Pyrimidinecarboxamides as CXCR2 modulators

Abstract

There is disclosed pyridine- and pyrimidinecarboxamide compounds useful as pharmaceutical agents, synthesis processes, and pharmaceutical compositions which include pyridine- and pyrimidinecarboxamides compounds. More specifically, there is disclosed a genus of CXCR2 inhibitor compounds that are useful for treating a variety of inflammatory and neoplastic disorders.

We claim: 
     
       1. A compound comprising a compound from of formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently is selected from hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or and heterocyclylalkyl; 
         wherein R 2  is selected from 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 3  is selected from —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and, heterocyclylalkyl, R 6 , —O—R 6 , —S(O) y —R 6  (wherein y= 0 ,  1 , or  2 ), wherein y is 0, 1, or 2, —P(O)—(R 4 R 5 ), —N(R 7 R 8 ), or C(O)—R 9  —C(O)—R 9 , and alkyl, wherein alkyl is unsubstituted or substituted with one or more substituents selected from hydroxy, amino, alkylamino, boronyl, nitro, and cyano; 
         wherein R 6  is selected from alkyl, aryl, arylalkyl, cycloalkyl with 5 to 7 ring atoms, heteroaryl, heteroarylalkyl, heterocyclyl or and heterocyclylalkyl; 
         wherein R 4  and R 5  are independently selected from hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R 4  and R 5  together form a cyclic ester, or an acid anhydride (either mixed or symmetrical), wherein the acid anyhydride is either mixed or symmetrical; 
         wherein R 7  and R 8  are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl or, and heterocyclylalkyl; R 7  and R 8  are both oxygen to form a nitro group; or R 7  and R 8  together with the nitrogen to which they are attached, form a heterocyclyl; 
         wherein R 9  is selected from an alkyl consisting of 1 or 3-18 carbon atoms or carbons, a unsaturated alkyl group consisting of 1-18 carbon atoms carbons, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or, and heterocyclylalkyl; and 
         wherein X 1  is nitrogen; X 2  is selected from NH or oxygen; and n is an integer between 0 and 8; 
       
       or a pharmaceutical compositions composition thereof. 
     
     
       2. The compound of  claim 1  wherein R 1  is hydrogen and R 2  is 4-fluoro-phenyl 4-fluorophenyl. 
     
     
       3. A composition comprising a compound of formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently is selected from hydrogen, 2- or or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or and heterocyclylkalkyl; 
         wherein R 2  is selected from 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 3  is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), R 6 , or —C(O)—R 6 , —O—R 6 —S(O) y —R 6  (wherein y= 0 ,  1 , or  2 ), wherein y is 0, 1, or 2, —P(O)—(R 4 R 5 ) or, and —N(R 7 R 8 ); 
         wherein R 6  is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or, and heterocyclylalkyl; 
         wherein R 4  and R 5  are independently selected from hydrogen, hydroxyl, aryloxy, or alkoxy or wherein R 4  and R 5  together form a cyclic ester, or an acid anhydride (either mixed or symmetrical), wherein the acid anyhydride is either mixed or symmetrical; 
         wherein R 7  and R 8  are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl or, and heterocyclylalkyl; R 7  and R 8  are both oxygen to form a nitro group; or R 6  and R 7  together with the nitrogen to which they are attached, form a heterocyclyl; and 
         wherein X 1  is nitrogen; X 2  is —S(O) y —, wherein y= is 0, 1, or 2; and n is an integer between 1 and 8; 
       
       or a pharmaceutical compositions composition thereof. 
     
     
       4. The pharmaceutical composition compound of  claim 3 , wherein R 1  is hydrogen and R 2  is 4-fluoro-phenyl 4-fluorophenyl. 
     
     
       5. A composition comprising a compound of formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently is selected from hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or and heterocyclylkalkyl; 
         wherein R 2  is selected from 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 3  is selected from —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), alkyl with 2-18 carbon atoms carbons, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or, heterocyclylalkyl, or —C(O)—R 6 , —O—R 6 , —S(O) y —R 6  (wherein y= 0 ,  1 , or  2 ), wherein y is 0, 1, or 2, —P(O)—(R 4 R 5 ), and —N(R 7 R 8 ); 
         wherein R 6  is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 4  and R 5  are independently selected from hydrogen, hydroxyl, aryloxy, or and alkoxy, or wherein R 4  and R 5  together form a cyclic ester, or an acid anhydride (either mixed or symmetrical), wherein the acid anyhydride is either mixed or symmetrical; 
         wherein R 7  and R 8  are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl or heterocyclylalkyl; R 7  and R 8  are both oxygen to form a nitro group; or R 6  and R 7  and R 8 , together with the nitrogen to which they are attached, form a heterocyclyl; and 
         wherein X 1  is nitrogen; X 2  is —S(O) y —, wherein y= is 0, 1, or 2; and n is an integer between 0 and 8; 
       
       or a pharmaceutical compositions composition thereof. 
     
