CN105254679B - Single 6- (azacyclo- substitution) anthraquinone platinous chloride complex and its preparation method and application - Google Patents
Single 6- (azacyclo- substitution) anthraquinone platinous chloride complex and its preparation method and application Download PDFInfo
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- CN105254679B CN105254679B CN201510759687.1A CN201510759687A CN105254679B CN 105254679 B CN105254679 B CN 105254679B CN 201510759687 A CN201510759687 A CN 201510759687A CN 105254679 B CN105254679 B CN 105254679B
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- anthraquinone
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- substitution
- azacyclo
- milliliters
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- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000006467 substitution reaction Methods 0.000 title claims abstract description 17
- -1 anthraquinone platinous chloride Chemical class 0.000 title claims description 18
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 2
- 150000004056 anthraquinones Chemical class 0.000 abstract description 13
- CLSUSRZJUQMOHH-UHFFFAOYSA-L platinum dichloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 abstract description 13
- 150000001875 compounds Chemical class 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 12
- 230000000259 anti-tumor effect Effects 0.000 abstract description 11
- 208000032839 leukemia Diseases 0.000 abstract description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 4
- 201000007270 liver cancer Diseases 0.000 abstract description 4
- 208000014018 liver neoplasm Diseases 0.000 abstract description 4
- 201000005202 lung cancer Diseases 0.000 abstract description 4
- 208000020816 lung neoplasm Diseases 0.000 abstract description 4
- 206010009944 Colon cancer Diseases 0.000 abstract description 3
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 3
- 239000003446 ligand Substances 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 229960001156 mitoxantrone Drugs 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 7
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 7
- 235000002597 Solanum melongena Nutrition 0.000 description 7
- 244000061458 Solanum melongena Species 0.000 description 7
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 150000003929 3-aminopyridines Chemical class 0.000 description 5
- PNWSHHILERSSLF-UHFFFAOYSA-N 4-methylbenzene-1,3-dicarboxylic acid Chemical class CC1=CC=C(C(O)=O)C=C1C(O)=O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 235000015097 nutrients Nutrition 0.000 description 5
- 235000011164 potassium chloride Nutrition 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 230000000118 anti-neoplastic effect Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000003536 tetrazoles Chemical class 0.000 description 4
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 229940009456 adriamycin Drugs 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 2
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 2
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001335 aliphatic alkanes Chemical group 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 150000003057 platinum Chemical class 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000003809 water extraction Methods 0.000 description 2
- 150000005208 1,4-dihydroxybenzenes Chemical class 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- JNETYVLEGPSOFY-UHFFFAOYSA-N 3-bromopyrrolidine-2,5-dione Chemical class BrC1CC(=O)NC1=O JNETYVLEGPSOFY-UHFFFAOYSA-N 0.000 description 1
- RZVHIXYEVGDQDX-UHFFFAOYSA-N 9,10-anthraquinone Chemical group C1=CC=C2C(=O)C3=CC=CC=C3C(=O)C2=C1 RZVHIXYEVGDQDX-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 206010051779 Bone marrow toxicity Diseases 0.000 description 1
- 0 C*C(*=***)N* Chemical compound C*C(*=***)N* 0.000 description 1
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 1
- GVUITOGHOXALHQ-UHFFFAOYSA-N CCCOC(C1C(c2cc(C)ccc22)=O)C=CC(OCOC)=C1C2=O Chemical compound CCCOC(C1C(c2cc(C)ccc22)=O)C=CC(OCOC)=C1C2=O GVUITOGHOXALHQ-UHFFFAOYSA-N 0.000 description 1
- MZPWYUCWLINFBI-UHFFFAOYSA-N COClC Chemical compound COClC MZPWYUCWLINFBI-UHFFFAOYSA-N 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical class [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 description 1
- FWYSEXBOCFRQRG-UHFFFAOYSA-L [Pt](Cl)Cl.C1=CC=CC=2C(C3=CC=CC=C3C(C12)=O)=O Chemical class [Pt](Cl)Cl.C1=CC=CC=2C(C3=CC=CC=C3C(C12)=O)=O FWYSEXBOCFRQRG-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 125000003712 glycosamine group Chemical group 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B1/00—Dyes with anthracene nucleus not condensed with any other ring
- C09B1/50—Amino-hydroxy-anthraquinones; Ethers and esters thereof
- C09B1/51—N-substituted amino-hydroxy anthraquinone
- C09B1/515—N-alkyl, N-aralkyl or N-cycloalkyl derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B1/00—Dyes with anthracene nucleus not condensed with any other ring
- C09B1/02—Hydroxy-anthraquinones; Ethers or esters thereof
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B1/00—Dyes with anthracene nucleus not condensed with any other ring
- C09B1/02—Hydroxy-anthraquinones; Ethers or esters thereof
- C09B1/06—Preparation from starting materials already containing the anthracene nucleus
- C09B1/14—Dyes containing ether groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses single 6 (azacyclo- substitution) anthraquinone ligand platinous chloride complexs and its preparation method and application.Single 6 (azacyclo- substitution) anthraquinone ligand platinous chloride complexs of the present invention have the structure of general formula II, the compound that the present invention obtains, with more preferable antitumor activity and security, it is to have very much application value to treat lung cancer, liver cancer, leukaemia, colon cancer, oophoroma in field of medicaments.
