Purine and Pyrimidine Cdk Inhitbitors and Their use for The Treatment of Autoimmune Diseases

Abstract

The present invention relates to the use of an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease associated with antinuclear antibodies, wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 or pharmaceutically acceptable salt thereof is administered in an amount sufficient to down-regulate the levels of antinuclear antibodies. A further aspect of the invention relates to a combination comprising an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof, and methylprednisolone, and its use in the treatment of diseases associated with antinuclear antibodies, such as SLE.

1 . (canceled) 
     
     
         2 . The method according to  claim 12  wherein the disease is an autoimmune rheumatic disease or organ specific autoimmunity. 
     
     
         3 . The method according to  claim 2  wherein the autoimmune rheumatic disease is selected from drug-induced lupus, systemic lupus erythematosis (SLE), and rheumatoid arthritis. 
     
     
         4 . The method according to  claim 3  wherein the autoimmune rheumatic disease is systemic lupus erythematosis (SLE). 
     
     
         5 . The method according to  claim 12  wherein the antinuclear antibodies are anti-DNA antibodies. 
     
     
         6 . The method according to  claim 12  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is in an amount sufficient to down-regulate the expression of Mcl-1. 
     
     
         7 . The method according to  claim 12  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is in an amount sufficient to delay the onset of proteinuria and renal function impairment. 
     
     
         8 . The method according to  claim 12  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is in an amount sufficient to reduce glomerular and tubointerstitial changes. 
     
     
         9 . The method according to  claim 12  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is in an amount sufficient to reduce the interstitial accumulation of mononuclear cells. 
     
     
         10 . The method according to  claim 12  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is in an amount sufficient to inhibit T-cell proliferation (induced by PMA and ConA). 
     
     
         11 . The method according to  claim 12  wherein the the inhibitor is administered in combination therapy with methylprednisolone. 
     
     
         12 . A method of treating a disease associated with antinuclear antibodies in a subject, said method comprising administering to the subject an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof, in an amount sufficient to down-regulate the level of antinuclear antibodies. 
     
     
         13 . A method of treating an autoimmune disease in a subject by down-regulating the level of antinuclear antibodies in said subject, said method comprising administering an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof, in an amount sufficient to down-regulate the level of antinuclear antibodies. 
     
     
         14 . A method of treating a disease associated with antinuclear antibodies in a subject by down-regulating the level of antinuclear antibodies, said method comprising administering an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof, such that said disease is treated. 
     
     
         15 . A method of down-regulating the level of antinuclear antibodies in a subject, said method comprising administering an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof, to said subject in an amount sufficient to down-regulate the level of antinuclear antibodies. 
     
     
         16 . A method according to any one of  claims 12  to  15  wherein the disease is an autoimmune rheumatic disease or organ specific autoimmunity. 
     
     
         17 . A method according to  claim 16  wherein the autoimmune rheumatic disease is selected from drug induced lupus, systemic lupus erythematosis (SLE), and rheumatoid arthritis. 
     
     
         18 . A method according  claim 17  wherein the autoimmune rheumatic disease is systemic lupus erythematosis (SLE). 
     
     
         19 . A method according to any one of  claims 12  to  15  wherein the antinuclear antibodies are anti-DNA antibodies. 
     
     
         20 . A method according to any one of  claims 12  to  15  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is in an amount sufficient to down-regulate the expression of Mcl-1. 
     
     
         21 . A method according to any one of  claims 12  to  15  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is in an amount sufficient to delay the onset of proteinuria and renal function impairment. 
     
     
         22 . A method according to any one of  claims 12  to  15  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is in an amount sufficient to reduce glomerular and tubulointerstitial changes. 
     
     
         23 . A method according to any one of  claims 12  to  15  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is in an amount sufficient to reduce the interstitial accumulation of mononuclear cells. 
     
     
         24 . A method according to any one of  claims 12  to  15  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is in an amount sufficient to inhibit T-cell proliferation induced by PMA and ConA. 
     
     
         25 . A method according to any one of  claims 12  to  15  which further comprises administrating methylprednisolone to the subject. 
     
     
         26 . A method according to  claim 25  wherein the methylprenisolone and the inhibitor of CDK2 and/or CDK7 and/or CDK9, or pharmaceutically acceptable salt thereof, are administered simultaneously, sequentially or separately. 
     
     
         27 . A method of down-regulating the level of antinuclear antibodies in a cell, said method comprising contacting said cell with an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof, in an amount sufficient to down-regulate the level of antinuclear antibodies in said cell. 
     
     
         28 . A pharmaceutical composition for treating a disease associated with antinuclear antibodies, said composition comprising an inhibitor of CDK2 and/or CDK7 and/or CDK9, in an amount sufficient to down-regulate the level of antinuclear antibodies, admixed with a pharmaceutically acceptable diluent, excipient or carrier. 
     
