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Cathepsin k inhibitors and uses thereof

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

Active Publication Date: 2020-10-09
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 uses thereof
  • Cathepsin k inhibitors and uses thereof
  • Cathepsin k inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0198] (S)-N-(1-cyanocyclopropyl)-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4'-((E)-2 -(oximino)piperidin-1-yl)-[1,1'-biphenyl]-4-yl)ethyl)amino)pentanamide

[0199]

[0200] Step 1: 1-(4-Bromophenyl)piperidin-2-one

[0201] Add 1-bromo-4-iodobenzene (500mg, 1.77mmol), 2-piperidone (175mg, 1.77mmol), potassium phosphate (0.75g, 3.54mmol), cuprous iodide in a pressure-resistant glass test tube (17mg, 0.09mmol) and anhydrous toluene (10mL), added N,N'-dimethylethylenediamine (8.0mg, 0.09mmol) 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 brine (10 mL), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V)=5 / 1) to obtain a ...

Embodiment 2

[0212] (S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4'-(( E)-2-(oximino)-piperidin-1-yl)-[1,1'-biphenyl]-4-yl)ethyl)amino)pentanamide

[0213]

[0214] Referring to the method of step 4 of Example 1, with (E)-1-(4-bromophenyl)piperidin-2-one oxime (69mg, 0.26mmol), (S)-N-(1-cyanocyclopropyl )-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4-(4,4,5,5-tetramethyl-1,3, Starting from 2-dioxaborolan-2-yl)phenyl)ethyl)amino)pentanamide (128mg, 0.26mmol), a white solid (89mg, 62%) was prepared.

[0215] MS(ESI,pos.ion)m / z:560.3(M+1);

[0216] 1 H NMR (400MHz, CDCl3 )δ (ppm) 7.65 (dd, J = 12.8, 8.3Hz, 4H), 7.44 (d, J = 8.1Hz, 3H), 7.30 (d, J = 8.5Hz, 2H), 5.37 (s, 1H), 4.20–4.02(m,1H),3.72(t,J=5.5Hz,2H),3.63(d,J=8.9Hz,1H),3.05(t,J=6.2Hz,3H),2.08–1.96(m ,4H),1.54–1.40(m,6H),1.10–0.98(m,2H),0.95-0.89(m,4H).

Embodiment 3

[0218] (S)-N-(1-cyanocyclopropyl)-2-(((S)-1-(4'-((E)-2-(cyanoimino)piperidin-1-yl) -[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethyl)amino)-4-fluoro-4-methylpentanamide

[0219]

[0220] Step 1: 1-(4-Bromophenyl)-6-(methylthio)-2,3,4,5-tetrahydropyridine iodide

[0221] Add acetonitrile (5mL) and 1-(4-bromophenyl)piperidine-2-thione (0.26g, 0.96mmol) in a two-necked flask, then add iodomethane (0.24mL, 3.85mmol), and stir at room temperature for 2 After one hour, it was diluted with diethyl ether, filtered with suction, and the solid was rinsed with diethyl ether, and dried to obtain a white solid (0.32 g, 82%). MS(ESI,pos.ion)m / z:286.0(M+2).

[0222] Step 2: (E)-N-(1-(4-bromophenyl)piperidin-2-ylidene)cyanamide

[0223] Add 1-(4-bromophenyl)-6-(methylthio)-2,3,4,5-tetrahydropyridine iodide (0.32g, 0.77mmol), cyanamide (0.26g, 6.21mmol), acetonitrile (8mL) and triethylamine (0.21mL, 1.55mmol), the reaction mixture was heated to 85°C and stirred for 15 hours. Cool to room tem...

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Abstract

The invention relates to compounds and pharmaceutical compositions thereof for treatment or prevention of cathepsin dependent diseases; the compounds and the compositions comprising the compounds can be used as bone absorption inhibitors for treatment of related diseases, wherein the cathepsin includes, but is 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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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/72C07D207/22C07D207/27C07D211/76C07D233/20C07D233/36C07D211/74C07D205/04C07C261/00C07C255/46A61K31/4402A61K31/4412A61K31/4168A61K31/402A61K31/397A61K31/277A61P19/10A61P19/08A61P19/02A61P1/02A61P3/14A61P35/00A61P25/28A61P21/04A61P17/06A61P17/10A61P5/14A61P37/06A61P29/00A61P11/06A61P9/10A61P3/04A61P35/04
CPCC07C255/46C07C261/00C07D205/04C07D207/22C07D207/27C07D211/72C07D211/74C07D211/76C07D233/20C07D233/36
Inventor 周平健阳传文林继华王晓军劳锦花薛亚萍曹生田吴方园张英俊
Owner SUNSHINE LAKE PHARM CO LTD
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