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Compound used as dual inhibitor for RAAS (rennin angiotensin aldosterone system)

A technology of compounds and drugs, applied in the field of compounds as dual inhibitors of RAAS system

Active Publication Date: 2015-04-08
ZHEJIANG YONGTAI TECH CO LTD
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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 used as dual inhibitor for RAAS (rennin angiotensin aldosterone system)
  • Compound used as dual inhibitor for RAAS (rennin angiotensin aldosterone system)
  • Compound used as dual inhibitor for RAAS (rennin angiotensin aldosterone system)

Examples

Experimental program
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Effect test

preparation example Construction

[0037] The preparation of formula (II) compound

[0038] 1.(2-Butyl-4-chloro-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl ) methyl)-1H-imidazole-5-yl)methanol chloroformate (intermediate 1) preparation

[0039]

[0040] Slowly drop the mixed solution of losartan and triethylamine into the dichloromethane solution of solid phosgene (the molar ratio of losartan and solid phosgene is 1:0.5) at low temperature. React at 10 °C for 1 hour. After the reaction is completed, slowly add a certain amount of water dropwise to the reaction solution to decompose the unreacted solid phosgene, and wash with water until the pH value is 5-6. Triethylamine was then added to the reaction mixture, stirred to mix, a solution of trityl chloride in dichloromethane was added, and the resulting reaction mixture was stirred at room temperature. The reaction mixture was washed with water, dried over magnesium sulfate, filtered, and distilled under reduced pressure to obtain the title com...

Embodiment 1

[0064] (3aS,6aR)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl (((1-((2'-(1H-tetrazol-5-yl)- [1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)methoxy)carbonyl)-L-alanyl-L- Preparation of proline ester (compound 1)

[0065]

[0066] 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 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 t...

Embodiment 2

[0069] (3aS,6aR)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl ((1-((2'-(1H-tetrazol-5-yl)-[ 1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)formyl)-L-alanyl-L-proline ester (Compound 2) Preparation

[0070]

[0071] Add Intermediate 5 (3.0mmol), Potassium Carbonate (3.0mmol) and DMF (100ml) to the four-necked flask, stir to dissolve, lower the temperature to 0°C, start to add Intermediate 2 (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 2.5 hours, then water 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 co...

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Abstract

The invention discloses a compound used as a dual inhibitor for RAAS (rennin angiotensin aldosterone system) and particularly relates to a compound shown in formula (I), a stereisomer thereof or a pharmaceutically acceptable salt thereof. The compound can be used for treating and blocking RAS-associated diseases such as hypertension and heart disease, can be used for preventing or treating hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, kidney failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications such as nephropathy caused by diabetes, vasculopathy, vasculopathy, glaucoma, intraocular pressure elevation, atherosis, restenosis after revascularization, complications after blood vessel or cardiac operation, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorder, complications caused by immunosuppressor treatment as well as other known diseases associated with the rennin angiotensin aldosterone system.

Description

technical field [0001] The invention relates to a compound as a dual inhibitor of renin-angiotensin-aldosterone (RAAS) system, which can be used for treating diseases related to the 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 converts angiotensinogen produced in the liver into angiotensin I, and angiotensin I generates blood vessels under the action of angiotensin I converting enzyme (ACE) Tensin II 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 activate prot...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D493/04C07H15/04C07H1/00A61K31/4178A61K31/7056A61P9/12A61P9/04A61P13/12A61P9/00A61P9/10A61P25/00A61P25/28A61P27/06A61P27/02A61P15/10A61P11/00A61P17/00A61P25/22
CPCC07D493/04
Inventor 邵鸿鸣何人宝王莺妹
Owner ZHEJIANG YONGTAI TECH CO LTD
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