Crystalline forms of compound for treating or preventing gout or hyperuricemia

Abstract

To provide a prospective therapeutic agent for treatment of hyperuricemia and gout with an improved hepatotoxicity profile.SOLUTION: There are described herein, crystalline forms of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d 4)methanone, and solvates thereof.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] cross reference This application claims the benefit of PCT / CN2018 / 119567, filed December 6, 2018, the entirety of which is incorporated herein by reference. [Background technology]

[0002] Hyperuricemia is caused by the overproduction or oversecretion of uric acid and is believed to be a causative factor for several diseases that significantly impair quality of life. For example, gout, a representative inflammatory arthritis, is believed to be caused by hyperuricemia and is characterized by severe pain and pressure in the joints due to the accumulation of urate crystals. Identification of a drug for the treatment of gout / hyperuricemia that is effective in lowering serum uric acid (sUA) and has low toxicity represents an unmet need that would beneficially impact patients. Summary of the Invention

[0003] In one aspect, a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, is described herein.

[0004] In one embodiment is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.8° 2-theta, 13.6° 2-theta, 14.6° 2-theta, 21.2° 2-theta, 24.2° 2-theta, 24.7° 2-theta, 26.7° 2-theta, and 27.5° 2-theta; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG. (d) A DSC thermogram substantially similar to that shown in FIG. (e) DSC thermogram with an endotherm with an onset at about 147° C. (f) non-hygroscopic, or (g) any combination thereof; and form 3 having at least one of the above.

[0005] In some embodiments, there is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG.

[0006] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.8° 2-theta, 13.6° 2-theta, 14.6° 2-theta, 21.2° 2-theta, 24.2° 2-theta, 24.7° 2-theta, 26.7° 2-theta, and 27.5° 2-theta.

[0007] In some embodiments, there is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in FIG.

[0008] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has a DSC thermogram substantially similar to that shown in FIG.

[0009] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 147° C.

[0010] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form is non-hygroscopic.

[0011] In some embodiments, there is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, wherein the crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1 ; (b) a crystalline form having a crystalline structure having at least one of the following peaks: 6.8° 2-theta, 13.6° 2-theta, 14.6° 2-theta, 21.2° 2-theta, 24.2° 2-theta, 24.7° 2-theta, 26.7° 2-theta, and 27.5° 2-theta. (c) an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 2-theta; (d) a DSC thermogram substantially similar to that shown in FIG. 2; (e) a DSC thermogram with an endotherm having an onset at about 147° C.; and (f) being non-hygroscopic.

[0012] In some embodiments, there is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form is obtained from toluene, toluene / heptane, or ethyl acetate / heptane.

[0013] In another embodiment is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.3° 2-theta, 10.7° 2-theta, 16.6° 2-theta, 19.7° 2-theta, 23.7° 2-theta, 25.0° 2-theta, 25.6° 2-theta, and 27.1° 2-theta; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG. 5; (d) A DSC thermogram substantially similar to that shown in FIG. (e) DSC thermogram with an endotherm with an onset at about 139° C. (f) non-hygroscopic, or (g) any combination thereof; and form 2 having at least one of the above.

[0014] In some embodiments, there is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG.

[0015] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.3° 2-theta, 10.7° 2-theta, 16.6° 2-theta, 19.7° 2-theta, 23.7° 2-theta, 25.0° 2-theta, 25.6° 2-theta, and 27.1° 2-theta.

[0016] In some embodiments, there is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in FIG.

[0017] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has a DSC thermogram substantially similar to that shown in FIG.

[0018] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 139° C.

[0019] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form is non-hygroscopic.

[0020] In some embodiments, there is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, wherein the crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 4 ; (b) a crystalline form having a diffraction pattern of 8.3° 2-theta, 10.7° 2-theta, 16.6° 2-theta, 19.7° 2-theta, 23.7° 2-theta, 25.0° 2-theta, 25.6° 2-theta, and 27.1° 2-theta. (c) a thermogravimetric analysis (TGA) pattern substantially similar to that shown in FIG. 5; (d) a DSC thermogram substantially similar to that shown in FIG. 6; (e) a DSC thermogram with an endotherm having an onset at about 139° C.; and (f) being non-hygroscopic.

[0021] In some embodiments are crystalline forms of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or solvates thereof, where the crystalline forms are obtained from heptane or ethyl acetate / heptane.

[0022] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, wherein the crystalline form is not solvated.

[0023] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, wherein the crystalline form is anhydrous.

[0024] In another embodiment is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 7; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.6° 2-theta, 11.5° 2-theta, 13.8° 2-theta, 14.3° 2-theta, 17.0° 2-theta, 18.9° 2-theta, 27.9° 2-theta, and 31.4° 2-theta; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG. (d) A DSC thermogram substantially similar to that shown in FIG. (e) a DSC thermogram with an endotherm having an onset at about 80° C.; or (f) any combination thereof; This is form 1 having at least one of the above.

[0025] In some embodiments, there is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG.

[0026] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.6° 2-theta, 11.5° 2-theta, 13.8° 2-theta, 14.3° 2-theta, 17.0° 2-theta, 18.9° 2-theta, 27.9° 2-theta, and 31.4° 2-theta.

[0027] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in FIG.

[0028] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has a DSC thermogram substantially similar to that shown in FIG.

[0029] In some embodiments is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 80° C.

[0030] In some embodiments, there is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, wherein the crystalline form has the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 7 ; (b) a crystalline form having a crystalline structure ... (c) a thermogravimetric analysis (TGA) pattern substantially similar to that shown in FIG. 8; (d) a DSC thermogram substantially similar to that shown in FIG. 9; and (e) a DSC thermogram with an endotherm having an onset at about 80° C.

[0031] In some embodiments are crystalline forms of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or solvates thereof, where the crystalline forms are obtained from methanol, ethanol, isopropanol, toluene, water, acetonitrile, heptane, acetone, tert-butyl methyl ether, 2-butanone, ethyl acetate, isopropyl acetate, tetrahydrofuran, or combinations thereof.

[0032] In some embodiments there is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof for use in medicine.

[0033] In some embodiments, there is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, wherein the (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone is amorphous.

[0034] In another aspect, described herein is a pharmaceutical composition comprising a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, and at least one inactive ingredient selected from pharma- ceutically acceptable carriers, diluents, and excipients.

[0035] In another aspect, described herein is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, formulated for oral, intravenous, intramuscular, or subcutaneous administration.

[0036] In another aspect, described herein are methods for treating hyperuricemia or gout in an individual, the methods comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, as described herein. In some embodiments, described herein are methods for treating hyperuricemia or gout in an individual, the methods comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, as described herein, where (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone is administered orally. In some embodiments, methods are described herein for treating hyperuricemia or gout in an individual, the methods comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, as described herein, wherein the therapeutically effective amount is taken with food. In some embodiments, methods are described herein for treating hyperuricemia or gout in an individual, the methods comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, as described herein, wherein the therapeutically effective amount is taken without food.In some embodiments, described herein are methods for treating hyperuricemia or gout in an individual, the methods comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, described herein, wherein (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone is administered to the individual once daily. In some embodiments, methods are described herein for treating hyperuricemia or gout in an individual, the methods comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, as described herein, wherein (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone is administered to the individual twice daily.

[0037] In some embodiments, methods for treating hyperuricemia or gout in an individual are described herein, the methods comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, as described herein, and further comprising administering at least one additional therapeutic agent. In some embodiments, methods for treating hyperuricemia or gout in an individual are described herein, the methods comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, as described herein, and further comprising administering a xanthine oxidase inhibitor. In some embodiments, a method for treating hyperuricemia or gout in an individual is described herein, the method comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, as described herein, and further comprising administering a xanthine oxidase inhibitor, wherein the xanthine oxidase inhibitor is allopurinol, oxypurinol, febuxostat, topiroxostat, or inositol. In some embodiments, methods for treating hyperuricemia or gout in an individual are described herein, the methods comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, as described herein, and further comprising administering a sodium glucose cotransporter 2 (SGLT2) inhibitor.In some embodiments, methods for treating hyperuricemia or gout in an individual are described herein, the methods comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, as described herein, and further comprising administering an SGLT2 inhibitor, wherein the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, empagliflozin / linagliptin, empagliflozin / metformin, and dapagliflozin / metformin. In some embodiments, methods for treating hyperuricemia or gout in an individual are described herein, the methods comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, as described herein, and further comprising administering a xanthine oxidase inhibitor and an SGLT2 inhibitor. In some embodiments, methods for treating hyperuricemia or gout in an individual are described herein, the methods comprising administering to the individual a therapeutically effective amount of a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, as described herein, and further comprising administering a xanthine oxidase inhibitor and an SGLT2 inhibitor, wherein the xanthine oxidase inhibitor is allopurinol, oxypurinol, febuxostat, topiroxostat, or inositol, and the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, empagliflozin / linagliptin, empagliflozin / metformin, and dapagliflozin / metformin.

[0038] INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are incorporated by reference herein, to the extent applicable and relevant, and to the same extent as if each individual publication, patent, or patent application was specifically and individually incorporated by reference herein. [Brief description of the drawings]

[0039] [Figure 1] 1 illustrates the X-ray powder diffraction (XRPD) pattern of crystalline (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), Form 3. [Diagram 2] 1 illustrates a thermogravimetric analysis (TGA) thermogram of crystalline (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), Form 3. [Diagram 3] 1 illustrates a differential scanning calorimetry (DSC) thermogram of crystalline (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), Form 3. [Figure 4] 1 illustrates the X-ray powder diffraction (XRPD) pattern of crystalline (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), Form 2. [Diagram 5] 1 illustrates a thermogravimetric analysis (TGA) thermogram of crystalline (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), Form 2. [Figure 6] 1 illustrates a differential scanning calorimetry (DSC) thermogram of crystalline (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), Form 2. [Figure 7]1 illustrates the X-ray powder diffraction (XRPD) pattern of crystalline (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), Form 1. [Figure 8] 1 illustrates a thermogravimetric analysis (TGA) thermogram of crystalline (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), Form 1. [Figure 9] 1 illustrates a differential scanning calorimetry (DSC) thermogram of crystalline (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), Form 1. [Figure 10] FIG. 1 illustrates the gravimetric vapor sorption (GVS) analysis of crystalline (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), Form 3. [Figure 11] FIG. 1 illustrates the gravimetric vapor sorption (GVS) analysis of crystalline (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), Form 2. [Figure 12] FIG. 1 illustrates the gravimetric vapor sorption (GVS) analysis of crystalline (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), Form 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] Benzbromarone is an effective uricosuric agent for lowering serum uric acid (sUA) and treating gout. Treatment with benzbromarone has been shown to lower sUA after a single dose, continues to lower after multiple doses, and can be used chronically to target sUA below 6 mg / dL. However, in certain patients, benzbromarone has been associated with hepatotoxicity. The majority of these patients have developed acute liver failure, leading to death or emergency liver transplantation. As a result, benzbromarone was not approved for use in the United States. In addition, benzbromarone was withdrawn from the European market in 2003 due to its hepatotoxicity. Benzbromarone is converted to reactive metabolites by CYP2C9. Benzbromarone is metabolized by CYP2C9 via 6-OH benzbromarone to 5,6-dihydroxybenzbromarone, which is then oxidized to a reactive orthoquinone intermediate. The mechanism of hepatotoxicity of benzbromarone is thought to be a result of hepatic metabolism by CYP2C9 and the possible effects of 6-OHbenzbromarone and its further metabolites on mitochondrial function (Iwamura et al., Drug Metabolism and Disposition, 2011, 39, 838-846; Uchida et al., Drug Metab. Pharmacokinet.,2010, 25, 605-610).

