2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide monohydrochloride | 1402152-26-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide monohydrochloride
• 英文别名: 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide monohydrochloride
• CAS: 1402152-26-4
• 化学式: C₂₃H₂₈N₈O₄*ClH
• 分子量: 516.987
• InChiKey: CLMVIXVYZUJPOI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.08
• 重原子数：
  36.0
• 可旋转键数：
  7.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  139.79
• 氢给体数：
  2.0
• 氢受体数：
  11.0

反应信息

• 作为产物：
  描述：

  4-羟基-3-甲氧基-2-硝基苯甲醛 在 盐酸 、 4-二甲氨基吡啶 、 C₉H₁₉N₃*ClH 、 5% Pd-1%Fe/C 、 氢气 、 potassium carbonate 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， -5.0~75.0 ℃ 、10.0 MPa 条件下， 反应 53.75h， 生成 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide monohydrochloride
  参考文献：
  名称：

  [EN] SYNTHESIS OF COPANLISIB AND ITS DIHYDROCHLORIDE SALT
  [FR] SYNTHÈSE DE COPANLISIB ET DE SON SEL DICHLORHYDRATE

  摘要：

  本发明涉及一种制备科帕利西布和科帕利西布盐酸二水合物的新方法，涉及新的中间化合物，以及利用这些新的中间化合物制备科帕利西布的用途。

  公开号：

  WO2016071426A1

文献信息

• Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts
  申请人：Bayer Pharma Aktiengesellschaft

  公开号：EP2508525A1

  公开（公告）日：2012-10-10

  The present invention relates : - to 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo-[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride salt of formula (II) : or a tautomer, solvate or hydrate thereof ; - to methods of preparing said dihydrochloride salt ; - to said dihydrochloride salt for the treatment and/or prophylaxis of a disease; - to the use of said dihydrochloride salt for the preparation of a medicament for the treatment and/or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, more particularly for the treatment or prophylaxis of a cancer, particularly lung cancer, in particular non-small cell lung carcinoma, colorectal cancer, melanoma, pancreatic cancer, hepatocyte carcinoma, pancreatic cancer, hepatocyte carcinoma or breast cancer ; - to a pharmaceutical composition comprising said dihydrochloride salt ; and - to a pharmaceutical combination comprising said dihydrochloride salt in combination with one or more further pharmaceutical agents.

  本发明涉及以下内容：公式（II）的2-氨基-N-[7-甲氧基-8-(3-吗啡啶-4-基丙氧基)-2,3-二氢咪唑[1,2-c]喹唑啉-5-基]嘧啶-5-羧酰胺二盐，或其互变异构体、溶剂合物或水合物；制备所述二盐的方法；所述二盐用于治疗和/或预防疾病；所述二盐用于制备用于治疗和/或预防疾病的药物，特别是用于治疗或预防癌症，尤其是肺癌、非小细胞肺癌、结直肠癌、黑色素瘤、胰腺癌、肝细胞癌或乳腺癌等高增殖和/或血管生成紊乱；包括所述二盐的药物组合物；以及包括所述二盐与一个或多个其他药物剂的药物组合。
• [EN] SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINE SALTS<br/>[FR] SELS DE 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINE SUBSTITUÉS
  申请人：BAYER PHARMA AG

  公开号：WO2012136553A1

  公开（公告）日：2012-10-11

  The present invention relates : - to 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo- [1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride salt of formula (II) : or a tautomer, solvate or hydrate thereof; - to methods of preparing said dihydrochloride salt; - to said dihydrochloride salt for the treatment and/or prophylaxis of a disease; - to the use of said dihydrochloride salt for the preparation of a medicament for the treatment and/or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, more particularly for the treatment or prophylaxis of a cancer, particularly lung cancer, in particular non-small cell lung carcinoma, colorectal cancer, melanoma, pancreatic cancer, hepatocyte carcinoma, pancreatic cancer, hepatocyte carcinoma or breast cancer; - to a pharmaceutical composition comprising said dihydrochloride salt; and - to a pharmaceutical combination comprising said dihydrochloride salt in combination with one or more further pharmaceutical agents.

