利莫那班 | 168273-06-1

• 物质功能分类: 生物化工 - 抑制剂 - G蛋白偶联受体(GPCR & G Protein)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: 利莫那班
• 中文别名: 5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-N-(1-哌啶基)-1H-吡唑-3-甲酰胺；利莫纳班
• 英文名称: rimonabant
• 英文别名: SR141716A；SR 141716；5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide；N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide；5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide；N-piperidino-5-(4-chlorophenyl)-1(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide；[3H]SR141716A；5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-piperidin-1-ylpyrazole-3-carboxamide
• CAS: 168273-06-1
• 化学式: C₂₂H₂₁Cl₃N₄O
• mdl: MFCD04034714
• 分子量: 463.794
• InChiKey: JZCPYUJPEARBJL-UHFFFAOYSA-N

物化性质

• 熔点：
  154.7 °C
• 密度：
  1.41±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（高达20mg/ml）或乙醇（高达20mg/ml）。
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.272
• 拓扑面积：
  50.2
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

肝脏的，涉及CYP3A4。

Hepatic, CYP3A4 involved.

来源:DrugBank

毒理性

• 蛋白质结合

几乎100%

Almost 100%

来源:DrugBank

吸收、分配和排泄

• 吸收

未确定

Undetermined

来源:DrugBank

安全信息

• 海关编码：
  2942000000
• 储存条件：
  2～8℃

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Rimonabant
Synonyms:

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Section 2. Hazards identification
Harmful by inhalation, in contact with skin, and if swallowed.

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Section 3. Composition/information on ingredients.
Ingredient name: Rimonabant
CAS number: 168273-06-1

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Section 4. First aid measures
Skin contact: Immediately wash skin with copious amounts of water for at least 15 minutes while removing
contaminated clothing and shoes. If irritation persists, seek medical attention.
Eye contact: Immediately wash skin with copious amounts of water for at least 15 minutes. Assure adequate
flushing of the eyes by separating the eyelids with fingers. If irritation persists, seek medical
attention.
Inhalation: Remove to fresh air. In severe cases or if symptoms persist, seek medical attention.
Ingestion: Wash out mouth with copious amounts of water for at least 15 minutes. Seek medical attention.

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Section 5. Fire fighting measures
In the event of a fire involving this material, alone or in combination with other materials, use dry
powder or carbon dioxide extinguishers. Protective clothing and self-contained breathing apparatus
should be worn.

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Section 6. Accidental release measures
Personal precautions: Wear suitable personal protective equipment which performs satisfactorily and meets local/state/national
standards.
Respiratory precaution: Wear approved mask/respirator
Hand precaution: Wear suitable gloves/gauntlets
Skin protection: Wear suitable protective clothing
Eye protection: Wear suitable eye protection
Methods for cleaning up: Mix with sand or similar inert absorbent material, sweep up and keep in a tightly closed container
for disposal. See section 12.
Environmental precautions: Do not allow material to enter drains or water courses.

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Section 7. Handling and storage
Handling: This product should be handled only by, or under the close supervision of, those properly qualified
in the handling and use of potentially hazardous chemicals, who should take into account the fire,
health and chemical hazard data given on this sheet.
Store in closed vessels.
Storage:

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Section 8. Exposure Controls / Personal protection
Engineering Controls: Use only in a chemical fume hood.
Personal protective equipment: Wear laboratory clothing, chemical-resistant gloves and safety goggles.
General hydiene measures: Wash thoroughly after handling. Wash contaminated clothing before reuse.

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Section 9. Physical and chemical properties
Appearance: Not specified
Boiling point: No data
No data
Melting point:
Flash point: No data
Density: No data
Molecular formula: C22H21Cl3N4O
Molecular weight: 463.8

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Section 10. Stability and reactivity
Conditions to avoid: Heat, flames and sparks.
Materials to avoid: Oxidizing agents.
Possible hazardous combustion products: Carbon monoxide, nitrogen oxides, hydrogen chloride.

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Section 11. Toxicological information
No data.

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Section 12. Ecological information
No data.

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Section 13. Disposal consideration
Arrange disposal as special waste, by licensed disposal company, in consultation with local waste
disposal authority, in accordance with national and regional regulations.

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Section 14. Transportation information
Non-harzardous for air and ground transportation.

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Section 15. Regulatory information
No chemicals in this material are subject to the reporting requirements of SARA Title III, Section
302, or have known CAS numbers that exceed the threshold reporting levels established by SARA
Title III, Section 313.

