CA1042428A - Amide derivatives of vlb and leurocristine - Google Patents
Amide derivatives of vlb and leurocristineInfo
- Publication number
- CA1042428A CA1042428A CA195,760A CA195760A CA1042428A CA 1042428 A CA1042428 A CA 1042428A CA 195760 A CA195760 A CA 195760A CA 1042428 A CA1042428 A CA 1042428A
- Authority
- CA
- Canada
- Prior art keywords
- desacetyl
- alk
- formula
- compound
- acid
- 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
- 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 title claims abstract description 46
- 150000001408 amides Chemical class 0.000 title claims description 38
- 238000000034 method Methods 0.000 claims abstract description 71
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims abstract description 70
- -1 AMIDE DERIVATIVES OF VLB Chemical class 0.000 claims abstract description 58
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical class 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 claims abstract description 49
- JXLYSJRDGCGARV-KSNABSRWSA-N ac1l29ym 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-KSNABSRWSA-N 0.000 claims abstract description 23
- JXLYSJRDGCGARV-PJXZDTQASA-N Leurosidine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-PJXZDTQASA-N 0.000 claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- NDMPLJNOPCLANR-PETVRERISA-N deacetylvinblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](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 NDMPLJNOPCLANR-PETVRERISA-N 0.000 claims description 86
- 150000001875 compounds Chemical class 0.000 claims description 79
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 claims description 57
- 229960003048 vinblastine Drugs 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 31
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 27
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 23
- 150000001540 azides Chemical class 0.000 claims description 23
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- 150000003857 carboxamides Chemical class 0.000 claims description 21
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 14
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- 229910021529 ammonia Inorganic materials 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- KERBAAIBDHEFDD-UHFFFAOYSA-N n-ethylformamide Chemical compound CCNC=O KERBAAIBDHEFDD-UHFFFAOYSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 8
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- CTKABCGZHPSDGL-UHFFFAOYSA-N n-methylformamide;sulfuric acid Chemical compound CNC=O.OS(O)(=O)=O CTKABCGZHPSDGL-UHFFFAOYSA-N 0.000 claims description 7
- 235000010288 sodium nitrite Nutrition 0.000 claims description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 5
- 239000007868 Raney catalyst Substances 0.000 claims description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 5
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims description 3
- 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 2
- IIBOGKHTXBPGEI-UHFFFAOYSA-N N-benzylformamide Chemical compound O=CNCC1=CC=CC=C1 IIBOGKHTXBPGEI-UHFFFAOYSA-N 0.000 claims description 2
- DFNYGALUNNFWKJ-UHFFFAOYSA-N aminoacetonitrile Chemical compound NCC#N DFNYGALUNNFWKJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 claims description 2
- HHENWUYAOCBSAE-UHFFFAOYSA-N n-(cyanomethyl)formamide Chemical compound O=CNCC#N HHENWUYAOCBSAE-UHFFFAOYSA-N 0.000 claims description 2
- KVTGAKFJRLBHLU-UHFFFAOYSA-N n-propan-2-ylformamide Chemical compound CC(C)NC=O KVTGAKFJRLBHLU-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 6
- 150000002431 hydrogen Chemical group 0.000 claims 6
- 229910017053 inorganic salt Inorganic materials 0.000 claims 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 2
- 229940071870 hydroiodic acid Drugs 0.000 claims 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 241000124008 Mammalia Species 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 230000001613 neoplastic effect Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 26
- 238000001228 spectrum Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- 238000001704 evaporation Methods 0.000 description 17
- 230000008020 evaporation Effects 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 238000005917 acylation reaction Methods 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 206010028980 Neoplasm Diseases 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 230000010933 acylation Effects 0.000 description 11
- 150000001793 charged compounds Chemical class 0.000 description 11
- 238000002329 infrared spectrum Methods 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 9
