CN101787053A - Platinum coordination compound as well as preparation method and medicinal application thereof - Google Patents
Platinum coordination compound as well as preparation method and medicinal application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry and medicines and relates to a patinum coordination compound with anti-tumor activity, a preparation method and a medicinal application thereof. The invention discloses the patinum coordination compound shown as the following formula (1) in the specification, and a pharmacological research result shows that the patinum coordination compound has obvious anti-tumor effect and good dose dependence. In a cytotoxin activity test of human lung adenocarcinoma cells (SPCA-1), a result shows that the anti-tumor activity of the patinum coordination compound is equivalent to the activity of Oxaliplatin and even superior to the activity of the Oxaliplatin. The patinum coordination compound can be prepared into various preparations containing a safe and effective quantity of patinum coordination compounds and medicinal carriers.
Description
Technical field
The invention belongs to pharmaceutical chemistry and medical technical field, be specifically related to a class new platinum complex with anti-tumor activity, preparation method and pharmaceutical usage thereof.
Background technology
Cancer is that modern society threatens one of the most serious disease of human life.The whole world has 1,000 ten thousand to increase cases of cancers, wherein dead 7,000,000 newly every year approximately at present; Expect the annual cancered number of the year two thousand twenty and will be increased to 2,000 ten thousand.It is reported that major part has teratogenesis, carcinogenic and mutagenesis in the existing antitumor drug, and toxicity is bigger.Therefore the antitumor drug of studying novel effective low toxicity is very urgent.Rosenberg in 1969, B. reported first the anti-tumor activity of cis-platinum, after this this area numerous studies person has carried out extensive research to platinum antineoplastic complex, has synthesized more than 2000 kind of platinum antineoplastic labile coordination compound, but actual have only twenties kinds that enter clinical stage.Clinical widely used platinum complex has cis-platinum, carboplatin and oxaliplatin at present, they have the anti-tumor activity of wide spectrum, become one of first-selected antitumor drug, showing better curative effect aspect some cancer of treatment, but still there is significant side effects, bone marrow toxicity as the kidney of cis-platinum and nervosa toxicity, carboplatin, simultaneously water-soluble low, the aqueous solution is stable inadequately and easily produce shortcoming such as resistance, therefore develops efficient, low toxicity, platinum complex water-soluble and good stability has considerable realistic meaning.
Summary of the invention
The objective of the invention is defective, the novel platinum complex of high-efficiency low-toxicity is provided at present prior art.
Another object of the present invention provides the preparation method of this novel platinum complex.
A further object of the present invention provides the application of this novel platinum complex in the preparation antitumor drug.
Novel platinum complex provided by the invention has as shown in the formula the structure shown in (1):
In the formula, R
1Branched-chain alkyl, the straight or branched thiazolinyl that contains 2～6 carbon atoms, the straight or branched alkynyl that contains 2～6 carbon atoms that replaces for the straight or branched alkyl that contains 1～6 carbon atom or 1～3 halogen, contain the cycloalkyl of 3～6 carbon atoms or contain the cycloalkenyl group of 4～6 carbon atoms;
R
2Be single the replacement or the polysubstituted straight or branched alkyl of 1～6 carbon atom, the straight chain alkoxyl group that contains 1～6 carbon atom or branched alkoxy, the alkyloyl that contains 1～6 carbon atom, chlorine, the bromine or iodine of containing on hydrogen, the optional position;
Two X can be respectively halogen, shown in (1a), or couple together and form a group Y, and shown in (1b), described Y is a dicarboxylic acid radical.
Platinum complex shown in the formula provided by the invention (1) can adopt but be not limited to following method preparation,
Preparation method's of the present invention illustrations is as follows:
Step I: the inferior potassium platinate reaction of diamines shown in the formula (2) and halo obtains the platinum compound shown in the formula (1a);
Step II: platinum compound shown in the formula (1a) and dicarboxylate reaction obtain the platinum complex shown in the formula (1b).
