硫酸茚地那韦 | 157810-81-6

• 物质功能分类: 原料药 - 人工合成抗感染类药 - 抗病毒类药
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 硫酸茚地那韦
• 中文别名: (1(1S,2R),5(S))-2,3,5-三脱氧-N-(2,3-二氢-2-羟基-1H-茚-1-基)-5-[2-[[(1,1-二甲基乙基)氨基]羰基]-4-(3-吡啶甲基)-1-哌嗪基]-2-(苯甲基)-D-赤式-戊酰胺硫酸盐；茚地那非硫酸盐
• 英文名称: indinavir sulfate
• 英文别名: indinavir sulphate；(2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl]-N-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide;sulfuric acid
• CAS: 157810-81-6
• 化学式: C₃₆H₄₇N₅O₄*H₂O₄S
• 分子量: 711.88
• InChiKey: NUBQKPWHXMGDLP-BDEHJDMKSA-N

物化性质

• 熔点：
  150-153°C (dec)
• 溶解度：
  易溶于水，溶于甲醇，几乎不溶于庚烷。
• 颜色/状态：
  Crystals from absolute ethanol
• 分解：
  When heated to decomposition it emits toxic vapors of nitrogen oxides and sulfur oxides.

计算性质

• 辛醇/水分配系数(LogP)：
  2.21
• 重原子数：
  50
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  201
• 氢给体数：
  6
• 氢受体数：
  11

ADMET

代谢

印地那韦被代谢成至少7种代谢物，包括1种葡萄糖醛酸苷结合物和6种氧化代谢物。已确定的主要代谢途径包括在吡啶氮上的葡萄糖醛酸化、吡啶N-氧化、苯甲基基团的对羟基化、印安的3-羟基化和N-脱吡啶甲基化。体外研究表明，细胞色素P-450同工酶CYP3A4是形成氧化代谢物的主要酶。

Indinavir is metabolized to at least 7 metabolites including 1 glucuronide conjugate and 6 oxidative metabolites. Major metabolic pathways identified include glucuronidation at the pyridine nitrogen, pyridine N-oxidation, para-hydroxylation of the phenylmethyl group, 3-hydroxylation of the indan, and N-depyridomethylation. In vitro studies indicate that cytochrome P-450 isoenzyme CYP3A4 is the major enzyme involved in the formation of the oxidative metabolites.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间的使用总结：Indinavir（印地那韦）已不再在美国市场销售。关于在母乳喂养期间使用印地那韦的已发表经验有限，但一些婴儿可能会在母乳中达到高浓度的药物。印地那韦在母乳喂养期间不是推荐的药物。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关的已发表信息。 ◉ 对泌乳和母乳的影响：在接受高效抗逆转录病毒治疗的男性中报告了男性乳房发育症。男性乳房发育症最初是单侧的，但在大约一半的病例中进展为双侧。没有观察到血清催乳素的变化，即使继续使用该方案，通常也会在一年内自发解决。一些病例报告和体外研究表明，蛋白酶抑制剂可能会在一些男性患者中引起高催乳素血症和乳汁分泌过多，尽管这一点存在争议。这些发现对哺乳母亲的相关性尚不清楚。已建立泌乳的母亲催乳素水平可能不会影响她的哺乳能力。

◉ Summary of Use during Lactation:Indinavir is no longer marketed in the US. Published experience with indinavir during breastfeeding is limited, but some infants may achieve high levels of the drug in breastmilk. Indinavir is not a recommended agent during breastfeeding. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. 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)

毒理性

• 相互作用

未对细胞色素P450 CYP3A4底物阿司咪唑、西沙必利、咪达唑仑、特非那定和三唑仑进行研究；因为印地那韦对CYP3A4的竞争可能导致这些药物的代谢抑制和血浆浓度升高，存在严重和/或危及生命的副作用的风险；不建议将印地那韦与这些药物中的任何一种同时使用。

