4,4’-(2-chloropyrimidine-4,6-diyl)dimorpholine | 479493-68-0

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 4,4’-(2-chloropyrimidine-4,6-diyl)dimorpholine
• 英文别名: 4,6-Dimorpholino-2-chloropyrimidine；4-(2-chloro-6-morpholin-4-ylpyrimidin-4-yl)morpholine
• CAS: 479493-68-0
• 化学式: C₁₂H₁₇ClN₄O₂
• 分子量: 284.746
• InChiKey: GPSXCDMMIZVRIP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  50.7
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4,4’-(2-chloropyrimidine-4,6-diyl)dimorpholine 在 双(三环己基膦)二氯化钯 、 carbonic acid monomethyl ester 、 溶剂黄146 、 cesium fluoride 作用下， 以 N-甲基吡咯烷酮 、 水 为溶剂， 反应 48.0h， 生成 4-[6-(morpholin-4-yl)-2-(4-nitro-phenyl)-pyrimidin-4-yl]-morpholine
  参考文献：
  名称：

  一种化合物及其制备方法和用途

  摘要：

  本发明公开了一类具有式X结构的化合物或其药学上可接受的盐及其制备方法和用途：其中R1是至少包含一个五元环或一个六元环的化学结构；R2是分子量大于100并且含有吸电子基团的化学结构。

  公开号：

  CN107793365B
• 作为产物：
  描述：

  2,4,6-三氯嘧啶 在 三乙胺 作用下， 以 乙醇 为溶剂， 反应 120.0h， 以80%的产率得到2,4-双(4-吗啉基)-6-氯嘧啶
  参考文献：
  名称：

  Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer

  摘要：

  Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocydic pyrirnidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrirnidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.

  DOI：

  10.1021/ml200156t

文献信息

• [EN] DIFLUOROMETHYL-AMINOPYRIDINES AND DIFLUOROMETHYL-AMINOPYRIMIDINES<br/>[FR] DIFLUOROMÉTHYL-AMINOPYRIDINES ET DIFLUOROMÉTHYL-AMINOPYRIMIDINES
  申请人：PIQUR THERAPEUTICS AG

  公开号：WO2016075130A1

  公开（公告）日：2016-05-19

  The invention relates to novel phosphoinositide 3-kinase (PI3K),mammalian target of rapamycin (mTOR)and PI3K-related kinase(PIKKs)inhibitor compounds of formula (I), wherein X1, X2 and X3 are N or CH, with the proviso that at least two of X1, X2 and X3 are N; Y is N or CH, These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.

  这项发明涉及一种新型的磷脂酰肌醇3-激酶（PI3K）、哺乳动物雷帕霉素靶蛋白（mTOR）和PI3K相关激酶（PIKKs）抑制剂化合物，其化学式为（I），其中X1、X2和X3为N或CH，但至少其中两个为N；Y为N或CH。这些化合物可用于单独使用或与其他治疗药物联合使用，用于治疗由脂质激酶介导的疾病。
• [EN] TREATMENT OF NEUROLOGICAL DISORDERS<br/>[FR] TRAITEMENT DES TROUBLES NEUROLOGIQUES
  申请人：PIQUR THERAPEUTICS AG

  公开号：WO2017198346A1

  公开（公告）日：2017-11-23

  The present invention is relates to a compound of formula (I), wherein X1, X2 andX3 are, independently of each other, N or CH; with the proviso that at least two of X1X2andX3 areN; Y is N or CH; R1 and R2 are independently of each other (iii)a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally substituted with one or two OH, C1-C2fhioroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C(0)0-C1- C2alkyl; or R3 and R4 form together a bivalent residue -R5R6- selected from Ci-C3alkylene optionally substituted with 1 to 4 F, -CH2-0-CH2-, -CH2-NH-CH2-, or any of the structures wherein the arrows denote the bonds in formula (II); or (iv) a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally substituted by 1 to 3 R7; wherein R7 is independently at each occurrence Ci-C3alkyl optionally substituted with one or two OH, C1-C2fluoroalkyl, C1- C2alkoxyC1-C3alkyl, C3-C6cycloalkyl; or two R7 substituents form together a bivalent residue -R8R9- selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-0-CH2- or -O- CH2CH2-0-; with the proviso that at least one of R1 and R2 is a morpholinyl of formula II; and prodrugs, metabolites, tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a neurological disorder in a subject.

  本发明涉及一种具有式(I)的化合物，其中X1、X2和X3独立地为N或CH；但至少两个X1、X2和X3为N；Y为N或CH；R1和R2独立地为(III)式的吗啉基，其中箭头表示式(I)中的键；且R3和R4独立地为H、C1-C3烷基，可选择地取代一个或两个OH、C1-C2氟烷基、C1-C2烷氧基、C1-C2烷氧基C1-C3烷基、CN或C(0)0-C1-C2烷基；或者R3和R4一起形成一种双价残基-R5R6-，所述残基选自C1-C3烷基，可选择地取代1至4个F，-CH2-0-CH2-，-CH2-NH-CH2-，或箭头表示式(II)中的键的任何结构；或者(IV)选择自硫吗啉基和哌嗪基的饱和6元杂环环Z，可选择地取代1至3个R7；其中R7在每次出现时独立地为C1-C3烷基，可选择地取代一个或两个OH、C1-C2氟烷基、C1-C2烷氧基C1-C3烷基、C3-C6环烷基；或两个R7取代基一起形成一种双价残基-R8R9-，所述残基选自C1-C3烷基，可选择地取代1至4个F，-CH2-0-CH2-或-O-CH2CH2-0-；但至少R1和R2中的一个为式II的吗啉基；以及其前药、代谢物、互变异构体、溶剂化合物和药学上可接受的盐，用于预防或治疗受体内神经系统疾病。
• [EN] TREATMENT OF SKIN LESIONS<br/>[FR] TRAITEMENT DE LÉSIONS CUTANÉES
  申请人：PIQUR THERAPEUTICS AG

