甘草酸 | 1405-86-3

• 物质功能分类: 原料药 - 消化系统用药 - 肝病用药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 中文名称: 甘草酸
• 中文别名: 甘草皂苷；强力宁；甘草甜素；α-甘草酸
• 英文名称: glycyrrhizin
• 英文别名: glycyrrhizic acid；glycyrrhizinic acid；18β-glycyrrhizic acid；(3β,20β)-20-carboxy-11-oxo-30-norolean-12-en-3-yl-2-O-β-D-glucopyranuronosyl-α-D-glucopyranosiduronic acid；glycyrrhetinic acid；20β-carboxyl-11-oxo-30-norolean-12-en-3β-yl-2-O-β-D-glucopyranuronosyl-β-D-glucopyranosiduronic acid；glycyrrhetinic acid glycoside；18-beta-glycyrrhizic acid；(2S,3S,4S,5R,6R)-6-[(2S,3R,4S,5S,6S)-2-[[(3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1H-picen-3-yl]oxy]-6-carboxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid
• CAS: 1405-86-3
• 化学式: C₄₂H₆₂O₁₆
• mdl: MFCD00065194
• 分子量: 822.945
• InChiKey: LPLVUJXQOOQHMX-QWBHMCJMSA-N

物化性质

• 熔点：
  220°C (rough estimate)
• 沸点：
  681.01°C (rough estimate)
• 比旋光度：
  D17 +46.2° (c = 1.5 in alc)
• 密度：
  1.1442 (rough estimate)
• 溶解度：
  DMSO（少量）、乙醇（少量）、甲醇（少量）、吡啶（少量）
• LogP：
  4.64
• 物理描述：
  Solid with intensely sweet taste; [Merck Index] Crystalline plates or prisms; [MSDSonline]
• 颜色/状态：
  Crystals from glacial acetic acid
• 味道：
  Intensely sweet taste
• 旋光度：
  Specific optical rotation: +46.2 deg @ 17 °C/D (alcohol, 1.5%)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  58
• 可旋转键数：
  7
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.857
• 拓扑面积：
  267
• 氢给体数：
  8
• 氢受体数：
  16

ADMET

代谢

当口服给药时，甘草酸几乎完全被肠道细菌水解生成甘草次酸，这是一种活性代谢物，可以进入全身循环，以及两分子葡萄糖醛酸。这种代谢物被转运并在肝脏中进行代谢，形成葡萄糖醛酸苷和硫酸盐结合物。

When orally administered, glycyrrhizic acid is almost completely hydrolyzed by intestinal bacteria for the formation of glycyrrhetinic acid, which is an active metabolite and can enter systemic circulation, and two molecules of glucuronic acid. This metabolite is transported and taken in the liver for its metabolization to form glucuronide and sulfate conjugates.

来源:DrugBank

代谢

给予大鼠门静脉注射甘草酸 bolus，导致血液中一种物质的水平升高，这种物质似乎是甘草次酸作为代谢物形成的葡萄糖醛酸结合物。

BOLUS INJECTION OF GLYCYRRHIZIN GIVEN RATS IN PORTAL VEIN, GAVE RISE IN BLOOD LEVEL OF SUBSTANCE WHICH APPEARS TO BE GLUCURONIC ACID CONJUGATE FORMED AS METABOLITE OF GLYCYRRHETINIC ACID.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

10-6 M 甘草酸在10-8 M 醛固酮存在的情况下添加，与仅用醛固酮处理的对照组皮肤相比，短路显著增加。

ADDITION OF 10-6 M GLYCYRRHETINIC ACID IN PRESENCE OF 10-8 M ALDOSTERONE STIMULATED SHORT-CIRCUIT SIGNIFICANTLY AS COMPARED WITH CONTROL SKIN TREATED WITH ALDOSTERONE ALONE.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

甘草素对皮质类固醇注射降低糖原储存效果和增强皮质类固醇免疫抑制作用的调节。

ADMIN OF GLYCYRRHIZIN DEPRESSED EFFECT OF INJECTED CORTISONE ON GLYCOGEN STORAGE AND ENHANCED IMMUNOSUPPRESSIVE ACTION OF CORTISONE.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

