利福霉素 | 6998-60-3

• 物质功能分类: 原料药 - 抗生素类药物 - 利福霉素类药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 中文名称: 利福霉素
• 英文名称: rifamycin SV
• 英文别名: rifamycin；rif；[(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(29),2,4,9,19,21,25,27-octaen-13-yl] acetate
• CAS: 6998-60-3
• 化学式: C₃₇H₄₇NO₁₂
• 分子量: 697.78
• InChiKey: HJYYPODYNSCCOU-ODRIEIDWSA-N

物化性质

• 熔点：
  300° (dec 140°)
• 比旋光度：
  D20 -4° (methanol)
• 沸点：
  701.9°C (rough estimate)
• 密度：
  1.2275 (rough estimate)
• 溶解度：
  Insoluble

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  50
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  201
• 氢给体数：
  6
• 氢受体数：
  12

ADMET

代谢

当利福霉素被吸收后，它主要在肝细胞和肠道微粒体中代谢为25-去乙酰代谢物。

When absorbed, rifamycin is mainly metabolzied in hepatocytes and intestinal microsomes to a 25-deacetyl metabolite.

来源:DrugBank

毒理性

• 肝毒性

在旅行者腹泻患者的上市前对照试验中，接受利福霉素治疗的患者与接受安慰剂或比较药物（环丙沙星）治疗的患者血清ALT升高率相似，没有参与者出现临床明显的肝损伤。自从获得批准以来，没有公开发表的归因于利福霉素的肝毒性的报告。由于利福霉素的吸收极少，被认为不太可能导致肝损伤。

In prelicensure controlled trials in patients with traveler’s diarrhea, rates of serum ALT elevations were similar in subjects treated with rifamycin compared to placebo or comparator agent (ciprofloxacin) and no participants developed clinically apparent liver injury. Since its approval, there have been no published reports of hepatotoxicity attributed to rifamycin. Because of its minimal absorption rifamycin is considered unlikely to cause liver injury.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：利福霉素口服吸收可忽略不计，仅用于胃肠道感染。它不太可能进入母乳或婴儿的血液，或在母亲使用后对哺乳婴儿产生任何不良反应。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，未找到相关的已发布信息。

◉ Summary of Use during Lactation:Rifamycin is negligibly absorbed orally and used only for gastrointestinal infections. It is not likely to reach the breastmilk or bloodstream of the infant or cause any adverse effects in breastfed infants after maternal use. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 蛋白质结合

利福霉素的蛋白质结合率大约为80-95%。

The protein binding of rifamycin is of about 80-95%.

来源:DrugBank

吸收、分配和排泄

• 吸收

利福霉素的吸收非常差，因此需要使用多矩阵结构技术来开发一种口服改良释放制剂，以生成FDA批准的产品。这种制剂可以在不影响上消化道菌群的情况下，将活性成分输送到远端小肠和结肠。多矩阵结构由亲脂性基质组成，外面包裹着亲水性基质，这样可以保护活性成分在小肠到达盲肠之前不被肠腔水分溶解。所有这些基质都被一种耐酸聚合物包围，这种聚合物只有在pH低于7的情况下才会分解。所有这些定制化的制剂使得生物利用度小于0.1%，据报道，接受400毫克剂量的患者的血浆浓度小于2 ng/ml。这证实了利福霉素的作用部位在小肠和结肠，这防止了特殊人群的剂量调整以及系统性的药物相互作用。据报道，服用250毫克利福霉素后的Cmax、tmax、AUC和平均滞留时间分别为36 mg/L、5分钟、11.84 mg.h/L和0.49小时。

