Substituted heterocyclic compounds with cxcr3 antagonist activity

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, wherein the various moieties are defined herein. 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, type I diabetes, viral meningitis and tumors using a compound of Formula (1).

Description

field of invention

[0001] The present invention relates to substituted heterocyclic compounds having CXCR3 antagonist activity; pharmaceutical compositions containing 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 a known immunosuppressant (one or more non-limiting examples include methotrexate, interferon, cyclosporine, FK-506, and FTY720); making this Antagonist-like methods and methods of modulating CXCR3 activity with such antagonists. Also disclosed are methods of treating diseases and disorders involving CXCR3, non-limiting examples including palliative, curative and prophylactic therapies, with such CXCR3 antagonists. Diseases and conditions in which CXCR3 is implicated include, but are not limited to, inflammation (psoriasis and inflammatory bowel disease), autoimmune disease (multiple sclerosis, rheumatoid arthritis), fixed drug eruptions, skin d...

Examples

Embodiment 1

[0352] Example 1: Step A - Method A

[0353]

[0354] 6-Amino 2,3-dichloropyrazine 5-methyl carboxylate (Aldrich, 25 g, 112.6 mmol), 2-S-ethylpiperazine (according to Williams et al J.Med.Chem 1996 , 39, prepared as described in 1345, 83% active, 15.7 g, 112.7 mmol), cesium carbonate (100 g, 300 mmol) and 1,4 dioxane (400 mL). A reflux condenser was installed on the flask and heated to 80°C. After 12 hours, the reaction was cooled and washed with CH 2 Cl 2 (~200 mL) and filter through celite. The filtrate was washed once with water, then concentrated to an oil. The crude product was subjected to silica gel column chromatography (3%-10% MeOH / CH 2 Cl 2 ) to obtain compound A3 (30.8 g, 91%).

[0355] MS: M+H=300

Embodiment 2

[0356] Example 2: Step A' - Method A

[0357]

[0358] A3 (19 g, 63 mmol) and triethylamine (26 mL, 189 mmol) in CH 2 Cl 2 (300 mL) solution was treated with trifluoroacetic anhydride (13 mL, 94 mmol). The reaction mixture was stirred at 0°C-25°C for 16 hours. The reaction mixture was washed with NaHCO 3 Aqueous work-up and stirring at 25°C for an additional 10 hours. The organic layer was washed with CH 2 Cl 2 Extraction, the combined organic liquid was washed with brine, dried (Na 2 SO 4 ), concentrated in vacuo. Crude product A4 (24.9 g, 100%) was pure enough to be used in the next step without further purification.

[0359] MS: M+H=396

Embodiment 3

[0360] Example 3: Step B - Method A

[0361]

[0362] A suspension of A4 (3.09 g, 7.8 mmol) in cold THF (78 mL) was washed with 50% H 2 SO 4 Aqueous solution (5 mL) was treated with tert-butyl nitrite (5 mL). The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was added to CH 2 Cl 2 and NaHCO 3 A mixture of aqueous solutions. The mixture was stirred for 0.5 h, and the organic layer was washed with CH 2 Cl 2 extraction. The combined organic solutions were washed with brine solution and dried (Na 2 SO 4 ), concentrated in vacuo. The crude product of formula B1 (3 g, 95%) was used in the next step without further purification.

[0363] MS: M+H=395

field of invention

[0001] The present invention relates to substituted heterocyclic compounds having CXCR3 antagonist activity; pharmaceutical compositions containing 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 a known immunosuppressant (one or more non-limiting examples include methotrexate, interferon, cyclosporine, FK-506, and FTY720); making this Antagonist-like methods and methods of modulating CXCR3 activity with such antagonists. Also disclosed are methods of treating diseases and disorders involving CXCR3, non-limiting examples including palliative, curative and prophylactic therapies, with such CXCR3 antagonists. Diseases and conditions in which CXCR3 is implicated include, but are not limited to, inflammation (psoriasis and inflammatory bowel disease), autoimmune disease (multiple sclerosis, rheumatoid arthritis), fixed drug eruptions, skin d...

Examples

Embodiment 1

[0352] Example 1: Step A - Method A

[0353]

[0354] 6-Amino 2,3-dichloropyrazine 5-methyl carboxylate (Aldrich, 25 g, 112.6 mmol), 2-S-ethylpiperazine (according to Williams et al J.Med.Chem 1996 , 39, prepared as described in 1345, 83% active, 15.7 g, 112.7 mmol), cesium carbonate (100 g, 300 mmol) and 1,4 dioxane (400 mL). A reflux condenser was installed on the flask and heated to 80°C. After 12 hours, the reaction was cooled and washed with CH 2 Cl 2 (~200 mL) and filter through celite. The filtrate was washed once with water, then concentrated to an oil. The crude product was subjected to silica gel column chromatography (3%-10% MeOH / CH 2 Cl 2 ) to obtain compound A3 (30.8 g, 91%).

[0355] MS: M+H=300

Embodiment 2

[0356] Example 2: Step A' - Method A

[0357]

[0358] A3 (19 g, 63 mmol) and triethylamine (26 mL, 189 mmol) in CH 2 Cl 2 (300 mL) solution was treated with trifluoroacetic anhydride (13 mL, 94 mmol). The reaction mixture was stirred at 0°C-25°C for 16 hours. The reaction mixture was washed with NaHCO 3 Aqueous work-up and stirring at 25°C for an additional 10 hours. The organic layer was washed with CH 2 Cl 2 Extraction, the combined organic liquid was washed with brine, dried (Na 2 SO 4 ), concentrated in vacuo. Crude product A4 (24.9 g, 100%) was pure enough to be used in the next step without further purification.

[0359] MS: M+H=396

Embodiment 3

[0360] Example 3: Step B - Method A

[0361]

[0362] A suspension of A4 (3.09 g, 7.8 mmol) in cold THF (78 mL) was washed with 50% H 2 SO 4 Aqueous solution (5 mL) was treated with tert-butyl nitrite (5 mL). The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was added to CH 2 Cl 2 and NaHCO 3 A mixture of aqueous solutions. The mixture was stirred for 0.5 h, and the organic layer was washed with CH 2 Cl 2 extraction. The combined organic solutions were washed with brine solution and dried (Na 2 SO 4 ), concentrated in vacuo. The crude product of formula B1 (3 g, 95%) was used in the next step without further purification.

[0363] MS: M+H=395

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