CN1613844A - Chiral 1,4 diamidogen and its complex of platinum II - Google Patents
Chiral 1,4 diamidogen and its complex of platinum II Download PDFInfo
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- CN1613844A CN1613844A CN200410041749.7A CN200410041749A CN1613844A CN 1613844 A CN1613844 A CN 1613844A CN 200410041749 A CN200410041749 A CN 200410041749A CN 1613844 A CN1613844 A CN 1613844A
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- Prior art keywords
- butanediamine
- platinum
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- gram
- slightly
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims description 24
- 229910052697 platinum Inorganic materials 0.000 title claims description 11
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims abstract description 138
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid group Chemical group C(C(=O)O)(=O)O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 86
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 50
- 239000002253 acid Substances 0.000 claims description 50
- -1 halogen ion diamines Chemical class 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 7
- 230000000259 anti-tumor effect Effects 0.000 claims description 5
- 201000005296 lung carcinoma Diseases 0.000 claims description 4
- 241000370738 Chlorion Species 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 claims description 2
- 229940089960 chloroacetate Drugs 0.000 claims description 2
- CCQPAEQGAVNNIA-UHFFFAOYSA-N cyclobutane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-N 0.000 claims description 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 claims description 2
- FOIXSVOLVBLSDH-UHFFFAOYSA-N Silver ion Chemical compound [Ag+] FOIXSVOLVBLSDH-UHFFFAOYSA-N 0.000 claims 1
- 230000000452 restraining effect Effects 0.000 claims 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 abstract 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical group OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 abstract 1
- 229940106681 chloroacetic acid Drugs 0.000 abstract 1
- 201000005202 lung cancer Diseases 0.000 abstract 1
- 208000020816 lung neoplasm Diseases 0.000 abstract 1
- 235000006408 oxalic acid Nutrition 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- 239000007787 solid Substances 0.000 description 39
- 239000000243 solution Substances 0.000 description 35
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 229910052757 nitrogen Inorganic materials 0.000 description 24
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 22
- 239000003643 water by type Substances 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- 238000010521 absorption reaction Methods 0.000 description 18
- 238000001816 cooling Methods 0.000 description 18
- 238000001035 drying Methods 0.000 description 15
- 239000011734 sodium Substances 0.000 description 14
- 239000000843 powder Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 229910001961 silver nitrate Inorganic materials 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- 150000004985 diamines Chemical class 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- SHLCGTACJPPATG-UHFFFAOYSA-N butanedioic acid;silver Chemical compound [Ag].OC(=O)CCC(O)=O SHLCGTACJPPATG-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- KHQLKFYEKVWKRW-UHFFFAOYSA-N propanedioic acid;silver Chemical compound [Ag].OC(=O)CC(O)=O KHQLKFYEKVWKRW-UHFFFAOYSA-N 0.000 description 4
- 230000003252 repetitive effect Effects 0.000 description 4
- 238000005201 scrubbing Methods 0.000 description 4
- XNGYKPINNDWGGF-UHFFFAOYSA-L silver oxalate Chemical compound [Ag+].[Ag+].[O-]C(=O)C([O-])=O XNGYKPINNDWGGF-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 3
- 229960001756 oxaliplatin Drugs 0.000 description 3
- 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 3
- 238000003825 pressing Methods 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- UHPKHFDDQWPOOX-UHFFFAOYSA-N 2,2-dichloroacetic acid silver Chemical compound [Ag].ClC(C(=O)O)Cl UHPKHFDDQWPOOX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 229960005215 dichloroacetic acid Drugs 0.000 description 2
- VKNUORWMCINMRB-UHFFFAOYSA-N diethyl malate Chemical compound CCOC(=O)CC(O)C(=O)OCC VKNUORWMCINMRB-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000009422 growth inhibiting effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229940116298 l- malic acid Drugs 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical class [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 1
- QILMIEMHJSZECS-UHFFFAOYSA-N [Pt].CCCCCCC Chemical compound [Pt].CCCCCCC QILMIEMHJSZECS-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000001457 metallic cations Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 238000000711 polarimetry Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000010850 salt effect Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Abstract
A chiral 1,4-bisamine compound and its platinum(II) complex compound are disclosed. The chiral 1,4-bisamine compound is (2R)-2-alkoxy-1, 4-butanediamine or (2S)-2-alkoxy-1, 4-butanediamine, the R group is C1-5 alkyl, X group is chloride, chloroacetic acid, and glycolic acid; R is oxalic acid, malonic acid, 1,1-cyclobutaly diacid, and chelating glycolic acid. It achieves to inhibit human body cell of colon cancer and lung cancer.
Description
Technical field
The present invention relates to a class chirality 1,4-diamines and contain this class chirality 1, the 4-diamines is novel platinum (II) title complex of part and preparation method thereof, and the extracorporeal anti-tumor character of typical compound in described platinum (II) title complex.
Background technology
Because chiral molecules has different optical configuration, caused they and some organisms to exist huge difference, so the introducing chiral centre has obtained people and pays close attention to greatly in drug molecular structure as the time spent.In the research of antitumor platinum medicine, after chiral diamine formed title complex as part and metal platinum (II) ion, the difference on its three-dimensional and space often can be improved the character and the curative effect of medicine.Such as the medicine oxaliplatin (Oxaliplatin) that has gone on the market and heptan platinum (Sunpla, SKI-2053R) and some just all contain chiral diamine at the medicine of clinical trial, therefore design and prepare novel chiral diamine be applied in the research and development of platinum-containing anticancer drug as part be very useful.
Summary of the invention
The objective of the invention is to be to provide a class chirality 1,4-diamine compound and with this class chirality 1, the 4-diamines is platinum (II) the class title complex of part, these title complexs have low toxicity, better water-soluble and effective antitumour is active, can be used for treating human tumor.The invention discloses a class chirality 1,4-diamine compound and with this class 1, the 4-chiral diamine is platinum (II) coordination compound of part, it is characterized in that using chirality 1, platinum (II) coordination compound that the platinum amine complex cation of 4-diamines preparation and multiple complex anion reaction form.Such chirality 1, the 4-diamine compound is represented by following formula (1):
Chirality 1 in its Chinese style (1), 4-diamines can be optically active isomer (2R)-2-alkoxyl groups-1,4-butanediamine or its enantiomer (S)-2-alkoxyl group-1, and the 4-butanediamine, wherein the R group is C
1-5Alkyl.
With above-mentioned chirality 1, the 4-diamines is that platinum (II) title complex that part forms is represented by following formula (2) and formula (3):
Chirality 1 in its Chinese style (2) and the formula (3), 4-diamines can be (2R)-2-alkoxyl groups-1, the 4-butanediamine or [(2S)-2-alkoxyl group-1, the 4-T diamines, wherein the R group is C
1-5Alkyl; X group in the formula (2) is respectively chlorion, chloroacetate root, ethanol acid group; R ' group in the formula (3) is a bidentate carboxylic-acid part, is respectively oxalate, malonate, 1,1-cyclobutanedicarboxylic acid, chelating ethanol acid group.Platinum of the present invention (II) title complex comprises all steric isomers shown in the above-mentioned chemical formula.
