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WO2023280817A1 - Novel compounds derived from schweinfurthins g, e and f - Google Patents

Novel compounds derived from schweinfurthins g, e and f Download PDF

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Publication number
WO2023280817A1
WO2023280817A1 PCT/EP2022/068525 EP2022068525W WO2023280817A1 WO 2023280817 A1 WO2023280817 A1 WO 2023280817A1 EP 2022068525 W EP2022068525 W EP 2022068525W WO 2023280817 A1 WO2023280817 A1 WO 2023280817A1
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Prior art keywords
group
methoxy
trimethyl
hexahydro
equal
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PCT/EP2022/068525
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French (fr)
Inventor
Fanny ROUSSI
Sandy DESRAT
Jérôme BIGNON
Céline RAMPAL
David Kovacs
Bruno ANTONNY
Joëlle BIGAY
Bruno MESMIN
Joël POLIDORI
Thierry Virolle
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Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Nice Sophia Antipolis UNSA
Original Assignee
Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Nice Sophia Antipolis UNSA
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Priority to CA3224533A priority Critical patent/CA3224533A1/en
Priority to EP22744437.9A priority patent/EP4366827A1/en
Publication of WO2023280817A1 publication Critical patent/WO2023280817A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel schweinfurthin derivatives. It also relates to the pharmaceutical application of these novel schweinfurthin derivatives, in particular on the basis of their anticancer biological action and also their biological action on oxysterol- binding protein 1 (OSBP or OSBP1), for the prevention and/or treatment notably of cancers, viral diseases and neurodegenerative diseases. It also relates to the synthetic process for obtaining them and also to medicaments containing them. It also relates to novel intermediate compounds.
  • OSBP or OSBP1 oxysterol- binding protein 1
  • SWs are natural products isolated from plants of the genus Macaranga (Euphorbiaceae). They have powerful and selective cytotoxic activity on the National Cancer Institute (NCI) panel of 60 human cancer cell lines. They are particularly active on glioblastoma, kidney and certain leukaemia lines (acute lymphoblastic leukaemia or myeloma). Their cytotoxicity profile bears no resemblance to the profiles of the molecules currently used in anticancer chemotherapy, indicating that they act via a new biological target. This targeted biological activity makes schweinfurthins attractive as the leading members of a new series of novel anticancer agents.
  • NCI National Cancer Institute
  • SW-G schweinfurthin G
  • OSBP oxysterol- binding protein
  • the schweinfurthins G and E are the ones with the best cytotoxic activity, which explains why research has rather been focused on these two schweinfurthin derivatives G and E.
  • schweinfurthin G and schweinfurthin E have a lack of metabolic stability and a short half-life. This feature is one of the reasons why schweinfurthin G or schweinfurthin E has never been used hitherto in vivo. This observation can be extended to schweinfurthine F.
  • Schweinfurthine H is, however, not very active. Only two publications report studies on schweinfurthin derivatives.
  • cancer treatment The main types of cancer treatment are surgery, radiotherapy, “conventional” chemotherapy (involving cytotoxic agents), targeted therapies (specifically targeting certain mechanisms involved in cell regulation and growth), hormone therapy (adapted in the case of cancers that are sensitive to the action of hormones naturally produced by the body), and immunotherapy (directed towards stimulating the patient’s immune system against the tumour cells).
  • chemotherapy which remains one of the most effective treatments, is based on a cytotoxic effect: a molecule kills cancer cells in order to stop tumour growth.
  • these treatments give rise to serious side effects for patients due to the lack of selectivity, which notably leads to damage to healthy cells.
  • drugs are often dosed at minimum levels, to the detriment of their efficacy.
  • Neurodegenerative diseases are, for their part, frequent, and their frequency increases with age, even though certain metabolic and degenerative diseases can occur as early as childhood. Due to the progressive ageing of the population and the lack of curative treatments, the number of people suffering from neurodegenerative diseases has considerably increased in recent decades and is likely to grow steadily in the years to come.
  • Leishmaniases are parasitic diseases that cause severely debilitating or even fatal skin or visceral conditions if left untreated. They are caused by various parasites of the genus Leishmania, transmitted by the bite of insects commonly known as sandflies. Each year, 700,000 to 1 million new cases of leishmaniasis are reported worldwide, and these parasites are now considered emerging neglected diseases in Europe.
  • the invention is specifically directed towards meeting these needs.
  • the present invention relates to novel compounds derived from schweinfurthins E, F and G of formula (I), pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof: in which: represents a single or double bond,
  • R 1 represents a hydroxyl group, a (C1-C5)alkoxy group, a (C 2 -C 5 )alkenyloxy group, a (C 2 -C 5 )alkynyloxy group, or a group -OCONH(CH 2 ) n COOR a , in which n represents an integer between 2 and 6, and R a : represents a (C 1 -C 4 )alkyl group - R 2 represents a hydrogen atom, or alternatively, R 1 and R 2 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation,
  • R 3 and R 7 independently represent a hydrogen atom
  • R 4 represents a hydroxyl group, a group , m being equal to 1, 2 or 3, a group , n being equal to 1, 2 or 3, preferably 1 or 2, a group or , in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are independently a (C1-C3)alkyl group, a group , in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(0)OCH 3 group; a halogen atom, in particular a chlorine atom, an amino group, or a group or a group -OCOR b , in which R b represents a (C 1 -C 4 )alkyl group, - R 5 represents
  • R 4 and R 5 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C 1 -C 4 )alkyl groups, - R 6 represents a hydroxyl group, a (C 1 -C 6 )alkoxy group, a group , m being equal to 1, 2 or 3, a group , n being equal to 1, 2 or 3, preferably 1 or 2, a group or
  • R is a hydrogen atom or a methyl group and R’ and R’ ’ are independently a (C 1 -C 3 )alkyl group, or a group , in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(O)OCH 3 group; a halogen atom, in particular a chlorine atom, or an amino group, a group -OCOR c , in which R c represents a (C 1 -C 4 )alkyl group, or a group -OCONH(CO) p R d , in which p represents an integer chosen from 0 or 1, R d represents a (C 1 -C 6 )alkyl group optional
  • R 8 and R 9 independently represent a hydrogen atom, a hydroxyl group, or a group -OCOR h , in which R h represents a hydrogen atom or a (C 1 -C 5 )alkyl group, and in which at least: a. R 4 and R 5 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C 1 -C 4 )alkyl groups, or b.
  • R 5 represents a group of formula and at least one of the following conditions is confirmed: i.
  • R 1 and R 2 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation, ii. at least one from among R 1 , R 4 and R 6 is a (C 2 -C 5 )alkenyloxy group or a (C 2 -C 5 )alkynyloxy group, iii.
  • R 8 represents a group -OCOR h , in which R h is a hydrogen atom or a (C 1 -C 5 )alkyl group, or iv. at least one from among R 3 and R 7 is a halogen atom, it being understood that when R 5 represents a group of formula then at least R 4 or R 6 is other than a hydroxyl group, and it being understood that the compound having the following formula is excluded
  • the present text also describes compounds derived from schweinfurthins E, F and G of formula (I), pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof: in which: represents a single or double bond, - R 1 represents a hydroxyl group, a (C 1 -C 5 )alkoxy group, a (C 2 -C 5 )alkenyloxy group, a (C 2 -C 5 )alkynyloxy group, or a group -OCONH(CH2) n COOR a , in which n represents an integer between 2 and 6, and R a represents a (C 1 -C 4 )alkyl group,
  • R 2 represents a hydrogen atom or a (C 2 -C 5 )alkenyl group, or alternatively,
  • Ri and R2 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation,
  • R 3 and R 7 independently represent a hydrogen atom or a halogen atom, for example a bromine atom,
  • R 4 represents a hydroxyl group, a group , m being equal to 1, 2 or 3, and a group , n being equal to 1, 2 or 3, preferably 1 or 2, a group or
  • R is a hydrogen atom or a methyl group and R’ and R’ ’ are independently a (C 1 -C 3 )alkyl group, a group , in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 2 or 3, q is equal to 1, 2,
  • X is a hydrogen or halogen atom, in particular a chlorine atom, or an amino group, or a group -OCOR b , in which R b represents a (C 1 -C 4 )alkyl group, - R 5 represents a group of formula or alternatively,
  • R 4 and R 5 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C 1 -C 4 )alkyl groups, - R 6 represents a hydroxyl group, a (C 1 -C 6 )alkoxy group, a group , m being equal to 1, 2 or 3, a group , n being equal to 1, 2 or 3, preferably 1 or 2, a group or
  • R is a hydrogen atom or a methyl group and R’ and R” are independently a (C 1 - C3)alkyl group, a group , in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom, a halogen atom, in particular a chlorine atom, or an amino group, a group -OCOR c , in which R c represents a (C 1 -C 4 )alkyl group, or a group -OCONH(CO) p R d , in which p represents an integer chosen from 0 or 1, R d represents a (C 1 -C 6 )alkyl group optionally substituted with a halogen atom such as a chlorine atom, with a sugar radical, with a group -COOR e , in which R e represents a (C 1 -C 4
  • R 8 and R 9 independently represent a hydrogen atom, a hydroxyl group, or a group -OCOR h , in which R h represents a hydrogen atom or a (C 1 -C 5 )alkyl group, and in which at least: a. R 4 and R 5 , together with the ring bearing them, form a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C 1 -C 4 )alkyl groups, or b.
  • R 5 represents a group of formula and at least one of the following conditions is confirmed: i.
  • R 1 and R 2 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation, ii. at least one from among R 1 , R 4 and R 6 is a (C 2 -C 5 )alkenyloxy group or a (C 2 -C 5 )alkynyloxy group, iii.
  • R 8 represents a group -OCOR h , in which R h is a hydrogen atom or a (C 1 -C 5 )alkyl group, iv.
  • R 2 represents a (C 2 -C 5 )alkenyl group, or v. at least one from among R 3 and R 7 is a halogen atom.
  • the present invention also relates to a compound of formula (I) according to the present invention, or to at least one compound (1) to (19), (21), (23), (31) to (46), (48) to (71) as defined below, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical compositions containing them, for its use as a medicament.
  • the present invention also relates to a compound of formula (I) according to the present invention, or to at least one compound (1) to (19), (21), (23), (31) to (46), (48) to (71) as defined below, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical compositions containing them, for its use as an oxysterol binding protein 1 (OSBP) inhibitor.
  • OSBP oxysterol binding protein 1
  • the present invention also relates to a compound of formula (I) according to the present invention, or to at least one compound (1) to (19), (21), (23), (31) to (46), (48) to (71) as defined below, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical compositions containing them, for its use in the prevention, inhibition and/or treatment of cancers, neurodegenerative diseases, dyslipidaemia, hypercholesterolaemia, parasitic diseases and/or viral diseases.
  • a compound of formula (I) according to the present invention or at least one compound (1) to (19), (21), (23), (31) to (46), (48) to (71) as defined below, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical compositions containing them, for its use for the prevention, inhibition and/or treatment of cancers, in particular breast cancer, including triple negative breast cancer, osteosarcoma, kidney cancer, head and neck cancer, prostate cancer, colorectal cancer, colon cancer, gall bladder cancer, bile duct cancer (cholangiocarcinoma), gastrointestinal cancer, gastric cancer, hepatocellular carcinoma, lymphoma, lung cancer, small cell lung cancer, non- small cell lung cancer, pancreatic cancer, pancreatic carcinoma, stomach cancer, brain cancer, metastasis, leukaemia, acute
  • the compound of formula (I) is as defined previously, it being understood that when R 4 and R 5 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C 1 -C 4 )alkyl groups, then R 1 is other than a hydroxyl group.
  • the compound of formula (I) is as defined previously, it being understood that when R 4 and R 5 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C 1 -C 4 )alkyl groups, then R 8 and R 9 are simultaneously other than a hydroxyl group.
  • the present invention also relates to a process for preparing a compound of formula (la”) in which R 1 and R 6 are as defined previously and at least one from among R 8 and R 9 represents a group -OCOR h as defined previously, and in particular an -OCHO group or an -OCOCH 3 group, and in which R 2 is a hydrogen atom, or a (C 2 -C 5 )alkenyl group, such as an allyl group or any of the pharmaceutically acceptable salts thereof, comprising at least one step of intramolecular cyclization of the geranyl chain into pyran, of a compound of general formula (II), accompanied by esterification of the secondary alcohol of the hexahydroxanthene unit
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I) according to the present invention or at least one compound (1) to (19), (21), (23), (31) to (46), (48) to (71) as defined below, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof, and at least one pharmaceutically acceptable excipient.
  • the inventors have found that the compounds of formula (I) according to the present invention show anticancer efficacy, in particular against glioblastoma, while at the same time demonstrating improved metabolic stability, in particular with respect to the reference schweinfurthin to be compared with the compound to be considered.
  • U87 cells are a human glioblastoma cancer cell line (GBM).
  • A549 cells are adenocarcinomic human alveolar basal epithelial cells and are a cell line of choice for confirming cytotoxic activity as they are known to be less sensitive to schweinfurthins.
  • the metabolic activity was evaluated in comparison with natural schweinfurthin, to which it is chemically the closest; making it possible to confirm the fact that all the compounds of the invention effectively show improved metabolic stability with respect to the structurally closest schweinfurthin.
  • OSBP oxy sterol binding protein 1
  • room temperature means a temperature of between 18°C and 30°C, preferably between 18°C and 25°C.
  • C t -C z denotes a carbon-based chain which may contain from t to z carbon atoms, where t and z may, for example, take values from 1 to 25; for example C 1 -C 3 is a carbon-based chain which may contain from 1 to 3 carbon atoms.
  • alkyl denotes a linear or branched monovalent saturated aliphatic group, which may, for example, comprise from 1 to 25 carbon atoms, and preferably from 1 to 5 carbon atoms. Examples that may be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. groups.
  • alkenyl denotes a linear or branched unsaturated aliphatic group comprising at least one double bond; for example, a Cx to Cz alkenyl group represents a linear or branched unsaturated carbon-based chain of x to z carbon atoms. Mention may notably be made of vinyl, 1-propenyl, 2-propenyl and butenyl groups or an allyl group.
  • alkynyl denotes a linear or branched, unsaturated aliphatic group comprising at least one triple bond; for example, a Cx to Cz alkynyl group represents a linear or branched unsaturated carbon-based chain of x to z carbon atoms. Mention may notably be made of an ethynyl group, a propynyl group or a pentynyl group.
  • alkoxy denotes an -O-alkyl group. Examples that may be mentioned include a methoxy group or an ethoxy group.
  • alkenyloxy denotes an -O-alkenyl group.
  • An example that may be mentioned is a propenyloxy group.
  • alkynyloxy denotes an -O-alkynyl group. Examples that may be mentioned include a propynyloxy or pentynyloxy group.
  • halogen denotes chlorine, fluorine, bromine or iodine, and notably denotes chlorine, fluorine or bromine, more particularly chlorine.
  • phenyloxo denotes a -CO-phenyl group.
  • sugar radical denotes a natural or non-natural furanose radical or hexose radical.
  • Non natural sugar radicals may, for example, comprise alkylated or acylated hydroxyl and/or amine residues on the ring, such as ether, ester and amide substituents.
  • Other non-natural sugar radicals may comprise H, hydroxyl, ether, ester or amide substituents in positions on the ring where these substituents are not present in natural sugars.
  • the sugar radical does not include a substituent in its usual position on the natural sugar; this case corresponds to the deoxy sugar radical.
  • Other examples of non-natural sugars include oxidized (e.g. -onic and -uronic acids) and reduced (sugar alcohol) carbohydrates.
  • the sugar residue may be a monosaccharide, oligosaccharide or polysaccharide.
  • glucose As natural sugar radicals that may be used in the context of the present invention, mention may be made of glucose, galactose, fucose, mannose, xylanose, ribose, N-acetylglucose (GlcNAc), sialic acid and N-acetylgalactose (GalNAc).
  • protecting group refers to a functional group introduced into the molecule from a chemical function to mask all or part of its reactivity.
  • pharmaceutically acceptable denotes 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 and/or human pharmaceutical use.
  • pharmaceutically acceptable salt of a compound is intended to denote salts that are pharmaceutically acceptable, as defined herein, and which have the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, glycolic acid, 2- hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid and the like; and (2) salts formed when an acid proton present in the parent compound is either replaced with a metal ion, for example an alkali metal ion (such as Na+, K+ or Li+), an alkaline-earth metal
  • Acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.
  • Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • hydrate or solvate refers to forms of association or combination with one or more water molecules or with a solvent.
  • racemic forms denote racemates, enantiomers, diastereoisomers, epimers, tautomers and conformational isomers.
  • a racemic form is a mixture of two enantiomers in a ratio of 55:45 to 45:55.
  • the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R 1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH2) n COOR a , in which n is equal to 3, 4 or 5, in particular equal to 3 or 5, and R a represents a methyl or ethyl group, in particular ethyl, a propenyloxy group or a propynyloxy group.
  • the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R 1 and R 2 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and an unsaturation, in particular a group
  • the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R 4 represents a hydroxyl group, a group , m being equal to 1 or 3, a group , n being equal to 1 or 2, a group or
  • R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups
  • a group in which s is equal to 0, 1 or 2, t is equal to 1 or 3, p is equal to 0, 2 or 3, q is equal to 6, and
  • X is a hydrogen atom, a halogen atom, in particular a chlorine atom, a phenyl group, a phenyloxo group, the phenyl group being substituted with a methoxy group, a -C(O)OCH 3 group or a group or a -OCOCH3 group.
  • the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R 5 represents a group of formula
  • the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R 4 and R 5 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two methyl groups, in particular a group
  • the present patent application relates to the compound of formula (I) as defined previously, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non- racemic mixtures thereof, in which R 6 represents a hydroxyl group, a methoxy or ethoxy group, a group , m being equal to 1 or 3, a group , n being equal to 1 or 2, a group or , in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups, an -OCOCH3 group, an -OCONHCOCH2CI group, a group , in which s is equal to 0, t is equal to 1, p is equal to 0, q is equal to 1, and X is a hydrogen atom, a phenyl or phenyloxo group, the phenyl group being substituted with a methoxy group or a -
  • the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R 8 and R 9 independently represent a hydrogen atom, a hydroxyl group, an -OCHO group, or an -OCOCH3 group.
  • substitution of the (C 1 -C 6 )alkyl group it may alternatively be located at the end of the chain or in any position on the chain. According to one variant of the invention, the substitution, when is present, is at the end of the chain. According to another of its aspects, the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, represented by formula (la):
  • R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are as defined above, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
  • the present patent application relates to the compound of formula (la) as defined previously, in which: represents a single or double bond,
  • R 3 and R 7 are as defined previously, and more particularly represent a hydrogen atom
  • R 1 represents a hydroxyl group, a (C 1 -C 5 )alkoxy group, a (C 2 -C 5 )alkenyloxy group, a (C 2 -C 5 )alkynyloxy group, or a group -OCONH(CH 2 ) n COOR a , in which n represents an integer between 2 and 6, and R a represents a (C 1 -C 4 )alkyl group,
  • R 2 represents a hydrogen atom, or alternatively,
  • R 1 and R 2 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation,
  • R 8 and R 9 independently represent a hydrogen atom, a hydroxyl group, or a group -OCOR h , in which R h represents a hydrogen atom or a (C 1 -C 5 )alkyl group.
  • the compound of formula (la) as defined above is such that
  • R 1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH2) n COOR a , in which n is equal to 3, 4 or 5, in particular equal to 3 or 5, and R a represents a methyl or ethyl group, in particular ethyl, a propenyloxy group, or a propynyloxy group,
  • R 2 represents a hydrogen atom or R 1 and R 2 form, together with the ring bearing them, a 6-membered ring comprising an oxygen atom and an unsaturation, in particular a group
  • - R 6 represents a hydroxyl group, a methoxy or ethoxy group, a propynyloxy group, an -OCOCH3 group, an -OCONHCOCH2CI group, or a group -OCONH(CH 2 ) q COOR k , in which q represents an integer chosen from 3, 4 or 5, in particular 3 and 5, and R k represents a methyl or ethyl group, in particular an ethyl group, and - R 8 and R 9 independently represent a hydrogen atom, a hydroxyl group, an -OCHO group, or an -OCOCH3 group.
  • the compound of formula (la) as defined above has the formula (la’)
  • R 6 is as defined previously and in particular represents a hydroxyl group
  • R 8 and R 9 are as defined previously, and in particular independently represent a hydrogen atom, a hydroxyl group, an -OCHO group or an -OCOCH3 group, and even more particularly a hydroxyl group, an -OCHO group or an -OCOCH3 group, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
  • the compound of formula (la) as defined above has the formula (la”) in which , R 1 , R 2 , R 6 , R 8 and R 9 are as defined previously, and in particular
  • R 1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH2) n COOR a , in which n is equal to 3, 4 or 5, in particular equal to 3 or 5, and R a represents a methyl or ethyl group, in particular ethyl, a propenyloxy group, or a propynyloxy group
  • R 2 represents a hydrogen atom
  • R 6 represents a hydroxyl group, a methoxy or ethoxy group, a propynyloxy group, an -OCOCO 3 group, an -OCONHCOCH 2 CI group, or a group -OCONH(CH 2 ) q COOR k , in which q represents an integer chosen from 3, 4 or 5, in particular 3 and 5, and R k represents a methyl or ethyl group, in particular ethyl, and
  • R 8 and R 9 independently represent a hydrogen atom, a hydroxyl group, an -OCHO group, or an -OCOCH3 group, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
  • formula (la”) is such that
  • R 1 represents a hydroxyl group, or a methoxy group
  • R 2 represents a hydrogen atom
  • R 6 represents a hydroxyl group
  • R 8 and R 9 independently represent a hydrogen atom, a hydroxyl group, or an -OCHO group.
  • this general formula (la) mention may notably be made of compounds (1), (2), (5), (6), (7), (8), (9), (10), (11) and (12).
  • the compound of formula (la) as defined above has the formula (la’”) in which
  • R 1 , R 2 , R 6 , R 9 and R h are as defined previously, notably with at least one of the groups R 1 and R 6 being a group -OCOR c or a group -OCONH(CO) p R d as defined below, and in particular - R 1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH 2 ) n COOR a , in which n is 3, 4 or 5, in particular 3 or 5, and R a represents a methyl or ethyl group, in particular ethyl, a propenyloxy group, or a propynyloxy group,
  • R 2 represents a hydrogen atom
  • - R 9 represents a hydrogen atom, a hydroxyl group, an -OCHO group or an -OCH3 group
  • R h represents a hydrogen atom or a methyl, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
  • formula (la’) is such that
  • R 1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH 2 ) n COOR a , in which n is equal to 3, 4 or 5, in particular 3 or 5, and R a represents a methyl or ethyl group, in particular ethyl,
  • R 2 and R 9 represent a hydrogen atom
  • R 6 represents a hydroxyl group, a methoxy or ethoxy group, an -OCONHCOCH2CI group, or a group -OCONH(CH2) q COOR b , in which q represents an integer chosen from 3, 4 or 5, in particular 3 and 5, and R b represents a methyl or ethyl group, in particular ethyl.
  • the present patent application relates to the compound of formula (I) as defined above, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, represented by formula (lb) in which , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and R 9 are as defined previously, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
  • the present patent application relates to the compound of formula (I) as defined above, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, represented by formula (lb)
  • R 1 , R 3 , R 4 , R 6 , R 7 , R 8 and R 9 are as defined previously, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
  • the present patent application relates to the compound of formula (lb) as defined previously, in which represents a single or double bond, in particular a double bond, - R 1 represents a hydroxyl group, a (C 1 -C 5 )alkoxy group, a (C 2 -C 5 )alkenyloxy group, a (C 2 -C 5 )alkynyloxy group, or a group -OCONH(CH2) n COOR a , in which n represents an integer between 2 and 6, and R a represents a (C 1 -C 4 )alkyl group,
  • R3 and R 7 independently represent a hydrogen atom or a halogen atom, for example a bromine atom,
  • R 4 represents a hydroxyl group, a group , m being equal to 1, 2 or 3, a group , n being equal to 1, 2 or 3, preferably 1 or 2, a group , in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are independently a (C 1 -C 3 )alkyl group, or a group , in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(0)0CH 3 group; a halogen atom, in particular a chlorine atom, an amino group or a group or a group -OCOR b , in which R b represents a (C 1 -C 4 )alkyl group, - R
  • R 1 , R 4 and R 6 is a (C 2 -C 5 )alkenyloxy group or a (C 2 -C 5 )alkynyloxy group, ii.
  • R 8 represents a group -OCOR h , in which R h represents a hydrogen atom or a (C 1 -C 5 )alkyl group, or iii. at least one from among R 3 and R 7 is a halogen atom.