     
         29 . A combination comprising an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof, and methylprednisolone. 
     
     
         30 . A pharmaceutical composition comprising a combination according to  claim 29  and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         31 . A pharmaceutical product comprising an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof, and methylprednisolone as a combined preparation for simultaneous, sequential or separate use in therapy. 
     
     
         32 . A pharmaceutical product according to  claim 31  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9, or pharmaceutically acceptable salt thereof, and methylprednisolone are administered simultaneously. 
     
     
         33 . A pharmaceutical product according to  claim 31  which further comprises a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         34 . A pharmaceutical product according to  claim 31  for use in the treatment of a disease associated with antinuclear antibodies. 
     
     
         35 . A pharmaceutical product according to  claim 34  wherein the disease is an autoimmune rheumatic disease or organ specific autoimmunity. 
     
     
         36 . A pharmaceutical product according to  claim 35  wherein the autoimmune rheumatic disease is selected from drug induced lupus, systemic lupus erythematosis (SLE), and rheumatoid arthritis. 
     
     
         37 . A pharmaceutical product according to  claim 36  wherein the autoimmune rheumatic disease is systemic lupus erythematosis (SLE). 
     
     
         38 . A pharmaceutical composition comprising:
 (i) an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof; and   (ii) methylprednisolone;   
       admixed with a pharmaceutically acceptable diluent, excipient or carrier. 
     
     
         39 . A pharmaceutical composition according to  claim 28 , wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is a purine derivative or a pyrimidine derivative. 
     
     
         40 . A pharmaceutical composition according to  claim 28 , wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         41 . A pharmaceutical composition according to  claim 28 , wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is selected from roscovitine, olomoucine and purvalanol A, and pharmaceutically acceptable salts thereof. 
     
     
         42 . A pharmaceutical composition according to  claim 28 , wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is roscovitine, or a pharmaceutically acceptable salt thereof. 
     
     
         43 - 50 . (canceled) 
     
     
         51 . A method according to  claim 53  wherein the antinuclear antibodies are anti-DNA antibodies. 
     
     
         52 . A method according to  claim 53  wherein the level of antinuclear antibodies is reduced. 
     
     
         53 . A method of treating a disease associated with antinuclear antibodies in a subject, said method comprising administering to the subject a therapeutically acceptable amount of:
 (i) an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof; and   (ii) methylprednisolone.   
     
     
         54 . A method according to  claim 53  wherein an inhibitor of CDK2 and/or CDK7 and/or CDK9, or pharmaceutically acceptable salt thereof, and methylprednisolone are admixed with a pharmaceutically acceptable diluent, excipient or carrier. 
     
     
         55 . A method according to  claim 53  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9, or pharmaceutically acceptable salt thereof, and methylprednisolone are administered simultaneously, separately or sequentially. 
     
     
         56 . A method according to  claim 55  which comprises administering an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof, to a subject prior to sequentially or separately administering methylprednisolone to said subject. 
     
     
         57 . A method according to  claim 55  which comprises administering methylprednisolone to a subject prior to sequentially or separately administering an inhibitor of CDK2 and/or CDK7 and/or CDK9, or a pharmaceutically acceptable salt thereof. 
     
     
         58 . A method according to  claim 53  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9, or pharmaceutically acceptable salt thereof, and methylprednisolone are each administered in a therapeutically effective amount with respect to the individual components. 
     
     
         59 . A method according to  claim 53  wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9, or pharmaceutically acceptable salt thereof, and methylprednisolone are each administered in a subtherapeutic amount with respect to the individual components. 
     
     
         60 . A method according to  claim 53  wherein the disease is an autoimmune rheumatic disease or organ specific autoimmunity. 
     
     
         61 . A method to  claim 60  wherein the autoimmune rheumatic disease is selected from drug induced lupus, systemic lupus erythematosis (SLE), and rheumatoid arthritis. 
     
     
         62 . A method according to  claim 61  wherein the autoimmune rheumatic disease is systemic lupus erythematosis (SLE). 
     
     
         63 . A method according  claim 12  or  53 , wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is a purine derivative or a pyrimidine derivative. 
     
     
         64 . A method according  claim 12  or  53 , wherein the inhibitor of CDK2 and/or CDK7 and/or CDK9 is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         65 . A method according  claim 12  or  53 , the inhibitor of CDK2 and/or CDK7 and/or CDK9 is selected from roscovitine, olomoucine and purvalanol A. 
     
     
         66 . A method according  claim 12  or  53 , the inhibitor of CDK2 and/or CDK7 and/or CDK9 is roscovitine, or a pharmaceutically acceptable salt thereof. 
     
     
         67 . (canceled)