     
       6. The compound of claim 1, wherein R 2  is heteroaryl, and wherein the heteroaryl is unsubstituted or substituted by one or more substituents selected from acyl, alkoxy, aryl, alkylamino, alkylthio, amino, azido, boronyl, carboxy, alkoxycarbonyl, aminocarbonyl, aminosulfonyl, alkylaminocarbonyl, cyano, halo, haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl, acyloxy, ketone, substituted halomethylketone, mercapto, and nitro. 
     
     
       7. The compound of claim 1, wherein R 3  is arylalkyl, and wherein the alkyl group in arylalkyl comprises a straight hydrocarbon chain of 1-18 carbon atoms. 
     
     
       8. The compound of claim 1, wherein the compound comprises the compound of formula (1) in a pharmaceutically acceptable solvated or unsolvated form or a pharmaceutically acceptable salt. 
     
     
       9. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1, wherein the composition is suitable for treating a CXC chemokine-mediated disease. 
     
     
       10. The composition of claim 9, wherein the composition is suitable for administration to a patient with a CXC chemokine-mediated disease. 
     
     
       11. The composition of claim 9, wherein the CXC chemokine-mediated disease comprises overproduction of glutamic acid-leucine-arginine (ELR)-CXC chemokine. 
     
     
       12. The composition of claim 9, wherein the CXC chemokine-mediated disease is a tumor or cancer. 
     
     
       13. The composition of claim 9, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis. 
     
     
       14. The composition of claim 9, wherein the CXC chemokine-mediated disease is multiple sclerosis. 
     
     
       15. The composition of claim 9, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis. 
     
     
       16. The composition of claim 9, wherein the composition is suitable for use in combination with a second medicament. 
     
     
       17. The composition of claim 16, wherein second medicament is an anti-rheumatic drug, a nonsteroidal anti-inflammatory drug, a COX-2 selective inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, a biological response modifier, or other anti-inflammatory agent or therapeutics useful for the treatment of CXCR1 and/or CXCR2 chemokine mediated diseases. 
     
     
       18. The composition of claim 17, wherein the CXC chemokine-mediated disease is cancer, and the second medicament is at least one antineoplastic agent selected from the group consisting of gemcitabine, paclitaxel, 5-fluorouracil, cyclophosphamide, temozolomide, and vincristine; or at least one agent selected from the group consisting of microtubule affecting agents, antineoplastic agents, anti-angiogenesis agents, VEGF receptor kinase inhibitors, antibodies against the VEGF receptor, interferon, and radiation. 
     
     
       19. The composition of claim 17, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis; and wherein the second medicament is selected from the group consisting of glucocorticoids, 5-lipoxygenase inhibitors, beta-2 adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-β agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IL-8 antibodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones. 
     
     
       20. The composition of claim 17, wherein the CXC chemokine-mediated disease is multiple sclerosis, wherein the second medicament is at least one compound selected from the group consisting of glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, CB2-selective inhibitors, cyclosporin, leflunimide, sulfasalazine, β-methasone, β-interferon, glatiramer acetate, prednisone, etonercept, and infliximab. 
     
     
       21. The composition of claim 17, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis, wherein the second medicament is at least one compound selected from the group consisting of COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, steroids, PDE 4 inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, and CB2-selective agents. 
     
     
       22. The composition of claim 10, wherein the composition is suitable for oral administration. 
     
     
       23. The composition of claim 22, wherein the composition is a tablet. 
     
     
       24. The compound of claim 3, wherein R 2  is heteroaryl, and wherein the heteroaryl is unsubstituted or substituted by one or more substituents selected from acyl, alkoxy, aryl, alkylamino, alkylthio, amino, azido, boronyl, carboxy, alkoxycarbonyl, aminocarbonyl, aminosulfonyl, alkylaminocarbonyl, cyano, halo, haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl, acyloxy, ketone, substituted halomethylketone, mercapto, and nitro. 
     
