WO2022040788A1 - Open-ring and lactone derivatives of unsaturated trihydroxy c-18 fatty acids and pharmaceutical compositions thereof having anti-cancer activity - Google Patents
Open-ring and lactone derivatives of unsaturated trihydroxy c-18 fatty acids and pharmaceutical compositions thereof having anti-cancer activity Download PDFInfo
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- 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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- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
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- 150000007530 organic bases Chemical class 0.000 description 1
- 208000013371 ovarian adenocarcinoma Diseases 0.000 description 1
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229940046159 pegylated liposomal doxorubicin Drugs 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 229960002087 pertuzumab Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
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- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
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- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical compound OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
Classifications
-
- 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
Anti -cancer, chemotherapeutic, or antiproliferative compositions comprising, as an active ingredient, a compound of formula (I0), or a salt, or prodrug thereof: and an anti-cancer, chemotherapeutic, or antiproliferative compound (A) or (B), or salt thereof, or composition comprising compound (A) or (B), or salt thereof, as an active ingredient:
Description
OPEN-RING AND LACTONE DERIVATIVES OF UNSATURATED TRIHYDROXY
C-18 FATTY ACIDS AND PHARMACEUTICAL COMPOSITIONS THEREOF HAVING ANTI-CANCER ACTIVITY
FIELD
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.
BACKGROUND
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.
SUMMARY
In a first aspect, described herein is a composition (e.g., a chemotherapy, anti-cancer, or an antiproliferative 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.
In a further aspect, described herein is a compound having the structure of formula (Io) or (I),
or a salt thereof, or a prodrug thereof lacking a lactone group, for use as an active ingredient in a medicament.
In a further aspect, described herein is a use of 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.
In a further aspect, 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.
In a further aspect, described herein is a method for treating cancer in a subject, the method 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.
In a further aspect, described herein is a process for preparing a compound of formula (I) or a relabelled equivalent thereof, the process comprising the following steps:
(d) removal of the protecting group PGi in compound 10 to form the compound of formula (I)
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes.
In a further aspect, described herein is a process for preparing the compound of formula (A)
comprising steps (a) to (c) of the process as defined herein, followed by
(e) removal of the protecting group PGi in compound 11 to form the compound of formula (II) wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes.
In a further aspect, described herein is an intermediate which is:
(a) compound 8
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(b) compound 9
wherein the C1 and C2 carbon atoms are 12C ortheir 13C isotopes and PGi is a protecting group;
(c) compound 10
wherein the C1 and C2 carbon atoms are 12C ortheir 13C isotopes and PGi is a protecting group;
(d) compound 11
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group; (e) compound 6
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(f) compound 5
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(g) compound 4
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(i) compound 3
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PG2 is a protecting group;
(j) the intermediate of any one of (g) to (i), wherein PG2 is tert-butyldimethylsilyl (TBS);
In a further aspect, described herein is a process for preparing compound (B), or a 13C-labelled equivalent thereof,
the process comprising the following steps:
(d) cyclization of compound 10-1 into compound 11-1
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes; and
(e) removal of the protecting group PGi in compound 11-1 to form the compound of claim 34, wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes.
In a further aspect, described herein is an intermediate which is:
(a) compound 9-1
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(b) compound 10-1
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group; or
(c) compound 11-1
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group.
In a further aspect, described herein is a process for preparing a compound of formula (J) or a Relabelled equivalent thereof, the process comprising the following steps:
(d) removal of the protecting group PGi in compound 10-1 to form the compound of formula (I)
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes.
BRIEF DESCRIPTION OF THE DRAWINGS
In the appended drawings:
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. 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 (mm3).
Fig. 6 shows synthesis of [13C2]-trans-2-Octen-ol C13-2: (a) DBU, LiCl, CH3CN (b) DIBAL-H, THF, -78°C.
Fig. 7A shows synthesis of [13C2] -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-TsOHH2O, CH2CI2, rt (e) TBAF, THF, 0 °C to rt (f) C1COCOC1, DMSO, NEt3, CH2C12, -70°C. Fig. 7B shows compounds 8 -12: (a) DBU, LiCl, CH3CN (b) (R)-CBS Reagent, BH3 THF, THF (c) LiOHH2O, MeOH (d) 2,4,6-trichlorobenzoyl chloride, NEt3, THF, then DMAP, toluene, reflux 4 h (e) p-TsOHH2O (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 13C-NMR (700 MHz), and Fig. 8C MS spectra analysis of compound C13-1 of the reaction scheme of Fig. 6.
Fig. 9A shows 'H-NMR, Fig. 9B 13C-NMR (700 MHz), and Fig. 9C MS spectra analysis of compound C13-2 of the reaction scheme of Fig. 6.
Fig. 10A shows ’H-NMR, and Fig. 10B MS spectra analysis of compound 1 from the reaction scheme of Fig. 7A.
Fig. 11A shows ’H-NMR, and Fig. 11B MS spectra analysis of compound 2 from the reaction scheme of Fig. 7A.
Fig 12A shows ’H-NMR, and Fig. 12B MS spectra analysis of compound 3 from the reaction scheme of Fig. 7A.
Fig. 13A shows ’H-NMR, and Fig. 13B MS spectra analysis of compound 4 from the reaction scheme of Fig. 7A.
Fig. 14A shows ’H-NMR, and Fig. 14B MS spectra analysis of compound 5 from the reaction scheme of Fig. 7A.
Fig. 15A shows ’H-NMR, and 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, and Fig. 17B MS spectra analysis of compound 8 from the reaction scheme of Fig. 7B.
