他克莫司 | 104987-11-3

• 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 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 中文名称: 他克莫司
• 中文别名: 藤霉素
• 英文名称: Tacrolimus
• 英文别名: FK-506；TAC；(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-prop-2-enyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetrone
• CAS: 104987-11-3
• 化学式: C₄₄H₆₉NO₁₂
• 分子量: 804.031
• InChiKey: QJJXYPPXXYFBGM-LFZNUXCKSA-N

物化性质

• 熔点：
  113-115°C
• 沸点：
  871.7±75.0 °C(Predicted)
• 密度：
  1.19±0.1 g/cm3(Predicted)
• 闪点：
  2℃
• 溶解度：
  二甲基亚砜：>3 mg/mL
• 蒸汽压力：
  8.37X10-32 mm Hg at 25 °C (est)
• 稳定性/保质期：
  遵照规定使用和储存，则不会发生分解。
• 解离常数：
  pKa1 = 2.94; pKa2 = 9.95; pKa3 = 14.07 (est)
• 碰撞截面：
  267 Ų [M+Na]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  57
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  178
• 氢给体数：
  3
• 氢受体数：
  12

ADMET

代谢

tacrolimus的代谢主要由CYP3A4介导，其次是CYP3A5。Tacrolimus被代谢成8种代谢物：13-去甲基他克莫司、31-去甲基他克莫司、15-去甲基他克莫司、12-羟基他克莫司、15,31-二去甲基他克莫司、13,31-二去甲基他克莫司、13,15-二去甲基他克莫司，以及一个最终代谢物涉及O-去甲基化和形成融合环。在用人肝微粒体进行的孵化中，主要的代谢物是13-去甲基他克莫司。在体外研究中，据报道，31-去甲基代谢物具有与他克莫司相同的活性。

The metabolism of tacrolimus is predominantly mediated by CYP3A4 and secondarily by CYP3A5. Tacrolimus is metabolized into 8 metabolites: 13-demethyl tacrolimus, 31-demethyl tacrolimus, 15-demethyl tacrolimus, 12-hydroxy tacrolimus, 15,31-didemethyl tacrolimus, 13,31-didemethyl tacrolimus, 13,15-didemethyl tacrolimus, and a final metabolite involving O-demethylation and the formation of a fused ring. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

来源:DrugBank

代谢

他克莫司通过混合功能氧化酶系统广泛代谢，主要是细胞色素P-450系统（CYP3A）。已经提出了一个代谢途径，形成8种可能的代谢物。在体外实验中，去甲基化和羟基化被确定为主要生物转化机制。在人肝微粒体培养中确定的主要代谢物是13-去甲基他克莫司。在体外研究中，据报道，31-去甲基代谢物具有与他克莫司相同的活性。

Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

来源:Hazardous Substances Data Bank (HSDB)

代谢

Fk_506 已知的人类代谢物包括 13-O-去甲基他克莫司和 15-O-去甲基他克莫司。

Fk_506 has known human metabolites that include 13-O-Desmethyltacrolimus and 15-O-Desmethyltacrolimus.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

