CN107001617B - Peg衍生物 - Google Patents
Peg衍生物 Download PDFInfo
- Publication number
- CN107001617B CN107001617B CN201580065673.8A CN201580065673A CN107001617B CN 107001617 B CN107001617 B CN 107001617B CN 201580065673 A CN201580065673 A CN 201580065673A CN 107001617 B CN107001617 B CN 107001617B
- Authority
- CN
- China
- Prior art keywords
- compound
- indicate
- salt
- formula
- alkyl
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 102
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 201000011510 cancer Diseases 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 25
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
- -1 acetenyl Chemical group 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 28
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 6
- 230000002045 lasting effect Effects 0.000 abstract description 5
- 206010028980 Neoplasm Diseases 0.000 description 27
- 229920001223 polyethylene glycol Polymers 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 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 24
- 239000002246 antineoplastic agent Substances 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000001990 intravenous administration Methods 0.000 description 15
- 239000002202 Polyethylene glycol Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 229960004857 mitomycin Drugs 0.000 description 12
- DCYBPMFXJCWXNB-PIWGOKLLSA-N (3s,4s,5r)-2-(4-amino-2-oxopyrimidin-1-yl)-4-hydroxy-5-(hydroxymethyl)oxolane-3-carbonitrile Chemical compound O=C1N=C(N)C=CN1C1[C@@H](C#N)[C@H](O)[C@@H](CO)O1 DCYBPMFXJCWXNB-PIWGOKLLSA-N 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 239000008280 blood Substances 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 239000012299 nitrogen atmosphere Substances 0.000 description 9
- 229930012538 Paclitaxel Natural products 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 229960001592 paclitaxel Drugs 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 7
- 229960005277 gemcitabine Drugs 0.000 description 7
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 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 description 7
- 229960004891 lapatinib Drugs 0.000 description 7
- 201000005202 lung cancer Diseases 0.000 description 7
- 208000020816 lung neoplasm Diseases 0.000 description 7
- 239000002504 physiological saline solution Substances 0.000 description 7
- 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 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000011729 BALB/c nude mouse Methods 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 6
- 208000026310 Breast neoplasm Diseases 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 6
- 210000001015 abdomen Anatomy 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000001647 drug administration Methods 0.000 description 6
- 229940090044 injection Drugs 0.000 description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 6
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 229940034785 sutent Drugs 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000009876 antimalignant effect Effects 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000003147 glycosyl group Chemical group 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 4
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 4
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 4
