CN1188134C - 具有增加的体内耐受性的制剂 - Google Patents
具有增加的体内耐受性的制剂 Download PDFInfo
- Publication number
- CN1188134C CN1188134C CNB981084753A CN98108475A CN1188134C CN 1188134 C CN1188134 C CN 1188134C CN B981084753 A CNB981084753 A CN B981084753A CN 98108475 A CN98108475 A CN 98108475A CN 1188134 C CN1188134 C CN 1188134C
- Authority
- CN
- China
- Prior art keywords
- preparation
- compound
- acid
- reactive compound
- oxygen
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 238000001727 in vivo Methods 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- 150000002500 ions Chemical class 0.000 claims abstract description 12
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 7
- -1 methoxyl group Chemical group 0.000 claims description 31
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 18
- 229930195725 Mannitol Natural products 0.000 claims description 18
- 239000000594 mannitol Substances 0.000 claims description 18
- 235000010355 mannitol Nutrition 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 15
- 229930195573 Amycin Natural products 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- 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 claims description 7
- 241001597008 Nomeidae Species 0.000 claims description 7
- 125000003147 glycosyl group Chemical group 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 229940124530 sulfonamide Drugs 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- JVJQPDTXIALXOG-UHFFFAOYSA-N nitryl fluoride Chemical compound [O-][N+](F)=O JVJQPDTXIALXOG-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 150000003456 sulfonamides Chemical class 0.000 claims description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 4
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 3
- 238000005336 cracking Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000002337 glycosamines Chemical class 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 150000002772 monosaccharides Chemical class 0.000 claims description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 3
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 claims description 2
- YTBSYETUWUMLBZ-UHFFFAOYSA-N D-Erythrose Natural products OCC(O)C(O)C=O YTBSYETUWUMLBZ-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- YTBSYETUWUMLBZ-IUYQGCFVSA-N D-erythrose Chemical compound OC[C@@H](O)[C@@H](O)C=O YTBSYETUWUMLBZ-IUYQGCFVSA-N 0.000 claims description 2
- RGHNJXZEOKUKBD-MGCNEYSASA-N D-galactonic acid Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-MGCNEYSASA-N 0.000 claims description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 2
- MNQZXJOMYWMBOU-VKHMYHEASA-N D-glyceraldehyde Chemical compound OC[C@@H](O)C=O MNQZXJOMYWMBOU-VKHMYHEASA-N 0.000 claims description 2
- RGHNJXZEOKUKBD-MBMOQRBOSA-N D-mannonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O RGHNJXZEOKUKBD-MBMOQRBOSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 2
- 206010056474 Erythrosis Diseases 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 2
- HSNZZMHEPUFJNZ-UHFFFAOYSA-N L-galacto-2-Heptulose Natural products OCC(O)C(O)C(O)C(O)C(=O)CO HSNZZMHEPUFJNZ-UHFFFAOYSA-N 0.000 claims description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 2
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 claims description 2
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 229930182830 galactose Natural products 0.000 claims description 2
- 239000000174 gluconic acid Substances 0.000 claims description 2
- 235000012208 gluconic acid Nutrition 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 229940097043 glucuronic acid Drugs 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims description 2
- 229960000367 inositol Drugs 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 229910021645 metal ion Inorganic materials 0.000 claims description 2
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 238000003754 machining Methods 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 description 30
- 239000001301 oxygen Substances 0.000 description 28
- 239000002585 base Substances 0.000 description 26
- 239000000243 solution Substances 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 11
- 229960000975 daunorubicin Drugs 0.000 description 11
- 229960002246 beta-d-glucopyranose Drugs 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 229940073608 benzyl chloride Drugs 0.000 description 9
- 229960005420 etoposide Drugs 0.000 description 9
- 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 8
- 125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 229960003082 galactose Drugs 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- GZCGUPFRVQAUEE-UHFFFAOYSA-N alpha-D-galactose Natural products OCC(O)C(O)C(O)C(O)C=O GZCGUPFRVQAUEE-UHFFFAOYSA-N 0.000 description 7
