苯海拉明 | 58-73-1

• 物质功能分类: 原料药 - 抗变态反应药 - 抗组胺药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 苯海拉明
• 中文别名: 2-(二苯甲氧基)-N,N-二甲基乙胺；二甲氨基乙醇二苯甲醚；N,N-二甲基-2-(二苯甲氧基)乙胺；苯那君；苯海拉明培司
• 英文名称: 2-diphenylmethoxy-N,N-dimethylethanamine
• 英文别名: diphenhydramine；diphenhydramine hydrochloride；2-benzhydryloxy-N,N-dimethylethanamine
• CAS: 58-73-1
• 化学式: C₁₇H₂₁NO
• 分子量: 255.36
• InChiKey: ZZVUWRFHKOJYTH-UHFFFAOYSA-N

物化性质

• 熔点：
  167-172°C
• 沸点：
  bp2.0 150-165°
• 密度：
  0.9889 (rough estimate)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）
• 物理描述：
  Solid
• 颜色/状态：
  Oil
• 蒸汽压力：
  5.8X10-6 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Slowly darkens on exposure to light. Stable under ordinary conditions /Diphenhydramine hydrochloride/
• 解离常数：
  pKa = 8.98
• 碰撞截面：
  161.7 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated]
• 保留指数：
  1870;1869;1873;1846;1852;1849;1849;1842;1841;1865;1865;1872;1868;1874;1890;1888;1857;1880;1870;1850;1870;1885;1885;1860;1855;1873;1864.8;1860.8;1847.5;1847.5;1873;1842;1865;1870;1860.5

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  12.5
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

苯海拉明经历快速而广泛的首过代谢。特别是，连续发生两次N-脱甲基反应，其中苯海拉明被脱甲基成为N-去甲苯海拉明（N-去甲基代谢物），然后这个代谢物本身再次被脱甲基成为N,N-二去甲苯海拉明（N,N-二去甲基代谢物）。随后，通过N,N-二去甲基代谢物的胺基部分生成了乙酰代谢物，如N-乙酰-N-去甲苯海拉明。此外，N,N-二去甲基代谢物还经历了一些氧化反应，生成了二苯基甲氧基乙酸代谢物。剩余的给药剂量百分比以原形排泄。代谢物进一步与甘氨酸和谷氨酰胺结合并随尿排出。此外，研究表明，多种细胞色素P450同工酶参与了苯海拉明的主要代谢途径N-脱甲基反应，包括CYP2D6、CYP1A2、CYP2C9和CYP2C19。特别是，CYP2D6与苯海拉明底物的亲和力催化作用高于其他已识别的同工酶。因此，这些CYP酶的诱导剂或抑制剂可能会影响血清浓度以及与苯海拉明暴露相关的不良反应的发生率和/或严重程度。

Diphenhydramine undergoes rapid and extensive first-pass metabolism. In particular, two successive N-demethylations occur wherein diphenhydramine is demethylated to N-desmethyldiphenhydramine (the N-desmethyl metabolite) and then this metabolite is itself demethylated to N,N-didesmethyldiphenhydramine (the N,N-didesmethyl metabolite). Subsequently, acetyl metabolites like N-acetyl-N-desmethyldiphenhydramine are generated via the amine moiety of the N,N-didesmethyl metabolite. Additionally, the N,N-didesmethyl metabolite also undergoes some oxidation to generate the diphenylmethoxyacetic acid metabolite as well. The remaining percentage of a dose of administered diphenhydramine is excreted unchanged. The metabolites are further conjugated with glycine and glutamine and excreted in urine. Moreover, studies have determined that a variety of cytochrome P450 isoenzymes are involved in the N-demethylation that characterizes the primary metabolic pathway of diphenhydramine, including CYP2D6, CYP1A2, CYP2C9, and CYP2C19. In particular, CYP2D6 demonstrates higher affinity catalysis with the diphenhydramine substrate than the other isoenzymes identified. Consequently, inducers or inhibitors of these such CYP enzymes may potentially affect the serum concentration and incidence and/or severity of adverse effects associated with exposure to diphenhydramine.

