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WO2023036995A1 - Alcynylcarbinols à cytotoxicité élevée - Google Patents

Alcynylcarbinols à cytotoxicité élevée Download PDF

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Publication number
WO2023036995A1
WO2023036995A1 PCT/EP2022/075358 EP2022075358W WO2023036995A1 WO 2023036995 A1 WO2023036995 A1 WO 2023036995A1 EP 2022075358 W EP2022075358 W EP 2022075358W WO 2023036995 A1 WO2023036995 A1 WO 2023036995A1
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Prior art keywords
group
alkyl
compound
alkynyl
formula
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PCT/EP2022/075358
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English (en)
Inventor
Sébastien BRITTON
Stéphanie BALLEREAU
Patrick Calsou
Rémi Chauvin
Hafida Gaspard
Yves Genisson
Dymytrii LISTUNOV
Valérie MARAVAL
Pauline RULLIERE
Margaux BOSSUAT
Original Assignee
Centre National De La Recherche Scientifique
Universite Paul Sabatier Toulouse Iii
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Publication of WO2023036995A1 publication Critical patent/WO2023036995A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/28—Alcohols containing only six-membered aromatic rings as cyclic part with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/28—Alcohols containing only six-membered aromatic rings as cyclic part with unsaturation outside the aromatic rings
    • C07C33/30—Alcohols containing only six-membered aromatic rings as cyclic part with unsaturation outside the aromatic rings monocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
    • C07C33/48—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts with unsaturation outside the aromatic rings
    • C07C33/483—Monocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms

Definitions

  • the present invention relates to alkynylcarbinols.
  • Naturally occurring acetylenic lipids constitute a rich family of bioactive compounds. For example, more than 100 natural acetylenic lipids have been identified from diverse species of marine sponges and shown to display various biological activities, including for most of them a pronounced cytotoxicity against several tumor cell lines. More precisely, the presence of a terminal alkynylcarbinol unit has been correlated with the antitumor activity of such natural compounds.
  • an acetylenic lipid with a terminal dialkynylca rbinol unit which exhibits a cytotoxicity against HCT116 tumor cells 100 times higher than the one of its natural parent (S,Ej-icos-4-en-l-yn-3-ol, which is a lipidic alkenylalkynylcarbinol isolated from the marine sponge Cribrochalina vasculum.
  • alkynylcarbinol motif is found in various cytotoxic natural or synthetic lipids, but the mechanism of action of those potential therapeutic agents remains unknown.
  • the present invention satisfies this need by providing novel alkynylcarbinols having a pronounced cytotoxicity against several tumor cell lines.
  • HSD17B11 i.e. 17-beta- hydroxysteroid dehydrogenase 11
  • a short-chain dehydrogenase/reductase expressed in cancer cells oxidizes these novel alkynylcarbinols into the corresponding ketones in the.
  • the generated alkynylketones, also called alkynylcarbinones are able to react with lysine and cysteine side chains, and thus covalently modify several proteins, thereby triggering endoplasmic reticulum stress, proteasome inhibition and apoptosis.
  • cytotoxic alkynylcarbinone species are instable in biological medium. It explains why the cytotoxicity of the chemically synthetized alkynylcarbinones is low when they are directly in contact with the cells and why the novel alkynylcarbinols thus may constitute a reservoir of cytotoxic prodrugs that can be used for the treatment of cancer.
  • R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -al lenyl or a C 1 -C 6 -a Ikyl group,
  • Ar is selected from the group consisting of aryl and heteroaryl, wherein
  • - aryl is a phenyl, naphthyl, indanyl, tetralinyl, biphenylyl, fluorenyl or anthacenyl group,
  • - heteroaryl is an aziridine, azepine, azetidine, benzimidazole, benzofuran, benzo[l,4]dioxine,
  • Ar may be substituted with 1 to 7 substituents independently chosen from halogen, OCF 3 , CF 3 , CH 2 OH, CCSi(i-Pr) 3 , CH 3 , OH, CHFCH 2 F, -O(CH 2 CH 2 O) n Et with n an integer comprised between 1 and 6, AC n H 2n B with n an integer comprised between 1 and 20 and A being selected from the group consisting of CH 2 , CF 2 , O and S, B being selected from the group consisting of H, CH 3 , CH 2 F, CHFCH 2 F, CF 3 , CH 2 OH, O-C 1 -C 20 alkyl, CCSi(i-Pr) 3 or C 2 -alkynyl.
