华法林 | 81-81-2

• 物质功能分类: 原料药 - 血液系统用药 - 抗凝血药及抗血小板药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 中文名称: 华法林
• 中文别名: 华法令；法华林；杀鼠灵；灭鼠灵；4-羟基-3-(3-氧代-1-苯基丁基)-2H-1-苯并吡喃-2-酮；3-(1-丙酮基苄基)-4-羟基香豆素；3-(α-丙酮基苄基)-4-羟基香豆素；华法灵
• 英文名称: warfarin
• 英文别名: (R,S)-warfarin；rac-warfarin；4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one；4-hydroxy-3-(3-oxo-1-phenylbutyl)chromen-2-one；3-(α-acetonylbenzyl)-4-hydroxycoumarin；4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one；4-hydroxy-3-(3-oxo-1-phenylbutyl)-2-benzopyran-2-one；Coumadin
• CAS: 81-81-2
• 化学式: C₁₉H₁₆O₄
• mdl: MFCD00006854
• 分子量: 308.334
• InChiKey: PJVWKTKQMONHTI-UHFFFAOYSA-N

物化性质

• 熔点：
  162-164 °C(lit.)
• 沸点：
  356°C
• 密度：
  1.1411 (rough estimate)
• 闪点：
  2℃
• 溶解度：
  Soluble in benzene, 1,4-dioxane (Weast, 1986), and acetone (Sax and Lewis, 1987). Moderately soluble in methanol, ethanol, isopropanol, and some oils (Windholz et al., 1983). Also soluble in toluene.
• 暴露限值：
  NIOSH REL: TWA 0.1 mg/m3, IDLH 100 mg/m3; OSHA PEL: 0.1 mg/m3; ACGIH TLV: TWA 0.1 mg/m3.
• LogP：
  2.600
• 物理描述：
  Warfarin is an odorless and colorless solid. Used as a rodenticide for Norway rats and for house mice. (EPA, 1998)
• 颜色/状态：
  Crystals from alcohol
• 气味：
  Odorless
• 味道：
  Tasteless
• 蒸汽密度：
  Relative vapor density (air = 1): 10.6
• 蒸汽压力：
  1.5X10-3 mPa /1.125X10-8 mm Hg/ at 25 °C
• 水溶性：
  -3.89
• 稳定性/保质期：
  Very stable, even to strong acids.
• 分解：
  When heated to decomposition it emits acrid smoke & fumes.
• 腐蚀性：
  Non-corrosive
• Caco2细胞的药物渗透性：
  -4.68
• 解离常数：
  pKa = 5.87
• 碰撞截面：
  166.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]
• 保留指数：
  2625;2586;2612;2625

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.157
• 拓扑面积：
  63.6
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

华法林的代谢是立体选择性和区域选择性的。[A2460]主要的代谢途径是氧化成各种羟基华法林，占总代谢物的80-85%。CYP2C9是主要的酶，催化S-华法林的6-和7-羟基化，而4'-羟基化是通过CYP2C18实现的，CYP2C19也有少量贡献。R-华法林通过CYP2C8代谢成4'-羟基华法林，CYP2C19也有一定贡献，6-和8-羟基华法林通过CYP1A2和CYP2C19代谢，7-羟基华法林通过CYP1A2和CYP2C8代谢，最后通过CYP3A4代谢成10-羟基华法林。10-羟基华法林代谢物以及一种苄醇代谢物经历一个消除步骤形成脱氢华法林。代谢的次要途径是将酮羰基还原成华法林醇，占总代谢物的20%。与硫酸盐和葡萄糖酸基团有限的结合反应发生，但这些代谢物只被证实存在于R-羟基华法林中。

