苯磺酸贝托司汀 | 190786-44-8

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 苯磺酸贝托司汀
• 中文别名: 苯磺酸贝他斯汀；苯磺酸贝托斯汀
• 英文名称: Bepotastine besilate
• 英文别名: (S)-bepotastine besilate；betotastine besilate；[14C]-Bepotastine besilate；benzenesulfonic acid;4-[4-[(S)-(4-chlorophenyl)-pyridin-2-ylmethoxy]piperidin-1-yl]butanoic acid
• CAS: 190786-44-8
• 化学式: C₆H₆O₃S*C₂₁H₂₅ClN₂O₃
• 分子量: 547.072
• InChiKey: UDGHXQPQKQPSBB-BOXHHOBZSA-N

物化性质

• 熔点：
  161-163°
• 比旋光度：
  D20 +6.0° (c = 5 in methanol)
• 溶解度：
  可溶于DMSO（略微加热）、甲醇（略微加热）

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  37
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  125
• 氢给体数：
  2
• 氢受体数：
  8

ADMET

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：目前没有报告在母亲使用bepotastine治疗期间母乳喂养的婴儿。由于眼部吸收有限，bepotastine预计不会对母乳喂养的婴儿产生任何不良反应。为了显著减少使用眼药水后药物到达母乳的量，可以在眼角按压泪囊1分钟或更长时间，然后用吸收性纸巾去除多余的溶液。 ◉ 对母乳喂养婴儿的影响：截至修订日期，未找到关于bepotastine的相关已发布信息。在一项电话随访研究中，母亲报告有10%的婴儿在接触各种抗组胺药后出现烦躁和肠绞痛症状，1.6%的婴儿出现嗜睡。所有反应均无需医疗注意，且没有患者使用bepotastine。 ◉ 对泌乳和母乳的影响：在非哺乳期妇女和产后早期妇女中，通过注射给予相对高剂量的抗组胺药可以降低基础血清催乳素。然而，哺乳诱导的催乳素分泌不会受到产后母亲使用抗组胺药预处理的影响。在已建立泌乳的母亲中，催乳素水平可能不会影响她的哺乳能力。低剂量的眼部bepotastine不太可能对血清催乳素有相同的影响。

◉ Summary of Use during Lactation:There are no reports of infants breastfed during maternal therapy with bepotastine. Because absorption from the eye is limited, bepotastine would not be expected to cause any adverse effects in breastfed infants. 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:Relevant published information on bepotastine was not found as of the revision date. In one telephone follow-up study, mothers reported irritability and colicky symptoms in 10% of infants exposed to various antihistamines and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention and none of the patients were using bepotastine. ◉ Effects on Lactation and Breastmilk:Antihistamines in relatively high doses given by injection can decrease basal serum prolactin in nonlactating women and in early postpartum women. However, suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. The prolactin level in a mother with established lactation may not affect her ability to breastfeed. Low ophthalmic doses of bepotastine are unlikely to have the same effect on serum prolactin.

来源:Drugs and Lactation Database (LactMed)

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  存储条件：<0°C，存放于惰性气体中，并避免接触湿气（吸湿性），同时需防热。

制备方法与用途

药理作用

苯磺酸贝托司汀（BB）是一种第二代H1抗组胺药物，作为滴眼液在美国通过FDA批准用于治疗过敏性结膜炎。在其他国家，口服的苯磺酸贝托司汀广泛用于治疗过敏性鼻炎（AR）、荨麻疹和慢性瘙痒症状，并且与其他药物的效果类似。

生物活性

BepoTAstine Besilate（TAU 284）是一种非镇静作用的选择性组胺1 (H1)受体拮抗剂，其pIC50值为5.7。

靶点

TArget	Value
HisTAmine H1 receptor	5.7(pIC50)

体外研究

在LLC-GA5-COL150细胞中，[14C]BepoTAstine (5 μM)的通量显著高于LLC-PK1细胞，表明在LLC-GA5-COL150细胞中的B-到-A通量超过另一个方向。BepoTAstine可刺激P-糖蛋白介导的ATP水解，其Km、Vmax和Vmax/Km分别为1.25 mM、108 nmol/min/mg蛋白质和0.087 mL/min/mg蛋白质。在培养的背根神经节神经元和中性粒细胞中，BepoTAstine besilate (100 μM)抑制Leukotriene B4（LTB4）诱导的Ca2+浓度；100 μM剂量依赖性地抑制LTB4诱导的豚鼠腹膜嗜酸细胞趋药性；1 mM剂量显著减少培养的大鼠腹腔肥大细胞中A23187诱导的组胺释放。

