3-[(1Z)-6-(dimethylamino)-6-oxohex-1-en-1-yl]benzoic acid | 1246959-90-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-[(1Z)-6-(dimethylamino)-6-oxohex-1-en-1-yl]benzoic acid
• 英文别名: 3-[(Z)-6-(dimethylamino)-6-oxohex-1-enyl]benzoic acid
• CAS: 1246959-90-9
• 化学式: C₁₅H₁₉NO₃
• 分子量: 261.321
• InChiKey: RQNMWYQJSQJPDI-DAXSKMNVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  57.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-[(1Z)-6-(dimethylamino)-6-oxohex-1-en-1-yl]benzoic acid 在 lithium hydroxide monohydrate 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 水 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 (Z)-(3-(6-(dimethylamino)-6-oxohex-1-en-1-yl)benzoyl)-D-alanine
  参考文献：
  名称：

  [EN] BENZAMIDE DERIVATIVES USEFUL IN THE TREATMENT OF MUSCULAR DISORDERSAND PAIN AND FOR CONTROLLING SPASTICITY AND TREMORS
  [FR] DÉRIVÉS DE BENZAMIDE UTILES DANS LE TRAITEMENT DES TROUBLES ET DE LA DOULEUR MUSCULAIRE(S) ET POUR LE CONTRÔLE DE LA SPASTICITÉ ET DES TREMBLEMENTS

  摘要：

  本发明涉及式I的化合物，或其药学上可接受的盐：（I）其中：n为0或1；R1从H、烷基和芳基中选择，其中所述烷基和芳基基团可以选择性地被一个或多个羟基取代；X是从-C≡C-(CH2)p-；-C(R5)=C(R6)-(CH2)q-；和-C(R5)(R6)C(R7)(R8)-(CH2)r-中选择的基团；其中R5、R6、R7和R8中的每一个独立地为H或烷基，p、q和r中的每一个独立地为1、2、3、4或5；Y是从中选择的基团：CN；COOR2；CONR3R4；SO2NR9R10；NR12COR13；NR14SO2R15；和从氧代噻二唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡唑基和咪唑基中选择的杂环基；其中R2、R3和R4中的每一个独立地为H或烷基；或R3和R4与它们附着的氮一起连接，形成一个5或6-成员杂环烷基或杂环烯基基团，所述杂环烷基或杂环烯基基团可以选择性地含有一个或多个进一步从O、N、CO和S中选择的基团，以及R9、R10、R11、R12、R13、R14和R15中的每一个独立地为H或烷基。该发明的进一步方面涉及在制备用于治疗肌肉障碍、疼痛、或用于控制痉挛或震颤的药物时使用这些化合物，例如，多发性硬化症中的痉挛。

  公开号：

  WO2015082938A1
• 作为产物：
  描述：

  间溴苯甲酸 在 哌啶 、 喹啉 、 bis-triphenylphosphine-palladium(II) chloride 、 5% palladium on barium sulphate 、 氢气 作用下， 以 甲醇 为溶剂， 反应 1.0h， 生成 3-[(1Z)-6-(dimethylamino)-6-oxohex-1-en-1-yl]benzoic acid
  参考文献：
  名称：

  [EN] BENZAMIDE DERIVATIVES USEFUL IN THE TREATMENT OF MUSCULAR DISORDERSAND PAIN AND FOR CONTROLLING SPASTICITY AND TREMORS
  [FR] DÉRIVÉS DE BENZAMIDE UTILES DANS LE TRAITEMENT DES TROUBLES ET DE LA DOULEUR MUSCULAIRE(S) ET POUR LE CONTRÔLE DE LA SPASTICITÉ ET DES TREMBLEMENTS

  摘要：

  本发明涉及式I的化合物，或其药学上可接受的盐：（I）其中：n为0或1；R1从H、烷基和芳基中选择，其中所述烷基和芳基基团可以选择性地被一个或多个羟基取代；X是从-C≡C-(CH2)p-；-C(R5)=C(R6)-(CH2)q-；和-C(R5)(R6)C(R7)(R8)-(CH2)r-中选择的基团；其中R5、R6、R7和R8中的每一个独立地为H或烷基，p、q和r中的每一个独立地为1、2、3、4或5；Y是从中选择的基团：CN；COOR2；CONR3R4；SO2NR9R10；NR12COR13；NR14SO2R15；和从氧代噻二唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡唑基和咪唑基中选择的杂环基；其中R2、R3和R4中的每一个独立地为H或烷基；或R3和R4与它们附着的氮一起连接，形成一个5或6-成员杂环烷基或杂环烯基基团，所述杂环烷基或杂环烯基基团可以选择性地含有一个或多个进一步从O、N、CO和S中选择的基团，以及R9、R10、R11、R12、R13、R14和R15中的每一个独立地为H或烷基。该发明的进一步方面涉及在制备用于治疗肌肉障碍、疼痛、或用于控制痉挛或震颤的药物时使用这些化合物，例如，多发性硬化症中的痉挛。

