4,5-二苯胺基酞酰亚胺 | 145915-58-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 中文名称: 4,5-二苯胺基酞酰亚胺
• 中文别名: 5,6-双(苯基氨基)-1H-异吲哚-1,3(2H)-二酮
• 英文名称: 5,6-bis-phenylamino-isoindole-1,3-dione
• 英文别名: 4,5-bis(anilino)phthalimide；CGP 52411；4,5-dianilino pthalimide；4,5-dianilinophthalimide；CGP-52411；DAPH；5,6-dianilinoisoindole-1,3-dione
• CAS: 145915-58-8
• 化学式: C₂₀H₁₅N₃O₂
• 分子量: 329.358
• InChiKey: AAALVYBICLMAMA-UHFFFAOYSA-N

物化性质

• 熔点：
  199-202℃
• 密度：
  1.374
• 溶解度：
  二甲基亚砜：~30 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  70.2
• 氢给体数：
  3
• 氢受体数：
  4

安全信息

• 安全说明：
  S36/37
• WGK Germany：
  3
• 储存条件：
  2-8°C

SDS

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Section 1. IDENTIFICATION OF THE SUBSTANCE/MIXTURE
Product identifiers
Product name : DAPH
CAS-No. : 145915-58-8

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Section 2. HAZARDS IDENTIFICATION
Classification of the substance or mixture
Not a hazardous substance or mixture according to Regulation (EC) No 1272/2008
This substance is not classified as dangerous according to Directive 67/548/EEC.
Label elements
The product does not need to be labelled in accordance with EC directives or respective national laws.
Other hazards - none

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Section 3. COMPOSITION/INFORMATION ON INGREDIENTS
Substances
Synonyms : 4,5-Dianilinophthalimide
5,6-Bis(phenylamino)-1H-isoindole-1,3(2H)-dione
Formula : C20H15N3O2
Molecular Weight : 329,35 g/mol

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Section 4. FIRST AID MEASURES
Description of first aid measures
General advice
Consult a physician. Show this safety data sheet to the doctor in attendance.
If inhaled
If breathed in, move person into fresh air. If not breathing, give artificial respiration. Consult a physician.
In case of skin contact
Wash off with soap and plenty of water. Consult a physician.
In case of eye contact
Flush eyes with water as a precaution.
If swallowed
Never give anything by mouth to an unconscious person. Rinse mouth with water. Consult a physician.
Most important symptoms and effects, both acute and delayed
To the best of our knowledge, the chemical, physical, and toxicological properties have not been
thoroughly investigated.
Indication of any immediate medical attention and special treatment needed
no data available

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Section 5. FIREFIGHTING MEASURES
Extinguishing media
Suitable extinguishing media
Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Special hazards arising from the substance or mixture
Carbon oxides, nitrogen oxides (NOx)
Advice for firefighters
Wear self contained breathing apparatus for fire fighting if necessary.
Further information
no data available

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Section 6. ACCIDENTAL RELEASE MEASURES
Personal precautions, protective equipment and emergency procedures
Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Avoid
breathing dust.
Environmental precautions
Do not let product enter drains.
Methods and materials for containment and cleaning up
Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed
containers for disposal.
Reference to other sections
For disposal see section 13.

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Section 7. HANDLING AND STORAGE
Precautions for safe handling
Avoid formation of dust and aerosols.
Provide appropriate exhaust ventilation at places where dust is formed.Normal measures for preventive fire
protection.
Conditions for safe storage, including any incompatibilities
Store in cool place. Keep container tightly closed in a dry and well-ventilated place.
Recommended storage temperature: 2 - 8 °C
Specific end uses
no data available

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Section 8. EXPOSURE CONTROLS/PERSONAL PROTECTION
Control parameters
Components with workplace control parameters
Exposure controls
Appropriate engineering controls
Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and
at the end of workday.
Personal protective equipment
Eye/face protection
Use equipment for eye protection tested and approved under appropriate government standards
such as NIOSH (US) or EN 166(EU).
Skin protection
Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique
(without touching glove's outer surface) to avoid skin contact with this product. Dispose of
contaminated gloves after use in accordance with applicable laws and good laboratory practices.
Wash and dry hands.
The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and
the standard EN 374 derived from it.
Body Protection
Choose body protection in relation to its type, to the concentration and amount of dangerous
substances, and to the specific work-place., The type of protective equipment must be selected
according to the concentration and amount of the dangerous substance at the specific workplace.
Respiratory protection
Respiratory protection is not required. Where protection from nuisance levels of dusts are desired,
use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and
approved under appropriate government standards such as NIOSH (US) or CEN (EU).

