10-[4-[(tetrahydropyran-2-yl)oxy]butyl]-10H-phenothiazine | 443309-21-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 英文名称: 10-[4-[(tetrahydropyran-2-yl)oxy]butyl]-10H-phenothiazine
• 英文别名: 10-[4-(Oxan-2-yloxy)butyl]phenothiazine
• CAS: 443309-21-5
• 化学式: C₂₁H₂₅NO₂S
• 分子量: 355.501
• InChiKey: IUDSXEKLKNVENM-UHFFFAOYSA-N

物化性质

• 沸点：
  512.0±50.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  47
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  10-[4-[(tetrahydropyran-2-yl)oxy]butyl]-10H-phenothiazine 在 氯化亚砜 、 4-甲基苯磺酸吡啶 、 sodium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 苯 为溶剂， 反应 4.0h， 生成 10-[4-(4-methylpiperazino)butyl]phenothiazine
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of New Chemosensitizers in Multi-Drug-Resistant Plasmodium falciparum

  摘要：

  A series of new chemosensitizers (modulators) against chloroquine-resistant Plasmodium falciparum were designed and synthesized in an attempt to fabricate modulators with enhancing drug-resistant reversing efficacy and minimal side effects. Four aromatic amine ring systems-phenothiazine, iminodibenzyl, iminostilbene, and diphenylamine-were examined. Various tertiary amino groups including either noncyclic or cyclic aliphatic amines were introduced to explore the steric tolerance at the end of the side chain. The new compounds showed better drug-resistant reversing activity in chloroquine-resistant than in mefloquine-resistant cell lines and were generally more effective against chloroquine-resistant P. falciparum isolates from Southeast Asian (W2 and TM91C235) than those from South America (PC49 and RCS). Structure-activity relationship studies revealed that elongation of the alkyl side chain of the molecule retained the chemosensitizing activity, and analogues with four-carbon side chains showed superior activity. Furthermore, new modulators with phenothiazine ring exhibited the best chemosensitizing activity among the four different ring systems examined. Terminal amino function has limited steric tolerance as evidenced by the dramatic lose of the modulating activity, when the size of substituent at the amino group increases. The best new modulator synthesized in this study possesses all three optimized structural features, which consist of a phenothiazine ring and a pyrrolidinyl group joined by a four-carbon alkyl bridge. The fractional inhibitory concentration TIC) index of the best compound is 0.21, which is superior to that of verapamil (0.51), one of the best-known multi-drug-resistant reversing agents. Some of the analogues displayed moderate intrinsic in vitro antimalarial activity against a W-2 clone of P. falciparum.

  DOI：

  10.1021/jm010549o
• 作为产物：
  描述：

  2-(4-氯丁氧基)四氢吡喃 、 吩噻嗪 在 sodium amide 作用下， 以 xylene 为溶剂， 反应 8.0h， 以46%的产率得到10-[4-[(tetrahydropyran-2-yl)oxy]butyl]-10H-phenothiazine
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of New Chemosensitizers in Multi-Drug-Resistant Plasmodium falciparum

  摘要：

  A series of new chemosensitizers (modulators) against chloroquine-resistant Plasmodium falciparum were designed and synthesized in an attempt to fabricate modulators with enhancing drug-resistant reversing efficacy and minimal side effects. Four aromatic amine ring systems-phenothiazine, iminodibenzyl, iminostilbene, and diphenylamine-were examined. Various tertiary amino groups including either noncyclic or cyclic aliphatic amines were introduced to explore the steric tolerance at the end of the side chain. The new compounds showed better drug-resistant reversing activity in chloroquine-resistant than in mefloquine-resistant cell lines and were generally more effective against chloroquine-resistant P. falciparum isolates from Southeast Asian (W2 and TM91C235) than those from South America (PC49 and RCS). Structure-activity relationship studies revealed that elongation of the alkyl side chain of the molecule retained the chemosensitizing activity, and analogues with four-carbon side chains showed superior activity. Furthermore, new modulators with phenothiazine ring exhibited the best chemosensitizing activity among the four different ring systems examined. Terminal amino function has limited steric tolerance as evidenced by the dramatic lose of the modulating activity, when the size of substituent at the amino group increases. The best new modulator synthesized in this study possesses all three optimized structural features, which consist of a phenothiazine ring and a pyrrolidinyl group joined by a four-carbon alkyl bridge. The fractional inhibitory concentration TIC) index of the best compound is 0.21, which is superior to that of verapamil (0.51), one of the best-known multi-drug-resistant reversing agents. Some of the analogues displayed moderate intrinsic in vitro antimalarial activity against a W-2 clone of P. falciparum.

