FR2902792A1 - New tetrahydro-7H-pyrano-(2,3-c)-acridin-7-one cinnamate derivatives, are specific cell cycle blockers useful as anticancer medicaments - Google Patents

Abstract

2-Cinnamoyl or 1,2-dicinnamoyl derivatives (I) of 1,2-di-(hydroxy or amino)-7-oxo-2,3,7,12-tetrahydro-1H-pyrano-(2,3-c)-acridines are new. Tetrahydro-7H-pyrano-(2,3-c)-acridin-7-one cinnamate derivatives of formula (I) (including enantiomers and diastereomers) and their acid or base addition salts, solvates and hydrates are new. X, Y 1H, halo, OH, alkoxy, NO 2, CN, alkyl (optionally substituted (os) by one or more of OH and halo), alkenyl or NR aR b; R a, R bH or alkyl; or NR aR b5-7 membered monocyclic heterocycle (optionally containing a second O or N heteroatom); Z : O or NR c; R cH, alkyl, aryl or aralkyl; Ar : aryl or heteroaryl; R 1, R 3, R 4H or alkyl; R 2H, alkyl, OR aor NR aR b; R 5H, OR c, NR cR d, -W 1-C(O)-U 1-V 1, -W 1-C(O)-W 3-T 1or -Z-CO-CH=CH-Ar; R das for R c; W 1, W 3O or NR c; U 1direct bond, 1-8C alkylene or 2-8C alkenylene; V 1H, aryl, heteroaryl, OR c, COOR c, COR c, CONR' aR' b, NR' aR' b, N(R c)COOR dor N(R c)COR c; R' a, R' bH, alkyl, aryl or aralkyl; or NR' aR' b= heterocycle as for NR aR b; T 1H, alkyl, alkenyl, aryl, aralkyl, -alkylene-OR c, -alkylene-NR' aR' b, -alkenylene-OR cor -alkenylene-NR' aR' b; aryl moieties : phenyl or naphthyl (both os by one or more of alkyl (os by one or more of halo and OH), OH, halo, COOH, NO 2, NH 2, mono- or dialkylamino, alkoxy, 1-6C acyl or alkylcarbonyloxy); heteroaryl moieties : 5-12C mono- or bicyclic aromatic group (one ring optionally being non-aromatic in bicyclic groups) containing 1-3 of O, N and S as heteroatom(s) (os by one or more of halo, alkyl (os by one or more of halo and OH), OH, alkoxy, NH 2or mono- or dialkylamino); alkyl or alkylene moieties have 1-6C and alkenyl or alkenylene moieties 1-6C unless specified otherwise. An independent claim is included for the preparation of (I). [Image] ACTIVITY : Cytostatic. (+- )-cis-1-Acetoxy-6-methoxy-3,3,12-trimethyl-7-oxo-2,3,7,12-tetrahydro-1H-pyrano-(2,3-c)-acridin-2-yl (2E)-3-phenyl-2-propenoate (Ia) had IC 509.3 mu M for inhibition of proliferation of L1210 murine leukemia cells in vitro. MECHANISM OF ACTION : Specific cell cycle blocker.

Description

The present invention relates to novel cinnamate derivatives of

  tetrahydro-7H-pyrano [2,3-c] acridin-7-one, process for their preparation and pharmaceutical compositions containing them.

  The compounds of the invention are derivatives of acronycin which is an alkaloid having antitumor properties demonstrated in experimental models (J. Pharm. Sci., 1966, 55 (8), 758-768). However, despite a fairly broad spectrum of activity, acronycin is weak and moderately active. In addition, this product has a low solubility limiting its bioavailability as well as its use in intravenous pharmaceutical compositions.

  Various modifications have been made to this molecule, such as those described in J Med. Chem., 1996, 39, 4762-4766, EP 1 042 326, EP 1 061 081 or EP 1 297 835, which have significantly improved the potency, antitumor efficacy and solubility of these products. Nevertheless, the needs of anti-cancer therapy require the constant development of new anti-tumor agents, with the aim of obtaining drugs that are both more active and better tolerated. More particularly, solid tumors pose a major problem to cancer chemotherapy, by their intrinsic and / or acquired resistance, to existing products. It is therefore essential to have access to the widest possible range of products expressing a strong cytotoxic activity in order to have the most effective treatments on all tumor diseases.

