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Differently substituted 2-aminopyridines have been prepared in two steps from pyridinium-N-(2-pyridyl)aminide, by reaction with the corresponding elect

A new, short and high-yield synthesis of 6-cyano-1-tetralones is described. Triflate intermediates 8 and 9 are versatile intermediates for the synthesis of other 6-substituted tetralones.

A new series of 2,2-dialkylnaphthalen-1-one potassium channel activators has been prepared, and their in vitro relaxant activities in isolated rat portal vein and guinea pig tracheal spirals as well as their oral antihypertensive effect in spontaneously hypertensive rats have been evaluated. The group of 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethylnaphthalen -1- ones with an electron-withdrawing substituent at the 6-position contain the most active compounds and 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-1-oxonaphtha lene-6- carbonitrile, 17f (UR-8225), has been selected for further pharmacological development.

The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the α-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the ref...

This paper describes the synthesis of a series of azo compounds able to deliver 5-aminosalicylic acid (5-ASA) and a potent platelet activating factor (PAF) antagonist in a colon-specific manner for the purpose of treating ulcerative colitis. We found it possible to add an amino group on the aromatic moiety of our reported 1-[(1-acyl-4-piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives or on British Biotech compounds BB-882 and BB-823 maintaining a high level of activity as PAF antagonist. A selected compound UR-12715 (49c) showed an IC50 of 8 nM in the in vitro PAF-induced aggregation assay, and an ID50 of 29 μg/kg in the in vivo PAF-induced hypotension test in normotensive rats. Through attachment of 49c to the 5-ASA via azo functionality we obtained UR-12746 (70). Pharmacokinetics experiments with [14C]-70 allow us to reach the following conclusions, critical in the design of these new prodrugs of 5-ASA. Neither the whole molecule 70 nor the carrier 49c were absorbed after oral administrati...

A new unexpected reaction of 1 -(4-fluorophenyl)-2-(4-pyridyl)ethanone 2 with 3-aminopyrazole, involving loss of a 4-pyridylmethyl group, afforded 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine 1 in good yields. Investigation of the features of this cyclization led to the development of a new three component coupling for the synthesis of pyrazolo[3,4-b]pyridines, from a ketone, an aldehyde and a 3-aminopyrazole in the presence of acid catalysis and a protic solvent. The study of the scope of this reaction showed its remarkable versatility and its usefulness in the preparation of other bicyclic systems, such as thieno[3,2-b]pyridines, pyrrolo[3,2-b]pyridines, imidazo[4,5-b]pyridines, furo[2,3-b]pyridines, isoxazolo[5,4-b]pyridines and, isothiazolo[5,4-b]pyridines. The three component nature of this reaction makes it suitable for the preparation of combinatorial libraries since scaffold decoration can be easily achieved in one step.