MXPA00001944A - Optically pure camptothecin analogues, optically pure synthesis intermediate and method for preparing same - Google Patents

Abstract

The invention concerns novel camptothecin analogues and in particular products corresponding to the following formulae:(+)-5-ethyl-9, 10-difluoro-5-hydroxy-4, 5,13,15-tetrahydro-1H, 3H-oxepino[3',4':6, 7]indolizino[1,2-b]quinoline-3,15-dione;(+)-1-[9-chloro-5- ethyl-5-hydroxy-10-methyl-3, 15-dioxo-4,5,13, 15-tetrahydro-1H,3H-oxepinol[3',4':6,7]indolizino [1,2-b]quinoline-12-ylmethyl]-4-methyl-hexahydropyridinium chloride;their application as medicine, pharmaceutical compositions containing them and their use for producing antitumoral, antiviral or antiparasitic medicines. The invention also concerns a novel synthesis intermediate of said products and a method for preparing said intermediate.

Description

OPTICALLY PURE ANALOGS OF CAMPTOTECINE, OPTICALLY PURE SYNTHETIC INTERMEDIARY AND ITS PREPARATION PROCESS.

DESCRIPTION OF THE INVENTION Camptothecin is a natural compound that was isolated for the first time from the leaves and bark of the Chinese plant called camptotheca acuminata (see Wall et al., J. 7 Amer Che. Soc, 88: 3888 (1996) ). Camptothecin is a pentacyclic compound consisting of an indolizine- [1,2-b] -quinoline fragment fused to an a-hydroxylactone with six bonds. The carbon in position 20, which is a carrier of the a-hydroxy group, is asymmetric and gives the molecule a rotational power. The natural form of camptothecin has an absolute configuration "S" with respect to carbon 20 and corresponds to the following Formula: Camptothecin has an antiproliferative activity in several cancer cell lines, including the cell lines of human tumors of the colon, lung and breast (Suffness, M. et al. 'The Alkaloids REF .: 32776 Chemistry and Pharmacology, Bross A., ed., Vol. 25, p. 73 (Academic Press, 1985)). It is suggested that the proliferative activity of camptothecin is related to its inhibitory activity on DNA topoisomerase I. It has been indicated that a-hydroxylactone was an absolute requirement for both in vivo activity and camptothecin in vi tro activity (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)). More recently, the applicant has perfected a new class of camptothecin analogues, in which a β-hydroxylactone replaces the natural a-hydroxylactone of camptothecin (cf Patent Application WO 97/00876). An object of the present invention is a new preparation process for an enantiomerically pure synthetic intermediate, as well as for new enantiomerically pure analogs of camptothecin. Firstly, an object of the present invention, therefore, are novel camptothecin analogs which are different from any known compound, characterized in that they have the respective Formulas (I) and (II) represented below or characterized in that they are salts of the compound of Formula (II) such as for example that of Formula (III) which represents below A key intermediate in the synthesis of this type of optically pure compounds is a product of General Formula M which is represented below M wherein R represents a straight or branched chain alkyl radical containing from 1 to 10 carbon atoms. Preferably, R represents an ethyl radical. The compounds of Formulas (I) and (II) can be prepared in the following manner: the compound of the Formula (+) - EHHOPD is coupled respectively with one or other of the compounds of the formula N or N2, which are represented below: Ni N2 in order to produce the compound of the Formula Oi or the compound of the Formula 02, respectively: I heard o2 after, the compound of Formula O? is cyclized and the compound of Formula (I) is obtained; the cyclization of the compound of the Formula 02 produces the compound of (II), which, after salification, produces the compound of the Formula (III). The formation of the compounds of the formulas Oi or 02 starting from the compound of the general formula M for which R represents an ethyl radical and Ni or N2 is carried out with a treatment known to those skilled in the art under the name of reaction from Mitsunobu (refer to Mitsunobu, 0., et al., Synthesis, p.1 (1981)). The hydroxyl function of the compound N is displaced by a nucleophile such as the compound M or a deprotonated derivative thereof, by a treatment with a phosphine, for example triphenylphosphine and an azodicarboxylate derivative, for example diethyl azodicarboxylate or diisopropyl, in an aprotic solvent such as, for example, tetrahydrofuran or N, N-dimethylformamide. The cyclization of the compounds of the formulas Oi and 02 in order to produce the compounds of the formulas (I) and (II), is preferably carried out in the presence of a palladium catalyst (for example palladium diacetate), under basic conditions (provided for example by an alkali acetate optionally combined with a phase transfer agent, such as for example tetrabutylammonium bromide), in an aprotic solvent such as acetonitrile or N, N-dimethyl formamide, at a temperature between 50 and 120 ° C (R. Grigg et al., Tetrahedron 46, page 4003 (1990)). The present invention also offers, as a new industrial product, a compound of the General Formula M as previously defined. This product can be used for the manufacture of medicines. The compound of the formula M is synthesized according to a new process that is part of the present invention that includes the following successive steps: the racemic t-butyl ester represented below (for its preparation, refer in particular to the patent application WO 97/00876) it is treated with trifluoroacetic acid for 18 hours at room temperature, in order to produce the corresponding carboxylic acid; then, the quinidine salt of the previously obtained acid is heated in isopropyl alcohol at a temperature greater than 30 ° C and preferably at about 50 ° C, before allowing the reaction medium to cool to room temperature, so that the salt of one of the enantiomers of the aforementioned acid is crystallized, while the salt of the other enantiomer, whose anion is represented below, remains in solution the solution in isopropyl alcohol of the salt of the enantiomer which has not crystallized, is concentrated and treated with hydrochloric acid and stirred, yielding the compound of the General Formula A which is represented below the compound of General Formula A, subsequently, is contacted with palladium on carbon, then or ammonium formate or formic acid is added to the reaction mixture, in order to produce the debenzylated product of Formula G which is subsequently represents B, the compound of the General Formula B is cyclized by the action of dicyclohexylcarbodiimide, in order to obtain the lactonic compound of the General Formula C which is represented below finally, the -OCH3 group of the lactone compound of the general formula C is converted into a carbonyl by the action of sodium iodide and trimethylsilyl chloride, in order to obtain a compound of the General Formula M, as represented below.