本研究调查了六名健康男性在口服甘cyrrhizin（GL）预处理或不预处理的情况下，总泼尼松龙（PSL）和游离泼尼松龙的药代动力学，以确认口服GL是否影响人体内泼尼松龙的代谢。每个受试者静脉注射0.096 mg/kg的泼尼松龙半琥珀酸酯（PSL-HS），并口服预处理或不预处理四次，每次50 mg的GL。在开始输注PSL-HS后5、10、15、30、45分钟和1、1.5、2、3、4、6、8、10、12和24小时从外周静脉采血。通过高效液相色谱法分析血浆中总泼尼松龙的浓度，通过等渗平衡透析法测量游离泼尼松龙。泼尼松龙的药代动力学参数通过非房室分析确定。研究发现，口服GL显著增加了在输注PSL-HS后6、8小时的总泼尼松龙浓度，以及在4、6和8小时的游离泼尼松龙浓度。此外，还发现口服GL改变了总泼尼松龙和游离泼尼松龙的药代动力学。口服GL后，曲线下面积（AUC）显著增加，总血浆清除率（CL）显著降低，平均滞留时间（MRT）显著延长。然而，分布容积（Vdss）没有明显变化。这表明口服GL通过抑制其代谢而不是影响其分布，增加了血浆泼尼松龙浓度并影响了其药代动力学。

The pharmacokinetics of total and free prednisolone (PSL) in six healthy men, with or without pretreatment with oral glycyrrhizin (GL), was investigated to confirm whether oral administration of GL influences the metabolism of prednisolone in man. Each subject received an intravenous administration of 0.096 mg/kg of prednisolone hemisuccinate (PSL-HS) with or without pretreatment with 50 mg of oral glycyrrhizin four times. Blood samples were taken from a peripheral vein at 5, 10, 15, 30, 45 min and 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after the start of prednisolone-HS infusion. The concentrations of total prednisolone in plasma were analyzed by high-performance liquid chromatography, and the free prednisolone was measured by an isocolloidosmolar equilibrium dialysis method. The pharmacokinetic parameters of prednisolone were determined by non-compartment analysis. Oral administration of glycyrrhizin was found to significantly increase the concentrations of total prednisolone at 6, 8 hr, and of free prednisolone at 4, 6 and 8 hr after prednisolone-hemisuccinate infusion. Moreover, oral administration of glycyrrhizin was also found to modify the pharmacokinetics of both total and free prednisolone. After oral administration of glycyrrhizin, the area under the curve (AUC) was significantly increased, the total plasma clearance (CL) was significantly decreased, and the mean residence time (MRT) was significantly prolonged. However, the volume of distribution (Vdss) showed no evident change. This suggests that oral administration of glycyrrhizin increases the plasma prednisolone concentrations and influences its pharmacokinetics by inhibiting its metabolism, but not by affecting its distribution.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

为了澄清甘草酸（甘草根的水提取物，用于治疗慢性活动性肝炎的药物）是否预防四氯化碳、丙烯甲酯和内毒素诱导的肝脏损伤的发展，本研究在大鼠中进行。在四氯化碳给药前20小时给予甘草酸治疗，可防止中央周围肝细胞坏死的形成。在丙烯甲酯给药前2小时给予甘草酸治疗，也抑制了门脉周围肝细胞坏死的形成。然而，甘草酸并未预防内毒素诱导的局灶性和随机性肝细胞坏死的形成。这些实验结果表明，甘草酸对内毒素引起的窦状循环障碍后的肝脏损伤没有保护作用，而甘草酸可以保护由肝毒素（如四氯化碳和丙烯甲酯）对肝细胞的直接作用引起的肝毒性。

To clarify whether glycyrrhizin, the aqueous extract of licorice root and a drug for treatment of chronic active hepatitis, prevents the development of hepatic injury induced by carbon tetrachloride, allyl formate, and endotoxin, the present study was undertaken in rats. The treatment with glycyrrhizin 20 hr before carbon tetrachloride administration protected the development of the pericentral hepatocellular necrosis. Glycyrrhizin treatment 2 hr prior to the administration of allyl formate also inhibited the development of the periportal hepatocellular necrosis. However, glycyrrhizin did not protect the development of endotoxin-induced focal and random hepatocellular necrosis. These experimental results suggest that glycyrrhizin has no protective effect on hepatic injury following sinusoidal circulatory disturbance as seen in the case of endotoxin and that glycyrrhizin can protect against hepatotoxicity induced by the direct action on the hepatocytes due to hepatotoxins, such as carbon tetrachloride and allyl formate.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