Description
The application is the applying date on November 19th, 2013, Application No. 201310589727.3, entitled《6-
(azacyclo- substitution) anthraquinone platinous chloride complex and its preparation method and application》Divisional application.
Technical field
The invention belongs to field of medicaments, more particularly to suppress growth of tumour cell, there is the 6- (azacyclo-s of antitumous effect
Substitution) anthraquinone platinous chloride complex and its preparation method and application.
Background technology
Anthraquinone analog compound is the broad-spectrum anti-cancer drug to grow up the 1970s, wherein adriamycin (ADR), soft
Erythromycin (DNR) and mitoxantrone (IDA) etc. represent medicine for it, to solid tumor and acute non-lymphocytics such as treatment breast cancer
Leukaemia has good result, is still the common antitumor drug of in the market so far.Wherein mitoxantrone active anticancer is adriamycin
5 times, it is relatively low to cardiac toxic and since it is without amino sugar structure, to non Hodgkin's disaese lymthoma, leukaemia, late period breast
The oncotherapy effect such as gland cancer is preferable.Its mechanism of action is DNA embedded type antitumor drugs, and antitumor activity mostlys come from it
Planar structure, this planar structure can be embedded between DNA base pair, crack DNA double chain, answered from prevention DNA is made
System, reaches antitumor purpose.Platinum series antineoplastic medicament is similar to Anthraquinones, mainly by being formed on DNA chain in chain
Crosslinking, interchain linkage, form DDP-DNA compounds, to disturb DNA replication dna function, or are combined to come with nucleoprotein and plasmosin
Realize antineoplastic action, antitumaous effect belongs to more by force cell cycle nonspecific agent (CCNSA).Different platinum-like compounds indication, toxicity
Reaction has very big difference, and toxicity spectrum is different, with the rare cross resistance of non-platinum-containing anticancer drug, is easy to clinical and joins with other drugs
Medicine is shared, main representative medicine there are the platinum series antineoplastic medicaments such as cis-platinum, carboplatin, oxaliplatin.
But Anthraquinones and platinum-like compounds as antitumor drug in itself also there are many shortcoming and defect, toxicity is big,
Such as bone marrow toxicity, renal toxicity, cardiac toxic.Targeting is poor, and bioactivity is single etc..
The content of the invention
It is more broader with more preferable active anticancer, security and therapeutic window than mitoxantrone the object of the present invention is to provide one kind
6- (azacyclo- substitution) anthraquinone platinous chloride series antineoplastic medicament.
It is a further object to provide the synthetic method of 6- (azacyclo- substitution) anthraquinone dichloride platinum complexes.
The present invention provides a kind of double 6- (azacyclo- substitution) anthraquinone platinous chloride complex with general formula [I] structure.
Wherein, A is selected from the chain alkane structure of 1~6 carbon containing imido grpup or sulfydryl or ether or methylene.It is excellent
Choosing, A is methylene or methylene sulfydryl.
Wherein, B is selected from the substituent containing aromatic aza ring structure, and the substituent of the aromatic aza ring structure is
Triazol radical, tetrazole base, imidazole radicals, pyrazolyl, benzimidazolyl, indyl, indazolyl, pyridine radicals, pyrazinyl or pyrimidine
Base, each group optionally can be by 1,2 or 3 R1Substituted, the R1It is independently selected from and amino, halogen, C1-6Alkyl, C1-6Hydroxyl
Alkyl, C1-6Haloalkyl.Preferably, B is tetrazole base or pyridine radicals or imidazole radicals.
Present invention also offers a kind of single 6- (azacyclo- substitution) anthraquinone platinous chloride cooperation with general formula [II] structure
Thing.
Wherein, A is selected from the chain alkane structure of 1~6 carbon containing imido grpup or sulfydryl or ether or methylene.It is excellent
Choosing, A is imido grpup.
Wherein, B is selected from the substituent containing aromatic aza ring structure.The substitution containing aromatic aza ring structure
Base be triazol radical, tetrazole base, imidazole radicals, pyrazolyl, benzimidazolyl, indyl, indazolyl, pyridine radicals, pyrazinyl or
Pyrimidine radicals, each group optionally can be by 1,2 or 3 R2Substituted, the R2It is independently selected from and amino, halogen, C1-6Alkyl,
C1-6Hydroxyalkyl, C1-6Haloalkyl.Preferably, B is imidazole radicals.
Double 6- (azacyclo- substitution) anthraquinone platinous chloride complexs provided by the present invention and list 6- (azacyclo- substitution) anthracene
In quinone platinous chloride complex, azepine ring substituents form coordinate bond with nitrogen-atoms and platinum.
Above-mentioned any compound or its pharmaceutically acceptable salt or prodrug, are preparing the medicine of anti-tumor disease
In application.The application in the medicine of anti-tumor disease is prepared, tumour include：Lung cancer, liver cancer, the carcinoma of the rectum, white blood
Disease, oophoroma, melanoma etc..
The beneficial effects of the invention are as follows：It has been investigated that when the anthraquinone ring parent nucleus for retaining mitoxantrone, in its 2 companies
Azepine ring substituents are connect, and a series of 6- (azacyclo- substitution) the anthraquinone dichloro being bonded by coordinate bond with platinum-like compounds
Change platinum compounds to lung cancer (H-522), liver cancer (SMMC-7721), leukaemia (K-562), breast cancer (T-47D), colon cancer
(HCC-2998), oophoroma (IGROV1) etc. has preferable antitumor activity.Antitumoral compounds 6- (the nitrogen that the present invention obtains
Heterocyclic substituted) anthraquinone platinous chloride complex, there is more preferable antitumor activity and security, in field of medicaments treat lung cancer,
Liver cancer, leukaemia, colon cancer, oophoroma are that have very much application value.
Embodiment
Embodiment is enumerated below, is to be described in further detail the present invention, but the present invention is from these embodiments
Limitation.The exemplary of the present invention is described more fully below.However, these embodiments are only for illustration purpose, not
It is intended to the scope that limitation is invented.
Embodiment 1：Double [6- tetrazole methyl isophthalic acids, 4- dihydroxy)-anthraquinone] platinous chloride complex (compound 1)
1st, 6- methyl isophthalic acids, the synthesis of 4- dihydroxy anthraquinones
Under nitrogen protective condition, in 37.1 grams of (0.28 mole) alchlors and 7.25 grams of (0.12 mole) sodium chloride heat
5.00 grams of (31 mMs) 4- methyl nadic anhydrides, 3.74 grams of (34 mMs) hydroquinones and 15.0 are added in mixture
Gram (0.11 mole) alchlor.Mixture stirred at 220 DEG C 2 it is small when after, be cooled to 25 DEG C, be subsequently poured into 300 milliliters of ice
In water, it is acidified with 12N hydrochloric acid, filters the solid precipitation of precipitation, be washed with water, product 6- methyl isophthalic acids, 4- bis- are obtained after vacuum drying
6.28 grams of (yields of hydroxy-anthraquione：80%).
MS:255m/z(M+H).1H-NMR(DMSO-d6):δ 12.94 (s, 1H), 12.90 (s, 1H), 8.22 (d, J=8Hz,
1H), 8.12 (s, 1H), 7.63 (d, J=8Hz, 1H), 7.29 (s, 2H), 2.55 (s, 3H)；
2nd, 6- methyl isophthalic acids, the synthesis of 4- bis- (methoxy methyl ether base)-anthraquinone
Under 0 DEG C of nitrogen protective condition, toward 100 milliliters of tetrahydrofurans of dry sodium hydride (4.32 grams, 0.18 mole)
It is slowly added dropwise 6- methyl isophthalic acids in suspension, 200 milliliters of tetrahydrofuran solutions of 4- dihydroxy anthraquinones (20.5 grams, 0.08 mole),
Reaction solution be stirred at room temperature 2 it is small when after, be slowly added to continue stirring 2 after adding methoxyl methyl chlorine (12.8 grams, 0.16 mole)
Hour, reaction mixture is concentrated under reduced pressure and uses the sodium hydrate aqueous solution extraction of ether, 0.1M, separates anhydrous slufuric acid after ether phase
Sodium is dried, and product column chromatography for separation obtains 24.34 grams of product, yield 88.6%.
MS:343m/z(M+H).
1H-NMR(DMSO-d6):δ 8.11 (d, J=8.2Hz, 1H), 8.05 (s, 1H), 7.65 (d, J=8.2Hz, 1H),
7.31(s,2H),6.05(s,4H),3.66(s,6H),2.51(s,3H)；
3rd, the synthesis of 6- bromomethyls-Isosorbide-5-Nitrae-two (methoxy methyl ether base)-anthraquinone
12.38 grams of (36 mMs) 6- methyl isophthalic acids, 4- bis- (methoxy methyl ether base)-anthraquinone are added in 500 milliliters of eggplant type bottles
With 6.1 grams of (34 mMs) bromo-succinimides, when 300 milliliters of carbon tetrachloride back flow reactions 21 are small, concentration of reaction solution, acetic acid
Ethyl ester, water extraction, separate column chromatography for separation after ethyl acetate phase, obtain product 6.74 grams (yields 47%).
MS:421m/z(M+H).
1H-NMR(DMSO-d6):δ 8.13 (d, J=8.2Hz, 1H), 8.07 (s, 1H), 7.66 (d, J=8.2Hz, 1H),
7.28(s,2H),6.15(s,4H),4.46(s,2H),3.65(s,6H)；
4th, the synthesis of 6- second cyano group-Isosorbide-5-Nitrae-two (methoxy methyl ether base)-anthraquinone
In 500 milliliters of eggplant type bottles, under nitrogen protection, 6- bromomethyls-Isosorbide-5-Nitrae-two (methoxy methyl ether base)-anthraquinone 5.06 is added
Gram (12 mMs), 0.59 gram of Cymag (12 mMs), when stirring reaction 4 is small at 100 milliliters, 50 DEG C of acetonitrile solvent after, will
Solution is spin-dried for, and 100 milliliters of ethyl acetate, 100 milliliters of water extractions, are concentrated under reduced pressure after separating ethyl acetate phase, crude product post separation
Obtain 4.03 grams of product.(yield 91%).
MS:368m/z(M+H).
1H-NMR(DMSO-d6):δ 8.17 (d, J=8.2Hz, 1H), 8.10 (s, 1H), 7.76 (d, J=8.2Hz, 1H),
7.38(s,2H),6.23(s,4H),4.36(s,2H),3.67(s,6H)；
5th, 6- tetrazoles methyl isophthalic acid, the synthesis of 4- bis- (methoxy methyl ether base)-anthraquinone
6- second cyano group-Isosorbide-5-Nitrae-two (methoxy methyl ether the base)-anthracene of 2.21 grams (6 mMs) is added in 100 milliliters of eggplant type bottles
Quinone, 50 milliliters of dry n,N-Dimethylformamide, 2.34 grams of (36 mMs) sodium azide, 2 grams of (38 mMs) ammonium chlorides, are mixed
When stirring 2.5 is small at 120 DEG C of compound, poured into after being cooled to room temperature in 100 milliliters of frozen water, 100 milliliters of ethyl acetate of addition, 2 grams
Sodium nitrite eliminates remaining sodium azide, and the acidifying of 2N dilute hydrochloric acid, then stirs 30 minutes, separate ethyl acetate phase, subtract at room temperature
Pressure concentration column chromatography for separation obtains 2.15 grams of product, yield 87%.
MS:411m/z(M+H).
1H-NMR(DMSO-d6):δ 8.22 (d, J=8.0Hz, 1H), 8.15 (s, 1H), 7.86 (d, J=8.2Hz, 1H),
7.32(s,2H),6.33(s,4H),5.08(br,1H),4.15(s,2H),3.54(s,6H)；
6th, the synthesis of double [6- tetrazole methyl isophthalic acids, 4- dihydroxy)-anthraquinone] platinous chloride complexs (compound 1)
(0.208 gram, 1 mM) Platinous Potassium Chloride 30 milliliters of water/hydrochloric acid (4M, 15:1) in solution, 6- tetra- is added
Nitrogen azoles methyl isophthalic acid, 4- bis- (methoxy methyl ether base) 0.82 gram of-anthraquinone (2 mMs), mixture be refluxed 6 it is small when after at room temperature after
When continuous stirring 8 is small.Filtering separates out solid, is washed with water, methanol, ether, is dried in vacuo, obtains 0.89 gram of (yield of product
98.0%).
1H-NMR(DMSO-d6):δ 13.11 (s, 1H), 12.97 (s, 1H), 8.26 (d, J=8.0Hz, 1H), 8.16 (s,
1H), 7.64 (d, J=8.0Hz, 1H), 7.27 (s, 2H), 4.11 (s, 2H)；
Elemental analysis:(C32H18Cl2N8O8Pt) calculated value：C,42.30；H,2.00；Measured value:C,42.28；H,2.02.
Embodiment 2：Double 6- [(3- aminopyridines) methyl]-Isosorbide-5-Nitraes-dihydroxy anthraquinone platinous chloride complex (compound 2)
1st, the synthesis of 6- [(3- aminopyridines) methyl]-Isosorbide-5-Nitrae-two (methoxy methyl ether base) anthraquinone
Under nitrogen protection, 6- bromomethyls-Isosorbide-5-Nitrae-two (methoxy methyl ether base)-anthraquinone 5.06 is added in 500 milliliters of eggplant type bottles
Gram (12 mMs), 1.32 grams of 3- aminopyridines (12 mMs), 3.31 grams of potassium carbonate (24 mMs), the milli of acetone solvent 300
Rise, be refluxed reaction 4 it is small when after, solution is spin-dried for, is extracted with 100 milliliters of ethyl acetate, 100 milliliters of water, separates acetic acid second
It is concentrated under reduced pressure after ester phase, crude product post separation obtains 4.35 grams of product.(yield 83%).
MS:435m/z(M+H).
1H-NMR(DMSO-d6):δ 8.28 (d, J=8.2Hz, 1H), 8.21 (s, 1H), 7.81 (dd, J=1.2, J=
4.0Hz, 1H), 7.68 (d, J=8.0Hz, 1H), 7.52 (dd, J=4.0, J=8.0Hz, 1H), 7.32 (s, 1H), 7.25 (s,
2H), 6.78 (dd, J=1.2Hz, J=4.0Hz, 1H), 5.66 (s, 4H), 4.12 (s, 2H), 3.76 (s, 6H)；
2nd, the synthesis of double 6- [(3- aminopyridines) methyl]-Isosorbide-5-Nitrae-dihydroxy anthraquinone platinous chloride complexs (compound 2)
(0.208 gram, 1 mM) Platinous Potassium Chloride 30 milliliters of water/hydrochloric acid (4M, 15:1) in solution, 6- is added
[(3- aminopyridines) methyl]-Isosorbide-5-Nitrae-two (methoxy methyl ether base) 0.87 gram of anthraquinone (2 mMs), mixture be refluxed 6 it is small when
Continue at room temperature afterwards stirring 8 it is small when.Filtering separates out solid, is washed with water, methanol, ether, is dried in vacuo, obtains 0.91 gram of product
(yield 95%)
1H-NMR(DMSO-d6):δ 13.11 (s, 1H), 12.97 (s, 1H), 8.26 (d, J=8.0Hz, 1H), 8.16 (s,
1H), 7.79 (dd, J=1.2, J=4.0Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.54 (dd, J=4.0, J=8.0Hz,
1H), 7.32 (s, 1H), 7.27 (s, 2H), 6.86 (dd, J=1.2Hz, J=4.0Hz, 1H), 4.11 (s, 2H)；
Elemental analysis:(C40H26Cl2N4O8Pt) calculated value：C,50.22；H,2.74；Measured value:C,50.21；H,2.75.
Embodiment 3：Double 6- [(- 5 sulfydryl of 1- methyl) methyl]-Isosorbide-5-Nitraes-dihydroxy anthraquinone platinous chloride complex (compound
3)
1st, the synthesis of 6- [(- 5 sulfydryl of 1- methyl) methyl]-Isosorbide-5-Nitrae-two (methoxy methyl ether base) anthraquinone
Under nitrogen protection, 6- bromomethyls-Isosorbide-5-Nitrae-two (methoxy methyl ether base)-anthraquinone 5.06 is added in 500 milliliters of eggplant type bottles
Gram (12 mMs), -5 sulfydryls of 1- methyl -1.74 grams of tetrazole (15 mMs), 0.6 gram of sodium hydroxide (15 mMs), N, N-
100 milliliters of solvent dimethylformamide, when 60 DEG C of stirring reactions 3 are small after, extracted with 100 milliliters of ethyl acetate, 100 milliliters of water,
It is concentrated under reduced pressure after separating ethyl acetate phase, crude product hot acetone recrystallization to 5.02 grams of product.(yield 91%).
MS:457m/z(M+H).
1H-NMR(DMSO-d6):δ 8.16 (d, J=8.0Hz, 1H), 8.10 (s, 1H), 7.77 (d, J=8.2Hz, 1H),
7.42(s,2H),6.24(s,4H),4.15(s,2H),3.57(s,6H),2.63(s,3H)；
2nd, the conjunction of double 6- [(- 5 sulfydryl of 1- methyl) methyl]-Isosorbide-5-Nitrae-dihydroxy anthraquinone platinous chloride complexs (compound 3)
Into
1.05 grams of (5 mMs) Platinous Potassium Chlorides 300 milliliters of water/hydrochloric acid (4M, 15:1) in solution, 6- [(1- are added
The sulfydryl of methyl -5) methyl]-Isosorbide-5-Nitrae-two (methoxy methyl ether base) 4.58 grams of anthraquinone (10 mMs), mixture be refluxed 6 it is small when after
Continue at room temperature stirring 8 it is small when.Filtering separates out solid, is washed with water, methanol, ether, is dried in vacuo, obtains 4.87 grams of product
(yield 97%).
1H-NMR(DMSO-d6):δ 13.31 (s, 1H), 12.98 (s, 1H), 8.33 (d, J=8.0Hz, 1H), 8.15 (s,
1H), 7.63 (d, J=7.2Hz, 1H), 7.26 (s, 2H), 4.05 (s, 2H), 2.77 (s, 3H)；
Elemental analysis:(C34H24Cl2N8O8PtS2) calculated value：C,40.73；H,2.41；Measured value:C,40.75；H,2.40.
Embodiment 4：Single 6- [(2- methylaminos imidazoles) methyl]-Isosorbide-5-Nitrae-dihydroxy anthraquinone platinous chloride complex (compound
4)
1st, the synthesis of 6- [(2- methylaminos imidazoles) methyl]-Isosorbide-5-Nitrae-two (methoxy methyl ether base) anthraquinone
Under nitrogen protection, 6- bromomethyls-Isosorbide-5-Nitrae-two (methoxy methyl ether base)-anthraquinone 5.06 is added in 500 milliliters of eggplant type bottles
Gram (12 mMs), 1.74 grams of 2- methylaminos imidazoles (12 mMs), 3.30 grams of potassium carbonate (24 mMs), N, N- dimethyl methyls
200 milliliters of amide solvent, when 80 DEG C of stirring reactions 12 are small after, extracted with 200 milliliters of ethyl acetate, 200 milliliters of water, separate acetic acid
It is concentrated under reduced pressure after ethyl ester phase, crude product column chromatography for separation to 3.71 grams of product.(yield 70%).
MS:438m/z(M+H).
1H-NMR(DMSO-d6):δ 8.12 (d, J=8.0Hz, 1H), 8.05 (s, 1H), 7.58 (d, J=8.0Hz, 1H),
7.54 (d, J=5.6Hz, 1H), 7.35 (d, J=5.6Hz, 1H), 7.28 (s, 2H), 5.81 (s, 4H), 5.61 (br, 1H),
4.42(s,2H),4.17(s,2H),3.78(s,6H),2.55(br,1H)；
2nd, the synthesis of 6- [(2- methylaminos imidazoles) methyl]-Isosorbide-5-Nitrae-dihydroxy anthraquinone platinous chloride complex (compound 4)
2.10 grams of (10 mMs) Platinous Potassium Chlorides 300 milliliters of water/hydrochloric acid (4M, 15:1) in solution, 6- is added
[(2- methylaminos imidazoles) methyl]-Isosorbide-5-Nitrae-two (methoxy methyl ether base) 4.39 grams of anthraquinone (10 mMs), it is small that mixture is refluxed 6
When after continue at room temperature stirring 8 it is small when.Filtering separates out solid, is washed with water, methanol, ether, is dried in vacuo, obtains product 5.81
Gram (yield 95%).
1H-NMR(DMSO-d6):δ 13.13 (s, 1H), 12.99 (s, 1H), 8.24 (d, J=8.0Hz, 1H), 8.17 (s,
1H), 7.62 (d, J=8.0Hz, 1H), 7.54 (d, J=5.6Hz, 1H), 7.33 (d, J=5.6Hz, 1H), 7.25 (s, 2H),
4.46(s,2H),4.17(s,2H)；
Elemental analysis:(C19H13Cl2N3O4Pt) calculated value：C,37.21；H,2.14；Measured value:C,37.17；H,2.13；
The list of embodiment 5 6- [(4- aminoethyls imidazoles) methyl]-Isosorbide-5-Nitrae-dihydroxy anthraquinone platinous chloride complex (compound 5)
1st, the synthesis of 6- [(4- aminoethyls imidazoles) methyl]-Isosorbide-5-Nitrae-two (methoxy methyl ether base) anthraquinone
Under nitrogen protection, 6- bromomethyls-Isosorbide-5-Nitrae-two (methoxy methyl ether base)-anthraquinone 5.06 is added in 500 milliliters of eggplant type bottles
Gram (12 mMs) .33 grams of histamine 1 (12 mMs), 3.30 grams of potassium carbonate (24 mMs), n,N-Dimethylformamide solvent
200 milliliters, when 80 DEG C of stirring reactions 12 are small after, extracted with 200 milliliters of ethyl acetate, 200 milliliters of water, after separating ethyl acetate phase
It is concentrated under reduced pressure, crude product column chromatography for separation to 3.11 grams of product.(yield 57%).
MS:452m/z(M+H).
1H-NMR(DMSO-d6):δ 8.14 (d, J=8.0Hz, 1H), 8.02 (s, 1H), 7.66 (d, J=8.0Hz, 1H),
7.58 (s, 1H), 7.28 (s, 2H), 7.02 (s, 1H), 5.73 (s, 4H), 4.56 (br, 1H), 4.42 (s, 2H), 3.73 (s,
6H),2.77-2.89(m,5H)；
2nd, the synthesis of 6- [(4- aminoethyls imidazoles) methyl]-Isosorbide-5-Nitrae-dihydroxy anthraquinone platinous chloride complex (compound 5)
2.10 grams of (10 mMs) Platinous Potassium Chlorides 300 milliliters of water/hydrochloric acid (4M, 15:1) in solution, 6- is added
[(4- aminoethyls imidazoles) methyl]-Isosorbide-5-Nitrae-two (methoxy methyl ether base) 4.53 grams of anthraquinone (10 mMs), it is small that mixture is refluxed 6
When after continue at room temperature stirring 8 it is small when.Filtering separates out solid, is washed with water, methanol, ether, is dried in vacuo, obtains product 6.01
Gram (yield 96%).
