Chemo- and stereoselective synthesis of benzocycloheptene and 1-benzoxepin derivatives as α-sympathomimetic and anorexigenic agents

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 11; pp. 2867 - 2870
• Main Authors: Tandon, Vishnu K., Singh, Kunwar A., Awasthi, Anoop K., M. Khanna, J., Lal, Bansi, Anand, Nitya
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 07.06.2004; Elsevier
• Subjects: Amphetamines - antagonists & inhibitors; Animals; Appetite Depressants - administration & dosage; Appetite Depressants - chemical synthesis; Appetite Depressants - pharmacology; Benzocycloheptenes - administration & dosage; Benzocycloheptenes - chemical synthesis; Benzocycloheptenes - pharmacology; Benzoxepins - administration & dosage; Benzoxepins - chemical synthesis; Benzoxepins - pharmacology; Biological and medical sciences; Blood Pressure - drug effects; Catecholaminergic system; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Antagonism; General and cellular metabolism. Vitamins; Life Sciences & Biomedicine; Medical sciences; Mice; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Obesity - drug therapy; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Science & Technology; Stereoisomerism; Sympathomimetics - administration & dosage; Sympathomimetics - chemical synthesis; Sympathomimetics - pharmacology; Aminoalcohol; Chemoselectivity; Rodentia; Benzocycloheptene derivatives; Sympathomimetic; Oxygen heterocycle; Biological activity; Stereoselectivity; Vertebrata; Mammalia; Mouse; Animal; Bicyclic compound; Aromatic compound; Anorectic; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.03.064

Chemo- and stereoselective synthesis of 4 and 5 is described. The synthesis and pharmacological evaluation of cis- and trans-6-amino-6,7,8,9-tetrahydro-5 H-benzocyclohepten-5-ols 4a– c and 5a– c and cis- and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ols 4d– f and 5d– f were carried out. Chemo- and stereoselective synthesis of 5a– f was achieved by reduction of corresponding α-amino ketones 3a– f with LiAl( t-BuO) 3H. cis-4-Amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 4d and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 5d exhibited marked anorexigenic activity in mice at a dose of LD 50 800 and 500 mg/kg and ED 50 75 and 55 mg/kg, respectively, while the analog cis-2,3-dihydroxy-6-amino-6,7,8,9-tetrahydro-5 H-benzocyclohepten-5-ol 8 showed typical α-sympathomimetic activity.