Sulindac | 38194-50-2

• 物质功能分类: 原料药 - 解热镇痛药 - 非甾抗炎药
• 分子结构分类: 有机化合物 - 苯类化合物 - 茚和异茚
• 英文名称: Sulindac
• 英文别名: (Z)-2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)acetic acid；2-[(3Z)-6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)methylidene]inden-1-yl]acetic acid
• CAS: 38194-50-2
• 化学式: C₂₀H₁₇FO₃S
• 分子量: 356.418
• InChiKey: MLKXDPUZXIRXEP-MFOYZWKCSA-N

物化性质

• 熔点：
  182-185°C
• 沸点：
  581.6±50.0 °C(Predicted)
• 密度：
  1.2581 (estimate)
• 溶解度：
  极微溶于水，溶于二氯甲烷，微溶于乙醇（96%）。溶于碱金属氢氧化物的稀溶液。
• 最大波长(λmax)：
  327nm(0.05mol/L methanolic HCl)(lit.)
• 物理描述：
  Solid
• 碰撞截面：
  192.6 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 稳定性/保质期：
  常规情况下不会分解，也没有危险反应。

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  73.6
• 氢给体数：
  1
• 氢受体数：
  5

ADMET

代谢

经历两个主要生物转化：可逆还原成硫代物代谢物，以及不可逆氧化成磺酰物代谢物。舒林酸及其硫代物和磺酰物代谢物经历广泛的肠肝循环。现有证据表明，生物活性存在于硫代物代谢物中。侧链羟基化和双键的水合也发生。

Undergoes two major biotransformations: reversible reduction to the sulfide metabolite, and irreversible oxidation to the sulfone metabolite. Sulindac and its sulfide and sulfone metabolites undergo extensive enterohepatic circulation. Available evidence indicates that the biological activity resides with the sulfide metabolite. Side chain hydroxylation and hydration of the double bond also occur.

来源:DrugBank

毒理性

• 肝毒性

长期使用舒林酸进行治疗与血清转氨酶水平升高率低有关，这种情况很少严重，通常为自限性。临床上明显的急性肝损伤已知与舒林酸有关，但很罕见（大约每10,000个处方中有5个病例，使用者的约0.1%）。舒林酸的肝毒性通常表现为发热、皮疹、恶心、呕吐和腹痛，这些症状通常在使用药物几天或几周内出现，随后不久出现黄疸。偶尔，发病可能延迟，尤其是如果治疗是间歇性的。临床模式提示为过敏性肝炎，与磺胺类药物的肝毒性有些相似。血清酶水平升高的模式通常在开始时为肝细胞型或混合型，但后来可能变为胆汁淤积型。然而，一旦停止使用舒林酸，恢复通常很快。组织学特征与过敏性肝炎一致，表现为点状坏死和明显的炎症细胞浸润，嗜酸性粒细胞突出。在许多情况下，超敏反应的特征（如面部肿胀、脱屑性皮疹、咽炎、口炎、淋巴结病和低血压）掩盖了肝损伤，这些症状更常是死亡的原因。舒林酸还可能引起急性肝损伤，潜伏期更长，几乎没有超敏反应的特征。这些病例通常是胆汁淤积型，可能持续较长时间，导致胆管消失综合征。

Chronic therapy with sulindac is associated with a low rate of serum aminotransferase elevations, which are rarely severe and usually self-limited. Clinically apparent acute liver injury from sulindac is well known, but rare (~5 cases in 100,000 prescriptions and ~0.1% of users). Sulindac hepatotoxicity typically presents with fever, rash, nausea and vomiting and abdominal pain arising within a few days or weeks of starting the medication and followed shortly thereafter by jaundice. Occasionally, the onset may be delayed, particularly if therapy is intermittent. The clinical pattern suggests an allergic hepatitis and is somewhat similar to the hepatotoxicity of the sulfonamides. The pattern of serum enzyme elevations is usually hepatocellular or mixed at the onset, but may then become cholestatic. However, recovery is usually rapid once sulindac is stopped. Histology is consistent with an allergic hepatitis with spotty necrosis and marked inflammatory cell infiltration with prominence of eosinophils. In many instances, the features of hypersensitivity (such as facial swelling, desquamating rash, pharyngitis, stomatitis, lymphadenopathy, and hypotension) overshadow the liver injury and are more commonly the cause of death. Sulindac can also cause acute liver injury with a more delayed latency with few or no features of hypersensitivity. These cases are usually cholestatic and can be prolonged and lead to vanishing bile duct syndrome.

