CN111718376A - Platinum compound with formula (J) structure, preparation and application thereof - Google Patents
Platinum compound with formula (J) structure, preparation and application thereof Download PDFInfo
- Publication number
- CN111718376A CN111718376A CN201910208959.7A CN201910208959A CN111718376A CN 111718376 A CN111718376 A CN 111718376A CN 201910208959 A CN201910208959 A CN 201910208959A CN 111718376 A CN111718376 A CN 111718376A
- Authority
- CN
- China
- Prior art keywords
- compound
- solution
- reaction
- mobile phase
- vol
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 150000003058 platinum compounds Chemical class 0.000 title claims abstract description 21
- 208000032839 leukemia Diseases 0.000 claims abstract description 13
- 208000008839 Kidney Neoplasms Diseases 0.000 claims abstract description 7
- 206010038389 Renal cancer Diseases 0.000 claims abstract description 7
- 201000010982 kidney cancer Diseases 0.000 claims abstract description 7
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 93
- 239000000243 solution Substances 0.000 claims description 74
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical group [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 42
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 39
- 229940125782 compound 2 Drugs 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 229940126214 compound 3 Drugs 0.000 claims description 33
- 239000011347 resin Substances 0.000 claims description 33
- 229920005989 resin Polymers 0.000 claims description 33
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000002253 acid Substances 0.000 claims description 24
- 239000000047 product Substances 0.000 claims description 20
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 19
- 239000000463 material Substances 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 229940125904 compound 1 Drugs 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 14
- 238000001514 detection method Methods 0.000 claims description 14
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 14
- 229910052700 potassium Inorganic materials 0.000 claims description 14
- 239000011591 potassium Substances 0.000 claims description 14
- 238000010828 elution Methods 0.000 claims description 13
- 150000002500 ions Chemical class 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 230000003247 decreasing effect Effects 0.000 claims description 10
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 229910001516 alkali metal iodide Inorganic materials 0.000 claims description 8
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 5
- 230000003078 antioxidant effect Effects 0.000 claims description 5
- 235000003599 food sweetener Nutrition 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000003765 sweetening agent Substances 0.000 claims description 5
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 4
- 239000000796 flavoring agent Substances 0.000 claims description 4
- 235000013355 food flavoring agent Nutrition 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 229910052697 platinum Inorganic materials 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 235000009518 sodium iodide Nutrition 0.000 claims description 4
- 239000000375 suspending agent Substances 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 239000011159 matrix material Substances 0.000 claims description 3
- 230000002335 preservative effect Effects 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims 1
- 230000002611 ovarian Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 19
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 8
- 201000005202 lung cancer Diseases 0.000 abstract description 8
- 208000020816 lung neoplasm Diseases 0.000 abstract description 8
- 206010033128 Ovarian cancer Diseases 0.000 abstract description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 abstract description 6
- 210000004027 cell Anatomy 0.000 description 48
- 239000000126 substance Substances 0.000 description 36
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 229950008991 lobaplatin Drugs 0.000 description 20
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 15
- 239000008213 purified water Substances 0.000 description 15
- 238000001228 spectrum Methods 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 9
- 239000011550 stock solution Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 238000005259 measurement Methods 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 239000012085 test solution Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 238000012790 confirmation Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000132 electrospray ionisation Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000012224 working solution Substances 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 241000187747 Streptomyces Species 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical group C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- -1 lobaplatin trihydrate Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 238000007747 plating Methods 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 238000010966 qNMR Methods 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 241000894007 species Species 0.000 description 2
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 2
- HKSZLNNOFSGOKW-HMWZOHBLSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@@H]1C[C@H](NC)[C@H](OC)[C@@]4(C)O1 HKSZLNNOFSGOKW-HMWZOHBLSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000012489 system suitability test solution Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- NSENZNPLAVRFMJ-UHFFFAOYSA-N 2,3-dibutylphenol Chemical compound CCCCC1=CC=CC(O)=C1CCCC NSENZNPLAVRFMJ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 101100223811 Caenorhabditis elegans dsc-1 gene Proteins 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000001382 Experimental Melanoma Diseases 0.000 description 1
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960002233 benzalkonium bromide Drugs 0.000 description 1
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229960003720 enoxolone Drugs 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000002098 selective ion monitoring Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003533 single concentration assay Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Images
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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- Food Science & Technology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a platinum compound with a structure shown as a formula (J), and a preparation method and application thereof. The invention provides a platinum compound, which has a structure shown in a formula (J):
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a platinum compound with a structure shown in a formula (J), a preparation method thereof and application thereof in medicines.
Background
Lobaplatin (Lobaplatin, D19466), also known as Lobaplatin, is a third-generation platinum-based antitumor drug following cisplatin and carboplatin, and its chemical name is: cis- [ trans-1, 2-cyclobutanebis (methylamine) -N, N']- [ (2S) -lactic acid-O1, O2]-platinum (II), formula C9H18N2O3Pt has a molecular weight of 397.34 and a chemical structural formula shown in the following formula (a):
lobaplatin has alkylating effect, belongs to alkylating agent (broad sense), and has good antitumor effect, such as inhibiting in vitro AH 135-tumor, B16-melanoma, colon cancer 115, and in vivo mouse P338 leukemia. Lobaplatin is characterized by strong anticancer activity, low toxicity, no accumulative toxicity and renal toxicity and less toxicity to bone marrow, and currently marketed lobaplatin for injection is mainly used for treating breast cancer, small cell lung cancer and chronic myelogenous leukemia.
Disclosure of Invention
In order to ensure the safety, effectiveness and controllable quality of the medicine, the research on related substances and detection methods of the related substances is very important. For the drug, due to the existence of three chiral carbons and related substances generated in the preparation process, confirming the structure of the related substances and finding a suitable detection method for controlling the product quality of the drug become technical problems to be solved urgently in the field.
The invention aims to provide a platinum compound with a structure shown in a formula (J), a preparation method thereof and application of the compound in tumor resistance.
One skilled in the art will recognize that any substance that affects the purity of a drug is collectively referred to as a related substance. Research on related substances is an important part of drug development, and comprises selecting a proper analysis method, accurately distinguishing and determining the content of the related substances, and determining the reasonable limit of the related substances by combining the results of pharmaceutical, toxicological and clinical researches. This study is throughout the entire process of drug development.
Specifically, the present invention is realized by the following technical means.
The invention provides a platinum compound, which has a structure shown as the following formula (J):
the invention provides a preparation method of a platinum compound, wherein a compound shown as a formula (J) is prepared from a compound 4 shown as a structural formula
Preferably, in the reaction for preparing the product by the compound 4, the obtained solution of the compound 3 is adjusted to be alkaline by an acidic regulator, and then is freeze-dried to obtain the final product; preferably, the acidity regulator is selected from one of p-toluenesulfonic acid or methanesulfonic acid, preferably p-toluenesulfonic acid; the concentration of the preferred aqueous solution of p-toluenesulfonic acid is 5 to 15 wt%, preferably 10 wt%; the pH value of the alkalescence is 7-8; preferably, after adjusting to be slightly alkaline, reacting for 15-25 hours at the temperature of 20-30 ℃; preferably, the reaction is carried out at 25 ℃ for 20 hours.
