DERIVATIVES OF FLAVAGLINES

专利摘要:
The present invention relates to compounds of the following general formula (I): in the form of one of their enantiomers or a mixture of their enantiomers, and their pharmaceutically acceptable salts and / or solvates thereof, in particular for their use as drug, especially in the treatment of cancer. The present invention also relates to pharmaceutical compositions containing them and processes for their preparation.
公开号:FR3023290A1
申请号:FR1456474
申请日:2014-07-04
公开日:2016-01-08
发明作者:Frederic Marion；El Bachir Kaloun；Frederic Lieby-Muller；Michel Perez；Jean Philippe Annereau；Laurent Creancier
申请人:Pierre Fabre Medicament SA；
IPC主号:

专利说明:

[0001] The present invention relates to new flavaglin derivatives, their manufacturing processes, the pharmaceutical compositions containing them and their use as a medicament, especially in the treatment of cancer. Flavaglins are a family of natural products comprising a unique cyclopenta [b] benzofuran skeleton with members such as silvestrol and rocaglamide. This family has many biological properties including anti-proliferative activities (Hausott et al., J. Cancer: 109, 933-940 (2004)). This ability to inhibit the growth of cancer cell lines has been linked for some of these members, such as silvestrol, to the inhibition of protein synthesis through the inactivation of eIF4A helicase (Cencic et al., P1oS ONE 2009). 4 (4): e5223). These properties make the family of flavaglines interesting for a potential application in the treatment of hyperproliferative diseases such as cancer for example. Despite several efforts (Ribeiro et al., Biochem, Chem Chem 20 (2012) 1857-1864, Liu et al, J. Med Chem 2012, 55, 8859-8878), to date no natural product or derivative of flavagline has demonstrated sufficient potential to lead to use as a drug. The present invention thus relates to new flavaglin derivatives having anti-proliferative activities of interest for an application as anti-cancer therapy in particular. The inventors have thus unexpectedly demonstrated that important modifications on the cyclopenta [b] benzofuran skeleton or sets of modifications lead to compounds that are more potent than silvestrol, having a greater anti-tumor activity. The subject of the present invention is thus a compound of the following general formula (I): (I) in the form of one of its enantiomers or a mixture of its enantiomers, such as a racemic mixture, or a salt and / or solvate a pharmaceutically acceptable salt thereof, wherein: = represents a single bond or a double bond, n represents an integer of from 1 to 10, R1 represents CO2Ri0, CONH2, NRi iR12, NRi3COR14, NRi5CONRi6R17, NRisCSNR19R20, NR21SO2R22, NR23 CO2R24. or an optionally substituted heteroaryl preferably chosen from triazoles and optionally substituted oxadiazoles, R2 represents OH, or R1 and R2 together with the carbon atoms which carry them form an optionally substituted heterocycle, preferably chosen from the pyrimidine, pyrazole and pyrazolone rings; , oxazoline, isoxazoline, oxazalanone, oxazalanethione, morpholinone and optionally substituted oxazepane, the heterocycle optionally Bstituted can not be: HN NN 'N 20 20 1 or 1, carbon 1 denoting the carbon atom bearing the group R1 and carbon 2 denoting the carbon atom carrying the group R2, R3 represents H, OR25, CHOHCH2OH , CHO, N3, NR26R27, CO2R28, CONR29R30, NR38COR39, (O (CH2)., O (CH2) p) r (CH2) qR3 1, (NR32 (CH2) wNR33 (CH2) x) y (CH2) zR34, ONR84R85, optionally substituted aryl, or optionally substituted heteroaryl, R4 is absent when = is a double bond and R4 is H or OH when = is a single bond, R10 to R30, R32, R33, R38 and R39 are, independently of one another, other, H or a (C1-C6) alkyl, aryl, aryl (C1-C6) alkyl or (C1-C6) alkyl-aryl group, said group being optionally substituted by one or more groups selected from (C1-C6) alkyl, OR35, and NR36R37, or R11 and R12, or R16 and R17, or R19 and R20, or R26 and R27, or R29 and R30, together with the nitrogen atom carrying them, form a nitrogen heterocycle optionally s R31 and R34 represent, independently of one another, H, OR35, NR36R37, ONR86R87 or (C1-C6) alkyl, aryl, aryl (C1-C6) alkyl or (C1-C6) alkyl aryl, said group being optionally substituted by one or more groups selected from (C1-C6) alkyl, OR35, and NR36R37, R35 to R37 and R84 to R87 represent, independently of each other, H or a group (C1-C6 ) alkyl, aryl or aryl (C1-C6) alkyl, Ra represents a halogen atom (e.g. Br or Cl), CN or (C1-C6) alkoxy (such as methoxy), Rb is H or (C1-C6) alkoxy (such as methoxy), or Ra and Rb together form a -OCH2O- , and m, p, r, q, w, x, y, z represent, independently of each other, an integer from 1 to 4, provided that when R1 is CO2R10 or CONH2 and n = 1 or 2 then R3 is OR25, CHOHCH2OH, CHO, N3, NR26R27, C 02R28, C ONR29R30, NR38COR39, (O (CH2) m0 (CH2) p) r (CH2) qR3i, (NR32 (CH2) wNR33 (CH2) x) y (CH2) zR34, or ONR84R85 with R25 H.
[0002] In the present invention, the term "pharmaceutically acceptable" is intended to mean that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary use as well as human pharmaceutical. The term "pharmaceutically acceptable salt and / or solvate" is intended to mean a compound, a salt and / or solvate which is pharmaceutically acceptable, as defined herein, and which has the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts include: (1) pharmaceutically acceptable acid addition salts formed with pharmaceutically acceptable inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and the like; or formed with pharmaceutically acceptable organic acids such as acetic, trifluoroacetic, propionic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, glutamic, benzoic, salicylic, toluenesulfonic, methanesulfonic, stearic, lactic and the like, and 2) the pharmaceutically acceptable base addition salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or a metal ion, aluminum; is coordinated with a pharmaceutically acceptable organic base such as lysine, arginine and the like; or with a pharmaceutically acceptable inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. These salts can be prepared from the compounds according to the invention containing a basic or acidic function and the corresponding acids or bases according to conventional chemical methods. Acceptable solvates for the pharmaceutical use of the compounds according to the present invention include conventional solvates such as those formed, during the last stage of the process for preparing the compounds according to the invention, with the reaction solvent (s). By way of example, mention may be made of solvates formed with water (commonly called hydrates) or with ethanol. By "enantiomers" is meant compounds which are images of one another in a mirror but not superimposable. A mixture containing equal amounts of two individual enantiomeric forms of opposite chirality is referred to as a "racemic mixture".
[0003] By "(C 1 -C 6) alkyl" is meant, in the sense of the present invention, a linear or branched saturated hydrocarbon chain comprising 1 to 6 carbon atoms. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl groups.
[0004] By "(C 1 -C 6) alkoxy" group is meant, within the meaning of the present invention, a (C 1 -C 6) alkyl group as defined above, linked to the remainder of the molecule via an atom oxygen. By way of example, mention may be made of methoxy, ethoxy, propoxy, isopropoxy, butoxy or even tert-butoxy groups. In particular, it will be a methoxy group.
[0005] By "aryl" is meant in the sense of the present invention, an aromatic hydrocarbon group preferably having 6 to 10 carbon atoms and may comprise one or two contiguous rings. By way of example, mention may be made of a phenyl or a naphthyl. Advantageously it is phenyl. For the purposes of the present invention, the term "heteroaryl" means an aromatic group comprising one or more, especially 1 or 2, conjugated hydrocarbon rings, in which one or more carbon atoms, advantageously 1 to 4 and even more advantageously 1 or 2, are each replaced by a heteroatom selected from sulfur, nitrogen and oxygen. Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl or indyl groups. For the purposes of the present invention, the term "heterocycle" is intended to mean a saturated, unsaturated or aromatic hydrocarbon group comprising 1 or 2 contiguous rings and in which one or more, advantageously 1 to 4, still more advantageously 1 or 2, atoms carbon atoms are each replaced by a heteroatom selected from oxygen, nitrogen and sulfur. Advantageously, the heterocycle will comprise 5 to 10 carbon atoms and heteroatoms. By way of example, mention may be made of the furan, pyrrole, thiophene, thiazole, triazole, isothiazole, oxadiazole, imidazole, oxazole, isoxazole, pyrazole, pyridine, pyrimidine, piperazine, piperidine, pyrazolone, oxazoline, isoxazoline, oxazalanone and oxazalanethione rings. morpholinone, oxazepane, quinazoline, quinoline, quinoxaline, benzofuran, benzothiophene, indoline, indolizine, benzothiazole, benzothiophene, benzopyran, benzoxazole, benzo [1,3] dioxole, benzoisoxazole, benzimidazole, chromane, chromene, dihydrobenzofuran, dihydrobenzothiophene, dihydroisoxazole, isoquinoline, dihydrobenzo [1,4] dioxin, imidazo [1,2-a] pyridine, furo [2,3-c] pyridine, 2,3-dihydro-1H-indene, [1,3] dioxolo [4,5-c] pyridine, pyrrolo [1,2-c] pyrimidine, pyrrolo [1,2-a] pyrimidine, tetrahydronaphthalene, and benzo [b] [1,4] oxazine. For the purposes of the present invention, the term "nitrogenous heterocycle" is intended to mean a heterocycle as defined above comprising at least one nitrogen atom, which is preferably saturated. It may be in particular a 5- or 6-membered ring optionally comprising, in addition to the nitrogen atom, another heteroatom chosen preferably from oxygen and nitrogen. It will be in particular a piperidine, piperazine, morpholine or pyrolidine group. For the purposes of the present invention, the term "aryl (C 1 -C 6) alkyl" means an aryl group as defined above bonded to the remainder of the molecule via an alkyl group as defined above. and comprising 1 to 6, preferably 1 to 4, preferably 1 or 2, carbon atoms. This will include a benzyl or phenethyl group. For the purposes of the present invention, the term "(C 1 -C 6) alkyl-aryl" means a (C 1 -C 6) alkyl group as defined above, linked to the remainder of the molecule by means of a aryl group as defined above. By way of example, mention may be made of the tolyl group (CH 3 Ph). By "optionally substituted" is meant, within the meaning of the present invention, that the group in question is optionally substituted by one or more substituents which may be chosen in particular from a halogen atom, a group SO 2, CN, NO 2, OR 95 , SR96, NR97R98, (C1-C6) alkyl, (C1-C6) alkyl-aryl, aryl (C1-C6) alkyl, heterocycle or aryl, with R95 to R98 being independently of one another H or group (C1-C6) alkyl, aryl, aryl- (C1-C6) alkyl or (C1-C6) alkyl-aryl, said group being optionally substituted with one or more groups selected from (C1C6) alkyl, OR99, and NR10o1i, R99 Rios representing, independently of each other, H or a group (C1-C6) alkyl, or R97 and R98, together with the nitrogen atom which carries them, an optionally substituted nitrogenous heterocycle.
[0006] Preferably, R95 to R98 are, independently of one another, H or (C1-C6) alkyl, aryl, aryl (C1-C6) alkyl or (C1-C6) alkyl-aryl, preferably H or (C 1 -C 6) alkyl group, or R97 and R98 together with the nitrogen atom carrying them, form a nitrogen heterocycle optionally substituted by a (C 1 -C 6) alkyl group, the heterocycle being in particular a 5-membered heterocyclic ring; or 6-membered ring optionally comprising, in addition to the nitrogen atom, another heteroatom selected from oxygen and nitrogen, such as a piperidine, piperazine, morpholine or pyrolidine group. For the purposes of the present invention, the term "halogen atom" means the fluorine, chlorine, bromine and iodine atoms. In particular, it will be a bromine atom or chlorine atom. For the purposes of the present invention, the term "polyamine" is intended to mean a linear hydrocarbon-based chain comprising from 4 to 15 carbon atoms, and at least two of which carbon atoms are replaced by nitrogen atoms, two carbon atoms and nitrogen can not be found on adjacent positions. Said polyamine may in particular be represented by the following formula: ## STR5 ## an integer between 1 and 5 and d and e each represent 0, 1 or 2 but can not represent 0 at the same time and d can not represent 1 when e = 0 and with R91 to R94 representing H or a group (C C6) alkyl, aryl, (C1-C6) alkyl-aryl or aryl- (C1-C6) alkyl. Advantageously, n is between 1 and 4. According to a particular embodiment, Ra = (C 1 -C 6) alkoxy such that OMe and Rb = H. A particularly preferred class of compounds corresponds to the compounds of formula (I) wherein: = represents a single bond, R1 represents CO2R10 or CONH2, especially CO2R10, R3 represents OR25, CHOHCH2OH, CHO, N3, NR26R27, CO2R28, CONR29R30, NR38COR39, (O (CH2) m0 (CH2) p) r ( CH2) qR31, (NR32 (CH2) wNR33 (CH2) x) y (CH2) zR34, ONR84R85, optionally substituted aryl, or optionally substituted heteroaryl, and R4 is H. In this case, R10 is preferably H or a group (Ci -C6) alkyl such as methyl. Preferably, R3 will represent OR25, CHOHCH2OH, CHO, N3, NR26R27, CO2R28, CONR29R30, NR3COR39, (O (CH2) m0 (CH2) p) r (CH2) qR31, (N-R32 (CH2) wNR33 ( CH2) x) y (CE12) zR34 or ONR84R85; including OR25, CHOHCH2OH, CHO, N3, NR26R27, CO2R28, CONR29R30, (NR32 (CH2) wNR33 (CH2) x) y (CH2) zR34 or ONR84R85 advantageously NR26R27, CONR29R30, (NR32 (CH2) wNR33 (CH2) x) y (CH2) zR34 or ONR84R85 with R25 to R34, R38, R39, R84 and R85 as defined above and in particular with: R25 being as defined above and preferably representing H or a group (C1-C6) alkyl, especially H, R26 and wherein R 27 is H or (C 1 -C 6) alkyl, aryl, aryl (C 1 -C 6) alkyl or (C 1 -C 6) alkyl-aryl, preferably H or (C 1 -C 6) alkyl, or R 26 and R27 together with the nitrogen atom carrying them, form a nitrogen heterocycle optionally substituted with a (C 1 -C 6) alkyl group, the heterocycle being in particular a 5- or 6-membered heterocycle optionally comprising, in addition to the nitrogen atom, another heteroatom selected from oxygen and nitrogen, such as a piperidine, piperazine, morpholine or pyrolidine group, R28, R32, R33, R38 and R39 representing, independently H or a (C 1 -C 6) alkyl or (C 1 -C 6) alkyl-aryl group, preferably H or a (C 1 -C 6) alkyl group, Wherein R 29 and R 30 are H or (C 1 -C 6) alkyl, aryl, aryl (C 1 -C 6) alkyl or (C 1 -C 6) alkyl-aryl, preferably H or (C 1 -C 6) alkyl, or R 29 and R 30 together with the nitrogen atom carrying them, form a nitrogen heterocycle optionally substituted by a (C 1 -C 6) alkyl group, the heterocycle being in particular a 5- or 6-membered heterocycle optionally comprising, in addition to the nitrogen atom, another heteroatom selected from oxygen and nitrogen, such as piperidine, piperazine, morpholine or pyrolidine, and R31 representing H, OR35, NR36R37, ONR86R87, or a (C1-C6) group; ) alkyl, aryl, aryl- (C1-C6) alkyl or (C1-C6) alkyl-aryl, preferably H, OR35, or (C1-C6) alkyl, where R34 is H, OR35, NR36R37, ONR86R87, or a (C 1 -C 6) alkyl, aryl, aryl (C 1 -C 6) alkyl or (C 1 -C 6) alkyl group -aryl, preferably H, NR36R37 or a (C1-C6) alkyl group, and R35 to R37 and R84 to R87 being as defined above and preferably representing H or a (C1-C6) alkyl group.
[0007] Another particularly preferred class of compounds corresponds to compounds of formula (I) in which: = represents a single bond, R1 represents NRiiRiz, NRi3COR14, NR15CONR16R17, NR18CSNR19R2o OR NR21 SO2R22, and R4 represents H. Preferably R3 is as defined herein above, preferably R 3 represents H. R 11 to R 22 are as defined above and preferably: R 11 to R 22 represent, independently of each other, H or a (C 1 -C 6) alkyl group, optionally substituted by one or more groups chosen from (C 1 -C 6) alkyl, OR 35, and NR 36 R 37, preferably chosen from (OR 35, and NR 36 R 37, such as NR 36 R 37, or R 11 and R 12, or R 16 and R 17, or R 19 and R 20, together with the atom form nitrogen which carries them, a nitrogen heterocycle optionally substituted by a (C 1 -C 6) alkyl group, the heterocycle being in particular a 5- or 6-membered heterocycle optionally comprising, in addition to the nitrogen atom, another heteroatom chosen by oxygen and nitrogen, such as piperidine, piperazine, morpholine or pyrolidine. Preferably, R 11 to R 22 represent, independently of one another, H or a (C 1 -C 6) alkyl group, optionally substituted with one or more groups chosen from (C 1 -C 6) alkyl, OR 35, and NR 36 R 37, preferably chosen from (OR35, and NR36R37, such as NR36R37.
[0008] Another particularly preferred class of compounds corresponds to the compounds of formula (I) in which: = represents a single bond, -N JI N y -R41 N-N CYN -Rzt2 -R43 R1 represents R40 .111. or R1 is H, R40 is H or (C1-C6) alkyl, aryl or aryl (C1-C6) alkyl, especially H or (C1-C6) alkyl, preferably H, R41 to R43 represent, independently of one another, H or (CiC6) alkyl, aryl, aryl (C1-C6) alkyl, OR44, SR45 or NR46R47, especially H or (C1-C6) alkyl, OR44, SR45 or NR46R47, especially (C1-C6) alkyl, OR44, SR45 or NR46R47, R44 to R47 are independently of each other H or (C1-C6) alkyl, aryl or aryl (C1-C6) ), said group being optionally substituted with one or more groups chosen from (C 1 -C 6) alkyl, OR 48, NR 49 R 50, and polyamines, especially chosen from (C 1 -C 6) alkyl, OR 48 and NR 49 R 50, in particular chosen from OR 48 and NR49R50, such as NR49R50, or R46 and R47 together with the nitrogen atom carrying them, form a nitrogenous heterocycle optionally substituted by a (C1-C6) alkyl group, and R48 to R50 represent, independently from each other, H or a (C 1 -C 6) alkyl, aryl or aryl (C 1 -C 6) alkyl group. The nitrogenous heterocycle will advantageously be a 5- or 6-membered heterocycle optionally comprising, in addition to the nitrogen atom, another heteroatom chosen from oxygen and nitrogen, such as a piperidine, piperazine, morpholine or pyrrolidine.
[0009] Preferably, R44 to R47 represent, independently of one another, H or a (C 1 -C 6) alkyl group optionally substituted by one or more groups chosen from (C 1 -C 6) alkyl, OR 48, NR 49 R 50, and the polyamines, in particular chosen from (CiC6) alkyl, OR48 and NR49R50, in particular selected from OR48 and NR49R50, such as NR49R50.
[0010] Advantageously, R3 will represent H, OR25, CHOHCH2OH, CHO, N3, NR26R27, CO2R28, CONR29R30, NR3COR39, (O (CH2) m0 (CH2) p) r (CH2) qR31, (NR32 (CH2) wNR33 (CH2 ) x) y (CH2) zR34 or ONR84R85; especially H, OR25, CHOHCH2OH, CHO, N3, NR26R27, CO2R28, CONR29R30, or (NR32 (CH2) wNR33 (CH2) x) y (CH2) zR34, with R25 to R34, R38, R39, R84 and R85 as defined previously and especially with: R 25 representing H or a group (C 1 -C 6) alkyl, especially H, R 26 and R 27 representing H or a group (C 1 -C 6) alkyl, aryl, aryl- (C 1 -C 6) alkyl or (C 1 -C 6) C6) alkyl-aryl, preferably H or a (C1-C6) alkyl group, or R26 and R27 together with the nitrogen atom carrying them, form a nitrogen heterocycle optionally substituted by a (C 1 -C 6) group alkyl, the heterocycle being in particular a 5- or 6-membered heterocycle optionally comprising, in addition to the nitrogen atom, another heteroatom chosen from oxygen and nitrogen, such as a piperidine, piperazine or morpholine group; or pyrrolidine, R28, R32, R33, R38 and R39 representing, independently of each other, H or a (C1-C6) alkyl, aryl, aryl (C1-C6) alkyl or (C1-C6) alkyl-aryl group , preferably H or a group (Ci-C 6) alkyl, R29 and R30 representing H or (C1-C6) alkyl, aryl, aryl (C1-C6) alkyl or (C1-C6) alkyl-aryl, preferably H or (C1-C6) alkyl, or R29 and R30 together with the nitrogen atom carrying them, form a nitrogen heterocycle optionally substituted by a (C 1 -C 6) alkyl group, the heterocycle being in particular a 5- or 6-membered heterocycle optionally comprising in addition to the nitrogen atom, another heteroatom selected from oxygen and nitrogen, such as piperidine, piperazine, morpholine or pyrolidine, and R31 representing H, OR35, NR36R37, ONR86R87, or a group (C1-C6) alkyl, aryl, aryl (C1-C6) alkyl or (C1-C6) alkyl-aryl, preferably H, OR35, or (C1-C6) alkyl, where R34 is H, OR35, NR36R37 , ONR86R87, or (C1-C6) alkyl, aryl, aryl- (C1-C6) alkyl or (C1-C6) alkyl-aryl, preferably H, NR36R37 or (C1-C6) alkyl, and R35 at R37 and R84 to R87 being as previously defined and either advantageously H or a (C 1 -C 6) alkyl group.
