tert-butyl N-[(1s,4s)-4-(2-chloro-5-fluoronicotinamido)cyclohexyl]carbamate | 582333-07-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: tert-butyl N-[(1s,4s)-4-(2-chloro-5-fluoronicotinamido)cyclohexyl]carbamate
• 英文别名: syn-{4-[(2-chloro-5-fluoro-pyridine-3-carbonyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester
• CAS: 582333-07-1
• 化学式: C₁₇H₂₃ClFN₃O₃
• 分子量: 371.839
• InChiKey: TVLSVTSCIHZHQO-TXEJJXNPSA-N

物化性质

• 沸点：
  496.8±45.0 °C(Predicted)
• 密度：
  1.26±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.44
• 重原子数：
  25.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  80.32
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  tert-butyl N-[(1s,4s)-4-(2-chloro-5-fluoronicotinamido)cyclohexyl]carbamate 在 2-双环己基膦-2',6'-二甲氧基联苯 、 1,1'-双(二苯基膦)二茂铁 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium acetate 、 palladium diacetate 、 potassium carbonate 、 caesium carbonate 、 溶剂黄146 、 sodium sulfate 、 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 72.67h， 生成 N-((1s,4s)-4-(2-(2'-((1,4-oxazepan-4-yl)methyl)-4'-hydroxybiphenyl-3-yloxy)-5-fluoronicotinamido)cyclohexyl)-2-methylthiazole-4-carboxamide trifluoroacetic acid salt
  参考文献：
  名称：

  Efficacious Inhaled PDE4 Inhibitors with Low Emetic Potential and Long Duration of Action for the Treatment of COPD

  摘要：

  Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.

  DOI：

  10.1021/jm5001216
• 作为产物：
  描述：

  cis tert-Butyl 4-aminocyclohexylcarbamate 、 2-氯-5-氟烟酸 在 草酰氯 、 N,N-二甲基甲酰胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 36.15h， 生成 tert-butyl N-[(1s,4s)-4-(2-chloro-5-fluoronicotinamido)cyclohexyl]carbamate
  参考文献：
  名称：

  Novel compounds

  摘要：

  这项发明涉及一般式（I）的烟酰胺衍生物： 其中R 1 ，X，Y，Z和R 2 具有本文中定义的含义，并且涉及用于制备、用于制备的中间体、含有和使用这种衍生物的组合物的过程。

  公开号：

  US20050020639A1

文献信息

• [EN] NICOTINAMIDE DERIVATIVES USEFUL AS PDE4 INHIBITORS<br/>[FR] DERIVES DE NICOTINAMIDE UTILES EN TANT QU'INHIBITEURS DE PDE4
  申请人：PFIZER LTD

  公开号：WO2005009964A1

  公开（公告）日：2005-02-03

  This invention relates to nicotinamide derivatives of general formuala (I) in which R1, R2, and R3 have the meanings defined herein, and to compositions containing and the uses of such derivatives as PDE4 inhibitors.

  该发明涉及一般式（I）中的烟酰胺衍生物，其中R1、R2和R3具有本文中定义的含义，以及含有这种衍生物并将其用作PDE4抑制剂的组合物。
• Nicotinamide derivatives useful as PDE4 inhibitors
  申请人：Bailey Simon

  公开号：US20050032838A1

  公开（公告）日：2005-02-10

  This invention relates to nicotinamide derivatives of formula (I) and to processes for the preparation of, intermediates used in the preparation of, pharmaceutical compositions containing, and the uses of such derivatives: wherein R 1 is selected from the group consisting of hydrogen, methyl or halo; R 7 is attached to the 3- or 4-position of the phenyl ring and is S(O) p R 8 , R 8 is (C 1 -C 4 )alkyl optionally substituted by (C 3 -C 6 )cycloalkyl; p is 0, 1 or 2; R 6 is selected from the group consisting of hydrogen, halo, (C 1 -C 3 )alkyl and (C 1 -C 3 )alkoxy; m is 0 or 1; L is a (C 3 -C 8 )carbocyclic non-aromatic ring; R 2 is hydrogen, hydroxy, (C 1 -C 3 )alkoxy, (C 1 -C 3 )alkyl (optionally substituted by hydroxy or by (C 1 -C 3 )alkoxy), CO 2 R 9 , NR 10 R 11 or CONR 10 R 11 ; R 3 is hydrogen or (C 1 -C 3 )alkyl; R 9 is hydrogen or (C 1 -C 3 )alkyl; R 10 and R 11 are each independently hydrogen, or, are selected from the group consisting of: (C 1 -C 6 )alkyl optionally substituted by phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl is optionally substituted by one or more subsituents selected from hydroxy, halo, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy and which heterocyclic ring is optionally substituted by one or more subsituents selected from hydroxy, halo, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or oxo; (C 3 -C 8 )cycloalkyl; CO((C 1 -C 6 )alkyl) optionally substituted by hydroxy, halo, (C 3 -C 8 )cycloalkyl, (C 1 -C 3 )alkoxy, phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl is optionally substituted by one or more subsituents selected from hydroxy, halo, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy and which heterocyclic ring is optionally substituted by one or more subsituents selected from hydroxy, halo, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or oxo; CO(R 12 ), wherein R 12 is (C 3 -C 8 )cycloalkyl optionally substituted by (C 1 -C 3 )alkyl or R 12 is phenyl or a 5- or 6-membered heterocyclic ring incorporating 1 to 3 heteroatom(s) independently selected from N, O and S, which phenyl is optionally substituted by one or more subsituents selected from hydroxy, halo, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy and which heterocyclic ring is optionally substituted by one or more subsituents selected from hydroxy, halo, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or oxo; and CO 2 (C 1 -C 3 )alkyl); or R 10 and R 11 are taken together with the N atom to which they are attached to form a 5- or 6-membered lactam.

