1-azetidin-3-ylpiperidin-4-ol | 178311-52-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 1-azetidin-3-ylpiperidin-4-ol
• 英文别名: 1-(Azetidin-3-YL)piperidin-4-OL
• CAS: 178311-52-9
• 化学式: C₈H₁₆N₂O
• 分子量: 156.228
• InChiKey: IHGNBJWWDCIHNA-UHFFFAOYSA-N

物化性质

• 沸点：
  289.3±25.0 °C(Predicted)
• 密度：
  1.155±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  35.5
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-carboxylic acid 、 1-azetidin-3-ylpiperidin-4-ol 在 2-氯-1-甲基吡啶碘化物 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.08h， 以26%的产率得到(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)(3-(4-hydroxypiperidin-1-yl)azetidin-1-yl)methanone
  参考文献：
  名称：

  [EN] BICYCLIC PYRIMIDINE PI3K INHIBITOR COMPOUNDS SELECTIVE FOR P110 DELTA, AND METHODS OF USE
  [FR] COMPOSÉS PYRIMIDINES BICYCLIQUES INHIBITEURS DE PI3K SÉLECTIFS POUR P110 DELTA, ET PROCÉDÉS D'UTILISATION

  摘要：

  公式（I）（（Ia）和（Ib））化合物，其中（i）X1为N且X2为S，（ii）X1为CR7且X2为S，（iii）X1为N且X2为NR2，或（iv）X1为CR7且X2为O，包括其立体异构体，互变异构体，代谢物和药用可接受盐，用于抑制PI3K的δ异构体，并用于治疗由脂质激酶介导的疾病，如炎症，免疫和癌症。公开了使用公式（I）化合物进行体外，体内和体内诊断，预防或治疗哺乳动物细胞中的这类疾病或相关病理状况的方法。

  公开号：

  WO2010138589A1
• 作为产物：
  描述：

  tert-Butyl 3-(4-hydroxypiperidin-1-yl)azetidine-1-carboxylate 在 甲醇 、 desired product 作用下， 以 trifluoracetic acid-dichloromethane 为溶剂， 反应 7.0h， 以to give 1-Azetidin-3-ylpiperidin-4-ol as a colourless oil (0.194 g, 94%)的产率得到1-azetidin-3-ylpiperidin-4-ol
  参考文献：
  名称：

  BICYCLIC PYRIMIDINE PI3K INHIBITOR COMPOUNDS SELECTIVE FOR P110 DELTA, AND METHODS OF USE

  摘要：

  Formula I（Ia和Ib）化合物中，其中（i）X1为N且X2为S，（ii）X1为CR7且X2为S，（iii）X1为N且X2为NR2，或（iv）X1为CR7且X2为0，包括立体异构体，互变异构体，代谢物和药学上可接受的盐，有用于抑制PI3K的δ异构体，并用于治疗由脂质激酶介导的疾病，例如炎症，免疫和癌症。公开了使用Formula I化合物的方法，用于哺乳动物细胞中的体外，体内和原位诊断，预防或治疗此类疾病或相关病理条件。

  公开号：

  US20120178736A1

文献信息

• Structure−Activity Relationships of 1-Alkyl-5-(3,4-dichlorophenyl)- 5-{2-[(3-substituted)-1-azetidinyl]ethyl}-2-piperidones. 1. Selective Antagonists of the Neurokinin-2 Receptor
  作者：A. Roderick MacKenzie、Allan P. Marchington、Donald S. Middleton、Sandra D. Newman、Barry C. Jones

  DOI：10.1021/jm0209331

  日期：2002.11.1

  The design, synthesis, and pharmacological evaluation of a novel class of neurokinin-2 (NK2) antagonists 1-alkyl-5-(3,4-dichlorophenyl)-5-[2-[(3-substituted)-1-azetidinyl]ethyl]-2-piperidones (5-44) are described. These compounds are formally derived from 2 by incorporating the metabolically vulnerable N-methylamide function into a more stable six-membered ring lactam 4, resulting in increased stability