  • the compounds of the formula (2) are dialkynylcarbinols
  • the compounds of the formula (3) are alkenylalkynylcarbinols
  • the compounds of the formula (4) are allenylalkynylcarbinols
  • the compounds of the formula (5) are alkylalkynylcarbinols.
  • Halogen is understood as meaning fluorine, chlorine, bromine, or iodine.
  • Alkyl includes both branched and linear saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms.
  • C 1 -C n alkyl means an alkyl group having from 1 to n carbon atoms.
  • Alkenyl is a branched or linear unsaturated hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon double bond without any carbon-carbon triple bond.
  • C 2 -alkenyl designates an ethenyl group.
  • Alkynyl is branched or linear unsaturated hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon triple bond.
  • C2 alkynyl designates an ethynyl group.
  • the asymmetric carbon atom present in the compounds of the present invention can have a R configuration or a S configuration.
  • the compounds can be in the form of enantioenriched enantiomers or in the form of a racemic mixture.
  • the present invention relates to enantioenriched enantiomers and racemic mixtures.
  • the compounds of the present invention may be in all their stereoisomeric forms and mixtures thereof in any ratio, and also may be in the form of physiologically tolerable salts.
  • Physiologically tolerable salts of the compounds of the present invention are nontoxic salts that are physiologically acceptable, in particular pharmaceutically utilizable salts.
  • Possible salts correspond to ionic substituents of the Ar group, anionic (carboxylates, sulfinates, sulfonates, phosphinates, phosphonates, phosphates) or cationic (ammoniums), with biologically compatible counterions.
  • Salts of the compounds of the present invention can be obtained by customary methods known to those skilled in the art, for example by combining a compound of the present invention with an inorganic or organic base in a solvent or diluent, or from other salts by cation exchange or anion exchange.
  • Ar is preferably selected from the group consisting of phenyl, naphthyl, furan, pyridine, pyrimidine, pyran, thiophene, pyrrole, 1,4-dioxine, dithiine, oxathiine, dihydropyrazine, 1,3-oxazine, 1,4-oxazine, 1,2,3-triazole and 1,2,4-triazole groups.
  • Ar is selected from the group consisting of phenyl, naphthyl, furan, and thiophene groups.
  • Ar is a thiophene group or a furan group that is substituted with 1 to 3 substituents, preferably with 1 substituent.
  • the thiophene group or the furan group may be substituted with a C 1 -C 20 -alkyl group (more preferably a C 4 -C 14 alkyl group).
  • the thiophene group or the furan group is substituted with a C 3 -C 20 -alkyl group (more preferably a C 4 -C 14 -alkyl group), the other substituent(s) if any being independently chosen from C 1 -C 20 -alkyl groups, preferably C 4 -C 14 -alkyl groups, F and OCF 3 .
  • R is preferably a C 2 -alkynyl group.
  • the compounds of the present invention are of the formula (6) : in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 9 or 11, and R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -a llenyl or a C 1 -C 6 -al kyl group.
  • R is a C 2 -alkynyl group and thus preferred compounds are of the formula
  • n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 9 or 11.
  • the compounds are of the formula (8) : in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 6 or 9 and R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -a I leny I or a C 1 -C 6 -a Iky I group.
  • R is a C2-alkynyl group and thus preferred compounds are of the formula (9) : in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 6 or 9.
  • Ar is a naphthyl group that is substituted with 1 to 7 substituents, at least one substituent having formula (a) AC n H 2n B as defined above, the other substituent(s), if any, being as defined above, preferably with 1 substituent.