  • the compound of formula (lb) as defined previously is such that represents a double bond
  • R 1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH 2 ) n COOR a , in which n is equal to 3, 4 or 5, in particular equal to 3 or 5, and R a represents a methyl or ethyl group, in particular ethyl, a propenyloxy group, or a propynyloxy group, and
  • - R 4 represents a hydroxyl group, a group , m being equal to 1 or 3, a group , n being equal to 1 or 2, a group or , in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups, a group in which s is equal to 0, 1 or 2, t is equal to 1 or 3, p is equal to 0, 2 or 3, q is equal to 6, and X is a halogen atom, in particular a chlorine atom, a phenyl group or a phenyloxo group, the phenyl group being substituted with a methoxy group, a -C(O)OCH 3 group or a group or a group -OCOCH3, - R 6 represents a hydroxyl group, a methoxy or ethoxy group, a group , m being equal to 1 or 3, a group , n being equal to 1 or 2 a group or
  • R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups, an -OCOCH3 group, an -OCONHCOCH2CI group, a group , in which s is equal to 0, t is equal to 1, p is equal to 0, q is equal to 1, and X is a hydrogen atom, a phenyl group or a phenyloxo group, the phenyl group being substituted with a methoxy group or a -(3(O)OCH 3 group, or a group -OCONH(CH2)qCOOR k , in which q represents an integer chosen from 3, 4 or 5, in particular 3 and 5, and R k represents a methyl or ethyl group, in particular ethyl, and in particular represents a hydroxyl group, a methoxy or ethoxy group, a -OCOCH3 group, a group , m being equal to 1 or 3, a group , n
  • R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups, or a group , in which s is equal to 0, t is equal to 1, p is equal to 0, q is equal to 1, and X is a hydrogen atom, a phenyl group or a phenyloxo group, the phenyl group being substituted with a methoxy group or a -(3(O)OCH 3 group,- R 8 and R 9 independently represent a hydrogen atom, a hydroxyl group, an -OCHO group, or an -OCOCH3 group.
  • the compound of formula (lb) as defined above is characterized in that at least one of R 4 or R 6 , and in particular one of R 4 and R 6 , comprises a group , in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(O)OCH 3 group; a halogen atom, in particular a chlorine atom; an amino group or a group , in particular a group in which s is equal to 0, t is equal to 1, p is equal to 0, q is equal to 1, and X is a hydrogen atom, a phenyl or phenyloxo group, the phenyl group being substituted with a methoxy group or
  • the compound of formula (lb) as defined above has the formula (Ibii) in which , R 1 , R 4 , R 6, R 8 and R 9 are as previously defined, and in which at least one from among R 1 , R 4 and R 6 is a (C 2 -C 5 )alkenyloxy group or a (C 2 -C 5 )alkynyloxy group, and in particular, represents a double bond,
  • R 1 represents a hydroxyl group, a (C 2 -C 5 )alkynyloxy group, or a (C 2 -C 5 )alkenyloxy group
  • R 4 and R 6 independently represent a hydroxyl group, a group , m being equal to 1, 2 or 3, a group , n being equal to 1, 2 or 3, preferably 1 or 2, a group or , in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are independently a (C 1 -C 3 )alkyl group, or a group , in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(0)OCH 3 group; a halogen atom, in particular a chlorine atom, or an amino group,
  • R 4 also possibly representing a group
  • R 8 and R 9 independently represent a hydrogen atom, or a hydroxyl group, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
  • this general formula (Ibii) mention may notably be made of compounds (17), (18), (19), (21), (31) to (43).
  • the compound of formula (lb) as defined above has the formula (Ibiii) in which , R 1 , R 4 , R 6 and R h are as defined previously, and in particular represents a double bond,
  • R 1 represents a methoxy group, a hydroxyl group or a (C 2 -C 5 )alkenyloxy group, such as an allyloxy group,
  • R 4 and R 6 independently represent a hydroxyl group or a group -OCOR b , in which R b represents a (C 1 -C 4 )alkyl group,
  • R h represents a hydrogen atom or a (C 1 -C 5 )alkyl group
  • R 9 represents a hydrogen atom, a hydroxyl group or a group -OCOR h , in particular a hydrogen atom, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
  • compound (10) is a metabolite of compound (9)
  • compound (2) is a metabolite of compound (1).
  • compound (9) is a prodrug of compound (10)
  • compound (1) is a prodrug of compound (2).
  • the compound of formula (I) is chosen from:
  • the invention relates to compounds (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (16), (50), (55), (56), (57), (58), (59), (60), (64), (65), (66), (67), (68), (70) and (71).
  • the compounds of the invention may exist in the form of free bases or of addition salts with pharmaceutically acceptable acids.
  • the compounds of formula (I) and/or salts thereof may form solvates or hydrates also included in the present invention.
  • hydrates and “solvates” mean that the compounds (I) according to the invention may exist in hydrate or solvate form, i.e. the compounds of formula (I) may be combined or associated with one or more water or solvent molecules.
  • the compounds of formula (I) and any of the compounds (1) to (19), (21), (23), (31) to (46), (48) to (71) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and mixtures thereof, including racemic mixtures, form part of the present invention.
  • the compounds of formula (I) and any of the compounds (1) to (19), (21), (23), (31) to (46) (48) to (71) may be in amorphous or crystalline forms and these forms also fall within the scope of the present invention.
  • the present invention also encompasses any of the metabolites or prodrugs of the compound of formula (I).
  • the compounds of the present invention can be prepared via conventional methods of organic synthesis known to those skilled in the art.
  • the general reaction sequences described below represent a general process that is useful for preparing the compounds of the present invention and are not intended to limit the scope thereof.
  • the compounds of the invention may be prepared from four molecules of formula II in which R 1 represents a hydroxyl group or a (C 1 -C 5 )alkoxy group, in particular a methoxy group, and R 9 represents a hydrogen atom or a hydroxyl group.
  • R 1 represents a hydroxyl group or a (C 1 -C 5 )alkoxy group, in particular a methoxy group
  • R 9 represents a hydrogen atom or a hydroxyl group.
  • These molecules are natural compounds of the schweinfurthin family, namely Treasurylianin, schweinfurthin G (SW-G), schweinfurthin E (SW-E) or schweinfurthin F (SW-F). They may be obtained by isolation from plants of the genus Macaranga or by total synthesis (general review: Harmalkar et al. RSCAdv., 2018, 8, 21191).
  • the first reaction scheme entitled Scheme 1 comprises steps (A), (B), (C), (D), (E) to give the compounds of formula (la) and the novel intermediate (III).
  • the second scheme entitled scheme 2 comprises steps (H), (D), (E), (F), (J), (K), (A) and (C) to give the compounds of formulae (Ibii) and (la”) as defined previously.
  • the third scheme entitled Scheme 3 comprises steps (F), (G), (I) to give the compounds of formula (Ibiii) as defined previously.
  • hexahydroxanthene or HHX unit corresponds to the unit Step (A)
  • Step (A) corresponds, starting from compounds of general formula (II), to the intramolecular cyclization of the geranyl chain into pyran, accompanied by esterification of the secondary alcohol of the hexahydroxanthene unit and, under certain conditions, to the reduction of the double bond of the stilbene unit, leading to the compounds of formula (la”), in which at least one from among R 8 and R 9 represents a group -OCOR h as defined previously and in particular an -OCHO group or an -OCOCH3 group. They are obtained from compounds of general formula (II), when R 2 is a hydrogen atom 2 .
  • the cyclization reaction may be performed via any conventional method known to those skilled in the art.
  • this reaction may be performed in formic acid.
  • this reaction may be performed in the presence of a palladium catalyst chosen from palladium(II) acetate (Pd(OAc)2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), or tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) and mixtures thereof, preferably tris(dibenzylideneacetone)dipalladium(0).
  • a palladium catalyst chosen from palladium(II) acetate (Pd(OAc)2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), or tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) and mixtures thereof, preferably tris(dibenzylideneacetone)dipalladium(0).
  • this reaction may be performed in the presence of a base as an additive, chosen from sodium acetate (NaOAc), sodium formate (HCOONa) or sodium tetraborate (Na2B4O7) and mixtures thereof, preferably sodium acetate.
  • a base chosen from sodium acetate (NaOAc), sodium formate (HCOONa) or sodium tetraborate (Na2B4O7) and mixtures thereof, preferably sodium acetate.
  • the mixture of the compound of formula (II), formic acid, palladium and base may be performed, at a temperature between 0°C and 100°C, preferably at room temperature, for a time of between 6h and 48h, preferably 18h or 24h if it is desired to obtain a compound with a reduced double bond (as according to J.M. Brunei in Synlett, 2007, No. 2, page 330).
  • this reaction may be performed under argon.
  • the product obtained of formula (la”) according to the invention can be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions that a person skilled in the art will know how to adapt.
  • the compounds of formula (la”) in which R 6 is other than OH may also be obtained starting from a compound of formula (II) in which one of the OH groups of ring D has been functionalized to give groups R 6 , as defined previously.
  • Such functionalization steps may be performed according to conventional methods.
  • the functionalization reaction may be performed via any conventional method known to those skilled in the art.
  • this reaction may be performed in the presence of a commercial isocyanate or prepared via any conventional method known to those skilled in the art.
  • this reaction may be performed in the presence of a solvent chosen from tetrahydrofuran (THF), acetonitrile (ACN), diethyl ether, DMF (N,N-dimethylformamide), toluene, dichloromethane (DCM) and mixtures thereof, preferably dichloromethane.
  • a solvent chosen from tetrahydrofuran (THF), acetonitrile (ACN), diethyl ether, DMF (N,N-dimethylformamide), toluene, dichloromethane (DCM) and mixtures thereof, preferably dichloromethane.
  • the solvent or solvent mixture may be degassed and anhydrous.
  • the mixing of the starting compound (la”), the solvent and the isocyanate may be performed at a temperature of between 0°C and 60°C, preferably at room temperature for a time of between lh and 24h, preferably 5h or 8h.
  • this reaction may be performed under argon.
  • the product obtained of formula (la”) according to the invention can be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions that a person skilled in the art will know how to adapt.
  • Step (C) corresponds to the saponification of the ester function of the hexahydroxanthene unit of the compounds of general formula (la”) to give the compounds of general formula (la”), in which at least one of the groups R 1 , R 6 , R 8 or R 9 is a hydroxyl group.
  • the saponification reaction may be performed via any conventional method known to those skilled in the art.
  • this reaction may be performed in the presence of a base chosen from potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydrogen carbonate (NaHCO3), potassium hydroxide (KOH) sodium hydroxide (NaOH), lithium hydroxide (LiOH), caesium carbonate (CS2CO3), potassium tert-butoxide, pyridine, aqueous ammonia, sodium ethoxide (EtONa), sodium methoxide (MeONa) and mixtures thereof, preferably lithium hydroxide.
  • a base chosen from potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydrogen carbonate (NaHCO3), potassium hydroxide (KOH) sodium hydroxide (NaOH), lithium hydroxide (LiOH), caesium carbonate (CS2CO3), potassium tert-butoxide, pyridine, aqueous ammonia, sodium ethoxide (EtONa), sodium methoxide (Me
  • this reaction may be performed in the presence of a solvent chosen from tetrahydrofuran (THF), water, a THF/water mixture, acetonitrile, diethyl ether, DMSO (dimethyl sulfoxide), acetone, dichloromethane, methanol, ethanol and mixtures thereof, preferably a THF/water mixture.
  • a solvent chosen from tetrahydrofuran (THF), water, a THF/water mixture, acetonitrile, diethyl ether, DMSO (dimethyl sulfoxide), acetone, dichloromethane, methanol, ethanol and mixtures thereof, preferably a THF/water mixture.
  • the mixing of the starting compound (la”), the base and the solvent may be performed at a temperature of between 0°C and 60°C, preferably at room temperature for a time of between 10 min and 3h, preferably lh.
  • the product obtained of formula (la”), in which at least one of the groups R 1 , R 6 , R 8 or R 9 is a hydroxyl group may be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions which a person skilled in the art will know how to adapt.
  • Step (D) corresponds to the alkylation of the phenol function(s) of the compounds of formula (la”), in which at least R 1 is a hydroxyl group, to give the intermediate of general formula (la”), in which at least R 1 is a (C 2 -C 5 )alkenyloxy group or a (C 2 -C 5 )alkynyloxy group, or of formula (III) as defined below.
  • This step (D) may also be performed in the context of obtaining compounds of formula (Ibii), in which at least R 1 is a (C 2 -C 5 )alkenyloxy group or a (C 2 -C 5 )alkynyloxy group, from a compound of formula (II), as indicated in Figure 2 above.
  • the alkylation reaction may be performed via any conventional method known to those skilled in the art.
  • this reaction may be performed in the presence of a base chosen from potassium carbonate (K 2 CO 3 ), sodium hydride (NaH), potassium hydroxide (KOH), sodium hydroxide (NaOH), caesium carbonate (CS 2 CO 3 ), N,N- diisopropylethylamine (DIPEA), pyridine and mixtures thereof, preferably sodium hydride or potassium carbonate.
  • a base chosen from potassium carbonate (K 2 CO 3 ), sodium hydride (NaH), potassium hydroxide (KOH), sodium hydroxide (NaOH), caesium carbonate (CS 2 CO 3 ), N,N- diisopropylethylamine (DIPEA), pyridine and mixtures thereof, preferably sodium hydride or potassium carbonate.
  • this reaction may be performed in the presence of a solvent chosen from acetonitrile, THF (tetrahydrofuran), DMF (N,N- dimethylformamide), DMM (dimethoxy methane), DCM (dichloromethane), dioxane, MTBE (methyl tert-butyl ether), diethyl ether, toluene, and mixtures thereof, preferably DMF.
  • a solvent chosen from acetonitrile, THF (tetrahydrofuran), DMF (N,N- dimethylformamide), DMM (dimethoxy methane), DCM (dichloromethane), dioxane, MTBE (methyl tert-butyl ether), diethyl ether, toluene, and mixtures thereof, preferably DMF.
  • the electrophile enabling this alkylation reaction may be an alkyl halide, an alkenyl halide, an alkynyl halide, the tosylate or the mesylate of the corresponding alcohols, alkenols or alkynols.
  • the solvent or solvent mixture may be degassed and anhydrous.
  • the base may be added dropwise to a solution of the starting compound.
  • the mixture formed of the base, the solvent and the starting compound may be made at a temperature of between -40°C and 10°C, preferably at -15°C, for a time ranging from 5 min to 45 min, preferably for 15 min.
  • the addition of the electrophile may be performed at a temperature of between -15°C and 25°C, preferably at 0°C for a time of between 30 min and 2 h, preferably 1 h.
  • this reaction may be performed under argon.
  • the product obtained of formula (Ibii) or (III) according to the invention may be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions that a person skilled in the art will know how to adapt.
  • Step (E) corresponds to the formation of the chromene unit from the intermediate of general formula (III) to give the compounds of formula (la’).
  • the cyclization reaction may be performed via any conventional method known to those skilled in the art.
  • this reaction may be performed in the presence of a catalyst chosen from gold(I)(acetonitrile)[(2-biphenyl)di-tert- butylphosphine]hexafluoroantimonate, gold(I)-
  • a catalyst chosen from gold(I)(acetonitrile)[(2-biphenyl)di-tert- butylphosphine]hexafluoroantimonate, gold(I)-
  • [bis(trifluoromethanesulfonyl)imidate] (triphenylphosphine), palladium(II) trifluoroacetate, platinum(II) chloride, palladium(II) diacetate, copper(I) iodide, gold(I) chloride (triphenylphosphine), silver trifluoromethane sulfonate, copper(II) bis(trifluoromethanesulfonate), gold(III) chloride, silver hexafluoroantimonate and mixtures thereof, preferably gold(I)-[bis(trifluoromethanesulfonyl)imidate](triphenylphosphine).
  • this reaction may be performed in the presence of a solvent chosen from 1,2-dichloroethane, dichloromethane, acetonitrile, toluene, DMF (N,N-dimethylformamide), 1,4-dioxane and mixtures thereof, preferably dichloromethane.
  • a solvent chosen from 1,2-dichloroethane, dichloromethane, acetonitrile, toluene, DMF (N,N-dimethylformamide), 1,4-dioxane and mixtures thereof, preferably dichloromethane.
  • the solvent or solvent mixture may be degassed and anhydrous.
  • the mixing of the starting compound (III), the catalyst and the solvent may be performed at a temperature of between 0°C and 60°C, preferably at room temperature for a time of between lh and 8h, preferably 4h.
  • this reaction may be performed under argon.
  • the product obtained of formula (la’) according to the invention can be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions that a person skilled in the art will know how to adapt.
  • This step (E) may be followed by a saponification step (C) as described previously, to obtain a compound of formula (la’), in which R 8 or R 9 is a hydroxyl group.
  • Step (F) corresponds to the esterification of a compound of formula (II), so as to obtain a compound of formula (Ibiii), containing a group -OCOR h as defined previously and in particular an -OCHO group or an -OCOCH3 group.
  • the esterification reaction may be performed via any conventional method known to those skilled in the art.
  • a large number of esterification methods are described in the literature and in reference chemistry books, for instance in March’s Advanced Organic Chemistry Reactions, Mechanisms and Structure, sixth edition, Michael B. Smith and Jerry March, Wiley-Interscience, a John Wiley & Sons, Inc. publication, 2007).
  • this reaction may be performed in the presence of an acid halide chosen from an acid chloride or an acid bromide, preferably an acid chloride.
  • this reaction may be performed in the presence of a base chosen from sodium hydride (NaH), potassium tert-butoxide (/BuOK), pyridine, dimethylaminopyridine (DMAP), triethylamine, potassium carbonate, N,N- diisopropylethylamine, preferably sodium hydride.
  • a base chosen from sodium hydride (NaH), potassium tert-butoxide (/BuOK), pyridine, dimethylaminopyridine (DMAP), triethylamine, potassium carbonate, N,N- diisopropylethylamine, preferably sodium hydride.
  • this reaction may be performed in the presence of a solvent chosen from 1,2-dichloroethane, dichloromethane, acetonitrile, toluene, DMF (N,N-dimethylformamide), 1,4-dioxane, tetrahydrofuran (THF) and a mixture thereof, preferably a THF/DMF mixture.
  • a solvent chosen from 1,2-dichloroethane, dichloromethane, acetonitrile, toluene, DMF (N,N-dimethylformamide), 1,4-dioxane, tetrahydrofuran (THF) and a mixture thereof, preferably a THF/DMF mixture.
  • the solvent or solvent mixture may be anhydrous.
  • the mixing of the solvents, the starting compound (II) and the base may be performed at a temperature of between 0°C and 60°C, preferably at room temperature for a time of between 5 min and 30 min, preferably 15 min.
  • the acid halide may then be added and the mixture may be stirred at a temperature of between 0°C and 60 °C, preferably at room temperature for a time of between 5 h and 30 h, preferably 16 h.
  • this reaction may be performed under argon.
  • the product obtained of formula (Ibiii) according to the invention can be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions that a person skilled in the art will know how to adapt.
  • Step (G) corresponds to the saponification of the methyl ester function of the dimethoxy nitrophenyl methoxy acetate unit of the compounds of general formula (Ibii) to lead to the compounds of general formula (Ibii), in which at least one of the groups R 4 or R 6 is a dimethoxy nitrophenyl methoxy acid group, as in compounds (45) and (48), for example.
  • the saponification reaction may be performed via any conventional method known to those skilled in the art.
  • this reaction may be performed in the presence of a base chosen from potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydrogen carbonate (NaHCO3), potassium hydroxide (KOH) sodium hydroxide (NaOH), lithium hydroxide (LiOH), trimethyltin hydroxide (Me3SnOH), caesium carbonate (CS2CO3), potassium tert-butoxide, pyridine, aqueous ammonia, sodium ethoxide (EtONa), sodium methoxide (MeONa) and mixtures thereof, preferably trimethyltin hydroxide.
  • a base chosen from potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydrogen carbonate (NaHCO3), potassium hydroxide (KOH) sodium hydroxide (NaOH), lithium hydroxide (LiOH), trimethyltin hydroxide (Me3SnOH), caesium carbonate (CS2CO3), potassium tert-butoxide
  • this reaction may be performed in the presence of a solvent chosen from tetrahydrofuran (THF), water, a THF/water mixture, acetonitrile, diethyl ether, DMSO (dimethyl sulfoxide), acetone, dichloromethane, methanol, ethanol and mixtures thereof, 1,2-dichloroethane, preferably 1,2-dichloroethane.
  • a solvent chosen from tetrahydrofuran (THF), water, a THF/water mixture, acetonitrile, diethyl ether, DMSO (dimethyl sulfoxide), acetone, dichloromethane, methanol, ethanol and mixtures thereof, 1,2-dichloroethane, preferably 1,2-dichloroethane.
  • the mixing of the starting compound (Ibii), the base and the solvent may be performed at a temperature of between 0°C and 120°C, preferably at 60°C for a time of between lh and 36h, preferably 16h.
  • the product obtained of formula (Ibii), in which at least one of the groups R 4 or R 6 is a dimethoxy nitrophenyl methoxy acid group, according to the invention may be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions which a person skilled in the art will know how to adapt.
  • Step (H) corresponds to a CuAAC-type 1,3-dipolar Huisgen cycloaddition reaction of an azide to the alkyne unit of the compounds of general formula (Ibii) to give the compounds of general formula (Ibii), in which at least one of the groups R 4 or R 6 comprises a 1H- 1,2,3- triazole unit, as in the case of compounds (49) to (56).
  • the CuAAC (copper-catalysed azide-alkyne cycloaddition) reaction may be performed via any conventional method known to those skilled in the art.
  • this reaction may be performed in the presence of a copper(I) salt such as copper iodide or copper bromide, or a copper(II) salt, for example copper sulfate or copper acetate, and sodium ascorbate which enables its reduction to copper(I), preferably a mixture of copper sulfate and sodium ascorbate.
  • a copper(I) salt such as copper iodide or copper bromide
  • a copper(II) salt for example copper sulfate or copper acetate, and sodium ascorbate which enables its reduction to copper(I), preferably a mixture of copper sulfate and sodium ascorbate.
  • this reaction may be performed in the presence of a large number of solvents including water, acetonitrile, methanol, ethanol, t-butanol and mixtures thereof, DMSO (dimethyl sulfoxide), dichloromethane, DMF and mixtures thereof, preferably a water/acetonitrile/t-butanol ternary mixture.
  • solvents including water, acetonitrile, methanol, ethanol, t-butanol and mixtures thereof, DMSO (dimethyl sulfoxide), dichloromethane, DMF and mixtures thereof, preferably a water/acetonitrile/t-butanol ternary mixture.
  • the mixing of the starting compound (Ibii), the copper(II) salt, sodium ascorbate, DABCO, acetic acid and the solvent may be performed at a temperature of between 0°C and 60°C, preferably at room temperature for a time of between lh and 36h, preferably 18h.
  • the product obtained of formula (Ibii), in which at least one of the groups R 4 or R 6 comprises a 1H- 1,2, 3-triazole unit, according to the invention may be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions which a person skilled in the art will know how to adapt.
  • the present invention relates to a synthetics process for preparing a compound of formula (la”)
  • R 1 and R 6 are as defined previously and at least one from among R 8 and R 9 represents a group -OCOR h as defined previously, and in particular an -OCHO group or an -OCOCH3 group, and in which R 2 is a hydrogen atom, or a (C2-C5)alkenyl group, such as an allyl group or any of the pharmaceutically acceptable salts thereof, comprising at least one step of intramolecular cyclization of the geranyl chain into pyran, of a compound of general formula (II), accompanied by esterification of the secondary alcohol of the hexahydroxanthene unit
  • R 1 , R 6 and R 8 are as defined previously.
  • the present invention relates to an intermediate compound of formula (III) in which
  • R h , R 9 and R 6 are as defined previously.
  • the chemical structures and the spectroscopic data of some of the compounds of formula (I) of the invention are illustrated, respectively, in Tables 1 and 2 below. [Table 2] PHARMACEUTICAL COMPOSITIONS
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I) as defined according to the invention and at least one pharmaceutically acceptable excipient.
  • it may comprise an amount of compounds of formula (I) as defined in the invention ranging from 0.05% to 10% by weight, in particular from 0.1% to 5% by weight, relative to the total weight of the composition.
  • composition according to the invention also comprises at least one pharmaceutically acceptable excipient.
  • This excipient may be solid or liquid. It may be chosen, for example, from purified water, ethyl alcohol, propylene glycol, glycerol, plant oils, animal oils, hydrocarbons, silicones, sugars such as glucose, levulose, wheat starch, com starch, potato starch, cyclodextrins, xanthan gum, pectins, alginates, magnesium stearate, gelatin, cellulose and derivatives thereof.
  • composition of the invention may be administered via any suitable route, for example orally, rectally, locally (e.g. topically), intraperitoneally, systemically, intravenously, intramuscularly, subcutaneously or mucosally, notably sublingually, or by using a patch, or in encapsulated form in, or immobilized on, liposomes, microparticles, microcapsules, combined with nanoparticles and the like.
  • excipients that are suitable for use in the present invention may be any excipient conventionally used in the therapeutic field.
  • excipients that are suitable for oral administration, mention may be made of talc, lactose, starch and derivatives thereof, cellulose and derivatives thereof, polyethylene glycols, acrylic acid polymers, gelatin, magnesium stearate, animal, plant or synthetic fats, paraffin derivatives, glycols, stabilizers, preserving agents, antioxidants, wetting agents, anticaking agents, dispersants, emulsifiers, taste modifiers, penetrants, and solubilizers.
  • a cosolvent for instance an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol.
  • At least one compound of formula (I) may be dissolved using a triglyceride or a glycerol ester.
  • the pharmaceutical composition may thus comprise one or more pharmaceutically acceptable diluents, supports, excipients, fillers, binders, lubricants, glidants, disintegrants, absorbents and/or preserving agents.
  • compositions may advantageously be administered orally or by intravenous injection.
  • compositions according to the invention are determined via standard clinical techniques at the discretion of the physician.
  • the composition according to the invention is suitable for administration orally or intravenously at a dose greater than or equal to 1 mg/kg/24h and less than or equal to 200 mg/kg/24h in one or more dosage intakes to a mammal in need thereof.
  • the compounds of formula (I) of the invention may be used in doses of between 0.01 mg and 5000 mg per day, given in a single dose once a day or administered in multiple doses throughout the day, for example twice a day in equal doses.
