5-氨基-3-苯甲基-2,3-二氢-7H-[1,2,3]三唑并[4,5-d]嘧啶-7-酮 | 17756-35-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三唑并嘧啶类
• 中文名称: 5-氨基-3-苯甲基-2,3-二氢-7H-[1,2,3]三唑并[4,5-d]嘧啶-7-酮
• 英文名称: 9-benzyl-8-azaguanine
• 英文别名: 5-amino-3-benzyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one；5-Amino-3-benzyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-on；5-Amino-3-benzyl-2,3-dihydro-7h-[1,2,3]triazolo[4,5-d]pyrimidin-7-one；5-amino-3-benzyl-6H-triazolo[4,5-d]pyrimidin-7-one
• CAS: 17756-35-3
• 化学式: C₁₁H₁₀N₆O
• 分子量: 242.24
• InChiKey: OLKBWLGASVXSJN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  98.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-氨基-3-苯甲基-2,3-二氢-7H-[1,2,3]三唑并[4,5-d]嘧啶-7-酮 在 盐酸 、 sodium nitrite 作用下， 生成 5,7-Dioxo-3-benzyl-4,5,6,7-tetrahydro-3H-vic.-triazolo<4,5-d>pyrimidin
  参考文献：
  名称：

  Potential Purine Antagonists. XIX. Synthesis of Some 9-Alkyl(aryl)-2-amino-6-substituted Purines and Related V-Triazolo [d]pyrimidines¹

  摘要：

  DOI：

  10.1021/ja01521a034
• 作为产物：
  描述：

  5-氨基-1-苄基-1H-1,2,3-噻唑-4-羧胺 在 sodium hydroxide 、 copper diacetate 、 potassium carbonate 作用下， 以 甲醇 、 丙酮 为溶剂， 反应 54.5h， 生成 5-氨基-3-苯甲基-2,3-二氢-7H-[1,2,3]三唑并[4,5-d]嘧啶-7-酮
  参考文献：
  名称：

  区域选择性合成9-取代的8-氮杂鸟嘌呤（5-氨基-3-取代的3,6-二氢-7 H -1,2,3-三唑并[4,5- d ]嘧啶-7-一）

  摘要：

  通过修改先前描述的由咪唑合成9-取代鸟嘌呤的方法，我们开发了9-取代-8-氮杂鸟嘌呤（5-氨基-3-取代-3,6-二氢-来自三唑的7 H -1,2,3-三唑并[4,5- d ]嘧啶-7-one）高产率。该方法似乎适合引入各种取代基，包括糖，碳环，无环和碳环链。

  DOI：

  10.1002/jhet.5570330609

文献信息

• [EN] BETA-GLUGURONIDASE CLEAVABLE PRODRUGS OF O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE INACTIVATORS<br/>[FR] PROMEDICAMENTS A BASE D'AGENTS D'INACTIVATION DE L'O6-ALKYLGUANINE-ADN ALKYLTRANSFERASE, CLIVABLES PAR LA BETA-GLUCURONIDASE
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2006029065A1

  公开（公告）日：2006-03-16

  Disclosed are prodrugs of inactivators of 06-alkylguanine-DNA alkyltransferase (AGT). The prodrugs are cleavable by the (3-glucuronidase enzyme, which is either administered to the patient or produced by necrotic tumor cells. The prodrugs are represented by the formula A-B-C, wherein A is a glucuronosyl residue linked through its 1-oxygen to the phenyl ring of B; B is a benzyloxycarbonyl group, optionally ring­ substituted with one or more electron withdrawing groups; and C is an inactivator of AGT, e.g., a substituted or unsubstituted 06-benzylguanine or 06-benzyl-2'-deoxyguanosine. Also disclosed are pharmaceutical compositions comprising a prodrug and a pharmaceutically acceptable carrier, and a method of use of the prodrugs in enhancing the chemotherapeutic treatment of tumor cells in a mammal, e.g., a human, with an antineoplastic alkylating agent that causes cytotoxic lesions at the 06-position of guanine.

