4-(吡咯烷-1-基)-2-丁炔-1-醇 | 14597-28-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 中文名称: 4-(吡咯烷-1-基)-2-丁炔-1-醇
• 英文名称: 4-(pyrrolidin-1-yl)but-2-yn-1-ol
• 英文别名: 4-pyrrolidin-1-ylbut-2-yn-1-ol；4-pyrrolidin-1-yl-but-2-yn-1-ol；4pyrrolidin-1-ylbut-2-yn-1-ol；4-Pyrrolidino-but-2-in-1-ol；4-Pyrrolidino-2-butynol
• CAS: 14597-28-5
• 化学式: C₈H₁₃NO
• 分子量: 139.197
• InChiKey: MDKIUCFNOSCYSJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  10
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-(吡咯烷-1-基)-2-丁炔-1-醇 在 lithium aluminium tetrahydride 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 20.0h， 生成 N-(4-cyano-2-fluorophenyl)-6-methoxy-7-{[(2E)-4-pyrrolidin-1-ylbut-2-enyl]oxy}quinazolin-4-amine hydrochloride
  参考文献：
  名称：

  Novel 4-Anilinoquinazolines with C-7 Basic Side Chains:  Design and Structure Activity Relationship of a Series of Potent, Orally Active, VEGF Receptor Tyrosine Kinase Inhibitors

  摘要：

  We have previously shown that 4-anilinoquinazolines can be potent inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt-1 and KDR) tyrosine kinase activity. A novel subseries of 4-anilinoquinazolines that possess basic side chains at the C-7 position of the quinazoline nucleus have been synthesized. This subseries contains potent, nanomolar inhibitors of KDR (median IC50 0.02 muM, range 0.001-0.04 muM), which are comparatively less potent vs Flt-1 tyrosine kinase (median IC50 0.55 muM, range 0.02-1.6 muM). The compounds also retain some inhibitory activity against the tyrosine kinase associated to the endothelial growth factor receptor (EGFR) (median IC50 0.2 muM, range 0.075-0.8 muM) but demonstrate selectivity vs that associated to the FGF receptor 1 (median IC50 2.5 muM, range 0.9-19 muM). This selectivity profile is also evident in a growth factor-stimulated human endothelial cell (HUVEC) proliferation assay (i.e., inhibition of VEGF > EGF > FGF), with inhibition of VEGF-induced proliferation being achieved at nanomolar concentrations (median IC50 0.06 muM). Further examination of compound 2 (ZD6474) in recombinant enzyme assays revealed excellent selectivity for the inhibition of KDR tyrosine kinase (IC50 0.04 muM) vs the kinase activity of erbB2, MEK, CDK-2, Tie-2, IGFR-1R, PDK, PDGFRbeta, and AKT (IC50 range: 1.1 to >100 muM). Anilinoquinazolines possessing basic C-7 side chains exhibited markedly improved aqueous solubility over previously described anilinoquinazolines possessing neutral C-7 side chains (up to 500-fold improvement at pH 7.4). In addition, aqueous solubility of the neutral fraction present at pH 7.4 of the basic subseries of anilinoquinazoline proved to be higher than that of the neutral analogue 1 (ZD4190). Oral administration of representative compounds to mice (50 mg/kg) produced plasma levels between 0.2 and 3 muM at 24 h after dosing. Our development candidate 2 demonstrated a very attractive in vitro profile combined with excellent solubility (330 muM at pH 7.4) and good oral bioavailability in rat and dog (>80 and >50%, respectively). This compound demonstrated highly significant, dose-dependent, antitumor activity in athymic mice. Once daily oral administration of 100 mg/kg of compound 2 for 21 days inhibited the growth of established Calu-6 lung carcinoma xenografts by 79% (P < 0.001, Mann Whitney rank sum test), and substantial inhibition (36%, P < 0.02) was evident with 12.5 mg/kg/day.

