(S)-马来酸噻吗洛尔 | 60469-65-0

• 物质功能分类: 生物化工 - 抑制剂 - 神经信号通路(Neuronal Signaling)
• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: (S)-马来酸噻吗洛尔
• 中文别名: 马来酸噻吗洛尔；奥沙拉秦钠；马来酸噻吗心安；(S)-3-[3-(叔丁基氨基)-2-羟基丙氧基]-4-吗啉基-1,2,5-噻二唑马来酸盐
• 英文名称: timolol maleate
• 英文别名: (S)-timolol maleate；timolol maleate salt；timoptic；(S)-1-[(1,1-dimethylethyl)amino]-3-[[4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy]-2-propanol (Z)-2-butenedioate；Temserin；tert-butyl-[(2S)-2-hydroxy-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]propyl]azanium;(Z)-4-hydroxy-4-oxobut-2-enoate
• CAS: 60469-65-0；26921-17-5
• 化学式: C₄H₄O₄*C₁₃H₂₄N₄O₃S
• 分子量: 432.498
• InChiKey: WLRMANUAADYWEA-NWASOUNVSA-N

物化性质

• 熔点：
  202-203 °C(lit.)
• 比旋光度：
  24405 -12.0° (c = 5 in 1N HCl); D25 -4.2°
• 溶解度：
  可溶于水中
• 碰撞截面：
  174.6 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)：
  0.21
• 重原子数：
  29
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  183
• 氢给体数：
  4
• 氢受体数：
  12

ADMET

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：由于噻吗洛尔进入母乳的排泄量变化较大，且在哺乳期间报告的经验有限，因此在哺乳新生儿或早产儿时，可能更倾向于使用其他药物。 母亲使用噻吗洛尔眼药水对哺乳婴儿的风险很小，尽管一些指南指出，凝胶制剂比溶液更受欢迎。为了显著减少使用眼药水后进入母乳的药物量，可以在眼角处对泪管施加压力1分钟或更长时间，然后用吸收性纸巾去除多余的溶液。 对哺乳婴儿的影响：没有报告，但是具有类似母乳排泄特性的β-肾上腺素能阻断药在哺乳新生儿中引起了不良反应。 在一例报告中，一位母亲每天在一眼中使用0.5%噻吗洛尔眼药水两次，她9周大的哺乳婴儿没有报告副作用。 一位母亲在孕期36周时早产，她每天使用2滴0.5%噻吗洛尔眼药水，同时还使用毛果芸香碱眼药水两次，口服乙酰唑胺250毫克两次。婴儿出生6小时后开始进行为期5个月的纯母乳喂养。在第2天，婴儿出现了低钙血症、低镁血症和代谢性酸中毒的电解质异常。婴儿接受了口服葡萄糖酸钙和一次肌内注射硫酸镁的治疗。尽管继续母乳喂养和母亲药物治疗，婴儿在生命第4天轻度代谢性酸中毒消失，并且在1、3和8个月时体重增长正常，但出现了轻度肌张力减退。作者认为代谢效应是由乙酰唑胺的跨胎盘传递引起的，尽管婴儿继续母乳喂养，但这些效应得到了解决。婴儿在母乳喂养期间体重增长适当，但下肢有轻度残余肌张力增高，需要物理治疗。 一名新生儿在母亲接受各种组合的眼用噻吗洛尔、二匹弗林、多佐拉米特、溴莫尼定和多次乙酰唑胺治疗期间进行母乳喂养。最终，母亲使用0.5%噻吗洛尔凝胶形成溶液和2%多佐拉米特滴眼液。药物在哺乳后立即给予，并封堵泪点，婴儿没有出现呼吸暂停或心动过缓。 对哺乳和母乳的影响：截至修订日期，没有找到关于β阻断或噻吗洛尔在正常哺乳期间影响的相关已发表信息。在一项对6名高催乳素血症和乳汁过多患者的研究中，发现使用普萘洛尔进行β-肾上腺素能阻断后，血清催乳素水平没有变化。