  本发明涉及以下内容： - 公式（II）的2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑[1,2-c]喹唑啉-5-基]嘧啶-5-羧酰胺二盐酸盐；或其互变异构体、溶剂合物或水合物； - 制备所述二盐酸盐的方法； - 用于治疗和/或预防疾病的该二盐酸盐； - 用于制备治疗和/或预防疾病的药物的该二盐酸盐的用途，特别是用于治疗和/或预防增殖过度和/或血管生成紊乱，更具体地用于治疗或预防癌症，特别是肺癌、非小细胞肺癌、结肠癌、黑色素瘤、胰腺癌、肝细胞癌或乳腺癌； - 包含所述二盐酸盐的药物组合物；以及 - 包含所述二盐酸盐与一个或多个其他药物制剂组合物的药物组合物。
• [EN] USE OF SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINES<br/>[FR] UTILISATION DE 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINES SUBSTITUÉES
  申请人：BAYER PHARMA AG

  公开号：WO2016142313A1

  公开（公告）日：2016-09-15

  The present invention relates to : - use of a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or of a pharmaceutical composition containing same, as a sole active agent, or of a combination of a) said compound or a pharmaceutical composition containing said compound and b) one or more further active agents, for the preparation of a medicament for the treatment or prophylaxis of endometrial cancer (hereinafter abbreviated to "EC"), particularly 1st line, 2nd line, relapsed, refractory, type I or type II EC, or endometriosis; - combinations of a) said compound and b) one or more further active agents; - a pharmaceutical composition comprising said compound as a sole active agent for the treatment of endometrial cancer (hereinafter abbreviated to "EC"), particularly 1st line, 2nd line, relapsed, refractory, type I or type II EC, or endometriosis; - a pharmaceutical composition comprising a combination of a) said compound and b) one or more further active agents; - use of biomarkers which is the loss of tumor suppressor PTEN or FBXW7, for predicting the sensitivity and/or resistance of a cancer patient to said compound and providing a rationale-based dosage to increase sensitivity and/or to overcome resistance; - a method of determining the loss of tumor suppressor PTEN or FBXW7; and - a method for determining perturbations in PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, FGFR1, FGFR2, FGFR3 and/or FGFR4.

  本发明涉及以下内容：- 使用2,3-二氢咪唑[1,2-c]喹唑啉化合物或含有该化合物的药物组成物作为唯一活性剂，或使用a) 该化合物或含有该化合物的药物组成物和b) 一种或多种进一步的活性剂的组合，用于制备治疗或预防子宫内膜癌（以下简称“EC”），特别是1线、2线、复发、难治、I型或II型EC或子宫内膜异位症的药物；- a) 该化合物和b) 一种或多种进一步的活性剂的组合；- 仅包含该化合物作为唯一活性剂的药物组成物，用于治疗子宫内膜癌（以下简称“EC”），特别是1线、2线、复发、难治、I型或II型EC或子宫内膜异位症；- 包含a) 该化合物和b) 一种或多种进一步的活性剂的药物组成物；- 使用生物标志物，即肿瘤抑制剂PTEN或FBXW7的丧失，来预测癌症患者对该化合物的敏感性和/或抗药性，并提供基于理性的剂量以增加敏感性和/或克服抗药性；- 确定肿瘤抑制剂PTEN或FBXW7的丧失的方法；以及- 确定PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4扰动的方法。
• [EN] USE OF SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINES FOR TREATING LYMPHOMAS<br/>[FR] UTILISATION DE 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINES SUBSTITUÉES POUR LE TRAITEMENT DE LYMPHOMES
  申请人：BAYER PHARMA AKTIENGESLLSCHAFT

  公开号：WO2014166820A1

  公开（公告）日：2014-10-16

  - use of a 2,3-dihydroimidazo[l,2-c]quinazoline compound, or of a pharmaceutical composition containing same, as a sole active agent, or of a combination of a) said compound or a pharmaceutical composition containing said compound and b) one or more fu rther active agents, for the preparation of a medicament for the treatment or prophylaxis of non-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL); - combinations of a) said compound and b) one or more further active agents; - a pharmaceutical composition comprising said compound as a sole active agent for the treatment of non-Hodgkin's lymphoma (NHL), particularly 1st line, 2nd line, relapsed, refractory, indolent or agressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed lymphoma (TL), or peripheral T-cell lymphoma (PTCL); - a pharmaceutical composition comprising a combination of a) said compound and b) one or more further active agents; - use of biomarkers involved in the modification of the expression of PI3K isoforms, BTK and IKK,, BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZH2, for predicting the sensitivity and/or resistance of a cancer patient to said compound and providing a rationale-based synergistic combination as defined herein to increase sensitivity and/or to overcome resistance; and - a method of determining the level of a component of one or more of the expression of PI3K isoforms, BTK and IKK„ BCR activation, BCR downstream activation of NFKB pathway, c-Myc, EZH2.

