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Protease inhibitors

A compound and medicinal salt technology, applied in the field of protease inhibitors, can solve problems such as poor solubility, lack of selectivity, and too fast serum clearance

Inactive Publication Date: 2006-04-26
SMITHKLINE BECKMAN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these known inhibitors are not suitable for use as therapeutic agents in animals, especially humans, because of their various disadvantages
These disadvantages include lack of selectivity, cytotoxicity, poor solubility and too rapid serum clearance

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0211] Example number Chemical name

[0212] 1 {(S)-1-[1-((S)-2-benzyloxycarbonylamino-4-methyl-pentanoyl

[0213] Base)-3-oxo-azepan (azepan)-4-ylcarbamoyl}

[0214] Benzyl carbamate

[0215] 2 Naphthylene-2-carboxylic acid [(S)-1-(1-benzyl-3-oxo-azepane-

[0216] 4-ylcarbamoyl)-3-methyl-butyl]amide

[0217] 3 Benzo[1,3]dioxol-5-carboxylic acid [(S)-1-(1-benzyl-

[0218] 3-oxo-azepan-4-ylcarbamoyl)-3-methyl-butyl]

[0219] Amide

[0220] 4 Benzofuran-2-carboxylic acid [(S)-1-(1-benzyl-3-oxo-azepane

[0221] Alk-4-ylcarbamoyl)-3-methyl-butyl]amide

[0222] 5 Benzo[b]thiophene-2-carboxylic acid[(S)-1-(1-benzyl-3-oxo-azacycle

[0223] Heptane-4-ylcarbamoyl)-3-methyl-butyl]amide

[0224] 6 naphthylene-2-sulfonyl[(S)-1-(1-benzyl-3-oxo-azepanyl

[0225] Alk-4-ylcarbamoyl)-3-methyl-butyl]-amide

[0226] 7 Quinoline-2-carboxylic acid [(S)-1-(1-benzyl-3-oxo-azepane-4-

[0227] Carbamoyl)-3-met...

Embodiment 192

[0977] The deuterated compound of Example 192 can be conveniently prepared according to Scheme 4. Those skilled in the art will understand from Example 192 and Scheme 4 how to prepare any of the deuterated compounds of the invention.

[0978] Single diastereoisomer benzofuran-2-carboxylic acid {(S)-3-methyl-1-[(2,2′,4-trideutero)-3-oxo-1-(pyridine- 2-Sulfonyl)-azepan-4-ylcarbamoyl]-butyl} amides 31 and 32 can be prepared as shown in Scheme 4. Alkylation of benzyl allylcarbamate 22 with 5-bromo-1-pentene in the presence of a base such as sodium hydride affords diene 23. Treatment of diene 23 with bis(tricyclohexylphosphine)phenylmethyleneruthenium(IV) dichloride by the method of Grubbs afforded 2,3,4,7-tetrahydro-azepine-1-carboxylic acid Benzyl esters 24. Epoxidation of azepane 24 with standard oxidizing agents common in the art, such as m-CPBA, affords epoxide 25. The nucleophilic epoxy ring of 25 can be opened with a reagent such as sodium azide to give the azido alcohol...

Embodiment 1

[1080] Preparation of {(S)-1-[1-((S)-2-benzyloxycarbonylamino-4-methyl-pentanoyl)-3-oxo-azepan-4-ylcarbamoyl ]} benzyl carbamate

[1081] a.) Allyl-pent-4-enyl-tert-butyl carbamate

[1082] To a suspension of NaH (3.05 g, 76.33 mmol of 60% NaH in oil; washed with hexanes) in DMF (30 mL) was added tert-butyl N-allylcarbamate (6.0 g, 38.2 mmol) dropwise . The mixture was stirred at room temperature for about 10 minutes, and 5-bromo-1-pentene (6.78 mL, 57.24 mmol) was added dropwise. The reaction was heated to 40°C for about 2 hours, and the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water (2x), brine, dried (magnesium sulfate), filtered and concentrated to afford 10 g of the title compound as an oil: MS (EI) 226 (M+H + ).

[1083] b.) tert-butyl 2,3,4,7-tetrahydro-azepane-1-carboxylate

[1084] To a solution of Example 1a (4.5 g) in benzene was added molybdenum 2,6-diisopropylphenyliminomethyl-2-phenylpropyl bis-tert-butoxid...

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Abstract

The present invention provides 4-amino-azepan-3-one protease inhibitors and pharmaceutically acceptable salts, hydrates and solvates thereof which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, novel intermediates of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and periodontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease; hypercalcemia of malignancy; and metabolic bone disease, comprising inhibiting said bone loss or excessive cartilage or matrix degradation by administering to a patient in need thereof a compound of the present invention.

Description

field of invention [0001] The present invention relates generally to 4-amino-azepane-3-ketoprotease inhibitors, in particular to such inhibitors of cysteine ​​and serine, and more particularly to the inhibition of cysteine Compounds that inhibit acid proteases, more specifically compounds that inhibit cysteine ​​proteases belonging to the papain superfamily, still more specifically compounds that inhibit cysteine ​​proteases of the cathepsin class, and most specifically inhibit tissue Compounds of proteinase K. These compounds are particularly useful in the treatment of diseases involving cysteine ​​proteases, especially diseases of excessive loss of bone or cartilage, such as osteoporosis, periodontitis and arthritis. Background of the invention [0002] Cathepsins are part of the papain superfamily of cysteine ​​proteases. Cathepsins B, H, L, N and S have been described in the literature. More recently, a cathepsin K polypeptide and a cDNA encoding the polypeptide were ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D223/08C07D401/02C07D403/02C07D405/02C07D409/02C07D411/02C07D413/02C07D417/02C07D419/02A61K31/55A61P19/08A61P19/02A61P1/02A61K31/4375A61P3/14A61P19/10A61P29/00A61P31/00A61P31/04A61P33/00A61P33/06A61P33/12A61P35/00A61P35/04A61P43/00C07D223/12C07D401/10C07D401/12C07D401/14C07D403/12C07D405/12C07D405/14C07D409/12C07D409/14C07D413/12C07D413/14C07D417/12C07D417/14C07D471/04C07D491/04C07D495/04
CPCC07D223/12C07D401/10C07D401/12C07D401/14C07D403/12C07D405/12C07D405/14C07D409/12C07D409/14C07D413/14C07D417/12C07D417/14C07D471/04C07D491/04C07D495/04A61P1/02A61P19/02A61P19/10A61P29/00A61P3/14A61P31/00A61P31/04A61P33/00A61P33/06A61P33/12A61P35/00A61P35/04A61P43/00A61K31/55
Inventor 小R·W·马奎斯玉汝D·F·维贝尔M·D·库明斯S·K·汤普森D·雅马施塔
Owner SMITHKLINE BECKMAN CORP
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