JP2018514514A - グローコカリキシンa誘導体及びその調製方法と応用 - Google Patents
グローコカリキシンa誘導体及びその調製方法と応用 Download PDFInfo
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- JP2018514514A JP2018514514A JP2017550599A JP2017550599A JP2018514514A JP 2018514514 A JP2018514514 A JP 2018514514A JP 2017550599 A JP2017550599 A JP 2017550599A JP 2017550599 A JP2017550599 A JP 2017550599A JP 2018514514 A JP2018514514 A JP 2018514514A
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- Prior art keywords
- acid
- solution
- hydrogen chloride
- ether
- cancer
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- 239000003814 drug Substances 0.000 claims abstract description 17
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 59
- 239000000243 solution Substances 0.000 claims description 49
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 34
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 34
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- -1 Preferably Chemical class 0.000 claims description 28
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- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
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- JRKICGRDRMAZLK-UHFFFAOYSA-N peroxydisulfuric acid Chemical compound OS(=O)(=O)OOS(O)(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229940005657 pyrophosphoric acid Drugs 0.000 claims description 2
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Chemical group OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 claims description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- MWNQXXOSWHCCOZ-UHFFFAOYSA-L sodium;oxido carbonate Chemical compound [Na+].[O-]OC([O-])=O MWNQXXOSWHCCOZ-UHFFFAOYSA-L 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims description 2
- HPQYKCJIWQFJMS-UHFFFAOYSA-N tetrathionic acid Chemical compound OS(=O)(=O)SSS(O)(=O)=O HPQYKCJIWQFJMS-UHFFFAOYSA-N 0.000 claims description 2
- 229960004365 benzoic acid Drugs 0.000 claims 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 229960004106 citric acid Drugs 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 238000005755 formation reaction Methods 0.000 claims 1
- 229960000448 lactic acid Drugs 0.000 claims 1
- 229940099690 malic acid Drugs 0.000 claims 1
- 229910017604 nitric acid Inorganic materials 0.000 claims 1
- 229960001367 tartaric acid Drugs 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 13
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
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- 206010006187 Breast cancer Diseases 0.000 description 9
- 208000026310 Breast neoplasm Diseases 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000000259 anti-tumor effect Effects 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 6
