TW201713675A - 新穎鉑(iv)錯合物 - Google Patents
新穎鉑(iv)錯合物 Download PDFInfo
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- TW201713675A TW201713675A TW105119624A TW105119624A TW201713675A TW 201713675 A TW201713675 A TW 201713675A TW 105119624 A TW105119624 A TW 105119624A TW 105119624 A TW105119624 A TW 105119624A TW 201713675 A TW201713675 A TW 201713675A
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- NDBYXKQCPYUOMI-UHFFFAOYSA-N platinum(4+) Chemical compound [Pt+4] NDBYXKQCPYUOMI-UHFFFAOYSA-N 0.000 title claims description 37
- 125000005843 halogen group Chemical group 0.000 claims abstract description 18
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical group OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 6
- 239000003446 ligand Substances 0.000 claims description 14
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical compound N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 25
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 18
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 229910052697 platinum Inorganic materials 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical group OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 abstract 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 50
- 230000000052 comparative effect Effects 0.000 description 20
- 239000007787 solid Substances 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 12
- 239000012153 distilled water Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 101100498160 Mus musculus Dach1 gene Proteins 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000002504 physiological saline solution Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 206010017758 gastric cancer Diseases 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 5
- 201000002528 pancreatic cancer Diseases 0.000 description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 description 5
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 5
- 201000011549 stomach cancer Diseases 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229960001756 oxaliplatin Drugs 0.000 description 4