[0011] Another particularly preferred class of compounds is R 1 R 2, R 1 compounds of formula (I) wherein the unit is: ## STR2 ## -64 -66 SSR 0 R71 S 0 R69 '-t r'sN /) - NN R68 N R70 R72 with: R60, R61, R65, R67, R68, R72 and R75 representing, independently of each other, H or (C 1 -C 6) alkyl, aryl or aryl (C 1 -C 6) alkyl, especially H or (C 1 -C 6) alkyl, preferably H, R 69 and R 70, independently of one of other, H or (C1-C6) alkyl, aryl or aryl (C1-C6) alkyl, or together with the nitrogen atom carrying them, a nitrogenous heterocycle optionally substituted with a (CiC6) group alkyl, R62, R63, R64, R66, R71, R73 and R74 representing, independently of each other, H or (C1-C6) alkyl, aryl, aryl (C1-C6) alkyl, OR76, SR77 or NR78R79 and R76 to R79, independently of one another, represent H or (C 1 -C 6) alkyl, RY, arY1- (C1-C6) alkyl, or CN, or R78 and R79 together with the nitrogen atom carrying them, a nitrogenous heterocycle optionally substituted by a (C1-C6) alkyl group. The nitrogenous heterocycle will advantageously be a 5- or 6-membered heterocycle optionally comprising, in addition to the nitrogen atom, another heteroatom chosen from oxygen and nitrogen, such as a piperidine, piperazine, morpholine or pyrrolidine. ## STR2 ## Preferably R69 and R70 represent, independently of one another, H or a (C 1 -C 6) alkyl, aryl or aryl group (C 1 -C 6). C6) alkyl, especially H or a (CiC6) alkyl group, in particular H. Advantageously, R62, R63, R64 and R66 represent, independently of each other, H or a (C1-C6) alkyl group, OR76, SR77 or NR78R79, especially a group OR76, SR77 or NR78R79. Advantageously, R 71, R 73 and R 74 represent, independently of each other, H or a (C 1 -C 6) alkyl, aryl, aryl (C 1 -C 6) alkyl group, in particular H or a (C 1 -C 6) alkyl group, in particular H.
[0012] According to a particular embodiment, when = represents a single bond, then R1 and R2 are located on the same side of the cyclopentane ring to which they are bonded, and preferably on the opposite side to the OH, phenyl and m-Rb-p-Ra groups. -phenyl also linked to this cyclopentane nucleus.
[0013] Advantageously, R3 will represent H, OR25, CHOHCH2OH, CHO, N3, NR26R27, CO2R28, C ONR29R30, NR3COR39, (O (CH2) m0 (CH2) p) r (CH2) qR31, or (NR32 (CH2) wNR33 (CH2) X) 5, (CH2) zR34, or ONR84R85; especially H, OR25, CHOHCH2OH, CHO, N3, NR26R27, C 02R28, CONR29R30, or (NR32 (CH2) wNR33 (CH2) x) y (CH2) zR34, with R25 to R34, R38, R39, R84 and R85 such that defined above and in particular with: R 25 representing H or a (C 1 -C 6) alkyl group, in particular H, R 26 and R 27 representing H or a (C 1 -C 6) alkyl, aryl, aryl (C 1 -C 6) alkyl or (Ci -C6) alkyl-aryl, preferably H or a group (C1-C6) alkyl, or R26 and R27 together with the nitrogen atom which carries them, a nitrogenous heterocycle optionally substituted by a group (Ci-C6) ), the heterocycle being in particular a 5- or 6-membered heterocycle optionally comprising, in addition to the nitrogen atom, another heteroatom chosen from oxygen and nitrogen, such as a piperidine or piperazine group, morpholine or pyrolidine, wherein R28, R32, R33, R38 and R39 represent, independently of one another, H or (C1-C6) alkyl, aryl, aryl (C1-C6) alkyl or (C1-C6) alkyl- aryl, preferably H or a group C6) alkyl, R29 and R30 representing H or (C1-C6) alkyl, aryl, aryl (C1-C6) alkyl or (C1-C6) alkyl-aryl, preferably H or (C1-C6) alkyl, or R29 and R30 together with the nitrogen atom carrying them, form a nitrogen heterocycle optionally substituted by a (C 1 -C 6) alkyl group, the heterocycle being in particular a 5- or 6-membered heterocycle optionally comprising in addition to the nitrogen atom, another heteroatom selected from oxygen and nitrogen, such as piperidine, piperazine, morpholine or pyrolidine, and R31 representing H, OR35, NR36R37, ONR86R87, or a group (C1-C6) alkyl, aryl, aryl (C1-C6) alkyl or (C1-C6) alkyl-aryl, preferably H, OR35, or (C1-C6) alkyl, where R34 is H, OR35, NR36R37 , ONR86R87, or (C1-C6) alkyl, aryl, aryl- (C1-C6) alkyl or (C1-C6) alkyl-aryl, preferably H, NR36R37 or (C1-C6) alkyl, and R35 at R37 and R84 to R87 being as defined above and represents preferably H or a (C 1 -C 6) alkyl group.
[0014] The compounds of the present invention may be chosen from compounds 1 to 55, exemplified hereinafter, in the form of one of their enantiomers or a mixture of their enantiomers, such as a racemic mixture, and the salts and / or pharmaceutically acceptable solvates thereof.
[0015] The present invention also relates to a compound according to the invention of formula (I) as defined above, for its use as a medicament, in particular for the treatment of cancer. The present invention also relates to the use of a compound of formula (I) as defined above, for the manufacture of a medicament, in particular for the treatment of cancer. The present invention also relates to a method of treating cancer, comprising administering to a person in need of an effective dose of a compound of formula (I) as defined above. The cancer may be more particularly in this case colon cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, glioblastoma, lung cancer-non-cancer. with small-cell, neuroblastoma, inflammatory myofibroblastic tumor, diffuse B-cell lymphoma or large-cell anaplastic lymphoma. The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined above, and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions according to the invention can be formulated especially for oral administration or by injection, said compositions being intended for mammals, including humans. The active ingredient can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to animals or humans. The compounds of the invention as active ingredients can be used at doses of between 0.01 mg and 1000 mg per day, given as a single dose once a day or administered in several doses throughout the day, for example twice a day in equal doses. The dose administered per day is advantageously between 5 mg and 500 mg, more advantageously between 10 mg and 200 mg. It may be necessary to use doses out of these ranges which the skilled person can realize himself. The pharmaceutical compositions according to the invention may also comprise at least one other active ingredient, such as an anticancer agent.
[0016] The present invention also relates to a pharmaceutical composition comprising: (i) at least one compound of formula (I) as defined above, and (ii) at least one other active ingredient, such as an anticancer agent, in as a combination product, for simultaneous, separate or spread use over time. The present invention also relates to a pharmaceutical composition as defined above for its use as a medicament, in particular for the treatment of cancer. The present invention also relates to a method of treating cancer, comprising administering to a person in need of an effective dose of a pharmaceutical composition as defined above.
[0017] The present invention also relates to processes for preparing the compounds of formula (I) according to the invention. A first process for the preparation of a compound of formula (I) according to the invention for which R3 = H comprises the reaction of a compound of formula (II) below: HO Rb Ra (II) for which Ra, Rb, R1 , R2 and R4 are as defined above, with an alcohol of formula H- (CH2), OH, for which n is as defined above, under Mitsunobu conditions. Such a reaction can be carried out in the presence of DEAD (diethyl azodicarboxylate) or DMEAD (bis (2-methoxyethyl) azodicarboxylate) and PPh3. A second process for preparing a compound of formula (I) according to the invention for which R3 = N3, NR38COR39 or NR26R27 comprises: (a1) to obtain a compound of formula (I) for which R3 = N3, the reaction of a compound of formula (III) below: LG1 Rb Ra (III) for which Ra, Rb, R1, R2, R4 and n are as defined above and LGi 20 represents a leaving group such as a halogen atom or an activated hydroxyl function, with an azide of formula MI 13, M representing an alkali metal or a group SiRR'R "with R, R 'and R" each representing, independently of one another, a group (C 1 -C 6) ) alkyl or aryl, (1) 1) to obtain a compound of formula (I) for which R3 = NH2, the reduction of the azide function of a compound of formula (I) for which R3 = N3 optionally obtained according to step (a1), (cl) to obtain a compound of formula (I) for which R3 = NR38COR39 or NR26R27 and at least one of R26 and R27 does not represent an atom of hyd the substitution of a compound of formula (I) for which R3 = NH2 optionally obtained according to step (1) 1). Step (a1a): For the purpose of the present invention, the term "leaving group" means a chemical group that can be easily displaced by a nucleophile during a nucleophilic substitution reaction, the nucleophile being in this case an azide. . Such a leaving group may be more particularly a halogen atom such as a chlorine or bromine atom or a sulfonate. The sulfonate may in particular be a group -SO 2 -R 90 with R 90 representing a (C 1 -C 6) alkyl, aryl, aryl- (C 1 -C 6) alkyl or (C 1 -C 6) alkyl-aryl group, said group being optionally substituted with one or several halogen atoms such as fluorine atoms. The sulphonate may be in particular a mesylate (-SO (O 2) -CEl), a triflate (-OS (O) 2-CF 3) or a tosylate (-SO (O) 2- (p-Me-C 6 H 4)) . The leaving group may also be an activated alcohol (OH) function in the presence of, for example, DPPA (diphenylphosphine azide) and DBU (1,8-diazabicyclo [5,44] undec-7-ene). The alkali metal may in particular be Na, K or Li .R, R 'and R "will each be, independently of one another, a methyl or phenyl group, especially methyl, M will in particular represent Na or SiMe3.
[0018] Step (b1): The azide reduction step may in particular be carried out in the presence of hydrogen. A hydrogenation catalyst such as palladium on carbon may be used. Step (cl): When R3 = NR26R27, the substitution of the amine function can be carried out by methods well known to those skilled in the art, in particular by a nucleophilic substitution reaction in the presence of R26La4 and / or R27LG5 where Lat and LG5 represent each, independently of each other, a leaving group. Such a reaction is advantageously carried out in the presence of a base. When R26 and R27 do not represent a hydrogen atom, two successive reactions can be carried out in order to successively introduce the groups R26 and R27. When NR38COR39, this step can be carried out by methods well known to those skilled in the art, for example by peptide coupling or by using acyl chlorides of formula R39COC1.
[0019] A third process for preparing a compound of formula (I) according to the invention, for which R3 = CHOHCH2OH, CHO, CO2R28, CONR29R30, OR25, (O (CH2) .O (CH2) p) r (CH2) ( 1R31, NR26R27 or (NR32 (CH2) wNR33 (CH2) x) y (CH2) zR34, comprises: (a2) to obtain a compound of formula (I) for which R3 = CHOHCH2OH, the dihydroxylation reaction of the vinyl function of a compound of the following formula (IV): ## STR1 ## for which Ra, Rb, R1, R2, R4 and n are as defined above, (b2) to obtain a compound of formula (I) for which R3 = CHO, the oxidative cleavage of the CHOHCH2OH group of a compound of formula (I) for which R3 = CHOHCH2OH optionally obtained according to step (a2), (c2) to obtain a compound of formula (I) for which R3 = CO2H the oxidation of the aldehyde function of a compound of formula (I) for which R3 = CHO optionally obtained according to step (b2), (d2) to obtain a compound of formula (I) for which R3 = CO2R28 and R28 H, the substitution of the funct carboxylic acid ion of a compound of formula (I) for which R3 = CO2H optionally obtained according to step (c2), (e2) to obtain a compound of formula (I) for which R3 = CONR29R30, the reaction of a compound of formula (I) for which R3 = CO2R28, optionally obtained according to step (b2) or (c2), with an amine of formula HNR29R30, (f2) to obtain a compound of formula (I) for which R3 = OH the reduction of the aldehyde function of a compound of formula (I) for which R3 = CHO optionally obtained according to step (b2), (g2) to obtain a compound of formula (I) for which R3 = OR25 or ( 0 (CH 2) 1110 (CH 2) p) r (CH 2) q R 31, NR 26 R 27 with R 25 H, the substitution of the hydroxyl function of a compound of formula (I) for which R 3 = OH optionally obtained according to step (f 2) (h2) to obtain a compound of formula (I) for which R3 = NR26R27, the reductive amination of the aldehyde function of a compound of formula (I) for which R3 = CHO, optionally obtained according to step (b2), in the presence of an amine of formula HNR26R27. Step (a2): Such a reaction can be carried out in particular in the presence of 0504 and NMO (4-methylmorpholine N-oxide). Step (b2): This reaction can be carried out in particular in the presence of NaIO4. Step (c2): The oxidation conditions are well known to those skilled in the art. Step (d2) or (g2): Such a reaction may be performed under nucleophilic substitution conditions well known to those skilled in the art. The carboxylic acid function may be activated beforehand, in particular in the form of acyl chloride or anhydride. Similarly, the alcohol function may be converted into a leaving group such as a halogen atom or a sulfonate, for example. Step (e2): Such a reaction may be carried out under peptide coupling conditions or by nucleophilic substitution after activation of the carboxylic acid function, especially in the form of acyl chloride or anhydride. Step (f2): The reduction conditions are well known to those skilled in the art. NaBH4 may especially be used as a reducing agent.
[0020] Step (h2): The reductive amination conditions are well known to those skilled in the art. Such a reaction can be carried out in the presence of NaBHOAc3 as reducing agent. the invention, for which R1 represents a fourth process for the preparation of a compound of formula (I) according to N -R 2, R 4, R 4, R 2, R 3, R 4 and R 4 are as defined above, with: (1) a cyanogen of formula Hal-CN, for which Hal represents a R4 (halogen atom such as Br, or an isothiocyanate of formula, especially in the presence of a base such as NaHCO3 optionally followed by one or more reactions of a compound of the following formula (V): R 4 R 10 R 9 R 11 NH-NH 2 (V) several substitution steps to give a compound of formula (I) for N 'N --NR 46 R 47 which R 1 represents II-O, or compound of formula (I) for which R 1 represents "lt °", or carbonyldiimidazole in the presence of a base such as triethylamine, optionally followed by one or more substitution steps to give a compound - NN 11 R44 of formula (I) for which R1 represents "lit0, or (4) a carboxylic acid of formula R42CO OH, wherein R42 is (C1-C6) alkyl, aryl or aryl (C1-C6) alkyl, in the presence of POC13 for N'N / - R42, giving a compound of formula (I) for which R1 represents "III-O, or NH R46 .N s_Alk (5) an isothiourea of formula R47, for which Alk represents a (C1-C6) alkyl group, in the presence of a base such as NaOH or KOH, optionally followed by one or more substitution steps to give a compound of formula (I) wherein R1 is - or NH NN, R46, R47, n, R40 Alk (6) an imidate of formula R 41 O, wherein R 41 is (C 1 -C 6) alkyl, aryl or aryl (C 1 -C 6) alkyl and Alk is (C 1 -C 6) alkyl, in the presence of a base such as triethylamine, followed by optionally one or (2) carbon disulfide (CS2) in the presence of a base such as NaOH or KOH, optionally followed by one or more substitution steps to give an N'N 11._. S R45 (3) several substitution steps to give a compound of formula (I) for N 'N -R41) 12. wherein R1 represents R40, or (7) triethyl orthoformate optionally followed by one or more substitution steps to give a compound of formula (I) for which R1 represents NNN The reaction conditions of these various reactions are well known to man of the art and are generally exemplified in the experimental part below. The same is true of substitution reactions.
[0021] When R1 represents R40 with R41 = H, the compound of formula (I) according to the invention may be prepared by reaction of a compound of formula (I) for which R1 = CONH2 with dimethylformamide dimethylacetate, then reaction of product obtained with hydrazine. When R1 represents R40 with R41 = OR44, the compound of formula (I) according to the invention may be prepared by reaction of a compound of formula (I) for N / LI -NH2, which R1 = by rearrangement of amino-oxadiazole in the presence of KOH and R440H alcohol.
[0022] N Z.41 When R1 represents R40 with R41 = SR45, the compound of formula (I) according to the invention may be prepared by reaction of a compound of formula (I) for which R1 = COOH with a thiosemicarbazide.
[0023] A fifth process for the preparation of a compound of formula (I) according to the invention, for which R1 represents `, 1% N, comprises the reaction of a compound of formula (I) with R1 = CO2R10 and R10 represents a (C1-C6) alkyl, N, OH group with a hydroxy-imidamide of formula R43 NH in the presence of a base such as K2CO3.
[0024] The reaction conditions of such a reaction are exemplified in the present patent application. A sixth process for the preparation of a compound of formula (I) according to the invention, for which 1 is O, comprises the reaction of a compound of formula (I). , for which = represents a double bond, R1 = CO2R10, R2 = OH, R4 = H and R10 = (C1-C6) alkyl, with a hydrazine of formula H2N-NH2, optionally followed by one or more substitution steps. The reaction conditions of such a coupling reaction with hydrazine are exemplified in the present patent application, and one skilled in the art knows how to carry out a substitution reaction.
[0025] A seventh process for the preparation of a compound of formula (I) according to the invention, for which R 1 represents R 63, comprises the reaction of a compound of formula (VI) below: Rb (VI) for wherein Ra, Rb, R3 and n are as defined above, and Rgo and R81 represent, independently of one another, a (C1-C6) alkyl, NH group with a guanidine derivative of formula H2 N R62 The reaction conditions of such a coupling reaction with a guanidine derivative are exemplified in the present patent application. the invention, for which a compound of rrss OH / N represents R64 formula (I) according to R65 ç-sss NR OR 66 An eighth process of preparation comprises the reaction of a compound of formula (VII) below: Alk Rb Ra (VII) for which Ra, Rb, R3 and n are as defined above, Alk represents a (C1-C6) alkyl group, and R82 represents R64 or R66, with: (1) the hydroxylamine of formula HO -NH2 in the presence of a base such as triethylamine, to give a compound of formula (I) for which OH represents R64, or (2) a hydrazine of formula H2N-NH2, followed by optionally one or more substitution steps to give a compound of formula (I) for which R 1 represents X66. The reaction conditions of these coupling reactions are exemplified in the present patent application. The person skilled in the art also knows how to implement a substitution reaction.
