cyclosporin A | 79217-60-0

• 物质功能分类: 生物化工 - 抑制剂 - 免疫抑制剂
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: cyclosporin A
• 英文别名: cyclosporine A；cyclosporine；CsA；cyclosporin；ciclosporin；ciclosporin A；Sandimmune；Neoral(R)；Sandimmun；CyA；cyclo[(E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]；sandimmun-neoral；(3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
• CAS: 79217-60-0
• 化学式: C₆₂H₁₁₁N₁₁O₁₂
• 分子量: 1202.63
• InChiKey: PMATZTZNYRCHOR-CGLBZJNRSA-N

物化性质

• 物理描述：
  Cyclosporin a appears as white prismatic needles (from acetone) or white powder. (NTP, 1992)
• 颜色/状态：
  Forms white prismatic crystals from acetone
• 沸点：
  838.63
• 熔点：
  148-151 °C
• 溶解度：
  Slightly soluble (NTP, 1992)
• 旋光度：
  Optical rotation: -244 degrees @ 20 °C (c = 0.6 in chloroform), - 189 degrees @ 20 °C (c = 0.5 in methanol)
• 分解：
  When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
• Caco2细胞的药物渗透性：
  -6.05
• 碰撞截面：
  350.3 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  85
• 可旋转键数：
  15
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  279
• 氢给体数：
  5
• 氢受体数：
  12

ADMET

代谢

环孢素在小肠和肝脏通过CYP450酶代谢，主要是CYP3A4，CYP3A5也有所贡献。CYP3A7的参与尚不明确。环孢素经过多种代谢途径，已经识别出大约25种不同的代谢物。根据一些研究，其主要活性代谢物AM1与原药相比，活性仅为10-20%。3个主要的代谢物是M1、M9和M4N，它们分别由1-beta位、9-gAMma位和4-N-去甲基位的氧化产生。

Cyclosporine is metabolized in the intestine and the liver by CYP450 enzymes, predominantly CYP3A4 with contributions from CYP3A5. The involvement of CYP3A7 is not clearly established. Cyclosporine undergoes several metabolic pathways and about 25 different metabolites have been identified. One of its main active metabolites, AM1, demonstrates only 10-20% activity when compared to the parent drug, according to some studies. The 3 primary metabolites are M1, M9, and M4N, which are produced from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively.

来源:DrugBank

代谢

环孢素在肝脏中被细胞色素P450 3A（CYP3A）酶系统广泛代谢，在一定程度上也会通过胃肠道和肾脏代谢。在人的胆汁、粪便、血液和尿液中已经鉴定出至少25种代谢物。尽管环孢素的环状肽结构相对抵抗代谢，但其侧链被广泛代谢。所有代谢物与母药相比，生物活性和毒性都降低了。

Cyclosporine is extensively metabolized in the liver by the cytochrome-P450 3A (CYP3A) enzyme system & to a lesser degree by the GI tract & kidneys. At least 25 metabolites have been identified in human bile, feces, blood, & urine. Although the cyclic peptide structure of cyclosporine is relatively resistant to metab, the side chains are extensively metabolized. All of the metabolites have both reduced biological activity & toxicity compared to the parent drug.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在几项大型临床试验中，环孢素治疗的开始与血清胆红素水平的轻度升高有关，通常没有血清ALT或碱性磷酸酶的显著增加。血清酶的升高也有描述，但较少见。最近，这些并发症似乎较少发生，这可能是因为对环孢素的剂量和水平监测更为谨慎。此外，在治疗没有移植诸多并发症的自身免疫疾病时，环孢素治疗与高达30%的患者出现轻度血清碱性磷酸酶升高有关，但异常是无症状的，通常是自限性的，很少需要调整剂量。在几个病例系列中，环孢素治疗也与胆泥和胆石症有关。有临床明显急性肝损伤的孤立病例报告归因于环孢素。发病时间在开始使用环孢素后的几周内，血清酶升高的模式是胆汁淤积。一旦停止使用环孢素，恢复就会很快，尚未有因环孢素引起的慢性肝炎或急性肝衰竭的报道。

