6-巯基嘌呤(一水合物) | 6112-76-1

• 物质功能分类: 生物化工 - 核苷类药物 - 核苷酸及其类似物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 中文名称: 6-巯基嘌呤(一水合物)
• 中文别名: 6-嘌呤硫醇；6-巯基嘌呤一水合物；6-巯(基)嘌呤一水合物；巯嘌呤；乐疾宁；6-硫代嘌呤；6-巯基嘌呤；6-巯基嘌呤水合物；6-巯基嘌呤,一水合物；6-巯基嘌呤(一水合物；6-巯基单酯；6-巯基嘌呤单水合物；嘌呤-6-硫醇；6-巯基嘌呤一水物；6-羟基嘌呤单水合物；疏嘌呤
• 英文名称: 6-mercaptopurine monohydrate
• 英文别名: 6-mercaptopurine*H2O；3,7-dihydropurine-6-thione;hydrate
• CAS: 6112-76-1
• 化学式: C₅H₄N₄S*H₂O
• mdl: MFCD01103236
• 分子量: 170.195
• InChiKey: WFFQYWAAEWLHJC-UHFFFAOYSA-N

物化性质

• 熔点：
  >300 °C(lit.)
• 溶解度：
  不溶的
• 物理描述：
  6-mercaptopurine monohydrate is an odorless light yellow to yellow crystalline powder. Becomes anhydrous at 284°F. (NTP, 1992)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.12
• 重原子数：
  11
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  86.2
• 氢给体数：
  3
• 氢受体数：
  3

ADMET

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间的总结使用：在治疗溃疡性结肠炎和克罗恩病等疾病时，大多数专业指南和其他专家认为在巯嘌呤治疗期间进行母乳喂养是可以接受的。在服用azathioprine的母亲所哺乳的婴儿中未发现巯嘌呤的活性代谢物，并且未注意到巯嘌呤或azathioprine引起的不良反应。有关详细信息，请参阅Azathioprine记录。如果母亲在巯嘌呤治疗期间进行母乳喂养，可能需要使用带有差别的完整血细胞计数和肝功能测试来监测完全母乳喂养的婴儿，尽管有些作者认为监测是不必要的。在服用剂量后避免4小时内的母乳喂养，可以显著降低婴儿通过母乳摄入的剂量。 大多数来源认为在母体抗肿瘤药物治疗期间母乳喂养是禁忌的，尽管像巯嘌呤这样的抗代谢药对哺乳婴儿的风险似乎最小。在高剂量化疗后，间歇性治疗期间可能会有一个适当的母乳喂养暂停期，从而可能安全地进行母乳喂养。尽管没有数据来确定一个适当的暂停母乳喂养的期限，但药物的终末半衰期表明暂停1到2天可能就足够了。化疗可能会对母乳的微生物组和化学成分产生不利影响。 ◉ 对哺乳婴儿的影响：在荷兰，对28位在孕期和产后因炎症性肠病服用azathioprine（n = 28）或巯嘌呤（n = 2）的母亲所生的30名婴儿进行了1到6年的随访，使用了一份包含43个问题的生活质量问卷。在这个队列中，9名婴儿平均哺乳了7个月（范围3到13个月），在调查的12个领域中，母乳喂养和配方奶喂养的婴儿之间没有发现统计学上的显著差异。 一项前瞻性队列研究跟踪了患有炎症性肠病的孕妇，从怀孕开始直到产后12个月。妇女被分配到以下各组之一：未暴露（无硫嘌呤或抗-TNF药物）；A组（azathioprine或巯嘌呤）；B组（infliximab、adalimumab或certolizumab pegol）和AB组（既有硫嘌呤又有抗-TNF药物）。在研究的1052名妇女中，72%的人给他们的婴儿哺乳，尽管在摘要中没有说明哺乳的程度和持续时间。总共264名妇女接触了硫嘌呤，59名妇女接触了硫嘌呤加抗-TNF药物。单独使用硫嘌呤与婴儿的任何并发症无关，并且他们的生长和发展在12个月内都是正常的。接触硫嘌呤和抗-TNF药物的婴儿在9到12个月大时感染数量增加了50%。从现有数据中无法确定这种增加与母乳喂养的关系。 一项针对澳大利亚胃肠病专家的全国性调查确定了21名通过母亲服用别嘌醇和硫嘌呤（例如azathioprine、巯嘌呤）组合治疗炎症性肠病而进行母乳喂养的婴儿。他们都在孕期也服用了这种组合。产后发生了两名婴儿死亡，都是在3个月大时。一个是双胞胎（与早产有关），另一个是婴儿猝死综合症。作者认为死亡与药物无关。没有提供关于哺乳程度、药物剂量或其他婴儿结果的信息。 ◉ 对泌乳和母乳的影响：在修订日期之前没有找到相关的已发布信息。