  The compounds of the invention, in addition to being novel, exhibit a cytotoxic activity in vitro and in vivo surprising and superior to that observed hitherto. Thus, the compounds discovered by the Applicant have antitumor properties which make them particularly useful for the treatment of cancers. Among the types of cancers that can be treated by the compounds of the present invention include, but are not limited to, adenocarcinomas and carcinomas, sarcomas, gliomas and leukemias. More particularly, the present invention relates to the compounds of formula (I): (I) in which:

  X and Y, which are identical or different, independently of one another, each represent a group chosen from: hydrogen atom, halogen, hydroxy group, linear or branched (C1-C6) alkoxy, nitro, cyano; linear or branched (C1-C6) alkyl, optionally substituted by one or more groups selected from hydroxy and halogen, and linear or branched (C2-C6) alkenyl, or - group of formula wherein R a and R b, which are identical or different, independently of each other, each represent a group selected from hydrogen atom, or linear or branched (C1-C6) alkyl group, or Ra and Rb together with the nitrogen atom which carry them a 5- to 7-membered monocyclic heterocycle optionally containing, within the ring system, a second heteroatom selected from oxygen and nitrogen,

  Z represents an oxygen atom or NRR in which Re represents a group chosen from hydrogen atom, linear or branched (C1-C6) alkyl group, or a linear or branched aryl, aryl (C1-C6) alkyl group, Ar represents an aryl or heteroaryl group,

  R1 represents a hydrogen atom or a linear or branched (C1-C6) alkyl group; R2 represents a group chosen from hydrogen atom, linear or branched (C1-C6) alkyl group, ORa; in which R a and R b are as defined above,

  R3, R4, which are identical or different, independently of each other, represent a hydrogen atom or a linear or branched (C1-C6) alkyl group,

  R5 represents a group chosen from:

1) hydrogen atom,

  2) a group ORS, NR, Rd in which: Ri, is as defined above and Rd, has the same definitions as R ,, 3) W1uC (W2) uuV in which: a) W1 represents an oxygen atom or NR , (wherein R, is as defined above), (3) W2 represents an oxygen atom, y) U represents a single bond or a linear or branched (C1-C8) alkylene chain or an alkenylene chain (C2- C8) linear or branched, 8) V represents a group chosen from: - hydrogen atom, - aryl group, heteroaryl, - ORS groups, CO2Rc, COR ,, CONR'aR'b, NR'aR'b, N ( Wherein Rc is as defined above, R ', has the same definitions as R, and R'a and R'b, identical or different, independently of one of the another, each represents a group chosen from hydrogen atom, linear or branched (C1-C6) alkyl group, aryl, linear or branched (C1-C6) arylalkyl, or R'a and R'b together with the at a nitrogen atom carrying them, a 5- to 7-membered monocyclic heterocycle optionally containing within the ring system a second heteroatom selected from oxygen and nitrogen,

  4) W1uC (W2) ùW3ùT1 in which: a) Wl and W2 are as defined above, ~ 3) W3 represents an oxygen atom or NR, wherein R, is as defined above, y) T1 represents a grouping chosen from: - hydrogen atom, - linear or branched (C1-C6) alkyl, - linear or branched (C2-C6) alkenyl, - linear or branched aryl, aryl (C1-C6) alkyl, - alkylene chain (C1- C6) linear or branched or a linear or branched (C2-C6) alkenylene chain, each being substituted by a group OR, in which R, is as defined above or by NR'aR'b in which R'a and R ' b are as defined above,

  5) Z-CO-CH = CAT in which Z and Ar are as defined above, their enantiomers, diastereoisomers, when they exist, as well as their addition salts with a pharmaceutically acceptable acid or base, as well as their hydrates and their solvates,

  It being understood that: aryl is understood to mean a phenyl or naphthyl group, optionally comprising one or more substituents, which may be identical or different, chosen from linear or branched (C1-C6) alkyl optionally substituted with one or more hydroxyl or halogen, hydroxy groups; linear or branched, halogen, carboxy, nitro, amino, monoalkylamino (C1-C6), or linear or branched (C1-C6) dialkylamino, linear or branched (C1-C6) alkoxy, linear or branched (C1-C6) acyl and linear or branched alkylcarbonyloxy (C1-C6) heteroaryl means a group of 5 to 12 members, either aromatic monocyclic or bicyclic in which at least one ring has an aromatic character and containing one, two or three heteroatoms selected from oxygen, nitrogen or sulfur, it being understood that the heteroaryl may be optionally substituted by one or more atoms or groups, identical or different, selected from the atoms of halogen and linear or branched (C1-C6) alkyl groups, optionally substituted by one or more hydroxyl or halogen groups, or hydroxy, linear or branched (C1-C6) alkoxy, or amino (optionally substituted with one or two alkyl groups ( C1-C6) linear or branched).

  Among the heteroaryl groups, mention may be made, without limitation, of the thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl and pyrimidinyl groups.

  Among the monocyclic 5 to 7-membered heterocycles, optionally containing a second heteroatom selected from oxygen and nitrogen in the cyclic system, mention may be made, without limitation, of pyrrolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl and oxazinanyl groups, morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, azepanyl, oxazepanyl, diazepanyl.

