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WO2024199098A1 - 一种黄嘌呤衍生物及其制备方法和应用 - Google Patents

一种黄嘌呤衍生物及其制备方法和应用 Download PDF

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Publication number
WO2024199098A1
WO2024199098A1 PCT/CN2024/083164 CN2024083164W WO2024199098A1 WO 2024199098 A1 WO2024199098 A1 WO 2024199098A1 CN 2024083164 W CN2024083164 W CN 2024083164W WO 2024199098 A1 WO2024199098 A1 WO 2024199098A1
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Prior art keywords
compound
preparation
xanthine derivative
blood pressure
reaction
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PCT/CN2024/083164
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English (en)
French (fr)
Inventor
刘兴新
宋兰兰
王科
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麦科奥特(苏州)科技有限公司
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Publication of WO2024199098A1 publication Critical patent/WO2024199098A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the field of medical technology, and in particular to a xanthine derivative and a preparation method and application thereof.
  • control drugs need to be used every day and maintained for a long time.
  • These drugs mainly maintain clinical control of asthma through anti-inflammatory effects, including inhaled corticosteroids (ICS), systemic hormones, leukotriene modifiers, long-acting ⁇ 2 receptor agonists (LABA), sustained-release theophylline, supelalast toluene, sodium cromoglycate, etc.
  • Relief drugs are also called emergency drugs. These drugs are used on demand when symptoms occur. They relieve asthma symptoms by quickly relieving bronchospasm, including rapid-acting inhaled and short-acting oral ⁇ 2 receptor agonists, inhaled anticholinergics, short-acting theophylline and systemic hormones.
  • Additional treatment drugs for severe asthma are mainly biological targeted drugs, such as anti-IgE monoclonal antibodies, anti-IL5 monoclonal antibodies, and anti-IL5 receptor monoclonal antibodies. There are also anti-IL4 receptor monoclonal antibodies, and other drugs such as macrolides.
  • the Global Guidelines for the Prevention and Treatment of Asthma recommends the combination of inhaled glucocorticoids and long-acting ⁇ -agonists as the first choice of drugs.
  • these two drugs can affect blood pressure.
  • Most antiasthmatic drugs can affect blood pressure.
  • the sympathomimetic amines, epinephrine, ephedrine, isoproterenol, etc. which are not highly selective for ⁇ 1, ⁇ 1, and ⁇ 2 receptors, have a greater impact on blood pressure and the heart, and should be avoided in patients with asthma and hypertension.
  • Drugs for the treatment of hypertension can induce or aggravate acute attacks of asthma. There is a certain risk in using diuretics to lower blood pressure.
  • the technical problem to be solved by the present invention is to provide a xanthine derivative and a preparation method and application thereof.
  • the provided xanthine derivative has the effect of lowering blood pressure, and can also relax the bronchus and relieve asthma.
  • the present invention provides a xanthine derivative having a structure shown in Formula I or a pharmaceutically acceptable salt thereof:
  • n 1-6.
  • n 1, 2, 3, 4, 5 or 6.
  • the xanthine derivative has the following structure or a pharmaceutically acceptable salt thereof:
  • the present invention provides a method for preparing the above xanthine derivatives, comprising the following steps:
  • n 1-6.
  • reaction route of the above preparation method is as follows:
  • the solvent for the first step reaction is an aprotic solvent, preferably one or more of N,N-dimethylformamide, dimethyl sulfoxide and acetone.
  • the first step reaction temperature is room temperature, and the reaction time is 10 to 20 hours.
  • NaH is used as an acid binding agent in the first step of the reaction.
  • the prepared intermediate is purified, specifically: water is added to the reaction solution, extracted with dichloromethane to obtain an organic phase, and the organic phase is concentrated to obtain a crude product;
  • the crude product is purified by column chromatography.
  • the eluent for the column chromatography is a mixed solvent of ethyl acetate and methyl tert-butyl ether.
  • the intermediate is then deprotected.
  • the present invention has no particular limitation on the deprotection operation, and it can be a general method for removing amino protecting groups in the art.
  • deprotection is performed using a dioxane hydrochloric acid solution.
