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Pyridyl and phenyl substituted piperazine-piperidines with CXCR3 antagonist activity

A technology of R30 and R31, which is applied in the fields of antagonists and known immunity, and can solve problems such as undetected

Inactive Publication Date: 2008-07-02
SCHERING AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The human receptor is highly expressed in IL-2-activated T lymphocytes but not detected in resting T lymphocytes, monocytes, or granulocytes (Qin, S. et al., J. Clin. Invest. 101:746- 754 (1998)

Method used

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  • Pyridyl and phenyl substituted piperazine-piperidines with CXCR3 antagonist activity
  • Pyridyl and phenyl substituted piperazine-piperidines with CXCR3 antagonist activity
  • Pyridyl and phenyl substituted piperazine-piperidines with CXCR3 antagonist activity

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Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0487]

[0488] To a round bottom flask was added 5,6-dichloronicotinic acid (30 g, 156 mmol), ethylamine HCl salt (14 g, 170 mmol), dimethylformamide (300 ml), dichloromethane (100 ml), triethylamine ( 26.1 ml, 187 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (32.9 g, 170 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate (500 mL) and washed with 1N HCl (2x), saturated aqueous sodium bicarbonate (1x), brine (1x), dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to give the desired 5,6-dichloro-N-ethyl-nicotinamide 2 (29 g, 85%). MS: M+H=219.

preparation Embodiment 2

[0490]

[0491] To a round bottom flask was added 5,6-dichloro-N-ethyl-nicotinamide (0.200 g, 1.3 mmol), Boc-2-(S)-ethyl-5-(R)-methyl-piperazine (0.200mg, 0.88mmol), potassium carbonate (1.2g, 8.8mmol) and dimethylformamide (5ml). The mixture was stirred overnight at 90°C. After filtration, the solvent was removed in vacuo and the residue was purified by flash chromatography to give the desired product 3 (0.172 g, 48%). MS: M+H=411.

preparation Embodiment 3

[0492] Preparation Example 3. Preparation of Compound No. 214 of Table 1

[0493]

[0494] Add intermediate to round bottom flask 3 (0.050 g, 0.161 mmol), dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The mixture was stirred for 1 hour and the volatiles were removed in vacuo. Triethylamine (0.1 ml) and dichloromethane (1 mL) were added to the crude material to neutralize the TFA salt. Volatiles were removed in vacuo. To the residue was added 1-(4-chloro-benzyl)-piperidin-4-one (0.036 g, 0.32 mmol) and 3% acetic acid / dichloroethane. Add NaBH(OAc) 3 (0.102 g, 0.48 mmol), the mixture was stirred overnight at room temperature. After routine work-up, the crude product was purified by preparative HPLC to afford the desired compound 4 (0.030 g, 36%). MS: M+H=518.

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PUM

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Abstract

The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having the general structure shown in Formula 1: and the pharmaceutically acceptable salts, solvates and esters thereof. Also disclosed is a method of treating chemokine mediated diseases, such as, palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non limiting example(s) include, psoriasis), autoimmune diseases (non limiting example(s) include, rheumatoid arthritis, multiple sclerosis), graft rejection (non limiting example(s) include, allograft rejection, xenograft rejection), infectious diseases (e.g , tuberculoid leprosy), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, ophthalmic inflammation, type I diabetes, viral meningitis and tumors using a compound of Formula 1.

Description

field of invention [0001] The present invention relates to novel pyridyl and phenyl substituted piperazine-piperidines having CXCR3 antagonistic activity, one or more compounds containing one or more such antagonists in combination with other compounds having chemokine activity Pharmaceutical combinations of two such antagonists, one or more such antagonists in combination with known immunosuppressants (non-limiting examples include methotrexate, interferon, cyclosporine, FK-506 and FTY720) substances, methods of making such antagonists and methods of modulating CXCR3 activity using such antagonists. The present invention also discloses methods of treating diseases and conditions in which CXCR3 is associated (non-limiting examples include palliative, curative and prophylactic therapies) using such CXCR3 antagonists. Diseases and symptoms related to CXCR3 include (but are not limited to) inflammatory diseases (psoriasis and inflammatory bowel disease), autoimmune diseases (mul...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D401/14C07D211/58C07D405/14C07D413/14C07D417/14A61K31/445A61K31/495
CPCC07D401/14C07D401/12C07D417/14C07D211/58C07D413/14C07D405/14A61P1/04A61P17/06A61P19/02A61P25/00A61P27/02A61P29/00A61P37/00A61P37/06A61P43/00A61K31/445
Inventor B·F·麦可格恩尼思S·B·罗森布朗J·A·寇兹罗斯基G·N亚倪尔库马金松宏石南洋简钟荷P·J·柴夫德尼D·W·哈布斯董贵岑邵月飞L·G·扎娃琪C·杨C·D·卡罗
Owner SCHERING AG
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