JPH08509959A - 新規タキソイド類、それらの製造及びそれらを含む製薬学的組成物 - Google Patents
新規タキソイド類、それらの製造及びそれらを含む製薬学的組成物Info
- Publication number
- JPH08509959A JPH08509959A JP6519652A JP51965294A JPH08509959A JP H08509959 A JPH08509959 A JP H08509959A JP 6519652 A JP6519652 A JP 6519652A JP 51965294 A JP51965294 A JP 51965294A JP H08509959 A JPH08509959 A JP H08509959A
- Authority
- JP
- Japan
- Prior art keywords
- group
- carbon atoms
- general formula
- alkyl
- substituted
- 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.)
- Granted
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 99
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 67
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 45
- 125000003118 aryl group Chemical group 0.000 claims abstract description 40
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 25
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 19
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 16
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 10
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 9
- 150000001602 bicycloalkyls Chemical group 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 156
- -1 Amino, piperidino, morpholino, 1-piperazinyl Chemical group 0.000 claims description 107
- 125000006239 protecting group Chemical group 0.000 claims description 59
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 48
- 125000003545 alkoxy group Chemical group 0.000 claims description 46
- 125000005843 halogen group Chemical group 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 32
- 125000004429 atom Chemical group 0.000 claims description 26
- 239000003960 organic solvent Substances 0.000 claims description 21
- 229920006395 saturated elastomer Polymers 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 18
- 230000009467 reduction Effects 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 125000003282 alkyl amino group Chemical group 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 125000004442 acylamino group Chemical group 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 11
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 230000002378 acidificating effect Effects 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- 150000007522 mineralic acids Chemical class 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- 230000010933 acylation Effects 0.000 claims description 7
- 238000005917 acylation reaction Methods 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 150000004820 halides Chemical class 0.000 claims description 7
- 150000007524 organic acids Chemical class 0.000 claims description 7
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 150000002170 ethers Chemical class 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 239000011630 iodine Substances 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 6
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 5
