6-amino-4-[(3-bromo-4-fluorophenyl)amino]pyrido[3,4-d]pyrimidine | 227311-92-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 6-amino-4-[(3-bromo-4-fluorophenyl)amino]pyrido[3,4-d]pyrimidine
• 英文别名: 6-amino-4-<(3-bromo-4-fluorophenyl)amino>pyrido<3,4-d>pyrimidine；N4-(3-bromo-4-fluorophenyl)pyrido[3,4-d]pyrimidine-4,6-diamine；4-N-(3-bromo-4-fluorophenyl)pyrido[3,4-d]pyrimidine-4,6-diamine
• CAS: 227311-92-4
• 化学式: C₁₃H₉BrFN₅
• 分子量: 334.15
• InChiKey: OMLMSJKVBNFVFY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  76.7
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-溴巴豆酸 、 6-amino-4-[(3-bromo-4-fluorophenyl)amino]pyrido[3,4-d]pyrimidine 在 N,N'-二环己基碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 异丁酰胺 为溶剂， 生成
  参考文献：
  名称：

  [EN] PRODRUG FORMS OF KINASE INHIBITORS AND THEIR USE IN THERAPY
  [FR] FORMES PROMÉDICAMENTS D'INHIBITEURS DE KINASE ET LEUR UTILISATION EN THÉRAPIE

  摘要：

  公开号：

  WO2010104406A8
• 作为产物：
  描述：

  4-<(3-bromo-4-fluorophenyl)amino>-6-<(4-methoxyphenyl)methylamino>pyrido<3,4-d>pyrimidine 在 三氟乙酸 作用下， 反应 0.5h， 以91%的产率得到6-amino-4-[(3-bromo-4-fluorophenyl)amino]pyrido[3,4-d]pyrimidine
  参考文献：
  名称：

  酪氨酸激酶抑制剂。15.4-（苯基氨基）喹唑啉和4-（苯基氨基）吡啶并[d]嘧啶丙烯酰胺，作为表皮生长因子受体的ATP结合位点的不可逆抑制剂。

  摘要：

  通过与丙烯酰氯/碱或丙烯酸/丙烯酰胺反应，由相应的氨基化合物制备了一系列4-（苯基氨基）喹唑啉和-吡啶并嘧啶类表皮生长因子受体（EGFR）抑制剂的6-和7-丙烯酰胺衍生物。 1-（3-二甲基氨基丙基）-3-乙基碳二亚胺盐酸盐。所有6-丙烯酰胺，但仅母体喹唑啉7-丙烯酰胺，都是分离的酶的不可逆抑制剂，证实与酶结合时，前者的位置更好，可以与关键的半胱氨酸-773反应。喹唑啉，吡啶并[3,4-d]嘧啶和吡啶并[3,2-d]嘧啶6-丙烯酰胺都是不可逆的抑制剂，在酶分析中显示出相似的高效力（可能是由于可用酶的滴定）。但是吡啶[3，在针对A431细胞中EGFR的细胞自磷酸化分析中，2-d]嘧啶类似物的效力比其他类似物低2-6倍。喹唑啉总体上对抑制调蛋白刺激的erbB2自身磷酸化作用（在MDA-MB-453细胞中）总体上作用较小，而吡啶嘧啶则等价。在A431表皮样和H125非小细胞肺癌人肿瘤异种移植物中

  DOI：

  10.1021/jm9806603

文献信息

• PRODRUG FORMS OF KINASE INHIBITORS AND THEIR USE IN THERAPY
  申请人：Smaill Jeffrey Bruce

  公开号：US20120077811A1

  公开（公告）日：2012-03-29

  The invention provides novel prodrug compounds comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, where the compound carries a positive charge. In preferred embodiments, the compounds are of Formula I: where: X is any negatively charged counterion; R 1 is a group of the formula —(CH 2 ) n Tr, where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and —(CH 2 ) n Tr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6; R 2 , R 3 and R 4 may each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R 2 )(R 3 )(R 4 )N, or two of R 2 , R 3 , and R 4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R 2 , R 3 and R 4 may be absent and two of R 2 , R 3 and R 4 form an aromatic heterocyclic amine ring of a kinase inhibitor. The compounds of the invention are useful in treating proliferative diseases such as cancer.