For the process described above, the reaction which leads the compound of the General Formula A to the compound of the General Formula B will preferably be carried out in methanol and preferably by heating the reaction medium to a temperature of about 40 ° C after the addition of the ammonium for iate. The cyclization of the compound of the General Formula B in order to produce the compound of the Formula C, can be carried out in tetrahydrofuran (THF), preferably at a temperature of about 50 ° C, while the reaction will preferably take performed at room temperature with acetonitrile as the solvent in the reaction which leads the compound of the general formula C to the compound of the general formula M. In the particular case where R represents an ethyl group, the compound of the formula M is synthesized from conformity to the process constituted by the following successive stages: - the racemic t-butyl ester represented below (for its preparation, refer in particular to Patent Application WO 97/00876) it is treated with trifluoroacetic acid for 18 hours at room temperature, in order to produce the corresponding carboxylic acid; the quinidine salt of 3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxypentanoic acid is heated in isopropyl alcohol at a temperature greater than 30 ° C and preferably at about 50 ° C, before allowing the reaction medium is cooled to room temperature so that the (+) enantiomer salt of 3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxypentanoic acid crystallizes, while the isomer salt (-), whose anion is represented below, remain in solution the solution in isopropyl alcohol of the (-) enantiomer salt of 3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxypentanoic acid is concentrated and treated with hydrochloric acid and stirred, yielding the the Formula A 'that is represented below The 'compound of Formula A' is subsequently contacted with palladium on carbon and then ammonium formate or formic acid is added to the mixture in order to produce the debenzylated product of Formula B 'which is represented then.

B 'subsequently, the compound of Formula B' is cyclized by the action of dicyclohexylcarbodiimide, in order to obtain the lactone compound of Formula C which is depicted below C finally, the -OCH3 group of the lactone compound of Formula C is converted into the corresponding carbonyl by the action of sodium iodide and trimethylsilyl chloride, in order to obtain (+) - 5-ethyl-5-hydroxy-1 , 3,4,5,8,9-hexahydrooxepino- [3, -c] -pyridin-3,9-dione (or (+) - EHHOPD), which is represented below (+) - EHHOPD The compound of Formula I can be obtained starting with the aniline of Formula Pi which is represented below according to the following process: the aniline of the Formula Pi is N-acetylated by treatment with an acetylating agent such as for example acetic anhydride. The acetanilide thus obtained is treated at a temperature comprised between 50 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 phosphoryl oxychloride on N, N-dimethylformamide, at a temperature comprised between 0 and 10 ° C) in order to produce the corresponding 2-chloro-3-quinolinocarbaldehyde (for example, refer to Meth-Cohn et al., J. Chem. Soc. ., Perkin Trans. 1, p.1520 (1981), Meth-Cohn et al., J. Chem. Soc., Perkin Trans. 1, p.2509 (1981), and Nakasimhan et al., J. Am. Chem. Soc., 112, p 4431 (1990)). 2-Chloro-6,7-difluoro-3-quinolinocarbaldehyde is easily reduced to the corresponding 2-chloro-6,7-difluoro-3-quinolinemethanol of Formula I, under standard conditions known to those skilled in the art, such as treatment in an alcoholic solvent (for example methanol), with sodium borohydride at a temperature between 0 and 40 ° C. The compound of Formula N2 can be obtained in accordance with the following process. The aniline of the Formula P2 represented below is ortho-acetylated by reaction with chloroacetonitrile in the presence of boron trichloride and another Lewis acid, such as aluminum trichloride, titanium tetrachloride or diethylaluminum chloride, in an aprotic solvent or in a mixture of aprotic solvents, followed by a hydrolysis (see Sugasawa T. et al., J. Am. Chem. Soc. 100, p.4842 (1978)). The intermediate thus obtained is subsequently treated with ethylmalonyl chloride in an aprotic solvent such as acetonitrile, in the presence of a base such as triethylamine, then treated with an alkali metal alcoholate, for example sodium methylate in methanol, in order to produce the Ethyl 7-chloro-4-chloromethyl-6-methyl-2-oxo-l, 2-dihydro-3-quinolinecarboxylate. The latter is converted to ethyl 2, 7-dichloro-4-chloromethyl-6-methyl-3-quinolinocarboxylate by treatment with phosphoryl oxychloride. Then, a nucleophilic substitution is carried out by a 4-methylpiperidine treatment. The ethyl carboxylate function, subsequently, is reduced with diisobutylaluminum hydride in an aprotic solvent such as dichloromethane, in order to produce the compound of Formula N2. The order in which the last two stages are carried out, could optionally be reversed. Analogs of the Ni or N2 type intermediates have been described in the scientific literature and in particular in PCT Patent Application 95/05427. The compound of Formula (II) can be transformed into a pharmaceutically acceptable salt form in accordance with the usual methods. Acceptable salts include, by way of example and without limitation, the addition salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate; or with organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, pamoate, salicylate, oxalate and stearate. For other examples of pharmaceutically acceptable salts, one may refer to "Pharmaceutical Salts", J. Pharm. Sci., 66: 1 (1977). The compounds of the present invention possess useful pharmacological properties. So that, the compounds of the present invention have an inhibitory effect on topoisomerase I and / or II and an antitumor activity. The state of the art suggests that the compounds according to the present invention have antiparasitic and / or antiviral activity. In this way, the compounds according to the present invention can be used in different therapeutic applications. An illustration of the pharmacological properties of the compounds of the present invention will be found later in the experimental part. The compounds can inhibit the topoisomerase, for example of type I and / or II, in a patient, for example a mammal such as a human, by administering to this patient a therapeutically effective amount of a compound of the Formula (I). ) or of Formula (II) or a pharmaceutically acceptable salt of a compound of Formula (II) or also any mixture of the latter compounds. The compounds according to the present invention have antitumor activity. They can be used for the treatment of tumors, for example tumors expressing a topoisomerase, in a patient by administering to said patient a therapeutically effective amount of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt of a compound of Formula (II), or also any mixture of the latter compounds. Examples of tumors or cancer include cancer of the esophagus, stomach, intestine, rectum, oral cavity, pharyngeal, laryngeal, lung, colon, mammary, cervical, endometrial, ovarian, prosthetic, testicular, bladder , kidney, liver, pancreas, bone, connective tissue, skin, eye, brain and central nervous system, as well as thyroid cancer, leukemia, Hodgkin's