  • the dose administered per day is advantageously between 5 mg and 2500 mg, even more advantageously between 10 mg and 1000 mg.
  • Suitable oral administration forms include tablets, gel capsules, powders, granules, syrups and oral solutions or suspensions.
  • aqueous suspensions For parenteral administration, use may be made of aqueous suspensions, isotonic saline solutions or injectable sterile solutions containing pharmaceutically acceptable and compatible dispersants and/or wetting agents.
  • the pharmaceutical composition as defined in the present invention may also comprise another active principle, which is useful notably in the treatment and/or prevention of neurodegenerative diseases, viral diseases, dyslipidaemia, hypercholesterolaemia, parasitic diseases and/or cancers.
  • the present invention also relates to a pharmaceutical preparation which comprises a pharmaceutical composition according to the invention, and, in addition, as a mixture or packaged separately, at least one antiviral agent and/or an anticancer agent and/or an agent that is efficacious against neurodegenerative diseases, and/or an agent that is efficacious against dyslipidaemia, an agent that is efficacious against hypercholesterolaemia and/or an agent that is efficacious against parasitic diseases for use in treating and/or preventing and/or inhibiting infections caused by pathogens such as viruses, cancers, neurodegenerative diseases, hypercholesterolaemia and dyslipidaemia, administered simultaneously, sequentially or spaced out over time.
  • pathogens such as viruses, cancers, neurodegenerative diseases, hypercholesterolaemia and dyslipidaemia
  • the present invention relates to a compound of formula (I) according to the invention or a pharmaceutical composition according to the invention, for use as a medicament, and notably for its use in preventing and/or treating and/or inhibiting cancers, neurodegenerative diseases, dyslipidaemia, hypercholesterolaemia and/or viral or parasitic diseases.
  • the compound of formula (I) as defined in the present invention makes it possible to inhibit OSBP (oxy sterol-binding protein), a protein responsible for the intracellular transfer of cholesterol.
  • OSBP oxy sterol-binding protein
  • the cancers are chosen from breast cancer, including triple negative breast cancer, osteosarcoma, kidney cancer, head and neck cancer, prostate cancer, colorectal cancer, colon cancer, gall bladder cancer, bile duct cancer (cholangiocarcinoma), gastrointestinal cancer, gastric cancer, hepatocellular carcinoma, lymphoma, lung cancer, small cell lung cancer, non- small cell lung cancer, pancreatic cancer, pancreatic carcinoma, stomach cancer, brain cancer, metastases, leukaemia, acute T- cell lymphoblastic leukaemia, chronic myeloid leukaemia, melanoma and glioblastoma, in particular osteosarcoma, kidney cancer, triple-negative breast cancer, melanoma, leukaemia and glioblastoma.
  • breast cancer including triple negative breast cancer, osteosarcoma, kidney cancer, head and neck cancer, prostate cancer, colorectal cancer, colon cancer, gall bladder cancer, bile duct cancer (cholangiocarcinoma), gastrointestinal cancer, gastric cancer
  • Glioblastoma or glioblastoma multiforme also known as grade 4 astrocytoma, is the most common and most aggressive brain tumour.
  • neurodegenerative diseases are chosen from amyotrophic lateral sclerosis (ALS or Charcot’s disease), Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease (Huntington’s chorea), and Niemann-Pick type C disease, in particular Alzheimer’s disease, Parkinson’s disease, Huntington’s disease (Huntington’s chorea), and Niemann-Pick type C disease.
  • ALS or Charcot’s disease amyotrophic lateral sclerosis
  • Alzheimer’s disease Parkinson’s disease
  • multiple sclerosis Huntington’s disease (Huntington’s chorea)
  • Niemann-Pick type C disease in particular Alzheimer’s disease, Parkinson’s disease, Huntington’s disease (Huntington’s chorea), and Niemann-Pick type C disease.
  • the term “viral diseases” means any benign or severe disease caused by a virus.
  • the viral diseases targeted by the compounds of the invention are mediated by RNA viruses.
  • RNA virus -mediated viral infection more particularly means a viral infection mediated by a virus belonging to group III (double- stranded RNA viruses (dsRNA)), group IV (positive-sense single-stranded RNA viruses: (+)-sense RNA), Group V (negative-sense single- stranded RNA viruses: (-)-sense RNA) or group VI (single-stranded RNA retroviruses: (+)-sense RNA with intermediate DNA in the life cycle).
  • group III double- stranded RNA viruses
  • group IV positive-sense single-stranded RNA viruses: (+)-sense RNA
  • Group V negative-sense single- stranded RNA viruses: (-)-sense RNA
  • group VI single-stranded RNA retroviruses: (+)-sense RNA with intermediate DNA in the life cycle
  • viruses belonging to group VI are not, strictly speaking, RNA viruses.
  • a well-studied example of a virus family belonging to group VI is the Retroviridae (retrovirus) family, which includes HIV.
  • viruses belonging to group IV are viruses that includes well-known viruses such as hepatitis A vims, enteroviruses, rhinoviruses, poliovirus and foot-and-mouth vims), SARS vims, hepatitis C vims, yellow fever vims and rubella vims.
  • the Togaviridae family also belongs to group IV and a known genus thereof is the alphavims, including chikungunya vims.
  • the Flaviridae is also a family belonging to group IV, including a renowned mosquito-bome vims, namely the dengue vims or the Zika vims.
  • coronavims 2019 disease COVID-19
  • SARS-CoV-2 previously known as 2019-nCoV
  • 2019-nCoV coronavims 2019 disease
  • viruses belonging to group V As representatives of viruses belonging to group V, mention may be made of the Filoviridae family of viruses including Ebola vims, the Paramyxoviridae family including respiratory syncytial vims (RSV), the Rhabdoviridae family, the Orthomyxoviridae family including influenzavims A, influenzavims B and influenza C. Measles is also caused by a group V vims of the paramyxovirus family.
  • RSV respiratory syncytial vims
  • influenzavims A influenzavims A
  • influenzavims B influenzavims B
  • Measles is also caused by a group V vims of the paramyxovirus family.
  • the viral diseases targeted by the compounds of the invention are infections caused by RNA viruses of classes IV and V of the Baltimore classification.
  • Viral angina can be caused by different viruses such as rhinovirus, coronavirus, respiratory syncytial virus (RSV), influenza virus and para influenza virus.
  • RSV respiratory syncytial virus
  • the viral diseases targeted by the compounds of the invention are chosen from dengue, Zika vims infection, influenza, viral angina, measles, AIDS, chikungunya, yellow fever, poliomyelitis, hepatitis A, hepatitis C, hepatitis E, SARS-CoV virus infection, SARS-CoV-2 vims infection, and rubella, in particular dengue, Zika vims infection, chikungunya, yellow fever, poliomyelitis, hepatitis A, hepatitis C, hepatitis E, SARS-CoV vims infection, SARS-CoV-2 vims infection and rubella.
  • the viral diseases are in particular those caused by a Baltimore Class IV (+)-strand RNA vims such as dengue, Zika vims infection, chikungunya, yellow fever, poliomyelitis, hepatitis A, hepatitis C, hepatitis E, SARS-CoV vims infection, SARS-CoV-2 vims infection, and rubella.
  • a Baltimore Class IV (+)-strand RNA vims such as dengue, Zika vims infection, chikungunya, yellow fever, poliomyelitis, hepatitis A, hepatitis C, hepatitis E, SARS-CoV vims infection, SARS-CoV-2 vims infection, and rubella.
  • RNA viruses may also be targeted in the context of the present invention, such as chickenpox.
  • a compound of formula (I) as defined in the invention may be administered alone or in combination with other active principles which may act synergistically with the compound of formula (I).
  • treatment techniques may be combined with the treatment performed via the administration of a pharmaceutical composition according to the invention or of a medicament comprising at least one compound of formula (I).
  • the pathology concerned is a cancer
  • radiotherapy possibly coupled with chemotherapy, with other active agents, in a first stage, and then to continue the treatment as a monotherapy by administering a pharmaceutical composition according to the invention or a medicament comprising at least one compound of formula (I).
  • the present invention also relates to a method for administering at least one compound of formula (I) as defined in the invention to an individual in need thereof, involving:
  • composition comprising at least one compound of formula (I) as defined in the invention, and at least one pharmaceutically acceptable excipient;
  • the present invention relates to methods for administering, notably orally or intravenously, a pharmaceutical composition according to the invention comprising at least one compound of formula (I) as defined in the invention and an additional active principle.
  • mammals for example humans, pets, farm animals or laboratory animals.
  • the present invention relates to the use of at least one compound of formula (I) as defined in the invention or a pharmaceutical composition according to the invention for the preparation of a medicament.
  • the present invention relates to the use of at least one compound of formula (I) as defined in the invention or a pharmaceutical composition according to the invention for the preparation of a medicament for treating and/or preventing and/or inhibiting cancers, neurodegenerative diseases, dyslipidaemia, hypercholesterolaemia, and/or viral diseases.
  • the present invention relates to a method for treating and/or preventing and/or inhibiting cancers, neurodegenerative diseases, dyslipidaemia, hypercholesterolaemia, parasitic diseases and/or viral diseases, involving the administration to an individual in need thereof of a pharmaceutical composition according to the invention comprising at least one compound of formula (I) as defined in the present invention.
  • the present invention relates to a method for treating and/or preventing and/or inhibiting cancers, neurodegenerative diseases, dyslipidaemia, hypercholesterolaemia, and/or viral or parasitic diseases, involving the administration to an individual in need thereof of a therapeutically effective amount of at least one compound of formula (I) as defined in the present invention.
  • the carbon nuclear magnetic resonance (13C NMR) spectra are recorded on a Briiker Avance machine (75 or 125 MHz), and the chemical shifts are expressed in ppm relative to the solvents used.
  • HRMS high-resolution mass spectra
  • the flash chromatography purifications are performed on a Teledyne Isco Combiflash Rf 200i with pre-packaged GraceResolv silica cartridges.
  • the organic solvents are dried or distilled before use and stored over molecular sieves under argon.
  • Compound (1) is a prodrug of compound (2).
  • SW-G (150 mg, 0.32 mmol), is dissolved in formic acid (1 ml) and placed under an argon atmosphere. The mixture is stirred at room temperature for 18 hours and then poured into a separating funnel. Dichloromethane (DCM: 2 ml) is added and the organic phase is separated out by settling, washed successively with water (twice), with saturated sodium hydrogen carbonate (NaHCO3) solution and then with sodium chloride (NaCl). The organic phase is dried over magnesium sulfate (MgSO 4 ) and then concentrated under reduced pressure.
  • DCM dichloromethane
  • SW-G 500 mg, 1.08 mmol
  • tris(dibenzylideneacetone)dipalladium(0) Pd 2 dba 3 : 19 mg, 0.02 mmol, 0.02 eq
  • sodium acetate NaOAc: 26 mg, 0.32 mmol, 0.3 eq
  • DCM dichloromethane
  • the reaction medium is stirred at room temperature for 18 hours, followed by addition of aqueous NH 4 Cl solution (10 mL).
  • the reaction medium is extracted three times with ethyl acetate (EtOAc).
  • the organic phases are combined, dried over MgSO 4 and concentrated under reduced pressure.
  • the crude reaction product is purified by reverse- phase silica chromatography (H 2 O/acetonitrile 8/2 to 0/1 gradient) to give the desired compound 31 in the form of a brown oil (28 mg, 26%).
  • the same procedure was followed to synthesize compounds (19) and (32) from SW-G and SW-E respectively.
  • reaction medium is stirred at room temperature for 18 hours, followed by addition of aqueous NH 4 Cl solution (10 mL).
  • the reaction medium is extracted three times with ethyl acetate (EtOAc).
  • the organic phases are combined, dried over MgSO 4 and concentrated under reduced pressure.
  • the crude reaction product is purified by flash chromatography on a column of silica (heptane/EtOAc 6/4 to 2/8 gradient) to give the desired compound (56) in the form of a pale yellow oil (21 mg, 51%).
  • Example 7 Preparation of (2S,3R,4aR,9aR)-7-((E)-3-hydroxy-5-((1-methyl-1H-1,2,3- triazol-4-yl)methoxy)-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,3-diol (57).
  • Example 8 preparation of (2S,3R,4aR,9aR)-7-((E)-3,5-bis((1-methyl-1H-1,2,3-triazol-4- yl)methoxy)-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a- hexahydro-1H-xanthene-2,3-diol (58).
  • Example 9 preparation of (2S,3R,4aR,9aR)-7-((E)-3-((1-benzyl-1H-1,2,3-triazol-4- yl)methoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,3-diol (59).
  • Example 10 preparation of (2S,3R,4aR,9aR)-7-((E)-3,5-bis((1-benzyl-1H-1,2,3-triazol-4- yl)methoxy)-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a- hexahydro-1H-xanthene-2,3-diol (60).
  • Example 11 preparation of 2-(4-((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-3-hydroxy-2-(3- methylbut-2-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-1-(4-methoxyphenyl)ethan-1- one (64).
  • Example 12 preparation of 2,2'-((((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1- yl)-1,3-phenylene)bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(4- methoxyphenyl)ethan-1-one) (65).
  • Example 13 Biological activity The biological inhibitory activities of oxysterol binding protein 1 (OSBP) and the cytotoxic activity on two cell lines, U87 and A549, were measured.
  • OSBP oxysterol binding protein 1
  • MATERIALS AND METHOD Measurement of the OSBP inhibitory activity is performed by an automated test on the purified ORD domain of the OSBP protein. The measurements are performed according to a protocol using two liposome preparations:
  • the donor liposomes (A) contain a fluorescent sterol (DHE);
  • the acceptor liposomes (B) contain a fluorescent lipid (dansyl PE) whose excitation spectrum overlaps with the emission spectrum of DHE.
  • the transport of DHE from the liposomes A to the liposomes B catalysed by the ORD domain is accompanied by a FRET signal between DHE and dansyl-PE.
  • the transport kinetics can be measured in real time.
  • the affinity constants Ki are classified as follows:
  • U87-MG and A549 lines were obtained from the American Type Culture Collection (Rockville, MD, USA) and were cultured according to the supplier’s instructions.
  • U87-MG human glioblastoma cells were cultured in Dulbecco’s minimal essential medium (DMEM) containing 10% FCS and 1% L-glutamine.
  • DMEM minimal essential medium
  • A549 lung cancer cells were grown in RPMI1640 medium containing 10% FCS and 1% L-glutamine.
  • the cell lines were maintained at 37°C in a humidified atmosphere containing 5% CO2.
  • the products were tested at 10 concentrations in triplicate and the cell viability was evaluated after 72h of treatment by means of the CellTiter Glo test (Promega) for measuring the number of living cells by luminescence (ATP quantification).
  • the cells were seeded in 96-well plates (2.5x10 3 cells/well) each containing 90 ⁇ L of growth medium. After 24 h of culture, the wells were supplemented with 10 ⁇ L of medium containing ten decreasing concentrations of the test compound dissolved in DMSO (less than 0.1% in each preparation). After 72 h of incubation, 100 ⁇ L of Cell Titer GLo reagent were added for 15 min, followed by quantifying the luminescence emitted by means of a microplate reader. The dose-response curve was analysed by means of the Graph Prism software and the activity of the molecules is expressed in the form of the IC50.
  • molecules with an IC 50 value on the U87 line below 100 nM, for example below 50 nM are considered highly active.
  • the commentary column to the right of the table indicates the differences and advantages observed relative to the reference schweinfurthin. It is also stated whether it is a prodrug of another compound.
  • the term “triazole series” is specified when the compound comprises a triazole group in at least one of the radicals R 4 or R 6 .
  • schweinfurthin H also corresponds to compound 2 of the publication by Thi Mai Huong Doan et al., “Cytotoxic phenolic compounds from fruit glandular trichomes of Macaranga ius ” Journal of Analytical Methods in Chemistry, volume 2019, article ID 2917032, 5 pages.
  • Plasma stability and liver microsomal stability assays were performed on SW-G, SW-E, compounds (1), (2), (5), (6), (9) (10), and (57) according to the invention.
  • the compounds are placed in mouse plasma and mouse microsomes, and their stability is evaluated by UPLC-MS/MS monitoring.
  • test concentration is 2.5 ⁇ M and the incubation volume is 50 ⁇ L.
  • the incubation times are 0, 15, 30, 45, 60 and 120 minutes. Protein precipitation is then performed on the samples, and said samples are then analysed by UPLC-MS/MS. The remaining percentage of the compound and its elimination half-life are thus obtained.
  • the concentration of the test compound is 2.5 ⁇ M, and the incubation volume is 400 ⁇ L.
  • the concentration in mouse microsomes is 0.5 mg/mL.
  • the incubation times are 0, 15, 30 and 45 minutes.
  • the cofactor used is NADPH.
  • Two negative controls are performed, one without microsomes and without cofactor at 0 and 45 minutes, and one without cofactor and with microsome at 0 and 45 minutes.
  • a positive control is performed in the presence of diphenhydramine.
  • the samples are analysed by LC- MS/MS. The intrinsic clearance and the half-life are thus obtained.
  • the LC-MS/MS is performed on an AcquityTM UPLC machine coupled with an XEVO TQ-S machine (Waters).
  • the liquid chromatography is performed on an Acquity UPLC BEH 1.7 ⁇ m, 2.1x50 mm column with a 4-minute gradient of water + 0.1% formic acid/acetonitrile + 0.1% formic acid 90:10 to 0:100.
  • the column temperature is +50°C and the injector temperature is +4°C.
  • the mass spectrometry acquisition is done by MRM (Multiple Reaction Monitoring), with positive electrospray ionization.
  • the intrinsic clearance is considered high if it is > 48 ⁇ L/min/mg protein and low if it is ⁇ 8.8 ⁇ L/min/mg protein.
  • mice plasma metabolic stability of SW-G at 120 minutes is 100%, its metabolic stability in mouse microsomes is 23% at 45 minutes and its microsomal clearance is 90 ⁇ L/min/mg protein.
  • the mouse plasma metabolic stability of SW-E at 120 minutes is 93%, its metabolic stability in mouse microsomes is 18% at 45 minutes and its microsomal clearance is 76 ⁇ L/min/mg protein.
  • the metabolic stability in mouse plasma at 120 minutes of compound (1) according to the invention is 20%, its metabolic stability in mouse microsomes is 5% at 45 minutes and its clearance in microsomal medium is 120 ⁇ L/min/mg protein.
  • This compound is transformed into compound (2) according to the invention.
  • Compound (1) is a prodrug of compound (2).
  • the metabolic stability in mouse plasma at 120 minutes of compound (2) according to the invention is 100%, its metabolic stability in mouse microsomes is 49% at 45 minutes and its clearance in microsomal medium is 32 ⁇ L/min/mg of protein.
  • the metabolic stability in mouse plasma at 120 minutes of compound (5) according to the invention is 1%, its metabolic stability in mouse microsomes is 29% at 45 minutes and its clearance in microsomal medium is 74 ⁇ L/min/mg protein.
  • This compound is transformed into compound (6) according to the invention.
  • Compound (5) is a prodrug of compound (6).
  • the metabolic stability in mouse plasma at 120 minutes of compound (6) according to the invention is 100%, its metabolic stability in mouse microsomes is 41% at 45 minutes and its clearance in microsomal medium is 40 ⁇ L/min/mg protein.
  • the metabolic stability in mouse plasma at 120 minutes of compound (9) according to the invention is 0%, its metabolic stability in mouse microsomes is 47% at 45 minutes and its clearance in microsomal medium is 396 ⁇ L/min/mg protein.
  • the metabolic stability in mouse plasma at 120 minutes of compound (10) according to the invention is 90%, its metabolic stability in mouse microsomes is 10% at 45 minutes and its clearance in microsomal medium is 98 ⁇ L/min/mg protein.
  • the metabolic stability in mouse plasma at 120 minutes of compound (57) according to the invention is 100%, its metabolic stability in mouse microsomes is 27% at 45 minutes and its clearance in microsomal medium is 58 ⁇ L/min/mg protein.
  • the compounds of formula (I) according to the invention may be used as medicaments, in particular in the treatment of cancer, more particularly glioblastoma.
  • OSBP oxysterol-binding protein

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Abstract

Novel compounds derived from schweinfurthins G, E and F The present invention relates to novel compounds derived from schweinfurthins of formula (I): (I). The invention also relates to pharmaceutical compositions containing them and also to the use thereof for the prevention, inhibition and/or treatment of cancers, neurodegenerative diseases, dyslipidaemia, hypercholesterolaemia, parasitic diseases and/or viral diseases and to processes for preparing them.

Description

Description
Title: Novel compounds derived from schweinfurthins G, E and F
Technical field
The present invention relates to novel schweinfurthin derivatives. It also relates to the pharmaceutical application of these novel schweinfurthin derivatives, in particular on the basis of their anticancer biological action and also their biological action on oxysterol- binding protein 1 (OSBP or OSBP1), for the prevention and/or treatment notably of cancers, viral diseases and neurodegenerative diseases. It also relates to the synthetic process for obtaining them and also to medicaments containing them. It also relates to novel intermediate compounds.
Prior art
Schweinfurthins (SWs) are natural products isolated from plants of the genus Macaranga (Euphorbiaceae). They have powerful and selective cytotoxic activity on the National Cancer Institute (NCI) panel of 60 human cancer cell lines. They are particularly active on glioblastoma, kidney and certain leukaemia lines (acute lymphoblastic leukaemia or myeloma). Their cytotoxicity profile bears no resemblance to the profiles of the molecules currently used in anticancer chemotherapy, indicating that they act via a new biological target. This targeted biological activity makes schweinfurthins attractive as the leading members of a new series of novel anticancer agents.
The publication by Dipesh S. Harmalkar el al. “Schweinfurthins A-Q: isolation, synthesis, and biochemical properties”, RSC. Adv. 2018, 8, 21191-21209, presents various schweinfurthin derivatives, including schweinfurthins E, F and G (SW-E, SW-F, and SW- G), and also their plant origin.
The publication by Anthony W.G. Burgett el al, Nature Chemical Biology, 2011, 7, 639- 647 describes the affinity, among other natural molecules, of schweinfurthin A, with respect to OSBP, and also its anti-proliferative activity towards the HCT116 and HeLa lines and highlights a potential link between this target and said anti-proliferative activity.
The involvement of OSBP in certain pathologies has moreover been recently highlighted, notably in the publication by Antonietta Pietrangelo et al, “Bridging the molecular and biological functions of the oxysterol-binding protein family”, Cellular and Molecular Life Sciences, Springer International Publishing AG, part of Springer Nature 2018.
Even more recently, the mechanism of action of schweinfurthin G (SW-G) was investigated in relation to protein targets consisting of intracellular lipid transfer proteins of the oxysterol- binding protein (OSBP) family (Bruno Mesmin et al, “Molecular and cellular dissection of the oxysterol-binding protein cycle through a fluorescent inhibitor”, JBC, first published on 19 February, 2020, doi: 10.1074/jbc.RAl 19.012012, jbc.RAl 19.012012).
As may be seen from the biological results below, among the four schweinfurthin derivatives E, F, G and H, the schweinfurthins G and E are the ones with the best cytotoxic activity, which explains why research has rather been focused on these two schweinfurthin derivatives G and E. However, it has been shown that schweinfurthin G and schweinfurthin E have a lack of metabolic stability and a short half-life. This feature is one of the reasons why schweinfurthin G or schweinfurthin E has never been used hitherto in vivo. This observation can be extended to schweinfurthine F. Schweinfurthine H is, however, not very active. Only two publications report studies on schweinfurthin derivatives. (Stevens, J. W., et al, Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society, 36:2017; 1283-1293; Kathleen M. Kokolus et al. Oncolmmun. 2019; 8(2): el539614).
Disclosure of the invention
The main types of cancer treatment are surgery, radiotherapy, “conventional” chemotherapy (involving cytotoxic agents), targeted therapies (specifically targeting certain mechanisms involved in cell regulation and growth), hormone therapy (adapted in the case of cancers that are sensitive to the action of hormones naturally produced by the body), and immunotherapy (directed towards stimulating the patient’s immune system against the tumour cells).
More particularly, chemotherapy, which remains one of the most effective treatments, is based on a cytotoxic effect: a molecule kills cancer cells in order to stop tumour growth. However, these treatments give rise to serious side effects for patients due to the lack of selectivity, which notably leads to damage to healthy cells. In order to limit these effects, drugs are often dosed at minimum levels, to the detriment of their efficacy.
Consequently, it remains important to find a way of targeting tumour cells more specifically. Moreover, the risk of emergence of new viral diseases such as dengue or Zika virus infection, or more recently SARS-CoV-2, remains a concern. This is because, nowadays, there are both imported and autochthonous cases of these types of diseases, the latter type implying that the virus is circulating in the territory concerned. Although most of the time, these diseases are asymptomatic, a non-negligible proportion of people (20-30%) develop flu-like symptoms (fever, headache, joint and muscle pain, or even a skin rash) that can lead to complications which are sometimes severe.
Neurodegenerative diseases are, for their part, frequent, and their frequency increases with age, even though certain metabolic and degenerative diseases can occur as early as childhood. Due to the progressive ageing of the population and the lack of curative treatments, the number of people suffering from neurodegenerative diseases has considerably increased in recent decades and is likely to grow steadily in the years to come. Leishmaniases are parasitic diseases that cause severely debilitating or even fatal skin or visceral conditions if left untreated. They are caused by various parasites of the genus Leishmania, transmitted by the bite of insects commonly known as sandflies. Each year, 700,000 to 1 million new cases of leishmaniasis are reported worldwide, and these parasites are now considered emerging neglected diseases in Europe.
