BMS-587101 | 509083-77-6

• 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: BMS-587101
• 英文别名: 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid；5-[(5s,9r)-9-(4-Cyanophenyl)-3-(3,5-Dichlorophenyl)-1-Methyl-2,4-Dioxo-1,3,7-Triazaspiro [4.4]non-7-Yl]methyl]-3-Thiophenecarboxylicacid；5-[[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl]methyl]thiophene-3-carboxylic acid
• CAS: 509083-77-6
• 化学式: C₂₆H₂₀Cl₂N₄O₄S
• 分子量: 555.441
• InChiKey: NXNKJLOEGWSJGI-BKMJKUGQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  37
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  133
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 BMS-587101 、 甲基磺酰胺 、 三乙胺 在 4-二甲氨基吡啶 SO2 、 二氯甲烷 、 Brine 、 silica gel 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 48.0h， 以to yield the above-titled compound (38.9 mg) as an amorphous solid along with 55.6 mg的产率得到N-{5-[(5S*,9R*)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carbonyl}-methanesulfonamide
  参考文献：
  名称：

  Spiro-hydantoin compounds useful as anti-inflammatory agents

  摘要：

  具有公式 (I) 的化合物、药学上可接受的盐、水合物、对映体、非对映异构体和其前药物，在抑制LFA-1/ICAM和作为抗炎剂方面是有用的，其中L和K是O或S；Z是N或CR4b；Ar是一个可选择的取代芳基或杂环芳基；G是连接到T或M或不存在的连接器；J、M和T被选择来定义一个三到六元饱和或部分不饱和的非芳香环；R2、R4a、R4b和R4c如规范中所定义。

  公开号：

  US06977267B2
• 作为产物：
  描述：

  3,5-二氯苯异氰酸酯 在 四氢吡咯 、 1-氯乙基氯甲酸酯 、 magnesium sulfate 、 sodium sulfate 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 70.0h， 生成 BMS-587101
  参考文献：
  名称：

  Discovery and Development of 5-[(5S,9R)-9- (4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1- methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non- 7-yl-methyl]-3-thiophenecarboxylic Acid (BMS-587101)A Small Molecule Antagonist of Leukocyte Function Associated Antigen-1

  摘要：

  LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.

  DOI：

  10.1021/jm0610806

文献信息

• Crystalline forms and process for preparing spiro-hydantoin compounds
  申请人：DelMonte J. Albert

  公开号：US20060074099A1

  公开（公告）日：2006-04-06

  A process is provided for preparing spiro-hydantoin compounds of the formula II wherein Z is N or CR 4b ; K and L are independently O or S; Ar is an optionally substituted aryl or heteroaryl; A 2 is a linker, G′ is a linker; Q is a linker; and R 2 , R 4a , R 4c , and R h are defined in the specification. The process optionally includes the enantiomeric separation of intermediates to allow preparation of enantiomers of the spiro-hydantoin compounds of formula II. Substituted spiro-hydantoin compounds may be prepared from the spiro-hydantoin compounds of formula II. The spiro-hydantoin compound of formula II and the substituted spiro-hydantoin compounds are useful in the treatment of immune or inflammatory diseases. Also, provided are products made by the instant inventive process and crystalline forms (prepared by any process) of the substituted spiro-hydantoin compound, 5-[(5S, 9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid, including solvates and salts thereof, as well as methods of use thereof. Crystalline forms of certain intermediates are provided.

  提供了一种用于制备公式II中的螺环咪唑烷酮化合物的过程，其中Z为N或CR4b；K和L分别为O或S；Ar为可选择取代的芳基或杂芳基；A2为连接物，G'为连接物；Q为连接物；R2、R4a、R4c和Rh在规范中有定义。该过程可选择包括对中间体进行对映体分离，以便制备公式II中的螺环咪唑烷酮化合物的对映体。可从公式II中的螺环咪唑烷酮化合物制备取代的螺环咪唑烷酮化合物。公式II的螺环咪唑烷酮化合物和取代的螺环咪唑烷酮化合物在治疗免疫或炎症性疾病方面具有用途。还提供了通过即时创新过程制备的产品以及取代的螺环咪唑烷酮化合物5-[(5S, 9R)-9-(4-氰基苯基)-3-(3,5-二氯苯基)-1-甲基-2,4-二氧代-1,3,7-三氮杂螺[4.4]壬-7-基甲基]-噻吩-3-羧酸的结晶形式（通过任何过程制备），包括其溶剂合物和盐，以及其使用方法。提供了某些中间体的结晶形式。
• Kilogram Synthesis of a LFA-1/ICAM Inhibitor
  作者：Albert J. DelMonte、Robert E. Waltermire、Yu Fan、Douglas D. McLeod、Zhinong Gao、Kirsten D. Gesenberg、Kevin P. Girard、Miguel Rosingana、Xuebao Wang、Jennifer Kuehne-Willmore、Alan D. Braem、John A. Castoro

  DOI：10.1021/op9003168

  日期：2010.5.21

  The process development and the kilogram-scale synthesis of BMS-587101 (1) are described. The synthesis features a [3 + 2] azomethine ylide cycloaddition to efficiently build the spirocyclic core in a diastereoselective fashion followed by a classical resolution which affords the desired enantiomer in >98% enantiomeric excess. The target was prepared in four steps in an overall yield of 22%.

  描述了BMS-587101（1）的工艺开发和千克规模的合成。合成的特征是[3 + 2]甲亚胺叶立德环加成反应，以非对映选择性方式有效构建螺环核，然后通过经典拆分得到所需对映体，其对映体过量> 98％。分四步制备靶标，总产率为22％。
• [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。