Lisinopril hydrate | 83915-83-7

• 物质功能分类: 原料药 - 循环系统用药 - 抗高血压病药
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: Lisinopril hydrate
• 英文别名: (2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-phenylpropyl]amino]hexanoyl]pyrrolidine-2-carboxylic acid;hydrate
• CAS: 83915-83-7
• 化学式: C21H33N3O6
• 分子量: 423.5
• InChiKey: BAVDEDVBIHTHJQ-UVJOBNTFSA-N

物化性质

• 熔点：
  148 °C
• 比旋光度：
  25405 -120° (c = 1 in 0.25M pH 6.4 zinc acetate); 25436 -96° (c = 1 in 0.25M pH 6.4 zinc acetate)
• 溶解度：
  H2O: ≥10 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  0.41
• 重原子数：
  30
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  134
• 氢给体数：
  5
• 氢受体数：
  8

ADMET

毒理性

• 肝毒性

Lisinopril, like other ACE inhibitors, has been associated with a low rate of serum aminotransferase elevations (

Lisinopril, like other ACE inhibitors, has been associated with a low rate of serum aminotransferase elevations (

来源:LiverTox

安全信息

• 危险等级：
  IRRITANT
• 危险品标志：
  Xn,Xi
• 安全说明：
  S22,S24/25
• 危险类别码：
  R20/21/22
• WGK Germany：
  3
• 海关编码：
  2933990090
• 危险性防范说明：
  P201,P202,P260,P280,P308+P313,P405,P501
• 危险性描述：
  H361,H373

制备方法与用途

根据提供的信息，赖诺普利主要通过两种方法合成：

方法一：

1. 原料准备：化合物(I)由DCC、三乙胺和脯氨酸苄酯在二氯甲烷中反应得到。
2. 还原处理：将化合物(Ⅱ)溶于乙醇，在钯-炭催化剂作用下进行氢化，得到化合物(Ⅲ)。
3. 缩合反应：化合物(Ⅲ)与2-氧-4-苯基丁酸在水溶液中进行缩合反应，通过Dowex柱分离出目标产物赖诺普利粗品。
4. 光学异构体分离：对粗品采用XAD-2聚苯乙烯树脂填充柱进行分离或结晶方法分离。

方法二：

1. 原料处理：通过苯丙醛的转化得到2-羟基-4-苯基丁酸，然后拆分获得D构型的该化合物。
2. 保护与取代：对该D构型的化合物进行甲磺酰化，并进一步用L型赖氨酸衍生物对其取代，形成新的酯键。
3. 氢化脱保护：通过氢化反应除去所有的保护基团，得到最终产物赖诺普利。

关键步骤：

• 氢化的还原处理：将中间体进行氢化以去除某些保护基。
• 光学异构体的分离：利用XAD-2聚苯乙烯树脂填充柱或其他方法分离出所需的光学纯度较高的化合物。
• 通过拆分与选择性反应控制产物的手性。

这两种方法分别从不同的起始原料出发，最终都得到了具有相同结构的目标分子——赖诺普利。每一步的化学反应原理清晰明了，有助于理解赖诺普利合成过程中的关键点和技术细节。

文献信息

• [EN] HYDANTOIN DERIVATIVE<br/>[FR] DÉRIVÉ D'HYDANTOÏNE
  申请人：ONO PHARMACEUTICAL CO

  公开号：WO2021043245A1

  公开（公告）日：2021-03-11

  A compound represented by general formula (I-a) : has a strong DDR1 inhibitory activity, and can be a therapeutic agent for DDR1-related diseases, for example, a cancer, a kidney disease, a cardiovascular disease, a central nervous system disease, or fibrosis.

  一种由一般化学式（I-a）表示的化合物具有强大的DDR1抑制活性，可作为DDR1相关疾病的治疗药物，例如癌症、肾脏疾病、心血管疾病、中枢神经系统疾病或纤维化病。
• PERCUTANEOUS ABSORPTION ENHANCER AND TRANSDERMAL PREPARATION USING THE SAME
  申请人：TOA Eiyo Ltd.

  公开号：EP2298352A1

  公开（公告）日：2011-03-23

  Provided are a percutaneous absorption enhancer excellent in an enhancing effect on percutaneous absorption of a wide range of drugs and excellent in compatibility with an adhesive base, and a transdermal preparation using the percutaneous absorption enhancer. The percutaneous absorption enhancer includes a sulfosuccinate or a salt thereof and an alkyl glycoside or an alkyl thioglycoside.