Thus, there remains a need for new derivatives of schweinfurthins E, F, G and H, which have both satisfactory cytotoxic biological activity and also good metabolic stability, in particular better metabolic stability than the reference schweinfurthin with respect to the schweinfurthin derivative considered.
The example below in particular illustrates how the derivatives of the present invention meet this need.
The need also remains for novel derivatives of schweinfurthins E, F, G and H, which have biological action on oxysterol binding protein 1.
Finally, the need remains for novel derivatives of schweinfurthins E, F, G and H, which can be prepared via a process comprising a reasonable number of steps, which uses readily available starting reagents while at the same time allowing the compounds to be obtained in good yields.
The invention is specifically directed towards meeting these needs.
The publication by Thoison O, “ Vedelianin , a hexahydroxanthene derivative isolated from Macaranga Vedelianan”, Phytochemistry, volume 31, No. 4, pages 1439-1442, 1992, describes the compound (compound 4, page
Figure imgf000006_0001
1440), without, however, associating any pharmacological activity therewith. Summary of the invention
According to one of its aspects, the present invention relates to novel compounds derived from schweinfurthins E, F and G of formula (I), pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof:
Figure imgf000006_0002
in which:
Figure imgf000006_0003
represents a single or double bond,
- R1 represents a hydroxyl group, a (C1-C5)alkoxy group, a (C2-C5)alkenyloxy group, a (C2-C5)alkynyloxy group, or a group -OCONH(CH2)nCOORa, in which n represents an integer between 2 and 6, and R a: represents a (C1-C4)alkyl group - R2 represents a hydrogen atom, or alternatively, R1 and R2 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation,
- R3 and R7 independently represent a hydrogen atom,
- R4 represents a hydroxyl group, a group
Figure imgf000007_0001
, m being equal to 1, 2 or 3, a group
Figure imgf000007_0002
, n being equal to 1, 2 or 3, preferably 1 or 2, a group
Figure imgf000007_0003
or
Figure imgf000007_0004
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are independently a (C1-C3)alkyl group, a group
Figure imgf000007_0005
, in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(0)OCH3 group; a halogen atom, in particular a chlorine atom, an amino group, or a group
Figure imgf000008_0001
or a group -OCORb, in which Rb represents a (C1-C4)alkyl group, - R5 represents a group of formula
Figure imgf000008_0002
or alternatively,
R4 and R5 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C1-C4)alkyl groups, - R6 represents a hydroxyl group, a (C1-C6)alkoxy group, a group
Figure imgf000008_0003
, m being equal to 1, 2 or 3, a group
Figure imgf000008_0004
, n being equal to 1, 2 or 3, preferably 1 or 2, a group or
Figure imgf000008_0005
Figure imgf000009_0001
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are independently a (C1-C3)alkyl group, or a group , in which s is equal to 0, 1 or 2,
Figure imgf000009_0002
t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(O)OCH3 group; a halogen atom, in particular a chlorine atom, or an amino group, a group -OCORc, in which Rc represents a (C1-C4)alkyl group, or a group -OCONH(CO)pRd, in which p represents an integer chosen from 0 or 1, Rd represents a (C1-C6)alkyl group optionally substituted with a halogen atom such as a chlorine atom, with a sugar radical, with a group -COORe, in which Re represents a (C1-C4)alkyl group or a hydrogen atom or with a group -O-P(=O)-(ORf)(ORg), in which Rf and Rg independently represent a (C1-C4)alkyl group,
- R8 and R9 independently represent a hydrogen atom, a hydroxyl group, or a group -OCORh, in which Rh represents a hydrogen atom or a (C1-C5)alkyl group, and in which at least: a. R4 and R5 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C1-C4)alkyl groups, or b. R5 represents a group of formula
Figure imgf000009_0003
and at least one of the following conditions is confirmed: i. R1 and R2 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation, ii. at least one from among R1, R4 and R6 is a (C2-C5)alkenyloxy group or a (C2-C5)alkynyloxy group, iii. R8 represents a group -OCORh, in which Rh is a hydrogen atom or a (C1-C5)alkyl group, or iv. at least one from among R3 and R7 is a halogen atom, it being understood that when R5 represents a group of formula
Figure imgf000010_0001
then at least R4 or R6 is other than a hydroxyl group, and it being understood that the compound having the following formula is excluded
Figure imgf000010_0002
The present text also describes compounds derived from schweinfurthins E, F and G of formula (I), pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof:
Figure imgf000010_0003
in which:
Figure imgf000010_0004
represents a single or double bond, - R1 represents a hydroxyl group, a (C1-C5)alkoxy group, a (C2-C5)alkenyloxy group, a (C2-C5)alkynyloxy group, or a group -OCONH(CH2)nCOORa, in which n represents an integer between 2 and 6, and Ra represents a (C1-C4)alkyl group,
- R2 represents a hydrogen atom or a (C2-C5)alkenyl group, or alternatively,
Ri and R2 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation,
- R3 and R7 independently represent a hydrogen atom or a halogen atom, for example a bromine atom,
- R4 represents a hydroxyl group, a group
Figure imgf000011_0001
, m being equal to 1, 2 or 3, and a group
Figure imgf000011_0002
, n being equal to 1, 2 or 3, preferably 1 or 2, a group or
Figure imgf000011_0003
Figure imgf000012_0001
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are independently a (C1-C3)alkyl group, a group
Figure imgf000012_0002
, in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 2 or 3, q is equal to 1, 2,
3, 4, 5 or 6, preferably 6, and X is a hydrogen or halogen atom, in particular a chlorine atom, or an amino group, or a group -OCORb, in which Rb represents a (C1-C4)alkyl group, - R5 represents a group of formula
Figure imgf000012_0003
or alternatively,
R4 and R5 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C1-C4)alkyl groups, - R6 represents a hydroxyl group, a (C1-C6)alkoxy group, a group
Figure imgf000012_0004
, m being equal to 1, 2 or 3, a group , n being equal to 1, 2 or 3, preferably
Figure imgf000012_0005
1 or 2, a group
Figure imgf000013_0001
or
Figure imgf000013_0002
, in which R is a hydrogen atom or a methyl group and R’ and R” are independently a (C1- C3)alkyl group, a group
Figure imgf000013_0003
, in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom, a halogen atom, in particular a chlorine atom, or an amino group, a group -OCORc, in which Rc represents a (C1-C4)alkyl group, or a group -OCONH(CO)pRd, in which p represents an integer chosen from 0 or 1, Rd represents a (C1-C6)alkyl group optionally substituted with a halogen atom such as a chlorine atom, with a sugar radical, with a group -COORe, in which Re represents a (C1-C4)alkyl group or a hydrogen atom or with a group -O-P(=O)-(ORf)(ORg), in which Rf and Rg independently represent a (C1-C4)alkyl group,
- R8 and R9 independently represent a hydrogen atom, a hydroxyl group, or a group -OCORh, in which Rh represents a hydrogen atom or a (C1-C5)alkyl group, and in which at least: a. R4 and R5, together with the ring bearing them, form a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C1-C4)alkyl groups, or b. R5 represents a group of formula
Figure imgf000014_0001
and at least one of the following conditions is confirmed: i. R1 and R2 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation, ii. at least one from among R1, R4 and R6 is a (C2-C5)alkenyloxy group or a (C2-C5)alkynyloxy group, iii. R8 represents a group -OCORh, in which Rh is a hydrogen atom or a (C1-C5)alkyl group, iv. R2 represents a (C2-C5)alkenyl group, or v. at least one from among R3 and R7 is a halogen atom.
According to another of its aspects, the present invention also relates to a compound of formula (I) according to the present invention, or to at least one compound (1) to (19), (21), (23), (31) to (46), (48) to (71) as defined below, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical compositions containing them, for its use as a medicament. According to another of its aspects, the present invention also relates to a compound of formula (I) according to the present invention, or to at least one compound (1) to (19), (21), (23), (31) to (46), (48) to (71) as defined below, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical compositions containing them, for its use as an oxysterol binding protein 1 (OSBP) inhibitor. According to another of its aspects, the present invention also relates to a compound of formula (I) according to the present invention, or to at least one compound (1) to (19), (21), (23), (31) to (46), (48) to (71) as defined below, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical compositions containing them, for its use in the prevention, inhibition and/or treatment of cancers, neurodegenerative diseases, dyslipidaemia, hypercholesterolaemia, parasitic diseases and/or viral diseases.
Also, according to another of its aspects, a compound of formula (I) according to the present invention, or at least one compound (1) to (19), (21), (23), (31) to (46), (48) to (71) as defined below, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical compositions containing them, for its use for the prevention, inhibition and/or treatment of cancers, in particular breast cancer, including triple negative breast cancer, osteosarcoma, kidney cancer, head and neck cancer, prostate cancer, colorectal cancer, colon cancer, gall bladder cancer, bile duct cancer (cholangiocarcinoma), gastrointestinal cancer, gastric cancer, hepatocellular carcinoma, lymphoma, lung cancer, small cell lung cancer, non- small cell lung cancer, pancreatic cancer, pancreatic carcinoma, stomach cancer, brain cancer, metastasis, leukaemia, acute T-cell lymphoblastic leukaemia, chronic myeloid leukaemia, melanoma, and glioblastoma, even more particularly osteosarcoma, kidney cancer, triple negative breast cancer, melanoma, leukaemia and glioblastoma.
According to a particular embodiment of the invention, the compound of formula (I) is as defined previously, it being understood that when R4 and R5 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C1-C4)alkyl groups, then R1 is other than a hydroxyl group.
According to a particular embodiment of the invention, the compound of formula (I) is as defined previously, it being understood that when R4 and R5 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C1-C4)alkyl groups, then R8 and R9 are simultaneously other than a hydroxyl group.
According to another of its aspects, the present invention also relates to a process for preparing a compound of formula (la”)
Figure imgf000016_0001
in which R1 and R6 are as defined previously and at least one from among R8 and R9 represents a group -OCORh as defined previously, and in particular an -OCHO group or an -OCOCH3 group, and in which R2 is a hydrogen atom, or a (C2-C5)alkenyl group, such as an allyl group or any of the pharmaceutically acceptable salts thereof, comprising at least one step of intramolecular cyclization of the geranyl chain into pyran, of a compound of general formula (II), accompanied by esterification of the secondary alcohol of the hexahydroxanthene unit
Figure imgf000016_0002
Finally, according to another of its aspects, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) according to the present invention or at least one compound (1) to (19), (21), (23), (31) to (46), (48) to (71) as defined below, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof, and at least one pharmaceutically acceptable excipient. The inventors have found that the compounds of formula (I) according to the present invention show anticancer efficacy, in particular against glioblastoma, while at the same time demonstrating improved metabolic stability, in particular with respect to the reference schweinfurthin to be compared with the compound to be considered.
Thus, the inventors have also confirmed the cytotoxic activity on cell lines, and more particularly on the U87 and A549 lines. U87 cells are a human glioblastoma cancer cell line (GBM). A549 cells are adenocarcinomic human alveolar basal epithelial cells and are a cell line of choice for confirming cytotoxic activity as they are known to be less sensitive to schweinfurthins. The metabolic activity was evaluated in comparison with natural schweinfurthin, to which it is chemically the closest; making it possible to confirm the fact that all the compounds of the invention effectively show improved metabolic stability with respect to the structurally closest schweinfurthin.
Furthermore, as emerges from the experimental section, the inventors demonstrated inhibitory biological activity towards oxy sterol binding protein 1 (OSBP).
Other characteristics, aspects and advantages of the invention will emerge on reading the detailed description that follows.
Definitions
In the present invention, the term “room temperature” means a temperature of between 18°C and 30°C, preferably between 18°C and 25°C.
In the context of the present invention, the following definitions are used:
- “Ct-Cz” denotes a carbon-based chain which may contain from t to z carbon atoms, where t and z may, for example, take values from 1 to 25; for example C1-C3 is a carbon-based chain which may contain from 1 to 3 carbon atoms.
- An “alkyl” denotes a linear or branched monovalent saturated aliphatic group, which may, for example, comprise from 1 to 25 carbon atoms, and preferably from 1 to 5 carbon atoms. Examples that may be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. groups.
- An “alkenyl” denotes a linear or branched unsaturated aliphatic group comprising at least one double bond; for example, a Cx to Cz alkenyl group represents a linear or branched unsaturated carbon-based chain of x to z carbon atoms. Mention may notably be made of vinyl, 1-propenyl, 2-propenyl and butenyl groups or an allyl group. - An “alkynyl” denotes a linear or branched, unsaturated aliphatic group comprising at least one triple bond; for example, a Cx to Cz alkynyl group represents a linear or branched unsaturated carbon-based chain of x to z carbon atoms. Mention may notably be made of an ethynyl group, a propynyl group or a pentynyl group.
- An “alkoxy” denotes an -O-alkyl group. Examples that may be mentioned include a methoxy group or an ethoxy group.
- An “alkenyloxy” denotes an -O-alkenyl group. An example that may be mentioned is a propenyloxy group.
- An “alkynyloxy” denotes an -O-alkynyl group. Examples that may be mentioned include a propynyloxy or pentynyloxy group.
- A “halogen” denotes chlorine, fluorine, bromine or iodine, and notably denotes chlorine, fluorine or bromine, more particularly chlorine.
- A “phenyloxo” denotes a -CO-phenyl group.
- A “sugar radical” denotes a natural or non-natural furanose radical or hexose radical. Non natural sugar radicals may, for example, comprise alkylated or acylated hydroxyl and/or amine residues on the ring, such as ether, ester and amide substituents. Other non-natural sugar radicals may comprise H, hydroxyl, ether, ester or amide substituents in positions on the ring where these substituents are not present in natural sugars. Alternatively, the sugar radical does not include a substituent in its usual position on the natural sugar; this case corresponds to the deoxy sugar radical. Other examples of non-natural sugars include oxidized (e.g. -onic and -uronic acids) and reduced (sugar alcohol) carbohydrates. The sugar residue may be a monosaccharide, oligosaccharide or polysaccharide.
As natural sugar radicals that may be used in the context of the present invention, mention may be made of glucose, galactose, fucose, mannose, xylanose, ribose, N-acetylglucose (GlcNAc), sialic acid and N-acetylgalactose (GalNAc).
- The term “protecting group” refers to a functional group introduced into the molecule from a chemical function to mask all or part of its reactivity.
- The term “pharmaceutically acceptable” denotes 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 and/or human pharmaceutical use. - In the present invention, the term “pharmaceutically acceptable salt” of a compound is intended to denote salts that are pharmaceutically acceptable, as defined herein, and which have the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, glycolic acid, 2- hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid and the like; and (2) salts formed when an acid proton present in the parent compound is either replaced with a metal ion, for example an alkali metal ion (such as Na+, K+ or Li+), an alkaline-earth metal ion (such as Ca2+ or Mg2+) or an aluminium ion; or coordinates with an organic or inorganic base. Acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
- The term “hydrate or solvate” refers to forms of association or combination with one or more water molecules or with a solvent.
- Isomeric forms denote racemates, enantiomers, diastereoisomers, epimers, tautomers and conformational isomers. A racemic form is a mixture of two enantiomers in a ratio of 55:45 to 45:55.
Compounds of formula (I)
According to one of its aspects, the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH2)nCOORa, in which n is equal to 3, 4 or 5, in particular equal to 3 or 5, and Ra represents a methyl or ethyl group, in particular ethyl, a propenyloxy group or a propynyloxy group.
According to another of its aspects, the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R1 and R2 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and an unsaturation, in particular a group
Figure imgf000020_0001
According to another of its aspects, the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R4 represents a hydroxyl group, a group
Figure imgf000020_0002
, m being equal to 1 or 3, a group
Figure imgf000020_0003
, n being equal to 1 or 2, a group
Figure imgf000020_0004
or
Figure imgf000021_0001
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups, a group
Figure imgf000021_0002
, in which s is equal to 0, 1 or 2, t is equal to 1 or 3, p is equal to 0, 2 or 3, q is equal to 6, and X is a hydrogen atom, a halogen atom, in particular a chlorine atom, a phenyl group, a phenyloxo group, the phenyl group being substituted with a methoxy group, a -C(O)OCH3 group or a group
Figure imgf000021_0003
or a -OCOCH3 group. According to another of its aspects, the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R5 represents a group of formula
Figure imgf000021_0004
According to another of its aspects, the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R4 and R5 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two methyl groups, in particular a group
Figure imgf000022_0001
According to another of its aspects, the present patent application relates to the compound of formula (I) as defined previously, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non- racemic mixtures thereof, in which R6 represents a hydroxyl group, a methoxy or ethoxy group, a group
Figure imgf000022_0002
, m being equal to 1 or 3, a group
Figure imgf000022_0003
, n being equal to 1 or 2, a group
Figure imgf000022_0004
or
Figure imgf000022_0005
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups, an -OCOCH3 group, an -OCONHCOCH2CI group, a group
Figure imgf000023_0001
, in which s is equal to 0, t is equal to 1, p is equal to 0, q is equal to 1, and X is a hydrogen atom, a phenyl or phenyloxo group, the phenyl group being substituted with a methoxy group or a -C(O)OCH3 group or a group -OCONH(CH2)qCOORk, in which q represents an integer chosen from 3, 4 or 5, in particular 3 and 5, and Rk represents a methyl or ethyl group, in particular ethyl.
According to another of its aspects, the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R8 and R9 independently represent a hydrogen atom, a hydroxyl group, an -OCHO group, or an -OCOCH3 group.
As regards the substitution of the (C1-C6)alkyl group, it may alternatively be located at the end of the chain or in any position on the chain. According to one variant of the invention, the substitution, when is present, is at the end of the chain. According to another of its aspects, the present patent application relates to the compound of formula (I) as defined previously, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, represented by formula (la):
Figure imgf000024_0001
in which
Figure imgf000024_0002
R1, R2, R3, R6, R7, R8 and R9 are as defined above, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
According to yet another of its aspects, the present patent application relates to the compound of formula (la) as defined previously, in which:
Figure imgf000024_0003
represents a single or double bond,
- R3 and R7 are as defined previously, and more particularly represent a hydrogen atom,
- R1 represents a hydroxyl group, a (C1-C5)alkoxy group, a (C2-C5)alkenyloxy group, a (C2-C5)alkynyloxy group, or a group -OCONH(CH2)nCOORa, in which n represents an integer between 2 and 6, and Ra represents a (C1-C4)alkyl group,
- R2 represents a hydrogen atom, or alternatively,
R1 and R2 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation,
- R6 represents a hydroxyl group, a (C1-C6)alkoxy group, a (C2-C5)alkynyloxy group, a group -OCORc, in which Rc represents a (C1-C4)alkyl group, or a group -OCONH(CO)pRd, in which p represents an integer chosen from 0 or 1 , Rd represents a (C1-C6)alkyl group optionally substituted with a halogen atom, such as a chlorine atom, with a sugar radical, with a group -COORe, in which Re represents a (C1-C4)alkyl group or a hydrogen atom or with a group -O-P(=O)-(ORf)(ORg), in which Rf and Rg independently represent a (C1-C4)alkyl group, and
- R8 and R9 independently represent a hydrogen atom, a hydroxyl group, or a group -OCORh, in which Rh represents a hydrogen atom or a (C1-C5)alkyl group.
According to a particular embodiment of this aspect of the invention, the compound of formula (la) as defined above is such that
- R1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH2)nCOORa, in which n is equal to 3, 4 or 5, in particular equal to 3 or 5, and Ra represents a methyl or ethyl group, in particular ethyl, a propenyloxy group, or a propynyloxy group,
- R2 represents a hydrogen atom or R1 and R2 form, together with the ring bearing them, a 6-membered ring comprising an oxygen atom and an unsaturation, in particular a group
Figure imgf000025_0001
- R6 represents a hydroxyl group, a methoxy or ethoxy group, a propynyloxy group, an -OCOCH3 group, an -OCONHCOCH2CI group, or a group -OCONH(CH2)qCOORk, in which q represents an integer chosen from 3, 4 or 5, in particular 3 and 5, and Rk represents a methyl or ethyl group, in particular an ethyl group, and - R8 and R9 independently represent a hydrogen atom, a hydroxyl group, an -OCHO group, or an -OCOCH3 group.
According to a particular embodiment of this aspect of the invention, the compound of formula (la) as defined above, has the formula (la’)
Figure imgf000026_0001
in which
Figure imgf000026_0002
is as defined previously and is in particular a double bond,
R6 is as defined previously and in particular represents a hydroxyl group, R8 and R9 are as defined previously, and in particular independently represent a hydrogen atom, a hydroxyl group, an -OCHO group or an -OCOCH3 group, and even more particularly a hydroxyl group, an -OCHO group or an -OCOCH3 group, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
Among the compounds of the invention falling within this general formula (la”), mention may notably be made of compounds (3) and (4).
According to yet another particular embodiment of this aspect of the invention, the compound of formula (la) as defined above has the formula (la”)
Figure imgf000026_0003
in which
Figure imgf000026_0004
, R1, R2, R6, R8 and R9 are as defined previously, and in particular
- R1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH2)nCOORa, in which n is equal to 3, 4 or 5, in particular equal to 3 or 5, and Ra represents a methyl or ethyl group, in particular ethyl, a propenyloxy group, or a propynyloxy group
- R2 represents a hydrogen atom,
- R6 represents a hydroxyl group, a methoxy or ethoxy group, a propynyloxy group, an -OCOCO3 group, an -OCONHCOCH2CI group, or a group -OCONH(CH2)qCOORk, in which q represents an integer chosen from 3, 4 or 5, in particular 3 and 5, and Rk represents a methyl or ethyl group, in particular ethyl, and
- R8 and R9 independently represent a hydrogen atom, a hydroxyl group, an -OCHO group, or an -OCOCH3 group, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
Still according to this particular embodiment of this aspect of the invention, formula (la”) is such that
- R1 represents a hydroxyl group, or a methoxy group,
- R2 represents a hydrogen atom,
- R6 represents a hydroxyl group, and
- R8 and R9 independently represent a hydrogen atom, a hydroxyl group, or an -OCHO group. Among the compounds of the invention falling within this general formula (la”), mention may notably be made of compounds (1), (2), (5), (6), (7), (8), (9), (10), (11) and (12).
According to yet another particular embodiment of this aspect of the invention, the compound of formula (la) as defined above has the formula (la’”)
Figure imgf000027_0001
in which
Figure imgf000027_0002
, R1, R2, R6, R9 and Rh are as defined previously, notably with at least one of the groups R1 and R6 being a group -OCORc or a group -OCONH(CO)pRd as defined below, and in particular - R1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH2)nCOORa, in which n is 3, 4 or 5, in particular 3 or 5, and Ra represents a methyl or ethyl group, in particular ethyl, a propenyloxy group, or a propynyloxy group,
- R2 represents a hydrogen atom,
- R6 represents a hydroxyl group, a (C1-C6)alkoxy group, a (C2-C5)alkynyloxy group, a group -OCORc, in which Rc represents a (C1-C4)alkyl group, or a group -OCONH(CO)pRd, in which p represents an integer chosen from 0 or 1 , Rd represents a (C1-C6)alkyl group optionally substituted with a halogen atom, such as a chlorine atom, with a sugar radical, with a group -COORe, in which Re represents a (C1-C4)alkyl group or a hydrogen atom, or with a group -O-P(=O)-(ORf)(ORg), in which Rf and Rg independently represent a (C1-C4)alkyl group
- R9 represents a hydrogen atom, a hydroxyl group, an -OCHO group or an -OCH3 group,
- Rh represents a hydrogen atom or a methyl, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
Still according to this particular embodiment of this aspect of the invention, formula (la’”) is such that
- R1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH2)nCOORa, in which n is equal to 3, 4 or 5, in particular 3 or 5, and Ra represents a methyl or ethyl group, in particular ethyl,
- R2 and R9 represent a hydrogen atom, and
- R6 represents a hydroxyl group, a methoxy or ethoxy group, an -OCONHCOCH2CI group, or a group -OCONH(CH2)qCOORb, in which q represents an integer chosen from 3, 4 or 5, in particular 3 and 5, and Rb represents a methyl or ethyl group, in particular ethyl.
Among the compounds of the invention falling within this general formula (la”), mention may notably be made of compounds (13), (14), (15) and (16).
