硫唑嘌呤 | 446-86-6

• 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 - 有机硫化合物 - 硫醚类
• 中文名称: 硫唑嘌呤
• 中文别名: 依米兰；6-[(1-METHYL-4-1H-NITROIMIDAZOL-5-YL)THIO]PURINE咪唑硫嘌呤；依木兰；6-[(1-甲基-4-硝基-1H-咪唑-5-基)硫代]-1H-嘌呤；6-[(1-甲基-4-1H-咪唑基-5)-硫代]-1H-嘌呤；6-(1-甲基-4-硝基咪唑-5-基)硫代嘌呤；6-(1-甲基-4-硝基咪唑-5-硫基)嘌呤；氮杂硫代嘌呤
• 英文名称: Azathioprin
• 英文别名: azathioprine；6-(3-methyl-5-nitroimidazol-4-yl)sulfanyl-7H-purine
• CAS: 446-86-6
• 化学式: C₉H₇N₇O₂S
• mdl: MFCD00055974
• 分子量: 277.266
• InChiKey: LMEKQMALGUDUQG-UHFFFAOYSA-N

物化性质

• 熔点：
  243-244°C
• 沸点：
  521.0±60.0 °C(Predicted)
• 密度：
  1.5379 (rough estimate)
• 溶解度：
  溶于二氯甲烷和二甲基亚砜。
• 物理描述：
  Azathioprine appears as pale yellow crystals or yellowish powder. Decomposes at 243-244°C. Used for the treatment of rheumatoid arthritis. A known carcinogen.
• 颜色/状态：
  Pale yellow crystals from 50% aq acetone
• 稳定性/保质期：

  按规格使用和储存，不会发生分解，请避免与氧化物接触。

• 分解：
  When heated to decomposition it emits toxic fumes of /nitric oxides & sulfur oxides/.
• 解离常数：
  pKa = 8.2
• 碰撞截面：
  155.1 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)：
  0.1
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.111
• 拓扑面积：
  143
• 氢给体数：
  1
• 氢受体数：
  7

ADMET

代谢

阿扎硫品非酶转化为6-巯基嘌呤。6-巯基嘌呤随后通过硫嘌呤甲基转移酶代谢为6-甲基巯基嘌呤，通过黄嘌呤氧化酶代谢为6-硫尿酸，或者通过次黄嘌呤磷酸核糖转移酶代谢为6-硫肌苷-5'-单磷酸。6-硫肌苷-5'-单磷酸通过硫嘌呤甲基转移酶代谢为6-甲基硫肌苷-5'-单磷酸，或者通过肌苷单磷酸脱氢酶代谢为6-硫异烟酸。6-硫异烟酸通过鸟苷单磷酸合成酶代谢为6-硫鸟嘌呤单磷酸，这是6-硫鸟嘌呤核苷酸的第一个。6-硫鸟嘌呤单磷酸被磷酸化以产生其余的6-硫鸟嘌呤核苷酸，6-硫鸟嘌呤二磷酸和6-硫鸟嘌呤三磷酸。

Azathioprine is converted to 6-mercaptopurine nonenzymatically. 6-mercaptopurine is then metabolized to 6-methylmercaptopurine by thiopurine methyltransferase, 6-thiouric acid by xanthine oxidase, or 6-thiosine-5'-monophosphate by hypoxanthine phosphoribosyltransferase. 6-thiosine-5'-monophosphate is metabolized to 6-methylthiosine-5'-monophosphate by thiopurine methyltransferase or 6-thioxanthylic acid by inosine monophosphate dehydrogenase. 6-thioxanthylic acid is metabolized by guanosine monophosphate synthetase to 6-thioguanine monophosphate, the first of the 6-thioguanine nucleotides. 6-thioguanine monophosphate is phosphorylated to produce the remaining 6-thioguanine nucleotides, 6-thioguanine diphosphate and 6-thioguanine triphosphate.

来源:DrugBank

代谢

口服的硫唑嘌呤在体内迅速分解成6-巯基嘌呤。

Orally administered azathioprine is rapidly divided in vivo to form 6-mercaptopurine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在体内代谢成6-巯基嘌呤，详见6-巯基嘌呤条目。

Metabolized in vivo to 6-mercaptopurine, q.v.

来源:Hazardous Substances Data Bank (HSDB)

代谢

硫唑嘌呤被代谢成6-巯基嘌呤。

Azathioprine is metabolized to 6-mercaptopurine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

主要通过非酶促过程和谷胱甘肽转移酶转化为活性代谢物6-巯基嘌呤和6-硫代肌苷酸。6-巯基嘌呤的活化通过次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HGPRT）和一系列涉及激酶的多酶过程，形成6-硫鸟嘌呤核苷酸（6-TGNs）作为主要代谢物。 消除途径：这两种化合物都迅速从血液中消除，并在红细胞和肝脏中被氧化或甲基化；8小时后尿液中检测不到氨甲蝶呤或巯基嘌呤。

Primarily converted to the active metabolites 6-mercaptopurine and 6-thioinosinic acid via a non-enzymatica process and glutathione transferases. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites Route of Elimination: Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