来源:LiverTox

毒理性

• 药物性肝损伤

复方磺胺二甲嘧啶

Compound:sulindac

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：警告和预防措施

Label Section:Warnings and precautions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

大约90%在口服给药后人被吸收。

Approximately 90% absorbed in humans following oral administration.

来源:DrugBank

吸收、分配和排泄

• 排除途径

.sulindac在大鼠乳汁中排泄；乳汁中的浓度是血浆中浓度的10%到20%。尚不清楚sulindac是否在人类乳汁中排泄。大约50%的服用.sulindac剂量通过尿液排泄，其中结合的磺酰亚胺代谢物占主要部分。肝脏代谢是一个重要的消除途径。

Sulindac is excreted in rat milk; concentrations in milk were 10 to 20% of those levels in plasma. It is not known if sulindac is excreted in human milk. Approximately 50% of the administered dose of sulindac is excreted in the urine with the conjugated sulfone metabolite accounting for the major portion. Hepatic metabolism is an important elimination pathway.

来源:DrugBank

吸收、分配和排泄

• 清除

肾小球滤过率=68.12 +/- 27.56 mL/min [正常 (19-41岁)]

Renal cl=68.12 +/- 27.56 mL/min [NORMAL (19-41 yrs)]

来源:DrugBank

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  Xn
• 安全说明：
  S
• 危险类别码：
  R22
• WGK Germany：
  3
• 海关编码：
  2930909090
• RTECS号：
  NK8226000
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 危险标志：
  GHS06,GHS08
• 危险品运输编号：
  3249
• 危险性描述：
  H301,H317,H334,H361
• 危险性防范说明：
  P261,P280,P301 + P310,P342 + P311
• 储存条件：
  密封、阴凉、干燥保存

SDS

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Section 1. IDENTIFICATION OF THE SUBSTANCE/MIXTURE
Product identifiers
Product name : Sulindac
CAS-No. : 38194-50-2
Relevant identified uses of the substance or mixture and uses advised against
Identified uses : Laboratory chemicals, Manufacture of substances

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Section 2. HAZARDS IDENTIFICATION
Classification of the substance or mixture
Classification according to Regulation (EC) No 1272/2008 [EU-GHS/CLP]
Acute toxicity, Oral (Category 3)
Respiratory sensitization (Category 1)
Skin sensitization (Category 1)
Reproductive toxicity (Category 2)
Classification according to EU Directives 67/548/EEC or 1999/45/EC
Harmful if swallowed. Harmful if swallowed. May cause sensitization by inhalation and skin contact.
Possible risk of harm to the unborn child.
Label elements
Labelling according Regulation (EC) No 1272/2008 [CLP]
Pictogram
Signal word Danger
Hazard statement(s)
H301 Toxic if swallowed.
H317 May cause an allergic skin reaction.
H334 May cause allergy or asthma symptoms or breathing difficulties if inhaled.
H361 Suspected of damaging fertility or the unborn child.
Precautionary statement(s)
P261 Avoid breathing dust/ fume/ gas/ mist/ vapours/ spray.
P280 Wear protective gloves.
P301 + P310 IF SWALLOWED: Immediately call a POISON CENTER or doctor/
physician.
P342 + P311 If experiencing respiratory symptoms: Call a POISON CENTER or doctor/
physician.
Supplemental Hazard none
Statements
According to European Directive 67/548/EEC as amended.
Hazard symbol(s)
R-phrase(s)
R22 Harmful if swallowed.
R42/43 May cause sensitization by inhalation and skin contact.
R63 Possible risk of harm to the unborn child.
S-phrase(s) none
Other hazards - none

