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Macitentan crystal and its preparation method, its pharmaceutical composition and use

A technology of macitentan and its composition, which is applied in the field of pharmaceutical chemical crystallization, can solve the problems of affecting drug efficacy, poor solubility, and slow dissolution rate of tablets, etc.

Active Publication Date: 2016-05-25
倪云
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The inventors found in the research that the crystal form I is hydrophobic, has extremely poor solubility in water, and its tablet dissolution rate is slow. These properties may limit the concentration and rate of the active ingredient in the patient's bloodstream after oral administration, affecting the efficacy of the drug

Method used

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  • Macitentan crystal and its preparation method, its pharmaceutical composition and use
  • Macitentan crystal and its preparation method, its pharmaceutical composition and use
  • Macitentan crystal and its preparation method, its pharmaceutical composition and use

Examples

Experimental program
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Effect test

preparation example 1

[0125] N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]- Form I of ethoxy]-4-pyrimidinyl]-N'-propylsulfonamide (macitentan). Specifically:

[0126] Sodium hydride (1.67g, 69.6mmol, 55% content in mineral oil) was washed twice with 10mL of n-hexane, the n-hexane solution was discarded, and the washed sodium hydride was dissolved in 200mL of tetrahydrofuran, and N-[5-(4 -Bromophenyl)-6-[2-[(hydroxyethoxy)-4-pyrimidinyl]-N'-propylsulfonamide (10.0g, 23.2mmol), the mixture was stirred for 15 minutes, diluted with 400mL DMF, and finally 5-Bromo-2-chloropyrimidine (5.38 g, 27.8 mmol) was added, the temperature of the reaction solution was raised to 60° C., and the temperature was maintained for 2 hours, and the reaction was completed. Pour the reaction solution into 250 mL of 10% citric acid aqueous solution, add ethyl acetate to extract twice, each time 300 mL of ethyl acetate, combine the organic phases, wash with water twice, each time 200 mL of water, add magnesium sulfa...

Embodiment 1

[0131] Take 9.8mg of macitentan in a 5mL glass vial, add 0.9mL of methanol to form a suspension, stir at 60°C for 1 day, white crystals precipitate, separate by filtration, wash twice with methanol, and dry in vacuum at room temperature for 1 hour. Crystals of macitentan methanolate were obtained. Yield 8.6 mg, 85% yield.

[0132] XRPD patterns such as Figure 8 shown.

[0133] 1 HNMR (CDCl 3 ): 8.52(s, 2H), 8.50(s, 1H), 7.59-7.61(m, 2H), 7.17-7.19(m, 2H), 5.65(t, J=6.2Hz, 1H), 4.73-4.76( m, 2H), 4.63-4.65(m, 2H), 3.52(s, 2H), 2.98(q, J=6.8Hz, 2H), 1.58-1.63(m, 2H), 1.30-1.52(m, 7H) , 0.97 (t, J=7.4Hz, 3H). It shows that compared with the macitentan crystal form I prepared in Preparation Example 1, the macitentan methanolate crystal contains methanol, and each molecule of macitentan contains about 2 / 3 methanol molecules.

[0134] PLM map such as Figure 9 As shown, it has a better morphology.

Embodiment 2

[0136] Take 50.0 mg of macitentan in a 5 mL glass vial, add 0.5 mL of methanol to form a suspension, stir at room temperature for 7 days, precipitate white crystals, separate by filtration, wash with methanol for 3 times, and dry in vacuum at room temperature for 24 hours to obtain macitentan Tetan methanolate crystals, yield 48.1mg, yield 93%.

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Abstract

The present invention relates to a new crystalline form of macitentan, which has advantages in terms of solubility. The present invention also relates to the preparation method of the new crystal form, its pharmaceutical composition and its use in the preparation of medicines for treating hypertension and pulmonary arterial hypertension.

Description

technical field [0001] This application relates to the technical field of medicinal chemical crystallization. More specifically, the present application relates to new crystal forms of macitentan, including macitentan crystal form II, macitentan methanolate crystals, macitentan nitromethanate crystals and macitentan methyl tertiary Butyl ether compound crystal, its preparation method and use. Background technique [0002] On October 18, 2013, the US Food and Drug Administration (FDA) approved the new drug macitentan (trade name Opsumit) of Actelion Pharmaceuticals of the United States for the treatment of adult patients with pulmonary arterial hypertension (PAH). PAH is a specific type of pulmonary hypertension (PH), which belongs to World Health Organization (WHO) PH grade I, and is a severe, progressive and life-threatening disease of the pulmonary vasculature characterized by extreme Vasoconstriction and abnormal proliferation of smooth muscle cells in the walls of the ...

Claims

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Application Information

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IPC IPC(8): C07D239/47A61K31/505A61P9/12
CPCC07D239/47C07B2200/13A61K31/505A61P11/06A61P13/12A61P25/06A61P25/28A61P27/02A61P35/00A61P9/04A61P9/08A61P9/10A61P9/12A61K9/2027A61K9/2018A61K9/2013A61K9/2059A61K9/2054
Inventor 劳海萍盛晓霞盛晓红
Owner 倪云
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