- 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 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- QOSATHPSBFQAML-UHFFFAOYSA-N hydrogen peroxide;hydrate Chemical compound O.OO QOSATHPSBFQAML-UHFFFAOYSA-N 0.000 description 2
- 229960000907 methylthioninium chloride Drugs 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000012192 staining solution Substances 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- GZKAUKVFYHIGEL-UHFFFAOYSA-N ClN=CC(CC)=N Chemical compound ClN=CC(CC)=N GZKAUKVFYHIGEL-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 206010028817 Nausea and vomiting symptoms Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- CCQPAEQGAVNNIA-UHFFFAOYSA-N cyclobutane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000001142 dicarboxylic acid group Chemical group 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229950010897 iproplatin Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- BDRTVPCFKSUHCJ-UHFFFAOYSA-N molecular hydrogen;potassium Chemical compound [K].[H][H] BDRTVPCFKSUHCJ-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- HJPHMPYPXOYPBI-UHFFFAOYSA-N n-chlorobutan-1-imine Chemical compound CCCC=NCl HJPHMPYPXOYPBI-UHFFFAOYSA-N 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 190014017285 satraplatin Chemical compound 0.000 description 1
- ROBLTDOHDSGGDT-UHFFFAOYSA-M sodium;pentane-1-sulfonate Chemical compound [Na+].CCCCCS([O-])(=O)=O ROBLTDOHDSGGDT-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- -1 that is Chemical compound 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/65—Metal complexes of amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
根據本發明,謀求一種充分具有作為醫藥所要求之水溶性、穩定性、及抗腫瘤活性等,可於臨床上使用之新穎鉑(IV)錯合物,提供一種下述通式(I)所表示之鉑(IV)錯合物[式中,X1及X2均表示鹵素原子、或共同一體表示選自由草酸根、丙二酸根、丁二酸根及鄰苯二甲酸根所組成之群中之二羧酸根,Y表示鹵素原子]。
□
Description
本發明係關於一種新穎鉑(IV)錯合物及以其作為有效成分之醫藥。
順鉑係具有較廣之抗癌光譜與較強之抗腫瘤活性之鉑(II)錯合物,作為癌化學療法中之多藥併用療法之中心藥劑,而用於各種癌之治療。然而,作為副作用,已知有產生腎臟損傷、噁心-嘔吐,使用時需要採取對策。又,於臨床使用上對順鉑具有耐性之細胞之出現成為問題。
作為臨床所使用之其他鉑(II)錯合物,已知雖然奧沙利鉑被用於結腸癌治療等,但會產生末梢神經損傷等副作用,此被視為治療上之問題。另一方面,認為奧沙利鉑顯示出與順鉑之交叉耐藥性,認為重要的是具有與順鉑不同之胺結構、即1,2-環己烷二胺(以下,有時亦簡稱為dach)結構之配位基。(參照非專利文獻1)