According to another of its aspects, the present patent application relates to the compound of formula (I) as defined above, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, represented by formula (lb)
Figure imgf000029_0001
in which , R1, R2, R3, R4, R6, R7, R8 and R9 are as defined previously,
Figure imgf000029_0002
and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
According to another of its aspects, the present patent application relates to the compound of formula (I) as defined above, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, represented by formula (lb)
Figure imgf000030_0001
in which
Figure imgf000030_0002
, R1, R3, R4, R6, R7, R8 and R9 are as defined previously, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
According to yet another of its aspects, the present patent application relates to the compound of formula (lb) as defined previously, in which
Figure imgf000030_0003
represents a single or double bond, in particular a double bond, - R1 represents a hydroxyl group, a (C1-C5)alkoxy group, a (C2-C5)alkenyloxy group, a (C2-C5)alkynyloxy group, or a group -OCONH(CH2)nCOORa, in which n represents an integer between 2 and 6, and Ra represents a (C1-C4)alkyl group,
- R3 and R7 independently represent a hydrogen atom or a halogen atom, for example a bromine atom,
- R4 represents a hydroxyl group, a group
Figure imgf000030_0004
, m being equal to 1, 2 or 3, a group
Figure imgf000030_0005
, n being equal to 1, 2 or 3, preferably 1 or 2, a group
Figure imgf000031_0001
Figure imgf000031_0002
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are independently a (C1-C3)alkyl group, or a group
Figure imgf000031_0003
, in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(0)0CH3 group; a halogen atom, in particular a chlorine atom, an amino group or a group
Figure imgf000031_0004
or a group -OCORb, in which Rb represents a (C1-C4)alkyl group, - R6 represents a hydroxyl group, a (C1-C6)alkoxy group, a (C2-C5)alkynyloxy group, a group
Figure imgf000032_0001
, m being equal to 1, 2 or 3, a group
Figure imgf000032_0002
, n being equal to 1, 2 or 3, preferably 1 or 2, a group
Figure imgf000032_0003
or
Figure imgf000032_0004
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are independently a (C1-C3)alkyl group, or a group
Figure imgf000032_0005
, in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(O)OCH3 group; a halogen atom, in particular a chlorine atom, or an amino group, or a group -OCORc, in which Rc represents a (C1-C4)alkyl group, or a group -OCONH(CO)pRd, in which p represents an integer chosen from 0 or 1 , Rd represents a (C1-C6)alkyl group optionally substituted with a halogen atom such as a chlorine atom, with a sugar radical, with a group -COORe, in which Re represents a (C1-C4)alkyl group or a hydrogen atom or with a group -O-P(=O)-(ORf)(ORg), in which Rf and Rg independently represent a (C1-C4)alkyl group, and - R8 and R9 independently represent a hydrogen atom, a hydroxyl group, or a group -OCORh, in which Rh represents a hydrogen atom or a (C1-C5)alkyl group, and in which at least one of the following conditions is confirmed: i. at least one from among R1, R4 and R6 is a (C2-C5)alkenyloxy group or a (C2-C5)alkynyloxy group, ii. R8 represents a group -OCORh, in which Rh represents a hydrogen atom or a (C1-C5)alkyl group, or iii. at least one from among R3 and R7 is a halogen atom.
According to a particular embodiment of this aspect of the invention, the compound of formula (lb) as defined previously is such that
Figure imgf000033_0001
represents a double bond,
- R1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH2)nCOORa, in which n is equal to 3, 4 or 5, in particular equal to 3 or 5, and Ra represents a methyl or ethyl group, in particular ethyl, a propenyloxy group, or a propynyloxy group, and
- R4 represents a hydroxyl group, a group
Figure imgf000033_0002
, m being equal to 1 or 3, a group
Figure imgf000034_0001
, n being equal to 1 or 2, a group
Figure imgf000034_0002
or
Figure imgf000034_0003
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups, a group
Figure imgf000034_0004
in which s is equal to 0, 1 or 2, t is equal to 1 or 3, p is equal to 0, 2 or 3, q is equal to 6, and X is a halogen atom, in particular a chlorine atom, a phenyl group or a phenyloxo group, the phenyl group being substituted with a methoxy group, a -C(O)OCH3 group or a group
Figure imgf000034_0005
or a group -OCOCH3, - R6 represents a hydroxyl group, a methoxy or ethoxy group, a group
Figure imgf000035_0001
, m being equal to 1 or 3, a group
Figure imgf000035_0002
, n being equal to 1 or 2 a group
Figure imgf000035_0003
or
Figure imgf000035_0004
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups, an -OCOCH3 group, an -OCONHCOCH2CI group, a group
Figure imgf000035_0005
, in which s is equal to 0, t is equal to 1, p is equal to 0, q is equal to 1, and X is a hydrogen atom, a phenyl group or a phenyloxo group, the phenyl group being substituted with a methoxy group or a -(3(O)OCH3 group, or a group -OCONH(CH2)qCOORk, in which q represents an integer chosen from 3, 4 or 5, in particular 3 and 5, and Rk represents a methyl or ethyl group, in particular ethyl, and in particular represents a hydroxyl group, a methoxy or ethoxy group, a -OCOCH3 group, a group
Figure imgf000036_0001
, m being equal to 1 or 3, a group
Figure imgf000036_0002
, n being equal to 1 or 2, or a group
Figure imgf000036_0003
Figure imgf000036_0004
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups, or a group
Figure imgf000036_0005
, in which s is equal to 0, t is equal to 1, p is equal to 0, q is equal to 1, and X is a hydrogen atom, a phenyl group or a phenyloxo group, the phenyl group being substituted with a methoxy group or a -(3(O)OCH3 group,- R8 and R9 independently represent a hydrogen atom, a hydroxyl group, an -OCHO group, or an -OCOCH3 group.
According to a particular embodiment of this aspect of the invention, the compound of formula (lb) as defined above is characterized in that at least one of R4 or R6, and in particular one of R4 and R6, comprises a group
Figure imgf000037_0001
, in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(O)OCH3 group; a halogen atom, in particular a chlorine atom; an amino group or a group
Figure imgf000037_0002
, in particular a group
Figure imgf000037_0003
in which s is equal to 0, t is equal to 1, p is equal to 0, q is equal to 1, and X is a hydrogen atom, a phenyl or phenyloxo group, the phenyl group being substituted with a methoxy group or a -C(O)OCH3 group.
According to a particular embodiment of this aspect of the invention, the compound of formula (lb) as defined above has the formula (Ibii)
Figure imgf000037_0004
in which
Figure imgf000037_0005
, R1, R4, R6, R8 and R9 are as previously defined, and in which at least one from among R1, R4 and R6 is a (C2-C5)alkenyloxy group or a (C2-C5)alkynyloxy group, and in particular,
Figure imgf000038_0001
represents a double bond,
- R1 represents a hydroxyl group, a (C2-C5)alkynyloxy group, or a (C2-C5)alkenyloxy group,
- R4 and R6 independently represent a hydroxyl group, a group
Figure imgf000038_0002
, m being equal to 1, 2 or 3, a group
Figure imgf000038_0003
, n being equal to 1, 2 or 3, preferably 1 or 2, a group
Figure imgf000038_0004
or
Figure imgf000038_0005
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are independently a (C1-C3)alkyl group, or a group
Figure imgf000039_0001
, in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(0)OCH3 group; a halogen atom, in particular a chlorine atom, or an amino group,
R4 also possibly representing a group
Figure imgf000039_0002
and
- R8 and R9 independently represent a hydrogen atom, or a hydroxyl group, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof. Among the compounds of the invention falling within this general formula (Ibii), mention may notably be made of compounds (17), (18), (19), (21), (31) to (43).
According to a particular embodiment of this aspect of the invention, the compound of formula (lb) as defined above has the formula (Ibiii)
Figure imgf000039_0003
in which
Figure imgf000040_0001
, R1, R4, R6 and Rh are as defined previously, and in particular
Figure imgf000040_0002
represents a double bond,
- R1 represents a methoxy group, a hydroxyl group or a (C2-C5)alkenyloxy group, such as an allyloxy group,
- R4 and R6 independently represent a hydroxyl group or a group -OCORb, in which Rb represents a (C1-C4)alkyl group,
- Rh represents a hydrogen atom or a (C1-C5)alkyl group, and
- R9 represents a hydrogen atom, a hydroxyl group or a group -OCORh, in particular a hydrogen atom, and also pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof.
Among the compounds of the invention falling within this general formula (Ibiii), mention may notably be made of compound (23).
Some of the compounds included in the general formula (I) as defined previously prove to be metabolites that are active towards the therapeutic target, of compounds which are themselves included in the general formula (I). This will become clearer on reading the experimental section. For example, compound (10) is a metabolite of compound (9), and compound (2) is a metabolite of compound (1). This is equivalent to stating that compound (9) is a prodrug of compound (10) and compound (1) is a prodrug of compound (2). This is also the case for compounds (3) and (4), (5) and (6), (7) and (8), (11) and (12), (13) and (6), (14) and (10), (15) and (10), (16) and (10).
According to a preferred embodiment of the present invention, the compound of formula (I) is chosen from:
(1): (2R,4aR,9aR)-5-hydroxy-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)- 1 , 1 ,4a-trimethyl-2,3 ,4,4a,9,9a-hexahydro- 1 H-xanthcn-2-yl formate,
(2): (2R,4aR,9aR)-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-l,l,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5-diol, - (3): (7aR,9R,11aR)-5-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-8,8,11a- trimethyl-2,7,7a,8,9,10,11,11a-octahydropyrano[3,2-c]xanthen-9-yl formate, - (4): (7aR,9R,11aR)-5-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-8,8,11a- trimethyl-2,7,7a,8,9,10,11,11a-octahydropyrano[3,2-c]xanthen-9-ol, - (5): (2R,4aR,9aR)-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-yl formate, - (6): (2R,4aR,9aR)-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (7): (2S,3R,4aR,9aR)-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,3-diyl diformate, - (8): (2S,3R,4aR,9aR)-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,3-diol, - (9): (2R,4aR,9aR)-5-hydroxy-7-(2-(5-hydroxy-2,2-dimethylchroman-7-yl)ethyl)-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-yl formate, - (10): (2R,4aR,9aR)-7-(2-(5-hydroxy-2,2-dimethylchroman-7-yl)ethyl)-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5-diol, - (11): (2R,4aR,9aR)-7-(2-(5-hydroxy-2,2-dimethylchroman-7-yl)ethyl)-5-methoxy-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-yl formate, - (12): (2R,4aR,9aR)-7-(2-(5-hydroxy-2,2-dimethylchroman-7-yl)ethyl)-5-methoxy-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (13): (2R,4aR,9aR)-7-((E)-2-(5-(((2-chloroacetyl)carbamoyl)oxy)-2,2-dimethylchroman- 7-yl)vinyl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-yl formate, - (14): ethyl 6-(((((2R,4aR,9aR)-7-((E)-2-(5-(((6-ethoxy-6-oxohexyl)carbamoyl)oxy)-2,2- dimethylchroman-7-yl)vinyl)-2-(formyloxy)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthen-5-yl)oxy)carbonyl)amino)hexanoate, - (15): ethyl 4-(((((2R,4aR,9aR)-7-((E)-2-(5-(((4-ethoxy-4-oxobutyl)carbamoyl)oxy)-2,2- dimethylchroman-7-yl)vinyl)-2-(formyloxy)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthen-5-yl)oxy)carbonyl)amino)butanoate, - (16): (2R,4aR,9aR)-7-((E)-2-(5-(((2-chloroacetyl)carbamoyl)oxy)-2,2-dimethylchroman- 7-yl)vinyl)-5-hydroxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-yl formate, - (17): (2R,4aR,9aR)-1,1,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-1-yl)-3,5-bis(prop-2-yn- 1-yloxy)styryl)-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5-diol, - (18): (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-1-yl)-5-(prop-2-yn-1- yloxy)styryl)-1,1,4a-trimethyl-5-(prop-2-yn-1-yloxy)-2,3,4,4a,9,9a-hexahydro-1H- xanthen-2-ol, - (19): (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-1-yl)-5-(prop-2-yn-1- yloxy)styryl)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5-diol, - (21): (2R,4aR,9aR)-1,1,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-1-yl)-3,5-bis(prop-2-yn- 1-yloxy)styryl)-5-(prop-2-yn-1-yloxy)-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - - (23): 5-((E)-2-((2R,4aR,9aR)-2-acetoxy-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a- hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1-yl)-1,3-phenylene diacetate,- - (31): (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-1-yl)-5-(prop-2-yn-1- yloxy)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (32): (2S,3R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-1-yl)-5-(prop-2-yn-1- yloxy)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,3-diol, - (33): methyl 2-(4,5-dimethoxy-2-nitrophenyl)-2-(5-((E)-2-((2R,4aR)-2-hydroxy-5- methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-2-(3- methylbut-2-en-1-yl)-3-(prop-2-yn-1-yloxy)phenoxy)acetate, - (34): methyl 2-(5-((E)-2-((2S,3R,4aR)-2,3-dihydroxy-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1-yl)-3-(prop-2-yn- 1-yloxy)phenoxy)-2-(4,5-dimethoxy-2-nitrophenyl)acetate, - (35): 2-(5-((E)-2-((2S,3R,4aR)-2,3-dihydroxy-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a- hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1-yl)-3-(prop-2-yn-1- yloxy)phenoxy)-2-(4,5-dimethoxy-2-nitrophenyl)acetic acid, - (36): (2R,4aR,9aR)-5-methoxy-1,1,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-1-yl)-3,5- bis(prop-2-yn-1-yloxy)styryl)-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, -(37): (2S,3R,4aR,9aR)-5-methoxy-1,1,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-1-yl)-3,5- bis(prop-2-yn-1-yloxy)styryl)-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,3-diol, - (38): (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-1-yl)-5-(pent-4-yn-1- yloxy)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (39): (2R,4aR,9aR)-5-methoxy-1,1,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-1-yl)-3,5- bis(pent-4-yn-1-yloxy)styryl)-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (40): (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-1-yl)-5-(2-(prop-2-yn-1- yloxy)ethoxy)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2- ol, - (41): (2R,4aR,9aR)-5-methoxy-1,1,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-1-yl)-3,5- bis(2-(prop-2-yn-1-yloxy)ethoxy)styryl)-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (42): (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-1-yl)-5-(2-(2-(prop-2-yn-1- yloxy)ethoxy)ethoxy)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthen-2-ol, - (43): (2R,4aR,9aR)-5-methoxy-1,1,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-1-yl)-3,5- bis(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)styryl)-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2- ol, - (44): methyl 2-(5-((E)-2-((2S,3R,4aR)-2,3-dihydroxy-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-3-hydroxy-2-(3-methylbut-2-en-1- yl)phenoxy)-2-(4,5-dimethoxy-2-nitrophenyl)acetate, - (45): 2-(5-((E)-2-((2S,3R,4aR)-2,3-dihydroxy-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a- hexahydro-1H-xanthen-7-yl)vinyl)-3-hydroxy-2-(3-methylbut-2-en-1-yl)phenoxy)-2-(4,5- dimethoxy-2-nitrophenyl)acetic acid, - (46): (2S,3R,4aR)-7-((E)-3-((4,5-dimethoxy-2-nitrobenzyl)oxy)-5-hydroxy-4-(3- methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthene-2,3-diol, - (48): 2,2’-((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1-yl)-1,3- phenylene)bis(oxy))bis(2-(4,5-dimethoxy-2-nitrophenyl)acetic acid, - (49): 2-(3-((1-(2-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4- yl)methoxy)-5-((E)-2-((2S,3R,4aR)-2,3-dihydroxy-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1-yl)phenoxy)-2- (4,5-dimethoxy-2-nitrophenyl)acetic acid, - (50): (2S,3R,4aR)-7-((E)-3-((1-(2-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,3-diol, - (51): (2R,4aR,9aR)-7-((E)-3-(3-(1-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)propoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (52): (2R,4aR,9aR)-7-((E)-3-(2-((1-(2-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)ethyl)- 1H-1,2,3-triazol-4-yl)methoxy)ethoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5- methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (53): (2R,4aR,9aR)-7-((E)-3-(2-((1-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methoxy)ethoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (54): (2R,4aR,9aR)-7-((E)-3-(2-(2-((1-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methoxy)ethoxy)ethoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5- methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (55): (2R,4aS,9aS)-7-((E)-3-((1-(2-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy- 1,1,4a-trimethyl-1,2,3,4,4a,9,9a,10-octahydroanthracen-2-ol, - (56): (2R,4aR,9aR)-7-((E)-3-((1-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol,c - (57): (2S,3R,4aR,9aR)-7-((E)-3-hydroxy-5-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-4- (3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthene-2,3-diol, - (58): (2S,3R,4aR,9aR)-7-((E)-3,5-bis((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-4-(3- methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthene-2,3-diol - (59): (2S,3R,4aR,9aR)-7-((E)-3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-hydroxy-4- (3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthene-2,3-diol, - (60): (2S,3R,4aR,9aR)-7-((E)-3,5-bis((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-4-(3- methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthene-2,3-diol - (61): methyl 2-(4-((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-3-hydroxy-2-(3-methylbut-2- en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)acetate, - (62): dimethyl 2,2'-((((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1-yl)-1,3- phenylene)bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))diacetate- - (63): tert-butyl (R)-2-((4-((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-3-hydroxy-2-(3-methylbut-2- en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)pyrrolidine-1-carboxylate, - (64): 2-(4-((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-3-hydroxy-2-(3-methylbut-2-en-1- yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-1-(4-methoxyphenyl)ethan-1-one, - (65): 2,2'-((((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1-yl)-1,3- phenylene)bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(4- methoxyphenyl)ethan-1-one) - (66): (2R,4aR,9aR)-7-((E)-3-hydroxy-5-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)- 4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthen-2-ol - (67): (2R,4aR,9aR)-7-((E)-3,5-bis((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-4-(3- methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthen-2-ol - (68): (2R,4aR,9aR)-7-((E)-3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-hydroxy-4-(3- methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthen-2-ol - (69): (2R,4aR,9aR)-7-((E)-3,5-bis((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-4-(3- methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthen-2-ol - (70): (2R,4aR,9aR)-7-((E)-3-hydroxy-5-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-4-(3- methylbut-2-en-1-yl)styryl)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5- diol - (71): (2R,4aR,9aR)-7-((E)-3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-hydroxy-4-(3- methylbut-2-en-1-yl)styryl)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5- diol, and pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof. According to a particular embodiment, the invention relates to compounds (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (16), (50), (55), (56), (57), (58), (59), (60), (64), (65), (66), (67), (68), (70) and (71).
The compounds of the invention may exist in the form of free bases or of addition salts with pharmaceutically acceptable acids.
The compounds of formula (I) and/or salts thereof may form solvates or hydrates also included in the present invention.
The terms “hydrates” and “solvates” mean that the compounds (I) according to the invention may exist in hydrate or solvate form, i.e. the compounds of formula (I) may be combined or associated with one or more water or solvent molecules.
The compounds of formula (I) and any of the compounds (1) to (19), (21), (23), (31) to (46), (48) to (71) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and mixtures thereof, including racemic mixtures, form part of the present invention.
The compounds of formula (I) and any of the compounds (1) to (19), (21), (23), (31) to (46) (48) to (71) may be in amorphous or crystalline forms and these forms also fall within the scope of the present invention.
The present invention also encompasses any of the metabolites or prodrugs of the compound of formula (I).
Preparation of the compounds of formula (I)
The compounds of the present invention can be prepared via conventional methods of organic synthesis known to those skilled in the art. The general reaction sequences described below represent a general process that is useful for preparing the compounds of the present invention and are not intended to limit the scope thereof.
In particular, the compounds of the invention may be prepared from four molecules of formula II in which R1 represents a hydroxyl group or a (C1-C5)alkoxy group, in particular a methoxy group, and R9 represents a hydrogen atom or a hydroxyl group. These molecules are natural compounds of the schweinfurthin family, namely vedelianin, schweinfurthin G (SW-G), schweinfurthin E (SW-E) or schweinfurthin F (SW-F). They may be obtained by isolation from plants of the genus Macaranga or by total synthesis (general review: Harmalkar et al. RSCAdv., 2018, 8, 21191).
Figure imgf000047_0001
The first reaction scheme entitled Scheme 1 comprises steps (A), (B), (C), (D), (E) to give the compounds of formula (la) and the novel intermediate (III).
The second scheme entitled scheme 2 comprises steps (H), (D), (E), (F), (J), (K), (A) and (C) to give the compounds of formulae (Ibii) and (la”) as defined previously.
The third scheme entitled Scheme 3 comprises steps (F), (G), (I) to give the compounds of formula (Ibiii) as defined previously.
Scheme 1: general scheme for the synthesis of the compounds of formula (la)
Figure imgf000047_0002
Scheme 2: general scheme for the synthesis of compounds of formula (Ibii) and (Ibiii)
Figure imgf000048_0001
In the following description, the hexahydroxanthene or HHX unit corresponds to the unit
Figure imgf000048_0002
Step (A)
Step (A) corresponds, starting from compounds of general formula (II), to the intramolecular cyclization of the geranyl chain into pyran, accompanied by esterification of the secondary alcohol of the hexahydroxanthene unit and, under certain conditions, to the reduction of the double bond of the stilbene unit, leading to the compounds of formula (la”), in which at least one from among R8 and R9 represents a group -OCORh as defined previously and in particular an -OCHO group or an -OCOCH3 group. They are obtained from compounds of general formula (II), when R2 is a hydrogen atom2.
The cyclization reaction may be performed via any conventional method known to those skilled in the art.
According to a particular embodiment, this reaction may be performed in formic acid. According to a particular embodiment, this reaction may be performed in the presence of a palladium catalyst chosen from palladium(II) acetate (Pd(OAc)2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), or tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) and mixtures thereof, preferably tris(dibenzylideneacetone)dipalladium(0). According to a particular embodiment, this reaction may be performed in the presence of a base as an additive, chosen from sodium acetate (NaOAc), sodium formate (HCOONa) or sodium tetraborate (Na2B4O7) and mixtures thereof, preferably sodium acetate.
According to another particular embodiment, the mixture of the compound of formula (II), formic acid, palladium and base may be performed, at a temperature between 0°C and 100°C, preferably at room temperature, for a time of between 6h and 48h, preferably 18h or 24h if it is desired to obtain a compound with a reduced double bond (as according to J.M. Brunei in Synlett, 2007, No. 2, page 330).
Advantageously, this reaction may be performed under argon.
Advantageously, the product obtained of formula (la”) according to the invention can be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions that a person skilled in the art will know how to adapt.
According to an alternative method, the compounds of formula (la”) in which R6 is other than OH may also be obtained starting from a compound of formula (II) in which one of the OH groups of ring D has been functionalized to give groups R6, as defined previously. Such functionalization steps may be performed according to conventional methods.
Step (B)
Step (B) corresponds to the functionalization of the phenol functions of the compounds of formula (la”), namely in which at least one of the groups R1 or R6 is a hydroxyl group, leading to the compounds of formula (la”’), namely in which R6 is a (C1-C6)alkoxy group, a (C2-C5)alkynyloxy group, a group -OCORc, a group -OCONH(CO)pRd or a group -O-P(=O)-(ORf)(ORg) group, as defined previously.
The functionalization reaction may be performed via any conventional method known to those skilled in the art.
According to a particular embodiment, this reaction may be performed in the presence of a commercial isocyanate or prepared via any conventional method known to those skilled in the art.
According to another particular embodiment, this reaction may be performed in the presence of a solvent chosen from tetrahydrofuran (THF), acetonitrile (ACN), diethyl ether, DMF (N,N-dimethylformamide), toluene, dichloromethane (DCM) and mixtures thereof, preferably dichloromethane.
Advantageously, the solvent or solvent mixture may be degassed and anhydrous.
According to another particular embodiment, the mixing of the starting compound (la”), the solvent and the isocyanate may be performed at a temperature of between 0°C and 60°C, preferably at room temperature for a time of between lh and 24h, preferably 5h or 8h. Advantageously, this reaction may be performed under argon.
Advantageously, the product obtained of formula (la”) according to the invention can be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions that a person skilled in the art will know how to adapt.
Step (C)
Step (C) corresponds to the saponification of the ester function of the hexahydroxanthene unit of the compounds of general formula (la”) to give the compounds of general formula (la”), in which at least one of the groups R1, R6, R8 or R9 is a hydroxyl group.
The saponification reaction may be performed via any conventional method known to those skilled in the art.
According to a particular embodiment, this reaction may be performed in the presence of a base chosen from potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydrogen carbonate (NaHCO3), potassium hydroxide (KOH) sodium hydroxide (NaOH), lithium hydroxide (LiOH), caesium carbonate (CS2CO3), potassium tert-butoxide, pyridine, aqueous ammonia, sodium ethoxide (EtONa), sodium methoxide (MeONa) and mixtures thereof, preferably lithium hydroxide.
According to another particular embodiment, this reaction may be performed in the presence of a solvent chosen from tetrahydrofuran (THF), water, a THF/water mixture, acetonitrile, diethyl ether, DMSO (dimethyl sulfoxide), acetone, dichloromethane, methanol, ethanol and mixtures thereof, preferably a THF/water mixture.
According to another particular embodiment, the mixing of the starting compound (la”), the base and the solvent may be performed at a temperature of between 0°C and 60°C, preferably at room temperature for a time of between 10 min and 3h, preferably lh. Advantageously, the product obtained of formula (la”), in which at least one of the groups R1, R6, R8 or R9 is a hydroxyl group, according to the invention may be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions which a person skilled in the art will know how to adapt.
Step (D)
Step (D) corresponds to the alkylation of the phenol function(s) of the compounds of formula (la”), in which at least R1 is a hydroxyl group, to give the intermediate of general formula (la”), in which at least R1 is a (C2-C5)alkenyloxy group or a (C2-C5)alkynyloxy group, or of formula (III) as defined below.
This step (D) may also be performed in the context of obtaining compounds of formula (Ibii), in which at least R1 is a (C2-C5)alkenyloxy group or a (C2-C5)alkynyloxy group, from a compound of formula (II), as indicated in Figure 2 above.
The alkylation reaction may be performed via any conventional method known to those skilled in the art.
According to a particular embodiment, this reaction may be performed in the presence of a base chosen from potassium carbonate (K2CO3), sodium hydride (NaH), potassium hydroxide (KOH), sodium hydroxide (NaOH), caesium carbonate (CS2CO3), N,N- diisopropylethylamine (DIPEA), pyridine and mixtures thereof, preferably sodium hydride or potassium carbonate.
According to another particular embodiment, this reaction may be performed in the presence of a solvent chosen from acetonitrile, THF (tetrahydrofuran), DMF (N,N- dimethylformamide), DMM (dimethoxy methane), DCM (dichloromethane), dioxane, MTBE (methyl tert-butyl ether), diethyl ether, toluene, and mixtures thereof, preferably DMF.
