CA3164897A1 - Analogues de diazonamide structurellement simplifies en tant qu'agents antimitotiques - Google Patents
Analogues de diazonamide structurellement simplifies en tant qu'agents antimitotiquesInfo
- Publication number
- CA3164897A1 CA3164897A1 CA3164897A CA3164897A CA3164897A1 CA 3164897 A1 CA3164897 A1 CA 3164897A1 CA 3164897 A CA3164897 A CA 3164897A CA 3164897 A CA3164897 A CA 3164897A CA 3164897 A1 CA3164897 A1 CA 3164897A1
- Authority
- CA
- Canada
- Prior art keywords
- 6alkyl
- butyl
- 6alkynyl
- mmol
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229930188453 diazonamide Natural products 0.000 title description 13
- 239000003080 antimitotic agent Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- 239000000203 mixture Substances 0.000 claims abstract description 40
- 230000003287 optical effect Effects 0.000 claims abstract description 20
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 11
- 206010061289 metastatic neoplasm Diseases 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000012453 solvate Substances 0.000 claims abstract description 6
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims abstract description 4
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract 7
- 238000000034 method Methods 0.000 claims description 70
- 239000000543 intermediate Substances 0.000 claims description 48
- 230000015572 biosynthetic process Effects 0.000 claims description 31
- 238000003786 synthesis reaction Methods 0.000 claims description 29
- 125000004122 cyclic group Chemical group 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 238000006116 polymerization reaction Methods 0.000 claims description 15
- 102000029749 Microtubule Human genes 0.000 claims description 12
- 108091022875 Microtubule Proteins 0.000 claims description 12
- 210000004688 microtubule Anatomy 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical group C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 11
- 239000003112 inhibitor Substances 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 238000005710 macrocyclization reaction Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims 4
- 125000005841 biaryl group Chemical group 0.000 claims 4
- 150000004703 alkoxides Chemical class 0.000 claims 1
- 238000010976 amide bond formation reaction Methods 0.000 claims 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims 1
- 229940127089 cytotoxic agent Drugs 0.000 claims 1
- 239000002254 cytotoxic agent Substances 0.000 claims 1
- 231100000599 cytotoxic agent Toxicity 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- 150000004679 hydroxides Chemical class 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 235000021317 phosphate Nutrition 0.000 claims 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims 1
- -1 C2-6alkeny Chemical group 0.000 abstract description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 238000004440 column chromatography Methods 0.000 description 67
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 62
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 61
- 238000005160 1H NMR spectroscopy Methods 0.000 description 60
- 239000013058 crude material Substances 0.000 description 51
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 49
- 239000007787 solid Substances 0.000 description 49
- 239000000741 silica gel Substances 0.000 description 47
- 229910002027 silica gel Inorganic materials 0.000 description 47
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 42
- 101150041968 CDC13 gene Proteins 0.000 description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- 239000012071 phase Substances 0.000 description 27
- YKBUODYYSZSEIY-PLSHLZFXSA-N diazonamide a Chemical compound N([C@H]([C@]12C=3O4)O5)C6=C2C=CC=C6C(C2=6)=CC=CC=6NC(Cl)=C2C(=C(N=2)Cl)OC=2C=3N=C4[C@H](C(C)C)NC(=O)[C@@H](NC(=O)[C@@H](O)C(C)C)CC2=CC=C5C1=C2 YKBUODYYSZSEIY-PLSHLZFXSA-N 0.000 description 26
- 239000012267 brine Substances 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- OALVLUFFPXEHFO-UHFFFAOYSA-N Diazonamide A Natural products O1C=2C34C(O)OC5=C3C=CC=C5C(C3=5)=CC=CC=5NC(Cl)=C3C(=C(N=3)Cl)OC=3C=2N=C1C(C(C)C)NC(=O)C(NC(=O)C(N)C(C)C)CC1=CC=C(O)C4=C1 OALVLUFFPXEHFO-UHFFFAOYSA-N 0.000 description 20
