内匹司他盐酸盐 | 183321-86-0

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 内匹司他盐酸盐
• 中文别名: 去甲基厄洛替尼；2-[[4-[(3-乙炔基苯基)氨基]-7-(2-甲氧基乙氧基)-6-喹唑啉基]氧基]乙醇
• 英文名称: desmethyl erlotinib
• 英文别名: 6-O-desmethyl erlotinib；OSI-420；2-((4-((3-Ethynylphenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)oxy)ethanol；2-[4-(3-ethynylanilino)-7-(2-methoxyethoxy)quinazolin-6-yl]oxyethanol
• CAS: 183321-86-0
• 化学式: C₂₁H₂₁N₃O₄
• 分子量: 379.415
• InChiKey: KOQIAZNBAWFSQM-UHFFFAOYSA-N

物化性质

• 熔点：
  140-142°C
• 密度：
  1.30
• 溶解度：
  不溶于水；不溶于乙醇； DMSO 中≥51 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  28
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  85.7
• 氢给体数：
  2
• 氢受体数：
  7

制备方法与用途

生物活性

Desmethyl Erlotinib (OSI-420 free base) 是 Erlotinib 的活性代谢物，Erlotinib 为 EGFR 酪氨酸激酶抑制剂。

体内研究

Desmethyl Erlotinib 在一项药代动力学研究中，于 Wistar 大鼠体内的半衰期（t_1/2）为 11.96±2.01 小时。

反应信息

• 作为反应物：
  描述：

  内匹司他盐酸盐 、 邻乙酰水杨酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 2-((4-((3-ethynylphenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)oxy)ethyl 2-acetoxybenzoate
  参考文献：
  名称：

  Synthesis and Evaluation of Novel Erlotinib–NSAID Conjugates as More Comprehensive Anticancer Agents

  摘要：

  A series of novel anticancer agents were designed and synthesized based on coupling of different nonsteroidal anti-inflammatory drugs (NSAIDs) with the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib. Both the antiproliferative and pharmacokinetic activity of the target compounds were evaluated using HCC827 and A431 tumor cell lines. Among the derivatives made, compounds 10a, 10c, and 21g showed superb potency, comparable to that of erlotinib. Furthermore, preliminary SAR analysis showed that when the NSAIDs were conjugated via linkage to C-6 OH versus linkage to C-7 OH of the quinazoline nucleus, superior anticancer activity was achieved. Finally, the in vitro pharmacokinetic profile of several conjugates demonstrated the desired dissociation kinetics as the coupled molecules were effectively hydrolyzed, releasing both erlotinib and the specific NSAID in a time-dependent manner. The conjugation strategy represents a unique and simplified approach toward combination therapy, particularly for the treatment of cancers where both EGFR overexpression and inflammation play a direct role in disease progression.

  DOI：

  10.1021/acsmedchemlett.5b00286
• 作为产物：
  描述：

  4-苄氧基-3-羟基苯甲酸乙酯 在 硫酸 、 palladium on activated charcoal 、 氢气 、 硝酸 、 甲酸铵 、 potassium carbonate 、 溶剂黄146 、 potassium hydroxide 、 三氯氧磷 作用下， 以 甲醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 生成 内匹司他盐酸盐
  参考文献：
  名称：

  新型七甲胺花青染料-埃罗替尼偶联物作为抗肿瘤剂的设计，合成和生物学评估。

  摘要：

  表皮生长因子受体酪氨酸激酶（EGFR-TK）已被证明是治疗具有特定基因突变的非小细胞肺癌（NSCLC）的靶标。但是，EGFR-TK抑制剂（EGFR-TKIs）需要进入癌细胞，然后与酪氨酸激酶受体的活性位点竞争性相互作用，以抑制下游信号通路来抑制肿瘤的增殖。在这项研究中，为了提高EGFR-TKI的肿瘤细胞靶向能力，将EGFR-TKI厄洛替尼与靶向癌细胞的七甲亚胺花青染料缀合，以形成17种新型厄洛替尼-染料缀合物。在体外评估了缀合物针对癌细胞生长和EGFR-TK抑制的肿瘤靶向特性的效率。结果显示，大多数厄洛替尼-染料偶联物比母体药物厄洛替尼对A549，H460，H1299和MDA-MB-231细胞系表现出更强的抑制作用。同时，代表性化合物对人正常乳腺上皮MCF-10A细胞表现出弱的细胞毒性。此外，共轭CE17也表现出〜14倍高的EGFR-TK抑制活性（IC 50  = 0.124μM）厄洛替尼相比（IC

  DOI：

  10.1016/j.bmcl.2020.127557

文献信息

• [EN] 4-AMINO-6-ARYL[2,3-D]PYRIMIDINES FOR THE INHIBITION OF EGFR TYROSINE KINASE<br/>[FR] 4-AMINO-6-ARYL[2,3-D]PYRIMIDINES POUR L'INHIBITION DE LA TYROSINE KINASE AU NIVEAU DE L'EGFR
  申请人：NORWEGIAN UNIV SCI & TECH NTNU

  公开号：WO2015000959A1

  公开（公告）日：2015-01-08

  This invention relates to certain new pyrrolo-, thieno-, and furo-[2,3- d]pyrimidine compounds, such as of general formula (I) These compounds are epidermal growth factor receptor tyrosine kinase inhibitors and therefore offer potential in the treatment of cancer.