Another object of the present invention provides the method for platinum (II) title complex shown in preparation formula (2) and the formula (3).In these divalence platinum complexes synthetic, they at first are to obtain containing dihalo-ion diamines coordinate platinic compound by potassium tetrachloroplatinate and chiral diamine ligands effect, are represented by formula (4); Then under the logical condition of nitrogen gas of lucifuge, by method A: use silver ions (I) to remove the halogen ion that the dihalo-diamines closes platinum (II), the gained intermediate obtains suitable-acid group diamines with the relevant carboxylate salt effect of monovalent base metallic cation and closes platinum (II) compound; Or by method B: use the relevant carboxylate salt that contains silver ions (I) and dihalo-diamines to close platinum (II) and act on and obtain suitable-acid group diamines and close platinum (II) compound.Hal in the formula (4) represents Cl
-, Br
-And I
-Ion, R group wherein is C
1-5Alkyl.
A further object of the invention is to disclose in above-mentioned platinum (II) title complex typical compound to the vitro inhibition effect of human colon cancer cell and human lung carcinoma cell.
The representational chirality 1 of the present invention, the 4-diamine compound comprises:
(2R)-and 2-methoxyl group-1, the 4-butanediamine; (2R)-and 2-oxyethyl group-1, the 4-butanediamine; (2R)-and 2-isopropoxy-1, the 4-butanediamine; (2R)-and 2-butoxy-1, the 4-butanediamine; (2R)-and 2-tert.-butoxy-1, the 4-butanediamine; (2R)-and 2-neopentyl oxygen-1, the 4-butanediamine; (2S)-and 2-methoxyl group-1, the 4-butanediamine; (2S)-and 2-oxyethyl group-1, the 4-butanediamine; (2S)-and 2-isopropoxy-1, the 4-butanediamine]; (2S)-and 2-butoxy-1, the 4-butanediamine; (2S)-and 2-tert.-butoxy-1, the 4-butanediamine); (2S)-and 2-neopentyl oxygen-1, the 4-butanediamine.
The representational platinum of the present invention (II) title complex comprises:
Suitable-dichloro [(2R)-and 2-methoxyl group-1, the 4-butanediamine] close platinum (II) (slightly: D1a); Suitable-dichloro [(2R)-and 2-oxyethyl group-1, the 4-butanediamine] close platinum (II) (slightly: D2a); Suitable-dichloro [(2R)-and 2-isopropoxy-1, the 4-butanediamine] close platinum (II) (slightly: D3a); Suitable-dichloro [(2R)-and 2-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: D4a); Suitable-dichloro [(2R)-and 2-tert.-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: D5a); Suitable-dichloro [(2R)-and 2-neopentyl oxygen-1, the 4-butanediamine] close platinum (II) (slightly: D6a); Suitable-dichloro [(2S)-and 2-methoxyl group-1, the 4-butanediamine] close platinum (II) (slightly: L1a); Suitable-dichloro [(2S)-and 2-oxyethyl group-1, the 4-butanediamine] close platinum (II) (slightly: L2a); Suitable-dichloro [(2S)-and 2-isopropoxy-1, the 4-butanediamine] close platinum (II) (slightly: L3a); Suitable-dichloro [(2S)-and 2-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: L4a); Suitable-dichloro [(S)-and 2-tert.-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: L5a); Suitable-dichloro [(2S)-and 2-neopentyl oxygen-1, the 4-butanediamine] close platinum (II) (slightly: L6a); Suitable-oxalate [(2R)-and 2-methoxyl group-1, the 4-butanediamine] close platinum (II) (slightly: D1b); Suitable-oxalate [(2R)-and 2-oxyethyl group-1, the 4-butanediamine] close platinum (II) (slightly: D2b); Suitable-oxalate [(2R)-and 2-isopropoxy-1, the 4-butanediamine] close platinum (II) (slightly: D3b); Suitable-oxalate [(2R)-and 2-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: D4b); Suitable-oxalate [(2R)-and 2-tert.-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: D5b); Suitable-oxalate [(2R)-and 2-neopentyl oxygen-1, the 4-butanediamine] close platinum (II) (slightly: D6b); Suitable-oxalate [(2S)-and 2-methoxyl group-1, the 4-butanediamine] close platinum (II) (slightly: L1b); Suitable-oxalate [(2S)-and 2-oxyethyl group-1, the 4-butanediamine] close platinum (II) (slightly: L2b); Suitable-oxalate [(2S)-and 2-isopropoxy-1, the 4-butanediamine] close platinum (II) (slightly: L3b); Suitable-oxalate [(2S)-and 2-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: L4b); Suitable-oxalate [(2S)-and 2-tert.-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: L5b); Suitable-oxalate [(2S)-and 2-neopentyl oxygen-1, the 4-butanediamine] close platinum (II) (slightly: L6b); Suitable-malonate [(2R)-and 2-methoxyl group-1, the 4-butanediamine] close platinum (II) (slightly: D1c); Suitable-malonate [(2R)-and 2-oxyethyl group-1, the 4-butanediamine] close platinum (II) (slightly: D2c); Suitable-malonate [(2R)-and 2-isopropoxy-1, the 4-butanediamine] close platinum (II) (slightly: D3c); Suitable-malonate [(2R)-and 2-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: D4c); Suitable-malonate [(2R)-and 2-tert.-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: D5c); Suitable-malonate [(2R)-and 2-neopentyl oxygen-1, the 4-butanediamine] close platinum (II) (slightly: D6c); Suitable-malonate [(2S)-and 2-methoxyl group-1, the 4-butanediamine] close platinum (II) (slightly: L1c); Suitable-malonate [(2S)-and 2-oxyethyl group-1, the 4-butanediamine] close platinum (II) (slightly: L2c); Suitable-malonate [(2S)-and 2-isopropoxy-1, the 4-butanediamine] close platinum (II) (slightly: L3c); Suitable-malonate [(2S)-and 2-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: L4c); Suitable-malonate [(2S)-and 2-tert.-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: L5c); Suitable-malonate [(2S)-and 2-neopentyl oxygen-1, the 4-butanediamine] close platinum (II) (slightly: L6c); Suitable-1, the 1-cyclobutanedicarboxylic acid [(2R)-and 2-methoxyl group-1, the 4-butanediamine] close platinum (II) (slightly: D1d); Suitable-1, the 1-cyclobutanedicarboxylic acid [(2R)-and 2-oxyethyl group-1, the 4-butanediamine] close platinum (II) (slightly: D2d); Suitable-1, the 1-cyclobutanedicarboxylic acid [(2R)-and 2-isopropoxy-1, the 4-butanediamine] close platinum (II) (slightly: D3d); Suitable-1, the 1-cyclobutanedicarboxylic acid [(2R)-and 2-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: D4d); Suitable-1, the 1-cyclobutanedicarboxylic acid [(2R)-and 2-tert.-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: D5d); Suitable-1, the 1-cyclobutanedicarboxylic acid [(2R)-and 2-neopentyl oxygen-1, the 4-butanediamine] close platinum (II) (slightly: D6d); Suitable-1, the 1-cyclobutanedicarboxylic acid [(2S)-and 2-methoxyl group-1, the 4-butanediamine] close platinum (II) (slightly: L1d); Suitable-1, the 1-cyclobutanedicarboxylic acid [(2S)-and 2-oxyethyl group-1, the 4-butanediamine] close platinum (II) (slightly: L2d); Suitable-1, the 1-cyclobutanedicarboxylic acid [(2S)-and 2-isopropoxy-1, the 4-butanediamine] close platinum (II) (slightly: L3d); Suitable-1, the 1-cyclobutanedicarboxylic acid [(2S)-and 2-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: L4d); Suitable-1, the 1-cyclobutanedicarboxylic acid [(2S)-and 2-tert.-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: L5d); Suitable-1, the 1-cyclobutanedicarboxylic acid [(2S)-and 2-neopentyl oxygen-1, the 4-butanediamine] close platinum (II) (slightly: L6d); Suitable-the ethanol acid group [(2R)-and 2-methoxyl group-1, the 4-butanediamine] close platinum (II) (slightly: D1e); Suitable-the ethanol acid group [(2R)-and 2-oxyethyl group-1, the 4-butanediamine] close platinum (II) (slightly: D2e); Suitable-the ethanol acid group [(2R)-and 2-isopropoxy-1, the 4-butanediamine] close platinum (II) (slightly: D3e); Suitable-the ethanol acid group [(2R)-and 2-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: D4e); Suitable-the ethanol acid group [(2R)-and 2-tert.