2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]-pyridazin-3(2H)-one | 118288-65-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫平类
• 英文名称: 2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]-pyridazin-3(2H)-one
• 英文别名: 2-(4'-Chlorophenyl)-5,6-dihydro-(1)benzothiepino<5,4-c>pyridazin-3(2H)-one；2-(4-chlorophenyl)-5,6-dihydro-(1)benzothiepino<5,4-c>pyridazin-3(2H)-one；2-(4-chlorophenyl)-5,6-dihydro-(1)benzothiepino[5,4-c]pyridazine-3(2H)-one；2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one；2-(4-Chlorophenyl)-5,6-dihydrobenzo[2,3]thiepino[4,5-c]pyridazin-3(2H)-one；2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3-one
• CAS: 118288-65-6
• 化学式: C₁₈H₁₃ClN₂OS
• 分子量: 340.833
• InChiKey: YIEYSFIVIUQNBF-UHFFFAOYSA-N

物化性质

• 熔点：
  185-186 °C
• 沸点：
  527.3±60.0 °C(Predicted)
• 密度：
  1.39±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  58
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]-pyridazin-3(2H)-one 在 甲酸 、 双氧水 作用下， 反应 1.0h， 以74%的产率得到2-(4-chlorophenyl)-5,6-dihydro-(1)benzothiepino[5,4-c]pyridazine-3(2H)-one 7-oxide
  参考文献：
  名称：

  缩合哒嗪衍生物的合成研究。IV。2-芳基-5,6-二氢-（1）苯并噻吩并[5,4-c]哒嗪-3（2H）-ones及其相关化合物的合成及抗焦虑活性。

  摘要：

  合成了一系列2-芳基-5,6-二氢-（1）苯并噻吩并[5,4-c]哒嗪-3（2H）-及其相关化合物，并评价了其从大鼠脑中置换3H-地西am的能力。并在体外防止细菌性惊厥引起的惊厥。具有4'-甲氧基苯基（36）或4'-氯苯基（37，39--42）作为2-芳基取代基的化合物在体外和体内试验中均显示出显着的活性。其中，2-（4'-氯苯基）-5,6-二氢-（37）和2-（4'-氯苯基）-5,6-二氢-10-氟-（1）苯并噻吩并[5,4- c] + ++哒嗪-3（2H）-1 7-氧化物（41）在抗冲突测试（Vogel型，大鼠）中显示的活性是地西az的两倍，而肌肉松弛程度（罗塔罗德测试，小鼠）和比地西epa增加了孤立的青蛙感觉神经元中的γ-氨基丁酸诱导的氯离子电流（Icl）。从该系列中选择化合物37（Y-23684）作为进一步开发的候选物。讨论了构效关系。

  DOI：

  10.1248/cpb.39.2556
• 作为产物：
  描述：

  2-(4-chlorophenyl)-4,4a,5,6-tetrahydro-(1)benzothiepino[5,4-c]pyridazine-3(2H)-one 在 溴 、 溶剂黄146 作用下， 反应 1.0h， 以88%的产率得到2-(4-chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]-pyridazin-3(2H)-one
  参考文献：
  名称：

  缩合哒嗪衍生物的合成研究。IV。2-芳基-5,6-二氢-（1）苯并噻吩并[5,4-c]哒嗪-3（2H）-ones及其相关化合物的合成及抗焦虑活性。

  摘要：

  合成了一系列2-芳基-5,6-二氢-（1）苯并噻吩并[5,4-c]哒嗪-3（2H）-及其相关化合物，并评价了其从大鼠脑中置换3H-地西am的能力。并在体外防止细菌性惊厥引起的惊厥。具有4'-甲氧基苯基（36）或4'-氯苯基（37，39--42）作为2-芳基取代基的化合物在体外和体内试验中均显示出显着的活性。其中，2-（4'-氯苯基）-5,6-二氢-（37）和2-（4'-氯苯基）-5,6-二氢-10-氟-（1）苯并噻吩并[5,4- c] + ++哒嗪-3（2H）-1 7-氧化物（41）在抗冲突测试（Vogel型，大鼠）中显示的活性是地西az的两倍，而肌肉松弛程度（罗塔罗德测试，小鼠）和比地西epa增加了孤立的青蛙感觉神经元中的γ-氨基丁酸诱导的氯离子电流（Icl）。从该系列中选择化合物37（Y-23684）作为进一步开发的候选物。讨论了构效关系。

  DOI：

  10.1248/cpb.39.2556

文献信息

• Anti-anxiety benzothiepino(5,4-c]pyridazines
  申请人：Yoshitomi Pharmaceutical Industries, Ltd.

