JP2001511807A - 高親油性カンプトテシン誘導体 - Google Patents
高親油性カンプトテシン誘導体Info
- Publication number
- JP2001511807A JP2001511807A JP53583598A JP53583598A JP2001511807A JP 2001511807 A JP2001511807 A JP 2001511807A JP 53583598 A JP53583598 A JP 53583598A JP 53583598 A JP53583598 A JP 53583598A JP 2001511807 A JP2001511807 A JP 2001511807A
- Authority
- JP
- Japan
- Prior art keywords
- added
- camptothecin
- hydrogen
- lower alkyl
- water
- 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
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title abstract description 76
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 238000000034 method Methods 0.000 claims abstract description 20
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
- 201000011510 cancer Diseases 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract 2
- 229940127093 camptothecin Drugs 0.000 claims description 61
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 60
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 60
- -1 ethyl camptothecin Chemical compound 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000005015 aryl alkynyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 3
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 2
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract description 11
- 239000000725 suspension Substances 0.000 abstract description 7
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 abstract 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 abstract 1
- 239000008024 pharmaceutical diluent Substances 0.000 abstract 1
- 229940124531 pharmaceutical excipient Drugs 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 239000011541 reaction mixture Substances 0.000 description 61
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 239000000047 product Substances 0.000 description 53
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 52
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 41
- 239000000203 mixture Substances 0.000 description 41
- 239000003153 chemical reaction reagent Substances 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
- 239000000543 intermediate Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 239000012043 crude product Substances 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 150000002596 lactones Chemical class 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000000843 powder Substances 0.000 description 14
- 241000894007 species Species 0.000 description 14
- 229910052786 argon Inorganic materials 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000005859 coupling reaction Methods 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 238000005917 acylation reaction Methods 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 150000003254 radicals Chemical class 0.000 description 7
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 7
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 230000010933 acylation Effects 0.000 description 6
- 230000029936 alkylation Effects 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000012429 reaction media Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 229920002554 vinyl polymer Polymers 0.000 description 6
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
- 238000006069 Suzuki reaction reaction Methods 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 5
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 5
- 229950009213 rubitecan Drugs 0.000 description 5
- DLZRCTHPQQALDW-UHFFFAOYSA-N 3-trimethylsilylpropanal Chemical compound C[Si](C)(C)CCC=O DLZRCTHPQQALDW-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- 238000006418 Brown reaction Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 230000026030 halogenation Effects 0.000 description 4