In several large clinical trials, initiation of cyclosporine therapy was associated with mild elevations in serum bilirubin levels, often without significant increases in serum ALT or alkaline phosphatase. Elevations in serum enzymes were also described, but less commonly. Recently, these complications appear to be less frequent, perhaps because of more careful dosing and monitoring of cyclosporine levels. Furthermore, in treatment of autoimmune diseases without the many complications of transplantation, cyclosporine therapy has been associated with mild serum alkaline phosphatase elevations in up to 30% of patients, but the abnormalities are asymptomatic, usually self-limiting and rarely require dose adjustment. In several case series, cyclosporine therapy has also been associated with biliary sludge and cholelithiasis. Isolated case reports of clinically apparent acute liver injury have been attributed to cyclosporine. The time to onset was within a few weeks of starting cyclosporine and the pattern of serum enzyme elevations was cholestatic. Recovery was prompt once cyclosporine was stopped and cases of chronic hepatitis or acute liver failure due to cyclosporine have not been reported.

来源:LiverTox

毒理性

• 药物性肝损伤

环孢素

Compound:cyclosporine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：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：7

Severity Grade:7

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

环孢素的吸收主要发生在肠道。环孢素的吸收非常不稳定，最高生物利用度为30%，有时在给药后1-8小时出现峰值，某些患者中观察到第二个峰值。从胃肠道吸收环孢素被发现是不完全的，可能是由于首次通过效应。血液和血浆中的Cmax大约在给药后3.5小时出现。0.1%环孢素眼用乳剂的Cmax为0.67 ng/mL，在每日四次滴眼后。关于不规则吸收的说明在长期给药期间，根据诺华公司的处方信息，观察到软胶囊和口服溶液的吸收是不规则的。长期服用软胶囊或口服溶液的人应通过测试环孢素血药浓度并相应调整剂量来定期监测。与其他口服形式的Sandimmune相比，Neoral胶囊和溶液的吸收率更高，导致Tmax更高，Cmax高出59%，生物利用度高出29%。

The absorption of cyclosporine occurs mainly in the intestine. Absorption of cyclosporine is highly variable with a peak bioavailability of 30% sometimes occurring 1-8 hours after administration with a second peak observed in certain patients. The absorption of cyclosporine from the GI tract has been found to be incomplete, likely due to first pass effects. Cmax in both the blood and plasma occurs at approximately 3.5 hours post-dose. The Cmax of a 0.1% cyclosporine ophthalmic emulsion is 0.67 ng/mL after instilling one drop four times daily. A note on erratic absorption During chronic administration, the absorption of Sandimmune Soft Gelatin Capsules and Oral Solution have been observed to be erratic, according to Novartis prescribing information. Those being administered the soft gelatin capsules or oral solution over the long term should be regularly monitored by testing cyclosporine blood concentrations and adjusting the dose accordingly. When compared with the other oral forms of Sandimmune, Neoral capsules and solution have a higher rate of absorption that results in a higher Tmax and a 59% higher Cmax with a 29 % higher bioavailability.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在硫酸盐结合之后，环孢素留在胆汁中，在那里它被分解回原始化合物，然后重新吸收进入循环。环孢素的排泄主要是通过胆汁，只有3-6%的剂量（包括母药和代谢物）通过尿液排出，而90%的给药剂量通过胆汁消除。在排出的比例中，不到1%的剂量以未改变的环孢素形式排出。

After sulfate conjugation, cyclosporine remains in the bile where it is broken down to the original compound and then re-absorbed into the circulation. Cyclosporine excretion is primarily biliary with only 3-6% of the dose (including the parent drug and metabolites) excreted in the urine while 90% of the administered dose is eliminated in the bile. From the excreted proportion, under 1% of the dose is excreted as unchanged cyclosporine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

环孢素在血液中的分布包括血浆中占33%-47%，淋巴细胞中占4%-9%，粒细胞中占5%-12%，红细胞中占41%-58%。环孢素的分布容积据报道为每千克体重4-8升。由于环孢素高度亲脂性，它主要集中在对白细胞丰富的组织以及含有大量脂肪的组织。环孢素眼药水制剂能够穿过血视网膜屏障。

The distribution of cyclosporine in the blood consists of 33%-47% in plasma, 4%-9% in the lymphocytes, 5%-12% in the granulocytes, and 41%-58% in the erythrocytes. The reported volume of distribution of cyclosporine ranges from 4-8 L/kg. It concentrates mainly in leucocyte-rich tissues as well as tissues that contain high amounts of fat because it is highly lipophilic. Cyclosporine, in the eye drop formulation, crosses the blood-retinal barrier.

