872873-97-7

Upstream product

• 1479-58-9 5-bromo-2'-fluoro-2-aminobenzophenone 

Downstream Products

• 1413433-15-4 (S)-8-ethynyl-6-(2-fluorophenyl)-4-methyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylic acid 
• 872873-98-8 SH-I-048B 

Relevant academic research and scientific papers

Improved Scale-up Synthesis and Purification of Clinical Asthma Candidate MIDD0301

We report an improved and scalable synthesis of MIDD0301, a positive GABAA receptor modulator that is under development as oral and inhaled treatments for asthma. In contrast to other benzodiazepines in clinical use, MIDD0301 is a chiral compound that has limited brain absorption. The starting material to generate MIDD0301 is 2-amino-5-bromo-2′-fluorobenzophenone, which has a nonbasic nitrogen due to electron-withdrawing substituents in the ortho and para positions, reducing its reactivity toward activated carboxylic acids. Investigations of peptide coupling reagents on a multigram scale resulted in moderate yields due to incomplete conversions. Second, the basic conditions used for the formation of the seven-membered 1,4-diazepine ring resulted in racemization of the chiral center. We found that neutral conditions comparable to the pKa of the primary amine were sufficient to support the formation of the intramolecular imine but did not enable the simultaneous removal of the protecting group. Both difficulties were overcome with the application of the N-carboxyanhydride of d-alanine. Activated in the presence of an acid, this compound reacted with nonbasic 2-amino-5-bromo-2′-fluorobenzophenone and formed the 1,4-diazepine upon neutralization with triethylamine. Carefully designed workup procedures and divergent solubility of the synthesic intermediates in solvents and solvent combinations were utilized to eliminate the need for column chromatography. To improve compatibility with large-scale reactors, temperature-controlled slow addition of reagents generated the imidazodiazepine at -20 °C. All intermediates were isolated with a purity of >97% and impurities were identified and quantified. After the final hydrolysis step, MIDD0301 was isolated in a 44% overall yield and a purity of 98.9% after recrystallization. The enantiomeric excess was greater than 99.0%.

TREATMENT OF COGNITIVE AND MOOD SYMPTOMS IN NEURODEGENERATIVE AND NEUROPSYCHIATRIC DISORDERS WITH ALPHA5-CONTAINING GABAA RECEPTOR AGONISTS

Provided herein are alpha5-containing GABAA receptor agonists and pharmaceutical compositions and methods of treatment of cognitive and mood symptoms in neurodegenerative and neuropsychiatric disorders using them.

Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedative-hypnotic and ataxic effects

The present invention provides compositions and methods of using stereospecific benzodiazepine derivatives, their salts and prodrugs for the treatment of anxiolytic or convulsant disorders having the side effects of reduced alcohol craving in human alcoholics and a concomitant reduced sedative, hypnotic, muscle relaxant and ataxic side-effects. The invention further provides pharmaceutical compositions for treatment of anxiolytic and convulsant disorders in subjects in need thereof, comprising a compound, prodrug or a salt having a chemical structure represented by any one of Formula I-XXI and a pharmaceutically-acceptable carrier.

CHEMICAL COMPOUNDS

The present invention relates to dihydrobenzodiazepine derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such dihydrobenzodiazepine derivatives