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims description 5
- 230000032050 esterification Effects 0.000 claims description 5
- 238000005886 esterification reaction Methods 0.000 claims description 5
- 125000000524 functional group Chemical group 0.000 claims description 5
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000003792 electrolyte Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 235000005985 organic acids Nutrition 0.000 claims description 4
- 125000000160 oxazolidinyl group Chemical class 0.000 claims description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 241001024304 Mino Species 0.000 claims description 3
- 239000012190 activator Substances 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 125000005107 alkyl diaryl silyl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 150000003927 aminopyridines Chemical class 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 125000005239 aroylamino group Chemical group 0.000 claims description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 125000005105 dialkylarylsilyl group Chemical group 0.000 claims description 3
- 150000003949 imides Chemical class 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 3
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 claims description 3
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 238000006073 displacement reaction Methods 0.000 claims description 2
- 230000002452 interceptive effect Effects 0.000 claims description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- GYPCWHHQAVLMKO-XXKQIVDLSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-[(e)-n-[(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-ylidene)amino]-c-methylcarbonimidoyl]-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical group Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\N=C1CC(C)(C)N(O)C(C)(C)C1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 GYPCWHHQAVLMKO-XXKQIVDLSA-N 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 150000004678 hydrides Chemical class 0.000 claims 1
- 125000005350 hydroxycycloalkyl group Chemical group 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract 1
- 125000003107 substituted aryl group Chemical group 0.000 abstract 1
- 239000000047 product Substances 0.000 description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 71
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 68
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 49
- 239000000243 solution Substances 0.000 description 49
- 229910001868 water Inorganic materials 0.000 description 48
- 230000002829 reductive effect Effects 0.000 description 43
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- 241000786363 Rhampholeon spectrum Species 0.000 description 29
- 239000006260 foam Substances 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 239000000377 silicon dioxide Substances 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 239000003480 eluent Substances 0.000 description 14
