Rinvanil | 457643-60-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: Rinvanil
• 英文别名: (Z,12R)-12-hydroxy-N-[(4-hydroxy-3-methoxyphenyl)methyl]octadec-9-enamide
• CAS: 457643-60-6
• 化学式: C₂₆H₄₃NO₄
• 分子量: 433.632
• InChiKey: FEARCXYRCLNTRM-JGDYFIEFSA-N

物化性质

• 沸点：
  633.0±55.0 °C(Predicted)
• 密度：
  1.025±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  31
• 可旋转键数：
  18
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  78.8
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  二碘甲烷 、 Rinvanil 在 diethylzinc 作用下， 以 正己烷 、 甲苯 为溶剂， 反应 7.0h， 以40%的产率得到9,10-methylene rivanil
  参考文献：
  名称：

  [EN] TRPV1 AGONISTS, FORMULATIONS CONTAINING THEM AND USES THEREOF
  [FR] AGONISTES DE TRPV1, FORMULATIONS CONTENANT CES AGONISTES ET LEURS UTILISATIONS

  摘要：

  通式（I）中的化合物，其中X代表两个氢原子、一个π键、氧或亚甲基；R2是C6-C12芳基或芳基烷基残基；R3是氢、2-羟乙基或2-氨基乙基，对于治疗由vanilloid受体类型I介导的病理是有用的。

  公开号：

  WO2006010445A1
• 作为产物：
  描述：

  蓖麻油酸 、 香兰素胺盐酸盐 在 propylphosphonic anhydride 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.25h， 以70%的产率得到Rinvanil
  参考文献：
  名称：

  N-Acylvanillamides:  Development of an Expeditious Synthesis and Discovery of New Acyl Templates for Powerful Activation of the Vanilloid Receptor

  摘要：

  A simple and general synthesis of vanillamides was developed and employed to screen acids from the fatty and isoprenoid pools for new acyl templates of biological relevance as capsaicin analogues. Potent activation of the human vanilloid receptor 1 (VR1) was observed for the vanillamides of certain polyfunctional acids from both pools, showing that the vanilloid activity of capsaicinoids can be. substantially improved by introducing polar groups and/or unsaturations on the acyl moiety. The activity of the unsaturated analogues was maintained or even increased by cyclopropAnation, while omega dimerization led to a substantial increase of activity. Because of the Wide structural diversity of the library of compounds screened, these observations could not be translated into a single framework of structure-activity relationships. Nevertheless, a series of new highly active leads was identified, validating the pharmacological potential of the unnatural combination of natural building blocks to provide new bioactive compounds.

  DOI：

  10.1021/jm020844o

文献信息

• Development of the First Ultra-Potent “Capsaicinoid” Agonist at Transient Receptor Potential Vanilloid Type 1 (TRPV1) Channels and Its Therapeutic Potential
  作者：Giovanni Appendino、Luciano De Petrocellis、Marcello Trevisani、Alberto Minassi、Nives Daddario、Aniello Schiano Moriello、David Gazzieri、Alessia Ligresti、Barbara Campi、Gabriele Fontana、Christian Pinna、Pierangelo Geppetti、Vincenzo Di Marzo

  DOI：10.1124/jpet.104.074864

  日期：2005.2

  Olvanil ( N -9- Z -octadecenoyl-vanillamide) is an agonist of transient receptor potential vanilloid type 1 (TRPV1) channels that lack the pungency of capsaicin and was developed as an oral analgesic. Vanillamides are unmatched in terms of structural simplicity, straightforward synthesis, and safety compared with the more powerful TRPV1 agonists, like the structurally complex phorboid compound resiniferatoxin. We have modified the fatty acyl chain of olvanil to obtain ultra-potent analogs. The insertion of a hydroxyl group at C-12 yielded a compound named rinvanil, after ricinoleic acid, significantly less potent than olvanil (EC50 = 6 versus 0.7 nM), but more versatile in terms of structural modifications because of the presence of an additional functional group. Acetylation and phenylacetylation of rinvanil re-established and dramatically enhanced, respectively, its potency at hTRPV1. With a two-digit picomolar EC50 (90 pM), phenylacetylrinvanil (PhAR, IDN5890) is the most potent vanillamide ever described with potency comparable with that of resiniferatoxin (EC50, 11 pM). Benzoyl- and phenylpropionylrinvanil were as potent and less potent than PhAR, respectively, whereas configurational inversion to ent -PhAR and cyclopropanation (but not hydrogenation or epoxidation) of the double bond were tolerated. Finally, iodination of the aromatic hydroxyl caused a dramatic switch in functional activity, generating compounds that behaved as TRPV1 antagonists rather than agonists. Since the potency of PhAR was maintained in rat dorsal root ganglion neurons and, particularly, in the rat urinary bladder, this compound was investigated in an in vivo rat model of urinary incontinence and proved as effective as resiniferatoxin at reducing bladder detrusor overactivity.

  Olvanil（N-9-Z-十八碳烯酰-香草酰胺）是一种瞬时受体电位香草素亚型1（TRPV1）通道的激动剂，不具备辣椒素的那种刺激性，开发用于口服镇痛。与结构复杂的树脂佛波酯类TRPV1激动剂（如resiniferatoxin）相比，香草酰胺因其结构简单、合成直接和安全性高等特点而独树一帜。我们对olvanil的脂肪酸酰基链进行了修饰，得到了超强活性的类似物。在C-12位插入一个羟基得到化合物rinvanil，其活性显著低于olvanil（EC50=6与0.7nM相比），但由于存在额外的官能团，使得结构修饰更加多样化。对rinvanil进行乙酰化和苯乙酰化后，其对人TRPV1的活性分别得到恢复和显著增强。苯乙酰基rinvanil（PhAR，IDN5890）的EC50为90皮摩尔，是迄今为止描述的最强效的香草酰胺，其活性与resiniferatoxin相当（EC50，11皮摩尔）。苯甲酰基-和苯丙酰基rinvanil的活性分别与PhAR相当和低于PhAR，而构型反转至ent-PhAR和双键的环丙烷化（而非氢化或环氧化）是可以接受的。最后，对芳香羟基进行碘化会导致功能活性发生剧烈转变，产生的化合物表现为TRPV1拮抗剂而非激动剂。由于PhAR在大鼠背根神经节神经元中的活性得以维持，特别是在大鼠膀胱中，该化合物在大鼠尿失禁体内模型中进行了研究，并证明其减少膀胱逼尿肌过度活动的效力与resiniferatoxin相当。
• Efficient Chemoenzymatic Synthesis of Phenylacetylrinvanil: An Ultrapotent Capsaicinoid
  作者：Edmundo Castillo、Ignacio Regla、Patricia Demare、Axel Luviano-Jardón、Agustín López-Munguía

  DOI：10.1055/s-0028-1083521

  日期：——

  synthesis of methyl ricinoleate (MeRic) by ' castor oil methanolysis. Afterwards, two alternative routes are possible: a) chemoselective vanillylamine aminolysis of MeRic catalyzed by Candida antarctica lipase-B (CaLB) to yield rinvanil, which after reaction with phenylacetic acid and DCC-DMAP followed by a regioselectively pyrrolidine deacylation results in PhAR with a 51% global yield, b) methyl 12-phe

  描述了一种超强效辣椒素类物质苯乙酰基苯环 (PhAR) 的直接合成。该过程从通过蓖麻油甲醇分解定量合成蓖麻油酸甲酯 (MeRic) 开始。之后，有两种替代途径是可能的：a) 由南极念珠菌脂肪酶-B (CaLB) 催化 MeRic 的化学选择性香草胺氨解以产生 rinvanil，在与苯乙酸和 DCC-DMAP 反应后进行区域选择性吡咯烷脱酰化产生 PhAR， 51% 的全球收率，b) 通过 MeRic 与苯乙酸和 DCC-DMAP 反应合成 12-苯基乙酰蓖麻油酸甲酯，然后由 CaLB 催化的化学选择性香草胺氨解以获得 PhAR，总收率为 70%。
• [EN] TRPV1 AGONISTS, FORMULATIONS CONTAINING THEM AND USES THEREOF<br/>[FR] AGONISTES DE TRPV1, FORMULATIONS CONTENANT CES AGONISTES ET LEURS UTILISATIONS
  申请人：INDENA SPA

  公开号：WO2006010445A1

  公开（公告）日：2006-02-02

  The compounds of the general formula (I) in which X is represents two hydrogen atoms, a π-bond, oxygen or methylene; R2 is a C6-C12 aryl, or arylalkyl residue; R3 is hydrogen, 2-hydroxyethyl or 2-aminoethyl are useful for the treatment of pathologies mediated by vanilloid receptors type I.

  通式（I）中的化合物，其中X代表两个氢原子、一个π键、氧或亚甲基；R2是C6-C12芳基或芳基烷基残基；R3是氢、2-羟乙基或2-氨基乙基，对于治疗由vanilloid受体类型I介导的病理是有用的。
• <i>N</i>-Acylvanillamides:  Development of an Expeditious Synthesis and Discovery of New Acyl Templates for Powerful Activation of the Vanilloid Receptor
  作者：Giovanni Appendino、Alberto Minassi、Aniello Schiano Morello、Luciano De Petrocellis、Vincenzo Di Marzo

  DOI：10.1021/jm020844o

  日期：2002.8.1

  A simple and general synthesis of vanillamides was developed and employed to screen acids from the fatty and isoprenoid pools for new acyl templates of biological relevance as capsaicin analogues. Potent activation of the human vanilloid receptor 1 (VR1) was observed for the vanillamides of certain polyfunctional acids from both pools, showing that the vanilloid activity of capsaicinoids can be. substantially improved by introducing polar groups and/or unsaturations on the acyl moiety. The activity of the unsaturated analogues was maintained or even increased by cyclopropAnation, while omega dimerization led to a substantial increase of activity. Because of the Wide structural diversity of the library of compounds screened, these observations could not be translated into a single framework of structure-activity relationships. Nevertheless, a series of new highly active leads was identified, validating the pharmacological potential of the unnatural combination of natural building blocks to provide new bioactive compounds.