MXPA00005845A - New compound of 7-oxo-2,3,7,14-tetrahydro-1h- benzo[b]pyrano[3,2-h]acridinecarboxylate, its production and medicine composition containing - Google Patents

Abstract

7-Oxo-2,3,7,14-tetrahydro-1H-benzo(b)pyrano(3,2-h) acridine derivatives (I), their salts with acids and bases, their isomers, N-oxides, their preparation, and pharmaceutical compositions containing them. The new compounds are of formula (I) X and Y=H, halogen, OH, SH, CN, NO2, 1-6C alkyl, alkoxy, or trihaloalkyl, amino (optionally by one or two 1-6C alkyl groups which may be substituted by alkoxy groups or by a group of formula NR7R8) or together form a methylenedioxy or ethylene dioxy group, the groups X and Y being present on either of the two adjacent benzene rings;R7 and R8=H or 1-6C alkyl, aryl, or aralkyl;R1=H or 1-6C alkyl;R2=H, OH, 1-6C alkyl or alkoxy (optionally substituted by NR9R10, or by a 5-7 membered saturated or unsaturated mono- or bicyclic heterocycle having one or two hetero atoms selected from O, N, and S), alkyl carbonyloxy, or amino (optionally substituted by one or two alkyl, aryl, or aralkyl groups, an alkylcarbonyl group that may be substituted by N R7R8, a group -R11-NR9R10, an alkylene group substituted by a heterocycle, or a group -R11-CO-R12;R9 and R10=H, or 1-6C alkyl or hydroxyalkyl;R11=1-6C alkylene;R12=OH or 1-6C alkoxy;R3 and R4=H or 1-6C alkyl;one or both of R5 and R6=a group -O-CO-U-V, and if only one has this meaning the other represents a group Z;U=1-8C alkylene, optionally substituted by one or more groups selected from aryl, OH, or 1-6C alkoxy;V=COOH, COOR13, OH, 1-6C alkoxy, -NR7R8, -NR7-COOR13, -NR7-CO-R13, -COR13, or CONR7R8;R13=1-6C alkyl optionally substituted OH, aryl, or aralkyl;Z=OH, 1-6C alkoxy, alkoxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, arylalkyl carbonyloxy, or amino optionally substituted by one or two alkyl groups

Description

NEW CARBOXYLATE COMPOUNDS OF 7-0X0-2,3,7,14 TETRAHIDR0-1H-BENZ0 [b] PIRAN [3, 2-h] -ACRIDINE, A PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM DESCRIPTION OF THE INVENTION The present invention relates to new compounds of 7 -oxo-2, 3, 7, 14-tetrahydro-H-benzo [b] -pyrano [3, 2-h] -acridine carboxylate, to a process for its preparation and to pharmaceutical compositions containing them. The compounds of the invention are derivatives of acronycin, which is an alkaloid having anti-tumor properties that have been demonstrated in experimental models (J. Pharm. Sci., 1966, 5_5_ (8), 758-768). Despite a broad spectrum of activity, however, acronycin is slightly soluble, which limits its bioavailability and its use in pharmaceutical compositions for administration by injection. Various modifications have been made to this molecule, such as those described in J. Med. Chem., 1996, 3_9, 4762-4766, and have made it possible to solve some of the difficulties associated with the problem of the solubility of these compounds. However, the requirements of anti-cancer therapy demand the constant development of new anti-tumor agents in order to obtain medicines that are simultaneously more active and better tolerated. In particular, solid tumors pose a significant problem in anti-cancer chemotherapy due to their intrinsic and / or acquired resistance to existing products. In addition to the fact that the compounds of the invention are new, they have a surprising in vivo and in vitro activity, which is superior to that observed hitherto. On the other hand, the compounds have valuable properties with respect to solubility, making them suitable for the administration of the compounds in liquid form. The compounds discovered by the Applicant thus have anti-tumor properties that make them especially useful in the treatment of cancer, especially of solid tumors. More specifically, the present invention relates to compounds of formula (I): wherein: X and Y, which may be identical or different, each independently of the other represents a selected group of a hydrogen atom, a halogen atom, a hydroxy group, a mercapto group, a cyano group, a nitro group , an alkyl group of 1 to 6 straight or branched carbon atoms, an alkoxy group of 1 to 6 straight or branched carbon atoms, a trihaloalkyl group of 1 to 6 carbon atoms, in which the alkyl portion is linear or branched , and an amino group (optionally substituted by one or two alkyl groups of 1 to 6 identical or different linear or branched carbon atoms, which may themselves be substituted by an alkoxy group of 1 to 6 linear or branched carbon atoms or by a group of formula -NR7Rs. wherein R7 and R8, which may be identical or different, each independently of the other represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms straight or branched or, an aryl group or an aryl-alkyl group of 1 to 6 carbon atoms, in which the alkyl portion is linear or branched), or X and Y together form a methylenedioxy or ethylenedioxy group, it being understood that the substituents X and Y they may be present on one or the other of the two adjacent benzene rings, Ra represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, linear or branched, R2 represents: - a hydrogen atom, - a hydroxy group, an alkyl group of 1 to 6 straight or branched carbon atoms, - an alkoxy group of 1 to 6 straight or branched carbon atoms, optionally substituted by a group selected from : * a group of formula NR9R? 0, wherein R9 and Rio, which may be identical or different, each independently of the other represents a hydrogen atom, an alkyl group of 1 to 6 linear or branched carbon atoms or a Hydroxyalkyl group of 1 to 6 carbon atoms straight or branched, and * a saturated or unsaturated monocyclic or bicyclic heterocycle, having from 5 to 7 members in the ring, containing one or two heteroatoms selected from oxygen, nitrogen and sulfur, - an alkylcarbonyloxy group having from 1 to 6 linear carbon atoms or branched, or - an amino group optionally substituted by: * one or two, linear or branched alkyl groups of 1 to 6 carbon atoms, identical or different, aryl groups or aryl-alkyl groups of 1 to 6 carbon atoms, which alkyl portion is linear or branched, * an alkylcarbonyl group of 1 to 6 straight or branched carbon atoms, optionally substituted by a group -NR R8 wherein R7 and Rβ are as defined above, * a group of formula -R1 _.- NR9R.10, wherein Rn represents an alkylene group of 1 to 6 straight or branched carbon atoms, and R9 and Rio, which may be identical or different, each independently of the other represents a hydrogen atom, a linear or branched alkyl group of 1 to 6 carbon atoms, or a hydroxyalkyl group of 1 to 6 straight or branched carbon atoms, * an alkylene group of 1 to 6 straight or branched carbon atoms, substituted by a monocyclic or bicyclic heterocycle saturated or unsaturated, having from 5 to 7 members in the ring, containing one or two heteroatoms selected from oxygen, nitrogen and sulfur, or * by a group of formula -Rn-CO-R? 2, wherein Rn is as was defined in the foregoing, and R12 represents a hydroxy group or an alkoxy group of 1 to 6 straight or branched carbon atoms, R3 and R4, which may be identical or different, each independently of the other represents a hydrogen atom or an alkyl group of 1 to 6 straight or branched carbon atoms, R5 and / or R6 represent (n) a group of formula -0-CO-UV, wherein: - ü represents an alkylene chain of 1 to 8 carbon atoms; linear or branched carbon, optionally substituted by one or more identical or different groups selected from linear or branched aryl, hydroxy and alkoxy of 1 to 6 carbon atoms, - V represents a group selected from: * carboxy, * -C02Ri3, where Ri3 represents an alkyl group of 1 to 6 linear or branched carbon atoms (optionally substituted by one or more hydroxy groups), an aryl group or an aryl-alkyl group of 1 to 6 straight or branched carbon atoms, in which the alkyl portion is straight or branched, * hydroxy, * straight or branched alkoxy of 1 to 6 carbon atoms, * -NR7R8, wherein R7 and R8, which may be identical or different, are as defined above, * -NR7-C02R 3, wherein R7 and Ri3 are as defined in the above, * -NR7-CORi3, where R7 and R13 are as defined above, * -C0Ri3A where Ri3 is as defined above, and * -CO-NR7R8 , wherein R7 and R8 / which may be identical or different, are as defined in the foregoing, and when only one of the two groups R5 and R6 represents a group of formula -0-CO-UV, then the other of groups R5 and R6 represents a group Z selected from: - hydroxy, - alkoxy of 1 to 6 carbon atoms linear or branched. - linear or branched alkylcarbonyloxy of 1 to 6 carbon atoms, - arylcarbonyloxy, - aryl-alkylcarbonyloxy of 1 to 6 carbon atoms in which the alkyl portion is linear or branched, and - amino optionally substituted by one or two alkyl groups of 1 to 6 identical or different linear or branched carbon atoms, their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base. "Aryl" is understood to mean a phenyl or naphthyl group, optionally containing one or more identical or different substituents selected from hydroxy, halogen, carboxy, nitro, amino, alkylamino of 1 to 6 carbon atoms or di-alkylamino of 1 to 6 carbon atoms in the (each) alkyl portion is linear or branched, straight or branched alkoxy of 1 to 6 carbon atoms, acyl of 1 to 6 straight or branched carbon atoms, and linear or branched alkylcarbonyloxy of 1 to 6 carbon atoms.

