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Compounds for the treatment of inflammatory disorders and microbial diseases

A compound and disease technology, applied in allergic diseases, metabolic diseases, drug combinations, etc., can solve problems such as lack of mechanical properties of cartilage

Inactive Publication Date: 2009-02-11
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Loss of a C-terminal fragment results in lack of mechanical properties in cartilage

Method used

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  • Compounds for the treatment of inflammatory disorders and microbial diseases
  • Compounds for the treatment of inflammatory disorders and microbial diseases
  • Compounds for the treatment of inflammatory disorders and microbial diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0310]

[0311] Part A:

[0312] To a stirred solution of dimethyl L-tartrate (1) (29.8 g, 136 mmol) in methanol (60 mL) over 30 minutes was added potassium hydroxide (6.9 g, 123 mmol) in water at 0°C (ice bath) (20mL). The reaction mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo, water (40 mL) was added, and the alkaline solution was washed with ether (30 mL x 3). The alkaline solution was acidified to pH 2.0 with 6N HCl, saturated with solid sodium chloride, and the product was extracted into ether (40 mL x 4). It was dried over magnesium sulfate and concentrated to obtain compound 2 (22.2 g, 79% yield) as a colorless oil.

[0313] Part B:

[0314] To compound 2 (1.13g, 5.53mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (3.2 g, 8.3 mmol) To the mixture in DMF (20 mL) was added amine building block (1.2 equivalents) and diisopropylethylamine (2.89 mL, 16.59 mmol). The reaction mixture was sti...

Embodiment 2A

[0321]

[0322] Part A:

[0323] To 4-iodoaniline (8) (440mg, 2mmol), copper iodide (7.6mg, 0.04mmol) and dichlorobis (triphenylphosphine) palladium (II) (14mg, 0.02mmol) in THF (5mL) Phenylacetylene (244.8 mg, 2.4 mmol) and triethylamine (556 μL, 4 mmol) were added to the mixture. The reactor was purged with argon, and the reaction mixture was stirred at room temperature for 16 hours. LC-MS analysis of the reaction showed that the reaction was complete. Ethyl acetate (5 mL) was added, and the precipitate was removed by passing through a celite column. The filtrate was concentrated, and the crude product was purified by flash column chromatography (SiO 2 , 6% ethyl acetate / hexane) to obtain compound 9 as a brown solid (321 mg, 82% yield). HPLC-MSt R =1.88min(UV 254nm ); The following formula quality calculation value C 14 H 11 N 193.1, found LCMS m / z 194.1 (M+H).

Embodiment 2B

[0325]

[0326] Part A:

[0327] Compound 11 was prepared from 5-iodoindole (10) using the Sonogashira coupling conditions described in Example 2A, Part A. HPLC-MS t R =2.06min(UV 254nm ); The following formula quality calculation value C 16 H 11 N 217.1, found LCMS m / z 218.1 (M+H).

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Abstract

This invention relates to compounds of the Formulae (I)-(IX), or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, aggrecanase, ADMP, LpxC, ADAMs, TACE, TNF-a or combinations thereof.

Description

Invention field [0001] The present invention generally relates to tartaric acid functional compounds, which can inhibit matrix metalloproteinases (MMPs), disaggregates and metalloproteinases (ADAMs), aggrecanase (aggrecanase) or aggrecan degrading metalloproteinases (ADMP) and / Or Tumor necrosis factor alpha-converting enzyme (TACE), which can prevent the release of tumor necrosis factor alpha (TNF-α) when exerting this effect; relates to pharmaceutical compositions containing these compounds and treatments using these compounds method. The present invention also relates to a tartaric acid functional compound, which can inhibit UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) and therefore has antimicrobial activity. Background of the invention [0002] Bone and rheumatoid arthritis (OA and RA, respectively) are destructive diseases of articular cartilage, characterized by local erosion of the cartilage surface. Some findings have shown that articular cartil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/06A61K31/16C07D209/08C07D211/16C07D211/18C07D211/52C07D215/08C07D215/14C07D217/06C07D295/18C07D401/06C07D403/06C07C235/06C07C235/12
CPCC07D295/185C07D401/06C07C235/16C07D209/08C07D217/06C07D207/06C07C235/06C07D211/16C07D215/14C07D211/52C07D215/08C07D211/18C07C235/12C07D403/06A61P1/02A61P1/04A61P1/16A61P11/00A61P11/02A61P11/06A61P13/12A61P17/04A61P17/06A61P19/00A61P19/02A61P19/10A61P21/00A61P25/00A61P25/32A61P27/02A61P29/00A61P31/00A61P31/04A61P31/10A61P31/12A61P31/18A61P33/06A61P35/00A61P37/00A61P37/06A61P37/08A61P43/00A61P7/00A61P7/02A61P9/10A61P3/10
Inventor M·A·西迪昆U·F·梅瑟P·A·兰迪V·S·麦迪森
Owner SCHERING AG
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