Studies have not been done with the cytochrome p450 CYP3A4 substrates astemizole, cisapride, midazolam, terfenadine, and triazolam; because competition for CYP3A4 by indinavir could result in inhibition of the metabolism of these medications and elevated plasma concentrations, there is a potential for serious and/or life-threatening side effects; concurrent use of indinavir with any of these medications is not recommended.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

西咪替丁和茚地那韦同时给药不影响茚地那韦的血浆浓度-时间曲线下面积（AUC）。

Concurrent administration /of cimetidine and indinavir/ does not affect the area under the plasma concentration-time curve (AUC) of indinavir.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

Amprenavir干扰利福布汀的代谢，显著增加利福布汀的血药浓度；建议将利福布汀的剂量至少减少到推荐剂量的一半；利福布汀使Amprenavir的AUC降低15%；如果利福布汀与Amprenavir同时给药，应每周监测一次中性粒细胞减少症，并根据临床指征进行监测。

Amprenavir interferes with the metabolism of rifabutin and significantly increases rifubutin serum concentrations; it is recommended that the dose of rifabutin be reduced by at least half of the recommended dose; rifabutin decreases the AUC of amprenavir by 15%; patients should be monitored for neutropenia once a week and as clinically indicated if rifabutin is given concurrently with amprenavir.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

克拉霉素与利托那韦同时使用会导致利托那韦的AUC（药时曲线下面积）增加29%，克拉霉素的AUC增加53%；不需要调整剂量。

Concurrent use /with clarithromycin/ results in a 29% increase in the AUC of indinavir and a 53% increase in the AUC of clarithromycin; dosing modification is not required.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在一项针对4至17岁的HIV感染儿童的研究中，这些儿童接受了一种包括口服印地那韦（初始剂量为每平方米500毫克，每8小时一次；随后平均剂量为每平方米每天2043毫克，分3或4次服用）的抗逆转录病毒治疗方案；平均血浆峰浓度为7.3微克/毫升，谷浓度为0.29微克/毫升。

In a study in HIV-infected children 4-17 years of age receiving an antiretroviral regimen that included oral indinavir (initial dosage of 500 mg/sq m every 8 hours; subsequent dosage averaging 2043 mg/sq m daily in 3 or 4 doses); peak and trough plasma concentrations averaging 7.3 and 0.29 ug/ml, respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

印地那韦口服给药后可迅速吸收，大约1小时达到峰值水平。与其他同类药物不同，食物可能会不利地影响印地那韦的生物利用度；高热量、高脂肪的餐食会降低血浆浓度达75%。

Indinavir is rapidly absorbed after oral administration, with peak levels achieved in approximately 1 hour. Unlike other drugs in this class, food can adversely affect indinavir bioavailability; a high-calorie, high-fat meal reduces plasma concentrations by 75%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

印地那韦主要通过粪便排泄，包括未吸收的药物和代谢物。在口服400毫克放射性标记的印地那韦后，剂量的83%在粪便中回收（19.1%为未改变的药物），19%在尿液中回收（9.4%为未改变的药物）。在口服单次700毫克或1000毫克的印地那韦剂量后，分别有10.4%或12%未改变的药物通过尿液排泄。

Indinavir is excreted principally in the feces, both as unabsorbed drug and metabolites. Following oral administration of 400 mg of radiolabeled indinavir, 83% of the dose is recovered in feces (19.1% as unchanged drug) and 19% is recovered in urine (9.4% as unchanged drug). Following oral administration of a single 700- or 1000-mg dose of indinavir, 10.4 or 12%, respectively, is excreted unchanged in urine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