Among the pharmaceutically acceptable acids, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid may be mentioned by way of non-limiting example. , tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, lysine, etc. Among the pharmaceutically acceptable bases can be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide , triethylamine, tert-butylamine, etc. The preferred substituents R3 and R4 according to the invention are linear or branched alkyl groups of 1 to 6 carbon atoms in which R3 and R4 can be identical or different, R3 and R4 are preferably identical, and each represents a methyl group. Preferred substituents R 2 according to the invention are linear or branched alkoxy groups of 1 to 6 carbon atoms, or amino groups optionally substituted by one or two substituents as defined for formula (I). According to an advantageous embodiment, the preferred compounds of the invention are those wherein R5 represents a group of formula -0-CO-UV, wherein U and V are as defined for formula (I), and R6 represents a group Z as defined for formula (I). According to another advantageous embodiment, the preferred compounds of the invention are those wherein R6 and R5 each represent an identical group of formula -O-CO-UV, wherein U and V are as defined for formula (I) . The preferred substituent R5 according to the invention is the group of formula -0-CO-UV, wherein U represents an alkylene chain of 1 to 4 linear carbon atoms, and V represents a group selected from carboxy, -NR7R8, -NR7-C02R13 and -NR-7-COR13, wherein R7, R8 and R13, which may be identical or different, represent a hydrogen atom or an alkyl group of 1 to 6 linear or branched carbon atoms. The preferred substituent R6 according to the invention is the linear or branched alkylcarbonyloxy group of 1 to 6 carbon atoms. The preferred compounds of the invention are: (±) -cis-4- acid. { [1- (acetyloxy) -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3,7, 14-tetrahydro-lH-benzo [b] irano- [3, 2-h] -acridin -2-il] oxy} -4-oxobutanoic, - (+) - cis-4- ( { 1- [3-carboxypropanoyl) oxy] -6-methoxy-3,3, 14-trimethyl-7-oxo-2,3,7-acid. , 14-tetra idro-lH-enzo [b] -pyrano [3,2-h] -acridin-2-yl] oxy} -4-oxobutanoic, acid (±) -cis-5-. { [1- (acetyloxy) -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3,7, 14-tetrahydro-lH-enzo [b] pyrano- [3, 2-h] -acridin -2-il] oxy} -5-oxopentanoic, cis- [1- (acetyloxy) -6-methoxy-3,3, 14-trimethyl-7-oxo-2, 3,7,14-tetrahydro-lH-benzo [(dimethylamino)] acetate ] -pirano [3, 2-h] -acridin-2-yl], and cis- [1- (acetyloxy) -6-methoxy-3, 3, 14-trimethyl-7- 4- (dimethylamino) butanoate oxo-2, 3,7,14-tetrahydro-lH-benzo [b] -pyrano [3,2-h] -acridi-2-yl]. The isomers, N-oxides, and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds are an integral part of the invention. The present invention also relates to a process for the preparation of compounds of formula (I), characterized in that: • either a compound (II) of 3-amino-2-naphtal enearboxylic acid: (ID wherein X and Y are as defined for formula "(I), is reacted with a phloroglucinol compound of formula (III): wherein R represents a hydrogen atom, a hydroxy group or an alkyl group of 1 to 6 carbon atoms, linear or branched, to provide the compounds of formula (IV): wherein X, Y and R are as defined in the foregoing, which are then treated under basic conditions in an aprotic solvent, such as, for example, dimethylformamide, with an alkyne of formula (V): Hal HC: (V) R. R4 wherein Hal represents a halogen atom, and R3 and R4 are as defined for formula (I), to provide compounds of formula (VI): wherein X, Y, R, R3 and R4 are as defined above, or a 3-halo-2-naphthalenecarboxylic acid, compound of formula (VII): wherein X and Y are as defined for formula (I), and Hal represents a halogen atom, such as chlorine or bromine, is reacted with an amino-chromene compound of formula (VIII): wherein R3 and R4 are as defined for formula (I), and R is as defined above, also to provide compounds of formula (VI): where X, Y, R, R3 and R4 are as defined in • 1, the nitrogen atom of the compounds of formula (VI) is optionally substituted, by the action of an alkyl halide or an alkyl sulfate in the presence of a deprotonation agent, such as sodium hydride, in an aprotic polar solvent, to provide the compounds of formula (IX): wherein X, Y, R, R3 and R4 are as defined above, and R'i represents an alkyl group of 1 to 6 straight or branched carbon atoms, the compounds of formula (IX) are subjected to the action of an alkylating agent, such as a dialkyl sulfate, or an acylating agent, to provide the compounds of formula (X): wherein X, Y, R'i / R3 and R4 are as defined in the above, and R'2 represents an alkoxy group (optionally substituted by a formula group NR9R10, wherein R9 and Rio are as defined for formula (I)), or an alkylcarbonyloxy group of 1 to 6 straight or branched carbon atoms, the compound of formula (X), when R'2 represents an alkoxy group for example, it is treated with a compound of formula (XI): HNRaRb (XI wherein Ra represents a hydrogen atom, an alkyl group of 1 to 6 straight or branched carbon atoms, an aryl group, or an aryl-alkyl group of 1 to 6 carbon atoms, in which the alkyl portion is linear 0 branched, and Rb represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms straight or branched, an aryl group, or an aryl-alkyl group of 1 to 6 carbon atoms, in which the alkyl portion is linear or branched, a group of formula -R11-NR9R10 / wherein RU / Ri0 and R9 are as defined for formula (I), an alkylcarbonyl group of 1 to 6 straight or branched carbon atoms, in which the alkyl portion is optionally substituted by a group NR7R8 as defined for formula (I), a heterocycloalkylene group (the terms "alkylene" and "heterocycle" are as defined for the formula (I)), or a group of formula -Rn-C0-R12, where Rn and R12 are as defined for formula (I), to provide compounds of formula (XII): wherein X, Y, R'i, R3, R4, Ra and Rb are as defined above, the totality of the compounds of formulas (VI), (IX), (X) and (XII) which constitute the compounds of formula (XIII): wherein X, Y, Rx, R2, R3 and are as defined in the general definition of formula (I), the compounds of formula (XIII) are attached a) = > either to the action of osmium tetroxide in a polar medium, and in the presence of 4-methylmorpholine N-oxide, to provide the compounds of the formulas (XlV / a) and (XlV / b): wherein X, Y, Ri, R, R3 and are as defined in the foregoing, it being possible for the compounds of formulas (XlV / a) and (XlV / b) to be obtained separately by chiral synthesis, and especially by cis dihydroxylation asymmetric, starting from the compound (XIII), using chiral ligands of the pyridine or phthalazine type bissubstituted by Cinchona alkaloids, such as dihydroquinine and its dextrorotatory diastereoisomer, dihydroquinidine, b) = - > or to the action of potassium permanganate in a polar medium, to provide the compounds of formula (XV): wherein X, Y, Rx, R2, R3 and R4 are as defined above, the compounds of formula (XV) are subjected to reductive conditions in the presence of NaBH4 for example, to provide the compounds of formula (XIV / c) ): wherein X, Y, Ri, R2, R3 and R4 are as defined in the above, all of the compounds of formulas (XlV / a), (XlV / b) and (XIV / c) constitute the compounds of formula (XIV): Where X, Y, Ri, R2, R3 and R4 are as defined in terior, omponents of formula (XIV) are attached: * > either to the action of an alcohol of formula R20OH, wherein R2o represents an alkyl group of 1 to 6 carbon atoms, linear or branched, to provide the compounds of formula (XVI / a): wherein X, Y, Ri, R2, R3, 4 and R20 are as defined above, the alcohol function of the compounds of formula (XVI / a) is esterified in the presence of a compound of formula VUC (0) - 0-W or (VU-CO) 20, where U and V are as park was defined the formula (I), and W represents a leaving group, to provide the compounds of formula (I / a), a particular case of the compounds of formula (I): wherein X, Y, Rx, R2, R3, R_, R20, U and V are as defined in the foregoing, * > or to the action of an alkyl iodide of formula R'20-I, wherein R'20 represents an alkyl group of 1 to 6 straight or branched carbon atoms, in the presence of a silver salt, to provide the compounds of formula (XVI / b): a particular case of the compounds of formula (I), wherein X, Y, R1 R2, R3, R4 and R2o are as defined above, the alcohol function of the compounds of formula (XVI / b) is esterified in the presence of a compound of formula VUC (0) -0-W or (VU-CO) as defined above, to provide the compounds of formula (I / b): a particular case of the compounds of formula (I), wherein X, Y, Ri, R2, R3, R4, R'20, U and V are as defined above, * t * or the direct action of a compound of formula VUC (O) -OW or (VU «-C0) as defined above, in the presence of a base, such as triethylamine or 4-dimethylaminopyridine, to obtain the compounds of formula (I / c), a particular case of the compounds of formula (I): wherein X, Y, Ri, R2, R3, R4, U and V are as defined above, the compound of formula (I / c) can be subjected to new, under the same operating conditions, to the action of an anhydride of formula (R30CO) 20, wherein R30 represents an alkyl group of 1 to 6 straight or branched carbon atoms, an aryl group or an aryl-alkyl group of 1 to 6 carbon atoms, in which the alkyl portion is linear or branched, to provide the compounds of formula (I / d): (I / d) wherein X, Y, Ri, R2, R3, R4, R30, U, and V are as defined above, or the compound of formula (I / c) can be re-treated with a compound of formula VUC (cf. ) -0-W or (V-ü-C0) 20 as defined above, to provide the compounds of formula (I / e), a particular case of the compounds of formula (I): wherein X, Y, Rx, R2, R3, R4, U and V are as defined for formula (I), it being understood that the two groups U and the two groups V may each be identical or different, c) = > or to the action of a peracid, such as m-chloroperbenzoic acid, to provide the compound of formula (XVII): wherein X, Y, Ri, R2, R3 and R4 are as defined above, the compound of formula (XVII) is optionally treated with ammonia or a primary or secondary amine to provide the compounds of formula (XVIII / a) I (XVIII / b) depending on the nature of the reagents: (XVIII / a) (XVIII / b) wherein X, Y, Rx, R2, R3 and R4 are as defined above, and Rc and Rd represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms straight or branched, the compounds of formulas ( XVIII / a) and (XVIII / b) are treated with a compound of formula VUC (0) -0-W as defined above, to provide the compounds of formulas (I / f) and (I / g) respectively , particular cases of the compounds of formula (I): where X, Y, Rx, R2, R3, R4, Rc / Rd, U and V are as defined in the above, the compounds (I / a) to (I / g) constitute all of the compounds of the invention, which are purified, if necessary, according to a conventional purification technique, they can be separated, if desired, in their various isomers according to a conventional separation technique, and are converted, if desired, into N-oxides thereof and, where appropriate, into addition salts thereof with a pharmaceutically acceptable acid or base. The compounds of formulas (II), (III), (V), (VII), (VIII) and (XI) are either commercial compounds, or are obtained according to conventional methods of organic synthesis. The compounds of formula (VIII), for example, are obtained according to the conditions described in Chem. Ber., 1978, 191, 439. The condensation reaction between the compounds of formula (VII) and the compounds of formula (VIII) ) is described, for example, in the journal Heterocycles, 1992, 34 (4), 799-806. The compounds of formula (I) have especially valuable anti-tumor properties. They have an excellent in vitro cytotoxicity on murine and human tumor cell lines due to specific blockage of the cell cycle, and have in vivo activity, in mice, on transplantable murine and human tumors. The characteristic properties of these compounds allow them to be used therapeutically as anti-tumor agents. The present invention also relates to pharmaceutical compositions comprising as an active ingredient at least one compound of formula (I), its optical isomers, N-oxides or an addition salt. thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more pharmaceutically acceptable excipients or carriers. Among the pharmaceutical compositions according to the invention, special mention is made of those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or lozenges, sublingual tablets, gelatin capsules, capsules, suppositories, creams, ointments, dermal gels, injectable or ingestible preparations, aerosols, ophthalmic or nasal drops, etc. The useful dosage varies according to age and weight of the patient, the route of administration, the nature and severity of the disorder and whether any associated treatment is being taken, and is in the range of 0.5 mg to 500 mg in one or more administrations per day. The following Examples illustrate the invention but do not limit it in any way. The starting materials used are known products, or they are prepared according to known procedures. The structures of the compounds described in the Examples and Preparations were determined according to the usual spectrophotometric techniques (infra red, nuclear magnetic resonance, etc.).

