G

where R ₁ , R ₂₀ , R ₂₄ , Z and Z 'have the above meanings,
- then the alcohol function of the compound of general formula G is protected to obtain a compound of general formula H

where R ₁ , R ₂₀ , R ₂₄ , Z and Z 'have the above meanings and R ₂₅ represents a protective group of the alcohol function,
- in acetal, compounds of general formula H are deprotected to obtain a compound of general formula I '

where R ₁ , R ₂₀ , R ₂₄ and R ₂₅ have the above meanings,
- the compound of formula I 'is treated with a functionalized alkylating agent to obtain a β-hydroxy ester of the general formula J

where R ₁ , R ₂₀ , R ₂₄ and R ₂₅ have the above meanings, R ₁₇ , R ₁₈ and R ₁₉ are as defined in General formula II,
- cleave the protective group R ₂₅ in the compound of General formula J to obtain a compound of General formula K

where R ₁ , R ₁₈ , R ₁₉ , R ₂₀ and R ₂₄ are as defined above, and R ₁₇ is OR ₆ or NHR ₆ , and R ₆ is H, lower alkyl, cycloalkyl, lower alkyl cycloalkyl, lower alkenyl, lower alkylalkoxy or aryl or lower alkylaryl,
- a compound of general formula K is cyclized to a compound of general formula L

where R ₁ , R ₁₈ , R ₁₉ , R ₂₀ and R ₂₄ have the above meanings, and finally
- the radical R _{24 of} compound L is converted to carbonyl to obtain a compound of general formula M

where R ₁ , R ₁₈ , R ₁₉ and R ₂₀ have the above meanings.

The carbonyl function of 4-acyl-2-halogen-pyridine (obtained, for example, in accordance with Lammattina JL, J. Heterocyclic Chem. 20, p. 553 (1983)) is preferably protected by an acetal function, preferably cyclic acetal, according to standard conditions known a person skilled in the art (Greene T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)). The intermediate thus obtained is treated with sodium or potassium alcoholate in an aprotic solvent (e.g. acetonitrile) or an alcohol derived from the alcoholate at a temperature between 0 ^{° C.} and 100 ^{° C.} to obtain a compound of general formula F. The latter can be lithiated to position 3 when treated with aryl or alkyl lithium (e.g. mesityllithium) in an ether solvent such as tetrahydrofuran, at a temperature between -100 ^° C and 0 ^° C. To the lithium intermediate thus obtained is added a formylating electrophile, such as N, N-dimethylformamide, and the aldehyde thus obtained are treated, after hydrolysis, with a reducing agent, such as sodium borohydride, to obtain a compound of general formula G. The alcohol function of compound G is protected according to standard conditions known to the person skilled in the art areas for the preparation of a compound of general formula N. Examples of protective groups of the alcohol function are those which form ethers (i.e. methyl, methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, benzyloxymethyl, tert-butyl and benzyl (substituted or unsubstituted) and esters (i.e. formate, acetate and isobutyrate). Other examples of primary hydroxyl protecting groups can be referenced in T. Greene, Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981). Deprotection of a compound of general formula H to produce a compound of general formula I ′ is carried out under selective conditions preserving the integrity of the radical R ₂₅ , for example, by treatment under acidic conditions (for example, trifluoroacetic acid). Selective conditions for protecting and deprotecting functional groups are known to those skilled in the art (Greene T., Protective Groups in Organic Synthesis 10-86 (John Wiley & Sons 1981)). The treatment of compound I ′ with a functionalized alkylating agent to produce a β-hydroxy ester of general formula J can be performed using a lithium enolate or a zinc derivative of a carboxylic ester in an anhydrous aprotic solvent, for example tetrahydrofuran. The protective group R _{25 of a} compound of general formula J is cleaved to give a compound of general formula K under deprotection conditions known to one skilled in the art. For example, when R ₂₅ is a benzyl group, an alcohol solution of a compound of general formula J with a palladium catalyst added thereto may be exposed to a hydrogen atmosphere at a pressure of from 0.5 to 10 bar. The thus obtained compound of general formula K can be cyclized under acidic conditions (for example, by treatment with trifluoroacetic acid or hydrogen chloride gas dissolved in an anhydrous solvent such as dichloromethane or dioxane) to give a 7-member β-hydroxylactone ring, such as in a compound of general formula L. Compounds of general formula L can be converted to pyridones of general formula K, for example, by treatment with warm hydrochloric acid or by treatment with trimethylsilyl iodide.

где R₂, R₃ и R₄ имеют значение, указанное в общих формулах соединений I и II. В способе, приведенном ниже, группы R₂, R₃ и R₄, если это необходимо, могут быть защищены в соответствии с обычными способами защиты (Greene Т., Protective Groups in Organic Synthesis (Защитные группы в органическом синтезе) 10-86 (John Wiley & Sons 1981)).2-halo-3-quinolinemethanols of the general formula N can be prepared starting from acetanilides of the general formula P

where R ₂ , R ₃ and R ₄ have the meaning indicated in the General formulas of compounds I and II. In the method below, groups R ₂ , R ₃ and R ₄ , if necessary, can be protected in accordance with the usual methods of protection (Greene T., Protective Groups in Organic Synthesis (Protective groups in organic synthesis) 10-86 ( John Wiley & Sons 1981)).

Thus, compounds of formula N can be prepared according to the following method: N-acetylated the indicated anilines of formula P by treatment with an acetylating agent, such as, for example, acetic anhydride. The acetanilides thus obtained are treated at a temperature ranging from 50 ^{° C.} to 100 ^{° C.} , preferably at 75 ^{° C.} , with a reagent known to those skilled in the art under the name Vilsmeier reagent (obtained by reacting phosphorus oxychloride with N, N-dimethylformamide at a temperature between 0 ^o C and 10 ^o C) to obtain the corresponding 2-chloro-3-quinolinecarbaldehyde (for example, referring to Meth-Cohn et al., J. Chem. Soc., Perkin Trans. I, p. 1520 (1981); Meth- Cohn et al., J. Chem. Soc. Perkin Trans. I, p. 2509 (1981); and Nakasimhan et al., J. Am. Chem. Soc., 112, p. 4431 (1990)). Chlorine at the 2-position of 2-chloro-3-quinolinecarbaldehyde can be replaced with iodine or bromine by heating the product in an inert solvent such as acetonitrile in the presence of an iodide or bromide salt, for example sodium iodide or tetrabutylammonium bromide). Trace amounts of acid, such as concentrated hydrochloric acid, may be necessary to catalyze such a conversion. 2-Halogen-3-quinolinecarbaldehydes are readily reduced to the corresponding 2-halogen-3-quinolinemethanols of the general formula N under standard conditions known to a person skilled in the art, such as treatment in an alcohol solvent (e.g. methanol) with sodium borohydride at a temperature between 0 ^{° C.} and 40 ^o C.

 Compounds of formula N can also be prepared according to the following method: anilines of general formula P as defined above are acylated by reaction with nitrile (such as chloroacetonitrile or propionitrile) in the presence of boron trichloride and other Lewis acid such as aluminum trichloride, titanium tetrachloride or chloride diethylaluminum, 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 compound thus obtained is then treated with ethyl malonyl chloride in an aprotic solvent such as acetonitrile in the presence of a base such as triethylamine, then treated with alkali in an alcohol, for example sodium methylate in methanol, to give ethyl 2-hydroxy-3-quinoline carboxylate substituted in position 4. It is converted to ethyl 2-chloro-3-quinoline carboxylate by treatment with phosphorus oxychloride. When a chloromethyl group is present at position 4 of the quinoline, nucleophilic substitution can be made by treatment with a secondary amine, such as, for example, dimethylamine, N-methyl-piperazine, morpholine or piperidine. Ethyl 2-chloro-3-quinoline carboxylate is then reduced with diisobutylaluminium hydride in an aprotic solvent such as dichloromethane to obtain 2-chloro-3-quinolinomethanol of the general formula N. Analogues of intermediate compounds (N) have been described in the literature and, in particular, in the application PCT 95/05427.

 Some compounds of the invention may be prepared by conventional methods as pharmaceutically acceptable salts. Suitable salts include, by way of example and without limitation, addition salts with inorganic acids, such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, nitrate, or with 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 also represent part of the claimed field of the present invention when they can be used. For other examples of pharmaceutically acceptable salts, reference may be made to Pharmaceutical Salts, J. Pharm. Sci., 66: 1 (1977).