- OEUGDMOJQQLVAZ-UHFFFAOYSA-N 5-Iodoisatin Chemical compound IC1=CC=C2NC(=O)C(=O)C2=C1 OEUGDMOJQQLVAZ-UHFFFAOYSA-N 0.000 description 18
- 239000007832 Na2SO4 Substances 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 229910052938 sodium sulfate Inorganic materials 0.000 description 16
- 235000011152 sodium sulphate Nutrition 0.000 description 16
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 102000004243 Tubulin Human genes 0.000 description 12
- 108090000704 Tubulin Proteins 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- OYUZOWVHVRMZMQ-UHFFFAOYSA-N 2-(1,3-oxazol-4-yl)-1,3-oxazole Chemical compound C1=COC(C=2N=COC=2)=N1 OYUZOWVHVRMZMQ-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
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- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
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- 239000002253 acid Substances 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- NSVNKQLSGGKNKB-LLVKDONJSA-N (2s)-3,3-dimethyl-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound CC(C)(C)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 NSVNKQLSGGKNKB-LLVKDONJSA-N 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
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- VIMNAEVMZXIKFL-UHFFFAOYSA-N 5-bromo-1,3-dihydroindol-2-one Chemical compound BrC1=CC=C2NC(=O)CC2=C1 VIMNAEVMZXIKFL-UHFFFAOYSA-N 0.000 description 4
- FVRVCKWJOSBBDD-UHFFFAOYSA-N 5-iodo-1-methylindole-2,3-dione Chemical compound IC1=CC=C2N(C)C(=O)C(=O)C2=C1 FVRVCKWJOSBBDD-UHFFFAOYSA-N 0.000 description 4
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- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
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- 150000005347 biaryls Chemical group 0.000 description 4
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- 238000004448 titration Methods 0.000 description 4
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- 239000011701 zinc Substances 0.000 description 2
- YBEAMOBHNFDQMM-UHFFFAOYSA-N 1,3-oxazol-5-amine Chemical class NC1=CN=CO1 YBEAMOBHNFDQMM-UHFFFAOYSA-N 0.000 description 1
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
- YCHPNSOKVRTPES-UHFFFAOYSA-N 2-bromo-1,3-oxazole Chemical compound BrC1=NC=CO1 YCHPNSOKVRTPES-UHFFFAOYSA-N 0.000 description 1
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- 206010012735 Diarrhoea Diseases 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 101000697529 Homo sapiens Stathmin-4 Proteins 0.000 description 1
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- UWGUOPHMFVFXHP-UHFFFAOYSA-N IC=1C=C2C(C(NC2=CC=1)=O)C(C)C Chemical compound IC=1C=C2C(C(NC2=CC=1)=O)C(C)C UWGUOPHMFVFXHP-UHFFFAOYSA-N 0.000 description 1
- ZUVNHPNLZQVMIR-UHFFFAOYSA-N IC=1C=C2C(C(NC2=CC=1)=O)C1=CC2=CC=CC=C2C=C1 Chemical compound IC=1C=C2C(C(NC2=CC=1)=O)C1=CC2=CC=CC=C2C=C1 ZUVNHPNLZQVMIR-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 238000006411 Negishi coupling reaction Methods 0.000 description 1
- 101000881330 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) Dynein heavy chain, cytoplasmic Proteins 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- KEBWZDPXBSTRGS-UHFFFAOYSA-N OC1(C(N(C2=CC=C(C=C12)I)C)=O)C1=CC=CC=C1 Chemical compound OC1(C(N(C2=CC=C(C=C12)I)C)=O)C1=CC=CC=C1 KEBWZDPXBSTRGS-UHFFFAOYSA-N 0.000 description 1
- MBWHRNKQGZDRMJ-UHFFFAOYSA-N OC1(C(NC2=CC=C(C=C12)I)=O)C(C)C Chemical compound OC1(C(NC2=CC=C(C=C12)I)=O)C(C)C MBWHRNKQGZDRMJ-UHFFFAOYSA-N 0.000 description 1
- KILSXDFLGPVDBA-UHFFFAOYSA-N OC1(C(NC2=CC=C(C=C12)I)=O)C1=CC2=CC=CC=C2C=C1 Chemical compound OC1(C(NC2=CC=C(C=C12)I)=O)C1=CC2=CC=CC=C2C=C1 KILSXDFLGPVDBA-UHFFFAOYSA-N 0.000 description 1
- OGDANTGETBDNIR-UHFFFAOYSA-N OC1(C(NC2=CC=C(C=C12)I)=O)C1=CC=CC2=CC=CC=C12 Chemical compound OC1(C(NC2=CC=C(C=C12)I)=O)C1=CC=CC2=CC=CC=C12 OGDANTGETBDNIR-UHFFFAOYSA-N 0.000 description 1