PREPARATION A: (±) -cis-1, 2-Dihydroxy -6-methoxy -3, 3, 14-trimethyl-2, 3,7, 14 -tetrahydro-1H-benzo- [b] pi-ano [3, 2 -h] acridin-7 -one Step A: 1,3-Dihydroxy-5,12-dihydro-benzo [b] acridin-12-one 3.5 g of 1, 3, 5-trihydroxybenzene and 62.5 g of p-toluenesulfonic acid were added to a solution of 5 g of 3-amino-2-naphthalenecarboxylic acid in 50 ml of 1-heptanol. The mixture was stirred for 48 hours at reflux, using a Dean-Stark apparatus, and then the reaction mixture was concentrated in vacuo. The residue was chromatographed on silica gel (eluent: cyclohexane / acetone: 90/10). The isolated product was crystallized from a cyclohexane / acetone mixture, and yielded 5.2 g of the expected product.

Step B: 6-Hydroxy-3, 3-dimethyl-7,14-dihydro-3H-benzo [b] pyran [3, 2-h] acridin-7-one 2 g of anhydrous potassium carbonate were added, under a inert atmosphere, to a solution of 2 g of the product of Step A in 50 ml of anhydrous dimethylformamide. After stirring for 15 minutes at 65 ° C, 2.4 g of anhydrous potassium iodide and 4.4 g of 3-chloro-3-methyl-1-butyl were added, and the reaction mixture was maintained at 65 ° C for 24 hours , and then at 130 ° C for 1 hour 30 minutes. After cooling, the solution was hydrolyzed and then extracted with dichloromethane. The combined organic phases were washed with water and then with a 1M potassium hydroxide solution, dried over magnesium sulfate and then evaporated. Chromatography on silica gel (cyclohexane / acetone: 90/10) gave 1.10 g of the expected product. Melting point: 225 ° C Step C: 6-Methoxy-3, 3, 14 -trimethyl-7,14-dihydro-3H-benzo [b] pyran [3, 2-h 3 acridin-7 -one 0.16 g of spdium hydride were slowly added and then, after 15 minutes, 0.65 ml of dimethyl sulfate (6 equivalents) at 0 ° C under an inert atmosphere to a solution of 0.5 g of the product of Step B in 20 ml of anhydrous dimethylformamide.

After 1 hour, the reaction mixture was hydrolyzed with ice, and then extracted with ethyl acetate.

