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Compound for renin-angiotensin-aldosterone system dual inhibitor

A compound, representative technology, applied in the compound field of dual inhibitors of renin-angiotensin-aldosterone system

Active Publication Date: 2015-04-08
ZHEJIANG YONGTAI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Both ARB and ACEI can block the adverse effects of RAAS, and the therapeutic mechanisms are different. The combined application of ACEI and ARB may produce a synergistic effect, but whether it has a general significance is still doubtful

Method used

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  • Compound for renin-angiotensin-aldosterone system dual inhibitor
  • Compound for renin-angiotensin-aldosterone system dual inhibitor
  • Compound for renin-angiotensin-aldosterone system dual inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0039] The preparation of formula (II) compound

[0040] 1. N-pentanoyl-N-(4-(2-(1-trityl-1H-tetrazol-5-yl)phenyl)phenyl)methyl-L-valyl chloride (intermediate 1) Preparation

[0041]

[0042] Step 1, the preparation of N-(4-(2-(1-trityl-1H-tetrazol-5-yl)phenyl)phenyl)methyl-L-valine

[0043] Add potassium carbonate (12.5g) and acetonitrile (85mL) to a 250mL three-necked flask, add L-valine (5.0g), stir, and react for 0.5h; add 2-N-trityl-5-(4' -Bromomethylbiphenyl-2-yl)tetrazolium (16.7g), heated to reflux for 8h, cooled to room temperature, filtered, washed filter cake with 10mL acetonitrile; combined filtrates, rotary evaporation under reduced pressure, recovered solvent. 100 mL of ethyl acetate was added to the residue, and the ethyl acetate layer was washed with brine (30 mL×2). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the solvent was recovered to obtain the title compound. Molecular formula: C 38 h 35 N 5 o 2 , mass spectro...

Embodiment 1

[0090] (3-((N-(4-(2-(1H-tetrazol-5-yl)phenyl)phenyl)methyl)-N-pentanoyl-L-valyl)thio)-2 -Preparation of -methylpropionyl)-L-proline (compound 1)

[0091]

[0092] Add Intermediate 5 (3.0mmol), Potassium Carbonate (3.0mmol) and DMF (100ml) to the four-neck flask, stir to dissolve, lower the temperature to 0°C, start to add Intermediate 1 (3.0mmol) dropwise, and simultaneously use potassium carbonate The solution maintains the pH of the reaction system at 7.0-8.0, and the temperature is maintained at 0°C. After the dropwise addition is completed, continue to drop the potassium carbonate solution to adjust the pH of the reaction system to 7 until it remains unchanged. The reaction was stirred at room temperature for 3 hours, then water (40 ml) was added thereto, extracted with ethyl acetate, and the solvent was recovered. The residue was adsorbed on silica gel and eluted with n-hexane / acetone to obtain the title compound.

[0093] Molecular formula: C 33 h 42 N 6 o 5 S, ...

Embodiment 2

[0097] (3aR,6aS)-3-(N-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-N-pentanoyl Preparation of -L-leucyl-L-alanyl-L-prolyloxy)-6-(nitroxy)hexahydrofuro[3,2-b]furan (compound 2)

[0098]

[0099] In a similar manner to Example 1, intermediate 2 and intermediate 7 were reacted in the presence of basic reagents such as potassium carbonate to obtain the title compound. Molecular formula: C 39 h 50 N 8 o 10 ; Mass spectral analysis (m / z): 790.36 (100.0%), 791.37 (43.1%); Elemental analysis: C, 59.23; H, 6.37; N, 14.17; O, 20.23.

[0100] 1 H-NMR (CDCl 3 ): 8.32(1H), 7.96(2H), 7.60(2H), 7.41-7.47(4H), 6.33(1H), 5.22(1H), 4.64(1H), 4.46(2H), 4.44(1H), 4.29 (1H), 4.14(4H), 3.85(3H), 3.46(2H), 2.30(2H), 1.97-2.05(4H), 1.76(2H), 1.38-1.53(8H), 0.93(9H).

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PUM

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Abstract

The invention relates to a compound for a renin-angiotensin-aldosterone system dual inhibitor, which can be used for treating and blocking diseases related to an RAS system such as hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, kidney failure, renal fibrosis, cardiac insufficiency, cardiomegaly, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complication caused by diabetes such as nephropathy, vasculopathy, neuropathy, glaucoma, intraocular pressure elevation, atherosclerosis, restenosis after the arteries transluminal angioplasty, complication of blood vessels or cardiac surgical procedures, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorder, complication caused by the treatment of immunosuppressor and other diseases associated to the renin-angiotensin system.

Description

technical field [0001] The invention relates to a compound used as a dual inhibitor of renin-angiotensin-aldosterone system, which can be used for treating diseases related to RAS system, including hypertension, heart disease and the like. Background technique [0002] The renin-angiotensin-aldosterone system (RAAS) is a complex and highly efficient system necessary for the regulation of blood flow, electrolyte balance, and arterial blood pressure. The two main parts of this system are renin and angiotensin transferase. Renin is an aspartyl protease that can convert angiotensinogen produced in the liver into angiotensin Ⅰ, angiotensin Ⅰ in angiotensin Ⅰ converting enzyme (Angiotensin Converting EnzyCH 3 , ACE) to generate angiotensin II, which is finally converted into angiotensin III that can promote aldosterone secretion and inactivated. Angiotensin Ⅱ is a powerful peptide vasoconstrictor that can promote the release of norepinephrine from nerve endings, and can also act...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D493/04C07H13/10C07K5/083A61K31/41A61K31/7024A61K38/06A61P9/12A61P9/04A61P13/12A61P9/10A61P9/00A61P3/10A61P25/00A61P27/06A61P15/10A61P11/00A61P17/00A61P25/22A61P25/28A61P43/00
CPCA61K31/41A61K31/7024A61K38/06C07D403/12C07D493/04C07H13/10C07K5/0802
Inventor 何人宝王莺妹邵鸿鸣
Owner ZHEJIANG YONGTAI PHARMA
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