CCR1 antagonists and methods of use therefor

Abstract

The invention provides compounds having the formula: wherein R 1 is halogen. The invention also provides compositions comprising the compounds, and methods of treating diseases or disorders that comprise administering one or more of the compounds to a subject in need thereof. The disclosed compounds have CCR1 antagonist activity.

1 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       or a physiologically acceptable salt thereof, wherein R 1  is a halogen.  
     
     
         2 . The compound of  claim 1  wherein R 1  is selected from the group consisting of chloro, fluoro and bromo.  
     
     
         3 . The compound of  claim 2  wherein R 1  is chloro.  
     
     
         4 . A pharmaceutical composition comprising the compound of  claim 1  and a physiologically acceptable carrier or excipient.  
     
     
         5 . A method for treating a disease characterized by pathogenic leukocyte recruitment, pathogenic leukocyte activation or pathogenic leukocyte recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .  
     
     
         6 . A compound having the structure:  
       
         
           
           
               
               
           
         
       
       or a physiologically acceptable salt thereof, wherein R 1  is a halogen.  
     
     
         7 . The compound of  claim 6  wherein R 1  is selected from the group consisting of chloro, fluoro and bromo.  
     
     
         8 . The compound of  claim 7  wherein R 1  is chloro.  
     
     
         9 . A pharmaceutical composition comprising the compound of  claim 6  and a physiologically acceptable carrier or excipient.  
     
     
         10 . A method for treating a disease characterized by pathogenic leukocyte recruitment, pathogenic leukocyte activation or pathogenic leukocyte recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound of  claim 6 .  
     
     
         11 . The method of  claim 10  wherein R 1  chloro.  
     
     
         12 . (canceled)  
     
     
         13 . The method of  claim 10  wherein said disease is selected from the group consisting of inflammatory arthritis, inflammatory demyelinating disease, atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes mellitus, psoriasis, inflammatory bowel diseases, rejection of a transplanted graft, graft versus host disease, allergy and asthma.  
     
     
         14 - 17 . (canceled)  
     
     
         18 . A method of antagonizing a C—C Chemokine Receptor 1 in a subject, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .  
     
     
         19 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       or a physiologically acceptable salt thereof, wherein R 1  is a halogen.  
     
     
         20 . A pharmaceutical composition comprising the compound of  claim 19  and a physiologically acceptable carrier or excipient.  
     
     
         21 . The compound of  claim 19  wherein R 1  is selected from the group consisting of chloro, fluoro and bromo.  
     
     
         22 . The compound of  claim 21  wherein R 1  is chloro.  
     
     
         23 . A method for treating a disease characterized by pathogenic leukocyte recruitment, pathogenic leukocyte activation or pathogenic leukocyte recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound of  claim 19 .  
     
     
         24 . The method of  claim 23  wherein said disease is selected from the group consisting of inflammatory arthritis, inflammatory demyelinating disease, atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes mellitus, psoriasis, inflammatory bowel diseases, rejection of a transplanted graft, graft versus host disease, allergy and asthma.  
     
     
         25 . The method of  claim 5  wherein said disease is selected from the group consisting of inflammatory arthritis, inflammatory demyelinating disease, atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes mellitus, psoriasis, inflammatory bowel diseases, rejection of a transplanted graft, graft versus host disease, allergy and asthma.  
     
     
         26 . A method for treating an inflammatory disease, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .  
     
     
         27 . The method of  claim 24 , wherein said inflammatory disease is an acute inflammatory disease.  
     
     
         28 . The method of  claim 24 , wherein said inflammatory disease is a chronic inflammatory disease.  
     
     
         29 . A method for treating an inflammatory disease, comprising administering to a subject in need thereof an effective amount of a compound of  claim 6 .  
     
     
         30 . The method of  claim 27 , wherein said inflammatory disease is an acute inflammatory disease.  
     
     
         31 . The method of  claim 27 , wherein said inflammatory disease is a chronic inflammatory disease.  
     
     
         32 . A method for treating an inflammatory disease, comprising administering to a subject in need thereof an effective amount of a compound of  claim 19 .  
     
     
         33 . The method of  claim 30  wherein said inflammatory disease is an acute inflammatory disease.  
     
     
         34 . The method of  claim 30  wherein said inflammatory disease is a chronic inflammatory disease.  
     
     
         35 . A method for treating inflammatory arthritis, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .  
     
