他米巴罗汀 | 94497-51-5

• 物质功能分类: 生物化工 - 抑制剂 - 代谢(Metabolism)
• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 中文名称: 他米巴罗汀
• 中文别名: 4-[(5,5,8,8-四甲基-6,7-二氢萘-2-基)氨基甲酰]苯甲酸
• 英文名称: Am80
• 英文别名: 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]benzoic acid；tamibarotene；4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)carbamoyl]benzoic acid
• CAS: 94497-51-5
• 化学式: C₂₂H₂₅NO₃
• mdl: MFCD00866188
• 分子量: 351.445
• InChiKey: MUTNCGKQJGXKEM-UHFFFAOYSA-N

物化性质

• 熔点：
  231-232°C
• 沸点：
  449.6±45.0 °C(Predicted)
• 密度：
  1.154±0.06 g/cm3(Predicted)
• 溶解度：
  在DMSO中溶解至50mM
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.363
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

毒理性

• 蛋白质结合

超过99%，主要是血清白蛋白。

Over 99%, predominantly to serum albumin.

来源:DrugBank

安全信息

• WGK Germany：
  3
• 海关编码：
  2924299090
• 危险性防范说明：
  P261,P280,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H332,H335
• 储存条件：
  室温且干燥

SDS

Material Safety Data Sheet

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Section 1. Identification of the substance
Product Name: Tamibarotene
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: Tamibarotene
CAS number: 94497-51-5

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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: C22H25NO3
Molecular weight: 351.4

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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.

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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

他米巴罗汀概述

他米巴罗汀，英文名为tamibarotene，化学名称为4-[(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)氨甲酰基]苯甲酸。商品名Amnolake，是一种维甲酸类化合物，具有独特的作用机制和药理特性。该药物可通过解除PML-RARa融合基因的变异性质，恢复早幼粒细胞性白血病细胞及RARα的正常功能，并对复发性难治性的急性早幼粒细胞白血病有显著分化诱导能力。他米巴罗汀是临床用于治疗的一种化学合成原料药。

作为一种新型维甲酸激动剂，它具有良好的生物活性，可抗光、热、氧化反应从而保持性质稳定。此外，在自身免疫性疾病中，它可以调控免疫细胞，并在蛋白和转录水平上抑制炎性细胞因子的产生。他米巴罗汀由日本住友制药公司研发，于2014年在日本上市。

作用机制

该药物是特异性的RARα/β激动剂，用于治疗全反式视黄酸耐受的急性白血病患者。其不良反应相对轻一些，常见症状包括高白细胞症、分化综合征、高甘油三酯、高胆固醇、皮肤瘙痒和头痛等。

合成路线

他米巴罗汀的合成路径如下图所示：

适用症状及不良反应

他米巴罗汀在全反式维甲酸类药物耐药及复发难治性急性早幼粒细胞白血病患者中疗效显著，具有较小的不良反应。此外，它还能调控自身免疫性疾病中的免疫细胞，并抑制炎性细胞因子的产生。

生物活性与靶点

他米巴罗汀是特异性的RARα/β激动剂，在体外研究中显示出对骨髓瘤、内皮细胞等有生长抑制作用；体内研究则显示了其在降低小鼠脑中不溶性Aβ水平方面的显著效果。

体内外实验结果

• 体外研究：他米巴罗汀能够抑制骨髓瘤和内皮细胞的生长，同时对血管生成具有一定的抑制作用。相较于全反式维甲酸（ATRA），它在诱导HL-60细胞粘附到内皮细胞方面效果较弱。
• 体内研究：他米巴罗汀治疗显著降低小鼠脑中不溶性Aβ水平，特别是Aβ42，但对可溶性Aβ没有明显影响。

以上信息由Chemicalbook的鲍泉编辑整理（2016-01-22）。

反应信息

• 作为反应物：
  描述：

  他米巴罗汀 在 草酰氯 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)carbamoyl]benzoyl chloride
  参考文献：
  名称：

  铜介导的氨基喹啉直接与K18 F芳香CH键的放射性氟化。

  摘要：

  描述了被保护为8-氨基喹啉苯甲酰胺的芳香族羧酸的Cu介导的邻位CH氟化。该方法使用K18 F，并且与多种官能团兼容。该反应在RARβ2激动剂[18 F] AC261066的高比活性自动合成中得到展示。

  DOI：

  10.1002/anie.201812701
• 作为产物：
  描述：

  4-((5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基)氨基甲酰基)苯甲酸甲酯 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 生成 他米巴罗汀
  参考文献：
  名称：

