(6-(溴甲基)-7-氯-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)乙酸甲酯 | 289686-86-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: (6-(溴甲基)-7-氯-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)乙酸甲酯
• 英文名称: 2-acetoxymethyl-6-bromomethyl-7-chloro-3-methyl-3,4-dihydroquinazolin-4-one
• 英文别名: (6-(Bromomethyl)-7-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl acetate；[6-(bromomethyl)-7-chloro-3-methyl-4-oxoquinazolin-2-yl]methyl acetate
• CAS: 289686-86-8
• 化学式: C₁₃H₁₂BrClN₂O₃
• 分子量: 359.607
• InChiKey: PYOBIHWREXAQQA-UHFFFAOYSA-N

物化性质

• 熔点：
  183-186 °C
• 沸点：
  492.1±55.0 °C(Predicted)
• 密度：
  1.62±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  59
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (6-(溴甲基)-7-氯-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)乙酸甲酯 在 2,6-二甲基吡啶 、 sodium hydroxide 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 13.84h， 生成 CB 300919; 4-[[[7-氯-3,4-二氢-3-甲基-2-[(4-甲基-1-哌嗪基)甲基]-4-氧代-6-喹唑啉基]甲基]-2-丙炔-1-基氨基]-N-(3-吡啶基甲基)苯甲酰胺
  参考文献：
  名称：

  The Design and Synthesis of Water-Soluble Analogues of CB30865, a Quinazolin-4-one-Based Antitumor Agent

  摘要：

  4-[N-[7-Bromo-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide (CB30865) is a quinazolin-4-one antitumor agent whose high growth-inhibitory activity (W1L2 IC50 = 2.8 +/- 0.50 nM) is believed to have a folate-independent locus of action. In addition, CB30865 represents a class of compounds with unique biochemical characteristics such as a delayed, non-phase specific, cell-cycle arrest. The low aqueous solubility of CB30865 prompted a search for more water-soluble analogues for in vivo evaluation of this class of compounds. It was thought that aqueous solubility could be increased by the introduction of amino functionalities at the 2-position of the quinazolin-4-one ring. A variety of compounds (5a-j, 31a-c, 32, and 33) were synthesized in a linear fashion starting from 3-chloro-4-methylaniline. Most of these compounds (e.g., 5a, 5b, 5g) were significantly more water-soluble than CB30865 (636 muM for 5a at pH 6 and 992 muM for 5g at pH 6). In addition, some of them were up to 6-fold more cytotoxic than CB30865 (e.g., for 5a, W1L2 IC50 = 0.49 +/- 0.24 nM) and retained its novel biochemical characteristics.

  DOI：

  10.1021/jm011081s
• 作为产物：
  描述：

  methyl 2-amino-4-chloro-5-methylbenzoate 在 吡啶 、 4-二甲氨基吡啶 、 N-溴代丁二酰亚胺(NBS) 、 三乙胺 、 过氧化苯甲酰 作用下， 以 四氢呋喃 、 甲醇 、 四氯化碳 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 39.33h， 生成 (6-(溴甲基)-7-氯-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)乙酸甲酯
  参考文献：
  名称：

  The Design and Synthesis of Water-Soluble Analogues of CB30865, a Quinazolin-4-one-Based Antitumor Agent

  摘要：

  4-[N-[7-Bromo-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide (CB30865) is a quinazolin-4-one antitumor agent whose high growth-inhibitory activity (W1L2 IC50 = 2.8 +/- 0.50 nM) is believed to have a folate-independent locus of action. In addition, CB30865 represents a class of compounds with unique biochemical characteristics such as a delayed, non-phase specific, cell-cycle arrest. The low aqueous solubility of CB30865 prompted a search for more water-soluble analogues for in vivo evaluation of this class of compounds. It was thought that aqueous solubility could be increased by the introduction of amino functionalities at the 2-position of the quinazolin-4-one ring. A variety of compounds (5a-j, 31a-c, 32, and 33) were synthesized in a linear fashion starting from 3-chloro-4-methylaniline. Most of these compounds (e.g., 5a, 5b, 5g) were significantly more water-soluble than CB30865 (636 muM for 5a at pH 6 and 992 muM for 5g at pH 6). In addition, some of them were up to 6-fold more cytotoxic than CB30865 (e.g., for 5a, W1L2 IC50 = 0.49 +/- 0.24 nM) and retained its novel biochemical characteristics.

  DOI：

  10.1021/jm011081s

文献信息

• Anti-quinazoline compounds
  申请人：Cancer Research Technology Limited

  公开号：US06699861B1

  公开（公告）日：2004-03-02

  Dihydroquinazoline derivatives of the formula where R3 is —(CH2)p—A where p is from 1 to 4 and A is a 5- or 6-membered N-containing heterocyclic ring attached via the N atom or A is —NA′A″ wherein A′ and A″ are the same or different and are each a C1-C4 alkyl group or their pharmaceutically acceptable salts possessing anti-cancer activity.

  Dihydroquinazoline衍生物的化学式中，其中R3为—(CH2)p—A，其中p为1至4，A是通过N原子连接的含有5个或6个成员的N-含氮杂环环，或者A是—NA′A″，其中A′和A″相同或不同，分别为C1-C4烷基或其药学上可接受的盐，具有抗癌活性。
• [EN] ANTI-CANCER DIHYDROQUINAZOLINE DERIVATIVES<br/>[FR] DERIVES DE DIHYDROQUINAZOLINE ANTICANCEREUX
  申请人：CANCER RES CAMPAIGN TECH

  公开号：WO2000050417A1

  公开（公告）日：2000-08-31

  A dihydroquinazoline derivative of formula (I), or a pharmaceutically acceptable salt thereof, wherein: either R1 and R1' together form an oxo group and R2 is hydrogen, C1-C4 alkyl, -(C1-C4 alkyl)-COB, -(C1-C4 alkyl)-CO-(C1-C4 alkyl)-B, -(C1-C4 alkyl)-CO2-(C1-C4 alkyl)-B, -(C1-C4 alkyl)-CO2-(C2-C4 alkenyl)-B or -(C1-C4 alkyl)-CONH-(C1-C4 alkyl)-B wherein B is -CO2H, hydroxy, C1-C4 alkoxy, amino, (C1-C4 alkyl)amino, di(C1-C4 alkyl)amino or a 5- or 6-membered heterocyclic group, or R1' and R2 together form a bond and R1 is -S-(C1-C4 alkyl), -NHR' or -NHCOR' wherein R' is aryl or C1-C4 alkyl; R3 is -(CH2)p-A wherein p is from 1 to 4 and A is a 5- or 6-membered N-containing heterocyclic ring attached via the N atom or A is -NA'A' wherein A' and A' are the same or different and are each a C1-C4 alkyl group; either R4 is hydrogen, oxo or C1-C4 alkyl and R5 is hydrogen, C1-C4 alkyl or halogen, or R4 and R5, together with the carbon atoms to which they are attached, form a 5- or 6-membered carbocyclic ring; X1 is -O-, -S- or -NR'- wherein R' is hydrogen, C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl; Y is a divalent aryl or heteroaryl group; R6 is hydrogen, oxo or C1-C4 alkyl; X2 is -O-, -S- or -NR'- wherein R' is as defined above; m is from 1 to 4; and R7 is pyridyl, pyrimidyl, imidazolyl, triazolyl, -(C1-C4 alkyl)-imidazolyl, or -(C1-C4 alkyl)-triazolyl.

  公式（I）的二氢喹唑啉衍生物，或其药学上可接受的盐，其中：R1和R1'要么一起形成一个氧代基，且R2为氢、C1-C4烷基、-(C1-C4烷基)-COB、-(C1-C4烷基)-CO-(C1-C4烷基)-B、-(C1-C4烷基)-CO2-(C1-C4烷基)-B、-(C1-C4烷基)- -(C2-C4烯基)-B或-(C1-C4烷基)-CONH-(C1-C4烷基)-B，其中B为- H、羟基、C1-C4烷氧基、氨基、(C1-C4烷基)氨基、二(C1-C4烷基)氨基或5-或6-成员杂环基；或者R1'和R2一起形成一个键，且R1为-S-(C1-C4烷基)、-NHR'或-NHCOR'，其中R'为芳基或C1-C4烷基；R3为-(CH2)p-A，其中p为1至4，A为通过N原子连接的5-或6-成员含N杂环环或A为-NA'A'，其中A'和A'相同或不同，且均为C1-C4烷基；要么R4为氢、氧代基或C1-C4烷基，且R5为氢、C1-C4烷基或卤素，或者R4和R5与它们所连接的碳原子一起形成一个5-或6-成员的碳环；X1为-O-、-S-或-NR'-，其中R'为氢、C1-C4烷基、C2-C4烯基或C2-C4炔基；Y为二价芳基或杂芳基基团；R6为氢、氧代基或C1-C4烷基；X2为-O-、-S-或-NR'-，其中R'如上所定义；m为1至4；R7为吡啶基、嘧啶基、咪唑基、三唑基、-(C1-C4烷基)-咪唑基或-(C1-C4烷基)-三唑基。
• Analogues of 4-[(7-Bromo-2-methyl-4-oxo-3<i>H</i>-quinazolin-6-yl)methylprop-2-ynylamino]-<i>N</i>-(3-pyridylmethyl)benzamide (CB-30865) as Potent Inhibitors of Nicotinamide Phosphoribosyltransferase (Nampt)
  作者：Jeffrey W. Lockman、Brett R. Murphy、Daniel F. Zigar、Weston R. Judd、Paul M. Slattum、Zhong-Hua Gao、Kirill Ostanin、Jeremy Green、Rena McKinnon、Ryan T. Terry-Lorenzo、Tracey C. Fleischer、J. Jay Boniface、Mark Shenderovich、J. Adam Willardsen

  DOI：10.1021/jm101145b

  日期：2010.12.23

  We have shown previously that the target of the potent cytatoxic agent 4-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino]-N-(3-pyridylmethyl)benzamide (CB38065, 1) is nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known we sought to optimize the biochemical and cellular Nampt activity of 1 as well as its cytotoxicity. It was found that a 3-pyridyl-methylamide substituent in the A region was critical to cellular Nampt activity and cytotoxicity, although other aromatic substitution did yield compounds with submicromolar enzymatic inhibition. Small unsaturated groups worked best in the D-region of the molecule, with 3,3-dimethylallyl providing optimal potency. The E region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for activity, and many substituents were tolerated at C(2) of the quinazolin-4-one. The best compounds showed subnanomolar inhibition of Nampt and low nanomolar cytotoxicity in cellular assays.
• ANTI-CANCER DIHYDROQUINAZOLINE DERIVATIVES
  申请人：CANCER RESEARCH TECHNOLOGY LIMITED

  公开号：EP1155012B1

  公开（公告）日：2004-04-14
• US6699861B1
  申请人：——

  公开号：US6699861B1

  公开（公告）日：2004-03-02