- 239000012458 free base Substances 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 229940073584 methylene chloride Drugs 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000000470 constituent Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- 125000003368 amide group Chemical group 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 239000011877 solvent mixture Substances 0.000 description 7
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 229930013930 alkaloid Natural products 0.000 description 5
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 240000001829 Catharanthus roseus Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000000118 anti-neoplastic effect Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 229940034982 antineoplastic agent Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 208000025036 lymphosarcoma Diseases 0.000 description 3
- 150000004702 methyl esters Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- PNVPNXKRAUBJGW-UHFFFAOYSA-N (2-chloroacetyl) 2-chloroacetate Chemical compound ClCC(=O)OC(=O)CCl PNVPNXKRAUBJGW-UHFFFAOYSA-N 0.000 description 2
- UKTNDLHXQNQKBH-UHFFFAOYSA-N 2,3-dihydro-1h-indole;1h-indole Chemical group C1=CC=C2NCCC2=C1.C1=CC=C2NC=CC2=C1 UKTNDLHXQNQKBH-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 2
- LPGWZGMPDKDHEP-GKWAKPNHSA-N Leurosine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@]6(CC)O[C@@H]6[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C LPGWZGMPDKDHEP-GKWAKPNHSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- WFPZPJSADLPSON-UHFFFAOYSA-N dinitrogen tetraoxide Chemical compound [O-][N+](=O)[N+]([O-])=O WFPZPJSADLPSON-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- AFENDNXGAFYKQO-VKHMYHEASA-N (S)-2-hydroxybutyric acid Chemical compound CC[C@H](O)C(O)=O AFENDNXGAFYKQO-VKHMYHEASA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- OAVBKHDCXXETQR-UHFFFAOYSA-N 2-chloropropanoyl 2-chloropropanoate Chemical compound CC(Cl)C(=O)OC(=O)C(C)Cl OAVBKHDCXXETQR-UHFFFAOYSA-N 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
-
- 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
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Fodder In General (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US34727573A | 1973-04-02 | 1973-04-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1042428A true CA1042428A (en) | 1978-11-14 |
Family
ID=23363051
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA195,760A Expired CA1042428A (en) | 1973-04-02 | 1974-03-22 | Amide derivatives of vlb and leurocristine |
Country Status (28)
| Country | Link |
|---|---|
| JP (2) | JPS5919117B2 (en, 2012) |
| AR (2) | AR204004A1 (en, 2012) |
| AT (1) | AT340605B (en, 2012) |
| BE (1) | BE813168A (en, 2012) |
| BG (3) | BG22831A3 (en, 2012) |
| CA (1) | CA1042428A (en, 2012) |
| CH (1) | CH603669A5 (en, 2012) |
| CS (1) | CS185223B2 (en, 2012) |
| CY (1) | CY1044A (en, 2012) |
| DD (1) | DD113538A5 (en, 2012) |
| DE (1) | DE2415980A1 (en, 2012) |
| DK (1) | DK141511B (en, 2012) |
| ES (2) | ES424882A1 (en, 2012) |
| FR (1) | FR2223044B1 (en, 2012) |
| GB (1) | GB1463575A (en, 2012) |
| HK (1) | HK20180A (en, 2012) |
| HU (1) | HU171572B (en, 2012) |
| IE (1) | IE39071B1 (en, 2012) |
| IL (1) | IL44415A (en, 2012) |
| KE (1) | KE3028A (en, 2012) |
| MY (1) | MY8100025A (en, 2012) |
| NL (1) | NL181079C (en, 2012) |
| PH (1) | PH13623A (en, 2012) |
| RO (2) | RO73524B (en, 2012) |
| SE (1) | SE416206B (en, 2012) |
| SU (4) | SU731900A3 (en, 2012) |
| YU (3) | YU39719B (en, 2012) |
| ZA (1) | ZA741674B (en, 2012) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USRE30561E (en) | 1976-12-06 | 1981-03-31 | Eli Lilly And Company | Vinca alkaloid intermediates |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL48685A (en) * | 1975-01-09 | 1980-03-31 | Lilly Co Eli | Amides of vincadioline and vinblastine |
| GR69783B (en, 2012) * | 1976-09-08 | 1982-07-07 | Lilly Co Eli | |
| US4096148A (en) * | 1976-12-06 | 1978-06-20 | Eli Lilly And Company | Oxazolidinedione derivatives of Vinca alkaloids |
| USRE30560E (en) * | 1976-12-06 | 1981-03-31 | Eli Lilly And Company | Oxazolidinedione derivatives of Vinca alkaloids |
| US4203898A (en) | 1977-08-29 | 1980-05-20 | Eli Lilly And Company | Amide derivatives of VLB, leurosidine, leurocristine and related dimeric alkaloids |
| US4199504A (en) * | 1978-05-15 | 1980-04-22 | Eli Lilly And Company | Bridged cathranthus alkaloid dimers |
| US4210584A (en) | 1979-01-15 | 1980-07-01 | Eli Lilly And Company | Vindesine synthesis |
| US4357334A (en) | 1980-03-20 | 1982-11-02 | Eli Lilly And Company | Use of VLB 3-(2-chloroethyl) carboxamide in treating neoplasms |