Fig. 18A shows ’H-NMR, and Fig. 18B MS spectra analysis of compound 9 from the reaction scheme of Fig. 7B.
Fig. 19A shows ’H-NMR, and Fig. 19B MS spectra analysis of compound 10 from the reaction scheme of Fig. 7B.
Fig. 20A shows ’H-NMR, and Fig. 20B MS spectra analysis of compound 11 from the reaction scheme of Fig. 7B.
Fig. 21A shows ’H-NMR, Fig. 21B 13C-NMR (700 MHz), and (C) MS spectra analysis of compound 12 from the reaction scheme of Fig. 7B.
Fig. 22A shows 'H-NMR, and Fig. 22B 13C-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, and Fig. 24B 13C-NMR (700 MHz) analysis of compound 11-1 from the reaction scheme of Fig. 7C.Fig. 25A shows 'H-NMR, and Fig. 25B 13C-NMR (700 MHz) analysis of compound 12-1 from the reaction scheme of Fig. 7C.
DETAILED DESCRIPTION
Definitions
As used herein the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and
reference to “the culture” includes reference to one or more cultures and equivalents thereof known to those skilled in the art, and so forth. All technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs unless clearly indicated otherwise.
The term “about” or “approximately” or “around” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Where particular values are described in the application and claims, unless otherwise stated the term "about" meaning within an acceptable error range for the particular value should be assumed.
As used in this specification and claim(s), 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.
As used herein, 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.
The term “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 term “separated” is used herein to indicate that the compound is present in diastereomer form that is enriched in one stereoisomer compared to another, for example, up to 100% pure diastereomer.
As used herein, 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). In some embodiments, 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. In some circumstances, 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. In other circumstances, the isolated molecule may be purified to essential homogeneity, for example as determined spectrophotometrically, by NMR or by chromatography (for example LC-MS). In certain embodiments, 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.
As used herein, 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. Preferably, as used herein, the term “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.
The term “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 terms “molecule” and “compound” are used herein interchangeably.
The compound(s)/molecule(s) described herein can be used in the form of their pharmaceutically acceptable salts. As used herein, the term “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). Examples of pharmaceutically acceptable 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. Other pharmaceutically acceptable 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, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. 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.
As used herein, “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. Compound X is a lactone and the ring opened version thereof encompassed by the “open ring fatty acid” is the acyclic fatty acid corresponding to the version of compound X opened at the O-C sigma bond adjacent the C=O group.
As used herein, the terms “treatment”, “treat” and “treating” refer 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. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, 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.
As used herein, the expression “active ingredient” or “therapeutic agent” 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. Hence, a compound or molecule that is involved in the mechanism of action resulting in the effective treatment of the disease or disorder qualifies as an active ingredient. In contrast, inactive ingredients include additives, carriers, excipients, and adjuvants (including a vaccine adjuvant). In the case where the disease or disorder is cancer, the active ingredient will be the compound leading to inhibition of cancer cell growth and/or cancer cell death.
Compounds and compositions
The PCT application publication numbers WO2017/124184 and WO2019/232639 demonstrated that extracts from the seaweed Chaetomorpha Cannabina comprising the compounds of formulas (Ao) and (A) possess potent anti -cancer activity in vitro and in vivo.
The pharmacokinetic and in vivo efficacy results presented herein in Examples 1-4 provide evidence that the above lactone-comprising parent compounds are subject to a rapid ester hydrolysis reaction in vivo to form an open-ring fatty acid compound, and that this open-ring metabolite may be responsible for the observed anti -cancer activity. In accordance with one embodiment of the invention, there is provided 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. Hence, the active compound for use in inhibiting growth of cancer cells can be the ring opened version of compound (Ao) and more particularly, the version of compound (Ao) that is ring opened at the O-C sigma bond adjacent to the C=O group. Hence, in some embodiments, the open ring fatty acid can be a compound of the following formula (Io)
In the compounds described hererin, the symbol A/w represents a sigma bond between a chiral carbon atom and an oxygen atom, where the stereochemistry at the carbon atom can be R or S. For compound (Ao) and the compound of formula (Io), each carbon atom bonded to a OH group can independently have a R or S configuration.
In one embodiment, 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. Hence, the active compound for use in inhibiting growth of cancer cells can be the ring opened version of compound (A) and more particularly, the version of compound (A) that is ring opened at the O-C sigma bond adjacent to the C=O group. Hence, in some embodiments, the open ring fatty acid can be the compound having the following formula (I)
In another embodiment, 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.
In some embodiments, the compound for use in inhibiting growth of cancer cells, can be an open ring fatty acid of compound (B)
In some embodiments, 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.
In accordance with another embodiment of the invention, there is provided a pharmaceutical composition (e.g., a chemotherapy, anti-cancer, or antiproliferative 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. Advantageously, 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.
In accordance with another embodiment of the invention, there is provided 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. In some embodiments, 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.
In some embodiments, 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.
In accordance with another embodiment of the invention, there is provided 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. In some embodiments, 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.
In some preferred embodiments, the injectable composition is free from any antigen. In another embodiment, the excipient in the injectable composition is an excipient that is acceptable for intravenous administration. In a further embodiment, the injectable composition can further comprise one or more other therapeutic agent such as a therapeutic agent that is an anti -cancer agent.
In some embodiments, 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.
In some embodiments, the 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, mitoxantrone, novantrone, oxaliplatin, paclitaxel, pegylated liposomal doxorubicin, pertuzumab, pomalidomide, prednisone, procarbazine, rituximab, thalidomide, tioguanine, trastuzumab, vinblastine, vincristine, vindesine, vinorelbine, or any combination thereof.
In some embodiments, 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.