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000012153 distilled water Substances 0.000 description 10
- 238000005868 electrolysis reaction Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- ZVAFCKLQJCZGAP-WDEREUQCSA-N (2r,3s)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H]([C@@H](O)C(O)=O)C1=CC=CC=C1 ZVAFCKLQJCZGAP-WDEREUQCSA-N 0.000 description 7
- VAHXMEZCPGHDBJ-QWHCGFSZSA-N (4s,5r)-2,2-dimethyl-3-[(2-methylpropan-2-yl)oxycarbonyl]-4-phenyl-1,3-oxazolidine-5-carboxylic acid Chemical compound OC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C1=CC=CC=C1 VAHXMEZCPGHDBJ-QWHCGFSZSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000000354 decomposition reaction Methods 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 7
- 229910052753 mercury Inorganic materials 0.000 description 7
- 229910052697 platinum Inorganic materials 0.000 description 7
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000005341 cation exchange Methods 0.000 description 6
- ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical class Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 230000002159 abnormal effect Effects 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 239000004593 Epoxy Substances 0.000 description 4
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical group OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000007872 degassing Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000012264 purified product Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000003115 supporting electrolyte Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- RZARFIRJROUVLM-JGVFFNPUSA-N (2r,3s)-3-azaniumyl-2-hydroxy-3-phenylpropanoate Chemical compound [O-]C(=O)[C@H](O)[C@@H]([NH3+])C1=CC=CC=C1 RZARFIRJROUVLM-JGVFFNPUSA-N 0.000 description 2
- SYVNVEGIRVXRQH-UHFFFAOYSA-N 3-fluorobenzoyl chloride Chemical compound FC1=CC=CC(C(Cl)=O)=C1 SYVNVEGIRVXRQH-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
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- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 229960002949 fluorouracil Drugs 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- HKIOYBQGHSTUDB-UHFFFAOYSA-N folpet Chemical group C1=CC=C2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C2=C1 HKIOYBQGHSTUDB-UHFFFAOYSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
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- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000003014 ion exchange membrane Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical class CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- POALUPLKPJWUJR-UHFFFAOYSA-N phenyl 1,3-oxazolidine-5-carboxylate Chemical compound O=C(Oc1ccccc1)C1CNCO1 POALUPLKPJWUJR-UHFFFAOYSA-N 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052573 porcelain Inorganic materials 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 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
- RJKFOVLPORLFTN-UHFFFAOYSA-N progesterone acetate Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 RJKFOVLPORLFTN-UHFFFAOYSA-N 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000005227 renal system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- MRYQZMHVZZSQRT-UHFFFAOYSA-M tetramethylazanium;acetate Chemical compound CC([O-])=O.C[N+](C)(C)C MRYQZMHVZZSQRT-UHFFFAOYSA-M 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 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
- 229960003087 tioguanine Drugs 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000005106 triarylsilyl group Chemical group 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- JFALSRSLKYAFGM-UHFFFAOYSA-N uranium(0) Chemical compound [U] JFALSRSLKYAFGM-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 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
- 229940102001 zinc bromide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.一般式: [式中、 Arはアリール基を示し、 Rは水素原子又はアセチルもしくはアルコキシアセチル基を示し、 R1はベンゾイル基又は基R2−O−COを示し、ここで R2は炭素数が1〜8の直鎖状もしくは分枝鎖状アルキル基、炭素数が2〜8 のアルケニル基、炭素数が3〜8のアルキニル基、炭素数が3〜6のシクロアル キル基、炭素数が4〜6のシクロアルケニル基又は炭素数が7〜11のビシクロ アルキル基を示し、これらの基は場合によりハロゲン原子及びヒドロキシル、炭 素数が1〜4のアルキルオキシ、各アルキル部分の炭素数が1〜4のジアルキル アミノ、ピペリジノ、モルホリノ、1−ピペラジニル(場合により4−位におい て炭素数が1〜4のアルキル基により、もしくはアルキル部分の炭素数が1〜4 のフェニルアルキル基により置換されていることができる)、炭素数が3〜6の シクロアルキル、炭素数が4〜6のシクロアルケニル、フェニル、シアノ、カル ボキシル又はアルキル部分の炭素数が1〜4のアルキルオキシカルボニル基から 選ばれる1つ又は複数の置換基により置換されていることができるか、 −あるいは場合によりハロゲン原子及び炭素数が1〜4のアルキル又は炭素数が 1〜4のアルキルオキシ基から選ばれる1つ又は複数の原子又は基により置換さ れていることができるフェニル基、 −あるいは場合により1つ又は複数の炭素数が1〜4のアルキル基により置換さ れていることができる4〜6員を含む飽和もしくは不飽和ヘテロ環式基を示し、 R3は −炭素数が1〜8の直鎖状もしくは分枝鎖状アルキル基、炭素数が2〜8のアル ケニル基、炭素数が3〜8のアルキニル基、炭素数が3〜6のシクロアルキル基 、炭素数が4〜6のシクロアルケニル基又は炭素数が7〜11のビシクロアルキ ル基を示し、これらの基は場合によりハロゲン原子及びヒドロキシル、炭素数が 1〜4のアルキルオキシ、各アルキル部分の炭素数が1〜4のジアルキルアミノ 、ピペリジノ、モルホリノ、1−ピペラジニル(場合により4−位において炭素 数が1〜4のアルキル基により、もしくはアルキル部分の炭素数が1〜4のフェ ニルアルキル基により置換されていることができる)、炭素数が3〜6のシクロ アルキル、炭素数が4〜6のシクロアルケニル、場合によりシアノ、カルボキシ ル又はアルキル部分の炭素数が1〜4のアルキルオキシカルボニル基から選ばれ る1つ又は複数の置換基により置換されていることができるフェニル基から選ば れる1つ又は複数の置換基により置換されていることができるか、 −あるいは場合によりハロゲン原子及び炭素数が1〜4のアルキル又は炭素数が 1〜4のアルキルオキシ基から選ばれる1つ又は複数の原子又は基により置換さ れていることができるアリール基を示し、R3は非置 換フェニル基を示すことはできないと理解されるか、 −あるいは場合によりハロゲン原子及び炭素数が1〜4のアルキル基及び炭素数 が1〜4のアルキルオキシ基から選ばれる1つ又は複数の原子又は基により置換 されていることができる4〜6員を含む飽和もしくは不飽和ヘテロ環式基を示し 、シクロアルキル、シクロアルケニル又はビシクロアルキル基は場合により1つ 又は複数の炭素数が1〜4のアルキル基により置換されていることができると理 解される] の新規タキソイド類。 2.R及びR1が請求の範囲第1項におけると同義であり、Ar及びR3により示 されるアリール基が、場合によりハロゲン原子(フッ素、塩素、臭素、ヨウ素) 及びアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アルコ キシ、アルキルチオ、アリールオキシ、アリールチオ、ヒドロキシル、ヒドロキ シアルキル、メルカプト、ホルミル、アシル、アシルアミノ、アロイルアミノ、 アルコキシカルボニルアミノ、アミノ、アルキルアミノ、ジアルキルアミノ、カ ルボキシル、アルコキシカルボニル、カルバモイル、ジアルキルカルバモイル、 シアノ、ニトロ及びトリフルオロメチル基から選ばれる1つ又は複数の原子又は 基により置換されていることができるフェニル又はα−もしくはβ−ナフチル基 であり、アルキル基及び他の基のアルキル部分の炭素数が1〜4であり、アルケ ニル及びアルキニル基の炭素数は2〜8であり、アリール基はフェニル又はα− もしくはβ−ナフチル基であり、R3基は非置換フェニル基を示すことはできな