识别：组：其他免疫抑制剂。 Azathioprine（硫唑嘌呤）：淡黄色，无味粉末。该药物不溶于水，在乙醇中微溶。人类暴露：摘要：主要风险和靶器官：硫唑嘌呤是一种骨髓毒性和肝毒性的免疫抑制剂。骨髓和肝脏是主要的靶标，但胃肠道的肾脏，肺，CNS和皮肤也可能受到影响。过量服用时可能会观察到短暂的胃肠炎。白细胞减少是主要的有毒效应，可能在硫唑嘌呤治疗期间和过量服用患者中发生。肝脏和肾脏功能测试可能会改变，但在停药后通常会恢复正常。临床效果摘要：口腔溃疡在治疗剂量下很少见，但在大剂量下可能会出现。恶心，呕吐，腹痛和腹泻等胃肠道不适主要在高剂量时出现。长期使用硫唑嘌呤治疗也报告了急性胰腺炎。骨髓抑制主要表现为白细胞减少，偶尔表现为全血细胞减少，在治疗剂量和硫唑嘌呤过量后可见。由于这种免疫抑制，可能会发生败血性休克。肝功能障碍（肝细胞和胆汁淤积性），肝静脉闭塞病和肝血管瘤在硫唑嘌呤治疗后的报道中有所记录。急性限制性肺病，间质性肾炎和4年后硫唑嘌呤治疗的进行性白质脑病也有所报告。皮肤皮疹，脱发和荨麻疹以及掌跖红斑伴脱屑和疼痛也有所记录。诊断：硫唑嘌呤过量诊断基于药物摄入史和主要胃肠道功能障碍，白细胞减少和肝功能异常的临床表现。需要外周血细胞计数和肝功能测试。估计红细胞中的6-硫鸟嘌呤核苷酸，一种硫唑嘌呤的细胞毒性代谢物，可能证实诊断，并可用于预测硫唑嘌呤的骨髓毒性。指示：用途：硫唑嘌呤用作预防肾脏异体移植排斥的辅助剂。该药物与其他免疫抑制疗法（包括局部放射疗法，皮质类固醇和其他细胞毒药物）联合使用。硫唑嘌呤可用于治疗涉及免疫系统失调的状况，包括慢性活动性肝炎，严重类风湿性关节炎，系统性红斑狼疮，皮肌炎，寻常天疱疮，结节性多动脉炎，获得性溶血性贫血，克罗恩病和特发性血小板减少性紫癜。禁忌症：对硫唑嘌呤过敏的患者禁用。硫唑嘌呤也禁用于有肾衰竭，肝功能受损的孕妇。进入途径：口服：硫唑嘌呤通常口服给药。肠道外：肾脏移植后，对于无法耐受口服药物的患者，可以最初静脉注射硫唑嘌呤。应尽快用口服治疗替代肠道外治疗。动力学：按暴露途径吸收：硫唑嘌呤从胃肠道中被迅速吸收，在48小时内只有12.6％的剂量在粪便中被检测到。按暴露途径分布：硫唑嘌呤迅速分布全身，在给药后1至2小时达到血浆浓度高峰。少量的硫唑嘌呤与血浆蛋白结合（最多30％）并且只有非常小的量进入大脑。硫唑嘌呤穿过胎盘，胎儿血液中已检测到6-巯基嘌呤代谢物的微量。生物学半衰期按暴露途径：硫唑嘌呤的血浆半衰期为3至5小时。新陈代谢：硫唑嘌呤在体内代谢为巯基嘌呤，显然是通过诸如谷胱甘肽之类的巯基化合物。巯基嘌呤被氧化并甲基化为几种衍生物，其中以6-硫尿酸为主；代谢物的比例因人而异。尚未完全阐明azathioprine的硝基甲基咪唑部分的作用。少量的硫唑嘌呤也会裂解产生1-甲基-4-硝基-5-硫代咪唑。负责治疗作用的活动代谢物，6-硫鸟嘌呤核苷酸，在细胞内形成，似乎具有非常长的半衰期。消除按暴露途径：硫唑嘌呤的代谢物由肾脏排泄；只有少量的硫唑嘌呤和巯基嘌呤以原形排出。在给药后的24小时内，最多有50％的剂量以尿中排出，其中10％为母药。没有关于硫唑嘌呤在母乳中排出的数据。药理学和毒理学：作用方式：毒效学：硫唑嘌呤的主要有毒作用是骨髓抑制，表现为白细胞减少，巨幼细胞性贫血，全血细胞减少和血小板减少，可能导致凝血时间延长和最终出血。药效学：尚未确定硫唑嘌呤的免疫抑制活性的确切机制。硫唑嘌呤是