Metabolism of warfarin is both stereo- and regio-selective.[A2460] The major metabolic pathway is oxidation to various hydroxywarfarins, comprising 80-85% of the total metabolites. CYP2C9 is the major enzyme catalyzing the 6- and 7-hydroxylation of S-warfarin while 4'-hydroxylation occurs through CYP2C18 with minor contributions from CYP2C19. R-warfarin is metabolized to 4'-hydroxywarfarin by CYP2C8 with some contirbuting by CYP2C19, 6- and 8-hydroxywarfarin by CYP1A2 and CYP2C19, 7-hydroxywarfarin by CYP1A2 and CYP2C8, and lastly to 10-hydroxywarfarin by CYP3A4. The 10-hydroxywarfarin metabolite as well as a benzylic alcohol metabolite undergo an elimination step to form dehydrowarfarin. The minor pathway of metabolism is the reduction of the ketone group to warfarin alcohols, comprising 20% of the metabolites. Limited conjugation occurs with sulfate and gluronic acid groups but these metabolites have only been confirmed for R-hydroxywarfarins.

来源:DrugBank

代谢

在所有回收的代谢物中，只有4'-羟基华法林和DHG/2,3-二氢-2-甲基-4-苯基-5-氧代-γ-吡喃醇(3.2-c)(1)苯并吡喃/显示出抗凝血活性。

Of all metabolites recovered, only 4'-hydroxywarfarin & DHG /2,3-dihydro-2-methyl-4-phenyl-5-oxo-gamma-pyranol(3.2-c)(1)benzopyran/ showed anticoagulant activity.

来源:Hazardous Substances Data Bank (HSDB)

代谢

(R)-华法林和(S)-华法林在人肝微粒体中的氧化生物转化进行了研究。在体外从华法林获得的氧化产物的定量模式随着底物浓度的变化而显著改变。形成4', 6, 7, 和8-羟基华法林的表观Km值表明存在两种易于区分的人肝细胞色素P450亚群：一种高亲和力亚群，其Km值为15微摩尔，另一种低亲和力亚群的同种酶Km值大于200微摩尔。高亲和力亚群主要负责生物活性更强的(S)-华法林体内的代谢轮廓，而低亲和力亚群主要负责(R)-华法林的代谢。表观Vmax值本身并不反映两种化合物的酚类代谢物在体内的相对形成，因为低亲和力、高容量的组分掩盖了(S)-华法林的代谢轮廓。每种代谢物的内在清除率(Vmax/Km)的排名与体内区域选择性和立体选择性代谢相符。

The oxidative biotransformation of (R)-warfarin and (S)-warfarin was studied in human liver microsomes. The quantitative pattern of oxidized products obtained from warfarin in vitro changed dramatically as a function of substrate concentration. Apparent Km values for the formation of 4', 6, 7, and 8-hydroxywarfarin showed the presence of two easily distinguishable subsets of human liver cytochrome p450: a high affinity subset with Km of to 15 uM and a low affinity subset of isozymes with Km >200 uM. The high affinity subset was primarily responsible for the metabolic profile of the biologically more potent (S)-warfarin in vivo, whereas the low affinity subset was largely responsible for metabolism of (R)-warfarin. Apparent Vmax values alone did not reflect the relative in vivo formation of the phenolic metabolites from either compound because the low affinity, high capacity component masked the metabolic profile of (S)-warfarin. The rank order of intrinsic clearance (Vmax/Km) for each metabolite agreed well with regioselective and steroeselective metabolism in vivo.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在人类中，(S)异构体主要被7-羟基化，而(R)形式被还原为(R,S)-醇。在大鼠中，(S)异构体主要被4'-羟基化，而(R)对映体被7-羟基化。利用不同的细胞色素P-450形式来解释这些结果。

In humans, the (S) isomer is primarily 7-hydroxylated, whereas the (R) form is reduced to the (R,S)-alcohol. In rats, the (S) isomer is primarily 4'-hydroxylated, whereas the (R) enantiomer is 7-hydroxylated. Involvement of different cytochrome P-450 forms were used to explain these results.