Preferably, for the above preparation method, wherein the compound 4 is prepared from the compound 3 of the following structural formula
Preferably, the solution of the compound 3 and the resin are mixed and stirred, and then the mixture is filtered to obtain a compound 4 solution; preferably, the mixing and stirring temperature of the compound 3 solution and the resin is 25-35 ℃; preferably, the stirring time is 0.5-2 hours; the stirring time is preferably 1 hour, and the stirring temperature is more preferably 30 ℃; more preferably, the resin is a resin that has been treated; preferably, the resin that has been treated is a resin treated with an aqueous solution of sodium hydroxide, preferably having a concentration of 1 to 2mol/L, preferably 1.5 mol/L.
Preferably, in the above preparation method, the compound 3 is prepared from the compound 2 of the following structural formula
Preferably, the compound 2 is added into water and a ketone solvent to obtain a material A, then a silver nitrate solution is added into the material A for reaction, and a solution of a compound 3 is obtained by filtration; preferably, the molar ratio of compound 2 to silver nitrate is 1 (1-2), preferably 1: 1.7; preferably, the reaction temperature is 25-35 ℃; more preferably, the reaction temperature is 30 ℃; preferably, the reaction time is 15 to 20 hours in a dark place; preferably, the reaction time is 18 hours in the absence of light; preferably, the ketone solvent is selected from one of acetone, methyl butanone, methyl ethyl ketone, or methyl isobutyl ketone, and acetone is more preferred.
Preferably, for the above preparation method, the compound 2 is prepared from the compound 1 of the following structural formula:
preferably, in the reaction for preparing compound 2 from compound 1, chloroplatinic acid salt or chloroplatinic acid salt and alkali metal iodide, and hydroxide are reacted to prepare compound 2; preferably, the molar ratio of compound 1 to chloroplatinic acid salt is 1:0.5-2, preferably 1: 0.85;
preferably, the chloroplatinic acid salt is selected from potassium or sodium chloroplatinic acid, preferably potassium chloroplatinic acid;
preferably, the alkali metal iodide is selected from potassium iodide or sodium iodide, preferably potassium iodide;
preferably, the hydroxide is selected from potassium hydroxide or sodium hydroxide, preferably potassium hydroxide.
The preparation method comprises the following steps:
wherein, in the reaction for preparing the compound 2 from the compound 1, chloroplatinic acid salt or chloroplatinic acid salt, alkali metal iodide and hydroxide are reacted to prepare a compound 2; preferably, the chloroplatinic acid salt is selected from potassium or sodium chloroplatinic acid, preferably potassium chloroplatinic acid; preferably, the alkali metal iodide is selected from potassium iodide or sodium iodide, preferably potassium iodide; preferably, the hydroxide is selected from potassium hydroxide or sodium hydroxide, preferably potassium hydroxide;
and/or in the reaction of preparing the compound 3 by the compound 2, adding the compound 2 into water and a ketone solvent to obtain a material A, then adding a silver nitrate solution into the material A for reaction, and filtering to obtain a solution of the compound 3;
and/or in the reaction for preparing the compound 4 by the compound 3, mixing and stirring the solution of the compound 3 and resin, and then filtering to obtain a compound 4 solution;
and/or, in the reaction for preparing the product by the compound 4, the obtained solution of the compound 4 is adjusted to be alkaline by an acidic regulator, and then the final product is obtained by freeze-drying.
Preferably, in the above production method, in the reaction step of producing the compound 2 from the compound 1, the compound 1 and an aqueous solution of potassium hydroxide are mixed to obtain a solution F, an aqueous solution of potassium chloroplatinite and potassium iodide are mixed to obtain a solution E, and the solution F and the solution E are mixed and reacted to obtain the compound 2; preferably, the reaction temperature is 25-35 ℃, preferably 30 ℃; preferably, the reaction time is 1 to 3 hours, preferably 2 hours; preferably, the molar ratio of compound 1 to chloroplatinic acid salt is 1:0.5-2, preferably 1: 0.85;
preferably, in the reaction step of preparing the compound 3 from the compound 2, the molar ratio of the compound 2 to the silver nitrate is 1 (1-2), preferably 1: 1.7; preferably, the reaction temperature is 25-35 ℃; more preferably, the reaction temperature is 30 ℃; preferably, the reaction time is 15 to 20 hours in a dark place; preferably, the reaction time is 18 hours in the absence of light; preferably, the ketone solvent is selected from one of acetone, methyl butanone, methyl ethyl ketone or methyl isobutyl ketone, and acetone is more preferred;
preferably, in the reaction for preparing the compound 4 by the compound 3, the temperature for mixing and stirring the compound 3 solution and the resin is 25-35 ℃; preferably, the stirring time is 0.5-2 hours, preferably the stirring time is 1 hour, and more preferably the stirring temperature is 30 ℃; preferably, the resin is a resin that has been treated; preferably, the resin which has been treated is a resin which has been treated with an aqueous solution of sodium hydroxide, preferably having a concentration of 1 to 2mol/L, more preferably 1.5 mol/L;
preferably, in the reaction for preparing the product by the compound 4, the acidity regulator is selected from one of p-toluenesulfonic acid or methanesulfonic acid, and is preferably p-toluenesulfonic acid; preferably, the concentration of the aqueous solution of p-toluenesulfonic acid is 5 to 15 wt%, preferably 10 wt%; the pH value of the alkalescence is 7-8; preferably, after adjusting to be slightly alkaline, reacting for 15-25 hours at the temperature of 20-30 ℃; preferably, the reaction is carried out at 25 ℃ for 20 hours.
The invention provides a detection method of a platinum compound, which is an HPLC-MS method or an HPLC method; preferably, the HPLC detection conditions of the HPLC-MS method are as follows: octadecylsilane chemically bonded silica is used as a filling agent, 18-22mmol/L ammonium formate is used as a mobile phase A, and methanol: the volume ratio of acetonitrile is 1, (0.8-1.2) is used as a mobile phase B, and gradient elution is carried out; preferably, the mobile phase A is 20mmol/L ammonium formate solution, and the mobile phase B is methanol: the volume ratio of acetonitrile is 1: 1; more preferably, the gradient elution is performed in the following order:
0-3 minutes: 97 vol% mobile phase a: 3 volume% mobile phase B;
3-10 minutes: mobile phase a decreased from 97 vol% to 92 vol%, mobile phase B increased from 3 vol% to 8 vol%;
10-18 minutes: mobile phase a decreased from 92% to 87% by volume and mobile phase B increased from 8% to 13% by volume;
18-25 minutes: mobile phase a decreased from 87 vol% to 10 vol%, mobile phase B increased from 13 vol% to 90 vol%;
25-26 minutes: mobile phase a increased from 10 vol% to 97 vol%, and mobile phase B decreased from 90 vol% to 3 vol%;
26-34 minutes: 97 vol% mobile phase a: 3 volume% mobile phase B;
wherein, each time range of the gradient elution can be increased by 1-2 minutes or the time range of the gradient elution from 3-10 minutes can be decreased by 1-2 minutes;
for example, the time range corresponding to gradient elution may be 0 to 4 minutes (or 0 to 5 minutes), 4 to 11 minutes (or 5 to 12 minutes), 11 to 19 minutes (or 12 to 20 minutes), 19 to 26 minutes (or 20 to 27 minutes), 26 to 27 minutes (or 27 to 28 minutes), 27 to 35 minutes (or 28 to 36 minutes); the time may be 0 to 3 minutes, 3 to 9 minutes (or 3 to 8 minutes), 9 to 17 minutes (or 8 to 16 minutes), 17 to 24 minutes (or 16 to 23 minutes), 24 to 25 minutes (or 23 to 24 minutes), or 25 to 33 minutes (or 24 to 32 minutes).
Preferably, the MS condition in the HPLC-MS is that an electrospray ion source is adopted, and m/z of a detected compound by a positive ion detection method is 326; further preferably, the flow rate is 0.8-1.2ml, preferably 1.0ml per minute; the column temperature is 39-41 deg.C, preferably 40 deg.C.
The invention provides a pharmaceutical composition containing the platinum compound, and the pharmaceutical composition is a pharmaceutical preparation; preferably, the pharmaceutical composition is a pharmaceutical preparation for injection.
Preferably, the pharmaceutical composition comprises an adjuvant, and preferably, the adjuvant is one or more selected from the group consisting of a filler, a disintegrant, a lubricant, a suspending agent, a binder, a sweetener, a flavoring agent, a preservative, an antioxidant, and a matrix; preferably, the auxiliary material is a filler and/or an antioxidant.
The invention provides an application of the platinum compound or the pharmaceutical composition in preparing an anti-tumor medicament.
Preferably, for the above-mentioned use, wherein the tumor is a lung cancer, ovarian cancer, leukemia and/or renal cancer cell; further preferably, the tumor is a leukemia cell.
Preferably, for the above application, the platinum compound or the pharmaceutical composition is applied to the preparation of anti-THP-1 tumor drugs.
To enable formulation in the compositions of the present invention, pharmaceutically acceptable excipients may be added in the preparation of these formulations, such as: fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, antioxidants, bases, and the like. The filler comprises: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc.; the disintegrating agent comprises: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crospolyvinylpyrrolidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, etc.; the lubricant comprises: magnesium stearate, sodium lauryl sulfate, talc, silica, and the like; the suspending agent comprises: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, and the like; the adhesive comprises: starch slurry, polyvinylpyrrolidone, hydroxypropylmethylcellulose, and the like; the sweetener comprises: saccharin sodium, aspartame, sucrose, sodium cyclamate, glycyrrhetinic acid, and the like; the flavoring agent comprises: sweeteners and various essences; the preservative comprises: parabens, benzoic acid, sodium benzoate, sorbic acid and its salts, benzalkonium bromide, chloroacetidine acetate, eucalyptus oil, etc.; the antioxidant includes: sodium sulfite, sodium metabisulfite, dibutyl phenol, sodium bisulfite, sodium thiosulfate, tert-butyl p-hydroxyanisole, thiourea, vitamin c, propyl gallate, alpha-tocopherol, ascorbyl palmitate; the matrix comprises: PEG6000, PEG4000, insect wax, etc. Therefore, it is within the scope of the present invention to add any other substance that contributes to the formation of a stable drug effect to the compound of the present invention.
The invention has the following beneficial effects:
the platinum compound prepared by the invention has good inhibitory activity on lung cancer, ovarian cancer, leukemia and renal cancer cells, and has an anti-tumor effect.
Drawings
FIG. 1-1A is an HPLC chromatogram (215nm) of the compound prepared in example 1-1 in an HPLC-MS structure confirmation assay;
FIG. 1-1B is an HPLC chromatogram (210nm) of the compound prepared in example 1-1 in an HPLC-MS structure confirmation assay;
FIG. 1-2A is an MS spectrum of the compound prepared in example 1-1 at an HPLC-MS structure confirmation detection time of 0.13 min;
FIG. 1-2B is an MS spectrum of the compound prepared in example 1-1, at an HPLC-MS structure confirmation detection time of 0.249 min;
FIG. 2 shows the preparation of the compound obtained in example 1-11An H-NMR spectrum;
FIG. 3 shows the preparation of the compound of example 1-113A C-NMR spectrum;
FIG. 4 is a QNMR spectrum of the compound prepared in example 1-1;
FIG. 5 is a UV spectrum of the compound prepared in example 1-1, wherein the wavelength of peak 1 is 256.5nm, the absorbance is 0.7763, the wavelength of peak 2 is 226.5nm, the absorbance is 0.3026, the wavelength of peak 3 is 218.5nm, the absorbance is 0.2872, the wavelength of peak 4 is 382.0nm, the absorbance is 0.0038, the wavelength of peak 5 is 229.0nm, the absorbance is 0.2932, and the wavelength of peak 6 is 220.5nm, the absorbance is 0.2746;
FIG. 6 is an IR spectrum of the compound prepared in example 1-1;
FIG. 7 is a DSC spectrum of the compound prepared in example 1-1;
FIG. 8 is a typical spectrum of the compound prepared in example 1-1 of example 2;
FIG. 9-1 is a graph showing the inhibitory activity of the compound prepared in example 1-1 of example 3 on lung cancer cell NCI-H460;
FIG. 9-2 is a graph showing the inhibitory activity of the positive control drug on lung cancer cell NCI-H460 in example 3;
FIG. 10-1 is a graph showing the inhibitory activity of the compound prepared in example 1-1 of example 3 on ovarian cancer cells SK-OV-3;
FIG. 10-2 is a graph showing the inhibitory activity of the positive control drug on ovarian cancer cells SK-OV-3 in example 3;
FIG. 11-1 is a graph showing the inhibitory activity of the compound prepared in example 1-1 of example 3 on leukemia cells Jurkat clone 6-1;
FIG. 11-2 is a graph showing the inhibitory activity of the positive control drug on leukemia cells Jurkat Clone E6-1 in example 3;
FIG. 12-1 is a graph showing the inhibitory activity of the compound obtained in example 1-1 in example 3 on THP-1 of leukemia cells;
FIG. 12-2 is a graph showing the inhibitory activity of the positive control drug on THP-1 leukemia cells in example 3;
FIG. 13-1 is a graph showing the inhibitory activity of the compound obtained in example 1-1 in example 3 on SK-NEP-1 renal cancer cells;
FIG. 13-2 is a graph showing the inhibitory activity of the positive control drug on the kidney cancer cell SK-NEP-1 in example 3.
Detailed Description
The invention provides a platinum compound with a structure shown in a formula (J), a preparation method thereof and application thereof in tumor resistance.
Herein, in the present invention, any substance affecting the purity of the drug is collectively referred to as "related substance affecting the quality of lobaplatin" or "related substance affecting the quality", and is simply referred to as "related substance", for example, a peak of related substance affecting the quality of lobaplatin appearing in an HPLC chromatogram peak for detecting the quality of lobaplatin, is simply referred to as "related substance peak"; the "related substance" in the present invention is sometimes an "impurity" known to those skilled in the art to affect the purity of the drug, however, the "related substance" in the present invention is not limited to the category of "impurity" but also includes substances having a certain anticancer activity even higher than that of lobaplatin, which belong to the category of substances related to lobaplatin with respect to the active molecule "lobaplatin", and the principles of their anticancer activity or other positive effects and functions in developing new drugs have not been fully studied.