  本发明提供了新型的前药化合物，包括一种激酶抑制剂和一种还原活化的破裂芳香族硝基杂环或芳香族硝基碳杂环触发剂，其中该化合物带有正电荷。在优选实施例中，该化合物为式I：其中：X是任何带负电的反离子；R1是公式—(CH2)nTr的基团，其中Tr是芳香族硝基杂环或芳香族硝基碳杂环，—(CH2)nTr作为还原活化的破裂触发器；n是0到6的整数；R2、R3和R4可以各自独立地选择来自三级胺激酶抑制剂的脂肪族或芳香族基团(R2)(R3)(R4)N，或者R2、R3和R4中的两个可以形成激酶抑制剂的脂肪族或芳香族杂环胺环，或者R2、R3和R4中的一个可以缺失，R2、R3和R4中的两个可以形成激酶抑制剂的芳香族杂环胺环。该发明的化合物可用于治疗增殖性疾病，如癌症。
• Prodrug forms of kinase inhibitors and their use in therapy
  申请人：Smaill Jeffrey Bruce

  公开号：US09073916B2

  公开（公告）日：2015-07-07

  The invention provides novel prodrug compounds comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, where the compound carries a positive charge. In preferred embodiments, the compounds are of Formula I: where: X is any negatively charged counterion; R1 is a group of the formula —(CH2)nTr, where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and —(CH2)nTr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6; R2, R3 and R4 may each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R2)(R3)(R4)N, or two of R2, R3, and R4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R2, R3 and R4 may be absent and two of R2, R3 and R4 form an aromatic heterocyclic amine ring of a kinase inhibitor. The compounds of the invention are useful in treating proliferative diseases such as cancer.

  本发明提供了新型的前药化合物，其中包含一种激酶抑制剂和一种还原活化的分裂芳香族硝基杂环或芳香族硝基碳环触发剂，该化合物带有正电荷。在优选实施例中，该化合物为公式I：其中：X是任何负电荷的反离子；R1是公式—（CH2）nTr的基团，其中Tr是一种芳香族硝基杂环或芳香族硝基碳环，—（CH2）nTr作为还原活化的分裂触发剂；n是从0到6的整数；R2、R3和R4可以各自独立地选择来自三级胺激酶抑制剂（R2）（R3）（R4）N的脂肪族或芳香族基团，或者R2、R3和R4中的两个可以形成激酶抑制剂的脂肪族或芳香族杂环胺环，或者R2、R3和R4中的一个可能不存在，并且R2、R3和R4中的两个可以形成激酶抑制剂的芳香族杂环胺环。本发明的化合物在治疗癌症等增殖性疾病方面是有用的。
• Tyrosine Kinase Inhibitors. 19. 6-Alkynamides of 4-Anilinoquinazolines and 4-Anilinopyrido[3,4-<i>d</i>]pyrimidines as Irreversible Inhibitors of the erbB Family of Tyrosine Kinase Receptors
  作者：Sylvester R. Klutchko、Hairong Zhou、R. Thomas Winters、Tuan P. Tran、Alexander J. Bridges、Irene W. Althaus、Danielle M. Amato、William L. Elliott、Paul A. Ellis、Mary Ann Meade、Billy J. Roberts、David W. Fry、Andrea J. Gonzales、Patricia J. Harvey、James M. Nelson、Veronica Sherwood、Hyo-Kyung Han、Gerry Pace、Jeff B. Smaill、William A. Denny、H. D. Hollis Showalter

  DOI：10.1021/jm050936o

  日期：2006.2.1

  Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of alkynamide analogues of quinazoline- and pyrido[3,4-d]pyrimidine-based compounds. The compounds were prepared by coupling the appropriate 6-aminoquinazolines or 6-aminopyrido[3,4-d]pyrimidines with alkynoic acids, using EDCI center dot HCl in pyridine. The compounds showed pan-erbB enzyme inhibition but were on average about 10-fold more potent against erbB1 than against erbB2 and erbB4. For cellular inhibition, the nature of the alkylating side chains was an important determinant, with 5-dialkylamino-2-pentynamide type Michael acceptors providing the highest potency. This is suggested to be due to an improved ability of the amine to participate in an autocatalysis of the Michael reaction with enzyme cysteine residues. Pyrido[3,4-d]pyrimidine analogue 39 was selected for in vivo evaluation and achieved tumor regressions at 10 mg/kg in the A431 human epidermoid carcinoma and at 40 mg/kg for the SF767 human glioblastoma and the SKOV3 human ovarian carcinoma. Complete stasis was observed at 40 mg/kg in the BXPC3 human pancreatic carcinoma as well as in the H125 human non-small-cell lung carcinoma.
• US9073916B2
  申请人：——

  公开号：US9073916B2

  公开（公告）日：2015-07-07
• [EN] PRODRUG FORMS OF KINASE INHIBITORS AND THEIR USE IN THERAPY<br/>[FR] FORMES PROMÉDICAMENTS D'INHIBITEURS DE KINASE ET LEUR UTILISATION EN THÉRAPIE
  申请人：AUCKLAND UNISERVICES LTD

  公开号：WO2010104406A8

  公开（公告）日：2011-10-06