RESUMO
Synthesis and SAR of N-[4-[(4,5-dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(2H)-y l)carbonyl]phenyl]benzamides as arginine vasopressin (AVP) receptor antagonists are discussed. Potent orally active AVP receptor antagonists are produced when the benzamide moiety contains a phenyl group at the 2-position. Similar analogues of 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepine and VPA-985 are reported.
Assuntos
Arginina Vasopressina/antagonistas & inibidores , Azepinas/síntese química , Azepinas/farmacologia , Animais , Arginina Vasopressina/metabolismo , Azepinas/química , Azepinas/metabolismo , Ratos , Receptores de Vasopressinas/metabolismo , Relação Estrutura-AtividadeAssuntos
Arginina Vasopressina/antagonistas & inibidores , Receptores de Vasopressinas/metabolismo , Administração Oral , Animais , Arginina Vasopressina/deficiência , Azepinas/administração & dosagem , Azepinas/síntese química , Azepinas/metabolismo , Azepinas/farmacologia , Benzamidas/administração & dosagem , Benzamidas/síntese química , Benzamidas/metabolismo , Benzamidas/farmacologia , Plaquetas/metabolismo , Água Corporal/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Cães , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Rim/metabolismo , Fígado/metabolismo , Concentração Osmolar , Pirróis , Ratos , Sódio/sangue , Relação Estrutura-Atividade , Urina/químicaAssuntos
Arginina Vasopressina/antagonistas & inibidores , Azepinas/farmacologia , Benzamidas/farmacologia , Receptores de Vasopressinas/metabolismo , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Pressão Sanguínea/efeitos dos fármacos , AMP Cíclico/metabolismo , Cães , Insuficiência Cardíaca/fisiopatologia , Humanos , Hiponatremia/etiologia , Hiponatremia/fisiopatologia , Síndrome de Secreção Inadequada de HAD/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiologia , Rim/fisiopatologia , PirróisRESUMO
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.
Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Imidazóis/síntese química , Pirimidinas/síntese química , Animais , Basófilos/efeitos dos fármacos , Basófilos/metabolismo , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacologia , Dose Letal Mediana , Macaca mulatta , Masculino , Camundongos , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Reaction of estradiol-17 beta with triethylamine-sulfur trioxide in pyridine gives exclusively monosulfation at the C17-hydroxyl group with the preparation of 17 beta-sulfooxyestra-1,3,5(10)-trien-3-ol triethylammonium salt (V). The structural assignment suggested by spectroscopic measurements was confirmed by synthetic studies. (Formula: see text) A synthesis of 3-sulfooxyestra-1,3,5(10)-trien-17 beta-ol triethylammonium salt (II) has been accomplished based on the preparation of 17 beta-formyloxyestra-1,3,5(10)-trien-3-ol (XIII). Fusion of the 3-sulfate triethylammonium salt II gives rise to the 17-sulfate triethylamine salt V. The preparation of estradiol-17 beta disulfate has also been achieved.
Assuntos
Estradiol/análogos & derivados , Fenômenos Químicos , Química , Estradiol/síntese química , Etilaminas , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Rotação Ocular , Espectrofotometria Infravermelho , Óxidos de EnxofreRESUMO
A method for the preparation of steroid triethylammonium sulfates is outlined which involves the fusion of triethylamine-sulfur trioxide and steroids. Experimental details are presented which define the process as a thermal equilibrium resulting in the preferential sulfation of aliphatic hydroxyl groups. Sulfation of an aromatic hydroxyl group can be achieved in the absence of an aliphatic hydroxyl group. With excess reagent both types of hydroxyl groups in the same molecule can be sulfated.