  Among the pharmaceutically acceptable acids, mention may be made, without limitation, of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic and methane acids. sulfonic, sulphonic benzene, camphoric, lysine, etc ...

  Among the pharmaceutically acceptable bases, there may be mentioned, without limitation, sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.

  The preferred X and Y substituents according to the invention are the hydrogen atom.

  The substituents R1, R3 and R4 which are preferred according to the invention are the linear or branched (C1-C6) alkyl group. The preferred substituent R2 according to the invention is the group -ORa in which Ra is as defined in formula (I).

  The preferred substituent R 5 according to the invention is the group ùOR, in which R, is as defined in formula (I) and the group W 1 (C 2) (W 2) ùU in which W 1, W 2, U and V are as defined in formula (I).

  Even more preferably, the preferred substituent R.sup.5 according to the invention is the group ## STR1 ## in which R.sub.1 represents a hydrogen atom and the group W.sub.1 -C.sub.C (W.sub.2) .sub.u.sub.V wherein W.sub.1 and W.sub.2 each represent an oxygen atom, U represents a linear or branched (C1-C8) alkylene chain and V represents a hydrogen atom.

  The preferred substituent Z according to the invention is the oxygen atom.

  The preferred substituent Ar according to the invention is an optionally substituted phenyl group.

  In a particularly advantageous manner, the preferred compounds of the invention are: - () -cis-1-hydroxy-6-methoxy-3,3,12-trimethyl-7-oxo-2,3,7,12 tetrahydro-1H-pyrano [2,3-e] acridin-2-yl (2E) -3-phenyl-2-propenoate, - () - cis-1 - (acetyloxy) -6-methoxy-3, 3, 12-trimethyl-7-oxo-2,3,7,12-tetrahydro-1H-pyrano [2,3-c] acridin-2-yl (2E) -3-phenyl-2-propenoate, - () -cis 6-methoxy-3,3, 12-trimethyl-7-oxo-1- {[(2E) -3-phenyl-2-propenoyl] oxy} -2,3,7,12-tetrahydro-1H-pyrano [2,3-C] acridin-2-yl (2E) -3-phenyl-2-propenoate, - () - cis-1-hydroxy-6-methoxy-3,3,12-trimethyl-7-oxo 2,3,7,12-Tetrahydro-1H-pyrano [2,3-c] acridin-2-yl (2E) -3- [4- (trifluoromethyl) phenyl] -2-propenoate, - () -cis-1 - (acetyloxy) -6-methoxy-3,3,12-trimethyl-7-oxo-2,3,7,12-tetrahydro-1H-pyrano [2,3-c] acridin-2-yl (2E) -3- [ 4- (trifluoromethyl) phenyl] -2-propenoate.

  The present invention also extends to the process for the preparation of compounds of formula (I), characterized in that a compound of formula (II) is used as starting material: R 4 in which X, Y, R 3 and R4 are as defined above, and R represents a hydrogen atom, a hydroxyl group, a linear or branched (C1-C6) alkyl group, compound of formula (II), the nitrogen atom of which is substituted or non-substituted; by the action of an alkyl halide or a dialkyl sulphate in the presence of a deprotonating agent, aprotic polar solvent or phase transfer condition, to obtain the compounds of formula (III): in which X, Y, R, R3 and R4 are as defined above, and R'1 represents a linear or branched (C1-C6) alkyl group,

  compounds of formula (III) which are subjected to the action of an alkylating agent under conventional conditions of organic synthesis, to yield compounds of formula (IV): ## STR1 ## wherein X, Y, R 1, R3 and R4 are as defined above and R'2 represents a group chosen from OR'a in which R'a represents a linear or branched (C1-C6) alkyl group, compounds of formula (IV) which are treated, in the case where R'2 represents an alkoxy group by a compound of formula (V): HNRaRb (V) in which Ra and Rb are as defined in formula (I), to give compounds of formula (VI): embedded image in which X, Y, R '1, R 3, R 4, Ra and Rb are as defined above, all of the compounds of formula (II), (III), (IV) and (VI) forming the compounds of formula (VII): (VII) R4 wherein X, Y, R1, R2, R3 and R4 are as defined in formula (I), compounds of formula (VII) which are subject: a) to the action of osmium tetroxide in polar medium and in the presence of 4-methylmorpholine-N-oxide, to yield compounds of formula (VIII / a): XO (VHUa) R 1 OH OH R 4 (cis) in which X, Y, R 1, R 2, R 3 and R 4 are as defined above, or b) to the action of potassium permanganate in a polar medium and then under reducing conditions in the presence of NaBH 4, to yield the compound of formula ( VIII / b): wherein R2, R1, R2, R3 and R4 are as defined above, the set of compounds of formulas (VIIUa) and (VIIUb) ) forming the compounds of formula (VIII) in which the 2 alcohol groups can be of cis or trans configuration with respect to each other: X (VIII) in which X, Y, R1, R2, R3 and R4 are such as defined above, compounds of formula (VIII) which are subjected to the action of one or two equivalents of an anhydride of formula (IX) or of an acid chloride of formula (X):

