9H-咔唑，2-[（2E）-2-（1-氮杂双环[2.2.2]辛-3-亚基）-2-氟乙氧基]-，一盐酸盐 | 182959-33-7

• 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
• 中文名称: 9H-咔唑，2-[（2E）-2-（1-氮杂双环[2.2.2]辛-3-亚基）-2-氟乙氧基]-，一盐酸盐
• 英文名称: YM-53601
• 英文别名: (E)-2-[2-fluoro-2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole monohydrochloride；2-{[(2E)-2-(1-Azabicyclo[2.2.2]oct-3-ylidene)-2-fluoroethyl]oxy}-9H-carbazole；2-[(2E)-2-(1-azabicyclo[2.2.2]octan-3-ylidene)-2-fluoroethoxy]-9H-carbazole;hydrochloride
• CAS: 182959-33-7
• 化学式: C₂₁H₂₁FN₂O*ClH
• 分子量: 372.87
• InChiKey: JWXYVHMBPISIJQ-TVWXOORISA-N

物化性质

• 熔点：
  236.5-237.2 °C
• 溶解度：
  DMF：20 mg/ml； DMSO：20 mg/ml； DMSO:PBS(pH 7.2)(1:3)：0.25 mg/ml；乙醇：2 mg/ml

计算性质

• 辛醇/水分配系数(LogP)：
  5.07
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  28.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  9H-咔唑，2-[（2E）-2-（1-氮杂双环[2.2.2]辛-3-亚基）-2-氟乙氧基]-，一盐酸盐 以 甲醇 为溶剂， 反应 0.5h， 以50%的产率得到1-((E)-2-fluoro-2-((1r,4r)-quinuclidin-3-ylidene)ethyl)-9H-carbazol-2-ol hydrochloride
  参考文献：
  名称：

  小分子依赖性光解肽的发现

  摘要：

  我们意外地发现 YM-53601，一种已知的角鲨烯合酶 (SQS) 小分子抑制剂，在紫外线 (UV) 照射下选择性地消耗哺乳动物细胞中的 SQS。进一步的分析表明，SQS 的光消耗需要其位于 COOH 末端的短肽段。值得注意的是，当 27 个氨基酸的肽在 NH2 或 COOH 末端与 GFP 或无关蛋白融合时，当细胞用 YM-53601 和紫外线照射处理时，这种融合蛋白会被选择性消耗。产物分析和 ESR 实验表明，紫外线照射促进了 YM-53601 中芳基醚基团的均裂 CO 键断裂。很可能由紫外线激活的 YM-53601 产生的自由基物质从 SQS 肽中提取氢原子，导致整个蛋白质的光解。

  DOI：

  10.1021/jacs.9b09178
• 作为产物：
  描述：

  3-奎宁环酮 在 盐酸 、 硼烷四氢呋喃络合物 、 sodium hydride 、 potassium carbonate 、 甲基磺酰氯 、 三乙胺 、 lithium chloride 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 37.0h， 生成 9H-咔唑，2-[（2E）-2-（1-氮杂双环[2.2.2]辛-3-亚基）-2-氟乙氧基]-，一盐酸盐
  参考文献：
  名称：

  Syntheses of 3-Ethylidenequinuclidine derivatives as squalene synthase inhibitors. Part 2: enzyme inhibition and effects on plasma lipid levels

  摘要：

  Squalene synthase (E.C. 2.5.1.21) is a microsomal enzyme which catalyzes the reductive dimerization of two molecules of farnesyl diphosphate to form squalene, and is involved in the first committed step in cholesterol biosynthesis. It is an attractive target for hypocholesterolemic and hypotriglyceridemic strategies. We synthesized a series of 3-ethylidenequinuclidine derivatives, and evaluated their ability to inhibit squalene synthase in vitro and to lower non-HDL cholesterol levels in hamsters. 3-Ethylidene-quinuclidine derivatives incorporating an unsubstituted 9H-carbazole moiety reduced plasma non-HDL cholesterol levels and did not affect plasma transaminase levels, indicating a lack of hepatotoxicity. Among the novel Compounds, (Z)-2-[2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole hydrochloride 8 (YM-53579) and (E)-2-[2-fluoro-2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole hydrochloride 28 (YM-53601) were potent inhibitors of squalene synthase derived from human hepatoma cells, with IC50 Values Of 160 and 79 nM. respectively. They also reduced plasma non-HDL cholesterol levels in hamsters by approximately 50 and 70%, respectively. at all oral dose of 50 mg/kg/day for 5 days. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00336-5

文献信息

• Quinuclidine derivative having tricyclic hetero condensed ring
  申请人：Yamanouchi Pharmaceutical Co., Ltd.