  • naphthyl may be substituted with a C 1 -C 20 -alkyl group (more preferably a C 8 -alkyl group).
  • naphthyl is substituted with 1 to 7 substituents, one substituent being a C 3 -C 20 -alkyl group (more preferably a C 8 - alkyl group), the other substituent(s) if any being independently chosen from C 1 -C 20 -alkyl groups.
  • R is preferably a C 2 -alkynyl group.
  • the compounds are of the formula (10) : in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 7 and R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -allenyl or a C 1 -C 6 -alkyl group.
  • R is a C 2 -alkynyl group and thus preferred compounds are of the formula (11) :
  • n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 7.
  • Ar may be a phenyl group that is substituted with 1 to 5 substituents, preferably with 1 to 3 substituents.
  • Ar is a phenyl group that is substituted with 1 to 5 substituents, at least one substituent having formula (a) AC n H 2n B as defined above, the other substituent(s), if any, being as defined above, preferably with 1 to 3 substituents.
  • the phenyl group is substituted with a group selected from the group consisting of C 3 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 - alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 3 and 18.
  • the substituent is a C 3 -C 20 -alkyl, it is preferably in meta or para position and more preferably in para position.
  • the phenyl group is substituted with a C 4 -C 14 -alkyl (preferably C 8 ) in para position and optionally substituted with an halogen atom (preferably F) in meta position.
  • R 1 , R?, R 3 , R 4 and R 5 is chosen from C 3 -C 20 -alkyl (more preferably C 4 -C 14 - alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 3 and 18, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl and CF 2 -C 2 -C 20 -alkyl, the other substituents, identical or different, are chosen independently of one another from hydrogen, C 1 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF 3 , CHFCH 2 F, CF 3 , CH 2 OH, CCSi(i- Pr) 3 , O
  • halogen
  • R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -allenyl or a C 1 -C 6 -a I kyl group.
  • R is a C 2 -alkynyl group.
  • the preferred compounds are of the formula (13) : in which at least one of R 1 , R 2 , R 3 , R 4 and R 5 is chosen from C 3 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 3 and 18, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl and CF 2 -C 2 -C 20 -alkyl, the other substituents, identical or different, and are chosen independently of one another from hydrogen, C 1 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 ) n -C 2 - alkynyl with n an integer comprised between 0 and
  • R 3 is selected from the group consisting of (CH 2 ) n CH 3 with n an integer comprised between 2 and 19, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl, CF 2 -C 2 -C 20 -alkyl and (CH 2 )n-C 2 -alkynyl with n an integer comprised between 3 and 18, and R 1 R 2 , R 4 and R 5 are identical or different and are chosen independently of one another from hydrogen, C 1 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF 3 , CHFCH 2 F, CF 3 , CH 2 OH, CCSi(i-Pr) 3 , O(CH 2 CH 2 O) n
  • R 3 is selected from the group consisting of (CH 2 ) n CH 3 with n an integer comprised between 2 and 19, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl, CF 2 -C 2 -C 20 -alkyl and (CH2)n-C2 -alkynyl with n an integer comprised between 3 and 18 and R 1 R 2 , R 4 and R 5 are identical or different and are chosen independently of one another from hydrogen, C 1 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF 3 , CHFCH 2 F, CF 3 , CH 2 OH, CCSi(i-Pr) 3 , O(CH 2 CH 2 O) n Et
  • R 2 is selected from the group consisting of (CH 2 ) n CH 3 with n an integer comprised between 2 and 19, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl, CF 2 -C 2 -C 20 -alkyl and (CH 2 ) n -C 2 -alkynyl with n an integer comprised between 3 and 18 and R 1 R 3 , R 4 and R 5 are identical or different and are chosen independently of one another from hydrogen, C 1 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF 3 , CHFCH 2 F, CF 3 , CH 2 OH, CCSi(i-Pr) 3 , O(CH 2 CH 2 O)
  • halogen preferably F
  • R 2 is selected from the group consisting of -(CH 2 )nCH 3 with n an integer comprised between 2 and 19, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl, CF 2 -C 2 -C 20 -alkyl and (CH 2 ) n -C 2 -alkynyl with n an integer comprised between 3 and 18 and R 1 R 3 , R 4 and R 5 are identical or different and are chosen independently of one another from hydrogen, C 1 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF 3 , CHFCH 2 F, CF 3 , CH 2 OH, CCSi(i-Pr) 3 , O(CH 2 CH 2
  • Some preferred compounds of the formula (12) are compounds of the formula (14): in which R 3 is selected from the group consisting of (CH 2 ) n CH 3 with n an integer comprised between 2 and 19, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl, CF 2 -C 2 -C 20 -alkyl and (CH 2 )n-C 2 -alkynyl with n an integer comprised between 3 and 18.