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- UCDVIBNDYLUWFP-MJTHGBBVSA-N glaucocalyxin a Chemical class C([C@@H]1[C@@H](O)[C@]2(C(C1=C)=O)[C@H](O)C1)C[C@H]2[C@@]2(C)[C@H]1C(C)(C)C(=O)CC2 UCDVIBNDYLUWFP-MJTHGBBVSA-N 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 3
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- 238000001228 spectrum Methods 0.000 description 3
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- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical group NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 102000003743 Relaxin Human genes 0.000 description 2
- 108090000103 Relaxin Proteins 0.000 description 2
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- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- BGTOWKSIORTVQH-HOSYLAQJSA-N cyclopentanone Chemical class O=[13C]1CCCC1 BGTOWKSIORTVQH-HOSYLAQJSA-N 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 2
- 125000005322 morpholin-1-yl group Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- SDHTXBWLVGWJFT-XKCURVIJSA-N oridonin Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12[C@@H](O)CCC(C)(C)[C@H]1[C@H](O)[C@@]3(O)OC2 SDHTXBWLVGWJFT-XKCURVIJSA-N 0.000 description 2
- CAQAFLRZJHXSIS-UHFFFAOYSA-N oridonin Natural products CC1(C)C=CC(O)C23COC(O)(C(O)C12)C45C(O)C(CCC34)C(=C)C5=O CAQAFLRZJHXSIS-UHFFFAOYSA-N 0.000 description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- ONVABDHFQKWOSV-UHFFFAOYSA-N 16-Phyllocladene Natural products C1CC(C2)C(=C)CC32CCC2C(C)(C)CCCC2(C)C31 ONVABDHFQKWOSV-UHFFFAOYSA-N 0.000 description 1
- RHLBRQUUVYXKLA-UHFFFAOYSA-N 2-methylpropan-1-ol;hydrochloride Chemical compound Cl.CC(C)CO RHLBRQUUVYXKLA-UHFFFAOYSA-N 0.000 description 1
- FEKWWZCCJDUWLY-UHFFFAOYSA-N 3-methyl-1h-pyrrole Chemical compound CC=1C=CNC=1 FEKWWZCCJDUWLY-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 1
- 206010071119 Hormone-dependent prostate cancer Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001365031 Isodon japonicus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- FDNDTQWNRFFYPE-UHFFFAOYSA-N carbonic acid;nitric acid Chemical compound OC(O)=O.O[N+]([O-])=O FDNDTQWNRFFYPE-UHFFFAOYSA-N 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- UYNPPIDGSVPVSW-UHFFFAOYSA-N ent-kaurane Natural products CC1(O)CC23CCC4C(CCCC4(C)C(=O)O)C2C=CC1C3 UYNPPIDGSVPVSW-UHFFFAOYSA-N 0.000 description 1
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 102000054896 human PML Human genes 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 150000002611 lead compounds Chemical group 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
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- 210000003470 mitochondria Anatomy 0.000 description 1
