Cathepsin k inhibitors and uses thereof

A compound, an independent technology, applied in anti-inflammatory agents, drug combinations, non-central analgesics, etc.

Active Publication Date: 2021-11-12
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, Merck's odanacatib is progressing rapidly, but it is still in the clinical stage due to some disturbing side effects in clinical research

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

[0217] Example 1N-(1-((1-cyanocyclopropyl)carbamoyl)cyclohexyl)-5-(4-(methylsulfonyl)phenyl)-benzofuran-2-carboxamide

[0218]

[0219] Step 1: Ethyl 5-bromobenzofuran-2-carboxylate

[0220] Add 5-bromo-2-hydroxybenzaldehyde (15g, 74.63mmol), ethyl bromoacetate (18.7g, 111.9mmol), potassium carbonate (31g, 223.9mmol) and anhydrous DMF (80mL) into a 250mL two-necked flask , the reaction mixture was heated to 130° C. for 5 hours to complete the reaction. After filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (50 mL×3), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was subjected to silica gel column chromatography (ethyl acetate:petroleum ether=1:20, V / V) to obtain 16.6 g of light yellow solid with a yield of 83%.

[0221] MS(ESI,pos.ion)m / z:269.9(M+2);

[0222] Step 2: 5-Bromobenzofuran-2...

Embodiment 2

[0235] Example 2N-(1-((1-cyanocyclopropyl)carbamoyl)cyclohexyl)-6-fluoro-5-(4-(methylsulfonyl)phenyl)-benzofuran-2-methyl Amide

[0236]

[0237] Step 1: Ethyl 5-bromo-4-fluorobenzofuran-2-carboxylate

[0238] Add 5-bromo-4-fluoro-2-hydroxybenzaldehyde (16.3g, 74.63mmol), ethyl bromoacetate (18.7g, 111.9mmol), potassium carbonate (31g, 223.9mmol) and no Water DMF (80mL), prepared according to the synthetic method of Example 1 Step 1, the crude product was subjected to silica gel column chromatography (ethyl acetate:petroleum ether=1:20, V / V) to obtain 16.1g of a light yellow solid, the yield 75%.

[0239] MS(ESI,pos.ion)m / z:287.9(M+2);

[0240] Step 2: 5-Bromo-4-fluorobenzofuran-2-carboxylic acid

[0241] Add ethyl 5-bromo-4-fluorobenzofuran-2-carboxylate (4.26g, 14.86mmol), methanol (50mL) and NaOH solution (22.3mL, 44.6mmol) into a 100mL two-necked flask, according to Example 1. Prepared by the synthetic method of step 2. After vacuum drying, 3.46 g of white solid wa...

Embodiment 3

[0250] Example 3 N-(1-((1-cyanocyclopropyl)carbamoyl)cyclohexyl)-5-(2-oxopyrrolidin-1-yl)benzofuran-2-carboxamide

[0251]

[0252] Step 1: Ethyl 5-bromobenzofuran-2-carboxylate

[0253] Add 5-bromo-2-hydroxybenzaldehyde (15g, 74.63mmol), ethyl bromoacetate (18.7g, 111.9mmol), potassium carbonate (31g, 223.9mmol) and anhydrous DMF (80mL) into a 250mL two-necked flask , was prepared according to the synthesis method in Step 1 of Example 1, and the crude product was subjected to silica gel column chromatography (ethyl acetate:petroleum ether=1:20, V / V) to obtain 16.6 g of a light yellow solid with a yield of 83%.

[0254] MS(ESI,pos.ion)m / z:269.9(M+2);

[0255] Step 2: 5-Bromobenzofuran-2-carboxylic acid

[0256] Add ethyl 5-bromobenzofuran-2-carboxylate (4g, 14.86mmol) and methanol (50mL) into a 100mL two-necked flask, then add NaOH solution (22.3mL, 44.6mmol), according to step 2 of Example 1 Prepared by the synthetic method, obtained white solid 3.30g after vacuum dryin...

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Abstract

The present invention relates to cathepsin K inhibitors and uses thereof, specifically a class of compounds (represented by formula (I)) for treating or preventing cathepsin-dependent diseases, including but not limited to cathepsin K inhibitors. The compound and its pharmaceutical composition can be used as a bone resorption inhibitor to treat related diseases.

Description

Background technique [0001] 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 and other drugs, but most of the drugs have relatively large side effects, and new therapeutic drugs are in urgent need. [0002] Cathepsin is the main member of the cysteine ​​protease family. More than 20 species have been found in the biological world, and 11 species mainly exist in the human body. They are closely related to many major diseases such as human tumors, osteopo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/85C07D333/70C07D405/04C07D417/04C07D209/42C07D209/46C07D471/04C07D409/10C07D409/04C07D405/10A61K31/381A61K31/343A61K31/4025A61K31/427A61K31/541A61K31/405A61K31/4035A61K31/437A61K31/4535A61K31/453A61K31/4196A61P19/10A61P19/02A61P29/00A61P19/08A61P1/02A61P3/10A61P35/00A61P17/06A61P11/06A61P9/10A61P3/04A61P3/14A61P21/04A61P37/02
CPCC07D209/42C07D209/46C07D307/85C07D333/70C07D405/04C07D405/10C07D409/04C07D409/10C07D417/04C07D471/04
Inventor 周平健阳传文熊绍辉肖瑛王慧欧阳罗张英俊张健存
Owner SUNSHINE LAKE PHARM CO LTD
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