来源:Hazardous Substances Data Bank (HSDB)

代谢

人类P450 2A6和鼠类P450 2a-5异酶都在香豆素7-羟基化中具有高度活性，本研究在几种使用人类和鼠类肝脏制备物的体外系统中探讨了它们对华法林代谢的贡献。从DBA/2鼠肝中纯化出来的重组P450 2a-5没有代谢华法林。尽管香豆素7-羟基化被抑制了超过90%，但抗P450 2a-5抗体并未一致地抑制人类或鼠类肝脏微粒体催化的任何华法林生物转化反应。在一些人类微粒体样本中，华法林的4-和8-羟基化在一定程度上被抗P450 2a-5抗体抑制。华法林（小于1 uM）并未在体外抑制人类或鼠类肝脏微粒体的香豆素7-羟基化。结果表明，鼠类和人类的香豆素7-羟基酶不会氧化华法林。

The contribution of human p450 2A6 and mouse p450 2a-5 isoenzymes both highly active in coumarin 7-hydroxylation to the metabolism of warfarin was studied in several in vitro systems with human and mouse liver preparations. The reconstituted p450 2a-5 purified from DBA/2 mouse liver did not metabolize warfarin. An anti-p450 2a-5 antibody did not consistently inhibit any of the warfarin biotransformation reactions catalyzed by human or mouse liver microsomes although coumarin 7-hydroxylation was inhibited by over 90%. In some human microsomal samples 4- and 8-hydroxylations of warfarin were inhibited to some extent by the anti-p450 2a-5 antibody. Warfarin (less than 1 uM) did not inhibit coumarin 7-hydroxylation by human or mouse liver microsomes in vitro. /Results indicate/ that mouse and human coumarin 7-hydroxylases do not oxidize warfarin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

华法林治疗导致的肝脏损伤是罕见的，但已经报道过因华法林治疗引起的临床上明显的急性肝脏损伤。与其他香豆素衍生物（如苯丙香豆素和醋硝香豆素）相比，肝脏损伤更为常见，这些药物在其他国家有售，但在美国没有。典型的急性肝脏损伤案例出现在开始服用华法林的3到8周内，尽管也有报道在华法林治疗数月或数年后出现的肝脏损伤案例（苯丙香豆素肝毒性的这种长期潜伏期很常见）。肝脏酶升高的模式通常是胆汁淤积性的，但也报道过肝细胞损伤和混合模式的案例。可以出现嗜酸性粒细胞增多，但其他免疫过敏表现并不常见，也没有自身抗体。恢复可能会延长，尤其是胆汁淤积性损伤。重新接触后复发的案例已有描述，可能会更严重，甚至导致死亡。 华法林过量可能导致过度出血和肝衰竭。此外，慢性华法林治疗与自发性出血有关，包括肝破裂和威胁生命的腹膜内出血，即使没有外伤，INR（国际标准化比率）也在适当范围内。 香豆素（相对于香豆素衍生物）是一种苯并吡喃，存在于许多植物中，具有甜味和类似香草的风味。香豆素本身并没有抗凝活性，这种活性只存在于其衍生物中。香豆素抑制巨噬细胞功能，曾被用作抗肿瘤剂和治疗富含蛋白质的淋巴水肿，例如乳腺癌治疗后的手臂淋巴水肿。香豆素在几例特异质、临床上明显的肝脏损伤中被涉及，估计在使用期间每1000名患者年中有2例发生。香豆素在美国没有商业销售。 可能性评分：C（可能是临床上明显肝脏损伤的罕见原因）。

