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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to novel tricyclic derivatives, process for their preparation and pharmaceutical compositions containing them.
• the compounds of the present invention are new and have very interesting pharmacological characteristics in the field of apoptosis and oncology.
• Apoptosis or programmed cell death, is a crucial physiological process for embryonic development and maintenance of tissue homeostasis.
• Apoptotic cell death involves morphological changes, such as core condensation, DNA fragmentation, as well as biochemical phenomena, such as activation of caspases that will degrade key structural components of the cell to induce disassembly and death.
• the regulation of the apoptosis process is complex and involves the activation or repression of several intracellular signaling pathways (Cory S. et al., Nature Review Cancer, 2002, 2, 647-656).
• apoptosis Deregulation of apoptosis is implicated in certain pathologies. Increased apoptosis is linked to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and ischemia. Conversely, deficiencies in the execution of apoptosis play an important role in the development of cancers and their chemoresistance, autoimmune diseases, inflammatory diseases and viral infections. Thus, escape to apoptosis is part of the phenotypic signatures of cancer (Hanahan D. et al., Cell 2000, 100, 57-70).
• the compounds of the present invention in addition to their novelty, have pro-apoptotic properties making it possible to use them in pathologies involving a lack of apoptosis, such as, for example, in the treatment of cancer.
• the present invention relates more particularly to the compounds of formula (I)
• Z 1 , Z 2 and Z 3 independently of one another represent a CH group or a nitrogen atom, knowing that at least one of these three groups is a nitrogen atom,
• R 2 represents an aryl or heteroaryl group
• X represents a linear or branched alkylene chain containing from 1 to 6 carbon atoms, one or two of the carbon atoms of which may be replaced by an oxygen atom, a cycloalkylene group, an arylene group, a heteroarylene group or an SO 2 group,
• R represents a group of formula (II): in which :
• R 4 represents a hydrogen atom and in this case R 5 represents a hydrogen atom or a group -NR 6 R ' 6 or -CH 2 -NR 6 R 5 O in which R 6 and R' 6 , which are identical, or different, each independently represent a hydrogen atom or a linear or branched (C 1 -C 6 ) alkyl group substituted with one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl, or -NR 9 R groups '9 wherein: * R 9 and R' 9, which are identical or different, are selected from hydrogen, alkyl (C 1 -
• R 3 represents a halogen atom or an NO 2 , R 7 , SO 2 -R 8 , linear or branched (C 1 -C 6 ) alkyl or linear or branched (C 1 -C 6 ) alkoxy group, where R 7 can take all the values of R 6 as defined above, - R ⁇ represents an amino group or a linear or branched (C 1 -C 6 ) alkyl group optionally substituted with one or more halogen atoms,
• aryl means a phenyl, naphthyl or biphenyl group, with “heteroaryl” is meant any mono or bicyclic group, having at least one aromatic part, and containing 5 to 10 members and possibly containing 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen such as furan, thiophene, pyrrole, imidazoline, pyridine, quinoline, isoquinoline, chroman, indole, benzothiophene, benzofuran, 1,3-benzodioxole and 2,3-dihydro-
• heterocycloalkyl any nonaromatic monocyclic or bicyclic group containing 4 to 10 members and which may contain 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, - "cycloalkyl” means any nonaromatic mono grouping or bi-cyclic containing 4 to 10 members,
• the aryl, heteroaryl, heterocycloalkyl and cycloalkyl groups thus defined being capable of being substituted with 1 to 3 groups chosen from linear or branched (C 1 -C 6 ) alkyl optionally substituted with a linear or hydroxy (C 1 -C 6 ) -submoxy or hydroxy group; or branched, hydroxy, carboxy, formyl, nitro, cyano, amino, linear or branched (C 1 -C 6 ) polyhaloalkyl, alkyloxycarbonyl, or halogen atoms,
• arylene is meant an aryl, heteroaryl and cycloalkyl group respectively as defined above, inserted in place of a carbon atom of the alkylene chain,
• hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic and methane acids. sulfonic, camphoric, etc.
• the preferred group R 3 is NO 2 .
