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A solid form of the mesylate salt of an antischizophrenia drug

A technology for schizophrenia and mesylate, applied in the preparation of sulfonate, drug combination, medical preparations containing active ingredients, etc., can solve the problems affecting the clinical efficacy, side effects, quality stability, melting point, and solubility of drugs , Different stability, affecting drug absorption and release, etc., to achieve good light resistance, high humidity resistance, and reduce toxic and side effects

Active Publication Date: 2022-03-15
武汉久安药物研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Due to different structures, polymorphic drugs may have different melting points, solubility, and stability, which will affect the absorption and release of drugs in the body, thereby affecting the clinical efficacy, side effects, and quality stability of drugs.
None of the known literature mentions 7-(4-(4-(3-(6-fluoro-benzisoxazole)-1-piperidinyl)-n-butoxy))-4-methyl-8 -Crystal form of chloro-2-hydrogen-benzopyran-2-one mesylate, therefore, in view of the pharmaceutical value of this compound, it is necessary to 7-(4-(4-(3-(6-fluoro -Benzisoxazole)-1-piperidinyl)-n-butoxy))-4-methyl-8-chloro-2-hydro-benzopyran-2-one mesylate pharmaceutical polymorph Type research, so as to select and improve the efficacy of anti-schizophrenia drugs, reduce toxic side effects and ensure the quality of the preparation and storage process, etc.

Method used

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  • A solid form of the mesylate salt of an antischizophrenia drug
  • A solid form of the mesylate salt of an antischizophrenia drug
  • A solid form of the mesylate salt of an antischizophrenia drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] A crystal form A of mesylate salt of an antischizophrenia drug, specifically a 7-(4-(4-(3-(6-fluoro-benzisoxazole)-1-piperidinyl)- Form A of n-butoxy))-4-methyl-8-chloro-2-hydro-chromen-2-one methanesulfonate, prepared by the following steps:

[0101] (1) Weigh 1g of 7-(4-(4-(3-(6-fluoro-benzoisoxazole)-1-piperidinyl)-n-butoxy))-4-methyl-8- Chloro-2-hydrogen-benzopyran-2-one base, put in a three-neck flask, add 50ml of absolute ethanol, stir in a water bath at 40°C for 0.5h, dissolve it, and obtain a solution with a concentration of 0.02g / ml ;

[0102] (2) Measure 0.135ml of methanesulfonic acid, add 5ml of absolute ethanol to dilute, then slowly drop into the three-necked bottle of step (1), stir at room temperature for 1h, white insoluble matter precipitates out;

[0103] (3) Filtrate to obtain white insoluble matter, and dry it at 50°C to obtain 7-(4-(4-(3-(6-fluoro-benzoisoxazole)-1-piperidinyl)-n-butyl Form A of oxy))-4-methyl-8-chloro-2-hydro-chromen-2-one meth...

Embodiment 2～12

[0106] The crystal form A of the mesylate salt of the anti-schizophrenia drug provided in Examples 2-12 is specifically a 7-(4-(4-(3-(6-fluoro-benzisoxazole)-1- The crystal form A of piperidinyl)-n-butoxy))-4-methyl-8-chloro-2-hydrogen-chromen-2-one mesylate, compared with Example 1, is different The difference is that the preparation conditions are shown in Table 1, and the others are basically the same as in Example 1, and will not be repeated here.

[0107] The preparation conditions of table 1 embodiment 2~12

[0108]

[0109] After testing, 7-(4-(4-(3-(6-fluoro-benzisoxazole)-1-piperidinyl)-n-butoxy))-4-methanol prepared in Example 1-12 Form A of methyl-8-chloro-2-hydro-chromen-2-one methanesulfonate is 5.14±0.2°, 9.39±0.2°, 11.90±0.2°, 14.57±0.2° at diffraction angle 2θ , 15.55±0.2°, 15.88±0.2°, 18.24±0.2°, 19.01±0.2°, 20.38±0.2°, 21.11±0.2°, 21.79±0.2°, 23.03±0.2°, 23.39±0.2°, 24.23±0.2° , 25.1±0.2°, 25.90±0.2°, 26.43±0.2°, 26.90±0.2°, 27.77±0.2°, 28.59±0.2° all h...

Embodiment 13

[0111] A crystal form B of the mesylate salt of an antischizophrenia drug, specifically a 7-(4-(4-(3-(6-fluoro-benzoisoxazole)-1-piperidinyl)- Form B of n-butoxy))-4-methyl-8-chloro-2-hydro-chromen-2-one methanesulfonate, prepared by the following steps:

[0112] (1) Weigh 1g of 7-(4-(4-(3-(6-fluoro-benzoisoxazole)-1-piperidinyl)-n-butoxy))-4-methyl-8- Chloro-2-hydrogen-chromen-2-one base was placed in a three-neck flask, 60ml of ethyl acetate was added, stirred in a water bath at 40°C for 2 hours, and dissolved to obtain a solution with a concentration of 0.017g / ml;

[0113] (2) Measure 0.14ml of methanesulfonic acid, add 5ml of absolute ethanol to dilute, then slowly drop into the three-necked bottle of step (1), stir in a water bath at 70°C for 2h, white insoluble matter precipitates out;

[0114] (3) The white insoluble matter was obtained by suction filtration, and dried at 50°C to obtain 7-(4-(4-(3-(6-fluoro-benzoisoxazole)-1-piperidinyl)-n- Form B of butoxy))-4-methyl...

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Abstract

The invention provides a solid form of an anti-schizophrenia drug mesylate, and successfully prepares three kinds of 7‑(4‑(4‑(3‑( 6-fluoro-benzoisoxazole)-1-piperidinyl)-n-butoxy))-4-methyl-8-chloro-2-hydrogen-benzopyran-2-one methanesulfonate crystalline form A, crystalline form B and crystalline form C. Among them, the crystal form B has the characteristics of high temperature resistance, high humidity resistance and light resistance, good stability and high purity. It is used as an active ingredient to make a pharmaceutical composition, which can be used for the prevention and treatment of neuropsychiatric diseases.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a solid form of an antischizophrenia drug mesylate, in particular to a 7-(4-(4-(3-(6-fluoro-benzisoxazole) Novel crystal form of -1-piperidinyl)-n-butoxy))-4-methyl-8-chloro-2-hydrogen-benzopyran-2-one methanesulfonate and its preparation method and application . Background technique [0002] 7-(4-(4-(3-(6-fluoro-benzoisoxazole)-1-piperidinyl)-n-butoxy))-4-methyl-8-chloro-2-hydrogen- Benzopyran-2-one is a kind of benzopyrone derivative, which is disclosed in the invention patent CN102206214, and its structural formula is shown in the following formula: [0003] [0004] The results of animal experiments show that the compound can not only significantly improve the hypermobility induced by MK-801, but also effectively improve the climbing symptoms induced by apomorphine, and does not cause EPS at an effective dose. Since these in vitro targets and in vivo pharmacol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14C07C303/32C07C309/04A61K31/454A61P25/18
CPCC07D413/14C07C303/32C07C309/04A61P25/18C07B2200/13
Inventor 江华陈寅金牮张桂森
Owner 武汉久安药物研究院有限公司
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