1'-methyl-2,3,6,7-tetrahydrospiroindole-3,4'-piperidine> | 180082-56-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1'-methyl-2,3,6,7-tetrahydrospiroindole-3,4'-piperidine>
• 英文别名: 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]-indole-3,4'-piperidine]；1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine]；1'-Methylspiro[2,5,6,7-tetrahydrofuro[2,3-f]indole-3,4'-piperidine]
• CAS: 180082-56-8
• 化学式: C₁₅H₂₀N₂O
• 分子量: 244.337
• InChiKey: FSMAYISEEYGVRG-UHFFFAOYSA-N

物化性质

• 沸点：
  402.5±45.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  18
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  24.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-biphenyl-4-carbonyl chloride 、 1'-methyl-2,3,6,7-tetrahydrospiroindole-3,4'-piperidine> 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 72.0h， 以30%的产率得到[2'-甲基-4'-(5-甲基-1,2,4-恶二唑-3-基)[1,1'-联苯基]-4-基](2,5,6,7-四氢-1'-甲基螺[3H-呋喃并[2,3-F]吲哚-3,4'-哌啶]-5-基)甲酮
  参考文献：
  名称：

  The Selective 5-HT_1B Receptor Inverse Agonist 1‘-Methyl-5-[[2‘-methyl-4‘- (5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro- spiro[furo[2,3-f]indole-3,4‘-piperidine] (SB-224289) Potently Blocks Terminal 5-HT Autoreceptor Function Both in Vitro and in Vivo

  摘要：

  5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are negatively Linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1D beta and 5-HT1D alpha, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagonist 4 was structurally modified to produce the selective 5-HT1B receptor inverse agonist 5, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.

  DOI：

  10.1021/jm970457s
• 作为产物：
  描述：

  1-acetyl-6-bromo-2,3-dihydro-5-<(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy>-1H-indole 在 盐酸 、 偶氮二异丁腈 、 三正丁基氢锡 作用下， 以 乙醇 、 苯 为溶剂， 反应 24.0h， 生成 1'-methyl-2,3,6,7-tetrahydrospiroindole-3,4'-piperidine>
  参考文献：
  名称：

  The Selective 5-HT_1B Receptor Inverse Agonist 1‘-Methyl-5-[[2‘-methyl-4‘- (5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro- spiro[furo[2,3-f]indole-3,4‘-piperidine] (SB-224289) Potently Blocks Terminal 5-HT Autoreceptor Function Both in Vitro and in Vivo

  摘要：

  5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are negatively Linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1D beta and 5-HT1D alpha, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagonist 4 was structurally modified to produce the selective 5-HT1B receptor inverse agonist 5, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.

  DOI：

  10.1021/jm970457s

文献信息

• Tetracyclic spiro compounds, process for their preparation and their use
  申请人：SmithKline Beecham plc

  公开号：US05972951A1

  公开（公告）日：1999-10-26

  Novel piperidine derivatives of formula (I), processes for their preparation, pharmaceutical compositions containing them and their use as medicaments for the treatment of CNS disorders are disclosed.

  披露了公式(I)的新哌啶衍生物，它们的制备过程，含有它们的药物组合物以及它们作为治疗中枢神经系统疾病的药物的应用。
• Tetracyclic spiro compounds as 5HT.sub.1B receptor antagonists
  申请人：SmithKline Beecham p.l.c.

  公开号：US06100272A1

  公开（公告）日：2000-08-08

  Compounds of formula(I) where B is oxygen or sulphur, D is nitrogen, R.sup.6 and R.sup.7 forms a ring, m is 2, R is a substituted latam ring of formula (i) ##STR1## where p is 1, P is a substituted or unsubstituted bicyclic ring containing one or two heteroatoms or P is an unsbustituted or substituted 5- to 7-memebered saturated ring containing one or two heteroatoms; X, Y, Z, E, G, R.sup.3, R.sup.4, R.sup.5, R.sup.8, R.sup.9, and R.sup.10 are as defined in the specification.