  [ArùCH =CHùC (O)] 20 (IX) ArùCH = CHùC (O) ùCl (X)

  in which Ar is as defined in formula (I) to yield compounds of formulas (I / a1) or (I / a2), in particular cases of compounds of formula (I): where X, Y , R1, R2, R3, R4 and Ar are as defined above,

  c) to the action of NaN3, in the presence of hydrogen peroxide, followed by a reduction step, to yield compounds of formula (XI): XO R2 compounds of formula (XI) which are subjected to the action compounds of formulas (I) C) or (X) as defined above under the same conditions as for the compounds of formula (VIII), to give compounds of formulas (Ub1) or (IIb2), particular cases of compounds of formula (I): embedded image in which X, Y, R 1, R 2, R 3 and R 4 are as defined above, Ar in which X, Y, R 1, R 2, R 3, R 4 and Ar are as defined above Compounds of formula (I / bl) or (Ub2) which are optionally subjected to the action of a compound of formula (XII): R'cuHal (XII) in which Hal represents a halogen and R ', represents a group selected from linear or branched (C1-C6) alkyl, or a linear or branched (C1-C6) aryl, arylalkyl group, to yield compounds of formula (I / cl) or (Uc2): wherein R2, R1, R2, R3, R4, R'c and Ar are as defined above, all of the compounds of formulas (Ual), (Ubl) and (Ucl) and (Ua2), (Ub2) and (Uc2) forming the compounds of formulas (Ud1) and (Ud2) respectively, wherein R5aO Ar (Ud2) in which X, Y, R1, R2, R3, R4, Y and Ar are as defined in formula (I) and R5a represents a hydroxy, NH2 or NHR'c group in which R'c is as defined above, the compounds of formula (Udl) which are optionally subjected to: a) the action of an alkylating agent, to give compounds of formula (IIc), a particular case of compounds of formula (I): in which X, Y R 1, R 2, R 3, R 4, Y and Ar are as defined above, and R 5b represents a group ORS, NR, Rd in which Re and Rd are as defined in formula (I),

  b) to the action of an anhydride of formula (XIII) or of an acid chloride of formula (XIV): (RIO) (XIII) Rlo · CiCl (XIV) in which Rio represents a group of formula Wherein W 2, W 3, U, V and Ti are as defined in formula (I), to give compounds of formula (11f), in particular the compounds of formula (I), In which X, Y, R 1, R 2, R 3, R 4, Y, Ar and R 10 are as defined above and W 1 is as defined in formula (I),

  the compounds (Pa) to (11f) forming all of the compounds of the invention which are purified, if appropriate, according to a conventional purification technique, which can, if desired, they are separated into their different isomers according to a conventional separation technique and which are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base.

  The compounds of formulas (II), (V), (IX), (X), (XII), (XIII) and (XIV) are either commercial products or obtained according to conventional methods of organic synthesis well known in the art. the skilled person.

  The compounds of formula (I) have particularly advantageous antitumor properties. They have excellent cytotoxicity in vitro on cell lines, derived from murine and human tumors, due to a specific block of the cell cycle, and are active in vivo in murine and human transplantable tumors. The characteristic properties of these compounds allow their therapeutic use as antitumor agents.

  The present invention also relates to pharmaceutical compositions containing as active ingredient at least one compound of formula (I), its enantiomers, diastereoisomers or one of its addition salts with a base or a pharmaceutically acceptable acid, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

  Among the pharmaceutical compositions according to the invention, mention will be made more particularly of those which are suitable for oral, parenteral (intravenous, intramuscular, or subcutaneous), per-or trans-cutaneous, intravaginal, rectal, nasal, perlingual, oral administration. , ocular or respiratory.

  The pharmaceutical compositions according to the invention for parenteral injections comprise, in particular, aqueous and non-aqueous sterile solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstituting injectable solutions or dispersions. The pharmaceutical compositions according to the invention, for oral solid administrations, comprise in particular simple or coated tablets, sublingual tablets, sachets, capsules, granules, and for oral, nasal, oral or ocular liquid administrations. , include emulsions, solutions, suspensions, drops, syrups and aerosols.

  The pharmaceutical compositions for rectal or vaginal administration are preferably suppositories, and those for per-trans-cutaneous administration include, in particular, powders, aerosols, creams, ointments, gels and patches.

  The pharmaceutical compositions cited above illustrate the invention but do not limit it in any way.

  Among the inert, non-toxic, pharmaceutically acceptable inert excipients or carriers, mention may be made, by way of indication and without limitation, of diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, blowing agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, dyes, flavoring agents, etc.

  The dosage varies depending on the age and weight of the patient, the route of administration, the pharmaceutical composition used, the nature and severity of the condition, and the taking of any associated treatments. The dosage ranges from 0.1 mg to 1000 mg in one or more doses per day.

  The following examples illustrate the invention but do not limit it in any way.

  The starting materials used are known products or prepared according to known procedures. The different preparations lead to synthetic intermediates useful for the preparation of the compounds of the invention.

  The structures of the compounds described in the examples and in the preparations were determined according to the usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, etc.).

  The melting points were determined either on the Kofler heating stage or on the heating stage under a microscope. When the compound exists in salt form, the melting point corresponds to that of the salified product.

  PREPARATIN 1: 4-trifluoromethylcinnamoyl chloride

  To a suspension of 1.75 g of 4-trifluoromethylcinnamic acid in 40 ml of anhydrous dichloromethane, with stirring at 43 ° C., 7 ml of thionyl chloride are added dropwise. After 3 hours of reaction, the excess unreacted acid remains insoluble and is removed by decantation. The filtrate is evaporated to dry yielding 4-chloracinnamic acid chloride.

  EXAMPLE 1 () cis-1-hydroxy-6-methoxy-3,3,12-trimethyl-7-oxo-2,3,7,12-tetrahydro-1H-pyranof 2,3-clacridin-2-yl (2E) ) -3-phenyl-2-propenoate

  In a flask under an inert atmosphere, 350 mg of () cis-1,2-dihydroxy-6-methoxy-3,3,12-trimethyl-1,2,3,12-tetrahydro-7Hpyrano [2,3-c] acridin-7-one, 260 mg of cinnamoyl chloride and 10 ml of anhydrous pyridine are stirred at room temperature for 16h. After addition of water, the reaction medium is extracted with dichloromethane. The organic phase is dried over magnesium sulphate and concentrated under vacuum on a rotary evaporator. Chromatography on a silica column (CH 2 Cl 2 and a gradient of MeOH) makes it possible to isolate 145 mg of the expected product. Mass spectrometry (ES +): m / z = 486 [MH +; 508 [MNa] +

  EXAMPLE 2 () -cis-1- (acetyloxy) -6-methoxy-3,3,12-trimethyl-7-oxo-2,3,7,12-tetrahydro-1H-pyranoyl-2,3-clacridin-2-yl (2E) ) -3-phenyl-2-propenoate

  In a flask under an argon inert atmosphere, 38.9 mg of the compound of Example 1 are dissolved in 5 ml of anhydrous pyridine. 300 μl of acetic anhydride and a catalytic amount of 4-DMAP are added. After stirring for 48 hours at room temperature, the reaction mixture is hydrolysed with water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. Chromatography on a silica column (CH 2 Cl 2 and a gradient of MeOH) makes it possible to isolate 6.5 mg of the expected product. Mass spectrometry (ES +): m / z = 550 [MNa] +; 566 [MK] +

  EXAMPLE 3 (t) -cis-6-methoxy-3,3,12-trimethyl-7-oxo-1 - {[(2E) -3-phenyl-2-propenoyloxy] -2,3,7,12-tetrahydro- 1H-pvranol 2,3-cl-acridin-2-yl (2E) -3-phenyl-2-propenoate

  The product is obtained during the process described in Example 1. Mass spectrometry (ES +): m / z = 638 [MNa] +; 654 [MKJ + EXAMPLE 4 (t) -cis-1-hydroxy-6-methoxy-3,3,12-trimethyl-7-oxo-2,3,7,12 tetrahydro-1H-pvranof 2,3-clacridin-2- v1 (2E) -3- [4- (trifluoromethyl) phenyl-2-propenoate

  In a flask under an inert atmosphere, 264 mg of () cis-1,2-dihydroxy-6-methoxy-3,3,12-trimethyl-1,2,3,12-tetrahydro-7Hpyrano [2,3-c] acridin-7-one, 264 mg of cinnamoyl chloride and 10 ml of anhydrous pyridine are stirred at room temperature for 24 hours. The reaction medium is evaporated on a rotary evaporator. Chromatography on a silica column (CH 2 Cl 2 and a gradient of MeOH) makes it possible to isolate 133 mg of the expected product.

  Mass spectrometry (ES +): m / z = 554 [MH] +; 576 [MNa] +

  EXAMPLE 5 (t) -cis-1- (acetyloxy) -6-methoxy-3,3,12-trimethyl-7-oxo-23,7,12-tetrahydro-1H-pyranol 2,3-clacridin-2-yl 2E) -3-14- (trifluoromethyl) phenyl-2-propenoate In a flask under an inert atmosphere of argon, 116.7 mg of the compound of Example 4 are dissolved in 10 ml of anhydrous pyridine. 600 μl of acetic anhydride and a catalytic amount of 4-DMAP are added. After stirring for 23 hours at room temperature, the reaction mixture is hydrolysed with water and extracted with dichloromethane. The organic phase is dried over magnesium sulphate and concentrated under vacuum on a rotary evaporator. Chromatography on a silica column (CH 2 Cl 2 and a gradient of MeOH) makes it possible to isolate 45.8 mg of the expected product. Mass spectrometry (ES +): m / z = 618 [MNa] +; 634 [MK] +

  PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION EXAMPLE A: In Vitro Toxicity

  Two cell lines were used: - 1 murine leukemia, L1210, -1 human squamous cell carcinoma: KB-3-1

  The cells are cultured in complete RPMI 1640 medium containing 10% fetal calf serum, 2 mM glutamine, 50 units / ml penicillin, 50 g / ml streptomycin and 10 mM Hepes, pH = 7.4. The cells are distributed in microplates and exposed to the cytotoxic compounds. The cells are then incubated for 2 days (L1210) or 4 days (KB-3-1) in an incubator at 37 ° C. in the presence of 5% CO 2. The number of viable cells is then quantified by a colorimetric assay, Microculture Tetrazolium Assay (Cancer Res., 1987, 47, 939-942). The results are expressed in IC50, a cytotoxic concentration which inhibits the proliferation of the treated cells by 50%. By way of example, the compound of Example 2 has an IC50 of 9.3 gM on L1210, respectively.

  EXAMPLE B Pharmaceutical Composition

  Preparation formula for 1000 tablets dosed at 10 mg Compound of Example 2 10 g Hydroxypropylcellulose 2 g Wheat starch 10 g

Claims (9)

  Compounds of formula (I): embedded image in which: X and Y, which are identical or different, independently of one another, each represent a group chosen from: hydrogen atom, halogen, hydroxy group, linear or branched (C1-C6) alkoxy, nitro, cyano, linear or branched (C1-C6) alkyl, optionally substituted with one or more groups chosen from hydroxy and halogen and linear or branched (C2-C6) alkenyl, or a group of formula: embedded image in which: Ra and Rb, which are identical or different, independently of each other, each represent a group chosen from hydrogen atom, or linear or branched (C1-C6) alkyl group, or Ra and Rb together with the nitrogen atom carrying them, form a 5- to 7-membered monocyclic heterocycle, optionally containing a second heteroatom selected from oxygen and nitrogen in the ring system, • Z represents an oxygen atom or NRc in which Rc represents a a group chosen from hydrogen atom, linear or branched (C1-C6) alkyl group, or a linear or branched aryl, aryl (C1-C6) aryl group, • Ar represents an aryl or heteroaryl group, - • R1 represents an atom of hydrogen or a linear or branched (C1-C6) alkyl group, R2 represents a group chosen from hydrogen atom, linear or branched (C1-C6) alkyl group, ORa; in which Ra and Rb are as defined above, R3, R4, which are identical or different, independently of one another, represent a hydrogen atom or a linear or branched (C1-C6) alkyl group; R5 represents a group chosen from: 1) hydrogen atom,   2) ORS group, NReRd in which: R1 is as defined above and Rd, has the same definitions as R1;   3) W1uC (W2) ùUvV wherein: a) W 1 represents an oxygen atom or NRc (wherein R, is as defined above), (3) W2 represents an oxygen atom, y) U represents a single bond or a linear or branched (C1-C8) alkylene chain or a linear or branched (C2-C8) alkenylene chain, 8) V represents a group chosen from: - hydrogen atom, - aryl group, heteroaryl, - groups OR4, CO2Rc, CORc, CONR'aR'b, NR'aR'b, N (R1CCO2R'c, N (R)) -COR ', wherein R, is as previously defined, R'c has the same definitions that R, and R'a and R'b, identical or different, independently of each other, each represent a group chosen from hydrogen atom, linear or branched (C1-C6) alkyl group, Linear or branched aryl, aryl (C1-C6) alkyl, or R'a and R'b together with the nitrogen atom carrying them, form a monocyclic 5 to 7-membered heterocycle, optionally containing of the ring system a second heteroatom selected from oxygen and nitrogen,   Wherein W1 and W2 are as defined above, P) W3 represents an oxygen atom or NR, wherein Re is as defined above, y) T1 represents a group selected from : - hydrogen atom, - linear or branched (C1-C6) alkyl, - linear or branched (C2-C6) alkenyl, - aryl, linear or branched (C1-C6) arylalkyl, - (C1-C6) alkylene chain linear or branched chain or a linear or branched (C2-C6) alkenylene chain, each being substituted by a group OR, in which Re is as defined above or by NR'aR'b in which R'a and R'b are such as previously defined,   5) Z-CO-CH = CAT in which Z and Ar are as defined above, their enantiomers, diastereoisomers, when they exist, as well as their addition salts with a pharmaceutically acceptable acid or base, as well as their hydrates and their solvates, it being understood that: by aryl, a phenyl or naphthyl group, comprising optionally one or more substituents, identical or different, chosen from linear or branched (C1-C6) alkyl optionally substituted by one or more, is understood; hydroxy or halogen, hydroxy, halogen, carboxy, nitro, amino, linear or branched (C1-C6) monoalkylamino, or linear or branched (C1-C6) dialkylamino, linear or branched (C1-C6) alkoxy, acyl (C1- C6) linear or branched, and alkylcarbonyloxy (C1-C6) linear or branched, by heteroaryl means a group of 5 to 12 members, either aromatic monocyclic or bicyclic which at least one ring has a charac aromatic, and containing one, two or three heteroatoms selected from oxygen, nitrogen or sulfur, it being understood that the heteroaryl may be optionally substituted by one or more atoms or groups, identical or different, selected from halogen atoms and linear or branched (C1-C6) alkyl groups, optionally substituted with one or more hydroxyl or halogen groups, or hydroxy, linear or branched (C1-C6) alkoxy, or amino (optionally substituted with one or two (C1-C6) alkyl groups ) linear or branched). 2-Compounds of formula (I) according to claim 1, characterized in that X and Y represent a hydrogen atom, their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to any one of claims 1 to 2, characterized in that R1, R3 and R4 represent a linear or branched (C1-C6) alkyl group, their enantiomers, diastereoisomers and also their salts. addition to a pharmaceutically acceptable acid or base. 4-Compounds of formula (I) according to any one of claims 1 to 3, characterized in that R2 represents the group -ORa in which Ra is as defined in formula (I), their enantiomers, diastereoisomers and their salts addition to a pharmaceutically acceptable acid or base.  5- Compounds of formula (I) according to any one of claims 1 to 4, characterized in that R5 represents the groups OR, or W1ûC (W2) ûUûV in which Re, W1, W2, U and V are as defined in the formula (I), their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.   6- Compounds of formula (I) according to claim 1 which are: (() cis-1-hydroxy-6-methoxy-3, 3,12-trimethyl-7-oxo-2,3,7,12- tetrahydro-1H-pyrano [2,3-c] acridin-2-yl (2K) -3-phenyl-2-propenoate, - 23 - - () - cis-1 - (acetyloxy) -6-methoxy-3 , 3,12-trimethyl-7-oxo-2,3,7,12-tetrahydro-1H-pyrano [2,3-c] acridin-2-yl (2E) -3-phenyl-2-propenoate, ( ) -cis-6-methoxy-3,3,12-trimethyl-7-oxo-1 - {[(2E) -3-phenyl-2-propenoyl] oxy} -2,3,7,12-tetrahydro-1H pyrano [2,3-e] acridin-2-yl (2E) -3-phenyl-2-propenoate, - () - cis-1-hydroxy-6-methoxy-3, 3, 12-trimethyl-7- oxo-2,3,7,12-tetrahydro-1H-pyrano [2,3-c] acridin-2-yl (2E) -3- [4- (trifluoromethyl) phenyl] -2-propenoate, - () - cis-1 - (acetyloxy) -6-methoxy-3,3,12-trimethyl-7-oxo-2,3,7,12-tetrahydro-1H-pyrano [2,3-c] acridin-2-yl ( 2E) -3- [4- (trifluoromethyl) phenyl] -2-propenoate. their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.   