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

利莫那班简介

利莫那班(Rimonabant Hydrochloride)是一种大麻素受体1(CB1)拈抗剂，通过阻断脑组织中的CB1受体来降低人的食欲和烟瘾。它可以用于肥胖、烟瘾、高血压、血脂异常和2型糖尿病及代谢综合症的治疗，并具有预防肥胖人群患上心脏病和糖尿病的功效，已于2006年在多个国家上市。

利莫那班不仅能够有效改善肥胖症伴发的高血糖、胰岛素抵抗以及脂代谢紊乱，还能显著降低体重、缩小腰围，减少心血管疾病等危险因素。不过其作用机制尚需进一步研究明确。

物理性质

• 性状：白色粉末
• 熔点：230℃～240℃
• 干燥失重：≤0.5%
• PH值（10%水溶液）：4-7
• 重金属含量：≤10ppm
• TLC检测：只有一个斑点
• 含量：≥99.5%

药理作用

利莫那班作为特异性CB1拮抗剂，通过作用于中枢和外周CB1受体两条途径实现其减肥效应。在药物治疗初期，体重减轻源于药物对中枢部位CB1受体的拮抗作用，产生明显的食欲抑制、摄食减少。随后机体对药物产生耐受性，食欲抑制效应减弱甚至消失。长时间的体重减轻效应来源于药物的外周作用机制：利莫那班通过作用于胃肠道、脂肪细胞、骨骼肌和肝脏上的CB1受体调节体内能量代谢，从而减轻体重。

应用

• 适应症：新型减肥药、戒烟、降血脂、医药原料
• 用途：利莫那班是一种大麻素受体(CB1)拈抗剂，通过阻断脑组织中的CB1受体来降低人的食欲和烟瘾。可用于肥胖、烟瘾、高血压、血脂异常和2型糖尿病及代谢综合症的治疗，并具有预防肥胖人群患上心脏病和糖尿病的功效。

不良反应

尽管利莫那班治疗减肥的效果显著，但近年来的研究表明其不良反应不容忽视。在RIO-Europe研究中，服用5mg和20mg剂量利莫那班的人比安慰剂对照组更频繁地出现恶心呕吐（分别为5.1%、12.9% 和4.3%）、腹泻（6.0%、7.2%和3.0%）、头晕（7.0%、8.7%和4.9%）及精神错乱（2.3%、3.7%和3.0%）。这些现象同样出现在RIO-Lipids的研究中。综合四项随机对照研究的分析表明，利莫那班可增加精神方面的严重不良反应，即抑郁和焦虑。

结论

作为一种新型减肥药，利莫那班不仅能够减重，还能降血压、胆固醇和血糖。国内进行的一年多临床研究表明，受试者服用一到两个月后体重平均减轻六到八公斤。尽管存在一定的副作用，但其显著的经济效益和社会价值使其具有广阔的市场前景。

反应信息

• 作为反应物：
  描述：

  利莫那班 在 盐酸 作用下， 以 甲醇 、 甲丁醚 为溶剂， 反应 2.0h， 生成 盐酸利莫那班
  参考文献：
  名称：

  Preparation of crystalline polymorphs of rimonabant hydrochloride

  摘要：

  该发明涉及晶体盐酸里莫那班的三种新溶剂结晶形式（A、B和C）和两种新的无水盐酸里莫那班的结晶多形式（D和E），以及制备这些多形式或溶剂结晶形式的过程，含有它们的药物组合物以及在医学上使用它们的用途。

  公开号：

  US20080004313A1
• 作为产物：
  描述：

  5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-羧酸乙酯 在 氯化亚砜 、 N,N-二异丙基乙胺 、 potassium hydroxide 作用下， 以 乙醇 、 氯仿 、 甲苯 为溶剂， 反应 18.5h， 生成 利莫那班
  参考文献：
  名称：

  Synthesis, hypoglycemic activity and molecular modeling studies of pyrazole-3-carbohydrazides designed by a CoMFA model

  摘要：

  Diabetes and obesity are two universal health problems that constitute a research objective of several groups due to the lack of efficient and safe drug treatment. In this sense, cannabinoid receptor 1 (CBI) has attracted interest because of its role in food intake and metabolic balance, two targets in the control of metabolic syndrome. In this work, novel 1,5-diaryl pyrazole derivatives were synthesized in accordance with the pKi prediction of a previously reported CoMFA model by our group. To further investigate the biological activity of these compounds in metabolic disorders, their hypoglycemic activity in an in vivo model was tested. Interestingly, a high degree of correlation was observed between the predicted pK(i) and hypoglycemic effect 7 h after administration. Compounds 4, 9 and 13 showed the most significant plasma glucose reduction with decreases of 60%, 64% and 60% respectively. This result not only surpasses the activity of the lead rimonabant, but also that of the reference drug glibenclamide. Moreover, PASS prediction and molecular docking in an excellent validated homology model of CBI suggest that these compounds would probably act as CBI antagonists/inverse agonists and therefore, antiobesity agents. The ligand receptor complexes demonstrate that 1,5-diaryl pyrazole derivatives bind to the proposed binding site where a hydrophobic moiety interacts with the phenyl rings in the pyrazole nucleus and Lys192 forms a hydrogen bond with the oxygen of the carbonyl group. Dynamics simulations were also carried out to study the stability of the ligand receptor complexes where the most active compounds showed smaller Delta G values and more hydrogen bonds throughout the simulation. These compounds are considered useful leads for further optimization in the treatment of such metabolic illnesses. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.07.054

