TW201331182A - 抗腫瘤劑之效果增強劑 - Google Patents
抗腫瘤劑之效果增強劑 Download PDFInfo
- Publication number
- TW201331182A TW201331182A TW101150217A TW101150217A TW201331182A TW 201331182 A TW201331182 A TW 201331182A TW 101150217 A TW101150217 A TW 101150217A TW 101150217 A TW101150217 A TW 101150217A TW 201331182 A TW201331182 A TW 201331182A
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- substituent
- atom
- antitumor
- compound
- Prior art date
Links
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 70
- 230000000694 effects Effects 0.000 title description 23
- 125000001424 substituent group Chemical group 0.000 claims abstract description 96
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 39
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 24
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 23
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 22
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 18
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 18
- 229910052801 chlorine Chemical group 0.000 claims abstract description 14
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 13
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims abstract description 7
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims abstract description 7
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims abstract description 6
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims abstract description 6
- 239000004480 active ingredient Substances 0.000 claims abstract description 3
- -1 mercaptothiourea compound Chemical class 0.000 claims description 88
- 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 claims description 38
- 229930012538 Paclitaxel Natural products 0.000 claims description 32
- 229960001592 paclitaxel Drugs 0.000 claims description 32
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 26
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 12
- 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 claims description 12
- 229960004891 lapatinib Drugs 0.000 claims description 12
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 229960001674 tegafur Drugs 0.000 claims description 11
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 claims description 11
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000003623 enhancer Substances 0.000 claims description 8
- 125000002757 morpholinyl group Chemical group 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 229960005277 gemcitabine Drugs 0.000 claims description 7
- 229960004768 irinotecan Drugs 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 108010012934 Albumin-Bound Paclitaxel Proteins 0.000 claims description 6
- 229940028652 abraxane Drugs 0.000 claims description 6
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 4
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- PKWAIEWKLUOAPO-UHFFFAOYSA-N FC1=C(OC2=CC=NC3=CC(=C(C=C23)C(=O)NC)OC)C=CC(=C1)NC(=S)NCCC1=CC=CC=C1 Chemical compound FC1=C(OC2=CC=NC3=CC(=C(C=C23)C(=O)NC)OC)C=CC(=C1)NC(=S)NCCC1=CC=CC=C1 PKWAIEWKLUOAPO-UHFFFAOYSA-N 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims 3
- ZPLQIPFOCGIIHV-UHFFFAOYSA-N Gimeracil Chemical compound OC1=CC(=O)C(Cl)=CN1 ZPLQIPFOCGIIHV-UHFFFAOYSA-N 0.000 claims 1
- IAPCTXZQXAVYNG-UHFFFAOYSA-M Potassium 2,6-dihydroxytriazinecarboxylate Chemical compound [K+].[O-]C(=O)C1=NC(=O)NC(=O)N1 IAPCTXZQXAVYNG-UHFFFAOYSA-M 0.000 claims 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims 1
- 238000013329 compounding Methods 0.000 claims 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims 1
- 229950009822 gimeracil Drugs 0.000 claims 1
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims 1
- 229950000193 oteracil Drugs 0.000 claims 1
- 125000005236 alkanoylamino group Chemical group 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 32
- 238000012360 testing method Methods 0.000 description 32
