RESUMO
Conversion of 5-nitro-1, 3-benzenedicarboxylic acid (1) to the diamide 2 followed by hypochlorite rearrangement to the idamine 3 and subsequent reaction with acetic anhydride gave the bisacetamide 4. Reduction to the amine 5 followed by treatment with ethylene oxide formed the diol 6. The latter was converted to the bistosylate 7, which undrewent facile displacement with lithium chloride in acetone to give the mustard 8. Removal of the acetyl groups with hydrochloric acid gave 9, which reacted with potassium cyanate to provide the bisurea 10. In an alternative, but less satisfactory synthesis of 10, the compound (5-nitro-1, 3-phenylene) biscarbamic acid diphenyl ester (11), or the corresponding diethyl ester 12, was converted by ammonolysis to 13. The nitrodiurea 13 was next reduced to the amine 14, the hydrochloride of which reacted with ethylene oxide to give the diol 15. Treatment of the latter in dimethylformamide with N-chlorosuccinimide in the presence of triphenylphosphine gave 10 in low yield. The nitrogen mustards 8, 9 and 10 showed significant antitumor activities against P388 lymphocytic leukemia in mice.
Assuntos
Antineoplásicos/síntese química , Compostos de Fenilureia/síntese química , Animais , Antineoplásicos/uso terapêutico , Leucemia Experimental/tratamento farmacológico , Camundongos , Compostos de Fenilureia/uso terapêutico , Espectrofotometria UltravioletaRESUMO
A series of 2-[4-[3-(substituted-amino)-2-hydroxypropoxy]phenyl]imidazoles is described. The compounds were investigated in vitro for beta-adrenoceptor antagonism, and several examples were found to be selective for the beta 1-adrenoceptor. The structure--activity relationship exhibited by this series of compounds is discussed. (S)-2-[p-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]phenyl]-4-(2 -thienyl)imidazole [(S)-13] was over 100 times more selective than atenolol for the beta 1-adrenergic receptor and has been selected for in-depth studies.
Assuntos
Agonistas alfa-Adrenérgicos/síntese química , Imidazóis/síntese química , Receptores Adrenérgicos beta/síntese química , Receptores Adrenérgicos/síntese química , Animais , Feminino , Cobaias , Coração/efeitos dos fármacos , Coração/fisiologia , Imidazóis/farmacologia , Indicadores e Reagentes , Isoproterenol/farmacologia , Espectroscopia de Ressonância Magnética , Receptores Adrenérgicos beta/farmacologia , Relação Estrutura-AtividadeRESUMO
An attempt to develop a highly cardioselective beta-adrenoceptor antagonist devoid of intrinsic sympathomimetic activity (ISA) focused on exploring structure-activity relationships around (S)-[p-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy] phenyl]-4-(2-thienyl)imidazole. Strategies to reduce or eliminate ISA centered on structural changes that could influence activation of the receptor by the drug itself or by a metabolite. The approaches involved (a) eliminating the acidic imidazole N-H proton, (b) incorporating substituents ortho to the beta-adrenergic blocking side chain, (c) increasing steric bulk around the N-H moiety, (d) decreasing lipophilicity, (e) introducing intramolecular hydrogen bonding involving the imidazole N-H, and (f) displacing the imidazole ring from an activating position by the incorporation of a spacer element. The compounds were investigated in vitro for beta-adrenoceptor antagonism and in vivo for ISA. From these studies, the most successful variation involved the insertion of a spacer between the imidazole and aryl rings. (S)-4-Acetyl-2-[[4-[3-[[2-(3, 4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]phenyl]methyl] imidazole (S-51) was demonstrated to be highly cardioselective (dose ratio beta 2/beta 1 greater than 9333) and devoid of ISA.
Assuntos
Antagonistas Adrenérgicos beta/síntese química , Imidazóis/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Animais , Feminino , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Ligação de Hidrogênio , Imidazóis/farmacologia , Técnicas In Vitro , Receptores Adrenérgicos beta/efeitos dos fármacos , Solubilidade , Relação Estrutura-AtividadeRESUMO
Several hydrogenated derivatives of the potent NMDA antagonist 1 have been prepared and evaluated as competitive inhibitors of [3H]-1 binding. These compounds were also tested for their ability to act as noncompetitive antagonists of NMDA in vitro. These studies indicate that two aromatic rings are not strictly required for high-affinity binding or NMDA antagonism.