2-(Chloromethyl)-4-(1-methylethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide | 133741-90-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻唑类
• 英文名称: 2-(Chloromethyl)-4-(1-methylethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide
• 英文别名: 2-Chloromethyl-4-isopropylsaccharin；2-(chloromethyl)-1,1-dioxo-4-propan-2-yl-1,2-benzothiazol-3-one
• CAS: 133741-90-9
• 化学式: C₁₁H₁₂ClNO₃S
• 分子量: 273.74
• InChiKey: DTRAMHZJAGWMIU-UHFFFAOYSA-N

物化性质

• 沸点：
  428.1±55.0 °C(Predicted)
• 密度：
  1.402±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  62.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(Chloromethyl)-4-(1-methylethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide 在 sodium azide 、 18-冠醚-6 作用下， 以 苯 为溶剂， 反应 60.0h， 以95%的产率得到2-(Azidomethyl)-4-(1-methylethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide
  参考文献：
  名称：

  Steric Effects on the Regioselectivity of an Azide-Alkyne Dipolar Cycloaddition Reaction: The Synthesis of Human Leukocyte Elastase Inhibitors

  摘要：

  The cycloaddition reaction of N-(azidomethyl)benzisothiazolone 4 with various electron-deficient acetylenes gave a novel series of 1,2,3-triazoles 5-15 that were prepared for testing as inhibitors of human leukocyte elastase (HLE). Steric effects controlled the reaction regioselectivity, since as the acetylene substituent size increased from hydrogen to phenyl, tert-butyl, and trimethylsilyl, the regioisomer ratios reversed. An electronic effect of silicon appears to be responsible for the formation of only one isomer with the trimethylsilyl acetylenecarboxylate and ethynyl sulfone. For example, the 5-(phenylsulfonyl)triazole 13b was the only regioisomer detected in the reaction of phenyl 2-(trimethylsilyl)ethynyl sulfone with the azide 4. The strongly electron-withdrawing sulfone exerted no control over the regioselectivity of the cycloaddition reaction in comparison to the dominating effect of the trimethylsilyl group. High pressure and water as solvent were separately shown to accelerate the rate of product formation. The structures were unambiguously assigned on the basis of an X-ray crystal structure determination and NOE difference experiments. The derivative 12a, WIN 68123, is a potent HLE inhibitor with an apparent binding constant (K-i*) of 0.38 nM.

  DOI：

  10.1021/jo00100a019
• 作为产物：
  描述：

  4-(1-Methylethyl)-2-<(phenylthio)methyl>-1,2-benzisothiazol-3(2H)-one 1,1-dioxide 在 磺酰氯 作用下， 以 二氯甲烷 为溶剂， 以80%的产率得到2-(Chloromethyl)-4-(1-methylethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide
  参考文献：
  名称：

  Steric Effects on the Regioselectivity of an Azide-Alkyne Dipolar Cycloaddition Reaction: The Synthesis of Human Leukocyte Elastase Inhibitors

  摘要：

  The cycloaddition reaction of N-(azidomethyl)benzisothiazolone 4 with various electron-deficient acetylenes gave a novel series of 1,2,3-triazoles 5-15 that were prepared for testing as inhibitors of human leukocyte elastase (HLE). Steric effects controlled the reaction regioselectivity, since as the acetylene substituent size increased from hydrogen to phenyl, tert-butyl, and trimethylsilyl, the regioisomer ratios reversed. An electronic effect of silicon appears to be responsible for the formation of only one isomer with the trimethylsilyl acetylenecarboxylate and ethynyl sulfone. For example, the 5-(phenylsulfonyl)triazole 13b was the only regioisomer detected in the reaction of phenyl 2-(trimethylsilyl)ethynyl sulfone with the azide 4. The strongly electron-withdrawing sulfone exerted no control over the regioselectivity of the cycloaddition reaction in comparison to the dominating effect of the trimethylsilyl group. High pressure and water as solvent were separately shown to accelerate the rate of product formation. The structures were unambiguously assigned on the basis of an X-ray crystal structure determination and NOE difference experiments. The derivative 12a, WIN 68123, is a potent HLE inhibitor with an apparent binding constant (K-i*) of 0.38 nM.

  DOI：

  10.1021/jo00100a019

文献信息

• A Novel Class of Cyclic .beta.-Dicarbonyl Leaving Groups and Their Use in the Design of Benzisothiazolone Human Leukocyte Elastase Inhibitors
  作者：Dennis J. Hlasta、James H. Ackerman、John J. Court、Robert P. Farrell、Judith A. Johnson、James L. Kofron、David T. Robinson、Timothy G. Talomie、Richard P. Dunlap、Catherine A. Franke

  DOI：10.1021/jm00023a008

  日期：1995.11

  Human leukocyte elastase (HLE) has been proposed to be a primary mediator of pulmonary emphysema, and inhibitors of this enzyme should be effective in the treatment of emphysema and other pulmonary diseases. We have discovered a novel class of alicyclic and heterocyclic leaving groups which share one common structural feature, a cyclic beta-dicarbonyl. This design concept for leaving groups has not

  已经提出人白细胞弹性蛋白酶（HLE）是肺气肿的主要介体，并且该酶的抑制剂在肺气肿和其他肺部疾病的治疗中应该是有效的。我们发现了一类新的脂环族和杂环离去基团，它们具有一个共同的结构特征，即环状β-二羰基。离开小组的这种设计概念以前没有被报道过。已经建立了结构-活性关系，并且该概念扩展到几种类型的脂环族和杂环β-二羰基系统。这项工作导致鉴定出强效（K * i为0.066 nM）和组织稳定（体外：血液t1 / 2 = 160分钟，肝脏t1 / 2> 240分钟）苯并异噻唑酮HLE抑制剂WIN 65936（13b）。
• Orally Bioavailable Benzisothiazolone Inhibitors of Human Leukocyte Elastase
  作者：Dennis J. Hlasta、Chakrapani Subramanyam、Malcolm R. Bell、Philip M. Carabateas、John J. Court、Ranjit C. Desai、Marion L. Drozd、W. Mark Eickhoff、Edward W. Ferguson、Robert J. Gordon、Richard P. Dunlap、Catherine A. Franke、Albert J. Mura、Anne Rowlands、Judith A. Johnson、Virendra Kumar、Alan L. Maycock、Karl R. Mueller、Edward D. Pagani、David T. Robinson、Manohar T. Saindane、Paul J. Silver、Sandhya Subramanian

  DOI：10.1021/jm00005a001

  日期：1995.3

  endogenous inhibitor (elevated elastase or insufficient inhibitor) that leads to the destruction of alveoli. We have identified WIN 64733 (2) and WIN 63759 (3) as potent (Ki* = 14 and 13 pM, respectively), selective, mechanism-based inhibitors of HLE which are orally bioavailable in the dog (absolute bioavailability 46% and 21%, respectively). In this series the in vitro stabilities of the inhibitors in blood

  已经提出人白细胞弹性蛋白酶（HLE）作为肺气肿和其他炎性气道疾病的主要介质。HLE能够裂解许多蛋白，包括弹性蛋白，结缔组织的其他成分，某些补体蛋白和受体。在正常情况下，HLE和内源性抑制剂之间在肺中存在适当的平衡，内源性抑制剂会在释放的酶对肺产生有害作用之前清除释放的酶。肺气肿被认为是由于HLE和内源性抑制剂（弹性蛋白酶升高或抑制剂不足）之间的肺部不平衡导致肺泡破坏。我们将WIN 64733（2）和WIN 63759（3）确定为有效的（选择性Ki * = 14和13 pM），基于机理的HLE抑制剂可在犬中口服生物利用度（绝对生物利用度分别为46％和21％）。在该系列中，抑制剂在血液，空肠匀浆和肝脏S9匀浆中的体外稳定性是口服生物利用度的有用预测指标。在对狗口服（30 mg / kg）后，在肺中发现了化合物2和3，它们在通过支气管肺泡灌洗获得的上皮衬里液中被检测到（Cmax分别为2.5和0.47微克/
• Saccharin derivative proteolytic enzyme inhibitors
  申请人：Sterling Winthrop Inc.

  公开号：US05378720A1

  公开（公告）日：1995-01-03

  Compounds having the structural formula ##STR1## which inhibit the enzymatic activity of proteolytic enzymes, and processes for preparation thereof, method of use thereof in treatment of degenerative diseases and pharmaceutical compositions thereof are disclosed.

  本发明揭示了具有结构式##STR1##的化合物，其抑制蛋白酶酶活性，以及其制备方法，治疗退行性疾病的使用方法和制药组合物。
• 2-saccharinylmethyl heterocyclic carboxylates useful as proteolytic
  申请人：Sterling Winthrop, Inc.

  公开号：US05563163A1

  公开（公告）日：1996-10-08

  4-R.sup.4 -R.sup.5 -2-Saccharinylmethyl heterocyclic carboxylates, useful in the treatment of degenerative diseases, are prepared by reacting a 4-R.sup.4 -R.sup.5 -2-halomethylsaccharin with either a heterocyclic carboxylic acid in the presence of an acid-acceptor or the alkali metal salt of a heterocyclic carboxylic acid.

  4-R.sup.4 -R.sup.5 -2-Saccharinylmethyl杂环羧酸酯是治疗退行性疾病的有用化合物，其制备方法为将4-R.sup.4 -R.sup.5 -2-卤代甲基糖精与杂环羧酸在酸接受剂的存在下或杂环羧酸的碱金属盐反应。
• 2-Substituted saccharin derivative proteolytic enzyme inhibitors
  申请人：STERLING WINTHROP INC.

  公开号：EP0542372A1

  公开（公告）日：1993-05-19

  Novel 2-substituted saccharins which inhibit the enzymatic activity of proteolytic enzymes are useful in the treatment of degenerative diseases and have the formula    wherein:    L is -O-, -S-, -SO- or -SO₂-;    m and n are each independently 0 or 1;    R₁ is substituted phenyl, heterocyclyl or substitued heterocyclyl or,    when L is -O- and n is 1, R₁ is cycloheptatrienon-2-yl or,    when L is -S- and n is 1, R₁ is cyano or lower-alkoxythiocarbonyl or,    when L is -SO₂- and n is 1, R₁ is lower-alkyl or trifluoromethyl;    R₂ is hydrogen, lower-alkoxycarbonyl, phenyl or phenylthio; and    R₃ and R₄ are each hydrogen or various substituents,    and processes for preparation and pharmaceutical compositions and method of use thereof are disclosed.

  新型 2-取代糖精能抑制蛋白水解酶的酶活性，可用于治疗退行性疾病，其分子式为 其中 L是-O-、-S-、-SO-或-SO₂-； m 和 n 各自独立地为 0 或 1； R₁ 是取代的苯基、杂环基或取代的杂环基；或 当 L 为-O-且 n 为 1 时，R₁ 为环庚三壬-2-基，或 当 L 为-S-且 n 为 1 时，R₁ 为氰基或低级烷氧基硫代羰基；或 当 L 为-SO₂- 且 n 为 1 时，R₁ 为低级烷基或三氟甲基； R₂ 是氢、低级烷氧基羰基、苯基或苯硫基；以及 R₃ 和 R₄ 各为氢或各种取代基、 本发明公开了制备工艺、药物组合物及其使用方法。