替拉那韦 | 174484-41-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二芳基庚烷
• 中文名称: 替拉那韦
• 中文别名: N-[3-[(1R)-1-[(6R)-2-羟基-4-氧代-6-苯乙基-6-丙基-5H-吡喃-3-基]丙基]苯基]-5-(三氟甲基)吡啶-2-磺酰胺
• 英文名称: tipranavir
• 英文别名: N-{3-[(1R)-1-[(2R)-6-hydroxy-4-oxo-2-(2-phenylethyl)-2-propyl-3,4-dihydro-2H-pyran-5-yl] propyl] phenyl }-5-(trifluoromethyl)pyridine-2-sulfonamide；N-{3-[(1R)-1-[(2R)-6-hydroxy-4-oxo-2-(2-phenylethyl)-2-propyl-3,4-dihydro-2H-pyran-5-yl]propyl]phenyl}-5-(trifluoromethyl)pyridine-2-sulfonamide；N-[3-[(1R)-1-[(2R)-4-hydroxy-6-oxo-2-(2-phenylelhyl)-2-propyl-3H-pyran-5-yl]propyl]phenyl]-5-(trifluoromethyl)pyridine-2-sulfonamide；N-[3-{(1R)-(5,6-dihydro-4-hydroxy-2-oxo-6(R)-phenethyl-6-propyl-2H-pyran-3-yl)propyl}phenyl]-5-trifluoromethylpyridine-2-sulfonamide；tipranavir or TPV；N-[3-[(1R)-1-[(2R)-4-hydroxy-6-oxo-2-(2-phenylethyl)-2-propyl-3H-pyran-5-yl]propyl]phenyl]-5-(trifluoromethyl)pyridine-2-sulfonamide
• CAS: 174484-41-4
• 化学式: C₃₁H₃₃F₃N₂O₅S
• 分子量: 602.675
• InChiKey: SUJUHGSWHZTSEU-FYBSXPHGSA-N

物化性质

• 熔点：
  86-890C
• 比旋光度：
  D +20° (ethanol)
• 沸点：
  712.3±70.0 °C(Predicted)
• 密度：
  1.313±0.06 g/cm3(Predicted)
• 溶解度：
  少许溶于甲醇
• 颜色/状态：
  White solid from ethyl acetate + heptane
• 蒸汽压力：
  4.38X10-21 mm Hg at 25 °C (est)
• 旋光度：
  Specific optical rotation (in ethanol): +20 deg at 25 °C/D
• 解离常数：
  pKa = 5.86 (hydroxyl) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  42
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  10

ADMET

代谢

肝脏。用人肝微粒体的体外代谢研究显示，CYP 3A4 是参与替普那韦代谢的主要CYP酶。

Hepatic. In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism.

来源:DrugBank

代谢

替拉那韦(TPV)是第一种用于治疗耐药HIV感染的非肽类蛋白酶抑制剂。临床上，TPV与利托那韦(RTV)联合给药，以提高血液浓度并增加治疗效果。目前对RTV增强TPV的代谢介导药物相互作用的机制尚不完全了解。在当前研究中，使用代谢组学方法研究了小鼠的TPV代谢。在小鼠的粪便中发现了TPV及其代谢物，但在尿液中没有发现。对粪便代谢组的主成分分析揭示了8种TPV代谢物，包括三种单羟基化、三种脱氢、一种脱烷基化和一种二羟基化。使用人肝微粒体的体外研究重现了五种TPV代谢物，RTV均能抑制这些代谢物的形成。CYP3A4被确认为主要参与形成四种TPV代谢物(代谢物II、IV、V和VI)的酶，包括一种由碳-碳键断裂产生的异常脱烷基化产物。多种细胞色素P450(2C19、2D6和3A4)参与形成一种单羟基化代谢物(代谢物III)。在体内，RTV联合治疗显著抑制了八种TPV代谢途径。总之，代谢组学分析在小鼠中揭示了两种已知的和六种新的TPV代谢物，所有这些代谢物都被RTV抑制。当前研究为RTV介导的TPV增强作用是由于调节P450依赖性代谢提供了确凿的证据。