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- 239000012452 mother liquor Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- HPOKESDSMZRZLC-UHFFFAOYSA-N propan-2-one;hydrochloride Chemical compound Cl.CC(C)=O HPOKESDSMZRZLC-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
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- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
Classifications
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- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/04—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
- C07C225/08—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
- C07C225/12—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings with doubly-bound oxygen atoms bound to carbon atoms being part of rings
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
Description
好ましくは、前記触媒とグローコカリキシンAのモル数比は(1〜10):1である。
好ましくは、前記反応は溶剤で行われ、
より好ましくは、前記溶剤は、アルコール、ケトン、エーテル、エステル及びハロアルカンのうちのいずれか1種又は複数種を含み、さらに好ましくは、前記アルコールは、メタノール、エタノール、イソプロパノール、イソブタノール、tert−ブタノールのうちのいずれか1種又は複数種を含み、前記ケトンは、アセトン、2−ブタノンのうちの1種又は複数種を含み、前記エーテルは、エーテル、ジオキサン、イソプロピルエーテル、メチルtert−ブチルエーテル、テトラヒドロフランのうちのいずれか1種又は複数種を含み、前記エステルは、酢酸メチル、酢酸エチル及び酢酸ブチルのうちのいずれか1種又は複数種を含み、前記ハロゲン化炭化水素は、ジクロロメタン、クロロホルムを含み、
より好ましくは、前記調製方法は、反応後に溶剤を蒸発除去し及び/又はTLC及び/又はHPLCで検出するステップをさらに含む。
前記グローコカリキシンA誘導体を有機溶剤に溶解して溶液を形成し、得た溶液と酸を塩形成反応させ、溶液のpH値を制御して、グローコカリキシンA誘導体塩を得るステップを含む。
より好ましくは、前記無機酸は、次亜ヨウ素酸、次亜塩素酸、次亜臭素酸、ヨウ素酸、過塩素酸、ペルオキソ二硫酸、ペルオキソ二炭酸、過炭酸、ピロリン酸、ピロ硫酸、ピロ亜硫酸、テトラチオン酸、リン酸、チオ硫酸、硫酸、塩素酸、メタリン酸、ヨウ化水素酸、アジ化水素酸、フッ化水素酸、硫化水素、塩化水素酸、臭化水素酸、四ホウ酸、炭酸、硝酸、臭素酸、亜硫酸、亜リン酸、亜塩素酸、塩酸、亜硝酸、オルトリン酸、オルト硫酸及びオルト炭酸のうちのいずれか1種を含み、
より好ましくは、前記有機酸は、酒石酸、蓚酸、リンゴ酸、クエン酸、アスコルビン酸、安息香酸、サリチル酸、カフェイン酸、乳酸、ソルビン酸、アロマレイン酸、蟻酸、酢酸、安息香酸、エタン二酸、コハク酸、アセトン酸、α−ケトコハク酸、ベンゼンスルホン酸、エタンスルホン酸、樹脂酸、トリフルオロ酢酸、マレイン酸、テトラスルホン酸、メタンスルホン酸、フマル酸及びアミノ酸のうちのいずれか1種を含む。
より好ましくは、前記アルコールは、メタノール、エタノール、イソプロパノール、イソブタノール、tert−ブタノールのうちのいずれか1種又は複数種を含み、前記ケトンは、アセトン、2−ブタノンのうちの1種又は複数種を含み、前記エーテルは、エーテル、ジオキサン、イソプロピルエーテル、メチルtert−ブチルエーテル、テトラヒドロフランのうちのいずれか1種又は複数種を含み、前記エステルは、酢酸メチル、酢酸エチル及び酢酸ブチルのうちのいずれか1種又は複数種を含み、前記ハロゲン化炭化水素は、ジクロロメタン、クロロホルムを含む。
より好ましくは、前記塩化水素溶液は、塩化水素の水溶液、塩化水素のメタノール溶液、塩化水素のエタノール溶液、塩化水素のイソプロパノール溶液、塩化水素のノルマルプロパノール溶液、塩化水素のイソブタノール溶液、塩化水素の酢酸エチル溶液、塩化水素のアセトン溶液、塩化水素のエーテル溶液、塩化水素のジオキサン溶液のうちのいずれか1種を含み、
好ましくは、溶液のpH値は6.0〜8.0に制御され、
好ましくは、前記反応は−30〜60℃の温度で行われる。
好ましくは、前記癌は、トリプルネガティブ乳癌、神経膠腫、子宮頸癌、食道癌、肺癌、肝癌、絨毛癌、口腔扁平上皮癌、前立腺癌、直腸癌のいずれか1種又は複数種を含む。
本実施例では、グローコカリキシンA誘導体の調製方法が開示されている。すなわち、グローコカリキシンAを修飾してグローコカリキシンA窒素置換誘導体を得て、次にグローコカリキシンA窒素置換誘導体と酸を反応させて、水溶性に優れたグローコカリキシンA窒素置換誘導体塩を生成する。
本実施例には、ジメチルアミノグローコカリキシンA塩酸塩の調製方法が開示されており、主に以下のステップを含む。
ステップ2においてジメチルアミノグローコカリキシンA塩酸塩を調製する時に制御した反応温度及びpH値と異なり、本実施例において、反応温度が−30℃に制御され、pH値が6に調整される以外、実施例3の各ステップは実施例2と同様である。
ステップ2においてジメチルアミノグローコカリキシンA塩酸塩を調製する時に制御した反応温度及びpH値と異なり、本実施例において、反応温度が60℃に制御され、pH値が8に調整される以外、実施例4の各ステップは実施例2と同様である。
実施例5と実施例2のステップの区別は、ステップ2においてジメチルアミノグローコカリキシンA塩酸塩を調製する時に、反応温度が−10℃に制御され、pH値が7に調整されることである。
