3-[4-(butylthio)-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[2.2.2]octane | 141593-42-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 奎宁环
• 英文名称: 3-[4-(butylthio)-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[2.2.2]octane
• 英文别名: Vedaclidine；3-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.-2.2]octane；3-(1-azabicyclo[2.2.2]octan-3-yl)-4-butylsulfanyl-1,2,5-thiadiazole
• CAS: 141593-42-2
• 化学式: C₁₃H₂₁N₃S₂
• 分子量: 283.462
• InChiKey: WZZPXVURFDJHGI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  82.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-[4-(butylthio)-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[2.2.2]octane 生成 (-)-3-(3-butylthio-1,2,5-thiadiazol-4-yl)-quinuclidine
  参考文献：
  名称：

  3-(3-Alkylthio-1,2,5-thiadiazol-4-yl)-1-azabicycles. Structure—activity relationships for antinociception mediated by central muscarinic receptors

  摘要：

  3-(3-Alkylthio-1,2,5-thiadiazol-4-yl)-1-azabicycles (quinuclidines 7a-f; exo-1-azanorbornanes 8a-f and endo-1-azanorbornanes 9a-f) constitute a new class of muscarinic antinociceptive agents. A novel route for the synthesis of these compounds was constructed starting from the azabicyclic ketones. The compounds showed high affinity for muscarinic receptors as evidenced by inhibition of [H-3]oxotremorine-M ([H-3]Oxo-M) binding to brain homogenate (IC50 = 0.49-26 nM). In vivo, the compounds produced antinociception in the mouse grid shock test at doses well below those that produced salivation and tremor, with more than a 50-fold separation for some compounds. The enantiomers of 3-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.2]octane 7d exhibited little enantioselectivity with regard to either receptor affinity or analgesic activity.

  DOI：

  10.1016/0223-5234(96)89138-0
• 作为产物：
  描述：

  3-奎宁环酮盐酸盐 在 palladium on activated charcoal 、 5% Pd on active carbon 二氯化二硫 、 sodium hydrogensulfide 、 氢气 、 sodium methylate 、 sodium ethanolate 、 potassium carbonate 、 三乙胺 、 亚硝酸异戊酯 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 25.0~80.0 ℃ 、101.33 kPa 条件下， 反应 4.0h， 生成 3-[4-(butylthio)-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[2.2.2]octane
  参考文献：
  名称：

  Muscarinic Analgesics with Potent and Selective Effects on the Gastrointestinal Tract:  Potential Application for the Treatment of Irritable Bowel Syndrome

  摘要：

  Irritable bowel syndrome (IBS) is a pathopysiolocal condition characterized by abnormal bowel habits that are frequently accompanied by abdominal pain. Current therapy based on reducing high-amplitude GI contractions with nonselective muscarinic antagonists is limited in efficacy due to typical muscarinic side effects and provides no pain relief. We have previously found potent antinociceptive agents acting through muscarinic receptors. In the present work, new 1,2,5-thiadiazole-based structures with muscarinic activity have been evaluated both for activity as analgesics in the mouse withing assay and for activity in normalizing spontaneous cluster contractions in ferret jejunum as a model of IBS in humans. (5R,6R)-exo-6-[4-[(4,4,4-Trifluorobutyl)thio]-1,2,5-thiadiazol-3-yl]-1-azabicyclo[3.2.1]octane (35, LY316108/NNC11-2192) was found to offer an exceptional profile combining analgesic potency in mouse writhing (ED(50) = 0.1 mg/kg) along with potency for normalization of GI motility (ED(50) = 0.17 mg/kg). This combination of GI and analgesic potency suggests 35 as an excellent candidate for evaluation as a potential treatment of IBS.