After washing the organic phase with an aqueous solution of sodium hydroxide, the organic phase was dried over sodium sulfate, and then evaporated in vacuo. Chromatography on silica gel (cyclohexane / acetone: 98/2) allowed the isolation of 0.42 g of the expected product. Melting point: 188 ° C Step D: (±) -cis-1, 2-Dihydroxy-6-methoxy-3, 3, 14-trimethyl-2, 3,7, 14-tetrahydro-1H-benzo-b] pyran [3, 2- h] acridin-7-one 3.8 ml of a 2.5% solution of osmium tetroxide in 2-methyl-2-propanol were added to a solution of 2 g of the product from Step C and 0.9 g of N-oxide monohydrate of 4-methylmorpholine in 40 ml of a mixture of tert-butanol / tetrahydrofuran / water (3/3/1). After 2 days at room temperature, 105 ml of a saturated solution of NaHS03 was added, and the reaction mixture was stirred for 1 hour, and then extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, and concentrated in vacuo. Chromatography on silica gel (dichloromethane / methanol: 95/5) allowed the isolation of 1.3 g of the expected product. Fusion point 4e: 194 ° C PREPARATION B: (±) -cis-1, 2-Dihydroxy-6- (dimethylamino-ethylamino) -3,3, 14 -trimethyl-2, 3, 7, 14-tetrahydro-lH-benzo [b] pyran [3 , 2-h] - acridin-7-one Step A: 6- (Dimethylaminoethylamino) -3,3, 14-trimethyl-7,14-dihydro-3H-benzo [b] pyran [3, 2-h] -acridin -7-one 4 ml of N, N-dimethylethylenediamine was added to 0.15 g of the product obtained in Step C of Preparation A. After a 5-day reaction at 70 ° C under an inert atmosphere, the reaction mixture evaporated under reduced pressure. The resulting residue was subjected to chromatography on silica gel (cyclohexane / ethyl acetate: 80/20) allowing the isolation of the expected product. Melting point: Mass Spectrum Oil: (DIC / NH3): m / z: 428 (M + H) + Etiapa B: (±) -cis-1, 2-Dihydroxy-6- (dimethylaminoethylamino) -3,3, 14 -trimethyl-2, 3,7,14-tetrahydro-lH-benzo [b] pyran [3, 2 -h] - acridin-7-one The procedure is as for Step D of Preparation A using the product obtained in the preceding Step as a substrate.

PREPARATION C: (±) -cis-1, 2-Dihydroxy-6- (diethylaminopropylamino) -3,3, 1 -trimethyl-2, 3,7,14-tetrahydro-lH-benzo [b] pyran [3 , 2-h] - acridin-7-one The procedure is as for Preparation B, Steps A and B, using N, N-diethylpropyldiamine as reagent in Step A.

PREPARATION D: cis-6- [(2-Morpholin-4-yl) ethylamino] -1,2-dihydroxy-3, 3, 1 -trimethyl-2, 3,7, 14-tetrahydro-lH-benzo [b] pyrano [3, 2-h] -acridin-7-one The procedure is as for Preparation B, Steps A and B, using 4- (2-aminoethyl) morpholine as reagent in Step A.

PREPARATION E: cis-10, 11-Dichloro-l, 2-Dihydroxy-6-methoxy-3, 3, 14 -trimethyl-2, 3,7,14-tetrahydro-lH-benzo [b] pyran [3, 2 -h] - acridin-7-one The procedure is as for Preparation B, Steps A and B, using 3-amino-6,7-dichloro-2-naphthalenecarboxylic acid as reagent in Step A.

PREPARATION F: cis-1, 2-Dihydroxy -6, 9, 12 -trimethoxy-3,3, 14 -trimethyl-2, 3,7, 14 -tetrahydro-1H-benzo [b] pyran [3, 2-h ] -acridin-7-one The procedure is as for Preparation A, Steps A to D, using 3-amino-5,8-dimethoxy-2-naphthalenecarboxylic acid as a reagent in Step A.

PREPARATION G: sis-1,2-dihydroxy-β-methoxy-3, 3-dimethyl-2,3,7,14-tetrahydro-lH-benzo [b] -pyrano [3, 2-h] cridin-7 ona Step A: 3- [(7-Methoxy-2, 2-dimethyl-2H-chromen-5-yl) amino] -2-naphthoic acid A mixture of 1.2 mmoles of 5-amino-6-methoxy-2, 2-dimethylchromene, 1.2 mmoles of 2-bromo-3-benzoic acid, 0.327 g of potassium acetate, and 12 mg of copper acetate were suspended in 8 ml of 2-propanol and 0.25 ml of triethylamine, and then heated at reflux for 24 hours. The reaction mixture was then concentrated under reduced pressure, dissolved in a mixture of CH2C12 / 1N HC1, extracted with dichloromethane, dried and evaporated. Chromatography of the residue on silica gel (cyclohexane / ethyl acetate: 1/1) allowed the isolation of the expected product.

Mass Spectrum: (DIC / NH3): 376 (M + H) + Step B: 6-Methoxy-3, 3-dimethyl-3,14-dihydro-7H-benzo [b] -pyrano [3, 2-h] acridi -7-lone 1.02 mmol of the compound obtained in the Step A in 14 ml of dichloromethane were treated with 1 ml of trifluoroacetic acid. After 2 hours at room temperature, the reaction mixture was evaporated. The residue was dissolved in a mixture of dichloromethane and a saturated solution of NaHCO 3, extracted with dichloromethane, washed with a 10% solution of sodium hydroxide and then extracted again with dichloromethane. After a conventional treatment, chromatography of the residue on silica gel (dichloromethane / methanol: 98/2) allowed the isolation of the expected product. Mass Spectrum E.I.:m/z: 357 (M +); 342 (M-15) + Step C: sis-1,2-Dihydroxy-6-methoxy-3,3-dimethyl-2,3,7,14-tetrahydro-lH-benzo [b] -pyrano [3, 2-h] acridin-7 - One mixture of 0.279 mmoles of the compound obtained in Step B, a 2.5% solution of osmium tetroxide in 3.8 ml of 2-methyl-2-propanol and 60 mg of 4-methylmorpholine N-oxide were dissolved in 5 ml of a 10/3/1 mixture of ter-BuOH / tetrahydrofuran / H20. After stirring for 24 hours at room temperature, 5 ml of a saturated solution of NaHS? 3 was added. After stirring for 1 hour, the reaction mixture was extracted with dichloromethane. The organic phase was subsequently dried, and then concentrated under reduced pressure. Chromatography of the residue on silica gel (dichloromethane / methanol: 97/3) allowed the isolation of the expected product. Mass Spectrum: (DIC /? H3): 392 (M + H) + EXAMPLE 1: Acid (±) -cis-4-. { [1- (acetyloxy) -6-methoxy-3,3,14-trimethyl-7-oxo-2,7,7,14-tetrahydro-1H-benzo [b] pyran [3, 2-h] acridin-2 -il] oxy} - oxobutanoic Five equivalents of succinic anhydride and 1 mg of dimethylaminopyridine were added to a solution of 0.74 mmol of the compound of preparation A in 7 ml of anhydrous pyridine. After stirring for 17 hours at room temperature and in the dark, 25 ml of acetic anhydride was added. The reaction mixture was cooled to -15 ° C and stirring was maintained for 1 hour 30 minutes. The reaction mixture was then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane / ethanol) allowed the isolation of the expected product. Mass Spectrum: (FAB): m / z: 548 (M + H) + Melting point: 154 ° C EXAMPLE 2: Acid (±) -cis-4-. { [1- (acetyloxy) -6-. { [2- (dimethylamino) ethyl] amino} -3,3, 14 -trimethyl-7 -oxo-2, 3,7, 14 -tetrahydro-1H-benzo [b] -pyrano [3, 2-h] acridin-2-yl] oxy} -4- oxobutanoic The procedure is as for Example 1, using the compound of preparation B as a substrate.