-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: D5e); Suitable-the ethanol acid group [(2R)-and 2-neopentyl oxygen-1, the 4-butanediamine] close platinum (II) (slightly: D6e); Suitable-the ethanol acid group [(2S)-and 2-methoxyl group-1, the 4-butanediamine] close platinum (II) (slightly: L1e); Suitable-the ethanol acid group [(2S)-and 2-oxyethyl group-1, the 4-butanediamine] close platinum (II) (slightly: L2e); Suitable-the ethanol acid group [(2S)-and 2-isopropoxy-1, the 4-butanediamine] close platinum (II) (slightly: L3e); Suitable-the ethanol acid group [(2S)-and 2-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: L4e); Suitable-the ethanol acid group [(2S)-and 2-tert.-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: L5e); Suitable-the ethanol acid group [(2S)-and 2-neopentyl oxygen-1, the 4-butanediamine] close platinum (II) (slightly: L6e); Suitable-the di-alcohol acid group [(2R)-and 2-methoxyl group-1, the 4-butanediamine] close platinum (II) (slightly: D1g); Suitable-the di-alcohol acid group [(2R)-and 2-oxyethyl group-1, the 4-butanediamine] close platinum (II) (slightly: D2g); Suitable-the di-alcohol acid group [(2R)-and 2-isopropoxy-1, the 4-butanediamine] close platinum (II) (slightly: D3g); Suitable-the di-alcohol acid group [(2R)-and 2-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: D4g); Suitable-the di-alcohol acid group [(2R)-and 2-tert.-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: D5g); Suitable-the di-alcohol acid group [(2R)-and 2-neopentyl oxygen-1, the 4-butanediamine] close platinum (II) (slightly: D6g); Suitable-the di-alcohol acid group [(2S)-and 2-methoxyl group-1, the 4-butanediamine] close platinum (II) (slightly: L1g); Suitable-the di-alcohol acid group [(2S)-and 2-oxyethyl group-1, the 4-butanediamine] close platinum (II) (slightly: L2g); Suitable-the di-alcohol acid group [(2S)-and 2-isopropoxy-1, the 4-butanediamine] close platinum (II) (slightly: L3g); Suitable-the di-alcohol acid group [(2S)-and 2-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: L4g); Suitable-the di-alcohol acid group [(2S)-and 2-tert.-butoxy-1, the 4-butanediamine] close platinum (II) (slightly: L5g); Suitable-the di-alcohol acid group [(2S)-and 2-neopentyl oxygen-1, the 4-butanediamine] close platinum (II) (slightly: L6g).
Chirality 2-alkoxyl group-1,4-butanediamine compounds is by following synthetic route preparation, and starting raw material is respectively has optically active D-oxysuccinic acid or L MALIC ACID.
Owing to used and had optically active starting raw material, and chiral carbon atom be maintained in responding, so final product has still kept polarimetry nature.
The present invention is further set forth by following embodiment, but these explanations are not restriction the present invention.
Structure by the prepared compound of the present invention is confirmed by different analytical procedures such as infrared spectra, proton magnetic resonance (PMR) spectrum and positively charged ion electrospray ionization mass spectrum.
The embodiment that below prepares some representative compounds for the inventive method.
Embodiment
Embodiment 1:(2R)-and 2-oxyethyl group-1,4-butanediamine and (2S)-2-oxyethyl group-1, the preparation of 4-butanediamine
(1) diethyl malate 1 is synthetic
100.00 gram D-oxysuccinic acid or L MALIC ACID are dissolved in 400 milliliters of dehydrated alcohols, add 10 milliliters of vitriol oils then, back flow reaction 24 hours.Cool to room temperature adds 120 milliliters of fresh ammoniacal liquor, and regulator solution pH=7 has a large amount of white solid precipitations to generate, filter, and absolute ethanol washing, merging filtrate and washings, rotary evaporation removes and desolvates.Underpressure distillation: 120 ℃ (2-3mmHg) obtains light yellow cut 95.15 grams (64.5%).
(2) 2-oxyethyl group diethyl malate 2 is synthetic
Mix 30.00 restrain 1 and 115.00 gram iodoethane, add silver suboxide then in batches, each 14.50 grams (adding altogether 6 times) stir, slowly reacting by heating.When the silver suboxide that adds 2/3, in reaction solution, replenish and add 50.00 gram iodoethane.Back flow reaction was continued 2 hours in the reinforced back of finishing, cooling, unreacted iodoethane is reclaimed in air distillation, add cold dry diethyl ether extraction then, organic phase is used anhydrous sodium sulfate drying a few hours, rotary evaporation is removed ether, gets brown liquid, and underpressure distillation obtains colourless organic liquid 22.49 grams (65.3%) then.
(3) 2-oxyethyl group-1,4-butyleneglycol 3 synthetic
7.10 the gram lithium aluminum hydride joins in 300 milliliters of anhydrous tetrahydro furans, refluxes 20 minutes, stops heating, drips the tetrahydrofuran solution of 20 milliliters of compounds 2 (23.70 gram), dropwises in 1 hour, continues back flow reaction 4 hours.Cooling drips 820 milliliters of ether, 20 milliliters of 4N NaOH solution then.And then add 200 milliliters of ether, and filter, use the ether washing precipitation, merging filtrate and washings, anhydrous magnesium sulfate drying spends the night.Rotary evaporation removes and desolvates, and obtains 11.25 gram brown liquids (77.2%).
(4) 2-oxyethyl group-1,4-fourth two p-toluenesulfonic esters 4 synthetic
Be dissolved in 170 milliliters of pyridines 9.50 restrain 3, add 28.15 gram Tosyl chlorides then, 0 ℃ of following stirring reaction 5 hours, the solution suspension liquid that takes on a red color.Refrigerator and cooled is frozen and is spent the night, there are a large amount of clear crystals to separate out, under the ice-water bath condition, add 340 ml distilled waters then, solution is orange red suspension liquid, and refrigerator and cooled is hidden and spent the night, and the bottom has sticking shape liquid to separate out, decant goes out supernatant liquid and filters, the sticking shape liquid in bottom with butanols repeatedly recrystallization have the white powder solid to separate out, mother liquor concentrates the back to be continued freezing and crystallizing and can continue to obtain portion of product, amounts to 10.97 grams (35.01%) after the vacuum-drying.
(5) 2-oxyethyl group-1,4-butanediamine 7 synthetic
Be dissolved in 100 milliliters of N 10.97 restrain 4, in the N-diformamide, add 3.30 gram sodium azides then, 60 ℃ of reactions of temperature control 12 hours, cool to room temperature adds 200 ml waters then.With 100 milliliters of/time extractions of ether 3-4 time, 150 milliliters of/time washed twice of water after organic phase is spent the night with anhydrous magnesium sulfate drying, are removed and are desolvated then, obtain 3.65 gram light yellow liquids 5.Not doing purifies is directly used in down step high-pressure hydrogenation, hydrogenation conditions: 50 normal atmosphere of initial hydrogen pressure, and the Pd/C of 0.5 gram 5%, 200 milliliters of dehydrated alcohols reacted 5-10 hour.After reaction finishes, remove by filter the Pd/C catalyzer, and with a small amount of absolute ethanol washing catalyzer, merging filtrate and washings, concentrate most of solvent and obtain oily matter 6, be acid with concentrated hydrochloric acid regulator solution pH then, adding acetone has crystal to separate out, filter and use washing with acetone, vacuum-drying to obtain white crystal 3.25 grams (63.6%).
