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Analogs of cyclobenzaprine and amitryptilene

A technology of cyclobenzaprine and analogues, applied in the fields of drug combination, medical preparations containing active ingredients, organic chemistry, etc.

Pending Publication Date: 2020-04-10
TONIX PHARMA HLDG LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These findings focus on the critical lack of evidence-based physical treatments for military-associated PTSD and highlight the urgent and unmet need for new pharmacologic approaches that are Different Mechanisms of Action Related to PTSD Products Operate

Method used

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  • Analogs of cyclobenzaprine and amitryptilene
  • Analogs of cyclobenzaprine and amitryptilene
  • Analogs of cyclobenzaprine and amitryptilene

Examples

Experimental program
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Effect test

example

[0112] Purification of Trialkylamine Final Products in Examples 1-4 and 7-18. As free base, the trialkylamine final product can optionally be purified as follows: 1) using silica gel chromatography hexane-ethyl acetate, hexane-diethyl ether, dichloromethane-ethyl acetate, dichloromethane-methanol. Volatile trialkylamines such as triethylamine, trimethylamine or DIPEA can optionally be added to the solvent at 1-3% by volume to improve separation.

[0113] 2) Use reverse phase chromatography on C18 silica or phenyl silica. As a salt (including but not limited to oxalate, chloride or benzoate), the trialkylamine final product can be purified by recrystallization from a suitable solvent or solvent mixture including but not Limited to isopropanol, methanol, ethanol and their mixtures with ethyl acetate, chloroform and / or toluene.

example 1

[0114] Example 1 - TXAA-1, (2,2-difluoro-ethyl)-[3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propane base]-methyl-amine; preparation of the hydrochloride salt

[0115]

[0116] Nortriptyline HCl (1.80 g, 6.00 mmol) was suspended in anhydrous THF (20 mL), and DIEA (2.30 mL, 13.2 mmol) was added at room temperature (RT) to obtain a suspension. The reaction mixture was briefly heated to gentle reflux, after which time a suspension remained. The suspension was cooled to 5 °C, 2,2-difluoro-ethyl trifluoromethanesulfonate (1.414 mL, 6.60 mmol) was added dropwise at 5 °C, then the reaction mixture was allowed to warm slowly to RT, and at RT Stirred at low temperature for 14 hours, after which an amber solution with a small amount of suspension was obtained. The solvent was evaporated in vacuo to give a solid which was washed with diethyl ether (Et 2 O) (200mL) extracted, washed with water (40mL), brine (40mL), washed with MgSO 4 After drying, the solvent was evaporated...

example 2

[0119] Example 2 - TXCB-1, (3-dibenzo[a,d]cyclohepten-5-ylidene-propyl)-(2,2-difluoro-ethyl)-methyl-amine; salt Salt preparation

[0120]

[0121] Norcyclobenzaprine (1.57 g, 6.00 mmol) was suspended in anhydrous tetrahydrofuran (THF) (20 mL), and N,N-diisopropylethylamine (DIEA) (1.25 mL, 7.20 mmol) was added at RT to obtain a suspension. The reaction mixture was briefly heated to gentle reflux to give a cloudy solution which was cooled to 5°C and 2,2-difluoro-ethyl trifluoromethanesulfonate (1.414 mL, 6.60 mmol), the reaction mixture was then allowed to warm slowly to RT and stirred at RT for 15 hours, after which a suspension was obtained. The solvent was evaporated in vacuo to give an oil which was washed with Et 2 O (120mL) extracted, washed with water (20mL), brine (20mL), washed with MgSO 4 dry. The solvent was evaporated in vacuo to give an oil which was dissolved in DCM (6 mL) and passed through SiO with Hex-EtOAc 2 Purification by chromatography gave an ambe...

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Abstract

The present invention relates to cyclobenzaprine analogs and amitryptilene analogs, including deuterated forms useful for treatment or prevention of symptoms associated with post-traumatic stress disorder.

Description

[0001] related application [0002] This PCT application claims priority to U.S. Serial No. 62 / 532353, filed July 13, 2017. technical field [0003] The present invention relates to novel analogues of cyclobenzaprine. The new analog has similar pharmacodynamic properties to cyclobenzaprine and could be used to treat the same conditions as cyclobenzaprine, such as muscle spasms, fibromyalgia syndrome, traumatic brain injury, sleep problems and containing Post Traumatic Stress Syndrome (PTSD) of sleep problems associated with the condition. Background technique [0004] Cyclobenzaprine or 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine was first approved by the U.S. Food and Drug Administration in 1977 For the treatment of acute muscle spasms of local origin. (Katz, W. et al., Cyclobenzaprine in the Treatment of Acute Muscle Spasm: Review of a Decade of Clinical Experience), Clinical Therapeutics 10:216-228 (1988)). Cyclobenzaprine has also been studi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/135A61K31/155C07C211/32
CPCA61K31/135A61K31/155C07C211/32A61P25/00A61P25/24A61K31/397A61K45/06C07D205/04
Inventor S·莱德曼D·里德欧G·沙利文
Owner TONIX PHARMA HLDG LTD
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