◉ Summary of Use during Lactation:In the treatment of conditions such as ulcerative colitis and Crohn's disease, most professional guidelines and other experts consider breastfeeding to be acceptable during mercaptopurine therapy. No active metabolites of mercaptopurine were found in the blood of breastfed infants whose mothers were taking azathioprine and no adverse effects attributable to mercaptopurine or azathioprine have been noted. See the Azathioprine record for details. Mothers with decreased activity of the enzyme that detoxifies mercaptopurine metabolites may transmit higher levels of drug to their infants in breastmilk. It might be desirable to monitor exclusively breastfed infants with a complete blood count with differential, and liver function tests if mercaptopurine is used during lactation, although some authors feel that monitoring is unnecessary. Avoiding breastfeeding for 4 hours after a dose should markedly decrease the dose received by the infant in breastmilk. Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy, although antimetabolites such as mercaptopurine appear to pose the least risk to breastfed infants. After high-dose chemotherapy, it might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence. Although no data are available to determine an appropriate period to withhold breastfeeding, the drug's terminal half-life suggests that withholding breastfeeding for 1 to 2 days may be sufficient. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. ◉ Effects in Breastfed Infants:In The Netherlands, 30 infants of mothers taking either azathioprine (n = 28) or mercaptopurine (n = 2) for inflammatory bowel disease during pregnancy and postpartum were followed at 1 to 6 years of age using a 43-item quality of life questionnaire. Of this cohort, 9 infants were breastfed for a mean of 7 months (range 3 to 13 months) No statistically significant differences were found between breastfed and formula-fed infants in any of the 12 domains of the survey. A prospective cohort study followed pregnant women with inflammatory bowel disease throughout pregnancy and for 12 months postpartum. Women were assigned to one of the following groups: unexposed (no thiopurines or anti-TNF agents); group A (azathioprine or mercaptopurine); group B (infliximab, adalimumab or certolizumab pegol) and group AB (both a thiopurine and an anti-TNF agent). Of 1052 women enrolled in the study, 72% breastfed their infants, although the extent and duration were not stated in the abstract. A total of 264 women were exposed to a thiopurine and 59 were exposed to a thiopurine plus an anti-TNF agent. The use of a thiopurine alone was not associated with any complication in the infants and their growth and development were normal throughout the 12 months. Infants exposed to both a thiopurine and an anti-TNF agent had a 50% increase in the number of infections between 9 and 12 months of age. The relationship of this increase with breastfeeding could not be determined from the available data. A national survey of gastroenterologists in Australia identified 21 infants who were breastfed by mothers taking a combination of allopurinol and a thiopurine (e.g. azathioprine, mercaptopurine) to treat inflammatory bowel disease. All had taken the combination during pregnancy also. Two postpartum infant deaths occurred, both at 3 months of age. One was a twin (premature birth-related) and the other from SIDS. The authors did not believe the deaths were medication related. No information was provided on the extent of breastfeeding, drug dosages or the outcomes of the other infants. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S22,S36/37/39,S45
• 危险类别码：
  R22,R36/37/38
• WGK Germany：
  3
• 海关编码：
  29335995
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  UP0400000
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335,H351,H361

