JPS6247193B2 - - Google Patents
Info
- Publication number
- JPS6247193B2 JPS6247193B2 JP13841081A JP13841081A JPS6247193B2 JP S6247193 B2 JPS6247193 B2 JP S6247193B2 JP 13841081 A JP13841081 A JP 13841081A JP 13841081 A JP13841081 A JP 13841081A JP S6247193 B2 JPS6247193 B2 JP S6247193B2
- Authority
- JP
- Japan
- Prior art keywords
- oxide
- reduced pressure
- under reduced
- camptothecin
- chloroform
- 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.)
- Expired
Links
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- -1 R 3 is not -OH Chemical group 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 229910052717 sulfur Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 32
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 31
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
- 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 description 20
- 230000015572 biosynthetic process Effects 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 229940127093 camptothecin Drugs 0.000 description 14
- 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 description 14
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 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 7
- 239000013078 crystal Substances 0.000 description 7
- 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 6
- SZTZIXLREYEION-QHCPKHFHSA-N 11-propylcamptothecin Chemical compound C1=CC=C2C(CCC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 SZTZIXLREYEION-QHCPKHFHSA-N 0.000 description 5
- NNFHDMYHXQYBDD-UHFFFAOYSA-N 5-methoxycamptothecin Chemical compound C1=CC=C2C=C(C(OC)N3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 NNFHDMYHXQYBDD-UHFFFAOYSA-N 0.000 description 5
- 150000001204 N-oxides Chemical class 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HPDRGGNSEBLDKL-NRFANRHFSA-N ac1l3zgz Chemical compound C1=CC=C2C(CO)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HPDRGGNSEBLDKL-NRFANRHFSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229960004926 chlorobutanol Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- IHCCLXNEEPMSIO-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 IHCCLXNEEPMSIO-UHFFFAOYSA-N 0.000 description 1
- ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 0.000 description 1
- JVKRKMWZYMKVTQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JVKRKMWZYMKVTQ-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- HAWSQZCWOQZXHI-UHFFFAOYSA-N CPT-OH Natural products C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-UHFFFAOYSA-N 0.000 description 1
- 241000759909 Camptotheca Species 0.000 description 1
- 241000759905 Camptotheca acuminata Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 208000007093 Leukemia L1210 Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000209018 Nyssaceae Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- UGJVZXBXVRMUSG-UHFFFAOYSA-K [B+3].[F-].[F-].[F-] Chemical compound [B+3].[F-].[F-].[F-] UGJVZXBXVRMUSG-UHFFFAOYSA-K 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- PVBRSNZAOAJRKO-UHFFFAOYSA-N ethyl 2-sulfanylacetate Chemical compound CCOC(=O)CS PVBRSNZAOAJRKO-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は、新規なカンプトテシン誘導体に関す
る。更に詳しく言えば、本発明は、一般式
(式中R1は水素原子、アルキル基、ヒドロキシル
基、アルコキシル基又はアシロキシル基であり、
R2は水素原子、アルキル基、アラルキル基、ヒ
ドロキシメチル基またはアシロキシメチル基であ
り、R3は水素原子、アルキル基又はアシル基で
あり、Xは酸素原子又はイオウ原子である。ただ
し、R1、R2がともに水素原子である場合は、R3X
は、−OH、−OCH3、−OCOCH3でないものとす
る)で表わされる新規なカンプトテシン誘導体に
関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel camptothecin derivatives. More specifically, the present invention relates to the general formula (In the formula, R 1 is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or an acyloxyl group,
R 2 is a hydrogen atom, an alkyl group, an aralkyl group, a hydroxymethyl group or an acyloxymethyl group, R 3 is a hydrogen atom, an alkyl group or an acyl group, and X is an oxygen atom or a sulfur atom. However, if R 1 and R 2 are both hydrogen atoms, R 3
relates to a novel camptothecin derivative represented by -OH, -OCH3 , -OCOCH3 ).
カンプトテシンは落葉喬木喜樹(Camptotheca
acuminata Nyssaceae)等から抽出・単離される
アルカロイドで、強力な核酸合成阻害作用を有
し、その作用は迅速かつ可逆性を示すことが特徴
で、既存の制癌剤と交叉耐性を示さないという独
特な作用機作をもつ抗腫瘍性物質であり、マウス
白血病L1210、ラツトウオーカー256肉腫など実
験移植癌に対して、強力な制ガン効果を示すこと
が認められているが、毒性作用を有するために、
医薬品としての有用性がおのずから、制限されて
いる現状にある。 Camptothecin is a deciduous tree (Camptotheca).
acuminata Nyssaceae), it has a strong nucleic acid synthesis inhibitory effect, and its action is rapid and reversible.It has a unique effect of not exhibiting cross-resistance with existing anticancer drugs. It is an antitumor substance with a mechanism and has been shown to have strong anticancer effects on experimentally transplanted cancers such as murine leukemia L1210 and rat Walker 256 sarcoma.
The current situation is that its usefulness as a medicine is naturally limited.
そこで、このカンプトテシンを化学的に他の物
質に変換することすなわち、カンプトテシン誘導
体に変えることにより、制ガン活性を保持しなが
ら、毒性の低下を図るという試みが従来なされて
来た。 Therefore, attempts have been made to chemically convert camptothecin into other substances, that is, to convert it into camptothecin derivatives, thereby reducing toxicity while retaining anticancer activity.
しかしながら、カンプトテシンそれ自体が各種
有機溶剤に難溶であることや、カンプトテシンが
その化学構造中に有するヘテロ環に由来して親電
子置換反応に対する抵抗性を有することなどの理
由で、誘導体に変換するのにも、種々の障害があ
り、机上で企画するほどに新規な誘導体を得るこ
とは容易ではないのが実情である。 However, camptothecin itself is poorly soluble in various organic solvents, and camptothecin has resistance to electrophilic substitution reactions due to the heterocycle it has in its chemical structure. However, there are various obstacles, and the reality is that it is not as easy to obtain new derivatives as planned on paper.
本発明者らは先に、カンプトテシンの5−位に
おける選択的な酸化、アルキル化、7−位への
種々の炭素官能基の導入等に成功し、それにより
各種の新規物質を提供することに成功したが、近
年、喜樹(Camptotheca acuminata)より単離
された10−ヒドロキシカンプトテシンがカンプト
テシンに比べ毒性が低く、更に優れた制ガン活性
を有することが報告されている(中〓医学〓志、
1978年)。本発明者らはカンプトテシン又はその
5−位置換誘導体及び7−位置換誘導体に対し、
それらの10−位への化学的修飾について検討して
来たところ、本発明により、カンプトテシン及び
その5−位置換誘導体又は7−位置換誘導体を、
それぞれ、そのN−オキシドとし、それを酸の存
在下に、活性水素を有する試薬(R3XH、R3は水
素原子、アルキル基、アシル基であり、Xは酸素
原子又はイオウ原子である)とともに紫外線照射
することにより前記、一般式で表わされる新規な
カンプトテシン誘導体を提供することに成功し
た。 The present inventors have previously succeeded in selective oxidation and alkylation at the 5-position of camptothecin, and introduction of various carbon functional groups into the 7-position, thereby providing various new substances. However, in recent years, it has been reported that 10-hydroxycamptothecin, isolated from Camptotheca acuminata, has lower toxicity and even better anticancer activity than camptothecin (Chinese Medical Science,
1978). The present inventors have demonstrated that camptothecin or its 5-position substituted derivatives and 7-position substituted derivatives
As a result of our studies on chemical modification at the 10-position, we found that according to the present invention, camptothecin and its 5-position substituted derivatives or 7-position substituted derivatives,
Reagents having active hydrogen ( R 3 By irradiating the compound with ultraviolet light, we succeeded in providing a novel camptothecin derivative represented by the above general formula.
