2',3'-二脱氧肌苷 | 69655-05-6

• 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 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 中文名称: 2',3'-二脱氧肌苷
• 中文别名: 地达诺辛；地丹诺辛；去羟肌苷；2',3'-双脱氧肌苷；2',3'-双脱氧肌甙；双脱氧肌苷
• 英文名称: Dideoxyinosine
• 英文别名: DIDANOSINE；2',3'‑dideoxyinosine；Didanosine；9-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]-1H-purin-6-one
• CAS: 69655-05-6
• 化学式: C₁₀H₁₂N₄O₃
• mdl: MFCD00077728
• 分子量: 236.23
• InChiKey: BXZVVICBKDXVGW-NKWVEPMBSA-N

物化性质

• 熔点：
  193-195 °C
• 沸点：
  193-195 C
• 比旋光度：
  D25 -26.3° (c = 10 in water)
• 密度：
  1.2917 (rough estimate)
• 溶解度：
  溶于DMSO或甲醇
• 物理描述：
  2',3'-dideoxyinosine appears as fluffy white solid or powder. Condenses at 347°F and darkens at approximately 572°F. Odorless. (NTP, 1992)
• 颜色/状态：
  White solid
• 蒸汽压力：
  6.6 mm Hg @ 25 °C /Estimated/
• 亨利常数：
  Henry's Law constant = 2.4X10-20 atm-cu m/mol @ 25 °C /Estimated/
• 稳定性/保质期：
  Didanosine unbuffered pediatric powder for oral solution should be stored at 15-30 °C. Following reconstitution with water and admixture with a liquid antacid as directed, didanosine pediatric oral suspensions contain 10 mg of the drug per ml and are stable for 30 days when refrigerated at 2-8 °C. Reconstituted and admixed pediatric oral suspensions of didanosine should be stored in tightly closed, flint glass bottles with child resistant closures and refrigerated at 2-8 °C. Unused portions of reconstituted and admixed pediatric didanosine oral suspension should be discarded after 30 days.
• 旋光度：
  (c = 1, H2O) [a]20D = -25.7 ± 2°
• 解离常数：
  pKa= 9.13

计算性质

• 辛醇/水分配系数(LogP)：
  -1.2
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  88.7
• 氢给体数：
  2
• 氢受体数：
  5

ADMET

代谢

迅速在细胞内代谢为其活性部分，2,3-双脱氧腺苷-5-三磷酸（ddA-TP）。然后它被肝脏进一步代谢，产生次黄嘌呤、黄嘌呤和尿酸。

Rapidly metabolized intracellularly to its active moiety, 2,3-dideoxyadenosine-5-triphosphate (ddA-TP). It is then further metabolized hepatically to yield hypoxanthine, xanthine, and uric acid.

来源:DrugBank

代谢

去氧腺苷的代谢命运在人类中尚未被完全评估；然而，由于去氧腺苷是肌苷的类似物，肌苷是一种天然存在的嘌呤核苷，药物的代谢可能通过负责消除内源性嘌呤的同一路径发生。

The metabolic fate of didanosine has not been fully evaluated in humans; however, because didanosine is an analog of inosine, a naturally occurring purine nucleoside, metabolism of the drug presumably would occur via the same pathways responsible for the elimination of endogenous purines.

来源:Hazardous Substances Data Bank (HSDB)

代谢

细胞内，地达诺新被转化为脱氧肌苷-5'-单磷酸盐...单磷酸盐衍生物随后可能通过腺苷酸琥珀酸合酶/裂合酶催化的反应氨基化成脱氧腺苷-5'-单磷酸盐，并通过其他酶（例如，嘌呤核苷单磷酸激酶，嘌呤核苷二磷酸激酶）磷酸化成脱氧腺苷-5'-二磷酸和脱氧腺苷-5'-三磷酸。地达诺新在细胞内（宿主细胞）转化为三磷酸衍生物是药物发挥抗病毒活性的必要条件。

Intracellularly, didanosine is converted to dideoxyinosine-5'-monophosphate. ...The monophosphate derivative may then be aminated to dideoxyadenosine-5'-monophosphate in a reaction catalysed by adenylosuccinate synthetase/lyase and phosphorylated to dideoxyadenosine-5'-diphosphate and to dideoxyadenosine-5'-triphosphate via other enzymes (eg, purine nucleoside monophosphate /kinase/, purine /nucleoside/ diphosphate kinase). Intracellular (host cell) conversion of didanosine to triphosphate derivative is necessary for the antiviral activity of the drug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