[0041] [ka]

[0042] Described herein is a crystalline form of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), a 4,5,6,7-tetradeutero analog of benzbromarone. Compound 1 exhibited superior in vitro URAT1 potency to benzbromarone. Compound 1 further demonstrated an improved metabolic profile compared to benzbromarone. Compound 1 is more stable than benzbromarone in human microsomes. The CYP2C9 metabolic pathway of the compound is significantly reduced and 6-OH benzbromarone, 6-di-OH benzbromarone metabolites are not formed. Thus, Compound 1 represents a promising therapeutic agent for the treatment of hyperuricemia and gout with an improved hepatotoxicity profile.

[0043] compound 1 In one embodiment, (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone. "Compound 1" or "(3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone" refers to a compound having the following structure:

[0044] [ka]

[0045] In some embodiments, compound 1 includes solvent addition forms (solvates). Solvates include solvates in either stoichiometric or non-stoichiometric amounts and are formed during the process of product formation or isolation using pharma- ceutically acceptable solvents, such as water, ethanol, methanol, tert-butyl methyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, and the like. In some embodiments, solvates are formed using, but not limited to, class 3 solvates. In some embodiments, solvates are formed using, but not limited to, class 2 solvates. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents, Q3C(R3),(R6)” (October 2016). Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol.

[0046] In other embodiments, Compound 1 is prepared in various forms, including but not limited to, amorphous phase, crystalline form, milled form, and nanoparticulate form.

[0047] Without being bound by any particular theory, a particular solid form is characterized by physical properties, such as stability, solubility, and dissolution rate, that are suitable for pharmaceutical and therapeutic dosage forms.Furthermore, without being bound by any particular theory, a particular solid form is characterized by physical properties (e.g., density, compressibility, hardness, morphology, shear, adhesion, solubility, water uptake, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that affect certain processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization) that make the particular solid form suitable for manufacturing solid dosage forms.These properties can be determined using certain analytical and chemical techniques, including solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis), as described herein.

[0048] Crystal morphology Identifying and selecting solid forms of pharmaceutical compounds is complex given that changes in solid form can affect various physical and chemical properties and may provide advantages or disadvantages in processing, formulation, stability, bioavailability, storage, and handling (e.g., shipping), among other important pharmaceutical characteristics. Useful pharmaceutical solids include crystalline and amorphous solids, depending on the product and its method of administration. Amorphous solids are characterized by a lack of long-term structural order, while crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends on the particular application. Amorphous solids are often selected for reasons such as enhanced dissolution profile, while crystalline solids may be selected for properties such as physical or chemical stability.

[0049] Solid forms of pharmaceutical compounds, whether crystalline or amorphous, include single-component solids and multiple-component solids. Single-component solids consist essentially of the pharmaceutical compound, or the active ingredient in the absence of other compounds. Variations in single-component crystalline materials can potentially arise from polymorphism, where a particular pharmaceutical compound exists in multiple three-dimensional configurations.

[0050] In particular, it is not possible to predict in advance whether crystalline forms of a compound will exist, let alone how to successfully prepare them (see, e.g., Braga and Grepioni, 2005, “Making crystals from crystals: a green route to crystal engineering and polymorphism,” Chem. Commun.:3635-3645 (with respect to crystal engineering, results can be unpredictable if the instructions are not precise and / or other external factors affect the process); Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement,” MRS Bulletin 31:875-879 (currently, it is generally not possible to computationally predict the number of observable polymorphs even for the simplest molecules); Price, 2004, “The computational prediction of pharmaceutical crystal structures and polymorphism,” Advanced Drug Delivery Reviews 56:301-319 (“Price”); and Bernstein, 2004, “Crystal Structure Prediction and Polymorphism,” ACA Transactions 39:14-23 (There is still much to be learned and done before we can confidently speak of our ability to predict crystal structures, much less polymorphism.)

[0051] The diversity of possible solid-state forms creates a potential diversity in the physical and chemical properties of a given pharmaceutical compound. The discovery and selection of solid-state forms is critical in the development of effective, stable, and marketable pharmaceuticals.

[0052] Crystalline compound 1, form 3 In some embodiments, Compound 1 is crystalline. In some embodiments, Compound 1 is crystalline and anhydrous. In some embodiments, crystalline Compound 1 has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 1; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.8° 2-theta, 13.6° 2-theta, 14.6° 2-theta, 21.2° 2-theta, 24.2° 2-theta, 24.7° 2-theta, 26.7° 2-theta, and 27.5° 2-theta; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG. (d) A DSC thermogram substantially similar to that shown in FIG. (e) DSC thermogram with an endotherm with an onset at about 147° C. (f) non-hygroscopic, or (g) any combination thereof; The present invention is characterized by having at least one of the following.

[0053] In some embodiments, crystalline Compound 1, Form 3 is characterized by having at least two of the properties selected from (a)-(f). In some embodiments, crystalline Compound 1, Form 3 is characterized by having at least three of the properties selected from (a)-(f). In some embodiments, crystalline Compound 1, Form 3 is characterized by having at least four of the properties selected from (a)-(f). In some embodiments, crystalline Compound 1, Form 3 is characterized by having at least five of the properties selected from (a)-(f). In some embodiments, crystalline Compound 1, Form 3 is characterized by having properties (a)-(f).

[0054] In some embodiments, crystalline Compound 1, Form 3 has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 1. In some embodiments, crystalline Compound 1, Form 3 has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.8° 2-theta, 13.6° 2-theta, 14.6° 2-theta, 21.2° 2-theta, 24.2° 2-theta, 24.7° 2-theta, 26.7° 2-theta, and 27.5° 2-theta. In some embodiments, crystalline Compound 1, Form 3 has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 2. In some embodiments, crystalline Compound 1, Form 3 has a DSC thermogram substantially similar to that shown in Figure 3. In some embodiments, crystalline Compound 1, Form 3 has a DSC thermogram with an endotherm having an onset at about 147°C. In some embodiments, crystalline Compound 1, Form 3 is non-hygroscopic. In some embodiments, crystalline Compound 1, Form 3 is obtained from toluene, toluene / heptane, or ethyl acetate / heptane. In some embodiments, crystalline Compound 1, Form 3 is obtained from toluene. In some embodiments, crystalline Compound 1, Form 3 is obtained from toluene / heptane. In some embodiments, crystalline Compound 1, Form 3 is obtained from ethyl acetate / heptane. In some embodiments, crystalline Compound 1, Form 3 is solvated. In some embodiments, crystalline Compound 1, Form 3 is not solvated.

[0055] Crystalline compound 1, form 2 In some embodiments, crystalline Compound 1 has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.3° 2-theta, 10.7° 2-theta, 16.6° 2-theta, 19.7° 2-theta, 23.7° 2-theta, 25.0° 2-theta, 25.6° 2-theta, and 27.1° 2-theta; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG. 5; (d) A DSC thermogram substantially similar to that shown in FIG. (e) DSC thermogram with an endotherm with an onset at about 139° C. (f) non-hygroscopic, or (g) any combination thereof; The present invention is characterized by having at least one of the following.

[0056] In some embodiments, crystalline Compound 1, Form 2 is characterized by having at least two of the properties selected from (a)-(f). In some embodiments, crystalline Compound 1, Form 2 is characterized by having at least three of the properties selected from (a)-(f). In some embodiments, crystalline Compound 1, Form 2 is characterized by having at least four of the properties selected from (a)-(f). In some embodiments, crystalline Compound 1, Form 2 is characterized by having at least five of the properties selected from (a)-(f). In some embodiments, crystalline Compound 1, Form 2 is characterized by having properties (a)-(f).

[0057] In some embodiments, crystalline Compound 1, Form 2 has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 4. In some embodiments, crystalline Compound 1, Form 2 has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.3° 2-theta, 10.7° 2-theta, 16.6° 2-theta, 19.7° 2-theta, 23.7° 2-theta, 25.0° 2-theta, 25.6° 2-theta, and 27.1° 2-theta. In some embodiments, crystalline Compound 1, Form 2 has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 5. In some embodiments, crystalline Compound 1, Form 2 has a DSC thermogram substantially similar to that shown in Figure 6. In some embodiments, crystalline Compound 1, Form 2 has a DSC thermogram with an endotherm having an onset at about 139°C. In some embodiments, crystalline Compound 1, Form 2 is non-hygroscopic. In some embodiments, crystalline Compound 1, Form 2 is obtained from toluene, toluene / heptane, or ethyl acetate / heptane. In some embodiments, crystalline Compound 1, Form 2 is obtained from toluene. In some embodiments, crystalline Compound 1, Form 2 is obtained from toluene / heptane. In some embodiments, crystalline Compound 1, Form 2 is obtained from ethyl acetate / heptane. In some embodiments, crystalline Compound 1, Form 2 is solvated. In some embodiments, crystalline Compound 1, Form 2 is not solvated.

[0058] Crystalline Compound 1, Form 1 In some embodiments, crystalline Compound 1 has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 7; (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.6° 2-theta, 11.5° 2-theta, 13.8° 2-theta, 14.3° 2-theta, 17.0° 2-theta, 18.9° 2-theta, 27.9° 2-theta, and 31.4° 2-theta; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG. (d) A DSC thermogram substantially similar to that shown in FIG. (e) a DSC thermogram with an endotherm having an onset at about 80° C.; or (f) any combination thereof; The present invention is characterized by having at least one of the following.

[0059] In some embodiments, crystalline Compound 1, Form 1 is characterized by having at least two of the properties selected from (a)-(e). In some embodiments, crystalline Compound 1, Form 1 is characterized by having at least three of the properties selected from (a)-(e). In some embodiments, crystalline Compound 1, Form 1 is characterized by having at least four of the properties selected from (a)-(e). In some embodiments, crystalline Compound 1, Form 1 is characterized by having properties (a)-(e).

[0060] In some embodiments, crystalline Compound 1, Form 1 has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 7. In some embodiments, crystalline Compound 1, Form 1 has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.6° 2-theta, 11.5° 2-theta, 13.8° 2-theta, 14.3° 2-theta, 17.0° 2-theta, 18.9° 2-theta, 27.9° 2-theta, and 31.4° 2-theta. In some embodiments, crystalline Compound 1, Form 1 has a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 8. In some embodiments, crystalline Compound 1, Form 1 has a DSC thermogram substantially similar to that shown in Figure 9. In some embodiments, crystalline Compound 1, Form 1 has a DSC thermogram with an endotherm having an onset at about 80°C. In some embodiments, crystalline Compound 1, Form 1 is non-hygroscopic. In some embodiments, crystalline Compound 1, Form 1 is obtained from toluene, toluene / heptane, or ethyl acetate / heptane. In some embodiments, crystalline Compound 1, Form 1 is obtained from toluene. In some embodiments, crystalline Compound 1, Form 1 is obtained from toluene / heptane. In some embodiments, crystalline Compound 1, Form 1 is obtained from ethyl acetate / heptane. In some embodiments, crystalline Compound 1, Form 1 is solvated. In some embodiments, crystalline Compound 1, Form 1 is not solvated.

[0061] Preparation of crystalline compound 1 In some embodiments, crystalline forms of Compound 1 are prepared as outlined in the Examples. It is noted that solvents, temperatures, and other reaction conditions presented herein may be varied.