IR(KBr)：3032(NH
3 +)，2010，1608，1497(δNH
3 +)，1163，1076，1032(C-O)cm
-1 1H-NMR(D
2O/TMS)：δ3.74(m，1H)，3.55-3.52(m，2H)，3.15-3.13(m，1H)，3.04-3.00(m，2H)，2.94-2.92(m，1H)，1.87-1.86(m，2H)，1.11-1.07(m，3H)
ESI-MS?m/z[M-2Cl-H]
+＝133(100％)。
Dextrorotation enantiomorph: [α]
D 25=+10.88 (c=1.0, H
2O), levo-enantiomer: [α]
D 25=-10.82 (c=1.0, H
2O).
Other chirality 1,4-diamine compound are also pressed embodiment 1 described method preparation.
Embodiment 2: synthetic suitable-dichloro [(2R)-2-methoxyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-2-methoxyl group-1,4-butanediamine] closes platinum (II) (1.13 grams, 2 mmoles), Silver Nitrate (0.68 gram, 4 mmoles) mixing adds entry (50 milliliters), and 40 ℃ of logical nitrogen of following lucifuges reacted the diatomite aided filter 24 hours, add sodium-chlor (0.24 gram, 4 mmoles) in the filtrate, 40 ℃ of following lucifuges were reacted 24 hours, with solution concentration, cooling has pale yellow crystals to separate out, filter, water, ethanol, ether repetitive scrubbing, vacuum-drying gets product 0.21 gram (27.3%).
IR(KBr)：3456m(br)，3256s，3220s，3177m，3132m，2971m，2942m，1601m，1449w，1384m，1210m，1094s
1H-NMR(D
2O/TMS)：δ2.11-2.22(m，2H)，2.66-2.75(m，2H)，2.83(m，2H)，3.25(s，3H)，3.90(m，1H)
ESI-MS?m/z[M-Cl
-+H
2O]
+＝366(100％)
Embodiment 3: synthetic suitable-dichloro [(2R)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-2-oxyethyl group-1,4-butanediamine] closes platinum (II) (1.16 grams, 2 mmoles), Silver Nitrate (0.68 gram, 4 mmoles) mixing adds entry (50 milliliters), and 40 ℃ of logical nitrogen of following lucifuges reacted the diatomite aided filter 24 hours, add sodium-chlor (0.24 gram, 4 mmoles) in the filtrate, 40 ℃ of following lucifuges were reacted 24 hours, with solution concentration, cooling has pale yellow crystals to separate out, filter, water, ethanol, ether repetitive scrubbing, vacuum-drying gets product 0.22 gram (27.6%).
IR(KBr)：3452m(br)，3229s，3207s，3132m，3065m，2985m，2932m，1596m，1562m，1448w，1384s，1227m，1096s
1H-NMR(D
2O/TMS)：δ1.01-1.05(m，3H)，2.08-2.20(m，2H)，2.66-2.75(m，2H)，2.78-2.86(m，2H)，3.48-3.52(m，3H)，4.05(m，1H)
ESI-MS?m/z[M-Cl
-+H
2O]
+＝381(100％)
Embodiment 4: synthetic suitable-dichloro [(2S)-2-methoxyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2S)-2-methoxyl group-1,4-butanediamine] closes platinum (II) (0.57 gram, 1 mmole), Silver Nitrate (0.34 gram, 2 mmoles) mixing adds entry (50 milliliters), and 40 ℃ of logical nitrogen of following lucifuges reacted the diatomite aided filter 24 hours, add sodium-chlor (0.12 gram, 2 mmoles) in the filtrate, 40 ℃ of following lucifuges were reacted 24 hours, with solution concentration, cooling has pale yellow crystals to separate out, filter, water, ethanol, ether repetitive scrubbing, vacuum-drying gets product 0.10 gram (26.0%).
IR(KBr)：3448m(br)，3229s，3202s，3131m，3061m，2931m，1595m，1561m，1461w，1330m，1227s，1212s，1107s，1095s
1H-NMR(D
2O/TMS)：δ2.22-2.25(m，2H)，2.68-2.77(m，2H)，2.85(m，2H)，3.25(m，3H)，3.91(m，1H)
ESI-MS?m/z[M-Cl
-+H
2O]
+＝366(100％)
Embodiment 5: synthetic suitable-dichloro [(2S)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2S)-2-oxyethyl group-1,4-butanediamine] closes platinum (II) (0.58 gram, 1 mmole), Silver Nitrate (0.34 gram, 2 mmoles) mixing adds entry (50 milliliters), and 40 ℃ of logical nitrogen of following lucifuges reacted the diatomite aided filter 24 hours, add sodium-chlor (0.12 gram, 2 mmoles) in the filtrate, 40 ℃ of following lucifuges were reacted 24 hours, with solution concentration, cooling has pale yellow crystals to separate out, filter, water, ethanol, ether repetitive scrubbing, vacuum-drying gets product 0.10 gram (25.1%).
IR(KBr)：3444m(br)，3255s，3220s，3177m，2971w，1601m，1449w，1384vs，1210m，1184m，1094m
1H-NMR(D
2O/TMS)：δ1.10(m，3H)，2.06-2.22(m，2H)，2.64-2.76(m，2H)，2.83(m，2H)，3.48(m，2H)，4.04(m，2H)
ESI-MS?m/z[M-Cl
-+H
2O]
+＝381(100％)
Embodiment 6: synthetic suitable-oxalate [(2R)-2-methoxyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-2-methoxyl group-1,4-butanediamine] closes silver oxalate (0.61 gram of platinum (II) (1.13 grams, 2 mmoles) and new system, 4 mmoles) mix adding 100 ml waters, 50 ℃ of logical nitrogen of following lucifuge reacted 24 hours, with solution concentration, separated out white solid.Cooling is filtered, and drying gets white powder 0.27 gram (33.7%).
IR(KBr)：3446m(br)，3231m，3138m，2941w，1691s，1669vs，1390s，1241m，1095m
1H-NMR(D
2O/TMS)：δ2.13-2.21(m，2H)，2.70-2.75(m，2H)，2.87(m，2H)，3.26(m，3H)，3.85(m，1H)
ESI-MS?m/z[M+Na]
+＝424(100％)
Embodiment 7: synthetic suitable-oxalate [(2R)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-2-oxyethyl group-1,4-butanediamine] closes silver oxalate (0.61 gram of platinum (II) (1.16 grams, 2 mmoles) and new system, 4 mmoles) mix adding 100 ml waters, 50 ℃ of logical nitrogen of following lucifuge reacted 24 hours, with solution concentration, separated out white solid.Cooling is filtered, and drying gets white powder 0.15 gram (18.1%).