いと理解され、ならびにAr及びR3により示されるヘテロ環式基が窒素、酸素 又は硫黄原子から選ばれる同一又は異なる1つ又は複数の原子を含み、場合によ りハロゲン原子(フッ 素、塩素、臭素、ヨウ素)及び炭素数が1〜4のアルキル、炭素数が6〜10の アリール、炭素数が1〜4のアルコキシ、炭素数が6〜10のアリールオキシ、 アミノ、炭素数が1〜4のアルキルアミノ、各アルキル部分の炭素数が1〜4の ジアルキルアミノ、アシル部分の炭素数が1〜4のアシルアミノ、炭素数が1〜 4のアルコキシカルボニルアミノ、炭素数が1〜4のアシル、アリール部分の炭 素数が6〜10のアリールカルボニル、シアノ、ニトロ、トリフルオロメチル、 カルボキシル、カルバモイル、アルキル部分の炭素数が1〜4のアルキルカルバ モイル、各アルキル部分の炭素数が1〜4のジアルキルカルバモイル又はアルコ キシ部分の炭素数が1〜4のアルコキシカルボニル基から選ばれる同一又は異な る1つ又は複数の置換基により置換されていることができる5員を有する芳香族 ヘテロ環式基である請求の範囲第1項に記載の新規タキソイド類。 3.R及びR1が請求の範囲第1項におけると同義であり、Arが、場合により ハロゲン原子及びアルキル、アルコキシ、アミノ、アルキルアミノ、ジアルキル アミノ、アシルアミノ、アルコキシカルボニルアミノ及びトリフルオロメチル基 から選ばれる同一又は異なる1つ又は複数の原子又は基により置換されているこ とができるフェニル、2−もしくは3−チエニル又は2−もしくは3−フリル又 は2−もしくは4−もしくは5−チアゾリル基を示し、R3がハロゲン原子及び アルキル、アルコキシ、アミノ、アルキルアミノ、ジアルキルアミノ、アシルア ミノ、アルコキシカルボニルアミノ、ニトロ及びトリフルオロメチル基から選ば れる同一又は異なる1つ又は複数の原子又は基により置換されているフェニル基 、あるいは場合によりハロゲン原子及びアルキル、アルコキシ、 アミノ、アルキルアミノ、ジアルキルアミノ、アシルアミノ、アルコキシカルボ ニルアミノ及びトリフルオロメチル基から選ばれる同一又は異なる1つ又は複数 の原子又は基により置換されていることができる2−もしくは3−チエニル又は 2−もしくは3−フリル又は2−もしくは4−もしくは5−チアゾリル基を示す 請求の範囲第1項に記載の新規タキソイド類。 4.Rが水素原子あるいはアセチル又はメトキシアセチル基を示し、Arがフェ ニル基を示し、R1がベンゾイル又はtert−ブトキシカルボニル基を示し、 R3が2−フルオロフェニル、3−フルオロフェニル、4−フルオロフェニル、 ペンタフルオロフェニル、4−エチルフェニル、4−tert−ブチルフェニル 、3−ニトロフェニル、4−ニトロフェニル又は4−(トリフルオロメチル)フ ェニル基を示す請求の範囲第1項に記載の新規タキソイド類。 5.一般式: [式中、Ar及びR1は請求の範囲第1、2又は3項の1つにおけると同義であ り、R4は水素原子を示し、R5はヒドロキシル官能基の保護基を示すか、あるい は他の場合R4及びR5は一緒になって飽和5−もしくは6−員ヘテロ環を形成し 、G1はヒドロキシル官能基の保護基を示し、G2はアセチル基又はヒドロキシル 官能基の保護基を示す] の生成物を一般式: R3−CO−OH (III) [式中、R3は請求の範囲第1、2又は3項の1つにおけると同義である] の酸又はこの酸の活性化誘導体を用いてエステル化し、一般式: [式中、Ar、R1、R3、R4、R5、G1及びG2は上記と同義である] の生成物を得、R4が水素原子を示す場合はその保護基R5、あるいは他の場合、 R4及びR5が一緒になって飽和5−もしくは6−員ヘテロ環を形成する場合はそ のR4及びR5、そのG1及び場合によりG2を水素原子により置換して一般式(I )の生成物に導き、場合によりR1、R4及びR5の意味に依存して一般式: [式中、Rは上記と同義である] の生成物を介し、それをベンゾイルクロリド又は一般式: R2−O−CO−X (VI) [式中、R2は上記と同義であり、Xはハロゲン原子又は−O−R2もしくは−O −CO−O−R2残基を示す] の生成物を用いてアシル化することを特徴とする請求の範囲第1、2、3又は4 項の1つに記載の新規タキソイド類の製造法。 6.一般式(II)の生成物のエステル化を、好ましくはハライドの形態の一般 式(III)の酸を、あらかじめアルカリ金属アルキリドを用いて金属化された 一般式(II)の生成物と反応させることにより行い、反応をエーテルなどの不 活性有機溶媒中で−50℃より低い温度で行うことを特徴とする請求の範囲第5 項に記載の方法。 7.水素原子によるヒドロキシル官能基の保護基の置換を: 1)R4が水素原子を示し、R5が上記と同義であり、G1がシリル化基を示し、 G2がアセチル基を示す場合、一般式(IV)の生成物を塩酸、硫酸及びフッ化 水素酸から選ばれる無機酸又は蟻酸、酢酸、メタンスルホン酸、トリフルオロメ タンスルホン酸及びp−トルエンスルホン酸から選ばれる有機酸を単独で又は混 合物として用いて処理することにより行い、反応をアルコール類、エーテル類、 エステル類、脂肪族炭化水素類、ハロゲン化脂肪族炭化水素類、芳香族炭化水素 類又はニトリル類から選ばれる有機溶媒中で、−10〜60℃の温度で行い、 2)R4及びR5が一緒になって一般式: [式中、R1は請求の範囲第1、2又は3項の1つにおけると同義であ り、R6及びR7は同一又は異なり水素原子あるいは炭素数が1〜4のアルキル基 、又はアルキル部分の炭素数が1〜4であり、アリール部分が好ましくは場合に より1つ又は複数の炭素数が1〜4のアルコキシ基により置換されていることが できるフェニルを示すアラルキル基、又は好ましくは場合により1つ又は複数の 炭素数が1〜4のアルコキシ基により置換されていることができるフェニルを示 すアリール基を示すか、あるいは他の場合、R6は炭素数が1〜4のアルコキシ 基、あるいはトリハロメチル基又はトリハロメチル基により置換されたフェニル 基を示し、R7は水素原子を示すか、あるいは他の場合、R6及びR7はそれらが 結合している炭素原子と一緒になって4〜7員環を形成し、G1はシリル化基を 示し、G2はアセチル基を示す] の飽和複素環を形成する場合、R1、R6及びR7の意味に依存して: a)R1がt−ブトキシカルボニル基を示し、R6及びR7が同一又は異なりア ルキル基又はアラルキルもしくはアリール基を示すか、あるいは他の場合、R6 がトリハロメチル基又はトリハロメチル基により置換されたフェニル基を示し、 R7が水素原子を示すか、あるいは他の場合、R6及びR7が一緒になって4〜7 員環を形成する場合、一般式(IV)の生成物を場合によりアルコールなどの有 機溶媒中で無機又は有機酸を用いて処理して一般式(V)の生成物を得、それを 一般式(VI)の生成物を用いてアシル化することにより行い、 b)R1がベンゾイル基又はR2が上記と同義であるR2−O−CO−を示し、 R6が水素原子又は炭素数が1〜4のアルコキシ基、又は1つもしくは複数の炭 素数が1〜4のアルコキシ基により置換されたフェニル基を示し、R7が水素原 子を示す場合、単独で又は混合物として用い られる触媒量又は化学量論的量の塩酸及び硫酸から選ばれる無機酸又は酢酸、メ タンスルホン酸、トリフルオロメタンスルホン酸及びp−トルエンスルホン酸か ら選ばれる有機酸の存在下でアルコール類、エーテル類、エステル類、脂肪族炭 化水素類、ハロゲン化脂肪族炭化水素類及び芳香族炭化水素類から選ばれる有機 溶媒中で、−10〜60℃の温度において一般式(IV)の生成物を処理するこ とにより行い、 3)G1がシリル化基を示し、G2がアルコキシアセチル基を示し、R4及びR5が 上記の1)と同義である場合、水素原子による保護基G1及びR5の置換を最初に 行い、反応は上記の1)に記載の酸性条件下で行われ、次いで保護基G2を、分 子の残りの部分に影響を与えない条件下でアンモニアを用いて、又はメタノール 中でハロゲン化亜鉛を用いてアルカリ性媒体中で処理することにより水素により 置換し 4)G1がシリル化基を示し、G2がアルコキシアセチル基を示し、R4及びR5が 上記の2−a)と同義である場合、最初に保護基G1を、分子の残りの部分に影 響を与えない条件下における酸性媒体中の処理により置換し、次いで保護基G2 を場合により上記の3)に記載の条件下で水素原子により置換し、次いで得られ る一般式(V)の生成物を上記の2−a)に記載の脱保護及びアシル化条件下で 処理することにより行い、 5)G1がシリル化基を示し、G2がアルコキシアセチル基を示し、R4及びR5が 上記の2−b)と同義である場合、最初に保護基G1を分子の残りの部分に影響 を与えない条件下における酸性媒体中の処理により置換し、次いで保護基G2を 場合により上記の3)に記載の条件下で水素原子により置換し、次いで得られる 生成物を上記の2−b)に記載の条件下で処理することにより行う ことを特徴とする請求の範囲第4項に記載の方法。 8.一般式: [式中、Ar及びR1は請求の範囲第1、2又は3項の1つにおけると同義であ り、R4は水素原子を示し、R5はヒドロキシル官能基の保護基を示すか、あるい は他の場合R4及びR5は一緒になって飽和5−もしくは6−員ヘテロ環を形成し 、G1はヒドロキシル官能基の保護基を示し、G2はアセチル基又はヒドロキシル 官能基の保護基を示す] の生成物。 9.Ar及びR1が請求の範囲第1、2、3又は4項の1つにおけると同義であ り、R4が水素原子を示し、R5が好ましくはメトキシメチル、1−エトキシエチ ル、ベンジルオキシメチル、トリメチルシリル、トリエチルシリル、(β−トリ メチルシリルエトキシ)メチル又はテトラヒドロピラニル基を示し、R4及びR5 が一緒になってヘテロ環を形成する場合、それは場合により2−位においてモノ 置換又はgem−置換されたオキサゾリジン環であり、G1がアルキル部分の炭 素数が1〜4であり、アリール部分が好ましくはフェニル基であるトリアルキル シリル、ジアルキルアリールシリル、アルキルジアリールシリル又はトリアール シリル基を示し、G2がアルコキシアセチル基を示すことを特徴とする請求の範 囲第8項に記載の新規生成物。 10.一般式: [式中、Ar、R1は請求の範囲第1、2、3又は4項の1つにおけると同義で あり、R’5は水素原子又はヒドロキシル官能基の保護基を示し、R4は水素原子 を示し、G’1は水素原子又はヒドロキシル官能基の保護基を示し、G’2は水素 原子、アセチル基又はヒドロキシル官能基の保護基を示す] の生成物の電解還元を行い、電解還元を有機溶媒又は水性/有機混合物中に可溶 性の第4アンモニウム塩から成る電解質中で、制御された電位において行うこと を特徴とする請求の範囲第8及び9項にいずれかに記載の生成物の製造法。 11.一般式: [式中、G1及びG2は請求の範囲第8及び9項のいずれかにおけると同義である ] の生成物を一般式: [式中、Ar、R1、R4及びR5は請求の範囲第8及び9項のいずれかにおける と同義である] の酸、あるいはハライド又は無水物もしくは混合無水物などのこの酸の誘導体を 用い、アミノピリジンなどの活性化剤及び場合によりイミドなどの縮合剤の存在 下においてエステル化し、反応を有機溶媒中で0〜90℃の温度において行うこ とを特徴とする請求の範囲第8及び9項のいずれかに記載の生成物の製造法。 12.一般式: [式中、G’1及びG’2は上記と同義であり、G’3は水素原子又はG’1と同一 のヒドロキシル官能基の保護基を示す] の生成物の電解還元を行い、電解還元を有機溶媒又は水性/有機混合物中に可溶 性の第4アンモニウム塩から成る電解質中で、制御された電位において行い、次 いで状況に依存して保護基G’3を水素原子により選択的に置換するか、あるい は7−及び10−位のヒドロキシル官能基を選択的に保護することを特徴とする 請求の範囲第11項に記載の一般式 (XI)の生成物の製造法。 13.少なくとも1種の請求の範囲第1、2、3又は4項に記載の生成物を、1 つ又は複数の製薬学的に許容し得る不活性又は生理学的活性生成物と組み合わせ て含むことを特徴とする製薬学的組成物。
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DE (1) | DE69402694T2 (ja) |
DK (1) | DK0687259T3 (ja) |
ES (1) | ES2101513T3 (ja) |
FI (1) | FI954111A0 (ja) |
FR (1) | FR2702212B1 (ja) |
GR (1) | GR3023162T3 (ja) |
NO (1) | NO953452L (ja) |
NZ (1) | NZ262137A (ja) |
PL (1) | PL310441A1 (ja) |
SK (1) | SK107295A3 (ja) |
WO (1) | WO1994020484A1 (ja) |
ZA (1) | ZA941387B (ja) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6794523B2 (en) | 1991-09-23 | 2004-09-21 | Florida State University | Taxanes having t-butoxycarbonyl substituted side-chains and pharmaceutical compositions containing them |