  公开号：

  WO2015082938A1

文献信息

• [EN] BENZAMIDE DERIVATIVES USEFUL IN THE TREATMENT OF MUSCULAR DISORDERSAND PAIN AND FOR CONTROLLING SPASTICITY AND TREMORS<br/>[FR] DÉRIVÉS DE BENZAMIDE UTILES DANS LE TRAITEMENT DES TROUBLES ET DE LA DOULEUR MUSCULAIRE(S) ET POUR LE CONTRÔLE DE LA SPASTICITÉ ET DES TREMBLEMENTS
  申请人：CANBEX THERAPEUTICS LTD

  公开号：WO2015082938A1

  公开（公告）日：2015-06-11

  The present invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof : (I) wherein: n is 0 or 1; R1 is selected from H, alkyl and aralkyl, wherein said alkyl and aralkyl groups may be optionally substituted by one or more OH groups; X is a group selected from -C≡C-(CH2)p-; -C(R5)=C(R6)-(CH2)q-; and -C(R5)(R6)C(R7)(R8)-(CH2)r-; where each of R5, R6, R7 and R8 is independently H or alkyl, and each of p, q and r is independently 1, 2, 3, 4 or 5; Y is a group selected from: CN; COOR2; CONR3R4; SO2NR9R10; NR12COR13; NR14SO2R15; and a heterocyclic group selected from oxadiazolyl, thiazolyl, iso- thiazolyl, oxazolyl, iso-oxazolyl, pyrazolyl and imidazolyl; where each of R2, R3 and R4 is independently H or alkyl; or R3 and R4 are linked, together with the nitrogen to which they are attached, to form a 5 or 6-membered heterocycloalkyl or heterocycloalkenyl group, said heterocycloalkyl or heterocycloalkenyl group optionally containing one or more further groups selected from O, N, CO and S, and where each of R9, R10, R11, R12, R13, R14 and R15 is independently H or alkyl. Further aspects of the invention relate to the use of such compounds in the preparation of a medicament for the treatment of a muscular disorder, pain, or for controlling spasticity or tremors, for example, spasticity in MS.

  本发明涉及式I的化合物，或其药学上可接受的盐：（I）其中：n为0或1；R1从H、烷基和芳基中选择，其中所述烷基和芳基基团可以选择性地被一个或多个羟基取代；X是从-C≡C-(CH2)p-；-C(R5)=C(R6)-(CH2)q-；和-C(R5)(R6)C(R7)(R8)-(CH2)r-中选择的基团；其中R5、R6、R7和R8中的每一个独立地为H或烷基，p、q和r中的每一个独立地为1、2、3、4或5；Y是从中选择的基团：CN；COOR2；CONR3R4；SO2NR9R10；NR12COR13；NR14SO2R15；和从氧代噻二唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡唑基和咪唑基中选择的杂环基；其中R2、R3和R4中的每一个独立地为H或烷基；或R3和R4与它们附着的氮一起连接，形成一个5或6-成员杂环烷基或杂环烯基基团，所述杂环烷基或杂环烯基基团可以选择性地含有一个或多个进一步从O、N、CO和S中选择的基团，以及R9、R10、R11、R12、R13、R14和R15中的每一个独立地为H或烷基。该发明的进一步方面涉及在制备用于治疗肌肉障碍、疼痛、或用于控制痉挛或震颤的药物时使用这些化合物，例如，多发性硬化症中的痉挛。
• [EN] PROCESS FOR PREPARING CARBOXYLIC ACID AMIDES USEFUL IN THE TREATMENT OF MUSCULAR DISORDERS<br/>[FR] PROCÉDÉ
  申请人：UCL BUSINESS PLC

  公开号：WO2010116116A1

  公开（公告）日：2010-10-14

  The present invention relates to a process for preparing a compound of formula wherein: R2 is cycloalkyl or alkyl, each of which may be optionally substituted; Y is -CONR3R4, -CN or CO2R5; R3, R4 and R5 are each independently H or alkyl; n is 1 to 6; wherein said process comprising the steps of : (i) treating a compound of formula (IV), where R1 is alkyl, with a compound of formula (V) and forming a compound of formula (IIIb); (ii) treating said compound of formula (IIIb) with a compound of formula (Il) to form a compound of formula (I).

  本发明涉及一种制备化合物的过程，其化学式为其中：R2为环烷基或烷基，每种均可选择性地被取代；Y为-CONR3R4，-CN或CO2R5；R3、R4和R5分别独立地为H或烷基；n为1至6；其中所述过程包括以下步骤：(i) 用具有化学式（IV）的化合物处理化学式（V）的化合物，并形成化学式（IIIb）的化合物；(ii) 用化学式（IIIb）的化合物处理化学式（Il）的化合物，形成化学式（I）的化合物。
• PROCESS FOR PREPARING CARBOXYLIC ACID AMIDES USEFUL IN THE TREATMENT OF MUSCULAR DISORDERS
  申请人：Selwood David

  公开号：US20120101301A1

  公开（公告）日：2012-04-26

  The present invention relates to a process for preparing a compound of formula wherein: R 2 is cycloalkyl or alkyl, each of which may be optionally substituted; Y is —CONR 3 R 4 , —CN or CO 2 R 5 ; R 3 , R 4 and R 5 are each independently H or alkyl; n is 1 to 6; wherein said process comprising the steps of: (i) treating a compound of formula (IV), where R 1 is alkyl, with a compound of formula (V) and forming a compound of formula (IIIb); (ii) treating said compound of formula (IIIb) with a compound of formula (I1) to form a compound of formula (I).

  本发明涉及一种制备以下式子化合物的方法：其中：R2是环烷基或烷基，每个基团都可以选择性地被取代；Y是—CONR3R4，—CN或CO2R5；R3、R4和R5分别是H或烷基；n为1到6；其中所述方法包括以下步骤：(i)用式子(IV)化合物（其中R1是烷基）处理式子(V)化合物，形成式子(IIIb)化合物；(ii)用式子(I1)化合物处理所述式子(IIIb)化合物，形成式子(I)化合物。
• Big conductance calcium-activated potassium channel openers control spasticity without sedation
  作者：David Baker、Gareth Pryce、Cristina Visintin、Sofia Sisay、Alexander I Bondarenko、W S Vanessa Ho、Samuel J Jackson、Thomas E Williams、Sarah Al-Izki、Ioanna Sevastou、Masahiro Okuyama、Wolfgang F Graier、Lesley A Stevenson、Carolyn Tanner、Ruth Ross、Roger G Pertwee、Christopher M Henstridge、Andrew J Irving、Jesse Schulman、Keith Powell、Mark D Baker、Gavin Giovannoni、David L Selwood

  DOI：10.1111/bph.13889

  日期：2017.8

  Background and PurposeOur initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis (MS), whilst avoiding the sedative side effects associated with cannabis. VSN16R was synthesized as an anandamide (endocannabinoid) analogue in an anti‐metabolite approach to identify drugs that target spasticity.Experimental ApproachFollowing the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue‐based assays and in vivo animal models, were used to demonstrate the activity, efficacy, pharmacokinetics and mechanism of action of VSN16R. Toxicological and safety studies were performed in animals and humans.Key ResultsVSN16R had nanomolar activity in tissue‐based, functional assays and dose‐dependently inhibited spasticity in a mouse experimental encephalomyelitis model of MS. This effect occurred with over 1000‐fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that are feasible and safe in humans. VSN16R did not bind to known CB1/CB2/GPPR55 cannabinoid‐related receptors in receptor‐based assays but acted on a vascular cannabinoid target. This was identified as the major neuronal form of the big conductance, calcium‐activated potassium (BKCa) channel. Drug‐induced opening of neuronal BKCa channels induced membrane hyperpolarization, limiting excessive neural‐excitability and controlling spasticity.Conclusions and ImplicationsWe identified the neuronal form of the BKCa channel as the target for VSN16R and demonstrated that its activation alleviates neuronal excitability and spasticity in an experimental model of MS, revealing a novel mechanism to control spasticity. VSN16R is a potential, safe and selective ligand for controlling neural hyper‐excitability in spasticity.
• CRYSTALLINE FORM OF VSN16
  申请人：UCL Business PLC

  公开号：EP2945619B1

  公开（公告）日：2019-05-08