Crystalline forms of ryanodine receptor modulators and uses thereof - Patents.com

Abstract

The present disclosure relates to crystalline forms of the compound 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, pharmaceutical compositions comprising these compounds, and their uses for treating diseases and conditions associated with ryanodine receptor (RyR) dysfunction, particularly cardiac and musculoskeletal disorders and diseases.

Description

[Technical field]

[0001] cross reference

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 135,083, filed January 8, 2021, the entire contents of which are incorporated by reference herein. [Background technology]

[0002]

[0002] The sarcoplasmic reticulum (SR) is a membrane protein that contains, among other things, specialized intracellular calcium (Ca 2+ Ryanodine receptors (RyRs) are intracellular structures that function as Ca2+ stores. They open and close to allow the passage of Ca2+ from the SR to the intracellular cytoplasm. 2+ It controls the release of Ca from the SR into the cytoplasm. 2+ Release of cytoplasmic Ca 2+ The open probability of an RyR determines how many RyRs are open at any given moment, thus increasing the Ca concentration from the SR to the cytoplasm. 2+ Three RyR isoforms are known: RyR1 is the predominant isoform expressed in mammalian skeletal muscle and is found primarily in cardiac muscle, whereas RyR3 expression is low in skeletal muscle.

[0003]

[0003] Ca from SR 2+ Release is regulated by several RyR-binding proteins. Calstabin1 (FKBP12) and calstabin2 (FKBP12.6) stabilize the closed state of RyR1 and RyR2, respectively. Mutations in RYR1 or RYR2 are characterized by reduced binding of calstabin1 or calstabin2, respectively, and inappropriate channel opening that is not related to contractile signals. This channel opening is further exacerbated by post-translational modifications such as PKA-phosphorylation, oxidation, or nitrosylation of RyR channels. The resulting dissociation of calstabins can result in leaky channels that exhibit a pathological increase in open probability at rest. SR Ca 2+ Leakage of SR Ca 2+ Ca content, resulting in a decrease in Ca available for release 2+This results in less muscle contraction. Summary of the Invention [Means for solving the problem]

[0004] In some embodiments, the present disclosure provides a composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, the melting point of which is between 208 and 210° C. (T) when obtained by (a) equilibrating a sample of said crystalline form in a temperature-controlled chamber at a temperature of about 20° C., and (b) increasing the temperature of the temperature-controlled chamber at about 10° C. / min to 250° C. using a differential scanning calorimeter instrument. onset The composition provides a melting point of

[0005] In some embodiments, the present disclosure provides a composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate for use in a method of treating a medical condition, the crystalline form having a melting point of 208-210° C. (T) when obtained by (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C., and (b) increasing the temperature of the temperature controlled chamber at about 10° C. / min to 250° C. using a differential scanning calorimeter instrument. onset The composition provides a melting point of

[0006] In some embodiments, the present disclosure provides a composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, the crystalline form having a melting point of 201-203° C. (T) when obtained by (a) equilibrating a sample of said crystalline form in a temperature-controlled chamber at a temperature of about 20° C., and (b) increasing the temperature of the temperature-controlled chamber to 250° C. at a scan rate of about 10° C. / min using a differential scanning calorimeter instrument. onset The composition provides a melting point of

[0007] In some embodiments, the present disclosure provides a composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate for use in a method of treating a medical condition, the crystalline form having a melting point of 201-203° C. (T) when obtained by (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C., and (b) increasing the temperature of the temperature controlled chamber at about 10° C. / min to 250° C. using a differential scanning calorimeter instrument. onset The composition provides a melting point of

[0008]

[0008] In some embodiments, the present disclosure provides a method for treating a medical condition, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a composition, the composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 shows a characteristic X-ray diffraction (XRD) pattern of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate salt Form 1. [Diagram 2]

[0010] FIG. 2 shows a characteristic differential scanning calorimetry (DSC) profile of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate salt Form 1. [Diagram 3]

[0011] FIG. 1 shows a characteristic thermogravimetric analysis (TGA) profile of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate salt Form 1. [Figure 4]

[0012] FIG. 1 shows a characteristic dynamic vapor sorption (DVS) profile of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate salt Form 1. [Diagram 5]

[0013] Figures 5A-D show characteristic X-ray diffraction (XRD) patterns of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate Form 1 at initiation (top panel - Figure 5A) and after 24 months (bottom three panels - Figures 5B-5D). [Figure 6]

[0014] FIG. 2 shows a characteristic X-ray diffraction (XRD) pattern of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate salt Form 2. [Figure 7]

[0015] FIG. 2 shows a characteristic differential scanning calorimetry (DSC) profile of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate salt Form 2. [Figure 8]

[0016] FIG. 2 shows a characteristic thermogravimetric analysis (TGA) profile of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate salt Form 2. [Figure 9]

[0017] FIG. 2 shows a characteristic dynamic vapor sorption (DVS) profile of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate salt Form 2. [Figure 10]

[0018] FIG. 1 shows characteristic X-ray diffraction (XRD) patterns of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate Form 2 at the start (top panel) and after 3, 6, 12, and 24 months. [Figure 11]

[0019] FIG. 1 shows a comparison of X-ray diffraction (XRD) patterns of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate Form 1 (top panel) and Form 2 (bottom panel). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010]

[0020] The present disclosure provides polymorphic forms of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt (Compound I), pharmaceutical compositions comprising same, methods for their preparation, and their use in treating RyR-related conditions including, for example, cardiac disorders or diseases, musculoskeletal disorders or diseases, cancer-related muscle weakness, malignant hyperthermia, and diabetes.

[0011]

[0021] Described herein are polymorphic forms of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt (Compound I) that have beneficial properties. For example, the Compound I polymorph can be stable for at least 24 months in a closed glass container at storage conditions of -18°C and 25°C / 60% relative humidity (RH). For example, the Compound I polymorph can be stable for at least 12 months in a closed glass container at 30°C / 65% relative humidity (RH). For example, the Compound I polymorph can be stable for at least 6 months in a closed glass container at 40°C / 75% relative humidity (RH).

[0012]

[0022] Polymorphs described herein include, for example, Rycal. 2+ It is a small molecule that functions as a channel stabilizer. The polymorph is useful for treating conditions, disorders, and diseases associated with leaky ryanodine receptors (RyR). Non-limiting examples of such conditions include cardiac conditions, musculoskeletal conditions, cancer-related muscle weakness, malignant hyperthermia, and diabetes.

[0013]

[0023] Polymorphs are different solid state phases of a given compound, differing in molecular arrangement and / or conformation. Polymorphism is the ability of a substance to exist in two or more different amorphous and crystalline forms. In some embodiments, the polymorphic forms disclosed herein are substantially anhydrous. In some embodiments, the polymorphic forms disclosed herein are stable for up to at least 6 months under humid conditions (75% RH) and for at least 24 months under ambient conditions 25° C. / 60% relative humidity (RH). The polymorphic forms are suitable for the preparation of pharmaceutical compositions for the treatment of RyR-related pathologies.

[0014]

[0024] The present disclosure provides two polymorphic forms of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt of formula (I), designated Form 1 and Form 2. In some embodiments, the polymorph is crystalline. In some embodiments, the polymorph is anhydrous. In some embodiments, the polymorph is substantially anhydrous.

[0015]

[0025] The compounds of formula (I) have the empirical formula having the following structure or an ionized form thereof:

[0016] [ka]

[0017] .

[0018]

[0026] For example, a compound of formula (I) may be in an ionized form that includes two ionized molecules of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0019] [ka]

[0020] 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt form 1

[0027] Provided herein is crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt, Form 1. Further provided herein is a composition comprising crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt, Form 1.

[0021]

[0028] In some embodiments, the crystalline form is an anhydrous, slightly hygroscopic crystalline form. The crystalline form has a T onset In some embodiments, the crystalline form exhibits a melting point of 201.4° C. (T onset ) and has a melting point of 202.6°C T peak It is an anhydrous, non-hygroscopic crystalline form with a melting / decomposition (melting / decomposition) phase. Based on the mass loss observed by TGA analysis, melting may be accompanied by immediate decomposition.

[0022]

[0029] In some embodiments, a composition comprises crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt, wherein the X-ray diffraction pattern of the crystalline form is: Start position [°2θ] 3.00 End position [°2θ] 54.99 Step size [°2θ] 0.018 Scan step time [s] 34.92 Measurement temperature [℃] 25.00 K-alpha 1 [Å] 1.54 K-alpha 2 [Å] 1.54 K-beta [Å] 1.39 Rotation Yes and wherein at least two X-ray diffraction peaks selected from 9.8±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 17.4±0.1, 18.9±0.1, 19.6±0.1, 22.1±0.1, 26.6±0.1, and 27.2±0.1 degrees two-theta (°θ) are observed when the composition is obtained using measurement conditions including:

[0023]

[0030] In some embodiments, when the X-ray diffraction pattern of the crystalline form is obtained using the above measurement conditions, X-ray diffraction peaks at 9.8±0.1, 11.0±0.1, 17.4±0.1, 21.6±0.1, and 22.6±0.1 degrees two-theta (°θ) are observed.

[0024]

[0031] In some embodiments, when the X-ray diffraction pattern of the crystalline form is obtained using the above measurement conditions, X-ray diffraction peaks at 9.8±0.1, 11.0±0.1, 11.8±0.1, 15.0±0.1, 17.4±0.1, 21.6±0.1, 22.1±0.1, and 22.6±0.1 degrees two-theta (°θ) are observed.

[0025]

[0032] In some embodiments, when the X-ray diffraction pattern of the crystalline form is obtained using the measurement conditions described above, X-ray diffraction peaks at 9.8±0.1, 11.0±0.1, 11.4±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 15.0±0.1, 17.4±0.1, 18.9±0.1, 19.3±0.1, 19.6±0.1, 20.3±0.1, 21.6±0.1, 22.1±0.1, 22.6±0.1, 26.6±0.1, and 27.2±0.1 degrees two-theta (°θ) are observed.

