PL197648B1 - Pochodna epotylonu, preparat farmaceutyczny zawierający pochodną epotylonu, zastosowanie pochodnej epotylonu oraz sposób jej wytwarzania - Google Patents

Info

Publication number

PL197648B1

PL197648B1 PL345327A PL34532799A PL197648B1 PL 197648 B1 PL197648 B1 PL 197648B1 PL 345327 A PL345327 A PL 345327A PL 34532799 A PL34532799 A PL 34532799A PL 197648 B1 PL197648 B1 PL 197648B1

Authority

PL

Poland

Prior art keywords

formula

mmol

equiv

silica gel

absent

Prior art date

1998-06-22

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• 150000003883 epothilone derivatives Chemical class 0.000 title claims abstract description 51
• 230000015572 biosynthetic process Effects 0.000 title description 49
• 238000003786 synthesis reaction Methods 0.000 title description 48
• 150000001875 compounds Chemical class 0.000 claims abstract description 90
• 150000003839 salts Chemical class 0.000 claims abstract description 38
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 36
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
• 125000006239 protecting group Chemical group 0.000 claims abstract description 20
• 239000001257 hydrogen Substances 0.000 claims abstract description 16
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 13
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 12
• 150000002431 hydrogen Chemical class 0.000 claims abstract description 9
• 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims abstract description 7
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 7
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 7
• 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims abstract description 7
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 7
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 7
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 7
• 239000000203 mixture Substances 0.000 claims description 79
• 238000000034 method Methods 0.000 claims description 72
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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
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• 238000005859 coupling reaction Methods 0.000 claims description 12
• 230000008878 coupling Effects 0.000 claims description 11
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• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 10
• 230000002062 proliferating effect Effects 0.000 claims description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
• 229940079593 drug Drugs 0.000 claims description 8
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 239000001301 oxygen Substances 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000001153 fluoro group Chemical group F* 0.000 claims description 4
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 4
• 150000003606 tin compounds Chemical class 0.000 claims description 4
• 230000003556 anti-epileptic effect Effects 0.000 claims 1
• 239000001961 anticonvulsive agent Substances 0.000 claims 1
• 238000004519 manufacturing process Methods 0.000 claims 1
• 230000037390 scarring Effects 0.000 claims 1
• 125000004430 oxygen atom Chemical group O* 0.000 abstract description 4
• ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 abstract description 3
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 395
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 193
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 179
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 148
• 239000000741 silica gel Substances 0.000 description 145
• 229910002027 silica gel Inorganic materials 0.000 description 145
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 118
• 239000000243 solution Substances 0.000 description 112
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• 239000010410 layer Substances 0.000 description 83
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• 238000005481 NMR spectroscopy Methods 0.000 description 72
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• 210000004027 cell Anatomy 0.000 description 56
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• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 40
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• 238000003818 flash chromatography Methods 0.000 description 36
• 238000006243 chemical reaction Methods 0.000 description 34
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
• CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 32
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 32
• 230000002829 reductive effect Effects 0.000 description 32
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
• 238000012746 preparative thin layer chromatography Methods 0.000 description 29
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 27
• 229930013356 epothilone Natural products 0.000 description 26
• 239000000284 extract Substances 0.000 description 25
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
• 229920006395 saturated elastomer Polymers 0.000 description 25
• 150000001299 aldehydes Chemical class 0.000 description 24
• 239000011541 reaction mixture Substances 0.000 description 24
• 125000006519 CCH3 Chemical group 0.000 description 23
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 23
• 239000002904 solvent Substances 0.000 description 23
• 201000011510 cancer Diseases 0.000 description 22
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 20
• 235000019341 magnesium sulphate Nutrition 0.000 description 20
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
• 238000002360 preparation method Methods 0.000 description 19
• 239000004480 active ingredient Substances 0.000 description 18
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
• KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 17
• 239000002253 acid Substances 0.000 description 17
• 238000012360 testing method Methods 0.000 description 17
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
• 102000029749 Microtubule Human genes 0.000 description 16
• 108091022875 Microtubule Proteins 0.000 description 16
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• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 16
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• -1 hydroxy, amino Chemical group 0.000 description 12
• 239000000543 intermediate Substances 0.000 description 12
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• 239000000047 product Substances 0.000 description 11
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