[0026] A ninth process for the preparation of the invention, for which a compound of formula (I) according to formula (I) represents R67 OR 0 R73 R74, sr% .-. N , O R75, comprises the reaction of a compound of formula (VIII) as follows: Ra, Rb, R3 and n are as defined above, and R83 represents a CO2H group optionally under an activated form, with: (1) an azide, under Curtius rearrangement conditions, optionally followed by one or more substitution steps, to give a compound of formula (I) for which `1 -. = '4- Rireprésente, or LG2 R73 ........., (2) an amine of formula HNR 2 R74, for which LG2 represents a leaving group such as a halogen, in the presence of a base such that the diisopropylethylamine (DIEA), optionally followed by one or more substitution steps, to give a compound of formula (I) for which rser 0 R73 R74 represents 0 R75 The Curtiu rearrangement s of step (1) is a reaction well known to those skilled in the art. It may be carried out especially in the presence of diphenylphosphoryl azide (DPPA) and a base such as triethylamine. The compound (VIII) bears more particularly a group R 83 = COOH. The reaction conditions of step (2) and any subsequent substitution reactions are well known to those skilled in the art.
[0027] A tenth process for the preparation of a compound of the formula (I) of the invention, for which: ## STR1 ## comprises the reaction of a compound of formula (I), for which represents a single bond, R1 = NH2, R2 = OH and R4 = H, with: (1) carbon disulfide (CS2) in the presence of a base such as sodium carbonate, optionally followed by one or more substitution steps, for to give a compound of formula (I) for which, or (2) a cyanogen of formula Hal-CN, for which Hal represents a halogen atom such as Br, in the presence of a base such as NaHCO3, optionally followed by one or more substitution steps, to give a compound of formula (I) for which i represents AIL (3) an ester of formula OO, for which Alk represents a (C 1 -C 6) alkyl group and LG 3 represents a leaving group such as a halogen atom such as Cl, in the form of sence of a base such as NaH, optionally followed by one or more substitution steps, to give a compound of formula (I) to R4 0 R71 rssi. Wherein the reaction conditions of these steps and any subsequent substitution reactions are known to those skilled in the art.
[0028] The compounds of formulas (II) to (VIII) may be prepared by methods described in the prior art or in the present patent application. The compound of formula (I) obtained by one of the processes mentioned above may be separated from the reaction medium by methods that are well known to those skilled in the art, for example by extraction, evaporation of the solvent or by precipitation. and filtration. The compound may be further purified if necessary by techniques well known to those skilled in the art, such as by recrystallization if the compound is crystalline, by distillation, by column chromatography on silica gel or by high performance liquid chromatography (HPLC ). The examples which follow illustrate the invention without, however, limiting its scope.
[0029] EXAMPLES 1- Synthesis of the compounds according to the invention The following abbreviations were used in the following examples: ES: Electrospray HPLC: high performance liquid chromatography HRMS: High resolution mass spectrum LCMS: liquid chromatography coupled to an NMR mass spectrometer: Nuclear Magnetic Resonance TA: Ambient Temperature The names of the compounds according to the present invention were assigned by Autonom. 1.1. Compounds with R1 = CO2Me, CO2H or CONH2 and R2 = OH The compounds according to the invention can be synthesized according to the following reaction scheme: Ni / Raney, H2MeOH, NH4OH (a) Procedure for the phenol substitution reaction (Example R = CO2Me, R2 = OH, n = 3, alcohol = 4-chloro-1-butanol): In a 1-liter flask, dissolve rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 1, 6,8-trihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] b-enzo furan-2-carboxyl ate (R 1 = CO2Me, R 2 = OH, 10.25 g, 21.42 mmol) in 200 ml of toluene and then add 4-chloro-butanol (12.57 ml, 107 mmol) and PPh 3 (28.1 g, 107 mmol). At 0 ° C. and under nitrogen, add dropwise bis (2-methoxyethyl) azodicarboxylate (DMEAD, 8.1 g, 120 mmol) dissolved in 155 ml of toluene. Leave to stir at 0 ° C for 10 min then at room temperature for 4h30. Add a little water and then extract twice with ethyl acetate, wash once with H2O / NaCl and then dry the organic phases over MgSO4, filter and evaporate under reduced pressure. The orange oil obtained is taken up in diethyl ether, a white precipitate is formed, the white solid is removed by filtration and the filtrate is evaporated. The residue is purified on silica gel using 80/20 to 50/50 cyclohexane / AcOEt as eluent. NaHCO3 (d) NaBCOAc3 HNRaRb (h) OR Ammonium 1. DBU, DPPA 2. NaN3 DMF HO (e) X = CN R2 0H - 30 R2 ^ 0H PPh3 0H DMEAD R2 HO -1 (a) n 0 PPh3 DMEAD / X 4), OH (a) "n (b) Procedure for the dihydroxylation reaction (example R 1 = CO2Me, R 2 = OH, n = 3): A solution of rac-methyl ( 1R, 2R, 3S, 3aR, 8bS) -1,8b-dihydroxy-8-methoxy3- (4-methoxyphenyl) -6- (p ent-4-en-1-yloxy) -3-phenyl-2,3 , 3a, 8b-tetrahydro-1Hcyclopenta [b] benzofuran-2-carboxylate (1.4g, 2.56mmol) in tetrahydrofuran (THF, 17mL), under argon, add 4-methylmorpholine N -oxide monohydrate (NMO, 0.535 g, 3.84 mmol) dissolved in water (2.5 mL) then osmic acid (3.24 mL, 0.512 mmol) Stir vigorously magnetically at room temperature for 1 hour Add a saturated solution of saturated NaHSO 3, extract with ethyl acetate twice, dry the organic phase over Na 2 SO 4, filter and then evaporate.The residue is purified on silica gel using as eluent a mixture CH2Cl2 / MeOH 95/5 to 80/20. (c) Procedure for the oxidative cleavage reaction (Example R 1 = CO2Me, R 2 = OH, n = 3): To a solution of rac-methyl (1R, 2R, 3S, 3aR, 8bS) -6 - ((4, 5-dihydroxypentyl) oxy) 1,8b-dihydroxy-8-methoxy-3- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate (102 mg, 0.176 mmol) in THF (1.5 mL) and water (1.5 mL), add sodium periodate (39 mg, 1.05 equiv) at 0 ° C, then let the medium return to room temperature and stir magnetically for 3 hours. Add water and dichloromethane (DCM), extract 3 times with dichloromethane and then with ethyl acetate. Dry the organic phases over Na 2 SO 4, filter and then evaporate. Use the raw product without further purification. (d) Procedure for the aldehyde reduction reaction (example R1 = CO2Me, R2 = OH, n = 3): In a flask, introduce rac-methyl (1R, 2R, 3S, 3aR, 8bS) -1, 8b dihydroxy-8-m-ethoxy-3- (4-methoxyphenyl) -6- (4-oxobutoxy) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2- carboxylate (2.66 g, 4.85 mmol) dissolved in methanol (50 mL), add NaBH4 (0.275 g, 7.27 mmol) and stir at room temperature for 1.5 hours. Add a solution of saturated NH4Cl (75 mL), concentrate and extract 3 times with ethyl acetate. Collect the organic phases, wash with NaCl and then dry over Na2SO4, filter and concentrate under reduced pressure. The residue is purified on silica gel using DCM / MeOH 80/20 as eluent. (e) Procedure for synthesizing the azide from the alcohol (example R1 = CO2Me, R2 = OH, n = 3): in the flask containing rac-methyl (1R, 2R, 3S, 3aR, 8bS) - 1,8b-dihydroxy-6- (4-hydroxybutyoxy) -8-methoxy-3- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8betrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate (1 g, 1.816 mmol), add tetrahydrofuran (8 mL). Lower the temperature to 0 ° C and add diphenylphosphoryl azide (DPPA, 0.866 mL, 4.00 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 0.706 mL, 4, 72 mmol). Allow to come to room temperature and stir magnetically for 1 hour. Evaporate the crude and then dilute with dimethylformamide (DMF, 20 mL), add the sodium azide (0.354 g, 5.44 mmol) and heat the mixture at 110 ° C for 5 hours. Evaporate the DMF under reduced pressure and purify the residue on silica gel using a CH 2 Cl 2 / AcOEt 100/0 to 85/15 mixture as eluent. (f) Procedure for the synthesis of azide from Chlorine (example R1 = CO2Me, R2 = OH, n = 3): in the flask containing rac-methyl (1R, 2R, 3S, 3aR, 8bS) -6- (4-chlorobutoxy) -1,8b-dihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8betaetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate (3.6 g, 6.34 mmol) add DMF (35 mL), add sodium azide (0.825 g, 12.69 mmol) and heat the mixture at 110 ° C for 5 hours. Evaporate the DMF under reduced pressure and purify the residue on silica gel using as eluent CH2Cl2 / AcOEt 100/0 to 85/15. (g) Azide reduction procedure (example Ri = CO2Me, R2 = OH, n = 3): In a 500 ml flask, dissolve rac- (1R, 2R, 3S, 3aR, 8bS) -methyl-6- ( 4-azidobutoxy) -1,8-dihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2 -carboxylate (3.65 g, 6.34 mmol) in ethanol (68 mL) and tetrahydrofuran (68.0 mL). Purge under nitrogen and then add the palladium on charcoal (1.350 g, 1.268 mmol) under nitrogen. Put the reaction medium under a hydrogen atmosphere and stir at room temperature for 3 hours. Filter the palladium on Dicalite® cake and then rinse with ethanol and THF, evaporate the filtrate under reduced pressure. The residue obtained is purified on silica gel using cyclohexane / AcOEt 30/70 and then CH 2 Cl 2 / MeOH / NH 4 OH (7 N in methanol) as eluent, 90/9/1. (h) Reductive amination procedure (example R1 = CO2Me, R2 = OH, n = 3): In a flask, introduce rac-methyl (1R, 2R, 3S, 3aR, 8b S) -1, 8b- dihydroxy-8-methoxy-3 - (4-methoxyphenyl) -6- (4-oxobutoxy) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclo [opal] benzofuran-2-carboxylate (0.050 g, 0.091 mmol) in solution in 1,2-dichloroethane (2 mL) and methanol (0.5 mL), add ammonium acetate (5 equiv) and then triacetoxyborohydride of sodium (2.0 equiv.), stir at room temperature for 18h. Add a saturated solution of NaHCO3 and then dilute with DCM, extract 2 times with DCM then collect the organic phases and wash with a saturated solution of NaCl, dry the organic phase over Na 2 SO 4, filter and concentrate under reduced pressure. The residue is purified on silica gel using a 90/10 DCM / MeOH mixture as eluent. (i) Nitrile reduction procedure (example R1 = CO2Me, R2 = OH, n = 3): In a hydrogen bomb, mix Raney nickel (100 mg, 0.852 mmol), rac- (1R, 2R, 3). S, 3 aR, 8b S) -methyl-6- (3-cyanopropoxy) -1,8-dihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3 a, 8b-tetrahydro-1H-cyclopenta [enzofuran-2-carboxylate (100 mg, 0.183 mmol) and 7N NH4OH in MeOH (5 mL) and some MeOH (= rinsing equipment used). The mixture is placed under a hydrogen atmosphere and stirred at room temperature for 18 hours. Filter on an acrodisc® 0.45 μm and then rinse well with methanol, evaporate, a white solid is obtained (m = 101 mg, quantitative yield). The compounds obtained by these various processes are characterized below. Compound 1 rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 6- (2,3-dihydroxypropoxy) -1,8b-dihydroxy-8-methoxy-3 - (4-methoxyphenyl) -3-phenyl-2 , 3,3a, 8b-tetrahydro-1Hcyclopenta [b] benzofuran-2-carboxylate 0 HO HO * Ho. 0- OH ° White solid, 30.1 mg (31%); obtained from rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 1,6,8b-trihydroxy-8-methoxy-3- (4-methoxyphenyl) -3-phenyl-2,3, 3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate following the procedure for substituting phenol with prop-2-en-1-ol as the alcohol, followed by the dihydroxylation procedure.
[0030] 1 H NMR (CDCl 3, 400 MHz, δ, ppm): 7.10 (d, 2H, J = 8.6 Hz), 7.06 (m, 3H), 6.87 (m, 2H), 6.67 ( d, 2H, J = 8.6 Hz), 6.29 (s, 1H), 6.15 (s, 1H), 5.02 (d, 1H, J = 6.5 Hz), 4.30 (b.p. d, 1H, J = 14.1Hz), 4.11 (m, 1H), 4.05 (m, 2H), 3.90 (dd, 1H, J = 6.6Hz, 14.1Hz) , 3.84dd, 1H, J = 3.6Hz, 11.7Hz), 3.78 (s, 3H), 3.73 (m, 1H), 3.70 (s, 3H), 3.64 (s, 3H); LCMS (ES +, m / z): 534.93 [M-OH] +; LCMS (ES-, m / z): 596.83 [M + HCOOT. Compound 2 rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 6- (2-aminoethoxy) -1,8b-dihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3 , 3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate C) I-12NOH O. OH ° White solid, 16 mg (66%); obtained from rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 1,6,8b-trihydroxy-8-methoxy-3- (4-methoxyphenyl) -3-phenyl-2,3, 3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate following the procedure for substituting phenol with 2-chloroethan-1-ol as the alcohol, followed by the procedures for synthesizing and reducing the azide. 1 H NMR (CDCl 3, 400 MHz, δ, ppm): 7.12 (d, 2H, J = 8.7 Hz), 7.05 (m, 3H), 6.83 (m, 2H), 6.67 ( d, 2H, J = 8.7 Hz), 6.20 (d, 1H, J = 1.6 Hz), 6.10 (d, 1H, J = 1.6 Hz), 5.02 (d, 1H, J = 6.7 Hz), 4.26 (d, 1H, J = 14.1 Hz), 3.84 (m, 6H), 3.71 (s, 3H), 3.63 (s, 3H), 2.87 (m, 2H); LCMS (ES +, m / z): 503.97 [M-OH] +; LCMS (ES-, m / z): 565.87 [M + HC001-. Compound 3 rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 6 - ((4,5-dihydroxypentyl) oxy) -1,8b-dihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3- phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate HO 0.10 1-10 O, OH0 0, White solid, obtained from (1R, 2R, 3S, 3aR, 8bS) -methyl 1,6,8b-trihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H cyclop enta [1)] benzofuran-2-carboxylate following the phenol substitution procedure with pent-4-en-1-ol as the alcohol, followed by the dihydroxylation procedure. 1 H NMR (CDCl 3, 400MHz, δ, ppm): 7.05 (m, 5H), 6.84 (m, 2H), 6.63 (m, 2H), 6.23 (d, 1H, J = 1, 4 Hz), 6.09 (d, 1H, J = 1.4 Hz), 4.99 (d, 1H, J = 6.7 Hz), 4.25 (d, 1H, J = 14.1 Hz). ), 3.96 (m, 2H), 3.86 (m, 1H), 3.82 (s, 3H), 3.65 (s, 3H), 3.62 (s, 3H), 3.51; (dd, 1H, J = 2.8 Hz, 11.2 Hz), 3.32 (dd, 1H, J = 7.6 Hz, 11.2 Hz), 1.84 (m, 2H), 1, 51 (m, 2H); LCMS (ES +, m / z): 563.0 [M-OH] +; LCMS (ES-, m / z): 625.0 [M + HCOOT. Compound 4 rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 1,8b-dihydroxy-8-methoxy-3α- (4-methoxyphenyl) -6- (4-oxobutoxy) -3-phenyl-2,3 , 3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate 0-0OH White solid; obtained from compound 3 following the oxidative cleavage procedure. 1 H NMR (CDCl 3, 400MHz, δ, ppm): 9.80 (s, 1H), 7.06 (m, 5H), 6.85 (m, 2H), 6.64 (m, 2H), 6.23. (d, 1H, J = 1.7 Hz), 6.08 (d, 1H, J = 1.7 Hz), 5.00 (d, 1H, J = 6.7 Hz), 4.27 (d. , 1H, J = 14.1 Hz), 3.99 (t, 2H, J = 6.1 Hz), 3.87 (dd, 1H, J = 6.7 Hz, 14.1 Hz), 3, 84 (s, 3H), 3.67 (m, 1H), 3.66 (s, 3H), 3.62 (s, 3H), 2.64 (dd, 2H, J = 6.7 Hz, , 2 Hz), 2.10 (m, 2H); LCMS (ES +, m / z): 530.98 [M-OH] +; LCMS (ES-, m / z): 592.97 [M + HCOOT. Ho compound 5 rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 1,8b-dihydroxy-6- (4-hydroxybutoxy) -8-methoxy-3a- (4-methoxyphenyl) -3-phenyl-2 3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate C) White foam, 1.72 g (64%); obtained from compound 4 following the reduction procedure. 1 H NMR (DMSO-D6, 400M1-1z, δ, ppm): 7.02 (m, 5H), 6.87 (d, 1H, J = 7.4Hz), 6.58 (d, 2H, J); = 8.7 Hz), 6.26 (s, 1H), 6.09 (s, 1H), 5.07 (s, 1H), 5.02 (d, 1H, J = 5.0 Hz), 4.68 (t, 1H, J = 5.0 Hz), 4.47 (t, 1H, J = 5.0 Hz), 4.13 (d, 1H, J = 14.0 Hz), 4, 00 (t, 2H, J = 6.5 Hz), 3.91 (dd, 1H, J = 5.0 Hz, 14.0 Hz), 3.73 (s, 3H), 3.60 (s, 3H), 3.54 (s, 3H), 3.47 (m, 2H), 1.75 (m, 2H), 1.58 (m, 2H); LCMS (ES +, m / z): 532.97 [M-OH] +; LCMS (ES-, m / z): 594.99 [M + HCOOT.
[0031] Compound 6 rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 6- (4 - ((3 - ((4 - ((3-aminopropyl) amino) butyl) amino) propyl) amino) butoxy) -1 8b-dihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate, hydrochloric acid is 0 NH 2 N White solid, 20 mg (66%); obtained from compound 4 by following the reductive amination procedure using tert-butyl (44 (3-aminopropyl) (tertbutoxycarbonyl) amino) butyl) (3 - ((tert-butoxycarbonyl) amino) propyl) carbamate as amine . The final deprotection is carried out according to the conditions described in [J. Org.
[0032] Chem. 2006, 71, 9045-9050]. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.03 (m, 5H), 6.87 (m, 2H), 6.59 (m, 2H), 6.29 (s, 1H), 6.09 (s, 1H), , 11 (m, 1H), 5.09 (s, 1H), 4.70 (m, 1H), 4.12 (d, 1H, J = 14.4 Hz), 4.05 (m, 2H), 3.94 (dd, 1H, J). = 14.4 Hz, 5.8 Hz), 3.73 (s, 3H), 3.61 (s, 3H), 3.55 (s, 3H), 3.16 (m, 5H), 2.94 (m, 7H), 2.03-1.58 (m, 11H). ); HRMS: C41H59N4O8 [M + H] + calc. 735.4327 found 735.4335. Compound 7 rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 1,8b-dihydroxy-8-methoxy-6- (4-methoxy-4-oxobutoxy) -3a- (4-methoxyphenyl) -3-phenyl -2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate 0 White solid, 3.8 mg (7%); obtained from compound 4 by performing oxidation as follows: To a mixture of compound 4 (1 equiv) and 2-methyl-2-butene (4.5 equiv) in acetone (0.1 M) are added a solution of NaH2PO4 (3 equiv, 0.5 M) in water and then sodium chlorite (3 equiv.), the reaction mixture is stirred vigorously for 18 hours. The mixture is diluted with water and ethyl acetate, the pH of the aqueous phase is adjusted to 6 by addition of HCl (1N), the organic phase is then extracted and then dried over sodium sulfate, filtered. and concentrated to give the carboxylic acid as a white foam. This compound is dissolved in a mixture of methanol and toluene 1/1 (0.05 M) and then trimethylsilyldiazomethane is added (4 equiv), the reaction mixture is stirred for 18 hours at room temperature. The solvents are then evaporated and the residue is purified on silica gel.