  本发明涉及化合物(I)的烟酰胺衍生物，以及制备这些衍生物的中间体的制备方法，含有这些衍生物的制药组合物，以及这些衍生物的用途：其中R1选自氢、甲基或卤素的群；R7附加到苯环的3-或4-位上，为S（O）pR8，R8为（C1-C4）烷基，可选地被（C3-C6）环烷基取代，p为0、1或2；R6选自氢、卤素、（C1-C3）烷基和（C1-C3）烷氧基的群；m为0或1；L为（C3-C8）非芳香环烷基；R2为氢、羟基、（C1-C3）烷氧基、（C1-C3）烷基（可选地被羟基或（C1-C3）烷氧基取代）、CO2R9、NR10R11或CONR10R11的群；R3为氢或（C1-C3）烷基；R9为氢或（C1-C3）烷基；R10和R11各自独立地选自以下群：（C1-C6）烷基，可选地被苯基或包含1至3个杂原子（独立选自N、O和S）的5-或6-成员杂环取代，其中苯基可选地被一个或多个亚基选自羟基、卤素、（C1-C3）烷基或（C1-C3）烷氧基，而杂环可选地被一个或多个亚基选自羟基、卤素、（C1-C3）烷基、（C1-C3）烷氧基或氧代基；（C3-C8）环烷基；CO（（C1-C6）烷基），可选地被羟基、卤素、（C3-C8）环烷基、（C1-C3）烷氧基、苯基或包含1至3个杂原子（独立选自N、O和S）的5-或6-成员杂环取代，其中苯基可选地被一个或多个亚基选自羟基、卤素、（C1-C3）烷基或（C1-C3）烷氧基，而杂环可选地被一个或多个亚基选自羟基、卤素、（C1-C3）烷基、（C1-C3）烷氧基或氧代基；CO（R12），其中R12为（C3-C8）环烷基，可选地被（C1-C3）烷基取代，或R12为苯基或包含1至3个杂原子（独立选自N、O和S）的5-或6-成员杂环，其中苯基可选地被一个或多个亚基选自羟基、卤素、（C1-C3）烷基或（C1-C3）烷氧基，而杂环可选地被一个或多个亚基选自羟基、卤素、（C1-C3）烷基、（C1-C3）烷氧基或氧代基；以及R10和R11一起与它们所附着的N原子形成5-或6-成员内酰胺。
• NOVEL COMPOUNDS
  申请人：Smith Mya Coral Helen

  公开号：US20070066645A1

  公开（公告）日：2007-03-22

  This invention relates to nicotinamide derivatives of general formula (I): in which R 1 , X, Y, Z and R 2 have the meanings defined herein, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of such derivatives.

  本发明涉及一般式（I）的烟酰胺衍生物： 其中R1、X、Y、Z和R2的含义如此定义，并涉及用于制备、制备中间体、含有和使用这些衍生物的组合物的过程。
• Compounds
  申请人：Barber Christohper Gordon

  公开号：US20090035313A1

  公开（公告）日：2009-02-05

  This invention relates to nicotinamide derivatives of general formula (I): in which R 1 , Z and R 2 have the meanings defined herein, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of such derivatives.

  本发明涉及一般式（I）的烟酰胺衍生物，其中R1、Z和R2具有本文所定义的含义，以及用于制备、制备中间体、含有和使用此类衍生物的组合物的过程。
• NICOTINAMIDE DERIVATIVES USEFUL AS PDE4 INHIBITORS
  申请人：Pfizer Limited

  公开号：EP1476158B1

  公开（公告）日：2007-11-14