去氧腺苷酸进一步通过嘌呤核苷酸激酶和嘌呤核苷二磷酸激酶磷酸化，生成三磷酸（ddATP）。细胞内ddATP的半衰期为1224小时，这表明与齐多夫定或扎西他滨相比，可能需要更少的给药频率。除了抑制病毒逆转录酶外，ddATP还会被并入DNA中，终止细胞和病毒DNA的复制链。尽管去氧腺苷酸磷酸化对药物的 抗病毒机制至关重要，但它仅占药物总处置的一小部分。大约40%的总剂量以未改变的药物形式在尿液中回收，约50%以次黄嘌呤形式，约4%以尿酸形式，而非肾脏清除则通过代谢和/或胆汁排泄发生。主要的代谢途径是通过嘌呤核苷酸磷酸化酶代谢成尿酸，该酶产生次黄嘌呤。这种化合物要么重新进入嘌呤核苷酸池，要么通过黄嘌呤氧化酶的作用进一步代谢成黄嘌呤和尿酸。

Didanosine is metabolized along two pathways. A quantitatively minor pathway that is responsible for the antiretroviral activity of the drug involves phosphorylation and reversible amination of didanosine monophosphate to dideoxyadenosine monophosphate through the action of adenylosuccinate synthetase and adenylosuccinate lyase. The dideoxyadenosine monophosphate is further phosphorylated to the triphosphate (ddATP) by purine nucleoside monophosphate kinase and purine nucleoside diphosphate kinase. The intracellular half-time of ddATP is 1224 hr, suggesting that less frequent dosing may be required than with zidovudine or zalcitabine. In addition to inhibiting the viral reverse transcriptase, ddATP becomes incorporated into DNA and terminates the replicating DNA chain in both cellular and viral DNA. Although dideoxyadenosine phosphorylation is critical to the mechanism of antiviral activity, it is responsible for only a small fraction of the total drug disposition. Approximately 40% of the total dose is recovered as unchanged drug in the urine, about 50% as hypoxanthine and about 4% as uric acid, while non-renal clearance occurs via metabolism and/or biliary excretion. The major metabolic pathway involves metabolism to uric acid through purine nucleotide phosphorylase, which produces hypoxanthine. This compound either re-enters the purine nucleotide pools or is further metabolized to xanthine and uric acid through the action of xanthine oxidase.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

副作用包括胰腺炎、周围神经病变、腹泻、高尿酸血症和肝功能不全。

Side effects include pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and hepatic dysfunction

来源:DrugBank

毒理性

• 肝毒性

温和且短暂的肝酶升高发生在多达9%的使用去羟肌苷的患者中，但这些通常是无症状的且自我限制的。临床上明显的肝毒性并不常见，但已有详细描述。与去羟肌苷使用相关的几种肝脏损伤形式包括：急性特异质性肝损伤、乳酸酸中毒伴脂肪变性和肝功能障碍（LASH）、以及由于结节性再生性增生或肝门脉硬化导致的非肝硬化性门脉高压。 去羟肌苷导致的急性、看似特异质性肝损伤的罕见实例已被描述，特别是在儿童中。这种损伤在开始治疗后的几周内出现，并与血清酶的肝细胞模式有关（案例3）。免疫过敏特征（皮疹、发热和嗜酸性粒细胞增多）可能出现，但并不突出，且自身抗体通常不存在。停止去羟肌苷后恢复迅速，但损伤可能严重，导致急性肝衰竭。这种去羟肌苷损伤形式罕见，类似于许多药物引起的特异质性急性肝炎样损伤。 去羟肌苷导致的第二种损伤模式更为常见，其特征是明显的乳酸酸中毒、微囊泡性脂肪变性和肝合成功能障碍（LASH）。这种肝脏损伤通常在至少两个月治疗后出现，之前会有非特异性前驱症状，如厌食、恶心、呕吐、腹泻和乏力，随后出现呼吸困难、黄疸和混乱。乳酸酸中毒通常伴随肝损伤，可能是主要临床表现。黄疸出现较晚，血清酶通常只是轻微或中度升高，模式为混合型或实际上为胆汁淤积型。还可能发生胰腺炎、肌病和神经病。与去羟肌苷相关的这种独特肝毒性可能导致快速死亡（案例1），但通过密集支持和早期停止治疗有潜在可逆性（案例2）。预先存在的肝脏损伤、女性、年龄较大、肥胖、酒精使用以及与司他夫定、利巴韦林或替诺福韦的并发治疗似乎增加了这种综合征的风险。LASH最常见于司他夫定治疗，但也可能发生在齐多夫定、法拉韦啶、静脉注射四环素、利奈唑胺和阿司匹林（Reye综合征）。 去羟肌苷相关的最后一种肝脏损伤形式是非肝硬化性门脉高压，由于结节性再生性增生或肝门脉硬化（案例4）。这种去羟肌苷引起的慢性肝脏损伤通常在治疗数年后出现。患者通常表现为门脉高压和晚期肝病的迹象，如腹水、静脉曲张出血、肌肉消瘦和乏力，没有明显的原因（无乙型或丙型肝炎，无酗酒史）。血清酶只是适度升高，胆红素水平可能正常。血小板计数往往较低，血小板计数的下降可能是发展为门脉高压的有用替代指标。这些患者通常使用多种抗逆转录病毒药物，损伤归因于去羟肌苷并不总是能够确定。临床表现在去羟肌苷停止后可能出现。司他夫定和齐多夫定也被牵涉其中，以及其他如硫唑嘌呤、巯嘌呤和硫鸟嘌呤的核苷类似物。与这种并发症相关的主要危险因素包括去羟肌苷使用的时间、低CD4细胞计数和与司他夫定的并发使用。肝脏活检显示没有肝硬化，有结节性再生性增生或肝门脉硬化或两者的变化。肝静脉压力梯度通常升高，但由于其前窦状性质，可能低估了门脉高压的程度。同样，用于检测肝纤维化的非侵入性测试，如瞬时弹性成像，通常异常，但并不达到通常与肝硬化时出现的门脉高压相关的程度。 有趣的是，发展非肝硬化性门脉高压的患者中有很大一部分有潜在的血栓性疾病，如蛋白S或蛋白C缺乏，容易发展为门脉静脉血栓形成，这可能是急性失代偿的原因。 可能性评分：A（已知是引起急性或慢性临床明显肝损伤的常见原因）。