[0062] In certain embodiments, provided herein is a method for making a solid form of Compound 1, the method comprising: 1) obtaining a saturated solution of Compound 1 in a solvent at a first temperature (e.g., about 50° C.); 2) adding an anti-solvent to the saturated solution at the first temperature; 3) cooling to a second temperature (e.g., about −5° C. to room temperature); 4) collecting solids if there is precipitation, and evaporating the solvent to collect solids if there is no precipitation; and 5) optionally drying. In certain embodiments, provided herein is a method for making a solid form of Compound 1, the method comprising: 1) obtaining a saturated solution of Compound 1 in a solvent at about 50° C.; 2) adding an anti-solvent to the saturated solution at about 50° C.; 3) cooling to about room temperature; 4) collecting solids if there is precipitation, and evaporating the solvent to collect solids if there is no precipitation; and 5) optionally air drying. In certain embodiments, the volume ratio of the solvent and the anti-solvent is about 1:9. In certain embodiments, the volume ratio of the solvent and the anti-solvent is about 1:4. In certain embodiments, the volume ratio of the solvent and the anti-solvent is about 1:2. In certain embodiments, the volume ratio of the solvent and the anti-solvent is about 1:1. In certain embodiments, the method for making the solid form of Compound 1 is anti-solvent recrystallization experiments.

[0063] In another embodiment, crystalline Compound 1, Form 3 is not substantially pure. In certain embodiments, substantially pure crystalline Compound 1, Form 3 is substantially free of other solid forms, e.g., amorphous solids. In certain embodiments, the purity of substantially pure crystalline Compound 1, Form 3 is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5% or more, or about 99.8% or more.

[0064] In another embodiment, crystalline Compound 1, Form 2 is not substantially pure. In certain embodiments, substantially pure crystalline Compound 1, Form 2 is substantially free of other solid forms, e.g., amorphous solids. In certain embodiments, the purity of substantially pure crystalline Compound 1, Form 2 is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5% or more, or about 99.8% or more.

[0065] In another embodiment, crystalline Compound 1, Form 1 is not substantially pure. In certain embodiments, substantially pure crystalline Compound 1, Form 1 is substantially free of other solid forms, e.g., amorphous solids. In certain embodiments, the purity of substantially pure crystalline Compound 1, Form 1 is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5% or more, or about 99.8% or more.

[0066] Suitable Solvent Therapeutic drugs that can be administered to mammals, such as humans, must be prepared according to regulatory guidelines. These government-regulated guidelines are called Good Manufacturing Practices (GMP). GMP guidelines outline acceptable levels of contamination of active therapeutic drugs, such as, for example, the amount of residual solvents in the final product. In some embodiments, the solvents disclosed herein are suitable for use in GMP facilities and are consistent with industrial safety concerns. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) “Impurities: Guidelines for Residual Solvents Q3C(R6),” (October 2016).

[0067] Solvents are divided into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents that are restricted for use during the manufacture of therapeutic drugs. Class 3 solvents are solvents that have low toxicity potential and low risk to human health. Data for Class 3 solvents indicate that they have low toxicity in acute or short-term studies and negative genotoxicity tests.

[0068] Class 1 solvents to be avoided include benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethene; and 1,1,1-trichloroethane.

[0069] Examples of class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methyl cyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, and xylene.

[0070] Class 3 solvents with low toxicity include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine.

[0071] Residual solvents in active pharmaceutical ingredients (APIs) result from the manufacturing of the APIs. In some cases, the solvents are not completely removed in the actual manufacturing techniques. The appropriate selection of solvents for the synthesis of APIs can enhance the yield or determine properties such as crystal form, purity, and solubility. Therefore, the solvent is a critical parameter in the synthesis process.

[0072] In some embodiments, the composition comprising Compound 1 comprises an organic solvent. In some embodiments, the composition comprising Compound 1 comprises a residual amount of an organic solvent. In some embodiments, the composition comprising Compound 1 comprises a residual amount of a Class 3 solvent. In some embodiments, the organic solvent is a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine. In some embodiments, the Class 3 solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

[0073] In some embodiments, the composition comprising Compound 1 comprises a residual amount of a Class 2 solvent. In some embodiments, the organic solvent is a Class 2 solvent. In some embodiments, the Class 2 solvent is selected from the group consisting of acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, methylisobutylketone, N-methylpyrrolidine, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, and xylene. In some embodiments, the Class 2 solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, and toluene. In some embodiments, the Class 2 solvent is acetonitrile.

[0074] In some embodiments, the composition comprising Compound 1 includes a residual amount of a solvent for which no adequate toxicological data has been found. In some embodiments, the organic solvent is a solvent for which no adequate toxicological data has been found. In some embodiments, the solvent is selected from the group consisting of 2-butanone and 2-methyltetrahydrofuran.

[0075] Specific Terms Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit the subject matter of any application. In this application, the use of the singular includes the plural unless expressly stated otherwise. As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "including" is not limiting, as are other forms such as "include," "includes," and "included." The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other embodiments, an embodiment, such as, for example, any composition, composition, method, or process described herein, may "consist of" or "consist essentially of" the recited feature. The term "about" when referring to a number or range of numbers means that the referenced number or range of numbers is an approximation within experimental variability (or within statistical experimental error), and thus the number or range of numbers may vary between 1% and 15% of the stated number or range of numbers.

[0076] The paragraph headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in the application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are expressly incorporated by reference in their entirety for the purposes of this application.

[0077] As used herein, the term "acceptable" or "pharmaceutical acceptable" with respect to a formulation, composition, or ingredient means having no lasting deleterious effects on the general health of the treated subject or abrogating the biological activity or properties of the compound, and being relatively non-toxic.

[0078] As used herein, "amelioration" of symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition refers to a decrease in severity, delay in onset, slowing in progression, or shortening in duration, whether permanent or temporary, persistent or transient, that can result from or be associated with the administration of the compound or composition.

[0079] "Bioavailability" refers to the percentage of administered Compound 1 that is delivered to the systemic circulation of the animal or human being studied. The total exposure (AUC( 0-∞ ) is generally defined as being 100% bioavailability (F%). "Oral bioavailability" refers to the extent to which Compound 1 is absorbed into the systemic circulation when a pharmaceutical composition is taken orally, as compared to intravenous injection.

[0080] "Plasma concentration" refers to the concentration of Compound 1 in the plasma component of a subject's blood. It is understood that the plasma concentration of Compound 1 may vary significantly from subject to subject due to variability associated with metabolism and / or potential interactions with other therapeutic agents. In accordance with one embodiment disclosed herein, the plasma concentration of Compound 1 may vary from subject to subject. Similarly, the maximum plasma concentration (C max ) or the time to reach maximum plasma concentration (T max ), or the total area under the plasma concentration-time curve (AUC( 0-∞ Values ​​such as )) may vary from subject to subject. Due to this variability, the amount necessary to constitute a "therapeutically effective amount" of Compound 1 may vary from subject to subject.

[0081] Terms such as "co-administration," as used herein, are intended to encompass the administration of selected therapeutic agents to one patient and are intended to include treatment regimens in which the therapeutic agents are administered by the same or different routes of administration or at the same or different times.

[0082] "Effective amount" or "therapeutically effective amount", as used herein, refers to a sufficient amount of an agent or compound being administered that alleviates to some extent one or more of the symptoms of the disease or disorder being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or other desired changes in a biological system. For example, an "effective amount" in therapeutic applications is the amount of a composition comprising a compound disclosed herein that is required to clinically significantly reduce disease symptoms without causing undue adverse side effects. An appropriate "effective amount" in any individual case can be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein is an amount that is effective to achieve a desired pharmacological effect or therapeutic improvement without causing undue adverse side effects. It should be noted that an "effective amount" or "therapeutically effective amount" may vary from subject to subject, depending on the variability of compound 1 metabolism, the subject's age, weight, general condition, the disorder being treated, the severity of the disorder being treated, and the judgment of the prescribing physician. By way of example only, a therapeutically effective amount may be determined through a dose escalation clinical trial.

[0083] The terms "enhance" or "enhancing" refer to increasing or prolonging a desired effect, either in potency or duration. By way of example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or prolong, either in potency or duration, the effect of the therapeutic agent during the treatment of a disease, disorder, or condition. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of the therapeutic agent in the treatment of a disease, disorder, or condition. When used in a patient, the amount effective for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0084] The term "prophylactically effective amount" as used herein refers to an amount of a composition applied to a patient that will relieve to some extent one or more of the symptoms of the disease, condition, or disorder being treated. In such prophylactic applications, such amounts may depend on the patient's health status, weight, and the like. As an example, such prophylactically effective amounts can be determined by a dose escalation clinical trial.

[0085] As used herein, the term "subject" refers to an animal that is the object of treatment, observation, or experiment. By way of example only, a subject may be a mammal, including, but not limited to, a human.

[0086] As used herein, the term "target activity" refers to a biological activity that can be modulated by a selective modulator. Some exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or disorder.

[0087] The terms "treat," "treating," and "treatment," as used herein, include alleviating, reducing, or ameliorating the symptoms of a disease or condition, preventing further symptoms, ameliorating or preventing the underlying metabolic cause of a condition, inhibiting a disease or condition, e.g., arresting the progression of a disease or condition, relieving a disease or condition, regressing a disease or condition, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition. The terms "treat," "treating," or "treatment" include, but are not limited to, prophylactic and / or therapeutic treatments.

[0088] As used herein, IC 50 refers to a single dose, concentration, or amount of a particular test compound that elicits a dose-dependent response at 50% of the maximum expression of a particular response induced, caused, or potentiated by the particular test compound.

[0089] Pharmaceutical Compositions / Formulations Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of active compounds into medicament that can be used.Suitable formulations depend on the route of administration selected.Summaries of pharmaceutical compositions described herein include those found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entirety.

[0090] Pharmaceutical composition, as used herein, refers to a mixture of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) and other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. The pharmaceutical composition facilitates administration of the compound to a mammal. In carrying out the methods of treatment or use provided herein, a therapeutically effective amount of compound 1 is administered as a pharmaceutical composition to a mammal suffering from the disease, disorder, or condition to be treated. Preferably, the mammal is a human. The therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds described herein are used alone or in combination with one or more therapeutic agents as components of a mixture.

[0091] In some embodiments, there is a pharmaceutical composition comprising (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1) and at least one inactive ingredient selected from pharma- ceutically acceptable carriers, diluents, and excipients. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1 and at least one inactive ingredient selected from pharma- ceutically acceptable carriers, diluents, and excipients. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1, Form 3, and at least one inactive ingredient selected from pharma- ceutically acceptable carriers, diluents, and excipients. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1, Form 2, and at least one inactive ingredient selected from pharma- ceutically acceptable carriers, diluents, and excipients. In some embodiments, there is a pharmaceutical composition comprising a crystalline form of Compound 1, Form 1, and at least one inactive ingredient selected from pharma- ceutically acceptable carriers, diluents, and excipients.

[0092] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combination of more than one active ingredient, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to both the active ingredient, e.g., Compound 1, and the co-agent being administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" refers to the active ingredient, e.g., Compound 1, and the co-agent being administered to the patient simultaneously, simultaneously, or sequentially as separate entities, without any specific intervening time limit, such administration providing an effective level of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., administration of three or more active ingredients.

[0093] Pharmaceutical compositions containing the compounds described herein may be manufactured by conventional means such as, by way of example only, conventional mixing, dissolving, granulating, dragee-making, gelling, emulsifying, encapsulating, entrapping, or compressing processes.

[0094] Dosage form The pharmaceutical compositions described herein can be formulated for administration to a mammal via any conventional means, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. As used herein, the term "subject" or "individual" is used to mean an animal, preferably a mammal, including a human or non-human. The terms individual, patient, and subject can be used interchangeably.

