CN1478785A - Antitumour platinum (II) compound using camphor acid radical as ligand - Google Patents
Antitumour platinum (II) compound using camphor acid radical as ligand Download PDFInfo
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- CN1478785A CN1478785A CNA031319254A CN03131925A CN1478785A CN 1478785 A CN1478785 A CN 1478785A CN A031319254 A CNA031319254 A CN A031319254A CN 03131925 A CN03131925 A CN 03131925A CN 1478785 A CN1478785 A CN 1478785A
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- camphor acid
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- 239000002253 acid Substances 0.000 title claims description 38
- 229960000846 camphor Drugs 0.000 title claims description 26
- 241000723346 Cinnamomum camphora Species 0.000 title claims description 14
- 229930008380 camphor Natural products 0.000 title claims description 14
- -1 platinum (II) compound Chemical class 0.000 title claims description 13
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 title claims description 10
- 230000000259 anti-tumor effect Effects 0.000 title claims description 8
- 239000003446 ligand Substances 0.000 title abstract 3
- 238000000034 method Methods 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 6
- 208000032839 leukemia Diseases 0.000 claims abstract description 6
- 201000007270 liver cancer Diseases 0.000 claims abstract description 6
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 4
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims abstract description 3
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims description 43
- 150000001875 compounds Chemical class 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 25
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 17
- 229910052697 platinum Inorganic materials 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- YMHQVDAATAEZLO-UHFFFAOYSA-N cyclohexane-1,1-diamine Chemical compound NC1(N)CCCCC1 YMHQVDAATAEZLO-UHFFFAOYSA-N 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 11
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 150000004985 diamines Chemical class 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 201000005296 lung carcinoma Diseases 0.000 claims description 5
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- LSPHULWDVZXLIL-LDWIPMOCSA-N (?)-Camphoric acid Chemical compound CC1(C)[C@@H](C(O)=O)CC[C@@]1(C)C(O)=O LSPHULWDVZXLIL-LDWIPMOCSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 150000001768 cations Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 238000012986 modification Methods 0.000 claims description 2
- 230000004048 modification Effects 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 239000004332 silver Substances 0.000 claims description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 229910021386 carbon form Inorganic materials 0.000 claims 1
- 230000000452 restraining effect Effects 0.000 claims 1
- 125000000129 anionic group Chemical group 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract 1
- 230000000118 anti-neoplastic effect Effects 0.000 abstract 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 abstract 1
- 125000002091 cationic group Chemical group 0.000 abstract 1
- 201000005202 lung cancer Diseases 0.000 abstract 1
- 208000020816 lung neoplasm Diseases 0.000 abstract 1
- 230000001629 suppression Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 229930007886 (R)-camphor Natural products 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 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 6
- 229960004562 carboplatin Drugs 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000003252 repetitive effect Effects 0.000 description 6
- 238000005201 scrubbing Methods 0.000 description 6
- 229910001961 silver nitrate Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 4
- 230000010261 cell growth Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical class CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229930008399 cantharidic acid Natural products 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- CCQPAEQGAVNNIA-UHFFFAOYSA-N cyclobutane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-N 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 230000012010 growth Effects 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
- 150000001457 metallic cations Chemical class 0.000 description 1
- ZZDBMDNRQQDSKG-UHFFFAOYSA-N methyl 5-bromo-1-benzofuran-2-carboxylate Chemical compound BrC1=CC=C2OC(C(=O)OC)=CC2=C1 ZZDBMDNRQQDSKG-UHFFFAOYSA-N 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/65—Metal complexes of amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C61/06—Saturated compounds having a carboxyl group bound to a five-membered ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (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)
Abstract
An antineoplastic Pt(II) match, its preparing process, and its external suppression action to human leukemia cells, ovarian cancer cells, liver cancer cells and lung cancer cells are disclosed. It features that said Pt(II) match is prepared through reaction between the radical of camphoric acid as anionic ligand and the platium amine as cationic ligand.
Description
One. technical field
The present invention relates to have the active novel platinum of effective antitumor (II) title complex, the extracorporeal anti-tumor character of typical compound in its preparation method and described platinum (II) title complex.
Two. background technology
In the research of cis-platinum kind anti-cancer drugs thing, very big to the activity influence of medicine as the anionic characteristic of leavings group.If adopt unsettled leavings group, the toxicity of compound will increase; If use the inert leavings group, the then common non-activity of compound.After the carboplatin that contains cyclobutanedicarboxylic acid was succeeded in developing, di-carboxylic acid was played the part of important role always in the research and development of antitumor platinum (II) title complex medicine.As oxalic acid, propanedioic acid with go the first Cantharidic acid all to obtain practical application.Therefore designing and improving anti-tumor agent with the synthetic cis-platinum compounds with low toxicity and good water solubility that contains the di-carboxylic acid root is an important approach.
Three. summary of the invention
The objective of the invention is to be the cis-platinum that contains the di-carboxylic acid root (II) the class title complex that provides novel, these title complexs have low toxicity, better water-soluble, effective antitumour is active, is used for the treatment of human tumor.The invention discloses the novel platinum of a class (II) coordination compound, it is characterized in that using the camphor acid group is novel platinum (II) coordination compound that complex anion and the reaction of platinum amine complex cation form.The composition of this compounds is represented by following (1), (2), (3) formula:
Camphor acid group in its Chinese style (1), formula (2) and the formula (3) can be its racemic modification, D type optically active isomer [(1R, 3S)-(+)-the camphor acid group] or L type optically active isomer [(1S, 3R)-(-)-the camphor acid group].R group in the formula (1) is identical, is respectively hydrogen atom, C
1-5Alkyl or C
1-8Oxa alkyl; Cyclohexanediamine in the formula (2) is 1, the trans cyclohexanediamine of 2-, and two chiral carbon atoms (indicate
*Number) absolute configuration all be R configuration or S configuration; In the formula (3) 4,5-two (aminomethyl)-2-alkyl-1, R shown in the 3-dioxolane
1And R
2Identical or inequality, be respectively hydrogen atom or C
1-5Alkyl, or can connect the formation cycloalkyl with a carbon atom, two chiral carbon atoms (indicate
*Number) absolute configuration all be R configuration or S configuration.Platinum complex of the present invention comprises all steric isomers shown in the above-mentioned chemical formula and composition thereof.
Another object of the present invention provides the method for platinum (II) title complex shown in preparation formula (1), formula (2) and the formula (3).In these divalence platinum complexes synthetic, they at first are to obtain containing two halogen ion diamines coordinate platinic compound by potassium tetrachloroplatinate with relevant diamines (ammonia) part effect, represent by formula (4a) with (4b).Then under the logical condition of nitrogen gas of lucifuge, by method A: use silver ions to remove the halide-ions that dihalo-diamines (ammonia) closes platinum (II), the camphorate effect of gained intermediate and monovalent base metallic cation or ammonium ion obtains, and suitable-(camphor acid group) diamines (ammonia) closes platinum (II) compound; Or by method B: use dextrocamphoric acid silver salt and dihalo-diamines (ammonia) to close platinum (II) and act on and obtain suitable-(camphor acid group) diamines (ammonia) and close platinum (II) compound.
Hal among formula (4a) and 4 (b) represents Cl
-, Br
-And I
-Ion, the R group of its Chinese style (4a) is identical, is respectively hydrogen atom or C
1-5Alkyl or C
1-8Two amidos of arc representation that oxa alkyl, formula (4b) are connected on the amine nitrogen atom are linked to each other by alkyl.
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 leukaemia cell, ovarian cancer cell, liver cancer cell and lung carcinoma cell.
The representational compound of the present invention comprises:
Suitable-(DL-camphor acid group) two ammino platinum (II) are (slightly: GS-1a);
Suitable-(D-camphor acid group) two ammino platinum (II) are (slightly: GS-1b);
Suitable-(DL-camphor acid group) Diisopropylamine closes platinum (II) (slightly: GS-2a);
Suitable-(D-camphor acid group) Diisopropylamine closes platinum (II) (slightly: GS-2b);
Suitable-(DL-camphor acid group) (1, the trans cyclohexanediamine of 2-) closes platinum (II) (slightly: GS-3a);
Suitable-(D-camphor acid group) (1, the trans cyclohexanediamine of 2-) closes platinum (II) (slightly: GS-3b);
Suitable-(DL-camphor acid group) [(1R, 2R)-1, the trans cyclohexanediamine of 2-] close platinum (II) (slightly: GS-4a);
Suitable-(D-camphor acid group) [(1R, 2R)-1, the trans cyclohexanediamine of 2-] close platinum (II) (slightly: GS-4b);
Suitable-(DL-camphor acid group) [(1S, 2S)-1, the trans cyclohexanediamine of 2-] close platinum (II) (slightly: GS-5a);
Suitable-(D-camphor acid group) [(1S, 2S)-1, the trans cyclohexanediamine of 2-] close platinum (II) (slightly: GS-5b);
Suitable-(DL-camphor acid group) [4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] closes platinum (II) (slightly: GS-6a);
Suitable-(D-camphor acid group) [4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] closes platinum (II) (slightly: GS-6b);
Suitable-(DL-camphor acid group) [(4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] close platinum (II) (slightly: GS-7a);
Suitable-(D-camphor acid group) [(4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] close platinum (II) (slightly: GS-7b);
Suitable-(DL-camphor acid group) [(4S, 5S)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] close platinum (II) (slightly: GS-8a).
Suitable-(D-camphor acid group) [(4S, 5S)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] close platinum (II) (slightly: GS-8b);
Suitable-(DL-camphor acid group) two (2-methoxy ethyl amine) closes platinum (II) (slightly: GS-9a);
Suitable-(D-camphor acid group) two (2-methoxy ethyl amine) closes platinum (II) (slightly: GS-9b).
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 ultimate analysis, 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 1: synthetic suitable-(DL-camphor acid group) two ammino platinum (II)
Suitable-diiodo-two ammino platinum (II) (0.97 gram, 2 mmoles), Silver Nitrate (0.68 gram, 4 mmoles) mixing adds entry (50 milliliters), and 60 ℃ of logical nitrogen of following lucifuges reacted the diatomite aided filter 24 hours, add DL-dextrocamphoric acid (0.40 gram in the filtrate, 4 mmoles) with the aqueous solution of sodium hydroxide (0.16 gram, 4 mmoles), 60 ℃ of logical nitrogen reactions of following lucifuges 16 hours, with solution concentration, separate out a large amount of white solids.Filter, water, ethanol, ether repetitive scrubbing, 60 ℃ of following vacuum-dryings get product 0.41g (48%).IR (KBr): 3424vs (br), 3266vs (br), 2967m, 2881w, 1594vs, 1544vs, 1460m, 1384vs, 1355vs
1H-NMR (D
2O/TMS): δ 0.47-0.67 (m, 3H), 0.91-1.08 (m, 6H), 1.24-1.31 (s, 1H), 1.60 (s, 1H), 1.74-1.75 (s, 1H), 2.08 (m, 1H), 2.55-2.56 (s, 1H) ESI-MS:[M+ methyl alcohol+H]
+=460 (30%), [M+H]
+=428 (6%) embodiment 2: synthetic suitable-(DL-camphor acid group) two (Isopropylamines) close platinum (II)
Suitable-diiodo-two (Isopropylamine) closes platinum (II) (1.13 grams, 2 mmoles), Silver Nitrate (0.68 gram, 4 mmoles) mixing adds entry (50 milliliters), and 60 ℃ of logical nitrogen of following lucifuges reacted the diatomite aided filter 24 hours, add DL-dextrocamphoric acid (0.40 gram in the filtrate, 4 mmoles) with the aqueous solution of sodium hydroxide (0.16 gram, 4 mmoles), 60 ℃ of logical nitrogen reactions of following lucifuges 16 hours, with solution concentration, separate out a large amount of white solids.Filter, water, ethanol, ether repetitive scrubbing, 60 ℃ of following vacuum-dryings get product 0.39g (38%).IR (KBr): 3430s (br), and 3217s (sh, br), 2971vs, 2880w, 1595vs (br), 1462m, 1383vs, 1351vs, 1164w, 1118w
1H-NMR (DMSO-d
6/ TMS): δ 0.70-0.85 (m, 3H), 0.97-1.26 (m, 18H), 1.44-2.36 (br, 4H), 2.64-2.70 (br, 1H, CH), 2.96-3.18 (m, 2H), 5.85-5.99 (br, NH
2) ESI-MS:[M+ methyl alcohol+H]
+=544 (100%), [M+H]
+=512 (44%) embodiment 3: synthetic suitable-(D-camphor acid group) [(1R, 2R)-1, the trans cyclohexanediamine of 2--] close platinum (II)
Suitable-dichloro [(1R, 2R)-1, the trans cyclohexanediamine of 2-] (0.76 restrains to close platinum (II), 2 mmoles), Silver Nitrate (0.68 gram, 4 mmoles) mixing adds entry (50 milliliters), and 60 ℃ of logical nitrogen of following lucifuges reacted the diatomite aided filter 24 hours, add D-dextrocamphoric acid (0.40 gram in the filtrate, 4 mmoles) with the aqueous solution of sodium hydroxide (0.16 gram, 4 mmoles), 60 ℃ of logical nitrogen reactions of following lucifuges 16 hours, with solution concentration, separate out a large amount of white solids.Filter, water, ethanol, ether repetitive scrubbing, 60 ℃ of following vacuum-dryings get product 0.65g (64%).IR (KBr): 3424vs (br), and 3226s (sh, br), 2939s, 2872w, 1598vs (br), 1457m, 1381vs, 1350s, 1169w, 1126w, 1063w
1H-NMR (DMSO-d
6/ TMS): δ 0.84-0.91 (m, 3H), 1.09-1.20 (m, 6H), 1.28 (m, 4H), 1.48 (m, 2H), 1.57-1.62 (m, 3H), 2.08-2.22 (m, 3H), 2.41-2.57 (m, 3H), 5.87-6.44 (br, NH
2) ESI-MS:[M+ methyl alcohol+H]
+=540 (100%), [M+H]
+=508 (40%) embodiment 4: synthetic suitable-(D-camphor acid group) [(4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] close platinum (II)
Suitable-diiodo-[(4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-1, the 3-dioxolane] close platinum (II) (1.25 gram, 2 mmoles), Silver Nitrate (0.68 gram, 4 mmoles) and mix and add entry (50 milliliters), 60 ℃ of logical nitrogen of following lucifuge reacted 24 hours, the diatomite aided filter adds D-dextrocamphoric acid (0.40 gram, 4 mmoles) and sodium hydroxide (0.16 gram in the filtrate, 4 mmoles) the aqueous solution, 60 ℃ of logical nitrogen of following lucifuge reacted 16 hours, with solution concentration, separated out a large amount of white solids.Filter, water, ethanol, ether repetitive scrubbing, 60 ℃ of following vacuum-dryings get product 0.55g (49%).IR (KBr): 3424s (br), and 3220s (sh, br), 2966m, 2881w, 1620-1559s (br), 1460m, 1383vs, 1357s, 1125m, 1093s
1H-NMR (DMSO-d
6/ TMS): δ 0.77-1.14 (m, 15H), 1.58-2.03 (m, 3H), 2.45-2.87 (m, 7H), 3.22-3.30 (m, 2H), 4.82 (s, 1H), 6.40-7.50 (br, NH
2) ESI-MS:[M+ methyl alcohol+H]
+=600 (34%) embodiment 5: synthetic suitable-(D-camphor acid group) [(4S, 5S)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] close platinum (II)
Suitable-diiodo-[(4S, 5S)-4,5-two (aminomethyl)-2-sec.-propyl-1, the 3-dioxolane] close platinum (II) (1.25 gram, 2 mmoles), Silver Nitrate (0.68 gram, 4 mmoles) and mix and add entry (50 milliliters), 60 ℃ of logical nitrogen of following lucifuge reacted 24 hours, the diatomite aided filter adds D-dextrocamphoric acid (0.40 gram, 4 mmoles) and sodium hydroxide (0.16 gram in the filtrate, 4 mmoles) the aqueous solution, 60 ℃ of logical nitrogen of following lucifuge reacted 16 hours, with solution concentration, separated out a large amount of white solids.Filter, water, ethanol, ether repetitive scrubbing, 60 ℃ of following vacuum-dryings get product 0.42g (37%).IR (KBr): 3427s (br), and 3218s (sh, br), 2966m, 2881w, 1621-1560s (br), 1461m, 1381vs, 1358s, 1124m, 1094s
1H-NMR (DMSO-d
6/ TMS): δ 0.72-1.14 (m, 15H), 1.58-1.95 (m, 3H), 2.45-2.87 (m, 7H), 3.15-3.20 (m, 2H), 4.80 (s, 1H), 6.50-7.20 (br, NH
2) ESI-MS:[M+ methyl alcohol+H]
+=600 (100%) embodiment 6: synthetic suitable-(DL-camphor acid group) two (2-methoxy ethyl amine) closes platinum (II)
Suitable-diiodo-two (2-methoxy ethyl amine) closes platinum (II) (1.20 grams, 2 mmoles), Silver Nitrate (0.68 gram, 4 mmoles) mixing adds entry (50 milliliters), and 60 ℃ of logical nitrogen of following lucifuges reacted the diatomite aided filter 24 hours, add DL-dextrocamphoric acid (0.40 gram in the filtrate, 4 mmoles) with the aqueous solution of sodium hydroxide (0.16 gram, 4 mmoles), 60 ℃ of logical nitrogen reactions of following lucifuges 16 hours, with solution concentration, separate out a large amount of white solids.Filter, water, ethanol, ether repetitive scrubbing, 60 ℃ of following vacuum-dryings get product 0.54g (50%).IR (KBr): 3447m (br), 3217m, 3122m, 2963m, 2882m, 2829w, 1610vs, 1457m, 1378vs, 1346vs, 1119s, 1052m
1H-NMR (DMSO-d
6/ TMS): δ 0.545-0.712 (m, 3H), 0.93-1.15 (m, 6H), 1.22-2.35 (m, 4H), 2.49 (m, 1H), 2.623 (m, 2H), 3.06 (s, 3H), 3.42 (s, 2H), 5.57-5.91 (br, NH
2) ESI-MS:[M+ methyl alcohol+H]
+=576 (40%) 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.Four. some typical compounds are to the vitro inhibition effect of human leukaemia cell, ovarian cancer cell, liver cancer cell and lung carcinoma cell
The monomeric compound therapeutic evaluation:
Experimental technique: platform expects that blue row dyes method, SRB colorimetry
Cell strain: HL-60 human leukemia cell, 3AO Proliferation of Human Ovarian Cell, BEL-7402 human liver cancer cell, A549 human lung carcinoma cell.
Experimental design: drug level is divided into 100,10, three groups of 1,0.1,0.01 (μ g/ml).Calculate inhibiting rate according to therapeutic evaluation.Medicine is to the inhibition situation of growth of tumour cell under different concns in observation, and cis-platinum and carboplatin are as reference.
Allied compound to the extracorporeal inhibiting rate data branch of four kinds of tumour cells see Table 1, table 2, table 3 and table 4.
Table 1. compound is to human leukemia cell's (HL-60) vitro inhibition activity ratio
| Each concentration (μ g/ml) is HL-60 cell viable count (* 10 down 4/ml) | Each concentration (μ g/ml) is cell growth-inhibiting percentage (%) down | |||
| The sample title | Time???Ctrl Zero????46 6 | ?100??10?????1????0.1????0.01 | ?100?????10????1??????0.1??0.01 | ??GI 50 |
| GS-1a GS-1b GS-2a GS-2b GS-4a GS-4b GS 7a GS-7b cis-platinum carboplatin | ??0????8?????37????48?????50 ??0????2?????34????41?????50 ??0????29????41????48?????50 ??0????26????32????36?????56 ??0????1?????22????49?????50 ??0????5?????25????40?????49 ??0????0?????22????47?????50 ??0????0?????1?????24?????37 ??0????0?????6?????28?????47 ??0????10????32????40?????49 | ??100????95?????23?????0?????0 ??100????100????30?????12????0 ??100????43?????13?????0?????0 ??100????50?????35?????25????0 ??100????100????60?????0?????0 ??100????100????53?????15????0 ??100????100????60?????0?????0 ??100????100????100????55????23 ??100????100????100????45????0 ??100????90?????35?????15????0 | ??2.57 ??0.42 ??3.75 ??2.61 ??0.97 ??0.34 ??0.97 ??0.03 ??0.10 ??1.06 | |
Table 2. compound is to the vitro inhibition activity ratio of people's gonad cell (3AO)
| Each concentration (μ g/ml) is 3AO cell viable count (* 10 down 4/ml) | Each concentration (μ g/ml) is cell growth-inhibiting percentage (%) down | |||
| The sample title | Time????Ctrl Zero????0.77 0.25 | 100??????10????????1???????0.1??????0.01 | ?100????10?????1????0.1????0.01 | ????GI 50 |
| GS-1a GS-1b GS-2a GS-2b GS-4a GS-4b GS-7a GS-7b cis-platinum carboplatin | 0.42?????0.53?????0.66?????0.66?????0.65 0.36?????0.59?????0.64?????0.69?????0.66 0.46?????0.55?????0.63?????0.55?????0.55 0.45?????0.49?????0.47?????0.51?????0.50 0.49?????0.43?????0.43?????0.56?????0.55 0.29?????0.4??????0.45?????0.55?????0.53 0.41?????0.36?????0.53?????0.55?????0.57 0.27?????0.41?????0.49?????0.52?????0.54 0.29?????0.28?????0.45?????0.52?????0.53 0.3??????0.52?????0.55?????0.55?????0.61 | ?67?????46?????21?????21?????23 ?79?????35?????25?????15?????21 ?60?????42?????27?????42?????42 ?62?????54?????58?????50?????52 ?54?????65?????65?????40?????42 ?92?????71?????62?????42?????46 ?69?????79?????46?????42?????38 ?96?????69?????54?????48?????44 ?92?????94?????62?????48?????46 ?90?????48?????42?????42?????31 | ????15.3 ????20.8 ????27.7 ????0.1 ????0.25 ????0.25 ????1.28 ????0.22 ????0.14 ????10.8 | |
