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WO2022040788A1 - Dérivés de lactone et à cycle ouvert d'acides gras en c-18 trihydroxy insaturés et compositions pharmaceutiques de ceux-ci ayant une activité anticancéreuse - Google Patents

Dérivés de lactone et à cycle ouvert d'acides gras en c-18 trihydroxy insaturés et compositions pharmaceutiques de ceux-ci ayant une activité anticancéreuse Download PDF

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Publication number
WO2022040788A1
WO2022040788A1 PCT/CA2021/051168 CA2021051168W WO2022040788A1 WO 2022040788 A1 WO2022040788 A1 WO 2022040788A1 CA 2021051168 W CA2021051168 W CA 2021051168W WO 2022040788 A1 WO2022040788 A1 WO 2022040788A1
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Prior art keywords
compound
pgi
protecting group
cancer
composition
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Inventor
Judith BOBBITT
Ahmed ZEIN
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Oceans Ltd
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Oceans Ltd
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Priority claimed from CA3102497A external-priority patent/CA3102497A1/fr
Application filed by Oceans Ltd filed Critical Oceans Ltd
Publication of WO2022040788A1 publication Critical patent/WO2022040788A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/14—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by free hydroxyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/20—Free hydroxyl or mercaptan
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom
    • 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
    • C07D407/06—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 only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl

Definitions

  • the present invention relates to an open ring fatty acid compound, which is a metabolite of a lactone-comprising parent compound originally extracted from seaweeds, a method of preparation thereof and the use of the open ring fatty acid compound as an anti -cancer, chemotherapeutic, and/or antiproliferative agent.
  • Cancer remains one of the most common causes of mortality worldwide. Despite recent advances in cancer treatments, chemotherapy remains among the most effective approaches for cancer management and there remains a need for the discovery of novel anti -cancer compounds.
  • composition e.g., a chemotherapy, anti-cancer, or an antiproliferative composition
  • a composition comprising, as an active ingredient, a compound having the structure of formula (Io) or a pharmaceutically acceptable salt thereof, or a prodrug thereof lacking a lactone group; and a pharamceutically acceptable excipient.
  • compound (B) an open-ring fatty acid compound thereof [compound (J)], or a composition (e.g., a chemotherapy, anti -cancer, or an antiproliferative composition) comprising compound (B), as an active ingredient for the manufacture of a medicament for the treatment of cancer or for the treatment of cancer.
  • a composition e.g., a chemotherapy, anti -cancer, or an antiproliferative composition
  • described herein is a use of a compound having the structure of formula (Io), (I), or (J), or a salt thereof, or a prodrug thereof lacking a lactone group, as an active ingredient for the manufacture of a medicament.
  • a method for treating cancer in a subject comprising: (a) providing the chemotherapy, anti -cancer, or antiproliferative composition as defined herein; and (b) administering the anti -cancer composition to the subject at a dose sufficient to exert an anti -cancer activity in the subject.
  • Fig. 1 shows the liquid chromatography (LC) and mass spectrometry (MS) analysis of the parent and metabolite compounds from primary hepatocyte digestion of the parent compound (10 pM) for 2 hours.
  • Fig. 1A shows the total LC analysis for the parent compound (4.45 minute peak) at 0 minutes, and the appearance of metabolite 1 (3.44 minute peak) at 120 minutes post-digestion with primary hepatocytes, compared to a standard (10 pM; parent compound) and a negative (blank; drug -free hepatocyte culture at 120 minutes) control.
  • Fig. IB shows the extracted LC at m/z 335.218 (parent compound, [M+Na]) in all samples.
  • Fig. 1 shows the liquid chromatography (LC) and mass spectrometry (MS) analysis of the parent and metabolite compounds from primary hepatocyte digestion of the parent compound (10 pM) for 2 hours.
  • Fig. 1A shows the total LC analysis for the parent
  • FIG. 1C shows the MS/MS spectrum analysis of the 4.45 minute peak (parent compound).
  • Fig. ID shows the extracted LC at m/z 353.229 (3.44 minute peak; metabolite 1) at 120 minutes post primary hepatocyte digestion.
  • Fig. IE shows the MS/MS spectrum analysis of the 3.44 minute peak (m/z 353.23; [M+Na]; metabolite).
  • Fig. 2 and 3 show the structures of parent compound and metabolite 1 thereof, respectively.
  • Fig. 4 shows mouse pharmacokinetic profiles of parent compound (Fig. 4A) and of metabolite 1 (Fig. 4B).
  • Fig. 5 shows in vivo effect of administration of the parent compound on MDA-MB-231 tumour volume (mm 3 ).
  • Fig. 6 shows synthesis of [ 13 C2]-trans-2-Octen-ol C13-2: (a) DBU, LiCl, CH 3 CN (b) DIBAL-H, THF, -78°C.
  • Fig. 7A shows synthesis of [ 13 C2] -aldehyde 6: (a)Ti(O-iPr)4, TBHP, (+)-DIPT, CH2CI2, -20 °C (b) 0.5M NaOH, 1,4-dioxane, reflux (c) TBSC1, imidazole, DMF, 0°C (d) (OMe)2C(Me)2, p-TsOHH 2 O, CH2CI2, rt (e) TBAF, THF, 0 °C to rt (f) C1COCOC1, DMSO, NEt 3 , CH 2 C1 2 , -70°C.
