Silyl-protected hydroxymethyl-carbamoylalkyl-ketones as intermediates in the preparation of dopamine-beta-hydroxylase inhibitors

摘要

Imidazole derivatives (I), their salts and (R) enantiomers and/or (S) enantiomers are new. Imidazole derivatives of formula (I), their salts and (R) enantiomers and/or (S) enantiomers are new. [Image] R 1, R 2, R 3H, halo, alkyl, alkyloxy, OH, NO 2, NH 2, alkylcarbonylamino, alkylamino or dialkylamino; R 4H, alkyl or alkylaryl; X : CH 2, O or S; n : 1-3; halo : F, Cl, Br or I; alkyl : 1-6C hydrocarbon chains optionally substituted by aryl, alkoxy, halo, alkoxycarbonyl or hydroxycarbonyl; aryl : phenyl or naphthyl optionally substituted by alkyloxy, halo or NO 2; provided that when n is 1, X is not CH 2. Independent claims are also included for: (1) a carbonyl compound of formula (III); (2) compound (III; n' = 3 and NR 4'R 6= phthalimido) (3) an amine of formula (II); and (4) preparation of (R) enantiomers and/or (S) enantiomers and salts of (I). [Image] R 1', R 2', R 3'F or H (provided that at least one of R 1', R 2' and R 3' is F); R 4'H or alkyl; R 5hydroxyl protecting group selected from trialkylsilyl, triphenylsilyl, phenyldialkylsilyl or alkyldiphenylsilyl; R 6amino protecting group selected from an alkyl carbamate or alkylaryl carbamate; and n' : 2. ACTIVITY : Cardiovascular-Gen.; Hypotensive; Cardiant. MECHANISM OF ACTION : Peripheral selective dopamine-beta-hydroxylase inhibitors; Dopamine-beta-hydroxylase inhibitor (claimed). The dopamine-beta-hydroxylase inhibitory activity of compounds (I) was determined in SK-N-SH cells. (R)-5-Aminomethyl-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride (Ia) exhibited a median inhibitory concentration value of 91 nM.