 The compounds of the present invention have useful pharmacological properties. Thus, the compounds of the present invention have an inhibitory effect on topoisomerase I and / or II and antitumor activity. The state of knowledge in this field suggests that the compounds according to the invention have antiparasitic and / or antiviral activities. The compounds of the present invention can also be used for various therapeutic applications.

 In the experimental part, an illustration of the pharmacological properties of the compounds of the invention is presented.

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

 The compounds of the invention also have antitumor activity. They can be used to treat tumors, for example, tumors expressing topoisomerase in a patient, by administering to the latter a therapeutically effective amount of a compound of formula (I). Examples of tumors or cancers include cancer of the esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland, cervix, pineal endometrium, ovaries, prostate, testes, bladder, kidney, liver, pancreas glands, bones, connective tissue, skin, eyes, brain and central nervous system, as well as thyroid cancer, leukemia, Hodgkin's disease (Hodgkin), lymphoma other than Hodgkin's, multiple myeloma and others.

 They can also be used to treat parasitic infections by inhibiting haemoglycemic infections (e.g., trypanosomal or leishmanic infections) or by inhibiting plasmodium (such as malaria), and also treating viral infections and diseases.

 These properties make the products of formula (I) suitable for pharmaceutical use. The subject of this application is also the use of products of formula (I) as defined above, as well as additive salts of these products of formula (I) with pharmaceutically acceptable mineral or organic acids, as medicines, as well as pharmaceutical compositions containing as active ingredient at least at least one of the medicines, as defined above.

 Thus, the invention relates to pharmaceutical compositions comprising a compound of the invention or an addition salt thereof with a pharmaceutically acceptable acid, in combination with a pharmaceutically acceptable carrier in accordance with the chosen route of administration (e.g., oral, intravenous, intraperitoneal, intramuscular, transdermal or subcutaneous). The pharmaceutical composition (eg, therapeutic) may be in solid, liquid, liposome forms or in the form of lipid micelles.

 The pharmaceutical composition may be in solid form, for example, in the form of powders, pills, granules, tablets, liposomes, gelatin capsules or suppositories. The pill, tablet or gelatin capsule may be coated with a substance capable of protecting the composition from the action of acid in the gastric tract or enzymes in the patient’s stomach for a sufficient period of time allowing the composition to pass into the patient’s small intestine in an undigested form. The compound can also be applied locally, for example at the location of the tumor. The compound may also be administered in accordance with a sustained release method (eg, sustained release composition or infusion injection). Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, magnesium carbonate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax. Pharmaceutical compositions containing a compound of the invention may also be presented in liquid form, such as, for example, solutions, emulsions, suspensions or sustained release formulations. Suitable liquid carriers may be, for example, water, organic solvents such as glycerol or glycols, such as polyethylene glycol, as well as mixtures thereof in various proportions in water.

 The subject of the invention is also the use of the products of formula (I) as defined above for the manufacture of drugs intended for the inhibition of topoisomerase, and more specifically, topoisomerase type I or type II, drugs intended for the treatment of tumors, drugs intended for treatment of parasitic infections, as well as drugs intended for the treatment of viral diseases.

 The dose of the compound according to the present invention, intended for the treatment of the above diseases or disorders, varies in accordance with the method of administration, age, body weight of the subject, as well as the state of the latter and will be finally determined by the attending physician or veterinarian. Such an amount, as determined by the attending physician or veterinarian, is referred to herein as an "effective therapeutic amount."

 Unless otherwise specified, all technical and scientific terms used here have the same meanings as is commonly understood by one of ordinary skill in the art to which the invention pertains. Similarly, all publications, patent applications, all patents, and all other references noted herein are incorporated herein by reference.

 The following examples are presented to illustrate the above methods and should not be construed as limiting the scope of the invention.

Preparation of 1: 5-Ethyl-4,5-dihydro-5-hydroxy-1H-oxepino- [3 ', 4': 6,7] indolysin [1,2-b] quinoline-3.15 (4H, 13H) dion
1.a. 4-Ethyl-3,4-dihydroxy-1H-pyrano [3 ', 4': 6,7] -indolisino [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, WI)) in methanol (750 ml) and the resulting mixture was gently heated to 55 ^{° C.} to obtain a clear solution, which was then stirred for 16 hours at ambient temperature. Then the solvent was evaporated under reduced pressure, the residue was taken up in water (250 ml), neutralized by addition of acetic acid (21 ml), and left for 2 hours at 4 ^° C. The resulting suspension was filtered and washed successively with cold water, acetone and diethyl ether, which leads after drying under reduced pressure to obtain the desired product in the form of a white solid, so pl. 280 ^o C.

lb 8-Formyloxymethyl-7-propionylindolisino [1,2-b] -quinolin-9 (11H) -one
A solution of sodium metaperiodate (14 g, 65 mmol) in water is added dropwise to a suspension of 4-ethyl-3,4-dihydroxy-1H-pyrano [3 ', 4': 6,7] indolysin [1,2-b] quinoline -14 (4H, 12H) -one (13.4 g, 38 mmol) in glacial acetic acid (720 ml) and the resulting solution was stirred for one hour at ambient temperature. Then the reaction mixture was poured into ice / water (650 ml), and then the resulting suspension was stirred for half an hour, then filtered and washed successively with water, isopropyl alcohol and diethyl ether, which, after drying under reduced pressure, yielded the desired product (11, 5 g) as a pale yellow solid, mp > 200 ^o C (decomp.).

1. c. tert-Butyl β-ethyl-β-hydroxy-β- (8-hydroxymethyl-9-oxo (11H) -indolisino [1,2-b] quinolin-7-yl) propionate
A zinc suspension (6.5 g, 100 mmol), stirred on a magnetic stir bar in anhydrous diethyl ether (50 ml) under argon, was activated by the addition of chlorotrimethylsilane (0.75 ml, 5.7 mmol) dropwise. Stirring is continued for 15 minutes at ambient temperature, after which the reaction mixture is heated to boiling under reflux. After that, the heating bath was removed and tert-butyl bromoacetate (15 ml, 100 mmol) was added dropwise at such a rate that reflux was maintained. External heating is returned to its place and heating is continued for one hour. The resulting ethereal solution of Reformatsky reagent was allowed to cool to ambient temperature, and then transferred using a cannula into a suspension of 8-formyloxymethyl-7-propionylindolisino [1,2-b] quinolin-9 (11H) -one (1.6 g, 4, 7 mmol) in anhydrous tetrahydrofuran (40 ml) under argon. The reaction mixture was stirred at reflux for one hour, then allowed to cool to ambient temperature and the reaction was stopped by adding saturated ammonium chloride (100 ml) and extraction was carried out with chloroform (3 • 100 ml). The combined chloroform extracts were dried over sodium sulfate, evaporated and the residue was purified by silica gel column chromatography. (1-2% MeOH / CH ₂ Cl ₂ ), which gives 0.64 g (31%) of the desired product as a pale yellow solid, mp 146-149 ^o C.

NMR-1H (CDCl ₃ ): 0.93 (t, 3H); 1.37 (s, 9H); 1.99 (m, 2H); 2.97 (dd, 2H); 3.5 (se, 1H); 5.10 (s, 2H); 5.24 (s, 2H); 7.40 (s, 1H); 7.59 (t, 1H); 7.83 (t, 1H); 7.90 (d, 1H); 8.20 (d, 1H); 8.34 (s, 1H).

NMR-C13 (CDCl ₃ ): 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
1. d. 5-Ethyl-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinoline-3.15 (4H, 13H) -dione
tert-Butyl-β-ethyl-β-hydroxy-β- (8-hydroxymethyl-9-oxo (11H) -indolisino [1,2-b] quinolin-7-yl) propionate (1.45 g, 3, 32 mmol) was dissolved in anhydrous dichloromethane (25 ml) and treated with a saturated solution of hydrogen chloride in dichloromethane (100 ml). The resulting mixture was kept at -20 ^o C for 16 hours. The precipitate was filtered off, washed with methanol and dried under reduced pressure to obtain 662 mg (55%) of the desired product as a yellow solid, mp > 300 ^o 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 (s, 1H).

 NMR-C13 (DMSO): 8.45; 36.48; 42.54; 50.68; 61.44; 73.34; 99.78; 122.71; 127.83; 128.15; 128.75; 129.08; 130.07; 130.61; 131.81; 144.66; 148.04; 152.80; 155.91; 159.26; 172.08.

 IR (KBr): 761; 1127; 1204; 1285; 1580; 1653; 1757.