  • the present invention provides a pharmaceutical composition, comprising the above xanthine derivative and pharmaceutically acceptable excipients.
  • auxiliary materials may be any suitable auxiliary materials known to those skilled in the art.
  • the invention proves through in vitro experiments that the xanthine derivatives have a dilating effect on both intact and deendothelialized blood vessels pre-contracted by PE and have a blood pressure lowering effect, and also have a dilating effect on bronchial smooth muscles pre-contracted by Ach.
  • the present invention provides the use of the above xanthine derivative or the above pharmaceutical composition in the preparation of a drug for vasodilation and/or bronchial relaxation and/or lowering of blood pressure.
  • the present invention also provides the use of the xanthine derivative or the pharmaceutical composition in preparing a drug for preventing, treating or alleviating hypertension and/or asthma.
  • the above xanthine derivatives or the above pharmaceutical composition can also be used in combination with other drugs for treating hypertension and/or asthma.
  • the present invention provides a xanthine derivative which has the effect of lowering blood pressure, and can also relax the bronchus and relieve asthma, thus providing a new solution for treating patients suffering from both hypertension and asthma.
  • Figure 1 is the H NMR spectrum of Compound 1
  • Figure 2 is a graph showing the relaxation effect of Compound 1 on PE pre-contracted endothelial-depleted blood vessels
  • FIG3 is a graph showing Ach-induced vasodilation of mesenteric arteries
  • FIG4 is a graph showing the results of a study on the correlation between the vasodilatory effect of Compound 1 and the Ca 2+ signaling pathway;
  • Figure 5 is a graph showing the effect of intravenous injection of different doses of Compound 1 on the blood pressure of normal rats;
  • Figure 6 is a graph showing the effect of intravenous injection of different doses of Compound 1 on the blood pressure of hypertensive rats;
  • Figure 7 shows the relaxation effect of Compound 1 on bronchial smooth muscle pre-contracted by Ach.
  • This study used an isolated vascular ring experiment to observe the vasodilatory effect of Compound 1 on rat mesenteric arteries and to clarify the vasodilatory effect of Compound 1 on peripheral blood vessels.
  • Compound 1 relaxes intact endothelial cells after PE precontraction
  • PE After binding to the ⁇ -receptor on the cell membrane of vascular smooth muscle cells (VSMC), PE induces the release of calcium from calcium stores through the PLC/IP3 signaling pathway, and promotes the entry of extracellular calcium into cells through voltage-dependent calcium channels (VDCC), receptor-operated calcium channels (ROCC) and store-operated calcium channels (SOCC), thereby increasing the intracellular Ca2 + level and inducing vasoconstriction.
  • VDCC voltage-dependent calcium channels
  • ROCC receptor-operated calcium channels
  • SOCC store-operated calcium channels
  • the calcium-free-recalcification experiment was used to observe the effect of Compound 1 on PE-induced intracellular calcium release under calcium-free conditions, as well as its blocking effect on extracellular calcium influx during recalcification.
  • Compound 1 has a dilating effect on both endothelial-intact and endothelial-depleted vessels pre-contracted by PE.
  • Methods Effect of single intravenous injection of Compound 1 on blood pressure in normal rats.
  • SD rats were randomly divided into 4 groups according to their body weight, namely blank control group, group injected with rapid intravenous injection of Compound 1 5, 10, 20 mg/kg within 2 min, and the effects of intravenous injection of Compound 1 5, 10, 20 mg/kg at different doses on blood pressure were observed.
  • the biofunction experimental system monitored the systolic, diastolic and mean blood pressure, and the blood pressure change rate was calculated.
  • the blood pressure of hypertensive rats decreased in a dose-dependent manner after intravenous injection of different doses of Compound 1.
  • the decrease rate of Compound 1 20 mg/kg group was statistically significant (P ⁇ 0.01), with a decrease rate of 45.2 ⁇ 11.3% in SBP and 48.8 ⁇ 12.2% in DBP.
  • the results are shown in Table 2 and Figure 6.
  • Compound 1 has the effect of lowering blood pressure.
  • This study used an isolated tracheal ring experiment to observe the relaxing effect of Compound 1 on rat bronchial smooth muscle and to clarify the relaxing effect of Compound 1 on bronchial smooth muscle.