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 3
- 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 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 210000001539 phagocyte Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 3
- 229940120982 tarceva Drugs 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 150000000000 tetracarboxylic acids Chemical class 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 244000162450 Taxus cuspidata Species 0.000 description 2
- 235000009065 Taxus cuspidata Nutrition 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 239000011149 active material Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 239000007767 bonding agent Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001983 dialkylethers Chemical class 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- 238000009499 grossing Methods 0.000 description 2
- 201000003911 head and neck carcinoma Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 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
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- RHCAZYILHJYUKB-CCXZUQQUSA-N 6-[[(2r,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]amino]-1h-pyrimidin-2-one Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1NC1=CC=NC(=O)N1 RHCAZYILHJYUKB-CCXZUQQUSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009944 Colon cancer Diseases 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
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 206010069351 acute lung injury Diseases 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 206010006007 bone sarcoma Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000001925 catabolic effect Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical class NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- KBHVEPCBCHPCDC-UHFFFAOYSA-N dichloro-propan-2-yl-tri(propan-2-yl)silyloxysilane Chemical class CC(C)[Si](Cl)(Cl)O[Si](C(C)C)(C(C)C)C(C)C KBHVEPCBCHPCDC-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 210000005096 hematological system Anatomy 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 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
- 239000002105 nanoparticle Substances 0.000 description 1
- 208000025189 neoplasm of testis Diseases 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 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 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 208000020615 rectal carcinoma Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/321—Polymers modified by chemical after-treatment with inorganic compounds
- C08G65/325—Polymers modified by chemical after-treatment with inorganic compounds containing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/70—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
- 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
-
- 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
- A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
- A61K31/77—Polymers containing oxygen of oxiranes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
- G01R33/00—Arrangements or instruments for measuring magnetic variables
- G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
- G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
- G01R33/46—NMR spectroscopy