上述のN−オキシドを得るには、以下のごとき
方法を用いる。すなわち、カンプトテシン及び5
−位置換誘導体又は7−位置換誘導体に対し、酢
酸中で、過酸化水素を作用させることにより、高
収率で対応するN−オキシドが得られる。過酸化
水素の代わりに過硫酸塩やメタクロロ過安息香酸
を用いても同様にN−オキシドを得ることができ
る。 To obtain the above-mentioned N-oxide, the following method is used. That is, camptothecin and 5
By reacting hydrogen peroxide in acetic acid with a derivative substituted at the -position or a derivative substituted at the 7-position, the corresponding N-oxide can be obtained in high yield. N-oxide can be similarly obtained by using persulfate or metachloroperbenzoic acid instead of hydrogen peroxide.
次いで、これらのN−オキシド、すなわち、カ
ンプトテシン1−オキシド、5−位置換カンプト
テシン1−オキシド又は7−位置換カンプトテシ
ン1−オキシドを、それぞれジオキサン、アセト
ニトリル、クロロホルム、塩化メチレン、グライ
ム、ジグライム等の溶媒又はそれらの任意の混合
溶媒に溶解し、式、R3XHで表わされる前述の試
薬、例えば水、メタノール、エタノール等のアル
コール類、有機酸、アルキルメルカプタン等とと
もに、硫酸、過塩素酸等の鉱酸、有機スルホン
酸、三フツ化−ホウ素・エーテル等のルイス酸、
有機カルボン酸等を用いて、紫外線照射下に処理
する。なお上述の酸類は10〜15当量の割合で用い
ると好結果が得られる。上記の有機カルボン酸と
して、例えば酢酸、プロピオン酸等を用いる場合
は、これらの酸に溶媒の役割を果たせしめること
ができる。このようにして調製した反応混合物中
には二種の生成物が生成する。一つは少量の脱オ
キシ化した化合物であり、もう一つは10−位に式
R3Xで表わされる置換基が導入された本発明目的
物質の新規なカンプトテシン誘導体である。 These N-oxides, i.e., camptothecin 1-oxide, 5-substituted camptothecin 1-oxide, or 7-substituted camptothecin 1-oxide, are then dissolved in a solvent such as dioxane, acetonitrile, chloroform, methylene chloride, glyme, diglyme, etc., respectively. Or dissolved in any mixed solvent thereof, the aforementioned reagents represented by the formula R 3 acid, organic sulfonic acid, Lewis acid such as trifluoride-boron ether,
Treatment is performed using an organic carboxylic acid or the like under ultraviolet irradiation. Note that good results can be obtained when the above-mentioned acids are used in an amount of 10 to 15 equivalents. When using, for example, acetic acid, propionic acid, etc. as the organic carboxylic acid, these acids can serve as a solvent. Two products are formed in the reaction mixture thus prepared. One is a small amount of deoxygenated compound and the other is a compound with formula at the 10-position.
This is a novel camptothecin derivative, which is the target substance of the present invention, into which a substituent represented by R 3 X has been introduced.
以上述べたように、カンプトテシン、その5−
位置換誘導体及び7−位置換誘導体をそれぞれ、
そのN−オキシドへ導き、それを酸性条件下に、
式、R3XHで表わされる活性水素を有する試薬と
紫外線照射下に反応せしめることにより本発明の
新規なカンプトテシン誘導体が得られる。 As mentioned above, camptothecin, part 5-
The position substituted derivative and the 7-position substituted derivative, respectively,
to its N-oxide, which under acidic conditions,
The novel camptothecin derivative of the present invention can be obtained by reacting it with a reagent having an active hydrogen represented by the formula R 3 XH under ultraviolet irradiation.
本発明に係る新規なカンプトテシン誘導体は医
薬品又はそれらの中間体として有用な物質であ
る。 The novel camptothecin derivative according to the present invention is a substance useful as a pharmaceutical or an intermediate thereof.
以下に実施例により本発明を更に詳細に説明す
るが、本発明はかかる実施例に限定されるもので
はない。 EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these Examples.
実施例 1−1
カンプトテシン1−オキシドの合成
カンプトテシン(1.04g、3mmol)を酢酸
(100ml)に懸濁し、これに30%過酸化水素(15
ml)を加え、60〜70℃で3時間撹拌する。得られ
た反応混合物を減圧により約35mlの容量まで濃縮
し、これを氷水(500ml)中に注ぐ。析出する黄
橙色針晶を取し、これを水で、次いでメタノー
ルで洗浄し、減圧で乾燥すると、866mg(90.6%
収率)のカンプトテシン1−オキシドが得られ
る。m.p.254゜(dec.)。Example 1-1 Synthesis of camptothecin 1-oxide Camptothecin (1.04 g, 3 mmol) was suspended in acetic acid (100 ml), and 30% hydrogen peroxide (15
ml) and stir at 60-70°C for 3 hours. The resulting reaction mixture is concentrated under reduced pressure to a volume of approximately 35 ml and poured into ice water (500 ml). The precipitated yellow-orange needles were collected, washed with water and then methanol, and dried under reduced pressure to yield 866 mg (90.6%
A yield of camptothecin 1-oxide is obtained. mp254゜(dec.).
実施例 1−2
10−〔(カルボエトキシメチル)チオ〕カンプト
テシンの合成
カンプトテシン1−オキシド(75mg、0.206m
mol)をエタノールを含まないクロロホルム(50
ml)とジオキサン(50ml)に溶解し、これに、三
フツ化ホウ素(50μl)とチオグリコール酸エチ
ル(5g)を加えて、40分間光照射する。反応混
合物を減圧で濃縮し、次いで、水(100ml)を加
え、クロロホルム(100ml×3)で抽出する。ク
ロロホルム層を硫酸マグネシウムで乾燥した後、
過し、減圧で乾固し、残留物をシリカゲル(5
g)で脱色し、高速液体クロマトグラフイ
(RiChrosorb SI−60カラム、10%−アセトン−
クロロホルム)で精製すると、カンプトテシン22
mgとともに標題の化合物20mg(20.8%)が得られ
る。Example 1-2 Synthesis of 10-[(carboethoxymethyl)thio]camptothecin Camptothecin 1-oxide (75 mg, 0.206 m
mol) in ethanol-free chloroform (50
ml) and dioxane (50 ml), add boron trifluoride (50 μl) and ethyl thioglycolate (5 g), and irradiate with light for 40 minutes. The reaction mixture is concentrated under reduced pressure, then water (100 ml) is added and extracted with chloroform (100 ml x 3). After drying the chloroform layer with magnesium sulfate,
The residue was filtered and dried under reduced pressure with silica gel (5
g) and high performance liquid chromatography (RiChrosorb SI-60 column, 10% acetone).
When purified with chloroform), camptothecin 22
mg along with 20 mg (20.8%) of the title compound are obtained.