[0095] Additionally, the pharmaceutical compositions described herein comprising Compound 1 may be formulated into suitable dosage forms, including, but not limited to, solid oral dosage forms, controlled release formulations, fast dissolving formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0096] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries as necessary to obtain tablets or dragee cores.Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.If necessary, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, can be added.

[0097] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient mixed with a filler, such as lactose, a binder, such as starch, and / or a lubricant, such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All preparations for oral administration should be in a dosage suitable for such administration.

[0098] In some embodiments, the solid dosage forms disclosed herein may be in the form of tablets (including suspension tablets, fast dissolving tablets, bite-disintegrating tablets, quick disintegrating tablets, effervescent tablets, or caplets), pills, powders (including sterile packaged powders, dispensable powders, or effervescent powders), capsules (both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules," solid dispersions, solid solutions, bioerodible dosage forms, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or aerosols. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to a fast dissolving tablet. Additionally, the pharmaceutical formulations described herein may be administered as a single capsule or in the form of multiple capsules. In some embodiments, the pharmaceutical formulation is administered in two, three, or four capsules or tablets.

[0099] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing Compound 1 particles with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as homogeneous, it is intended that Compound 1 particles are evenly distributed throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. Individual unit dosages may further include a film coating that disintegrates after oral ingestion or contact with a diluent. Such formulations may be manufactured by conventional pharmacological techniques.

[0100] Conventional pharmaceutical techniques include, for example, one or a combination of the following methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or nonaqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Worcester coating), tangential coating, top spraying, tabletting, extrusion, and the like.

[0101] The pharmaceutical solid dosage forms described herein may include Compound 1 and one or more pharma- ceutically acceptable additives, such as compatible carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, humectants, plasticizers, stabilizers, percutaneous absorption enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. In yet another aspect, a film coating is applied around the formulation of Compound 1 using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, some or all of the particles of Compound 1 are coated. In another embodiment, some or all of the particles of Compound 1 are microencapsulated. In yet another embodiment, the particles of Compound 1 are neither microencapsulated nor coated.

[0102] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0103] Suitable fillers for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0104] In order to release Compound 1 from the solid dosage form matrix as efficiently as possible, especially when the dosage form is compressed with a binder, a disintegrant is often used in the formulation. Disintegrants help burst the dosage form matrix by expansion or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include natural starches such as corn starch or potato starch, pregelatinized starches such as National1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, celluloses such as wood products, methyl crystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked cellulose, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®, crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starches, such as sodium starch glycolate, crosslinked polymers, such as crospovidone, crosslinked polyvinylpyrrolidone, alginates, such as alginic acid or salts of alginic acid, such as sodium alginate, clays, such as Veegum® HV (magnesium aluminum silicate), gums, such as agar, guar, locust bean, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponges, surfactants, resins, such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like.In some embodiments provided herein, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch, such as sodium starch glycolate, cross-linked polymers, such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments provided herein, the disintegrant is croscarmellose sodium.

[0105] Binders provide cohesiveness to solid oral dosage formulations: in powder-filled capsule formulations, binders aid in the formation of a fillable plug in a soft or hard shell capsule, and in tablet formulations, binders ensure that the tablet remains intact after compression and help ensure blend uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603), hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids (e.g., cellulose acetate ... Examples of suitable glycerols include glycerol, glycerol, glycerols ...

[0106] Generally, powder filled gelatin capsule formulations use binder levels of 20-70%. Binder usage levels in tablet formulations vary depending on whether they are direct compressed, wet granulated, roller compacted, or use other excipients such as fillers that may act as moderate binders themselves. Formulators in the art can determine the binder level of their formulation, but binder usage levels of up to 70% are common in tablet formulations.

[0107] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts such as calcium, magnesium, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearone®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol, or methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium, or sodium lauryl sulfate. In some embodiments provided herein, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and wax. In some embodiments provided herein, the lubricant is magnesium stearate.

[0108] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like. In some embodiments provided herein, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrins, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, fine cellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.

[0109] The term "water-insoluble diluent" includes calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, fine cellulose (e.g., about 0.45 g / cm 3 These represent compounds typically used in the formulation of pharmaceuticals, such as Avicel, powdered cellulose, having a density of 1000 nm, and talc.

[0110] Suitable humectants for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.

[0111] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF). In some embodiments provided herein, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide. In some embodiments provided herein, the surfactant is sodium lauryl sulfate.

[0112] Suitable suspending agents for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol (e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, alternatively about 3350 to about 4000, alternatively about 7000 to about 5400), vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropyl ... Examples of suitable cellulose derivatives include dimethyl cellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as gum tragacanth and gum acacia, guar gum, xanthan including xanthan gum, sugars, cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0113] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0114] It should be recognized that there is considerable overlap between the additives used in the solid dosage forms described herein. Therefore, the additives listed above should be considered merely as examples and not as limitations of the types of additives that can be included in the solid dosage forms described herein. The amount of such additives can be easily determined by those skilled in the art according to the specific properties desired.

[0115] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, plasticizers are generally high-boiling solids or liquids. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0116] Compressed tablets are solid dosage forms prepared by compressing a bulk mixture of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth include one or more flavoring agents. In other embodiments, compressed tablets include a film surrounding the finished compressed tablet. In some embodiments, the film coating can provide delayed release of Compound 1 from the formulation. In other embodiments, the film coating aids in patient compliance (e.g., Opadry® coating or sugar coating). Film coatings including Opadry® typically range from about 1% to about 3% by weight of the tablet. In other embodiments, compressed tablets include one or more excipients.

[0117] Capsules can be prepared, for example, by placing a bulk mixture of a compound 1 formulation into a capsule. In some embodiments, the formulation (non-aqueous suspensions and solutions) is placed into a soft gelatin capsule. In some embodiments, the formulation (non-aqueous suspensions and solutions) is placed into a hard shell gelatin capsule. In other embodiments, the formulation is placed into a standard gelatin capsule or a non-gelatin capsule, such as a capsule containing HPMC. In other embodiments, the formulation is placed into a sprinkle capsule, where the capsule can be swallowed whole or the capsule can be opened and its contents sprinkled on food before a meal. In some embodiments, the therapeutic dose is divided into multiple (e.g., 2, 3, or 4) capsules. In some embodiments, the entire dose of the formulation is delivered in capsule form.

[0118] In various embodiments, particles of Compound 1 and one or more excipients are dry mixed and compressed into a mass, such as a tablet, that has sufficient hardness to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, thereby releasing the formulation into the gastrointestinal fluids.

[0119] In another aspect, the dosage form may comprise microencapsulated formulation.In some embodiments, one or more other compatible materials are present in the microencapsulated material.Typical materials include, but are not limited to, pH adjusters, erosion promoters, antifoaming agents, antioxidants, flavoring agents, and carrier materials, such as binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0120] Materials useful for microencapsulation as described herein include materials compatible with Compound 1 that sufficiently separate Compound 1 from other incompatible excipients. Materials compatible with Compound 1 are those that delay the release of Compound 1 in vivo.

[0121] Exemplary microencapsulation materials useful for delaying the release of formulations comprising the compounds described herein include, but are not limited to, hydroxypropyl cellulose ethers (HPC), such as Klucel® or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methylcellulose ethers (HPMC), such as Seppifilm LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers, such as Methocel®-A, hydroxypropyl methylcellulose acetate stearate (HF-LS, HF-LG, HF-MS) and Metolose®, ethylcellulose (EC) and mixtures thereof, such as E461, Ethocel®, Aqualon®-EC, Surelease®, polyvinyl alcohol (PVA), such as Opadry®, AMB, hydroxyethylcellulose, e.g. Natrosol®, carboxymethylcellulose and salts of carboxymethylcellulose (CMC), e.g. Aqualon®-CMC, polyvinyl alcohol, and polyethylene glycol copolymers, e.g. Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starches, acrylic polymers, and mixtures of cellulose ethers and acrylic polymers, e.g. Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrin, and mixtures of these materials.

[0122] In yet other embodiments, plasticizers such as polyethylene glycols, e.g., PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, microencapsulation materials useful for delaying the release of pharmaceutical compositions are from the USP or National Formulary (NF). In yet other embodiments, the microencapsulation material is Klucel. In yet other embodiments, the microencapsulation material is methocel.

[0123] Microencapsulated compound 1 can be formulated by various methods, illustrative examples of which include, for example, spray drying process, spinning disk solvent process, hot melt process, spray cryogenic method, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath. In addition to these, various chemical techniques can also be used, such as complex coacervation, melt evaporation, polymer-polymer incompatibility, interfacial polymerization in liquid medium, in situ polymerization, submerged drying, and desolvation in liquid medium. In addition, other methods such as roller compaction, extrusion / spheronization, coacervation, or nanoparticle coating may also be used.

[0124] In one embodiment, the particles of Compound 1 are microencapsulated before being formulated into one of the above forms. In yet another embodiment, some or most of the particles are coated using standard coating procedures (such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000)) before being further formulated.

[0125] In other embodiments, the solid dosage formulation of Compound 1 is plasticized (coated) with one or more layers. Illustratively, the plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0126] In other embodiments, the powder containing the formulation having Compound 1 may be formulated to include one or more pharmaceutical excipients and flavorings. Such powders may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and / or a wetting agent. This bulk blend is uniformly subdivided into unit-dose packages or multi-dosage packaging units.

[0127] In yet another embodiment, effervescent powders are also prepared according to the present disclosure. Effervescent salts are used to disperse drugs in water for oral administration. Effervescent salts are granules or coarse powders that contain drugs in a dry mixture, typically composed of sodium bicarbonate, citric acid, and / or tartaric acid. When the salts of the compositions described herein are added to water, the acid and base react to liberate carbon dioxide gas, thereby causing "effervescence." Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate, or a mixture of sodium bicarbonate and sodium carbonate, citric acid, and / or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate, citric acid, and tartaric acid, as long as the ingredients are suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

[0128] In some embodiments, the solid dosage forms described herein can be formulated as enteric-coated delayed release oral dosage forms, i.e., oral dosage forms of the pharmaceutical compositions described herein that utilize an enteric coating to affect release in the small intestine of the gastrointestinal tract. The enteric-coated dosage form can be a compressed, molded, or extruded tablet / mold (coated or uncoated) that contains granules, powders, pellets, beads, or microparticles of the active ingredient and / or other compositional ingredients, which may themselves be coated or uncoated. The enteric-coated oral dosage form can also be a capsule (coated or uncoated) that contains pellets, beads, or granules of the solid carrier or composition, which may themselves be coated or uncoated.

[0129] As used herein, the term "delayed release" refers to delivery that can achieve release at a generally predictable location in the intestinal tract that is distal to the location that would have been achieved without the delayed release modification. In some embodiments, the method for delaying release is a coating. The coating must be applied in a sufficient thickness such that the entire coating is insoluble in gastrointestinal fluids at a pH below about 5, but soluble at a pH above 5. It is anticipated that any anionic polymer that exhibits pH-dependent solubility properties may be used as an enteric coating in the methods and compositions described herein for achieving delivery to the lower gastrointestinal tract. In some embodiments, the polymers described herein are anionic carboxylic acid polymers. In other embodiments, the polymers and compatible mixtures thereof, as well as some of their properties, include, but are not limited to, the following:

[0130] Shellac, also called purified lac, is a refined product obtained from the resin secretion of insects. This coating dissolves in media with a pH > 7;

[0131] Acrylic polymers. The performance of acrylic polymers (mainly solubility in biological fluids) can vary with the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS, and NE (Rohm Pharma) are available solubilized in organic solvents, aqueous dispersions, or dry powders. Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but permeable and are primarily used for colonic targeting. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D, and S are insoluble in the stomach and dissolve in the intestine.