- 238000002360 preparation method Methods 0.000 description 19
- 206010028980 Neoplasm Diseases 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- 230000037396 body weight Effects 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 11
- 238000007920 subcutaneous administration Methods 0.000 description 10
- 238000002054 transplantation Methods 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 208000005718 Stomach Neoplasms Diseases 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 206010017758 gastric cancer Diseases 0.000 description 9
- 201000011549 stomach cancer Diseases 0.000 description 9
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 7
- 201000005202 lung cancer Diseases 0.000 description 7
- 208000020816 lung neoplasm Diseases 0.000 description 7
- 230000001988 toxicity Effects 0.000 description 7
- 231100000419 toxicity Toxicity 0.000 description 7
- 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 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 210000000038 chest Anatomy 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 208000029742 colonic neoplasm Diseases 0.000 description 5
- 230000002708 enhancing effect Effects 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 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 4
- 229960005144 gemcitabine hydrochloride Drugs 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 231100000682 maximum tolerated dose Toxicity 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin 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-TZSSRYMLSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000835 fiber Substances 0.000 description 3
- 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 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 3
- 229960005079 pemetrexed Drugs 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 description 2
- 208000031648 Body Weight Changes Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- 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 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 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 description 2
- 230000004579 body weight change Effects 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 230000002301 combined effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 229960000304 folic acid Drugs 0.000 description 2
- 235000019152 folic acid Nutrition 0.000 description 2
- 239000011724 folic acid Substances 0.000 description 2
- 239000003205 fragrance Substances 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
- 235000001727 glucose Nutrition 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003589 local anesthetic agent 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
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 150000003248 quinolines Chemical class 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229940035893 uracil Drugs 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 239000002759 woven fabric Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical group C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 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
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 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 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
- 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
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 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
- 239000004166 Lanolin Substances 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000012805 animal sample Substances 0.000 description 1
- 230000006909 anti-apoptosis Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- BTFJIXJJCSYFAL-UHFFFAOYSA-N arachidyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N beta-monoglyceryl stearate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 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