実施例6と実施例2の区別は、ステップ2においてジメチルアミノグローコカリキシンA塩酸塩を調製する時に、反応温度が20℃に制御され、pH値が7に調整されることである。
細胞増殖実験(MTT)
ジメチルアミノグローコカリキシンA塩酸塩(以下、GH02と呼ばれる)とグローコカリキシンA(すなわちGLA)による腫瘍細胞系に対する細胞増殖抑制実験:腫瘍細胞系の細胞密度を104/100μlに調整して、各ウェルに100μlを加えて96ウェルプレートに接種し、一晩培養する。細胞が完全に付着して、70〜80%まで成長すると、完全培地を用いてGH02とGLA母液(濃度はいずれも100mMである)を希釈し、その最終濃度を1、3.125、6.25、12.5、25、50、100μmol/Lにして、96ウェルプレートに接種し、各濃度ごとに4つのウェルを繰り返し、同時に空白対照群(すなわち無細胞群)を設置して、5%CO2を含有する37℃のインキュベータにおいて48h培養した後、各ウェルにMTTを最終濃度が0.5mg/mlになるまで加え、次に5%CO2を含有する37℃のインキュベータにおいて4h培養して、上澄みを捨て、各ウェルに150μlのDMSOを加えて、10min振盪培養し、マイクロプレートリーダーを用いて490nmでの吸光度値を検出する。
Claims (10)
- 式(I)に示されるグローコカリキシンA誘導体又はその塩。
- グローコカリキシンAとR基のドナー化合物を触媒の作用下で付加反応させて得るステップを含む請求項1に記載のグローコカリキシンA誘導体の調製方法。
- 前記触媒は、ナトリウムメトキシド、ナトリウムエトキシド、ピリジン、炭酸ナトリウム、炭酸カリウムのうちのいずれか1種又は複数種であることを特徴とする請求項2に記載の調製方法。
- R基とグローコカリキシンAのモル数比は(1〜10):1であり、
好ましくは、前記触媒とグローコカリキシンAのモル数比は(1〜10):1であることを特徴とする請求項2又は3に記載の調製方法。 - 前記反応は−30〜60℃で行われ、
好ましくは、前記反応は溶剤で行われ、
より好ましくは、前記溶剤は、アルコール、ケトン、エーテル、エステル及びハロアルカンのうちのいずれか1種又は複数種を含み、さらに好ましくは、前記アルコールは、メタノール、エタノール、イソプロパノール、イソブタノール、tert−ブタノールのうちのいずれか1種又は複数種を含み、前記ケトンは、アセトン、2−ブタノンのうちの1種又は複数種を含み、前記エーテルは、エーテル、ジオキサン、イソプロピルエーテル、メチルtert−ブチルエーテル、テトラヒドロフランのうちのいずれか1種又は複数種を含み、前記エステルは、酢酸メチル、酢酸エチル及び酢酸ブチルのうちのいずれか1種又は複数種を含み、前記ハロゲン化炭化水素は、ジクロロメタン、クロロホルムを含み、
より好ましくは、前記調製方法は、反応後に溶剤を蒸発除去し及び/又はTLC及び/又はHPLCで検出するステップをさらに含むことを特徴とする請求項2〜4のいずれか1項に記載の調製方法。 - 前記グローコカリキシンA誘導体を有機溶剤に溶解して溶液を形成し、得た溶液と酸を塩形成反応させ、溶液のpH値を制御して、グローコカリキシンA誘導体塩を得るステップを含む請求項1に記載のグローコカリキシンA誘導体の塩の調製方法。
- 前記酸は有機酸と無機酸を含み、
好ましくは、前記無機酸は、次亜ヨウ素酸、次亜塩素酸、次亜臭素酸、ヨウ素酸、過塩素酸、ペルオキソ二硫酸、ペルオキソ二炭酸、過炭酸、ピロリン酸、ピロ硫酸、ピロ亜硫酸、テトラチオン酸、リン酸、チオ硫酸、硫酸、塩素酸、メタリン酸、ヨウ化水素酸、アジ化水素酸、フッ化水素酸、硫化水素、塩化水素酸、臭化水素酸、四ホウ酸、炭酸、硝酸、臭素酸、亜硫酸、亜リン酸、亜塩素酸、塩酸、亜硝酸、オルトリン酸、オルト硫酸及びオルト炭酸のうちのいずれか1種を含み、
好ましくは、前記有機酸は、酒石酸、蓚酸、リンゴ酸、クエン酸、アスコルビン酸、安息香酸、サリチル酸、カフェイン酸、乳酸、ソルビン酸、アロマレイン酸、蟻酸、酢酸、安息香酸、エタン二酸、コハク酸、アセトン酸、α−ケトコハク酸、ベンゼンスルホン酸、エタンスルホン酸、樹脂酸、トリフルオロ酢酸、マレイン酸、テトラスルホン酸、メタンスルホン酸、フマル酸及びアミノ酸のうちのいずれか1種を含むことを特徴とする請求項6に記載の調製方法。 - 前記有機溶剤は、アルコール、ケトン、エーテル、エステル及びハロアルカンのうちのいずれか1種又は複数種を含み、
好ましくは、前記アルコールは、メタノール、エタノール、イソプロパノール、イソブタノール、tert−ブタノールのうちのいずれか1種又は複数種を含み、前記ケトンは、アセトン、2−ブタノンのうちの1種又は複数種を含み、前記エーテルは、エーテル、ジオキサン、イソプロピルエーテル、メチルtert−ブチルエーテル、テトラヒドロフランのうちのいずれか1種又は複数種を含み、前記エステルは、酢酸メチル、酢酸エチル及び酢酸ブチルのうちのいずれか1種又は複数種を含み、前記ハロゲン化炭化水素は、ジクロロメタン、クロロホルムを含むことを特徴とする請求項6又は7に記載の調製方法。 - 塩化水素溶液で溶液のpH値を制御し、
好ましくは、前記塩化水素溶液は、塩化水素の水溶液、塩化水素のメタノール溶液、塩化水素のエタノール溶液、塩化水素のイソプロパノール溶液、塩化水素のノルマルプロパノール溶液、塩化水素のイソブタノール溶液、塩化水素の酢酸エチル溶液、塩化水素のアセトン溶液、塩化水素のエーテル溶液、塩化水素のジオキサン溶液のうちのいずれか1種を含み、
好ましくは、溶液のpH値は6.0〜8.0に制御され、
好ましくは、前記反応は−30〜60℃の温度で行われることを特徴とする請求項6〜8のいずれか1項に記載の調製方法。 - 請求項1に記載のグローコカリキシンA誘導体又はその塩の、自己免疫疾患及び/又は癌を治療するための薬物の調製における用途であって、
好ましくは、前記自己免疫疾患は全身性エリテマトーデス又は乾癬であり、
好ましくは、前記癌は、トリプルネガティブ乳癌、神経膠腫、子宮頸癌、食道癌、肺癌、肝癌、絨毛癌、口腔扁平上皮癌、前立腺癌、直腸癌のいずれか1種又は複数種を含む用途。
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