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Section 3. COMPOSITION/INFORMATION ON INGREDIENTS
Substances
Synonyms : (Z)-5-Fluoro-2-methyl-1-[p-(methylsulfinyl)benzylidene]indene-3-acetic
acid
Formula : C20H17FO3S
Molecular Weight : 356,41 g/mol
Component Concentration
Sulindac
CAS-No. 38194-50-2 -
EC-No. 253-819-2

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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. Take victim immediately to hospital. 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
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, Sulphur oxides, Hydrogen fluoride
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
Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate
ventilation. Evacuate personnel to safe areas. Avoid breathing dust.
Environmental precautions
Prevent further leakage or spillage if safe to do so. 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 contact with skin and eyes. 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.
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
Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling
the product.
Personal protective equipment
Eye/face protection
Face shield and safety glasses 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
Complete suit protecting against chemicals, The type of protective equipment must be selected
according to the concentration and amount of the dangerous substance at the specific workplace.
Respiratory protection
Where risk assessment shows air-purifying respirators are appropriate use a full-face particle
respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering
controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. 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
b) Odour no data available
c) Odour Threshold no data available
d) pH no data available
e) Melting point/freezing no data available
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 insoluble
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
LD50 Oral - rat - 264 mg/kg
Skin corrosion/irritation
no data available
Serious eye damage/eye irritation
no data available
Respiratory or skin sensitization
no data available
May cause allergic respiratory and skin reactions
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
Possible risk of congenital malformation in the fetus.
Suspected human reproductive toxicant
Developmental Toxicity - mouse - Oral
Specific Developmental Abnormalities: Craniofacial (including nose and tongue).
Developmental Toxicity - mouse - Intramuscular
Specific Developmental Abnormalities: Craniofacial (including nose and tongue).
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 Toxic if swallowed.
Skin May be harmful if absorbed through skin. May cause skin irritation.
Eyes May cause eye irritation.
Additional Information
RTECS: NK8226000

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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: 2811 IMDG: 2811 IATA: 2811
UN proper shipping name
ADR/RID: TOXIC SOLID, ORGANIC, N.O.S. (Sulindac)
IMDG: TOXIC SOLID, ORGANIC, N.O.S. (Sulindac)
IATA: Toxic solid, organic, n.o.s. (Sulindac)
Transport hazard class(es)
ADR/RID: 6.1 IMDG: 6.1 IATA: 6.1
Packaging group
ADR/RID: III IMDG: III IATA: III
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
no data available

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Section 16. OTHER INFORMATION
Further information
Copyright 2012 Co. LLC. License granted to make unlimited paper copies for internal use
only.
The above information is believed to be correct but does not purport to be all inclusive and shall be
used only as a guide. The information in this document is based on the present state of our knowledge
and is applicable to the product with regard to appropriate safety precautions. It does not represent any
guarantee of the properties of the product. Corporation and its Affiliates shall not be held
liable for any damage resulting from handling or from contact with the above product. See
and/or the reverse side of invoice or packing slip for additional terms and conditions of sale.

制备方法与用途

舒林酸概述

舒林酸（Sulindac）是一种非甾体抗炎药，用于治疗结肠性息肉病。尽管舒林酸本身属于亚砜类药物，在临床上对风湿性和类风湿性关节炎没有直接疗效，但它可被肝脏中的酶转化为具有抑制前列腺素合成的硫化物，并能在体内代谢为能抑制早期癌症恶化和治疗结肠性息肉的砜类化合物。

生物活性

舒林酸是一种非甾体类COX抑制剂，有效抑制前列腺素的合成，用于治疗急性或慢性炎症。其活性形式（硫化物）通过抑制环氧酶减少前列腺素的生成，进而发挥镇痛、抗炎和解热作用。

体外研究

在结肠癌和其他细胞系中，舒林酸及其代谢产物如sulindac sulfide和sulindac sulfone能够抑制NF-κB途径。Sulindac sulfide显著降低了HT-29细胞的生长，并抑制多种肿瘤细胞系的增殖，特别对β-catenin/TCF介导的基因转录有抑制作用，减少非磷酸化的β-catenin水平。