IDENTIFICATION: Group: Other Immunosuppressive agents. Azathioprine: pale yellow, odorless powder. The drug is insoluble in water and very slightly soluble in ethanol. HUMAN EXPOSURE: Summary: Main risks and target organs: Azathioprine is a myelotoxic and hepatotoxic immunosuppressive agent. Bone marrow and liver are the main targets but gastrointestinal tract, kidney, lungs, CNS and skin may also be affected. Transient gastroenteritis may be observed with massive overdose. Leukopenia is the main toxic effect which may occur during azathioprine therapy and in the overdose patient. Liver and kidney function tests may be altered but usually returned to normal after discontinuation of the drug. Summary of clinical effects: Oral ulceration occurs rarely with therapeutic doses but may be seen with large doses. Gastrointestinal disturbances such as nausea, vomiting, abdominal pain and diarrhea can appear mainly at higher doses. Acute pancreatitis was also reported following long term azathioprine treatment. Suppression of the bone marrow mainly leukopenia and occasionally pancytopenia may be seen after therapeutic doses and overdoses of azathioprine. Septic shock due to this immunosuppression may occur. Hepatic dysfunction (hepatocellular and cholestatic), venocclusive disease and hemangioma of the liver following azathioprine therapy were documented. Acute restrictive lung disease, interstitial nephritis and a case of progressive leukoencephalopathy after 4 years azathioprine therapy were reported. Skin rash, alopecia and urticaria and a case of palmar-plantar erythema with desquamation and pain were also documented. Diagnosis: Diagnosis of azathioprine overdose is based on history of the drug taken and clinical findings mainly gastrointestinal dysfunction, leukopenia and liver dysfunction. Peripheral cell blood counts and liver function tests are required. Estimation of 6-thioguanine nucleotide, a cytotoxic metabolite of azathioprine in red blood cell may confirm the diagnosis and could also be used to predict bone marrow toxicity of azathioprine. Indications: Uses: Azathioprine is used as an adjunct for the prevention of the rejection of kidney allografts. The drug is used in conjunction with other immunosuppressive therapy including local radiation therapy, corticosteroids, and other cytotoxic agents. Azathioprine may be used for the treatment of conditions which involve derangement of the immune system including chronic active hepatitis, severe rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, pemphigus vulgaris, polyarteritis nodosa, acquired hemolytic anemia, Crohn's disease and idiopathic thrombocytopenia. Contraindications: Azathioprine is contraindicated in patients who are hypersensitive to the drug. Azathioprine is also contraindicated in those patients with renal failure, impaired hepatic function and in pregnant women. Routes of entry: Oral: Azathioprine is usually administered orally. Parenteral: Following renal transplantation, azathioprine may initially be given intravenously to patients unable to tolerate oral medication. Oral therapy should replace parenteral therapy as soon as possible. Kinetics: Absorption by route of exposure: Azathioprine is readily absorbed from the gastrointestinal tract with only 12.6% of the dose being detected in the stool over a 48 hour period. Distribution by route of exposure: Azathioprine is rapidly distributed throughout the body with peak plasma concentrations being reached at 1 to 2 hours after dosing. Small amounts of azathioprine bind to plasma proteins (to a maximum of 30%) and only very small amounts enter the brain. Azathioprine crosses the placenta and trace amounts of the 6-mercaptopurine metabolite have been detected in fetal blood. Biological half-life by route of exposure: The plasma half-life of azathioprine is 3 to 5 hours. Metabolism: Azathioprine is metabolized in vivo to mercaptopurine, apparently by sulfhydryl compounds such as glutathione. Mercaptopurine is oxidized and methylated to several derivatives among which 6-thiouric acid predominates; the proportion of metabolites varies amongst individuals. The fate of the nitromethylimidazole portion of azathioprine has not been completely elucidated. Small amounts of azathioprine are also split to give 1-methyl-4-nitro-5-thioimidazole. The active metabolites, 6-thioguanine nucleotides, responsible for the therapeutic action, are formed intracellularly and appear to have very long half-lives. Elimination by route of exposure: The metabolites of azathioprine are excreted by the kidneys; only small amounts of azathioprine and mercaptopurine are excreted intact. In the 24 hour period after administration up to 50% of the dose is excreted in the urine with 10% as the parent drug. There is no data concerning azathioprine excretion in breast milk. Pharmacology and toxicology: Mode of action: Toxicodynamics: The principal toxic effect of azathioprine is bone marrow depression manifested by leukopenia, macrocytic anemia, pancytopenia, and thrombocytopenia, which may result in prolongation of clotting time and eventual hemorrhage. Pharmacodynamics: The exact mechanism of immunosuppressive activity of azathioprine has not been determined. Azathioprine which is an antagonist to purine metabolism may inhibit RNA and DNA synthesis. The drug may also be incorporated into nucleic acids resulting in chromosome breaks, malfunctioning of the nucleic acids, or synthesis of fraudulent proteins. The drug may also inhibit coenzyme formation and functioning, thereby interfering with cellular metabolism. Mitosis may be inhibited by the drug. In patients who undergo renal transplantation, azathioprine suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Human data: Adults: Severe pancytopenia has been observed in about 1% of the patients. Children: Lymphopenia, decreased IgG and IgM concentrations, cytomegalovirus infection. Cytogenetic damage was observed in human lymphocytes in vitro. Acute myelogenous leukemia and solid tumours have occurred in patients with rheumatoid arthritis who received the drug. Mutagenicity: Azathioprine is mutagenic in animals and humans, chromosomal abnormalities have been documented in humans receiving azathioprine, but the abnormalities were reversed following discontinuance of the drug. Interactions: Azathioprine dose should be reduced 75% when administered with allopurinol, as allopurinol affects the metabolism of mercaptopurine, a metabolite of azathioprine. Azathioprine may reduce the effect of certain neuromuscular blocking agents including curare and related non-depolarizing drugs. Certain cytotoxic agents may be additive or synergistic in producing toxicity when used in conjunction with azathioprine. The Committee on Safety of Medicines have advised that azathioprine and penicillamine should not be used concurrently. The effects of azathioprine and corticosteroids could be synergistic. Azathioprine may reduce the anticoagulant effect of warfarin. ANIMAL/PLANT STUDIES: Studies with animals have shown that the haemopoietic system is affected by azathioprine with depression of granulopoiesis, megakaryocytes and, hence, platelet formation. Reversible hepatoxicity has been observed in dogs. Various teratogenic effects have been observed in rabbits, showing skeletal abnormalities. In mice embryolethalite was observed. Carcinogenicity: Azathioprine is carcinogenic in animals. Teratogenicity: Azathioprine is teratogenic in rabbits and mice when given in dosages equivalent to the human dosage. Abnormalities included skeletal malformations and visceral anomalies. Mutagenicity: Azathioprine is mutagenic in the Ames test.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