[0026]

[0033] In some embodiments, when an X-ray diffraction pattern of the crystalline form is obtained using the measurement conditions described above, X-ray diffraction peaks substantially as shown in FIG. 1 are observed.

[0027]

[0034] In some embodiments, the X-ray diffraction (XRD) pattern of Form 2 comprises at least two diffraction peaks selected from 9.8±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 17.4±0.1, 18.9±0.1, 19.6±0.1, 22.1±0.1, 26.6±0.1, and 27.2±0.1 degrees two-theta (°θ). In some embodiments, the X-ray diffraction (XRD) pattern comprises at least three diffraction peaks selected from 9.8±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 17.4±0.1, 18.9±0.1, 19.6±0.1, 22.1±0.1, 26.6±0.1, and 27.2±0.1 degrees two-theta (°θ). In some embodiments, the X-ray diffraction (XRD) pattern comprises at least four diffraction peaks selected from 9.8±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 17.4±0.1, 18.9±0.1, 19.6±0.1, 22.1±0.1, 26.6±0.1, and 27.2±0.1 degrees two-theta (°θ). In some embodiments, the X-ray diffraction (XRD) pattern comprises at least five diffraction peaks selected from 9.8±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 17.4±0.1, 18.9±0.1, 19.6±0.1, 22.1±0.1, 26.6±0.1, and 27.2±0.1 degrees two-theta (°θ). In some embodiments, the X-ray diffraction pattern comprises a peak at 9.8±0.1 degrees two-theta (°θ).

[0028]

[0035] In some embodiments, the crystalline form is characterized by an X-ray diffraction (XRD) pattern comprising diffraction peaks at 9.8±0.1, 11.0±0.1, 17.4±0.1, 21.6±0.1, and 22.6±0.1 degrees two theta (°θ).

[0029]

[0036] In some embodiments, the crystalline form is characterized by an X-ray diffraction (XRD) pattern comprising diffraction peaks at 9.8±0.1, 11.0±0.1, 11.8±0.1, 15.0±0.1, 17.4±0.1, 21.6±0.1, 22.1±0.1, and 22.6±0.1 degrees two theta (°θ).

[0030]

[0037] In some embodiments, the crystalline form is characterized by an X-ray diffraction (XRD) pattern comprising diffraction peaks at 9.8±0.1, 11.0±0.1, 11.4±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 15.0±0.1, 17.4±0.1, 18.9±0.1, 19.3±0.1, 19.6±0.1, 20.3±0.1, 21.6±0.1, 22.1±0.1, 22.6±0.1, 26.6±0.1, and 27.2±0.1 degrees two-theta (°θ).

[0031]

[0038] In some embodiments, the crystalline form is characterized by an X-ray diffraction (XRD) pattern substantially as shown in FIG.

[0032]

[0039] In some embodiments, the crystalline form is characterized by an X-ray diffraction (XRD) pattern substantially as shown in Table 1.

[0033] [Table 1]

[0034]

[0040] In some embodiments, a composition comprising crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt, wherein the melting point of the crystalline form is between 201 and 203° C. (T) when obtained by (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C., and (b) increasing the temperature of the temperature controlled chamber to 250° C. at a scan rate of about 10° C. / min using a differential scanning calorimeter instrument. onsetCompositions are provided herein that provide a melting point of 0.01 to 0.01 mm. The differential scanning calorimetry instrument can be, for example, a DSC Q1000 or a DSC Q2000.

[0035]

[0041] In some embodiments, provided herein are compositions comprising crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate, characterized by a differential scanning calorimetry (DSC) profile substantially as shown in Figure 2. In some embodiments, the crystalline form has a T onset As shown in FIG. 2, an exemplary sample of the crystalline form is characterized by a melting point of T onset : 201.4℃, T peak : 202.6℃ (melt / decomposition).

[0036]

[0042] In some embodiments, the crystalline form is further characterized by a thermogravimetric analysis (TGA) profile. In some embodiments, a composition is provided herein that comprises crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate, wherein when a thermogravimetric analysis of the crystalline form is obtained by (a) equilibrating a sample of the crystalline form at 25°C in a temperature-controlled chamber, and (b) increasing the temperature to 250°C at a scan rate of about 10°C / min using a thermogravimetric analyzer, a thermogravimetric analysis profile substantially as shown in Figure 3 is obtained. In some embodiments, the loss of mass before melting decomposition is about 1%. The thermogravimetric analyzer can be, for example, a TGAQ5000.

[0037]

[0043] In some embodiments, provided herein is a composition comprising crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt, the crystalline form of which is characterized by a thermogravimetric analysis profile substantially as shown in FIG.

[0038]

[0044] In some embodiments, the crystalline form is further characterized by a Dynamic Vapor Sorption (DVS) profile. In some embodiments, a composition comprising crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate, wherein the dynamic vapor sorption of the crystalline form is measured using a DVS intrinsic instrument. Provided herein is a composition, wherein the dynamic vapor sorption profile is obtained by measuring the mass variation of the crystalline form as a function of relative humidity using a temperature and humidity controlled instrument, said measuring comprising: (a) equilibrating a sample of the crystalline form at 25° C. and 50% relative humidity in a temperature and humidity controlled chamber until a mass variation of less than 0.002% per minute for 6 hours is observed; (b) increasing the relative humidity from 50% to 90% at a rate of 10% per hour; (c) equilibrating the sample at 90% relative humidity until a mass variation of less than 0.002% per minute is observed for 6 hours; (d) decreasing the relative humidity from 90% to 0% at a rate of 10% per hour; (e) equilibrating the sample at 0% relative humidity until a mass variation of less than 0.002% per minute is observed for 6 hours; and (f) increasing the relative humidity from 0% to 50% at a rate of 10% per hour.

[0039]

[0045] In some embodiments, provided herein is a composition comprising crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt, wherein the crystalline form is characterized by a dynamic vapor sorption profile substantially as depicted in FIG.

[0040]

[0046] In some embodiments, the crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt is anhydrous. In some embodiments, the crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt is substantially anhydrous.

[0041] 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt form 2

[0047] Provided herein is crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt, Form 2. Provided herein is a composition comprising crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt, Form 2.

[0042]

[0048] In some embodiments, the crystalline form is at a temperature between 208 and 210° C. (T onset ) in an anhydrous, non-hygroscopic crystalline form having a melting point of 209.5° C. (T onset ) and has a melting point of 210.7°C T peak It is an anhydrous, non-hygroscopic crystalline form with a melting / decomposition (melting / decomposition) phase. Based on the mass loss observed by TGA analysis, melting may be accompanied by immediate decomposition.

[0043]

[0049] In some embodiments, a composition comprises crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt, wherein the crystalline form has an X-ray diffraction pattern (XRD): Start position [°2θ] 3.00 End position [°2θ] 54.99 Step size [°2θ] 0.018 Scan step time [s] 34.92 Measurement temperature [℃] 25.00 K-alpha 1 [Å] 1.54 K-alpha 2 [Å] 1.54 K-beta [Å] 1.39 Rotation Yes and wherein at least two X-ray diffraction peaks selected from 7.3±0.1, 13.2±0.1, 14.6±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two-theta (°θ) are observed when the composition is obtained using measurement conditions including:

[0044]

[0050] In some embodiments, when the X-ray diffraction pattern of the crystalline form is obtained using the above measurement conditions, X-ray diffraction peaks at 7.3±0.1, 14.6±0.1, 18.0±0.1, 22.4±0.1, and 24.4±0.1 degrees two-theta (°θ) are observed.

[0045]

[0051] In some embodiments, when the X-ray diffraction pattern of the crystalline form is obtained using the measurement conditions described above, X-ray diffraction peaks at 7.3±0.1, 11.1±0.1, 14.6±0.1, 18.0±0.1, 19.2±0.1, 22.4±0.1, 23.2±0.1, and 24.4±0.1 degrees two-theta (°θ) are observed.

[0046]

[0052] In some embodiments, when the X-ray diffraction pattern of the crystalline form is obtained using the measurement conditions described above, X-ray diffraction peaks at 7.3±0.1, 11.0±0.1, 11.1±0.1, 11.5±0.1, 13.2±0.1, 14.6±0.1, 15.2±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 19.2±0.1, 20.2±0.1, 21.4±0.1, 22.4±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two-theta (°θ) are observed.

[0047]

[0053] In some embodiments, when an X-ray diffraction pattern of the crystalline form is obtained using the measurement conditions described above, X-ray diffraction peaks substantially as shown in FIG. 6 are observed.

[0048]

[0054] In some embodiments, the X-ray diffraction (XRD) pattern comprises at least two diffraction peaks selected from 7.3±0.1, 13.2±0.1, 14.6±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two-theta (°θ). In some embodiments, the X-ray diffraction (XRD) pattern comprises at least three diffraction peaks selected from 7.3±0.1, 13.2±0.1, 14.6±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two-theta (°θ). In some embodiments, the X-ray diffraction (XRD) pattern comprises at least four diffraction peaks selected from 7.3±0.1, 13.2±0.1, 14.6±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two-theta (°θ). In some embodiments, the X-ray diffraction (XRD) pattern comprises at least five diffraction peaks selected from 7.3±0.1, 13.2±0.1, 14.6±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two-theta (°θ). In some embodiments, the X-ray diffraction pattern includes a peak at 7.3±0.1 degrees two theta (°θ).

[0049]

[0055] In some embodiments, the crystalline form is characterized by an X-ray diffraction (XRD) pattern comprising diffraction peaks at 7.3±0.1, 14.6±0.1, 18.0±0.1, 22.4±0.1, and 24.4±0.1 degrees two-theta (°θ).