  • the main trachea of about 0.5 cm near the lungs was selected to prepare tracheal rings.
  • pins were prepared, and the lungs and trachea were laid flat on a culture dish and fixed with pins. The surface tissue was bluntly peeled off horizontally with dissecting forceps, and the trachea could not be pulled to expose the direction of the trachea.
  • the trachea was carefully separated, and the clamping was gentle. The excess tissue around the artery was carefully removed. The separated trachea was cut from one end to the other, and spirally cut into strips, with one spiral cut for every 2-3 cartilages. The entire spiral strip cut was used as a specimen. The tracheal segment was transferred to a bath containing KH solution for standby use. Connect to BL420S physiological signal acquisition system. Use two homemade triangular hooks to pass through the cartilage on both sides of the tracheal spiral strip, and then connect the two sides to the recording device, one connected to the fixator, and the other connected to the pressure fine-tuning device (to adjust the load tension).
  • the tracheal tension is recorded by the Thaimeng biological signal measurement system.
  • the tracheal ring is immersed in an 8mL constant temperature tissue bath containing KH solution, maintained at 37°C and continuously passed with a mixed gas containing 95% O 2 and 5% CO 2 .
  • Compound 1 relaxes the bronchi in response to Ach preconstriction
  • Compound 1 has a relaxing effect on bronchial smooth muscle pre-contracted by Ach.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

提供了一种黄嘌呤衍生物及其制备方法和应用，其具有降低血压的作用，同时能够舒张支气管，缓解哮喘，为治疗同时患有高血压和哮喘的患者提供了新的方案。所述黄嘌呤衍生物具有式Ⅰ所示结构或其药学上可接受的盐。

Description

一种黄嘌呤衍生物及其制备方法和应用
本申请要求于2023年03月24日提交中国专利局、申请号为202310297282.5、发明名称为“一种黄嘌呤衍生物及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及医药技术领域，尤其涉及一种黄嘌呤衍生物及其制备方法和应用。