- 238000005658 halogenation reaction Methods 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000013256 coordination polymer Substances 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 238000006880 cross-coupling reaction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000012039 electrophile Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 229930182480 glucuronide Natural products 0.000 description 3
- 150000008134 glucuronides Chemical class 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 238000006396 nitration reaction Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 description 3
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 description 2
- QOJFTZYHCMXUHG-FQEVSTJZSA-N (4s)-4-ethyl-4-hydroxy-1h-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4h,12h)-dione 6-oxide Chemical compound C1=C2C=CC=CC2=[N+]([O-])C2=C1CN(C1=O)C2=CC2=C1COC(=O)[C@]2(O)CC QOJFTZYHCMXUHG-FQEVSTJZSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- MYQKIWCVEPUPIL-QFIPXVFZSA-N 7-ethylcamptothecin Chemical compound C1=CC=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 MYQKIWCVEPUPIL-QFIPXVFZSA-N 0.000 description 2
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 102000013392 Carboxylesterase Human genes 0.000 description 2
- 108010051152 Carboxylesterase Proteins 0.000 description 2
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000012223 aqueous fraction Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000023611 glucuronidation Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- NEXSMEBSBIABKL-UHFFFAOYSA-N hexamethyldisilane Chemical compound C[Si](C)(C)[Si](C)(C)C NEXSMEBSBIABKL-UHFFFAOYSA-N 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 125000001979 organolithium group Chemical group 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
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- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- ULYLMHUHFUQKOE-UHFFFAOYSA-N trimethyl(prop-2-ynyl)silane Chemical compound C[Si](C)(C)CC#C ULYLMHUHFUQKOE-UHFFFAOYSA-N 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 229940094989 trimethylsilane Drugs 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General 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)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
- Silicon Polymers (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.一般式 (式中R1は、アシル、C2〜C8アルケニルあるいはC2〜C8アルキニルであっ て、任意に、一つ以上のハロゲン原子もしくはOR4または低級アルキルにより 、相当するその水素原子が置換されたもの;オキソ;アリール;アリールアルキ ル;アリールアルケニル;アリールアルキニル;複素環;SR5;−S(O)− 低級アルキル;−低級アルキル−P(O)R6R7、あるいはX−(C0〜C6アル キル、C0〜C8アルケニル、またはC0〜C8アルキニル)−SiR8R9R10; R2は、水素、ハロ、低級アルキル、アミノまたはニトロ; R4は、水素、または低級アルキル; R5は、水素、または低級アルキル; R6およびR7は、各々独自に水素または低級アルキル; R8、R9、およびR10は、各々独自に水素または低級アルキル; R11は、水素、ヒドロキシ、またはアセトキシ;且つ Xはイオウ、またはXは非存在)を有する化合物;又は 薬剤学的に許容されるその塩。 2.R1が−X−(C0〜C6アルキル、アルケニル、またはアルキニル)−Si R8R9R10であり、R2がハロである、請求項1に記載の化合物。 3.R2が10−位でA環に結合する、請求項1または2に記載の化合物。 4.R2が11−位でA環に結合する、請求項1または2に記載の化合物。 5.R2が12−位でA環に結合する、請求項1または2に記載の化合物。 6.R2が9−位でA環に結合する、請求項1または2に記載の化合物。 7.前記化合物が7−(β−トリメチルシリル)エチルカンプトテシンである、 請求項1に記載の化合物。 8.前記化合物が10−フルオロ−7−(β−トリメチルシリル)エチルカンプ トテシンである、請求項1に記載の化合物。 9.前記化合物が9−フルオロ−7−(β−トリメチルシリル)エテニルカンプ トテシンである、請求項1に記載の化合物。 10.癌または白血病と診断された哺乳類患者の治療方法であって、前記哺乳類 患者へ、有効量の前記式I化合物の一つを投与することを含む治療方法。 11.有効量の式I化合物および一つ以上の薬剤学的に許容できる希釈物または 賦形剤から実質的になる調合薬。
Applications Claiming Priority (3)
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US3714897P | 1997-02-14 | 1997-02-14 | |
US60/037,148 | 1997-02-14 | ||
PCT/US1998/002375 WO1998035940A1 (en) | 1997-02-14 | 1998-02-11 | Highly lipophilic camptothecin derivatives |
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JP2009047622A Division JP5264561B2 (ja) | 1997-02-14 | 2009-03-02 | 高親油性カンプトテシン誘導体 |
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JP2001511807A true JP2001511807A (ja) | 2001-08-14 |
JP2001511807A5 JP2001511807A5 (ja) | 2005-10-06 |