制备方法与用途

羟基脲简介

巯嘌呤（Mercaptopurine，简称6-MP），又称6-巯基嘌呤、巯基嘌呤或巯唑嘌呤，是一种硫嘌呤类化疗药物和免疫抑制剂。

适应症

巯嘌呤主要用于急性白血病（包括急性粒细胞白血病和急性淋巴细胞白血病）的维持治疗。此外，它也被用于治疗恶性葡萄胎、绒毛膜上皮癌、真红细胞增多症、银屑病关节炎以及炎症性肠病（如克罗恩病和溃疡性结肠炎）。有研究表明，巯嘌呤在体外具有抗副结核分枝杆菌活性。

作用机理

作为一种嘌呤类似物，巯嘌呤属于嘌呤拮抗剂类的抗代谢药物。它通过抑制酰胺转移酶来干扰嘌呤核苷酸合成；抑制次黄嘌呤核苷酸转化为腺嘌呤核苷酸及黄嘌呤核苷酸、鸟嘌呤核苷酸的过程；还能够抑制烟酰胺腺嘌呤二核苷酸（NAD+）的合成，并引起脱氧腺苷三磷酸（dATP）和脱氧鸟苷三磷酸（dGTP）水平下降。这些作用使得巯嘌呤能有效抑制DNA的合成，从而抑制肿瘤细胞的生长。

生物活性

6-Mercaptopurine (6-MP) Monohydrate 是一种广泛使用的抗白血病药和免疫抑制剂，能够通过将巯嘌呤甲基转移酶代谢产物整合到 DNA 和 RNA 中来抑制嘌呤从头合成。

体外研究

Mercaptopurine 被广泛应用治疗恶性肿瘤、风湿性疾病、皮肤病、炎性肠道疾病以及实体器官移植排斥反应。它通过抑制磷酸核糖焦磷酸酰胺转移酶 (PRPP酰胺转移酶)，抑制嘌呤核苷酸的合成和代谢，而 PRPP酰胺转移酶是嘌呤和嘧啶生物合成过程中的限速酶。这会改变 RNA 和 DNA 的合成与功能。Mercaptopurine 还干扰了核苷互变现象和糖蛋白的合成。

化学性质

单水合物为微黄色结晶粉末，熔点在312-314℃之间，易溶于碱性溶液，略溶于热水，不溶于水、丙酮或乙醚。

用途

6-巯基嘌呤是溶癌呤和硫唑嘌呤的中间体，并可作为抗肿瘤药物使用。它也是一种免疫抑制剂，用于治疗白血病。此外，还适用于儿科非霍奇金淋巴瘤、真红细胞增多症及银屑病关节炎。

生产方法

巯嘌呤可通过从7-氨基噻唑并[5,4-d]嘧啶制备或通过使用硫化磷置换6-羟基嘌呤来获得。

反应信息

• 作为反应物：
  描述：

  6-巯基嘌呤(一水合物) 在 硫酸 、 氧气 作用下， 以 水 为溶剂， 生成 次黄嘌呤
  参考文献：
  名称：

  水溶液中6-巯基嘌呤的光氧化

  摘要：

  用近紫外光照射6-巯基嘌呤的含氧水溶液会导致嘌呤-6-硫酸盐作为主要产物。亚硫酸盐本身对于紫外线是不稳定的，并且进一步被氧化为嘌呤-6-磺酸盐。次黄嘌呤是直接光解的次要产品（<10％），但也源自磺酸盐的降解。使用染料（亚甲基蓝，玫瑰红或若丹明B）进行敏化的光氧化可得到相同的产物，并且在D 2 O中的反应发生的速率更高，这表明主要的光反应是通过添加单重态分子氧而发生的。

