Structure−Activity Relationships of a Series of Substituted Benzamides:  Potent D₂/5-HT₂ Antagonists and 5-HT_1a Agonists as Neuroleptic Agents

Abstract

A series of substituted (4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide derivatives was prepared and evaluated as potential atypical antipsychotic agents. The target compounds were readily prepared from their benzoyl chloride, benzoic acid, or isatoic anhydride precursors, and they were evaluated in vitro for their ability to bind to dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors. To assess the potential antipsychotic activity of these compounds, we investigated their ability to inhibit the apomorphine-induced climbing response in mice. Selected compounds were evaluated further to determine their side-effect potentials. Structure-activity relationships of both mono- and polysubstituted benzamides are discussed herein. While several analogues had potent in vitro and in vivo activities indicative of potential atypical antipsychotic activity, anthranilamide 77 (1192U90) ddemonstrated a superior pharmacological profile. As a result of this investigation, 1192U90 (2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)ben zamide hydrochloride) was selected for further evaluation and is currently in phase I clinical trials as a potential atypical antipsychotic agent.

Synthesis and Biological Evaluation of Novel Eg5 Inhibitors

“…A conceptually attractive approach to these thioureas is through commercially available or synthesised aminobenzophenones 7 . As a first step, we synthesised isatoic anhydrides 5 from anthranilic acids 4 by treatment with trichloromethyl chloroformate 16. Reaction of isatoic anhydrides with N , O ‐dimethylhydroxylamine gave Weinreb amide precursors 6 in good to excellent yields.…”

2-Amino-6-chloro-N-methylbenzamide

“…For background information on substituted anthranilamides, see: Bharate et al (2013); Gnamm et al (2012); Lahm et al (2005); Norman et al (1996); Roe et al (1999). For the synthesis, see: Witt & Bergman (2000); Coppola (1980).…”

“…(2013). E69, o1642 (Bharate et al, 2013;Gnamm et al, 2012;Lahm et al, 2005;Norman et al, 1996;Roe et al, 1999). We report here the crystal structure of the title compound, 2-amino-6-chloro-N-methylbenzamide, an important organic intermediate in the synthesis of medicines, agricultural chemicals and animal drugs.…”

2-Amino-N,3-dimethylbenzamide

“…For background to substituted anthranilamides, see: Gnamm et al (2012); Lahm et al (2005); Norman et al (1996); Roe et al (1999). For the synthesis, see: Staiger & Wagner (1953); Coppola (1980); Witt & Bergman (2000).…”

“…Rigaku MM007-HF CCD (Saturn 724+) diffractometer Absorption correction: multi-scan (CrystalClear;Rigaku, 2007) T min = 0.970, T max = 0.992 3828 measured reflections 1939 independent reflections 1884 reflections with I > 2(I) Data collection: CrystalClear (Rigaku, 2007); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: OLEX2 (Dolomanov et al, 2009); software used to prepare material for publication: SHELXL97. (Gnamm et al, 2012;Lahm et al, 2005;Norman et al, 1996;Roe et al, 1999). We report here the crystal structure of the title compound 2-amino-N,3-dimethylbenzamide, an important organic intermediate in the synthesis of medicines, agricultural chemicals, and animal drugs.…”