4-amino-N-{4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl}-3-thiophenecarboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-amino-N-{4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl}-3-thiophenecarboxamide
• 英文别名: 4-Amino-thiophene-3-carboxylic acid [4-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-butyl]-amide；4-amino-N-[4-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]butyl]thiophene-3-carboxamide
• 化学式: C₂₀H₂₅N₅OS₂
• 分子量: 415.583
• InChiKey: ANZGKDRXGOPIJA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  131
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3-氨基噻吩-4-羧酸甲酯盐酸盐 在 sodium hydroxide 、 sodium carbonate 、 1-羟基苯并三唑 、 苯甲醚 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 乙醇 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 111.33h， 生成 4-amino-N-{4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl}-3-thiophenecarboxamide
  参考文献：
  名称：

  Synthesis and Evaluation of Heterocyclic Carboxamides as Potential Antipsychotic Agents

  摘要：

  Heterocyclic analogues of 1192U90, 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)- butyl)benzamide hydrochloride (1), were prepared and evaluated as potential antipsychotic agents. These analogues were evaluated in vitro for their binding to the dopamine D-2, serotonin 5-HT2, and serotonin 5-HTL(1a) receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. Nine different types of heterocyclic carboxamides were studied in this investigation (i.e., pyridine-, thiophene-, benzothiophene-, quinoline-, 1,2,3,4-tetrahydroquinoline-,2,3-dihydroindole-, indole-, benzimidazole-, and indazolecarbox-amides), Two derivatives exhibited potent in vivo activities comparable to 1: 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-pyridinecarboxamide (16) and 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-thiophenecarboxamide (29). Furthermore, these derivatives were found to be much less active in behavioral models predictive of extrapyramidal side effects than in the mouse climbing assay, which predicts antipsychotic activity. Carboxamides 16 and 29 were selected for further evaluation as potential backup compounds to 1.

  DOI：

  10.1021/jm9603375

文献信息

• HETEROAROMATIC COMPOUNDS WITH ANTIPSYCHOTIC ACTIVITY
  申请人：THE WELLCOME FOUNDATION LIMITED

  公开号：EP0683778A1

  公开（公告）日：1995-11-29
• [EN] HETEROAROMATIC COMPOUNDS WITH ANTIPSYCHOTIC ACTIVITY<br/>[FR] COMPOSES HETEROAROMATIQUES A ACTIVITE ANTIPSYCHOTIQUE
  申请人：THE WELLCOME FOUNDATION LIMITED

  公开号：WO1994018196A1

  公开（公告）日：1994-08-18

  (EN) The present invention relates to a group of piperazine and piperidine derivatives of formula (I), wherein Y is a heteroaryl group optionally substituted by one or more halogen, nitro, C1-6alkyl, C1-6alkoxy, aryloxy, arylC1-6alkylenoxy, hydroxy, S(O)nR2 or S(O)nN(R2)2 where n is 0, 1 or 2, CN, CON(R2)2, COR2, CO2R2, CO-aryl, azido, -N(R2)2, -NR2N(R2a)2, -NR2N = C(R2a)2, -NR2(C = O)CH(N(R2a)2)R2b, -NR2(C = O)R2a, NR2CO2R2a, C1-6alkoxycarbonylamino or PhN = N; with the proviso that Y does not include benzisothiazolyls or benzisoxazolyis, V is O or S; Z is C1-8alkylene optionally interrupted by -O- or -S(O)n- where n is 0, 1 or 2, C2-8alkenylene or C2-8alkynylene; X is N, CR3 or COR3; A is CR4 or N; B is oxygen, NR5 or S(O)n, where n is 0, 1 or 2; and R1 is hydrogen or one or more halogen, hydroxy, nitro, CN, NR62, C1-6alkoxy, aryloxy, arylC1-6alkylenoxy, or COR6, R, R2, R2a, R2b, R3, R4, R5 and R6, are each hydrogen or C1-6alkyl; or a salt, solvate, N-oxide or physiologically functional derivative thereof, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy, in particular in the treatment of psychotic disorders.(FR) La présente invention se rapporte à un groupe de dérivés de pipérazine et de pipéridine répondant à la formule (I), dans laquelle Y représente un groupe hétéroaryle éventuellement substitué par au moins un élément choisi entre halogène, nitro, C1-6 alkyle, C1-6 alcoxy, aryloxy, aryle C1-6 alkylenoxy, hydroxy, S(O)nR2 ou S(O)nN(R2)2 n valant 0, 1 or 2, CN, CON(R2)2, COR2, CO2R2, CO-aryle, azido, -N(R2)2, -NR2N(R2a)2, -NR2N = C(R2a)2, -NR2(C = O)CH(N(R2a)2)R2b, -NR2(C = O)R2a, NR2CO2R2a, C1-6 alcoxycarbonylamino ou PhN = N; à condition qu'Y ne comprenne pas benzisothiazolyles ou benzisoxazolyles, V représente 0 ou S; Z représente C1-8 alkylène éventuellement interrompu par -O- ou -S(O)n-, n valant 0, 1 ou 2, C2-8 alcénylène ou C2-8 alkynylène; X représente N, CR3 ou COR3; A représente CR4 ou N: B représente oxygène, NR5 ou S(O)n, n valant 0, 1 ou 2; et R1 représente hydrogène ou au moins un élément choisi entre halogène, hydroxy, nitro, CN, NR62, C1-6 alcoxy, aryloxy, aryle C1-6 alkylenoxy, ou COR6, R, R2, R2a, R2b, R3, R4, R5 et R6 représentent chacun hydrogène ou C1-6 alkyle. L'invention se rapporte également à un sel, solvate, N-oxyde ou dérivé physiologiquement fonctionnel de ces composés, ainsi qu'à des procédés de préparation de ces derniers, des compositions pharmaceutiques les contenant et leur utilisation en thérapie, en particulier pour le traitement de troubles psychotiques.
• Synthesis and Evaluation of Heterocyclic Carboxamides as Potential Antipsychotic Agents
  作者：Mark H. Norman、Frank Navas、James B. Thompson、Greg C. Rigdon

  DOI：10.1021/jm9603375

  日期：1996.1.1

  Heterocyclic analogues of 1192U90, 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)- butyl)benzamide hydrochloride (1), were prepared and evaluated as potential antipsychotic agents. These analogues were evaluated in vitro for their binding to the dopamine D-2, serotonin 5-HT2, and serotonin 5-HTL(1a) receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. Nine different types of heterocyclic carboxamides were studied in this investigation (i.e., pyridine-, thiophene-, benzothiophene-, quinoline-, 1,2,3,4-tetrahydroquinoline-,2,3-dihydroindole-, indole-, benzimidazole-, and indazolecarbox-amides), Two derivatives exhibited potent in vivo activities comparable to 1: 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-pyridinecarboxamide (16) and 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-thiophenecarboxamide (29). Furthermore, these derivatives were found to be much less active in behavioral models predictive of extrapyramidal side effects than in the mouse climbing assay, which predicts antipsychotic activity. Carboxamides 16 and 29 were selected for further evaluation as potential backup compounds to 1.