As mentioned previously, the compositions described herein may be used orally or parenterally. When used orally, the compositions can be formulated in liquid or solid dosage forms. When the compositions are for “parenteral” use, 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. In one particular embodiment, 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. In addition to the active compounds, 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. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Solid dosage forms for oral administration include can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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 alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
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.
Uses and methods
In accordance with a further embodiment, 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. In some embodiments, there is provided the use of 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. In one embodiment, 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. In another embodiment, the use can allow for the treatment or prevention of cancer in a mammal. In some embodiments, the mammal can be a human. In some embodiments, the use can involve an oral or parenteral administration, e.g. an intravenous administration.
In accordance with a further embodiment, 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. In some embodiments, there is provided the use of 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. In some embodiments, the mammal can be a human. In some embodiments, the medicament can be prepared for oral or parenteral administration, e.g. for intravenous administration.
In accordance with another embodiment, 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. In some embodiments, there is provided 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. In some embodiments, the mammal can be a human. In some embodiments, the method can involve administering the open ring fatty acid orally or parenterally, e.g. intravenously.
In accordance with the uses and method of treatment as defined herein, the cancer can be selected from the group consisting of: brain, lung, prostate, blood, breast and ovarian cancers. Particularly, the cancer is brain cancer. Particularly, the cancer is lung cancer. Particularly, the cancer is prostate cancer.
Particularly, the cancer is leukemia (i.e., blood cancer). Particularly, the cancer is breast cancer. Particularly, the cancer is ovarian cancer.
In accordance with the uses and method of treatment as defined herein, the open ring fatty acid can be used or administered in combination with one or more other therapeutic agent. In some embodiments, the other therapeutic agent can be an anti -cancer agent as described above.
In the uses and method of treatment described herein, 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.
Pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally or parenterally. In certain embodiments, 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.
Process and intermediate compounds
In accordance with a further embodiment, 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 12C carbon atoms throughout the molecule, but also 13C-labelled equivalents wherein two of the 12C carbon atoms are replaced with their 13C isotopes in the molecule.
According to one embodiment, the invention thus provides a process for preparing a compound of formula (I) or a 13C-labelled equivalent thereof comprising the following steps.
In a first step a) of the process, the following compound 6
where PGi is a divalent protecting group and the C1 and C2 carbon atoms are 12C or their 13C 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.
According to one embodiment, the protecting group PGi can be
. In another embodiment, the coupling between compound 6 and 7 can be performed according to the Homer-Wadsworth-Emmons (HWE) reaction.
In the next step b) of the process for preparing the compound of formula (I), compound 8 is reduced to form compound 9
According to one embodiment, the reduction of compound 8 into compound 9 can be the Corey- Bakshi-Shibata (CBS) reduction.
Then, in the next step c) of the process, the methyl ester group in compound 9 is hydrolyzed to form compound 10
According to one embodiment, the hydrolysis of the methyl ester group in compound 9 can be performed with LiOH.H2O. However, other reactants known in the art can be used to carry out this hydrolysis step.
Finally, in a last step d), the compound of formula (I) or the 13C-labelled equivalent at carbon C1 and C2,
can be obtained by removing the protecting group PGi in compound 10. In one embodiment, the removal of the protecting group in compound 10 can be performed with p-TsOH.IrbO.
In some embodiments, in the above described process for preparing the compound of formula (I), the starting compound 6 can be prepared by a process involving the following steps i) to vi).
In one embodiment, the first step i) for preparing compound 6 can involve an epoxidation of the following compound
into compound 1
The next step iii) involves a reaction to protect the hydroxyl group on the carbon C2 with a protecting group PG2 which is different than PGi, to form compound 3
Here again, the protecting group PG2 can be any known protecting group capable of masking the hydroxyl group on the carbon C2. In one embodiment, the protecting group PG2 can be tertbutyldimethylsilyl (TBS).
In the next step iv) the two free hydroxyl groups of compound 3 are protected with the protecting group PGi to form compound 4
Then, the protecting group PG2 in compound 4 is removed in step v) to form the partially deprotected compound 5 with the hydroxyl on the C2 carbon being freed for reacting in the next step vi).
More particularly, in 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).
In accordance with another embodiment, there is provided a process for preparing the compound (A) described herein or a 13C-labelled equivalent thereof. The process 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.
More particularly, the process for preparing compound (A) or the 13C-labelled equivalent thereof includes after steps a) to c), a step d’) wherein compound 10 described above is cyclized into the following compound 11
Then, in step e), the protecting group PGi in compound 11 is removed to form the compound of formula (II)
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes. The compound (A) corresponds to the compound 12 (i.e. compound 12-2) of formula (II) wherein the C1 and C2 carbon atoms are both the 12C isotope. In one embodiment, the protecting group in compound 11 can be removed by reaction with p- TSOH.H2O.
In accordance with another embodiment, there is provided a process for preparing the compound (B) described herein or a 13C-labelled equivalent thereof. The process 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. According to one embodiment, the protecting group PGi can be
In another embodiment, the coupling between compound 6 and 7 can be performed according to the Homer-Wadsworth-Emmons (HWE) reaction.
In the next step of the process for preparing the compound (B), compound 8 is reduced to form compound 9-1
According to one embodiment, the reduction of compound 8 into compound 9-1 can be the
Corey-Bakshi-Shibata (CBS) reduction.
Then, in the next step of the process, the methyl ester group in compound 9-1 is hydrolyzed to form compound 10-1
According to one embodiment, the hydrolysis of the methyl ester group in compound 9 can be performed with LiOH.H2O. However, 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).
