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O,O'-amino malonate and N, O-amino malonate platinum complex compound

A technology of aminomalonate and aminomalonic acid, which is applied in the field of O, O'-aminomalonate and N, O-aminomalonate platinum complexes, and can solve problems that have not been evaluated clinically. question

Inactive Publication Date: 2009-01-21
爱克斯制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Pt pairs with monoclonal antibodies (Mclntosh et al., 1997; Hata et al., 1992), steroids (Gust et al., 1995; DiZio et al., 1992; Gibson et al., 1990) and folic acid (Vitols et al., 1987) have been reported, but None of these have been clinically evaluated
[0009] Combined passive and active targeting is also possible

Method used

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  • O,O'-amino malonate and N, O-amino malonate platinum complex compound
  • O,O'-amino malonate and N, O-amino malonate platinum complex compound
  • O,O'-amino malonate and N, O-amino malonate platinum complex compound

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Experimental program
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Embodiment

[0192] chemical reagent

[0193] Sigma-Aldrich of the United States provides cisplatin, pyrimidine, ethanol, ethyl acetate, diethyl ether, diethylaminomalonate, diethyl N-acetylmalonate, silver nitrate, sodium hydroxide, 1R, 2R- Diaminocyclohexane, polyglutamic acid sodium salt, potassium iodide and PBS buffer. Solvents are of HPLC grade, while reagents are of ACS grade or higher. BioRad Laboratories offers ion exchange media, AG 501-X8(D)H + ,HO - Dosage Form, AG 50W-X8H + , and Chelex100 biotech grade. Grade 1 water was obtained using the Milli-Q water system. K 2 PtCl 4 Provided by All-Chemie., Mt. Pleasant, SC. Acid Filtration Slurry No. 289 was from Schleicher and Schuell. Poly(HPMA)-GFLG-ONp, poly(HPMA)-GFLG-Ama-diEt (45kDa), and poly(HPMA)-GFLG-Ama-diEt (351kDa) were synthesized by Polymer Laboratories, Shropshire, UK. Amino acid analysis as well as MALDI-TOF-MS were performed by Gaithersburg, MD, Peptide Technologies Corp.

[0194] Instruments and Equipment ...

example 1

[0208] Example 1: Preparation of p(HPMA)-GFLG-Ama-diEt, about 25kDa

[0209] A dry 1 L round bottom flask with a magnetic stir bar was capped with a septum and cooled in a vacuum. Once cooled, nitrogen was added, the septum was opened, and 29.79 g (140.8 mmol) of diethylaminomalonate was added. The septum was removed and 800 ml of anhydropyrimidine was cannulated into the flask. Add 50g poly(HPMA)-GFLG-ONp (compound 1, US5,965,118 figure 1 A) one-third of the amount. When nearly dissolved, another third of the amount of ONp-polymer was added. When the second third of the volume is nearly dissolved, the final third of the ONp-polymer is added.

[0210] The free and total p-nitrophenols in the reaction were monitored by HPLC, using C18 column, pH4.5MeCN mobile phase, and 316nm ultraviolet detection. After basic hydrolysis (pH 12, 5 minutes), the quantitative solution was analyzed for free and total p-nitrophenol. After stirring for 20-24 hours at 23°C, the reaction was sub...

example 2

[0213] Example 2: the preparation of cis-cisplatin (II) nitrate

[0214] At room temperature, a suspension consisting of cisplatin (8.996g, 29.98mmol), silver nitrate (9.959g, 58.62mmol), 3-5 drops of 5% nitric acid and 190ml of water was placed in a low transmittance bottle and sealed with foil , stirred overnight, then heated at 60-65°C for 3.5 hours. After cooling below 30°C, the mixture was filtered through a 0.22 μm filter to obtain a clear solution at pH 2. Platinum and Silver Elemental Analysis (ICP-OES), typically platinum in the range of 15,000-25,000 ppm and silver in the range of 4-14 ppm. Each formulation was analyzed for Pt, and was heated at 55°C for 5 minutes prior to use and then cooled to room temperature.

[0215] cis-cisplatin(II) nitrate di- 15 N isotope preparation shows that at -1582ppm 195 Pt NMR three times, close to the -1580ppm literature value reported by Appleton et al. in 1989.

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Abstract

The invention relates to a chelate compound of amino malonic ester O, O'-Pt and N, O-Pt and a method for preparing the chelate compound almost purified.

Description

technical field [0001] The present invention relates to an aminomalonate O, O'-Pt and N, O-Pt chelate and a method for preparing substantially pure said chelate. Background technique [0002] Cisplatin (cDDP or cis-diamminediaquaplatinum), figure 1 ) is the most widely used platinum-based chemotherapy compound approved for use in humans and is currently used to treat tumors of the testis, ovary, head and neck, and in combination with other drugs for squamous cell and small cell lung cancer. The antitumor activity of cisplatin is thought to be through the dissociation of chloroligands in vivo to form active mono- or dihydrate complexes, followed by the formation of DNA intrastrand and interstrand cross-links in tumor cells, eventually leading to cell death. [0003] However, due to the nephrotoxicity and cytotoxicity of cisplatin, its application is obviously limited to a great extent. In order to discover new compounds with better therapeutic indices (the ratio of the maxi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00A61K31/555A61P35/00
Inventor 保罗·索迪唐纳德·R·斯蒂瓦特大卫·P·诺沃特尼克塞吉伊·维克多洛维奇·舍夫查克肯尼斯·布鲁斯·瑟蒙德二世
Owner 爱克斯制药有限公司
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