- 229960004117 capecitabine Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000007765 cera alba Substances 0.000 description 1
- 229910000420 cerium oxide Inorganic materials 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 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
- MXHRCPNRJAMMIM-UHFFFAOYSA-N desoxyuridine Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229940115080 doxil Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 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
- 239000006260 foam Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- ZRCVYEYHRGVLOC-HYARGMPZSA-N gemifloxacin Chemical compound C1C(CN)C(=N/OC)/CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 ZRCVYEYHRGVLOC-HYARGMPZSA-N 0.000 description 1
- 229960003170 gemifloxacin Drugs 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 231100000782 microtubule inhibitor Toxicity 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229940124303 multikinase inhibitor Drugs 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000002004 n-butylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004888 n-propyl amino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 208000025189 neoplasm of testis Diseases 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
- 229960001420 nimustine Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- CKNAQFVBEHDJQV-UHFFFAOYSA-N oltipraz Chemical compound S1SC(=S)C(C)=C1C1=CN=CC=N1 CKNAQFVBEHDJQV-UHFFFAOYSA-N 0.000 description 1
- 229950008687 oltipraz Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane 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
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000004382 potting Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- YMNAJWHTELQUJU-UHFFFAOYSA-N quinoline-6-carboxamide Chemical compound N1=CC=CC2=CC(C(=O)N)=CC=C21 YMNAJWHTELQUJU-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- LEHYMIDUFPRGJC-UHFFFAOYSA-N sulfanylthiourea Chemical compound NC(=S)NS LEHYMIDUFPRGJC-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 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
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本發明提供一種抗腫瘤劑效果增強劑,其係其他抗腫瘤劑之抗腫瘤效果增強劑,且以通式(I)所表示之醯基硫脲化合物或其藥學上所容許之鹽為有效成分:(式中,R1表示亦可具有取代基之C1-6烷基,作為該取代基,表示羥基、C3-10環烷基、亦可具有取代基之C1-6烷氧基、亦可具有取代基之C1-6烷基胺基、C1-6烷醯基胺基、C1-6烷基磺醯基、亦可具有取代基之C6-14芳香族烴基、亦可具有取代基之飽和或不飽和雜環基、亦可具有取代基之C1-6烷基胺基羰基、亦可具有取代基之飽和或不飽和雜環羰基中任一種,R2表示氟原子或氯原子,R3表示氫原子、氟原子、或氯原子),□
Description
本發明係關於一種抗腫瘤之效果增強劑與其他抗腫瘤劑組合而成之抗腫瘤藥。
抗腫瘤劑之目標涉及多方面,大致分類為:烷基化藥、鉑化合物、代謝拮抗藥、拓撲異構酶抑制藥、微管抑制藥、抗腫瘤性抗生素、分子鏈藥等。並且近年來,並不單獨投予抗腫瘤劑,而廣泛進行併用療法。
例如報告有具有VEGF(vascular endothelial growth factor,血管內皮生長因子)受體激酶抑制作用,且作為血管抑制劑之4-(3-氯-4-(環丙基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉甲醯胺與紫杉烷的併用療法(專利文獻1)。
另一方面,c-Met係以Proto-oncogene之一種而鑑定之受體型酪胺酸激酶。報告有如下情況:於多數之癌(腎細胞癌、胃癌、肺癌、結腸癌、胰腺癌、卵巣癌、肝細胞癌、頭頸部癌、黑色素瘤等)中,c-Met以高頻率過量表現,從而變異或易位,藉此活化狀態亢進,從而有助於細胞增生、浸潤.轉移、腫瘤形成、血管新生或抗細胞凋亡(例如,非專利文獻1)。因此,已知具有c-Met抑制效果之化合物用作抗腫瘤劑(專利文獻2)。亦報告有喹啉衍生物與ErbB抑制劑之併用(專利文獻3),上述喹啉衍生物係c-Met抑制劑之一種,且係含有c-Met與AXL之多激酶抑制劑。
[專利文獻1]國際公開第2009/096377號
[專利文獻2]國際公開第2009/125597號
[專利文獻3]國際公開第2009/137429號
[非專利文獻1] J. Cell Biol. 111, p2097 - 2108 (1990)
然而,併用任何抗腫瘤劑與抗腫瘤劑之情形時,對於係增加該等之抗腫瘤效果,或抵消效果,完全不確定。
本發明之課題在於提供一種藉由併用2種抗腫瘤劑而增強該等之抗腫瘤效果之組合。
因此,本發明者著眼於c-Met抑制劑之一種,而對併用該化合物與其他抗腫瘤劑之情形時的作用進行研究,結果發現,具有胺基羰基作為下述式(I)所表示之喹啉環6位取代基,且具有烷氧基作為7位取代基之醯基硫脲化合物或其藥學上所容許的鹽作為減輕副作用之有力的c-Met抑制劑而發揮作用,且於與其他抗腫瘤劑之併用時,藉由優異之抗腫瘤效果增強作用而擴大效果範圍或抗腫瘤頻譜,從而完成本發明。
即,本發明係關於以下之[1]~[8]者。
[1]一種其他抗腫瘤劑之抗腫瘤效果增強劑,其以下述式(I)
(式中,R1表示亦可具有取代基之C1-6烷基,作為該取代基,表示羥基、C3-10環烷基、亦可具有取代基之C1-6烷氧基、亦可具有取代基之C1-6烷基胺基、C1-6烷醯基胺基、C1-6烷基磺醯基、亦可具有取代基之C6-14芳香族烴基、亦可具有取代基之飽和或不飽和雜環基、亦可具有取代基之C1-6烷基胺基羰基、亦可具有取代基之飽和或不飽和雜環羰基中任一種,R2表示氟原子或氯原子,R3表示氫原子、氟原子、或氯原子)所表示之醯基硫脲化合物或其藥學上所容許之鹽為有效成分。
[2]一種抗腫瘤藥,其係組合上述式(I)所表示之醯基硫脲化合物或其藥學上所容許之鹽與其他抗腫瘤劑而成。
[3]一種式(I)所表示之醯基硫脲化合物或其藥學上所容許之鹽,其係用以增強其他抗腫瘤劑之抗腫瘤效果。
[4]一種式(I)所表示之醯基硫脲化合物或其藥學上所容許之鹽,其係用以藉由與其他抗腫瘤劑以一劑型之製劑形態或不同製劑形態進行投予而治療腫瘤。