  公开号：WO2017198347A1

  公开（公告）日：2017-11-23

  The present invention is relates to a compound of formula (I), wherein X1, X2 and X3 are, independently of each other, N or CH; with the proviso that at least two of X1 X2 and X3 are N; Y is N or CH; W is H or F; with the proviso that when W is F, then X1, X2 and X3 are N; R1 and R2 are independently of each other (i) a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1alkoxyC1-C3alkyl, CN, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue -R5R6- selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures wherein the arrows denote the bonds in formula (II); or (ii) a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally substituted by 1 to 3 R7; wherein R7 is independently at each occurrence C1-C3alkyl optionally substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxyC1-C3alkyl, C3-C6cycloalkyl; or two R7 substituents form together a bivalent residue-R8R9- selected from Ci-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2- or -O-CH2CH2-O-; with the proviso that at least one of R1 and R2is a morpholinyl of formula II; and prodrugs, metabolites, tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subject.

  本发明涉及一种具有式(I)的化合物，其中X1、X2和X3分别独立地为N或CH；但至少两个X1、X2和X3为N；Y为N或CH；W为H或F；但当W为F时，X1、X2和X3为N；R1和R2独立地为(i)式(II)的吗啡啉基，其中箭头表示式(I)中的键；且R3和R4独立地为H、C1-C3烷基，可选地取代一个或两个OH、C1-C2氟烷基、C1-C2烷氧基、C1烷氧基C1-C3烷基、CN或C(O)O-C1-C2烷基；或R3和R4共同形成一种双价残基-R5R6-，选择自C1-C3烷基，可选地取代1至4个F，-CH2-O-CH2-，-CH2-NH-CH2-，或箭头表示式(II)中的键的任何结构；或(ii)选择自硫吗啡啉基和哌嗪基的饱和6元杂环环Z，可选地取代1至3个R7；其中R7在每次出现时独立地为C1-C3烷基，可选地取代一个或两个OH、C1-C2氟烷基、C1-C2烷氧基C1-C3烷基、C3-C6环烷基；或两个R7取代基共同形成一种双价残基-R8R9-，选择自C1-C3烷基，可选地取代1至4个F，-CH2-O-CH2-或-O-CH2CH2-O-；但至少R1和R2中的一个为式II的吗啡啉基；以及其前药、代谢物、互变异构体、溶剂化合物和药学上可接受的盐，用于预防或治疗受试者的皮肤病变。
• [EN] METHOD OF INHIBITING HAMARTOMA TUMOR CELLS<br/>[FR] PROCÉDÉ D'INHIBITION DE CELLULES TUMORALES D'HAMARTOME
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2012109423A1

  公开（公告）日：2012-08-16

  Dimorpholinopyrimidines are useful for inhibiting growth or proliferation of hamartoma tumor cells. Because the Dimorpholinopyrimidines inhibit the growth and proliferation of hamartoma tumor cells they are also useful in treating PTEN hamartoma tumor syndromes. The therapeutic and prophylactic treatments provided by this invention are practiced by administering to a patient in need thereof an amount of a compound of dimorpholinopyrimidine derivative that is effective to inhibit growth or proliferation of the hamartoma tumor cells.

  二咪嗪吡啶是用于抑制错构瘤细胞生长或增殖的有效物质。由于二咪嗪吡啶抑制错构瘤细胞的生长和增殖，因此它们也可用于治疗PTEN错构瘤综合征。该发明提供的治疗和预防治疗方法是通过向需要的患者施用足够量的二咪嗪吡啶衍生物化合物，以有效抑制错构瘤细胞的生长或增殖。
• [EN] NOVEL MANUFACTURING PROCESS FOR TRIAZINE, PYRIMIDINE AND PYRIDINE DERIVATIVES<br/>[FR] NOUVEAU PROCÉDÉ DE FABRICATION DE DÉRIVÉS DE TRIAZINE, PYRIMIDINE ET PYRIDINE
  申请人：UNIV BASEL

  公开号：WO2015162084A1

  公开（公告）日：2015-10-29

  The invention relates to a method of manufacturing triazine, pyrimidine and pyridine derivatives of formula (I), wherein U, V, W and Z are nitrogen or carbon atoms, whereby at least one of U, V and W is nitrogen, and the other substituents are defined as in the specification, by condensing a corresponding halo-triazine, pyrimidine or pyridine in a type of Suzuki coupling with a pyridyl- or pyrimidinyl-borane, wherein the amino function is protected as a formamidine. The invention further relates to suitable intermediates and methods of manufacturing of such intermediates. Furthermore the invention relates to pure 5-(4,6-dimorpholino-1,3,5- triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine in solid form.

  该发明涉及一种制造三嗪、嘧啶和吡啶衍生物的方法，其化学式为(I)，其中U、V、W和Z为氮或碳原子，其中至少一个为氮，其他取代基如说明书中所定义，通过将相应的卤代三嗪、嘧啶或吡啶与吡啶基或嘧啶基硼烷进行铂铃偶联反应，其中氨基功能以甲酰胺基进行保护。该发明还涉及适当的中间体和制造这些中间体的方法。此外，该发明还涉及固态纯的5-(4,6-二吗啉基-1,3,5-三嗪-2-基)-4-(三氟甲基)吡啶-2-胺。