  DOI：

  10.1021/jm9602470

文献信息

• [EN] HETEROCYCLIC COMPOUNDS AND THEIR PREPARATION AND USE
  申请人：NOVO NORDISK A/S

  公开号：WO1992003433A1

  公开（公告）日：1992-03-05

  (EN) The present invention relates to therapeutically active piperidine compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds of formula (I), wherein X is oxygen or sulphur; wherein G is selected from the group of azabicyclic ring systems consisting of (1), (2), or (3) wherein the oxadiazole or thiadiazole ring can be attached at any position. The novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer's disease, severe painful conditions and glaucoma.(FR) La présente invention se rapporte à des composés de pipéridine thérapeutiquement actifs, à un procédé de préparation de ceux-ci et à des compositions pharmaceutiques comprenant les composés. Dans la formule (I), X représente de l'oxygène ou du soufre; G étant sélectionné dans le groupe de systèmes de cycles azabicycliques de formules (1), (2) ou (3), où le cycle d'oxadiazole ou de thiadiazole peut être rattaché en n'importe quelle position. Les nouveaux composés sont utiles comme stimulants de la fonction cognitive du cerveau antérieur et de l'hippocampe des mammifères et, en particulier, dans le traitement de la maladie d'Alzheimer, des états douloureux aigus ainsi que du glaucome.

  本发明涉及治疗活性哌啶化合物，其制备方法以及包含式(I)化合物的制药组合物，其中X代表氧或硫；G选择自由氮杂双环环系的组中，包括式(1)、(2)或(3)，其中氧二唑或硫二唑环可以连接在任何位置。这些新化合物可用作哺乳动物前脑和海马的认知功能刺激剂，特别适用于治疗阿尔茨海默病、严重疼痛和青光眼。
• Method for treating anxiety using an azabicyclic oxadiazole or thiadiazole compound
  申请人：ELI LILLY AND COMPANY

  公开号：EP0709093A2

  公开（公告）日：1996-05-01

  The present invention provides the use of a compound wherein X is oxygen or sulphur; R is hydrogen, amino, halogen, -CHO, -NO₂, -OR⁴, -SR⁴, -SOR⁴, -SO₂R⁴, C₃₋₇-cycloalkyl, C₄₋₈-(cycloalkylalkyl), -Z-C₃₋₇-cycloalkyl, and -Z-C₄₋₈-(cycloalkylalkyl) wherein R⁴ is straight or branched C₁₋₁₅-alkyl, straight or branched C₂₋₁₅-alkenyl, straight or branched C₂₋₁₅-alkynyl, each of which is optionally substituted with one or more halogens, -CF₃, -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, C₁₋₄-alkyl, C₁₋₄-alkoxy, -OCF₃, -CONH₂ or -CSNH₂; or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, C₁₋₄-alkyl, C₁₋₄-alkoxy, -OCF₃, -CONH₂ or -CSNH₂; or R is -OR⁵Y, -SR⁵Y, -OR⁵ZY, -SR⁵ZY, -O-R⁴-Z-R⁵ or -S-R⁴-Z-R⁵ wherein Z is oxygen or sulphur, R5 is straight or branched C₁₋₁₅-alkynyl, and Y is a 5 or 6 membered heterocyclic group containing one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched C₁₋₆-alkyl, phenyl or benzyl, or which heterocyclic group is optionally fused with a phenyl group; and G is selected from one of the following azabicyclic rings wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R¹ and R may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C₁₋₅-alkyl, straight or branched C₂₋₅ alkenyl, straight or branched C₂₋₅-alkynyl, straight or branched C₁₋₁₀-alkoxy, straight or branched C₁₋₅-alkyl substituted with -OH, OR⁴, halogen, -NH₂ or carboxy; R³ is H, straight or branched C₁₋₅-alkyl, straight or branched C₂₋₅-alkenyl or straight or branched C₂₋₅-alkynyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; q is 1 or 2; and --- is a single or double bond; or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of anxiety.

  本发明提供了一种化合物的用途 其中 X 是氧或硫 R 是氢、氨基、卤素、-CHO、-NO₂、-OR⁴、-SR⁴、-SOR⁴、-SO₂R⁴、C₃₋₇-环烷基、C₄₋₈-(环烷基)、-Z-C₃₋₇-环烷基、和 -Z-C₄₋₈-(环烷基)，其中 R⁴ 是直链或支链 C₁₋₁₅-烷基、直链或支链 C₂₋₁₅- 烷基、直链或支链 C₂₋₁₅-炔基，其中每个均任选被一个或多个卤素、-CF₃、-CN、苯基或苯氧基，其中苯基或苯氧基任选被卤素、-CN、C₁₋₄-烷基、C₁₋₄-烷氧基、-OCF₃、-CONH₂或-CSNH₂取代；或 R 是苯基或苄氧羰基，它们各自被卤素、-CN、C₁₋₄-烷基、C₁₋₄-烷氧基、-OCF₃、-CONH₂或-CSNH₂任选取代；或 R 是 -OR⁵Y、-SR⁵Y、-OR⁵ZY、-SR⁵ZY、-O-R⁴-Z-R⁵ 或 -S-R⁴-Z-R⁵，其中 Z 是氧或硫、R5 是直链或支链 C₁₋₁₅-炔基，Y 是含有 1 至 4 个 N、O 或 S 原子的 5 或 6 位杂环基团、O 原子或 S 原子或其组合，该杂环基团可选择在碳原子或氮原子上被直链或支链 C₁₋₆-烷基、苯基或苄基取代，或该杂环基团可选择与苯基融合；G 选自下列偶氮双环之一 其中噻二唑或噁二唑环可连接在氮杂环的任何碳原子上；R¹ 和 R 可存在于任何位置，包括噻二唑或噁二唑环的连接点，且独立地为氢、直链或支链 C₁₋₅ 烷基、直链或支链 C₂₋₅ 烯基、直链或支链 C₂₋₅ 炔基、直链或支链 C₁₋₁₀-烷氧基、被 -OH、OR⁴、卤素、-NH₂ 或羧基取代的直链或支链 C₁₋₅-烷基；R³ 是 H、直链或支链 C₁₋₅-烷基、直链或支链 C₂₋₅-烯基或直链或支链 C₂₋₅-炔基；n 是 0、1 或 2；m 是 0、1 或 2；p 是 0、1 或 2；q 是 1 或 2；以及---是单键或双键；或 其药学上可接受的盐，用于制造治疗焦虑症的药物。
• Method for treating anxiety using a tetrahydropyridine or azabicyclic oxadiazole or thiadiazole compound
  申请人：ELI LILLY AND COMPANY

  公开号：EP0709095A2

  公开（公告）日：1996-05-01

  The present invention provides a method for treating anxiety in humans using heterocyclic compounds as listed in Claim 1.

  本发明提供了一种使用权利要求 1 所列杂环化合物治疗人类焦虑症的方法。
• METHODS AND COMPOSITIONS FOR TREATMENT OF DISORDERS AMELIORATED BY MUSCARINIC RECEPTOR ACTIVATION
  申请人：Puretech Ventures

  公开号：EP3061821A1

  公开（公告）日：2016-08-31

  Methods for the treatment of CNS disorders using combinations of muscarinic activators and inhibitors, and medicaments comprising muscarinic activators and inhibitors.

  使用毒蕈碱激活剂和抑制剂组合治疗中枢神经系统疾病的方法，以及包含毒蕈碱激活剂和抑制剂的药物。
• NICOTINIC CHANNEL SUBUNITS OF POLLINATOR INSECTS AND THEIR USES THEREOF
  申请人：Centre National de la Recherche Scientifique (C.N.R.S.)

  公开号：EP3118219A1

  公开（公告）日：2017-01-18

  The present invention relates to the cloning of the nicotinic acetylcholine receptors (nAChR) subunits in species from the phylum arthropoda and in particular a pollinator insect such as Apis mellifera and their uses thereof.

  本发明涉及节肢动物门物种，特别是授粉昆虫（如蜜蜂）中烟碱乙酰胆碱受体（nAChR）亚基的克隆及其用途。