RESUMEN
The role of immunologically released mediators, such as histamine, leukotrienes, and platelet-activating factor, is well-established for asthma and other allergic disorders. Developing therapeutic agents which would block mediator release from mast cells and other relevant cell types would provide a rational approach to asthma therapy. Using human basophil as a screen, a series of 4-aryl-2-(phenylamino)pyrimidines was found which inhibited mediator release. These compounds were prepared by condensing acetyl heterocycles with dimethylformamide dimethyl acetal to form enaminones which are cyclized with aryl guanidines to give pyrimidines. After examining a large number of analogs, N-[3-(1H-imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2- pyrimidinamine (1-27) was chosen for toxicological evaluation.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Imidazoles/síntesis química , Pirimidinas/síntesis química , Animales , Basófilos/efectos de los fármacos , Basófilos/metabolismo , Femenino , Humanos , Imidazoles/química , Imidazoles/farmacología , Dosificación Letal Mediana , Macaca mulatta , Masculino , Ratones , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
With the use of the human basophil histamine release assay, 5-aryl-2-amino[1,2,4]triazolo[1,5-c]pyrimidines were found to be active as mediator release inhibitors. These compounds were prepared by reacting arylamidines with sodium ethyl formylacetate or with ethyl propiolate to give pyrimidinones. Treatment with phosphorus oxychloride gave a chloropyrimidine, which was converted to a hydrazinopyrimidine with hydrazine. Cyclization, using cyanogen bromide, gave the triazolo[1,5-c]pyrimidines, after a Dimroth rearrangement. Following a structure-activity evaluation, the 5-[3-(trifluoromethyl)phenyl]-2-amino (8-10), 5-(3-bromophenyl)-2-amino (8-13), 5-[3-(difluoromethoxy)-phenyl]-2-amino (8-11), and 5-(4-pyridinyl)-2-amino (6-7) compounds were found to have the best activity. They were chosen for further pharmacological and toxicological study.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/síntesis química , Pirimidinas/síntesis química , Animales , Asma/tratamiento farmacológico , Fenómenos Químicos , Química , Femenino , Ratones , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Pirimidinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
By using inhibition of histamine release from antigen-challenged, sensitized human basophils as a means of identifying a potentially prophylactic drug for the treatment of asthma, a series of substituted imidazo[1,5-d][1,2,4]triazines were found, which were active. These compounds were prepared by treating imidazolecarboxaldehydes with excess Grignard agent and then oxidizing the resulting alcohols to ketones with Jones reagent. Pyrolysis of a mixture of ketone and methyl carbazate at 200 degrees C in diphenyl ether produced the desired imidazo[1,5-d][1,2,4]triazines. Those compounds with the greatest basophil activity were tested for in vivo activity in the mouse passive cutaneous anaphylaxis (PCA) and the guinea pig passive anaphylaxis tests. The best compounds, 1-ethyl-8-methyl-6-propylimidazo[1,5-d][1,2,4]triazin-4(3H)- one (4-17) and 1,8-dimethyl-6-propylimidazo[1,5-d][1,2,4]triazin-4-(3H)-one (4-16) were chosen for further study.
Asunto(s)
Asma/tratamiento farmacológico , Imidazoles/uso terapéutico , Triazinas/uso terapéutico , Anafilaxia , Animales , Basófilos/metabolismo , Fenómenos Químicos , Química , Cobayas , Liberación de Histamina/efectos de los fármacos , Humanos , Hipersensibilidad/sangre , Imidazoles/síntesis química , Imidazoles/farmacología , Ratones , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Relación Estructura-Actividad , Triazinas/síntesis química , Triazinas/farmacologíaRESUMEN
Several formamidine and acetamidine derivatives prepared from 3-amino-1,2,4-benzotriazine and 3-amino-1,2,4-benzotriazine-1-oxide displayed an aspirin-like anti-inflammatory and analgesic profile. The test systems include adjuvant-induced arthritis in rats, carrageenan-induced edema in rats, UV-induced erythema in guinea pigs, the analgesic gait test, the antipyretic test, and GI ulcer studies.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Triazinas/farmacología , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Carragenina , Fenómenos Químicos , Química , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/tratamiento farmacológico , Eritema/tratamiento farmacológico , Cobayas , Ratas , Úlcera Gástrica/inducido químicamente , Triazinas/síntesis química , Triazinas/uso terapéuticoRESUMEN
Benzoylacetonitrile and beta-aminocinnamonitrile are shown to possess potent antiinflammatory activity in the rat adjuvant arthritis model. In a series of phenyl-substituted analogues, only o-, m-, and p-fluorobenzoylacetonitrile and m- and p-fluoro-beta-aminocinnamonitrile retained activity. Additionally, beta-amino-2- and beta-amino-3-thiopheneacrylonitrile and beta-oxo-2- and beta-oxo-3-thiophenepropionitrile exhibited similar activity. These agents are not believed to be acting via prostaglandin synthetase inhibition. The metabolic profile of benzoylacetonitrile is also described.