雷沙吉兰 | 136236-51-6

• 物质功能分类: 原料药 - 消化系统用药 - 食欲抑制药及其它减肥药
• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 中文名称: 雷沙吉兰
• 中文别名: (R)-N-(2-丙炔基)-2,3-二氢茚-1-胺；(R)-2,3-二氢-N-2-丙烯基-1H-茚-1-胺
• 英文名称: rasagiline
• 英文别名: N-propargyl-1-(R)-aminoindan；R-(+)-N-propargyl-1-aminoindan；R-PAI；(R)-N-(2-propynyl)-2,3-dihydroinden-1-amine；rasagiline mesylate；Azilect；(1R)-N-prop-2-ynyl-2,3-dihydro-1H-inden-1-amine
• CAS: 136236-51-6
• 化学式: C₁₂H₁₃N
• mdl: MFCD00866571
• 分子量: 171.242
• InChiKey: RUOKEQAAGRXIBM-GFCCVEGCSA-N

物化性质

• 熔点：
  148 °C
• 沸点：
  305.5±30.0 °C(Predicted)
• 密度：
  1.05±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二氯甲烷
• 物理描述：
  Solid
• 蒸汽压力：
  3.7X10-3 mm Hg at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.333
• 拓扑面积：
  12
• 氢给体数：
  1
• 氢受体数：
  1

ADMET

代谢

雷沙吉兰在排泄前在肝脏中几乎完全生物转化。体外实验表明，雷沙吉兰的代谢途径依赖于细胞色素P450（CYP）系统，其中CYP 1A2是参与雷沙吉兰代谢的主要同工酶。

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP 1A2 being the major isoenzyme involved in rasagiline metabolism.

来源:DrugBank

代谢

拉沙吉林在口服给药后在肝脏中广泛代谢。体外研究表明，CYP1A2是参与拉沙吉林代谢消除的主要P450同型物。拉沙吉林生物转化后形成的主要人体血浆代谢物是氨基茚满。拉沙吉林在人中的主要生物转化途径包括N-脱烷基化、茚满环的羟基化以及包括母药及其代谢物的N-葡萄糖苷酸化在内的第二相N或O结合。在健康志愿者服用拉沙吉林的血浆样本中，没有发现拉沙吉林甲磺酸盐（R对映体）转化为其S对映体。拉沙吉林不会代谢成安非他命或甲基安非他命。

Rasagiline is extensively metabolized in the liver following oral administration. In vitro studies have shown that CYP1A2 is the predominant P450 isoform involved in the metabolic elimination of rasagiline. The primary human plasma metabolite formed following biotransformation of rasagiline is aminoindan. The proposed principal biotransformation pathways of rasagiline in human are N-dealkylation, hydroxylation of the indan ring, along with Phase II N or O-conjugation, including N-glucuronidation of the parent drug and of its metabolites. There was no bioconversion of rasagiline mesylate (R enantiomer) to its S enantiomer within the human body, as determined in plasma samples for healthy volunteers dosed with rasagiline. Rasagiline is not metabolized to amphetamine or methamphetamine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

拉沙吉林在通过肝脏之前与肠道中的MAO位点结合，表现出明显的首次通过代谢效应。代谢过程迅速而广泛，在所有测试物种中呈现出相似的代谢轮廓。生物转化的主要途径是通过N-脱烷基化形成氨基茚满，以及通过羟基化形成3-羟基-N-炔丙基-1-氨基茚满。还会发生硫化物或葡萄糖醛酸的结合反应。微粒体研究表明CYP1A2是主要的代谢同型酶，但拉沙吉林既不是细胞色素P450的诱导剂也不是抑制剂。已经临床研究了在CYP1A2抑制、诱导或存在酶的共同底物时拉沙吉林的代谢情况。

An extensive first pass metabolism effect is evident, likely due to rasagiline binding to MAO sites in the intestine prior to passing the liver. Metabolism is rapid and extensive, with a similar profile in all tested species. The primary route of biotransformation is via N-dealkylation to form aminoindan and by hydroxylation to form 3-hydroxy-N-propargyl-1-aminoindan. Conjugation by sulfide or glucuronic acid occurs. Microsomal studies indicate CYP1A2 as the primary metabolising isotype, but rasagiline is neither an inducer nor inhibitor of cytochrome p450. The metabolism of rasagiline under inhibition, induction of CYP1A2 or in presence of concomitant substrate to the enzyme has been addressed clinically.

