CN1127984C - 含抗肿瘤药物和羟肟酸衍生物且具有抗肿瘤增强活性和/或副作用降低的药物组合物 - Google Patents
含抗肿瘤药物和羟肟酸衍生物且具有抗肿瘤增强活性和/或副作用降低的药物组合物 Download PDFInfo
- Publication number
- CN1127984C CN1127984C CN98807103A CN98807103A CN1127984C CN 1127984 C CN1127984 C CN 1127984C CN 98807103 A CN98807103 A CN 98807103A CN 98807103 A CN98807103 A CN 98807103A CN 1127984 C CN1127984 C CN 1127984C
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- chemical compound
- cisplatin
- amino
- 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 - Fee Related
Links
- 230000000694 effects Effects 0.000 title claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 24
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 22
- 239000002246 antineoplastic agent Substances 0.000 title claims description 10
- 239000002253 acid Substances 0.000 title abstract description 21
- 230000002829 reductive effect Effects 0.000 title abstract description 4
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 48
- 229960004316 cisplatin Drugs 0.000 claims description 47
- -1 nicotinoyl amidoxime Chemical compound 0.000 claims description 30
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 9
- 229960002949 fluorouracil Drugs 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 150000003230 pyrimidines Chemical class 0.000 claims description 4
- 108010006654 Bleomycin Proteins 0.000 claims description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 2
- 229960001561 bleomycin Drugs 0.000 claims description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 2
- 229960004562 carboplatin Drugs 0.000 claims description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims 3
- 229940088710 antibiotic agent Drugs 0.000 claims 3
- 150000003057 platinum Chemical class 0.000 claims 3
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 69
- 210000004027 cell Anatomy 0.000 description 25
- 238000012360 testing method Methods 0.000 description 24
- 241000699666 Mus <mouse, genus> Species 0.000 description 21
- 238000007912 intraperitoneal administration Methods 0.000 description 19
- 229910052760 oxygen Inorganic materials 0.000 description 17
- 239000001301 oxygen Substances 0.000 description 17
- 206010028980 Neoplasm Diseases 0.000 description 16
- 230000004083 survival effect Effects 0.000 description 16
- 239000003814 drug Substances 0.000 description 14
- 239000000824 cytostatic agent Substances 0.000 description 13
- 230000001085 cytostatic effect Effects 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 230000002401 inhibitory effect Effects 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 150000002576 ketones Chemical class 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- 241001655322 Streptomycetales Species 0.000 description 7
- 230000003115 biocidal effect Effects 0.000 description 7
- 230000002255 enzymatic effect Effects 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000006378 damage Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 125000005594 diketone group Chemical group 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 229940017687 beta-d-ribose Drugs 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 230000004217 heart function Effects 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 125000004423 acyloxy group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000890 drug combination Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.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 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 208000013600 Diabetic vascular disease Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229960003328 benzoyl peroxide Drugs 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 201000009101 diabetic angiopathy Diseases 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 125000003147 glycosyl group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000002962 histologic effect Effects 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 150000004880 oxines Chemical class 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229960003087 tioguanine Drugs 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 229960004982 vinblastine sulfate Drugs 0.000 description 2
- OYACSIBPSQCBNX-UHFFFAOYSA-N (1,3,5-triazin-2-ylamino)methanol Chemical compound OCNC1=NC=NC=N1 OYACSIBPSQCBNX-UHFFFAOYSA-N 0.000 description 1
- WTCMQMTZVIVOJR-XCADPSHZSA-N (3z,5z,7z)-2h-oxocine Chemical compound C\1O\C=C/C=C\C=C/1 WTCMQMTZVIVOJR-XCADPSHZSA-N 0.000 description 1