[0033] 1 H NMR (CDCl 3, 400 MHz, δ, ppm): 7.12 (d, 2H, J = 8.7 Hz), 7.08 (m, 3H), 6.89 (m, 2H), 6.70 ( d, 2H, J = 8.7 Hz), 6.28 (d, 1H, J = 1.9 Hz), 6.14 (d, 1H, J = 1.9 Hz), 5.04 (d, 1H, J = 6.7 Hz), 4.32 (d, 1H, J = 14.1 Hz), 4.06 (t, 2H, J = 6.0 Hz), 3.92 (dd, 1H, J = 6.7 Hz, 14.1 Hz), 3.89 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H), 3.68 (m, 1H), 3. , 67 (s, 3H), 2.57 (m, 2H), 2.16 (m, 2H); LCMS (ES +, m / z): 561.0 [M-OH] +; LCMS (ES-, m / z): 622.9 [M + HC001-. Compound 8 rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 6- (4-aminobutoxy) -1,8b-dihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3 , 3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate H 2 N 0 - OH ° White solid, 45 mg (7%); obtained from compound 5 following the procedure for the synthesis of azide and then reduction of the azide, this compound can also be obtained from rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 1,6,8b-trihydroxy-8-m ethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [Wb enzofuran-2-carboxylate by following the procedure of substitution of phenol with 4-chlorobutan-1-ol as alcohol, then the procedures of synthesis and reduction of azide. This compound can also be obtained from rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 1,6,8b-trihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3-phenyl. 2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate following the phenol substitution procedure with 4-hydroxybutanenitrile followed by the nitrile reduction procedure. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.02 (m, 5H), 6.87 (m, 2H), 6.59 (d, 2H, J = 8.9Hz), 6.26. (d, 1H, J = 1.9 Hz), 6.10 (d, 1H, J = 1.9 Hz), 5.07 (bs, 1H), 5.01 (d, 1H, J = 4, 4 Hz), 4.68 (m, 1H), 4.14 (d, 1H, J = 14.1 Hz), 3.99 (t, 2H, J = 6.5 Hz), 3.91 (dd , 5.7 Hz, 14.1 Hz), 3.73 (s, 3H), 3.60 (s, 3H), 3.54 (s, 3H), 2.60 (t, 2H, J = 6. 5 Hz), 1.74 (m, 2H), 1.50 (m, 2H); LCMS (ES +, m / z): 550.0 [M + H] +; LCMS (ES-, m / z): 593.98 [M + HC001-. Compound 50 methyl (1R, 2R, 3S, 3aR, 8bS) -6- (4-aminobutoxy) -1,8b-dihydroxy-8-methoxy-3a- (4-methoxyphenyl) -3-phenyl-2 , 3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate 101 Beige solid, obtained from compound 8 by chiral separation by HPLC using a Chiralpak® IC 4.6 * 250mm DAICEL column using as eluent heptane / ethanol / BUA (butylamine) 50/50 / 0.05 mixture. NMR and mass identical to compound 8; ee 93%; [a] i) 2 ° = -54.0 ° (c 0.43 MeOH). Compound 51 methyl (1S, 2S, 3R, 3aS, 8bR) -6- (4-aminobutoxy) -1,8b-dihydroxy-8-methoxy-3 - (4-methoxyphenyl) -3-phenyl-2,3,3a , 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate 101H2N / HO OH ° Beige solid, obtained from compound 8 by chiral separation by HPLC using a Chiralpak®IC 4.6 * 250mm DAICEL column using as eluent a heptane / ethanol / BUA 50/50 / 0.05 mixture. NMR and mass identical to compound 8; ee 99%; [a] D2 ° = + 61.5 ° (c 0.47 MeOH). Compound 52 rac-methyl (1R, 2R, 3S, 3aR, 8bS) -6- (4- (dimethylamino) butoxy) -1,8b-dihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3- phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate O-, NO. White solid, m = 40.5 mg (38%); obtained from the chlorinated compound according to the following procedure: in a pillbox, mix rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 6- (4-chlorobutoxy) -1,8-dihydroxy-8-m ethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8betaetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate (100mg, 0.176mmol) in DMI (1.5mg); mL) and then add 40% dimethylamine in water (50 μl, 3.95 mmol). Heat at 90 ° C for 1 hour. Evaporate to dryness. A yellow oil is obtained. Purify on silica gel using 90/10 CH 2 Cl 2 / MeOH as eluent. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.01 (m, 5H), 6.86 (m, 2H), 6.58 (m, 2H), 6.28 (m, 1H), 6.10 (m, 1H), 5.07. (s, 1H), 5.045 (m, 1H), 4.68 (m, 1H), 4.13 (m, 1H), 4.02 (m, 2H), 3.91 (m, 1H), 3.73 (s, 3H), 3.59 ( s, 3H), 3.53 (s, 3H), 2.96 (m, 2H), 2.64 (s, 6H), 1.76 (m, 4H); LCMS (ES +, m / z): 578.05 [M + H] +; LCMS (ES-, m / z): 622.01 [M + HC001-.
[0034] Compound 53 rac- (1R, 2R, 3S, 3aR, 8bS) -6- (4-aminobutoxy) -1,8b-dihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3, 3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylic acid OH1H2NO-OH ° White solid, 366 mg (88%); obtained from compound 8: in a 20 ml flask, dissolve compound 8 (500 mg, 0.774 mmol) and K2CO3 (535 mg, 3.87 mmol) in methanol (5.00 mL) and water (5 mL) . Stir at 70 ° C. for 4 h 30, after returning to ambient temperature, the crude is evaporated and then the residue is purified on silica using as eluent a CH 2 Cl 2 / MeOH / Water: 50/50/4 mixture. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.02 (m, 5H), 6.89 (m, 2H), 6.58 (m, 2H), 6.28 (m, 1H), 6.07 (m, 1H), 4.98. (m, 2H), 4.65 (m, 1H), 4.09 (m, 1H), 4.02 (m, 2H), 3.73 (s, 3H), 3.59 (s, 3H), 2.88 (m, 2H), 1.74 (m, 1H), m, 4H); LCMS (ES +, m / z): 535.97 [M + H] +; LCMS (ES-, m / z): 533.87 [M-11] -. Compound 54 rac- (1R, 2R, 3S, 3aR, 8bS) -1,8b-dihydroxy-6- (4-hydroxybutoxy) -8-methoxy-3 - (4-methoxyphenyl) -3-phenyl-2,3, 3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxamide 0 NH 2 HO 2 H 6 O -H 2 O. White solid, 475 mg (99%); obtained from compound 5 by following the procedure for synthesizing the hydrazide (vacuum infra) and then the hydrazide obtained (490 mg, 0.890 mmol) is reduced by addition to a suspension of Raney nickel (313 mg, 2.67 mmol) in DMI (3 mL) and water (3 mL). The mixture obtained is heated at 100 ° C. for 1 hour 30 minutes. After returning to ambient temperature, the nickel is removed by filtration (AcOEt, CH 2 Cl 2, MeOH) and the filtrate is concentrated under reduced pressure. The residue is purified on silica gel using a 90/10 CH 2 Cl 2 / MeOH mixture as eluent.
[0035] 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.66 (s, 1H), 6.99 (m, 8H), 6.58 (m, 2H), 6.24 (s, 1H), 6.08 (s, 1H), 4.95 (s, 1H), 4.64 (d, 1H, J = 3.2 Hz), 4.54 (m, 1H), 4.69 (t, 1H). , J = 5.3 Hz), 4.14 (d, 1H, J = 14.0 Hz), 3.99 (m, 1H), 3.78 (dd, 1H, J = 5.3 Hz, , 0 Hz), 3.72 (s, 3H), 3.59 (s, 3H), 3.46 (m, 2H), 1.75 (m, 2H), 1.57 (m, 2H); LCMS (ES +, m / z): 536.03 [M + H] +. Compound 55 rac- (1R, 2R, 3S, 3aR, 8bS) -6- (4-aminobutoxy) -1,8b-dihydroxy-8-methoxy-3 - (4-methoxyphenyl) -3-phenyl-2,3, 3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxamide formate 0 White solid, 105 mg (42%): obtained from compound 54 following the procedure for synthesizing the azide from the alcohol then the procedure of reducing the azide. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 8.42 (s, 1H), 7.69 (s, 1H), 7.04 (m, 3H), 6.97 (m, 3H), 6.59 (d, 2H, J = 8.9 Hz), 6.27 (d, 1H, J = 1.9 Hz), 6.09 (d, 1H, J = 1.9 Hz), 4, 92 (bs, 1H), 4.66 (bs, 1H), 4.56 (d, 1H, J = 5.5 Hz), 4.15 (d, 1h, J = 14.3 Hz), 4, 01 (t, 2H, J = 6.0 Hz), 3.80 (dd, 1H, J = 6.0 Hz, 14.3 Hz), 3.73 (s, 3H), 3.61 (s, 3H), 2.82 (t, 2H, J = 7.5 Hz), 1.77 (m, 2H), 1.68 (m, 2H); LCMS (ES +, m / z): 535.02 [M + H] +; LCMS (ES-, m / z): 579.02 [M + HCOOT. 1.2. Compounds with RI NR'R "and R2 = OH The compounds according to the invention can be synthesized according to the following reaction scheme: KOH dioxane water (i) KOH MeOH water DPPA, Et3N (k) O (I) Ra OH 0 HO N-Rb 0 NH 2 H HO - - I. (j) Saponification procedure: In a 250 mL flask, introduce rac (1R, 2R, 3S, 3aR, 8b S) -methyl 1,8b-dihy 6-hydroxy-6-ethoxy-3- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclohexane [b] benzofuran-2-carboxylate ( 1.93 g, 3.92 mmol) in 24 mL of 1,4-dioxane Prepare a solution of potassium hydroxide (0.930 g, 16.58 mmol) in water (3 mL) and add to 0 ° C. in the reaction medium, allow to return to room temperature and stir at 60 ° C. for 4 hours, reduce the temperature of the medium to 0 ° C., then add water (5 mL) and acidify the medium with 1N HCl solution. until reaching a pH of 5. Extract the product with ethyl acetate (twice) Dry the organic phase over Na2SO4, filter and concentrate the medium The acid is obtained in quantitative yield (k) Curtius rearrangement procedure: In a pillbox and under nitrogen, introduce the carboxylic acid (200 mg, 0.418 mmol) in 10 mL of toluene. Add, at RT, diphenylphosphoryl azide (162 μl, 0.752 mmol) followed by triethylamine (58.1 μl, 0.418 mmol). Stir at 80 ° C for 7h and shake at RT overnight. Concentrate toluene. Take up the solid in water and rinse with ethyl acetate. The solid is not pure. Resume the solid in methanol, sonicate and filter. A white solid is recovered. In the case where the product does not precipitate, the residue is purified on silica gel. (1) Procedure for hydrolysis of oxazolidinone: In a flask, introduce rac (3 aR, 4R, 4 aR, 9b S, 9cR) -9b-hydroxy-7,9-dimethoxy-4α- (4-methoxyphenyl) 4-phenyl-3,3a, 4,4a, 9b, 9c-hexahydro-2H-benzofuro [3 ', 2': 3,4] cyclopenta [1,2-d] oxazol-2-one (1,45g) 3.05 mmol) in 6 mL of methanol. Add KOH at room temperature (1.027 g, 18.30 mmol) dissolved in water (3 mL). The medium is heterogeneous (white solid in suspension). The reaction medium is stirred at 75 ° C. for 72 hours. Evaporate the methanol then adjust the pH to 8 with saturated NH4Cl solution. A brown solid is still in suspension. Filter and rinse with water and then with diethyl ether and finally dry in vacuo to obtain the amine with a yield of 93%.
[0036] The compounds obtained by these various processes are characterized below. Compound 9 rac- (1R, 2R, 3R, 3aR, 8bS) -2-amino-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H- cyclopenta [b] benzofuran-1,8b-diol White solid, 44 mg (93%); obtained from compound 40 following the procedure of hydrolysis of the oxazolidinone. 1 H NMR (DMSO-D6, 4001 → 417, δ, ppm): 7.04 (m, 7H), 6.58 (d, 2H, J = 8.8 Hz), 6.21 (d, 1H, J); = 1.8 Hz), 6.08 (d, 1H, J = 1.8 Hz), 4.82 (s, 1H), 4.16 (d, 1H J = 4.7 Hz), 4.02 (dd , 1H, J = 4.7 Hz, 13.0 Hz), 3.76 (s, 3H), 3.74 (s, 3H), 3.60 (s, 3H), 3.54 (d, 1H). J = 13.0 Hz); LCMS (ES +, m / z): 450.0 [M + H] +; LCMS (ES-, m / z): 493.9 [M + HC001-. Compound 10 rac-N - ((1R, 2R, 3R, 3aR, 8bS) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b tetrahydro-1H-cyclopenta [b] benzofuran-2-yl) formamide Pale yellow solid, 134 mg (84%); obtained from compound 9 as follows: In a flask and under nitrogen, introduce rac- (1R, 2R, 3R, 3aR, 8b S) -2-amino-6,8-dimethoxy-3α- (4-methoxyphenyl) ) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [Wb enzofuran-1,8b-diol (50 mg, 0.111 mmol) in 1 mL of THF, add Ethyl formate (135. 1.669 mmol) and a drop of acetic acid. Stir at reflux for 18 hours. The solvents are evaporated, the solid obtained is taken up in ethanol. A solid precipitates, filter it and rinse it with ethanol. After drying under vacuum a light yellow solid is recovered. 1H NMR (DMSO-D6, 400MHz, δ, ppm): 8.00 (d, 1H, J = 9.4Hz), 7.96 (d, 1H, J = 1.4Hz), 7.01 ( m, 7H), 6.60 (d, 2H, J = 6.6Hz), 6.25 (d, 1H, J = 1.9Hz), 6.10 (d, 1H, J = 1.9). Hz), 5.19 (m, 1H), 5.10 (d, 1H, J = 4.9 Hz), 5.04 (s, 1H), 4.27 (t, 1H, J = 4.9; Hz), 3.93 (d, 1H, J = 13.9 Hz), 3.77 (s, 3H), 3.73 (s, 3H), 3.60 (s, 3H); LCMS (ES +, m / z): 460.0 [M-OH] +; LCMS (ES-, m / z): 522.1 [M + HCOOT.
[0037] Compound 11 rac-14 (1R, 2R, 3R, 3aR, 8bS) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro -1H-cyclopenta [b] benzofuran-2-yl) urea 0 / White solid, 22 mg (50%); obtained from compound 9 as follows: In a flask and under nitrogen, introduce rac- (1R, 2R, 3R, 3aR, 8bS) -2-amino-6,8-dimethoxy-3a- (4-methoxyphenyl) -3 -phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol (40 mg, 0.089 mmol) in a mixture of dichloromethane and propan-2-ol. Add, at ambient temperature, trimethylsilyl isocyanate (9.04 μl, 0.067 mmol). The environment is limpid. Stir at room temperature for 4 hours. Concentrate dry, take up the solid in a minimum volume of ethanol: filter the solid in suspension. After drying, a white solid is recovered. 1 H NMR (DMSO-D6, 4001 → 417, δ, ppm): 7.03 (m, 7H), 6.59 (d, 2H, J = 8.8 Hz), 6.24 (d, 1H, J); = 1.7 Hz), 6.09 (d, 1H, J = 1.7 Hz), 5.83 (d, 1H, J = 9.5 Hz), 5.53 (s, 2H), 5, 04 (m, 2H), 4.93 (s, 1H), 4.18 (m, 1H), 3.81 (m, 1H), 3.77 (s, 3H), 3.73 (s, 3H); ), 3.59 (s, 3H); LCMS (ES +, m / z): 492.9 [M + H] +; LCMS (ES-, m / z): 536.9 [M + HCOOT. Compound 12 rac-N4 (1R, 2R, 3R, 3aR, 8bS) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro -1H-cyclopentylbenzofuran-2-yl) methanesulfonamide O pale yellow solid, 1.8 mg (3%); obtained from compound 9 as follows: In a flask and under nitrogen, introduce rac- (1R, 2R, 3R, 3aR, 8bS) -2-amino-6,8-dimethoxy-3a- (4-methoxyphenyl) -3 -phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol (50 mg, 0.111 mmol) in 1.05 mL of dichloromethane, add at 0 ° C a mixture of N, N-diisopropylethylamine (DIEA, 29.1 μl, 0.167 mmol) and methanesulfonyl chloride (10.33 μl, 0.133 mmol). Stir at room temperature for 2 hours. Add 3 mL of 1N HC1. Extract the organic phase and then dry over MgSO 4, filter and concentrate the medium. Purify the residue on silica using as eluent a DCM / AcOEt 100/0 to 90/10 mixture. 1 H NMR (DMSO-D6, 4001 → 417, δ, ppm): 7.04 (m, 8H), 6.62 (m, 2H), 6.25 (m, 1H), 6.12 (m, 1H), 5.14 (m, 1H). , 5.08 (s, 1H), 4.56 (m, 1H), 4.45 (m, 1H), 3.80 (m, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.61 (s, 3H), 3.00 (s, 3H); LCMS (ES +, m / z): 509.9 [M-OH] +; LCMS (ES-, m / z): 525.9 [M-Hf.
[0038] Compound 13 rac-14 (1R, 2R, 3R, 3aR, 8bS) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro -1H-cyclopenta [b] benzofuran-2-yl) -3-methylthiourea 0 / Beige solid, 33 mg (58%); obtained from compound 9 as follows: In a flask, introduce rac- (1R, 2R, 3R, 3aR, 8b S) -2-amino-6,8-dimethoxy-3α- (4-methoxyphenyl) -3 -phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [enzofuran-1, 8b-diol (50 mg, 0.111 mmol) dissolved in tetrahydrofuran (2 mL). Add isothiocyanatethane (9.76 mg, 0.133 mmol) and stir at room temperature for 2 hours. Concentrate the reaction medium and then add diethyl ether. Precipitation is observed. Filter the solid and rinse with diethyl ether. 1H NMR (DMSO-D6, 400MHz, δ, ppm): 7.06 (m, 9H), 6.25 (m, 1H), 6.09 (m, 1H), 5.04 (m, 1H), 4.92 (s, 1H), 4 , 34 (m, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 3.60 (s, 3H), 2.53 (s, 3H); LCMS (ES +, m / z): 522.97 [M + H] +; LCMS (ES-, m / z): 521.0 [M-Hf.
[0039] Compound 14 rac-1- (3- (diethylamino) propyl) -34 (1R, 2R, 3R, 3aR, 8bS) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3- phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-yl) thiourea O / NH N 2 O brown solid, 3.9 mg (5 ° A); obtained from compound 9 following a procedure identical to that for synthesizing compound 13 using N, N-diethyl-3-isothiocyanatopropan-1-amine in place of isothiocyanatethane. LCMS (ES +, m / z): 622.1 [M + H] +; LCMS (ES-, m / z): 620.0 [M-F1] -.
[0040] Compound 15 rac- (1R, 2R, 3R, 3aR, 8bS) -6,8-dimethoxy-3α- (4-methoxyphenyl) -2- (methylamino) -3-phenyl-1,2,3,3a-tetrahydro- 8bH-cyclopenta 1131 benzofuran-1,8b-diol O- Brown solid, 3 mg (7 ° A); obtained from compound 40 as follows: in a flask and under nitrogen, introduce rac- (3aR, 4R, 4aR, 9bS, 9cR) -9b-hydroxy-7,9-dimethoxy-4a- (4-methoxyphenyl) -4 -phenyl-3,3,3,4,4a, 9b, 9c-hexahydro-2H-benzofuro [3,2 '3,4] cyclopenta [1,2-d] oxazol-2-one (43.4 mg, 0.091); mmol) in 1 mL of THF, add at 0 ° C, lithium aluminum hydride (15.31 μL, 0.365 mmol) and heat at 80 ° C for 3 hours. Add to 0 ° C 30! IL water. Stir at room temperature for 5 minutes. Then add 30 μl of 10% NaOH and then 100 μl of water. Stir at room temperature for 5 min. Filter through Dicalite® and rinse with THF and ethyl acetate, concentrate the filtrate. The residue is purified on silica gel using a DCM / MeOH mixture 100/0 to 80/20 as eluent.
[0041] NMR 1F1 (CD 3 OD, 400MHz, δ, ppm): 7.14 (m, 2H), 7.05 (m, 3H), 6.93 (m, 2H), 6.63 (m, 2H), 6.23 (m, 1h), 6.16 (m. , 1H), 4.65 (d, 1H), 3.85 (s, 3H), 3.83 (m, 1H), 3.81 (s, 3H), 3.67 (s, 3H), 3.63 (m, 1H), 2.46 (s, 3H); LCMS (ES +, m / z): 464.0 [M + H] +; LCMS (ES-, m / z): 507.9 [M + HC001-.
[0042] Compound 16 rac-N - ((1R, 2R, 3R, 3aR, 8bS) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b -tetrahydro-1H-cyclopenta [b] benzofuran-2-yl) acetamide Beige solid, 12 mg (23%); obtained from compound 9 as follows: In a flask, introduce rac- (1R, 2R, 3R, 3R, 8b S) -2-amino-6,8-dimethoxy-3a- (4-methoxyphenyl) -3 -phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol (50 mg, 0.111 mmol) dissolved in tetrahydrofuran (500 1.1.1). Cool to 0 ° C and add DIEA (38.9 μl, 0.222 mmol) and acetyl chloride (8.73 mg, 0.111 mmol), then allow to rise to room temperature and stir for 4 hours. Add water and ethyl acetate, combine the organic phases and wash with saturated NaCl solution, then with water, dry the organic phase over Na 2 SO 4 and concentrate. Triturate the crude in diethyl ether and filter the solid. LCMS (ES +, m / z): 491.9 [M + H] +; LCMS (ES-, m / z): 535.9 [M + HCOOT. Compound 17 rac- (1R, 2R, 3R, 3aR, 8bS) -2-amino-6- (4-aminobutoxy) -8-methoxy-3 - (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol, di-formic acid. 0 White solid, 1.2 mg (3%); obtained from compound 43 following the procedures for reducing the azide and then hydrolyzing the oxazolidinone.
[0043] 1 H NMR (CD 3 OD, 400 μM, δ, ppm): 8.51 (bs, 2H), 7.12 (m, 5H), 6.90 (m, 2H), 6.68 (m, 2H, J = 8); , 7 Hz), 6.28 (s, 1H), 6.20 (s, 1H), 4.74 (d, 1H, J = 5.9 Hz), 4.39 (dd, 1H, J = 5 , 9 Hz, 13.7 Hz), 4.06 (m, 2H), 3.89 (d, 1H, J = 13.7 Hz), 3.87 (s, 3H), 3.69 (s, 3H), 3.02 (m, 2H), 1.88 (m, 4H); LCMS (ES +, m / z): 506.89 [M + H] +; LCMS (ES-, m / z): 550.84 [M + HCOOT. 1.3. Compounds with R1 = Heterocycle and R2 = OH The compounds according to the invention can be synthesized according to the following reaction scheme: NH2NH2 EtOH (m) (ri) and (n1 0 HO HO NN 0 "-R (m) Synthesis procedure of hydrazide (Example n = 1, R3 = H): In a sealed tube, introduce rac- (1R, 2R, 3S, 3aR, 8b S) -methyl 1,8b-dihydroxy-6,8-dim ethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [2-enzofuran-2-carboxylate (2 g, 4.06 mmol) in Add the hydrazine hydrate (1.275 ml, 40.6 mmol) at 0 ° C. and stir at 80 ° C. for 24 hours.Concentrate the medium to dryness and then take the solid in ethanol. solid, rinse with cold ethanol and dry (n) Oxadiazole synthesis procedure (example n = 1, R3 = H, R = NH2): In a flask, introduce rac- (1R, 2R , 3S, 3aR, 8b S) -1,8b-dihydroxy-6,8-dimethoxy-3a- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro- 1H-cyclop enta [Wb enzofuran-2 carboh ydrazide (200 mg, 0.406 mmol) in 700 μl of 1,4-dioxane. Add, room temperature, NaHCO3 (34.1 mg, 0.406 mmol) and water (70 1.1.1). At 0 ° C., add cyanogen bromide (162 μl, 0.487 mmol) and then at room temperature for 5 hours. After concentrating the medium, add water, sonicate, a solid is in suspension. Solubilize the solid in ethyl acetate. Extract the organic phase and wash with saturated NaHCO3 solution. Dry the organic phase over Na 2 SO 4, filter and concentrate. Purify the residue on silica gel using DCM / MeOH 100/0 to 95/5 as eluent. (n ') Procedure for the synthesis of substituted amino-oxadiazole (example n = 1, R3 = H, R = NHMe): To a solution of rac- (1R, 2R, 3 S, 3aR, 8b S) -1.8b 1-hydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclohexylbenzofuran-2-carboxyhydrazide (40%). mg, 0.081 mmol) in tetrahydrofuran (1.5 mL) is added isothiocyanatomethane (7.54 mg, 0.103 mmol) then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (15.57 mg, 0.081 mmol) at 0 ° C. The mixture is stirred at 80 ° C for 18 hours. The reaction medium is concentrated and the residue obtained is purified on silica gel using as eluent a DCM / MeOH mixture 100/0 to 97/3. Compound 18 rac- (1R, 2R, 3S, 3aR, 8bS) -2- (5-amino-1,3,4-oxadiazol-2-yl) -6,8-dimethoxy-3α- (4-methoxyphenyl) - 3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol White solid, 99 mg (47%); obtained from the compound rac- (1R, 2R, 3S, 3aR, 8bS) -1,8bdihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3 a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carbohydrazide following the procedure for synthesizing the oxadiazole. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.02 (m, 5H), 6.86 (m, 2H), 6.73 (s, 2H), 6.60 (d, 2H, J = 8.9 Hz), 6.28 (d, 1H, J = 1.8 Hz), 6.11 (d, 1H, J = 1.8 Hz), 5.16 (s, 1H), 4.99. (d, 1H, J = 4.4 Hz), 4.61 (m, 1H), 4.26 (m, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3 , 60 (s, 3H); LCMS (ES +, m / z): 518.0 [M + H] +; LCMS (ES-, m / z): 516.0 [M-Hf. Compound 19 (1R, 2R, 3S, 3aR, 8bS) -2- (5-amino-1,3,4-oxadiazol-2-yl) -6,8-dimethoxy-3α- (4-methoxyphenyl) -3- phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol C) White solid, 205 mg (41%); obtained from compound 18 by chiral separation on HPLC using a Chiralpak® IC 4.6 * 250mm DAICEL column and as eluent Heptane / Ethanol / Methanol / diethylamine 80/10/10 / 0.05 LCMS (ES +, m / z) mixture : 518.0 [M + H] +; LCMS (ES-, m / z): 516.0 [M-Hf e.e. 96.7%; [ ] D2 ° = -27.7 (c 0.59 MeOH) Compound 20 rac- (1R, 2R, 3S, 3aR, 8bS) -2- (5-amino-1,3,4-oxadiazol-2) 1H-6- (2-hydroxyethoxy) -8-methoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol NI-12 White solid, 51 mg (51%); obtained from the compound rac-methyl (1R, 2R, 3S, 3aR, 8bS) -1,6,8b-trihydroxy-8-methoxy-3a- (4-methoxyphenyl) -3-phenyl-2,3 , 3a, 8b-tetrahydro-1H-cyclohexylfluoro-2-carboxylate by following the procedures for substituting phenol with prop-2-en-1-ol, hydrazide synthesis , formation of oxadiazole, dihydroxylation, oxidative cleavage and finally reduction of the aldehyde. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.03 (m, 5H), 6.87 (m, 2H), 6.74 (s, 2H), 6.61 (d, 2H, J = 8.8 Hz), 6.28 (m, 1H), 6.12 (m, 1H), 5.17 (s, 1H), 5.01 (d, 1H, J = 4.4 Hz), 4; , 88 (t, 1H, J = 5.5 Hz), 4.61 (m, 1H), 4.27 (m, 2H), 4.01 (m, 2H), 3.73 (m, 2H +), 3H), 3.61 (s, 3H); LCMS (ES +, m / z): 548 [M + H] +; LCMS (ES-, m / z): 592 [M + HCOOT. Compound 21 rac- (1R, 2R, 3S, 3aR, 8bS) -2- (5-amino-1,3,4-oxadiazol-2-yl) -6- (2- (dimethylamino) ethoxy) -8-methoxy 3- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol C1 White solid; obtained from the rac-methyl compound (1R, 2R, 3S, 3aR, 8bS) -1,6,8btrihydroxy-8-methoxy-3- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate by following phenol substitution procedures with prop-2-en-1-ol, hydrazide synthesis, oxadiazole formation, dihydroxylation, oxidative cleavage and finally reductive amination using dimethylamine. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.03 (m, 5H), 6.87 (m, 2H), 6.74 (s, 2H), 6.61 (d, 2H, J = 8.9 Hz), 6.29 (m, 1H), 6.11 (m, 1H), 5.17 (s, 1H), 5.00 (d, 1H, J = 4.3 Hz), 4 , 61 (m, 1H), 4.27 (s, 2H), 3.73 (s, 3H), 3.61 (s, 3H), 2.63 (m, 2H), 2.23 (s, 6H); LCMS (ES +, m / z): 575.01 [M + H] +; LCMS (ES-, m / z): 572.94 [M-Hf. Compound 22 rac- (1R, 2R, 3S, 3aR, 8bS) -2- (5-amino-1,3,4-oxadiazol-2-yl) -8-methoxy-3α- (4-methoxyphenyl) -6- (2- (4-methylpiperazin-1-yl) ethoxy) -3-phenyl-2,3,3a, 8betaetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol White solid, 56 mg (24%); obtained from rac-methyl compound (1R, 2R, 3S, 3aR, 8b S) -1,6,8b-trihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3-phenyl-2-one , 3, 3a, 8btetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate following the procedures for substitution of phenol with prop-2-en-1-ol, hydrazide synthesis, formation of oxadiazole, dihydroxylation, oxidative cleavage and finally reductive amination using 1-methylpiperazine. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.03 (m, 5H), 6.87 (m, 2H), 6.74 (s, 2H), 6.61 (m, 2H), 6.29 (s, 1H), 6.12 ( s, 1H), 5.17 (s, 1H), 5.01 (m, 1H), 4.61 (m, 1H), 4.26 (s, 2H), 4.10 (m, 2H), 3.73 (s, 3H), 3.61 (s). , 3H), 2.50 (m, 8H), 2.16 (s, 3H); LCMS (ES +, m / z): 630.07 [M + H] +; LCMS (ES-, m / z): 674.00 [M + HCOOT. Compound 23 rac- (1R, 2R, 3S, 3aR, 8bS) -2- (5-amino-1,3,4-oxadiazol-2-yl) -8-methoxy-3α- (4-methoxyphenyl) -6- (2-Morpholinoethoxy) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8bdiol 0 White solid, 60 mg (26%); obtained from rac-methyl compound (1R, 2R, 3S, 3R, 8b S) -1,6,8b-trihydroxy-8-methoxy-3- (4-methoxyphenyl) -3-phenyl-2, 3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate following the procedures for substitution of phenol with prop-2-en-1-ol, hydrazide synthesis, oxadiazole, dihydroxylation, oxidative cleavage and finally reductive amination using morpholine. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.03 (m, 5H), 6.87 (m, 2H), 6.74 (s, 2H), 6.61 (m, 2H), 6.29 (s, 1H), 6.12 ( s, 1H), 5.17 (s, 1H), 5.01 (m, 1H), 4.61 (m, 1H), 4.26 (s, 2H), 4.12 (m, 2H), 3.73 (s, 3H), 3.60 (m). , 7H), 2.70 (m, 4H), 2.50 (m, 4H); LCMS (ES +, m / z): 616.98 [M + H] +; LCMS (ES-, m / z): 660.87 [M + HCOOT. Compound 24 rac- (1R, 2R, 3S, 3aR, 8bS) -6,8-dimethoxy-3α- (4-methoxyphenyl) -2- (5- (methylamino) -1,3,4-oxadiazol-2-yl) ) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol White solid, 100 mg (30%); obtained from rac- (1R, 2R, 3S, 3aR, 8b5) -1,8bdihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a; , 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2carbohydrazide previously described and applying the procedure for synthesizing substituted amino-oxadiazoles using isothiocyanatomethane. 1 H NMR (DMSO-D6, 400 MHz, δ, ppm): 7.14 (q, 1H, J = 5.0 Hz), 7.03 (m, 5H), 6.87 (m, 2H), 6, 61 (d, 2H, J = 8.9 Hz), 6.29 (d, 1H, J = 1.8 Hz), 6.12 (d, 1H, J = 1.8 Hz), s, 1H), 5.01 (d, 1H, J = 4.3 Hz), 4.61 (m, 1H), 4.27 (m, 2H), 3.78 (s, 3H), 3, 73 (s, 3H), 3.61 (s, 3H), 2.66 (d, 3H, J = 5.0 Hz); LCMS (ES +, m / z): 532 [M + H] +; LCMS (ES-, m / z): 576 [M + HCOOT. Compound 25 rac- (1R, 2R, 3S, 3aR, 8bS) -6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2- (5- (propylamino) -1,3,4-oxadiazole -2-yl) -2,3,3a, 8b-tetrahydro-1Hcyclopenta [b] benzofuran-1,8b-diol 0-OH NN H 2 O 0 H White solid, 63 mg (37%); obtained from rac- (1R, 2R, 3S, 3aR, 8bS) -1,8bdihydroxy-6,8-dimethoxy-3a- (4-methoxyphenyl) -3-phenyl-2,3,3a , 8b-tetrahydro-1Hcyclopenta [b] benzofuran-2carbohydrazide previously described and applying the procedure for synthesizing substituted amino-oxadiazoles using Siothyronatopropane. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.25 (t, 1H, J = 5.8Hz), 7.03 (m, 5H), 6.87 (m, 2H), 6, 61 (d, 2H, J = 8.9 Hz), 6.29 (d, 1H, J = 1.9 Hz), 6.12 (d, 1H, J = 1.9 Hz), bs, 1H), 5.01 (bs, 1H), 4.62 (bs, 1H), 4.27 (m, 2H), 3.10 (s, 3H), 3.73 (s, 3H), 3.61 (s, 3H), 2.98 (m, 2H), 1.43 (hex, 2H, J = 7.2 Hz), 0.8 (t, 3H, J = 7.2 Hz) ; LCMS (ES +, m / z): 560.1 [M + H] +; LCMS (ES-, m / z): 604.1 [M + HCOOT. Compound 26 rac- (1R, 2R, 3S, 3aR, 8bS) -2- (54 (3- (diethylamino) propyl) amino) -1,3,4-oxadiazol-2-yl) -6,8-dimethoxy- 3- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-beige solid, 2.8 mg (5%); obtained from rac- (1R, 2R, 3S, 3aR, 8bS) -1,8bdihydroxy-6,8-dimethoxy-3a- (4-methoxyphenyl) -3-phenyl-2,3,3a , 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2carbohydrazide previously described and applying the procedure for synthesizing substituted amino-oxadiazoles using N, N-diethyl-3-isothio cyan atopropan-1-amine LCMS (ES + m / z): 631.1 [M + H] +; LCMS (ES-, m / z): 663.1 [M + HCOOT cyclopenta [b] benzofuran-1,8b-diol 0-OH HO = NN H 57 Compound 27 rac- (1R, 2R, 3S, 3aR, 8bS ) -2- (5-hydroxy-1,3,4-oxadiazol-2-yl) -6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro- 1 H-cyclopenta [b] benzofuran-1,8b-diol C1 White solid, 82 mg (65%); obtained from the compound rac- (1R, 2R, 3S, 3aR, 8bS) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3 , 3a, 8b-tetrahyl-1H-cyclopenta [b] benzofuran-2-carboxhydrazide as follows: In a flask and under nitrogen, introduce rac- (1R, 2R, 3S, 3aR, 8b S) -1, 8b-dihydroxy 6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclohexylbenzofuran -2-carbohydrazide (40 mg, 0.081 g). mmol) in 0.4 mL of tetrahydrofuran followed by Et3N (23.66 μL, 0.170 mmol). Add, at room temperature, 1,1'-carbonyldiimidazole (16.33 mg, 0.101 mmol). Stir at room temperature for 18 hours. Dilute the medium with ethyl acetate. Wash with 1N HCl solution and then with saturated NaCl solution. Dry the organic phase over MgSO 4, filter and concentrate. A white solid is recovered. 1 H NMR (DMSO-D6, 400 MHz, δ, ppm): 11.92 (s, 1H), 7.00 (m, 7H), 6.59 (d, 2H, J = 8.9 Hz), 6, 28 (d, 1H, J = 1.9 Hz), 6.11 (d, 1H, J = 1.9 Hz), 5.17 (m, 2H), 4.63 (m, 1H), 4, (M, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 3.60 (s, 3H); LCMS (ES +, m / z): 501.0 [M20 OH] +; LCMS (ES-, m / z): 517.0 [M-Hf. Compound 28 rac- (1R, 2R, 3S, 3aR, 8bS) -2- (5-mercapto-1,3,4-oxadiazol-2-yl) -6,8-dimethoxy-3α- (4-methoxyphenyl) - 3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol White solid, 26 mg (49%); obtained from the compound rac- (1R, 2R, 3S, 3aR, 8bS) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3 , 3a, 8b-tetrahydroH-cyclopenta [b] benzofuran-2-carbohydrazide as follows: In a flask, introduce rac- (1R, 2R, 3S, 3aR, 8b S) -1, 8b-dihydroxy-6 8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclohexylbenzofuran-2-carbohyrazide (50%). mg, 0.102 mmol) in ethanol (1 mL). Add KOH (17.09 mg, 0.305 mmol) and C52 (12.24 μl, 0.203 mmol) and heat at 90 ° C for 1 hour. Concentrate the reaction medium and take up in ethyl acetate and water. Add a saturated solution of NaHCO3 to the aqueous phase and extract again with ethyl acetate. Collect the organic phases and wash with saturated NaCl solution and dry over Na2SO4 and concentrate. The residue is purified on silica gel using a DCM / MeOH 98/2 mixture as eluent. 1 H NMR (DMSO-D6, 400 MHz, δ, ppm): 14.19 (s, 1H), 7.01 (m, 7H), 6.59 (d, 2H, J = 9.0 Hz), 6, 28 (d, 1H, J = 1.9 Hz), 6.11 (d, 1H, J = 1.9 Hz), 5.26 (d, 1H, J = 4.6 Hz), 5.22 ( s, 1H), 4.67 (t, 1H, J = 4.6 Hz), 4.43 (dd, 1H, J = 4.6 Hz, 14.1 Hz), 4.25 (d, 1H, J = 14.1 Hz), 3.77 (s, 3H), 3.72 (s, 3H), 3.60 (s, 3H); LCMS (ES +, m / z): 535.0 [M + H] +; LCMS (ES-, m / z): 532.9 [M-Hf Compound 29 rac- (1R, 2S, 3S, 3aR, 8bS) -2- (5-amino-4H-1,2,4-triazole) 3-yl) -6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol White solid, 1 mg (2%); obtained from the compound rac- (1R, 2R, 3S, 3aR, 8bS) -1,8bdihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3 a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxhydrazide as follows: To a solution of rac- (1R, 2R, 3S, 3aR, 8b S) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxhydrazide (50 mg, 0.102 mmol) in water (0.6 mL) is added. Methyl isothiourea (9.15 mg, 0.102 mmol) followed by sodium hydroxide (6.09 mg, 0.152 mmol) at 0 ° C. The mixture is stirred at 75 ° C for 5h. Purification of the crude by preparative HPLC.
[0044] 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.05 (m, 2H), 6.96 (m, 4H), 6.90 (m, 1H), 6.57 (m, 2H), 6.24 (m, 1H), 6.08. (m, 1H), 5.60 (bs, 2H), 4.95 (m, 3H), 4.40 (m, 1H), 4.34 (m, 1H), 4.11 (m, 1H), 3.76 (s, 3H), 3.70 ( s, 3H), 3.58 (s, 3H); HRMS: C28H29N4O6 [M + H] + Cald 517.2082 Found 517.2060.
[0045] Reac- (1R, 2S, 3S, 3aR, 8bS) -6,8-dimethoxy-3α- (4-methoxyphenyl) -2- (5-methyl-4H-1,2,4-triazol-3-yl) compound ) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol O -NH 2 O - White solid, 59 mg (37%); obtained from the compound rac- (1R, 2R, 3S, 3aR, 8bS) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b -tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxhydrazide as follows: To a solution of hydrochloric acid salt of ethyl acetimidate (301 mg, 2,436 mmol) in acetonitrile (16 mL) is added triethylamine (849 .il, 6.09 mmol) then rac- (1R, 2R, 3S, 3aR, 8b S) -1,8-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3- phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxhydrazide (600 mg, 1.218 mmol). The mixture is stirred at 90 ° C for 48 hours. Concentrate the reaction medium and purify the residue on silica gel using a 98/2 DCM / MeOH mixture as eluent. 1 H NMR (CDCl 3, 400 MHz, δ, ppm): 7.19 (d, 2H, J = 8.9 Hz), 7.00 (m, 5H), 6.65 (d, 2H, J = 8.9; Hz), 6.29 (d, 1H, J = 1.9 Hz), 6.13 (d, 1H, J = 1.9 Hz), 4.91 (d, 1H, J = 5.0 Hz) , 4.51 (dd, 1H, J = 5.0 Hz, 14.1 Hz), 4.37 (d, 1H, J = 14.1 Hz), 3.86 (s, 3H), 3.84 (s, 3H), 3.70 (s, 3H), 3.07 (m, 1H), 2.32 (s, 3H); LCMS (ES +, m / z): 516.0 [M + H] +; LCMS (ES-, m / z): 513.9 [M-Hf. Compound 31 rac- (1R, 2R, 3S, 3aR, 8bS) -2- (3-isopropyl-1,2,4-oxadiazol-5-yl) -6,8-dimethoxy-3α- (4-methoxyphenyl) - 3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol C1 White solid, 6.4 mg (11%); obtained from the compound rac- (1R, 2R, 3S, 3aR, 8bS) -methyl 1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2, 3, 3a, 8btetrahydro-1Hcyclopenta [b] benzofuran-2-carboxylate as follows: In a flask and under nitrogen, introduce rac- (1R, 2R, 3S, 3aR, 8b S) -m ethyl 1, 8b-di 6-hydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahyl-1-cyclopenta [2-enzofuran-2-carboxylate (50 mg, 0.102 mmol); ) in 0.5 mL of toluene. The environment is limpid. Add at room temperature (Z) -N'-hydroxyisobutyrimidamide (11.41 mg, 0.112 mmol) and then K2CO3 (15.43 mg, 0.112 mmol). Stir at reflux After 4 hours, there is very little product that is formed. Reflux for 18 hours. Dilute the medium with ethyl acetate and wash with water. Dry the organic phase over MgSO 4, filter and concentrate. Purify the residue on silica using 95/5 DCM / MeOH as eluent.
[0046] 1 H NMR (DMSO-D6, 400 MHz, δ, ppm): 7.11 (d, 2H, J = 8.9 Hz), 7.01 (m, 3H), 6.86 (m, 2H), 6, 61 (d, 2H, J = 8.9 Hz), 6.30 (d, 1H, J = 1.7 Hz), 6.11 (d, 1H, J = 1.7 Hz), 5.24 ( s, 1H), 5.14 (m, 1H), 4.71 (m, 1H), 4.59 (dd, 1H, J = 5.1 Hz, 14.2 Hz), 4.41 (d, 1H, J = 14.2 Hz), 3.78 (s, 3H), 3.71 (s, 3H), 3.61 (s, 3H), 2.91 (hept, 1H, J = 6, 9 Hz), 1.15 (d, 6H, J = 6.9 Hz); LCMS (ES +, m / z): 545.0 [M + H] +; LCMS (ES-, m / z): 588.9 [M + HC001-. 1.4. Compounds with R 1 and R 2 forming a heterocycle The compounds according to the invention can be synthesized according to the following reaction scheme: ## STR1 ## (OH) O (NH) O (NH 2) q) O (o) Phenol deprotection procedure: rac-methyl (3R, 3aR, 8bS) -6- (benzyloxy) -1,8-dihydroxy-8-methoxy-3-a- (4-methoxyphenyl) ) -3-phenyl-3α, 8bdihydro-3H-cyclopenta [b] benzofuran-2-carboxylate (inter-1 described in: Journal of the American Chemical Society, 2009, 131, 1607-1616) (1 g, 1.765 mmol) in ethyl acetate (10 mL) degassed with nitrogen is added palladium hydroxide. The medium is then stirred under hydrogen pressure (1 bar) for 18 hours at room temperature. The palladium is filtered through Celite® and rinsed with ethyl acetate and then a CH 2 Cl 2 / MeOH mixture: 80/20 to 10/90. The filtrate is evaporated and the residue obtained (inter-2) is used without further purification. (p) Methylation procedure of phenol: In a 100 ml Heck tube introduce the previously obtained compound (0.869 g, 1.824 mmol), add the solvents (MeOH 10 mL and toluene 5 mL). Add dropwise a solution of trimethylsilyl diazomethane (2M in hexane), cap the flask and stir at room temperature for 18 hours. Repeat several times with dichloromethane and acetonitrile and evaporate to obtain a homogeneous foam. Purify the residue on silica gel using DCM / AcOEt as 100/0 to 80/20 eluent to obtain rac-methyl (3R, 3aR, 8bS) -8b-hydroxy-1,6,8-trimethoxy-3 α- (4-methoxyphenyl) -3-phenyl-3α, 8β-dihydro-3H-cyclopenta [b] benzofuran-2-carboxylate as a white solid (inter-3,540 mg, 58% over 2 steps). 1 H NMR (CDCl 3, 400 MHz, δ, ppm): 7.10 (m, 5H), 6.98 (m, 2H), 6.57 (d, 2H, J = 8.9 Hz), 6.22 (m.p. d, 1H, J = 1.9 Hz), 6.06 (d, 1H, J = 1.9 Hz), 4.51 (s, 1H), 4.19 (s, 3H), 3.83 ( s, 3H), 3.82 (s, 3H), 3.68 (s, 3H), 3.52 (s, 3H); LCMS (ES +, m / z): 487.25 [M-OH] +; LCMS (ES-, m / z): 549.32 [M + HCOO-f. (q) Procedure for formation of the pyrazolone ring: The compound obtained above (0.250 g, 0.496 mmol), ethanol (4 ml) and then the hydrazine monohydrate are added to a microwave flask equipped with a magnetized bar. (2.070 ml, 27.3 mmol). The capped bottle is placed in a microwave apparatus and the reaction medium is subjected to two heating cycles of 1 minute at 180 ° C. After evaporation to dryness, take up with the solid with a minimum of methanol, filter the solid and dry under vacuum. Compound 32 rac- (4R, 4aR, 9bS) -9b-hydroxy-7,9-dimethoxy-4- (4-methoxyphenyl) -4-phenyl-1,2,4,4a-tetrahydrobenzofuro [2 ', 3': 4,5] cyclopenta [1,2-c] pyrazol-3 (9bH) -one O beige solid, 136 mg (58%); obtained according to the procedure described above.
[0047] 1H NMR (DMSO-D6, 400MHz, δ, ppm): 11.73 (bs, 1H), 9.53 (bs, 1H), 7.06 (m, 4H), 6.98 (m, 3H), 6.37 (d, 1H, J = 1.9 Hz), 6.14 (d, 1H, J = 1.9 Hz), 5.41 (bs, 1H), 4.21 (s, 1H), 3.78 (s, 6H), 3.57 (s, 3H); LCMS (ES +, m / z): 473.18 [M + H] +.
[0048] The compounds according to the invention can also be synthesized according to the following reaction scheme: (r) Procedure for the formation of the enamine: rac- (3R, 3aS, 8bS) -8b-hydroxy-6,8-dimethoxy-3 α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclo [1)] benzofuran-1-one (Journal of the American Chemical Society, 2006, 128 (24), 77547755) and dimethylformamide dimethylacetal (DMFDMA, equiv.) Are stirred in DMF (0.5M) at 60 ° C for 5 hours. The DMF is evaporated under vacuum and the residue is taken up and then evaporated three times with dichloromethane to yield a yellow foam (accompanied by a by-product of mass M - H2O). (s) Procedure for addition of guanidines: In a flask, introduce rac (3R, 3 aR, 8bR, Z) -2 - ((dimethylamino) methylene) -8b-hydroxy-6,8-dimethoxy-3 a- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [1-enzofuran-1-one obtained above, potassium carbonate (3 equiv.) And guanidine hydrochloride. (2 equiv.) As well as ethanol (0.2 M). Stir magnetically at 60 ° C for 18h. The precipitate is filtered, then rinsed with water and then with ethyl ether, it is finally dried under vacuum at 40 ° C. When the product does not precipitate, the solvents are evaporated and the residue is purified on silica gel.
[0049] Compound 33 rac- (5aR, 10bS) -2-amino-8,10-dimethoxy-5- (4-methoxyphenyl) -5-phenyl-5α, 10b-dihydro-5H-benzofuro [2 ', 3': 4, Cyclopenta [1,2-d] pyrimidin-10b-ol DMFDMA (r) (s) O White solid, 549 mg (63%); obtained from the compound rac- (3R, 3aR, 8bR, Z) -2- ((dimethylamino) methylene) -8b-hydroxy-6,8-dimethoxy-3a- (4-methoxyphenyl) -3-phenyl-2, 3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1-one following the procedure of adding guanidines using guanidine. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.80 (s, 1H), 7.08 (m, 3H), 6.83 (m, 4H), 6.74 (bs, 2H), 6.58. (m, 2H), 6.42 (s, 1H), 6.16 (s, 1H), 5.58 (s, 1H), 4.22 (s, 1H), 3.79 (s, 3H); 3.71 (s, 3H), 3.59 (s, 3H); LCMS (ES +, m / z): 484.18 [M + H] +.
[0050] Compound 34 rac- (5aR, 10bS) -8,10-dimethoxy-5α- (4-methoxyphenyl) -2-morpholino-5-phenyl-5α, 10b-dihydro-5H-benzofurop ', 3': 4.5] cyclopenta [1,2-d] pyrimidin-10b-ol O- (N) N-OH = (11 iN O Beige solid, 9 mg (15%), obtained from the compound rac- (3R) 3aR, 8bR, Z) -2- ((dimethylamino) methylene) -8b-hydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro- 1H-cyclopenta [b] benzofuran-1-one following the procedure of adding guanidines using morpholine-4-carboximidamide.1H NMR (DMSO-D6, 400MHz, δ, ppm): 7.97 (s, 1H) , 7.08 (m, 3H), 6.88 (m, 2H), 6.82 (d, 2H, J = 8.5 Hz), 6.56 (d, 2H, J = 8.5 Hz), , 41 (s, 1H), 6.14 (s, 1H), 5.70 (s, 1H), 4.27 (s, 1H), 3.85 (m, 4H), 3.79 (s, 3H), 3.73 (m, 4H), 3.71 (s, 3H), 3.58 (s, 3H), LCMS (ES +, m / z): 554.07 [M + H] + Compound 35 rac-N - ((5R, 5aR, 1013s) -10b-hydroxy-8,10-dimethoxy-5α- (4-methoxyphenyl) -5-phenyl-5α, 10b-dihydro-5H-benzofurop ', 3': 4 51cyclopenta [1,2-d] pyrimidin-2-yl) cyanamide N White solid, 24 mg (46%); from the compound rac- (3R, 3aR, 8bR, Z) - 2 - ((dimethylamino) methylene) -8b-hydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3, 3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1-one following the procedure for addition of guanidines using cyano-guanidine. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.70 (s, 1H), 7.06 (m, 3H), 6.83 (m, 4H), 6.55 (m, 2H), 6H NMR (CDCl3) , 38 (s, 1H), 6.14 (s, 1H), 5.60 (bs, 1H), 4.20 (s, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.58 (s, 3H); LCMS (ES +, m / z): 508.96 [M + H] + Compound 36 rac- (5aR, 10bS) -8,10-dimethoxy-5α- (4-methoxyphenyl) -2- (methylthio) -5- phenyl-5α, 10b-dihydro-5H-benzofuropyl, 3 ': 4,5] cyclopenta [1,2-d] pyrimidin-10b-ol ## STR1 ## (28%): obtained from the compound rac- (3R, 3aR, 8bR, Z) -2- ((dimethylamino) methylene) -8b-hydroxy-6,8-dimethoxy-3a- (4-methoxyphenyl) -3 phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1-one following the procedure for addition of guanidines using methyl carbamimidothioate .1H NMR (DMSO-D6, 400MHz, δ, ppm ): 8.21 (s, 1H), 7.10 (m, 3H), 6.88 (m, 2H), 6.79 (d, 2H, J = 8.5 Hz), 6.58 (d, , 2H, J = 8.5 Hz), 6.44 (s, 1H), 6.17 (s, 1H), 5.99 (s, 1H), 4.40 (s, 1H), 3.80. (s, 3H), 3.72 (s, 3H), 3.59 (s, 3H), 2.65 (s, 3H), LCMS (ES +, m / z): 514.90 [M + H] Compound 37 rac- (5R, 5aR, 10bS) -2-amino-4-ethoxy-8,10-dimethoxy-5α- (4-methoxyphenyl) -5-phenyl-5α, 10b-dihydro-5H-benzofuro12 ' 3 ': 4,51cyclopenta [1,2-d] pyrimidin-10b-ol 0 pale yellow solid, 6 mg (7%); obtained from rac- (3R, 3aR, 8bR) -2- (bis (methylthio) methylene) -6,8-dimethoxy-3a- (4-methoxyphenyl) -3-phenyl-8b ((trimethyl silyl) oxy ) 2,3,3a, 8b-tetrahydro-1H-cyclohexylactanone (described in the Journal of Organic Chemistry, 1989, 54 (1), 77-83) following guanidine addition procedure using guanidine. 1 H NMR (CDCl 3, 400MHz, δ, ppm): 7.02 (m, 5H), 6.82 (m, 2H), 6.55 (m, 2H), 6.26 (d, 1H, J = 1, 9 Hz), 6.05 (d, 1H, J = 1.9 Hz), 5.42 (bs, 2H), 5.49 (s, 1H), 4.26 (qd, 1H, J = 7, 0 Hz, 10.6 Hz), 4.14 (qd, 1H, J = 7.0 Hz, 10.6 Hz), 3.81 (s, 3H), 3.79 (s, 3H), 3, 66 (s, 3H), 1.02 (t, 3H, J = 7.0 Hz); LCMS (ES +, m / z): 528.24 [M + H] +.
