4-amino-2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 4-amino-2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole
• 英文别名: 2-(4-amino-2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine；2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-4-ylamine；2-(Difluoromethyl)-1-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)benzimidazol-4-amine
• 化学式: C₁₉H₂₂F₂N₈O₂
• 分子量: 432.433
• InChiKey: LRYSHDDWCVYSPV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  107
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  4-amino-2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole 在 sodium hydride 、 三氟乙酸 作用下， 以 1,3-二噁烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 48.75h， 生成 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-4-(methylamino)-1H-benzimidazole
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Novel Analogues of the Pan Class I Phosphatidylinositol 3-Kinase (PI3K) Inhibitor 2-(Difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474)

  摘要：

  A structure activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110 alpha, p110 beta, and p110 delta) and also displayed significant potency against two mutant forms of the p110 alpha isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Ragl(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd x 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.

  DOI：

  10.1021/jm200688y
• 作为产物：
  描述：

  2,4-二氯-6-吗啉基-1,3,5-三嗪 在 5%-palladium/activated carbon 、 氢气 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 1.0h， 生成 4-amino-2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Novel Analogues of the Pan Class I Phosphatidylinositol 3-Kinase (PI3K) Inhibitor 2-(Difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474)

  摘要：

  A structure activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110 alpha, p110 beta, and p110 delta) and also displayed significant potency against two mutant forms of the p110 alpha isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Ragl(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd x 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.

  DOI：

  10.1021/jm200688y

文献信息

• [EN] PYRIMIDINYL AND 1,3,5 TRIAZINYL BENZIMIDAZOLES AND THEIR USE IN CANCER THERAPY<br/>[FR] PYRIMIDINYL ET 1,3,5-TRIAZINYL BENZIMIDAZOLES ET LEUR UTILISATION EN THÉRAPIE ANTICANCÉREUSE
  申请人：PATHWAY THERAPEUTICS LTD

  公开号：WO2010110686A1

  公开（公告）日：2010-09-30

  Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazoles, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.

  本文提供了嘧啶基和1,3,5-三嗪基苯并唑类化合物，以及它们的药物组合、制备方法，以及作为抗癌治疗药物或药剂的用途，可以单独使用，也可以与放疗和/或其他抗癌药物联合使用。
• Heterocyclic compound and antitumor agent containing the same as effective ingredient
  申请人：Kawashima Seiichiro

  公开号：US20060247232A1

  公开（公告）日：2006-11-02

  The present invention relates to heterocyclic compounds represented by the formula I or pharmaceutically acceptable salts thereof and antitumor agents containing the heterocyclic compounds as effective components: wherein X represents nitrogen atom or CH; R 1 represents CH n F 3-n (wherein n is 1 or 2), hydroxy C 1 -C 6 alkyl, NHR 6 [wherein R 6 represents hydrogen atom or COR (wherein R represents hydrogen atom, C 1 -C 6 alkyl or C 1 -C 6 alkoxy)]; R 2 represents morpholino (which may be substituted with one to four C 1 -C 6 alkyl), thiomorpholino, piperidino, pyrrolidinyl (which may be substituted with hydroxy C 1 -C 6 alkyl), oxazolidinyl (which may be substituted with one or two C 1 -C 6 alkyl) or tetrahydro-1,4-thiazin-1-oxo-4-yl; R 3 and R 4 each represent hydrogen atom or C 1 -C 6 alkyl; and R 5 represents hydrogen atom, amino or hydroxyl.

  本发明涉及由式I表示的杂环化合物或其药学上可接受的盐，以及含有该杂环化合物作为有效成分的抗肿瘤剂： 其中X代表氮原子或CH；R1代表CHnF3-n（其中n为1或2），羟基C1-C6烷基，NHR6（其中R6代表氢原子或COR（其中R代表氢原子，C1-C6烷基或C1-C6烷氧基））；R2代表吗啡环（可以被取代为一到四个C1-C6烷基），硫代吗啡环，哌啶环，吡咯烷基（可以被羟基C1-C6烷基取代），噁唑烷基（可以被一到两个C1-C6烷基取代）或四氢-1,4-噻唑-1-氧-4-基；R3和R4各自代表氢原子或C1-C6烷基；R5代表氢原子，氨基或羟基。
• Heterocyclic compound and antitumor agent containing the same as active ingredient
  申请人：——