作為具有抗癌活性之鉑錯合物,除鉑(II)錯合物以外,亦已知有鉑(IV)錯合物。作為鉑(IV)錯合物之特徵,可列舉:可期待藉由使軸向位之配位基轉化為各種取代基而產生之水溶性等物性之變化、藉由使靶向分子向目標鍵結而產生之活性提高等。(參照非專利文獻2)
作為具有與奧沙利鉑相同之dach結構之配位基的鉑(IV)錯合物,例如已知有:於軸向位具有兩個鹵素原子之錯合物(參照專利文獻1)、於軸向位具有鹵素原子及羧酸根之錯合物(參照專利文獻2)、於軸
向位具有鹵素原子及取代烷氧基之錯合物(參照專利文獻3)、於軸向位具有兩個羧酸根之錯合物(參照專利文獻4)等。
又,於非專利文獻3及非專利文獻4中,關於在軸向位具有鹵素原子及羥基之鉑(IV)錯合物有所記載。然而,共同具有dach結構之配位基及草酸根結構或鹵素原子之脫離基之化合物並無記載。
目前為止,雖然嘗試有作為鉑(IV)錯合物之賽特鉑(satraplatin)、奧馬鉑(tetraplatin)、異丙鉑(iproplatin)等(參照非專利文獻2)之臨床試驗,但開發被中止,謀求有效性較高之新穎鉑(IV)錯合物。
[專利文獻1]
國際公開第90/05734號
[專利文獻2]
國際公開第96/26949號
[專利文獻3]
法國專利發明第2954321號說明書
[專利文獻4]
國際公開第2014/100417號
[非專利文獻1]
Critical Reviews in Oncology : Hematology, 2000, 35, 75-93
[非專利文獻2]
Chemical Reviews, 2014, 114, 4470-4495
[非專利文獻3]
Inorganic Chemistry, 2014, 53, 9326-9335
[非專利文獻4]
European Journal of Inorganic Chemistry, 2006, 1168-1173
尚無充分發揮作為醫藥所要求之水溶性、穩定性或抗腫瘤效果之鉑(IV)錯合物,業界期待可於臨床上使用之新穎鉑(IV)錯合物。
本發明者等為了解決上述課題而努進行力研究,結果發現,藉由選擇鹵素原子及羥基作為具有dach結構之配位基之鉑(IV)錯合物之軸向配位基,可獲得具有優異之抗腫瘤活性,化學上穩定且溶解性優異之錯合物,從而完成本發明。
即,本發明係關於下述(1)~(4)。
(1)一種鉑(IV)錯合物,其下述通式(I)表示:
[式中,X1及X2均表示鹵素原子,或共同一體表示選自由草酸根(oxalate)、丙二酸根(malonate)、丁二酸根(succinate)及鄰苯二甲酸根(o-phthalate)所組成之群中之二羧酸根,Y表示鹵素原子]。
(2)如上述(1)所記載之鉑(IV)錯合物,其中X1及X2均為氯原子或溴原子,或共同為草酸根,Y為氯原子或溴原子。
(3)如上述(1)或(2)所記載之鉑(IV)錯合物,其中1,2-環己烷二胺配位基為(1R,2R)-環己烷二胺配位基。
(4)一種醫藥,其係以如上述(1)至(3)中任一項所記載之鉑(IV)錯合物作為有效成分。
根據本發明,可提供一種具有優異之抗腫瘤活性,化學上穩定且具有水溶性之鉑(IV)錯合物及以其作為有效成分之醫藥。
圖1係表示作為實施例1化合物及比較例5化合物於37℃下之水溶液中之穩定性試驗的試驗例3之結果的圖。
以下,對本發明進行詳細說明。
於本發明中,所謂鹵素原子係指氟原子、氯原子、溴原子或碘原子。作為X1及X2,較佳為共同為相同之鹵素原子,其中尤佳為共同為氯原子或溴原子。作為Y,較佳為氯原子或溴原子。
於本發明中,作為脫離基之二羧酸根並無特別限定,可列舉:具有兩個羧基之(C1-C6)烷基或(C6-C10)芳基。其中,較佳為以下所示之草酸根、丙二酸根、丁二酸根、鄰苯二甲酸根。
作為本發明之鉑(IV)錯合物,尤佳可列舉下述通式(II)或通式(IV)所表示之化合物。
[式中,Y表示鹵素原子]
作為本發明之鉑(IV)錯合物之1,2-環己烷二胺配位基之立體結構,就生理活性等方面而言,較佳為1R、2R之反式組態。
即,作為本發明之鉑(IV)錯合物,進而較佳為下述通式(III)或通式(V)所表示之化合物。
[式中,Y表示鹵素原子]
本發明之鉑(IV)錯合物可應用非專利文獻2等文獻所記載之方法而製造。即,為如下方法:藉由將鉑(II)錯合物於溶劑中進行過氧化氫等氧化劑處理或氧化性鹵素處理,而製成作為目標之鉑(IV)錯合物之方法;或藉由將鉑(IV)錯合物供於取代反應而製成目標之鉑(IV)錯合物。將該等製造方法之例示揭示於下述實施例。
以本發明之鉑(IV)錯合物作為有效成分之醫藥亦包含於本發明
中。本發明之鉑(IV)錯合物只要為顯示出藥效之醫藥用途,則無特別限定,較佳為作為抗癌劑之用途。關於作為抗癌劑之用途,可單獨使用,或者亦可與載體、賦形劑、崩解劑、結合劑、潤滑劑、流動化劑、塗佈劑、懸浮劑、乳化劑、穩定劑、保存劑、矯味劑、著香劑、稀釋劑、溶解助劑等製藥上可容許之添加劑進行混合,而以粉劑、顆粒劑、錠劑、片劑(tablette)、膠囊劑、注射劑、栓劑、軟膏劑等製劑形態,進行經口或非經口(全身投予、局部投予等)投予。製劑中之本發明之鉑(IV)錯合物係根據製劑而各有不同,通常為0.1~100重量%。投予量係根據投予途徑、患者之年齡及待預防或治療之實際之症狀等而不同,例如於對成人投予之情形時,作為有效成分,可設為1天0.01mg~2000mg,較佳為可設為0.1mg~1000mg,可1天1次或分為數次而投予。