  一类新型神经激肽2（NK2）拮抗剂1-烷基-5-（3,4-二氯苯基）-5- [2-[（3-取代）-1-氮杂环丁烷基]拮抗剂的设计，合成和药理学评估描述了乙基] -2-哌啶酮（5-44）。这些化合物通过将易代谢的N-甲基酰胺功能并入更稳定的六元环内酰胺4中而正式从2衍生而来，从而相对于2（T1 / 2（HLM） 30分钟vs <10分钟2）。通过用简单的3-取代的氮杂环丁烷取代4中发现的4,4-二取代的哌啶官能团，进一步优化了该系列。该系列以1-苄基-5-（3,4-二氯苯基）-5- [2- [3-（4-吗啉基）-1-氮杂环丁烷基]乙基] -2-哌啶酮5为例 相对于4种药物，发现其在兔肺动脉（RPA）分析中对NK2受体具有出色的功能效能（pA2 = 9.3），并具有更高的体外代谢稳定性（T1 / 2（HLM）= 70分钟）。代谢途径鉴定研究结果表明，在这种相对亲脂的铅中，N-苄基氧化是主要途径（log
• Azetidine compounds
  申请人：Johansson Anders

  公开号：US20060172988A1

  公开（公告）日：2006-08-03

  The present invention relates to a compound of the general formula (I) wherein Het is an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring having at least one nitrogen atom; R1 is hydrogen, hydroxy, C 1 -C 4 alkyl, C 3 -C 4 C 2 -C 4 alkenyl or C 2 -C 4 alkynyl; R2 and R3 is each and independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, halogen and cyano, provided that R2 and R3 may not both be hydrogen; R4 is C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl; Ar is an optionally substituted aromatic ring system selected from pyridinyl; 1-naphthyl; 5,6,7,8-tetrahydro-1-naphthyl; quinolinyl; 2,3-dihydro-1,4-benzodioxinyl; 1,3-benzodioxolyl; 5,6,7,8-tetrahydroquinolinyl; 5,6,7,8-tetrahydroisoquinolinyl; 5,6,7,8-tetrahydroquinazolin-4-yl; 1-benzo[b]thiophen-7-yl; 1-benzo[b]thiophen-4-yl; 1-benzo[b]thiophen-3-yl; isoquinolinyl; quinazolinyl; and indan-4-yl; or Ar is substituted phenyl; or an enantiomer thereof or any salt thereof; to a pharmaceutical composition containing said compounds and to the use of said compounds in therapy. The present invention further relates to processes for the preparation of compounds of formula I and to new intermediates used in the preparation thereof.

  本发明涉及一种通式（I）的化合物，其中Het是具有至少一个氮原子的可选取代的4-、5-、6-或7-成员杂环环；R1是氢、羟基、C1-C4烷基、C3-C4C2-C4烯基或C2-C4炔基；R2和R3各自独立地选自氢、C1-C4烷基、C3-C4环烷基、C2-C4烯基、C2-C4炔基、C1-C4烷氧基、卤素和氰基，但R2和R3不能同时为氢；R4是C1-C4烷基、C3-C4环烷基、C2-C4烯基或C2-C4炔基；Ar是从吡啶基；1-萘基；5,6,7,8-四氢-1-萘基；喹啉基；2,3-二氢-1,4-苯并二氧杂环基；1,3-苯并二氧杂环基；5,6,7,8-四氢喹啉基；5,6,7,8-四氢异喹啉基；5,6,7,8-四氢喹唑啉-4-基；1-苯并[b]噻吩-7-基；1-苯并[b]噻吩-4-基；1-苯并[b]噻吩-3-基；异喹啉基；喹唑啉基和茚-4-基中选择的可选取代芳环系统；或Ar是取代的苯基；或其对映体或任何盐；以及包含该化合物的制药组合物和在治疗中使用该化合物的用途。本发明还涉及制备式I化合物的方法以及用于制备其中间体的新中间体。
• 3-aza and 3-oxa piperidone tachykinin antagonists
  申请人：Pfizer Inc.