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Polymers & Plastics (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polyethers (AREA)
- Epoxy Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明提供一种安全性高、抗肿瘤效果持续、能够改善给药方法、给药次数的新型恶性肿瘤治疗药。一种通式(1)所示的化合物或其盐〔式中,R1表示单键、-N(R3)(CH2)n1CO-或-N(R4)(CH2)n2N(R5)CO(CH2)n3CO-;R2表示式(a)、(b)、(c)、(d)、(e)或(f)所示的基团;m表示10~1000的数;箭头表示键合部位。〕。C[CH2O(CH2CH2O)mCH2CO‑R1‑R2]4(1)
Description
技术领域
本发明涉及作为恶性肿瘤治疗药有用的新型PEG衍生物和含有其的医药品。
背景技术
阿糖胞苷、1-(2’-氰基-2’-脱氧-β-D-阿拉伯呋喃糖基)胞嘧啶、吉西他滨、地西他滨、5-氮胞苷、RX-3117(Rexahn)、SGI -110(Astex)等的胞嘧啶衍生物具有抑制癌的DNA聚合酶、或者调节癌的细胞周期(G2/M阻滞)、诱导白血病细胞的分化的作用,因此,作为急性骨髄性白血病、急性淋巴细胞性白血病、恶性淋巴瘤、多发性骨髓瘤、胰腺癌、肺癌、乳腺癌等的恶性肿瘤治疗药是有用的 (专利文献1、非专利文献1~3)。利用这些胞嘧啶衍生物的恶性肿瘤的治疗方法通常进行数小时~数周的持续点滴静脉内注射的给药(非专利文献1等)。
另外,丝裂霉素C是用于慢性淋巴细胞性白血病、慢性骨髄性白血病、胃癌、结肠–直肠癌、肺癌、胰腺癌、肝癌、子宫颈癌、子宫癌、头颈部肿瘤、膀胱肿瘤的治疗的抗癌剂。然而,丝裂霉素C通常也进行连日静脉内给药。另外,吉非替尼、厄洛替尼是选择性地抑制表皮生长因子受体(EGFR)的酪氨酸激酶的分子靶向抗癌剂,被用于非小细胞肺癌、胰腺癌、脑胶质瘤病、头颈部扁平上皮癌等。进一步而言,拉帕替尼、舒尼替尼也是酪氨酸激酶抑制剂,被用于乳腺癌等。然而,这些分子靶向药也具有急性肺损伤、间质性肺炎等副作用的问题。
另外,紫杉醇、多西他赛是被用于肺癌、卵巢癌、乳腺癌、头颈部癌、进行性卡波西肉瘤(progressive Kaposi's sarcoma)等的治疗的抗癌剂。然而,这些紫杉系的抗癌剂也具有白细胞减少等的骨髄抑制、末梢神经病变(peripheral nerve disorder)等的副作用,除此之外,水溶性也不足,不得不使用溶解辅助剂的克列莫佛(CREMOPHOR),但由于出现严重的过敏症状,利用组胺H1、H2的拮抗剂的预处理是必不可少的,给药时在临床现场要求繁杂的作业。另外,也存在作为溶解辅助剂使用人血清白蛋白的情况,但有人血清白蛋白不足和艾滋病等的病毒感染的危险等的担忧。
现有的由低分子化合物形成的抗癌剂通过静脉内给药、经口给药等进行临床应用,但现状是其有效利用率极低,只有所给药量的极少一部分的量到达肿瘤。另外,由于分布于全身,结果,全身毒性成为问题,根据效果与毒性的权衡来决定用量,因此,大多数情况是产生全身毒性而无法给药显现药效所需要的充分的量的抗癌剂。
近年来,以克服以上的问题为目的,开发了几种药物传递系统。例如其代表例是,利用将低分子的抗癌剂在物理上包埋于由生物相容性的原材料成分形成的磷脂脂质体、高分子胶束或者水溶性高分子中或者在化学上形成共价键的方法的药物传递系统(以下,称为DDS)。
在静脉内给药用的脂质体制剂的情况下,为了没有问题地在毛细血管内通过,另外,以能够通过肿瘤附近的新生血管的方式,将颗粒尺寸控制在200~300nm,除此以外,脂质体颗粒的膜表面还被分子量 2,000左右的聚乙二醇(以下,称为PEG)覆盖,因此,能够基本避免向生物体内的吞噬细胞的摄入。
在高分子胶束制剂的情况下,报告有:将粒径控制在50nm,该颗粒的膜表面还被PEG覆盖,因此,基本避免向生物体内的吞噬细胞的摄入,能够容易地通过肿瘤附近的新生血管。
然而,现状是使用了以上的纳米微粒的制剂的血中半衰期比较短,对肿瘤的靶向也不充分,无法充分地达到本来的目的。
另一方面,最近开始了将抗癌剂与生物体适应性高且水溶性也高的合成高分子的PEG、特别是不容易形成高粘度溶液的4条链的PEG (分子量为4万)在化学上共价结合的衍生物的临床应用尝试。
现有技术文献
专利文献
非专利文献1:J.Med.Chem.1991年,34卷,2917-2919
非专利文献2:J.Med.Chem.1993年,36卷,4183-4189
非专利文献3:CYLOCIDETM注射剂药品说明书
发明内容
发明所要解决的课题
然而,因过于关注在血中的缓释,该PEG与抗癌剂之间的化学结合限于比较容易被血中内的酯酶和羧化酶等的分解酶分解的酯键和氨基甲酸酯键,在血中的长时间稳定性不足,对肿瘤组织的靶向效率也不太好,无法达到DDS本来的目的。
另外,最近有利用不容易被酸和碱分解的氨基甲酸酯键使4条链的PEG与作为抗癌剂(CPT-11)的活性成分的SN-38共价结合的报告,但这仅仅是在某种程度上克服了氨基甲酸酯键的弱点。而且,合成氨基甲酸酯键合体时的化学反应的条件过于苛刻(强碱条件),不适合于分子内酯结合或对碱敏感的抗癌剂的结合。
因此,本发明的课题在于:提供一种严重的消化道毒性和骨髄毒性等的副作用少、抗肿瘤效果持续、能够改善给药方法、给药次数的新型恶性肿瘤治疗药。
用于解决课题的方法
因此,本发明的发明人着眼于PEG衍生物在血中的持续性和对肿瘤组织的高的集聚性,为了提高抗肿瘤剂的作用持续性,鉴于伴随血中的酶分解的血中的缓释性,研究了利用酯键或氨基甲酸酯键对作为 CPT-11的活性物质的SN-38等的羟基和聚乙二醇的修饰等,但血中的抗肿瘤活性物质的释放在人体中预想不到地早,需要大量投予该聚乙二醇衍生物,没有获得充分的作用持续性的提高效果和安全性提高。
进一步重复研究的结果发现,使末端导入有甲基羧基的4条链的聚乙二醇与胞嘧啶衍生物、丝裂霉素C、紫杉醇等的抗肿瘤剂、吉非替尼、厄洛替尼、拉帕替尼、舒尼替尼等的癌的分子靶向药的伯氨基或仲氨基直接、或隔着β-丙氨酸等的氨基酸系间隔基形成酰胺键的式 (1)所示的化合物,其抗肿瘤效果的持续性优异,并且安全性也高,与现有的抗肿瘤剂相比,以少的给药量和少的给药次数实现更优异的恶性肿瘤治疗效果,完成了本发明。
即,本发明提供以下的〔1〕~〔11〕。
〔1〕一种通式(1)所示的化合物或其盐,其中,
〔式中,R1表示单键、-N(R3)(CH2)n1CO-或-N(R4)(CH2)n2N(R5) CO(CH2)n3CO-(其中,R3表示氢原子或烷基,R4和R5相同或不同,表示氢原子或烷基,或者R4和R5一起表示碳原子数1~4的亚烷基,n 1、n2和n3相同或不同,表示1~3的整数);
R2表示式(a)、(b)、(c)、(d)、(e)或(f)所示的基团,
(其中,R6表示羟基、氰基或卤原子,R7表示氢原子或卤原子, R8表示氢原子或乙炔基,R9和R10相同或不同,表示氢原子或三烷基甲硅烷基,或者R9和R10一起表示四烷基甲硅烷氧基甲硅烷基,R11表示卤原子或乙炔基,R12表示氢原子或卤原子,R13表示烷基或烷氧基烷基,R14表示烷氧基烷基或吗啉代烷基,R15表示烷基,R16表示氢原子或烷酰基。);
m表示10~1000的数;
箭头表示键合部位。〕。
〔2〕如〔1〕所述的化合物或其盐,其中,R2为式(a)或(b) 所示的基团。
〔3〕如〔1〕或〔2〕所述的化合物或其盐,其中,R2为式(a) 所示的基团。
〔4〕如〔1〕~〔3〕中任一项所述的化合物或其盐,其中,R2为式(a)所示的基团,R6为羟基、氰基或卤原子,R7为氢原子或卤原子,R8为氢原子或乙炔基,R9和R10为氢原子。