以下,藉由實施例更詳細地說明本發明。然而,本發明並不限定於該等實施例。
於本發明之實施例中,使用以下之簡稱。
ox:草酸根
cbdc:1,1-環丁烷二羧酸根
1-OHP:奧沙利鉑
本實施例中之化合物之純度測定係使用高效液相層析法,使用L-column2 ODS(4.6mmI.D.x250mm:自一般財團法人 化學物質評價研究機構購入)作為管柱,使用將磷酸二氫鉀2.72g、1-戊烷磺酸鈉1.89g及三乙胺0.5ml溶劑於蒸餾水2000ml中並利用磷酸製備為pH值4.3之緩衝液作為流動相(A),使用甲醇作為流動相(B),於下述分析條件1或2之條件下實施。
分析條件1(等度分析):
流動相(B)濃度:15%(0min)-15%(20min)、流動相流速1ml/min,檢測210nm。
分析條件2(梯度分析):流動相(B)濃度:15%(0min)-90%(10min)、流動相流速1ml/min,檢測210nm。
實施例1 反式,順式,順式-[PtCl(OH)(R,R-dach)(ox)]:通式(III)之Y=Cl之合成
將N-氯代丁二醯亞胺(66.8mg)溶解至蒸餾水14ml中,添加使1-OHP(200mg)懸浮於蒸餾水6ml中而成之液體,於遮光下,於室溫下攪拌4小時。反應結束後,濾除反應液中之不溶物,將濾液進行減壓濃縮,藉此獲得固體。藉由將所獲得之固體於乙醇/水中進行再結晶,而獲得標記化合物(114mg)。1H-NMR(D2O):δ 2.89-2.72(2H,m),2.15(2H,d,J=12.2Hz),1.53-1.41(4H,m),0.97-0.90(2H,m),MS(ESI;Electrospray Ionization):450(M+1)、451(M+2)、純度(HPLC,分析條件2):99.4%。
實施例2 反式,順式,順式-[PtBr(OH)(R,R-dach)(ox)]:通式(III)之Y=Br之合成
將N-溴代丁二醯亞胺(89.6mg)溶解至蒸餾水14ml中,添加使1-OHP(200mg)懸浮於蒸餾水6ml中而成之液體,於遮光下,於室溫下攪拌3小時。反應結束後,濾除反應液中之不溶物,將濾液進行減壓濃縮,藉此獲得固體。使所獲得之固體懸浮於水中,再次進行過濾收集,而獲得標記化合物(216mg)。1H-NMR(DMSO-d6):δ 7.91-7.65(2H,m),7.14-7.03(2H,m),2.65-2.55(2H,m),2.07-1.94(2H,m),1.50-1.46(4H,m),1.15-1.02(2H,m),MS(ESI):495(M+1)、純度(HPLC,分析條件2):98.9%。
實施例3 反式,順式,順式-[PtCl(OH)(R,R-dach)(Cl)2]:通式(I)之
X1、X2、Y=Cl之合成
將N-氯代丁二醯亞胺(105.4mg)溶解至蒸餾水7ml中,並添加至使Pt(R,R-dach)Cl2(300mg)懸浮於四氫呋喃60ml中而成之液體中,於遮光下,於室溫下攪拌4小時。反應結束後,濾除反應液中之不溶物,將濾液進行減壓濃縮,藉此獲得固體。使所獲得之固體懸浮於乙醇中,再次過濾收集,而獲得標記化合物(322mg)。1H-NMR(DMSO-d6):δ 7.53-7.29(2H,m),6.89-6.78(2H,m),2.75-2.60(2H,m),2.10-2.00(2H,m),1.47(2H,d,J=8.0Hz),1.10-0.93(2H,m),MS(ESI):433(M+1)、純度(HPLC,分析條件2):98.1%。
比較例1 反式,順式,順式-[Pt(OH)(OAc)(R,R-dach)(ox)]之合成
向使1-OHP(200mg)懸浮於乙酸9ml中而成之液體中,添加30%過氧化氫水0.135ml,於遮光下,於室溫下攪拌19小時。反應結束後,一面添加水一面數次減壓濃縮,獲得固體。藉由將所獲得之固體利用乙醇/甲醇進行再結晶而獲得標記化合物(55mg)。1H-NMR(D2O):δ 2.78-2.73(2H,m),2.17(2H,d,J=9.2Hz),1.94(3H,s)、1.54-1.44(4H,m),1.20-1.05(2H,m),純度(HPLC,分析條件1):94.0%。
比較例2 反式,順式,順式-[PtCl(OCH2CH2OH)(R,R-dach)(ox)]之合成
向使1-OHP(200mg)懸浮於乙二醇2ml中而成之液體中,添加N-氯代丁二醯亞胺(66.8mg),於遮光下,於室溫下攪拌3小時。反應結束後,向反應液中添加丙酮10ml及二乙醚30ml,將所析出之固體進行過濾收集。藉由將所獲得之固體於乙醇/水中進行再結晶,而獲得標記化合物(154mg)。1H-NMR(D2O):δ 3.58-3.45(2H,m),3.22-3.08(2H,m),2.85-2.83(2H,m),2.14(2H,d,J=11.2Hz),1.53-1.44(4H,m),1.15-1.07(2H,m),純度(HPLC,分析條件1):98.0%。
比較例3 反式,順式,順式-[Pt(OH)2(R,R-dach)(ox)]之合成
向使1-OHP(900mg)懸浮於蒸餾水12ml中而成之液體中,添加30%過氧化氫水2.58ml,於遮光下,於室溫下攪拌20.5小時。反應結束後,一面添加水一面數次減壓濃縮,而獲得固體。藉由將所獲得之固體於蒸餾水中進行再結晶,而獲得標記化合物(422mg)。1H-NMR(D2O):δ 2.74-2.72(2H,m),2.17(2H,d,J=12.8Hz),1.54-1.45(4H,m),1.18-1.12(2H,m),純度(HPLC,分析條件1):>98.0%。
比較例4 反式,順式,順式-[Pt(OCOCH2CH2C6H5)2(R,R-dach)(ox)]之合成
將3-苯基丙酸(77mg)、N,N-二甲胺基吡啶(5.7mg)溶解至N,N-二甲基甲醯胺2ml中,添加二異丙基碳二醯亞胺0.086ml後,於室溫下攪拌0.5小時。向反應液中,添加使比較例3中所獲得之反式,順式,順式-[Pt(OH)2(R,R-dach)(ox)](200mg)懸浮於N,N-二甲基甲醯胺2ml中而成之液體,於遮光下,於室溫下攪拌23小時。藉由過濾反應液而將未反應之鉑錯合物去除,藉由向所獲得之濾液中添加水,而使固體析出。將固體進行過濾收集,利用冰冷之乙醇進行清洗,藉此獲得標記化合物(38mg)。1H-NMR(DMSO-d6):δ 8.30(4H,brs)、7.27-7.14(10H,m),2.80-2.76(4H,m),2.60-2.56(4H,m),2.40-2.30(2H,m),2.05(2H,d,J=12.4Hz),1.47(2H,d,J=8.0Hz),1.40-1.22(2H,m),1.15-1.14(2H,m),純度(HPLC,分析條件2):98.0%。
比較例5 反式,順式,順式-[PtCl(OH)(R,R-dach)(cbdc)]之合成
依據非專利文獻3中記載之方法,合成標記化合物。1H-NMR(DMSO-d6):δ 7.71-7.43(2H,m),7.00-6.90(2H,m),2.60-2.29(6H,m),2.03-1.93(2H,m),1.84-1.49(2H,m),1.50-1.30(4H,m),1.05-0.95(2H,m),MS(ESI):504(M+1)、486(M-OH)、純度(HPLC,分析條件2):95.6%。
比較例6 反式,順式,順式-[Pt(OH)2(R,R-dach)(cbdc)]之合成
將依據非專利文獻3中記載之方法所合成之順式,順式-[Pt(R,R-dach)(cbdc)](100mg)溶解至50%丙酮溶液14ml中,添加30%過氧化氫水14ml,於遮光下,於室溫下攪拌4小時。反應結束後,一面添加水一面數次減壓濃縮,而獲得固體。將所獲得之固體於丙酮中進行懸浮精製,藉此獲得標記化合物(41mg)。1H-NMR(D2O):2.97(2H,d,J=10.0Hz),2.77-2.72(4H,m),2.36-2.32(2H,m),2.14-2.10(2H,m),1.74-1.64(4H,m),1.37-1.34(2H,m),MS(ESI):486(M+1)、486(M-OH)、純度(HPLC,分析條件2):96.8%。
試驗例1 實施例化合物及比較例化合物之活體外(in vitro)抗腫瘤試驗
將胃癌及胰腺癌細胞株分別接種至96孔培養盤中。以胃癌細胞KATOIII為1×104細胞/well,胃癌細胞MKN-1為5×105細胞/well,胃癌細胞MKN-45為1×104細胞/well,胃癌細胞MKN-74為1×104細胞/well,胰腺癌細胞AsPC-1為5×105細胞/well,胰腺癌細胞BxPC-3為5×105細胞/well,胰腺癌細胞DAN-G為5×105細胞/well,胰腺癌細胞SUIT-2為5×105細胞/well分別進行接種。培養24小時後,將各實施例化合物或各比較例化合物以公比4自最終濃度0.0244μmol/L添加至100μmol/L。技術複製設為3點。設置作為對照之不添加藥劑之孔、與作為空白對照之不添加細胞及藥劑之孔。培養72小時後,將培養液去除,利用甲醇將細胞固定後,使用亞甲基藍染色液將細胞染色。將過量之亞甲基藍染色液清洗後,向各孔(well)中添加0.1%鹽酸200μL,將色素提取。使用微培養盤讀取器測定660nm之吸光度,根據以下之式,由所獲得之吸光度算出細胞增殖阻礙活性(GI%)。
GIXY%=(1-(AXY-B)/(C-B))×100
此處,GIXY%表示化合物X之濃度為Y μM之時之細胞增殖阻礙活性,AXY表示添加有Y μM之化合物X的孔之平均吸光度,B表示空白
對照孔之吸光度,C表示對照孔之吸光度。
針對各化合物濃度,求出GIXY%,由濃度與細胞增殖阻礙活性將增殖阻礙曲線作圖,將細胞增殖阻礙活性成為50%之濃度設為化合物X之IC50值。將其結果示於表1、2及3。
實施例1化合物係與軸向配位基之組合不同之比較例1~4化合物相比,對所有細胞株均顯示出較高之抗腫瘤效果。由此可明確,關於具有dach結構之鉑(IV)錯合物之軸向配位基之組合,實施例1化合物所具有之羥基及鹵素原子之組合優異。再者,實施例1化合物係顯示出與用作抗癌劑之1-OHP同等之活性,與Pt(dach)Cl2相比為高活性。
雖然活性遜於本發明之化合物,但由比較例5化合物及比較例6化合物之結果可知,即便於將X1,X2轉化為cbdc之情形時,關於具有dach結構之鉑(IV)錯合物之軸向配位基之組合,羥基及氯原子或溴原子之組合優異。進而,由實施例3化合物之結果可明確,即便Y為氯原子、X1、X2共同為氯原子亦顯示出較高之抗腫瘤活性。
試驗例2 實施例1化合物及比較例5化合物於水中之溶解性試驗
稱取實施例1化合物及比較例5化合物,對各者緩慢添加蒸餾水,測定結晶完全溶解之濃度。將其結果示於表4。再者,1-OHP之溶解度係由文獻值所算出之參考值。
其結果可明確,關於作為導入羥基及鹵素原子作為本發明之軸向配位基的鉑(IV)錯合物之實施例1化合物於水中之溶解度,與所對應之鉑(II)錯合物即1-OHP相比上升3倍左右。又,與已知之鉑(IV)錯合物即比較例5化合物相比,溶解度高2倍以上。
試驗例3 實施例1化合物及比較例5化合物於蒸餾水中之溶液穩定性試驗
稱取實施例1化合物及比較例5化合物置於容器中,使用蒸餾水,以成為1mg/ml之方式進行溶解。將各者之水溶液使用0.45μm之注射器式濾器進行過濾,於遮光下,於37℃之水浴中使其振盪,經時地進行取樣,藉由液相高效層析法而測試穩定性。將其結果示於圖1。
試驗之結果為,74小時後之實施例1化合物之殘存率為99.1%,相對於此,已知之鉑(IV)錯合物即比較例5化合物之殘存率為63.7%。可明確,本發明之實施例1化合物係於水溶液中長時間穩定,即便與比較例5化合物相比亦穩定。
試驗例4 實施例1化合物於生理食鹽水中之溶液穩定性試驗
稱取實施例1化合物置於容器中,使用生理食鹽水,以成為1mg/ml之方式進行溶解。將溶解液於遮光下5℃下進行靜置,或不遮光而於37℃之水浴中進行振盪,並藉由高效液相層析法對殘存量進行定量,將殘存率示於表5。
通常,具有氯原子以外之脫離基之鉑錯合物、例如1-OHP由於與生理食鹽水之氯離子引起交換,故而於生理食鹽水中不穩定。然而,如本試驗結果所示,本發明之以二羧酸根作為脫離基之鉑(IV)錯合物即實施例1化合物即便於生理食鹽水中,於遮光下5℃下於24小時後亦幾乎不分解,即便於作為更嚴酷之條件之不遮光而於37℃下進行振盪,殘存率亦為94.4%,即便於生理食鹽水中亦穩定。
由以上之各試驗結果可明確,本發明之鉑(IV)錯合物具有優異之
抗腫瘤活性,並且為溶解性優異,即便製成溶液亦化學上穩定之優異性能。
Claims (4)
- 一種鉑(IV)錯合物,其下述通式(I)表示:
- 如請求項1之鉑(IV)錯合物,其中X1及X2均為氯原子或溴原子,或共同為草酸根。
- 如請求項1或2之鉑(IV)錯合物,其中1,2-環己烷二胺配位基為(1R,2R)-環己烷二胺配位基。
- 一種醫藥,其係以如請求項1至3中任一項之鉑(IV)錯合物作為有效成分。
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TW105119624A TWI703151B (zh) | 2015-06-24 | 2016-06-22 | 新穎鉑(iv)錯合物 |
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US (1) | US10988496B2 (zh) |
EP (1) | EP3315487B1 (zh) |
JP (1) | JP6797116B2 (zh) |
KR (1) | KR20180019536A (zh) |
CN (1) | CN107709286B (zh) |
AU (1) | AU2016284156B2 (zh) |
CA (1) | CA2990369A1 (zh) |
RU (1) | RU2695357C1 (zh) |
TW (1) | TWI703151B (zh) |
WO (1) | WO2016208481A1 (zh) |
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JP6725520B2 (ja) | 2015-09-14 | 2020-07-22 | 日本化薬株式会社 | 6配位白金錯体の高分子結合体 |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SU1186617A1 (ru) | 1980-01-03 | 1985-10-23 | Нидерландзе Сентрале Организати Фор Тегепаст-Натурветеншаппелийк Ондерцоек (Фирма) | Платино ( @ )-диаминовые комплексы,про вл ющие противоопухолевую активность |
NL181434C (nl) | 1980-01-03 | 1987-08-17 | Tno | Platina(iv)-diamine-complexen, alsmede hun bereiding en toepassing. |
JPS617283A (ja) | 1984-06-20 | 1986-01-13 | Shionogi & Co Ltd | 新規白金錯体および抗悪性腫瘍剤 |
JPS62207283A (ja) * | 1986-03-07 | 1987-09-11 | Yoshinori Kitani | 新規な白金錯体 |
DE68918878T2 (de) | 1988-02-02 | 1995-02-23 | Johnson Matthey Inc | Pt(IV) Komplexe. |
US5072011A (en) | 1988-02-02 | 1991-12-10 | Johnson Matthey, Inc. | Pt(IV) complexes |
US5434256A (en) * | 1988-11-22 | 1995-07-18 | Board Of Regents, The University Of Texas System | Diamine platinum complexes as antitumor agents |
US5393909A (en) * | 1988-11-22 | 1995-02-28 | Board Of Regents, The University Of Texas System | Diamine platinum complexes as antitumor agents |
US5041578A (en) | 1988-11-22 | 1991-08-20 | Board Of Regents, The University Of Texas System | Water soluble 1,2-diaminocyclohexane platinum (IV) complexes as antitumor agents |
JPH03279392A (ja) | 1990-03-29 | 1991-12-10 | Sankyo Co Ltd | 4価白金錯体 |
JPH05117385A (ja) | 1991-10-31 | 1993-05-14 | Res Dev Corp Of Japan | ブロツク共重合体の製造法、ブロツク共重合体及び水溶性高分子抗癌剤 |
JP3268913B2 (ja) | 1992-10-27 | 2002-03-25 | 日本化薬株式会社 | 高分子担体 |
WO1996026949A1 (fr) | 1995-02-28 | 1996-09-06 | Debiopharm Sa | Nouveaux complexes de platine (iv), leur procede de production et agents cancerostatiques les contenant |
KR100729015B1 (ko) | 2000-01-04 | 2007-06-14 | 어섹스 팔마큐티칼스 인코포레이티드 | N,o-아미도말로네이트 백금 착화합물 |
US7166733B2 (en) | 2000-01-04 | 2007-01-23 | Access Pharmaceuticals, Inc. | O,O'-Amidomalonate and N,O-Amidomalonate platinum complexes |
CN1681558A (zh) | 2002-09-11 | 2005-10-12 | 得克萨斯州大学系统董事会 | 作为抗肿瘤剂的铂复合物与生物化学调节剂的组合 |
US7495099B2 (en) | 2002-10-31 | 2009-02-24 | Nippon Kayaku Kabushiki Kaisha | High-molecular weight derivatives of camptothecins |
EP1695991B1 (en) | 2003-12-10 | 2010-02-17 | TOUDAI TLO, Ltd. | Coordination complex of diaminocyclohexaneplatinum(ii) with block copolymer containing poly(carboxylic acid) segment and antitumor agent comprising the same |
JP2006248978A (ja) | 2005-03-10 | 2006-09-21 | Mebiopharm Co Ltd | 新規なリポソーム製剤 |
EP2305275B1 (en) | 2008-06-24 | 2013-07-10 | NanoCarrier Co., Ltd. | Liquid composition comprising cisplatin-coordinating compound |
JP2011105792A (ja) | 2009-11-12 | 2011-06-02 | Japan Science & Technology Agency | ブロックコポリマー、ブロックコポリマー−金属錯体複合体、及びそれを用いた中空構造体キャリア |
FR2954321A1 (fr) | 2010-07-15 | 2011-06-24 | Sanofi Aventis | Derives de platine (iv) - couples a un agent de ciblage antitumoral |
EP2754682B1 (en) | 2011-09-11 | 2017-06-07 | Nippon Kayaku Kabushiki Kaisha | Method for manufacturing block copolymer |
US9556214B2 (en) | 2012-12-19 | 2017-01-31 | Placon Therapeutics, Inc. | Compounds, compositions, and methods for the treatment of cancers |
JP6725520B2 (ja) * | 2015-09-14 | 2020-07-22 | 日本化薬株式会社 | 6配位白金錯体の高分子結合体 |
-
2016
- 2016-06-16 RU RU2017140223A patent/RU2695357C1/ru active
- 2016-06-16 US US15/579,754 patent/US10988496B2/en active Active
- 2016-06-16 CA CA2990369A patent/CA2990369A1/en not_active Abandoned
- 2016-06-16 CN CN201680035654.5A patent/CN107709286B/zh not_active Expired - Fee Related
- 2016-06-16 JP JP2017525288A patent/JP6797116B2/ja active Active
- 2016-06-16 AU AU2016284156A patent/AU2016284156B2/en not_active Ceased
- 2016-06-16 KR KR1020177034814A patent/KR20180019536A/ko not_active Application Discontinuation
- 2016-06-16 EP EP16814252.9A patent/EP3315487B1/en active Active
- 2016-06-16 WO PCT/JP2016/067903 patent/WO2016208481A1/ja active Application Filing
- 2016-06-22 TW TW105119624A patent/TWI703151B/zh not_active IP Right Cessation
Also Published As
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CN107709286A (zh) | 2018-02-16 |
TWI703151B (zh) | 2020-09-01 |
CA2990369A1 (en) | 2016-12-29 |
AU2016284156A1 (en) | 2017-12-21 |
JP6797116B2 (ja) | 2020-12-09 |
US20180179239A1 (en) | 2018-06-28 |
RU2695357C1 (ru) | 2019-07-23 |
KR20180019536A (ko) | 2018-02-26 |
WO2016208481A1 (ja) | 2016-12-29 |
US10988496B2 (en) | 2021-04-27 |
EP3315487A1 (en) | 2018-05-02 |
EP3315487B1 (en) | 2020-10-28 |
EP3315487A4 (en) | 2019-03-13 |
AU2016284156B2 (en) | 2020-01-30 |
JPWO2016208481A1 (ja) | 2018-05-17 |
CN107709286B (zh) | 2021-02-19 |
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