IR(KBr)：3441m(br)，3230m，3137m，2972w，2941w，2880w，1690s，1668vs，1391s，1236m，1096m
1H-NMR(D
2O/TMS)：δ1.08(m，3H)，2.11-2.19(m，2H)，2.70-2.78(m，2H)，2.84-2.87(m，2H)，3.48-3.50(m，3H)，4.00(m，1H)
ESI-MS?m/z[M+Na]
+＝438(100％)
Embodiment 8: synthetic suitable-oxalate [(2S)-2-methoxyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2S)-2-methoxyl group-1,4-butanediamine] closes silver oxalate (0.46 gram of platinum (II) (0.85 gram, 1.5 mmoles) and new system, 3 mmoles) mix adding 100 ml waters, 50 ℃ of logical nitrogen of following lucifuge reacted 24 hours, with solution concentration, separated out white solid.Cooling is filtered, and drying gets white powder 0.15 gram (24.9%).
IR(KBr)：3451m(br)，3238m，3193m，3155m，2977w，1692s，1668vs，1388s，1095m
1H-NMR(D
2O/TMS)：δ2.10-2.17(m，2H)，2.67-2.75(m，2H)，2.84(m，2H)，3.24(m，3H)，3.83(m，1H)
ESI-MS?m/z[M+Na]
+＝424(100％)
Embodiment 9: synthetic suitable-oxalate [(2S)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2S)-2-oxyethyl group-1,4-butanediamine] closes silver oxalate (0.46 gram of platinum (II) (1.16 grams, 1.5 mmoles) and new system, 3 mmoles) mix adding 100 ml waters, 50 ℃ of logical nitrogen of following lucifuge reacted 24 hours, with solution concentration, separated out white solid.Cooling is filtered, and drying gets white powder 0.20 gram (31.3%).
IR(KBr)：3411m(br)，3208s，3112m，3155m，2965w，2921w，1694s，1672vs，1398s，1189m，1098m
1H-NMR(D
2O/TMS)：δ1.03(m，3H)，2.03-2.17(m，2H)，2.64-2.85(m，4H)，3.45(m，2H)，3.96(m，1H)
ESI-MS?m/z[M+Na]
+＝438(100％)
Embodiment 10: synthetic suitable-malonate [(2R)-2-methoxyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-2-methoxyl group-1,4-butanediamine] closes propanedioic acid silver (0.63 gram of platinum (II) (1.13 grams, 2 mmoles) and new system, 4 mmoles) mix adding 100 ml waters, 50 ℃ of following lucifuges were led to ammonia gas react 24 hours, with solution concentration, separated out white solid.Cooling is filtered, and drying gets white powder 0.20 gram (24.1%).
IR(KBr)：3441m(br)，3219m，3127m，2947w，1626vs，1387s，1094m
1H-NMR(D
2O/TMS)：δ2.17(m，2H)，2.68-2.70(m，2H)，2.87-2.88(m，2H)，3.27(m，3H)，3.51-3.57(m，2H)，3.83(m，1H)
ESI-MS?m/z[M+Na]
+＝438(100％)
Embodiment 11: synthetic suitable-malonate [(2R)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-2-oxyethyl group-1,4-butanediamine] closes propanedioic acid silver (0.63 gram of platinum (II) (1.16 grams, 2 mmoles) and new system, 4 mmoles) mix adding 100 ml waters, 50 ℃ of logical nitrogen of following lucifuge reacted 24 hours, with solution concentration, separated out white solid.Cooling is filtered, and drying gets white powder 0.21 gram (24.5%).
IR(KBr)：3442m(br)，3212m，3122m，2972m，2940w，1667s，1643vs，1384s，1247m，1097m
1H-NMR(D
2O/TMS)：δ1.04-1.06m(3H)，2.13(m，2H)，2.67-2.75(m，2H)，2.81-2.84(m，2H)，3.47-3.49(m，2H)，3.51-3.60(m，2H)，3.95(m，1H)
ESI-MS?m/z[M+Na]
+＝452(100％)
Embodiment 12: synthetic suitable-malonate [(2S)-2-methoxyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2S)-2-methoxyl group-1,4-butanediamine] closes propanedioic acid silver (0.63 gram of platinum (II) (1.13 grams, 2 mmoles) and new system, 4 mmoles) mix adding 100 ml waters, 50 ℃ of logical nitrogen of following lucifuge reacted 24 hours, with solution concentration, separated out white solid.Cooling is filtered, and drying gets white powder 0.10 gram (12.0%).
IR(KBr)：3441m(br)，3219m，3128m，3155m，2947w，1627vs，1387s，1288w，1240m，1227m，1094m
1H-NMR(D
2O/TMS)：δ2.15(m，2H)，2.67-2.73(m，2H)，2.85(m，2H)，3.26(m，3H)，3.59(m，2H)3.93(m，1H)
ESI-MS?m/z[M+Na]
+＝438(100％)
Embodiment 13: synthetic suitable-malonate [(2S)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2S)-2-oxyethyl group-1,4-butanediamine] closes propanedioic acid silver (0.63 gram of platinum (II) (1.16 grams, 2 mmoles) and new system, 4 mmoles) mix adding 100 ml waters, 50 ℃ of logical nitrogen of following lucifuge reacted 24 hours, with solution concentration, separated out white solid.Cooling is filtered, and drying gets white powder 0.27 gram (31.5%).
IR(KBr)：3441m(br)，3219m，3128m，3155m，2947w，1627vs，1387s，1288w，1240m，1227m，1094m
1H-NMR(D
2O/TMS)：δ1.07(m，3H)，2.12(m，2H)，2.68-2.85(m，4H)，3.49-3.56(m，4H)，3.95(m，1H)
ESI-MS?m/z[M+H]
+＝430(100％)
Embodiment 14: synthetic suitable-1,1-cyclobutanedicarboxylic acid [(2R)-2-methoxyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-2-methoxyl group-1, the 4-butanediamine] (1.13 restrain to close platinum (II), 2 mmoles) with 1 of new system, 1-ring Succinic Acid silver (0.72 gram, 4 mmoles) mix adding 100 ml waters, 50 ℃ of logical nitrogen of following lucifuges reacted 24 hours, and solution concentration is closely dried, add ethanol and ether, separate out white solid.Cooling is filtered, and drying gets white powder 0.26 gram (28.6%).
IR(KBr)：3444s(br)，3138m，2947w，1627vs，1459w，1384vs，1252w，1221m，1115m，1096m
1H-NMR(D
2O/TMS)：δ1.74-1.81(m，2H)，2.11-2.15(m，2H)，2.71-2.80(m，6H)，2.87(m，2H)，3.27(m，3H)，3.82(m，1H)
ESI-MS?m/z[M+H]
+＝456(100％)
Embodiment 15: synthetic suitable-1,1-cyclobutanedicarboxylic acid [(2R)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-2-oxyethyl group-1, the 4-butanediamine] (1.16 restrain to close platinum (II), 2 mmoles) with 1 of new system, 1-ring Succinic Acid silver (0.72 gram, 4 mmoles) mix adding 100 ml waters, 50 ℃ of logical nitrogen of following lucifuges reacted 24 hours, and solution concentration is closely dried, add ethanol and ether, separate out white solid.Cooling is filtered, and drying gets white powder 0.22 gram (23.4%).
IR(KBr)：3444s(br)，3138m，2947w，1627vs，1459w，1384vs，1252w，1221m，1115m，1096m
1H-NMR(D
2O/TMS)：δ1.02-1.06(m，3H)，1.70-1.77(m，2H)，2.05-2.13(m，2H)，2.66-2.78(m，6H)，2.84(m，2H)，3.46(m，3H)，3.95(m，1H)
ESI-MS?m/z[M+H]
+＝470(100％)
Embodiment 16: synthetic suitable-1,1-cyclobutanedicarboxylic acid [(2S)-2-methoxyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2S)-2-methoxyl group-1, the 4-butanediamine] (1.13 restrain to close platinum (II), 2 mmoles) with 1 of new system, 1-ring Succinic Acid silver (0.72 gram, 4 mmoles) mix adding 100 ml waters, 50 ℃ of logical nitrogen of following lucifuges reacted 24 hours, and solution concentration is closely dried, add ethanol and ether, separate out white solid.Cooling is filtered, and drying gets white powder 0.32 gram (35.2%).
IR(KBr)：3445m(br)，3229s，3138m，2947w，1627vs，1459w，1384vs，1252w，1221m，1115m，1096m
1H-NMR(D
2O/TMS)：δ1.77(m，2H)，2.15(m，2H)，2.71-2.82(m，6H)，2.87(m，2H)，3.27(m，3H)，3.82(m，1H)
ESI-MS?m/z[M+Na]
+＝478(100％)
Embodiment 17: synthetic suitable-1,1-cyclobutanedicarboxylic acid [(2S)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2S)-2-oxyethyl group-1, the 4-butanediamine] (1.16 restrain to close platinum (II), 2 mmoles) with 1 of new system, 1-ring Succinic Acid silver (0.72 gram, 4 mmoles) mix adding 100 ml waters, 50 ℃ of logical nitrogen of following lucifuges reacted 24 hours, and solution concentration is closely dried, add ethanol and ether, separate out white solid.Cooling is filtered, and drying gets white powder 0.22 gram (23.4%).
IR(KBr)：3454br，3237sh，3109m，2967w，1654vs，1614vs，1374vs，1225w，1112m，1098m
1H-NMR(D
2O/TMS)：δ1.02(m，3H)，1.73(m，2H)，2.02-2.07(m，2H)，2.66-2.86(m，8H)，3.46(m，2H)，3.94(m，1H)
ESI-MS?m/z[M+Na]
+＝492(100％)
Embodiment 18: synthetic suitable-ethanol acid group [(2R)-2-methoxyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-and 2-methoxyl group-1, the 4-butanediamine] (0.68 restrains with Silver Nitrate to close platinum (II) (1.13 grams, 2 mmoles), 4 mmoles) mix adding 50 ml waters, 40 ℃ of logical nitrogen of following lucifuge reacted 24 hours, and the diatomite aided filter adds oxyacetic acid (0.15 gram in the filtrate, 2 mmoles) and sodium hydroxide (0.16 the gram, 4 mmoles) the aqueous solution, 40 ℃ of following lucifuges were reacted 24 hours, and solution concentration is closely dried, add ethanol, separate out solid, filter, filtrate is concentrated, be yellow oil, add ethanol and ether, have a large amount of solids to separate out, filter, drain rapidly, get solid 0.16 gram (20.7%) of the easy moisture absorption.
IR (KBr): very easily the moisture absorption can't detect by compressing tablet
1H-NMR(D
2O/TMS)：δ2.20-2.34(m，2H)，2.79-2.90(m，2H)，2.94-3.02(m，2H)，3.39(m，3H)，3.94(m，1H)，4.09-4.11(m，2H)
ESI-MS?m/z[M+Na]
+＝410(100％)；
Embodiment 19: synthetic suitable-ethanol acid group [(2R)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-and 2-oxyethyl group-1, the 4-butanediamine] (0.68 restrains with Silver Nitrate to close platinum (II) (1.16 grams, 2 mmoles), 4 mmoles) mix adding 50 ml waters, 40 ℃ of logical nitrogen of following lucifuge reacted 24 hours, and the diatomite aided filter adds oxyacetic acid (0.15 gram in the filtrate, 2 mmoles) and sodium hydroxide (0.16 the gram, 4 mmoles) the aqueous solution, 40 ℃ of following lucifuges were reacted 24 hours, and solution concentration is closely dried, add ethanol, separate out solid, filter, filtrate is concentrated, be yellow oil, add ethanol and ether, have a large amount of solids to separate out, filter, drain rapidly, get solid 0.25 gram (31.2%) of the easy moisture absorption.
IR (KBr): very easily the moisture absorption can't detect by compressing tablet
1H-NMR(D
2O/TMS)：δ1.20(m，3H)2.25-2.36(m，2H)，2.83(m，2H)，2.96-3.00(m，2H)，3.58-3.64(m，2H)，4.14(m，1H)，4.18-4.21(m，2H)
ESI-MS?m/z[M+H
2O+H]
+＝420(100％)；
Embodiment 20: synthetic suitable-ethanol acid group [(2S)-2-methoxyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2S)-and 2-methoxyl group-1, the 4-butanediamine] (0.68 restrains with Silver Nitrate to close platinum (II) (1.13 grams, 2 mmoles), 4 mmoles) mix adding 50 ml waters, 40 ℃ of logical nitrogen of following lucifuge reacted 24 hours, and the diatomite aided filter adds oxyacetic acid (0.15 gram in the filtrate, 2 mmoles) and sodium hydroxide (0.16 the gram, 4 mmoles) the aqueous solution, 40 ℃ of following lucifuges were reacted 24 hours, and solution concentration is closely dried, add ethanol, separate out solid, filter, filtrate is concentrated, be yellow oil, add ethanol and ether, have a large amount of solids to separate out, filter, drain rapidly, get solid 0.27 gram (34.9%) of the easy moisture absorption.
IR (KBr): very easily the moisture absorption can't detect by compressing tablet
1H-NMR(D
2O/TMS)：δ2.20-2.35(m，2H)，2.79-2.91(m，2H)，2.95-3.02(m，2H)，3.39(m，3H)，3.94(m，1H)，4.10-4.11(m，2H)
ESI-MS?m/z[M+Na]
+＝410(100％)；
Embodiment 21: synthetic suitable-ethanol acid group [(2S)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2S)-and 2-oxyethyl group-1, the 4-butanediamine] (0.68 restrains with Silver Nitrate to close platinum (II) (1.16 grams, 2 mmoles), 4 mmoles) mix adding 50 ml waters, 40 ℃ of logical nitrogen of following lucifuge reacted 24 hours, and the diatomite aided filter adds oxyacetic acid (0.15 gram in the filtrate, 2 mmoles) and sodium hydroxide (0.16 the gram, 4 mmoles) the aqueous solution, 40 ℃ of following lucifuges were reacted 24 hours, and solution concentration is closely dried, add ethanol, separate out solid, filter, filtrate is concentrated, be yellow oil, add ethanol and ether, have a large amount of solids to separate out, filter, drain rapidly, get solid 0.17 gram (21.2%) of the easy moisture absorption.
IR (KBr): very easily the moisture absorption can't detect by compressing tablet
1H-NMR(D
2O/TMS)：δ1.03-1.06(m，3H)2.17-2.18(m，2H)，2.66-2.67(m，2H)，2.76-2.83m，2H)，3.47-3.51(m，2H)，3.96-4.05(m，3H)
ESI-MS?m/z[M+H]
+＝402(100％)；
Embodiment 22: synthetic suitable-di-alcohol acid group [(2R)-2-methoxyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-and 2-methoxyl group-1, the 4-butanediamine] (0.68 restrains with Silver Nitrate to close platinum (II) (1.13 grams, 2 mmoles), 4 mmoles) mix adding 50 ml waters, 40 ℃ of logical nitrogen of following lucifuges reacted the diatomite aided filter 24 hours, take by weighing oxyacetic acid (0.15 gram, 2 mmoles) be dissolved in less water, transferring pH with aqueous sodium hydroxide solution is 8-9, adds in the filtrate, 40 ℃ of following lucifuges were reacted 24 hours, solution concentration is closely dried, add ethanol, separate out solid, filter, filtrate is concentrated, be yellow oil, add ethanol and ether, there are a large amount of solids to separate out, filter, drain rapidly, get solid 0.16 gram (34.6% amount of pressing oxyacetic acid is calculated) of the easy moisture absorption.
