6-chloro-4-cyclopropyl-3,4-dihydro-4-((2-pyrimidinyl)ethynyl)quinazolin-2(1H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 6-chloro-4-cyclopropyl-3,4-dihydro-4-((2-pyrimidinyl)ethynyl)quinazolin-2(1H)-one
• 英文别名: 6-Chloro-4-cyclopropyl-4-(2-pyrimidin-2-ylethynyl)-1,3-dihydroquinazolin-2-one
• 化学式: C₁₇H₁₃ClN₄O
• 分子量: 324.769
• InChiKey: QRWQZWCAXMZOPV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  66.9
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2-氨基-5-氯苯腈 在 bis-triphenylphosphine-palladium(II) chloride 、 正丁基锂 、 三乙胺 、 magnesium triflate 、 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 49.5h， 生成 6-chloro-4-cyclopropyl-3,4-dihydro-4-((2-pyrimidinyl)ethynyl)quinazolin-2(1H)-one
  参考文献：
  名称：

  Synthesis of a Series of 4-(Arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones as Novel Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

  摘要：

  As part of an ongoing effort to prepare novel non-nucleoside inhibitors of human immunodeficiency virus type-1 (HTV-1) reverse transcriptase (RT), a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones 4aa-1 has been prepared. Target compounds 4a-e were synthesized via addition of various 1-lithio-2-(aryl)alkyne nucleophiles to a 1-protected-4-cyclopropylquinazolin-2(1H)-one (7), followed by deprotection. The 3-methyl compound 4aa was prepared in an analogous manner, with the 3-alkylation performed prior to deprotection. Alternatively, the target compounds 4f-1 were prepared by addition of 1-lithio-2-(trimethylsilyl)acetylene to 7, followed by deprotection and subsequent palladium-catalyzed coupling with various aryl halides, By incorporating an aryl group onto the end of the 4-acetylene functionality, the requirement for a metabolically labile 3-methyl group on the dihydroquinazolinone nucleus has been eliminated. A number of the target compounds were shown to be potent inhibitors of HTV-1 RT. Compound 4a, which had exhibited the most favorable overall biological profile, was' resolved via a four-step procedure to provide the enantiomers 13a and 13b. Compound 13a having the (-)-4(S) configuration was shown to be the active enantiomer and was selected as a candidate for further investigation.

  DOI：

  10.1021/jm00041a023

文献信息

• New quinazolines as inhibitors of HIV reverse transcriptase
  申请人：MERCK & CO. INC.

  公开号：EP0569083A1

  公开（公告）日：1993-11-10

  Compounds having a quinazolin-2-one nucleus with a substituted alkynyl or substituted alkenyl at the 4-position are described. These compounds are useful in the inhibition of HIV reverse transcriptase (including its resistant varieties), the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

  描述了在喹唑啉-2-酮核上具有取代炔基或取代烯基的化合物。这些化合物在抑制HIV逆转录酶（包括其耐药品种）、预防或治疗HIV感染以及治疗艾滋病方面具有用途，无论是作为化合物、药学上可接受的盐、药用组分成分，还是与其他抗病毒药物、免疫调节剂、抗生素或疫苗组合使用。还描述了治疗艾滋病的方法以及预防或治疗HIV感染的方法。
• NEW QUINAZOLINES AS INHIBITORS OF HIV REVERSE TRANSCRIPTASE
  申请人：MERCK & CO. INC.

  公开号：EP0639184A1

  公开（公告）日：1995-02-22
• [EN] NEW QUINAZOLINES AS INHIBITORS OF HIV REVERSE TRANSCRIPTASE<br/>[FR] NOUVELLES QUINAZOLINES INHIBANT LA TRANSCRIPTASE INVERSE DU VIH
  申请人：MERCK & CO., INC.

  公开号：WO1993022292A1

  公开（公告）日：1993-11-11

  (EN) Compounds having a quinazolin-2-one nucleus with a substituted alkynyl or substituted alkenyl at the 4-position are described. These compounds are useful in the inhibition of HIV reverse transcriptase (including its resistant varieties), the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.(FR) On décrit des composés comportant un noyau quinazolin-2-one et un alkynyle ou un alcényle substitué en position 4. Ces composés permettent d'inhiber la transcriptase inverse du VIH (y compris ses variantes résistantes) et de prévenir ou de traiter l'infection due au VIH et de traiter le SIDA, soit en tant que composés soit en tant que sels ou ingrédients de composition pharmaceutiquement acceptables, combinés ou non avec d'autres anti-viraux, immuno-modulateurs, antibiotiques ou vaccins. On décrit aussi des procédés concernant le traitement du SIDA et la prévention ou le traitement de l'infection due au VIH.
• [EN] NEW QUINAZOLINES AS INHIBITORS OF HIV REVERSE TRANSCRIPTASE<br/>[FR] NOUVELLES QUINAZOLINES UTILISEES COMME INHIBTITEURS DE LA TRANSCRIPTASE INVERSE DU VIH
  申请人：MERCK & CO., INC.

  公开号：WO1995012583A1

  公开（公告）日：1995-05-11

  (EN) Compounds having a quinazolin-2-one nucleus with a substituted alkynyl or substituted alkenyl at the 4-position are described. These compounds are useful in the inhibition of HIV reverse transcriptase (including its resistant varieties), the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.(FR) L'invention concerne des composés présentant un noyau quinazolin-2-one présentant un alkynyle ou un alcényle substitué en position 4. Ces composés sont utiles dans l'inhibition de la transcriptase inverse du VIH (y compris ses varités résistantes), la prévention ou le traitement d'infections à VIH ainsi que le traitement du SIDA, comme composés, sels pharmaceutiquement acceptables, ingrédients de compositions pharmaceutiques, en combinaison ou non avec d'autres antiviraux, immunomodulateurs, antibiotiques ou vaccins. L'invention concerne également des méthodes de traitement du SIDA ainsi que des méthodes de prévention ou de traitement d'infections à VIH.
• Synthesis of a Series of 4-(Arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones as Novel Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors
  作者：Thomas J. Tucker、Terry A. Lyle、Catherine M. Wiscount、Susan F. Britcher、Steven D. Young、William M. Sanders、William C. Lumma、Mark E. Goldman、Julie A. O'Brien

  DOI：10.1021/jm00041a023

  日期：1994.7

  As part of an ongoing effort to prepare novel non-nucleoside inhibitors of human immunodeficiency virus type-1 (HTV-1) reverse transcriptase (RT), a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones 4aa-1 has been prepared. Target compounds 4a-e were synthesized via addition of various 1-lithio-2-(aryl)alkyne nucleophiles to a 1-protected-4-cyclopropylquinazolin-2(1H)-one (7), followed by deprotection. The 3-methyl compound 4aa was prepared in an analogous manner, with the 3-alkylation performed prior to deprotection. Alternatively, the target compounds 4f-1 were prepared by addition of 1-lithio-2-(trimethylsilyl)acetylene to 7, followed by deprotection and subsequent palladium-catalyzed coupling with various aryl halides, By incorporating an aryl group onto the end of the 4-acetylene functionality, the requirement for a metabolically labile 3-methyl group on the dihydroquinazolinone nucleus has been eliminated. A number of the target compounds were shown to be potent inhibitors of HTV-1 RT. Compound 4a, which had exhibited the most favorable overall biological profile, was' resolved via a four-step procedure to provide the enantiomers 13a and 13b. Compound 13a having the (-)-4(S) configuration was shown to be the active enantiomer and was selected as a candidate for further investigation.