Rifamycin has a very poor absorption and thus, the generation of an oral modified-release formulation using the technology of the multi-matrix structure was required for the generation of the FDA approved product. This preparation allows the delivery of the active ingredient in the distal small bowel and colon without interfering with the flora in the upper gastrointestinal tract. The multi-matrix is made by a lipophiic matrix surrounded in a hydrophilic matrix which allows for the protection of the active ingredient from dissolution in the intestinal aqueous fluids before it arrives in the cecum. All this matrix is surrounded by a gastro-resistant polymer that only desintegrate in a pH lower than 7. All this administration-customed formulation allows for a bioavailability of <0.1% and the plasma concentrations are reported to be of <2 ng/ml in patients receiving a dose of 400 mg. This confirms that the site of action of rifamycin stays in the small intestine and colon which prevents the need for dose adjustments in special populations as well as systemic drug interactions. The reported Cmax, tmax, AUC and mean residence time after a dosage of 250 mg of rifamycin is 36 mg/L, 5 min, 11.84 mg.h/L and 0.49 h respectively.

来源:DrugBank

吸收、分配和排泄

• 消除途径

从给药剂量中，在给药后的前24小时、48小时和72小时内，分别有18%、50%和21%在粪便中回收。这代表了大约90%的给药剂量通过粪便排出，而尿液分泌可以忽略不计。

From the administered dose, 18%, 50% and 21% is recovered in feces during the first 24, 48 and 72h after administration. This will represent about 90% of the administered dose eliminated by the feces while the urinary secretion is negligible.

来源:DrugBank

吸收、分配和排泄

• 分布容积

250毫克利福霉素给药后测得的分布体积为101.8升。

The reported volume of distribution after measured after a dosage of 250 mg of rifamycin is 101.8 L.

来源:DrugBank

吸收、分配和排泄

• 清除

当给予250毫克利福霉素时，报告的清除率为23.3 L/h。

The reported clearance when a dose of 250 mg of rifamycin was administered is 23.3 L/h.

来源:DrugBank

安全信息

• 海关编码：
  2941903000

制备方法与用途

简介

利福霉素是一类于1957年首次被发现的抗生素，以其治疗结核病 (TB) 而闻名。这种药物通过抑制 RNA 聚合酶（RNAP）对多种革兰氏阳性与阴性细菌表现出杀菌活性；然而，耐药性较为普遍，其机制多样，包括主要目标修饰、抗生素失活以及细胞质排斥。

用途

利福霉素主要用于合成利福平。

反应信息

• 作为反应物：
  描述：

  利福霉素 在 吡啶 、 盐酸羟胺 作用下， 以 甲醇 为溶剂， 以85%的产率得到4,11-dideoxy-4,11-dihydroxyiminorifamycin S
  参考文献：
  名称：

  Preparation and in vitro anti-staphylococcal activity of novel 11-deoxy-11-hydroxyiminorifamycins

  摘要：

  We report herein the preparation and anti-staphylococcal activity of a series of novel 11-deoxy-11-hydroxyiminorifamycins. Many of the compounds synthesized exhibit potent activity against wild-type Staphylococcus aureus with MICs equivalent to, or better than, rifamycin reference agents. In addition, some of the compounds retain potent activity against an intermediate rifamycin-resistant strain of Staphylococcus aureus. For instance, compound 5k exhibits an MIC of 0.12 mu g/mL against an intermediate rifamycin-resistant strain, while the rifamycin reference agents, rifampin and rifalazil, exhibit MICs of 16 mu g/mL and 2 mu g/mL, respectively, against the same strain. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.08.048
• 作为产物：
  描述：

  利福霉素 在 甲醇 、 利福霉素 、 维生素 C 、 水 、 final solution 、 利福霉素 作用下， 以 Rifamycin B-<4-jod-anilid> 为溶剂， 反应 55.0h， 以2.4 gr of deep yellowish rifamycin SV crystals were obtained的产率得到利福霉素
  参考文献：
  名称：

  Biological process for the preparation of rifamycin derivatives

  摘要：

  提供一种通过使用Humicola spp.（ATCC 20620）或Monocillium spp.（ATCC 20621）的整个细胞、细胞提取物或固定化酶将利福霉素B转化为利福霉素O、利福霉素S或利福霉素SV的生物过程。该过程还包括将转化为利福霉素O、利福霉素S或利福霉素SV的利福霉素B从发酵液中回收。

  公开号：

  US04431735A1
• 作为试剂：
  描述：

  利福霉素 在 甲醇 、 利福霉素 、 维生素 C 、 水 、 final solution 、 利福霉素 作用下， 以 Rifamycin B-<4-jod-anilid> 为溶剂， 反应 55.0h， 以2.4 gr of deep yellowish rifamycin SV crystals were obtained的产率得到利福霉素
  参考文献：
  名称：

  Biological process for the preparation of rifamycin derivatives

  摘要：

  提供一种通过使用Humicola spp.（ATCC 20620）或Monocillium spp.（ATCC 20621）的整个细胞、细胞提取物或固定化酶将利福霉素B转化为利福霉素O、利福霉素S或利福霉素SV的生物过程。该过程还包括将转化为利福霉素O、利福霉素S或利福霉素SV的利福霉素B从发酵液中回收。

  公开号：

  US04431735A1

文献信息

• [EN] PYRIDO-IMIDAZO RIFAMYCIN DERIVATIVES AS ANTIBACTERIAL AGENT<br/>[FR] DÉRIVÉS DE PYRIDO-IMIDAZO-RIFAMYCINE UTILISÉS EN TANT QU'AGENT ANTIBACTÉRIEN
  申请人：BIOFER SPA

  公开号：WO2019003076A1

  公开（公告）日：2019-01-03

  The present invention relates to novel pyrido-imiddazo rifamycines of Formula (I) as defined below and characterized by a highly selective antibacterial activity and low absorption by oral route. (I) wherein R and R1 may be H, (AA) with the proviso that: when I (BB) then R1 = H and R2 = CH3 CO- or H; when (CC) then R= H and R2= CH3 CO- or H; when (DD) then Rj = H and R2 = CH3 CO- or H; and when (EE) then R = H and R2 = CH3 CO- or H; wherein R3 and R4 are the same or different and selected from the group comprising hydrogen, linear or branched C1 -C10 alkyl, optionally substituted with one or more substituents selected from aminoalkyi, alkoxy, phenoxy, or sulfo, and aryl, optionally mono- or disubstituted with C1 -C4 alkyl or alkoxy groups, halogen, amino, nitro; or R3 and R4 taken together with two consecutive carbon atoms of the pyridine core may form a phenyl ring, optionally substituted with C1 -C4 alkyl, or a 5- or 6-membered heterocyclic ring, optionally substituted with C1_ C4 alkyl, R5 is selected from the group comprising hydrogen, hydroxy, linear or branched C1 -C10 alkyl, optionally substituted with one or more substituents selected from aminoalkyi, alkoxy, phenoxy, or sulfo, and aryl optionally mono- or disubstituted with C1 -C4 alkyl or alkoxy groups, halogen, amino, nitro.

  本发明涉及以下定义的新型吡啶咪唑呋喃霉素化合物的化学式(I)，其具有高度选择性抗菌活性和口服途径低吸收的特征。其中R和R1可以是H，(AA)条件是：当I (BB)时，R1 = H且R2 = CH3 CO-或H；当(CC)时，R= H且R2= CH3 CO-或H；当(DD)时，Rj = H且R2 = CH3 CO-或H；当(EE)时，R = H且R2 = CH3 CO-或H；其中R3和R4相同或不同，选自氢、线性或支链的C1-C10烷基，可选地取代为来自氨基烷基、烷氧基、苯氧基或磺酰基的一个或多个取代基，以及芳基，可选地单取代或双取代为C1-C4烷基或烷氧基、卤素、氨基、硝基；或者R3和R4连同吡啶核的两个相邻碳原子可以形成一个苯环，可选地取代为C1-C4烷基，或者一个5-或6-成员杂环，可选地取代为C1-C4烷基，R5选自氢、羟基、线性或支链的C1-C10烷基，可选地取代为来自氨基烷基、烷氧基、苯氧基或磺酰基的一个或多个取代基，以及芳基可选地单取代或双取代为C1-C4烷基或烷氧基、卤素、氨基、硝基。
• [EN] TARGETING COMPOUNDS<br/>[FR] COMPOSÉS DE CIBLAGE
  申请人：ZAFGEN INC