JP4311765B2 JP4311765B2 (ja) | 2009-08-12 |
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JP53583598A Expired - Lifetime JP4311765B2 (ja) | 1997-02-14 | 1998-02-11 | 高親油性カンプトテシン誘導体 |
JP2009047622A Expired - Lifetime JP5264561B2 (ja) | 1997-02-14 | 2009-03-02 | 高親油性カンプトテシン誘導体 |
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JP2009047622A Expired - Lifetime JP5264561B2 (ja) | 1997-02-14 | 2009-03-02 | 高親油性カンプトテシン誘導体 |
Country Status (10)
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EP (1) | EP1017675B1 (ja) |
JP (2) | JP4311765B2 (ja) |
AT (1) | ATE329903T1 (ja) |
AU (1) | AU6272598A (ja) |
CA (1) | CA2280905C (ja) |
DE (1) | DE69834923T2 (ja) |
DK (1) | DK1017675T3 (ja) |
ES (1) | ES2262223T3 (ja) |
PT (1) | PT1017675E (ja) |
WO (1) | WO1998035940A1 (ja) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001513567A (ja) * | 1997-08-29 | 2001-09-04 | ユニヴァーシティ オブ ピッツバーグ | カンプトテシン類似体及びその調製方法 |
JP2005535633A (ja) * | 2002-06-26 | 2005-11-24 | メディゲーネ オンコロギー ゲゼルシャフト ミット ベシュレンクテル ハフツング | カンプトテシン‐カルボキシレート配合物 |
JP2007514778A (ja) * | 2003-12-17 | 2007-06-07 | バイオニューメリック・ファーマスーティカルズ・インコーポレイテッド | カンプトテシン医薬処方物およびその製法 |
JP2008504235A (ja) * | 2004-05-13 | 2008-02-14 | シグマ−タウ・インドゥストリエ・ファルマチェウチケ・リウニテ・ソシエタ・ペル・アチオニ | 細胞分裂阻害剤として7位にて環状ペプチドと接合したカンプトテシン |
JP2010500350A (ja) * | 2006-08-11 | 2010-01-07 | ザ クリストゥス ステーリン ファウンデーション フォー キャンサー リサーチ | カンプトテシンのエステルの製造法 |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6136978A (en) * | 1993-06-30 | 2000-10-24 | University Of Pittsburgh | Camptothecin analogs and methods of preparation thereof |
US6743917B2 (en) | 1993-06-30 | 2004-06-01 | University Of Pittsburgh | Camptothecin analogs and methods of preparation thereof |
FR2790261B1 (fr) * | 1999-02-26 | 2004-09-10 | Sod Conseils Rech Applic | Nouveaux analogues optiquement purs de la camptothecine et leurs procedes de preparation |
WO1998035940A1 (en) * | 1997-02-14 | 1998-08-20 | Bionumerik Pharmaceuticals, Inc. | Highly lipophilic camptothecin derivatives |
US6057303A (en) * | 1998-10-20 | 2000-05-02 | Bionumerik Pharmaceuticals, Inc. | Highly lipophilic Camptothecin derivatives |
US6207832B1 (en) | 1999-04-09 | 2001-03-27 | University Of Pittsburgh | Camptothecin analogs and methods of preparation thereof |
WO2000066127A1 (en) * | 1999-05-04 | 2000-11-09 | Bionumerik Pharmaceuticals, Inc. | Novel highly lipophilic camptothecin analogs |
US6350756B1 (en) * | 2001-01-18 | 2002-02-26 | California Pacific Medical Center | Camptothecin derivatives |
US6855720B2 (en) | 2001-03-01 | 2005-02-15 | California Pacific Medical Center | Nitrogen-based camptothecin derivatives |
US6372906B1 (en) | 2001-04-12 | 2002-04-16 | University Of Pittsburgh | Synthesis of silyl camptothecins and silyl homocamptothecins |
US6723853B2 (en) | 2001-08-27 | 2004-04-20 | University Of Pittsburgh | Intermediates and methods of preparation of intermediates in the enantiomeric synthesis of (20R)homocamptothecins and the enantiomeric synthesis of (20R)homocamptothecins |
KR100895746B1 (ko) | 2001-11-30 | 2009-04-30 | 추가이 세이야쿠 가부시키가이샤 | 헥사사이클릭 화합물 |
AU2003243380A1 (en) | 2002-06-03 | 2003-12-19 | California Pacific Medical Center | Nitrogen-based homo-camptothecin derivatives |
US7067666B2 (en) * | 2003-06-27 | 2006-06-27 | Research Triangle Institute | 7-substituted camptothecin and camptothecin analogs and methods for producing the same |
NZ550665A (en) | 2004-04-09 | 2010-05-28 | Chugai Pharmaceutical Co Ltd | Novel water-soluble prodrugs of camptothecin derivatives |
TW200744603A (en) | 2005-08-22 | 2007-12-16 | Chugai Pharmaceutical Co Ltd | Novel anticancer concomitant drug |
US7875602B2 (en) | 2005-10-21 | 2011-01-25 | Sutter West Bay Hospitals | Camptothecin derivatives as chemoradiosensitizing agents |
US7786134B2 (en) | 2005-12-16 | 2010-08-31 | Sonus Pharmaceuticals, Inc. | Lipophilic anticancer drug compounds, compositions and related methods |
