2,4-diamino-5-chloroquinazoline-6-carbonitrile | 18917-75-4

• 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: 2,4-diamino-5-chloroquinazoline-6-carbonitrile
• 英文别名: 5-chloro-6-cyano-2,4-diaminoquinazoline；2,4-diamino-5-chloro-quinazoline-6-carbonitrile；2,4-Diamino-5-chlor-chinazolin-6-carbonitril；2,4-Diamino-5-chloro-6-cyano-chinazolin
• CAS: 18917-75-4
• 化学式: C₉H₆ClN₅
• 分子量: 219.633
• InChiKey: NWZLURIMHYEUSU-UHFFFAOYSA-N

物化性质

• 沸点：
  583.2±60.0 °C(Predicted)
• 密度：
  1.59±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,4-diamino-5-chloroquinazoline-6-carbonitrile 在 镍 氰基磷酸二乙酯 、 氢气 、 三乙胺 、 三氟乙酸 作用下， 以 氯仿 、 溶剂黄146 为溶剂， 反应 22.5h， 生成 5-chloro-5,8-dideazaaminopterin
  参考文献：
  名称：

  叶酸和氨基蝶呤的5-氯-5,8-二叠氮基类似物的合成靶向结肠腺癌。

  摘要：

  几个经典的叶酸在5位带有氯或甲基取代基的喹唑啉类似物被评估为体外抑制四种人胃肠道腺癌细胞系生长的抑制剂。首次报道了其中的两种化合物，即5-氯-5,8-二叠氮杂异叶酸1e和5-氯-5,8-二叠氮杂异氨蝶呤2a的制备。另外，描述了合成5-氯-5，8-二叠氮基氨基蝶呤2b的新途径。对于具有2，4-二氨基构型的化合物，在位置5处存在氯提供了优异的生长抑制效能。但是，化合物1e的效力远不及其5-甲基类似物。

  DOI：

  10.1021/jm00391a042
• 作为产物：
  描述：

  氰化钾 、 2,4,6-三氨基-5-氯喹唑啉 在 盐酸 、 copper(l) chloride 、 sodium nitrite 作用下， 生成 2,4-diamino-5-chloroquinazoline-6-carbonitrile
  参考文献：
  名称：

  曲美曲塞和匹利特辛的2,4-二氨基-5-氯喹唑啉类似物：合成和抗叶酸活性。

  摘要：

  合成了十种迄今为止未描述的曲美曲塞（TMQ）和派瑞特辛（PTX）的2,4-二氨基-5-氯喹唑啉类似物，并作为大鼠肝，卡氏肺孢子虫和弓形虫的二氢叶酸还原酶（DHFR）抑制剂进行了测试。对抗卡氏疟原虫和弓形虫的最活跃的喹唑啉是具有ArCH2-NH或ArNHCH2侧链的喹唑啉。在n = 1-3和2'，5'-二甲氧基苯基或3'，4'，5'-三甲氧基苯基作为Ar部分的ArNH（CH2）n化合物中，活性按n = 1> n = 2的顺序降低> n =3。Carinii DHFR的最佳抑制剂，2,4-二氨基-5-氯-6-[（N-甲基-3'，4'，5'-三甲氧基苯胺基）甲基l]喹唑啉（10） IC50为0.012 microM，比TMQ和PTX的效力略高。化合物10还是弓形虫DHFR的最佳抑制剂，IC50为0.0064 microM，再次对应于TMQ和PTX活性的轻微增加。但是，与这些标准试剂一样，相对于大

  DOI：

  10.1021/jm00052a011

文献信息

• Brominated trimetrexate analogues as inhibitors of<i>pneumocystis carinii</i>and<i>toxoplasma gondii</i>dihydrofolate reductase
  作者：Andre Rosowsky、Clara E. Mota、Sherry E. Queener

  DOI：10.1002/jhet.5570330665

  日期：1996.11

  2-amino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methyl-thiophene-3-carbonitrile (15) and 2-amino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethyl]thiophene-3-car-bonitrile (16). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methylthieno[2,3-d]pyrimidine (8a) and 2,4-diamino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethylthieno[2

  为了评估该结构修饰对二氢叶酸还原酶抑制的影响，合成了五个先前未描述的苯环上具有庞大的2'-溴取代的曲美曲酯类似物。在N，N-二乙胺存在下2- [2-（2-溴-3,4,5-三甲氧基苯基）乙基] -1,1-二氰丙烯与硫的缩合得到2-氨基-5-（2'- bromo-3'，4'，5'-三甲氧基苄基）-4-甲基-噻吩-3-腈（15）和2-氨基-4- [2-（2'-bromo-3'，4'，5' -三甲氧基苯基）乙基]噻吩-3-碳腈（16）。与氯甲am盐酸盐进一步反应，将15和16转化为2,4-二氨基-5-（2'-溴-3'，4'，5'-三甲氧基苄基）-4-甲基硫代[2,3- d]嘧啶（8a）和2,4-二氨基-4- [2-（2'-溴-3'，4'，5'-三甲氧基苯基）乙基噻吩并[2,3- d ]嘧啶（12）。通过将适当的2,4-二氨基喹唑啉-6（或5）-腈与2-溴-3,4,5-三甲氧基苯胺还原偶联获得的其他类似物是2
• Selective Inhibitors of Candida albicans Dihydrofolate Reductase: Activity and Selectivity of 5-(Arylthio)-2,4-diaminoquinazolines
  作者：Joseph H. Chan、Jean S. Hong、Lee F. Kuyper、David P. Baccanari、Suzanne S. Joyner、Robert L. Tansik、Christine M. Boytos、Sharon K. Rudolph