The chemical substances in the examples are not indicated to be chemical pure grades of conventional reagents, wherein the compound 1 is prepared according to the method disclosed in example 1 of the patent No. CN102093226B and is confirmed by structural identification;
potassium chloroplatinite was purchased from shanghai jieyei chemical company;
potassium iodide was purchased from guangzhou chemical reagent factory for analytical purity.
Preparation of the Compound of example 1-1
The preparation method comprises the following steps:
1) preparation of Compound 2
Compound 1(30.0g,101.9mmol), potassium chloroplatinite (36.0g,86.7mmol), potassium iodide (86.0g,518.1mmol) and potassium hydroxide (24.0g,427.7mmol) were dissolved in 170mL,180mL,87mL and 120mL of purified water, respectively, to give solutions A, B, C and D.
And ii, heating the liquid B to 30 ℃. Stirring and scattering the material A.
And iii, adding the solution C to the solution B, and stirring for 0.5h to obtain a solution E.
And iv, adding the solution D to the solution A, stirring, clarifying the system, and filtering by using a 0.45-micrometer filter membrane to obtain a solution F.
V. add F to E and precipitate a yellow solid, continue stirring at 30 ℃ for 2 hours.
Filter, and wash the filter cake with purified water (100mL × 6) to halogen-free ionic residues. The filter cake was dried by rotary evaporator to give compound 2(35g) as a yellow powder.
2) Preparation of Compound 3
Dispersing compound 2(8.0g,14.2mmol) into purified water (33.6mL) and acetone (4.8mL) to obtain material A, dissolving silver nitrate (4.13g,24.3mmol) in purified water (12.8mL), adding to material A, stirring at 30 ℃ in the dark for 18 hours, filtering, washing the filter cake with water for 6 times (20mL x 3), and combining the filtrates to obtain 110mL of compound 3 solution which is directly used in the next step;
3) preparation of Compound 4
The resin (80g, from Mitsubishi chemical corporation, type DIAION SA10AX) was treated with 1.5mol/L aqueous sodium hydroxide (120mL) three times; 110mL of the solution of Compound 3 and the treated resin (32g) were placed in a three-necked flask and stirred at 30 ℃ for 1 hour; filtration, resin washing with purified water (25mL x 3), and combining the washings and filtrate to give compound 4(185mL) solution for the next step;
4) preparation of the product
Adjusting pH of the solution of the compound 4 to 7-8 with 10 wt% of p-toluenesulfonic acid aqueous solution, stirring at 25 ℃ for 20 hours, freeze-drying to obtain a product, sampling and detecting LCMS,13CNMR,1HNMR and Q NMR.
The structure of the product obtained by the preparation is confirmed
1)HPLC-MS:
The instrument model is Agilent 1200LC & Agilent 6110MSD
HPLC conditions: gradient elution was performed using octadecylsilane bonded silica as a filler (Agilent ZORBAX SB-Aq,2.1 x 50mm, 5 μm), 0.0375 vol% trifluoroacetic acid as mobile phase A, and acetonitrile (+0.01875 vol% trifluoroacetic acid) as mobile phase B according to the following procedure; the detection wavelengths were 210nm and 215nm (DAD detector) and the column temperature was 50 ℃.
TABLE 1 gradient elution conditions
| Time (minutes) | Mobile phase a (% by volume) | Mobile phase B (% by volume) | Flow rate (ml/min) |
| 0.00 | 10 | 90 | 1.2 |
| 1.50 | 10 | 90 | 1.2 |
MS conditions: and (3) detecting by using a single four-level rod tandem mass spectrometer, wherein the ion source is an electrospray ionization (ESI) ion source, a positive ion scanning mode is used, a monitoring mode is full scanning, and the scanning range is 100-1000-.
The result is:
TABLE 2 measurement results
| m/e | Fragment ion peak | Remarks for note |
| 651.2 | [M’+H]+ | Peak of excimer ion of sample |
M' is the molecular weight of Compound J
The detection results are shown in the attached figures 1-1A, 1-1B, 1-2A and 1-2B, and it can be seen that the compound is a platinum-containing organic substance, and the isotopes with high abundance of platinum element have194Pt、195Pt、196Pt, and thus in the LCMS of the sample, [ M' + H appears around 651.2]+The peak is the sample excimer peak, corresponding to Compound J (C)12H28N4O2Pt2) Molecular weight of 650.54, mass spectral information and Compound J (C)12H28N4O2Pt2) The molecular structures are consistent.
2)1H-NMR:
The instrument name: BRUKERBV-400 model NMR spectrometer
Its hydrogen spectrum (1H NMR DMSO 400MHz) and assignments were as follows:
TABLE 3 chemical shifts of hydrogen spectra
| Chemical shift (ppm) | Multiplicity of properties | Number of protons | Attribution of hydrogen |
| 1.60 | s | 4 | 8,8’ |
| 1.91 | s | 4 | 1,1’ |
| 2.15-2.50 | |
8 | 2,2’,7,7’,13 |
| 2.63-2.78 | |
8 | 3,3’,6,6’ |
| 4.95-5.34 | |
8 | 4,4 ', 5, 5' (active hydrogen) |
| 7.15-7.17 | m | 3 | 11,11’ |
| 7.53-7.55 | m | 3 | 10,10’ |
The spectrogram is shown in figure 2, and can be seen that the compound contains 4 active hydrogens and 24 non-active hydrogens, and the hydrogen spectrum data of the sample are matched with the molecular structure of the compound J.
3)13C-NMR:
The instrument name: BRUKERBV-400 model NMR spectrometer
Carbon spectrum (C)13NMR DMSO 400MHz) and assignments were as follows:
TABLE 4 chemical shifts of carbon spectra
| Chemical shift (ppm) | Type of carbon atom | Number of carbon atoms | Attribution of carbon |
| 20.08-20.78 | |
1 | 13 |
| 22.27 | Secondary carbon | 4 | 1,1’,8,8’ |
| 49.35-50.26 | Secondary carbon | 4 | 3,3’,6,6’ |
| 125.46 | |
2 | 10,10’ |
| 130.71 | |
2 | 11,11’ |
| 138.02 | |
1 | 12 |
| 145.09 | |
1 | 9 |
The spectrum is shown in figure 3, and it can be seen that,13there were 1 saturated primary carbon peak, 8 saturated secondary carbon peaks, 4 unsaturated tertiary carbon peaks, and 2 unsaturated quaternary carbon peaks in the C-NMR chart, which substantially coincided with the molecular structure of Compound J shown (where there were 4 saturated tertiary carbon peaks overlapping with the solvent peak).
4)QNMR：
The determination is carried out by adopting BrukeraVANCE NEO 400, the used solvent is DMSO, the determination is carried out by adopting an internal standard method, the internal standard substance is benzyl benzoate (99.8 percent), and the determination results are as follows:
TABLE 5 measurement results
The calculation formula of W% is as follows:
in the formula, WISTDMass (mg) of internal standard;
WSammass of sample (mg);
ASam/AISTDis the area ratio of the sample and the internal standard substance;
MWSAMis the molecular weight of the sample;
MWISTDis the molecular weight of the internal standard;
nISTDand nSamIs the number of protons per functional group;
WISTD% is the mass percentage of the internal standard substance,
the spectrum is shown in FIG. 4, and it can be seen from the above table that the calibration content is 68.2%.
5) Ultraviolet absorption spectrum (UV):
UV-2600Series ultraviolet visible spectrometer; measuring the temperature at room temperature; the measuring range is 190-400 nm; measuring solvent water; the map is shown in figure 5.
As can be seen from FIG. 5, Compound J has a maximum UV absorption at a wavelength of 265.5 nm.
6) Infrared spectrum (IR)
An infrared spectrometer: ALPHA-BRUKER; the measurement conditions were as follows: solid KBr pellets were formed. Measurement range: 4000cm-1～400cm-1The measurement results and analysis were as follows:
TABLE 6 measurement results
The map is shown in figure 6.
7) Optical Rotation (OR)
Polarimeters: anton Paar MCP 500; the measurement conditions were 0.5mol/L (water) and the results were as follows:
table 7 measurement results
8) Differential Scanning Calorimetry (DSC)
Instrument model METTELER DSC 1; the heating rate is 10.0 ℃/min; the temperature range is 40-350 DEG C
The map is shown in figure 7.
As can be seen from FIG. 7, the p-toluenesulfonate salt of Compound J decomposed from 153.28 ℃.
It was confirmed from the above map that compound J of the present invention has the p-toluenesulfonate structure
Preparation of the Compounds of examples 1-2
1) Preparation of Compound 2
Compound 1(30.0g,101.9mmol), potassium chloroplatinite (36.0g,86.7mmol), potassium iodide (86.0g,518.1mmol) and potassium hydroxide (24.0g,427.7mmol) were dissolved in 170mL,180mL,87mL and 120mL of purified water, respectively, to give solutions A, B, C and D.
And ii, heating the liquid B to 30 ℃. Stirring and scattering the material A.
And iii, adding the solution C to the solution B, and stirring for 0.5h to obtain a solution E.
And iv, adding the solution D to the solution A, stirring, clarifying the system, and filtering by using a 0.45-micrometer filter membrane to obtain a solution F.
V. add F to E and precipitate a yellow solid, continue stirring at 25 ℃ for 3 hours.
Filter, and wash the filter cake with purified water (100mL × 6) to halogen-free ionic residues. The filter cake was dried by rotary evaporator to give Compound 2(34.1g) as a yellow powder.
2) Preparation of Compound 3
Dispersing compound 2(8.0g,14.2mmol) into purified water (33.6mL) and acetone (4.8mL) to obtain material A, dissolving silver nitrate (4.13g,24.3mmol) in purified water (12.8mL), adding to material A, stirring at 25 ℃ in the dark for 20 hours, filtering, washing the filter cake with water for 6 times (20mL x 3), and combining the filtrates to obtain 110mL of compound 3 solution which is directly used in the next step;
3) preparation of Compound 4
The resin (80g, same manufacturer and model as in example 1-1) was treated with 1mol/L aqueous sodium hydroxide (120mL) for three times; 110mL of the solution of Compound 3 and the treated resin (32g) were placed in a three-necked flask and stirred at 25 ℃ for 2 hours; filtration, resin washing with purified water (25mL x 3), and combined washings and filtrate gave compound 4(185mL) solution for the next step.
4) Preparation of the product
Adjusting the pH of the solution of the compound 4 to 7-8 by using a 5 wt% p-toluenesulfonic acid aqueous solution, and stirring the solution at 20 ℃ for 25 hours; then freeze-drying to obtain the product, sampling and detecting LCMS,13CNMR,1HNMR and Q NMR.
The compounds of the present invention are identified by structurally carrying out the preparation of the obtained product.
Preparation of the Compounds of examples 1-3
1) Preparation of Compound 2
Compound 1(30.0g,101.9mmol), potassium chloroplatinite (36.0g,86.7mmol), potassium iodide (86.0g,518.1mmol) and potassium hydroxide (24.0g,427.7mmol) were dissolved in 170mL,180mL,87mL and 120mL of purified water, respectively, to give solutions A, B, C and D.
And ii, heating the liquid B to 30 ℃. Stirring and scattering the material A.
And iii, adding the solution C to the solution B, and stirring for 0.5h to obtain a solution E.
And iv, adding the solution D to the solution A, stirring, clarifying the system, and filtering by using a 0.45-micrometer filter membrane to obtain a solution F.
V. add F to E and precipitate a yellow solid, continue stirring at 35 ℃ for 1 h.
Filter, and wash the filter cake with purified water (100mL × 6) to halogen-free ionic residues. The filter cake was dried by rotary evaporator to give Compound 2(33.8g) as a yellow powder.
2) Preparation of Compound 3
Dispersing compound 2(8.0g,14.2mmol) into purified water (33.6mL) and acetone (4.8mL) to obtain material A, dissolving silver nitrate (4.13g,24.3mmol) in purified water (12.8mL), adding to material A, stirring at 35 ℃ in the dark for 15 hours, filtering, washing the filter cake with water for 6 times (20mL x 3), and combining the filtrates to obtain 110mL of compound 2 solution which is directly used for the next step;
3) preparation of Compound 4
The resin (80g, same manufacturer and model as in example 1-1) was treated with 2mol/L aqueous sodium hydroxide (120mL) for three times; 110mL of the solution of Compound 3 and the treated resin (32g) were placed in a three-necked flask and stirred at 35 ℃ for 0.5 hour; filtration, resin washing with purified water (25mL x 3), and combined washings and filtrate gave compound 4(185mL) solution for the next step.
4) Preparation of the product
Adjusting pH of the solution of the compound 4 to 7-8 with 15 wt% of p-toluenesulfonic acid aqueous solution, stirring at 30 ℃ for 15 hours, freeze-drying to obtain a product, sampling and detecting LCMS,13CNMR,1HNMR and Q NMR.
The compounds of the present invention are identified by structurally carrying out the preparation of the obtained product.
Example 2 detection method
Measured according to mass spectrometry (Chinese pharmacopoeia 2015 year version of the general rules of the four parts 0431)
Chromatographic conditions and System suitability test
The instrument model is as follows: agilent 1260+6130MS, packed with octadecylsilane bonded silica gel (waters xselect CSH 4.6 × 150mm, 3.5 μm), mobile phase a of 20mmol/L ammonium formate, methanol: the volume ratio of acetonitrile is 1:1, the mobile phase B is used, and gradient elution is carried out according to the following procedure; the flow rate was 1.0ml per minute and the column temperature was 40 ℃. And (3) detecting by using a single quadrupole tandem mass spectrometer, wherein the ion source is an electrospray ionization (ESI) ion source, a positive ion scanning mode is used, the monitoring mode is selected ion monitoring, the monitored ions are 326, the acquisition time is 13-20 min, and the outlet voltage of a capillary tube is 70V. In the chromatogram of the system suitability test solution, the separation degree of the peak of the compound J from the peak of the adjacent lobaplatin related substance should be not less than 1.5; the system applicability test solution is continuously injected for 6 times, and the relative standard deviation of the compound J peak area is not more than 10.0%.
TABLE 8 gradient elution conditions
Preparation of System suitability test solution/control solution
About 10mg of a lobaplatin related substance J control (the compound prepared in example 1-1) was precisely weighed, placed in a 20mL volumetric flask, ultrasonically dissolved with an appropriate amount of water, diluted to a scale with water, and shaken up to serve as a control stock solution (1); precisely measuring 1ml of the reference product stock solution (1), putting the reference product stock solution into a10 ml volumetric flask, adding water to dilute the reference product stock solution to a scale, and shaking up to obtain a reference product stock solution (2); precisely measuring 1ml of the reference stock solution (2), putting the reference stock solution into a10 ml volumetric flask, adding water to dilute the reference stock solution to a scale, shaking the reference stock solution uniformly to serve as a system applicability solution and a reference solution.
Preparation of test solution
About 10mg of lobaplatin to be tested (a lobaplatin sample prepared by the method disclosed in example 2 of the specification of patent CN 102020679B and confirmed by structure identification, namely the lobaplatin trihydrate is added as lobaplatin to be tested in the example, and the content of the lobaplatin in each example is calculated as lobaplatin anhydride) is precisely weighed, placed in a10 ml volumetric flask, added with water and ultrasonically dissolved and diluted to a scale, and shaken up to be used as a test solution.
Assay method
And (3) respectively taking 20 mu l of the system applicability test solution and the test sample solution, injecting the solutions into a liquid chromatography-mass spectrometer, and recording mass spectrograms for 25 minutes.
A typical spectrum of compound J is shown in FIG. 8.
If the compound J exists in the chromatogram of the test solution, the peak area of the compound J is not larger than that of the compound J of the reference solution.
Example 3: determination of antitumor Activity in vitro (Activity test experiment of Compound J of the present invention)
Reagent and consumable
1. Cell line from the cell bank of Chinese academy of sciences
TABLE 9 cell lines
| Species of species | Cell name |
| Lung cancer cell | NCI-H460 |
| Ovarian cancer cells | SK-OV-3 |
| Leukemia cells | Jurkat Clone E6-1 |
| Leukemia cells | THP-1 |
| Renal cancer cell | SK-NEP-1 |
RPMI medium, chinese excell, cat No.: PM150110
McCoy's 5A medium, chinese Procell, cat # 3: PM150710
4.
Luminescent Cell visual Assay, Promega, usa, cat #: g7572
5.96 well cell culture plates, Corning, cat No.: 3610
Envision, PerkinElmer, USA
FBS, lonera, cat # s: S711-001S
8. Sodium pyruvate, chinese excell, cat #: PB180422
9.β -mercaptoethanol, Gibco, cat No.: 21985
DMSO, Sigma, usa, cat #: d8418
Penicilin & Streptomyces (P/S), China Procell, Cat #: PB180120
12.0.25% pancreatin-EDTA, Chinese Procell, cat #: PB180228
Second, solution and buffer solution
1. Cell growth medium
After the preparation, the mixture is stored at 4 ℃ for later use.
TABLE 10 cells and media thereof
| Cell name | Culture medium |
| NCI-H460 | RPMI-1640+10 vol% FBS +1 vol% P/S |
| SK-OV-3 | McCoy' S5A +10 vol% FBS +1 vol% P/S |
| Jurkat Clone E6-1 | RPMI-1640+10 vol% FBS +1 vol% P/S |
| THP-1 | RPMI-1640+10 vol% FBS +0.05mM β - |
| SK-NEP-1 | McCoy' S5A +15 vol% FBS +1 vol% P/S |
Heat-inactivated serum of Heat-inactivated FBS
And (3) carrying out water bath on the serum at the temperature of 56 ℃ for 30 minutes.
3. Compound treatment:
compound J (3.37g) prepared in example 1-1 was dissolved in DMSO to prepare a 30mM solution, which was stored at-20 ℃ until use. The positive control Staurosporine (Staurosporine), abbreviated as STSP (available from MedChemexpress (MCE) under the trade designation HY-15141), is a natural product originally isolated in 1977 from the bacterium Streptomyces staurosporius.
Thirdly, an experimental method:
(1) reviving cells
The cells to be revived are quickly taken out from the liquid nitrogen tank, melted in a water bath at 37 ℃ and quickly added into the preheated culture medium. Centrifuging for 5 min at 1000 rpm, taking out the tube, discarding supernatant, adding fresh preheated culture medium into the tube, resuspending cells, adding cell suspension into culture dish, and centrifuging at 37 deg.C and 5 vol% CO2And (5) culturing.
(2) Cell passage
Cell passage: adherent cells, when the cells grow to be 80-90% of the culture dish, digesting the cells by using 0.25% pancreatin (prepared by adding 0.25g pancreatin into 100ml pbs solution), then re-suspending the cells by using a new culture medium, and carrying out passage on the cells according to a proper proportion for about 1 passage for 2-3 d. Suspending cells, collecting cell suspension, centrifuging at 800rpm for 5 minutes, removing supernatant, resuspending with fresh culture medium, and passaging according to a proper proportion for 1 time of about 2-3 d.
(3) Preparation of compound working solution concentration
A. Compound single concentration assay
On the day of the experiment, compound J prepared in example 1-1 was diluted to 1mM mother liquor using DMSO and further diluted to 50uM (5X final concentration) working solution with medium, the test concentration of compound was 10 micromolar and the incubation time of compound was 72 hours, according to the assay requirements.
B. Compound IC50Testing
On the day of the experiment, compounds were diluted to 1mM mother liquor as the highest concentration using DMSO and subjected to 2-fold, 3-fold or 5-fold gradient dilutions, followed by further dilutions to 5X final concentration of working solution per concentration point with medium, according to assay requirements.
(4) Cell inoculation and drug treatment
1. 1 day before detection, according to finenessCell growth Rate cells were seeded at varying densities in 96-well cell plates, 80. mu.L of cell suspension per well, 37 ℃ and 5 vol.% CO2Incubate overnight.
The specific plating density of the cells is as follows:
TABLE 11 cell plating Density
| Cell name | Density (cells/well) |
| NCI-H460 | 4000 |
| SK-OV-3 | 2000 |
| Jurkat Clone E6-1 | 10000 |
| THP-1 | 15000 |
| SK-NEP-1 | 3000 |
2. According to the experimental requirements, 20 mul of compound working solution is added into each hole, the temperature is 37 ℃, and the CO content is 5 vol%2Incubate for 72 hours.
3. After the incubation was completed, detection was performed according to the operation requirements of CTG kit (purchased from Promega, Cat. No. G7572, named celltiter-glo) to obtain the corresponding chemiluminescence value, and the cell activity was calculated.
4. Computing
Cell viability ═ additive group RLU value/control group (solvent) RLU value × 100%
(5) The experimental results are as follows:
the inhibitory activity of a single concentration of 10 μ M compound was as follows:
TABLE 12 inhibitory Activity of Compound J
As can be seen from the table above, the compound J has better THP-1 inhibition activity, and the inhibition rate reaches more than 90%.
The dose-response curves measured are shown in figures 9-1 to 13-2, where the concentration is plotted on the abscissa in micromolar and the cell viability is plotted on the ordinate.
IC of the Compound50The values are as follows:
TABLE 13 IC50 for Compound J
| Cell name | Compound IC50 | Control (STSP) |
| NCI-H460 | ＞10μM | 40.35nM/40.41nM |
| SK-OV-3 | 4.44μM | 8.46nM |
| Jurkat Clone E6-1 | 3.23μM | 14.67/11.63/12.12/12.84nM |
| THP-1 | 4.54μM | 73.02/74.45/42.58nM |
| SK-NEP-1 | 2.95μM | 12.09/12.38/11.81/10.72nM |
As can be seen from the activity data, the compound has the largest inhibitory activity on human lung cancer cell strains THP-1, has certain inhibitory activity on other tumor cells, and has smaller inhibitory activity on NCI-H460 of lung cancer cells.
In conclusion, the compound has better inhibitory activity on the cancer cells under the concentration of 10 mu M, particularly has the inhibition rate of more than 90 percent on THP-1, has obvious tumor inhibitory activity, and can be further developed into an anti-cancer medicament for clinical application.
The foregoing is considered as illustrative and not restrictive in character, and that various modifications, equivalents, and improvements made within the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (13)
1. A platinum compound, the structure of which is shown as the following formula (J):
2. the method of preparing a platinum compound according to claim 1, wherein the compound of formula (J) is prepared from compound 4 of formula
Preferably, in the reaction for preparing the product by the compound 4, the obtained solution of the compound 4 is adjusted to be alkaline by an acidic regulator, and then is freeze-dried to obtain the final product; preferably, the acidity regulator is selected from one of p-toluenesulfonic acid or methanesulfonic acid, preferably p-toluenesulfonic acid; preferably, the concentration of the aqueous solution of p-toluenesulfonic acid is 5 to 15 wt%, preferably 10 wt%; the pH value of the alkalescence is 7-8; preferably, after adjusting to be slightly alkaline, reacting for 15-25 hours at the temperature of 20-30 ℃; preferably, the reaction is carried out at 25 ℃ for 20 hours.
3. The preparation method of claim 2, wherein the compound 4 is prepared from the compound 3 with the following structural formula
Preferably, the solution of the compound 3 and the resin are mixed and stirred, and then the mixture is filtered to obtain a compound 4 solution; preferably, the mixing and stirring temperature of the compound 3 solution and the resin is 25-35 ℃; preferably, the stirring time is 0.5-2 hours; the stirring time is preferably 1 hour, and the stirring temperature is more preferably 30 ℃; more preferably, the resin is a resin that has been treated; preferably, the resin that has been treated is a resin treated with an aqueous solution of sodium hydroxide, preferably having a concentration of 1 to 2mol/L, preferably 1.5 mol/L.
4. The preparation method according to claim 3, wherein the compound 3 is prepared from a compound 2 of the following structural formula
Preferably, the compound 2 is added into water and a ketone solvent to obtain a material A, then a silver nitrate solution is added into the material A for reaction, and a solution of a compound 3 is obtained by filtration; preferably, the ketone solvent is selected from one of acetone, methyl butanone, methyl ethyl ketone, or methyl isobutyl ketone, and acetone is more preferred.
5. The method of claim 4, wherein the compound 2 is prepared from the compound 1 of the following formula:
preferably, in the reaction for preparing compound 2 from compound 1, chloroplatinic acid salt or chloroplatinic acid salt and alkali metal iodide, and hydroxide are reacted to prepare compound 2; preferably, the molar ratio of compound 1 to chloroplatinic acid salt is 1:0.5-2, preferably 1: 0.85;
preferably, the chloroplatinic acid salt is selected from potassium or sodium chloroplatinic acid, preferably potassium chloroplatinic acid;
preferably, the alkali metal iodide is selected from potassium iodide or sodium iodide, preferably potassium iodide;
preferably, the hydroxide is selected from potassium hydroxide or sodium hydroxide, preferably potassium hydroxide.
6. The production method according to any one of claims 2 to 5, wherein the steps of the production method are as follows:
wherein, in the reaction for preparing the compound 2 from the compound 1, chloroplatinic acid salt or chloroplatinic acid salt, alkali metal iodide and hydroxide are reacted to prepare a compound 2; preferably, the chloroplatinic acid salt is selected from potassium or sodium chloroplatinic acid, preferably potassium chloroplatinic acid; preferably, the alkali metal iodide is selected from potassium iodide or sodium iodide, preferably potassium iodide; preferably, the hydroxide is selected from potassium hydroxide or sodium hydroxide, preferably potassium hydroxide;
and/or in the reaction of preparing the compound 3 by the compound 2, adding the compound 2 into water and a ketone solvent to obtain a material A, then adding a silver nitrate solution into the material A for reaction, and filtering to obtain a solution of the compound 3;
and/or in the reaction for preparing the compound 4 by the compound 3, mixing and stirring the solution of the compound 3 and resin, and then filtering to obtain a compound 4 solution;
and/or, in the reaction for preparing the product by the compound 4, the obtained solution of the compound 4 is adjusted to be alkaline by an acidic regulator, and then the final product is obtained by freeze-drying.
7. The production method according to claim 6, wherein, in the reaction step of producing the compound 2 from the compound 1, the compound 1 is mixed with an aqueous solution of potassium hydroxide to obtain a solution F, an aqueous solution of potassium chloroplatinite and potassium iodide is mixed to obtain a solution E, and the solution F and the solution E are mixed and reacted to obtain the compound 2; preferably, the reaction temperature is 25-35 ℃, preferably 30 ℃; preferably, the reaction time is 1 to 3 hours, preferably 2 hours; preferably, the molar ratio of compound 1 to chloroplatinic acid salt is 1:0.5-2, preferably 1: 0.85;
preferably, in the reaction step of preparing the compound 3 from the compound 2, the molar ratio of the compound 2 to the silver nitrate is 1 (1-2), preferably 1: 1.7; preferably, the reaction temperature is 25-35 ℃; more preferably, the reaction temperature is 30 ℃; preferably, the reaction time is 15 to 20 hours in a dark place; preferably, the reaction time is 18 hours in the absence of light; preferably, the ketone solvent is selected from one of acetone, methyl butanone, methyl ethyl ketone or methyl isobutyl ketone, and acetone is more preferred;
preferably, in the reaction for preparing the compound 4 by the compound 3, the temperature for mixing and stirring the compound 3 solution and the resin is 25-35 ℃; preferably, the stirring time is 0.5-2 hours; the stirring time is preferably 1 hour, and the stirring temperature is more preferably 30 ℃; more preferably, the resin is a resin that has been treated; preferably, the resin that has been treated is a resin treated with an aqueous solution of sodium hydroxide, preferably having a concentration of 1 to 2mol/L, preferably 1.5 mol/L;
preferably, in the reaction for preparing the product by the compound 4, the acidity regulator is selected from one of p-toluenesulfonic acid or methanesulfonic acid, and is preferably p-toluenesulfonic acid; the concentration of the preferred aqueous solution of p-toluenesulfonic acid is 5 to 15 wt%, preferably 10 wt%; the pH value of the alkalescence is 7-8; preferably, after adjusting to be slightly alkaline, reacting for 15-25 hours at the temperature of 20-30 ℃; preferably, the reaction is carried out at 25 ℃ for 20 hours.
