CN1296377C - Preparation of platinum (II) complex containing ether bond carboxylic radical as ligand - Google Patents
Preparation of platinum (II) complex containing ether bond carboxylic radical as ligand Download PDFInfo
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- CN1296377C CN1296377C CNB031318517A CN03131851A CN1296377C CN 1296377 C CN1296377 C CN 1296377C CN B031318517 A CNB031318517 A CN B031318517A CN 03131851 A CN03131851 A CN 03131851A CN 1296377 C CN1296377 C CN 1296377C
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- platinum
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- acetic acid
- alkyl
- diamines
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- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 239000003446 ligand Substances 0.000 title abstract 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 title description 17
- -1 platinum amine Chemical class 0.000 claims abstract description 27
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 17
- YMHQVDAATAEZLO-UHFFFAOYSA-N cyclohexane-1,1-diamine Chemical compound NC1(N)CCCCC1 YMHQVDAATAEZLO-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 3
- 150000001450 anions Chemical class 0.000 claims abstract 2
- 150000001768 cations Chemical class 0.000 claims abstract 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- 150000004985 diamines Chemical class 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 125000003368 amide 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
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 239000004332 silver Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 11
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 abstract 1
- YZGQDNOIGFBYKF-UHFFFAOYSA-N Ethoxyacetic acid Chemical compound CCOCC(O)=O YZGQDNOIGFBYKF-UHFFFAOYSA-N 0.000 description 26
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 14
- WEZYFYMYMKUAHY-UHFFFAOYSA-N tert-butyl 2,4-dibenzylpiperazine-1-carboxylate Chemical compound C1C(CC=2C=CC=CC=2)N(C(=O)OC(C)(C)C)CCN1CC1=CC=CC=C1 WEZYFYMYMKUAHY-UHFFFAOYSA-N 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 8
- 229940043279 diisopropylamine Drugs 0.000 description 6
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 6
- 230000003252 repetitive effect Effects 0.000 description 4
- 238000005201 scrubbing Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910001961 silver nitrate Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002500 ions Chemical group 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- ALPHSAWEOKVWID-UHFFFAOYSA-L (2-azanidylcyclohexyl)azanide;7,7-dimethyloctanoate;platinum(4+) Chemical compound [Pt+4].[NH-]C1CCCCC1[NH-].CC(C)(C)CCCCCC([O-])=O.CC(C)(C)CCCCCC([O-])=O ALPHSAWEOKVWID-UHFFFAOYSA-L 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940045985 antineoplastic platinum compound 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
- 201000011510 cancer Diseases 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical group [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000000155 isotopic effect Effects 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
- 125000004433 nitrogen atom Chemical group N* 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
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The present invention discloses a platinum (II) coordination compound taking alkoxyl group acetic acid radicals as ligands. The present invention is characterized in that alkoxyl group acetic acid radicals simultaneously having water solubility and fat solubility are used as complex anions and react with platinum amine complex cations for forming a new platinum (II) coordination compound; a preparation method thereof is disclosed. The composition of the compound is shown by the chemical formulas; in the chemical formula (1) to the chemical formula (3), R is C1 to 6 alkyl groups; in the chemical formula (1), R groups are identical, are respectively hydrogen atoms or C1 to 5 and alkyl groups; in the chemical formula (2), cyclohexanediamine is 1, 2-trans-form cyclohexanediamine, and both of the absolute configurations of two chiral carbon atoms (marked with * numbers) are R conformations or S configurations; in the chemical formula (3), R1 and R2 shown by 4, 5-bi(aminomethyl)-2-alkyl-1 and 3-dioxolane are identical or not identical, are respectively hydrogen atoms or C1 to 5 alkyl groups or can be connected with a carbon atom for forming cycloalkyl, and the absolute configurations both of two chiral carbon atoms (marked with * numbers) are R conformations or S configurations. The platinum coordination compound of the present invention comprises all of stereo isomers and mixtures thereof shown in the chemical formulas.
Description
One. technical field
The present invention relates to have good aqueous solubility and fat-soluble novel platinum (II) title complex and preparation method thereof.
Two. background technology
Studies show that metal platinum (II) title complex and its anti-tumor activity are though have exception, the structure activity relationship that big multiple coincidence Cleare in 1973 and Hoeschele sum up
[1], showing that promptly active platinum (II) title complex should be cis-structure, its general molecular formula is:
cis-[Pt(Am)
2X
2]
Am is an inertia amine, and a H atom will be arranged on the N atom at least; X is a leavings group, is monovalence negative ion group, with platinum medium binding force is arranged, and faint trans-effect is arranged to avoid activating amine.The platinum medicine of listing all meets this classics structure activity relationship basically at present, and they are the analogue of cis-platinum and carboplatin all based on the tetragonal structure in cis-platinum plane.
Except the structure that changes amine, also be that an important approach improves the water-soluble and fat-soluble of platinum (II) title complex to the transformation of leavings group X.This is because suitable water-soluble and fat-solublely help drug conveying and stride film.For the carboxylate radical leavings group, bibliographical information in the past lay particular emphasis on two extreme, a water-soluble that is to use water-soluble good short-chain alkyl carboxylate radical or little cycloalkyl carboxylate radical to increase platinum (II) title complex; Two are to use many carbon chain alkyl carboxylate radical to increase the fat solvability of platinum (II) title complex, as enter clinical L-NDDP/AR-726 of II phase
[2]And SM-11355
[3]
Three. summary of the invention
The present invention is a leavings group to have water-soluble and fat-soluble ether-containing key carboxylate radical concurrently, designs and has synthesized water-soluble and fat-soluble good cis-platinum compounds and improve anti-tumor agent.The objective of the invention is to be cis-platinum (II) the class title complex that provides novel, these title complexs may have low toxicity, good water solubility, effective antitumour activity, are used for the treatment of human tumor.The present invention discloses a class and has antitumour activity platinum (II) coordination compound, it is characterized in that with the ether-containing key acetate moiety be leavings group.The composition of this compounds is represented by following (1), (2), (3) formula:
R group in the formula (1) is identical, is respectively hydrogen atom or C
1-5Alkyl; 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 form cycloalkyl with a carbon atom, the absolute configuration of two chiral carbon atoms (indicating * number) all is R configuration or S configuration.R ' is C among formula (1)-Shi (3)
1-6Alkyl.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 the platinic compound that is obtained containing diamines coordination and two halogen ion coordinations by potassium tetrachloroplatinate and relevant diamines (ammonia) part effect, are represented by formula (4).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), gained intermediate and monovalent base metallic cation alkoxy acetic acid salt action obtain suitable-two (alkoxy acetic acid root) diamines (ammonia) and close platinum (II) compound; By method B: use alkoxy acetic acid silver salt and dihalo-diamines (ammonia) to close platinum (II) and act on and obtain suitable-two (alkoxy acetic acid root) diamines (ammonia) and close platinum (II) compound.
Hal among formula (4a) and 4 (b) represents Cl
-, Br
-And I
-Halide-ions, the R group of its Chinese style (4a) is identical, is respectively hydrogen atom or C
1-5Alkyl, two amidos of arc representation that formula (4b) is connected on the amine nitrogen atom are linked to each other by alkyl.
The representational compound of the present invention comprises:
Suitable-two (ethoxyacetic acid root) two ammino platinum (II); Suitable-two (butoxy acetic acid root) two ammino platinum (II); Suitable-two (ethoxyacetic acid root) Diisopropylamine closes platinum (II); Suitable-two (butoxy acetic acid root) Diisopropylamine closes platinum (II); Suitable-two (ethoxyacetic acid roots) (1, the trans cyclohexanediamine of 2-) close platinum (II); Suitable-two (butoxy acetic acid roots) (1, the trans cyclohexanediamine of 2-) close platinum (II); Suitable-two (ethoxyacetic acid roots) [(1R, 2R)-1, the trans cyclohexanediamine of 2-] close platinum (II); Suitable-two (ethoxyacetic acid roots) [(1S, 2S)-1, the trans cyclohexanediamine of 2-] close platinum (II); Suitable-two (butoxy acetic acid roots) [(1R, 2R)-1, the trans cyclohexanediamine of 2-] close platinum (II); Suitable-two (butoxy acetic acid roots) [(1S, 2S)-1, the trans cyclohexanediamine of 2-] close platinum (II); Suitable-two (ethoxyacetic acid roots) [4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] close platinum (II); Suitable-two (butoxy acetic acid roots) [4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] close platinum (II); Suitable-two (ethoxyacetic acid roots) [(4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] close platinum (II); Suitable-two (ethoxyacetic acid roots) [(4S, 5S)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] close platinum (II); Suitable-two (butoxy acetic acid roots) [(4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] close platinum (II); Suitable-two (butoxy acetic acid roots) [(4S, 5S)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] close platinum (II).
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: usefulness method B synthesizes suitable-two (ethoxyacetic acid root) two ammino platinum (II)
Suitable-diiodo-two ammino platinum (II) (0.97 gram, 2 mmoles) with the ethoxyacetic acid silver of new system (0.84 gram, 4 mmoles), it is mixed to add water (100 milliliters), and 60 ℃ of logical nitrogen of following lucifuge reacted 24 hours, use the diatomite aided filter then, filtrate is concentrated, separate out light yellow solid, filter, 60 ℃ of following vacuum-dryings get product 0.30 gram (35%).
IR(KBr)：3497m，3260sh，2978w，2885w，1631vs，1451w，1420s，1387s，1330s，1121vs，1036w
1H-NMR(D
2O/TMS)：δ1.20(m，6H)，3.60(m，4H)，3.94-4.07(m，4H)
ESI-MS：[M-C
2H
5OCH
2COO-+H
2O]
+＝350(100％)
Embodiment 2: usefulness method B synthesizes suitable-two (butoxy acetic acid root) two ammino platinum (II)
Suitable-diiodo-two ammino platinum (II) (0.97 gram, 2 mmoles) with the butoxy acetic acid silver of new system (0.96 gram, 4 mmoles), it is mixed to add water (100 milliliters), and 60 ℃ of logical nitrogen of following lucifuge reacted 24 hours, use the diatomite aided filter then, filtrate is concentrated, separate out solid, filter, with a small amount of washing 3 times, get pure white crystal.60 ℃ of following vacuum-dryings get product 0.56 gram (57%).
IR(KBr)：3460m，3381m，3270s，3111s，2958m，2932m，2871m，1651vs，1601vs，1577vs，1461w，1388vs，1339m，1292s，1136s，1116s
1H-NMR(D
2O/TMS)：δ0.83(m，6H)，1.28(m，4H)，1.49(m，4H)，3.45(m，4H)，3.84-3.99(m，4H)
ESI-MS：[M-C
4H
9OCH
2COO
-+H
2O]
+＝378(100％)
Embodiment 3: close platinum (II) with synthetic suitable-two (ethoxyacetic acid root) Diisopropylamine of method B
Suitable-diiodo-Diisopropylamine closes platinum (II) (1.13 grams, 2 mmoles) with the ethoxyacetic acid silver of new system (0.84 gram, 4 mmoles), it is mixed to add water (100 milliliters), and 40 ℃ of logical nitrogen of following lucifuge reacted 18 hours, use the diatomite aided filter, filtrate is concentrated, separate out white solid, filter, 60 ℃ of following vacuum-dryings get product 0.28 gram (27%).
IR(KBr)：3448m，3196sh，2973m，2933w，2876w，1642vs，1569m，1384vs，1339vs，1172w，1118s，1016w
1H-NMR(D
2O/TMS)：δ1.18(m，12H)，1.20(m，6H)，3.59(m，2H)，3.64(m，4H)，3.9-4.1(m，4H)
ESI-MS：[M-C
2H
5OCH
2COO
-+H
2O]
+＝434(100％)
Embodiment 4: close platinum (II) with synthetic suitable-two (butoxy acetic acid root) Diisopropylamine of method B
Suitable-diiodo-Diisopropylamine closes platinum (II) (1.13 grams, 2 mmoles) with the butoxy acetic acid silver of new system (0.96 gram, 4 mmoles), it is mixed to add water (100 milliliters), 50 ℃ of logical nitrogen of following lucifuge reacted 12 hours, use the diatomite aided filter, filtrate is concentrated, separate out white solid, filter, wash 3 times with a small amount of ether, 60 ℃ of following vacuum-dryings get product 0.46 gram (40%).
IR(KBr)：3448w(br)，3223sh，2964m，2935m，2875m，1633vs，1575w，1465w，1382vs，1342vs，1273w，1159w，1120s
1H-NMR(D
2O/TMS)：δ0.89(m，6H)，1.30(m，16H)，1.55(m，4H)，2.81(m，2H)，3.50(m，4H)，3.89-4.03(m，4H)
ESI-MS：[M-C
4H
9OCH
2COO
-+H
2O]
+＝462(100％)，[M+Na]
+＝598(16％)
Embodiment 5: usefulness method A synthesizes suitable-two (ethoxyacetic acid roots) [(1R, 2R)-1, the trans cyclohexanediamine of 2-] and closes 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 ethoxyacetic acid (0.42 gram in the filtrate, 4 mmoles) with the aqueous solution of sodium hydroxide (0.16 gram, 4 mmoles), 50 ℃ of logical nitrogen reactions of following lucifuges 16 hours, with solution concentration, separate out a large amount of light yellow solids.Filter, water, ethanol, ether repetitive scrubbing, 60 ℃ of following vacuum-dryings get product 0.30 gram (29%).
IR(KBr)：3442m，3199m，3112m，2936m，2817w，1620vs，1385s，1342m，1306m，1200m，1123s，1064w
1H-NMR(DMSO/TMS)：δ1.06(m，6H)，1.25(m，2H)，1.60(m，2H)，1.96(m，2H)，2.35(m，2H)，3.4-3.9(10H)
ESI-MS：[M-C
2H
5OCH
2COO
-+H
2O]
+＝430(100％)
Embodiment 6: usefulness method A synthesizes suitable-two (butoxy acetic acid roots) [(1R, 2R)-1, the trans cyclohexanediamine of 2-] and closes 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 butoxy acetic acid (0.53 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 0.37 gram (32%).
IR(KBr)：3449w(br)，3199s，3104m，2957s，2933s，2867s，1614vs，1454w，1383s，1336m，1297m，1205w，1122s，1064w，1030w
1H-NMR(D
2O/TMS)：δ0.84(m，6H)，1.11(m，2H)，1.29(m，6H)，1.49(m，6H)，1.99(m，2H)，2.33(m，2H)，3.45(m，4H)，3.84-3，97(m，4H)
ESI-MS：[M-C
4H
9OCH
2COO
-+H
2O]
+＝458(100％)
Embodiment 7: usefulness method B synthesizes suitable-two (ethoxyacetic acid roots) [(4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] and closes platinum (II)
Suitable-diiodo-[(4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-1, the 3-dioxolane] close the ethoxyacetic acid silver (0.84 gram, 4 mmoles) of platinum (II) (1.25 gram, 2 mmoles) and new system, it is mixed to add water (100 milliliters), and the 50 ℃ of logical nitrogen reaction of following lucifuge 18h use the diatomite aided filter, filtrate is concentrated, separate out white solid, filter, with less water, ethanol, ether repetitive scrubbing, 60 ℃ of following vacuum-dryings get product 0.22g (19%).
IR(KBr)：3449m，3212sh，2974m，2878m，1637s，1384vs，1302w，1116m，1011w
1H-NMR(D
2O/TMS)：δ0.86(d，6H)，1.12(m，6H)，1.84(m，1H)，3.2(m，4H)，3.5(m，4H)，3.8-4.0(m，6H)，4.93(d，1H)
ESI-MS：[M-C
2H
5OCH
2COO
-+H
2O]
+＝490(100％)
Embodiment 8: usefulness method A synthesizes suitable-two (butoxy acetic acid roots) [(4R, 5R)-4,5-two (aminomethyl)-2-sec.-propyl-1,3-dioxolane] and closes 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 butoxy acetic acid (0.53 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 0.44g (35%).
IR(KBr)：3448br，3233s，3124m，2960s，2934m，2871m，1660vs，1640vs，1581m，1458w，1421m，1371m，1335m，1279m，1129s
1H-NMR(DMSO-d
6/TMS)：δ0.87(m，12H)，1.31(m，4H)，1.46(m，4H)，1.77(m，1H)，2.81(m，4H)，3.10-3.40(m，6H)，3.60-3.88(m，4H)，4.80(d，1H)，4.54-4.78(br，NH
2)
ESI-MS：[M+Na]
+＝654(100％)，[M+Na+H
2O]
+＝672(40％)，[M+H]
+＝632(16％)，[M-C
4H
9OCH
2COO
-+H
2O]
+＝518(24％)
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. reference
[1]M.J.Cleare，J.D.Hoeschele，Bioinorg.Chem.，1973，2，187.
[2]D.S.MacLean，A.R.Khokhar，Cancer?Biother.Radiopharm.，2000，15，253.
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Claims (2)
1, a class alkoxy acetic acid root is platinum (II) coordination compound of part, it is characterized in that using having novel platinum (II) coordination compound of water-soluble and fat-soluble alkoxy acetic acid root as complex anion and platinum amine complex cation reaction formation concurrently, the composition of this compounds is expressed from the next:
R ' is C among formula (1)-Shi (3)
1-6Alkyl; R group in the formula (1) is identical, is respectively hydrogen atom or C
1-5Alkyl; Cyclohexanediamine in the formula (2) is 1, the trans cyclohexanediamine of 2-, and the absolute configuration that indicates two chiral carbon atoms of * 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 form cycloalkyl with a carbon atom, the absolute configuration that indicates two chiral carbon atoms of * number all is R configuration or S configuration; Described platinum complex 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 (4a) or formula (4b) 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), gained intermediate and monovalent base metallic cation alkoxy acetic acid salt action obtain suitable-two (alkoxy acetic acid root) diamines (ammonia) and close platinum (II) compound; Or by method B: use alkoxy acetic acid silver salt and dihalo-diamines (ammonia) to close platinum (II) and act on and obtain suitable-two (alkoxy acetic acid root) diamines (ammonia) and close platinum (II) compound;
Hal in formula (4a) and the formula 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, two amidos of arc representation that formula (4b) is connected on the amine nitrogen atom are linked to each other by alkyl.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0328274A1 (en) * | 1988-02-02 | 1989-08-16 | Johnson Matthey, Inc., | Pt (IV) complexes |
| EP0503830A1 (en) * | 1991-03-09 | 1992-09-16 | Johnson Matthey Public Limited Company | Trans-platinum compounds with anti-tumor activity, process for their preparation and compositions containing them |
| US5547982A (en) * | 1995-02-27 | 1996-08-20 | Johnson Matthey, Inc. | Anti-tumor platinum complexes |
| CN1339439A (en) * | 2001-09-14 | 2002-03-13 | 南京大学 | A method for preparing platinum (II) compound |
| CN1569862A (en) * | 2003-06-11 | 2005-01-26 | 南京大学 | Anti-tumor platinum (II) complex |
-
2003
- 2003-06-11 CN CNB031318517A patent/CN1296377C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0328274A1 (en) * | 1988-02-02 | 1989-08-16 | Johnson Matthey, Inc., | Pt (IV) complexes |
| EP0503830A1 (en) * | 1991-03-09 | 1992-09-16 | Johnson Matthey Public Limited Company | Trans-platinum compounds with anti-tumor activity, process for their preparation and compositions containing them |
| US5547982A (en) * | 1995-02-27 | 1996-08-20 | Johnson Matthey, Inc. | Anti-tumor platinum complexes |
| CN1339439A (en) * | 2001-09-14 | 2002-03-13 | 南京大学 | A method for preparing platinum (II) compound |
| CN1569862A (en) * | 2003-06-11 | 2005-01-26 | 南京大学 | Anti-tumor platinum (II) complex |
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