RESUMO
Bioassays were conducted to determine various endocrinological properties of two spirolactone derivatives, 4',5'-dihydrospiro-[estr-4-ene-17,2'(3'H)-furan]-3-one (Compound I) and dispiro[cyclopropane-1,6'-estr-4'-ene-17',2"(3"h)-furan]-3'-one (Compound II). They proved to be very potent estrogen antagonists in immature mice and castrate ewes and neither exhibited inherent estrogenicity. They were moderately active as progestins and gonadotropin inhibitors. Compound II possessed slight androgenic activity and was more active orally than I. Compound I underwent a limited amount of testing in normally cycling rhesus monkeys. It was found to increase viscosity of the cervical mucus and, in oral doses of 0.5 or 2.0 mg/day, prevented pregnancy. One animal given 0.5 mg/day did become pregnant in her first treatment cycle, probably before a drug effect had been established. The results obtained indicate both compounds have potential utility as low-dose oral contraceptives.
Assuntos
Espironolactona/análogos & derivados , Androgênios , Animais , Castração , Anticoncepcionais Orais Sintéticos , Relação Dose-Resposta a Droga , Implantação do Embrião/efeitos dos fármacos , Antagonistas de Estrogênios , Feminino , Haplorrinos , Camundongos , Ovulação/efeitos dos fármacos , Gravidez , Congêneres da Progesterona , Ratos , Espironolactona/farmacologiaAssuntos
Antagonistas de Androgênios , Androstenos/uso terapêutico , Furanos/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Administração Oral , Animais , Biópsia por Agulha , Cães , Injeções Subcutâneas , Células Intersticiais do Testículo/efeitos dos fármacos , Masculino , Placebos , Próstata/anatomia & histologia , Próstata/efeitos dos fármacos , Próstata/patologia , Espermatogênese/efeitos dos fármacos , Compostos de Espiro/uso terapêutico , Fatores de TempoAssuntos
Fosfatase Ácida/metabolismo , Antagonistas de Androgênios , Androstenos/farmacologia , Furanos/farmacologia , Próstata/enzimologia , Androstenos/administração & dosagem , Animais , Cães , Furanos/administração & dosagem , Masculino , Próstata/efeitos dos fármacos , Próstata/metabolismo , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacologiaRESUMO
PIP: The syntheses of several 1,2alpha-methylene steroids containing a sp irotetrahydrofuran ring at the 17 position are described. The antiandro genic activity of these compounds was determined in immature male castrate rats treated with testosterone enanthate. The ability of the compounds to antagonize the androgen-stimulated weight gain of the simin al vesicle and ventral prostate serves as a measure of their activity. From the results, the antiandrogenic activity associated with the Tetrah ydrofuran-2'-spiro-17 androstenones I and II has been increased by addit ion of a 1,2alpha-methylene function and by incorporation of either a 6- chloro-delta6 or 6,7alpha-difluoromethylene group to the basic steroid s keleton. These compounds show minimal other hormonal activity. Tert-Butyl chromate oxidation of the spirotetrahydrofuran XIII affords the corresponding spirolactone XIV in high yield.^ieng
