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      POLYMORPHIC, CRYSTALLINE AND MESOPHASE FORMS OF 2 - (5-BROMO- 4- (4 -CYCLOPROPILNAFTALEN-1-IL) - 4H-1, 2, 4-TRIAZOL-3-ILTHIO) SODIUM ACETATE AND ITS USES.Crystalline polymorphs and solid mesophase forms are described 2 - (5-bromo- 4- (4-cyclopropylnaphthalen-1-yl) - 4h-1, 2, 4-triazol-3-ylthio) acetate. In addition, pharmaceutical compositions and uses of these compositions are provided for the treatment of various diseases and conditions.
    公开号:BR112012016795A2
    申请号:R112012016795-2
    申请日:2011-01-05
    公开日:2020-09-01
    发明作者:Irina Zamansky；Gabriel Galvin；Jean-Luc Girardet
    申请人:Ardea Biosciences Inc.；
    IPC主号:
    专利说明:

    Po - POLYMORPHIC, CRYSTALLINE AND MESOPHASE FORMS OF 2- (5- PP BROMO-4- (4-CYCLOPROPILNAFTALEN-1-IL) -4H-1,2,4-TRIAZOL-3- 1 ILTHIUM) SODIUM ACETATE AND ITS USES 'CROSS REFERENCE This order claims the benefit of US Provisional Order No. 61 / 293,602, filed on January 8, 2010, which is hereby incorporated by reference in its entirety.
    FIELD OF THE INVENTION The present invention relates to the polymorphic, crystalline and mesophase forms of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-11) -4H-1,2,4-triazole-3-yl) sodium acetate, which lowers uric acid levels.
    BACKGROUND OF THE INVENTION Gout is associated with high levels of uric acid that crystallize and settle in joints, tendons and surrounding tissues. Gout is marked by recurrent attacks of red, sensitive, hot and / or swollen joints.
    SUMMARY OF THE INVENTION Crystal polymorphs, mesophases and other forms of sodium 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) - 4H-1,2,4-triazol-3-yl) acetate are described herein :
    AND ! 25 gos NO! The Na ”'| À A | One aspect described here consists of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) - crystalline polymorphs - |
    | | | '2/83' - '4H-1,2,4-triazol-3-ylthio) sodium acetate characterized * by peaks at 4.90, 9.83 and 25.29º206 + 0.1º26. In an additional embodiment, such a crystalline polymorph is | still characterized by at least two additional peaks in: & 6.86, 8.41, 10.13, 17.92 and 23.10º26 + 0.1º26, Still in Í other additional modalities, the crystalline polymorph exhibits a diffraction pattern of X-ray powder substantially | | equal to the X-ray powder diffraction pattern shown in | i FIGURE 1. In a related aspect, crystalline polymorphs of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate are described herein sodium, characterized by a start point: endothermic, as determined by scanning calorimetry | differential, around 62ºC.
    In an additional embodiment, the crystalline polymorph is characterized by a differential scanning calorimetry pattern substantially equal to the differential scanning calorimetry pattern shown in FIGURE 2. In another related aspect, Form A of the crystalline polymorph is described here.
    In a related aspect, solid pharmaceutical compositions comprising an effective amount of the polymorph | crystalline "characterized by the diffraction patterns | mentioned above, an effective amount of the | crystalline polymorph characterized by the aforementioned differential scanning calorimetry patterns | or an effective amount of Form A of the | crystalline polymorph as an active ingredient; and at least one excipient or vehicle.
    A method for treating or preventing hyperuricemia or a disease caused by high levels of uric acid, comprising |
    | 3/83 | «7 administration, to an individual in need, of a | SÍ effective amount of the crystalline polymorph characterized by the diffraction patterns mentioned above, of a | effective amount of the crystalline polymorph characterized by the aforementioned differential scanning calorimetry I standards, or an effective amount of: Crystalline polymorph form A, A method for treating or preventing gout, comprising administering, to a 'needy individual, an effective amount of the crystalline polymorph characterized by the aforementioned diffraction patterns, an effective amount of the crystalline polymorph characterized by the aforementioned differential scanning calorimetry patterns, or an effective amount of Form A crystalline polymorph.
    One aspect described here consists of crystalline polymorphs of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) - 4H-1,2,4-triazol-3-ylthio) sodium acetate characterized by peaks in 4 , 22, 8.51 and 16.95º206 + 0.1º26. In an additional modality, such a crystalline polymorph is further characterized by a peak at 12.80º26 + 0.1º29. Still ; in other additional modalities, the crystalline polymorph! exhibits an X-ray powder diffraction pattern | substantially equal to the powder diffraction pattern of: 25 X-rays shown in FIGURE 5. In a related aspect, crystalline polymorphs of 2- (5-bromo-4- | (4-cyclopropylnaftalen-1-11) - are described herein 4H-1,2,4-triazol-3-ylthio) | sodium acetate, characterized by a beginning of the endothermic point, as determined by differential scanning calorimetry, around 173ºC. In one mode |
    ! | 4/83; | = 'additionally, the crystalline polymorph is characterized by a | | the differential scanning calorimetry standard | 'substantially equal to the differential scanning calorimetry pattern shown in FIGURE 6. In another | 5 related aspect, crystalline polymorph 'Form B is described herein.
    In a related aspect, they are described here | | solid pharmaceutical compositions comprising a | 'effective amount of the crystalline polymorph featured!
    by the previously mentioned diffraction patterns, an effective amount of the crystalline polymorph characterized by the differential scanning calorimetry patterns mentioned above, or an effective amount of
    : Form B of the crystalline polymorph, as an active ingredient; and at least one excipient or vehicle.
    A method for treating or preventing hyperuricemia or a disease caused by high levels of uric acid, comprising administering to an individual in need an effective amount of the crystalline polymorph characterized by the diffraction patterns mentioned above, an effective amount of crystalline polymorph characterized by the differential scanning calorimetry patterns mentioned above, or an effective amount of
    'Form B of the crystalline polymorph.
    A method for treatment | or prevention of gout, comprising administration, to a | 25 individual in need, an effective amount of the crystalline polymorph i characterized by the! diffraction mentioned above, of an amount: effective of the crystalline polymorph characterized by the differential scanning calorimetry standards mentioned
    |
    | : 5/83 - 'previously, or an effective amount of Form B of - crystalline polymorph. "One aspect described here consists of crystalline polymorphs of 2- (S-bromo-4- (4-cyclopropylnaphthalen-1-11) -: 5 4H-1,2,4-triazol-3-ylthio) characterized by an X-ray powder diffraction pattern substantially equal to the X-ray powder diffraction pattern shown in! FIGURE 7. In a related aspect, crystalline polymorphs of 2- (S-bromo-4- ( 4- cyclopropylnaphthalen-1-1i1) -4H-1,2,4-triazol-3-ylthio) sodium acetate characterized by a differential scanning calorimetry pattern substantially equal to the differential scanning calorimetry pattern shown in FIGURE 8. In another related aspect, Form B 'of the crystalline polymorph is described here.
    In a related aspect, solid pharmaceutical compositions are described herein comprising an effective amount of the crystalline polymorph characterized by the aforementioned diffraction patterns, an effective amount of the crystalline polymorph characterized by the aforementioned differential scanning calorimetry patterns, or an effective amount Form B 'of the crystalline polymorph, as an active ingredient; and at least one excipient or vehicle.
    A method for treating or preventing hyperuricemia or a disease caused by high levels of uric acid, comprising administering to an individual in need an effective amount of the crystalline polymorph characterized by the aforementioned diffraction patterns of a effective amount of the crystalline polymorph characterized by differential scanning calorimetry patterns |
    | 6/83 (the + - Ú mentioned above, or an effective amount of the S Form B 'of the crystalline polymorph. A method for treating or preventing gout, comprising administering to an individual in need an effective amount of the crystalline polymorph characterized by the aforementioned diffraction patterns, an effective amount of the crystalline polymorph characterized by the differential scanning calorimetry patterns mentioned above, or an effective amount of Form B 'of the crystalline polymorph 10.
    One aspect described here consists of crystalline polymorphs of sodium 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) - 4H-1,2,4-triazol-3-yl) acetate characterized by peaks in 6 , 9, 10.1 and 22.6º26 + 0.1º20. In additional modalities, the crystalline polymorph is still characterized by at least two peaks at 23.3, 23.9, 25.2, 28.3 or 29.0º20 + 0.1º20. In yet other additional embodiments, the crystalline polymorph exhibits an X-ray powder diffraction pattern substantially equal to the X-ray powder diffraction pattern shown in FIGURE 9. In another related aspect, polymorph Form C is described here. | crystalline. In a related aspect, they are described here | solid pharmaceutical compositions comprising one! effective amount of the crystalline polymorph characterized: 25 by the aforementioned diffraction patterns or an effective amount of Form C of the crystalline polymorph as an active ingredient; and at least one excipient Ou | vehicle. A method for treating or preventing hyperuricemia or a disease caused by high levels of uric acid, comprising administering, to a |
    | 7/83 '-' individual 'in need, an effective amount of the - crystalline polymorph characterized by the aforementioned' diffraction patterns or an effective amount 'of Form C of the crystalline polymorph.
    A method for: treating or preventing gout, comprising administering to an individual in need an effective amount of the crystalline polymorph characterized by the aforementioned diffraction patterns or an effective amount of Form C of the crystalline polymorph.
    One aspect described here consists of crystalline polymorphs of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) - 4H-1,2,4-triazol-3-ylthio) sodium acetate characterized by peaks in 10 , 3, 17.8 and 25.2º26 + 0.1º20. In yet other additional embodiments, the crystalline polymorph exhibits an X-ray powder diffraction pattern substantially equal to the X-ray powder diffraction pattern shown in FIGURE 10. In another related aspect, the polymorph Form D is described here. crystalline.
    In a related aspect, solid pharmaceutical compositions are described herein comprising an effective amount of the crystalline polymorph characterized by the aforementioned diffraction patterns or an effective amount of crystalline polymorph Form D as an active ingredient; and at least one excipient or vehicle.
    A method for treatment: 25 or prevention of hyperuricemia or a disease caused by high levels of uric acid, which comprises administering to an individual in need an effective amount of the crystalline polymorph characterized by the aforementioned diffraction patterns or an amount of Form D of the crystalline polymorph. |
    ! 8/83 '*' A method for treating or preventing gout, which. includes administering to an individual in need an 'effective amount of the crystalline polymorph characterized: by the aforementioned diffraction patterns or | 5 an effective amount of Form D of the crystalline polymorph. i One aspect described here consists of polymorphs | crystalline 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-11) - 4H-1,2,4-triazol-3-ylthio) sodium acetate characterized by at least three peaks in 10.5, 22 , 9, 23.2 or 24.6º20 + 0.1º26. In yet other additional embodiments, the crystalline polymorph exhibits an X-ray powder diffraction pattern substantially equal to the X-ray powder diffraction pattern shown in FIGURE 11. In another related aspect, Form E of the crystalline polymorph.
    In a related aspect, solid pharmaceutical compositions are described herein which comprise an effective amount of the crystalline polymorph characterized by the aforementioned diffraction patterns or an effective amount of Form E of the crystalline polymorph as an active ingredient; and at least one excipient or vehicle, a method for treating or preventing | hyperuricemia or a disease caused by elevated levels of uric acid, comprising administering to an 'individual' in need either an effective amount of the crystalline polymorph t characterized by the aforementioned diffraction patterns or an effective amount of Form E of the crystalline polymorph.
    A method for treating or preventing gout, comprising administering to an individual in need an effective amount of the characterized crystalline polymorph |
    | I 9/83! 1 DO | - by the aforementioned diffraction patterns or an effective amount of Form E of the crystalline polymorph. 'In additional aspects, a form of! solid mesophase of 2- (5S-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) sodium acetate, which exhibits a powder powder diffraction pattern -X substantially equal to the X-ray powder diffraction pattern shown in FIGURE 12, FIGURE 13, FIGURE 14 or FIGURE 15, in modalities! In addition, solid pharmaceutical compositions are provided that comprise an effective amount of any of the aforementioned solid mesophasic forms of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1yl) -4H-1,2,4-triazole -3-ylthio) sodium acetate, or a combination thereof; and at least one excipient or vehicle. In an additional embodiment, methods are provided for treating or preventing hyperuricemia or a disease caused by elevated levels of uric acid, comprising administering an effective amount of any of the solid mesophases mentioned above, or a combination thereof. In an additional embodiment, methods for treating or preventing gout are provided, which include administering an effective amount of | any of the solid mesophases mentioned | previously, or a combination of these.
    : 25 In an additional aspect, solid pharmaceutical compositions are provided which comprise an effective amount of at least two of the forms of crystalline polymorphs or! previously mentioned solid mesophases of 2- (5-bromo- 4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazole-3- |
    | 10/83 - (ilthium) sodium acetate; and at least one excipient or. vehicle. 'In an additional aspect, methods are provided for: treating or preventing hyperuricemia or a disease' 5 caused by elevated levels of uric acid, which include administering an effective amount of at least two: of the forms of crystalline polymorphs or mesophases previously mentioned solids of sodium 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-yl) acetate; and at least one excipient or vehicle.
    INCORPORATION BY REFERENCE All publications and patent applications mentioned in this specification are hereby incorporated by reference to the same degree as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference,
    BRIEF DESCRIPTION OF THE DRAWINGS The new features of the invention are presented with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the detailed description | next one that presents illustrative modalities, in which; the principles of the invention are used, and in the drawings! accompanying it. FIGURE 1 represents an illustrative X-ray diffraction pattern of polymorph Form A. FIGURE 2 represents an illustrative pattern of polymorph Form A differential scanning calorimetry. |
    | | 11/83 | ”: FIGURE 3 represents an infrared spectrum t: illustrative of Form A of the polymorph.
    | : FIGURE 4 represents an illustrative Raman spectrum of polymorph Form A.
    | FIGURE 5 represents an illustrative pattern of: polymorph Form B X-ray diffraction.
    ; FIGURE 6 represents an illustrative pattern of differential scanning calorimetry of polymorph Form B.
    FIGURE 7 represents an illustrative X-ray diffraction pattern of Polymorph Form B '.
    FIGURE 8 represents an illustrative pattern of differential scanning calorimetry of Form B 'of the polymorph.
    FIGURE 9 represents an illustrative pattern of. X-ray diffraction of Form C of the polymorph.
    FIGURE 10 represents an illustrative X-ray diffraction pattern of polymorph Form D.
    FIGURE 11 represents an illustrative X-ray diffraction pattern of polymorph Form E.
    FIGURE 12 represents an illustrative pattern of | X-ray diffraction from mesophase 1, 'FIGURE 13 represents a cyclic pattern of differential scanning calorimetry illustrative of: 25 mesophase 1, FIGURE 14 represents an illustrative X-ray diffraction pattern from mesophase 2.
    FIGURE 15 represents an illustrative X-ray diffraction pattern from mesophase 3,
    DETAILED DESCRIPTION OF THE INVENTION |
    | 12/83 - a -, Although they have been shown and described here | . modalities of the present invention, it will be obvious to those skilled in the art that these modalities are provided | just as an example.
    Various variations, changes and | 5 substitutions will occur to those qualified in the technique without; depart from the invention.
    It should be understood that several alternatives to the modalities of the invention described herein can be employed in the practice of the invention.
    The following claims are intended to define the scope of the invention and! 10 that the methods and structures within the scope of these claims and their equivalents are covered by them.
    The section headings used here are for organizational purposes only, and should not be considered as limiting the theme described.
    All documents, or portions of documents, cited in the application, including, without limitation, patents, patent applications, articles, books, manuals and treaties, are hereby expressly incorporated by reference in their purpose for any purpose.
    The present invention relates to the polymorphic, crystalline and mesophase forms of sodium 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-11) -4H-1,2,4-triazol-3-ylthio) acetate , which decrease uric acid levels. 'The term “Polymorph Form A” refers to a form | crystalline 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1yl) -4H- | 25 1,2,4-triazol-3-ylthio) sodium acetate which exhibits a powder powder diffraction pattern -X substantially equal to that 'shown in FIGURE 1, and a differential scanning calorimetry profile substantially equal to that shown in FIGURE 2. | |
    | 13/83! Poe '«' The term“ Polymorph Form B ”refers to a form | . crystalline 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H- '1,2,4-triazol-3-ylthio) sodium acetate which exhibits a' powdery powder diffraction pattern ' -X substantially equal to that | | 5 shown in FIGURE 5, and a calorimetry profile of | differential sweep substantially equal to that shown in FIGURE 6.:: The term "Polymorph Form B" refers to a form | crystalline 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1yl) -4H- 1,2,4-triazol-3-ylthio) sodium acetate that exhibits an X-ray powder diffraction pattern substantially the same as that shown in FIGURE 7, and a differential scanning calorimetry profile substantially equal to that shown in FIGURE 8. Three other crystalline forms exhibit X-ray powder diffraction patterns C, De E substantially equal to those shown in FIGURES 9, 10 and 11, respectively.
    Three solid mesophasic forms 1, 2 and 3 exhibit X-ray powder diffraction patterns substantially the same as those shown in FIGURES 12, 14 and 15, respectively.
    The present invention is also related to the | methods for treating or preventing disease, comprising administering an effective amount of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazole-3-ylthio) sodium acetate, such as polymorph Form A; crystalline, Form B of the crystalline polymorph, Form B '! of the crystalline polymorph, the crystalline form exhibiting a pattern | of XRPD C, the crystalline form exhibiting XRPD D pattern, the crystalline form exhibiting XRPD E pattern, the form of |
    | '' 14/83 -, solid mesophase 1, the form of solid mesophase 2, the form of - solid mesophase 3, or a combination of these. 'The present invention is also related to | solid pharmaceutical composition comprising, as a | ! 5 active ingredient, an effective amount of 2- (5-bromo-4- | (4-cyclopropylnaphthalen-1-11) -4H-1,2,4-triazol-3-ylthio) sodium acetate, as Form A polymorph G | crystalline, Form B of the crystalline polymorph, Form B '| of the crystalline polymorph, the crystalline form exhibiting XRPD C pattern, the crystalline form exhibiting XRPD D pattern, the crystalline form exhibiting XRPD E pattern, the solid mesophase form 1, the solid mesophase form 2, the solid mesophase form 3, or a combination of these.
    Also described are processes for preparing crystalline polymorph Form A, crystalline polymorph Form B, crystalline polymorph Form B ', the crystalline form exhibiting XRPD C pattern, the crystalline form | . exhibiting XRPD D pattern, the crystalline form exhibiting XRPD E pattern, the solid mesophase form 1, the solid mesophase form 2, the solid mesophase 3 form of 2- (5- bromo-4- (4-cyclopropylnaphthalen) 1-11) -4H-1,2,4-triazol-3-ylthio) sodium acetate. In certain cases, it has been found that the crystalline polymorphs of 2- (5-bromo-4- (4-cyclopropylnaphthalen) 1-yl) - 4H-1,2,4-triazol-3-ylthio) sodium acetate exhibit increased stability compared to the solid-state amorphous form of carboxylic acid.
    In some cases, the increased stability of crystalline polymorphs of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) allows the preparation of forms of | |
    | | 15/83 | Po | [LS pharmaceutical dosage that exhibit reduced variability in the dosage present in a certain dosage form, reduction in the presence of impurities in the final pharmaceutical product, and a | increased validity of formulated dosage forms, when | compared to the pharmaceutical dosage form prepared with the solid amorphous form of carboxylic acid. ! 'In some embodiments, a polymorph described here (for example, Form A or Form B or Form B') shows no degradation (for example, less than 0.01%, less than 0.1%, less than 0 , 5% by weight) (i) for at least 3 months under accelerated conditions (for example, 40ºC-75% relative humidity), for at least 4 months under accelerated conditions (for example, 40ºC-75% relative humidity) , for at least 5 months under accelerated condition (for example, 40ºC-75% relative humidity), for at least 6 months under accelerated condition (for example, 40ºC-75% relative humidity), for at least 9 months under condition accelerated (for example, 40ºC-75% relative humidity), for at least 12 months under condition accelerated (for example, 40ºC-75% relative humidity), and / or (ii) for at least 12 months under 'conditions of long term (for example, 25ºC-60% relative humidity), for at least 18 months under long term conditions | term (eg 25ºC-60% relative humidity), for at least '24 months under long term conditions (eg: 25 25ºC-60% relative humidity). 2- (5-Bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-i triazol-3-ylthio) sodium acetate Various polymorphic, crystalline and mesophasic forms of 2 are described herein - (5-bromo-4- (4-cyclopropylnaphthalen-11-yl) -4H-1,2,4-triazol-3-yl) acetate |
    : 16/83 | . sodium that lower uric acid levels (see, for example, U.S. Patent Publication 2009/0197825, U. U.S. Patent Publication 2010/0056464 and U.S. Patent Publication 2010/0056465). Details of clinical studies j 5 involving 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1yl) -4H- t | 1,2,4-triazol-3-ylthio) sodium acetate have been described in ' International Patent Application PCT / US2010 / 052958. | Polymorph form A | In one embodiment, polymorph Form A of sodium 2- (5- 10 bromo-4- (4-cyclopropylnaphthalen-11-yl) -4H-1,2,4-triazol-3-ylthio) exhibits a X-ray powder diffraction pattern characterized by the diffraction pattern summarized in Table 1A or Table 1B.
    In some ways, it is here; A '2- (5-bromo-4- (4- u 15 cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate' polymorph is provided which comprises at least 3 peaks (+ 0.1º20) of Table 1A or 1B.
    In certain embodiments, a polymorph of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1i1) -4aH- 1,2,4-triazol-3-ylthio) sodium acetate comprising at least 20 minus 4 peaks of (+ 0.1º26) from Table 1A or 1B, at least peaks of (+ 0.1º26) from Table 1A or 1B, at least 6 peaks of (+ 0.1º26) from Table 1A Or 1B, at least minus 8 peaks of (+ 0.1º26) from Table 1A or 1B, at least 10 peaks of (+] 0.1º20) from Table 1A, at least 15 peaks of (+ 0.1º20) from! 25 Table 1A, at least 20 peaks of (+ 0.1º280) from Table 1A, at least 25 peaks of (+ 0.1º20) from Table 1A, or at least 30 peaks of (+ 0.1º26) from Table 1A. | Table 1A [2% | space to [rmeensiaaas (o) | | |
    It is j: 8.41 + 0.10 10.512 + 0.126 61 | 9.83 + 0.10 2 8.996 + 0.092 - 8d -: 10.13 + 0.10 8.730 + 0.087 97 10.60 + 0.10 8.346 + 0.079 28. 12.32 + 0.10 7.183 + 0.059 45 [ 12.67.2010 | 7.041 + 0.056 | 45 13.07 + 0.10 6.772 + 0.052 42 14.01 + 0.10 6.322 + 0.045 22 14.48 + 0.10 | 6.118 + 0.042 35: 14.80 + 0.10 5.988 + 0.041 23 | '15.15 + 0.10 5.850 + 0.039 52 | 16.28 + 0.10 5.444 + 0.033 18 16.70 + 0.10 5.309 + 0.032 Is' 5.246 + 0.031 22 [17.92 + 0.20 | 4.950 + 0.028 70 4.255 + 0.020 42 4.163 + 0.019 25 1 21.68 + 0.10 4.099 + 0.012 18: | 23.10 + 0.10 3.850 + 0.027 55 '! 23.54 + 0.10 3.780 x 0.016 20 '| 23.95 + 0.10 3.715 2 0.015 37 | 24.67 + 0.10 3.609 + 0.014 4th oo 26.96 + 0.10 [s307 1 01022 BB |
    ; Í 18/83 | | : Table 1B | > las29 20120 | 35222004 | 6 = In an embodiment provided here, Form A of the polymorph of sodium 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1yl) -4H- 1,2,4-triazol-3-ylthio) acetate is characterized by X-ray powder diffraction pattern peaks at 4.90, 9.83 and 25.29º26 + 0.1º206. In additional modalities, Form A: of the polymorph is still characterized by at least one peak that appears in 6.86, 8.41, 10.13, 17.92 and 23.10º20 + 0.1º20, In additional modalities, the Polymorph form A is further characterized by at least two peaks that appear | in 6.86, 8.41, 10.13, 17.92 and 23.10º20 + 0.1º20, Still in the! other additional modalities, the polymorph exhibits an X-ray powder diffraction pattern substantially the same as! X-ray powder diffraction pattern shown in FIGURE 1. | 15 Polymorph Form B: In one embodiment, Polymorph Form B of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazole-3-: iltio) sodium acetate exhibits a powder diffraction pattern of | t | i; 19/83
    | | 7 X-rays characterized by the diffraction pattern summarized in Table 2A or 2B.
    In some embodiments, a polymorph of 2- (S-bromo-4- (4-cyclopropylnaphthalene-1-11) - 4H-1,2,4-triazol-3-yl) acetate is provided here. understands | 5 at least 2 peaks of (+ 0.1º26) from Table 2A or 2B.
    In certain embodiments, a polymorph of 2- (5- | | bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3- | | ylthio) acetate is provided herein that comprises at least 3 peaks of! (+ 0.1º20) of Table 2A or 2B, at least 4 peaks of (+ 0.1º20) of Table 2A or 2B, at least 5 peaks of (+: 0.1º26) of Table 2A, at least 6 peaks of (+ 0.1º20) from | Table 2A, at least 8 peaks of (+ 0.1º20) from Table 2A, | at least 10 peaks of (+ 0.1º26) from Table 2A, at least 12 peaks of (+ 0.1º26) from Table 2A, at least 14 peaks of "7 15 (+ 0.1º20) from Table 2A, or at least minus 16 peaks of (+ 0.1º28) from Table 2A.
    Table 2A '| 2nd: 26! |
    | 20/83:: | Table 2B | 2 | space a (à) - | rncensiade (s) | 8.51 + 0.10 10.392 + 0.123: In an embodiment provided herein, the polymorph form B of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1yl) -4H- 1,2,4- triazole-3-ylthio) sodium acetate is characterized by C peaks of X-ray powder diffraction pattern at 4.22, 8.51, and 16.95º206 + 0.1º20. In an additional modality, the polymorph form B o is further characterized by a peak that appears: at 12.80º26 + 0.1º28. In yet other additional embodiments, the polymorph exhibits an X-ray powder diffraction pattern substantially equal to the X-ray powder diffraction pattern shown in FIGURE 5. Form B 'of the polymorph In one embodiment, Form B' of the polymorph of 2- (5- bromo-4- (4-cyclopropylnaphthalen-1-11) -4H-1,2,4-triazole-3- | 15thio) sodium acetate exhibits a powder diffraction pattern of SC X-rays characterized by the diffraction pattern summarized in FIGURE 7.: o Form C of the polymorph |
    | 21/83 '-! 7 In one embodiment, polymorph Form C of 2- (5-] "bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazole-3 'ylthio sodium acetate exhibits an X-ray powder diffraction pattern characterized by the diffraction pattern summarized in | Table 3A or 3B.
    In some modalities, it is provided here | a polymorph of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-11) - | 4H-1,2,4-triazol-3-ylthio) sodium acetate comprising at least 3 peaks of (+ 0 , 1º26) of Table 3A or 3B.
    In certain embodiments, a polymorph of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-11) -4H-1,2,4-triazole-3- = ylethyl) acetate comprising at least 4 peaks of (+ 0.1º20) from Table 3A Or 3B, at least 5 peaks of (+ 0.1º286) from Table 3A or 3B, at least 6 peaks of (+ | 0.1º20) from Table 3A or 3B, at least 8 peaks of (+ * 15 0.1º26) from Table 3A or 3B, at least 10 peaks of (+. 0.1º26) from Table 3A, at least 15 peaks of (+ 0.1º20) from " Table 3A, at least 20 peaks of (+ 0.1º26) from Table 3A, or at least 25 peaks of (+ 0.1º26) from Table 3A. | Table 3A | |: '6.308 + 0.045 14 | |
    | ; | 22/83: '| ; : 4,215 + 0,020 19:! | 2319202 | 3726200s | ão | : 3.295 + 0.012 34 Table 3B. | | so: 3.534 + 0.014 84:; In an embodiment provided herein, the polymorph Form "ec of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4sH- 1,2,4-triazol-3-ylthio) sodium acetate is characterized by. |
    | 23/83 '| To. X-ray powder diffraction pattern peaks at 6.9, 10.1, '- and 22.6º206 + 0.1º20. In additional modalities, the Cc Form of the 'polymorph is further characterized by at least one peak that: appears at 23.3, 23.9, 25.2, 28.3 and 29.0º26 + 0.1º20, Em | 5 additional modalities, Form C of the polymorph is further characterized by at least two peaks that appear at 23.3, 23.9, 25.2, 28.3 and 29.0º20 + 0.1º26. In yet other additional embodiments, the polymorph exhibits an X-ray powder diffraction pattern substantially equal to the X-ray powder diffraction pattern shown in FIGURE 9. Polymorph form D; In one embodiment, Form D of the polymorph of 2- (5- | bromo-4- (4-cyclopropylnaphthalen-1-1yl) -4H-1,2,4-triazol-3'-yl) acetate exhibits a X-ray powder diffraction pattern characterized by the diffraction pattern summarized in Table 4A or 4B.
    In some embodiments, it is provided here. a polymorph of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-11) - 4H-1,2,4-triazol-3-ylthio) sodium acetate comprising at least 2 peaks of (+ 0, 1º20) of Table 4A or 4B.
    In certain embodiments, a polymorph of 2- (5-:: bromo-4- (4-cyclopropylnaphthalen-1-1yl) -4H-1,2,4-triazol-3-ylthio) acetate comprising at least 3 peaks. of the (+ 0.1º20) of Table 3A or 3B, at least 4 peaks of (+ '0.1º268) of Table 3A, at least 5 peaks of (+ 0.1º20) of | 25 Table 3A, at least 6 peaks of (+ 0.1º26) from Table 3A, cc at least 8 peaks of (+ 0.1º20) from Table 3A, at least | | 10 peaks of (+ 0.1º26) from Table 3A, at least 15 peaks of | (+ 0.1º20) from Table 3A, or at least 20 peaks of (+ i 0.1º20) from Table 3A.
    Table 4A. |
    ] 24/83 “a. - EEA | o | errors 65201 69201 n | ; "o; j 6,042 + 0,053: | 4,994 + 0,028 | at 4,896 + 0,027 21 '22: o 3,959 + 0,017 2,674 + 0,017': | 2522202 | 3538 200m | 6 | o! o | 3,087 + 0,010 3,012 4 0,010 vo i Table 4B -: | [2% | Space d (À) Intensity (%) o 8.605 à 0.084 | 25.2 20011 | asso. | ss |: |
    | 25/83 | "In one embodiment provided herein, Form D of ': 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1yl) -aH- polymorph. 1,2,4-triazole-3-yl ) sodium acetate is characterized by X-ray powder diffraction pattern peaks at 10.3, 17.8! and 25.2º20 + 0.1º206., In yet other additional modalities, o the polymorph exhibits a pattern of X-ray powder diffraction substantially equal to the X-ray powder diffraction pattern shown in FIGURE 10. 2! Form E of the polymorph, In one embodiment, Form E of the polymorph of 2- (5- bromo- 4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) sodium acetate exhibits a "X-ray" powder diffraction pattern characterized by the diffraction pattern summarized in i Table 5, In some embodiments, a * 15 polymorph of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1yl1) -4H- | '1,2,4-triazol-3-ylthio) acetate is provided here sodium which comprises at least 2 peaks of (+ 0.1º209) from Table 5A or 5B.
    In certain embodiments, a polymorph of 2- (5-bromo-4- o (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate comprising at least minus 3 peaks of (+ | 0.1º20) from Table 5A or 5B, at least 4 peaks of (+.; 0.1º20) from Table 5A or 5B, at least 5 peaks of E: '0.1º28) from Table 5A or 5B, at least 6 peaks of (+:: 0.1º20) from Table 5A or 5B, at least 8 peaks of (+ i '25 0.1º26) from Table 5A Or 5B, at least 10 peaks of (+ |; 0.1º20) of Table 5A, at least 15 peaks of (+ 0.1º20) of M i Table 5A, at least 20 peaks of (+ 0.1º26) of Table 52, i at least 25 peaks of (+ 0.1º20) of Table 5A, or at least 30 peaks of (+ 0.1º28) of Table 524.: Table 5A '|
    ! 26/83 [NS -: UT º20. Space d (À) ': 6.8 + 0.1 13.038 + 0.195; | an | 32 ':
    SAS 17.1 + 0.1 5.198 + 0.030 28 | | 17.5 + 0.1 5.068 + 0.029 as “. | 2942002 | assess 003 [| | ”; 3.973 + 0.018 33:; 3.890 + 0.017 64 P | nn. |
    | : | 27/83. as a | '28.7 + 0.1 3.115 + 0.011 35 | | ! 29.1 + 0.1 3.071 + 0.010 32 | : Table 5B: 22.9 + 0.1 3.890 + 0.017 lo | | : 3.834 + 0.016 70 s. In a modality provided herein, Form E of the polymorph of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -aH- '1,2,4-triazol-3-ylthio) sodium acetate is characterized by the X-ray powder diffraction pattern peaks at 120.5 ,. 22.9,. : 23.2 & and 24.6º20 + 0.1º26. In yet other "additional modalities, the polymorph exhibits an X-ray powder diffraction pattern substantially equal to the 'X-ray powder diffraction pattern shown in FIGURE 11.:' In certain embodiments, any of the polymorphs here 'described (for example, Form A) optionally comprises (or is mixed or in combination with) a certain amount of i 2- (S5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2, 4-triazole- | 3-ylthio) amorphous sodium acetate.
    In some embodiments, the amorphous component of the polymorph (for example, Form A) or: polymorph combination comprises less than 50% by weight | polymorph or polymorph combination, less than 25% | of the weight of the polymorph or polymorph combination, less than. . than 15% by weight of the polymorph or polymorph combination,. "|
    Í! | 28/83 | h less than 10% by weight of the polymorph or combination of: ': polymorph, or less than 5% by weight of the polymorph Or | "polymorph combination. er! Hydrates:! 5 In certain embodiments, oo 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazole hydrate is provided here -, 3-ylthio) sodium acetate.
    In some embodiments, sodium hydrate 2- (5-bromo-4- (4-cyclopropylnaphthalen 1-11) -4H-1,2,4-triazol-3-ylthio) acetate is provided here. crystalline.
    Still in additional modalities, hydrate | crystalline 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H- 1,2,4-triazol-3-ylthio) acetate comprises 2- (5-bromo-4- (4-cyclopropylnaphthalen) -1-yl) -4H-1,2,4-triazol-3-ylthio) acetate ie water in a 1: 1 to 1: 5 molar ratio. In some * 15 embodiments, the crystalline hydrate of 2- (5-bromo-4- (4-:: cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate. comprises 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H- 1,2,4-triazol-3-ylthio) acetate and water in a molar ratio between 1: 1.5 and 1: 3, 5, or between 1: 1.8 and 1: 3, or between 1: 2 is | 1: 2.8, OR about 1: 2, or about 1: 2.5. In some - . | embodiments, a hydrate of 2- (S-bromo-4- i (4-cyclopropylnaphthalen-11-yl) -4H-1,2,4-triazole-3-: sodium chloride) comprising at least 5% by weight O i of water.
    In certain embodiments, a hydrate is provided here. | 25 of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) shit, 2,4-oO: | triazol-3-ylthio) sodium acetate comprising at least i 9% by weight of water, 9-15% by weight of water, 10-13% by weight of water, 5-25% by weight of water, or the like. ; Particle size '| 1st |
    29/83 'i | 4 MANN In certain embodiments, a particle is provided here:: polymorph of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) - 1 ”4H-1,2,4-triazole-3-yl ) sodium acetate (eg: | crystalline, or which comprises a crystalline component). In | In some embodiments, a polymorph of 2- (5- 'bromo-4- (4-cyclopropylnaphthalen-1-11) -4H-1,2,4-triazol-3-ylthio) sodium acetate (e.g. , crystalline, or "comprising a crystalline component) that has a particle size of about 5-50 microns. In some embodiments, the average particle size is at least | 10 microns, 15-50 microns, 15-35 microns, 35-45 microns, 35-40 microns, about 40 microns, or the like In some embodiments, particles of 2- (5-bromo-4- (4- C cyclopropylnaftalen-1-yl) -4H-1, 2,4-triazol-3-ylthio) acetate | ”15 sodium (for example, crystalline, or comprising one: crystalline component, for example, a polymorph of Form; A) has an average diameter greater than 5 or 10 microns o have increased stability parameters compared to ES with smaller diameters. In some embodiments, a 2- (5-bromo-4- (4- 'cyclopropylnafta) polymorph is provided or used in any composition or method here. len-1-yl) -4H-1,2,4-triazol-3-yl) sodium acetate i which is not micronized.
    Uric acid is the result of xanthine oxidation. | 25 Disorders of uric acid metabolism include, - without limitation, polycythemia, myeloid metaplasia, gout, attack .-, | recurrent gout, gouty arthritis, hyperuricemia,: | : hypertension, cardiovascular disease, coronary heart disease or i, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidney stones, failure |
    | | i 30/83 and 'Í | 7 renal, joint inflammation, arthritis, urolylithiasis, 'Í “saturnism, hyperparathyroidism, psoriasis or sarcoidosis.
    Í 'Definitions The term "individual", as used herein in reference to individuals suffering from a disorder, and the like, includes both mammals and non-mammals.
    Examples of mammals include, without limitation, any member of the Mammalian class: humans, non-human primates such as'; chimpanzees, and other apes and monkey species; farmed animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents, for example, rats, mice and guinea pigs, and the like.
    Examples of non-mammals include,. 15 without limitation, birds, fish, and the like.
    In a : . modality of the methods and compositions provided herein, the mammal is a human. o the terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount =" effective ", as used herein, refer to an amount of - at least one administered agent or compound that is sufficient to treat or prevent the disease or condition in particular i.
    The result may be a reduction and / or relief of the signs, symptoms or causes of an illness, or any | : 25 another desired change to a biological system.
    For example, an “effective amount” for therapeutic uses is .a s | | amount of the composition comprising a compound as disclosed herein necessary to provide a decrease and clinically significant in a disease.
    An appropriate “effective” amount in any individual case can be:
    o 31/83 ES cr a determined using techniques such as, for example, a 2 ”CW dose escalation study. | o '"2 o:.. The term“ substantially equal to “, as used herein,: and o refers to an X-ray powder diffraction pattern or pattern. |.
    of differential scanning calorimetry that may not be the e and the e: identical to those revealed here, but that falls within the Vo 7:. limits of experimental error, when considered "by ', õ those enabled in the technique. | oo: oo" Representative peaks "are the prominent peaks: de. | ç an X-ray powder diffraction pattern. Note that peaks: o.: Prominent are identified only if multiple patterns. v Ú - XRPD multiple diffractometers are available e. ” ”X" if the effects of both particle statistics 2. oO (reproducibility between XRPD standards) and Do. * 15 preferred orientation (consistency of relative intensity. Oo between XRPD standards) is negligible. 7 - oo “Characteristic peaks” are a subset of: peaks: 4 | representative and are used to differentiate a polymorph '. : "or crystalline form of another polymorph or crystalline form. oo Characteristic peaks can be determined by evaluating - - which representative peaks, if present, are present in flights: in a crystalline polymorph of a compound against all” C o other polymorphs known crystalline polymorphs of that compound:> os Not all crystalline polymorphs of a compound. o “: 25 necessarily have at least one characteristic peak. oc - i & i Modulation of URAT-1 - SRT activity: The invention is also related to Vs o methods = modulation of URAT-1 activity by contacting URAT-1 with flown an amount of a polymorphic, crystalline form or 2 SC mesophase of 2- (S-bromo-4- (4-cyclopropylnaftalen-1- il) -4H- “hi o
    32/83's sodium 1,2,4-triazol-3-ylthio) acetate, as described herein, is sufficient to modulate URAT-1 activity. Modular can be the inhibition or activation of URAT-1 activity. In some embodiments, the invention provides methods of inhibiting URAT-1 activity by contacting URAT-1 with a | ! amount of a polymorphic, crystalline or. 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1i1) -4H- 1,2,4-triazol-3-ylthio) acetate mesophase, as described herein, sufficient to inhibit URAT activity -1. In some ": & modalities, the invention provides methods of inhibiting the activity of URAT-1 in a contact solution of said, solution with a quantity of a polymorphic, crystalline or mesophase form of 2- (5-bromo-4- (4- | 'cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate. pd 15 sodium, as described herein, sufficient to inhibit. URAT-l activity in that solution.
    In some ":: embodiments, the invention provides methods of inhibiting URAT-1 activity in a cell by contact of said] cell with an amount of a polymorphic, | crystalline or mesophase form of 2- (5-bromo- Sodium 4- (42 Co cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-yl) acetate *: i, as described herein, sufficient to inhibit URAT-1 activity in said cell.
    In some embodiments, the invention provides methods of inhibiting:; 25 URAT-1 activity in a tissue by reference contact. fabric with a quantity of a polymeric shape, | crystalline or mesophase 2- (S-bromo-4- (4- | cyclopropylnaphthalen-1-1yl) -4H-1,2,4-triazol-3-ylthio) sodium acetate, as described herein, sufficient to inhibit URAT-1 activity in said tissue.
    In some Ú |
    : 33/83 'sv ... modalities, the invention provides methods of inhibiting. :
    URAT-1 activity in the blood by blood contact with .a
    7 amount of a polymorphic, crystalline or gold
    | 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-- mesophase--
    ; 5 1,2,4-triazol-3-ylthio) sodium acetate, as described herein, sufficient to inhibit the activity of URAT-1 in the blood: In some embodiments, the invention provides methods of inhibiting the activity of URAT-1 in the plasma by contacting the plasma with an amount of a polymorphic, crystalline or. mesophase of sodium 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H- 1,2,4-triazol-3-ylthio) acetate, as described herein, sufficient to inhibit the activity of URAT-1 in plasma ... In. 'in some embodiments, the invention provides methods of inhibiting: the activity of URAT-1 in an animal by contact of said * 15 animal with an amount of a polymorphic form,'. crystalline or mesophase 2- (S-bromo-4- (4- '| S cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate. sodium, as described herein, sufficient to inhibit. the activity of URAT-l in that animal.
    In some embodiments, the invention provides methods of inhibiting ENA to URAT-1 activity in a mammal by contact of said i
    I mammal with an amount of a polymorphic form,. crystalline or mesophase 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate |
    | 25 sodium, as described herein, sufficient to inhibit
    | URAT-1 activity in said mammal.
    In some .o |
    | embodiments, the invention provides methods of inhibiting: |
    Only URAT-1 activity in a human by contact of said '4 - human with an amount of a polymorphic, crystalline or mesophase oO form of 2- (5-bromo-4 :-( 4- Vi | j oo SN ; 34/83 '7 | - cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate * Ns | | sodium, as described herein, sufficient to inhibit URAT-1 activity in said human. . . Po 7:; : Pharmaceutical compositions: Ss | "| Pharmaceutical compositions are described herein; i comprise an effective amount of a polymorphic, crystalline or mesophase of 2- (5-bromo-4- (4 -—. I! Cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) sodium acetate, as described herein.
    In some embodiments, the pharmaceutical compositions comprise an effective NE amount in a polymorphic, crystalline or mesophase form of 2-. "|:, (5-bromo-4- (4-cyclopropylnaphthalen-1-3yl) -4H-1,2,4-triazol-3- | ylthio) sodium acetate, as described herein, and at least one ': pharmaceutically acceptable carrier, In some |. "- 15 embodiments, pharmaceutical compositions are for NE the treatment of disorders.
    In some embodiments, "pharmaceutical compositions are for the treatment of] disorders in a mammal.
    In some embodiments, the pharmaceutical compositions are for the treatment of disorders in a human being.
    In some embodiments, "pharmaceutical" compositions "are for treatment or. prophylaxis of uric acid metabolism disorders.
    In: some embodiments, the pharmaceutical compositions are for the treatment or prophylaxis of hyperuricemia.
    In some: Co S | In the embodiments, the pharmaceutical compositions are for the treatment or prophylaxis of gout. 'oo
    ! 35/83 | ! 7 mesophase of sodium 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-, 1,2,4-triazol-3-ylthio) acetate, as described herein. | | "The compound, compound forms and compositions described herein | t may be administered alone or in combination 'with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, in accordance with standard pharmaceutical practice.
    Administration can be carried out by any method that allows the release of the 'compounds to the site of action.
    These methods include, without limitation, delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, 'intradermal, intraduodenal, intramedullary, intramuscular, .15 intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), by: inhalation, transdermal, transmucosal administration: '. sublingual, buccal and topical (including epicutaneous, dermal, | enema, eye drops, ear drops, intranasal, vaginal), although most suitable pathways depend, for example, on SN. condition and disorder of the recipient.
    Those qualified in. technique will be familiar with the techniques | de - administration that can be used with the compounds e. : the methods of the invention.
    As an example only, the compounds,: 25 forms of the compound and compositions described herein can be | administered locally to the area that needs. ” O ! treatment, for example, local infusion during surgery, a. topical application such as, for example, creams or ointments, injection, catheter or implant, said implant is made, for example, by a porous, non-porous or non-porous material | | to: 36/83 S - gelatinous, including membranes, for example, silastic membranes or fibers.
    Administration can also be by direct injection into the site of a diseased tissue or organ. . "| The pharmaceutical compositions described herein may, for example | | be in a form suitable for oral administration |! As a tablet, capsule, pill, powder, formulations, sustained release HA, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream, or for rectal administration as a suppository.
    The pharmaceutical composition can be in unit dosage forms suitable for single administration of accurate dosages.
    The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to: the invention as an active ingredient.
    In addition, it may include other medicinal or pharmaceutical agents,. . vehicles, adjuvants etc. :. :: Formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods in the pharmacy technique.
    All methods include the step of associating a compound or | form of the compound of the present invention or a salt, ester, | prodrug or pharmaceutically acceptable solvate thereof. (“Active ingredient”) with the vehicle that constitutes one or | 25 more accessory ingredients.
    In general, formulations are vm. prepared by associating uniformly and intimately the ”| active ingredient with liquid vehicles or solid vehicles i: i finely divided, or both, and then, if necessary,: | product modeling in the desired formulation.
    ENA methods ... preparation of several pharmaceutical compositions with one ”|
    '! : i 37/83 oo 1 | - specific amount of active compound are known, Qu | will be evident to those skilled in the art. 'Doses' | The amount of pharmaceutical compositions administered i5 will primarily depend on the mammal being treated. i When pharmaceutical compositions are administered to a '| ! human being, the daily dosage will normally be determined by the doctor responsible for the prescription with the dosage 'generally varying according to age, sex, diet,: weight, general health and response of the individual patient, the severity of the patient's symptoms, the indication or precise condition being treated, the severity of the indication. or 1 condition being treated, the time of administration, * the route of administration, the disposition of the composition, the "rate of excretion, combination of drugs, € to the evaluation of the doctor responsible for the prescription, In addition, the route of : administration may vary, depending on the condition and its severity.
    The pharmaceutical composition can be in unit dosage form.
    In this form, the preparation is subdivided Na into unit doses that contain appropriate amounts of. active component, for example, an effective amount to 'achieve the desired goal.
    Determination of the GC oe: appropriate dosage for a particular situation is within the | oo: knowledge of the technique, For convenience, dosage * | 25 total daily can be divided and administered in portions i! during the day, if desired.
    The amount and frequency of ': administration will be regulated according to the evaluation of the. : 'responsible doctor considering factors such as. described. above.
    Thus, the amount of pharmaceutical composition | to be administered can vary widely.
    The administration | i ': | '38/83:: - may occur in an amount between about 0.001 mg / kg, | body weight up to about 100 mg / kg body weight | 'per day (administered in a single dose or in 1 | divided doses), or at least about 0.1 ma / kg body weight per day.
    A particular therapeutic dosage can include, for example, from about 0.01 mg to about; ; 7,000 mg of compound Or, for example, from about 0.05 mg to about 2500 mg.
    In other embodiments, a particular "therapeutic" dosage is selected from about 200 mg, about 300 mg, about 400 mg, about 500 mg, about | 600 mg, or about 700 mg.
    The amount of active compound in a unit dose of preparation can be “varied or: adjusted from about 0.1 mg to 1,000 mg, from about 1 mg. up to 300 mg, or 10 mg up to 200 mg, depending on the particular application.
    In other embodiments, a particular unit dose is selected from 100 mg, 200 mg or 300 mg.
    In some cases, dosage levels below the lower limit: the range mentioned above may be more than | adequate, while in other cases even higher doses can be used without causing any side effects, i: for example, by dividing larger doses into several smaller i doses for administration throughout the day.
    In combinatorial applications in which the compound is not the only therapy, "i it may be possible to administer lesser amounts of | 25 compound and still have a therapeutic or prophylactic effect.
    NS | : Combined therapies CG The compounds and forms of the compound described herein can. | be administered as the sole therapy or in combination with other therapy or therapies. | i i | |
    ; | 39/83: 7 Just as an example, if one of the side effects | presented by a patient after receiving a compound. or form of the compound as described herein is hypertension, so it may be appropriate to administer an antihypertensive agent 15 in combination with the compound.
    Or, just as an example, the therapeutic effectiveness of a compound or form of the compound | as described herein can be increased by administration. of an adjuvant (that is, by itself the adjuvant may have only minimal therapeutic benefit, but in combination with.; another therapeutic agent the overall therapeutic benefit for the patient is increased). Or, just as an example, The benefit presented by a patient can be increased by administering a compound or form of the compound as described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has a therapeutic benefit.
    Regardless of the disease, disorder. or the condition being treated, the overall benefit presented by the patient may simply be additive to:. two therapeutic agents or the patient may have a 'synergistic benefit.
    CSA When the compounds or forms of the compound as described herein are administered with other therapeutic agents: i, they can be administered “anyway. i o pharmaceutical composition than the other therapeutic agents Voo, i 25 e, because of physical and chemical characteristics: Í: o | different, can be administered by a different route. ! For example, the compound or form of the compound as here | ] described can be administered orally to generate .ê | maintain good blood levels of this, while the other, a therapeutic agent can be administered intravenously.
    Õ |
    : 40/83 | ! 7 The determination of the mode of administration and the convenience of] administration, when possible, in the same pharmaceutical composition, are within the knowledge of those% qualified in the technique.
    The initial administration can be i: | made, for example, according to established protocols known in the art, and then, based on the observed effects, the dosage, modes of administration and timing of | | administration can be modified by those qualified:: in the technique. O
    The compounds, compound forms and compositions described herein (and, where appropriate, another chemotherapeutic agent) can be administered concomitantly (for example, ': simultaneously, essentially simultaneously Or within the same treatment protocol), sequentially or separately, depending on the nature of the disease, of. | . : condition of the patient and the actual choice of another agent. chemotherapy to be administered.
    For combinatorial applications and uses, compounds, forms of - compound and | compositions described here and the chemotherapeutic agent does not:
    they need to be administered simultaneously or i essentially simultaneously. Thus, the compounds, i forms of the compound and compositions as described herein can: be administered first, followed by the administration of: -. . chemotherapeutic agent; or the chemotherapeutic agent can be. | administered first, followed by administration of the compounds, forms of the compound and compositions as herein. oO i
    'described.
    This alternate administration can be repeated: during a single treatment protocol.
    The determination of the order of administration, and the number of repetitions of:
    administration of each therapeutic agent during one ”::
    |
    ''! 41/83 | r treatment protocol, is within the knowledge. qualified doctor after evaluation of the disease that is ”being | | Ú treated and the condition of the patient, For example; the agent | chemotherapy can be administered first, | 5 especially if it is a cytotoxic agent, and then the treatment continues with the administration of the compounds, forms of the compound and compositions as described herein, "followed, when deemed advantageous, by the administration: of the chemotherapeutic agent, and so on until the protocol of treatment is complete, that way, according to experience and knowledge, the physician in charge can modify each administration protocol for treatment according to the needs of the individual patient, as the treatment proceeds.
    The attending physician, when assessing whether the treatment is effective 'in:'. | dosage administered, will consider the general well-being of the: patient, as well as more definitive signs such as, for example, the relief of symptoms related to the disease. the relief of symptoms related to the disease like ,. by | : example, pain, and the improvement of the global condition, can also | OS be used to help assess the effectiveness of treatment. & Specific non-limiting examples of possible combination therapies include the use of the compounds and the | i compositions described here with febuxostat, allopurinol, eve mo. 25 probenecid, sulfinpyrazone, losartan ,. fenofibrate, '| benzobromarone or PNP inhibitors (as, for example, without SA. 'limitation, phorodesin, BCX-1777 or BCX-4208). “That list:: | it should not be considered to be closed, but instead serves as an illustrative example common to the relevant therapeutic area at present.
    In addition, schemes |
    | '; ; 42/83 | The combination may include several routes of administration, including, without limitation, oral, intravenous, intra-. | inhaled, subcutaneous, dermal and topical. 'o' | Diseases. . .
    | 5 Methods for treating. a disease . or disorder in an individual suffering from said disease 'c | | or disorder comprising the administration to said.
    individual of an effective amount of a polymorph, crystalline form or mesophase as described herein 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1yl) -4H-1,2,4-triazole-3-yl ), sodium acetate.
    i The invention extends to the use of the compounds and forms of the: compound described herein in manufacture. of a medicine "to treat a disease or disorder.
    In some embodiments, the disease or disorder is. : i hyperuricemia, In certain cases, hyperuricemia is. : characterized by blood levels higher than normal: uric acid, sustained over periods of time. 'long. In certain cases, increased blood levels: from urate may be caused by increased acid production | uric acid (approximately 10-20%) and / or reduced renal excretion i 1 (approximately 80-90%) of uric acid. In certain cases, the causes of hyperuricemia may include obesity / 'gain' | weight, excessive use of alcohol, excessive dietary intake:: 25 of purine (foods such as mollusc, roe of.
    'fish, scallops, lentils, beans and red meat,.
    | particularly viscera - brains, kidneys, gut, liver), to 'certain medications, including low dose aspirin, - the i: diuretics, niacin, cyclosporine, pyrazinamide, ethambutol,: some drugs for high blood pressure and some ”|
    U 1 | 43/83 '|
    7 chemotherapeutics for cancer, ilfunosuppressive agents, € e., | cytotoxic, specific disease states, particularly '| those associated with a high cell turnover rate. : |
    | (such as, for example, malignancy, leukemia, lymphoma Ou '
    psoriasis), which also include high blood pressure,:
    ! diseases like hemoglobin, hemolytic anemia, anemia. ! sickle cell disease, various kidney diseases, myeloproliferative diseases'. | and lymphoproliferative, hyperparathyroidism, kidney disease, 'Ú conditions associated with insulin resistance and diabetes;
    mellitus and transplant recipients, and possibly heart disease, inherited enzyme defects, abnormal kidney function (e.g., increased ATP turnover, | reduced urate glomerular filtration) and lead exposure (saturnism or "saturnine drop"). '
    In certain cases, hyperuricemia can be asymptomatic, although it is associated with the following: conditions: gout, gouty arthritis, uric acid lithiasis in the
    'urinary tract (urolylithiasis), deposits of uric acid in soft tissues (tophi), deposits of uric acid in the kidneys
    (uric acid nephropathy) and deficit. kidney function, 'possibly leading to failure. chronic kidney and
    acute. i o To
    In additional modalities, to the disease or disorder. It is
    'gout, which is a condition that results in crystals of "acid:
    | 25 uric that are deposited in tissues of the body.
    It is often related to an abnormality inherited from the body's ability to process uric acid, but also:
    : 'can be exacerbated by a diet rich in purines. o | Defective processing of uric acid can lead to high ES levels of uric acid in the blood, causing attacks:
    |
    ! 44/83 | | - recurrent joint inflammation (arthritis), deposits of "| uric acid in and around joints, gout, topology, formation of tophi, decreased kidney function and | renal lithiasis.
    Approximately 3-5 million people in the United States suffer from gout attacks with attacks 6 a. 9 times more common in men than in women (see. Sanders and Wortmann, “Harrison's Principles of Internal: 'Medicine”, 16th Edition; 2005; “Food and Drug Administration” | (FDA) “Advisory Committee Meeting”, presentation | Terkeltaub, June 2004; Terkeltaub, "“ Gout ”, Nu.
    Engl. | JMed., 349, 1,647-55, 2003). In certain cases, gout is: one of the most common forms of arthritis, accounting for approximately 5% of all cases of arthritis.
    In certain | cases, renal failure and urolilithiasis occur in 10-18% of individuals with gout and are common sources of morbidity and mortality from the disease. o] i | : Gout is associated with hyperuricemia.
    In certain 7 cases, individuals who suffer from gout excrete | approximately 40% less uric acid than individuals without: gout for a certain plasma urate concentration.
    In certain. cases, urate levels increase up to .that i point. saturation is achieved.
    In certain cases, it occurs: ”precipitation of urate crystals when theThe saturation port is reached.
    In certain cases, these deposits | hardened, crystallized (tophi), are formed: nas. | joints and skin, causing joint inflammation. :: (arthritis). In certain cases, deposits are produced at '' | joint fluid (synovial fluid) and / or lining: from the joint (synovial lining) .. Common areas for «these deposits are the big toe, feet, ankles and hands |
    ! 45/83 o 7 (less common areas include ears and eyes) .. In | | certain cases, the skin around the affected joint if | makes it red and shiny with the affected area being more '| | sensitive and painful to the touch. In certain cases, attacks * | j 5 drops increase in frequency. In certain pits, 'untreated' acute gout attacks lead to permanent joint damage and disability. In some cases, the deposition of urate in tissue leads to acute inflammatory arthritis, chronic arthritis, deposition of urate crystals in the renal parenchyma and urolilithiasis. In certain cases, the incidence of gouty arthritis increases 5-fold in individuals with serum urate levels of 7 to 8.9 mg / dl and up to 50-fold in individuals with: levels> 9 mg / dl (530 pmol / 1). In certain cases, individuals; with gout develop kidney failure and kidney disease in.
    final stage (ie, “gouty nephropathy”). In certain '. cases, gouty nephropathy is characterized by one:,. chronic interstitial nephropathy, which is promoted by 'spinal deposition of monosodium urate. i i 'In certain cases, gout includes painful attacks of acute, monarticular, inflammatory arthritis, deposition of. crystals of urate in joints, deposition of eristais of:: urate in the renal parenchyma, urolilithiasis (formation of stones in the urinary tract), and nephrolithiasis (formation of,:; renal lithiasis). In certain cases, secondary gout occurs: 25 in individuals with cancer, particularly leukemia, .e -. those with other blood disorders (for example, i 'polycythemia, myeloid metaplasia, etc.). oo | In some cases, gout attacks develop very quickly, often the first attack: occurring at night. In certain cases, symptoms include pain: | y; 1 ' ' ! j 46/83 Í
    Í | | 7 severe, sudden joint, and extreme sensitivity in the area | Joint S, joint edema is shiny skin .or | purplish around the joint. In certain cases, 6OS: attacks are infrequent lasting 5-10 days, with no symptoms: between episodes. In certain cases, attacks become more frequent and last longer, especially if the disease is not controlled. In certain cases, the episodes damage the affected joint (or joints), resulting in. | stiffness, edema, limited movement and / or persistent mild to moderate pain. 'Saturnism or' saturnine drop 'is a hyperuricemia' induced by lead that results from lead inhibition of tubular urate transport, causing rent excretion | ', decreased by uric acid. In certain cases, more than 50% of individuals suffering from lead nephropathy suffer from gout. In certain cases, acute attacks of saturnine gout occur in the knee more often than in the big toe. In certain cases, kidney disease is more frequent and more severe in saturnine gout than in primary gout. In certain cases, treatment consists of; : exclusion of the individual from additional lead exposure, Ps:. use of chelating agents to remove lead, and "" .control of acute gouty arthritis and hyperuricemia. In certain cases, saturnine gout is characterized by less frequent attacks than the primary gout. In certain cases, gout associated with lead occurs in pre-menopausal women, one. DS: unusual occurrence in gout not associated with lead. +: ”| In certain cases, Lesch-Nyhan syndrome (LNS ': or “Nyhan's syndrome) affects about one in 100,000 nests. the living. In certain cases, LNS is caused by a G deficiency |
    | 47/83 NA o | “Hypoxanthine-guanine enzyme i i phosphoribosyltransferase (HGPRT)., In certain cases, LNS is | an X-linked recessive disease.
    In certain cases, LNS: | | it is present at birth in boys.
    In certain cases, | disease leads to severe gout, poor muscle control and moderate mental retardation, which appear in the first year of “'; life.
    In certain cases, the disease also results in | self-mutilation behaviors (for example, bites on the lips and fingers, blows to the head) that start in the second year of life.
    In certain cases, the disease also | results in gout-type swelling and severe kidney problems.
    In certain cases, the disease. leads to symptoms': neurological which include facial sketches, torsions: involuntary and repetitive movements of the arms and legs similar to those seen in Huntington's disease.
    The prognosis for individuals with LNS is poor.
    In certain cases, the life expectancy of an individual with INS does not. - treaty is less than about 5 years old.
    In certain shores, '' the life expectancy of an individual with treated SNN is: | greater than about 40 years old. = ": In certain cases, hyperuricemia is found in o 'individuals with cardiovascular disease (CVD) and / or o: renal disease.
    In certain cases, hyperuricemia 'is found in | individuals with prehypertension, hypertension, oe resorption | 25 proximal increased sodium, microalbuminuria, proteinuria,: | kidney disease, obesity, hypertriglyceridemia, cholesterol i! of low high density lipoprotein, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, arterial disease -. peripheral, carotid and coronary, atherosclerosis, '. congestive heart failure, stroke - V |
    '48/83: i - brain, tumor lysis syndrome, endothelial dysfunction: oxidative stress, elevated renin levels, elevated endothelin levels and / or C-reactive protein levels'. high.
    In certain cases, hyperuricemia is found in | individuals with obesity (eg central obesity), i! high blood pressure, hyperlipidemia and / or glucose from ':
    ! altered fasting.
    In certain cases, hyperuricemia is found "in individuals with metabolic syndrome.
    In certain cases, the:! Gouty arthritis is indicative of an increased risk of acute myocardial infarction.
    In some embodiments, administration of a compound described herein to an individual is: useful for decreasing the likelihood of a clinical event 'associated with a disease or condition linked to hyperuricemia,' including, without limitation, prehypertension, hypertension, proximal resorption increased sodium, microalbuminuria,: i proteinuria, kidney disease, obesity, hypertriglyceridemia, low high density lipoprotein cholesterol. 'hyperinsulinemia, hyperleptinemia, hypoadiponectinemia,. peripheral, carotid and coronary artery disease, atherosclerosis, congestive heart failure, stroke, tumor lysis syndrome, endothelial dysfunction, oxidative stress, elevated renin levels,. . :: high endothelin levels and / or levels. elevated C-2 ce: reactive protein levels. :. SS oo | 25 In some modalities, a compound or form. do: compound as described herein is administered to an individual -. i suffering from a disease or condition requiring treatment: | Ú with a diuretic.
    In some embodiments, a compound or form of the compound as described herein is administered to an 'individual suffering from a disease or condition that requires it' | so | 49/83 '') '| | - treatment with a diuretic, where the diuretic causes' | renal urate retention.
    In some modalities, the disease a. i or condition is congestive heart failure- or, essential hypertension.
    In some embodiments, the administration of a compound; 'or form of the compound as described herein to an individual is | useful for improving motility or improving quality at | | life. | In some embodiments, administration of a compound or form of the compound as described herein to an individual is: useful for treating or lessening side effects: of cancer treatment. : | . In some embodiments, administration of a compound * or form of the compound as described herein to one. individual is useful for decreasing renal toxicity of cisplatin. i In certain cases, gout is treated by reducing: the production of uric acid.
    In certain cases, gout is treated. by increased excretion of uric acid.
    In certain cases, | gout is treated by URAT-l1, xanthine oOxidase, xanthine. dehydrogenase, xanthine oxidoreductase, an inhibitor of i purine mnucleoside phosphorylase (PNP), an inhibitor of: uric acid transporter (URAT), an inhibitor of -. 'glucose transporter (GLUT), a GLUT-9 inhibitor, one. : 'inhibitor of family member 2 of the transporter | ':! 25 solute (facilitated glucose transporter) (SLC2A9), an "'organic anion transporter (oAT) inhibitor,' um: OAT-4 inhibitor, or combinations thereof.
    In general, those! gout treatment goals are: i) to reduce pain, | : edema and duration of an acute attack, and ii) avoid future attacks and joint damage.
    In certain cases, attacks by. & |
    ! 50/83! | :! - gout are successfully treated with the use of a combination | of treatments.
    In some cases, gout is one of the ways | | more treatable arthritis. ; | i) Treatment of gout attack.
    In certain cases, '1 pain and edema associated with an acute attack of gout can be treated with medications such as acetaminophen, steroids, non-steroidal anti-inflammatory drugs (NSAIDsS), adrenocorticotropic hormone (ACTH) Na or colchicine .
    In certain cases, proper medication controls gout within 12 to 24 hours and treatment is stopped after a few days.
    In certain cases, the medication: is used in conjunction with rest, increased fluid intake, ice packs, elevation and / or protection of the affected area (or areas).
    In certain cases, the treatments: mentioned above do not prevent recurrent attacks and: do not affect the underlying diseases of the abnormal metabolism of =, uric acid. : ii) Prevention of future attacks.
    In certain cases, the reduction of serum uric acid levels below the saturation: saturation level is the goal for the prevention of additional gout attacks.
    In some cases, this is achieved by: decreased production of uric acid (eg '.: Allopurinol), or increased excretion of uric acid ". With. | Uricosuric agents (eg' probenecid ,.:: | 25 sulfinpyrazone, benzobromarone).:: In certain cases, allopurinol inhibits acid formation;: uric, resulting in a reduction in both serum and urinary levels of uric acid, and becomes fully effective after 2 to 3 months.: ENS% | | * | |
    51/83 SS '': - o o o | Í KR Guanina A. HN NY HN Xanthine —tf—> Urate OS OS x o N N N N Hypoxanthine NX> Allopurinol Hypoxanthine Tapio By opurinol! | 5 In certain cases, allopurinol is a structural analogue: de 'i hypoxanthine (differing only in the transposition of the carbon and nitrogen atoms in positions 7 and 8) that inhibits the action of xanthine oxidase, the enzyme responsible for the conversion of: hypoxanthine to xanthine , and xanthine in uric acid.
    In certain cases, it is metabolized to the corresponding xanthine analog, alloxanthin (oxipurinol), which is also an xanthine oxidase inhibitor.
    In certain cases, 'alloxanthin, although more potent in inhibiting xanthine oxidase, is less, pharmaceutically acceptable due to low oral bioavailability.
    In certain cases, fatal reactions as a result. | hypersensitivity, bone marrow suppression, hepatitis. '. o and vasculitis have been reported with Allopurinol.
    In certain cases: the incidence of side effects may total '20% of all individuals treated with the drug: O. treatment for diseases of uric acid metabolism has not evolved significantly in the next two decades since: the introduction of allopurinol. i; . : In certain cases, uricosuric agents (eg; -. | Probenecid, sulfinpyrazone and benzobromarone) increase o | 25 uric acid excretion, In certain cases, probenecid causes an increase in uric acid secretion by the renal tubules. and, when used chronically, mobilizes “do. O . | urate body.
    In certain cases, 25-50% of individuals'. treated with probenecid do not achieve a reduction in serum uric acid levels <6 mg / dl.
    In certain cases: i. |
    | | oO | 52/83! | Í 7 insensitivity to probenecid results from intolerance to | drug, concomitant with ingestion. salicylate, 'and renal deficit.
    In certain cases, a third of - individuals: | 'develops intolerance to probenecid.
    In certain cases, | | | administration of uricosuric agents also results in | 'Urinary stones, gastrointestinal obstruction, jaundice and; anemia. 1 | Successful treatment aims to reduce | both the pain associated with the acute attack of gout and the | long-term data of the affected joints (Emerson, “The Management of Gout" ”, N.
    Engl. J.
    Med., 334 (7), 445-451, 1996). therapeutic goals include providing fast and safe pain relief, preventing further attacks, preventing toph formation and subsequent arthritis, and preventing exacerbation of. other medical conditions.
    The start of treatment depends on the underlying causes of hyperuricemia, for example, kidney function, diet and medications.
    Although gout is a 'treatable' condition, there are limited treatments available for. o & management of acute and chronic gout, and various effects. Adverse events are associated with current therapies.
    The drug treatment of gout includes pain management, prevention. or decreased joint inflammation during an 'acute gout attack and long-term chronic therapy to maintain | :! 25 decreased serum uric acid levels.
    Ú '' Ts; Non-steroidal anti-inflammatory drugs (NSAIDS). : i Vc are effective anti-inflammatory medications for: acute gout, o. but are often associated with systemic, gastrointestinal (GI) irritation, ulceration of the stomach and intestines, and occasionally intestinal bleeding '|
    :: | ! 53/83: | F (Schlesinger, “Management of Acute, and. Chronic Gouty ': Arthritis Present State-of-the-Art"; Medications; 64 (21), 2,399-2,416, 2004; Pascual and Sivera, “Therapeutic advanceés'' in gout ”; Curr.
    Opin.
    Rheumatol., Mar; 19 (2), 122-7, 2007). 'Colchicine for acute gout is most commonly administered' orally as tablets (every 1-2 hours until there is | a significant improvement in pain or the patient | develops GI side effects such as' i severe diarrhea, nausea and vomiting), or intravenously.
    Corticosteroids, administered in short periods, can be administered orally or injected directly into the inflamed joint. : Medications to reduce levels are available. uric acid blood cells that increase renal uric acid excretion by inhibiting reuptake or reducing to | production of uric acid by blockage. of xanthine oxidase. i These medications are generally not started until after the inflammation of acute gouty arthritis has subsided, as they can intensify the attack.
    If they are already being taken before the attack, they are continued and | 'only adjusted after the attack has passed.
    As many + 'i individuals with elevated blood uric acid levels may not develop attacks of gout or Penal lithiasis, the' 'decision for prolonged treatment with medications that. I | 25 reduce uric acid is individualized. - "': ENA kits: | The compounds, compound forms, compositions and methods described herein provide kits for the treatment of diseases and disorders, such as those described herein. 'These kits comprise a compound, form of the compound, |
    '54/83 i | 7 compounds, compound forms or compositions described here! in a container and, optionally, instructions that teach the use of the kit according to the various methods and approaches,: 'here, described.
    These kits may also include information, for example, references from scientific literature, materials with instructions for use, results of 'clinical experiments and / or summaries of these' and: similar, which indicate or establish to á / nu activities. advantages of the composition and / or that describe the dosage, administration, side effects, -—. pharmacological interactions or other useful information for. healthcare professional.
    This information can be based | | 'in the results of several studies, for example, studies' that use experimental animals that involve models and: in vivo studies based on human clinical experiments. . the kits described here can be provided ooo: marketed and / or promoted to health professionals, & o including doctors, nurses, pharmacists, public officials responsible for pharmaceutical products, and the like.
    Kits, in some modalities, can also: be sold directly to the consumer. 2 Also available, in certain modalidádes, DO: 1 compositions or kits comprising 2- (S-bromo-4- (4- si cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazole-3-yl ) sodium acetate: 25 (for example, a polymorph of this, for example, a. i Form A), a low-density double polyethylene plastic bag, and an HDPE container.
    In additional NS i modalities, the composition or kit still comprises the bag of a. , foil (for example, a foil pouch, anhydrous%, for example, an anhydrous foil pouch. o "|
    ! 55/83: 'r sealed by heating). In some embodiments, the composition or kit still comprises a desiccant; in still other modalities, a desiccant is not necessary and / or is not present.
    In some cases, this packaging increases the ''! 5 stability of sodium 2- (S-bromo-4- (4-cyclopropylnaphthalen-T-yl) - 4H-1,2,4-triazol-3-ylthioacetate (e.g., Form A). the compounds, compound forms and pharmaceutical compositions described herein can be used to | diagnosis and as research reagents.
    For example, compounds, compound forms and pharmaceutical compositions, alone or in combination with other compounds, can! be used as tools in analysis. differential and / or combinatorics to elucidate gene expression patterns | expressed within cells and tissues.
    As an example not the limiting, expression patterns within cells or. : tissues treated with one or more compounds are compared | with control cells or tissues not: treated “with compounds, and the standards produced are checked for | differential levels of .genic expression, since they are linked, for example, to the association of disease, via | signaling, cell location, expression level,. the size, structure or function of the genes examined.
    Essás o | analyzes can be performed on stimulated cells or not. | 25 stimulated and in the presence or absence of other compounds. oo 'that affect expression patterns,: i | O: In addition to being useful for human treatment, oS o: compounds, compound forms and pharmaceutical compositions. described here are also useful for veterinary treatment::. pet animals (eg dogs, cats), animals o |
    '56/83' - exotic and farmed animals (for example, Horses), including mammals, rodents, and the like. to.
    The examples and preparations provided below are still | ! illustrate and exemplify the compounds of the present invention and: 5 the methods of preparing those compounds.
    Must be . it is understood that the scope of the present invention is in no way limited by the scope of the following examples and preparations.
    Examples I - Preparation of compounds; z. = Example 1: Preparation of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) sodium acetate NS 2- (5-Bromo -4- (4-cyclopropylnaftalen-1-yl) -4H-1,2,4- | triazol-3-ylthio) sodium acetate was prepared according to & previously described procedures (see Publication of: US Patent 2009/0197825 ) and as described below,! From AX OH AD AAÇONE 'Bê x NaOH (aq) Bos o. i: 'Sa NE Aqueous sodium hydroxide solution (1 M, 2.0 ml, 2.0 "mmol) was added dropwise over 5 min to a” GC |. 2- ( 5-bromo-4- (1-cyclopropilhaftalen-4-i1) n o tc 25 4H-1,2,4-triazol-3-ylthio) acetic acid (810 mg, 2.0 mmol) in ethanol (10 ml) a 10ºC.
    The mixture was stirred at. 10ºC per neo! another 10 min
    Volatile solvents were removed in-vacuo = | | : | to dryness to provide 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate i. sodium as a solid (850 mg, 100%). :. o |
    MO! 57/83 i | 4th Example 2: Preparation of 2- (5-bromo-4- (4-; |,: cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetic acid! 7 2- (5-Bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-: | 1,2,4-triazol-3-ylthio) acetic acid was prepared according to previously described procedures (see Publication from: US Patent 2009/0197825) and as described below.
    Via i: NN H NºeN, 'PONTA, BA Ass no! ro sound, ES ÕS º] o - DM Z Sodium hydroxide solution (2 M aqueous, 33.7 ml, 67 mmol, 2 eq) was added to a suspension of 2- (5-bromo-4- (4- cyclopropylnaphthalen-l1-1yl) -4H-1,2,4-triazol-3-ylthio) -N- '' (2-chloro-4-sulfamoylphenyl) acetamide (prepared = by. i previously published procedures; see US 2009 / 0197825;: ig, 34 mmol) in ethanol (200 ml), and the mixture was heated '. at reflux for 4 hours.
    Coal (10 q was added, a.] Mixture stirred at room temperature for 12 hours and the coal removed by filtration.
    The charcoal was washed several times with ethanol and the filtrate was then concentrated.
    Water (200 µl & ml) was added and then concentrated to approximately one third to one third of the volume to remove all ethanol.
    Water (200 EF!. Ml) and ethyl acetate (250 ml) were added to the | 25 vigorously stirred mixture for 15 min and the layer. -. De: organic removed, The aqueous layer was cooled to 0º and:. acidified by treatment with HCl (1 resulting in the formation of a turbid oily precipitate.
    The mixture was extracted with ethyl acetate (3x) and the organic extracts o: o combined dried over sodium sulfate and concentrated to | 58/83; . : & 4 7 generate 2- (5S-bromo-4- (4-cyclopropylnaphthalen-l1-11) -4H-. 1,2,4-triazol-3-ylthio) acetic acid as an off-white solid 'GC (11, 2 g, 82%). ::: Via ii: is' 5 E no; and. nes ES A NaNO, POC.
    Ho EINGP), & HAN NH Ca Ni NiCodppaICk Á Á thiopagene Á DMF. 50 C À,; | 1 fo a 'Steel but OS YEAR: NS -; To Lou! o, K, CO ,, CMF OS NaNO>, CI; CCOM THFEOHHO: 'À BABJNBO ve' e 1 A. STEP A: Cyclopropylnaphthalene Cyclopropylmagnesium bromide (150, ml, 0.5 M. in y. Tetrahydrofuran) was slowly added to a - = solution. 1-bromonaphthalene (10 g, so mmol) and [1.3]:. bis (diphenylphosphino) propane] dichloro nickel (IT) in i tetrahydrofuran (10 ml) stirred at 0ºC, “and the reaction mixture” stirred at room temperature for 16 hours.
    O : . solvent was removed under reduced pressure and ethyl acetate and aqueous ammonium chloride were added.
    After . extraction, the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. . The oo: '25 residue was purified by chromatography on silica gel to:: generate 1-cyclopropylnaphthalene (6.4 g, 76%). oo | : STEP B: 1-Cyclopropyl-4-nitronaphthalene 7. NO, - ço - 'LI i: - oo:
    59/83 | t “| E Sodium nitrite (30 ml) was slowly added (to: Cc over 2 hours) to 1-cyclopropylnaphthalene (6.49, 38 mmol) * is stirred at 0 ° C.
    The reaction mixture was stirred at 0 ° C for; ! another 30 min and then slowly poured into the ice.
    Water was added, followed by ethyl acetate.
    After extraction, the organic layer was washed with hydroxide. aqueous sodium (1%) and water, dried over sodium sulfate, filtered and concentrated under reduced pressure.
    The residue was purified by chromatography on silica gel to generate 1-cyclopropyl-4- "nitronaphthalene (5.2 g, 64%).: |, STEP C: 1-Amino-4-cyclopropylnaphthalene: NH,;”; : A solution of 1-cyclopropyl-4-nitronaphthalene (5 g, 23 mmol) in ethanol (200 ml) was stirred. Under hydrogen in the presence of Pd / C (10% liquid, 1.8 g). The Te | reaction was stirred overnight, filtered over celite, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to generate. 1-. "amino-4-cyclopropylnaphthalene ( 3.1 g, 73%) hi '. | STEP D: 1-Cyclopropyl-4-isothiocyanatonaphthalene. |: Ns.. I:.' | | 25 o 'o vn SÍ Thiophosgene (1.1 g, 9 , 7 mmol) was added to a stirred solution of 1-amino-4-cyclopropylnaphthalene (1.8 q, 9.7 mmol) and diisopropylethylamine (2 eq) in dichloromethane (50 ml) at 0 ° C.
    The reaction mixture was stirred for 5 min. :. 30 ° C and then aqueous HCl (1% solution) was added. a |
    I 60/83 is | |. os' | 1 4 organic layer was separated, washed with brine, dried "." On sodium sulfate, filtered and the solvent removed under "reduced pressure. Hexane was added, it was the precipitate and the resulting was filtered. The solvent was evaporated to give 5-cyclopropyl-4-isothiocyanatonaphthalene (1.88 q, 86%). STEP E; 5-Amino-4- (1-cyclopropylnaphthalen-4-11) -aH- 1,2,4-triazole-3-thiol Ú;
    HAN ONT SH. o A mixture of aminoguanidine hydrochloride (3.18 q, o '29 mmol), 1-cyclopropyl-4-isothiocyanate naphthalene (3.24 g. 14 mmol) and diisopropylethylamine (3 eq) in DMF (20 ml) was: stirred at 50ºC for 15 hours. The solvent was removed under reduced pressure, toluene was added, and the solvent was ". Evaporated again. Sodium hydroxide solution (2M, 30 ml) was added and the reaction mixture" heated "to 50º € for 60 hours. The reaction mixture was filtered and. the filtrate NS: neutralized with aqueous HCl (2 M). The mixture was filtered::: again and the solvent removed under reduced pressure. The i:: residue was purified by chromatography on silica gel. | generate 5-amino-4- (1-cyclopropylnaphthalen-a-yl) T4H- = 1,2,4-, triazole-3-thiol (2.0 g, 49%). "Í | 25 STEP F: Methyl 2- (5-amino-4- (1-cyclopropylnaphthalene-4- |. | | Il) -4H-1,2,4-triazol-3-ylthio) acetate hi: ip Aa ão ': - & o: Tn. SS) |
    | : | ; | 61/83:; : To Methyl 2-chloroacetate (0.73 ml, 8.3 mmol) was the. - added dropwise over 5 min to a suspension of | 7 5-amino-4- (1-cyclopropylnaphthalen-4-yl) -4H-1,2,4-triazole-3-thiol (2.24 gq, 7.9 mmol) and potassium carbonate (1.21 g, 8.7 mmol) in DMF (40 ml) at room temperature.
    The reaction was stirred at room temperature for 24 h and slowly poured into a stirred solution of ice water. o: brown precipitate was collected by vacuum filtration. and dried under high vacuum at 50ºC for 16 h in the presence of PzOs '' to generate methyl 2- (5-amino-4- (1-cyclopropylnaphthalen-4-yl) - 4H-1,2,4-triazole-3- ilithium) acetate (2.24 g, 80%). STEP G: Methyl 2- (5-bromo-4- (1-cyclopropylnaphthalen-4- 11) -4H-1,2,4-triazol-3-ylthio) acetate there Action: e. "o: Sodium nitrite (2.76 g, 40 mmol) was added to-: a solution of methyl 2- (S-amino-4- (1-cyclopropylnaphthalen-4- | yl) -4H-1, 2,4-triazol-3-ylthio) acetate (0.71 9. 2 mmol) and; 20 ammonium benzyl triethyl chloride (1.63 g, 6 mmol) in o 'bromoform (10 ml). Dichloruacetic acid (0.33 ml, 4 mmol) ç was then added and the reaction mixture stirred at: room temperature for 3 h.
    The mixture was loaded: directly onto a 17.78 cm column of silica 'Do 25 gel, compacted with dichloromethane (DCM), The column: | initially it was eluted with DCM until all the bromoform i eluted, and then eluted with acetone / DCM (5:95) to generate Ú i methyl 2- (5-bromo-4- (1-cyclopropylnaphthalen-4-yl) -4H -1,2,4- | triazol-3-ylthio) acetate (713 mg, 85%). co:::: 30 STEP H: Acid 2- (5-bromo-4- (1-cyclopropylnaphthalen-4- "|
    1 t | 62/83 NS '! | ES | ae 11) -4H-1,2,4-triazol-3-ylthio) acetic '| o: 1 5 A solution of lithium hydroxide (98 ng, 4.1 mmol) in water (10 ml) was added dropwise over 5 min at a. a solution of methyl 2- (5-bromo-4- (1-cyclopropylnaphthalen-4-: 11) -4H-1,2,4-triazol-3-ylthio) acetate (1.14 gq, 2.7 mmol) in ethanol (10 ml) and THF (10 ml) at 0ºC.
    The mixture was stirred at. 0ºC for another 45 min and then neutralized to "pH 7 'by adding 0.5 N HCl solution at 0ºC.
    The resulting mixture was concentrated in vacuo to 1 / 5º of its original volume, that is. . then diluted with water (approximately 20 ml) and ”; acidified to pH 2-3 by adding 0.5 N HCl to produce a sticky solid (if the product turns out to be an oil: during acidification, extraction with dichloromethane is recommended). The brown solid was collected by filtration. : Ú in vacuum and dried under high vacuum at 50ºC for 16 h in the presence: of P2O5 to generate 2- (5-bromóo-4- (1-: cyclopropylnaphthalen-4-yl) -4H-1,2,4- triazole-3-11thio) acidic (1.02 g, 93%). o Do, IT - Preparation and analysis in various ways C. polymorphic, crystalline and mesophase o | 'General solvent techniques o. . | . 25 Solvents: The solvents were HPLC grade or ACS grade. | o | Evaporation: Solvents were added to the weighed and heated solids, stirred and / or sonified to facilitate dissolution, as needed. the resulting solutions were filtered in clean containers and the] |
    ] | 63/83 .. | | mo À left uncovered (rapid evaporation) or with 'one: loose cap 1 (slow evaporation) in an' fume hood '| ! laboratory under ambient conditions or in a stirring plate at elevated ambient temperatures or: i sub-environments.
    The samples were evaporated until: none | '1 solvent was visible, usually until dry. ; Broth: The broths were prepared by adding sufficient solids for a certain solvent or mixture: solvent, in such a way that excess solids were present.
    The mixture was then stirred in a sealed C flask (unless it was an evaporation broth) at ambient, elevated or sub-ambient temperatures. the solids. were . vacuum insulated or positive pressure filtration or | solvent decantation.
    Low solvent broths. 15 solubility was sprayed with a small volume of high solubility Cc 'solvent to encourage conversion. ::] High temperature broths that seek increased solids yield and / or initiation of crystallization were 2 "cooled slowly by turning off the heating. O Crushing: Samples that generated oil and / or gel were 'scraped / scratched with a toothpick. teeth or spatula ': to encourage crystallization..: Polymorphic forms A, B and B' '|:. ”;' Three polymorphic forms of 2- (5-bromo-4- (4- Ú:: | 25 cyclopropylnaphthalen- 1-yl) -4H-1,2,4-triazol-3-ylthio) acetate '; sodium' were prepared. O | 'For example, For example, For example, |: | Anorph— - »Polymorphic porn in Forma polymorphic B Yeah.
    Polymorphic form B; . ”|
    64/83. | 1 | “| | : Example 3A: Preparation of Form A of crystalline polymorph I of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1yl) -4H- | | 1,2,4-triazole-3- iltio) sodium acetate: Deionized water (0.5 ml) was added. 'to one | i 5 stirred suspension of amorphous 2- (5-bromo-4- (4-cyclopropylnaphthalene-1-11 ') -4H-1,2,4-triazol-3-yl) acetate (1.00 g containing 1.8% by weight of water) and ethyl acetate (4 ml) Í producing a biphasic mixture, which was stirred in! at room temperature for 18 hours, the resulting broth was filtered under vacuum and the solids washed with ethyl acetate (2 x 10 ml). The filter cake was dried in vacuo at 18 - 20 ° C with a nitrogen sweep for 4.5 hours. To generate; . 0.78 g of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -aH- 1,2,4-triazol-3-ylthio) sodium acetate containing 13.0% by weight of water (70.3% recovery, anhydrous basis). The isolated solid was designated Form A. ': Yes. Example 3B: Analysis of Form A of the 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-1l) -4H-1,2,4-i triazol-3-ylthio) acetate eristaline polymorph i | 2 X-ray powder diffraction: | A pan-analytical XRPD pattern and one: Inel, were analyzed.
    Reproducibility and peak intensities ”. Relative i were consistent between X-ray powder diffraction patterns, indicating good particle statistics e. ] | - 25 orientation.
    The XRPD pattern for Form à is shown in. | Figure 1; observed and representative peaks in the = 'XRPD pattern are shown in the tables below: E oo ES:. | : Form A Observed and o: 10.027 to 0.275 | dm: |
    65/83 i. '| 4 La | and. 6.86 + 0.20 260: e 8.41 + 0.10 10.512 + 0.126 62 -: 8.996 2 0.002 | a | 10.13 + 0.10 8.730 + 0.087 | Bo: 10.60 + 0.10 8.346 + 0.079 so | 11.92 + 0.10 7424 + 0.068 | as = 0. 12.32 + 0.10 7.183 + 0.059 AB 11042 + 0.056 | as o 6,772 4 0,082 | air
    A 6128 2 0.042 | as 5.908 + 0.04 2 o Soo 5.850 + 0.039 | 82 o 16.28 + 0.10 5.444 + 0.033 | “8 o” i 16.70 + 0.10 5.309 + 0.032 20 "'i 16.90 4 0.10 5.246 + 0.081 | * 22 et. | 17.92 + 0.10 4.950 + 0.028 Mod: 18.64 + 0,10 4,761 + 0,025 ECA 4,265 + 0,020 | ÉÚJaga 'o 4,163 + 0,019 as' Bo; Bro! 2,650 2 0,027 | + ss. EEN 3,780 + 0,016 20 ao! 24,67 + 0,10 3,609 + 0,014 44. cd; o 3.622 x 0.024 | Gg 32379 2 0.013 | 1a |: 213074 0.012 | = aa [o |
    : 66/83 | : 'rt = 2' q 27.63 * 0.10 3.229 + 0.012. 22 o '| À 28.36 + 0.10 3.147 + 0.011]. == oo 29.07 + 0.10 3.072 + 0.010 asc of; Form A Representatives + == | 2 | space a (dy | intensity (9) i 4.90 + 0.10 18.027 4 0.375 mo.! 6.86 + 0.10 12.891 + 0.191 200 9.83 + 0.10 8.996 + 0.092 63 oz. | ss: The trace of the differential scanning calorimetry |> for Form A is shown in Figure 2. - EN. The infrared absorption spectrum of Form A is. i shown in Figure 3. i 'no | The Raman spectrum of Form A is shown in Figure 4.: Form A of sodium 2- (S-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) was i | F tested under various conditions to determine thermodynamic stability.
    No degradation of the packed Form A was P! observed for 6 months under accelerated conditions (40ºC-75% of! relative humidity). In addition, no degradation of the Form. The pack was observed for 12 months under conditions. de "e: long term (25ºC-60% relative humidity). The packaging was: |: 15 a double-density polyethylene plastic bag | in an anhydrous sealed foil pouch - by: S heating in an HDPE container.
    The results of |
    : 67/83 o '- stability of Form A demonstrated an improvement in o 1. relation to free amorphous acid in solid state. | . Example 7A: Preparation of Form B of. polymorph. Crystalline powder of 2- (5-bromo-4- (4-cyelopropylnaftalen-1-11) -4H- = 1,2,4-triazol-3-ylthio) sodium acetate 'Preparation 1: A mixture of 2- ( 5-bromo-4- (4-cyclopropylnaphthalen-1-1i1) -4H-1,2, d-triazol-3-ylthio) acetate | sodium (3.02 g, Form A) and ethyl acetate saturated with water (6 ml) was stirred at 45-50ºC for 16 hours producing a biphasic mixture, which was gradually cooled to room temperature over 2 hours and stirred for another 21 hours to generate a uniform suspension.
    The foji suspension. vacuum filtered, washed with ethyl acetate and the filter cake dried in vacuo at 18-20ºC with a sweep of 4 nitrogen for 2 hours to generate 2.77 q of 2- (S-bromo-4-: 'e ( 4-cyclopropylnaphthalen-1-311) -4H-1,2,4-triazole-3->: ylthio) sodium acetate containing 12.9%. of the water weight. i '(91.7% recovery, anhydrous basis). 'o | ; : | Preparation ii: 2- (5-Bromo-4- (4-cyclopropylnaphthalen-l- | | 1il) -4H-1,2,4-triazol-3-ylthio) sodium acetate (Form A) was stirred at - 50ºC in ethyl acetate saturated with water (0.5 i 'ml) overnight, converting the solids into oil. - o The oil was scraped with a toothpick and left in% agitation at room temperature.
    After approximately 3 SN: 25 days, optical microscopy indicated crystalline solids. o: 'liquid was removed by decantation and isolated solids: o: Isolated solids were designated Form EB. "a: i Example 4B: Analysis of crystalline polymorph Form B: 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-i1) -4H-1,2,4-" Ca 30 triazole-3- iltio) sodium acetate oo: |
    ! a | '68/83 | J: | ! is | ! and X-ray powder diffraction 'i! | A pan-analytical XRPD pattern and an Inel 'toxin | i 7 analyzed. The reproducibility and peak intensities: 4, relative, were consistent between the diffraction patterns of: 5 X-ray powder, indicating good particle and orientation statistics. The XRPD pattern for Form B is shown in - Figure 5; observed and representative peaks in the XRPD pattern are shown in the tables below: | and Form B Observed | | 2 |] sspace action | intonation (6) -. 8.51 + 0.10 10.392 + 0.123 Mo "i: o 6.917 + 0.064 | ——— a9": EEN
    AB o | o: as of o o '3,883 + 0,017 act SANA o CENA |
    | 69/83 ':; ]] - -: Ss 8 2 Form B Representatives SN; “The | | seas a) | intensity (e) | 4.22 + 0.10 20.939 + 0.508 | 100 sa: i 2 A Lo | The trace of the differential scanning calorimetry for Form B is shown in Figure 6.: Example 5A: Preparation of Form B '| of the crystalline polymorph "5 of 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) 4 | 1,2,4-triazol-3-ylthio) sodium acetate i - 2- (5-Bromo- 4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4- 'triazol-3-ylthio) sodium acetate (Form B containing 12.9% water weight) was dried under vacuum in room temperature oO for 1-3 days resulting in a solid: strangled, designated Form B '.: |':: 'Example 5B: Analysis of Form B' of the 2- (5-bromo-4- crystalline polymorph) (4-cyclopropylnaphthalen-1-11) -4H-: eos 1,2,4-triazol-3-ylthio) sodium acetate. *: &. A oo 15 The X-ray powder diffraction pattern for Form B ',… the one shown in Figure 7, looks like… that “da.
    Form B,. . : however with peak changes not uniform among the patterns, the:. suggesting a different solvation state. . Polymorphic VC.
    The layout of the scanning calorimetry. oo! '20 differential of Form B' is shown in Figure 8.: i Stability of the crystalline polymorph of 2- (S-bromo-d-; (4-cyclopropylnaphthalen-1-1yl) -4H-1,2,4-triazole -3- ilthium) sodium acetate i |
    '. ; 70/83: From ES OO It was found that the crystalline polymorphs of 2- (5- = t - bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazole-3-: (Ilthium) sodium acetate exhibit increased stability compared to the solid amorphous form of carboxylic acid.
    The increased stability of. Crystalline polymorphs of 2- (S-bromo-4- (4 cyclopropylnaphthalent1-i1) - 4H-1,2,4-triazol-3-ylthio) sodium acetate allows for: preparation of pharmaceutical dosage forms. that exhibit reduced variability in the dosage present in a certain dosage form, reduction in the presence of impurities in the product 7: final pharmaceutical, and an increased validity of formulated dosage forms, when compared to the form of i: pharmaceutical dosage prepared with amorphous state: solid carboxylic acid. o: 15 Unique crystalline X-ray powder diffraction patterns ". C.DekE a" q Example 6: 2- (5-Bromo-4- (4-cyclopropylnaphthalen-1-11) -: 4H-1, 2,4-triazol-3-ylthio) acetate. of sodium generated. three | : Additional CU unique crystalline X-ray powder diffraction patterns - C, D and E patterns, prepared as follows: o: i Pattern e: “rapid evaporation of methanol a. "O. : approximately 97% relative humidity.
    Meo:. i 'Standard D; cold ethanol / water crystallization. . i! 25 Standard E: cold crystallization of 2-propario1 / water. io Example 6A: 2- (5-Bromo-4- (4-cyclopropylnaphthalen-1-yl) - ". | 4H-1,2,4-triazol-3-ylthio) sodium acetate showing pattern:: crystalline X-ray powder diffraction single "A portion of Form A was. dissolved in methanol,: “30 followed by rapid evaporation at 97% relative humidity: One. ]: |
    | . 71/83: 2 Bruker's XRPD pattern was analyzed for this material, 'ú - and the effects of the preferred orientation and. | 'particle evaluated by means of evaluation. of the two-dimensional dispersion pattern. Consistent, unbroken rings, devoid of stains, suggest good | particle and orientation statistics. The XRPD C SAR pattern is shown in Figure 9; observed and representative peaks i in the XRPD pattern are shown in the table below: | 52 | space a (à) | rmtensiaaae (9) | 200 SN 13.1 + 0.1 6.779 + 0.052 26 Ú | : hand by hand - 20 SAN
    PE od |
    72/83 MM:; LO 3.811 + 0.016 74 Ns o 3.726 + 0.015 80 3.376 + 0.013 40: 1 3.295 + 0.012 34:. 3.158 + 0.011 | 66: '“o 3.075 + 0.010 .7o! Standard C Representative,: Intensity (%) os o | 3.075 + 0.010 2] 70 ': Example 6B: Preparation of 2- (5-bromo-4- (4-. Cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate i. . sodium which exhibits crystalline powder diffraction pattern of:: 5 single X-rays D i a | ,:: A portion of Form A was crystallized in an o. | freezer of an ethanol / water solution (1/1) .: A standard: o | of Bruker's XRPD was analyzed for this material, and Os Vac. | the effects of preferred orientation statistics E! to the particle evaluated by evaluating the dé pattern | Two-dimensional dispersion.
    Uninterrupted rings, "consistent, without stains, suggest - good | |
    '| 73/83: | and ”particle and orientation statistics.
    The default, from XRPD D | ú - is shown in Figure 10; observed and representative peaks | 7 in the XRPD pattern are shown in the table below: i: | Standard D Observed:: | and Space d (À) Intensity (%): | ; 14.585 + 0.244 20 Ns | : 13.599 + 0.212 RO: 12.9 + 0.1 6.842 + 0.053 23: 18.1 + 0.1 4.896 + 0.027 2. as 3.959 + 0.017 | BB o | : 23.0 + 0.1 3.874 + 0.017 6 | . i 3.815 + 0.016 20 dec o 3.764 + 0.016 | the Po 3,531 + 0,014 -. 66 = '. :: | Fo 27.3 + 0.1 3.267 + 0.012 = aa o | | | 27.9 + 0.1 3.198 + 0.011 NO A es | 3,132 + 0,011 air Po | aommavomo [as SS 3,012 + 0,010 1 38 | d dos' |
    : the 74/83: | E e ”Standard D Representative = 0. | á - º20 Space d (Á) Intensity (%): 2 | e.60s «x 0.004 | to 1 | That NA | Example 6C: Preparation of 2- (5-bromo-4- (4-: cyclopropylnaphthalen-1-1yl) -4H-1,2,4-triazole: 3-yl) acetate | :; sodium which exhibits crystalline powder diffraction pattern; X-rays single E "o.: Preparation i: A portion of Form A was mixed; with ethanol and water (1/1) to form a broth, which: then passed through slow evaporation / rapid evaporation in a cold room. Preparation ii: A portion of the.
    Form A was mixed with isopropyl alcohol and water (9/1) to form a broth, which was slowly cooled to 50 ° C, and then passed through | by slow evaporation / rapid evaporation in a refrigerator. and A Bruker pattern was analyzed for this material, and we. The effects of the preferred orientation statistics and the particle evaluated through evaluation of the two-dimensional dispersion pattern.
    Unbroken rings,. : consistent, without stains, suggest good | particle and orientation statistics. the XRPD E 'standard. is shown in Figure 11; observed and representative peaks. | io. in the XRPD standard are shown in the table below:. i; Standard E Observed 7 -: | . Lo 2o | space a) -] rntensiaão (o) | |
    | 75/83, 4 EA> 10.5 + 0.1 8.425 + 0.081 200 | : the BO | 6,863 + 0,053 3300. eo 13,3 + 0,1 6,647 + 0,050 as co p | 13.8 + 0.1 6.417 + 0.047 4 14.7 + 0.1 6.026 + 0.044 | co:. 15.5 + 0.1 5.724 + 0.037 - io 13. 15.8 + 0.1 5.623 + 0.036 as To / 16.6 + 0.1 5.328 + 0.032 nO | 5.198 + 0.030 228. co | : "SN ai '4,215 + 0,020 26 MN | o 4,081 x 0,019 | o 320 | i 22,4 + 0,1 3,973 + 0,018 BB: i 22,9 + 0,1 3,890 + 0,017 ma 6 ni o: 23, 2 + 0.1 3,834 + 0,016 7 oo: 3,739 + 0,016 49: ': 3,616 + 0,015 + 60 | Dot:' a | 3,396 + 0,013 Mo |. | TREO 10 —as | 291401 Bio |: | oo oo |
    76/83; | 'Standard E Representatives A, º20 Space d (À) Intensity (%) 10.5 + 0.1 8.425 + 0.081 100. o ': 22.9 + 0.1 3.890 + 0.017 6 | 3.834 + 0.016 2270 SO: 24.6 + 0.1 3.616 + 0.015 cos j Mesophase standards 1, 2 and 3: Example 7A: 2- (5-Bromo-4- (4-cyclopropylnaphthalen-1-yl) -. 4H -1,2,4-triazol-3-ylthio) sodium acetate that exhibits i 5 pattern of mesophase 1. Solids isolated by means. of several prodedinisntos, | described below produced a mesophase material ,. 'designated mesophase 1 (mesophase indicates x-ray pattern: amorphous with relatively few reflections, suggesting order. ESA limited in solids), which shows a strong ampãa A. reflexion | at approximately 4º20, but without birefringence for. 'Optical microscopy:: "::. A) evaporation of methanol, ethanol, acetone, methyl ethyl -, ketone, methyl ethyl ketone + heptanes or water;." B) vacuum drying of Form A; '| c) vacuum drying a mixture of Form A and standard | . 'it C at room temperature for approximately 23 hours; : | READ d) precipitation of an acetonitrile broth; ". |: | 'e) precipitation of Form A and Form B' broths in 2- | propanol, prepared at room and ambient temperatures. ': cold (approximately 2-8ºC). | o ESA" "The diffraction pattern X-ray powder of the mesophase o Standard 1 is shown in Figure 12, Na F Ú; & ss' |
    '!
    | 717/83 i
    | '| Pp | ns The cyclic tracing of the calorimetry, scanning 'Tr differential of the Standard 1 mesophase is shown in Figure 13. | | 7 Example 7B ;: 2- (5-Bromo-4- (4-cyclopropylnaphthalen-1-yl) - | '4H-1,2,4-triazol-3-ylthio) sodium acetate which: exhibits pattern | | mesophase 2 | ! Standard 2 mesophase solids were prepared by precipitation of 2-propanol / ethanol, and exhibit one. strong or acute reflection at approximately -3º20 It is several reflections are wide weak potentials, à The X-ray powder diffraction pattern of the mesophase. Pattern 2 is shown in Figure 14.; Example 7C: 2- (5-Bromo-4- (4-cyclopropylnaphthalen-1-yl) - 4H-1,2,4-triazol-3-ylthio) sodium acetate which exhibits a pattern | mesophase 3 ç Standard 3 mesophase solids were prepared by evaporation under vapor stress.
    Dichloromethane solutions:
    , and tetrahydrofuran were evaporated to approximately 297% | i of relative humidity initially generating oils, that IS 7 gradually exhibited partial and crystallization;
    hardening in a gel. i: The X-ray powder diffraction pattern of the mesophasis' Pattern 3 is shown in Figure 15. Notice which signs. of the . crystalline solids can be obscured by the gel. i ": Example 8: Karl water content determination 7 | 25 Fischer io No NE Karl Fischer coulometric analysis (KF) for io: water determination was performed using an oo titrator. CG KF from Mettler Toledo DL39 A blank titration was performed before the analysis.
    The sample was prepared under a | the dry nitrogen atmosphere; where approximately 17-13 | |
    | 78/83! SEA | ! in the sample mg were dissolved .in approximately 1, mMl of | = z Hydranal section - Coulomat AD in a pre-dried bottle.
    All i, solution was added to the Karl coulometer.
    Fischer '1 through a septum and mixed for 10 seconds.
    The sample | I was then titrated by means of a generator electrode, which:! produces iodine by electrochemical oxidation (2.1> L + 207). : The samples were processed in duplicate; the & average values are shown below, measured to the nearest tenth '; one percent. o "ES [o] Karl Fisher analysis (% of water weight) | 10.2% (average of two 16tes) '|: 2.3 o; 10 IIT Instrument Techniques, i;' Example 9: Diffraction of X-ray powder (XRPD): S X-ray powder diffraction patterns were collected. '
    'using an Inel XRG-3000 diffractometer equipped with a curved position sensitive detector with an amplitude of ”120º, an incident beam of Ka radiation (40 .kV, 30'
    J mA) was used to collect data in: real time in one. resolution of 0.03º20. Before analysis, a pattern of “1 *. silicon (NIST SRM 640c) was analyzed to verify the ':
    peak position of Si 111. Eúcem samples prepared for:: “20 analysis for its placement in capillaries.wall glass. . : | | thin.
    Each capillary was mounted on the head of a goniometer: | ] and rotated during acquisition of dices.
    The crack of the. . | monochromator was adjusted to 5 mm by 160 pm. i «| Alternatively, X-ray powder diffraction patterns i
    '25 were collected using a Biruker D-8 Discover diffractometer and “Bruker's General Detector System” (GADDS, see 4.1.20). An incident Cu Ka radiation micro-beam was produced ESA
    |
    ; : | Of ! 79/83 À. "using a thin focus tube (40.kV, 40 mA), an i. x Gôbel mirror, and a 0.5'mm double micro-hole collimator." 7 Before analysis, a silicon standard (NIST. SRM 6406) was i | analyzed to verify the position of the Si 111 peak. A | : '5 sample was compacted between films. Thickness 3; pm to form a portable disk-shaped specimen, A | prepared sample was loaded on a rack fixed to an i; translation stage. A video camera and laser were 'used to position the area of interest to intersect.
    the incident beam in transmission geometry. The beam: the incident has been scanned and tracked to optimize 'guidance statistics. A stoneware pad was used | to minimize air dispersion by the incident beam.
    | Diffraction patterns were collected using a detector:: i5 Hi-Star area located 15 cm from the sample and processed ": | using GADDS. The image intensity of: GADDS of the 7 i diffraction pattern was integrated using a step size from ”i:: 0.04º286, Integrated patterns exhibit Na | diffraction intensity as a function of 260. | | |] i Alternatively, x-ray powder diffraction patterns were collected using a pah-analytical diffractometer x 'Pert | "ms Pro. An incident beam of Cu Ka radiation was produced NM using a long fine-focus Optix source. An elliptically graduated multilayer i ”mirror was used for | 25 Focus the Cu Ka X-rays of the source through the sample and * Í i on the detector. The data went. collected and analyzed "using the software“ X'Pert Pro Data Collector ”Tv. 2.25). ii: Before analysis, a silicon sample (NIST SRM 640c) &. was analyzed to verify the position of the peak of Si 111, À o sample was sandwiched between films with 3 pum: o | t 280/83 | SJ thick, analyzed in transmission geometry, and, z rotated to optimize orientation statistics. * A 7 beam stop was used to minimize the bottom level, generated by air dispersion.
    Soller slits were used; 5 for incident and diffracted beams to minimize: axial divergence.
    Diffraction patterns were “collected; using a position sensitive scan detector,: | (X'Celerator) located 240 mm from the sample. : Co Peaks within the range of up to, about 30º26 are: listed in the tables, although different. rounding algorithms have been used to round each peak to the nearest 0.1º or 0.01º206, depending on:: instrument used to collect data and / or resolution: inherent peak.
    The location of the peaks along the axis. 15 X (º20) in the tables was automatically determined using Ú] the PatternMatch "" 3.0.1 and rounded to one or two: 2 significant figures after the decimal point based on the above criteria.
    Variability of position * of. peak, "" are presented within + 0.1º20 based on recommendations.. 20 described in “United States Pharmacopeia”, USb 32, NE 27, o: Vol. 1, page 392, 2009. The wavelength used to: calculate the spacing d was 1.541874 Á, a weighted average of the Cu-Kai E Cu-Ko wavelengths.
    THE : . The variability associated with the d spacing estimates was * ”i 25 calculated by the USP recommendation, in each d spacing. '1 If multiple patterns of * are available
    diffraction, then the particle statistics evaluations co | | : (PS) and / or preferred orientation (PO) are possible.
    A:: | reproducibility between multiple XRPD standards:
    '30 samples analyzed on a single diffractometer indicates that. as e)
    |
    81/83: t =:: o | ! P particle statistics are adequate.
    The consistency of the z relative intensity between XRPD 'multiples' patterns! diffractometers indicate good orientation statistics. Alternatively, the observed XRPD pattern can be compared with a calculated XRPD pattern: based on one. single crystal structure, if available.
    Patterns "- two-dimensional dispersion using: area detectors. Can also be used to assess PS / PO.
    If the effects * of both PS and PO are considered negligible,. then the XRPD pattern is representative of the average powder intensity for the sample and prominent peaks can be identified as representative peaks.
    Characteristic peaks are a subset of. representative peaks and are used to differentiate a crystalline polymorph from another crystalline polymorph. - Peaks o: 'characteristics are determined by evaluation' of “which representative peaks, if any, are present in a crystalline polymorph of one compound against all others | 'crystalline polymorphs known from that compound up to. within + 0.1º26. Not all crystalline polymorphs of -: a compound necessarily have at least one peak o 1, | characteristic. . Example 10: Differential scanning calorimetry .. o (DsC) | : o o | ; 25 Differential scanning calorimetry was performed o: a using a differential scanning calorimeter TA o: Instruments Q2000. The temperature calibration was: i performed using NIST traceable indium metal.
    The sample: was placed in a .DSC aluminum boiler, & The weight was | '30 recorded accurately.
    The boiler was "covered: with an o | r“ | 82/83 "i '' | "lid, and the lid has been crimped.
    An aluminum boiler o | '% heavy and crimped% was placed on the reference side: gives the cell, The sample cell was equilibrated at the initial temperature and heated under a nitrogen discharge.
    Paraã .. | ; 5 measure the glass transition temperature (T4), the sample cell was initially equilibrated to approx. . 30ºC, and then heated under nitrogen gas at a rate of 10ºC / min, cycling three times to 90ºC.
    In each cycle, | the sample cell was allowed to cool and run. balance at approximately 30ºC.
    The sample cell was then heated at 10ºC / min to a final temperature of 250ºC,: | . Example 11: Infrared (IR) spectroscopy 'i IR spectra were acquired in an infrared spectrophotometer with Fourier transform (FT-IR) “Magna-TR É 860º“ (Thermo Nicolet) equipped “with an IR source | medium / distant Ever-Glo, to a potassium bromide (KBr) extended beam divider and a: detector. D deuterated triglycine sulfate (DTGS). The verification of the: 3rd wave beam was performed using NIST SRM 1921b (polystyrene). A diffuse reflectance accessory (the "Collector", Thermo Spectra-Tech) was used to collect A 'samples.
    Sample preparation consisted of. physical mixing of the sample with KBr, placing the sample in one: bowl =. i 25 of 13 mm in diameter and leveling of the material.
    The set | the - basic data was acquired with KBr powder. the spectrum e: o: of Log 1 / R (R = reflectance) was obtained by “obtaining: | i a proportion of these two sets of dices one against the.
    NE VC another and then converting the Kubelka-Munk into units. . Example 12: FT-Raâman spectroscopy. o: '% |
    ! 83/83 '| ! | - The ENS “Raman Spectra were acquired in one, | z FT-Raman 960 spectrometer (Thermo Nicolet) equipped with a .. i: gallium arsenide detector. Indian. (InGaAs). à:: verification of the wave beam was performed using sulfur and co. 5 cyclohexane.
    Each sample was prepared for analysis. by ': | placing the sample in a glass tube and positioning it. of the tube in a gold-plated tube holder. The o: sample was irradiated with an Nd: YVO laser (excitation wavelength 1.064 nm). : |
    权利要求:
    Claims (16)
    [1]
    1/9: | ! | : "| '% AMENDED CLAIMS - |. 1. Crystalline polymorph of 2- (5-bromo-4- (4-:: | cyclopropylnaphthalen-1-yl) -4H-1,2, a-trisol-3" 110io ) acetate | sodium::; | No no 'gr Ns Ao | ; : RW O "Na *: | ES 120 | '| characterized by. | Oa) peaks at 4.90, 9.83 and 25.29º20 + 0.1º26; | b) peaks at 4.90, 9.83 and 25; 29º28 + 0.1º20, further characterized by at least two additional peaks in: 15 6.86, 8.41, 10.13, 17.92 and 23.10º26 + 0.1º26; oo c) exhibit a pattern of X-ray powder diffraction oo cs substantially equal to the diffraction pattern of, “X-ray powder” shown in FIGURE 1; | 'ue: i.' d) a beginning of the endothermic point, as determined by differential scanning calorimetry, is atino of 'hi 62ºC;':: "'e) a differential scanning calorimetry pattern: substantially the same as the" 2 | differential scanning Galorimetry pattern shown in FIGURE 2; Or' o: £ f) as Form A of the crystalline polymorph of 2- (5-bromo-o | 4- (4-cyclopropylnaphthalen-1-1l) -4H-1,2,41-triazole-3-: ylethyl) acetate sodium co: '
    [2]
    2. Crystalline polymorph of 2- (5-bromo-4- (4- i cyclopropylnaphthalen-1-11) -4H-1,2,4-triazol-3-ylthio) acetate: i: | sodium: | :: ". o. 4 | h 2/9 | | | | é.:: | Y NN NEL a« gr Nas No!::,: | SS O Na *: '3' | '5.' characterized by ], | a) peaks at 4.22, 8.51 is 16.95º20 + 0.1º20;::;; b) peaks at 4.22, 8.51 and 16.95º26 + 0.1º20, Ee further characterized by a peak at 12.80º26 + 0.1º289; AN c) exhibit a CG X-ray powder diffraction pattern substantially equal to the X-ray powder diffraction pattern shown in FIGURE 5; oO i: | d) a start of the endothermic point, as determined by 'differential scanning calorimetry', around n 173ºC;::.:: oo: 'e) a differential scanning calorimetry pattern substantially equal to the | scanning calorimetry pattern differential shown in FIGURE 6; or oo: o £) as Form B of the crystalline polymorph of .2- (5-bromo-i. NS 4- (4-cyclopropylnaphthalen-1-yl) -4H-L, 2, 4A- triazole-3-oo:: | iltio) sodium acetate. 1 o BR 3. Crystalline polymorph of .º 2-15-bromo-4- (4-.: cyclopropylnaphthalen-1-yl) -4H-1,2 , 4-triazol-3-ylthio) ac sodium etate: | i a - N-N: vo: Teo 'gr Ns and o: o o O Na *. '7' |
    [3]
    3/9! | | . characterized by o; 7 a) exhibit an X-ray powder diffraction pattern | : | substantially equal to the powder diffraction pattern of | X-rays shown in FIGURE 7; '| b) a differential scanning calorimetry pattern substantially equal to the 'calorimetry pattern of: the differential scanning shown in FIGURE 8; or c) as Form B 'of the crystalline polymorph of sodium 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-11) -4H-1,2,4-triazol-3-ylthio) acetate. , | '
    [4]
    4. Crystalline polymorph of 2- (S-bromo-4- (4-: cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) sodium acetate:; »: Br N ARE SOO O O O 'Na”. ", characterized by:,. | 'a) peaks at 6.9, 10.1 is 22.6º20 + 0/1936; EN ob) peaks at 6.9, 10.1 and 22.6º28« 4 0.1º26 , plus: characterized by at least two additional peaks at 23.3, i: | 23.9, 25.2, 28.3 or 29.0º26 + 0.1º20; / = | io:: c) display a pattern X-ray powder diffraction o | | 25 substantially equal to the standard, X-ray powder diffraction shown in FIGURE 9; or 'i RCA e ao': d) as Form C of the crystalline polymorph of 2- (5-bromo- o cs. 4- (4-cyclopropylnaphthalen-1-1l) -4H-1,2,4-thiazol-3- 'glycosyl) sodium acetate.' o oC - oo 2 30 5. Crystalline polymorph “of, 2- (S-bromo-4- (4- = | i; i 4/9 hi |!:> Cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazole- 3-ylthio) acetate or sodium: 'oe "OS Na! 'o eg Ns o *. ;
    [5]
    5 A * O "Na *: 'oo SW! = - characterized by a) peaks at 10.3, 17.8 and 25.2º20 + 0.1º20,: b) exhibiting a diffraction pattern in X-ray dust : substantially equal to the X-ray powder diffraction pattern shown in FIGURE 10; or * |: 'c) as Form D of the 2- (5-bromo- 4- (4-cyclopropylnaphthalen-1-yl) crystalline polymorph ) -4H-1, 2,4-triazole-3-:, yl) sodium acetate, ". SS. ::.
    [6]
    6. Crystalline polymorph | of 2- (S-bromo-4- (4-: cyclopropylnaphthalen-1-1yl) -4H-1,2,4-triazol-3-ylthio) sodium acdeetate: i 220 NNO i 4: | | . : ag A ENO À: ca “o. O Na * oo i - | | 225 characterized by i If: o: 'a) at least three peaks at 120.5; 22.9, 23.2 or i | 24.6º20 + 0.1º20; : o: | b) exhibit an X-ray powder diffraction pattern substantially equal to the X-ray powder diffraction pattern. X-rays shown in FIGURE 11; Or + ". Eos' o ao |
    | 'eo: | 8/9 '| ao o: | % c) as Form E of the crystalline polymorph of 2- (5-bromo- "'4- (4-cyclopropylnaphthalen-1-1yl) -4H-1,2,4-triazole-3- | | ilium) acetate sodium.:: |: | 7; solid mesophase form of 2- (5-bromo-4- (4- | | 5 cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazole-3-11tio ) sodium acetate: & | | NA '::; gr Ns Oo | S í O "Na *:'“. ” o 1 '"Es i, DN! A". characterized by: ". |: a) exhibiting an X-ray powder diffraction pattern substantially equal to the. X-ray powder diffraction pattern shown in FIGURE 12; or
    [7]
    7 NES] '7 b) display a differential scanning calorimetry pattern substantially equal to "the differential scanning calorimetry pattern" shown in' FIGURE eo:
    23. i i | :
    [8]
    8. Solid “a- (5-bromo-4- (4- Te cyclopropylnaphthalen-1-1yl) -4H-1, 2,4-triazole-3-ylthio) acetate v solid form: JU. Do ': "N-N ua Jos | AAA aa ND, ONa * t oo' 28: 25 i Cv"! : characterized by exhibiting a powder diffraction gadiide substantially equal to the X - ray pattern. i: 30 X-ray powder shown in FIGURE 14,:. o |
    6/9: s
    [9]
    9. Solid mesophase form of 2- (5-bromo-4- (4-SO. Cyclopropylnaphthalen-1-yl) 4H) 2,4-triazolyl-3-yl) sodium acetate selected from: is i
    EN ': BANS eo | | : * E O "Na * and no: characterized by 'i |. - a mesophase that exhibits an X-ray powder diffraction pattern substantially equal to the.! X-ray powder diffraction pattern shown in FIGURE 15. |
    [10]
    10. Solid pharmaceutical composition characterized by:; understand::: Õ. | o - an effective amount of the erystaline polymorph of claim 1 as an active ingredient; and so i. Cs - at least one excipient or vehicle. ": Ac
    [11]
    11. Solid pharmaceutical composition characterized by - comprising an effective amount of hair. at least two 'forms of 2-7 (S-bromo-4- (4-cyclopropylnaphthalen-1-11) -4H-1,2,4-. eU i. triazol-3-ylthio) sodium acetate selected from the group that : : It consists: . Cs: i: i: - in the crystalline polymorph of claim 1 as an i. j 25 active ingredient; Er TOS | o From CG. - in the crystalline polymorph of claim. 2 as one! i active ingredient; ". 2;: | - in the crystalline polymorph of claim 3 as an." Active ingredient;: ",: | i: "7/9 | | |! Po istali iwintdicaçã | | * - in the crystalline form of, claim 4 as a: | active ingredient;,;: | -» in the crystalline form of claim 5: as a CO |: active ingredient; ':: ”- in the crystalline form of claim 6 as an active ingredient;'. '- in the solid mesophase, of claim 7 as an active ingredient;. | |' - in the solid mesophase of claim 8 as an | ingredient active; and: i, - in the solid mesophase of claim 9 as an active ingredient; DAS e - and at least one excipient or vehicle.
    [12]
    12. Use of the crystalline polymorph of claim 1, characterized in that it is in the manufacture of a medicament for the '' treatment or prevention of. hyperuricemia, or a disease. i caused by high levels. of uric acid. AND :
    [13]
    13. Use of at least two. forms of 2- (5-bromo-4- (4- i Cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate. | : sodium characterized by being in the manufacture of one; | medicine for treatment or prevention of hyperuricemia. ES ... or a disease caused by high levels of uric acid, in which the (at least) two symptoms. of 2- (5-bromo-4-ohi (4-cyclopropylnaphthalen-1-yl) -4H-1,4,4-triazole-3-,: o | | 25 iltio) sodium acetate are selected from the group that: | consists of: Co. ::. o = in the crystalline polymorph of claim 1 as 7. Is an active ingredient; the 8th Do - in the crystalline polymorph of claim 2, as the active ingredient; o: 'Ú ”|
    | ': i 8/9'! "- in the crystalline polymorph of claim 3 as an:" active ingredient; : - in the crystalline form of claim 4 as a '; active ingredient; ": 5 - in the crystalline form of claim 5 as an; active ingredient; '- in the crystalline form of claim 6 as an active ingredient; and Cv] - in the solid mesophase of claim 7 as an' active ingredient;: '; |: : - in the solid mesophase of claim 8 as an. | active ingredient; and O. - in the solid mesophase of claim 9 as an | 'active ingredient. |':
    [14]
    14. Use of the crystalline polymorph of claim L, which is characterized by the manufacture of a medicine for: treatment or prevention of gout. . :. i oo
    [15]
    15. Use of at least two forms of 2- (5-bromo-4- (4-. Cyclopropylnaphthalen-1-1yl) -4H-1,2,4-triazol-3-ylthio) sodium acetate: 20 characterized for making “one | "*. medicine for the treatment or prevention of gout, in which: (at least) two forms of 2- (5-bromo-4- (4- o. cyclopropylnaphthalen-1-11) -4H-1, 2, 4-triazol-3-ylthio) acetate. -: and sodium are selected from the group fue. "Consists of: o 25 - in the crystalline polymorph of claim 1 as one: i | active ingredient; : Ns. a:: t - in the crystalline polymorph of claim 2 as uM | o 'i active ingredient; just a. Na: i - in the crystalline polymorph of claim 3 as a co - 30 active ingredient; "DO |
    9/9: & t $ - in the crystalline form of claim 4 as an active ingredient; i look. : - in the crystalline form of claim 5. as “one; | | active ingredient; ":! 5 - in the crystalline form of claim '6 as a! | Active ingredient;: |. |, |' |: - in the solid mesophase of claim 7 as a:; 'active ingredient; oo]! - in the solid mesophase of claim 8 as an active ingredient; and; '- in the solid mesophase of claim 9 as an .- active ingredient., i'
    [16]
    16. Method for preparing a crystalline polymorph. . sodium 2- (S5-bromo-4- (4-cyclopropylnaphthalen-1-yl1) -4H- | 1,2,4-triazol-3-ylthio) acetate, - characterized by - ': understand: * From SA: : 2 a) contact of 2- (S-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) acetate. amorphous sodium with water and an aprotic solvent; and ' : : ] . 'b) isolation of the mixture solids - prepared in' 'step (a). | ES:: 1
    17. Method according to claim 16; It is characterized by the fact that '"the solvent: aprotic is: ethyl acetate.:..: |
    | '| | 2/15. ! | : "| |: FIGURE 1 2- (S-bromo-4- (A4-cyclopropylnaphthalen-1-1i1) -4H-1,2,4-triazole-3- | ylthio) sodium acetate, Polymorph Form A: standard of diffraction, of ray powder-% a |: | Â i EE i + À À | t E CS | so â ú É Ft; PR Ú + o doa E! Hs MS A goto as ai Í i - í E 4 di: Í H 3 Ade RES i "go Ad dio ag Po so d ARSEI, O; & Í po po donates 7 GA GE st in FECAL pd 1 i dE IS FROM Vo nt LT HiBIDA DE SÁ t 7 Po A Hop Oo A do 8 URIA AS! ; o ”46 dE, 4: ET (BA TRE IREI Guddairio. '4 THE NWRAAO A TA ER SEEN: 4 SE RO E GV RUSSIA DO d À T' Vi OO, io 1 RUA A, t É j RPA ". & |: SE = Te Ta. Íurrcnaonsnfosiiaiegiagumas age sq - 4 w" & 2 »* 90-28 (degrees) i: |
    | 2/15. FIGURE 2 2- (S-bromo-4- (4-cyclopropylnaphthalen-1-11) -4H-1,2,4-triazol-3-ylthio) sodium acetate, Polymorph Form A; differential scanning calorimetry 't
    Í PS x o E m o ”. | i- e and E DN ms ef [AAA:: E | ! ONE AND 1 VP 4 | Í: Í $: 3 | Í à Í Í e + H BR 6178O t oi Í: | | s and am ESA Temperature (ºC) | :: 'Í:
    3/15 '' FIGURE 3, 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3- | ylthio) sodium acetate, Polymorph Form A: spectrum IR i À ii É; : o: Yeah; i Po: it Í: i io; Í H of RAR 3; old i jo dE j mw IS: PRB o ú i Te Dojo 214º io =. PG ii i sm 'Pgdao Ed E À o ii dpocodieso alhos: = id dl BERSAS ij É Ho A A Hei 4 A PR o gBiiica E t A RN O fh r ET SANA i; NE * ee Í | Í No To water; ; i; Im ee Te TO; IO nm FO sm SE re se Wave numbers (1 / cm) '
    | 4/15: | 'FIGURE 4 oo' 2- (5-bromo-4- (A-cyclopropylnaphthalen-1-11) -4H-1,2,4-triazol-3-. Ylthio) sodium acetate, Polymorph Form A: Raman spectrum : | % t i í Ígm oo; : 8 I can use 7. 8 Po doo 't a + o dog À FS | uncle ; a: E Zig pod do da jm do: o, Est: o FE NARRA A ED O] DA wire e.
    VA: gens II, aqua ENE Aa veces à cms itches sp gypsy guaranis, and qr, ges ces À 3 2 ES xs os o se. Raman's change (1 / cm) | NS:
    | 5/15 'i': | | ; : & | :! FIGURE 5: | í 2- (S-bromo-4- (A-cyclopropylnafrtalen-1-i1) -4H-1,2,4-triazol-3-ylthio) sodium acetate, Polymorph Form B: 'ray powder diffraction pattern -X mo | |
    Í! | o & í io. & ii À: i o 'k i, j' 3 É | o: 7; $:. the FS q i. :: P à z 'às' "â Po * t - j. É PN TO ii Í: bs hoo AP AE A po À a, A' PO ta meto MA Ra RO uh oa bs À Í ar AA of E: io ST SASE SA B-20 (degrees): |.: o |: |
    ! "o Oo ó: i; 6/15:: | 1 o.! 1 | i 7 FIGURE 6. 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-i1) -4H-1,2,4 -triazole-3- 'ylthio) sodium acetate, Polymorph Form B;' 'differential scanning calorimetry
    O A AAA A: as' Í 5º, IA -: SA TT FM: E. E. io fingers | 6 E -. i $ i. - What if ' I saw this. go: jo g: À FS 1 i À co Í. Ao À 'kt í L "oo À.: I AAA: co:::: Dt ju irrctttetÉ o”:: e' DN É ii '' mother: f2g hurts area sa] gs & o ão 1st Es 759 'Temperature ( ºC) the Ú
    | : i Í: oo '' ': 7/15: Jo FIGURE 7; 1 2- (5-bromo-4- (á-cyclopropylnaphthalen-1-11) -4H-1,2,4-triazole-3-yl) sodium acetate, Polymorph B ': powder dispersion pattern X-ray. '' FO::: hi; O.
    AND ' : . í 8 o 2! j "1.: i: 3 É É, i + 1 i 7 'É H |:' Í E co oo 7 É É 7 Po,:: oo: i punch Í Í ie: si À Ao ii Ros RO: V Dense Taste lat Sad GIVE Po aÃ É A,:, + tw * s = so. Bd A 89-20 steps):
    | : o '' | 8/15 oO do, N 7 1. . : | . :; 'Í: Ú :, 1st o | : o | FIGURE 8,, oo 2- (5-bromo- 4- (4-cyclopropylnaphthalen-1-i1) -4H-1,2,4-triazole- ”; 3-ylthio) sodium acetate, Polymorph Form B ': calorimetry & a. differential scanning> 1 '; . a: Teak “a, oo 'G: Er CMAS NT OEA À' TF Mo Beata SN '-. SS as, N; I . Uncle Nr ea: É, À x ONE o j & &: Í 7 i 8 OO fecnaniaoto do z 3 "mos Pos] á: nO J. E | o Í BR.: Í,. = Í:“. I "| : e * s: nn a: '' Temperature (* C). t e
    9/15 i i - ao: | . '. . Í:: 'FIGURE 9º 0' in: '2- (5-bromo-4- (d4-cyclopropylnaphthalen-1-yl) -AH-1,2,4-triazol-. 3-ylthio) sodium acetate; X-ray powder dispersion pattern O s. DS o i j "" "RE. : i Po Vo o o, t [A 2. | and the "É Ft BELO"; '' uv 'Is À: tos t 1 ax &: E! . GG: How do I call ct + ã Í VC GAR E::. Er ij 4 RE E dos,, ':' FS o gas ER co "- * E Ss FA OPEN DES EE oa" 4 AR Eco wWESASiZTAA Th = "ú Doo à MÁ Rormeo ESNMA Do qo co:.: Do na É ! do NE: ROS, í NS A o AX MART Rr AR to SS Í o LUA ARO as OO: 'Í dra A Pud PRÇOA ME: ". . i [ESTAARA ROTA CATA So e. gdtadado THE YEAR: Mer. . to 1 ”1” iam eco TA ”o.
    BR 88-98 (uraus):
    20/15,: "o: o FIGURE 10:: 2- (5-bromomo-4- (4-cyclopropylnaphthalen-1-11) -4H-1,2,4-triazole-. I 3-ylthio) acetate sodium; XD ray powder dispersion pattern. À Í: i ':: + 1:' Loco Í i Ê "ij:: É. Í | A Pes do 8 À oo io o É Ê, Iodo: 'Í' 'zm É: s á:' do *. ç.: go; do Po ee E É ij do Po * h à t FE. i '5 E à t.:' ú Í 6 1 2.8 A: in AA oo Pod Ro IRAN ESA Í gh dio o The inaecA lirodoco, 0 cc Po.: Í neo dio pod Tu PIE ARARAS AurassAat É Vuamê I GO OUT TO ME Vo Ô: | '|:; =.
    ! 11/15 ':
    Í '| FIGURE 11 | 2- (5-bromo- 4- (A-cyclopropylnaphthalen-1-i1) -4H-1,2,4-triazole-: 3-ylthio) sodium acetate; X-ray powder dispersion pattern E o É É í É: í É ':; E H t í z Ê & É É i = r Í É i a F | í 3 Í ER Í FZ ú dis: "Ê E Ç do do, 1 go Â Í dj EE Í i: À sh E 1 SA A Aa agENA ARE, | Í Í FER E TR aro SA i os to, ERES dio AB CR 1 2 to Í i NEN IA PERES EO i did SARA is the “so & As RIR E er í 3” ”» »R v * 89-28 taraus)
    '. | i! 12/15:! FIGURE 12 | 2- (5S-hromp-4- (A-cyclopropylnaphthalen-1-yl) -4H-1,2,4-triazol-3-ylthio) sodium acetate; 'X-ray powder diffraction mesophase pattern 1 | ER! if i g ii; and. & io E do So Aa,; í ERAS AT A n ao 4, be Pa t li li Ye and the actor “%. "E IS sa a x the PN, F í TA% j o" s i To Bras ss VA i: Hunger, mild germ, mother and ditch, 98-28 taraus): 1: '
    '13/15! ; i: | | 1 | | | ': FIGURE 13 2- (5-bromo- 4- (A4-cyclopropilhaftalen-1-11) -AH-1,2,4-triazol-3-ylthio) sodium acetate Cyclic differential scanning calorimetry mesophase pattern 1 : 3 paes ra - ww i
    Í i 7 | s !
    E: Go q Na o t i 3 1: LA j [2 '8 sd 2 7 Í - FS o Í j 8 É ”CR Po: E - *
    PD FÃ Í é à rmttamttais wire: Í 1 UN [rr creates octsicarrmntaa— “o“ so E ES o 150 200 E: Temperature (ºC)
    | 14/15 '| Po | ! FIGURE 14 - sodium 2- (5-bromo-4- (4-cyclopropylnaphthalen-1-11) -AN-1,2,4-triazol-3-yl) acetate; X-ray powder diffraction mesophase pattern 2: | : | &Í,; E Í i E IS EE is 1 "à es & i a &:: i ê e. 4 j oO i s ni 7: É k o ES): F Hs À ã ij di
    E 70i j i À A. - ... 'PS Praga minutes E A TR a ANA nt. . : Area iframes tatoo fest on dad 89-28 taraus) o:
    '! 15/15 | | | | | Í! ! '':! | FIGURE 15: sodium 2- (5-bromo-4- (A-cyclopropylnaphthalen-1-11) - 4H-1,2,4-triazole-3-ylthio acetate; X-ray powder diffraction mesophase pattern 3 | Í! la | í A Í 8 $ Í EM Í - Í,: Po 4 / “o Ss 3 À Í X 3 ii j S.:: q Í Í%: i E É N 2 HR Í; 'â oa "À / S FA ao%: E Na No amooo Í o | e SN To tincture raseeaqesçências mreminiO," »» »x» ": 89-28 (araus): | SEAL |; |
    1 ; 1 ! ! 1/1 2: POLYMORPHIC, CRYSTALLINE AND MESOPHASE FORMS OF 2- (5-. ': BROMO - 4 - (4- CYCLOPROPILNAFTALEN-1-IL) -4H-1,2,4-TRIAZOL-3- À; ILTIO ) SODIUM ACETATE AND ITS USES | 5 Polymorphs are described | crystalline and forms of. ! solid mesophase of sodium 2- (5-bromo-4- (4-cyclopropylnaphthalen-11; 11) -4H-1,2,4-triazol-3-yl) acetate.
    In addition, pharmaceutical compositions and uses of those compositions are provided for the treatment of. various diseases and | conditions. | 1 flight:: 1 7 1 1: U |
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    法律状态:
    2020-10-20| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-10-20| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-10-27| B25G| Requested change of headquarter approved|Owner name: ARDEA BIOSCIENCES INC. (US) |
    2021-02-23| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2021-03-02| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-06-15| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|
    2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    US29360210P| true| 2010-01-08|2010-01-08|
    US61/293,602|2010-01-08|
    PCT/US2011/020233|WO2011085009A2|2010-01-08|2011-01-05|Polymorphic, crystalline and mesophase forms of sodium 2--4h-1,2,4-triazol-3-ylthio)acetate, and uses thereof|
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