  公开号：US20040116421A1

  公开（公告）日：2004-06-17

  The present invention relates to heterocyclic compounds represented by the formula I or pharmaceutically acceptable salts thereof and antitumor agents containing the heterocyclic compounds as effective components: 1 wherein X represents nitrogen atom or CH; R 1 represents CH n F 3-n (wherein n is 1 or 2), hydroxy C 1 -C 6 alkyl, NHR 6 [wherein R 6 represents hydrogen atom or COR (wherein R represents hydrogen atom, C 1 -C 6 alkyl or C 1 -C 6 alkoxy)]; R 2 represents morpholino (which may be substituted with one to four C 1 -C 6 alkyl), thiomorpholino, piperidino, pyrrolidinyl (which may be substituted with hydroxy C 1 -C 6 alkyl), oxazolidinyl (which may be substituted with one or two C 1 -C 6 alkyl) or tetrahydro-1,4-thiazin- 1 -oxo-4-yl; R 3 and R 4 each represent hydrogen atom or C 1 -C 6 alkyl; and R 5 represents hydrogen atom, amino or hydroxyl.

  本发明涉及由式I表示的杂环化合物或其药学上可接受的盐以及含有该杂环化合物为有效成分的抗肿瘤剂： 1其中X代表氮原子或CH；R1代表CHnF3-n（其中n为1或2）、羟基C1-C6烷基、NHR6[其中R6代表氢原子或COR（其中R代表氢原子、C1-C6烷基或C1-C6烷氧基）]；R2代表吗啡啶基（可用一到四个C1-C6烷基取代）、硫代吗啡啶基、哌啶基、吡咯烷基（可用羟基C1-C6烷基取代）、噁唑烷基（可用一到两个C1-C6烷基取代）或四氢-1,4-噻唑-1-氧-4-基；R3和R4各自代表氢原子或C1-C6烷基；R5代表氢原子、氨基或羟基。
• IMMUNOSUPPRESSIVE AGENT AND ANTI-TUMOR AGENT COMPRISING HETEROCYCLIC COMPOUND AS ACTIVE INGREDIENT
  申请人：Haruta Kazuhiko

  公开号：US20080113987A1

  公开（公告）日：2008-05-15

  A novel method for immunosuppressive in a mammal suffering from an immune disease, including administering to the mammal a therapeutically effective amount of a heterocyclic compound represented by the general formula (I) (wherein X or other variables are as defined in the specification) or a pharmaceutically acceptable salt thereof is disclosed. A novel heterocyclic compound represented by the general formula (II) (wherein X or other variables are as defined in the specification) or a pharmaceutically acceptable salt thereof is also disclosed.

  本发明涉及一种治疗免疫性疾病的哺乳动物的免疫抑制新方法，包括向哺乳动物施用一种由通式（I）表示的杂环化合物的治疗有效量或其药学上可接受的盐。其中X或其他变量的定义见说明书。本发明还涉及一种由通式（II）表示的新型杂环化合物或其药学上可接受的盐。
• AMORPHOUS FORM OF HETEROCYCLIC COMPOUND, SOLID DISPERSION AND MEDICINAL PREPARATION EACH COMPRISING THE SAME, AND PROCESS FOR PRODUCTION OF THE SAME
  申请人：ZENYAKU KOGYO KABUSHIKIKAISHA

  公开号：EP2218718A1

  公开（公告）日：2010-08-18

  [PROBLEMS] The object is to improve the absorbability of a heterocyclic compound including s-triazine and a pyrimidine derivative in vitro. [MEANS FOR SOLVING PROBLEMS] Disclosed is, for example, an amorphous body of a heterocyclic compound as represented by the general formula (I) [wherein each of R's and others is as defined in the description] including s-triazine and a pyrimidine derivative, or a hydrate, a solvate or a pharmaceutically acceptable salt of the heterocyclic compound. Also disclosed is a process for producing the amorphous body Further disclosed are: a solid dispersion comprising the amorphous body; and a medicinal preparation comprising the solid dispersion.

  [问题] 目的是提高包括 s-三嗪和嘧啶衍生物在内的杂环化合物在体外的可吸收性。[解决问题的方法]例如，公开了通式(I)所代表的杂环化合物的无定形体[其中各 R 和其它如描述中所定义]，包括 s-三嗪和嘧啶衍生物，或该杂环化合物的水合物、溶液或药学上可接受的盐。还公开了一种生产该无定形体的工艺 进一步公开了：一种包含该无定形体的固体分散体；以及一种包含该固体分散体的药物制剂。