N-(3-piperidyl)-N-(1H-5-indazolyl)amine | 478836-48-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: N-(3-piperidyl)-N-(1H-5-indazolyl)amine
• 英文别名: (1H-indazol-5-yl)-piperidin-3-yl-amine；N-piperidin-3-yl-1H-indazol-5-amine
• CAS: 478836-48-5
• 化学式: C₁₂H₁₆N₄
• 分子量: 216.286
• InChiKey: DZCXFGNWECEITN-UHFFFAOYSA-N

物化性质

• 沸点：
  451.8±35.0 °C(Predicted)
• 密度：
  1.249±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  52.7
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(3-piperidyl)-N-(1H-5-indazolyl)amine 在 4-二甲氨基吡啶 、 硼烷四氢呋喃络合物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 生成 N-[1-(3-furylmethyl)-3-piperidyl]-N-(1H-5-indazolyl)amine
  参考文献：
  名称：

  Design and synthesis of Rho kinase inhibitors (II)

  摘要：

  In a previous study, we identified several structurally unrelated scaffolds of the Rho kinase inhibitor using pharmacophore information obtained from the results of a high-throughput screening and structural information from a homology model of Rho kinase. 1H-Indazole is one of the candidate scaffolds on which a new series of potent Rho kinase inhibitors could be developed. In this study, the detailed structure-activity relationship of 1H-indazole analogues was studied. During this study, we found that the cell-free enzyme inhibitory potential of Rho kinase inhibitors having the 1H-indazole scaffold did not necessarily correlate with their inhibitory potential toward the chemotaxis of cultured cells. The choice of the linker substructure was shown to be an important factor for the 1H-indazole analogues to inhibit the chemotaxis of cells. Optimization of the 1H-indazole inhibitors with respect to the in vitro inhibition of monocyte chemotaxis induced by MCP-1 was carried out. The inhibitory potential was improved both in the cell-free enzyme assay and in the chemotaxis assay. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.09.052
• 作为产物：
  描述：

  N-BOC-3-羟基哌啶 在 吡啶硼烷 、 三甲基氨基磺酸 、 溶剂黄146 、 二甲基亚砜 、 三乙胺 、 三氟乙酸 作用下， 以 甲醇 、 氯仿 为溶剂， 反应 39.0h， 生成 N-(3-piperidyl)-N-(1H-5-indazolyl)amine
  参考文献：
  名称：

  Design and synthesis of Rho kinase inhibitors (II)

  摘要：

  In a previous study, we identified several structurally unrelated scaffolds of the Rho kinase inhibitor using pharmacophore information obtained from the results of a high-throughput screening and structural information from a homology model of Rho kinase. 1H-Indazole is one of the candidate scaffolds on which a new series of potent Rho kinase inhibitors could be developed. In this study, the detailed structure-activity relationship of 1H-indazole analogues was studied. During this study, we found that the cell-free enzyme inhibitory potential of Rho kinase inhibitors having the 1H-indazole scaffold did not necessarily correlate with their inhibitory potential toward the chemotaxis of cultured cells. The choice of the linker substructure was shown to be an important factor for the 1H-indazole analogues to inhibit the chemotaxis of cells. Optimization of the 1H-indazole inhibitors with respect to the in vitro inhibition of monocyte chemotaxis induced by MCP-1 was carried out. The inhibitory potential was improved both in the cell-free enzyme assay and in the chemotaxis assay. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.09.052

文献信息

• [EN] METHOD FOR TREATING OPHTHALMIC DISEASES USING KINASE INHIBITOR COMPOUNDS IN PRODRUG FORMS<br/>[FR] MÉTHODE DE TRAITEMENT DE MALADIES OPHTALMIQUES À L'AIDE DE COMPOSÉS D'INHIBITEURS DE KINASE SOUS FORME DE PROMÉDICAMENTS
  申请人：INSPIRE PHARMACEUTICALS INC

  公开号：WO2012015760A1

  公开（公告）日：2012-02-02

  This invention is directed to prodrugs of rho kinase (ROCK) inhibitors. These prodrugs are in general the ester or the amide derivatives of the parent compounds. These prodrugs are often weak inhibitors of ROCK, but their parent compounds have good activities. Upon instillation into the eyes, the ester or the amide group of these prodrugs is rapidly hydrolyzed into alcohol, amine, or acid, and the prodrugs are converted into the active base compounds. The prodrugs of ROCK inhibitors provide several advantages such as delivery of higher concentrations of the active species into the target site and reduction of ocular discomfort. The invention is also directed to a method of treating ophthalmic diseases such as glaucoma, allergic conjunctivitis, macular edema, macular degeneration, and blepharitis, by administering an effective amount of a ROCK prodrug compound of Formula (I) to the eyes of the patient in need of.

  这项发明涉及罗激酶（ROCK）抑制剂的前药。这些前药通常是母化合物的酯或酰胺衍生物。这些前药通常是ROCK的弱抑制剂，但它们的母化合物具有良好的活性。将这些前药滴入眼中后，其酯或酰胺基团会迅速水解成醇、胺或酸，前药会转化为活性的基本化合物。ROCK抑制剂的前药提供了几个优点，如将更高浓度的活性物质传递到目标部位，减少眼部不适。该发明还涉及通过向需要的患者眼部给予公式（I）的ROCK前药化合物的有效量来治疗青光眼、过敏性结膜炎、黄斑水肿、黄斑变性和睑缘炎等眼科疾病的方法。
• CYTOSKELETAL ACTIVE RHO KINASE INHIBITOR COMPOUNDS, COMPOSITION AND USE
  申请人：Lampe John W.

  公开号：US20080214614A1

  公开（公告）日：2008-09-04

  The present invention is directed to synthetic cytoskeletal active compounds that are inhibitors of rho-associated protein kinase. The present invention is also directed to pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier. The invention is additionally directed to a method of preventing or treating diseases or conditions associated with cytoskeletal reorganization. In one embodiment of the invention, the method treats increased intraocular pressure, such as primary open-angle glaucoma. The method comprises administering to a subject a therapeutically effective amount of a cytoskeletal active compound of Formula I or Formula II, wherein said amount is effective to influence the actomyosin interactions, for example by leading to cellular relaxation and alterations in cell-substratum adhesions.

  本发明涉及一种合成的细胞骨架活性化合物，其为rho相关蛋白激酶的抑制剂。本发明还涉及包含此类化合物和药用载体的制药组合物。此外，本发明还涉及一种预防或治疗与细胞骨架重组相关的疾病或病症的方法。在本发明的一个实施例中，该方法治疗增加的眼内压，如原发性开角型青光眼。该方法包括向受体施用公式I或公式II的细胞骨架活性化合物的治疗有效量，其中该量能够影响肌动蛋白相互作用，例如通过导致细胞松弛和细胞基质附着的改变。
• Rho kinase inhibitors
  申请人：——

  公开号：US20040138286A1

  公开（公告）日：2004-07-15

  A compound represented by the formula (1): 1 wherein R 1 —X— indicates that 1 to 4 R 1 —X— groups are present which may be the same or different, the ring A is a saturated or unsaturated 5-membered heterocyclic ring, X is a single bond, a group represented by the formula: —N(R 3 )—, —O— or —S—, or the like. R 1 is a hydrogen atom, a halogen atom, a nitro group, a carboxyl group, a substituted or unsubstituted alkyl group, or the like, R 2 is a hydrogen atom, a halogen atom, a nitro group, a carboxyl group, a substituted or unsubstituted alkyl group, or the like, and R 3 is a hydrogen atom, a substituted or unsubstituted alkyl group, or the like; a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug is a useful compound as a therapeutic agent for diseases for which Rho kinase is responsible.

  化合物的化学式为（1）：1，其中R1—X—表示存在1到4个R1—X—基团，可以相同也可以不同，环A是饱和或不饱和的5元杂环，X是单键，一个由式子表示的基团：—N（R3）—，—O—或—S—等。R1是氢原子，卤素原子，硝基，羧基，取代或未取代的烷基或类似物，R2是氢原子，卤素原子，硝基，羧基，取代或未取代的烷基或类似物，R3是氢原子，取代或未取代的烷基或类似物；该化合物的前药或药物可接受的盐是治疗Rho激酶相关疾病的有用化合物。
• METHOD FOR TREATING OPHTHALMIC DISEASES USING KINASE INHIBITOR COMPOUNDS IN PRODRUG FORMS
  申请人：Inspire Pharmaceuticals, Inc.

  公开号：US20130131059A1

  公开（公告）日：2013-05-23

  This invention is directed to prodrugs of rho kinase (ROCK) inhibitors. These prodrugs are in general the ester or the amide derivatives of the parent compounds. These prodrugs are often weak inhibitors of ROCK, but their parent compounds have good activities. Upon instillation into the eyes, the ester or the amide group of these prodrugs is rapidly hydrolyzed into alcohol, amine, or acid, and the prodrugs are converted into the active base compounds. The prodrugs of ROCK inhibitors provide several advantages such as delivery of higher concentrations of the active species into the target site and reduction of ocular discomfort. The invention is also directed to a method of treating ophthalmic diseases such as glaucoma, allergic conjunctivitis, macular edema, macular degeneration, and blepharitis, by administering an effective amount of a ROCK prodrug compound of Formula I to the eyes of the patient in need of.

  本发明涉及rho激酶（ROCK）抑制剂的前药。这些前药通常是母化合物的酯或酰胺衍生物。这些前药通常是ROCK的弱抑制剂，但它们的母化合物具有良好的活性。将这些前药滴入眼睛后，其酯或酰胺基团会迅速水解为醇，胺或酸，并将前药转化为活性基础化合物。ROCK抑制剂的前药提供了几个优点，如将更高浓度的活性物种输送到目标部位以及减少眼部不适。本发明还涉及通过向需要的患者眼睛中投与公式I的ROCK前药化合物的有效量来治疗眼科疾病，如青光眼，过敏性结膜炎，黄斑水肿，黄斑变性和睑缘炎的方法。
• BIFUNCTIONAL RHO KINASE INHIBITOR COMPOUNDS, COMPOSITION AND USE
  申请人：INSPIRE PHARMACEUTICALS, INC.

  公开号：US20130131106A1

  公开（公告）日：2013-05-23

  This invention relates to synthetic bifunctional compounds comprising a first rho-associated kinase (ROCK) inhibiting compound and a second pharmaceutically active compound with complementary activity; the first and the second compounds are covalently linked by a biologically labile bond. This invention also relates to methods of making such compounds. The invention also relates to methods of using such bifunctional compounds in the prevention or treatment of diseases or conditions that are affected or can be assisted by altering the integrity or rearrangement of the cytoskeleton. Particularly, this invention relates to methods of treating ophthalmic diseases such as disorders in which intraocular pressure is elevated, for example primary open-angle glaucoma, using the bifunctional compounds.

  本发明涉及合成的双功能化合物，包括第一种抑制rho相关激酶(ROCK)的化合物和具有互补活性的第二种药物活性化合物；第一种和第二种化合物由生物可降解的化学键共价连接。本发明还涉及制备这种化合物的方法。本发明还涉及使用这种双功能化合物预防或治疗受到细胞骨架完整性或重组影响的疾病或病况的方法。特别地，本发明涉及使用这种双功能化合物治疗眼科疾病，例如原发性开角型青光眼等眼内压升高的疾病。