N-[4-(2-Dimethylaminoethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-[4-(2-Dimethylaminoethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide
• 英文别名: N-[4-[2-(dimethylamino)ethyl]-2,3-dihydro-1,4-benzoxazin-6-yl]-4-[2-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]benzamide
• 化学式: C₂₉H₃₁N₅O₃
• 分子量: 497.597
• InChiKey: CLSGNFLCVLTDRU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  83.7
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2'-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxylic acid 在 氯化亚砜 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 20.0h， 生成 N-[4-(2-Dimethylaminoethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide
  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

• Substituted 1,2,3,4-tetrahydrocyclopent[b]indoles, 1,2,3,3a,4,8a-hexahydrocyclopent[b]indoles and related compounds, intermediates and a process for the preparation thereof and their use as medicaments
  申请人：HOECHST MARION ROUSSEL, Inc.

  公开号：EP0496314B1

  公开（公告）日：1997-10-01
• AMIDE DERIVATIVES HAVING 5HT1D-ANTAGONIST ACTIVITY
  申请人：SMITHKLINE BEECHAM PLC

  公开号：EP0763034A1

  公开（公告）日：1997-03-19
• US5756496A
  申请人：——

  公开号：US5756496A

  公开（公告）日：1998-05-26
• [EN] AMIDE DERIVATIVES HAVING 5HT1D-ANTAGONIST ACTIVITY<br/>[FR] DERIVES AMIDE A ACTIVITE ANTAGONISTE PAR RAPPORT A 5HT1D
  申请人：SMITHKLINE BEECHAM PLC

  公开号：WO1995032967A1

  公开（公告）日：1995-12-07

  (EN) Compound of formula (I), processes for their preparation and their use as CNS agents are disclosed, in which A is CONR where R is hydrogen or C1-6alkyl; Q is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; R1 is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, COC1-6alkyl, C1-6alkoxy, hydroxy, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkoxy, acyl, nitro, trifluoromethyl, cyano, SR9, SOR9, SO2R9, SO2NR10R11, CO2R10, CONR10R11, CO2NR10R11, CONR10(CH2)aCO2R11, (CH2)aNR10R11, (CH2)aCONR10R11, (CH2)aNR10COR11, (CH2)aCO2C1-6alkyl, CO2(CH2)aOR10, NR10R11, NR10CO2R11, NR10CONR10R11, CR10=NOR11, CNR10=NOR11, where R10 and R11 are independtly hydrogen or C1-6alkyl and a is 1 to 4 or R1 is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; R2 and R3 are independently hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, C1-6alkoxy, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R10, CONR10R11, NR10R11 where R10 and R11 are as defined for R1; R4 and R5 are independently hydrogen or C1-6alkyl; R6 is halogen, hydroxy, C1-6alkyl or C1-6alkoxy; R7 and R8 are independently hydrogen, C1-6alkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5 to 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulphur; m is 0 to 4; and n is 0, 1 or 2.(FR) Composés de la formule (I), procédés pour leur préparation et leur utilisation comme agents thérapeutiques destinés aux troubles du système nerveux central. Dans cette formule, A représente CONR, R représentant hydrogène ou alkyle C1-6; Q représente un noyau hétérocyclique contenant de 5 à 7 éléments et éventuellement substitué, renfermant 1 à 3 hétéroatomes choisis entre oxygène, azote et soufre; R1 représente hydrogène, halogène, alkyle C1-6, cycloalkyle C3-6, COalkyle C1-6, alcoxy C1-6, hydroxy, hydroxyalkyle C1-6, hydroxyalcoxy C1-6, alcoxy C1-6alcoxy C1-6, acyle, nitro, trifluorométhyle, cyano, SR9, SOR9, SO2R9, SO2NR10R11, CO2R10, CONR10R11, CO2NR10R11, CONR10(CH2)aCO2R11, (CH2)aNR10R11, (CH2)aCONR10R11, (CH2)aNR10COR11, (CH2)aCO2alkyle C1-6, CO2(CH2)aOR10, NR10R11, NR10CO2R11, NR10CONR10R11, CR10=NOR11, CNR10=NOR11, R10 et R11 représentant indépendamment hydrogène ou alkyle C1-6 et a valant de 1 à 4, ou R1 représente un noyau hétérocyclique contenant de 5 à 7 éléments et éventuellement substitué, renfermant 1 à 3 hétéroatomes choisis entre oxygène, azote et soufre; R2 et R3 représentent indépendamment hydrogène, halogène, alkyle C1-6, cycloalkyle C3-6, cycloalcényle C3-6, alcoxy C1-6, acyle, aryle, acyloxy, hydroxy, nitro, trifluorométhyle, cyano, CO2R10, CONR10R11, NR10R11, R10 et R11 étant tels que définis en R1; R4 et R5 représentent indépendamment hydrogène ou alkyle C1-6; R6 représente halogène, hydroxy, alkyle C1-6 ou alcoxy C1-6; R7 et R8 représentent indépendamment hydrogène, alkyle C1-6, aralkyle, ou forment, avec l'atome d'azote auquel ils sont rattachés, un noyau hétérocyclique contenant de 5 à 7 éléments et éventuellement substitué, renfermant 1 à 3 hétéroatomes choisis entre oxygène, azote et soufre; m vaut de 0 à 4; et n vaut 0, 1 ou 2.
• 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-<i>f</i>]indole-3,4‘-piperidine] (SB-224289) Potently Blocks Terminal 5-HT Autoreceptor Function Both in Vitro and in Vivo
  作者：Laramie M. Gaster、Frank E. Blaney、Susannah Davies、D. Malcolm Duckworth、Peter Ham、Sarah Jenkins、Andrew J. Jennings、Graham F. Joiner、Frank D. King、Keith R. Mulholland、Paul A. Wyman、Jim J. Hagan、Jon Hatcher、Brian J. Jones、Derek N. Middlemiss、Gary W. Price、Graham Riley、Claire Roberts、Carol Routledge、Julie Selkirk、Paula D. Slade

  DOI：10.1021/jm970457s

  日期：1998.4.1

  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.