IR (KBr): very easily the moisture absorption can't detect by compressing tablet
1H-NMR(D
2O/TMS)：δ2.18-2.26(m，2H)，2.66-2.78(m，2H)，2.86-2.88(m，2H)，3.28(m，3H)，3.88(m，1H)，3.94-4.00(m，4H)
ESI-MS?m/z[M+Na]
+＝486(100％)；[M-OCOCH
2OH+H
2O]
+＝406(80％)
Embodiment 23: synthetic suitable-di-alcohol acid group [(2R)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-and 2-oxyethyl group-1, the 4-butanediamine] (0.68 restrains with Silver Nitrate to close platinum (II) (1.16 grams, 2 mmoles), 4 mmoles) mix adding 50 ml waters, 40 ℃ of logical nitrogen of following lucifuges reacted the diatomite aided filter 24 hours, take by weighing oxyacetic acid (0.15 gram, 2 mmoles) be dissolved in less water, transferring pH with aqueous sodium hydroxide solution is 8-9, adds in the filtrate, 40 ℃ of following lucifuges were reacted 24 hours, solution concentration is closely dried, add ethanol, separate out solid, filter, filtrate is concentrated, be yellow oil, add ethanol and ether, there are a large amount of solids to separate out, filter, drain rapidly, get solid 0.12 gram (25.1% amount of pressing oxyacetic acid is calculated) of the easy moisture absorption.
IR (KBr): very easily the moisture absorption can't detect by compressing tablet
1H-NMR(D
2O/TMS)：δ1.08-1.11(m，3H)，2.15-2.25(m，2H)，2.68-2.72(m，2H)，2.81-2.89(m，2H)，3.45-3.57(m，2H)，3.93-4.12(m，5H)
ESI-MS?m/z[M-OCOCH
2OH+H
2O]
+＝420(10％)；[M+Na]
+＝500(80％)
Embodiment 24: synthetic suitable-di-alcohol acid group [(2S)-2-methoxyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2S)-and 2-methoxyl group-1, the 4-butanediamine] (0.68 restrains with Silver Nitrate to close platinum (II) (1.13 grams, 2 mmoles), 4 mmoles) mix adding 50 ml waters, 40 ℃ of logical nitrogen of following lucifuges reacted the diatomite aided filter 24 hours, take by weighing oxyacetic acid (0.15 gram, 2 mmoles) be dissolved in less water, transferring pH with aqueous sodium hydroxide solution is 8-9, adds in the filtrate, 40 ℃ of following lucifuges were reacted 24 hours, solution concentration is closely dried, add ethanol, separate out solid, filter, filtrate is concentrated, be yellow oil, add ethanol and ether, there are a large amount of solids to separate out, filter, drain rapidly, get solid 0.18 gram (38.9% amount of pressing oxyacetic acid is calculated) of the easy moisture absorption.
IR (KBr): very easily the moisture absorption can't detect by compressing tablet
1H-NMR(D
2O/TMS)：δ2.17-2.26(m，2H)，2.66-2.78(m，2H)，2.86(m，2H)，3.28(m，3H)，3.90-4.00(m，5H)
ESI-MS?m/z[M+Na]
+＝486(100％)；[M-OCOCH
2OH+H
2O]
+＝406(80％)
Embodiment 25: synthetic suitable-dichloro acetic acid root [(2R)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2R)-2-oxyethyl group-1, the 4-butanediamine] (1.16 restrain to close platinum (II), 2 mmoles) the dichloro acetic acid silver (0.72 gram, 4 mmoles) with new system mixes adding 100 ml waters, and 50 ℃ of following lucifuges are led to nitrogen reaction 24 hours, solution concentration is closely dried, add ethanol and ether, have a large amount of solids to separate out, filter, drain rapidly, get solid 0.17 gram (16.5%) of the easy moisture absorption.
IR (KBr): very easily the moisture absorption can't detect by compressing tablet
1H-NMR(D
2O/TMS)：δ1.04-1.08(m，3H)，2.10-2.26(m，2H)，2.67-2.69(m，2H)，2.77-2.86(m，2H)，3.44-3.51(m，2H)，3.90-4.11(m，5H)
ESI-MS?m/z[M-OCOCH
2Cl+H
2O]
+＝438(100％)
Embodiment 26: synthetic suitable-dichloro acetic acid root [(2S)-2-oxyethyl group-1,4-butanediamine] closes platinum (II)
Suitable-diiodo-[(2S)-2-oxyethyl group-1, the 4-butanediamine] (1.16 restrain to close platinum (II), 2 mmoles) the dichloro acetic acid silver (0.72 gram, 4 mmoles) with new system mixes adding 100 ml waters, and 50 ℃ of following lucifuges are led to nitrogen reaction 24 hours, solution concentration is closely dried, add ethanol and ether, have a large amount of solids to separate out, filter, drain rapidly, get solid 0.12 gram (11.6%) of the easy moisture absorption.
IR (KBr): very easily the moisture absorption can't detect by compressing tablet
1H-NMR(D
2O/TMS)：δ1.04-1.09(m，3H)，2.11-2.26(m，2H)，2.68-2.69(m，2H)，2.77-2.86(m，2H)，3.43-3.51(m，2H)，3.90-4.11(m，5H)
ESI-MS?m/z[M-OCOCH
2Cl+H
2O]
+＝438(100％)
Annotate: the coordination higher because of the Pt elemental abundance have
194Pt,
195Pt and
196Pt is so the mass spectral quasi-molecular ion peak of above-claimed cpd ESI-MS all has three isotopic peaks that abundance is higher
Some typical platinum (II) title complexs are to the vitro inhibition effect of A549 human lung carcinoma cell and HCT-116 human colon cancer cell
The monomeric compound therapeutic evaluation:
Experimental technique: SRB colorimetry
Cell strain: A549 human lung carcinoma cell, HCT-116 human colon cancer cell
Experimental design: drug level is divided into 100,10, five groups of 1,0.5,0.1 (ug/ml).Calculate inhibiting rate according to therapeutic evaluation.Observation under different concns medicine to the inhibition situation of growth of tumour cell.
Allied compound sees Table 1 and table 2 to the extracorporeal inhibiting rate data branch of two kinds of tumour cells.
