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THR1442/L-aspartic acid co-crystal, and preparation method thereof and pharmaceutical composition thereof

A technology of aspartic acid and C1-C3, which is applied in the direction of drug combination, organic chemical method, cyanide reaction preparation, etc., can solve the problems of irregular particle shape, oil formation in water, high hygroscopicity, etc., and achieve good stability The effect of sex and mobility

Active Publication Date: 2018-07-03
SOLIPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] During the research process, the inventor found that the THR1442 diproline eutectic solid prepared according to the information provided by the prior art CN102933592B patent has the defects of high hygroscopicity, oil formation when meeting water, and irregular particle shape

Method used

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  • THR1442/L-aspartic acid co-crystal, and preparation method thereof and pharmaceutical composition thereof
  • THR1442/L-aspartic acid co-crystal, and preparation method thereof and pharmaceutical composition thereof
  • THR1442/L-aspartic acid co-crystal, and preparation method thereof and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0072] THR1442 was prepared according to the method described in Example [0110-0123] in the patent document CN102933592B.

[0073] 1 HNMR (500MHz, Methanol-d4): δ 7.38-7.27 (m, 3H), 7.13 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 4.13-4.03 (m, 5H), 3.91-3.87 (m, 1H), 3.87-3.83 (m, 2H), 3.71 (dd, J=11.9, 5.0 Hz, 1H), 3.50-3.40 (m, 4H), 3.30 (d, J= 9.1Hz, 1H), 0.59 (d, J=3.4Hz, 2H), 0.53-0.48 (m, 2H). Displayed as a known THR1442.

preparation example 2

[0075] The THR1442 diproline co-crystal was prepared by referring to the method described in Example 1F in the patent document CN102933592B.

[0076] Its X-ray powder diffraction pattern is as follows figure 1 Shown.

[0077] Its PLM map is as follows figure 2 Shown.

[0078] Its isotherm adsorption spectrum is as follows image 3 Shown.

Embodiment 1

[0080] Take 40 mg of THR1442 solid sample obtained in Preparation Example 1, add 0.2 mL of ethanol to form a clear solution, take 11.4 mg of L-aspartic acid, add 4 mL of water and ultrasound to form a clear solution, add the L-aspartic acid aqueous solution to the ethanol of THR1442 White turbidity precipitated in the solution. After stirring for 5 days at room temperature, it was filtered under reduced pressure and the solid was dried under vacuum at 40° C. for 10 hours to obtain 47.3 mg of THR1442L-aspartic acid co-crystal with a yield of 92%.

[0081] Its X-ray powder diffraction pattern is as follows Figure 4 Shown.

[0082] Its DSC spectrum is as Figure 5 Shown.

[0083] Its IR spectrum is as Image 6 Shown.

[0084] Its isotherm adsorption spectrum is as Figure 7 Shown.

[0085] Its PLM map is as follows Picture 8 Shown.

[0086] The proton nuclear magnetic spectrum data is: 1 HNMR (500MHz, DMSO-d6): δ7.33-7.22 (m, 2H), 7.16 (dd, J=8.2, 2.1Hz, 1H), 7.02 (d, J=8.5Hz, 2H), 6.77 ...

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Abstract

The invention relates to a SGLT2 inhibitor, i.e., a co-crystal of THR1442 (bexagliflozin) and L-aspartic acid. Compared with conventional THR1442 / diproline co-crystals the THR1442 / L-aspartic acid co-crystal of the invention has one or more improved features. The invention further relates to a preparation method for the THR1442 / L-aspartic acid co-crystal, a pharmaceutical composition of the THR1442 / L-aspartic acid co-crystal and methods for applying the THR1442 / L-aspartic acid co-crystal and the pharmaceutical composition to treatment of diseases or illnesses caused by inhibition of SGLT or SGLT2.

Description

Technical field [0001] This application relates to the technical field of medicinal chemical crystallization. Specifically, this application relates to a co-crystal of THR1442 and L-aspartic acid, its preparation method and use, and a pharmaceutical composition containing the co-crystal. Background technique [0002] THR1442 is a sodium-glucose cotransporter 2 (SGLT2) inhibitor, which can reduce blood glucose concentration and glycosylated hemoglobin in the blood of diabetic patients, and reduce weight. [0003] The chemical name of THR1442 is (2S,3R,4R,5S,6R)-2-(4-chloro-3-(-(4-(2-cyclopropoxyethoxy)benzyl)phenyl-6-( (Hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol, English name is bexagliflozin, molecular formula is C 24 H 29 ClO 7 , The molecular weight is 464.94, the CAS number is 1118567-05-7, and its chemical structure is as follows: [0004] [0005] Patent CN102933592B and CN102177147A disclose the crystal form of THR1442 and its diproline co-crystal and its preparation meth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/10C07C229/24C07C227/42A61K31/351A61P3/10A61P5/50A61P9/12A61P19/06A61P3/04A61P3/06A61P9/04A61P9/10A61P35/00
CPCC07C229/24C07D309/10C07B2200/13
Inventor 盛晓红盛晓霞
Owner SOLIPHARMA
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