| OA06421A (fr) * | 1980-06-10 | 1981-09-30 | Omnium Chimique Sa | Procédé de préparation de dérivés N-(vinblastinoyl-23) d'acides aminés et de peptides. |
| LU83822A1 (fr) * | 1981-12-08 | 1983-09-01 | Omnichem Sa | Derives n-(vinblastinoyl-23)d'acides amines,leur preparation et leur application therapeutique |
| FR2623504B1 (fr) * | 1987-11-25 | 1990-03-09 | Adir | Nouveaux derives n-(vinblastinoyl-23) d'acide amino-1 methylphosphonique, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent |
| HUT76925A (hu) * | 1995-04-04 | 1998-01-28 | MTA Enzimológiai Intézet | Bisz-indol-származékok, eljárás előállításukra és az azokat tartalmazó gyógyszerkészítmények |
| US5948750A (en) * | 1996-10-30 | 1999-09-07 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
| US6326402B1 (en) | 1998-08-12 | 2001-12-04 | Octamer, Inc. | Methods for treating viral infections using a compound capable of inhibiting microtubules |
| AU2006207321B2 (en) | 2005-01-21 | 2012-09-06 | Astex Therapeutics Limited | Pharmaceutical compounds |
| RU2447889C2 (ru) | 2005-07-18 | 2012-04-20 | Бипар Сайенсиз, Инк. | Способ лечения рака (варианты) |
| US8143447B2 (en) | 2006-09-05 | 2012-03-27 | Bipar Sciences, Inc. | Treatment of cancer |
| CN101534836B (zh) | 2006-09-05 | 2011-09-28 | 彼帕科学公司 | Parp抑制剂在制备治疗肥胖症的药物中的用途 |
| EP2073807A1 (en) | 2006-10-12 | 2009-07-01 | Astex Therapeutics Limited | Pharmaceutical combinations |
| EP2073803B1 (en) | 2006-10-12 | 2018-09-19 | Astex Therapeutics Limited | Pharmaceutical combinations |
| EP2217227B1 (en) | 2007-11-12 | 2013-08-21 | BiPar Sciences, Inc. | Treatment of breast cancer with 4-iodo-3-nitrobenzamide in combination with anti-tumor agents |
| WO2014169697A1 (zh) * | 2013-04-19 | 2014-10-23 | 暨南大学 | 长春碱类衍生物及其制备方法和应用 |
| CN113456797B (zh) * | 2021-06-18 | 2024-03-08 | 暨南大学 | 长春碱类衍生物在制备治疗骨肉瘤和/或软组织肉瘤药物中的应用 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3097137A (en) * | 1960-05-19 | 1963-07-09 | Canadian Patents Dev | Vincaleukoblastine |
-
1974
- 1974-01-01 AR AR253105A patent/AR204004A1/es active
- 1974-03-13 ZA ZA00741674A patent/ZA741674B/xx unknown
- 1974-03-13 IL IL44415A patent/IL44415A/xx unknown
- 1974-03-13 IE IE532/74A patent/IE39071B1/xx unknown
- 1974-03-22 CA CA195,760A patent/CA1042428A/en not_active Expired
- 1974-03-25 YU YU817/74A patent/YU39719B/xx unknown
- 1974-03-25 GB GB1310174A patent/GB1463575A/en not_active Expired
- 1974-03-25 CY CY1044A patent/CY1044A/xx unknown
- 1974-03-29 CH CH446374A patent/CH603669A5/xx not_active IP Right Cessation
- 1974-03-29 PH PH15676A patent/PH13623A/en unknown
- 1974-03-29 FR FR7411519A patent/FR2223044B1/fr not_active Expired
- 1974-04-01 NL NLAANVRAGE7404423,A patent/NL181079C/xx not_active IP Right Cessation
- 1974-04-01 HU HU74EI00000538A patent/HU171572B/hu unknown
- 1974-04-01 DK DK178774AA patent/DK141511B/da not_active IP Right Cessation
- 1974-04-01 CS CS7400002335A patent/CS185223B2/cs unknown
- 1974-04-01 SE SE7404380A patent/SE416206B/xx not_active IP Right Cessation
- 1974-04-01 SU SU742013753A patent/SU731900A3/ru active
- 1974-04-01 AT AT267974A patent/AT340605B/de not_active IP Right Cessation
- 1974-04-02 ES ES424882A patent/ES424882A1/es not_active Expired
- 1974-04-02 DD DD177632A patent/DD113538A5/xx unknown
- 1974-04-02 RO RO78274A patent/RO73524B/ro unknown
- 1974-04-02 DE DE2415980A patent/DE2415980A1/de active Granted
- 1974-04-02 BG BG026279A patent/BG22831A3/xx unknown
- 1974-04-02 BG BG028513A patent/BG21612A3/xx unknown
- 1974-04-02 JP JP49037765A patent/JPS5919117B2/ja not_active Expired
- 1974-04-02 BG BG028514A patent/BG21235A3/xx unknown
- 1974-04-02 BE BE1005847A patent/BE813168A/xx not_active IP Right Cessation
- 1974-04-02 RO RO7498695A patent/RO77533A/ro unknown
-
1975
- 1975-01-08 AR AR257228A patent/AR203882A1/es active
- 1975-07-04 SU SU752151512A patent/SU784783A3/ru active
- 1975-07-09 SU SU752152020A patent/SU652896A3/ru active
-
1976
- 1976-03-31 ES ES446571A patent/ES446571A1/es not_active Expired
- 1976-12-20 SU SU762429453A patent/SU623522A3/ru active
-
1980
- 1980-02-27 KE KE3028A patent/KE3028A/xx unknown
- 1980-04-17 HK HK201/80A patent/HK20180A/xx unknown
- 1980-04-25 YU YU1138/80A patent/YU39875B/xx unknown
- 1980-04-25 YU YU1139/80A patent/YU39876B/xx unknown
-
1981
- 1981-12-30 MY MY25/81A patent/MY8100025A/xx unknown
-
1983
- 1983-12-16 JP JP58238722A patent/JPS6033837B2/ja not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USRE30561E (en) | 1976-12-06 | 1981-03-31 | Eli Lilly And Company | Vinca alkaloid intermediates |
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