鉴定和使用：他克莫司是一种白色至类白色的结晶性粉末。它是一种钙神经素抑制剂免疫抑制剂，有几种制剂。他克莫司的口服胶囊和静脉注射溶液用于预防接受肝脏、肾脏或心脏移植的患者器官排斥。他克莫司外用软膏作为二线治疗，用于非免疫受损的成人和儿童中至重度异位性皮炎的短期和非连续性慢性治疗。人类暴露和毒性：尽管大多数急性他克莫司过量（达到预期剂量的30倍）是无症状的，所有患者均无后遗症康复，但一些急性过量后出现了不良反应，包括震颤、肾功能异常、高血压和周围性水肿。在治疗剂量下，接受他克莫司治疗的患者发展淋巴瘤和其他恶性肿瘤的风险增加，特别是皮肤，以及发展细菌、病毒、真菌和原虫感染的风险增加，包括机会性感染。这些感染可能导致严重，包括致命的后果。尽管没有对孕妇进行充分和良好的控制研究，但在人类中使用他克莫司与新生儿高钾血症和肾功能不全有关。动物研究：大鼠和狒狒在口服或静脉注射他克莫司后显示出类似的毒理学特征。静脉给药后的毒性比口服给药在大鼠和狒狒中的剂量更低。在大鼠中观察到比狒狒更低的剂量出现毒性。主要靶器官是肾脏、胰岛细胞和胰腺外分泌部分、脾脏、胸腺、胃肠道和淋巴结。此外，还观察到红细胞参数的减少。他克莫司还在大鼠和兔中产生了生殖和发育毒性。在大鼠中，长期口服高剂量的他克莫司导致了性别器官的改变以及青光眼/眼部变化。口服剂量为1和3.2 mg/kg/天的他克莫司在大鼠中产生了明显的亲代毒性以及生育力和一般生殖性能的改变。对生殖的影响包括一些胚胎致死性、植入数量的减少、植入后损失的发生率增加以及胚胎和后代存活率的降低。在兔的致畸研究中，所有口服剂量的他克莫司（0.1、0.32或1 mg/kg/天）都产生了母体毒性迹象，包括体重减轻。剂量为0.32和1 mg/kg/天的他克莫司产生了发育毒性的迹象，如植入后损失的发生率增加、存活胎儿数量减少以及形态变异的发生率增加。在大鼠的致畸研究中，3.2 mg/kg/天的剂量观察到植入后损失增加。母体剂量为1 mg/kg/天的F1后代体重减轻。在母体剂量为3.2 mg/kg/天的情况下，F1后代的体重减轻、存活数量减少以及一些骨骼改变。他克莫司在体外细菌试验（使用沙门氏菌属和大肠杆菌）和哺乳动物试验（使用中国仓鼠肺细胞）中没有表现出基因毒性活性。在体外CHO/HGPRT试验（中国仓鼠卵巢细胞试验，测量HGPRT位点的正向突变）或体内小鼠的染色体畸变试验中，没有观察到致突变性的证据。他克莫司也没有在啮齿动物肝细胞中引起非计划性DNA合成。

IDENTIFICATION AND USE: Tacrolimus is white to off-white crystalline powder. It is a calcineurin-inhibitor immunosuppressant available in several preparations. Tacrolimus in both oral capsules and a solution for IV injection is used for prophylaxis of organ rejection in patients receiving liver, kidney or heart transplants. Tacrolimus topical ointment is used as a second-line therapy for the short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis in non-immunocompromised adults and children. HUMAN EXPOSURE AND TOXICITY: While most acute overdosages of tacrolimus at up to 30 times the intended dose have been asymptomatic and all patients recovered with no sequelae, some acute overdosages were followed by adverse reactions including tremors, abnormal renal function, hypertension, and peripheral edema. At therapeutic doses, patients receiving tacrolimus are at increased risk of developing lymphomas and other malignancies, particularly of the skin, as well as an increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. While there are no adequate and well-controlled studies in pregnant women, the use of tacrolimus during pregnancy in humans has been associated with neonatal hyperkalemia and renal dysfunction. ANIMAL STUDIES: Both rats and baboons showed a similar toxicologic profile following oral or intravenous administration of tacrolimus. Toxicity following intravenous administration was evident at lower doses than after oral administration for both rats and baboons. Toxicity was seen at lower doses in rats than in baboons. The primary target organs were the kidneys, pancreatic islets of Langerhans and exocrine pancreas, spleen, thymus, gastrointestinal tract, and lymph nodes. In addition, decreases in erythrocyte parameters were seen. Tacrolimus also produced reproductive and developmental toxicity in both rats and rabbits. In rats, chronic oral administration of tacrolimus at high doses resulted in changes in sex organs, and glaucoma/eye changes. Oral doses of tacrolimus at 1 and 3.2 mg/kg/day produced overt signs of parental toxicity and changes in the fertility and general reproductive performance of rats. Effects on reproduction included some embryo lethality, reduced number of implantations, increased incidence of post-implantation loss, and reduced embryo and offspring viability. In a rabbit teratology study, signs of maternal toxicity including reduced body weight were produced at all oral doses of tacrolimus administered (0.1, 0.32, or 1 mg/kg/day). Doses of 0.32 and 1 mg/kg/day produced signs of developmental toxicity, such as increased incidence of post-implantation losses, reduced number of viable fetuses, and increased incidences of morphological variations. In a rat teratology study, increased post-implantation loss was observed at 3.2 mg/kg/day. Maternal doses of 1 mg/kg/day decreased the body weight of F1 offspring. Decreased body weight, reduced survival number, and some skeletal alterations were seen in F1 offspring at maternal doses of 3.2 mg/kg/day. Tacrolimus did not exhibit genotoxic activity in vitro in bacterial asaays in Salmonella typhimurium and Escherichia coli or mammalian assays in Chinese hamster lung-derived cells assays. No evidence of mutagenicity was observed in vitro in the CHO/HGPRT assay (the Chinese hamster ovary cell assay (CHO), which measures forward mutation of the HGPRT locus) or in vivo in clastogenicity assays performed in mice. Tacrolimus also did not cause unscheduled DNA synthesis in rodent hepatocytes.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

