Amphoteric drugs. I. Synthesis and antiallergic activity of [4-(diphenylmethoxy)piperidino]-, [4-(diphenylmethyl)piperazinyl]- and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives.

A simple method of transforming classical antihistaminics into nonsedative antiallergic agents with strong effects in rat models is described. Various [4-(diphenylmethoxy)piperidino]- (series A), [4-(diphenylmethyl)piperazinyl]-(series B) and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives (series C) were synthesized and examined for antiallergic activities and effects on the central nervous system (CNS), in comparison with the corresponding N-methyl derivatives (1a--c). N-Alkylcarboxylic acids (5a--c) showed stronger inhibitory effects on compound 48/80-induced lethality in rats than the corresponding N-methyl derivatives (1a--c). In particular, N-alkylcarboxylic acids (5a) in series A exhibited approximately 100-fold stronger inhibitory effects than 1a, and were the least effective in prolonging the sleeping time on hexobarbital-induced anesthesia in mice in all series. As a result of chemical modification in series A, it was found that introduction of a methyl group at the para-position on one benzene ring in the (diphenylmethoxy)piperidine system effectively reduced CNS side-effects without reducing antiallergic activity. (+)-3-[4-[(4-Methylphenyl)phenylmethoxy]piperidino]propionic acid ((+)-5l), an optically active isomer of 5l, exhibited a stronger antiallergic effect (ED50 = 0.17 mg/kg, p.o.) than ketotifen and terfenadine in the 48 h homologous passive cutaneous anaphylaxis (PCA) test, and moreover exhibited no CNS side-effects, such as prolongation of the sleeping time on hexobarbital-induced anesthesia, at an oral dose of 30 mg/kg. Compound (+)-5l was thus proved to be a promising candidate as a nonsedative antiallergic agent.

Novel phenoxyalkylamine derivatives. VII. Synthesis and pharmacological activities of 2-alkoxy-5-[(phenoxyalkylamino)alkyl]benzenesulfonamide derivatives.

To find a novel alpha-blocker with high alpha-blocking selectivity against dopamine D2-receptor affinity, we performed structural modification of the alkylene chains and the substituents on two benzene rings of 2-alkoxy-5-[(phenoxyalkylamino)alkyl]benzenesulfonamide derivatives. The modification of the alkylene chain between the amino moiety in the center of the molecule and the benzene ring (ring A) was found to be the most significant. 5-[2-[[2-(5-Fluoro-2-methoxyphenoxy)ethyl]amino]propyl]-2- methoxybenzenesulfonamide (II-4), which possesses 1-methylethyl as the alkylene chain, exhibited high alpha-blocking selectivity as well as potent alpha-blocking activity.

Pharmacological studies of 1-(2-chloro-4-hydroxyphenyl)-2-t-butylaminoethanol (HOKU-81), a new bronchodilator. 1st Communication: Bronchodilator and cardiovascular actions.

Bronchodilating action and influence on the cardiovascular system of 1-(2-chloro-4-hydroxyphenyl)-2-t-butylaminoethanol (HOKU-81), which is one of metabolites of tulobuterol obtained from rat urine, were examined using the isolated tracheae and atria of guinea pigs in vitro and dogs in vivo in comparison with those of the parent drug, i.e., tulobuterol isoprenaline, salbutamol and other reference bronchodilators. HOKU-81 was approximately 8 times more potent than tulobuterol, approximately twice as potent as salbutamol, and approximately as potent as isoprenaline in relaxing effect on the isolated tracheal smooth muscle preparation of guinea pigs. This effect of HOKU-81 seems to be due to direct action on the adrenergic beta-receptor. In anaesthetized dogs, bronchodilating effect of HOKU-81 was much more potent than that of tulobuterol and was approximately as potent as that of salbutamol when administered i.v., and its effect lasted for many hours. When administered orally, the duration of bronchodilating effect of HOKU-81 was almost as long as that of salbutamol. The cardiac stimulating effect of HOKU-81 examined in the isolated guinea pig artia and in anaesthetized dogs was weaker than those of isoprenaline and salbutamol, though stronger than that of tulobuterol. In the present studies in vitro as well as in vivo, the selectivity ratio of HOKU-81 for beta-adrenoceptors in the tracheal smooth muscle vs. those in the right atrial muscle was the largest of all the bronchodilators used.