disease, lymphomas other than those related to Hodgkin, multiple myelomas and others. They can also be used for the treatment of parasitic infections by inhibiting hemoflagellates (for example in infections by trypanosomes or leishmania) or by inhibiting plasmodia (such as for example in malaria), but also the treatment of infections and diseases viral These properties make the products of the Formula (I) and (II) suitable for their pharmaceutical use. An object of the present application also, as medicaments, are the products of Formulas (I) and (II) as defined above, as well as the pharmaceutically acceptable mineral or organic acid addition salts of the product of Formula (II) ), such as for example the salt of the formula (III) previously described or also any mixture of the latter compounds. Similarly, the present invention relates to pharmaceutical compositions containing at least one of the medicaments such as those defined above as an active ingredient. Therefore, the present invention relates to pharmaceutical compositions containing a compound according to the present invention or an addition salt with a pharmaceutically acceptable acid thereof, in combination with a pharmaceutically acceptable carrier according to the method of administration selected (for example oral, intravenous, intraperitoneal, intramuscular, transdermal or subcutaneous). The pharmaceutical composition (for example therapeutic) can be in the form of a solid, liquid, liposome or lipid micelles. The pharmaceutical composition may be in solid form, such as for example powders, pills, granules, tablets, liposomes, gelatin capsules or suppositories. The pill, tablet, or gelatin capsule can be coated with a substance that is capable of protecting the composition from the action of gastric acid or gastric enzymes in the subject's stomach, for a sufficient period, to allow this composition to pass through. in undigested form to the patient's small intestine. The compound can also be administered locally, for example, in the same location as the tumor. The compound can also be administered according to a sustained release process (e.g., a sustained release composition or a fusion pump). Suitable solid supports can be, for example, calcium phosphate, magnesium stearate, magnesium carbonate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and wax. Pharmaceutical compositions containing a compound according to the present invention may also be presented in liquid form such as for example solutions, emulsions, suspensions or a sustained release formulation. Suitable liquid supports can be for example water, organic solvents such as glycerol or glycols such as polyethylene glycol, similarly their mixtures, in varying proportions, in water. An object of the present invention is also the use of the products of Formulas (I) and (II) such as those defined above or pharmaceutically acceptable mineral or organic acid addition salts of a product of Formula (II), such such as for example the salt of the formula (III) previously described, or also a mixture of these compounds, for the preparation of medicaments that are intended to inhibit the topoisomerase and more particularly the type II topoisomerases, drugs intended for the treatment of tumors, medicines that are intended for the treatment of parasitic infections, as well as drugs that are intended for the treatment of infections or viral diseases. The dose of a compound according to the present invention for the treatment of the aforementioned diseases or disorders, varies according to the method of administration, the age and body weight of the subject to be treated, as well as the state of the latter and they will be definitively decided by the doctor or veterinarian who treats the patient. Such amount determined by the physician or veterinarian, herein will be referred to as "therapeutically effective amount". Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by an ordinary specialist in the subject to which the invention pertains. Similarly, all publications, Patent Applications, all Patents and other references mentioned herein are incorporated by reference. The following Examples are presented to illustrate the above procedures and in no case should they be considered as limiting the scope of the present invention. EXPERIMENTAL PART: EXAMPLE 1 (+) - 5-ethyl-5-hydroxy-1, 3, 4, 5, 8, 9-hexahydrooxep ± im? - [3,4-c] -pyridin-3,9-dione [ (+) -EHHOPD] 1.a. Quinidine salt of 3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxypentanoic acid: 3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxypentanoate of tert-butyl was treated (40 g, 100 mmol) with trifluoroacetic acid (150 ml) and the reaction mixture was stirred for 18 hours at 20 ° C. After evaporation of the trifluoroacetic acid, methylene chloride (200 ml) was added and a saturated solution of sodium bicarbonate was added until pH = 7.5-8. After decanting, the aqueous phase was washed with 100 ml of methylene chloride. The pH of the aqueous phase was subsequently adjusted to 1 by the addition of a 6 N hydrochloric acid solution. The product was then extracted from the aqueous phase with methylene chloride (2 times, 200 ml). The solution was dried over magnesium sulfate and concentrated. The 3- (3-benzyloxymethyl-2-methoxy-4-pyridine) -3-hydroxypentanoic acid thus obtained (31.1 g, 90 mmol) was collected with isopropyl alcohol (30 ml), treated with a quinidine solution (29.2). g, 90 mmol) in isopropyl alcohol (30 ml) at 50 ° C under stirring, until its complete dissolution. Subsequently, the reaction mixture was allowed to cool to a temperature of 40 ° C, stirring was stopped and the temperature dropped to 20 ° C. The medium was then brought to 0 ° C without stirring and kept at this temperature for 16 hours. Subsequently, the temperature was allowed to rise to 20 ° C and stirring was carried out until crystallization. The reaction mixture was diluted with isopropyl alcohol and then filtered. The precipitate was rinsed with isopropyl alcohol. The salt of the (+) enantiomer is precipitated (m = 26.6 g), while the salt of the (-) enantiomer remains in solution in the isopropyl alcohol. Thus, the filtrate was recovered and concentrated to obtain an oil (34 g), which was used without further purification in the next step. The products were analyzed by HPLC in a 5 μg AGP CHIRAL column (10 cm x 4 mm) eluting with a 30/920/50 isopropyl alcohol / water / phosphate buffer solution, pH = 6.5, at a flow rate of 1.2 ml / min, UV detection at 280 nm. The retention times obtained were 6.4 minutes for the enantiomer (-) and 2.8 minutes for the enantiomer (+). The enantiomer ratio (-) / enantiomer (+) was 83/17. l.b. (-) - 3 - (3-Benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxypentanoic acid: The solution in isopropyl alcohol of the quinidine salt of the (-) enantiomer of 3- (3-benzyloxymethyl-2) -methoxy-4-pyridyl) -3-hydroxypentanoic acid (Stage 1.1) was concentrated. The concentrate was collected with 270 ml of methylene chloride and 270 ml of a 1 N solution of hydrochloric acid. The reaction mixture was stirred for 16 hours at 20 ° C. After decanting, the organic phase was concentrated, the concentrate was collected with methanol in order to be used in the next step. 13.5 g of the product were obtained (yield of 87%) and a proportion of the enantiomer (-) / enantiomer (+) of 85/15.