背景技术
2012年我国18岁及以上人口的高血压患病率为25.20％，2015年上升至27.90％。根据2012-2015年的年均复合增长率，结合国家疾控中心发布的关于高血压的人口年增长数量新闻，预测2019年中国高血压患病率达到31.89％，患病人数达到3.58亿人。根据2019年6月由国家呼吸临床研究中心公布的我国成人哮喘流行病学相关研究数据，我国20岁及以上人群哮喘患病率为4.2％，患者人数达4570万，患病率为4.2％。
根据2021年8月世卫组织首次发布的《WHO成人高血压药物治疗指南》，对于需要药物治疗的高血压成人，世卫组织建议使用以下三类降压药中的任何一种作为初始治疗：1.噻嗪类药物(利尿剂)；2.血管紧张素转化酶抑制剂(ACEis，“普利”类)，或血管紧张素受体阻滞剂(ARBs，“沙坦”类)；3.长效二氢吡啶类钙通道阻滞剂(CCBs，“地平”类)。
根据2021年4月全球哮喘防治倡议组织(GINA)更新的2021版全球哮喘管理和预防策略(GINA2021)和我国指南，治疗哮喘的药物可以分为控制药物和缓解药物，以及重度哮喘的附加治疗药物。
其中，控制药物需要每天使用并长时间维持，这些药物主要通过抗炎作用使哮喘维持临床控制，其中包括吸入性糖皮质激素(ICS)、全身性激素、白三烯调节剂、长效β2受体激动剂(LABA)、缓释茶碱、甲磺司特、色甘酸钠等。缓解药物又称急救药物，这些药物在有症状时按需使用，通过迅速解除支气管痉挛从而缓解哮喘症状，包括速效吸入和短效口服β2受体激动剂、吸入性抗胆碱能药物、短效茶碱和全身性激素等。重度哮喘的附加治疗药物主要为生物靶向药物，如抗IgE单克隆抗体、抗IL5单克隆抗体、抗IL5受体单克隆抗 体和抗IL4受体单克隆抗体等，其他还有大环内酯类药物等。
全球哮喘防治指南(GINA)推荐以吸入型糖皮质激素和长效β受体激动剂联合治疗作为首选药物。但是这两种药物会影响血压。大多数平喘药物可影响血压，例如拟交感胺类药物中肾上腺素、麻黄碱、异丙肾上腺素等对α1、β1、β2受体选择性不强的药物对血压和心脏的影响较大，应避免用于哮喘伴高血压的患者。治疗高血压的药物可诱发或加重哮喘的急性发作，应用利尿剂来降低血压有一定的风险，它能引起痰液粘稠，可能导致哮喘患者黏液栓塞小气道而使哮喘症状加重。同时患有这两种疾病时在用药选择方面就存在着矛盾现象。因此，临床急需一种既能降低血压，又能缓解哮喘的药物。
发明内容
有鉴于此，本发明要解决的技术问题在于提供一种黄嘌呤衍生物及其制备方法和应用，提供的黄嘌呤衍生物具有降低血压的作用，同时能够舒张支气管，缓解哮喘。
为实现上述目的，本发明提供了一种黄嘌呤衍生物，具有式Ⅰ所示结构或其药学上可接受的盐：
其中，n＝1-6。
可选的，所述n为1、2、3、4、5或6。
可选的，所述黄嘌呤衍生物具有以下结构或其药学上可接受的盐：
本发明提供了上述黄嘌呤衍生物的制备方法，包括以下步骤：
式a化合物和式b化合物进行反应，脱保护得到式Ⅰ所示化合物；
其中，n＝1-6。
在本发明的一些实施例中，以n为3为例，上述制备方法的反应路线如下：

可选的，第一步反应的溶剂为非质子溶剂，优选N,N-二甲基甲酰胺、二甲亚砜和丙酮中的一种或多种。
可选的，第一步反应的温度为室温，反应的时间为10～20h。
可选的，第一步反应以NaH作为缚酸剂。
可选的，所述反应结束后，对制备的中间体进行纯化操作，具体的：向反应液中加入水，采用二氯甲烷萃取得到有机相，有机相浓缩得到粗品；
可选的，通过柱层析对上述粗品进行纯化。
可选的，所述柱层析的洗脱剂为乙酸乙酯和甲基叔丁基醚的混合溶剂。
然后对中间体进行脱保护。本发明对所述脱保护的操作并无特殊限定，可以为本领域一般脱除氨基保护基团的方法。
可选的，所述脱保护的溶剂为二氧六环、三氟乙酸(TFA)或三氟乙酸-二氯甲烷的混合溶液；所述三氟乙酸-二氯甲烷的混合溶液优选为50％TFA(TFA:CH2Cl2＝1:1,v/v)。
可选的，采用二氧六环盐酸溶液进行脱保护。
本发明提供了一种药物组合物，包括上述黄嘌呤衍生物和药学上可接受的辅料。
本发明对上述辅料的种类并无特殊限定，可以为本领域技术人员熟知的适用辅料。
本发明通过体外试验证明上述黄嘌呤衍生物对PE预收缩的内皮完整和去内皮血管均具有舒张作用，并具有降低血压的作用，同时对Ach预收缩的支气管平滑肌具有舒张作用。
