Metabolically inert antifolates for treating disorders of abnormal cellular proliferation and inflammation

Abstract

The present invention provides compositions and methods for the treatment of disorders of abnormal cell proliferation and/or inflammation, such as psoriasis and inflammatory bowel disease, in a human or other host animals.

1 . A method for treating a condition responsive to inhibition of one or more of dihydrofolate reductase (DHFR), thymidylate synthase (TS), folylpolyglutamyl synthase (FPGS), glycinamide ribonucleotide transformylase (GAR), and aminoimidazole carboxamide ribonucleotide transformylase (AICAR), the method comprising administering to a patient in need of treatment for the condition an effective amount of methotrexate and a compound of formula (I): 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salt, wherein: 
         X is CH 2 , CHCH 3 , CH(CH 2 CH 3 ), NH, NCH 3 , or NR 7 ; 
         R 1 , R 2 , R 3 , R 4 , and R 7  are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y 3 )V 3 , lipid, phospholipid, carbohydrate, peptide, cholesterol, an amino acid residue, an amino acid acyl residue, or other pharmaceutically acceptable leaving group that is capable of providing a free amine when administered in vivo; 
         R 5  and R 6  are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, lipid, phospholipid, carbohydrate, peptide, cholesterol, an amino acid residue, or other pharmaceutically acceptable leaving group that is capable of providing a —C(═Y)V −  or —C(═Y)VH moiety when administered in vivo; 
         each Y 1 , Y 2 , and Y 3  independently is O, S, or NJ 1 ; 
         each V 1  and V 2  independently is O, S, or NJ 1 ; 
         each V 3  independently is OH, OJ 1 , SH, SJ 1 , NH 2 , NHJ 1 , NJ 1 J 2 , CH 3 , CH 2 R 101 , CHR 101 R 102 , or CR 101 R 102 R 103 ; 
         each J 1  and J 2  independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, heteroalkyl, heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and 
         each R 101 , R 102 , and R 103  are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, heteroaryl, heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO 2 , SO 3 , thioalkyl, or amino. 
       
     
     
         2 . The method of  claim 1 , wherein the compound of formula (I) and the methotrexate are administered separately. 
     
     
         3 . The method of  claim 1 , wherein the compound of formula (I) and the methotrexate are administered in an effective ratio of dosages. 
     
     
         4 . The method of  claim 1 , wherein the condition is a condition of abnormal cellular proliferation, inflammation, or both abnormal cellular proliferation and inflammation. 
     
     
         5 . The method of  claim 1 , wherein the condition is selected from the group consisting of psoriasis, psoriatic arthritis, atherosclerosis, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), sarcoidosis, asthma, arthritis, osteoarthritis, cardiovascular disease, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, and systemic lupus erythematosus. 
     
     
         6 . The method of  claim 5 , wherein the condition is rheumatoid arthritis. 
     
     
         7 . The method of  claim 1 , wherein the compound of formula (I) is in the form of a pharmaceutically acceptable salt. 
     
     
         8 . The method of  claim 7 , wherein the salt is an alkali metal salt. 
     
     
         9 . The method of  claim 8 , wherein the alkali metal is sodium or potassium. 
     
     
         10 . The method of  claim 1 , wherein Y 1 , Y 2 , V 1 , and V 2  are O. 
     
     
         11 . The method of  claim 1 , wherein R 1 , R 2 , R 3 , and R 4  are H. 
     
     
         12 . The method of  claim 1 , wherein X is CH 2 . 
     
     
         13 . The method of  claim 1 , wherein R 5  and R 6  are independently a pharmaceutically acceptable leaving group that is capable of providing a —C(═Y)V −  moiety when administered in vivo. 
     
     
         14 . The method of  claim 1 , wherein the compound of formula (I) is the compound of the following structure: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salt. 
       
     
     
         15 . The method of  claim 14 , wherein the compound is in the form of a pharmaceutically acceptable salt. 
     
     
         16 . The method of  claim 15 , wherein the salt is an alkali metal salt. 
     
     
         17 . The method of  claim 16 , wherein the alkali metal is sodium or potassium. 
     
     
         18 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, methotrexate, and a compound according to formula (I): 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salt, wherein: 
         X is CH 2 , CHCH 3 , CH(CH 2 CH 3 ), NH, NCH 3 , or NR 7 ; 
         R 1 , R 2 , R 3 , R 4 , and R 7  are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, acyl, —C(O)-(alkyl), —C(O)-(alkenyl), —C(O)-(alkynyl), —C(═Y 3 )V 3 , lipid, phospholipid, carbohydrate, peptide, cholesterol, an amino acid residue, an amino acid acyl residue, or other pharmaceutically acceptable leaving group that is capable of providing a free amine when administered in vivo; 
         R 5  and R 6  are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl or alkynyl, lipid, phospholipid, carbohydrate, peptide, cholesterol, an amino acid residue, or other pharmaceutically acceptable leaving group that is capable of providing a —C(═Y)V −  or —C(═Y)VH moiety when administered in vivo; 
         each Y 1 , Y 2 , and Y 3  independently is O, S, or NJ 1 ; 
         each V 1  and V 2  independently is O, S, or NJ 1 ; 
         each V 3  independently is OH, OJ 1 , SH, SJ 1 , NH 2 , NHJ 1 , NJ 1 J 2 , CH 3 , CH 2 R 101 , CHR 101 R 102 , or CR 101 R 102 R 103 ; 
         each J 1  and J 2  independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, heteroalkyl, heterocycle, heteroaryl, hydroxyl, alkoxy, or amine; and 
         each R 101 , R 102 , and R 103  are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, heteroaryl, heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO 2 , SO 3 , thioalkyl, or amino. 
       
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the compound of formula (I) is in the form of a pharmaceutically acceptable salt. 
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein Y 1 , Y 2 , V 1 , and V 2  are O. 
     
     
         21 . The pharmaceutical composition of  claim 18 , wherein R 1 , R 2 , R 3 , and R 4  are H. 
     
     
         22 . The pharmaceutical composition of  claim 18 , wherein X is CH 2 . 
     
     
         23 . The pharmaceutical composition of  claim 18 , wherein R 5  and R 6  are independently a pharmaceutically acceptable leaving group that is capable of providing a —C(═Y)V −  moiety when administered in vivo. 
     
     
         24 . The pharmaceutical composition of  claim 18 , wherein the compound of formula (I) is the compound of the following structure: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salt. 
       
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein the compound is in the form of the pharmaceutically acceptable salt. 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein the salt is an alkali metal salt. 
     
     
         27 . The pharmaceutical composition of  claim 26 , wherein the alkali metal is sodium or potassium.