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[0363] To a stirred THF solution (30 mL) of 3,17-dioxoandrostane-6α-ylnitrate (II-aa, Preparation 1, 1.14 g) was rapidly added dropwise 2-aminoethoxyamino di Hydrochloride (223mg), Na 2 HPO 4 12H 2 O (2.30 g) in water (11.6 mL). After 1.5 hours, NaCl (1.8 g) was added and the mixture was stirred for 10 minutes. The phases were separated and the aqueous phase was extracted with THF (2x). The combined organic extracts were washed with Na 2 SO 4 Dry, filter and evaporate to dryness. By flash chromatography (SiO 2 , CHCl 3 / MeOH / 26% NH4OH 90 / 10 / 1) to purify the crude product. To this concentrated fraction was added a stoichiometric amount of fumaric acid in MeOH. Add EtOAc / Et 2 After a 1 / 1 mixture of O, the precipitate was filtered to give the title compound I-aa (0.57 g, 33%) as a white solid. 1 H-NMR (300MHz, DMSO-d 6 , ppm from TMS): δ 8.76 (bb, 4H), 6.41 (s, 1H), 4.98 ...
[0369] Starting from 6α-cyanoandrostane-3,17-dione (II-ac, preparation 3) and 2-aminoethoxyamino dihydrochloride as described in Example 1, in 65% yield prepared. 1 H-NMR (300MHz, DMSO-d 6 , ppm from TMS): δ 9.07 (bb, 4H), 6.40 (s, 2H), 4.07 (m, 2H), 3.24 (m, 0.5H), 3.06 (m, 0.5H), 2.99 (m, 2H ), 2.77 (m, 1H), 2.45-0.70 (m, 19H), 0.88 (s, 1.5H), 0.87 (s, 1.5H), 0.77 (s, 3H).
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PUM
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Abstract
Compounds of formula (I) wherein: the groups are as defined in the description, are useful for the preparation of medicaments for the treatment of cardiovascular disorders, in particular heart failure and hypertension. The compounds are inhibitors of the enzymatic activity of the Na<+>,K<+>-ATPase. Said compounds are used for the preparation of a medicament for the treatment of a disease caused by the hypertensive effects of endogenous ouabain, such as renal failure progression in autosomal dominant polycystic renal disease (ADPKD), preeclamptic hypertension and proteinuria and renal failure progression in patients with adducin polymorphisms.
Description
technical field [0001] The present invention relates to novel amino derivatives at position 3 of 5- and / or 6- and / or 7-substituted androstane and androstene, processes for their preparation, and to compositions containing them for use in the treatment of cardiovascular disorders such as Pharmaceutical composition for heart failure and hypertension. Background technique [0002] Cardiovascular disease remains the number one cause of morbidity and mortality in the Western world; of these, hypertension and heart failure are two frequently occurring diseases. Hypertension is one of the most important cardiovascular risk factors, affecting more than a third of people over the age of 60. Congestive heart failure affects 1-2% of the population, 10% of the very elderly; this proportion is expected to increase (Sharpe N., et al., The Lancet, 1998, 352, (suppl.1), 3-17 ). In addition, hypertension may be one of the most important factors causing heart failure in the elderly (Eur. H...
Claims
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