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N-hydroxyamide derivatives and use thereof

A technology of hydroxyamides and derivatives, which is applied in the field of N-hydroxyamide derivatives and their applications, and can solve the problems of dose-limiting side effects and the like

Inactive Publication Date: 2008-06-25
MERCK SERONO SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many MMPIs present with musculoskeletal syndromes (tendonitis, fibroplasia, mylasia, arthralgia), which is a dose-limiting side effect

Method used

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  • N-hydroxyamide derivatives and use thereof
  • N-hydroxyamide derivatives and use thereof
  • N-hydroxyamide derivatives and use thereof

Examples

Experimental program
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preparation example Construction

[0154] In another specific embodiment, the present invention provides the preparation method of N-hydroxyl amide derivative of the present invention, comprises making formula (IV) compound and H 2 NO-R 8 Steps in the derivative reaction:

[0155]

[0156] where A, R 1 , R 2 , R 4 , R 5 , R 6 and R 7 As defined above, R 8 selected from H and a protecting group such as tert-butyl, benzyl, trialkylsilyl, tetrahydropyranyl.

[0157] In yet another specific embodiment, the present invention provides the preparation method of N-hydroxyamide derivatives of the present invention, optionally further comprising a deprotection step (when R 8 When not H, remove R 8 ).

[0158] In another specific embodiment, the present invention provides compounds represented by formula (IV):

[0159]

[0160] where A, R 1 , R 2 , R 4 , R 5 , R 6 and R 7 as defined above.

[0161] In yet another specific embodiment, the present invention provides a compound of formula (IV) selecte...

Embodiment 1

[0244] Example 1: (2R)-4-[4-(4-fluorophenyl)piperazin-1-yl]-N,2-dihydroxy-4-oxobutanamide (1)

[0245]

[0246] Step a) generates (5R)-5-{2-[4-(4-fluorophenyl)piperazin 1-yl]-2-oxoethyl}-2,2-dimethyl-1,3-di Oxolane-4-one

[0247]

[0248]HOBt (2.97 g; 22.0 mmol; 1.1 eq.) was added to [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (3.48 g; 20.0 mmol; 1.0 eq.), TEA (6.07 g; 60.0 mmol; 3.0 eq.) in DCM (60 mL), and the mixture was cooled to 0 °C. EDC (4.6 g; 24.0 mmol; 1.2 eq.) was then added and the resulting reaction mixture was stirred at 0° C. for 15 minutes. 1-(4-Fluorophenyl)piperazine dihydrochloride (5.57 g; 22.0 mmol; 1.1 eq.) was added and the resulting reaction mixture was stirred at room temperature overnight. Purification by flash chromatography (AcOEt / c-Hex: 50 / 50) afforded the title compound as a colorless oil (5.12 g, 76%). m + (ESI): 337.2. HPLC (Condition A): Rt: 2.5 min (HPLC purity: 97.4%).

[0249] Step b) generates (2R)-4-[4-(4-fluorophe...

Embodiment 2

[0251] Example 2: (2S)-4-[4-(4-fluorophenyl)piperazin-1-yl]-N,2-dihydroxy-4-oxobutanamide (2)

[0252]

[0253] Step a) generates (5S)-5-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}-2,2-dimethyl-1,3- Dioxolan-4-one

[0254]

[0255] The title product was prepared following the procedure of Preparative Example 1 (step a), but starting from [(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (300 mg ; 1.72 mmol; 1.0 eq.), the title compound was obtained as a white foam (350 mg, 60%). m + (ESI): 337.1. 1 H NMR (CDCl 3 , 300 MHz) δ7.12-6.83(m, 4H), 4.94(dd, J=3.0Hz, J=7.5Hz, 1H), 3.90-3.68(m, 2H), 3.70-3.57(m, 2H), 3.19-3.08(m, 4H), 3.05(dd, J=3.0Hz, J=16.6Hz, 1H), 2.85(dd, J=7.5Hz, J=16.6Hz, 1H), 1.68(s, 3H), 1.63 (s, 3H). HPLC (condition A): Rt: 2.6 min (HPLC purity: 96.9%).

[0256] Step b) generates (2S)-4-[4-(4-fluorophenyl)piperazin-1-yl]-N,2-dihydroxy-4-oxobutyramide (2)

[0257] The title product was prepared following the procedure of Preparative E...

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Abstract

The present invention relates to N-hydroxyamide derivatives represented by formula (I) and their use in the treatment and / or prevention of autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, cancer, respiratory diseases and fibrosis ( Including applications in multiple sclerosis, arthritis, emphysema, chronic obstructive pulmonary disease, liver and pulmonary fibrosis).

Description

technical field [0001] The present invention relates to N-hydroxyamide derivatives shown in formula (I), their pharmaceutical compositions, their preparation methods and their usefulness in the treatment and / or prevention of autoimmune diseases and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases Uses in Disease, Cancer, Respiratory Disease and Fibrosis. In particular, the present invention relates to N-hydroxyamide derivatives useful for modulating, especially inhibiting, the activity or function of matrix metalloproteases, especially gelatinases and metalloelastases. Background technique [0002] Metalloproteases belong to the superfamily of proteases (enzymes) and are named for their dependence on a metal ion (zinc) at the active site. [0003] Matrix metalloproteinases (MMPs) form a subfamily of metalloproteases, one of their main biological functions is through the ability to hydrolyze various components of tissues or matrices, such as coll...

Claims

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Application Information

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IPC IPC(8): C07D295/18C07D317/34A61K31/495A61P29/00
CPCC07D295/185C07D317/34A61P1/00A61P1/02A61P1/16A61P1/18A61P11/00A61P11/06A61P11/16A61P13/00A61P17/00A61P19/02A61P19/08A61P21/04A61P25/00A61P25/28A61P27/02A61P29/00A61P35/00A61P43/00A61P9/00A61P9/08A61P9/10A61P9/12A61P9/14C07D295/18A61K31/495
Inventor D·斯维能J·冈萨雷斯
Owner MERCK SERONO SA
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