Butylphthalide-oxadiazole/thiadiazole compound as well as preparation method and application thereof

A technology of thiadiazoles and compounds, applied in the field of pharmacy, can solve the problems of low overall curative effect and limited use, and achieve excellent anti-platelet aggregation activity in vitro

Pending Publication Date: 2022-07-22
GUIZHOU MEDICAL UNIV
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  • Description
  • Claims
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Problems solved by technology

Butylphthalide plays a therapeutic role in multiple pathological aspects of cerebral ischemia by improving blood circulation in the brain, improving cerebral edema and antithrombotic, but its overall curative effect is not high, and it needs to be used in combination with other drugs in clinical practice. its use, so it is necessary to develop a new compound structure

Method used

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  • Butylphthalide-oxadiazole/thiadiazole compound as well as preparation method and application thereof
  • Butylphthalide-oxadiazole/thiadiazole compound as well as preparation method and application thereof
  • Butylphthalide-oxadiazole/thiadiazole compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] of 3-butyl-6-((5-(isopropylsulfoxide)-1,3,4-oxadiazol-2-yl)methoxy)isobenzofuran-1(3H)-one The preparation method includes the following steps:

[0034] (1) Synthesis of 3-butyl-6-nitroisobenzofuran-1(3H)-one (Compound 1): butylphthalide (10 g, 52.6 mmol) was dissolved in 40 mL of 98% H 2 SO 4 Medium, at 0-5℃, add KNO in batches 3 (6.9 g, 67.6 mmol), stirred at room temperature for 3 h; TLC detected the completion of the reaction, added ice-water mixture (150 mL), extracted three times with ethyl acetate (3×300 mL), washed with saturated brine (100 mL), Anhydrous Na 2 SO 4 After drying, concentration, and silica gel column chromatography with PE:EA=10:1, compound 1 (9.3 g, 75.2%) was obtained as a pale yellow liquid; 1 HNMR (400MHz, CDCl 3 )δ8.72(d,1H,J=2.0Hz),8.57(dd,1H,J=8.4,2.0Hz),7.68(d,1H,J=8.4Hz),5.62-5.59(m,1H), 2.16-2.08(m, 1H), 1.87-1.78(m, 1H), 1.45-1.36(m, 4H), 0.94(t, 3H, J=6.8Hz, CH 3 ); 13 C NMR (100MHz, CDCl 3 )δ168.0,155.3,149.0,128.8,127.9,123...

Embodiment 2

[0043]3-Butyl-6-((5-(cyclopropylmethyl)sulfoxide)-1,3,4-oxadiazole-2-methoxy)isobenzofuran-1(3H)-one Preparation of:

[0044] Identical to the preparation procedure of embodiment 1, the difference is only that the isopropyl bromide in the step (7) is replaced with the cyclopropyl bromide of the amount of equivalent substance;

[0045] 3-Butyl-6-((5-(cyclopropylmethylthio)-1,3,4-oxadiazol-2-yl)methoxy)isobenzofuran-1(3H)-one (7b): white solid, yield 74.2%; m.p.74-75°C; 1 H NMR (600MHz, CDCl 3 )δ7.43(d,J=2.0Hz,1H),7.37(d,J=8.4Hz,1H),7.34(dd,J=8.4,2.4Hz,1H),5.44(dd,J=7.8,4.0 Hz, 1H), 5.27(s, 2H), 3.23(d, J=7.4Hz, 2H), 2.03-1.98(m, 1H), 1.80-1.66(m, 1H), 1.52-1.32(m, 4H) ,1.31-1.16(m,1H),0.91(t,J=7.0Hz,3H),0.70-0.64(m,2H),0.40-0.34(m,2H); 13 CNMR (150MHz, CDCl 3 )δ170.2,166.7,162.4,158.4,143.9,127.8,123.0,109.1,81.3,60.1,38.7,34.5,26.8,22.4,13.9,10.5,6.2; HRMS(ESI)calcd for C 19 H 23 N 2 O 4 S[M+H] + m / z:375.1379,found 375.1374;

[0046] 3-Butyl-6-((5-(cyclopropylmethy...

Embodiment 3

[0048] 3-butyl-6-(5-benzylsulfoxide)-1,3,4-oxadiazole-2-methoxy)-3-butylbenzofuranone-1(3H)-one preparation:

[0049] The same as the preparation step of Example 1, the difference is only that the isopropyl bromide in the step (7) is replaced by the benzyl bromide of an equivalent amount;

[0050] 6-(5-(Benzylthio)-1,3,4-oxadiazol-2-yl)methoxy-3-butylbenzofuran-1(3H)-one (7c): colorless liquid , the yield is 73.1%; 1 H NMR (400MHz, CDCl 3 )δ7.46-7.42(m,3H),7.41-7.31(m,5H),5.45(dd,J=7.8,4.2Hz,1H),5.28(s,2H),4.51(s,2H),2.07 -1.99(m,1H),1.82-1.68(m,1H),1.47-1.38(m,4H),0.95-0.91(m,3H); 13 C NMR (100MHz, CDCl 3 )δ170.2,162.6,158.4,144.0,135.2,129.2,128.9,128.2,127.8,123.0,109.2,81.4,60.1,36.8,34.5,26.9,22.4,13.9; HRMS(ESI)calcd for C 22 H 23 N 2 O 4 S[M+H] + m / z:411.1379,found411.1372;

[0051] 3-Butyl-6-(5-benzylsulfoxide)-1,3,4-oxadiazole-2-methoxy)-3-butylbenzofuranone-1(3H)-one ( 8c): colorless liquid, yield 53.8%; 1 H NMR (600MHz, CDCl 3 )δ7.41(d,J=2.4Hz,1H),7.39...

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Abstract

The invention belongs to the technical field of pharmacy, and particularly relates to a butylphthalide-oxadiazole/thiadiazole compound and a preparation method and application thereof.The butylphthalide is used as a raw material, and a series of butylphthalide-oxadiazole/thiadiazole derivatives are prepared through the steps of nitration, reduction, Sandmeyer reaction, cyclization, substitution and oxidation in sequence. The prepared butylphthalide-oxadiazole/thiadiazole compound has an excellent anti-platelet aggregation effect, and derivatives, isomers or optical isomers, racemate, pharmaceutical salts, hydrates, solvates and pharmaceutical carriers or excipients of the butylphthalide-oxadiazole/thiadiazole compound can be applied to preparation of drugs for preventing or treating cardiovascular and cerebrovascular diseases and complications thereof caused by thrombus.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, in particular to a butylphthalide-oxa / thiadiazole compound and a preparation method and application thereof. Background technique [0002] Acute cerebrovascular disease, or stroke, is a major cardiovascular and cerebrovascular disease with cerebral ischemia and hemorrhagic injury as the main clinical manifestations. It has high mortality, high morbidity, high recurrence rate, high disability rate, and complications. It has the characteristics of "four highs and one more". According to statistics, ischemic stroke accounts for about 70-80% of all stroke patients. Ischemic stroke is a complex systemic disease. Although clinical measures such as thrombolysis, anticoagulation, and repair of damaged nerves can be used to control the patient's condition, the overall effect is not ideal. Such drugs are effective for all ischemic stroke patients, that is, there is no real specific drug for stroke. Ther...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D417/12C07D413/14A61P9/10A61P7/02A61P25/28
CPCC07D413/12C07D417/12C07D413/14A61P9/10A61P7/02A61P25/28
Inventor 樊玲玲李永罗忠福罗碧兰汤磊
Owner GUIZHOU MEDICAL UNIV
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