基于此，本发明提供了上述黄嘌呤衍生物或上述药物组合物在制备用于血管和/或支气管舒张和/或降低血压的药物中的应用。
本发明还提供了上述黄嘌呤衍生物或上述药物组合物在制备用于预防、治疗或减轻高血压和/或哮喘疾病的药物中的应用。
上述黄嘌呤衍生物或上述药物组合物还可以和其他的治疗高血压和/或哮喘的药物联用。
与现有技术相比，本发明提供了一种黄嘌呤衍生物，其具有降低血压的作用，同时能够舒张支气管，缓解哮喘，为治疗同时患有高血压和哮喘的患者提供了新的方案。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图获得其他的附图。
图1为Compound 1的核磁氢谱图；
图2为Compound 1在PE预收缩去内皮血管的舒张效应图；
图3为Ach诱导的肠系膜动脉血管舒张曲线图；
图4为Compound 1血管舒张作用与Ca2+信号通路相关性研究结果图；
图5为静脉推注不同剂量Compound 1对正常大鼠血压的影响曲线图；
图6为静脉推注不同剂量Compound 1对高血压大鼠血压的影响曲线图；
图7为Compound 1在Ach预收缩支气管平滑肌的舒张效应结果图。
具体实施方式
为了进一步说明本发明，下面结合实施例对本发明提供的黄嘌呤衍生物及其制备方法和应用进行详细描述。
实施例1
第一步：
操作步骤
1.向1000mL三口瓶中加入DMF(500mL)，开启搅拌；
2.控制温度0-10℃，缓慢加入NaH(27.6g)；
3.控制温度0-10℃，缓慢加入黄嘌呤(21g)；
4.升至室温搅拌1小时；
5.缓慢加入N-Boc-溴丙胺(115g)；
6.室温搅拌过夜停止；
后处理：
7.将反应液加入到1000mL的冰水中用1000mL的二氯甲烷萃取两次(1000mL*2)；
8.有机相用500mL的饱和食盐水洗两次(500mL*2)；
9.有机相浓缩干；
10.将浓缩剩余用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲基叔丁基醚＝1/1)；
11.将含有产品的组分浓缩至干；
12.得到2.7g无色油状物。
第二步：
操作步骤：
1.向装有CG659A油状物的瓶中，加入二氧六环，搅拌溶解；
2.控制温度10±5℃，慢慢滴加二氧六环盐酸溶液；
3.控制温度20±5℃，搅拌16h；
4.析出固体产品；
后处理:
5.氮气保护下抽滤，滤饼用二氧六环(25mL*2)洗涤；
6.将上述滤饼加入甲叔醚(150mL)，室温搅拌1h；
7.氮气保护下抽滤，滤饼用甲叔醚(25mL)洗涤。
产物(Compound 1)核磁图谱如图1所示。
实施例2
对大鼠肠系膜动脉血管舒张作用研究
(1)Compound 1对大鼠肠系膜动脉血管舒张作用研究
目的：本试验通过离体血管环实验，观察Compound 1对大鼠肠系膜动脉血管的舒张作用，明确Compound 1对外周血管的舒张效应。
方法：正常雄性SD大鼠，麻醉后立即取出肠系膜动脉，4℃K-H液中分离、制作约2mm长度的血管环，转移至浴槽，连接BL420S生理信号采集系统。调节基础值至0.6g左右，平衡大约1h。用高钾K-H液试血管活性2次，两次加液后的血管收缩幅度差异大约在10％以内，提示该血管稳定性符合实验要求。同时考察苯肾上腺素(Phenylephrine，PE)预收缩肠系膜动脉的舒张作用和PE+Ca2+收缩肠系膜动脉的舒张作用，记录血管舒张后的张力。依据公式计算血管舒张率。
实验结果：
Compound 1在PE预收缩完整内皮血管的舒张作用
内皮完整血管以PE预收缩达到平台期后，以累积给药法向浴槽内加入不同容积的Compound 1储存液，使其终浓度从1×10-13～1×10-6mol/L，观察Compound 1的舒张效应。对照组以等体积注射用水代替Compound 1。在PE预收缩血管，Compound 1(1×10-13～1×10-6mol/L)的舒张率为27％～90％。将舒张率与Compound  1绘图，并将点拟合到Hill方程，得到其最大舒张效应Emax是88.1±3.6％，EC50＝3.40×10-10mol/L(图2，n＝6，mean±SEM)。阳性对照药ACh浓度从1×10-13～1×10-6mol/L对PE预收缩的大鼠肠系膜动脉血管环有不同程度的舒张作用)，其最大舒张效应Emax是83.9±3.5％，EC50＝1.39×10-8mol/L(图3，n＝6，mean±SEM)。结果提示：在PE预收缩的内皮完整血管，Compound1能剂量依赖性引起血管舒张。