  • FIG. 7B shows compounds 8 -12: (a) DBU, LiCl, CH 3 CN (b) (R)-CBS Reagent, BH 3 THF, THF (c) LiOHH 2 O, MeOH (d) 2,4,6-trichlorobenzoyl chloride, NEt 3 , THF, then DMAP, toluene, reflux 4 h (e) p-TsOHH 2 O (cat.), MeOH.
  • Fig. 7C shows steps c-e for preparing compound 12-1 and 12-2, from compound 8.
  • Fig. 8A shows 'H-NMR
  • Fig. 8B 13 C-NMR (700 MHz)
  • Fig. 8C MS spectra analysis of compound C13-1 of the reaction scheme of Fig. 6.
  • Fig. 9A shows 'H-NMR
  • Fig. 9B 13 C-NMR (700 MHz)
  • Fig. 9C MS spectra analysis of compound C13-2 of the reaction scheme of Fig. 6.
  • Fig. 10A shows ’H-NMR
  • Fig. 10B MS spectra analysis of compound 1 from the reaction scheme of Fig. 7A.
  • Fig. 11A shows ’H-NMR
  • Fig. 11B MS spectra analysis of compound 2 from the reaction scheme of Fig. 7A.
  • Fig 12A shows ’H-NMR
  • Fig. 12B MS spectra analysis of compound 3 from the reaction scheme of Fig. 7A.
  • Fig. 13A shows ’H-NMR
  • Fig. 13B MS spectra analysis of compound 4 from the reaction scheme of Fig. 7A.
  • Fig. 14A shows ’H-NMR
  • Fig. 14B MS spectra analysis of compound 5 from the reaction scheme of Fig. 7A.
  • Fig. 15A shows ’H-NMR
  • Fig. 15B MS spectra analysis of compound 6 from the reaction scheme of Fig. 7A and 7B.
  • Fig. 16 shows 'H-NMR of compound 7 from the reaction scheme of Fig. 7B.
  • Fig. 17A shows ’H-NMR
  • Fig. 17B MS spectra analysis of compound 8 from the reaction scheme of Fig. 7B.
  • Fig. 18A shows ’H-NMR
  • Fig. 18B MS spectra analysis of compound 9 from the reaction scheme of Fig. 7B.
  • Fig. 19A shows ’H-NMR
  • Fig. 19B MS spectra analysis of compound 10 from the reaction scheme of Fig. 7B.
  • Fig. 20A shows ’H-NMR
  • Fig. 20B MS spectra analysis of compound 11 from the reaction scheme of Fig. 7B.
  • Fig. 21A shows ’H-NMR, Fig. 21B 13 C-NMR (700 MHz), and (C) MS spectra analysis of compound 12 from the reaction scheme of Fig. 7B.
  • Fig. 22A shows 'H-NMR
  • Fig. 22B 13 C-NMR (700 MHz) analysis of compound 9-1 from the reaction scheme of Fig. 7C.
  • Fig. 23 shows 'H-NMR analysis of compound 10-1 from the reaction scheme of Fig. 7C.
  • Fig. 24A shows 'H-NMR
  • Fig. 24B 13 C-NMR (700 MHz) analysis of compound 11-1 from the reaction scheme of Fig. 7C
  • Fig. 25A shows 'H-NMR
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, un-recited elements or method steps.
  • the terms “disease” and “disorder” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
  • subject or “patient” as used herein refers to an animal, preferably a mammal, and most preferably a human who is the object of treatment, observation, or experiment.
  • “Mammal” includes humans and both domestic animals such as laboratory animals and household pets, (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
  • the terms “pure” or “purified” indicate that a compound described herein may be substantially enriched with respect to the complex cellular milieu in which it naturally occurs, such as in a crude extract, or may be substantially enriched with respect to other stereoisomers of the same compound (e.g., stereoisomers that are naturally found in a crude seaweed extract).
  • compounds described herein may be produced in synthetic manner (chemically synthesized), distinct from the isolation or extraction from its natural milieu, while still having the same molecular structure. When the molecule is purified, the absolute level of purity is not critical and those skilled in the art can readily determine appropriate levels of purity according to the use to which the biomass is to be put.
  • the isolated molecule forms part of a composition (for example a more or less crude extract containing many other substances) or buffer system, which may for example contain other components.
  • the isolated molecule may be purified to essential homogeneity, for example as determined spectrophotometrically, by NMR or by chromatography (for example LC-MS).
  • the term “purified” means: at least 90%, for example, 90% or 91% or 92% or 93% or 94% or 95% or 96% or 97% or 98% or 99% or 99.5% or 99.6% or 99.8% or 99.9% or 100% pure.
  • the compound(s) or molecule(s) described herein can be formulated as pharmaceutical compositions by formulation with additives such as pharmaceutically acceptable excipients, pharmaceutically acceptable carriers, and pharmaceutically acceptable vehicles.
  • the term “pharmaceutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar unwanted reaction, such as gastric upset, dizziness and the like, when administered to human.
  • pharmaceutically acceptable means approved by regulatory agency of the federal or state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • excipient refers to a diluent or vehicle with which the compounds of the present invention may be administered.
  • Sterile water or aqueous saline solutions and aqueous dextrose and glycerol solutions may be employed as carrier, particularly for injectable solutions.
  • Suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E.W. Martin.
  • the compound(s)/molecule(s) described herein can be used in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to those salts of the compounds of the present description which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the present description, or separately by reacting a free base function of the compound with a suitable organic or inorganic acid (acid addition salts) or by reacting an acidic function of the compound with a suitable organic or inorganic base (base -addition salts).
  • salts include, but are not limited to, nontoxic acid addition salts, or salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2 -naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,
  • Representative base addition alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, or magnesium salts, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate and aryl sulfonate.
  • an open ring fatty acid of compound X is a compound that is an acyclic fatty acid, i.e. comprising a carboxylic acid moiety at an end of the aliphatic chain, wherein the acyclic fatty acid corresponds to a ring opened version of compound X.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • active ingredient refers to a compound or molecule that is active on its own to treat and/or prevent a disease or disorder, e.g., a cancer.
  • a disease or disorder e.g., a cancer.
  • inactive ingredients include additives, carriers, excipients, and adjuvants (including a vaccine adjuvant).
  • the active ingredient will be the compound leading to inhibition of cancer cell growth and/or cancer cell death.
  • a compound for use in inhibiting growth of cancer cells wherein the compound is an open ring fatty acid of compound (Ao) or a pharmaceutically acceptable salt thereof, or prodrug thereof.
  • the open ring fatty acid can be a compound of the following formula (Io)
  • each carbon atom bonded to a OH group can independently have a R or S configuration.
  • the compound for use in inhibiting growth of cancer cells can be an open ring fatty acid of compound or a pharmaceutically acceptable salt thereof.
  • Compound (A) is also known under the name 12R, 13S- Dihydroxy-10-Octadecen-9S-olide.
  • the open ring fatty acid can be the compound having the following formula (I)
  • the compound for use in inhibiting growth of cancer cells is the fatty acid of compound (B), or an active metabolite thereof,
  • Compound (B) is also known under the name 12R, 13S-Dihydroxy-10-Octadecen-9R-olide.
  • the compound for use in inhibiting growth of cancer cells can be an open ring fatty acid of compound (B)
  • the open ring fatty acid compounds described herein can be used in combination with one or more other therapeutic agent, which can for example include another anti-cancer agent.
  • a pharmaceutical composition e.g., a chemotherapy, anti-cancer, or antiproliferative composition
  • a pharmaceutical composition comprising, as an active ingredient, a compound having the structure of formula (Io), (I), or (J) or a pharmaceutically acceptable salt thereof, or a prodrug thereof (e.g., a prodrug lacking a lactone group); and a pharamceutically acceptable excipient.
  • Parent compounds (Ao), (A), and (B) possess lactone-groups, rendering them more difficult or complex to synthesize chemically.
  • the discovery herein that the principal metabolite thereof, such as the lactone-free structure of formula (Io), (I), or (J) facilitates chemical synthesis and opens the door to the design and synthesis of prodrugs that are converted to the compound of formula (Io) or (I) in vivo.
  • a pharmaceutical composition comprising compound (B) or an open ring fatty acid of compound (Ao), (A), or (B) as decribed above, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, as a first therapeutic ingredient and at least one second therapeutic ingredient selected from anti -cancer drugs.
  • the pharmaceutical composition can comprise the compound of formula (Io) or formula (I) as described above, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, as a first therapeutic ingredient and at least one second therapeutic ingredient selected from anti -cancer drugs.
  • the compositions described herein may also comprise at least one pharmaceutically acceptable excipient. In some embodiments, said excipient can be acceptable for oral or parenteral administration, for intravenous administration for instance.
  • compositions described herein are not immunomodulatory compositions or are not for use in stimulating or suppressing a subject’s immunity (e.g., mucosal immunity). In some embodiments, compositions described herein are not vaccines or does not comprise a vaccine antigen.
  • an injectable composition comprising an compound (B) or an open ring fatty acid of compound (Ao), (A), or (B) as decribed above, or a pharmaceutically acceptable salt thereof, or prodrug thereof, as a therapeutic agent and at least one excipient acceptable for parenteral administration.
  • the pharmaceutical composition can comprise the compound of formula (Io) or of formula (I) or (J) as described above, or a pharmaceutically acceptable salt thereof, or prodrug thereof, as a therapeutic agent and at least one excipient acceptable for parenteral administration.
  • the injectable composition is free from any antigen.
  • the excipient in the injectable composition is an excipient that is acceptable for intravenous administration.
  • the injectable composition can further comprise one or more other therapeutic agent such as a therapeutic agent that is an anti -cancer agent.
  • anyone of the above open ring fatty acid compounds, pharmaceutical composition and injectable composition can be used for inhibiting growth of cancer cells in a mammal.
  • the above open ring fatty acid compounds can be useful for the treatment or prevention of cancer in a mammal (e.g., a human), for instance for the treatment or prevention of brain, lung, prostate, blood, breast or ovarian cancer.
  • compositions described herein may further comprise or be used in chemotherapy treatment regimen comprising: 6-mercaptopurine, actinomycin, amsacrine, bleomycin, bortezomib, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, clarithromycin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, dexamethasone, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, G-CSF, gemcitabine, hydroxydaunorubicin, idarubicin, ifosfamide, irinotecan, lenalidomide, leucovorin, lomustine, mechlorethamine, melphalan, mesna, methotrexate, methylprednisolone, mitomycin, mit
  • the compositions described herein may comprise a compound as described herein in an amount sufficient to exhibit anti -cancer or anti -proliferative effects on a subject to be administered.