  公开号：US05830902A1

  公开（公告）日：1998-11-03

  A quinuclidine derivative represented by the following general formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which has strong squalene synthase inhibiting activity and is useful as a cholesterol lowering agent without causing side effects. ##STR1## (Symbols in the formula represent the following meanings; R.sub.1 : a hydrogen atom, a halogen atom or a lower alkyl group, R.sub.2 : a hydrogen atom, a hydroxyl group or a lower alkoxy group, . . : a single bond or a double bond, with the proviso that R.sub.2 does not exist when . . . is a double bond, X and Y: the same or different from each other and each represents a bond, an oxygen atom (--O--), a carbonyl group (--CO--), a group represented by the formula --S(O).sub.p -- or a group represented by the formula --NR.sub.3 --, p: 0, 1 or 2, R.sub.3 : a hydrogen atom or a lower alkyl group which may have a substituent, A: a saturated or unsaturated lower alkylene group, a group of the formula --(CH.sub.2).sub.m Z(CH.sub.2).sub.n -- or a group of the formula --(CH.sub.2).sub.m Z(CH.sub.2).sub.n CR.sub.4 =, Z: an oxygen atom (--O--), a group of the formula --S(O).sub.q --, a carbonyl group (--CO--) or a group of the formula --NR.sub.5 --, R.sub.4 : a hydrogen atom, a halogen atom or a lower alkyl group, R.sub.5 : a hydrogen atom or a lower alkyl group, m and n: the same or different from each other and each is 0 or an integer of 1 to 5, m+n: an integer of 1 to 5 q: 0, 1 or 2, with the proviso that, when either one of X and Y is a bond, A is a group represented by the formula --(CH.sub.2).sub.m Z(CH.sub.2).sub.n CR.sub.4 =.)

  以下是一种由以下通式（I）表示的喹诺啡衍生物，其药物可接受的盐，其水合物或溶剂化合物，具有强烈的角鲨烷合成酶抑制活性，并且可用作降低胆固醇的药物，不会引起副作用。 ##STR1##（公式中的符号表示以下含义; R.sub.1：氢原子，卤原子或较低的烷基，R.sub.2：氢原子，羟基或较低的烷氧基，...：单键或双键，条件是当...为双键时，R.sub.2不存在，X和Y：相同或不同，每个代表键，氧原子（-O-），羰基（-CO-），由公式-S（O）.sub.p-表示的基团或由公式-NR.sub.3-表示的基团，p：0,1或2，R.sub.3：氢原子或可能具有取代基的较低烷基，A：饱和或不饱和的较低烷基，公式-（CH.sub.2）.sub.m Z（CH.sub.2）.sub.n-的基团或公式-（CH.sub.2）.sub.m Z（CH.sub.2）.sub.n CR.sub.4 =的基团，Z：氧原子（-O-），由公式-S（O）.sub.q-表示的基团，羰基（-CO-）或由公式-NR.sub.5-表示的基团，R.sub.4：氢原子，卤原子或较低的烷基，R.sub.5：氢原子或较低的烷基，m和n：相同或不同，每个为0或1至5的整数，m + n：1至5的整数q：0,1或2，条件是当X和Y中的任一个是键时，A是由公式-（CH.sub.2）.sub.m Z（CH.sub.2）.sub.n CR.sub.4 =表示的基团。
• NOVEL QUINUCLIDINE DERIVATIVES HAVING TRICYCLIC FUSED HETERO RING
  申请人：YAMANOUCHI PHARMACEUTICAL CO. LTD.

  公开号：EP0812840A1

  公开（公告）日：1997-12-17

  A quinuclidine derivative represented by the following general formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, which has strong squalene synthase inhibiting activity and is useful as a cholesterol lowering agent without causing side effects. (Symbols in the formula represent the following meanings; R1: a hydrogen atom, a halogen atom or a lower alkyl group, R2: a hydrogen atom, a hydroxyl group or a lower alkoxy group, : a single bond or a double bond, with the proviso that R2 does not exist when is a double bond, X and Y: the same or different from each other and each represents a bond, an oxygen atom (-O-), a carbonyl group (-CO-), a group represented by the formula -S(O)p- or a group represented by the formula -NR3-, p: 0, 1 or 2, R3: a hydrogen atom or a lower alkyl group which may have a substituent, A: a saturated or unsaturated lower alkylene group, a group of the formula -(CH2)mZ(CH2)n- or a group of the formula -(CH2)mZ(CH2)nCR4=, Z: an oxygen atom (-O-), a group of the formula -S(O)q-, a carbonyl group (-CO-) or a group of the formula -NR5-, R4: a hydrogen atom, a halogen atom or a lower alkyl group, R5: a hydrogen atom or a lower alkyl group, m and n: the same or different from each other and each is 0 or an integer of 1 to 5, m + n: an integer of 1 to 5 q: 0, 1 or 2, with the proviso that, when either one of X and Y is a bond, A is a group represented by the formula -(CH2)mZ(CH2)nCR4=.)

  一种由以下通式（I）代表的喹烯酮衍生物、其药学上可接受的盐、其水合物或其溶液，该衍生物具有很强的角鲨烯合成酶抑制活性，可用作降低胆固醇的药物，且不会产生副作用。 (式中符号代表以下含义； R1：氢原子、卤素原子或低级烷基、 R2：氢原子、羟基或低级烷氧基、 R2：单键或双键，但 R2 为双键时不存在、 X和Y：彼此相同或不同，各自代表一个键、一个氧原子（-O-）、一个羰基（-CO-）、一个由式-S(O)p-代表的基团或一个由式-NR3-代表的基团、 p:0、1 或 2、 R3：氢原子或可带有取代基的低级烷基、 A：饱和或不饱和低级亚烷基、式-(CH2)mZ(CH2)n-或式-(CH2)mZ(CH2)nCR4=的基团、 Z：氧原子（-O-）、式-S(O)q-的基团、羰基（-CO-）或式-NR5-的基团、 R4：氢原子、卤素原子或低级烷基、 R5：氢原子或低级烷基、 m 和 n：相同或互不相同，各自为 0 或 1 至 5 的整数、 m+n：1 至 5 的整数 q：0、1 或 2、 但条件是，当 X 和 Y 中任何一个是键时，A 是由式-(CH2)mZ(CH2)nCR4=代表的基团。）
• Modulation of squalene synthase expression
  申请人：Isis Pharmaceuticals Inc.

  公开号：US20040102405A1

  公开（公告）日：2004-05-27

  Compounds, compositions and methods are provided for modulating the expression of squalene synthase. The compositions comprise oligonucleotides, targeted to nucleic acid encoding squalene synthase. Methods of using these compounds for modulation of squalene synthase expression and for diagnosis and treatment of disease associated with expression of squalene synthase are provided.

  提供了调节角鲨烯合成酶表达的化合物、组合物和方法。这些组合物包括寡核苷酸，以编码角鲨烯合成酶的核酸为靶标。提供了使用这些化合物调节角鲨烯合成酶表达以及诊断和治疗与角鲨烯合成酶表达相关疾病的方法。
• PRODUCTION OF CAROTENOIDS IN OLEAGINOUS YEAST AND FUNGI
  申请人：Bailey Richard B.

  公开号：US20110039299A1

  公开（公告）日：2011-02-17

  The present invention provides systems for producing engineered oleaginous yeast or fungi that express carotenoids.
• RETT SYNDROME AND TREATMENTS THEREFORE
  申请人：RETT SYNDROME RESEARCH TRUST

  公开号：US20160193231A1

  公开（公告）日：2016-07-07

  The present invention provides new strategies for the treatment of Rett Syndrome and other MECP2-associated disorders, including for the identification and/or characterization of useful therapeutic modalities and/or for the stratification of Rett Syndrome patients to identify those more or less likely to respond to a particular therapy. In some embodiments, the present invention defines certain components of metabolic pathways, and particularly of lipid and/or cholesterol metabolism (e.g., biosynthesis) pathways, most particularly of lipid and/or cholesterol metabolism (e.g., biosynthesis) pathways in the brain, as targets useful in the identification and/or characterization of potential Rett Syndrome treatment agents. Among other things, the present invention provides systems for identifying and/or characterizing such agents by contacting them with a system that comprises one or more such metabolic pathway components, and assessing their impact on presence, level, activity, and/or form of one or more indicators (e.g., components, products, and/or markers of the relevant pathway(s)).