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Hydroxy-ethylene derivatives for the treatment of arthrosis

A technology of derivatives and groups, applied in the field of hydroxyethylene derivatives for the treatment of joint diseases, can solve problems such as low stability, and achieve the effects of high selectivity, good stability and less side effects

Inactive Publication Date: 2016-01-20
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, peptidic compounds in particular have low stability and are therefore not considered for oral or systemic administration

Method used

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  • Hydroxy-ethylene derivatives for the treatment of arthrosis
  • Hydroxy-ethylene derivatives for the treatment of arthrosis
  • Hydroxy-ethylene derivatives for the treatment of arthrosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0249] Example 1: Exemplary Compounds of Formula I

[0250] Table 2

[0251] The following compounds are according to the invention

[0252] Table 2a

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] Table 2b

[0260] compound Total MW Cath D IC 50 [nM] Renin IC 50 [nM] retention time [min] method M+H A1 768.9946 4.30E-07 3.20E-07 2.17 polar coordinate method 769.5 A2 761.9953 4.10E-08 1.10E-06 2.72 polar coordinate method 762.5 A3 627.7

> 30μM 2.47 polar coordinate method 628.3 A4 657.7258 4.00E-06 > 30μM 2.50 polar coordinate method 658.3 A5 603.7555

> 30μM 2.15 polar coordinate method 604.3 A6 635.8005 1.20E-05 > 30μM 2.53 polar coordinate method 636.3 A7 573.7297

> 30μM 2.25 polar coordinate method 574.3 A8 573.7297

> 30μM 2.26 polar coordinate method 574.3 A9 573.7297

> 30μM 2.30 polar coordinate m...

Embodiment 2

[0272] Embodiment 2: prepare formula I compound of the present invention

[0273] The compounds of the invention can be prepared, for example, by the following synthetic sequences in a manner known to those skilled in the art. The given examples describe syntheses, but the invention is not limited to these examples.

[0274] Composition order:

[0275]

[0276] Starting from the doubly protected structure A-2 obtained by hydrolysis of A1, the corresponding amine, amino acid derivative, dipeptide or tripeptide (usually C -end-protected) to form new peptide bonds.

[0277] In a second step, the BOC protecting group and acetal are cleaved under suitable conditions (for example by HCl / dioxane or TFA / DCM) and the obtained structure is combined with the corresponding acid, amino acid derivative, dipeptide or tripeptide Peptide coupling (usually N-terminally protected respectively). Coupling reagents suitable for suppressing racemization, such as HATU or similar reagents, ar...

Embodiment 3

[0283] Example 3: Preparation of (4S,5S)-4-benzyl-5-(2-carboxyethyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester:

[0284]

[0285] Dissolve (S)-tert-butyl 4-benzyl-5-(2-cyanoethyl)-2,2-dimethyloxazolidine-3-carboxylate (30.0 g; 87 mmol; 100.00 mol%) In 300 ml of methanol, and potassium hydroxide (300 ml, 40% solution in water) was added. The reaction mixture was refluxed until the nitrile was completely hydrolyzed. The acidity was then adjusted with citric acid solution (1.5 equivalents based on KOH) with cooling. The aqueous phase is extracted three times with dichloromethane, the combined organic phases are washed neutral with NaCl solution, dried and freed from the solvent. 25.3 g of (4S,5S)-4-benzyl-5-(2-carboxyethyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester were thus obtained as an oil (yield 73.5%, content ~92%).

[0286] Chromatography on silica gel (eluent: DCM / methanol) from 5.0 g of crude product gave 4.6 g of an oil. MS-FAB(...

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PUM

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Abstract

The invention relates to compositions of formula (I), and in particular medications containing at least one composition of formula (I), for use in the treatment and / or prophylaxis of physiological and / or pathophysiological conditions triggered in part by cathepsin D, in particular for use in the treatment and / or prophylaxis of arthrosis, traumatic cartilage injuries, arthritis, pain, allodynia, or hyperalgesia.

Description

[0001] The present invention relates to the use in the treatment and / or prevention of physiological and / or pathophysiological states in which the release of cathepsin D is involved, in particular in the treatment and / or prevention of arthropathy, traumatic cartilage damage, arthritis, pain, abnormalities Compounds of formula I for pain or hyperalgesia, especially to medicaments comprising at least one compound of formula I. Background of the invention [0002] Arthropathy is the most widely distributed joint disease in the world, and the radiological signs of arthrosis are seen in most people over 65 years old. Despite its importance for the healthcare system, the cause of joint disease remains unclear to date, and effective preventive measures remain a distant goal. Decreased joint space (caused by destruction of articular cartilage) with changes in subchondral bone and spur formation are the radiographic hallmarks of the disease. For patients, however, it is primarily pain ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C235/08A61K38/08
CPCC07K7/02C07K5/0207A61K38/06A61K38/07A61K38/08A61P13/08A61P15/00A61P17/02A61P17/06A61P19/02A61P19/08A61P25/02A61P25/04A61P25/14A61P25/16A61P25/28A61P29/00A61P35/00A61P3/06A61P37/02A61P37/04A61P37/06A61P37/08A61P43/00C07C231/12A61K9/0019
Inventor M.克莱因
Owner MERCK PATENT GMBH
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