Preparation 2: Separation of 5-ethyl-4,5-dihydro-5-hydroxy-lH-oxepino [3 ', 4': 6,7] -indolysine [1,2-b] -quinoline-3.15 (4H, 13H) dione
A mixture of β-ethyl-β-hydroxy-β- (8-hydroxymethylindolisino- [1,2-b] quinolin-9- (11H-one-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, followed by warm filtration and allowed to stand for 68 hours. The precipitate is filtered off and washed with ethanol and diethyl ether to give 9 , 8 g of a white solid product. Analysis by high pressure liquid chromatography on a chiral stationary phase ("Chiral HPLC" on a Chiral-AGP column (Chromtech, Stockholm, Sweden) 100 x 4 mm, eluent 2% acetonitrile in 10 mM f in pH 6.9, peaks elute at 4.5 and 7.5 minutes) reveals two peaks integrated as 24% and 76% of the total area of the two peaks respectively.The solid is dissolved in 93% ethanol (350 ml) at refluxing, then allowed to stand for 48 hours, the precipitate is filtered off, then washed with ethanol and diethyl ether to obtain 4.8 g of a white solid, which gives two peaks, which are integrated as 9% and 91% of the total area of the two peaks, respectively, when using chiral HPLC. The solid is dissolved in 50% ethanol (48 ml) under reflux and left for 48 hours. The precipitate is filtered off, then washed with ethanol and ether to obtain 2.7 g of a white solid, which gives two peaks that integrate as 3% and 97% of the total area of two peaks, respectively, using chiral HPLC. The solid is dissolved in 50% ethanol (22 ml) at the boil under reflux and left for 48 hours. The precipitate was filtered off, then washed with ethanol and diethyl ether, to give 1.6 g of a white solid, which gave two peaks, integrated as 1% and 99% of the total area of two peaks, respectively, using chiral HPLC. The resulting diastereomerically enriched salt dissolved in distilled water (20 ml) was treated with acetic acid (0.35 ml, 6.4 mmol) for 15 minutes. The resulting precipitate was filtered off, washed with water, acetone and diethyl ether, then dried in vacuo at 80 ^{° C.} to obtain 1.1 g of a white solid. The latter was dissolved in absolute ethanol (55 ml) with concentrated hydrochloric acid (11.5 N, 11 ml) added to it, to obtain a yellow solution, which was kept under stirring at ambient temperature for 68 hours. The precipitate thus obtained is filtered off and washed with water, ethanol and ether, then dried in vacuo at 80 ^{° C.} to obtain 770 mg of enantiomerically enriched 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino- [3 ', 4 ': 6,7] -indolysine [1,2-b] quinolin-3.15 (4H, 13H) -dione. Chiral HPLC analysis (Chiral-AGP column, eluting with a gradient of 2% to 5% acetonitrile in 10 mM phosphate buffer at pH 6.9, peaks eluting at 15 and 20 minutes) show an enantiomeric excess of 98%. The method described above is repeated, replacing L - (-) - α-methylbenzylamine with D - (+) - α-methylbenzylamine. Thus, the other enantiomer of 5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,7] -indolysine [1,2-b] quinoline-3.15 (4H, 13H) dione.

Preparation of 3: 5,12-diethyl-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,7] -indolisino [1,2-b] quinoline-3.15 (4H, 13H) dion
This compound is obtained in a manner analogous to Example 1, except that in step 1.a. instead of camptothecin, 7-ethyl camptothecin is used (Sawada et al., Chem. Pharm. Bull. 39: 2574 (1991)). The title compound is obtained as a bright yellow solid, mp. > 270 ^o C.

 NMR-1H (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-C13 (DMSO): 8.46; 14.15; 22.42; 36.50; 42.54; 49.95; 61.45; 73.35; 99.68; 122.61; 124.27; 126.76; 127.70; 128.27; 129.92; 130.18; 145.17; 145.82; 148.57; 152.15; 155.89; 159.26; 172.08.

Preparation of 4: 5-Ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,7] -indolisino [1,2-b] -quinoline-3 , 15 (4H, 13H) -dione
4.a. 2-Ethyl-2- (2-methoxy-4-pyridyl) -1,3-dioxolane
From a mixture of 2-chloro-4-propionylpyridine (10 g, 59 mmol) obtained as described in Lamattina JL, J. Heterocyclic Chem., 20, p. 553 (1983), ethylene glycol (20 ml) and p-toluenesulfonic acid (250 mg) in toluene (150 ml) are distilled off water (overnight) by an azeotropic method using a Dean-Stark nozzle. Then, the solvent was removed under reduced pressure, the acid was neutralized with saturated aqueous sodium bicarbonate (100 ml), and the product was extracted with ether. The combined ether extracts were washed with brine, dried over sodium sulfate and evaporated, resulting in 13.3 g (96%) of the carbonyl group protected crude product, which was heated to reflux with 3 equivalents of sodium methoxide in acetonitrile until completion reactions (control by thin layer chromatography: SiO ₂ , tert-butyl methyl oxide / hexane (TBMO / HA, 50/50). After that, the acetonitrile solution was filtered and evaporated. The residue was dissolved in ether, washed with water and brine. m, dried over sodium sulfate and evaporated, getting a brown oil, which is distilled (70-75 ^o C, 0.04 mbar); collecting 10.7 g (total yield 81%) of the product (F) as a clear oil.

4.b. 2-Ethyl-2- (3-hydroxymethyl-2-methoxy-4-pyridyl) -1,3-dioxolane
To a solution of bromomesitylene (13 ml, 85 mmol) in anhydrous tetrahydrofuran (300 ml) at -78 ^° C under argon was added dropwise using a cannula of tert-butyllithium (1.7 M in pentane, 100 ml, 170 mmol). The resulting white precipitate was stirred at -78 ^° C for one hour, then 2-ethyl-2- (2-methoxy-4-pyridyl) -1,3-dioxolane (10 g, 44.8 mmol) was added and the reaction mixture was stirred for 15 minutes at -78 ^o C, for one hour at 0 ^o C and for one hour at ambient temperature. After repeated cooling to -78 ^{° C.} , anhydrous N, N-dimethylformamide (100 ml) was added and the reaction mixture was allowed to warm to ambient temperature, then stirred for 16 hours, followed by analysis by thin layer chromatography (SiO ₂ , TBMO / HA , 50/50) shows that the original product has been used up completely. The reaction was stopped with saturated ammonium chloride and the reaction mixture was extracted with diethyl ether (200 ml, 50 ml, 50 ml). The combined extracts were dried over sodium sulfate and evaporated to give a yellow oil, which was purified by column chromatography (SiO ₂ , TBMO / HA: 0/100 to 5/95, eluting with mesitylene derivatives, then 20/80 to 50/50, eluting with the product) obtaining an intermediate aldehyde (7 g). The aldehyde was dissolved in methanol (100 ml) and treated with sodium borohydride (5 g, 132 mmol) and the resulting mixture was stirred until the intermediate aldehyde was completely consumed (approximately 1 hour) with analytical control by thin layer chromatography. Then the solvent was evaporated, the residue was dissolved in ether, washed with water and brine, dried and the solvent was evaporated. Column chromatography (SiO ₂ , TBMO / HA; 10/90 to 50/50) of the residue gives 7 g (total yield 62%) of product (G) as a yellow oil.

4.s 2- (3-Benzyloxymethyl-2-methoxy-4-pyridyl) -2-ethyl-1,3-dioxolane
A solution of 2-ethyl-2- (3-hydroxymethyl-2-methoxy-4-pyridyl) -1,3-dioxolane (7 g, 30 mmol) and benzyl chloride (5 ml, 45 mmol) in anhydrous tetrahydrofuran (50 ml) was 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 was kept at reflux for 16 hours. Then the reaction mixture was allowed to cool to ambient temperature, the reaction was stopped with water (50 ml) and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in diethyl ether (150 ml), washed with water and brine, dried and evaporated. Purification by column chromatography (SiO ₂ , TBMO / HA: 5/95 to 20/80) afforded benzyl (H) protected product, 9 g (87%) as a clear oil.

4.d. 1- (3-Benzyloxymethyl-2-methoxy-4-pyridyl) propan-1-one
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 ^o C for 3 hours. The reaction mixture was concentrated under reduced pressure and the residual acids were neutralized by the addition of saturated aqueous sodium bicarbonate. Extraction is carried out with diethyl ether followed by column chromatography (SiO ₂ , TBMO / HA: 10/90), which gives 5.5 g (70%) of product (I).

4. E. tert-Butyl-β-ethyl-β-hydroxy-β- (3-benzyloxymethyl-2-methoxy-4-pyridyl) propionate
tert-Butyl bromoacetate (13 ml, 80 mmol) was added dropwise to a suspension of zinc (5.3 g, 80 mmol, activated with 6 N HCl for 10 seconds, then washed successively with water until neutral pH, acetone and diethyl ether) were added to anhydrous tetrahydrofuran (60 ml) at the boil under reflux. Upon completion of the dropwise addition, the reaction medium was kept at the boil under reflux for another 10 minutes. Then a solution of 1- (3-benzyloxymethyl-2-methoxy-4-pyridyl) propan-1-one (5.8 g, 20 mmol) in anhydrous tetrahydrofuran (20 ml) was added and the reaction mixture was stirred at reflux in for one hour. The reaction was stopped at 0 ^{° C.} with saturated aqueous ammonium chloride (100 ml) and the reaction mixture was extracted with diethyl ether. The combined extracts were dried over sodium sulfate and evaporated to give a yellow oil, which was purified by column chromatography (SiO ₂ , TBMO / HA: 5/95 to 10/90) to give tert-butyl ester (J) (7 g, 85%) in the form of a clear oil.

4.f. tert-Butyl-β-ethyl-β-hydroxy-β- (3-hydroxymethyl-2-methoxy-4-pyridyl) propionate
tert-Butyl-β-ethyl-β-hydroxy-β- (3-benzyloxymethyl-2-methoxy-4-pyridyl) propionate (1 g, 2.5 mmol) is subjected to hydrogenolysis at atmospheric pressure and at ambient temperature using as a catalyst, 5% palladium-carbon (50 mg) and absolute ethanol as a solvent (10 ml). After completion of the reaction (6 hours), the catalyst was separated by filtration and the solvent was evaporated, which afforded 0.7 g (90%) of product (K) of sufficient purity for subsequent synthetic use.

4. g. 5-Ethyl-1,5-dihydro-5-hydroxy-9-methoxy-oxepino- [3,4-C] pyridin-3 (4H) -one
tert-Butyl-β-ethyl-β-hydroxy-β- (3-hydroxymethyl-2-methoxy-4-pyridyl) propionate (8.8 g, 28 mmol) is treated with trifluoroacetic acid (30 ml) for 3 hours at ambient temperature. Volatile components are evaporated and the residue is purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH: 100/0 to 98/2), which gives a clear oil, which after treatment with toluene gives 5.9 g of product (L) (89 %) in the form of white crystals, so pl. 97-98 ^o C.

4. h. 5-Ethyl-1,5-dihydro-5-hydroxy-oxepino [3,4-c] pyridin-3,9 (4H, 8H) -dione
5-Ethyl-1,5-dihydro-5-hydroxy-9-methoxy-oxepino [3,4-c] pyridin-3 (4H) -one (0.5 g, 2.1 mmol) is heated at the boil with reflux for 9 hours in 1 N. hydrochloric acid (20 ml). The reaction mixture was concentrated under reduced pressure and the residue was again dried by adding and evaporating toluene twice, then left overnight under reduced pressure in the presence of phosphorus pentoxide. The resulting oil was dissolved in anhydrous acetonitrile (5 ml) and stirred under argon for 24 hours. The precipitate was filtered off and dried, yielding 0.23 g (49%) of a white solid (M), mp 118-119 ^o C.

4.i. 2-Chloro-6,7-difluoro-3-quinoline-methanol
The method described by Meth-Cohn et al., J. Chem. Is used. Soc. Perkin Trans. I, p. 1520 (1981); Meth-Cohn, J. Chem. Soc. Perkin Trans. I, p. 2509 (1981). 3,4-Difluoroacetanilide (38 g, 22 mmol) was added to the Vilsmeier reagent obtained by adding dropwise phosphorus oxychloride (103 ml, 1.1 mol) to anhydrous dimethylformamide (34 ml, 44 mmol), cooled in a water / ice bath and again stirred for 0.5 hours in an argon atmosphere. The resulting mixture was heated at 70 ^{° C.} for 16 hours. After cooling to ambient temperature, the reaction mixture was added to a mixture of ice and water (400 ml), which was kept under stirring for 2 hours, then filtered and washed successively with water, ethanol and ether to obtain 9 g of 2-chloro-6,7- difluoroquinoline-3-carbaldehyde as a yellow solid, mp. 222-224 ^o C. This intermediate compound is treated with sodium borohydride (2 g, 52 mmol) in methanol (400 ml) at ambient temperature for 0.5 hours, then the excess reagent is destroyed by adding acetic acid (2 ml). The solvent was removed under reduced pressure, the residue was taken up in ethyl acetate and washed successively with dilute sodium bicarbonate, water and a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and concentrated. The resulting solid was recrystallized from 1,2-dichloroethane to give 8 g of 2-chloro-6,7-difluoro-3-quinolinomethanol as a beige solid.

4. j. 5-Ethyl-8- (2-chloro-6,7-difluoro-3-quinodinmethyl) -1,5-dihydro-5-hydroxy-oxepino [3,4-c] pyridin-3,9 (4H, 8H) dion
To a solution of 5-ethyl-1,5-dihydro-5-hydroxy-oxepino [3,4-c] pyridin-3,9 (4H, 8H) -dione (400 mg, 1.79 mmol), the compound obtained in the previous step 4.i., (770 mg, 2.23 mmol) and triphenylphosphine (934 mg, 3.58 mmol) in anhydrous N, N-dimethylformamide (45 ml), diethyl azodicarboxylate (570 ml, 3.6) was added dropwise. mmol) for 5 minutes and the resulting mixture was stirred in argon at ambient temperature for 16 hours. Then the reaction mixture was concentrated under reduced pressure and the residue was dissolved in diethyl ether (100 ml). The resulting solution was washed with brine (4 x 50 ml), dried over sodium sulfate and evaporated. The residue was purified by column chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH: 99/1 to 98/2), which afforded 650 mg (66%) of the product (0) as a white solid, mp. 165-167 ^o C.

4. k. 5-Ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinoline-3.15 (4H, 13H) dion
5-Ethyl-8- (2-chloro-6,7-difluoro-3-quinolinomethyl) -1,5-dihydro-5-hydroxy-oxepino [3,4-c] pyridin-3,9 (4H, 8H) -dione (600 mg, 1.1 mmol), tetrabutylammonium bromide (352 mg, 1.1 mmol), sodium acetate (359 mg, 4.4 mmol) and palladium II acetate (98 mg, 0.43 mmol) are dissolved in anhydrous acetonitrile (40 ml) and heated at 90 ^o C in argon for 16 hours. After cooling to ambient temperature, a white precipitate is isolated from the reddish solution. This precipitate is filtered off and dried under reduced pressure. The crude product is suspended in water, filtered and dried under reduced pressure over phosphorus pentoxide, which gives 250 mg of the target compound as a beige solid product, so pl. > 250 ^o C.

 NMR-1H (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 (sextet, 1H); 7.33 (s, 1H); 7.54 (s, 1H); 7.55 (s, 1H); 8.43 (s, 1H).

 NMR-C13 (DMSO): 8.43; 36.47; 42.54; 50.52; 61.43; 64.43 (2C); 73.31; 99.07; 112.27; 113.14; 122.00; 124.24; 128.18; 129.74; 144.59; 145.01; 145.33; 147.63; 150.88; 155.88; 159.23; 172.07.

Preparation of 5: 5-Ethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinoline-3.15 (4H, 13H ) -dion
10-Benzyloxy-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino- [3 ', 4': 6,7] indolisino [1,2-b] quinoline-3.15 (4H, 13H ) -dione (370 mg, 0.79 mmol) is treated with hydrogen at atmospheric pressure and ambient temperature using 10% palladium on carbon (60 mg) and trifluoroacetic acid (15 ml) as a solvent as a catalyst. After completion of the reaction (16 hours), dichloromethane (50 ml) and methanol (50 ml) were added to the reaction mixture, the catalyst was filtered off and the volatile components were evaporated under reduced pressure, resulting in a crude target product containing trace amounts of trifluoroacetic acid. These trace amounts are removed by co-distillation with 1,4-dioxane. The product is obtained in the form of an orange solid, so pl. 150 ^o C (decomp.), A sufficient degree of purity for subsequent synthetic use.

 NMR-1H (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 (sextet, 1H); 7.26 (s, 1H); 7.31 (s, 1H); 7.40 (d, 1H); 8.00 (d, 1H); 8.42 (s, 1H); 10.32 (s, 1H).