Azathioprine拮抗嘌呤代谢，可能抑制DNA、RNA和蛋白质的合成。它还可能干扰细胞代谢并抑制有丝分裂。其作用机制可能是由于嘌呤类似物掺入DNA结构中，导致链终止和细胞毒性。

Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins. It may also interfere with cellular metabolism and inhibit mitosis. Its mechanism of action is likely due to incorporation of thiopurine analogues into the DNA structure, causing chain termination and cytotoxicity.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

硫唑嘌呤与多种形式的肝毒性有关，包括血清转氨酶水平轻度、暂时和无症状的升高，在开始治疗的第一年内发展的急性胆汁淤积性损伤，以及在开始硫唑嘌呤治疗1至5年后出现的慢性肝损伤，其特征为肝窦状隙扩张、肝静脉闭塞性疾病或结节性再生性增生。在硫唑嘌呤治疗期间，尤其是在治疗的前12周内高剂量时，可能会出现轻度血清转氨酶升高。这些升高通常无症状、良性且自限性，停止治疗或降低剂量继续治疗通常会迅速解决。硫唑嘌呤治疗期间的ALT升高可能是由于药物的直接毒性作用；ALT升高以及骨髓毒性已与较高水平的甲基巯嘌呤相关联，这是硫唑嘌呤代谢的一个代谢途径的产物。 硫唑嘌呤还可能引起急性、临床上明显的胆汁淤积性肝病。这种并发症不常见但也不罕见，大约每千名治疗患者中就有1例。硫唑嘌呤引起的急性胆汁淤积性损伤通常在开始治疗2至12个月后表现为疲劳和黄疸。血清ALT和碱性磷酸酶通常只是轻度或中度升高，呈混合胆汁淤积-肝细胞模式。皮疹、发热和嗜酸性粒细胞增多不常见，自身抗体通常未发现。肝脏活检通常显示肝内胆汁淤积伴局部肝细胞坏死和少量炎症，提示胆汁淤积性肝炎。在某些情况下，损伤类似于雌激素或同化类固醇引起的“无特色胆汁淤积”。停止治疗后，肝脏损伤通常会迅速解决，但已报告有持续性胆汁淤积，有些病例与消失性胆管综合征相关，这可能是进行性的，最终致命。这种形式的硫唑嘌呤肝毒性似乎是特异质性的，并且可能与硫唑嘌呤的硝基咪唑组分相关的其他非肝超敏反应（发热、皮疹、血管炎）有关。 与其他硫嘌呤类药物一样，硫唑嘌呤还可能引起慢性肝损伤，长期治疗与门脉高压和结节性再生性增生的发生有关。这种形式的慢性硫唑嘌呤肝毒性通常表现为疲劳和门脉高压的迹象和症状，伴有轻度肝酶异常和最小黄疸，这些症状在开始硫唑嘌呤治疗6个月至多年后出现。肝脏活检显示结节性再生性增生和不同程度的肝窦状隙扩张和中央静脉损伤。这种情况可能进展为肝衰竭，尤其是如果继续使用硫唑嘌呤，但停止治疗后临床改善是典型的。这种综合征的发作可能是急性的，伴有腹痛和腹水，在这种情况下，肝脏活检通常显示肝窦状隙扩张、中央充血和肝窦内皮细胞损伤，这目前被称为窦状隙阻塞性综合征。通常，即使存在高胆红素血症和肝功能障碍及门脉高压的其他表现（如血小板减少），血清转氨酶水平和碱性磷酸酶水平也仅略有升高。 最后，长期使用硫唑嘌呤和其他硫嘌呤类药物与肝细胞癌（HCC）和肝脾T细胞淋巴瘤（HSTCL）的发展有关。这两种并发症都很罕见，但已经在几十个病例报告和小型病例系列中报道。在这两种情况下，尚未证实硫嘌呤治疗在引发恶性肿瘤中的作用，类似病例已在未接受硫嘌呤的自身免疫性疾病患者或实体器官移植患者中描述。肝细胞癌通常在硫唑嘌呤或巯嘌呤治疗多年后出现，且不伴有伴随的肝病（尽管有时伴有局部肝糖原病）。HCC最常见于对无关条件的成像研究中发现。预后比与肝硬化相关的HCC更佳。肝脾T细胞淋巴瘤主要在长期使用硫嘌呤进行免疫抑制的炎症性肠病年轻男性患者中报告，可能伴随或不伴随抗肿瘤坏死因子治疗。典型的表现是疲劳、发热、肝脾肿大和全血细胞减少。诊断是通过骨髓或肝脏活检显示恶性T细胞大量浸润来确定的。HSTCL对抗肿瘤治疗效果不佳，死亡率高。 可能性评分：A（已知的临床明显肝损伤原因）。