FR2698361B1 (fr) * | 1992-11-20 | 1995-01-13 | Rhone Poulenc Rorer Sa | Procédé de préparation d'un acide oxazolidine-1,3 carboxylique-5. |
FR2706457B1 (fr) * | 1993-06-16 | 1995-07-28 | Rhone Poulenc Rorer Sa | Procédé de préparation d'un acide oxazolidinecarboxylique utile pour préparer des taxoïdes thérapeutiquement actifs. |
US5760251A (en) * | 1995-08-11 | 1998-06-02 | Sepracor, Inc. | Taxol process and compounds |
CA2255891C (en) | 1996-05-24 | 2007-12-04 | Angiotech Pharmaceuticals, Inc. | Compositions and methods for treating or preventing diseases of body passageways |
FR2750989B1 (fr) * | 1996-07-09 | 1998-09-25 | Rhone Poulenc Rorer Sa | Procede de monoacylation d'hydroxy taxanes |
US6515016B2 (en) | 1996-12-02 | 2003-02-04 | Angiotech Pharmaceuticals, Inc. | Composition and methods of paclitaxel for treating psoriasis |
US6495579B1 (en) | 1996-12-02 | 2002-12-17 | Angiotech Pharmaceuticals, Inc. | Method for treating multiple sclerosis |
US20030157187A1 (en) * | 1996-12-02 | 2003-08-21 | Angiotech Pharmaceuticals, Inc. | Compositions and methods for treating or preventing inflammatory diseases |
US7288665B1 (en) * | 1997-08-18 | 2007-10-30 | Florida State University | Process for selective derivatization of taxanes |
ATE256117T1 (de) | 1999-05-17 | 2003-12-15 | Bristol Myers Squibb Co | Neue umsetzungsbedingungen für die spaltung von silylethern bei der herstellung von paclitaxel (taxol(r)) und paclitaxel -analogen |
EP1165068B1 (en) * | 2000-02-02 | 2007-12-19 | Florida State University Research Foundation, Inc. | C10 heterosubstituted acetate taxanes as antitumor agents |
SK13632001A3 (sk) | 2000-02-02 | 2002-06-04 | Florida State University Research Foundation, Inc. | C10 karbonátom substituované taxány ako protinádorové činidlá |
US6649632B2 (en) | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
ATE431343T1 (de) * | 2002-10-09 | 2009-05-15 | Chatham Biotec Ltd | Thio-analoga von paclitaxel und deren vorprodukte |
US7202370B2 (en) * | 2003-10-27 | 2007-04-10 | Conor Medsystems, Inc. | Semi-synthesis of taxane intermediates from 9-dihydro-13-acetylbaccatin III |
PE20050693A1 (es) | 2004-02-13 | 2005-09-27 | Univ Florida State Res Found | Taxanos sustituidos con esteres de ciclopentilo en c10 |
US8242166B2 (en) | 2008-03-31 | 2012-08-14 | Florida State University Research Foundation, Inc. | C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes |
CN102408397B (zh) * | 2011-10-19 | 2014-08-20 | 上海贝美医药科技有限公司 | 紫杉烷类衍生物及其制备方法 |
EP3316880B1 (en) | 2015-07-01 | 2021-09-01 | The Research Foundation for The State University of New York | Third generation taxoids and use thereof |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2601675B1 (fr) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | Derives du taxol, leur preparation et les compositions pharmaceutiques qui les contiennent |
