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Salts of phenylalanine compound and amorphous form of salts

A compound and amorphous technology, applied in the field of drugs for diseases, salts of phenylalanine compounds, and amorphous forms, can solve problems affecting drug safety and effectiveness, low bioavailability, easy decomposition, etc. To achieve the effect of improving bioavailability

Active Publication Date: 2016-07-27
SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the stability of 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propionic acid Poor, it was placed under high temperature (60°C), high humidity (90%) and strong light irradiation (4500Lx) for 10 days, the content decreased significantly, and related substances increased significantly, which shows that 2-(2-(4-fluorobenzene Formyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propionic acid is easy to decompose during the process of drug manufacturing, storage and transportation, affecting the drug The safety and effectiveness of the drug limit its application in the preparation of drugs for the treatment of metabolic syndrome
[0006] In addition, 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propanoic acid in water Very little solubility, almost insoluble, low bioavailability
This greatly affects its therapeutic effect

Method used

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  • Salts of phenylalanine compound and amorphous form of salts
  • Salts of phenylalanine compound and amorphous form of salts
  • Salts of phenylalanine compound and amorphous form of salts

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Sodium 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propionate preparation of

[0042]

[0043] Add 487.4g (12.18mol) of NaOH and 10.85kg of anhydrous methanol into a 50L plastic bucket, stir and dissolve at room temperature. Add 184kg tetrahydrofuran and 6.90kg (12.06mol) 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2- (9H-carbazol-9-yl)ethoxy)phenyl)propionic acid was stirred and dissolved at room temperature, and the above-mentioned methanol solution in which sodium hydroxide was dissolved was added to the reaction kettle, and stirring was continued for 30 minutes after the addition was completed. Concentrate in vacuo to remove tetrahydrofuran and methanol to obtain a concentrate. Dissolve the concentrate in 18.29kg of dichloromethane, add it dropwise to 149kg of isopropyl ether at room temperature with stirring, centrifuge, collect the solid, and dry it in vacuum at 105°C for 3 hours to obtain 2-(2-(4-fluorobenzyl Sodium ac...

Embodiment 2

[0045] Example 2: Potassium 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propionate preparation of

[0046]

[0047] Add 0.495g (8.84mmol) KOH and 10mL anhydrous methanol into a 100mL single-necked bottle, stir at room temperature to dissolve. Add 5.00g (8.74mmol) 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy Base) phenyl) propionic acid and 150ml tetrahydrofuran, stirring at room temperature to dissolve, adding the above-mentioned methanol solution in which potassium hydroxide was dissolved, and continuing to stir for 30 minutes after the addition. Concentrate in vacuo to remove tetrahydrofuran and methanol to obtain a concentrate. Dissolve the concentrate in 10 mL of dichloromethane, add dropwise to 150 mL of anhydrous diethyl ether at room temperature with stirring, filter, collect the solid, and dry it in vacuum at 60°C for 10 h to obtain 2-(2-(4-fluorobenzoyl) Potassium phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy...

Embodiment 3

[0049] Embodiment 3: stability test

[0050] 1. Test sample

[0051] 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propanoic acid: according to Chinese patent application 03126974.5 was prepared in Example 20, batch number: T1263-07-12-02, purity (HPLC): 99.34%.

[0052]Sodium 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propionate amorphous form: Prepared according to the preparation method of Example 1 of the present invention, batch number: 20130606, purity (HPLC): 99.61%.

[0053] Potassium 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propionate amorphous form: Prepared according to the preparation method of Example 2 of the present invention, batch number: 20130619, purity (HPLC): 99.52%.

[0054] 2. Test plan

[0055] According to the "Chinese Pharmacopoeia" 2010 edition two appendix XIXC to carry out the high temperature (60 ℃), high humidity (90%) and strong light (45001x) inf...

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Abstract

The invention discloses salts of a phenylalanine compound as shown in a general formula (I), and an amorphous form of the salts. In the general formula (I), M is as defined in the specification. The invention also discloses a preparation method and application for the above-mentioned salts. The salts can be applied in treatment of diseases associated with metabolic syndrome.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, in particular to a salt of a phenylalanine compound, more specifically to the amorphous form of the salt; the present invention also relates to a preparation method of the salt and its amorphous form and its Use in the preparation of medicines for preventing or treating diseases related to metabolic syndrome. Background technique [0002] 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propanoic acid is a Diseases and disorders have therapeutic and prophylactic activity of phenylalanine compounds, the chemical structure of which is as follows: [0003] [0004] The pharmacological activity of this compound is described in Chinese patent application CN03126974.5 and US patent application US7,268,157. 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propionic acid selectively activates PPAR -α, PPAR-γ and PPAR-δ capabilities can be used to ...

Claims

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Application Information

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IPC IPC(8): C07D209/86A61K31/403A61P3/00A61P3/10
CPCA61K31/403C07D209/86
Inventor 鲁先平李志斌宁志强
Owner SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD
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