Table 3. compound is to the vitro inhibition activity ratio of human liver cancer cell (BEL-7402)
| Each concentration (μ g/ml) is BEL-7402 cell viable count (* 10 down 4/ml) | Each concentration (μ g/ml) is cell growth-inhibiting percentage (%) down | |||
| The sample title | Time????Ctrl Zero????1.44 0.43 | ?100????????10??????1????????0.1?????0.01 | ?100????10????1??????0.1????0.01 | ?GI 50 |
| GS-1a GS-1b GS-2a GS-2b GS-4a GS-4b GS-7a GS-7b cis-platinum carboplatin | ?0.28??????1.07????1.22?????1.22?????1.16 ?0.36??????0.76????1.29?????1.33?????1.22 ?0.85??????1.24????1.2??????1.21?????1.24 ?0.99??????1.03????1.15?????1.16?????1.18 ?0.4???????0.85????0.97?????1.12?????1.21 ?0.43??????0.9?????1.01?????1.14?????1.2 ?0.53??????0.53????1.21?????1.19?????1.07 ?0.37??????0.5?????1.17?????1.21?????1.14 ?0.31??????0.30????0.96?????1.00?????1.13 ?0.31??????1.23????1.26?????1.21?????1.23 | ?100????37?????22?????22?????28 ?100????67?????15?????11?????22 ?58?????20?????24?????23?????20 ?45?????41?????29?????28?????26 ?100????58?????47?????32?????23 ?100????53?????43?????29?????24 ?90?????90?????23?????24?????37 ?100????93?????27?????22?????30 ?100????100????48?????44?????31 ?100????21?????18?????23?????21 | ??11.3 ??5.13 ??64.7 ?＞100 ??1.86 ??5.02 ??2.26 ??1.89 ??0.23 ??13.4 | |
Table 4. compound is to the vitro inhibition activity ratio of human lung carcinoma cell (A549)
| Each concentration (μ g/ml) is A549 cell viable count (* 10 down 4/ml) | Each concentration (μ g/ml) is cell growth-inhibiting percentage (%) down | |||
| The sample title | Time????Ctrl Zero????1.95 0.34 | ?100?????10????????1??????0.1??????0.01 | ?100???10????1????0.1????0.01 | ???GI 50 |
| GS-1a GS-1b GS-2a GS-2b GS-4a GS-4b GS-7a GS-7b cis-platinum carboplatin | ?0.43????1.28?????1.84????1.92?????1.74 ?0.47????1.06?????1.76????1.86?????1.84 ?1.25????1.68?????1?79????1?82?????1.57 ?1.11????1.52?????1.71????1.67?????1.56 ?0.57????1.83?????1.54????1.68?????1.69 ?0.73????0.96?????1.77????1.76?????1.56 ?0.56????1.12?????1.64????1.7??????1.55 ?0.81????0.91?????1.68????1.82?????1.77 ?0.40????0.32?????1.04????1.62?????1.58 ?0.39????1.46?????1.56????1.49?????1.57 | ?94????42????7?????2?????13 ?92????55????12????6?????7 ?43????17????10????8?????24 ?52????27????15????17????24 ?86????7?????25????17????16 ?76????61????11????12????24 ?86????52????19????16????25 ?71????65????17????8?????11 ?96????100???57????21????23 ?97????30????24????29????24 | ????78.5 ????8.1 ??＞100 ????84 ????38.7 ????6.66 ????8.87 ????5.23 ????0.67 ????15.7 | |
Compound is to corresponding tumour cell GI
50Value figure sees Figure of description.Wherein: Fig. 1 is that compound is to HL-60 cell GI
50Value, Fig. 2 is that compound is to 3AO cell GI
50Value, Fig. 3 is that compound is to BEL-7402 cell GI
50Value, Fig. 4 is that compound is to A549 cell GI
50Value.
