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Solid forms of adamantyl compound, compositions and uses thereof

A compound and composition technology, applied in the field of preparation of medicines for treating central nervous system diseases

Active Publication Date: 2019-06-07
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, memantine has certain physical and chemical properties that limit its therapeutic use
Memantine, for example, has a fairly high water solubility, which poses a challenge for drug formulation

Method used

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  • Solid forms of adamantyl compound, compositions and uses thereof
  • Solid forms of adamantyl compound, compositions and uses thereof
  • Solid forms of adamantyl compound, compositions and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0179] Example 1. ((((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)carbamoyl)oxy)methylbenzoate (compound (I)) preparation of

[0180]

[0181] In a 100mL single-necked bottle, add ((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)chloromethyl carbamate (2.0g, 7.35mmol), benzoic acid (0.98 g, 8.09mmol), triethylamine (0.89g, 8.82mmol), sodium iodide (0.55g, 3.67mmol) and N,N-dimethylformamide (8mL), heated to 85°C. After reacting for 2 h, samples were taken for TLC detection. After the reaction, cool down to room temperature, add water (30mL) and ethyl acetate (30mL); after stirring at room temperature for 30min, static layering; separate the organic layer, and wash the organic layer once with saturated aqueous sodium bicarbonate (30mL) , washed once with HCl (0.5M, 30mL), and finally washed once with water (30mL); the organic layer was separated, and ethyl acetate was distilled off under reduced pressure to obtain a brown oil (1.2g); a white solid was obtained after column chromatogr...

Embodiment 2

[0185] Example 2. ((((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)carbamoyl)oxy)methylbenzoate (compound (I)) In vivo pharmacokinetic analysis

[0186] In the experiment, the in vivo conversion of compound (I) to the active compound memantine was tested.

[0187] Materials and methods

[0188] LC / MS / MS analysis system: Agilent 1200 series vacuum degasser, binary syringe pump, orifice autosampler, column oven, charged spray ionization (ESI) source and Agilent G6430 triple quadrupole mass spectrometer. Quantitative analysis was performed in MRM mode, and the MRM conversion parameters were as follows:

[0189] multiple reaction detection scan

180.2→163.1

Fragmentation voltage

15V

capillary voltage

3500V

Dryer temperature

350℃

atomizer

40psi

Dryer flow rate

9L / min

[0190] A Waters XBridge TMC 18, 2.1 x 30 mm, 3.5 μM column was used to inject 20 μL of sample each time. Analysis conditions: the mobile phase includ...

Embodiment 3

[0199] Example 3. Preparation of ((((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)carbamoyl)oxy)methylbenzoate Form I

[0200] Crude ((((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)carbamoyl)oxy)methylbenzoate (2.00 g) was added to dry iso in propanol (20mL); placed in a 40°C oil bath and stirred to obtain a clear solution, then slowly cooled to room temperature, and then slowly added water (20mL); a white solid precipitated, suction filtered, and the filter cake was placed in a drying oven at room temperature under vacuum After drying, white crystals (1.88 g, yield 94%) were obtained, which were confirmed to be Form I by XPRD and DSC.

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Abstract

Provided herein are crystalline forms of ( ( ( ( (1r, 3R, 5S, 7r) -3, 5-dimethyladamantan-1-yl)carbamoyl) oxy) methyl benzoate (Compound (I)): Also provided are compositions comprising the crystallineforms of Compound (I), processes of manufacture and methods of using the crystalline forms of Compound (I).

Description

technical field [0001] The present invention relates to a crystal form of ((((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)carbamoyl)oxy)methylbenzoate, which The preparation method of the crystal form, the pharmaceutical composition of the crystal form, and the use of the crystal form or its pharmaceutical composition in the preparation of drugs for treating central nervous system diseases. Background technique [0002] Many neurodegenerative diseases result from neurodegenerative processes. Neurodegeneration is the progressive loss of neuronal structure or function, including neuronal death. Neurodegenerative diseases are incurable and result in progressive degeneration and / or death of neuronal cells. [0003] Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist that works by binding to NMDA receptors on brain cells and blocking the activity of the neurotransmitter glutamate to reduce certain types of brain activity. Memantine has been shown to be effective in th...

Claims

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Application Information

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IPC IPC(8): A61K31/13A61P25/16A61P3/10A61P25/00A61P25/28
CPCA61K31/27A61K31/445A61K31/473A61K31/4748A61K31/55A61P3/10A61P25/00A61P25/16A61P25/28C07B2200/13C07C271/24C07C2603/74A61K2300/00
Inventor 叶辉青徐巾超何必飞刘光元樊玉平王仲清罗忠华
Owner SUNSHINE LAKE PHARM CO LTD
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