  DOI：

  10.1039/p29840000209
• 作为产物：
  描述：

  7-(dimethylamino)methyl-6-mercaptopurine 、 乙酸酐 生成 6-巯基嘌呤(一水合物)
  参考文献：
  名称：

  SIVER, KEVIN G.;SLOAN, KENNETH B.;WARANIS, ROBERT P.;SAAB, AKRAM, J. HETEROCYCL. CHEM., 25,(1988) N 4, C. 1077-1081

  摘要：

  DOI：

文献信息

• The reactivity of complexes containing the [Mo3(μ3S)(μS2)3]4+ core. Ligand substitution, sulfur elimination and sulfide binding
  作者：Marc D. Meienberger、Kaspar Hegetschweiler、Heinz Rüegger、Volker Gramlich

  DOI：10.1016/s0020-1693(00)83826-8

  日期：1993.11

  5-tris(dimethylamino)- cis -inositol. The complexes were characterized by one- and two-dimensional NMR spectroscopy and FAB mass spectrometry. In the presence of a weak base and 6-mercaptopurine (Hmp) or 8-hydroxyquinoline (Hoxq), the six Br atoms were replaced by these bidentate ligands forming [Mo 3 S(S 2 ) 3 (oxq) 3 ] + and [Mo 3 S(S 2 ) 3 (mp) 3 ] + . In addition, the three oxq ligands could be quantitatively

  在溶液中研究了含有[Mo 3（μ3 S）（μS2）3] 4+核的配合物的反应性。两种类型的亲电子中心，（i）三个Mo原子，（ii）三个赤道（平面内）和（iii）三个轴向（平面外）硫原子与二亲核试剂的相互作用明显不同。通过使用（），选择性反应可以特异性合成含有[Mo 3（μ3 S）（μS2）3] 4+或[Mo 3（μ3 S）（μS）3] 4+核的新配合物。 NEt 4）2 [Mo 3 S（S 2）3 Br 6]作为起始原料。硫提取和配体取代的组合导致形成[Mo 3 S 4 L 3] 4+的复合物，其中L代表三齿N，O供体1,3,5-三氨基-1,3,5 -三甲氧基-顺式肌醇和1,3,5-三甲氧基-1,3,5-三（二甲基氨基）-顺式肌醇。通过一维和二维NMR光谱法和FAB质谱法对络合物进行表征。在弱碱和6-巯基嘌呤（Hmp）或8-羟基喹啉（Hoxq）的存在下，六个Br原子被这些双齿配体取代，形成[Mo
• Auranofin and related heterometallic gold(I)–thiolates as potent inhibitors of methicillin-resistant Staphylococcus aureus bacterial strains
  作者：Yozane Hokai、Boruch Jurkowicz、Jacob Fernández-Gallardo、Nuruddinkodja Zakirkhodjaev、Mercedes Sanaú、Theodore R. Muth、María Contel

  DOI：10.1016/j.jinorgbio.2014.05.008

  日期：2014.9

  series of new heterometallic gold(I) thiolates containing ferrocenyl-phoshines were synthesized. Their antimicrobial properties were studied and compared to that of FDA-approved drug, auranofin (Ridaura), prescribed for the treatment of rheumatoid arthritis. MIC in the order of one digit micromolar were found for most of the compounds against Gram-positive bacteria Staphylococcus aureus and CA MRSA

  合成了一系列含有二茂铁基膦的新型异金属金（I）硫醇盐。研究了它们的抗菌特性，并将其与 FDA 批准的用于治疗类风湿性关节炎的药物金诺芬 (Ridaura) 的抗菌特性进行了比较。大多数针对革兰氏阳性菌金黄色葡萄球菌和 CA MRSA 菌株 US300 和 US400的化合物的 MIC 为一位数微摩尔。值得注意的是，金诺芬以 150–300 nM 的量级抑制金黄色葡萄球菌、US300 和 US400。这是首次描述了金诺芬对 MRSA 菌株的有效抑制作用。还在非致瘤性人胚胎肾细胞系 (HEK-293) 中研究了选定的异金属化合物和金诺芬的作用。
• 6-substituted purinyl piperazine derivatives
  申请人：Ortho Pharmaceutical Corporation

  公开号：US05164390A1

  公开（公告）日：1992-11-17

  6-substituted purinyl piperazine derivatives and a method of synthesis for the derivatives are described. The 6-substituted purinyl piperazine derivatives are useful as cardiotonic agents and antiarrhythmic agents.

  描述了6-取代嘌呤基哌嗪衍生物及其合成方法。这些6-取代嘌呤基哌嗪衍生物可用作心力增强剂和抗心律失常剂。
• Inhibitors of human phosphatidylinositol 3-kinase delta
  申请人：——

  公开号：US20020161014A1

  公开（公告）日：2002-10-31

  Methods of inhibiting phosphatidylinositol 3-kinase delta isoform (PI3K&dgr;) activity, and methods of treating diseases, such as disorders of immunity and inflammation, in which PI3K&dgr; plays a role in leukocyte function are disclosed. Preferably, the methods employ active agents that selectively inhibit PI3K&dgr;, while not significantly inhibiting activity of other PI3K isoforms. Compounds are provided that inhibit PI3K&dgr; activity, including compounds that selectively inhibit PI3K&dgr; activity. Methods of using PI3K&dgr; inhibitory compounds to inhibit cancer cell growth or proliferation are also provided. Accordingly, the invention provides methods of using PI3K&dgr; inhibitory compounds to inhibit PI3K&dgr;-mediated processes in vitro and in vivo.

  揭示了抑制磷脂酰肌醇3-激酶δ异构体（PI3Kδ）活性的方法，以及治疗疾病的方法，例如免疫和炎症紊乱，其中PI3Kδ在白细胞功能中发挥作用。最好的方法是使用能够选择性抑制PI3Kδ的活性的活性剂，同时不显著抑制其他PI3K异构体的活性。提供了抑制PI3Kδ活性的化合物，包括选择性抑制PI3Kδ活性的化合物。还提供了使用PI3Kδ抑制性化合物抑制癌细胞生长或增殖的方法。因此，该发明提供了使用PI3Kδ抑制性化合物在体外和体内抑制PI3Kδ介导的过程的方法。
• Synthesis and solution studies of ruthenium(II) complexes with thiazole and antileukaemic drug thiopurines. Crystal structure of trans-dichlorotris(1,3-thiazole)(triphenylphosphine)ruthenium(II) ‡
  作者：Claudia Pifferi、Renzo Cini

  DOI：10.1039/a802175i

  日期：——

  [RuCl3(AsPh3)2(MeOH)] and the base in alcoholic solution under nitrogen. The structures of the complexes were investigated by X-ray diffraction (2), NMR, conventional spectroscopic techniques and electrochemical methods. All the complex molecules have a pseudo-octahedral co-ordination geometry. The donor set of 2 consists of a phosphorus atom, two chloride anions trans to each other and three thz ligands

  结晶络合物[RuCl 2（PPh 3）2（thz）2 ] 1，[RuCl 2（PPh 3）（thz）3 ] 2，[Ru（H 2 tp）2（PPh 3）（thz）] Cl 2 ·2H 2 O 3·2H 2 O，[Ru（H 2 tg）2（PPh 3）2 ] Cl 2 ·2H 2 O·EtOH 4·2H 2 O·EtOH，[Ru（H 2 tprta）2（PPh 3）2 ] Cl 2 ·3H2 O 5·3H 2 O，[Ru（H 2 tp） 2（PPh 3） 2 ] [CF 3 SO 3 ] 2 ·H 2 O·EtOH 6·H 2 O·EtOH，[Ru（H 2 tg） 2（PPh 3） 2 ] [CF 3 SO 3 ] 2 ·3H 2 O 7·3H 2 O，[Ru（H 2 tp） 2（AsPh 3）（MeOH）] Cl 2 ·MeOH 8·MeOH，[Ru （bzim） 2 Cl 2（PPh 3）2