  • the compositions described herein may be used orally or parenterally.
  • the compositions can be formulated in liquid or solid dosage forms.
  • parenteral this can include subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • Other modes of administration also include intradermal or transdermal administration.
  • the compositions can be used for intravenous injection.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents,
  • Solid dosage forms for oral administration include can include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone (PVP), sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the present invention provides the use of compound (A) and/or (B) or an or an open ring fatty acid of compound (Ao), compound (A), or compound (B) as described above, or a pharmaceutically acceptable salt thereof, or prodrug thereof, for inhibiting growth of cancer cells.
  • compound (A) and/or (B) or an or an open ring fatty acid of compound (Ao), compound (A), or compound (B) as described above, or a pharmaceutically acceptable salt thereof, or prodrug thereof, for inhibiting growth of cancer cells for inhibiting growth of cancer cells.
  • an open ring fatty acid of formula (Io) or formula (I) or (J) as described herein, or a pharmaceutically acceptable salt thereof, for inhibiting growth of cancer cells.
  • the use of compound (B) or the open ring fatty acid of compound (Ao), compound (A), or of compound (B), or the use of the open ring fatty acid of formula (Io) or formula (I) or (J), can allow for inhibiting growth of cancer cells in a mammal.
  • the use can allow for the treatment or prevention of cancer in a mammal.
  • the mammal can be a human.
  • the use can involve an oral or parenteral administration, e.g. an intravenous administration.
  • the present invention provides the use of compound (A) and/or (B) or an open ring fatty acid of compound (Ao) or compound (A) as described above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing cancer in a mammal.
  • an open ring fatty acid of formula (Io) or formula (I) or (J) as described herein, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing cancer in a mammal.
  • the mammal can be a human.
  • the medicament can be prepared for oral or parenteral administration, e.g. for intravenous administration.
  • the present invention provides a method for treating or preventing cancer in a mammal comprising administering compound (A) and/or (B) or an open ring fatty acid of compound (Ao), compound (A), or compound (B), or a pharmaceutically acceptable salt thereof to the mammal.
  • a method for treating or preventing cancer in a mammal comprising administering an open ring fatty acid of formula (Io) or formula (I) or (J) or a pharmaceutically acceptable salt thereof to the mammal.
  • the mammal can be a human.
  • the method can involve administering the open ring fatty acid orally or parenterally, e.g. intravenously.
  • the cancer can be selected from the group consisting of: brain, lung, prostate, blood, breast and ovarian cancers.
  • the cancer is brain cancer.
  • the cancer is lung cancer.
  • the cancer is prostate cancer.
  • the cancer is leukemia (i.e., blood cancer).
  • the cancer is breast cancer.
  • the cancer is ovarian cancer.
  • the open ring fatty acid can be used or administered in combination with one or more other therapeutic agent.
  • the other therapeutic agent can be an anti -cancer agent as described above.
  • the compounds or compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of the disorders or diseases as contemplated herein.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Provided compounds are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.
  • the expression "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • compositions of this disclosure can be administered to humans and other animals orally or parenterally.
  • provided compounds may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • the present invention provides a process for the synthesis of compound (A), compound (B), and the open ring fatty acid of formula (I) or (J) as defined herein.
  • the synthetic process allows to prepare compounds having 12 C carbon atoms throughout the molecule, but also 13 C-labelled equivalents wherein two of the 12 C carbon atoms are replaced with their 13 C isotopes in the molecule.
  • the invention thus provides a process for preparing a compound of formula (I) or a 13 C-labelled equivalent thereof comprising the following steps.
  • a) of the process the following compound 6 where PGi is a divalent protecting group and the C 1 and C 2 carbon atoms are 12 C or their 13 C isotopes, is coupled with compound 7 to form compound 8
  • the protecting group PGi can be any protecting group known in the art to allow protecting the hydroxyl groups on the carbon atoms in alpha and beta position of the double bond of the enone moiety.
  • the protecting group PGi can be .
  • the coupling between compound 6 and 7 can be performed according to the Homer-Wadsworth-Emmons (HWE) reaction.
  • the reduction of compound 8 into compound 9 can be the Corey- Bakshi-Shibata (CBS) reduction.
  • the methyl ester group in compound 9 is hydrolyzed to form compound 10
  • the hydrolysis of the methyl ester group in compound 9 can be performed with LiOH.H 2 O.
  • other reactants known in the art can be used to carry out this hydrolysis step.
  • the compound of formula (I) or the 13 C-labelled equivalent at carbon C 1 and C 2 can be obtained by removing the protecting group PGi in compound 10.
  • the removal of the protecting group in compound 10 can be performed with p-TsOH.IrbO.
  • the starting compound 6 in the above described process for preparing the compound of formula (I), can be prepared by a process involving the following steps i) to vi).
  • the first step i) for preparing compound 6 can involve an epoxidation of the following compound into compound 1
  • step ii) the epoxide in compound 1 is opened to form compound 2
  • the next step iii) involves a reaction to protect the hydroxyl group on the carbon C 2 with a protecting group PG2 which is different than PGi, to form compound 3
  • the protecting group PG2 can be any known protecting group capable of masking the hydroxyl group on the carbon C 2 .