  公开号：WO2019118612A1

  公开（公告）日：2019-06-20

  The disclosure provides, at least in part, liver, intestine and/or kidney-targeting compounds and their use in treating liver, intestine and/or kidney disorders, such as non-alcoholic steatohepatitis, alcoholic steatohepatitis, hepatocellular carcinoma, liver cirrhosis, and hepatitis B; and/or chronic kidney disease, glomerular disease such as IGA nephropathy, lupus nephritis, or polycystic kidney disease. The compounds are contemplated to have activity against methionyl aminopeptidase 2.

  该披露提供了至少部分针对肝脏、肠道和/或肾脏的化合物，以及它们在治疗肝脏、肠道和/或肾脏疾病中的用途，如非酒精性脂肪肝、酒精性脂肪肝、肝细胞癌、肝硬化和乙型肝炎；和/或慢性肾脏疾病、肾小球疾病，如IgA肾病、狼疮性肾炎或多囊肾病。这些化合物被认为对甲硫氨酰氨肽酶2具有活性。
• [EN] PROGRAMMABLE POLYMERIC DRUGS<br/>[FR] MÉDICAMENTS POLYMÈRES PROGRAMMABLES
  申请人：SONY CORP

  公开号：WO2020210689A1

  公开（公告）日：2020-10-15

  Compounds useful as biologically active compounds are disclosed. The compounds have the following structure (I): or a stereoisomer, tautomer or salt thereof, wherein R1, R2, R3, R4, R5, L, L1, L2, M and n are as defined herein. Methods associated with preparation and use of such compounds are also provided.

  披露了作为生物活性化合物有用的化合物。这些化合物具有以下结构（I）：或其立体异构体、互变异构体或盐，其中R1、R2、R3、R4、R5、L、L1、L2、M和n如本文所定义。还提供了与这些化合物的制备和使用相关的方法。
• [EN] ANTI-STAPHYLOCOCCUS AUREUS ANTIBODY RIFAMYCIN CONJUGATES AND USES THEREOF<br/>[FR] CONJUGUÉS D'ANTICORPS ANTI STAPHYLOCOQUE DORÉ ET DE RIFAMYCINE ET UTILISATIONS DE CEUX-CI
  申请人：GENENTECH INC

  公开号：WO2016090038A1

  公开（公告）日：2016-06-09

  The invention provides anti-Staphylococcus aureus antibody rifamycin antibiotic conjugates and methods of using same.

  本发明提供了抗金黄色葡萄球菌抗体利福霉素抗生素偶联物及其使用方法。
• FUNCTIONALLY-MODIFIED OLIGONUCLEOTIDES AND SUBUNITS THEREOF
  申请人：Sarepta Therapeutics, Inc.

  公开号：US20140330006A1

  公开（公告）日：2014-11-06

  Functionally-modified oligonucleotide analogues comprising modified intersubunit linkages and/or modified 3′ and/or 5′-end groups are provided. The disclosed compounds are useful for the treatment of diseases where inhibition of protein expression or correction of aberrant mRNA splice products produces beneficial therapeutic effects.

  提供了包含修改的亚单位间连接和/或修改的3'和/或5'-末端基团的功能修饰寡核苷酸类似物。所公开的化合物对于治疗需要抑制蛋白质表达或纠正异常mRNA剪接产物以产生有益治疗效果的疾病是有用的。