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A kind of crystalline form of opioid receptor (mor) agonist and preparation method

A crystal form and drug technology, which is applied in the field of crystallization and preparation of opioid receptor (MOR) agonists, can solve the problems of poor product stability, poor fluidity, and easy agglomeration, and achieve stable production process and high solubility. Good effect with good crystal stability

Active Publication Date: 2022-04-12
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In general, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, difficult filtration, easy caking, poor fluidity, etc.

Method used

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  • A kind of crystalline form of opioid receptor (mor) agonist and preparation method
  • A kind of crystalline form of opioid receptor (mor) agonist and preparation method
  • A kind of crystalline form of opioid receptor (mor) agonist and preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] (1S, 4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl)- Preparation of 1,2,3,4-tetrahydronaphthalene-1-amine fumarate (III crystal form)

[0095]

[0096] (1S, 4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl) -1,2,3,4-Tetralin-1-amine (2.6g, 5.96mmol) was dissolved in isopropanol (10mL), heated to 80°C, fumaric acid (695mg, 5.96mmol) and isopropanol Propanol (10 mL) was added to another reaction flask, heated to 80°C and stirred to dissolve, then added dropwise to the above solution, refluxed and stirred for 10 minutes, cooled naturally to 40°C, a white solid precipitated in the solution, and then cooled to room temperature, The reaction was stirred for 1.5 hours. The reaction solution was filtered, and the filter cake was rinsed with isopropanol (2mL×5) and ethyl acetate (2mL×3) successively. The filter cake was collected and vacuum-dried to obtain a white solid product (2.0g, yield 60%). The XRPD pattern of the sample i...

Embodiment 2、II

[0103] Embodiment 2, investigation on stability of influencing factors of III crystal form

[0104] The III crystal sample obtained in Example 1 was placed open and flat, and the chemical stability of the sample was investigated under the conditions of light (4500Lux), high temperature (40°C, 60°C), and high humidity (RH75%, RH90%). The sampling time is 10 days and 17 days, and the chemical purity and chiral purity of the samples are investigated, and the HPLC detection purity is shown in the table below.

[0105] test results:

[0106] Table 2, Stability of Influencing Factors of Form III Crystalline Samples (HPLC Purity)

[0107]

[0108] Test Conclusions:

[0109] The crystal form III was kept open for 17 days under the conditions of light and high temperature (40°C, 60°C), and the chemical purity and chiral purity decreased significantly. Purity and chiral purity have little change; XRPD detection of crystal form III was placed under light (4500Lux), high temperature...

Embodiment 3、II

[0110] Embodiment 3, long-term and accelerated stability investigation of III crystal form

[0111] The crystal form III sample obtained in Example 1 was protected from light, sealed and laid flat to investigate the stability of the sample under long-term (25°C, 60%RH) and accelerated (40°C, 75%RH), and the sampling time was 0.5 Month, 1 month, 2 months, 3 months, XRPD detects whether the crystal form changes.

[0112] test results:

[0113] The stability (HPLC purity) of table 3, III crystal form sample

[0114]

[0115] Test Conclusions:

[0116] The crystal form III has good stability under long-term (25°C, 60% RH) and accelerated (40°C, 75% RH) conditions for 3 months in the dark and sealed condition, and 3 months at 25°C and 60% RH XRPD pattern see Figure 4 , 40 ℃, 75% RH placed 3 months XRPD pattern see Figure 5 , the XRPD peak shape of the III crystal form basically does not change, and the crystal form is stable.

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Abstract

The present disclosure provides a crystalline form of an opioid receptor (MOR) agonist and a preparation method thereof. Specifically, the present disclosure provides (1S,4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9- Base) ethyl)-1,2,3,4-tetrahydronaphthalene-1-amine fumarate III crystal form and preparation method thereof. The III crystal form of the compound of formula (I) in the present disclosure has good crystal stability and can be better used in clinical treatment.

Description

[0001] This application claims the priority of the Chinese patent application 201811186743.7 with the filing date of 2018 / 10 / 12. This application cites the full text of the above-mentioned Chinese patent application. technical field [0002] The present disclosure provides (1S,4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl Base)-1,2,3,3, the III crystal form of 4-tetrahydronaphthalene-1-amine fumarate and its preparation method, the application of III crystal form in pharmaceutical composition and the III crystal form, composition in the preparation Use in a medicament for the treatment and / or prevention of diseases associated with opioid receptor (MOR) agonists. Background technique [0003] Opioid receptors are an important class of G protein coupled receptors (GPCRs), which are the binding targets of endogenous opioid peptides and opioids. After activation, opioid receptors have negative effects on the immune system and endocrine system. Opioids a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D407/14A61K31/4433A61P29/00
CPCA61P29/00A61K31/4433C07D407/14
Inventor 王林杜振兴
Owner JIANGSU HENGRUI MEDICINE CO LTD
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