〔5〕如〔1〕~〔4〕中任一项所述的化合物或其盐,其中,R1为单键、-NH(CH2)n1CO-、-NH(CH2)n2NHCO(CH2)n3CO-或
(n1、n2和n3与上述意义相同)。
〔6〕一种含有〔1〕~〔5〕中任一项所述的化合物或其盐的医药。
〔7〕如〔6〕所述的医药,其特征在于:其为恶性肿瘤治疗药。
〔8〕一种医药组合物,其特征在于:含有〔1〕~〔5〕中任一项所述的化合物或其盐、以及药学上允许的盐。
〔9〕〔1〕~〔5〕中任一项所述的化合物或其盐在制造恶性肿瘤治疗药中的应用。
〔10〕如〔1〕~〔5〕中任一项所述的化合物或其盐,其特征在于:其用于恶性肿瘤治疗。
〔11〕一种恶性肿瘤的治疗方法,其特征在于:
给药有效量的〔1〕~〔5〕中任一项所述的化合物或其盐。
发明效果
本发明的化合物(1)具有优异的抗恶性肿瘤效果,并且其作用持续性优异,与现有的抗肿瘤剂相比,以少的给药量(以原抗肿瘤剂的活性物质的量换算)、少的给药次数、少的给药频率发挥优异的抗恶性肿瘤作用,并且副作用也少。因此,使用本发明的化合物(1)进行恶性肿瘤治疗时,患者的负担和医生的负担均被减轻,并可以获得优异的抗恶性肿瘤效果。
附图说明
图1表示化合物(1a)的NMR谱图。
图2表示化合物(1b)的NMR谱图。
图3表示化合物(1c)的NMR谱图。
图4表示化合物(1d)的NMR谱图。
图5表示化合物(1e)的NMR谱图。
图6表示化合物(1f)的NMR谱图。
图7表示化合物(1g)的NMR谱图。
图8表示化合物(1h)的NMR谱图。
图9表示化合物(1i)的NMR谱图。
图10表示化合物(1j)的NMR谱图。
图11表示肿瘤移植后的肿瘤体积的变化。括号内的给药量表示换算成DFP-10917的给药量。
图12表示肿瘤移植后的体重变化率(%)。括号内的给药量表示换算成DFP-10917的给药量。
图13表示肿瘤移植后的肿瘤体积的变化。括号内的给药量表示换算成MMC的给药量。
图14表示肿瘤移植后的体重变化率(%)。括号内的给药量表示换算成MMC的给药量。
图15表示肿瘤移植后的肿瘤体积的变化。
图16表示肿瘤移植后的体重变化率(%)。
具体实施方式
通式(1)中,R1表示单键、-N(R3)(CH2)n1CO-或-N(R4)(CH2)n2N(R5)CO(CH2)n3CO-(其中,R3表示氢原子或烷基,R4和R5相同或不同,表示氢原子或烷基,或者R4和R5一起表示碳原子数1~4的亚烷基,n1、n2和n3相同或不同,表示1~3的整数)。
作为R3、R4和R5所示的基团,优选氢原子,在为烷基的情况下,可以列举碳原子数1~6的直链或支链的烷基。其中,优选碳原子数1~4的直链或支链的烷基,更优选甲基、乙基、异丙基等。
另外,作为R4和R5一起形成的碳原子数1~4的亚烷基,可以列举亚甲基、亚乙基、三亚甲基或四亚甲基,更优选亚乙基。
作为R3,更优选氢原子。作为R4和R5,更优选两者表示氢原子,或者R4和R5形成C1-3亚烷基。
n1、n2和n3分别表示1、2或3的整数,其中更优选2。
如果列举R1的更优选的例子,可以列举单键、-NH(CH2)n1CO-、-NH(CH2)n2NHCO(CH2)n3CO-或
R1的进一步优选的具体例为单键、-NHCH2CH2CO-或
R2表示式(a)、(b)、(c)、(d)、(e)或(f)所示的基团,
(其中,R6表示羟基、氰基或卤原子,R7表示氢原子或卤原子, R8表示氢原子或乙炔基,R9和R10相同或不同,表示氢原子或三烷基甲硅烷基,或者R9和R10一起表示四烷基甲硅烷氧基甲硅烷基,R11表示卤原子或乙炔基,R12表示氢原子或卤原子,R13表示烷基或烷氧基烷基,R14表示烷氧基烷基或吗啉代烷基,R15表示烷基,R16表示氢原子或烷酰基,箭头表示键合部位。)。
R6表示羟基、氰基或卤原子,特别优选氰基。R7表示氢原子或卤原子。其中,作为卤原子,优选氟原子。
R8表示氢原子或乙炔基。
作为R9和R10所示的三烷基甲硅烷基,可以列举三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、二甲基丁基甲硅烷基、二甲基戊基甲硅烷基等。另外,作为R9和R10一起形成的四烷基甲硅烷氧基甲硅烷基,优选下式(g)所示的基团。
(其中,R17、R18、R19、R20表示烷基,优选甲基、乙基、异丙基、丁基、戊基等。)
R11表示卤原子或乙炔基。R12表示氢原子或卤原子。
R13表示烷基或烷氧基烷基。其中,作为烷基,优选碳原子数1~6 的烷基,更优选甲基。作为烷氧基烷基,优选C1-6烷氧基C1-6烷基,更优选甲氧基乙基、甲氧基丙基、乙氧基乙基等,特别优选甲氧基乙基。
R14表示烷氧基烷基或吗啉代烷基。其中,作为烷氧基烷基,优选 C1-6烷氧基C1-6烷基,更优选甲氧基乙基、甲氧基丙基、乙氧基乙基,特别优选甲氧基乙基。作为吗啉代烷基,优选吗啉代C1-4烷基,更优选吗啉代丙基。
作为R15,优选C1-6烷基,更优选甲基、乙基、丙基、丁基。
作为R16,优选氢原子或碳原子数2~6的烷酰基,更优选氢原子或乙酰基。
式(a)、(b)、(c)、(d)、(e)和(f)所示的基团为来自抗癌剂的基团。式(a)为来自阿拉伯呋喃糖基胞嘧啶系的抗癌剂的基团。式(b)为来自丝裂霉素C的基团。式(c)为来自吉非替尼、厄洛替尼等的EGFR的酪氨酸激酶抑制剂的基团。式(d)为来自舒尼替尼等的PDGFR的酪氨酸激酶抑制剂的基团。式(e)为来自拉帕替尼等的EGFR的酪氨酸激酶抑制剂的基团。式(f)为来自紫杉醇、多西他赛等的紫杉系的抗癌剂的基团。
作为式(a)所示的结构的优选例,可以列举β-D-阿拉伯呋喃糖基胞嘧啶、2’-氰基-2’-脱氧-β-D-阿拉伯呋喃糖基胞嘧啶、2’-脱氧-2’,2’-二氟-β-D-阿拉伯呋喃糖基胞嘧啶、3’-乙炔基-β-D-阿拉伯呋喃糖基胞嘧啶。
另外,作为式(c)所示的基团的具体例,可以列举式(c1)或式 (c2)所示的基团。
作为式(f)所示的基团的具体例,可以列举式(f1)或式(f2) 所示的基团。
m表示10~1000的数。更优选的m为100~500,进一步优选的 m为200~300。其中,m为来自聚乙二醇基的数,通常为平均数。
作为本发明化合物(1)的盐,只要是药学上允许的盐就没有特别限定,可以列举盐酸盐、硫酸盐、硝酸盐等的无机酸盐、乙酸盐、柠檬酸盐、酒石酸盐、草酸盐、苹果酸盐等的有机酸盐。另外,在本发明化合物(1)或其盐中,存在不对称碳原子,因此,存在立体异构体,包括它们的旋光物、对映体、它们的混合物。
本发明的化合物(1)或其盐例如可以按照以下的反应式制造。
(式中,X表示羟基、卤原子或羧基的活性酯残基,R1、R2和m 与上述意义相同)
即,通过使式(2)所示的四羧酸衍生物的羧基与式(3)所示的化合物的氨基结合,能够制造本发明化合物(1)或其盐。
四羧酸衍生物(2)例如可以通过使环氧乙烷与季戊四醇反应,接着羧甲基化,然后将羧基卤化或活性酯化而得到。作为卤原子,可以列举氯原子、溴原子。另外,作为活性酯,可以列举琥珀酰亚胺、混合酸酐等。
化合物(3)中,R1为-N(R3)(CH2)n1CO-或-N(R4)(CH2)n2N(R5) CO(CH2)n3CO-的化合物,例如,可以通过使HN(R3)(CH2)n1COY或H N(R4)(CH2)n2N(R5)CO(CH2)n3COY与R1为单键的化合物(3)反应而得到。其中,R3、R4、R5、n1、n2和n3的意义与上述意义相同,Y表示羟基、卤原子或活性酯残基。
该反应是羧酸酰胺形成反应,可以在碱基的存在下,使用HBTU、 DCC等的缩合剂进行。
四羧酸衍生物(2)与化合物(3)的反应是羧酸酰胺形成反应,可以在通常的酰胺化反应条件下实施。例如,可以在三乙胺、N,N-二甲基苯胺等的胺类的存在下,在0℃~150℃的条件下进行。
反应结束后,利用清洗、再结晶、各种色谱法等的方法对目标物进行精制、分离。