来源:DrugBank

吸收、分配和排泄

• 清除

环孢素表现出从0.38到3 Lxh/kg的线性清除率，然而，患者之间的变异性很大。在脂质微乳剂型的口服软胶囊中，250毫克的环孢素剂量大约有22.5 L/h的清除率。

Cyclosporin shows a linear clearance profile that ranges from 0.38 to 3 Lxh/kg, however, there is substantial inter- patient variability. A 250 mg dose of cyclosporine in the oral soft gelatin capsule of a lipid micro-emulsion formulation shows an approximate clearance of 22.5 L/h.

来源:DrugBank

吸收、分配和排泄

在口服环孢素后，达到最高血药浓度的时间为1.5-2.0小时。与食物同服会延迟并减少吸收。在给药后30分钟内摄入高脂肪和低脂肪餐分别会使曲线下面积（AUC）减少约13%，使最高浓度减少33%。这使得个体化门诊病人的剂量方案变得至关重要。环孢素在血管外分布广泛。在静脉给药后，稳态分布容积在实体器官移植受者中可高达3-5升/千克。仅有0.1%的环孢素以原形从尿液中排出。...环孢素及其代谢物主要通过胆汁进入粪便排出，只有大约6%通过尿液排出。环孢素也通过人乳排出。

Following oral admin of cyclosporine, the time to peak blood concns is 1.5-2.0 hr. Admin with food both delays & decreases absorption. High & low fat meals consumed within 30 min of admin decr the AUC by approx 13% & the max concn by 33%. This makes it imperative to individualize dosage regimens for outpatients. Cyclosporine is distributed extensively outside the vascular compartment. After iv dosing, the steady-state volume of distribution has been reported to be as high as 3-5 liters/kg in solid-organ transplant recipients. Only 0.1% of cyclosporine is excreted unchanged in urine. ... Cyclosporine & its metabolites are excreted principally through the bile into the feces, with only approx 6% being excreted in the urine. Cyclosporine also is excreted in human milk.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  T
• 危险类别码：
  R40,R22,R60,R45
• 安全说明：
  S22,S24/25,S36/37,S45,S53
• 储存条件：
  -20°C

制备方法与用途

疏水性多肽药物

环孢菌素又称环孢霉素、环孢菌素A或山地明。这种由某些丝孢纲真菌，如光泽柱孢菌和膨大弯颈霉产生的疏水性多肽药物，是一种强力的T细胞免疫抑制剂。它能够选择性地抑制辅助性T细胞，从而抑制细胞免疫反应和体液免疫反应。辅助性T细胞负责传递抗原信息给B细胞，并诱导其产生抗体；同时还能协助杀伤性T细胞及巨噬细胞发挥免疫作用。

• 杀伤性T细胞能够直接或间接地杀死带有抗原标记的靶细胞，释放多种淋巴因子，引发迟发型变态反应。环孢菌素广泛应用于临床上的器官移植（尤其是肾脏和肝脏）或骨髓移植时，用于防止发生危险的排异反应。

使用历史

环孢素(英语：Cyclosporine A，简称CsA)，于1969年首次从土壤样本中的多孔木霉中分离出来，并在1972年被发现具有免疫抑制功能。此后陆续证实其可用于肾脏移植、肝脏移植的免疫抑制治疗。第一个商品药Sandimmune于1983年在瑞士上市，开始正式用于临床。

药理作用

环孢菌素是一种新型T淋巴细胞调节剂，主要通过选择性地作用于辅助性T淋巴细胞(TH)，阻断抗原或有丝分裂原刺激的淋巴增生、分化和成熟过程。它还能减少白细胞介素-2等淋巴因子的产生，并能阻滞细胞周期G0/G1早期相中休止的淋巴细胞，从而抑制体内抗移植物抗体的产生。

