ABSTRACT
The synthesis and gastric acid antisecretory properties of several N-substituted thieno[3,4-d]isothiazol-3-amine 1,1-dioxides and analogues are described. Two of the more potent compounds, N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno[3,4-d] isothiazol-3-amine 1,1-dioxide (6a) and N-[4-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno[3,4-d] isothiazol-3-amine 1,1-dioxide, showed greater potencies as H2-receptor antagonists (in vitro) than ranitidine. They also had potent gastric acid antisecretory activities in vivo, inhibiting basal acid secretion in the rat, histamine-stimulated acid secretion in the dog, and food-stimulated acid secretion in the dog. These were selected for further pharmacological evaluation.
Subject(s)
Gastric Acid/metabolism , Histamine H2 Antagonists , Thiazoles/pharmacology , Thiophenes/pharmacology , Animals , Atrial Function , Chemical Phenomena , Chemistry , Dogs , Dose-Response Relationship, Drug , Female , Gastric Mucosa/drug effects , Guinea Pigs , Heart Atria/drug effects , Heart Rate/drug effects , Histamine/pharmacology , Ligation , Male , Phenoxypropanolamines , Pylorus , Ranitidine/pharmacology , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiophenes/chemical synthesisABSTRACT
The syntheses of 2-oxo-1,8-naphthyridine-3-carboxylic acid derivatives having potent gastric antisecretory properties in the pyloric-ligated (Shay) rat model are described. Two of the more potent compounds tested that were selected for more detailed dose-response evaluation were 4-amino-1-ethyl-1,2-dihydro-2-oxonaphthyridine-3-carboxylic acid ethyl ester (35) and 1-ethyl-1,2-dihydro-7-methyl-4-(4-methyl-1-piperazinyl)-2- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (77). These compounds lowered total acid output in the rat in a dose-related fashion. Both compounds were more potent than cimetidine when tested in the rat. Both 35 and 77 showed inhibitory activity in food-stimulated acid secretion in the Pavlov-pouch, conscious dog. The mechanism of action for this series is not known. Details of structure-activity relationships are described.
Subject(s)
Gastric Acid/metabolism , Naphthyridines/chemical synthesis , Animals , Cimetidine/pharmacology , Dogs , Dose-Response Relationship, Drug , Female , Guinea Pigs , Male , Naphthyridines/pharmacology , Rats , Rats, Inbred Strains , Structure-Activity RelationshipABSTRACT
Several salts of thiazinamium, a quaternary analogue of promethazine, administered by aerosol, possessed equipotent anticholinergic activity in anesthetized guinea pigs but the duration of this effect differed somewhat. N-Butyl substitution in the side chain, but not the corresponding ethyl or n-propyl substitutions, reduced the aerosol anticholinergic potency and duration. There was also a tendency for a corresponding reduction in antihistaminic activity with different alkyl substitutions and for a greatly reduced duration of this effect.
Subject(s)
Asthma/drug therapy , Bronchodilator Agents/pharmacology , Promethazine/analogs & derivatives , Promethazine/pharmacology , Aerosols , Animals , Guinea Pigs , Histamine H1 Antagonists/pharmacology , Parasympatholytics/pharmacology , Promethazine/administration & dosage , Time FactorsABSTRACT
When tested in a series of immunopharmacologic assays, the interferon inducer, WY-15297, was shown to lack activity in early vascular and humoral phases of the inflammatory response, while it was quite effective against the immunologic phase. The profile of activity of Wy-15927 was, however, unlike those previously described for reference antiinflammatory and immunosuppressive drugs and this may represent one of a new class of immunopharmacologic agents capable of selectively modulating the lymphoreticular system.
Subject(s)
Immunity/drug effects , Interferon Inducers/pharmacology , Xanthenes/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal , Antibody Formation/drug effects , Dogs , Guinea Pigs , Immunity, Cellular/drug effects , In Vitro Techniques , Male , Mice , Rabbits , Rats , Rats, Inbred StrainsABSTRACT
A series of 1,2,3,4-tetrahydro-4-oxo-1,8-naphthyridine-3-carboxylic acid esters, carbonitriles, and carboxamides (2a-k) was synthesized and initially evaluated (dose range 50-400 mg/kg) in mice infected with Escherichia coli. Only two derivatives, the ethyl and butyl esters of 1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid, protected the animals against E. coli and several other gram-negative bacterial pathogenic infections. A pro-drug type of mechanism appears to be operable since neither agent showed in vitro activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Naphthyridines/chemical synthesis , Amides/chemical synthesis , Amides/pharmacology , Anti-Bacterial Agents/pharmacology , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Escherichia coli/drug effects , Esters , Microbial Sensitivity Tests , Naphthyridines/pharmacology , Nitriles/chemical synthesis , Nitriles/pharmacology , Proteus mirabilis/drug effects , Proteus vulgaris/drug effects , Salmonella typhi/drug effects , Salmonella typhimurium/drug effectsABSTRACT
A series of (2-pyrimidinylthiomethyl)carbonitriles and -carboxamidoximes was synthesized and the antiarrhythmic effects were evaluated against ventricular arrhythmias as measured by the electrical fibrillatory threshold in the anesthetized dog. Structure-activity studies indicated 2-[4-(p-chlorobenzylamino)-6-methyl-2-pyrimidinylthio]acetamidoxime dihydrochloride (6a) and 2-[4-(1,3-benzodioxol-5-ylmethylamino-6-propyl-2-pyrimidinylthio]acetamidoxime (6g) to be the most potent members of the series.
Subject(s)
Acetamides/chemical synthesis , Anti-Arrhythmia Agents/chemical synthesis , Pyrimidines/chemical synthesis , Acetamides/therapeutic use , Animals , Anti-Arrhythmia Agents/therapeutic use , Dogs , Electric Stimulation , Pyrimidines/therapeutic use , Ventricular Fibrillation/prevention & controlABSTRACT
Several novel pyrazolin-5-ones prepared by the cyclization of variously substituted thiosemicarbazone derivatives of ethyl formylsuccinate, ethyl acetylsuccinate, and ethyl acetylglutarate were tested for antitubercular activity against Mycobacterium tuberculosis, human type, strain H37Rv, by a tube dilution technique. Minimum inhibitory concentrations (MIC) for these derivatives ranged from 0.05 to 100 mug/ml. The most active compound was ethyl 3-methyl-1-methylthiocarbamoyl-5-oxo-3-pyrazoline-4-acetate (MIC=0.05-0.1 mug/ml).
