硝酸异山梨酯 | 87-33-2

• 物质功能分类: 原料药 - 循环系统用药 - 防治心绞痛药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 呋喃类
• 中文名称: 硝酸异山梨酯
• 中文别名: 异山梨醇硝酸酯；1,4:3,6-二脱水-D-山梨醇二硝酸酯；硝酸异山梨醇酯；硝异山梨酯；消心痛
• 英文名称: isosorbide dinitrate
• 英文别名: isosorbide-dinitrate；[(3S,3aS,6R,6aS)-3-nitrooxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] nitrate
• CAS: 87-33-2
• 化学式: C₆H₈N₂O₈
• mdl: MFCD00868238
• 分子量: 236.138
• InChiKey: MOYKHGMNXAOIAT-JGWLITMVSA-N

物化性质

• 熔点：
  700C
• 比旋光度：
  D20 +135° (alc)
• 沸点：
  378.59°C (rough estimate)
• 密度：
  1.7503 (rough estimate)
• 溶解度：
  未稀释的硝酸异山梨酯极微溶于水，极易溶于丙酮，微溶于乙醇（96%）。溶解度取决于稀释剂及其浓度。
• LogP：
  1.31 at 25℃
• 物理描述：
  Solid
• 颜色/状态：
  Hard, colorless crystals
• 气味：
  ODORLESS
• 水溶性：
  -2.63
• 稳定性/保质期：
  Isosorbide dinitrate tablets should be stored in tight, light-resistant containers at room temperature (25 °C) and should not be exposed to extremes in temperature.
• 旋光度：
  Specific optical rotation: +135 deg @ 20 °C/D (alcohol, 1%)
• 碰撞截面：
  151.6 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  129
• 氢给体数：
  0
• 氢受体数：
  8

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

静脉或口服给药后，血浆中的主要代谢物是5-单硝酸异山梨酯。

After intravenous or oral admin, primary metabolite in plasma is 5-isosorbide mononitrate.

来源:Hazardous Substances Data Bank (HSDB)

代谢

isosorbide dinitrate 在人体内的主要代谢途径也是通过酶促脱硝，随后形成葡萄糖醛酸苷。

Major route of metabolism of isosorbide dinitrate in man is also by enzymatic denitration followed by formation of glucuronides.

来源:Hazardous Substances Data Bank (HSDB)

代谢

有机硝酸盐的生物转化是有机硝酸盐经过肝脏酶谷胱甘肽-有机硝酸盐还原酶催化的还原性水解的结果。这种酶将脂溶性的有机硝酸盐酯转化为更亲水性的脱硝代谢物和无机亚硝酸盐。

Biotransformation of organic nitrates is result of reductive hydrolysis catalyzed by hepatic enzyme glutathione-organic nitrate reductase. Enzyme converts lipid-soluble organic nitrate esters into more water-soluble denitrated metabolites & inorganic nitrite. /organic nitrates/

来源:Hazardous Substances Data Bank (HSDB)