 NMR-C13 (DMSO): 8.47; 36.50; 42.61; 50.57; 61.46; 73.35; 98.84; 109.02; 121.83; 123.18; 129.50; 129.85; 130.12; 130.80; 143.39; 145.10; 149.69; 155.97; 156.82; 159.30; 172.11.

Preparation of 6: 5-Ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino [3 ', 4': 6,7] indolisino- [1,2-b] quinoline- 3.15 (4H, 13H) -dione
This compound is prepared from 3-fluoro-4-methoxyaniline according to the method illustrated in steps 4i, 4j and 4k of Preparation 4. Yellow solid, mp. > 250 ^o C.

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

 NMR-C13 (DMSO): 8.43; 36.48; 42.51; 50.68; 56.60; 61.42; 73.29; 99.25; 108.68; 113.52; 122.23; 126.33; 129.99; 130.30; 143.79; 144.70; 148.42; 151.18; 153.19; 155.81; 159.20; 172.06.

 IR (KBr): 1259; 1503; 1602; 1737.

Preparation 7: 9-Chloro-5-ethyl-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino [3 ', 4': 6,7] indolisino- [1,2-b] quinoline- 3.15 (4H, 13H) -dione
This compound is obtained from 3-chloro-4-methoxyaniline in accordance with the method illustrated in steps 4i, 4j and 4k of Preparation 4, as a yellow solid, mp. > 250 ^o C.

NMR-1H (DMSO): 0.35 (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 (s, 1H)
NMR-C13 (DMSO): 8.43; 20.20; 36.47; 42.49; 50.67; 61.41; 73.28; 99.87; 122.82; 126.98; 127.99; 129.60; 130.53; 131.08; 135.64; 136.56; 144.39; 147.11; 153.10; 155.85; 159.18; 172.03.

 IR (KBr): 1208; 1479; 1606; 1656; 1724.

Preparation 8: 8-Ethyl-2,3,8,9-tetrahydro-8-hydroxy-10H, 12H- [1,4] dioxino [2,3-g] oxepino- [3 ', 4': 6.7 ] indolisino [1,2-b] quinoline-10,13 (15H) -dione
This compound is obtained from 3,4-ethylenedioxyaniline in accordance with the method illustrated in steps 4i, 4j and 4k of Preparation 4, as a yellow solid, mp. > 250 ^o C.

 NMR-1H (DMSO); 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.47 (d, 1H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H); 7.39 (s, 1H); 8.15 (q, 1H); 8.25 (q, 1H); 8, 68 (s, 1H).

 NMR-C13 (DMSO): 8.41; 36.45; 42.48; 50.68; 61.40; 73.25; 99.92; 114.44; 115.42; 115.58; 122.96; 125.52; 130.56; 131.46; 144.21; 145.25; 142.36; 153.41; 155.85; 159.15; 172.00.

 IR (KBr): 1266; 1512; 1581; 1618; 1751.

Preparation 9: 7-Ethyl-7,8-dihydro-7-hydroxy-9H, 11H- [1,3] dioxolo [4,5-g] oxepino [3 ', 4': 6,7] -indolisino [1 , 2-b] quinoline-9,12 (14H) -dione
This compound is obtained from 3,4-methylenedioxyaniline in accordance with the method illustrated in steps 4i, 4j and 4k of Preparation 4, as a cream-colored solid, mp. > 250 ^o C.

 NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 5.20 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.00 (s, 1H); 6.30 (s, 2H); 7.30 (s, 1H); 7.49 (d, 2H); 8.45 (s, 1H).

 NMR-C13 (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; 1458; 1606; 1731.

Preparation 10: 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 in accordance with the method illustrated in steps 4i, 4j and 4k of Preparation 4, as a white solid, mp. > 250 ^o C.

 NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 4.01 (s, 3H); 5.22 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.02 (s, 1H); 7.31 (s, 1H); 7.68 (s, 1H); 8.20 (s, 1H); 8.55 (s, 1H).

 NMR-C13 (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.

Preparation 11: 5-Ethyl-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] -quinoline-3.15 ( 4H, 13H) -dion
This compound is obtained from 4-methoxyaniline in accordance with the method illustrated in steps 4i, 4j and 4k of Preparation 4. Yellow solid, mp. > 250 ^o C.

 NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 3.95 (s, 3H); 5.28 (s, 2H); 5.40 (d, 1H); 5.51 (d, 1H); 6.00 (s, 1H); 7.38 (s, 1H); 7.51 (d, 2H); 8.07 (d, 1H); 8.55 (s, 1H).

 NMR-C13 (DMSO): 8.45; 36.48; 42.51; 50.64; 55.92; 61.42; 73.33; 99.01; 106.49; 122.02; 123.19; 129.59; 130.20; 130.43; 144.17; 144.94; 150.40; 155.92; 158.31; 159.26; 172.07.

 IR (KBr): 1251; 1604; 1655; 1735.

Preparation 12: 9,11-Dichloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] -quinoline-3, 15 (4H, 13H) -dione
This compound is obtained from 3,5-dichloroaniline in accordance with the method illustrated in steps 4i, 4j and 4k of Preparation 4, as a yellow solid, mp. > 250 ^o C.

 NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 5.30 (s, 2H); 5.41 (d, 1H); 5.55 (d, 1H); 6.08 (s, 1H); 7.41 (s, 1H); 8.05 (s, 1H); 8.21 (s, 1H); 8.91 (s, 1H).

 NMR-C13 (DMSO): 8.39; 36.45; 42.51; 51.03; 61.39; 73.25; 100.62; 123.55; 124.63; 127.60; 128.08; 128.56; 132.06; 132.19; 134.53; 143.77; 148.80; 154.88; 155.82; 159.13; 171.98.

 IR (KBr): 1064; 1275; 1586; 1651; 1743.

Preparation 13: 5-Ethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methyl-1H-oxepino [3 ', 4': 6,7] indolisino- [1,2-b] quinoline- 3.15 (4H, 13H) -dione
This compound is obtained from 3-fluoro-4-methylaniline in accordance with the method illustrated in steps 4i, 4j and 4k of Preparation 4. Yellow solid, mp. > 250 ^o C.

 NMR-1H (DMSO): 0.89 (t, 3H); 1.85 (q, 2H); 2.49 (s, 3H); 3.08 (d, 1H); 3.49 (d, 1H); 5.21 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H); 7.39 (s, 1H); 7.87 (d, 1H); 8.05 (d, 1H); 8.61 (s, 1H).

 NMR-C13 (DMSO): 8.40; 15.14; 36.45; 42.52; 50.60; 61.41; 73.28; 99.71; 112.00; 122.66; 125.38; 127.66; 129.59; 130.28; 144.49; 147.88; 152.88; 155.85; 159.18; 162.25; 172.02.

 IR (KBr): 1054; 1580; 1651; 1760.

Preparation 14: 5-Ethyl-10-fluoro-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] -quinoline-3.15 ( 4H, 13H) -dion
This compound is obtained from 4-fluoroaniline in accordance with the method illustrated in steps 4i, 4j and 4k of Preparation 4, as a white solid, mp. > 250 ^o C.

 NMR-1H (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-C13 (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.

Getting 15: 10-Chloro-5-ethyl-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] -quinoline-3.15 ( 4H, 13H) -dione
This compound is obtained from 4-chloroaniline in accordance with the method illustrated in steps 4i, 4j and 4k of preparation 4. Yellow solid, mp. > 250 ^o C.

 NMR-1H (DMSO); 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.47 (d, 1H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H); 7.39 (s, 1H); 7.89 (d, 1H); 8.19 (d, 1H); 8.29 (s, 1H); 8.67 (s, 1H).

 NMR-C13 (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.

Preparation 16: 9-Chloro-5-ethyl-10-fluoro-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinolin-3 , 15 (4H, 13H) -dione
This compound is obtained from 4-chloro-3-fluoroaniline in accordance with the method illustrated in steps 4i, 4j and 4k of Preparation 4, as a yellow solid, mp. > 250 ^o C.

 NMR-1H (DMSO); 0.85 (t, 3H); 1.85 (q, 2H); 3.07 (d, 1H); 3.45 (d, 1H); 5.25 (s, 2H); 5.39 (d, 1H); 5.51 (d, 1H); 6.05 (s, 1H); 7.40 (s, 1H); 8.20 (d, 1H); 8.40 (d, 1H); 8.68 (s, 1H).

NMR-C13 (DMSO): 8.38; 36.47; 42.58; 50.71; 61.40; 73.26; 99.99; 113.59; 123.09; 124.28; 127.74; 130.64; 131.31; 144.13; 145.08; 153.57; 154.13; 155.84; 156.61, 159.14; 172.00,
IR (KBr): 1488; 1583; 1655; 1743.

