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Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives

a technology of phenyl carbamate and substituted amino, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, organic chemistry, etc., can solve the problems of depression and sexual function, memory decline or worsening, depression and other lifestyle limitations, and many patients are not adequately treated with the current available options, so as to achieve the effect of treating or preventing

Inactive Publication Date: 2017-12-14
SCIFLUOR LIFE SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present patent application describes a new compound, called A, and its use in treating or preventing diseases or disorders that can be ameliorated by opening KCNQ2 / 3 potassium channels. The compound has been found to be effective in modulating these channels and has shown promise in treating epilepsy. The patent also includes a pharmaceutical composition containing the compound and a method of treating or preventing the diseases or disorders by administering the compound to patients in need. The technical effects of the patent include providing a new compound for treating KCNQ2 / 3 potassium channel-related diseases or disorders and providing a method for treating or preventing these diseases or disorders using the new compound.

Problems solved by technology

Decline in or worsening of memory, cognition, depression and sexual function and other lifestyle limitations occur frequently in epilepsy patients.
Epilepsy patients also have an increased risk of mortality compared to the general population.
Although various pharmacologic agents are approved to treat epilepsy, many patients are not adequately treated with the currently available options.
Occasional instances of urinary difficulty may require surveillance.

Method used

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  • Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives
  • Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives
  • Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1a

[0314]

Step 1: Synthesis of Compound a

[0315]To a stirred solution of 4-fluorobenzylamine (1 equivalent (equiv)) dissolved in dimethylformamide (DMF) is added allyl bromide (1.5 equiv) and diisopropyl ethylamine (2 equiv) dropwise, and the resulting mixture is heated to 80° C. After 2 hours, the reaction mixture is cooled, diluted with water, and extracted with ethyl acetate (EtOAc). The organic layer is then washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue is purified by silica gel liquid chromatography to provide Compound a.

Step 2: Synthesis of Compound b

[0316]To a stirred suspension of 2,3-difluoro-6-nitroaniline (1 equiv) in dry dimethyl sulfoxide (DMSO) is added Compound a (3 equiv) followed by Et3N (1.2 equiv) and I2 (catalytic amount). The resulting mixture is heated to 120° C. and stirred at 120° C. for 24 hours. Upon complete consumption of the starting material (as determined by thin layer chroma...

example 1b

Step 1: Synthesis of 2-Fluoro-N1-(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine

[0318]2,3-Difluoro-6-nitroaniline (10.0 g, 79.9 mmole) was dissolved in anhydrous dimethylsulfoxide (90 mL). 4-fluorobenzylamine (9.3 g, 53.3 mmole) was added triethylamine (17.7 mL) and solid iodine (80 mg) were added and the mixture was heated at reflux for 4 h. under argon. The reaction was dissolved in ethyl acetate (200 mL) and extracted with water (3×100 mL). A yellow solid precipitated out of the organic layer to give 2-fluoro-N1-(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine (13.6 g, 91% yield).

Step 2: Synthesis of di-tert-butyl (3-fluoro-4-((4-fluorobenzyl)amino)-1,2-phenylene)dicarbamate

[0319]2-Fluoro-N1-(4-fluorobenzyl)-4-nitrobenzene-1,3-diamine (13.55 g, 48.53 mmole) was dissolved in methanol (60 mL) and tetrahydrofuran (60 mL). The mixture was cooled in an ice bath and zinc powder (31.70 g, 485.3 mmole) was added followed by ammonium chloride (26.0 g, 485.3 mmole) in DI water (64 mL) over 30 min. ...

example 2a

[0324]

Step 1: Synthesis of Compound c

[0325]To a stirred solution of 4-trifluoromethylbenzylamine (1 equiv) dissolved in DMF is added allyl bromide (1.5 equiv) and diisopropyl ethylamine (2 equiv) dropwise, and the resulting mixture is heated to 80° C. After 2 hours, the reaction mixture is cooled, diluted with water, and extracted with ethyl acetate. The organic layer is then washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue is purified by silica gel liquid chromatography to give Compound c.

Step 2: Synthesis of Compound d

[0326]To a stirred suspension of 2, 3-difluoro-6-nitroaniline (1 equiv) in dry DMSO is added Compound c (3 equiv) followed by Et3N (1.2 equiv) and I2 (catalytic amount). The reaction mixture is heated to 120° C. and stirred at 120° C. for 24 h. Upon complete consumption of the starting material (as determined by TLC), the reaction mixture is cooled to RT, diluted with water (25 mL), and e...

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Abstract

The application relates to 2-amino-4-(substituted amino)phenyl carbamate derivatives, or pharmaceutically acceptable salts or solvates thereof, as KCNQ2 / 3 potassium channel modulators, and methods of their uses.

Description

RELATED APPLICATION[0001]This application claims priority to, and the benefit of, U.S. Ser. No. 62 / 348,481, filed on Jun. 10, 2016, the entire contents of which are incorporated herein by reference.BACKGROUND[0002]Epilepsy is one of the most common chronic neurological disorders, and affects approximately 50 million people worldwide. Epilepsy patients have significantly increased morbidity, including closed head injury, fractures, burns, dental injury and soft tissue injury. Decline in or worsening of memory, cognition, depression and sexual function and other lifestyle limitations occur frequently in epilepsy patients. Epilepsy patients also have an increased risk of mortality compared to the general population.[0003]Although various pharmacologic agents are approved to treat epilepsy, many patients are not adequately treated with the currently available options. It is estimated that nearly a third of patients with epilepsy have either intractable or uncontrolled seizures or signif...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D217/04C07D209/44C07C233/43C07C271/28
CPCC07D217/04C07C233/43C07D209/44C07C271/28A61P25/00A61K31/13A61K31/403A61K31/47C07C269/00
Inventor EDWARDS, D. SCOTTASKEW, BEN C.FURUYA, TAKERU
Owner SCIFLUOR LIFE SCI
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