来源:Hazardous Substances Data Bank (HSDB)

代谢

雷沙吉兰在排泄前几乎完全在肝脏进行生物转化。雷沙吉兰的代谢主要通过两个途径：N-脱烷基化和/或羟基化，产生1-氨基茚满（AI）、3-羟基-N-炔丙基-1-氨基茚满（3-OH-PAI）和3-羟基-1-氨基茚满（3-OH-AI）。体外实验表明，雷沙吉兰的代谢途径都依赖于细胞色素P450（CYP）系统，其中CYP 1A2是参与雷沙吉兰代谢的主要同工酶。雷沙吉兰及其代谢物的葡萄糖苷酸结合，随后通过尿液排泄，是主要的消除途径。

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. The metabolism of rasagiline proceeds through two main pathways: N-dealkylation and/or hydroxylation to yield 1-aminoindan (AI), 3-hydroxy-N-propargyl-1 aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI). In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP 1A2 being the major isoenzyme involved in rasagiline metabolism. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

拉沙吉林据报道在长期治疗的小部分患者中会导致血清酶水平升高，尽管这些异常通常是轻微且自限性的。拉沙吉林并未被牵涉在急性肝损伤的案例中，但是其他不太特异的MAO抑制剂有过此类报道。

Rasagiline has been reported to cause serum enzyme elevations in a small proportion of patients treated long term, although the abnormalities were usually mild and self-limiting. Rasagiline has not been implicated in cases of acute liver injury, but such instances have been reported with other less specific MAO inhibitors.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：雷萨吉林

Compound:rasagiline

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：模糊的 DILI 关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重性等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

不良反应部分

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

拉沙吉林在口服给药后迅速吸收。拉沙吉林的绝对生物利用度约为36%。

Rasagiline is rapidly absorbed following oral administration. The absolute bioavailability of rasagiline is about 36%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

拉沙吉林在排泄前几乎完全在肝脏进行生物转化。拉沙吉林及其代谢物的葡萄糖醛酸苷结合，随后通过尿液排泄，是主要的消除途径。在口服14C标记的拉沙吉林后，消除主要通过尿液，其次通过粪便（7天内62%的总剂量通过尿液，7%的总剂量通过粪便），在38天内总计算回收量为剂量的84%。少于1%的拉沙吉林以未改变药物的形态通过尿液排泄。

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway. After oral administration of 14C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

87升

87 L

来源:DrugBank

吸收、分配和排泄

口服(14)C标记的雷沙吉兰后，消除主要通过尿液进行，其次是粪便（7天内尿液中有总剂量的62%，粪便中有总剂量的7%），在38天内总共回收了剂量的84%。尿液中未改变药物的雷沙吉兰排泄量小于1%。

After oral administration of (14)C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

雷萨吉兰吸收迅速；口服给药后，大约1小时达到血浆峰浓度。雷萨吉兰的绝对生物利用度约为36%。高脂肪餐后给药，雷萨吉兰的血浆峰浓度和药时曲线下面积（AUC）分别降低约60%和20%；因为AUC没有明显受影响，所以雷萨吉兰可以在餐前或餐后给药。雷萨吉兰容易通过血脑屏障。雷萨吉兰的平均稳态或终末半衰期分别为31小时或1.342小时；然而，雷萨吉兰的药代动力学特征与其药理效果之间没有相关性，因为该药物不可逆地抑制MAO-B，恢复正常酶活性的速度取决于新酶合成的速度。雷萨吉兰大约有88-94%与血浆蛋白结合，其中61-63%与白蛋白结合。