[5]一種式(I)所表示之醯基硫脲化合物或其藥學上所容許之鹽之用以製造其他抗腫瘤劑的抗腫瘤效果增強劑之用途。
[6]一種式(I)所表示之醯基硫脲化合物或其藥學上所容許之鹽之用以製造與其他抗腫瘤劑組合而成的抗腫瘤藥之用途。
[7]一種其他抗腫瘤劑之抗腫瘤效果增強方法,其特徵在於,向必需之患者投予式(I)所表示之醯基硫脲化合物或其藥學上所容許之鹽與其他抗腫瘤劑。
[8]一種腫瘤之治療方法,其特徵在於,向必需之患者投予式(I)所表示之醯基硫脲化合物或其藥學上所容許之鹽與其他抗腫瘤劑。
醯基硫脲化合物(I)或其藥學上所容許之鹽藉由與各種抗腫瘤劑併用,而增強該等抗腫瘤劑之效果。即,1)醯基硫脲化合物(I)幾乎不增強併用之抗腫瘤劑單劑之副作用,因此不減量併用之抗腫瘤劑之效果用量而可併用各自藥劑單劑中之最大效果發揮用量彼此,2)不涉及到併用之抗腫瘤劑之藥劑敏感性,而增強該併用藥劑之抗腫瘤效果,進而3)即便於醯基硫脲化合物(I)本身未顯示抗腫瘤效果之低用量時,亦發現其抗腫瘤效果。以上之結果,本發明提供一種癌治療效果範圍之擴大,治療效果之提高等臨床上之有用性較高之治療方法。
於本發明之醯基硫脲化合物(I)或其藥學上所容許之鹽中,對一種結構稱為「亦可具有取代基」之情形時,表示有於該結構上之化學上可能之位置上具有1個或2個以上「取代基」的情形。
存在於該結構中之取代基之種類、取代基之個數、取代位置並無特別限定,存在2個以上取代基之情形時,該等可相同亦可不同。作為「取代基」,可例示:鹵素原子、羥基、氰基、硝基、C1-6烷醯基、C1-6烷基、C3-10環烷基、C2-6烯基、C1-6烷氧基、胺基、C1-6烷基胺基、C1-6烷醯基胺基、C1-6烷基胺基羰基、C1-6烷基磺醯基、C6-14芳香族烴基、飽和或不飽和雜環基、飽和或不飽和雜環羰基、側氧基等,存在上述取代基之情形時,其個數典型為1~3個。
式(I)中,R1所示之「亦可具有取代基之C1-6烷基」之「C1-6烷基」表示碳數1~6之直鏈狀或支鏈狀烷基,可例示:甲基、乙基、正丙基、異丙基、正丁基、第二丁基、第三丁基、正戊基、異戊基、正己基、異己基,更佳為C1-4烷基,特佳為甲基、乙基、正丙基、異丙基、正丁基、第二丁基。
式(I)中,以R1之「亦可具有取代基之C1-6烷基」之取代基而表示之「C3-10環烷基」表示碳數3~10之環烷基,可例示:環丙基、環丁基、環戊基、環己基,更佳為環己基。
式(I)中,以R1之「亦可具有取代基之C1-6烷基」之取代基而表示之「亦可具有取代基之C1-6烷氧基」的「C1-6烷氧基」表示碳數1~6之直鏈狀或支鏈狀烷氧基,可例示:甲
氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第二丁氧基、第三丁氧基、正戊氧基、正己氧基,特佳為甲氧基、乙氧基、異丙氧基。
式(I)中,以R1之「亦可具有取代基之C1-6烷基」之取代基而表示之「亦可具有取代基之C1-6烷氧基」的「取代基」較佳為羥基。
式(I)中,以R1之「亦可具有取代基之C1-6烷基」之取代基而表示之「亦可具有取代基之C1-6烷基胺基」的「C1-6烷基胺基」表示經上述之C1-6烷基單取代或雙取代之胺基,可例示:甲基胺基、乙基胺基、二甲基胺基、甲基乙基胺基、正丙基胺基、異丙基胺基、正丁基胺基、第二丁基胺基、第三丁基胺基、正戊基胺基、正己基胺基,更佳為二乙基胺基。
式(I)中,以R1之「亦可具有取代基之C1-6烷基」之取代基而表示之「C1-6烷醯基胺基」可列舉:甲醯基、乙醯基、丙醯基、丁醯基等,更佳為乙醯基胺基。
式(I)中,以R1之「亦可具有取代基之C1-6烷基」之取代基而表示之「C1-6烷基磺醯基」表示經上述之C1-6烷基取代之磺醯基,更佳為甲基磺醯基。
式(I)中,以R1之「亦可具有取代基之C1-6烷基」之取代基而表示之「亦可具有取代基之C6-14芳香族烴基」的「C6-14芳香族烴基」表示碳數6~14之芳香族烴基,可例示:苯基、萘基等,更佳為苯基。
式(I)中,以R1之「亦可具有取代基之C1-6烷基」之取代
基而表示之「亦可具有取代基之飽和或不飽和雜環基」的「飽和或不飽和雜環基」表示具有氧原子、氮原子、硫原子中任一種原子1個或2個之單環性或二環性飽和或不飽和雜環基,例如可列舉:吡咯啶基、哌啶基、哌嗪基、嗎啉基、硫代嗎啉基、高哌啶基、四氫噻吩基、咪唑基、噻吩基、呋喃基、吡咯基、噁唑基、異噁唑基、噻唑基、異噻唑基、吡唑啉基、三唑基、四唑基、吡啶基、吡嗪基、嘧啶基、嗒基、吲哚基、異吲哚基、吲唑基、亞甲基二氧基苯基、伸乙基二氧基苯基、苯并呋喃基、二氫苯并呋喃基、苯并咪唑基、苯并唑基、苯并噻唑基、嘌呤基、喹啉基、異喹啉基、喹唑啉基、喹啉基等。更佳為具有1~4個氮原子及/或氧原子之5~7員雜環基,特佳為吡咯啶基、嗎啉基、二氧戊環基、四氫吡喃基、吡啶基、四唑基。該飽和或不飽和雜環基亦可進而具有取代基,作為取代基,較佳為C1-6烷基(特別是甲基)、側氧基。
式(I)中,以R1之「亦可具有取代基之C1-6烷基」之取代基而表示之「亦可具有取代基之C1-6烷基胺基羰基」的「C1-6烷基胺基羰基」表示具有上述之C1-6烷基胺基之羰基,更佳為乙基胺基羰基、二甲基胺基、甲基丁基胺基。該C1-6烷基胺基羰基亦可進而具有取代基,作為取代基,較佳為羥基、C1-6烷氧基(特別是甲氧基)。
式(I)中,以R1之「亦可具有取代基之C1-6烷基」之取代基而表示之「亦可具有取代基之飽和或不飽和雜環基羰基」的「飽和或不飽和雜環基羰基」表示具有上述飽和或
不飽和雜環基之羰基,更佳為具有氮原子及/或氧原子1~2個之5~7員飽和雜環羰基,特佳為吡咯啶基羰基、嗎啉基羰基。該飽和或不飽和雜環羰基亦可進而具有取代基,作為取代基,較佳為鹵素原子(特別是氟原子)、亦可具有羥基之C1-6烷基(特別是甲基)。
作為R1所示之亦可具有取代基之C1-6烷基之C1-6烷基,較佳為甲基、乙基、正丙基、異丙基、正丁基、或第二丁基,作為該烷基上之取代基,較佳為羥基、環己基、甲氧基、乙氧基、異丙氧基、二乙基胺基、乙醯基胺基、甲基磺醯基、苯基、吡咯啶基、嗎啉基、二氧戊環基、四氫哌喃基、吡啶基、三唑基、乙基胺基羰基、二甲基胺基羰基、甲基丁基胺基羰基、吡咯啶基羰基、或嗎啉基羰基,該烷氧基亦可進而具有羥基作為取代基,該雜環基亦可進而具有甲基或側氧基作為取代基,該烷基胺基羰基亦可進而具有羥基、或甲氧基作為取代基,該雜環羰基亦可進而具有氟原子、亦可具有羥基之甲基作為取代基。
作為R1所示之亦可具有取代基之C1-6烷基之C1-6烷基,較佳為甲基、乙基、正丙基、異丙基、正丁基、或第二丁基,作為該烷基上之取代基,較佳為羥基、甲氧基、或嗎啉基。
作為R1,更佳為甲基、甲氧基乙基、嗎啉基乙基、嗎啉基羰基甲基、2-羥基-正丁基、2-羥基-2-甲基-正丙基、1-羥基-正丁烷-2-基,於1-羥基-正丁烷-2-基之情形時,較佳為S體。
作為R2之取代位置,較佳為2位或3位,特佳為2位。又,作為R2,較佳為氟原子或氯原子,進而較佳為氟原子。
作為R3之取代位置,較佳為2位或4位。又,作為R1,較佳為氫原子、氟原子或氯原子,更佳為氫原子或氟原子。
式(I)所表示之化合物中,R1較佳為亦可具有取代基之甲基、乙基、正丙基、異丙基、正丁基、或第二丁基,該烷基上之取代基較佳為羥基、甲氧基、或嗎啉基,R2較佳為氟原子,R3較佳為氫原子或氟原子。
進而,作為式(I)所表示之化合物之較佳具體例,可列舉以下之化合物。
(1)4-(2-氟-4-(3-(2-苯基乙醯基)硫脲基)苯氧基)-7-甲氧基-N-甲基喹啉-6-甲醯胺(化合物(1))
(2)4-(2-氟-4-(3-(2-苯基乙醯基)硫脲基)苯氧基)-7-甲氧基-N-(2-嗎啉基乙基)喹啉-6-甲醯胺(化合物(2))
(3)(S)-4-(2-氟-4-(3-(2-(4-氟苯基)乙醯基)硫脲基)苯氧基)-N-(1-羥基丁烷-2-基)-7-甲氧基喹啉-6-甲醯胺(化合物(3))
作為醯基硫脲化合物(I)之藥學上所容許之鹽,可列舉與鹽酸、氫溴酸、氫碘酸、硫酸、硝酸、磷酸等無機酸或甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富馬酸、馬來酸、乳酸、蘋果酸、檸檬酸、酒石酸、碳酸、苦味酸、甲磺酸、對甲苯磺酸、麩胺酸等有機酸之酸加成鹽;與鈉、鉀、鎂、鈣、鋁等無機鹼或甲基胺、乙基胺、葡甲胺、乙
醇胺等有機鹼、或離胺酸、精胺酸、鳥胺酸等鹼性胺基酸之鹽或銨鹽。又,於醯基硫脲化合物(I)中,亦含有光學異構物,且亦含有水合物。
藉由本發明而顯示抗腫瘤效果增強作用之醯基硫脲化合物(I)可利用國際公開第2009/125597號說明書所記載之方法而製造。
醯基硫脲化合物(I)係具有優異之c-Met抑制作用,且減輕副作用之抗腫瘤劑,但與各種其他抗腫瘤劑(以下,稱為抗腫瘤劑A)併用之情形時,不顯示明顯之毒性惡化而具有增強該抗腫瘤劑A之抗腫瘤效果之作用。