Liver injury due to warfarin therapy is rare, but clinically apparent acute liver injury attributable to it has been reported. Liver injury is more common with other coumarin derivatives such as phenprocoumon and acenocoumarol, which are available in other countries but not in the United States. The typical case of acute liver injury arises within 3 to 8 weeks of starting warfarin, although rare instances of liver injury arising after months or years of therapy have been reported (and these long latencies are common with phenprocoumon hepatotoxicity). The pattern of liver enzyme elevations is typically cholestatic, but hepatocellular and mixed patterns have also been reported. Eosinophilia can occur, but other immunoallergic manifestations are not common nor are autoantibodies. Recovery can be prolonged, particularly with cholestatic injury. Recurrence upon reexposure has been described and can be more severe and result in death. Overdose with warfarin can result in excessive bleeding and hepatic failure. In addition, chronic warfarin therapy has been associated with spontaneous bleeding including hepatic rupture and life-threatening intraperitoneal bleeding, even without trauma and with INR in the appropriate range. Coumarin (as opposed to coumarin derivatives) is a benzopyrone, which is found in many plants and has a sweet, vanilla-like flavor. Coumarin itself does not have anticoagulant activity, which is only found in its derivatives. Coumarin inhibits macrophage function and has been used as an antineoplastic agent and to treat protein rich lymphedema, such as occurs in the arm after breast cancer therapy. Coumarin has been implicated in several cases of idiosyncratic, clinically apparent liver injury which is estimated to occur in 2 per 1000 patient years of use. Coumarin is not commercially available in the United States. Likelihood score: C (probable rare cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：华法林

Compound:warfarin

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

严重等级：5

Severity Grade:5

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

完全从胃肠道吸收。华法林钠片的平均达峰时间（Tmax）为4小时。

Completely absorbed from the GI tract. The mean Tmax for warfarin sodium tablets is 4 hours.[label,L6616,A2460]

来源:DrugBank

吸收、分配和排泄

• 消除途径

华法林的消除几乎完全通过代谢，只有一小部分以原形排出体外。[标签，L6616，A2460] 总剂量的80%通过尿液排出，剩余的20%出现在粪便中。[A2460]

The elimination of warfarin is almost entirely by metabolism with a small amount excreted unchanged.[label,L6616,A2460] 80% of the total dose is excreted in the urine with the remaining 20% appearing in the feces.[A2460]

来源:DrugBank

吸收、分配和排泄

• 分布容积

Vd为0.14 L/kg。[标签,L6616,A2460] 华法林有一个持续6-12小时的分布相。[L6616] 它已知能穿过胎盘，并达到与母体浓度相似的胎儿血清浓度。

Vd of 0.14 L/kg.[label,L6616,A2460] Warfarin has a distrubution phase lasting 6-12 hours.[L6616] It is known to cross the placenta and achieves fetal serum concentrations similar to maternal concentrations.

来源:DrugBank

吸收、分配和排泄

• 清除

华法林的清除率根据CYP2C9基因型不同而有所变化。[标签,L6616] *2和*3等位基因在高加索人群中的频率分别为11%和7%，已知这两种等位基因会降低华法林的清除率。其他降低清除率的基因型包括*5、*6、*9和*11等位基因。已经找到人群清除率估计值的基因型如下。*1/*1 = 0.065 mL/min/kg，*1/*2, *1/*3 = 0.041 mL/min/kg，*2/*2, *2/*3, *3/*3 = 0.020 mg/min/kg。

Clearance of warfarin varies depending on CYP2C9 genotype.[label,L6616] The \*2 and \*3 alleles appear in the Caucasian population at frequencies of 11% and 7% and are known to reduce clearance warfarin. Additional clearance reducing genotypes include the \*5, \*6, \*9 and \*11 alleles. Genotypes for which population clearance estimates have been found are listed below. \*1/\*1 = 0.065 mL/min/kg \*1/\*2, \*1/\*3 = 0.041 mL/min/kg \*2/\*2, \*2/\*3, \*3/\*3 = 0.020 mg/min/kg

来源:DrugBank

吸收、分配和排泄

华法林钠从胃肠道被迅速且广泛吸收，但个体间的吸收差异较大。口服华法林钠的吸收受溶解速率控制，不同商业片剂的药物吸收速率和程度可能有所不同。使用华法林钠的研究表明，虽然食物在胃肠道中的存在会降低药物的吸收速率，但不会影响吸收的程度。

Warfarin sodium is rapidly and extensively absorbed from the GI tract, but considerable interindividual variation in absorption exists. Absorption of oral warfarin sodium is dissolution-rate controlled, and the rate and extent of absorption of the drug may vary from one commercially available tablet to another. Studies using warfarin sodium indicate that the rate, but not the extent, of absorption of the drug is decreased by the presence of food in the GI tract. /Warfarin sodium/