  本发明公开了06-烷基鸟嘌呤-DNA烷基转移酶（AGT）失活剂的前药。这些前药可以被（3-葡萄糖醛酸酶酶）水解，该酶可以被注射到患者体内或由坏死肿瘤细胞产生。前药由公式A-B-C表示，其中A是通过其1-氧原子与B的苯环连接的葡萄糖醛酸残基；B是苄氧羰基基团，可以选择性地被一个或多个电子提取基团取代；而C是AGT的失活剂，例如取代或未取代的06-苄基鸟嘌呤或06-苄基-2'-脱氧鸟苷。本发明还公开了包含前药和药学上可接受的载体的制药组合物，以及在增强哺乳动物（例如人类）中肿瘤细胞的化疗治疗中使用前药的方法，该方法使用一种抗肿瘤烷基化剂，在鸟嘌呤的06位引起细胞毒性损伤。
• Substituted O6-benzyl-8-aza-guanines
  申请人：The Government of the United States of America, Department of Health and Human Services

  公开号：US20020013299A1

  公开（公告）日：2002-01-31

  The present invention provides AGT inactivating compounds such as substituted O 6 -benzylguanines of the formula 1 7- or 9-substituted 8-aza-O 6 -benzylguanines, 7,8-disubstituted O 6 -benzylguanines, 7,9-disubstituted O 6 -benzylguanines, 4(6)-substituted 2-amino-5-nitro-6 (4) -benzyloxypyrimidines, and 4 (6) -substituted 2-amino-5-nitroso-6(4)-benzyloxypyrimidines, as well as pharmaceutical compositions comprising such compounds along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent, which causes cytotoxic lesions at the O 6 -position of guanine, by administering to a mammal an effective amount of one of the aforesaid compounds, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O 6 -benzylguanine, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the Deposition of guanine.

  本发明提供了AGT失活化合物，例如公式17-或9-取代的8-aza-O6-苄基鸟嘌呤、7,8-二取代的O6-苄基鸟嘌呤、7,9-二取代的O6-苄基鸟嘌呤、4（6）-取代的2-氨基-5-硝基-6（4）-苄氧嘧啶和4（6）-取代的2-氨基-5-亚硝基-6（4）-苄氧嘧啶，以及包含这些化合物和药用载体的制药组合物。本发明还提供了一种增强抗肿瘤烷化剂治疗哺乳动物肿瘤细胞的方法，该方法通过向哺乳动物投与上述化合物、2,4-二氨基-6-苄氧基-s-三嗪、5-取代的2,4-二氨基-6-苄氧基嘧啶或8-aza-O6-苄基鸟嘌呤的有效量，并向哺乳动物投与一种在鸟嘌呤O6位引起细胞毒性损伤的抗肿瘤烷化剂的有效量。
• O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE INACTIVATORS AND BETA-GLUCURONIDASE CLEAVABLE PRODRUGS
  申请人：MOSCHEL C. Robert

  公开号：US20070213279A1

  公开（公告）日：2007-09-13

  Disclosed are prodrugs of inactivators of O 6 -alkylguanine-DNA alkyltransferase (AGT). The prodrugs are cleavable by the β-glucuronidase enzyme, which is either administered to the patient or produced by necrotic tumor cells. The prodrugs are represented by the formula A-B-C, wherein A is a glucuronosyl residue linked through its 1-oxygen to the phenyl ring of B; B is a benzyloxycarbonyl group, optionally ring-substituted with one or more electron withdrawing groups; and C is an inactivator of AGT, e.g., a substituted or unsubstituted O 6 -benzylguanine or O 6 -benzyl-2′-deoxyguanosine, Also disclosed are additional inactivators of AGT, pharmaceutical compositions comprising an inactivator or prodrug and a pharmaceutically acceptable carrier, and a method of use of the inactivator or prodrug in enhancing the chemotherapeutic treatment of tumor cells in a mammal, e.g., a human, with an antineoplastic alkylating agent that causes cytotoxic lesions at the O 6 -position of guanine.

  本发明公开了O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）不活化剂的前药。这些前药可被β-葡萄糖醛酸酶酶水解，该酶可由患者口服或由坏死的肿瘤细胞产生。该前药的化学式为A-B-C，其中A是葡萄糖醛酸残基，通过其1-氧原子与B的苯环连接；B是苄氧羰基基团，可选地带有一个或多个电子吸引基；C是AGT的不活化剂，例如取代或未取代的O6-苄基鸟嘌呤或O6-苄基-2'-脱氧鸟苷。本发明还公开了其他AGT不活化剂、包含不活化剂或前药及其药学可接受载体的制药组合物，以及在使用抗肿瘤烷基化剂在哺乳动物（例如人类）中增强肿瘤细胞的化疗治疗中使用不活化剂或前药的方法。
• Substituted O6-benzylguanines and 6(4)-benzyloxypyrimidines
  申请人：THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, Department of Health and Human Services

  公开号：EP1142893A1

  公开（公告）日：2001-10-10

  The present invention provides AGT inactivating compounds such as substituted O6-benzylguanines, 7- or 9-substituted 8-aza-O6-benzylguanines, 7,8-disubstituted O6-benzylguanines, 7,9-disubstituted O6-benzylguanines, 4(6)-substituted 2-amino-5-nitro-6(4)-benzyloxypyrimidines, and 4(6)-substituted 2-amino-5-nitroso-6(4)-benzyloxypyrimidines, as well as pharmaceutical compositions comprising such compounds along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesion at the O6-position of guanine, by administering to a mammal an effective amount of one of the aforesaid compounds, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O6-benzylguanine, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions of the O6-postion of guanine.

  本发明提供 AGT 失活化合物，如取代的 O6-苄基鸟嘌呤、7-或 9-取代的 8-氮杂-O6-苄基鸟嘌呤、7,8-二取代的 O6-苄基鸟嘌呤、7,9-二取代的 O6-苄基鸟嘌呤、4(6)-取代的 2-氨基-5-亚硝基-6(4)-苄氧基嘧啶，和 4(6)-取代的 2-氨基-5-亚硝基-6(4)-苄氧基嘧啶，以及包含这些化合物和药学上可接受的载体的药物组合物。本发明进一步提供了一种方法，通过向哺乳动物施用有效量的上述化合物之一，用能在鸟嘌呤的 O6 位引起细胞毒性病变的抗肿瘤烷化剂加强对哺乳动物体内肿瘤细胞的化疗、2,4-二氨基-6-苄氧基-s-三嗪、5-取代的 2,4-二氨基-6-苄氧基嘧啶或 8-氮杂-O6-苄基鸟嘌呤，并向哺乳动物施用有效量的抗肿瘤烷化剂，使鸟嘌呤的 O6 位发生细胞毒性病变。
• Substituted 06- benzylguanines and 7- or 9- substituted 8-aza-06-benzylguanines
  申请人：THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, Department of Health and Human Services

  公开号：EP1518854A1

  公开（公告）日：2005-03-30

  The present invention provides AGT inactivating compounds such as 7- or 9-substituted 8- aza- O6-benzylguanines of formula (III) or (IV), and related substituted O6-benzyl guanines, as well as pharmaceutical compositions comprising such compounds along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumour cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O6- position of guanine, by administering to a mammal an effective amount of one of the aforesaid compounds, 2,4-diamino-6-benzyloxy-s-triazine, or 8-aza-O6-benzylguanine, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O6- position of guanine.

  本发明提供了AGT失活化合物，如式(III)或(IV)的7-或9-取代的8-氮杂O6-苄基鸟嘌呤和相关的取代的O6-苄基鸟嘌呤，以及包含此类化合物和药学上可接受的载体的药物组合物。本发明进一步提供了一种用抗肿瘤烷化剂加强对哺乳动物体内肿瘤细胞的化疗治疗的方法，该抗肿瘤烷化剂可在鸟嘌呤的 O6-位上引起细胞毒性病变、向哺乳动物施用有效量的上述化合物之一、2,4-二氨基-6-苄氧基-s-三嗪或 8-氮杂-O6-苄基鸟嘌呤，并向哺乳动物施用有效量的抗肿瘤烷化剂，这种抗肿瘤烷化剂可在鸟嘌呤的 O6-位上引起细胞毒性病变。