Nitric oxide donor type 3-butylphthalide derivates, method for preparing same and pharmaceutical use

A technology of butylphthalide and derivatives, applied in the field of antithrombotic and anti-cerebral ischemia drugs, can solve problems to be strengthened, and achieve the effect of enhancing anti-cerebral ischemia, antithrombotic and obvious effects

Inactive Publication Date: 2009-01-07
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Its antithrombotic effect is only comparable t

Method used

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  • Nitric oxide donor type 3-butylphthalide derivates, method for preparing same and pharmaceutical use
  • Nitric oxide donor type 3-butylphthalide derivates, method for preparing same and pharmaceutical use
  • Nitric oxide donor type 3-butylphthalide derivates, method for preparing same and pharmaceutical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Preparation of 3-butylphthalide (III)

[0104] Add 1.5g (0.01mol) o-formylbenzoic acid and 30mL Et 2 O, N 2 Protect, stir to dissolve. At -5°C, add 30 mL of diethyl ether suspension containing 3.6 g (22 mmol) n-BuMgBr dropwise. 4 The reaction was quenched with Cl solution, and 15 mL of 10% hydrochloric acid was added, and stirred at room temperature for 2 h. Separate the organic phase, extract the aqueous layer with 3×30mL ether, combine the organic layers, Na 2 SO 4 After drying, concentration, and column chromatography [petroleum ether: ethyl acetate (v:v) = 15:1], 1.24 g of light yellow oil was obtained, with a yield of 75%. ESIMS (m / z): 213 [M+Na]+; 1 HNMR (CDCl 3 )δ: 0.93(t, 3H, CH 3 , J=6.2Hz), 1.37-1.45(m, 4H, 2×CH 2 ), 1.86-1.89 (m, 2H, CH 2 ), 5.49 (q, 1H, CH, J=12.3Hz), 7.37-7.39 (m, 1H, ArH, H-4), 7.56-7.5 (m, 2H, ArH), 8.05 (d, 1H, ArH, H-7, J=6.5Hz).

Embodiment 2

[0106] Preparation of 2-(1-hydroxy-n-pentyl)benzoic acid (IV)

[0107] Dissolve 1.24g (6.5mmol) III in a 50mL single-neck flask containing 10mL of methanol, add 10mL of 2M NaOH solution, stir at 50°C for 1h, evaporate methanol under reduced pressure, add 10mL of distilled water to dilute, cool to -5°C, and vigorously Acidify with 5% hydrochloric acid to pH 2-3 under stirring, extract with ether, Na 2 SO 4 dry. Ether was vacuum-dried under 0°C to obtain 1.32 g of white solid, yield 90%. The product was unstable and was directly put into the next reaction without purification.

Embodiment 3

[0109] Preparation of 2-(1-chloroacetoxy-n-pentyl)benzoic acid (V)

[0110] Put 1.04g (5mmol) of IV, 2mL of triethylamine, 0.5g of DMAP and 20mL of dichloromethane into a 50mL two-neck flask, stir and dissolve at -10°C-0°C, add dropwise 1.2mL (15mmol) of chloroacetyl chloride, Insulated and stirred for 5h. Add 10 mL of water, stir at room temperature for 0.5 h, separate the organic layer, Na 2 SO 4 Dry, filter, and concentrate to obtain a waxy solid, which is recrystallized from n-hexane to obtain 0.92 g of white needle-shaped crystals, with a yield of 65%. m.p.67-68°C; ESIMS: m / z 283[ 35 ClM-H + ], 285[ 37 ClM-H + ]; 1 HNMR (300MHz, CDCl 3 , δppm): 0.91 (t, 3H, CH 3 , J=6.9Hz), 1.32-1.41(m, 4H, 2×CH 2 ), 1.86-1.91 (m, 2H, CH 2 ), 4.11 (s, 2H, CH 2 CO), 6.76-6.79(m, 1H, CH), 7.36-7.42(m, 1H, ArH, H-4), 7.56-7.62(m, 2H), 8.08(d, 1H, ArH, H-7, J=8.1Hz), 10.89 (s, br, 1H, COOH); IR (KBr, v): 1412, 1691, 1734, 2958, 3450cm -1 ;

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Abstract

The invention relates to the pharmaceutical chemistry filed, and particularly relates to novel nitric oxide donor butyl phthalide derivatives (I), the preparation method thereof, a drug preparation containing the derivatives (I) and the application as a drug for resisting thrombosis and cerebral ischemia. Wherein, the definitions of R and A are shown in the instruction.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new class of nitric oxide donating butylphthalide derivatives, a preparation method thereof, pharmaceutical preparations containing them and their use as antithrombotic and anticerebral ischemia drugs. Background technique [0002] Cerebral ischemia, also known as ischemic stroke, ischemic stroke or cerebral ischemic injury, is a highly lethal disease with a very complex pathogenesis. It is reported that butylphthalide (3-n-butylphthalide, NBP, III) can act on multiple links of the disease, mainly showing antithrombotic effect and improving cerebral microcirculation. Its antithrombotic effect is only comparable to that of aspirin and needs to be strengthened. Clinically, in order to achieve better therapeutic effect, it is used in combination with antithrombotic drugs. 2-(1-Hydroxy-n-pentyl)benzoic acid is the ring-opening product of butylphthalide, which has similar pharma...

Claims

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Application Information

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IPC IPC(8): C07C203/02C07C201/02A61K31/21A61P7/02A61P9/10
Inventor 张奕华闵真立庄佩季晖赖宜生彭司勋
Owner CHINA PHARM UNIV
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