来源:DrugBank

代谢

苯海拉明被迅速并且几乎完全代谢。口服给药后，药物在肝脏经历显著的首过代谢。苯海拉明主要代谢为二苯基甲氧基乙酸，这可能会进一步发生结合反应。药物还发生脱烷基化，形成N-去甲基和N，N-二去甲基衍生物。苯海拉明及其代谢物主要通过尿液排出。

Diphenhydramine is rapidly and apparently almost completely metabolized. Following oral administration, the drug apparently undergoes substantial first-pass metabolism in the liver. Diphenhydramine appears to be metabolized principally to diphenylmethoxyacetic acid, which may further undergo conjugation. The drug also undergoes dealkylation to form the N-demethyl and N, N-didemethyl derivatives. Diphenhydramine and its metabolites are excreted principally in urine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

苯海拉明作为一种非处方抗组胺药被广泛使用。然而，在临床相关浓度范围内（0.14-0.77微摩尔），具体介导苯海拉明代谢的人细胞色素P450（P450）同工酶尚不清楚。因此，通过我们实验室开发的液相色谱-质谱方法，确定了参与苯海拉明N-脱甲基（苯海拉明的主要代谢途径）的P450同工酶。在14种重组P450同工酶中，CYP2D6显示出最高的苯海拉明N-脱甲基活性（0.5微摩尔时为0.69皮摩尔/分钟/皮摩尔P450）。CYP2D6作为一种高亲和力的P450同工酶催化苯海拉明N-脱甲基，其K(m)值为1.12 +/- 0.21微摩尔。此外，CYP1A2、CYP2C9和CYP2C19被鉴定为低亲和力组分。在使用人肝微粒体时，通过使用特定的P450同工酶抑制剂，证实了CYP2D6、CYP1A2、CYP2C9和CYP2C19参与苯海拉明N-脱甲基。此外，通过相对活性因子估计的这些P450同工酶的贡献与抑制研究的结果一致。尽管之前有报道称苯海拉明对CYP2D6的代谢活性有抑制作用，但本研究的结果表明，它不仅是CYP2D6的强抑制剂，也是CYP2D6的高亲和力底物。因此，值得一提的是，苯海拉明的镇静效果可能是由CYP2D6底物/抑制剂共同给药引起的。此外，CYP2D6与CYP1A2、CYP2C9和CYP2C19的代谢活性之间的较大差异可能导致苯海拉明抗过敏疗效和镇静效果的个体差异。

Diphenhydramine is widely used as an over-the-counter antihistamine. However, the specific human cytochrome P450 (P450) isozymes that mediate the metabolism of diphenhydramine in the range of clinically relevant concentrations (0.14-0.77 microM) remain unclear. Therefore, P450 isozymes involved in N-demethylation, a main metabolic pathway of diphenhydramine, were identified by a liquid chromatography-mass spectrometry method developed in our laboratory. Among 14 recombinant P450 isozymes, CYP2D6 showed the highest activity of diphenhydramine N-demethylation (0.69 pmol/min/pmol P450) at 0.5 uM. CYP2D6 catalyzed diphenhydramine N-demethylation as a high-affinity P450 isozyme, the K(m) value of which was 1.12 +/- 0.21 uM. In addition, CYP1A2, CYP2C9, and CYP2C19 were identified as low-affinity components. In human liver microsomes, involvement of CYP2D6, CYP1A2, CYP2C9, and CYP2C19 in diphenhydramine N-demethylation was confirmed by using P450 isozyme-specific inhibitors. In addition, contributions of these P450 isozymes estimated by the relative activity factor were in good agreement with the results of inhibition studies. Although an inhibitory effect of diphenhydramine on the metabolic activity of CYP2D6 has been reported previously, the results of the present study suggest that it is not only a potent inhibitor but also a high-affinity substrate of CYP2D6. Therefore, it is worth mentioning that the sedative effect of diphenhydramine might be caused by coadministration of CYP2D6 substrate(s)/inhibitor(s). In addition, large differences in the metabolic activities of CYP2D6 and those of CYP1A2, CYP2C9, and CYP2C19 could cause the individual differences in anti-allergic efficacy and the sedative effect of diphenhydramine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