代谢

...硝酸异山梨酯在狗和人体内的生物转化导致去酯化。异山梨酯是主要的尿液代谢物，伴随有极少量的2-和5-单硝酸盐。狗和人体尿液中未检测到硝酸异山梨酯。

...Biotransformation of isosorbide dinitrate in dogs and in man caused de-esterification. Isosorbide is major urinary metabolite, together with very small amount of the 2- and 5-mononitrates. /isosorbide dinitrate/ was absent from urine of dogs & man.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别：硝酸异山梨酯是一种血管扩张剂，抗心绞痛药物。硝酸异山梨酯是一种精细的白色至象牙白色的无味结晶固体。它在水中的溶解度很小；在丙酮、氯仿、酒精和醚中易溶。适应症：硝酸异山梨酯主要用于治疗缺血性心脏病患者。它减少了心绞痛发作的次数、持续时间和严重程度。运动耐量增加，对硝酸甘油的需用量减少。它对所有形式的心绞痛（稳定劳累性心绞痛、混合性心绞痛、不稳定心绞痛和血管痉挛性或变异性心绞痛）都有效。它用于急性心肌梗塞，以控制缺血性疼痛、降低高血压，并治疗肺水肿和充血性心力衰竭。它也用于治疗严重高血压。静脉输液可用于精确控制血压。在需要精确控制血压的全身麻醉期间，它用于控制血压。它也可用于食管痉挛。人类暴露：主要风险和靶器官：硝酸异山梨酯过量的主要风险是血管扩张和低血压（及其伴随的并发症）。心脏和血管是靶器官。可能会发生高铁血红蛋白血症。临床效果概述：暴露后几分钟到一小时或更长时间内可能出现中毒特征。可能出现心动过速、低血压随后出现心动过缓和晕厥、搏动性头痛、头晕、不安、晕厥、惊厥和昏迷。其他可能出现的特征包括呕吐、腹泻、发绀和高铁血红蛋白血症。严重病例可能出现呼吸衰竭。临床诊断基于暴露史和观察到的体征和症状：心动过速、低血压、搏动性头痛、面部潮红。禁忌症：对硝酸异山梨酯过敏。预先存在的高铁血红蛋白血症。严重贫血、头部创伤或脑出血。进入途径：口服：口服进入和通过胃肠道的吸收是最常见的中毒途径。可以通过舌下吸收。皮肤：关于硝酸异山梨酯乳膏的经验的初步报告可用。parenteral：接受静脉注射硝酸异山梨酯的患者可能会发生中毒。暴露途径的吸收：口服：硝酸异山梨酯易于从口腔黏膜吸收，作用时间短。口服给药后，它从胃肠道良好吸收。由于其首过效应和血浆半衰期短，有缓释制剂。舌下给药在6分钟内产生药物在血浆中的最大浓度。皮肤：硝酸异山梨酯也可以从乳膏基质的皮肤吸收。硝酸异山梨酯的口服或舌下给药的生物利用度约为29%。暴露途径的分布：无数据可用。生物半衰期：硝酸异山梨酯的终末消除半衰期分别为静脉注射后54.7分钟、舌下给药后48.8分钟和口服给药后47.7分钟。代谢：硝酸异山梨酯在人中的主要代谢途径是通过酶促脱硝化随后形成葡萄糖苷酸。主要的初始代谢物，异山梨醇-2-单硝酸酯和异山梨醇-5-单硝酸酯具有更长的半衰期（2-5小时），被认为是硝酸异山梨酯治疗功效的部分原因。由于“首过”效应，大量药物可以被代谢。暴露途径的消除：大部分以异山梨醇葡萄糖苷酸的形式从尿液中排出。作用方式：毒动力学：硝酸异山梨酯几乎对所有血管床的血管平滑肌具有扩张作用。硝酸盐扩张静脉、动脉，并且在高浓度时扩张小动脉。治疗剂量下的有益效果和过量时看到的效果归因于系统静脉和小动脉血管扩张的生理后果。心脏前负荷、系统血压和系统血管阻力都显示出逐渐下降。可能会导致低血压、循环衰竭和休克的状态。在中毒或治疗期间可能会发生高铁血红蛋白血症。药效学：有机硝酸盐可以激活鸟苷酸环化酶，增加平滑肌和其他组织中鸟苷酸3', 5' - 单磷酸（环状GMP）的合成。反应性自由基一氧化氮（NO）形成，与鸟苷酸环化酶相互作用并激活它。相互作用：与其他心血管药物可能会发生几种重要的相互作用。在接受硝酸异山梨酯和肼屈嗪治疗慢性心力衰竭的患者中观察到严重的姿势性低血压。在使用舌下硝酸盐和β-肾上腺素受体阻滞剂时，可能会出现过度的头晕和晕厥。在静脉输注利多卡因的患者使用舌下硝酸盐后，已报告完全房室传导阻滞。甚至可能发生心脏停搏。异丙吡胺、三环类抗抑郁药和其他具有抗胆碱能作用的药物可能会阻止舌下硝酸异山梨酯片的溶解，导致口干。硝酸异山梨酯可以拮抗乙酰胆碱、肾上腺素和组胺的作用。与酒精一起使用时，可能会看到增强的降压效果。主要不良影响：硝酸盐的毒性作用不受化学形式或给药途径的影响，所有硝酸盐都具有共同的不良反应特征。可能出现低血压、反射性

