WO2011160597A1

WO2011160597A1 - Furocoumarin compounds with antihypertensive activity and preparation methods thereof

Info

Publication number: WO2011160597A1
Application number: PCT/CN2011/076242
Authority: WO
Inventors: 贺浪冲; 张�杰; 李娜; 贺建宇; 张彦民; 周楠; 李西玲; 王嗣岑; 贺怀贞; 卢闻
Original assignee: 西安交通大学
Priority date: 2010-06-25
Filing date: 2011-06-24
Publication date: 2011-12-29
Also published as: CN101857598A; CN101857598B

Abstract

Disclosed are furocoumarin compounds with antihypertensive activity and preparation methods thereof. The furocoumarin compounds have similar properties to that of imperatorin, show the activity of dilating blood vessels in isolated vascular ring tension research, and can be applied to the preparation of antihypertensive drugs.

Description

一种具有降高血压活性的呋喃香豆素类化合物及其制备方法技术领域 Furan coumarin compound having hypotensive activity and preparation method thereof

本发明涉及生物医药技术领域，涉及一种降高血压的化合物，特别涉及一种具有降高血压活性的呋喃香豆素类化合物及其制备方法。 The invention relates to the field of biomedical technology, and relates to a compound for lowering blood pressure, in particular to a furocoumarin compound having hypotensive activity and a preparation method thereof.

背景技术 Background technique

高血压是当前严重影响人类健康、威胁人类生命的主要疾病之一，是最常见的心血管疾病，与心肌梗死、脑卒中、冠心病、心力衰竭、肾功能衰竭等关系密切。我国每年死于心脑血管疾病近 300万人，占我们国每年总死亡病因的 51%; 而幸存下来的患者 75%的人不同程度丧失劳动能力， 40%的人重残。心血管疾病已成为人类的第一大杀手。而防治心脑血管疾病的关键是高血压病的防治。 Hypertension is one of the major diseases that currently seriously affect human health and threaten human life. It is the most common cardiovascular disease and is closely related to myocardial infarction, stroke, coronary heart disease, heart failure, and renal failure. China suffers from nearly 3 million cardiovascular and cerebrovascular diseases each year, accounting for 51% of the total cause of death in our country each year; 75% of the surviving patients lose their ability to work to varying degrees, and 40% are severely disabled. Cardiovascular disease has become the number one killer of human beings. The key to prevention and treatment of cardiovascular and cerebrovascular diseases is the prevention and treatment of hypertension.

据报道，高血压的发病率是随着年龄的增长而呈上升趋势的，但伴随着近年来社会压力、环境因素、生活条件的改善以及饮食构的改变，使高血压的发病年龄段日趋偏低， 30岁以上已变成高血压的重点防治人群，这表明高血压的发病正在日趋年轻化。 According to reports, the incidence of hypertension is increasing with age, but with the recent social pressure, environmental factors, improvement of living conditions and changes in diet, the age of hypertension is becoming more and more biased. Low, over 30 years old has become a key prevention and treatment group of hypertension, which indicates that the onset of hypertension is becoming younger.

高血压的化学药物治疗是高血压防治的基本手段之一，经过数十年的发展，用于高血压治疗的化学药物研究取得了巨大的成功，得到了一大批具有不同作用机制的临床抗高血压药物。但是由于化学药物本身不同程度的毒副作用，不同作用机制的高血压药物都存在着不同的缺点，常常会使高血压的化学药物治疗达不到预期的效果；且增强抗高血压药物的长效性和平稳性是提高抗高血压药物作用的有效方法。因此，新的降压药物的研究与开发是目前药学领域的热点与难点问题之一。 Chemotherapy for hypertension is one of the basic means of prevention and treatment of hypertension. After decades of development, the research on chemical drugs used in the treatment of hypertension has achieved great success, and a large number of clinical anti-high with different mechanisms of action have been obtained. Blood pressure drugs. However, due to the different degree of toxic and side effects of chemical drugs, different mechanisms of hypertension drugs have different shortcomings, which often make the chemical treatment of hypertension less than expected; and enhance the long-term effect of antihypertensive drugs. Sex and stability are effective ways to improve the action of antihypertensive drugs. Therefore, the research and development of new antihypertensive drugs is one of the hot and difficult issues in the field of pharmacy.

发明内容 Summary of the invention

本发明解决的问题在于提供一种具有抗高血压活性的呋喃香豆素类化合物及其制备方法，该呋喃香豆素类化合物表现出舒张血管、抗高血压的本发明是通过以下技术方案来实现: The problem to be solved by the present invention is to provide a furocoumarin compound having antihypertensive activity and a preparation method thereof, wherein the furocoumarin compound exhibits diastolic blood vessels and antihypertensive The invention is achieved by the following technical solutions:

其中， n为 1〜4， R二甲基或者双取代氨基。 Wherein n is 1 to 4, R dimethyl or disubstituted amino.

所述的 n为 2〜4个碳原子，碳链为直连垸烃， R为二甲基或者双取代基。 The n is 2 to 4 carbon atoms, the carbon chain is a straight hydrazine hydrocarbon, and R is a dimethyl group or a disubstituted group.

所述的 R为双取代氨基，其取代基为垸基、环垸基或环氧垸基。 The R is a disubstituted amino group, and the substituent is a fluorenyl group, a cyclodecyl group or an epoxy fluorenyl group.

一种具有降高血压的呋喃香豆素类化合物的制备方法，包括以下步骤: A method for preparing a furocoumarin compound having reduced hypertension comprises the following steps:

1 ) 花椒毒素在三溴化硼的作用下脱去甲基，得到花椒毒酚； 1) Xanthotoxin is demethylated under the action of boron tribromide to obtain xanthohumol;

2)花椒毒酚的酚羟基发生醚化反应，与至少含有 2个碳原子的侧链连，得到呋喃香豆素类化合物；其中，与酚羟基连接的侧链为： 2) The phenolic hydroxyl group of xanthophylls is etherified and linked with a side chain containing at least two carbon atoms to obtain a furocoumarin compound; wherein the side chain linked to the phenolic hydroxyl group is:

nR nR

n为 1〜4， R为氢原子、二甲基或者双取代氨基，双取代氨基的取代基为垸基、环垸基或环氧垸基。 n is 1 to 4, R is a hydrogen atom, a dimethyl group or a disubstituted amino group, and the substituent of the disubstituted amino group is an anthracenyl group, a cyclodecyl group or an epoxy fluorenyl group.

所述的花椒毒酚的制备为： The preparation of the xanthophylls is:

冰浴条件下，在将三溴化硼-二氯甲垸溶液滴加到花椒毒素 -二氯甲垸溶液中，其中，三溴化硼与花椒毒素的摩尔比为 3:1，然后在室温条件下反应 4h_; Under ice bath conditions, the boron tribromide-dichloroformamidine solution is added dropwise to the xanthotoxin-dichloroformamidine solution, wherein the molar ratio of boron tribromide to xanthotoxin is 3:1, and then at room temperature. The reaction was carried out for 4 h under the conditions _;

反应完成后，将反应体系转移到饱和碳酸氢钠溶液中充分搅拌反应，然后再整体转移到水中充分搅拌反应；抽滤，滤饼用水洗涤多次，滤液调至中性后再次产生沉淀；将产生的沉淀抽滤后，合并两次滤饼，真空干燥过夜，得到花椒毒酚。将花椒毒酚溶解于无水 Ν,Ν-二甲基甲酰胺中，然后再加入过量的无水碳酸钾，室温搅拌溶解后，再加入足量的与酚羟基发生醚化反应的提供侧链的化合物，氮气保护下， 80°C油浴控温反应 10〜30h。 After the reaction is completed, the reaction system is transferred to a saturated sodium hydrogencarbonate solution, the reaction is stirred well, and then the whole is transferred to water to thoroughly stir the reaction; the filtration cake is washed with water several times, and the filtrate is adjusted to neutrality to produce a precipitate again; After the resulting precipitate was suction filtered, the filter cake was combined twice and dried under vacuum overnight to give the. The xanthophylls are dissolved in anhydrous hydrazine, hydrazine-dimethylformamide, and then an excess of anhydrous potassium carbonate is added, stirred at room temperature, and then a sufficient amount of side chain to be etherified with the phenolic hydroxyl group is added. The compound, under nitrogen protection, is heated at 80 ° C in an oil bath for 10 to 30 h.

所述的至少含有 2个碳原子的侧链为异戊烯基、异戊垸基、烯丙基、 Ν,Ν-二甲基乙基、乙垸基吗啉、 Ν-苄基 -Ν-甲基乙基、 3-二甲基氨基丙基或哌啶乙基。 The side chain having at least 2 carbon atoms is isopentenyl, isoamyl, allyl, anthracene, fluorenyl-dimethylethyl, ethionylmorpholine, fluorenyl-benzyl-hydrazine- Methyl ethyl, 3-dimethylaminopropyl or piperidinylethyl.