  本发明提供了一种经皮吸收促进剂，它对多种药物的经皮吸收具有极佳的促进作用，并且与粘合剂基质具有极佳的相容性，还提供了一种使用该经皮吸收促进剂的透皮制剂。经皮吸收促进剂包括磺基琥珀酸酯或其盐和烷基糖苷或烷基硫代糖苷。
• SELF-EMULSIFYING COMPOSITION OF 3 FATTY ACID
  申请人：Mochida Pharmaceutical Co., Ltd.

  公开号：EP2433630A1

  公开（公告）日：2012-03-28

  This invention provides a self-emulsifying composition comprising 50 to 95% by weight in total of at least one compound selected from the group consisting of ω3 polyunsaturated fatty acids and their pharmaceutically acceptable salts and esters; and 5 to 50% by weight of an emulsifier having a hydrophilic lipophilic balance of at least 10. The composition has no or reduced ethanol content, and exhibits excellent self-emulsifying property, dispersibility in the composition, emulsion stability, and absorption property. The composition is adapted for use as a drug.

  本发明提供了一种自乳化组合物，该组合物包含至少一种选自ω3 多不饱和脂肪酸及其药学上可接受的盐类和酯类的化合物，其总重量占 50%至 95%；以及一种乳化剂，其亲水亲油平衡至少为 10，其重量占 5%至 50%。该组合物不含乙醇或乙醇含量较低，具有优异的自乳化性、在组合物中的分散性、乳液稳定性和吸收性。该组合物可用作药物。
• DISINTEGRATING PARTICLE COMPOSITION AND ORALLY RAPIDLY DISINTEGRATING TABLET
  申请人：FUJI CHEMICAL INDUSTRY CO., LTD.

  公开号：EP2465539A1

  公开（公告）日：2012-06-20

  There has been a need for an orally rapidly disintegrating tablet which has a good texture and taste in the oral cavity, such a sufficient hardness as not giving any worry of being chipped or dusted during production or transportation and good disintegrating properties in the oral cavity and can sustain a sufficient hardness even under humid conditions after opening. Disclosed are a disintegrating particle composition which is prepared by dispersing, in the presence of water, mannitol, xylitol, an inorganic excipient, a disintegrating agent and carmellose and drying, and an orally rapidly disintegrating tablet which comprises said disintegrating particle composition, an active substance and a disintegrating agent. The disintegrating tablet has a good texture and taste, an appropriate hardness and good disintegrating properties and can sustain a sufficient hardness under humid conditions.

  人们需要一种口服快速崩解片剂，这种片剂在口腔中具有良好的质地和口感，有足够的硬度，不会担心在生产或运输过程中碎裂或沾上灰尘，在口腔中具有良好的崩解性能，即使在开封后潮湿的条件下也能保持足够的硬度。本发明公开了一种崩解颗粒组合物，其制备方法是在有水存在的情况下，将甘露醇、木糖醇、无机赋形剂、崩解剂和卡麦芽糖分散并干燥；还公开了一种口服快速崩解片剂，其包括所述崩解颗粒组合物、活性物质和崩解剂。该崩解片具有良好的质地和口感、适当的硬度和良好的崩解性能，并能在潮湿条件下保持足够的硬度。
• COMBINATION OF SGLT2 INHIBITOR AND ANTI-HYPERTENSION DRUG
  申请人：Taisho Pharmaceutical Co., Ltd.

  公开号：EP2891499A1

  公开（公告）日：2015-07-08

  Medicaments that depend on a combination of SGLT 2 inhibitors and antihypertensive drugs and which are useful in the treatment of diseases involving at least hypertension or diabetes mellitus as a risk factor of cardiovascular events, as well as methods of treating the diseases are provided. Since the present invention exhibits a superior hypotensive action that cannot be attained by any single antihypertensive drugs, the conventional problems associated with the use of two or more antihypertensive drugs in order to lower the blood pressure to the desired level can be solved. In addition, the present invention shows a marked therapeutic efficacy in diabetes mellitus, a disease associated with diabetes mellitus, or complications of diabetes mellitus, in particular, diabetic nephropathy. As a further advantage, the present invention is also useful for the treatment of diseases involving lowered renal function.

  本发明提供了依赖于 SGLT 2 抑制剂和降压药组合的药物，这些药物可用于治疗至少涉及高血压或作为心血管事件危险因素的糖尿病的疾病，以及治疗这些疾病的方法。由于本发明具有任何单一降压药都无法达到的卓越降压作用，因此可以解决为将血压降至所需水平而使用两种或两种以上降压药的传统问题。此外，本发明对糖尿病、糖尿病相关疾病或糖尿病并发症，特别是糖尿病肾病具有明显的治疗效果。本发明的另一个优点是还可用于治疗肾功能减退的疾病。