  • the protecting group PG2 can be tertbutyldimethylsilyl (TBS).
  • step v) the protecting group PG2 in compound 4 is removed in step v) to form the partially deprotected compound 5 with the hydroxyl on the C 2 carbon being freed for reacting in the next step vi).
  • step vi) the deprotected alcohol moiety in compound 5 is oxidized into a ketone to form compound 6 that can then be used in step a) of the process for preparing the compound of formula (I).
  • a process for preparing the compound (A) described herein or a 13 C-labelled equivalent thereof comprises steps a) to c) of the process for synthesizing the compound of formula (I) described above, followed by steps d’) and e) detailed below.
  • the process for preparing compound (A) or the 13 C-labelled equivalent thereof includes after steps a) to c), a step d’) wherein compound 10 described above is cyclized into the following compound 11
  • step e) the protecting group PGi in compound 11 is removed to form the compound of formula (II) wherein the C 1 and C 2 carbon atoms are 12 C or their 13 C isotopes.
  • the compound (A) corresponds to the compound 12 (i.e. compound 12-2) of formula (II) wherein the C 1 and C 2 carbon atoms are both the 12 C isotope.
  • the protecting group in compound 11 can be removed by reaction with p- TSOH.H 2 O.
  • a process for preparing the compound (B) described herein or a 13 C-labelled equivalent thereof comprises preparing compound 8, from compound 6 or by first preparing compound 6, as described above.
  • the protecting group PGi can be any protecting group known in the art to allow protecting the hydroxyl groups on the carbon atoms in alpha and beta position of the double bond of the enone moiety.
  • the protecting group PGi can be
  • the coupling between compound 6 and 7 can be performed according to the Homer-Wadsworth-Emmons (HWE) reaction.
  • the reduction of compound 8 into compound 9-1 can be the
  • the hydrolysis of the methyl ester group in compound 9 can be performed with LiOH.H2O.
  • other reactants known in the art can be used to carry out this hydrolysis step.
  • Compound 10-1 described above is cyclized into the following compound 11-1 Then, in the final step, the protecting group PGi in compound 11-1 is removed to form compound of formula (III).
  • the compound (B) corresponds to the compound 12-1 of formula (III) wherein the C 1 and C 2 carbon atoms are both the 12 C isotope.
  • the invention thus provides a process for preparing a compound of formula (J) or a 13 C-labelled equivalent thereof by removing the protecting group PGi in compound 10-1.
  • the removal of the protecting group in compound 10-1 can be performed with p-TsOH.ITO.
  • the present invention provides for several intermediate compounds that can be useful in the preparation of compound (A) and/or the open ring fatty acid compound of formula (I) described above.
  • the present invention also concerns at least one of the following intermediate compounds:
  • the present invention also concerns at least one of the following intermediate compounds:
  • the following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
  • Example 2 In silico pharmacokinetic profiles of parent compound and metabolite 1
  • BBB - model predicts whether or not a small molecule will likely traverse the complex filtering mechanism of the capillaries that carry blood to the brain and spinal cord tissue.
  • Caco2 - model for Intestinal Absorption that predicts if query ligands will be permeable in a Caco- 2 cell monolayer experiment.
  • HIA - model for Human Intestinal Absorption that predicts whether a query ligand will likely be absorbed from the gut into to bloodstream.
  • HOB - binary classifier of Human Oral Bioavailability that predicts in an orally administered drug is absorbed and reaches systemic circulation
  • CYP - cytochrome P450 enzymes are essential for the metabolism of many medications. Model predicts for the three most important whether the ligand will likely inhibit CYP activity (important consideration for drug-contraindications, efficacy, and overall drug safety) or be a substrate and metabolised by the enzyme (important consideration for drug half-life, efficacy, and overall drug safety)
  • AMES - model that assesses the mutagenic potential of chemical compounds. Query predicts the likelihood that a ligand will test positive for being mutagenic in an Ames test.
  • Carcinogenic potency - metric used to quantify the cancer risk associated with exposure to a given chemical
  • LogS - the aqueous solubility, logS, of organic molecules plays a large role in the expected ADME properties.
  • a conventional definition for a soluble substance is one that dissolves in water at a concentration greater than Ig/L; thus, an organic substance with a molecular weight of 316.2 Da will be considered soluble if its logS is greater than -2.5.
  • Example 3 In vivo pharmacokinetic profiles of parent compound and metabolite 1
  • mice Male CD-I mice (25-30 g) (Charles River Laboratories; Massachusetts, USA) were acclimatized for a minimum of 5 days prior to dosing. Body weights were recorded on the day of dosing. Animals dosed p.o. (orally) were deprived of food overnight and fed 2 h following dosing. Animals were observed at the time of dosing and each sample collection and any abnormalities were documented.
  • Formulations were administered intravenously (i.v.) via the tail vein, orally (p.o.) via gavage using disposable feeding needles, or intraperitoneally (i.p.) into the lower right quadrant of the abdomen. Terminal blood samples were then collected under isoflurane anesthesia by cardiac puncture. All blood samples were transferred into K2EDTA tubes on wet ice and centrifuged within 5 min (3200 x g for 5 min at 4°C) to obtain plasma. Plasma samples were analyzed, and any remaining samples were stored frozen at -80°C.