  这项发明涉及某些新的吡咯基、噻吩基和呋喃基[2,3-d]嘧啶化合物，如一般式(I)所示。这些化合物是表皮生长因子受体酪氨酸激酶抑制剂，因此在癌症治疗中具有潜力。
• Identifying erlotinib-sensitive non-small cell lung carcinoma tumors in mice using [11C]erlotinib PET
  作者：Galith Abourbeh、Batel Itamar、Olga Salnikov、Sergey Beltsov、Eyal Mishani

  DOI：10.1186/s13550-014-0080-0

  日期：2015.12

  Non-small cell lung carcinoma (NSCLC) represents approximately 80% of lung cancer cases, and over 60% of these tumors express the epidermal growth factor receptor (EGFR). Activating mutations in the tyrosine kinase (TK) domain of the EGFR are detected in 10% to 30% of NSCLC patients, and evidence of their presence is a prerequisite for initiation of first-line therapy with selective TK inhibitors (TKIs), such as gefitinib and erlotinib. To date, the selection of candidate patients for first-line treatment with EGFR TKIs requires an invasive tumor biopsy to affirm the mutational status of the receptor. This study was designed to evaluate whether positron emission tomography (PET) of NSCLC tumor-bearing mice using [11C]erlotinib could distinguish erlotinib-sensitive from erlotinib-insensitive or erlotinib-resistant tumors. Four human NSCLC cell lines were employed, expressing either of the following forms of the EGFR: (i) the wild-type receptor (QG56 cells), (ii) a mutant with an exon 19 in-frame deletion (HCC827 cells), (iii) a mutant with the exon 21 L858R point mutation (NCI-H3255 cells), and (iv) a double mutant harboring the L858R and T790M mutations (NCI-H1975 cells). Sensitivity of each cell line to the anti-proliferative effect of erlotinib was determined in vitro. In vivo PET imaging studies following i.v. injection of [11C]erlotinib were carried out in nude mice bearing subcutaneous (s.c.) xenografts of the four cell lines. Cells harboring activating mutations in the EGFR TK domain (HCC827 and NCI-H3255) were approximately 1,000- and 100-fold more sensitive to erlotinib treatment in vitro, respectively, compared to the other two cell lines. [11C]Erlotinib PET scans could differentiate erlotinib-sensitive tumors from insensitive (QG56) or resistant (NCI-H1975) tumors already at 12 min after injection. Nonetheless, the uptake in HCC827 tumors was significantly higher than that in NCI-H3255, possibly reflecting differences in ATP and erlotinib affinities between the EGFR mutants. [11C]Erlotinib imaging in mice differentiates erlotinib-sensitive NSCLC tumors from erlotinib-insensitive or erlotinib-resistant ones.

  非小细胞肺癌（NSCLC）约占肺癌病例的80%，其中超过60%的肿瘤表达表皮生长因子受体（EGFR）。在EGFR的酪氨酸激酶（TK）结构域中，激活突变在NSCLC患者中的检出率为10%至30%，而这些突变的存在是启动选择性TK抑制剂（如吉非替尼和厄洛替尼）一线治疗的前提。迄今为止，为了确认受体的突变状态，选择适合一线EGFR TKI治疗的候选患者需要进行侵入性的肿瘤活检。本研究旨在评估使用[11C]厄洛替尼对NSCLC荷瘤小鼠进行正电子发射断层扫描（PET）是否能区分对厄洛替尼敏感、不敏感或耐药的肿瘤。研究采用了四种人类NSCLC细胞系，它们表达以下形式的EGFR之一：（i）野生型受体（QG56细胞），（ii）含有外显子19移码缺失的突变体（HCC827细胞），（iii）含有外显子21 L858R点突变的突变体（NCI-H3255细胞），以及（iv）携带L858R和T790M双重突变的突变体（NCI-H1975细胞）。在体外测定了各细胞系对厄洛替尼抗增殖作用的敏感性。对移植了这四种细胞系皮下异种移植瘤的裸鼠进行了静脉注射[11C]厄洛替尼后的体内PET成像研究。携带EGFR TK域激活突变的细胞系（HCC827和NCI-H3255）在体外对厄洛替尼治疗的敏感性分别比其他两个细胞系高出约1000倍和100倍。[11C]厄洛替尼PET扫描能在注射后12分钟就区分出对厄洛替尼敏感的肿瘤与不敏感（QG56）或耐药（NCI-H1975）的肿瘤。然而，HCC827肿瘤中的摄取显著高于NCI-H3255肿瘤，这可能反映了EGFR突变体之间在ATP和厄洛替尼亲和力上的差异。在鼠中，[11C]厄洛替尼成像能区分对厄洛替尼敏感的NSCLC肿瘤与不敏感或耐药的肿瘤。
• Methods of using death receptor agonists and EGFR inhibitors
  申请人：Ashkenazi J. Avi