本发明的化合物(1)或其盐具有优异的抗恶性肿瘤活性,体重减少等的副作用低,并且不需要多达数小时以上的持续注入就可以获得优异的抗恶性肿瘤效果。因此,作为对患者和医生的负担少的优异的恶性肿瘤治疗药是有用的。
关于本发明的化合物(1)或其盐,PEG与抗癌剂之间的结合只是酰胺键,能够避免由于酯酶或羧化酶等的血中的分解酶引起的迅速的分解,除此以外,还与容易成为吞噬细胞的攻击对象的微粒制剂的脂质体或高分子胶束不同,由于其自身的分子尺寸非常小,并且因PEG 的特性也不容易受到吞噬细胞的攻击,在血中颇为稳定,而且因分子量大,肾排泄速度也极慢,因此,对肿瘤的靶向是高效率的。作为其结果,与现有的利用静脉内给药或经口给药等方法进行的低分子抗癌剂的情况相比,不仅能够使给药量变得极少,并且使给药次数也大大减少,而且,目前依赖于长时间的持续点滴的抗癌剂的每一次的给药时间也可以在30分钟左右内完成。
作为本发明的化合物(1)或其盐的适用对象的恶性肿瘤,可以列举头颈部癌、食道癌、胃癌、结肠癌、直肠癌、肝癌、胆囊–胆管癌、胆道癌、胰腺癌、肺癌、乳腺癌、卵巢癌、子宫颈癌、子宫癌、肾癌、膀胱癌、前列腺癌、睾丸瘤、骨与软组织肉瘤、白血病、恶性淋巴瘤、多发性骨髓瘤、皮肤癌、脑肿瘤、间皮瘤等。
在将本发明的化合物(1)或其盐用作医药时,根据需要,可以配合药学上允许的载体而制成各种形态的医药组合物。作为医药组合物的形态,可以列举口服剂、注射剂、栓剂、贴剂、软膏剂,优选制成注射剂。
作为药学上允许的载体,可以使用作为制剂原材料惯用的各种有机或者无机载体物质,作为固状制剂中的赋形剂、结合剂、崩解剂、光滑剂、着色剂、液状制剂中的溶剂、溶解辅助剂、悬浮剂、等渗剂、缓冲剂、无痛剂等而配合。另外,根据需要,也可以使用防腐剂、抗氧化剂、着色剂、甜味剂、稳定剂等的制剂添加物。
在制备经口用固状制剂时,可以在向本发明的化合物(1)中添加赋形剂、根据需要的赋形剂、结合剂、崩解剂、光滑剂、着色剂、矫味矫臭剂等后,利用常用方法制造片剂、包衣片剂、颗粒剂、散剂、胶囊剂等。
在制备注射剂时,可以向本发明的化合物(1)中添加pH调节剂、缓冲剂、稳定剂、等渗剂、局部麻醉剂等,利用常用方法制造皮下、肌肉内和静脉内用注射剂。
在将本发明的医药用于血液系统的恶性肿瘤的治疗时,优选以1 小时以内的静脉内给药的方式给药,或者稀释于生理盐水或葡萄糖注射液等,以数小时以内的点滴静注的方式给药。
实施例
以下,利用实施例、试验例对本发明进行具体说明,但这些只是出于例示的目的所记载的例子,并不限定本发明的范围。
实施例1
在氮气氛下,将1-(2’-氰基-2’-脱氧-β-D-阿拉伯呋喃糖基)胞嘧啶盐酸盐5.0摩尔、三乙胺10.0摩尔和二甲基甲酰胺8摩尔加入反应容器中,再加入四(琥珀酰亚胺基羧甲基聚乙二醇)季戊四醇1.0 摩尔。加热到100℃,反应搅拌3小时。冷却到20~25℃后,将反应混合物投入甲基叔丁基醚100mL中,搅拌1小时,过滤原料。以50~ 60°加入乙醇,搅拌后,冷却到20±5℃,搅拌16小时,用甲基叔丁基醚清洗,重复该操作,将乙醇溶液冷却,以白色粉末的形式获得化合物(1a)(m=平均230)(收率88%)。熔点54℃。将化合物(1a) 的NMR谱图示于图1。
实施例2
(1)在氮气氛下,将1-(2’-氰基-2’-脱氧-β-D-阿拉伯呋喃糖基)胞嘧啶盐酸盐1摩尔和吡啶100mL投入反应容器中,以20~ 25℃滴加二氯四异丙基二硅氧烷1.2摩尔。加热到45±5℃,搅拌2小时。以20~25℃加入己烷,分离作为固体的生成物。以20~25℃投入水中,搅拌1小时30分钟,过滤后用水和己烷清洗,蒸发干燥为固体,获得化合物(3a)。
(2)在氮气氛下,向反应容器中投入N-叔丁氧基羰基丙氨酸1.2 摩尔、HBTU 1.5摩尔、三乙胺2.0摩尔和二氯甲烷300mL,以20~25℃搅拌1小时。以20~25℃添加化合物(3a)1摩尔,加热到35±5℃,搅拌16小时。添加饱和NaHCO3水溶液,分离有机相。分别用饱和NaHCO3水溶液、饱和NH4Cl和生理盐水清洗有机相,用无水Na2SO4干燥。过滤后减压浓缩,应用硅胶柱色谱法(用乙酸乙酯洗脱),获得化合物(3b)(收率77%)。
(3)在氮气氛下,向反应容器中投入化合物(3b)1摩尔、乙酸 2摩尔和四氢呋喃200mL,冷却到0±5℃后,以0±5℃加入四正丁基氟化铵(TBAF)1.5摩尔。反应1小时后,蒸馏除去溶剂。
在氮气氛下,向反应容器中投入上述反应混合物和乙酸乙酯 300mL,以25±5℃加入HCl/乙酸乙酯2M。起始物质快速地溶解于浓HCl/乙酸乙酯溶液中,5分钟后开始分离作为固体成分的目标物。搅拌1小时,过滤后用乙酸乙酯清洗,获得化合物(3c)。
(4)与实施例1同样使化合物(3c)和四(琥珀酰亚胺基羧甲基聚乙二醇)季戊四醇醚反应,以白色粉末的形式获得目标化合物(1b)(m =平均230)(收率83%)。将化合物(1b)的NMR谱图示于图2。
实施例3
(1)在氮气氛下,将实施例2(1)所得到的化合物(3a)1摩尔、琥珀酰酐4摩尔和吡啶50mL投入反应容器中,加热到40±5℃,搅拌 2小时。将反应混合物添加至水和乙酸乙酯的混合物中,用1M盐酸将pH调至5,以30±5℃搅拌30分种。分离有机相,从水相用乙酸乙酯提取3次,合并有机相,用生理盐水清洗。用无水Na2SO4干燥,过滤后,将滤液减压浓缩后干燥,获得化合物(3d)。
(2)在氮气氛下,将化合物(3d)1摩尔、HBTU2摩尔、三乙胺4摩尔和二甲基甲酰胺100mL投入反应容器中,以30±5℃搅拌5分钟。添加哌啶4摩尔,以30±5℃搅拌1小时。加入乙酸乙酯和水,分离有机相,将有机相用生理盐水清洗2次,用无水Na2SO4干燥。过滤后将滤液减压浓缩,应用硅胶柱色谱法,用二氯甲烷/MeOH洗脱。将溶出部分减压干燥为固体,获得化合物(3e)。
(3)与实施例1同样使化合物(3e)和四(琥珀酰亚胺基羧甲基聚乙二醇)季戊四醇醚反应,以白色粉末的形式获得目标化合物(1c)(m =平均230)(收率94%)。将化合物(1c)的NMR谱图示于图3。
实施例4
(1)在氮气氛下,向反应容器中投入实施例3(2)的化合物(3e) 1摩尔、乙酸2.3摩尔和二甲基甲酰胺50mL,冷却到0±5℃。以0±5℃加入四正丁基氟化铵(TBAF)1.6摩尔,搅拌1小时,制造化合物(3g)。
(2)与实施例1同样使化合物(3g)和四(琥珀酰亚胺基羧甲基聚乙二醇)季戊四醇醚反应,获得化合物(1d)(m=平均230)。将化合物(1d)的NMR谱图示于图4。
实施例5
在氮气氛下,将四(羧甲基聚乙二醇)季戊四醇1.0摩尔、丝裂霉素 C4.8摩尔、HBTU5.0摩尔、三乙胺8摩尔、二甲基甲酰胺300mL加入反应容器中,以40±5℃反应3小时。冷却到20~25℃后,与实施例1 同样进行处理,以白色粉末的形式获得化合物(1e)(m=平均230) (收率91.4%)。将化合物(1e)的NMR谱图示于图5。
实施例6
(1)使用丝裂霉素C代替化合物(3a),与实施例3(1)同样操作,获得化合物(3h)。
(2)使用化合物(3h)代替化合物(3e),与实施例4(1)同样操作,获得化合物(3i)。
(3)使用化合物(3i)代替化合物(3g),与实施例4(2)同样操作,获得化合物(1f)(m=平均230)。将化合物(1f)的NMR 谱图示于图6。
实施例7
使用吉西他滨和四(琥珀酰亚胺基羧甲基聚乙二醇)季戊四醇,与实施例1同样操作,以白色粉末的形式获得化合物(1g)(m=平均230) (收率82.3%)。熔点57℃。将1H-NMR谱图示于图7。
实施例8
使用舒尼替尼的脱乙基体和四(琥珀酰亚胺基羧甲基聚乙二醇)季戊四醇,与实施例1同样操作,以黄色粉末的形式获得化合物(1h) (m=平均230)(收率87%)。熔点55℃。将1H-NMR谱图示于图 8。
实施例9
使用拉帕替尼、四(羧甲基聚乙二醇)季戊四醇和HBTU,与实施例 4同样操作,以白色粉末的形式获得化合物(1i)(收率87.8%)。熔点56℃。将1H-NMR谱图示于图9。