黄色針晶、m.p.228−231(dec.)〔クロロホルム
−n−ヘキサン〕
NMR(in CDCl3):1.04(3H、t、J=7.8Hz)、
1.25(3H、t、J=7.3Hz)、1.90(2H、q、J
=7.8Hz)、3.81(2H、s)、4.21(2H、q、J
=7.3Hz)、5.28(1H、d、J=16.6Hz)、5.27
(2H、s)、5.75(2H、d、J=16.6Hz)、7.64
(1H、s)、7.70(2H、m)、8.17(1H、d、J
=9Hz)、8.26(1H、br、s)
MS:m/e 466〔M+〕(C24H22N2O6S=466と
して)
実施例 2−1
5−メチルカンプトテシン1−オキシドの合成
5−メチルカンプトテシン(362mg、1m
mol)を酢酸(25ml)に溶解し、これに30%過酸
化水素(2.5ml、0.0245mol)を加え、65〜70℃で
3時間加温する。反応混合物を減圧で約1/5容量
まで濃縮し、これを氷水(250ml)で希釈し、析
出する黄橙色針晶を取し、減圧下60℃で6時間
乾燥すると、5−メチルカンプトテシン1−オキ
シド、234mgが得られる(収率62.0%)m.p.226〜
(dec.)。Yellow needles, mp228-231 (dec.) [chloroform- n -hexane] NMR (in CDCl 3 ): 1.04 (3H, t, J = 7.8Hz),
1.25 (3H, t, J = 7.3Hz), 1.90 (2H, q, J
=7.8Hz), 3.81 (2H, s), 4.21 (2H, q, J
= 7.3Hz), 5.28 (1H, d, J = 16.6Hz), 5.27
(2H, s), 5.75 (2H, d, J=16.6Hz), 7.64
(1H, s), 7.70 (2H, m), 8.17 (1H, d, J
= 9 Hz), 8.26 (1H, br, s) MS: m/e 466 [M + ] (as C 24 H 22 N 2 O 6 S = 466) Example 2-1 Synthesis of 5-methylcamptothecin 1-oxide 5-methylcamptothecin (362mg, 1m
mol) in acetic acid (25 ml), add 30% hydrogen peroxide (2.5 ml, 0.0245 mol), and heat at 65-70°C for 3 hours. The reaction mixture was concentrated to about 1/5 volume under reduced pressure, diluted with ice water (250 ml), and the precipitated yellow-orange needles were collected and dried under reduced pressure at 60°C for 6 hours to give 5-methylcamptothecin 1- Oxide, 234 mg is obtained (yield 62.0%) mp226~
(dec.).
MS:m/e 378〔M+〕(C21H18N2O5=378とし
て)
実施例 2−2
10−ヒドロキシ−5−メチルカンプトテシンの
合成
5−メチルカンプトテシン1−オキシド(27
mg、0.0714mmol)をアセトニトリル(20ml)−ジ
オキサン(25ml)−水(5ml)に溶解し、これに
濃硫酸(50μ)を加え30分間光照射する。反応
混合物を減圧で濃縮し、水(50ml)で希釈し、不
溶物を取し、乾燥し、シリカゲル・カラムクロ
マトグラフイ(2%−メタノール−クロロホル
ム)により精製すると、5−メチルカンプトテシ
ン5mgとともに標記の目的物11mg(収率:50.6
%)が淡黄白色の結晶として得られる。MS: m/e 378 [M + ] (as C 21 H 18 N 2 O 5 = 378) Example 2-2 Synthesis of 10-hydroxy-5-methylcamptothecin 5-methylcamptothecin 1-oxide (27
mg, 0.0714 mmol) was dissolved in acetonitrile (20 ml), dioxane (25 ml), and water (5 ml), and concentrated sulfuric acid (50 μ) was added thereto and irradiated with light for 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with water (50 ml), the insoluble material was removed, dried, and purified by silica gel column chromatography (2% methanol-chloroform) to give the title compound along with 5 mg of 5-methylcamptothecin. of target product 11 mg (yield: 50.6
%) is obtained as pale yellow-white crystals.
NMR(in DMSO−d6)δ:0.87(3H、t、J=
7Hz)、1.77(3H、br d、J=6Hz、C5−
CH3)、1.84(2H、q、J=7Hz)、5.36
(2H、br s、C17−H2)、5.60(1H、m、C5−
H)、6.43(1H、br s、D2O−
exchangeable)、7.07(2H、m、C9−H and
C14−H)、7.14(1H、d×d、J=9Hz、2
Hz、C11−H)、7.84(1H、d、J=9Hz、C12
−H)、8.41(1H、br s、C7−H)、10.34
(1H、s、D2O−exchangeable)。NMR (in DMSO−d 6 ) δ: 0.87 (3H, t, J=
7Hz), 1.77 (3H, br d, J=6Hz, C5-
CH 3 ), 1.84 (2H, q, J = 7Hz), 5.36
(2H, br s, C 17 − H 2 ), 5.60 (1H, m, C 5 −
H), 6.43 (1H, br s, D 2 O−
exchangeable), 7.07 (2H, m, C 9 −H and
C 14 −H), 7.14 (1H, d×d, J=9Hz, 2
Hz, C 11 −H), 7.84 (1H, d, J=9Hz, C 12
-H), 8.41 (1H, br s, C 7 -H), 10.34
(1H, s, D2O -exchangeable).
MS:m/e 378〔M+〕(C21H18N2O5=378とし
て)
実施例 3−1
5−メトキシカンプトテシン1−オキシドの合
成
5−メトキシカンプトテシン(190mg、0.5m
mol)を酢酸(15ml)に溶解し、これに、30%過
酸化水素(1.25ml、0.0125mol)を加え、65〜70
℃で3時間撹拌する。反応混合物を減圧下約1/4
容量まで濃縮し、これを氷水(200ml)で希釈
し、析出する黄橙色針晶を取し、減圧下に60℃
で6時間乾燥すると、5−メトキシカンプトテシ
ン1−オキシド、145mg(収率:73.6%)が得ら
れる。m.p.208゜〜(dec.)
NMR(in CDCl3):1.03(3H、t、J=7Hz)、
1.92(2H、q、J=7Hz)、3.51、3.66(1.5H
×2、s、s)、5.30(1H、d、J=16Hz)、
5.59(1H、d、J=16Hz)、6.73、6.85(0.5H
×2、s、s)、7.72−8.01(4H、m)、8.24
(1H、s)、8.76(1H、m)
MS:m/e 394〔M+〕(C21H18N2O6=394とし
て)
実施例 3−2
10−ヒドロキシ−5−メトキシカンプトテシン
の合成
5−メトキシカンプトテシン1−オキシド(98
mg、0.248mmol)をアセトニトリル(50ml)−ジ
オキサン(50ml)−水(5ml)に溶解し、これに
濃硫酸(100μ)を加え、30分間光照射する。
反応混合物を減圧で濃縮し、水(100ml)で希釈
する。不溶物を取し、乾燥し、シリカゲル・カ
ラムクロマトグラフイ(2%−メタノール−クロ
ロホルム)により精製すると、5−メトキシカン
プトテシン7mgとともに標記の目的物23.5mg(収
率:26.1%)が得られる。MS: m/e 378 [M + ] (as C 21 H 18 N 2 O 5 = 378) Example 3-1 Synthesis of 5-methoxycamptothecin 1-oxide 5-methoxycamptothecin (190 mg, 0.5 m
mol) in acetic acid (15 ml), to which 30% hydrogen peroxide (1.25 ml, 0.0125 mol) was added, and 65 to 70
Stir at ℃ for 3 hours. Reduce the reaction mixture to about 1/4 under reduced pressure.