     
       25. The compound of claim 3, wherein R 3  is —R 6 —B(OH) 2 . 
     
     
       26. The compound of claim 3, wherein y is 0. 
     
     
       27. The compound of claim 3, wherein R 6  is an aryl. 
     
     
       28. The compound of claim 3 in a pharmaceutically acceptable solvated or unsolvated form, or a pharmaceutically acceptable salt. 
     
     
       29. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of claim 3, wherein the composition is suitable for treating a CXC chemokine-mediated disease. 
     
     
       30. The composition of claim 28, wherein the composition is suitable for administration to a patient with a CXC chemokine-mediated disease. 
     
     
       31. The composition of claim 30, wherein the composition is suitable for use in combination with a second medicament. 
     
     
       32. The composition of claim 31, wherein second medicament is an anti-rheumatic drug, a nonsteroidal anti-inflammatory drug, a COX-2 selective inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, a biological response modifier, or other anti-inflammatory agent or therapeutics useful for the treatment of CXCR1 and/or CXCR2 chemokine mediated diseases. 
     
     
       33. The composition of claim 28, wherein pharmaceutical composition is administered orally. 
     
     
       34. The composition of claim 28, wherein the pharmaceutical composition is a tablet. 
     
     
       35. A compound of formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 2  is selected from 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 3  is selected from —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, R 6 , —O—R 6 , —S(O) y —R 6 , wherein y is 0, 1, or 2, —P(O)—(R 4 R 5 ), —N(R 7 R 8 ), and —C(O)—R 9 ; 
         wherein R 6  is selected from alkyl, aryl, arylalkyl, cycloalkyl with 5 to 7 ring atoms, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 4  and R 5  are independently selected from hydrogen, hydroxyl, aryloxy, and alkoxy, or wherein R 4  and R 5  together form a cyclic ester or an acid anhydride, wherein the acid anhydride is either mixed or symmetrical; 
         wherein R 7  and R 8  are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, and heterocyclylalkyl; R 7  and R 8  are both oxygen to form a nitro group; or R 7  and R 8  together with the nitrogen to which they are attached, form a heterocyclyl; 
         wherein R 9  is selected from an alkyl consisting of 1 or 3-18 carbons, a unsaturated alkyl group consisting of 1-18 carbons, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; and 
         wherein X 1  is nitrogen; X 2  is oxygen; and n is an integer between 0 and 8; 
       
       or a pharmaceutical composition thereof. 
     
     
       36. A composition comprising a compound of formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 2  is selected from 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 3  is selected from —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —O—R 6 , —S(O) y —R 6 , wherein y is 0, 1, or 2, —P(O)—(R 4 R 5 ), —N(R 7 R 8 ), and —C(O)—R 9 , and alkyl, wherein alkyl is unsubstituted or substituted with one or more substituents selected from hydroxy, amino, alkylamino, boronyl, nitro, and cyano; 
         wherein R 6  is selected from alkyl, aryl, arylalkyl, cycloalkyl with 5 to 7 ring atoms, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 4  and R 5  are independently hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R 4  and R 5  together form a cyclic ester, or an acid anhydride, wherein the acid anhydride is either mixed or symmetrical; 
         wherein R 7  and R 8  are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, and heterocyclylalkyl; R 7  and R 8  are both oxygen to form a nitro group; or R 7  and R 8  together with the nitrogen to which they are attached, form a heterocyclyl; 
         wherein R 9  is selected from an alkyl consisting of 1 or 3-18 carbons, an unsaturated alkyl group consisting of 1-18 carbons, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; and 
         wherein X 1  is nitrogen; X 2  is NH; and n is an integer between 0 and 8; 
       
       or a pharmaceutical composition thereof. 
     
     
       37. The composition of claim 36, wherein R 2  is heteroaryl, and wherein the heteroaryl is unsubstituted or substituted by one or more substituents selected from acyl, alkoxy, aryl, alkylamino, alkylthio, amino, azido, boronyl, carboxy, alkoxycarbonyl, aminocarbonyl, aminosulfonyl, alkylaminocarbonyl, cyano, halo, haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl, acyloxy, ketone, substituted halomethylketone, mercapto, and nitro. 
     