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Section 9. PHYSICAL AND CHEMICAL PROPERTIES
Information on basic physical and chemical properties
a) Appearance Form: solid
Colour: orange
b) Odour no data available
c) Odour Threshold no data available
d) pH no data available
e) Melting point/freezing Melting point/range: 207 - 208 °C
point
f) Initial boiling point and no data available
boiling range
g) Flash point no data available
h) Evaporation rate no data available
i) Flammability (solid, gas) no data available
j) Upper/lower no data available
flammability or
explosive limits
k) Vapour pressure no data available
l) Vapour density no data available
m) Relative density no data available
n) Water solubility no data available
o) Partition coefficient: n- no data available
octanol/water
p) Autoignition no data available
temperature
q) Decomposition no data available
temperature
r) Viscosity no data available
s) Explosive properties no data available
t) Oxidizing properties no data available
Other safety information
no data available

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Section 10. STABILITY AND REACTIVITY
Reactivity
no data available
Chemical stability
no data available
Possibility of hazardous reactions
no data available
Conditions to avoid
no data available
Incompatible materials
Strong oxidizing agents
Hazardous decomposition products
Other decomposition products - no data available

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Section 11. TOXICOLOGICAL INFORMATION
Information on toxicological effects
Acute toxicity
no data available
Skin corrosion/irritation
no data available
Serious eye damage/eye irritation
no data available
Respiratory or skin sensitization
Prolonged or repeated exposure may cause allergic reactions in certain sensitive individuals. The
preceding data, or interpretation of data, was determined using Quantitative Structure Activity Relationship
(QSAR) modeling.
Germ cell mutagenicity
no data available
Carcinogenicity
IARC: No component of this product present at levels greater than or equal to 0.1% is identified as
probable, possible or confirmed human carcinogen by IARC.
Reproductive toxicity
no data available
Specific target organ toxicity - single exposure
no data available
Specific target organ toxicity - repeated exposure
no data available
Aspiration hazard
no data available
Potential health effects
Inhalation May be harmful if inhaled. May cause respiratory tract irritation.
Ingestion May be harmful if swallowed.
Skin May be harmful if absorbed through skin. May cause skin irritation.
Eyes
May cause eye irritation.
Signs and Symptoms of Exposure
To the best of our knowledge, the chemical, physical, and toxicological properties have not been
thoroughly investigated.
Additional Information
RTECS: Not available

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Section 12. ECOLOGICAL INFORMATION
Toxicity
no data available
Persistence and degradability
no data available
Bioaccumulative potential
no data available
Mobility in soil
no data available
Results of PBT and vPvB assessment
no data available
Other adverse effects
no data available

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Section 13. DISPOSAL CONSIDERATIONS
Waste treatment methods
Product
Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed
professional waste disposal service to dispose of this material. Dissolve or mix the material with a
combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber.
Contaminated packaging
Dispose of as unused product.

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Section 14. TRANSPORT INFORMATION
UN number
ADR/RID: - IMDG: - IATA: -
UN proper shipping name
ADR/RID: Not dangerous goods
IMDG: Not dangerous goods
IATA: Not dangerous goods
Transport hazard class(es)
ADR/RID: - IMDG: - IATA: -
Packaging group
ADR/RID: - IMDG: - IATA: -
Environmental hazards
ADR/RID: no IMDG Marine pollutant: no IATA: no
Special precautions for user
no data available

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Section 15. REGULATORY INFORMATION
This safety datasheet complies with the requirements of Regulation (EC) No. 1907/2006.
Safety, health and environmental regulations/legislation specific for the substance or mixture
no data available
Chemical Safety Assessment

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SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

生物活性

CGP52411 (DAPH) 是一种高选择性、有效且口服活性的 ATP 竞争性 EGFR 抑制剂，IC50 值为 0.3 μM。它能够阻止有毒 Ca2+ 离子流入神经元细胞，并显著抑制和逆转与阿尔茨海默症相关的 β-amyloid (Aβ42) 原纤维聚集物的形成。

靶点

EGFR	0.3 μM (IC50)
Amyloid-β

体外研究

CGP52411 (DAPH; 0-100 μM; 90 分钟; A431 细胞) 处理能以剂量依赖性方式抑制自磷酸化和 c-src 自磷酸化，IC50 值分别为 1 μM 和 16 μM。同时，它还表现出浓度依赖性的 p185c-erbB2 酪氨酸磷酸化降低，其 IC50 值为 10 μM。

CGP52411 (DAPH) 抑制 c-src 磷酸激酶，IC50 值为 16 μM。它还抑制猪脑分离的 PKC 同源物，IC50 值为 80 μM。CGP52411 拮抗传统型 PKC (cPKCs α, β-1, β-2, 和 γ) 但不拮抗非传统型 PKC (nPKCs δ, ε, 和 ζ) 或非典型 PKC (aPKC η)。

Western Blot 分析

细胞系	A431 细胞
浓度	0 μM, 0.1 μM, 1 μM, 10 μM, 50 μM, 100 μM
孵化时间	90 分钟
结果	剂量依赖性地抑制细胞内自磷酸化，IC50 值为 1 μM。c-src 自磷酸化被 IC50 值为 16 μM 的 CGP52411 抑制。同时，p185c-erbB2 酪氨酸磷酸化浓度依赖性地降低，其 IC50 值约为 10 μM。

体内研究

CGP52411 (3.2 mg/kg, 6.3 mg/kg, 12.5 mg/kg, 25 mg/kg, 和 50 mg/kg；口服给药；每日一次；持续 15 天；雌性 BALB/c 裸鼠) 治疗对 A431 和 SK-OV-3 实体瘤异种移植具有抗肿瘤活性。

动物模型

动物模型	雌性 BALB/c 裸鼠注射 A431 细胞
用药剂量	3.2 mg/kg, 6.3 mg/kg, 12.5 mg/kg, 25 mg/kg, 和 50 mg/kg
给药方式和频率	口服给药；每日一次；持续 15 天
结果	在 50 mg/kg 至 6.3 mg/kg 的剂量范围内获得了抗肿瘤疗效。

反应信息

• 作为反应物：
  描述：

  4,5-二苯胺基酞酰亚胺 、 碘甲烷 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以85.8%的产率得到4,5-bis(anilino)-N(2)-methyl-phthalimide
  参考文献：
  名称：

  Novel anilinophthalimide derivatives as potential probes for β-amyloid plaque in the brain

  摘要：

  A group of novel 4,5-dianilinophthalimide derivatives has been synthesized in this study for potential use as beta-amyloid (A beta) plaque probes. Staining of hippocampus tissue sections from Alzheimer's disease (AD) brain with the representative compound 9 indicated selective labeling of it to A beta plaques. The binding affinity of radioiodinated [I-125]9 for AD brain homogenates was 0.21 nM (K-d), and of other derivatives ranged from 0.9 to 19.7 nM, except for N-methyl-4,5-dianilinophthalimide (K-i > 1000 nM). [I-125]9 possessed the optimal lipophilicity with Log P value of 2.16, and its in vivo biodistribution in normal mice exhibited excellent initial brain uptake (5.16% ID/g at 2 min after injection) and a fast washout rate (0.56% ID/g at 60 min). The encouraging results suggest that this novel derivative of [I-123]9 may have potential as an in vivo SPECT probe for detecting amyloid plaques in the brain. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.12.023
• 作为产物：
  描述：

  4,5-二氯邻苯二甲酸二甲酯 在 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 氨 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 乙二醇 、 甲苯 为溶剂， 110.0~120.0 ℃ 、310.26 kPa 条件下， 反应 45.0h， 生成 4,5-二苯胺基酞酰亚胺
  参考文献：
  名称：

  4,5-二苯胺基邻苯二甲酰亚胺的合成及相关类似物，通过钯催化胺化处理阿尔茨海默氏病

  摘要：

  DAPH（4,5-二苯并邻苯二甲酰亚胺）先前已被证明可以逆转与阿尔茨海默氏病相关的神经毒性原纤维的形成。我们已经开发了一种合成DAPH和结构相关类似物的合成途径，该途径采用钯催化的胺化作用作为关键的键形成步骤。容易获得所需的底物，并且它们与取代的苯胺的偶联通常以高收率进行。因此，可以以模块化方式快速访问各种DAPH类似物。另外，本文描述的途径也应适合于将其他种类的亲核试剂掺入分子框架。

  DOI：

  10.1021/jo051096o

文献信息

• [EN] POLYMERIC HYPERBRANCHED CARRIER-LINKED PRODRUGS<br/>[FR] PROMÉDICAMENTS LIÉS À DES EXCIPIENTS POLYMÉRIQUES HYPERBRANCHÉS
  申请人：ASCENDIS PHARMA AS

  公开号：WO2013024048A1

  公开（公告）日：2013-02-21

  The present invention relates to water-soluble carrier-linked prodrugs of formula (I),wherein POL is a polymeric moiety,each Hyp is independently a hyperbranched moiety,each moiety SP is independently a spacer moiety, each L is independently a reversible prodrug linker moiety, m is 0 or 1, each n is independently an integer from 2 to 200 and each x is independently 0 or 1. It further relates to pharmaceutical compositions comprising said water- soluble carrier-linked prodrugs and methods of treatment.

  本发明涉及水溶性载体连接的前药，其化学式为（I），其中POL是聚合物基团，每个Hyp是独立的超支化基团，每个基团SP是独立的间隔基团，每个L是独立的可逆前药连接基团，m为0或1，每个n是独立的整数，范围从2到200，每个x是独立的0或1。此外，还涉及包含所述水溶性载体连接的前药的药物组合物和治疗方法。
• [EN] HIGH-LOADING WATER-SOLUBLE CARRIER-LINKED PRODRUGS<br/>[FR] PROMÉDICAMENTS LIÉS À DES EXCIPIENTS HYDROSOLUBLES DE FORTE CHARGE
  申请人：ASCENDIS PHARMA AS

  公开号：WO2013024047A1

  公开（公告）日：2013-02-21

  The present invention relates to water-soluble carrier-linked prodrugs of formula (I), wherein B, A and Hyp form the carrier, B is a branching core, each A is independently a poly(ethylene glycol)-based polymeric chain, each Hyp is independently a branched moiety, each SP is independently a spacer moiety, each L is independently a reversible prodrug linker moiety, each D is independendly a biologically active moiety, each x is independently 0 or 1, each m is independently an integer of from 2 to 64, n is an integer from 3 to 32; or the pharmaceutically acceptable salt thereof. It further relates to pharmaceutical compositions comprising said water-soluble carrier-linked prodrugs, their use asmedicament or diagnostic, and methods of treatment.

  本发明涉及水溶性载体连接的前药，其化学式为(I)，其中B、A和Hyp形成载体，B是一个分支核心，每个A独立地是一条聚乙二醇基聚合链，每个Hyp独立地是一个分支基团，每个SP独立地是一个间隔基团，每个L独立地是一个可逆前药连接基团，每个D独立地是一个生物活性基团，每个x独立地为0或1，每个m独立地是从2到64的整数，n是从3到32的整数；或其药学上可接受的盐。进一步涉及包括所述水溶性载体连接的前药的药物组合物，其用作药物或诊断，以及治疗方法。
• Conjugates of biologically active compounds, methods for their preparation and use, formulation and pharmaceutical applications thereof
  申请人：——

  公开号：US20040005641A1

  公开（公告）日：2004-01-08

  This invention features a method of identifying a compound useful for enhancing efficacy of a therapeutic agent. The method includes incubating a compound in blood cells; separating immune cells from erythrocytic cells; and determining the ratio of the concentration of the compound in the immune cells to the concentration of the compound in the erythrocytic cells; wherein the compound comprises a transportophore and a therapeutic agent, in which the transportophore is covalently bonded to the therapeutic agent via a bond or a linker.

  这项发明涉及一种用于增强治疗剂效的化合物识别方法。该方法包括将化合物孵育在血细胞中；将免疫细胞与红细胞分离；并确定免疫细胞中化合物浓度与红细胞中化合物浓度的比率；其中该化合物包括一种传输体和一种治疗剂，其中传输体通过键或链接物与治疗剂共价结合。
• [EN] RELEASABLE CONJUGATES<br/>[FR] CONJUGUÉS LIBÉRABLES
  申请人：QUIAPEG PHARMACEUTICALS AB

  公开号：WO2018163131A1

  公开（公告）日：2018-09-13

  The present application provides compounds of Formula (B), or pharmaceutically acceptable salts thereof, wherein D is a residue of a biologically active drug, which underdo hydrolysis under physiological conditions to release the biologically active drug and which are useful in the treatment of disorders that could be beneficially treated with the drug.

  本申请提供了化合物的公式（B），或其药用盐，其中D是生物活性药物的残留物，在生理条件下经过水解释放出生物活性药物，并且对可能受益于该药物治疗的疾病具有用处。
• [EN] PROTEIN CARRIER-LINKED PRODRUGS<br/>[FR] PROMÉDICAMENTS LIÉS À UN EXCIPIENT PROTÉIQUE
  申请人：ASCENDIS PHARMA AS

  公开号：WO2013024049A1

  公开（公告）日：2013-02-21

  The present invention relates to water-soluble protein carrier- linked prodrugs wherein the protein carrier comprises an amino acid sequence consisting of at least 100 amino acid residues forming random coil conformation and comprising alanine, serine and proline residues. It further relates to pharmaceutical compositions comprising said water-soluble protein carrier- linked prodrugs, their use as a medicament as well as methods of treatment and administration.

  本发明涉及水溶性蛋白载体连接的前药，其中蛋白载体包括至少100个氨基酸残基组成的氨基酸序列，形成随机卷曲构象，包括丙氨酸、丝氨酸和脯氨酸残基。还涉及包含上述水溶性蛋白载体连接的前药的药物组合物，它们作为药物的用途，以及治疗和管理的方法。