所述的具有降高血压活性的呋喃香豆素类化合物应用于抗高血压药物的制备。 The furocoumarin compound having hypotensive activity is applied to the preparation of an antihypertensive drug.

与现有技术相比，本发明具有以下有益的技术效果： Compared with the prior art, the present invention has the following beneficial technical effects:

本发明提供的呋喃香豆素类化合物是一种新的具有抗高血压活性的化合物，其是在天然植物提取物欧前胡素的基础上进行结构修饰与优化，保留其药理活性的基础上，改善其理化性质，增强其成药性。 The furocoumarin compound provided by the invention is a novel compound with antihypertensive activity, which is based on the structural modification and optimization of the natural plant extract imperatorin, and retains its pharmacological activity. , improve its physical and chemical properties and enhance its drug-forming properties.

本发明提供的呋喃香豆素类化合物的制备方法，具有原料来源易得，反应条件温和，反应过程操作简单，所用试剂便宜易得的优点。为获得具有抗高血压活性的药效成分，本发明相较于天然植物提取获得作为抗高血压活性的欧前胡素，能够显著的降低成本。 The preparation method of the furocoumarin compound provided by the invention has the advantages that the raw material source is easy to obtain, the reaction condition is mild, the reaction process is simple, and the reagent used is cheap and easy to obtain. In order to obtain a medicinal ingredient having antihypertensive activity, the present invention can obtain an imperatorin having high antihypertensive activity as compared with natural plant extract, and can significantly reduce the cost.

通过细胞膜色谱（CMC) 技术对欧前胡素进行了深入研究：离体血管环张力实验研究表明欧前胡素对大鼠不同组织和脏器的微血管都有舒张作用，且对其作用机制的研究也表明它是抑制外钙内流和内钙释放的；细胞水平的研究结果表明欧前胡素在血管平滑肌细胞膜色谱上的保留与抗高血压药物维拉帕米有相似的保留置换作用，且欧前胡素能够明显抑制大鼠的血管平滑肌细胞的增值、迁移即能够抑制血管壁的增厚，它能够关闭电压依赖性钙离子通道，降低心肌和血管平滑肌细胞内 Ca²⁺浓度，且从而表现出其降压作用；整体动物实验研究表明欧前胡素对于原发性高血压大鼠及肾性高血压大鼠有明显的降压作用并伴随着抑制左心室肥大、降低心肌纤维化程度和血管壁厚度，保护肾脏的作用，且这些作用都表现出它的剂量依赖性。推测欧前胡素是一种新型的钙离子拮抗剂，期望以其为药物先导物可以被开发成为一种新型的降压药物。 The in vitro study of imperatorin by cell membrane chromatography (CMC): The experimental study of ex vivo vascular ring tension showed that imperatorin has a relaxing effect on the microvessels of different tissues and organs in rats, and its mechanism of action Studies have also shown that it inhibits extra-calcium influx and intracellular calcium release; cell-level studies have shown that the retention of imperatorin on vascular smooth muscle cell membrane chromatography has a similar retention and replacement effect with the antihypertensive drug verapamil, And imperatorin can significantly inhibit the proliferation and migration of rat vascular smooth muscle cells, which can inhibit the thickening of blood vessel walls, which can turn off voltage-dependent calcium channels and reduce the concentration of Ca ^{2+ in} myocardial and vascular smooth muscle cells, and Thus, it shows its antihypertensive effect; the whole animal experiment shows that imperatorin has obvious antihypertensive effect on primary hypertensive rats and renal hypertensive rats, accompanied by inhibition of left ventricular hypertrophy and reduction of myocardial fibrosis Degree and thickness of the vessel wall, protect the kidneys, and these effects show its dose Dependence. It is speculated that imperatorin is a novel calcium ion antagonist, and it is expected that it can be developed as a novel antihypertensive drug by using it as a drug lead.

本发明所制备的呋喃香豆素类抗高血压类化合物是欧前胡素的衍生物，具有和欧前胡素相类似的作用，离体血管环张力研究表明呋喃香豆素类化合物对大鼠肠系膜微血管有舒张作用，可应用于抗高血压药物的制备。附图说明 The furocoumarin antihypertensive compound prepared by the present invention is a derivative of imperatorin and has a similar effect to imperatorin. The study of exovascular ring tension shows that the furocoumarin compound on the rat mesentery Microvessels have a relaxing effect and can be applied to the preparation of antihypertensive drugs. DRAWINGS

图 1为具有抗高血压活性的呋喃香豆素类化合物的合成路线图；其中，化合物 1为花椒毒素，化合物 2为花椒毒酚，化合物 3为呋喃香豆素类化合物。图中标注的反应条件具体为： a为 BBr₃,CH₂Cl_2; b 为 DMF, K₂C0₃。 Fig. 1 is a synthetic route diagram of a furocoumarin compound having antihypertensive activity; wherein, compound 1 is xanthotoxin, compound 2 is xanthophylls, and compound 3 is a furocoumarin compound. The reaction conditions indicated in the figure are specifically as follows: a is BBr ₃ , CH ₂ Cl _{2 ;} b is DMF, K ₂ C0 ₃ .

图 2为血管环的舒张量效图对比结果图，其中，图 2-1〜图 2-9为不同的呋喃香豆素类化合物与欧前胡素、 Control (空白对照）的舒张量效图对比，横坐标为浓度的对数，纵坐标为最大舒张率。 Figure 2 is a comparison of the diastolic dose-effect diagrams of the vascular rings, wherein Figure 2-1 to Figure 2-9 show the diastolic dose-effect diagrams of different furocoumarins and imperatorin, Control (blank control). In contrast, the abscissa is the logarithm of the concentration and the ordinate is the maximum diastolic rate.

具体实施方式 detailed description

本发明提供一种具有抗高血压活性的呋喃香豆素类化合物，该呋喃香豆素类化合物具有与欧前胡素相似的性质，在离体血管环张力研究中表现出其舒张血管的活性，能够应用于抗高血压药物的制备。下面结合附图和实施例对本发明做详细说明，所述是对本发明的解释而不是限定。 The present invention provides a furocoumarin compound having antihypertensive activity, the furocoumarin compound having properties similar to imperatorin, exhibiting diastolic blood vessel activity in an isolated vascular ring tension study , can be applied to the preparation of antihypertensive drugs. The invention is described in detail below with reference to the drawings and embodiments, which are to be construed as illustrative and not limiting.

本发明提供具有抗高血压活性的呋喃香豆素类化合物，其化学结构式为： The present invention provides a furocoumarin compound having antihypertensive activity, and its chemical structural formula is:

其中， n为 1〜4， R为氢原子、二甲基或者双取代氨基。

Wherein n is 1 to 4, and R is a hydrogen atom, a dimethyl group or a disubstituted amino group.

所述的 n为 2〜4个碳原子，末端的两个碳原子之间形成双键， R为氢原子。所述的 n为 2〜4个碳原子，碳链为直连垸烃， R为二甲基或者双取代氨基。所述的 R为双取代氨基，其取代基为垸基、环垸基或环氧垸基。下面结合图 1 所示的合成路线和具体的合成实施例来详细说明具有抗高血压活性的呋喃香豆素类化合物的制备方法。 The n is 2 to 4 carbon atoms, and a double bond is formed between two carbon atoms at the terminal, and R is a hydrogen atom. The n is 2 to 4 carbon atoms, the carbon chain is a direct alkylene hydrocarbon, and R is a dimethyl group or a double Alkenyl. The R is a disubstituted amino group, and the substituent is a fluorenyl group, a cyclodecyl group or an epoxy fluorenyl group. The preparation method of the furocoumarin compound having antihypertensive activity will be described in detail below with reference to the synthetic route shown in Fig. 1 and specific synthetic examples.

实施例 1 结构式中 n为 2且形成双键、 R为二甲基的化合物，通过以下步骤制备： EXAMPLE 1 A compound wherein n is 2 and a double bond and R is a dimethyl group is prepared by the following procedure:

1 ) 花椒毒素（1 ) 通过三溴化硼脱去甲基得到化合物花椒毒酚（2 ) 取 4.32g (20.00mmol) 花椒毒素置于 250ml茄形瓶中，加入 73ml无水二氯甲垸，摇匀使其溶解，氮气保护下将其置于冰浴中，搅拌 10〜15min; 同时，将 6.88ml三溴化硼溶解于 73ml无水二氯甲垸中，配制成 lmol/L的三溴化硼 -二氯甲垸溶液待用。 1) Xanthotoxin (1) Decarboxylation of boron tribromide to obtain compound xanthohumol (2) 4.32 g (20.00 mmol) of xanthotoxin was placed in a 250 ml eggplant-shaped flask, and 73 ml of anhydrous dichloromethane was added. Shake well to dissolve, place it in an ice bath under nitrogen protection, stir for 10~15min; At the same time, dissolve 6.88ml of boron tribromide in 73ml anhydrous dichloromethane to prepare 1mol/L tribromide Boron-dichloromethane solution is used.