他克莫司治疗与5%至10%的患者血清转氨酶水平轻至中度升高有关。这些升高通常是轻微的、无症状的且自我限制的，但偶尔会持续存在，可能需要调整剂量。他克莫司还与胆汁淤积性肝炎的实例有关，但临床上明显的肝损伤是罕见的。因为他克莫司用于器官移植的背景下，常常用于肝移植，所以在治疗期间出现的肝功能测试异常的原因有很多，而他克莫司引起的药物性肝损伤足够罕见，其临床特征和典型病程尚未被定义。

Tacrolimus therapy is associated with mild to moderate elevations in serum aminotransferase levels in 5% to 10% of patients. These elevations are usually mild, asymptomatic and self-limited, but are occasionally persistent and may require dose modification. Tacrolimus has also been implicated in instances of cholestatic hepatitis, but clinically apparent liver injury is rare. Because tacrolimus is used in the context of organ transplantation and often in liver transplantation, the causes of liver test abnormalities arising during therapy are many, and drug induced liver injury due to tacrolimus is sufficiently rare that its clinical features and typical course have not been defined.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：他克莫司

Compound:tacrolimus

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：5

Severity Grade:5

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

从胃肠道吸收Tacrolimus在成人肾移植患者中的绝对生物利用度为17±10%;成年肝移植患者为22±6%;健康受试者为18±5%。儿童肝移植患者的绝对生物利用度为31±24%。在18例健康志愿者空腹单次口服3、7和10mg的Tacrolimus后，Tacrolimus最大血药浓度(Cmax)和药时曲线下面积(AUC)呈剂量依赖性增加。在没有食物的情况下，吸收速率和程度最大。用餐时间也会影响生物利用度。在饭后立即服用时，平均Cmax降低了71%，平均AUC降低了39%，相对于空腹状态。在饭后1.5小时给药，平均Cmax降低了63%，平均AUC降低了39%，相对于空腹状态。

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±24%. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.

来源:DrugBank

吸收、分配和排泄

• 消除途径

在人体中，给药剂量的不到1%以未改变的形式通过尿液排出。当通过静脉给药时，粪便消除占92.6±30.7%，尿液消除占2.3±1.1%。

In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.

来源:DrugBank

吸收、分配和排泄

• 分布容积

2.6 ± 2.1 L/kg [儿科肝移植患者] 1.07 ± 0.20 L/kg [肾功能损害患者，0.02 mg/kg/4小时剂量，静脉注射] 3.1 ± 1.6 L/kg [轻度肝功能损害，0.02 mg/kg/4小时剂量，静脉注射] 3.7 ± 4.7 L/kg [轻度肝功能损害，7.7 mg剂量，口服] 3.9 ± 1.0 L/kg [严重肝功能损害，0.02 mg/kg/4小时剂量，静脉注射] 3.1 ± 3.4 L/kg [严重肝功能损害，8 mg剂量，口服]