文献信息

• NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
  申请人：Ryono Denis E.

  公开号：US20080009465A1

  公开（公告）日：2008-01-10

  Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R 4 is —(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 ), —(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g , —(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g , —(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10 ), or —(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10 ); R 5 and R 6 are independently selected from H, alkyl and halogen; Y is R 7 (CH 2 ) s or is absent; and X, n, Z, m, R 4 , R 5 , R 6 , R 7 , and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.

  提供了磷酸酯和磷酸酯激活剂，因此在治疗糖尿病和相关疾病方面非常有用，并具有以下结构： 其中 是杂环芳基环； R 4 为—(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 )、—(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g 、—(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g 、—(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10) 或—(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10) ； R 5 和R 6 分别选择自H、烷基和卤素； Y为R 7 (CH 2 ) s 或不存在；以及 X、n、Z、m、R 4 、R 5 、R 6 、R 7 和s如本文所定义；或其药用盐。 还提供了一种利用上述化合物治疗糖尿病和相关疾病的方法。
• [EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016089721A1

  公开（公告）日：2016-06-09

  The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及甲基噁唑化合物，其为促进睡眠的受体拮抗剂。本发明还涉及所述化合物在潜在治疗或预防涉及促进睡眠的神经和精神疾病和疾病中的用途。本发明还涉及包含这些化合物的组合物。本发明还涉及这些组合物在潜在预防或治疗涉及促进睡眠的疾病中的用途。
• Dibenzyl Amine Compounds and Derivatives
  申请人：Chang George

  公开号：US20070213371A1

  公开（公告）日：2007-09-13

  Dibenzyl amine compounds and derivatives, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.

  二苯基胺化合物及其衍生物，含有这种化合物的药物组合物以及使用这种化合物提高某些血浆脂质水平，包括高密度脂蛋白胆固醇，并降低其他一些血浆脂质水平，如低密度脂蛋白胆固醇和甘油三酯，并据此治疗由高密度脂蛋白胆固醇水平低和/或低密度脂蛋白胆固醇和甘油三酯水平高加重的疾病，如动脉粥样硬化和心血管疾病在某些哺乳动物，包括人类。
• [EN] FTO INHIBITORS<br/>[FR] INHIBITEURS DE FTO
  申请人：NAT INST OF BIOLOGICAL SCIENCES BEIJING

  公开号：WO2016206573A1

  公开（公告）日：2016-12-29

  The invention provides compounds that inhibit FTO (fat mass and obesity), including pharmaceutically acceptable salts, hydrides and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof, particularly obesity, with an effective amount of the compound or composition, and detecting a resultant improvement in the person's health or condition.

  这项发明提供了抑制FTO（脂肪质量和肥胖）的化合物，包括药用可接受的盐、氢化物和立体异构体。这些化合物用于制备药物组合物，以及制备和使用的方法，包括使用有效量的化合物或组合物治疗有需要的人，特别是肥胖症，并检测人的健康或状况的改善。
• [EN] PLANT STEROIDS AND USES THEREOF<br/>[FR] STÉROÏDES VÉGÉTAUX ET LEURS UTILISATIONS
  申请人：DAVIDSON LOPEZ LLC

  公开号：WO2013040441A1

  公开（公告）日：2013-03-21

  The invention relates to a drug conjugate including a drug and a plant steroid. The drug conjugate may target the drug for intestinal cell delivery, and thus may be used to treat diseases, including intestinal diseases, or to affect intestinal metabolism. The invention therefore also relates to treating intestinal diseases and affecting intestinal metabolism with the drug conjugate.

  这项发明涉及一种药物结合物，包括药物和植物类固醇。该药物结合物可以将药物定位到肠细胞传递，因此可用于治疗疾病，包括肠道疾病，或影响肠道代谢。因此，该发明还涉及使用药物结合物治疗肠道疾病和影响肠道代谢。