- WQZGKKKJIJFFOK-UHFFFAOYSA-N alpha-D-glucopyranose Natural products OCC1OC(O)C(O)C(O)C1O WQZGKKKJIJFFOK-UHFFFAOYSA-N 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 4
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 4
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 4
- 229960004397 cyclophosphamide Drugs 0.000 description 4
- 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 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 3
- 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 3
- 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 3
- 238000010171 animal model Methods 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229960004961 mechlorethamine Drugs 0.000 description 3
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 229960003147 reserpine Drugs 0.000 description 3
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 2
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- JILCEWWZTBBOFS-UHFFFAOYSA-N 4-(methylamino)antipyrine Chemical compound O=C1C(NC)=C(C)N(C)N1C1=CC=CC=C1 JILCEWWZTBBOFS-UHFFFAOYSA-N 0.000 description 2
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N 4-aminoantipyrine Chemical compound CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 2
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 description 2
- 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 2
- 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 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- 150000008151 D-glucosides Chemical group 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229930192392 Mitomycin Natural products 0.000 description 2
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 2
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 2
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 2
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 2
- VVDRDLMZLNTLEB-UHFFFAOYSA-N Rohitukin Natural products CC(C)CC(=O)OC1C(C(C(=C)C2(O)C(=O)CC(c3cocc3)C12C)C4(C)C(CC(=O)OC5(C)COC(=O)CC45)OC(=O)C)C(=O)O VVDRDLMZLNTLEB-UHFFFAOYSA-N 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-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
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-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
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- YQCUZBLLIDLHIP-CKSHBZRKSA-N [(3s,3ar,4r,5r,6s,7as)-6-[(4s,5r,5ar,9as)-4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl]-5-formyloxy-3-(furan-2-yl)-7a-hydroxy-3a-methyl-7-methylidene-1-oxo-3,4,5,6-tetrahydro-2h-inden-4-yl] 3-methylbutanoate Chemical compound C1([C@H]2CC(=O)[C@]3(O)C(=C)[C@@H]([C@@H](OC=O)[C@@H]([C@@]23C)OC(=O)CC(C)C)[C@@]2(C)[C@H](CC(=O)O[C@]3(C)COC(=O)C[C@@H]32)OC(C)=O)=CC=CO1 YQCUZBLLIDLHIP-CKSHBZRKSA-N 0.000 description 2
- 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 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 2
- SHZGCJCMOBCMKK-PHYPRBDBSA-N alpha-D-fucose Chemical compound C[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O SHZGCJCMOBCMKK-PHYPRBDBSA-N 0.000 description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 2
- 229960002170 azathioprine Drugs 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 229960001022 fenoterol Drugs 0.000 description 2
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 2
- 229960004369 flufenamic acid Drugs 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000006539 genistein Nutrition 0.000 description 2
- 229940045109 genistein Drugs 0.000 description 2
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 2
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 2
- 125000004395 glucoside group Chemical group 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000008101 lactose Substances 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
- 229960004857 mitomycin Drugs 0.000 description 2
- 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 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 229950006344 nocodazole Drugs 0.000 description 2
- 229960000649 oxyphenbutazone Drugs 0.000 description 2
- HFHZKZSRXITVMK-UHFFFAOYSA-N oxyphenbutazone Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 HFHZKZSRXITVMK-UHFFFAOYSA-N 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- RJXQSIKBGKVNRT-UHFFFAOYSA-N phosphoramide mustard Chemical compound ClCCN(P(O)(=O)N)CCCl RJXQSIKBGKVNRT-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 235000005875 quercetin Nutrition 0.000 description 2
- 229960001285 quercetin Drugs 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 229960000948 quinine Drugs 0.000 description 2
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 2