(2)Compound 1的无钙-复钙实验
PE在结合血管平滑肌细胞(vascular smooth muscle cell，VSMC)细胞膜α-受体后通过PLC/IP3信号通路诱导钙库内钙释放，并促进细胞外钙通过电压依赖性钙通道(voltage dependent calciumchannel，VDCC)、受体操纵性钙通道(receptor operated calciumchannel，ROCC)及钙池操纵性钙通道(store operated calcium channel，SOCC)进入细胞，升高细胞内Ca2+水平从而诱导血管收缩。
利用无钙-复钙实验，观察无钙条件下Compound1对PE诱导的细胞内钙释放的影响，以及复钙过程中它对细胞外钙内流的阻断作用。将去内皮血管在无钙K-H溶液稳定30min后，加入注射用水或Compound 1(0.01、0.1、1、10、100或300μM)孵育10min，再加入PE观察血管张力的改变。当血管收缩达平台期后立即向无钙K-H溶液中加入梯度浓度的CaCl2直到收缩达到最大张力。可观察到细胞外[Ca2+]([Ca2+]out)从0、0.1、0.3、1、3增加到10mM时，动脉环以剂量依赖的方式进一步收缩。
为了观察Compound 1对Ca2+引起的去内皮血管进一步收缩的舒张效应，在PE预收缩血管前10min将Compound 1(0.01、0.1、1、10、100或300μM)加入腔室内。结果表明，Compound1在0.01～300μmol/L浓度范围内剂量依赖性抑制Ca2+诱导的去内皮血管收缩，随着Compound1浓度增加，血管舒张百分比逐渐增加。当Compound 1浓度为100～300μmol/L时，舒张率接近100％，结果见图4(n＝6，mean±SEM)。结果显示Compound1预处理使无钙条件下PE诱导的最大张力明显降低，并且明显抑制复钙后的最大张力，提示Compound 1对PE诱导的胞内钙释放和胞外钙内流均有抑制作用。
实验结论：
Compound 1对PE预收缩的内皮完整和去内皮血管均具有舒张作用。
实施例3
单次静脉注射Compound 1对SD大鼠血压的影响
目的：本实验采用SD大鼠(正常大鼠及高血压模型大鼠)分别单次静脉推注不同剂量Compound 1，观察给药后血压的变化，为Compound 1的探索提供参考。
方法：单次静脉注射Compound 1对正常大鼠血压影响方法：SD大鼠按体重随机分为4组，即空白对照组、2min内静脉快速推注Compound 1 5、10、20mg/kg组，观察静脉推注Compound 1 5、10、20mg/kg不同剂量对血压的影响，生物机能实验系统监测收缩、舒张及平均血压，计算血压变化率。
单次静脉注射Compound 1对高血压大鼠血压影响方法：动物适应性饲养1周，行两肾一夹型(左侧肾动脉狭窄，右侧肾保留)，常规饲养3天-5天，测定血压，以与空白对照组相比，动脉压出现显著性升高为模型成功标准，将 模型成功动物随机分为：模型对照组(Vehicle)、Compound 1 5、10、20mg/kg剂量组。模型对照组静脉推注给予等体积的生理盐水，观察静脉推注Compound 15、10、20mg/kg不同剂量对高血压大鼠血压的影响，生物机能实验系统监测收缩、舒张及平均血压，计算血压变化率。
结果：
(1)单次静脉注射Compound 1对正常大鼠血压影响
为了确证Compound 1体内的降压作用，采用静脉推注不同剂量的Compound 1，正常大鼠血压呈现剂量依赖性下降。与Control组比较，Compound 1的10mg/kg、20mg/kg剂量组下降率有统计学差异(P＜0.05，P＜0.01)。20mg/kg剂量组SBP下降率47.4±12.6％，DBP下降率51.8±16.2％，结果见表1、图5。
表1静脉推注不同剂量Compound 1对正常大鼠血压下降率的影响

注：与Control比较**P＜0.01
(2)单次静脉注射Compound 1对高血压模型大鼠血压影响
