(2R*,3R*)-2-[2,4-Difluorophenyl]-3-[N-[4-(trifluoromethyl)benzoyl]-N-(2-benzyloxyethyl)amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol

• 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: (2R*,3R*)-2-[2,4-Difluorophenyl]-3-[N-[4-(trifluoromethyl)benzoyl]-N-(2-benzyloxyethyl)amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol
• 英文别名: N-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]-N-(2-phenylmethoxyethyl)-4-(trifluoromethyl)benzamide
• 化学式: C₂₉H₂₇F₅N₄O₃
• 分子量: 574.55
• InChiKey: IUQFQYFSVCRWAF-PIIWDFAUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  41
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  80.5
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (2R*,3R*)-2-[2,4-Difluorophenyl]-3-[N-[4-(trifluoromethyl)benzoyl]-N-(2-benzyloxyethyl)amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 为溶剂， 反应 18.0h， 以51%的产率得到(2R^*,3R^*)-2-(2,4-difluorophenyl)-3--N-(2-hydroxyethyl)amino>-1-(1H-1,2,4-triazol-1-yl)-2-butanol
  参考文献：
  名称：

  Synthesis and Antifungal Activity of New Azole Derivatives Containing an N-Acylmorpholine Ring

  摘要：

  A series of azole derivatives carrying an N-acylmorpholine ring are described. The compounds were chemically designed to simulate the lanosterol D ring, taking advantage of the conformational preferences of 2-alkyl-1-acylmorpholines. Three structural variables, the nature of the N-benzoyl group, the phenyl substituents, and the degree of oxidation at carbon 2 of the morpholine, were optimized for maximum activity. Only the (5R,6R) isomers showed antifungal activity. Cyclic hemiacetal(-)-39a (UR-9746) and cyclic ether (-)-41 (UR-9751) were selected for further development. In vitro, (-)-41 was clearly more active than (-)-39a and somewhat less active than the acyclic counterpart (-)-7. lit vivo activity was assessed by a systemic (mouse) and a vaginal (rat) candidosis model. In the former, (-)-39a, (-)-41, and (-)-7 at 1 mg/kg given 1, 4, and 24 h postinfection displayed 90-100% protection from mortality on day 9. Compound (-)-39a was slightly more potent than (-)-41 and similar in potency to (-)-7. The three compounds were superior in potency to fluconazole and similar in potency to SCH-42427 in this test. In the vaginal model, (-)-39a and (-)-41 given daily during 3 days after infection at 0.5 mg/kg showed high levels of protection on days 10 and 15. At 0.25 mg/kg, (-)-39a was slightly more potent than SCH-42427 and (-)-7 and superior in potency to (-)-41 and fluconazole in this model. Preliminary 28-day toxicity tests at 100 mg/kg/day po in rats indicated no or very mild adverse effects for the two UR compounds.

  DOI：

  10.1021/jm00020a005
• 作为产物：
  描述：

  (2S,3S)-2-(2,4-difluorophenyl)-3-(2-phenylmethoxyethylideneamino)-1-(1,2,4-triazol-1-yl)butan-2-ol 在 lithium aluminium tetrahydride 、 TEA 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 23.0h， 生成 (2R*,3R*)-2-[2,4-Difluorophenyl]-3-[N-[4-(trifluoromethyl)benzoyl]-N-(2-benzyloxyethyl)amino]-1-(1H-1,2,4-triazol-1-yl)-2-butanol
  参考文献：
  名称：

  Synthesis and Antifungal Activity of New Azole Derivatives Containing an N-Acylmorpholine Ring

  摘要：

  A series of azole derivatives carrying an N-acylmorpholine ring are described. The compounds were chemically designed to simulate the lanosterol D ring, taking advantage of the conformational preferences of 2-alkyl-1-acylmorpholines. Three structural variables, the nature of the N-benzoyl group, the phenyl substituents, and the degree of oxidation at carbon 2 of the morpholine, were optimized for maximum activity. Only the (5R,6R) isomers showed antifungal activity. Cyclic hemiacetal(-)-39a (UR-9746) and cyclic ether (-)-41 (UR-9751) were selected for further development. In vitro, (-)-41 was clearly more active than (-)-39a and somewhat less active than the acyclic counterpart (-)-7. lit vivo activity was assessed by a systemic (mouse) and a vaginal (rat) candidosis model. In the former, (-)-39a, (-)-41, and (-)-7 at 1 mg/kg given 1, 4, and 24 h postinfection displayed 90-100% protection from mortality on day 9. Compound (-)-39a was slightly more potent than (-)-41 and similar in potency to (-)-7. The three compounds were superior in potency to fluconazole and similar in potency to SCH-42427 in this test. In the vaginal model, (-)-39a and (-)-41 given daily during 3 days after infection at 0.5 mg/kg showed high levels of protection on days 10 and 15. At 0.25 mg/kg, (-)-39a was slightly more potent than SCH-42427 and (-)-7 and superior in potency to (-)-41 and fluconazole in this model. Preliminary 28-day toxicity tests at 100 mg/kg/day po in rats indicated no or very mild adverse effects for the two UR compounds.

  DOI：

  10.1021/jm00020a005

文献信息

• Orally active azole derivatives
  申请人：J. Uriach & Cia. S.A.