[0051] Compound 38 O pale yellow solid, 15 mg (90%); obtained from rac- (3R, 3aR, 8bR) -2- (bis (methylthio) methylene) -6,8-dimethoxy-3a- (4-methoxyphenyl) -3-phenyl-8b ((trimethylsilyl) oxy 2, 3, 3a, 8b-tetrahydro-1H-cyclohexylantan-1-one (described in the Journal of Organic Chemistry, 1989, 54 (1), 77-83) as follows: In a flask, mix the hydroxylamine hydrochloride (11.41 mg, 0.164 mmol) and the triethylamine (22.83 μl, 0.164 mmol) in ethanol (0.5 mL), stir at 50 ° C. for 15 minutes. then add the rac- (3R, 3 aR, 8bR) -2- (bis (m ethylthi) methyl ethyl) -6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-8b ((Trimethylsilyl) oxy) -2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1-one (20mg, 0.033mmol), stir at 65 ° C for 24 hours. Add water and ethyl acetate, extract twice with ethyl acetate, wash once with H2O / NaCl, dry over Mg504, filter and evaporate. The residue is purified on silica gel using as eluent CH2Cl2 / AcOEt 90/10.
[0052] 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.09 (d, 2H, J = 8.7 Hz), 7.05 (m, 3H), 6.80 (m, 2H), 6, 66 (d, 2H, J = 8.7 Hz), 6.17 (d, 1H, J = 1.9 Hz), 6.08 (d, 1H, J = 1.9 Hz), 5.26 ( s, 1H), 3.85 (s, 3H), 3.82 (d, 1H, J = 13.5 Hz), 3.76 (s, 3H), 3.66 (s, 3H), 3, 37 (d, 1H, J = 13.5 Hz), 2.35 (s, 1H), 2.24 (s, 3H); LCMS (ES +, m / z): 504.0 [M-OH] +; LCMS (ES-, m / z): 520.0 [M-Hf Compound 39 rac- (4R, 4aR, 9bS) -7,9-dimethoxy-4- (4-methoxyphenyl) -3- (methylthio) -4 phenyl-1,4,4a, 9b-tetrahydrobenzofuro [2 ', 3': 4,5] cyclopenta [1,2-c] pyrazol-9b-ol-Pale yellow solid, 8.8 mg (53%); obtained from rac- (3R, 3aR, 8bR) -2- (bis (methylthio) methylene) -6,8-dimethoxy-3a- (4-methoxyphenyl) -3-phenyl-8b ((trimethylsilyl) oxy 2, 3, 3a, 8b-tetrahydro-1H-cyclohexylantan-1-one (described in the Journal of Organic Chemistry, 1989, 54 (1), 77-83) as follows: In a flask, mix rac- (3R, 3aR, 8bR) -2- (bis (methylthio) methylene) -6,8-dimethoxy-3a- (4-methoxyphenyl) -3-phenyl-8b ((trimethylsilyl) oxy) -2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1-one (20mg, 0.033mmol) in ethanol (0.5mL) and then add the hydrazine monohydrate ( 17 μl, 0.164 mmol), heat at 50 ° C for 24 hours. Add water and ethyl acetate, extract twice with ethyl acetate, wash once with H 2 O / NaCl, dry over MgSO 4, filter and evaporate. The residue is purified on silica gel. using Cyclohexane / AcOEt 40/60 and then 20/80 as eluent. 1 H NMR (CDCl 3, 400 MHz, δ, ppm): 7.01 (m, 7H), 6.50 (d, 2H, J = 8.9 Hz), 6.22 (d, 1H, J = 1.9 Hz), 5.99 (d, 1H, J = 1.9 Hz), 4.49 (s, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 3.58 (b.p. s, 3H), 2.27 (s, 3H); LCMS (ES +, m / z): 500.9 [M + H] +; LCMS (ES-, m / z): 502.9 [M-Hf. The compounds according to the invention can be synthesized according to the following reaction scheme: 0 DPPA (k) O (k) Procedure for Curtius rearrangement: Described previously for the Example with R3 = H and n = 1.
[0053] Compound 40 rac- (3aR, 4R, 4aR, 9bS, 9cR) -9b-hydroxy-7,9-dimethoxy-4- (4-methoxyphenyl) -4-phenyl-3,3a, 4,4a, 9b, 9c- hexahydro-2H-benzofuropol, 2 ': 3,41cyclopenta [1,2-d] oxazol-2-one O0 White solid, 93 mg (47%); obtained from the compound rac- (1R, 2R, 3S, 3aR, 8bS) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3 , 3a, 8b-tetrahydroH-cyclopenta [b] benzofuran-2-carboxylic acid following the Curtius rearrangement procedure.
[0054] 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 8.15 (s, 1H), 7.11 (m, 3H), 7.01 (d, 2H J = 8.5Hz), 6.9 ( m, 2H), 6.70 (d, 2H, J = 8.5 Hz), 6.34 (d, 1H, J = 1.8 Hz), 6.22 (d, 1H, J = 1.8). Hz), 5.37 (s, 1H), 5.32 (d, 1H, J = 8.7 Hz), 4.79 (dd, 1H, J = 8.7 Hz, 10.5 Hz), 3 79 (s, 6H), 3.66 (s, 3H), 3.36 (d, 1H, J = 10.5 Hz); LCMS (ES +, m / z): 457.88 [M-OH] +; LCMS (ES-, m / z): 473.92 [M-Hf, 519.92 [M + HCOO-f.
[0055] 41- (3aR, 4R, 4aR, 9bS, 9cR) -7 - ((4,5-dihydroxypentyl) oxy) -9b-hydroxy-9-methoxy-4- (4-methoxyphenyl) -4-phenyl-3-compound , 3a, 4,4a, 9b, 9c-hexahydro-2H-benzofuro [1,2 '], 3,41cyclopenta [1,2-d] oxazol-2-one 0H0 0 White solid, 41mg (77%): obtained from rac-methyl (1R, 2R, 3S, 3aR, 8bS) -1,6,8b-trihydroxy-8-methoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b -tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate following the procedures for substitution of phenol with pent-4-en-1-ol, saponification, rearrangement of Curtius, and then dihydroxylation. 1 H NMR (CDCl 3, 400MHz, δ, ppm): 7.14 (m, 3H), 7.05 (m, 2H), 6.86 (m, 2H), 6.74 (m, 2H), 6, 21 (d, 1H, J = 1.9 Hz), 6.115 (m, 1H, J = 1.9 Hz), 5.56 (d, 1H, J = 8.1 Hz), 5.04 (s, 1H), 4.66 (dd, 1H, J = 8.2 Hz, 10.8 Hz), 4.03 (m, 2H), 3.91 (s, 3H), 3.80 (m, 1H) , 3.74 (s, 3H), 3.70 (dd, 1H, J = 3.1 Hz, 10.8 Hz), 3.63 (d, 1H, J = 10.8 Hz), 3.49 (dd, 1H, J = 7.5 Hz, 10.8 Hz), 1.92 (m, 2H), 1.66 (m, 2H); LCMS (ES +, m / z): 563.99 [M + H] +.
[0056] Compound 42 rac- (3aR, 4R, 4aR, 9bS, 9cR) -9b-hydroxy-7- (4-hydroxybutoxy) -9-methoxy-4- (4-methoxyphenyl) -4-phenyl-3,3a, 4, 4a, 9b, 9c-hexahydro-2H-benzofuran-13 ', 2': 3,41cyclopenta [1,2-d] oxazol-2-one 0/0 White solid, 249 mg (98%): obtained from 41 following the oxidative cleavage procedure followed by the aldehyde reduction procedure. 1 H NMR (CDCl 3, 400MHz, δ, ppm): 7.14 (m, 3H), 7.05 (m, 2H), 6.86 (m, 2H), 6.74 (m, 2H), 6, 21 (d, 1H, J = 1.9 Hz), 6.15 (d, 1H, J = 1.9 Hz), 5.56 (d, 1H, J = 8.2 Hz), 5.05 ( s, 1H), 4.65 (dd, 1H, J = 8.3 Hz, 10.8 Hz), 4.03 (t, 1H, J = 6.3 Hz), 3.91 (s, 3H); , 3.74 (t, 1H, J = 6.3 Hz), 3.73 (s, 3H), 3.63 (d, 1H, J = 10.8 Hz), 1.91 (m, 2H). 1.77 (m, 2H); LCMS (ES +, m / z): 534.00 [M + H] +. Compound 43 rac- (3aR, 4R, 4aR, 9bS, 9cR) -7- (4-azidobutoxy) -9b-hydroxy-9-methoxy-4- (4-methoxyphenyl) -4-phenyl-3,3a, 4, 4a, 9b, 9c-hexahydro-2H-benzofuro-13 ', 2': 3,41cyclopenta [1,2-d] oxazol-2-one beige solid, 104 mg (39%); obtained from compound 42 following the procedure for synthesizing azide from alcohol. 1 H NMR (CDCl 3, 400MHz, δ, ppm): 7.14 (m, 3H), 7.05 (m, 2H), 7.86 (m, 2H), 6.74 (m, 2H), 6, (D, 1H, J = 1.9 Hz), 6.15 (d, 1H, J = 1.9 Hz), 5.56 (d, 1H, J = 8.3 Hz), 5.00 ( s, 1H), 4.66 (dd, 1H, J = 8.3 Hz, 10.8 Hz), 4.02 (m, 2H), 3.91 (s, 3H), 3.74 (s, 3H), 3.65 (m, 2H), 3.40 (t, 1H, J = 6.7 Hz), 2.01 (m, 2H), 1.90 (m, 2H), 1.82 (m.p. m, 2H); LCMS (ES-, m / z): 556.84 [M-H].
[0057] Compound 44 rac- (3aR, 4R, 4aR, 9bS, 9cR) -7- (4-aminobutoxy) -9b-hydroxy-9-methoxy-4- (4-methoxyphenyl) -4-phenyl-3,3a, 4, 4a, 9b, 9c-hexahydro-2H-benzofuro-13 ', 2': 3, 41cyclopenta [1,2-d] oxazol-2-one HAN Beige solid, 26 mg (54%); obtained from compound 43 following the azide reduction procedure. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 8.15 (s, 1H), 7.51 (bs, 1H), 7.11 (m, 3H), 7.00 (m, 2H), 6 , 94 (m, 2H), 6.69 (m, 2H), 6.33 (d, 1H, J = 1.9 Hz), 6.18 (d, 1H, J = 1.9 Hz), , 36 (s, 1H), 5.32 (d, 1H, J = 8.4 Hz), 4.78 (dd, 1H, J = 8.4 Hz, 10.4 Hz), 4.03 (t , 1H, J = 6.4 Hz), 3.79 (s, 3H), 3.66 (s, 3H), 3.33 (m, 1H), 2.85 (t, 1H, J = 7, 3 Hz), 1.78 (m, 2H), 1.71 (m, 2H); LCMS (ES +, m / z): 533.01 [M + H] +.
[0058] Compound 45 rac- (3aR, 4R, 4aR, 9bS, 9cR) -7- (2-aminoethoxy) -9b-hydroxy-9-methoxy-4- (4-methoxyphenyl) -4-phenyl-3,3a, 4, 4a, 9b, 9c-hexahydro-2H-benzofuro13 ', 2': 3,41cyclopenta [1,2-d] oxazol-2-one O H2N 0 White solid, 332 mg (63%); obtained from the compound rac-methyl (1R, 2R, 3S, 3aR, 8bS) -1,6,8b-trihydroxy-8-methoxy-3a- (4-methoxyphenyl) -3-phenyl-2,3 , 3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylate following the procedures for phenol substitution, saponification and Curtius rearrangement. Finally, the procedures of dihydroxylation, oxidative cleavage, reduction of the alcohol, transformation into azide then reduction of the azide led to the desired product. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 8.14 (s, 1H), 7.11 (m, 3H), 7.00 (m, 2H), 6.94 (m, 2H), 6. , 69 (m, 2H), 6.32 (d, 1H, J = 1.9 Hz), 6.21 (d, 1H, J = 1.9 Hz), 5.37 (bs, 1H), , 32 (d, 1H, J = 8.6 Hz), 4.78 (dd, 1H, J = 8.6 Hz, 10.8 Hz), 3.96 (t, 2H, J = 5.6 Hz ), 3.78 (s, 3H), 3.65 (s, 3H), 3.35 (d, 1H, J = 10.8 Hz), 2.88 (t, 2H, J = 5.6 Hz). ), 1.90 (bs, 2H); LCMS (ES +, m / z): 504.94 [M + H] +. Compound 46 rac- (3aR, 4R, 4aR, 9bS, 9cR) -9b-hydroxy-7,9-dimethoxy-4- (4-methoxyphenyl) -4-phenyl-3,3a, 4,4a, 9b, 9c- hexahydro-2H-benzofuropyl, 2 ': 3,41cyclopenta [1,2-d] oxazol-2-thione OO pale yellow solid, 54 mg (33%); obtained from compound 9 as follows: In a flask, introduce rac- (1R, 2R, 3R, 3aR, 8bS) -2-amino-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl -2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol (150 mg, 0.334 mmol) in a 1M solution of sodium carbonate (667 μl, 0.667 mmol), add CS2 ( 30.2 μl, 0.501 mmol) and heat at 110 ° C for 15 minutes. Allow to come to room temperature. A precipitate forms, filter and dry. The product is obtained in the form of a pale yellow solid. 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 10.45 (bs, 1H), 7.12 (m, 3H), 7.99 (m, 4H), 6.69 (m, 2H), 6.35 (d, 1H, J = 1.9 Hz), 6.25 (d, 1H, J = 1.9 Hz), 5.64 (m, 1H), 5.50 (s, 1H), 5.04 (m, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.65 (s, 3H), 3.39 (d, 1H, J = 10.9 Hz. ); LCMS (ES +, m / z): 491.88 [M + H] + Compound 47 rac- (3aR, 4R, 4aR, 9bS, 9cR) -2-amino-7,9-dimethoxy-4a- (4-methoxyphenyl) Phenyl-4, 4a, 9b, 9c-tetrahydro-3aH-benzofurop ', 2': 3,41-cyclopenta [1,2-d] oxazol-9b-ol) NI-12 White solid, 12 mg ( 35%); obtained from compound 9 as follows: In a pillbox and under nitrogen, introduce rac- (1R, 2R, 3R, 3aR, 8b S) -2-amino-6,8-dimethoxy-3a- (4-methoxyphenyl) - 3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [enzofuran-1,8b-diol (34 mg, 0.076 mmol) in 1.0 mL of ethanol, add, at room temperature, Cyanogen bromide (30.3 μl, 0.091 mmol) and stir for 18 hours. Concentrate the reaction medium and then add a saturated solution of NaHCO3. A solid remains in suspension. Filter and rinse with water and dry under vacuum. The product is purified on silica using a 95/5 DCM / MeOH mixture as eluent.
[0059] 1 H NMR (DMSO-D6, 400MHz, δ, ppm): 7.05 (m, 7H), 6.69 (m, 2H), 6.29 (s, 1H), 6.18 (s, 1H), , 72 (s, 1H), 5.13 (d, 2H, J = 8.4 Hz), 4.75 (t, 1H, J = 10.4 Hz), 3.80 (s, 3H), 3 77 (s, 3H), 3.65 (s, 3H); LCMS (ES +, m / z): 475.01 [M + H] +.
[0060] Compound 48 rac- (4aR, 5R, 5aR, 10bS, 10cR) -1013-hydroxy-8,10-dimethoxy-5α- (4-methoxyphenyl) -5-phenyl-4,4a, 5,5a, 10b, 10c- hexahydrobenzofuro 12 ', 3': 4,5] cyclopenta [1,2-b] [1,4] oxazin-3 (2H) -one O 0- White solid, 1.7 mg (2%); obtained from compound 9 as follows: In a flask, introduce rac- (1R, 2R, 3R, 3aR, 8b S) -2-amino-6,8-dimethoxy-3α- (4-methoxyphenyl) -3- phenyl-2,3,3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-1,8b-diol (69mg, 0.154mmol) dissolved in THF (2.5mL). Cool to 0 ° C and add 60% NaH in the oil (6.45 mg, 0.161 mmol) then methyl 2-chloroacetate (18.32 mg, 0.169 mmol). Stir at 0 ° C for 3 hours and then at 30 ° C for 3 hours. Hydrolyse with a saturated solution of NaHCO 3 and extract 2 times with ethyl acetate, combine the organic phases, wash with a saturated solution of NH 4 Cl and then with a saturated solution of NaCl. Dry the organic phase over Na2SO4 and concentrate. The residue is purified on silica gel using a 99/1 DCM / MeOH mixture as eluent.
[0061] LCMS (ES-, m / z): 488.1 [M-Hf. Compound 49 rac- (6R, 6aS, 11bR) -11b-hydroxy-9,11-dimethoxy-6α- (4-methoxyphenyl) -6-phenyl-3,4,6,6a, 11b, 11c-hexahydro-2H- benzofuro 13 ', 2': 3,4] cyclopenta 11,2-1111,41oxazepin-5 (5aH) -one 0 White foam, 6 mg (15%); obtained from the compound rac- (1R, 2R, 3S, 3aR, 8bS) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3 , 3a, 8b-tetrahydroH-cyclopenta [b] benzofuran-2-carboxylic acid as follows: In a flask, introduce rac- (1R, 2R, 3S, 3aR, 8b S) -1, 8b-dihydroxy- 6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclohexylbenzofuran-2-carboxylic acid (b. 300 mg, 0.627 mmol) in solution in DCM (7 mL), add di (1H-imidazol-1-yl) methanone (122 mg, 0.752 mmol, CDI) and stir for 18 hours at room temperature. Add water and let settle. Recover and dry the organic phase on Na2SO4 and concentrate. In a vial, introduce rac- (1R, 2R, 3S, 3aR, 8bS) -1,8b-dihydroxy-6,8-dimethoxy-3α- (4-methoxyphenyl) -3-phenyl-2,3 , 3a, 8b-tetrahydro-1H-cyclopenta [b] benzofuran-2-carboxylic 1H-imidazole-1-carboxylic anhydride (100mg, 0.175mmol) in THF (2mL). Add the hydrochloric acid salt of 2-chloroethanamine (60.8 mg, 0.524 mmol) and DIEA (183 μL, 1.048 mmol) and heat at 50 ° C for 6 hours. Filter the precipitate and concentrate the filtrate, the residue is used as it is. In a flask, introduce rac- (1R, 2R, 3S, 3aR, 8bS) -N- (2-chloroethyl) -1,8-dihydroxy-6,8-dimethoxy-3a- (4-methoxyphenyl) ) -3-phenyl-2,3,3a, 8b-tetrahydro-1H-cyclo [1)] benzofuran-2-carboxamide (45 mg, 0.083 mmol) in THF (1 mL). Cool to 0 ° C and add NaH (4.00 mg, 0.100 mmol). Leave to stir at room temperature for 30 minutes and then heat at 50 ° C for 2 hours. Add water and extract 2 times with ethyl acetate, combine the organic phases and dry over Na 2 SO 4, concentrate. The residue is purified on silica gel using a 97.5 / 2.5 DCM / MeOH mixture as eluent.
[0062] 1 H NMR (DMSO-D6, 4001 → 417, δ, ppm): 6.99 (m, 5H), 6.88 (d, 2H, J = 7.4 Hz), 6.58 (d, 2H, J); = 9.0 Hz), 6.27 (d, 1H, J = 1.9 Hz), 6.10 (d, 1H, J = 1.9 Hz), 5.76 (s, 1H), 5, Δ (s, 1H), 4.81 (d, 1H, J = 4.0 Hz), 4.59 (m, 1H), 4.18 (d, 1H, J = 14.0 Hz), 4, 06 (m, 2H), 3.80 (m, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.59 (s, 3H), 3.55 (m, 2H). ); LCMS (ES +, m / z): 504.30 [M + H] +. 2- Biological activity of the compounds according to the invention 2.1. Anti-proliferative activity of the compounds according to the invention (1050 in M) Culture of the lines and measurement of the cell viability: The line HCT116 (ATCC, CCL-247) resulting from a colon cancer was cultured in the MEM medium ( Minimum Essential Medium Eagle) supplemented with 2 mM LGlutamine (Sigma, G7513), 5% fetal calf serum (Sigma, F7524) and antibiotics (Sigma, A59-55). The protocol for determining the cytotoxic activity consists in seeding cells on 96-well plates (Perkin Elmer, 6005668) in a density of 1500 cells per well. After 24 hours of incubation, the test compound is applied to each well, using a series of diluted dilutions in dimethylsulfoxide solvent (DMSO) (Sigma, D8418), and this, from stock solutions at 10 mM in 100 % DMSO. Each of the dilutions was added to the cells 24 hours after seeding. Under these conditions, the final solvent concentration is 0.1% DMSO. A reading of the cell proliferation was made 72 hours after adding the products with the ATPLiteTM kit (Perkin Elmer, 6016947) and according to the manufacturer's recommendations. The analysis of the proliferation results was made by comparing with conditions where only the vehicle solvent (0.1% DMSO culture medium) was added to the cells. The dose-response curves obtained were analyzed using Prism 4.03 software (GraphPad Software Inc.), or by an equivalent analytical method, to determine the concentration of each compound to inhibit 50% of cell proliferation. (EC50).
[0063] By way of example, the cytotoxic properties of some compounds of the invention evaluated on the HCT116 line (human cell line of colon cancer) are reported in Table 1. product HCT116 (ECso) silvestrol 2.46E-09 47 1 , 10E-09 50 1.22E-09 42 2.16E-09 40 2.52E-09 46 2.59E-09 8 2.61E-09 15 3.83E-09 2 4.03E-09 41 4.20E Table 1. EC50 value of the compounds according to the invention and silvestrol. EC50 values are expressed in units of concentration (mol / L). 2.2. Anti-tumor activity of the compounds according to the invention The xenografts were established from MDA-MD-231 breast cancer cells (ATCC: HTB-26) in SCID mice (Harlan, UK) subcutaneously. The animals were treated and cared for in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996) and the European Directive EEC / 86/609, under the supervision of expert and authorized personnel. to carry out experimental studies with laboratory animals. All experiments were carried out in compliance with French and local regulations (Veterinary Services Department, Haute-Garonne, Toulouse) following the guidelines of an ethics committee, based on the UKCCCR guidelines for animal welfare. for experimental purposes in experimental oncology as previously indicated. Implantation of MDA-MB231 human tumor fragments is performed subcutaneously in the SCID mouse flank by trocar and for the study of tumor growth, the tumors are allowed to reach a median volume of 70-130 mm3. before starting the studies. After randomization in the treatment cages, the inhibitors were administered intravenously following a q1d5x3 treatment regimen (5 injections per week for 3 weeks). The mice were monitored and weighed daily. Tumors were measured with calipers and tumor volumes (mm3) were estimated by the following formula: volume = 0.5 (length X width2). Each experimental group contains 5 individuals. The efficacy of the treatment was evaluated by analyzing the median volume of the treated tumors relative to the median volume of the tumors treated by the vehicle (control). The evaluation criterion T / C corresponds to: [(median volume of the treated group, T / median volume of the control group, C) x 100]. This T / C ratio is expressed as a percentage. The optimal T / C value is the ratio that reflects the maximum growth inhibition achieved during the study. Maximum weight gains or losses, expressed as a percentage of the animals' initial weight, as well as the percentage of drug-related deaths (that is, percentage of treated animals that died before the control) were used to provide an evaluation of the toxicity of the compounds. In accordance with the NCI (National Cancer Institute) criterion, a dose is considered toxic if it induces a weight loss greater than -20% compared to the initial weight of the mouse or if it induces more than 20% of deaths ( Corbett et al J Exp Ther Oncol 1996, 1: 95-108). The results obtained are reported in Table 2.
[0064] 1VIDA-MB-231 Compound Dose Death T / C opt. Treatment schedule Activity (mg / kg) (%) (%) 1.4 100 Toxic 1 100 Toxic Silvestrol q1d5 x3 0.7 40 63 Toxic 0.5 0 83 No activity 0.2 0 92 No activity 2 q1d5 x3 0.2 0 37 Active 24 q1d5 x3 2.8 0 25 Active 30 q1d5 x3 0.7 0 15 Active 46 q1d5 x3 1.4 0 39 Active 19 q1d5 x3 1.3 0 26 Active 18 q1d5 x3 3, Active Active 2.5 0 40 Active 21 q1d5 x3 1 0 22 Active 22 q1d5 x3 1.4 0 21 Active Table 2. Anti-tumor activity of the compounds according to the invention and silvestrol20 Silvestrol is highly toxic from a dose of 0.7 mg / kg. Below this dose, silvestrol no longer shows any anti-tumor activity. The compounds according to the invention are on the contrary active at low doses to which they induce a significant decrease in the size of the tumors. No toxicity was found during the administration of the compounds according to the invention.