藉由醯基硫脲化合物(I)而增強其作用之抗腫瘤劑A並無特別限定,例如可列舉:多柔比星、多喜(Doxil)、表柔比星等抗腫瘤性抗生素;環磷醯胺、尼莫司汀等烷基化劑;順鉑、卡鉑、奧沙利鉑等鉑製劑;5-氟尿嘧啶(5-FU)、替加氟.吉莫斯特.奧替拉西鉀(TS-1,非專有名「替加氟.吉莫斯特.奧替拉西鉀調配劑」(商品名:「替吉奧」))、替加氟.尿嘧啶(UFT,非專有名「替加氟.尿嘧啶調配劑」(商品名:「優福定」))、卡培他濱、去氧氟尿苷、5-氟-2'-脫氧尿苷(deoxyuridine)(FdUrd)、吉西他濱、阿糖胞苷等嘧啶系代謝拮抗劑;氟達拉濱、克拉屈濱(cladribine)、奈拉濱等嘌呤系代謝拮抗劑;培美曲塞、甲胺喋呤等葉酸代謝拮抗劑;紫杉醇(Taxol、Abraxane等)、歐洲紫杉醇、伊立替康等植物生物鹼系抗腫瘤劑;吉米沙星、埃羅替尼、拉帕替尼(Lapatinib)、依維莫司、西羅莫司(Temsirolimus)等
低分子分子鏈藥;貝伐單抗(bevacizumab)、曲妥珠單抗(Trastuzumab)、西妥昔單抗(Cetuximab)、利妥昔單抗(rituximab)等抗體分子鏈藥等。其中,較佳為嘧啶系代謝拮抗劑、葉酸代謝拮抗劑、植物生物鹼系抗腫瘤劑、低分子分子鏈藥。
作為藉由醯基硫脲化合物(I)而增強其作用之抗腫瘤劑A,較佳為紫杉醇[泰克索(Taxol)、凱素(Abraxane)等]、吉西他濱、拉帕替尼、替加氟.吉莫斯特.奧替拉西鉀調配劑、伊立替康。
作為醯基硫脲化合物(I)可與增強其作用之抗腫瘤劑A共同治療之惡性腫瘤,並無特別限制,例如可列舉:頭頸部癌、食道癌、胃癌、結腸癌、直腸癌、肝臓癌、膽嚢.膽管癌、胰腺癌、肺癌、乳癌、卵巣癌、子宮頸癌、子宮體癌、腎癌、膀胱癌、前列腺癌、睾丸瘤、骨.軟部肉瘤、白血病、惡性淋巴瘤、多發性骨髓瘤、皮膚癌、腦腫瘤等。
若將醯基硫脲化合物(I)或其藥學上所容許之鹽與抗腫瘤劑A組合,則獲得增強抗腫瘤效果之抗腫瘤藥。作為此種新穎之抗腫瘤藥之形態,可為含有醯基硫脲化合物(I)或其藥學上所容許之鹽與抗腫瘤劑A之一劑型製劑形態,亦可為含有醯基硫脲化合物(I)或其藥學上所容許之鹽的製劑與含有抗腫瘤劑A之製劑為不同之製劑形態。又,含有醯基硫脲化合物(I)之組合物之投予方法與含有抗腫瘤劑A之組合物的投予方法可相同亦可不同(例如,口服投予與注射)。
使醯基硫脲化合物(I)或其藥學上所容許之鹽含有於醫藥組合物中之情形時,可根據需要而與藥學支持體進行調配,且根據預防或治療目的而採用各種投予形態,作為該形態,例如可列舉:口服劑、注射劑、栓劑、軟膏劑、黏附劑等,但較佳為口服劑。該等投予形態可藉由各業者所公知慣用之製劑方法而製造。
藥學支持體係使用慣用之各種有機或無機載體物質作為製劑原材料,且以固形製劑中之賦形劑、結合劑、崩解劑、潤滑劑、著色劑;液狀製劑中之溶劑、溶解助劑、懸浮劑、等張劑、緩衝劑、鎮靜劑等進行調配。又,亦可根據需要而使用防腐劑、抗氧化劑、著色劑、甜味劑、穩定劑等製劑添加物。
調製口服用固形製劑之情形時,可於本發明化合物中加入賦形劑,且根據需要加入結合劑、崩解劑、潤滑劑、著色劑、矯味.矯臭劑等後,藉由常法而製造片劑、被覆片劑、顆粒劑、散劑、膠囊劑等。
作為賦形劑,可列舉:乳糖、白糖、D-甘露醇、葡萄糖、澱粉、碳酸鈣、高嶺土、微晶纖維素、矽酸酐等。
作為結合劑,可列舉:水、乙醇、1-丙醇、2-丙醇、單糖漿、葡萄糖液、α-澱粉液、明膠液、D-甘露醇、羧甲基纖維素、羥丙基纖維素、羥丙基澱粉、甲基纖維素、乙基纖維素、蟲膠、磷酸鈣、聚乙烯吡咯啶酮等。
作為崩解劑,可列舉:乾燥澱粉、海藻酸鈉、瓊脂末、碳酸氫鈉、碳酸鈣、月桂基硫酸鈉、硬脂酸單甘油酯、乳
糖等。
作為潤滑劑,可列舉:精製滑石、硬脂酸鹽鈉、硬脂酸鎂、硼砂、聚乙二醇等。
作為著色劑,可列舉:氧化鈦、氧化鉄等。
作為矯味.矯臭劑,可列舉:白糖、橙皮、檸檬酸、酒石酸等。
亦可根據需要而實施腸溶塗膜(enteric coating),或為了持續效果,而藉由公知之方法對口服製劑實施塗膜。就此種塗佈劑而言,可列舉:羥丙基甲基纖維素、乙基纖維素、羥甲基纖維素、羥丙基纖維素、聚氧乙二醇、Tween80(註冊商標)等。
調製口服用液體製劑之情形時,可於醯基硫脲化合物(I)中加入矯味劑、緩衝劑、穩定劑、矯臭劑等,並藉由常法而製造內服液劑、糖漿劑、酒劑等。作為該情形時之矯味.矯臭劑,可為上述所列舉者,作為緩衝劑,可列舉檸檬酸鈉等,作為穩定劑,可列舉:黃耆膠、阿拉伯膠、明膠等。
調製注射劑之情形時,可於醯基硫脲化合物(I)中添加pH值調節劑、緩衝劑、穩定劑、等張劑、局部麻醉劑等,並藉由常法而製造皮下、肌內及靜脈內用注射劑。作為該情形時之pH值調節劑及緩衝劑,可列舉:檸檬酸鈉、乙酸鈉、磷酸鈉等。作為穩定劑,可列舉:焦亞硫酸鈉、EDTA(ethylenediamine tetraacetic acid,四乙酸乙二胺)、硫代乙醇酸、硫代乳酸等。作為局部麻醉劑,可列舉:鹽
酸普魯卡因、鹽酸利多卡因等。作為等張劑,可列舉:氯化鈉、葡萄糖、D-甘露醇、甘油等。
調製栓劑之情形時,可於本發明化合物中加入業界中公知之製劑用載體,例如聚乙二醇、羊毛脂、可可油脂、脂肪酸三酸甘油脂等,進而根據需要加入Tween80(註冊商標)之類之界面活性劑等,之後藉由常法而製造。
調製軟膏劑之情形時,根據需要而於本發明化合物中調配通常使用之基劑、穩定劑、濕潤劑、保存劑等,並藉由常法而進行混合、製劑化。作為基劑,可列舉:液態石蠟、白凡士林、白蜂蠟、辛基十二醇、石蠟等。作為保存劑,可列舉:對羥基苯甲酸甲酯、對羥基苯甲酸乙酯、對羥基苯甲酸丙酯等。
調製黏附劑之情形時,只要藉由常法,將上述軟膏、乳霜、凝膠、糊劑等塗佈於通常之支持體上即可。作為支持體,適當為包含綿、人造短纖維、化學纖維之織布、不織布或軟質氯乙烯、聚乙烯、聚胺基甲酸酯等膜或發泡體片材。
欲調配於上述各投予單位形態中之醯基硫脲化合物(I)之量根據欲應用其之患者的症狀,或其劑形等,並不固定,但通常平均投予單位形態,就口服劑而言,為約0.05~2,000 mg,就注射劑而言,為約0.01~100 mg,就栓劑而言,為約1~2,000 mg左右。
又,具有上述投予形態之藥劑之每天之投予量根據患者的症狀、體重、年齡、性別等而有所不同,而無法一概地
決定,但通常每人(體重50 kg)每天為約0.05~5,000 mg左右,較佳為0.1~2,000 mg,較佳為1天投予1次或分2~3次左右投予該藥劑。
含有醯基硫脲化合物(I)或其鹽之製劑與含有抗腫瘤劑A之製劑為不同之製劑的情形時,各製劑可同時投予,或於投予一種成分前或後之任意之時間投予其他成分。
醯基硫脲化合物(I)或其藥學上所容許之鹽與抗腫瘤劑A之投予或調配比率只要為可實現抗腫瘤效果之增強效果的範圍,則無特別限制,相對於1莫耳抗腫瘤劑A,只要將醯基硫脲化合物(I)或其藥學上所容許之鹽設為0.001~100莫耳左右,較佳為0.005~50莫耳左右即可。
例如抗腫瘤劑A為紫杉醇(Taxol、Abraxane等)之情形時,相對於紫杉醇(Taxol、Abraxane等)1莫耳,將醯基硫脲化合物(I)或其藥學上所容許之鹽設為0.05~50莫耳左右。抗腫瘤劑A為吉西他濱之情形時,相對於吉西他濱1莫耳,將醯基硫脲化合物(I)或其藥學上所容許之鹽設為0.005~5莫耳左右。抗腫瘤劑A為拉帕替尼之情形時,相對於拉帕替尼1莫耳,將醯基硫脲化合物(I)或其藥學上所容許之鹽設為0.01~20莫耳左右。抗腫瘤劑A為替加氟.吉莫斯特.奧替拉西鉀調配劑之情形時,相對於替加氟1莫耳,將醯基硫脲化合物(I)或其藥學上所容許之鹽設為0.05~50莫耳左右。抗腫瘤劑A為伊立替康之情形時,相對於伊立替康1莫耳,將醯基硫脲化合物(I)或其藥學上所容許之鹽設為0.05~30莫耳左右。抗腫瘤劑A為培美曲塞之情形時,
相對於培美曲塞1莫耳,將醯基硫脲化合物(I)或其藥學上所容許之鹽設為0.05~20莫耳左右。
於以下表示實施例、試驗例,而對本發明進行進而詳細說明,但本發明並不限定於該等實施例。又,關於以下之試驗例所示之藉由本發明化合物而增強抗腫瘤效果之各種抗腫瘤劑的用量設定,使用論文報告等所示之最大耐用量(Maximum tolerated dose;MTD)或物性上可投予之最大用量。
抗腫瘤劑顯示最大藥效之用量與毒性表現用量極為接近,為了利用動物樣本評價該藥劑具有之最大抗腫瘤效果,而通常於MTD附近進行評價,於以下之試驗例中,將MTD與最大效果揮發用量設為同義。
4-(2-氟-4-(3-(2-苯基乙醯基)硫脲基)苯氧基)-7-甲氧基-N-甲基喹啉-6-甲醯胺(化合物(1))係藉由國際公開第2009/125597號說明書所記載之方法而合成。
將人類肺癌株(NCI-H460)移植於出生5~6週齡之雄性BALB/cA Jcl-nu小鼠之右側胸部中。於腫瘤移植後測定腫瘤之長徑(mm)及短徑(mm),而算出腫瘤體積(tumor volume:TV),之後以各群之平均TV成為均等之方式而將小鼠分配於各群中,且將實施該群分配(n=5)之日設為day 1。
紫杉醇(Taxol注射液,Bristol製藥股份有限公司)單獨群之受檢液係以紫杉醇投予用量成為60 mg/kg/day之方式進行調製。又,化合物(1)單獨群之受檢液係以化合物(1)成為200 mg/kg/day之方式進行調製。化合物(1)係自day 1開始連續14天口服投予,紫杉醇係於day 1自小鼠尾靜脈投予。於併用投予群中,以200 mg/kg/day投予化合物(1),以60 mg/kg/day投予紫杉醇。