Concentrate to volume, dilute this with ice water (200 ml), collect the precipitated yellow-orange needles, and incubate at 60°C under reduced pressure.
After drying for 6 hours, 145 mg (yield: 73.6%) of 5-methoxycamptothecin 1-oxide is obtained. mp208゜~(dec.) NMR (in CDCl 3 ): 1.03 (3H, t, J=7Hz),
1.92 (2H, q, J = 7Hz), 3.51, 3.66 (1.5H
×2, s, s), 5.30 (1H, d, J = 16Hz),
5.59 (1H, d, J = 16Hz), 6.73, 6.85 (0.5H
×2, s, s), 7.72−8.01 (4H, m), 8.24
(1H, s), 8.76 (1H, m) MS: m/e 394 [M + ] (as C 21 H 18 N 2 O 6 = 394) Example 3-2 Synthesis of 10-hydroxy-5-methoxycamptothecin 5-methoxycamptothecin 1-oxide (98
mg, 0.248 mmol) was dissolved in acetonitrile (50 ml), dioxane (50 ml), and water (5 ml), concentrated sulfuric acid (100 μ) was added thereto, and the mixture was irradiated with light for 30 minutes.
The reaction mixture is concentrated under reduced pressure and diluted with water (100ml). The insoluble matter is removed, dried, and purified by silica gel column chromatography (2% methanol-chloroform) to obtain 23.5 mg (yield: 26.1%) of the desired product along with 7 mg of 5-methoxycamptothecin.
NMR(in DMSO−d6)δ:0.87(3H、t、J=
7Hz)、1.83(2H、q、J=7Hz)、3.46、3.54
(1.5H×2、s、s、C5−OCH3)、5.39(2H、
br s、C17−H)、6.28(1H、br s、D2O−
exchangeable)、6.80、6.86(0.5H×2、s、
s、C5−H)、7.02(1H、d、J=2Hz、C9−
H)、7.21(1H、br s、C14−H)、7.25
(1H、d、d、J=9Hz、2Hz、C11−H)、
7.90(1H、d、J=9Hz、C12−H)、8.48
(1H、br s、C7−H)、10.36(1H、s、D2O
−exchangeable)。NMR (in DMSO−d 6 ) δ: 0.87 (3H, t, J=
7Hz), 1.83 (2H, q, J=7Hz), 3.46, 3.54
(1.5H×2, s, s, C 5 −OCH 3 ), 5.39 (2H,
br s, C 17 −H), 6.28 (1H, br s, D 2 O−
exchangeable), 6.80, 6.86 (0.5H×2, s,
s, C 5 −H), 7.02 (1H, d, J=2Hz, C 9 −
H), 7.21 (1H, br s, C14 -H), 7.25
(1H, d, d, J = 9Hz, 2Hz, C 11 −H),
7.90 (1H, d, J=9Hz, C12 -H), 8.48
(1H, br s, C 7 −H), 10.36 (1H, s, D 2 O
−exchangeable).
MS:m/e 394〔M+〕(C21H18N2O6=394とし
て)
実施例 4−1
7−エチルカンプトテシン1−オキシドの合成
7−エチルカンプトテシン(1.00g、2.65m
mol)を酢酸(300ml)に溶解し、これに、30%
−過酸化水素(7.5ml、0.0736mol)を加え、65〜
70゜で3時間撹拌する。反応混合物を減圧下約1/
4容量まで濃縮し、氷水(500ml)で希釈し、析出
する黄橙色針晶を取し、減圧下に60℃で6時間
乾燥すると7−エチルカンプトテシン1−オキシ
ド808mg(収率:77.7%)が得られる。MS: m/e 394 [M + ] (as C 21 H 18 N 2 O 6 = 394) Example 4-1 Synthesis of 7-ethylcamptothecin 1-oxide 7-ethylcamptothecin (1.00 g, 2.65 m
mol) in acetic acid (300 ml) and add 30%
− Add hydrogen peroxide (7.5 ml, 0.0736 mol), 65 ~
Stir at 70° for 3 hours. The reaction mixture was heated under reduced pressure to approximately 1/2
Concentrate to 4 volumes, dilute with ice water (500 ml), collect precipitated yellow-orange needles, and dry under reduced pressure at 60°C for 6 hours to obtain 808 mg of 7-ethylcamptothecin 1-oxide (yield: 77.7%). can get.
m.p.255゜〜(dec.)
NMR(in DMSO−d6):0.87(3H、t、J=7
Hz)、1.28(3H、t、J=7Hz)、1.84(2H、
q、J=7Hz)、3.10(2H、q、J=7Hz)、
5.26(2H、s)、5.36(2H、s)、6.24(1H、
s、D2O−exchangeable)、7.80(3H、m)、
8.10(1H、s)、8.35(1H、m)
MS:m/e 392〔M+〕(C22H20N2O5=392とし
て)
実施例 4−2
7−エチル−10−ヒドロキシカンプトテシンの
合成
7−エチルカンプトテシン1−オキシド(100
mg、0.255mmol)をアセトニトリル(65ml)−ジ
オキサン(30ml)−水(5ml)に溶解し、これ
に、濃硫酸(0.1ml)を加え、25分間光照射す
る。反応混合物を減圧で濃縮し、水(100ml)を
加え、クロロホルム(100ml×3)で抽出する。
クロロホルム層を硫酸マグネシウムで乾燥し、
過し、減圧で乾固し、残留物をシリカゲルカラム
クロマトグラフイ(2%−メタノール−クロロホ
ルム)により精製すると、7−エチルカンプトテ
シン12mgとともに標記の目的化合物43mg(収率:
49.1%)が淡黄白色の結晶として得られる。m.
p.231゜〜(dec.)〔EtOH〕
NMR(in CDCl3)δ:0.98(3H、t、J=7
Hz)、1.38(3H、t、J=7Hz)、1.90(2H、
q、J=7Hz)、3.08(2H、q、J=7Hz)、
5.17(2H、s)、5.23(1H、d、J=16Hz)、
5.54(1H、d、J=16Hz)、7.34(2H、m)、
7.39(1H、s)、7.92(1H、d、J=9Hz)
MS:m/e 392〔M+〕(C22H20N2O5=392とし
て)
実施例 4−3
7−エチル−5・10−ジヒドロキシカンプトテ
シンの合成
7−エチル−10−ヒドロキシカンプトテシン
(50mg、0.128mmol)をDMF(20ml)に溶解し、
これに無水炭酸カリウム(150mg)とヨウ素(40
mg、0.157mmol)を加え室温で5時間撹拌する。
その後、不溶物を過により除去し、液を乾固
し、残留物をシリカゲルカラムクロマトグラフイ
ーにより精製すると、標記の化合物35mg(67.0
%)が得られる。mp255゜~(dec.) NMR (in DMSO−d 6 ): 0.87 (3H, t, J=7
Hz), 1.28 (3H, t, J=7Hz), 1.84 (2H,
q, J=7Hz), 3.10 (2H, q, J=7Hz),
5.26 (2H, s), 5.36 (2H, s), 6.24 (1H,
s, D 2 O-exchangeable), 7.80 (3H, m),
8.10 (1H, s), 8.35 (1H, m) MS: m/e 392 [M + ] (as C 22 H 20 N 2 O 5 = 392) Example 4-2 of 7-ethyl-10-hydroxycamptothecin Synthesis 7-ethylcamptothecin 1-oxide (100
mg, 0.255 mmol) was dissolved in acetonitrile (65 ml), dioxane (30 ml), and water (5 ml), to which concentrated sulfuric acid (0.1 ml) was added and irradiated with light for 25 minutes. The reaction mixture was concentrated under reduced pressure, water (100 ml) was added, and the mixture was extracted with chloroform (100 ml x 3).