采用静脉推注不同剂量的Compound 1，高血压大鼠血压呈现剂量依赖性下降。与vehicle组比较，Compound 1 20mg/kg剂量组下降率有统计学差异(P＜0.01)，SBP下降率45.2±11.3％，DBP下降率48.8±12.2％，结果见表2、图6。
表2静脉推注不同剂量Compound 1对高血压大鼠血压下降率的影响

注：与Control比较**P＜0.01
实验结论：
Compound 1对具有降低血压的作用。
实施例4
Compound 1对大鼠支气管平滑肌舒张作用探讨
目的：本试验通过离体气管环实验，观察Compound 1对大鼠支气管平滑肌的舒张作用，明确Compound 1对支气管平滑肌的舒张效应。
方法：实验中选取靠近肺部的0.5cm左右的主气管制备气管环。正常雄性SD大鼠，体重在300-350g之间，水合氯醛腹腔注射麻醉，剪开胸腔，快速的分离出从咽喉部位往下至肺器官的气管，浸入预冷的K-H液(充以95％O2和5％CO2混和气体，pH＝7.4)中，准备大头针若干，将肺和气管平铺于培养皿，用大头针固定，解剖镊水平钝性剥离表面组织，不能撤拉气管，暴露气管走向，解剖显微镜、显微手术器械辅助，仔细分离气管，夹取轻柔，小心剔除动脉周围多余组织，将分离好的气管由一端剪向另一端，螺旋形剪成条状，每2-3个软骨剪一个螺旋。将剪成的整个螺旋条作为一个标本。将气管段转移至盛有K-H液的浴槽中备用。连接BL420S生理信号采集系统。将气管螺旋条两边分别用两个自制的三角形挂钩穿过软骨上，再将两边分别连于描记装置，一个连接固定器，另一个连接压力微调装置(调节负荷张力)，气管张力被泰盟生物信号测定系统记录。气管环浸润在含有K-H液的8mL恒温组织浴槽中，维持在37℃并持续通入含95％ O2和5％CO2的混合气体。
37℃平衡大约1h后，调节基础值至3.5g，平衡过程中每15min换K-H液一次，气管预收缩保持，待气管张力不自行掉落或掉落较慢时，浴槽中加入乙酰胆碱(Ach)，等气管收缩到最大时，加入受试物，记录气管舒张后的张力。
结果：
Compound 1在Ach预收缩支气管的舒张作用
气管以Ach预收缩达到平台期后，向浴槽内加入Compound 1储存液，观察Compound 1的舒张效应。对照组以等体积注射用水代替Compound 1。在Ach预收缩气管，Compound 1的舒张率为25％～86％。将舒张率与Compound 1绘图，并将点拟合到Hill方程，得到其最大舒张效应Emax是86.0±2.6％，
EC50＝6.63×10-8mol/L(图7，n＝6，mean±SEM)。
实验结论：
Compound 1对Ach预收缩的支气管平滑肌具有舒张作用。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (10)

  1. 一种黄嘌呤衍生物，具有式Ⅰ所示结构或其药学上可接受的盐：
    其中，n＝1-6。
  2. 根据权利要求1所述的黄嘌呤衍生物，其特征在于，具有以下结构或其药学上可接受的盐：
  3. 一种黄嘌呤衍生物的制备方法，包括以下步骤：
    式a化合物和式b化合物进行反应，脱保护得到式Ⅰ所示化合物；
    其中，n＝1-6。
  4. 根据权利要求3所述的制备方法，其特征在于，所述反应的溶剂为N,N-二甲基甲酰胺、二甲亚砜和丙酮中的一种或多种；
    所述脱保护的溶剂为二氧六环、三氟乙酸或三氟乙酸-二氯甲烷的混合溶液。
  5. 根据权利要求3所述的制备方法，其特征在于，所述反应的温度为室温，所述反应的时间为10～20h。
  6. 根据权利要求3所述的制备方法，其特征在于，所述反应结束后，反应液中加入水，采用二氯甲烷萃取得到有机相，有机相浓缩得到粗品；
    通过柱层析对上述粗品进行纯化。
  7. 根据权利要求6所述的制备方法，其特征在于，所述柱层析的洗脱剂为乙酸乙酯和甲基叔丁基醚的混合溶剂。
  8. 一种药物组合物，包括权利要求1～2任一项所述的黄嘌呤衍生物和药学上可接受的辅料。
  9. 权利要求1～2任一项所述的黄嘌呤衍生物或权利要求8所述的药物组合物在制备用于血管和/或支气管舒张和/或降低血压的药物中的应用。
  10. 权利要求1～2任一项所述的黄嘌呤衍生物或权利要求8所述的药物组合物在制备用于预防、治疗或减轻高血压和/或哮喘疾病的药物中的应用。
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