[0132] Cellulose derivatives. Examples of suitable cellulose derivatives are ethyl cellulose; and reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance may vary with the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH>6. Aquateric (FMC) is an aqueous-based system, spray-dried CAP psuedolatex with particles <1 μm. Other ingredients in Aquateric may include Pluronic, Tween, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose flatate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). The performance may vary with the degree and type of substitution. For example, HPMCP such as grades HP-50, HP-55, HP-55S, or HP-55F are suitable. The performance may vary depending on the degree and type of substitution. For example, suitable grades of hydroxypropyl methylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are presented as granules, or fine powders for aqueous dispersion; polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH>5 and is less permeable to water vapor and gastric juices.

[0133] In some embodiments, the coating can and usually does include a plasticizer, and optionally other coating excipients, such as colorants, talc, and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers usually include 10-25% by weight of the plasticizer, particularly dibutyl phthalate, polyethylene glycol, triethyl citrate, and triacetin. Conventional coating techniques, such as spray coating or pan coating, are used to apply the coating. The thickness of the coating must be sufficient so that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached.

[0134] In addition to plasticizers, colorants, detackifiers, surfactants, defoamers, lubricants (e.g., carnauba wax or PEG) may be added to the coating to solubilize or disperse the coating material and to improve coating performance and the coated product.

[0135] In other embodiments, the formulations described herein that contain Compound 1 are delivered using a pulsatile dosage form. Pulsatile dosage forms can provide one or more immediate release pulses at a predetermined time point after a controlled delay time or at a specific site. Other types of controlled release systems may be used. Examples of such delivery systems include polymer-based systems, such as polylactic acid and polyglycolic acid, polyanhydrides, and polycaprolactone; non-polymer-based systems, such as porous matrices, lipids such as sterols, such as cholesterol, cholesterol esters, and fatty acids, or neutral fats, such as monoglycerides, diglycerides, and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, biodegradable dosage forms, compressed tablets using conventional binders, and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2nd Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983, each of which is specifically incorporated by reference.

[0136] In some embodiments, a pharmaceutical formulation is provided comprising Compound 1 and at least one dispersing or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension, which upon mixing with water provides a substantially uniform suspension.

[0137] It should be recognized that there is overlap between the above-listed additives used in the aqueous dispersion or suspension described herein, because a given additive is often classified differently by various practitioners in the field or generally used for any of several different actions.Therefore, the above-listed additives should be interpreted as merely illustrative of the types of additives that can be included in the formulation described herein, and not as limiting.The amount of such additives can be easily determined by those skilled in the art according to the specific properties desired.

[0138] method In some embodiments, there is a method for treating hyperuricemia or gout comprising administering to an individual a therapeutically effective amount of a crystalline form of Compound 1 described herein. In some embodiments, there is a method for treating hyperuricemia comprising administering to an individual a therapeutically effective amount of a crystalline form of Compound 1 described herein. In some embodiments, there is a method for treating gout comprising administering to an individual a therapeutically effective amount of a crystalline form of Compound 1 described herein. In some embodiments, there is a method for treating hyperuricemia or gout comprising administering to an individual a therapeutically effective amount of crystalline Compound 1, Form 3 described herein. In some embodiments, there is a method for treating hyperuricemia comprising administering to an individual a therapeutically effective amount of crystalline Compound 1, Form 3 described herein. In some embodiments, there is a method for treating gout comprising administering to an individual a therapeutically effective amount of crystalline Compound 1, Form 3 described herein. In some embodiments, there is a method for treating hyperuricemia comprising administering to an individual a therapeutically effective amount of crystalline Compound 1, Form 3 described herein. In some embodiments, there is a method for treating gout comprising administering to an individual a therapeutically effective amount of crystalline Compound 1, Form 3 described herein. In some embodiments, there is a method for treating hyperuricemia or gout comprising administering to an individual a therapeutically effective amount of crystalline Compound 1, Form 2 described herein. In some embodiments, there is a method for treating hyperuricemia comprising administering to an individual a therapeutically effective amount of crystalline compound 1, form 2 as described herein. In some embodiments, there is a need for a method for treating gout comprising administering to an individual a therapeutically effective amount of crystalline compound 1, form 2 as described herein. In some embodiments, there is a method for treating hyperuricemia or gout comprising administering to an individual a therapeutically effective amount of crystalline compound 1, form 1 as described herein. In some embodiments, there is a method for treating hyperuricemia comprising administering to an individual a therapeutically effective amount of crystalline compound 1, form 1 as described herein. In some embodiments, there is a method for treating gout comprising administering to an individual a therapeutically effective amount of crystalline compound 1, form 1 as described herein.

[0139] Dosage and treatment regimens In some embodiments, crystalline Compound 1 is used in the preparation of a medicament for the treatment of a disease or condition that would benefit from lowering serum uric acid (sUA). Additionally, a method for treating any of the diseases or conditions described herein includes administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition containing crystalline Compound 1, or a pharma- ceutically acceptable solvate thereof, to the individual.

[0140] In some embodiments, the composition containing crystalline Compound 1 is administered for preventative, therapeutic, or maintenance treatment. In some embodiments, the composition containing Compound 1 is administered for therapeutic use. In some embodiments, the composition containing Compound 1 is administered for prophylactic use.

[0141] In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the attending physician.

[0142] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." For this application, the precise amount also depends on the patient's health, weight, and the like. When used in a patient, the amount effective for this application will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status, response to the drugs, and the judgment of the treating physician.

[0143] In some embodiments, crystalline Compound 1 is administered daily. In some embodiments, crystalline Compound 1 is administered every other day.

[0144] In some embodiments, crystalline Compound 1 is administered once per day. In some embodiments, crystalline Compound 1 is administered twice per day. In some embodiments, crystalline Compound 1 is administered three times per day. In some embodiments, crystalline Compound 1 is administered four times per day.

[0145] If the patient's disease does not improve, the compounds may be administered chronically, i.e., long-term, as determined by the physician, including the entire life span of the patient, to ameliorate or otherwise control or limit the symptoms of the disease or condition in said patient.

[0146] Once the patient's condition has improved, a maintenance dose is administered as needed. Thereafter, the dosage, frequency of administration, or both, depending on the symptoms, may be reduced to a level at which improvement in the disease, disorder, or condition is maintained. However, patients may require intermittent treatment over the long term upon recurrence of symptoms.

[0147] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease or condition and its severity, the identity (e.g., body weight) of the subject or host requiring treatment, and the like, but can nevertheless be determined in an art-recognized manner according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, dosages employed for treatment of adult humans will typically be from about 0.002 to about 5000 mg / day, and in some embodiments, from about 1 to 1500 mg / day. The desired dosage may be conveniently provided in a single dose, or may be administered as divided doses, either simultaneously (or over a short period of time) or at suitable intervals, e.g., as subdoses two, three, four or more times daily.

[0148] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of a precise dose. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dose may be in the form of a package containing a discrete amount of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers may be used, in which case it is common to include a preservative in the composition. By way of example only, formulations for parenteral injection may be provided in unit dosage form with additional preservative, including but not limited to ampoules, or multi-dose containers.

[0149] Suitable daily doses for the compounds described herein are from about 0.01 mg / kg to about 20 mg / kg. In one embodiment, the daily dose is from about 0.1 mg / kg to about 10 mg / kg. The daily doses specified for large mammals, including but not limited to humans, range from about 0.5 mg to about 1000 mg, conveniently administered in a single dose, in divided doses, including but not limited to up to four times a day, or in sustained release form. Suitable unit dosage forms for oral administration contain from about 1 to about 500 mg of active ingredient. In one embodiment, the unit dose is about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg. Given the large number of variables associated with individual treatment regimens, the foregoing ranges are merely suggestive, and substantial deviations from these recommendations are not uncommon. Such dosages may vary depending on a number of variables, including, but not limited to, the activity of the compound being used, the disease or condition being treated, the mode of administration, the requirements of the particular subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0150] The toxicity and efficacy of these treatment regimens are discussed in detail below. 50 (a lethal dose for 50% of the population) and ED 50This can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 The data obtained from cell culture assays and animal studies can be used to formulate a range of doses for use in humans. The dose of such compounds can be determined to be the dose that results in minimal toxicity and can be expressed as a ratio of the ED 50 It is preferred that the blood concentration range includes the range of 100-150 mg / kg / day. This dosage may vary within said range depending on the dosage form and route of administration utilized.

[0151] Combination treatment Compound 1, as described herein, and compositions thereof, may further be used in combination with other therapeutic agents selected for their therapeutic value in the disease being treated. In general, the compositions described herein and, in embodiments in which combination therapy is used, the other agents need not be administered in the same pharmaceutical composition, but may need to be administered by different routes due to different physical and chemical properties. The determination of the mode of administration and the appropriateness of administration is well within the scope of the clinician's discretion, if possible in the same pharmaceutical composition. Initial administration can be performed according to established protocols recognized in the art, which can then be modified by the clinician based on observed effects, dosage, mode of administration, and frequency of administration.

[0152] In some instances, it may be appropriate to administer crystalline compound 1 described herein in combination with another therapeutic agent. By way of example only, if nausea is one of the side effects experienced by a patient when administered one of the compounds described herein, such as crystalline compound 1, it may be appropriate to administer an antiemetic agent in combination with the first therapeutic agent. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by administration of an adjuvant (where the therapeutic benefit of the adjuvant alone is minimal, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by the patient may be increased by administration of one of the compounds described herein with another therapeutic agent (including a treatment regimen) that has a therapeutic benefit. In each case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may result from the additive nature of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0153] In some embodiments, crystalline compound 1 is administered in combination with a xanthine oxidase inhibitor. In some embodiments, crystalline compound 1 is administered in combination with a xanthine oxidase inhibitor, and the xanthine oxidase inhibitor is allopurinol, oxypurinol, febuxostat, topiroxostat, or inositol. In some embodiments, crystalline compound 1 is administered in combination with a xanthine oxidase inhibitor, and the xanthine oxidase inhibitor is allopurinol. In some embodiments, crystalline compound 1 is administered in combination with a xanthine oxidase inhibitor, and the xanthine oxidase inhibitor is oxypurinol. In some embodiments, crystalline compound 1 is administered in combination with a xanthine oxidase inhibitor, and the xanthine oxidase inhibitor is febuxostat. In some embodiments, crystalline compound 1 is administered in combination with a xanthine oxidase inhibitor, and the xanthine oxidase inhibitor is topiroxostat. In some embodiments, crystalline Compound 1 is administered in combination with a xanthine oxidase inhibitor, and the xanthine oxidase inhibitor is ositol.

[0154] In some embodiments, crystalline Compound 1 and a xanthine oxidase inhibitor are administered together in a single dosage form. In some embodiments, crystalline Compound 1 and a xanthine oxidase inhibitor are administered together in separate dosage forms.

[0155] In some embodiments, crystalline compound 1 is administered in combination with an SGLT2 inhibitor. In some embodiments, crystalline compound 1 is administered in combination with an SGLT2 inhibitor, and the SGLT2 inhibitor is canagliflozin, dapagliflozin, empagliflozin, empagliflozin / linagliptin, empagliflozin / metformin, or dapagliflozin / metformin. In some embodiments, crystalline compound 1 is administered in combination with an SGLT2 inhibitor, and the SGLT2 inhibitor is canagliflozin. In some embodiments, crystalline compound 1 is administered in combination with an SGLT2 inhibitor, and the SGLT2 inhibitor is dapagliflozin. In some embodiments, crystalline compound 1 is administered in combination with an SGLT2 inhibitor, and the SGLT2 inhibitor is empagliflozin. In some embodiments, crystalline compound 1 is administered in combination with an SGLT2 inhibitor, and the SGLT2 inhibitor is empagliflozin / linagliptin. In some embodiments, crystalline Compound 1 is administered in combination with an SGLT2 inhibitor, and the SGLT2 inhibitor is empagliflozin / metformin. In some embodiments, crystalline Compound 1 is administered in combination with an SGLT2 inhibitor, and the SGLT2 inhibitor is dapagliflozin / metformin.