Tipranavir (TPV) is the first nonpeptidic protease inhibitor used for the treatment of drug-resistant HIV infection. Clinically, TPV is coadministered with ritonavir (RTV) to boost blood concentrations and increase therapeutic efficacy. The mechanism of metabolism-mediated drug interactions associated with RTV-boosted TPV is not fully understood. In the current study, TPV metabolism was investigated in mice using a metabolomic approach. TPV and its metabolites were found in the feces of mice but not in the urine. Principal component analysis of the feces metabolome uncovered eight TPV metabolites, including three monohydroxylated, three desaturated, one dealkylated, and one dihydroxylated. In vitro study using human liver microsomes recapitulated five TPV metabolites, all of which were suppressed by RTV. CYP3A4 was identified as the primary enzyme contributing to the formation of four TPV metabolites (metabolites II, IV, V, and VI), including an unusual dealkylated product arising from carbon-carbon bond cleavage. Multiple cytochromes P450 (2C19, 2D6, and 3A4) contributed to the formation of a monohydroxylated metabolite (metabolite III). In vivo, RTV cotreatment significantly inhibited eight TPV metabolic pathways. In summary, metabolomic analysis revealed two known and six novel TPV metabolites in mice, all of which were suppressed by RTV. The current study provides solid evidence that the RTV-mediated boosting of TPV is due to the modulation of P450-dependent metabolism.

来源:Hazardous Substances Data Bank (HSDB)

代谢

The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 uCi of [(14)C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. ... The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. ... 抗逆转录病毒药物替拉那韦（TPV）与利托那韦（RTV）联合给药时，在九名健康男性志愿者体内的药代动力学和代谢物轮廓得到了特征描述。受试者连续6天每天两次接受500毫克TPV胶囊和200毫克RTV胶囊。然后在第7天接受单次口服剂量551毫克的TPV，其中含有90微居里的[(14)C]TPV和200毫克的RTV，随后在长达20天内每天两次接受未标记的500毫克TPV和200毫克RTV的剂量。...在粪便中最丰富的代谢物是羟基代谢物H-1，占粪便放射活性的4.9%。TPV葡萄糖苷酸代谢物H-3是尿液中药物相关成分中最丰富的，对应于尿液中放射活性的11%。...

The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 uCi of [(14)C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. ... The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

体外代谢研究表明，CYP3A4是人类体内参与替普那韦代谢的主要CYP同型物。在大鼠中也发现了CYP3A同种型，作为参与替普那韦代谢的主要CYP同型物。

In vitro metabolism studies indicated that CYP3A4 is the predominant CYP isoform involved in tipranavir metabolism in humans. CYP3A isozyme was also identified in rat as the predominant CYP isoform involved in tipranavir metabolism.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在大鼠和人体中，通过给予与利托那韦联合使用的替拉那韦，进行研究以评估代谢物。血浆中未改变的替拉那韦是主要形式（>85.7%）。未改变的替拉那韦也是粪便和尿液中主要排泄的形式。在大鼠的粪便和尿液中排出的代谢物总水平分别约占4.8%和7.4%。在粪便中只观察到少量的葡萄糖苷酸。

Studies in rats and humans dosed by tipranavir co-administered with ritonavir were conducted to assess metabolites. The unchanged tipranavir was the predominant form in plasma (>85.7%). Unchanged tipranavir was also the major form excreted in feces and urine. Combined levels of excreted metabolites in feces and urine accounted for approximately 4.8% and 7.4% in male and female rats. Only small amounts of a glucuronide were observed in faeces.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

一些血清转氨酶水平升高在服用含有替拉那韦的抗逆转录病毒方案的病人中发生的比例很高。中到重度血清转氨酶水平升高（超过正常上限的5倍）在3%到10%的病人中发现，尽管在HIV-HCV共感染的病人中发生率可能更高。这些升高通常是无症状的，自我限制的，即使继续用药也可以解决。临床上明显的替拉那韦引起的肝损伤是罕见的，肝损伤的临床模式、潜伏期和恢复期尚未得到很好的定义。几种蛋白酶抑制剂与在开始后1到8周出现的急性肝损伤有关，肝酶升高的模式各不相同，从肝细胞到胆汁淤积。免疫过敏特征（皮疹、发热、嗜酸性粒细胞增多）是不常见的，自身抗体的形成也是罕见的。由于替拉那韦引起的急性肝损伤通常是自我限制的，但它可能是严重的，而且已经向赞助商报告了急性肝衰竭的孤立病例。在HBV或HCV共感染的病人中，一些病例似乎是由于基础慢性肝病的加重，可能是突然免疫重建的结果。替拉那韦治疗与乳酸酸中毒和急性脂肪肝没有明确的联系，而后者是与几种核苷类似物逆转录酶抑制剂相关的报道。因此，替拉那韦与血清酶升高的发生率较高，这通常高于其他蛋白酶抑制剂，这也是它被认为是二线HIV蛋白酶抑制剂的原因。

Some degree of serum aminotransferase elevations occur in a high proportion of patients taking tipranavir containing antiretroviral regimens. Moderate-to-severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Clinically apparent liver injury from tipranavir is rare, and the clinical pattern of liver injury, latency and recovery have not been well defined. Several protease inhibitors have been associated with acute liver injury arising 1 to 8 weeks after onset, with variable patterns of liver enzyme elevation, from hepatocellular to cholestatic. Immunoallergic features (rash, fever, eosinophilia) are uncommon, as is autoantibody formation. The acute liver injury due to tipranavir is usually self-limited, but it can be severe, and isolated cases of acute liver failure have been reported to the sponsor. In HBV or HCV coinfected patients, some instances appear to be due to exacerbation of the underlying chronic liver disease, perhaps as a result of sudden immune reconstitution. Tipranavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors. Thus, tipranavir is associated with a high rate of serum enzyme elevations which is generally higher than with other protease inhibitors, for which reason it is considered a second-line HIV protease inhibitor.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：替拉那韦

Compound:tipranavir

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：最令人关注的药物性肝损伤

DILI Annotation:Most-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重等级：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：盒装警告

Label Section:Box warning

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

尽管没有可用的吸收量的绝对量化，但吸收是有限的。

Absorption is limited, although no absolute quantification of absorption is available.

来源:DrugBank

吸收、分配和排泄

替拉那韦与血浆蛋白广泛结合（>99.9%）。它与人血清白蛋白和α-1-酸性糖蛋白结合。在没有利托那韦的情况下，健康志愿者和HIV-1阳性患者的临床样本中，替拉那韦的游离分数相似。这些样本的总血浆替拉那韦浓度范围从9到82微摩尔。在这个浓度范围内，替拉那韦的游离部分似乎与总药物浓度无关。

Tipranavir is extensively bound to plasma proteins (>99.9%). It binds to both human serum albumin and a-1-acid glycoprotein. The mean fraction of tipranavir (dosed without ritonavir) unbound in plasma was similar in clinical samples from healthy volunteers and HIV-1 positive patients. Total plasma tipranavir concentrations for these samples ranged from 9 to 82 uM. The unbound fraction of tipranavir appeared to be independent of total drug concentration over this concentration range.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

将（14）C-替拉那韦给药给接受Aptivus/利托那韦500/200 mg稳态给药的受试者（n=8）表明，大部分放射性物质（中位数82.3%）通过粪便排出，而只有中位数的4.4%放射性剂量在尿液中回收。此外，大部分放射性物质（56%）在给药后24至96小时内排出。在健康志愿者（n=67）和HIV-1感染的成人患者（n=120）中，替拉那韦/利托那韦的有效平均消除半衰期分别约为4.8和6.0小时，在每日两次随轻餐服用500/200 mg的稳态下。

Administration of (14)C-tipranavir to subjects (n=8) that received Aptivus/ritonavir 500/200 mg dosed to steady-state demonstrated that most radioactivity (median 82.3%) was excreted in feces, while only a median of 4.4% of the radioactive dose administered was recovered in urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The effective mean elimination half-life of tipranavir/ritonavir in healthy volunteers (n=67) and HIV-1 infected adult patients (n=120) was approximately 4.8 and 6.0 hours, respectively, at steady state following a dose of 500/200 mg twice daily with a light meal.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

抗逆转录病毒药物替拉那韦（TPV）与利托那韦（RTV）联合给药时，在九名健康男性志愿者中的药代动力学和代谢物特征已得到表征。受试者连续6天每天两次接受500毫克TPV胶囊和200毫克RTV胶囊。然后在第7天，他们接受单次口服含有90微居里的[(14)C]TPV的551毫克TPV和200毫克RTV，随后在长达20天内每天两次服用未标记的500毫克TPV和200毫克RTV。收集血液、尿液和粪便以进行质量平衡和代谢物分析。使用流动闪烁分析仪结合液相色谱-串联质谱进行代谢物分析和鉴定。放射性活性的中位回收率为87.1%，其中82.3%的总回收放射性通过粪便排出，尿液中的回收率不到5%。大多数放射性活性在[(14)C]TPV剂量后的24至96小时内排出。血液中的放射性活性主要与血浆相关，而不是红细胞。未改变的TPV占血浆放射性活性的98.4至99.7%。同样，粪便中排出的最常见的放射性形式是未改变的TPV，平均占粪便放射性活性的79.9%。粪便中最丰富的代谢物是羟基代谢物H-1，占粪便放射性活性的4.9%。TPV葡萄糖苷酸代谢物H-3是尿液中药物相关成分中最丰富的，对应于尿液中放射性活性的11%。总之，联合给药TPV和RTV后，未改变的TPV是循环和排泄的TPV的主要形式，主要的提取途径是通过粪便。

The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 uCi of [(14)C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. Blood, urine, and feces were collected for mass balance and metabolite profiling. Metabolite profiling and identification was performed using a flow scintillation analyzer in conjunction with liquid chromatography-tandem mass spectrometry. The median recovery of radioactivity was 87.1%, with 82.3% of the total recovered radioactivity excreted in the feces and less than 5% recovered from urine. Most radioactivity was excreted within 24 to 96 hr after the dose of ((14)C)TPV. Radioactivity in blood was associated primarily with plasma rather than red blood cells. Unchanged TPV accounted for 98.4 to 99.7% of plasma radioactivity. Similarly, the most common form of radioactivity excreted in feces was unchanged TPV, accounting for a mean of 79.9% of fecal radioactivity. The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. In conclusion, after the coadministration of TPV and RTV, unchanged TPV represented the primary form of circulating and excreted TPV and the primary extraction route was via the feces.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

体外血浆蛋白结合率在所有物种包括人类中非常高（> 99.9%），在10至100微摩尔的浓度范围内仅呈现轻微的饱和趋势。替拉那韦单独使用或与利托那韦联合使用时，主要分布在肝脏、小肠、大肠、肾脏和肺部。替拉那韦不会穿过血脑屏障，也不容易进入红细胞。

The in vitro plasma protein binding of tipranavir was very high (> 99.9%) in all species including humans, with only a slight trend towards saturation over the concentration range of 10 to 100 um. Tipranavir with or without ritonavir co-administration, distributed primarily in the liver, small intestine, large intestine, kidney and lung. Tipranavir did not cross the blood-brain barrier and did not readily partitioning into red blood cells.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 储存条件：
  2-8℃

制备方法与用途

抗病毒药：替拉那韦

概述 替拉那韦是一种抗病毒药物，常用剂型为胶囊。它与利托那韦合用，用于治疗具有HIV-1复制且已接受长时间治疗或感染HIV-1且对多种蛋白酶抑制剂耐药的成年患者。

生物活性 Tipranavir (PNU-140690) 有效抑制 HIV-1 蛋白酶活性和二聚化，对抗多种蛋白酶抑制剂(PI)的HIV-1分离株具有有效的活性，IC50 为 66-410 nM。

靶点 IC50: 66-410 nM (HIV-1 isolates)

体外研究 Tipranavir (PNU-140690) 抑制 HIV-1 蛋白酶的酶活性，阻止蛋白酶亚单位二聚化，并对野生型及多种耐药HIV-1变异株表现出强大的作用。当选择对抗 Tipranavir 的 11 种多 PI 耐药但 TPV 敏感的临床分离株 (HIV 11MIX)，包括 HIV B 和 HIV C，经过十代传代后 (HIV 11MIX P10) ，HIV 11MIX 显著获得高水平的 Tipranavir 耐药性，并在较高浓度的 Tipranavir 下复制。cHIV B I54V 和 cHIV B I54V/V82T 对 Tipranavir (PNU-140690) 的 IC50 分别为 2.9 μM 和 3.2 μM，分别是 cHIV B 的 11 倍和 12 倍。