7 Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that a compound of formula (II) is used as starting material: R 3 in which X, Y, R 3 and R 4 are as defined previously and R represents a hydrogen atom, a hydroxyl group, a linear or branched (C1-C6) alkyl group, a compound of formula (II), the nitrogen atom of which is substituted or not, by the action of a halide of alkyl or of a dialkyl sulphate in the presence of a deprotonating agent, in aprotic polar solvent or in a phase transfer condition, making it possible to obtain the compounds of formula (III): X (1) in which X , Y, R, R3 and R4 are as defined above, and R'1 represents a linear or branched (C1-C6) alkyl group, compounds of formula (III) which are subjected to the action of a alkylating agent according to conventional conditions of organic synthesis, to yield compounds of formula (IV): R4 in X, Y, R'1, R3 and R4 are as defined above and R'2 represents a group chosen from OR'a in which R'a represents a linear or branched (C1-C6) alkyl group, compounds of formula (IV) which are treated, in the case where R'2 represents an alkoxy group by a compound of formula (V): HNRaRb (V) in which Ra and Rb are as defined in formula (I), to lead to compounds of formula (VI): embedded image in which X, Y, R '1, R 3, R 4, Ra and Rb are as defined above, all the compounds of formula (II), (III), (IV) and (VI) forming the compounds of formula (VII): wherein X, Y, R 1, R 2, R 3 and R 4 are as defined in formula (I), compounds of formula ( VII) which are subjected: a) to the action of osmium tetroxide in polar medium and in the presence of 4-methylmorpholine-N-oxide, to yield compounds of formula (VIIUa): XO (VIIUa) ROH OH R4 (cis) in which X, Y, R1, R2, R3 and R4 are as defined above, b) the action of potassium permanganate in a polar medium and then under reducing conditions in the presence of NaBH4, to yield the compound of formula (VIIUb): XO R2 (VIII / b) ROH OH R 4 (trans) in which X, Y, R 1, R 2, R 3 and R 4 are as defined above, the combination of compounds of formulas (VIIUa) and (VIII / b) forming the compounds of formula (VIII ) whose 2 alcohol groups may be of cis or trans configuration with respect to each other: (VIII) in which X, Y, R 1, R 2, R 3 and R 4 are as defined above, composed of formula (VIII) which are subjected to the action of one or two equivalents of an anhydride of formula (IX) or of an acid chloride of formula (X): [ArûCH = CHûC (0)] 2O (IX) wherein Ar is as defined in formula (I) to give compounds of formula (IIa) or (IIa2), in particular cases of compounds of formula (I): d wherein X, Y, R 1, R 2, R 3, R 4 and Ar are as defined above, c) the action of NaN 3, in the presence of hydrogen peroxide, followed by a reduction step, to lead to compounds of formula (XI): embedded image in which X, Y, R 1, R 2, R 3 and R 4 are as defined above, compounds of formula (XI) which are subjected to the action of compounds of formulas ( IX) or (X) as defined above under the same conditions as for the compounds of formula (VIII), to give compounds of formulas (I / b1) or (I / b2), particular cases of compounds of formula ( Embedded image in which X, Y, R 1, R 2, R 3, R 4 and Ar are as defined above, compounds of formula (I / bl) or (Pb 2) which are optionally subjected to the action of a compound of formula (XII): R'cuHal (XII) in which Hal represents a halogen and R'e represents a group chosen from linear or branched (C1-C6) alkyl, or a group linear or branched aryl, aryl (C1-C6) alkyl, to yield compounds of formula (Uc1) or (Uc2): wherein R2, R2, R3, R4 , R'c and Ar are as defined above, all of the compounds of formulas (Pal), (Ub1) and (PO and (Paz), (Pb2) and (Fez) forming the compounds of formulas (Ud1) and (Ud2) respectively, -28- (I / di) (I / d2) wherein X, Y, R1, R2, R3, R4, Y and Ar are as defined in formula (I) and R5a represents a grouping hydroxy, NH2 or NHR'C in which R'c is as defined above, the compounds of formula (11dl) which are optionally subjected: a) to the action of an alkylating agent, to give compounds of formula ( embedded image), a particular case of the compounds of formula (I): wherein R2, X, Y, R1, R2, R3, R4, Y and Ar are as defined above, and R5b represents a group ORS, NRcRd in which R , and Rd are as defined in formula (I), b) to action of an anhydride of formula (XIII) or of an acid chloride of formula (XIV): (R10) 20 (XIII), wherein R1 represents a group of formula C (W2), or Wherein W2, W3, U, V and Ti are as defined in formula (I), for R5b Y x4 O-Ar, to give compounds of formula (I / f), a particular case of compounds of formula (I): ## STR2 ## wherein X, Y, R 1, R 2, R 3, R 4, Y, Ar and R 10 are as defined above and W 1 is as defined in formula (I), the compounds ( 11a) to (bed) forming all of the compounds of the invention which are purified, if appropriate, according to a conventional purification technique, which can, if desired, be separated into their different isomers according to a conventional technique of separation and which are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base.   8-Pharmaceutical compositions containing as active ingredient at least one compound according to any one of claims 1 to 6, in combination with one or more excipients or inert vehicles, non-toxic, pharmaceutically acceptable.   9- Pharmaceutical compositions according to claim 8 containing at least one active ingredient according to any one of claims 1 to 6 useful as drugs, in the treatment of cancers.