According to another particular embodiment, the electrophile enabling this alkylation reaction may be an alkyl halide, an alkenyl halide, an alkynyl halide, the tosylate or the mesylate of the corresponding alcohols, alkenols or alkynols.
Advantageously, the solvent or solvent mixture may be degassed and anhydrous.
According to another particular embodiment, the base may be added dropwise to a solution of the starting compound. Advantageously, the mixture formed of the base, the solvent and the starting compound may be made at a temperature of between -40°C and 10°C, preferably at -15°C, for a time ranging from 5 min to 45 min, preferably for 15 min.
According to another particular embodiment, the addition of the electrophile may be performed at a temperature of between -15°C and 25°C, preferably at 0°C for a time of between 30 min and 2 h, preferably 1 h.
Advantageously, this reaction may be performed under argon.
Advantageously, the product obtained of formula (Ibii) or (III) according to the invention may be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions that a person skilled in the art will know how to adapt.
Step (E)
Step (E) corresponds to the formation of the chromene unit from the intermediate of general formula (III) to give the compounds of formula (la’).
The cyclization reaction may be performed via any conventional method known to those skilled in the art.
According to a particular embodiment, this reaction may be performed in the presence of a catalyst chosen from gold(I)(acetonitrile)[(2-biphenyl)di-tert- butylphosphine]hexafluoroantimonate, gold(I)-
[bis(trifluoromethanesulfonyl)imidate] (triphenylphosphine), palladium(II) trifluoroacetate, platinum(II) chloride, palladium(II) diacetate, copper(I) iodide, gold(I) chloride (triphenylphosphine), silver trifluoromethane sulfonate, copper(II) bis(trifluoromethanesulfonate), gold(III) chloride, silver hexafluoroantimonate and mixtures thereof, preferably gold(I)-[bis(trifluoromethanesulfonyl)imidate](triphenylphosphine). According to another particular embodiment, this reaction may be performed in the presence of a solvent chosen from 1,2-dichloroethane, dichloromethane, acetonitrile, toluene, DMF (N,N-dimethylformamide), 1,4-dioxane and mixtures thereof, preferably dichloromethane. Advantageously, the solvent or solvent mixture may be degassed and anhydrous.
According to another particular embodiment, the mixing of the starting compound (III), the catalyst and the solvent may be performed at a temperature of between 0°C and 60°C, preferably at room temperature for a time of between lh and 8h, preferably 4h. Advantageously, this reaction may be performed under argon.
Advantageously, the product obtained of formula (la’) according to the invention can be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions that a person skilled in the art will know how to adapt.
This step (E) may be followed by a saponification step (C) as described previously, to obtain a compound of formula (la’), in which R8 or R9 is a hydroxyl group.
Step (F) corresponds to the esterification of a compound of formula (II), so as to obtain a compound of formula (Ibiii), containing a group -OCORh as defined previously and in particular an -OCHO group or an -OCOCH3 group.
The esterification reaction may be performed via any conventional method known to those skilled in the art. A large number of esterification methods are described in the literature and in reference chemistry books, for instance in March’s Advanced Organic Chemistry Reactions, Mechanisms and Structure, sixth edition, Michael B. Smith and Jerry March, Wiley-Interscience, a John Wiley & Sons, Inc. publication, 2007).
According to another particular embodiment, this reaction may be performed in the presence of an acid halide chosen from an acid chloride or an acid bromide, preferably an acid chloride.
According to another particular embodiment, this reaction may be performed in the presence of a base chosen from sodium hydride (NaH), potassium tert-butoxide (/BuOK), pyridine, dimethylaminopyridine (DMAP), triethylamine, potassium carbonate, N,N- diisopropylethylamine, preferably sodium hydride.
According to another particular embodiment, this reaction may be performed in the presence of a solvent chosen from 1,2-dichloroethane, dichloromethane, acetonitrile, toluene, DMF (N,N-dimethylformamide), 1,4-dioxane, tetrahydrofuran (THF) and a mixture thereof, preferably a THF/DMF mixture.
Advantageously, the solvent or solvent mixture may be anhydrous. According to another particular embodiment, the mixing of the solvents, the starting compound (II) and the base may be performed at a temperature of between 0°C and 60°C, preferably at room temperature for a time of between 5 min and 30 min, preferably 15 min. According to another particular embodiment, the acid halide may then be added and the mixture may be stirred at a temperature of between 0°C and 60 °C, preferably at room temperature for a time of between 5 h and 30 h, preferably 16 h.
Advantageously, this reaction may be performed under argon.
Advantageously, the product obtained of formula (Ibiii) according to the invention can be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions that a person skilled in the art will know how to adapt.
Step (G)
Step (G) corresponds to the saponification of the methyl ester function of the dimethoxy nitrophenyl methoxy acetate unit of the compounds of general formula (Ibii) to lead to the compounds of general formula (Ibii), in which at least one of the groups R4 or R6 is a dimethoxy nitrophenyl methoxy acid group, as in compounds (45) and (48), for example. The saponification reaction may be performed via any conventional method known to those skilled in the art.
According to a particular embodiment, this reaction may be performed in the presence of a base chosen from potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydrogen carbonate (NaHCO3), potassium hydroxide (KOH) sodium hydroxide (NaOH), lithium hydroxide (LiOH), trimethyltin hydroxide (Me3SnOH), caesium carbonate (CS2CO3), potassium tert-butoxide, pyridine, aqueous ammonia, sodium ethoxide (EtONa), sodium methoxide (MeONa) and mixtures thereof, preferably trimethyltin hydroxide. According to another particular embodiment, this reaction may be performed in the presence of a solvent chosen from tetrahydrofuran (THF), water, a THF/water mixture, acetonitrile, diethyl ether, DMSO (dimethyl sulfoxide), acetone, dichloromethane, methanol, ethanol and mixtures thereof, 1,2-dichloroethane, preferably 1,2-dichloroethane.
According to another particular embodiment, the mixing of the starting compound (Ibii), the base and the solvent may be performed at a temperature of between 0°C and 120°C, preferably at 60°C for a time of between lh and 36h, preferably 16h. Advantageously, the product obtained of formula (Ibii), in which at least one of the groups R4 or R6 is a dimethoxy nitrophenyl methoxy acid group, according to the invention may be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions which a person skilled in the art will know how to adapt.
Step (H)
Step (H) corresponds to a CuAAC-type 1,3-dipolar Huisgen cycloaddition reaction of an azide to the alkyne unit of the compounds of general formula (Ibii) to give the compounds of general formula (Ibii), in which at least one of the groups R4 or R6 comprises a 1H- 1,2,3- triazole unit, as in the case of compounds (49) to (56).
The CuAAC (copper-catalysed azide-alkyne cycloaddition) reaction may be performed via any conventional method known to those skilled in the art.
According to a particular embodiment, this reaction may be performed in the presence of a copper(I) salt such as copper iodide or copper bromide, or a copper(II) salt, for example copper sulfate or copper acetate, and sodium ascorbate which enables its reduction to copper(I), preferably a mixture of copper sulfate and sodium ascorbate.
According to another particular embodiment, this reaction may be performed in the presence of a large number of solvents including water, acetonitrile, methanol, ethanol, t-butanol and mixtures thereof, DMSO (dimethyl sulfoxide), dichloromethane, DMF and mixtures thereof, preferably a water/acetonitrile/t-butanol ternary mixture.
Advantageously, it has been shown in the literature that the addition of a mixture of 1,4- diazabicyclo[2,2,2]octane (DABCO) and acetic acid to the reaction medium reduces the formation of by-products.
According to another particular embodiment, the mixing of the starting compound (Ibii), the copper(II) salt, sodium ascorbate, DABCO, acetic acid and the solvent may be performed at a temperature of between 0°C and 60°C, preferably at room temperature for a time of between lh and 36h, preferably 18h.
Advantageously, the product obtained of formula (Ibii), in which at least one of the groups R4 or R6 comprises a 1H- 1,2, 3-triazole unit, according to the invention may be purified by means of any conventional method known to those skilled in the art, for example by column chromatography on silica gel using a heptane/ethyl acetate mixture in proportions which a person skilled in the art will know how to adapt.
Thus, according to one embodiment, the present invention relates to a synthetics process for preparing a compound of formula (la”)
Figure imgf000056_0001
(la”), in which R1 and R6 are as defined previously and at least one from among R8 and R9 represents a group -OCORh as defined previously, and in particular an -OCHO group or an -OCOCH3 group, and in which R2 is a hydrogen atom, or a (C2-C5)alkenyl group, such as an allyl group or any of the pharmaceutically acceptable salts thereof, comprising at least one step of intramolecular cyclization of the geranyl chain into pyran, of a compound of general formula (II), accompanied by esterification of the secondary alcohol of the hexahydroxanthene unit
Figure imgf000056_0002
(P)
, in which R1, R6 and R8 are as defined previously.
According to a particular embodiment, the present invention relates to an intermediate compound of formula (III)
Figure imgf000057_0001
in which
Rh, R9 and R6 are as defined previously. The chemical structures and the spectroscopic data of some of the compounds of formula (I) of the invention are illustrated, respectively, in Tables 1 and 2 below.
Figure imgf000057_0002
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
[Table 2]
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
PHARMACEUTICAL COMPOSITIONS
The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined according to the invention and at least one pharmaceutically acceptable excipient.
By way of example, it may comprise an amount of compounds of formula (I) as defined in the invention ranging from 0.05% to 10% by weight, in particular from 0.1% to 5% by weight, relative to the total weight of the composition.
The composition according to the invention also comprises at least one pharmaceutically acceptable excipient.
This excipient may be solid or liquid. It may be chosen, for example, from purified water, ethyl alcohol, propylene glycol, glycerol, plant oils, animal oils, hydrocarbons, silicones, sugars such as glucose, levulose, wheat starch, com starch, potato starch, cyclodextrins, xanthan gum, pectins, alginates, magnesium stearate, gelatin, cellulose and derivatives thereof.
The composition of the invention may be administered via any suitable route, for example orally, rectally, locally (e.g. topically), intraperitoneally, systemically, intravenously, intramuscularly, subcutaneously or mucosally, notably sublingually, or by using a patch, or in encapsulated form in, or immobilized on, liposomes, microparticles, microcapsules, combined with nanoparticles and the like.
The excipients that are suitable for use in the present invention may be any excipient conventionally used in the therapeutic field.
As non-limiting examples of excipients that are suitable for oral administration, mention may be made of talc, lactose, starch and derivatives thereof, cellulose and derivatives thereof, polyethylene glycols, acrylic acid polymers, gelatin, magnesium stearate, animal, plant or synthetic fats, paraffin derivatives, glycols, stabilizers, preserving agents, antioxidants, wetting agents, anticaking agents, dispersants, emulsifiers, taste modifiers, penetrants, and solubilizers. For example, to prepare an intravenously injectable aqueous solution, use may be made of a cosolvent, for instance an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol. According to another example, to prepare an intramuscularly injectable oily solution, at least one compound of formula (I) may be dissolved using a triglyceride or a glycerol ester. The pharmaceutical composition may thus comprise one or more pharmaceutically acceptable diluents, supports, excipients, fillers, binders, lubricants, glidants, disintegrants, absorbents and/or preserving agents.
The techniques for formulating and administering medicaments and pharmaceutical compositions are well known in the art under consideration here by a skilled person. According to the invention, the composition may advantageously be administered orally or by intravenous injection.
A therapeutically efficacious dose of the pharmaceutical compositions according to the invention is determined via standard clinical techniques at the discretion of the physician. Advantageously, the composition according to the invention is suitable for administration orally or intravenously at a dose greater than or equal to 1 mg/kg/24h and less than or equal to 200 mg/kg/24h in one or more dosage intakes to a mammal in need thereof.
Thus, the compounds of formula (I) of the invention may be used in doses of between 0.01 mg and 5000 mg per day, given in a single dose once a day or administered in multiple doses throughout the day, for example twice a day in equal doses. The dose administered per day is advantageously between 5 mg and 2500 mg, even more advantageously between 10 mg and 1000 mg.
Suitable oral administration forms include tablets, gel capsules, powders, granules, syrups and oral solutions or suspensions.
For parenteral administration, use may be made of aqueous suspensions, isotonic saline solutions or injectable sterile solutions containing pharmaceutically acceptable and compatible dispersants and/or wetting agents.
According to a particular embodiment, the pharmaceutical composition as defined in the present invention may also comprise another active principle, which is useful notably in the treatment and/or prevention of neurodegenerative diseases, viral diseases, dyslipidaemia, hypercholesterolaemia, parasitic diseases and/or cancers.
Thus, the present invention also relates to a pharmaceutical preparation which comprises a pharmaceutical composition according to the invention, and, in addition, as a mixture or packaged separately, at least one antiviral agent and/or an anticancer agent and/or an agent that is efficacious against neurodegenerative diseases, and/or an agent that is efficacious against dyslipidaemia, an agent that is efficacious against hypercholesterolaemia and/or an agent that is efficacious against parasitic diseases for use in treating and/or preventing and/or inhibiting infections caused by pathogens such as viruses, cancers, neurodegenerative diseases, hypercholesterolaemia and dyslipidaemia, administered simultaneously, sequentially or spaced out over time.
THERAPEUTIC APPLICATIONS
As mentioned above, the present invention relates to a compound of formula (I) according to the invention or a pharmaceutical composition according to the invention, for use as a medicament, and notably for its use in preventing and/or treating and/or inhibiting cancers, neurodegenerative diseases, dyslipidaemia, hypercholesterolaemia and/or viral or parasitic diseases.
The compound of formula (I) as defined in the present invention makes it possible to inhibit OSBP (oxy sterol-binding protein), a protein responsible for the intracellular transfer of cholesterol.
According to a particular embodiment, the cancers are chosen from breast cancer, including triple negative breast cancer, osteosarcoma, kidney cancer, head and neck cancer, prostate cancer, colorectal cancer, colon cancer, gall bladder cancer, bile duct cancer (cholangiocarcinoma), gastrointestinal cancer, gastric cancer, hepatocellular carcinoma, lymphoma, lung cancer, small cell lung cancer, non- small cell lung cancer, pancreatic cancer, pancreatic carcinoma, stomach cancer, brain cancer, metastases, leukaemia, acute T- cell lymphoblastic leukaemia, chronic myeloid leukaemia, melanoma and glioblastoma, in particular osteosarcoma, kidney cancer, triple-negative breast cancer, melanoma, leukaemia and glioblastoma.
Glioblastoma or glioblastoma multiforme (GBM), also known as grade 4 astrocytoma, is the most common and most aggressive brain tumour.
According to another particular embodiment, neurodegenerative diseases are chosen from amyotrophic lateral sclerosis (ALS or Charcot’s disease), Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease (Huntington’s chorea), and Niemann-Pick type C disease, in particular Alzheimer’s disease, Parkinson’s disease, Huntington’s disease (Huntington’s chorea), and Niemann-Pick type C disease.
In the present invention, the term “viral diseases” means any benign or severe disease caused by a virus. According to one embodiment of the invention, the viral diseases targeted by the compounds of the invention are mediated by RNA viruses.
According to an even more particular embodiment, in the context of the present invention, the term “RNA virus -mediated viral infection” more particularly means a viral infection mediated by a virus belonging to group III (double- stranded RNA viruses (dsRNA)), group IV (positive-sense single-stranded RNA viruses: (+)-sense RNA), Group V (negative-sense single- stranded RNA viruses: (-)-sense RNA) or group VI (single-stranded RNA retroviruses: (+)-sense RNA with intermediate DNA in the life cycle).
According to this classification, the viruses belonging to group VI are not, strictly speaking, RNA viruses. A well-studied example of a virus family belonging to group VI is the Retroviridae (retrovirus) family, which includes HIV.
As representatives of viruses belonging to group III, mention may be made of the Reoviridae and Birnaviridae .
As representatives of viruses belonging to group IV, mention may be made of the Picornaviridae (which is a family of viruses that includes well-known viruses such as hepatitis A vims, enteroviruses, rhinoviruses, poliovirus and foot-and-mouth vims), SARS vims, hepatitis C vims, yellow fever vims and rubella vims. The Togaviridae family also belongs to group IV and a known genus thereof is the alphavims, including chikungunya vims. The Flaviridae is also a family belonging to group IV, including a renowned mosquito-bome vims, namely the dengue vims or the Zika vims. An acute respiratory disease was recently caused by a new coronavims (SARS-CoV-2, previously known as 2019-nCoV), also referred to here as coronavims 2019 disease (COVID-19), which belongs to the Coronaviridae and forms part of group IV of the Baltimore classification.
As representatives of viruses belonging to group V, mention may be made of the Filoviridae family of viruses including Ebola vims, the Paramyxoviridae family including respiratory syncytial vims (RSV), the Rhabdoviridae family, the Orthomyxoviridae family including influenzavims A, influenzavims B and influenza C. Measles is also caused by a group V vims of the paramyxovirus family.
According to another embodiment of the invention, the viral diseases targeted by the compounds of the invention are infections caused by RNA viruses of classes IV and V of the Baltimore classification. Viral angina can be caused by different viruses such as rhinovirus, coronavirus, respiratory syncytial virus (RSV), influenza virus and para influenza virus.
According to yet another particular embodiment, the viral diseases targeted by the compounds of the invention are chosen from dengue, Zika vims infection, influenza, viral angina, measles, AIDS, chikungunya, yellow fever, poliomyelitis, hepatitis A, hepatitis C, hepatitis E, SARS-CoV virus infection, SARS-CoV-2 vims infection, and rubella, in particular dengue, Zika vims infection, chikungunya, yellow fever, poliomyelitis, hepatitis A, hepatitis C, hepatitis E, SARS-CoV vims infection, SARS-CoV-2 vims infection and rubella.
Thus, according to a particularly preferred embodiment, the viral diseases are in particular those caused by a Baltimore Class IV (+)-strand RNA vims such as dengue, Zika vims infection, chikungunya, yellow fever, poliomyelitis, hepatitis A, hepatitis C, hepatitis E, SARS-CoV vims infection, SARS-CoV-2 vims infection, and rubella.
Other viral infections not caused by RNA viruses may also be targeted in the context of the present invention, such as chickenpox.
As already mentioned above, a compound of formula (I) as defined in the invention may be administered alone or in combination with other active principles which may act synergistically with the compound of formula (I).
Moreover, other treatment techniques may be combined with the treatment performed via the administration of a pharmaceutical composition according to the invention or of a medicament comprising at least one compound of formula (I).
For example, when the pathology concerned is a cancer, it is possible to combine radiotherapy, possibly coupled with chemotherapy, with other active agents, in a first stage, and then to continue the treatment as a monotherapy by administering a pharmaceutical composition according to the invention or a medicament comprising at least one compound of formula (I).
The present invention also relates to a method for administering at least one compound of formula (I) as defined in the invention to an individual in need thereof, involving:
- providing a pharmaceutical composition comprising at least one compound of formula (I) as defined in the invention, and at least one pharmaceutically acceptable excipient; and
- administering the pharmaceutical composition in an effective amount to an individual in need thereof. According to other embodiments, the present invention relates to methods for administering, notably orally or intravenously, a pharmaceutical composition according to the invention comprising at least one compound of formula (I) as defined in the invention and an additional active principle.
An “individual” (including a patient) includes mammals (for example humans, pets, farm animals or laboratory animals).
According to another of its aspects, the present invention relates to the use of at least one compound of formula (I) as defined in the invention or a pharmaceutical composition according to the invention for the preparation of a medicament.
According to another aspect, the present invention relates to the use of at least one compound of formula (I) as defined in the invention or a pharmaceutical composition according to the invention for the preparation of a medicament for treating and/or preventing and/or inhibiting cancers, neurodegenerative diseases, dyslipidaemia, hypercholesterolaemia, and/or viral diseases.
According to yet another aspect, the present invention relates to a method for treating and/or preventing and/or inhibiting cancers, neurodegenerative diseases, dyslipidaemia, hypercholesterolaemia, parasitic diseases and/or viral diseases, involving the administration to an individual in need thereof of a pharmaceutical composition according to the invention comprising at least one compound of formula (I) as defined in the present invention. According to yet another aspect, the present invention relates to a method for treating and/or preventing and/or inhibiting cancers, neurodegenerative diseases, dyslipidaemia, hypercholesterolaemia, and/or viral or parasitic diseases, involving the administration to an individual in need thereof of a therapeutically effective amount of at least one compound of formula (I) as defined in the present invention.
Throughout the description, including the claims, the term “comprising a” should be understood as being synonymous with “comprising at least one”, unless otherwise mentioned. The terms “between... and...” and “ranging from... to...” should be understood as being limits inclusive, unless otherwise mentioned.
In the description and the examples, the temperature is expressed in degrees Celsius unless otherwise indicated, and the pressure is atmospheric pressure, unless otherwise indicated. Example
MATERIALS AND METHODS
The proton nuclear magnetic resonance (1H NMR) spectra are recorded in deuterated CDCL3 or CD3CN on a Briiker Avance machine (300 MHz or 500 MHz). The chemical shifts (δ) are expressed in parts per million (ppm) relative to the non-deuterated solvent residue. The coupling constants ( J) are in Hertz (Hz). For the signal multiplicity, the following abbreviations are used: s (singlet), d (doublet), t (triplet), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), q (quartet), m (multiplet).
The carbon nuclear magnetic resonance (13C NMR) spectra are recorded on a Briiker Avance machine (75 or 125 MHz), and the chemical shifts are expressed in ppm relative to the solvents used.
The high-resolution mass spectra (HRMS) are obtained on a Waters LCT Premier XE spectrometer in ESI (electro spray ionization) mode.
The flash chromatography purifications are performed on a Teledyne Isco Combiflash Rf 200i with pre-packaged GraceResolv silica cartridges.
When necessary, the organic solvents are dried or distilled before use and stored over molecular sieves under argon.
Example 1: Preparation of (2R,4aR,9aR)-5-hydroxy-7-((E)-2-(5-hydroxy-2,2- dimethylchroman-7-yl)vinyl)-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H -xanthen-2-yl formate - compound (1)
Compound (1) is a prodrug of compound (2).