IDENTIFICATION: Isosorbide dinitrate is a vasodilator, anti-anginal drug. Isosorbide dinitrate is a fine white to ivory-white odorless crystalline solid. It is sparingly soluble in water; freely soluble in acetone, chloroform, alcohol and ether. Indications: Isosorbide dinitrate is used principally in the management of patients with ischemic heart disease. It reduces the number, duration and severity of episodes of angina pectoris. Exercise tolerance is increased and the requirements for nitroglycerin are reduced. It is effective in all forms of angina, (stable effort angina, mixed angina, unstable angina and vasospastic or variant angina). It is used in acute myocardial infarction in control of ischemic pain, reduction of elevated blood pressure and in the treatment of pulmonary edema and congestive cardiac failure. It is also useful in the treatment of severe hypertension. The iv infusion can be used for precise control of blood pressure. It is used to control blood pressure during general anaesthesia when precise control of blood pressure is important. It may also be used in oesophageal spasm. HUMAN EXPOSURE: Main risks and target organs: Vasodilatation and hypotension (with their accompanying complications) are the main risks with overdose of isosorbide dinitrate. Heart and blood vessels are the target organs. Methemoglobinemia can occur. Summary of clinical effects: Features of poisoning may appear within few minutes to one hour or more after exposure. Tachycardia, hypotension followed by bradycardia and collapse, throbbing headache, dizziness, restlessness, syncope, convulsions and coma could occur. Some of the other features that can be seen include vomiting, diarrhea, cyanosis and methemoglobinemia. Respiratory failure may occur in severe cases. Clinical diagnosis is based on the history of exposure, and signs and symptoms observed: tachycardia, hypotension, throbbing headache, flushing of the face. Contraindications: Hypersensitivity to isosorbide dinitrate. Pre-existing methemoglobinemia. Marked anaemia, head trauma or cerebral hemorrhage. Routes of entry: Oral: Oral entry and absorption through gastro-intestinal tract is the most frequent route of intoxication. Absorption can occur sublingually. Dermal: A preliminary report of experience with isosorbide dinitrate cream is available. Parenteral: Intoxication may occur in patients treated with intravenous isosorbide dinitrate. Absorption by route of exposure: Oral: Isosorbide dinitrate is readily absorbed from the oral mucosa and has a short duration of action. Following oral administration it is well absorbed from the gastrointestinal tract. In view of its first pass effect and short plasma half life, slow release formulations are available. Sublingual administration produces maximal concentration of the drug in plasma within 6 minutes. Dermal: Isosorbide dinitrate is also absorbed through the skin from an ointment base. The bioavailability of isosorbide dinitrate is about 29% following oral or sublingual dosing. Distribution by route of exposure: No data available. Biological half-life by route of exposure: The terminal elimination half-life of isosorbide dinitrate is 54.7 minutes, 48.8 minutes and 47.7 minutes respectively following IV injection, sublingual and oral administration. Metabolism: The major route of metabolism of isosorbide dinitrate in man is by enzymatic denitration followed by formation of glucuronides. The primary initial metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate have longer half-lives (2-5 hours) and are presumed to be responsible, at least in part, for the therapeutic efficacy of isosorbide dinitrate. A substantial amount of drug can be metabolized due to the "first pass" effect. Elimination by route of exposure: Largely excreted in urine as isosorbide glucuronide. Mode of action: Toxicodynamics: Isosorbide dinitrate has dilator properties on vascular smooth muscle in virtually all vascular beds. Nitrates dilate veins, arteries, and, in high concentrations, arterioles. The beneficial effects in therapeutic doses and the effects seen with overdose are attributable to the physiologic consequences of systemic venous and arteriolar vasodilation. Cardiac preload, systemic blood pressure and systemic vascular resistance all show a progressive decrease. A state of hypotension, circulatory collapse and shock may result. Methemoglobinemia may occur following overdose of isosorbide dinitrate or during therapy. Pharmacodynamics: Organic nitrates can activate guanylate cyclase and increase the synthesis of guanosine 3', 5' - monophosphate (cyclic GMP) in smooth muscle and other tissues. The reactive free radical nitric oxide (NO) is formed which interacts with and activates guanylate cyclase. Interactions: Several important interactions may occur with other cardiovascular drugs. Severe postural hypotension has been observed in patients given isosorbide dinitrate and hydralazine for chronic cardiac failure.Undue dizziness and faintness may occur with sublingual nitrates and beta-adrenoceptor blocking drugs. Complete AV block has been reported after use of sublingual nitrates in patients receiving lignocaine by infusion. Even cardiac asystole may occur. Disopyramide, tricyclic antidepressants and other drugs with anticholinergic effects may prevent dissolution of sublingual isosorbide dinitrate tablets by causing dry mouth. The effects of acetylcholine, epinephrine and histamine can be antagonized by isosorbide dinitrate. An enhanced hypotensive effect may be seen with alcohol. Main adverse effects: The toxic effects of the nitrates are unaffected by the chemical form or by the route of administration and all the nitrates have a common profile of adverse effects. Hypotension, reflex tachycardia and palpitations may occur. Postural hypotension and syncope are seen, especially in elderly patients. Rarely severe bradycardia has been reported. Throbbing headache is quite common. This symptom is likely to recede as tolerance develops. Peripheral oedema is also frequently seen. Transient hypoxaemia with precipitation of angina is seen occasionally. Transient cerebral ischaemic episodes unrelated to changes in blood pressure are rarely seen. It is therefore advisable to initiate treatment with small doses in patients with cerebrovascular disease. Methaemoglobinaemia may be seen after therapeutic doses. Weakness, transient dizziness, restlessness and collapse may occur. Cutaneous flushing, perspiration and exfoliative dermatitis have all been reported. Nausea and vomiting are not frequent. Although tolerance has long been associated with nitrates, its clinical implications are not clear. Tolerance is best defined as a decreasing pharmacological effect over time, often with a need for an increasing dose to achieve a given action. Tolerance may be partial or complete and may occur with one type of nitrate therapy and not with others; disappearance of the throbbing headache is a useful sign. However, due to an attenuation of the antihypertensive effect, these agents are not useful in the long term management of hypertension. The part played by the arterial and venous sides of the circulation pertaining to the development of tolerance is not clear. By providing a long (approximately 8 hours) nitrate-free interval, the development of tolerance may be avoided or reduced. Decreasing the number of daily doses of isosorbide dinitrate also helps to achieve this effect. Sustained release preparations are more likely to produce tolerance than the short acting preparations.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 药物性肝损伤