EXAMPLE 3: Acid (±) -cis-5-. { [1- (acetyloxy) -6-methoxy-3,3, 14-trimethyl-7-oxo-2,7,7,14-tetrahydro-1H-benzo [b] pyran [3, 2-h] acridin-2 -il] oxy} -5- oxopentanoic The procedure is as for Example 1, using glutaric anhydride as a reagent instead of succinic anhydride. Mass Spectrum: (DIC / NH3): / z: 562 (M + H) + Melting point: 155 ° C EXAMPLE 4 2, 3-Dihydroxypropanoate of (±) -cis-l- (acetyloxy) -6-methoxy-3, 3, 14 -trimethyl-7-oxo-2,3,7, 14-tetrahydro-lH-benzo [ b] pyrano [3,2-h] acridin-2-yl Stage A: (±) -cis-1- (acetyloxy) -6-methoxy-3,3,1-trimethyl-7-oxo-2,3,7,1-tetrahydro-lH-benzo [b] pyran acrylate [3, 2-h] acridin-2-yl 0.6 mmoles of acryloyl chloride were added to a solution of 0.5 mmoles of the compound of Preparation A in 3 ml of anhydrous pyridine. After stirring for 2.5 days at room temperature and in the dark, 2 ml of acetic anhydride was added and the stirring was maintained for 48 hours. The reaction mixture was then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane) allowed the isolation of the expected product. Mass Spectrum: (DIC / NH3): m / z: 502 (M + H) + Step B: 2, 3-Dihydroxypropanoate of (+) - cis-1- (acetyloxy) -6-methoxy-3, 3, 14 -trimethyl-7-oxo-2, 3,7,14-tetrahydro-lH-benzo [b] pyrano [3,2-h] acridin-2-yl 1 ml of 2.5% solution of osmium tetroxide in tert-butanol and 4.4 mmol of monohydrate were added of 4-methylmorpholine N-oxide to a suspension of 0.4 mmoles of the compound obtained in Step A in 5 ml of a mixture of tert-butanol / tetrahydrofuran / water (10/3/1 volume by volume). After stirring for 2 days at room temperature, 50 ml of a saturated aqueous solution of NaHCO 3 was added. After stirring for 1 hour, extraction with dichloromethane and concentration under reduced pressure, chromatography on silica gel (dichloromethane / methanol: 96/4) allowed the isolation of the expected product. Mass Spectrum: (DIC / NH3): / z: 536 (M + H) + EXAMPLE 5: 2- (Tert-butoxycarbonyl) amino] cetato of (±) - cis-1- (acetyloxy) -6-methoxy-3,3,14-trimethyl-7-oxo-2, 3,7, 14 -tetrahydro-lH-benzo [b] -pyrate [3, 2-h] acridin-2-yl 0.6 mmol of di.cyclohexylcarbodiimide was slowly added to a solution, cooled at 0 ° C, of 0.5 mmol of the compound of Preparation A and 0.5 mmole of 2- [(tert-butoxycarbonyl) amino] -acetic acid in 10 ml of dimethylformamide. The reaction mixture was kept at 0 ° C for 5 hours, and at room temperature for 16 hours. After filtration and evaporation under reduced pressure, the residue was dissolved in 2 ml of anhydrous pyridine, 2 ml of acetic anhydride was added, and the mixture was stirred at room temperature and in the dark for 48 hours. After concentration of the reaction mixture under reduced pressure, chromatography of the residue on silica gel (dichloromethane) allowed the isolation of the expected product. Mass Spectrum: (DIC / NH3): m / z: 605 (M + H) + EXAMPLE 6: 2-Aminoacetate of (±) -cis-1- (acetyloxy) -6-methoxy-3, 3, 14 -trimethyl-7 -oxo-2, 3,7,14-tetrahydro-lH-benzo [b ] pyrano [3, 2-h] acridin-2-yl 0.14 μl of iodotrimethylsilane at room temperature was added to a solution of 0.1 mmol of the compound of Example 5 in 1 ml of chloroform. The reaction mixture was stirred for 5 minutes at room temperature, and then evaporated to dryness under reduced pressure. Chromatography on silica gel (dichloromethane / methanol: 85/15) allowed the isolation of the expected product. Mass Spectrum: (DIC / NH3): m / z: 505 (M + H) + EXAMPLE 7: Acid (±) -cis-4- ( { 1- [(3-3-carboxypropanoyl) -oxy] -6-methoxy -3,3, 14 -trimethyl -7-oxo-2,3,7,14-tetrahydro-lH-benzo [b] pyran [3,2-h] acridin-2-yl.} Oxy ) -4-oxobutanoic The product was isolated in the course of chromatography of the compound of Example 1. Mass Spectrum: (FAB): m / z: 606 (M + H) + Melting point: 128 ° C EXAMPLE 8: cis-4-acid. { [1- (acetyloxy) -10,1-dichloro-6-methoxy-3,3,14-trimethyl-7-oxo-2,7,7,14-tetrahydro-lH-benzo [b] pyran [3, 2 -h] cridin-2-yl oxy} -4-oxobutanoic The procedure is as for Example 1, using the compound of Preparation E as a substrate.

EXAMPLE 9: cis-4-acid. { [1- (acetyloxy) -6, 9, 12-trimethoxy-3,3, 1-trimethyl-7-oxo-2, 3,7,14-tetrahydro-1H-benzo [b] pyran [3, 2-h ] acridin-2-yl] oxy} - -oxobutanoic The procedure is as for Example 1, using the compound of Preparation F as a substrate.

EXAMPLE 10: cis-4- [(1- (acetyloxy) -6- { [3- (diethylamino) propyl] amino] -3,3,14-trimethyl-7-oxo-2,3 acid; 7,14-tetrahydro-lH-be zo [b] pyran [3, 2-h] acridin-2-yl) oxy] -4-oxobutanoic The procedure is as for Example 1, using the compound of Preparation C as a substrate.

EXAMPLE 11: cis-4- [(1- (acetyloxy) -3,13-trimethyl-6- {2- [4 (morpholinyl) ethyl] amino] -7-oxo-2 acid, 3,7, 14-tetrahydro-1H-benzo [b] pyran [3, 2-h] acridin-2-yl) oxy] -4-oxobutanoic The procedure is as for Example 1, using the compound of Preparation D as a substrate.

EXAMPLE 12: cis-4 - acid. { [6-methoxy-3, 3, 14 -trimethyl-7-oxo-l- (propionyloxy) -2,3,7,14-tetrahydro-lH-benzo [b] pyran [3, 2-h] acridin-2 -yl) oxy] -4-oxobutanoic The procedure is as for Example 1, using propionic anhydride as a reagent instead of acetic anhydride.

EXAMPLE 13: cis- - acid. { [1- (isobutyryloxy) -6-methoxy-3,3, 14-trimethyl-7-oxo-2,7,7,14-tetrahydro-1H-benzo [b] pyran [3, 2-h] cridin-2 -yl) oxy] -4-oxobutanoic The procedure is as for Example 1, using isobutyric anhydride as a reagent instead of acetic anhydride.

EXAMPLE 14: cis-4- acid. { [1- (benzoyloxy) -6-methoxy-3,3,1-trimethyl-7-oxo-2,7,7,14-tetrahydro-1H-benzo [b] pyran [3, 2-h] acridin-2 -yl) oxy] -4-oxobutanoic The procedure is as for Example 1, using benzoic anhydride as a reagent instead of acetic anhydride.

EXAMPLE 15: cis-4-acid. { [6-methoxy-3, 3, 14-trimethyl-7- oxo-1- (pentanoyloxy) -2,3,7,14-tetrahydro-1H-benzo [b] pyran [3, 2-h] acridin-2 yl) oxy] -4-oxobutanoic The procedure is as for Example 1, using valeric anhydride as a reagent instead of acetic anhydride.

EXAMPLE 16: cis- [l- (acetyloxy) -6-methoxy -3,3,1-trimethyl-7-oxo-2,3,7,14-tetrahydro-lH-benzo [dimethylamino] acetate. pyran [3,2-h] acridin-2-yl] 300 mg of the compound of the Preparation A in 4 ml of anhydrous dimethylformamide at 0 ° C. 90 mg of 4-dimethylaminopyridine and 152 mg of N, N-dimetyl glycine were added to the mixture. After a 5 minute pause at 0 ° C, 142 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added. The reaction mixture was stirred for 4 hours, and then 2 ml of ice water was added. The mixture was extracted with dichloromethane. The organic solutions were combined, dried over anhydrous sodium sulfate, filtered and then distilled under reduced pressure. The resulting residue was subjected to chromatography on silica gel (CH2Cl2 / MeOH: 85/15) to provide the expected product. Mass Spectrum: (DIC /? H3): m / z: 533 (M + H) + EXAMPLE 17: 4- (Dimethylamino) utanoate of cis- [l- (acetyloxy) -6-me oxy -3,3,14 -trimethyl-7 -oxo-2,3,7,14-tetrahydro-lH-benzo [ b] pyran [3,2-h] acridin-2-yl] The procedure is as for Example 16, using 4-dimethylaminobutyric acid as a reagent instead of N, N-dimethylglycine.