待茄形瓶内温度恒定时，将配制好的三溴化硼-二氯甲垸溶液置于恒压滴液漏斗中，缓滴于冰浴中搅拌着的茄形瓶中， 30min中滴完。滴完后撤去冰浴，室温反应 4h。 When the temperature inside the eggplant bottle is constant, the prepared boron tribromide-dichloroformamidine solution is placed in a constant pressure dropping funnel, and slowly dripped in an eggplant-shaped bottle stirred in an ice bath, and dripped in 30 minutes. . After the completion of the dropwise addition, the ice bath was removed and reacted at room temperature for 4 hours.

室温反应完成后，将反应体系倒入搅拌着的饱和碳酸氢钠溶液 160ml 中搅拌 lh，然后再整体转移到 160ml水中搅拌 lh_; 抽滤，滤饼用水洗涤多次，滤液用 2mol/L的盐酸调至中性后再次产生沉淀，将产生的沉淀抽滤后，合并两次滤饼，真空干燥器干燥过夜后，得到白色固体产物 3.64g ( 18.00mmol)，产率 90.0%。 After the reaction at room temperature is completed, the reaction system is poured into 160 ml of a stirred saturated sodium hydrogencarbonate solution and stirred for 1 hour, and then transferred to 160 ml of water and stirred for 1 hour _; filtered, the filter cake is washed several times with water, and the filtrate is diluted with 2 mol/L hydrochloric acid. After the neutralization, the precipitate was again produced. After the resulting precipitate was suction filtered, the filter cake was combined twice and dried in vacuo to give a white solid product 3.64 g ( 18.00 mmol), yield 90.0%.

2 )花椒毒酚与异戊烯基溴发生醚化反应，异戊烯基作为侧链与其连接，制备异戊烯基溴发生醚化反应得到化合物 9- (3-甲基 -2-丁烯氧基） -7H-呋喃 [3,2-g]色烯 -7-酮（IMP-1 ) 2) The etherification reaction of xanthophylls with isopentenyl bromide, the isopentenyl group as a side chain, and the etherification of isopentenyl bromide to give compound 9-(3-methyl-2-butene) Oxy))-7H-furan[3,2-g]chromen-7-one (IMP-1)

取 0.81g (4.00mmol) 化合物（2 ) 溶解于重蒸的无水 Ν,Ν-二甲基甲酰胺 (DMF ) 10ml中，加入无水碳酸钾 1.66g ( 12.00mmol) , 室温搅拌 30min，再加入异戊烯基溴 0.69ml ( 6.00mmol)，氮气保护下， 80°C油浴（甲基硅油）控温反应 10h。 0.81 g (4.00 mmol) of the compound (2) was dissolved in anhydrous distilled hydrazine, hydrazine-dimethylformamide (DMF) (10 ml), and anhydrous potassium carbonate (1.66 g, 12.00 mmol) was added and stirred at room temperature for 30 min. Add 0.69 ml (6.00 mmol) of isopentenyl bromide under nitrogen atmosphere, and control the temperature in an 80 ° C oil bath (methyl silicone oil) for 10 h.

待反应冷却至室温后，将整个体系倒入冰水中，静止至冰融化，有淡黄色针状晶体析出，抽滤，用水少量多次洗涤，干燥后得到淡黄色固体 0.90g G.OOmmol) 产率 83.3% After the reaction is cooled to room temperature, the whole system is poured into ice water, and it is still frozen until the ice melts. The needle-like crystals were precipitated, suction filtered, washed with a small amount of water, and dried to give a pale yellow solid (yield: 0.90 g, g.

其理化性质为： m.p. 88-92°C; 质谱为： EI-MS(m/z): 270.09 ([M+H]⁺); 核磁共振氢谱为： lH-NMR(400MHz, CDC13) 5:7.77(d, J=10.00Hz, 1H), 7.70(d, J=1.60Hz, 1H),7.37(S,1H), 6.82(d, J=2.00Hz,lH), 6.37(d, J=9.60Hz, 1H)_: 5.61(t, J=7.00Hz, 2H), 5.00(d, J=3.20Hz, 2H), 1.73(d, J=8.80Hz, 6H), 1.63(s,lH)。 Its physicochemical properties are: mp 88-92 ° C; mass spectrum: EI-MS (m/z): 270.09 ([M+H] ⁺ ); NMR spectrum: lH-NMR (400 MHz, CDC13) 5: 7.77 (d, J = 10.00 Hz, 1H), 7.70 (d, J = 1.60 Hz, 1H), 7.37 (S, 1H), 6.82 (d, J = 2.00 Hz, lH), 6.37 (d, J = 9.60) Hz, 1H) _: 5.61 (t, J = 7.00 Hz, 2H), 5.00 (d, J = 3.20 Hz, 2H), 1.73 (d, J = 8.80 Hz, 6H), 1.63 (s, lH).

所得呋喃香豆素类化合物 9- (3-甲基 -2-丁烯氧基） -7H-呋喃 [3,2-g]色烯 -7-酮相当于图 1所示的化（IMP-1 ), 其结构式如下： The obtained furocoumarin compound 9-(3-methyl-2-butenyloxy)-7H-furan [3,2-g]chromen-7-one corresponds to the conversion shown in Fig. 1 (IMP- 1), its structural formula is as follows:

实施例 2 结构式中 n为 2， R为步骤 1 ) 与实施例 1相同，也即从化合物花椒毒素（1 ) 到化合物花椒毒酚（2) 的制备步骤相同；之后酚羟基与异戊垸基溴发生醚化反应，具体为： Example 2 wherein n is 2 and R is the step 1) is the same as in the first embodiment, that is, the preparation steps are the same from the compound xanthotoxin (1) to the compound xanthohumol (2); then the phenolic hydroxyl group and the isopentenyl group The bromination reaction of bromine is specifically as follows:

取 0.40g (2.00mmol) 化合物（2) 溶解于处理过的无水 Ν,Ν-二甲基甲酰胺（DMF) 10ml中，加入无水碳酸钾 0.83g (6.00mmol)，室温搅拌 30min，再加入异戊垸基溴 0.37ml (3.00mmol)，氮气保护下 80°C油浴控温反应 20h。待反应冷却至室温后将整个体系倒入冰水中，静止至冰融化，用乙酸乙酯少量多次萃取至乙酸乙酯层无色， TLC显示水相没有产物后，用 2mol/LHCl 0.40 g (2.00 mmol) of the compound (2) was dissolved in 10 ml of treated anhydrous hydrazine, hydrazine-dimethylformamide (DMF), and anhydrous potassium carbonate (0.83 g (6.00 mmol) was added, and stirred at room temperature for 30 min. 0.37 ml (3.00 mmol) of isoamyl bromide was added, and the temperature was controlled by an oil bath at 80 ° C for 20 h under nitrogen atmosphere. After the reaction was cooled to room temperature, the whole system was poured into ice water, allowed to stand until the ice melted, and extracted with a small amount of ethyl acetate to a small amount of ethyl acetate to be colorless. TLC showed that the aqueous phase had no product and then used 2 mol/L HCl.

(3 X 30ml)、饱和 NaHC0₃ (3 X 30ml) 饱和 NaCl (3 X 30ml) 分别洗涤，有机相用无水硫酸钠干燥后减压蒸去溶剂，残留物有 0.57g; 经硅胶柱层析分离洗脱（洗脱剂：石油醚：乙酸乙酯 =5 : 1 ) 得到白色针状晶体 0.39g(1.4mmol), 产率 72.2%。其理化性质为： m.p.73-75°C ; 质谱为： EI-MS(m/z): 272.10 ([M+H]⁺); lH-NMR(300MHz, CDC13)5:7.76(d, J=9.00Hz,lH), 7.69(s,lH), 7.35(s,lH), 6.82(s,lH), 6.37(d, J=9.00Hz, 1H), 4.52(t, J=7.50Hz, 2H), 1.91-2.04 (m,lH), 1.80-1.74(q, 2H), 1.0(d, J=6.00Hz, 6H)。 (3 X 30 ml), saturated NaHC0 ₃ (3 X 30 ml), saturated NaCl (3×30 ml) were washed separately, the organic phase was dried over anhydrous sodium sulfate and evaporated. Separation and elution (eluent: petroleum ether: ethyl acetate = 5:1) gave white crystals (yield: 0.39 g, 1.4 mmol), yield 72.2%. Its physicochemical properties are: mp73-75 ° C; mass spectrum: EI-MS (m/z): 272.10 ([M+H] ⁺ ); lH-NMR (300 MHz, CDC13) 5:7.76 (d, J = 9.00) Hz,lH), 7.69(s,lH), 7.35(s,lH), 6.82(s,lH), 6.37(d, J=9.00Hz, 1H), 4.52(t, J=7.50Hz, 2H), 1.91-2.04 (m, lH), 1.80-1.74 (q, 2H), 1.0 (d, J = 6.00 Hz, 6H).

