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5-amino-4-hydroxy-N-aryl azelamide derivatives as well as preparation methods and medical applications thereof

An alkyl and compound technology, which is applied to 5-amino-4-hydroxy-N-aryl azelaic amide derivatives, their preparation and their application in medicine, can solve the problems of low human bioavailability and the like

Inactive Publication Date: 2011-05-18
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the renin inhibitors that have been developed so far have low bioavailability in the human body due to their large molecular weight. Therefore, improving the activity and pharmacokinetic properties of renin inhibitors will be the main research direction of renin inhibitors in the future.

Method used

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  • 5-amino-4-hydroxy-N-aryl azelamide derivatives as well as preparation methods and medical applications thereof
  • 5-amino-4-hydroxy-N-aryl azelamide derivatives as well as preparation methods and medical applications thereof
  • 5-amino-4-hydroxy-N-aryl azelamide derivatives as well as preparation methods and medical applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0156] (2S, 4S, 5S, 7R)-5-amino-N 1 -(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-2,7-diisopropyl-N 9 -(2-(3-Methoxypropoxy)phenyl)azalamide

[0157]

[0158]

[0159] first step

[0160] 3-Methoxypropyl 4-toluenesulfonate

[0161] Under ice-cooling, 3-methoxy-1-propanol 1a (45.01g, 0.50mol) was dissolved in 200mL of dichloromethane and triethylamine (252.50g, 2.50mol) mixed solvent, p-toluenesulfonyl chloride ( 104.80g, 0.55mol), stirred at room temperature for 3 hours. Add 200mL water to the reaction solution, extract with dichloromethane (150mL×3), combine the organic phases, and successively wash with saturated sodium bicarbonate solution (50mL×2), saturated ammonium chloride solution (50mL×2) and saturated saline Wash (50mL×2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: system B in appropriate proportion) to obtain the title product 3-methoxy Pro...

Embodiment 2

[0193] (2S, 4S, 5S, 7R)-5-amino-N 1 -(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-2,7-diisopropyl-N 9 -(3-(3-Methoxypropoxy)phenyl)azelamide

[0194]

[0195] first step

[0196] 1-(3-Methoxypropoxy)-3-nitrobenzene

[0197] 3-Nitrophenol (2.08g, 15.01mmol) was dissolved in 30mL of acetonitrile, 3-methoxypropyl 4-tosylate 1b (4.03g, 16.50mmol) and anhydrous potassium carbonate (6.21g, 45.01 mmol), stirred and reacted at 70°C for 12 hours. Filter, add 150mL ethyl acetate to the filtrate, wash with saturated sodium bicarbonate solution (50mL×2), saturated ammonium chloride solution (50mL×2) and saturated brine (50mL×2) successively, wash with anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to obtain the crude product of the title product 1-(3-methoxypropoxy)-3-nitrobenzene 2a (3.17 g, yellow oil).

[0198] second step

[0199] 3-(3-Methoxy-propoxy)aniline

[0200] Dissolve 1-(3-methoxypropoxy)-3-nitrobenzene 2a (3.17g, 15.02mmol...

Embodiment 3

[0217] (2S, 4S, 5S, 7R)-5-amino-N 1 -(4-fluorobenzyl)-4-hydroxy-2,7-diisopropyl-N 9 -(2-(3-Methoxypropoxy)-5-(trifluoromethyl)phenyl)azelaamide

[0218]

[0219] first step

[0220] 1-(3-Methoxypropoxy)-2-nitro-4-(trifluoromethyl)benzene

[0221] 2-Nitro-4-(trifluoromethyl)phenol (0.63 g, 3.01 mmol) was dissolved in 20 mL of tetrahydrofuran, 3-methoxy-1-propanol 1a (308 mg, 3.42 mmol) and triphenyl Phosphine (927mg, 3.54mmol) was added to diethyl azodicarboxylate (783mg, 4.50mmol), and the reaction was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: appropriate proportion of system B) to obtain the title product 1-(3-methoxypropoxy)-2-nitro-4 -(Trifluoromethyl)benzene 3a (800 mg, yellow oil), yield 95.6%.

[0222] second step

[0223] 2-(3-Methoxypropoxy)-5-(trifluoromethyl)aniline

[0224] 1-(3-Methoxypropoxy)-2-nitro-4-(trifluoromethyl)benzene 3a ...

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Abstract

The invention relates to 5-amino-4-hydroxy-N-aryl azelamide derivatives as well as preparation methods and medical applications thereof, and in particular relates to new 5-amino-4-hydroxy-N-aryl azelamide derivatives shown in the general formula (I) and preparation methods thereof as well as drug compositions containing the derivatives and applications of the derivatives as treatment agents, especially renin inhibitors, and as drugs for treating such diseases related to activity of renin as resistant hypertension, wherein each substituent group in the general formula (I) is as defined in the specification.

Description

technical field [0001] The present invention relates to a novel 5-amino-4-hydroxy-N-aryl azelaic amide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a renin inhibitor And as a medicine for treating diseases related to renin activity such as antihypertensive. Background technique [0002] Aspartic Proteinase (Aspartic Proteinase) is an important class of proteolytic enzymes, involved in the body's metabolism and biological regulation. In general, their active centers consist of two highly conserved catalytic aspartic acid residues. Common aspartic proteases include: pepsin, renin (Renin), β-secretase (β-site amyloid precursor protein cleaving enzyme, BACE), human immunodeficiency virus protease, Human T-cell leukemia virus protease, etc. They are related to the occurrence of many diseases, such as: in hypertensive patients, the level of angiotensin I increases due to the ca...

Claims

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Application Information

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IPC IPC(8): C07C237/12C07C231/12A61K31/167C07C317/28C07C315/04C07D307/33C07D405/12C07F7/18C07D213/75C07C237/08A61K31/44A61P9/12A61P9/10A61P9/04A61P9/00A61P13/12A61P1/16A61P27/02A61P27/06A61P25/28A61P25/22
CPCY02P20/55
Inventor 邓炳初吴清泉潘耀辉胡兵张蕾
Owner JIANGSU HENGRUI MEDICINE CO LTD
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