两种细丝状真菌 Cunninghamella elegans（ATCC 9245 和 ATCC 36112）在 Sabouraud 葡萄糖肉汤中培养，并筛选其代谢乙醇胺类抗组胺药盐酸苯海拉明的能力。根据7天培养后回收的母药量，两种 C. elegans 菌株代谢了大约74%的苯海拉明，其中58%被鉴定为有机可提取代谢物。通过反相高效液相色谱法分离有机可提取代谢物，并通过分析它们的质量和核磁共振谱进行鉴定。使用氘代氨的脱附化学电离质谱（DCIMS）来区分可能的等压苯海拉明代谢物，并探测氨 DCIMS 条件下离子形成机制。C. elegans 通过脱甲基、氧化和N-乙酰化转化苯海拉明。观察到的的主要代谢物有苯海拉明-N-氧化物（3%）、N-去甲基苯海拉明（30%）、N-乙酰二去甲基苯海拉明（13%）和N-乙酰-N-去甲基苯海拉明（12%）。这些化合物是已知的哺乳动物苯海拉明代谢物...。

Two strains of the filamentous fungus Cunninghamella elegans (ATCC 9245 and ATCC 36112) were grown in Sabouraud dextrose broth and screened for the ability to metabolize the ethanolamine-type antihistamine diphenhydramine. Based on the amount of parent drug recovered after 7 days incubation, both C. elegans strains metabolized approximately 74% of the diphenhydramine, 58% of this being identified as organic extractable metabolites. The organic extractable metabolites were isolated by reversed-phase high-performance liquid chromatography and identified by analyzing their mass and nuclear magnetic resonance spectra. Desorption chemical ionization mass spectrometry (DCIMS) with deuterated ammonia was used to differentiate possible isobaric diphenhydramine metabolites and to probe the mechanisms of ion formation under ammonia DCIMS conditions. C. elegans transformed diphenhydramine by demethylation, oxidation, and N-acetylation. The major metabolites observed were diphenhydramine-N-oxide (3%), N-desmethyldiphenhydramine (30%), N-acetyldidesmethyldiphenhydramine (13%), and N-acetyl-N-desmethyldiphenhydramine (12%). These compounds are known mammalian metabolites of diphenhydramine ... .

来源:Hazardous Substances Data Bank (HSDB)

代谢

苯海拉明已知的人类代谢物包括苯海拉明N-葡萄糖苷酸和N-去甲基苯海拉明。

Diphenhydramine has known human metabolites that include Diphenhydramine N-glucuronide and N-Desmethyldiphenhydramine.

来源:NORMAN Suspect List Exchange

毒理性

• 毒性总结

Diphenhydramine与游离组胺竞争结合在HA受体位点。这拮抗了组胺对HA受体的作用，从而减少由组胺HA受体结合引起的负面症状。

Diphenhydramine competes with free histamine for binding at HA-receptor sites. This antagonizes the effects of histamine on HA-receptors, leading to a reduction of the negative symptoms brought on by histamine HA-receptor binding.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

尽管在过去几十年里被广泛使用，苯海拉明并未与肝功能测试异常或临床上明显的肝损伤有关联。其安全性可能与它较短的半衰期和有限的使用时长有关。 可能性评分：E（不太可能是临床上明显肝损伤的原因）。 关于抗组胺药的安全性和潜在肝毒性的参考资料，在抗组胺药概述部分之后给出。 药物类别：抗组胺药

Despite widespread use over many decades, diphenhydramine has not been linked to liver test abnormalities or to clinically apparent liver injury. The reason for its safety may relate its short half-life and limited duration of use. Likelihood score: E (unlikely to be a cause of clinically apparent liver injury). References on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines. Drug Class: Antihistamines

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：二苯羟胺

Compound:diphenhydramine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：无 DILI 关注

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：没有匹配项

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

苯海拉明口服给药后能迅速吸收，大约在一小时后达到最大活性。苯海拉明的口服生物利用度已记录在40%到60%之间，给药后大约2到3小时血浆浓度达到峰值。

Diphenhydramine is quickly absorbed after oral administration with maximum activity occurring in approximately one hour. The oral bioavailability of diphenhydramine has been documented in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

苯海拉明代谢物与甘氨酸和谷氨酰胺结合，并随尿液排出体外。单次剂量的约1%以原形随尿液排出。该药物最终由肾脏缓慢消除，主要是以无活性的代谢物形式。

The metabolites of diphenhydramine are conjugated with glycine and glutamine and excreted in urine. Only about 1% of a single dose is excreted unchanged in urine. The medication is ultimately eliminated by the kidneys slowly, mainly as inactive metabolites.

