(S)-8-(hydroxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole | 150114-27-5

• 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: (S)-8-(hydroxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole
• 英文别名: (S)-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-methanol；8(S)-hydroxymethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole；[(8S)-6,7,8,9-tetrahydropyrido[1,2-a]indol-8-yl]methanol
• CAS: 150114-27-5
• 化学式: C₁₃H₁₅NO
• 分子量: 201.268
• InChiKey: FTNSMTLJHGYOIV-JTQLQIEISA-N

物化性质

• 沸点：
  401.4±18.0 °C(Predicted)
• 密度：
  1.22±0.1 g/cm3(Predicted)

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：

  (S)-8-(hydroxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole 在 咪唑 、 三乙基硅烷 、 sodium tetrahydroborate 、 potassium tert-butylate 、 溶剂黄146 、 三乙胺 、 三氟乙酸 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， 反应 7.5h， 生成 3-[(S)-8-(tert-Butyl-diphenyl-silanyloxymethyl)-6,7,8,9-tetrahydro-pyrido[1,2-a]indol-10-yl]-4-phenylamino-pyrrole-2,5-dione
  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 (S)-8-(hydroxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indole
  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

• Substituted pyrroles
  申请人：Hoffmann-La Roche Inc.

  公开号：US05721230A1

  公开（公告）日：1998-02-24

  Compounds of the formula ##STR1## wherein R.sup.1 is lower alkyl, lower cycloalkyl, aryl or lower aralkyl; R.sup.2 is hydrogen, aryl or lower alkyl optionally substituted by hydroxy, acyloxy, amino, mono(lower alkyl)amino, di(lower alkyl)amino, carboxy, lower alkoxycarbonyl or aminocarbonyl; and m and n are, independently, the numerals 1 or 2, and pharmaceutically acceptable salts of acidic compounds of formula I with bases and of basic compounds of formula I with acids are useful in the control or prevention of illnesses, particularly, in the control or prevention of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular disorders, in the treatment of asthma, AIDS or diabetic complications or for the stimulation of hair growth.

  式##STR1##化合物，其中R1为低级烷基、低级环烷基、芳基或低级芳烷基；R2为氢、芳基或可被羟基、酰氧基、氨基、单(低级烷基)氨基、二(低级烷基)氨基、羧基、低级烷氧羰基或氨基羰基取代的低级烷基；m和n独立地为数字1或2，以及式I酸性化合物的药学上可接受的与碱形成的盐和式I碱性化合物的与酸形成的盐，可用于控制或预防疾病，特别是控制或预防炎症、免疫性、肿瘤、支气管肺、皮肤病和心血管疾病，治疗哮喘、艾滋病或糖尿病并发症或刺激头发生长。
• Process for the preparation of 2-substituted and 2,3-disubstituted
  申请人：Hoffmann-La Roche Inc.

  公开号：US05399712A1

  公开（公告）日：1995-03-21

  The invention relates to a process for the manufacture of substituted maleimides of the formula ##STR1## wherein R.sup.1 is alkyl, aryl or heteroaryl and R.sup.2 is hydrogen, alkyl, alkoxycarbonyl, aryl or heteroaryl, by reacting an activated glyoxylate of the formula ##STR2## wherein R.sup.1 has the above significance and X is a leaving atom or group, with an imidate of the formula ##STR3## wherein R.sup.2 has the above significance, R.sup.3 is alkyl, aryl or trialkylsilyl and Y is oxygen or sulfur, in the presence of a base and, after treating the resulting reaction product obtained in which R.sup.2 is hydrogen or alkyl with a strong base, hydrolyzing and dehydrating the resulting hydroxy-pyrrolinone of the formula ##STR4## wherein R.sup.1, R.sup.2, R.sup.3 and Y have the above significance. The substituted maleimides of formula I are pharmacologically active, for example as protein kinase C inhibitors and which a useful, for example, in the treatment and prophylaxis of inflammatory, immunological, bronchopulmonary and cardiovascular disorders, or as antiproliferative agents useful, for example, in the treatment of immune diseases and allergic disorders.

  本发明涉及一种制备式为##STR1##的取代马来酰亚胺的方法，其中R.sup.1是烷基、芳基或杂芳基，R.sup.2是氢、烷基、烷氧羰基、芳基或杂芳基，通过将式为##STR2##的活化乙二酸酯（其中R.sup.1具有上述含义，X是一个离去基团）与式为##STR3##的亚胺（其中R.sup.2具有上述含义，R.sup.3是烷基、芳基或三烷基硅基，Y是氧或硫）在碱的存在下反应，然后将得到的反应产物（其中R.sup.2为氢或烷基）用强碱处理后，水解和脱水生成式为##STR4##的羟基吡咯烷酮，其中R.sup.1、R.sup.2、R.sup.3和Y具有上述含义。式I的取代马来酰亚胺具有药理活性，例如作为蛋白激酶C抑制剂，可用于治疗和预防炎症、免疫、支气管肺和心血管疾病，或作为抗增殖剂，可用于治疗免疫性疾病和过敏性疾病。
• 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。
• Process for the manufacture of substituted maleimides
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0540956B1

  公开（公告）日：1997-09-03