methyl 2-((pyridin-4-ylmethyl)amino)benzoate | 267891-88-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: methyl 2-((pyridin-4-ylmethyl)amino)benzoate
• 英文别名: Methyl 2-[(pyridin-4-ylmethyl)amino]benzoate；methyl 2-(pyridin-4-ylmethylamino)benzoate
• CAS: 267891-88-3
• 化学式: C₁₄H₁₄N₂O₂
• mdl: MFCD11177324
• 分子量: 242.277
• InChiKey: GMNHZZBEKCHKJE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.142
• 拓扑面积：
  51.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 2-((pyridin-4-ylmethyl)amino)benzoate 在 lithium aluminium tetrahydride 作用下， 以 乙醚 为溶剂， 反应 2.0h， 以77%的产率得到(2-((pyridin-4-ylmethyl)amino)phenyl)methanol
  参考文献：
  名称：

  2-Sec-Aminobenzilidene Imidazolones 的化学发散性螺环化：Lewis 与布朗斯台德酸催化

  摘要：

  具有邻仲氨基的亚苄基咪唑酮经历酸促进的化学发散螺环化。尽管存在游离的仲氨基，但强路易斯酸通过 [1,5]-氢化物移位触发的环化作用提供了获得螺环四氢喹啉的途径。布朗斯台德酸促进前所未有的分子内 umpolung 加氢胺化反应，形成螺环二氢吲哚。每个过程都以排他的原子经济方式进行。

  DOI：

  10.1002/adsc.202200109
• 作为产物：
  描述：

  邻氨基苯甲酸甲酯 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 20.0h， 生成 methyl 2-((pyridin-4-ylmethyl)amino)benzoate
  参考文献：
  名称：

  邻氨基苯甲酰胺：一类新型的抗血管生成的VEGF受体激酶抑制剂。

  摘要：

  已经制备了两种易于合成的邻氨基苯甲酰胺，VEGF受体酪氨酸激酶抑制剂，并将其评估为血管生成抑制剂。2-[（4-吡啶基）甲基]氨基-N- [3-（三氟甲基）苯基]苯甲酰胺（5）和N-3-异喹啉基-2-[（4-吡啶基甲基）氨基]苯甲酰胺（7）抑制重组VEGFR-2和VEGFR-3激酶。由于其物理化学性质，这些邻氨基苯甲酰胺很容易穿透细胞，并且在每天一次口服给小鼠后被吸收。在植入模型中，5和7均能有效抑制VEGF诱导的血管生成，ED（50）值为7 mg / kg。在黑色素瘤的小鼠原位模型中，5和7能有效抑制原发性肿瘤的生长以及自发性外周转移的形成。

  DOI：

  10.1021/jm020899q

文献信息

• N-aryl(thio)anthranilic acid amide derivatives, their preparation and their use as VEGF receptor tyrosine kinase inhibitors
  申请人：——

  公开号：US20020019414A1

  公开（公告）日：2002-02-14

  1 Described are compounds of formula (I), wherein W is O or S; X is NR 8 ; Y is CR 9 R 10 -(CH 2 )n wherein R 9 and R 10 are independently of each other hydrogen or lower alkyl, and n is an integer of from and including 0 to and including 3; or Y is SO 2 ; R 1 is aryl; R 2 is a mono- or bicyclic heteroaryl group comprising one or more ring nitrogen atoms with the exception that R 2 cannot represent 2-phthalimidyl, and in case of Y═SO 2 cannot represent 2,1,3-benzothiadiazol-4-yl; any of R 3 , R 4 , R 5 and R 6 , independently of the other, is H or a substituent other than hydrogen; and R 7 and R 8 , independently of each other, are H or lower alkyl; or a N-oxide or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical product for the treatment of a neoplastic disease which responds to an inhibition of the VEGF receptor tyrosine kinase activity. The compounds of formula (I) can be used for the treatment e.g. of a neoplastic disease, such as a tumor disease, of retinopathy and age-related macular degeneration.