[0050]

[0056] In some embodiments, the crystalline form is characterized by an X-ray diffraction (XRD) pattern comprising diffraction peaks at 7.3±0.1, 11.1±0.1, 14.6±0.1, 18.0±0.1, 19.2±0.1, 22.4±0.1, 23.2±0.1, and 24.4±0.1 degrees two theta (°θ).

[0051]

[0057] In some embodiments, the crystalline form is characterized by an X-ray diffraction (XRD) pattern comprising diffraction peaks at 7.3±0.1, 11.0±0.1, 11.1±0.1, 11.5±0.1, 13.2±0.1, 14.6±0.1, 15.2±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 19.2±0.1, 20.2±0.1, 21.4±0.1, 22.4±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two-theta (°θ).

[0052]

[0058] In some embodiments, the crystalline form is characterized by an X-ray diffraction (XRD) pattern substantially as shown in Figure 6. Form 2 is characterized by an X-ray diffraction (XRD) pattern substantially as shown in Table 2.

[0053] [Table 2]

[0054]

[0059] In some embodiments, a composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein the melting point of the crystalline form is between 208 and 210° C. (T) when obtained by (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C., and (b) increasing the temperature of the temperature controlled chamber at about 10° C. / min to 250° C. using a differential scanning calorimeter instrument. onset Compositions are provided herein that provide a melting point of 0.01 to 0.01 mm. The differential scanning calorimetry instrument can be, for example, a DSC Q1000 or a DSC Q2000.

[0055]

[0060] In some embodiments, provided herein are compositions comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein the crystalline form is characterized by a differential scanning calorimetry (DSC) profile substantially as depicted in Figure 7. In some embodiments, the crystalline form has a T onset As shown in FIG. 7, an exemplary sample of the crystalline form has a melting point of T onset : 209.5℃, T peak : 210.7°C (melt / decomposition).

[0056]

[0061] In some embodiments, the crystalline form is further characterized by a thermogravimetric analysis (TGA) profile. In some embodiments, provided herein is a composition comprising crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate, wherein when a thermogravimetric analysis of the crystalline form is obtained by (a) equilibrating a sample of the crystalline form at 25° C. in a temperature controlled chamber, and (b) increasing the temperature to 250° C. at a scan rate of about 10° C. / min using a thermogravimetric analyzer, a thermogravimetric profile substantially as shown in FIG. 8 is obtained. In some embodiments, the loss of mass before melt decomposition is about <0.1%. In some embodiments, the crystalline form is not hygroscopic. The thermogravimetric analyzer can be, for example, a TGAQ5000.

[0057]

[0062] In some embodiments, provided herein is a composition comprising crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt, the crystalline form of which is characterized by a thermogravimetric analysis profile substantially as shown in FIG.

[0058]

[0063] In some embodiments, the crystalline form is further characterized by a Dynamic Vapor Sorption (DVS) profile. In some embodiments, a composition comprising crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate, wherein the Dynamic Vapor Sorption profile of the crystalline form is determined by: (a) equilibrating a sample of the crystalline form at 25° C. and 50% relative humidity in a temperature and humidity controlled chamber until the mass fluctuation is less than 0.002% per minute for 6 hours; (b) increasing the relative humidity from 50% to 90% at a rate of 10% per hour; and (c) increasing the sample to 25° C. and 50% relative humidity until the mass fluctuation is less than 0.002% per minute for 6 hours. Provided herein is a composition which, when obtained by: (a) equilibrating the sample at 90% relative humidity until a mass change of less than 0.002% per minute is observed for 6 hours; (b) decreasing the relative humidity from 90% to 0% at a rate of 10% per hour; (c) equilibrating the sample at 0% relative humidity until a mass change of less than 0.002% per minute is observed for 6 hours; and (d) increasing the relative humidity from 0% to 50% at a rate of 10% per hour, results in a dynamic vapor sorption profile substantially as shown in FIG. 9.

[0059]

[0064] In some embodiments, provided herein is a composition comprising crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt, wherein the crystalline form is characterized by a dynamic vapor sorption profile substantially as depicted in FIG.

[0060]

[0065] In some embodiments, the crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt is anhydrous. In some embodiments, the crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt is substantially anhydrous.

[0061] Comparison of Form 1 and Form 2

[0066] Form 1 and Form 2 can be distinguished, for example, by the overlay of XRD analyses shown in Figure 11. Top: Form 1. Bottom: Form 2. Form 1 includes unique peaks at at least 9.8±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 17.4±0.1, 18.9±0.1, 19.6±0.1, 22.1±0.1, 26.6±0.1, and 27.2±0.1 degrees two-theta (°θ). Form 2 includes unique peaks at at least 7.3±0.1, 13.2±0.1, 14.6±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and / or 28.6±0.1 degrees two theta (°θ).

[0062] Method of preparation

[0067] The present disclosure further deals with methods for preparing the polymorphs described herein.

[0063]

[0068] In some embodiments, the present disclosure provides a method for synthesizing a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, comprising the steps of: a. reacting 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or an ionized form thereof, with fumaric acid in the presence of isopropanol to produce a reaction mixture, the reaction mixture including a precipitate; b. isolating the precipitate from a; and c. isolating the precipitate from b. with isopropanol. and drying the precipitate from dc to obtain particles, the particles comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, the melting point of the crystalline form being between 201 and 203° C. (T) when obtained by (a) equilibrating a sample of the crystalline form in a temperature controlled chamber at a temperature of about 20° C., and (b) increasing the temperature of the temperature controlled chamber to 250° C. at a scan rate of about 10° C. / min using a differential scanning calorimeter. onset) is obtained.

[0064]

[0069] In some embodiments, the present disclosure provides a method for the synthesis of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate comprising: a. reacting 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or an ionized form thereof with fumaric acid in the presence of isopropanol to produce a reaction mixture, wherein the reaction mixture comprises a precipitate; isolating the precipitate from ba; washing the precipitate from cb with isopropanol; and drying the precipitate from dc to obtain particles, wherein the particles comprise the crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0065]

[0070] In some embodiments, the present disclosure provides a method for synthesizing a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, comprising the steps of: a. reacting 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or an ionized form thereof, with fumaric acid in the presence of a mixture of dimethylsulfoxide (DMSO) and water to produce a reaction mixture, the reaction mixture comprising a precipitate; b. isolating the precipitate from; and c. isolating the precipitate from the precipitate from the reaction mixture. and drying the precipitate from dc to obtain particles, the particles comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, the melting point of which is between 208 and 210° C. (T) when obtained by (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C., and (b) increasing the temperature of the temperature controlled chamber to 250° C. at a scan rate of about 10° C. / min using a differential scanning calorimeter. onset ) is obtained.

[0066]

[0071] In some embodiments, the present disclosure provides a method for the synthesis of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate comprising: a. reacting 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid or an ionized form thereof with fumaric acid in the presence of a mixture of dimethylsulfoxide (DMSO) and water to produce a reaction mixture, wherein the reaction mixture comprises a precipitate; isolating the precipitate from ba; washing the precipitate from cb with water and acetone; and drying the precipitate from dc to obtain particles, wherein the particles comprise the crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0067]

[0072] In some embodiments, the method further comprises (i) cooling the reaction mixture produced in a. when (i) occurs prior to b. Cooling the reaction mixture comprises, for example, lowering the reaction temperature from about room temperature (about 25° C.) to less than about 15° C., or, for example, to less than about 15° C. or less than about 5° C.

[0068] particle size

[0073] In some embodiments, the size of the particles or the average particle size of a population of particles can be reduced to an appropriate value. The crystalline forms of 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt, Form 1 and Form 2, can be provided in micronized or non-micronized form. The formulations can be prepared to have desired characteristics, such as a desired range of particle sizes or a desired average particle size. The population of particles can have a particle size distribution in which a portion of the particles have a longest diameter that is shorter than each given value. The portion can be, for example, 90% by weight (D 90 ), 50% by mass (D 50 ), or 10% by mass (D 10 ).

[0069]

[0074] For example, the particle size can be reduced by grinding or polishing, or any other process that reduces the particle size. Impact grinding, such as pin grinding, results in higher blend uniformity for the final composition compared to other types of grinding. For example, liquid nitrogen is used to cool the material being ground during grinding to avoid heating the compound to undesirable temperatures. The D particle size during this grinding process can be reduced to, for example, about 100 μm or less or about 50 μm or less. For example, the ground form can have a D particle size of about 100 μm or less, about 95 μm or less, about 90 μm or less, about 85 μm or less, about 80 μm or less, about 75 μm or less, about 70 μm or less, about 65 μm or less, about 60 μm or less, about 55 μm or less, or about 50 μm or less. 90 For example, the pulverized form may be reduced to a particle size of about 50 μm to about 100 μm (i.e., 50 μm≦D 90 ≦100μm), about 50μm to about 90μm (i.e., 50μm≦D 90 ≦90μm), about 60μm to about 90μm (i.e., 60μm≦D 90 ≦90μm), about 70μm to about 90μm (i.e., 70μm≦D 90 ≦90μm), or about 80μm to about 90μm (i.e., 80μm≦D 90 D ≦90μm 90 The particle size can be reduced.

[0070]

[0075] Alternatively, the milled form has a D of about 50 μm or less, about 45 μm or less, about 40 μm or less, about 35 μm or less, about 30 μm or less, about 25 μm or less, about 20 μm or less, about 15 μm or less, or about 10 μm or less. 50 For example, the pulverized form may be reduced to a particle size of about 10 μm to about 50 μm (i.e., 10 μm≦D 50 ≦50μm), about 10μm to about 40μm (i.e., 10μm≦D 50 ≦40μm), about 10μm to about 30μm (i.e., 10μm≦D 50 ≦30 μm), and about 10 μm to about 20 μm (i.e., 10 μm≦D 50 D ≦20μm 50 The particle size can be reduced.