  公开号：US04849421A1

  公开（公告）日：1989-07-18

  A benzothiepino 5,4-c]pyridazine compound of the formula: ##STR1## wherein R.sup.1 and R.sup.2 are the same or different and each is hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, or C.sub.2-5 alkanoylamino, R.sup.3 is hydrogen, C.sub.1-8 alkyl, hydroxy-C.sub.1-4 alkyl, C.sub.2-5 alkanoyloxy-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, heteroaryl, or substituted aryl, aryl-C.sub.1-4 alkyl or heteroaryl by 1 to 3 substituents selected from the group consisting of halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy and C.sub.2-5 alkanoylamino on the armoatic ring, n is 0, 1 or 2, and the bond between the 4-position and the 4a-position is single bond or double bond. Said compounds exhibit anti-anxietic activity and are useful as anti-anxiety agent.

  一种苯并噻吩并[5,4-c]吡啶嗪化合物的化学式如下：##STR1##其中R.sup.1和R.sup.2相同或不同，每个都是氢、卤素、三氟甲基、羟基、氨基、硝基、氰基、C.sub.1-4烷基、C.sub.1-4烷氧基或C.sub.2-5烷酰氨基，R.sup.3是氢、C.sub.1-8烷基、羟基-C.sub.1-4烷基、C.sub.2-5烷酰氧基-C.sub.1-4烷基、芳基、芳基-C.sub.1-4烷基、杂环芳基或芳基、芳基-C.sub.1-4烷基或杂环芳基，芳环上的1到3个取代基选自卤素、三氟甲基、羟基、氨基、硝基、氰基、C.sub.1-4烷基、C.sub.1-4烷氧基和C.sub.2-5烷酰氨基，n为0、1或2，4位和4a位之间的键为单键或双键。该化合物表现出抗焦虑活性，并且可用作抗焦虑剂。
• Synthesis and Biological Activities of Optical Isomers of 2-(4-Chlorophenyl)-5,6-dihydro-(1)benzothiepino(5,4-c)pyridazin-3(2H)-one 7-Oxide.
  作者：Tohru NAKAO、Minoru OBATA、Yuko YAMAGUCHI、Nobuhiro MARUBAYASHI、Kuniki IKEDA、Yasuto MORIMOTO

  DOI：10.1248/cpb.40.117

  日期：——

  Two enantiomers of 2-(4-chlorophenyl)-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-one 7-oxide ((±)-1 : Y-23684) were synthesized in high yields by asymmetric oxidation of the synthetic precursor (2) using modified Sharpless reagent. Among the oxidants tested, cumene hydroperoxide (CHP) gave the highest optical and chemical yields, while tert-butyl, tert-amyl, and 1, 1, 3, 3-tetramethylbutyl hydroperoxides did not show such high enantio-selectivities. The absolute configuration of (+)-1 enantiomer synthesized form 2, Ti(O-iso-Pr)4, (-)-diethyl tartarate, and CHP was determined to be S by X-ray crystallographic analysis. Both enantiomers, S-(+)-1 and R-(-)-1, and (±)-1 had approximately equivalent in vivo activities to antibicuculline test in mice and anticonflict test in rats, although S-(+)-1 showed about three times higher affinity to benzodiazepine receptor than R-(-)-1 in [3H]diazepam binding assay.

  通过使用改良夏普莱斯试剂对合成前体 (2) 进行不对称氧化，高产率地合成了 2-(4-氯苯基)-5, 6-二氢-(1)苯并噻吩并[5, 4-c]哒嗪-3(2H)-酮 7-氧化物 ((±)-1：Y-23684) 的两种对映体。在测试的氧化剂中，过氧化积苯（CHP）的光学产率和化学产率最高，而叔丁基、叔戊基和 1, 1, 3, 3-四甲基丁基过氧化氢则没有显示出如此高的对映选择性。通过 X 射线晶体学分析，合成 2、Ti(O-异-Pr)4、(-)-酒石酸二乙酯和 CHP 的 (+)-1 对映异构体的绝对构型被确定为 S。尽管在[3H]地西泮结合试验中，S-(+)-1 与苯并二氮杂卓受体的亲和力比 R-(-)-1高出约三倍，但两种对映体（S-(+)-1 和 R-(-)-1）和 (±)-1 在小鼠抗杜仲碱试验和大鼠抗冲突试验中的体内活性大致相当。
• Thiophene compounds and their pharmaceutical uses
  申请人：YOSHITIOMI PHARMACEUTICAL INDUSTRIES, LTD.

  公开号：EP0426018A2

  公开（公告）日：1991-05-08

  Thiophene compounds of the formula: wherein R¹ is hydrogen, nitro, amino, halogen or C₁₋₄ alkyl; R² is hydrogen, nitro, amino, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, acyl, C₂₋₅ alkoxycarbonyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, aryloxy-C₁₋₄ alkyl, acyloxy-C₁₋₄ alkyl, hydroxy-C₁₋₄ alkyl, acyloxy-C₂₋₅ alkanoyl, C₁₋₄ alkoxy-C₂₋₅ alkanoyl, hydroxy-­C₂₋₅ alkanoyl, aryloxy-C₂₋₅ alkanoyl or C₂₋₅ haloalkanoyl; R³ is hydrogen, C₁₋₈ alkyl, hydroxy-C₁₋₄ alkyl, C₂₋₅ alkanoyloxy-C₁₋₄ alkyl, aryl, aryl-C₁₋₄ alkyl, heteroaryl, heteroaryl-C₁₋₄ alkyl or aryl, aryl-C₁₋₄ alkyl, heteroaryl or heteroaryl-C₁₋₄ alkyl substituted by at least one substituent selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₂₋₅ alkanoylamino, C₁₋₄ haloalkyl, acyloxy, C₂₋₅ alkoxycarbonyl and carboxyl on the aromatic ring; m is 0, 1 or 2; n is 1 or 2; the bond represented by --- is a single bond or a double bond. Thiophene compounds (I) are useful as antianxiety drugs, hypnotics, antiepileptic drugs or nootropics. Thiophene compounds ( II ) are useful as intermediates for said thiophene compounds (I).

  式中的噻吩化合物： 其中 R¹ 是氢、硝基、氨基、卤素或 C₁₋₄ 烷基；R² 是氢、硝基、氨基、卤素、C₁₋₄ 烷基、C₁₋₄ 卤代烷基、酰基、C₂₋₅ 烷氧基羰基、C₁₋₄ 烷氧基-C₁₋₄ 烷基、芳氧基-C₁₋₄ 烷基、酰氧基-C₁₋₄ 烷基、羟基-C₁₋₄烷基、酰氧基-C₂₋₅ 烷酰基、C₁₋₄烷氧基-C₂₋₅ 烷酰基、羟基-C₂₋₅ 烷酰基、芳氧基-C₂₋₅ 烷酰基或 C₂₋₅ 卤代烷酰基；R³ 是氢、C₁₋₈烷基、羟基-C₁₋₄ 烷基、C₂₋₅烷酰氧基-C₁₋₄ 烷基、芳基、芳基-C₁₋₄ 烷基、杂芳基、杂芳基-C₁₋₄ 烷基或芳基、芳基-C₁₋₄ 烷基、杂芳基或杂芳基-C₁₋₄烷基被至少一个选自卤素、羟基、氨基、硝基、氰基组成的取代基取代、C₁₋₄ 烷基、C₁₋₄ 烷氧基、C₂₋₅烷酰氨基、C₁₋₄ 卤代烷基、酰氧基、C₂₋₅烷氧羰基和芳香环上的羧基；m 是 0、1 或 2；n 是 1 或 2；由----表示的键是单键或双键。 噻吩化合物（I）可用作抗焦虑药、催眠药、抗癫痫药或促智药。噻吩化合物（II）可用作上述噻吩化合物（I）的中间体。
• FUSED PYRIDAZINE COMPOUND AND PHARMACEUTICAL USE THEREOF
  申请人：YOSHITOMI PHARMACEUTICAL INDUSTRIES, LTD.

  公开号：EP0601184A1

  公开（公告）日：1994-06-15

  A fused pyridazine compound represented by the general formula (I) and an antianxiety drug containing the same as the active ingredient: wherein R¹ represents carboxyl, formyl, cyano, hydroxy-iminomethyl, acyl, etc.; R² represents hydrogen, C₁ to C₈ alkyl, hydroxyalkyl, alkanoyloxyalkyl, aryl, aralkyl, heteroaryl, etc.; A represents sulfur or -CH=CH-; E represents -CH₂- or -S(O)m-, wherein m represents 0, 1 or 2; n represents 1 or 2; and the bond represented by both solid and broken lines is either a single or a double bond; provided that when A represents sulfur, E represents -CH₂-, while when A represents -CH=CH-, E represents -S(O)m-, wherein m represents 0, 1 or 2, and n represents 2. This compound is reduced in side effects such as muscular relaxation, anesthesia potentiation, sedation, sleep/alcohol potentiation, etc., thus being useful as an antianxiety drug which selectively acts against anxiety.

  一种由通式(I)代表的融合哒嗪化合物和一种以其为有效成分的抗焦虑药物： 其中R¹代表羧基、甲酰基、氰基、羟基亚氨甲基、酰基等；R²代表氢、C₁至C₈烷基、羟基烷基、烷酰氧基烷基、芳基、芳烷基、杂芳基等。A代表硫或-CH＝CH-；E代表-CH₂-或-S(O)m-，其中m代表0、1或2；n代表1或2；实线和断线所代表的键为单键或双键；条件是当A代表硫时，E代表-CH₂-，而当A代表-CH＝CH-时，E代表-S(O)m-，其中m代表0、1或2，n代表2。这种化合物可减少副作用，如肌肉松弛、麻醉增效、镇静、睡眠/酒精增效等，因此可作为抗焦虑药物，选择性地对抗焦虑。
• Thiophene compounds and their use as intermediates in the preparation of antianxiety drugs, hypnotics, antiepileptic drugs and nuotropics
  申请人：YOSHITOMI PHARMACEUTICAL INDUSTRIES, LTD.

  公开号：EP0729960A1

  公开（公告）日：1996-09-04

  Thiophene compounds of the formula: wherein R1 is hydrogen, nitro, amino, halogen or C1-4 alkyl; R2 is hydrogen, nitro, amino, halogen, C1-4 alkyl, C1-4 haloalkyl, acyl, C2-5 alkoxycarbonyl, C1-4 alkoxy-C1-4 alkyl, aryloxy-C1-4 alkyl, acyloxy-C1-4 alkyl, hydroxy-C1-4 alkyl, acyloxy-C2-5 alkanoyl, C1-4 alkoxy-C2-5 alkanoyl, hydroxy-C2-5 alkanoyl, aryloxy-C2-5 alkanoyl or C2-5 haloalkanoyl; R3 is hydrogen, C1-8 alkyl, hydroxy-C1-4 alkyl, C2-5 alkanoyloxy-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl or aryl, aryl-C1-4 alkyl, heteroaryl or heteroaryl-C1-4 alkyl substituted by at least one substituent selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, C2-5 alkanoylamino, C1-4 haloalkyl, acyloxy, C2-5 alkoxycarbonyl and carboxyl on the aromatic ring; m is 0, 1 or 2; n is 1 or 2; the bond represented by ---- is a single bond or a double bond. Thiophene compounds () are useful as antianxiety drugs, hypnotics, antiepileptic drugs or nootropics. Thiophene compounds () are useful as intermediates for said thiophene compounds ().

  式中的噻吩化合物： 其中R1是氢、硝基、氨基、卤素或C1-4烷基；R2是氢、硝基、氨基、卤素、C1-4烷基、C1-4卤代烷基、酰基、C2-5烷氧基羰基、C1-4烷氧基-C1-4烷基、芳氧基-C1-4烷基、酰氧基-C1-4烷基、羟基-C1-4烷基、酰氧基-C2-5烷酰基、C1-4烷氧基-C2-5烷酰基、羟基-C2-5烷酰基、芳氧基-C2-5烷酰基或C2-5卤代烷酰基；R3 是氢、C1-8 烷基、羟基-C1-4 烷基、C2-5 烷酰氧基-C1-4 烷基、芳基、芳基-C1-4 烷基、杂芳基、杂芳基-C1-4 烷基或芳基、芳基-C1-4 烷基、在芳香环上被至少一个取代基取代的杂芳基或杂芳基-C1-4 烷基，该取代基选 自卤素、羟基、氨基、硝基、氰基、C1-4 烷基、C1-4 烷氧基、C2-5 烷酰氨基、C1-4 卤代烷基、酰氧基、C2-5 烷氧羰基和羧基组成的组；m 是 0、1 或 2；n 是 1 或 2；---- 所代表的键是单键或双键。 噻吩化合物（）可用作抗焦虑药、催眠药、抗癫痫药或健脑药。噻吩化合物（）可用作上述噻吩化合物（）的中间体。