SW-G (150 mg, 0.32 mmol), is dissolved in formic acid (1 ml) and placed under an argon atmosphere. The mixture is stirred at room temperature for 18 hours and then poured into a separating funnel. Dichloromethane (DCM: 2 ml) is added and the organic phase is separated out by settling, washed successively with water (twice), with saturated sodium hydrogen carbonate (NaHCO3) solution and then with sodium chloride (NaCl). The organic phase is dried over magnesium sulfate (MgSO4) and then concentrated under reduced pressure. The crude reaction product is purified by flash chromatography on a column of silica (solvent: heptane/ethyl acetate: 2/8) to give compound (1) in the form of a brown oil (80 mg, 55%). Example 2: Preparation of (2R,4aR,9aR)-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7- yl)vinyl)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5-diol - compound (2) To a solution of (2R,4aR,9aR)-5-hydroxy-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7- yl)vinyl)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-yl formate (compound (1): 61 mg, 0.12 mmol) in tetrahydrofuran (THF: 1 ml) is added an aqueous solution (0.2 ml) of lithium hydroxide monohydrate (LiOH·H2O: 13 mg, 0.31 mmol, 2.5 eq). The resulting brown solution is stirred at room temperature for 1 hour and 1 ml of 1N hydrochloric acid (HCl) solution is then added. The reaction medium is extracted three times with ethyl acetate (EtOAc). The organic phases are combined, dried over MgSO4 and concentrated under reduced pressure. The crude reaction product is purified by silica preparative plates using a heptane/EtOAc (4/6) eluent to give compound (2) in the form of a yellow oil (36 mg, 62%). Example 3: Preparation of (2R,4aR,9aR)-5-hydroxy-7-(2-(5-hydroxy-2,2- dimethylchroman-7-yl)ethyl)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-yl formate - compound (9) Compound (9) is a prodrug of compound (10). SW-G (500 mg, 1.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3: 19 mg, 0.02 mmol, 0.02 eq), sodium acetate (NaOAc: 26 mg, 0.32 mmol, 0.3 eq) are dissolved in formic acid (3.3 ml) and placed under an argon atmosphere. The mixture is stirred at room temperature for 24 hours and then poured into a separating funnel. Dichloromethane (DCM: 2 ml) is added and the organic phase is separated out by settling, washed successively with water (twice), with saturated sodium hydrogen carbonate (NaHCO3) solution and then with sodium chloride (NaCl). The organic phase is dried over magnesium sulfate (MgSO4) and then concentrated under reduced pressure. The crude reaction product is purified by flash chromatography on a column of silica (solvent: heptane/ethyl acetate: 2/8) to give compound (1) in the form of a brown oil (204 mg, 38%) and also compound (9) (73 mg, 13%). Example 4: Preparation of (2R,4aR,9aR)-7-(2-(5-hydroxy-2,2-dimethylchroman-7- yl)ethyl)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5-diol - compound (10) To a solution of (2R,4aR,9aR)-5-hydroxy-7-(2-(5-hydroxy-2,2-dimethylchroman-7- yl)ethyl)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-yl formate (compound (9): 25 mg, 0,051 mmol) in tetrahydrofuran (THF: 0.4 ml) is added an aqueous solution (0.1 ml) of lithium hydroxide monohydrate (LiOH·H2O: 5 mg, 0.13 mmol, 2.5 eq). The resulting brown solution is stirred at room temperature for 1 hour and 1 ml of 1N hydrochloric acid (HCl) solution is then added. The reaction medium is extracted three times with ethyl acetate (EtOAc). The organic phases are combined, dried over MgSO4 and concentrated under reduced pressure. The crude reaction product is purified by silica preparative plates using heptane/EtOAc (3/7) as eluent to give compound (10) in the form of a yellow oil (12 mg, 49%). After adding saturated sodium hydrogen carbonate (NaHCO3) solution, the mixture is extracted four times with ethyl acetate (EtOAc). Example 5: Preparation of (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-1-yl)-5- (prop-2-yn-1-yloxy)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthen-2-ol (31) NaH (32 mg, 0.82 mmol) is added portionwise to a solution of SW-F (96 mg, 0.20 mmol) in anhydrous DMF (2 mL) at 0°C. After stirring for 20 minutes, propargyl bromide (20 µL, 0.22 mmol) is added. The reaction medium is stirred at room temperature for 18 hours, followed by addition of aqueous NH4Cl solution (10 mL). The reaction medium is extracted three times with ethyl acetate (EtOAc). The organic phases are combined, dried over MgSO4 and concentrated under reduced pressure. The crude reaction product is purified by reverse- phase silica chromatography (H2O/acetonitrile 8/2 to 0/1 gradient) to give the desired compound 31 in the form of a brown oil (28 mg, 26%). The same procedure was followed to synthesize compounds (19) and (32) from SW-G and SW-E respectively. Example 6: Preparation of (2R,4aR,9aR)-7-((E)-3-((1-(2-(2-((6- chlorohexyl)oxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-hydroxy-4-(3-methylbut- 2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (56) To a solution of (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-1-yl)-5-(prop-2-yn-1- yloxy)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (compound (31): 28 mg, 0.054 mmol) in acetonitrile (1 mL) at room temperature are successively added 1-[2-(2-azidoethoxy)ethoxy]-6-chlorohexane (14 mg, 0.056 mmol), CuSO4·5 H2O (22 mg, 0.089 mmol), sodium ascorbate (47 mg, 0.24 mmol), DABCO (13 mg, 0.12 mmol) and acetic acid (6 µL, 0.11 mmol). The reaction medium is stirred at room temperature for 18 hours, followed by addition of aqueous NH4Cl solution (10 mL). The reaction medium is extracted three times with ethyl acetate (EtOAc). The organic phases are combined, dried over MgSO4 and concentrated under reduced pressure. The crude reaction product is purified by flash chromatography on a column of silica (heptane/EtOAc 6/4 to 2/8 gradient) to give the desired compound (56) in the form of a pale yellow oil (21 mg, 51%). Example 7: Preparation of (2S,3R,4aR,9aR)-7-((E)-3-hydroxy-5-((1-methyl-1H-1,2,3- triazol-4-yl)methoxy)-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,3-diol (57). To a solution of compound (32) (15mg, 0.028 mmol, 1 eq) in a mixture of isopropanol (1 mL) and water (0.5 mL), was added sodium azide (3 mg, 0.043 mmol, 1.5 eq) , DIEA (4 μL, 0.02 mmol, 0.7 eq), CuI (2 mg, 0.012 mmol, 0.4 eq) and MeI (3 μL, 0.045 mmol, 1.5 eq). The reaction mixture was heated in a microwave at 70 °C for 30 min then concentrated in vacuo. The crude mixture was purified by chromatography on a C18-reversed phase silica gel using a gradient of H2O and ACN (1:1 to 0:1) to give compound (57) as a dark yellow solid (12mg, 71%). The same procedure was followed to synthesize compounds (66) and (70) from compounds (31) and (19) respectively. Example 8: preparation of (2S,3R,4aR,9aR)-7-((E)-3,5-bis((1-methyl-1H-1,2,3-triazol-4- yl)methoxy)-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a- hexahydro-1H-xanthene-2,3-diol (58). To a solution of compound (37) (23 mg, 0.040 mmol, 1 eq) in a mixture of isopropanol (1 mL) and water (0.5 mL), was added sodium azide (8 mg, 0.13 mmol, 3 eq), DIEA (23 μL, 0.13 mmol, 3 eq), CuI (8 mg, 0.040 mmol, 1 eq) and MeI (8 μL, 0.13 mmol, 3 eq). The reaction mixture was heated in a microwave at 70 °C for 1 h then concentrated in vacuo. The crude mixture was purified by chromatography on a C18-reversed phase silica gel using a gradient of H2O and ACN (1:1 to 0:1) to give compounds (58) as a dark yellow solid (15 mg, 52%). The same procedure was followed to synthesize compound (67) from compound (36). Example 9: preparation of (2S,3R,4aR,9aR)-7-((E)-3-((1-benzyl-1H-1,2,3-triazol-4- yl)methoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,3-diol (59). To a solution of compound (32) (22 mg, 0.042 mmol, 1 eq) in a mixture of ACN (0.4 mL), t-BuOH (0.4 mL) and H2O (0.4 mL) at room temperature, was added benzyl azide (8 μL, 0.6 mmol, 1.5 eq) followed by CuSO4.5H2O (24 mg, 0.096 mmol, 2.3 eq), sodium ascorbate (33 mg, 0.17 mmol, 4 eq) , DABCO (9 mg, 0.084 mmol, 2 eq) and acetic acid (5 μL, 0.084 mmol, 2 eq). The reaction mixture was stirred for 24 h at room temperature, after which 1.5 eq of benzyl azide were added and the reaction was stirred for other 24 hours. The crude mixture was washed with water (2 mL) and extracted with n-butanol. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by chromatography on a C18-reversed phase silica gel using a gradient of H2O and ACN (1:1 to 0:1) to give compound (59) (18 mg, 65%). The same procedure was followed to synthesize compounds (68) and (71) from compounds (31) and (19) respectively. Example 10: preparation of (2S,3R,4aR,9aR)-7-((E)-3,5-bis((1-benzyl-1H-1,2,3-triazol-4- yl)methoxy)-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a- hexahydro-1H-xanthene-2,3-diol (60). To a solution of compound (37) (22 mg, 0.038 mmol, 1 eq) in ACN (0.4 mL), t-BuOH (0.4 mL), H2O (0.4 mL) at room temperature, was added benzyl azide (14 μL, 0.11 mmol, 3 eq) followed by CuSO4.5H2O (22 mg, 0.087 mmol, 2.3 eq), sodium ascorbate (30 mg, 0.15 mmol, 4 eq), DABCO (9 mg, 0.076 mmol, 2 eq) and acetic acid (4.33 μL, 0.076 mmol, 2 eq). The reaction mixture was stirred for 47 h at room temperature. The crude mixture was washed with water (2 mL) and extracted with n-butanol. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by chromatography on a C18-reversed phase silica gel using a gradient of H2O and ACN (1:1 to 0:1) to give compound (60) (12 mg, 37%). The same procedure was followed to synthesize compound (69) from compound (36). Example 11: preparation of 2-(4-((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-3-hydroxy-2-(3- methylbut-2-en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-1-(4-methoxyphenyl)ethan-1- one (64).To a solution of compound (32) (23 mg, 0.044 mmol, 1 eq) in ACN (0.4 mL), t- BuOH (0.4 mL) and H2O (0.4 mL), at room temperature, were added successively CuSO4.5H2O (25 mg, 0.10 mmol, 2.3 eq), sodium ascorbate (35 mg, 0.18 mmol, 4 eq), DABCO (10 mg, 0.088 mmol, 2 eq), 2-azido-1-(4methoxyphenyl)-ethanone (13 mg, 0.067 mmol, 1.5 eq) and acetic acid (5 μL, 0.088 mmol, 2 eq). The reaction was stirred for 5 hours. The crude mixture was washed with water (2 mL) and extracted with n-butanol. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by chromatography on a C-18-reversed phase silica gel using a gradient of H2O and ACN (1 :1 to 0 :1) to give compound (64) as a brown powder (19 mg, 0.026 mmol, 59%). Example 12: preparation of 2,2'-((((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1- yl)-1,3-phenylene)bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(4- methoxyphenyl)ethan-1-one) (65). To a solution of compound (37) (15 mg, 0.027 mmol, 1 eq) in ACN (0.4 mL), t-BuOH (0.4 mL) and H2O (0.4 mL), at room temperature, were added successively CuSO4.5H2O (15.5 mg, 0.062 mmol, 2.3 eq), sodium ascorbate ( 21 mg, 0.11 mmol, 4 eq), DABCO (6 mg, 0.054 mmol, 2 eq), 2-azido-1-(4methoxyphenyl)-ethanone (13 mg, 0.067 mmol, 2.5 eq) and acetic acid (3.25 μL, 0.054 mmol , 2 eq). The reaction was stirred for 24 hours. The crude mixture was washed with water (2 mL) and extracted with n-butanol. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by chromatography on a C-18-reversed phase silica gel using a gradient of H2O and ACN (1 :1 to 0 :1) to give compound (65) as a brown powder (22 mg, 0.023 mmol, 85%). Example 13: Biological activity The biological inhibitory activities of oxysterol binding protein 1 (OSBP) and the cytotoxic activity on two cell lines, U87 and A549, were measured. MATERIALS AND METHOD Measurement of the OSBP inhibitory activity is performed by an automated test on the purified ORD domain of the OSBP protein. The measurements are performed according to a protocol using two liposome preparations:
- The donor liposomes (A) contain a fluorescent sterol (DHE);
- The acceptor liposomes (B) contain a fluorescent lipid (dansyl PE) whose excitation spectrum overlaps with the emission spectrum of DHE.
The transport of DHE from the liposomes A to the liposomes B catalysed by the ORD domain is accompanied by a FRET signal between DHE and dansyl-PE. By means of this signal, the transport kinetics can be measured in real time. This fluorescence measurement is performed on a microplate on a TECAN Infinite 1000 Pro machine (temperature = 37°C). Initially, each measurement well contains liposomes B (130 μM), the ORD domain (200 nM) and the test compound. At time t = 5 min, liposomes A (130 μM) are added to start the exchange reaction. Each compound is tested in triplicate for final concentrations of from 50 nM to 3 pM. The time constant (k) obtained for each kinetic is then represented as a function of the concentration of the analogue. From this representation, an inhibition constant is determined for each compound. The affinity constants Ki are classified as follows:
- Very high affinity Ki < 1 nM
- Good affinity Ki from 1 to 100 nM
- Low affinity Ki from 100 to 2000 nM
- Very low Ki affinity > 2000 nM
Compounds, other than prodrugs, with a Ki < 100 nM are considered as being active on OSBP.
The U87-MG and A549 lines were obtained from the American Type Culture Collection (Rockville, MD, USA) and were cultured according to the supplier’s instructions. U87-MG human glioblastoma cells were cultured in Dulbecco’s minimal essential medium (DMEM) containing 10% FCS and 1% L-glutamine. A549 lung cancer cells were grown in RPMI1640 medium containing 10% FCS and 1% L-glutamine. The cell lines were maintained at 37°C in a humidified atmosphere containing 5% CO2. The products were tested at 10 concentrations in triplicate and the cell viability was evaluated after 72h of treatment by means of the CellTiter Glo test (Promega) for measuring the number of living cells by luminescence (ATP quantification).
Thus, the cells were seeded in 96-well plates (2.5x103 cells/well) each containing 90 μL of growth medium. After 24 h of culture, the wells were supplemented with 10 μL of medium containing ten decreasing concentrations of the test compound dissolved in DMSO (less than 0.1% in each preparation). After 72 h of incubation, 100 μL of Cell Titer GLo reagent were added for 15 min, followed by quantifying the luminescence emitted by means of a microplate reader. The dose-response curve was analysed by means of the Graph Prism software and the activity of the molecules is expressed in the form of the IC50.
RESULTS
The results are shown in the table below. The same measurements were taken on the schweinfurthins E, F, G and H indicated as SW-G, SW-E, SW-F and SW-H in the table below. From the results collated in the following table, a significant difference can be concluded when there is a one log difference between two IC50 measurements.
According to a particular embodiment of the invention, molecules with an IC50 value on the U87 line below 100 nM, for example below 50 nM, are considered highly active. The commentary column to the right of the table indicates the differences and advantages observed relative to the reference schweinfurthin. It is also stated whether it is a prodrug of another compound. Moreover, the term “triazole series” is specified when the compound comprises a triazole group in at least one of the radicals R4 or R6.
The structures of the natural schweinfurthins are recalled below. It is moreover noted that schweinfurthin H also corresponds to compound 2 of the publication by Thi Mai Huong Doan et al., “Cytotoxic phenolic compounds from fruit glandular trichomes of Macaranga tanarius ” Journal of Analytical Methods in Chemistry, volume 2019, article ID 2917032, 5 pages.
Schweinfurthin E
Schweinfurthin F
Schweinfurthin G
Schweinfurthin H
Figure imgf000104_0001
[Table 3]
Figure imgf000104_0002
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
It is observed that compounds (1), (3), (5), (9), (11), (13), (14), (15), (16), the compounds of the invention, have a low Ki on OSBP, while having powerful activity on U-87 and improved metabolic stability. For all the synthesized compounds presented in the above table, improved metabolic stability is observed. The more detailed illustration of this improved stability is reported in the following examples. As shown in these results, the compounds according to the invention, which are otherwise not prodrugs, have inhibitory activity on oxysterol binding protein 1 (OSBP).
It emerges that certain compounds included in the general formula (I) are indeed metabolites of other compounds included in the same general formula (I) as defined according to the present invention. This situation is identifiable for the pair of compounds (1) and (2), for which compound (2) is the metabolite of compound (1), or for the pair of compounds (9) and (10), for which compound (10) is the metabolite of compound (9). This case is also observed with regard to compounds (3) and (4), (5) and (6), (7) and (8), (11) and (12), (13) and (6), (14) and (10), (15) and (10), (16) and (10).
Plasma stability and microsomal stability evaluation
Plasma stability and liver microsomal stability assays were performed on SW-G, SW-E, compounds (1), (2), (5), (6), (9) (10), and (57) according to the invention.
Protocols
The compounds are placed in mouse plasma and mouse microsomes, and their stability is evaluated by UPLC-MS/MS monitoring.
For the plasma stability, the test concentration is 2.5 μM and the incubation volume is 50 μL. The incubation times are 0, 15, 30, 45, 60 and 120 minutes. Protein precipitation is then performed on the samples, and said samples are then analysed by UPLC-MS/MS. The remaining percentage of the compound and its elimination half-life are thus obtained.
For the metabolic stability in microsomes, the concentration of the test compound is 2.5 μM, and the incubation volume is 400 μL. The concentration in mouse microsomes is 0.5 mg/mL. The incubation times are 0, 15, 30 and 45 minutes. The cofactor used is NADPH. Two negative controls are performed, one without microsomes and without cofactor at 0 and 45 minutes, and one without cofactor and with microsome at 0 and 45 minutes. A positive control is performed in the presence of diphenhydramine. The samples are analysed by LC- MS/MS. The intrinsic clearance and the half-life are thus obtained.
The LC-MS/MS is performed on an AcquityTM UPLC machine coupled with an XEVO TQ-S machine (Waters). The liquid chromatography is performed on an Acquity UPLC BEH 1.7 μm, 2.1x50 mm column with a 4-minute gradient of water + 0.1% formic acid/acetonitrile + 0.1% formic acid 90:10 to 0:100. The column temperature is +50°C and the injector temperature is +4°C. The mass spectrometry acquisition is done by MRM (Multiple Reaction Monitoring), with positive electrospray ionization.
The intrinsic clearance is considered high if it is > 48 μL/min/mg protein and low if it is < 8.8 μL/min/mg protein.
Results
The mouse plasma metabolic stability of SW-G at 120 minutes is 100%, its metabolic stability in mouse microsomes is 23% at 45 minutes and its microsomal clearance is 90 μL/min/mg protein.
The mouse plasma metabolic stability of SW-E at 120 minutes is 93%, its metabolic stability in mouse microsomes is 18% at 45 minutes and its microsomal clearance is 76 μL/min/mg protein.
The metabolic stability in mouse plasma at 120 minutes of compound (1) according to the invention is 20%, its metabolic stability in mouse microsomes is 5% at 45 minutes and its clearance in microsomal medium is 120 μL/min/mg protein. This compound is transformed into compound (2) according to the invention. Compound (1) is a prodrug of compound (2). The metabolic stability in mouse plasma at 120 minutes of compound (2) according to the invention is 100%, its metabolic stability in mouse microsomes is 49% at 45 minutes and its clearance in microsomal medium is 32 μL/min/mg of protein.
The metabolic stability in mouse plasma at 120 minutes of compound (5) according to the invention is 1%, its metabolic stability in mouse microsomes is 29% at 45 minutes and its clearance in microsomal medium is 74 μL/min/mg protein. This compound is transformed into compound (6) according to the invention. Compound (5) is a prodrug of compound (6). The metabolic stability in mouse plasma at 120 minutes of compound (6) according to the invention is 100%, its metabolic stability in mouse microsomes is 41% at 45 minutes and its clearance in microsomal medium is 40 μL/min/mg protein.
The metabolic stability in mouse plasma at 120 minutes of compound (9) according to the invention is 0%, its metabolic stability in mouse microsomes is 47% at 45 minutes and its clearance in microsomal medium is 396 μL/min/mg protein.
The metabolic stability in mouse plasma at 120 minutes of compound (10) according to the invention is 90%, its metabolic stability in mouse microsomes is 10% at 45 minutes and its clearance in microsomal medium is 98 μL/min/mg protein. The metabolic stability in mouse plasma at 120 minutes of compound (57) according to the invention is 100%, its metabolic stability in mouse microsomes is 27% at 45 minutes and its clearance in microsomal medium is 58 μL/min/mg protein. It emerges from these results that the compounds of formula (I) according to the invention are stable in plasma and for the most part have good microsomal stability. In particular, certain compounds of formula (I) according to the invention have a better clearance than that of SW G and SW-E.
It emerges from all the biological tests presented above that the compounds of formula (I) according to the invention may be used as medicaments, in particular in the treatment of cancer, more particularly glioblastoma.
It also emerges that certain compounds are useful as OSBP (oxysterol-binding protein) inhibitors, notably for preventing, inhibiting and/or treating cancers, neurodegenerative diseases, alcohol addiction, atherosclerosis, type 2 diabetes, dyslipidaemia, hypercholesterolaemia, autosomal dominant non-syndromic hearing loss, infertility, hypertension, and/or viral or parasitic diseases.

Claims

Claims
1. Compound of formula (I), pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof:
Figure imgf000115_0001
in which:
Figure imgf000115_0002
represents a single or double bond,
- R1 represents a hydroxyl group, a (C1-C5)alkoxy group, a (C2-C5)alkenyloxy group, a (C2-C5)alkynyloxy group, or a group -OCONH(CH2)nCOORa, in which n represents an integer between 2 and 6, and Ra represents a (C1-C4alkyl group,
- R2 represents a hydrogen atom, or alternatively,
R1 and R2 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation,
- R3 and R7 independently represent a hydrogen atom,
- R4 represents a hydroxyl group, a group m being equal to 1, 2 or 3,
Figure imgf000115_0003
a group
Figure imgf000116_0001
, n being 1, 2 or 3, preferably 1 or 2, a group
Figure imgf000116_0002
or
Figure imgf000116_0003
, in which R is a hydrogen atom or a methyl group and R’ and R” are independently a (C1-C3)alkyl group, a group
Figure imgf000116_0004
, in which s is equal to 0, 1 or
2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(0)0CH3 group; a halogen atom, in particular a chlorine atom; an amino group or a group
Figure imgf000116_0005
, or a group -OCORb, in which Rb represents a (C1-C4)alkyl group, - R5 represents a group of formula
Figure imgf000117_0001
or alternatively,
R4 and R5 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C1-C4)alkyl groups, - R6 represents a hydroxyl group, a (C1-C6)alkoxy group, a group
Figure imgf000117_0002
, m being equal to 1, 2 or 3, a group
Figure imgf000117_0003
, n being 1, 2 or 3, preferably 1 or 2, a group
Figure imgf000117_0004
or
Figure imgf000117_0005
, in which R is a hydrogen atom or a methyl group and R’ and R” are independently a (C1- C3)alkyl group, a group
Figure imgf000118_0001
, in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(O)OCH3 group; a halogen atom, in particular a chlorine atom, or an amino group, a group -OCORc, in which Rc represents a (C1-C4)alkyl group, or a group -OCONH(CO)pRd, in which p represents an integer chosen from 0 or 1 , Rd represents a (C1-C6)alkyl group optionally substituted with a halogen atom, such as a chlorine atom, with a sugar radical, with a group -COORe, in which Re represents a (C1-C4)alkyl group or a hydrogen atom, or with a group -O-P(=O)-(ORf)(ORg), in which Rf and Rg independently represent a (C1-C4)alkyl group - R8 and R9 independently represent a hydrogen atom, a hydroxyl group, or a group -OCORh, in which Rh represents a hydrogen atom or a (C1-C5)alkyl group, and in which at least: a. R4 and R5 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two (C1-C4)alkyl groups, or b. R5 represents a group of formula
Figure imgf000118_0002
and at least one of the following conditions is verified: i. R1 and R2 form, together with the ring that bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation ii. at least one from among R1, R4 and R6 is a (C2-C5)alkenyloxy group or a (C2-C5)alkynyloxy group, iii. R8 represents a group -OCORh, in which Rh represents a hydrogen atom or a (C1-C5)alkyl group, or iv. at least one from among R3 and R7 is a halogen atom, it being understood that when R5 represents a group of formula
Figure imgf000119_0001
then at least R4 or R6 is other than a hydroxyl group, it being understood that the compound having the following formula is excluded
Figure imgf000119_0002
2. Compound of formula (I) according to Claim 1, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R1 represents a hydroxyl group, a methoxy group, a group -OCONH(CH2)nCOORa, in which n is equal to 3, 4 or 5, in particular equal to 3 or 5, and Ra represents a methyl or ethyl group, in particular ethyl, a propenyloxy group or a propynyloxy group.
3. Compound of formula (I) according to Claim 1, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R1 and R2 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and an unsaturation, in particular a group
Figure imgf000119_0003
4. Compound of formula (I) according to any one of Claims 1 to 3, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R4 represents a hydroxyl group, a group
Figure imgf000120_0001
, m being equal to 1 or 3, a group , n being equal to 1 or 2,
Figure imgf000120_0002
a group
Figure imgf000120_0003
or
Figure imgf000120_0004
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups, a group
Figure imgf000120_0005
, in which s is equal to 0, 1 or 2, t is equal to 1 or 3, p is equal to 0, 2 or 3, q is equal to 6, and X is a hydrogen atom, a halogen atom, in particular a chlorine atom, a phenyl or phenyloxo group, the phenyl group being substituted with a methoxy group, a -C(O)OCH3 group or a group
Figure imgf000121_0001
or an -OCOCH3 group.
5. Compound of formula (I) according to any one of Claims 1 to 4, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R5 represents a group of formula
Figure imgf000121_0002
6. Compound of formula (I) according to any one of Claims 1 to 3, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R4 and R5 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally substituted with one or two methyl groups, in particular a group
Figure imgf000121_0003
7. Compound of formula (I) according to any one of Claims 1 to 6, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R6 represents a hydroxyl group, a methoxy or ethoxy group, a group , m being equal to 1 or 3,
Figure imgf000121_0004
a group
Figure imgf000122_0001
, n being equal to 1 or 2 a group
Figure imgf000122_0002
or
Figure imgf000122_0003
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups, an -OCOCH3 group, an -OCONHCOCH2CI group, a group , in which s is equal to 0, t is
Figure imgf000122_0004
equal to 1, p is equal to 0, q is equal to 1, and X is a hydrogen atom, a phenyl group or a phenyloxo group, the phenyl group being substituted with a methoxy group or a -C(o)OCH3 group, or a group -OCONH(CH2)qCOORk, in which q represents an integer chosen from 3, 4 or 5, in particular 3 and 5, and Rk represents a methyl or ethyl group, in particular ethyl.
8. Compound of formula (I) according to any one of Claims 1 to 7, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R8 and R9 independently represent a hydrogen atom, a hydroxyl group, an -OCHO group, or an -OCOCH3 group.
9. Compound of formula (I) according to any one of the preceding claims, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, represented by formula (la):
Figure imgf000123_0001
in which:
Figure imgf000123_0002
represents a single or double bond,
- R3 and R7 are as defined in Claim 1, and more particularly represent a hydrogen atom,
- R1 represents a hydroxyl group, a (C1-C5)alkoxy group, a (C2-C5)alkenyloxy group, a (C2-C5)alkynyloxy group, or a group -OCONH(CH2)nCOORa, in which n represents an integer between 2 and 6, and R a: represents a (C1-C4)alkyl group,
- R2 represents a hydrogen atom, or alternatively,
R1 and R2 form, together with the ring which bears them, a 6-membered ring comprising an oxygen atom and optionally an unsaturation,
- R6 represents a hydroxyl group a (C1-C6)alkoxy group, a (C2-C5)alkynyloxy group, a group -OCORc, in which Rc represents a (C1-C4)alkyl group, or a group -OCONH(CO)pRd, in which p represents an integer chosen from 0 or 1 , Rd represents a (C1-C6)alkyl group optionally substituted with a halogen atom, such as a chlorine atom, with a sugar radical, with a group -COORe, in which Re represents a (C1-C4)alkyl group or a hydrogen atom or with a group -O-P(=O)-(ORf)(ORg), in which Rf and Rg independently represent a (C1-C4)alkyl group, and - R8 and R9 independently represent a hydrogen atom, a hydroxyl group, or a group -OCORh, in which Rh represents a hydrogen atom or a (C1-C5)alkyl group.
10. Compound of formula (la) according to the preceding claim, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which R1 and R2 are as defined in Claim 2 or R1 and R2 are as defined in Claim 3, R6 is as defined in Claim 7, and R8 and R9 are as defined in Claim
8.