为了描述脑脊液和血浆中稳态下印地那韦的药代动力学，8名感染人类免疫缺陷病毒的成年人在接受印地那韦（每8小时800毫克）加核苷逆转录酶抑制剂治疗期间进行了密集的脑脊液采样。从每位受试者分别获得了9份和11份连续的脑脊液和血浆样本。脑脊液中游离印地那韦占药物总量的94.3%，血浆中占41.7%。游离印地那韦的脑脊液峰浓度、8小时浓度以及0至8小时时间间隔内浓度-时间曲线下面积（AUC(0-8)）的平均值分别为294 nmol/L、122 nmol/L和1616 nmol/L x 小时。游离印地那韦的脑脊液-血浆AUC(0-8)比率为14.7% +/- 2.6%，与血脑屏障完整性的指标或鞘内免疫激活无关。印地那韦在脑脊液中达到的浓度有助于控制该部位人类免疫缺陷病毒1型的复制。脑脊液-血浆AUC(0-8)比率表明除了通过血脑脊液屏障的被动扩散外，还有清除机制，可能是通过P-糖蛋白介导的排出。

To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours (AUC(0-8)) for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x hr, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC (0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933990090
• 安全说明：
  S36/37

制备方法与用途

概述

硫酸茚地那韦片（Indinavir Sulfate Tablets），商品名又欣、欧直。它与其他抗逆转录病毒药物联合使用，适用于成人及儿童HIV—1感染的治疗。

生物活性

Indinavir sulfate（Crixivan, L-735524, MK-639）是一种有效的特异性HIV-1蛋白酶抑制剂，广泛应用于艾滋病的治疗。

用途

作为抗病毒药物使用。

反应信息

• 作为反应物：
  描述：

  6-[(2S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino]-hexanoic acid 、 硫酸茚地那韦 在 4-二甲氨基吡啶 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 以20%的产率得到(1S,2R)-1-((2R,4S)-2-benzyl-5-((S)-2-(tert-butylcarbamoyl)-4-(pyridin-3-ylmethyl)piperazin-1-yl)-4-hydroxypentanamido)-2,3-dihydro-1H-inden-2-yl 6-((S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanamido)hexanoate
  参考文献：
  名称：

  衍生自临床使用的HIV蛋白酶抑制剂的含缬氨酸前药的合成和体外生物学评估。

  摘要：

  为了改善目前临床上使用的蛋白酶抑制剂（PIs）的药理特性和药代动力学特性，进而改善其治疗潜力，我们合成了PI-间隔物-缬氨酸前药（PI = saquinavir，nelfinavir和indinavir; spacer = -C（O）（CH（2））（5）NH-），并评估了它们在体外水解，抗HIV活性，细胞毒性和通过单层Caco-2细胞渗透方面的稳定性（已使用与肠道亲本PI和第一代缬氨酸-PI相比（其中缬氨酸通过其羧基直接与PI相连）。通过将合适的受保护缬氨酸-间隔物部分的酸衍生物与PI缩合，可分两步以高收率制备PI-间隔物-缬氨酸共轭物，然后使缬氨酸保护基脱保护。关于水解，我们发现PI-spacer-缬氨酸前药在化学上比第一代PI-Val前药更稳定。它们的稳定性与对前药测得的低至非常低的体外抗HIV活性有关，其中缬氨酸-间隔基残基与PI的偶联是在拟肽PI的羟基上进行的。其中缬氨酸-间隔基残

  DOI：

  10.1016/j.ejmech.2007.08.016
• 作为产物：
  描述：

  (S)-1-[(2S,4R)-4-Benzyl-5-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-3-yl)-2-hydroxy-5-oxo-pentyl]-4-pyridin-3-ylmethyl-piperazine-2-carboxylic acid tert-butylamide 以90的产率得到硫酸茚地那韦
  参考文献：
  名称：

  [EN] PROCESS TO MAKE HIV PROTEASE INHIBITOR FROM 2(S)-4-PICOLYL-2-PIPERAZINE-t-BUTYLCARBOXAMIDE
  [FR] PROCEDE DE FABRICATION D'UN INHIBITEUR DE LA PROTEASE DU VIRUS VIH A PARTIR DU 2(S)-4-PICOLYL-2-PIPERAZINE-t-BUTYLCARBOXAMIDE