硝酸异山梨酯

Compound:isosorbide dinitrate

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：无匹配

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后，异山梨酯二硝酸盐的吸收几乎完全，但生物利用度差异很大（10%至90%），肝脏首过代谢广泛。异山梨酯二硝酸盐的平均生物利用度约为25%。

Absorption of isosorbide dinitrate after oral dosing is nearly complete, but bioavailability is highly variable (10% to 90%), with extensive first-pass metabolism in the liver. The average bioavailability of isosorbide dinitrate is about 25%.

来源:DrugBank

吸收、分配和排泄

• 分布容积

2到4升/千克

2 to 4 L/kg

来源:DrugBank

吸收、分配和排泄

舌下给药后，起效时间为2-3分钟，药效消失大约需要2小时。

After sublingual admin, onset of effect is 2-3 min & offset of effect is about 2 hr.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

舌下给药5毫克、口服普通片5毫克和口服缓释片20毫克后，平均峰浓度分别为8.9、3.1和1.4纳克/毫升，分别在30、40和40分钟达到。在缓释剂量给药后...血浆水平...在10小时内保持在平均峰浓度的一半以上。

Following sublingual doses of 5 mg, oral conventional tablets of 5 mg, and oral sustained-release tablets of 20 mg, mean peak isosorbide dinitrate levels of 8.9, 3.1, and 1.4 ng/ml, occurred at 30, 40, and 40 min respectively. Plasma levels...after sustained-release dosage...maintained above half of mean peak level for 10 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