  描述的是化合物的结构式（I），其中W是O或S；X是NR8；Y是CR9R10-(CH2)n，其中R9和R10彼此独立地是氢或较低的烷基，n是从0到3的整数；或Y是SO2；R1是芳基；R2是一个含有一个或多个环氮原子的单环或双环杂环基团，但R2不能代表2-邻苯二甲酰胺，并且在Y为SO2的情况下不能代表2,1,3-苯并噻二唑-4-基；R3、R4、R5和R6中的任何一个，独立于其他，是H或除氢之外的取代基；R7和R8，彼此独立地是H或较低的烷基；或其N-氧化物或药用可接受的盐，用于制备用于治疗对VEGF受体酪氨酸激酶活性抑制产生反应的恶性疾病的药物产品。结构式（I）的化合物可用于治疗恶性疾病，如肿瘤疾病，视网膜病和老年性黄斑变性等。
• Synthesis and evaluation of novel radioiodinated anthranilate derivatives for in vivo imaging of vascular endothelial growth factor receptor with single-photon emission computed tomography
  作者：Masahiko Hirata、Akihiko Asano、Yasuhiro Magata、Yoshiro Ohmomo、Takashi Temma

  DOI：10.1007/s12149-020-01475-6

  日期：2020.7

  Angiogenesis facilitates tumor survival and promotes malignancy. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) tyrosine kinase (TK) signaling pathway is a key factor mediating angiogenesis, suggesting that this pathway may be a target for diagnosis and therapy. In this study, we aimed to develop small molecule radioiodinated probes applicable for in vivo VEGFR imaging considering the versatility and usefulness of single-photon emission computed tomography (SPECT). We designed and synthesized four radioiodinated anthranilate compounds (6a–d) based on the structure of an anticancer drug targeting VEGFR-TK. The inhibitory potencies of corresponding cold compounds 4a–d and in vitro stability of compounds 6a–d were assessed by cellular proliferation inhibition assays and radio thin-layer chromatography after incubation in neutral solution. In vivo biodistributions were evaluated by determining radioactivity in tissues of interest after intravenous injection of test compounds in tumor-bearing mice. In vitro and in vivo blocking experiments using a selective VEGFR-TK inhibitor and SPECT/computed tomography (CT) imaging were performed in tumor-bearing mice. The radioiodinated compounds 6a–d were obtained with more than 68.0% radiochemical yield and more than 95% radiochemical purity. Because compounds 4a–d showed high inhibitory potencies and compounds 6c and 6d showed high in vitro stability, 6c ([125I]m-NPAM) and 6d ([125I]p-NPAM) were further evaluated. Analysis of the in vivo biodistribution revealed a tumor to blood radioactivity ratio of greater than 4 at 24 h after [125I]p-NPAM administration. Accumulation of radioactivity in cultured tumor cells and tumor xenografts after [125I]p-NPAM administration was significantly blocked by inhibitor pretreatment. Tumors were clearly imaged at 24 h after [125I]p-NPAM injection with SPECT/CT in comparison to that in inhibitor-pretreated tumor-bearing mice. [125I]p-NPAM may have potential applications as a lead compound for future development of a clinically usable VEGFR imaging probe for SPECT.