  公开号：US05846965A1

  公开（公告）日：1998-12-08

  Compounds of the formula: ##STR1## wherein: X is O, NH or NR.sup.1 ; R.sup.1 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.7 cycloalkyl(C.sub.1 -C.sub.4)alkyl, aryl or aryl (C.sub.1 -C.sub.4)alkyl; wherein the C.sub.1 -C.sub.6 alkyl group is optionally substituted by fluorine and the C.sub.3 -C.sub.7 cycloalkyl or C.sub.3 -C.sub.7 cycloalkyl(C.sub.1 -C.sub.4 )alkyl group is optionally substituted in the cycloalkyl ring by up to two substituents each independently selected from halo, C.sub.1 -C.sub.4 alkoxy or halo(C.sub.1 -C.sub.4)alkoxy; R.sup.2 is phenyl optionally substituted with one or two halo substituents, indolyl or thienyl; R.sup.3 is NH.sub.2, --NR.sup.4 SO.sub.2 (C.sub.1 -C.sub.6 alkyl), --NR.sup.4 SO.sub.2 aryl, --NR.sup.4 CO(C.sub.1 -C.sub.6 alkyl), --NR.sup.4 CO aryl or a 5 to 7-membered N-linked cyclic group incorporating W in the ring wherein W is O, NR.sup.5, CH(OH), CHCO.sub.2 H, CHN(R.sup.4).sub.2, CHF, CF.sub.2, C.dbd.O or CH.sub.2 ; R.sup.4 is H or C.sub.1 -C.sub.6 alkyl; R.sup.5 is H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.7 cycloalkyl(C.sub.1 -C.sub.6)alkyl, C.sub.2 -C.sub.6 alkanoyl, C.sub.4 -C.sub.8 cycloalkanoyl, C.sub.3 -C.sub.7 cycloalkyl(C.sub.2 -C.sub.6)alkanoyl, aryl CO--, C.sub.1 -C.sub.6 alkyl SO.sub.2 --, C.sub.3 -C.sub.7 cycloalkyl SO.sub.2 --, C.sub.3 -C.sub.7 cycloalkyl(C.sub.1 -C.sub.6)alkyl SO.sub.2 --, aryl-SO.sub.2 -- or (R.sup.6).sub.2 NSO.sub.2 --, wherein each R.sup.6 is independently H or C.sub.1 -C.sub.4 alkyl or the two groups may be joined to form with the nitrogen atom to which they are attached, a pyrrolidinyl, piperidino, morphlino or piperazinyl group; m is 0, 1 or 2 with the proviso that m is not 0 when W is NR.sup.5, C.dbd.O, or O; and n is an integer of from 1 to 4; are neurokinin receptor antagonists of utility in the treatment of a variety of medical conditions including urinary incontinence, asthma and related conditions.