  DOI：

  10.1021/jm011022e
• 作为产物：
  描述：

  四氢吡咯 、 4-氯-2-丁炔-1-醇 在 methanol-dichloromethane 作用下， 以 甲苯 为溶剂， 反应 1.0h， 以to give 4-(pyrrolidin-1-yl)but-2-yn-1-ol (4.3 g, 69%)的产率得到4-(吡咯烷-1-基)-2-丁炔-1-醇
  参考文献：
  名称：

  Quinazoline derivatives and pharmaceutical compositions containing them

  摘要：

  本发明涉及式（I）的喹唑啉衍生物，其中m是1至2的整数；R1代表氢、羟基、卤素、硝基、三氟甲基、氰基、C1-13烷基、C1-3烷氧基、C1-3烷基硫基，或—NR5R6（其中R5和R6，可以相同也可以不同，分别代表氢或C1-3烷基）；R2代表氢、羟基、卤素、甲氧基、氨基或硝基；R3代表羟基、卤素、C1-3烷基、C1-3烷氧基、C1-3烷酰氧基、三氟甲基、氰基、氨基或硝基；X1代表—O—、—CH2—、—S—、—SO—、—SO2—、—NR7CO—、—CONR8—、—SO2NR9—、—NR10SO2—或—NR11—（其中R7、R8、R9、R10和R11各自独立地代表氢、C1-3烷基或C1-3烷氧基C2-3烷基）；R4代表一个可选取代的5或6成员饱和碳环或杂环基团或烯基、炔基或可选取代的烷基，其中烷基基团可以包含一个杂原子连接基团，烯基、炔基或烷基基团可以携带一个末端可选取代的基团，所述基团选自烷基和一个5或6成员饱和碳环或杂环基团，以及其盐；制备它们的方法，含有式（I）的化合物或其药学上可接受的盐作为活性成分的制药组合物。式（I）的化合物和药学上可接受的盐抑制VEGF的作用，这是治疗包括癌症和类风湿性关节炎在内的多种疾病状态的有价值的特性。

  公开号：

  US20020173646A1

文献信息

• Quinazoline derivatives and pharmaceutical compositions containing them
  申请人：Zeneca Limited

  公开号：US06414148B1

  公开（公告）日：2002-07-02

  The invention relates to quinazoline derivatives of formula (1) wherein m is an integer from 1 to 2; R1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or —NR5R6 (wherein R5 and R6, which may be the same or different, each represents hydrogen or C1-3alkyl); R2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R3 represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X1 represents —O—, —CH2—, —S—, —SO—, —SO2—, —NR7CO—, —CONR8—, —SO2NR9—, —NR10SO2— or —NR11— (wherein R7, R8, R9, R10 and R11 each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl); R4 represents an optionally substituted 5 or 6 membered saturated carbocyclic or heterocyclic group or a group which is alkenyl, alkynyl or optionally substituted alkyl, which alkyl group may contain a heteroatom linking group, which alkenyl, alkynyl or alkyl group may carry a terminal optionally substituted group selected from alkyl and a 5 or 6 membered saturated carbocyclic or heterocyclic group, and salts thereof; processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula (I) and pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

  该发明涉及式（1）的喹唑啉衍生物， 其中m是1到2之间的整数；R1代表氢、羟基、卤素、硝基、三氟甲基、氰基、C1-3烷基、C1-3烷氧基、C1-3烷硫基，或-NR5R6（其中R5和R6，可以相同也可以不同，各自代表氢或C1-3烷基）；R2代表氢、羟基、卤素、甲氧基、氨基或硝基；R3代表羟基、卤素、C1-3烷基、C1-3烷氧基、C1-3烷酰氧基、三氟甲基、氰基、氨基或硝基；X1代表-O-、-CH2-、-S-、-SO-、-SO2-、-NR7CO-、-CONR8-、-SO2NR9-、-NR10SO2-或-NR11-（其中R7、R8、R9、R10和R11各自独立地代表氢、C1-3烷基或C1-3烷氧基C2-3烷基）；R4代表可选择地取代的5或6成员饱和碳环或杂环基团，或者是烯基、炔基或可选择地取代的烷基，该烷基可能含有连接基团的杂原子，该烯基、炔基或烷基基团可能携带一个末端可选择地取代的基团，所选自烷基和5或6成员饱和碳环或杂环基团，以及其盐；它们的制备方法，含有式（I）的化合物或其药学上可接受的盐作为活性成分的药物组合物。式（I）的化合物和其药学上可接受的盐抑制VEGF的作用，这是治疗多种疾病状态的一种有价值的特性，包括癌症和类风湿性关节炎。
• Therapy
  申请人：——

  公开号：US20030225111A1

  公开（公告）日：2003-12-04

  The invention concerns the use of a quinazoline derivative of Formula (I) wherein Q 1 includes a quinazoline ring optionally substituted with a group such as halogeno, trifluoromethyl and cyano, or a group of the formula: Q 3 —X 1 — wherein X 1 includes a direct bond and O and Q 3 includes aryl, aryl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl; each of R 2 and R 3 is hydrogen or (1-6C)alkyl; Z includes O, S and NH; and Q 2 includes aryl and aryl-(1-3C)alkyl or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human. 1

  该发明涉及使用式（I）的喹唑啉衍生物，其中Q1包括一个喹唑啉环，可选地取代为卤、三氟甲基和氰等基团，或者具有式Q3-X1-的基团，其中X1包括直接键和O，Q3包括芳基、芳基-(1-6C)烷基、杂环基和杂环基-(1-6C)烷基；R2和R3中的每一个是氢或(1-6C)烷基；Z包括O、S和NH；Q2包括芳基和芳基-(1-3C)烷基或其药用可接受盐，在制备药物时用于在温血动物（如人类）中产生抗血管生成和/或降低血管通透性的效果。
• Quinazoline derivatives
  申请人：AstraZeneca UK Limited

  公开号：US06806274B1

  公开（公告）日：2004-10-19

  The invention concerns quinazoline derivatives of Formula (I) wherein Q1 includes a quinazoline ring optionally substituted with a group such as halogeno, trifluoromethyl and cyano, or a group of the formula: Q3—X1— wherein X1 includes a direct bond and O and Q3 includes aryl, aryl-(1-6C)alkyl, heterocyclyl and heterocyclyl-(1-6C)alkyl; each of R2 and R3 is hydrogen or (1-6C)alkyl; Z includes O, S and NH; and Q2 includes aryl and aryl-(1-3C)alkyl or a pharmaceutically-acceptable salt thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the prevention or treatment of T cell mediated diseases or medical conditions in a warm-blooded animal.

  该发明涉及式(I)的喹唑啉衍生物，其中Q1包括一个喹唑啉环，可选择地取代为卤素、三氟甲基和氰基等基团，或者具有以下式的基团：Q3—X1—，其中X1包括直接键和O，Q3包括芳基、芳基-(1-6C)烷基、杂环基和杂环基-(1-6C)烷基；R2和R3中的每一个是氢或(1-6C)烷基；Z包括O、S和NH；Q2包括芳基和芳基-(1-3C)烷基或其药用可接受盐；它们的制备方法，含有它们的药物组合物以及它们在制造用于预防或治疗温血动物T细胞介导疾病或医疗状况的药物中的用途。
• Mild and efficient synthesis of propargylamines by copper-catalyzed Mannich reaction
  作者：Lothar W. Bieber、Margarete F. da Silva

  DOI：10.1016/j.tetlet.2004.09.079

  日期：2004.11

  Terminal alkynes undergo mild and efficient aminomethylation with aqueous formaldehyde and secondary amines under CuI catalysis. In most cases high to nearly quantitative yields of tertiary propargylamines are obtained in DMSO solution at room temperature. Aromatic, aliphatic and silylated acetylenes as well as alkynols can be used. Primary amines are less reactive and satisfactory yields of secondary propargylamines

  末端炔烃在CuI催化下与甲醛水溶液和仲胺进行温和有效的氨甲基化反应。在大多数情况下，室温下在DMSO溶液中可获得高至接近定量的叔炔丙胺收率。可以使用芳族，脂族和甲硅烷基化乙炔以及炔醇。伯胺的反应性较低，仅用苯乙炔才能获得令人满意的仲炔丙基胺收率。
• Rearrangement–cyclization of dialkyl(4-hydroxybut-2-ynyl)meth-allyl- and dialkylcrotyl(4-hydroxy-but-2-ynyl) ammonium halides
  作者：E. O. Chukhajian、A. S. Gabrielyan、El. O. Chukhajian、K. G. Shahkhatuni、H. A. Panosyan

  DOI：10.1007/s10593-010-0425-1

  日期：2009.11

  It was found that dialkyl(4-hydroxybut-2-ynyl)methallyl- and dialkylcrotyl(4-hydroxybut-2-ynyl)- ammonium halides undergo a Stevens rearrangement under the influence of aqueous alkali with transfer of the reaction center in the receiving group and inversion of the migrating group followed by cyclization to amino derivatives of furan.

  发现二烷基（4-羟基丁-2-炔基）甲基烯丙基-和二烷基巴甲基（4-羟基丁-2-炔基）-卤化铵在碱水溶液的影响下随着接收中心中反应中心的转移而经历了史蒂文斯重排。迁移基团的转化，然后环化成呋喃的氨基衍生物。