Amino-acid biphenyl compound and medicine usage thereof

A technology of compounds and amino acids, applied in the field of medicinal chemistry, can solve the problems of low oral bioavailability, toxicity, and easy explosion.

Inactive Publication Date: 2007-10-03
DONGHUA UNIV +1
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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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  • Amino-acid biphenyl compound and medicine usage thereof
  • Amino-acid biphenyl compound and medicine usage thereof
  • Amino-acid biphenyl compound and medicine usage thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] [Example 1] N-[4-(2-(5-oxo-1,2,4-oxadiazole)phenyl)benzyl]-N-butyryl-L-valine

[0034] Step 1: (L)-Valine Methyl Ester Hydrochloride

[0035]Add 2 mL of anhydrous methanol to a 50 mL three-necked flask, stir, add 0.615 mL of thionyl chloride (8.55 mmol) and 1 g (L)-valine (8.55 mmol), stir for 2 h, and evaporate the solvent. Recrystallized from methanol-ether (1:15) to obtain 1.35 g of a colorless needle-like solid, yield 94.8%, mp: 128-132°C.

[0036] Step 2: N-[4-(2-cyanophenyl)benzyl]-L-valine methyl ester

[0037] Dissolve 2.0g (L)-valine methyl ester hydrochloride (12.0mmol) in 30mL DMF, stir, add 1.53mL triethylamine (12.0mmol), then add 3.0g 2'-cyano-4- Bromomethylbiphenyl (11 mmol). React at 50°C for 1 h, add 15 mL of distilled water, and extract with ethyl acetate (20 mL×2). Combine the organic phases, saturate with KHCO 3 The solution was washed with 30 mL×2, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obt...

Embodiment 2

[0048] [Example 2] N-[4-(2-(5-oxo-1,2,4-oxadiazole)phenyl)benzyl]-N-pentanoyl-L-valine

[0049] The experimental procedure is as described in Example 1, and the yield is 82.4%.1 H-NMR (CDCl 3 , 500.12MHz, doubling due to amide rotamers) δ: 7.64-7.22 (m, 8H, Ph-H), 4.70 (d, J=16.0Hz), 4.22-4.10 (m, 2H, -N-CH 2 -), 4.02-3.72(m, 1H, -CHN-), 2.75-2.38(m, 3H, -C H CH 3 ,-CO-CH 2 -), 1.78-1.68 (m, 2H, -CH 2 -C H 2 -CH 2 ), 1.49-1.25 (m, 2H, -CH 2 -C H 2 -CH 3 ), 1.01-0.87(m, 9H); MS(m / z): 452.3[M+1] + , 474.3[M+Na] + .

Embodiment 3

[0050] [Example 3] N-[4-(2-(5-oxo-1,2,4-oxadiazole)phenyl)benzyl]-N-butyryl-L-phenylalanine

[0051] The experimental procedure is as described in Example 1, and the yield is 89.4%. 1 H-NMR (CDCl 3 , 500.12MHz, doubling due to amide rotamers) δ: 7.61-7.41 (13H, m, Ph-H), 4.43 (d, 1H, J=14.2Hz, -N-CH-), 4.30-4.27 (m), 3.63(d, J=16.3Hz, -CH 2 -N-), 3.27(d, 2H, J=7.8Hz, -CH-C H 2 -Ph), 2.31-2.27(m, 2H, -CO-CH 2 -), 1.31-1.28 (m, 2H, -CH 2 -C H 2 -CH 3 ), 0.91-0.85 (m, 3H, -CH 3 ); MS(m / z): 486.1[M+1] + , 508.2[M+Na] + .

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Abstract

This invention relates to a kind of amino acid diphenyl compound and its medicine application. This compound is organically joined up by diphenyl and amino acid oxadiazole, is receptor blocking agent of angiotensin ii, could be used in preparing drug that prevent or treatment hypertension, coronary heart disease, heart- brain- renal vascular disease, migraine, pulmonary hypertension and so on.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an amino acid biphenyl compound capable of treating hypertension and 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 receptor antagonist ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/07A61K31/4245A61P9/00A61P9/10A61P9/12A61P25/06
Inventor 陈志龙王俊丽贾琳温彩红余秀峰田娟朱泉
Owner DONGHUA UNIV
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