1H-NMR(DMSO-d6):δ 10.12 (s, 1H), 9.91 (s, 1H), 8.07 (d, J=8.0Hz, 1H), 8.01 (s,
1H), 7.67 (d, J=8.0Hz, 1H), 7.66 (s, 1H), 7.31 (s, 2H), 7.12 (s, 1H), 4.43 (s, 2H), 2.71-2.85
(m,4H)；
Elemental analysis:(C20H15Cl2N3O4Pt) calculated value：C,38.29；H,2.41；Measured value:C,38.30；H,2.42；
The pharmacodynamic experiment of 6 compound 1-5 of embodiment
Compound 1-5, the reference substance mitoxantrone prepared using embodiment 1-5 carries out pharmacodynamic evaluation as given the test agent, shows
Show 6- (azacyclo- substitution) outstanding antitumor action of anthraquinone platinous chloride complex.
(1) the suppression growth activity (GI for various cancer cells50) assay method：
Tumour cell is dispersed into individual cells after Trypsin Induced, and it is suspended in containing penicillin (25ug/
Ml) and in 1640 culture mediums of RPMI of streptomysin (25ug/ml).By cell inoculation in 96 well culture plates, at 37 DEG C, containing 5%
CO2Air, when culture 24 is small under the conditions of relative humidity 100% after, discard nutrient solution, addition contains a series of concentration of test samples
Nutrient solution, each concentration sets parallel hole, when culture 24 is small after, separate the nutrient solution containing given the test agent, add cellar culture liquid
Cultivate 48 it is small when after, discard nutrient solution, then change into containing tetrazolium bromide (MTT) nutrient solution, the final concentration of 0.5g/L of MTT, continue incubation 4
Hour after plus dmso solution liquid, 1 it is small when after purple crystal be completely dissolved, SK601 types microplate reader detect 570nm/
The optical density (OD) of 630mm.Half growth inhibition ratio of the given the test agent to tumour cell is calculated as follows：
(T-T0)/(C-C0) × 100%
Note：C represents the OD values of cellular control unit, and T is represented plus the OD values T of test sample group cell0Represent to add given the test agent
When compare plates of cells OD values
Given the test agent the results are shown in Table 1 for the inhibitory action of various cancer cells
Compound 1-5 provided by the invention, compared with control compound mitoxantrone, it is shown that such as above-mentioned pharmacological evaluation
As a result shown more excellent antitumor action.
Claims (2)
- List 6- 1. (azacyclo- substitution) anthraquinone platinous chloride complex, it is characterised in that structural formula is：
- 2. single 6- (azacyclo- substitution) the anthraquinone platinous chloride complexs or its pharmaceutically acceptable salt described in claim 1 exist Prepare the application in antitumor drug.
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| CN108752389A (en) * | 2018-08-22 | 2018-11-06 | 广西师范学院 | Treat the aryl ruthenium complex and its preparation method and application of hypertension |
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| US4732893A (en) * | 1984-08-03 | 1988-03-22 | Boehringer Biochemia Robin S.P.A. | Amino-anthracenediones-platinum complexes useful as anticancer compounds |
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| WO2000061590A1 (en) * | 1999-04-13 | 2000-10-19 | Anormed, Inc. | Process for preparing amine platinum complexes |
| US7658937B2 (en) * | 2004-05-11 | 2010-02-09 | Board Of Trustees Of Michigan State University | Anthraquinones and process for the preparation and method of use thereof |
| CN102731285B (en) * | 2012-06-28 | 2014-06-25 | 大连理工大学 | Anthraquinone compounds and applications thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4732893A (en) * | 1984-08-03 | 1988-03-22 | Boehringer Biochemia Robin S.P.A. | Amino-anthracenediones-platinum complexes useful as anticancer compounds |
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| Cytotoxic effect of (1-methyl-1H-imidazol-2-yl)-methanamine and its derivatives in PtII complexes on human carcinoma cell lines: A comparative study with cisplatin;Nicola Ferri等;《Bioorganic & Medicinal Chemistry》;20130205;第2379-2386页 * |
| Preparation, Characterization, and Antitumor Properties of cis-PtCl2 Complexes Linked to Anthraquinones through Position Number 2;Dan Gibson等;《Journal of Inorganic Biochemistry》;19950501;第79-88页 * |
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| CN103554188A (en) | 2014-02-05 |
| CN105254679A (en) | 2016-01-20 |
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