外消旋依法韦仑 | 177530-93-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 中文名称: 外消旋依法韦仑
• 中文别名: 依非韦伦(外消旋）标准品
• 英文名称: rac-efavirenz
• 英文别名: efavirenz；(±)-efavirenz；6-chloro-4(S)-cyclopropylethynyl-4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one；6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one；6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1H-3,1-benzoxazin-2-one
• CAS: 177530-93-7
• 化学式: C₁₄H₉ClF₃NO₂
• mdl: MFCD00927196
• 分子量: 315.679
• InChiKey: XPOQHMRABVBWPR-UHFFFAOYSA-N

物化性质

• 熔点：
  107-109oC
• 沸点：
  340.6±42.0 °C(Predicted)
• 密度：
  1.53±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于丙酮（轻微）、氯仿（轻微）、DMSO（轻微）、甲醇（轻微）

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  5

ADMET

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用概要：依法韦仑会排入母乳中，一些婴儿的血清中会发现少量。对HIV阳性母亲的依法韦仑治疗似乎不会影响他们HIV阴性婴儿的生长和发育。在美国和其他可以获取清洁水源和负担得起的替代喂养的国家，建议HIV阳性母亲不要哺乳，以避免产后HIV-1感染传播。通过抗逆转录病毒疗法实现并维持病毒抑制，可以将哺乳传播风险降低到1%以下，但并非零。HIV阳性且持续不可检测病毒载量的个体，如果选择哺乳，应在这一决定中得到支持。 哺乳婴儿的影响：十三位母亲在服用每日600毫克依法韦仑、每日150毫克拉米夫定和每日300毫克齐多夫定（n=12）或每日60毫克司他夫定（n=1）的同时哺乳了他们的婴儿。在哺乳6个月后，没有报告婴儿出现不良反应，没有感染HIV，并且所有婴儿都正常发育。 在乌干达进行的一项非盲研究比较了哺乳婴儿及其HIV阳性母亲接受基于每日一次600毫克依法韦仑或每日两次400毫克洛匹那韦加100毫克利托那韦的抗逆转录病毒治疗的结果。所有母亲接受每日两次150毫克拉米夫定、300毫克齐多夫定和每日一次甲氧苄啶-磺胺甲恶唑。所有婴儿接受了预防治疗，要么是出生后1周的齐多夫定，要么是6周的奈韦拉平，加上从6周龄到断奶后6周的甲氧苄啶-磺胺甲恶唑。几乎所有婴儿在6个月大之前都是纯母乳喂养，约73%的婴儿在12个月大之前部分母乳喂养。两组婴儿的住院或不良事件（包括贫血、中性粒细胞减少或死亡）没有统计学差异。 在接受每日600毫克依法韦仑作为多药治疗HIV感染一部分的32位哺乳母亲（哺乳程度未说明）的婴儿中，研究者在1、3和6个月龄时没有注意到不良影响，母亲也没有报告。 马拉维的一项前瞻性队列研究比较了接受依法韦仑和替诺福韦酯（n=260）的HIV阳性母亲的婴儿与HIV阴性母亲（n=125）的婴儿。婴儿在长达18个月的时间内被跟踪观察生长和发育，此时治疗组有169对母婴，HIV阴性组有54对。接受治疗的女性哺乳婴儿与未接受治疗母亲的婴儿在生长和发育方面没有差异。 对哺乳和母乳的影响：在接受依法韦仑治疗的男性和至少一位女性中报告了男性乳房发育。依法韦仑似乎比其他抗逆转录病毒药物更可能引起男性乳房发育。男性乳房发育最初是单侧的，但可能会进展到双侧。即使继续用药，通常也会在一年内自发解决。这些发现与哺乳母亲的相关性尚不清楚。已建立哺乳的母亲体内的催乳素水平可能不会影响她的哺乳能力。

