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Polymorphic substance of triarylated dimethylpiperazine di-hydrochloride and preparation method and application thereof

A technology of dimethylpiperazine and ketone dihydrochloride, applied in the field of medicine, can solve problems such as long onset time, inability to concentrate, sexual dysfunction, and confusion of thinking

Inactive Publication Date: 2017-04-26
YUNNAN INST OF MATERIA MEDICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs, while effective, often have problematic side effects, such as lethargy, confusion, inability to concentrate, and sexual dysfunction
Also, these drugs suffer from long onset times, requiring about 6 to 8 weeks to show any desired therapeutic effect

Method used

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  • Polymorphic substance of triarylated dimethylpiperazine di-hydrochloride and preparation method and application thereof
  • Polymorphic substance of triarylated dimethylpiperazine di-hydrochloride and preparation method and application thereof
  • Polymorphic substance of triarylated dimethylpiperazine di-hydrochloride and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1 (4-((R)-((2S,5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl) Preparation of polymorph B of methyl)phenyl)(4-methylpiperidin-1-yl)methanone dihydrochloride

[0077] Take 10g (4-((R)-((2S,5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl Base) phenyl) (4-methylpiperidin-1-yl) ketone into a glass bottle, add 200mL ethyl acetate to the glass bottle and stir evenly, then add 3.5mL concentrated hydrochloric acid with a volume percentage of 37.5%, at room temperature Stir, react for 3 hours, and dry in vacuo to obtain (4-((R)-((2S,5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazin-1-yl ) (3-hydroxyphenyl)methyl)phenyl)(4-methylpiperidin-1-yl)methanone dihydrochloride polymorph B.

[0078] (4-((R)-((2S,5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazin-1-yl)(3-hydroxy The XRPD pattern of polymorph B of phenyl)methyl)phenyl)(4-methylpiperidin-1-yl)methanone dihydrochloride is shown in figure 1 The peak information of its spectrum...

Embodiment 2

[0082] Example 2 (4-((R)-((2S,5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl) Preparation of polymorph E of methyl)phenyl)(4-methylpiperidin-1-yl)methanone dihydrochloride

[0083] (4-((R)-((2S,5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazin-1-yl)( 3-Hydroxyphenyl) methyl) phenyl) (4-methylpiperidin-1-yl) polymorph B of ketone dihydrochloride is used as a starting sample, placed in a glass bottle; the glass bottle Place it open in a large glass bottle filled with 100mL of acetonitrile or dichloromethane; seal the large glass bottle and place it at room temperature for 5 days, and take out the solid, which is polymorph E.

[0084] (4-((R)-((2S,5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazin-1-yl)(3-hydroxy The XRPD pattern of polymorph E of phenyl)methyl)phenyl)(4-methylpiperidin-1-yl)methanone dihydrochloride is shown in image 3 The peak information of its spectrum is shown in Table 2. TGA and DSC diagrams of polymorph E Figure 4 shown by Figure 4 It ...

Embodiment 3

[0088] Example 3 (4-((R)-((2S,5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl) Preparation of polymorph H of methyl)phenyl)(4-methylpiperidin-1-yl)methanone dihydrochloride

[0089] (4-((R)-((2S,5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazin-1-yl)( 3-Hydroxyphenyl) methyl) phenyl) (4-methylpiperidin-1-yl) ketone dihydrochloride polymorph B as the starting sample, add 100mL dimethyl sulfoxide to make the solid Completely dissolve; slowly add methyl isobutyl ketone dropwise until a precipitate is formed. Separate the precipitate, or transfer the sample to room temperature to quickly evaporate to obtain a solid, which is polymorph H.

[0090] (4-((R)-((2S,5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazin-1-yl)(3-hydroxy The XRPD pattern of polymorph H of phenyl)methyl)phenyl)(4-methylpiperidin-1-yl)methanone dihydrochloride is shown in Figure 5 As shown, the peak information of its spectrum is shown in Table 3. TGA and DSC diagrams of polymorph H Figure 6 sh...

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Abstract

The invention discloses four polymorphic substances B, E, H and D of (4-((R)-((2S, 5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazine-1-base)(3-hydroxyphenyl)methyl)phenyl)(4-methylpiperidine-1-base)ketone di-hydrochloride, a preparation method thereof, and application in preparing a drug.

Description

technical field [0001] The present invention relates to but not limited to the technical field of medicine, in particular to but not limited to a polymorphic form of triaryldimethylpiperazine dihydrochloride and its preparation method and application. Background technique [0002] Depression is a common mental illness, mainly manifested as low mood, loss of interest, pessimism, slow thinking, lack of initiative, self-blame, poor diet and sleep, worry that you have various diseases, and feeling that you are suffering from various diseases in your body. Discomfort, and in severe cases, suicidal thoughts and behaviors may appear. In the fourth edition of the "Diagnostic and Statistical Manual of Mental Disorders" published by the American Psychiatric Association, depression is classified under mood disorders and is divided into three types: major depressive disorder, dysthymic disorder and other Unspecified depression. [0003] Factors causing depression include: genetic fact...

Claims

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Application Information

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IPC IPC(8): C07D401/10A61K31/496A61P25/24A61P25/04A61P29/00A61P9/10A61P1/04
CPCC07D401/10C07B2200/13
Inventor 王京昆宋鹤孙敏王泽人杨志苏敏刘红斌师冰毛勇刘慧浪李泽千崔涛赵春梅苏梅袁芳张天财刘勇张宽仁魏云林沈悦海
Owner YUNNAN INST OF MATERIA MEDICA
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