2.6 ± 2.1 L/kg [pediatric liver transplant patients] 1.07 ± 0.20 L/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV] 3.1 ± 1.6 L/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV] 3.7 ± 4.7 L/kg [Mild Hepatic Impairment, 7.7 mg dose, PO] 3.9 ± 1.0 L/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV] 3.1 ± 3.4 L/kg [Severe hepatic impairment, 8 mg dose, PO]

来源:DrugBank

吸收、分配和排泄

• 清除

0.040 升/小时/千克 [健康受试者，静脉注射] 0.172 ± 0.088 升/小时/千克 [健康受试者，口服] 0.083 升/小时/千克 [成人肾脏移植患者，静脉注射] 0.053 升/小时/千克 [成人肝脏移植患者，静脉注射] 0.051 升/小时/千克 [成人心脏移植患者，静脉注射] 0.138 ± 0.071 升/小时/千克 [儿童肝脏移植患者] 0.12 ± 0.04 (范围 0.06-0.17) 升/小时/千克 [儿童肾脏移植患者] 0.038 ± 0.014 升/小时/千克 [肾功能损害患者，0.02 毫克/千克/4 小时剂量，静脉注射] 0.042 ± 0.02 升/小时/千克 [轻度肝功能损害，0.02 毫克/千克/4 小时剂量，静脉注射] 0.034 ± 0.019 升/小时/千克 [轻度肝功能损害，7.7 毫克剂量，口服] 0.017 ± 0.013 升/小时/千克 [严重肝功能损害，0.02 毫克/千克/4 小时剂量，静脉注射] 0.016 ± 0.011 升/小时/千克 [严重肝功能损害，8 毫克剂量，口服]

0.040 L/hr/kg [healthy subjects, IV] 0.172 ± 0.088 L/hr/kg [healthy subjects, oral] 0.083 L/hr/kg [adult kidney transplant patients, IV] 0.053 L/hr/kg [adult liver transplant patients, IV] 0.051 L/hr/kg [adult heart transplant patients, IV] 0.138 ± 0.071 L/hr/kg [pediatric liver transplant patients] 0.12 ± 0.04 (range 0.06-0.17) L/hr/kg [pediatric kidney transplant patients] 0.038 ± 0.014 L/hr/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV] 0.042 ± 0.02 L/hr/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV] 0.034 ± 0.019 L/hr/kg [Mild Hepatic Impairment, 7.7 mg dose, PO] 0.017 ± 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV] 0.016 ± 0.011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO]

来源:DrugBank

吸收、分配和排泄

本研究旨在评估哺乳期间母乳中他克莫司的水平和新生儿的暴露情况。在一项观察性队列研究中，对两个三级转诊高风险妇产医学诊所进行了研究。研究了14名在孕期和哺乳期服用他克莫司的妇女及其15名婴儿，其中11名婴儿为纯母乳喂养。通过液相色谱-串联质谱法分析他克莫司水平。在可能的情况下，收集了母亲、脐带血以及产后母亲、婴儿和母乳的样本。所有进行系列抽样的婴儿的他克莫司水平都有下降，大约每天下降15%（几何平均浓度比率为0.85；95%置信区间，0.82-0.88；P<0.001）。母乳喂养的婴儿与奶瓶喂养的婴儿在他克莫司水平上没有差异（中位数1.3微克/升[范围，0.0-4.0]对1.0微克/升[范围，0.0-2.3]；P=0.91）。从母乳中吸收的最大估计量为母亲剂量的0.23%（按体重调整）。通过母乳摄入他克莫司的量可以忽略不计。母乳喂养似乎不会减缓婴儿从他克莫司在出生时较高水平的下降。