EP2586463B1 (en) | 2010-06-11 | 2016-08-17 | Japan Science and Technology Agency | Pharmaceutical multimeric particles, and manufacturing method for same |
US9556192B2 (en) | 2012-10-30 | 2017-01-31 | Nerviano Medical Sciences S.R.L. | Functionalized 9-bromo-camptothecin derivatives |
FR3029637B1 (fr) | 2014-12-05 | 2018-01-05 | Universite De Strasbourg | Microdispositif de detection de composes organiques volatils et methode de detection d'au moins un compose organique volatil compris dans un echantillon gazeux |
CN111194341B (zh) | 2018-09-14 | 2022-09-23 | 美国陶氏有机硅公司 | 压敏粘合剂及其制备和用途 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5004758A (en) * | 1987-12-01 | 1991-04-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs useful for inhibiting the growth of animal tumor cells |
JPH0615547B2 (ja) * | 1988-01-20 | 1994-03-02 | 株式会社ヤクルト本社 | 新規なカンプトテシン誘導体 |
US5446047A (en) * | 1992-07-23 | 1995-08-29 | Sloan-Kettering Institute For Cancer Research | Camptothecin analogues |
US5468754A (en) * | 1994-04-19 | 1995-11-21 | Bionumerik Pharmaceuticals, Inc. | 11,7 substituted camptothecin derivatives and formulations of 11,7 substituted camptothecin derivatives and methods for uses thereof |
GB9510716D0 (en) * | 1995-05-26 | 1995-07-19 | Pharmacia Spa | Substituted camptothecin derivatives and process for their preparation |
WO1998035940A1 (en) * | 1997-02-14 | 1998-08-20 | Bionumerik Pharmaceuticals, Inc. | Highly lipophilic camptothecin derivatives |
-
1998
- 1998-02-11 WO PCT/US1998/002375 patent/WO1998035940A1/en active IP Right Grant
- 1998-02-11 DK DK98904990T patent/DK1017675T3/da active
- 1998-02-11 JP JP53583598A patent/JP4311765B2/ja not_active Expired - Lifetime
- 1998-02-11 AU AU62725/98A patent/AU6272598A/en not_active Abandoned
- 1998-02-11 DE DE69834923T patent/DE69834923T2/de not_active Expired - Lifetime
- 1998-02-11 PT PT98904990T patent/PT1017675E/pt unknown
- 1998-02-11 EP EP98904990A patent/EP1017675B1/en not_active Expired - Lifetime
- 1998-02-11 AT AT98904990T patent/ATE329903T1/de active
- 1998-02-11 CA CA002280905A patent/CA2280905C/en not_active Expired - Lifetime
- 1998-02-11 ES ES98904990T patent/ES2262223T3/es not_active Expired - Lifetime
-
2009
- 2009-03-02 JP JP2009047622A patent/JP5264561B2/ja not_active Expired - Lifetime
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001513567A (ja) * | 1997-08-29 | 2001-09-04 | ユニヴァーシティ オブ ピッツバーグ | カンプトテシン類似体及びその調製方法 |
JP2005535633A (ja) * | 2002-06-26 | 2005-11-24 | メディゲーネ オンコロギー ゲゼルシャフト ミット ベシュレンクテル ハフツング | カンプトテシン‐カルボキシレート配合物 |
JP2007514778A (ja) * | 2003-12-17 | 2007-06-07 | バイオニューメリック・ファーマスーティカルズ・インコーポレイテッド | カンプトテシン医薬処方物およびその製法 |
JP2012214509A (ja) * | 2003-12-17 | 2012-11-08 | Bionumerik Pharmaceuticals Inc | カンプトテシン医薬処方物およびその製法 |
JP2008504235A (ja) * | 2004-05-13 | 2008-02-14 | シグマ−タウ・インドゥストリエ・ファルマチェウチケ・リウニテ・ソシエタ・ペル・アチオニ | 細胞分裂阻害剤として7位にて環状ペプチドと接合したカンプトテシン |
JP4805917B2 (ja) * | 2004-05-13 | 2011-11-02 | シグマ−タウ・インドゥストリエ・ファルマチェウチケ・リウニテ・ソシエタ・ペル・アチオニ | 細胞分裂阻害剤として7位にて環状ペプチドと接合したカンプトテシン |
JP2010500350A (ja) * | 2006-08-11 | 2010-01-07 | ザ クリストゥス ステーリン ファウンデーション フォー キャンサー リサーチ | カンプトテシンのエステルの製造法 |
Also Published As
Publication number | Publication date |
---|---|
ES2262223T3 (es) | 2006-11-16 |
JP4311765B2 (ja) | 2009-08-12 |
JP2009149680A (ja) | 2009-07-09 |
EP1017675B1 (en) | 2006-06-14 |
WO1998035940A1 (en) | 1998-08-20 |
AU6272598A (en) | 1998-09-08 |
DK1017675T3 (da) | 2006-10-16 |
DE69834923D1 (en) | 2006-07-27 |
ATE329903T1 (de) | 2006-07-15 |
CA2280905A1 (en) | 1998-08-20 |
PT1017675E (pt) | 2006-09-29 |
EP1017675A4 (en) | 2001-08-22 |
DE69834923T2 (de) | 2006-10-19 |
EP1017675A1 (en) | 2000-07-12 |
CA2280905C (en) | 2006-08-29 |
JP5264561B2 (ja) | 2013-08-14 |
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