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Dihydroxy dimethyl isochroman-3-formyl aromatic amino acid and preparation, thrombolytic activity and application thereof

A technology of dimethylisochroman and dihydroxyphenyl, which is used in thrombolytic activity, -6,7-dihydroxy-1,1-dimethylisochroman-3-formyl-AA, to prepare thrombolytic fields of application in medicine

Active Publication Date: 2020-12-01
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because of these contraindications to thrombolytics and bleeding rates of 20% to 50%, the management of pulmonary embolism remains a clinical challenge for physicians

Method used

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  • Dihydroxy dimethyl isochroman-3-formyl aromatic amino acid and preparation, thrombolytic activity and application thereof
  • Dihydroxy dimethyl isochroman-3-formyl aromatic amino acid and preparation, thrombolytic activity and application thereof
  • Dihydroxy dimethyl isochroman-3-formyl aromatic amino acid and preparation, thrombolytic activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1 Preparation of D(+)-β-(3,4-dihydroxyphenyl) benzyl lactate (1)

[0019] Slowly add 91.0 mL of thionyl chloride dropwise into 150 mL of benzyl alcohol stirred at 0°C. After dropping, stir at room temperature for 1h, add 55.0g (250mmol) danshensu sodium, stir at room temperature for 48h, and the reaction is complete. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate, washed with saturated NaCl aqueous solution (30 mL×3), washed with anhydrous NaCl 2 SO 4 Dry for 12 h, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain 20.1 g (35%) of the title compound as a yellow oil. 1 HNMR (300M Hz, DMSO-d 6 ):δ / ppm=8.75(s,1H),8.67(s,1H),7.31(m,5H),6.61(s,1H),6.58(s,1H),6.42(dd,J 1 =1.8Hz,J 2 =2.1Hz,1H),5.55(d,J=6.0Hz,1H),5.12(s,2H),4.19(q,J 1 =6.9Hz,J 2 =6.0Hz,1H),2.73(qd,J 1 =8.1Hz,J 2 =5.4Hz, 2H); ESI-MS (m / e): 287 [M-H] ...

Embodiment 2

[0020] Example 2 Preparation of (R)-6,7-dihydroxy-1,1-dimethylisochroman-3-carboxylic acid benzyl ester (2)

[0021] 10.0 g (30.6 mmol) of benzyl D(+)-β-(3,4-dihydroxyphenyl)lactate (1) was dissolved in 104 mL of acetone. Slowly add 4.4mL of boron trifluoride diethyl ether dropwise under stirring at 0°C. After dropping, stirring at room temperature for 4h, compound 1 disappeared completely. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 100 mL of ethyl acetate. The resulting solution was washed with saturated NaCl aqueous solution (30mL×3), washed with anhydrous NaCl 2 SO 4 Dry for 12 h, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain 11.4 g (80%) of the title compound as a yellow oil. 1 H NMR (300MHz, DMSO-d 6 ):δ / ppm=1.58(s,1H),1.54(s,1H),7.39(m,5H),6.52(s,1H),6.47(s,1H),1.93(s,1H),4.47( m,1H),2.71(m,2H),1.40(m,6H); ESI-MS(m / e):327[M-H] -...

Embodiment 3

[0022] Example 3 Preparation of (R)-6,7-dihydroxy-1,1-dimethylisochroman-3-carboxylic acid (3)

[0023] 11.4 g (34.8 mmol) of benzyl (R)-6,7-dihydroxy-1,1-dimethylisochroman-3-carboxylate (2) were dissolved in 60 mL of methanol. Then add 1.14g Pd / C, stir evenly, pass hydrogen, react at room temperature for 24h, compound 2 disappears completely. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 10.5 g (95%) of the title compound as a colorless solid. 1 H NMR (300MHz, DMSO-d 6 ):δ / ppm=12.60(s,1H),8.82(d,J=6.9Hz,2H),8.66(d,J=5.4Hz,2H),6.52(s,1H),6.46(s,1H) ,4.34(m,1H),2.68(d,J=7.2Hz,2H),1.37(d,J=3.8Hz,6H); ESI-MS(m / e):237[M-H] - .

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Abstract

The invention discloses four (R)-6, 7-dihydroxy-1, 1-dimethyl isochroman-3-formyl-AA (AA is L-Phe, L-His, L-Trp and L-Tyr residues) of the following formula, a preparation method thereof and an application of the (R)-6, 7-dihydroxy-1, 1-dimethyl isochroman-3-formyl-AA in thrombolytic drug preparation. Therefore, the invention discloses an application of the compounds in preparation of thrombolyticdrugs.

Description

technical field [0001] The present invention relates to (R)-6,7-dihydroxy-1,1-dimethylisochroman-3-formyl-AA of the following formula, to their preparation method, and to their thrombolytic activity. The present invention therefore relates to their use in the preparation of thrombolytic drugs. The invention belongs to the field of biomedicine. [0002] technical background [0003] Among the morbidity and mortality of cardiovascular diseases, the morbidity and mortality of acute pulmonary embolism ranks third. If left untreated, approximately 30% of patients die. From the perspective of the pathogenesis process, the blood clot formed in the deep vein leaves the deep vein through the venous system, passes through the right ventricle and enters the pulmonary artery to form pulmonary embolism. Pulmonary parenchymal necrosis can result due to deterioration of arterial circulation. If treated, approximately 8% of patients die. Among the patients who died, about a quarter died...

Claims

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Application Information

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IPC IPC(8): C07D311/20C07D405/06A61P7/02
CPCC07D311/20C07D405/06A61P7/02
Inventor 赵明彭师奇张佩雯
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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