8. A method for detecting a platinum compound according to claim 1, wherein the method is an HPLC-MS method or an HPLC method; preferably, the HPLC detection conditions of the HPLC-MS method are as follows: octadecylsilane chemically bonded silica is used as a filling agent, 18-22mmol/L ammonium formate is used as a mobile phase A, and methanol: the volume ratio of acetonitrile is 1, (0.8-1.2) is used as a mobile phase B, and gradient elution is carried out; preferably, the mobile phase A is 20mmol/L ammonium formate solution, and the mobile phase B is methanol: the volume ratio of acetonitrile is 1: 1; more preferably, the gradient elution is performed in the following order:
0-3 minutes: 97 vol% mobile phase a: 3 volume% mobile phase B;
3-10 minutes: mobile phase a decreased from 97 vol% to 92 vol%, mobile phase B increased from 3 vol% to 8 vol%;
10-18 minutes: mobile phase a decreased from 92% to 87% by volume and mobile phase B increased from 8% to 13% by volume;
18-25 minutes: mobile phase a decreased from 87 vol% to 10 vol%, mobile phase B increased from 13 vol% to 90 vol%;
25-26 minutes: mobile phase a increased from 10 vol% to 97 vol%, and mobile phase B decreased from 90 vol% to 3 vol%;
26-34 minutes: 97 vol% mobile phase a: 3 volume% mobile phase B;
wherein, the range of each section of time of the gradient elution can be increased by 1-2 minutes or the range of the gradient elution time from 3-10 minutes can be decreased by 1-2 minutes;
preferably, the MS condition in the HPLC-MS is that an electrospray ion source is adopted, and m/z of a detected compound by a positive ion detection method is 326; further preferably, the flow rate is 0.8-1.2ml, preferably 1.0ml per minute; the column temperature is 39-41 deg.C, preferably 40 deg.C.
9. A pharmaceutical composition comprising the platinum-based compound of claim 1, wherein the pharmaceutical composition is a pharmaceutical formulation; preferably, the pharmaceutical composition is a pharmaceutical preparation for injection.
10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical preparation comprises an adjuvant, preferably, the adjuvant is selected from one or more of a filler, a disintegrant, a lubricant, a suspending agent, a binder, a sweetener, a flavoring agent, a preservative, an antioxidant, and a matrix; preferably, the auxiliary material is a filler and/or an antioxidant.
11. Use of the platinum compound according to claim 1 or the pharmaceutical composition according to claim 9 or 10 for the preparation of an anti-tumor medicament.
12. The use according to claim 11, wherein the tumor is a lung, ovarian, leukemia and/or renal cancer cell; preferably, the tumor is a leukemia cell.
13. Use according to claim 11, wherein the platinum compound or the pharmaceutical composition is used for preparing an anti-THP-1 tumour medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910208959.7A CN111718376B (en) | 2019-03-19 | 2019-03-19 | Platinum compound with structure of formula (J), preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910208959.7A CN111718376B (en) | 2019-03-19 | 2019-03-19 | Platinum compound with structure of formula (J), preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111718376A true CN111718376A (en) | 2020-09-29 |
| CN111718376B CN111718376B (en) | 2023-11-14 |
Family
ID=72562956
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910208959.7A Active CN111718376B (en) | 2019-03-19 | 2019-03-19 | Platinum compound with structure of formula (J), preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111718376B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4248840A (en) * | 1979-03-07 | 1981-02-03 | Engelhard Minerals And Chemicals Corporation | Cis-diammineplatinum(II) orthophosphate complexes |
| CN101918379A (en) * | 2008-01-16 | 2010-12-15 | 天真堂制药株式会社 | Platinum complex compound and utilization of the same |
| CN102020679A (en) * | 2010-11-24 | 2011-04-20 | 贵州益佰制药股份有限公司 | Method for preparing lobaplatin trihydrate by usingoxalate |
-
2019
- 2019-03-19 CN CN201910208959.7A patent/CN111718376B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4248840A (en) * | 1979-03-07 | 1981-02-03 | Engelhard Minerals And Chemicals Corporation | Cis-diammineplatinum(II) orthophosphate complexes |
| CN101918379A (en) * | 2008-01-16 | 2010-12-15 | 天真堂制药株式会社 | Platinum complex compound and utilization of the same |
| CN102020679A (en) * | 2010-11-24 | 2011-04-20 | 贵州益佰制药股份有限公司 | Method for preparing lobaplatin trihydrate by usingoxalate |
Non-Patent Citations (2)
| Title |
|---|
| FERNANDE D. ROCHON等: "Synthesis and structure of dinuclear complexes of platinum(IV) having cis-diamine geometry", 《INORGANICA CHIMICA ACTA》 * |
| PERITZ ADAM等: "Antitumor and DNA-binding properties of a group of oligomeric complexes of platinum(II) and platinum(IV)", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111718376B (en) | 2023-11-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3647312B1 (en) | Crystal form of deuterated azd9291, preparation method therefor, and use thereof | |
| US12103939B2 (en) | Solid pharmaceutical gold-based composition | |
| Huang et al. | Evaluation of meisoindigo, an indirubin derivative: in vitro antileukemic activity and in vivo pharmacokinetics | |
| Kozsup et al. | Synthesis, characterization and albumin binding capabilities of quinizarin containing ternary cobalt (III) complexes | |
| EP3159349A1 (en) | Lobaplatin crystal, preparation method and pharmaceutical application | |
| EP4206201A1 (en) | Crystal form of azetidine-substituted compound | |
| CN111721841B (en) | Detection of lobaplatin-related substances | |
| CN111718376B (en) | Platinum compound with structure of formula (J), preparation and application thereof | |
| US6319956B1 (en) | Linear polyamine compounds and polyamine based anti-tumor agents | |
| CN111718373A (en) | Platinum compound with structure of formula (I), preparation and application thereof | |
| Wang et al. | Synthesis, characterization and anti-ovarian cancer activities of novel biphenyl-NHC-gold (I) complexes | |
| CN111718377A (en) | Platinum substance with structural formulas H1 and H2, preparation and application thereof | |
| CN111721842B (en) | Method for detecting related substances in lobaplatin | |
| Maggio et al. | Synthesis and antiproliferative activity of a natural like glycoconjugate polycyclic compound | |
| CN111721840B (en) | Detection of related substances in lobaplatin | |
| CN111718375A (en) | Platinum substance with G1 and G2 structures and preparation method and application thereof | |
| CN118561815A (en) | Crystal of trifluoroethyl substituted indole aniline pyrimidine compound and salt thereof | |
| CN111718378B (en) | Platinum compound with structure of formula (K), preparation and detection method thereof | |
| CN111718379A (en) | Platinum substance with structures of L1 and L2 and preparation method and application thereof | |
| US20110077230A1 (en) | Copper organocomplexes, use thereof as antitumor means and for protecting healthy tissue from ionizing radiation | |
| Gialelis et al. | Inhibition of mitochondrial metabolism by (−)-jerantinine A: synthesis and biological studies in triple-negative breast cancer cells | |
| Atienza et al. | In silico evaluation of the inhibitory property of Holothuria scabra (sea cucumber) with the catalytic domain of matrix metalloproteinase-1 for collagen degradation via interaction of triterpenoid saponins | |
| Pham | New prodrugs of the natural product myxin as new potential drugs against acute myeloid leukemia (AML) | |
| Guerrero | Investigation of the Cellular Uptake and Cytotoxicity of Ruthenium (II) Polypyridyl Complexes as a Function of Lipophilicity | |
| CN114839291A (en) | Method for detecting multiple tyrosine kinase inhibitor medicines |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |