[(1S,4aR,11aR,12aS)-3-carbamoyl-10-(dimethylamino)-4,4a,6,7-tetrahydroxy-2,5-dioxo-11,11a,12,12a-tetrahydro-1H-tetracen-1-yl]-dimethylazanium;chloride

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 四环素类
• 英文名称: [(1S,4aR,11aR,12aS)-3-carbamoyl-10-(dimethylamino)-4,4a,6,7-tetrahydroxy-2,5-dioxo-11,11a,12,12a-tetrahydro-1H-tetracen-1-yl]-dimethylazanium;chloride
• 化学式: C23H28ClN3O7
• 分子量: 493.9
• InChiKey: WTJXVDPDEQKTCV-VQAITOIOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.45
• 重原子数：
  34
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  165
• 氢给体数：
  6
• 氢受体数：
  9

ADMET

毒理性

• 肝毒性

米诺环素治疗与两种临床上明显的肝脏损伤有关，一种是在开始治疗1到3个月内出现的急性肝炎样综合征，另一种是在长期治疗中出现的慢性肝炎样综合征，通常具有自身免疫特征，有时在使用几年后发生。这两种米诺环素肝毒性的表现有部分重叠，都与血清酶升高的肝细胞模式有关，并且都可能伴有自身抗体和免疫学特征。 米诺环素还与急性肝炎伴黄疸的病例有关，通常在开始治疗后的几周或几个月内出现。酶升高通常是肝细胞的，类似于急性病毒性肝炎。免疫过敏特征很常见，可能伴有发热、皮疹和嗜酸性粒细胞增多，有些病例还伴有面部水肿、淋巴腺病和淋巴细胞增多，可能类似于急性单核细胞增多症。肝脏损伤通常是自限性的，停药后1到2个月内完全缓解。一些患者有自身免疫标记物，停用米诺环素后这些标记物也会改善。 米诺环素还与慢性肝炎伴或不伴黄疸的病例有关，通常在长期治疗中出现，有时在使用几年后发生。最常见的表现是类似于自身免疫性肝炎的综合征，可能会很严重，甚至致命，特别是如果米诺环素没有及时停药的话。患者可能会急性发作黄疸和疲劳，或者慢性发作隐匿性疲劳、关节痛和黄疸，通常在治疗6个月到多年后出现。典型的酶升高模式是肝细胞的，ALT水平根据损伤的严重程度和持续时间可升高3到20倍。通常存在自身抗体，通常是抗核抗体（ANA）滴度大于1:160。在某些情况下，ANA可能最初是阴性的，随着疾病进展或开始改善而出现。免疫球蛋白通常也会升高，肝脏活检显示典型的自身免疫性肝炎改变，包括活动性界面肝炎、点状嗜酸性坏死和富含淋巴细胞和浆细胞的门脉浸润。纤维化不常见，但可能会发生，特别是如果疾病持续并且米诺环素在肝脏损伤的情况下继续使用。如果停用米诺环素，这种情况会自行缓解，但通常会使用皮质类固醇。在停用米诺环素后的长期随访中，慢性损伤很少见，如果有的话，通常所有症状和实验室检测异常在停药后6到12个月内缓解，尽管患者可能继续有低滴度的ANA。 与米诺环素使用相关的其他免疫介导综合征包括血清病样综合征（通常在开始治疗后3到12周内），狼疮样综合征和溶血性贫血（后两者与长期治疗有关）。肝脏损伤可以伴随这些其他自身免疫疾病，但通常是非黄疸性的、轻微的并且迅速可逆。血清酶升高的模式通常是肝细胞的，自身抗体很常见。 可能性评分：A（临床上明显肝脏损伤的已知原因）。

Minocycline therapy is associated with two forms of clinically apparent liver injury, an acute hepatitis-like syndrome that arises within 1 to 3 months of starting therapy and a chronic hepatitis-like syndrome typically with autoimmune features that occurs with long term therapy, sometimes after several years of use. There is some overlap between these two presentations of minocycline hepatotoxicity, both are associated with a hepatocellular pattern of serum enzyme elevations and both can be associated with autoantibodies and immunological features. Minocycline has been linked to cases of an acute hepatitis with jaundice that typically arises within a few weeks or months of starting therapy. The enzyme elevations are typically hepatocellular and resemble acute viral hepatitis. Immunoallergic features are common and may be prominent with fever, rash and eosinophilia and some cases with facial edema, lymphoadenopathy and lymphocytosis that may resemble acute mononucleosis. The liver injury is usually self limited with complete resolution within 1 to 2 months of stopping. Some patients have autoimmune markers and these also improve upon stopping minocycline. Minocycline has also been linked to cases of chronic hepatitis with or without jaundice that typically arise during long term therapy, sometimes after years of use. The most common presentation is with an autoimmune hepatitis-like syndrome that can be severe and even fatal, particularly if minocycline is not stopped promptly. Patients can present acutely with jaundice and fatigue or chronically with insidious onset of fatigue, joint aches and jaundice, usually after 6 months to many years of therapy. A hepatocellular pattern of enzyme elevations is typical with ALT levels ranging from 3- to 20-fold elevated depending upon the severity and duration of the injury. Autoantibodies are usually present, typically antinuclear antibody (ANA) at titers of >1:160. In some cases, ANA may initially be negative, arising later as the disease progresses or starts to improve. Immunoglobulins are also usually elevated and liver biopsy demonstrates changes typical of autoimmune hepatitis with active interface hepatitis, spotty eosinophilic necrosis and portal infiltrates rich in lymphocytes and plasma cells. Fibrosis is uncommon, but can occur, particularly if the disease is prolonged and minocycline continued in the face of hepatic injury. The condition will resolve spontaneously if minocycline is withdrawn, but corticosteroids are often used. In long term follow up after stopping minocycline, chronic injury is rare, if it occurs at all and generally all symptoms and laboratory test abnormalities resolve within 6 to 12 months of stopping, although patients may continue to have low titers of ANA. Other immunologically mediated syndromes associated with minocycline use include a serum sickness like syndrome (generally within 3 to 12 weeks of starting), a lupus-like syndrome and hemolytic anemia (the latter two with chronic therapy). Liver injury can accompany these other autoimmune conditions, but is generally anicteric, mild and rapidly reversible. The pattern of serum enzyme elevations is typically hepatocellular and autoantibodies are common. Likelihood score: A (well known cause of clinically apparent liver injury).

来源:LiverTox

反应信息

• 作为反应物：
  描述：

  [(1S,4aR,11aR,12aS)-3-carbamoyl-10-(dimethylamino)-4,4a,6,7-tetrahydroxy-2,5-dioxo-11,11a,12,12a-tetrahydro-1H-tetracen-1-yl]-dimethylazanium;chloride 生成
  参考文献：
  名称：

  7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines

  摘要：

  本发明涉及式子为##STR1##的7-取代-9-(取代氨基)-6-去甲基-6-脱氧四环素化合物，其中R，X，R.sup.5和R.sup.6在规范中有定义。本发明的化合物可用作广谱抗生素。

  公开号：

  US05494903A1
• 作为产物：
  描述：

  7-iodosancycline 以68的产率得到[(1S,4aR,11aR,12aS)-3-carbamoyl-10-(dimethylamino)-4,4a,6,7-tetrahydroxy-2,5-dioxo-11,11a,12,12a-tetrahydro-1H-tetracen-1-yl]-dimethylazanium;chloride
  参考文献：
  名称：

  J. Org. Chem. 2002, 67, 5025-5027

  摘要：

  DOI：
• 作为试剂：
  描述：

  [(1S,4aR,11aR,12aS)-3-carbamoyl-10-(dimethylamino)-4,4a,6,7-tetrahydroxy-2,5-dioxo-11,11a,12,12a-tetrahydro-1H-tetracen-1-yl]-dimethylazanium;chloride 、 [(2-Chloroacetyl)(2,2-dimethylpropyl)amino]methyl 2-chloroacetate 在 [(1S,4aR,11aR,12aS)-3-carbamoyl-10-(dimethylamino)-4,4a,6,7-tetrahydroxy-2,5-dioxo-11,11a,12,12a-tetrahydro-1H-tetracen-1-yl]-dimethylazanium;chloride 作用下， 以83的产率得到(4S,4aS,5aR,12aS)-9-((2-chloro-N-neopentylacetamido)methyl)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-N-(hydroxymethyl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide
  参考文献：
  名称：

  Tetrahedron. Lett. 2008, 49, 6095-6100

  摘要：

  DOI：

文献信息

• 7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
  申请人：American Cyanamid Company

  公开号：US05494903A1

  公开（公告）日：1996-02-27

  The invention is drawn to 7-substituted-9-(substituted amino)-6-demethyl-6-deoxytetracycline compounds of the formula ##STR1## wherein R, X, R.sup.5 and R.sup.6 are defined in the specification. The compounds of the invention are useful as broad spectrum antibiotics.

  本发明涉及式子为##STR1##的7-取代-9-(取代氨基)-6-去甲基-6-脱氧四环素化合物，其中R，X，R.sup.5和R.sup.6在规范中有定义。本发明的化合物可用作广谱抗生素。
• Novel 7-substituted-9-substituted amino-6-demethyl-6-deoxytetracyclines
  申请人：AMERICAN CYANAMID COMPANY

  公开号：EP0536515B1

  公开（公告）日：2001-12-19
• J. Med. Chem. 1994, 37, 184-188
  作者：

  DOI：——

  日期：——
• RESORBABLE NONWOVEN POUCHES FOR MEDICAL DEVICE IMPLANTS
  申请人：Tepha, Inc.

  公开号：EP3897452A1

  公开（公告）日：2021-10-27
• [EN] RESORBABLE NONWOVEN POUCHES FOR MEDICAL DEVICE IMPLANTS<br/>[FR] POCHES RÉSORBABLES NON TISSÉES POUR IMPLANTS DE DISPOSITIFS MÉDICAUX
  申请人：TEPHA INC

  公开号：WO2020131172A1

  公开（公告）日：2020-06-25

  Nonwoven resorbable pouches that at least partially enclose implantable medical devices and improved methods for producing the implantable medical device pouches are described. The nonwoven pouches may comprise one or more drugs. Implantable medical devices that are placed in the pouches prior to implantation are prevented from migrating from the site of implantation by tissue ingrowth into the pouch. Antibiotics may be incorporated into the pouches to prevent post-operative infections. The pouches may be formed in fewer steps than conventional pouches, and without polymer coatings. Nonwoven pouches can be formed in one step by dry spinning instead of using multiple processing steps. In embodiments, the nonwoven pouches are smoother on the inside than the outside to tightly fit the implantable medical devices internally while encouraging external tissue ingrowth. In embodiments, the nonwoven pouches eliminate the use of knitted or woven multifilament fibers that can trap bacteria and result in post-operative infection.