EXAMPLE 18: cis- [1- (acetyloxy) -6-methoxy-3,3,14-trimethyl-7-oxo-2, 3,7,14-tetrahydro-lH-benzo [b] pyran (Acetylamino) acetate [3, 2-h] acridin-2-yl] The procedure is as for Example 16, using N-acetylglycine as the reagent instead of N, N-dimethylglycine. Mass Spectrum: (DIC / NH3): m / z: 547 (M + H) + EXAMPLE 19: cis-4- acid. { [1- (acetyloxy) -6-methoxy-3, 3-dimethyl-7-oxo-2, 3,7, 14-tetrahydro-1H-benzo [b] pyran [3, 2-h] acridin-2-yl ] oxy} -4- oxobutaenoic The procedure is as for Example 1, using the compound of preparation G as a substrate.

EXAMPLE 20: Salt of lysine of acid (±) -cis-4-. { [1- (acetyloxy) -6-methoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo [b] pyran [3,2-h] acridin-2 -il] oxy} -4-oxobutanoic 0.1 g of the compound of Example 1 was dissolved in 2Q ml of ethanol, in the presence of an equivalent of lysine hydrate. The solution was stirred for 30 minutes, and then evaporated and concentrated under reduced pressure, allowing the isolation of the expected product in the form of a salt.

EXAMPLE 21: (l) -cis-4- ( { 1- [(3-carboxypropanoyl) oxy] -6-methoxy-3,1,14-trimethyl-7-oxo-2 (3) acid lysine salt , 7,14-tetrahydro-1H-benzo [b] pyrano [3, 2-h] acridin-2-yl}. Oxy) -4-oxobutanoic The procedure is as for Example 20, using the compound of Example 7 as a substrate, and 2 equivalents of lysine.

EXAMPLE 22: cis-5- ( { 1- [(4-carboxybutanoyl) oxy] -6-methoxy -3,3,1-trimethyl-7-oxo-2, 3,7,14-tetrahydro-lH acid -benzo [b] pyrano [3, 2-h] acridin-2-yl.} oxy) -5-oxopentanoic acid The product was isolated in the course of chromatography of the compound of Example 3. Mass Spectrum: (DIC / NH3): m / z: 634 (M + H) + Melting point: 118 ° C EXAMPLE 23: cis-5- acid. { [1-acetyloxy) ~ 6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3,7, 14-tetrahydro-1H-benzo [b] pyran [3, 2-h] acridin-2- il} oxy) -2,4-dimethyl-5-oxopentanoic The procedure is as for Example 1, by supplying 2,4-dimethylglutaric acid as reagent instead of succinic anhydride.

EXAMPLE 24: cis-5- acid. { [1- (acetyloxy) -6-methoxy-3,3, 14-trimethyl-1-7 -oxo-2,3,7,14-tetrahydro-1H-benzo [bl-pyrano [3, 2-h] acridin-2-yl] } oxy) -3-hydroxy-3-methyl-5-oxopentanoic The procedure is as for Example 1, using 3-hydroxy-3-methyl glutaric acid as a reagent instead of succinic anhydride.

EXAMPLE 25: 5- (Benzylamino) -5-oxopentanate of cis-1- (acetyloxy) -6-methoxy-3,3,14-trimethyl-7-oxo-2,3,7,14-tetrahydro-1H-benzo [b] pyran [3,2-h] acridin-2-yl The procedure is as for Example 1, using benzylglutaric acid as a reagent instead of succinic anhydride.

EXAMPLE 26: 5- cis-1- (acetyloxy) -6-methoxy -3,13,14-trimethyl-7-oxo-2,3,7, 14 -tetr hydroxy-5- (4-methoxy-enyl) -5-oxopentanate -lH-benzo [b] pyrano [3,2-h] acridin-2-yl The procedure is as for Example 1, using 5- (4-methoxyphenyl) -5-oxovaleric acid as a reagent instead of succinic anhydride.

PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION EXAMPLE 27: In vitro activity L1210 murine leukemia and human colon HT-29 carcinoma were used in vitro. The cells were cultured in complete RPMI 1640 culture medium containing 10% fetal calf serum, 2 mM glutamine, 50 U / ml penicillin, 50 μg / ml streptomycin and 10 mM Hepes, pH = 7.4. the cells were distributed in microplates, and exposed to the cytotoxic compounds for 4 periods of duplication, ie 48 hours (L1210) or 96 hours (HT-29). The number of viable cells was then quantified by a coloritric test, the Tetrazolium Assay for Microculture (J. Carmichael et al., Cancer Res., 47, 936-942 (1987)), the results are expressed as IC50 values. , which is the cytotoxic concentration that inhibits the proliferation of treated cells by 50%. By way of example, the compounds of Examples 1 and 7 exhibited an IC50 of 2 μM and 2.3 μM, respectively, thus demonstrating that their activity was greater than that of the reference compound acronycin.

EXAMPLE 28: In vivo activity 1- Anti-tumor activity on P 388 leukemia _ Line P 388 (murine leukemia) was supplied by the National Cancer Institut (Frederick, USA). Tumor cells (106 cells) were inoculated on day 0 in the peritoneal cavity of female B6D2F1 mice (Iffa Credo, France). Six mice weighing 18 to 20 g were used per experimental group. The compounds were administered by the intraperitoneal route on day 1. Anti-tumor activity is expressed as% T / C: T / C% (survival) = Average survival time of treated animals x 100 Average survival time of control animals The compounds of the invention are very active in this model, whereas acronycin is only marginally active, and induces T / C > 150% in doses of less than 100 mg / kg. 2- Anti-tumor activity on C38 colon adenocarcinoma The C38 colon adenocarcinoma tumor fragments, weighing about 30 g, were implanted on day 0 under the skin of B6D2F1 mice (Iffa Credo, France). After tumor growth, the mice were divided into control groups (18 animals) and treated groups (6 to 7 animals), the groups were homogeneous with respect to tumor size. The compounds were administered i.v. once a week for 3 weeks (on days 10, 17 and 24), at its maximum tolerated dose (MTD), MTD / 2 and MTD / 4. The tumors were measured twice a week, and the volume of the tumors was calculated according to the formula: Volume (mm3) = length (mm) x width (mm2) / 2. The anti-tumor activity was expressed as a% of T / C: % T / C = Vt / VO intermediate of treated animals x 100 Vt / VO intermediate control animals Vo and Vt are the initial volume of the tumor and its volume in the t? EmP ° ° -e to measurement, respectively. The optimal dose is the dose that provides the lowest T / C without toxicity (premature death or weight loss of more than 20%). The compounds of the invention have proven to be more active, in this model, than the reference compound that is acronycin, thus demonstrating its strong therapeutic potential.

EXAMPLE 29: Armaceutical composition: injectable solution Compound of Example 1 10 mg Distilled water for injectable preparations. . .25 ml

Claims (12)

1. RE IVIND ICAC IONE S I 1. Compounds of formula (I): wherein: X and Y, which may be identical or different, each independently of the other represents a selected group of a hydrogen atom, a halogen atom, a hydroxy group, a mercapto group, a cyano group, a nitro group , an alkyl group of 1 to 6 straight or branched carbon atoms, an alkoxy group of 1 to 6 straight or branched carbon atoms, a trihaloalkyl group of 1 to 6 carbon atoms, in which the alkyl portion is linear or branched , and an amino group (optionally substituted by one or two alkyl groups of 1 to 6 identical or different linear or branched carbon atoms, which may themselves be substituted by an alkoxy group of 1 to 6 linear or branched carbon atoms or by a group of formula -NR7R8, wherein R7 and R8, which may be identical or different, each independently of the other represents a hydrogen atom, an alkyl group of 1 to 6 linear or branched carbon atoms, an aryl group or an aryl-alkyl group of 1 to 6 carbon atoms, in which the alkyl portion is linear or branched), or X and Y together form a methylenedioxy or ethylenedioxy group, it being understood that the X and Y substituents may be present on one or the other of the two adjacent benzene rings, has a hydrogen atom or an alkyl group of 1 to 6 carbon atoms straight or branched, has: - a hydrogen atom, - a hydroxy group, - a group straight or branched alkyl of 1 to 6 carbon atoms, - an alkoxy group of 1 to 6 straight or branched carbon atoms, optionally substituted by a group selected from: * a group of formula NR9R? or, wherein R9 and Rio, which may be identical or different, each independently of the other represents a hydrogen atom, an alkyl group of 1 to 6 straight or branched carbon atoms or a hydroxyalkyl group of 1 to 6 straight or branched carbon atoms, and * a heterocycle mon saturated or unsaturated bicyclic or occyclic, having from 5 to 7 members in the ring, containing one or two heteroatoms selected from oxygen, nitrogen and sulfur, - a linear or branched alkylcarbonyloxy group of 1 to 6 carbon atoms, or - a amino group optionally substituted by: * one or two, linear or branched alkyl groups of 1 to 6 carbon atoms, identical or different, aryl groups or aryl-alkyl groups of 1 to 6 carbon atoms, in which the alkyl portion is linear or branched, * a linear or branched alkylcarbonyl group of 1 to 6 carbon atoms, optionally substituted by a group -NR7R8 wherein R7 and R8 are as defined above, * a group of formula -R11-JTR9R10, in where p represents a linear or branched alkylene group of 1 to 6 carbon atoms, and R9 and Ri0, which may be identical or different, each independently of the other represents a hydrogen atom, an alkyl group of from 1 to 6 a t linear or branched carbon atoms, or a linear or branched hydroxyalkyl group of 1 to 6 carbon atoms, * an alkylene group of 1 to 6 straight or branched carbon atoms, substituted by a monocyclic or saturated bicyclic or unsaturated heterocycle, which from 5 to 7 members in the ring, which contains one or two heteroatoms selected from oxygen, nitrogen and sulfur, or * by a group of formula -Rn-CO-R? , wherein Rn is as defined above, and R12 represents a hydroxy group or an alkoxy group of 1 to 6 straight or branched carbon atoms, R3 and R4, which may be identical or different, each independently of the other represents a hydrogen atom or an alkyl group of 1 to 6 carbon atoms straight or branched, R5 and / or R6 represents (n) a group of formula -O-CO-UV, wherein: - U represents an alkylene chain from 1 to 8 straight or branched carbon atoms, optionally substituted by one or more identical or different groups selected from aryl, hydroxy and linear or branched alkoxy of 1 to 6 carbon atoms, - V represents a group selected from: * carboxy, * -C02Ri3, wherein R13 represents an alkyl group of 1 to 6 straight or branched carbon atoms (optionally substituted by one or more groups -hydroxy), an aryl group or an aryl-alkyl group of 1 to 6 straight or branched carbon atoms, in which the alkyl portion is linear or branched, * hydroxy, * alkoxy of 1 to 6 linear or branched carbon atoms, * -NR7R8, wherein R7 and R8, which may be identical or different, are as defined above, * -IR7-C02Ri3, wherein R7 and Ri3 are as defined in above, * -NR7-COR? 3, where R7 and R? 3 are as defined in the above, * -COR13, where R? 3 is as defined in the above, and * -CO-NR7R8, in where R7 and R8, which may be identical or different, are as defined above, and when only one of the two groups R5 and R6 represents u n group of formula -O-CO-U-V, then the other of groups R5 and Re represents a group Z selected from: - linear or branched hydroxy, - alkoxy of 1 to 6 carbon atoms. - linear or branched alkylcarbonyloxy of 1 to 6 carbon atoms, - arylcarbonyloxy, - aryl-alkylcarbinyloxy of 1 to 6 carbon atoms in which the alkyl portion is linear or branched, and - amino optionally substituted by one or two alkyl groups of 1 to 6 identical or different linear or branched carbon atoms, their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base.
2. 2. Compounds of formula (I) according to claim 1, characterized in that R3 and R4, which may be identical or different, represent an alkyl group of 1 to 6 straight or branched carbon atoms, their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base.
3. 3. Compounds of formula (I) according to any of claims 1 or 2, characterized in that R3 and R, which are identical, each represent a methyl group, its isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base.
4. 4. Compounds of formula (I) according to claim 1, characterized in that R 2 represents an alkoxy group of 1 to 6 straight or branched carbon atoms, or an optionally substituted amino group as defined for formula (I), its isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base.
5. 5. Compounds of formula (I) according to claim 1, characterized in that R5 represents a group of formula -O-CO-UV wherein U and V are as defined for formula (I), and Re represents a group Z as it was defined for the formula (I), its isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base.
6. 6. Compounds of formula (I) according to claim 1, characterized in that R6 and Rs, which are identical, each represent a group of formula ^ 0-CO-UV, where U and V are as defined for the formula (I), their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base.
7. 7. Compounds of formula (I) according to any of claims 1 or 5, characterized in that R 5 represents a group of formula -Q-CO-UV, wherein U represents an alkylene chain of 1 to 4 linear carbon atoms, and V represents a group selected from carboxy, -NR7R8, -NR7-C02Ri3 and -NR7-COR? 3, wherein R7, R8 and Ri3, which may be identical or different, represent a hydrogen atom or an alkyl group of 1 to 6 straight or branched carbon atoms, their isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base.
8. 8. Compounds of formula (I) according to claim 1, characterized in that R6 represents a linear or branched alkylcarbonyloxy group of 1 to 6 carbon atoms, its isomers, N-oxides, and addition salts thereof with an acid or base pharmaceutically acceptable.
9. 9. Compounds of formula (I) according to claim 1, which are: - acid (±) -cis-4-. { [1- (acetyloxy) -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3,7, 14-tetrahydro-lH-benzo [b] pyrano- [3,2-h] -acridin -2-il] oxy} -4-oxobutanoic, - (±) -cis-4- ( { 1- [3-carboxypropanoyl) oxy] -6-methoxy-3,3, 14-trimethyl-7-oxo-2, 3,7 acid , 14-tetrahydro-lH-benzo [b] -pyrano [3, 2-h] -acridin-2-yl] oxy} -4-oxobutanoic, - acid (±) -cis-5-. { [1- (acetyloxy) -6-methoxy-3, 3, 14-trimethyl-7-oxo-2, 3,7, 14-tetrahydro-lH-benzo [b] irano- [3, 2-h] -acridin -2-il] oxy} -5-oxopentanoic, cis- [1- (acetyloxy) -6-methoxy-3,3, 14-trimethyl-7-oxo-2,3,7,14-tetrahydro-lH-benzo- (dimethylamino) acetate. b] -pirano [3, 2-hl-acridin-2-yl], and cis- [1- (acetyloxy) -6-methoxy-3, 3, 14-trimethyl-7- (4- (dimethylamino) butanoate] oxo-2, 3, 7, 14-tetrahydro-lH-benzo [b] -pyrano [3, 2-h] -acridin-2-yl], its isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base.