  公开号：US20060188498A1

  公开（公告）日：2006-08-24

  Methods for using death receptor ligands, such as Apo-2 ligand/TRAIL polypeptides or death receptor antibodies, and EGFR inhibitors to treat pathological conditions such as cancer are provided. Embodiments of the invention include methods of using Apo2L/TRAIL or death receptor antibodies such as DR5 antibodies and DR4 antibodies in combination with EGFR inhibitors, such as Tarceva™.

  提供了使用死亡受体配体（如Apo-2配体/TRAIL多肽或死亡受体抗体）和EGFR抑制剂治疗癌症等病理条件的方法。发明的实施例包括使用Apo2L/TRAIL或死亡受体抗体（如DR5抗体和DR4抗体）与EGFR抑制剂（如Tarceva™）结合的方法。
• Combination therapy of her expressing tumors
  申请人：Sliwkowski X. Mark

  公开号：US20070020261A1

  公开（公告）日：2007-01-25

  The invention relates to tumors expressing HER2 and EGFR, using HER2-dimerization inhibitors (HDIs) and EGFR inhibitors.

  该发明涉及使用HER2二聚体化抑制剂（HDIs）和EGFR抑制剂来治疗表达HER2和EGFR的肿瘤。
• [EN] TUMOR TARGETING VITAMIN B12 DERIVATIVES FOR X-RAY ACTIVATED CHEMOTHERAPY<br/>[FR] DÉRIVÉS DE VITAMINE B12 CIBLANT UNE TUMEUR POUR UNE CHIMIOTHÉRAPIE ACTIVÉE PAR RAYONS X
  申请人：DARTMOUTH COLLEGE

  公开号：WO2020113130A1

  公开（公告）日：2020-06-04

  A therapeutic agent has an antineoplastic drug bonded with an X-ray-cleavable bond to cobalt of cobalamin. In embodiments, the drug is doxorubicin, paclitaxel, methotrexate, erlotinib, chlorambucil, dasatinib, SN38, colchicine, or gefitinib; and in embodiments a Cy5 fluorophore bonded to ribose of the cobalamin. The agent is formed by reducing hydroxocobalamin with zinc, reacting with 3-bromopropylamine to form aminopropyl cobalamin; and linking the drug to the aminopropyl cobalamin by conjugation through a hydroxyl group by carbamate formation with 1,1'-Carbonyl-di-(1,2,4-triazole). An optional Cy5 handle is added by coupling a 5' hydroxyl group of a ribose first with ethylene diamine and then with N-hydroxysuccinimide of Cy5. The agent treats cancer by administration in a dose expected to induce apoptosis in cells of the cancer when the light-cleavable bond is cleaved, the cancer absorbs the agent; and the cancer is exposed to X-ray or visible light to cleave the X-ray-light-cleavable bond.

  一种治疗剂，其中抗肿瘤药物与钴胺素的钴键结合，并且具有X射线可切割键。在实施例中，药物可以是阿霉素、紫杉醇、甲氨蝶呤、厄洛替尼、氯氨丁胺、达沙替尼、SN38、秋水仙碱或吉非替尼；在实施例中，Cy5荧光团结合到钴胺素的核糖上。该治疗剂通过将羟基钴胺素与锌还原，与3-溴丙胺反应形成氨基丙基钴胺素；然后通过羧酸酯化与1,1'-碳酰二-(1,2,4-三唑)将药物与氨基丙基钴胺素结合。可选地，通过首先将核糖的5'羟基与乙二胺偶联，然后与Cy5的N-羟基丁二酰亚胺偶联来添加Cy5手柄。该治疗剂通过给予预期引起癌细胞凋亡的剂量来治疗癌症，当光可切割键被切割时，癌细胞吸收该治疗剂；然后将癌细胞暴露于X射线或可见光以切割X射线光可切割键。