spiro[benzo[c]thiophene-1(3H),4'-piperidine]-2-oxide | 173944-44-0

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: spiro[benzo[c]thiophene-1(3H),4'-piperidine]-2-oxide
• 英文别名: spiro[benzo[c]thiophene-1(3H),4'-piperidine] 2-oxide；spiro[1H-2-benzothiophene-3,4'-piperidine] 2-oxide
• CAS: 173944-44-0
• 化学式: C₁₂H₁₅NOS
• 分子量: 221.323
• InChiKey: QHQVQVARAGAWCR-UHFFFAOYSA-N

物化性质

• 沸点：
  452.9±45.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  48.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  spiro[benzo[c]thiophene-1(3H),4'-piperidine]-2-oxide 生成 (2S)-spiro[benzo[c]thiophene-1(3H),4'-piperidine] 2-oxide
  参考文献：
  名称：

  通过拆分和不对称磺化氧化制备螺[苯并[ c ]噻吩-1（3 H），4'-哌啶]-（2 S）-氧化物的实用方法

  摘要：

  我们报告了简单而有效的方法来制备对映体纯的螺[苯并[ c ]噻吩-1（3 H），4'-哌啶]-（2 S）-氧化物（S）-1，这是合成的关键中间体速激肽受体拮抗剂的作用，是通过拆分和不对称的硫氧化作用实现的。外消旋（RS）-1可用乙腈中的（S）-（+）-扁桃酸拆分，得到（S）-1的ee > 99％。我们还描述了通过使用Davis试剂以优异的对映异构体过量和高化学收率实现硫化物5的不对称硫氧化。

  DOI：

  10.1016/s0957-4166(98)00257-2
• 作为产物：
  描述：

  2-溴苄硫醇 在 盐酸 、 正丁基锂 、 硫酸 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 生成 spiro[benzo[c]thiophene-1(3H),4'-piperidine]-2-oxide
  参考文献：
  名称：

  通过拆分和不对称磺化氧化制备螺[苯并[ c ]噻吩-1（3 H），4'-哌啶]-（2 S）-氧化物的实用方法

  摘要：

  我们报告了简单而有效的方法来制备对映体纯的螺[苯并[ c ]噻吩-1（3 H），4'-哌啶]-（2 S）-氧化物（S）-1，这是合成的关键中间体速激肽受体拮抗剂的作用，是通过拆分和不对称的硫氧化作用实现的。外消旋（RS）-1可用乙腈中的（S）-（+）-扁桃酸拆分，得到（S）-1的ee > 99％。我们还描述了通过使用Davis试剂以优异的对映异构体过量和高化学收率实现硫化物5的不对称硫氧化。

  DOI：

  10.1016/s0957-4166(98)00257-2

文献信息

• Spiro-Substituted Piperidines as Neurokinin Receptor Antagonists. II. Syntheses and NK2 Receptor-Antagonistic Activities of N-(2-Aryl-4-(spiro-substituted piperidin-1'-yl)butyl)carboxamides.
  作者：Hirokazu KUBOTA、Akio KAKEFUDA、Hitoshi NAGAOKA、Osamu YAMAMOTO、Ken IKEDA、Makoto TAKEUCHI、Tadao SHIBANUMA、Yasuo ISOMURA

  DOI：10.1248/cpb.46.242

  日期：——

  In the course of our research on spiro-compounds as neurokinin receptor antagonists, N-[2-aryl-4-(spiro-substituted piperidin-1'-yl)butyl]carboxamides were designed, based on YM-35375 (3) as a lead compound, and evaluated for NK2 receptor-antagonistic activities. Some derivatives inhibited the binding of radio-labeled neurokinin A to the NK2 receptor with IC50 values at the level of 10-9M. Among these compounds, (±)-1'-[4-(N-benzoyl-N-methylamino)-3-(3, 4-dichlorophenyl)butyl]spiro[benzo[c]thiophene-1(3H), 4'-piperidine] 2-oxide (58, YM-38336) showed 10 times more potent NK2 receptor binding affinity than compound 3 (IC50 values of 8.9 and 84nM, respectively). It showed more potent inhibitory activity (ID50 20μg/kg (i.v.)) against [β-Ala8]-NKA(4-10)-induced bronchoconstriction in guinea pigs than compound 3 (ID50 41μg/kg (i.v.)). This compound was also effective intraduodenally in the same model, exhibiting an ID50 value of 0.41μg/kg.