     
         36 . The method of  claim 33  wherein said inflammatory arthritis is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, Reiter's syndrome, psoriatic arthritis, psoriatic spondylitis, enteropathic arthritis, enteropathic spondylitis, juvenile-onset spondyloarthropathy and undifferentiated spondyloarthropathy.  
     
     
         37 . A method for treating inflammatory arthritis, comprising administering to a subject in need thereof an effective amount of a compound of  claim 6 .  
     
     
         38 . The method of  claim 35  wherein said inflammatory arthritis is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, Reiter's syndrome, psoriatic arthritis, psoriatic spondylitis, enteropathic arthritis, enteropathic spondylitis, juvenile-onset spondyloarthropathy and undifferentiated spondyloarthropathy.  
     
     
         39 . A method for treating inflammatory arthritis, comprising administering to a subject in need thereof an effective amount of a compound of  claim 19 .  
     
     
         40 . The method of  claim 37  wherein said inflammatory arthritis is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, Reiter's syndrome, psoriatic arthritis, psoriatic spondylitis, enteropathic arthritis, enteropathic spondylitis, juvenile-onset spondyloarthropathy and undifferentiated spondyloarthropathy.  
     
     
         41 . A method for treating inflammatory demyelinating disease, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .  
     
     
         42 . The method of  claim 39  wherein said inflammatory demyelinating disease is acute inflammatory demyelinating disease.  
     
     
         43 . The method of  claim 40  wherein said acute demyelinating disease is selected from the group consisting of acute disseminated encephalomyelitis, Guillain-Barre syndrome and acute hemorrhagic leukoencephalitis.  
     
     
         44 . The method of  claim 39  wherein said inflammatory demyelinating disease is chronic inflammatory demyelinating disease.  
     
     
         45 . The method of  claim 42  wherein said chronic inflammatory demyelinating disease is multiple sclerosis or chronic inflammatory demyelinating polyradiculoneuropathy.  
     
     
         46 . A method for treating inflammatory demyelinating disease, comprising administering to a subject in need thereof an effective amount of a compound of  claim 6 .  
     
     
         47 . The method of  claim 44  wherein said inflammatory demyelinating disease is acute inflammatory demyelinating disease.  
     
     
         48 . The method of  claim 45  wherein said acute demyelinating disease is selected from the group consisting of acute disseminated encephalomyelitis, Guillain-Barre syndrome and acute hemorrhagic leukoencephalitis.  
     
     
         49 . The method of  claim 44  wherein said inflammatory demyelinating disease is chronic inflammatory demyelinating disease.  
     
     
         50 . The method of  claim 47  wherein said chronic inflammatory demyelinating disease is multiple sclerosis or chronic inflammatory demyelinating polyradiculoneuropathy.  
     
     
         51 . A method for treating inflammatory demyelinating disease, comprising administering to a subject in need thereof an effective amount of a compound of  claim 19 .  
     
     
         52 . The method of  claim 49  wherein said inflammatory demyelinating disease is acute inflammatory demyelinating disease.  
     
     
         53 . The method of  claim 50  wherein said acute demyelinating disease is selected from the group consisting of acute disseminated encephalomyelitis, Guillain-Barre syndrome and acute hemorrhagic leukoencephalitis.  
     
     
         54 . The method of  claim 49  wherein said inflammatory demyelinating disease is chronic inflammatory demyelinating disease.  
     
     
         55 . The method of  claim 52  wherein said chronic inflammatory demyelinating disease is multiple sclerosis or chronic inflammatory demyelinating polyradiculoneuropathy.  
     
     
         56 . A method of antagonizing a C—C Chemokine Receptor 1 in a subject, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .  
     
     
         57 . A method of antagonizing a C—C Chemokine Receptor 1 in a subject, comprising administering to a subject in need thereof an effective amount of a compound of  claim 19 .  
     
     
         58 . A method for treating rheumatoid arthritis, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .  
     
     
         59 . A method for treating rheumatoid arthritis, comprising administering to a subject in need thereof an effective amount of a compound of  claim 6 .  
     
     
         60 . A method for treating rheumatoid arthritis, comprising administering to a subject in need thereof an effective amount of a compound of  claim 19 .  
     
     
         61 . A method for treating multiple sclerosis, comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .  
     
     
         62 . A method for treating multiple sclerosis, comprising administering to a subject in need thereof an effective amount of a compound of  claim 6 .  
     
     
         63 . A method for treating multiple sclerosis, comprising administering to a subject in need thereof an effective amount of a compound of  claim 19.