Azathioprine has been associated with several forms of hepatotoxicity, including mild, transient and asymptomatic rises in serum aminotransferase levels, an acute cholestatic injury developing during the first year of starting therapy, and a chronic hepatic injury marked by peliosis hepatis, veno-occlusive disease or nodular regenerative hyperplasia that typically arises 1 to 5 years after starting azathioprine. Mild serum aminotransferase elevations can occur during azathioprine therapy, particularly with high doses during the first 12 weeks of therapy. These elevations are generally asymptomatic, benign and self-limited, resolving rapidly either with stopping therapy and often even with continuing treatment at a lower dose. ALT elevations during azathioprine therapy may be due to a direct toxic effect of the drug; ALT elevations as well as myelotoxicity have been linked to higher levels of methyl-mercaptopurine, a product of one of the metabolic pathways of azathioprine metabolism. Azathioprine can also cause an acute, clinically apparent liver injury that is typically cholestatic. This complication is uncommon but not rare, occurring in approximately one in a thousand treated patients. The acute cholestatic injury due to azathioprine usually presents with fatigue and jaundice after 2 to 12 months of starting therapy. The serum ALT and alkaline phosphatase tend to be only mildly or moderately elevated and in a mixed cholestatic-hepatocellular pattern. Rash, fever and eosinophilia are uncommon and autoantibodies are generally not found. Liver biopsy typically shows intrahepatic cholestasis with focal hepatocellular necrosis and scant inflammation suggestive of a cholestatic hepatitis. In some cases, the injury resembles the "bland cholestasis" as occurs with estrogens or anabolic steroids. The liver injury usually resolves rapidly on stopping, but prolonged cholestasis has been reported and some cases have been associated with vanishing bile duct syndrome, which can be progressive and eventually fatal. This form of azathioprine hepatotoxicity appears to be idiosyncratic and, with other nonhepatic hypersensitivity reactions (fever, rash, vasculitis), is possibly linked to the nitroimidazole component of azathioprine. Azathioprine, like other thiopurines, can also cause chronic liver injury and long term therapy has been linked to the development of portal hypertension and nodular regenerative hyperplasia. This form of chronic azathioprine hepatotoxicity typically presents with fatigue and signs and symptoms of portal hypertension accompanied by mild liver enzyme abnormalities and minimal jaundice arising 6 months to many years after starting azathioprine. Liver biopsy shows nodular regenerative hyperplasia and varying amounts of sinusoidal dilation and central vein injury. This syndrome can progress to hepatic failure, particularly if azathioprine is continued, but clinical improvement after stopping therapy is typical. The onset of this syndrome may be acute with abdominal pain and ascites, in which situation liver biopsy usually shows sinusoidal dilation, central congestion and injury to sinusoidal endothelial cells suggestive of veno-occlusive disease which is currently referred to as sinusoidal obstructive syndrome. Typically, serum aminotransferase levels and alkaline phosphatase levels are minimally elevated, even in the presence of hyperbilirubinemia and other manifestations of hepatic dysfunction and portal hypertension (thrombocytopenia). Finally, long term therapy with azathioprine and other thiopurines has been implicated in leading to the development of malignancies, including hepatocellular carcinoma (HCC) and hepatosplenic T cell lymphoma (HSTCL). Both of these complications are rare, but have been reported in several dozen case reports and small case series. In neither instance has the role of thiopurine therapy in causing the malignacies been proven, and similar cases have been described in patients with autoimmune conditions or after solid organ transplantation who have not received thiopurines. Hepatocellular carcinoma typically arises after years of azathioprine or mercaptopurine therapy and in the absence of accompanying liver disease (although sometimes with focal hepatic glycogenosis). The HCC is most frequently found on an imaging study done of an unrelated condition. The prognosis is more favorable than that of HCC associated with cirrhosis. Hepatosplenic T cell lymphoma has been reported largely among young men with inflammatory bowel disease and long term immunosuppression with a thiopurine, with or without anti-tumor necrosis factor therapy. The typical presentation is with fatigue, fever, hepatosplenomegaly and pancytopenia. The diagnosis is made by bone marrow or liver biopsy showing marked infiltration with malignant T cells. HSTCL is poorly responsive to antineoplastic therapy and has a high mortality rate. Likelihood score: A (well known cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：硫唑嘌呤

Compound:azathioprine

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

吸收、分配和排泄

• 吸收

口腔服用硫酸阿扎硫品吸收良好，达峰时间为1-2小时。关于硫酸阿扎硫品吸收的进一步数据不易获得。

Oral azathioprine is well absorbed, with a Tmax of 1-2h. Further data regarding the absorption of azathioprine is not readily available.

来源:DrugBank

吸收、分配和排泄

• 消除途径

氮芥和巯嘌呤在8小时后无法在尿液中检测到。关于氮芥消除途径的进一步数据尚未获得。

Azathioprine and mercaptopurine are not detectable in urine after 8 hours. Further data regarding the route of elimination of azathioprine are not available.