来源:DrugBank

吸收、分配和排泄

• 分布容积

Diphenhydramine 在体内广泛分布，包括中枢神经系统。在口服 50 毫克苯海拉明后，其分布体积范围在 3.3 - 6.8 升/公斤。

Diphenhydramine is widely distributed throughout the body, including the CNS. Following a 50 mg oral dose of diphenhydramine, the volume of distribution is in the range of 3.3 - 6.8 l/kg.

来源:DrugBank

吸收、分配和排泄

• 清除

口服50毫克苯海拉明的血浆清除率的值已被记录在600-1300毫升/分钟的范围之内。

Values for plasma clearance of a 50 mg oral dose of diphenhydramine has been documented as lying in the range of 600-1300 ml/min.

来源:DrugBank

吸收、分配和排泄

二苯拉林在人体组织和体液中的分布尚未完全表征。在大鼠静脉给药后，药物在肺、脾和大脑中的浓度最高，而在心脏、肌肉和肝脏中的浓度较低。在健康成年人静脉给药后，据报道二苯拉林的表现分布体积为188-336升。据报道，该药物在亚洲成年人（大约480升）中的分布体积比白人成年人要大。

Distribution of diphenhydramine into human body tissues and fluids has not been fully characterized. Following IV administration in rats, highest concentrations of the drug are attained in the lungs, spleen, and brain, with lower concentrations in the heart, muscle, and liver. Following IV administration in healthy adults, diphenhydramine reportedly has an apparent volume of distribution of 188-336 L. Volume of distribution of the drug reportedly is larger in Asian (about 480 L) than white adults.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2922199090
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302
• 储存条件：
  应存放在通风、低温和干燥的地方，并与库房内的食品原料分开存放。

制备方法与用途

苯海拉明是合成抗组胺药晕海宁和盐酸苯海拉明的关键中间体，主要用于治疗过敏症，也可用于治疗失眠、感冒和恶心。

化学性质 苯海拉明为油状液体。其沸点在163-167℃（0.40kPa）或150-165℃（0.267kPa）。苯海拉明盐酸盐（[147-24-0]）是一种白色结晶性粉末，熔点为161-162℃。该化合物易溶于水和醇，无臭且味苦。

用途 苯海拉明与盐酸成盐后制成的苯海拉明盐酸盐是《国家基本药物》中列出的一种抗组织胺类药。它能降低组织对机体的反应，消除各种过敏症状，并具有较强的中枢神经抑制作用和轻度的镇静及镇吐作用。用于治疗荨麻疹、枯草热、血管神经性水肿、血清病、接触性皮炎、过敏性结膜炎等皮肤黏膜的过敏性疾病；也可防止晕动症，如晕船、晕车、孕期呕吐及震颤性麻痹。

生产方法 苯海拉明由双苯甲醇（[91-01-0]）经氯乙醇醚化与二甲胺缩合而得。

类别 有毒物品

毒性分级 高毒

急性毒性 口服：大鼠 LD50: 390 毫克/公斤；小鼠 LD50: 160 毫克/公斤

可燃性危险特性 可燃，燃烧产生有毒氮氧化物烟雾。药物副作用包括梦幻和心理生理学测试改变。

储运特性 需在通风、低温及干燥条件下储存，并与库房内的食品原料分开存放。

灭火剂 干粉、泡沫、沙土、二氧化碳或雾状水均可用于灭火。

反应信息

• 作为反应物：
  描述：

  苯海拉明 在 盐酸 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以9.6 mmol的产率得到盐酸苯海拉明
  参考文献：
  名称：

  一种甲苯苄位苯基取代化合物的制备方法

  摘要：

  为解决现有技术的不足，本发明提供了一种甲苯苄位苯基取代化合物制备方法，该方法首先在反应容器中加入反应基质和进攻试剂，并混合；然后，在上述混合物中加入催化剂，并混合均匀；之后，将上述混合均匀的物质，在70‑110℃下反应12‑48小时；最后，去除溶剂并纯化产物，得到所述甲苯苄位苯基取代产物；所述反应基质为：含有苯基且苯基上连接有至少1个α氢的化合物；所述进攻试剂为：苯基硼酸。所述催化剂为：过氧化二叔丁基和乙酰丙酮镍的混合物。采用本发明合成方法合成2kg盐酸苯海拉明可节约成本15万元人民币。

