4-<2-(dimethylamino)ethyl>-6-nitro-2H-1,4-benzoxazin-3(4H)-one | 174567-29-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: 4-<2-(dimethylamino)ethyl>-6-nitro-2H-1,4-benzoxazin-3(4H)-one
• 英文别名: 4-(2-Dimethylaminoethyl)-6-nitro-2H-1,4-benzoxazin-3(4H)-one；4-[2-(dimethylamino)ethyl]-6-nitro-1,4-benzoxazin-3-one
• CAS: 174567-29-4
• 化学式: C₁₂H₁₅N₃O₄
• 分子量: 265.269
• InChiKey: QWEXSIKKPGKLIZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  78.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-<2-(dimethylamino)ethyl>-6-nitro-2H-1,4-benzoxazin-3(4H)-one 在 sodium tetrahydroborate 、 三氟化硼乙醚 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以92%的产率得到3,4-dihydro-4-<2-(dimethylamino)ethyl>-6-nitro-2H-1,4-benzoxazine
  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：

  6-硝基-2H-1,4-苯并噁嗪-3(4H)-酮 、 二甲氨基氯乙烷盐酸 在 sodium hydride 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 19.0h， 以79%的产率得到4-<2-(dimethylamino)ethyl>-6-nitro-2H-1,4-benzoxazin-3(4H)-one
  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

• Biphenyl(thio)amide and bipennylethan(thi) one derivatives, their
  申请人：SmithKline Beecham p.l.c.

  公开号：US05972935A1

  公开（公告）日：1999-10-26

  The invention relates to novel heterocyclic compounds of formula (I) or a salt or N-oxide thereof, in which R is a group of formulae (i), (ii) or (iii), where R.sup.1 is hydrogen, halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, COC.sub.1-6 akyl, C.sub.1-6 alkoxy, hydroxy, hydroxyC.sub.1-6 alkyl, hydroxyC.sub.1-6 alkoxy, C.sub.1-6 alkoxyC.sub.1-6 alkoxy, acyle, nitro, trifluoromethyl, cyano, SR.sup.9, SOR.sup.9, SO.sub.2 R.sup.9, NR.sup.9 CONR.sup.10 R.sup.11, NR.sup.10 SO.sub.2 R.sup.11, SO.sub.2 NR.sup.11 r.sup.11, SO.sub.2 NR.sup.10 R.sup.11, CO.sub.2 R.sup.10, CONR.sup.10 R.sup.11, CO.sub.2 NR.sup.10 R.sup.11, CONR.sup.10 (CH.sub.2).sub.a CO.sub.2 R.sup.11, (CH.sub.2).sub.a NR.sup.10 R.sup.11, ##STR1## (CH.sub.2).sub.a CONR.sup.10 R.sup.11, (CH.sub.2).sub.a COR.sup.11, (CH.sub.2).sub.a CO.sub.2 C.sub.1-6 alkyl, CO.sub.2 (CH.sub.2).sub.a OR.sup.10, NR.sup.10 R.sup.11, N.dbd.CNR.sup.9 NR.sup.10 R.sup.11, NR.sup.10 CO(CH.sub.2).sub.a NR.sup.10 R.sup.11, NR.sup.10 CO.sub.2 R.sup.11, CONHNR.sup.10 R.sup.11, CR.sup.10 .dbd.NOR.sup.11, CNR.sup.10 .dbd.NOR.sup.11, where R.sup.9, R.sup.10 and R.sup.11 are independently hydrogen or C.sub.1-6 alkyl and a is 1 to 4; or R.sup.1 is a group --X--R.sup.12 where R.sup.12 is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur and X is a bond, O, S, CH.sub.2, C.dbd.O, NR.sup.13 CO or NR.sup.13 where R.sup.13 is hydrogen or C.sub.1-6 alkyl; R.sup.4 and R.sup.5 are independently hydrogen, halogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.1-6 alkoxy, hydroxyC.sub.1-6 alkyl, C.sub.1-6 alkylOC.sub.1-6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO.sub.2 R.sup.10, CONR.sup.10 R.sup.11, NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are independently hydrogen or C.sub.1-6 alkyl, or R.sup.4 and R.sup.5 together form a group --CH.sub.2).sub.r --R.sup.14 --(CH.sub.2).sub.s -- where R.sup.14 is O, S, CH.sub.2 or NR.sup.15 where R.sup.15 is hydrogen or C.sub.1-6 alkyl and r and s are independently 0, 1 or 2; R.sup.2 is hydrogen, C.sub.1-6 alkyl, optionally substituted aryl or optionally substituted heteroaryl; R.sup.3 is hydrogen or C.sub.1-6 alkyl or together with R.sup.8 forms a group (CH.sub.2).sub.q where q is 2, 3 or 4; Z is oxygen or sulphur, p is 1 or 2; P is an optionally substituted bicyclic ring optionally containing one to four heteroatoms; or P is an optionally substituted 5- to 7-membered saturated or partially saturated ring optionally containing one to three heteroatoms; and B is oxygen or sulphur, D is nitrogen, carbon or a CH group; R.sup.6 is hydrogen or C.sub.1-6 alkyl and R.sup.7 is C.sub.1-6 alkyl, C.sub.1-6 alkoxy or halogen, or R.sup.6 together with R.sup.7 forms a group --A-- where A is (CR.sup.16 R.sup.17).sub.t where t is 1, 2 or 3 and R.sup.16 and R.sup.17 are independently hydrogen or C.sub.1-6 alkyl or A is (CR.sup.16 R.sup.17).sub.u --J where u is 0, 1, or 2 and J is oxygen, sulphur, CR.sup.16 .dbd.C.sup.17, CR.sup.16 .dbd.N, CR.sup.16 NR.sup.17 or N.dbd.N; R.sup.18 and R.sup.19 are independently hydrogen or C.sub.1-6 alkyl; R.sup.20 and R.sup.21 are independently hydrogen, C.sub.1-6 alkyl, 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 Q is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, processes for their preparation, and their use as 5-HT.sub.1D receptor antagonists.

  本发明涉及式（I）的新型杂环化合物或其盐或N-氧化物，其中R是式（i），（ii）或（iii）的基团，其中R.sup.1是氢，卤素，C.sub.1-6烷基，C.sub.3-6环烷基，COC.sub.1-6烷基，C.sub.1-6烷氧基，羟基，羟基C.sub.1-6烷基，羟基C.sub.1-6烷氧基，C.sub.1-6烷氧基C.sub.1-6烷氧基，酰基，硝基，三氟甲基，氰基，SR.sup.9，SOR.sup.9，SO.sub.2R.sup.9，NR.sup.9CONR.sup.10R.sup.11，NR.sup.10SO.sub.2R.sup.11，SO.sub.2NR.sup.11r.sup.11，SO.sub.2NR.sup.10R.sup.11，CO.sub.2R.sup.10，CONR.sup.10R.sup.11，CO.sub.2NR.sup.10R.sup.11，CONR.sup.10（CH.sub.2）.sub.aCO.sub.2R.sup.11，（CH.sub.2）.sub.aNR.sup.10R.sup.11，##STR1##（CH.sub.2）.sub.aCONR.sup.10R.sup.11，（CH.sub.2）.sub.aCOR.sup.11，（CH.sub.2）.sub.aCO.sub.2C.sub.1-6烷基，CO.sub.2（CH.sub.2）.sub.aOR.sup.10，NR.sup.10R.sup.11，N.dbd.CNR.sup.9NR.sup.10R.sup.11，NR.sup.10CO（CH.sub.2）.sub.aNR.sup.10R.sup.11，NR.sup.10CO.sub.2R.sup.11，CONHNR.sup.10R.sup.11，CR.sup.10.dbd.NOR.sup.11，CNR.sup.10.dbd.NOR.sup.11，其中R.sup.9，R.sup.10和R.sup.11独立地为氢或C.sub.1-6烷基，a为1至4；或R.sup.1为--X--R.sup.12的基团，其中R.sup.12是含有1至4个氧，氮或硫杂原子的可选择取代的5-至7元杂环环，X为键，O，S，CH.sub.2，C.dbd.O，NR.sup.13CO或NR.sup.13，其中R.sup.13为氢或C.sub.1-6烷基；R.sup.4和R.sup.5独立地为氢，卤素，C.sub.1-6烷基，C.sub.3-6环烷基，C.sub.3-6环烯基，C.sub.1-6烷氧基，羟基C.sub.1-6烷基，C.sub.1-6烷氧基C.sub.1-6烷基，酰基，芳基，酰氧基，羟基，硝基，三氟甲基，氰基，CO.sub.2R.sup.10，CONR.sup.10R.sup.11，NR.sup.10R.sup.11，其中R.sup.10和R.sup.11独立地为氢或C.sub.1-6烷基，或R.sup.4和R.sup.5一起形成基团--CH.sub.2）.sub.r--R.sup.14--（CH.sub.2）.sub.s--，其中R.sup.14为O，S，CH.sub.2或NR.sup.15，其中R.sup.15为氢或C.sub.1-6烷基，r和s独立地为0，1或2；R.sup.2为氢，C.sub.1-6烷基，可选择取代的芳基或可选择取代的杂芳基；R.sup.3为氢或C.sub.1-6烷基，或与R.sup.8一起形成基团（CH.sub.2）.sub.q，其中q为2、3或4；Z为氧或硫，p为1或2；P是可选择取代的双环环，可选择包含一到四个杂原子；或P是可选择取代的5-至7元饱和或部分饱和环，可选择包含一到三个杂原子；B为氧或硫，D为氮，碳或CH基团；R.sup.6为氢或C.sub.1-6烷基，R.sup.7为C.sub.1-6烷基，C.sub.1-6烷氧基或卤素，或R.sup.6与R.sup.7一起形成基团--A--，其中A为（CR.sup.16R.sup.17）.sub.t，其中t为1、2或3，R.sup.16和R.sup.17独立地为氢或C.sub.1-6烷基，或A为（CR.sup.16R.sup.17）.sub.u--J，其中u为0、1或2，J为氧，硫，CR.sup.16.dbd.C.sup.17，CR.sup.16.dbd.N，CR.sup.16NR.sup.17或N.dbd.N；R.sup.18和R.sup.19独立地为氢或C.sub.1-6烷基；R.sup.20和R.sup.21独立地为氢，C.sub.1-6烷基，芳基烷基，或与它们所连接的氮原子一起形成可选择取代的5-至7元杂环环，其中选自氧，氮或硫的一个或两个杂原子，m为0至4；Q为可选择取代的5-至7元杂环环，其中选自氧，氮或硫的1至3个杂原子，以及它们的制备方法和作为5-HT.sub.1D受体拮抗剂的用途。
• AMIDE DERIVATIVES HAVING 5HT1D-ANTAGONIST ACTIVITY
  申请人：SMITHKLINE BEECHAM PLC

  公开号：EP0763034A1

  公开（公告）日：1997-03-19
• BIPHENYL(THIO)AMIDE AND BIPHENYLETHAN(THI)ONE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS 5-HT 1D? RECEPTOR ANTAGONISTS
  申请人：SMITHKLINE BEECHAM PLC

  公开号：EP1019412A1

  公开（公告）日：2000-07-19
• US5756496A
  申请人：——

  公开号：US5756496A

  公开（公告）日：1998-05-26
• US5972935A
  申请人：——

  公开号：US5972935A

  公开（公告）日：1999-10-26