ethyl (8-methyl-8-azabicyclo<3.2.1>oct-3-ylidene)acetate | 2858-77-7

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 托烷生物碱
• 英文名称: ethyl (8-methyl-8-azabicyclo<3.2.1>oct-3-ylidene)acetate
• 英文别名: (8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene)acetic acid ethyl ester；Ethyl (tropan-2-ylidene)acetate；tropan-3-ylidene-acetic acid ethyl ester；3-Ethoxycarbonylmethylen-tropan；3-Carbethoxymethylen-tropan；Acetic acid, (8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene)-, ethyl ester；ethyl 2-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylidene)acetate
• CAS: 2858-77-7
• 化学式: C₁₂H₁₉NO₂
• 分子量: 209.288
• InChiKey: SQNOQCVPMVYWBB-UHFFFAOYSA-N

物化性质

• 沸点：
  297.5±15.0 °C(Predicted)
• 密度：
  1.114±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl (8-methyl-8-azabicyclo<3.2.1>oct-3-ylidene)acetate 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 14.0h， 以96%的产率得到(8-methyl-8-azabicyclo<3.2.1>oct-3-ylidene)acetic acid
  参考文献：
  名称：

  新的5-HT3（5-羟色胺3）受体拮抗剂。IV。氮杂双环烷乙酰胺衍生物的合成及其构效关系。

  摘要：

  描述了一系列新型的氮杂双环烷作为5-HT3（5-羟色胺-3）受体拮抗剂的合成与构效关系。我们对氮杂双环烷乙酰胺衍生物的研究表明，由2，3-二氢吲哚作为芳香环部分提供了有效的5-HT3受体拮抗剂活性，这是通过在麻醉的大鼠中静脉注射2-甲基5-羟色胺诱导的心动过缓而判断的。7-氮杂吲哚作为芳族部分提供弱的5-HT 3受体拮抗剂活性。这项研究中最好的5-HT3拮抗剂是3,3-二乙基-（9k）和3,3-二甲基-2,3-二氢-1-[[（8-甲基-8-氮杂双环）[3.2.1]]。辛基-3-羟基）乙酰基1H-吲哚（9d），其效力比恩丹西酮（1）高约10倍。

  DOI：

  10.1248/cpb.43.1351
• 作为产物：
  描述：

  磷酰基乙酸三乙酯 、 托品酮 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以99.4%的产率得到ethyl (8-methyl-8-azabicyclo<3.2.1>oct-3-ylidene)acetate
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Tropane-like 1-{2-[Bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909) Analogues

  摘要：

  We have prepared azabicyclo [3.2.1] derivatives (C-3-substituted tropanes) that bind with high affinity to the dopamine transporter and inhibit dopamine reuptake. Within the series, 3-{2-[bis-(4-fluorophenyl)methoxyl ethylidene}-8-methyl-8-azabicyclo [3.2.1] octane (8) was found to have the highest affinity and selectivity for the dopamine transporter. These azabicyclo [3.2.1] (bridged piperidine) series of compounds differ from the well-known benztropines by a 2-carbon spacer between C-3 and a diarylmethoxy moiety. Interestingly, these new compounds demonstrated a much lower affinity for the muscarinic-1 site, at least a 100-fold decrease compared to benztropine. Replacing N-methyl with N-phenylpropyl in two of the compounds resulted in a 3-10-fold increase in binding affinity for the dopamine transporter. However, those compounds lost selectivity for the dopamine transporter over the serotonin transporter. Replacement of the ether oxygen in the diarylmethoxy moiety with a nitrogen atom gave relatively inactive amines, indicating the important role which is played by the ether oxygen in transporter binding. Reduction of the C-3 double bond in 8 gave 3 alpha -substituted tropanes, as shown by X-ray crystallographic analyses of 11, 12, and 19. The 3 alpha -substituted tropanes had lower affinity and less selectivity than the comparable unsaturated ligands.

  DOI：

  10.1021/jm0101592

文献信息

• The synthesis, conformation and antimuscarinic properties of ketone analogues of tropane esters
  作者：Mustafa Tavasli、David O’Hagan、Andrei S. Batsanov、Graham R. Foxon、Robert F. Halliwell、Judith A. K. Howard

  DOI：10.1039/a907130j

  日期：——

  three naturally occurring tropane esters has been developed and one of the ketones has been evaluated for its efficacy as a muscarinic acetylcholine receptor (mAChR) antagonist in guinea-pig ileum. The ketone analogue of apoatropine displayed an IC50 value in the micromolar range when compared to atropine, which has antagonist activity in the nanomolar range. The conformational change in replacing the

  已经开发了三种天然存在的对苯二酸酯的酮类似物的合成，并且已评估了其中一种酮作为豚鼠回肠中毒蕈碱乙酰胆碱受体（mAChR）拮抗剂的功效。与阿托品相比，阿托品的酮类似物在微摩尔范围内显示IC 50值，而阿托品在纳摩尔范围内具有拮抗活性。已通过化合物之一的X射线结构分析评估了用CH 2取代酯部分的桥联氧的构象变化，并已在Cambridge Crystallographic Database调查中进行了更广泛的评估。结构数据表明，托烷酯和托烷酮均采用相似的构象。
• Design and Synthesis of Potent Antileishmanial Cycloalkylidene-Substituted Ether Phospholipid Derivatives
  作者：Theodora Calogeropoulou、Panagiotis Angelou、Anastasia Detsi、Irene Fragiadaki、Effie Scoulica

  DOI：10.1021/jm701166b

  日期：2008.2.1

  Two series of novel ether phospholipids (EPs) have been synthesized. The first includes cyclodecylideneor cyclopentadecylidene-substituted EPs carrying N,N,N-trimethylammonium or N-methylpiperidino or N-methylmorpholino head groups. The second series encompasses more rigid head groups in combination with cycloalkylidene moieties in the lipid portion. In addition, hydrogenated derivatives were obtained. All the new analogues, except 33, were 1.5- to 62-fold more potent than miltefosine against the intracellular L. infantum, and the most active ones were also less cytotoxic against the human monocytic cell line THP1 and less hemolytic than miltefosine. The analogues that combine high potency with low cytotoxicity and hemolytic activity were 19, 37, 2123, 38, 39, and 40. Cyclopentadecylpentylphosphocholine (38) possesses an IC50 of 0.7 mu M against L. infantum amastigotes and is the least cytotoxic analogue, since it does not present toxicity against THP1 macrophages, even at a concentration that is 800-fold the antiparasitic IC50 value, and does not present significant hemolytic activity.
• COMPOUNDS AS CALCIUM CHANNEL ANTAGONISTS
  申请人：SMITHKLINE BEECHAM PLC

  公开号：EP0629190A1

  公开（公告）日：1994-12-21
• [EN] COMPOUNDS AS CALCIUM CHANNEL ANTAGONISTS
  申请人：SMITHKLINE BEECHAM PLC

  公开号：WO1993015052A1

  公开（公告）日：1993-08-05

  (EN) Compounds of formula (I) in which W is -CH2-, a bond, O or S; k is 0, or when W represents -CH2- k may also be 2, in which case the dotted lines represent single bonds; R is C1-8alkyl(phenyl)p, C2-8alkenyl(phenyl)p, C2-8alkynyl(phenyl)p, C3-8cycloalkyl or C1-8alkylC3-8cycloalkyl, or R may also represent hydrogen when k is 2; p is 0 to 2; n is 0 to 6; m is 0 to 6; and A is a bond, -CH=CH- or -C=C- oxygen, sulphur or NR1; R1 is hydrogen, C1-8alkyl or phenylC1-4alkyl; and Ar is aryl or heteroaryl, each of which may be optionally substituted; with the provisos that: when W is a bond the side chain is $g(a) to the ring nitrogen atom; when W is CH2, k is zero, the side chain is at the 3- or 4-position of the piperidine ring and A is a bond, oxygen, sulphur or NR1 then Ar is aryl substituted by phenoxy or substituted phenoxy or is a tricyclic heteroaryl group as hereinafter defined; and when W is CH2 and k is 2 the side chain -(CH2)nA(CH2)mAr is not $g(a) to the nitrogen atom, and salts thereof, have activity as calcium channel antagonists. Processes for preparing compounds (I) and compositions containing them are also described.(FR) Cette invention concerne des composés de formule (I) dans laquelle W représente -CH2-, une liaison, O ou S; k représente 0, ou bien lorsque W représente -CH2- k peut également représenter 2 et dans ce cas les lignes en pointillés représentent des liaisons simples; R représente alkyleC1-8(phényle)p, alcényleC2-8(phényle)p, alcynyleC2-8(phényle)p, cycloalkyleC3-8 ou alkyleC1-8cycloalkyleC3-8, ou bien R peut également représenter hydrogène lorsque k représente 2; p représente un entier compris entre 0 et 2, n représente un entier compris entre 0 et 6; m représente un entier compris entre 0 et 6; et A représente une liaison, -CH=CH- ou -C=C- oxygène, soufre ou NR1; R1 représente hydrogène, alkyleC1-8 ou phényleC1-4alkyle; et Ar représente aryle ou hétéroaryle, chacun pouvant être facultativement substitué; aux conditions que: 1) lorsque W représente une liaison la chaîne latérale représente $g(a) par rapport à l'atome d'azote du cycle; 2) lorsque W représente CH2 k représente O, la chaîne latérale se situe à la position 3- ou 4- du cycle pipéridine et A représente une liaison, oxygène, soufre ou NR1 alors Ar représente aryle substitué par phénoxy ou phénoxy substitué ou un groupe hétéroaryle tricyclique défini ci-après; 3) lorsque W représente CH2 et k représente 2, la chaîne latérale -(CH2)nA(CH2)mAr ne représente pas $g(a) par rapport à l'atome d'azote. Ces composés et leurs sels présentent une activité comme antagonistes des canaux calciques. Cette invention concerne également des procédés de préparation desdits composés (1) ainsi que des compositions les renfermant.
• Synthesis and Biological Evaluation of Tropane-like 1-{2-[Bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909) Analogues
  作者：Ying Zhang、David B. Joseph、Wayne D. Bowen、Judith L. Flippen-Anderson、Christina M. Dersch、Richard B. Rothman、Arthur E. Jacobson、Kenner C. Rice

  DOI：10.1021/jm0101592

  日期：2001.11.1

  We have prepared azabicyclo [3.2.1] derivatives (C-3-substituted tropanes) that bind with high affinity to the dopamine transporter and inhibit dopamine reuptake. Within the series, 3-2-[bis-(4-fluorophenyl)methoxyl ethylidene}-8-methyl-8-azabicyclo [3.2.1] octane (8) was found to have the highest affinity and selectivity for the dopamine transporter. These azabicyclo [3.2.1] (bridged piperidine) series of compounds differ from the well-known benztropines by a 2-carbon spacer between C-3 and a diarylmethoxy moiety. Interestingly, these new compounds demonstrated a much lower affinity for the muscarinic-1 site, at least a 100-fold decrease compared to benztropine. Replacing N-methyl with N-phenylpropyl in two of the compounds resulted in a 3-10-fold increase in binding affinity for the dopamine transporter. However, those compounds lost selectivity for the dopamine transporter over the serotonin transporter. Replacement of the ether oxygen in the diarylmethoxy moiety with a nitrogen atom gave relatively inactive amines, indicating the important role which is played by the ether oxygen in transporter binding. Reduction of the C-3 double bond in 8 gave 3 alpha -substituted tropanes, as shown by X-ray crystallographic analyses of 11, 12, and 19. The 3 alpha -substituted tropanes had lower affinity and less selectivity than the comparable unsaturated ligands.