N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide | 335640-32-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide
• 英文别名: 4-hydroxy-N,1,5-trimethyl-2-oxo-N-phenylquinoline-3-carboxamide
• CAS: 335640-32-9
• 化学式: C₁₉H₁₈N₂O₃
• 分子量: 322.364
• InChiKey: HNXHHPUDXFCAAW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  60.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide 以 二氯甲烷 、 三氯氧磷 为溶剂， 生成 N-Methyl-N-phenyl-4-chloro-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide
  参考文献：
  名称：

  Drugs for the treatment of malignant tumors

  摘要：

  本发明涉及一种方法，通过给哺乳动物注射一般式（I）的化合物来治疗肿瘤，其中A为O41或NR42R43，其中R41为氢或药学上可接受的无机或有机阳离子，或CORA，其中RA为烷基和芳基；R42和R43为氢、C1-C4烷基、环丙基、环戊基或环己基；或R42为苄基或苯乙基，可选地单取代或二取代为甲基、异丙基甲氧基、氟、氯、溴、二甲基氨基、三氟甲基或硝基，且R43为氢；或R42和R43形成5-或6-成员环；或R42为CORB，其中RB为烷基或芳基，-CH2N（CH3）2或-CH2CH2COOH或CORB为2-酰氧甲基苯甲酰基基团，其中RC为甲基、乙基、苯基或苄基；R42为COORD，其中RD为C1-C4烷基、苯基或苄基；或R42为-CH2OCO-叔丁基或R42为CONRFRG，其中RF和RG为C1-C4烷基；或R42为CXNHRE，其中X为O或S，RE为C1-C4烷基、带有三级氨基团的C2-C4烷基，或苯基，可选地功能化为p-氯基；或R42为CH2NRHRI，其中RH和RI为C1-C4烷基，RH和RI形成吗啡环，且R43为氢、C1-C2烷基或环丙基；R为氢、C1-C4烷基或烯丙基；但当A为OR41时，R不为氢；R'为氢、甲基、甲氧基、氟、氯、溴、氰、硝基、偶氮基、三氟甲基或OCHxFy，其中x=0-2，y=1-3，但x+y=3；当R为甲基且A为OR41时，R'不为氢；R''为氢、氟或氯，但仅当R'为氟或氯时，R''为氟或氯；R5为氢、C1-C3烷基、甲氧基、乙氧基、硫代C1-C3烷基、氟、氯、溴、三氟甲基、硝基、氨基、二甲基氨基或OCHxFy，或OCH2CHxFy，其中x=0-2，y=1-3，但当A为OR41时，R5不为氟或氨基；当A为NR42R43且R'为三氟甲基时，R5仅为氢；R6为氢；或R5和R6共同为亚甲二氧基，或其任何互变异构体、光学异构体或外消旋体。本发明还包括新化合物、治疗组合物和制备式I化合物的方法。

  公开号：

  US06395750B1
• 作为产物：
  描述：

  2-氨基-6-甲基苯甲酸 在 盐酸 、 氯化亚砜 、 sodium hydride 、 三乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 21.5h， 生成 N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide
  参考文献：
  名称：

  Synthesis and Biological Evaluation of New 1,2-Dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for Treatment of Autoimmune Disorders:  Structure−Activity Relationship

  摘要：

  Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II).

  DOI：

  10.1021/jm031044w

文献信息

• DRUGS FOR THE TREATMENT OF MALIGNANT TUMOURS
  申请人：Active Biotech AB

  公开号：EP1224172A1

  公开（公告）日：2002-07-24
• US6395750B1
  申请人：——

  公开号：US6395750B1

  公开（公告）日：2002-05-28
• [EN] DRUGS FOR THE TREATMENT OF MALIGNANT TUMOURS<br/>[FR] MEDICAMENTS DE TRAITEMENT DE TUMEURS MALIGNES
  申请人：ACTIVE BIOTECH AB

  公开号：WO2001030758A1

  公开（公告）日：2001-05-03

  The invention relates to the use of compounds of general formula (I) or any tautomer, optical isomer or racemate thereof for the manufacturing of a medicament for the treatment of cancer. The invention also comprises novel compounds, pharmaceutical compositions, and processes for the preparation of the compounds of formula (I).
• Synthesis and Biological Evaluation of New 1,2-Dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for Treatment of Autoimmune Disorders:  Structure−Activity Relationship
  作者：Stig Jönsson、Gunnar Andersson、Tomas Fex、Tomas Fristedt、Gunnar Hedlund、Karl Jansson、Lisbeth Abramo、Ingela Fritzson、Olga Pekarski、Anna Runström、Helena Sandin、Ingela Thuvesson、Anders Björk

  DOI：10.1021/jm031044w

  日期：2004.4.1

  Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II).
• Drugs for the treatment of malignant tumors
  申请人：Active Biotech AB

  公开号：US06395750B1

  公开（公告）日：2002-05-28

  The invention relates to a method for the treatment of tumors in mammals by the administration of compounds of the general formula (I) wherein A is O41 or NR42 R43 wherein R41 is hydrogen or a pharmaceutically acceptable inorganic or organic cation, or CORA wherein RA is alkyl and aryl; R42 and R43 are hydrogen, C1-C4-alkyl, cyclopropyl, cyclopentyl or cyclohexyl; or R42 is benzyl or phenethyl, optionally mono- or disubstituted by methyl, iso-propyl methoxy, fluoro, chloro, bromo, dimethylamino, trifluoromethyl or nitro and R43 is hydrogen; or R42 and R43 form a 5- or 6-membered ring; or R42 is CORB wherein RB is alkyl or aryl, —CH2N(CH3)2 or —CH2CH2COOH or CORB is a 2-acyloxymethylbenzoyl group wherein RC is methyl, ethyl, phenyl or benzyl; R42 is COORD wherein RD is C1-C4-alkyl, phenyl or benzyl; or R42 is —CH2OCO-tert.-butyl or R42 is CONRFRG wherein RF and RG are C1-C4-alkyl; or R42 is CXNHRE wherein X is O or S and RE is C1-C4-alkyl, C2-C4-alkyl functionalized with an tertiary amino group, or phenyl, optionally functionalised with a p-chloro group; or R42 is CH2NRHRI wherein RH and RI are C1-C4-alkyl and RH and RI form a morpholine ring and R43 is hydrogen, C1-C2-alkyl or cyclopropyl; R is hydrogen, C1-C4-alkyl or allyl; with the proviso that R is not hydrogen when A is OR41; R′ is hydrogen, methyl, methoxy, fluoro, chloro, bromo, cyano, nitro, azido, trifluoromethyl, or OCHxFy, wherein x=0-2, y=1-3 with the proviso that x+y=3; and that R′ is not hydrogen when R is methyl and A is OR41; R″ is hydrogen, fluoro or chloro, with the proviso that R″ is fluoro or chloro only when R′ is fluoro or chloro; R5 is hydrogen, C1-C3-alkyl; methoxy, ethoxy, thio-C1-C3-alkyl fluoro, chloro, bromo, trifluoromethyl, nitro, amino, dimethylamino or OCHxFy, or OCH2CHxFy wherein x=0-2, y=1-3 with the proviso that x+y=3 and that R5 is not fluoro or amino when A is OR41; and that R5 is hydrogen only when A is NR42 R43 and R′ is trifluoromethyl; R6 is hydrogen; or R5 and R6 taken together are methylenedioxy, or any tautomer, optical isomer or racemate thereof. The invention also comprises novel compounds, therapeutic compositions and processes for the preparation of the compounds of formula I.

  本发明涉及一种方法，通过给哺乳动物注射一般式（I）的化合物来治疗肿瘤，其中A为O41或NR42R43，其中R41为氢或药学上可接受的无机或有机阳离子，或CORA，其中RA为烷基和芳基；R42和R43为氢、C1-C4烷基、环丙基、环戊基或环己基；或R42为苄基或苯乙基，可选地单取代或二取代为甲基、异丙基甲氧基、氟、氯、溴、二甲基氨基、三氟甲基或硝基，且R43为氢；或R42和R43形成5-或6-成员环；或R42为CORB，其中RB为烷基或芳基，-CH2N（CH3）2或-CH2CH2COOH或CORB为2-酰氧甲基苯甲酰基基团，其中RC为甲基、乙基、苯基或苄基；R42为COORD，其中RD为C1-C4烷基、苯基或苄基；或R42为-CH2OCO-叔丁基或R42为CONRFRG，其中RF和RG为C1-C4烷基；或R42为CXNHRE，其中X为O或S，RE为C1-C4烷基、带有三级氨基团的C2-C4烷基，或苯基，可选地功能化为p-氯基；或R42为CH2NRHRI，其中RH和RI为C1-C4烷基，RH和RI形成吗啡环，且R43为氢、C1-C2烷基或环丙基；R为氢、C1-C4烷基或烯丙基；但当A为OR41时，R不为氢；R'为氢、甲基、甲氧基、氟、氯、溴、氰、硝基、偶氮基、三氟甲基或OCHxFy，其中x=0-2，y=1-3，但x+y=3；当R为甲基且A为OR41时，R'不为氢；R''为氢、氟或氯，但仅当R'为氟或氯时，R''为氟或氯；R5为氢、C1-C3烷基、甲氧基、乙氧基、硫代C1-C3烷基、氟、氯、溴、三氟甲基、硝基、氨基、二甲基氨基或OCHxFy，或OCH2CHxFy，其中x=0-2，y=1-3，但当A为OR41时，R5不为氟或氨基；当A为NR42R43且R'为三氟甲基时，R5仅为氢；R6为氢；或R5和R6共同为亚甲二氧基，或其任何互变异构体、光学异构体或外消旋体。本发明还包括新化合物、治疗组合物和制备式I化合物的方法。