[0156] In some embodiments, the crystalline Compound 1 and the SGLT2 inhibitor are administered together in a single dosage form. In some embodiments, the crystalline Compound 1 and the SGLT2 inhibitor are administered together in separate dosage forms.

[0157] In some embodiments, crystalline Compound 1 is administered in combination with a xanthine oxidase inhibitor and an SGLT2 inhibitor. In some embodiments, crystalline Compound 1 is administered in combination with a xanthine oxidase inhibitor and an SGLT2 inhibitor, wherein the xanthine oxidase inhibitor is allopurinol, oxypurinol, febuxostat, topiroxostat, or inositol, and the SGLT2 inhibitor is canagliflozin, dapagliflozin, empagliflozin, empagliflozin / linagliptin, empagliflozin / metformin, or dapagliflozin / metformin.

[0158] In some embodiments, crystalline compound 1, a xanthine oxidase inhibitor, and an SGLT2 inhibitor are administered together in a single dosage form. In some embodiments, crystalline compound 1, a xanthine oxidase inhibitor, and an SGLT2 inhibitor are administered together in separate dosage forms.

[0159] The particular choice of compounds to be used will depend on the attending physician's diagnosis and judgment of the patient's condition and the appropriate treatment protocol. The compounds may be administered simultaneously (e.g., simultaneously, near simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder, or condition, the patient's condition, and the actual choice of compounds to be used. The order of administration during a treatment protocol, and the number of repetitions of administration of each therapeutic agent, are well within the purview of the physician after evaluating the disease being treated and the patient's condition.

[0160] The therapeutically effective amount may vary when drugs are used in combination treatment.The method of experimentally determining the therapeutically effective dose of drugs and other agents for use in combination treatment regimens is described in the literature.For example, the use of metronomic administration, i.e., administering more frequently and at lower doses to minimize toxic side effects, is widely described in the literature.Combination treatment also includes cyclical treatment that is started and stopped at various times to assist in the clinical management of patients.

[0161] In the combination therapy described herein, the dose of the co-administered compound will of course vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In addition, when co-administered with one or more biologically active agents, the compounds provided herein may be administered simultaneously with the biologically active agent or sequentially. If administered sequentially, the attending physician will determine the appropriate sequence for administering the protein in combination with the biologically active agent.

[0162] In all cases, the multiple therapeutic agents (one of which is crystalline compound 1 described herein) may be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents may be administered in a single, uniform form or in multiple doses (by way of example only, as a single pill or two separate tablets). One of the therapeutic agents may be administered in multiple doses or as multiple doses. If not simultaneously, the timing between the multiple doses may vary from more than 0 weeks to less than 4 weeks. Furthermore, the combination methods, compositions, and formulations are not limited to the use of only two agents. The use of multiple therapeutic combinations is also envisioned.

[0163] The dosage regimen for treating, preventing, or ameliorating the disease for which relief is sought can be modified according to various factors. These factors include the subject's disorder or disease, as well as the subject's age, weight, sex, diet, and medical condition. Thus, the dosage regimen actually employed may vary widely and may therefore deviate from the dosage regimen set forth herein.

[0164] The pharmaceutical agents constituting the combination therapy disclosed herein may be in a combination of dosage forms or in separate dosage forms intended for near-simultaneous administration. The pharmaceutical agents constituting the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen requiring two-step administration. The two-step administration regimen may require sequential administration of the active ingredients or spaced-apart administration of the separate active ingredients. The period between the multiple administration steps may be minutes to hours, depending on the properties of each pharmaceutical agent, such as its potency, solubility, bioavailability, plasma half-life, and kinetic profile. Circadian variations in target molecule concentrations may also determine the optimal administration interval.

[0165] In addition, the compounds described herein may also be combined with treatments that may provide an additive or synergistic effect on the patient. In just one example, the patient is expected to receive therapeutic and / or prophylactic benefit in the methods described herein. In this case, the pharmaceutical compositions of the compounds disclosed herein and / or combinations with other therapeutic agents are combined with genetic testing to determine whether an individual is a carrier of a mutant gene that correlates with a particular disease or disorder.

[0166] The compounds and combination therapies described herein can be administered before, during, or after the onset of a disease or condition, and the timing of administration of the composition containing the compounds can vary. Thus, for example, the compounds can be used as prophylactic agents and can be administered continuously to subjects prone to the development of a disease or condition to prevent the onset of the disease or condition. Initial administration can be via any practical route, such as intravenous injection, bolus injection, infusion over about 5 minutes to about 5 hours, pill, capsule, transdermal patch, buccal delivery, or combinations thereof. The compounds are preferably administered as soon as possible after the onset of a disease or condition is detected or suspected, and for the period of time required to treat the disease or condition. The treatment period can vary for each subject, and the length can be determined using certain criteria.

[0167] Kits / Products Also described herein are kits and articles of manufacture for use in the therapeutic methods described herein. Such kits include carriers, packages, or containers that are partitioned to accommodate one or more containers, such as vials or tubes, each of which contains one of the separate elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In other embodiments, the containers are formed of various materials, such as glass or plastic.

[0168] The product provided herein includes packaging materials.Packaging materials for use in packaging pharmaceutical products include, for example, those described in U.S. Patent No. 5,323,907.Packaging materials for pharmaceutical products include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging materials suitable for the selected formulation and intended mode of administration and treatment.

[0169] In some embodiments, the compounds or compositions described herein are administered in a package or dispenser device that may contain one or more unit dosage forms containing the active ingredient. The compounds or compositions described herein are packaged alone or together with another compound, another ingredient, or an additive. In some embodiments, the package includes one or more containers filled with one or more of the components of the pharmaceutical composition. In some embodiments, the package includes a metal or plastic foil, such as a blister pack. In some embodiments, the package or dispenser device is accompanied by instructions for administration, such as instructions for administration of the compound or composition to treat a tumor disease. In some embodiments, the package or dispenser device is accompanied by a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the form of the drug for human or animal use. In some embodiments, such notice is, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. In some embodiments, the compositions comprise a compound described herein formulated in a compatible pharmaceutical carrier, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0170] For example, the container contains crystalline Compound 1, optionally in a composition or in combination with another agent as disclosed herein. Such kits optionally include an identifying statement or label, or instructions for use in the methods described herein.

[0171] The kit typically includes a label listing the contents and / or instructions for use, as well as a package insert with instructions for use. A set of instructions is also typically included.

[0172] In one embodiment, the label is on or associated with the container. In one embodiment, the label is attached onto the container when letters, numbers, or other characters forming the label are affixed, molded, or engraved into the container itself. When present in a receptacle or carrier that also holds the container, the label is associated with the container, for example, as a package insert. In one embodiment, the label is used to indicate that the contents are intended for use in a particular therapeutic application. The label further indicates instructions for the use of the contents, for example, in the methods described herein.

[0173] In some embodiments, the pharmaceutical compositions are provided in a pack or dispenser device that contains one or more unit dosage forms containing the compounds provided herein. The pack contains, for example, metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In another embodiment, the pack or dispenser is also accompanied by a notice attached to the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the drug form for human or animal use. Such notice is, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. In one embodiment, compositions containing the compounds provided herein that are formulated in a compatible pharmaceutical carrier are also prepared, placed in a suitable container, and labeled for the treatment of an indicated disease. EXAMPLES

[0174] List of abbreviations Throughout the description of the present invention, the following abbreviations shall be understood to have the following meanings, unless otherwise specified: ACN or MeCN Acetonitrile Bn Benzyl BOC or Boc tert-butyl carbamate t-Bu tert-Butyl Cy Cyclohexyl DCE Dichloroethane (ClCH2CH2Cl) DCM Dichloromethane (CH2Cl2) DIPEA or DIEA Diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DMF Dimethylformamide DMA N,N-Dimethylacetamide DMSO Dimethyl sulfoxide eq or equiv equivalent Et Ethyl Et2O Diethyl ether EtOH Ethanol EtOAc Ethyl acetate HPLC High Performance Liquid Chromatography Me Methyl MeOH Methanol MS mass spectrometry GC Gas Chromatography h time KF Karl Fischer min MsOH Methanesulfonic acid NMR nuclear magnetic resonance RP-HPLC Reversed-phase high-performance liquid chromatography rt room temperature TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography V volume

[0175] I. Chemical synthesis Reagents and solvents were used as received from commercial suppliers unless otherwise specified. Anhydrous solvents and oven-dried glassware were used for moisture- and / or oxygen-sensitive synthetic transformations. Yields were not optimized. Reaction times are approximate and not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise specified. EXAMPLES

[0176] Preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1)

[0177] [ka]

[0178] Step 1: 2-Hydroxybenzaldehyde-3,4,5,6-d4 (Int-1)

[0179] [ka]

[0180] A solution of phen-d6-ol (1.0 eq), magnesium chloride (1.5 eq), and triethylamine (3.7 eq) in ACN (10 V) was stirred at 20 °C for 0.5 h. Formaldehyde (8.0 eq) was added and the reaction mixture was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and 10% HCl solution (10 V) was added. The mixture was extracted with EtOAc (3 × 6 V). The combined organic layers were washed with brine (6 V), dried over Na2SO4, and concentrated to give 2-hydroxybenzaldehyde-3,4,5,6-d4 (Int-1) as a yellow oil.

[0181] Step 2: 1-(benzofuran-2-yl-4,5,6,7-d4)ethan-1-one (Int-2)

[0182] [ka]

[0183] A solution of 2-hydroxybenzaldehyde-3,4,5,6-d4 (Int-1) (1.0 eq), bromopropanone (1.0 eq), and potassium carbonate (3.0 eq) in acetone (14 V) was heated to reflux for 6 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the crude product was recrystallized (petroleum ether / EtOAc 10:1) to give 1-(benzofuran-2-yl-4,5,6,7-d4)ethan-1-one (Int-2) as a yellow solid.

[0184] Step 3: 2-Ethylbenzofuran-4,5,6,7-d4 (Int-3)

[0185] [ka]

[0186] A solution of 1-(benzofuran-2-yl-4,5,6,7-d4)ethan-1-one (Int-2) (1.0 eq) in diethylene glycol (16 V) was heated at 120 °C. N2H4.H2O (2.0 eq) and water (1 V) were added. The reaction mixture was heated at 180 °C for 10 min and then cooled to 120 °C. KOH (2.0 eq) was added and the reaction mixture was heated at 120 °C for 6 h. The reaction mixture was cooled, poured into water and extracted with EtOAc (20 V x 3). The combined organic layers were washed with brine (20 V) and concentrated to give 2-ethylbenzofuran-4,5,6,7-d4 (Int-3) as a colorless oil.

