Antifolate combinations

Abstract

The present invention provides combinations of active agents, such combinations comprising one or more antifolate compounds. The particularly can include methotrexate and one or more further antifolate compounds. In specific embodiments, the combinations are useful for treating certain conditions, such as rheumatoid arthritis. The invention also provides articles useful to provide the combinations in desirable dosage forms and combinations. The combinations further may be useful in the treatment of further conditions, including abnormal cell proliferation, inflammatory diseases, asthma, and arthritis.

1 - 46 . (canceled) 
     
     
         47 . A method for treating a subject suffering from a skin disorder, the method comprising administering to the subject a first compound according to a first dosing schedule and a second compound according to a second, different dosing schedule, wherein the first compound is methotrexate or a derivative thereof and the second compound is an antifolate compound according to Formula (6): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CHR 3  or NR 8 ; 
 Y 1 , Y 2 , and Y 3  independently are O or S; 
 V 1  and V 2  independently are O, S, or NZ; 
 Z is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl; 
 R 1  and R 2  independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl; 
 R 3  is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and 
 R 4 , R 5 , R 6 , R 7 , and R 8  independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-alkynyl; or a pharmaceutically acceptable ester, amide, salt, solvate, enantiomer, or prodrug thereof. 
 
     
     
         48 . The method of  claim 47 , wherein the first dosing schedule comprises administering the first compound once or twice per week. 
     
     
         49 . The method of  claim 47 , wherein the second dosing schedule comprises administering the second compound at least once per day. 
     
     
         50 . The method of  claim 47 , wherein the second compound is an antifolate compound according to formula (7): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CHR 8  or NR 8 ; 
 R 3  is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and 
 R 4 , R 5 , R 6 , R 7 , and R 8  independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-alkynyl; or a pharmaceutically acceptable ester, amide, salt, solvate, enantiomer, or prodrug thereof. 
 
     
     
         51 . The method of  claim 47 , wherein the second compound is an antifolate compound according to Formula (9): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable ester, amide, salt, solvate, enantiomer, or prodrug thereof. 
     
     
         52 . The method of  claim 47 , wherein the second compound is an antifolate compound according to Formula (11): 
       
         
           
           
               
               
           
         
       
       or an enantiomer thereof, wherein each X +  independently is a salt-forming counterion. 
     
     
         53 . The method of  claim 52 , wherein X +  is an alkali metal cation. 
     
     
         54 . The method of  claim 53 , wherein X +  is sodium or potassium. 
     
     
         55 . The method of  claim 52 , wherein the antifolate compound is a crystalline salt. 
     
     
         56 . The method of  claim 52 , wherein the antifolate compound is a racemic salt. 
     
     
         57 . The method of  claim 52 , wherein the second compound is an antifolate compound according to Formula (12): 
       
         
           
           
               
               
           
         
       
       wherein each X +  independently is a salt-forming counterion, and wherein the antifolate compound is in the (S) enantiomeric form. 
     
     
         58 . The method of  claim 57 , wherein the antifolate compound exhibits an enantiomeric purity for the (S) enantiomer of at least about 95%. 
     
     
         59 . The method of  claim 57 , wherein the second compound is an antifolate compound according to Formula (12) that is a crystalline, disodium salt in the (S) enantiomeric form exhibiting an enantiomeric purity for the (S) enantiomer of at least about 99%. 
     
     
         60 . The method of  claim 57 , wherein the second compound is an antifolate compound according to Formula (12) that is a crystalline, dipotassium salt in the (S) enantiomeric form exhibiting an enantiomeric purity for the (S) enantiomer of at least about 99%. 
     
     
         61 . The method of  claim 47 , wherein the skin disorder is an inflammatory skin disorder. 
     
     
         62 . The method of  claim 47 , wherein the skin disorder is a hyperproliferative skin disorder. 
     
     
         63 . The method of  claim 47 , wherein the skin disorder is psoriasis 
     
     
         64 . The method of  claim 47 , wherein the skin disorder is dermatitis. 
     
     
         65 . A kit providing a defined dosing regimen of at least a first pharmaceutical composition and a second pharmaceutical composition, the first pharmaceutical composition comprising a pharmaceutically acceptable carrier and methotrexate or a derivative thereof, and the second pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antifolate compound according to Formula (6): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is CHR 8  or NR 3 ; 
 Y 1 , Y 2 , and Y 3  independently are O or S; 
 V 1  and V 2  independently are O, S, or NZ; 
 Z is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl; 
 R 1  and R 2  independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl; 
 R 3  is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and 
 R 4 , R 5 , R 6 , R 7 , and R 8  independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-alkynyl; or a pharmaceutically acceptable ester, amide, salt, solvate, enantiomer, or prodrug thereof; 
 wherein the kit includes a sufficient number of doses of each of the first and second pharmaceutical compositions such that the compositions are dosed in a regimen of at least two doses of the second pharmaceutical composition for each one dose of the first pharmaceutical composition. 
 
     
     
         66 . The kit of  claim 65 , wherein the second pharmaceutical composition comprises an antifolate compound according to Formula (9): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable ester, amide, salt, solvate, enantiomer, or prodrug thereof. 
     
     
         67 . The kit of  claim 65 , wherein the second compound is an antifolate compound according to Formula (11): 
       
         
           
           
               
               
           
         
       
       or an enantiomer thereof, wherein each X +  independently is a salt-forming counterion. 
     
     
         68 . The kit of  claim 67 , wherein X +  is an alkali metal cation. 
     
     
         69 . The kit of  claim 65 , further comprising indicia of the defined dosing regimen instructing proper dosing of the first pharmaceutical composition and the second pharmaceutical composition.