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- KOTXAHKUCAQPQA-AAUVPWARSA-N taxine Chemical compound C1([C@@H]([C@@H](O)C(=O)O[C@@H]2C=3/C[C@@](C([C@H](O)C4=C(C)[C@@H](OC(C)=O)CC(C4(C)C)[C@@H](OC(C)=O)\C=3)=O)(C)[C@@H](O)C2)N(C)C)=CC=CC=C1 KOTXAHKUCAQPQA-AAUVPWARSA-N 0.000 description 2
- 229930189271 taxine Natural products 0.000 description 2
- 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 2
- 229960000195 terbutaline Drugs 0.000 description 2
- 229960000278 theophylline Drugs 0.000 description 2
- 229960001727 tretinoin Drugs 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- NLUGUZJQJYVUHS-IDXDZYHTSA-N verrucarin A Chemical compound C([C@@]12[C@@]3(C)[C@@]45CCC(C)=C[C@H]4O[C@@H]1C[C@H]3OC(=O)\C=C/C=C/C(=O)OCC[C@H]([C@@H](C(=O)OC5)O)C)O2 NLUGUZJQJYVUHS-IDXDZYHTSA-N 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- 229960004355 vindesine Drugs 0.000 description 2
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine 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(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 1
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- QQDPEIBVHOIXMB-IHWYPQMZSA-N (z)-2-hydroxybut-2-enamide Chemical compound C\C=C(/O)C(N)=O QQDPEIBVHOIXMB-IHWYPQMZSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- IDINUJSAMVOPCM-UHFFFAOYSA-N 15-Deoxyspergualin Natural products NCCCNCCCCNC(=O)C(O)NC(=O)CCCCCCN=C(N)N IDINUJSAMVOPCM-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 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
- DATJHFMEARFPDT-UHFFFAOYSA-N 4-(2-chloroethylamino)phenol Chemical class OC1=CC=C(NCCCl)C=C1 DATJHFMEARFPDT-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010005042 Bladder fibrosis Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- 102000000584 Calmodulin Human genes 0.000 description 1
- 108010041952 Calmodulin 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
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 229930193152 Dynemicin Natural products 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 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
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 240000004859 Gamochaeta purpurea Species 0.000 description 1
- 108010081687 Glutamate-cysteine ligase Proteins 0.000 description 1
- 102100039696 Glutamate-cysteine ligase catalytic subunit Human genes 0.000 description 1
- 102000005720 Glutathione transferase Human genes 0.000 description 1
- 108010070675 Glutathione transferase Proteins 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 102000005548 Hexokinase Human genes 0.000 description 1
- 108700040460 Hexokinases Proteins 0.000 description 1
- 244000153234 Hibiscus abelmoschus Species 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-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
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- KJQFBVYMGADDTQ-CVSPRKDYSA-N L-buthionine-(S,R)-sulfoximine Chemical compound CCCCS(=N)(=O)CC[C@H](N)C(O)=O KJQFBVYMGADDTQ-CVSPRKDYSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- UQOFGTXDASPNLL-XHNCKOQMSA-N Muscarine Chemical compound C[C@@H]1O[C@H](C[N+](C)(C)C)C[C@H]1O UQOFGTXDASPNLL-XHNCKOQMSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229940049937 Pgp inhibitor Drugs 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001323 aldoses Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000003555 analeptic effect Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 101150117004 atg18 gene Proteins 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- AOXPWRXSNLNCIH-UHFFFAOYSA-N benzoic acid;2-(4-nitrophenyl)guanidine Chemical compound OC(=O)C1=CC=CC=C1.NC(=N)NC1=CC=C([N+]([O-])=O)C=C1 AOXPWRXSNLNCIH-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 108700004675 bleomycetin Proteins 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- 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 description 1
- QYOAUOAXCQAEMW-UTXKDXHTSA-N bleomycin A5 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)NCCCNCCCCN)[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 QYOAUOAXCQAEMW-UTXKDXHTSA-N 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(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=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002719 buserelin Drugs 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
- 235000012241 calcium silicate Nutrition 0.000 description 1
- DKVNPHBNOWQYFE-UHFFFAOYSA-N carbamodithioic acid Chemical compound NC(S)=S DKVNPHBNOWQYFE-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 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
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 239000002748 glycoprotein P inhibitor Substances 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 239000003667 hormone antagonist Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000010453 lymph node cancer Diseases 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229940041290 mannose Drugs 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 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