[0187] Step 4: (2-Ethylbenzofuran-3-yl-4,5,6,7-d4)(4-methoxyphenyl)methanone (Int-4)

[0188] [ka]

[0189] A solution of 2-ethylbenzofuran-4,5,6,7-d4 (Int-3) (1.0 eq) and 4-methoxybenzoyl chloride (1.15 eq) in DCM (30 V) was cooled to 0 °C and charged with AlCl3 (1.1 eq). The reaction mixture was stirred at 0 °C for 2 h. D2O (2 V) was added dropwise to the mixture at 5 °C and the mixture was stirred for 0.5 h. Water (8 V) was added. The organic layer was separated, washed with brine (10 V), dried over Na2SO4 and concentrated under vacuum at 40 °C to give (2-ethylbenzofuran-3-yl-4,5,6,7-d4)(4-methoxyphenyl)methanone (Int-4) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ7.81-7.77(dd,2H),7.12-7.08(dd,2H),3.88(s,3H),2.86-2.78(q,2H),1.28-1.23(t,3H);LCMS:285[M+H] + .

[0190] Step 5: (2-Ethylbenzofuran-3-yl-4,5,6,7-d4)(4-hydroxyphenyl)methanone (Int-5)

[0191] [ka]

[0192] To a solution of (2-ethylbenzofuran-3-yl-4,5,6,7-d4)(4-methoxyphenyl)methanone (Int-4) (1.0 eq) in DCM (10 V) at 0 °C, BBr3 (2.2 eq) was added dropwise at 0-5 °C. The reaction mixture was warmed to room temperature and stirred for 14 h. Ice water (10 V) was added and the mixture was stirred for 0.5 h. The organic layer was separated, washed with brine (10 V), dried over Na2SO4 and concentrated under vacuum at 40 °C to give (2-ethylbenzofuran-3-yl-4,5,6,7-d4)(4-hydroxyphenyl)methanone (Int-5) as a brown solid. 1H NMR(400MHz,DMSO-d6):δ10.47(s,1H),7.71-7.68(dd,2H),6.92-6.88(dd,2H),2.84-2.78(q,2H),1.28-1.24(t,3H);LCMS:271[M+H] + .

[0193] Step 6: (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl-4,5,6,7-d4)methanone (Int-6)

[0194] [ka]

[0195] To a solution of (2-ethylbenzofuran-3-yl-4,5,6,7-d4)(4-hydroxyphenyl)methanone (Int-5) (1.0 eq) in DCM (10 V) at 10 °C, NBS (1.7 eq) was added dropwise at 0-5 °C. The reaction mixture was warmed to 18 °C and stirred for 16 h. The reaction mixture was charged with additional NBS (0.14 eq) at 10 °C and stirred at 18 °C for 16 h. The reaction mixture was charged with additional NBS (0.05 eq) at 10 °C and stirred at 18 °C for 3 h. Water (15 V) was added and the mixture was stirred for 0.5 h. The organic layer was separated, washed with brine (15 V), dried over Na2SO4 and concentrated under vacuum at 40 °C to give a yellow solid. The yellow solid was slurried in EtOAc / n-heptane (1 V / 10 V) at 60 °C for 2 h. The mixture was cooled to 10° C. and filtered to give (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl-4,5,6,7-d4)methanone (Int-6) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ11.05(s,1H),7.92(s,2H),2.84-2.75(q,2H),1.27-1.20(t,3H);LCMS:429[M+H] + .

[0196] Step 7: 2,6-dibromo-4-(2-ethylbenzofuran-3-carbonyl-4,5,6,7-d4)phenylacetate (Int-7)

[0197] [ka]

[0198] To a solution of (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl-4,5,6,7-d4)methanone (Int-6) (1.0 eq) and triethylamine (2.5 eq) in DCM (10 V) was added dropwise at 0-5 °C. The reaction mixture was warmed to 15 °C and stirred for 2 h. Water (10 V) was added. The organic layer was separated, washed with brine (10 V), dried over Na2SO4 and concentrated under vacuum at 40 °C to give a crude solid. The crude solid was decolorized with activated charcoal (0.5 w / w) in EtOAc (10 V) at 50 °C for 1 h. The mixture was cooled to 30 °C and the activated charcoal was removed by filtration through a kieselguhr aid. The filtrate was concentrated under vacuum at 40 °C. The residue was dissolved in i-PrOH (2V) and heated at 60° C. for 1 h. The solution was cooled to 45° C., charged with seed crystals (0.5% w / w) and stirred for 1 h. The mixture was cooled to 25° C. and stirred for 16 h. The mixture was filtered and the solid was dried to give 2,6-dibromo-4-(2-ethylbenzofuran-3-carbonyl-4,5,6,7-d4)phenylacetate (Int-7) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ8.08(s,2H),2.81-2.74(q,2H),2.44(s,3H),1.27-1.22(t,3H);LCMS:471[M+H] + .

[0199] Step 8: 2,6-dibromo-4-(2-(1-bromoethyl)benzofuran-3-carbonyl-4,5,6,8-d4)phenylacetate (Int-7)

[0200] [ka]

[0201] A mixture of 2,6-dibromo-4-(2-ethylbenzofuran-3-carbonyl-4,5,6,7-d4)phenylacetate (Int-7) (1.0 eq), NBS (1.1 eq), and AIBN (0.1 eq) in chlorobenzene (10 V) was heated with stirring at 55 °C for 6 h. The reaction mixture was cooled to 25 °C, water (10 V) was added, and the mixture was stirred for 1 h. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to 1.5-2 V. The solution was charged with heptane (5 V) and concentrated under vacuum to 1.5-2 V. This was repeated three times. The solution was charged with heptane (3 V), cooled to 5 °C, and stirred for 4 h. The mixture was filtered and the solid was washed with heptane (1V×2) and dried to give 2,6-dibromo-4-(2-(1-bromoethyl)benzofuran-3-carbonyl-4,5,6,7-d4)phenylacetate (Int-8) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ8.11(s,2H),5.47-5,40(q,1H),2.46(s,3H),2.05-2.03(d,3H);LCMS:469[M+H-HBr] + .

[0202] Step 9: 1-(3-(3,5-dibromo-4-hydroxybenzoyl)benzofuran-2-yl-4,5,6,7-d4)ethyl acetate (Int-9)

[0203] [ka]

[0204] A mixture of 2,6-dibromo-4-(2-(1-bromoethyl)benzofuran-3-carbonyl-4,5,6,7-d4)phenylacetate (Int-8) (1.0 eq) and CsOAc (5.0 eq) in N-methylpyrrolidine (8 V) was stirred at 25 °C for 12 h. The reaction mixture was filtered. To the filtrate was added water (15 V) and EtOAc (10 V). The pH of the resulting mixture was adjusted to 2-3 with 12 N HCl. The mixture was stirred for 1 h and then allowed to stand for 0.5 h. The organic solution was collected and the aqueous solution was extracted with EtOAc (10 V). The combined organic solution was washed with water (10 V × 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography to give 1-(3-(3,5-dibromo-4-hydroxybenzoyl)benzofuran-2-yl-4,5,6,7-d4)ethyl acetate (Int-9) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ7.93(s,2H),5.88-5.87(q,1H),1.99(s,3H),1.63-1.61(d,3H);LCMS:427[M+H-CH3CO2H] + .

[0205] Step 10: (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1)

[0206] [ka]

[0207] To a mixture of 1-(3-(3,5-dibromo-4-hydroxybenzoyl)benzofuran-2-yl-4,5,6,7-d4)ethyl acetate (Int-9) (1.0 eq) in methanol (10 V) was added Cs2CO3 (3.0 eq). The reaction mixture was stirred at 28 °C for 12 h. Water (20 V) was added and the pH of the resulting mixture was adjusted to 2-3 with 12 N HCl. The mixture was stirred for 1 h. The mixture was filtered and the filter cake was washed with water (2 V x 2). A solution of the filter cake, EtOAc (15 V), and 1 N HCl (5 V) was stirred at 25 °C for 1 h. The organic solution was collected, dried over Na2SO4, and concentrated under vacuum to 2-3 V. The solution was heated at 50 °C for 1 h, charged with seed crystals (1% w / w) and heated at 50 °C for 2 h. n-Heptane (10V) was added dropwise and the mixture was heated at 50° C. for 2 h. The mixture was cooled to 25° C. and stirred for 12 h. The solid was collected by filtration and dried to give (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ11.11(bs,1H),7.95(s,1H),5.60(bs,1H),4.88-4.83(q,1H),1.49-1.48(d,3H);LCMS:427[M+H-H2O] + .

[0208] II. Polymorph Characterization EXAMPLES

[0209] X-ray powder diffraction (XRPD) X-ray powder diffraction studies were performed using a Bruker D8 Advance with the following instrument parameters: Scan: 3°(2θ)~40°(2θ) Increment: 0.02°(2θ) Scan speed: 0.3 seconds / step Voltage: 40kV Current: 40mA Rotation: On Sample Retention: Zero Background Sample Holder

[0210] XRPD analysis of Form 3 of Compound 1 (FIG. 1) showed that Form 3 was crystalline with characteristic peaks at 6.8° 2-theta, 13.6° 2-theta, 14.6° 2-theta, 21.2° 2-theta, 24.2° 2-theta, 24.7° 2-theta, 26.7° 2-theta, and 27.5° 2-theta.

[0211] XRPD analysis of Form 2 of Compound 1 (FIG. 4) showed that Form 2 was crystalline with characteristic peaks at 8.3° 2-theta, 10.7° 2-theta, 16.6° 2-theta, 19.7° 2-theta, 23.7° 2-theta, 25.0° 2-theta, 25.6° 2-theta, and 27.1° 2-theta.

[0212] XRPD analysis of Form 1 of Compound 1 (FIG. 7) showed that Form 1 was crystalline with characteristic peaks at 5.6° 2-theta, 11.5° 2-theta, 13.8° 2-theta, 14.3° 2-theta, 17.0° 2-theta, 18.9° 2-theta, 27.9° 2-theta, and 31.4° 2-theta. EXAMPLES

[0213] Polarized Light Microscopy (PLM) Optical microscopy was performed using a Nikon Eclipse LV100N POL. The solids were placed on glass slides and dispersed with cedar oil before observation at appropriate magnification.

[0214] PLM analysis of Form 3 of compound 1 revealed irregular crystals up to 50 μm in size.

[0215] PLM analysis of Form 2 of Compound 1 revealed irregular particles up to 100 μm in size.

[0216] PLM analysis of Form 1 of Compound 1 showed needle-like crystals up to 50 μm in size. EXAMPLES

[0217] thermogravimetric analysis Thermogravimetric analysis of solids was performed using a TA Discovery TGA 55 or equivalent. Samples were placed in open aluminum pans and automatically weighed. Samples were heated at a heating rate of 10°C / min until the final temperature was reached.

[0218] TGA for Form 3 of Compound 1 (Figure 2) showed no weight loss until decomposition began at approximately 147°C.

[0219] TGA for Form 2 of Compound 1 (FIG. 5) showed no weight loss until decomposition began at approximately 139° C.

[0220] TGA for Form 1 of Compound 1 (FIG. 8) showed a weight loss of approximately 4% at 100° C. consistent with the monohydrate. EXAMPLES

[0221] Differential Scanning Calorimetry (DSC) DSC testing was performed using a TA Discovery DSC 250. Samples were weighed into pinhole aluminum pans and the exact volume was recorded. Samples were heated at a heating rate of 10 °C / min with a nitrogen purge of 50 mL / min from 25 °C to the final temperature.

[0222] DSC analysis for Form 3 of Compound 1 (FIG. 3) showed a melting endotherm with an onset at 147° C. (81 J / g).

[0223] DSC analysis for Form 2 of Compound 1 (FIG. 6) showed a melting endotherm with an onset at 139° C. (77 J / g).

[0224] DSC analysis for Form 1 of Compound 1 (FIG. 9) showed a broad endotherm with an onset at 80° C. (74 J / g). EXAMPLES

[0225] Dynamic Vapor Sorption (DV) DVS testing was performed using DVS Intrinsic (SMS, UK) or IGASORP (Hiden, UK). 10–50 mg of compound was transferred to the DVS and weight change was recorded against variable atmospheric humidity at 25 °C with the following parameters: Dry at 40℃ until dm / dt<±0.002% / min Minimum time: 30 minutes, maximum time: 120 minutes (for IGASORP) Equilibrium: 60 minutes Cycles: 0, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, 0 Characterize the samples after the DVS experiment by XRPD

[0226] DVS analysis for Form 3 of compound 1 (Figure 10) showed moisture absorption of 0.04% from 0 to 90% RH. Post-GVS analysis by XRPD showed no change. This material was non-hygroscopic.

[0227] DVS analysis for Form 2 of Compound 1 (Figure 11) showed moisture absorption of 0.08% from 0 to 90% RH. Post-GVS analysis by XRPD showed no change. This material was non-hygroscopic.

[0228] DVS analysis for Form 1 of compound 1 (FIG. 12) showed that the dehydrated form was converted to the hydrated form at RH above 20%.

[0229] III. Polymorph Screen Polymorph screen examples 7, 8, and 9 were performed using Form 1 of Compound 1. EXAMPLES

[0230] Binary Solvent Test Binary solvent testing was performed using a combination of 13 solvents (acetone, acetonitrile, 2-butanone, ethanol, ethyl acetate, heptane, isopropanol, isopropyl acetate, methanol, methyl t-butyl ether (MTBE), tetrahydrofuran (THF), toluene, and water) utilizing slow evaporation. Ninety-one vials, each containing compound 1 form 1 (40-80 mg), were filled with 3 mL of solvent. 2 mL of compound 1 solution / suspension were filtered into centrifuge tubes (the remaining 1 mL of compound 1 suspension was used in Example 8). 100 μL of each filtrate was dispensed into a 96-well plate. The plate was covered by sealing with a film with a pinhole and allowed to evaporate slowly in a fume hood under air atmosphere. 21 solid samples were tested by XRPD. The results are shown in Table 1.

[0231] [Table 1] EXAMPLES

[0232] Slurry Test The remaining Compound 1 suspension from Example 7 was stirred for 4 days. The solids were collected by filtration and analyzed by XRPD. Additionally, a slurry of Compound 1 Form 1 (50 mg) in 1.5 mL of solvent was heated at 50° C. for a specified time. The solids were collected by filtration and analyzed by XRPD. The results are shown in Table 2.

[0233] [Table 2] EXAMPLES

[0234] Antisolvent precipitation test Compound 1, Form 1 (approximately 50 mg) was weighed into a sample vial and various solvents were added to dissolve the solids. Heptane was slowly added to create a suspension, which was stirred at room temperature or 50° C. for a specified period of time. The solids were collected by filtration and analyzed by XRPD. The results are shown in Table 3.

[0235] [Table 3] EXAMPLES

[0236] Interconversion test Equal amounts of Compound 1, Form 2 and Compound 1, Form 3 were added to an EtOAc / heptane mixture and stirred at room temperature (rt) or 50° C. for the specified time. The solids were collected by filtration and analyzed by XRPD. Upon interconversion, it was observed that Form 3 was more stable at elevated temperatures and room temperature. The results are shown in Table 4.

[0237] [Table 4] EXAMPLES

[0238] In vitro interaction study of compound 1 and benzbromarone with human URAT1 uptake transporter Uptake experiments were performed using MDCKII cells stably expressing the human URAT1 uptake transporter. Cells were cultured at 37±1°C in an atmosphere of 95:5 air:CO2 and plated in standard 96-well tissue culture plates at the cell numbers listed in Table 5.

[0239] [Table 5]

[0240] Before the experiment, remove the medium and - The cells were washed twice with 100 μL of HBSS without Cl. - Uptake experiments were performed in 50 μL of HBSS, free of uric acid, pH 7.4, containing the probe substrate (uric acid 20 μM) and the test article (TA) or vehicle at 37 ± 1° C. Organic solvent concentrations were equal in all wells and did not exceed 1% (v / v).

[0241] The treatment groups are presented in Table 6.

[0242] [Table 6]

[0243] After the experiment, Cl - Cells were washed twice with 100 μL of ice-cold HBSS without HO and lysed with 50 μL of 0.1 M NaOH. Radiolabeled probe substrate transport was determined by liquid scintillation counting of an aliquot (35 μL) from each well.

[0244] Results: Both test substances (compound 1 and benzbromarone) were soluble in HBSS buffer at all concentrations tested. The highest test concentration was 10 μM. Compound 1 inhibited URAT1-mediated uric acid accumulation by 100% at a concentration of 10 μM, with an IC 50 = 0.067 μM. Benzbromarone inhibited URAT1-mediated uric acid accumulation by 98% at a concentration of 10 μM, with an IC 50 =0.196 μM.

Claims

1. (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d ４ ) A crystalline form of methanone or a solvate thereof.

2. (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d ４ ) The crystalline form of methanone has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 6.8° 2-theta, 13.6° 2-theta, 14.6° 2-theta, 21.2° 2-theta, 24.2° 2-theta, 24.7° 2-theta, 26.7° 2-theta, and 27.5° 2-theta; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG. (d) a DSC thermogram substantially similar to that shown in FIG. (e) A DSC thermogram with an endotherm with an onset at about 147° C. (f) being non-hygroscopic; or (g) combinations thereof; Form 3 having at least one of: The crystalline form of claim 1.

3. 3. The crystalline form of claim 1 or 2, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG.

4. 3. The crystalline form of claim 1 or 2, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.8° 2-theta, 13.6° 2-theta, 14.6° 2-theta, 21.2° 2-theta, 24.2° 2-theta, 24.7° 2-theta, 26.7° 2-theta, and 27.5° 2-theta.

5. 3. The crystalline form of claim 1 or 2, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in Figure 2.

6. 3. The crystalline form of claim 1 or 2, wherein the crystalline form has a DSC thermogram substantially similar to that shown in FIG.

7. 3. The crystalline form of claim 1 or 2, wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 147°C.

8. 3. The crystalline form of claim 1 or 2, wherein the crystalline form is non-hygroscopic.

9. 3. The crystalline form of claim 2, wherein the crystalline form is characterized as having properties (a), (b), (c), (d), (e), and (f).

10. 10. The crystalline form of any one of claims 1-9, wherein the crystalline form is obtained from toluene, toluene / heptane, or ethyl acetate / heptane.

11. (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d ４ ) The crystalline form of methanone has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.3° 2-theta, 10.7° 2-theta, 16.6° 2-theta, 19.7° 2-theta, 23.7° 2-theta, 25.0° 2-theta, 25.6° 2-theta, and 27.1° 2-theta; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG. (d) a DSC thermogram substantially similar to that shown in FIG. (e) a DSC thermogram with an endotherm with an onset at about 139° C.; (f) being non-hygroscopic; or (g) combinations thereof; The crystalline form of claim 1, which is form 2 having at least one of:

12. 12. The crystalline form of claim 1 or 11, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 4.

13. 12. The crystalline form of claim 1 or 11, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.3° 2-theta, 10.7° 2-theta, 16.6° 2-theta, 19.7° 2-theta, 23.7° 2-theta, 25.0° 2-theta, 25.6° 2-theta, and 27.1° 2-theta.

14. 12. The crystalline form of claim 1 or 11, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in Figure 5.

15. 12. The crystalline form of claim 1 or 11, wherein the crystalline form has a DSC thermogram substantially similar to that shown in Figure 6.

16. 12. The crystalline form of claim 1 or 11, wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 139°C.

17. 12. The crystalline form of claim 1 or 11, wherein the crystalline form is non-hygroscopic.

18. 12. The crystalline form of claim 11, wherein the crystalline form is characterized as having properties (a), (b), (c), (d), (e), and (f).

19. The crystalline form of any one of claims 11-18, wherein the crystalline form is obtained from heptane or ethyl acetate / heptane.

20. The crystalline form of any one of claims 1-19, wherein the crystalline form is not solvated.

21. 21. The crystalline form of any one of claims 1-20, wherein the crystalline form is anhydrous.

22. (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d ４ ) The crystalline form of methanone has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 7; (b) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.6° 2-theta, 11.5° 2-theta, 13.8° 2-theta, 14.3° 2-theta, 17.0° 2-theta, 18.9° 2-theta, 27.9° 2-theta, and 31.4° 2-theta; (c) Thermogravimetric analysis (TGA) substantially similar to that shown in FIG. (d) a DSC thermogram substantially similar to that shown in FIG. (e) a DSC thermogram with an endotherm having an onset at about 80° C.; or (f) combinations thereof; The crystalline form of claim 1, which is form 1 having at least one of:

23. 23. The crystalline form of claim 1 or 22, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 7.

24. 23. The crystalline form of claim 1 or 22, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.6° 2-theta, 11.5° 2-theta, 13.8° 2-theta, 14.3° 2-theta, 17.0° 2-theta, 18.9° 2-theta, 27.9° 2-theta, and 31.4° 2-theta.

25. 23. The crystalline form of claim 1 or 22, wherein the crystalline form has a thermogravimetric analysis (TGA) substantially similar to that shown in Figure 8.

26. 23. The crystalline form of claim 1 or 22, wherein the crystalline form has a DSC thermogram substantially similar to that shown in Figure 9.

27. 23. The crystalline form of claim 1 or 22, wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 80°C.

28. 23. The crystalline form of claim 22, wherein the crystalline form is characterized as having properties (a), (b), (c), (d), and (e).

29. 29. The crystalline form of any one of claims 22-28, wherein the crystalline form is obtained from methanol, ethanol, isopropanol, toluene, water, acetonitrile, heptane, acetone, tert-butyl methyl ether, 2-butanone, ethyl acetate, isopropyl acetate, tetrahydrofuran, or a combination thereof.

30. 30. The crystalline form of any one of claims 1-29 for use in medicine.

31. 30. A pharmaceutical composition comprising the crystalline form of any one of claims 1-29 and at least one inactive ingredient selected from pharma- ceutically acceptable carriers, diluents, and excipients.

32. 32. The pharmaceutical composition of claim 31 formulated for oral, intravenous, intramuscular, or subcutaneous administration.

33. 30. A method for treating hyperuricemia or gout in an individual, said method comprising administering to the individual a therapeutically effective amount of a crystalline form of any one of claims 1-29.

34. 34. The method of claim 33, wherein the crystalline form is administered orally.

35. 35. The method of claim 33 or 34, wherein the therapeutically effective amount is taken with food.

36. 35. The method of claim 33 or 34, wherein the therapeutically effective amount is taken without food.

37. 37. The method of any one of claims 33-36, wherein the therapeutically effective amount is administered to the individual once daily.

38. 37. The method of any one of claims 33-36, wherein the therapeutically effective amount is administered to the individual twice daily.

39. 39. The method of any one of claims 33-38, further comprising administering at least one additional therapeutic agent.

40. 40. The method of any one of claims 33-39, further comprising administering a xanthine oxidase inhibitor.

41. 41. The method of claim 40, wherein the xanthine oxidase inhibitor is allopurinol, oxypurinol, febuxostat, topiroxostat, or inositol.

42. 42. The method of any one of claims 33-41, further comprising administering an SGLT2 inhibitor.

43. 43. The method of claim 42, wherein the SGLT2 inhibitor is canagliflozin, dapagliflozin, empagliflozin, empagliflozin / linagliptin, empagliflozin / metformin, and dapagliflozin / metformin.

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