The retention times in CLAR (same protocol as in Step 1.a) were: enantiomer (-): 6.4 minutes enantiomer (+): 2.8 minutes l.c. (+) -5-ethyl-5-hydroxy-l, 3,4,5,8,9-hexahydro-oxepino- [3,4-c] -pyridin-3,9-dione: (-) -3- (3-benzyloxymethyl-2-methoxy-4-pyridyl) -3-hydroxypentanoic acid (13.5 g, 39 mmol, Step lb) was dissolved in 87 ml of methanol. This solution was drained under a nitrogen atmosphere in 10% Palladium to 50% carbon (27.7 g, 13 mmol). The reaction mixture was stirred for 5 minutes, then it was poured into a solution of ammonium formate (11.5 g, 183 mmol) in 135 ml of methanol. The reaction mixture was stirred for 30 minutes while the temperature was allowed to rise, then heated to 40 ° C for 30 minutes. Subsequently, the reaction medium was filtered on a Clarcel bed and concentrated. 40 ml of toluene were drained and then evaporated; this operation was repeated in order to eliminate methanol. The residue thus obtained was taken up in 45 ml of THF. Then a solution of dicyclohexylcarbodiimide (7,180 g, 34.5 mmol) in ml of THF was added. The reaction mixture was heated at 50 ° C for 1 hour. The mixture was brought to 20 ° C and then the dicyclohexylurea was filtered. The filtrate was concentrated to dryness. The residue was dissolved in 46 ml of acetonitrile, 6.0 g (40.5 mmol) of sodium iodide and then 5.13 ml (40.5 mmol) of trimethylsilyl chloride were added. The reaction mixture was allowed to stir at room temperature for 5 hours. Then, 28 ml of acetonitrile and 5.6 ml of water were added. The precipitate obtained was filtered and then taken up with 1 ml of water and the pH adjusted to 7.5 by the addition of an ammonium hydroxide solution. The solid obtained was filtered and dried. M = 4.2 g of the final product was obtained with a yield of 34% and an enantiomer (+) / enantiomer (-) ratio of 88.4 / 11.6. The analysis by HPLC was carried out in a Chiralcel OD column of 25 cm x 4.6 mm, the eluents used were heptane 600 and ethanol 400, the flow rate was 1 ml / min, 210 nm. The retention times obtained were: (-) enantiomer: 7.1 minutes (+) enantiomer: 9 minutes The product was taken up in acetone (40 ml) and then water (150 ml) was added. The reaction mixture was allowed to precipitate and 3 g of the product were obtained with a proportion of the (+) enantiomer / (-) enantiomer of 99.4 / 0.6. 1 H NMR (250 MHz, DMSO D6): 0.8 (t, 3H, CH 3 -CH 2); 1. 65 { m, 2H, CH2-CH3); 3.00-3.35 (g, 1H + 1H, -CH2-C = 0); 5.3 (g, 2H, CH2-0); 5.7 (s, -OH); 6.35 (d, aromatic 1H); 7.3 (d, aromatic 1H); eleven . 7 (s, N-H). EXAMPLE 2 (+) - 5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H, 3H-oxepino- [3 ', 4': 6,7] -indolizine- [1, 2-b] -quinine-3, 15-dione 2.a. N- (3, -difluorophenyl) -acetamide: A mixture of 3, -difluoroaniline (50 ml, 0.5 mol) and triethylamine (70 ml, 0.5 mol) in dichloromethane (1.5 1) was cooled using an ice bath. Acetic anhydride (71.5 ml, 0.75 mol) was added dropwise and the reaction mixture was stirred for 1 hour at room temperature. The obtained mixture was washed repeatedly with water, with a 10% solution of sodium bicarbonate and with a saturated salt solution. The organic fraction was dried over sodium sulfate and concentrated under reduced pressure. The residue was suspended in pentane, filtered and dried, under reduced pressure in order to obtain the title product (78 g, 91% yield) as an off-white solid (mp 126-127.5 ° C). 2 H NMR (DMSO): 2.15 (s, 3 H); 7.10-7.65 (m, 2H); 7. 65-8.10 (, 1H); 10.30 (broad peak, 1H). 2.b. 2-chloro-6,7-difluoro-3-quinoline-3-carbaldehyde: The general procedure described by Meth-Cohn et al. , J. Chem. Soc. Perkin Trans. I, 1981, 1520 and 2509.