药代动力学

环孢菌素口服吸收不规则且差异大，生物利用度为30%，但可随治疗时间延长和剂量增大而增加。肝移植后、肝病或胃肠功能混乱患者可能吸收减少。本品与血浆蛋白结合率高达约90%，主要与脂蛋白结合。口服达峰时间为3～4小时，全血浓度可为血浆的2～9倍。成人的血浆T1/2为19(10～27)小时，儿童仅为7(7～19)小时。

适应证

环孢菌素适用于预防同种异体肝、肾、肺、骨髓、心脏等器官或组织移植所发生的排斥反应，也可用于预防及治疗骨髓移植时发生的移植物抗宿主反应。常与肾上腺皮质激素等免疫制剂联合应用以提高疗效。

用途

山地明环孢灵被认为是一种免疫抑制剂，能够与T淋巴细胞中的亲环素结合。

不良反应

环孢菌素的毒性比其他免疫抑制剂低，但可引起肝、肾损害、高血压及中枢神经症状；易引发继发感染；大剂量快速静脉注射（约6.25mg/kg）可导致震颤、抽搐和癫痫样症状。不良反应还包括多毛症、牙龈肿胀和胃肠不适。

生物活性

环孢菌素通过与亲环素形成复合物，抑制钙调磷酸酶的磷酸酶活性，并调节核转运及随后NFAT转录因子的活化。它也能阻断抗原识别引起的JNK 和p38激活，成为T细胞活化的特异性抑制剂。

体内研究

环孢菌素可增强免疫缺陷的SCID浅褐色小鼠体内的肿瘤生长，并在小鼠体内抑制诱发型创伤后肌肉再生。在血液、脾脏和肾脏中1小时内达到最高浓度，且脾脏和肾脏中的浓度高于血液中的浓度。

• 用途：用于治疗白血病、癌、肾移植、结核病等。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	cyclosporin A	59865-13-3	C62H111N11O12	1202.63
  环孢菌素 H	cyclo-[MeBmt-Abu-Sar-MeLeu-Val-MeLeu-Ala-D-Ala-MeLeu-MeLeu-DMeVal]	83602-39-5	C62H111N11O12	1202.63

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	[(R)-2-methyl-Sar]-3-cyclosporin	——	C63H113N11O12	1216.66
  ——	[L-MeSar]3-CsA	——	C63H113N11O12	1216.66
  环孢菌素 H	cyclo-[MeBmt-Abu-Sar-MeLeu-Val-MeLeu-Ala-D-Ala-MeLeu-MeLeu-DMeVal]	83602-39-5	C62H111N11O12	1202.63
  ——	[(R)-α-hydroxymethyl-sar]-3-cyclosporin	108466-69-9	C63H113N11O13	1232.66
  环孢菌素 C	cyclosporin C	59787-61-0	C62H111N11O13	1218.63
  挥发性孢子蛋白	Voclosporin	515814-01-4	C63H111N11O12	1214.64
  ——	(5R,6R,E)-6-((2S,5S,11S,14S,17S,20S,23R,26S,29S,32S)-5-ethyl-11,17,26,29-tetraisobutyl-14,32-diisopropyl-1,7,10,16,20,23,25,28,31-nonamethyl-3,6,9,12,15,18,21,24,27,30,33-undecaoxo-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2-yl)-6-hydroxy-5-methylhex-2-enoic acid	100364-58-7	C62H109N11O14	1232.61
  SCY-635前体	[(γ-hydroxy)-N-MeLeu]-4-cyclosporin	107335-26-2	C62H111N11O13	1218.63
  ——	[(R)-α-hydroxymethyl-Sar]-3-[(γ-hydroxy)-NMeLeu]-4-cyclosporin	——	C63H113N11O14	1248.66
  ——	[(3R,4R)-3-hydroxy-4-methyl-6-(2-hydroxyethyl)-N-MeNle]-1-cyclosporin	——	C62H113N11O13	1220.65

反应信息

• 作为反应物：
  描述：

  cyclosporin A 在 臭氧 、 sodium tetrahydroborate 作用下， 以 二氯甲烷 、 甲醇 为溶剂， 反应 0.5h， 以81%的产率得到33-(1,4-dihydroxy-2-methyl-butyl)-30-ethyl-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31undecaaza-cyclotritriacontan-2,5,8,11,14,17,20,23,26,29,32-undecaone
  参考文献：
  名称：