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 职业暴露等级：
  D
• 职业暴露限值：
  TWA: 0.1 mg/m3
• 危险等级：
  6.1(a)
• 立即威胁生命和健康浓度：
  100 mg/m3
• 危险品标志：
  T
• 安全说明：
  S45,S52,S53,S61
• 危险类别码：
  R52/53,R48/25,R61
• WGK Germany：
  3
• 海关编码：
  29322090
• 危险品运输编号：
  UN 2811 6.1/PG 1
• 危险类别：
  6.1(a)
• RTECS号：
  GN4550000
• 包装等级：
  I
• 储存条件：
  本品应密封存放在干燥避光的地方。

制备方法与用途

华法林简介

华法林是一种仅可口服的抗凝血素，学名苄丙酮香豆素，通常以苄丙酮香豆素钠的形式储存和处方。知名的品牌有Coumadin®。由于其化学结构与维生素K相似，它能干扰血液中的凝血酶原功能，降低患者血液凝结的风险。然而，由于其强效特性，华法林一般只在血凝风险较高的患者中使用，例如心律不整或装有人工心脏瓣膜的患者。

药理机制

通常情况下，维生素K会在肝脏内转化为氧代维生素K（维生素K epoxide），随后由“环氧化物还原酶”进一步转化。华法林能够抑制这种肝脏内的酶作用，使凝血酶原失去功能，从而防止血液凝固。

副作用

华法林俗称“薄血丸”，但服用后需注意饮食，因维生素E和维生素K会影响其药效：

• 维生素E会加强华法林的作用，可能导致内出血。
• 维生素K则会减弱华法林的疗效。

毒性 对家鼠急性LD₅₀

• 3mg/kg (14mg/kg)

小鼠急性经口LD₅₀

• 374mg/kg

狗的LD₁₀₀

• 20～50mg/kg （200～300mg/kg）

猫的LD₁₀₀

• 5mg/kg

华法林对鸡、鸭、牛、羊毒性较小，但对猪、狗和猫较为敏感。

化学性质

外消旋体为无色、无臭、无味结晶。熔点（m.p.）159～161℃。易溶于丙酮，能溶于醇，不溶于苯和水。烯醇式呈酸性，并可与金属形成盐：钠盐溶于水而不溶于有机溶剂；烯醇乙酸酯的熔点（m.p.）为117～118℃，酮式的熔点（m.p.）为182～183℃。

用途 杀鼠剂

• 抗凝血型杀鼠剂，在全球广泛使用。
• 主要用于消灭小家鼠、大家鼠和褐家鼠等家庭栖息的鼠类，也可用于灭野鼠。投药后三周内灭鼠率可达90%以上。
• 也用作口服抗凝血药物，预防和治疗血栓栓塞性疾病。

生产方法

1. 4-羟基香豆素的制备：以水杨酸为原料，先与甲醇进行酯化，然后在醋酐作用下于40℃酰化，再在金属钠存在下240～250℃闭环、酸化合成。
2. 取代丁烯-[3]-酮-[2]-的制备：苯甲醛与丙酮在氢氧化钠存在下缩合制得。
3. 杀鼠灵的合成：将上述两个中间体在吡啶中回流24小时，除去吡啶后注入水中并酸化至pH约2，放置固化、重结晶得到华法林。

类别

• 农药

毒性分级

• 剧毒

急性毒性

• 口服-大鼠 LD50: 1.6 毫克/公斤；口服-小鼠 LD50: 3 毫克/公斤

可燃性危险特性

• 可燃；火场中可排放剧毒烟雾

储运特性

• 库房通风低温干燥；与食品原料分开储运

灭火剂

• 砂土、干粉、泡沫

职业标准

• TWA 0.1 毫克/立方米
• STEL 0.3 毫克/立方米

反应信息

• 作为反应物：
  描述：

  华法林 在 甲烷 、 potassium hydroxide 作用下， 以 水 、 异丙醇 为溶剂， 反应 8.0h， 以81%的产率得到potassium warfarin
  参考文献：
  名称：