为了调查Potenlini对肝 cirrhosis 动物模型肝脏核因子-kappa B (NF-kappa B)结合活性的影响，并阐述Potenlini生物活性的分子机制。方法：雄性SD大鼠随机分为正常对照组、模型对照组和Potenlini组。后两组大鼠用四氯化碳（CCl4）和乙醇溶液处理，以诱导慢性肝损伤。Potenlini组大鼠同时给予Potenlini治疗。所有大鼠在CCl4给药后第9周处死。收集血清和肝脏标本，评估血清ALT活性和组织学发现。从肝脏组织中制备核提取物，并进行凝胶阻滞试验以评估NF-kappa B活性。结果：(1)与模型对照组相比，Potenlini处理的大鼠血清ALT水平显著降低，后者ALT水平显著升高。(2)组织学上，模型组大鼠肝脂肪变性和纤维化严重，但Potenlini组大鼠显著改善。(3)与正常肝脏相比，模型对照组大鼠肝脏标本中NF-kappa B结合活性显著增加，但Potenlini组大鼠肝脏的结合水平几乎正常。结论：Potenlini可以抑制CCl4和乙醇诱导的慢性肝损伤中的NF-kappa B结合活性，这可能是Potenlini保护肝脏免受肝毒素诱导的肝损伤和肝硬化的部分机制。

To investigate the effects of Potenlini on nuclear factor-kappa B (NF-kappa B) binding activity in the livers of animals models with liver cirrhosis, and to delineate the molecular mechanism of the bioactivities of Potenlini. METHODS: Male SD rats were randomly allocated into a normal control group, a model control group, and a Potenlini group. Rats in the latter two groups were treated with CCl4 and Ethanol solution in order to induce chronic liver injury. Rats in Potenlini group were given Potenlini treatment at the same time. All rats were killed at the 9th week after CCl4 administration. Serum and liver specimens were collected, serum ALT activities and histological findings were assessed. Nuclear extracts from liver tissues were prepared and gel retardation assays were performed for the evaluation of NF-kappa B activity. RESULTS: (1) Serum ALT levels were significantly reduced in rats treated with Potenlini compared with those in rats of the model control group, which had dramatically increased ALT levels. (2) Histologically, liver steatosis and fibrosis were severe in the rats of the model group, but were significantly improved in rats of the Potenlini group. (3) NF-kappa B binding activity was markedly increased in the liver specimens taken from the rats of the model control group in comparison with the binding of normal livers, but the binding levels were nearly normal in the livers of the Potenlini group. CONCLUSION: Potenlini can inhibit the NF-kappa B binding activity in CCl4 and ethanol induced chronic liver injury, and that may partially be the mechanism by which Potenlini protects liver from hepatotoxin-induced liver injury and cirrhosis.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

甘草酸在经过系统前水解并形成甘草次酸后主要被吸收。因此，在口服100毫克甘草酸后，这种主要代谢物以200 ng/ml的浓度出现在血浆中，而甘草酸则无法检测到。在尿液中检测到极少量的甘草酸表明胃肠道存在部分吸收。

Glycyrrhizic acid is mainly absorbed after presystemic hydrolysis and formation of glycyrrhetinic acid. Therefore, after oral administration of a dose of 100 mg of glycyrrhizic acid, this major metabolite appears in plasma in a concentration of 200 ng/ml while glycyrrhizic acid cannot be found. The finding of a minimal amount of glycyrrhizic acid in urine suggests the existence of a partial absorption in the gastrointestinal tract.

来源:DrugBank

吸收、分配和排泄

• 消除途径

甘草酸在中央室的消除表现出双相性，有一个剂量依赖的第二消除相。大部分给药剂量通过胆汁消除，甘草酸可以不变地通过胆汁消除并经历肠肝循环。另一方面，主要代谢物甘草次酸形成葡萄糖醛酸和硫酸共轭物。这些共轭物有效地被运输到胆汁和十二指肠，在那里共生细菌水解共轭物以形成甘草次酸并进一步被重吸收。这种重吸收行为似乎与3-α-羟基类固醇脱氢酶的活动有关，该酶非常有效地将代谢物从血浆运输到胆汁。大约1.1-2.5%的甘草酸给药剂量可以在尿液中找到，这对应于这种化合物的最小循环和重吸收。

Glycyrrhizic acid presents a biphasic elimination from the central compartment with a dose-dependent second elimination phase. The majority of the administered dose is eliminated by the bile in which glycyrrhizic acid can be eliminated unchanged and undergoes enterohepatic cycling. On the other hand, the major metabolite, glycyrrhetinic acid, forms glucuronide and sulfate conjugates. These conjugates are efficiently transported into the bile and duodenum where commensal bacteria hydrolizes the conjugate for the formation of glycyrrhetinic acid and further reabsorption. This reabsorption behavior seems to be related to the activity of 3-alpha-hydroxysteroid dehydrogenase which transports very efficiently the metabolite from the plasma to the bile. About 1.1-2.5% of the administered dose of glycyrrhizic acid can be found in urine which corresponds to the minimal cycling and reabsorption of this compound.

来源:DrugBank

吸收、分配和排泄

• 分布容积

甘草酸在中心室和稳态下的表观分布容积分别在37-64毫升/千克和59-98毫升/千克的范围内。

The apparent volume of distribution of glycyrrhizic acid either in the central compartment and in steady-state are in the range of 37-64 ml/kg and 59-98 ml/kg, respectively.

来源:DrugBank

吸收、分配和排泄

• 清除

常量甘草酸在十二指肠的再吸收导致终末血浆清除延迟。据报道，甘草酸的总清除率在16-25 ml/kg/h的范围内。

The constant reabsorption of glycyrrhetic acid in the duodenum causes a delay in the terminal plasma clearance. The reported total body clearance of glycyrrhizic acid is reported to be in the range of 16-25 ml.kg/h.

来源:DrugBank

吸收、分配和排泄

甘草酸在大鼠小肠中被吸收；在门静脉注射甘草酸后，血液中没有检测到甘草次酸；口服给药后，血液中存在可检测到的甘草次酸。

GLYCYRRHIZIN WAS ABSORBED IN RAT SMALL INTESTINE; THERE WAS NO DETECTABLE AMT OF GLYCYRRHETINIC ACID IN BLOOD AFTER BOLUS INJECTION OF GLYCYRRHIZIN INTO PORTAL VEIN; GLYCYRRHETINIC ACID WAS PRESENT IN DETECTABLE AMT IN BLOOD AFTER ORAL ADMIN.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S22,S24/25
• WGK Germany：
  3
• 海关编码：
  1211903600
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  MD2025000

制备方法与用途

以下是关于甘草酸的生产方法、用途及特点：

生产方法

1. 由甘草提取：首先将甘草根茎干燥并粉碎成粉末（保留纤维部分），取200kg粉末及纤维，加水1200kg，在85-100℃下浸提2小时。过滤后滤渣再用1000kg水提取2小时，过滤后再重复浸提一次。合并三次滤液，在搪瓷蒸发器中浓缩至原体积的1/5。

2. 加入乙醇：冷却后的滤液加入95%乙醇使乙醇浓度达65%，静置24小时后过滤，除去植物蛋白和多糖等杂质。

3. pH调节与沉淀：将滤液调至pH值为3，甘草酸析出沉淀。过滤洗涤后，加入3倍体积的丙酮，加热回流3小时，倾倒丙酮提取液。残渣再反复回流提取两次，合并三次提取液，过滤回收丙酮。

4. 干燥与粉碎：滤干的湿甘草酸在45℃下干燥1小时，然后缓缓升温至85-95℃，快烘干时升至100-105℃烘5分钟。最终经粉碎后即得成品。

用途

1. 食品工业：

   • 可作为调味料和甜味剂添加于饼干、肉禽罐头、调味料、糖果、蜜饯、凉果和饮料中。
   • 在酱油中用于改善咸味，提高固有味道并消除糖精的苦味。在腌制咸菜卤水中可消除糖精的苦味，在腌制过程中防止因少加糖而引起的发酵败坏、变色及硬化等问题。
   • 增加豆酱甜味，使味道均匀。

2. 医疗与保健：

   • 具有抗炎、抗变态反应作用；肾上腺皮质激素样效果如抑制毛细血管通透性，减轻过敏性休克症状等。
   • 降低高血压患者的血清胆固醇水平，并可作为抗癌防癌药物使用。具有类似糖皮质激素的药理作用但无严重不良反应。

3. 其他用途：

   • 可用作食品添加剂如豆酱、酱油中的甜味剂。

特点

• 甘草酸是从天然植物甘草中提取的主要活性成分，具有较强的甜度（约为砂糖的250倍）。
• 作为药物时可用于治疗各种急慢性肝炎、支气管炎及艾滋病等。
• 在临床应用中，甘草酸因其类似肾上腺皮质激素的作用而被广泛应用。

反应信息

• 作为反应物：
  描述：

  甘草酸 在 甲醇 、 硫酸 作用下， 反应 24.0h， 生成 甘草次酸
  参考文献：
  名称：

  甘草甜素作为选择性抗阿尔茨海默病药物的衍生化，分子对接和体外乙酰胆碱酯酶抑制活性。

  摘要：

  乙酰胆碱酯酶抑制剂（AChE-Is）可增加乙酰胆碱（ACh）的作用水平和作用持续时间；因此，减轻了阿尔茨海默氏病（AD）的症状。甘草甜素是甘草根中的主要活性化合物。它的糖苷配基，甘草次酸显示出几种有益的药理活性。该研究报告了一系列甘草次酸类似物AChE-Is的合成和筛选。制备了十四个衍生物，其中五个衍生物被记录为新的，即3-苯基氨基甲酰基-18β-甘草次酸（J9），3-乙酰基-18β-甘草次酸-30-苯胺（J10），3-乙酰基-18β -甘草次酸30-乙醇酰胺（J11），3-乙酰基18β-甘草次酸30-正丁酰胺（J12）和18β-甘草次酸30-异戊二烯酯（J14），以及九种已知衍生物（J1 - J8和J13）。化合物J12，J11，J0和J3表现出显着的AChE-1活性，IC 50值分别为3.43、5.39、6.27和8.68μM。这些结果与对接研究完全一致。活性化合物对正常细胞（WI-38）无细胞毒性。

  DOI：

  10.1080/14786419.2018.1462177
• 作为产物：
  描述：

  在 calcium sulfate 、 氢氧化钾 、 sodium methylate 、 silver trifluoromethanesulfonate 、 1,1,3,3-四甲基脲 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 6.0h， 生成 甘草酸
  参考文献：
  名称：

  Syntheses of Glycyrrhetic Acid .ALPHA.-Diglycosides and Enol .ALPHA.-Glycosides.

  摘要：

  甘草酸α-单糖苷衍生物 8、10 和 12 均在吡喃糖环的 C-2 位上具有三氯乙酰基，在 0°C 下用 NH3 饱和醚处理后，可分别得到相应的醇 13、15 和 17 以及 2'-氯二衍生物 14、16 和 18。在 AgOTf 存在下，醇 13、15 和 17 与 2，3，4-三-O-乙酰基-α-D-葡糖酸吡喃糖基溴化物 19 在干燥的 CH2Cl2 中发生糖基化反应，分别得到相应的 α-二糖苷 20、22 和 24 以及烯醇 α-糖苷 21、23 和 25。将分子中没有反应性 OH 基团的二糖苷衍生物 20、22 和 35 与反应时间较长的 19 进行糖基化，可分别定量得到烯醇 α-糖苷衍生物 21、23 和 36。单糖苷衍生物 37 在吡喃糖环的 C-4 位上有一个反应性很差的 OH 基团，用 19 进行糖基化反应可得到烯醇 α-糖苷 38。研究了形成烯醇 α-糖苷的机理。用 1.5N NaOMe in MeOH 和 5% KOH in EtOH-H2O (1 : 1) 相继处理 20、22 和 24，去除其保护基团，得到游离的 α-二糖苷 26-28；用 5% KOH in EtOH-H2O (1 : 1) 在回流下处理 31、21、23、25 和 36，去除其保护基团，分别得到游离的烯醇 α-糖苷 41-45。

  DOI：

  10.1248/cpb.42.1016

文献信息

• Novel triterpene derivatives
  申请人：onepharm Research & Development GmbH

  公开号：EP2228380A1

  公开（公告）日：2010-09-15

  The present invention encompasses novel triterpene compounds of general formula I wherein R3a R3b R11a R11b R31 and R32 are defined as in claim 1, which are suitable for the prevention and/or treatment of diseases mediated by 11β-HSD and the use thereof for preparing a medicament having the above-mentioned properties.

