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Amino acid diphenyl compound

A compound and amino acid technology, applied in the field of medicinal chemistry, can solve problems such as explosives, shortened existence time of compounds, toxicity, etc., and achieve good preventive or therapeutic effects

Inactive Publication Date: 2007-08-01
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 MedChem Lett, 1944,4:201 -206)

Method used

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  • Amino acid diphenyl compound
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Examples

Experimental program
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Effect test

Embodiment 1

[0028] [Example 1] (S)-N-n-butyryl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylisobright amino acid

[0029] Step 1: (L)-Isoleucine Methyl Ester Hydrochloride

[0030] Add 5 mL of anhydrous methanol to a 50 mL three-necked flask under ice-bath conditions, stir, slowly add 1 mL of thionyl chloride dropwise, after the dropwise addition, stir for 30 min, add 1 g (L)-isoleucine, and stir overnight, The solvent was evaporated under reduced pressure. Recrystallized from methanol-ether to obtain 1.4 g of a colorless needle-like solid, mp: 153-160°C.

[0031] Step 2: N-[4-(2-cyanophenyl)]benzyl-L-isoleucine methyl ester

[0032] in N 2 Under protective conditions, dissolve 2.0g (L)-isoleucine 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 ethy...

Embodiment 2

[0043] [Example 2] (S)-N-n-butyryl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylbenzenepropane amino acid

[0044] 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, -CH3); MS (m / z): 486.1 [M+1] + , 508.2[M+Na] + .

Embodiment 3

[0045] [Example 3] (S)-N-n-pentanoyl-N-[4-(2-(5-oxo-1,2,4-oxadiazole-3)phenyl)]benzylbenzenepropane amino acid

[0046] The experimental procedure is as described in Example 1, and the yield is 89.1%. 1 H-NMR (CDCl 3 , 500.12MHz, doubling due to amide rotamers) δ: 7.77-7.16 (13H, m, Ph-H), 4.42 (d, J=16.3Hz), 4.28 (m, -N-CH 2 -), 3.64(d, 1H, J=17.1Hz, -CH-N-), 3.31-3.24(m, 2H, -CH-C H 2 -Ph), 2.34-2.24(m, 2H, -CO-CH 2 -), 1.58-1.53 ​​(m, 2H, -CH 2 -C H 2 -CH 2 ), 1.39-132 (m, 2H, -CH 2 -C H 2 -CH 3 ), 0.91-0.84 (m, 3H, -CH 3 ); MS(m / z): 500.1[M+1] + , 522.1[M+Na] + .

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Abstract

The invention discloses an amino acid phenyl benzene, which is comprised of phenyl benzene, amino acid and oxdiazole organically. It is the receptor blocking agent for angiotensin II and can be used for preparing medicine for treating or preventing high blood pressure, coronary disease, cerebrovascular disease, cephalagra, pulmonary arterial hypertension and so on.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of amino acid biphenyl compounds 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 an...

Claims

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Application Information

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IPC IPC(8): C07D271/07A61K31/4245A61P9/12A61P9/10A61P25/06
Inventor 陈志龙王俊丽贾琳温彩红余秀峰田娟朱世根
Owner DONGHUA UNIV
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