所得呋喃香豆素类化合物 9- (异戊氧基） -7H-呋喃 [3,2-g]色烯 -7-酮相当于图 1所示的化合物（IMP-2), ： The obtained furocoumarin compound 9-(isopentyloxy)-7H-furan [3,2-g]chromene-7-one is equivalent to the compound shown in Fig. 1 (IMP-2), :

实施例 3 结构式中 n为 2且形成双键， R为氢原子的化合物，通过以下步骤制备： Embodiment 3 A compound wherein n is 2 and a double bond and R is a hydrogen atom in the structural formula is prepared by the following steps:

步骤 1 ) 与实施例 1相同，也即从化合物花椒毒素（1 ) 到化合物花椒毒酚（2)的制备步骤相同；之后酚羟基与烯丙基溴发生醚化反应，具体为：取 0.40g (2.00mmol) 化合物（2) 溶解于处理过的无水 Ν,Ν-二甲基甲酰胺（DMF) 10ml中，加入无水碳酸钾 0.83g (6.00mmol)，室温搅拌 30min，再加入烯丙基溴 0.25ml G.OOmol), 氮气保护下 80°C油浴控温反应 19h。待反应冷却至室温后将整个体系倒入冰水中，静止至冰融化，有浅褐色晶体析出，抽滤，用水少量多次洗涤，干燥后得到褐色固体，用硅胶柱层析分离洗脱（洗脱剂：石油醚：乙酸乙酯 =3 : 1 ) 得到白色片絮状晶体 0.45g ( 1.90mmol) 产率 93·0%。 Step 1) Same as Example 1, that is, the preparation steps from the compound xanthotoxin (1) to the compound xanthohumol (2) are the same; after that, the phenolic hydroxyl group and the allyl bromide are etherified, specifically: 0.40 g (2.00 mmol) Compound (2) was dissolved in 10 ml of treated anhydrous hydrazine, hydrazine-dimethylformamide (DMF), anhydrous potassium carbonate (0.83 g (6.00 mmol)), stirred at room temperature for 30 min, then ally Base bromine 0.25 ml G. OOmol), temperature control reaction in an oil bath at 80 ° C for 19 h under nitrogen protection. After the reaction was cooled to room temperature, the whole system was poured into ice water, and the mixture was allowed to stand until the ice was melted. The light brown crystals were precipitated, filtered, and washed with a small amount of water. After drying, a brown solid was obtained, which was separated by silica gel column chromatography. Detachment: petroleum ether: ethyl acetate = 3 : 1 ) 0.45 g ( 1.90 mmol) of a white flake crystal was obtained. Yield: 93.0%.

其理化性质为： m.p.80-81 °C ; 质谱为： EI-MS(m/z): 242.06 ([M+H]⁺); 核磁共振氢谱为： 1H-NMR (400MHz, CDC13) 5:7.77(d, J=9.6Hz, 1H), 7.69(s, 1H), 7.37(s, 1H), 6.82(d, J=1.60Hz, 1H), 6.38(d, J=9.60Hz, 1H), 6.15-6.17 (m,lH),5.43(d, J=17.20Hz, 1H), 5.25(d, J=10.40Hz, 1H) 5.03 (d, J=5.20Hz, 2H)。 Its physicochemical properties are: mp80-81 °C; mass spectrum: EI-MS (m/z): 242.06 ([M+H] ⁺ ); NMR spectrum: 1H-NMR (400MHz, CDC13) 5:7.77 (d, J=9.6Hz, 1H), 7.69(s, 1H), 7.37(s, 1H), 6.82(d, J=1.60Hz, 1H), 6.38(d, J=9.60Hz, 1H), 6.15 - 6.17 (m, lH), 5.43 (d, J = 17.20 Hz, 1H), 5.25 (d, J = 10.40 Hz, 1H) 5.03 (d, J = 5.20 Hz, 2H).

所得呋喃香豆素类化合物 9- (异戊氧基： )-7H-呋喃 [3,2-g]色烯 -7-酮相当于图 1所示的化合物（IMP-3 ), 其结构式如下： The resulting furocoumarin compound 9-(isopentyloxy: )-7H-furan [3,2-g]chromen-7-one is equivalent The compound (IMP-3) shown in Figure 1 has the following structural formula:

实施例 4 结构式中 n为 1， R为垸基双取代氨基的化合物，通过以下步骤制备： EXAMPLE 4 A compound wherein n is 1, and R is a fluorenyl disubstituted amino group is prepared by the following procedure:

步骤 1 ) 与实施例 1相同，也即从化合物花椒毒素（1 ) 到化合物花椒毒酚（2)的制备步骤相同；之后酚羟基与 Ν,Ν-二甲基氯乙胺盐酸盐发生醚化反应，具体为： Step 1) The same as in Example 1, that is, the preparation steps from the compound xanthotoxin (1) to the compound xanthohumol (2) are the same; after that the phenolic hydroxyl group is ether with hydrazine, hydrazine-dimethylchloroethylamine hydrochloride The reaction is specifically:

取 0.81g (4.00mmol) 化合物（2) 溶解于处理过的无水 Ν,Ν-二甲基甲酰胺（DMF) lOml中，加入无水碳酸钾 2.21g ( 16.00mmol)，室温搅拌 30min，再加入 0.86g (6.00mmol) Ν,Ν-二甲基氯乙胺盐酸盐，氮气保护下， 80°C油浴控温反应 25h。待反应冷却至室温后，将整个体系倒入冰水中，静止至冰融化，用氯仿少量多次萃取后，有机相无水硫酸钠干燥后，减压蒸除溶剂，用硅胶柱层析分离洗脱（洗脱剂：氯仿：甲醇 =30: 1 ) 得到微黄色固体粉末，用少量石油醚洗涤色素后得到乳白色固体 0.61g(2.20mmol)产率 56.0%。 0.81 g (4.00 mmol) of the compound (2) was dissolved in anhydrous hydrazine, hydrazine-dimethylformamide (DMF) (10 ml), and anhydrous potassium carbonate (2.21 g, 16.00 mmol) was added and stirred at room temperature for 30 min. 0.86 g (6.00 mmol) of hydrazine, hydrazine-dimethylchloroethylamine hydrochloride was added, and the temperature was controlled by an oil bath at 80 ° C for 25 h under a nitrogen atmosphere. After the reaction is cooled to room temperature, the whole system is poured into ice water, and the mixture is allowed to stand until the ice is melted. After extraction with a small amount of chloroform, the organic phase is dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. De-eluting (eluent: chloroform:methanol = 30:1) gave a pale-yellow solid powder, which was washed with a small amount of petroleum ether to give a white solid (0.61 g, 2.20 mmol) yield of 56.0%.

其理化性质为： m.p.77-78°C ; 质谱为： EI-MS(m/z): 273.10 ([M+H]⁺); 核磁共振氢谱为： 1H-NMR (400MHz, CDC13) 5:7.77(d, J=9.6Hz, IH), 7.69(s, IH), 7.37(s, IH), 6.82(s, IH), 6.37(d, J=10.0Hz, IH), 4.57(t, J=5.4Hz, 2H), 2.84(t, J=5.6Hz, 2H) 2.40 (s, 6H)。 Its physicochemical properties are: mp77-78 ° C; mass spectrum: EI-MS (m/z): 273.10 ([M+H] ⁺ ); NMR spectrum: 1H-NMR (400MHz, CDC13) 5:7.77 (d, J=9.6Hz, IH), 7.69(s, IH), 7.37(s, IH), 6.82(s, IH), 6.37(d, J=10.0Hz, IH), 4.57(t, J= 5.4 Hz, 2H), 2.84 (t, J = 5.6 Hz, 2H) 2.40 (s, 6H).