(12-1) or (III) wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes. The compound (B) corresponds to the compound 12-1 of formula (III) wherein the C1 and C2 carbon atoms are both the 12C isotope.
According to one embodiment, the invention thus provides a process for preparing a compound of formula (J) or a 13C-labelled equivalent thereof
by removing the protecting group PGi in compound 10-1. In one embodiment, the removal of the protecting group in compound 10-1 can be performed with p-TsOH.ITO.
As can be appreciated by the skilled artisan, the methods of synthesizing the compounds described herein or at least some steps of such methods can be varied. Additionally, in some embodiments, certain synthetic steps could be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art. The synthesized compounds can be separated from a reaction mixture and further purified by standard methods such as column chromatography, high pressure liquid chromatography, or recrystallization.
In accordance with a further embodiment, 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.
10 wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and the groups PGi and PG2 are as described hereinabove.
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.
EXAMPLES Example 1: Identification of principal metabolite of parent compound
The PCT application publication numbers WO2017/124184 and WO2019/232639 demonstrated that extracts from the seaweed Chaetomorpha Cannabina comprising the compounds of formulas (Ao) and (A) possess potent anti -cancer activity in vitro and in vivo.
In order to better understand the metabolism of the above compounds, 10 pM the compound of formula (A) (hereinafter referred to as the “parent compound”) was incubated with primary human hepatocytes at 37°C for 2h and its metabolites were analyzed by LC-MS as shown in Fig. 1A-1E. Control (Blank; drug-free) hepatocyte incubations were included, and the reaction was stopped by addition of acetonitrile. MS was performed using a Waters Xevo™ G2 QTof spectrometer.
The LC-MS analyses revealed the presence of at least three distinct metabolites, with only 12% of the parent compound remaining after the 2h incubation. As shown in Table 1, the vast majority (73%) of the lactone-comprising parent compound (Fig. 2) underwent an ester hydrolysis reaction to form an openring structure (Fig. 3).
Example 2: In silico pharmacokinetic profiles of parent compound and metabolite 1
In silico ADME (absorption, distribution, metabolism, and excretion) predictions showed similar profiles for both the parent compound and its metabolites (Table 2). In particular, the parent compound and metabolite 1 were predicted to be available through most routes other than oral and to possess limited potential for toxicity or adverse effects. The intrinsic aqueous solubility value of -3.7 to -3.9 placed both compounds at the median range for most drugs currently on the market and was consistent with their high absorption properties. Interestingly, metabolite 1 was predicted to be less permeable in a Caco-2 cell (intestinal cell line) monolayer experiment.
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
Oct2 - model for whether a ligand affects Organic Cationic Transporter 2 that mediates the first step of renal secretion and plays a major role in eliminating cationic xenobiotic compounds from the body
Pgpl - model for whether a ligand will be an Inhibitor of p-glycoprotein 1 and potentially cause an accumulation of xenobiotic compounds that is a consideration in drug safety and drug-drug interactions PgpR - model for whether a ligand will be a substrate of p-glycoprotein 1 and likely cause the molecule to be rapidly cleared from the cell impacting the drug efficacy
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
Materials and Methods
The parent compound was administered acutely to mice by three routes of administration, IV (intravenous), IP (intraperitoneal), and PO (oral). 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. Chromatographic peaks with the appropriate m/z ratios (based on known MW) of the parent compound (MW:312.44 g/mol) and its metabolite (ester ring hydrolysis, Exact Mass: 330.2406 g/mol) were detected using an AB Sciex QTRAP™ 4000 or 6500 MS/MS system equipped with an LC system with a binary pump, a solvent degasser, a thermostatted column compartment and a multiplate autosampler. Determination of the quantification dynamic range was done using non-zero calibration standards (STDs). 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 Phoenix™ WinNonlins™ 8.0 (Pharsight, Certera, Mountainview, CA) by non-compartmental
analysis, linear up/log down trapezoidal rule. T1/2, AUCo-tiast, AUCo-<», MRT, tmax, Cmax, as appropriate, for the parent compound; peak areas and/or peak area ratios (analyte/IS) for metabolite 1 was reported.
Results
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. 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).
Co = concentration extrapolated to time zero following an i.v. dose tmax = time at which maximum concentration is observed Cmax = maximum observed concentration Apparent ti/2 = apparent terminal half-life
AUCo-tiast = area under the concentration vs time curve from time 0 to the time of the last measurable concentration
AUCo-inf = area under the concentration vs time curve from time 0 to infinity
CL = systemic clearance
MRTo-mf = mean residence time from time zero to infinity
Vss = steady-state volume of distribution
F = bioavailability = (Doseiv*AUCpo/ip)/(Dosepo/ip*AUCiv)* 100.
The results in this Example strongly suggest that the parent compound is rapidly converted to metabolite 1 in vivo upon administration and that metabolite 1 is the form that lingers in circulation and may be responsible for biological activity in vivo.
Example 4: In vivo anti-cancer activity
Mice with tumours established for 6-weeks following flank injections of 2.5 x 106 cells/100 pL (50:50 in matrigekDMEM) of MDA-MB-231 breast cancer cells were randomized into different treatment groups based on the tumour volume and body weight. All animals were treated every second day by intraperitoneal injections of the parent compound (synthesized as described in Example 5) over a 3 -5 -week time course. From each group, a minimum of 20 tumours were selected for analysis. Tumours were measured weekly using slide calipers and volumes established using the modified ellipsoidal formula: tumour volume = 0.5 (length x width2). Body weights and general animal health were assessed twice weekly during the treatment period. At study termination, mice were sacrificed, and tumours excised from each flank were weighed. To evaluate 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
No differences in average animal weight changes were observed between study groups (Table 4), with all animals found to be in good general health and manifesting no adverse clinical symptoms.