体内研究 Tipranavir (PNU-140690) 口服每日两次给药，并需与低剂量利托那韦 (RTV) 联合使用以提高 Tipranavir 生物利用度。在 Tipranavir/r 与 Tipranavir 单独治疗的小鼠中，肝脏、脾脏和眼中的 Tipranavir 含量显著较高。在单独接受 Tipranavir 治疗的组别中，Tipranavir (PNU-140690) 代谢物分别占血清和肝内含量的 31% 和 38%，而在 Tipranavir (PNU-140690) 和 Tipranavir (TPV/r)-联合治疗的小鼠中，仅检测到 1% 和 2% 的代谢物。在 Sprague-Dawley 大鼠中单次给予 [14C]Tipranavir (PNU-140690)，并同时给予 RTV 共同给药。粪便中最丰富的代谢产物是氧化代谢产物，在尿液中未发现显著存在的单一代谢物。

反应信息

• 作为反应物：
  描述：

  替拉那韦 在 N-氯代丁二酰亚胺 作用下， 以 四氯化碳 为溶剂， 以99%的产率得到
  参考文献：
  名称：

  Tipranavi® 药物产品中一组独特的痕量杂质的结构解析和全合成

  摘要：

  在 30 °C/70% RH 下长期储存后，在 HIV 药物 Tipranavi® 的胶囊制剂中观察到四种未知的痕量杂质 (7–10)。广泛的 NMR 和 LC/MS 分析表明，这些化合物是 TRIS（制剂的赋形剂）与通过药物缓慢空气氧化形成的非对映异构体替拉那韦醇之间的共价加合物。结构最终通过全合成确认，并通过手性制备型超临界流体色谱进行最终纯化。在合成过程中还发现了提供丁内酯的新型 Favorskii 重排。版权所有 © 2005 John Wiley & Sons, Ltd.

  DOI：

  10.1002/mrc.1672
• 作为产物：
  描述：

  (E)-pent-2-enoyl chloride 在 palladium on activated charcoal 吡啶 、 正丁基锂 、 2,3-二巯基丁二酸 、 oxonium 、 potassium tert-butylate 、 氢气 、 sodium carbonate 、 copper(I) bromide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 1.0h， 生成 替拉那韦
  参考文献：
  名称：

  Asymmetric Syntheses and Absolute Stereochemistry of 5,6-Dihydro-α-pyrones, A New Class of Potent HIV Protease Inhibitors

  摘要：

  DOI：

  10.1021/ja963434w

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。
• [EN] DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE<br/>[FR] DÉRIVÉS DE TOXINES D'AMANITES ET LEUR CONJUGAISON À UNE MOLÉCULE DE LIAISON CELLULAIRE
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2017046658A1

  公开（公告）日：2017-03-23

  Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.

  Amernita毒素的衍生物的化学式（I），其中，化学式（a）中的R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、X、L、m、n和Q在此处被定义。这些衍生物的制备。这些衍生物在靶向治疗癌症、自身免疫性疾病和传染病中的治疗用途。
• [EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020257998A1

  公开（公告）日：2020-12-30

  Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

  提供了一种将细胞毒性药物与一个侧链连接分子结合的共轭物。它提供了制备细胞毒性分子与细胞结合配体的共轭物的侧链连接方法，以及在靶向治疗癌症、感染和免疫性疾病中使用该共轭物的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。
• [EN] AZADECALIN DERIVATIVES AS INHIBITORS OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION<br/>[FR] DÉRIVÉS D'AZADÉCALINE EN TANT QU'INHIBITEURS DE LA RÉPLICATION DU VIRUS DE L'IMMUNODÉFICIENCE HUMAINE
  申请人：VIIV HEALTHCARE UK (NO 5) LTD

  公开号：WO2018002848A1

  公开（公告）日：2018-01-04

  Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, azadecaline derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formula (I). These compounds are useful for the treatment of HIV and AIDS.

  具有药物和生物影响特性的化合物，其药物组合物和使用方法已列出。具体来说，提供了具有独特抗病毒活性的阿扎德卡林衍生物，作为HIV成熟抑制剂，如化合物(I)的公式所代表的那样。这些化合物对于治疗HIV和艾滋病是有用的。