10. 10. Process for the preparation of compounds of formula (I) according to claim 1, characterized in that: • either a compound (II) of 3-amino-2-naphthalenecarboxylic acid: wherein X and Y are as defined for formula (I), is reacted with a phloroglucinol compound of formula (III): wherein R represents a hydrogen atom, a hydroxy group or an alkyl group of 1 to 6 carbon atoms, linear or branched, to provide the compounds of formula (IV): wherein X, Y and R are as defined in the foregoing, which are then treated under basic conditions in an aprotic solvent, such as, for example, dimethylformamide, with an alkyne of formula (V): Hal HC! (V) R., wherein Hal represents a halogen atom, and R3 and R4 are as defined for formula (I), to provide compounds of formula (VI): wherein X, Y, R, R3 and 4 are as defined above, or a 3-halo-2-naphthalenecarboxylic acid, compound of formula (VII): where X and Y are as defined for the formula I (I), and Hal represents a halogen atom, such as chlorine or bromine, is reacted with an amino-chromene compound of formula (VIII): wherein R3 and R4 are as defined for formula (I), and R is as defined above, also to provide compounds of formula (VI): wherein X, Y, R, R3 and R4 are as defined above, the nitrogen atom of the compounds of formula (VI) is optionally substituted, by the action of an alkyl halide or an alkyl sulfate in the presence of a deprotonation agent, such as sodium hydride, in a polar aprotic solvent, to provide the compounds of formula (IX): wherein X, Y, R, R3 and R are as defined above, and R'i represents an alkyl group of 1 to 6 straight or branched carbon atoms, the compounds of formula (IX) are subjected to the action of an alkylating agent, such as a dialkyl sulfate, or an acylating agent, to provide the compounds of formula (X): wherein X, Y, R'i, R3 and R4 are as defined in the above, and R1 represents an alkoxy group (optionally substituted by a group of formula NR9R10, wherein R9 and Rio are as defined for formula (I)), or an alkylcarbonyloxy group of 1 to 6 straight or branched carbon atoms, the compound of formula (X), when R'2 represents an alkoxy group for example, it is treated with a compound of formula (XI): HNRaRb (XI) wherein Ra represents a hydrogen atom, an alkyl group of 1 to 6 straight or branched carbon atoms, an aryl group, or an aryl-alkyl group of 1 to 6 carbon atoms, in which the alkyl portion is linear 0 xami _fi.cada, and Rb represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms straight or branched, an aryl group, or an aryl-alkyl group of 1 to 6 carbon atoms, in which the alkyl portion is linear or branched, a group of formula -R ??-NR 9 R 0, wherein R n, Rio and R 9 are as defined for formula (I), a linear or branched alkylcarbonyl group of 1 to 6 carbon atoms, in which the alkyl portion is optionally substituted by a group NR7R8 as defined for formula (I), a heterocycloalkylene group (the terms "alkylene" and "heterocycle") are as defined for formula (I)), or a group of formula -Rn-CO-R? 2, wherein Rp and 1 Ri2 are as defined for formula (I), to provide compounds of formula ( XII): wherein X, Y, R '_., R3, R4, Ra and Rb are as defined above, all of the compounds of formulas (VI), (IX), (X) and (XII) which constitute the compounds of formula (XIII): wherein X, Y, Ri, R2, R3 and R4 are as defined in the general definition of formula (I), the compounds of formula (XIII) are attached to) - = > either to the action of osmium tetroxide in a polar medium, and in the presence of 4-methylmorpholine N-oxide, to provide the compounds of the formulas (XlV / a) and (XlV / b): wherein X, Y, Ri, R2, R3 and R4 are as defined in the foregoing, it being possible for the compounds of formulas (XlV / a) and (XlV / b) to be obtained separately by chiral synthesis, and especially by dihydroxylation asymmetric cis, starting from the compound (XIII), using chiral ligands of the type pyridine or phthalazine bisubstiuides by Cinchona alkaloids, such as dihydroquinine and its dextrorotatory diastereoisomer, dihydraquinidine, b) = > or to the action of potassium permanganate in a polar medium, to provide the compounds of formula (XV): wherein X, Y, Ri, R2, R3 and R4 are as defined above, the compounds of formula (XV) are subjected to reductive conditions in the presence of NaBH4 for example, to provide the compounds of formula (XIV / c) ): wherein X, Y, Ri, R2, R3 and 4 are as defined in the above, all of the compounds of formulas (XlV / a), (XlV / b) and (XIV / c) constitute the compounds of formula (XIV): Where X, Y, Ri, R2, R3 and R are as defined above, omponents of formula (XIV) are attached: * X * either to the action of an alcohol of formula R20OH, wherein R20 represents an alkyl group from 1 to 6 straight or branched carbon atoms, to provide the compounds of formula (XVI / a): wherein X, Y, Ri, R2, R3, R4 and R2o are as defined above, the alcohol function of the compounds of formula (XVI / a) is esterified in the presence of a compound of formula VUC (0) - 0-W or (VU-CO) 20, where U and V are as defined for the formula (I), and W represents a leaving group, to provide the compounds of formula (I / a), a particular case of the compounds of formula (I): wherein X, Y, Ri, R2, R3, R4, R2o, U and V are as defined above, * t * or the action of an alkyl iodide of formula R'20-I, where R ' 20 represents an alkyl group of 1 to 6 straight or branched carbon atoms, in the presence of a silver salt, to provide the compounds of formula (XVI / b): a particular case of the compounds of formula (I), wherein X, Y, Ri, R2, R3, 4 and R20 are as defined above, the * alcohol function of the compounds of formula (XVI / b) is esterified in the presence of a compound of formula VUC (O) -OW or (VU-C0) as defined above, to provide the compounds of formula (I / b): a particular case of the compounds of formula (I), wherein X, Y, Ri, R2, R3, R, R'2o, U and V are as defined above, * > or to the direct action of a compound of formula VUC (O) -OW or (VU-CO) as defined above, in the presence of a base, such as triethylamine or 4-dimethylaminopyridine, to obtain the compounds of formula ( I / c), a particular case of the compounds of formula (I): where X, Y, Ri, R2, R3, R4, U and V are as defined above, the compound of formula (I / c) can be subjected again, under the same operating conditions, to the action of an anhydride of formula (R3oCO) 20, wherein R30 represents an alkyl group of 1 to 6 straight or branched carbon atoms, an aryl group or an aryl-alkyl group of 1 to 6 carbon atoms, in which the alkyl is linear or branched, to provide the compounds of formula (I / d): wherein X, Y, R1 R2, R3, R4, R30, U and V are as defined above, or the compound of formula (I / c) can be treated again with a compound of formula VUC (O -OW or (VU-CO) 20 as defined above, to provide the compounds of formula (I / e), a particular case of the compounds of formula (I): wherein X, Y, Rx, R2, R3, R4, U and V are as defined for formula (I), it being understood that the two groups U and the two groups V may each be identical or different, c) = > or to the action of a peracid, such as m-chloroperbenzoic acid, to provide the compound of formula (XVII): wherein X, Y, Ri, R2, R3 and R are as defined above, the compound of formula (XVII) is optionally treated with ammonia or a primary or secondary amine to provide the compounds of formula (XVIII / a) and / or (XVIII / b) depending on the nature of the reagents: wherein X, Y, R 1 R2, R 3 and R 4 are as defined above, and R c and R d represent a hydrogen atom or an alkyl group of 1 to 6 straight or branched carbon atoms, the compounds of formulas ( XVIII / a) and (XVIII / b) are treated with a compound of formula VUC (O) -OW as defined above, to provide the compounds of formulas (I / f) and (I / g) respectively, Particular cases of the compounds of formula (I): wherein X, Y, Rx, R2, R3, R4, R, a, U and V are as defined above, the compounds (I / a) to (I / g) conute the totality of the compounds of the invention, which are purified, if necessary, according to a conventional purification technique, can be separated, if desired, into their various isomers according to a conventional separation technique, and are converted, if desired, into N-oxides thereof and, when appropriate, in addition salts thereof with a pharmaceutically acceptable acid or base.
11. 11. Pharmaceutical compositions comprising as active ingredient at least one compound according to any one of claims 1 to 9, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
12. 12. Pharmaceutical compositions according to claim 11, comprising at least one active ingredient according to any of claims 1 to 9 for use in the treatment of cancer. SUMMARY OF THE INVENTION The present invention describes compounds of formula (I): wherein: X and Y represent a hydrogen atom, a halogen atom, or a hydroxy, mercapto, cyano, nitro, alkyl, alkoxy, trihaloalkyl, optionally subuted amino, methylenedioxy or ethylenedioxy group, Ri represents a hydrogen atom or a alkyl group, R2 represents a hydrogen atom, or a hydroxy, alkyl, alkoxy, alkylcarbonyloxy or an amino group : optionally subuted, R3 and R4 represent a hydrogen atom or an alkyl group, and Re represent a group of formula -O-CO-UV, wherein U and V are as defined in the description, or a group Z as defined above. defined in the description, it being understood that at least one of the groups R5 and Rβ represents a group of formula -O-CO-UV, its isomers, N-oxides, and addition salts thereof with a pharmaceutically acceptable acid or base. Medicines .