Mild and transient elevations in liver enzymes occur in up to 9% of patients on didanosine, but these are generally asymptomatic and self-limited. Clinically apparent hepatotoxicity is uncommon, but well described. Several forms of liver injury have been associated with didanosine use: acute idiosyncratic liver injury, lactic acidosis with steatosis and hepatic dysfunction (LASH), and noncirrhotic portal hypertension due to nodular regenerative hyperplasia or hepatoportal sclerosis. Rare instances of acute, seemingly idiosyncratic liver injury due to didanosine have been described, particularly in children. The injury arises within a few weeks of starting therapy and is associated with hepatocellular pattern of serum enzymes (Case 3). Immunoallergic features (rash, fever and eosinophilia) may occur, but are not prominent and autoantibodies are generally not present. Recovery is rapid with stopping didanosine, but the injury can be severe and lead to acute liver failure. This form of didanosine injury is rare and resembles the idiosyncratic acute hepatitis-like injury that occurs with many medications. The second pattern of injury due to didanosine is more common and is characterized by development of marked lactic acidosis, microvesicular steatosis, and hepatic synthetic dysfunction (LASH). This form of liver injury typically arises after at least two months of therapy and is preceded by nonspecific prodromal symptoms of anorexia, nausea, vomiting, diarrhea, and weakness which is followed by dyspnea, jaundice and confusion. Lactic acidosis usually accompanies the hepatic injury and may be the predominant clinical feature. Jaundice arises late and serum enzymes are unusually only mildly or moderated elevated, the pattern being mixed or actually cholestatic. Pancreatitis, myopathy and neuropathy may also occur. This distinctive form of hepatotoxicity associated with didanosine can be rapidly fatal (Case 1), but is potentially reversible with intensive support and early withdrawal of therapy (Case 2). Preexisting liver injury, female sex, older age, obesity, alcohol use and concurrent therapy with stavudine, ribavirin or tenofovir appear to increase the risk of this syndrome. LASH is most commonly associated with stavudine therapy, but can also occur with zidovudine, fialuridine, intravenous tetracycline, linezolid and aspirin (Reye syndrome). A final form of didanosine associated liver injury is noncirrhotic portal hypertension due to nodular regenerative hyperplasia or hepatoportal sclerosis (Case 4). This chronic form of liver injury due to didanosine generally arises after several years of therapy. Patients usually present with signs of portal hypertension and advanced liver disease, ascites, variceal hemorrhage, muscle wasting and weakness with no obvious cause (absence of hepatitis B or C and no history of alcoholism). Serum enzymes are only modestly elevated and bilirubin levels can be normal. Platelet counts tend to be low and a fall of platelet count can be a useful surrogate marker for the development of portal hypertension. These patients have typically been on multiple antiretroviral agents and the attribution of injury to didanosine cannot always be made. The clinical presentation can be after didanosine has been discontinued. Stavudine and zidovudine have also been implicated as have other nucleoside analogues such as azathioprine, mercaptopurine and thioguanine. Major risk factors associated with this complication include duration of didanosine use, low CD4 cell counts and concurrent use of stavudine. Liver biopsy shows the absence of cirrhosis and changes of nodular regenerative hyperplasia or hepatoportal sclerosis or both. Hepatic venous pressure gradients are usually elevated, but probably underestimate the degree of portal hypertension because of its presinusoidal nature. Similarly, noninvasive tests for hepatic fibrosis, such a transient elastography, are usually abnormal but not to the degree that is usually associated with the portal hypertension that occurs with cirrhosis. Interestingly, a high proportion of patients who develop noncirrhotic portal hypertension have an underlying thrombophilic condition such as protein S or protein C deficiency and are prone to develop portal vein thrombosis which can be the cause of acute decompensation. Likelihood score: A (well known cause of both acute and chronic forms of clinically apparent liver injury).

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：去氧腺苷酸

Compound:didanosine

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

吸收、分配和排泄

• 吸收

迅速吸收（生物利用度30-40%），血浆峰浓度在0.5到1.5小时内出现。

Rapidly absorbed (bioavailability 30-40%) with peak plasma concentrations appearing within 0.5 and 1.5 hrs.

来源:DrugBank

吸收、分配和排泄

• 消除途径

根据体外和动物研究的数据，推测人体对去羟肌苷的代谢是通过与内源性嘌呤消除相同的途径进行的。嘌呤通过肾脏排出。

Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines. Purines are eliminated by the kidneys.

来源:DrugBank

吸收、分配和排泄

给予两名孕妇单次口服375毫克地丹诺辛（停经时长分别为21周和24周）。通过静脉穿刺收集母体血液，并在治疗后65分钟和78分钟分别取得羊水和胎儿血液样本。地丹诺辛穿过胎盘，胎儿与母体的比率分别为0.14和0.19。

A single oral dose of 375 mg didanosine was administered to two pregnant women (length of amenorrhoea, 21 and 24 weeks). Maternal blood was collected by venepuncture, and amniotic fluid and fetal blood samples were taken 65 and 78 min after treatment. Didanosine crossed the placenta, with fetal:maternal ratios of 0.14 and 0.19.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

食物在胃肠道中的存在通常会降低口服地丹诺辛的吸收速率和程度。如果地丹诺辛的缓释胶囊与食物一起服用，药物的血浆峰浓度和药时曲线下面积（AUC）分别降低大约46%和19%。在一项研究中，餐前30分钟内服用地丹诺辛咀嚼/分散、缓冲片的生物利用度与空腹条件下相似。当药片在饭后2小时内服用时，地丹诺辛的血浆峰浓度和AUC大约降低55%。

Presence of food in the GI tract generally decreases the rate and extent of absorption of oral didanosine. If didanosine delayed-release capsules are administered with food, peak plasma concentrations and AUC of the drug are decreased approximately 46 and 19%, respectively. In one study, the bioavailability of chewable/dispersible, buffered tablets of didanosine administered up to 30 minutes prior to a meal was similar to the drug's bioavailability under fasting conditions. When the tablets were administered up to 2 hours after a meal, peak plasma concentrations and AUC of didanosine were decreased approximately 55%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

抗酸药提高了地丹诺辛的口服生物利用度。

Antacids increase the oral bioavailability of didanosine.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  C
• 安全说明：
  S26,S27,S36/37/39,S45
• 危险类别码：
  R34
• WGK Germany：
  2
• 海关编码：
  29335990,2942000000
• RTECS号：
  NM7460700
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

适应症

去羟肌苷对齐多夫定耐药的HIV病毒株仍有作用。主要适用于不能耐受齐多夫定、在应用齐多夫定过程中产生耐药性或病情反复恶化的艾滋病患者。

药理作用

去羟肌苷是一种HIV反转录酶抑制剂，在细胞酶的作用下转化为具有抗病毒活性的代谢物双去氧三磷酸腺苷而起作用，掺入病毒DNA，使病毒的延长终止。其作用机制与齐多夫定相似。不能预防HIV通过性接触或血液污染造成的传染。与其他抗病毒药物联合使用（鸡尾酒疗法）用于治疗I型HIV感染。

抗病毒药和抗艾滋病药

地达诺辛是一种抗病毒药和抗艾滋病药，又称惠妥滋、地丹诺辛、二脱氧胸苷、双脱氧肌苷或去羟肌苷。为人免疫缺陷病毒（HIV）复制抑制剂，干扰和抑制病毒逆转录酶而阻止病毒的复制，作用机制与齐多夫定相似，但活性更高且选择性更强。由人工化学合成，在1991年11月首次在美国上市，为美国第二个被批准用来治疗HIV感染的药物，作为齐多夫定的替代品。是2′，3′-双脱氧腺苷（ddA）的前体药。

本品在病毒感染细胞内通过细胞酶的作用转化为有抗病毒活性的代谢物三磷酸双脱氧腺苷（ddA-TP）。ddA-TP是一种选择性很强的反转录酶抑制剂，干扰和抑制病毒的复制。临床使用后可使病情改善、CD4+ T淋巴细胞计数增加、HIV RNA水平降低等。

合成方法

去羟肌苷可以通过多种合成路线制备：

1. 第一种合成路径：将化合物进行脱保护基反应，经过多次纯化步骤最终得到产品。该过程包括脱保护、氢化和醇解等多个关键步骤。
2. 第二种合成路径：通过有机溶剂中的酰氯化、取代及还原等工艺，实现从肌苷到去羟肌苷的转化。
3. 第三种合成路径：采用特定的化学反应（5’-O-苯甲酰化、3’-0-(1-咪唑基)硫代羰基化）完成目标产物的合成。
4. 第四种合成路径：通过微生物发酵技术，利用不同菌株进行生产。该方法包括对6-羟基嘌呤及其衍生物的发酵过程。

每一种方法都体现了去羟肌苷工业化生产的科学性和复杂性，适用于不同的需求和条件。

反应信息

• 作为反应物：
  描述：

  2',3'-二脱氧肌苷 在 超重氢 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 55.0 ℃ 、90.0 kPa 条件下， 反应 16.0h， 生成
  参考文献：
  名称：

  使用氢同位素交换有效地获得氘代和Tri化的Nucleobase药品和寡核苷酸。

  摘要：

  描述了一种有效的氢-同位素交换核碱基衍生物的通用方法。在温和的反应条件下，以钌纳米颗粒为催化剂，并以D 2或T 2为同位素源，该反应具有较宽的底物范围和较高的耐溶剂性。这种新颖的方法有助于在药物发现和开发中使用基本的诊断工具：具有高比活性的tri代药物和适合在LC-MS定量过程中用作内部标准品的氘代寡核苷酸。

  DOI：

  10.1002/anie.201813946
• 作为产物：
  描述：

  Methanesulfonic acid (2R,3R,4R,5R)-5-hydroxymethyl-4-methanesulfonyloxy-2-(6-oxo-1,6-dihydro-purin-9-yl)-tetrahydro-furan-3-yl ester 在 钯 Dowex anion-exchange resin 、 氢气 、 potassium hydrogencarbonate 作用下， 以 水 、 异丙醇 为溶剂， 70.0 ℃ 、3.04 MPa 条件下， 反应 70.0h， 以48%的产率得到2',3'-二脱氧肌苷
  参考文献：
  名称：

  Antonov; Konstantinova; Miroshnikov, Nucleosides and Nucleotides, 1998, vol. 17, # 1-3, p. 153 - 159

  摘要：

  DOI：

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] METALLOENZYME INHIBITOR COMPOUNDS<br/>[FR] COMPOSÉS INHIBITEURS DE MÉTALLOENZYMES
  申请人：VPS 3 INC

  公开号：WO2018165520A1

  公开（公告）日：2018-09-13

  Provided are compounds having HDAC6 modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by HDAC6.

  提供具有HDAC6调节活性的化合物，以及通过HDAC6介导的治疗疾病、疾病或症状的方法。
• Integrase inhibitors
  申请人：Cai R. Zhenhong

  公开号：US20080058315A1

  公开（公告）日：2008-03-06

  Tricyclic compounds, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed.

  三环化合物，其受保护的中间体，以及用于抑制HIV整合酶的方法被披露。
• 3-Aminocyclopentanecarboxamides as modulators of chemokine receptors
  申请人：Xue Chu-Biao

  公开号：US20060004018A1

  公开（公告）日：2006-01-05

  The present invention is directed to compounds of Formula I: which are modulators of chemokine receptors. The compounds of the invention, and compositions thereof, are useful in the treatment of diseases related to chemokine receptor expression and/or activity.

  本发明涉及以下式的化合物： 这些化合物是趋化因子受体的调节剂。本发明的化合物及其组合物在治疗与趋化因子受体表达和/或活性相关的疾病方面是有用的。
• [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。

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