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Crystalline forms of (s)-2-(7-cyano-1h-benzimidazol-1 yl)-n-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}acetamide

A crystallization and compound technology, applied in the field of crystal form of compound-2--N-{1-[4-phenyl]ethyl}acetamide, which can solve the limitations of agonist use, irritation, neurotoxicity and induction hypothermia

Pending Publication Date: 2021-11-09
NEOMED INST INST NEOMED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although agonists of the VR1 receptor can act as analgesics through nociceptor disruption, the use of agonists (such as capsaicin and its analogs) has been limited due to their irritative, neurotoxic, and hypothermic induction

Method used

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  • Crystalline forms of (s)-2-(7-cyano-1h-benzimidazol-1 yl)-n-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}acetamide
  • Crystalline forms of (s)-2-(7-cyano-1h-benzimidazol-1 yl)-n-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}acetamide
  • Crystalline forms of (s)-2-(7-cyano-1h-benzimidazol-1 yl)-n-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}acetamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0369] Example 1: Synthesis of Form A of Compound 1 - Experimental Procedure for Step 3

[0370] Carry out the preparation method of the crystal form A of the compound of formula (I): (S)-2-(7-cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano 1-methylethyl)phenyl]ethyl}acetamide (also referred to herein as 15).

[0371]

[0372] Step 3: Synthesis of 15 / compound 1

[0373] A 500 mL 3-neck round bottom flask equipped with a thermometer, mechanical stirrer, condenser and nitrogen inlet was charged with 20.71 g of 11 (60.8 mmol, 1.02 eq wrt 13) and 60.85 mL of 2M NaOH (2.04 eq wrt 13 ) solution. The resulting yellow slurry was stirred at 20-25°C for 15 minutes. 120 mL of methyl tert-butyl ether (MTBE, 10 parts wrt 13) was added in one portion and the resulting mixture was stirred for a minimum of 15 minutes to obtain a biphasic yellow solution. The biphasic yellow solution was separated using a separatory funnel and the upper organic layer was set aside. The aqueous layer (pH>1...

Embodiment 2

[0381]Embodiment 2: Solubility experiment of the crystal of crystal form A

[0382] Experiments were carried out to evaluate the solubility of the crystals of Form A at room temperature (25°C ± 2°C). Approximately 2 mg of solid was added to a 3-mL glass vial. The solvents listed in Table 7 were then gradually added to the vial until the solid dissolved or a total volume of 1 mL was reached. The results are summarized in Table 7 and used to guide solvent selection in polymorph screening.

[0383] Table 7

[0384] Approximate solubility of crystals of Form A at room temperature

[0385]

Embodiment 3

[0386] Example 3: Solid-Vapor Diffusion

[0387] Solid-vapor diffusion experiments were performed using 12 different solvents. For each experiment, approximately 15 mg of Form A crystals were weighed and placed into 3 mL vials. Place the 3 mL vial into a 20 mL vial containing approximately 2 mL of volatile solvent. The 20 mL vials were sealed with caps and kept at room temperature for 2 to 7 days to allow solvent vapors to interact with the samples. The solids were tested by XRPD and the results summarized in Table 8 indicate that either Form A or Form C crystals were obtained.

[0388] Table 8

[0389] Summary of Solid Vapor Diffusion Experiments

[0390]

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Abstract

Crystalline Forms of a compound of Formula I are provided. Crystalline Form A is among the crystalline Forms identified. Form A has an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2[theta] (+0.2 degrees 2[Theta]) at 3.07, 5.96, 11.89 and 17.85, and a Differential Scanning Calorimetry (DSC) thermogram that exhibits an endotherm having a peak temperature of about 168.9 DEG C. Crystalline Form A is useful as a pharmaceutical composition and can be used as an antagonist of VR1.

Description

[0001] related application [0002] This application claims priority to U.S. Provisional Application No. 62 / 789,740, filed January 8, 2019, which is hereby incorporated by reference in its entirety for all purposes. technical field [0003] The technical field relates to compound (S)-2-(7-cyano-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)phenyl Crystalline forms of ]ethyl}acetamide, as well as pharmaceutical compositions, therapeutic uses and manufacturing methods thereof. Background technique [0004] Pain perception in mammals is due to the activation of the peripheral terminals of specialized groups of sensory neurons called nociceptors. Capsaicin, the active ingredient in peppers, produces sustained activation of nociceptors and also dose-dependent pain sensation in humans. Cloning of the vanilloid receptor 1 (VR1 or TRPV1) indicated that VR1 is a molecular target of capsaicin and its analogues. (Caterina, M.J., Schumacher, M.A., et. al. Nature (1997) v. 389p...

Claims

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Application Information

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IPC IPC(8): C07D235/06A61K31/4184A61P25/02A61P29/00G01N23/2055G01N25/20
CPCA61P25/02A61P29/00C07D235/16A61K31/4184A61P19/02A61P1/04A61P3/10A61P3/04A61P11/14A61P11/00A61P13/10C07B2200/13
Inventor J·江A·谢
Owner NEOMED INST INST NEOMED
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