N²-Cyclohexyl-2,6-diaminonebularin | 53296-12-1

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: N²-Cyclohexyl-2,6-diaminonebularin
• 英文别名: 2-(Cyclohexylamino)adenosine；(2R,3R,4S,5R)-2-[6-amino-2-(cyclohexylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol
• CAS: 53296-12-1
• 化学式: C₁₆H₂₄N₆O₄
• 分子量: 364.404
• InChiKey: UHJRJLPSYJUCPF-SDBHATRESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  152
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  6-氯鸟嘌呤核苷 在 copper(l) iodide 、 氨 、 碘 、 亚硝酸异戊酯 作用下， 以 四氢呋喃 、 乙二醇甲醚 为溶剂， 反应 42.5h， 生成 N²-Cyclohexyl-2,6-diaminonebularin
  参考文献：
  名称：

  Adenosine Analogues as Inhibitors of Trypanosoma brucei Phosphoglycerate Kinase:  Elucidation of a Novel Binding Mode for a 2-Amino-N⁶-Substituted Adenosine

  摘要：

  As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N-6-, 2-amino-N-6-, and N-2-substituted adenosine analogues were synthesized and tested to establish structure-activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and glycerol-3-phosphate dehydrogenase (GPDH). Evaluation of X-ray structures of parasite PGK, GAPDH, and GPDH complexed with their adenosyl-bearing substrates led us to generate a series of adenosine analogues which would target all three enzymes simultaneously. There was a modest preference by PGK for NG-substituted analogues bearing the 2-amino group. The best compound in this series, 2-amino-N-6-[2 "-(p-hydroxyphenyl)ethyl]adenosine (46b), displayed a 23-fold improvement over adenosine with an IC50 of 130 muM. 2-[[2 "-(p-Hydroxyphenyl)ethyl]amino]adenosine (46c) was a weak inhibitor of T. brucei PGK with an IC50 of 500 muM. To explore the potential of an additive effect that having the N-6 and N-2 substitutions in one molecule might provide, the best ligands from the two series were incorporated into N-6,N-2-disubstituted adenosine analogues to yield N-6-(2 " -phenylethyl)-2-[(2 " -phenylethyl)amino]adenosine (69) as a 30 muM inhibitor of T. brucei PGK which is 100-fold more potent than the adenosine template. In contrast, these series gave no compounds that inhibited parasitic GAPDH or GPDH more than 10-20% when tested at 1.0 mM. A 3.0 Angstrom X-ray structure of a T, brucei PGK/46b complex revealed a binding mode in which the nucleoside analogue was flipped and the ribosyl moiety adopted a syn conformation as compared with the previously determined binding mode of ADP. Molecular docking experiments using QXP and SAS program suites reproduced this "flipped and rotated" binding mode.

  DOI：

  10.1021/jm000287a

文献信息

• Therapeutic compounds
  申请人：Savory D. Edward

  公开号：US20080009461A1

  公开（公告）日：2008-01-10

  The invention relates to a method of improving oral drug absorption of adenosine analogues by the use of 2′-methoxy adenosine pro-drugs and to the use of these pro-drugs as medicaments. The invention further relates to compounds that are pro-drugs of adenosine receptor agonists, and to their use as therapeutic compounds, in particular as analgesic or anti-inflammatory compounds, or as disease modifying antirheumatic drugs (DMARDs), and to methods of preventing, treating or ameliorating pain or inflammation using these compounds.

  本发明涉及一种通过使用2'-甲氧基腺苷前药来改善腺苷类似物口服吸收的方法，并将这些前药用作药物。本发明还涉及腺苷受体激动剂的前药化合物及其作为治疗化合物的用途，特别是作为镇痛或抗炎化合物，或作为疾病改变抗风湿药物（DMARDs），以及使用这些化合物预防、治疗或缓解疼痛或炎症的方法。
• Therapeutic Compounds
  申请人：Pritchard Martyn

  公开号：US20080221060A1

  公开（公告）日：2008-09-11

  Use of compounds of general formula (A) as medicaments is described, in particular for the treatment of pain or inflammation; wherein: (I) when X=OH, R 2 =NH 2 , R 5 =CH 2 OH, R 6 =H, R 1 is C 5 -C 6 alkoxy, OCH 2 Cyclopropyl, O-(2,2,3,3-tetrafluoro-cycloButyl), phenoxy, substituted phenoxy, OCH 2 CH 2 OH, or OCH 2 CHF 2 , (5-indanyl)oxy, C 1 , C 2 , C 5 , or C 6 alkylamino, (R) or (S)-sec-Butylamino, C 5 or C 6 cycloalkylamino, exo-norbornane amino, (N-methyl, N-isoamylamino), phenylamino, phenylamino with either methoxy or fluoro substituents, a C 2 sulfone group, a C 2 alkyl group, a cyano group, a CONH 2 group, or 3,5-dimethylphenyl; or when X=H, R 2 =NH 2 , R 5 =CH 2 OH, R 6 =H, R 1 is n-hexyloxy; or (II) when X=OH, R 1 =H, R 5 =CH 2 OH, R 6 =H, R 2 is NMe 2 , N-(2-isopentenyl), piperazinyl, (N-Me, N-benzyl), (N-Me, N—CH 2 Ph(3-Br)), (N-Me, N—CH 2 Ph(3-CF 3 )), or (N-Me, N-(2-methoxyethyl)), or OCH 2 Cyclopentyl; or (III) when X=OH, R 5 =CONHR 3 , R 6 =H: R 1 is H, R 3 is an isopropyl group, and R 2 is either NH 2 or a methylamino group (NHMe) or an isoamyl group (CH 2 CH 2 CHMe 2 ); or R 1 is H, R 3 is H, and R 2 is NH 2 ; or R 1 is OMe, R 3 is Ph, and R 2 is NH 2 ; or R 1 is NHCH 2 CH 2 CH 2 CH 2 CH 2 Me, R 3 is CH 2 CH 2 CH 2 Me, and R 2 is NH 2 ; or (IV) when X=OH, R 1 =H, R 2 =NH 2 , R 5 =CH 2 NHCOR 4 , R 6 =H, R 1 is n-propyl or NHCH 2 CH 3 ; or (V) when X=OH, R 5 =CH 2 OH, R 6 =H: R 1 is NHCyclohexyl when R 2 is NMe 2 ; or R 1 is OMe when R 2 is NHBenzyl; or (VI) when X=OH, R 2 =NH 2 , R 5 =CH 2 OH, R 6 =Me, R1 is NHCyclohexyl or NHCyclopentyl.

  描述了一般式（A）化合物的药物应用，特别是用于治疗疼痛或炎症；其中：（I）当X = OH，R2 = NH2，R5 = CH2OH，R6 = H，R1为C5-C6烷氧基，OCH2环丙基，O-（2,2,3,3-四氟-环丁基），苯氧基，取代苯氧基，OCH2CH2OH或OCH2CHF2，（5-吲哚基）氧基，C1，C2，C5或C6烷基氨基，（R）或（S）-sec-丁基氨基，C5或C6环烷基氨基，外-去环辛烷氨基，（N-甲基，N-异戊基氨基），苯基氨基，带有甲氧基或氟代取代基的苯基氨基，C2磺酰基，C2烷基，氰基，CONH2基或3,5-二甲基苯基；或当X = H，R2 = NH2，R5 = CH2OH，R6 = H，R1为正己氧基；或（II）当X = OH，R1 = H，R5 = CH2OH，R6 = H，R2为NMe2，N-（2-异戊烯基），哌嗪基，（N-Me，N-苄基），（N-Me，N-CH2Ph（3-Br）），（N-Me，N-CH2Ph（3-CF3））或（N-Me，N-（2-甲氧基乙基）），或OCH2环戊基；或（III）当X = OH，R5 = CONHR3，R6 = H：R1为H，R3为异丙基基团，R2为NH2或甲基氨基（NHMe）或异戊基基团（CH2CH2CHMe2）；或R1为H，R3为H，R2为NH2；或R1为OMe，R3为Ph，R2为NH2；或R1为NHCH2CH2CH2CH2CH2Me，R3为CH2CH2CH2Me，R2为NH2；或（IV）当X = OH，R1 = H，R2 = NH2，R5 = CH2NHCOR4，R6 = H，R1为正丙基或NHCH2CH3；或（V）当X = OH，R5 = CH2OH，R6 = H：当R2为NMe2时，R1为NHCyclohexyl；或当R2为NHBenzyl时，R1为OMe；或（VI）当X = OH，R2 = NH2，R5 = CH2OH，R6 = Me，R1为NHCyclohexyl或NHCyclopentyl。
• ADENOSINE RECEPTOR AGONISTS
  申请人：Cambridge Biotechnology Ltd

  公开号：EP1749016A2

  公开（公告）日：2007-02-07
• US7820811B2
  申请人：——

  公开号：US7820811B2

  公开（公告）日：2010-10-26
• [EN] THERAPEUTIC COMPOUNDS<br/>[FR] COMPOSES THERAPEUTIQUES
  申请人：CAMBRIDGE BIOTECHNOLOGY LTD

  公开号：WO2005084653A2

  公开（公告）日：2005-09-15

  Use of compounds of general formula (A) as medicaments is described, in particular for the treatment of pain or inflammation; wherein: (I) when X = OH, R2 = NH2, R5 = CH2OH, R6 = H , R1 is C5-C6 alkoxy, OCH2Cyclopropyl, O-(2,2,3,3-tetrafluoro-cycloButyl), phenoxy, substituted phenoxy, OCH2CH2OH, or OCH2CHF2, (5-indanyl)oxy, C1, C2, C5, or C6 alkylamino, (R) or (S)-sec-Butylamino, C5 or C6 cycloalkylamino, exo-norbornane amino, (N-methyl, N-­isoamylamino), phenylamino, phenylamino with either rnethoxy or fluoro substituents, a C2 sulfone group, a C2 alkyl group, a cyano group, a CONH2 group, or 3,5-dimethylphenyl; or when X = H, R2 = NH2, R5 = CH2OH , R6 = H, R1 is n-hexyloxy; or (II) when X = OH , R1 = H, R5 = CH2OH, R6 = H, R2 is NMe2, N-(2-isopentenyl), piperazinyl, (N-Me, N-benzyl), (N-Me, N-CH2Ph(3-Br)), (N-Me, N-­CH2Ph(3-CF3)), or (N-Me, N-(2-rnethoxyethyl)), or OCH2Cyclopentyl; or (III) when X = OH, R5 = CONHR3, R6 = H: R1 is H, R3 is an isopropyl group, and R2 is either NH2 or a methylamino group (NHMe) or an isoamyl group (CH2CH2CHMe2); or R1 is H, R3 is H, and R2 is NH2; or R1 is OMe, R3 is Ph, and R2 is NH2; or R1 is NHCH2CH2CH2CH2CH2Me, R3 is CH2CH2CH2Me, and R2 is NH2; or (IV) when X = OH, R1 = H, R2 = NH2, R5 = CH2NHCOR.4, R6 = H, R4 is n-propyl or NHCH2CH3; or (V) when X = OH, R5 = CH2OH, R6 = H: R1 is NHCyclohexyl when R2 is NMe2; or R1 is OMe when R2 is NHBenzyl; or (VI) when X = OH , R2 = NH2, R5 = CH2OH, R6 = Me, R1 is NHCyclohexyl or NHCyclopentyl.