  angiogenesis 促进肿瘤存活并促进恶性肿瘤的发展。血管内皮生长因子 (VEGF)/VEGF 受体 (VEGFR) 酪氨酸激酶 (TK) 信号通路是介导血管生成的关键因素，这表明该通路可能是诊断和治疗的目标。在本研究中，我们旨在开发适用于体内 VEGFR 成像的小分子放射碘化探针，考虑到单光子发射计算机断层扫描 (SPECT) 的多功能性和实用性。我们基于针对 VEGFR-TK 的抗癌药物结构设计并合成了四种放射碘化的氨基苯甲酸化合物 (6a–d)。通过细胞增殖抑制测定和中性溶液中孵育后的放射薄层色谱评估了相应冷化合物 4a–d 的抑制效力和化合物 6a–d 的体外稳定性。通过在肿瘤小鼠中静脉注射测试化合物后测定感兴趣组织的放射性来评估体内生物分布。在肿瘤小鼠中使用选择性 VEGFR-TK 抑制剂进行的体外和体内封闭实验，以及 SPECT/计算机断层扫描 (CT) 成像。放射碘化化合物 6a–d 的放射化学产率超过 68.0%，放射化学纯度超过 95%。由于化合物 4a–d 显示出较强的抑制效力，而化合物 6c 和 6d 显示出较高的体外稳定性，因此对 6c ([125I]m-NPAM) 和 6d ([125I]p-NPAM) 进行了进一步评估。体内生物分布分析显示，[125I]p-NPAM 给药后肿瘤与血液的放射活性比在 24 小时后超过 4。给予 [125I]p-NPAM 后，培养的肿瘤细胞和肿瘤异种移植体中放射活性的累积显著被抑制剂预处理所阻断。与抑制剂预处理的肿瘤小鼠相比，使用 SPECT/CT 在 [125I]p-NPAM 注射后 24 小时清晰显示肿瘤。 [125I]p-NPAM 可能作为未来开发临床可用 VEGFR 成像探针的先导化合物具有潜在的应用价值。
• [EN] N-ARYL(THIO)ANTHRANILIC ACID AMIDE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS VEGF RECEPTOR TYROSINE KINASE INHIBITORS<br/>[FR] DERIVES DE N-ARYL(THIO)ANTHRANILIQUE ACIDE AMIDE, LEUR PREPARATION ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE LA TYROSINE KINASE DU RECEPTEUR VEGF
  申请人：NOVARTIS AG

  公开号：WO2000027820A1

  公开（公告）日：2000-05-18

  Described are compounds of formula (I), wherein W is O or S; X is NR8; Y is CR9R10-(CH2)n wherein R9 and R10 are independently of each other hydrogen or lower alkyl, and n is an integer of from and including 0 to and including 3; or Y is SO2; R1 is aryl; R2 is a mono- or bicyclic heteroaryl group comprising one or more ring nitrogen atoms with the exception that R2 cannot represent 2-phthalimidyl, and in case of Y = SO2 cannot represent 2,1,3-benzothiadiazol-4-yl; any of R3, R4, R5 and R6, independently of the other, is H or a substituent other than hydrogen; and R7 and R8, independently of each other, are H or lower alkyl; or a N-oxide or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical product for the treatment of a neoplastic disease which responds to an inhibition of the VEGF receptor tyrosine kinase activity. The compounds of formula (I) can be used for the treatment e.g. of a neoplastic disease, such as a tumor disease, of retinopathy and age-related macular degeneration.

  本文描述了式(I)的化合物，其中W是O或S；X是NR8；Y是CR9R10-(CH2)n，其中R9和R10独立地是氢或低级烷基，n是0至3的整数；或者Y是SO2；R1是芳基；R2是一个含有一个或多个环氮原子的单环或双环杂环基团，但R2不能代表2-苯甲酰亚胺基，且在Y = SO2的情况下不能代表2,1,3-苯并噻二唑-4-基；R3、R4、R5和R6中的任何一个，除了氢之外，都是取代基；R7和R8独立地是氢或低级烷基；或其N-氧化物或药学上可接受的盐，用于制备用于治疗对VEGF受体酪氨酸激酶活性抑制有反应的肿瘤疾病的制药产品。式(I)的化合物可用于治疗肿瘤疾病、视网膜病变和年龄相关性黄斑变性等疾病。
• N-aryl (THIO) anthranilic acid amide derivatives, their preparation and their use as VEGF receptor tyrosine kinase inhibitors
  申请人：——

  公开号：US20040198782A1

  公开（公告）日：2004-10-07

  1 Described are compunds of formula (I), wherein W is O or S; X is NR 8 ; Y is CR 9 R 10 —(CH 2 ) n wherein R 9 and R 10 are independently of each other hydrogen or lower alkyl, and n is an integer of from and including 0 to and including 3; or Y is SO 2 ; R 2 is aryl; R 2 is a mono- or bicyclic heteroaryl group comprising one or more ring nitrogen atoms with the exception that R 2 cannot represent 2-phthalimidyl, and in case of Y=SO 2 cannot represent 2,1,3-benzothiadiazol-4-yl; any of R 3 , R 4 , R 5 and R 6 , independently of the other, is H or a substituent other than hydrogen; and R 7 and R 8 , independently of each other, are H or lower alkyl; or a N-oxide or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical product for the treatment of a neoplastic disease which responds to an inhibition of the VEGF receptor tyrosine kinase activity. The compounds of formula (I) can be used for the treatment e.g. of a neoplastic disease, such as a tumor disease, of retinopathy and age-related macular degeneration.

  描述了化合物的公式(I)，其中W为O或S; X为NR8; Y为CR9R10—(CH2)n，其中R9和R10独立地为氢或低烷基，n为0至3的整数，包括0和3; 或Y为SO2; R2为芳基; R2为一种单环或双环杂环芳基，包括一个或多个环氮原子，但R2不能表示2-邻苯二甲酰亚胺基，且在Y = SO2的情况下不能表示2,1,3-苯并噻二唑-4-基; R3、R4、R5和R6中的任何一个，除了氢之外，都是取代基; R7和R8独立地为氢或低烷基; 或其N-氧化物或药学上可接受的盐，用于制备治疗对VEGF受体酪氨酸激酶活性抑制有反应的肿瘤疾病的制药产品。公式(I)的化合物可用于治疗肿瘤疾病，如肿瘤疾病，视网膜病和年龄相关性黄斑变性等。
• N-aryl (thio) anthranilic acid amide derivatives, their preparation and their use as VEGF receptor tyrosine kinase inhibitors
  申请人：——

  公开号：US20030064992A1

  公开（公告）日：2003-04-03

  1 Described are compunds of formula (I), wherein W is O or S; X is NR 8 ; Y is CR 9 R 10 —(CH 2 )n wherein R 9 and R 10 are independently of each other hydrogen or lower alkyl, and n is an integer of from and including 0 to and including 3; or Y is SO 2 ; R 1 is aryl; R 2 is a mono- or bicyclic heteroaryl group comprising one or more ring nitrogen atoms with the exception that R 2 cannot represent 2-phthalimidyl, and in case of Y=SO 2 cannot represent 2,1,3-benzothiadiazol-4-yl; any of R 3 , R 4 , R 5 and R 6 , independently of the other, is H or a substituent other than hydrogen; and R 7 and R 8 , independently of each other, are H or lower alkyl; or a N-oxide or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical product for the treatment of a neoplastic disease which responds to an inhibition of the VEGF receptor tyrosine kinase activity. The compounds of formula (I) can be used for the treatment e.g. of a neoplastic disease, such as a tumor disease, of retinopathy and age-related macular degeneration.

  本文描述了式(I)的化合物，其中W为O或S；X为NR8；Y为CR9R10—(CH2)n，其中R9和R10独立地为氢或低碳基，n为0至3的整数，或Y为SO2；R1为芳基；R2为一个单环或双环杂芳基，其中包含一个或多个环氮原子，但R2不能代表2-苯酰亚胺基，且在Y=SO2的情况下不能代表2,1,3-苯并噻二唑-4-基；R3、R4、R5和R6中的任意一个，独立于其他的，为H或除氢以外的取代基；且R7和R8独立地为H或低碳基；或其N-氧化物或药学上可接受的盐，用于制备治疗对VEGF受体酪氨酸激酶活性抑制有反应的肿瘤疾病的药物产品。式(I)的化合物可用于治疗肿瘤疾病，如肿瘤疾病、视网膜病变和老年性黄斑变性等。