来源:DrugBank

吸收、分配和排泄

• 分布容积

关于硫唑嘌呤的分布体积的数据并不容易获得。

Data regarding the volume of distribution of azathioprine is not readily available.

来源:DrugBank

吸收、分配和排泄

• 清除

关于硫唑嘌呤清除的数据并不容易获得。

Data regarding the clearance of azathioprine is not readily available.

来源:DrugBank

吸收、分配和排泄

硫唑嘌呤和巯嘌呤与血浆蛋白中等程度结合，并且部分可通过透析移除。它们通过肝脏和/或红细胞中的氧化或甲基化迅速从血液中清除。肾脏清除对生物有效性和毒性影响很小，但在肾功能衰竭的患者中会减少剂量。

Azathioprine and mercaptopurine are moderately bound to plasma proteins and are partially dialyzable. They are rapidly removed from the blood by oxidation or methylation in the liver and/or erythrocytes. Renal clearance is of little impact in biological effectiveness or toxicity, but dose reduction is practiced in patients with renal failure.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  IRRITANT
• 危险品标志：
  Xn,Xi,T
• 安全说明：
  S22,S26,S36/37,S45,S53
• 危险类别码：
  R45
• WGK Germany：
  3
• 海关编码：
  2933990090
• RTECS号：
  UO8925000
• 危险标志：
  GHS07,GHS08
• 危险性描述：
  H302,H315,H319,H335,H350
• 危险性防范说明：
  P201,P261,P305 + P351 + P338,P308 + P313
• 储存条件：
  密封冷藏保存，置于通风、干燥处，并远离其他氧化物。

SDS

1.1 产品标识符
: 硫唑嘌呤
产品名称
1.2 鉴别的其他方法
6-(1-Methyl-4-nitroimidazol-5-yl)thiopurine
1.3 有关的确定了的物质或混合物的用途和建议不适合的用途
仅供科研用途，不作为药物、家庭备用药或其它用途。

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模块 2. 危险性概述
2.1 GHS分类
急性毒性, 经口 (类别4)
皮肤刺激 (类别2)
眼刺激 (类别2A)
致癌性 (类别1B)
特异性靶器官系统毒性（一次接触） (类别3)
2.2 GHS 标记要素，包括预防性的陈述
象形图
警示词 危险
危险申明
H302 吞咽有害。
H315 造成皮肤刺激。
H319 造成严重眼刺激。
H335 可能引起呼吸道刺激。
H350 可能致癌。
警告申明
预防
P201 在使用前获取特别指示。
P202 在读懂所有安全防范措施之前切勿操作。
P261 避免吸入粉尘/烟/气体/烟雾/蒸气/喷雾.
P264 操作后彻底清洁皮肤。
P270 使用本产品时不要进食、饮水或吸烟。
P271 只能在室外或通风良好之处使用。
P280 穿戴防护手套/ 眼保护罩/ 面部保护罩。
措施
P301 + P312 如果吞下去了: 如感觉不适，呼救解毒中心或看医生。
P302 + P352 如与皮肤接触，用大量肥皂和水冲洗受感染部位.
P304 + P340 如吸入，将患者移至新鲜空气处并保持呼吸顺畅的姿势休息.
P305 + P351 + P338 如与眼睛接触，用水缓慢温和地冲洗几分钟。如戴隐形眼镜并可方便地取
出，取出隐形眼镜，然后继续冲洗.
P308 + P313 如接触到或有疑虑：求医/ 就诊。
P321 具体治疗(见本标签上提供的急救指导)。
P330 漱口。
P332 + P313 如发生皮肤刺激：求医/ 就诊。
P337 + P313 如仍觉眼睛刺激：求医/就诊。 如仍觉眼睛刺激：求医/就诊.
P362 脱掉沾染的衣服，清洗后方可重新使用。
储存
P403 + P233 存放于通风良的地方。 保持容器密闭。
P405 存放处须加锁。
处理
P501 将内容物/ 容器处理到得到批准的废物处理厂。
只限于专业使用者。
2.3 其它危害物 - 无

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模块 3. 成分/组成信息
3.1 物 质
: 6-(1-Methyl-4-nitroimidazol-5-yl)thiopurine
别名
: C9H7N7O2S
分子式
: 277.26 g/mol
分子量
组分 浓度或浓度范围
Azathioprine
-
CAS 号 446-86-6
EC-编号 207-175-4

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模块 4. 急救措施
4.1 必要的急救措施描述
一般的建议
请教医生。 出示此安全技术说明书给到现场的医生看。
吸入
如果吸入,请将患者移到新鲜空气处。 如果停止了呼吸,给于人工呼吸。 请教医生。
皮肤接触
用肥皂和大量的水冲洗。 请教医生。
眼睛接触
用大量水彻底冲洗至少15分钟并请教医生。
食入
切勿给失去知觉者从嘴里喂食任何东西。 用水漱口。 请教医生。
4.2 主要症状和影响，急性和迟发效应
恶心, 头痛, 呕吐, 消化系统失调, 皮炎, 发烧, 秃头症, 休克
4.3 及时的医疗处理和所需的特殊处理的说明和指示
无数据资料

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模块 5. 消防措施
5.1 灭火介质
灭火方法及灭火剂
用水雾,耐醇泡沫,干粉或二氧化碳灭火。
5.2 源于此物质或混合物的特别的危害
碳氧化物, 氮氧化物, 硫氧化物
5.3 给消防员的建议
如必要的话,戴自给式呼吸器去救火。
5.4 进一步信息
无数据资料

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模块 6. 泄露应急处理
6.1 人员的预防,防护设备和紧急处理程序
使用个人防护设备。 防止粉尘的生成。 防止吸入蒸汽、气雾或气体。 保证充分的通风。
将人员撤离到安全区域。 避免吸入粉尘。
6.2 环境保护措施
在确保安全的前提下，采取措施防止进一步的泄漏或溢出。 不要让产物进入下水道。
6.3 抑制和清除溢出物的方法和材料
收集、处理泄漏物，不要产生灰尘。 扫掉和铲掉。 存放进适当的闭口容器中待处理。
6.4 参考其他部分
丢弃处理请参阅第13节。

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模块 7. 操作处置与储存
7.1 安全操作的注意事项
避免曝露：使用前需要获得专门的指导。避免接触皮肤和眼睛。 防止粉尘和气溶胶生成。
在有粉尘生成的地方,提供合适的排风设备。
7.2 安全储存的条件,包括任何不兼容性
贮存在阴凉处。 容器保持紧闭，储存在干燥通风处。
建议的贮存温度： -20 °C
对光线敏感
7.3 特定用途
无数据资料

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模块 8. 接触控制和个体防护
8.1 容许浓度
最高容许浓度
没有已知的国家规定的暴露极限。
8.2 暴露控制
适当的技术控制
按照良好工业和安全规范操作。 休息前和工作结束时洗手。
个体防护设备
眼/面保护
带有防护边罩的安全眼镜符合 EN166要求请使用经官方标准如NIOSH (美国) 或 EN 166(欧盟)
检测与批准的设备防护眼部。
皮肤保护
戴手套取 手套在使用前必须受检查。
请使用合适的方法脱除手套(不要接触手套外部表面),避免任何皮肤部位接触此产品.
使用后请将被污染过的手套根据相关法律法规和有效的实验室规章程序谨慎处理. 请清洗并吹干双手
所选择的保护手套必须符合EU的89/686/EEC规定和从它衍生出来的EN 376标准。
身体保护
全套防化学试剂工作服, 防护设备的类型必须根据特定工作场所中的危险物的浓度和含量来选择。
呼吸系统防护
如危险性评测显示需要使用空气净化的防毒面具，请使用全面罩式多功能微粒防毒面具N100型（US
）或P3型（EN
143）防毒面具筒作为工程控制的候补。如果防毒面具是保护的唯一方式，则使用全面罩式送风防毒
面具。 呼吸器使用经过测试并通过政府标准如NIOSH（US）或CEN（EU）的呼吸器和零件。

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模块 9. 理化特性
9.1 基本的理化特性的信息
a) 外观与性状
形状: 固体
b) 气味
无数据资料
c) 气味阈值
无数据资料
d) pH值
无数据资料
e) 熔点/凝固点
无数据资料
f) 起始沸点和沸程
无数据资料
g) 闪点
无数据资料
h) 蒸发速率
无数据资料
i) 易燃性(固体,气体)
无数据资料
j) 高的/低的燃烧性或爆炸性限度 无数据资料
k) 蒸汽压
无数据资料
l) 蒸汽密度
无数据资料
m) 相对密度
无数据资料
n) 水溶性
无数据资料
o) n-辛醇/水分配系数
无数据资料
p) 自燃温度
无数据资料
q) 分解温度
无数据资料
r) 粘度
无数据资料

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模块 10. 稳定性和反应活性
10.1 反应性
无数据资料
10.2 稳定性
无数据资料
10.3 危险反应的可能性
无数据资料
10.4 应避免的条件
发光。
10.5 不兼容的材料
强氧化剂
10.6 危险的分解产物
其它分解产物 - 无数据资料

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模块 11. 毒理学资料
11.1 毒理学影响的信息
急性毒性
半数致死剂量 (LD50) 经口 - 大鼠 - 400 mg/kg
皮肤刺激或腐蚀
无数据资料
眼睛刺激或腐蚀
无数据资料
呼吸道或皮肤过敏
无数据资料
生殖细胞突变性
实验室测试表明由诱变效应
致癌性
该产品是或包含被IARC, ACGIH, EPA, 和 NTP 列为致癌物的组分
可能的人类致癌物
IARC:
1 - 第1组：对人类致癌 (Azathioprine)
生殖毒性
实验室试验表明有畸胎生成效应
特异性靶器官系统毒性（一次接触）
吸入 - 可能引起呼吸道刺激。
特异性靶器官系统毒性（反复接触）
无数据资料
吸入危险
无数据资料
潜在的健康影响
吸入 吸入可能有害。 引起呼吸道刺激。
摄入 误吞对人体有害。
皮肤 如果通过皮肤吸收可能是有害的。 造成皮肤刺激。
眼睛 造成严重眼刺激。
接触后的征兆和症状
恶心, 头痛, 呕吐, 消化系统失调, 皮炎, 发烧, 秃头症, 休克
附加说明
化学物质毒性作用登记: UO8925000

