2-(tert-Butoxycarbonylamino)-3-(N-methyl-3,4-dichlorobenzylamino)propionic acid | 178261-29-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-(tert-Butoxycarbonylamino)-3-(N-methyl-3,4-dichlorobenzylamino)propionic acid
• 英文别名: 3-[(3,4-dichlorophenyl)methyl-methylamino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid
• CAS: 178261-29-5
• 化学式: C₁₆H₂₂Cl₂N₂O₄
• 分子量: 377.268
• InChiKey: BCDDDVOFWZPZHI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  24
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  78.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(tert-Butoxycarbonylamino)-3-(N-methyl-3,4-dichlorobenzylamino)propionic acid 在 双(2-氧代-3-恶唑烷基)次磷酰氯 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 2-amino-3-((3,4-dichlorobenzyl)(methyl)amino)-1-(1-(methylsulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)propan-1-one
  参考文献：
  名称：

  Serine derived NK1 antagonists 1: The effect of modifications to the serine substituents

  摘要：

  A series of novel serine derived NK, antagonists is described. The effect of variations in the N-benzyl, O-benzyl and serine groups are used to define the elements which are necessary for binding. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(98)00320-5
• 作为产物：
  描述：

  2-叔丁氧羰基氨基丙烯酸甲酯 在 lithium hydroxide 、 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙腈 为溶剂， 生成 2-(tert-Butoxycarbonylamino)-3-(N-methyl-3,4-dichlorobenzylamino)propionic acid
  参考文献：
  名称：

  Serine derived NK1 antagonists 1: The effect of modifications to the serine substituents

  摘要：

  A series of novel serine derived NK, antagonists is described. The effect of variations in the N-benzyl, O-benzyl and serine groups are used to define the elements which are necessary for binding. (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(98)00320-5

文献信息

• Spiro-substituted azacyclic derivatives and their use as therapeutic
  申请人：Merck Sharp & Dohme Ltd.

  公开号：US05811431A1

  公开（公告）日：1998-09-22

  The present invention relates to compounds of formula (I), wherein n is zero, 1, 2 or 3; R represents C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy, halogen, cyano, trifluoromethyl SO.sub.2 C.sub.1-6 alkyl, NR.sup.a R.sup.b, NR.sup.a COR.sup.b or CONR.sup.a R.sup.b, where R.sup.a and R.sup.b are each H, C.sub.1-4 alkyl, phenyl or trifluoromethyl; R.sup.1 represents phenyl optionally substituted by 1, 2 or 3 of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4 alkyl, --O(CH.sub.2).sub.p O-- (where p is 1 or 2), halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, NR.sup.a R.sup.b, NR.sup.a COR.sup.b, NR.sup.a CO.sub.2 R.sup.b, COR.sup.a, CO.sub.2 R.sup.a or CONR.sup.a R.sup.b ; naphthyl; benzhydryl; or benyl, where the naphthyl group or each phenyl moiety of benzyl and benzhydryl may be substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or trifluoromethyl; R.sup.2 represents hydogen, a substituent as defined for R.sup.1 or heteroaryl selected from indazolyl, thienyl, furanyl, pyridyl, thiazolyl, tetrazolyl and quinolinyl; wherein each heteroaryl may be substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or trifluoromethyl; R.sup.3 and R.sup.4 are each H or C.sub.1-6 alkyl or R.sup.3 and R.sup.4 together are linked so as to form a C.sub.1-3 alkylene chain; R.sup.5 represents H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-4 alkyl, phenylC.sub.1-4 alkyl, CO.sub.2 R.sup.a, CONR.sup.a R.sup.b, SOR.sup.a or SO.sub.2 R.sup.a, wherein the phenyl moiety may be substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or trifluoromethyl; X and Y are each H, or together represents .dbd.O; and Z represents a bond, O, S, SO, SO.sub.2, NR.sup.6, or --(CR.sup.6 R.sup.6)-- where R.sup.6 is H or C.sub.1-6 alkyl; or a pharmaceutically acceptable salt thereof. The compounds are of particular use in the treatment or prevention of pain, inflammation, migraine, emesis and postherpetic neuralgia. ##STR1##

