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Methods for treating pulmonary emphysema using substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin c

a technology of heptane-3-carboxylic acid and inhibitor of cathepsin c, which is applied in the direction of antibacterial agents, immune disorders, extracellular fluid disorders, etc., can solve the problems of tissue damage and chronic inflammation, and achieve the effects of inhibiting downstream serine protease activity, potent cathepsin c activity, and high selectivity

Inactive Publication Date: 2015-04-16
BOEHRINGER INGELHEIM INT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

These compounds effectively inhibit Cathepsin C activity, potentially reducing downstream serine protease activity and alleviating inflammatory conditions like COPD, asthma, and rheumatoid arthritis by minimizing tissue damage and chronic inflammation.

Problems solved by technology

Once activated, these proteases are capable of degrading various extracellular matrix components, which can lead to tissue damage and chronic inflammation.

Method used

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  • Methods for treating pulmonary emphysema using substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin c
  • Methods for treating pulmonary emphysema using substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin c
  • Methods for treating pulmonary emphysema using substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin c

Examples

Experimental program
Comparison scheme
Effect test

example 344

[0493]

Step 1: Synthesis of Intermediate I-20.1

[0494]To I-2.2 (300 mg, 0.64 mmol) in anhydrous dioxane (8 mL) are added 3-dimethylamino-piperidine (164.96 mg, 1.29 mmol) and cesium carbonate (846.87 mg, 2.57 mmol). The mixture is purged with argon and chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (95.05 mg, 0.13 mmol) is added and stirred at 90° C. for 2 h. The reaction mixture is filtered and concentrated. The residue is diluted with dichlormethane and water. The organic layer is separated, dried and concentrated. The crude product is purified by reversed phase HPLC. Yield 12%.

Step 2: Synthesis of Example 344

See Method A5, Step 3

[0495]To I-20.1 (53 mg, 0.1 mmol) in acetonitrile (8 mL) p-toluenesulfonic acid monohydrate (68.70 mg, 0.36 mmol) is added and stirred at r.t. for 6 h. The mixture is concentrated, diluted with methanol and purified by reversed phase HPLC. Yield 28%, m / z 414 [M+H]+, rt 0.74 min, LC-MS Method 004_CA05...

example 315

[0496]

Step 1: Synthesis of Intermediate I-21.1

[0497]To I—18.1 (1.5 g, 2.7 mmol) in anhydrous THF (1 mL) under argon atmosphere lithium borhydride (59 m g, 2.7 mmol) is added. The mixture is heated to 50° C. overnight. The reaction mixture is carefully diluted with water and extracted with ethyl acetate. The organic layer is separated, dried and concentrated. The crude residue is filtered through a pad of silica gel (cyclohexane / ethyl acetate 1:2). Yield 37%.

Step 2: Synthesis of Intermediate I-21.2

[0498]To I-21.1 (260 m g, 0.495 mmol) in anhydrous ACN (5 mL) 5-fluoro-2-iodo-aniline (117.28 m g, 0.495 mmol), 1,1 bis(diphenylphosphino)ferrocene palladium dichloride (36.21 mg, 0.049 mmol) and a solution of sodium carbonate in water 2 mol / L (0.742 mL, 1.48 mmol) are added and purged with argon and heated to 80° C. for 1 h. The reaction mixture is diluted with DCM and water. The organic layer is separated, dried and concentrated. The crude residue is purified by reversed phase HPLC. Yield...

examples

[0764](rt=retention time) Deprotection Methods: TSA (toluene sulfonic acid cf. Example 1), SI (trimethylsilyl iodide cf. example 2 or 3), FA (formic acid cf. example 4 or 7), TFA (trifluoroacetic acid). Stereochemistry at the carbon atom adjacent to the nitrile group is assigned: Stereo bond means S-isomer, non-stereo bond means 1:1 mixture of stereoisomers.

TABLE 62Syn. / Deprot.YieldExampleStructureEductMethod[%] 1I-1.5A / TSA 47 2I-2.3A1 / SI 44 3I-3.3A2.1 / SI 62 4I-4.3A3 / FA 86 5I-5.2A4 / FA 34 6I-6.2A5 / TSA 86 7I-7.3B / FA 39 8I-8.2C / SI 19 9I-9.1D / SI 32 10I-3.3.1A2.1 / SI 25 11I-3.2.2A2.1 / SI 17 12I-2.3.1A1 / FA 36 13I-2.3.7.1A1 / FA 56 14I-4.3.1A3 / SI 43 15I-4.3.2A3 / SI 21 16I-4.3.3A3 / TSA 93 17I-2.3.2A1 / TSA 16 18I-2.3.3A1 / TSA 36 19I-4.3.1A3 / SI 59 20I-2.3.7.3A1 / TSA 22 21I-2.3.7.4A1 / FA 49 22I-4.3.5A3 / SI 70 23I-2.3.4A1 / TSA 37 24I-2.3.74.1A1 / TFA 45 25I-4.3.6A3 / TSA 45 26I-2.3.5A1 / TSA 49 27I-2.3.6A1 / TSA 38 28I-2.3.7.5A1 / FA 75 29I-4.3.7A3 / SI 40 30I-2.3.8A1 / TSA 46 31I-4.3.8A3 / SI 39 32I-3.2.4A2.2 / TSA 31 33I-...

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Abstract

This invention relates to 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides of formula 1and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and / or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.

Description

FIELD OF INVENTION[0001]This invention relates to substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides of formula 1and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and / or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.BACKGROUND INFORMATION[0002]WO2004110988 discloses peptidyl nitrile inhibitors as dipeptidyl-peptidase I (DPPI) inhibitors for the treatment of a series of diseases.[0003]WO2009074829 and WO2010142985 also disclose peptidyl nitrile inhibitors as dipeptidyl-peptidase I (DPPI) inhibitors for the treatment asthma, COPD or allergic rhinitis.BRIEF SUMMARY OF THE INVENTION[0004]Dipeptidyl-aminopeptidase I (DPPI or Cathepsin C; EC3.4.141), is a lysosomal cysteine protease capable of removing dipeptides from the amino terminus of protein substrates. DPPI was first discovered by Gutman and Fruton in...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D487/10A61K31/4035A61K31/404C07D405/12A61K31/403C07D209/52C07D403/14A61K31/4192A61K31/496A61K31/4155A61K31/416C07D401/10A61K31/473C07D409/12C07D417/12C07D413/14A61K31/5383A61K31/551A61K31/397A61K45/06C07D403/12
CPCC07D487/10C07D403/12A61K31/4035A61K31/404C07D405/12A61K31/403C07D209/52C07D403/14A61K31/4192A61K31/496A61K31/4155A61K31/416C07D401/10A61K31/473C07D409/12C07D417/12C07D413/14A61K31/5383A61K31/551A61K31/397A61K45/06A61K31/4045A61K31/438C07D401/12C07D471/08C07D498/04A61K31/423A61P1/04A61P11/00A61P11/06A61P15/00A61P17/00A61P17/06A61P19/02A61P25/04A61P27/00A61P29/00A61P31/00A61P31/04A61P31/12A61P31/18A61P35/00A61P37/00A61P37/06A61P37/08A61P43/00A61P7/00A61P9/10Y02A50/30
Inventor ANDERSKEWITZ, RALFBINDER, FLORIANGRAUERT, MATTHIASGRUNDL, MARCHAEBEL, PETER WILHELMOOST, THORSTENPAUTSCH, ALEXANDERPETERS, STEFANVINTONYAK, VIKTOR
Owner BOEHRINGER INGELHEIM INT GMBH
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