Crystal form of oxytocin receptor inhibitor and preparation method thereof

A technology of crystal form and solvent, applied in the field of crystal form and preparation of oxytocin receptor inhibitor, can solve problems such as difference in bioavailability

Active Publication Date: 2022-04-12
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The bioavailability of different crystal forms of the same drug may also be different due to the difference in arrangement

Method used

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  • Crystal form of oxytocin receptor inhibitor and preparation method thereof
  • Crystal form of oxytocin receptor inhibitor and preparation method thereof
  • Crystal form of oxytocin receptor inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Example 1: Compound 5-(3-(3-(6-fluoronaphthalen-1-yl)azetidin-1-yl)-5-(methoxymethyl)-4H-1,2, Preparation of 4-triazol-4-yl)-2-methoxypyridine

[0098] The first step: tert-butyl 3-(6-fluoro-3,4-dihydronaphthalen-1-yl)azetidine-1-carboxylate 1c

[0099] tert-butyl 3-iodoazetidine-1-carboxylate 1b (1134.58mg, 4.01mmol, prepared by the known method "Organic Letters, 2014, 16(23), 6160-6163"), iodine (39.12mg, 0.15mmol), zinc (604.65mg, 9.25mmol) were added to the reaction flask, protected by argon, and reacted for 0.5 hours. Bis(dibenzylideneacetone)palladium (141.15mg, 0.15mmol), 2-di Cyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (73.48mg, 0.15mmol) and 4-bromo-7-fluoro-1,2-dihydronaphthalene 1a (700mg, 3.08mmol, using Prepared by the known method "Chemistry-A European Journal, 2015, 21(14), 5561-5583") Add the above reaction solution, after the addition is complete, heat and stir at 50°C for 3 hours. After cooling to , the reaction solution was concentrated under...

Embodiment 2

[0241] Example 2 compound, Example 17 compound, Example 34 compound, Example 37 compound, Example 38 compound, Example 39 compound, Example 42 compound and Example 43 compound.

[0242] 2.2 Test animals

[0243] Twenty-four healthy adult SD rats were divided into 8 groups on average, with 3 rats in each group, purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2013-0006.

[0244] 2.3 Drug preparation

[0245]Weigh a certain amount of drug, add 2.5% volume of DMSO and 97.5% volume of 10% solutol HS-15 to prepare a 0.2 mg / mL colorless, clear and transparent liquid.

[0246] 2.4 Administration

[0247] SD rats were fasted overnight and administered intragastrically. The dosage was 30.0 mg / kg, and the volume was 10.0 mL / kg.

[0248] 3. Operation

[0249] Rats were administered the compound of Example 2, the compound of Example 17, the compound of Example 34, the compound of Example 37, the compound of Example 38, t...

Embodiment 3

[0260] Embodiment 3: A crystal form

[0261] 1.2g compound 5-(3-(3-(6-fluoronaphthalen-1-yl)azetidin-1-yl)-5-(methoxymethyl)-4H-1,2,4 -Triazol-4-yl)-2-methoxypyridine was added to 8ml ethyl acetate and 24ml n-hexane, heated and stirred to dissolve, stirred and cooled to crystallize, filtered, and vacuum-dried to obtain the product (985mg, yield: 82.1 %).

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Abstract

Provides the oxytocin receptor (OTR) inhibitor compound 5‑(3‑(3‑(6‑fluoronaphthalene‑1‑yl)azetidin‑1‑yl)5‑(methoxymethyl)‑4H Polymorphs of -1,2,4-triazole-4-yl)-2-methoxypyridine and methods for their preparation. Compared with the amorphous form, the polymorphic OTR inhibitor has higher purity and better chemical stability, which is of great significance for the development of drugs suitable for industrial production and with good biological activity.

Description

technical field [0001] Provided in this disclosure is the compound 5-(3-(3-(6-fluoronaphthalen-1-yl)azetidin-1-yl)-5-(methoxymethyl)-4H-1,2 , Crystal form of 4-triazol-4-yl)-2-methoxypyridine and preparation method thereof. Background technique [0002] PCT / CN2017 / 117421 (application date 2017.12.20) describes a compound 5-(3-(3-(6-fluoronaphthalen-1-yl)azetidin-1-yl)-5-(methyl Oxymethyl)-4H-1,2,4-triazol-4-yl)-2-methoxypyridine, pharmacodynamic experiments have shown that this compound has highly selective inhibitory effect on OTR, and has better Brain permeability, can effectively block the downstream function of oxytocin receptor mediated by oxytocin. [0003] Polymorphism refers to the existence of two or more different spatial arrangements of solid substances, thus having different physical and chemical properties. The bioavailability of different crystal forms of the same drug may also be different due to the difference in arrangement. At the same time, in view of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14A61K31/397A61K31/4196A61P15/00
CPCC07D401/14A61P15/00A61K31/4196A61K31/397
Inventor 邵启云杨俊然徐超杜振兴王捷
Owner JIANGSU HENGRUI MEDICINE CO LTD
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