体内研究

在家族性腺瘤性息肉病的小鼠模型中，Sulindac不仅能抑制肿瘤形成，还能降低小肠COX-2和前列腺素E（2）到基准水平，并恢复细胞凋亡的正常水平。Min/+小鼠肠组织中，Sulindac显著减少了95%的肿瘤数量，尽管未改变PGE 2和LTB 4的水平。在相同模型下，花生酸水平仍然升高，但舒林酸能引起70-80%的肿瘤消退。

化学性质

舒林酸是一种黄色结晶，无臭无味，易潮解，并微溶于乙醇、丙酮、乙酸乙酯或氯仿，难溶于甲醇。在pH值＜4.5时几乎不溶于水，在pH值为7时溶解度约为3.0mg/ml。熔点为182～185℃（分解）。UV最大吸收波长分别为：327, 285, 256, 226nm，其ε_1cm^1%值分别为375, 420, 410, 540。pKa（25℃）为4.7。

用途

舒林酸于1978年获得美国FDA批准，作为一种前体药物，在口服吸收后转化为活性硫化物发挥作用，主要用于治疗类风湿性关节炎、臂部和膝关节炎、强直性脊椎炎、滑囊炎及急性痛风等疾病。此外，它还用作消炎镇痛药，用于风湿性和类风湿性关节炎、急性痛风等症状的缓解。

生产方法 方法1

4-硝基邻苯二甲酸经氢化还原为4-氨基邻苯二甲酸，然后进行Sehiernann反应生成4-氟邻苯二甲酸，进一步酯化并缩合环合成二氢茚。再与有机膦化合物反应，在3位引入乙酸甲酯，接着和对甲亚磺酰基苄基溴进行格氏反应后水解得到舒林酸。

方法2

5-氟-2-甲基-3-氧代-2, 3-二氢-1H-茚与2-氰基乙酸缩合，在3位引入乙酸后，再与对甲硫基苯甲醛缩合。最后通过氧化步骤得到舒林酸。

方法3

此方法类似于方法2，仅在侧链引入的顺序上有所不同。

方法4

5-氟-2-甲基-1-氧代-2, 3-二氢-1H-茚与对甲硫基苄基氯进行格氏反应，在1位引入对甲硫基苄基。随后在酸性条件下脱水形成双键，再通过乙醛酸的反应引入3位乙酸基，并经双氧水分解使双键位置改变后得到舒林酸。

反应信息

• 作为反应物：
  描述：

  Sulindac 在 Oxone 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 24.0h， 以75%的产率得到2-[(3Z)-6-氟-2-甲基-3-[(4-甲基磺酰基苯基)亚甲基]茚-1-基]乙酸
  参考文献：
  名称：

  舒林酸异羟肟酸对人胰腺癌和结肠癌细胞的治疗潜力

  摘要：

  非甾体抗炎药（NSAID）舒林酸在人类癌症中表现出环加氧酶（COX）依赖性和COX依赖性化学预防特性。本研究旨在研究用异羟肟酸取代羧酸基团是否可以增强舒林酸的体外抗肿瘤和抗血管生成活性。这项研究中使用的表征工具包括细胞活力分析，胱天蛋白酶3/7诱导，DNA片段化和基因表达。我们的研究结果表明，新合成的舒林酸异羟肟酸衍生物及其砜和硫化物代谢物的功效对人胰腺癌和结肠癌细胞具有良好的抗癌活性（IC 50平均值从6±1.1μM到64 ±1.1μM）和功效（Ë最大〜100％）。异羟肟酸衍生物比羧酸对应物触发更高程度的凋亡，增加bax / bcl-2表达比并诱导caspase 3/7活化。最值得注意的是，这些化合物在亚微摩尔浓度下显着抑制了促血管生成生长因子刺激的血管内皮细胞（HUVEC）的增殖。我们的数据还提供了证据，舒林酸异羟肟酸的COX活性代谢产物是该系列中最活跃的，选择性抑制COX-1而不是C

  DOI：

  10.1016/j.ejmech.2010.08.019
• 作为产物：
  描述：

  对氟苯甲醛 在 碘 、 sodium methylate 、 potassium carbonate 、 锌 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 8.5h， 生成 Sulindac
  参考文献：
  名称：

  作为具有潜在抗糖尿病功效的 PPARγ 部分激动剂的新型舒林酸衍生物的设计、合成和生物学评价

  摘要：

  过氧化物酶体增殖物激活受体 γ (PPARγ) 是治疗糖尿病的重要药物靶点，PPARγ 的配体已显示出强大的抗糖尿病功效。然而，为了克服当前 PPARγ 靶向药物的严重副作用，需要开发新的 PPARγ 配体。Sulindac 是一种已鉴定的 PPARγ 配体，作为非甾体抗炎药广泛应用于临床。为了探索其在糖尿病方面的潜在应用，我们设计并合成了一系列舒林酸衍生物，以研究它们作为 PPARγ 配体的构效关系和潜在的抗糖尿病作用。我们发现舒林酸的亚苄基部分中的间位取代有利于 PPARγ 结合和反式激活。Z而不是E亚苄基双键的构型赋予了具有 PPARγ 激活选择性的衍生物。茚氟对于结合和调节 PPARγ 是必不可少的。与罗格列酮相比，具有苄氧基间位取代和Z亚苄基双键的化合物6b弱诱导脂肪生成和PPARγ靶向基因表达。然而，6b有效地改善了糖尿病小鼠模型的葡萄糖耐量。与罗格列酮不同，6b对成骨细胞的形成没有明显的毒性。因此，我们为基于

  DOI：

  10.1016/j.ejmech.2021.113542

文献信息

• [EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2010144486A1

  公开（公告）日：2010-12-16

  Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

  揭示了式(I)的JAK抑制剂，其中G1、R1、R2、R3、R4、R5、R6和R7在规范中定义。还披露了含有这些化合物的药物组合物、试剂盒和制造物品，制备这些化合物的方法和材料，以及使用这些化合物治疗涉及免疫系统和炎症的疾病、紊乱和症状的方法，包括类风湿关节炎、血液恶性肿瘤、上皮癌（即癌症）和其他与JAK相关的疾病、紊乱或症状。
• [EN] CATHEPSIN CYSTEINE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE PROTÉASES À CYSTÉINE DE TYPE CATHEPSINES
  申请人：MERCK SHARP & DOHME

  公开号：WO2015054038A1

  公开（公告）日：2015-04-16

  This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.

  这项发明涉及一类新型化合物，它们是半胱氨酸蛋白酶抑制剂，包括但不限于对卡特普辛K、L、S和B的抑制剂。这些化合物可用于治疗需要抑制骨吸收的疾病，如骨质疏松症。
• Eflornithine Prodrugs, Conjugates and Salts, and Methods of Use Thereof
  申请人：Xu Feng

  公开号：US20100120727A1

  公开（公告）日：2010-05-13

  In one aspect, the present invention provides a composition of a covalent conjugate of an eflornithine analog with an anti-inflammatory drug. In another aspect, the present invention provides a composition of an eflornithine prodrug. In another aspect, the present invention provides a composition of an eflornithine or its derivatives aspirin salt. In another aspect, the present invention provides methods for treating or preventing cancer using the conjugates or salts of eflornithine analogs or eflornithine prodrugs.

  在一个方面，本发明提供了一种氟硝西汀类似物与抗炎药物的共价结合物的组合物。在另一个方面，本发明提供了一种氟硝西汀前药的组合物。在另一个方面，本发明提供了一种氟硝西汀或其衍生物水杨酸盐的组合物。在另一个方面，本发明提供了使用氟硝西汀类似物或氟硝西汀前药的共轭物或盐来治疗或预防癌症的方法。
• SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
  申请人：BLUM Andreas

  公开号：US20140135309A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I wherein Ar, R 1 and R 2 are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及公式I的新型磺酰胺取代的喹唑啉衍生物，其中Ar、R1和R2如本文所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2014072244A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的配方(I)的磺酰胺取代喹唑啉衍生物，其中Ar、R1和R2如描述和声明中所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。