diethyl N-(4-(((1,2-dihydro-3-methyl-1-oxobenzoquinazolin-9-yl)methyl)methylamino)benzoyl)-L-glutamate | 139988-42-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: diethyl N-(4-(((1,2-dihydro-3-methyl-1-oxobenzoquinazolin-9-yl)methyl)methylamino)benzoyl)-L-glutamate
• 英文别名: diethyl N-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)methylamino)benzoyl)-L-glutamate；diethyl N-(4-{[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]methylamino}benzoyl)-L-glutamate；diethyl (2S)-2-[[4-[methyl-[(3-methyl-1-oxo-2H-benzo[f]quinazolin-9-yl)methyl]amino]benzoyl]amino]pentanedioate
• CAS: 139988-42-4
• 化学式: C₃₁H₃₄N₄O₆
• 分子量: 558.634
• InChiKey: RUCVVGQNYWJOSZ-SANMLTNESA-N

物化性质

• 密度：
  1.26±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  41
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  126
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  diethyl N-(4-(((1,2-dihydro-3-methyl-1-oxobenzoquinazolin-9-yl)methyl)methylamino)benzoyl)-L-glutamate 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 以94%的产率得到N-(4-(((1,2-dihydro-3-methyl-1-oxobenzoquinazolin-9-yl)methyl)methylamino)benzoyl)-L-glutamic acid
  参考文献：
  名称：

  Benzo[f]quinazoline Inhibitors of Thymidylate Synthase: Methyleneamino-Linked Aroylglutamate Derivatives

  摘要：

  Syntheses of several new inhibitors of thymidylate synthase (TS) structurally related to folic acid are described in which the pterin portion of the folate molecule is replaced by a benzo[f]quinazoline moiety, but which retain the natural methyleneamino link to the benzoylglutamate side chain. The effect on enzyme activity and cytotoxicity of various changes in the structure of the (p-aminobenzoyl)glutamate side chain are reported. Replacement of the benzamide portion of the (p-aminobenzoyl)glutamate moiety with 2-fluorobenzamido, 2-isoindolinyl, 1,2-benzisothiazol-2-yl, and 2-thenamido moieties varied in effect from a 9-fold diminution of TS activity to a 5-fold enhancement, while cytotoxic potency on SW-480 and MCF-7 tumor lines showed increases ranging from 3.6-to 450-fold. The detrimental effect on enzyme activity and cytotoxicity of alkyl substitution on the PABA nitrogen is confirmed for these compounds, in contrast with several series of previously reported quinazoline antifolates (2). Substitution of a C3-methyl substituent for 3-amino had little effect on TS activity but was beneficial in terms of solubility and cytotoxicity. The excellent combination of TS inhibitory activity, FPGS substrate activity, and affinity for the reduced folate transport system in the most potent of these derivatives, 3e, resulted in IC50 values of 0.2-0.8 nM against these tumor lines.

  DOI：

  10.1021/jm00032a019
• 作为产物：
  描述：

  3,9-dimethylbenzoquinazolin-1(2H)-one 在 N-溴代丁二酰亚胺(NBS) 作用下， 以 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 1.0h， 生成 diethyl N-(4-(((1,2-dihydro-3-methyl-1-oxobenzoquinazolin-9-yl)methyl)methylamino)benzoyl)-L-glutamate
  参考文献：
  名称：

  Benzo[f]quinazoline Inhibitors of Thymidylate Synthase: Methyleneamino-Linked Aroylglutamate Derivatives

  摘要：

  Syntheses of several new inhibitors of thymidylate synthase (TS) structurally related to folic acid are described in which the pterin portion of the folate molecule is replaced by a benzo[f]quinazoline moiety, but which retain the natural methyleneamino link to the benzoylglutamate side chain. The effect on enzyme activity and cytotoxicity of various changes in the structure of the (p-aminobenzoyl)glutamate side chain are reported. Replacement of the benzamide portion of the (p-aminobenzoyl)glutamate moiety with 2-fluorobenzamido, 2-isoindolinyl, 1,2-benzisothiazol-2-yl, and 2-thenamido moieties varied in effect from a 9-fold diminution of TS activity to a 5-fold enhancement, while cytotoxic potency on SW-480 and MCF-7 tumor lines showed increases ranging from 3.6-to 450-fold. The detrimental effect on enzyme activity and cytotoxicity of alkyl substitution on the PABA nitrogen is confirmed for these compounds, in contrast with several series of previously reported quinazoline antifolates (2). Substitution of a C3-methyl substituent for 3-amino had little effect on TS activity but was beneficial in terms of solubility and cytotoxicity. The excellent combination of TS inhibitory activity, FPGS substrate activity, and affinity for the reduced folate transport system in the most potent of these derivatives, 3e, resulted in IC50 values of 0.2-0.8 nM against these tumor lines.

