(R)-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-methanol | 154230-87-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (R)-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-methanol
• 英文别名: [(8R)-6,7,8,9-tetrahydropyrido[1,2-a]indol-8-yl]methanol
• CAS: 154230-87-2
• 化学式: C₁₃H₁₅NO
• 分子量: 201.268
• InChiKey: FTNSMTLJHGYOIV-SNVBAGLBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  25.2
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  (R)-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-methanol 在 咪唑 、 sodium tetrahydroborate 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 2-[(R)-8-(tert-Butyl-diphenyl-silanyloxymethyl)-6,7,8,9-tetrahydro-pyrido[1,2-a]indol-10-yl]-2-hydroxy-acetamide
  参考文献：
  名称：

  Synthesis, SAR studies, and pharmacological evaluation of 3-anilino-4-(3-indolyl) maleimides with conformationally restricted structure as orally bioavailable PKCβ-selective inhibitors

  摘要：

  Conformationally restricted 3-anilino-4-(3-indolyl)maleimide derivatives were designed and synthesized aiming at discovery of novel protein kinase C beta (PKC beta)-selective inhibitors possessing oral bioavailability. Among them, compounds having a fused five-membered ring at the indole 1,2-position inhibited PKC beta 2 with IC50 of nM-order and showed good oral bioavailability. One of the most potent compounds was found to be PKC beta-selective over other 6 isozymes and exhibited ameliorative effects in a rat diabetic retinopathy model via oral route. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.05.033
• 作为产物：
  描述：

  6,7,8,9-tetrahydropyrido<1,2-a>indole-8-carboxylic acid 在 4-二甲氨基吡啶 、 lithium aluminium tetrahydride 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 0.67h， 生成 (R)-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-methanol
  参考文献：
  名称：

  Inhibitors of protein kinase C. 3. Potent and highly selective bisindolylmaleimides by conformational restriction

  摘要：

  The protein kinase inhibitor staurosporine has been used to design a series of selective bisindolylmaleimide inhibitors of protein kinase C (PKC). Guided by molecular graphics, conformational restriction of the cationic side chain has led to ATP competitive inhibitors of improved potency and selectivity. Two compounds have been further evaluated and were shown to inhibit PKC of human origin and prevent T-cell activation in a human allogeneic mixed lymphocyte reaction. One of these compounds was orally absorbed in mice and antagonized a phorbol ester induced paw edema in a dose-dependent manner. This compound also selectively inhibited the secondary T-cell mediated response in a developing adjuvant arthritis model in rats and provides evidence for the potential use of PKC inhibitors as therapeutic immunomodulators.

  DOI：

  10.1021/jm00053a003

文献信息

• Asymmetric hydrogenation of dihydro-pyrido [1,2-a]indoles
  申请人：Hoffmann-La Roche Inc.

  公开号：US05374727A1

  公开（公告）日：1994-12-20

  A process for the asymmetric hydrogenation of 6,7-dihydropyrido[1,2-a]indole-8-methanol or its aromatically-substituted derivatives of the formula ##STR1## wherein R.sup.1, R.sup.2 and R.sup.3 each, independently, is hydrogen, halogen, C.sub.1-7 -alkyl, C.sub.1-7 -haloalkyl, hydroxy, C.sub.1-7 -alkoxy, C.sub.1-7 -alkylthio, C.sub.1-7 -alkylsulfinyl, C.sub.1-7 -alkylsulfonyl, nitro, amino or acylamino, to (S)- or (R)-compounds of the formula ##STR2## wherein R.sup.1, R.sup.2 and R.sup.3 have the significances given above and the asterisk (*) denotes the chiral center, carried out using optically active rhodium-diphosphine complexes as catalysts, is described. The production of the compounds II, which also form an object of the invention, is also described. The compounds I and II are valuable intermediates, for example, for the preparation of pharmaceutically active substances.

  本发明涉及一种用于不对称氢化6,7-二氢吡啶[1,2-a]吲哚-8-甲醇或其芳基取代衍生物的方法，其化学式为##STR1##其中R.sup.1，R.sup.2和R.sup.3各自独立地为氢，卤素，C.sub.1-7-烷基，C.sub.1-7-卤代烷基，羟基，C.sub.1-7-烷氧基，C.sub.1-7-烷基硫醚，C.sub.1-7-烷基亚磺酰基，C.sub.1-7-烷基磺酰基，硝基，氨基或酰胺基，得到公式为##STR2##其中R.sup.1，R.sup.2和R.sup.3具有上述给定的意义，星号(*)表示手性中心，使用光学活性的铑-二膦配合物作为催化剂进行。本发明还描述了化合物II的生产，化合物I和II是有价值的中间体，例如，用于制备药物活性物质。
• Asymmetrische Hydrierung
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0574783A2

  公开（公告）日：1993-12-22

  Ein Verfahren zur asymmetrischen Hydrierung von 6,7-Dihydropyrido[1,2-a]indol-8-methanol oder von deren aromatisch substituierten Derivaten der allgemeinen Formel worin R1, R2 und R3 unabhängig voneinander Wasserstoff, Halogen, C1-7-Alkyl, C1-7-Halogenalkyl, Hydroxy, C1-7-Alkoxy, C1-7-Alkylthio, C1-7-Alkylsulfinyl, C1-7-Alkylsulfonyl, Nitro, Amino oder Acylamino bedeuten, zu (S)- oder (R)-Verbindungen der allgemeinen Formel worin R1, R2 und R3 die oben angegebenen Bedeutungen besitzen und * das chirale Zentrum bezeichnet, erfolgt unter Verwendung von optisch aktiven Rhodium-Diphosphin-Komplexen als Katalysatoren. Die Herstellung der neuen Verbindungen II, die einen weiteren Gegenstand der vorliegenden Erfindung bilden, wird ebenfalls beschrieben. Die Verbindungen I und II sind wertvolle Zwischenprodukte, z.B. für die Herstellung von pharmazeutischen Wirkstoffen.

  一种 6,7-二氢吡啶并[1,2-a]吲哚-8-甲醇或其芳香取代的通式衍生物的不对称氢化工艺 其中 R1、R2 和 R3 独立地为氢、卤素、C1-7-烷基、C1-7-卤代烷基、羟基、C1-7-烷氧基、C1-7-烷硫基、C1-7-烷基亚磺酰基、C1-7-烷基磺酰基、硝基、氨基或酰氨基，从而得到通式的 (S)- 或 (R)- 化合物的工艺 其中 R1、R2 和 R3 具有上述含义，* 表示手性中心。本发明的另一个目的是制备新化合物 II。化合物 I 和 II 是有价值的中间体，例如用于生产活性药物成分。
• US5374727A
  申请人：——

  公开号：US5374727A

  公开（公告）日：1994-12-20
• Synthesis, SAR studies, and pharmacological evaluation of 3-anilino-4-(3-indolyl) maleimides with conformationally restricted structure as orally bioavailable PKCβ-selective inhibitors
  作者：Masahiro Tanaka、Shoichi Sagawa、Jun-ichi Hoshi、Fumito Shimoma、Katsutaka Yasue、Minoru Ubukata、Tomoyuki Ikemoto、Yasunori Hase、Mitsuru Takahashi、Tomohiko Sasase、Nobuhisa Ueda、Mutsuyoshi Matsushita、Takashi Inaba

  DOI：10.1016/j.bmc.2006.05.033

  日期：2006.9

  Conformationally restricted 3-anilino-4-(3-indolyl)maleimide derivatives were designed and synthesized aiming at discovery of novel protein kinase C beta (PKC beta)-selective inhibitors possessing oral bioavailability. Among them, compounds having a fused five-membered ring at the indole 1,2-position inhibited PKC beta 2 with IC50 of nM-order and showed good oral bioavailability. One of the most potent compounds was found to be PKC beta-selective over other 6 isozymes and exhibited ameliorative effects in a rat diabetic retinopathy model via oral route. (c) 2006 Elsevier Ltd. All rights reserved.
• Inhibitors of protein kinase C. 3. Potent and highly selective bisindolylmaleimides by conformational restriction
  作者：Rino A. Bit、Peter D. Davis、Lucy H. Elliott、William Harris、Christopher H. Hill、Elizabeth Keech、Hari Kumar、Geoffrey Lawton、Anna Maw、John S. Nixon、David R. Vesey、Julie Wadsworth、Sandra E. Wilkinson

  DOI：10.1021/jm00053a003

  日期：1993.1

  The protein kinase inhibitor staurosporine has been used to design a series of selective bisindolylmaleimide inhibitors of protein kinase C (PKC). Guided by molecular graphics, conformational restriction of the cationic side chain has led to ATP competitive inhibitors of improved potency and selectivity. Two compounds have been further evaluated and were shown to inhibit PKC of human origin and prevent T-cell activation in a human allogeneic mixed lymphocyte reaction. One of these compounds was orally absorbed in mice and antagonized a phorbol ester induced paw edema in a dose-dependent manner. This compound also selectively inhibited the secondary T-cell mediated response in a developing adjuvant arthritis model in rats and provides evidence for the potential use of PKC inhibitors as therapeutic immunomodulators.