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Azaheterocyclyl derivatives of androstanes and androstenes as medicaments for cardiovascular disorders

A compound, branched chain alkyl technology, applied in the field of new 3-position nitrogen heterocyclic derivatives, can solve side effects and other problems, and achieve high efficacy, long duration of action, and good therapeutic ratio

Inactive Publication Date: 2009-06-24
CVIE THERAPEUTICS LTD
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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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  • Azaheterocyclyl derivatives of androstanes and androstenes as medicaments for cardiovascular disorders
  • Azaheterocyclyl derivatives of androstanes and androstenes as medicaments for cardiovascular disorders
  • Azaheterocyclyl derivatives of androstanes and androstenes as medicaments for cardiovascular disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0299] (E) 3-(4-piperidinyl)oxyiminoandrostane-6,17-dione hydrochloride (I-aa)

[0300] A solution of androstane-3,6,17-trione (160 mg) in THF (3.2 mL) was added to 4-piperidinyloxyamine dihydrochloride (III-a, Preparation 1, 100 mg) and Na 2 HPO 4 12H 2 A solution of O (380 mg) in water (1.6 mL). After 2 hours at room temperature, NaCl (150 mg) was added and stirred for 15 minutes. The mixture was extracted with THF (2 x 2 mL), and the combined organic phases were washed with brine (3 x 3 mL), washed with Na 2 SO 4 Dry and evaporate to dryness. The residue was analyzed by flash column chromatography (SiO 2 , CH 2 Cl 2 :MeOH:NH3 9:1:0.1) purification. 5M HCl / EtOAc was added to the concentrated fraction. with Et 2 After O dilution, the solid was collected by filtration to afford the title compound I-aa (140 mg, 60%). 1 H-NMR (300MHz, DMSO-d 6 , ppm from TMS): δ 8.68 (2H, bb), 4.17 (1H, m), 3.15-2.90 (5H, m), 2.60-1.10 (23H, m), 0.79 (3H, s), 0.78 (3H, s).

example 2

[0302] (E, Z) 3-(3-azetidine)oxyiminoandrostane-6,17-dione fumarate (I-ab)

[0303] Following the procedure described in Example 1, starting from androstane-3,6,17-trione (950 mg) and 3-azetidinoxamine dihydrochloride (III-b, Preparation 2,500 mg), The title compound I-ab was obtained as a white solid (1.21 g, 80%). 1 H-NMR (300MHz, DMSO-d 6 , ppm from TMS): δ 6.50 (2H, s), 4.87 (1H, m), 4.10-2.90 (5H, m), 2.50-1.20 (19H, m), 0.79 (6H, s).

example 3

[0305] (E) 3-[3-(RS)-pyrrolidinyl]oxyiminoandrostane-6,17-dione hydrochloride (I-ac)

[0306] 3-(RS)-Pyrrolidinyloxyamine dihydrochloride (III-c, Preparation 3, 227 mg) was mixed with androstane-3,6,17-trione (495 mg) in THF:water (2 / 1 , 27 mL) solution was stirred for 30 minutes. NaCl was added and stirred until the two phases separated. After extracting the aqueous layer with THF, the combined organic phases were washed with brine, dried and evaporated. Flash column chromatography (SiO 2 , CH 2 Cl 2 :MeOH:NH 3 9:1:0.1) method for purification. To this concentrated fraction was added 5M HCl in EtOAc. After dilution with Et2O, the solid was collected by filtration to afford the title compound I-ac (464 mg, 60%). 1 H-NMR (300MHz, DMSO-d 6 , ppm from TMS): δ 9.59 (1H, bb), 9.41 (1H, bb), 4.74 (1H, m), 3.80-2.90 (5H, m), 2.60-1.20 (21H, m), 0.78 (6H, s).

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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. They are useful 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 3-position azacyclic derivatives of 5- and / or 6- and / or 7-substituted androstane and androstene, a preparation process thereof, and compounds containing these derivatives for treating cardiovascular disorders Pharmaceutical compositions such as heart failure and hypertension. Background technique [0002] Cardiovascular disease remains the number one cause of morbidity and mortality in Western countries. Among them, 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 this group, and even 10% of the very elderly. This percentage 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 causes of heart failure in the elderly (Eur. Heart J., 20...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00A61K31/58A61K31/565A61P9/04
CPCC07J43/003A61P13/12A61P43/00A61P9/04A61P9/10A61P9/12C07J43/00A61K31/565A61K31/58
Inventor 阿尔贝托·切里乔治·费德里奇亚历山德拉·贝尼基奥朱塞佩·比安基帕特里夏·法拉利毛罗·戈比尼罗莎玛丽亚·米凯莱蒂马尔科·波济皮耶罗·恩里科·斯科蒂
Owner CVIE THERAPEUTICS LTD
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