- 239000007990 PIPES buffer Substances 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- 229910008066 SnC12 Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- UAYWVJHJZHQCIE-UHFFFAOYSA-L Zinc iodide Inorganic materials I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000001503 aryl iodides Chemical class 0.000 description 1
- WATIQRWSIYVNAJ-PMCHYTPCSA-N benzyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(2-oxo-3-phenyl-1,3-dihydroindol-5-yl)butanoate Chemical compound C(C)(C)(C)OC(=O)N[C@H](C(=O)OCC1=CC=CC=C1)CCC=1C=C2C(C(NC2=CC=1)=O)C1=CC=CC=C1 WATIQRWSIYVNAJ-PMCHYTPCSA-N 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 description 1
- 229960001573 cabazitaxel Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 230000003749 cleanliness Effects 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 description 1
- 229960003649 eribulin Drugs 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 230000002431 foraging effect Effects 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 1
- 229960002014 ixabepilone Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- UWIBIDGHIMGNRC-UHFFFAOYSA-M magnesium;1,3-dimethylbenzene-5-ide;bromide Chemical compound [Mg+2].[Br-].CC1=C[C-]=CC(C)=C1 UWIBIDGHIMGNRC-UHFFFAOYSA-M 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- GFTXWCQFWLOXAT-UHFFFAOYSA-M magnesium;cyclohexane;bromide Chemical compound [Mg+2].[Br-].C1CC[CH-]CC1 GFTXWCQFWLOXAT-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000003744 tubulin modulator Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Il est décrit un composé représenté par la formule générale (I). R1 est H, alkyle en C1-6, alkény en C2-6, alcinyle en C2-6, aryle, biaryle, alkyle aryIe en C1-6, alkényle aryle en C2-6, alcinyle aryle en C2-6, hétéroaryle, alkyle hétéroaryle en C1-6, ou alkényle hétéroaryle en C2-6; R2 est H, alkyle en C1-6, alkény en C2-6, alcinyle en C2-6, aryle, biaryle, alkyle aryIe en C1-6, alkényle aryle en C2-6, alcinyle aryle en C2-6, hétéroaryle, alkyle hétéroaryle en C1-6, ou alkényle hétéroaryle en C2-6; R3 est F, -Cl, -CN, -C(=O)R4, -C(=O)OR4, -CR5R6OR4, ou -CR5R6N(R7)R8. R4, R5, R6, R7 et R8 représentent indépendamment H, alkyl en C1-6, alcényl en C2-6, alcynyl en C2-6, aryle, biaryle, alkyl aryle en C1-6, alcényl aryle en C2-6, alcynyl aryle en C2-6, hétéroaryle, alkyl hétéroaryle en C1-6, ou alcényl hétéroaryle en C2-6; n'importe lesquels de R5, R6, R7 et R8 sont liés ensemble pour former, conjointement avec l'atome auquel ils sont attachés, un noyau à trois à six chaînons, X étant une liaison directe ou un groupe alkylène en C1-4, un isomère optique, stéréoisomère, racémate, énantiomère ou diastéréomère, ou bien des mélanges connexes, ou un sel, hydrate ou solvate connexes acceptables sur le plan pharmaceutique. Les composés ci-décrits sont utiles dans le traitement de tumeurs métastatiques, y compris le cancer du sein et les tumeurs cérébrales.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2019/061264 WO2021130515A1 (fr) | 2019-12-23 | 2019-12-23 | Analogues de diazonamide structurellement simplifiés en tant qu'agents antimitotiques |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3164897A1 true CA3164897A1 (fr) | 2021-07-01 |
Family
ID=69159875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3164897A Pending CA3164897A1 (fr) | 2019-12-23 | 2019-12-23 | Analogues de diazonamide structurellement simplifies en tant qu'agents antimitotiques |
Country Status (3)
| Country | Link |
|---|---|
| CA (1) | CA3164897A1 (fr) |
| DK (1) | DK202270354A1 (fr) |
| WO (1) | WO2021130515A1 (fr) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999143B (zh) * | 2021-12-06 | 2023-06-23 | 南华大学 | 一种氟芳烃氨基酸及其合成方法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK2699580T3 (en) * | 2011-04-22 | 2018-01-08 | Joyant Pharmaceuticals Inc | DIAZONAMI DISEASES |
-
2019
- 2019-12-23 CA CA3164897A patent/CA3164897A1/fr active Pending
- 2019-12-23 WO PCT/IB2019/061264 patent/WO2021130515A1/fr active Application Filing
-
2022
- 2022-06-30 DK DKPA202270354A patent/DK202270354A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK202270354A1 (en) | 2022-07-08 |
| WO2021130515A1 (fr) | 2021-07-01 |
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