Dry the chloroform layer with magnesium sulfate,
The residue was purified by silica gel column chromatography (2% methanol-chloroform) to give 12 mg of 7-ethylcamptothecin as well as 43 mg of the title compound (yield:
49.1%) is obtained as pale yellow-white crystals. m.
p.231゜〜(dec.) [EtOH] NMR (in CDCl 3 ) δ: 0.98 (3H, t, J=7
Hz), 1.38 (3H, t, J=7Hz), 1.90 (2H,
q, J=7Hz), 3.08 (2H, q, J=7Hz),
5.17 (2H, s), 5.23 (1H, d, J=16Hz),
5.54 (1H, d, J = 16Hz), 7.34 (2H, m),
7.39 (1H, s), 7.92 (1H, d, J = 9Hz) MS: m/e 392 [M + ] (as C 22 H 20 N 2 O 5 = 392) Example 4-3 7-ethyl-5・Synthesis of 10-dihydroxycamptothecin Dissolve 7-ethyl-10-hydroxycamptothecin (50 mg, 0.128 mmol) in DMF (20 ml),
This is combined with anhydrous potassium carbonate (150mg) and iodine (40mg).
mg, 0.157 mmol) and stirred at room temperature for 5 hours.
Thereafter, insoluble matter was removed by filtration, the liquid was dried and the residue was purified by silica gel column chromatography to obtain 35 mg (67.0 mg) of the title compound.
%) is obtained.
1H−NMR(DMSO−d6中)δppm:0.90(3H、
t、J=7.5Hz)、1.30(3H、t、J=7.5Hz)、
1.90(2H、q、J=7.5Hz)、3.30(2H、q、J
=7.5Hz)、5.40(2H、s)、6.50(1H、s)、
7.0−8.0(6H、m)、10.30(1H、s)。 1H -NMR (in DMSO- d6 ) δppm: 0.90 (3H,
t, J=7.5Hz), 1.30 (3H, t, J=7.5Hz),
1.90 (2H, q, J = 7.5Hz), 3.30 (2H, q, J
=7.5Hz), 5.40 (2H, s), 6.50 (1H, s),
7.0−8.0 (6H, m), 10.30 (1H, s).
MS:m/e 408〔M+〕、(C22H20N2O6=408と
して)
実施例 4−4
7−エチル−10−ヒドロキシ−5−メトキシカ
ンプトテシンの合成
7−エチル−5・10−ジヒドロキシカンプトテ
シン(20mg、0.049mmol)をメタノール(30ml)
に懸濁し濃硫酸(0.5ml)を加え48時間撹拌す
る。その後溶媒を減圧留去し、残留物をクロロホ
ルムに溶解し、水で洗滌する。クロロホルム層を
無水硫酸マグネシウムで乾燥した後、減圧乾固
し、残留物をシリカゲルカラムクロマトグラフイ
ーで精製すると標記の化合物(18mg、87.0%)が
得られる。MS: m/e 408 [M + ], (as C 22 H 20 N 2 O 6 = 408) Example 4-4 Synthesis of 7-ethyl-10-hydroxy-5-methoxycamptothecin 7-ethyl-5・10 - Dihydroxycamptothecin (20 mg, 0.049 mmol) in methanol (30 ml)
Add concentrated sulfuric acid (0.5 ml) and stir for 48 hours. Thereafter, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform and washed with water. The chloroform layer is dried over anhydrous magnesium sulfate, dried under reduced pressure, and the residue is purified by silica gel column chromatography to obtain the title compound (18 mg, 87.0%).
1H−NMR(CDCl3中)ppm:1.00(3H、t、J
=7.5Hz)、1.25(3H、t、J=7.5Hz)、1.95
(2H、q、J=7.5Hz)、3.40(2H、q、J=7.5
Hz)、4.00(3H、s)、5.44(2H、ABq)、6.80
−8.10(5H、m)。 1H -NMR (in CDCl 3 ) ppm: 1.00 (3H, t, J
= 7.5Hz), 1.25 (3H, t, J = 7.5Hz), 1.95
(2H, q, J=7.5Hz), 3.40 (2H, q, J=7.5
Hz), 4.00 (3H, s), 5.44 (2H, ABq), 6.80
−8.10 (5H, m).
MS:m/e:422M+(C23H22N2O6=422とし
て)
実施例 5
7−エチル−10−メトキシカンプトテシンの合
成
7−エチルカンプトテシン1−オキシド(100
mg、0.255mmol)をメタノール(50ml)−ジオキ
サン(50ml)に溶解し、これに、濃硫酸(0.1
ml)を加え、30分間光照射する。反応混合物を減
圧で濃縮し、水(100ml)で希釈、クロロホルム
(100ml×3)で抽出し、クロロホルム層を硫酸マ
グネシウムで乾燥し、過し、減圧で乾固し、残
留物をシリカゲル(5g)で脱色後高速液体クロ
マトグラフイ(RiChrosorb SI−60カラム、10%
−アセトン−クロロホルム)により精製すると、
18mgの7−エチルカンプトテシンとともに、27mg
(収率:33.2%)の標記の目的物が得られる。淡
黄白色針晶、m.p.261゜〜(dec.)〔n−ヘキサン
−クロロホルム〕
NMR(in CDCl3)δ:1.28(3H、t、J=7
Hz)、1.49(3H、t、J=7Hz)、1.97(2H、
q、J=7Hz)、3.24(2H、q、J=7Hz)、
4.30(3H、s)、5.27(2H、s)、5.25(1H、
d、J=16Hz)、5.70(1H、d、J=16Hz)、
7.20(1H、d、J=3Hz)、7.47(1H、d×
d、J=9Hz、3Hz)、7.72(1H、s)、8.53
(1H、d、J=9Hz)
MS:m/e 406〔M+〕(C23H22N2O5=406とし
て)
実施例 6−1
7−プロピルカンプトテシン1−オキシドの合
成
7−プロピルカンプトテシン(390mg、1m
mol)を酢酸(55ml)に溶解し、これに、30%−
過酸化水素(3ml、0.0294mol)を加え、65〜70
℃で4時間、撹拌する。反応混合物を減圧で約10
ml容量になるまで濃縮し、氷水(250ml)で希釈
し、析出する黄橙色の針晶を取し、減圧下に60
℃で6時間、乾燥すると、7−プロピルカンプト
テシン1−オキシド278mg(収率:68.4%)が得
られる。m.p.238゜〜(dec.)、MS:m/e 406
〔M+〕(C23H22N2O5=406として)
実施例 6−2
10−ヒドロキシ−7−プロピルカンプトテシン
の合成
7−プロピルカンプトテシン1−オキシド
(200mg、0.493mmol)をジオキサン(60ml)−ア
セトニトリル(20ml)−水(5ml)に溶解し、こ
れに、濃硫酸(100μ)を加え、30分間光照射
する。反応混合物を減圧で濃縮し、水(100ml)
で希釈する。不溶物を取し、乾燥し、シリカゲ
ル・カラムクロマトグラフイー(2%−メタノー
ル−クロロホルム)により精製すると7−プロピ
ルカンプトテシン11mgとともに標記の目的物
(121mg、収率60.5%)が得られる。MS: m/e: 422M + (as C 23 H 22 N 2 O 6 = 422) Example 5 Synthesis of 7-ethyl-10-methoxycamptothecin 7-ethylcamptothecin 1-oxide (100
mg, 0.255 mmol) in methanol (50 ml)-dioxane (50 ml), and concentrated sulfuric acid (0.1
ml) and irradiate with light for 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with water (100 ml), extracted with chloroform (100 ml x 3), the chloroform layer was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure, and the residue was purified with silica gel (5 g). High performance liquid chromatography (RiChrosorb SI-60 column, 10%
-acetone-chloroform)
27mg with 18mg 7-ethylcamptothecin
The title target product (yield: 33.2%) is obtained. Pale yellow-white needle crystals, mp261°~(dec.) [ n -hexane-chloroform] NMR (in CDCl3 ) δ: 1.28 (3H, t, J=7
Hz), 1.49 (3H, t, J=7Hz), 1.97 (2H,
q, J=7Hz), 3.24 (2H, q, J=7Hz),
4.30 (3H, s), 5.27 (2H, s), 5.25 (1H,
d, J=16Hz), 5.70 (1H, d, J=16Hz),
7.20 (1H, d, J = 3Hz), 7.47 (1H, d×
d, J=9Hz, 3Hz), 7.72 (1H, s), 8.53
(1H, d, J = 9Hz) MS: m/e 406 [M + ] (as C 23 H 22 N 2 O 5 = 406) Example 6-1 Synthesis of 7-propylcamptothecin 1-oxide 7-propylcamptothecin (390mg, 1m
mol) in acetic acid (55 ml) and add 30% -
Add hydrogen peroxide (3 ml, 0.0294 mol) to 65-70
Stir at ℃ for 4 hours. The reaction mixture was heated under reduced pressure for approximately 10 min.
Concentrate to a volume of 60 ml, dilute with ice water (250 ml), remove the precipitated yellow-orange needles, and boil for 60 mL under reduced pressure.
After drying for 6 hours at <0>C, 278 mg (yield: 68.4%) of 7-propylcamptothecin 1-oxide is obtained. mp238゜~(dec.), MS: m/e 406
[M + ] (as C 23 H 22 N 2 O 5 = 406) Example 6-2 Synthesis of 10-hydroxy-7-propylcamptothecin 7-propylcamptothecin 1-oxide (200 mg, 0.493 mmol) was dissolved in dioxane (60 ml) - Dissolve in acetonitrile (20 ml) - water (5 ml), add concentrated sulfuric acid (100μ), and irradiate with light for 30 minutes. The reaction mixture was concentrated under reduced pressure and added to water (100ml).
Dilute with The insoluble matter is removed, dried, and purified by silica gel column chromatography (2% methanol-chloroform) to obtain the title target compound (121 mg, yield 60.5%) along with 11 mg of 7-propylcamptothecin.
淡黄白色針晶、m.p.237゜〜(dec.)〔トルエン〕
NMR(in DMSO−d6)δ:0.89(3H、t、J=
7Hz)、1.06(3H、t、J=7Hz)、1.60−1.90
(5H、m)、3.00(2H、t、J=7Hz)、5.24
(2H、s)、5.40(2H、s)、6.24(1H、s、
D2O−exchangeable)、7.35(1H、s)、7.30
(2H、m)、7.99(1H、d、J=9Hz)
MS:m/e 406〔M+〕(C23H22N2O5=406とし
て)
実施例 7−1
7−ベンジルカンプトテシン1−オキシドの合
成
7−ベンジルカンプトテシン(250mg、0.570m
mol)を酢酸(50ml)に溶解し、これに、30%−
過酸化水素(2ml、0.0196mol)を加え、65〜70
℃で3時間撹拌する。反応混合物を減圧下に約10
ml容量になるまで濃縮し、次いで氷水(250ml)
で希釈する。これを12時間室温で放置した後、析
出した黄橙色の針晶を取し、減圧下に60℃で6
時間乾燥すると、7−ベンジルカンプトテシン1
−オキシド164mg(収率:63.5%)が得られる。Pale yellow-white needle crystals, mp237゜~ (dec.) [Toluene] NMR (in DMSO- d6 ) δ: 0.89 (3H, t, J=
7Hz), 1.06 (3H, t, J=7Hz), 1.60−1.90
(5H, m), 3.00 (2H, t, J=7Hz), 5.24
(2H, s), 5.40 (2H, s), 6.24 (1H, s,
D 2 O−exchangeable), 7.35 (1H, s), 7.30
(2H, m), 7.99 (1H, d, J = 9Hz) MS: m/e 406 [M + ] (as C 23 H 22 N 2 O 5 = 406) Example 7-1 7-Benzylcamptothecin 1- Synthesis of oxide 7-benzylcamptothecin (250mg, 0.570m
mol) in acetic acid (50 ml) and add 30% -
Add hydrogen peroxide (2 ml, 0.0196 mol) to 65-70
Stir at ℃ for 3 hours. The reaction mixture was heated under reduced pressure for approximately 10 min.
Concentrate to ml volume, then ice water (250ml)
Dilute with After this was left at room temperature for 12 hours, the yellow-orange needle crystals that had precipitated were removed and heated at 60℃ under reduced pressure for 6 hours.
When dried for an hour, 7-benzylcamptothecin 1
-164 mg (yield: 63.5%) of oxide are obtained.
m.p.220゜〜(dec.)
NMR(in CDCl3):1.09(3H、t、J=7.5Hz)、
1.87(2H、q、J=7.5Hz)、4.48(2H、s)、
5.16(2H、s)、5.20(1H、d、J=16Hz)、
5.64(1H、s、J=16Hz)、7.05−8.12(8H、
m)、8.32(1H、s)、8.80(1H、m)。mp220゜~(dec.) NMR (in CDCl 3 ): 1.09 (3H, t, J = 7.5Hz),
1.87 (2H, q, J = 7.5Hz), 4.48 (2H, s),
5.16 (2H, s), 5.20 (1H, d, J=16Hz),
5.64 (1H, s, J=16Hz), 7.05−8.12 (8H,
m), 8.32 (1H, s), 8.80 (1H, m).
MS:m/e 457〔M+〕(C27H22N2O5=454とし
て)
実施例 7−2
10−アセトキシ−7−ベンジルカンプトテシン
の合成
7−ベンジルカンプトテシン1−オキシド
(100mg、0.22mmol)を酢酸(100ml)に溶解し、
1時間光照射する。反応混合物を減圧下に乾固
し、シリカゲル(5g)で脱色した後高速液体ク
ロマトグラフイ〔RiChrosorb SI−60カラム、4
%−アセトン−クロロホルム〕により精製する
と、7−ベンジル−カンプトテシン14mgとともに
標記の目的物28mg(収率:29.9%)が得られる。
このものをn−ヘキサン−クロロホルムより再結
晶すると淡黄白色の針晶となる。MS: m/e 457 [M + ] (as C 27 H 22 N 2 O 5 = 454) Example 7-2 Synthesis of 10-acetoxy-7-benzylcamptothecin 7-Benzylcamptothecin 1-oxide (100 mg, 0.22 mmol ) in acetic acid (100ml),
Irradiate with light for 1 hour. The reaction mixture was dried under reduced pressure, decolorized with silica gel (5 g), and then subjected to high performance liquid chromatography [RiChrosorb SI-60 column, 4
%-acetone-chloroform] to obtain 28 mg (yield: 29.9%) of the desired product along with 14 mg of 7-benzyl-camptothecin.