- 229960001924 melphalan Drugs 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 1
- 229960003248 mifepristone Drugs 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- BLUYEPLOXLPVCJ-INIZCTEOSA-N n-[(1s)-2-[4-(3-aminopropylamino)butylamino]-1-hydroxyethyl]-7-(diaminomethylideneamino)heptanamide Chemical compound NCCCNCCCCNC[C@H](O)NC(=O)CCCCCCNC(N)=N BLUYEPLOXLPVCJ-INIZCTEOSA-N 0.000 description 1
- 208000018389 neoplasm of cerebral hemisphere Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 229960002657 orciprenaline Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000734 parasympathomimetic agent Substances 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical compound C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 125000005555 sulfoximide group Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 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
- 229960000351 terfenadine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
包含糖基-Y[-C(＝Y)-X-]p-W-(R)n-X-C(＝Y)-活性化合物，糖或糖醇和，如果适宜，二价离子和药物可耐受载体的制剂，具有改善的体内耐受性。
Description
恶性肿瘤的治疗，与炎性疾病或自动免疫疾病相关，除该疗法作用不够外，总有严重的副作用。这种不足可主要通过所采用的活性化合物体内耐受性非常低来解释。
本发明通过对制剂的改进来改善治疗中的活性化合物的耐受性并可选择性地增加其功效。
因此，本发明涉及包含下面成分的制剂：
1)式I化合物
糖基-Y[-C(＝Y)-X-]P-W(R)n-X-C(＝Y)-活性化合物 (I)
其中
糖基为可酶解的多，寡或单糖，
W为具有共轭双键的芳香基或杂芳基或脂族基或在糖基裂解后环化的氨基酸衍生物，其中取代基
R为氢原子、甲基、甲氧基、羧基、CN、甲基羰基、羟基、硝基、氟、氯、溴、磺酰基、氨磺酰或嗍砜-(C1-C4)-烷基酰胺，
p为0或1，
n为整数，
X为氧原子、NH、亚甲基氧、亚甲基氨基或亚甲基-(C1-C4)
-烷基氨基而
Y为氧原子或NH，且
活性化合物为借助羟基、氨基和亚氨基相连的具有生物活性的化合物，
和/或式I化合物的生理上可耐受的盐，
2)糖和/或糖醇和
3)药学上可耐受的载体。
术语活性化合物被理解为指化合物，例如蒽环霉素，优选阿霉素、4’-表-阿霉素、4-或4’-脱氧阿霉素或化合物优选来自依托泊甙、N-双(2-氯乙基)-4-羟基苯胺、4-羟基环磷酰胺、长春地辛、长春碱、长春新碱、特非那定、特布他林、非诺特罗、沙丁胺醇、毒覃碱、羟布宗、水杨酸、对氨基水杨酸、5-氟尿嘧啶、氨甲喋呤、双氯芬酸、氟芬那酸、4-甲基氨基非那宗、茶碱、硝苯地平、丝裂霉素、米托恩醌、喜树碱和喜树碱衍生物，胺苯吖啶、紫杉酚、和其它紫杉碱、诺考达唑(nocodaxol)、秋水仙碱、非唑非那定(fexofenadine)、环磷酰胺、雷彻霉素(rachelmycin)、顺铂、米尔法兰、博来霉素、氮芥子气、磷酰胺芥子气、疣孢菌素A、新制癌菌素、刺孢霉素、动力霉素(dynemicin)、埃斯波霉素A、懈皮素、金雀异黄素、制表霉素、酪氨酸磷酸化抑制剂、罗奇图金(rohitukin)衍生物、视黄酸、丁酸、佛皮醇酯、二甲亚砜、阿克拉霉素、孕酮、布舍瑞林、他莫甘芬、米非司酮、奥那斯酮、N-(4-氨基丁基)-5-氯-2-萘磺酰胺、吡啶噁唑-2-酮、喹啉噁唑-2-酮、异喹啉噁唑-2-酮、星形孢菌素、乙醇胺、维拉帕米、弗司扣林、1，9-双去氧弗司扣林、奎宁、奎尼丁、利血平、18-O-(3，5-二甲氧基-4-羟基苄氧基)-利血平、氯达尼明、布松宁砜亚胺(buthionine sulfoximine)、二硫代氨基甲酸二乙酯、环孢菌素A、雷帕霉素、硫唑嘌呤、苯丁酸氮芥、羟基巴豆酰胺衍生物2、来氟米物、15-脱氧精胍菌素、FK506、布洛芬、吲哚美辛、阿司匹林、柳氮磺胺吡啶、青霉胺、氯喹、地赛米松、泼尼松尼、美福那米酸(mefonamidic acid)、4-乙酰氨基酚、4-氨基非那宗、麝香辛(muskosine)、奥西那林、异丙肾上腺素、阿米洛列、苯甲酸对硝基苯基胍或它们另外被一个或多个羟基、氨基或亚氨基取代的衍生物。
n为1-8，优选1-6。
术语糖被理解为具有3-7个碳原子的醛糖，它可属于D或L系列；这还包括氨基糖或糖醛酸。可以提到的实例为葡萄糖、甘露糖、果糖、半乳糖、核糖、赤藓糖、甘油醛、景天庚糖、葡糖胺、半乳糖胺、葡糖醛酸半乳糖醛酸、葡糖酸、半乳糖酸或甘露糖酸。
通过例如将上述糖还原形成糖醇；包括葡糖醇、甘露糖醇、山梨糖醇、甘油或肌醇。
适宜的式I化合物生理上可耐受的盐为例如碱金属盐，碱土金属盐和包括它们的有机铵碱的铵盐和质子化的氨基酸基团的盐。优选碱金属盐，如钠盐或钾盐。
尤其是，根据本发明的制剂还包含二价离子。术语“二价离子”被理解为指，例如Ca，Mg，Fe，Cu或Ni二价金属离子。
优选采用下面的式I化合物，其中
W为苯基或多取代的苯基，其中取代基
R为氢原子、甲基、甲氧基、羧基、甲氧基羰基、CN、羟基、硝基、氟、氯、溴、磺酰基、氨磺酰或嗍砜-(C1-C4)-烷基酰胺，
p为0或1，
n为1-4，
X为氧原子、NH、亚甲基氧、亚甲基氨基或亚甲基-(C1-C4)
-烷基氨基而
Y为氧原子或NH，
且活性化合物为上述化合物。
尤其优选采用下面的式I化合物，其中糖基为多，寡或单糖，尤其是α或β-O-糖苷键连接的D-葡糖苷基、D-吡喃葡糖基、D-吡喃半乳糖苷基、N-乙酰-D-氨基葡糖苷基、N-乙酰-D-氨基半乳糖苷基、D-吡喃甘露糖苷基或L-吡喃岩藻糖苷基，
W为苯基或单取代的苯基，其中取代基
R为甲氧基、甲氧基羰基、CN、羟基、硝基、氟、氯、溴、磺酰基、氨磺酰和其他为氢原子，
X为O、NH、亚甲基氧、亚甲基氨基或亚甲基甲基氨基而
Y为O或NH，且
活性化合物为上述化合物。
优选采用其中糖基可通过酶水解裂解，间隔基可通过化学水解自发裂解的化合物，活性化合物为一种通过导入其他羟基、氨基或亚氨基获得的药物或其一种衍生物，它比活性化合物亲水性强，因此，它比活性化合物体内毒性反应更低，该活性化合物是药学上的活性化合物，该活性化合物另外被一个或多个羟基、氨基或亚氨基取代并减缓肿瘤的生长，活性化合物是标准的细胞抑制剂，活性化合物是一种抗代谢物，活性化合物为5-氟胞苷、5-氟尿苷、胞嘧啶阿拉伯糖苷或氨甲喋呤，活性化合物为插入到DNA中的物质，活性化合物为阿霉素、柔红霉素、伊达比星、表柔比星或米托蒽醌，活性化合物抑制拓扑异构酶I+II，活性化合物为喜树碱和喜树碱衍生物，依托泊苷或M-AMSA，活性化合物为微管蛋白抑制剂，活性化合物为长春新碱、长春碱、长春地辛、紫杉酚和紫杉碱，诺考达唑/colchicine或依托泊苷，活性化合物为烷基化试剂，活性化合物为环磷酰胺、丝裂霉素C、雷彻霉素、顺铂、磷酰胺芥子气、苯丙胺酸氮芥、争光霉素、氮芥子气或N-双(2-氯乙基-4-羟基苯胺)，活性化合物为新制癌菌素、刺孢霉素、依波希隆(epothilone)A-C、动力霉素或埃斯波霉素A，活性化合物为使核糖体失活的化合物，活性化合物为疣孢菌素A，活性化合物为酪氨酸磷酸激酶抑制剂，活性化合物为栎皮酮、染料木黄酮、制表霉素、酪氨酸磷酸化抑制剂或rohitukin衍生物，活性化合物为分化诱导物，活性化合物为视黄酸、丁酸、佛皮醇酯、二甲亚砜或阿克拉霉素，活性化合物为激素，激素兴奋剂或激素拮抗剂，活性化合物为黄体酮、布赛来灵、tamoxifen或奥那斯酮，活性化合物为修饰针对抑制细胞多效抗性的物质，活性化合物为calmodulin抑制剂，活性化合物为蛋白激酶C抑制剂，活性化合物为P-糖蛋白抑制剂，活性化合物为与线粒体结合的己糖激酶调节因子，活性化合物为γ-谷氨酰半胱氨酸合成酶，或谷胱甘肽S-转移酶的抑制剂，活性化合物为过氧化氢歧化酶抑制剂，活性化合物为在分裂细胞的细胞核中的与增殖有关的蛋白的抑制剂，定义为MabKi67，活性化合物为产生免疫抑制效果的物质，活性化合物为标准的免疫抑制剂，活性化合物为大环内酯，活性化合物为环孢菌素A、雷帕菌素，FK506，活性化合物为硫唑嘌呤、氨甲喋呤、环磷酰胺或苯丁酸氮芥，活性化合物为具有抗炎作用的物质，活性化合物为非甾类抗炎物质，活性化合物为缓慢抗风湿药物，活性化合物为甾类，活性化合物为具有抗炎，止痛或退热作用的物质，活性化合物为有机酸的衍生物，活性化合物为非酸止痛或抗炎化合物，活性化合物为羟布宗，活性化合物为局部麻醉化合物，活性化合物为抗心律不齐化合物，活性化合物为Ca++拮抗剂，活性化合物为抗组胺化合物，活性化合物为磷酸二酯酶抑制剂，活性化合物为类副交感神经药，活性化合物为类交感神经药或活性化合物为对人尿激酶具有抑制作用的物质；和其他的化合物，其中糖基分别为α或β-O-糖苷键连接的D-葡糖苷基、D-吡喃葡糖基、D-吡喃半乳糖苷基、N-乙酰-D-氨基葡糖苷基、N-乙酰-D-氨基半乳糖苷基、D-吡喃甘露糖苷基或L-吡喃岩藻糖苷基，或它为4’-O-[4-(α-D-吡喃葡糖基氧)苯基氨基羰基]依托泊甙、
N-[4-O-(β-D-吡喃葡糖醛酸)-3-硝基苄基氧羰基]-阿霉素钠盐(化合物II)、
N-[4-O-(β-D-吡喃葡糖醛酸)-3-氯苄基氧羰基]-阿霉素钠盐、
N-[4-O-(β-D-吡喃葡糖醛酸)-3-氟苄基氧羰基]-阿霉素钠盐、
N-[4-O-(β-D-吡喃葡糖醛酸)-3-硝基苄基氧羰基]-柔红霉素钠盐、