The aim of this study was to assess tacrolimus levels in breast milk and neonatal exposure during breastfeeding. An observational cohort study was performed in two tertiary referral high-risk obstetric medicine clinics. Fourteen women taking tacrolimus during pregnancy and lactation, and their 15 infants, 11 of whom were exclusively breast-fed, were assessed. Tacrolimus levels were analyzed by liquid chromatography-tandem mass spectrometry. Samples from mothers and cord blood were collected at delivery and from mothers, infants, and breast milk postnatally where possible. All infants with serial sampling had a decline in tacrolimus level, which was approximately 15% per day (ratio of geometric mean concentrations 0.85; 95% confidence interval, 0.82-0.88; P<0.001). Breast-fed infants did not have higher tacrolimus levels compared with bottle-fed infants (median 1.3 ug/L [range, 0.0-4.0] versus 1.0 ug/L (range, 0.0-2.3), respectively; P=0.91). Maximum estimated absorption from breast milk is 0.23% of maternal dose (weight-adjusted). Ingestion of tacrolimus by infants via breast milk is negligible. Breastfeeding does not appear to slow the decline of infant tacrolimus levels from higher levels present at birth.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  6.1
• 危险品标志：
  Xi,T
• 安全说明：
  S26,S36,S45
• 危险类别码：
  R36/37/38,R25
• WGK Germany：
  3
• 海关编码：
  29349990
• 危险品运输编号：
  UN 2811 6.1/PG 3
• RTECS号：
  KD4201200
• 危险类别：
  6.1
• 包装等级：
  III
• 危险性防范说明：
  P264,P270,P301+P310+P330,P405,P501
• 危险性描述：
  H301
• 储存条件：
  存储于-20 ºC阴凉干燥处

制备方法与用途

他克莫司是一种大环内酯类免疫抑制剂,主要通过以下机制发挥作用:

1. 与FK506结合蛋白(FKBP)形成复合体。

2. 降低T细胞中肽酰脯氨酰异构酶活性。

3. 抑制白细胞介素-2的合成。

4. 主要用于预防器官移植后的排异反应,对急性排异反应疗效更佳。

他克莫司的生产工艺如下:

1. 发酵生产:从Streptomyces tsukubaensis菌种发酵得到。

2. 提取分离:将发酵液过滤后用丙酮提取,通过树脂柱层析纯化。

3. 净化:经过硅胶色谱和反相高效液相色谱进一步纯化。

4. 结晶:浓缩溶液重结晶得到无色棱状结晶的纯品。

他克莫司的主要用途:

1. 器官移植后预防排异反应

2. 治疗某些自身免疫性疾病,如肾炎、视网膜炎等

需要注意的是,他克莫司是一种处方药,需在医生指导下使用。由于其较强的免疫抑制作用,可能存在感染风险和肾毒性等不良反应。

反应信息

• 作为反应物：
  描述：

  他克莫司 在 臭氧 作用下， 以 二氯甲烷 为溶剂， 生成 5-methoxy-6-(1-methoxy-3-methyl-5-oxohexyl)-3-methyloxan-2-one
  参考文献：
  名称：

  Structure of FK506, a novel immunosuppressant isolated from Streptomyces

  摘要：

  DOI：

  10.1021/ja00250a050
• 作为产物：
  描述：

  14-((tert-butyldimethylsilyl)oxy)-24,32-bis((triisopropylsilyl)oxy)-FK506 在 氢氟酸 作用下， 以 乙腈 为溶剂， 反应 18.0h， 以73%的产率得到他克莫司
  参考文献：
  名称：

  Total synthesis of FK506 and an FKBP probe reagent, [C(8),C(9)-13C2]-FK506

  摘要：

  DOI：

  10.1021/ja00170a024

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。
• 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。
• [EN] 3,5-DIAMINO-6-CHLORO-N-(N-(4-PHENYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2- CARBOXAMIDE COMPOUNDS<br/>[FR] COMPOSÉS 3,5-DIAMINO -6-CHLORO-N-(N- (4-PHÉNYLBUTYL)CARBAMIMIDOYL) PYRAZINE-2-CARBOXAMIDE
  申请人：PARION SCIENCES INC

  公开号：WO2014099673A1

  公开（公告）日：2014-06-26

  The present invention relates compounds of the formula: or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.

  本发明涉及以下化合物的公式：或其药学上可接受的盐，用作钠通道阻滞剂，以及含有这些化合物的组合物，制备这些化合物的方法，以及在促进粘膜表面水合和治疗包括囊性纤维化、慢性阻塞性肺病、哮喘、支气管扩张、急性和慢性支气管炎、肺气肿和肺炎等疾病的治疗方法。