Treatment of Gout and Hyperuricemia

Abstract

Sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate is described. In addition, pharmaceutical compositions and uses of such compositions for the treatment of a variety of diseases and conditions are described.

What is claimed is: 
     
         1 . A method of treating gout comprising co-administration of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, and febuxostat to a subject, wherein said method provides:
 a. serum urate levels of less than 6 mg/dL;   b. serum urate levels of less than 5 mg/dL;   c. serum urate levels of less than 4 mg/dL;   d. serum urate levels of less than 3 mg/dL;   e. serum urate levels intraday change of more than 50%;   f. serum urate levels intraday change of more than 60%;   g. or a combination thereof.   
     
     
         2 . A method of reducing serum uric acid levels in a human comprising co-administration of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, and febuxostat to a subject, wherein said method provides:
 a. serum urate levels of less than 6 mg/dL;   b. serum urate levels of less than 5 mg/dL;   c. serum urate levels of less than 4 mg/dL;   d. serum urate levels of less than 3 mg/dL;   e. serum urate levels intraday change of more than 50%;   f. serum urate levels intraday change of more than 60%;   g. or a combination thereof.   
     
     
         3 . A method of treating hyperuricemia in a human comprising co-administration of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, and febuxostat to a subject, wherein said method provides:
 a. serum urate levels of less than 6 mg/dL;   b. serum urate levels of less than 5 mg/dL;   c. serum urate levels of less than 4 mg/dL;   d. serum urate levels of less than 3 mg/dL;   e. serum urate levels intraday change of more than 50%;   f. serum urate levels intraday change of more than 60%;   g. or a combination thereof.   
     
     
         4 . A method of treating hyperuricemia in a human with gout comprising co-administration of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, and febuxostat to a subject, wherein said method provides:
 a. serum urate levels of less than 6 mg/dL;   b. serum urate levels of less than 5 mg/dL;   c. serum urate levels of less than 4 mg/dL;   d. serum urate levels of less than 3 mg/dL;   e. serum urate levels intraday change of more than 50%;   f. serum urate levels intraday change of more than 60%;   g. or a combination thereof.   
     
     
         5 . A method of treating or preventing a condition characterized by abnormal tissue or organ levels of uric acid in an individual comprising co-administration of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, and febuxostat to a subject, wherein said method provides:
 a. serum urate levels of less than 6 mg/dL;   b. serum urate levels of less than 5 mg/dL;   c. serum urate levels of less than 4 mg/dL;   d. serum urate levels of less than 3 mg/dL;   e. serum urate levels intraday change of more than 50%;   f. serum urate levels intraday change of more than 60%;   g. or a combination thereof.   
     
     
         6 . The method of any  claims 1 - 5 , wherein the gout condition in the subject is characterized by the presence of large accumulated deposits of uric acid or tophi. 
     
     
         7 . The method of any of  claims 1 - 6  wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is about 750 mg. 
     
     
         8 . The method of any of  claims 1 - 7  wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is about 600 mg. 
     
     
         9 . The method of any of  claims 1 - 6  wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is about 500 mg. 
     
     
         10 . The method of any of  claims 1 - 6  wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is about 400 mg. 
     
     
         11 . The method of any of  claims 1 - 6  wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is about 200 mg. 
     
     
         12 . The method of any of  claims 1 - 6  wherein the daily dose is administered orally. 
     
     
         13 . The method of any of  claims 1 - 6  wherein the daily dose is administered in the morning. 
     
     
         14 . The method of any of  claims 1 - 6  wherein the daily dose is administered with food. 
     
     
         15 . A method of treating gout comprising co-administration of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, and allopurinol to a subject, wherein said method provides:
 a. serum urate levels of less than 6 mg/dL;   b. serum urate levels of less than 5 mg/dL;   c. serum urate levels of less than 4 mg/dL;   d. serum urate levels of less than 3 mg/dL;   e. serum urate levels intraday change of more than 50%;   f. serum urate levels intraday change of more than 60%;   g. a mean change in serum urate levels of greater than 8%;   h. or a combination thereof.   
     
     
         16 . A method of reducing serum uric acid levels in a human comprising co-administration of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, and allopurinol to a subject, wherein said method provides:
 a. serum urate levels of less than 6 mg/dL;   b. serum urate levels of less than 5 mg/dL;   c. serum urate levels of less than 4 mg/dL;   d. serum urate levels of less than 3 mg/dL;   e. serum urate levels intraday change of more than 50%;   f. serum urate levels intraday change of more than 60%;   g. a mean change in serum urate levels of greater than 8%;   h. or a combination thereof.   
     
     
         17 . A method of treating hyperuricemia in a human comprising co-administration of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, and allopurinol to a subject, wherein said method provides:
 a. serum urate levels of less than 6 mg/dL;   b. serum urate levels of less than 5 mg/dL;   c. serum urate levels of less than 4 mg/dL;   d. serum urate levels of less than 3 mg/dL;   e. serum urate levels intraday change of more than 50%;   f. serum urate levels intraday change of more than 60%;   g. a mean change in serum urate levels of greater than 8%;   h. or a combination thereof.   
     
     
         18 . A method of treating hyperuricemia in a human with gout comprising co-administration of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, and allopurinol to a subject, wherein said method provides:
 a. serum urate levels of less than 6 mg/dL;   b. serum urate levels of less than 5 mg/dL;   c. serum urate levels of less than 4 mg/dL;   d. serum urate levels of less than 3 mg/dL;   e. serum urate levels intraday change of more than 50%;   f. serum urate levels intraday change of more than 60%;   g. a mean change in serum urate levels of greater than 8%;   h. or a combination thereof.   
     
     
         19 . A method of treating or preventing a condition characterized by abnormal tissue or organ levels of uric acid in an individual comprising co-administration of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, and allopurinol to a subject, wherein said method provides:
 a. serum urate levels of less than 6 mg/dL;   b. serum urate levels of less than 5 mg/dL;   c. serum urate levels of less than 4 mg/dL;   d. serum urate levels of less than 3 mg/dL;   e. serum urate levels intraday change of more than 50%;   f. serum urate levels intraday change of more than 60%;   g. a mean change in serum urate levels of greater than 8%;   h. or a combination thereof.   
     
     
         20 . The method of any of  claims 15 - 19  wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is about 750 mg. 
     
     
         21 . The method of any of  claims 15 - 19  wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is about 600 mg. 
     
     
         22 . The method of any of  claims 15 - 19  wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is about 500 mg. 
     
     
         23 . The method of any of  claims 15 - 19  wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is about 400 mg. 
     
     
         24 . The method of any of  claims 15 - 19  wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, is about 200 mg. 
     
     
         25 . A method of treating gout comprising co-administration of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, and allopurinol to a subject, wherein said method provides a response rate (e.g., ITT analysis) of greater than 50%. 
     
     
         26 . A method of treating gout comprising co-administration of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt thereof, and allopurinol to a subject, wherein said method results in an adverse event in less than 15% of the subjects.