  [EN] POLYMORPHIC FORMS OF WARFARIN POTASSIUM AND PREPARATIONS THEREOF
  [FR] FORMES POLYMORPHES DE LA WARFARINE POTASSIQUE ET SES PRÉPARATIONS

  摘要：

  提供了晶体溶剂形式的华法林钾，称为APO-I和APO-II，并提供了制备APO-I和APO-II的方法。APO-I和APO-II是华法林钾的多形溶剂形式。

  公开号：

  WO2011143747A1
• 作为产物：
  描述：

  2-methoxywarfarin 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 生成 华法林
  参考文献：
  名称：

  R和S的第一个实用的不对称合成-Warfarin

  摘要：

  通过使用新颖的两步“手性转换”策略和DuPHOS-Rh（I）催化的不对称氢化反应，开发了华法林Ia和Ib两种对映体的高效合成方法。

  DOI：

  10.1016/0040-4039(96)01796-0

文献信息

• Central nervous system antiischemic agents
  申请人：Bristol-Myers Squibb Company

  公开号：EP0559569A1

  公开（公告）日：1993-09-08

  A series of phenylalkylaminoalkyl derivatives of Formula I wherein Ar is naphtyl or phenyl;    R¹ is hydrogen, fluoro or R⁴CONH-;    R² is hydrogen or C₁-₆ alkyl;    R₃ is C₁-₆ alkyl;    R⁴ is C₁-₆ alkyl or phenyl- C₁-₆ alkyl;    x is zero or the integers 1 and 2;    m is selected from the integers 1 to 6; and    n is selected from the integers 2 and 3, has been found to provide effective antiischemic protection for CNS tissue, particularly neurons. A method of treatment to protect against CNS ischemia, such as that resulting from trauma or stroke or other ischemic conditions, comprises administration of these novel compounds to an individual in need of such treatment.

  一系列的Formula I的苯基烷基氨基烷基衍生物已被发现能够为中枢神经系统组织，特别是神经元，提供有效的抗缺血保护。一种治疗方法用于保护中枢神经系统缺血，例如由创伤、中风或其他缺血病症引起的缺血情况，包括将这些新化合物用于需要此类治疗的个体。其中Ar为萘基或苯基；R¹为氢、氟或R⁴CONH-；R²为氢或C₁-₆烷基；R₃为C₁-₆烷基；R⁴为C₁-₆烷基或苯基-C₁-₆烷基；x为零或整数1和2；m从整数1到6中选择；n从整数2和3中选择。
• [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] COMPOUNDS AND METHODS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR LE TRAITEMENT DE MALADIES NEURODÉGÉNÉRATIVES
  申请人：TAVARES FRANCIS XAVIER

  公开号：WO2016168118A1

  公开（公告）日：2016-10-20

  Novel compounds of formula (II) are disclosed. Compounds of formula (II) comprise ornithine derivatives or compounds that may metabolize to ornithine. Also disclosed are methods for the treatment of neurodegenerative diseases such as Alzheimer's Disease using compounds of formula (II).

  公开了化学式（II）的新化合物。化学式（II）的化合物包括鸟氨酸衍生物或可能代谢成鸟氨酸的化合物。还公开了使用化学式（II）的化合物治疗神经退行性疾病，如阿尔茨海默病的方法。
• [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] MICROBIOCIDAL OXADIAZOLE DERIVATIVES<br/>[FR] DÉRIVÉS D'OXADIAZOLE MICROBIOCIDES
  申请人：SYNGENTA PARTICIPATIONS AG

  公开号：WO2017157962A1

  公开（公告）日：2017-09-21

  Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as a pesticides, especially fungicides.

  式(I)的化合物，其中取代基如权利要求1所定义，作为杀虫剂特别是杀菌剂有用。

表征谱图