  • At least 75% of non-zero STDs must be included in the calibration curve with all back-calculated concentrations within ⁇ 20% deviation from nominal concentrations ( ⁇ 25% for the lower level of quantification, LLOQ).
  • the correlation coefficient (r) of the calibration curve must be greater than or equal to 0.99.
  • the area ratio variation between the pre- and postrun injections of the system suitability samples was within ⁇ 25%.
  • Pharmacokinetic data analysis was done using PhoenixTM WinNonlinsTM 8.0 (Pharsight, Certera, Mountainview, CA) by non-compartmental analysis, linear up/log down trapezoidal rule.
  • the parent compound was administered acutely to mice by IV, IP, and PO, and the pharmacokinetics of the parent compound and metabolite 1 were determined.
  • the IV, IP and PO doses were 2, 10 and 10 mg/kg respectively.
  • the parent compound and metabolite 1 levels in the plasma for the first 4 hours following compound administration are shown in Fig. 4A and 4B for the parent and metabolite compounds, respectively.
  • the disappearance of the parent compound from the plasma was very rapid for all routes of administration, with very little of the parent compound detected in mice dosed orally (PO). This suggests rapid metabolism of the parent compound by all routes of administration with enhanced metabolism in the gastrointestinal compartment. The majority of this metabolism was to metabolite 1 that was identified in human hepatocyte studies (Example 1) and monitored in this study.
  • metabolite 1 As standards for the metabolite was not available, the plasma concentrations of metabolite 1 were not quantitative, and the plasma concentrations of the parent compound cannot be directly compared to the peak areas of metabolite 1. The rapid appearance of metabolite 1 in the plasma of orally treated animals suggests that at least some of the administered parent compound may be converted to metabolite 1 in the gastrointestinal tract.
  • the calculated pharmacokinetic parameters upon administration of the parent compound are summarized in the Table 3. Given the low level of absorption of the parent compound by the oral route (Fig. 4A), several parameters for the PO route were either not applicable or not calculable. Clearance of the parent compound for the IP and IV routes were nearly identical at a rapid 0.2 h. Since an IV dose was used, the bioavailability (F%) of the IP route can be determined and, after adjusting for the differences in dose, was determined to be 102%, which indicates complete absorption by IP administration. The peak plasma levels by IP administration were at 15 min (0.25 h).
  • AUCo-tiast area under the concentration vs time curve from time 0 to the time of the last measurable concentration
  • Vss steady-state volume of distribution
  • Example 4 In vivo anti-cancer activity
  • mice were sacrificed, and tumours excised from each flank were weighed.
  • tumour metastasis an explorative necropsy was conducted in each mouse and the presence of additional tumours at sites distal to the flank were assessed.
  • Test groups were as follows: Table 3: Treatment groups of in vivo MDA-MB-231 tumour model
  • Table 4 Summary of animal weights (g) for MDA-MB-231 tumor model
  • tumour volumes were reduced by approximately from week 2 onwards, strongly suggesting anti-cancer activity.
  • Table 5 Summary of tumour volumes (mm 3 ) for MDA-MB-231 tumour model
  • Table 6 Summary of tumour volume (mm 3 ) changes for MDA-MB-231 tumour model
  • Example 4 suggest that the parent compound was rapidly converted to metabolite 1 upon administration to the mice and that circulating metabolite 1 may be responsible for the observed anti -cancer activity.
  • Triethyl phosphonoacetate- 13 C2 was purchased from Santa Cruz Biotechnology Inc. (SC-258290, Dallas, USA). All other reagents and anhydrous solvents were purchased from Sigma-Aldrich (Oakville, Canada).
  • the ’H NMR spectra were measured on a Bruker 500 MHz and the 13 C NMR spectra were measured on a Bruker 700 MHz or 800 MHz spectrometer, respectively.
  • Enantiomeric excess (ee) values were acquired using an analytical HPLC (Waters MilleniumTM System 4.0) with a chiral OJ-H column (250 x 4.6mm x 5pm) and PDA-detector (230 nm channel extracted).
  • Thin layer chromatography was performed on glass-backed silica gel 60 A F254 pre-coated plates and visualized by UV lamp or KMnO4 stain.
  • MS analysis was performed with a Bruker MicroTOF-QTM mass analyzer using electrospray ionization in positive or negative mode. Samples were directly infused to the MS instrument with a syringe pump. The scan range was m/z 80-1500. The capillary voltage was set to 4000 V, the nebulizer gas was at 0.4 bar, and the dry gas was 180°C at a flow rate of 4L/min.
  • the MS was calibrated using a sodium formate calibrant. In addition, all data files were recalibrated with an internal standard of sodium formate injected prior to the infusion of each sample.
  • Fig. 6- step a An oven dried 250 mL round bottom flask, equipped with a magnetic stirrer was charged LiCl (0.8 g, 18.9 mmol) in 116 mL of anhydrous acetonitrile. The solution was stirred at room temperature for 5 minutes and [ 13 C2] -triethyl phosphonoacetate (3.89 g, 17.2 mmol) in 77.0 mL acetonitrile was added to the flask.