作為抗腫瘤效果之指標,測定各藥劑投予群中day 15中之TV,並藉由下述式,算出相對於day 1之相對腫瘤體積(relative tumor volume:RTV)及T/C(%),而評價抗腫瘤效果。併用效果之評價判定係以如下方式判定:於併用投予群之平均RTV值於統計學上明顯(Welch's IUT,over all maximum p<0.05)小於各個單獨投予群之平均RTV值的情形時,有併用效果。將結果示於圖1及表1。圖中,*記號表示相對於單獨群,發現統計學上明顯差異之情況。
TV(mm3)=(長徑×短徑2)/2
RTV=(Day 15中之TV)/(Day 1中之TV)
T/C(%)=(受檢液投予群之平均RTV值)/(對照群之平均RTV值)×100
又,作為毒性之指標,測定經時體重[body weight:BW],並藉由下述式,算出(n:以2次/週實施之體重測定日,最終測定日適用於作為最終評價日之day 15)相對於day 1之至day 15為止之平均體重變化率[body weight change:BWC(%)]。將結果示於圖2。
BWC(%)=[(Day n中之BW)-(Day 1中之BW)]/(Day 1中之BW)×100
將人類肺癌株(NCI-H441)移植於出生5~6週齡之雄性BALB/cA Jcl-nu小鼠之右側胸部中,並以與試驗例1同樣之方式使用。
吉西他濱鹽酸鹽(Gemzar,Eli Lilly公司製造)單獨群之受檢液係以投予量成為240 mg/kg/day之方式進行調製。又,化合物(1)之受檢液係以化合物(1)成為200 mg/kg/day之方式進行調製。
化合物(1)係自day 1開始連續14天口服投予,吉西他濱鹽酸鹽係於day 1及day 8自小鼠尾靜脈投予。於併用投予群中,以200 mg/kg/day投予化合物(1),以240 mg/kg/day投予吉西他濱鹽酸鹽,並以與試驗例1同樣之方式進行評價。將結果示於圖3及表2中。圖中,*記號表示相對於各單獨群,發現統計學上明顯差異之情況。
將人類胃癌株(NUGC-4)移植於出生5~6週齡之雄性裸大白鼠之右側胸部中,並以與試驗例1同樣之方式使用。TS-1(替吉奧,大鵬藥品工業公司製造)單獨群之受檢液係以替加氟投予量成為18 mg/kg/day之方式進行調製。又,化合物(1)之受檢液係以化合物(1)成為250及50 mg/kg/day之方式進行調製。
自day 1開始連續14天口服投予化合物(1)及TS-1。於併用投予群中,以250及50 mg/kg/day投予化合物(1),以18 mg/kg/day投予TS-1,並以與試驗例1同樣之方式進行評價。將結果示於圖4及表3。
將人類胃癌株(NCI-N87)移植於出生5~6週齡之雄性BALB/cA Jcl-nu小鼠之右側胸部中,並以與試驗例1同樣之方式使用。拉帕替尼(LC laboratories公司製造)單獨群之受檢液係以投予量成為100 mg/kg/day之方式進行調製。又,化合物(1)之受檢液係以化合物(1)成為200 mg/kg/day之方式進行調製。
自day 1開始連續14天口服投予化合物(1)及拉帕替尼。於併用投予群中,以200 mg/kg/day投予化合物(1),以100 mg/kg/day投予拉帕替尼,並以與試驗例1同樣之方式進行評價。將結果示於圖5及表4中。圖中,*記號表示相對於各單獨群,發現統計學上明顯差異之情況。
將人類結腸癌株(HT-29)移植於出生5~6週齡之雄性BALB/cA Jcl-nu小鼠之右側胸部中,並以與試驗例1同樣之方式使用。
鹽酸伊立替康(CAMPTO注射液,Yakult公司製造)單獨群之受檢液係以投予量成為50 mg/kg/day之方式進行調製。
化合物(1)單獨群之受檢液係以化合物(1)成為50
mg/kg/day之方式進行調製。於併用投予群中,以50 mg/kg/day投予化合物(1),以50 mg/kg/day投予鹽酸伊立替康。化合物(1)係自day 1開始連續14天口服投予,鹽酸伊立替康係於day 1、5、9自小鼠尾靜脈投予,並以與試驗例1同樣之方式進行評價。將結果示於圖6及表5。圖中,*記號表示相對於單獨群,發現統計學上明顯差異之情況。
又,關於作為毒性之指標之經時體重變化,亦以與試驗例1同樣之方式進行評價。將結果示於圖7。
將人類胃癌株(NUGC-4)移植於出生5~6週齡之雄性BALB/cA Jcl-nu小鼠之右側胸部中,並以與試驗例1同樣之方式使用。
紫杉醇(Taxol注射液,Bristol製藥股份有限公司製造)單獨群之受檢液係以紫杉醇投予量成為60 mg/kg/day之方式進行調製。
化合物(1)單獨群之受檢液係以化合物(1)成為12.5 mg/kg/day之方式進行調製。於併用投予群中,以12.5 mg/kg/day投予化合物(1),以60 mg/kg/day投予紫杉醇。化合物(1)係自day 1開始連續14天口服投予,紫杉醇係於day
1自小鼠尾靜脈投予,並以與試驗例1同樣之方式進行評價。將結果示於圖8及表6。圖中,*記號表示相對於單獨群,發現統計學上明顯差異之情況。
又,關於作為毒性之指標之経時體重變化,亦以與試驗例1同樣之方式進行評價。將結果示於圖9。
根據圖1、3、4、5、6及8可明確,醯基硫脲化合物(I)或其藥學上所容許之鹽明顯地增強各種抗腫瘤劑之抗腫瘤效果。其效果係根據作為醯基硫脲化合物(I)之低用量(未顯示抗腫瘤效果之用量,圖8,表6)之12.5 mg/kg/day發現,且就作為裸小鼠中之高用量(最大效果揮發用量)之200 mg/kg/day,及作為裸大白鼠中之高用量(最大效果揮發用量)之250 mg/kg/day而言,藉由併用而誘導明顯之腫瘤之縮小(表1、2、3及4)。又,於併用投予中,未發現體重減少之惡化(圖2、7、9)。根據上述情況,從而藉由本發明化合物與各種抗腫瘤劑之併用而確保效果範圍為至少16倍以上。
又,例如由圖1與圖8之比較所示,發現就紫杉醇而言,即便使用相同投予量,其抗腫瘤效果(藥劑敏感性)亦根據腫瘤而不同,但發現藉由與醯基硫脲化合物(I)併用,而均
增強效果。即,即便於對作為併用藥劑之紫杉醇敏感性較低之腫瘤中,亦期待藉由與醯基硫脲化合物(I)併用而增強紫杉醇之腫瘤增殖抑制效果。該情況表示藉由醯基硫脲化合物(I)之併用,從而其他抗腫瘤劑之抗腫瘤頻譜擴大之情況。
進而如圖2所示,於醯基硫脲化合物(I)與各種抗腫瘤劑之併用中,即便於使用作為高用量之200 mg/kg/day之情形時,亦無與抗腫瘤劑單獨投予相比,明顯之體重減少之差,因此暗示未增強毒性。
即,於醯基硫脲化合物(I)或其藥學上所容許之鹽與各種抗腫瘤劑之併用中,發現如下情況:未顯示明顯之毒性之惡化,而顯現併用效果,且擴大其治療效果範圍或抗腫瘤頻譜。又,醯基硫脲化合物(I)或其藥學上所容許之鹽之投予量只要相對於其他抗腫瘤劑1莫耳,設為0.005~50莫耳左右即可。
圖1係針對人類肺癌株NCI-H460皮下移植系(裸小鼠)之化合物(1)200 mg/kg/day與紫杉醇之併用效果。
圖2係針對人類肺癌株NCI-H460皮下移植系(裸小鼠)之化合物(1)200 mg/kg/day與紫杉醇併用時的體重變化。
圖3係針對人類肺癌株NCI-H441皮下移植系(裸小鼠)之化合物(1)200 mg/kg/day與吉西他濱之併用效果。
圖4係針對人類胃癌株NUGC-4皮下移植系(裸大白鼠)之化合物(1)50 mg/kg/day、及250 mg/kg/day與TS-1之併用
效果。
圖5係針對人類胃癌株NCI-N87皮下移植系(裸小鼠)之化合物(1)200 mg/kg/day與拉帕替尼(lapatinib)之併用效果。
圖6係針對人類結腸癌株HT-29皮下移植系(裸小鼠)之化合物(1)50 mg/kg/day與鹽酸伊立替康之併用效果。
圖7係針對人類結腸癌株HT-29皮下移植系(裸小鼠)之化合物(1)50 mg/kg/day與鹽酸伊立替康併用時之體重變化。
圖8係針對人類胃癌株NUGC-4皮下移植系(裸小鼠)之化合物(1)12.5 mg/kg/day與紫杉醇之併用效果。
圖9係針對人類胃癌株NUGC-4皮下移植系(裸小鼠)之化合物(1)12.5 mg/kg/day與紫杉醇併用時之體重變化。
Claims (10)
- 一種其他抗腫瘤劑之抗腫瘤效果增強劑,其以通式(I)
- 如請求項1之抗腫瘤效果增強劑,其中式(I)中,R1為亦可具有取代基之甲基、乙基、正丙基、異丙基、正丁基、或第二丁基,該烷基上之取代基為羥基、環己基、甲氧基、乙氧基、異丙氧基、二乙基胺基、乙醯基胺基、甲磺醯基、苯基、吡咯啶基、嗎啉基、二氧戊環 基、四氫哌喃基、吡啶基、三唑基、乙基胺基羰基、二甲基胺基羰基、甲基丁基胺基羰基、吡咯啶基羰基、或嗎啉基羰基,該烷氧基亦可進而具有羥基作為取代基,該雜環基亦可進而具有甲基或側氧基作為取代基,該烷基胺基羰基亦可進而具有羥基或甲氧基作為取代基,該雜環羰基亦可進而具有氟原子、亦可具有羥基之甲基作為取代基,R2為氟原子或氯原子,R3為氫原子、氟原子、或氯原子。
- 如請求項1之抗腫瘤效果增強劑,其中R1表示氫原子,R1為亦可具有取代基之甲基、乙基、正丙基、異丙基、正丁基、或第二丁基,該烷基上之取代基為羥基、甲氧基、或嗎啉基,R2為氟原子,R3為氫原子或氟原子。
