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 a compound of the formula: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salt, wherein: 
         if Y 1  and Y 2  are both oxygen, and V 1  and V 2  are both oxygen, then at least two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are not H; 
         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, or an amino acid acyl residue; 
         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, cycloaryl, 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 condition is a condition of abnormal cellular proliferation, inflammation, or both abnormal cellular proliferation and inflammation. 
     
     
         3 . The method of  claim 2 , wherein the condition is a condition of abnormal cellular proliferation. 
     
     
         4 . The method of  claim 3 , wherein the condition is a non-neoplastic abnormal cellular proliferation disorder. 
     
     
         5 . The method of  claim 4 , wherein the condition is psoriasis. 
     
     
         6 . The method of  claim 4 , wherein the condition is psoriatic arthritis. 
     
     
         7 . The method of  claim 4 , wherein the condition is atherosclerosis. 
     
     
         8 . The method of  claim 3 , wherein the condition is a neoplastic abnormal cellular proliferation disorder. 
     
     
         9 . The method of  claim 8 , wherein the condition is cancer. 
     
     
         10 . The method of  claim 9 , wherein the cancer is selected from the group consisting of breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, larynx cancer, gallbladder cancer, pancreatic cancer, rectal cancer, parathyroid cancer, thyroid cancer, adrenal cancer, neural tissue cancer, colon cancer, stomach cancer, bronchial cancer, renal cancer, basal cell carcinoma, squamous cell carcinoma, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, myeloma, giant cell tumor, small-cell lung tumor, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, mucosal neuronas, intestinal ganglioneuromas, hyperplastic corneal nerve tumor, Wilm's tumor, seminoma, ovarian tumor, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, Kaposi's sarcoma, malignant hypercalcemia, renal cell tumor, polycythemia vera, adenocarcinoma, glioblastoma multiforma, leukemia, lymphoma, malignant melanoma, and epidermoid carcinoma. 
     
     
         11 . The method of  claim 2 , wherein the condition is a condition of inflammation. 
     
     
         12 . The method of  claim 11 , wherein the condition is selected from the group consisting of inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), sarcoidosis, asthma, arthritis, osteoarthritis, cardiovascular disease, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. 
     
     
         13 . The method of  claim 12 , wherein the condition is Crohn's disease. 
     
     
         14 . The method of  claim 12 , wherein the condition is ulcerative colitis. 
     
     
         15 . The method of  claim 12 , wherein the condition is rheumatoid arthritis. 
     
     
         16 . The method of  claim 12 , wherein the condition is systemic lupus erythematosus. 
     
     
         17 . The method of  claim 1 , further comprising administering a second therapeutic agent. 
     
     
         18 . The method of  claim 17 , wherein the second therapeutic agent is an anti-neoplastic agent. 
     
     
         19 . The method of  claim 17 , wherein the second therapeutic agent is selected from the group consisting of anti-angiogenic agents, alkylating agents, anti-metabolites, cytotoxic agents, and anti-rheumatoid arthritis agents. 
     
     
         20 . The method of  claim 17 , wherein the second therapeutic agent is selected from the group consisting of non-steroidal anti-inflammatory agents, analgesics, corticosteroids, and disease-modifying anti-rheumatic agents. 
     
     
         21 . The method of  claim 20 , wherein the disease-modifying anti-rheumatic agent is a TNF blocker. 
     
     
         22 . The method of  claim 21 , wherein the TNF blocker is selected from the group consisting of etanercept, infliximab, adalimumab, and CDP-870. 
     
     
         23 . The method of  claim 17 , wherein the second therapeutic agent is an anti-autoimmune disease agent. 
     
     
         24 . The method of  claim 17 , wherein the second therapeutic agent is selected from the group consisting of rituximab, abatacept, actemra, leflunomide, and methotrexate. 
     
     
         25 . The method of  claim 17 , wherein the second therapeutic agent and the compound of said formula are administered separately. 
     
     
         26 . The method of  claim 17 , wherein the second therapeutic agent and the compound of said formula are administered in an effective ratio of dosages. 
     
     
         27 . The method of  claim 1 , wherein the compound of said formula is in the form of a pharmaceutically acceptable salt. 
     
     
         28 . The method of  claim 27 , wherein the salt is an alkali metal salt. 
     
     
         29 . The method of  claim 28 , wherein the alkali metal is sodium or potassium.