4-((5S,9R)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-7-(pyridin-2-yl)-1,3,7-triazaspiro[4.4]nonan-9-yl)benzonitrile | 1224465-04-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: 4-((5S,9R)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-7-(pyridin-2-yl)-1,3,7-triazaspiro[4.4]nonan-9-yl)benzonitrile
• 英文别名: 4-[(5S,9R)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-7-pyridin-2-yl-1,3,7-triazaspiro[4.4]nonan-9-yl]benzonitrile
• CAS: 1224465-04-6
• 化学式: C₂₅H₁₉Cl₂N₅O₂
• 分子量: 492.364
• InChiKey: OERBTZBYLXYWQC-SQJMNOBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  34
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  80.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-溴吡啶 、 (+/-)-4-((5S,9R)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-9-yl)benzonitrile 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 以25%的产率得到4-((5S,9R)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-7-(pyridin-2-yl)-1,3,7-triazaspiro[4.4]nonan-9-yl)benzonitrile
  参考文献：
  名称：

  Small Molecule Antagonist of Leukocyte Function Associated Antigen-1 (LFA-1): Structure−Activity Relationships Leading to the Identification of 6-((5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic Acid (BMS-688521)

  摘要：

  Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3, 5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.

  DOI：

  10.1021/jm100348u

文献信息

• Spiro-hydantoin compounds useful as anti-inflammatory agents
  申请人：——

  公开号：US20040009998A1

  公开（公告）日：2004-01-15

  Compounds having the formula (I), and pharmaceutically-acceptable salts, hydrates, enantiomers, and diastereomers, and prodrugs thereof, 1 are useful as inhibitors of LFA-1/ICAM and as anti-inflammatory agents, wherein L and K are O or S; Z is N or CR 4b ; Ar is an optionally-substituted aryl or heteroaryl; G is a linker attached to T or M or is absent; J, M and T are selected to define a three to six membered saturated or partially unsaturated non-aromatic ring; and R 2 R 4a , R 4b , and R 4c are as defined in the specification.

  具有公式(I)的化合物，以及药用可接受的盐、水合物、对映异构体、非对映异构体和前药，可用作LFA-1/ICAM的抑制剂和作为抗炎剂，其中L和K是O或S；Z是N或CR4b；Ar是可选地取代的芳基或杂芳基；G是连接到T或M的连接剂或不存在；J、M和T被选用来定义一个三到六成员的饱和或部分不饱和的非芳香环；R2R4a, R4b, 和R4c如说明书所定义。
• [EN] SPIRO-HYDANTOIN COMPOUNDS USEFUL AS ANTI-INFLAMMATORY AGENTS<br/>[FR] COMPOSES DE SPIRO-HYDANTOINE UTILES EN TANT QU'AGENTS ANTI-INFLAMMATOIRES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2003029245A1

  公开（公告）日：2003-04-10

  Compounds having the formula (I), and pharmaceutically-acceptable salts, hydrates,enantiomers, and diastereomers, and prodrugs thereof, (I) are useful as inhibitors of LFA-1/ICAM and as anti-inflammatory agents, wherein L and K are O or S; Z is N or CR4b; Ar is an optionally-substituted aryl or heteroaryl; G is a linker attached to T or M or is absent; J, M and T are selected to define a three to six membered saturated or partially unsaturated non-aromatic ring; and R2 ,R4a, R4b, and R4c are as defined in the specification.

  具有公式（I）的化合物，以及药学上可接受的盐、水合物、对映体和二对映异构体及其前药，（I）可用作LFA-1 / ICAM的抑制剂和抗炎剂，其中L和K为O或S; Z为N或CR4b; Ar是可选取代的芳基或杂环芳基; G是连接到T或M或不存在的连接剂; J，M和T被选择为定义一个三至六元的饱和或部分不饱和非芳香族环; R2，R4a，R4b和R4c如规范中所定义。
• Pyridyl-substituted spiro-hydantoin crystalline forms and process
  申请人：Chen Bang-Chi

  公开号：US20060142319A1

  公开（公告）日：2006-06-29

  The invention provides crystalline forms of 6-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]nicotinic acid, its pharmaceutically acceptable salts, or solvates, thereof Further, a process is provided for preparing substituted spiro-hydantoin compounds of the formula I wherein Z is N or CR 4b ; K and L are independently O or S; Ar is an optionally substituted aryl or heteroaryl; A 1 , A 2 , G, and Q are linkers; and R 2 , R 4a , R 4c , and R 16 are defined in the specification. The process includes the reaction of N-substituted glycine compound and methylene precursor compound with an alkene compound. The substituted spiro-hydantoin compounds of formulae I and II are useful in the treatment of immune and/or inflammatory diseases.

  本发明提供了6-[(5S,9R)-9-(4-氰基苯基)-3-(3,5-二氯苯基)-1-甲基-2,4-二氧杂-1,3,7-三氮杂螺[4.4]壬-7-基]烟酸的晶体形式，其药学上可接受的盐或其溶剂。此外，还提供了一种制备式I的取代螺内酰脲化合物的方法，其中Z为N或CR4b；K和L独立地为O或S；Ar为可选的取代芳基或杂环芳基；A1、A2、G和Q为连接基；而R2、R4a、R4c和R16在规范中有定义。该方法包括将N-取代的甘氨酸化合物和亚甲基前体化合物与烯烃化合物反应。式I和式II的取代螺内酰脲化合物在治疗免疫和/或炎症性疾病方面是有用的。
• Pyridyl-substituted spiro-hydantoin compounds and use thereof
  申请人：Dhar Murali T.G.

  公开号：US20060148836A1

  公开（公告）日：2006-07-06

  A class of substituted spiro-hydantoin compounds (II) having the formula: its pharmaceutically acceptable salts, enantiomers, solvates, or prodrugs thereof, wherein R 16 is a substituted pyridinyl group, as defined herein, is provided. Pharmaceutical compositions and methods of treating anti-inflammatory and/or immune diseases with the pyridyl-substituted spiro-hydantoin compounds are also objectives of this invention.

  本发明提供了一类具有以下式子的取代螺内酰脲化合物(II)：其药学上可接受的盐、对映体、溶剂合物或者前药，其中R16是一种取代的吡啶基团，如本文所定义。本发明的目标还包括使用这些吡啶基取代的螺内酰脲化合物治疗抗炎和/或免疫疾病的制药组合物和方法。
• EP1432700A4
  申请人：——

  公开号：EP1432700A4

  公开（公告）日：2004-12-22