- 如請求項1之抗腫瘤效果增強劑,其中式(I)之化合物係選自以下之群,(1)4-(2-氟-4-(3-(2-苯基乙醯基)硫脲基)苯氧基)-7-甲氧基-N-甲基喹啉-6-甲醯胺,(2)4-(2-氟-4-(3-(2-苯基乙醯基)硫脲基)苯氧基)-7-甲氧基-N-(2-嗎啉基乙基)喹啉-6-甲醯胺,(3)(S)-4-(2-氟-4-(3-(2-(4-氟苯基)乙醯基)硫脲基)苯氧基)-N-(1-羥基丁烷-2-基)-7-甲氧基喹啉-6-甲醯胺。
- 如請求項1之抗腫瘤效果增強劑,其中其他抗腫瘤劑為紫杉醇[泰克索(Taxol)、凱素(Abraxane)等]、吉西他濱(Gemcitabine)、拉帕替尼(Lapatinib)、替加氟.吉莫斯特.奧替拉西鉀(Tegafur.Gimeracil.Oteracil potassium)調配 劑、伊立替康(Irinotecan)中任一種。
- 一種抗腫瘤藥,其係組合通式(1)所表示之醯基硫脲化合物或其藥學上所容許之鹽與其他抗腫瘤劑而成,
- 如請求項6之抗腫瘤藥,其中其他抗腫瘤劑為紫杉醇(Taxol、Abraxane等)、吉西他濱、拉帕替尼、替加氟.吉莫斯特.奧替拉西鉀調配劑、伊立替康中任一種。
- 如請求項6之抗腫瘤藥,其中式(I)中,R1為亦可具有取代基之甲基、乙基、正丙基、異丙基、正丁基、或第二丁基,該烷基上之取代基為羥基、環己基、甲氧基、乙 氧基、異丙氧基、二乙基胺基、乙醯基胺基、甲磺醯基、苯基、吡咯啶基、嗎啉基、二氧戊環基、四氫哌喃基、吡啶基、三唑基、乙基胺基羰基、二甲基胺基羰基、甲基丁基胺基羰基、吡咯啶基羰基、或嗎啉基羰基,該烷氧基亦可進而具有羥基作為取代基,該雜環基亦可進而具有甲基或側氧基作為取代基,該烷基胺基羰基亦可進而具有羥基或甲氧基作為取代基,該雜環羰基亦可進而具有氟原子、亦可具有羥基之甲基作為取代基,R2為氟原子或氯原子,R3為氫原子、氟原子、或氯原子。
- 如請求項6之抗腫瘤藥,其中R1表示氫原子,R1為亦可具有取代基之甲基、乙基、正丙基、異丙基、正丁基、或第二丁基,該烷基上之取代基為羥基、甲氧基、或嗎啉基,R2為氟原子,R3為氫原子或氟原子。
- 如請求項6之抗腫瘤藥,其中式(I)之化合物係選自以下之群,(1)4-(2-氟-4-(3-(2-苯基乙醯基)硫脲基)苯氧基)-7-甲氧基-N-甲基喹啉-6-甲醯胺,(2)4-(2-氟-4-(3-(2-苯基乙醯基)硫脲基)苯氧基)-7-甲氧基-N-(2-嗎啉基乙基)喹啉-6-甲醯胺,(3)(S)-4-(2-氟-4-(3-(2-(4-氟苯基)乙醯基)硫脲基)苯氧基)-N-(1-羥基丁烷-2-基)-7-甲氧基喹啉-6-甲醯胺。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011290125 | 2011-12-28 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201331182A true TW201331182A (zh) | 2013-08-01 |
TWI594986B TWI594986B (zh) | 2017-08-11 |
Family
ID=48697493
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW101150217A TWI594986B (zh) | 2011-12-28 | 2012-12-26 | Antineoplastic agent effect enhancer |
Country Status (13)
Country | Link |
---|---|
US (1) | US20140378409A1 (zh) |
EP (1) | EP2799070B1 (zh) |
JP (1) | JP5852678B2 (zh) |
KR (1) | KR101668931B1 (zh) |
AU (2) | AU2012361581B2 (zh) |
DK (1) | DK2799070T3 (zh) |
ES (1) | ES2717898T3 (zh) |
HU (1) | HUE043991T2 (zh) |
PL (1) | PL2799070T3 (zh) |
PT (1) | PT2799070T (zh) |
RU (1) | RU2589713C2 (zh) |
TW (1) | TWI594986B (zh) |
WO (1) | WO2013100014A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107614489A (zh) * | 2015-04-30 | 2018-01-19 | 大鹏药品工业株式会社 | 酰基硫脲化合物的甲磺酸盐及其晶体、以及它们的制造方法 |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2014309788B2 (en) | 2013-08-22 | 2017-02-16 | Taiho Pharmaceutical Co., Ltd. | Novel quinoline-substituted compound |
US9149471B2 (en) | 2013-09-30 | 2015-10-06 | National University Corporation Tokyo University Of Agriculture And Technology | Therapeutic agent for osteoporosis |
RU2729630C2 (ru) | 2015-06-25 | 2020-08-11 | Тайхо Фармасьютикал Ко., Лтд. | Терапевтическое средство для фиброза |
SG11201901815WA (en) * | 2016-08-31 | 2019-04-29 | Fujifilm Corp | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit |
JOP20190073A1 (ar) | 2016-10-31 | 2019-04-07 | Taiho Pharmaceutical Co Ltd | مثبط انتقائي لمستقبل عامل نمو بشروي (egfr) لطافر إدخال exon 20 |
CN110312511B (zh) | 2017-02-15 | 2023-10-27 | 大鹏药品工业株式会社 | 医药组合物 |
AU2018325819B2 (en) | 2017-09-01 | 2024-02-01 | Taiho Pharmaceutical Co., Ltd. | Exon 18 and/or exon 21 mutant EGFR selective inhibitor |
MA50251A (fr) | 2017-09-08 | 2021-06-02 | Taiho Pharmaceutical Co Ltd | Agent antitumoral et potentialisateur d'effet antitumoral |
CA3089728C (en) | 2018-01-29 | 2023-01-10 | Fujifilm Corporation | Antitumor agent for biliary tract cancer and method for treating biliary tract cancer |
JP6974585B2 (ja) | 2018-03-13 | 2021-12-01 | 富士フイルム株式会社 | 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット |
EP3854395A4 (en) | 2018-09-18 | 2022-06-15 | Taiho Pharmaceutical Co., Ltd. | COMBINATION THERAPY OF AN ACYLTHIOREA COMPOUND AND ABIRATERON |
TW202140426A (zh) * | 2020-02-14 | 2021-11-01 | 日商大鵬藥品工業股份有限公司 | 醯基硫脲化合物的製造方法 |
CN117820332B (zh) * | 2024-03-04 | 2024-05-14 | 烟台大学 | 苯并噻吩-硫脲类化合物及其制备方法和应用 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE399766T1 (de) * | 2000-10-20 | 2008-07-15 | Eisai R&D Man Co Ltd | Stickstoff enthaltende aromatische heterozyklen |
