Optically Pure Diastereomers of 10-Propargyl-10-Deazaaminopterin and Methods of Using Same

Abstract

The present invention relates to diastereomers of 10-propargyl-10-deazaminopterin, compositions comprising optically pure diastereomers of 10-propargyl-10-deazaminopterin, in particular the two (R,S) diastereomers about the C10 position. Methods of preparation of these diastereomers, compositions containing them, and their use for the treatment of conditions related to inflammatory disorders and cancer are also disclosed.

1 . A compound comprising a substantially pure diastereomer of 10-propargyl-10-deazaminopterin, or a salt thereof, wherein the diastereomer is (2S)-2-[[4-[(1S)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid or (2S)-2-[[4-[(1R)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid. 
     
     
         2 . The compound according to  claim 1 , wherein the substantially pure diastereomer is (2S)-2-[[4-[(1S)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid or a salt thereof. 
     
     
         3 . The compound according to  claim 1  wherein the substantially pure diastereomer is (2S)-2-[[4-[(1R)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid or a salt thereof. 
     
     
         4 . The compound according to  claim 1 , wherein the salt thereof is the hydrochloride salt. 
     
     
         5 . A pharmaceutical composition, comprising substantially pure (2S)-2-[[4-[(1S)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid or salt thereof, or substantially pure (2S)-2-[[4-[(1R)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid or salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         6 . The pharmaceutical composition of  claim 5 , for use in a method of treating cancer. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the cancer is selected from the group consisting of prostate cancer, T-cell lymphoma, breast cancer, lung cancer, hematologic malignancies, head and neck cancer, cancer of the gastrointestinal tract, ovarian cancer, and osteosarcoma. 
     
     
         8 . The pharmaceutical composition of  claim 5 , for use in treating an inflammatory disorder. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the inflammatory disorder is rheumatoid arthritis. 
     
     
         10 . The pharmaceutical composition according to  claim 5 , wherein said composition is formulated for oral administration. 
     
     
         11 . The pharmaceutical composition according to  claim 5 , wherein said composition is formulated for intravenous administration. 
     
     
         12 . A method for treating cancer, comprising administering to a mammal in need of said treatment a therapeutically effective amount of a substantially pure diastereomer of 10-propargyl-10-deazaminopterin, or a salt thereof, said diastereomer being (2S)-2-[[4-[(1S)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid or (2S)-2-[[4-[(1R)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid. 
     
     
         13 . The method of  claim 12 , wherein the cancer is selected from the group consisting of prostate cancer, T-cell lymphoma, breast cancer, lung cancer, hematologic malignancies, head and neck cancer, cancer of the gastrointestinal tract, ovarian cancer, and osteosarcoma. 
     
     
         14 . A method for treating inflammation, comprising administering to a mammal in need of said treatment a therapeutically effective amount of a substantially pure diastereomer of 10-propargyl-10-deazaminopterin, or a salt thereof, said diastereomer being (2S)-2-[[4-[(1S)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid or (2S)-2-[[4-[(1R)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid. 
     
     
         15 . The method of  claim 14 , wherein the inflammatory disorder is rheumatoid arthritis. 
     
     
         16 . The method according to  claim 14 , wherein the substantially pure diastereomer is (2S)-2-[[4-[(1S)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid in an amount greater than about 90% by weight of the total amount of 10-propargyl-10-deazaminopterin or the substantially pure diastereomer is (2S)-2-[[4-[(1R)-1-[(2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid in an amount greater than about 90% by weight of the total amount of 10-propargyl-10-deazaminopterin. 
     
     
         17 . The method according to  claim 14 , wherein the salt thereof is the hydrochloride salt. 
     
     
         18 . The method according to  claim 14  wherein the substantially pure diastereomer is administered orally. 
     
     
         19 . The method according to  claim 18  wherein the oral dosage is between 1 mg and 30 mg per week.