  DOI：

  10.1021/jm00032a019

文献信息

• [EN] PHARMACEUTICALLY ACTIVE BENZOQUINAZOLINE COMPOUNDS
  申请人：THE WELLCOME FOUNDATION LIMITED

  公开号：WO1991019700A1

  公开（公告）日：1991-12-26

  (EN) Compounds of formula (I) or salts thereof, wherein the dotted line represents a single or double bond, R1 is alkyl or amino optionally substituted by alkyl, alkanoyl or benzyl group; R2, R3, R4 and R5 are the same or different and each is selected from hydrogen, phenyl, halo, nitro, a group S(O)nR8 wherein n is the integer 0, 1 or 2 and R8 is halo or alkyl or a group NR9R10 wherein R9 and R10 are both hydrogen, a group NR11R12 wherein R11 and R12 are the same or different and each is hydrogen or alkyl, a group OR13 wherein R13 is hydrogen or C1-4 of alkyl optionally substituted by halo; a C1-4 aliphatic group optionally substituted by a group OR14 or NR14R15 wherein R14 and R15 are the same or different and each is hydrogen or alkyl; or two of R2 to R5 are linked together to form a benzo group, or one of R2 to R5 is a group X-Y-R16 wherein X is CH2, NR17, CO or S(O)m and Y is CH2, NR17, O or S(O)m, or X-Y is O, NR17, -CH=CH- or N=N-, are disclosed as pharmacological agents useful in the treatment of tumours. Pharmaceutical compositions and methods for the preparation of compounds of formula (I) are also described.(FR) Composés de formule (I), ou leurs sels, dans laquelle la ligne en pointillés représente une liaison simple ou double, R1 représente alkyle ou amino facultativement remplacé par un groupe alkyle alcanoyle ou benzyle; R2, R3, R4 et R5 sont identiques ou différents et sont choisis chacun parmi hydrogène, phényle, halo, nitro, un groupe S(O)n R8 dans lequel n représente le nombre entier 0, 1 ou 2 et R8 représente halo ou alkyle ou un groupe NR9R10 dans lequel R9 et R10 représentent l'un et l'autre hydrogène, un groupe NR11R12 dans lequel R11 et R12 sont identiques ou différents et représentent chacun hydrogène ou alkyle, un groupe OR13 dans lequel R13 représente hydrogène ou alkyle facultativement remplacé par halo; un groupe aliphatique contenant un à 4 atomes de carbone facultativement remplacé par un groupe OR14 ou NR14R15 dans lequel R14 et R15 sont identiques ou différents et représentent chacun hydrogène ou alkyle; ou deux des éléments compris entre R2 et R5 sont liés ensemble afin de former un groupe benzo ou un des éléments compris entre R2 et R5 représente un groupe X-Y-R16 dans lequel X représente CH2, NR17, CO ou S(O)m et Y représente CH2, NR17, O ou S(O)m, ou X-Y représente O, NR17, -CH=CH- ou N=N-, lesdits composés de l'invention constituant des agents pharmacologiques utiles dans le traitement de tumeurs. L'invention concerne également des compositions pharmaceutiques ainsi que des procédés de préparations de composés de formule (I).

  (I)式化合物或其盐，其中虚线表示单键或双键，R1是烷基或氨基，可选择地被烷基、酰基或苄基取代；R2、R3、R4和R5相同或不同，每个都选自氢、苯基、卤素、硝基、S（O）nR8基团，其中n是整数0、1或2，R8是卤素或烷基或NR9R10基团，其中R9和R10都是氢，或NR11R12基团，其中R11和R12相同或不同，每个是氢或烷基，或OR13基团，其中R13是氢或C1-4烷基，可选择地被卤素取代；C1-4脂肪基，可选择地被OR14或NR14R15基团取代，其中R14和R15相同或不同，每个是氢或烷基；或R2到R5中的两个相互连接形成苯环，或R2到R5中的一个是X-Y-R16基团，其中X是CH2、NR17、CO或S（O）m，Y是CH2、NR17、O或S（O）m，或X-Y是O、NR17、-CH=CH-或N=N-，作为治疗肿瘤的药理学药剂。还描述了制备(I)式化合物的制药组合物和方法。
• Pharmaceutically active benzoquinazoline compounds
  申请人：THE WELLCOME FOUNDATION LIMITED

  公开号：EP1199307B1

  公开（公告）日：2004-02-25
• US5405851A
  申请人：——

  公开号：US5405851A

  公开（公告）日：1995-04-11
• US5661155A
  申请人：——

  公开号：US5661155A

  公开（公告）日：1997-08-26
• US5663337A
  申请人：——

  公开号：US5663337A

  公开（公告）日：1997-09-02