Table 1. compound is to the growth-inhibiting effect of A549 cell
| ????ug/ml | ????100 | ????10 | ????1 | ????0.5 | ????0.1 | ????IC50 |
| Sample | ||||||
| ????D1a | ????100％ | ????100％ | ????49％ | ????32％ | ????8％ | ????1.01 |
| ????D1b | ????100％ | ????88％ | ????24％ | ????20％ | ????-3％ | ????2.33 |
| ????D1c | ????100％ | ????86％ | ????26％ | ????15％ | ????1％ | ????2.32 |
| ????D1d | ????100％ | ????64％ | ????13％ | ????11％ | ????2％ | ????5.86 |
| ????D1f | ????93％ | ????34％ | ????-4％ | ????1％ | ????4％ | ????15.90 |
| ????D2a | ????99％ | ????100％ | ????82％ | ????66％ | ????13％ | ????0.33 |
| ????D2b | ????100％ | ????100％ | ????25％ | ????32％ | ????30％ | ????1.28 |
| ????D2c | ????100％ | ????76％ | ????13％ | ????11％ | ????5％ | ????4.19 |
| ????D2d | ????98％ | ????40％ | ????2％ | ????12％ | ????0％ | ????12.40 |
| ????D2f | ????100％ | ????91％ | ????5％ | ????-12％ | ????-21％ | ????3.63 |
| ????D2g | ????100％ | ????100％ | ????55％ | ????26％ | ????15％ | ????0.89 |
| ????L1a | ????100％ | ????100％ | ????61％ | ????40％ | ????-1％ | ????0.69 |
| ????L1b | ????98％ | ????90％ | ????38％ | ????-1％ | ????14％ | ????1.52 |
| ????L1c | ????100％ | ????73％ | ????22％ | ????17％ | ????8％ | ????3.63 |
| ????L1d | ????78％ | ????25％ | ????13％ | ????17％ | ????1％ | ????29.20 |
| ????L1f | ????100％ | ????94％ | ????34％ | ????15％ | ????-6％ | ????1.56 |
| ????L2a | ????99％ | ????100％ | ????77％ | ????62％ | ????18％ | ????0.36 |
| ????L2b | ????100％ | ????100％ | ????58％ | ????42％ | ????13％ | ????0.71 |
| ????L2c | ????100％ | ????90％ | ????30％ | ????30％ | ????7％ | ????1.89 |
| ????L2d | ????94％ | ????46％ | ????7％ | ????16％ | ????16％ | ????11.35 |
| ????L2e | ????100％ | ????100％ | ????57％ | ????26％ | ????16％ | ????0.86 |
| Cis-platinum | ????100％ | ????100％ | ????100％ | ????98％ | ????55％ | ????0.09 |
| Carboplatin | ????100％ | ????93％ | ????14％ | ????-2％ | ????0％ | ????2.58 |
Table 2. compound is to the growth-inhibiting effect of HCT-116 cell
| ????ug/ml | ??100 | ????10 | ????1 | ????0.5 | ????0.1 | ????IC50 |
| Sample | ||||||
| ????Control | ||||||
| ????D1a | ??100％ | ????84％ | ????23％ | ????1％ | ????10％ | ????2.64 |
| ????D1b | ??100％ | ????72％ | ????2％ | ????-11％ | ????46％ | ????6.38 |
| ????D1c | ??99％ | ????42％ | ????-5％ | ????-12％ | ????-3％ | ????11.63 |
| ????D1d | ??61％ | ????3％ | ????-2％ | ????3％ | ????1％ | ????76.90 |
| ????D1f | ??32％ | ????-5％ | ????-4％ | ????-4％ | ????1％ | ????100.00 |
| ????D2a | ??100％ | ????100％ | ????62％ | ????38％ | ????-2％ | ????0.71 |
| ????D2b | ??100％ | ????82％ | ????19％ | ????0％ | ????-8％ | ????3.08 |
| ????D2c | ??98％ | ????37％ | ????8％ | ????13％ | ????-3％ | ????13.20 |
| ????D2d | ??67％ | ????15％ | ????0％ | ????0％ | ????-4％ | ????51.30 |
| ????D2f | ??100％ | ????37％ | ????-9％ | ????0％ | ????-8％ | ????11.30 |
| ????D2g | ??100％ | ????80％ | ????7％ | ????3％ | ????-2％ | ????4.47 |
| ????L1a | ??100％ | ????99％ | ????61％ | ????29％ | ????15％ | ????0.78 |
| ????L1b | ??100％ | ????65％ | ????8％ | ????9％ | ????7％ | ????6.27 |
| ????L1c | ??100％ | ????46％ | ????4％ | ????2％ | ????7％ | ????10.40 |
| ????L1d | ??49％ | ????5％ | ????-13％ | ????20％ | ????17％ | ????100.00 |
| ????L1f | ??98％ | ????6％ | ????-8％ | ????10％ | ????-4％ | ????25.90 |
| ????L2a | ??100％ | ????100％ | ????43％ | ????40％ | ????5％ | ????1.07 |
| ????L2b | ??100％ | ????72％ | ????33％ | ????13％ | ????1％ | ????2.63 |
| ????L2c | ??100％ | ????68％ | ????11％ | ????3％ | ????5％ | ????5.43 |
| ????L2d | ??69％ | ????10％ | ????-1％ | ????4％ | ????17％ | ????54.10 |
| ????L2e | ??100％ | ????73％ | ????14％ | ????10％ | ????13％ | ????4.43 |
| Oxaliplatin | ??100％ | ????95％ | ????90％ | ????47％ | ????19％ | ????0.51 |
Allied compound is to corresponding tumour cell IC
50Value figure sees Figure of description, and wherein: Fig. 1 is that compound is to A549 cell IC
50Value, Fig. 2 is that compound is to HCT-116 cell IC
50Value.
Claims (4)
1, a class have optically active 1, the 4-diamine compound, its optical isomer is characterized in that this compounds represented by formula (1):
Chirality 1 in its Chinese style (1), 4-diamines can be optically active isomer (2R)-2-alkoxyl groups-1,4-butanediamine or its enantiomer (2S)-2-alkoxyl group-1, and the 4-butanediamine, wherein the R group is C
1-5Alkyl.
2, a class has effective antitumor active platinum (II) coordination compound, and its steric isomer is characterized in that this compounds is by the expression of formula (2) and formula (3):
In its Chinese style (2) and the formula (3) as the chirality 1 of part, the 4-diamines defines as claim 1, X group in the formula (2) is respectively chlorion, chloroacetate root, ethanol acid group, R ' group in the formula (3) is a bidentate carboxylic-acid part, be respectively oxalate, malonate, 1,1-cyclobutanedicarboxylic acid, chelating ethanol acid group.
3, according to the preparation method of the defined platinum of claim 2 (II) title complex, it is characterized in that two halogen ion diamines coordinate platinum (II) compounds of formula (4) representative are led under the condition of nitrogen gas in lucifuge, close halide-ions in the platinum (II) by using silver (I) ion to remove the dihalo-diamines, obtain the defined platinum of claim 2 (II) compound;
Hal in its Chinese style (4) represents Cl
-, Br
-And I
-Ion, the R group defines by the formula (1) in the claim 1.
4, the anti-tumor activity of platinum according to claim 2 (II) title complex is characterized in that the effective restraining effect of this eka-platinium (II) title complex to human colon cancer cell and lung carcinoma cell.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010043186A1 (en) * | 2008-10-17 | 2010-04-22 | 东南大学 | New pt(ii) complex and antitumor activity thereof |
| CN108148080A (en) * | 2018-02-05 | 2018-06-12 | 广西师范大学 | Organic golden (III) complex of metal and its synthetic method and application |
| WO2021143617A1 (en) * | 2020-01-16 | 2021-07-22 | 郑州手性药物研究院有限公司 | Cyclohexadiene oxime ether compound, synthesis method therefor and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010043186A1 (en) * | 2008-10-17 | 2010-04-22 | 东南大学 | New pt(ii) complex and antitumor activity thereof |
| CN101381380B (en) * | 2008-10-17 | 2011-05-11 | 东南大学 | Platinum (II) complexes and antineoplastic activity thereof |
| CN108148080A (en) * | 2018-02-05 | 2018-06-12 | 广西师范大学 | Organic golden (III) complex of metal and its synthetic method and application |
| CN108148080B (en) * | 2018-02-05 | 2019-07-09 | 广西师范大学 | Organic golden (III) complex of metal and its synthetic method and application |
| WO2021143617A1 (en) * | 2020-01-16 | 2021-07-22 | 郑州手性药物研究院有限公司 | Cyclohexadiene oxime ether compound, synthesis method therefor and application thereof |
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