权利要求:
Claims (21)
[0001]
REVENDICATIONS1. Compound of the following general formula (I): (I) in the form of one of its enantiomers or a mixture of its enantiomers such as a racemic mixture, or a pharmaceutically acceptable salt and / or solvate thereof, in where: = represents a single bond or a double bond, n represents an integer from 1 to 10, R1 represents CO2Ri0, CONH2, NR1iR12, NRi3CORl4, NRi5CONRi6R17, NRisCSNR19R20, NR21SO2R22, NR23 CO2R24 or an optionally substituted heteroaryl preferably selected of the optionally substituted triazoles and oxadiazoles, R2 represents OH, or R1 and R2 together with the carbon atoms which carry them form an optionally substituted heterocycle, preferably chosen from the pyrimidine, pyrazole, pyrazolone, oxazoline, isoxazoline and oxazalanone rings, oxazalanethione, morpholinone and oxazepane optionally substituted, the optionally substituted heterocycle not being: HN NN 'N 20 1 or 1, carbon 1 denoting the carbon atom bearing the group R 1 and carbon 2 denoting the carbon atom carrying the group R 2, R 3 represents H, OR 25, CHOHCH 2 OH, CHO, N 3, NR 26 R 27, CO2R 28, CONR 29 R 30, NR38COR39, (O (CH2) m0 (CH2) p) r (CH2) qR31, (NR32 (CH2) wNR33 (CH2) x) y (CH2) zR34, ONR84R85, optionally substituted aryl, or optionally substituted heteroaryl, R4 is absent when = represents a double bond and R4 represents H or OH when = represents a single bond, R10 to R30, R32, R33, R38 and R39 represent, independently of each other, H or a (C1-C6) alkyl, aryl group , aryl- (C1-C6) alkyl or (C1-C6) alkyl-aryl, said group being optionally substituted by one or more groups selected from (C1-C6) alkyl, OR35, and NR36R37, or R11 and R12, or R16 and R17, or R19 and R20, or R26 and R27, or R29 and R30, together with the nitrogen atom carrying them, form an optionally substituted nitrogenous heterocycle, R31 and R34 represent, independently H, OR35, NR36R37 or a (C1-C6) alkyl, aryl, aryl- (C1-C6) alkyl, ONR86R87 or (C1-C6) alkyl-aryl group, said group optionally being substituted with one or more groups selected from (C1-C6) alkyl, OR35, and NR36R37, R35-R37 and R84-R87 represent, independently of each other, H or (C1-C6) alkyl, aryl or aryl- (C1-C6) alkyl, Ra represents a halogen atom (e.g. Br or Cl), CN or (C1-C6) alkoxy (such as methoxy), Rb is H or (C1-C6) alkoxy (such as methoxy), or Ra and Rb together form a -OCH2O- , and m, p, r, q, w, x, y, z represent, independently of each other, an integer from 1 to 4, provided that when R1 is CO2R10 or CONH2, R3 is OR25, CHOHCH2OH, CHO, N3, NR26R27, CO2R28, CONR29R30, NR38COR39, (O (CH2) m0 (CH2) p) r (CH2) qR31, or (NR32 (CH2) wNR33 (CH2) x) y (CH2) zR34 with R25 H.
[0002]
2. Compound according to claim 1, characterized in that n is between 1 and 4.
[0003]
3. Compound according to claim 1 or 2, characterized in that: = represents a single bond, R1 represents CO2R10 or CONH2, R3 represents OR25, CHOHCH2OH, CHO, N3, NR26R27, CO2R28, CONR29R30, NR38COR39, (O (CH2) m0 (CH2) p) r (CH2) qR31, (NR32 (CH2) wNR33 (CH2) x) y (CH2) zR34, ONR84R85, optionally substituted aryl, or optionally substituted heteroaryl, R4 is H, and R10 is H or (C 1 -C 6) alkyl group.
[0004]
4. Compound according to claim 1 or 2, characterized in that: - = represents a single bond, - R1 represents NR11R12, NR 13CORH, NR 1 C 5 NR 1 6 Ri 7, NR 1 8CS NR 1 9 R 2 o OR NR 2 1 S 02R22, and - R4 represents H, and preferably R3 represents H.
[0005]
5. Compound according to claim 1 or 2, characterized in that: = represents a single bond, N - N, - R41 N - N 0 - N ') - (N - R42, L, - R43 R1 represents i : Z40, R0 is H or (C1-C6) alkyl, aryl or aryl (C1-C6) alkyl, R41 to R43 are independently another, H or (CiC6) alkyl, aryl, aryl (C1-C6) alkyl, OR44, SR45 or NR46R47, R44 to R47 are independently of each other H or (C1C6) alkyl, aryl or ary1- (C1-C6) alkyl, said group being optionally substituted by one or more groups selected from (C1-C6) alkyl, OR48, NR49R50, and polyamines, or R46 and R47 together with the atom nitrogen which carries them, a nitrogen heterocycle optionally substituted with a (C 1 -C 6) alkyl group, and -R 48 to R 50 represent, independently of each other, H or a (C 1 -C 6) alkyl, aryl or aryl (C 1 -C 6) group ) alkyl.
[0006]
6. Compound according to claim 1 or 2, characterized in that the unit R4 is R2 R1 represents: ## STR2 ## R65 ## STR2 ## 66,,,,,,,,,,,,,,,,,,,,,,,,,,, In which: R 60, R 61, R 65, R 67, R 68, R 72 and R 75 represent, independently of one another, H or a compound of formula (I); (C1-C6) alkyl, aryl or aryl (C1-C6) alkyl group, R69 and R70 representing, independently of one another, H or a (C1-C6) alkyl, aryl or aryl group (Ci -C6) alkyl, or together with the nitrogen atom carrying them, a nitrogen heterocycle optionally substituted by a (CiC6) alkyl group, R62, R63, R64, R66, R71, R73 and R74 representing, independently of each other, H or a (C1-C6) alkyl, aryl, aryl (C1-C6) alkyl, OR76, SR77 or NR78R79 group, and R76 to R79 representing, independently of one another, H or a group (CiC6 ) alkyl, aryl, aryl- (C1-C6) alkyl, or CN or R78 and R79 together with the nitrogen atom carrying them a nitrogenous heterocycle optionally substituted by a (C 1 -C 6) alkyl group.
[0007]
7. Compound according to any one of claims 1 to 6, characterized in that, when = represents a single bond, R1 and R2 are located on the same side of the noncyclopentane to which they are attached, and preferably on the opposite side to the OH groups. , phenyl and m-Rb-p-Ra-phenyl also bound to this cyclopentane ring.
[0008]
8. Compound according to claim 1, characterized in that it is chosen from the following compounds, in the form of one of their enantiomers or a mixture of their enantiomers such as a racemic mixture: H2N HOW ° OH o, NH H2 --- / ----- 1 N0 0 0 * * * * 0 the »0, II. c) H2N H6 HC5 O H2N O- OH O 0 -OH 0 ----- N 0 le0 - 0 - H2Nr ______ r ____ / HO: H6 0 0 -OH ° 0-OH 0 /_____y_..._/0 HO 0 0 * * - 0 0 'OH. . ## STR2 ## ## STR1 ## ## STR2 ## ## STR2 ## wherein Y is 0, ## STR2 ## ## STR2 ## ## STR2 ## ## STR6 ## ## STR2 ## O-OH ## STR13 ## ## STR2 ## ## STR2 ## ## STR1 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR1 ## 0HO HO N-N 0 le. °. ## STR2 ## ## STR2 ## where: ## STR1 ## - Z 11111 ', Z - z.,... - to' ... a = Op 0 i 0 * 0 / -0 (--0 ° 0H N --- / II ..). 0 // a a 1 1 1 1 1 01 01 ((((((((((((((((((((( Z --- (* __ I Z1 the Z ---: (- I 0 *, -: I zi 0 no. A I 0 1 i 0 * / ° 0 0 -0 (--- N 0 - ## EQU1 ## where ## EQU1 ## where ## STR2 ## ## STR2 ## ## STR1 ## ## STR2 ## where ## STR2 ## where ## STR2 ## where ## STR2 ## ## STR5 ## wherein R 1, R 2, R 4, NH 4, NH 4, NH 4, NH 4, NH 4, NH 4, NH 4, NH 4, NH 4, OH c) - 0 0 O- 0 HO / 0 -N --- N + N / 0 * 4. * 4. 0 * NH 0- NH H 11 0 0 4. H O- 0 O- H2N / 0 H2N ## STR2 ## ## STR2 ## ## STR2 ## / 0 0 111 - 0 li the O 0 ## STR2 ## and their pharmaceutically acceptable salts and / or solvates.
[0009]
9. A compound according to any one of claims 1 to 8 for use as a medicament.
[0010]
10. A compound according to any one of claims 1 to 8 for its use in the treatment of cancer.
[0011]
11. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 8 and at least one pharmaceutically acceptable excipient.
[0012]
12. Process for the preparation of a compound of formula (I) according to claim 1 wherein R3 = H comprising the reaction of a compound of formula (II) below: HO Rb Ra (II) for which Ra, Rb, R1 , R2 and R4 are as defined in claim 1, with an alcohol of the formula H- (CH2) .OH, for which n is as defined in claim 1, under Mitsunobu conditions.
[0013]
13. Process for the preparation of a compound of formula (I) according to claim 1 wherein R3 = N3, NR38COR39 or NR26R27 comprising: (a1) to obtain a compound of formula (I) for which R3 = N3, the reaction of a compound of formula (III) below: LG1 Rb Ra (III) for which Ra, Rb, R1, R2, R4 and n are as defined in claim 1 and LG1 represents a leaving group such as an atom of halogen or an activated hydroxyl function, with an azide of formula MN3, M representing an alkali metal or a group SiRR'R "with R, R 'and R" each representing, independently of one another, a group (Ci-C6) alkyl or aryl, (b1) to obtain a compound of formula (I) for which R3 = NH2, the reduction of the azide function of a compound of formula (I) for which R3 = N3 optionally obtained according to step (a); ), (cl) to obtain a compound of formula (I) for which R3 = NR38COR39 or NR26R27 and at least one of R26 and R27 does not represent a hydrogen atom ene, the substitution of a compound of formula (I) for which R3 = NH2 optionally obtained according to step (31).
[0014]
14. Process for the preparation of a compound of formula (I) according to claim 1 wherein R3 = CHOHCH2OH, CHO, CO2R28, CONR29R30, OR25, (O (CH2) m0 (CH2) p), (CH2) qR3i, NR26R27 or (NR32 (CH2) wNR33 (CH2) x) y (CH2) zR34, comprising: (a2) to obtain a compound of formula (I) wherein R3 = CHOHCH2OH, the vinyl function dihydroxylation reaction of compound of formula (IV) below: Rb Ra (IV) wherein Ra, Rb, R1, R2, R4 and n are as defined in claim 1, (b2) to obtain a compound of formula (I) for which R3 = CHO, the oxidative cleavage of the CHOHCH2OH group of a compound of formula (I) for which R3 = CHOHCH2OH optionally obtained according to step (a2), (c2) to obtain a compound of formula (I) for which R3 = CO2H the oxidation of the aldehyde function of a compound of formula (I) for which R3 = CHO optionally obtained according to step (b2), (d2) to obtain a compound of formula (I) for which R3 = CO2R28 and R28 H, substitution of the function carboxylic acid of a compound of formula (I) for which R3 = CO2H optionally obtained according to step (c2), (e2) to obtain a compound of formula (I) for which R3 = CONR29R30, the reaction of a compound of formula (I) for which R3 = CO2R28, optionally obtained according to step (b2) or (c2), with an amine of formula HNR29R30, (f2) to obtain a compound of formula (I) for which R3 = OH the reduction of the aldehyde function of a compound of formula (I) for which R3 = CHO optionally obtained according to step (b2), (g2) to obtain a compound of formula (I) for which R3 = OR25 or ( 0 (CH 2) 1110 (CH 2) p) r (CH 2) q R 31 with R 25 H, the substitution of the hydroxyl function of a compound of formula (I) for which R 3 = OH optionally obtained according to step (f 2), ( h2) to obtain a compound of formula (I) for which R3 = NR26R27, the reductive amination of the aldehyde function of a compound of formula (I) for which R3 = CHO, optionally obtained according to step (b2), in the presence of an amine of formula HNR26R27.
[0015]
15. Process for the preparation of a compound of formula (I) according to claim 5, wherein R1 represents R40 or t0, comprising the reaction of a compound of following formula (V): (V) wherein Ra, Rb, R2, R3, R4 and n are as defined in claim 1, with: (1) a cyanogen of formula Hal-CN, for which Hal represents an atom R46 N., halogen, or an isothiocyanate of formula S optionally followed by one or more substitution steps to give a compound of formula (I) NN -NR46R47 wherein R1 represents 3- 0, or (2) sulfide of carbon (CS2) in the presence of a base, optionally followed by one or more substitution steps to give a compound of formula (I) for - NN 11._. Wherein R 1 represents "III-O, or (3) carbonyldiimidazole in the presence of a base, optionally followed by one or more substitution steps to give a compound of formula (I) for --NN 2 -> 0 Wherein R 1 represents "1'-O, or (4) a carboxylic acid of formula R42COOH, wherein R42 represents a (C1-C6) alkyl, aryl or aryl (C1-C6) alkyl group, in the presence of POC13. for NN / R42 give a compound of formula (I) wherein R1 represents "III-O, or NH R46 s (5) an isothiourea of formula R47, for which Alk is (C1-C6) alkyl, in the presence of a base, optionally followed by one or more substitution steps to give a compound of formula (I) for which R1 represents R4o, or NH Alk (6) an imidate of formula R41O, wherein R41 is (C1-C6) alkyl, aryl or aryl (C1-C6) alkyl and Alk is (C1-C6) alkyl, in the presence of a base, optionally followed by or a plurality of substitution steps to give a compound of formula (I) wherein R1 is N 'N1) - R41 N, or (7) triethyl orthoformate optionally followed by one or more substitution steps to give a compound of formula (I) for which R1 represents -NN R4o for which R1 represents "111-N comprising the reaction of a compound of
[0016]
16. Process for the preparation of a compound of formula (I) according to claim 5, wherein R1 = CO2R10 and R10 represents a (C1-C6) alkyl group, with an INII, OH hydroxy-imidamide. of formula R43 NH in the presence of a base.
[0017]
17. A process for the preparation of a compound of formula (I) according to claim 6, wherein R 1 is N, N-R 61 for which R 1 is R 11, comprising the reaction of a compound of formula a double bond, R1 = CO2R10, R2 (I), for which = represents = OH, R4 = H and R10 = (C1-C6) alkyl, with a hydrazine of formula H2N-NH2, optionally followed by one or several substitution steps.
[0018]
18. A process for the preparation of a compound of formula (I) according to claim 6, wherein RY represents a reaction of a compound of the following formula (VI): Rb Ra (VI) for which Ra, Rb, R3 and n are as defined in claim 1, and Rgo and R81 represent, independently of one another, a (C 1 -C 6) alkyl group, NH 2 NH R 62 with a guanidine derivative of the formula
[0019]
19. Process for the preparation of a compound of formula (I) according to claim 6, for which R65 is a compound comprising: ## STR1 ## wherein R6 is a reaction of a compound of formula (VII) below: wherein Ra, Rb, R3 and n are as defined in claim 1, Alk is (C1-C6) alkyl, and R82 is R64 or R66, with: (1) hydroxylamine of formula HO-NH2 in the presence of a base, to give one (2) R4 js OH -L, `11, R2 0 compound of formula (I) for which I-R1 N a hydrazine of formula H2N-NH2, followed substitution steps for give a represents -64, or optionally of a compound of formula or more (I) for which R65 rrss R4 R2 'sss N represents R66 s'Alk Rb Ra (VII)
[0020]
20. Process for the preparation of a compound of formula (I) according to claim 6, wherein rsss R4 R2 represents OR% A R1 comprising the reaction of a compound of formula (VIII) below: HO 0 HO R83 Rb Ra ( VIII) for which Ra, Rb, R3 and n are as defined in claim 1, and R83 represents a CO2H group optionally in an activated form, with: (1) an azide, under Curtius rearrangement conditions, optionally followed one or more substitution steps, to give a compound R2 5-Ser O ) `1 . R1 N R67 - of formula (I) for which I- represents, or LG2 ..... '.. R73 ........, (2) an amine of formula H2 N R74, for which LG2 represents a leaving group such as halogen, in the presence of a base, optionally followed by one or more substitution steps, to give a compound of formula (I) for which R 4 s I-Ri represents 0 R73 R74 R75 0 N.15
[0021]
21. A process for the preparation of a compound of formula (I) according to claim 6, wherein epsilonates for which sres-. R71 - /. N0 R72, comprising the reaction of a compound of formula (I), for which = represents a single bond, R1 = NH2, R2 = OH and R4 = H, with: (1) carbon disulfide (CS2) in the presence of a base, optionally followed by one or more substitution steps, to give a compound of formula (I ) for which R1 represents 68, or (2) a cyanogen of formula Hal-CN, for which Hal represents a halogen atom, in the presence of a base, optionally followed by one or more substitution steps, to give a compound of formula (I) wherein R4 R2 is rsssOv, R69 /) - N R1 N R70 is, or LG3 R71 AIL (3) an ester of formula Wherein Alk represents a (C 1 -C 6) alkyl group and LG 3 represents a leaving group such as a halogen, in the presence of a base, followed optionally by one or more steps of the substitution, to give a compound of formula (I) for which rssi.0 R71 N 0 represents R72

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同族专利:

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公开号 | 公开日

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JP2017519796A|2017-07-20|

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TR201819805T4|2019-01-21|

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EP3164393A1|2017-05-10|

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US20170137400A1|2017-05-18|

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US10519125B2|2019-12-31|

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DK3164393T3|2019-01-21|

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US20180086729A1|2018-03-29|

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WO2016001441A1|2016-01-07|

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ES2700156T3|2019-02-14|

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EP3418273B1|2022-01-12|

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JP2022000455A|2022-01-04|

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US10047064B2|2018-08-14|

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JP6951406B2|2021-10-20|

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JP6637954B2|2020-01-29|

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EP3418273A1|2018-12-26|

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JP2020063289A|2020-04-23|

---

PL3164393T3|2019-03-29|

---

EP3164393B1|2018-09-19|

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FR3023290B1|2016-08-19|

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法律状态:
2015-07-31| PLFP| Fee payment|Year of fee payment: 2 |

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2016-01-08| PLSC| Publication of the preliminary search report|Effective date: 20160108 |

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2016-07-29| PLFP| Fee payment|Year of fee payment: 3 |

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2017-07-31| PLFP| Fee payment|Year of fee payment: 4 |

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2018-07-27| PLFP| Fee payment|Year of fee payment: 5 |

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2019-07-31| PLFP| Fee payment|Year of fee payment: 6 |

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2020-07-31| PLFP| Fee payment|Year of fee payment: 7 |

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2021-07-29| PLFP| Fee payment|Year of fee payment: 8 |

优先权:

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申请号 | 申请日 | 专利标题

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FR1456474A|FR3023290B1|2014-07-04|2014-07-04|DERIVATIVES OF FLAVAGLINES|FR1456474A| FR3023290B1|2014-07-04|2014-07-04|DERIVATIVES OF FLAVAGLINES|

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JP2017500083A| JP6637954B2|2014-07-04|2015-07-06|Flabagulin derivative|

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TR2018/19805T| TR201819805T4|2014-07-04|2015-07-06|FLAVAGLIN DERIVATIVES.|

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PCT/EP2015/065294| WO2016001441A1|2014-07-04|2015-07-06|Flavagline derivatives|

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US15/323,650| US10047064B2|2014-07-04|2015-07-06|Flavagline derivatives|

---

EP18187037.9A| EP3418273B1|2014-07-04|2015-07-06|Flavagline derivatives|

---

PL15733767T| PL3164393T3|2014-07-04|2015-07-06|Flavagline derivatives|

---

DK15733767.6T| DK3164393T3|2014-07-04|2015-07-06|Flavagline derivatives|

---

ES15733767T| ES2700156T3|2014-07-04|2015-07-06|Derivatives of flavaglins|

---

EP15733767.6A| EP3164393B1|2014-07-04|2015-07-06|Flavagline derivatives|

---

US15/829,630| US10519125B2|2014-07-04|2017-12-01|Flavagline derivatives|

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JP2019230768A| JP6951406B2|2014-07-04|2019-12-20|Flabagulin derivative|

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JP2021154798A| JP2022000455A|2014-07-04|2021-09-22|Hula bagulin derivative|