所得呋喃香豆素类化合物 9- (2- (二甲氨基）乙氧基） -7H-呋喃 [3,2-g] 色烯 -7-酮相当于图 1所示的化合物（IMP-4), 其结构式如下： The obtained furocoumarin compound 9-(2-(dimethylamino)ethoxy)-7H-furan [3,2-g]chromen-7-one corresponds to the compound shown in Fig. 1 (IMP-4) ), its structural formula is as follows:

实施例 5 结构式中 n为 1， R为环氧垸基取代的双取代氨基的化合物，通过以下步骤制备：

EXAMPLE 5 A compound of the formula wherein n is 1 and R is an epoxy-substituted disubstituted amino group is prepared by the following procedure:

步骤 1 ) 与实施例 1相同，也即从化合物花椒毒素（1 ) 到化合物花椒毒酚（2) 的制备步骤相同；之后酚羟基与氯代乙垸吗啉盐酸盐发生醚化反应，具体为： Step 1) The same as in Example 1, that is, the preparation steps from the compound xanthotoxin (1) to the compound xanthohumol (2) are the same; after that, the phenolic hydroxyl group is etherified with chloroacetic acid morpholine hydrochloride, specifically For:

取 0.53g (2.62mmol) 化合物（2) 溶解于处理过的无水 Ν,Ν-二甲基甲酰胺（DMF) lOml中，加入无水碳酸钾 2.17g ( 15.72mmol)，室温搅拌 30min，再加入 0.98g (5.25mmol)氯代乙垸吗啉盐酸盐，氮气保护下， 80°C油浴控温反应 22h。待反应冷却至室温后，过滤，滤除碳酸钾后将体系倒入冰水中，静止至冰融化，用乙酸乙酯少量多次萃取后，部分产物仍溶在水相中，分别减压蒸除水和乙酸乙酯，合并两部分所得的固体物，用硅胶柱层析分离洗脱（洗脱剂：氯仿：甲醇 =10: 1 )得到白色絮状晶体， 0.58g ( 1.80mmol) 产率 68.7%。 0.53 g (2.62 mmol) of the compound (2) was dissolved in anhydrous hydrazine, hydrazine-dimethylformamide (DMF) (10 ml), and anhydrous potassium carbonate (2.17 g, 15.72 mmol) was added and stirred at room temperature for 30 min. 0.98 g (5.25 mmol) of chloroacetyl morpholine hydrochloride was added, and the temperature was controlled by an oil bath at 80 ° C for 22 h under a nitrogen atmosphere. After the reaction was cooled to room temperature, filtered, the potassium carbonate was filtered off, the system was poured into ice water, and the mixture was allowed to stand until the ice was melted. After extraction with a small amount of ethyl acetate, some of the products were still dissolved in the aqueous phase and evaporated under reduced pressure. Water and ethyl acetate, the combined solids were combined and purified by silica gel column chromatography (eluent: chloroform:methanol = 10:1) to give white crystals of white crystals, 0.58 g ( 1.80 mmol) yield 68.7 %.

其理化性质为： m.p.87-89°C ; 质谱为： EI-MS(m/z):315.11 ([M+H]⁺); 核磁共振氢谱为： lH-NMR(300MHz, CDC13) 5:7.77(d, J=9.6Hz,lH), 7.69(d, J=1.74Hz,lH), 7.38(s,lH), 6.83(d, J=1.86Hz, 1H), 6.37(d, J=9.6Hz,lH)， 4.65(s, 2H), 4.13(t, J=7.10Hz, 4H), 3.75 (s, 2H), 1.25(t, J=7.11Hz, 4H)。 Its physicochemical properties are: mp87-89 ° C; mass spectrum: EI-MS (m/z): 315.11 ([M+H] ⁺ ); NMR spectrum: lH-NMR (300 MHz, CDC13) 5:7.77 (d, J = 9.6 Hz, lH), 7.69 (d, J = 1.74 Hz, lH), 7.38 (s, lH), 6.83 (d, J = 1.86 Hz, 1H), 6.37 (d, J = 9.6 Hz) , lH), 4.65 (s, 2H), 4.13 (t, J = 7.10 Hz, 4H), 3.75 (s, 2H), 1.25 (t, J = 7.11 Hz, 4H).

所得呋喃香豆素类化合物 9- (2-吗啉基乙氧基） -7H-呋喃 [3,2-g]色烯 -7- The resulting furocoumarin compound 9-(2-morpholinylethoxy)-7H-furan [3,2-g]chromene-7-

反应得到化合物 N-苄基 -2-氯 -N-甲基乙胺（b)，之后化合物（2) 的酚羟基与 N-苄基 -2-氯 -N-甲基乙胺（b) 发生醚化反应，具体为：

The reaction gives the compound N-benzyl-2-chloro-N-methylethylamine (b), after which the phenolic hydroxyl group of the compound (2) and N-benzyl-2-chloro-N-methylethylamine (b) occur. The etherification reaction is specifically as follows:

取 4.88ml(30mmol)N-苄基 -N-甲基乙醇胺溶解于 20ml 甲苯中，加入 1.42ml(20mmoi:)氯化亚砜，回流反应 2h，减压蒸除溶剂后，用丙酮：乙醇 3:1(_V/_V)重结晶后得到 N-苄基 -2-氯 -N-甲基乙胺（b) 的盐酸盐形式，将其溶解于 20ml水中，加入等当量的 NH₃摇匀中和，使 N-苄基 -2-氯 -N-甲基乙胺4.88 ml (30 mmol) of N-benzyl-N-methylethanolamine was dissolved in 20 ml of toluene, and 1.42 ml (20 mm oi:) thionyl chloride was added thereto, and refluxed for 2 hours. The solvent was evaporated under reduced pressure, and then acetone and ethanol were used. :1 ( _V / _V ), after recrystallization, the hydrochloride salt of N-benzyl-2-chloro-N-methylethylamine (b) is obtained, dissolved in 20 ml of water, and shaken with an equivalent amount of NH ₃ Neutralizing, making N-benzyl-2-chloro-N-methylethylamine

(b) 释放出来，用甲苯少量多次萃取分离，有机相用无水硫酸钠干燥后，减压蒸除溶剂，残余物用正己垸重结晶得到白色结晶 2.20g(12mm_Ol)，产率 40%。 (b) released, separated and extracted a few times with toluene and the organic phase was dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure, the residue was recrystallized with n-hexyl embankment white crystals, yield 2.20g (12mm _O l) 40%.

取 0.40g (2.00mmol) 花椒毒酚（2) 溶解于处理过的无水 Ν,Ν-二甲基甲酰胺（DMF)lOml中，加入无水碳酸钾 1.10g(8.00mmol)，室温搅拌 30min，再加入 0.66g G.OOmmol) N-苄基 -2-氯 -N-甲基乙胺（b)，氮气保护下， 80°C 油浴控温反应 26h。待反应冷却至室温后，将体系倒入冰水中，静止至冰融化，用氯仿少量多次萃取后，无水硫酸钠干燥，减压蒸除溶剂，硅胶柱层析分离洗脱（洗脱剂：石油醚乙：酸乙酯 =10: 1 ) 得到淡褐色针状晶体， 0.50g ( 1.42mmol) 产率 72·1%。 0.40 g (2.00 mmol) of xanthophylls (2) was dissolved in treated anhydrous hydrazine, hydrazine-dimethylformamide (DMF) 10 ml, and anhydrous potassium carbonate 1.10 g (8.00 mmol) was added, and stirred at room temperature for 30 min. Then, 0.66 g of G.OOmmol) N-benzyl-2-chloro-N-methylethylamine (b) was added, and the temperature was controlled by an oil bath at 80 ° C for 26 h under a nitrogen atmosphere. After the reaction is cooled to room temperature, the system is poured into ice water, and the mixture is allowed to cool to ice. The mixture is extracted with chloroform in small portions, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. : petroleum ether B: ethyl acetate = 10: 1 ) Obtained pale brown needle crystals, yield 0.51 g ( 1.42 mmol), 72.1%.

其理化性质为： m.p.H9-121 °C ;质谱为： EI-MS(m/z):315.11 ([M+H]⁺)_; 核磁共振氢谱为： lH-NMR(300MHz, CDC13) 5:7.75(d, J=9.50Hz,lH), 7.69(s,lH), 7.57(s,lH), 7.30-7.36(m,5H) 6.81(s,lH), 6.37(d, J=9.40Hz, 1H), 5.55(s, 2H), 4.11-4.13(m,2H), 2.05-2.06(m,2H),1.61(s,3H)。 Its physicochemical properties are: mpH9-121 °C; mass spectrum: EI-MS (m/z): 315.11 ([M+H] ⁺ ) _; nuclear magnetic resonance spectrum: lH-NMR (300MHz, CDC13) 5:7.75 (d, J=9.50Hz, lH), 7.69(s,lH), 7.57(s,lH), 7.30-7.36(m,5H) 6.81(s,lH), 6.37(d, J=9.40Hz, 1H ), 5.55 (s, 2H), 4.11-4.13 (m, 2H), 2.05-2.06 (m, 2H), 1.61 (s, 3H).