实施例10
(1)使三氟乙酸与紫杉醇反应,使紫杉醇的叔丁氧基羰基脱离。
(2)使用紫杉醇叔丁氧基羰基脱离体和四(琥珀酰亚胺基羧甲基聚乙二醇)季戊四醇,与实施例1同样操作,获得化合物(1j)(收率84.2%)。将1H-NMR图示于图10。
试验例1
向BALB/c裸鼠的右侧腹部移植5×106个细胞的胰腺癌细胞,7 天后在平均肿瘤达到100mm3时开始药物给药。从药物给药至29天后测定小鼠的体重和肿瘤体积。将其结果示于图11、图12和表1。关于 1-(2’-氰基-2’-脱氧-β-D-阿拉伯呋喃糖基)胞嘧啶盐酸盐 (DFP-10917),使用埋入小鼠的体内的微型泵,连续2周以4.5mg /kg/day进行向皮下的持续注入。另一方面,每周1次以100mg/kg、 200mg/kg或300mg/kg静脉内给药化合物(1a)。该化合物(1a) 的给药量换算成DFP-10197为每周1次以2.4mg/kg、4.8mg/kg和 7.2mg/kg给药。关于对照,给药乙酸钠的缓冲液(pH=5.0)。
从图11和图12可以确认,通过每周1次的静脉内给药,化合物 (1a)几乎没有使体重减少,显示优异的肿瘤治疗效果。
[表1]
注:a.平均±SEM;b.TGl:肿瘤生长抑制.c.:与空白对照之比.
P值:G2vs.G3=0.027,G2vs.G4=0.001,G3vs.G4=0.004.
括号内的给药量表示换算成DFP-10917的给药量。
试验例2
与试验例1同样操作,研究丝裂霉素C和化合物(1e)的抗肿瘤作用。每周一次以3mg/kg/day静脉内给药丝裂霉素C(MMC)。另一方面,每周1次以25mg/kg、50mg/kg、100mg/kg和200mg /kg静脉内给药化合物(1e)。该化合物(1e)的给药量换算成MMC 为每周1次以0.8mg/kg、1.7mg/kg、3.3mg/kg和6.7mg/kg给药。
从图13和图14可以确认,通过每周1次的静脉内给药,化合物 (1e)几乎没有使体重减少,显示了优异的肿瘤治疗效果。
试验例3
向BALB/c裸鼠的右侧腹部移植5×106个细胞的人肺癌细胞 A549,14天后在平均肿瘤达到127mm3时开始药物给药。化合物(1a) 按1周1次以200mg/kg(换算成DFP-10917的量为4.8mg/kg)静脉内给药,作为肺癌的标准药的培美曲塞,按1周1次以300mg/kg 腹腔内给药。关于对照,1周1次静脉内给药生理盐水。观察2周(合计2次给药)。
作为其结果,化合物(1a)以换算成DFP-10917的量4.8mg/kg 给药,显示了与培美曲塞300mg/kg给药组同等的肿瘤治疗效果。
[表2]
*:换算成DFP-10917的给药量
试验例4
向BALB/c裸鼠的右侧腹部移植1×107个细胞的人乳腺癌细胞 BT474,与试验例3同样操作,关于药物给药的DFP-10917和化合物 (1a),1周1次静脉内给药计2次。关于对照,1周1次给药生理盐水。
作为其结果,如(表3)所示,化合物(1a)与DFP-10917本身相比,尽管以17.6/200的换算成DFP-10917的量给药,也显示了与吉西他滨同等的抗肿瘤效果。
[表3]
*:换算成DFP-10917的给药量
试验例5
向BALB/c裸鼠的右侧腹部移植5×106个细胞的人胰腺癌细胞 Panc-1,与试验例3同样操作,进行药物给药。关于化合物(1g), 1周1次静脉内给药计2次,或者1周2次静脉内给药。关于吉西他滨,将100mg/kg在3天内分4次给药,并将其静脉内给药总计4次。关于对照,1周1次给药生理盐水。
作为其结果,如(表4)所示,化合物(1g)与吉西他滨本身相比,尽管以1/35~1/40的换算成吉西他滨的量给药,也显示了吉西他滨的约1/2的抗肿瘤效果。
[表4]
*:换算成吉西他滨的给药量
试验例5
向BALB/c裸鼠的右侧腹部移植人肺癌细胞A549细胞,11天后在平均肿瘤达到200mm3时开始给药。将给药疗程示于表5、表6。
将其结果示于表5、表6和图15、图16。
[表5]
*:换算成舒尼替尼的量
[表6]
*1:换算成拉帕替尼的量
根据表5,化合物(1h)以换算成舒尼替尼的量4/50~8/50的给药量,显示了与舒尼替尼脱乙基体同等的抗肿瘤效果。另外,根据表6和图15,化合物(1i)以换算成拉帕替尼的量11.6/100~17.4/ 100的给药量,显示了比拉帕替尼更优异的抗肿瘤效果。
还可以确认,化合物(1h)和化合物(1i)以上述的给药量看不到任何体重减少,安全性也高(图16)。
试验例6
向BALB/c裸鼠的右侧腹部移植1×107个细胞的人乳腺癌细胞 BT474,在肿瘤体积成为100~150mm3时进行药物给药。给药为1周1 次,给药2周。
作为其结果,如(表7)所示,可以确认化合物(1j)显示36%~ 37.5%的肿瘤增殖抑制率,显示与对照的紫杉醇的29.8%同等或其以上的效果,是效果与安全性的平衡优异的化合物,还可以确认,其自身具有高的水溶性,与难溶于水的紫杉醇相比,可以成为能够大大改善临床上的给药方法的新型恶性肿瘤治疗药。
[表7]
Claims (8)
1.一种通式(1)所示的化合物或其盐,其中:
C[CH2O(CH2CH2O)mCH2CO-R1-R2]4
(1)
式中,R1表示单键、-N(R3)(CH2)n1CO-或-N(R4)(CH2)n2N(R5)CO(CH2)n3CO-,其中,R3表示氢原子或烷基,R4和R5相同或不同,表示氢原子或烷基,或者R4和R5一起表示碳原子数1~4的亚烷基,n1、n2和n3相同或不同,表示1~3的整数;
R2表示2’-氰基-2’-脱氧-β-D-阿拉伯呋喃糖基胞嘧啶、3’-乙炔基-β-D-阿拉伯呋喃糖基胞嘧啶、式(b)、(c)、(d)、(e)或(f)所示的基团,
其中,R11表示卤原子或乙炔基,R12表示氢原子或卤原子,R13表示烷基或烷氧基烷基,R14表示烷氧基烷基或吗啉代烷基,R15表示烷基,R16表示氢原子或烷酰基;
R2为式(d)所示的基团时,R1不为单键;
m表示10~1000的数;
箭头表示键合部位。
2.如权利要求1所述的化合物或其盐,其特征在于:
R2为2’-氰基-2’-脱氧-β-D-阿拉伯呋喃糖基胞嘧啶、3’-乙炔基-β-D-阿拉伯呋喃糖基胞嘧啶或式(b)所示的基团。
3.如权利要求1或2所述的化合物或其盐,其特征在于:
R2为2’-氰基-2’-脱氧-β-D-阿拉伯呋喃糖基胞嘧啶或3’-乙炔基-β-D-阿拉伯呋喃糖基胞嘧啶。
4.如权利要求1或2所述的化合物或其盐,其特征在于:
R1为单键、-NH(CH2)n1CO-、-NH(CH2)n2NHCO(CH2)n3CO-或
n1、n2和n3与上述意义相同。
5.一种含有权利要求1~4中任一项所述的化合物或其盐的医药。
6.如权利要求5所述的医药,其特征在于:
其为恶性肿瘤治疗药。
7.一种医药组合物,其特征在于:
含有权利要求1~4中任一项所述的化合物或其盐、以及药学上允许的盐。
8.权利要求1~4中任一项所述的化合物或其盐在制造恶性肿瘤治疗药中的应用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2014246110 | 2014-12-04 | ||
JP2014-246110 | 2014-12-04 | ||
PCT/JP2015/084068 WO2016088858A1 (ja) | 2014-12-04 | 2015-12-03 | 新規peg誘導体 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107001617A CN107001617A (zh) | 2017-08-01 |
CN107001617B true CN107001617B (zh) | 2019-08-27 |
Family
ID=56091797
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201580065673.8A Active CN107001617B (zh) | 2014-12-04 | 2015-12-03 | Peg衍生物 |
Country Status (10)
Country | Link |
---|---|
US (1) | US10111955B2 (zh) |
EP (1) | EP3228650B1 (zh) |
JP (1) | JP6542799B2 (zh) |
KR (1) | KR102138415B1 (zh) |
CN (1) | CN107001617B (zh) |
AU (1) | AU2015355965B2 (zh) |
ES (1) | ES2910659T3 (zh) |
PL (1) | PL3228650T3 (zh) |
RU (1) | RU2697551C2 (zh) |
WO (1) | WO2016088858A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3928835B1 (en) * | 2020-05-14 | 2023-10-25 | Delta-Fly Pharma, Inc. | Water-soluble polymeric derivative of venetoclax |
JP6801908B1 (ja) * | 2020-05-14 | 2020-12-16 | Delta−Fly Pharma株式会社 | ベネトクラクスの水溶性高分子誘導体 |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
US7238368B2 (en) * | 1999-04-23 | 2007-07-03 | Alza Corporation | Releasable linkage and compositions containing same |
US6376470B1 (en) * | 1999-09-23 | 2002-04-23 | Enzon, Inc. | Polymer conjugates of ara-C and ara-C derivatives |
US6756037B2 (en) * | 2000-03-31 | 2004-06-29 | Enzon, Inc. | Polymer conjugates of biologically active agents and extension moieties for facilitating conjugation of biologically active agents to polymeric terminal groups |
US8394365B2 (en) | 2003-09-17 | 2013-03-12 | Nektar Therapeutics | Multi-arm polymer prodrugs |
WO2005028539A2 (en) | 2003-09-17 | 2005-03-31 | Nektar Therapeutics Al, Corporation | Multi-arm polymer prodrugs |
DE10355904A1 (de) * | 2003-11-29 | 2005-06-30 | Merck Patent Gmbh | Feste Formen von anti-EGFR-Antikörpern |
WO2007076160A2 (en) * | 2005-12-28 | 2007-07-05 | Acidophil Llc | C-10 carbamates of taxanes |
EP1977765A1 (en) * | 2007-04-03 | 2008-10-08 | Diatos | Peptide prodrugs |
US9517201B2 (en) * | 2008-04-04 | 2016-12-13 | Rutgers, The State University Of New Jersey | Nanocarrier and nanogel compositions |
CN102159250B (zh) | 2008-08-11 | 2014-08-06 | 尼克塔治疗公司 | 多臂的聚合烷酸酯偶联物 |
WO2010083154A2 (en) * | 2009-01-13 | 2010-07-22 | The Uab Research Foundation | Heterofunctional segment-poly(ethylene glycol) polymers as delivery vehicles |
US8722732B2 (en) * | 2009-09-29 | 2014-05-13 | Nektar Therapeutics | Oligomer-calcimimetic conjugates and related compounds |
MX338134B (es) | 2009-11-18 | 2016-04-01 | Nektar Therapeutics | Formas salinas de adicion de acido de conjugados de polimeros-farmaco y metodos de alcoxilacion. |
US20130018010A1 (en) * | 2010-04-16 | 2013-01-17 | Enzon Pharmaceuticals, Inc. | Polymeric conjugates of adenine nucleoside analogs |
JP2012116821A (ja) * | 2010-12-03 | 2012-06-21 | Univ Of Tokushima | パクリタキセル誘導体 |
WO2012088422A1 (en) * | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
US9827326B2 (en) * | 2010-12-23 | 2017-11-28 | Nektar Therapeutics | Polymer-sunitinib conjugates |
EP2654797B1 (en) * | 2010-12-23 | 2017-11-08 | Nektar Therapeutics | Polymer-des-ethyl sunitinib conjugates |
WO2012098557A1 (en) * | 2011-01-20 | 2012-07-26 | Institute Of Life Sciences | Pegylated gemcitabine derivative and process for preparing the same |
EP2707033A1 (en) * | 2011-05-11 | 2014-03-19 | Ramot at Tel Aviv University, Ltd. | Targeted polymeric conjugates and uses thereof |
CN102649841B (zh) * | 2012-04-06 | 2013-09-04 | 东南大学 | 苯胺基喹唑啉为靶向配体的聚乙二醇修饰磷脂衍生物及制法 |
JP5721806B2 (ja) * | 2013-10-04 | 2015-05-20 | Delta−Fly Pharma株式会社 | 副作用のない抗癌剤 |