Rasagiline is rapidly absorbed; following oral administration, peak plasma concentrations are achieved in approximately 1 hour. The absolute bioavailability of rasagiline is about 36%. Following administration with a high-fat meal, peak plasma rasagiline concentrations and area under the plasma concentration-time curve (AUC) decreased by approximately 60 and 20%, respectively; because AUC is not substantially affected, rasagiline may be administered with or without food. Rasagiline readily crosses the blood-brain barrier. The mean steady-state or terminal half-life of rasagiline is 31 or 1.342 hours, respectively; however, there is no correlation between rasagiline's pharmacokinetic profile and its pharmacologic effects because the drug irreversibly inhibits MAO-B, and restoration of normal enzyme activity depends on the rate of de novo enzyme synthesis. Rasagiline is approximately 88-94% bound to plasma proteins, with 61-63% bound to albumin.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2921499090
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  2-8°C

SDS

Material Safety Data Sheet

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

---

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: Rasagiline
CAS number: 136236-51-6

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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: C12H13N
Molecular weight: 171.2

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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

根据您提供的信息，我将总结和整理关于雷沙吉兰、司来吉兰以及左旋多巴的作用机制、药物相互作用、禁忌等内容。

1. 雷沙吉兰

• 作用机制：

  • 不可逆的单胺氧化酶B型抑制剂。
  • 延缓帕金森病进展（约9个月）并推迟左旋多巴的使用时间，改善运动症状。

• 药物相互作用：

  • 不能与其它MAO 抑制剂或哌替啶合用，以免出现高血压危象。若必须使用，则两者用药时间应至少间隔14天。
  • 与CYP4501A2抑制剂（如环丙沙星）合用后雷沙吉兰的血浆水平可能增加，需注意监测其药效和副作用。

• 禁忌：

  • 轻度肝功能损害者：谨慎使用。
  • 欲怀孕或哺乳期妇女：慎用。
  • 对本制剂中任何成分过敏者禁用。
  • 严重肝功能损害者禁用。
  • 同时使用单胺氧化酶抑制剂或哌替啶者禁用。

2. 司来吉兰

• 作用机制：
  • 不可逆的单胺氧化酶B型抑制剂，能延缓疾病进展（约9个月），并推迟左旋多巴的使用时间。
  • 能显著改善运动症状，并减少“开-关”现象和剂末效应。

3. 左旋多巴

• 作用机制：
  • 治疗帕金森病最有效的口服药物，起着补充多巴胺( DA) 神经递质的作用。
  • 能减轻震颤，尤其对动作过缓与强直的改善最为显著。

4. 左旋多巴与其他药物联合使用

• 左旋多巴可以与DA受体激动剂、单胺氧化酶B(MAO)-B抑制剂及儿茶酚胺-O-甲基转移酶(COMT) 抑制剂合用，以减少不良反应。

5. 药物相互作用和禁忌

• 雷沙吉兰不能与左旋多巴联合使用。
• 不可以与其它MAO抑制剂或哌替啶、三环类/四环类抗抑郁剂等有严重交互作用的药物合用，以免出现不良反应。

希望这些信息对您有所帮助。如有更多具体问题，请随时告知。

反应信息

• 作为反应物：
  描述：

  雷沙吉兰 在 氢溴酸 、 sodium hydroxide 作用下， 以 乙酸乙酯 为溶剂， 反应 5.0h， 生成 甲磺酸雷沙吉兰
  参考文献：
  名称：

  [EN] RASAGILINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
  [FR] RASAGILINE ET SES SELS PHARMACEUTIQUEMENT ACCEPTABLES

  摘要：

  公开号：

  WO2012153349A9
• 作为产物：
  描述：

  甲磺酸雷沙吉兰 以 水 为溶剂， 反应 0.6h， 生成 雷沙吉兰
  参考文献：
  名称：

  Dosage forms with an enterically coated core tablet

  摘要：

  本发明提供了一种口服制剂给患者使用，包括一种经肠包被的核心片剂，套在压缩粉末或颗粒材料的环状体内。本发明还提供了一种联合使用两种或多种活性药物成分的药物剂型。本发明还提供了一种方法，包括将本发明的药物剂型用于患有胃动力障碍的患者，例如帕金森病患者。

  公开号：

  US20060153918A1
• 作为试剂：
  描述：

  酒石酸雷沙吉兰 、 水 、 sodium hydroxide 、 甲烷磺酸 在 雷沙吉兰 、 水 、 乙酸乙酯 、 异丙醇 作用下， 以 异丙醇 为溶剂， 反应 8.42h， 以to give rasagiline mesylate in 83% yield的产率得到甲磺酸雷沙吉兰
  参考文献：
  名称：

  PREPARATION OF RASAGILINE AND SALTS THEREOF

  摘要：

  本发明涉及制备拉沙吉林甲磺酸盐的工艺。同时提供了具有90体积百分比粒径小于约6μm的颗粒（D90）的拉沙吉林甲磺酸盐及其制备工艺。

  公开号：

  US20110218360A1

文献信息

• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• [EN] COMPOUNDS INHIBITING LEUCINE-RICH REPEAT KINASE ENZYME ACTIVITY<br/>[FR] COMPOSÉS INHIBANT L'ACTIVITÉ ENZYMATIQUE DE LA KINASE À MOTIFS RÉPÉTÉS RICHES EN LEUCINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2014137723A1

  公开（公告）日：2014-09-12

  The present invention is directed to indazole compounds which are potent inhibitors of LRRK2 kinase and useful in the treatment or prevention of diseases in which the LRRK2 kinase is involved, such as Parkinson's Disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which LRRK-2 kinase is involved.

  本发明涉及吲唑类化合物，这些化合物是LRRK2激酶的有效抑制剂，并且在治疗或预防LRRK2激酶参与的疾病，如帕金森病中有用。该发明还涉及包含这些化合物的药物组合物，以及在预防或治疗LRRK-2激酶参与的这类疾病中使用这些化合物和组合物。
• [EN] COMPOUNDS INHIBITING LEUCINE-RICH REPEAT KINASE ENZYME ACTIVITY<br/>[FR] COMPOSÉS INHIBANT L'ACTIVITÉ ENZYMATIQUE DE LA KINASE À SÉQUENCE RÉPÉTÉE RICHE EN LEUCINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2014134774A1

  公开（公告）日：2014-09-12

  Disclosed are indazole compounds which are potent inhibitors of LRRK2 kinase and useful in the treatment or prevention of diseases in which LRRK2 kinase is involved. Also disclosed are pharmaceutical compositions in the prevention or treatment of such diseases in which LRRK2 kinase is involved.

  揭示了一种indazole化合物，它们是LRRK2激酶的有效抑制剂，并且在涉及LRRK2激酶的疾病的治疗或预防中有用。还揭示了在涉及LRRK2激酶的这类疾病的预防或治疗中使用的药物组合物。
• [EN] IMIDAZOPYRIDINE COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS IMIDAZOPYRIDINE ET LEURS UTILISATIONS
  申请人：NEOMED INST

  公开号：WO2014117274A1

  公开（公告）日：2014-08-07

  This invention generally relates to substituted imidazopyridine compounds, particularly substituted 4-(imidazo[1,2-a]pyridin-2-yl)benzamide compounds and salts thereof. This invention also relates to pharmaceutical compositions and kits comprising such a compound, uses of such a compound (including, for example, treatment methods and medicament preparations), processes for making such a compound, and intermediates used in such processes.

  这项发明通常涉及取代咪唑吡啶化合物，特别是取代的4-(咪唑[1,2-a]吡啶-2-基)苯甲酰胺化合物及其盐。这项发明还涉及包含这种化合物的药物组合物和试剂盒，以及这种化合物的用途（包括治疗方法和药物制剂等），制备这种化合物的方法，以及用于这些方法的中间体。
• [EN] MODULATORS OF THE INTEGRATED STRESS PATHWAY<br/>[FR] MODULATEURS DE LA VOIE DE RÉPONSE INTÉGRÉE AU STRESS
  申请人：CALICO LIFE SCIENCES

  公开号：WO2017193063A1

  公开（公告）日：2017-11-09

  Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases; disorders and conditions.

  本文提供了用于调节综合应激反应（ISR）并治疗相关疾病、疾患和症状的化合物、组合物和方法。