Claims (3)
1, a class has effective antitumor active platinum (II) coordination compound, and it is characterized in that using the camphor acid group is novel platinum (II) coordination compound that complex anion and the reaction of platinum amine complex cation form.The composition of this compounds is expressed from the next:
Camphor acid group in its Chinese style (1), formula (2) and the formula (3) can be its DL racemic modification, D type optically active isomer [(1R, 3S)-(+)-the camphor acid group] or L type optically active isomer [(1S, 3R)-(-)-the camphor acid group].R group in the formula (1) is identical, is respectively hydrogen atom, C
1-5Alkyl or C
1-8Oxa alkyl; Cyclohexanediamine in the formula (2) is 1, the trans cyclohexanediamine of 2-, and the absolute configuration of two chiral carbon atoms (indicating * number) all is R configuration or S configuration; In the formula (3) 4,5-two (aminomethyl)-2-alkyl-1, R shown in the 3-dioxolane
1And R
2Identical or inequality, be respectively hydrogen atom or C
1-5Alkyl, or can connect with-carbon atom and form cycloalkyl, the absolute configuration of two chiral carbon atoms (indicating * number) all is R configuration or S configuration.Platinum complex of the present invention comprises all steric isomers shown in the above-mentioned chemical formula and composition thereof.
2, according to the preparation method of the described platinum of claim 1 (II) title complex, it is characterized in that two halogen ion diamines coordinate platinic compound of formula (4) representative are led under the condition of nitrogen gas in lucifuge, by method A: use silver ions to remove the halide-ions that dihalo-diamines (ammonia) closes platinum (II), the camphorate effect of gained intermediate and-valency alkali metal cation or ammonium ion obtains suitable-(camphor acid group) diamines (ammonia) and closes platinum (II) compound; Or by method B: use dextrocamphoric acid silver salt and dihalo-diamines (ammonia) to close platinum (II) and act on and obtain suitable-(camphor acid group) diamines (ammonia) and close platinum (II) compound.
Hal among formula (4a) and 4 (b) represents Cl
-, Br
-And I
-Ion, the R group of its Chinese style (4a) defines by right 1, and two amidos of arc representation that formula (4b) is connected on the amine nitrogen atom are defined by right 1 by alkyl is continuous.
3, the anti-tumor activity of platinum according to claim 1 (II) title complex and platinum (II) title complex that obtains according to the described preparation method of claim 2 is characterized in that the effective restraining effect of this eka-platinium (II) title complex to human leukaemia cell, ovarian cancer cell, liver cancer cell and lung carcinoma cell.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031319254A CN1203080C (en) | 2003-06-19 | 2003-06-19 | Antitumour platinum (II) compound using camphor acid radical as ligand |
| PCT/CN2004/000585 WO2004110973A1 (en) | 2003-06-19 | 2004-06-02 | Anti-tumour platinum (ii) complexes with camphoric radicals as ligands |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031319254A CN1203080C (en) | 2003-06-19 | 2003-06-19 | Antitumour platinum (II) compound using camphor acid radical as ligand |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1478785A true CN1478785A (en) | 2004-03-03 |
| CN1203080C CN1203080C (en) | 2005-05-25 |
Family
ID=32001496
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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|---|---|
| CN (1) | CN1203080C (en) |
| WO (1) | WO2004110973A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110218230A (en) * | 2018-03-02 | 2019-09-10 | 天津谷堆生物医药科技有限公司 | Vitamin C is coupled platinum complex, wherein mesosome, preparation method, pharmaceutical composition and purposes |
-
2003
- 2003-06-19 CN CNB031319254A patent/CN1203080C/en not_active Expired - Fee Related
-
2004
- 2004-06-02 WO PCT/CN2004/000585 patent/WO2004110973A1/en active Application Filing
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110218230A (en) * | 2018-03-02 | 2019-09-10 | 天津谷堆生物医药科技有限公司 | Vitamin C is coupled platinum complex, wherein mesosome, preparation method, pharmaceutical composition and purposes |
| CN110218230B (en) * | 2018-03-02 | 2022-06-28 | 天津谷堆生物医药科技有限公司 | Vitamin C coupled platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and application |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004110973A1 (en) | 2004-12-23 |
| CN1203080C (en) | 2005-05-25 |
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