N-[4-O-(β-D-吡喃葡糖醛酸)-3-氯苄基氧羰基]-柔红霉素钠盐、
N-[4-O-(α-D-吡喃半乳糖基)-3-硝基苄基氧羰基]-柔红霉素钠盐、
N-[4-O-(α-D-吡喃半乳糖基)-3-氯苄基氧羰基]-柔红霉素钠盐、
N-[4-O-(α-D-吡喃半乳糖基)-3-氟苄基氧羰基]-柔红霉素钠盐、
N-[4-O-(β-D-吡喃葡糖醛酸)-3-硝基苄基氧羰基]-阿霉素钠盐、
N-[2-O-(β-D-吡喃葡糖醛酸)-5-氯苄基氧羰基]-阿霉素钠盐、
N-[2-O-(β-D-吡喃葡糖醛酸)-5-氟苄基氧羰基]-阿霉素钠盐、
N-[2-O-(β-D-吡喃葡糖醛酸)-5-硝基苄基氧羰基]-柔红霉素钠盐、
N-[2-O-(β-D-吡喃葡糖醛酸)-5-氯苄基氧羰基]-柔红霉素钠盐、
N-[2-O-(α-D-吡喃半乳糖基)-5-硝基苄基氧羰基]-柔红霉素、
N-[2-O-(α-D-吡喃半乳糖基)-5-氯苄基氧羰基]-柔红霉素、
N-[2-O-(α-D-吡喃半乳糖基)-5-氟苄基氧羰基]-柔红霉素、
4’-O-[4-(β-D-吡喃葡糖基氧)苯基氨基羰基]-依托泊甙、
4’-O-[4-(α-D-吡喃半乳糖基氧)苯基氨基羰基]-依托泊甙、
4’-O-[4-(β-D-葡糖醛酸氧)苯基氨基羰基]-依托泊甙、
4’-O-[4-(β-D-葡糖醛酸氧)-3-硝基苄基氨基羰基]-依托泊甙、
4’-O-[4-(β-D-葡糖醛酸氧)-3-氯苄基氨基羰基]-依托泊甙、
1-N-[4-(β-D-葡糖醛酸氧)苄氧羰基]丝裂霉素、
14-O-[4-(β-D-葡糖醛酸氧)-3-硝基苄基氨基羰基]阿霉素、
4-O-[4-(β-D-葡糖醛酸氧)苄基氨基羰基]-4-羟基-1-N-(双-2-氯乙基)苯胺、
4-O-[4-(β-D-葡糖醛酸氧)苄基氨基羰基]三氟拉嗪、
3’-O-[4-(β-D-葡糖醛酸氧)苄基氨基羰基]特布他林、
3’-O-[4-(β-D-葡糖醛酸氧)苄基氨基羰基]非诺特罗、
1”-O-[4-(β-D-葡糖醛酸氧)苄基氨基羰基]沙丁胺醇、
3-O-[4-(β-D-葡糖醛酸氧)苄基氨基羰基]毒蕈碱、
4’-O-[4-(β-D-葡糖醛酸氧)苄基氨基羰基]羟苯保泰松、
2-O-[4-(β-D-葡糖醛酸氧)苄基氨基羰基]水杨酸、
N-[4-(β-D-葡糖醛酸氧)苄基氧羰基]双氯芬酸、
N-[4-(β-D-葡糖醛酸氧)苄基氧羰基]氟芬那酸、
4-N-[4-(β-D-葡糖醛酸氧)苄基氧羰基]-4-甲基氨基非那宗、
7-N-[4-(β-D-葡糖醛酸氧)苄基氧羰基]茶碱、
1-N-[4-(β-D-葡糖醛酸氧)苄基氧羰基]硝苯地辛、
[4-(β-D-葡糖醛酸氧)-3-硝基苄基]-2-[1-氰基-1-(N-4-三氟甲基苯基)氨基甲酰基]丙烯-1-基碳酸酯、
3’-N-[4-N-(α-D-半乳糖基氧羰基)-4-氨基苄基氧羰基]阿霉素、
9-O-[4-(β-D-葡糖醛酸氧)-3-氯苄基氧羰基]奎宁
或18-O-[3，5-二甲氧基-4-[4-β-D-葡糖醛酸基氧)-3-氯苄基氧羰基]-苯甲酰基]利血平。
尤其优选采用化合物II作为活性化合物，并且还有甘露糖醇作为糖醇，Ca2+作为二价离子。
式I化合物如EP0751144中所描述的制备。
化合物II以1-1000mg/Kg体重的量采用，优选5-500mg/kg。
如果为溶液剂，采用的甘露糖醇的量为1mg/ml-150mg/ml，优选10-100mg/ml，尤其优选50mg/ml。
在溶液剂中，Ca2+离子，例如CaCl2，以0.01mg/ml-10mg/ml CaCl2×2H2O，优选为0.05-2mg/ml，尤其为0.4mg/ml的量采用。
优选地，在所述溶液剂中含有50mg/ml甘露糖醇，0.4mg/mlCaCl2×2H2O和25mg/ml上述式II化合物。
根据本发明的固体剂适宜于，例如治疗：
-急性免疫疾病，例如脓毒症，过敏反应，移植物抗宿主反应，宿主抗移植物反应，
-自动免疫疾病，尤其是类风湿性关节炎，系统性红斑狼疮，多层性硬化，
-牛皮癣，特异反应性皮炎，气喘，寻麻疹，鼻炎，眼色素层炎
-肝纤维化，膀胱纤维化，结肠炎
-癌症，例如肺癌，白血病，卵巢癌，肉瘤，卡波济肉瘤，脑膜瘤，肠癌，淋巴结癌，脑肿瘤，乳腺癌，胰腺癌，前列腺癌或皮肤癌。
根据本发明的固体剂还可包含混合包装或组合物，其中各组分依次放置，因此可同时，分别，或间隔施用于同一或同样的病人和动物个体。尤其是就空间直径而言，如果药物形式使施用发生困难时，根据本发明，组分1，2和任选的二价离子还可以分别的药物形式依次放置。由于经常在为老年患者时，他们对大片剂和胶囊剂反感，因此，这尤其适宜于口服形式。制备的依次放置的分别的药物形式必须能同时服用。在这方面，不同的剂型，例如片剂和胶囊剂也可依次放置。
本发明进一步涉及一种制备根据本发明的制剂的方法，它包括加工组分1)，2)，如果适宜还有二价离子以及药物载体，得到药物施用剂型。
根据本发明的固体剂型可以剂量单元的药物剂型的形式存在，例如胶囊剂(包括微胶囊)，片剂(包括包衣片剂和丸剂)或栓剂，其中当使用胶囊剂时，胶囊物质可起载体的作用，内含物可以例如粉末，凝胶体，乳液，分散体或溶液的形式存在。然而，在制备含有三种成分1)，2)和如果适宜时的二价离子的含有计算量的活性化合物和各种所需的药物载体的口服(通过口的)制剂时尤为有利和简便。适宜的制剂(栓剂)还可用于直肠治疗。包含本发明的制剂的油膏，霜剂的透皮施用或溶液剂的口服也是可以的。式I化合物也可以冷冻干燥物的形式存在，它在施用之前，用包含5％甘露糖醇和0.4mg的CaCl2×2H2O/ml(pH约7)的溶液再配制。除开活性化合物之外，油膏，膏剂，霜剂，和粉剂可含有常规的赋形剂，例如动物和植物脂肪，蜡，石蜡，淀粉，西黄蓍胶，纤维素衍生物，聚乙二醇，硅氧烷，膨润土，滑石，氧化锌，乳糖，硅酸，氢氧化铝，硅酸钙和聚酰胺粉末或这些物质的混合物。
片剂，丸剂或颗粒剂可通过常规方法制备，例如挤压，浸渍或流化床方法或锅包衣，并包含赋形剂和其他常规辅剂，例如明胶，琼脂糖，淀粉(例如土豆，玉米或小麦淀粉)，纤维素，例如乙基纤维素，硅胶，各种糖，例如乳糖，碳酸镁和/或磷酸钙。包衣溶液通常由糖和/或淀粉糖浆组成，通常还另外含有明胶，阿拉伯胶，聚乙烯吡咯烷酮，合成纤维素酯，表面活性物质，增塑剂，颜料和根据现有技术类似的添加剂。为了生产制剂，可使用任何常规的流动调节剂，滑移剂或润滑剂，例如硬脂酸镁和脱模剂。
当然，使用的剂量取决于各种因素，例如被治疗者(例如人或动物)，年龄，体重，通常的健康状况，症状的严重程度，要治疗的疾病，可能伴随的疾病(如果存在)，用其他药物相伴治疗的性质，或治疗的频率。施用剂量为例如每周1-3次(静脉，i.v.)。
各活性成分的量自然取决于单剂量的数量，并取决于治疗的疾病。单剂量还可由同时施用的几种剂量单元组成。
实施例
药物学试验
使用的试验动物为NMR1饲养品系的体重为17-25g的患有肿瘤的裸鼠。每个试验组采用6-8个动物。动物通过静脉给药接受溶解形式的化合物II和生理盐水(化合物II的剂量为如表1所描述的，在0.9％ NaCl中)，甘露糖醇(化合物II的剂量为如表1所描述的在5％浓的甘露糖醇的水溶液中，pH 7)，和根据本发明的包含化合物II，CaCl2和甘露糖醇(化合物II的剂量为如表1所描述的在含有0.4mgCaCl2×2H2O的5％浓的甘露糖醇的水溶液中)的制剂。在第1，4和8天进行给药。在整个试验期间，以3-4天间隔测定动物的重量和LOVO肿瘤的生长。每天记录存活率。表1显示结果。
表1
| 药物制剂 | 剂量mg/kg(3X) | 肿瘤T-C生长的延迟(200％) (400％) | 最小T/C比例(％) (天) | 最低重量的平均值(％) (天) | 死亡的动物(％) (天) |
| 生理盐水 | 225350 | 3.9 19.3n.a. n.a. | 40 4185 4 | 76 978 4 | 33 6.11100 4.8 |
| 甘露糖醇 | 350 | 17.3 18.8 | 17 14 | 72 8 | 17 19 |
| Ca/甘露糖醇 | 400 | 19.6 28 | 13 23 | 82 10 | 0 |
n.a.指未达到
T-C(200％)：数天内在用相应制剂中的化合物II治疗下的肿瘤(肿瘤体积)增倍的时间减去数天内用没有化合物II的相应制剂治疗下的肿瘤(肿瘤体积)增倍的时间。
T-C(400％)：数天内在用相应制剂中的化合物II治疗下的肿瘤(肿瘤体积)的增加四倍的时间减去数天内用没有化合物II的相应制剂治疗下的肿瘤(肿瘤体积)增加四倍的时间。
最小T/C比例(％)指：与对照组比较，治疗组肿瘤生长的最小值％。
最小T/C比例(天)指：与对照组比较，治疗组肿瘤生长最少的天数。
通过静脉以3×225mg/kg的剂量注射化合物II的生理盐水溶液仅获得微弱的抗肿瘤效果。T-C(200％)：3.9天。然而，体重的减少(化合物II副作用的测定)已经是非常严重的(体重减少24％和33％动物死亡)。静脉注射3×350mg/kg的化合物II的生理盐水溶液导致了所有实验动物的快速死亡。注射3×350mg/kg的化合物II的甘露糖醇溶液产生明显的抗肿瘤效果(T-C(200％)：17.3天)和适中的耐受性(体重减少28％和17％动物死亡)。注射3×400mg/kg的化合物II的Ca/甘露糖醇溶液诱导强的抗肿瘤效果(T-C(200％)：19.6天)和对于试验动物高的可耐受性(体重减少18％和没有动物死亡)。
在以3×120mg/kg的化合物II的Ca/甘露糖醇溶液静脉注射给恒河猴的试验中获得了相似的有利结果。动物在这种及其高的剂量下存活，而没有明显的副作用的表现。化合物II在0.1M磷酸缓冲溶液，pH7.35中的溶液的最大耐受量为1×40mg/kg。这些研究证实了化合物II在根据本发明的Ca/甘露糖醇溶液中具有明显较好的耐受性，而且还显著的更具有活性。
Claims (10)
1.一种制剂，包含
1)式I化合物
糖基-Y[-C(＝Y)-X-]p-W(R)n-X-C(＝Y)-活性化合物 (I)
其中
糖基为可酶解的多，寡或单糖，
W为具有共轭双键的芳香基或杂芳基或脂族基或在糖基裂解后环化的氨基酸衍生物，其中取代基
R为氢原子、甲基、甲氧基、羧基、CN、甲基羰基、羟基、硝基、氟、氯、溴、磺酰基、氨磺酰或嗍砜-(C1-C4)-烷基酰胺，
p为0或1，
n为整数，
X为氧原子、NH、亚甲基氧、亚甲基氨基或亚甲基-(C1-C4)-烷基氨基而
Y为氧原子或NH，且
活性化合物为借助羟基、氨基和亚氨基相连的蒽环霉素化合物，或它们另外被一个或多个羟基、氨基或亚氨基取代的衍生物，
和/或式I化合物的生理上可耐受的盐，
2)糖和/或糖醇和
3)药学上可耐受的载体。
2.权利要求1所述的制剂，其中还存在二价离子。
3.根据权利要求3的制剂，其中所述蒽环霉素为阿霉素、4′-表-阿霉素、4-或4′-脱氧阿霉素。
4.根据权利要求1的制剂，其中所述式(I)化合物为下式(II)化合物：
5.根据权利要求1或2的制剂，其中使用的式I化合物中
W为苯基或多取代的苯基，其中取代基
R为氢原子、甲基、甲氧基、羧基、甲氧基羰基、CN、羟基、硝基、氟、氯、溴、磺酰基、氨磺酰或嗍砜-(C1-C4)-烷基酰胺，
p为0或1，