  Selective Inhibition of Engineered Receptors via Proximity-Accelerated Alkylation

  摘要：

  [GRAPHICS]A new approach for creating allele-specific inhibitors is demonstrated. In this approach, a receptor and ligand are engineered to contain complementary reactive groups that form a covalent bond via a proximity-accelerated reaction upon formation of the receptor-ligand complex, irreversibly modulating the biological function of the receptor. This approach is demonstrated in the cyclophilin-cyclosporin receptor-ligand system by introducing thiol and acrylamide functional groups in the receptor and ligand, respectively.

  DOI：

  10.1021/ol027448k
• 作为产物：
  描述：

  7,8-Secocyclosporin-7-carboxylic acid 在 异氰环已烷 、 1-羟基苯并三唑 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 以6.4 mg的产率得到cyclosporin A
  参考文献：
  名称：

  环孢菌素的全合成：通过异腈偶联反应获得 N-甲基化肽

  摘要：

  使用异腈提供仲和叔酰胺键形成的最新进展已应用于重要环状多肽环孢菌素 A 的新型全合成。 具体而言，所公开的合成路线证明了微波介导的羧酸异腈偶联、硫代酸的效用环境温度下的异腈偶联，以及异腈介导的羧酸和硫代酸与胺的偶联以形成具有挑战性的酰胺键。

  DOI：

  10.1021/ja100517v
• 作为试剂：
  描述：

  cyclosporin A 、 甲烷磺酸 、 sodium hydroxide 在 二氯甲烷 、 crude material 、 丙酮 、 cyclosporin A 、 环孢菌素 H 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.0h， 以Approximately, 9 mg of cyclosporin H was isolated with a melting point 150-160° C.的产率得到环孢菌素 H
  参考文献：
  名称：

  Synthesis of Cyclosporin H

  摘要：

  一种制备纯化环孢霉素H的方法，包括将环孢霉素A溶解在第一有机溶剂中，并在酸催化剂的存在下加热第一有机溶剂；向第一有机溶剂中加入碱；在第二溶剂中重结晶环孢霉素H；并通过层析法纯化重结晶的环孢霉素H，从而获得纯化的环孢霉素H，但不包括在醚的存在下重结晶环孢霉素H。在进一步的方面，该方法包括在加入碱之后，在重结晶之前，将第一有机溶剂与比第一有机溶剂极性更高的溶剂混合，分离第一有机溶剂，并干燥第一有机溶剂。据本文所述制备的环孢霉素H被发现具有生物活性，而不像以前描述的方法制备的那样。

  公开号：

  US20120253007A1

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。
• [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。
• SULFONAMIDE, SULFAMATE, AND SULFAMOTHIOATE DERIVATIVES
  申请人：Wang Zhong

  公开号：US20120077814A1

  公开（公告）日：2012-03-29

  The disclosure provides biologically active compounds of formula (I): and pharmaceutically acceptable salts thereof, compositions containing these compounds, and methods of using these compounds in a variety applications, such as treatment of diseases or disorders associated with E1 type activating enzymes, and with Nedd8 activating enzyme (NAE) in particular.

  该披露提供了化学式(I)的生物活性化合物及其药用盐，含有这些化合物的组合物，以及在各种应用中使用这些化合物的方法，例如用于治疗与E1型激活酶相关的疾病或紊乱，特别是与Nedd8激活酶(NAE)相关的疾病或紊乱。
• [EN] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
  申请人：GALAPAGOS NV

  公开号：WO2017012647A1

  公开（公告）日：2017-01-26

  The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.

  本发明公开了根据式（I）的化合物，其中R1、R3、R4、R5、L1和Cy如本文所定义。本发明还提供了该发明的化合物、制备该化合物的方法、包括相同化合物的药物组合物以及它们在过敏或炎症症状、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨周转障碍的疾病、先天软骨畸形和/或与IL6和/或干扰素过度分泌相关的疾病中的使用。本发明还提供了通过给予该发明的化合物来预防和/或治疗上述疾病的方法。