◉ Summary of Use during Lactation:Efavirenz is excreted into breastmilk and small amounts are found in the serum of some infants. Treatment of mothers of HIV-positive mothers with efavirenz does not appear to affect growth and development of their HIV-negative breastfed infants. In the US and other countries where access to clean water and affordable replacement feeding are available, it is recommended that mothers living with HIV not breastfeed their infants to avoid postnatal transmission of HIV-1 infection. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. ◉ Effects in Breastfed Infants:Thirteen mothers nursed their infants while they were taking efavirenz 600 mg daily, lamivudine 150 mg and zidovudine 300 mg daily (n = 12) or stavudine 60 mg daily (n = 1) . No adverse reactions were reported in the infants after 6 months of breastfeeding, none had developed HIV infection and all were developing normally. An unblinded study in Uganda compared the outcomes of breastfed infants and their HIV-positive mothers who were randomized to receive antiretroviral therapy that was based either on efavirenz 600 mg once daily or lopinavir 400 mg plus ritonavir 100 mg twice daily during breastfeeding. All mothers received lamivudine 150 mg, zidovudine 300 mg twice daily and trimethoprim-sulfamethoxazole once daily. All infants received prophylaxis with either zidovudine for 1 week or nevirapine for 6 weeks, plus trimethoprim-sulfamethoxazole from 6 weeks of age to 6 weeks after weaning. Almost all of the infants were exclusively breastfed until 6 months of age and about 73% were partially breastfed until 12 months of age. There was no statistical difference in hospitalizations or adverse events including anemia, neutropenia or deaths among infants in the two groups. Among 32 breastfed (extent not stated) infants whose mothers were taking efavirenz 600 mg daily as part of a multi-drug treatment for HIV infection, no adverse effects were noted by investigators or reported by mothers at 1, 3 and 6 months of age. A prospective cohort study in Malawi compared the infants of HIV+ mothers taking efavirenz and tenofovir disoproxil fumarate (n = 260) to infants of mothers who were HIV negative (n = 125). Infants were followed for growth and development for up to 18 months at which time there were 169 mother-infant pairs in the treatment group and 54 in the HIV-negative group. No difference was found in the growth and development of the breastfed infants of treated women compared to the infants of untreated mothers. ◉ Effects on Lactation and Breastmilk:Gynecomastia has been reported among men and at least one woman receiving efavirenz therapy. Efavirenz appears to be much more likely to cause gynecomastia than other antiretroviral agents. Gynecomastia is unilateral initially, but can progress to bilateral. Spontaneous resolution usually occurred within one year, even with continuation of the regimen. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

来源:Drugs and Lactation Database (LactMed)

安全信息

• WGK Germany：
  3

制备方法与用途

Rac-Efavirenz 是Efavirenz的一种非立体异构体结构。

反应信息

• 作为反应物：
  描述：

  外消旋依法韦仑 在 盐酸 、 4-二甲氨基吡啶 作用下， 以 乙醇 为溶剂， 生成 依法韦仑
  参考文献：
  名称：

  L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase

  摘要：

  人类免疫缺陷病毒 1 型（HIV-1）非核苷类逆转录酶（RT）抑制剂（NNRTIs）的临床疗效因抑制剂耐药病毒变异体的快速选择而受到限制。然而，通过开发既具有高水平抗病毒活性又具有增强药代动力学特征的化合物，有可能提高该类抑制剂的临床实用性。因此，我们开发了一类新的 NNRTIs，即 1，4-二氢-2H-3，1-苯并恶嗪-2-酮。L-743, 726（DMP-266）是这类药物中的一种，因其体外特性而被选中进行临床评估。该化合物是野生型 HIV-1 RT 的强效抑制剂（Ki = 2.93 nM），在细胞培养中抑制 HIV-1 复制扩散的 95% 抑制浓度为 1.5 nM。此外，研究还发现 L-7743, 7726 能够抑制一组耐 NNRTI 的突变病毒，95% 的抑制浓度为 1.5 微摩尔，每种病毒都表达了一个 RT 氨基酸替代。病毒对抑制剂的敏感性明显降低，这需要长时间的细胞培养选择，并由至少两个 RT 氨基酸替代组合介导。对大鼠、猴子和黑猩猩进行的 L-743, 726 研究表明，该化合物具有良好的口服生物利用度和人体药代动力学潜力。

  DOI：

  10.1128/aac.39.12.2602
• 作为产物：
  描述：

  1,4-二氯苯 在 trans-N,N'-dimethyl-1,2-cyclohexyldiamine 、 potassium phosphate 、 copper(l) iodide 、 正丁基锂 作用下， 以 四氢呋喃 、 正己烷 、 乙酸乙酯 为溶剂， 反应 52.0h， 生成 外消旋依法韦仑
  参考文献：
  名称：

  [EN] DMP-266 BY CYCLISATION
  [FR] DMP-266 PAR CYCLISATION

  摘要：

  揭示了一种制备HIV药物Efavirenz（也称为DMP-266）的方法，从1,4-二氯苯和其中间体开始。

  公开号：

  WO2012097511A1

文献信息

• HIV INTEGRASE INHIBITORS
  申请人：ViiV Healthcare Company

  公开号：US20150225399A1

  公开（公告）日：2015-08-13

  The present invention features compounds that are HIV integrase inhibitors and therefore are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC.