长期口服给予硝酸异山梨酯（每日120至720毫克）导致母体化合物在血浆中持续存在，并且代谢物浓度更高。

Chronic oral administration of isosorbide dinitrate (120 to 720 mg daily) has resulted in persistence of parent compound and higher concentration of metabolite in plasma.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  4.1
• 危险品标志：
  Xn
• 安全说明：
  S36
• 危险类别码：
  R5,R22
• 海关编码：
  3004909090
• 危险品运输编号：
  UN 2907
• 危险类别：
  1.1A
• 包装等级：
  II
• WGK Germany：
  3

制备方法与用途

简介

硝酸异山梨酯于1946年在瑞典上市，商品名为Harrical。美国50年代也独立合成了该药物，并将其命名为Isordil。从此，硝酸异山梨酯在全球范围内广泛应用。该药又名消心痛、硝酸脱水山梨醇酯等。

作用机制

硝酸异山梨酯抗心绞痛的作用机制较为复杂，主要包括以下几个方面：（1）降低心肌耗氧量。通过扩张静脉血管增加静脉容量，减少回心血量，从而减小心室容积和心肌壁张力；同时舒张动脉血管，降低左心室后负荷，达到降低心肌耗氧量的目的。（2）改善心肌血流分布，有利于缺血区的灌注。选择性扩张大冠状动脉输送血管，增加缺血区域的血液供应；减少左心室充盈压，提高心内膜供血，改善左心室顺应性；还可刺激生成侧枝血管，开放已有侧枝，增加营养血流灌注缺血区。（3）在动脉粥样硬化或急性缺血时，内皮细胞不能释放NO和PGI，却加速血小板聚集及血管内皮细胞释放收缩物质。外源性硝酸异山梨酯可补充内源性NO的不足，并促进PGI的释放。此外，硝酸异山梨酯还具有显著的抗血小板聚集和抗血栓形成作用。

适应症

本品主要用于冠心病长期治疗及预防血管痉挛型和混合型心绞痛，也适用于心肌梗死后的治疗以及慢性心衰的长期治疗。

药代动力学

硝酸异山梨酯口服后吸收完全，但肝脏首过效应较为显著，被代谢成2-单硝异山梨酯和5-单硝异山梨酯。血浆半衰期为30～60分钟，由于显著的首过效应和短的半衰期，硝酸异山梨酯更适合制成缓释制剂。硝酸异山梨酯缓释制剂的吸收相显著延长，达峰时间推后，峰值浓度较低，血浆中硝酸异山梨酯及其代谢物的浓度随时间变化平缓，其血液动力学效应表现较为平稳。该药可克服普通制剂的“突释”引起的病人不适，并能减少用药次数，提高患者的顺应性。

制备

山梨醇溶液经脱水环合、与硝酸酯化而得。具体步骤如下：在装有搅拌器和温度计的反应瓶中加入发烟硝酸50克、浓硫酸7.5克，冷却至10℃下滴加由脱水山梨醇10克固体与1毫升水微热溶解得到的液体，保持反应液温度在10～15℃。加完后保温反应2小时。搅拌下将反应物倒入等体积冰水中，充分搅拌析晶。抽滤，用水洗涤至中性，干燥得粗品。将粗品加入1.5倍量95%乙醇加热溶解，活性炭脱色回流30分钟。趁热抽滤，冷至10℃以下，抽滤析出的结晶，用乙醇洗涤，低温干燥，得到硝酸异山梨酯，收率70%。

不良反应

较硝酸甘油轻。常见有头痛、恶心等不适症状。

用途

该品为速效、长效硝酸酯类抗心绞痛药物，作用与硝酸甘油相同，主要用于预防和缓解心绞痛发作。它也是一种冠状动脉扩张剂，用于治疗心绞痛。

生产方法

山梨醇溶液经脱水环合、与硝酸酯化而得。

类别

易燃固体

毒性分级

中毒

急性毒性

口服-大鼠 LD50: 747 毫克/公斤；口服-小鼠 LD50: 1050 毫克/公斤

刺激数据

皮肤-兔 500 毫克/24小时 轻度

可燃性危险特性

遇热, 火焰可燃; 热分解排出有毒氮氧化物烟雾

储运特性

库房低温通风干燥；防火；与氧化剂分开存放

灭火剂

水、二氧化碳、泡沫、干粉

反应信息

• 作为反应物：
  描述：

  硝酸异山梨酯 在 ferrous sulfate 、 水 作用下， 以 甲醇 为溶剂， 以69.65%的产率得到2-硝酸异山梨酯(STORE BELOW +4 DEGR C)
  参考文献：
  名称：

  发现“真正的”阿司匹林前药。

  摘要：

  通过苯甲酸酯基团的衍生形成的阿司匹林前药非常难以获得，因为该肽原促进了邻近乙酰基团上血浆酯酶的水解速度，从而产生了水杨酸衍生物。通过追踪人血浆溶液中阿司匹林前药异山梨醇-2,5-二氢阿司匹林酸酯（ISDA）的水解模式，我们能够鉴定出代谢物异山梨醇-2-aspirinate-5-salicylate，该代谢物几乎完全转化为阿司匹林人血浆丁酰胆碱酯酶，使其成为迄今为止发现的最成功的阿司匹林前药。

  DOI：

  10.1021/jm801094c
• 作为产物：
  描述：

  异山梨醇 在 硝酸 、 乙酸酐 作用下， 以 溶剂黄146 为溶剂， 反应 2.0h， 以92%的产率得到硝酸异山梨酯
  参考文献：
  名称：

  Highly Chemoselective Reduction of 2,5-Dinitro-1,4:3,6-dianhydro-D-glucitol with Titanium(III) Tetrahydroborates: Efficient Synthesis of Isomerically Pure 2- and 5-Nitro-1,4:3,6-dianhydro-D-glucitols

  摘要：

  研究发现，2,5-二硝基-1,4:3,6-二氢-D-葡萄糖醇（1）被四氢硼酸钛（III）（2）（-78 → 0°C）还原后，只能得到 2-硝基-1,4:3,6-二氢-D-葡萄糖醇（3）。另一方面，用二异丙氧基钛（III）四氢硼酸酯（4）（-78 → 0°C）还原二硝酸酯 1，得到的唯一产物是 5-硝基-1,4:3,6-二氢-D-葡萄糖醇（5）。

  DOI：

  10.1055/s-1994-25631
• 作为试剂：
  描述：

  香草酸甲酯 在 正丁基锂 、 硝酸异山梨酯 作用下， 以 四氢呋喃 为溶剂， 生成
  参考文献：
  名称：

  立体选择性合成高度取代和氧化的顺式十氢化萘

  摘要：

  从市售邻苯二酚衍生物和各种亲双烯体中高效，立体控制的四步制备高度取代和氧化的顺式十氢化萘。

  DOI：

  10.1016/s0040-4039(97)10711-0

文献信息

• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
  申请人：BLUM Andreas

  公开号：US20140135309A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I wherein Ar, R 1 and R 2 are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及公式I的新型磺酰胺取代的喹唑啉衍生物，其中Ar、R1和R2如本文所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2014072244A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的配方(I)的磺酰胺取代喹唑啉衍生物，其中Ar、R1和R2如描述和声明中所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] QUINONE BASED NITRIC OXIDE DONATING COMPOUNDS<br/>[FR] COMPOSÉS DONNEURS D'OXYDE NITRIQUE À BASE DE QUINONE
  申请人：NICOX SA

  公开号：WO2013060673A1

  公开（公告）日：2013-05-02

  The present invention relates to nitric oxide donor compounds having a quinone based structure, to processes for their preparation and to their use in the treatment of pathological conditions where a deficit of NO plays an important role in their pathogenesis.

  本发明涉及具有喹诚基结构的一氧化氮供体化合物，涉及其制备方法以及它们在治疗病理状况中的应用，其中一氧化氮缺乏在它们的发病机制中起重要作用。
• [EN] SULFOXIMINE SUBSTITUTED PYRROLOTRIAZINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] PYRROLOTRIAZINES À SUBSTITUTION SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2015091156A1

  公开（公告）日：2015-06-25

  This invention relates to novel sulfoximine substituted pyrrolotriazine derivatives of formula wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1 a or MNK1 b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1 a or MNK1 b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的噻氧亚胺取代吡咯三嗪衍生物，其化学式中Ar、R1和R2的定义如描述和权利要求中所定义，并且它们作为MNK1（MNK1 a或MNK1 b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1 a或MNK1 b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。