  DOI：

  10.1021/jm010549o

文献信息

• Chemosensitizing agents against chloroquine resistant plasmodium falciparum and methods of making and using thereof
  申请人：——

  公开号：US20030032801A1

  公开（公告）日：2003-02-13

  A compound having the structural formula 1 or a pharmaceutically acceptable salt or prodrug thereof, wherein X is a substituted or unsubstituted alkyl or a heteroatom; n is 4, 5 or 6; Y is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or 2 wherein R 1 and R 2 are each independently, H, a heteroatom, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and wherein each ring structure are independently substituted or unsubstituted is disclosed. Also disclosed are chemosensitizing agents and methods of modulating, attenuating, reversing, or affecting a cell's or organism's resistance to a given drug such as an antimalarial.

  一种具有结构式1的化合物，或其药物可接受的盐或前药，其中X是取代或未取代的烷基或杂原子; n为4、5或6; Y是取代或未取代的烷基、环烷基、杂环烷基、芳基、杂芳基或2，其中R1和R2各自独立地为H、杂原子、取代或未取代的烷基、环烷基、杂环烷基、芳基或杂芳基;并且每个环结构都是独立取代或未取代的。还公开了化学增敏剂和调节、减弱、逆转或影响细胞或生物对给定药物（如抗疟药）的耐药性的方法。
• US6800618B2
  申请人：——

  公开号：US6800618B2

  公开（公告）日：2004-10-05
• Design, Synthesis, and Evaluation of New Chemosensitizers in Multi-Drug-Resistant <i>Plasmodium </i><i>f</i><i>alciparum</i>
  作者：Jian Guan、Dennis E. Kyle、Lucia Gerena、Quan Zhang、Wilbur K. Milhous、Ai J. Lin

  DOI：10.1021/jm010549o

  日期：2002.6.1

  A series of new chemosensitizers (modulators) against chloroquine-resistant Plasmodium falciparum were designed and synthesized in an attempt to fabricate modulators with enhancing drug-resistant reversing efficacy and minimal side effects. Four aromatic amine ring systems-phenothiazine, iminodibenzyl, iminostilbene, and diphenylamine-were examined. Various tertiary amino groups including either noncyclic or cyclic aliphatic amines were introduced to explore the steric tolerance at the end of the side chain. The new compounds showed better drug-resistant reversing activity in chloroquine-resistant than in mefloquine-resistant cell lines and were generally more effective against chloroquine-resistant P. falciparum isolates from Southeast Asian (W2 and TM91C235) than those from South America (PC49 and RCS). Structure-activity relationship studies revealed that elongation of the alkyl side chain of the molecule retained the chemosensitizing activity, and analogues with four-carbon side chains showed superior activity. Furthermore, new modulators with phenothiazine ring exhibited the best chemosensitizing activity among the four different ring systems examined. Terminal amino function has limited steric tolerance as evidenced by the dramatic lose of the modulating activity, when the size of substituent at the amino group increases. The best new modulator synthesized in this study possesses all three optimized structural features, which consist of a phenothiazine ring and a pyrrolidinyl group joined by a four-carbon alkyl bridge. The fractional inhibitory concentration TIC) index of the best compound is 0.21, which is superior to that of verapamil (0.51), one of the best-known multi-drug-resistant reversing agents. Some of the analogues displayed moderate intrinsic in vitro antimalarial activity against a W-2 clone of P. falciparum.