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Novel choline cocrystal of epalrestat

A technology of co-crystallization and choline dihydrogen, which is applied in the direction of medical preparations containing active ingredients, metabolic diseases, extracellular fluid diseases, etc., can solve the problem that there is no way to predict the co-crystal characteristics of compounds, and it takes a lot of time, issues of effort and resources

Inactive Publication Date: 2014-11-05
BIONEVIA PHARMACEUTICALS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, co-crystal formation is not predictable and in practice is not always possible
Furthermore, there is no way to predict the properties of a co-crystal of a particular compound until it forms
As such, discovering the correct conditions to obtain a specific co-crystal of a compound with pharmaceutically acceptable properties can take significant time, effort and resources

Method used

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  • Novel choline cocrystal of epalrestat
  • Novel choline cocrystal of epalrestat
  • Novel choline cocrystal of epalrestat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] The preparation of embodiment 1-intermediate product

[0064] With 0.187mL 50% choline hydroxide aqueous solution (0.187mL, with a density of 1.073g / mL = 201mg 50% choline hydroxide (by weight) = 101mg, 0.83mmol choline hydroxide) treatment 265mg (0.83mmol) A slurry of parerestat free acid and 20 mL of absolute ethanol. During the addition, all solids dissolved. The resulting solution was poured into 400 mL of diethyl ether and the precipitated solid was collected by filtration to give 282 mg of product. The solid was dried overnight in a vacuum oven at 1-5 Torr pressure at ambient temperature. Collect solid, obtain analysis data to intermediate product: XRPD pattern such as Figure 4 as shown, 1 H-NMR spectrum as Figures 5A-5C shown.

Embodiment 2

[0065] Preparation of the choline diacid hydrogen cocrystal of embodiment 2-epalrestat

[0066] Briefly sonicate a mixture of 209 mg epalrestat free acid and 11 mL acetone and filter through a 0.2 micron nylon filter. The filtrate was treated with 39 mg of the intermediate product of Example 1 to give a slurry. The slurry was stirred for about 4 days by placing it in a capped vial on a rotating wheel. Filtration gave 56 mg of di-epalrestat hydrocholine as a solid. Obtain analytical data on the product: XRPD patterns such as figure 1 As shown, the DSC thermal analysis chart is shown as figure 2 as shown, 1 H-NMR spectrum as Figure 3A-3D shown. Elemental analysis is as follows:

[0067]

Embodiment 3

[0068] Preparation of the choline diacid hydrogen cocrystal of embodiment 3-epalrestat

[0069] Briefly sonicate a mixture of 85 mg of epalrestat free acid and 20 mL of absolute ethanol and filter through a 0.2 micron nylon filter. The filtrate was treated with 26 mg of the intermediate product of Example 1 while sonicating to give a slurry. The slurry was stirred for about 4 days by placing it in a capped vial on a rotating wheel. Filtration gave 36 mg of di-epalrestat hydrocholine as a solid. Obtain analytical data to the product: the XRPD pattern is basically as figure 1 shown. Solubility data in water were obtained for the final product, with solubility properties such as Figure 6A shown. as can be found in Figure 6A As observed in , the dissolved concentration of epalrestat increased over time to 249 μg / mL after about 24 hours. as can be found in Figure 6B As observed in , the choline dihydrogen diacid cocrystal of epalrestat shows a solubility in water that is...

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Abstract

The invention relates to a novel choline cocrystal of 5-[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid. The preparation and characterization of the novel choline cocrystal according to various embodiments of the invention is described. The invention also relates to pharmaceutical compositions containing the novel choline cocrystal and the therapeutic use of the novel choline cocrystal to treat and / or prevent various conditions, including treating and / or preventing diabetic complications, treating and / or preventing homocystinuria reducing levels of homocysteine in blood serum, inhibiting aldose reductase, and affording cardioprotection in non-diabetic patients.

Description

[0001] Cross References to Related Applications [0002] Pursuant to 35 U.S.C. §119, this application claims priority to US Provisional Application US 61 / 094,904, filed September 6, 2008, which is incorporated herein by reference. technical field [0003] The present invention relates to novel choline cocrystals of 5-[(1Z,2E)-2-methyl-3-phenylpropenylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid, such The preparation method of the new co-crystal, the pharmaceutical composition containing the new choline co-crystal and the method of treating and / or preventing various diseases by administering the new choline co-crystal. Background technique [0004] The common name of the compound 5-[(1Z,2E)-2-methyl-3-phenylpropenylene]-4-oxo-2-thio-3-thiazolidineacetic acid (shown below) is "according to parerestat", which is an active pharmaceutical ingredient ("API") known to have beneficial therapeutic activity, for example as an aldose reductase inhibitor: [0005] [0006] The pre...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/36C07D277/32A61K31/19A61P3/10
CPCA61K31/427C07D277/36A61P1/00A61P1/04A61P17/02A61P25/00A61P25/02A61P25/16A61P25/28A61P27/12A61P3/00A61P7/00A61P9/00A61P9/10A61P3/10A61K31/19A61K31/426A61K31/14C07B2200/13C07C215/40
Inventor I·卡洛弗诺斯G·P·斯塔利W·马丁多伊尔D·卡洛弗诺斯J·S·斯塔尔茨T·L·休斯顿
Owner BIONEVIA PHARMACEUTICALS INC
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