  • R 1 , R 2 , R 4 and R 5 are hydrogen and R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -a lleny I or a C 1 -C 6 -a I ky I group.
  • R is preferably a C 2 -alkynyl group or a C 2 - alkenyl group.
  • R is a C 2 -alkenyl group
  • preferred compounds are compounds of the formulas (15) and (16):
  • Some preferred compounds of (12) are compounds of the formula (17) : in which R 2 is selected from the group consisting of (CH 2 ) n CH 3 with n an integer comprised between 2 and 19, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl, CF 2 -C 2 -C 20 -alkyl and (CH 2 )n-C 2 -alkynyl with n an integer comprised between 3 and 18.
  • R 1 , R 3 , R 4 and R 5 are hydrogen and R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -allenyl or a C 1 -C 6 -a I ky I group.
  • R is preferably a C 2 -alkynyl group or a C 2 - alkenyl group.
  • n is an integer comprised between 2 and 19, R 1 , R 2 , R 3 and R 4 are halogen
  • R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -allenyl or a C 1 -C 6 -a Ikyl group.
  • R is a C 2 -alkynyl group.
  • Some other preferred compounds of the compounds of the formula (12) are the compounds of the formulas (22) and (23) : in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 7, R 2 and R 4 are halogen identical or different of one another (preferably F) and R 1 and R 3 are halogen identical or different of one another (preferably F), and R is a C 2 - alkynyl, a C 2 -alkenyl, a C 3 -allenyl or a C 1 -C 6 -alkyl group.
  • R is a C 2 -alkynyl group.
  • the compounds of the present invention are prepared according to any conventional methods and known for those of skill in the art. For example, two embodiments of the preparation of compounds according to the invention are here below disclosed in the experimental part.
  • the compounds of the present invention are valuable pharmacologically active compounds. As explained above, they may act as prodrug and especially exhibit a cytotoxicity that is suitable, for example, for the treatment of cancer.
  • a further subject of the present invention is a pharmaceutical composition, which comprises at least one compound of the present invention and/or a physiologically tolerable salt thereof and together with at least one pharmaceutically acceptable carrier.
  • composition of the invention comprises at least one compound of the formula (1), or physiologically tolerable salt thereof in which:
  • R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -al lenyl or a C 1 -C 6 -a Ikyl group,
  • Ar is selected from the group consisting of aryl and heteroaryl, wherein
  • - aryl is a phenyl, naphthyl, indanyl, tetralinyl, biphenylyl, fluorenyl or anthacenyl group,
  • - heteroaryl is an aziridine, azepine, azetidine, benzimidazole, benzofuran, benzofl, 4]dioxine, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, chromane, cinnoline, dihydropyrazine, dithiine, 1,2-diazepine, 1,3- diazepine, 1,4-diazepine, 1,4-dioxine, furan, dioxole, imidazole, indazole, indole, isochromane, isoindole, isoquinoline, isothiazole, isoxazole, oxathiine, 1,2-oxazine, 1,3- oxazine, 1,4-oxazine, oxazole, 1,3-o
  • Ar being substituted with 1 to 7 substituents independently chosen from halogen, OCF 3 , CF 3 , CH 2 OH, CCSi(i-Pr) 3 , CH 3 , OH, CHFCH 2 F, -O(CH 2 CH 2 O) n Et with n an integer comprised between 1 and 6,
  • Carrier means a diluent, excipient, or vehicle with which at least one compound of the present invention is administered.