     
       38. The composition of claim 36, wherein R 3  is aryl, and wherein the aryl is unsubstituted, or substituted by one or more substituents selected from acyl, alkoxy, aryl, alkylamino, alkylthio, amino, azido, boronyl, carboxy, alkoxycarbonyl, aminocarbonyl, aminosulfonyl, alkylaminocarbonyl, cyano, halo, haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl, acyloxy, ketone, substituted halomethylketone, mercapto, and nitro. 
     
     
       39. The composition of claim 36, wherein R 2  is arylalkyl, and wherein the alkyl group in arylalkyl comprises a straight hydrocarbon chain of 1-18 carbon atoms. 
     
     
       40. The composition of claim 36, wherein R 3  is arylalkyl, and wherein the alkyl group in arylalkyl comprises a straight hydrocarbon chain of 1-18 carbon atoms. 
     
     
       41. The composition of claim 36 in a pharmaceutically acceptable solvated or unsolvated form, or a pharmaceutically acceptable salt. 
     
     
       42. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 36, wherein the composition is suitable for treating a CXC chemokine-mediated disease. 
     
     
       43. The composition of claim 42, wherein the composition is suitable for administration to a patient with a CXC chemokine-mediated disease. 
     
     
       44. The composition of claim 42, wherein the composition is administered to the patient in combination with a second medicament useful for treating the CXC chemokine-mediated disease. 
     
     
       45. The composition of claim 42, wherein pharmaceutical composition is administered orally. 
     
     
       46. The composition of claim 45, wherein the pharmaceutical composition is a tablet. 
     
     
       47. The compound of claim 35, wherein the compound comprises the compound of formula (1) in a pharmaceutically acceptable solvated or unsolvated form or a pharmaceutically acceptable salt. 
     
     
       48. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 35, wherein the composition is suitable for treating a CXC chemokine-mediated disease. 
     
     
       49. The composition of claim 48, wherein the composition is suitable for administration to a patient with a CXC chemokine-mediated disease. 
     
     
       50. The composition of claim 48, wherein the CXC chemokine-mediated disease comprises overproduction of glutamic acid-leucine-arginine (ELR)-CXC chemokine. 
     
     
       51. The composition of claim 48, wherein the CXC chemokine-mediated disease is a tumor or cancer. 
     
     
       52. The composition of claim 48, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis. 
     
     
       53. The composition of claim 48, wherein the CXC chemokine-mediated disease is multiple sclerosis. 
     
     
       54. The composition of claim 48, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis. 
     
     
       55. The composition of claim 48, wherein the composition is suitable for use in combination with a second medicament. 
     
     
       56. The composition of claim 55, wherein second medicament is an anti-rheumatic drug, a nonsteroidal anti-inflammatory drug, a COX-2 selective inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, a biological response modifier, or other anti-inflammatory agent or therapeutics useful for the treatment of CXCR1 and/or CXCR2 chemokine mediated diseases. 
     
     
       57. The composition of claim 56, wherein the CXC chemokine-mediated disease is cancer, and the second medicament is at least one antineoplastic agent selected from the group consisting of gemcitabine, paclitaxel, 5-fluorouracil, cyclophosphamide, temozolomide, and vincristine; or at least one agent selected from the group consisting of microtubule affecting agents, antineoplastic agents, anti-angiogenesis agents, VEGF receptor kinase inhibitors, antibodies against the VEGF receptor, interferon, and radiation. 
     
     
       58. The composition of claim 56, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis; and wherein the second medicament is selected from the group consisting of glucocorticoids, 5-lipoxygenase inhibitors, beta-2 adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-β agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IL-8 antibodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones. 
     
     
       59. The composition of claim 56, wherein the CXC chemokine-mediated disease is multiple sclerosis, wherein the second medicament is at least one compound selected from the group consisting of glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, CB2-selective inhibitors, cyclosporin, leflunimide, sulfasalazine, β-methasone, β-interferon, glatiramer acetate, prednisone, etonercept, and infliximab. 
     
     
       60. The composition of claim 56, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis, wherein the second medicament is at least one compound selected from the group consisting of COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, steroids, PDE 4 inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, and CB2-selective agents. 
     
     
       61. The composition of claim 49, wherein the composition is suitable for oral administration. 
     
     
       62. The composition of claim 61, wherein the composition is a tablet.