Preparation 17: 5,12-Diethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinoline -3.15 (4H, 13H) -dione
17.a. 5-fluoro-4-methoxy-2-propionylaniline
(This product was obtained according to Sugasawa T .; Toyoda T .; Adachi M .; Sasakura K., J. Am. Chem. Soc., 100 (1978), p. 4842-4852). Boron trichloride (1 M in heptane, 156 ml, 156 mmol) at 0 ^{° C.} under argon is added dropwise to a solution of 3-fluoro-4-methoxyaniline (20 g, 142 mmol) in anhydrous dichloromethane (200 ml). The pink suspension thus obtained was kept under stirring for 5 minutes, then propionitrile (33 ml, 420 mmol) was added dropwise, and then aluminum trichloride (20.8 g, 156 mmol) was added in small portions. The reaction mixture was refluxed for 3 hours, cooled to 0 ^{° C.} , hydrolyzed, carefully adding 2N. hydrochloric acid (100 ml), then refluxed for 45 minutes. After cooling to 0 ^{° C., the} precipitate formed is filtered off, washed with dichloromethane, and then placed in water (300 ml). The aqueous phase is made basic to an alkaline pH, extracted with dichloromethane and then with ethyl acetate. The organic phase was dried (MgSO ₄ ) and then evaporated to give a crude product, which was purified by column chromatography (SiO ₂ , AcOEt / heptane: 1/99 to 20/80). 15.3 g of a yellow solid are obtained.

NMR-1H (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.

17.b. Ethyl 4-ethyl-7-fluoro-2-hydroxy-6-methoxy-3-quinolinecarboxylate
A solution of ethyl malonyl chloride (12.9 ml, 100 mmol) in anhydrous acetonitrile (30 ml) was added dropwise in argon at 0 ^{° C.} 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). The reaction mixture was allowed to warm to ambient temperature, a solution of sodium ethylate (obtained from 1.8 g, 78 mmol of sodium in 80 ml of ethanol) was added dropwise through a cannula in argon, then the reaction mixture was stirred for 12 hours at ambient temperature. The reaction mixture was poured into ice-cooled water (100 ml) and stirred for two hours, then the precipitate was filtered off and washed with water, ethanol and ether. 19.4 g of a white solid are obtained.

 NMR-1H (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 (s, 1H).

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

17.c. Ethyl 2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate
A suspension of ethyl 4-ethyl-7-fluoro-2-hydroxy-6-methoxy-3-quinoline carboxylate (19.4 g, 0.066 mol) in phosphoryl chloride (243 ml) was heated at the boil under reflux for 6 hours. Phosphoryl chloride is distilled off. The reaction mixture is decanted into ice-cooled water, then placed in dichloromethane to dissolve. The organic phase is washed with water, then with a saturated solution of sodium chloride. The organic phase was dried over magnesium sulfate and the solvent was evaporated. The residue was suspended in diethyl ether and the unreacted starting material (4 g) was filtered off. The filtrate was evaporated and the residue was purified by column chromatography (SiO ₂ , AcOEt / heptane: 5/95 to 20/80). 10.9 g of a white solid are obtained.

 NMR-1H (DMSO): 1.30 (t, 3H); 1.39 (t, 3H); 3.08 (q, 2H); 4.09 (s, 3H); 4.49 (q, 2H); 7.64 (d, 2H); 7.86 (d, 2H).

 IR (KBr): 865; 1016; 1082; 1190; 1224; 1253; 1272; 1508; 1571; 1732.

17.d. 2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinomethanol
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) was treated dropwise at ambient temperature in an inert atmosphere diisobutylaluminum hydride (1 M in dichloromethane, 65 ml, 65 mmol), then heated at 40 ^{° C.} for 4 hours. After cooling to 0 ^{° C.} , a 20% aqueous solution of Rochelle's salt (Ro-cheile) (105 ml) and dichloromethane (200 ml) are carefully added and the reaction mixture is kept under stirring for 1 hour, after which it is decanted and washed three times with water. The organic phase was dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography (SiO ₂ , AcOEt / heptane: 5/95 to 50/50). 6 g of a white solid are obtained.

 NMR-1H (DMSO): 1.28 (t, 3H); 3.25 (q, 2H); 4.04 (s, 3H); 4.77 (d, 2H); 5.27 (t, 1H); 7.55 (d, 2H); 7.73 (d, 2H).

 IR (KBr): 840; 864; 1023; 1232; 1267; 1317; 1444; 1511; 1569.

 17. E. 5,12-Diethyl-9-fluoro-4,5-dihydro-5-hydroxy-10-methoxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] -quinoline-3.15 (4H, 13H) -dione.

2-Chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinomethanol was reacted with the compound (M) as described in Step 4j of Preparation 4. The resulting product was cyclized in accordance with the method described in Step 4. k. Get a yellow solid product, so pl. > 275 ^o C.

 NMR-1H (CF3COOD); 1.07 (m, 3H); 1.62 (m, 3H); 2.27 (m, 2H); 3.44 (d, 1H); 3.54 (m, 2H); 3.91 (d, 1H); 4.25 (s, 3H); 5.60 (d, 1H); 5.74 (s, 2H); 5.98 (d, 1H); 7.85 (m, 1H); 8.16 (m, 1H); 8.31 (s, 1H).

 NMR-C13 (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.

Getting 18: 5-Ethyl-4,5-dihydro-5-hydroxy-12-methyl-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] -quinoline-3.15 ( 4H, 13H) -dione
To obtain 2-chloro-4-methyl-3-quinolinomethanol, the method described in examples 17.b., 17.c. and 17.d. applied to 2-acetaniline. The latter is reacted with compound (M) as described in step 4.j. 4. The resulting product is cyclized in accordance with the method described in stage 4.k. Get a yellow solid product, so pl. > 260 ^o C.

 NMR-1H (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-C13 (DMSO): 8.23; 36.26; 42.36; 62.00; 73.11; 78.65; 79.13; 79.25; 99.52; 122.36; 124.30; 127.67; 129.54; 129.55; 129.56; 140.11; 145.06; 148.07; 152.00; 155.79; 159.09; 171.89.

 IR (KBr): 1649; 1751; 3404.

Preparation 19: 10-Benzyloxy-5-ethyl-9-fluoro-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinolin-3 , 15 (4H, 13H) -dione
The method presented in step 4.i. is used for 3-fluoro-4-methoxyacetanilide to obtain 2-chloro-7-fluoro-6-methoxyquinoline-3-carbaldehyde, which is treated with excess boron tribromide in dichloromethane at ambient temperature for 24 hours The resulting 2-chloro-7-fluoro-6-hydroxyquinoline-3-carbaldehyde O-benzylated in dimethylformamide in the presence of benzyl bromide and potassium carbonate to obtain 6-benzyloxy-2-chloro-7-fluoroquinoline-3-carbaldehyde, which is reduced with sodium borohydride in methanol to obtain the corresponding quinolinomethanol. The latter is introduced into the coupling reaction with the compound (M) as described in step 4.j. 4. The resulting product of the coupling reaction is cyclized in accordance with the method described in step 4.k. Get a yellow solid product, so pl. > 275 ^o C.

 NMR-1H (DMSO); 0.86 (t, 3H); 1.85 (q, 2H); 3.5 (d, 1H); 5.25 (s, 2H); 5.37 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.4-7.6 (m, 5H); 7.88 (d, 1H]; 7.95 (d, 1H); 8.56 (s, 1H).

Preparation of 20: 5-Ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy-1H-oxepino [3 ', 4', 6,7] indolisino- [1,2-b] quinolin-3 , 15 (4H, 13H) -dione
The compound of Example 19 (0.79 mmol) dissolved in trifluoroacetic acid (15 ml) was treated with hydrogen using 10% palladium-carbon (60 mg). Get a yellow solid product, so pl. > 275 ^o C.

 NMR-1H (DMSO); 0.86 (t, 3H); 1.85 (q, 2H); 3.05 (d, 1H); 5.25 (s, 2H); 5.37 (s, 2H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.8 (d, 1H); 7.90 (d, 1H); 8.56 (s, 1H).

 The above production methods illustrate the invention using the following examples.