CA2958495C (en) * | 2014-08-22 | 2023-04-18 | Yafei Shanghai Biolog Medicine Science & Technology Co., Ltd. | Small molecule conjugates specifically activated in tumor microenvironment for targeting and use thereof |
CN104987504B (zh) * | 2015-04-23 | 2018-05-01 | 南京明臻医药科技有限公司 | 聚乙二醇化拉帕替尼及其注射剂和制备方法 |
-
2015
- 2015-12-03 PL PL15864609T patent/PL3228650T3/pl unknown
- 2015-12-03 JP JP2016562685A patent/JP6542799B2/ja active Active
- 2015-12-03 CN CN201580065673.8A patent/CN107001617B/zh active Active
- 2015-12-03 AU AU2015355965A patent/AU2015355965B2/en active Active
- 2015-12-03 EP EP15864609.1A patent/EP3228650B1/en active Active
- 2015-12-03 WO PCT/JP2015/084068 patent/WO2016088858A1/ja active Application Filing
- 2015-12-03 KR KR1020177014667A patent/KR102138415B1/ko active IP Right Grant
- 2015-12-03 RU RU2017122971A patent/RU2697551C2/ru active
- 2015-12-03 US US15/520,956 patent/US10111955B2/en active Active
- 2015-12-03 ES ES15864609T patent/ES2910659T3/es active Active
Also Published As
Publication number | Publication date |
---|---|
US20170368177A1 (en) | 2017-12-28 |
RU2697551C2 (ru) | 2019-08-15 |
JP6542799B2 (ja) | 2019-07-10 |
PL3228650T3 (pl) | 2022-06-27 |
EP3228650A4 (en) | 2018-10-17 |
ES2910659T3 (es) | 2022-05-13 |
RU2017122971A3 (zh) | 2019-02-11 |
KR20170091610A (ko) | 2017-08-09 |
KR102138415B1 (ko) | 2020-07-27 |
RU2017122971A (ru) | 2019-01-09 |
EP3228650B1 (en) | 2022-03-09 |
AU2015355965B2 (en) | 2019-07-04 |
JPWO2016088858A1 (ja) | 2017-09-07 |
AU2015355965A1 (en) | 2017-04-27 |
EP3228650A1 (en) | 2017-10-11 |
WO2016088858A1 (ja) | 2016-06-09 |
US10111955B2 (en) | 2018-10-30 |
CN107001617A (zh) | 2017-08-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1761485B (zh) | 含略微水溶性抗癌剂和新型嵌段共聚物的胶束制剂 | |
EP3181553B1 (en) | Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof | |
CN101420963A (zh) | 用于治疗乳腺癌、结肠直肠癌、胰腺癌、卵巢癌和肺癌的7-乙基-10-羟基喜树碱的多臂聚合轭合物 | |
WO2018133661A1 (zh) | 一种新的硼酸衍生物及其药物组合物 | |
CN105985323A (zh) | 新型表皮生长因子受体抑制剂及其应用 | |
WO2018084321A1 (ja) | Egfr阻害及び腫瘍治療に有用な新規化合物 | |
EP2615092A1 (en) | Heterocyclic amino berbamine derivatives, preparation method and use thereof | |
CN102675323A (zh) | 吡咯并[2,1-f][1,2,4]三嗪衍生物及其抗肿瘤用途 | |
CN107001617B (zh) | Peg衍生物 | |
WO2022262516A1 (zh) | 连接子及其缀合物 | |
US20220175756A1 (en) | Application of combination of quinoline derivative and immunomodulator in preparation of antitumor drugs | |
US20180105550A1 (en) | Cytidine derivative dimers and applications thereof | |
CN103965175A (zh) | 4-(取代苯氨基)喹唑啉类化合物、其制备方法及应用 | |
CN103304573B (zh) | 石蒜碱类化合物在制备抗肿瘤药物的应用 | |
KR20240012513A (ko) | 세스퀴테르펜 유도체, 그의 약학적 조성물 및 그의 제조 방법과 용도 | |
EP3378495B1 (en) | Composition comprising novel glutamic acid derivative and block copolymer, and use thereof | |
CA3217111A1 (en) | Use of medicament in treatment of tumor disease | |
CN114716440A (zh) | 吡咯并三嗪衍生物及其制备方法和应用 | |
CN103755695B (zh) | 一种具有抗肿瘤活性的酰胺类化合物及其应用 | |
WO2012000182A1 (en) | Quinazoline compounds | |
CN103896860B (zh) | 含有锌结合基的不可逆egfr抑制剂 | |
CN110981803B (zh) | 一种抗肿瘤化合物及其合成方法与应用 | |
JP2021147340A (ja) | 化合物、そのナノ粒子及び癌疾患の治療剤 | |
EP4442684A1 (en) | A class of pyrimidine compounds, and preparation method therefor and use thereof | |
CN101747300B (zh) | 基于紫杉醇和氮芥的协同前药及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1240958 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant |