Process for preparing supramolecular platinum-based compounds

A platinum compound, precipitate technology, applied in the fields of nanotechnology and cancer treatment, can solve the problem of low biological activity

Active Publication Date: 2018-03-27
阿卡马拉医疗公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this case, the biological ac...

Method used

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  • Process for preparing supramolecular platinum-based compounds
  • Process for preparing supramolecular platinum-based compounds
  • Process for preparing supramolecular platinum-based compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0211] Example 1: Schematic of an Exemplary Synthetic Procedure

[0212]

[0213] A similar procedure was used for the synthesis of compounds 25-28 and other lipid-bound platinum compounds. These exemplary procedures work well for all of the compounds described. Introducing additional washing steps helped to increase the purity of compound 26 up to 93% (Table 2).

[0214] Table 2: Yield and Purity of Compounds Prepared Using Embodiments of the Invention

[0215]

[0216] figure 1 shows the HPLC profile of compound 26 before washing with water and acetone, figure 2 The HPLC profile of compound 26 after washing with water and acetone is shown. This is the highest purity achieved by washing.

[0217] Detailed methods for the synthesis of the above exemplary compounds are described in International Patent Application PCT / US2014 / 042339 published as WO / 2014 / 201376, which is incorporated herein by reference.

Embodiment 2

[0218] Embodiment 2: the improved synthetic route of the intermediate 6 of compound 25

[0219] A multi-step synthesis of compound 25 can be found in WO / 2014 / 201376. The reduction in the number of ligand synthesis steps will help improve the yield of compound 25 (API). The referenced procedure involved six steps to reach intermediate 6, whereas the procedure disclosed herein would take two steps to reach the same intermediate. The overall yield of intermediate 6 in the reference procedure (Scheme 2) was 13%. A significant increase (50%) in the yield of intermediate 6 was observed in the new route (Scheme 5).

[0220] Scheme 2: Synthetic steps before compound 25

[0221]

[0222] Scheme 3A. Route 1 for the synthesis of intermediate 6 in fewer steps

[0223]

[0224] Scheme 3B. Route 1B for the synthesis of intermediate 6

[0225]

[0226] Experimental details for Route 1B (Scheme 3B): 2-Bromoethylamine hydrobromide (5.0 g, 25 mmol) was added portionwise to ethyl b...

Embodiment 3

[0243] Embodiment 3: HPLC purification and analysis

[0244] The lipid-bound platinum compounds of the disclosure can then be purified by preparative reverse phase HPLC. The compound can be used on a C18 stationary phase, NH 2 On-column purification of stationary or phenyl stationary phases. Some of the compounds have been found to be unstable on C18, C8, cyano and PFP stationary phases, leading to miscalculations of purity. Therefore, estimates of purity are based on the NH in which the compound has been found to be stable. 2 column or phenyl column.

[0245] Purification on a C18 column involved an isocratic method with a mobile phase comprising 98% methanol and 2% water. Monitor UV absorbance at 210 nm. Compound peaks were collected, pooled and solvent removed by evaporation and lyophilization to obtain >99.5% pure compound in powder form.

[0246] in NH 2 Or purification on a phenyl column involves a gradient method starting with a higher percentage of water and pro...

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Abstract

The present invention is in relation to the fields of nanotechnology and cancer therapeutics. In particular, the present disclosure relates to improved methods for preparing lipid- conjugated platinumcompounds with high purity and good yields. The present disclosure also relates to nanoparticles comprising lipid-conjugated platinum compounds with high drug loading efficiency for use in chemotherapy, and to methods for producing said nanoparticles.

Description

[0001] related application [0002] This application claims the benefit under one or more of 35 U.S.C. §119(a)-119(d) of Indian Patent Application No. 1418 / DEL / 2015, filed May 19, 2015, the contents of which Incorporated herein by reference in its entirety. technical field [0003] The present invention relates to the fields of nanotechnology and cancer therapy. In particular, the present disclosure relates to the synthesis of lipid-bound platinum compounds, and also to methods of preparing lipid-bound platinum compounds in high purity and good yield. The present disclosure also relates to nanoparticles comprising a lipid-bound platinum compound and having high drug loading efficiency for use in chemotherapy, and methods of making the nanoparticles. Background technique [0004] Platinum-based chemotherapeutic agents are used as first-line therapy in more than 70% of all cancers. Cisplatin rapidly forms cis-[Pt(NH 3 ) 2 Cl(OH 2 )] + Heshun-[Pt(NH 3 ) 2 (OH 2 )] 2...

Claims

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Application Information

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IPC IPC(8): A61K9/51
CPCA61K9/1271A61K47/543A61P35/00A61K47/6911A61K47/6929A61K9/1272A61K9/1277A61K9/5123A61K9/5146A61K9/5192A61K31/28A61K9/5115A61K9/5161C07F15/0013
Inventor 尼米什·古普塔阿伦达姆·萨卡尔希拉拉尔·巴西普拉迪普·杜塔
Owner 阿卡马拉医疗公司
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