WO2014067336A1 - 抗肿瘤二价铂配合物以及该配合物和其配体的制备方法 - Google Patents
抗肿瘤二价铂配合物以及该配合物和其配体的制备方法 Download PDFInfo
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- WO2014067336A1 WO2014067336A1 PCT/CN2013/082513 CN2013082513W WO2014067336A1 WO 2014067336 A1 WO2014067336 A1 WO 2014067336A1 CN 2013082513 W CN2013082513 W CN 2013082513W WO 2014067336 A1 WO2014067336 A1 WO 2014067336A1
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- Prior art keywords
- ketocyclobutane
- complex
- platinum
- dicarboxylic acid
- aqueous solution
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 230000000259 anti-tumor effect Effects 0.000 title claims description 25
- 239000003446 ligand Substances 0.000 title claims description 16
- 238000010668 complexation reaction Methods 0.000 title description 2
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical group N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 7
- MUCRYNWJQNHDJH-OADIDDRXSA-N Ursonic acid Chemical compound C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C MUCRYNWJQNHDJH-OADIDDRXSA-N 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 35
- QTZIWJVUUXVIKM-UHFFFAOYSA-N 3-oxocyclobutane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CC(=O)C1 QTZIWJVUUXVIKM-UHFFFAOYSA-N 0.000 claims description 31
- 239000007864 aqueous solution Substances 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000011734 sodium Substances 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 150000004985 diamines Chemical class 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- -1 silver ions Chemical class 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 6
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052709 silver Inorganic materials 0.000 claims description 5
- 239000004332 silver Substances 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- QRVSDVDFJFKYKA-UHFFFAOYSA-N dipropan-2-yl propanedioate Chemical compound CC(C)OC(=O)CC(=O)OC(C)C QRVSDVDFJFKYKA-UHFFFAOYSA-N 0.000 claims description 3
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- HCKIBPMKPDOKPC-UHFFFAOYSA-L [Ag+2].O=C1CC(C1)(C(=O)[O-])C(=O)[O-] Chemical compound [Ag+2].O=C1CC(C1)(C(=O)[O-])C(=O)[O-] HCKIBPMKPDOKPC-UHFFFAOYSA-L 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 239000001103 potassium chloride Substances 0.000 claims 1
- 235000011164 potassium chloride Nutrition 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 17
- 150000003057 platinum Chemical class 0.000 abstract description 7
- CCQPAEQGAVNNIA-UHFFFAOYSA-N cyclobutane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-N 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 16
- 229960004316 cisplatin Drugs 0.000 description 16
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 16
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 11
- 229960004562 carboplatin Drugs 0.000 description 11
- 229960001756 oxaliplatin Drugs 0.000 description 10
- 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 10
- 239000007787 solid Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- CFQCIHVMOFOCGH-UHFFFAOYSA-N platinum ruthenium Chemical compound [Ru].[Pt] CFQCIHVMOFOCGH-UHFFFAOYSA-N 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 102100028735 Dachshund homolog 1 Human genes 0.000 description 5
- 101000915055 Homo sapiens Dachshund homolog 1 Proteins 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 231100001231 less toxic Toxicity 0.000 description 4
- 229910052707 ruthenium Inorganic materials 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- JKFYKCYQEWQPTM-UHFFFAOYSA-N 2-azaniumyl-2-(4-fluorophenyl)acetate Chemical compound OC(=O)C(N)C1=CC=C(F)C=C1 JKFYKCYQEWQPTM-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- 229910021607 Silver chloride Inorganic materials 0.000 description 2
- 229910021612 Silver iodide Inorganic materials 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229940045105 silver iodide Drugs 0.000 description 2
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 206010023774 Large cell lung cancer Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- RKFCTSKCUGACSD-UHFFFAOYSA-N [Ag].O=C1CC(C1)(C(=O)O)C(=O)O Chemical compound [Ag].O=C1CC(C1)(C(=O)O)C(=O)O RKFCTSKCUGACSD-UHFFFAOYSA-N 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 201000009546 lung large cell carcinoma Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
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- 238000005556 structure-activity relationship Methods 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- 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
- C07F15/006—Palladium compounds
- C07F15/0066—Palladium compounds without a metal-carbon linkage
Definitions
- the present invention relates to a novel platinum complex for treating cancer and a process for the preparation thereof, and more particularly to an antitumor platinum (ruthenium) complex containing a 3-ketocyclobutane-U-dicarboxylate as a leaving group.
- An object of the present invention is to provide an antitumor platinum (ruthenium) complex and a preparation method thereof, and the complex of the present invention is less toxic than cisplatin and oxaliplatin, particularly a complex GSH-
- the toxicity of 5 is also less than that of carboplatin; the antitumor activity is generally higher than that of carboplatin, especially the complex GSH-5, its antitumor activity is comparable to that of cisplatin and oxaliplatin, and it also has good water solubility and certain resistance to overcome sexual characteristics are a potentially effective, low-toxic anti-tumor platinum drug.
- 3-ketocyclobutane-1,1-dicarboxylate is a leaving group ligand of a platinum complex; and the platinum complex is cis-[ 3-ketocyclobutane-1,1-dicarboxylate*diammineplatinum ( ⁇ )], abbreviation: GSH-5, chemical structural formula from formula C1):
- the platinum complex is cis-[3-keto-1,1-cyclobutanedicarboxylate ⁇ trans-1,2-cyclohexanediamine platinum ( ⁇ )], abbreviation: GSH-6, chemical structural formula Equation (2) means:
- the two chiral carbon atoms marked with an * in the trans 1,2-cyclohexanediamine group are in the R configuration or the S configuration.
- antitumor divalent platinum complex represented by the formula (1) and the formula (2), it is prepared by the following method;
- a solution of cis-[dihalo-diamine (or diamine) platinum (ruthenium)] is obtained by reacting potassium tetrahalide with potassium or trans 1,2-cyclohexanediamine in an aqueous solution, and then In the absence of light and nitrogen, in aqueous solution, by method A: removal of the halide of [dihalo-diamine (or diamine) platinum ( ⁇ )] using silver ions, the resulting intermediate and 3-ketone ring Alkali-1,1-dicarboxylic acid alkali metal salt to obtain the target product; or by method B: using 3-ketocyclobutane-U-dicarboxylic acid silver salt and [dihalo-diamine (or diamine) Platinum ( ⁇ )] gives the desired product.
- the alkali metal salt of 3-ketocyclobutane-1,1-dicarboxylate referred to in Process A by one equivalent of 3-ketocyclobutane-1,1-dicarboxylic acid and two equivalents of MOH or MHC0 3 is obtained by reaction in an aqueous solution, or by reacting an equivalent amount of 3-ketocyclobutane-1,1-dicarboxylic acid and M 2 C0 3 in an aqueous solution, wherein M is Na + or K + .
- the silver salt of 3-ketocyclobutane-1,1-dicarboxylate involved in the process consisting of one equivalent of 3-ketocyclobutane-1,1-dicarboxylic acid and two equivalents of silver nitrate in an aqueous solution Medium reaction preparation.
- the 3-ketocyclobutane-1,1-dicarboxylate is a leaving group ligand of the platinum complex, which is prepared by the following reaction scheme:
- the reaction of acetone, methanol and bromine is brominated by condensation to obtain Ia, followed by la and diisopropyl malonate in sodium hydride.
- Ib is obtained by the lower ring-forming reaction, then lb is hydrolyzed in a sodium hydroxide solution to obtain Ic, and Ic is acidified with hydrochloric acid to obtain Id, ie, 3-ketocyclobutane-1, 1-dicarboxylic acid;
- the ligand is 3-ketocyclobutane alkoxy -U- dicarboxylate by one equivalent and two equivalents of MOH Id MHC0 3 or reaction in an aqueous solution, or 2 C0 3 obtained by reaction of equivalent amounts of Id and M in an aqueous solution; wherein M + is Na +, K + .
- the divalent platinum complex of the present invention has good water solubility, particularly the complex GSH-5, which can be used as a conventional lyophilized powder and an injection preparation.
- a series of human tumor cells were studied for anticancer activity in vitro using the complex GSH-5 of the present invention and the complex GSH-6, and related IC 5 .
- the values are shown in Table 1. It can be seen from the data in Table 1 that the inhibitory effect of the complex GSH-5 on different tumor cells is close to that of cisplatin to some extent, and some even better than oxaliplatin, and the anticancer effect is much better than carboplatin.
- the complex GSH-5 also has a significant inhibitory effect on human breast cancer resistant cell MCF-7, and its activity exceeds that of cisplatin.
- the mouse transplanted tumor animal model was used to examine the inhibitory effects of the complex GSH-5 and the complex GSH-6 on the S180 sarcoma and Heps tumors of the animal transplanted tumor.
- the relevant data are shown in Table 2 and Table 3, respectively.
- the results in Table 2 show that compared with the model control group, the samples GSH-5 and GSH-6 significantly inhibited the tumor growth of S 180 and the body weight of the experimental animals (P ⁇ 0.05). In comparison, the former was the latter. Has a better anti-tumor growth effect.
- the results in Table 3 show that compared with the model control group, the sample GSH-5 has a significant inhibitory effect on the tumor growth of Heps and the body weight of the experimental animals (PO.01). In comparison, the sample GSH-5 has a higher GSH-6 than the GSH-6. Better anti-tumor growth.
- the complex of the present invention is less toxic than cisplatin and oxaliplatin, and in particular, the complex GSH-5 is less toxic than carboplatin; the antitumor activity of the complex of the present invention is generally higher than that of carboplatin, especially It is a complex GSH-5 with anti-tumor activity comparable to that of cisplatin and oxaliplatin. It also has good water solubility and certain resistance to drug resistance. It is a potentially effective and low-toxic anti-tumor platinum drug. . detailed description
- the present invention provides two divalent platinum complexes having effective antitumor biological activity and low toxicity, and 3-ketocyclobutane-1,1-dicarboxylate is a leaving group ligand of the two platinum complexes;
- One of the complexes is cis-[3-ketocyclobutane-U-dicarboxylate*diammineplatinum ( ⁇ )] (abbreviation: GSH-5), (1) means:
- Equation (2) means:
- the two chiral carbon atoms (labeled with *) in the trans 1,2-cyclohexanediamine group are in the R configuration or the S configuration.
- the antitumor platinum (ruthenium) complex represented by the formula (1) and the formula (2) of the present invention it is prepared by the following method; firstly, potassium tetrafluoronate and ammonia or trans 1,2-ring The hexamethylene diamine acts in an aqueous solution to obtain a cis-[dihalo-diamine (or diamine) platinum (ruthenium) complex, which is then protected from light and nitrogen in an aqueous solution.
- Method A Use of silver ions
- the halide ion of [dihalo-diamine (or diamine) platinum (ruthenium)] is removed, and the obtained intermediate and the alkali metal salt of 3-ketocyclobutane-1,1-dicarboxylate (sodium salt or potassium salt M)
- the target product is obtained by the use of the desired product; or by the method B: using a 3-ketocyclobutane-U-dicarboxylic acid silver salt and [dihalo-diamine (or diamine) platinum (ruthenium)] to obtain the target product.
- the alkali metal 3-ketocyclobutane-1,1-dicarboxylate referred to in the above Process A can be Na + by one equivalent of 3-ketocyclobutane-U-dicarboxylic acid and two equivalents of MOHCM.
- K + ) or MHC0 3 CM is Na + , K + ) obtained by reaction in aqueous solution, or may be equivalent to 3-ketocyclobutane-1,1-dicarboxylic acid and M 2 C0 3 (M is Na + , K + ) is obtained by reaction in an aqueous solution.
- the 3-ketocyclobutane-1, 1-dicarboxylic acid silver salt referred to in the above Process B consists of one equivalent of 3-ketocyclobutane-1, 1-dicarboxylic acid and two equivalents of silver nitrate in an aqueous solution. Reaction preparation.
- the platinum complex prepared by the method of the present invention determines the molecular structure of the compound by nuclear magnetic resonance spectroscopy and high resolution electrospray ionization mass spectrometry and elemental analysis, and determines the solubility of the compound in water.
- DACH represents the backbone of trans 1,2-cyclohexanediamine, and cyclobutyl represents cyclobutane.
- Elemental analysis data (Molecular formula: C 12 H 18 N 2 0 5 Pt): Theoretical value C 30.97%, H 3.90%, N 6.02%, Pt 41.92%; Measured value C 31.02%, H 3.93%, N 6.03%, Pt 41.87%.
- the solubility of the complex GSH-5 in water was 16 mg/mL, and the solubility of the complex GSH-6 in water was 2 mg/mL.
- the present invention also provides an efficient process for the preparation of 3-ketocyclobutane-1, 1-dicarboxylate as a leaving group ligand, prepared by the following Scheme A:
- Id (3- Ketone cyclobutane-U-dicarboxylic acid); ligand (3-ketocyclobutane-1,1-dicarboxylate) can pass one equivalent of Id and two equivalents of MOH (M is Na + , K + ) Or MHC0 3 (M is Na + , K + ) is obtained by reaction in an aqueous solution, and can also be obtained by reacting an equivalent of Id and M 2 C0 3 CM as Na + , K + ) in an aqueous solution.
- the starting material dihalodiamine (or trans-1,2-cyclohexanediamine) platinum (ruthenium) is prepared by a known method and has been described in the specification.
- the cis-diiododiamine platinum (II) (4.83 g, 10 mmol) was suspended in 400 mL of water under nitrogen, and AgN0 3 C 3.40 g, 20 mmol) in 30 mL of aqueous solution was added, and the mixture was incubated at 40 ° C. The reaction was stirred for 12 hours with light, and silver iodide was removed by filtration. A 40 mL aqueous solution of 3- ketocyclobutane-1,1-dicarboxylic acid (1.58 g, 10 mmol) and NaOH (0.80 g, 20 mmol) or Na 2 CO 3 (1.06 g, 10 mmol) was added to the filtrate.
- the intermediates la and lb were prepared according to literature procedures.
- the intermediate lb 15 g was dissolved in 200 mL of ethanol, and 30 mL of an aqueous solution of NaOH (12 g, 0.3 mol) was added.
- the reaction solution was refluxed for 3 hours, and filtered to give a white solid, which was washed three times with ethanol to give Intermediate Ic.
- Ligands can be obtained in the following three ways:
- 3-ketocyclobutane-1,1-dicarboxylic acid (1.58 g, 10 mmol) was suspended in 100 mL of water in the dark, and added to a solution of AgN0 3 (3.40 g, 20 mmol) in 20 mL of water at room temperature The reaction was stirred for 1-2 hours, filtered, and the white solid crystals were washed with water and dried in vacuo to give 3.41 g.
- the cytotoxic activity test was carried out on the complex of the present invention and the commonly used anti-cancer platinum drug by the MTT method.
- MTT method The cell count in the logarithmic growth phase was inoculated into a 96-well culture plate with about 8000-10000 cells per well. After overnight culture, the cells were administered after adherence to the cells, and the administration group, the positive control group and the negative control group were respectively set.
- the complex to be tested was formulated into a stock solution with a 5% aqueous solution of glucose, and diluted to a series of concentrations using a cell culture medium before use. Three replicate holes are provided for each concentration. After dosing for 48 hours, add 2 ( ⁇ L concentration of 5 mg/mL MTT, incubate at 37 °C for 4 hours, remove the supernatant, add 15 ( ⁇ L of DMSO to dissolve the formazan.
- MDA-MB-231 human gastric adenocarcinoma cell line BGC823, human hepatoma cell line HepG-2, human erythroleukemia cell K562 human acute promyelocytic leukemia cell ⁇ 4, human large cell lung cancer cell NCI-H460, human liver cancer cell SMMC- 7721) tested
- the cytotoxic activities of the complexes GSH-5 and GSH-6 were determined by using cisplatin, oxaliplatin and carboplatin as positive controls. Since the prepared platinum complex has good water solubility, it is determined by using a sample of 5% glucose solution, and the results are shown in Table 1. Table 1. IC 5 of the complex to some human tumor cells. Value ( ⁇ )
- mice inoculate solid tumors according to the transplant tumor research method.
- the rats were weighed 24 hours after inoculation and randomly divided into 7 groups, and 8 rats in each group. 24 hours after inoculation (d the first dose, intravenous administration, once every other day, a total of 4 times, the dosage volume is 0.4ml / 20g.
- d 1Q On the 10th day after inoculation (d 1Q ) Killing tumor
- the rats were weighed and the tumor pieces were weighed and the data were statistically processed (t-test).
- the inhibitory effects of the complexes on mouse transplanted tumor S180 and Heps are shown in Tables 2 and 3, respectively.
- mice 50 clean-type Kunming mice were selected, male and female, weighing 18-22 g, randomly divided into 5 groups, with 10 animals in each group and fasting time of 12 hours.
- the complex GSH-5 and the complex GSH-6 were dissolved in a 5% dextrose solution and divided into 5 doses, and GV was administered to the tail vein of the mice, and each animal received a volume of 0.4 mL/20 g. After 14 days of continuous administration, various symptoms and deaths of the mice were recorded.
- the experimental results were calculated by the Bliss method, and the LD 5 of the mouse Civ) complex GSH-5 and the complex GSH-6 were measured. Values were 150 mg/kg and 100 mg/kg, respectively (95% confidence limit).
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EP13851191.0A EP2913335B1 (en) | 2012-10-29 | 2013-08-29 | Anti-tumor bivalent platinum complex and preparation method for complex and ligand of complex |
ES13851191.0T ES2629356T3 (es) | 2012-10-29 | 2013-08-29 | Complejo de platino bivalente antitumoral y método de preparación para el complejo y ligado del complejo |
JP2015545643A JP6159818B2 (ja) | 2012-10-29 | 2013-08-29 | 抗腫瘍二価白金錯体並びに錯体および錯体のリガンドの製造方法 |
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IL291110A (en) * | 2019-09-05 | 2022-07-01 | Vuab Pharma A S | New iv platinum complexes with significantly increased antitumor activity |
CN113444085B (zh) * | 2020-03-26 | 2022-04-08 | 东南大学 | 一种具有克服顺铂耐药的抗肿瘤化合物及其制备与应用 |
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CN114957340B (zh) * | 2022-05-06 | 2023-12-26 | 湖南科技大学 | 一种诱导铁死亡的双核铱配合物的制备方法及其应用 |
CN114907417B (zh) * | 2022-06-10 | 2024-04-19 | 中国人民解放军空军军医大学 | 一类含有青蒿琥酯及非甾体抗炎药的四价铂三元配合物及其制备方法与应用 |
CN114891044B (zh) * | 2022-06-13 | 2024-04-19 | 南京迈金生物科技有限公司 | 一种具有抗肿瘤活性的四价铂配合物及其制备方法与应用 |
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