  在我们对作为神经激肽受体拮抗剂的螺旋化合物的研究中，基于YM-35375 (3)作为先导化合物，设计了N-[2-芳基-4-(螺旋取代吡啶-1'-基)丁基]羧酰胺，并评估了其对NK2受体的拮抗活性。一些衍生物以IC50值在10^-9M水平上抑制了放射性标记的神经激肽A与NK2受体结合。在这些化合物中，(±)-1'-[4-(N-苯甲酰-N-甲基氨基)-3-(3, 4-二氯苯基)丁基]螺[苯并[c]噻吩-1(3H), 4'-吡啶] 2-氧化物 (58，YM-38336) 的NK2受体结合亲和力比化合物3强10倍 (IC50值分别为8.9和84nM)。该化合物对由[β-Ala8]-NKA(4-10)诱导的豚鼠支气管收缩表现出更强的抑制活性 (ID50 20μg/kg (静脉注射))，相比之下化合物3的ID50为41μg/kg (静脉注射)。在同一模型中，该化合物在十二指肠给药时也显示出有效性，ID50值为0.41μg/kg。
• Heterocyclic compounds having tachykinin receptor antagonist activity
  申请人：Sankyo Company, Limited

  公开号：US06159967A1

  公开（公告）日：2000-12-12

  Compounds of the formula and quaternary ammonium ions thereof, wherein R.sup.1 and R.sup.2 are the same or different and are carbocyclic aryl or aromatic heterocyclic; A is methylene, carbonyl or sulfonyl; B is a single bond, C.sub.1 -C.sub.4 alkylene or C.sub.2 -C.sub.4, alkenylene; D is oxygen; E is C.sub.2 alkylene; G is C.sub.1 -C.sub.4 alkylene or C.sub.2 -C.sub.4 alkenylene; and L is --C(R.sup.4)(R.sup.5), wherein R.sup.4 and R.sup.5 together with the carbon atom to which they are attached represent a C.sub.5 -C.sub.10 cycloalkyl or a C.sub.5 -C.sub.10 heterocyclic. Especially preferred are compounds wherein L represents ##STR1## wherein J is a C.sub.1 -C.sub.6 alkylene; Ar is a ring carbocyclic or aromatic heterocyclic and S*.fwdarw.O is a sulfoxide in which the sulfur atom is in the 5-configuration. The compounds have tachykinin receptor antagonist activity and exhibit an activity against both the NK.sub.1 and NK.sub.2 receptors.

  式中的化合物及其季铵盐，其中R.sup.1和R.sup.2相同或不同，为碳环芳基或芳香杂环基；A为亚甲基、羰基或砜基；B为单键、C.sub.1-C.sub.4烷基或C.sub.2-C.sub.4烯基；D为氧；E为C.sub.2烷基；G为C.sub.1-C.sub.4烷基或C.sub.2-C.sub.4烯基；L为--C(R.sup.4)(R.sup.5)，其中R.sup.4和R.sup.5与其连接的碳原子一起表示C.sub.5-C.sub.10环烷基或C.sub.5-C.sub.10杂环基。特别优选的是L代表##STR1##其中J为C.sub.1-C.sub.6烷基；Ar为环状碳环或芳香杂环，S*.fwdarw.O为亚砜，其中硫原子处于5-构型。这些化合物具有肽激肽受体拮抗活性，并对NK.sub.1和NK.sub.2受体均表现出活性。
• Synthesis and NK1 receptor antagonistic activity of (±)-1-Acyl-3-(3,4-dichlorophenyl)-3-[2-(spiro-substituted piperidin-1′-yl)ethyl]piperidines
  作者：Hirokazu Kubota、Yoshinori Okamoto、Masahiro Fujii、Ken Ikeda、Makoto Takeuchi、Tadao Shibanuma、Yasuo Isomura

  DOI：10.1016/s0960-894x(98)00260-1

  日期：1998.6

  4-dichlorophenyl)-3-[2-(spiro-substituted piperidin-1'-yl)ethyl]piperidines and their quaternary ammonium salts were prepared and evaluated for their NK1 receptor antagonistic activity. Some of these inhibited SP-induced contraction in guinea pig ileum with IC50 values at a level of 10(-9) M and showed potent inhibitory activity against selective NK1 receptor agonist-induced bronchoconstriction in guinea pigs

  制备了（+/-）-1-酰基-3-（3,4-二氯苯基）-3- [2-（螺取代的哌啶-1'-基）乙基]哌啶及其季铵盐，并对其进行了评估。 NK1受体拮抗活性。其中一些抑制SP诱导的豚鼠回肠收缩，IC50值为10（-9）M，并显示出对豚鼠选择性NK1受体激动剂诱导的支气管收缩的有效抑制活性。
• Method for treating an inflammatory disease
  申请人：Sankyo Company, Limited

  公开号：US06448247B1

  公开（公告）日：2002-09-10

  Compounds of the formula and quaternary ammonium ions thereof, wherein R1 and R2 are the same or different and are carbocyclic aryl or aromatic heterocyclic; A is methylene, carbonyl or sulfonyl; B is a single bond, C1-C4 alkylene or C2-C4 alkenylene; D is oxygen or sulfur; E is C2-C6 alkylene, C1-C6 haloalkylene, C3-C6 cycloalkane-1,1-diyl or C3-C6-cycloalkane-1,1-diylmethyl; G is C1-C4 alkylene or C2-C4 alkenylene; and L is —NR3 or —C(R4)(R5), wherein R3 is a carbocyclic aryl or an aromatic heterocyclic; R4 is hydrogen, carbocyclic aryl or aromatic heterocyclic; R5 is —COR6, C1-C6 alkyl, C1-C6 alkoxy, amino, or acylamino, wherein R6 is C1-C6 alkyl or C1-C6 alkoxy, or R4 and R5 together with the carbon atom to which they are attached represent a C5-C10 cycloalkyl or a C5-C10 heterocyclic. The compounds have tachykinin receptor antagonist activity and exhibit an activity against both the NK1 and NK2 receptors.

  该分子式的化合物及其季铵盐，其中R1和R2相同或不同，为碳环芳基或芳香族杂环；A为亚甲基，羰基或磺酰基；B为单键，C1-C4烷基或C2-C4烯基；D为氧或硫；E为C2-C6烷基，C1-C6卤代烷基，C3-C6环烷-1,1-二基或C3-C6-环烷-1,1-二基甲基；G为C1-C4烷基或C2-C4烯基；L为—NR3或—C（R4）（R5），其中R3为碳环芳基或芳香族杂环；R4为氢，碳环芳基或芳香族杂环；R5为—COR6，C1-C6烷基，C1-C6烷氧基，氨基或酰胺基，其中R6为C1-C6烷基或C1-C6烷氧基，或R4和R5与它们连接的碳原子一起代表C5-C10环烷基或C5-C10杂环。这些化合物具有缓激肽受体拮抗活性，并对NK1和NK2受体均表现出活性。
• Salts of an optically-active sulfoxide derivative
  申请人：Sankyo Company, Limited

  公开号：US06362179B1

  公开（公告）日：2002-03-26

  Hydrochloride of fumarate of 1-{2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethyoxybenzoyl)morpholin-2-yl]ethyl}spiro[benzo(c)thiophene-1(3H),4′-piperidin]-(2S)-oxide. These compounds have good oral adsorption and exhibit markedly excellent antagonistic action against both NK1 receptors and NK2 receptors. These compounds are useful as an active ingredient in pharmaceutical compositions for administering to patients for treatment of tachykinin-medicated diseases.

  富马酸氢氯酸盐的1-＆lcub;2-＆lsqb;（2R）-（3,4-二氯苯基）-4-（3,4,5-三甲氧基苯甲酰）吗啡啶-2-基＆rsqb;乙基＆rcub;螺＆lsqb;苯并（c）噻吩-1（3H），4'-哌啶＆rsqb; -（2S）-氧化物。这些化合物具有良好的口服吸收性，并且对NK1受体和NK2受体均表现出显著的拮抗作用。这些化合物可用作制药组合物的活性成分，用于治疗Tachykinin介导的疾病。