Esters of N-tert-butylarterenol. Long-acting new bronchodilators with reduced cardiac effects

Abstract

The preparation of various esters of N-tert-butylarterenol is described. Esterification of the phenolic OH groups has increased bioavailability, prolonged bronchodilation, and reduced tachycardia. The substitution of aromatic esters compared with simple aliphatic esters improved markedly these pharmacological properties. Of a number of esters tested, compound 45 (bitolterol) demonstrated the most favorable pharmacological properties as a bronchodilator. Its long duration of action and significant bronchodilator-cardiovascular separation are briefly described.

Isolated Perfused Rabbit Lung as a Model for Intravascular and Intrabronchial Administration of Bronchodilator Drugs II: Isoproterenol Prodrugs

“…Di-p-toluoylisoproterenol-Synthetic procedures were modeled after published methods for preparation of esters of isoproterenol (7) and N-tertbutylarterenol (9). The overall reaction scheme is shown in Scheme I.…”

Isomers of erythro-5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril, a new bronchodilator

“…To a solution of 32.7 g (0.1 mol) of rac-erythro-1 hydrochloride in 105 mL of 2 N NaOH and 200 mL of MeOH was added 15.2 g (0.12 mol) of benzyl chloride and the mixture was refluxed for 3 h. The solvent was evaporated and the residue was extracted with CHC13. The CHC13 layer was washed with water, dried over anhydrous MgS04, and evaporated to give 35.8 g (94%) of compound 2: mp 142-143 "C (AcOEt); NMR (CDC13) 6 To a solution of 11.4 g (0.03 mol) of 2 and 6.1 g (0.06 mol) of triethylamine in 120 mL of CHC13 was added dropwise 4.7 g (0.06 mol) of acetyl chloride with stirring and cooling in ice-water. After 1 h the CHC13 layer was washed with 10% Na2C03 solution and water and dried over MgS04.…”

Designing Prodrugs and Bioprecursors

“…Since this group is highly protonated at pH 7.4, the compound shows low lipophilicity at physiological pH (log P 5 À0.04), which is unfavorable for corneal penetration. For dipivaloyl-epinephrine and dibenzoyl-ADTN, the selective acylation of the phenolic hydroxyl groups was achieved in a strong acidic medium, the amino function being protected by protonation [35,38]. In a similar manner, dibenzoyl-2-amino-6,7-dihydroxy-tetrahydronaphthalene (DB-ADTN) reaches the central nervous system (CNS), whereas the parent dopamine agonist ADTN does not [35,36].…”