When this product is recrystallized from n -hexane-chloroform, pale yellow-white needle crystals are obtained.
m.p.226゜〜(dec.)。m.p.226゜~ (dec.).
NMR(in CDCl3)δ:1.03(3H、t、J=7.3
Hz)、1.85(2H、q、J=7.3Hz)、2.37(3H、
s)、4.52(2H、s)、5.11(2H、s)、5.26
(1H、d、J=16Hz)、5.73(1H、d、J=16
Hz)、7.10(5H、m)、7.53(1H、d×d、J
=9Hz、3Hz)、7.65(1H、s)、7.89(1H、
d、J=3Hz)、8.27(1H、d、J=9Hz)
MS:m/e 496〔M+〕(C29H24N2O6=496とし
て)
実施例 8−1
7−アセトキシメチルカンプトテシン1−オキ
シドの合成
7−アセトキシメチルカンプトテシン(1.0
g、2.38mmol)を酢酸(150ml)に溶解し、これ
に、30%−過酸化水素(10ml、0.0981mol)を加
え、65〜70℃で3.5時間撹拌する。反応混合物を
減圧で、約50mlまで濃縮し、氷水(350ml)で希
釈し、クロロホルム(300ml×3)で抽出する。
クロロホルム層を7%−炭酸水素ナトリウム水溶
液で洗い、次いで硫酸マグネシウムで乾燥し、減
圧で乾固し、残留物をクロロホルム−n−ヘキサ
ンにより再沈澱させることにより精製すると7−
アセトキシメチルカンプトテシン1−オキシド
679mg(収率:65.9%)が黄色の針晶として得ら
れる。NMR (in CDCl 3 ) δ: 1.03 (3H, t, J = 7.3
Hz), 1.85 (2H, q, J = 7.3Hz), 2.37 (3H,
s), 4.52 (2H, s), 5.11 (2H, s), 5.26
(1H, d, J=16Hz), 5.73 (1H, d, J=16
Hz), 7.10 (5H, m), 7.53 (1H, d×d, J
=9Hz, 3Hz), 7.65 (1H, s), 7.89 (1H,
d, J = 3 Hz), 8.27 (1H, d, J = 9 Hz) MS: m/e 496 [M + ] (as C 29 H 24 N 2 O 6 = 496) Example 8-1 7-acetoxymethylcamptothecin Synthesis of 1-oxide 7-acetoxymethylcamptothecin (1.0
g, 2.38 mmol) was dissolved in acetic acid (150 ml), 30% hydrogen peroxide (10 ml, 0.0981 mol) was added thereto, and the mixture was stirred at 65-70°C for 3.5 hours. The reaction mixture is concentrated under reduced pressure to approximately 50 ml, diluted with ice water (350 ml) and extracted with chloroform (3 x 300 ml).
The chloroform layer was washed with a 7% aqueous sodium bicarbonate solution, then dried over magnesium sulfate, evaporated to dryness under reduced pressure, and the residue was purified by reprecipitation with chloroform- n -hexane to give 7-
Acetoxymethylcamptothecin 1-oxide
679 mg (yield: 65.9%) are obtained as yellow needles.
m.p.250゜〜(dec.)
NMR(in DMSO−d6):0.87(3H、t、J=7
Hz)、1.83(2H、q、J=7Hz)、2.05(3H、
s)、5.42(4H、br s)、5.61(2H、s)、6.42
(1H、s、D2O−exchangeable)、7.80(2H、
m)、7.91(1H、s)、8.20(1H、m)、8.63
(1H、m)、
MS:m/e 436〔M+〕(C23H20N2O7=436とし
て)
実施例 8−2
7−アセトキシメチル−10−ヒドロキシカンプ
トテシンの合成
7−アセトキシメチルカンプトテシン1−オキ
シド(75mg、0.172mmol)をジオキサン(40ml)
−アセトニトリル(50ml)−水(10ml)に溶解
し、これに、濃硫酸(0.1ml)を加え、45分間光
照射する。反応混合物を減圧で約半量に濃縮し、
水(100ml)で希釈し、クロロホルム(200ml×
2)で抽出する。クロロホルム層を硫酸マグネシ
ウムで乾燥し、過し、減圧で乾固し、残留物を
シリカゲル・カラム・クロマトグラフイー(2%
−メタノール−クロロホルム)により分離すると
7−アセトキシメチルカンプトテシン(22mg)と
ともに標記の化合物24mg(収率:32%)が得られ
る。mp250゜~(dec.) NMR (in DMSO−d 6 ): 0.87 (3H, t, J=7
Hz), 1.83 (2H, q, J=7Hz), 2.05 (3H,
s), 5.42 (4H, br s), 5.61 (2H, s), 6.42
(1H, s, D 2 O−exchangeable), 7.80 (2H,
m), 7.91 (1H, s), 8.20 (1H, m), 8.63
(1H, m), MS: m/e 436 [M + ] (as C23H20N2O7 =436) Example 8-2 Synthesis of 7- acetoxymethyl - 10 - hydroxycamptothecin 7-acetoxymethylcamptothecin 1-oxide (75mg, 0.172mmol) in dioxane (40ml)
- Acetonitrile (50 ml) - Dissolve in water (10 ml), add concentrated sulfuric acid (0.1 ml), and irradiate with light for 45 minutes. The reaction mixture was concentrated to about half its volume under reduced pressure.
Dilute with water (100 ml) and chloroform (200 ml
2) Extract. The chloroform layer was dried over magnesium sulfate, filtered and dried under reduced pressure, and the residue was subjected to silica gel column chromatography (2%
-methanol-chloroform) to give 24 mg (yield: 32%) of the title compound along with 7-acetoxymethylcamptothecin (22 mg).
淡黄白色針晶、m.p.257゜(dec.)〔n−ヘキサン
−クロロホルム〕
NMR(in DMSO−d6)δ:0.98(3H、t、J=
7Hz)、1.38(3H、t、J=7Hz)、1.90
(2H、q、J=7Hz)、3.08(2H、q、J=7
Hz)、5.17(2H、s)、5.23(2H、s)、5.54
(2H、s)、6.34(1H、br、D2O−
exchangeable)、7.34(2H、m)、7.39(1H、
s)、7.92(1H、d、J=9Hz)
MS:m/e 436〔M+〕(C23H20N2O7=436とし
て)
実施例 9−1
7−ヒドロキシメチルカンプトテシン1−オキ
シドの合成
7−ヒドロキシメチルカンプトテシン(300
mg、0.794mmol)を氷酢酸(70ml)に懸濁し、こ
れに、30%過酸化水素(30ml)を加え、70〜80℃
で1時間撹拌する。これに、30%過酸化水素(20
ml)を追加し、更に70〜80℃で1.5時間撹拌を続
ける。反応混合物を40ml容量になるまで、減圧で
濃縮し、氷水(60ml)を加え12時間放置する。析
出した黄色結晶を取し、減圧下で乾燥すると、
標記化合物142mg(収率:45.4%)が黄色針晶と
して得られる。Pale yellow-white needles, mp257° (dec.) [ n -hexane-chloroform] NMR (in DMSO- d6 ) δ: 0.98 (3H, t, J=
7Hz), 1.38 (3H, t, J=7Hz), 1.90
(2H, q, J=7Hz), 3.08 (2H, q, J=7
Hz), 5.17 (2H, s), 5.23 (2H, s), 5.54
(2H, s), 6.34 (1H, br, D 2 O−
exchangeable), 7.34 (2H, m), 7.39 (1H,
s), 7.92 (1H, d, J = 9Hz) MS: m/e 436 [M + ] (as C 23 H 20 N 2 O 7 = 436) Example 9-1 of 7-hydroxymethylcamptothecin 1-oxide Synthesis 7-hydroxymethylcamptothecin (300
mg, 0.794 mmol) in glacial acetic acid (70 ml), added 30% hydrogen peroxide (30 ml), and
Stir for 1 hour. Add to this 30% hydrogen peroxide (20
ml) and continue stirring at 70-80°C for an additional 1.5 hours. The reaction mixture was concentrated under reduced pressure to a volume of 40 ml, added with ice water (60 ml) and left for 12 hours. The precipitated yellow crystals are collected and dried under reduced pressure.