  公开号：US05478826A1

  公开（公告）日：1995-12-26

  The present invention relates to new orally active azole derivatives with antifungal activity of formula I ##STR1## wherein: X is CH or N; Ar represents phenyl substituted with halogen and/or trifluoromethyl; Z is --C(=O)-- or --SO.sub.2 --; R.sub.1 is CN, CO.sub.2 H, CO.sub.2 R.sub.7, CONR.sub.8 R.sub.9 or CH.sub.2 Y and then R.sub.3 is hydrogen, or R.sub.1 together with R.sub.3 forms a ring of formula I' ##STR2## wherein B is O, hydroxy or hydrogen; R.sub.4 is C.sub.1-4 alkyl; R.sub.5, R.sub.6, R.sub.8 and R.sub.9 are hydrogen or C.sub.1-4 alkyl; Y is --OH, --OR.sub.7, --OC(=O)R.sub.7, --NR.sub.8 R.sub.9, --NHC(=O)OR.sub.7 ; R.sub.7 is C.sub.1 -C.sub.4 -alkyl, phenyl-C.sub.1 -C.sub.4 -alkyl or optionally substituted phenyl; when Z is --C(=O)--, R.sub.2 is optionally susbtituted phenyl, or naphtyl; when Z is --SO.sub.2 --, R.sub.2 is C.sub.1-4 alkyl, phenyl-C.sub.1-4 -alkyl or optionally susbtituted phenyl.

  本发明涉及具有抗真菌活性的新的口服活性唑类衍生物，其化学式为I： 其中：X为CH或N；Ar代表取代有卤素和/或三氟甲基的苯基；Z为--C（=O）--或--SO.sub.2--；R.sub.1为CN，CO.sub.2H，CO.sub.2R.sub.7，CONR.sub.8R.sub.9或CH.sub.2Y，然后R.sub.3为氢，或者R.sub.1与R.sub.3一起形成公式I'的环： 其中B为O，羟基或氢；R.sub.4为C.sub.1-4烷基；R.sub.5，R.sub.6，R.sub.8和R.sub.9为氢或C.sub.1-4烷基；Y为--OH，--OR.sub.7，--OC（=O）R.sub.7，--NR.sub.8R.sub.9，--NHC（=O）OR.sub.7；R.sub.7为C.sub.1-C.sub.4烷基，苯基-C.sub.1-C.sub.4烷基或可选取代的苯基；当Z为--C（=O）--时，R.sub.2为可选取代的苯基或萘基；当Z为--SO.sub.2--时，R.sub.2为C.sub.1-4烷基，苯基-C.sub.1-4烷基或可选取代的苯基。
• Orally active azole derivates
  申请人：J. URIACH & CIA. S.A.

  公开号：EP0617031A1

  公开（公告）日：1994-09-28

  The present invention relates to new orally active azole derivatives with antifungal activity of formula I wherein: X is CH or N; Ar represents phenyl substituted with halogen and/or trifluoromethyl; Z is -C(=O)- or -SO₂-; R₁ is CN, CO₂H, CO₂R₇, CONR₈R₉ or CH₂Y and then R₃ is hydrogen, or R₁ together with R₃ forms a ring of formula I' wherein B is O, hydroxy or hydrogen; R₄ is C₁₋₄ alkyl; R₅, R₆, R₈ and R₉ are hydrogen or C₁₋₄ alkyl; Y is -OH, -OR₇, -OC(=O)R₇, -NR₈R₉,-NHC(=O)OR₇; R₇ is C₁-C₄-alkyl, phenyl-C₁-C₄-alkyl or optionally substituted phenyl; when Z is -C(=O)-, R₂ is optionally susbtituted phenyl, naphtyl, or an heterocycle; when Z is -SO₂-, R₂ is C₁₋₄ alkyl, phenyl-C₁₋₄-alkyl or optionally susbtituted phenyl.

  本发明涉及具有抗真菌活性的新型口服活性唑衍生物，其式为 I 其中X是CH或N；Ar代表被卤素和/或三氟甲基取代的苯基；Z是-C(=O)-或-SO₂-；R₁ 是 CN、CO₂H、CO₂R₇、CONR₈R₉ 或 CH₂Y，然后 R₃ 是氢，或者 R₁ 与 R₃ 一起形成式 I' 的环 其中 B 是 O、羟基或氢；R₄ 是 C₁₋₄ 烷基；R₅、R₆、R₈ 和 R𠢙 是氢或 C₁₋₄ 烷基；Y 是-OH、-OR₇、-OC(=O)R₇、-NR₈R₉、-NHC(=O)OR₇；R₇ 是 C₁-C₄ 烷基、苯基-C₁-C₄ 烷基或任选取代的苯基；当 Z 是-C(=O)-时，R₂是任选被疑基的苯基、萘基或杂环；当 Z 是-SO₂-时，R₂是 C₁₋₄ 烷基、苯基-C₁₋₄-烷基或任选被疑基的苯基。
• EP0617031B1
  申请人：——

  公开号：EP0617031B1

  公开（公告）日：1998-09-16
• US5478826A
  申请人：——

  公开号：US5478826A

  公开（公告）日：1995-12-26
• US5646294A
  申请人：——

  公开号：US5646294A

  公开（公告）日：1997-07-08