  本发明涵盖了一般式I的新型三萜化合物， 其中 R3a、R3b、R11a、R11b、R31和R32如权利要求1所定义，适用于预防和/或治疗由11β-HSD介导的疾病，并用于制备具有上述特性的药物。
• Substituted 1,3-thiazole compounds, their production and use
  申请人：——

  公开号：US20040053973A1

  公开（公告）日：2004-03-18

  (1) A 1,3-thiazole compound of which the 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group or (2) a 1,3-thiazole compound of which the 5-position is substituted with a pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group has an excellent p38 MAP kinase inhibitory activity.

  (1) 一种1,3-噻唑化合物，其5位被取代为含有一个取代基的4-吡啶基团，该取代基不包括芳香基，或者(2) 一种1,3-噻唑化合物，其5位被取代为一个吡啶基团，该吡啶基团的氮原子邻近位置有一个取代基，该取代基不包括芳香基，具有出色的p38 MAP激酶抑制活性。
• SUBSTITUTED 2,4 DIAMINO-QUINOLINE AS NEW MEDICAMENT FOR FIBROSIS, AUTOPHAGY AND CATHEPSINS B (CTSB), L (CTSL) AND D (CTSD) RELATED DISEASES
  申请人：Genoscience Pharma SAS

  公开号：EP3620164A1

  公开（公告）日：2020-03-11

  The present invention relates to novel 2-primary amino-4-secondary amino-quinoline derivatives, their manufacture, pharmaceutical compositions comprising them and their use as medicaments. The active compounds of the present invention can be useful as a medicament in the treatment and/or the decreasing and/or the prevention of fibrosis and/or fibrosis related diseases, or for use as a medicament in the treatment and/or the decreasing and/or the prevention of the autophagy and/or autophagy related diseases and for the inhibition of the autophagy flux, or for use in the inhibition of cathepsins B (CTSB), L (CTSL) and/or D (CTSD) and/or cathepsins B (CTSB), L (CTSL) and/or D (CTSD) related diseases; with the proviso that said compounds are not to be used for the treatment of any forms of cancers.

  本发明涉及新型2-初级氨基-4-次级氨基喹啉衍生物，其制备方法，包含它们的药物组合物以及它们作为药物的用途。本发明的活性化合物可用作药物治疗和/或减少和/或预防纤维化和/或与纤维化相关疾病，或用作药物治疗和/或减少和/或预防自噬和/或与自噬相关疾病以及抑制自噬通量，或用于抑制蛋白酶B（CTSB）、L（CTSL）和/或D（CTSD）和/或与蛋白酶B（CTSB）、L（CTSL）和/或D（CTSD）相关疾病；但所述化合物不得用于治疗任何形式的癌症。
• [EN] CHEMOKING RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DES RÉCEPTEURS DE CHIMIOKINES
  申请人：ABBOTT LAB

  公开号：WO2013010453A1

  公开（公告）日：2013-01-24

  Disclosed herein are chemokine receptor antagonists of formula (I) wherein G1, X1, X2, and X3 are as defined in the specification. Compositions comprising such compounds; and methods for treating conditions and disorders using such compounds and compositions are also described.

  本文揭示了化学受体拮抗剂的化学式(I)，其中G1、X1、X2和X3如规范中所定义。还描述了包含这种化合物的组合物；以及使用这种化合物和组合物治疗疾病和疾病的方法。
• [EN] PYRROLOPYRIDAZINE DERIVATIVES<br/>[FR] DERIVES DE PYRROLOPYRIDAZINE
  申请人：FUJISAWA PHARMACEUTICAL CO

  公开号：WO2004063197A1

  公开（公告）日：2004-07-29

  The invention relates to compound of the formula (I) or its salt, in which R1, R2, R3 and R4 are as defined in the description, their use of as medicament, the process for their preparation and use for the treatment of PDE-IV or TNF-α mediated diseases.

  这项发明涉及公式（I）的化合物或其盐，其中R1、R2、R3和R4如描述中所定义，它们作为药物的用途，它们的制备过程以及用于治疗PDE-IV或TNF-α介导的疾病的用途。