Example 1: 5-Ethyl-9,10-difluoro-4,5-dihydro-5- (2-amino-1-oxoethoxy) -1H-oxepino [3 ', 4',: 6,7] indolysino- [1 , 2-b] quinolin-3.15 (4H, 13H) -dione
a. 5-Ethyl-9,10-difluoro-4,5-dihydro-5- (2- (tert-butyloxycarbonyl-amino) -1-oxoethoxy) -1H-oxepino hydrochloride [3 ', 4', 6.7] indolisino [1,2-b] quinolin-3.15 (4H, 13H) dione
Mixture of 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinoline-3.15 (4H , 13H) of a dione (200 mg, 0.526 mmol obtained according to Preparation 4), N-Boc-glycine (185 mg, 1.051 mmol) and a catalytic amount of 4-dimethylaminopyridine (20 mg) in anhydrous pyridine (10 ml) was treated at 0 ^o C in argon with dicyclohexylcarbodiimide (239 mg, 1.16 mmol), then stirred at ambient temperature for 48 hours. Volatiles were evaporated in vacuo and the residue was chromatographed (SiO ₂ , 1% methanol in chloroform) to give the desired intermediate (40 mg, 14%) as a yellow solid.

NMR-1H (CDCl ₃ ): 1.20 (t, 3H); 1.38 (s, 9H); 1.40-1.70 (m, 2H); 3.10 (d, 1H); 4.00 (d, 2H); 4.30 (d, 1H); 5.00 (t, 1H); 5.20 (s, 2H); 5.30-5.90 (dd, 2H); 7.20 (s, 1H); 7.50-8.10 (m, 2H); 8.50 (s, 1H).

b. 5-Ethyl-9,10-difluoro-4,5-dihydro-5- (2-amino-1-oxoethoxy) -1H-oxepino hydrochloride [3 ', 4': 6,7] indolisino- [1,2- b] quinoline-3.15 (4H, 13H) -dione
The intermediate obtained above (40 mg, 0.072 mmol) in a dichloromethane solution (10 ml) was maintained at 0 ^{° C.} and dioxane saturated with hydrogen chloride (8 ml) was added dropwise. The yellow suspension thus obtained was kept under stirring for 2 hours, then the volatile components were removed in vacuo. The residue, placed in water (5 ml), is washed with dichloromethane (3 • 30 ml). The aqueous phase is frozen and lyophilized to obtain the desired salt as a hygroscopic yellow solid (20 mg, 50%).

NMR-1H (CDC1 ₃ ): 1.00 (t, 3H); 2.15 (m, 1H); 2.30 (m, 1H); 3.60 (d, 1H); 3.90 (d, 1H); 4.15 (s, 2H); 5.10 (s, 2H); 5.40 (d, 1H); 5.70 (d, 2H); 7.40 (s, 1H); 7.80 (m, 2H); 8.50 (s, 1H).

Example 2: 5-Ethyl-9,10-difluoro-4,5-dihydro-5- (2-amino-1-oxopropoxy) -1H-oxepino [3 ', 4': 6,7] indolisino [1,2 -b] quinoline-3.15 (4H, 13H) -dione
The method according to example 1 is used for 5-ethyl-9,10-difluoro-4,5-dihydro-5-hydroxy-1H-oxepino [3 ', 4',: 6,7] indolisino- [1,2-b] quinoline-3.15 (4H, 13H) -dione using N-Boc-b-alanine instead of N-Boc-glycine, then the Boc protection of the intermediate thus obtained is cleaved by treatment with trifluoroacetic acid in dichloromethane. Volatiles were evaporated in vacuo and the residue was taken up in dichloromethane. The resulting solution was washed with diluted bicarbonate, dried and evaporated. A yellow solid is obtained.

 Using the method of Examples 1 and 2 for other compounds, similar results were obtained. Thus, the entire class of camptothecin analogues is available as a “prodrug” form.

Example 3: 1,8-Diethyl-8,9-dihydro-8-hydroxy-2H, 10H, 12H- [1,3] oxazino [5,6-f] oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinoline-10.13 (15H) -dione
Suspension of 5-ethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinoline-3.15 (4H, 13H) - dione (84 mg, obtained in obtaining 5) in acetic acid (2.5 ml) is treated with 1,3,5-triethylhexahydrotriazine (0.5 ml). The reaction mixture was stirred at 70 ^{° C.} for 30 minutes, then evaporated in vacuo. The residue was taken up in ethanol, filtered and washed with ether. Get a solid product, so pl. > 275 ^o C.

 NMR-1H (DMSO): 0.87 (t, 3H); 1.50 (t, 3H); 1.85 (q, 2H); 2.77 (q, 2H); 3.05 (d, 1H); 3.47 (d, 1H); 4.37 (s, 2H); 5.00 (s, 2H); 5.22 (s, 2H); 5.45 (dd, 2H); 6.00 (s, 1H); 7.34 (s, 1H); 7.36 (d, 1H); 7.93 (d, 1H); 8.53 (s, 1H).

 NMR-C13 (DMSO): 8.46; 13.48; 36.46; 42.49; 45.49; 46.44; 50.75; 61.43; 73.33; 82.06; 99.02; 112.90; 122.00; 122.98; 125.42; 127.04; 129.04; 130.20; 144.09; 144.97; 149.87; 152.92; 155.98; 172.07.

 IR (KBr): 1045; 1215; 1502; 1604; 1657; 1722.

Example 4: 8-Ethyl-8,9-dihydro-8-hydroxy-1-methyl-2H, 10H, 12H [1, 3] oxazino [5,6-f] oxepino 3 ', 4': 6.7] indolisino [1,2-b] quinoline-10,13 (15H) -dione
Suspension of 5-ethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepino- [3 ', 4': 6,7] indolisino [1,2-b] quinolin-3.15 (4H, 13H) -dione (200 mg, obtained in preparation 5) in acetic acid (5 ml) is treated with hexahydro-1,3,5-trimethyltriazine (110 mg). The reaction mixture was stirred at 70 ^{° C.} for 30 minutes, then evaporated in vacuo. The residue is taken up in ethanol, filtered.
and washed with diethyl ether. Get a solid product, so pl. > 275 ^o C.

 NMR-1H (DMSO): 0.87 (t, 3H); 1.85 (q, 2H); 3.04 (d, 1H); 3.48 (d, 1H); 4.33 (s, 2H); 4.93 (s, 2H); 5.28 (s, 2H); 5.45 (dd, 2H); 6.01 (s, 1H); 7.35 (s, 1H); 7.38 (d, 1H); 7.94 (d, 1H); 8.49 (s, 1H).

 NMR-C13 (DMSO): 8.46; 36.43; 37.85; 42.55; 48.68; 50.79; 61.43; 73.35; 83.82; 99.04; 112.49; 122.04; 123.00; 125.46; 127.14; 129.07; 130.27; 144.99; 149.95; 152.46; 155.99; 172.09.

 IR (KBr): 1047; 1058; 1219; 1246; 1295; 1439; 1504; 1604; 1655; 1735.

Example 5: 8-Ethyl-8,9-dihydro-8-hydroxy-1-benzyl-2H, 10H, 12H- [1,3] oxazino [5,6-f] oxepino- [3 ', 4': 6 , 7] indolisino [1,2-b] quinoline-10,13 (15H) -dione
Suspension of 5-ethyl-4,5-dihydro-5,10-dihydroxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinoline-13.15 (4H, 13H) - dione (200 mg, obtained on behalf of 5) in acetic acid (5 ml) is treated with 1,3,5-tribenzylhexahydrotriazine (285 mg). The reaction mixture was stirred at 70 ^{° C.} for 30 minutes, then evaporated in vacuo. The residue was taken up in ethanol, filtered and washed with ether. Get a solid product, so pl. > 275 ^o C.

 NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.05 (d, 1H); 3.47 (d, 1H); 3.96 (s, 2H); 4.33 (s, 2H); 5.04 (s, 2H); 5.17 (s, 2H); 5.44 (dd, 2H); 6.01 (s, 1H); 7.38 (m, 6H); 7.42 (d, 1H); 7.97 (d, 1H); 8.42 (s, 1H).

 NMR-C13 (DMSO): 8.42; 19.96; 36.45; 42.51; 46.36; 50.78; 55.38; 61.39; 73.31; 99.00; 112.55; 122.01; 123.08; 125.38; 127.09; 127.47; 128.70; 129.14; 130.35; 128.40; 139.19; 144.18; 149.99; 152.84; 155.92; 159.24; 172.05.

 IR (KBr) 1056, 1205, 1225, 1248, 1504, 1535, 1599, 1655, 1726.

