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Novel heterocyclic substituted pyridine or phenyl compounds with CXCR3 antagonist activity

A compound, heterocyclic group technology, applied in the field of new heterocyclic substituted pyridine or phenyl compounds with CXCR3 antagonist activity, can solve the problems of not identifying the receptor, not showing the effect, etc.

Inactive Publication Date: 2008-03-19
SCHERING AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although IP-10 has been reported to induce monocyte chemotaxis in vitro (Taub, D.D. et al., J. Exp. Med., 177:1809-1814 (1993), no functional receptor has been identified, Human Mig and I-TAC appear to be highly selective, but no such effect has been shown (Liao, F. et al., J. Exp. Med., 182:1301-1314 (1995); Cole, K.E. et al., J. Exp. Med., 187: 2009-2021 (1998))

Method used

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  • Novel heterocyclic substituted pyridine or phenyl compounds with CXCR3 antagonist activity
  • Novel heterocyclic substituted pyridine or phenyl compounds with CXCR3 antagonist activity
  • Novel heterocyclic substituted pyridine or phenyl compounds with CXCR3 antagonist activity

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0461] Preparation Example 1. EN=CO 2 PR 1 =CO 2 CH 3

[0462]

[0463] 2,3-Dichloropyridine 5-carboxylate methyl ester (5,6-dichloronicotinic acid methyl ester, BIONET) was prepared from 5,6-dichloronicotinic acid (ALDRICH): by using excess SOCl 2 Work-up and reflux for 1.5 hours converted the acid to the acid halide followed by methylation in near quantitative yield in methanol / pyridine as solvent. Ref. Musso et al., Bioorg. Med. Chem. Lett., 1997, 7, 1-6.

[0464] The round bottom flask was loaded with methyl 2,3-dichloropyridine 5-carboxylate 1 (7 g, 34 mmol), 2-S-ethylpiperazine (as prepared by Williams et al. J. Med. Chem 1996, 39, 1345) (75% active, 5.2g, 34mmol), cesium carbonate (12.15g, 68mmol), DBPD (0.74g, 2.48mmol), palladium acetate (0.55g, 2.48mmol) and 1,4 dioxane (170ml). The flask was equipped with a reflux condenser and heated to 80 °C. After 36 hours, the reaction was cooled, diluted with dichloromethane (-200ml) and washed with water (2x50ml). T...

preparation Embodiment 2

[0465] Preparative Example 2. EN = Nitrile

[0466]

[0467] 2,3-Dichloro5-cyanopyridine 4 was prepared from 5,6-dichloronicotinic acid (ALDRICH). by using excess SOCl 2 Work-up and reflux for 1.5 hours converted the acid to the acid halide. Reaction of the intermediate acid chloride with ammonia (aq) affords the primary amide, which is treated with excess SOCl at reflux 2 Dehydration was carried out to obtain 2,3-dichloro-5-cyanopyridine 4. [Ref George et al. J.Org.Chem, 1979, 44, 2697.]

[0468]The round bottom flask was loaded with 2,3-dichloro5-cyanopyridine 4 (20 g, 95.5 mmol), 2-S-ethylpiperazine (as prepared by Williams et al. J. Med. Chem 1996, 39, 1345) (80% active, 13.7g, 95.5mmol), cesium carbonate (62.2g, 191mmol), DBPD (2.07g, 6.97mmol), palladium acetate (1.56g, 6.97mmol) and 1,4 dioxane (475ml). The flask was equipped with a reflux condenser and heated to 80°C under nitrogen. After 48 hours, the reaction was cooled, diluted with dichloromethane (-200ml) ...

preparation Embodiment 3

[0470] Preparative Example 3. EN = Nitrile

[0471]

[0472] The flask was loaded with 5 (16.3 g, 65.2 mmol), N-Boc piperidin-4-one (16.88 g, 84.76 mmol) and 1,2-dichloroethane (170 ml) and stirred at 60° C. for 20 minutes. Add reducing agent NaB(OAc) slowly under stirring 3 H (1.5 equiv). The resulting suspension was stirred at 60° C. for 3 days, then treated with saturated sodium bicarbonate solution to pH=13, extracted with dichloromethane and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using 1.5% then 5.0% methanol in dichloromethane as eluent to afford 7 (25.1 g, 89%). MS: m / e, M+H=434.

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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 or a pharmaceutically acceptable salt, solvate or ester 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, zenograft 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 heterocyclic substituted piperazine compounds having CXCR3 antagonist activity, pharmaceutical compositions containing one or more such antagonists, one or more compounds in combination with other compounds having chemokine activity A plurality of such antagonists, one or more of such antagonists in combination with known immunosuppressants - non-limiting examples include methotrexate, interferon, cyclosporine, FK-506 and FTY720, Methods of making such antagonists and methods of modulating CXCR3 activity using such antagonists. Also disclosed are methods of using such CXCR3 antagonists to treat (non-limiting examples include ameliorating, curative and preventive treatments) diseases or conditions implicated in CXCR3. Diseases or conditions implicated in CXCR3 include, but are not limited to, inflammatory disorders (psoriasis and inflammatory bowel disease), autoimmune diseases (multiple sclerosis, rheumatoid art...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D413/14C07D417/14A61K31/497A61P31/00A61P29/00
CPCC07D401/14C07D413/14C07D417/14C07D401/04A61P1/00A61P17/00A61P17/06A61P19/02A61P25/00A61P27/02A61P29/00A61P31/00A61P35/00A61P37/02A61P43/00A61P3/10A61K31/497
Inventor G·N·亚倪尔库马曾逵秉S·B·罗森布朗J·A·寇兹罗斯基B·F·麦克格恩尼思D·W·哈布斯
Owner SCHERING AG
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