Substituted 3-amino-1,1-diaryl-2-propanols as potential antidepressant agents

Abstract

Following the discovery that 3-(dimethylamino)-1,1-diphenyl-2-propanol hydrobromide (1) possesses potent reserpine-prevention activity in mice, a series of analogues of 1 was synthesized and evaluated as potential antidepressant agents. Several routes to analogues of 1 were evaluated, the most generally applicable of which was the regiospecific ring opening of a suitably functionalized 1,1-diaryl-2,3-epoxypropane (obtained in three stages from the corresponding benzophenone) with the appropriate amine. The more interesting compounds of the series were evaluated for their propensity to cause undesirable peripheral anticholinergic effects, all compounds tested being markedly less active than imipramine on this parameter. On the basis of its good activity in biochemical and pharmacological animal models of depression, together with its relative lack of anticholinergic side effects, 1-(3-chlorophenyl)-3-(dimethylamino)-1-phenyl-2-propanol hydrochloride (20, BRL 14342) was chosen for further evaluation.

Structural Exploration of (3S,6S)‐6‐Benzhydryl‐N‐benzyltetrahydro‐2H‐pyran‐3‐amine Analogues: Identification of Potent Triple Monoamine Reuptake Inhibitors as Potential Antidepressants

“…[21] In this regard, FST is a well-recognized animal model for preclinical screening of potential antidepressants. [21][22][23][24][25][26][27][28][29] Furthermore, in another recent report we have described potent in vivo activity of a trisubstituted pyran derivative, D-142, in both FST and mouse tail suspension tests. [24] In this study, we further expanded our SAR studies with 3,6disubstituted compounds.…”

“…[25] Compound 7 was converted to the corresponding aldehyde 8 in the presence of glacial acetic acid and concentrated sulfuric acid. [26] Without further purification, the aldehyde 8 was immediately utilized to obtain the racemic epoxide 9 via the Corey-Chakovsky method. [27] The racemate 9 was then subjected to the kinetic hydrolytic resolution in the presence of Jacobsen’s catalyst to obtain the ( R )-epoxide 10 and diol 11 in 48% yield (over 99% ee).…”

Palladium‐Catalyzed Carbo‐Oxygenation of Propargylic Amines using in Situ Tether Formation

“…Examples of α‐amino ketones include the protease inhibitor Rupintrivir ( 1 ) and the antidepressant Bupropion ( 2 ) (Figure ) . Bioactive amino alcohols are even more widespread, with a broad range of bioactivities, as shown by the well‐known stimulant pseudoephedrine ( 3 ), the gastroprotective AI‐77‐B ( 4 ) or the antidepressant 5 . Chiral amino alcohols have also found applications as ligands or organocatalysts in asymmetric synthesis, as exemplified by the Jorgensen–Hayashi catalyst 6 …”

Enantioselective Carboetherification/Hydrogenation for the Synthesis of Amino Alcohols via a Catalytically-Formed Chiral Auxiliary

“…[14][15][16] After removal of the tether molecule, this process would provide amino alcohols, key building blocks in synthetic and medicinal chemistry, which have been the focus of intensive methodology development recently. [17][18][19][20][21][22][23][24] In particular, the diaryl-substituted amino alcohols obtained using this strategy can be found in antidepressants 25,26 and have served as intermediates for the synthesis of antimycotic, antibacterials 27 and antiviral molecules. 28,29 However, the selective synthesis of one of the four possible stereoisomers of the amino alcohols generally requires multi-step processes.…”

“…The nitrile and the carbonyl group within 25 and 27, were reduced to the corresponding amine 48 and alcohol 50. Interestingly, 5, 36, 45, 46, 47 and 54 are precursors of bioactive compounds with antidepressive activity, 25,26 while the amino alcohols derived from 36 and 47 are intermediates for the synthesis of patented antiviral drugs candidates. 28 Remarkably, our method provide high level of asymmetric induction even in the presence of sterically and electronically similar aryl substituents on the olefin, thus overcoming a common obstacle in the development of catalytic asymmetric reactions.…”