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- DLWOTOMWYCRPLK-UVTDQMKNSA-N (4z)-5-amino-6-(7-amino-6-methoxy-5,8-dioxoquinolin-2-yl)-4-(4,5-dimethoxy-6-oxocyclohexa-2,4-dien-1-ylidene)-3-methyl-1h-pyridine-2-carboxylic acid Chemical compound C1=CC(OC)=C(OC)C(=O)\C1=C\1C(N)=C(C=2N=C3C(=O)C(N)=C(OC)C(=O)C3=CC=2)NC(C(O)=O)=C/1C DLWOTOMWYCRPLK-UVTDQMKNSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- AGNGYMCLFWQVGX-AGFFZDDWSA-N (e)-1-[(2s)-2-amino-2-carboxyethoxy]-2-diazonioethenolate Chemical compound OC(=O)[C@@H](N)CO\C([O-])=C\[N+]#N AGNGYMCLFWQVGX-AGFFZDDWSA-N 0.000 description 1
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical compound C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 description 1
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 0.000 description 1
- KRHQRJXHSUXNQY-UHFFFAOYSA-N 2-(2-hydroxyphenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1O KRHQRJXHSUXNQY-UHFFFAOYSA-N 0.000 description 1
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 description 1
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 1
- VNBAOSVONFJBKP-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)propan-1-amine;hydrochloride Chemical compound Cl.CC(Cl)CN(CCCl)CCCl VNBAOSVONFJBKP-UHFFFAOYSA-N 0.000 description 1
- WVDGHGISNBRCAO-UHFFFAOYSA-N 2-hydroxyisophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1O WVDGHGISNBRCAO-UHFFFAOYSA-N 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-n-methyl-1,3,5-triazine-2,4,6-triamine Chemical compound CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- IGMMTYZWNUSEEU-UHFFFAOYSA-N 3-(2-chloroethyl)-1-cyclohexyl-1-nitrosourea Chemical compound ClCCNC(=O)N(N=O)C1CCCCC1 IGMMTYZWNUSEEU-UHFFFAOYSA-N 0.000 description 1
- LMHIBYREWJHKNZ-UHFFFAOYSA-N 3-methylpyridine-2-carboxylic acid Chemical compound CC1=CC=CN=C1C(O)=O LMHIBYREWJHKNZ-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- BMKGHLRYSVRTGW-UHFFFAOYSA-N 4-(hydrazinylmethyl)-n-propan-2-ylbenzamide Chemical compound CC(C)NC(=O)C1=CC=C(CNN)C=C1 BMKGHLRYSVRTGW-UHFFFAOYSA-N 0.000 description 1
- LNRZWAHOOLIOLA-MYINAIGISA-N 4-amino-1-[(2s,4s,5r)-2-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical class O=C1N=C(N)C=CN1[C@]1(F)O[C@H](CO)[C@@H](O)C1 LNRZWAHOOLIOLA-MYINAIGISA-N 0.000 description 1
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- WYXSYVWAUAUWLD-SHUUEZRQSA-N 6-azauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=N1 WYXSYVWAUAUWLD-SHUUEZRQSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- 102000055025 Adenosine deaminases Human genes 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- LJZPVWKMAYDYAS-UHFFFAOYSA-N Aklavine Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC1CC(N(C)C)C(O)C(C)O1 LJZPVWKMAYDYAS-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229930195573 Amycin Natural products 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- GGBDLBLBZPWPJP-KVTDHHQDSA-N BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C GGBDLBLBZPWPJP-KVTDHHQDSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 241000208328 Catharanthus Species 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- XCDXSSFOJZZGQC-UHFFFAOYSA-N Chlornaphazine Chemical compound C1=CC=CC2=CC(N(CCCl)CCCl)=CC=C21 XCDXSSFOJZZGQC-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 238000011765 DBA/2 mouse Methods 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 229920004011 Macrolon® Polymers 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Mitomycin E Natural products O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- JJIHLJJYMXLCOY-UHFFFAOYSA-N N-acetyl-DL-serine Natural products CC(=O)NC(CO)C(O)=O JJIHLJJYMXLCOY-UHFFFAOYSA-N 0.000 description 1
- JJIHLJJYMXLCOY-BYPYZUCNSA-N N-acetyl-L-serine Chemical compound CC(=O)N[C@@H](CO)C(O)=O JJIHLJJYMXLCOY-BYPYZUCNSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 1
- FFEYJKFKBAUWCK-UHFFFAOYSA-N O1COCC2=C1C=C1C=CC=CC1=C2 Chemical compound O1COCC2=C1C=C1C=CC=CC1=C2 FFEYJKFKBAUWCK-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 229930187135 Olivomycin Natural products 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 241000187392 Streptomyces griseus Species 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- UCTLHLZWKJIXJI-LXIBVNSESA-N [(3s,8r,9s,10r,13s,14s)-17-chloro-16-formyl-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C([C@@H]12)C[C@]3(C)C(Cl)=C(C=O)C[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 UCTLHLZWKJIXJI-LXIBVNSESA-N 0.000 description 1
- NYJRSYHHHBHHOR-UHFFFAOYSA-N [2-[2-[2-[[6-amino-2-[3-amino-1-[(2,3-diamino-3-oxopropyl)amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[[5-[[1-[2-[4-(4-carbamoyl-1,3-thiazol-2-yl)-1,3-thiazol-2-yl]ethylamino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-hydroxy-4-methyl-5-oxopentan- Chemical compound N=1C(C=2SC=C(N=2)C(N)=O)=CSC=1CCNC(=O)C(C(O)C)NC(=O)C(C)C(O)C(C)NC(=O)C(C(OC1C(C(O)C(O)C(CO)O1)OC1C(C(OC(N)=O)C(O)C(CO)O1)O)C=1NC=NC=1)NC(=O)C1=NC(C(CC(N)=O)NCC(N)C(N)=O)=NC(N)=C1C NYJRSYHHHBHHOR-UHFFFAOYSA-N 0.000 description 1
- GJUPDXTVUWKKFL-UHFFFAOYSA-N [O].C(CCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC Chemical compound [O].C(CCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC GJUPDXTVUWKKFL-UHFFFAOYSA-N 0.000 description 1
- XLIJUKVKOIMPKW-BTVCFUMJSA-N [O].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O Chemical compound [O].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O XLIJUKVKOIMPKW-BTVCFUMJSA-N 0.000 description 1
- USDJGQLNFPZEON-UHFFFAOYSA-N [[4,6-bis(hydroxymethylamino)-1,3,5-triazin-2-yl]amino]methanol Chemical compound OCNC1=NC(NCO)=NC(NCO)=N1 USDJGQLNFPZEON-UHFFFAOYSA-N 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- LJZPVWKMAYDYAS-QKKPTTNWSA-N aclacinomycin T Chemical compound O([C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 LJZPVWKMAYDYAS-QKKPTTNWSA-N 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 1
- 229950000242 ancitabine Drugs 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 150000001454 anthracenes Chemical class 0.000 description 1
- VGQOVCHZGQWAOI-YQRHFANHSA-N anthramycin Chemical compound N1[C@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-YQRHFANHSA-N 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229950006345 antramycin Drugs 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Natural products CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 229950011321 azaserine Drugs 0.000 description 1
- 150000001538 azepines Chemical class 0.000 description 1
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 1
- YAVVGPBYBUYPSR-UHFFFAOYSA-N benzene;oxygen Chemical compound [O].C1=CC=CC=C1 YAVVGPBYBUYPSR-UHFFFAOYSA-N 0.000 description 1
- 229950005567 benzodepa Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- VFIUCBTYGKMLCM-UHFFFAOYSA-N benzyl n-[bis(aziridin-1-yl)phosphoryl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NP(=O)(N1CC1)N1CC1 VFIUCBTYGKMLCM-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- ZPFKRQXYKULZKP-UHFFFAOYSA-N butylidene Chemical group [CH2+]CC[CH-] ZPFKRQXYKULZKP-UHFFFAOYSA-N 0.000 description 1
- 108700002839 cactinomycin Proteins 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000003683 cardiac damage Effects 0.000 description 1
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 1
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229950008249 chlornaphazine Drugs 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- ZYVSOIYQKUDENJ-WKSBCEQHSA-N chromomycin A3 Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1OC(C)=O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@@H](C)[C@H](OC(C)=O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@@H]1C[C@@H](O)[C@@H](OC)[C@@H](C)O1 ZYVSOIYQKUDENJ-WKSBCEQHSA-N 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 229940064302 folacin Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229960002899 hydroxyprogesterone Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 description 1
- 229950008612 mannomustine Drugs 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 0.000 description 1
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- QTFKTBRIGWJQQL-UHFFFAOYSA-N meturedepa Chemical compound C1C(C)(C)N1P(=O)(NC(=O)OCC)N1CC1(C)C QTFKTBRIGWJQQL-UHFFFAOYSA-N 0.000 description 1
- 229950009847 meturedepa Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HOWGUJZVBDQJKV-UHFFFAOYSA-N n-propyl-nonadecane Natural products CCCCCCCCCCCCCCCCCCCCCC HOWGUJZVBDQJKV-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000012758 nuclear staining Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 1
- 229950005848 olivomycin Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002916 oxazoles Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229950004406 porfiromycin Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229940117820 purinethol Drugs 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- HZGCZRCZOMANHK-UHFFFAOYSA-N pyrimidin-2-ylmethanol Chemical compound OCC1=NC=CC=N1 HZGCZRCZOMANHK-UHFFFAOYSA-N 0.000 description 1
- FUXJMHXHGDAHPD-UHFFFAOYSA-N pyrimidine-2-carboxamide Chemical compound NC(=O)C1=NC=CC=N1 FUXJMHXHGDAHPD-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 229950006216 rufocromomycin Drugs 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical compound C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 230000002476 tumorcidal effect Effects 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.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=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明涉及具有增强的抗肿瘤活性或副作用降低的药物组合物,包括已知的具有抗肿瘤作用的活性物质,或其药物可接受的酸加成盐,和式I羟肟酸衍生物或其可药用酸加成盐。
Description
本发明涉及具有抗肿瘤活性增强和/或副作用降低的药物组合物。
抗肿瘤药物(细胞抑制剂)的有效部分通过抑制DNA和RNA的合成,特别是通过破坏完整的DNA来破坏肿瘤细胞的活动。已知的抗肿瘤药物会严重破坏健康细胞,导致线粒体和核染色体发生突变和缺失。除了主要的抗肿瘤作用,抗肿瘤药物经常造成细胞的普遍破坏。这样,治疗往往由于副作用而不能继续下去,甚至造成患者死亡。因此,抗肿瘤治疗中最关键的问题是患者对细胞抑制剂的严重副作用的敏感性。
由于上述问题,制备具有细胞抑制剂的抗肿瘤活性或增强的抗肿瘤活性、同时没有副作用或至少副作用降低的药物组合物非常重要。
本发明的目的是提供一种药物组合物,其中已知的抗肿瘤活性物质的活性或被增强或被保持而同时已知活性物质的副作用则被降低。
式I的羟肟酸衍生物是现有技术中已知的:
其中
R1是氢或C1-5烷基;
R2代表氢;C1-5烷基;C3-8环烷基;或选择性地被羟基或苯基取代的苯基;或者
R1和R2和相邻的氮原子形成5-8元环,该环选择性地含有其他的氮、氧或硫原子;所述的环可以与其他脂环烃或杂环稠合,优选与苯、萘、喹啉、异喹啉、吡啶或吡唑啉环稠合;此外,如果需要或可能,氮和/或硫作为杂原子以氧化物或二氧化物形式存在;
R3代表氢或选择性地被一个或多个卤素原子或C1-4烷氧基取代的苯基、萘基或吡啶基;
Y是氢;羟基;选择性地被氨基取代的C1-24烷氧基;含有1-6个双键的C2-24多烯基氧基C1-25烯酰基;C3-9烯酰基;或式R7-COO-基团,其中R7是有1-6个双键的C2-30多烯基;
X代表卤素原子;氨基;或C1-4烷氧基;或
X和B一起形成氧原子;或
X和Y与相邻的碳原子和中间的-NR-O-CH2-基团形成式(a)的环,
其中
Z是氧或氮;
R是氢;或
R和B一起形成化学键;
其中
R4代表氢;C1-5烷基;C3-8环烷基;或优选被卤原子,C1-4烷氧基或C1-5烷基取代的苯基;
R5 代表氢;C1-4烷基;或苯基;
m 是0,1或2;和
n 是0,1或2。
US 4308399公开了属于式(I)羟肟酸衍生物范围的化合物,用于治疗糖尿病性血管疾病。
EP-PS No.417210描述了也属于式(I)化合物的范围的羟肟酸卤化物,具有选择性的β-阻断作用,用于治疗糖尿病性血管疾病。
HU-PS在No.T/66350中公开了一些其他属于式(I)化合物范围的羟肟酸衍生物。这些已知的物质被用于治疗血管变形,特别是糖尿病。
从PCT专利申请No.WO 97/13504中可以了解到,式(I)羟肟酸衍生物可用于预防和治疗线粒体源疾病。
本发明的目的是提供一种具有已知细胞抑制剂的作用但将其副作用程度降低的药物组合物。
已经发现上述目的可以通过本发明药物组合物来实现。本组合物包括已知的细胞抑制剂或,如果需要或可能,其可治疗用的酸加成盐或其治疗适用盐和式(I)羟肟酸衍生物,其中R,R1,R2,R3,A,B,X和Y如上所述,或其治疗适用的酸加成盐和一种或多种可用的载体。
从本发明的角度,与式(I)有关的取代基如下:
-C1-5烷基代表例如甲基、乙基、正丙基、异丙基、正丁基或正戊基,优选甲基或乙基;
-C3-8环烷基是,例如环丙基、环戊基、环己基、环庚基或环辛基,优选环戊基或环己基;
-5-8元环可以是,例如吡咯、吡唑、咪唑、噁唑、噻唑、吡啶、哒嗪、嘧啶、哌嗪、吗啉、吲哚或喹啉环等;
-C1-24烷氧基可以是,例如甲氧基、乙氧基、正丙氧基、叔丁氧基、正戊氧基、癸氧基、十二烷氧基、十八烷氧基等;
-C1-25烷酰基代表,例如甲酰基、乙酰基、丙酰基、丁酰基、己酰基、棕榈酰基、或硬脂酰基等;
-C3-9烯酰基表示,例如丙烯酰基、戊烯酰基、己烯酰基、庚烯酰基、辛烯酰基等;
C1-4亚烷基可以是,例如亚甲基、1,2-亚乙基、亚丙基或亚丁基;
-卤素为,例如氟、氯、溴或碘,优选氯或溴。
Y为R7-COO-基团时可以是,例如亚麻酰氧基、亚油酰氧基、二十二碳己酰氧基、二十碳五酰氧基或花生四烯酸酰氧基等;
式(I)化合物的生理学(治疗)适用的酸加成盐指与治疗适用的无机酸如盐酸或硫酸等形成的酸加成盐;或与治疗适用的有机酸,如乙酸、富马酸或乳酸等形成的酸加成盐。
式(I)化合物中,优选式(II)羟肟酸衍生物,
其中R1,R2,R3,R4,R5,m和n如式(I)所定义的,X指卤素或氨基;Y代表羟基。
式(II)化合物,其中R1和R2与相邻的氮原子一起形成哌啶子基;R3是吡啶基;m和n都是0;X如上定义,特别优选这些:
O-(3-哌啶子基-2-羟基-1-丙基)烟酸酰氨肟二盐酸盐(化合物“L”)是特别适宜的。
其中R1,R2,R3和A如式(I)定义。
其中R1,R2,R3和A如式(I)定义,Z是氧或氮。
其中R1,R2,R3和A如式(I)定义,R6代表C1-4烷基。
式(I)化合物可以用US-PS 4308399,EP-PS 417210以及已公开的匈牙利专利申请T/66350中述及的方法制备。
从活性角度说,已知的细胞抑制剂(物质)具有这样的活性成分,能直接或间接地抑制肿瘤细胞的DNA合成和/或转录(RNA合成)和/或翻译;或破坏已形成的DNA。
具有抗肿瘤活性的已知药物化合物是能够直接或间接抑制DNA合成和/或转录(RNA合成)和/或翻译,及破坏癌细胞中的完整DNA的化合物。
详细地说,有抗肿瘤活性的已知药物化合物抑制:
-腺苷脱氨酶,
-嘌呤碱基的生物合成及核苷酸的转化,
-嘧啶碱基的生物合成,
-核糖核甙酸的还原,
-胸腺嘧啶单磷酸酯(盐)的合成,
-RNA的合成
-DNA的加成,
-DNA的合成,
-DNA的损坏,
-嘌呤碱基的合成和二氢叶酸盐的还原,
-蛋白合成和天门冬酰胺的脱氨基化;
-增殖作用。
从化学结构的角度讲,已知的细胞抑制剂可以是:
-烷基化剂,包括含氮芥子衍生物、吖丙啶和甲基蜜胺衍生物;烷基磺酸酯;亚硝基脲;吖丙啶;三氮烯等;
-抗代谢物,有叶酸类似物、嘧啶类似物、嘌呤类似物等;
-天然物质,包括长春花属生物碱、鬼臼毒素、抗生素等;
-激素,包括肾上腺皮脂类固醇、雌激素、雄激素、抗雌激素等,和
-其他物质,如复合成形剂。
在已知的细胞抑制剂中,例如优选的烷基化剂如下:氮芥 2-氯-N-(2-氯乙基)-N-甲基-乙胺盐酸盐,氮芥氧化物 2-氯-N-(2-氯乙基)-N-甲基-乙胺N-氧化物,环磷酰胺 N,N-双(2-氯乙基)-四氢-2H-1,3,2-氧氮杂膦
英(oxazaphosphorin)-2-胺-2-氧化物,异环磷酰胺 N,3-双(2-氯乙基)-四氢-2H-1,3,2-氧氮杂膦
英-2-胺-2-氧化物,苯丙氨酸氮芥 4-[双(2-氯乙基)氨基]-L-苯基-丙氨酸,苯丁酸氮芥 4-[双(2-氯乙基)氨基]-苯基丁酸,噻替派 三亚乙基-硫代磷酸酰胺,白消安 二甲磺酸1,4-丁二醇酯,卡氮芥 1,3-双(2-氯乙基)-1-亚硝基脲,罗氮芥 1-(2-氯乙基)-3-环己基-1-亚硝基脲,司莫司汀 1-(2-氯乙基)-3-(4-甲基环己基)-1-亚硝基
脲,英丙舒凡 N,N-双(3-甲基磺酰氧-丙基)-胺,哌泊舒凡 1,4-双(3-甲磺酰基氧-1-氧代-丙基)哌嗪,苯佐替派 双(1-吖丙啶基)氧膦基氨基甲酸苯基甲基酯,美妥替哌 双(2,2-二甲基-1-吖丙啶基)氧膦基氨基甲酸
乙基酯,乌瑞替哌 双(1-吖丙啶基)氧膦基氨基甲酸乙基酯,卡波醌 2-[(2-氨基羰基氧)-1-甲氧基乙基]-3,6-双
(1-吖丙啶基)-5-甲基-2,5-环己二烯-1,4-二
酮,六甲蜜胺 N,N,N’,N’,N”,N”-六甲基-1,3,5-三嗪-
2,4,6-三胺,三亚乙基磷酰三(1’-吖丙啶基)膦氧化物,胺三羟甲蜜胺 2,4,6-三(羟甲基氨基)-1,3,5-三嗪萘氮芥 N,N-双(2-氯乙基)-2-萘胺,环磷酰胺 N,N-双(2-氯乙基)-四氢-2H-1,3,2-氧氮杂膦
英-2-胺2-氧化物,雌莫司汀 雌-1,3,5(10)-三烯-3,17-二醇-3-[双(2-氯
乙基)氨基甲酸酯],新恩比兴 2-氯-N,N-双(2-氯乙基)丙-胺盐酸盐,苯芥胆甾醇 胆甾-5-烯-3β-醇-4-[双(2-氯乙基)氨基]-苯
基乙酸酯,泼尼莫司汀 21-{4-[4-[双(2-氯乙基)氨基]苯基]-1-氧代
丁氧基}-11,17-二羟基孕烷-1,4-双烯-3,20-
二酮,氯乙环磷酰胺 N,N,3-三(2-氯乙基)四氢-2H-1,3,2-氧氮杂
膦英-2-胺2-氧化物,乌拉莫司汀 5-[双(2-氯乙基)氨基]-2,4(1H,3H)-嘧啶二
酮,氯尿菌素 2-[(2-氯乙基)-亚硝基氨基羰基氨基]-2-脱
氧-D-葡萄糖,福莫司汀 [1-[(2-氯乙基)-亚硝基氨基羰基氨基]乙基]
磷酸二乙基酯,尼莫司汀 N’-[(4-氨基-2-甲基-5-嘧啶基)甲基]-N-(2-
氯乙基)-N-亚硝基脲,雷莫司汀 甲基6-[(2-氯乙基)亚硝基氨基羰基氨基]-6-
脱氧-D-吡喃葡萄糖苷,甘露莫司汀 1,6-双(2-氯乙基氨基)-1,6-二脱氧-D-甘露
醇二盐酸盐,二溴甘露醇 1,6-二溴-1,6-二脱氧-D-甘露醇,二溴卫矛醇 1,6-二溴-1,6-二脱氧半乳糖醇,哌泊溴烷 1,4-双(3-溴-1-氧代丙基)-哌嗪,迪卡泊嗪 5-(3,3-二甲基-1-三氮烯基)咪唑-4-羧酰
胺。
优选的代谢拮抗物如下:甲氨蝶呤 N-[4-[(2,4-二氨基-6-蝶啶基)甲基-甲基氨
基]苯甲酰基]-L-谷氨酸或其钠盐;三甲曲沙 5-甲基-6-[(3,4,5-三甲氧基苯基)-氨基甲
基]-2,4-间二氮杂萘-二胺,氟尿嘧啶 5-氟-2,4(1H,3H)嘧啶二酮或其钠盐,氟尿苷 5-氟-2’-脱氧尿苷,碘苷 5-碘-2’-脱氧尿苷,去氧氟尿苷 5’-脱氧-5-氟尿苷,阿糖孢苷 4-氨基-1β-D阿拉伯呋喃糖基-2(1H)-嘧啶
酮,氮杂孢苷 4-氨基-1β-D核糖呋喃糖基-1,3,5-三嗪-
2(1H)-酮,吉西他滨 2’,2’-二氟-脱氧胞苷,巯基嘌呤 6-巯基嘌呤,硫代鸟嘌呤 6-硫代鸟嘌呤,氟达拉滨 9β-D-阿拉伯呋喃糖基-2-氟-9H-嘌呤-6-胺磷
酸盐,喷司他丁 (R)-3-(2-脱氧-β-D-赤-五呋喃糖基)-
3,6,7,8-四氢咪唑并[4,5-d][1,3]二吖庚因
(二氮杂)-8-醇,克拉屈滨 2-氯-脱氧腺苷,硫咪嘌呤 6-(1-甲基-4-硝基-1H-咪唑-5-基硫基)-1H-
嘌呤-2-胺,安西他滨 2,3,3a,9a-四氢-3-羟基-6-亚氨基-6H-呋
[2’,3’,4,5]噁唑并[3,2-a]嘧啶-2-甲醇,氮杂胞苷 4-氨基-1-β-D-核糖呋喃糖基-1,3,5-三嗪-
2(1H)-酮,氮尿苷 2β-D-核糖呋喃糖基-1,2,4-三嗪-
3,5(2H,4H)-二酮,卡莫氟 5-氟-N-己基-3,4-二氢-2,4-二氧代-1(2H)-
嘧啶甲酰胺,依诺他滨 N-(1β-D-阿拉伯糖呋喃糖基-1,2-二氢-2-氧
代-4-嘧啶基)二十二烷酰胺,替加氟 5-氟-1-(四氢-2-呋喃基)-2,4(1H,3H)嘧啶二
酮。
在已知的细胞抑制活性药物中,下面例举的天然来源物质是优选的:硫酸长春碱 硫酸长春碱,硫酸长春新碱 22-氧代长春花碱硫酸盐,长春地辛 3-(氨基羰基)-O-4-脱乙酰-3-脱-(甲氧基羰
基)长春花碱硫酸盐,Paclitaxel [2aR,4S,4aS,6R,9S(αR,βS),11S,12S,12aR,
12bS]-β-苯甲酰基氨基-α-(羟基苯基)丙酸
[6,12b-(乙酰氧基)-12-苯甲酰氧基-
2a,3,4,4a,5,6,9,10,11,12,12a,12b-十二
氢-4,11-二羟基-4a,8,13,13-四甲基-5-氧代
-7,11-亚甲基-1H-环十[3,4]苯并[1,2-b]氧
杂环丁-9-基]酯,Docetaxel [2aR-[2aα,4β,4aβ,6β,9α(αR*,βS*),11β,
12α,12aα,12aα,12bα]]-β-(叔-丁氧基羰基
氨基)α-(羟基苯基)丙酸[12b-乙酰氧基-12-
苄氧-1,2,3,4,4a,6,9,10,11,12,12a,12b-
十二氢-4,6,11-三羟基-4a,8,13,13-四甲基-
5-氧代-7,11-亚甲基-5H-环十[3,4]苯并
[1,2-b]氧杂环丁-9-基]酯,依托泊苷 [5R-[5α,5αβ,8aα,9β-(R)]-[9-(4,6-O-亚
乙基-β-D-葡萄糖呋喃糖基氧)-5,8,8a,9-四
氢-5-(4-羟基-3,5-二甲氧基苯基)-呋喃并
[3’,4’:6,7]萘并[2,3-d]-1,3-二氧杂环戊二
烯-6-(5aH)酮,替尼泊苷 [5R-[5α,5αβ,8aα,9β-(R)]-[5,8,8a,9-四
氢-5-(4-羟基-3,5-二甲氧基苯基)-9-[4,6-
O-(2-噻吩基亚甲基)-β-D-葡萄糖吡喃糖基氧
-呋喃并[3’,4’:6,7]萘并[2,3-d]-1,3-二氧杂
环戊二烯-6-(5aH)酮,放线菌素D 放线菌素D柔红霉素 (8S-顺式)-8-乙酰-10-(3-氨基-2,3,6-三脱
氧-α-L-来苏-己吡喃糖基氧)-7,8,9,10-四氢
-6,8,11-三羟基-1-甲氧基-5,12-并四苯二
酮,阿霉素 (8S-顺式)-8-(羟基乙酰)-10-(3-氨基-
2,3,6-三脱氧-α-L-来苏己吡喃糖基氧)-
7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-
5,12-并四苯二酮,表柔比星 (8S-顺式)-10-(3-氨基-2,3,6-三脱氧-α-L-
阿拉伯己吡喃糖基氧)-7,8,9,10-四氢-
6,8,11-三羟基-8-(羟基乙酰)-1-甲氧基-
5,12-并四苯二酮,伊达比星 (7S-顺式)-9-乙酰-7-(3-氨基-2,3,6-三脱氧
-α-L-来苏-六吡喃糖基氧)-7,8,9,10-四氢-
6,9,11-三羟基-5,12-并四苯二酮,米托蒽醌 1,4-二羟基-5,8-双[2-(2-羟基乙基)氨基乙
基氨基]-9,10-蒽二酮或其二盐酸盐,博莱霉素 从轮枝链霉菌种分离出的糖肽抗生素的混合(A2,B2) 物,多为硫酸盐或盐酸盐的形式,普卡霉素 泥质链霉菌、田无链霉菌和褶皱链霉菌产生的
抗生素,丝裂霉素 [1aR-(1aα,8β,8aα,8bα)]-6-氨基-8-氨基羰
基氧杂-甲基-1,1a,2,8,8a,8b-六氢-8a甲氧
基-5-甲基-氮丙啶并[2’,3’:3,4]-吡咯并
[1,2-a]吲哚-4,7-二酮,阿克拉霉素(A属于蒽环的抗生素,由加利利链霉菌产生,和B)安曲霉素 3-(5,10,11,11a-四氢-9,11-二羟基-8-甲基-
5-氧代-1H-吡咯并[2,1-c][1,4]苯并二氮杂
-2-基)-2-丙烯酰胺,偶氮丝氨酸 O-二偶氮基乙酰-L-丝氨酸,卡柔比星 8-乙酰-10-(3-氨基-2,3,6-三脱氧-α-L-来苏
-六吡喃糖基氧)-7,8,9,10-四氢-1,6,8,11-
四羟基-5,12-并四苯二酮,放线菌素C 放线菌素C,一种由金羊毛链霉菌产生的抗生
素,嗜癌素 一种由左八郎链霉菌产生的抗生素,色霉素 一种由灰色链霉菌产生的抗生素,橄榄霉素 一种由橄榄色网状链霉菌产生的抗生素,诺加霉素 [2R-(2α,3β,4α,5β,6α,11β,13α,14α)]-11-
(6-脱氧-3-C-甲基-2,3,4-三-O-甲基-α-L-甘
露吡喃糖基氧)-4-二甲基氨基-
3,4,5,6,9,11,12,13,14,16-十氢-
3,5,8,10,13-五羟基-6,13-二甲基-9,16-二
氧代-2,6-环氧-2H-并四苯并[1,2-b]噁辛英
(oxocin)-14-甲酸甲酯培洛霉素 N’-[3-(1-苯基乙基)氨基丙基]博莱霉素酰胺,泊非霉素 6-氨基-8-(氨基羰基氧甲基)-1,1 a,2,8,8a,
8b-六氢-8a-甲氧基-1,5-二甲基氮丙啶并
[2’,3’:3,4]吡咯并[1,2-a]吲哚-4,7-二酮,链黑霉素 5-氨基-6-(7-氨基-5,8-二氢-6-甲氧基-5,8-
二氧代-2-喹啉基)-4-(2-羟基-3,4-二甲氧基
-苯基)-3-甲基-2-吡啶甲酸,链脲霉素 2-脱氧-2-(甲基-亚硝基氨基羰基氨基)-D-吡
喃葡萄糖,块菌素 7β-D-核糖呋喃糖基-7H-吡咯并[2,3-d]嘧啶-
4-胺,乌苯美司 [2S,3R]-3-氨基-2-羟基-4-苯基-丁酰基-L-
亮氨酸,佐柔比星 苯甲酸[1-[4-(3-氨基-2,3,6-三脱氧-α-L-来
苏-己吡喃糖基氧)-1,2,3,4,6,11-六氢-
2,5,12-三羟基-7-甲氧基-6,11-二氧-2-并四
苯基]-亚乙基]-酰肼。
在已知的细胞抑制活性药物中,下面述及的激素是优异的:泼尼松龙 (11-β)-11,17,21-三羟基孕-1,4-二烯-
3,20-二酮,羟基孕酮 17-羟基孕-4-烯-3,20-二酮或其己酸盐,甲羟孕酮 (6α)-17-羟基-6-甲基孕-4-烯-3,20-二酮或
其乙酸盐,甲地孕酮 17-羟基-6-甲基孕-1,4-二烯-3,20-二酮或其
乙酸盐,己烯雌酚 (E)4,4’-(1,2-二乙基-1,2-亚乙烯二基)-双
(酚),乙炔基雌二醇 (17α)-19-去甲孕-1,3,5(10)-三烯-20-炔-
3,17-二醇,他莫昔芬 (Z)-2-[4-(1,2-二苯基-1-丁烯基)苯氧
基]N,N-二甲基乙胺或其柠檬酸盐,睾酮 (17-β)-17-(1-氧代丙氧基)-雄甾-4-烯-3-
酮或其丙酸盐,氟甲睾酮 (11-β,17β-9-氟-11,17-二羟基-17-甲基雄
甾-4-烯-3-酮。
在已知的细胞抑制活性药物中,其他类优选物质为,例如:顺铂 顺式-二氨-二氯铂,卡铂 顺式-二氨-[1,1-环丁烷-二甲酸基(2)]合铂,L-天门冬酰胺已知例如由大肠杆菌产生的酶,酶丙卡巴肼 N-(1-甲基乙基)-4-(2-肼基甲基)苯甲酰胺米托坦 1-氯-2-[2,2-二氯-1-(4-氯苯基)乙基]苯,氟他胺 2-甲基-N-(4-硝基-3-三氟甲基苯基)丙酰胺,亮丙瑞林 5-氧代-L-脯氨酰-L-组氨酰-L-色氨酰-L-丝
氨酰-L-酪氨酰-D-亮氨酰-L-亮氨酰-L-精氨
酰-N-乙基-L-脯氨酸酰胺或其乙酸盐。
已知的细胞抑制活性药物也可以以其治疗适用酸加成盐的形式使用,只要其化学结构允许制备酸加成盐。类似地,当已知细胞抑制活性药物的化学结构适于制备治疗适用盐的时候,也可以以这样的盐形式使用,如金属盐、铵盐或与有机碱所成的盐。
本发明的细胞抑制药物组合物优选含有顺铂作为细胞抑制(抗肿瘤)活性成分,和O-(3-哌啶子基-2-羟基-1-丙基)烟酸氨肟或其可治疗用酸加成盐作为式(I)羟肟酸衍生物。
本发明药物组合物一般含有0.1-95wt%,优选1-50wt%,优选5-30wt%的活性剂(成分)以及药物组合物的常规载体。
在本发明的药物组合物中,两种活性成分(试剂)的重量比最好为(1-50)∶(50-1),特别优选(1-10)∶(10-1)。
本发明药物组合物可以是固体或液体组合物,用于口服、非肠道或直肠给药或局部治疗。
用于口服给药的固体药物组合物可以是粉末、胶囊剂、片剂、膜包衣片剂、微胶囊等;可以含有粘合剂作为载体,如明胶、山梨醇、聚乙烯吡咯烷酮等;填充材料,如乳糖、葡萄糖、淀粉、磷酸钙等;制片助剂,如硬脂酸镁、滑石、聚乙二醇、二氧化硅等;以及湿润剂,如月桂基硫酸钠等。
口服给药的液体药物组合物是溶液、悬浮液或乳剂,其含有载体如悬浮剂如明胶、羧甲基纤维素等;乳化剂,如脱水山梨醇一油酸酯;溶剂如水、油、甘油、丙二醇、乙醇;以及防腐剂如对-羟基苯甲酸甲基或丙基酯等。
非肠道给药的药物组合物通常为活性成分的无菌溶液。
上述例举的剂量(剂量单位)以及其他剂量形式本身是已知的,参见如题目为《雷明顿药物科学》(Remington’s Pharmaceutical Sciences)的手册,第18版,Mack出版公司,Easton,USA(1990)。
在多数情况下,本发明的药物组合物含有给成人的剂量单位,其特征是每日剂量为0.1-1000mg已知细胞抑制活性成分和0.1-1000mg式(I)化合物,可以一次给药或多次给药。实际的剂量由多种因素决定,应由医师确定。
本发明药物组合物的制备是将活性试剂(成分)与一种或多种载体混合,然后用本身已知的方法将所得混合物转变成药物组合物。使用的方法是现有技术中已知的,如参考手册Remington’sPharmaceutical Sciences。
I。细胞抑制剂副作用的减弱
通过对羟肟酸衍生物化合物“L”进行试验来研究式(I)羟肟酸衍生物的细胞抑制剂副作用的减弱效果。下面介绍试验及其结果。
用鼠进行体内试验 用顺铂(50mg/kg体重日剂量)和化合物“L”(40mg/kg体重日剂量)对6组Wistar大鼠进行治疗,分别单独给药和联合给药。试验开始时试验鼠是健康的(没有任何的肿瘤接种),抗肿瘤化合物的剂量激发性(provocatively)地/相当地高,其本身即有很高的导致组织损害的可能性。对照组不接受任何活性化合物。在治疗中,用ECG跟踪试验鼠的心脏功能,治疗两周后测定试验鼠血液中的酶活性。总结酶活性的值,得到顺铂给组织造成的损害程度。
组织损害的研究
通过测定酶在细胞内的释放来评价组织的损害。用H.U.Bergmeyer法测定酶活性。(酶分析方法,第2板,Academic出版社(1974))。测定下面的酶:
GOT =谷氨酸-草酰乙酸-转氨酶,
GPT =乳酸-丙酮酸-转氨酶,
LDH =乳酸脱氢酶,
CK =肌酸-激酶,
LipDH=硫辛酰胺脱氢酶,
CS =柠檬酸-合成酶。
下面给出m单位/ml血清中的酶活性。结果列于表1。
表1
酶 酶活性(mU/ml)
顺铂 顺铂+“L” 对照GOT 273 131 94GPT 87 47 45LDH 5136 1950 1523CK 9776 1445 1200LipDH 69 41 43CS 22 8 6
如表1所示,用顺铂治疗,酶活性提高,表明组织受到损害。当顺铂和化合物“L”结合给药时,酶活性与对照组中观察到的结果很接近。因此,化合物“ L”的共同给药明显给组织提供了保护,免受顺铂造成的损害。
心脏功能的研究
用AT-6 ECG在四肢上监测心脏功能。测定QRS、RR、PR和TQ距和J点的抑制。结果列于表2。
表2
J点阻抑mm QRSms QRS强度
普通 0.1±0.1 67 恒量
顺铂 2.1±0.3 102 波动顺铂+化合物“L” 0.3±0.3 77 恒量
如表2所示,化合物“L”和顺铂的共同给药对心脏功能有明显的保护作用,使其免受顺铂的损害。应当注意的是,QRS的波动表明由顺铂治疗造成的明显心脏损害,在有化合物“L”的存在下此波动停止。
治疗一个月后的存活情况
研究经过上述两周治疗后有百分之几的试验鼠仍然活着。结果列于表3。
表3
治疗 1个月存活(%)
顺铂 25顺铂+化合物“L” 83
未治疗 100
如表3所示,由于顺铂的极度毒性,经一个月治疗后只有25%的试验鼠活着,而所有的未治疗试验鼠均活着。相反,接受顺铂和化合物“L”结合用药的试验鼠有83%还活着,死亡率降低。
用小鼠进行体内试验 用正常小鼠研究化合物“L”对已知细胞抑制剂顺铂(Platidiam,50 La Chema,Brno)系统毒性的调整作用。[c.f.肿瘤学报告(REP/O.O.I/1988/01)]用第一代杂交BDF1(C57B1雌性x DBA/2雄性)成年雄性,重22-24g,非特异病原体(SPF)小鼠进行这些试验。试验小鼠被放在22-24℃(40-50%湿度)的macrolon笼中,光照制度为12/12h光/暗。试验鼠可以自由使用自来水,并随意食用无菌标准膳食(Altromin1324片,Altromin公司,德国)。为了进行毒性试验,将化合物“L”、顺铂及其混合物溶解在无菌生理盐水中,其浓度使给药剂量以体积计为0.1ml/10g体重,腹膜内给药或口服。
化合物“L”、顺铂和化合物“L”+顺铂的混合的急性毒性作用
用不同剂量的化合物“L”、顺铂和化合物“L”+顺铂的混合物治疗BDF1雄性鼠的存活率列于表4。
表4
治疗组 | 化合物 | 治疗剂量mg/kg途径次数 | 存活/总共 | 存活% |
1 | 化合物“L” | 200 | 腹膜内给药 | 1qd | 7/7 | 100 |
2 | 化合物“L” | 750 | 腹膜内给药 | 1qd | 0/7 | 0 |
3 | 化合物“L” | 2000 | 口服 | 1qd | 7/7 | 100 |
4 | 化合物“L” | 100 | 腹膜内给药 | 5qd | 7/7 | 100 |
5 | cisPt | 10 | 腹膜内给药 | 1qd | 6/7 | 86 |
6 | cisPt | 15 | 腹膜内给药 | 1qd | 2/7 | 29 |
7 | cisPt | 4 | 腹膜内给药 | 5qd | 1/7 | 14 |
8 | 化合物“L”+cisPt | 500+10 | 腹膜内给药 | 1qd | 7/7 | 100 |
9 | 化合物“L”+cisPt | 500+10 | 腹膜内给药 | 1qd | 6/7 | 86 |
25天后结束观察阶段。化合物“L”的剂量中,750mg/kg体重剂量,腹膜内给药是致死的(表4)。其他的单独化合物“L”治疗对BDF1鼠的存活均没有影响(表4)。观察顺铂的毒性对剂量的依赖性。在存活率基础上评价的细胞抑制剂的毒性在高剂量和反复治疗下特别显著。剂量4mg/kg,腹膜内给药,重复5次(Sqd)接近致死(表4)。但顺铂(15mg/kg,腹膜内给药)与化合物“L”(500mg/kg,腹膜内给药)结合起来,毒性则大大地降低(表4)。
当顺铂以10mg/kg剂量与化合物“L”联合给药时,所有动物都存活(表4)。
II、抗肿瘤活性
用羟肟酸衍生化合物“L”进行试验,研究细胞抑制剂与式I羟肟酸衍生物相结合的抗肿瘤效果。下面讨论试验及其结果。
用细胞培养进行试验将Sp-2(鼠骨髓瘤,悬浮液)细胞涂在有10%FCS(胎儿腓肠血清)的DMEM(Dubelso改性的Eagle培养基)上。将细胞涂在96孔板上,初始细胞计数为104/250μl。
一部分细胞在不加药物的情况下涂布,一部分细胞在有0.35微克/ml顺铂下涂布,另一部分在有40微克/ml化合物“L”下涂布,还有一部分在有0.35微克/ml顺铂+40微克/ml化合物“L”下涂布。治疗即加入上述化合物48小时后,对孔中的细胞计数,方法是用10微升台盼蓝着色然后悬浮。计数是在Burker室中进行的。
对肿瘤生长的影响
表6总结了治疗后存活的细胞量,以百分数计。
表5
治疗 存活细胞(%)
未治疗 100
化合物“L” 51±8
顺铂 12±4
顺铂+化合物“L” 10±5
如表5所示,所有的未治疗细胞均存活。顺铂自己可使肿瘤细胞明显减少,当顺铂与化合物“L”结合起来时,这一效果不改变。
用氟尿嘧啶代替顺铂重复上述试验时观察到类似的效果。此时,一部分细胞在不加药物的情况下涂布,一部分细胞在有13微克/ml氟尿嘧啶下涂布,另一部分在有13克/ml氟尿嘧啶+40微克/ml化合物“L”下涂布。治疗后40小时后测定存活率。表6列出了治疗后存活细胞的量,以百分数计。
表6
治疗 存活细胞(%)
未治疗 100
化合物“L” 51±8
氟尿嘧啶 13±3氟尿嘧啶+化合物“L” 10±4
如表6所示,氟尿嘧啶自己使肿瘤细胞明显减少,当顺铂与化合物“L”结合起来时,这一效果不受影响。这些单独用抗肿瘤试剂(顺铂或氟尿嘧啶)或结合使用化合物“L”进行的体外试验表明它们明显降低细胞培养中的肿瘤细胞。这样,在体内条件下,化合物“L”不影响所研究的抗肿瘤试剂的抗肿瘤能力。
上述观察结果表明式I药物组合物降低了抗肿瘤试剂的副作用,同时其抗肿瘤活性保持不受影响。
用小鼠进行体内试验在P-388或S-180肿瘤移植后的第一天开始进行一次或重复治疗。在存活时间和肿瘤体积基础上评价治疗效果。45天后结束试验。超过45天后试验小鼠的长时间存活不再跟踪,终点定于肿瘤移植后的第46天。各个治疗组经过治疗后的平均存活天数与对照组进行对比,评价抗肿瘤效果,用T/C表示。
在S-180实体肿瘤的情况中,用数字式测径规对化合物对肿瘤生长的抑制作用进行控制,一周三次。用下式计算肿瘤的体积:
V=a2×b2×π/6
其中“a”和“b”分别是给定肿瘤的最小和最大半径(Tomayko M.M.和Reynolds C.P.:无胸腺/裸/鼠的皮下肿瘤大小的测定)。计算平均值(X)和标准误差(S.D.)。适宜时用t检验测定统计上明显的差异(p)。
化合物“L”在体内对细胞抑制剂顺铂的抗肿瘤活性的影响
顺铂自己或化合物“L”+顺铂对接种了1×106 P-388白血病细胞的BDF1小鼠的存活率的影响列于表7。
表7
治疗组1 | 化合物 | 治疗2剂量mg/kg 途径 日程 | 平均存活(天) | T/C% | 长期3存活/百分数总存活 | |||
10 | cisPt | 10 | 腹膜内给药 | 1pd | 16.6±4.6/5鼠 | 147.0 | 2/7 | 29 |
11 | cisPt+化合物“L” | 10+100 | 腹膜内给药 | 1pd | 32.6±3.5/5鼠 | 289.0 | 2/7 | 29 |
12 | cisPt+化合物“L” | 10+200 | 腹膜内给药口服 | 1pd | 19.0±3.9/4鼠 | 168.0 | 3/7 | 43 |
13 | cisPt | 3 | 腹膜内给药 | 5pd | 29.0±6.1/4鼠 | 257.0 | 3/7 | 43 |
14 | cisPt+化合物“L” | 3+20 | 腹膜内给药 | 5pd | 30.0/1鼠 | 266.0 | 6/7 | 86 |
15 | 对照(p-388) | - | - | - | 11.3±1.2/7鼠 | 100.0 | - | - |
腹膜内肿瘤移植后的第一天开始治疗。第45天结束试验,长时间存活的数目列于表7。如表7所示,在有化合物“L”的存在下,顺铂的作用被增强。尽管当与顺铂结合给药时,化合物“L”还将平均存活时间大大延长,但这一结合在重复给药后特别有效,特别是对长时间存活(即,长至45天)。相对于对照值(0%),用化合物“L”+顺铂治疗有P-388肿瘤的试验鼠后的长期存活率为86%。但用顺铂单独治疗的试验鼠的长期存活率仅43%(表7)。
化合物“L”对顺铂对S-180肉瘤的生长抑制作用的影响
在肿瘤生长曲线和平均肿瘤体积的基础上,观察到一次注射(图1)或重复注射(图2)后,顺铂和化合物“L”+顺铂混合物有明显的抑制效果。
图3示意的是在肿瘤移植后的第18天,顺铂和混合物“L”+顺铂的混合物对肿瘤生长的抑制作用的对比。化合物“L”的存在明显地提高了顺铂对肿瘤生长的抑制作用(图3)。
本发明药理学化合物被证明非常安全(即,即使对有肿瘤的动物也非常无毒),可以用来增强癌症患者抗肿瘤治疗的效果和降低副作用。在治疗中,以(1-50)∶(1-50)%质量比例补充入式I羟肟酸衍生物或其药物可接受的酸加成盐的已知抗肿瘤化合物或其药物可接受的酸加成盐对患者进行治疗。
Claims (8)
1、具有降低的副作用的抗肿瘤活性的药物组合物,其包含a)O-(3-哌啶子基-2-羟基-1-丙基)烟酰氨肟或其生理可接受的酸加成盐和b)具有抗肿瘤作用的已知活性物质,其选自铂衍生物、嘧啶类似物、紫杉-11-烯-9-酮衍生物和抗菌素。
2、权利要求1所要求的药物组合物,其包含顺铂作为铂衍生物。
3、权利要求1所要求的药物组合物,其包含卡铂作为铂衍生物。
4、权利要求1所要求的药物组合物,其包含氟尿嘧啶或其药学上可接受的碱金属盐作为嘧啶类似物。
5、权利要求1所要求的药物组合物,其包含帕尼特西作为紫杉-11-烯-9-酮衍生物。
6、权利要求1所要求的药物组合物,其包含多西特西作为紫杉-11-烯-9-酮衍生物。
7、权利要求1所要求的药物组合物,其包含博莱霉素作为抗菌素。
8、O-(3-哌啶子基-2-羟基-1-丙基)烟酰氨肟或其生理上可接受的酸加成盐用于制备降低已知抗肿瘤剂副作用的药物组合物的用途,其中的抗肿瘤剂选自铂衍生物,嘧啶类似物,紫杉-11-烯-9-酮衍生物和抗菌素。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU9701081A HU9701081D0 (en) | 1997-06-23 | 1997-06-23 | Pharmaceutical composition of antitumoral activity |
HUP9701081 | 1997-06-23 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2003101006948A Division CN1494905A (zh) | 1997-06-23 | 1998-06-22 | 含抗肿瘤药物和羟肟酸衍生物且具有抗肿瘤增强活性和/或副作用降低的药物组合物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1263471A CN1263471A (zh) | 2000-08-16 |
CN1127984C true CN1127984C (zh) | 2003-11-19 |
Family
ID=89995266
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN98807103A Expired - Fee Related CN1127984C (zh) | 1997-06-23 | 1998-06-22 | 含抗肿瘤药物和羟肟酸衍生物且具有抗肿瘤增强活性和/或副作用降低的药物组合物 |
Country Status (25)
Country | Link |
---|---|
US (4) | US6440998B1 (zh) |
EP (1) | EP0993304B1 (zh) |
JP (1) | JP2002508762A (zh) |
KR (1) | KR20010020496A (zh) |