  本发明涉及化合物的公式（I），其中n为0、1、2或3；R代表C.sub.1-6烷基，C.sub.1-6烷氧基，羟基，卤素，氰基，三氟甲基SO.sub.2C.sub.1-6烷基，NR.sup.aR.sup.b，NR.sup.aCOR.sup.b或CONR.sup.aR.sup.b，其中R.sup.a和R.sup.b分别为H，C.sub.1-4烷基，苯基或三氟甲基；R.sup.1代表苯基，可选择性地被1、2或3个C.sub.1-6烷基，C.sub.2-6烯基，C.sub.2-6炔基，C.sub.3-7环烷基，C.sub.3-7环烷基C.sub.1-4烷基，--O（CH.sub.2）.sub.pO--（其中p为1或2），卤素，氰基，硝基，三氟甲基，三甲基硅基，OR.sup.a，SR.sup.a，SOR.sup.a，SO.sub.2R.sup.a，NR.sup.aR.sup.b，NR.sup.aCOR.sup.b，NR.sup.aCO.sub.2R.sup.b，COR.sup.a，CO.sub.2R.sup.a或CONR.sup.aR.sup.b取代；萘基；苯甲基；或苄基，其中萘基或苄基的每个苯基部分可以被C.sub.1-6烷基，C.sub.1-6烷氧基，卤素或三氟甲基取代；R.sup.2代表氢，如定义R.sup.1的取代基或从indazolyl，thienyl，furanyl，pyridyl，thiazolyl，tetrazolyl和quinolinyl选择的杂环芳基；其中每个杂环芳基可以被C.sub.1-6烷基，C.sub.1-6烷氧基，卤素或三氟甲基取代；R.sup.3和R.sup.4分别为H或C.sub.1-6烷基，或R.sup.3和R.sup.4一起连接形成C.sub.1-3烷基链；R.sup.5代表H，C.sub.1-6烷基，C.sub.3-7环烷基，C.sub.3-7环烷基C.sub.1-4烷基，苯基C.sub.1-4烷基，CO.sub.2R.sup.a，CONR.sup.aR.sup.b，SOR.sup.a或SO.sub.2R.sup.a，其中苯基部分可以被C.sub.1-6烷基，C.sub.1-6烷氧基，卤素或三氟甲基取代；X和Y分别为H，或一起代表.dbd.O；Z代表键，O，S，SO，SO.sub.2，NR.sup.6或--（CR.sup.6R.sup.6）--，其中R.sup.6为H或C.sub.1-6烷基；或其药学上可接受的盐。这些化合物在治疗或预防疼痛，炎症，偏头痛，呕吐和带状疱疹后神经痛方面特别有用。
• SPIRO-SUBSTITUTED AZACYCLIC DERIVATIVES AND THEIR USE AS THERAPEUTIC AGENTS
  申请人：MERCK SHARP & DOHME LTD.

  公开号：EP0775140A1

  公开（公告）日：1997-05-28
• US5811431A
  申请人：——

  公开号：US5811431A

  公开（公告）日：1998-09-22
• [EN] SPIRO-SUBSTITUTED AZACYCLIC DERIVATIVES AND THEIR USE AS THERAPEUTIC AGENTS<br/>[FR] DERIVES AZACYCLIQUES SPIRO-SUBSTITUES ET LEUR UTILISATION COMME AGENTS THERAPEUTIQUES
  申请人：MERCK SHARP & DOHME LIMITED

  公开号：WO1996005203A1

  公开（公告）日：1996-02-22

  (EN) The present invention relates to compounds of formula (I), wherein n is zero, 1, 2 or 3; R represents C1-6alkyl, C1-6alkoxy, hydroxy, halogen, cyano, trifluoromethyl, SO2C1-6alkyl, NRaRb, NRaCORb or CONRaRb, where Ra and Rb are each H, C1-6alkyl, phenyl or trifluoromethyl; R1 represents phenyl optionally substituted by 1, 2 or 3 of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, -O(CH2)pO- (where p is 1 or 2), halogen, cyano, nitro, trifluoromethyl, trimethylsilyl, ORa, SRa, SORa, SO2Ra, NRaRb, NRaCORb, NRaCO2Rb, CORa, CO2Ra or CONRaRb; naphthyl; benzhydryl; or benzyl, where the naphthyl group or each phenyl moiety of benzyl and benzhydryl may be substituted by C1-6alkyl, C1-6alkoxy, halogen or trifluoromethyl; R2 represents hydrogen, a substituent as defined for R1 or heteroaryl selected from indazolyl, thienyl, furanyl, pyridyl, thiazolyl, tetrazolyl and quinolinyl; wherein each heteroaryl may be substituted by C1-6alkyl, C1-6alkoxy, halogen or trifluoromethyl; R3 and R4 are each H or C1-6alkyl or R3 and R4 together are linked so as to form a C1-3alkylene chain; R5 represents H, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenylC1-4alkyl, CO2Ra, CONRaRb, SORa or SO2Ra, wherein the phenyl moiety may be substituted by C1-6alkyl, C1-6alkoxy, halogen or trifluoromethyl; X and Y are each H, or together represent =O; and Z represents a bond, O, S, SO, SO2, NR6, or -(CR6R6)- where R6 is H or C1-6alkyl; or a pharmaceutically acceptable salt thereof. The compounds are of particular use in the treatment or prevention of pain, inflammation, migraine, emesis and postherpetic neuralgia.(FR) La présente invention se rapporte à des composés de la formule (I) dans laquelle n vaut zéro, 1, 2 ou 3; R représente alkyle en C1-6, alcoxy en C1-6, hydroxy, halogène, cyano, trifluorométhyle, SO2C1-6alkyle, NRaRb, NRaCORb, ou CONRaRb où Ra et Rb représentent chacun H, alkyle en C1-6, phényle ou trifluorométhyle; R1 représente phényle éventuellement substitué par 1, 2 ou 3 atomes d'alkyle en C1-6, alcényle en C2-6, alkynyle en C2-6, cycloalkyle en C3-7, C3-7cycloalkylC1-4alkyle, -O(CH2)pO- (où p vaut 1 ou 2), halogène, cyano, nitro, trifluorométhyle, triméthylsilyle, Ora, Sra, SORa, SO2Ra, NRaRb, NRaCORb, NRaCO2Rb, CORa, CO2Ra ou CONRaRb; naphtyle; benzhydryle; ou benzyle, où le groupe naphtyle ou bien chaque fraction phényle de benzyle et benzhydryle peut être substituée par alkyle en C1-6, alcoxy en C1-6, halogène ou trifluorométhyle; R2 représente hydrogène, un substituant tel que défini pour R1 ou hétéroaryle sélectionné parmi indazolyle, thiényle, furanyle, pyridyle, thiazolyle, tétrazolyle et quinolinyle; chaque hétéroaryle peut être substitué par alkyle en C1-6, alcoxy en C1-6, halogène ou trifluorométhyle; R3 et R4 représentent chacun H ou alkyle en C1-6 ou R3 et R4, réunis, sont liés de façon à former une chaîne alkylène en C1-3; R5 représente H, alkyle en C1-6, cycloalkyle en C3-7, C3-7cycloalkylC1-4alkyle, phénylC1-4alkyle, CO2Ra, CONRaRb, SORa ou SO2Ra, où la fraction phényle peut être substituée par alkyle en C1-6, alcoxy en C1-6, halogène ou trifluorométhyle; X et Y représentent chacun H ou, réunis, représentent =O; et Z représente une liaison O, S, SO, SO2, NR6 ou -(CR6R6)- dans laquelle R6 représente H ou alkyle en C1-6. La présente invention se rapporte également à un sel pharmaceutiquement acceptable de ces composés. Ceux-ci sont notamment utilisés dans le traitement ou la prévention de la douleur, des inflammations, de la migraine, des vomissements et des algies post-zostériennes.
• Serine derived NK1 antagonists 1: The effect of modifications to the serine substituents
  作者：J.M. Elliott、M.A. Cascieri、G. Chicchi、S. Davies、F.J. Kelleher、M. Kurtz、T. Ladduwahetty、R.T. Lewis、A.M. MacLeod、K.J. Merchant、S. Sadowski、G.I. Stevenson

  DOI：10.1016/s0960-894x(98)00320-5

  日期：1998.7

  A series of novel serine derived NK, antagonists is described. The effect of variations in the N-benzyl, O-benzyl and serine groups are used to define the elements which are necessary for binding. (C) 1998 Elsevier Science Ltd. All rights reserved.