  视黄苯甲酸。1.芳族酰胺与类视色素活性的结构-活性关系。

  摘要：

  已显示两种类型的芳族酰胺，对苯二甲酸单苯胺和（芳基甲酰胺基）苯甲酸具有有效的类维生素A活性，可以归类为类维生素A。基于对人早幼粒细胞白血病细胞HL-60的分化诱导活性，讨论了这些酰胺的构效关系。在通式4（X ＝ NHCO或CONH）中，引起类视色素活性的必要因素是在其间位的中等尺寸烷基（异丙基，叔丁基等）和在其对位的羧基。另一个苯环。酰胺结构的键可以颠倒，该部分显然具有将两个苯环相对于彼此定位在适当位置的作用。推测是由于所得的构象变化，在酰胺基邻位的环位置取代或酰胺基的N-甲基化导致活性降低。显然，苄基甲基和羧基的相互取向以及它们之间的距离是决定类视色素活性的必要因素。在合成的化合物中，4-[（（5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基）氨基甲酰基]苯甲酸（Am80）和4-[（5,6，在该测定中，7,8-四氢-5,5,8,8-四甲基-2-萘基[羧酰胺基]苯甲酸（Am580）的

  DOI：

  10.1021/jm00119a021

文献信息

• [EN] SUBSTITUTED BENZYLAMINE COMPOUNDS, THEIR USE IN MEDICINE, AND IN PARTICULAR THE TREATMENT OF HEPATITIS C VIRUS (HCV) INFECTION<br/>[FR] COMPOSÉS DE BENZYLAMINE SUBSTITUÉS, LEUR UTILISATION EN MÉDECINE, EN PARTICULIER DANS LE TRAITEMENT D'UNE INFECTION PAR LE VIRUS DE L'HÉPATITE C (VHC)
  申请人：ASTEX THERAPEUTICS LTD

  公开号：WO2013064538A1

  公开（公告）日：2013-05-10

  The invention provides compounds of the formula (I): or a salt, N-oxide or tautomer thereof, wherein A is CH, CF or nitrogen; E is CH, CF or nitrogen; and R0 is hydrogen or C1-2 alkyl; R1a is selected from CONH2; CO2H; an optionally substituted acyclic C1-8 hydrocarbon group; and an optionally substituted monocyclic carbocyclic or heterocyclic group of 3 to 7 ring members, of which 0, 1, 2, 3 or 4 are heteroatom ring members selected from O, N and S; R2 is selected from hydrogen and a group R2a; R2a is selected from an optionally substituted acyclic d-8 hydrocarbon group; an optionally substituted monocyclic carbocyclic or heterocyclic group of 3 to 7 ring members, of which 0, 1 or 2 ring members are heteroatom ring members selected from O, N and S; and an optionally substituted bicyclic heterocyclic group of 9 or 10 ring members, of which 1 or 2 ring members are nitrogen atoms; wherein at least one of R1 and R2 is other than hydrogen; R3 is an optionally substituted 3- to 10-membered monocyclic or bicyclic carbocyclic or heterocyclic ring containing 0, 1, 2 or 3 heteroatom ring members selected from N, O and S; R4a is selected from halogen; cyano; C1-4 alkyl optionally substituted with one or more fluorine atoms; C1-4 alkoxy optionally substituted with one or more fluorine atoms; hydroxy-C1-4 alkyl; and C1-2 alkoxy-C1-4 alkyl; R5 is selected from hydrogen and a substituent R5a; and R5a is selected from C1-2 alkyl optionally substituted with one or more fluorine atoms; C1-3 alkoxy optionally substituted with one or more fluorine atoms; halogen; cyclopropyl; cyano; and amino, The compounds have activity against hepatitis C virus and can be used in the prevention or treatment of hepatitis C viral infections.

  该发明提供了以下式（I）的化合物，或其盐、N-氧化物或互变异构体，其中A为CH、CF或氮；E为CH、CF或氮；R0为氢或C1-2烷基；R1a选自CONH2；CO2H；一个可选择取代的非环状C1-8碳氢化合物基团；以及一个可选择取代的含有3至7个环成员的单环碳环或杂环基团，其中0、1、2、3或4个是从O、N和S中选择的杂原子环成员；R2选自氢和一个基团R2a；R2a选自一个可选择取代的非环状d-8碳氢化合物基团；一个可选择取代的含有3至7个环成员的单环碳环或杂环基团，其中0、1或2个环成员是从O、N和S中选择的杂原子环成员；以及一个可选择取代的含有9或10个环成员的双环杂环基团，其中1或2个环成员是氮原子；其中R1和R2中至少一个不是氢；R3选自一个可选择取代的含有0、1、2或3个从N、O和S中选择的杂原子环成员的3至10个成员的单环或双环碳环或杂环环；R4a选自卤素；氰基；C1-4烷基，可选择取代一个或多个氟原子；C1-4烷氧基，可选择取代一个或多个氟原子；羟基-C1-4烷基；和C1-2烷氧基-C1-4烷基；R5选自氢和一个取代基R5a；R5a选自C1-2烷基，可选择取代一个或多个氟原子；C1-3烷氧基，可选择取代一个或多个氟原子；卤素；环丙基；氰基；和氨基。这些化合物对丙型肝炎病毒具有活性，并可用于预防或治疗丙型肝炎病毒感染。
• Benzene Sulfonamide Thiazole and Oxazole Compounds
  申请人：Adams Jerry Leroy