  本发明具有作为HIV整合酶抑制剂的化合物，因此在抑制HIV复制、预防及/或治疗HIV感染以及治疗艾滋病及/或艾滋病相关综合症方面具有用途。
• [EN] INDANE COMPOUNDS AS CCR5 ANTAGONISTS<br/>[FR] COMPOSES INDANE UTILISES COMME ANTAGONISTES DE CCR5
  申请人：SMITHKLINE BEECHAM CORP

  公开号：WO2004055012A1

  公开（公告）日：2004-07-01

  The present invention relates to compounds of formula (I), or pharmaceutically acceptable derivatives thereof, useful in the treatment of CCR5-related diseases and disorders, for example, useful in the inhibition of HIV replication, the prevention or treatment of an HIV infection, and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).

  本发明涉及公式(I)的化合物，或其药用可接受的衍生物，用于治疗CCR5相关疾病和障碍，例如，用于抑制HIV复制，预防或治疗HIV感染，以及治疗由此导致的获得性免疫缺陷综合症（艾滋病）。
• Chemoselective Tertiary C−H Hydroxylation for Late‐Stage Functionalization with Mn(PDP)/Chloroacetic Acid Catalysis
  作者：Rachel K. Chambers、Jinpeng Zhao、Connor P. Delaney、M. Christina White

  DOI：10.1002/adsc.201901472

  日期：2020.1.23

  oxidizing remote tertiary C(sp 3)-H bonds in the presence of a broad range of aromatic and heterocyclic moieties. Although catalyst loadings can be lowered to 0.1 mol% under a Mn(PDP)/acetic acid system for aromatic and non-basic nitrogen heterocycle substrates, the Mn(PDP)/chloroacetic acid system generally affords 10-15% higher isolated yields on these substrates and is uniquely effective for remote C(sp

  芳香族和杂环官能团在药物中无处不在。在这里，我们公开了一种新的Mn（PDP）催化剂体系，它使用氯乙酸添加剂，能够在宽范围的芳族和杂环基团存在下化学选择性氧化远端C（sp 3）-H键。尽管对于芳香族和非碱性氮杂环底物，在Mn（PDP）/乙酸体系下催化剂负载量可降低至0.1 mol％，但Mn（PDP）/氯乙酸体系通常可将这些化合物的分离产率提高10-15％底物，并且对于容纳碱性氮杂环的底物中的远程C（sp 3）-H羟基化作用特别有效。
• Inhibitors of aspartyl protease
  申请人：Vertex Pharmaceuticals Incorporated.

  公开号：US20040122000A1

  公开（公告）日：2004-06-24

  The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.

  本发明涉及一类新型磺胺类化合物，其为天冬氨酸蛋白酶抑制剂。在一个实施例中，本发明涉及一类新型HIV天冬氨酸蛋白酶抑制剂，其具有特定的结构和理化特征。本发明还涉及包含这些化合物的药物组合物。本发明的化合物和药物组合物特别适用于抑制HIV-1和HIV-2蛋白酶活性，因此，可以有利地用作抗HIV-1和HIV-2病毒的抗病毒剂。本发明还涉及使用本发明的化合物抑制HIV天冬氨酸蛋白酶活性的方法以及筛选具有抗HIV活性的化合物的方法。
• [EN] PARTICLES CONTAINING BRANCHED POLYMERS<br/>[FR] PARTICULES CONTENANT DES POLYMÈRES RAMIFIÉS
  申请人：UNIV LIVERPOOL

  公开号：WO2016009227A1

  公开（公告）日：2016-01-21

  Particles comprising a branched polymer and either a block copolymer or a linear dendritic hybrid represent a category of useful materials. They may be used in for example drug delivery applications. They may be prepared by a method comprising the steps of: dissolving the branched polymer and block copolymer or linear dendritic hybrid, and optionally other component(s),in a solvent to form a solution; adding said solution to a different liquid; and removing said solvent to form a dispersion of co-precipitated particles.

  由支化聚合物和块共聚物或线性树状混合物组成的微粒代表一类有用材料。它们可以用于例如药物传递应用。它们可以通过以下步骤制备：将支化聚合物和块共聚物或线性树状混合物以及可选的其他组分溶解在溶剂中形成溶液；将该溶液加入到另一种液体中；并去除溶剂以形成共沉淀微粒的分散体。