Among the step I, the diamines shown in the formula (2) is reacted with the inferior potassium platinate of halo in solvent.The inferior potassium platinate of halo can be the inferior potassium platinate of chloro, the inferior potassium platinate of bromo, the inferior potassium platinate of iodo etc.Employed solvent can be any solvent in this preparation method, as long as this solvent is an inert in reaction originally, and can inhibited reaction.Described solvent comprises water, methyl alcohol, ethanol; Halogenated hydrocarbon solvent, as methylene dichloride, chloroform, 1,2-ethylene dichloride etc.; The aromatic hydrocarbons solvent is as benzene and toluene etc.; Non-proton transitivity solvent, as acetone, acetonitrile, N, dinethylformamide, N-N-methyl-2-2-pyrrolidone N-, dimethyl sulfoxide (DMSO), tetramethylene sulfone, ring fourth sulfoxide and hexa-methylene phosphoryl triamide etc.; Esters solvent is as ethyl acetate and methyl acetate etc.; Ether solvent is as tetrahydrofuran (THF), ether and 1,4-diox etc.; The organic bases solvent is as pyridine, picoline etc.; Or the mixture of these solvents.Temperature of reaction can preferably adopt 0 ℃ to room temperature between-20 ℃ to 50 ℃; Material molar ratio can preferably use 1: 2 for arbitrarily.
In the Step II, platinum compound shown in the formula (1a) and dicarboxylate reaction.Dicarboxylate can be oxalate, propane dicarboxylic acid salt, cyclobutanedicarboxylic acid's salt etc., and salt can be sylvite, mercurous salt etc.Employed solvent can be any solvent in this preparation method, as long as this solvent is an inert in reaction originally, and can inhibited reaction.Described solvent comprises water, methyl alcohol, ethanol; Halogenated hydrocarbon solvent, as methylene dichloride, chloroform, 1,2-ethylene dichloride etc.; The aromatic hydrocarbons solvent is as benzene and toluene etc.; Non-proton transitivity solvent, as acetone, acetonitrile, N, dinethylformamide, N-N-methyl-2-2-pyrrolidone N-, dimethyl sulfoxide (DMSO), tetramethylene sulfone, ring fourth sulfoxide and hexa-methylene phosphoryl triamide etc.; Esters solvent is as ethyl acetate and methyl acetate etc.; Ether solvent is as tetrahydrofuran (THF), ether and 1,4-diox etc.; The organic bases solvent is as pyridine, picoline etc.; Or the mixture of these solvents.Temperature of reaction can preferably adopt 30 ℃ to 70 ℃ between-20 ℃ to 100 ℃; Material molar ratio can preferably use 1: 2 for arbitrarily.
Wherein the diamines shown in the step I Chinese style (2) can prepare by following steps, also can prepare (Zhong, Yu-Wu et al, Org.Lett., 2004,6 (22), 3953～3956) according to literature method.
A) aldehyde shown in N-benzyl hydroxylamine (3) and the formula (4) is at dewatering agent such as MgSO
4Effect under condensation obtain the nitrone shown in the corresponding formula (5);
B) (R)-aldehyde shown in N-tertiary butyl sulfinyl amine (6) and the formula (7) is at dewatering agent such as MgSO
4, CuSO
4, or Ti (OCH
2CH
3)
4Deng effect under condensation obtain (the R)-N-tertiary butyl sulfenimide shown in the corresponding formula (8);
C) imines shown in nitrone shown in the formula (5) and the formula (8) is at catalyzer such as SmI
2Induce down, carry out cross-coupling reaction in the low temperature and obtain the compound shown in the formula (9);
D) compound shown in the formula (9) obtains the compound shown in the formula (10) after with the catalytic zinc powder reduction of neutralized verdigris;
E) idic acid shown in the formula (10) is separated and is sloughed tertiary butyl sulfinyl protection and obtain the compound shown in the formula (11);
F) compound shown in the formula (11) carries out hydrogenation and sloughs benzyl protecting group and obtain the compound shown in the formula (2).
The schema of its preparation method is as follows:
The present invention further provides the application of above-mentioned platinum complex on the preparation antitumor drug.
Platinum complex disclosed by the invention finds that through pharmacological evaluation part of compounds has the anti-tumor activity stronger than oxaliplatin.
Pharmacological experiments shows that the platinum complex shown in the formula (1) has obvious antitumor action and good dose-dependent relationship.In the cytotoxic activity test to human lung adenocarcinoma cell (SPCA-1), the result shows that described platinum complex and oxaliplatin are quite active, even are better than oxaliplatin.
Therefore, platinum complex of the present invention can be made into the various preparations that comprise safe and effective amount platinum complex and pharmaceutical carrier.
" safe and effective amount " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Safe and effective amount is determined according to waiting age, the state of an illness, the course of treatment of treatment target.
" pharmaceutical carrier " refers to: one or more consistency solids or liquid filler or gelatinous mass, they are suitable for the people uses, and enough purity and enough low toxicity must be arranged." consistency " referred to herein as each component energy and compound of the present invention and blending mutually between them in the composition, and the drug effect of not obvious reduction compound.Pharmaceutically acceptable carrier part example has sugar (as glucose, sucrose, lactose etc.), starch (as W-Gum, yam starch etc.), Mierocrystalline cellulose and derivative thereof (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent is (as tween
), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
For the ease of understanding, below will describe in detail the present invention by specific embodiment.It needs to be noted, specific examples only is in order to illustrate, obviously those of ordinary skill in the art can illustrate according to this paper, within the scope of the invention the present invention is made various corrections and change, and these corrections and change are also included in the scope of the present invention.
Embodiment
Embodiment 1
Get 50mL two neck bottles, add 5-I (247mg, 1.4mmol), (209mg, 1.0mmol) and the 0.2mL trimethyl carbinol, 5mL THF dissolving cools to-78 ℃ to 8-I, slowly drips 3.0mmol new system SmI
2, keeping-78 ℃ of stir about 7h, 5mL Sulfothiorine collection is gone out, ethyl acetate extraction 3 times, the saturated common salt water washing, anhydrous sodium sulfate drying concentrates, rapid column chromatography (PE: EA=4: get 170mg yellow solid 9-I, productive rate 44% 1).The Zn powder (2.5mmol) that 160mg was activated, 9mg neutralized verdigris (0.05mmol) is dissolved in the 1mL acetic acid, stirring at room 15min, add the about 1mL of acetic acid/water (3: 1) mixed solution that contains 140mg compound 9-I (0.36mmol), 70 ℃ of reaction 1h are cooled to room temperature, add EDTA-2Na 0.5g, stir 10min, regulate pH to 10 with 3N KOH, ethyl acetate extraction 3 times merges organic phase, saturated EDTA-2Na solution washing, use the saturated common salt water washing again, anhydrous sodium sulfate drying concentrates, rapid column chromatography (PE: EA=3: 1) obtain 105mg white solid 10-I, productive rate 65%.100mg compound 10-I (0.27mmol) is dissolved in the 2mL methyl alcohol, drips the 0.3mL10N hydrogen chloride methanol solution, concentrate behind the stirring 1h, the gained solid obtains 64mg colourless oil liquid 11-I, productive rate 70% with methyl alcohol and ether mixed solvent recrystallization.55mg compound 11-I (0.16mmol) is dissolved in the 2mL methyl alcohol, splashes into and be added with 11mg Pd (OH)
2In two mouthfuls of bottles of/C, feed hydrogen, reaction 1d filters, and filtrate concentrates after with methanol wash, and the gained solid is with methyl alcohol and ether mixed solvent recrystallization, 40mg white solid 2-I, productive rate 100%.With compound 2-I (25mg, 0.1mmol) water-soluble, drip the aqueous solution 0.5mL of potassium platinochloride 40mg, lucifuge is placed 1h, filters, and wash 3 times, ethanol is washed 1 time, must 40mg yellow solid 1a-I, productive rate 90%.This yellow solid is suspended in water again, add 46mg new system cyclobutanedicarboxylic acid's mercurous (0.085mmol), 55 ℃ of lucifuge reaction 10h filter, and wash 3 times, and after filtrate concentrated, decrease temperature crystalline got 15mg white solid 1b-I, productive rate 34%.
Compound 1a-I:
1H-NMR (400MHz, d
6-DMSO): δ 0.61 (d, 3H), 0.72 (d, 3H), 1.23 (m, 1H), 2.80 (m, 1H), 3.43 (m, 1H), 4.91 (t, 1H), 5.44 (t, 1H), 5.52 (d, 1H), 6.00 (d, 1H), 7.28-7.41 (m, 5H); ESIMS m/z 444[M+1]
+
Compound 1b-I:
1H-NMR (400MHz, D
2O): δ 0.57 (d, 3H), 0.70 (d, 3H), 1.36 (m, 1H), 1.71 (m, 2H), 2.69 (t, 4H), 2.93 (m, 1H), 3.57 (d, 1H), 7.23-7.28 (m, 5H); ESIMSm/z 516[M+1]
+
Embodiment 2
(40mg 0.09mmol) suspends in water, and adds 17mg new system potassium oxalate (0.10mmol), and 70 ℃ of lucifuge reaction 24h filter, and wash 3 times, and after filtrate concentrated, decrease temperature crystalline got 10mg white solid 1b-II, productive rate 24% with this 1a-I.
Compound 1b-II:
1H-NMR (400MHz, D
2O): 0.60 (d, 3H), 0.72 (d, 3H), 1.38 (m, 1H), 2.93 (d, 1H), 3.56 (m, 1H), 7.27 (m, 5H); ESIMS m/z 462[M+1]
+
Embodiment 3
(40mg 0.09mmol) suspends in water, and adds 36mg new system propanedioic acid potassium (0.20mmol), and 60 ℃ of lucifuge reaction 12h filter, and wash 3 times, and after filtrate concentrated, decrease temperature crystalline got 20mg white solid 1b-III, productive rate 47% with this 1a-I.
Compound 1b-III:
1H-NMR (400MHz, D
2O): 0.59 (d, 3H), 0.72 (d, 3H), 1.36 (m, 1H), 2.96 (m, 2H), 3.46 (d, 1H), 3.61 (d, 1H), 7.28 (m, 5H); ESIMS m/z 476[M+1]
+
Embodiment 4
The preparation method of compound 1a-II-1a-VI is with embodiment 1.
Compound 1a-II:
1H-NMR (400MHz, d
6-DMSO): 0.65 (d, 3H), 0.78 (d, 3H), 1.24 (m, 1H), 2.81 (m, 1H), 3.30 (s, 3H), 3.41 (m, 1H), 4.86 (t, 1H), 5.34 (t, 1H), 5.46 (d, 1H), 5.90 (d, 1H), 6.86 (d, 2H), 7.30 (d, 2H); ESIMS m/z 474[M+1]
+
Compound 1a-III, ESIMS m/z 514[M+1]
+
Compound 1a-IV, ESIMS m/z 484[M+1]
+
Compound 1a-V, ESIMS m/z 519[M+1]
+
Compound 1a-VI, ESIMS m/z 472[M+1]
+
Embodiment 5
(30mg 0.06mmol) suspends in water, and adds 17mg new system potassium oxalate (0.10mmol), and 80 ℃ of lucifuge reaction 24h filter, and wash 3 times, and after filtrate concentrated, decrease temperature crystalline got 12mg white solid 1b-VI, productive rate 41% with this 1a-II.
Compound 1b-VI:
1H-NMR (400MHz, D
2O): 0.61 (d, 3H), 0.75 (d, 3H), 1.21 (m, 1H), 2.63 (m, 1H), 3.72 (s, 3H), 3.73 (m, 1H), 5.32 (t, 1H), 5.72 (t, 1H), 6.21 (d, 1H), 6.51 (d, 1H), 6.88 (d, 2H), 7.30 (d, 2H); ESIMS m/z 492[M+1]
+
Embodiment 6
(30mg 0.06mmol) suspends in water, and adds 46mg cyclobutanedicarboxylic acid's mercurous (0.085mmol), and 50 ℃ of lucifuge reaction 10h filter, and wash 3 times, and after filtrate concentrated, decrease temperature crystalline got 14mg white solid 1b-V, productive rate 43% with this 1a-II.
Compound 1b-V:
1H-NMR (400MHz, D
2O): 0.56 (d, 3H), 0.71 (d, 3H), 1.34 (m, 1H), 1.72 (m, 2H), 2.70 (t, 4H), 2.90 (m, 1H), 3.55 (d, 1H), 3.66 (s, 3H), 6.88 (d, 2H), 7.18 (d, 2H); ESIMS m/z 546[M+1]
+
The experiment of embodiment 7 anti tumor activity in vitro
The present invention tests used cell strain and experiment reagent all can obtain by commercial channel.
1) material
1.1 cell strain: human lung adenocarcinoma cell line (SPCA-1).
1.2 positive control: oxaliplatin.
1.3 reagent: HyQR modified form RPMI 1640 substratum, DMEN substratum, GIBCO; MTT; Pancreatin; Three solubilising reagents;
1.4 the configuration of three joint-trial agent: 20%SDS, 10% isopropylcarbinol, 0.024mol/L HCL, dissolved in distilled water.
1.5 equipment: CO
2Incubator, aseptic technique platform, microplate reader, whizzer etc., liquid-transfering gun, transfer pipet, centrifuge tube, 96 orifice plates etc.
2) experimental technique step
2.1 cell cultures: human lung adenocarcinoma cell line (SPCA-1): with F-12Kaighn ' the S substratum of 10% foetal calf serum, in 37 ℃, 5%CO
2Incubator in cultivate.
2.2 cell is handled: get and be in exponential phase of growth, cell in good condition adds an amount of trypsin digestion cell, and collecting cell is centrifugal, abandons supernatant.With the nutrient solution that contains serum suspendible cell again, count then, and cell density is diluted to 2 * 104/ml density.
2.3 cell inoculation: obtained cell suspension is inoculated on 96 orifice plates, 150 μ l/ holes (containing 3000/hole of tumour cell).Change culture plate over to constant temperature CO
2In the incubator, at 37 ℃, 5%CO
2And cultivated 24 hours under the saturated humidity condition.
2.4 compound configuration: planted experimentally compound is mixed with 0.01M earlier with DMSO storage liquid, again dilute sample as required.
2.5 adding test-compound: 50 μ L/ holes, cultivated 72 hours, establish 3 parallel holes for every group, and repeated experiments.
2.6 the result measures: compound effects is after 72 hours, and the MTT of 5mg/ml is added in 96 orifice plates, and 20 μ L/ holes place incubator to hatch 4 hours, add three joint-trial agent then, 50 μ L/ holes, and the back of spending the night is at 570nm place survey light absorption value.
2.7 try to achieve inhibiting rate according to following formula:
2.8 IC
50Calculating: inhibiting rate is higher than 50% compound, with SPSS computed in software IC
50Value.
3) experimental result
Table 1 compound is to the inhibition of tumor cell line SPCA-1 growth
Claims (9)
1. the platinum complex of structure shown in the formula (1):
In the formula, R
1Branched-chain alkyl, the straight or branched thiazolinyl that contains 2～6 carbon atoms, the straight or branched alkynyl that contains 2～6 carbon atoms that replaces for the straight or branched alkyl that contains 1～6 carbon atom or 1～3 halogen, contain the cycloalkyl of 3～6 carbon atoms or contain the cycloalkenyl group of 4～6 carbon atoms;
R
2Be single the replacement or the polysubstituted straight or branched alkyl of 1～6 carbon atom, the straight chain alkoxyl group that contains 1～6 carbon atom or branched alkoxy, the alkyloyl that contains 1～6 carbon atom, chlorine, the bromine or iodine of containing on hydrogen, the optional position;
Two X are respectively halogen, shown in (1a), or couple together and form a group Y, and shown in (1b), described Y is a dicarboxylic acid radical.
2. platinum complex as claimed in claim 1 is characterized in that, described R
1Be the straight chained alkyl that contains 1～6 carbon atom such as methyl, ethyl, propyl group; Or branched-chain alkyl such as sec.-propyl, isobutyl-, the tertiary butyl; Or the branched-chain alkyl of 1～6 carbon atom of 1～3 halogen replacement; Contain the straight or branched thiazolinyl of 2～6 carbon atoms such as vinyl, propenyl; Contain the straight or branched alkynyl of 2～6 carbon atoms such as ethynyl, proyl; Contain the cycloalkyl of 3～6 carbon atoms such as cyclopropyl, cyclohexyl; The cycloalkenyl group that contains 4～6 carbon atoms;
R
2Be hydrogen, the straight chain that contains 1～6 carbon atom such as methyl, ethyl, propyl group; Or branched-chain alkyl such as sec.-propyl, isobutyl-, the tertiary butyl; Contain the straight chain alkoxyl group of 1～6 carbon atom such as methoxyl group, oxyethyl group, propoxy-; Or branched alkoxy such as isopropoxy, isobutoxy, tert.-butoxy; Contain the alkyloyl of 1～6 carbon atom such as ethanoyl, propionyl, caproyl; Chlorine, bromine or iodine;
Two X are respectively fluorine, chlorine, bromine or iodine suc as formula shown in (1a); Or suc as formula coupling together group Y of formation shown in (1b), Y is a dicarboxylic acid radical, as oxalate, malonate, succinic, cyclobutane dicarboxylic acid radical.
3. platinum complex as claimed in claim 1 or 2 is characterized in that 1～3 halogenic substituent that contains in the branched-chain alkyl of described 1～6 carbon atom is fluorine, chlorine, bromine or iodine.
4. the preparation method of claim 1 or 2 described platinum complexes is characterized in that by following flow process and step:
Step I: the inferior potassium platinate reaction of diamines shown in the formula (2) and halo obtains the platinum compound shown in the formula (1a);
Step II: platinum compound shown in the formula (1a) and dicarboxylate reaction obtain the platinum complex shown in the formula (1b).
5. preparation method as claimed in claim 4 is characterized in that, the inferior potassium platinate of the halo described in the step I is selected from the inferior potassium platinate of chloro, the inferior potassium platinate of bromo or the inferior potassium platinate of iodo.
6. preparation method as claimed in claim 4 is characterized in that, the dicarboxylate described in the Step II is selected from oxalate, propane dicarboxylic acid salt or cyclobutanedicarboxylic acid's salt.
7. as claim 4 or 6 described preparation methods, it is characterized in that the dicarboxylate described in the Step II is selected from sylvite or mercurous salt.
8. claim 1 or 2 described platinum complexes are in the purposes of preparation in the medicine.
9. purposes as claimed in claim 8 is characterized in that described medicine is an antitumor drug.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1903864A (en) * | 2005-07-25 | 2007-01-31 | 海南和信堂药业有限公司 | Bisulfonate radical substituted 1,2-diphenyl ethylene diamine platinum compound and its preparation |
| CN101475600A (en) * | 2009-01-20 | 2009-07-08 | 昆明贵研药业有限公司 | Novel method for synthesizing antineoplastic medicament carboplatin |
| WO2009139939A2 (en) * | 2008-02-22 | 2009-11-19 | The University Of North Carolina At Chapel Hill | Hybrid nanoparticles as anti-cancer therapeutic agents and dual therapeutic/imaging contrast agents |
-
2010
- 2010-03-05 CN CN 201010118943 patent/CN101787053A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1903864A (en) * | 2005-07-25 | 2007-01-31 | 海南和信堂药业有限公司 | Bisulfonate radical substituted 1,2-diphenyl ethylene diamine platinum compound and its preparation |
| WO2009139939A2 (en) * | 2008-02-22 | 2009-11-19 | The University Of North Carolina At Chapel Hill | Hybrid nanoparticles as anti-cancer therapeutic agents and dual therapeutic/imaging contrast agents |
| CN101475600A (en) * | 2009-01-20 | 2009-07-08 | 昆明贵研药业有限公司 | Novel method for synthesizing antineoplastic medicament carboplatin |
Non-Patent Citations (1)
| Title |
|---|
| 《Journal of Inorganic Biochemistry》 19791231 Larry M. Hall et al. "Unsymmetrical C-Substituted Ethylenediamine Platinum Coordination Complexes: Synthesis and Activity Against Mouse Leukemia L1210 第144页表2 1-3 第11卷, 2 * |
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Application publication date: 20100728 |