DNK 333 | 398507-81-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: DNK 333
• 英文别名: 5-(3,4-dichlorophenyl)-4(R)-[N-methyl-3,5-bis(trifluoromethyl)-benzamido]-N-[2-oxoperhydroazepin-3(R)-yl]-2(E)-pentenamide；N-[(E,R)-1-(3,4-dichloro-benzyl)-3-((R)-2-oxo-azepan-3-ylcarbamoyl)-allyl]-N-methyl-3,5-bis-trifluoromethyl-benzamide；(4R)-4-[N'-methyl-N'-(3,5-bisfluoromethylbenzoyl)amino]-4-(3,4-dichlorobenzyl)-but-2-enoic acid N-[(R)-ε-caprolactam-3-yl]-amide；(4R)-4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(3,4-dichlorobenzyl)-but-2-enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide；Benzamide, N-((1R,2E)-1-((3,4-dichlorophenyl)methyl)-4-(((3R)-hexahydro-2-oxo-1H-azepin-3-yl)amino)-4-oxo-2-butenyl)-N-methyl-3,5-bis(trifluoromethyl)-；N-[(E,2R)-1-(3,4-dichlorophenyl)-5-oxo-5-[[(3R)-2-oxoazepan-3-yl]amino]pent-3-en-2-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide
• CAS: 398507-81-8
• 化学式: C₂₇H₂₅Cl₂F₆N₃O₃
• 分子量: 624.41
• InChiKey: BHCJHYIMNHXLOM-WVDRJWPYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  41
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  78.5
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  DNK 333 在 水 作用下， 以 甲醇 为溶剂， 反应 2.5h， 生成 N-[(E,R)-1-(3,4-dichloro-benzyl)-3-((R)-2-oxo-azepan-3-ylcarbamoyl)-allyl]-N-methyl-3,5-bis-trifluoromethyl-benzamide hemihydrate
  参考文献：
  名称：

  WO2007/118651

  摘要：

  公开号：
• 作为产物：
  描述：

  [(R)-1-(3,4-dichlorobenzyl)-2-oxoethyl]methylcarbamic acid tert-butyl ester 在 4-二甲氨基吡啶 、 正丁基锂 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 28.5h， 生成 DNK 333
  参考文献：
  名称：

  Stereoselective Preparation of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3- (2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide, a Potent and Orally Active Dual Neurokinin NK₁/NK₂ Receptor Antagonist

  摘要：

  In a program aimed at the development of neurokinin antagonists, N- [(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1, DNK333) has been discovered as a potent and balanced neurokinin (tachykinin) NK1/NK2 receptor antagonist. Enantiomerically pure (>99.5% ee) 1 can be prepared in 6 + 1 synthetic steps starting from commercially available optically active BOC-D-3,4-dichlorophenylalanine in an overall yield of ca. 25-30%. 1 showed potent affinities to cloned human NK1 (pK(i) = 8.38) and NK2 (pK(i) = 8.02) receptors. When 1 was compared to the other possible three diastereoisomers, it could be demonstrated that only the R,R-isomer (1) exhibits potent and balanced affinity for the cloned human NK1 and NK2 receptors. 1 exhibited favorable pharmacokinetic properties in guinea pigs following oral administration and demonstrated in vivo activity in pharmacological models of substance P- and neurokinin A (NKA)-induced bronchoconstriction in guinea pigs after intravenous and in squirrel monkeys after oral application.

  DOI：

  10.1021/jm030786m

文献信息

• Organic Compounds
  申请人：PORTMANN Robert

  公开号：US20110282053A1

  公开（公告）日：2011-11-17

  A process for preparing compounds of formula I or a solvate or hydrate thereof, where R, R 1 , R 2 , R 3 and R 5 have the meanings as indicated in the specification. Such compounds are useful in the treatment of a number of conditions associated with substance P and neurokinin.

  一种制备式I化合物或其溶剂化物或水合物的方法，其中R、R1、R2、R3和R5的含义如规范中所示。这些化合物在治疗与P物质和神经激肽相关的多种疾病方面具有用途。
• Organic compounds
  申请人：Novartis AG

  公开号：US08008479B2

  公开（公告）日：2011-08-30

  A process for preparing compounds of formula (I) or a solvate or hydrate thereof, where R, R1, R2, R3 and R5 have the meanings as indicated in the specification. Such compounds are useful in the treatment of a number of conditions associated with substance P and neurokinin.

  制备式(I)化合物或其溶剂化物或水合物的方法，其中R、R1、R2、R3和R5的含义如规范所示。这些化合物对与物质P和神经激肽相关的多种疾病的治疗有用。
• Pharmaceutical formulation comprising neurokinin antagonist
  申请人：Novartis AG

  公开号：EP1938804A1

  公开（公告）日：2008-07-02

  Pharmaceutical compositions in the form of a solid dispersion comprising (4R)-4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(3,4-dichlorobenzyl)-but-2-enoic acid N-[(R)-cpsilon-caprolactam-3-yl]-amidc or a pharmaceutically acceptable salt or solvate thereof and a carrier. Such compositions are useful to treat patients who have functional motility disorders of the viscera, especially irritable bowel syndrome or functional dyspepsia, or urinary bladder disorders, especially urinary incontinence.

  固体分散体形式的药物组合物，包含(4R)-4-[N'-甲基-N'-(3,5-二氟甲基-苯甲酰基)-氨基]-4-(3,4-二氯苄基)-丁-2-烯酸 N-[(R)-癸基己内酰胺-3-基]-酰胺c或其药学上可接受的盐或溶液以及载体。此类组合物可用于治疗内脏功能性运动障碍，尤其是肠易激综合征或功能性消化不良，或膀胱功能障碍，尤其是尿失禁的患者。
• Dual neurokinin NK1/NK2 antagonists: N-[(R,R)-(E)-1-arylmethyl-3-(2-oxo-azepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamides and 3-[N′-3,5-bis(trifluoromethyl)benzoyl-N-arylmethyl-N′-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamides
  作者：Marc Gerspacher、Luigi La Vecchia、Robert Mah、Andreas von Sprecher、Gary P. Anderson、Natarajan Subramanian、Kathleen Hauser、Heinrich Bammerlin、Sabine Kimmel、Viviane Pawelzik、Karin Ryffel、Howard A. Ball

  DOI：10.1016/s0960-894x(01)00631-x

  日期：2001.12

  Based on the structure of N-[(R,R)-(E)-1-(4-chlorobenzyl)- 3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1), attempts to improve the NK2 affinity have resulted in the discovery of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3- yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (9, DNK333) exhibiting a 5-fold improved affinity to the NK2 receptor in comparison to 1. Simplification of the structure via elimination of a chiral centre led to 3-[N'-3,5-bis(trifluoromethyl)benzoyl-N-(3,4-dichlorobenzyl)-N'-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamide (22), a potent and fairly balanced NK1/NK2 antagonist. (C) 2001 Elsevier Science Ltd. All rights reserved.
• SYNTHESIS OF ACYLAMINOALKENYLENE AMIDES USEFUL AS SUBSTANCE P ANTAGONISTS
  申请人：Novartis AG

  公开号：EP2010498B1

  公开（公告）日：2010-11-03