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Cathepsin K inhibitors and application thereof

A technology of compounds and atoms, applied in the direction of anti-inflammatory agents, drug combinations, non-central analgesics, etc., can solve the problems of unsatisfactory selective inhibition of various cathepsins and disturbing side effects

Active Publication Date: 2017-07-04
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, Odanacatib of Merck & Co. is progressing rapidly. However, because it also has a good inhibitory effect on cathepsin S, its selective inhibitory effect on various cathepsins is not ideal, so there have also been some surprising results in clinical research. disturbing side effects signs

Method used

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  • Cathepsin K inhibitors and application thereof
  • Cathepsin K inhibitors and application thereof
  • Cathepsin K inhibitors and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0191] (S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4-(4' -(2-oxopyrrolidin-1-yl)-1',3'-dihydrospiro[cyclopentane-1,2'-indene]-7'-yl)phenyl)ethyl)amino)pentyl Amide

[0192]

[0193] Step 1: 4'-(2-oxopyrrolidin-1-yl)-1',3'-dihydrospiro[cyclopentane-1,2'-indene]-7'-yltrifluoromethanesulfonic acid ester

[0194] Add 4'-iodo-1',3'-dihydrospiro[cyclopentane-1,2'-indene]-7'-yl triflate (522mg, 1.77 mmol) [refer to the synthesis method of patent WO 2014082379, the synthetic route of intermediate 1-8 on page 113-115], 2-pyrrolidone (151mg, 1.77mmol), potassium phosphate (0.75g, 3.54mmol), cuprous iodide ( 17mg, 0.09mmol) and anhydrous toluene (10mL), N,N'-dimethylethylenediamine (8.0mg, 0.09mmol) was added under nitrogen flow, sealed and heated to 130°C for overnight reaction. After the reaction was completed, it was cooled to room temperature, quenched with water, extracted with ethyl acetate (30 mL×2), the organic phase was washed with saturated br...

Embodiment 2

[0200] (2S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((1S)-2,2,2-trifluoro-1-(4-(8- (2-Oxopyrrolidin-1-yl)-1,2,3,4-tetrahydro-1,4-methyconaphthalene-5-yl)phenyl)ethyl)amino)pentanamide

[0201]

[0202] Step 1: 5-Methoxy-1,4-dihydro-1,4-methaphthalene

[0203] Add magnesium chips (600mg, 24.9mmol), a small particle of elemental iodine and anhydrous tetrahydrofuran (10mL) to the dry reaction flask, install a reflux condenser, and protect it with nitrogen, first add 2-bromo-1-fluoro-3 -Methoxybenzene (0.5g) after initiation of the reaction, additional 2-bromo-1-fluoro-3-methoxybenzene (2.5g, 12.2mmol) and freshly distilled 1,3-cyclopentadiene (1.05g.17.56mmol) was dissolved in anhydrous tetrahydrofuran (20mL) and added slowly in a constant pressure dropping funnel to keep the reaction system slightly refluxed. After the dropwise addition was completed, the reaction system continued to be heated under reflux for 1 hour. After cooling, the reaction was quenched with satur...

Embodiment 3

[0225] (S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4-(4' -(2-oxopyrrolidin-1-yl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-7-yl)phenyl)ethyl)amino)pentanamide

[0226]

[0227] Step 1: 7-Methoxy-1-methylene-2,3-dihydro-1H-indene

[0228] Potassium tert-butoxide (3.50g, 30.86mmol), methyltriphenylphosphine iodide (13.7g, 33.9mmol) and anhydrous tetrahydrofuran (200mL) were added to the reaction flask, and protected with nitrogen, reacted at room temperature for 1 hour . Then a solution of 7-methoxy-2,3-dihydro-1H-inden-1-one (5.0g, 30.86mmol) in anhydrous tetrahydrofuran (20mL) was added dropwise to the reaction flask, and after the addition was complete, the reaction mixture Stir overnight at room temperature. After the reaction was complete, it was quenched by adding water (80 mL), extracted with ethyl acetate (80 mL×3), and the organic phase was washed with saturated brine (60 mL), and dried over anhydrous sodium sulfate. The solvent was...

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Abstract

The invention provides cathepsin K inhibitors and application thereof. The invention relates to compounds used for treating or preventing cathepsin-dependent diseases and pharmaceutical compositions thereof. The compounds and the pharmaceutical compositions containing the compounds can be used as bone resorption inhibitors for treatment of related diseases. Cathepsins in the invention include, but not limited to, cathepsin K.

Description

[0001] field of invention [0002] The invention belongs to the field of pharmacy. The present invention relates to a class of compounds and pharmaceutical compositions thereof for treating or preventing cathepsin-dependent disorders. These compounds and compositions containing these compounds can be used as bone resorption inhibitors to treat related diseases. Background technique [0003] Osteoporosis is a common and frequently-occurring disease among the elderly, especially menopausal and postmenopausal women. With the changes in the spectrum of contemporary diseases, WHO has listed osteoporosis as one of the three major diseases of middle-aged and elderly people, ranking seventh among common diseases. About 50% of women and 20% of men over the age of 50 suffer a fracture caused by osteoporosis. At present, the common drugs for osteoporosis include anti-resorptive drugs, drugs that promote bone formation, dual-action drugs of the former two, biological drugs or other dru...

Claims

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Application Information

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IPC IPC(8): C07D207/27C07C255/46C07C317/32C07D311/04C07D335/06C07D307/82C07D333/66C07D333/62C07D277/76A61K31/402A61K31/277A61K31/382A61K31/352A61K31/343A61K31/381A61K31/428A61P19/10A61P19/00A61P1/02A61P19/02A61P19/08A61P35/00A61P29/00A61P3/14
CPCC07C255/46C07C317/32C07D207/27C07D277/76C07D307/82C07D311/04C07D333/62C07D333/66C07D335/06
Inventor 周平健王晓军阳传文林继华曹生田杨新业张英俊
Owner SUNSHINE LAKE PHARM CO LTD
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