氯胍 | 500-92-5

• 物质功能分类: 原料药 - 抗寄生虫病药 - 抗疟药
• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 氯胍
• 中文别名: N-(4-氯苯基)-N'-(异丙基)-双胍；氯苯胍
• 英文名称: (1E)-1-[amino-(4-chloroanilino)methylidene]-2-propan-2-ylguanidine
• 英文别名: proguanil；(1Z)-1-[amino-(4-chloroanilino)methylidene]-2-propan-2-ylguanidine
• CAS: 500-92-5
• 化学式: C₁₁H₁₆ClN₅
• 分子量: 253.735
• InChiKey: SSOLNOMRVKKSON-UHFFFAOYSA-N

物化性质

• 熔点：
  129°
• 沸点：
  399.65°C (rough estimate)
• 密度：
  1.2039 (rough estimate)
• 溶解度：
  DMF：2mg/mL；二甲基亚砜：3mg/mL； DMSO:PBS (pH 7.2) (1:10)：0.09mg/mL；乙醇：1mg/mL
• 物理描述：
  Solid
• 碰撞截面：
  161.3 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  88.8
• 氢给体数：
  3
• 氢受体数：
  1

ADMET

代谢

在肝脏中通过细胞色素P450同工酶可变地代谢为活性三嗪代谢物，环桂酸。这种前瞻素的变量代谢在亚洲和非洲易患疟疾的人群中可能具有深远的重要临床意义。使用前瞻素预防可能对这些人无效，因为他们可能无法达到足够的治疗水平，即使是在多次剂量之后。

Variably metabolized in the liver by cytochrome P450 isoenzymes to the active triazine metabolite, cycloguanil. This variable metabolism of proguanil may have profound clinical importance in poor metabolizers such as the Asian and African populations at risk for malaria infection. Prophylaxis with proguanil may not be effective in these persons because they may not achieve adequate therapeutic levels of the active compound, cycloguanil, even after multiple doses.

来源:DrugBank

代谢

Proguanil 已知的人类代谢物包括环戊烷咪唑和 4-氯苯基双胍。

Proguanil has known human metabolites that include Cycloguanil and 4-Chlorophenylbiguanide.

来源:NORMAN Suspect List Exchange

毒理性

• 肝毒性

阿托伐醌和普龙胍联合使用已在小部分患者中与短暂的、轻微的血清转氨酶升高有关。更重要的 是，有罕见报道称患者在服用阿托伐醌/普龙胍后出现了特应性急性肝损伤，但病例数量太少，无法确定典型的临床过程。在一个报道的病例中，损伤发生 在服药后3周，表现为乏力、黄疸和血清酶升高的胆汁淤积模式。停药后2个月内损伤得以解决（病例1）。 另一份关于氯喹和普龙胍的病例报告中，肝损伤在开始联合用药后几天内出现，血清酶升高的模式是混合的。在这两例中，过敏特征 最小，自身抗体不存在。在这两例中，联合治疗被使用，任何一种药物可能是损伤的原因。阿托伐醌和普龙胍还与罕见 的史蒂文斯-约翰逊综合征有关，这通常伴有轻度肝损伤或肝酶升高。

The combination of atovaquone and proguanil has been associated with transient and minor serum aminotransferase elevations in a small proportion of patients. More importantly, there have been rare reports of idiosyncratic acute liver injury due in patients on atovaquone/ proguanil but the number of cases has been too few to define a typical clinical course. In one reported case, the onset of injury was after 3 weeks and presentation was with fatigue and jaundice and a cholestatic pattern of serum enzyme elevations. The injury resolved within 2 months of stopping the medication (Case 1). In another case report of chloroquine and proguanil, liver injury arose within days of starting the combination and the pattern of serum enzyme elevations was mixed. In both cases, allergic features were minimal and autoantibodies were not present. In both cases, combination therapy was used and either agent may have been the cause of the injury. Atovaquone and proguanil have also been linked to rare instances of Stevens Johnson syndrome which is often accompanied by mild liver injury or liver enzyme elevations.

来源:LiverTox

毒理性

• 蛋白质结合

大约 75%

Approximately 75%

来源:DrugBank

吸收、分配和排泄

• 吸收

在50到500毫克口服剂量下，人体能够快速且良好地吸收。

Rapidly and well absorbed in humans following oral doses ranging from 50 to 500 mg.

来源:DrugBank

安全信息

• 储存条件：
  2-8℃

制备方法与用途

生物活性

Proguanil（chlorguanide）是一种预防性抗疟药。它能抑制疟原虫的二氢叶酸还原酶，从而阻止嘌呤和嘧啶的合成。

体外研究

Proguanil本身在体外具有较弱的抗疟疾活性（IC50 =2.4-19 μM），其有效性依赖于活性代谢物Cycloguanil（IC50 =0.5-2.5 nM）。Cycloguanil是二氢叶酸还原酶(DHFR)抑制剂。Atovaquone与Proguanil的组合在体外表现出协同作用。这两种药物也对疟原虫的配子细胞和预红细胞（肝内）阶段有活性。

Proguanil通过作为biguanide而不是其代谢物Cycloguanil（一种DHFR抑制剂）来增强Atovaquone的效果。这种增强仅限于Atovaquone，其他如Myxothiazole和Antimycin等线粒体电子传递抑制剂的存在对Proguanil的影响并不改变。

Proguanil、其代谢物4-氯苯基-1-biguanide (CPB) 和活性代谢物Cycloguanil (CG) 可逆地抑制5-HT3受体响应，各自的IC50分别为1.81, 1.48和4.36 μM。

体内研究

Proguanil（口服；2.9 mg/kg体重；连续五天并持续六周）在Wistar种大鼠中表现出轻微的退行性变化，但在六周内则表现严重退行性变化。经Proguanil治疗的大鼠血清睾酮水平显著下降。

使用Malarone（atovaquone和proguanil）对实验感染B. gibsoni的狗进行治疗，在慢性阶段和急性阶段分别观察到寄生虫数量减少，临床症状改善。

生产方法

由硫氯酸钠与水合肼加成、重排，最后经甲醛在乙醇中缩合而制得。

反应信息

• 作为反应物：
  描述：

  氯胍 在 ruthenium(IV) chloride 、 hydrazonium chloride 作用下， 以 氢溴酸 为溶剂， 生成
  参考文献：
  名称：

  Spacu, P.; Gheorghiu, C., Revue Roumaine de Chimie, 1967, vol. 12, p. 1459 - 1468

  摘要：

  DOI：
• 作为产物：
  描述：

  1-异丙基-5-苯基双胍 在 氯 作用下， 生成 氯胍
  参考文献：
  名称：

  Crowther et al., Journal of the Chemical Society, 1951, p. 1774,1778

  摘要：

  DOI：

文献信息

• [EN] TRICYCLIC TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY<br/>[FR] COMPOSÉS TRIAZOLES TRICYCLIQUES MODULANT L'ACTIVITÉ HSP90
  申请人：SYNTA PHARMACEUTICALS CORP

  公开号：WO2009139916A1

  公开（公告）日：2009-11-19

  The present invention relates to substituted tricyclic triazole compounds and compositions comprising substituted tricyclic triazole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for preventing or treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a compound of the invention, or a composition comprising such a compound.

  本发明涉及替代三环三唑化合物和包含替代三环三唑化合物的组合物。该发明还涉及在需要的受体中抑制Hsp90活性的方法，以及预防或治疗高增殖性疾病（如癌症）的方法，其中包括向受体施用本发明的化合物或包含这种化合物的组合物。
• Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith
  申请人：D'Sidocky Neil R.

  公开号：US20080242694A1

  公开（公告）日：2008-10-02

  Provided herein are Heterocyclic Compounds having the following structure: wherein R 1 , R 2 , X, Y and Z are as defined herein, compositions comprising an effective amount of a Heterocyclic Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heterocyclic Compound to a patient in need thereof.

  本文提供具有以下结构的杂环化合物： 其中R1、R2、X、Y和Z如本文所定义，包含有效量杂环化合物的组合物，以及治疗或预防癌症、炎症性疾病、免疫疾病、代谢性疾病以及通过给予患者需要的有效量杂环化合物来抑制激酶途径治疗或预防的疾病的方法。
• [EN] AZEPANYL-DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME WITH ANTIPARASITIC ACTIVITY<br/>[FR] DÉRIVÉS D'AZÉPANYLE ET COMPOSITIONS PHARMACEUTIQUES À ACTIVITÉ ANTI-PARASITAIRE LES CONTENANT
  申请人：MERCK PATENT GMBH

  公开号：WO2016000827A1

  公开（公告）日：2016-01-07

  The present invention provides compounds of Formula (i). Furthermore, pharmaceutical compositions are provided comprising at least one compound of Formula (i), for the treatment of parasitic diseases including malaria, as well as neurodegenerative diseases.

  本发明提供了化合物的结构式（i）。此外，提供了包含至少一种结构式（i）化合物的药物组合物，用于治疗包括疟疾在内的寄生虫病以及神经退行性疾病。
• SILICON BASED DRUG CONJUGATES AND METHODS OF USING SAME
  申请人：BlinkBio, Inc.

  公开号：US20170202970A1

  公开（公告）日：2017-07-20

  Described herein are silicon based conjugates capable of delivering one or more payload moieties to a target cell or tissue. Contemplated conjugates may include a silicon-heteroatom core, one or more optional catalytic moieties, a targeting moiety that permits accumulation of the conjugate within a target cell or tissue, one or more payload moieties (e.g., a therapeutic agent or imaging agent), and two or more non-interfering moieties covalently bound to the silicon-heteroatom core.

  本文描述了基于硅的共轭物，能够将一个或多个有效载荷基团传递到靶细胞或组织。考虑到的共轭物可能包括一个硅-杂原子核心，一个或多个可选的催化基团，一个定位基团，允许共轭物在靶细胞或组织内积累，一个或多个有效载荷基团（例如，治疗剂或成像剂），以及与硅-杂原子核心共价结合的两个或更多个不干扰基团。
• 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。