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模块 12. 生态学资料
12.1 生态毒性
无数据资料
12.2 持久存留性和降解性
无数据资料
12.3 潜在的生物蓄积性
无数据资料
12.4 土壤中的迁移性
无数据资料
12.5 PBT 和 vPvB的结果评价
无数据资料
12.6 其它不利的影响
无数据资料

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模块 13. 废弃处置
13.1 废物处理方法
产品
将剩余的和未回收的溶液交给处理公司。
与易燃溶剂相溶或者相混合，在备有燃烧后处理和洗刷作用的化学焚化炉中燃烧
受污染的容器和包装
作为未用过的产品弃置。

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模块 14. 运输信息
14.1 联合国危险货物编号
欧洲陆运危规: - 国际海运危规: - 国际空运危规: -
14.2 联合国（UN）规定的名称
欧洲陆运危规: 非危险货物
国际海运危规: 非危险货物
国际空运危规: 非危险货物
14.3 运输危险类别
欧洲陆运危规: - 国际海运危规: - 国际空运危规: -
14.4 包裹组
欧洲陆运危规: - 国际海运危规: - 国际空运危规: -
14.5 环境危险
欧洲陆运危规: 否 国际海运危规 海运污染物: 否 国际空运危规: 否
14.6 对使用者的特别提醒
无数据资料

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模块 15 - 法规信息
N/A

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模块16 - 其他信息
N/A

制备方法与用途

硫唑嘌呤简介

硫唑嘌呤（Azathioprine）是一种巯嘌呤的咪唑衍生物，在体内分解为巯嘌呤而起作用。其免疫抑制机制与巯嘌呤相同，通过嘌呤拮抗作用，抑制淋巴细胞增殖和DNA、RNA及蛋白质合成，从而抑制免疫反应。

药理作用

硫唑嘌呤是一种临床常用的免疫抑制剂，系6-MP的衍生物，对体液免疫和细胞免疫均有显著抑制作用，主要通过转化为6-巯基嘌呤起效。它广泛用于异体移植时抑制免疫排斥，与皮质激素合用治疗类风湿性关节炎、全身性红斑狼疮等自身免疫性疾病。

生产方法

1. 胺化：将草酸二乙酯及甲醇投入反应锅中，冷却至20℃以下，通入干燥的甲胺气体到饱和后冷却到10℃以下，析出结晶，过滤烘干。

2. 环合、氯化：过量的乙二酰二甲胺和五氯化磷分次投入反应锅中，在70-80℃下保温2h，放置过夜。减压蒸出氧氯化磷后冷却，加入冰水搅拌，并用30-40%碱液调节pH为9-10，静置分层。

3. 硝化：将1-甲基-5-氯咪唑加入搪玻璃反应锅中，冷却下加入硝酸。继续在冷却下滴加硫酸，再冷却后析出产品，经过滤干燥得5-氯-1-甲基-4-硝基咪唑。

4. 缩合：将6-巯基嘌呤、氢氧化钠、水和5-氯-1-甲基-4-硝基咪唑一起煮沸4h。反应产物用乙酸调节pH至析出硫唑嘌呤。

化学性质

本品为淡黄色粉末或结晶性粉末；无臭，味微苦，在乙醇中极微溶解，在水中几乎不溶；在稀氨溶液中易溶。

用途

主要用于异体移植时抑制免疫排斥，多与皮质激素合用。也广泛用于类风湿性关节炎、全身性红斑狼疮、自身免疫性溶血性贫血、血小板减少性紫癜、活动性慢性肝炎、溃疡性结肠炎、重症肌无力、硬皮病等自身免疫性疾病。

安全与存储

• 类别：有毒物品
• 毒性分级：中毒
• 急性毒性：口服-大鼠 LD50: 535 毫克/公斤；口服-小鼠 LD50: 1389 毫克/公斤
• 可燃性危险特性：可燃烧产生有毒氮、硫氧化物烟雾
• 病人用后副作用：肝功变化，肠胃运动过强，恶心，呕吐，腹泻，体温上升，血压低，尿量少，无尿
• 储运特性：通风低温干燥
• 灭火剂：干粉、泡沫、沙土、二氧化碳、雾状水

以上信息为硫唑嘌呤的基本介绍及应用。在使用过程中需严格遵守安全操作规范，并注意对患者的密切观察与监测。

反应信息

• 作为反应物：
  描述：

  硫唑嘌呤 生成 5-巯基-1-甲基-4-硝基咪唑
  参考文献：
  名称：

  GUPTA, R. L.;KUMAR, MUNISH;SINGLA, R. K.;SINGH, SARANJIT, INDIAN J. PHARM. SCI., 49,(1987) N 5, 169-171

  摘要：

  DOI：
• 作为产物：
  描述：

  9-acetyl-6-[(1-methyl-4-nitro-5-imidazolyl)thio]purine 以 甲醇 为溶剂， 反应 0.17h， 生成 硫唑嘌呤
  参考文献：
  名称：

  Chemical transformations of 6-[(1-methyl-4-nitro-5-imidazolyl)-thio]purine (azathioprine)

  摘要：

  DOI：

  10.1007/bf02256869

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。