  使用2,3-二氢咪唑[1,2-c]喹唑啉化合物或含有该化合物的药物组合物作为唯一活性剂，或使用a)该化合物或含有该化合物的药物组合物和b)一个或多个其他活性剂的组合，用于制备用于治疗或预防非霍奇金淋巴瘤（NHL）的药物，特别是一线、二线、复发、难治、慢性或侵袭性非霍奇金淋巴瘤（NHL），特别是滤泡性淋巴瘤（FL）、慢性淋巴细胞白血病（CLL）、边缘区淋巴瘤（MZL）、弥漫性大B细胞淋巴瘤（DLBCL）、曼托细胞淋巴瘤（MCL）、转化淋巴瘤（TL）或外周T细胞淋巴瘤（PTCL）；a)该化合物和b)一个或多个其他活性剂的组合；仅包含该化合物作为唯一活性剂的药物组合物，用于治疗非霍奇金淋巴瘤（NHL），特别是一线、二线、复发、难治、慢性或侵袭性非霍奇金淋巴瘤（NHL），特别是滤泡性淋巴瘤（FL）、慢性淋巴细胞白血病（CLL）、边缘区淋巴瘤（MZL）、弥漫性大B细胞淋巴瘤（DLBCL）、曼托细胞淋巴瘤（MCL）、转化淋巴瘤（TL）或外周T细胞淋巴瘤（PTCL）；仅包含a)该化合物和b)一个或多个其他活性剂的药物组合物；使用涉及PI3K亚型、BTK和IKK、BCR激活、BCR下游NFKB通路激活、c-Myc、EZH2表达修饰的生物标志物，预测癌症患者对该化合物的敏感性和/或耐药性，并提供基于理性的协同组合，以增加敏感性和/或克服耐药性；以及确定PI3K亚型、BTK和IKK、BCR激活、BCR下游NFKB通路激活、c-Myc、EZH2表达的一个或多个组分水平的方法。
• Use of substituted 2,3-dihydroimidazo[1,2-C]quinazolines
  申请人：Liu Ningshu

  公开号：US10202385B2

  公开（公告）日：2019-02-12

  The present invention relates to: —use of a 2,3-dihydroimidazo[1,2-c]quinazoline compound, or of a pharmaceutical composition containing same, as a sole active agent, or of a combination of a) said compound or a pharmaceutical composition containing said compound and b) one or more further active agents, for the preparation of a medicament for the treatment or prophylaxis of cancer; —combinations of a) said compound and b) one or more further active agents; —a pharmaceutical composition comprising said compound as a sole active agent for the treatment of breast cancer; —a pharmaceutical composition comprising a combination of a) said compound and b) one or more further active agents; —use of biomarkers involved in the modification of Bel expression, HER family expression and/or activation, PIK3CA signaling and/or loss of PTEN for predicting the sensitivity and/or resistance of a cancer patient to said compound and providing a rationale-based synergistic combination as defined herein to increase sensitivity and/or to overcome resistance; and —a method of determining the level of a component of one or more of Bcl expression, HER family expression and/or activation, PIK3CA signaling and/or loss of PTEN.

  本发明涉及以下内容：-使用2,3-二氢咪唑并[1,2-c]喹唑啉化合物或含有该化合物的药物组合物作为唯一活性成分，或a)该化合物或含有该化合物的药物组合物和b)一个或多个进一步的活性成分的组合，用于制备用于治疗或预防癌症的药物；-a)该化合物和b)一个或多个进一步的活性成分的组合；-仅含有该化合物作为唯一活性成分的药物组合物，用于治疗乳腺癌；-含有a)该化合物和b)一个或多个进一步的活性成分的药物组合物；-使用涉及Bel表达的修饰、HER家族表达和/或激活、PIK3CA信号传导和/或PTEN丧失的生物标志物来预测癌症患者对该化合物的敏感性和/或耐药性，并提供基于理性的协同组合，以增强敏感性和/或克服耐药性；以及-确定Bcl表达、HER家族表达和/或激活、PIK3CA信号传导和/或PTEN的一个或多个组分的水平的方法。