  • a “pharmaceutically acceptable carrier” means a substance, e.g., excipient, diluent, or vehicle, which is useful in preparing the pharmaceutical composition that is safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier” includes both one and more than one such carrier.
  • Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents.
  • Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
  • Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils.
  • Optional active and/or inactive agents may be included in the pharmaceutical compositions, provided that such agents do not substantially interfere with the activity of the compounds of the present invention.
  • the optional active agent is an additional active agent that is not a compound or salt of the present invention.
  • the compounds of the present invention may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
  • the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution.
  • Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • compositions are preferably formulated for oral administration.
  • compositions may contain between 0.1 % and 99 % by weight of a compound of the present invention.
  • a further subject of the present invention is a compound of the present invention and/or a physiologically tolerable salt thereof for use as a medicament.
  • a further subject of the present invention is a compound of the present invention and/or a physiologically tolerable salt thereof for use as a prodrug.
  • a further subject of the present invention is a compound of the present invention or a physiologically tolerable salt thereof for use in the treatment of a disease selected from the group consisting of cancer or metastasis thereof, bacterial, parasitic or fungal infections.
  • the cancer may be selected from the group consisting of colon cancer, renal-cell carcinoma, prostate cancer, testicular cancer, lung cancer, cancer of the small intestine and cancer of the esophagus, breast cancer, colon cancer, bone cancer, neuroblastoma, hematological malignancies such as B-cell lymphoid neoplasm, T-cell lymphoid neoplasm, non-Hodgkin lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), NK-cell lymphoid neoplasm and myeloid cell lineage neoplasm including acute myeloid leukemia.
  • B-cell lymphoid neoplasm non-Hodgkin lymphoma
  • B-NHL non-Hodgkin lymphoma
  • B-NHL non-Hodgkin lymphoma
  • the cancer may be selected from the group consisting of lung cancer, breast cancer, colon cancer, bone cancer and neuroblastoma.
  • the bacterial infection may be selected from the group consisting of pneumonia, bacterial meningitis, cholera, diphtheria, tuberculosis, anthrax, botulism, brucellosis, campylobacteriosis, typhus, gonorrhea, listeriosis, lyme disease, rheumatic fever, pertussis (Whooping Cough), plague, salmonellosis, scarlet fever, shigellosis, syphilis, tetanus, trachoma, tularemia, typhoid fever, and urinary tract infections, or caused by Coxiella burnetii, Brucella abortus, Tropheryma whipplei, Mycobacterium tuberculosis and Mycobacterium canettii.
  • the parasitic infection may be selected from the group consisting of malaria, leishmaniasis, trypanosomiasis, chagas disease, cryptosporidiosis, fascioliasis, filariasis, amebic infections, giardiasis, pinworm infection, schistosomiasis, taeniasis, toxoplasmosis, trichi nellosis, and trypanosomiasis.
  • the fungal infection may be selected from the group consisting of candidiasis, aspergillosis, coccidioidomycosis, cryptococcosis, histoplasmosis and tinea pedis.
  • Another application of the present invention is the use of at least one of the described compounds of the invention which contains a functional group, or one of these compounds on which at least one functional group would be added, to functionalize a protein of interest.
  • Functional groups may include, but are not limited to, a fluorophore, a biotin, a peptide, a drug or a "clickable" group, such as a C 2 -alkynyl group or an azido group.
  • This functional group can be added anywhere on the compound of the present invention, providing that it does not interfere with its bioactivation.
  • the HSD17Bll-mediated oxidation of the functionalized compound generates a protein reactive species which will covalently modify the protein of interest with the desirable functional group through Michael addition of one or several cysteine and lysine side chains with the functionalized bioactivated compound.
  • the use of "click- chemistry" reactions allows to subsequently modify the protein with another functional group, including large functional groups, providing that it carries a function amenable to the selected "click chemistry” reaction.
  • the protein of interest can be any protein with lysines and/or cysteines residues, but is preferably an antibody, and the functional group is preferentially a drug (i.e. an antibody-drug conjugates).
  • a further subject of the present invention is the use of at least one of the compounds of the present invention to select genome edited cells (i.e. by CRISPR/Cas9-mediated genome editing technology) through the co-inactivation of the HSD17B11 gene (i.e. knock-out or knock-in impacting on HSD17B11 catalytic activity) and of the gene(s) of interest in a target cell population.
  • the HSD17B11 gene coinactivation provides a resistance to some of the compounds described in the present invention which is used to enrich the edited cells and kill the unedited one by treating the cell population, comprising properly edited cells with non-edited ones, with the chosen compound(s).
  • the gene editing strategies amenable to this approach may comprise, but is not limited to, CRISPR/Cas9 genome editing.
  • Figure 1 is a scheme of the steps of a 1 st method for preparing compounds according to the present invention.
  • Figure 2 is a scheme of the steps of a 2 nd method for preparing compounds according to the present invention.
  • the starting compound of these two methods was a compound of the formula (X) : in which B is halogen (i.e. fluorine, chlorine, bromine, or iodine) and Ar has the meaning as above detailed.
  • B is halogen (i.e. fluorine, chlorine, bromine, or iodine) and Ar has the meaning as above detailed.
  • the 3 rd step of the 1 st method may be carried out according to a 1 st alternative (i.e. 3a) or a 2 nd alternative (i.e. 3'a).
  • step lb) of the 2 nd method was carried out as follows: [100] A Schlenk flask charged with Na 2 PdCI 4 (1 mol%), 2-(di-tert-butylphosphino)-N- phenylindole (PlntB, 2 mol%), Cul (2 mol%), propargyl alcohol (2.0 eq.), aryl halide of formula (X) (1.1 equiv), H2O (0.2 mL/mmol) and TMEDA (1.8 mL/mmol) was evacuated and backfilled with argon 3 times, and heated to 80 °C under stirring. After consumption of the compound of the formula (X), the reaction mixture was cooled to room temperature.
  • the 2 nd step of the 2 nd method may be carried out according to a 1 st alternative (i.e. 2b) or a 2 nd alternative (i.e. 2'b).
  • step 2'b) was carried out as below detailed if Ar of the compound of the formula (X) comprised a triisopropylsilyl-protected terminal alkyne.
  • the 3 rd step of the 2 nd method may be carried out according to a 1 st alternative (i.e. 3b) or a 2 nd alternative (i.e. 3'b) or a 3 rd alternative (i.e. 3"b) or a 4 th alternative (i.e. 3"'b).
  • the resulting mixture was stirred at room temperature for 45 minutes before dropwise addition of the propargylic aldehyde (1 eq.) in anhydrous CH 2 CI 2 (1 mL/mmol) (final concentration in starting terminal alkyne 0.3 M).
  • the reaction mixture was stirred at room temperature for 12 hours before being quenched by addition of aqueous saturated NH4CI solution and extracted 3 times with CH 2 CI 2 .
  • the combined organic layers were then washed with water and brine, dried over MgSO4 and concentrated under reduced pressure.
  • Example 8 l-(3-Nonylphenyl)penta-1,4-diyn-3-ol of the formula (36):
  • Example 10 l-(6-Octylnaphthalen-2-yl)penta-1,4-diyn-3-ol of the formula (40):
  • Example 11 l-(3-Fluoro-4-octylphenyl)penta-1,4-diyn-3-ol of the formula (42):
  • Example 12 l-(2-Fluoro-4-octylphenyl)penta-1,4-diyn-3-ol of the formula (44):
  • Example 15 l-(4-(2-(2-Ethoxyethoxy)ethoxy)phenyl)penta-1,4-diyn-3-ol of the formula (50):
  • Example 16 l-(4-(Heptyloxy)phenyl)penta-1,4-diyn-3-ol of the formula (52): [173] This compound (183 mg, 8 % yield from the starting compound (53)) was obtained in the form of a racemic mixture according to the 1 st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3 rd step) with the starting compound: l-lodo-4-(heptyloxy)benzene (CAS 116223-56-4 Commercial) of the formula (53):
  • Example 20 l-(5-Decylthiophen-2-yl)penta-1,4-diyn-3-ol of the formula (58):
  • Example 22 l-(4-(Oct-7-yn-l-yl)phenyl)penta-1,4-diyn-3-ol of the formula (62):
  • Example 27 1-(3-Fluoro-4-((6,6,6-trifluorohexyl)oxy)phenyl)penta-1,4-diyn-3-ol of the formula (71):
  • Example 28 l-(5-Decylfuran-2-yl)penta-1,4-diyn-3-ol of the formula (73):
  • Example 32 1-(4-Octylphenyl)hexa-4,5-dien-l-yn-3-ol of the formula (81): [226] This compound (42 mg, 35 % yield from the starting compound (28)) was obtained in the form of a racemic mixture according to the 2 nd method with the alternative 2b) for the 2 nd step, the alternative 3b) for the 3 rd step and 4b) for the 4 th step with the starting compound: l-Bromo-4-octyl benzene: (CAS 51554-93-9 Commercial) of the formula (28):
  • Wild-type human HCT116 colon cancer cells were seeded in 96-well plates together with the tested compound. Cells were grown and treated in DMEM 10% FBS. Two-fold serial dilutions were performed. After 72 hours, cell viability was measured using a MTT assay.
  • these 23 compounds of the present invention have all a high cytotoxicity (i.e. I C50 from 0.05 to 5 pM) and thus exhibit an antitumor activity on HCT116 cells;
  • the compound of the example 4 has the highest cytotoxicity ;
  • the compound of the example 6 has a cytotoxicity (i.e. IC 50 0.100 ⁇ M) 100 times higher than the compound of the comparative example A (i.e. IC 50 10 pM).
  • the compound of the example 6 only differs from the compound of the comparative example A in that it includes a further alkynyl group ;
  • the compound of the example 7 has a cytotoxicity (i.e. IC 50 0.400 pM) 125 times higher than the compound of the comparative example B (i.e. IC 50 50 pM).
  • the compound of the example 7 only differs from the compound of the comparative example B in that it includes a further alkynyl group.
  • Wild-type human HAP1 cells or HAP1 DACRWA4 (HSD17B11 carrying the S172L mutation) were seeded in 96-well plates (3500 cells/well) 24 hours before being treated for 72 hours with the tested compounds.
  • IC 50 were computed from at least three independent experiments using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve (log[inhibitor] vs response; variable slope).
  • these 3 compounds of the present invention have all a high cytotoxicity (i.e. ICso from 0.85 to 0.187 pM) and thus exhibit an antitumor activity on HAP1 WT cells ;
  • the compound of the example 4 has the highest cytotoxicity ;
  • Wild-type human osteosarcoma cells U2OS or U2OS inactivated for HSD17B11 using CRISPR/Cas9 (clone #B3) were seeded in 96-well plates (1500 cells/well) 24 hours before being treated for 72 hours with the tested compounds.
  • IC 50 were computed from at least three independent experiments using the GraphPad Prism software using a nonlinear regression to a four-parameter logistic curve (log[inhibitor] vs response; variable slope).
  • these 9 compounds of the present invention have all a high cytotoxicity (i.e. IC 50 from 0.040 to 1.552 pM) and thus exhibit an antitumor activity on U2OS cells ;
  • the compound of the example 4 has the highest cytotoxicity ;
  • IC 50 were computed from at least three independent experiments using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve [log[inhibitor] vs response; variable slope). Note that in complemented U2OS, HSD17B11 is overexpressed as compared to U2OS WT, explaining the lower (+)-PAC IC 50 in these cells.
  • the cytotoxicity of these 2 compounds of the present invention is much lower in U2OS cells inactivated for HSD17B11 and complemented with a control plasmid or a plasmid expressing the catalytically inactive S172L HSD17B11 mutant as compared to U2OS cells inactivated for HSD17B11 and complemented with the wild-type HSD17B11 enzyme.
  • SCLC Small Cell Lung Carcinoma
  • control cells were seeded in 96-well plates 24 hours before being treated for 72 hours with the compound of the example 4.
  • the plate was cooled down to room temperature and the CellTiterGlo® reagent (CTG, Promega) was added to each well and homogenized by pipetting. 100 pL of lysate was transferred to black plates and after a 15 minutes incubation at room temperature the luminescence was measured on a FLX800 plate reader. For normalization, the background value was subtracted to each value, the duplicates averaged and the value for the untreated condition set to 100% cell viability.
  • CCG CellTiterGlo® reagent
  • IC 50 were computed using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve ( log[i nhibitor] vs response; variable slope).
  • the compound of the example 4 exhibits high cytotoxicity for different lung cancer cell lines.
  • SCLC Small Cell Lung Carcinoma
  • HSD17B11 using CRISPR/Cas9 (KO HSD17B11 clone #1 and clone #6) were seeded in 96- well plates (2000 cells/well) 24 hours before being treated for 72 hours with the indicated molecules.
  • Cells were grown and treated in RPMI164010% FBS.
  • DMSO was at 0.5% final concentration in each well, including in the untreated conditions.
  • the plate was cooled down to room-temperature and the CellTiterGlo® reagent (Promega) was added to each well and homogenized by pipetting.
  • IC 50 were computed from at least three independent experiments using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve (log[i nhibitor] vs response; variable slope).
  • the compound of the example 4 exhibits high cytotoxicity for NCI-H446 SCLC cells ;
  • I C 50 were computed from at least three independent experiments using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve (log[in hibitor] vs response; variable slope).
  • the compound of the example 4 has a high cytotoxicity and thus exhibits an antitumor activity on neuroblastoma cell lines.
  • HSD17B13 (aka SCDR9 or SDR16C3) is the closest human homologue of HSD17B11 (63.3 % of sequence identity between them). Considering the high degree of sequence identity between HSD17B11 and HSD17B13, the selectivity for bioactivation by HSD17B11 over HSD17B13 was tested for a set of compounds of the invention.
  • IC50 were computed from at least three independent experiments using the GraphPad Prism software using a non- linear regression to a four-parameter logistic curve (log[inhibitor] vs response; variable slope).
  • HSD17B13 can bioactivate some of the compounds described, albeit less efficiently than HSD17B11. These data also support that the specificity towards HSD17B11 versus HSD17B13 can be modulated by subtle structural modifications. Compound of the example 14 shows the highest selectivity among the tested compounds.

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Abstract

La présente invention concerne des composés de formule (1), ou un sel physiologiquement tolérable associé, dans laquelle R représente un alcynyle en C2, un alcényle en C2, un allényle en C3 ou un groupe alkyle en C1-C6, Ar est choisi dans le groupe constitué par aryle et hétéroaryle. Les composés de formule (1) sont des composés pharmacologiquement actifs. Ils présentent une cytotoxicité élevée contre les cellules cancéreuses.
PCT/EP2022/075358 2021-09-13 2022-09-13 Alcynylcarbinols à cytotoxicité élevée WO2023036995A1 (fr)

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WO2021040333A1 (fr) * 2019-08-23 2021-03-04 고려대학교 세종산학협력단 Composition pour prévenir ou traiter une maladie infectieuse bactérienne comprenant un composé dérivé de 4-gingérol en tant que principe actif

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