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Heterocyclic compounds with cxcr3 antagonist activity

A compound, R30 technology, applied in the direction of organic active ingredients, sexual diseases, anti-inflammatory agents, etc., can solve problems such as unshown

Inactive Publication Date: 2009-11-18
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 chemotaxis of monocytes in vitro (Taub, D.D. et al., J. Exp. Med., 177:1809-1814 (1993), relevant receptors have not yet been identified), human Mig and I-TAC appear to be highly selective and did not demonstrate this effect (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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  • Heterocyclic compounds with cxcr3 antagonist activity
  • Heterocyclic compounds with cxcr3 antagonist activity
  • Heterocyclic compounds with cxcr3 antagonist activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0440] Embodiment 1, step A, method A and method B

[0441]

[0442] A 500ml round bottom flask was charged with methyl 2-aminopyridine 3-carboxamide 1 (4.5g, 29.76mmol) and 1,2-dichloroethane (150ml). The resulting solution was cooled to -40°C while slowly adding triphosgene (7 g, 23.59 mmol). Triethylamine (4.4 g, 43.48 mmol) was then added dropwise via a syringe at this temperature. The reaction mixture was stirred at -40°C for two hours, then gradually warmed to room temperature and kept at this temperature overnight. The suspension was treated with water (100ml) and saturated sodium carbonate (100ml) and separated. The aqueous solution was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and dried on a rotary evaporator. The residue was dried under housevacuam to give a dark brown solid (4.1 g). This material was mixed with phosphorus oxychloride (50ml) in a 250ml flask. The resulting suspension was refluxed for 4 hours. ...

Embodiment 2

[0443] Embodiment 2, step B, method A and method B

[0444]

[0445] A round bottom flask was charged with crude material 2 (1.4 g, about 7 mmol), 2-S-ethylpiperazine (prepared according to Williams et al., J. Med. Chem 1996, 39, 1345; 80% active, 1.6 g, about 11 mmol), cesium carbonate (4.2 g, 12.9 mmol) and 1,4-dioxane (40 ml). The resulting suspension was stirred at room temperature for 5 days, diluted with dichloromethane (ca. 200 ml) and filtered through celite. The filtrate was washed once with water and then concentrated to an oil. The crude product was purified by silica gel chromatography using methanol / dichloromethane eluent (5% to 10% MeOH) to afford 0.7 g (9% based on compound 1) of the title compound.

Embodiment 3

[0446] Example 3. Step D, Method A

[0447]

[0448] Charge 4 (0.77g, 2.56mmol), 5 (1.4g, 7.03mmol), sodium triacetoxyborohydride (1.4g, 6.6mmol) and 1,2-dichloroethane into a 250ml round bottom flask (100ml). The resulting suspension was stirred at room temperature for 5 days and then quenched with 1.0 M sodium hydroxide solution. After separation, the aqueous solution was extracted with dichloromethane. The combined organic solutions were dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel using 5% methanol in dichloromethane as eluent afforded the title compound (0.25 g, 21%) as a gel.

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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 Formula 5: [Chemical formulas should be inserted here as they appear on abstract in paper form.] 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

technical field [0001] The present invention relates to heterocyclic compounds having CXCR3 antagonistic activity, comprising one or more such antagonists, one or more such antagonists in combination with other compounds having chemokine activity, one or more such antagonists in combination with Pharmaceutical compositions of such antagonists in combination with known immunosuppressants (non-limiting examples include methotrexate (methotrexate), interferon, cyclosporine, FK-506 and FTY720), preparation of such antagonists Methods and methods of using such antagonists to modulate CXCR3 activity. Also disclosed are methods of using such CXCR3 antagonists to treat (non-limiting examples include palliative, curative and preventive therapies) diseases and conditions involving CXCR3. Diseases and conditions involving CXCR3 include (but are not limited to) inflammatory conditions (psoriasis and inflammatory bowel disease), autoimmune diseases (multiple sclerosis, rheumatoid arthriti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/495A61P29/00
CPCC07D401/14A61P1/04A61P1/16A61P3/10A61P9/00A61P9/04A61P9/10A61P11/00A61P11/02A61P11/06A61P13/12A61P15/00A61P17/00A61P17/06A61P17/08A61P19/02A61P19/06A61P25/00A61P25/28A61P27/02A61P27/16A61P29/00A61P31/04A61P31/12A61P35/00A61P37/00A61P37/06A61P43/00
Inventor Q·曾S·B·罗珊伯伦J·A·克斯洛斯基石南阳B·F·麦可吉尼斯D·W·贺伯斯
Owner SCHERING AG
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