◉ Summary of Use during Lactation:Because of the variability in excretion of timolol into breastmilk and minimal reported experience during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant. Ophthalmic use of timolol by the mother should pose little risk to the breastfed infant, although some guidelines state that gel formulations are preferred over solutions. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue. ◉ Effects in Breastfed Infants:None reported, but beta-adrenergic blocking drugs with similar breastmilk excretion characteristics have caused adverse effects in breastfed newborns. No side effects were reported in one case report of a 9-week-old breastfed infant whose mother was using 0.5% ophthalmic timolol drops twice daily in one eye. A mother who was taking 2 drops of timolol 0.5% eye drops daily as well as using pilocarpine eye drops twice daily and acetazolamide 250 mg orally twice daily and delivered a preterm infant at 36 weeks of gestation. The infant began 5 months of exclusive breastfeeding at 6 hours after birth. On day 2, the infant developed electrolyte abnormalities consisting of hypocalcemia, hypomagnesemia, and metabolic acidosis. The infant was treated with oral calcium gluconate and a single dose of intramuscular magnesium sulfate. Despite continued breastfeeding and maternal drug therapy, the infant's mild metabolic acidosis disappeared on day 4 of life and the infant was gaining weight normally at 1, 3 and 8 months, but had mild hypotonicity. The authors considered the metabolic effects to be caused by transplacental passage of acetazolamide that resolved despite the infant being breastfed. The infant gained weight adequately during breastfeeding, but had some mild, residual hypertonicity of the lower limbs requiring physical therapy. A newborn infant was breastfed during maternal therapy with various combinations of ocular timolol, dipivifrin, dorzolamide, brimonidine and several doses of acetazolamide. Ultimately, the mother was treated with timolol gel-forming solution 0.5% and dorzolamide 2% drops. The drugs were given immediately following breastfeeding with punctal occlusion and no apnea or bradycardia was observed in the infant. ◉ Effects on Lactation and Breastmilk:Relevant published information on the effects of beta-blockade or timolol during normal lactation was not found as of the revision date. A study in 6 patients with hyperprolactinemia and galactorrhea found no changes in serum prolactin levels following beta-adrenergic blockade with propranolol.

来源:Drugs and Lactation Database (LactMed)

制备方法与用途

简介

(S)-马来酸噻吗洛尔是一种新的强效β受体阻断药，对β1和β2受体都有阻断作用，其作用强度为普萘洛尔的8倍。它无膜稳定作用，无内源性拟交感活性，也无直接抑制心脏的作用，却有明显的降低眼压效果。临床用于治疗高血压病、心绞痛、心动过速及青光眼。对于轻至中度高血压疗效较好，且无明显不良反应，可以与利尿剂合用。心肌梗死病人长期用药后能显著降低再次梗死发生率和死亡率。对原发性和开角型青光眼具有良好的治疗效果，优于传统的降眼压药物。

生物活性

Timolol Maleate（MK-950）是一种非选择性的β-肾上腺素能受体拮抗剂，作用于β1/β2受体，Ki值分别为1.97 nM和2.0 nM。

靶点

Target	Value
β1-adrenergic receptor	1.97 nM (Ki)
β2-adrenergic receptor	2.0 nM (Ki)

体外研究

Timolol Maleate是一种β-肾上腺素能受体拮抗剂，其作用与普萘洛尔相似。左旋异构体更为有效。Timolol被提议用于治疗高血压、抗心律失常、抗心绞痛和青光眼。类似普萘洛尔和纳多洛尔，它是一种非选择性的β-肾上腺素能受体拮抗剂。在人中庭中，Timolol对β2-肾上腺素的亲和力高于β1-肾上腺素。Timolol没有内源性拟交感活性、直接心脏抑制作用或局部麻醉（膜稳定）活性，但具有较高的脂溶性。外敷眼部时，它能降低眼内压，无论是否伴有青光眼均有效。升高的眼内压是青光眼中视野缺损和视神经损伤发病机理的主要危险因素。像普萘洛尔和纳多洛尔一样，Timolol与肾上腺素能神经递质如儿茶酚胺竞争性结合心脏中的β1肾上腺素能受体以及支气管、血管平滑肌中的β2肾上腺素能受体。阻断β1受体可导致静止和运动心脏速率减少，心输出量降低，心脏收缩和舒张压下降，并可能减弱直立性低血压反射。阻断β2受体会增加外周血管阻力。Timolol通过减少房水分泌来降低眼内压的确切机制尚不完全清楚。

体内研究

研究表明，(R)-异构体的生物活性低于(S)-异构体。具体而言，在动物中，(R)-timolol对β-肾上腺素受体的效力仅为(S)-timolol的1/49；而在正常人的气道收缩方面，其效力仅为后者的1/13。

反应信息

• 作为反应物：
  描述：

  (S)-马来酸噻吗洛尔 在 水 、 sodium hydroxide 作用下， 反应 0.25h， 生成 噻吗洛尔
  参考文献：
  名称：

  [EN] COMPOSITIONS AND METHODS FOR THE TREATMENT OF PAIN AND DEPENDANCE DISORDERS
  [FR] COMPOSITIONS ET MÉTHODES DE TRAITEMENT DE LA DOULEUR ET DE TROUBLES DE LA DÉPENDANCE

  摘要：

  本文提供了用于治疗急性或慢性疾病或障碍的（例如，控释）组合物。本文描述了可加工的阿片类结合物。本文还描述了用于治疗中枢神经系统（CNS）疾病或障碍的组合物和方法，包括慢性疼痛（例如，癌症疼痛）、急性疼痛、阿片类成瘾、酒精成瘾、酒精依赖、阿片类引起的便秘和麻醉性抑郁症。所述组合物和方法包括表现出CNS活性和/或其他理想活性的阿片类激动剂和/或阿片类拮抗剂。将所述组合物皮下或脊髓内注射可为患有中枢神经系统疾病或障碍的个体提供治疗益处。