Example 6: 8-Ethyl-8,9-dihydro-4-fluoro-8-hydroxy-1-benzyl-2H, 10H, 12H [1,3] oxazino [5,6-f] oxepino [3 ', 4 ': 6,7] indolisino [1,2-b] quinoline-10,13 (15H) -dione
Suspension of 5-ethyl-9-fluoro-4,5-dihydro-5,10-dihydroxy-1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinoline-3.15 (4H , 13H) -dione (200 mg, obtained as obtained in 20) in acetic acid (5 ml) is treated with 1,3,5-tribenzylhexahydrotriazine (285 mg). The reaction mixture was stirred at 70 ^{° C.} for 30 minutes, then evaporated in vacuo. The residue was taken up in ethanol, filtered and washed with ether. Get a solid product, so pl. > 250 ^o C.

 NMR-1H (DMSO): 0.85 (t, 3H); 1.85 (q, 2H); 3.05 (d, 1H); 3.48 (d, 1H); 3.95 (s, 2H); 4.45 (s, 2H); 5.20 (s, 4H); 5.45 (dd, 2H); 6.05 (s, 1H); 7.40 (s, 7H); 7.90 (d, 1H); 8.45 (s, 1H).

 IR (KBr): 1248; 1451; 1501; 1598; 1657; 1727.

Pharmacological studies of products according to the invention
Investigation of the relaxation activity of DNA induced by topoisomerase 1.

All reactions were carried out in 20 μl of a reaction buffer consisting of 50 mM Tris-Hcl (pH 7.5), 50 mM KCl, 0.5 mM dithiothreitol, 10 mM MgCl ₂ , 0.1 mM ethyldiaminetetraacetic acid (EDTA), 30 mg / ml bovine serum albumin and 300 ng supercoiled pUC19 (Pharmacia Biotech, Orsay, France) in the presence or absence of test compounds at certain concentrations. All test compounds were initially dissolved in dimethyl sulfoxide (DMSO) or water, in the case of water-soluble compounds, other dilutions were carried out using distilled water. The final concentration of DMSO should not exceed 1% (vol./vol.). The reaction was initiated by the addition of a topoisomerase 1 DNA unit from purified calf goiter (Life Technologies / Gibco-BRL, Paisley, United Kingdom) so that the reaction was completed in 15 minutes at 37 ^° C. The reaction was stopped by adding 3 μl of a mixture containing 1% dodecyl sulfate sodium with a concentration of 1%, 20 mM EDTA and 500 μg / ml proteinase K (Boehringer Mannheim, Meylan, France). After an additional incubation period of 30 minutes at 37 ^{° C.,} 2 μl of buffer containing 10 mM Na ₂ HPO ₄ , 0.3% blue bromphenol and 16% ficoll, which were subjected to agarose gel electrophoresis at 1.2% at 1 V / cm for 20 hours in a buffer containing 36 mm Tris-Hcl at pH 7.8, 30 mm Na ₂ HPO ₄ , 1 mm EDTA and 2 μg / ml chloroquine. The gels showed 2 μg / ml ethidium bromide, photographed in ultraviolet light at 312 nm using a camera with charge-coupled devices (CCD) and the fluorescence intensity was measured using a bioProfil video analyzer (Vilber Lourmat, Lyon, France) to determine the percentage of relaxed DNA.

 In each experiment, the supercoiled DNA plasmid was incubated on its own or in the presence of topoisomerase 1. The reaction is completed in 15 minutes, for each test compound or control (the carrier itself is called the control), the supercoiled DNA plasmid was incubated in the presence of the maximum concentration of the test compound selected for the experiment or a control without an enzyme, or in the presence of a test compound in concentrations ranging from 1 μM to 200 μM, or a control in the presence of enzymes. As indicated in the table, the compounds of examples 3-6 inhibit in a concentration-dependent manner the relaxation activity caused by topoisomerase 1.

Claims (13)

1. An analogue of camptothecin of formula (I)

in racemic or enantiomeric forms or in the form of any combination of these forms,
where R ₁ is lower alkyl, low alkenyl, lower alkynyl;
R ₂ , R ₃ and R ₄ independently, —H, halogen, lower haloalkyl, lower alkyl, lower alkenyl, - (CH) _m OR ₆ , substituted or unsubstituted phenyl or phenylalkyl, wherein the substituent is lower alkyl, halogen, or R ₃ and R ₄ form together a chain with 3-4 members, in which the elements of the chain are selected from the group consisting of CH, CH ₂ , O, N or NR ₉ ;
R ₅ is H, halogen, lower haloalkyl, lower alkyl, lower alkoxy, substituted or unsubstituted phenyl or phenylalkyl, wherein the substituent is lower alkyl, halogen;
R ₆ is H, lower alkyl;
R ₉ is H, lower alkyl;
R ₁₈ and R ₁₉ independently are H, halogen, lower alkyl, lower alkoxy or hydroxy;
R ₂₀ is H or halogen;
R _p is H or an easily cleavable group, preferably selected from the groups corresponding to the formula —C (O) —A — NR ₂₂ R ₂₃ , where A is a linear or branched alkylene radical, while R ₂₂ and R _{23 are} independently H, lower alkyl, if R _p is a hydrogen atom, R ₃ and R ₄ together form a chain with 3 or 4 members;
m = 0 - 6, an integer,
or its pharmaceutically acceptable salts. 2. The compound according to claim 1, characterized in that R ₁ is an ethyl group, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, characterized in that R ₅ is H, lower alkyl, or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, characterized in that R ₃ and R ₄ form, if necessary, a substituted oxazine ring, or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, characterized in that R _p is an easily cleavable group, or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 5, characterized in that R _p is a group C (O) - (A ₁ ) -NR ₂₂ -R ₂₃ where A ₁ is (CH ₂ ) _m or a branched lower alkylene radical, m = 0 - 6, an integer, or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 4, characterized in that the compound is selected from the group of compounds, including
1,8-diethyl-8,9-dihydro-8-hydroxy-2H, 10H, 12H- [1,3] oxazino [5,6-f] oxepino [3 ', 4': 6,7] indolisino [1 , 2-b] quinolin-10, 13 (15H) -dione;
8-ethyl-8,9-dihydro-8-hydroxy-1-methyl-2H, 10H, 12H- [1,3] oxazino [5,6-f] oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinolin-10, 13 (15H) -dione;
8-ethyl-8,9-dihydro-8-hydroxy-1-benzyl-2H, 10H, 12H- [1,3] oxazino [5,6-f] oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinolin-10, 13 (15H) -dione;
8-ethyl-8,9-dihydro-4-fluoro-8-hydroxy-1-benzyl-2H, 10H, 12H- [1,3] oxazino [5,6-f] oxepino [3 ', 4': 6 , 7] indolisino [1,2-b] quinoline-10,13 (15H) -dione,
or its pharmaceutically acceptable salts. 8. The compound according to claim 5, characterized in that the compound is selected from the group of compounds, including
5-ethyl-9,10-difluoro-4,5-dihydro-5- (2-amino-1-oxoethoxy) -1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinoline-3.15- (4H, 13H) -dione;
5-ethyl-9,10-difluoro-4,5-dihydro-5- (2-amino-1-oxopropoxy) -1H-oxepino [3 ', 4': 6,7] indolisino [1,2-b] quinoline-3.15- (4H, 13H) -dione, or its pharmaceutically acceptable salts.  9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, used as a medicament having inhibitory activity against tonisomerase I.  10. The compound according to one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, used as an active ingredient to obtain a pharmaceutical composition having inhibitory activity against tonisomerase I.  11. A pharmaceutical composition having tono isomerase I inhibitory activity, comprising an active ingredient and a pharmaceutically acceptable carrier, characterized in that at least one of the compounds according to any one of claims 1 to 8 is an active ingredient. 12. A method of obtaining compounds of formula Ia corresponding to compounds of formula I, where R ₃ and R ₄ form an oxazine ring according to any one of claims 1, 4 or 7, characterized in that the β-hydroxylactone compound of formula D

where R ₃ is a hydroxyl radical, R ₄ is H and R ₁ , R ₂ , R ₁₈ , R ₁₉ and R ₂₀ have the above meanings,
treated with primary amine under Mannich conditions to obtain a β-hydroxylactone compound of the general formula Ia

where R ₁ , R ₂ , R ₅ , R ₉ , R ₁₈ , R ₁₉ and R ₂₀ have the above meanings. 13. The method of obtaining compounds of formula Ib corresponding to the products of formula I, in which R _{p is} not a hydrogen atom according to claim 1, characterized in that the compound of General formula D

or Ia

preferably acylated with a C (O) -A-NR ₂₂ R ₂₃ derivative of the radical as defined in paragraph I, to obtain a β-hydroxylactone compound of general formula I with R _p other than H.

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