所得呋喃香豆素类化合物 9-(2- (苄基 (甲基:)氨基:)乙氧基 )-7H呋喃 [3,2-g] 色烯 -7-酮相当于图 1所示的化合物（IMP-6), 其结构式如下： The obtained furocoumarin compound 9-(2-(benzyl(methyl:)amino:)ethoxy)-7H furan [3,2-g] chromen-7-one corresponds to the one shown in FIG. Compound (IMP-6), its structural formula is as follows:

实施例 7 结构式中 n为 2， R为垸基双取代氨基的化合物，通过以下步骤制备： EXAMPLE 7 A compound wherein n is 2 and R is a fluorenyl disubstituted amino group is prepared by the following procedure:

步骤 1 ) 与实施例 1相同，也即从化合物花椒毒素（1 ) 到化合物花椒毒酚（2) 的制备步骤相同；之后酚羟基与 3-二甲基氨基丙基氯盐酸盐发生醚化反应，具体为： Step 1) The same as in Example 1, that is, the preparation steps from the compound xanthotoxin (1) to the compound xanthohumol (2) are the same; after that, the phenolic hydroxyl group is etherified with 3-dimethylaminopropyl chloride hydrochloride. The reaction is specifically as follows:

取 0.81g (4.00mmol) 化合物（2) 溶解于处理过的无水 Ν,Ν-二甲基甲酰胺（DMF) 10ml中，加入无水碳酸钾 2.20g (8.00mmol)，室温搅拌 30min，再加入 1.26g (6.00mmol) 3-二甲基氨基丙基氯盐酸盐，氮气保护下， 80°C 油浴控温反应 18h。待反应冷却至室温后，将体系倒入冰水中，静止至冰融化，用氯仿少量多次萃取后，无水硫酸钠干燥，减压蒸除溶剂，硅胶柱层析分离洗脱（氯仿：甲醇 =10: 1 )得到淡褐色针状晶体， 0.50g ( 1.74mmol) 产率 43.9%。 0.81 g (4.00 mmol) of the compound (2) was dissolved in 10 ml of treated anhydrous hydrazine, hydrazine-dimethylformamide (DMF), and anhydrous potassium carbonate (2.20 g (8.00 mmol) was added, and stirred at room temperature for 30 min. 1.26 g (6.00 mmol) of 3-dimethylaminopropyl chloride hydrochloride was added, and the temperature was controlled by an oil bath at 80 ° C for 18 h under a nitrogen atmosphere. After the reaction was cooled to room temperature, the system was poured into ice water, and the mixture was allowed to cool to ice. The mixture was extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by silica gel column chromatography (chloroform: methanol = 10: 1 ) A pale brown needle crystal was obtained, yield 0.50 g ( 1.74 mmol), 43.9%.

其理化性质为： m.p.l88-191 °C ;质谱为： EI-MS(m/z):287.12 ([M+H]⁺); 核磁共振氢谱为： 1H-NMR (400MHz, CDC13) 5:7.81(d, J=9.6Hz, 1H), 7.72(s, 1H), 7.45(s, 1H), 6.85(s, 1H), 6.39(d, J=9.60Hz, 1H), 4.55(s, 2H), 3.58(s, 2H), 2.93(s, 6H) 2.45(s, 2H)。 Its physicochemical properties are: mpl88-191 °C; mass spectrum: EI-MS (m/z): 287.12 ([M+H] ⁺ ); NMR spectrum: 1H-NMR (400MHz, CDC13) 5:7.81 (d, J=9.6Hz, 1H), 7.72(s, 1H), 7.45(s, 1H), 6.85(s, 1H), 6.39(d, J=9.60Hz, 1H), 4.55(s, 2H) , 3.58(s, 2H), 2.93(s, 6H) 2.45(s, 2H).

所得呋喃香豆素类化合物 9-(3- (二甲氨基:)丙氧基 )-7H 呋喃 [3,2-g]色烯 -7-酮相当于图 1所示的化（IMP-7), 其结构式如下： The obtained furocoumarin compound 9-(3-(dimethylamino:)propoxy)-7H furan [3,2-g]chromen-7-one corresponds to the conversion shown in Fig. 1 (IMP-7) ), its structural formula is as follows:

实施例 8 结构式中 n为 1， R为环垸基双取代氨基的化合物，通过以下步骤制备：

Embodiment 8 A compound wherein n is 1 and R is a cyclodecyl disubstituted amino group, The next step is to prepare:

步骤 1 ) 与实施例 1相同，也即从化合物花椒毒素（1 ) 到化合物花椒毒酚（2) 的制备步骤相同；之后酚羟基与 1-(2-氯乙基:)哌啶盐酸盐发生醚化反应，具体为： Step 1) Same as Example 1, that is, the preparation steps from the compound xanthotoxin (1) to the compound xanthohumol (2) are the same; then the phenolic hydroxyl group and 1-(2-chloroethyl:) piperidine hydrochloride The etherification reaction occurs, specifically:

取 0.40g (2.00mmol) 化合物（2) 溶解于处理过的无水 Ν,Ν-二甲基甲酰胺（DMF) 10ml中，加入无水碳酸钾 1.10g (8.00mmol)，室温搅拌 30min，再加入 0.55g G.OOmmol) 1-(2-氯乙基)哌啶盐酸盐，氮气保护下， 80°C油浴控温反应 30h。待反应冷却至室温后，将体系倒入冰水中，静置至冰融化，用氯仿少量多次萃取后，无水硫酸钠干燥，减压蒸除溶剂，硅胶柱层析分离洗脱（氯仿：甲醇 =30: 1 ) 得到淡褐色针状晶体， 0.42g ( 1.34mmol) 产率 67% 。 0.40 g (2.00 mmol) of the compound (2) was dissolved in 10 ml of treated anhydrous hydrazine, hydrazine-dimethylformamide (DMF), and 1.10 g (8.00 mmol) of anhydrous potassium carbonate was added, and stirred at room temperature for 30 min. 0.55 g of G.OOmmol) 1-(2-chloroethyl)piperidine hydrochloride was added, and the temperature was controlled by an oil bath at 80 ° C for 30 h under a nitrogen atmosphere. After the reaction is cooled to room temperature, the system is poured into ice water, allowed to stand until the ice is melted, and extracted with a small amount of chloroform, then dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. Methanol = 30: 1) Obtained pale brown needle crystals, yield 0.46 g ( 1.34 mmol).

其理化性质为： m.p.l98-199°C ;质谱为： EI-MS(m/z):313.13 ([M+H]⁺); 核磁共振氢谱为： lH-NMR(400MHz, CDC1₃) 5:7.80(d, J=9.20Hz,lH), 7.71(s,lH), 7.45(s,lH), 6.85(s,lH), 6.39(d, J=9.40Hz, 1H), 5.01(t, J=9.40Hz, 2H), 3.82(d,J=11.60Hz,2H), 3.06-3.14(m,2H) ， 2.26-2.36(m,2H), 1.92-1.99(m,3H), 1.52-1.71(m,3H)。 Its physicochemical properties are: mpl98-199 ° C; mass spectrum: EI-MS (m/z): 313.13 ([M+H] ⁺ ); NMR spectrum: lH-NMR (400 MHz, CDC1 ₃ ) 5: 7.80(d, J=9.20Hz, lH), 7.71(s,lH), 7.45(s,lH), 6.85(s,lH), 6.39(d, J=9.40Hz, 1H), 5.01(t, J = 9.40 Hz, 2H), 3.82 (d, J = 11.60 Hz, 2H), 3.06-3.14 (m, 2H), 2.26-2.36 (m, 2H), 1.92-1.99 (m, 3H), 1.52-1.71 ( m, 3H).

所得呋喃香豆素类化合物 9-(2- (哌啶 -1-基:)乙氧基:） -7H呋喃 [3,2-g]色烯 -7-酮相当于图 1所示的化合物（IMP-8), 其结构式如下： The resulting furocoumarin compound 9-(2-(piperidin-1-yl:)ethoxy:)-7H furan [3,2-g]chromen-7-one corresponds to the compound shown in Figure 1. (IMP-8), its structural formula is as follows:

呋喃香豆素类化合物的舒张血管、抗高血压活性验证实验

Verification experiment of diastolic blood vessels and antihypertensive activity of furocoumarins

本发明提供的呋喃香豆素类化合物具有抗高血压作用，对大鼠肠系膜微血管有舒张作用，可用于高血压的治疗；与阳性对照药欧前胡素相比，个别化合物显示了更高的抗高血压活性。抗高血压验证采用血管环张力法检测待测呋喃香豆素类化合物对肠系膜微血管的舒张： The furocoumarin compound provided by the invention has antihypertensive effect and has a relaxing effect on rat mesenteric microvasculature, and can be used for treatment of hypertension; compared with the positive control drug imperatorin, individual compounds show higher anti-high resistance. Blood pressure activity. Antihypertensive verification The vascular ring tension method was used to detect the relaxation of mesenteric microvasculature by the furocoumarin compound to be tested:

1 ) Kreb， s 溶液的配制： 1) Preparation of Kreb, s solution:

(1)制备新鲜的超纯水 1000mL。 (1) Prepare fresh ultrapure water 1000 mL.

(2)精确称取氯化钙 0.617g，加入少量超纯水超声振荡溶解，溶解完全后待用。 (2) Accurately weigh 0.617g of calcium chloride, add a small amount of ultrapure water to dissolve by ultrasonic vibration, dissolve it completely and use it.

(3)按照表 1所示配制出氯化钙的缓冲盐体系，将其溶于超纯水总量的 2/3中，用干净的玻璃棒搅拌使其全部溶解。 (3) A buffer salt system of calcium chloride was prepared as shown in Table 1, dissolved in 2/3 of the total amount of ultrapure water, and completely dissolved by stirring with a clean glass rod.

