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Mavacamten crystal form I and preparation method thereof

A crystal form, cu-k technology, applied in the field of crystal form I of Mavacamten, a new drug for the treatment of hypertrophic cardiomyopathy, and its preparation, can solve the problem that there is no report of Mavacamten crystal form, which affects drug stability, bioavailability, curative effect, and dissolution rate , bioavailability and other issues, to achieve the effect of simple preparation process, easy operation and easy storage

Pending Publication Date: 2021-06-11
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] We all know that different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., thereby affecting the stability, bioavailability and efficacy of the drug. It is particularly evident in solid preparations, but the crystal form of Mavacamten has not been reported in the existing patents

Method used

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  • Mavacamten crystal form I and preparation method thereof
  • Mavacamten crystal form I and preparation method thereof
  • Mavacamten crystal form I and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Add Mavacamten (1.0g, purity 98.0%) and 5mL of anhydrous methanol into a three-necked flask, stir evenly, heat up to 55-60°C, stir for 4-6 hours, slowly cool to 0-5°C for crystallization, and keep stirring for 16 After ~24 hours, centrifuge and dry to obtain 0.81 g of Form I (purity 99.9%, yield 82.6%).

[0036] The X-ray powder diffraction data of the crystal form I obtained in this embodiment are shown in Table 1, and its XRPD pattern is as follows figure 1 As shown, its DSC diagram is shown in figure 2 As shown, its TGA diagram is shown in image 3 shown.

[0037] Table 1

[0038]

[0039]

[0040] Anhydrous methanol can be used ethanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N , N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone or acetonitrile instead; the amount of methanol is feasible within the range of 0.5 ~ 40ml.

Embodiment 2

[0042] Add Mavacamten (1.0g, purity 98.0%) and 10mL of absolute ethanol into a three-necked flask, stir well, heat up to 55-60°C, stir for 4-6 hours, slowly cool to 0-5°C for crystallization, and keep stirring for 16 After ~24 hours, centrifuge and dry to obtain 0.86 g of Form I (purity 99.8%, yield 87.6%).

[0043] Table 2 shows the X-ray powder diffraction data of Form I obtained in this example.

[0044] Table 2

[0045]

[0046]

[0047] Dehydrated alcohol can be available methanol, isopropanol, n-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N , N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone or acetonitrile instead; the amount of ethanol is feasible within the range of 0.5-40ml.

Embodiment 3

[0049] Add Mavacamten (1.0 g, purity 98.0%) and 10 mL of isopropanol into a three-necked flask, stir evenly, heat up to 55-60°C, stir for 4-6 hours, slowly cool to 0-5°C for crystallization, and keep stirring for 16 After ~24 hours, centrifuge and dry to obtain 0.91 g of Form I (purity 99.8%, yield 92.7%).

[0050] Table 3 shows the X-ray powder diffraction data of Form I obtained in this example.

[0051] table 3

[0052]

[0053]

[0054] Virahol can be used ethanol, methanol, n-butanol, ethyl acetate, isopropyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N - Dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone or acetonitrile instead; the amount of isopropanol is feasible within the range of 0.5-40ml.

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Abstract

The invention provides a Mavacamten crystal form I. According to the Mavaamten crystal form I, characteristic peaks exist at the positions of 18.73 + / -0.2 degrees and 11.64 + / - 0.2 degrees when 2Theta values of an X-ray powder diffraction pattern measured by using Cu-K[alpha] rays. The crystal form is simple in preparation process, simple and convenient to operate, very good in stability and easy to store in the production circulation process, provides a very good choice for preparation of a pharmaceutical preparation of the crystal form, and has very important significance for drug development.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a crystal form I of Mavacamten, a new drug for treating hypertrophic cardiomyopathy, and a preparation method thereof. Background technique [0002] Mavacamten (codenamed MYK-461) is a cardiomyosin regulator developed by the American biotechnology company MyoKardia, a heavy basic research (A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice) published in Science magazine in 2016, Researched the theoretical basis of Mavacamten for the treatment of hypertrophic cardiomyopathy (HCM), and proposed for the first time that Mavacamten as a small molecule inhibitor of sarcomere contractile protein is expected to be an effective attempt in the treatment of HCM. In May 2020, MyoKardia announced that mavacamten had reached the primary endpoint and all secondary endpoints in the Phase III clinical trial for HCM patient...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/545
CPCC07D239/545C07B2200/13
Inventor 郑旭春张一平付晨晨娄恒桥
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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