(1R,2R)-2-(4-苯基哌啶-1-基)环己烷-1-醇 | 112709-59-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: (1R,2R)-2-(4-苯基哌啶-1-基)环己烷-1-醇
• 英文名称: (+/-)-(1S,2S)-2-(4-phenylpiperidin-1-yl)cyclohexanol
• 英文别名: trans-2-(4-phenylpiperidino)cyclohexanol；(±)-vesamicol；(+/-)-vesamicol；vesamicol；(+/-)-trans-vesamicol；(1R,2R)-2-(4-phenylpiperidin-1-yl)cyclohexan-1-ol
• CAS: 112709-59-8
• 化学式: C₁₇H₂₅NO
• 分子量: 259.392
• InChiKey: YSSBJODGIYRAMI-IAGOWNOFSA-N

物化性质

• 熔点：
  238.5-240.0 °C
• 沸点：
  393.5±42.0 °C(Predicted)
• 密度：
  1.086±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

铜主要通过胃肠道吸收，但也可以通过吸入和皮肤吸收。它通过基底外侧膜，可能是通过调节铜转运蛋白，并与血清白蛋白结合被运输到肝脏和肾脏。肝脏是铜稳态的关键器官。在肝脏和其他组织中，铜以与金属硫蛋白、氨基酸以及与依赖铜的酶结合的形式储存，然后分配到通过胆汁排出或纳入细胞内和细胞外蛋白中。铜通过血浆中与血清白蛋白、铜蓝蛋白或低分子量复合物结合被运输到外周组织。铜可能诱导金属硫蛋白和铜蓝蛋白的产生。膜结合的铜转运腺苷三磷酸酶（Cu-ATPase）将铜离子输送到细胞内和细胞外。体内生理正常水平的铜通过改变铜的吸收速率和数量、分布区域以及排泄来保持恒定。(L277, L279)

Copper is mainly absorbed through the gastrointestinal tract, but it can also be inhalated and absorbed dermally. It passes through the basolateral membrane, possibly via regulatory copper transporters, and is transported to the liver and kidney bound to serum albumin. The liver is the critical organ for copper homoeostasis. In the liver and other tissues, copper is stored bound to metallothionein, amino acids, and in association with copper-dependent enzymes, then partitioned for excretion through the bile or incorporation into intra- and extracellular proteins. The transport of copper to the peripheral tissues is accomplished through the plasma attached to serum albumin, ceruloplasmin or low-molecular-weight complexes. Copper may induce the production of metallothionein and ceruloplasmin. The membrane-bound copper transporting adenosine triphosphatase (Cu-ATPase) transports copper ions into and out of cells. Physiologically normal levels of copper in the body are held constant by alterations in the rate and amount of copper absorption, compartmental distribution, and excretion. (L277, L279)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

过量的铜被储存在肝细胞溶酶体中，在那里它与金属硫蛋白结合。当溶酶体饱和，铜在细胞核中积累，导致核损伤时，铜的肝毒性被认为会发生。这种损伤可能是氧化损伤的结果，包括脂质过氧化。铜抑制了诸如葡萄糖-6-磷酸1-脱氢酶、谷胱甘肽还原酶和对氧磷酶等含有巯基团的酶，这些酶保护细胞免受自由氧自由基的侵害。它还影响基因表达，并且是诸如细胞色素C氧化酶和赖氨氧化酶等氧化酶的辅因子。此外，由铜引起的氧化应激被认为会激活酸性鞘磷脂酶，导致神经酰胺的产生，这是一种凋亡信号，同时也会引起溶血性贫血。铜诱导的呕吐是由于迷走神经的刺激所致。

Excess copper is sequestered within hepatocyte lysosomes, where it is complexed with metallothionein. Copper hepatotoxicity is believed to occur when the lysosomes become saturated and copper accumulates in the nucleus, causing nuclear damage. This damage is possibly a result of oxidative damage, including lipid peroxidation. Copper inhibits the sulfhydryl group enzymes such as glucose-6-phosphate 1-dehydrogenase, glutathione reductase, and paraoxonases, which protect the cell from free oxygen radicals. It also influences gene expression and is a co-factor for oxidative enzymes such as cytochrome C oxidase and lysyl oxidase. In addition, the oxidative stress induced by copper is thought to activate acid sphingomyelinase, which lead to the production of ceramide, an apoptotic signal, as well as cause hemolytic anemia. Copper-induced emesis results from stimulation of the vagus nerve. (L277, T49, A174, L280)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

人们每天必须吸收少量铜，因为铜对健康至关重要。然而，高水平的铜可能有害。极高的铜剂量可能对肝脏和肾脏造成损害，甚至可能导致死亡。铜可能在敏感人群中引发过敏反应。

People must absorb small amounts of copper every day because copper is essential for good health, however, high levels of copper can be harmful. Very-high doses of copper can cause damage to your liver and kidneys, and can even cause death. Copper may induce allergic responses in sensitive individuals. (L278, L279)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

口服 (L277) ; 吸入 (L277) ; 皮肤给药 (L277)

Oral (L277) ; inhalation (L277) ; dermal (L277)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

呼吸高浓度的铜可以导致鼻子和喉咙的刺激。摄入高浓度的铜可以引起恶心、呕吐、腹泻、头痛、眩晕和呼吸困难。

Breathing high levels of copper can cause irritation of the nose and throat. Ingesting high levels of copper can cause nausea, vomiting, diarrhea, headache, dizziness, and respiratory difficulty. (L278, L279)

来源:Toxin and Toxin Target Database (T3DB)

安全信息

• 安全说明：
  S22,S24/25
• WGK Germany：
  3
• RTECS号：
  GW0765050

反应信息

• 作为反应物：
  描述：

  (1R,2R)-2-(4-苯基哌啶-1-基)环己烷-1-醇 在 硫酸 、 硝酸 作用下， 生成 2-(4-(4-nitrophenyl)piperidin-1-yl)cyclohexanol
  参考文献：
  名称：

  In vitro characterization of radioiodinated (+)-2-[4-(4-iodophenyl) piperidino]cyclohexanol [(+)-pIV] as a sigma-1 receptor ligand

  摘要：

  We investigated the binding characteristics of a (+)-enantiomer of radioiodinated 2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[I-125]pIV], radioiodinated at the para-position of the 4-phenylpiperidine moiety, to sigma receptors ((sigma-1, (sigma-2) and to vesicular acetylcholine transporters (VAChT) in membranes of the rat brain and liver. In competitive inhibition studies, (+)pIV (K-i = 1.30 nM) had more than 10 times higher affinity to the sigma-1 ((sigma-1) receptor than (+)-pentazoeine (K-i = 19.9 nM) or haloperidol (K-i = 13.5 nM) known as sigma ligands. Also, the binding affinity of (+)-pIV for the sigma-1 receptor (K-i = 1.30 nM), was about 16 times higher than the sigma-2 ((sigma-2) receptor (K-i = 20.4 nM). (+)-pIV (K-i = 1260 nM) had a much lower affinity for VAChT than (-)-vesamicol (K-i = 13.0 nM) or (-)-pIV (K-i = 412 nM). (+)-[ (125)]pIV had low affinity for the dopamine, serotonin, adrenaline, and acetylcholine receptors. Furthermore, in a saturation binding study, (+)-[I-125]pIV exhibited a K-d of 6.96 nM with a B-max of 799 fmol/ mg of protein. These results showed that (+)-pIV binds to the (sigma-1 receptor with greater affinity than sigma receptor ligands such as (+)-pentazocine or haloperidol, and that radioiodinated (+)-pIV is suitable as radiotracer for (sigma-1 receptor studies in vitro. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.11.029
• 作为产物：
  描述：

  (+/-)-(1S,2S)-2-(4-phenyl-1,2,5,6-tetrahydropyridin-1-yl)cyclohexanol 在 palladium on activated charcoal Pseudomonas cepacia lipase 、 氢气 作用下， 以 甲醇 为溶剂， 反应 38.0h， 生成 (1R,2R)-2-(4-苯基哌啶-1-基)环己烷-1-醇
  参考文献：
  名称：

  Chemoenzymatic preparation of optically active β-amino-cyclohexanols and their application in the enantioselective addition of diethylzinc to benzaldehyde

  摘要：

  Optically active vesamicol and other trans-2-(N,N-dialkylamino)cyclohexanols have been easily prepared in a two step sequence: opening of the oxirane ring of cyclohexene oxide with a secondary amine and subsequent resolution of the resulting racemic amino alcohol by transesterification catalyzed by Pseudomonas ccpacia lipase. The utility of these beta-aminocyclohexanols as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde has also been investigated. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetasy.2004.03.002

文献信息

• Compounds comprising 4-benzoylpiperidine as a Sigma-1-selective ligand
  申请人：Tu Zhude

  公开号：US20110311447A1

  公开（公告）日：2011-12-22

  Bipiperidinyl compounds and salts thereof are disclosed. The compounds include high affinity ligands for σ 1 receptors. Some compounds are also highly selective for σ 1 receptor compared to σ 2 receptor. Compounds can comprise radioisotopes, including 18 F or 11 C. Radiolabeled compounds can be used as probes for imaging distribution of σ 1 receptor in a subject such as a human using positron emission tomography (PET) scanning.

  双哌啶基化合物及其盐被披露。这些化合物包括对σ1受体具有高亲和力的配体。一些化合物相对于σ2受体也具有高选择性。化合物可以包含放射性同位素，包括18F或11C。放射标记的化合物可用作探针，用于通过正电子发射断层扫描（PET扫描）在受试者（如人类）中成像σ1受体的分布。
• Direct access to the optically active VAChT inhibitor vesamicol and its analogues via the asymmetric aminolysis of meso-epoxides with secondary aliphatic amines
  作者：Arun Sharma、Jyoti Agarwal、Rama Krishna Peddinti

  DOI：10.1039/c6ob02479c

  日期：——

  biologically important vesamicol, benzovesamicol, and their derivatives was achieved via the desymmetrization of meso-epoxides with secondary aliphatic amines (4-phenylpiperidine derivatives) using a chiral [salenCo(III)-BF4] catalyst at room temperature. All products were obtained in good yield and with excellent optical induction.

  通过使用手性 [salenCo( III ) -BF 4 ] 催化剂在室温下使内消旋环氧化物与脂肪族仲胺（4-苯基哌啶衍生物）去对称化，首次实现了具有重要生物学意义的 vesamicol、benzovesamicol 及其衍生物的高度对映选择性合成。所有产品均以良好的收率和优异的光诱导获得。
• Production Method of Optically Active Cyclohexane Ether Compounds
  申请人：Machiya Koji

  公开号：US20090005576A1

  公开（公告）日：2009-01-01

  The present invention relates to an industrial synthetic method of an optically active cyclohexane ether compound (IIIa) or a salt thereof, which is useful as a pharmaceutical agent, and an intermediate useful for the production method of the present invention. The production method of the present invention is as shown below: wherein each symbol is as defined in the specification. According to the production method of the present invention, efficient and stable supply of an optically active cyclohexane ether compound (IIIa) in a high yield at a lower cost can be afforded. Therefore, an optically active cyclohexane ether compound (IIIa) extremely useful as a pharmaceutical agent can be provided by an industrially highly advantageous method.

  本发明涉及一种工业合成方法，用于制备一种光学活性的环己烷醚化合物（IIIa）或其盐，该化合物在制药上有用，并提供了一种用于本发明生产方法的中间体。本发明的生产方法如下所示：其中每个符号如规范中定义。根据本发明的生产方法，可以以较低成本高产率地提供一种光学活性的环己烷醚化合物（IIIa），从而提供了一种在工业上极具优势的方法，极其有用于制药的光学活性环己烷醚化合物（IIIa）。
• Synthesis, in vitro acetylcholine-storage-blocking activities, and biological properties of derivatives and analogs of trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol)
  作者：Gary A. Rogers、Stanley M. Parsons、D. C. Anderson、Lena M. Nilsson、Ben A. Bahr、Wayne D. Kornreich、Rose Kaufman、Robert S. Jacobs、Bernard Kirtman

  DOI：10.1021/jm00126a013

  日期：1989.6

  Eighty-four analogues and derivatives of the acetylcholine-storage-blocking drug trans-2-(4-phenylpiperidino)-cyclohexanol (vesamicol) were synthesized, and their potencies were evaluated with the acetylcholine active-transport assay utilizing purified synaptic vesicles from Torpedo electric organ. The parent drug exhibits enantioselectivity, with (-)-vesamicol being 25-fold more potent than (+)-vesamicol. The atomic structure and absolute configuration of (+)-vesamicol were determined by X-ray crystallography. The absolute configuration of (-)-vesamicol is 1R,2R. Structure-activity evidence indicates that (-)-vesamicol does not act as an acetylcholine analogue. Alterations to all three rings can have large effects on potency. Unexpectedly, analogues locking the alcohol and ammonium groups trans-diequatorial or trans-diaxial both exhibit good potency. A potent benzovesamicol family has been discovered that is suitable for facile elaboration of the sort useful in affinity labeling and affinity chromatography applications. A good correlation was found between potencies as assessed by the acetylcholine transport assay and LD50 values in mouse.
• ROGERS, GARY A.;PARSONS, STANLEY M.;ANDERSON, D. C.;NILSSON, LENA M.;BAHR+, J. MED. CHEM., 32,(1989) N, C. 1217-1230
  作者：ROGERS, GARY A.、PARSONS, STANLEY M.、ANDERSON, D. C.、NILSSON, LENA M.、BAHR+

  DOI：——

  日期：——