Pharmacology of rioprostil, a new gastric cytoprotective/antisecretory agent.

Rioprostil (2-decarboxy-2-hydroxymethyl-15-deoxy-16RS-hydroxy-16-methyl prostaglandin (PG)E1) is a potent orally active inhibitor of gastric acid secretion in both rats and dogs. It prevents gastric lesions in rats induced by ethanol, acetylsalicylic acid, strong acid, strong base, hypertonic saline and thermal injury at doses 100 times less than its antisecretory dose. The cytoprotective effect of rioprostil can be observed when given 4 min before challenge with ethanol and measured 60 min later. The peak antiulcer effect is observed when rioprostil is given 30 min before ethanol challenge and the oral ED50 is 1.93 (1.74-2.15) micrograms/kg. Rioprostil possesses weak PGE-like activity in an isolated tissue cascade, no contragestational activity in rats, hamsters or rabbits, and no remarkable cardiovascular or pulmonary activity in dogs. The animal pharmacology of this compound suggests that it should be useful in the treatment or prophylaxis of peptic ulcer disease and gastric lesions associated with noxious irritants such as ethanol and nonsteroidal antiinflammatory drugs.

Tryptophan analogues. 1. Synthesis and antihypertensive activity of positional isomers.

A series of tryptophan analogues having the carboxyl function at the beta-position was synthesized and tested for antihypertensive activity. The 5-methoxy analogue 46 exhibited antihypertensive activity in the rat via the oral route and was much more potent than the normal tryptophan analogue. The methyl ester was found to be a critical structural feature for activity.

Analgesic narcotic antagonists. 2. 8-Alkymorphinan-6-ones.

A series of 8-alkyl-3-methoxy-17-methylmorphinan-6-ones (3C) and -isomorphinan-6-ones (3T) were prepared by conjugate addition of lithium dialkylcuprates to the corresponding 7,8-didehydro-6-ones 2C and 2T. These 17-methyl compounds were potent analgesics and were converted to mixed narcotic agonists-antagonists 7-10, by replacement of the 17-methyl groups with cycloalkylmethyl moieties. The 8 substituent modified the type of activity observed. One of these compounds, 17-(cyclobutylmethyl)-3-hydroxy-8 beta-methylmorphinan-6-one (10Ca), had an agonist-antagonist ratio of 0.1. Compound 10Ca did not support or cause dependence in rats. This compound, however, appeared to be a typical narcotic agent in morphine-dependent monkeys.

Analgesic narcotic antagonists. 1. 8 beta-Alkyl-, 8 beta-acyl-, and 8 beta-(tertiary alcohol)dihydrocodeinones and -dihydromorphinones.

Conjugate addition of lithium dialkyl cuprates to codeinone (3) gave as the major product a series of 8 beta-alkyldihydrocodeinones 4a-m. A low yield of the 8 alpha-isomer 6 was isolated in several cases. 8 beta-Acyldihydrocodeinones 10 were prepared by the addition of acyl carbanion equivalents (protected cyanohydrin method or lithium bis(alpha-ethoxyvinyl)cuprate) to 3 followed by hydrolysis. 8 beta-Acetyldihydrocodeine (12) was reacted with MeLi or n-BuLi to give tertiary alcohols 13, which were oxidized to target dihydrocodeinones 14. The 8 beta-substituted compounds with unsaturated (4c,f,m), branched (4d,g,i-k), or large straight-chain (4h,l) alkyl groups, as well as the acyl (10a-d) and tertiary alcohol (14a,b) derivatives, were less active than dihydrocodeinone (4n) in the mouse writhing and rat tail-flick analgesic assays. The analgesically active 8 beta-methyl (4a) and 8 beta-ethyl (4b) compounds were converted to N-(cyclopropylmethyl)- and N-(cyclobutylmethyl)dihydronorcodeinones (17 and 18) and -dihydronormorphinones (19 and 20). Some of these compounds had mixed agonist-antagonist profiles of action. One of these compounds, N-(cyclopropylmethyl)-8 beta-ethyldihydronorcodeinone (17b), has been selected for further study in man.