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Cathepsin C inhibitors

A C1-C4, C1-C6 technology, applied in the field of 4-amino-2-butenamide compounds, can solve problems such as unverified processing

Inactive Publication Date: 2012-07-11
GLAXO GRP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, cathepsin C is highly expressed in lung epithelial cells, and its possible role in the processing of other enzymes has not been tested

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0751] (2E,4S)-4-(L-alanylamino)-6-phenyl-N-(phenylmethyl)-2-hexenamide hydrochloride

[0752]

[0753] [(1S)-1-methyl-2-oxo-2-({(1S, 2E)-4-oxo-1-(2-phenylethyl)-4-[(phenylmethyl A solution of 1,1-dimethylethyl)amino]-2-buten-1-yl}amino)ethyl]carbamate (2.00 g, 4.3 mmol) in concentrated HCl (2.0 mL) was stirred at room temperature for 1 h . The reaction mixture was washed with saturated NaHCO 3 The aqueous solution was basified to pH 8 or 9, and then extracted with EtOAc (4x100 mL). The combined organic layers were washed with water (2x50 mL), washed with Na 2 SO 4 Dry, filter, and concentrate in vacuo to give the free base of the title compound (0.60 g). The free base was dissolved in 1M HCl in Et 2 O solution (20 mL) was stirred for 2 h. The resulting solid was collected by filtration and washed with Et 2 O (10 mL) wash gave the title compound (0.30 g, 18%) as a white solid. LC-MS m / z 366(M+H) + , 1.59min (retention time).

Embodiment 2

[0755] (2E,4S)-4-(L-alanylamino)-N-methyl-6-phenyl-2-hexenamide hydrochloride

[0756]

[0757] To ((1S)-1-methyl-2-{[(1S,2E)-4-(methylamino)-4-oxo-1-(2-phenylethyl)-2-butene- CH 2 Cl 2 (30 mL) solution was added TFA (10 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo, and Et was added 2 O (30 mL). The solid was filtered and washed with saturated NaHCO 3 Aqueous solution (20 mL), and then washed with water (10 mL) gave the free base of the title compound (400 mg). Dissolve the free base in 1M HCl in Et 2 O solution (20 mL) was stirred for 2 h. The resulting solid was collected by filtration and washed with Et 2 O (20 mL) washed to afford the title compound (0.28 g, 20%) as a white solid. LC-MS m / z 290(M+H) + , 1.34min (retention time).

Embodiment 3

[0759](2E,4S)-4-(L-alanylamino)-N,N-dimethyl-6-phenyl-2-hexenamide hydrochloride

[0760]

[0761] ((1S)-2-{[(1S,2E)-4-(dimethylamino)-4-oxo-1-(2-phenylethyl)-2-buten-1-yl] A solution of 1,1-dimethylethyl amino}-1-methyl-2-oxoethyl)carbamate (2.00 g, 4.96 mmol) in concentrated HCl (2.0 mL) was stirred at room temperature for 1 h. The reaction mixture was washed with saturated NaHCO 3 The aqueous solution was basified to pH 8 or 9, and then extracted with EtOAc (4x100 mL). The combined organic layers were washed with water (2x50 mL), washed with Na 2 SO 4 Dry, filter, and concentrate in vacuo to give the free base of the title compound. Dissolve the free base in 1M HCl in Et 2 O solution (20 mL) was stirred for 2 h. The resulting solid was collected by filtration and washed with Et 2 O (10 mL) washed to afford the title compound (0.30 g, 20%) as a white solid. LC-MS m / z 304(M+H) + , 1.39min (retention time).

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Abstract

Disclosed are 4-amino-2-butenamides of Formula (I) having pharmacological activity, pharmaceutical compositions containing them, and methods for the treatment of diseases mediated by the cathepsin C enzyme such as chronic obstructive pulmonary disease.

Description

field of invention [0001] The present invention relates to certain 4-amino-2-butenamide compounds which are cathepsin C inhibitors, pharmaceutical compositions containing these compounds, and their usefulness in the treatment of diseases mediated by cathepsin C such as chronic obstructive pulmonary disease use in . Background of the invention [0002] Cathepsins are a family of enzymes included in the papain superfamily of cysteine ​​proteases. Cathepsins B, C, F, H, K, L, S, V and X have been described in the scientific literature. Cathepsin C is also known in the literature as dipeptidyl peptidase I or "DPPI". [0003] A number of recently published studies have begun to describe the role played by cathepsin C in certain inflammatory processes. See, eg, Adkison et al., The Journal of Clinical Investigation 109:363-371 (2002); Tran et al., Archives of Biochemistry and Biophysics 403:160-170 (2002); Thiele et al., The Journal of Immunology 158:5200- 5210 (1997); Bidere e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00
CPCC07D205/04C07D231/40C07C2101/18C07D295/185C07D211/58C07C2101/08C07D285/135C07D403/12C07D277/46C07D333/36C07D213/75C07C2101/02C07C2102/42C07D209/44C07D307/22C07D401/12C07B2200/07C07D309/14C07D333/24C07C237/22C07D211/56C07C2101/14C07D417/12C07D209/14C07C2601/02C07C2601/08C07C2601/14C07C2601/18C07C2602/42A61P11/00A61P11/08A61P43/00C07C233/02A61K31/16A61K38/00
Inventor N.安德森J.布希-彼得森B.伊万斯李惠洁N.尼文斯M.R.帕洛维科S.L.索里斯M.D.沃尔A.M.布莱昂
Owner GLAXO GRP LTD
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