  分子式为：##STR1## 其中：X为O、NH或NR.sup.1；R.sup.1为C.sub.1-C.sub.6烷基、C.sub.3-C.sub.7环烷基、C.sub.3-C.sub.7环烷基(C.sub.1-C.sub.4)烷基、芳基或芳基(C.sub.1-C.sub.4)烷基；其中，C.sub.1-C.sub.6烷基可以选择性地被氟取代，C.sub.3-C.sub.7环烷基或C.sub.3-C.sub.7环烷基(C.sub.1-C.sub.4)烷基可以在环烷基环中被最多两个取代基取代，每个取代基可以独立地选择自卤素、C.sub.1-C.sub.4烷氧基或卤代(C.sub.1-C.sub.4)烷氧基；R.sup.2为苯基，可以选择性地用一个或两个卤素取代基、吲哚基或噻吩基；R.sup.3为NH.sub.2、--NR.sup.4 SO.sub.2 (C.sub.1-C.sub.6烷基)、--NR.sup.4 SO.sub.2芳基、--NR.sup.4 CO(C.sub.1-C.sub.6烷基)、--NR.sup.4 CO芳基或包含W的5至7成员N-连接环状基团，其中W为O、NR.sup.5、CH(OH)、CHCO.sub.2H、CHN(R.sup.4).sub.2、CHF、CF.sub.2、C.dbd.O或CH.sub.2；R.sup.4为H或C.sub.1-C.sub.6烷基；R.sup.5为H、C.sub.1-C.sub.6烷基、C.sub.3-C.sub.7环烷基、C.sub.3-C.sub.7环烷基(C.sub.1-C.sub.6)烷基、C.sub.2-C.sub.6烷酰基、C.sub.4-C.sub.8环烷酰基、C.sub.3-C.sub.7环烷基(C.sub.2-C.sub.6)烷酰基、芳基CO--、C.sub.1-C.sub.6烷基SO.sub.2--、C.sub.3-C.sub.7环烷基SO.sub.2--、C.sub.3-C.sub.7环烷基(C.sub.1-C.sub.6)烷基SO.sub.2--、芳基-SO.sub.2--或(R.sup.6).sub.2NSO.sub.2--，其中每个R.sup.6独立地为H或C.sub.1-C.sub.4烷基，或这两个基团可以连接到它们附着的氮原子上，形成吡咯烷基、哌嗪基、吗啉基或哌嗪基；m为0、1或2，但当W为NR.sup.5、C.dbd.O或O时，m不为0；n为1至4的整数。这些神经激肽受体拮抗剂可用于治疗多种医疗条件，包括尿失禁、哮喘及相关疾病。
• Bicyclic pyrimidine PI3K inhibitor compounds selective for P110 delta, and methods of use
  申请人：Genentech, Inc.

  公开号：US08173650B2

  公开（公告）日：2012-05-08

  Formula I (Ia and Ib) compounds wherein (i) X1 is N and X2 is S, (ii) X1 is CR7 and X2 is S, (iii) X1 is N and X2 is NR2, or (iv) X1 is CR7 and X2 is O, including stereoisomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting the delta isoform of PI3K, and for treating disorders mediated by lipid kinases such as inflammation, immunological, and cancer. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

  Formula I（Ia和Ib）化合物，其中（i）X1为N且X2为S，（ii）X1为CR7且X2为S，（iii）X1为N且X2为NR2，或（iv）X1为CR7且X2为O，包括立体异构体，互变异构体，代谢物和其药学上可接受的盐，对于抑制PI3K的δ异构体以及治疗由脂质激酶介导的疾病如炎症，免疫和癌症等有用。公开了使用Formula I化合物的方法，用于哺乳动物细胞中体外，体内和原位诊断，预防或治疗此类疾病或相关病理条件。
• Structure–activity relationships of 1-alkyl-5-(3,4-dichlorophenyl)-5-{2-[3-(substituted)-1-azetidinyl]-ethyl}-2-piperidones. Part 2: Improving oral absorption
  作者：Donald S. Middleton、A. Roderick MacKenzie、Sandra D. Newman、Martin Corless、Andrew Warren、Allan P. Marchington、Barry Jones

  DOI：10.1016/j.bmcl.2005.05.134

  日期：2005.9

  A series of piperidone analogues of 1b-q, seeking replacements for the polar sulfamide moiety in clinical candidate UK-224,671- 1a, possessing reduced H-bonding potential as a strategy to improve oral absorption, were prepared. These studies led to the successful identification of In, which demonstrated equivalent pharmacology and metabolic stability to la, and greatly improved oral absorption as assessed in rat PK studies. (c) 2005 Elsevier Ltd. All rights reserved.