142 mg (yield: 45.4%) of the title compound is obtained as yellow needles.
m.p.255−260℃(dec.)
IRνKBr naxcm-1;3400、2940、1755、1650、1600
、
1460、1160、1100、765
実施例 9−2
7−ヒドロキシメチル−10−ヒドロキシカンプ
トテシンの合成
7−ヒドロキシメチルカンプトテシン1−オキ
シド(50mg、0.127mmol)をジオキサン(40
ml)、アセトニトリル(40ml)、及び水(10ml)の
混合溶媒に溶解し、これに、濃硫酸(3滴)を加
え、10分間光照射する。反応混合物を減圧下に濃
縮し、残留物に水(20ml)を加え不溶物を取乾
燥すると、40mg(80%)の標記化合物が得られ
る。これをシリカゲルクロマトグラフイーにより
精製した。mp255−260℃(dec.) IRν KBr nax cm -1 ; 3400, 2940, 1755, 1650, 1600
,
1460, 1160, 1100, 765 Example 9-2 Synthesis of 7-hydroxymethyl-10-hydroxycamptothecin 7-hydroxymethylcamptothecin 1-oxide (50 mg, 0.127 mmol) was dissolved in dioxane (40 mg, 0.127 mmol).
ml), acetonitrile (40 ml), and water (10 ml), add concentrated sulfuric acid (3 drops), and irradiate with light for 10 minutes. The reaction mixture was concentrated under reduced pressure, water (20 ml) was added to the residue, and the insoluble matter was dried to obtain 40 mg (80%) of the title compound. This was purified by silica gel chromatography.
m.p.260−263℃(dec.)
IRνKBr naxcm-1;3400、2980、1735、1650、1590
、
1240、1160、1100、800、775mp260−263℃(dec.) IRν KBr nax cm -1 ; 3400, 2980, 1735, 1650, 1590
,
1240, 1160, 1100, 800, 775
Claims (1)
基、アルコキシル基又はアシロキシル基であり、
R2は水素原子、アルキル基、アラルキル基、ヒ
ドロキシメチル基またはアシロキシメチル基であ
り、R3は水素原子、アルキル基又はアシル基で
あり、Xは酸素原子又はイオウ原子である。ただ
し、R1、R2がともに水素原子である場合は、R3X
は、−OH、−OCH3、−OCOCH3でないものとす
る)で表わされるカンプトテシン誘導体。[Claims] 1. General formula (In the formula, R 1 is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or an acyloxyl group,
R 2 is a hydrogen atom, an alkyl group, an aralkyl group, a hydroxymethyl group or an acyloxymethyl group, R 3 is a hydrogen atom, an alkyl group or an acyl group, and X is an oxygen atom or a sulfur atom. However, if R 1 and R 2 are both hydrogen atoms, R 3
is not -OH, -OCH3 , -OCOCH3 ).
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP13841081A JPS5839683A (en) | 1981-09-04 | 1981-09-04 | Novel camptothecin derivative |
US06/413,879 US4473692A (en) | 1981-09-04 | 1982-09-01 | Camptothecin derivatives and process for preparing same |
CA000410691A CA1246576A (en) | 1981-09-04 | 1982-09-02 | Camptothecin derivatives and process for preparing same |
DE8282304649T DE3274351D1 (en) | 1981-09-04 | 1982-09-03 | Camptothecin derivatives, processes for preparing same, formulations containing such derivatives and their use |
EP82304649A EP0074256B1 (en) | 1981-09-04 | 1982-09-03 | Camptothecin derivatives, processes for preparing same, formulations containing such derivatives and their use |
US06/632,039 US4545880A (en) | 1981-09-04 | 1984-07-18 | Photochemical process for preparing camptothecin derivatives |
BR1100879-2A BR1100879A (en) | 1981-09-04 | 1997-05-14 | New camptothecin derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP13841081A JPS5839683A (en) | 1981-09-04 | 1981-09-04 | Novel camptothecin derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5839683A JPS5839683A (en) | 1983-03-08 |
JPS6247193B2 true JPS6247193B2 (en) | 1987-10-06 |
Family
ID=15221303
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP13841081A Granted JPS5839683A (en) | 1981-09-04 | 1981-09-04 | Novel camptothecin derivative |
Country Status (2)
Country | Link |
---|---|
JP (1) | JPS5839683A (en) |
BR (1) | BR1100879A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH04137596A (en) * | 1990-09-27 | 1992-05-12 | Shimadzu Corp | Preventing mechanism for wrong insertion of card of control system |
US8476438B2 (en) | 2006-04-27 | 2013-07-02 | Kabushiki Kaisha Yakult Honsha | Process for production of camptothecin derivative |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0615546B2 (en) * | 1986-02-24 | 1994-03-02 | 株式会社ヤクルト本社 | Novel camptothecin derivative |
JPH0615547B2 (en) * | 1988-01-20 | 1994-03-02 | 株式会社ヤクルト本社 | Novel camptothecin derivative |
US6214836B1 (en) | 1995-06-06 | 2001-04-10 | Dr. Reddy's Research Foundation | Water soluble analogues of 20(S)-camptothecin |
US6177439B1 (en) | 1995-06-06 | 2001-01-23 | Reddy's Research Foundation | Water soluble analogues of 20(S)-camptothecin |
CN1309763C (en) * | 2002-10-31 | 2007-04-11 | 日本化药株式会社 | High-molecular weight derivatives of camptothecins |
US7067666B2 (en) * | 2003-06-27 | 2006-06-27 | Research Triangle Institute | 7-substituted camptothecin and camptothecin analogs and methods for producing the same |
US7897772B2 (en) | 2004-10-01 | 2011-03-01 | Kabushiki Kaisha Yakult Honsha | Acid addition salt of irinotecan |
WO2009002489A2 (en) * | 2007-06-25 | 2008-12-31 | Scinopharm Taiwan Ltd. | Crystalline polymorph of 7-ethyl-10-hydroxycamptothecin |
-
1981
- 1981-09-04 JP JP13841081A patent/JPS5839683A/en active Granted
-
1997
- 1997-05-14 BR BR1100879-2A patent/BR1100879A/en active IP Right Grant
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH04137596A (en) * | 1990-09-27 | 1992-05-12 | Shimadzu Corp | Preventing mechanism for wrong insertion of card of control system |
US8476438B2 (en) | 2006-04-27 | 2013-07-02 | Kabushiki Kaisha Yakult Honsha | Process for production of camptothecin derivative |
Also Published As
Publication number | Publication date |
---|---|
JPS5839683A (en) | 1983-03-08 |
BR1100879A (en) | 2000-03-14 |
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