• the preferred XR 2 groups are ([l, r-biphenyl] -2-yl) methyl groups optionally substituted with one or more halogen atoms.
• R 4 preferably represents a hydrogen atom.
• the preferred R 6 group is 1- (N, N-dimethylamino) -4- (phenylsulfanyl) butan-3-yl.
• R 6 preferably represents a hydrogen atom.
• the invention relates to the compounds of formula (I) which are: • N - ( ⁇ 2 - [(4 1- chloro [1,1'-biphenyl] -2-yl) methyl] -1, February 5 3,4,10,10a-hexahydropyrido
• the invention also extends to the process for preparing the compounds of formula (I), characterized in that the compound of formula (III) used is the starting material:
• Cy, Y, R 3 , R 6 and R ' 6 are as defined above, which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and from which the isomers are optionally separated by a conventional separation technique.
• An advantageous variant relates to the process for the preparation of the compounds of formula (I), characterized in that the compound of formula (HI ') is used as starting material:
• R 3 , R 4 and R 5 are as defined in formula (I), to yield the compound of formula (I) which can be purified by a conventional separation technique, which is transformed, if it is It desires, in its addition salts with a pharmaceutically acceptable acid or base, from which the isomers are optionally separated by a conventional separation technique.
• the pharmacological study of the derivatives of the invention has shown that they have pro-apoptotic properties.
• the ability to reactivate the apoptotic process in cancer cells represents a major therapeutic interest in the treatment of cancers.
• the compounds according to the invention will be useful in the treatment of chemo or radio-resistant cancers, as well as in hematological malignancies and small cell lung cancer.
• treatments for the cancers contemplated mention may be made of, but not limited to, cancers of the bladder, brain, breast, uterus, chronic lymphoid leukemias, cancers of the colon, esophagus, liver , lymphoblastic leukemias, follicular lymphomas, melanomas, hematological malignancies, myelomas, ovarian cancers, non-small cell lung cancers, prostate cancers and small cell lung cancers.
• the present invention also relates to pharmaceutical compositions containing at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients.
• compositions according to the invention mention may be made, more particularly, of those which are suitable for oral, parenteral, nasal, percutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets. , sachets, packets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and oral or injectable ampoules.
• the dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possibly associated treatments and ranges between 0.01 mg and 1 g per 24 hours. in one or more takes.
• the present invention also relates to the combination of a compound of formula (I) with an anticancer agent chosen from genotoxic agents, mitotic poisons, antimetabolites, proteasome inhibitors, or kinase inhibitors. as well as the use of this type of association for the manufacture of drugs useful in the treatment of cancer.
• an anticancer agent chosen from genotoxic agents, mitotic poisons, antimetabolites, proteasome inhibitors, or kinase inhibitors.
• the compounds of the invention may also be used in combination with radiotherapy in the treatment of cancer.
• Step E S-Methoxy-S l j-dihydro-Lji-pyrroloPjS-cJpyridine-l-carboxylate
• Stage F 8-Methoxy-2,3,10,10a-tetrahydropyrido [4 ', 3': 4,5] pyrrolo [1,2-t] pyrazine-1,4-dione
• reaction medium After returning to ambient temperature, the reaction medium is stirred for 12 hours. The reaction mixture is hydrolyzed at 0 ° C, dropwise, and then extracted with ethyl acetate. The organic phases are washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. After filtration on silica, the solid obtained is dissolved in 100 mL of tetrahydrofuran and 350 mL of methanol. The ammonium formate (4.8 g) is then added portionwise, and the reaction medium is refluxed for 10 hours. After filtration and rinsing with hot tetrahydrofuran and hot dimethylformamide,. the filtrate is concentrated and taken up in cold methanol to yield the title product in the form of a white solid.
• Step H 2-Benzyl-8-methoxy-1,2,3,4,10,10a-hexahydropyrido [4 ', 3': 4,5] pyrrolo [1,2-a] pyrazine
• the filtrate is concentrated and taken up in an ethyl acetate mixture and a saturated aqueous solution of sodium hydrogencarbonate.
• the product is then extracted with ethyl acetate. After concentration of the organic phases, the residue is purified by flash chromatography on silica gel (dichloromethane / methanol) to yield the title product in the form of a brown oil.
• a solution of the compound of Stage H (2.6 g) in a 33% solution of hydrobromic acid in acetic acid is refluxed for 3 hours.
• an aqueous solution of sodium hydrogencarbonate is added, dropwise, at 0 ° C. to a pH of 8.
• the product is extracted with dichloromethane and the organic phases are then combined, dried over sodium sulfate magnesium, filtered and concentrated.
• To a solution of the residue thus obtained in 70 ml of pyridine is added, dropwise, at 0 ° C in 50 minutes triflic anhydride (13 ml).
• the reaction medium is raised to room temperature in 16 hours and then concentrated.
• the residue is taken up in a mixture of ethyl acetate and water.
• the product is extracted with ethyl acetate and the organic phases are washed with an aqueous solution of sodium hydrogencarbonate, dried over magnesium sulphate, filtered and concentrated.
• the residue is purified by flash chromatography on silica gel (heptane / ethyl acetate) to yield the title product in the form of a green oil.
• the product is extracted with ethyl acetate and the organic phases are washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated. After lyophilization in dioxane, the residue is purified by flash chromatography on silica gel (dichloromethane / methanol) to yield the title product.
• Stage M 2 - [(4'-chloro [1,1'-biphenyl] -2-yl) methyl] -1,2,3,4,10,10a-hexahydro-pyrido [4 ', 3': 4,5] pyrrolo [1,2-a] pyrazine-8-carboxylic acid, tris (trifluoroacetate)
• the reaction medium of the preceding stage is stirred at ambient temperature for 2 hours and 15 minutes and then poured gently onto 30 ml of a 5N hydrochloric acid solution at a temperature not exceeding 10 ° C.
• the solution obtained is refluxed. during 2 hours. After returning to ambient temperature, it is neutralized to pH 3 with a 5N sodium hydroxide solution.
• the product is extracted with ether and the organic phases are washed with a saturated solution of potassium carbonate, dried over magnesium sulfate, filtered and concentrated. The residue is taken up in methanol to yield the title product in the form of a beige solid.
• Stage E 5,5a, 7,8-Tetrahydropyrido [3 ', 2': 4,5] pyrrolo [1,2-a] pyrazine-6,9-dione
• Step H 7-Benzyl-3-bromo-5,5a, 6,7,8,9-hexahydropyrido [3 ', 2': 4,5] pyrrolo [1,2-a] pyrazine
• Step 1 Methyl 7-Benzyl-5,5a, 6,7,8,9-hexahydropyrido [3 ', 2': 4,5] pyrrolo [1,2-a] pyrazine-3-carboxylate
• the compound of the preceding stage is applied to the procedure described in Stage J of Preparation 1.
• the title product is finally in the form of a brown oil.
• Stage L 7 - [(4'-chloro [1,1'-biphenyl] -2-yl) methyl] -5,5a, 6,7,8,9-hexahydropyrido [3 ', 2': 4, 5] pyrrolo [1,2- ⁇ ] pyrazine-3-carboxylic acid trifluoroactetate
• Steps F to M of Preparation 1 are repeated, replacing in Step F the compound of Step E with 6-methoxy-1,2,3,4-tetrahydro [1,5] naphthyridine-2-carboxylate. methyl.
• Steps F to M of Preparation 1 are repeated, replacing in Step F the compound of Step E with 6-methoxy-1,2,3,4-tetrahydro [1,8] naphthyridine-2-carboxylate. methyl.
• Example 1 iV - ( ⁇ 2 - [(4'-chloro [l, l-biphenyl] -2-yl) methyl!] -L, 2,3,4,10,10a- hexahydropyrido [4 ', 3' : 4,5] pyrrolo [1,2-t] pyrazin-8-yl ⁇ carbonyl) -4 - ( ⁇ (1 R) -3- (dimethylamino) -1 - [(phenylsulfanyl) methyl] propyl ⁇ amino) -3 - nitrobenzenesulfonamide, trihydrochloride
• Step A N - ( ⁇ 2 - [(4'-Chloro [1,1'-biphenyl] -2-yl) methyl] -1,2,3,4,10,10-hexahydropyrido [4 ', 3' : 4,5] pyrrolo [l, 2- ⁇ ] pyrazm-8-yl ⁇ carbonyl) -4 - ( ⁇ (LII) -3-
• reaction mixture is stirred at room temperature for 6 days and then hydrolyzed with a saturated aqueous solution of ammonium chloride.
• the product is extracted with ethyl acetate.
• the organic phases are dried over magnesium sulfate, filtered and concentrated.
• the residue is purified by flash chromatography on silica gel (dichloromethane / ammoniacal methanol) to yield the title product in the form of a pale yellow solid.
• Step B N - ( ⁇ 2 - [(4'-Chloro [1,1'-biphenyl] -2-yl) methyl] -1,2,3,4,10,10-hexahydropyrido [4 ', 3' : 4,5] pyrrolo [l, 2-fl] pyrazin-8-yl ⁇ carbonyl) -4 - ( ⁇ (lif) -3-
• Step A The compound of Step A is dissolved in 4 mL of dichloromethane, and then a solution of IN hydrochloric ether (805 ⁇ L) is added. The reaction mixture is stirred at room temperature for 2 hours and then concentrated to yield the title product as a yellow solid after lyophilization. Elemental microanalysis:
• Example 2 T - ( ⁇ 8 - [(4'-Chloro [1,1'-biphenyl] -2-yl) metl pyrido [2 ', 3': 4,5] pyrrolo [1,2- ⁇ ] pyrazin-2-yl ⁇ carbonyl) -4 - ( ⁇ (1R) -3- (dimethylamino) -1 - [(phenylsulfanyl) methyl] propyl ⁇ amino) -3-nitrobenzenesulfonamide, bischlorhydrate
• Example 3 7V - ( ⁇ 7 - [(4'-Chloro [1,1'-biphenyl] -2-yl) met] hexahydropyrido [3 ', 2': 4,5] pyrrolo [1,2-a] ] pyrazin-3-yl ⁇ carbonyl) -4- ( ⁇ (1H) -3- (dimethylamino) -1 - [(phenylsulfanyl) methyl] propyl ⁇ amino) -3-nitrobenzenesulfonamide, trihydrochloride
• Example 84 (4'-Chloro [1,1'-biphenyl] -2-yl) methyl] -6,6a, 7,8,940-hexahydro-5-pyrazino [1,2-a] [1] 8] naphthyridin-3-yl ⁇ carbonyl) -4 - ( ⁇ (li?) - 3-
• This cell line is cultured in an incubator at 37 ° C in the presence of 5% CO 2 .
• the H 146 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 buffer, pH ⁇ 7.4.
• the cells are distributed in 6-well plates and exposed to the test compounds for 6 hours. They are then collected and lysed and the caspase activity is measured in the cell lysates.
• This enzymatic measurement is carried out by assaying the appearance of a fluorigenic cleavage product (Pharmacia).
• the compounds of the invention are potent inducers of apoptosis, evaluated by measuring the caspase 3 activity, in the tumor line tested.
• the compounds of Examples 1 to 3 respectively show an activity at 10 ⁇ M of 15395, 9948 and 17776 RFU (Relative Fluorescence Units).
• the cells are distributed in microplates and exposed to the test compounds for 48 hours. Cell viability is then quantified by a colorimetric assay, Microculture Tetrazolium Assay (Cancer Res., 1987, 47, 939-942).
• the ability of the compounds of the invention to activate caspase 3 is evaluated in a model of xenograft of H146 small cell lung carcinoma cells. 5.10 6 H1 cells are grafted subcutaneously into immunocompromised mice (NOD strain). SCID). 25 to 30 days after the grafting, the compounds to be tested are injected intraperitoneally into a tween80 / water mixture. Sixteen hours after the treatment, the tumor masses are recovered, lysed and the caspase 3 activity is measured in the tumor lysates.

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