  公开号：

  WO2021024039A1
• 作为产物：
  描述：

  3-氯-4-吗啉基-1,2,5-噻二唑 在 sodium hydroxide 、 potassium tert-butylate 作用下， 以 四氢呋喃 、 甲醇 、 叔丁醇 为溶剂， 反应 21.0h， 生成 (S)-马来酸噻吗洛尔
  参考文献：
  名称：

  Enantioselective synthesis of (S)-timolol via kinetic resolution of terminal epoxides and dihydroxylation of allylamines

  摘要：

  An efficient enantioselective synthesis of (S)-timolol has been described using chiral Co-salen-catalyzed kinetic resolution of less expensive (+/-)-epichlorohydrin with 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole in good overall yield (55%) and excellent enantioselectivity (98%). Synthesis of (S)-timolol has also been achieved using hydrolytic kinetic resolution as well as asymmetric dihydroxylation routes in 90% ee and 56% ee, respectively. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2007.01.057

文献信息

• 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
  申请人：DeAngelis Alan

  公开号：US20060058393A1

  公开（公告）日：2006-03-16

  The invention features 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs, compositions containing them, and methods of using them as PPAR modulators to treat or inhibit the progression of, for example, dyslipidemia.

  这项发明涉及4-((苯氧烷基)硫基)-苯氧乙酸及其类似物，含有它们的组合物，以及将它们用作PPAR调节剂来治疗或抑制例如脂质代谢异常的进展的方法。
• [EN] TARGETED DRUG DELIVERY THROUGH AFFINITY BASED LINKERS<br/>[FR] ADMINISTRATION CIBLÉE D'UN MÉDICAMENT FAISANT APPEL À DES COUPLEURS FONDÉS SUR L'AFFINITÉ
  申请人：INVICTUS ONCOLOGY PVT LTD

  公开号：WO2015148126A1

  公开（公告）日：2015-10-01

  The current invention discloses targeted drug delivery conjugates comprising a targeting moiety linked to a drug via a molecule having an affinity for the targeting moiety. Typically, the conjugate comprises a targeting ligand and a molecule of interest, e.g., a therapeutic agent. The targeting ligand and the molecule of interest are linked to each other via an affinity ligand. The affinity ligand is further covalently or non-covalently linked to a drug or therapeutic agent. The drug can be modified to make it more soluble and so that it cleaves from the linking molecule at the target site.

  当前的发明揭示了包括通过具有与靶向基团亲和力的分子连接到药物的靶向药物传递共轭物。通常，该共轭物包括一个靶向配体和一个感兴趣的分子，例如，一个治疗剂。靶向配体和感兴趣的分子通过一个亲和配体相互连接。该亲和配体进一步以共价或非共价方式连接到药物或治疗剂。药物可以被修改以使其更溶解，并使其在靶点处从连接分子中解离。
• Novel Bicyclic Pyridinones
  申请人：Pettersson Martin Youngjin

  公开号：US20120252758A1

  公开（公告）日：2012-10-04

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  所述化合物及其药用可接受的盐被披露，其中所述化合物具有如本文所定义的Formula I的结构。相应的药物组合物、治疗方法、合成方法和中间体也被披露。
• THERAPEUTIC CYCLOPENTANOLS, COMPOSITIONS THEREOF, AND METHODS FOR USE THEREOF
  申请人：Allergan, Inc.

  公开号：US20150119454A1

  公开（公告）日：2015-04-30

  Described herein are well-defined cyclopentanols useful for treating glaucoma and ocular hypertension.

  本文描述了用于治疗青光眼和眼压增高的明确定义的环戊醇。
• Novel Compounds for the Treatment of Diseases Associated with Amyloid or Amyloid-Like Proteins
  申请人：Kroth Heiko

  公开号：US20110280808A1

  公开（公告）日：2011-11-17

  The present invention relates to novel compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein, such as Alzheimer's disease, and of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used in the treatment of ocular diseases associated with pathological abnormalities/changes in the tissues of the visual system. The present invention further relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the preparation of medicaments for treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins. A method of treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins is also disclosed.

  本发明涉及一种新型化合物，可用于治疗与淀粉样蛋白相关的一组疾病和异常，如阿尔茨海默病，以及与淀粉样蛋白类似蛋白相关的疾病或病况。本发明的化合物还可用于治疗与视觉系统组织中的病理异常/变化相关的眼部疾病。本发明还涉及包含这些化合物的药物组合物，以及利用这些化合物制备用于治疗或预防与淀粉样和/或淀粉样类似蛋白相关的疾病或病况的药物的用途。还公开了一种治疗或预防与淀粉样和/或淀粉样类似蛋白相关的疾病或病况的方法。