(1'S,8a'S)-N-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-N-methyl-6'-oxo-1'-o-tolyloctahydro-1'H-spiro[pyran-4,7'-pyrrolo[1,2-a]pyrazine]-2'(6'H)-carboxamide | 1453069-14-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (1'S,8a'S)-N-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-N-methyl-6'-oxo-1'-o-tolyloctahydro-1'H-spiro[pyran-4,7'-pyrrolo[1,2-a]pyrazine]-2'(6'H)-carboxamide
• 英文别名: (1S,8aS)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-N-methyl-1-(2-methylphenyl)-6-oxospiro[3,4,8,8a-tetrahydro-1H-pyrrolo[1,2-a]pyrazine-7,4'-oxane]-2-carboxamide
• CAS: 1453069-14-1
• 化学式: C₃₀H₃₃F₆N₃O₃
• 分子量: 597.601
• InChiKey: ZNCWEDZUZVLDMM-NGXZDTIWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  42
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  53.1
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  (R)-N-甲基-1-[3,5-二(三氟甲基)苯基]乙胺 在 甲醇 、 sodium tetrahydroborate 、 氧气 、 臭氧 、 甲基磺酰氯 、 三乙胺 作用下， 以 乙醇 、 正己烷 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 76.0h， 生成 (1'S,8a'S)-N-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-N-methyl-6'-oxo-1'-o-tolyloctahydro-1'H-spiro[pyran-4,7'-pyrrolo[1,2-a]pyrazine]-2'(6'H)-carboxamide
  参考文献：
  名称：

  [EN] NOVEL NEUROKININ 1 RECEPTOR ANTAGONIST COMPOUNDS
  [FR] NOUVEAUX COMPOSÉS ANTAGONISTES DU RÉCEPTEUR DE LA NEUROKININE 1

  摘要：

  本发明涉及一种根据公式（A）的化合物，其中n为1或2；R1和R2独立为氢，C1-4烷基，C1-4卤代烷基，C1-4烷氧基，CD3或卤素；R3为氢，C(=O)OR7或C1-4烷基，可选地被羟基或NR8R9取代；R4为氢或氧代；R5和R6独立为氢，羟基，NR8R9，C(=O)R7，C(=O)OR7，C(=O)NR8R9，C1-4烷基，其中所述C1-4烷基可选地被羟基，NR8R9或5-或6-成员的杂环环取代，其中所述5-或6-成员的杂环环可选地被C1-4烷基或C(=O)R7取代；或R5和R6与它们所连接的碳原子一起形成=CH2或5-或6-成员的杂环烷基，其中所述杂环烷基可选地被C1-4烷基取代；R7为氢或C1-4烷基；R8和R9独立为氢或C1-4烷基，或R8和R9与它们所连接的氮原子一起形成一个5-或6-成员的杂环环，或其药用可接受的盐或溶剂化物。本发明进一步涉及用于制备所述化合物的中间体，所述化合物用于治疗，包含所述化合物的药物组合物，使用所述化合物治疗或改善瘙痒性皮肤病或状况的方法，以及所述化合物在药物制造中的用途。

  公开号：

  WO2013124286A1

文献信息

• NOVEL NEUROKININ 1 RECEPTOR ANTAGONIST COMPOUNDS
  申请人：LEO PHARMA A/S

  公开号：US20150018345A1

  公开（公告）日：2015-01-15

  The present invention relates to a compound according to formula (A) wherein n is 1 or 2; R1 and R2 are independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, CD3 or halogen; R3 is hydrogen, C(═O)OR7 or C 1-4 alkyl optionally substituted with hydroxy or NR8R9; R4 is hydrogen or oxo; R5 and R6 are independently hydrogen, hydroxy, NR8R9, C(═O)R7, C(═O)OR7, C(═O)NR8R9, C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with hydroxy, NR8R9 or a 5- or 6-membered heterocyclic ring, wherein said 5- or 6-membered heterocyclic ring is optionally substituted with C 1-4 alkyl or C(═O)R7; or R5 and R6, together with the carbon atom to which they are attached, form ═CH 2 or a 5- or 6-membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with C 1-4 alkyl; R7 is hydrogen or C 1-4 alkyl; R8 and R9 are independently hydrogen or C 1-4 alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring, or a pharmaceutically acceptable salt or solvate thereof. The invention relates further to intermediates for the preparation of said compounds, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating or ameliorating pruritic dermal diseases or conditions with said compounds, and to the use of said compounds in the manufacture of medicaments.

  本发明涉及一种化合物，其化学式为（A），其中n为1或2；R1和R2分别为氢、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、CD3或卤素；R3为氢、C（═O）OR7或C1-4烷基，该C1-4烷基可选择性地被羟基或NR8R9取代；R4为氢或氧代基；R5和R6分别为氢、羟基、NR8R9、C（═O）R7、C（═O）OR7、C（═O）NR8R9、C1-4烷基，其中所述的C1-4烷基可选择性地被羟基、NR8R9或一个5-或6-成员杂环环取代，所述的5-或6-成员杂环环可选择性地被C1-4烷基或C（═O）R7取代；或者R5和R6与它们连接的碳原子一起形成═CH2或一个5-或6-成员杂环烷基，其中所述的杂环烷基可选择性地被C1-4烷基取代；R7为氢或C1-4烷基；R8和R9分别为氢或C1-4烷基，或者R8和R9与它们连接的氮原子一起形成一个5-或6-成员杂环环，或其药学上可接受的盐或溶剂。本发明还涉及制备该化合物的中间体，所述化合物用于治疗、缓解瘙痒性皮肤疾病或状况的制剂，以及所述化合物用于制造药物的用途。
• Substituted pyrrolo[1,2-a]piperazines and pyrrolo[1,2-a][1,4]diazepines as neurokinin 1 receptor antagonists
  申请人：LEO PHARMA A/S

  公开号：US09181259B2

  公开（公告）日：2015-11-10

  The present invention relates to a compound according to formula (A) wherein n is 1 or 2; R1 and R2 are independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, CD3 or halogen; R3 is hydrogen, C(═O)OR7 or C1-4 alkyl optionally substituted with hydroxy or NR8R9; R4 is hydrogen or oxo; R5 and R6 are independently hydrogen, hydroxy, NR8R9, C(═O)R7, C(═O)OR7, C(═O)NR8R9, C1-4 alkyl, wherein said C1-4 alkyl is optionally substituted with hydroxy, NR8R9 or a 5- or 6-membered heterocyclic ring, wherein said 5- or 6-membered heterocyclic ring is optionally substituted with C1-4 alkyl or C(═O)R7; or R5 and R6, together with the carbon atom to which they are attached, form ═CH2 or a 5- or 6-membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with C1-4 alkyl; R7 is hydrogen or C1-4 alkyl; R8 and R9 are independently hydrogen or C1-4 alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring, or a pharmaceutically acceptable salt or solvate thereof. The invention relates further to intermediates for the preparation of said compounds, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating or ameliorating pruritic dermal diseases or conditions with said compounds, and to the use of said compounds in the manufacture of medicaments.

  本发明涉及一种化合物，其化学式为(A)，其中n为1或2；R1和R2分别为氢、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、CD3或卤素；R3为氢、C(═O)OR7或C1-4烷基，其可选地被羟基或NR8R9取代；R4为氢或氧代基；R5和R6分别为氢、羟基、NR8R9、C(═O)R7、C(═O)OR7、C(═O)NR8R9、C1-4烷基，其中所述的C1-4烷基可选地被羟基、NR8R9或5-或6-成员杂环环取代，所述的5-或6-成员杂环环可选地被C1-4烷基或C(═O)R7取代；或者R5和R6与它们所连接的碳原子一起形成═CH2或5-或6-成员杂环烷基，其中所述的杂环烷基可选地被C1-4烷基取代；R7为氢或C1-4烷基；R8和R9分别为氢或C1-4烷基，或者R8和R9与它们所连接的氮原子一起形成5-或6-成员杂环环，或其药学上可接受的盐或溶剂。本发明还涉及制备该化合物的中间体，使用该化合物进行治疗的药物组合物，使用该化合物治疗或改善瘙痒性皮肤病或病症的方法，以及使用该化合物制造药物的用途。
• US9181259B2
  申请人：——

  公开号：US9181259B2

  公开（公告）日：2015-11-10
• [EN] NOVEL NEUROKININ 1 RECEPTOR ANTAGONIST COMPOUNDS<br/>[FR] NOUVEAUX COMPOSÉS ANTAGONISTES DU RÉCEPTEUR DE LA NEUROKININE 1
  申请人：LEO PHARMA AS

  公开号：WO2013124286A1

  公开（公告）日：2013-08-29

  The present invention relates to a compound according to formula (A) wherein n is 1 or 2; R1 and R2 are independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, CD3 or halogen; R3 is hydrogen, C(=O)OR7 or C1-4 alkyl optionally substituted with hydroxy or NR8R9; R4 is hydrogen or oxo; R5 and R6 are independently hydrogen, hydroxy, NR8R9, C( =O)R7, C( =O)OR7, C( =O)NR8R9, C1-4 alkyl, wherein said C1-4 alkyl is optionally substituted with hydroxy, NR8R9 or a 5- or 6-membered heterocyclic ring, wherein said 5- or 6-membered heterocyclic ring is optionally substituted with C1-4 alkyl or C(=O)R7; or R5 and R6, together with the carbon atom to which they are attached, form =CH2 or a 5- or 6-membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with C1-4 alkyl; R7 is hydrogen or C1-4 alkyl; R8 and R9 are independently hydrogen or C1-4 alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring, or a pharmaceutically acceptable salt or solvate thereof. The invention relates further to intermediates for the preparation of said compounds, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating or ameliorating pruritic dermal diseases or conditions with said compounds, and to the use of said compounds in the manufacture of medicaments.

  本发明涉及一种根据公式（A）的化合物，其中n为1或2；R1和R2独立为氢，C1-4烷基，C1-4卤代烷基，C1-4烷氧基，CD3或卤素；R3为氢，C(=O)OR7或C1-4烷基，可选地被羟基或NR8R9取代；R4为氢或氧代；R5和R6独立为氢，羟基，NR8R9，C(=O)R7，C(=O)OR7，C(=O)NR8R9，C1-4烷基，其中所述C1-4烷基可选地被羟基，NR8R9或5-或6-成员的杂环环取代，其中所述5-或6-成员的杂环环可选地被C1-4烷基或C(=O)R7取代；或R5和R6与它们所连接的碳原子一起形成=CH2或5-或6-成员的杂环烷基，其中所述杂环烷基可选地被C1-4烷基取代；R7为氢或C1-4烷基；R8和R9独立为氢或C1-4烷基，或R8和R9与它们所连接的氮原子一起形成一个5-或6-成员的杂环环，或其药用可接受的盐或溶剂化物。本发明进一步涉及用于制备所述化合物的中间体，所述化合物用于治疗，包含所述化合物的药物组合物，使用所述化合物治疗或改善瘙痒性皮肤病或状况的方法，以及所述化合物在药物制造中的用途。