Adrenergic agents. 6. Synthesis and potential .beta.-adrenergic agonist activity of some meta-substituted p-hydroxyphenylethanolamines related to salbutamol

Abstract

Salbutamol, an adrenergic receptor agonist with selectivity for tracheobronchial vs. cardiac muscle, differs from the catecholamine N-tert-butylnorepinephrine in that it bears a hydroxymethyl, rather than a phenolic, group in the meta position. In a search for new bronchodilating agents with minimal cardiovascular side effects, a series of derivatives, in which this m-hydroxymethyl group is modified, was prepared. These compounds were examined for potential bronchodilator activity in an in vitro test that measures relaxation of guinea pig tracheal smooth muscle. Potential cardiac stimulant activity was evaluated in vitro by monitoring changes in the rate of contraction of spontaneously beating guinea pig right atria. Although many of these compounds retained a high degree of potency, all were less effective than salbutamol in the tracheal test. Several of the derivatives, notably ones bearing 1-hydroxyethyl (1d), 1,2-dihydroxyethyl (1f), 1-hydroxy-2-methoxyethyl (1g), and 2-hydroxy-1-methoxyethyl (1h) substituents in place of the parent's m-hydroxymethyl group, however, were considerably more selective for tracheobronchial vs. cardiac muscle in the in vitro tests utilizing guinea pig tracheal and right atrial muscle.

Synthesis of Chiral 1,2-Amino Alcohol-Containing Compounds Utilizing Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Unprotected α-Ketoamines

“…This methodology can also be applied to sterically hindered substrates, such as compound 2d with an adjacent t -butylamine group, which was achieved in 76% yield and high enantioselectivity of >99.9:0.1 er. The compound 2d was reported only in racemic synthesis from hydrogenation of a benzyl-protected derivative . Next, we investigated other drug candidates having the monohydroxy substitution on the aromatic ring with the free amines, as in octopamine ( 2e ).…”

Soft Drugs. 12. Design, Synthesis, and Evaluation of Soft Bufuralol Analogues

“…After esterification of 4 with methanol, the resulting methyl ester 5 was reacted with bromine in chloroform to give 6 , which was then reduced with diborane in tetrahydrofuran 40 to alcohol 7 . Epoxidation of 7 followed by opening of the resulting epoxide with tert -butylamine in 2-propanol produced 8b .…”

“…10% DMSO in 30% HPBCD) was injected into the jugular vein as bolus injections. Heart rate and blood pressure were registered at 1, 3,5,10,15,20,25,30,40,45,50, 60, 70, 80, 90, 105 and 120 min. The percent changes in heart rate were calculated as follows: % change in HR ) (HRt -HR-2)/HR-2 × 100, relative to the maximal isoproterenolinduced heart rate increase registered at -2 min, where t ) 0, 1, 3, ... 120 min.…”

New Aspects of β-Adrenergic Bronchodilator Drugs

“…Branching of the methylene bridge of salbutamol (5b) with a methyl (38), hydroxymethyl (39), methoxymethyl (40) or methylsulfonylmethyl (41) group permits the retention of a high order of 32" a drenoreceptor agonist potency which decreases as the size of the branch ing group is increased. Branching with two methyl groups, as in 42^changes activity from 3-adrenergic agonist to antagonist (35).…”