The product of Step 2.a (32 g, 220 mmol) was added to a Vilsmeyer reagent, obtained by the dropwise addition of an atmosphere of phosphorus oxychloride (103 ml, 1.1 mol) in anhydrous dimethylformamide (DMF) ( 34 ml, 440 mmol), cooling in an ice bath and stirring for 30 minutes before allowing the temperature to rise to room temperature. The mixture thus obtained was stirred at 70 ° C for 16 hours. After the reaction mixture returned to room temperature, it was added dropwise to a water-ice mixture (400 ml) and stirred for 2 hours. The precipitate obtained was filtered and washed with water and then dried in order to obtain the title product (9 g, 18% yield) as a yellow solid (mp 226.5-229 ° C). X H NMR (DMSO): 8.17 (dd, 1H); 8.39 (dd, 1H); 8.97 (d, 1H); 10.34 (d, 1H). IR (KBr): 888, 1061, 1262, 1507, 1691 cm "1. 2.c. 2-Chloro-6,7-difluoro-3-quinolylmethanol: A suspension of the product of Step 2.b (9 g, 39 mmol) in methanol (400 ml) was treated with sodium borohydride (2 g, 53 mmol) at room temperature for half an hour, the excess borohydride was destroyed with acetic acid (2 ml). reduced pressure The residue was dissolved in ethyl acetate (500 ml), and the obtained mixture was washed successively with a dilute solution of sodium bicarbonate, with water and with brine, followed by drying over magnesium sulfate and concentration under pressure. The residue was recrystallized from 1,2-dichloroethane in order to obtain the title product (8 g, 80% yield) as a beige solid (mp 166.5-167 ° C). DMSO): 4.67 (d, 2H), 5.80 (t, 1H), 8.01 (dd, 1H), 8.22 (dd, 1H), 8.48 (s, 1H), IR (KBr): 871, 1038, 1253, 1513 cm "1. 2.d. (+) -8- (2-chloro-6,7-di luoro-3-quinolinomethanol) -5- ethyl-5-hydroxy-l, 3,4, 5, 8, 9-hexahydro-oxepino- [3,4- c] - pyridine-3,9-dione: Diethyl azodicarboxylate (1.24 ml, 7.87 mmol) was added dropwise at room temperature and under an argon atmosphere, to a solution of (+) - EHHOPD (1.58 g, 7.08 mmol; Step l.c), the product from Step 2.c (1.62 g, 7.06 mmol) and tributylphosphine (1.91 ml, 7.87 mmol), in anhydrous DMF (30 ml). The mixture thus obtained was stirred for 16 hours. The reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate). The solid obtained was taken up in diethyl ether, filtered and dried in order to obtain the title product (1.56 g, 51% yield) as an off-white solid (mp 196 ° C).

X H NMR (DMSO): 0.84 (t, 3H); 1.74 (m, 2H); 3.02 (d, 1H); 3.34 (d, 1H); 5.29 (s, 2H); 5.31 (dd, 2H); 5.75 (s, 1H); 6.51 (d, 1H); 7.80 (d, 1H); 8.03 (dd, 1H); 8.07 (s, 1H); 8.17 (dd, 1H). IR (KBr): 875, 1057, 1360, 1507, 1574, 1647, 1749 cm-1. 2. e. (+) -5-ethyl-9, 10-difluoro-5-hydroxy-4,5,13, 15-tetrahydro-lH, 3H-oxepino- [3 ', 4': 6, 7] -indolizin- [1 , 2- b] -quinoline-3,15-dione: A mixture of the product from Step 2.d (1.53 g, 3. 52 mmol; Step 2.d), tetrabutylammonium bromide (1.25 g, 3.87 mmol), potassium acetate (520 mg, 5.28 mmol), triphenylphosphine (180 mg, 0.70 mmol) and palladium (II) acetate (79 mg, 0.35 mmol) it was stirred under an argon atmosphere in anhydrous acetonitrile and heated to reflux for 22 hours. After the reaction mixture returned to room temperature, it was concentrated under reduced pressure and subjected to chromatography on a column of silica gel (eluent: CH2Cl2 / MeOH, mixture 98/2). The title product was obtained (960 mg, yield 68%, purity determined by HPLC: 97.1%): This product was collected with anhydrous CH2C12 (100 ml) and stirred for 24 hours, followed by filtration and dehydration under reduced pressure , in order to obtain the purified product of the title (850 g; 61% yield; purity determined by HPLC: 99.6%) in the form of a white solid. X H NMR (DMSO): 0.87 (t, 3H); 1.85 (m, 2H); 3.08 (d, 1H); 3.44 (d, 1H); 5.26 (s, 2H); 5.39 (d, 2H); 5.52 (d, 2H); 5.99 (broad peak, 1H); 7.39 (s, 1H); 8.15 (dd, 1H); 8.23 (dd, 1H); 8.68 (s, 1H). IR (KBr): 871, 1261, 1512, 1579, 1654, 1746 cm "1. EXAMPLE 3 Chloride of (+) 1- [9-chloro-5-ethyl-5-hydroxy-10-methyl-3, 15- d-oxo-4, 5, 13, 15-tetrahydro-lH, 3H-oxepino- [3 ', 4': 6, 7] - indolizine- [1,2-b] -quinolin-12- il-methyl] -4- m ti lhexahi dropiri din 3.a. 1- (2-amino-4-chloro-5-methylphenyl) -2-chloroethanone: It was cooled in an ice bath and under an atmosphere of argon, 3-chloro-4-methylaniline (44.4 ml, 0.366 mol) in 1,2-dichloroethane (440 ml) The following was added dropwise in the order of this mixture: boron trichloride (1 M in heptane, 400 mL, 0.4 mol), chloroacetonitrile (28 mL, 0.44 mol) and diethylaluminum chloride (1 M in heptane, 400 mL, 0.4 mol). For the addition, the temperature was kept below 20 ° C. The resulting mixture was subsequently heated to reflux for 3 hours and then cooled to 10 ° C. Hydrolysis of the reaction mixture was carried out carefully using 2 N hydrochloric acid (240 ml) and heating to reflux for 1 hour. Water (11) and ethyl acetate (11) were added, the obtained mixture was stirred for 15 minutes before separating the phases. The aqueous phase was again extracted with ethyl acetate (200 ml) and the organic phases were combined and the combined was washed with water (500 ml). After drying over magnesium sulfate, the organic phase was concentrated. The residue was taken up in petroleum ether (fraction with a boiling point of 45 to 60 ° C, 150 ml) and the mixture thus obtained was left for 16 hours at 4 ° C. The resulting precipitate was collected by filtration, washed with petroleum ether and dried under reduced pressure in order to obtain the title product (25 g, 31% yield). p.f. 129-130 ° C. X H NMR (DMSO): 2.20 (s, 3H); 4.98 (s, 2H); 6.90 (s, 1H); 7.15 (broad peak, 2H); 7.70 (s, 1H). IR (KBr): 871, 1018, 1183, 1225, 1270, 1533, 1577, 1619, 1662 cm "1. 3.b. 7-chloro-4-chloromethyl-6-methyl-2-oxo-l, 2- ethyl dihydro-3-quinolinocarboxylate: The product of Step 3.a (25 g, 0.11 mol) and triethylamine (30.6 ml, 0.22 mol) was mixed with acetonitrile (520 ml) ethylmalonyl chloride (28.1 ml, 0.22 g. mol) at room temperature and under an argon atmosphere The mixture obtained was heated for 3 hours Sodium ethanolate (prepared by the solution of 3 g, ie 0.13 mol, of sodium in 140 ml of absolute ethanol) was added dropwise and the resulting mixture was stirred at room temperature for 16 hours.The precipitate was collected by filtration, washed successively with ethanol, water, ethanol and ether, then dried under reduced pressure at 70 ° C over phosphorus pentoxide, in order to obtain the title product (28.6 g, 83% yield) as a whitish solid XH NMR (DMSO): 1.30 (t, 3H), 2.40 (s, 3H), 4.35 (q, 2H), 4.85 (s, 2H); 7.41 (s, 1H); 7.91 (s, 1H); 12.15 (broad peak, 1H). IR (KBr): 879, 1108, 1250, 1288, 1483, 1664, 1721 cm "1, 3.c, ethyl 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolinecarboxylate: The product of the Step 3.b (28.4 g, 90 mmol) was heated for 4 hours at reflux in phosphorus oxychloride (400 ml) The mixture obtained was concentrated under reduced pressure (20 mmHg) at 80 ° C. The residue was taken up in ether diisopropyl ether (400 ml) The resulting precipitate was collected by filtration, washed with ether and with petroleum ether and then dried under reduced pressure in order to obtain the title product (25.4 g, 85% yield) in a of a whitish powder (mp 126-127 ° C) XH NMR (DMSO): 1.37 (t, 3H); 2.58 (s, 3H); 4.49 (q, 2H); 5.14 (s, 2H); 8 > 16 (s, 1H), 8.35 (s, 1H), IR 8KBr): 874, 1006, 1163, 1243, 1278, 1577, 1723 cm "1. 3.d. 2,7-dichloro-4-chloromethyl-6-methyl-3-quinolylmethanol: The product from Step 3.c (25.2 g, 76.5 mmol) was mixed under an atmosphere of argon with dichloroethane (630 ml). Diisobutylaluminum hydride (1 M in dichloromethane, 307 mL, 307 mmol) was added dropwise while the reaction mixture was stirred and the temperature was maintained below 20 ° C. Subsequently, the reaction mixture was stirred at room temperature for 3 hours and then emptied into an aqueous solution of potassium tartrate (concentrated to 20% by weight, 1.5 1). The emulsion thus obtained was stirred vigorously for 1 hour, filtered on celite and the two phases were separated. The aqueous phase was extracted with ethyl acetate (200 ml) and the organic phases were combined and the combined was washed with an aqueous solution of sodium chloride (concentrated to 20% by weight, 500 ml). The organic phase obtained was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in diethyl ether (50 ml) and the resulting precipitate was collected by filtration. After drying under reduced pressure, the title product (18.3 g, 93% yield) was obtained as an off-white powder (mp 169-170 ° C).

X H NMR (DMSO): (t, 3H); 4.84 (s, 2H); 5.36 (s, 2H); 8.06 (s, 1H); 8.27 (s, 1H). IR (KBr): 870, 1022, 1102, 1304, 1482, 1567 c "1. 3.e. 2,7-dichloro-6-methyl-4- (4-methylpiperidinomethyl) -3-quinolylmethanol: A solution of the product from Step 3.b (16.2 g, 55.7 mmol) in THF (70 ml), was treated with a solution of 4-methylpiperidine (23 ml, 195 mmol). The product obtained was stirred at room temperature for 2 hours. Water (200 ml) and dichloroethane (200 ml) were added. The organic phase was washed with an aqueous solution of sodium chloride (concentrated to 20% by weight, 100 ml), dried over magnesium sulfate and concentrated under reduced pressure. (after crystallizing the residue from diethyl ether, the title product was obtained (18.3 g, 93% yield) as a white crystalline solid (mp 170-171, t ° C) XH NMR (CDC13): 0.88 (d, 3H); 1.17 (m, 2H); 1.42 (m, 1H); 1.60 (, 2H); 2.19 (t, 2H); 2.56 (s, 3H); 2.82 (d, 2H); 4.02 (s, 2H); 4.93 (s, 2H); 6.36 (broad peak, 1H); 7.95 (s, 1H); 8.02 (s, 1H). IR (KBr): 971, 1013, 1105, 1293, 1479, 1559 cm "1. 3.f. (+) 8- [2,7-dichloro-6-methyl-4- (4-methylpiperidinomethyl) -3- quinolylmethyl] -5-ethyl-5-hydroxy-l, 3,4,5,8,9-hexahydro-oxepino- [3,4-c] -pyridin-3,9-dione: A suspension of (+) - EHHOPD (obtained in Step 1.c, 1.56 g, 7.0 mmol) in anhydrous dioxane (70 ml) is treated successively, under an argon atmosphere, with the product of Step 3.e (2.47 g). 7.0 mmol), triphenylphosphine (2.02 g, 7.7 mmol) and diisopropyl azodicarboxylate (1.07 ml, 10.5 mmol). The mixture is stirred at room temperature for 16 hours. The volatiles are evaporated under reduced pressure. The residue is purified by chromatography on a silica gel column (eluent: ethyl acetate). The solid obtained is taken up in diethyl ether, filtered and dried to obtain the title product (1.96 g, 50% yield) as an off-white solid (mp 182 ° C). 1 H NMR (DMSO): 0.89 (m, 8H); 1.23 (m, 1H); 1.41 (t, 2H); 1.64 (m, 2H); 2.09 (qm, 2H); 2.59 (m, 5H); 3.15 (dd, 2H); 4.06 (dd, 2H); 5.31 (dd, 2H); 5.35 (dd, 2H); 5.75 (s, 1H); 6.29 (d, 1H); 7.17 (d, 1H); 8.06 (s, 1H); 8.46 (s, 1H). IR (KBr): 878, 1053, 1275, 1474, 1572, 1648, 1747 cm "1. 3.g. (+) - 9-chloro-5-ethyl-5-hydroxy-10-methyl-12- (4 - methylpiperidinomethyl) -4,5,13,15-tetrahydro-lH, 3H-oxepino- [3 ', 4': 6,7] -indolizine- [1,2-c] -quinolino-3,15-dione: A mixture of the product of Step 3.f (3.80 g, 6.80 mmol), tetrabutylammonium bromide (2.42 g, 7.5 mmol), potassium acetate (1.00 g, 10.2 mmol), triphenylphosphine (890 mg, 3.4 mmol) and acetate of palladium (II) (220 mg, 0.68 mmol) was stirred under an argon atmosphere in anhydrous acetonitrile (85 mg) under reflux for 24 hours.After cooling to room temperature, the resulting precipitate was collected by filtration and washed successively with acetonitrile, with water, with acetone and with diethyl ether, to obtain, after drying under reduced pressure, the title product (2.5 g, 70% yield) as an off-white powder XH NMR (DMSO): 0.86 (m, 6H); 1.12 (q, 2H); 1.36 (m, 1H); 1.56 (d, 2H); 1.84 (q, 2H); 2.12 (t, 2H); 2.56 (s, 3H); 2.83 (dd, 2H); 3.26 (dd, 2H); 4.03 (dd, 2H); 5.28 (dd, 2H); 5.45 (dd, 2H); 6.04 (s, 1H); 7.34 (s, 1H); 8.14 (s, 1 HOUR); 8.38 (s, 1H). IR (KBr): 870, 1058, 1208, 1280, 1477, 1593, 1655, 1749 cm "1. 3.h. Chloride of (+) -1- [(5R) -9-chloro-5-ethyl-5 -hydroxy-10-methyl-3, 15-dioxo-4, 5,13, 15-tetrahydro-lH, 3H-oxepino- [3 ', 4': 6,7] -indolizin- [1,2-c] -quinolin-12-yl-methyl] -4-methylhexahydropyridinium: A mixture of the product of Step 3.g (2.3 g, 7.7 mmol) and absolute ethanol (300 ml) was sonicated for 2 minutes. The mixture was stirred and treated with hydrochloric acid (1 N solution, 13.2 ml, 13.2 mmol) in order to produce a light yellow solution which, after standing, forms a gel-like precipitate.The precipitate was collected by filtration. in a Büchner funnel and washed successively with ethanol and ether, then dried under reduced pressure in order to obtain the title product (2.1 g, 85% yield). 1 H NMR (DMSO): 0.87 (m, 6H); 1.59 (m, 5H); 1.84 (q, 2H); 2.64 (s, 3H); 3.28 (dd, 2H); 3.45 (s, 2H); 4.93 (s, 2H); 5.47 (dd, 2H); 5.61 (s, 2H); 6.04 (broad peak, 1H); 7.41 (s, 1H); 8.28 (s, 1H); 8.63 (s, 1H); 10.30 (broad peak, 1H). IR (KBr): 1043, 1212, 1479, 1585, 1655, 1751 cm. PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION Test on cell proliferation. Five tumor cell lines were used in this study: SW620 (human colon adenocarcinoma), OVCAR-5 (human ovarian adenocarcinoma), PC-3 and DU 145 (human prostate cell line) and NCI-H69 (human lung adenocarcinoma). These lines were at the Cancer Research and Development Center NCI / Frederick (Frederic, MD). These lines were cultured in complex medium containing RMPI-1640 enriched with 10% fetal calf serum and 2 mM L-glutamine. They were incubated at 37 ° C in a humidified atmosphere with 5% C02. Adherent cells were detached by treatment with a 0.25% trypsin solution and 0.2% EDTA (Worthington Biochemical Corp., Freehold, NJ) for 5 minutes at 37 ° C. The count of these cells was carried out using a Coulter Zl counter (Coulter Corp., Hialea, FL). Viability was assessed by staining the cells with propidium iodide and then counted with an EPICS elite flow cytometer (Coulter). The compound of Examples 2 and 3 to be tested, was dissolved at a concentration of 5 mM in a solution of N, N-dimethylacetamine (DMA, Aldrich). Subsequent dilutions were carried out with the culture medium. The final molar concentrations tested were: 1 x 10, 2 x 10"7m 4 x 10 ~ 8, 8 x 10" 9, 1.6 x 10"9, 3.2 x 10" 10, 6.4 x "11, 1.28 x 10" 11, 2.56 x 10"12 and 5.12 x 10" 13. Each concentration was tested in 8 wells. The verification of the influence of the DMA was carried out in all cell lines. The result of these verifications is that at the maximum concentration used (0.02%), the DMA has no effect. Doxorubicin was used at 1 x concentrations -. 10 -7 M and 2 x 10-7 M as a positive control. 3 Cells were selected at 5 x 10 cells per well in a 96-well microplate (Costar Corporation, Cambridge, MA). The cells were incubated for 24 hours at 37 ° C in order to allow cell multiplication. The compound of Examples 2 and 3 to be tested was added to the concentrations indicated above and the cells were incubated at 37 ° C in a humidified atmosphere, with 5% C02, for 3 days for the adherent cells (SW620, OVCAR-5, PC-3 and DU 145) and for 5 days for cells in suspension (NCI-H69). Adherent cells were tested by the method SRB (described by LV Rubenstein, RH Shoemaker, KD Paull, RM Simón, S. Tosini, P. Skedan, DA Scudiero, A. Monks and MR Boyd, "Comparison of in tro tro anticancer-drug-screening data generated with tetrazolium assay versus a protein assay against a diverse panel of human tumor cell lines, "J. Na t.Cancer Inst., 82: 1113-1118, 1990). After incubation for 3 days, the supernatant was removed and 200 μl of RPMI-1640 was added without fetal calf serum. The cells were fixed by the addition of 50 μl of 50% trifluoroacetic acid (final concentration of trichloroacetic acid, 10%) and incubated at 4 ° C for 1 hour. The wells were washed 5 times and then stained with 50 μl of a 0.4% sulforhodamine B solution (SRB, Sigma) in 1% acetic acid, at room temperature for 10 minutes. The staining was solubilized with 100 μl of 10 mM TRIS buffer solution, pH 10, for approximately 5 minutes with shaking, the microplates were read by spectrophotometry at 570 nm. Suspended cells were tested by the XTT method (described by DA Scudiero, RH Shoemaker, KD Paull, A. Monks, S. Tierney, TH Nofziger, MJ Currens, D. Seniff and MR Boyd: "Evaluation of a soluble tetrazolium / formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines ", Cancer Research 48: 4827-4833). After incubation in the presence of the compound of Examples 2 and 3 to be tested, XTT [sodium salt of 2,3-bis- (2-methoxy-4-nitro-5-sulfophenyl) -2H-tetrazolium-5 was added. -carboxanilide (Sigma)] and phenazine metasulfate (PMS, Sigma) dissolved in phosphate buffer and the cells were incubated for 4 hours at 37 ° C in an atmosphere with 5% C02. The final concentrations of XTT and PMS were 50 and 0.38 μg / well, respectively. Formazan production was stopped by the addition of 10 μl of 10% sodium dodecylsulfate (Sigma) and the absorbance was read by spectrophotometry at 450 nm with a reference filter at 600-650 nm.

Results: The molar concentrations of the compounds of Examples 2 and 3 that caused an inhibition of cell proliferation of 50% are presented in the following Table: It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (8)

1. CLAIMS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. A product characterized in that it has as formula one of the formulas (I) or (II) represented below or salts of a compound of the formula (II) such as for example that of the formula (III) represented below
2. 2. As a novel industrial product, a product of General Formula M represented below M characterized in that R represents an ethyl radical.
3. 3. A process for preparing a product of General Formula M represented below M wherein R represents an ethyl radical, characterized in that it is constituted by the following successive steps: the racemic t-butyl ester represented below is treated with trifluoroacetic acid for 18 hours at room temperature, to obtain the corresponding carboxylic acid; then the quinidine salt of the obtained acid is heated in isopropyl alcohol at a temperature above 30 ° C and preferably at about 50 ° C, and then the reaction medium is allowed to cool to room temperature, so that the salt of one of the enantiomers of the aforementioned acid is crystallized, while the salt of the other enantiomer, whose anion is represented below, remains in solution - the solution in isopropyl alcohol of the salt of the enantiomer that did not crystallize, is concentrated and treated with hydrochloric acid and stirred, obtaining the compound of the General Formula A which is represented below the compound of the General Formula A is contacted with palladium on wet carbon and then ammonium formate or formic acid is added to the mixture, to obtain the debenzylated product of Formula B, which is depicted below B - after, the compound of the General Formula B is cyclized by the action of dicyclohexylcarbodiimide to obtain the lactone compound of General Formula C which is represented below finally, the -OCH3 group of the lactone compound of the general formula C is converted to carbonyl by the action of sodium iodide and trimethylsilyl chloride, to obtain a compound of the general formula M which is represented below. M
4. 4. As a medicine, a product characterized in that it has as formula one of Formulas (I) or (II) which are represented below or an addition salt with pharmaceutically acceptable mineral or organic acids of the product of Formula (II), such as for example that of Formula (III) which is depicted below or a mixture of any of these latter compounds.
5. 5. A pharmaceutical composition containing as an active principle, at least one of the compounds according to claim 4.
6. 6. The use of a compound according to claim 1, for the preparation of antitumor drugs.
7. 7. The use of a compound according to claim 1, for the preparation of antiviral drugs.
8. 8. The use of a compound according to claim 1, for the preparation of antiparasitic drugs.