11. Compound of formula (I) as defined in any one of Claims 1 to 8, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, represented by formula (Ib)
Figure imgf000124_0001
in which
Figure imgf000124_0002
represents a single or double bond, in particular a double bond, - R1 represents a hydroxyl group, a (C1-C5)alkoxy group, a (C2-C5)alkenyloxy group, a (C2-C5)alkynyloxy group, or a group -OCONH(CH2)nCOORa, in which n represents an integer between 2 and 6, and Ra represents a (C1-C4)alkyl group,
- R3 and R7 independently represent a hydrogen atom or a halogen atom, for example a bromine atom,
- R4 represents a hydroxyl group, a group
Figure imgf000125_0001
, m being equal to 1, 2 or 3, a group
Figure imgf000125_0002
, n being equal to 1, 2 or 3, preferably 1 or 2, a group
Figure imgf000125_0003
Figure imgf000125_0004
, in which R is a hydrogen atom or a methyl group and R’ and R” are independently a (C1-C3)alkyl group, or a group
Figure imgf000125_0005
, in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(O)OCH3 group; a halogen atom, in particular a chlorine atom; an amino group or a group
Figure imgf000126_0001
or a group -OCORb, in which Rb represents a (C1-C4)alkyl group, - R6 represents a hydroxyl group, a (C1-C6)alkoxy group, a (C2-C5)alkynyloxy group, a group
Figure imgf000126_0002
, m being equal to 1, 2 or 3, a group
Figure imgf000126_0003
, n being 1, 2 or 3, preferably 1 or 2, a group
Figure imgf000126_0004
or
Figure imgf000126_0005
, in which R is a hydrogen atom or a methyl group and R’ and R” are independently a (C1-
C3)alkyl group, a group , in which s is equal to 0, 1 or 2, t is equal
Figure imgf000126_0006
to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(O)OCH3 group; a halogen atom, in particular a chlorine atom, or an amino group, or a group -OCORc, in which Rc represents a (C1-C4)alkyl group, or a group -OCONH(CO)pRd, in which p represents an integer chosen from 0 or 1 , Rd represents a (C1-C6)alkyl group optionally substituted with a halogen atom, such as a chlorine atom, with a sugar radical, with a group -COORe, in which Re represents a (C1-C4)alkyl group or a hydrogen atom, or with a group -O-P(=O)-(ORf)(ORg), in which Rf and Rg independently represent a (C1-C4)alkyl group, and - R8 and R9 independently represent a hydrogen atom, a hydroxyl group, or a group -OCORh, in which Rh represents a hydrogen atom or a (C1-C5)alkyl group, and at least one of the following conditions is verified: i. at least one from among R1, R4 and R6 is a (C2-C5)alkenyloxy group or a (C2-C5)alkynyloxy group, ii. R8 represents a group -OCORh, in which Rh represents a hydrogen atom or a (C1-C5)alkyl group, or iii. at least one from among R3 and R7 is a halogen atom.
12. Compound of formula (lb) according to the preceding claim, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, in which represents a double bond,
- R4 is as defined in Claim 4,
- R6 is as defined in Claim 7, and in particular represents a hydroxyl group, a methoxy or ethoxy group, an -OCOCH3 group, a group
Figure imgf000128_0001
, m being equal to 1 or 3, a group
Figure imgf000128_0002
, n being equal to 1 or 2, or a group
Figure imgf000128_0003
Figure imgf000128_0004
, in which R is a hydrogen atom or a methyl group and R’ and R’ ’ are methyl groups, or a group
Figure imgf000128_0005
, in which s is equal to 0, t is equal to 1, p is equal to 0, q is equal to 1, and X is a hydrogen atom, a phenyl or phenyloxo group, the phenyl group being substituted with a methoxy group or a -C(0)OCH3 group, - R8 and R9 are as defined in Claim 9.
13. Compound of formula (lb) according to claim 11, wherein at least one of R4 or R6, and in particular one of R4 and R6, comprises a group
Figure imgf000128_0006
, in which s is equal to 0, 1 or 2, t is equal to 1, 2 or 3, p is equal to 0, 2 or 3, q is equal to 1, 2, 3, 4, 5 or 6, preferably 6, and X is a hydrogen atom; a phenyl or phenyloxo group, said phenyl group being optionally substituted with a methoxy group; a -C(0)OCH3 group; a halogen atom, in particular a chlorine atom; an amino group or a group , in particular a group
Figure imgf000129_0001
w c s s equal to 0, t is equal to 1,
Figure imgf000129_0002
atom, a phenyl or phenyloxo group, the phenyl group being substituted with a methoxy group or a -C(O)OCH3 group. 14. Compound of formula (I) according to any one of the preceding claims, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, chosen from: - (1): (2R,4aR,9aR)-5-hydroxy-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-yl formate, - (2): (2R,4aR,9aR)-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5-diol, - (3): (7aR,9R,11aR)-5-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-8,8,11a- trimethyl-2,7,7a,8,9,10,11,11a-octahydropyrano[3,2-c]xanthen-9-yl formate, - (4): (7aR,9R,11aR)-5-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-8,8,11a- trimethyl-2,7,7a,8,9,10,11,11a-octahydropyrano[3,2-c]xanthen-9-ol, - (5): (2R,4aR,9aR)-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-yl formate, - (6): (2R,4aR,9aR)-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (7): (2S,3R,4aR,9aR)-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,3-diyl diformate, - (8): (2S,3R,4aR,9aR)-7-((E)-2-(5-hydroxy-2,2-dimethylchroman-7-yl)vinyl)-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,3-diol, - (9): (2R,4aR,9aR)-5-hydroxy-7-(2-(5-hydroxy-2,2-dimethylchroman-7-yl)ethyl)-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-yl formate, - (10): (2R,4aR,9aR)-7-(2-(5-hydroxy-2,2-dimethylchroman-7-yl)ethyl)-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5-diol, - (11): (2R,4aR,9aR)-7-(2-(5-hydroxy-2,2-dimethylchroman-7-yl)ethyl)-5-methoxy-1,1,4a- trimethyl-2, 3, 4, 4a, 9, 9a-hexahydro- lH-xanthen-2-yl formate,
- (12): (2R,4aR,9aR)-7-(2-(5-hydroxy-2,2-dimethylchroman-7-yl)ethyl)-5-methoxy-l,l,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-lH-xanthen-2-ol,
- (13): (2R,4aR,9aR)-7-((E)-2-(5-(((2-chloroacetyl)carbamoyl)oxy)-2,2-dimethylchroman- 7-yl)vinyl)-5-methoxy-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-lH-xanthen-2-yl formate,
- (14): ethyl 6-(((((2R,4aR,9aR)-7-((E)-2-(5-(((6-ethoxy-6-oxohexyl)carbamoyl)oxy)-2,2- dimethylchroman-7-yl)vinyl)-2-(formyloxy)-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-lH- xanthen-5-yl)oxy)carbonyl)amino)hexanoate,
- (15): ethyl 4-(((((2R,4aR,9aR)-7-((E)-2-(5-(((4-ethoxy-4-oxobutyl)carbamoyl)oxy)-2,2- dimethylchroman-7-yl)vinyl)-2-(formyloxy)-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-lH- xanthen-5-yl)oxy)carbonyl)amino)butanoate,
- (16): (2R,4aR,9aR)-7-((E)-2-(5-(((2-chloroacetyl)carbamoyl)oxy)-2,2-dimethylchroman- 7-yl)vinyl)-5-hydroxy-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-lH-xanthen-2-yl formate,
- (17): (2R,4aR,9aR)-l,l,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-l-yl)-3,5-bis(prop-2-yn- l-yloxy)styryl)-2,3,4,4a,9,9a-hexahydro-lH-xanthene-2,5-diol,
(18): (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-l-yl)-5-(prop-2-yn-l- yloxy)styryl)-l,l,4a-trimethyl-5-(prop-2-yn-l-yloxy)-2,3,4,4a,9,9a-hexahydro-lH- xanthen-2-ol,
(19): (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-l-yl)-5-(prop-2-yn-l- yloxy)styryl)-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-lH-xanthene-2,5-diol,
- (21): (2R,4aR,9aR)-l,l,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-l-yl)-3,5-bis(prop-2-yn- l-yloxy)styryl)-5-(prop-2-yn-l-yloxy)-2,3,4,4a,9,9a-hexahydro-lH-xanthen-2-ol,
(23): 5-((E)-2-((2R,4aR,9aR)-2-acetoxy-5-methoxy-l,l,4a-trimethyl-2,3,4,4a,9,9a- hexahydro- lH-xanthen-7 -yl)vinyl)-2-(3 -methylbut-2-en- 1 -yl)- 1 ,3-phenylene diacetate,
(31): (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-l-yl)-5-(prop-2-yn-l- yloxy)styryl)-5-methoxy-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-lH-xanthen-2-ol,
(32): (2S,3R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-l-yl)-5-(prop-2-yn-l- yloxy)styryl)-5-methoxy-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-lH-xanthene-2,3-diol,
(33): methyl 2-(4,5-dimethoxy-2-nitrophenyl)-2-(5-((E)-2-((2R,4aR)-2-hydroxy-5- methoxy-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-lH-xanthen-7-yl)vinyl)-2-(3- methylbut-2-en-l-yl)-3-(prop-2-yn-l-yloxy)phenoxy)acetate,
(34): methyl 2-(5-((E)-2-((2S,3R,4aR)-2,3-dihydroxy-5-methoxy-l,l,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-lH-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-l-yl)-3-(prop-2-yn- l-yloxy)phenoxy)-2-(4,5-dimethoxy-2-nitrophenyl)acetate,
- (35): 2-(5-((E)-2-((2S,3R,4aR)-2,3-dihydroxy-5-methoxy-l,l,4a-trimethyl-2,3,4,4a,9,9a- hexahydro-lH-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-l-yl)-3-(prop-2-yn-l- yloxy)phenoxy)-2-(4,5-dimethoxy-2-nitrophenyl)acetic acid,
- (36): (2R,4aR,9aR)-5-methoxy-l,l,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-l-yl)-3,5- bis(prop-2-yn-l-yloxy)styryl)-2,3,4,4a,9,9a-hexahydro-lH-xanthen-2-ol,
-(37): (2S,3R,4aR,9aR)-5-methoxy-l,l,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-l-yl)-3,5- bis(prop-2-yn-l-yloxy)styryl)-2,3,4,4a,9,9a-hexahydro-lH-xanthene-2,3-diol,
(38): (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-l-yl)-5-(pent-4-yn-l- yloxy)styryl)-5-methoxy-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-lH-xanthen-2-ol,
- (39): (2R,4aR,9aR)-5-methoxy-l,l,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-l-yl)-3,5- bis(pent-4-yn-l-yloxy)styryl)-2,3,4,4a,9,9a-hexahydro-lH-xanthen-2-ol,
(40): (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-l-yl)-5-(2-(prop-2-yn-l- yloxy)ethoxy)styryl)-5-methoxy-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-lH-xanthen-2- ol,
- (41): (2R,4aR,9aR)-5-methoxy-l,l,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-l-yl)-3,5- bis(2-(prop-2-yn-l-yloxy)ethoxy)styryl)-2,3,4,4a,9,9a-hexahydro-lH-xanthen-2-ol,
- (42): (2R,4aR,9aR)-7-((E)-3-hydroxy-4-(3-methylbut-2-en-l-yl)-5-(2-(2-(prop-2-yn-l- yloxy)ethoxy)ethoxy)styryl)-5-methoxy-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-lH- xanthen-2-ol,
- (43): (2R,4aR,9aR)-5-methoxy-l,l,4a-trimethyl-7-((E)-4-(3-methylbut-2-en-l-yl)-3,5- bis(2-(2-(prop-2-yn-l-yloxy)ethoxy)ethoxy)styryl)-2,3,4,4a,9,9a-hexahydro-lH-xanthen-2- ol,
(44): methyl 2-(5-((E)-2-((2S,3R,4aR)-2,3-dihydroxy-5-methoxy-l,l,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-lH-xanthen-7-yl)vinyl)-3-hydroxy-2-(3-methylbut-2-en-l- yl)phenoxy)-2-(4,5-dimethoxy-2-nitrophenyl)acetate,
- (45): 2-(5-((E)-2-((2S,3R,4aR)-2,3-dihydroxy-5-methoxy-l,l,4a-trimethyl-2,3,4,4a,9,9a- hexahydro-lH-xanthen-7-yl)vinyl)-3-hydroxy-2-(3-methylbut-2-en-l-yl)phenoxy)-2-(4,5- dimethoxy-2-nitrophenyl)acetic acid,
(46): (2S,3R,4aR)-7-((E)-3-((4,5-dimethoxy-2-nitrobenzyl)oxy)-5-hydroxy-4-(3- methylbut-2-en-l-yl)styryl)-5-methoxy-l,l,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-lH- xanthene-2,3-diol, - (48): 2,2’-((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1-yl)-1,3- phenylene)bis(oxy))bis(2-(4,5-dimethoxy-2-nitrophenyl)acetic acid, - (49): 2-(3-((1-(2-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4- yl)methoxy)-5-((E)-2-((2S,3R,4aR)-2,3-dihydroxy-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1-yl)phenoxy)-2- (4,5-dimethoxy-2-nitrophenyl)acetic acid, - (50): (2S,3R,4aR)-7-((E)-3-((1-(2-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,3-diol, - (51): (2R,4aR,9aR)-7-((E)-3-(3-(1-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)propoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (52): (2R,4aR,9aR)-7-((E)-3-(2-((1-(2-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)ethyl)- 1H-1,2,3-triazol-4-yl)methoxy)ethoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5- methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (53): (2R,4aR,9aR)-7-((E)-3-(2-((1-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methoxy)ethoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy- 1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (54): (2R,4aR,9aR)-7-((E)-3-(2-(2-((1-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methoxy)ethoxy)ethoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5- methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, - (55): (2R,4aS,9aS)-7-((E)-3-((1-(2-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)methoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy- 1,1,4a-trimethyl-1,2,3,4,4a,9,9a,10-octahydroanthracen-2-ol, - (56): (2R,4aR,9aR)-7-((E)-3-((1-(2-(2-((6-chlorohexyl)oxy)ethoxy)ethyl)-1H-1,2,3- triazol-4-yl)methoxy)-5-hydroxy-4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol, (57): (2S,3R,4aR,9aR)-7-((E)-3-hydroxy-5-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-4- (3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthene-2,3-diol, - (58): (2S,3R,4aR,9aR)-7-((E)-3,5-bis((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-4-(3- methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthene-2,3-diol - (59): (2S,3R,4aR,9aR)-7-((E)-3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-hydroxy-4- (3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthene-2,3-diol, - (60): (2S,3R,4aR,9aR)-7-((E)-3,5-bis((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-4-(3- methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthene-2,3-diol - (61): methyl 2-(4-((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-3-hydroxy-2-(3-methylbut-2- en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)acetate, - (62): dimethyl 2,2'-((((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1-yl)-1,3- phenylene)bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))diacetate- - (63): tert-butyl (R)-2-((4-((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy-1,1,4a- trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-3-hydroxy-2-(3-methylbut-2- en-1-yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)pyrrolidine-1-carboxylate, - (64): 2-(4-((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-3-hydroxy-2-(3-methylbut-2-en-1- yl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-1-(4-methoxyphenyl)ethan-1-one, - (65): 2,2'-((((5-((E)-2-((2S,3R,4aR,9aR)-2,3-dihydroxy-5-methoxy-1,1,4a-trimethyl- 2,3,4,4a,9,9a-hexahydro-1H-xanthen-7-yl)vinyl)-2-(3-methylbut-2-en-1-yl)-1,3- phenylene)bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(4- methoxyphenyl)ethan-1-one) - (66): (2R,4aR,9aR)-7-((E)-3-hydroxy-5-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)- 4-(3-methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthen-2-ol - (67): (2R,4aR,9aR)-7-((E)-3,5-bis((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-4-(3- methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthen-2-ol - (68): (2R,4aR,9aR)-7-((E)-3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-hydroxy-4-(3- methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthen-2-ol - (69): (2R,4aR,9aR)-7-((E)-3,5-bis((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-4-(3- methylbut-2-en-1-yl)styryl)-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H- xanthen-2-ol - (70): (2R,4aR,9aR)-7-((E)-3-hydroxy-5-((1-methyl-1H-1,2,3-triazol-4-yl)methoxy)-4-(3- methylbut-2-en-1-yl)styryl)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5- diol - (71): (2R,4aR,9aR)-7-((E)-3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-5-hydroxy-4-(3- methylbut-2-en-1-yl)styryl)-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5- diol, and more particularly chosen from compounds (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (16), (50), (55), (56), (57), (58), (59), (60), (64), (65), (66), (67), (68), (70) and (71). 15. Synthetic process for the preparation of a compound of formula (Ia’’)
Figure imgf000134_0001
in which R1 and R6 are as defined in Claims 1, 2 and 7, and at least one from among R8 and R9 represents a group -OCORh as defined in Claim 1, and in particular an -OCHO group or an -OCOCH3 group, and in which R2 is a hydrogen atom, or any of the pharmaceutically acceptable salts thereof, comprising at least one step of intramolecular cyclization of the geranyl chain into pyran, of a compound of general formula (II), accompanied by esterification of the secondary alcohol of the hexahydroxanthene unit
Figure imgf000134_0002
, in which R1, R6 and R8 are as defined above.
16. Intermediate compounds of formula (III)
Figure imgf000135_0001
in which Rh, R9 and R6 are as defined in Claim 1.
17. Pharmaceutical composition comprising at least one compound of formula (I) as defined in any of Claims 1 to 13, at least one compound as defined in Claim 14, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof, and at least one pharmaceutically acceptable excipient.
18. Compound of formula (I) as defined in Claims 1 to 13 or at least one compound as defined in Claim 14, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof, or pharmaceutical composition according to Claim 17, for its use as a medicament.
19. Compound of formula (I) as defined in Claims 1 to 13 or at least one compound as defined in Claim 14, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical composition according to Claim 17, for its use as an oxysterol binding protein 1 (OSBP) inhibitor.
20. Compound of formula (I) as defined in Claims 1 to 13 or at least one compound as defined in Claim 14, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical composition according to Claim 17, for its use according to Claim 18 for the prevention, inhibition and/or treatment of cancers, neurodegenerative diseases, dyslipidaemia, hypercholesterolaemia, and/or viral or parasitic diseases. 21. Compound of formula (I) as defined in Claims 1 to 13 or at least one compound as defined in Claim 14, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical composition according to Claim 17, for its use according to the preceding claim, the neurodegenerative diseases being chosen from amyotrophic lateral sclerosis (ALS or Charcot’s disease), Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease (Huntington’s chorea), and Niemann-Pick type C disease, in particular Alzheimer’s disease, Parkinson’s disease, Huntington’s disease (Huntington’s chorea), and Niemann-Pick type C disease.
22. Compound of formula (I) as defined in Claims 1 to 13 or at least one compound as defined in Claim 14, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical composition according to Claim 17, for its use according to Claim 19, the cancers being chosen from breast cancer, including triple negative breast cancer, kidney cancer, head and neck cancer, prostate cancer, colorectal cancer, colon cancer, gall bladder cancer, bile duct cancer (cholangiocarcinoma), gastrointestinal cancer, gastric cancer, hepatocellular carcinoma, lymphoma, lung cancer, small cell lung cancer, non- small cell lung cancer, pancreatic cancer, osteosarcoma, pancreatic carcinoma, stomach cancer, brain cancer, metastasis, leukaemia, acute T-cell lymphoblastic leukaemia, chronic myeloid leukaemia, melanoma, and glioblastoma, in particular kidney cancer, triple negative breast cancer, melanoma, leukaemia and glioblastoma.
23. Compound of formula (I) as defined in any one of Claims 1 to 13 or at least one compound as defined in Claim 14, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, and also the tautomeric forms, stereoisomers, mixtures of stereoisomers, pure enantiomers and racemic or non-racemic mixtures thereof, or mixtures thereof or pharmaceutical composition according to Claim 17, for use according to Claim 19, in which the viral diseases are chosen from viral infections caused by RNA viruses, even more particularly infections caused by RNA viruses of classes IV and V of the Baltimore classification, and even more particularly chosen from dengue, Zika virus infection, influenza, viral angina, measles, AIDS, chikungunya, yellow fever, poliomyelitis, hepatitis A hepatitis C, hepatitis E, SARS-CoV virus infection, SARS-CoV-2 virus infection, and rubella, in particular dengue, Zika virus infection, chikungunya, yellow fever, polio, hepatitis A, hepatitis C, hepatitis E, SARS-CoV virus infection, SARS-CoV-2 virus infection and rubella.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010127235A1 (en) * 2009-04-30 2010-11-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Schweinfurthins and uses thereof
WO2013148584A1 (en) * 2012-03-26 2013-10-03 University Of Iowa Research Foundation Schweinfurthin analogues

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010127235A1 (en) * 2009-04-30 2010-11-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Schweinfurthins and uses thereof
WO2013148584A1 (en) * 2012-03-26 2013-10-03 University Of Iowa Research Foundation Schweinfurthin analogues

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
ANTHONY W.G. BURGETT ET AL., NATURE CHEMICAL BIOLOGY, vol. 7, 2011, pages 639 - 647
ANTONIETTA PIETRANGELO ET AL.: "Cellular and Molecular Life Sciences", 2018, SPRINGER INTERNATIONAL PUBLISHING AG, article "Bridging the molecular and biological functions of the oxysterol-binding protein family"
BAO XINGFENG ET AL: "Small molecule schweinfurthins selectively inhibit cancer cell proliferation and mTOR/AKT signaling by interfering with trans-Golgi-network trafficking", vol. 16, no. 4, 3 April 2015 (2015-04-03), US, pages 589 - 601, XP055884601, ISSN: 1538-4047, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622430/pdf/kcbt-16-04-1019184.pdf> DOI: 10.1080/15384047.2015.1019184 *
BRUNO MESMIN ET AL.: "JBC", 19 February 2020, article "Molecular and cellular dissection of the oxysterol-binding protein cycle through a fluorescent inhibitor"
DIPESH S. HARMALKAR ET AL.: "Schweinfurthins A-Q: isolation, synthesis, and biochemical properties", RSC. ADV., vol. 8, no. 21, 2018, pages 191 - 21209
DOAN THI MAI HUONG ET AL: "Cytotoxic Phenolic Compounds from Fruit Glandular Trichomes of Macaranga tanarius", vol. 2019, 13 October 2019 (2019-10-13), pages 1 - 5, XP055884586, ISSN: 2090-8865, Retrieved from the Internet <URL:https://downloads.hindawi.com/journals/jamc/2019/2917032.pdf> DOI: 10.1155/2019/2917032 *
HARMALKAR DIPESH S. ET AL: "Schweinfurthins A-Q: isolation, synthesis, and biochemical properties", vol. 8, no. 38, 1 January 2018 (2018-01-01), pages 21191 - 21209, XP055884596, Retrieved from the Internet <URL:https://pubs.rsc.org/en/content/articlepdf/2018/ra/c8ra02872a> DOI: 10.1039/C8RA02872A *
HARMALKAR ET AL., RSC ADV., vol. 8, 2018, pages 21191
J.M. BRUNEL, SYNLETT, no. 2, 2007, pages 330
KATHLEEN M. KOKOLUS ET AL., ONCOLMMUN, vol. 8, no. 2, 2019, pages e1539614
MENTE ET AL: "Total synthesis of (R,R,R)- and (S,S,S)-schweinfurthin F: Differences of bioactivity in the enantiomeric series", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 17, no. 4, 1 February 2007 (2007-02-01), pages 911 - 915, XP005868808, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2006.11.096 *
MICHAEL B. SMITHJERRY MARCH: "Mechanisms and Structure", 2007, JOHN WILEY & SONS, article "March's Advanced Organic Chemistry Reactions"
PÉRESSE TIPHAINE ET AL: "Molecular and cellular dissection of the oxysterol-binding protein cycle through a fluorescent inhibitor", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 295, no. 13, 1 March 2020 (2020-03-01), US, pages 4277 - 4288, XP055884665, ISSN: 0021-9258, DOI: 10.1074/jbc.RA119.012012 *
STEVENS, J. W. ET AL., JOURNAL OF ORTHOPAEDIC RESEARCH: OFFICIAL PUBLICATION OF THE ORTHOPAEDIC RESEARCH SOCIETY, vol. 36, 2017, pages 1283 - 1293
THI MAI HUONG DOAN ET AL.: "Cytotoxic phenolic compounds from fruit glandular trichomes of Macaranga tanarius", JOURNAL OF ANALYTICAL METHODS IN CHEMISTRY, vol. 2019, no. 2917032, pages 5
THOISON O ET AL: "Vedelianin, a hexahydroxanthene derivative isolated from Macaranga vedeliana", PHYTOCHEMISTRY, ELSEVIER, AMSTERDAM , NL, vol. 31, no. 4, 1 April 1992 (1992-04-01), pages 1439 - 1442, XP028087534, ISSN: 0031-9422, [retrieved on 19920401], DOI: 10.1016/0031-9422(92)80315-6 *
THOISON O.: ""Vedelianin, a hexahydroxanthene derivative isolated from Macaranga Vedelianan"", PHYTOCHEMISTRY, vol. 31, no. 4, 1992, pages 1439 - 1442
ULRICH NATALIE C ET AL: "Structural analogues of schweinfurthin F: Probing the steric, electronic, and hydrophobic properties of the D-ring substructure", BIOORGANIC, vol. 18, no. 4, 1992, pages 1676 - 1683, XP028649821, ISSN: 0968-0896, DOI: 10.1016/J.BMC.2009.12.063 *

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