Treatment with the parent compound at 10 mg/kg significantly reduced tumour volumes compared to vehicle controls over the course of the six-week study (see Tables 5-7; Fig. 5). Tumour volumes were reduced by approximately from week 2 onwards, strongly suggesting anti-cancer activity.
Table 5: Summary of tumour volumes (mm3) for MDA-MB-231 tumour model
Table 6: Summary of tumour volume (mm3) changes for MDA-MB-231 tumour model
No obvious abnormalities related to distant tumour metastasis were detected in any of the animals. Average final tumour mass was reduced by more than 35% in the parent compound-treated group compared to untreated controls (Table 7), a result comparable to the observed reduction in tumour volumes.
Taken together with the results shown in Examples 1-3, the results in 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.
Example 5: Synthesis protocol
In the following description of the synthesis protocol, reference will be made to the synthesis schemes represented in Figs. 5 and 6. In addition, reference will be made to Figs. 7-20 showing the ’H NMR, 13C NMR and/or MS analysis of the different compounds involved in the syntheses.
A- Materials and Methods
Triethyl phosphonoacetate-13C2 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 13C 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 Millenium™ 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 (TLC) 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-Q™ 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. Prior to the analysis of samples, 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.
In the following described synthesis protocol, 13C-labelled starting compound was used to facilitate the subsequent pharmacological and toxicological studies of the compounds of interest. However, the same synthesis protocol can be used to prepare the corresponding compounds with the 12C isotope.
B- Summary of the chemical synthesis of l ('-:l-l 2R. 13S-Dihydroxy-10-Qctadecen-9S-olide f13C-lahelled Compound (A) ]
The chemical synthesis of [13C2]-12R, 13S-Dihydroxy-10-Octadecen-9S-olide first required the synthesis of [13C2]-trans-2-octen-ol (C13-2) from a commercially-available CIS-labelled precursor (Fig. 6). The Homer-Wadsworth-Emmons (HWE) reaction between hexanal and [13C2] -triethyl phosphonoacetate using MeMgBr as a base yielded [13C2]-ethyl-E-2-octenoate (C13-1) in modest yields (< 40%) even under optimized conditions. Higher isolated yields (>78 %) were obtained under LiCl/DBU reaction conditions and reduction of C13-1 with diisobutylaluminum hydride (DIBAL-H), afforded [13C2]-trans-2-octen-ol (C13-2) in >94% yield. The 13C-labelled alcohol was then introduced into a multi- step process (Fig. 7).
The chemicals structures of all 13C-labelled synthetic intermediates were confirmed by ’H NMR and MS analysis. Overall, the synthesis produced 390 mg of [13C2]-12R,13S-Dihydroxy-10-Octadecen- 9S-olide. The chemical structure and purity of [13C2]-12R,13S-Dihydroxy-10-Octadecen-9S-olide were confirmed by 'H NMR, 13C NMR, and MS analysis.
C- Detailed steps of the chemical synthesis of f13C2]-12R, 13S-Dihydroxy-10-Octadecen-9S-olide Relabelled Compound (A)]
C.l- Synthesis of f13C21-trans-2-Octen-ol
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 [13C2] -triethyl phosphonoacetate (3.89 g, 17.2 mmol) in 77.0 mL acetonitrile was added to the flask. DBU (l,8-Diazabicyclo(5.4.0)undec-7-ene) (2.8 mL, 18.7 mmol) was added to the reaction mixture, followed by a solution of hexanal (2.3 mL, 18.9 mmol) in 40 mL acetonitrile. After 2 h of stirring at room temperature, solvents were removed and the reaction mixture was diluted in 1: 1 water/ethyl acetate. The layers were separated, and the organic layer was washed with NH4CI, brine, dried with sodium sulfate, filtered, and concentrated to afford a colourless oil. The crude product was purified by silica gel column chromatography (2.5% ethyl acetate/hexane) to yield 2.3 grams (78 % yield) of [13C2]-ethyl-E-2-octenoate. Additional batches were performed at 2 x 1.0 g-scale and 3.0 g-scale using the same procedure. The final overall yield of the four batches was 6.7 grams of [13C2] - ethyl-E-2-octenoate (compound C13-1 characterized in Fig. 8).
Fig. 6- step b: A flame dried 250 mL 3 -neck round bottom flask equipped with a magnetic stirrer and temperature probe was charged [13C2]-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. The reaction was cooled down to -78 °C and quenched with acetone, then 3M HC1 was added until acidic pH. Ethyl acetate and a saturated solution of Rochelle’s salt were added, and the resulting mixture was stirred at room temperature overnight. The layers were separated and the aqueous was re-extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated to afford 1.88 g (94 % yield) of [13C2]-trans-2-Octen-ol as a colourless oil (compound C13-2). The product was pure and used for the next step without further purification. Additional batches were performed at 1g and 3.0 g-scale using the same procedure. The final overall yield of the three batches was 4.2 grams of [13C2]-trans-2-Octen-ol. Compound C13-2 is characterized in Fig. 9.
