CN1821253A - Novel water soluble Pt (II) anti-cancer ligand and its preparing method - Google Patents
Novel water soluble Pt (II) anti-cancer ligand and its preparing method Download PDFInfo
- Publication number
- CN1821253A CN1821253A CN 200610010756 CN200610010756A CN1821253A CN 1821253 A CN1821253 A CN 1821253A CN 200610010756 CN200610010756 CN 200610010756 CN 200610010756 A CN200610010756 A CN 200610010756A CN 1821253 A CN1821253 A CN 1821253A
- Authority
- CN
- China
- Prior art keywords
- water
- cis
- hydroxyl
- dicarboxylic acid
- cyclobutane dicarboxylic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a new kind of water soluble anticancer Pt (II) compound, cis-[2-substitutent- (4R,5R)-4,5-bis(aminoethyl)-l,3-dioxycyclopentane .3-hydroxy-1,1-cyclobutane dicarboxylic radical- Pt (II)], with the substitutent being methyl, ethyl or isopropyl radical. One of the preparation process includes the reaction of material cis-[PtA2I2], with A2 being 2-substitutent- (4R,5R)-4,5-bis(aminoethyl)-l,3-dioxycyclopentane, and 3-hydroxy-1,1- cyclobutane dicarboxyl-Ag, filtering to separate AgI, concentrating the mother liquid and freeze drying to obtain the coarse product. The other preparation process includes the first reaction of cis-[PtA2I2] and Ag2SO4, filtering to separate AgI, the reaction of the mother liquid and 3-hydroxyl-1,1-cyclobutane dicarboxylic Ba, filtering to separate BaSO4, concentrating mother liquid, and freeze drying to obtain the coarse product. The coarse product is re-crystallized in water/alcohol system to obtain refined product. The compound of the present invention has anticancer activity and less toxic side effect, and may be clinical use for treating cancers.
Description
Technical field
The present invention relates to field of biological pharmacy, particularly relate to a class and have water miscible platinum (II) anticancer complex and preparation method thereof.
Background technology
Carboplatin is the s-generation platinum as anti-cancer medicine behind cis-platinum, and its chemistry is called cis-1,1-cyclobutane dicarboxylic acid radical two ammino platinum (II).Kept anticancer active part (NH in the structure of carboplatin
3)
2Pt
2+And introduce hydrophilic 1, the 1-cyclobutane dicarboxylic acid radical is made leavings group, solubleness is improved greatly, and the water-soluble 17mg/ml that reaches is higher 17 times than the solubleness (1mg/ml) of cis-platinum, so toxicity of carboplatin, particularly renal toxicity and digestive tract side effects are starkly lower than cis-platinum, one of the most effective cancer therapy drug that makes that carboplatin becomes that the present whole world generally acknowledges, classified as world's essential drugs by WHO, income comprises that being widely used, [Li Yixin translates, the choice drug of cancer chemotherapeutic in most of in the world national pharmacopeia of China in clinical anticancer,. external medicine-synthetic drug, biochemical medicine preparation fascicle, 1998,19 (2): 89-101].But the antitumour activity of carboplatin is still not high, also has bigger toxic side effect such as bone marrow depression etc. simultaneously.Therefore the platinum-containing anticancer drug of design and synthesizing new be present anticarcinogen research focus [Liu Weiping, Gao Wengui. the platinum metals title complex of treatment cancer, pharmacy is made progress, 2001,25 (1): 27-31].Although also released some new platinum kind anti-cancer drugs in recent years, as S 254 (Nadaplatin), oxaliplatin (Oxaliplatin), platinum (Eptaplatin) relaxes, happy platinum (Loplatin), but they water-soluble all is lower than carboplatin, comprehensive therapeutic effect also is not so good as carboplatin and toxic side effect than the big [You Qidong of carboplatin, Gou Shaohua, the progress of antitumor platinum complexes, the pharmaceutical chemistry progress, 2003,2:161-187], so the development good water solubility, active high, the platinum antineoplastic complex that toxicity is low is one of developing direction of platinum-containing anticancer drug [Ernest Wong, Christen M G, Current Status of Platinum-based AntitumorDrugs, Chem.Rev., 1999,99:2451-2466].
Summary of the invention
By to the analysis of former research results and summary and to the deep understanding of carboplatin chemical structure, we think why have preferably by carboplatin clinical efficacy is because carboplatin has the comparatively ideal chemical constitution of blocking-up cancer cells dna replication dna.For this reason, the present invention is lead compound with the carboplatin, by the leavings group 1 to carboplatin, 1-cyclobutane dicarboxylic acid radical and carrier group carry out chemically modified, and a design and a synthetic class are with 3-hydroxyl-1, the 1-cyclobutane dicarboxylic acid radical is leavings group, with 2-substituting group-(4R, 5R)-4, two (aminomethyl)-1 of 5-, the 3-dioxolanes is new type anticancer platinum (II) title complex of carrier group, this class title complex good water solubility, antitumour activity height, toxic side effect are low, have great development prospect.
Platinum of the present invention (II) title complex, chemistry cis-[2-substituting group by name-(4R, 5R)-4, two (aminomethyl)-1 of 5-, 3-dioxolanes 3-hydroxyl-1, the 1-cyclobutane dicarboxylic acid radical closes platinum (II)], its chemical structure is as follows:
R＝CH
3，C
2H
5，CH(CH
3)
2
The preparation method of platinic compound of the present invention is with K
2PtCl
4Be starting raw material, add KI, change into K
2PtI
4, with carrier group A
2(A
2=2-substituting group-(4R, 5R)-4, two (aminomethyl)-1 of 5-, 3-dioxolanes) reaction, prepare corresponding cis-[Pt (II) A
2I
2] intermediate, again in water with 3-hydroxyl-1,1-cyclobutane dicarboxylic acid silver etc. moles quantitative reaction, the after-filtration that reacts completely separates AgI, mother liquor concentrates and lyophilize obtains crude product; Or cis-[Pt (II) A
2I
2] elder generation and Ag
2SO
4In the medium mole of water quantitative reaction, the after-filtration that reacts completely separates AgI, mother liquor with wait a mole 3-hydroxyl-1,1-cyclobutane dicarboxylic acid barium quantitative reaction, filtering separation BaSO
4, mother liquor concentrates and lyophilize obtains crude product.Crude product is through water: recrystallization obtains the pure product of title complex of the present invention in the system of ethanol=1: 1.
Preparation method of the present invention has productive rate height, product characteristics pure, simple to operate, prepares related chemical reaction to be:
Compound of the present invention is characterized in that its solubleness is littler than carboplatin apparently higher than carboplatin, toxic side effect greater than carboplatin, antitumour activity, can be used for clinical anticancer.Preparation-lyophilized powder and injection liquid that compound of the present invention can be made two kinds of routines use in clinical.
Antitumous effect for the title complex of inventing: the title complex of invention is soluble in water, compare employing SRB method with carboplatin and measure the title complex of different concns (μ g/ml) NCI-H460 (people's non-small cell lung cancer cell), HT-29 (human colon cancer cell) Ls174t (human colon cancer cell) inhibition of proliferation degree, calculate inhibiting rate, adopt the Logit method to calculate IC according to inhibiting rate
50(μ g/ml), result show that the antitumour activity of the title complex LLC-0601 that is invented is apparently higher than carboplatin.
Title complex is to the inhibiting rate (%) of Ls-174t cell growth under each concentration
| Concentration | 100 | 50 | 10 | 5 | 0.5 | 0.1 | 0.05 | IC 50 |
| LLC-0601 | 98 | 100 | 65 | 48 | 43 | 20 | 20 | 5.41 |
| Carboplatin | 49 | 2 | 2 | 0 | 1 | 1 | 2 | ＞100 |
Title complex is to the inhibiting rate (%) of H46O cell growth under each concentration
| Concentration | 100 | 50 | 10 | 5 | 1 | 0.5 | 0.1 | 0.05 | IC 50 |
| LLC-0601 | 98 | 100 | 87 | 85 | 51 | 11 | 0 | 0 | 0.99 |
| Carboplatin | 90 | 86 | 48 | 15 | 0 | 0 | 0 | 0 | 10.70 |
Title complex is to the inhibiting rate (%) of HT29 cell growth under each concentration
| Concentration | 100 | 50 | 10 | 5 | 1 | 0.5 | 0.1 | 0.05 | IC 50 |
| LLC-0601 | 77 | 87 | 35 | 20 | 7 | 0 | 1 | 0 | 14.85 |
| Carboplatin | 21 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | ＞100 |
Acute toxicity for the title complex of inventing: Kunming mouse, body weight 20-22 gram, female, hero half and half, available from Shanghai Si Laike experimental animal limited liability company, credit number: SCXK (Shanghai) 2004-0005.LLC-0601 prepares with 5% glucose solution.The LLC-0601 of mouse single intravenous injection various dose.Observe mortality ratio and toxicity situation after the administration, observed altogether 14 days, use the Bliss method according to mortality ratio and calculate LD
10, LD
50, LD
90
| LD50(mg/kg) | LD 10(mg/kg) | LD 90(mg/kg) | |
| LLC-0601 | 372.7 | 216.5 | 641.4 |
| 95% fiducial limit | 305.2～454.9 | 156.6～299.3 | 440.8～933.4 |
Test records the LD of the title complex LLC-0601 drug administration by injection of being invented
50(95% confidence level 305.2～454.9mg/kg), identical experiment records the LD of carboplatin drug administration by injection to=372.7mg/kg
50=130mg/kg, so the LLC-0601 acute toxicity is obvious lower than carboplatin.
Embodiment
(1) 3-hydroxyl-1, the preparation of 1-cyclobutane dicarboxylic acid silver
Press earlier method [Inorganica Chimica Acta, 2004,357,4452-4466] the preparation 3-hydroxyl-1 of bibliographical information, 1-cyclobutane dicarboxylic acid (151 ℃-152 ℃ of mp).Get 3-hydroxyl-1,1-cyclobutane dicarboxylic acid 10g is dissolved in the water of 100ml, regulates PH=6-7 with 1mol/L NaOH, adds 130mmol, 100mlAgNO
3(excessive 5%) obtains 3-hydroxyl-1, and 1-cyclobutane dicarboxylic acid silver precipitation is filtered and collected, and 60-70 ℃ of following vacuum-drying 4 hours, obtains 21.7g 3-hydroxyl-1 after water, the washing with alcohol, 1-cyclobutane dicarboxylic acid silver, productive rate 94.2%.
(2) cis-[Pt (II) A
2I
2] preparation of intermediate
Press operational path [J.Med.Chem., 1994,37,1471-1485] the synthetic vectors group A of bibliographical information
2[A
2=2-methyl-(4R, 5R)-4, two (aminomethyl)-1 of 5-, 3-dioxolanes; The 2-ethyl-(4R, 5R)-4, two (aminomethyl)-1 of 5-, 3-dioxolanes; The 2-sec.-propyl-(4R, 5R)-4, two (aminomethyl)-1 of 5-, 3-dioxolanes].
Take by weighing 5g K
2PtCl
4(12mmol) be dissolved in the 50ml water, remove by filter insolubles, under 60 ℃, slowly add the aqueous solution 50ml that contains KI 12g (72mmol), the lucifuge reaction dripped equimolar carrier group A after 1 hour
2(12mmol), obtain yellow mercury oxide, filter and collect, 60-70 ℃ of following vacuum-drying 4 hours, obtain cis-[Pt (II) A respectively after water, the washing with alcohol
2I
2] 6.7g (R=CH
3), 7.1g (R=C
2H
5) 7.0g (R=CH (CH
3)
2), productive rate 92-95%.
(3) the cis-[2-sec.-propyl-(4R, 5R)-4, two (aminomethyl)-1 of 5-, 3-dioxolanes 3-hydroxyl-1, the 1-cyclobutane dicarboxylic acid radical closes platinum (II)] (LLC-0601) synthetic
Get cis-[Pt (II) A of 5g
2I
2] (R=CH (CH
3)
2), in the suspension 100ml water, the 1-cyclobutane dicarboxylic acid silver 3g that adds equimolar amount, 45 ℃ of following stirring reactions 15 hours, check that the after-filtration that reacts completely removes the AgI precipitation, the mother liquor concentrating under reduced pressure is to 20ml, lyophilize gets white crystal, at water: recrystallization is purified and is obtained elaboration 3.2 grams in the system of ethanol=1: 1, productive rate 76%, and water-soluble is 40mg/ml (room temperature).
The feature structure parameter is:＜1〉ultimate analysis: C 31.7%, N 5.34%, and H 4.61%, Pt 37.2% and theoretical value C 31.9%, N 5.31%, and H 4.55%, Pt 37.0% unanimity.<2>FAB
+-MS(m/e，RI)：527(M
+，100％)，368(M
+-C
6H
6O
5，20％)，368(A
2 +，60％)。＜3〉IR (cm
-1, the KBr compressing tablet): 3225 (s, vNH
3), 2937 (w, vCH
2), 1623 (ws vas (COO)), 1392 (s vs (COO)), 1094 (m, vC-OH).These parameters meet the chemical structure of the title complex of being invented.
(4) the cis-[2-ethyl-(4R, 5R)-4, two (aminomethyl)-1 of 5-, 3-dioxolanes 3-hydroxyl-1, the 1-cyclobutane dicarboxylic acid radical closes platinum (II)] (LLC-0602) synthetic
Get 3-hydroxyl-1,1-cyclobutane dicarboxylic acid 10g is dissolved in the water of 100ml, regulates PH=6-7 with 1mol/L NaOH, adds 65mmol, 100ml BaCl
2(excessive 5%) obtains 3-hydroxyl-1, and 1-cyclobutane dicarboxylic acid precipitated barium filters and collects, and 60-70 ℃ of following vacuum-drying 4 hours, obtains 16.9g 3-hydroxyl-1 after water, the washing with alcohol, 1-cyclobutane dicarboxylic acid barium, productive rate 91.8%.
Get the cis-[PtA of 5g
2I
2] (R=C
2H
5), in the suspension 100ml water, add the Sulfuric acid disilver salt 2.58g of equimolar amount, 45 ℃ of following black out stirring reactions 8 hours, check that the after-filtration that reacts completely removes the AgI precipitation.The 3-hydroxyl-1 that adds equimolar amount in mother liquor again, 1-cyclobutane dicarboxylic acid barium 2.44g again 45 ℃ of following stirring reactions 6 hours, checks that the after-filtration that reacts completely removes BaSO
4Precipitation, the mother liquor concentrating under reduced pressure is to 15ml, and lyophilize gets white crystal, and at water: recrystallization is purified and is obtained elaboration 3.3 and restrain in the system of ethanol=1: 1, and productive rate 80% is water-soluble greater than 50mg/ml (room temperature).
The feature structure parameter is:＜1〉ultimate analysis: C 30.2%, N 5.41%, and H 4.31%, Pt 37.8% and theoretical value C 30.4%, N 5.45%, and H 4.29%, Pt 38.0% unanimity.＜2〉FAB
+-MS (m/e, RI): 514 (M
+, 100%), meet the chemical structure of the title complex of being invented.
Claims (4)
1. chemical cis-[2-substituting group by name-(4R, 5R)-4, two (aminomethyl)-1 of 5-, 3-dioxolanes 3-hydroxyl-1, the 1-cyclobutane dicarboxylic acid radical closes platinum (II)] platinum (II) title complex, substituting group is methyl or ethyl or sec.-propyl, has the following chemical structure formula:
R＝CH
3，C
2H
5，CH(CH
3)
2
2. the preparation method of claim 1 title complex comprises the following steps and reacts:
With cis-[PtA
2I
2] be raw material (A
2=2-substituting group-(4R, 5R)-4, two (aminomethyl)-1 of 5-, the 3-dioxolanes), in water with 3-hydroxyl-1,1-cyclobutane dicarboxylic acid silver etc. moles quantitative reaction, the after-filtration that reacts completely separates AgI, mother liquor concentrates and lyophilize obtains the crude product of compound of the present invention, and crude product is through water: recrystallization obtains pure product in the system of ethanol=1: 1.
3. the preparation method of claim 1 title complex comprises the following steps and reacts:
With cis-[PtA
2I
2] elder generation and Ag
2SO
4In the medium mole of water quantitative reaction, the after-filtration that reacts completely separates AgI, mother liquor with wait a mole 3-hydroxyl-1,1-cyclobutane dicarboxylic acid barium quantitative reaction, filtering separation BaSO
4, AgI, mother liquor and a hydroxyl-1 such as 3-such as mole such as grade, 1-cyclobutane dicarboxylic acid barium quantitative reaction, filtering separation BaSO
4, mother liquor concentrates and lyophilize obtains the crude product of compound of the present invention, and crude product is through water: recrystallization obtains pure product in the system of ethanol=1: 1.
4. the purposes of claim 1 title complex:
The compound of claim 1 has good water solubility, antitumour activity height, characteristic that toxicity is low, can make lyophilized powder or injection liquid, is used for clinical anticancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200610010756XA CN100413874C (en) | 2006-03-17 | 2006-03-17 | Novel water soluble Pt (II) anti-cancer ligand and its preparing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200610010756XA CN100413874C (en) | 2006-03-17 | 2006-03-17 | Novel water soluble Pt (II) anti-cancer ligand and its preparing method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1821253A true CN1821253A (en) | 2006-08-23 |
| CN100413874C CN100413874C (en) | 2008-08-27 |
Family
ID=36922843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200610010756XA Expired - Fee Related CN100413874C (en) | 2006-03-17 | 2006-03-17 | Novel water soluble Pt (II) anti-cancer ligand and its preparing method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100413874C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101532997B (en) * | 2009-04-24 | 2011-06-01 | 昆明贵研药业有限公司 | Production control of platinum-based anti-cancer drugs and method for measuring micro silver in product |
| CN102079761A (en) * | 2010-10-13 | 2011-06-01 | 昆明贵金属研究所 | Water-soluble S, S-heptaplatin derivative |
| CN103224533A (en) * | 2012-01-30 | 2013-07-31 | 东南大学 | Antitumor platinum (II) complex by taking alkyl carboxylate radical as ligand |
| WO2019161526A1 (en) * | 2018-02-22 | 2019-08-29 | 昆明贵研药业有限公司 | One-pot method for preparing twin dicarboxylic acid diamine complex platinum (ii) derivatives |
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634946A (en) * | 2004-11-24 | 2005-07-06 | 昆明贵金属研究所 | Platinum complex for treating cancer and method for making same |
-
2006
- 2006-03-17 CN CNB200610010756XA patent/CN100413874C/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101532997B (en) * | 2009-04-24 | 2011-06-01 | 昆明贵研药业有限公司 | Production control of platinum-based anti-cancer drugs and method for measuring micro silver in product |
| CN102079761A (en) * | 2010-10-13 | 2011-06-01 | 昆明贵金属研究所 | Water-soluble S, S-heptaplatin derivative |
| CN102079761B (en) * | 2010-10-13 | 2012-09-19 | 昆明贵金属研究所 | Water-soluble S, S-heptaplatin derivative |
| CN103224533A (en) * | 2012-01-30 | 2013-07-31 | 东南大学 | Antitumor platinum (II) complex by taking alkyl carboxylate radical as ligand |
| CN103224533B (en) * | 2012-01-30 | 2015-10-07 | 东南大学 | Alkyl carboxylic acid root containing nitric ether group is anti-tumor platinum (II) title complex of part |
| WO2019161526A1 (en) * | 2018-02-22 | 2019-08-29 | 昆明贵研药业有限公司 | One-pot method for preparing twin dicarboxylic acid diamine complex platinum (ii) derivatives |
| 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 |
|---|---|
| CN100413874C (en) | 2008-08-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108030921B (en) | Preparation method and application of albumin-loaded metalloporphyrin complex nanoparticles | |
| CN101289468A (en) | New oxaliplatin derivate | |
| CN100413874C (en) | Novel water soluble Pt (II) anti-cancer ligand and its preparing method | |
| CN111171080B (en) | High-efficiency low-toxicity anticancer compound synthesized by autocatalysis in cells and living bodies and synthesis method thereof | |
| CN109293702B (en) | Tetravalent platinum polyamine complex, preparation method and application thereof | |
| CN101787051B (en) | Water-soluble carboxyl-bridge dicaryon Pt (II) anti-tumor complex | |
| CN110183494B (en) | Preparation method and application of novel orally-administrable anti-tumor Pt (IV) complex | |
| CN102491997A (en) | Cholic acid-molybdenum polyoxometallate-cholic acid compound and synthetic method | |
| CN101289467A (en) | Platinum salts of organic acids, preparation thereof and applications in preparation of anticancer drugs | |
| CN1298727C (en) | Novel liposoluble platinum (II) anti-tumor ligand | |
| CN101386629B (en) | Water-soluble Pt(II) anticancer complexes using 3-acetoxy-1,1-cyclobutane dicarboxylic acid radical as leaving group | |
| CN101768191A (en) | Novel method for synthesizing anti-tumor drug Miriplatin | |
| CN1923837A (en) | Lipophilic platinum antineoplastic complex | |
| KR100314720B1 (en) | Platinum complex conjugated to cyclotriphosphazene, prepration thereof, and anticancer agent comprising the same | |
| CN1948323A (en) | Platinum (II)- anticancer compound using 2-hydroxy-1,3-propane diamine as carrier group | |
| CN113786411B (en) | Orally administered oxaliplatin prodrug, preparation method and application thereof as antitumor drug | |
| CN104086597B (en) | With platinum (II) antineoplastic compound that 3-oxo-tetramethylene-1,1-dicarboxylic acid radical is part | |
| CN1634946A (en) | Platinum complex for treating cancer and method for making same | |
| CN113307829B (en) | Platinum (II) complex with hydroxamic acid derivative as ligand and preparation method and application thereof | |
| CN101134601A (en) | Novel water-soluble platinum (II) small molecule anticancer complex | |
| CN1557822A (en) | Platinum complex having anti-tumor activity | |
| CN115536713B (en) | Method for preparing nanoparticles from micromolecular glycosylated tetravalent platinum antitumor compounds | |
| US7205287B2 (en) | Platinum complexes having antitumor activity | |
| CN101914117A (en) | Dichloroacetoxyl-containing platinum (II) anticancer coordination compound | |
| CN1263764C (en) | Platinum complex having anticancer activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080827 Termination date: 20170317 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |