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(12) Patent Application Publication (10) Pub. No.: US 2013/0059868 A1 Miner Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2013/0059868 A1 Miner Et Al US 2013 0059868A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0059868 A1 Miner et al. (43) Pub. Date: Mar. 7, 2013 (54) TREATMENT OF GOUT Publication Classification (75) Inventors: Jeffrey Miner, San Diego, CA (US); Jean-Luc Girardet, San Diego, CA (51) Int. Cl. (US); Barry D. Quart, Encinitas, CA A613 L/496 (2006.01) (US) A6IP 29/00 (2006.01) (73) Assignee: Ardea Biociences, Inc., San Diego, CA A6IP 9/06 (2006.01) (US) A613 L/426 (2006.01) A 6LX3/59 (2006.01) (21) Appl. No.: 13/637,343 (52) U.S. Cl. ...................... 514/262.1: 514/384: 514/365 (22) PCT Fled: Mar. 29, 2011 (86) PCT NO.: PCT/US11A3O364 (57) ABSTRACT S371 (c)(1), (2), (4) Date: Oct. 24, 2012 Sodium 2-(5-bromo-4-(4-cyclopropyl-naphthalen-1-yl)-4H Related U.S. Application Data 1,2,4-triazol-3-ylthio)acetate is described. In addition, phar (60) Provisional application No. 61/319,014, filed on Mar. maceutical compositions and uses Such compositions for the 30, 2010. treatment of a variety of diseases and conditions. Patent Application Publication Mar. 7, 2013 Sheet 1 of 10 US 2013/00598.68A1 FIGURE 1 S. C SOC 55000 40 S. s 3. s Patent Application Publication Mar. 7, 2013 Sheet 2 of 10 US 2013/00598.68A1 ~~~::CC©>???>©><!--->?©><??--~~~~~·%~~}--~~~~~~~~*~~~~~~~~·;--~~~~~~~~~;~~~~~~~~~~}--~~~~~~~~*~~~~~~~~;·~~~~~ |×.> |||—||--~~~~ ¿*|¡ MSU No IL-1ra MSU50 IL-1ra MSU 100 IL-1ra MSU500 IL-1ra cells Only No IL-1 ra Patent Application Publication Mar. 7, 2013 Sheet 3 of 10 US 2013/00598.68A1 FIGURE 3 A: 50000 40000 R 30000 2 20000 10000 O -7 -6 -5 -4 -3 Lesinurad (log)M B: Lesinurad (log)M Patent Application Publication Mar. 7, 2013 Sheet 4 of 10 US 2013/00598.68A1 FIGURE 4 ;o z--; ºu ? }} } }} } } }} } } } }} } ;~~~~~~~~~~~~~~~~;~~~~~~~~~~~~~~~~;~~~~~~~~~~~~~~~~;~~~~~~~~~~~~~~~~~;~~~~~~~~~~~~~~~~);- }• Patent Application Publication Mar. 7, 2013 Sheet 5 of 10 US 2013/00598.68A1 FIGURES Iota WBC CO:cticite 3.438 & S.S.S. is: i: sis. Crix Patent Application Publication Mar. 7, 2013 Sheet 6 of 10 US 2013/00598.68A1 FIGURE 6 (a) Plasma Extravasation (b) Exudate Volume Patent Application Publication Mar. 7, 2013 Sheet 7 of 10 US 2013/00598.68A1 FIGURE 6 Continued Patent Application Publication Mar. 7, 2013 Sheet 8 of 10 US 2013/00598.68A1 FIGURE 7 Patent Application Publication Mar. 7, 2013 Sheet 9 of 10 US 2013/00598.68A1 FIGURE 8 Screening: Period Washout Randomize of urate if no gout lowering flare during therapy 1-2 weeks of colchicine -> Placcbo i. Patent Application Publication Mar. 7, 2013 Sheet 10 of 10 US 2013/00598.68A1 FIGURE 9 T 9-o-o-o-o-o-o-o-e- 8 f & US 2013/00598.68 A1 Mar. 7, 2013 TREATMENT OF GOUT wherein the mean duration of the gout flares in a patient undergoing uric acid level reduction is less than four days. CROSS-REFERENCE Another embodiment provides the method, wherein the mean 0001. This application claims priority to U.S. Provisional duration of the gout flares is less than three days. Another Application 61/319,014, filed Mar. 30, 2010, which is incor embodiment provides the method wherein the mean duration porated by reference in its entirety. of the gout flares is less than two days. 0010. One embodiment provides a method for treating FIELD OF THE INVENTION gout comprising administration to a patient in need a thera peutic agent that is a dual inhibitor of URAT1 and inflamma 0002 The present invention relates to the treatment of some. Another embodiment provides the method wherein the gout while Substantially reducing the duration and frequency dual inhibitor of URAT1 and inflammasome is 2-(5-bromo of gout flares associated with reductions of uric acid levels. 4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3- ylthio)acetate, or a polymorph thereof, or a pharmaceutically BACKGROUND OF THE INVENTION acceptable salt of 2-(5-bromo-4-(4-cyclopropylnaphthalen 0003 Gout is associated with elevated levels of uric acid 1-yl)-4H-1,2,4-triazol-3-ylthio)acetate or a polymorph that crystallize and deposit in joints, tendons, and Surround thereof. ing tissues. Gout is marked by recurrent attacks of red, tender, 0011. One embodiment provides a method of reducing hot, and/or Swollen joints. monosodium urate induced inflammation comprising admin istering a pharmaceutical composition comprising a pharma SUMMARY OF THE INVENTION ceutical agent having both uricoSuric and anti-inflammatory activity. Another embodiment provides the method wherein 0004. The treatment of gout typically involves the reduc the pharmaceutical agent is a URAT1 inhibitor with anti tion of serum uric acid levels. However, gout flares are asso inflammatory activity. Another embodiment provides the ciated with the reduction of uric acid levels. Drugs such as method wherein the pharmaceutical agent is 2-(5-bromo-4- colchicine can reduce the pain associated with gout flares (4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio) while a patient’s serum uric acid levels are being reduced, acetate, or a pharmaceutically acceptable salt thereof. however, colchicine is associated with several undesired side 0012. In another embodiment is provided the method effects, including gastrointestinal disorders. wherein the daily dose of 2-(5-bromo-4-(4-cyclopropylnaph 0005 Accordingly, described herein are methods, compo thalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharma sitions and dosing regimens for reducing serum uric acid ceutically acceptable salt thereof, is about 750 mg. In another levels while providing for a concomitant reduction in the embodiment is provided the method wherein the daily dose of intensity and duration of gout flares associated with other 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4- gout medications. Furthermore, described herein are meth triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt ods, compositions and dosing regimens for weaning a patient thereof, is about 600 mg. In another embodiment is provided off of co-administered colchicine; such weaning includes the method wherein the daily dose of 2-(5-bromo-4-(4-cyclo lower doses of colchicine and less time on colchicine relative propylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or to other gout medications. a pharmaceutically acceptable salt thereof, is about 500 mg. 0006. One embodiment provides a method of treating gout In another embodiment is provided the method wherein the comprising co-administration of 2-(5-bromo-4-(4-cyclopro daily dose of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)- pylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a 4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically pharmaceutically acceptable salt thereof, and colchicine to a acceptable salt thereof, is about 400 mg. In another embodi Subject, wherein said method provides greater mean gout ment is provided the method wherein the daily dose of 2-(5- flare reduction than co-administration of colchicine and bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol therapeutic agent that is not a dual inhibitor of URAT1 and an 3-ylthio)acetate, or a pharmaceutically acceptable salt inflammasome. thereof, is about 200 mg. 0007 Another embodiment provides the method wherein 0013. In another embodiment is provided the method the total dosage of colchicine administered during co-admin wherein the daily dose is administered orally. In another istration with 2-(5-bromo-4-(4-cyclopropylnaphthalen-1- embodiment is provided the method wherein the daily dose is yl)-4H-1,2,4-triazol-3-ylthio)acetate, or a pharmaceutically administered in the morning. In another embodiment is pro acceptable salt thereof, is at least 50% less than the total vided the method wherein the daily dose is administered with dosage of colchicine co-administered with a therapeutic food. agent that is not a dual inhibitor of URAT1 and an inflamma SO. 0014) Another embodiment provides the above listed 0008 Another embodiment provides the method wherein methods of reducing the duration of gout flares further com the amount of time that colchicine is co-administered with prising administration of a second serum uric acid lowering 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4- agent. In another embodiment is provided the method triazol-3-ylthio)acetate, or a pharmaceutically acceptable salt wherein the second serum uric acid lowering agent is a Xan thereof, is at least one week less than when colchicine is thine oxidase inhibitor. In another embodiment is provided co-administered with a therapeutic agent that is not a dual the method wherein the Xanthine oxidase inhibitor is febux inhibitor of URAT1 and an inflammasome. ostat or allopurinol. 0009. One embodiment provides a method of reducing the duration of gout flares comprising administration of a phar INCORPORATION BY REFERENCE maceutical composition comprising 2-(5-bromo-4-(4-cyclo 00.15 All publications and patent applications mentioned propylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, or in this specification are herein incorporated by reference for a pharmaceutically acceptable salt thereof, to a subject, the purposes cited. US 2013/00598.68 A1 Mar. 7, 2013 BRIEF DESCRIPTION OF THE DRAWINGS 0028. The treatment of gout typically involves the reduc tion of serum uric acid levels. However, gout flares are asso 0016. The novel features of the invention are set forth with ciated with the reduction of uric acid levels. Drugs such as particularity in the appended claims. A better understanding colchicine can reduce the pain associated with gout flares of the features and advantages of the present invention will be while a patient’s serum uric acid levels are being reduced, obtained by reference to the following detailed description however, colchicine is associated with several undesired side that sets forth illustrative embodiments, in which the prin effects, including gastrointestinal disorders.
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