CN (1) | CN1127984C (zh) |
AT (1) | ATE235918T1 (zh) |
AU (1) | AU735922B2 (zh) |
BR (1) | BR9810312A (zh) |
CA (1) | CA2294913C (zh) |
CZ (1) | CZ298468B6 (zh) |
DE (1) | DE69812949T2 (zh) |
DK (1) | DK0993304T3 (zh) |
ES (1) | ES2195344T3 (zh) |
HK (1) | HK1029941A1 (zh) |
HU (1) | HU9701081D0 (zh) |
IL (1) | IL133508A (zh) |
NO (1) | NO322206B1 (zh) |
NZ (1) | NZ502039A (zh) |
PL (1) | PL191718B1 (zh) |
PT (1) | PT993304E (zh) |
RU (2) | RU2254129C2 (zh) |
SK (1) | SK282877B6 (zh) |
TR (1) | TR199903214T2 (zh) |
UA (1) | UA64757C2 (zh) |
WO (1) | WO1998058676A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104447746A (zh) * | 2013-09-18 | 2015-03-25 | 华安医学股份有限公司 | 一种活化ampk的化合物及其用途 |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6884424B2 (en) * | 1995-12-22 | 2005-04-26 | N-Gene Research Laboratories Inc. | Method for treating the pathological lesions of the skin that develop by ultraviolet radiation of the sunlight |
US20030158220A1 (en) * | 1997-11-03 | 2003-08-21 | Foss Joseph F. | Use of methylnaltrexone and related compounds to treat chronic opioid use side effects |
PT1615646E (pt) * | 2003-04-08 | 2015-02-12 | Progenics Pharm Inc | Formulações farmacêuticas com metilnaltrexona |
US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
CN101171010B (zh) * | 2005-03-07 | 2014-09-17 | 芝加哥大学 | 阿片样物质拮抗剂用于减少内皮细胞增殖和迁移的用途 |
US8524731B2 (en) * | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
AR057325A1 (es) | 2005-05-25 | 2007-11-28 | Progenics Pharm Inc | Sintesis de (s)-n-metilnaltrexona, composiciones farmaceuticas y usos |
AR057035A1 (es) * | 2005-05-25 | 2007-11-14 | Progenics Pharm Inc | SíNTESIS DE (R)-N-METILNALTREXONA, COMPOSICIONES FARMACÉUTICAS Y USOS |
TW200817048A (en) * | 2006-09-08 | 2008-04-16 | Wyeth Corp | Dry powder compound formulations and uses thereof |
US7763601B2 (en) * | 2006-11-02 | 2010-07-27 | N-Gene Research Laboratories, Inc. | Prevention and treatment of obesity |
US20080108602A1 (en) * | 2006-11-02 | 2008-05-08 | N-Gene Research Laboratories, Inc. | Prevention of obesity in antipsychotic, antidepressant and antiepileptic medication |
CA2682129A1 (en) | 2007-03-29 | 2008-10-09 | Progenics Pharmaceuticals, Inc. | Crystal forms and uses thereof |
JP5469593B2 (ja) | 2007-03-29 | 2014-04-16 | ワイス・エルエルシー | 末梢性オピオイド受容体アンタゴニストおよびその使用 |
TWI553009B (zh) | 2007-03-29 | 2016-10-11 | 普吉尼製藥公司 | 末梢性類鴉片受體拮抗劑及其用途 |
US20100310674A1 (en) * | 2007-10-30 | 2010-12-09 | Trophos | Novel composition for treating the side effects of anticancer treatments |
US20090281143A1 (en) * | 2007-12-10 | 2009-11-12 | N-Gene Research Laboratories, Inc. | Dose Reduction of a Cannabinoid CB1 Receptor Antagonist in the Treatment of Overweight or Obesity |
WO2009099411A1 (en) | 2008-02-06 | 2009-08-13 | Progenics Pharmaceuticals, Inc. | Preparation and use of (r),(r)-2,2'-bis-methylnaltrexone |
EP2278966B1 (en) | 2008-03-21 | 2019-10-09 | The University of Chicago | Treatment with opioid antagonists and mtor inhibitors |
CA2676881C (en) | 2008-09-30 | 2017-04-25 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
ITMI20110792A1 (it) | 2011-05-09 | 2012-11-10 | Probiotical Spa | Ceppi di batteri appartenenti al genere bifidobacterium per uso nel trattamento della ipercolesterolemia. |
ITMI20110791A1 (it) | 2011-05-09 | 2012-11-10 | Probiotical Spa | Ceppi di batteri in grado di metabolizzare gli ossalati. |
ITMI20110793A1 (it) | 2011-05-09 | 2012-11-10 | Probiotical Spa | Ceppi di batteri probiotici e composizione sinbiotica contenente gli stessi destinata alla alimentazione dei neonati. |
HUP1100444A2 (en) | 2011-08-17 | 2013-02-28 | Pharma Gene Sa | Pharmaceutical composition |
HUP1100445A2 (en) * | 2011-08-17 | 2013-02-28 | Pharma Gene Sa | Pharmaceutical composition |
RU2522548C2 (ru) * | 2012-09-26 | 2014-07-20 | Федеральное государственное бюджетное учреждение науки Институт кристаллографии им. А.В. Шубникова Российской академии наук (ИК РАН) | Ингибитор уридинфосфорилаз |
US9938279B2 (en) * | 2013-04-09 | 2018-04-10 | Energenesis Biomedical Co., Ltd | Method for treating disease or condition susceptible to amelioration by AMPK activators and compounds of formula which are useful to activate AMP-activated protein kinase (AMPK) |
RU2679136C1 (ru) * | 2018-03-13 | 2019-02-06 | Федеральное государственное бюджетное научное учреждение "Федеральный исследовательский центр "Красноярский научный центр Сибирского отделения Российской академии наук" (ФИЦ КНЦ СО РАН, КНЦ СО РАН) | Способ получения препарата на основе взаимодействия цис-диамин(циклобутан-1,1-дикарбоксилат-о,о')платины(ii) с арабиногалактаном |