  摘要：

  一个制作临床有效的HIV蛋白酶抑制剂的过程，通过使用2(S)-4-吡啶基-2-哌嗪基-t-丁基羧酰胺作为中间体，通过另一种汇合合成方法来消除其合成中的一步；如上所示。

  公开号：

  WO1996028439A1

文献信息

• [EN] SPIROCYCLIC HETEROCYCLE COMPOUNDS USEFUL AS HIV INTEGRASE INHIBITORS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES SPIROCYCLIQUES UTILES COMME INHIBITEURS DU VIH
  申请人：MERCK SHARP & DOHME

  公开号：WO2016094198A1

  公开（公告）日：2016-06-16

  The present invention relates to Spirocyclic Heterocycle Compounds of Formula (I): (I) and pharmaceutically acceptable salts thereof, wherein A, B, X, R1, R2, R3 and R4 are as defined herein. The present invention also relates to compositions comprising at least one Spirocyclic Heterocycle Compound, and methods of using the Spirocyclic Heterocycle Compounds for treating or preventing HIV infection in a subject.

  本发明涉及式(I)的螺环杂环化合物及其药学上可接受的盐，其中A、B、X、R1、R2、R3和R4如本文所定义。本发明还涉及包含至少一种螺环杂环化合物的组合物，以及使用螺环杂环化合物治疗或预防受试者的HIV感染的方法。
• IRAK DEGRADERS AND USES THEREOF
  申请人：Kymera Therapeutics, Inc.

  公开号：US20190192668A1

  公开（公告）日：2019-06-27

  The present invention provides compounds, compositions thereof, and methods of using the same.

  本发明提供了化合物、其组合物以及使用这些化合物的方法。
• [EN] AMINE-LINKED C3-GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN DEGRADATION<br/>[FR] DÉGRONIMÈRES DE C3-GLUTARIMIDE LIÉS À UNE AMINE POUR LA DÉGRADATION DE PROTÉINES CIBLES
  申请人：C4 THERAPEUTICS INC

  公开号：WO2017197051A1

  公开（公告）日：2017-11-16

  This invention provides amine-linked C3-glutarimide Degronimers and Degrons for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods for their preparation.

  这项发明提供了胺连接的C3-戊二酰亚胺Degronimers和Degrons，用于治疗应用，如本文进一步描述的，以及它们的使用方法、组合物以及它们的制备方法。
• [EN] PYRIDINE CARBOXAMIDE AND METHODS FOR INHIBITING HIV INTEGRASE<br/>[FR] CARBOXAMIDE DE PYRIDINE ET METHODES PERMETTANT D'INHIBER L'INTEGRASE DU VIH
  申请人：VIROCHEM PHARMA INC

  公开号：WO2005042524A1

  公开（公告）日：2005-05-12

  Compounds of formula (I): wherein R1, R2, R4, R10, R11, and Q are as defined herein, and their pharmaceutically acceptable salts, are useful in the prevention or treatment of HIV infections.

  式(I)的化合物：其中R1、R2、R4、R10、R11和Q如本文所定义，并且它们的药用盐，在预防或治疗HIV感染方面是有用的。
• [EN] LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS<br/>[FR] PROMÉDICAMENTS LIPIDIQUES ORIENTANT VERS LE SYSTÈME LYMPHATIQUE
  申请人：ARIYA THERAPEUTICS INC

  公开号：WO2019046491A1

  公开（公告）日：2019-03-07

  The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.

  本发明提供了淋巴系统定向脂质前药，其制药组合物，制备这种前药和组合物的方法，以及改善作为脂质前药一部分的治疗剂的生物利用度或其他性质的方法。本发明还提供了治疗疾病、紊乱或症状的方法，包括向需要的患者施用所提供的脂质前药或其制药组合物。