(4)将 (2)中配制好的待用溶液加入至 (3)中，搅拌后加入水定容至终体积，配制成终浓度。 (4) Add the prepared solution prepared in (2) to (3), stir and add water to the final volume to prepare the final concentration.

(5)测定 Kreb's溶液的 PH值，用 lmol/LHCl调节 ΡΗ=7·4。 (5) Determine the pH value of Kreb's solution, and adjust ΡΗ=7·4 with lmol/L HCl.

表 1 Kreb's溶液配制 Table 1 Kreb's solution preparation

完，不可放置过夜后再次使用。

End, do not place overnight and use again.

2 ) 供试液的配制 2) Preparation of test solution

(1)精密量取去甲肾上腺素（NE) 注射液适量，加生理盐水配制成 3 X 10-⁶mol/L的储备液， 4°C冰箱中避光保存。 (1) Precisely take the appropriate amount of norepinephrine (NE) injection, add 3 X 10- ⁶ mol/L stock solution with normal saline, and store in the refrigerator at 4 °C in the dark.

(2)精密量取欧前胡素，用水或 DMSO稀释，确定欧前胡素的终浓度为 l X 10^-7mol/L、 3 X 10"⁷mol/L 、 1 X 10"⁶ mol/L, 3 X 10"⁶ mol/L, 1 X 10"⁵ mol/L, 3 X 10"⁵ mol/L、 1 X 10"⁴ mol/L的系列溶液， 4°C冰箱中避光保存。 (3) 呋喃香豆素类化合物溶液的配制，精密量取呋喃香豆素类化合物，用水或 DMSO稀释，确定呋喃香豆素类化合物的终浓度为 l X 10_⁷mol/L、 3 X 10"⁷mol/L 、 1 X 10"⁶ mol/L, 3 X 10"⁶ mol/L, 1 X 10"⁵ mol/L, 3 X 10"⁵ mol/L, 1 X 10"⁴ mol/L的系列溶液， 4°C冰箱中避光保存。 (2) Precision extraction of imperatorin, diluted with water or DMSO, to determine the final concentration of imperatorin is l X 10 ^-7 mol / L, 3 X 10" ⁷ mol / L, 1 X 10" ⁶ mol / L, 3 X 10" ⁶ mol / L, 1 X 10" ⁵ mol / L, 3 X 10" ⁵ mol / L, 1 X 10" ⁴ mol / L series of solutions, stored in the refrigerator at 4 ° C protected from light. (3) Preparation of furan coumarin compound solution, precise measurement of furocoumarin compound, diluted with water or DMSO, to determine the final concentration of furocoumarin compound is l X 10_ ⁷ mol/L, 3 X 10 " ⁷ mol/L , 1 X 10" ⁶ mol/L, 3 X 10" ⁶ mol/L, 1 X 10" ⁵ mol/L, 3 X 10" ⁵ mol/L, 1 X 10" ⁴ mol/L The series of solutions are stored in a 4 ° C refrigerator protected from light.

3 ) 微血管的分离 3) Separation of microvessels

雄性 SD 大鼠，脱颈处死，迅速打开胸腔取出一段空肠，置于冰浴的 Kreb's溶液中，不断通入含有 95%的氧气和 5%的二氧化碳的混合气（体积比），以维持它的活性。具体选用的是肠系膜动脉的二级分支，取出肠系膜组织（空肠），显微镜下剥离脂肪，分离肠系膜动脉二级分支，剪成每段约 3mm的血管环。 Male Sprague-Dawley rats were sacrificed by cervical dislocation. The jejunum was quickly opened and the jejunum was removed. The Kreb's solution was placed in an ice bath, and a mixture (volume ratio) containing 95% oxygen and 5% carbon dioxide was continuously introduced to maintain it. active. Specifically selected is the secondary branch of the mesenteric artery, the mesenteric tissue (jejunum) is removed, the fat is removed under the microscope, the secondary branch of the mesenteric artery is isolated, and the vascular ring is cut into about 3 mm each.

4) 实验测定 4) Experimental determination

将分离好的血管环两端分别与浴槽内的两个灌流针连接，用尼龙线固定好即挂于浴槽中，打开加热温度，设定温度 37°C。调零稳定后，血管环静息负荷预张力约为 3mN，平衡 2h， 20min更换 Kreb's液一次， 2h后，浴槽内加入终浓度为 3 X 10_⁶mol/L去甲状肾上腺素 (NE)，以 NE检验血管动脉环收缩性，两次收缩幅度相差小于 10 %者用于实验。 The two ends of the separated blood vessel ring are respectively connected with the two perfusion needles in the bath, and are fixed in the bath by the nylon wire, and the heating temperature is turned on, and the temperature is set at 37 °C. After zero-stabilization, the pre-tension of the vascular ring resting load is about 3mN, the balance is 2h, and the Kreb's solution is replaced once in 20min. After 2h, the final concentration of 3 X 10_ ⁶ mol/L norepinephrine (NE) is added to the bath to NE examined the contractility of the vascular arteries, and the difference between the two contractions was less than 10% for the experiment.

(2) 待血管环收缩稳定后依次加入待测药物的浓度梯度溶液（7 个梯度），考察欧前胡素及呋喃香豆素类化合物对去甲肾上腺素所致的血管收缩的舒张作用，同时以 DMSO溶液空白对照作为 Control。欧前胡素和呋喃香豆素类化合物的舒张血管活性实验结果如表 2和图 2所示。 (2) After the vascular ring contraction is stabilized, the concentration gradient solution (7 gradients) of the drug to be tested is sequentially added to investigate the relaxation effect of imperatorin and furocoumarin on vasoconstriction induced by norepinephrine. At the same time, a blank control of DMSO solution was used as Control. The experimental results of the diastolic vasoactivity of imperatorin and furan coumarin compounds are shown in Table 2 and Figure 2.

IMP-7 7 5.83 ± 0.18 100.00 ± 1.34

IMP-8 7 6.23 ± 0.17 102.31 ± 1.12IMP-8 7 6.23 ± 0.17 102.31 ± 1.12

IMP-9 7 6.31 ± 0.12 101.40 ± 1.13IMP-9 7 6.31 ± 0.12 101.40 ± 1.13

IMP- 10 7 5.53 ± 0.13 100.33 ± 1.00IMP- 10 7 5.53 ± 0.13 100.33 ± 1.00

Control 7 1 15.94 ± 5.70 其中，半数有效浓度对数值是 -logEC₅。，其代表的意义是化合物诱导血管环舒张率达到 50%时的浓度；最大舒张率是 Emax %，其代表的意义是欧前胡素或呋喃香豆素衍生物诱导的血管环的最大舒张率； IMP1 为欧前胡素， IMP2〜10分别为呋喃香豆素衍生物： 9- (异戊氧基) -7H-呋喃 [3,2-g]色烯 -7-酮 (IMP-2); 9- (异戊氧基) -7H-呋喃 [3,2-g]色烯 -7-酮 (IMP-3); 9-(2- (二甲氨基)乙氧基 )-7H-呋喃 [3,2-g]色烯 -7-酮 (IMP-4); 9-(2-吗啉基乙氧基 )-7H-呋喃 [3,2-g]色烯 -7-酮 (IMP-5); 9-(2- (苄基 (甲基)氨基)乙氧基 )-7H呋喃 [3,2-g]色烯 -7-酮 (IMP-6); 9-(3- (二甲氨基)丙氧基 )-7H 呋喃 [3,2-g]色烯 -7-酮 (IMP-7); 9-(2- (哌啶 -1-基)乙氧基） -7H呋喃 [3,2-g]色烯 -7-酮 (IMP-8); 9-(2- (氮杂环庚 -1 基)乙氧基） -7H呋喃 [3,2-g]色烯 -7-酮（IMP-9); 9-(1- (二甲氨基)丙垸 -2-氧基) -7H呋喃 [3,2-g]色烯 -7-酮（IMP-10)。 Control 7 1 15.94 ± 5.70 where the logarithm of the effective concentration is -logEC ₅ . , the representative of which is the concentration at which the compound induces a vascular ring relaxation rate of 50%; the maximum relaxation rate is Emax %, which represents the maximum relaxation rate of the vascular ring induced by imperatorin or furocoumarin derivative IMP1 is imperatorin, and IMP2~10 is furocoumarin derivative: 9-(isopentyloxy)-7H-furan[3,2-g]chromen-7-one (IMP-2) 9-(isopentyloxy)-7H-furan[3,2-g]chromen-7-one (IMP-3); 9-(2-(dimethylamino)ethoxy)-7H-furan [3,2-g]chromen-7-one (IMP-4); 9-(2-morpholinylethoxy)-7H-furan[3,2-g]chromen-7-one (IMP -5); 9-(2-(benzyl(methyl)amino)ethoxy)-7H furan[3,2-g]chromen-7-one (IMP-6); 9-(3- Dimethylamino)propoxy)-7H furan [3,2-g]chromen-7-one (IMP-7); 9-(2-(piperidin-1-yl)ethoxy)-7H furan [3,2-g]chromen-7-one (IMP-8); 9-(2-(azetidin-1yl)ethoxy)-7H furan[3,2-g]chromene- 7-keto (IMP-9); 9-(1-(dimethylamino)propan-2-yloxy)-7H furan [3,2-g]chromen-7-one (IMP-10).