  公式（I）的化合物，其中B为氧或硫，D为氮，R.sup.6和R.sup.7形成一个环，m为2，R为公式（i）的取代的拉丹环 ##STR1## 其中p为1，P为含有一个或两个杂原子的取代或未取代的双环烷基环，或P为未取代或取代的含有一个或两个杂原子的5到7成员饱和环；X、Y、Z、E、G、R.sup.3、R.sup.4、R.sup.5、R.sup.8、R.sup.9和R.sup.10如规范中定义。
• Use of 5HT.sub.1B receptor antagonist for the treatment of vascular
  申请人：SmithKline Beecham p.l.c.

  公开号：US06107328A1

  公开（公告）日：2000-08-22

  The present application is directed to the use of 5HT.sub.1B or 5HT.sub.1D receptor antagonists in the treatment of vascular diseases, in particular angina, Raynaud's syndrome, peripheral vascular syndrome or portal hypertension.

  本申请涉及使用5HT.sub.1B或5HT.sub.1D受体拮抗剂治疗血管疾病，特别是心绞痛、雷诺氏综合症、外周血管症候群或门脉高压。
• [EN] TETRACYCLIC SPIRO COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THEIR USE AS 5HT1D RECEPTOR ANTAGONISTS<br/>[FR] COMPOSES SPIRO TETRACYCLIQUES, PROCEDES DE PREPARATION ET UTILISATION COMME ANTAGONISTES DU RECEPTEUR 5HT1D
  申请人：SMITHKLINE BEECHAM PLC

  公开号：WO1996019477A1

  公开（公告）日：1996-06-27

  (EN) Novel piperidine derivatives of formula (I), processes for their preparation, pharmaceutical compositions containing them and their use as medicaments for the treatment of CNS disorders are disclosed.(FR) La présente invention concerne de nouveaux dérivés de pipéridine représentés par la formule générale (I), des procédés permettant leur préparation, des compositions pharmaceutiques à base de ces dérivés, ainsi que leur utilisation en tant que médicaments destinés au traitement de troubles du système nerveux central.

  （中文）本发明涉及一种新的哌啶衍生物，其化学式为（I），其制备方法，包含它们的药物组合物以及它们作为治疗中枢神经系统疾病的药物的使用。
• Multikilogram-Scale Synthesis of a Biphenyl Carboxylic Acid Derivative Using a Pd/C-Mediated Suzuki Coupling Approach
  作者：David S. Ennis、Julie McManus、Wladyslaw Wood-Kaczmar、John Richardson、Gillian E. Smith、Alexis Carstairs

  DOI：10.1021/op980079g

  日期：1999.7.1

  Reaction of 4-bromo-3-methylanaine with 4-chlorobutyryl chloride/TEA and subsequent treatment of the resulting secondary amide intermediate with KOt-Bu gives 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one in 65% yield, This procedure has been optimised (74-76% overall yield) and has been carried out on 41 molar scale. In a variation of this process, we have employed NaOH as the ring-closing base under phase-transfer conditions, NaOH is added to a mixture of 4-bromo-3-methylaniline, 4-chlorobutyryl chloride, and catalytic TBAC in THF/ H2O, A further 2 equiv of aqueous NaOH is added, and the mixture is heated at 40-45 degrees C, providing access to cyclised product In an improved 86% yield. 1-(4-Bromo-3-methylphenyl)pyrrolidin-2-one is subsequently coupled with 4-carboxyphenylboronic acid under standard Suzuki coupling conditions [Pd(PPh3)(4), Na2CO3, DME/H2O] to give 2'-methyl-4'-(2-oxo-1-pyrrolidinyl)biphenyl-4-carboxylic acid in 64% yield, contaminated with 40-80 ppm of residual Pd, In a modification of this process, we have used Pd/C as the catalyst, Reaction in MeOH/ H2O gives an improved yield of the biphenylcarboxyiic acid with residual Pd levels of <6 ppm, This process has been carried out on 24 molar scale, The synthesis of the arylpyrrolidinone and subsequent Suzuki coupling have been combined into a one-pot procedure, providing access to 2'-methyl-4'-(2-oxo-1-pyrrolidinyl)biphenyl-4-carboxylic acid in 82% overall yield from 4-bromo-3-methylaniline.