diethyl 5,6-dihydro-5-hydroxy-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6,6-dicarboxylate | 183550-77-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡喃吡啶类
• 英文名称: diethyl 5,6-dihydro-5-hydroxy-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6,6-dicarboxylate
• 英文别名: 5,6-dihydro-5-hydroxy-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6, 6-dicarboxylic acid diethyl ester；5,6-dihydro-5-hydroxy-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6,6-dicarboxylic acid diethyl ester；diethyl 5,6-dihydro-5-hydroxy-5-(4-methylphenyl)-8-oxo-8H-pyrano[3, 4-b]pyridine-6,6-dicarboxylate；Diethyl 5-hydroxy-5-(4-methylphenyl)-8-oxopyrano[3,4-b]pyridine-6,6-dicarboxylate
• CAS: 183550-77-8
• 化学式: C₂₁H₂₁NO₇
• 分子量: 399.4
• InChiKey: LSGXSUCAOFNLEI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  112
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  diethyl 5,6-dihydro-5-hydroxy-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6,6-dicarboxylate 在 盐酸 、 氯化亚砜 、 溶剂黄146 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 1,2-二氯乙烷 为溶剂， 反应 4.5h， 生成 8-Oxo-5-p-tolyl-8H-pyrano[3,4-b]pyridine-6-carbonyl chloride
  参考文献：
  名称：

  Axially Chiral 1,7-Naphthyridine-6-carboxamide Derivatives as Orally Active Tachykinin NK₁ Receptor Antagonists:  Synthesis, Antagonistic Activity, and Effects on Bladder Functions

  摘要：

  Cyclic analogues of N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1) having a 6-9-membered ring (6-9) were synthesized and evaluated for NK1 antagonistic activities. The 8-membered ring compound with a beta-methyl group at the C-(9)-position, (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,-11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-di-one [(aR,9R)-8b], was atropodiastereoselectively synthesized by cyclization of a chiral intermediate, 10g. On the other hand, the 7-membered ring compound with a beta-methyl group at the C-(9)-position [(9S)-7b] was obtained as an equilibrium mixture of atropisomers with a ratio of ca. 3:2 in solution at room temperature (measured by NMR in CDCl3). Compounds (9S)-7b and (aR,9R)-8b exhibited excellent antagonistic activities both in vitro [IC50 (inhibition of [I-125]BH-SP binding in human IM-9 cells) = 0.28 and 0.45 nM, respectively] and in vivo (iv and po). Significantly, the in vitro activity of (aR,9R)-8b was ca. 750-fold higher than that of its enantiomer (aS,9S)-8b, ca. 40-fold higher than its atropisomer (aS,9R)-8b, and ca. 20-fold higher than its diastereomer (aR,9S)-8b. The structure-activity relationships in this series, along with the X-ray analysis of (aR,9R)-8b, indicated that the stereochemistry around the -C-(6)(=O)-N-(7)-CH2Ar moiety is important for NK1 receptor recognition. The NK1 antagonists showed effects on bladder functions in guinea pigs upon intravenous injection: i.e., the antagonists increased the shutdown time of distension-induced rhythmic bladder contractions and the bladder volume threshold, and the effects on the shutdown time were found to correlate well with the NK1 antagonistic activities. Compound (aR,9R)-8b has been identified as a potential clinical candidate for the treatment of bladder function disorders.

  DOI：

  10.1021/jm990220r
• 作为产物：
  描述：

  3-(4-甲基苯甲酰基)吡啶-2-羧酸 在 氯化亚砜 、 sodium hydride 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 为溶剂， 反应 2.5h， 生成 diethyl 5,6-dihydro-5-hydroxy-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6,6-dicarboxylate
  参考文献：
  名称：

  Axially Chiral 1,7-Naphthyridine-6-carboxamide Derivatives as Orally Active Tachykinin NK₁ Receptor Antagonists:  Synthesis, Antagonistic Activity, and Effects on Bladder Functions

  摘要：

  Cyclic analogues of N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1) having a 6-9-membered ring (6-9) were synthesized and evaluated for NK1 antagonistic activities. The 8-membered ring compound with a beta-methyl group at the C-(9)-position, (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,-11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-di-one [(aR,9R)-8b], was atropodiastereoselectively synthesized by cyclization of a chiral intermediate, 10g. On the other hand, the 7-membered ring compound with a beta-methyl group at the C-(9)-position [(9S)-7b] was obtained as an equilibrium mixture of atropisomers with a ratio of ca. 3:2 in solution at room temperature (measured by NMR in CDCl3). Compounds (9S)-7b and (aR,9R)-8b exhibited excellent antagonistic activities both in vitro [IC50 (inhibition of [I-125]BH-SP binding in human IM-9 cells) = 0.28 and 0.45 nM, respectively] and in vivo (iv and po). Significantly, the in vitro activity of (aR,9R)-8b was ca. 750-fold higher than that of its enantiomer (aS,9S)-8b, ca. 40-fold higher than its atropisomer (aS,9R)-8b, and ca. 20-fold higher than its diastereomer (aR,9S)-8b. The structure-activity relationships in this series, along with the X-ray analysis of (aR,9R)-8b, indicated that the stereochemistry around the -C-(6)(=O)-N-(7)-CH2Ar moiety is important for NK1 receptor recognition. The NK1 antagonists showed effects on bladder functions in guinea pigs upon intravenous injection: i.e., the antagonists increased the shutdown time of distension-induced rhythmic bladder contractions and the bladder volume threshold, and the effects on the shutdown time were found to correlate well with the NK1 antagonistic activities. Compound (aR,9R)-8b has been identified as a potential clinical candidate for the treatment of bladder function disorders.

  DOI：

  10.1021/jm990220r

文献信息

• Cyclic compounds, their prudiction and use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US05770590A1

  公开（公告）日：1998-06-23

  Novel compounds of the following general formula or salts thereof. ##STR1## wherein Ring M is a heterocyclic ring having --N.dbd.C<, --CO--N< or --CS--N< as the partial structure --X . . . Y<; R.sup.a and R.sup.b are bonded to each other to form Ring A, or they are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M; Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, and at least one of them is optionally substituted heterocyclic ring; Rng C is optionally substituted homocyclic or heterocyclic ring; Rng Z is an optionally substituted ring; and n represents an integer of from 1 to 6, or a salt thereof, which has anexcellent tachykinin receptor antagonistic effect, and their production, and pharmaceutical compositions.

  具有以下通式的新化合物或其盐：##STR1##其中，环M是一个具有--N.dbd.C<、--CO--N<或--CS--N<作为部分结构--X . . . Y<的杂环环；R.sup.a和R.sup.b相互连接形成环A，或者它们相同或不同，独立地代表氢原子或环M上的取代基；环A和环B独立地代表可选择性取代的碳环或杂环，其中至少有一个是可选择性取代的杂环；环C是可选择性取代的碳环或杂环；环Z是可选择性取代的环；n代表1至6的整数，或其盐，具有优异的速激肽受体拮抗作用，以及它们的制备方法和药物组合物。
• Heterocyclic compounds, their production and use
  申请人：——

  公开号：US20020132817A1

  公开（公告）日：2002-09-19

  A compound represented by the formula: 1 wherein ring M is a heterocyclic ring wherein —X═Y< is one of —N═C<, —CO—N< or —CS—N<; R a and R b are bonded to each other to form Ring A, or they are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M; Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, with the proviso that at least one of them is an optionally substituted heterocyclic ring; Ring C is an optionally substituted homocyclic or heterocyclic ring; Ring Z is an optionally substituted nitrogen-containing heterocyclic ring; and n is an integer from 1 to 6, or a salt thereof has a tachykinin receptor antagonistic activity in vitro, and is useful for preventing or treating depression, anxiety, manic-depressive illness or psychopathy.

  一种由以下通式表示的化合物：1，其中环M为杂环环，其中—X═Y<为—N═C<、—CO—N<或—CS—N<之一；Ra和Rb彼此连接形成环A，或者它们相同或不同，独立地表示氢原子或环M上的取代基；环A和环B独立地表示可任选取代的碳环或杂环环，条件是至少一个为可任选取代的杂环环；环C为可任选取代的碳环或杂环环；环Z为可任选取代的含氮杂环环；n为1至6的整数，或其盐在体外具有速激肽受体拮抗活性，并可用于预防或治疗抑郁症、焦虑症、双相情感障碍或精神病。
• EP1145714
  申请人：——

  公开号：——

  公开（公告）日：——
• HETEROCYCLIC COMPOUNDS, THEIR PRODUCTION AND USE AS TACHYKININ RECEPTOR ANTAGONISTS
  申请人：Takeda Chemical Industries, Ltd.

  公开号：EP1061926A2

  公开（公告）日：2000-12-27
• US5770590A
  申请人：——

  公开号：US5770590A

  公开（公告）日：1998-06-23