体内研究

对于WT和P-糖蛋白KO小鼠，给予BepoTAstine (0.8 mg/kg)后6分钟血浆中的总浓度分别为580 ng/mL 和467 ng/mL，血浆结合蛋白分别为41.1%和45.9%。Verapamil存在或不存在时，从近端区域的吸收分别占63.0%和72.4%，从远端区域的吸收分别占10.9%和62.7%。

BepoTAstine besilate (10 mg/kg)能抑制组胺皮内注射(100 nmol/site)诱导的瘙痒，但对血清素(100 nmol/site)无效。剂量为1 mg/kg-10 mg/kg（口服）时，BepoTAstine besilate能够剂量依赖性地抑制P物质(100 nmol/site)和白三烯B4 (0.03 nmol/site)诱发的瘙痒。BepoTAstine besilate能剂量依赖性地显著抑制结膜血管通透性的增高，在豚鼠过敏性结膜炎模型中的最大作用为1.5%。口服给予BepoTAstine (3 mg/kg 和10 mg/kg) 1小时后，能够有效抑制BALB/c小鼠体内化合物48/80诱导的瘙痒；在过敏性皮炎NC/Nga小鼠模型中，BepoTAstine (10 mg/kg)同样显著抑制了瘙痒，并降低了血清LTB(4)水平。

用途

苯磺酸贝托司汀是一种强效、长效的组胺H1受体拮抗剂，还具有类似血小板活化因子（PAF）拮抗剂的作用。在人体外周血单核细胞实验中，表明其抗过敏作用可能与白介素-5的介导有关；苯磺酸贝托司汀能够快速而有效地抑制过敏性鼻炎的三个主要症状：打喷嚏、流鼻涕和鼻塞。

反应信息

• 作为反应物：
  描述：

  苯磺酸贝托司汀 在 sodium hydroxide 作用下， 以 水 为溶剂， 反应 120.0h， 以2.64%的产率得到4-(4-hydroxypiperidin-1-yl)butanoic acid
  参考文献：
  名称：

  Characterization of Photodegradation Products of Bepotastine Besilate and In Silico Evaluation of Their Physicochemical, Absorption, Distribution, Metabolism, Excretion and Toxicity Properties

  摘要：

  Bepotastine (BPT) is a H-1-receptor antagonist. It is used as a besilate salt in ophthalmic solution for allergic conjunctivitis and orally for the treatment of allergic rhinitis and urticaria/pruritus. Its systematic forced degradation study is unreported. The same was carried out in different conditions prescribed by International Conference on Harmonisation. The stressed solutions were subjected to reversed phase liquid chromatographic analysis, and BPT was observed to be labile under photobasic condition only, yielding 5 photodegradation products. The structures of the latter were elucidated from data generated by liquid chromatography-high-resolution mass spectrometry and multistage mass spectrometry. Of the 5, 4 products were further isolated and subjected to nuclear magnetic resonance spectroscopy to justify the proposed structures. Two of them, with similar accurate mass, were additionally and unambiguously characterized from their heteronuclear multiple bond correlation data, hydrogen deuterium exchange mass data, and quantum chemical analysis using density functional theory calculations. One degradation product had a structure that could only be explained by unusual rearrangement involving conversions of N-oxide into hydroxylamine, similar to Meisenheimer rearrangement. The physicochemical, as well as absorption, distribution, metabolism, excretion, and toxicity properties of BPT and its characterized photodegradation products were evaluated in silico by ADMET Predictor (TM) software. (C) 2020 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.xphs.2020.03.004
• 作为产物：
  描述：

  在 sodium hydride 、 氯化铵 、 锌 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 193.0h， 生成 苯磺酸贝托司汀
  参考文献：
  名称：

