{(S)-1-[(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-2-methyl-propyl}-carbamic acid tert-butyl ester | 251540-54-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: {(S)-1-[(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-2-methyl-propyl}-carbamic acid tert-butyl ester
• 英文别名: 1,1-Dimethylethyl N-[(1S)-1-[[5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2-yl]hydroxymethyl]-2-methylpropyl]carbamate；tert-butyl N-[(2S)-1-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-hydroxy-3-methylbutan-2-yl]carbamate
• CAS: 251540-54-2
• 化学式: C₁₆H₂₉N₃O₄
• 分子量: 327.424
• InChiKey: VMKVKYDLCFGNMZ-VUWPPUDQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  97.5
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  {(S)-1-[(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-2-methyl-propyl}-carbamic acid tert-butyl ester 在 N-甲基吗啉 、 盐酸 、 草酰氯 、 1-羟基苯并三唑 、 二甲基亚砜 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.5h， 生成 N-[2-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(methylethyl)-2-oxoethyl]-2-{6-oxo-2-phenyl-5-[(phenylmethoxy)carbamido]hydropyrimidinyl}acetamide
  参考文献：
  名称：

  Development of Orally Active Nonpeptidic Inhibitors of Human Neutrophil Elastase

  摘要：

  5-Amino-2-phenylpyrimidin-6-ones, some of their desamino derivatives, and miscellaneous derivatives were synthesized and biologically evaluated on both in vitro activity and oral activity in an acute hemorrhagic assay. These compounds contained an alpha -keto-1,3,4-oxadiazole moiety to bind covalently to the Ser-195 hydroxy group of human neutrophil elastase (HNE). Among those tested, compounds 11a-c,e,i-1(F), 11d,e,k(H), ald,e,k(F), and ald,e(H) showed a good oral profile. RS-Mixture 3(H) was selected for clinical evaluation based on its oral potency, duration of action, enzyme selectivity, safety profile, and ease of synthesis. Structure-activity relationships (SARs) are discussed.

  DOI：

  10.1021/jm000410y
• 作为产物：
  描述：

  2,2-二甲基丙酰肼 在 正丁基锂 、 对甲苯磺酸 、 magnesium bromide 作用下， 以 正己烷 为溶剂， 反应 1.5h， 生成 {(S)-1-[(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-2-methyl-propyl}-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Development of Orally Active Nonpeptidic Inhibitors of Human Neutrophil Elastase

  摘要：

  5-Amino-2-phenylpyrimidin-6-ones, some of their desamino derivatives, and miscellaneous derivatives were synthesized and biologically evaluated on both in vitro activity and oral activity in an acute hemorrhagic assay. These compounds contained an alpha -keto-1,3,4-oxadiazole moiety to bind covalently to the Ser-195 hydroxy group of human neutrophil elastase (HNE). Among those tested, compounds 11a-c,e,i-1(F), 11d,e,k(H), ald,e,k(F), and ald,e(H) showed a good oral profile. RS-Mixture 3(H) was selected for clinical evaluation based on its oral potency, duration of action, enzyme selectivity, safety profile, and ease of synthesis. Structure-activity relationships (SARs) are discussed.

  DOI：

  10.1021/jm000410y

文献信息

• Tri-peptide Inhibitors of Serine Elastases
  申请人：Cheronis John C.

  公开号：US20090156509A1

  公开（公告）日：2009-06-18

  The present invention provides compounds of formula (I): where X is R 1 —(CR 3 R 4 ) n OC(O)—; R 1 —(CR 3 R 4 ) n C(O)—; R 1 —C(O)NH(CR 3 R 4 ) n OC(O)—; R 1 —C(O)NH(CR 3 R 4 ) n C(O)—; R 1 —C(O)(CR 3 R 4 ) n OC(O)—; or R 1 —C(O)(CR 3 R 4 ) n C(O)—; where R 1 is optionally substituted C 5-10 aryl or heteroaryl; OH or NH 2 ; where R 3 and R 4 are independently H or methyl; and n is 0 to 6; and Y is —CF 3 or one of: where R 2 is C 1-8 alkyl optionally substituted with halo or —OH; —(CR 6 R 7 ) p —C 5-6 aryl optionally substituted with halo, —OH, C 1-8 alkyl, C 1-8 haloalkyl, —(CH 2 ) m C(O)NH 2 or —(CH 2 ) m OCH 3 ; where R 6 and R 7 are independently H or methyl; m is 0 to 4, and p is 0 or 1 or a pharmaceutically acceptable salt, ester, metabolite or prodrug thereof

  本发明提供了式(I)的化合物：其中X为R1—(CR3R4)nOC(O)—; R1—(CR3R4)nC(O)—; R1—C(O)NH(CR3R4)nOC(O)—; R1—C(O)NH(CR3R4)nC(O)—; R1—C(O)(CR3R4)nOC(O)—; 或R1—C(O)(CR3R4)nC(O)—;其中R1为可选择的取代C5-10芳基或杂环芳基; OH或NH2;其中R3和R4独立地为H或甲基; n为0到6;以及Y为—CF3或下列之一：其中R2为C1-8烷基，可选择地取代卤或—OH; —(CR6R7)p—C5-6芳基，可选择地取代卤，—OH，C1-8烷基，C1-8卤代烷基，—(CH2)mC(O)NH2或—(CH2)mOCH3;其中R6和R7独立地为H或甲基; m为0到4，p为0或1或其药学上可接受的盐，酯，代谢物或前药。
• [EN] TRI-PEPTIDE INHIBITORS OF SERINE ELASTASES<br/>[FR] INHIBITEURS TRIPEPTIDIQUES DES ÉLASTASES À SÉRINE
  申请人：ACCUTHERA INC

  公开号：WO2010065461A1

  公开（公告）日：2010-06-10

  The present invention provides compounds of formula (I): where X is R1-(CR3R4)nOC(O)-; R1-(CR3R4)nC(O)-; R1-C(O)NH(CR3R4)nOC(O)-; R1-C(O)NH(CR3R4)nC(O)-; R1-C(O)(CR3R4)nOC(O)-; or R1-C(O)(CR3R4)nC(O)-; where R1 is optionally substituted C5-10 aryl or heteroaryl; OH or NH2; where R3 and R4 are independently H or methyl; and Y is CF to 6; and formula (II) where R2 is C1-8 alkyl optionally substituted with halo or-OH; -(CR6R7)P-C5-6 aryl optionally substituted with halo, -OH, C1-8 alkyl, C1-8 haloalkyl, -(CH2)mC(O)NH2 or -(CH2)mOCH3; where R6 and R7 are independently H or methyl; m is O to 4, and p is O or 1 or a pharmaceutically acceptable salt, ester, metabolite or prodrug thereof.
• Development of Orally Active Nonpeptidic Inhibitors of Human Neutrophil Elastase
  作者：Kazuyuki Ohmoto、Tetsuya Yamamoto、Motohiro Okuma、Toshihide Horiuchi、Hirotoshi Imanishi、Yoshihiko Odagaki、Kazuhito Kawabata、Tomohiko Sekioka、Yasushi Hirota、Shozo Matsuoka、Hisao Nakai、Masaaki Toda、John C. Cheronis、Lyle W. Spruce、Albert Gyorkos、Maciej Wieczorek

  DOI：10.1021/jm000410y

  日期：2001.4.1

  5-Amino-2-phenylpyrimidin-6-ones, some of their desamino derivatives, and miscellaneous derivatives were synthesized and biologically evaluated on both in vitro activity and oral activity in an acute hemorrhagic assay. These compounds contained an alpha -keto-1,3,4-oxadiazole moiety to bind covalently to the Ser-195 hydroxy group of human neutrophil elastase (HNE). Among those tested, compounds 11a-c,e,i-1(F), 11d,e,k(H), ald,e,k(F), and ald,e(H) showed a good oral profile. RS-Mixture 3(H) was selected for clinical evaluation based on its oral potency, duration of action, enzyme selectivity, safety profile, and ease of synthesis. Structure-activity relationships (SARs) are discussed.