Heterocyclic substituted piperazine 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: Chemical formula should be inserted here as it appears on the 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

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 such compounds in combination with other compounds having chemokine activity class antagonists, one or more such antagonists in combination with known immunosuppressants, non-limiting examples of which include methotrexate, interferon, cyclosporine, FK-506 and FTY720; methods of making such antagonists and methods of modulating CXCR3 activity using such antagonists. The present invention also discloses methods of treating (non-limiting examples including palliative, curative and prophylactic therapy) diseases and disorders involving CXCR3 using such CXCR3 antagonists. Diseases and disorders involving CXCR3 include, but are not limited to, inflammatory diseases (psoriasis and inflammatory bowel disease), autoimmune diseases (multiple sclerosis, rheumatoid...

Examples

Embodiment 1

[0401]

[0402] To a cold (-78°C) 1000ml round bottom flask containing 200ml methanol was added dropwise thionyl chloride (10ml, 140mmol) followed by 5-bromopyridinecarboxylic acid (15g, 75mmol). After stirring at -78°C for 10 minutes, the reaction was allowed to warm to room temperature and stirred for 16 hours. Excess thionyl chloride and methanol were removed in vacuo to give A2 (18 g, 95%) as a light brown solid. M+H=216

Embodiment 2

[0404]

[0405] A 250 ml round bottom flask was charged with A2 (4 g, 15.9 mmol), 1-Boc-2-S-ethylpiperazine A3 (prepared according to Kiley et al., Org. Prep. Proc. Int. 1990, 22, 761; 4.2 g, 18.6 mmol), tris(dibenzylideneacetone)dipalladium (340 mg, 0.37 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP ) (495 mg, 0.74 mmol), cesium carbonate (12 g, 37.2 mmol) and toluene (80 ml). After heating the mixture at 100°C for 16 hours, fresh tris(dibenzylideneacetone)dipalladium (340 mg, 0.37 mmol) and BINAP (495 mg, 0.74 mmol) were added and heating continued for 3 days. The solvent was removed in vacuo and the residue was suspended in 100 ml of ethyl acetate. The mixture was extracted with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified via silica gel flash chromatography (5% methanol / 95% DCM) to yield 5.3 g of partially purified material which was used directly in the next step. M+H=350

Embodiment 3

[0407]

[0408] Intermediate A4 (5.28 g, 15.1 mmol) was stirred with N-bromo-succinimide (5.4 g, 30.2 mmol) in 30 ml DMF at room temperature for 24 hours. The solvent was removed in vacuo and the residue was purified directly by flash chromatography on silica gel eluting with 50% ethyl acetate / 50% hexanes to afford A5 (1.22 g, 19% yield, M+H=428). The column was further eluted with 10% 7N ammonia in methanol / 90% DCM to afford A6 (1.28 g, 25%, M+H=328).

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 such compounds in combination with other compounds having chemokine activity class antagonists, one or more such antagonists in combination with known immunosuppressants, non-limiting examples of which include methotrexate, interferon, cyclosporine, FK-506 and FTY720; methods of making such antagonists and methods of modulating CXCR3 activity using such antagonists. The present invention also discloses methods of treating (non-limiting examples including palliative, curative and prophylactic therapy) diseases and disorders involving CXCR3 using such CXCR3 antagonists. Diseases and disorders involving CXCR3 include, but are not limited to, inflammatory diseases (psoriasis and inflammatory bowel disease), autoimmune diseases (multiple sclerosis, rheumatoid...

Examples

Embodiment 1

[0401]

[0402] To a cold (-78°C) 1000ml round bottom flask containing 200ml methanol was added dropwise thionyl chloride (10ml, 140mmol) followed by 5-bromopyridinecarboxylic acid (15g, 75mmol). After stirring at -78°C for 10 minutes, the reaction was allowed to warm to room temperature and stirred for 16 hours. Excess thionyl chloride and methanol were removed in vacuo to give A2 (18 g, 95%) as a light brown solid. M+H=216

Embodiment 2

[0404]

[0405] A 250 ml round bottom flask was charged with A2 (4 g, 15.9 mmol), 1-Boc-2-S-ethylpiperazine A3 (prepared according to Kiley et al., Org. Prep. Proc. Int. 1990, 22, 761; 4.2 g, 18.6 mmol), tris(dibenzylideneacetone)dipalladium (340 mg, 0.37 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP ) (495 mg, 0.74 mmol), cesium carbonate (12 g, 37.2 mmol) and toluene (80 ml). After heating the mixture at 100°C for 16 hours, fresh tris(dibenzylideneacetone)dipalladium (340 mg, 0.37 mmol) and BINAP (495 mg, 0.74 mmol) were added and heating continued for 3 days. The solvent was removed in vacuo and the residue was suspended in 100 ml of ethyl acetate. The mixture was extracted with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified via silica gel flash chromatography (5% methanol / 95% DCM) to yield 5.3 g of partially purified material which was used directly in the next step. M+H=350

Embodiment 3

[0407]

[0408] Intermediate A4 (5.28 g, 15.1 mmol) was stirred with N-bromo-succinimide (5.4 g, 30.2 mmol) in 30 ml DMF at room temperature for 24 hours. The solvent was removed in vacuo and the residue was purified directly by flash chromatography on silica gel eluting with 50% ethyl acetate / 50% hexanes to afford A5 (1.22 g, 19% yield, M+H=428). The column was further eluted with 10% 7N ammonia in methanol / 90% DCM to afford A6 (1.28 g, 25%, M+H=328).

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