HUP1800298A1 (hu) | 2018-08-30 | 2020-05-28 | N Gene Res Laboratories Inc | Gyógyszerkombináció béta-receptor blokkolók hatásának módosítására és a mellékhatások csökkentésére |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4308399A (en) * | 1977-08-30 | 1981-12-29 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. | O-(3-Amino-2-hydroxy-propyl)-amidoxime derivatives, process for the preparation thereof and pharmaceutical compositions containing same |
HU207988B (en) * | 1988-10-20 | 1993-07-28 | Biorex Kutato Fejlesztoe Kft | Process for producing halogenides of o-/3-amino-2-hydroxy-propyl/hydroximic acid and pharmaceutical compositions containing them as active components |
HUT54347A (en) * | 1989-01-10 | 1991-02-28 | Chinoin Gyogyszer Es Vegyeszet | Improved process for producing amidoximes |
SI9420017B (sl) * | 1993-03-31 | 2003-12-31 | Merck & Co. Inc. | Inhibitorji proteaze hiv-a v farmacevtskih kombinacijah za zdravljenje aids-a |
TW381025B (en) * | 1993-08-05 | 2000-02-01 | Hoffmann La Roche | Pharmaceutical composition containing a glucosidase inhibitor and a lipase inhibitor |
HU9502843D0 (en) * | 1995-09-29 | 1995-11-28 | Livigene Ltd | Pharmaceutical composition |
UA64716C2 (en) * | 1996-08-09 | 2004-03-15 | Pharmaceuticals for therapy or prevention of illnesses connected with dysfunction of vascular endothelial cells |
-
1997
- 1997-06-23 HU HU9701081A patent/HU9701081D0/hu unknown
-
1998
- 1998-06-22 BR BR9810312-1A patent/BR9810312A/pt active Search and Examination
- 1998-06-22 DE DE69812949T patent/DE69812949T2/de not_active Expired - Fee Related
- 1998-06-22 NZ NZ502039A patent/NZ502039A/xx unknown
- 1998-06-22 WO PCT/IB1998/000961 patent/WO1998058676A1/en active IP Right Grant
- 1998-06-22 PT PT98925873T patent/PT993304E/pt unknown
- 1998-06-22 US US09/446,064 patent/US6440998B1/en not_active Expired - Fee Related
- 1998-06-22 CN CN98807103A patent/CN1127984C/zh not_active Expired - Fee Related
- 1998-06-22 PL PL337719A patent/PL191718B1/pl unknown
- 1998-06-22 AU AU77837/98A patent/AU735922B2/en not_active Ceased
- 1998-06-22 SK SK1764-99A patent/SK282877B6/sk not_active IP Right Cessation
- 1998-06-22 CA CA002294913A patent/CA2294913C/en not_active Expired - Fee Related
- 1998-06-22 IL IL13350898A patent/IL133508A/xx not_active IP Right Cessation
- 1998-06-22 RU RU2003101319/15A patent/RU2254129C2/ru not_active IP Right Cessation
- 1998-06-22 RU RU2000102359/14A patent/RU2214238C2/ru not_active IP Right Cessation
- 1998-06-22 UA UA2000010341A patent/UA64757C2/uk unknown
- 1998-06-22 EP EP98925873A patent/EP0993304B1/en not_active Expired - Lifetime
- 1998-06-22 KR KR1019997012198A patent/KR20010020496A/ko not_active Application Discontinuation
- 1998-06-22 TR TR1999/03214T patent/TR199903214T2/xx unknown
- 1998-06-22 DK DK98925873T patent/DK0993304T3/da active
- 1998-06-22 AT AT98925873T patent/ATE235918T1/de not_active IP Right Cessation
- 1998-06-22 JP JP50404999A patent/JP2002508762A/ja not_active Withdrawn
- 1998-06-22 CZ CZ0462599A patent/CZ298468B6/cs not_active IP Right Cessation
- 1998-06-22 ES ES98925873T patent/ES2195344T3/es not_active Expired - Lifetime
-
1999
- 1999-12-20 NO NO19996349A patent/NO322206B1/no unknown
-
2001
- 2001-02-09 HK HK01100914A patent/HK1029941A1/xx not_active IP Right Cessation
-
2002
- 2002-02-28 US US10/084,183 patent/US6656955B2/en not_active Expired - Fee Related
- 2002-02-28 US US10/084,095 patent/US6838469B2/en not_active Expired - Fee Related
- 2002-03-27 US US10/106,227 patent/US6720337B2/en not_active Expired - Fee Related
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104447746A (zh) * | 2013-09-18 | 2015-03-25 | 华安医学股份有限公司 | 一种活化ampk的化合物及其用途 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1127984C (zh) | 含抗肿瘤药物和羟肟酸衍生物且具有抗肿瘤增强活性和/或副作用降低的药物组合物 | |
CN1119146C (zh) | 提高药剂口服生物可利用率的组合物及试剂盒 | |
CN1304005C (zh) | 受体酪氨酸激酶抑制剂和α1-酸性糖蛋白结合化合物的联合形式 | |
CN1729012A (zh) | 预防和治疗实体瘤的组合物和方法 | |
CN1419452A (zh) | 协同治疗癌症的方法和组合物 | |
CN1254281A (zh) | 人类免疫缺陷病毒和癌治疗 | |
CN1960733A (zh) | 包含src激酶抑制剂azd0530和抗雌激素或egfr-tk抑制剂的组合产品 | |
CN101044150A (zh) | 生物还原活化的前药 | |
CN1314900A (zh) | 含有稠合吡咯并咔唑的可形成粒子的组合物 | |
EP3585789A1 (en) | Inhibitors of bruton's tyrosine kinase | |
CN1950341A (zh) | 用于治疗癌症的萘二甲酰亚胺衍生物 | |
CN1805749A (zh) | 星孢素衍生物的新药物用途 | |
CN1139384C (zh) | 用于与细胞毒性剂治疗肿瘤的基于类黄酮的治疗组合物 | |
CN1423564A (zh) | 癌症的aplidine治疗 | |
CN1220490C (zh) | 哌嗪环氧乙烷衍生物在制备用于诱导肿瘤细胞死亡的药物中的应用 | |
CN1711099A (zh) | 具有抗肿瘤和抗毒活性的提取物 | |
CN113116895A (zh) | 用于治疗神经母细胞瘤的喹啉衍生物 | |
CN1942189A (zh) | 5,10-亚甲基四氢叶酸在癌症治疗中的用途 | |
CN1494905A (zh) | 含抗肿瘤药物和羟肟酸衍生物且具有抗肿瘤增强活性和/或副作用降低的药物组合物 | |
CN1050996C (zh) | 用酰化嘧啶核苷处理化学疗法试剂和抗病毒试剂的毒性 | |
CN1615314A (zh) | 用作抗肿瘤药的核苷的磷脂衍生物 | |
CN1720226A (zh) | 用于治疗和控制骨髓增生性疾病的选择性的细胞因子抑制药物的使用方法和包括其的组合物 | |
CN1812780A (zh) | 使用埃坡霉素的癌症治疗 | |
CN1628852A (zh) | 一种抗实体肿瘤药物组合物 | |
CN1887896A (zh) | 抑制肿瘤的反义核苷酸 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20031119 |