  铱催化的高对映选择性氢转移反应中芳基的ñ -杂芳基酮与Ñ氧化物为可移动的邻-取代

  摘要：

  使用容易获得的手性二胺衍生的铱络合物（S，S）-1f作为催化剂，甲酸钠作为氢源的H 2 O混合物，对非邻位取代的芳基N-杂芳基酮进行高度对映选择性转移氢化/我的i-PrOH（v / v = 1：1）在环境条件下，进行说明。通过引入N-氧化物作为可除去的邻位取代基，获得具有高达98.2％ee的手性芳基N-杂芳基甲醇。相反，在不存在氮的情况下，观察到的ee不超过15.1％-氧化物部分。此外，该协议的实用性还通过克规模的苯磺酸他莫司汀的克级不对称合成以51％的总收率和99.9％的ee进行了证明。

  DOI：

  10.1021/acs.orglett.7b03878

文献信息

• 一种改进的苯磺贝他斯汀的制备方法
  申请人：石家庄格瑞药业有限公司

  公开号：CN105669652B

  公开（公告）日：2018-06-15

  本发明涉及一种改进的苯磺贝他斯汀的制备方法，包括如下步骤：第一步，将2‑[(4‑氯苯基)(4‑哌啶基氧基)甲基]吡啶与拆分剂反应，得到S‑2‑[(4‑氯苯基)(4‑哌啶基氧基)甲基]吡啶N‑乙酰基‑L‑苯丙氨酸盐，第二步，将S‑2‑[(4‑氯苯基)(4‑哌啶基氧基)甲基]吡啶N‑乙酰基‑L‑苯丙氨酸盐加酸萃取得S‑2‑[(4‑氯苯基)(4‑哌啶基氧基)甲基]吡啶，第三步，在乙腈中顺序进行S‑2‑[(4‑氯苯基)(4‑哌啶基氧基)甲基]吡啶与4‑溴代丁酸乙酯偶联反应，水解反应和成盐反应，得到苯磺贝他斯汀。本发明技术方案大大提高收率，缩短工艺时间，所得产品纯度高，安全稳定。
• PROCESS FOR PREPARING BEPOTASTINE AND INTERMEDIATES USED THEREIN
  申请人：Ha Tae Hee

  公开号：US20100168433A1

  公开（公告）日：2010-07-01

  A process for stereospecific preparation of bepotastine of formula (I) and novel intermediates used therein having formulae (II) to (IV) are provided. The inventive process comprises subjecting (RS)-4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine to a reaction with a 4-halobutanoic acid l-menthyl ester, halo being chloro, bromo or iodo, in an organic solvent in the presence of a base to produce (RS)-bepotastine l-menthyl ester of formula (II), conducting a reaction of the compound of formula (II) with N-benzyloxycarbonyl L-aspartic acid in an organic solvent to induce selective precipitation of bepotastine l-menthyl ester.N-benzyloxycarbonyl L-aspartate of formula (III), filtering the precipitates formed in step 2) to isolate the compound of formula (III), treating the compound of formula (III) with a base to liberate bepotastine l-menthyl ester of formula (IV), and hydrolyzing the compound of formula (IV) in the presence of a base. The inventive process can provide bepotastine having a high optical purity of not less than 99.5% in a high yield, and thus, is useful in the development of anti-histamines and anti-allergic agents.

  提供了一种用于立体特异性制备化学式(I)的倍他司汀以及在其中使用的具有化学式(II)至(IV)的新型中间体的方法。这种创新的方法包括将(RS)-4-[(4-氯苯基)(2-吡啶基)甲氧基]哌啶与一种有机溶剂中的碱反应，生成(RS)-倍他司汀l-薄荷酸薄荷酯化合物(II)，然后将化合物(II)与N-苄氧羰基L-天冬氨酸酸在有机溶剂中反应，诱导倍他司汀l-薄荷酸薄荷酯的选择性沉淀。将沉淀物在步骤2)中形成的化合物(III)进行过滤以分离出化合物(III)，然后用碱处理化合物(III)以释放倍他司汀l-薄荷酸薄荷酯化合物(IV)，最后在碱的存在下水解化合物(IV)。这种创新的方法可以提供具有99.5%以上高光学纯度且高收率的倍他司汀，因此在抗组胺药物和抗过敏药物的开发中非常有用。
• Car-Parrinello Molecular Dynamics Study for the Isotope Effect on OH Vibration in Ice Ih
  作者：Yeohoon Yoon

  DOI：10.5012/bkcs.2013.34.2.553

  日期：2013.2.20

  The stretching vibration of OH of ice Ih is studied by Car-Parrinello molecular dynamics in regarding the effect of mixed H/D contamination while the vibrational spectrum is considered by velocity-velocity autocorrelations of the sampled ensemble. When hydrogen atoms are immersed randomly into the deuterated ice, a typical vibrational frequency of OH stretching mode is observed to be similar to that from the pure $H_2O$ ice. When focusing on the correlation of isolated neighboring OH stretching, a narrower and blue shifted peak is observed at the high frequency range as a result of the screening from the complex many body correlations by $D_2O$ environment. It is also specifically related to the symmetric intermolecular correlations between neighboring OH stretching modes. More enhanced high frequency range can be explained by the expansion of such two body correlations to collective many body correlations among all possible OH stretching modes. This contribution becomes important when it involves in chemical interactions via excitation of such vibrational states.

  利用 Car-Parrinello 分子动力学研究了 Ih 冰的 OH 拉伸振动，其中考虑到了 H/D 混合污染的影响，同时通过采样集合的速度-速度自相关性考虑了振动谱。当氢原子随机浸入氚化冰时，观察到 OH 拉伸模式的典型振动频率与纯 $H_2O$ 冰的振动频率相似。当关注孤立邻域 OH 拉伸的相关性时，由于 $D_2O$ 环境屏蔽了复杂的多体相关性，在高频范围观察到一个较窄的蓝移峰值。这也与相邻 OH 拉伸模式之间的对称分子间相关性密切相关。这种两体相关性扩展到所有可能的 OH 拉伸模式之间的集体多体相关性，可以解释更多增强的高频范围。当涉及到通过激发这些振动状态而产生的化学相互作用时，这种贡献就变得非常重要。
• 一种眼科药物苯磺酸贝他斯汀的不对称合成 方法
  申请人：宜昌人福药业有限责任公司

  公开号：CN106938995B

  公开（公告）日：2019-05-28

  本发明涉及眼科药物苯磺酸贝他斯汀不对称的合成方法，具体将(4‑氯苯基)(2‑吡啶基)甲酮氧化得到(4‑氯苯基)(2‑吡啶基)甲酮‑N‑氧化物；用单磺酰手性二胺与金属钌、铑、铱的配合物作催化剂，甲酸钠、或者甲酸与三乙胺的混合物、或者异丙醇为氢源，通过不对称转移氢化还原(4‑氯苯基)(2‑吡啶基)甲酮‑N‑氧化物制备(S)‑(4‑氯苯基)(2‑吡啶基)甲醇‑N‑氧化物；将(S)‑(4‑氯苯基)(2‑吡啶基)甲醇‑N‑氧化物还原制备(S)‑(4‑氯苯基)(2‑吡啶基)甲醇；(S)‑(4‑氯苯基)(2‑吡啶基)甲醇与4‑(4‑溴哌啶‑1‑基)丁酸乙酯缩合得到眼科药物苯磺酸贝他斯汀，总产率61.6%。
• METHOD OF SYNTHESIZING BEPOTASTINE OR BENZENESULFONIC ACID SALT THEREOF AND INTERMEDIATES USED THEREIN
  申请人：EVERLIGHT USA, INC.

  公开号：US20140046068A1

  公开（公告）日：2014-02-13

  The present invention relates to a novel method of synthesizing bepotastine or its benzenesulfonic acid salt and novel intermediates used therein. The present invention uses L-α-hydroxy acid for chiral resolution to form an L-α-hydroxy acid salt of a compound represented by the following formula (VII-1), so as to synthesize bepotastine or its benzenesulfonic acid salt in high optical purity.

  本发明涉及一种合成贝泼替丁或其苯磺酸盐的新方法以及其中使用的新中间体。本发明利用L-α-羟基酸进行手性分离，形成由以下式（VII-1）所代表的化合物的L-α-羟基酸盐，从而在高光学纯度下合成贝泼替丁或其苯磺酸盐。