  DOI：10.1021/jm00018a021

  日期：1995.9

  The recent increase in fungal infections, especially among AIDS patients, has resulted in the need for more effective antifungal agents. In our search for such agents, we focused on developing compounds which inhibit fungal dihydrofolate reductase (DHFR). A series of 25 5-(arylthio)-2,4-diaminoquinazolines were synthesized as potentially selective inhibitors of Candida albicans DHFR. The majority of the compounds were potent inhibitors of C. albicans DHFR and much less active against human DHFR. High selectivity, as defined by the ratio of the I-50 values for human and C. albicans DHFR, was achieved by compounds with bulky and rigid 4-substituents in the phenylthio moiety. For example, 5-[(4-morpholinophenyl)thio]-2,4-diaminoquinazoline displayed a selectivity ratio of 540 and was the most selective inhibitor synthesized to date. Substitution in the 2- or 3-position of the 5-phenylthio group provided only marginal selectivity. 6-Substituted-5-[(4-tert-butylphenyl)thio]-2,4-diaminoquinazolines showed potent activity against the C. albicans enzyme but were equally active against human DHFR. Most of the selective compounds were also good inhibitors of C. albicans cell growth, with minimum inhibitory concentration values as low as 0.05 mu g/mL.
• Folate antagonists. 20. Synthesis and antitumor and antimalarial properties of trimetrexate and related 6-[(phenylamino)methyl]-2,4-quinazolinediamines
  作者：Edward F. Elslager、Judith L. Johnson、Leslie M. Werbel

  DOI：10.1021/jm00366a018

  日期：1983.12

  A series of 6-[(arylamino)methyl]-2,4-quinazolinediamines have been prepared by catalytic hydrogenation of the requisite 2,4-diamino-6-quinazolinecarbonitriles in the presence of the appropriate benzenamine. Formylation, acetylation, and nitrosation provided N omega derivatives of these compounds. A variety of the compounds exhibited potent antimalarial, antibacterial, and antitumor activity. In particular, 5-methyl-6-[[(3,4,5-trimethoxyphenyl)-amino]methyl]-2, 4-quinazolinediamine (trimetrexate, 15) has shown a broad spectrum of antitumor effects and is undergoing preclinical toxicology evaluation prior to trial in man.
• Synthesis and Potent Antifolate Activity and Cytotoxicity of B-Ring Deaza Analogues of the Nonpolyglutamatable Dihydrofolate Reductase Inhibitor <i>N</i>^α-(4-Amino-4-deoxypteroyl)-<i>N</i>^δ-hemiphthaloyl-<scp>l</scp>-ornithine (PT523)
  作者：Andre Rosowsky、Joel E. Wright、Chitra M. Vaidya、Henry Bader、Ronald A. Forsch、Clara E. Mota、Jorge Pardo、Cindy S. Chen、Ying-Nan Chen

  DOI：10.1021/jm980477+

  日期：1998.12.1

  Six new B-ring analogues of the nonpolyglutamatable antifolate N-alpha-(4-amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithine (PT523, 3) were synthesized with a view to determining the effect of modifications at the 5- and/or 8-position on dihydrofolate reductase (DHFR) binding and tumor cell growth inhibition The 5- and 8-deaza analogues were prepared from methyl 2-L-amino-5-phthalimidopentanoate and 4-amino-4-deoxy-N-10-formyl-5-deaza- and -8-deazapteroic acid, respectively. The 5,8-dideaza analogues were prepared from methyl 2-L-[(4-aminobenzoyl)-amino]-5-phthalimidopentanoate and 2,4-diaminoquinazoline-6-carbonitriles. The K-i for inhibition of human DHFR by the 5-deaza and 5-methyl-5-deaza analogues was about the same as that of 3 (0.35 pM), 11-fold lower than that of aminopterin (AMT, 1), and 15-fold lower than that of methotrexate (MTX, 2). However the K-i of the 8-deaza analogue was 27-fold lower than that of 1, and that of the 5,8-dideaza, 5-methyl-5,8-dideaza, and 5-chloro-5,8-dideaza analogues was approximately 50-fold lower. This trend was consistent with the published literature on the corresponding DHFR inhibitors with a glutamate side chain. In colony formation assays against the human head and neck squamous carcinoma cell line SCC25 after 72 h of treatment, the 5- and 8-deaza analogues were approximately as potent as 3, whereas the 5,8-dideaza analogue was 3 times more potent. 5-Methyl and 5-chloro substitution was also favorable, with the 5-methyl-5-deaza analogue being 2.5-fold more potent than the 5-deaza analogue. However the effect of 5-methyl substitution was less pronounced in the 5,8-dideaza analogues than in the 5-deaza analogues. The 5-chloro-5,8-dideaza analogue of 3 was the most active member of the series, with an IC50 = 0.33 nM versus 1.8 nM for 3 and 15 nM for MTX. The 5-methyl-5-deaza analogue of 3 was also tested at the National Cancer Institute against a panel of 50 human tumor cell lines in culture and was consistently more potent than 3, with IC50 values in the low nanomolar to subnanomolar range against most of the tumors. Leukemia and colorectal carcinoma cell lines were generally most sensitive, though good activity was also observed against CNS tumors and carcinomas of the breast and prostate. The results of this study demonstrate that B-ring analogues of 3 inhibit DHFR activity and tumor cell colony formation as well as, or better than, the parent compound. In view of the fact that 3 and its B-ring analogues cannot form polyglutamates, their high cytotoxicity relative to the corresponding B-ring analogues of AMT is noteworthy.
• HYNES, J. B.;KUMAR, A.;TOMAZIC, A.;WASHTIEN, W. L., J. MED. CHEM., 30,(1987) N 8, 1515-1519
  作者：HYNES, J. B.、KUMAR, A.、TOMAZIC, A.、WASHTIEN, W. L.

  DOI：——

  日期：——