C.2- Synthesis of f13C2] -aldehyde intermediate compound 6
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) was added dropwise to the flask over 5 min. The resulting mixture was stirred between -20 °C and -15 °C for 30 mins. [13C2]-trans-2-Octen-ol (3.5 g, 26.9 mmol) dissolved in 14 mL of dry dichloromethane was added dropwise to flask. The reaction was stirred for an additional 3h between -20 °C and -15 °C. The reaction was warmed to 0°C, quenched with 100 mL of water, then stirred for 30 min and warmed to room temperature. 40 mL of 30% NaOH/saturated NaCl was added and the mixture was stirred vigorously for 20 mins. The mixture was transferred to a IL separatory funnel, and the lower organic layer was separated and combined with two X 200-mL dichloromethane extractions of the aqueous phase. The combined organic extracts were washed with water, brine, dried with sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (9: 1-1.5: 1 hexanes/EtOAc, R = 0.4 in 1.5: 1 hexane s/EtO Ac) to yield 2.7 g (70% yield) of the epoxide as a white solid (compound 1). Enantiomeric excess of the epoxy alcohol benzoate was determined to be 96% ee. Compound 1 is characterized in Fig. 10.
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. Two crude products were combined and the residue was purified by silica gel column chromatography (1: 1-4: 1 EtOAc/hexanes, R = 0.2 in 4: 1 EtOAc/hexanes) to yield the triol compound 2 (1.76 g, 58 %) as a white solid. Compound 2 is characterized in Fig. 11.
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. The crude product was purified by silica gel column chromatography (9: 1-6: 1 hexanes/EtOAc; R = 0.14 in 6: 1 hexanes/EtOAc) to yield the mono-protected diol compound 3 (2.53 g, 84 % yield) as a colourless oil. Compound 3 is characterized in Fig. 12.
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. The residue was purified by silica gel column chromatography (9: 1 hexanes/EtOAc; R = 0.7 in 9: 1 hexanes/EtOAc) to yield the acetonide compound 4 (2.44 g, 85 %) as a colourless oil. Compound 4 is characterized in Fig. 13.
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. The residue was purified by silica gel column chromatography (9: 1-4: 1 hexanes/EtOAc; R/ = 0.33 in 4: 1 hexanes/EtOAc) to yield the acetonide alcohol compound 5 (1.54 g, 98 %) as a colourless oil. Compound 5 is characterized in Fig. 14.
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. After stirring for 15 mins at -70 °C, triethylamine (5.2 mL, 37.1, 5 eq.) was added to the mixture. The reaction was stirred for 5 mins at -70 °C then warmed to room temperature. When the reaction was complete, approximately 2h, it was quenched with 40 mL of water and extracted with 2 x 40 mL of dichloromethane. The organic layers were combined and washed with 1 volume of 1% HC1, 1 volume of water, 1 volume of 5% Na2COs, 1 volume of water, and 1 volume of brine, dried with sodium sulfate and concentrated to afford the aldehyde compound 6 (1.53
hexane/ethyl acetate;) as a yellow oil. Compound 6 is characterized in Fig. 15.
C.3- Synthesis of [13C2]-12R, 13S-Dihydroxy-10-Qctadecen-9S-olide and [13C2]-12R, 13S-Dihydroxy-10- Octadecen-9R-olide
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. The product was purified by silica gel column chromatography (100% EtOAc-95:5 EtOAc/MeOH; R/ = 0.5 in 9: 1 EtOAc/MeOH) to yield the phosphonate compound 7 (6.91 g, 20 % yield) as a colourless oil. Compound 7 is characterized in Fig. 16.
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. After 1.5 hour of stirring, the reaction was poured into a separatory funnel containing 150 mb of water and extracted three times with 250 mb of ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, and then concentrated. The crude product was purified by silica gel column chromatography (9: 1-6: 1 hexanes/EtOAc; R/ = 0.3 in 7: 1 hexanes/EtOAc) to yield the enone compound 8 (1.97 g, 69% yield) as a yellow oil. Compound 8 is characterized in Figure 17.
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. The crude residue was purified by silica gel column chromatography (9: 1-4: 1 hexanes/EtOAc) to yield isomer 9-1 (0.57 g, 30% yield, R/ = 0.62 in 1.5: 1 hexanes/EtOAc) and the product isomer 9-2 (compound 9) (1.1 g, 60% yield, R = 0.54 in 1.5: 1 hexanes/EtOAc). Compound 9 is characterized in Fig. 18.
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. The four organic layers were combined, washed with brine, dried with sodium sulfate, and concentrated to yield 1.0 g (94% yield) of the crude carboxylic acid compound 10 which is characterized in Fig. 19. The crude acid was used without further purification in the next step.
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). After 2 additional hours of refluxing, the two reaction mixtures were concentrated to yield 21 .3 grams of a yellow paste. The crude product was purified by silica gel column chromatography (9.5:0.5-9: 1 hexanes/EtOAc) to yield the lactone compound 11 (0.54 g, 56% yield, R/ = 0.65 in 4: 1 hexanes/EtOAc) as a yellow oil. Compound 11 is characterized in Fig. 20.
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. The residue was purified by silica gel column chromatography (9: 1-1.5: 1 hexanes/EtOAc) to yield compound 12 (0.39 g, 83% yield, R = 0.37 in 1.5: 1 hexanes/EtOAc). Compound 12 ([13C2]- 12R,13S-Dihydroxy-10-Octadecen-9S-olide; 13C-labelled compound A) is characterized in Fig. 21.
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 ([13C2]-12R,13S- Dihydroxy-10-Octadecen-9R-olide; 13C-labelled compound (B)) is characterized in Fig. 25.
D- Chemical synthesis of compound of formula (I) and (J)
The compound of formula (I) (13C-labelled or compound with 12C 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.H2O, similarly to step (e) in Fig. 7B, to form the compound of formula (I).
The compound of formula (J) (13C-labelled or compound with 12C 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).
Example 5: Anti-cancer activity of compound (B)
To test the anti-cancer effect of 12R, 13S-Dihydroxy-10-Octadecen-9R-olide [compound (B)], a stock solution of the compound was first prepared in dimethylsulfoxide (DMSO) at 10 mg/ml and stored at -20°C until used. This preparation ensures that the DMSO content delivered to cells in culture never
exceeds 1%. Appropriate cell number, based on previous assays as described in WO2019/232639, were seeded in 96 well plate and incubated with compound (B) (up to 8 log concentrations, 0 to 50 or 100 pg/ml) for 72 h. Cell proliferation was initially assessed using a standard colorimetric indicator of metabolic activity (CIMA) assay. In this assay, reduction of yellow tetrazolium salt (MTT) to purple formazan by mitochondrial reductases enzymes in viable cells were measured as a change in absorbance (1=500-600). Seven human cell lines were evaluated: U373 (glioblastoma-astrocytoma), A549 (lung carcinoma), PC3 (prostate adenocarcinoma), THP1 (acute monocytic leukemia), MDA-MB-231 (mammary gland adenocarcinoma), SKOV3 (ovarian adenocarcinoma) and CCD1079Sk (skin fibroblast) cells.
Compound (B) was tested in tumour cell lines and found to exhibit broad spectrum antiproliferative activity (Table 8).
The present invention has been described in terms of particular embodiments found or proposed by the present inventor to comprise preferred modes for the practice of the invention. It will be appreciated by those of skill in the art that, in light of the present disclosure, numerous modifications and changes can be made in the particular embodiments exemplified without departing from the intended scope of the invention. All such modifications are intended to be included within the scope of the appended claims.
All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.
Claims
1. A chemotherapy or antiproliferative 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. 2. The composition of claim 1, wherein the compound has the structure of formula (I)
4. The composition of any one of claims 1 to 3, which is formulated for oral administration or for parenteral administration (e.g., intravenous administration).
5. The composition of any one of claims 1 to 4, which is not a vaccine or does not comprise a vaccine antigen.
6. The composition of any one of claims 1 to 5, which further comprises an additional chemotherapy agent.
7. The composition of any one of claims 1 to 6, for use in the treatment of cancer in a mammal.
8. The composition for use of claim 7, wherein the mammal is a human.
9. The composition for use of claim 7 or 8, wherein the cancer is brain, lung, prostate, blood, breast, or ovarian cancer.
10. The composition of any one of claims 1 to 6, or the composition for use of any one of claims 7 to 9, wherein chemotherapy is for use with a further anti-cancer agent.
11. A compound having the structure of formula (Io), (I), or (J), or a salt thereof, or a prodrug thereof lacking a lactone group, for use as an active ingredient in a medicament.
12. 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.
13. The compound for use of claim 11, or the use of claim 12, wherein the medicament is an anti -cancer medicament (e.g., a chemotherapy drug).
14. The compound for use of claim 11 or 13, or the use of claim 12 or 13, wherein the medicament is for oral or parenteral administration (e.g., intravenous administration).
15. The compound for use of claim 11, 13, or 14, or the use of any one of claims 12 to 14, wherein the medicament of for treating brain, lung, prostate, blood, breast, or ovarian cancer.
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16. The compound for use of claim 11 or 13 to 15, or the use of any one of claims 12 to 15, wherein the medicament further comprises an additional anti-cancer agent, or the medicament is for use with an additional anti -cancer agent.
17. A method for treating cancer in a subject, the method comprising: (a) providing the chemotherapy or antiproliferative composition as defined in any one of claims 1 to 6; and (b) administering composition to the subject at a dose sufficient to exert an anti -cancer activity in the subject.
18. The method of claim 17, wherein the subject is a human.
19. The method of claim 17 or 18, wherein the composition is administered to the subject orally or parenterally (e.g., intravenously).
20. The method of any one of claims 17 to 19, wherein the cancer is brain, lung, prostate, blood, breast, or ovarian cancer.
21. The method of any one of claims 17 to 20, further comprising administering an additional anticancer agent to the subject.
22. A process for preparing a compound of formula (I) or a 13C-labelled equivalent thereof, the process comprising the following steps:
(d) removal of the protecting group PGi in compound 10 to form the compound of formula (I)
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes.
23. The process of claim 22, wherein the coupling between compounds 6 and 7 is performed according to the Homer-Wadsworth-Emmons (HWE) reaction.
24. The process of claim 22 or 23, wherein the reduction of compound 8 into compound 9 is the Corey-
Bakshi-Shibata (CBS) reduction.
25. The process of any one of claims 22 to 24, wherein the hydrolysis of the methyl ester group in compound 9 is performed with LiOH.H2O.
26. The process of any one of claims 22 to 25, wherein the removal of the protecting group in compound 10 is performed with p-TsOH.H2O.
28. The process of any one of claims 22 to 27, wherein the compound 6 is prepared by:
(i) epoxidation of
(iii) protection of the hydroxyl group on the carbon C2 to form compound 3
wherein PG2 is a protecting group that is different from PGi
(vi) oxidation of the alcohol moiety of compound 5 into a ketone moiety to form compound 6. 29. The process of claim 28, wherein PG2 is tert-butyldimethylsilyl (TBS).
30. A process for preparing the compound (A) of formula (II)
comprising steps (a) to (c) of the process according to any one of claims 22 to 29 followed by (d’) cyclization of compound 10 into compound 11
(e) removal of the protecting group PGi in compound 11 to form the compound of formula (II) wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes.
31. The process of claim 30, wherein the removal of the protecting group in compound 11 is performed with p-TsOH.H2O.
33. The process of any one of claims 30 to 32, wherein the compound 6 used in step (c) is prepared by the process of claim 28 or 29.
34. An intermediate which is:
(a) compound 8
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(b) compound 9
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(c) compound 10
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(d) compound 11
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(e) compound 6
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(f) compound 5
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(g) compound 4
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(i) compound 3
(j) the intermediate of any one of (g) to (i), wherein PG2 is tert-butyldimethylsilyl (TBS);
35. A compound (B) of formula (III) or a compound (A) of formula (II):
or a pharmaceutically acceptable salt thereof.
36. The compound of claim 35, which is a purified compound and/or a chemically synthesized compound.
37. Use of the compound as defined in claim 35 or 36, for inhibiting growth of cancer cells in vitro.
38. Use of the compound as defined in claim 35 or 36, for inhibiting growth of cancer cells in a mammal.
39. The compound of claim 35 or 36, for use in the treatment or prevention of cancer in a mammal.
40. Use of the compound as defined in claim 35 or 36, for the manufacture of a composition for treating or preventing cancer in a mammal.
41. The compound of claim 35 or 36, incorporated into a formulation for oral or parenteral use.
42. A composition comprising the compound of claim 35 or 36, in admixture with a physiologically- acceptable excipient.
43. The composition of claim 42, wherein the compound is substantially enantiomerically pure or is enriched compared to another stereoisomer thereof.
44. The composition of claim 42 or 43, wherein said excipient is acceptable for oral or parenteral administration.
45. The composition of any one of claims 42 to 44, for use in the treatment or prevention of cancer in a mammal.
46. Use of the composition of any one of claims 42 to 44, for the treatment or prevention of cancer in a mammal.
47. The composition of any one of claims 42 to 44, in combination with one or more other therapeutic agent.
48. The composition of claim 47, wherein said other therapeutic agent is an anti -cancer agent.
49. A method for the treatment of cancer, the method comprising administering a growth-inhibiting concentration of the compound of claim 35 or 36, or the composition of any one of claims 42 to 44, to a mammal in need thereof.
50. The method of claim 49, wherein the mammal is a human.
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51. The method of claim 49 or 50, wherein the cancer is selected from the group consisting of: brain, lung, prostate, blood, breast, skin, and ovarian cancers.
52. The use of claim 37 or 38, wherein the cancer cells are selected from the group consisting of: brain, lung, prostate, blood, breast, skin, and ovarian cancer cells.
53. The use of claim 40, wherein the cancer is selected from the group consisting of: brain, lung, prostate, blood, breast, skin and ovarian cancers.
54. The compound for use of claim 39, wherein the cancer is selected from the group consisting of: brain, lung, prostate, blood, breast, skin, and ovarian cancers.
55. The use of claim 46, wherein the cancer is selected from the group consisting of: brain, lung, prostate, blood, breast, skin, and ovarian cancers.
56. The composition of any one of claims 42 to 44, incorporated into a formulation for oral or parenteral use.
57. A process for preparing the compound of claim 35 of formula (III), or a 13C-labelled equivalent thereof, the process comprising the following steps:
(d) cyclization of compound 10-1 into compound 11-1
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes; and
(e) removal of the protecting group PGi in compound 11-1 to form the compound of formula (III) of claim 35, wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes.
58. The process of claim 57, wherein the coupling between compounds 6 and 7 is performed according to the Homer-Wadsworth-Emmons (HWE) reaction.
59. The process of claim 57 or 58, wherein the reduction of compound 8 into compound 9-1 is the Corey-Bakshi-Shibata (CBS) reduction.
60. The process of any one of claims 57 to 59, wherein the hydrolysis of the methyl ester group in compound 9-1 is performed with LiOH.H2O.
61. The process of any one of claims 57 to 60, wherein the removal of the protecting group in compound 10-1 is performed with P-TSOH.H2O.
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The process of any one of claims 57 to 62, wherein the compound 6 is prepared by:
(iii) protection of the hydroxyl group on the carbon C2 to form compound 3
wherein PG2 is a protecting group that is different from PGi
(vi) oxidation of the alcohol moiety of compound 5 into a ketone moiety to form compound 6. The process of claim 63, wherein PG2 is tert-butyldimethylsilyl (TBS).
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65. The process of claim 57, wherein the removal of the protecting group in compound 11-1 is performed with p-TsOH.H2O.
67. An intermediate which is:
(a) compound 9-1
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group;
(b) compound 10-1
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group; or
(c) compound 11-1
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes and PGi is a protecting group.
68. A process for preparing a compound of formula (J) or a 13C-labelled equivalent thereof, the process comprising the following steps:
(d) removal of the protecting group PGi in compound 10-1 to form the compound of formula (J)
wherein the C1 and C2 carbon atoms are 12C or their 13C isotopes.
69. The process of claim 68, wherein the coupling between compounds 6 and 7 is performed according to the Homer-Wadsworth-Emmons (HWE) reaction.
70. The process of claim 68 or 69, wherein the reduction of compound 8 into compound 9-1 is the Corey-Bakshi-Shibata (CBS) reduction.
71. The process of any one of claims 68 to 70, wherein the hydrolysis of the methyl ester group in compound 9-1 is performed with LiOH.fTO.
72. The process of any one of claims 68 to 71, wherein the removal of the protecting group in compound 10-1 is performed with p-TsOH.ITO.
55
H3C^ /C The process of any one of claims 68 to 72, wherein PGi is H3C The process of any one of claims 68 to 73, wherein the compound 6 is prepared by:
(iii) protection of the hydroxyl group on the carbon C2 to form compound 3
wherein PG2 is a protecting group that is different from PGi
(vi) oxidation of the alcohol moiety of compound 5 into a ketone moiety to form compound 6.
56
75. The process of claim 74, wherein PG2 is tert-butyldimethylsilyl (TBS).
57
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