  公开号：US20090298815A1

  公开（公告）日：2009-12-03

  The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.

  本发明提供了噻唑磺胺和噁唑磺胺化合物，含有这些化合物的组合物，以及用作药物制剂的制备方法和使用方法。
• [EN] COMBINATIONS OF INHIBITORS OF IRAK4 WITH INHIBITORS OF BTK<br/>[FR] COMBINAISONS D'INHIBITEURS DE L'IRAK4 À L'AIDE D'INHIBITEURS DE LA BTK
  申请人：BAYER PHARMA AG

  公开号：WO2016174183A1

  公开（公告）日：2016-11-03

  The present application relates to novel combinations of at least two components, component A and component B: · component A is an IRAK4-inhibiting compound of the formula (I) as defined herein, or a diastereomer, an enantiomer, a metabolite, a salt, a solvate or a solvate of a salt thereof; · component B is a BTK-inhibiting compound, or a pharmaceutically acceptable salt thereof; and, optionally, · one or more components C which are pharmaceutical products; in which one or two of the above-defined compounds A and B are optionally present in pharmaceutical formulations ready for simultaneous, separate or sequential administration, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of endometriosis, lymphoma, macular degeneration, COPD, neoplastic disorders and psoriasis.

  本申请涉及至少两种组分的新型组合，组分A和组分B：·组分A是根据本文所定义的式(I)的IRAK4抑制化合物，或其对映体、对映异构体、代谢物、盐、溶剂合物或其盐的溶剂合物；·组分B是BTK抑制化合物，或其药学上可接受的盐；以及，可选地，·一种或多种组分C，它们是药用产品；其中上述定义的化合物A和B中的一种或两种可选择地存在于用于治疗和/或预防疾病的制剂中，准备用于同时、分开或顺序给药，用于治疗和/或预防疾病，以及用于生产用于治疗和/或预防疾病的药物的用途，特别是用于治疗和/或预防子宫内膜异位症、淋巴瘤、黄斑变性、慢性阻塞性肺病、肿瘤性疾病和牛皮癣。
• [EN] AMIDOIMIDAZOPYRIDAZINES AS MKNK-1 KINASE INHIBITORS<br/>[FR] AMIDOIMIDAZOPYRIDAZINES À TITRE D'INHIBITEURS DE KINASES MKNK-1
  申请人：BAYER PHARMA AG

  公开号：WO2014118135A1

  公开（公告）日：2014-08-07

  The present invention relates to amido-substituted imidazopyridazine compounds of general formula (I) : in which A, R1, R2, R3, R4 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

  本发明涉及一般式(I)的酰胺取代咪唑吡啶化合物，其中A、R1、R2、R3、R4和n如权利要求中所定义，以及制备所述化合物的方法，用于制备所述化合物的有用中间体化合物，包括所述化合物的药物组合物和组合物，以及利用所述化合物制造用于治疗或预防疾病的药物组合物，特别是用作唯一药剂或与其他活性成分结合。
• [EN] INHIBITORS OF THE WNT SIGNALLING PATHWAYS<br/>[FR] INHIBITEURS DES VOIES DE SIGNALISATION WNT
  申请人：BAYER PHARMA AG

  公开号：WO2015140196A1

  公开（公告）日：2015-09-24

  The present invention relates to inhibitors of the Wnt signalling pathways of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper- proliferative disorder, as a sole agent or in combination with other active ingredients.

  本发明涉及通式（I）所述和定义的Wnt信号通路抑制剂，涉及制备该类化合物的方法，有用于制备该类化合物的中间化合物，包含该类化合物的药物组合物和组合物，以及利用该类化合物制造用于治疗或预防疾病的药物组合物，特别是用作唯一药剂或与其他活性成分组合使用时，用于治疗或预防过度增殖性疾病。