可以看出呋喃香豆素类化合物 IMP2〜10 对大鼠肠系膜微血管细胞具有不同程度的舒张血管作用。 It can be seen that furan coumarin compounds IMP2~10 have different degrees of vasodilating effects on rat mesenteric microvascular cells.

而检测 7个浓度梯度 1 X 10— ⁷mol/L、 3 X 10— ⁷mol/L 、 1 X 10— ⁶ mol/L、 3 X 10"⁶ mol/L、 1 X 10"⁵ mol/L、 3 X 10"⁵ mol/L、 1 X 10"⁴ mol/L的 IMP1、待测的呋喃香豆素类化合物（IMP2〜10)、 Control (空白对照）的舒张量效图对比结果分别如图 2-1〜图 2-9所示，其中横坐标为半数有效浓度的对数值、纵坐标为最大舒张率，可以看出 IMP2〜10与 Control相比均有明显的舒张量，并且 IMP2、 IMP3、 IMP 4、 IMP 6、 IMP 7的舒张效果与欧前胡素相当，而 IMP8、 IMP9的舒张效果强于欧前胡素。 7 detects a concentration gradient ^{1 X 10- 7 mol / L,} 3 X 10- 7 mol / L, 1 X 10- 6 mol / L, 3 X 10 "6 mol / L, 1 X 10" 5 mol / L , 3 X 10" ⁵ mol / L, 1 X 10" ⁴ mol / L IMP1, the furocoumarin compounds to be tested (IMP2 ~ 10), Control (blank control), the results of the diastolic dose-effect diagrams are as follows Figure 2-1 to Figure 2-9, where the abscissa is the logarithm of the half effective concentration and the ordinate is the maximum relaxation rate. It can be seen that IMP2~10 has significant diastolic amount compared with Control, and IMP2 The diastolic effects of IMP3, IMP 4, IMP 6, and IMP 7 are comparable to those of imperatorin, while the relaxation effects of IMP8 and IMP9 are stronger than that of imperatorin.

5 ) 呋喃香豆素类化合物具有舒张血管的作用，应用于抗高血压药物的制备 5) Furan coumarin compounds have the function of relaxing blood vessels and are used in the preparation of antihypertensive drugs

所述的抗高血压的药物的制备为：具有抗高血压活性的呋喃香豆素类化合物或其药物可接受的盐、衍生物、前药或立体异构体，应用于抗高血压的药物的制备； The preparation of the antihypertensive drug is: a furocoumarin compound having antihypertensive activity or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer thereof, for use in the preparation of an antihypertensive drug;

或者具有抗高血压活性的呋喃香豆素类化合物或其药物可接受的盐、衍生物、前药或立体异构体作为药物组合物之一，结合药物可接受的赋形剂或稀释剂应用于抗高血压的药物的制备。 Or a furanocoumarin compound having antihypertensive activity or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer thereof as one of the pharmaceutical compositions, in combination with a pharmaceutically acceptable excipient or diluent Preparation of antihypertensive drugs.

应用于抗高血压的药物的制备时，通过制药领域常用的手段可以制备成多种剂型，可以是口服剂型和注射剂，包括胶囊剂、片剂、颗粒剂、分散片、软胶囊、注射液、注射用冻干粉或注射用无菌分装粉。 When preparing for antihypertensive drugs, various dosage forms can be prepared by means commonly used in the pharmaceutical field, and can be oral dosage forms and injections, including capsules, tablets, granules, dispersible tablets, soft capsules, injections, Lyophilized powder for injection or sterile powder for injection.

Claims

权利要求书 Claim

其中， n为 1〜4个碳原子， R为二甲基或者双取代氨基。 Wherein n is 1 to 4 carbon atoms, and R is a dimethyl group or a disubstituted amino group.

2、如权利要求 1所述的具有降高血压活性的呋喃香豆素类化合物，其特征在于，所述的 n为 2〜4个碳原子，碳链为直连垸烃， R为二甲基或者双取代氨基。 The furocoumarin compound having hypotensive activity according to claim 1, wherein the n is 2 to 4 carbon atoms, the carbon chain is a direct azide hydrocarbon, and R is a dimethyl group. Base or disubstituted amino group.

3、如权利要求 1所述的具有降高血压活性的呋喃香豆素类化合物，其特征在于，所述的 R为双取代氨基，其取代基为垸基、环垸基或环氧垸基。 The furocoumarin compound having hypotensive activity according to claim 1, wherein R is a disubstituted amino group, and the substituent is an anthracenyl group, a cyclodecyl group or an epoxy fluorenyl group. .

4、一种具有降高血压的呋喃香豆素类化合物的制备方法，其特征在于，包括以下步骤： 4. A method for preparing a furocoumarin compound having hypotensive hypertension, comprising the steps of:

2)花椒毒酚的酚羟基发生醚化反应，与至少含有 2个碳原子的侧链连接，得到呋喃香豆素类化合物；羟基连接的侧链为： 2) The phenolic hydroxyl group of xanthophylls is etherified and linked with a side chain containing at least two carbon atoms to obtain a furocoumarin compound; the hydroxyl-linked side chain is:

n为 1〜4个碳原子， R为二甲基或者双取代氨基，双取代氨基的取代基为垸基、环垸基或环氧垸基。 n is 1 to 4 carbon atoms, R is a dimethyl group or a disubstituted amino group, and the substituent of the disubstituted amino group is an indenyl group, a cyclodecyl group or an epoxy fluorenyl group.

5、如权利要求 4所述的具有降高血压的呋喃香豆素类化合物的制备方法，其特征在于，所述的花椒毒酚的制备为： The method for preparing a furocoumarin compound having hypotensive effect according to claim 4, wherein the preparation of the xanthophylls is:

反应完成后，将反应体系转移到饱和碳酸氢钠溶液中充分搅拌反应，然后再整体转移到水中充分搅拌反应；抽滤，滤饼用水洗涤多次，滤液调至中性后再次产生沉淀；将产生的沉淀抽滤后，合并两次滤饼，真空干燥过夜，得到花椒毒酚。 After the reaction is completed, the reaction system is transferred to a saturated sodium hydrogencarbonate solution and the reaction is stirred well. Then, the whole reaction is transferred to water and stirred thoroughly; the filter cake is washed with water several times, and the filtrate is adjusted to neutral and then precipitated again; after the resulting precipitate is filtered, two filter cakes are combined and dried under vacuum overnight to obtain pepper. Toxic phenol.

6、如权利要求 4所述的具有降高血压的呋喃香豆素类化合物的制备方法，其特征在于，花椒毒酚的酚羟基发生的醚化反应为： The method for preparing a furocoumarin compound having hypotensive effect according to claim 4, wherein the etherification reaction of the phenolic hydroxyl group of xanthophylls is:

将花椒毒酚溶解于无水 Ν,Ν-二甲基甲酰胺中，然后再加入过量的无水碳酸钾，室温搅拌溶解后，再加入足量的与酚羟基发生醚化反应的提供侧链的化合物，氮气保护下， 80°C油浴控温反应 10〜30h。 The xanthophylls are dissolved in anhydrous hydrazine, hydrazine-dimethylformamide, and then an excess of anhydrous potassium carbonate is added, stirred at room temperature, and then a sufficient amount of side chain to be etherified with the phenolic hydroxyl group is added. The compound, under nitrogen protection, is heated at 80 ° C in an oil bath for 10 to 30 h.

7、如权利要求 4所述的具有降高血压的呋喃香豆素类化合物的制备方法，其特征在于，所述的至少含有 2个碳原子的侧链为异戊烯基、异戊垸基、烯丙基、 Ν,Ν-二甲基乙基、乙垸基吗啉、 Ν-苄基 -Ν-甲基乙基、 3-二甲基氨基丙基或哌啶乙基。 The method for producing a furocoumarin compound having hypotensive effect according to claim 4, wherein the side chain having at least two carbon atoms is isopentenyl or isonyl group. , allyl, hydrazine, hydrazine-dimethylethyl, ethionylmorpholine, hydrazino-benzyl-hydrazine-methylethyl, 3-dimethylaminopropyl or piperidinylethyl.

8、权利要求 1〜3任何一项所述的具有降高血压活性的呋喃香豆素类化合物应用于抗高血压药物的制备。 The furocoumarin compound having hypotensive activity according to any one of claims 1 to 3, which is applied to the preparation of an antihypertensive drug.