US5430160A (en) * | 1991-09-23 | 1995-07-04 | Florida State University | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
US5254703A (en) * | 1992-04-06 | 1993-10-19 | Florida State University | Semi-synthesis of taxane derivatives using metal alkoxides and oxazinones |
ATE181551T1 (de) * | 1992-04-17 | 1999-07-15 | Abbott Lab | Taxol-derivate |
IL108444A0 (en) * | 1993-01-29 | 1994-04-12 | Univ Florida State | C2 taxane derivatives and pharmaceutical compositions containing them |
-
1993
- 1993-03-02 FR FR9302370A patent/FR2702212B1/fr not_active Expired - Fee Related
-
1994
- 1994-02-28 WO PCT/FR1994/000222 patent/WO1994020484A1/fr not_active Application Discontinuation
- 1994-02-28 KR KR1019950703730A patent/KR960701034A/ko not_active Application Discontinuation
- 1994-02-28 DE DE69402694T patent/DE69402694T2/de not_active Expired - Lifetime
- 1994-02-28 ZA ZA941387A patent/ZA941387B/xx unknown
- 1994-02-28 ES ES94908385T patent/ES2101513T3/es not_active Expired - Lifetime
- 1994-02-28 CZ CZ952237A patent/CZ223795A3/cs unknown
- 1994-02-28 AU AU61446/94A patent/AU683449B2/en not_active Expired - Fee Related
- 1994-02-28 JP JP51965294A patent/JP3782443B2/ja not_active Expired - Lifetime
- 1994-02-28 EP EP94908385A patent/EP0687259B1/fr not_active Expired - Lifetime
- 1994-02-28 SK SK1072-95A patent/SK107295A3/sk unknown
- 1994-02-28 PL PL94310441A patent/PL310441A1/xx unknown
- 1994-02-28 DK DK94908385.1T patent/DK0687259T3/da active
- 1994-02-28 NZ NZ262137A patent/NZ262137A/en unknown
- 1994-02-28 AT AT94908385T patent/ATE151763T1/de active
- 1994-03-02 US US08/204,128 patent/US5556877A/en not_active Expired - Lifetime
-
1995
- 1995-09-01 NO NO953452A patent/NO953452L/no unknown
- 1995-09-01 FI FI954111A patent/FI954111A0/fi not_active Application Discontinuation
-
1996
- 1996-02-27 US US08/607,854 patent/US5654449A/en not_active Expired - Lifetime
-
1997
- 1997-04-17 GR GR960402947T patent/GR3023162T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
US5556877A (en) | 1996-09-17 |
NO953452D0 (no) | 1995-09-01 |
NZ262137A (en) | 1997-11-24 |
EP0687259A1 (fr) | 1995-12-20 |
EP0687259B1 (fr) | 1997-04-16 |
JP3782443B2 (ja) | 2006-06-07 |
FI954111A (fi) | 1995-09-01 |
DE69402694D1 (de) | 1997-05-22 |
NO953452L (no) | 1995-09-01 |
CZ223795A3 (en) | 1995-12-13 |
AU6144694A (en) | 1994-09-26 |
PL310441A1 (en) | 1995-12-11 |
GR3023162T3 (en) | 1997-07-30 |
FI954111A0 (fi) | 1995-09-01 |
FR2702212A1 (fr) | 1994-09-09 |
SK107295A3 (en) | 1996-06-05 |
DK0687259T3 (da) | 1997-05-26 |
AU683449B2 (en) | 1997-11-13 |
ES2101513T3 (es) | 1997-07-01 |
ZA941387B (en) | 1994-09-29 |
ATE151763T1 (de) | 1997-05-15 |
US5654449A (en) | 1997-08-05 |
WO1994020484A1 (fr) | 1994-09-15 |
FR2702212B1 (fr) | 1995-04-07 |
DE69402694T2 (de) | 1997-10-16 |
KR960701034A (ko) | 1996-02-24 |
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