Amino derivatives of androstanes and androstenes as medicaments for cardiovascular disorders

A technology of androstane and alkyl groups, applied in the field of new amino derivatives, can solve problems such as side effects

Inactive Publication Date: 2009-06-24
SIGMA TAU IND FARMACEUTICHE RIUNITE SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A well-known drawback of digitalis drugs is their arrhythmogenic side effect

Method used

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  • Amino derivatives of androstanes and androstenes as medicaments for cardiovascular disorders
  • Amino derivatives of androstanes and androstenes as medicaments for cardiovascular disorders
  • Amino derivatives of androstanes and androstenes as medicaments for cardiovascular disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0362] (E, Z) 3-(2-Aminoethoxyimino)-17-oxoandrostane-6α-yl fumarate nitrate Ester (I-aa)

[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 ...

Embodiment 2

[0365] (E, Z) 3-(2-Aminoethoxyimino)-17-oxoandrostane-6β-ylfumarate nitrate Ester (I-ab)

[0366] Starting from 3,17-dioxoandrostane-6β-ylnitrate (II-ab, preparation 2) and 2-aminoethoxyamino dihydrochloride as described in Example 1, at 60% prepared in high yields. 1 H-NMR (300MHz, DMSO-d 6 , ppm from TMS): δ 8.41 (bb, 4H), 6.40 (s, 2H), 5.23 (m, 0.5H), 5.19 (m, 0.5H), 4.03 (m, 2H), 3.05 (m, 1H ), 2.96 (m, 2H), 2.45-0.70 (m, 19H), 1.00 (s, 1.5H), 0.99 (s, 1.5H), 0.80 (s, 3H).

Embodiment 3

[0368] (E, Z) 3-(2-Aminoethoxyimino)-6α-cyanoandrostan-17-one fumarate (I-ac)

[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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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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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00C07J43/00A61K31/58A61K31/565A61P9/04
CPCC07J41/0038C07J41/0016C07J43/003A61P13/12A61P43/00A61P9/00A61P9/04A61P9/12C07J1/00A61K31/565A61P35/00C07J41/00C07J43/00A61K31/58
Inventor 阿尔贝托·切里马尔科·托里西尔维亚·阿尔马罗利莱昂纳多·班菲朱塞佩·比安基朱利奥·卡萨纳帕特里夏·法拉利罗莎玛丽亚·米凯莱蒂西蒙娜·斯普托雷玛丽亚·皮亚·扎帕维尼亚
Owner SIGMA TAU IND FARMACEUTICHE RIUNITE SPA
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