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A compound butyryl biphenyl of valine

A technology for valine butyryl biphenyl and compound, which is applied in the field of medicinal chemistry and can solve the problems of easy explosion, toxicity, shortening of the existence time of the compound and the like

Inactive Publication Date: 2007-07-25
陈志龙
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Most of the currently marketed drugs and compounds entering clinical trials contain tetrazole groups, but due to certain defects in the synthesis and metabolism of tetrazole, such as the synthesis of toxic and explosive azide compounds, It is easily metabolized in the form of glucuronidation in the body, resulting in a shortened existence time of the compound in the body (Drug Metab Dispos, 1993, 21: 792-799)
And when containing 2 acid groups (tetrazolium and carboxyl) in the compound, because its polarity is big, general oral bioavailability is not high, needs to form prodrug to improve oral (Bioorg Med Chem Lett, 1944,4: 201-206)

Method used

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  • A compound butyryl biphenyl of valine
  • A compound butyryl biphenyl of valine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] [Example 1] (S)-N-n-butyryl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzyl valline acid

[0018] Step 1: (L)-Valine Methyl Ester Hydrochloride

[0019] Add 5mL of anhydrous methanol to a 50mL three-necked flask under ice-bath conditions, stir, slowly add 1mL of thionyl chloride dropwise, after the dropwise addition, stir for 30min, add 1g (L)-valine, stir overnight, reduce Solvent was removed by autoclaving. Recrystallized from methanol-ether to obtain 1.35 g of a colorless needle-like solid, mp: 128-132°C.

[0020] Step 2: N-[4-(2-cyanophenyl)]benzyl-L-valine methyl ester

[0021] Under N2 protection conditions, dissolve 2.0g (L)-valine methyl ester hydrochloride in 15mL DMF, cool in an ice bath, stir, add 5mL triethylamine dropwise, and then add 3.0g 2'-cyano- 4-Bromomethylbiphenyl. React at 70°C and monitor by TLC. After the reaction is complete, cool down rapidly, add 15 mL of distilled water, and extract with ethyl acetate. Combined organic phases, KHCO 3 ...

Embodiment 2

[0033] [Example 2] Antihypertensive drug activity screening experiment

[0034] Experimental animals: 30 spontaneously hypertensive rats (SHR), healthy, half ♀♂ (female not pregnant), purchased from Shanghai Bikai Experimental Animal Co., Ltd., certificate number: Shanghai Dynamic Hezheng Zi No. 152 ;

[0035] Drug under test: antihypertensive active compound (S)-N-n-butyryl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzo valine (compound 1).

[0036] Positive control drug: losartan, the clinical dosage is 50mg / kg, assuming that the body weight is 60kg, the human dosage is 5 / 6mg / kg, converted to a rat dosage of 5mg / kg, the molecular weight of losartan is 461, converted into moles The concentration is 1.86mol / L, and the positive control drug is equivalent to the dose in the efficacy experiment (the ratio of low, medium and high doses is 1:2:4), which is set at 3.72mol / L.

[0037] Experimental method: 30 spontaneously hypertensive rats (SHR) models were selected and divided i...

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Abstract

This invention discloses valine butanoyl biphenyl compound, which is prepared by connecting biphenyl, valine and furodiazole, and is a receptor blocker of angiotensin II. The compound can be used to manufacture drugs for preventing or treating hypertension, coronary artery disease, cardiovascular, cerebrovascular and nephric vascular diseases, migraine, and pulmonary artery hypertension.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a valine butyryl biphenyl compound capable of preventing and treating hypertension, other cardiovascular and cerebrovascular diseases, migraine, pulmonary hypertension and other diseases. Background technique [0002] Since the identification of hypertension in the 1940s, antihypertensive drugs have experienced the following development process. In the 1940s, malignant hypertension was first treated with the nerve blocker hexacarbonate quaternary ammonium, diuretics in the 1950s, anti-adrenaline blockers in the 1960s, further development of α-receptor blockers in the 1970s, and vascular tension in the 1980s In the 1990s, a new generation of antihypertensive drugs such as angiotensin-converting enzyme inhibitors, calcium channel blockers, and angiotensin receptor antagonists began to be used and developed vigorously. [0003] In 1970, Marshall et al. synthesized the first recep...

Claims

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Application Information

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IPC IPC(8): C07D271/07A61K31/4245A61P9/12A61P9/00A61P25/06
Inventor 陈志龙
Owner 陈志龙
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