  • Fig. 6- step b A flame dried 250 mL 3 -neck round bottom flask equipped with a magnetic stirrer and temperature probe was charged [ 13 C2]-ethyl-E-2-octenoate (compound C13-1, 2.6 g, 15.3 mmol) in anhydrous THF (50 mL). The resulting solution was cooled down to -78°C and DIBAL-H (Diisobutylaluminium hydride) (46.0 mL, 46.0 mmol, 3 equivalents) was added dropwise over 20 min. The reaction mixture was stirred at -78 °C for 1 h, then warmed up to -10°C and stirred for an additional hour.
  • DIBAL-H Diisobutylaluminium hydride
  • Fig. 7A- step a An oven dried 500 mL three-necked round-bottomed flask under argon and equipped with a magnetic stir bar was charged with 210 mL of dry dichloromethane (CH2CI2). The flask was cooled to -20 °C, and (+) -diisopropyl L-tartrate (1.36 mL, 6.4 mmol, 0.24 eq) and titanium isoproxide (1.59 mL, 5.4 mmol, 0.2 eq) were added sequentially with stirring.
  • Tert-butyl hydroperoxide solution (TBHP) 5.5 M, 9.78 mL, 53.8 mmol
  • Fig. 7A- step b An oven dried 500 mL round-bottomed flask equipped with a magnetic stir bar was charged with compound 1 (2.7 g, 18.7 mmol) and 94 mL of dry dioxane. 94 mL of 0.5 M NaOH (66.6 mmol, 2.5 eq.) was added to the flask at room temperature and the mixture was stirred under reflux for 3.5 hours. The reaction was cooled to room temperature and extracted with 250 mL of ethyl acetate. The organic layer was separated and the aqueous layer was extracted four additional times with ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated to yield 5.94 grams of crude material.
  • Fig. 7A- step c compound 2 (1.76 g, 11 mmol) was dissolved in dry DMF (20 mL) under argon at room temperature and imidazole (1.85 g, 27 mmol, 2.5 eq) was added to the solution. The solution was cooled to 0 °C and TBS-C1 (1.82 g, 12 mmol) was added. The reaction mixture was stirred at 0 °C for 2h and followed by TLC. When the reaction was complete, it was quenched with 20 mL saturated NILCl solution and extracted three times with ethyl acetate. The organic layers were combined, washed three times to remove residual DMF, dried with sodium sulfate and concentrated.
  • Fig. 7A- step d Compound 3 (2.5 g, 9.0 mmol) was dissolved in dry CH2CI2 (225 mL) under argon and p-TsOH monohydrate (0.06 g, 0.32 mmol, 0.035 eq) and 2,2-dimethoxypropane (3.3 g, 3.9 mL, 31.7 mmol, 3.5 eq) were added sequentially. The reaction was stirred for 4h at room temperature, then quenched with 250 mL of saturated NaHCOs. After stirring for 15 mins, the solution was extracted with 2 x 250 mL of CH2CI2. The organic layers were combined and washed with 1 volume of brine, dried with sodium sulfate, and concentrated.
  • Fig. 7A- step e Compound 4 (2.44 g, 7.7 mmol) was dissolved in dry THF (150 mL) under argon and the solution was cooled to 0 °C. TBAF (IM, 11 .6 mL, 11.6 mmol) was added and the reaction was allowed to warm to room temperature, then quenched after 2.5 h of stirring with 350 mL H2O. After stirring for 15 mins, the solution was extracted with 2 x 500 mL of EtOAc. The organic layers were combined and washed with I volume of brine, dried with sodium sulfate, and concentrated.
  • TBAF IM, 11 .6 mL, 11.6 mmol
  • Fig. 7A- step f Oxalyl chloride (1.4 g, 0.94 mL, 11.1 mmol, 1.5 eq) was dissolved in 26 mL of dry CH2Q2, and the flask was cooled to -70 °C. DMSO (1.2 mL, 16.3 mmol, 2.2 eq) was dissolved in 3.8 mL of dry CH2Q2 and added to the flask. The mixture was stirred for 2 mins. Then, compound 5 (1.5 g, 7.4 mmol) was dissolved in 7.5 mL of dry CH2CI2 and added dropwise to the flask.
  • Synthesis of phosphonate compound 7 A 3-neck 500 mL round bottom flask equipped with magnetic stirrer was charged dimethyl methyl phosphonate (19.71 g, 158.8 mmol, 1.4 equiv.) in THF (171 mL). The resulting solution was cooled down to -78 °C and n-BuLi (65 mL of 2.5 M solution in hexane, 162.5 mmol, 1.4 equiv.) was added dropwise over 10 mins. In a IL 1-neck round bottom flask equipped with a magnetic stirrer was charged azelaic acid dimethylester (24.64 g, 113.3 mmol) in 392 mL of THF.
  • the resulting solution was cooled down to -5 °C. Then the phosphonate/nBuLi solution was transferred to the azelate solution dropwise using a canula over 1.5 hours. The reaction mixture was stirred at -5°C for Ih, then at room temperature for another hour, then quenched with saturated NH4CI. The layers were separated and the aqueous was extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried with sodium sulfate, and concentrated.
  • Fig. 7B- step a LiCl (0.349 g, 8.99 mmol, 1.1 eq) was dissolved in 76 mb of anhydrous acetonitrile. The solution was stirred under argon for 5 mins at room temperature. Then, compound 7 (2.5 g, 8.99 mmol, 1.1 eq) was dissolved in 50 mb of acetonitrile and added to the flask. DBU (1.25 g, 1.2 mb, 7.5 mmol) was added to the stirring solution, followed by a solution of compound 6 (1.5 g, 7.5 mmol) in 25 mb of acetonitrile.
  • Fig. 7B- step b To a stirring solution of compound 8 (1.9 g, 5.0 mmol) in 40 mb of dry THF under argon was added (R)-CBS reagent (500 ph of 1 M in toluene, 0.50 mmol). The mixture was cooled to -20 °C and BH3.THF (5.0 mb of 1 M in THF, 5.0 mmol) was added dropwise. After stirring for 1 h, the reaction was quenched with methanol and the solvent was evaporated.
  • R R-CBS reagent
  • Fig. 7B- step c To a solution of compound 9 (1.1 g, 2.9 mmol) in methanol (74 mb) was added EiOHH2O (2.7 g, 64 mmol) and the reaction was stirred for 48 h at room temperature. The reaction mixture was slowly acidified to pH 4.5 with 3M HC1 (15 mb) and extracted twice with 150 mb of ethyl acetate. The aqueous layer still contained product and was acidified to pH 1 and extracted twice with 150 mb of ethyl acetate.
  • Fig. 7B- step d This step was carried out in two batches as follows: Triethylamine (0.8 g, 1.11 mb, 7.9 mmol) and 2,4,6-trichlorobenzoyl chloride (1.6 g, 1.0 mb, 6.6 mmol) were added to a stirring solution of compound 10 (0.5 g, 1.35 mmol) in dry THF (16 mb). After 1 hour of stirring, the mixture was diluted with 100 mb of dry toluene and added dropwise over 4 h to a refluxing solution of DMAP (3.88 g, 31.7 mmol) in dry toluene (1000 mL).
  • Fig. 7B- step e To compound 11 (0.53g, 1.5 mmol) was added 165 mL of a 1.0 mg/mL (5.25 mM) stock solution of p-TsOH.EEO in MeOH (equivalent to 0.87 mmol p-TsOH.EEO in the reaction). The reaction was stirred at 0°C for 18 h. The reaction was diluted with 200 mL of CH2CI2, washed with 1 equivalent of NaHCCf and brine, dried with sodium sulfate, and concentrated to yield 0.46 g of a pale yellow oil.
  • Fig. 7C-steps c-e Asymmetric reduction of compound 8 in step b with the (R)-CBS reagent and borane-THF complex can result in two isomers (9-1 and 9-2 [i.e. compound 9]) that could be separated by silica gel column chromatography. After separation of isomers 9-1 and 9-2, isomers 12-1 and 12-2 (i.e. compound 12) were prepared by carrying out the same steps as steps c-e in Fig. 7B. Compounds 9-1, 10-1, and 11-1 are characterized in Figs. 22-24, respectively. Compound 12-1 ([ 13 C2]-12R,13S- Dihydroxy-10-Octadecen-9R-olide; 13 C-labelled compound (B)) is characterized in Fig. 25.
  • the compound of formula (I) ( 13 C-labelled or compound with 12 C isotopes depending on the starting material used) can be synthesized using the reaction schemes described in section C above, up to step (c) in Fig. 7B, which leads to compound 10. Then, the protecting group can be removed from compound 10 in the presence of p-TsOH.H 2 O, similarly to step (e) in Fig. 7B, to form the compound of formula (I).
  • the compound of formula (J) ( 13 C-labelled or compound with 12 C isotopes depending on the starting material used) can be synthesized using the reaction schemes described in section C above, up to step (c) in Fig. 7C, which leads to compound 10-1. Then, the protecting group can be removed from compound 10-1 in the presence of p-TsOH.lEO. similarly to step (e) in Fig. 7C, to form the compound of formula (J).
  • Compound (B) was tested in tumour cell lines and found to exhibit broad spectrum antiproliferative activity (Table 8).

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Abstract

L'invention concerne des compositions anticancéreuses, chimiothérapeutiques ou antiprolifératives comprenant, comme principe actif, un composé de formule (I0), ou un sel, ou un promédicament de celui-ci : et un composé anticancéreux, chimiothérapeutique ou antiprolifératif (A) ou (B), ou un sel de celui-ci, ou une composition comprenant le composé (A) ou (B), ou un sel de celui-ci, comme principe actif :
PCT/CA2021/051168 2020-08-24 2021-08-23 Dérivés de lactone et à cycle ouvert d'acides gras en c-18 trihydroxy insaturés et compositions pharmaceutiques de ceux-ci ayant une activité anticancéreuse Ceased WO2022040788A1 (fr)

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SAMRA REHAM M., AMAL F. SOLIMAN, AHMED A. ZAKI, AHMED ASHOUR, AHMED A. AL-KARMALAWY, MADIHA A. HASSAN, AHMED M. ZAGHLOUL: "Bioassay-guided isolation of a new cytotoxic ceramide from Cyperus rotundus L", SOUTH AFRICAN JOURNAL OF BOTANY, vol. 139, 10 March 2021 (2021-03-10), pages 210 - 216, XP055909289, DOI: 10.1016/j.sajb.2021.02.007 *
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