n为1-4，
X为氧原子、NH、亚甲基氧、亚甲基氨基或亚甲基-(C1-C4)-烷基氨基而
Y为氧原子或NH，
且活性化合物为上述化合物。
6.根据权利要求1或2的制剂，其中加入的糖和/或糖醇为葡萄糖、甘露糖、果糖、半乳糖、核糖、赤藓糖、甘油醛、景天庚糖、葡糖胺、半乳糖胺、葡糖醛酸半乳糖醛酸、葡糖酸、半乳糖酸或甘露糖酸、葡糖醇、甘露糖醇、山梨糖醇、甘油或肌醇。
7.根据权利要求2的制剂，其中加入的二价离子为Ca，Mg，Fe，Cu或Ni的金属离子。
8.根据权利要求2的制剂，其中制剂以溶液的形式存在，含有Ca2+离子，甘露糖醇和化合物II：
9.如权利要求8所述的制剂，其中制剂含有50mg/ml甘露糖醇，0.4mg/mlCaCl2×2H2O和25mg/ml如权利要求8所述的化合物II。
10.一种制备根据权利要求1-9的任一项制剂的方法，包括加工式I化合物，糖和/或糖醇，和如果适宜，二价离子和药物载体，产生药物施用剂型。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19720312A DE19720312A1 (de) | 1997-05-15 | 1997-05-15 | Zubereitung mit erhöhter in vivo Verträglichkeit |
| DE19720312.4 | 1997-05-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1199613A CN1199613A (zh) | 1998-11-25 |
| CN1188134C true CN1188134C (zh) | 2005-02-09 |
Family
ID=7829495
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB981084753A Expired - Fee Related CN1188134C (zh) | 1997-05-15 | 1998-05-14 | 具有增加的体内耐受性的制剂 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US6020315A (zh) |
| EP (1) | EP0879605B1 (zh) |
| JP (1) | JP4367798B2 (zh) |
| KR (1) | KR100547923B1 (zh) |
| CN (1) | CN1188134C (zh) |
| AR (1) | AR012694A1 (zh) |
| AT (1) | ATE333899T1 (zh) |
| AU (1) | AU740694B2 (zh) |
| BR (1) | BR9801632A (zh) |
| CA (1) | CA2237450A1 (zh) |
| CZ (1) | CZ149398A3 (zh) |
| DE (2) | DE19720312A1 (zh) |
| HU (1) | HUP9801087A3 (zh) |
| ID (1) | ID20283A (zh) |
| PL (1) | PL193478B1 (zh) |
| RU (1) | RU2234322C2 (zh) |
| TR (1) | TR199800848A3 (zh) |
Families Citing this family (52)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0812195T3 (da) * | 1995-02-28 | 2003-03-03 | Aventis Pharma Inc | Farmaceutisk sammensætning til piperidinoalkanolforbindelser |
| EP1186606B2 (de) | 1995-11-17 | 2011-09-07 | Gesellschaft für Biotechnologische Forschung mbH (GBF) | Epothilon-Derivate, ihre Herstellung und Verwendung |
| CN1196698C (zh) | 1996-11-18 | 2005-04-13 | 生物技术研究有限公司(Gbf) | Epothilone D、E和F,其制备方法,以及作为细胞抑制剂和植物保护剂的应用 |
| DE69734362T2 (de) | 1996-12-03 | 2006-07-20 | Sloan-Kettering Institute For Cancer Research | Synthese von epothilonen, zwischenprodukte dazu, analoga und verwendungen davon |
| US6204388B1 (en) | 1996-12-03 | 2001-03-20 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| US6605599B1 (en) | 1997-07-08 | 2003-08-12 | Bristol-Myers Squibb Company | Epothilone derivatives |
| UA60335C2 (uk) * | 1997-08-26 | 2003-10-15 | Хехст Маріон Рассел, Інк. | Фармацевтична композиція, яка об'єднує піперидиноалканол з протинабряковим агентом |
| US6365749B1 (en) | 1997-12-04 | 2002-04-02 | Bristol-Myers Squibb Company | Process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs |
| US6320045B1 (en) | 1997-12-04 | 2001-11-20 | Bristol-Myers Squibb Company | Process for the reduction of oxiranyl epothilones to olefinic epothilones |
| FR2775187B1 (fr) * | 1998-02-25 | 2003-02-21 | Novartis Ag | Utilisation de l'epothilone b pour la fabrication d'une preparation pharmaceutique antiproliferative et d'une composition comprenant l'epothilone b comme agent antiproliferatif in vivo |
| US6399638B1 (en) | 1998-04-21 | 2002-06-04 | Bristol-Myers Squibb Company | 12,13-modified epothilone derivatives |
| US6498257B1 (en) | 1998-04-21 | 2002-12-24 | Bristol-Myers Squibb Company | 2,3-olefinic epothilone derivatives |
| US6780620B1 (en) | 1998-12-23 | 2004-08-24 | Bristol-Myers Squibb Company | Microbial transformation method for the preparation of an epothilone |
| ATE254615T1 (de) | 1999-02-22 | 2003-12-15 | Biotechnolog Forschung Gmbh | C-21 modifizierte epothilone |
| US6291684B1 (en) | 1999-03-29 | 2001-09-18 | Bristol-Myers Squibb Company | Process for the preparation of aziridinyl epothilones from oxiranyl epothilones |
| IL146284A0 (en) | 1999-05-04 | 2002-07-25 | Strakan Ltd | Androgen glycosides and pharmaceutical compositions containing the same |
| MY164077A (en) * | 1999-05-13 | 2017-11-30 | Pharma Mar Sa | Compositions and uses of et743 for treating cancer |
| GB2355007A (en) * | 1999-10-08 | 2001-04-11 | Michael Francis Holick | Tamoxifen analogue glycosides and use thereof |
| US7732404B2 (en) * | 1999-12-30 | 2010-06-08 | Dexcel Ltd | Pro-nanodispersion for the delivery of cyclosporin |
| US6518421B1 (en) | 2000-03-20 | 2003-02-11 | Bristol-Myers Squibb Company | Process for the preparation of epothilone analogs |
| US6593115B2 (en) | 2000-03-24 | 2003-07-15 | Bristol-Myers Squibb Co. | Preparation of epothilone intermediates |
| CA2307278A1 (en) * | 2000-04-28 | 2001-10-28 | University Of British Columbia | Use of n-heterocyclic substituted salicylic acids for inhibition of cellular uptake of cystine |
| UA75365C2 (en) | 2000-08-16 | 2006-04-17 | Bristol Myers Squibb Co | Epothilone analog polymorph modifications, a method for obtaining thereof (variants), a pharmaceutical composition based thereon |