  公开号：

  CN107673945A
• 作为产物：
  描述：

  苯甲醛 在 magnesium 作用下， 以 甲苯 为溶剂， 反应 29.67h， 生成 苯海拉明
  参考文献：
  名称：

  由化学编程语言驱动的模块化机器人系统中的有机合成

  摘要：

  机器人平台的明确方向 化学文献包含一个多世纪以来制造分子的指导，所有这些都是由人类编写的，也是为人类编写的。施泰纳等人。开发了一个自主编译器和机器人实验室平台，以在标准化方法描述的基础上合成有机化合物（参见 Milo 的观点）。该平台包括常规设备，如圆底烧瓶、分液漏斗和旋转蒸发器，以最大限度地提高其与现有文献的兼容性。作者通过三种常见药物的短合成展示了该系统，这些合成与手动合成相当。科学，这个问题 p。eaav2211; 另见第。122 编译器指示机器人平台使用标准协议和实验室设备进行简短的有机合成。引言 除了多肽和寡核苷酸化学等几个明确定义的领域之外，化学合成的自动化仅限于大规模定制工业过程，实验室规模和发现规模的合成主要是手动过程。这些领域通常由通过类似反应组的连续迭代来合成复杂分子的能力来定义，允许通过相对较小的标准化反应调色板的自动化来合成产品。流动化学、寡糖合成和迭代交叉偶联等领

  DOI：

  10.1126/science.aav2211

文献信息

• N-type calcium channel blockers
  申请人：Pajouhesh Hassan

  公开号：US20050165065A1

  公开（公告）日：2005-07-28

  The invention relates to novel 3-amino pyrrolidine derivatives, as well as methods for modulating calcium channel activity and for treating conditions associated with calcium channel function. In particular, the compounds generally contain at least one benzhydril moiety, and are useful in treating conditions which benefit from blocking calcium ion channels.

  这项发明涉及新型3-氨基吡咯烷衍生物，以及调节钙通道活性和治疗与钙通道功能相关疾病的方法。具体来说，这些化合物通常至少含有一个苯基甲酰基团，可用于治疗受益于阻断钙离子通道的疾病。
• Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
  申请人：Vertex Pharmaceuticals Incorporated

  公开号：US20150231142A1

  公开（公告）日：2015-08-20

  The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.

  本发明涉及含有上皮钠通道活性抑制剂与至少一种ABC转运蛋白调节剂化合物（A式、B式、C式或D式）的药物组合物。该发明还涉及这些药物配方，以及使用这些组合物治疗CFTR介导的疾病，特别是囊性纤维化的方法。
• [EN] SUBSTITUTED 4-PYRIDONES AND THEIR USE AS INHIBITORS OF NEUTROPHIL ELASTASE ACTIVITY<br/>[FR] 4-PYRIDONES SUBSTITUÉES ET LEUR UTILISATION COMME INHIBITEURS DE L'ACTIVITÉ DE L'ÉLASTASE NEUTROPHILE
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2014029831A1

  公开（公告）日：2014-02-27

  This invention relates to substituted 4-pyridones of formula 1 and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other auto-immune and allergic disorders, allograft rejection, and oncological diseases.

  这项发明涉及式1的取代4-吡啶酮及其作为中性粒细胞弹性蛋白酶活性抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗和/或预防肺部、胃肠道和泌尿系统疾病、皮肤和眼部炎症性疾病以及其他自身免疫和过敏性疾病、移植物排斥和肿瘤性疾病的药剂的方法。
• SUBSTITUTED 4-PYRIDONES AND THEIR USE AS INHIBITORS OF NEUTROPHIL ELASTASE ACTIVITY
  申请人：OOST Thorsten

  公开号：US20140057916A1

  公开（公告）日：2014-02-27

  This invention relates to substituted 4-pyridones of formula 1 and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other auto-immune and allergic disorders, allograft rejection, and oncological diseases.

  这项发明涉及式1的取代4-吡啶酮及其作为中性粒细胞弹性蛋白酶活性抑制剂的用途，包含这些化合物的药物组合物，以及将其用作治疗和/或预防肺部、胃肠道和泌尿系统疾病、皮肤和眼睛的炎症性疾病以及其他自身免疫和过敏性疾病、移植物排斥反应和肿瘤性疾病的药剂的方法。
• [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。

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