CA2603748A1 (en) * | 2005-04-06 | 2006-10-12 | Exelixis, Inc. | C-met modulators and methods of use |
EP2248804A4 (en) * | 2008-01-29 | 2014-09-10 | Eisai R&D Man Co Ltd | COMBINED USE OF AN ANGIOGENESIS INHIBITOR AND A TAXANE |
CN102014913A (zh) * | 2008-03-06 | 2011-04-13 | 健泰科生物技术公司 | C-met和egfr拮抗剂的联合疗法 |
BRPI0911679B8 (pt) * | 2008-04-10 | 2021-05-25 | Taiho Pharmaceutical Co Ltd | composto aciltioureia ou um sal do mesmo, uso do dito composto para tratar câncer, bem como agente farmacêutico, agente antitumoral e composição farmacêutica compreendendo dito composto |
UY31800A (es) | 2008-05-05 | 2009-11-10 | Smithkline Beckman Corp | Metodo de tratamiento de cancer usando un inhibidor de cmet y axl y un inhibidor de erbb |
US20110104161A1 (en) * | 2008-05-14 | 2011-05-05 | Burgess Teresa L | Combinations vegf(r) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer |
KR101620654B1 (ko) * | 2009-02-12 | 2016-05-12 | 아르퀼 인코포레이티드 | 제2 항증식제와 조합하여 (-)-트랜스-3-(5,6-디하이드로-4h-피롤로[3,2,1-ij]퀴놀린-1-일)-4-(1h-인돌-3-일)피롤리딘-2,5-디온을 포함하는 조성물 |
-
2012
- 2012-12-26 TW TW101150217A patent/TWI594986B/zh active
- 2012-12-27 HU HUE12863476A patent/HUE043991T2/hu unknown
- 2012-12-27 AU AU2012361581A patent/AU2012361581B2/en active Active
- 2012-12-27 WO PCT/JP2012/083794 patent/WO2013100014A1/ja active Application Filing
- 2012-12-27 PL PL12863476T patent/PL2799070T3/pl unknown
- 2012-12-27 KR KR1020147016594A patent/KR101668931B1/ko active IP Right Grant
- 2012-12-27 JP JP2013551770A patent/JP5852678B2/ja active Active
- 2012-12-27 PT PT12863476T patent/PT2799070T/pt unknown
- 2012-12-27 ES ES12863476T patent/ES2717898T3/es active Active
- 2012-12-27 RU RU2014131058/04A patent/RU2589713C2/ru active
- 2012-12-27 DK DK12863476.3T patent/DK2799070T3/en active
- 2012-12-27 EP EP12863476.3A patent/EP2799070B1/en active Active
- 2012-12-27 US US14/369,060 patent/US20140378409A1/en not_active Abandoned
-
2016
- 2016-06-16 AU AU2016204054A patent/AU2016204054A1/en not_active Abandoned
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107614489A (zh) * | 2015-04-30 | 2018-01-19 | 大鹏药品工业株式会社 | 酰基硫脲化合物的甲磺酸盐及其晶体、以及它们的制造方法 |
Also Published As
Publication number | Publication date |
---|---|
EP2799070B1 (en) | 2019-02-13 |
PL2799070T3 (pl) | 2019-07-31 |
WO2013100014A1 (ja) | 2013-07-04 |
DK2799070T3 (en) | 2019-04-23 |
PT2799070T (pt) | 2019-04-03 |
JP5852678B2 (ja) | 2016-02-03 |
RU2589713C2 (ru) | 2016-07-10 |
AU2012361581A1 (en) | 2014-07-24 |
EP2799070A4 (en) | 2015-05-27 |
HUE043991T2 (hu) | 2019-09-30 |
JPWO2013100014A1 (ja) | 2015-05-11 |
KR20140096375A (ko) | 2014-08-05 |
ES2717898T3 (es) | 2019-06-26 |
US20140378409A1 (en) | 2014-12-25 |
EP2799070A1 (en) | 2014-11-05 |
RU2014131058A (ru) | 2016-02-20 |
TWI594986B (zh) | 2017-08-11 |
AU2012361581B2 (en) | 2016-06-30 |
AU2016204054A1 (en) | 2016-07-07 |
KR101668931B1 (ko) | 2016-10-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI594986B (zh) | Antineoplastic agent effect enhancer | |
TWI816881B (zh) | 用於治療三陰性乳癌之組合療法 | |
KR101950044B1 (ko) | Akt 억제제 화합물 및 베무라페닙의 조합물, 및 사용 방법 | |
CN104119350B (zh) | 氨基喹唑啉类衍生物及其盐和使用方法 | |
EP3290038A1 (en) | Agent for alleviating adverse reaction to antitumor drug | |
WO2012144463A1 (ja) | 腫瘍治療剤 | |
KR20160045900A (ko) | 아자 2 고리형 화합물을 사용한 암 병용 요법 | |
KR20190110581A (ko) | 암 치료 | |
CN112912075B (zh) | 治疗前列腺癌的组合疗法 | |
CN106916112B (zh) | 嘧啶衍生物及其制备方法和在医药上的应用 | |
CN103319468B (zh) | 取代的螺双环化合物及其使用方法和用途 | |
JP2019519573A (ja) | がんを処置するための方法 | |
WO2010038428A1 (ja) | タキサン系抗がん剤の置き換え薬 | |
TWI769395B (zh) | 以吡唑并[3,4-d]嘧啶化合物為有效成分之治療劑 | |
CN106279045B (zh) | 环丙烷衍生物及其制备方法和在医药上的应用 | |
WO2010032436A1 (ja) | 4-[[3,5-ビス(トリメチルシリル)ベンゾイル]アミノ]安息香酸を含有する抗腫瘍剤 | |
TW201213333A (en) | Crystal forms of tricyclic pyrazolopyrimidine derivative | |
JP2022506289A (ja) | インダゾールキナーゼ阻害剤及びその使用 | |
WO2011152516A1 (ja) | キナーゼ阻害剤を組み合わせた抗腫瘍剤 | |
TW201143766A (en) | Antitumor agent containing indole compound |