| CA2424345A1 (en) * | 2000-10-16 | 2002-04-25 | Neopharm, Inc. | Liposomal formulation of mitoxantrone |
| ES2304240T3 (es) | 2001-01-25 | 2008-10-01 | Bristol-Myers Squibb Company | Procedimientos para la preparacion de preparaciones farmaceuticas que contienen analogos de epotilona para el tratamiento de cancer. |
| WO2002062338A1 (en) | 2001-01-25 | 2002-08-15 | Bristol-Myers Squibb Company | Parenteral formulation containing epothilone analogs |
| NZ526871A (en) | 2001-01-25 | 2006-01-27 | Bristol Myers Squibb Co | Pharmaceutical dosage forms of epothilones for oral administration |
| MXPA03007423A (es) | 2001-02-20 | 2003-11-18 | Bristol Myers Squibb Co | Derivados de epotilona para tratamiento de tumores refractarios. |
| KR20040025895A (ko) | 2001-02-20 | 2004-03-26 | 브리스톨-마이어스스퀴브컴파니 | 에포틸론 유도체를 사용하는 치료불응성 종양의 치료 |
| BRPI0207961B8 (pt) | 2001-03-14 | 2021-05-25 | Bristol Myers Squibb Co | uso de análogos de epotilona e capecitabina para fabricar medicamento para tratar tumores cancerosos sólidos e kit compreendendo os referidos compostos. |
| EP1392664A4 (en) | 2001-06-01 | 2005-01-26 | Bristol Myers Squibb Co | EPOTHILONE DERIVATIVES |
| ATE371458T1 (de) * | 2001-08-14 | 2007-09-15 | Valderm Aps | Behandlung von hyperproliferativen zuständen von körperoberflächen |
| US20030194421A1 (en) * | 2001-12-28 | 2003-10-16 | Angiotech Pharmaceuticals, Inc. | Treatment of uveitis |
| WO2003077903A1 (en) | 2002-03-12 | 2003-09-25 | Bristol-Myers Squibb Company | C12-cyano epothilone derivatives |
| TW200403994A (en) | 2002-04-04 | 2004-03-16 | Bristol Myers Squibb Co | Oral administration of EPOTHILONES |
| TW200400191A (en) | 2002-05-15 | 2004-01-01 | Bristol Myers Squibb Co | Pharmaceutical compositions and methods of using C-21 modified epothilone derivatives |
| US7008936B2 (en) | 2002-06-14 | 2006-03-07 | Bristol-Myers Squibb Company | Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases |
| US7649006B2 (en) | 2002-08-23 | 2010-01-19 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| ES2281692T3 (es) | 2002-08-23 | 2007-10-01 | Sloan-Kettering Institute For Cancer Research | Sintesis de epotilones, sus intermediarios, sus analogos y sus usos. |
| HRP20050278A2 (en) | 2002-09-23 | 2005-10-31 | Bristol-Myers Squibb Company | Methods for the preparation, isolation and purification of epothilone b, and x-ray crystal structures of epothilone b |
| ZA200507752B (en) * | 2003-03-28 | 2007-01-31 | Threshold Pharmaceuticals Inc | Compositions and methods for treating cancer |
| CA2613312C (en) | 2005-06-29 | 2014-10-14 | Threshold Pharmaceuticals, Inc. | Phosphoramidate alkylator prodrugs |
| US8425459B2 (en) | 2006-11-20 | 2013-04-23 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent |
| US9700704B2 (en) | 2006-11-20 | 2017-07-11 | Lutonix, Inc. | Drug releasing coatings for balloon catheters |
| US8414526B2 (en) * | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising oils, fatty acids, and/or lipids |
| US8414910B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
| US9737640B2 (en) * | 2006-11-20 | 2017-08-22 | Lutonix, Inc. | Drug releasing coatings for medical devices |
| US20080175887A1 (en) | 2006-11-20 | 2008-07-24 | Lixiao Wang | Treatment of Asthma and Chronic Obstructive Pulmonary Disease With Anti-proliferate and Anti-inflammatory Drugs |
| US8552048B2 (en) * | 2006-12-26 | 2013-10-08 | Threshold Pharmaceuticals, Inc. | Phosphoramidate alkylator prodrugs for the treatment of cancer |
| US20090118031A1 (en) * | 2007-11-01 | 2009-05-07 | Qualizza Gregory K | Shaft Structure with Configurable Bending Profile |
| WO2013026453A1 (en) * | 2011-08-22 | 2013-02-28 | Valderm Aps | Treatment of inflammatory disorders with anthracyclines |
| GB201414806D0 (en) * | 2014-08-20 | 2014-10-01 | Ucl Business Plc | Cyclosporin conjugates |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ225599A (en) * | 1987-08-04 | 1991-09-25 | Bristol Myers Co | Antibody-enzyme conjugates and combinations with prodrugs for the treatment of tumour cells |
| FR2676058B1 (fr) * | 1991-04-30 | 1994-02-25 | Hoechst Lab | Prodrogues glycosylees, leur procede de preparation et leur utilisation dans le traitement des cancers. |
| DE4236237A1 (de) * | 1992-10-27 | 1994-04-28 | Behringwerke Ag | Prodrugs, ihre Herstellung und Verwendung als Arzneimittel |
| EP0647450A1 (en) * | 1993-09-09 | 1995-04-12 | BEHRINGWERKE Aktiengesellschaft | Improved prodrugs for enzyme mediated activation |
| DE4417865A1 (de) * | 1994-05-20 | 1995-11-23 | Behringwerke Ag | Kombination von Tumornekrose-induzierenden Substanzen mit Substanzen, die durch Nekrosen aktiviert werden, zur selektiven Tumortherapie |
| EP0751144B1 (en) * | 1995-06-27 | 2004-10-06 | Pharmachemie B.V. | Novel anthracycline prodrugs, method for preparation as well as their use in selective chemotherapy |
| ES2257756T3 (es) * | 1996-03-12 | 2006-08-01 | Sanofi-Aventis Deutschland Gmbh | Nuevos profarmacos para la terapia de tumores y enfermedades inflamatorias. |
-
1997
- 1997-05-15 DE DE19720312A patent/DE19720312A1/de not_active Withdrawn
-
1998
- 1998-05-02 DE DE59813653T patent/DE59813653D1/de not_active Expired - Lifetime
- 1998-05-02 AT AT98108041T patent/ATE333899T1/de not_active IP Right Cessation
- 1998-05-02 EP EP98108041A patent/EP0879605B1/de not_active Expired - Lifetime
- 1998-05-13 ID IDP980708A patent/ID20283A/id unknown
- 1998-05-13 TR TR1998/00848A patent/TR199800848A3/tr unknown
- 1998-05-13 CZ CZ981493A patent/CZ149398A3/cs unknown
- 1998-05-13 US US09/076,878 patent/US6020315A/en not_active Expired - Lifetime
- 1998-05-13 CA CA002237450A patent/CA2237450A1/en not_active Abandoned
- 1998-05-13 AR ARP980102233A patent/AR012694A1/es unknown
- 1998-05-14 HU HU9801087A patent/HUP9801087A3/hu unknown
- 1998-05-14 CN CNB981084753A patent/CN1188134C/zh not_active Expired - Fee Related
- 1998-05-14 RU RU98109154/15A patent/RU2234322C2/ru not_active IP Right Cessation
- 1998-05-14 BR BR9801632A patent/BR9801632A/pt not_active Application Discontinuation
- 1998-05-15 JP JP13323198A patent/JP4367798B2/ja not_active Expired - Fee Related
- 1998-05-15 KR KR1019980018269A patent/KR100547923B1/ko not_active Expired - Fee Related
- 1998-05-15 PL PL326336A patent/PL193478B1/pl unknown
- 1998-05-15 AU AU66005/98A patent/AU740694B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| RU2234322C2 (ru) | 2004-08-20 |
| TR199800848A2 (xx) | 1998-12-21 |
| DE59813653D1 (de) | 2006-09-07 |
| US6020315A (en) | 2000-02-01 |
| CZ149398A3 (cs) | 1998-12-16 |
| JP4367798B2 (ja) | 2009-11-18 |
| HU9801087D0 (en) | 1998-07-28 |
| JPH1129497A (ja) | 1999-02-02 |
| DE19720312A1 (de) | 1998-11-19 |
| TR199800848A3 (tr) | 1998-12-21 |
| EP0879605A2 (de) | 1998-11-25 |
| EP0879605B1 (de) | 2006-07-26 |
| AU740694B2 (en) | 2001-11-15 |
| HUP9801087A3 (en) | 1999-05-28 |
| KR19980087239A (ko) | 1998-12-05 |
| PL193478B1 (pl) | 2007-02-28 |
| ATE333899T1 (de) | 2006-08-15 |
| CN1199613A (zh) | 1998-11-25 |
| ID20283A (id) | 1998-11-19 |
| AU6600598A (en) | 1998-11-19 |
| BR9801632A (pt) | 1999-06-29 |
| PL326336A1 (en) | 1998-11-23 |
| AR012694A1 (es) | 2000-11-08 |
| HUP9801087A2 (hu) | 1998-12-28 |
| KR100547923B1 (ko) | 2006-04-12 |
| EP0879605A3 (de) | 1998-12-02 |
| CA2237450A1 (en) | 1998-11-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1188134C (zh) | 具有增加的体内耐受性的制剂 | |
| RU98109154A (ru) | Препарат с улучшенной переносимостью in vivo | |
| US20090176717A1 (en) | Galactosides and thiodigalactosides as inhibitors of pa-il lectin from pseudomonas | |
| BRPI0613705A2 (pt) | terapia combinada para o tratamento de distúrbios imunoinflamatórios | |
| CN1297350A (zh) | 副作用减轻剂 | |
| WO2002079748A2 (en) | Withasol and methods of use | |
| CN101039699B (zh) | 用于减小药物化合物毒性的方法和组合物 | |
| CN1117711A (zh) | 治疗人肿瘤细胞药替莫唑胺的增效方法 | |
| KR19990076695A (ko) | 시티딘 데아미나제 혹은 데옥시시티딘 데아미나제의 과발현과연관된 질병들을 치료하기 위한 활성제_및 방법 | |
| US20050065114A1 (en) | Therapeutical treatment with oligo-beta- (1,3) -glucans, drugs used in said treatment | |
| Parker et al. | N-Trifluoroacetyladriamycin-14-valerate: additional mouse antitumor and toxicity studies | |
| CN101553218A (zh) | 当给予乳清酸盐衍生物时降低组织药物水平的组合物和方法 | |
| NZ517634A (en) | Compositions and methods for L-nucleosides, L-nucleotides, and their analogs | |
| CN1258362C (zh) | 取代的丙烯酰基司他霉素衍生物在治疗与高水平谷胱甘肽相关的肿瘤中的用途 | |
| KR20010072228A (ko) | 위장 독성이 감소된 캠프토테신 유도체의 용도 | |
| US10065978B2 (en) | Cysteine-modifying substrate analogue inhibitors of ribose 5-phosphate isomerase for parasitic diseases, along with methods of their formation and use | |
| DE69529575T2 (de) | Arzneimittel zur behandlung von parasitischen und pilzartigen infektionen | |
| JP2019131508A (ja) | ペンタアザ大環状環複合体および白金を基にした抗癌剤による組み合わせ癌療法 | |
| JP2010535702A (ja) | 薬剤をオロチン酸誘導体として投与することで薬剤の組織内濃度を下げる組成物及びその方法 | |
| Christensen et al. | Reversal of multidrug resistance by derivatives of acrivastine | |
| JP2003506101A (ja) | 免疫無防備状態宿主における侵襲性肺アスペルギルス症の大型動物モデル | |
| Waites et al. | Biochemical and functional analysis of rat bronchoalveolar macrophages containing chemically induced phospholipid inclusions | |
| CN115192522A (zh) | 一种含有伊布替尼的组合物及其制备方法和应用 | |
| Sanjukta et al. | ROLE OF ISOFLAVONES IN DRUG DELIVERY WITH SPECIAL REFERENCE TO CHICKEN EGG LYSOZYME ON ASCITE CARCINOMA CELL: EXPERIENCED BASED RESEARCH | |
| CN100438913C (zh) | 一种抗癌药物组合物 |
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 | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |