4-(4-methoxy-2-methylthiophenyl)-N-Cbz-piperidine | 255050-45-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-(4-methoxy-2-methylthiophenyl)-N-Cbz-piperidine
• 英文别名: Benzyl 4-(4-methoxy-2-methylsulfanylphenyl)piperidine-1-carboxylate
• CAS: 255050-45-4
• 化学式: C₂₁H₂₅NO₃S
• 分子量: 371.5
• InChiKey: QMJCSDQVXJTUGV-UHFFFAOYSA-N

物化性质

• 沸点：
  499.8±45.0 °C(Predicted)
• 密度：
  1.20±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  64.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(4-methoxy-2-methylthiophenyl)-N-Cbz-piperidine 在 titanium(IV) isopropylate 、 叔丁基过氧化氢 、 氢氧化钾 、 D-(-)-酒石酸二乙酯 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 162.0h， 生成 4-(4-methoxy-2-(S)-methylsulfinylphenyl)piperidine
  参考文献：
  名称：

  Design, Synthesis, and SAR of Tachykinin Antagonists:  Modulation of Balance in NK₁/NK₂ Receptor Antagonist Activity

  摘要：

  Through optimization of compounds based on the dual NK1/NK2 antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK1 and NK2 potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK1 potency and thus afforded NK1 preferential antagonists. Alterations of the piperidine region could then increase NK2 potency to restore dual NK1/NK2 selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK1/NK2 antagonists, and the third is an NK1 preferential antagonist. In this paper, the factors affecting the balance of NK1 and NK2 selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.

  DOI：

  10.1021/jm020094i
• 作为产物：
  描述：

  2-溴-5-甲氧基苯酚 在 三乙烯二胺 、 三乙基硅烷 、 氢氧化钾 、 正丁基锂 、 potassium carbonate 、 三氟乙酸 、 N,N-二乙基苯胺 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 80.5h， 生成 4-(4-methoxy-2-methylthiophenyl)-N-Cbz-piperidine
  参考文献：
  名称：

  Design, Synthesis, and SAR of Tachykinin Antagonists:  Modulation of Balance in NK₁/NK₂ Receptor Antagonist Activity

  摘要：

  Through optimization of compounds based on the dual NK1/NK2 antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK1 and NK2 potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK1 potency and thus afforded NK1 preferential antagonists. Alterations of the piperidine region could then increase NK2 potency to restore dual NK1/NK2 selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK1/NK2 antagonists, and the third is an NK1 preferential antagonist. In this paper, the factors affecting the balance of NK1 and NK2 selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.

  DOI：

  10.1021/jm020094i

文献信息

• N-substituted naphthalene carboxamides as neurokinin-receptor antagonists
  申请人：Astra Zeneca AB

  公开号：US06365602B1

  公开（公告）日：2002-04-02

  A compound of formula I wherein: R is alkyl; R1 is optionally substituted phenyl 2-oxo-tetrahydro-1(2H)-pyrimidinyl, or 2-oxo-1-piperidinyl; R2 is hydrogen, alkoxy, alkanoyloxy, alkoxycarbonyl, alkanoylamino, acyl, alkyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl where the alkyl groups are the same or different, hydroxy, thioacyl, thiocarbamoyl, N-alkylthiocarbamoyl, or N,N-dialkylthiocarbamoyl where the alkyl groups are the same or different. X1 and X2 are independently hydrogen or halo, provided that at least one of X1 or X2 is halo; and R3, R4, R5 and R6 are independently hydrogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, or alkylsulfonyl are antagonists of at least one tachykinin receptor and are useful in the treatment of depression, anxiety, asthma, pain, inflammation, urinary incontinence and other disease conditions. Process for their preparation are described, as are compositions containing them and their use.

  公式I的化合物中：R是烷基；R1是可选择地取代的苯基2-氧代四氢-1(2H)-嘧啶基，或2-氧代-1-哌啶基；R2是氢、烷氧基、烷酰氧基、烷氧羰基、烷酰胺基、酰基、烷基、氨基甲酰基、N-烷基氨基甲酰基、N,N-二烷基氨基甲酰基（其中烷基基团相同或不同）、羟基、硫代酰基、硫代氨基甲酰基、N-烷基硫代氨基甲酰基、或N,N-二烷基硫代氨基甲酰基（其中烷基基团相同或不同）。X1和X2独立地为氢或卤素，但至少X1或X2中的一个为卤素；R3、R4、R5和R6独立地为氢、氰基、硝基、三氟甲氧基、三氟甲基、或烷基磺酰基，它们是至少一种催吐肽受体的拮抗剂，对治疗抑郁症、焦虑症、哮喘、疼痛、炎症、尿失禁和其他疾病情况有用。描述了它们的制备方法，以及含有它们和它们的用途的组合物。
• A New Approach to Rapid Parallel Development of Four Neurokinin Antagonists. Part 4. Synthesis of ZD2249 Methoxy Sulfoxide
  作者：Sharon A. Bowden、J. Nigel Burke、Fiona Gray、Steven McKown、Jonathan D. Moseley、William O. Moss、Paul M. Murray、Matthew J. Welham、Maureen J. Young

  DOI：10.1021/op030039z

  日期：2004.1.1

  The manufacture of ZD2249 methoxy sulfoxide (1) using a new project approach is described. Research department processes were scaled up to 100 L if process safety and robustness were not compromised; other factors were treated according to the new approach. Using this strategy, we were able to manufacture a key intermediate on sufficient scale to support delivery of 1 kg quantities of bulk drug within

  描述了使用新的项目方法制造 ZD2249 甲氧基亚砜 (1)。如果过程安全性和稳健性不受影响，研究部门的过程可扩大到 100 L；其他因素按照新方法处理。使用这种策略，我们能够在实验室工作开始后的 6 个月内制造出足够规模的关键中间体，以支持交付 1 公斤的原料药。
• [EN] NAPHTHALENECARBOXAMIDES AS TACHYKININ RECEPTOR ANTAGONISTS<br/>[FR] NAPHTALENE-CARBOXAMIDES UTILISES EN TANT QU'ANTAGONISTES DES RECEPTEURS DES TACHYKININES
  申请人：ZENECA LTD

  公开号：WO2000020389A1

  公开（公告）日：2000-04-13

  A compound having formula (I) wherein R1 is oxo, -ORa, -OC(=O)Rb; or (A); R2 is H; or R?1 is -ORc and R2 is -ORd; or R1 and R2¿ together form -O(CH¿2?)mO-; and any pharmaceutically-acceptable salt thereof along with their use in treating depression, anxiety, asthma, rheumatoid arthritis, Alzheimer's disease, cancer, schizophrenia, oedema, allergic rhinitis, inflammation, pain, gastrointestinal-hypermotility, anxiety, emesis, Huntington's disease, psychoses including depression, hypertension, migraine, bladder hypermotility, or urticaria, along with methods of making the compounds and pharmaceutical compositions containing the compounds.

  化合物式(I)的化合物，其中R1是氧代、-ORa、-OC（=O）Rb；或（A）；R2是H；或者R1是-ORc且R2是-ORd；或者R1和R2在一起形成-O（CH2）mO-；以及其任何药学上可接受的盐，用于治疗抑郁症、焦虑症、哮喘、类风湿性关节炎、阿尔茨海默病、癌症、精神分裂症、水肿、过敏性鼻炎、炎症、疼痛、胃肠过度运动、焦虑症、呕吐、亨廷顿病、包括抑郁症、高血压、偏头痛、膀胱过度运动或荨麻疹的方法，以及制备这些化合物和含有这些化合物的制药组合物。
• [EN] N-SUBSTITUTED NAPHTHALENE CARBOXAMIDES AS NEUROKININ-RECEPTOR ANTAGONISTS<br/>[FR] NAPHTALENE CARBOXAMIDES N-SUBSTITUES EN TANT QU'ANTAGONISTES DE RECEPTEURS DES NEUROKININES
  申请人：ZENECA LTD

  公开号：WO2000002859A1

  公开（公告）日：2000-01-20

  A compound of formula (I) wherein: R is alkyl; R1 is optionally substituted phenyl, 2-oxo-tetrahydro-1(2H)-pyrimidinyl, or 2-oxo-1-piperidinyl; R2 is hydrogen, alkoxy, alkanoyloxy, alkoxycarbonyl, alkanoylamino, acyl, alkyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl where the alkyl groups are the same or different, hydroxy, thioacyl, thiocarbamoyl, N-alkylthiocarbamoyl, or N,N-dialkylthiocarbamoyl where the alkyl groups are the same or different. X¿1? and X2 are independently hydrogen or halo, provided that at least one of X1 or X2 is halo; and R?3, R4, R5, and R6¿ are independently hydrogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, or alkylsulfonyl are antagonists of at least one tachykinin receptor and are useful in the treatment of depression, anxiety, asthma, pain, inflammation, urinary incontinence and other disease conditions. Processes for their preparation are described, as are compositions containing them and their use.

  化合物的化学式(I)，其中：R为烷基; R1为可选取代的苯基，2-氧代-四氢-1(2H)-嘧啶基或2-氧代-1-哌啶基; R2为氢、烷氧基、烷酰氧基、烷氧羰基、烷酰胺、烷基、氨基甲酰、N-烷基氨基甲酰、N,N-二烷基氨基甲酰，其中烷基团相同或不同，羟基、硫代酰基、硫代氨基、N-烷基硫代氨基、N,N-二烷基硫代氨基，其中烷基团相同或不同。X1和X2独立地为氢或卤素，但至少其中之一为卤素; R3、R4、R5和R6独立地为氢、氰基、硝基、三氟甲氧基、三氟甲基或烷基磺酰基，是至少一种快速激动肽受体的拮抗剂，可用于治疗抑郁症、焦虑症、哮喘、疼痛、炎症、尿失禁和其他疾病。描述了它们的制备过程，以及包含它们和它们的使用的组合物。
• Naphthalenecarboxamides as tachykinin receptor antagonists
  申请人：AstraZeneca AB

  公开号：EP1433783A2

  公开（公告）日：2004-06-30

  A compound having the formula (I) wherein R1 is oxo, -ORa, -OC(=O)Rb; or (A); R2 is H; or R1 is -ORc and R2 is -ORd; or R1 and R2 together form -O(CH2)mO-; R3 is H or alkyl; R4, R5 and R6 are independently selected from hydroxy, cyano, nitro, trifluoromethoxy, trifluoromethyl, alkylsulfonyl, halo, alkoxy, alkyl, cyanoalkyl, alkenyl, alkynyl, carboxy, alkoxy-carbonyl, carbamoyl, alkylcarbamoyl, di-alkylcarbamoyl, alkanoyl, alkanoylamino, aminosulfonyl, and substituted alkyl; or R4 and R5 together form -OCH2O- or -OC(CH3)2O-; R6 may additionally be hydrogen; R7 is substituted phenyl; R8 is selected from hydrogen, hydroxy, alkoxy, alkanoyloxy, alkanoyl, alkoxycarbonyl, alkanoylamino, alkyl, carbamoyl, alkylcarbamoyl, and bis(alkyl)carbamoyl; Ra is hydrogen or alkyl; Rb is alkyl, aryl or arylalkyl; Rc and Rd are independently selected from alkyl; m is 2, 3, or 4; and X1 and X2 are independently H or halogen, wherein at least one of X1 and X2 are halogen; and any pharmaceutically-acceptable salt thereof along with their use in treating depression, anxiety, asthma, rheumatoid arthritis, Alzheimer's disease, cancer, schizophrenia, oedema, allergic rhinitis, inflammation, pain, gastrointestinal-hypermotility, anxiety, emesis, Huntington's disease, psychoses including depression, hypertension, migraine, bladder hypermotility, or urticaria, along with methods of making the compounds and pharmaceutical compositions containing the compounds.

  具有式 (I) 的化合物 其中 R1 是氧代、-ORa、-OC(=O)Rb；或 (A)； R2 是 H；或 R1 是-ORc，R2 是-ORd；或 R1 和 R2 共同形成-O(CH2)mO-； R3 是 H 或烷基；R4、R5 和 R6 独立选自羟基、氰基、硝基、三氟甲氧基、三氟甲基、烷基磺酰基、卤代、烷氧基、烷基、氰基烷基、烯基、炔基、羧基、烷氧基羰基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、烷酰基、烷酰氨基、氨基磺酰基和取代烷基；或 R4 和 R5 共同形成 -O O- 或 -OC(CH3)2O-；R6 还可以是氢；R7 是取代的苯基；R8 选自氢、羟基、烷氧基、烷酰氧基、烷酰基、烷氧羰基、烷酰氨基、烷基、氨基甲酰基、烷基氨基甲酰基和双(烷基)氨基甲酰基；Ra 是氢或烷基；Rb 是烷基、芳基或芳烷基；Rc 和 Rd 独立地选自烷基；m 是 2、3 或 4；以及 X1 和 X2 独立地是 H 或卤素，其中 X1 和 X2 中至少有一个是卤素；及其任何药学上可接受的盐，以及它们在治疗抑郁症、焦虑症、哮喘、类风湿性关节炎、阿尔茨海默病、癌症、精神分裂症、水肿、过敏性鼻炎、炎症、疼痛、胃肠道过度运动、焦虑症、呃逆、亨廷顿氏病、包括抑郁症在内的精神病、高血压、偏头痛、膀胱过度运动或荨麻疹中的用途，以及制造这些化合物和含有这些化合物的药物组合物的方法。