6-溴吡啶并[2,3-D]-2,4-二氨基嘧啶 | 152941-69-0

• 物质功能分类: 医药中间体 - 吡啶类化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 中文名称: 6-溴吡啶并[2,3-D]-2,4-二氨基嘧啶
• 中文别名: 2,4-氨基-6-溴吡啶[2,3-d]并嘧啶
• 英文名称: 2,4-diamino-6-bromopyrido<2,3-d>pyrimidine
• 英文别名: 2,4-diamino-5-bromopyrido[2,3-d]pyrimidine；6-bromo-2,4-diamino-5-deazapteridine；6-Bromopyrido[2,3-d]pyrimidine-2,4-diamine
• CAS: 152941-69-0
• 化学式: C₇H₆BrN₅
• 分子量: 240.062
• InChiKey: KCUKOBPJXGXIKX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  90.7
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 海关编码：
  2933990090

反应信息

• 作为反应物：
  描述：

  6-溴吡啶并[2,3-D]-2,4-二氨基嘧啶 在 吡啶 、 palladium diacetate 、 copper(l) iodide 、 三乙胺-硼烷 、 sodium methylate 、 臭氧 、 溶剂黄146 、 三乙胺 、 三(邻甲基苯基)磷 作用下， 以 甲醇 、 二氯甲烷 、 溶剂黄146 、 乙腈 为溶剂， 反应 114.0h， 生成 6-[(3,4,5-Trimethoxyanilino)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine
  参考文献：
  名称：

  Synthesis and Dihydrofolate Reductase Inhibitory Activities of 2,4-Diamino-5-deaza and 2,4-Diamino-5,10-dideaza Lipophilic Antifolates

  摘要：

  Two series of nonclassical antifolates (2,4-diamino-5-deaza compounds 2-5 and 5,10-dideaza compounds 6-13) were synthesized as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) organisms that are responsible for fatal opportunistic infections in AIDS patients. Rat liver (rl) DHFR served as the mammalian reference enzyme to determine selectivity. Syntheses of the target 5-deaza compounds were achieved by initial construction of the pivaloyl-protected 2,4-diamino-6-bromopyrido[2,3-d]-pyrimidine 17 via a cyclocondensation of 2,4,6-triaminopyrimidine with bromomalonaldehyde. Sequential Heck coupling of 17 with styrene followed by ozonolysis afforded the g-formyl derivative 19. Reductive amination of 19 with 3,4,5-trimethoxyaniline afforded the N10-H analog. The NIO-Me and NIO-Et analogs were synthesized by nucleophilic displacement of the 6-bromomethyl derivative 22 (obtained from the g-formyl derivative 19 by reduction and bromination) with the appropriate N-alkylaniline. The trans-5,10-dideaza analogs 6-8 were synthesized via a Heck coupling of the appropriate methoxystyrene with 17, and selective reduction of the resulting 9,10-double bond afforded target compounds 9-11. Further reduction to the tetrahydro derivatives afforded analogs 12 and 13. The 5-deaza NIO-Me 3,4,5-trimethoxy analog 3 maintained the best balance of potency and selectivity against both tgDHFR and pcDHFR. Compared to trimethoprim, compound 3 was only slightly less selective but was 300-fold more potent against tgDHFR. The 5,10-dideaza analogs were generally less potent and selective than the 5-deaza compounds.

  DOI：

  10.1021/jm9606913
• 作为产物：
  描述：

  6-bromo-2-pivaloylamino-4<1'-(1,2,4-triazolyl)>-5-deazapteridine 在 ammonium hydroxide 作用下， 以 1,4-二氧六环 为溶剂， 反应 120.5h， 生成 6-溴吡啶并[2,3-D]-2,4-二氨基嘧啶
  参考文献：
  名称：

  Taylor, Edward C.; Otiv, S. R.; Durucasu, Inci, Heterocycles, 1993, vol. 36, # 8, p. 1883 - 1895

  摘要：

  DOI：

文献信息

• Aryl nitrogen-containing bicyclic compounds and methods of use
  申请人：Patel F. Vinod

  公开号：US20070054916A1

  公开（公告）日：2007-03-08

  The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation, cancer and related conditions. The compounds have a general Formula I wherein A 1 , A 2 , A 3 , B, R 1 , R 2 , R 3 and R 4 are defined herein. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds of the invention, methods for the prophylaxis and treatment of kinase mediated diseases using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of compounds of the invention.

  这项发明涉及一类新的化合物，用于预防和治疗蛋白激酶介导的疾病，包括炎症、癌症和相关疾病。这些化合物具有一般的化学式I，其中A1、A2、A3、B、R1、R2、R3和R4在此有定义。因此，该发明还涉及包括该发明的化合物的药物组合物，使用该发明的化合物和组合物预防和治疗激酶介导的疾病的方法，以及用于制备该发明的化合物的中间体和方法。
• Synthesis of 2,4-diamino-5,10-dideaza nonclassical antifolates
  作者：Aleem Gangjee、Rajesh Devraj、Fu-Tyan Lin

  DOI：10.1002/jhet.5570280717

  日期：1991.11

  6-triaminopyrimidine (8) with bromomalonaldehyde (9) afforded, after pivaloylation, 2,4-dipivaloyl-6-bromopyrido[2,3-d]pyrimidine (11). This 6-bromo derivative served as a key intermediate for the synthesis of 2,4-diamino-6-[2-(3′,4′-dimethoxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine (5) via a palladium catalyzed carbon-carbon coupling with 3,4-dimethoxystyrene (12). Compound 5, its 9,10-dihydro analogue

  吡咯烷酮化后，将2,4,6-三氨基嘧啶（8）与溴代丙二醛（9）缩合，得到2,4-二哌戊酰基-6-溴代吡啶并[2,3- d ]嘧啶（11）。这个6-溴衍生物充当关键中间体2,4-二氨基-6-的合成[2-（3'，4'-二甲氧基苯基）乙烯基〕吡啶并[2,3- d ]嘧啶（5）通过一个钯催化的碳-碳与3,4-二甲氧基苯乙烯的偶联（12）。作为二氢叶酸还原酶的潜在抑制剂，化合物5，其9,10-二氢类似物6和5,6,7,8,9,10-六氢类似物7是令人感兴趣的。化合物通过5％Pd-C的催化加氢从5合成6和7。
• Design, Synthesis, and Molecular Modeling of Novel Pyrido[2,3-<i>d</i>]pyrimidine Analogues As Antifolates; Application of Buchwald–Hartwig Aminations of Heterocycles
  作者：Aleem Gangjee、Ojas A. Namjoshi、Sudhir Raghavan、Sherry F. Queener、Roy L. Kisliuk、Vivian Cody

  DOI：10.1021/jm400086g

  日期：2013.6.13

  (AIDS). The absence of any animal models for human Pneumocystis jirovecii pneumonia and the lack of crystal structures of pjDHFR and tgDHFR make the design of inhibitors challenging. A novel series of pyrido[2,3-d]pyrimidines as selective and potent DHFR inhibitors against these opportunistic infections are presented. Buchwald–Hartwig coupling reaction of substituted anilines with pivaloyl protected 2

  由吉氏肺孢子菌（P. jirovecii , pj）、弓形虫（T. gondii , tg）和鸟分枝杆菌（M. avium , ma）引起的机会性感染是获得性免疫缺陷综合征（AIDS）患者发病和死亡的主要原因。 ）。缺乏人类肺孢子菌肺炎的任何动物模型以及缺乏pj DHFR 和tg DHFR的晶体结构使得抑制剂的设计具有挑战性。吡啶并[2,3- d]的新系列]嘧啶作为选择性和有效的 DHFR 抑制剂来对抗这些机会性感染。取代苯胺与新戊酰基保护的 2,4-diamino-6-bromo-pyrido[2,3- d ]pyrimidine 的Buchwald-Hartwig 偶联反应被成功探索以合成这些类似物。化合物26是最具选择性的抑制剂，对pj DHFR具有优异的效力。使用pj DHFR 同源模型进行的分子建模研究解释了26的效力和选择性。结构数据还报告了26与PC DHFR和16以及22与变种PC
• Synthesis of new 2,4-Diaminopyrido[2,3-d]pyrimidine and 2,4-Diaminopyrrolo[2,3-d]pyrimidine inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase
  作者：Andre Rosowsky、Han Chen、Hongning Fu、Sherry F. Queener

  DOI：10.1016/s0968-0896(02)00325-5

  日期：2003.1

  groups with base. Also prepared via a scheme based on the Taylor ring expansion/ring annulation synthesis were three heretofore undescribed 2,4-diamino-5-(substituted benzyl)-7H-pyrrolo[2,3-d]pyrimidines (3b-c). Standard spectrophotometric assays were used to compare the ability of 2a-e and 3b-c to inhibit dihydrofolate reductase (DHFR) from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium

  开发了一条简洁的新路线，可轻松获得五个以前未报告的2,4-二氨基-6-（取代的苄基）吡啶并[2,3-d]嘧啶（2a-e），涉及2,4-二戊酰氨基-5的缩合。催化量的[1,1'-双（二苯基膦基）二茂铁]二氯钯（II）.CH（2）Cl（2）存在下，将溴化吡啶并[2,3-d]嘧啶（6）与有机锌卤化物，然后用碱除去新戊酰基。还通过基于泰勒环膨胀/环环合成的方案制备了三个迄今为止未描述的2,4-二氨基-5-（取代的苄基）-7H-吡咯并[2,3-d]嘧啶（3b-c）。使用标准分光光度法比较了2a-e和3b-c抑制卡氏肺孢子虫，弓形虫和鸟分枝杆菌的二氢叶酸还原酶（DHFR）的能力，艾滋病患者由于免疫功能低下而极易受到机会病原体侵害的三个例子。为了进行比较，还评估了13种先前未经测试的2,4-二氨基-6-（取代的苄基）喹唑啉（17a-m）作为这些酶以及大鼠肝脏酶的抑制剂。测试的喹唑啉或吡啶嘧啶类化合物对卡
• Methods for synthesis of diarylmethanes
  申请人：Dana-Farber Cancer Institute

  公开号：US20040267011A1

  公开（公告）日：2004-12-30

  The present invention relates to dihydrofolate reductase inhibitors having an aromatic group and a heteroaromatic group linked by a methylene group; methods of preparation of dihydrofolate reductase inhibitors that include metal mediated cross coupling of an aromatic halide or heteroaromatic halide with an organozinc reagent; and methods of treatment and pharmaceutical compositions that utilize or comprise one or more of such dihydrofolate reductase inhibitors.

  本发明涉及具有芳香基和杂环芳基的二氢叶酸还原酶抑制剂，它们由一个亚甲基连接；制备二氢叶酸还原酶抑制剂的方法包括通过金属介导的芳基卤化物或杂环芳基卤化物与有机锌试剂的交叉偶联；以及利用或包含其中一种或多种二氢叶酸还原酶抑制剂的治疗方法和制药组合物。