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5-hydroxytryptamine receptor agonist and its preparation method and use

A technology of crystal and volume ratio, which is applied in the preparation of carboxylate, organic chemical methods, pharmaceutical formulations, etc., can solve the problems of poor solubility, poor drug solubility, and low stability, so as to facilitate absorption and be suitable for medicinal use , good reproducibility

Active Publication Date: 2021-03-26
SICHUAN CREDIT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In order to ensure the stable quality of the drug and exert a good therapeutic effect, the drug needs to have high stability and good solubility at the same time. In the prior art, crystals of tandospirone citrate are usually used. However, the existing Among the technical crystals, although the solubility of tandospirone citrate crystal form I is better, its stability is relatively low (see: Chinese patent CN102344442A)
Although the stability of tandospirone citrate crystal form II and crystal form III is high, their solubility is relatively poor (see: Chinese patents CN 103641817A and CN 103641818A); it can be seen that the stability and solubility of the drug ( Solubility) is a pair of contradictions that restrict each other, that is, the improvement of the stability of the drug usually leads to the deterioration of the solubility of the drug. Page last paragraph of the fourth section, People's Health Publishing House, 2009)

Method used

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  • 5-hydroxytryptamine receptor agonist and its preparation method and use
  • 5-hydroxytryptamine receptor agonist and its preparation method and use
  • 5-hydroxytryptamine receptor agonist and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1 Preparation of Tandospirone Citrate Monohydrate Crystal and Its Physicochemical Properties

[0053] 1. Preparation of tandospirone citrate monohydrate crystals

[0054] Weigh 60g of tandospirone citrate, add 400mL of tetrahydrofuran, 100mL of acetonitrile and 50mL of water, heat up to solvent reflux, wait for complete dissolution, continue to stir for 1 hour, then stop heating, naturally cool to room temperature, stand for 8h to crystallize, After filtering and drying, 60.7 g of white powdery crystals of tandospirone citrate monohydrate were obtained, with a yield of 98.1% and a purity of 99.92%.

[0055] 2. Physical and chemical properties of tandospirone citrate monohydrate crystals

[0056] 2.1 Mass Spectrometry and Melting Point Determination

[0057] After testing, the obtained crystal mass spectrum is ESI m / z: 383, and the melting point is 166.0-167.5°C

[0058] 2.2 Moisture determination

[0059] Get product of the present invention and dry to const...

Embodiment 2

[0078] Embodiment 2 Preparation of tandospirone citrate monohydrate crystal

[0079] Weigh 120g of tandospirone citrate, add 150mL of tetrahydrofuran, 150mL of acetonitrile and 300mL of water, heat up to 50°C, wait for complete dissolution, continue stirring for 1 hour, then stop heating, naturally cool to room temperature for 20h, filter, and dry , 121.0 g of white powdery tandospirone citrate monohydrate crystals were obtained, with a yield of 97.8% and a purity of 99.91%. The structural analysis results and X-ray powder diffraction patterns of the obtained product are not significantly different from those in Example 1.

Embodiment 3

[0080] Example 3 Preparation of Tandospirone Citrate Monohydrate Crystals

[0081] Weigh 60g of tandospirone citrate, add 800mL of tetrahydrofuran, 800mL of acetonitrile and 80mL of water, heat up to 65°C, wait for complete dissolution, continue stirring for 1 hour, then stop heating, naturally cool to room temperature for 6h, filter, and dry , 60.9 g of white powdery tandospirone citrate monohydrate crystals were obtained, with a yield of 98.4% and a purity of 99.93%. The structural analysis results and X-ray powder diffraction patterns of the obtained product are not significantly different from those in Example 1.

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Abstract

A novel crystal of (3a[alpha],4[beta],7[beta],7a[alpha])-hexahydro-2-[4[4-(2-pyrimidinyl)-1-(piperazinyl)]-butyl]-4,7-methylene-1H-isoindole-1,3(2H)-dione citrate monohydrate, a preparing method thereof and uses of the crystal are disclosed. The molecular formula of the (3a[alpha],4[beta],7[beta],7a[alpha])-hexahydro-2-[4[4-(2-pyrimidinyl)-1-(piperazinyl)]-butyl]-4,7-methylene-1H-isoindole-1,3(2H)-dione citrate monohydrate is C<21>H<29>N5O<2>.C6H8O<7>.H2O. The novel crystal increases stability and solubility of products at present, thus facilitating product preparation and application and increasing medicine safety and effectiveness.

Description

technical field [0001] The invention relates to a new crystal of tandospirone citrate monohydrate, a preparation method and application thereof. belongs to the field of medicinal chemistry. Background technique [0002] Tandospirone is a serotonin receptor agonist, belonging to the third generation of anxiolytic drugs, mainly used for the treatment of anxiety or other diseases accompanied by anxiety state. In the brain, it can be concentrated in the emotional center of the hippocampus, septum, interpeduncular nucleus, amygdala and other brain limbic systems and 5-HT in the suture gland nucleus. 1A Receptors selectively bind by agonizing 5-HT 1A Autoreceptors, regulate the 5-HT projected from the raphe nucleus to the hippocampus, inhibit the 5-HT effect of the action inhibition system, and exert anxiolytic effects. [0003] Compared with the original drug azaspirenone and its derivative buspirone, tandospirone has a higher selective anxiolytic effect, which is similar to t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12C07C59/265C07C51/41C07C51/43A61K31/506A61P25/00A61P27/02A61P25/18A61P25/20A61P25/22A61P25/24A61P3/04A61P25/30A61P25/32A61P15/00A61P15/10A61P25/08A61P25/16A61P27/06A61P3/10A61P25/04
CPCC07B2200/13C07D403/12
Inventor 陈刚李晓莉刘志鸿傅霖邓丽敏
Owner SICHUAN CREDIT PHARMA