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Solid forms of transthyretin dissociation inhibitors

A form, crystal technology, applied in the field of solid forms of transthyretin dissociation inhibitors, which can solve the problem of incomparability of accurate dosage forms

Inactive Publication Date: 2016-04-13
PFIZER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If the solid form is not held constant during clinical studies or stability studies, the exact dosage form used or studied may not be comparable between batches

Method used

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  • Solid forms of transthyretin dissociation inhibitors
  • Solid forms of transthyretin dissociation inhibitors
  • Solid forms of transthyretin dissociation inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Embodiment 1--the preparation of crystal compound 1

[0138] 6-Carboxy-2-(3,5-dichlorophenyl)-benzoxazole free acid (2.5 g, 8.1 mmol) and 2-propanol (49 mL) were added to a 100 mL jacketed flask with a magnetic stirrer 2 neck round bottom flask. The resulting slurry was warmed to 70°C with stirring. Water (8.8 mL) was then added. In a separate 15 mL round bottom flask, a solution of N-methyl-D-glucamine (1.58 g, 8.1 mmol) in 5 mL of water was prepared and dissolved with stirring. The aqueous N-methyl-D-glucamine solution was then transferred to the reaction flask over 2 minutes. At the end of this addition, most (but not all) of the solids had dissolved. After stirring for 5 minutes and warming to 79°C a light yellow solution was obtained. Pass the solution through Celite TM The layer was filtered, cooled to 60°C, then to 10°C over 2 hours. The resulting solid was collected by filtration and washed with 10 mL of 2-propanol. 3.35 g of product were obtained (82% y...

Embodiment 2

[0139] Embodiment 2--The preparation of compound 1 liquid crystal

[0140] Crystalline Compound 1 (505 mg) was dissolved in 60 mL of water at room temperature. Transfer the solution to a lyophilization vessel and freeze with rotation in an acetone / dry ice bath. The vessel was transferred to a benchtop lyophilizer and allowed to dry under vacuum for approximately 19 hours to yield a white solid.

Embodiment 3

[0141] Embodiment 3--preparation of amorphous compound 1

[0142] Crystalline Compound 1 (approximately 500 mg) was transferred to an aluminum pan and placed on a hot plate at 200°C. Melting occurred within 1 min, at which point the pan was removed from the heating plate and placed immediately in liquid nitrogen. A glassy solid was obtained.

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Abstract

The present invention relates to solid forms of the N-methyl-D-glucamine (meglumine) salt of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole and a process for its preparation. The invention also relates to pharmaceutical compositions comprising at least one solid form, and the therapeutic or prophylactic use of such solid forms and compositions.

Description

field of invention [0001] The present invention relates to solid forms of the N-methyl-D-glucamine (meglumine) salt of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole and a process for its preparation. The invention also relates to pharmaceutical compositions comprising at least one solid form, and the therapeutic or prophylactic use of such solid forms and compositions. Background of the invention [0002] The present invention relates to 6-6-aminoethanoids for the treatment of transthyretin amyloidosis (e.g. senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC)) in mammals. Solid form of carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine (also known as "Compound 1"). The invention also relates to compositions comprising such solid forms, and methods of using such compositions in the treatment of transthyretin amyloidosis in mammals, especially humans. [0003] Carboxy-2-phenyl-benzoxazoles (e.g., 6-carboxy-2-(3,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/57A61K31/4245
CPCC07D263/57C07H5/06A61P17/00A61P25/00A61P25/02A61P27/02A61P43/00A61P7/02A61P9/00A61P9/04
Inventor R·F·拉博迪尼埃M·H·奥尼尔
Owner PFIZER INC
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