[0071]

[0076] In some embodiments, the particle size can be further reduced to obtain micronized particles having a particle size of about 10 μm or less, or about 1 to about 10 μm. Such micronized forms can have a D of about 10 μm or less, about 9 μm or less, about 8 μm or less, about 7 μm or less, about 6 μm or less, about 5 μm or less, about 4 μm or less, about 3 μm or less, about 2 μm or less, about 1 μm, or less than 1 μm. 90 For example, the micronized form can have a particle size of about 1 μm to about 10 μm (i.e., 1 μm≦D 90 ≦10μm), about 2μm to about 9μm (i.e., 2μm≦D 50 ≦9μm), about 5μm to about 9μm (i.e., 5μm≦D 90 ≦9μm), or about 1μm to about 5μm (i.e., 1μm≦D 90 D ≦5μm 90 The particle size can be reduced.

[0072]

[0077] Alternatively, the micronized form has a D of up to about 5 μm, up to about 4 μm, up to about 3 μm, up to about 2 μm, up to about 1 μm, or less than 1 μm. 50 For example, the micronized form may have a particle size of about 1 μm to about 10 μm (i.e., 1 μm≦D 50 ≦10μm), about 1μm to about 5μm (i.e., 1μm≦D 50 ≦5μm), and about 1μm to about 3μm (i.e., 1μm≦D 50 D ≦3μm 50 The particle size can be reduced.

[0073]

[0078] In some embodiments, the crystalline form comprises a population of particles, at least about 90% by weight of the particles have a diameter of about 20 microns or less. In some embodiments, the crystalline form comprises a population of particles, at least about 50% by weight of the particles have a diameter of 10 microns or less. In some embodiments, the crystalline form comprises a population of particles, at least about 50% by weight of the particles have a diameter of about 6.9 microns to about 9.75 microns.

[0074]

[0079] In some embodiments, the crystalline form comprises a population of particles, at least about 90% of the particles by weight have a diameter of about 90 microns or less. In some embodiments, the crystalline form comprises a population of particles, at least about 50% of the particles by weight have a diameter of about 30 microns or less. In some embodiments, the crystalline form comprises a population of particles, at least about 50% of the particles by weight have a diameter of about 10 microns to about 30 microns.

[0075] therapeutic use

[0080] The present disclosure provides crystalline polymorphic forms of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, Form 1 and Form 2, which can treat conditions, disorders, and diseases associated with, for example, the ryanodine receptor (RyR).

[0076]

[0081] In some embodiments, the present disclosure provides compounds that are RyR modulators, e.g., Rycal compounds. Rycal compounds are, for example, small molecules that can bind to leaky RyR subunits, restore calstabin binding, and repair channel leakage. In some embodiments, Rycal binds to leaky RyR channels, restores calstabin binding, and repairs channel leakage without blocking the RyR channel. In some embodiments, Rycal compounds can repair leakage of RyR channels, e.g., RyR1, RyR2, and / or RyR3 channels. In some embodiments, the crystal forms of the present disclosure enhance the association and / or inhibit dissociation of RyR and calstabins (e.g., RyR1 and calstabin1, RyR2 and calstabin2, and RyR3 and calstabin1).

[0077]

[0082] Non-limiting examples of RyR-related conditions, disorders, and diseases include disorders and diseases that can be treated and / or prevented by modulating RyR, such as cardiac disorders or diseases, musculoskeletal disorders or diseases, cancer-related muscle weakness, malignant hyperthermia, and diabetes. The compounds herein can also reduce the likelihood of such conditions occurring.

[0078]

[0083] Non-limiting examples of routes of administration of the compounds herein include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, and infusion), topical, and rectal administration. In some embodiments, the compounds and compositions described herein are administered orally.

[0079]

[0084] In some embodiments, the present disclosure provides a method of treating or preventing a medical condition by administering to a subject in need thereof a therapeutically effective amount of a composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, Form 1, or a pharmaceutical composition in unit dosage form comprising such a compound.

[0080]

[0085] In some embodiments, the present disclosure provides a method of treating or preventing a medical condition by administering to a subject in need thereof a therapeutically effective amount of a composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, Form 2, or a pharmaceutical composition in unit dosage form comprising such a compound.

[0081]

[0086] In some embodiments, the disclosure provides a therapeutically effective amount of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, Form 1, or a pharmaceutical composition in unit dosage form comprising such a compound, for use in a method of treating or preventing a medical condition.

[0082]

[0087] In some embodiments, the disclosure provides a therapeutically effective amount of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, Form 2, or a pharmaceutical composition in unit dosage form comprising such a compound, for use in a method of treating or preventing a medical condition.

[0083]

[0088] In some embodiments, the disclosure relates to the use of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, Form 1, or a pharmaceutical composition in unit dosage form comprising such a compound, for the manufacture of a medicament.

[0084]

[0089] In some embodiments, the disclosure relates to the use of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, Form 2, or a pharmaceutical composition in unit dosage form comprising such a compound, for the manufacture of a medicament.

[0085]

[0090] In some embodiments, the condition, disorder, or disease is associated with abnormal functioning of RyR1. In some embodiments, the condition, disorder, or disease is associated with abnormal functioning of RyR2. In some embodiments, the condition, disorder, or disease is associated with abnormal functioning of RyR3.

[0086]

[0091] In some embodiments, the condition is a cardiac disorder or disease. In some embodiments, the condition is a musculoskeletal disorder or disease. In some embodiments, the condition is cancer-related muscle weakness. In some embodiments, the condition is malignant hyperthermia. In some embodiments, the condition is diabetes.

[0087] Ryanodine receptors: the excitation-contraction coupling (ECC) process

[0092] The sarcoplasmic reticulum (SR) is, among other things, a specialized intracellular calcium (Ca 2+Ryanodine receptors (RyRs) are intracellular structures that function as Ca2+ stores. The ryanodine receptors (SRs) are channels that reside in the SR and open and close to control the release of Ca2+ from the SR into the intracellular cytoplasm. 2+ Release of cytoplasmic Ca 2+ The open probability of an RyR determines how many RyRs are open at any given moment, thus increasing the Ca concentration from the SR to the cytoplasm. 2+ This refers to the possibility of being able to release

[0088]

[0093] RyR is the major Ca receptor on the SR involved in excitation-contraction coupling (ECC) in striated muscles. 2+ RyR is a Ca release channel. Of the three known RyR isoforms (RyR1, RyR2, and RyR3), RyR1 is widely expressed and is the predominant isoform expressed in mammalian skeletal muscle, while RyR2 is also widely expressed and is the predominant form found in cardiac muscle. RyR3 expression is low in adult skeletal muscle. RyR subtypes show a high degree of structural and functional homology. The subtypes are Ca receptors that associate with proteins such as kinases, phosphatases, phosphodiesterases, and other regulatory subunits. 2+ It forms a large sarcoplasmic reticulum membrane complex consisting of four monomers that constitute the release channel.

[0089]

[0094] Ca from SR 2+ Release is regulated by several RyR-binding proteins. 2+ Calmodulin, a key mediator of signal transduction, exerts both positive and negative effects on RyR open probability. Calstabin1 (FKBP12) and calstabin2 (FKBP12.6) stabilize the closed states of RyR1 and RyR2, respectively. Calstabin1 associates primarily with skeletal muscle RyR1, whereas cardiac muscle RyR2 has the highest affinity for calstabin2.

[0090]

[0095] Mutations in RYR1 or RYR2 can cause decreased binding of calstabin1 and calstabin2, respectively. Stress-induced post-translational modifications of RyR, including PKA phosphorylation, oxidation, and nitrosylation, can also cause decreased binding of calstabins to the RyR channel. Genetic mutations and / or stress-induced post-translational modifications of the channel can cause dissociation of calstabins from RyR, rendering the channel leaky. Dissociation of calstabins can result in leaky channels that exhibit a pathological elevation of open probability at rest. SR Ca 2+ Leakage of SR Ca 2+ Ca content, resulting in a decrease in Ca available for release 2+ Intracellular calcium leak leads to different pathological consequences depending on which tissue is involved.

[0091] Ryanodine receptor 2 and heart disease

[0096] In some embodiments, the RyR-associated condition is a cardiac disorder or disease involving ryanodine receptor 2 (RyR2). RyR2 channels mediate Ca release from the sarcoplasmic reticulum (SR) of cardiomyocytes, which is required for ECC of the myocardium. 2+ RyR2 channels play a major role in intracellular calcium handling by controlling the release of calcium from the SR. The RyR2 channel is a macromolecular complex that contains four identical RyR2 subunits, each of which binds one calstabin2 (FKBP12.6), as well as other interacting proteins such as phosphatases and kinases. Calstabin2 binding stabilizes the channel in a closed state during cardiac rest (diastole), thereby preventing diastolic calcium leakage from the SR, and functionally couples groups of RyR2 channels during excitation-contraction coupling, allowing for coordinated opening.

[0092]

[0097] Phosphorylation of RyR2 by protein kinase A (PKA) is an important part of the fight-or-flight response. Phosphorylation regulates the release of Ca in response to a given trigger. 2+By increasing the amount of SR, it increases the increase in EC coupling in the heart, strengthening muscle contraction and improving exercise capacity in the process. This signaling pathway provides a mechanism by which the sympathetic nervous system (SNS) is activated in response to stress, increasing cardiac output. Phosphorylation of RyR2 by PKA increases the sensitivity of the channel to calcium-dependent activation. Increased sensitivity increases the open probability and increases calcium release from the SR into the intracellular cytoplasm.

[0093]

[0098] Heart failure (HF) is characterized by a persistent state of adrenergic hyperactivity in which serum catecholamine levels are chronically elevated. One consequence of this chronic state of adrenergic hyperactivity is persistent PKA hyperphosphorylation of RyR2, such that three to four of the four Ser2808s in each of the homotetrameric RyR2 channels are chronically phosphorylated. Chronic PKA hyperphosphorylation of RyR2 is associated with depletion of the channel-stabilizing subunit calstabin2 from the RyR2 channel macromolecular complex. Calstabin2 depletion results in the depletion of diastolic SR Ca from the RyR complex. 2+ This causes leakage and contributes to a decrease in contractile force. Due to the activation of the inward depolarizing current, this diastolic SR Ca 2+ Leakage is also associated with fatal cardiac arrhythmias. Indeed, mice engineered with RyR2 lacking PKA phosphorylation sites (RyR-S2808A) are protected from HF progression after myocardial infarction (MI). Furthermore, chronic PKA hyperphosphorylation of RyR2 in HF is associated with remodeling of the RyR2 macromolecular complex. The remodeling involves depletion of the phosphatases PP1 and PP2a from the RyR2 complex (which reduces the dephosphorylation of Ser2808) as well as depletion of cAMP-specific type 4 phosphodiesterase (PDE4D3). Depletion of PDE4D3 from the RyR2 complex causes a sustained elevation of local cAMP levels. Thus, diastolic SR Ca 2+ Leakage contributes to HF progression and arrhythmias. Further post-translational modifications of RyR channels (oxidation and nitrosylation) further promote leakage.

[0094]

[0099] RyR leakage is associated with various cardiac disorders, conditions, and diseases. In some embodiments, the cardiac disorder or disease is heart failure. In some embodiments, the cardiac disorder or disease is myocardial infarction (MI). In some embodiments, the cardiac failure is congestive heart failure. In some embodiments, the cardiac failure is chronic heart failure. In some embodiments, the cardiac failure is systolic heart failure. In some embodiments, the cardiac failure is diastolic heart failure. In some embodiments, the cardiac failure is acute decompensated heart failure. In some embodiments, the cardiac failure is heart failure with reduced or preserved ejection fraction. In some embodiments, the cardiac failure is acute cardiac failure, for example, for the maintenance of cardiac function after myocardial infarction or cardiomyopathy.

[0095]

[0100] In some embodiments, the cardiac injury or disease comprises cardiac ischemia / reperfusion (I / R) injury, which may occur after coronary angioplasty or thrombolysis for the treatment of myocardial infarction (MI), or during / after cardiac bypass surgery or cardiac transplantation.

[0096]

[0101] In some embodiments, the cardiac disorder or disease is characterized by an irregular heartbeat or arrhythmia. In some embodiments, the cardiac disorder or disease is catecholaminergic polymorphic ventricular tachycardia (CPTV). In some embodiments, the cardiac disorder or disease is, or is characterized by, atrial arrhythmia. In some embodiments, the cardiac disorder or disease is, or is characterized by, ventricular arrhythmia. In some embodiments, the cardiac disorder or disease is, or is characterized by, atrial fibrillation. In some embodiments, the cardiac disorder or disease is, or is characterized by, ventricular fibrillation. In some embodiments, the cardiac disorder or disease is, or is characterized by, atrial tachyarrhythmia. In some embodiments, the cardiac disorder or disease is, or is characterized by, ventricular tachyarrhythmia. In some embodiments, the cardiac disorder or disease is, or is characterized by, atrial tachycardia. In some embodiments, the cardiac disorder or disease is, or is characterized by, ventricular tachycardia. In some embodiments, the cardiac disorder or disease is or is characterized by sick sinus syndrome. In some embodiments, the cardiac disorder or disease is or is characterized by sudden infant death syndrome (SIDS). In some embodiments, the cardiac disorder or disease is or is characterized by sudden unexplained death (SUD).

[0097]

[0102] In some embodiments, the cardiac disorder or disease is catecholamine-induced polymorphic ventricular tachycardia (CPVT). CPVT is one of the most fatal inherited arrhythmogenic disorders. CPVT is characterized by adrenergic-mediated ventricular arrhythmias that occur in the absence of structural heart disease and are associated with a high incidence of sudden cardiac death (SCD). Patients usually present with stress-induced syncope in the first or second decade of life. CPVT is associated with mutations in two genes that code for proteins that associate with the sarcoplasmic reticulum (SR) of cardiomyocytes. The most frequently observed form is CPVT type 1, an autosomal dominant type caused by mutations in RyR2. This type codes for the intracellular SR calcium release channel. RyR2 mutations associated with CPVT result in leaky RyR2 channels due to reduced binding of calstabin2 (FKBP12.6) subunits, which stabilize the closed state of the channel. Mice heterozygous for the RyR2 R2474S mutation (which occurs in humans in CPVT1) (RyR2-R2474S mice) can exhibit exercise-induced ventricular arrhythmias and sudden cardiac death. Treatment with Rycal, which enhances binding of calstabin2 to mutant RyR2-R2474S channels, can inhibit channel leakage and prevent cardiac arrhythmias.

[0098] Ryanodine receptor 1 and musculoskeletal disorders

[0103] In some embodiments, the RyR-related pathology is a musculoskeletal disorder or disease involving ryanodine receptor 1 (RyR1). The RyR1 macromolecular complex consists of a tetramer of 560 kDa RyR1 subunits that form a scaffold for proteins that control channel function, including PKA and phosphodiesterase 4D3 (PDE4D3), protein phosphatase 1 (PP1) and calstabin1. Kinase anchor protein (mAKAP) guides PKA and PDE4D3 to RyR1, while spinophilin guides PP1 to the channel. The catalytic and regulatory subunits of PKA, PP1, and PDE4D3, control PKA-mediated phosphorylation of RyR1 at Ser2843 (Ser2844 in mice). PKA-mediated phosphorylation of RyR1 at Ser2844 promotes cytoplasmic Ca2+ It increases the sensitivity of the channel to α-terminal β-lactams, reduces the binding affinity of calstabin1 for RyR1, and destabilizes the closed state of the channel.

[0099]

[0104] Calstabin1 concentrations in skeletal muscle can be approximately 200 nM. PKA phosphorylation of RyR1 can reduce the binding affinity of calstabin1 for RyR1 from approximately 100-200 nM to over 600 nM. Thus, in physiological conditions, the reduction in the binding affinity of calstabin1 for RyR1 resulting from PKA phosphorylation at Ser2843 of RyR1 is sufficient to greatly reduce the amount of calstabin1 present in the RyR1 complex. Chronic PKA hyperphosphorylation of RyR1 at Ser2843 results in leaky channels (i.e., channels that tend to open at rest), which contributes to skeletal muscle dysfunction associated with persistent hyperadrenergic states such as those seen in individuals with heart failure.

[0100]

[0105] Furthermore, regulation of RyR1 by post-translational modifications other than phosphorylation, such as nitrosylation of free sulfhydryl groups on cysteine ​​residues (S-nitrosylation), and channel oxidation, can enhance RyR1 channel activity. S-nitrosylation and oxidation of RyR1 can each decrease calstabin1 binding to RyR1.

[0101]

[0106] In some embodiments, the musculoskeletal disorder or disease is a congenital myopathy or congenital muscular dystrophy (CMD). Congenital muscular dystrophies are present at birth. CMDs are classified based on genetic mutations: 1) genes that code for structural proteins of the basement membrane or extracellular matrix of skeletal muscle fibers, 2) genes that code for putative or proven glycosyltransferases that in turn affect the glycosylation of dystroglycan, an outer membrane protein of the basement membrane, and 3) others. Non-limiting examples of CMD include RYR1-related myopathy (RYR1-RM), laminin-α2-deficient CMD (MDC1A), Ullrich CMG (UCMD1, 2, and 3), Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), Fukuyama CMD (FCMD), CMD + secondary laminin deficiency 1 (MDC1B), CMD + secondary laminin deficiency 2 (MDC1C), CMD with mental retardation and macrogyrus (MDC1D), and stiff spine with muscular dystrophy type 1 (RSMD1).

[0102]

[0107] In some embodiments, the musculoskeletal disease is RYR1-related congenital myopathy (RYR1-RM). RYR1-RM comprises a group of rare neuromuscular diseases. Affected individuals generally exhibit delayed motor milestones, muscle weakness, decreased gait, and in severe cases, scoliosis, ophthalmoplegia, and respiratory distress, all due to skeletal muscle weakness. The main calcium (Ca) deficiency syndrome in skeletal muscle is 2+ Causative variants in RYR1, which encodes a Ca release channel, have different effects on the RyR1 channel. The variants generally disrupt normal Ca transport between the sarcoplasmic reticulum (SR) and muscle cell cytoplasm. 2+ This disrupts the flow of Ca, which normally allows excess Ca into the cytoplasm. 2+ Sustained Ca leakage 2+ Leakage of SR Ca required for ECC 2+ Furthermore, chronic SR Ca 2+ Leakage leads to mitochondrial calcium overload, which impairs mitochondrial function and is manifested as oxidative overload and reduced ATP production. SR Ca 2+Leakage can also activate the calcium-activated protease calpain, which can cause cell damage. In turn, oxidative stress can deplete the Ca2+ receptors in RyR1 by oxidizing and nitrosylating the channel. 2+ This may further contribute to leakage.

[0103]

[0108] In some embodiments, the musculoskeletal disorder or disease is muscular dystrophy.Non-limiting examples of muscular dystrophy include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral dystrophy, myotonic muscular dystrophy, congenital muscular dystrophy (CMD), distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, and oculopharyngeal muscular dystrophy.

[0104]

[0109] Duchenne muscular dystrophy (DMD) is one of the leading fatal genetic diseases of childhood. Dystrophin mutations associated with DMD result in a complete loss of dystrophin protein, which disrupts the link between the cytoskeleton and the extracellular matrix beneath the sarcolemma. This link is essential to protect and stabilize muscles against contraction-induced damage. Sarcolemmal instability due to dystrophin mutations has cascading effects. One of the main effects is the depletion of cytoplasmic Ca 2+ This is an increase in Ca 2+ This leads to activation of IL-1-dependent proteases (calpains). Another effect is inflammation and elevated iNOS activity, which can lead to oxidation / nitrosylation of proteins, lipids, and DNA. DMD muscle pathology is progressive and goes far beyond sarcolemmal instability. Thus, the pathology is consistent with sarcolemmal instability increasing susceptibility to further damage. Excessive oxidation or nitrosylation of RyR1 disrupts the interaction of calstabin1 with the RyR1 complex, resulting in RyR1 leakiness and muscle weakness. Treatment with Rycal improves indices of muscle function.

[0105]

[0110] In some embodiments, the musculoskeletal disorder or disease is cancer cachexia, i.e., cancer-related muscle weakness. In some embodiments, the cancer-related muscle weakness is cancer cachexia, for example, resulting from cancer with bone metastasis. Muscle weakness and muscle atrophy (cachexia) are common paraneoplastic conditions in cancer patients. These conditions cause significant fatigue and dramatically reduce the quality of life of patients. In certain cancers, for example, prostate and breast cancer with bone metastasis, RyR1 is oxidized and induced to become leaky. Repairing the leakiness by administering Rycal compounds improves muscle function. Non-limiting examples of cancers with cachexia that can be treated with the compounds herein include breast cancer, prostate cancer, bone cancer, pancreatic cancer, lung cancer, colon cancer, and gastrointestinal cancer. These conditions cause significant fatigue and dramatically reduce the quality of life of patients. The present disclosure provides methods for treating, preventing, and reducing the likelihood of developing muscle weakness in cancer patients, for example, based on the presence of modified (e.g., oxidative state of RyR1) that induces RyR1 to become leaky. Prevention of leakage by administration of Rycal compounds can improve muscle function.

[0106]

[0111] In some embodiments, the musculoskeletal condition or disease is age-related loss of muscle mass and strength (sarcopenia). Sarcopenia contributes to increased disability and mortality. RyR1 in aged mice may be oxidized, cysteine ​​nitrosylated, and depleted of calstabin1 compared to RyR1 in young (3-6 months) adults. Treatment of aged mice with Rycal stabilizes calstabin1 binding to RyR1, reduces intracellular calcium leak, reduces reactive oxygen species (ROS), and increases tetanic Ca2+ expression. 2+ may enhance release, muscle specific force, and athletic performance.

[0107]

[0112] In some embodiments, the crystalline polymorphs of the present disclosure are useful for treating type II diabetes by reducing the likelihood of intracellular calcium leak occurring through leaky RyR2. This leak causes mitochondrial calcium overload and reduces ATP production, which in turn reduces K ATP Decreased channel activation prevents cell membrane depolarization, which reduces activation of cell membrane voltage-gated calcium channels, the main source of calcium required for insulin secretion.

[0108] Pharmaceutical Compositions

[0113] The polymorphs of the present disclosure may be administered as is or as a pharmaceutical composition for administration to a human or animal subject in a biologically compatible form suitable for administration in vivo. The subject may be, for example, an older adult, an adult, an adolescent, a pre-adolescent, a child, a toddler, an infant, a neonate, and a non-human animal. In some embodiments, the subject is a patient.

[0109]

[0114] In some embodiments, the disclosure provides a pharmaceutical composition form comprising a unit dosage amount of crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate Form 1 in admixture with a pharma- ceutically acceptable excipient, diluent, and / or carrier. In some embodiments, the disclosure provides a pharmaceutical composition form comprising a unit dosage amount of crystalline 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate Form 2 in admixture with a pharma- ceutically acceptable excipient, diluent, and / or carrier.

[0110]

[0115] Non-limiting examples of routes of administration include oral, sublingual, buccal, parenteral (intravenous, intramuscular, or subcutaneous), transdermal, per- or trans-cutaneous, intranasal, intravaginal, rectal, ocular, and respiratory (by inhalation administration). Administration can be to the subject's muscle, for example, the subject's cardiac muscle or skeletal muscle. In some embodiments, the compound is administered to the subject by way of targeted delivery to cardiac muscle cells via a catheter inserted into the subject's heart. In some embodiments, the compound is administered orally.

[0111]

[0116] Pharmaceutical compositions for solid oral administration include tablets or dragees, sublingual tablets, gastro-resistant tablets, sachets, capsules including gelatin capsules, powders, and granules. Those for liquid oral, nasal, buccal, or ocular administration include emulsions, solutions, suspensions, drops, syrups, and aerosols. The compounds may also be administered as suspensions or solutions via drinking water or with food.

[0112]

[0117] Non-limiting examples of pharma- ceutically acceptable excipients or carriers include organic or inorganic materials used as ingredients in pharmaceutical formulations and incorporated as any one or more of the following: fillers, diluents, binders, disintegrants, lubricants, glidants, plasticizers, surfactants (wetting agents), buffers (pH adjusters), suspending agents, colorants, emulsifiers, flavor improvers, gelling agents, preservatives, solubilizers, stabilizers, sweeteners, isotonicity agents, dispersants, swelling agents, retardants, absorption agents, and / or viscosity enhancers.

[0113]

[0118] Non-limiting examples of pharma- ceutically acceptable fillers / diluents include microcrystalline cellulose, silicified microcrystalline cellulose, carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose derivatives including ethylcellulose, starch, sugars such as mannitol, sucrose, lactose, sorbitol, dextrins (e.g., maltodextrin), and amino sugars.

[0114]

[0119] Non-limiting examples of pharma- ceutically acceptable binders include microcrystalline cellulose, gum tragacanth, gelatin, polyvinylpyrrolidone, copovidone, hydroxypropyl methylcellulose, and starch.

[0115]

[0120] Non-limiting examples of pharma-ceutically acceptable disintegrants include croscarmellose sodium, sodium carboxymethyl starch, and crospovidone.

[0116]

[0121] Non-limiting examples of pharma-ceutically acceptable lubricants include stearates, such as magnesium stearate or zinc stearate, stearic acid, sodium stearyl fumarate, talc, glyceryl behenate, sodium lauryl sulfate, polyethylene glycol, and hydrogenated vegetable oils.

[0117]

[0122] Non-limiting examples of pharma- ceutically acceptable glidants include colloidal silicon dioxide, talc, tricalcium phosphate, calcium silicate, cellulose, magnesium silicate, magnesium trisilicate, starch, magnesium stearate, talc, and mineral oil.

[0118]

[0123] A non-limiting example of a moisture barrier agent includes stearic acid.

[0119]

[0124] A non-limiting example of a pharma-ceutically acceptable plasticizer includes triethyl citrate.

[0120]

[0125] Non-limiting examples of pharma- ceutically acceptable surfactants include sodium lauryl sulfate or polysorbates, polyvinyl alcohol (PVA), polyethylene glycols, polyoxyethylene-polyoxypropylene block copolymers known as "poloxamers", polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate (Tween), polyethylene glycol fatty acid esters such as polyoxyethylene monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, and hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil.

[0121]

[0126] Non-limiting examples of pharma- ceutically acceptable flavoring agents include sweeteners such as sucralose and synthetic flavor oils and flavoring aromatics, natural oils, extracts from plants, leaves, flowers, and fruits, and combinations thereof.Non-limiting examples of flavoring agents include cinnamon oil, wintergreen oil, peppermint oil, clover oil, hay oil, anise oil, eucalyptus, peppermint, vanilla, citrus oils such as lemon oil, orange oil, grape and grapefruit oil, and fruit essences such as apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0122]

[0127] Non-limiting examples of pharma- ceutically acceptable pigments or colorants include alumina (dried aluminum hydroxide), annatto extract, calcium carbonate, canthaxanthin, caramel, beta-carotene, cochineal extract, carmine, sodium potassium copper chlorophyllin (chlorophyllin-copper complex), dihydroxyacetone, bismuth oxychloride, synthetic iron oxide, ferric ammonium ferrocyanide, ferric ferrocyanide, chromium hydroxide green, chromium oxide green, guanine, mica-based pearlescent pigments, pyrophyllite, mica, dentifrice, talc, titanium dioxide, aluminum powder, bronze powder, copper powder, and zinc oxide.

[0123]

[0128] Non-limiting examples of buffers or pH adjusters include acidic buffers such as short chain fatty acids, citric acid, acetic acid, hydrochloric acid, sulfuric acid, and fumaric acid, and basic buffers such as Tris, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and magnesium hydroxide.

[0124]

[0129] Non-limiting examples of tonicity enhancing agents include ionic and non-ionic agents, such as alkali metal or alkaline earth metal halides, urea, glycerol, sorbitol, mannitol, propylene glycol, and dextrose.

[0125]

[0130] Non-limiting examples of humectants include glycerin, cetyl alcohol, and glycerol monostearate.

[0126]

[0131] Non-limiting examples of preservatives include benzalkonium chloride, benzoxonium chloride, thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenyl alcohol, chlorhexidine, and polyhexamethylene biguanide.

[0127]

[0132] Non-limiting examples of antioxidants include sorbic acid, ascorbic acid, ascorbate, glycine, α-tocopherol, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).

[0128]

[0133] In some embodiments, the solid dosage form is coated. In some embodiments, the solid dosage form comprises a core, a subcoating layer substantially surrounding the core, and a coating layer substantially surrounding the subcoating layer.

[0129]

[0134] In some embodiments, the subcoating layer comprises a swellable hydrophobic polymer layer (e.g., a swellable polymer such as hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose (HPMC).

[0130]

[0135] In some embodiments, the coating layer comprises an enteric polymer. Non-limiting examples of enteric polymers include hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate, HPMC-AS), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, methacrylic acid / methacrylic acid ester copolymers (e.g., poly(methacrylic acid-co-methyl methacrylate), methacrylic acid / acrylic acid ester copolymers, shellac (esters of aleurtic acid).

[0131]

[0136] In some embodiments, pharma- ceutically acceptable carriers or excipients are used to formulate liquids, gels, syrups, elixirs, slurries, or suspensions for oral ingestion by subjects.Non-limiting examples of solvents used in oral dissolution formulations may include water, ethanol, isopropanol, saline, saline, DMSO, potassium phosphate buffer, phosphate buffered saline (PBS), sodium phosphate buffer, 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC).Non-limiting examples of co-solvents used in oral dissolution formulations may include sucrose, urea, cremaphor, and potassium phosphate buffer.

[0132]

[0137] Pharmaceutical compositions for parenteral injection may also include sterile solutions, dispersions, suspensions, emulsions, which may be aqueous or non-aqueous, and sterile powders for reconstitution of injectable solutions or dispersions. The polymorph may be combined with a sterile aqueous solution that is isotonic with the blood of the subject. The formulation is provided in a unit dose or multi-dose container, such as a sealed ampoule or vial. The formulation is delivered by any mode of injection, including, but not limited to, epifascial, intra-articular, intracranial, intradermal, intrathecal, intramuscular, intraorbital, intraperitoneal, intraspinal, intrasternal, intravascular, intravenous, intraparenchymal, subcutaneous, or sublingual, or by means of a catheter into the heart of the subject.

[0133]

[0138] Pharmaceutical compositions for rectal or vaginal administration may be suppositories, and those for per- or trans-cutaneous administration include powders, aerosols, creams, ointments, gels, and patches.

[0134]

[0139] For transdermal administration, the compound may be combined with a skin penetration enhancer, such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, or N-methylpyrrolidone. These agents increase the permeability of the skin, allowing the compound to penetrate through the skin and into the bloodstream. The compound / enhancement composition may be further combined with a polymeric substance, such as ethyl cellulose, hydroxypropyl cellulose, ethylene / vinyl acetate, or polyvinylpyrrolidone, to provide a composition in the form of a gel, which is dissolved in a solvent, evaporated to a desired viscosity, and applied to a backing material to provide a patch.

[0135]

[0140] The pharma- ceutically acceptable excipient can be present in the pharmaceutical composition at a mass of about 0.1% to about 99% by mass of the composition. For example, the pharma- ceutically acceptable excipient can be present in the pharmaceutical composition at a mass of about 0.1% to about 95% by mass, about 0.11% to about 90% by mass, about 0.1% to about 85% by mass, about 0.1% to about 80% by mass, about 0.1% to about 75% by mass, about 0.1% to about 70% by mass, about 0.1% to about 65% by mass, about 0.1% to about 60% by mass, about 0.1% to about 55% by mass, about 0.1% to about 50% by mass, or the like. %, about 0.1% to about 45% by mass, about 0.11% to about 40% by mass, about 0.1% to about 35% by mass, about 0.1% to about 30% by mass, about 0.1% to about 25% by mass, about 0.1% to about 20% by mass, about 0.1% to about 15% by mass, about 0.1% to about 10% by mass, about 0.1% to about 5% by mass, or about 0.1% to about 1% by mass.

[0136]

[0141] Pharmaceutically acceptable excipients can be present in about 0.1% by mass, 0.2% by mass, 0.3% by mass, 0.4% by mass, 0.5% by mass, 0.6% by mass, 0.7% by mass, 0.8% by mass, 0.9% by mass, 1% by mass, about 2% by mass, about 3% by mass, about 4% by mass, about 5% by mass, about 6% by mass, about 7% by mass, about 8% by mass, about 9% by mass, about 10% by mass, about 11% by mass, about 12% by mass, about 13% by mass, about 14% by mass, about 15% by mass, about 16% by mass, about 17% by mass, about 18% by mass, about 19% by mass, about 20% by mass, about 21% by mass, about 22% by mass, about 23% by mass, about 24% by mass, about 25% by mass, about 26% by mass, about 27% by mass, about 28% by mass, about 29% by mass, about 30% by mass, about 31% by mass, about 32% by mass, about 33% by mass, about 34% by mass, about 35% by mass, about 36% by mass, about 37% by mass, about 38% by mass, about 39% by mass, about 40% by mass, about 41% by mass, about 42% by mass, about 43% by mass, about 44% by mass, about 45% by mass, about 46% by mass, about 47% by mass, about 48% by mass, about 49% by mass, about 50% by mass, about 51% by mass, about 52% by mass, about 53% by mass, about 54% by mass, about 55% by mass, about 56% by mass, about 57% by mass, about 58% by mass, about 59% by mass, about 60% by mass, about 61% by mass, about 62% by mass, about 63% by mass, about 64% by mass, about 65% by mass, about 66% by mass, about 67% by mass, about 68% by mass, about 69% by mass, about 70% by mass, about 71% by mass, about 72% by mass, about 73% by mass, about 74% by mass, about 75% by mass, about 76% by mass, about 77% by mass, about 78% by mass, about 79% by mass, about 80% by mass, about 81% by mass, about 82% by mass, about 83% by mass, about 84% by mass, about 85% by mass, about 86% by mass, about 87% by mass, about 88% by mass, about 89% by mass, about 90% by mass, about 91% by mass, about 92% by mass, about 93% by mass, about 94% by mass, about 95% by mass, about 96% by mass, about 97% by mass, about 98% by mass, about 99% by mass, about 99.1% by mass, about 99.2% by mass, about 99.3% by mass, about 99.4% by mass, about 99.5% by mass, about 99.6% by mass, about 99.7% by mass, about 99.8% by mass, or about 99.9% by mass of the formulation.

[0137]

[0142] According to the methods of the present disclosure, any of these compounds can be administered to a subject (or contacted with a cell of a subject) in an amount effective to limit or prevent a decrease in the level of RyR-bound calstabins in the subject, particularly in the cells of the subject. Alternatively, the methods of the present disclosure include administering a compound in an amount effective to treat or prevent an RyR-associated condition described herein.

[0138]

[0143] In some embodiments, a suitable amount of a compound effective to limit or prevent a decrease in the level of RyR-bound calstabins in a subject and / or treat or prevent an RyR-related condition is in the range of about 100 to about 500 mg per day, e.g., about 100 mg per day, about 120 mg per day, about 140 mg per day, about 160 mg per day, about 180 mg per day, about 200 mg per day, about 250 mg per day, about 300 mg per day, about 350 mg per day, about 400 mg per day, about 450 mg per day, about 500 mg per day, about 500 mg per day, about 600 mg per day, about 700 mg per day, about 800 mg per day, about 900 mg per day, about 1000 mg per day, about 1100 mg per day, about 120 mg per day, about 140 mg per day, about 160 mg per day, about 180 mg per day, about 190 mg per day, about 200 mg per day, about 300 mg per day, about 400 mg per day, about 500 mg per day, about 600 mg per day, about 700 mg per day, about 800 mg per day, about 900 mg per day, about 1000 mg per day, about 1100 mg per day, about 120 mg per day, about 140 mg per day, about 160 mg per day, about 180 mg per day, about 190 mg per day, about 200 mg per day, about 300 mg per day, about 350 mg per day, about 400 mg per day, about 400 mg per day, about 500 mg per day, about 500 mg per day, about 600 mg per day, about 700 mg per day, about 80 mg per day, about 220 mg per day, about 240 mg per day, about 260 mg per day, about 280 mg per day, about 300 mg per day, about 320 mg per day, about 340 mg per day, about 360 mg per day, about 380 mg per day, about 400 mg per day, about 420 mg per day, about 440 mg per day, about 460 mg per day, about 480 mg per day, or about 500 mg per day.

[0139]

[0144] The compounds described herein may be present in the composition in an amount of from about 1 mg to about 2000 mg; from about 1 mg to about 1000 mg; from about 1 mg to about 500 mg; from about 5 mg to about 1000 mg, from about 5 mg to about 500 mg, from about 5 mg to about 100 mg, from about 10 mg to about 50 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, It may be present in the range of 300 mg to about 350 mg, about 350 mg to about 400 mg, about 400 mg to about 450 mg, about 450 mg to about 500 mg, about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1000 mg.

[0140]

[0145] The compounds described herein may be present in a composition in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg , about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg.

[0141]

[0146] In some embodiments, the dose may be expressed as the amount of drug divided by the mass of the subject, e.g., milligrams of drug per kilogram of subject body weight. In some embodiments, the compound is administered in an amount ranging from about 5 mg / kg to about 50 mg / kg, about 250 mg / kg to about 2000 mg / kg, about 10 mg / kg to about 800 mg / kg, about 50 mg / kg to about 400 mg / kg, about 100 mg / kg to about 300 mg / kg, or about 150 mg / kg to about 200 mg / kg.

[0142]

[0147] In some embodiments, the therapeutically effective dose is about 100 mg to about 200 mg per day. In some embodiments, the therapeutically effective dose is 200 mg per day. In some embodiments, the therapeutically effective dose is 120 mg per day. EXAMPLES

[0143] Example 1 Preparation of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid

[0148] 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid was prepared as described below.

[0144]

[0149] Step 1: 7-Methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine ("amine")

[0145] [ka]

[0146] 2-(4-Methoxyphenylthio)ethanamine (1)

[0150] 4-Methoxythiophenol (50 g, 0.357 mol), 2-chloroethylamine monohydrochloride (39.8 g, 0.343 mol), K 2 CO 3(78.8 g, 0.57 mol), and diisopropylethylamine (32 mL, 0.178 mol) were mixed in tetrahydrofuran (THF). The mixture was degassed under reduced pressure for 5 minutes and heated at reflux under argon overnight. The solvent was removed and water was added to the flask. The mixture was extracted with dichloromethane. The organic layer was collected, the dichloromethane was removed, concentrated HCl was added, and then water was added. The solution was extracted with 1:1 ethyl acetate (EtOAc) / hexanes. The aqueous layer was adjusted to pH 10 with 2M NaOH and extracted with dichloromethane. The combined organic solution was dried over anhydrous sodium sulfate. The solvent was removed to give the target compound.

[0147] Benzyl 2-(4-methoxyphenylthio)ethylcarbamate (2)

[0151] Benzyl chloroformate (8.2 g, 48.1 mmol, diluted in 100 mL dichloromethane) was added dropwise at 0° C. to a flask containing compound 1 (8.0 g, 43.7 mmol), sodium bicarbonate (12.1 g, 144 mmol), water, and dichloromethane. After the addition, the mixture was stirred at rt for 5 h. The organic layer was collected and the aqueous solution was extracted with 100 mL dichloromethane. The combined organic solution was dried over sodium sulfate. The solvent was removed and the resulting solid was triturated with THF / hexane (1:10). The solid was collected and dried to leave the target product.

[0148] Benzyl 7-methoxy-2,3-dihydrobenzo[f][1,4]thiazepine-4(5H)-carboxylate (3)

[0152] A mixture of compound 2 (7.3 g, 23 mmol), paraformaldehyde (6.9 g 0.23 mol), and p-toluenesulfonic acid (1.45 g, 7.6 mmol) in toluene was stirred at 70 °C overnight. After cooling to rt, the solid was filtered off. The solution was extracted with saturated sodium carbonate, the organic layer was dried over anhydrous sodium sulfate, and the target product was obtained as a liquid after removal of the solvent.

[0149] 7-Methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine hydrobromide (amine)

[0153] Compound 3 (10 g, 30 mmol) was mixed with concentrated HCl, water, and dioxane. The mixture was stirred at 100° C. overnight. After cooling to room temperature, the solvent and most of the HCl were removed under reduced pressure. Water was added to the solution and the solid was filtered off. The aqueous solution was extracted with EtOAc / Hexane (1:1) and basified by adding 15 g of NaOH. The mixture was extracted with dichloromethane. The combined solution was dried over anhydrous sodium sulfate. The solvent was removed to give a liquid that solidified after standing at room temperature (rt) to give the target compound.

[0150]

[0154] Stage 2: -[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid

[0151] [ka]

[0152]

[0155] In Scheme 2, L is a leaving group, which may be, for example, a halogen or a sulfonate (OSO where R′ is alkyl or aryl). 2 R' is, for example, OMs (mesylates) or OTs (tosylates). Amine (4) (1 mmol) was dissolved in dichloromethane. To the solution was added alkylating reagent (5) (1 mmol), followed by N,N-diisopropylethylamine (2 mmol). The mixture was stirred at room temperature overnight. The solution was directly loaded onto a silica gel column and eluted with hexane / EtOAc (2:1, v / v) to give the desired product.

[0153] Example 2 Preparation of 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate-Form 1

[0156] 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid was prepared similarly to Example 1. To form the hemifumarate salt, 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid was salified with fumaric acid in the presence of isopropanol as depicted in Scheme 3. After cooling, the resulting product was filtered and washed with isopropanol to give the title product.

[0154] [ka]

[0155]

[0157] Form 1 can optionally be ground to a particle size distribution as set forth in Table 3.

[0156] [Table 3]

[0157] Example 3 Preparation of 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate-form 2

[0158] 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid was prepared similarly to Example 1. To form the hemifumarate salt, 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid was salified with fumaric acid in the presence of a mixture of dimethylsulfoxide and water as depicted in Scheme 4. After cooling, the resulting product was filtered and washed with water and acetone to obtain the desired product.

[0158] [ka]

[0159] Form 2 can optionally be ground to the particle size distribution set forth in Table 4.

[0160] [Table 4]

[0161] Example 4 Stability of 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate Form 1 and Form 2 As shown in Figure 5, Form 1 was stable after 24 months. The top panel shows the starting polymorph and the bottom three panels show the polymorph after 24 months. Figure 5 Panel A: Initial control; Figure 5 Panel B: Sample stored in an open bottle in a stability chamber at 25°C / 60% relative humidity (RH) for 2 years; Figure 5 Panel C: Sample stored in a closed bottle in a stability chamber at 40°C / 75% RH for 2 years; Figure 5 Panel D: Sample stored in an open bottle in a stability chamber at 40°C / 75% RH for 2 years;

[0161] As shown in Figure 10, Form 2 was stable after 24 months. The top panel shows the starting polymorph, and the bottom panel shows the polymorph after 3, 6, 12, and 24 months.

[0162] Competitive slurry experiments were performed at 15° C. (Table 5) or 40° C. (Table 6) by mixing Form 1 and Form 2 in various solvents in acetonitrile / water, acetone / water, and methanol / water mixtures. In methanol / water mixtures, Form 1 and Form 2 slurries converted to the methanol solvate at all solvent mixing ratios tested at 15° C. or 40° C., except for methanol / water (20 / 80 v / v), where a mixture of Form 2 and the methanol solvate (Form 3) was observed. In acetonitrile / water mixtures, Form 1 and Form 2 slurries converted to the acetonitrile solvate (Form 4) at all solvent mixing ratios tested at 15° C. (Table 5) or 40° C. (Table 6). In acetone / water mixtures, Form 1 and Form 2 slurries converted to Form 2 at all tested conditions. From the results, water, acetone, or water / acetone mixtures yielded crystalline Form 2.

[0163] [Table 5]

[0164] [Table 6]

[0165] In these experiments, Form 2 was more stable than Form 1. DSC analysis showed that Form 2 had a higher melting point and a higher enthalpy of fusion than Form 1 (compare Figures 2 and 7), supporting the conclusion that Form 2 is more stable than Form 1. However, Form 1 can be stored for at least 24 months without any detectable conversion to Form 2 (Figure 5).

[0166] Example 5 Stability of 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate form 2

[0164] The stability of 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate Form 2 was evaluated for up to 24 months under various conditions. The results are shown in Tables 7-10.

[0167]

[0165]

[0168] [Table 7]

[0169]

[0166]

[0170] [Table 8]

[0171]

[0167]

[0172] [Table 9]

[0173]

[0168]

[0174] [Table 10]

[0175] Example 6 method

[0169] XRD: The measurement conditions are listed in Table 11.

[0176] [Table 11]

[0177]

[0170] Peak search Peak searches were performed using Highscore Plus v4.6. The following parameters were applied for the automatic peak search: - Minimum significance = '1' - Minimum tip width = "0.01" - Maximum tip width = "1" - Peak Base Width = "2" - method = "Smoothed Peak Top"

[0171] After performing a default profile fit, undetected peaks were manually added, after which the default profile fit was performed again.

[0178] proofreading

[0172] Calibration and validation of the XRD instrument was performed once a year with a full validation in reflection mode and a linearity check in transmission mode.

[0179] Performance check in reflection mode Linearity: Performed using a Panalytical 640 silicon tablet reference sample at the following angles: 28.441°, 47.300°, 56.119°, 69.126°, 76.372°, 88.025°, 94.946°, 106.701°, and 114.083° 2-theta. Linearity coefficient was less than or equal to 0.03° 2-theta.

[0180] Quantitative analysis: performed using NIST sintered alumina disks (waserformed) at the following angles: 25.6°, 35.1°, 43.4°, 52.5°, 57.5°, 76.9°, and 77.2°, 89.0°, and 101.1° 2-theta. The relative intensity of each diffraction peak was less than 14% compared to the theoretical value given by NIST.

[0181] Resolution: Performed using a NIST sintered alumina disk at the following angle: 57.5° 2-theta. Results were within 0.09° 2-theta.

[0182] Linearity check in transmission mode: performed using NIST silicon powder reference at the following angles: 28.441°, 47.300°, 56.119°, 69.126°, and 76.372° 2-theta. Linearity coefficient was less than or equal to 0.03° 2-theta.

[0183] Thermal Analysis - Differential Scanning Calorimetry

[0177] Melting points were determined by differential scanning calorimetry (DSC) by (a) equilibrating a sample of the crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate at 20°C and (b) increasing the temperature at 10°C / min to 250°C using a DSC Q1000 or DSC Q2000 differential scanning calorimeter instrument.

[0184] Thermal analysis - thermogravimetric analysis Thermogravimetric analysis (TGA) was performed. A 10-20 mg sample of the crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate was placed in a nitrogen purged aluminum pan. The sample was equilibrated at 25° C. in a temperature controlled chamber. The sample was heated to 250° C. under a nitrogen purge at a scan rate of approximately 10° C. / min. A TGA Q5000 thermogravimetric analyzer was used.

[0185] Thermal Analysis – Dynamic Vapor Sorption Dynamic Vapor Sorption (DVS) analysis was performed by measuring the mass variation of the crystalline form of 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt as a function of relative humidity using a DVS specific instrument. A 5-10 mg sample of the crystalline form of 4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, hemifumarate salt was placed in the sample pan of the DVS specific instrument at 25° C. under humidity control. The mass variation was recorded as a function of relative humidity.

[0186]

[0180] The measurement of DVS involves (a) equilibrating a sample of the crystalline form at 25°C and 50% relative humidity in a temperature- and humidity-controlled chamber until a mass change of less than 0.002% per minute is observed for 6 hours; (b) increasing the relative humidity from 50% to 90% at a rate of 10% per hour; (c) equilibrating the sample at 90% relative humidity until a mass change of less than 0.002% per minute is observed for 6 hours; (d) decreasing the relative humidity from 90% to 0% at a rate of 10% per hour; (e) equilibrating the sample at 0% relative humidity until a mass change of less than 0.002% per minute is observed for 6 hours; and (f) increasing the relative humidity from 0% to 50% at a rate of 10% per hour.

[0187] Incorporation by Reference

[0181] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0188] Embodiment

[0182] Embodiment 1. A composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein the melting point of the crystalline form is: (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature-controlled chamber to 250° C. at a scan rate of approximately 10° C. / min. If it is obtained by 201 to 203°C (T onset ) the composition.

[0189]

[0183] Embodiment 2. The composition described in embodiment 1, wherein the crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate is characterized by a differential scanning calorimetry profile substantially as shown in Figure 2.

[0190]

[0184] Embodiment 3. The X-ray diffraction pattern of the crystalline form is Start position [°2θ] 3.00 End position [°2θ] 54.99 Step size [°2θ] 0.018 Scan step time [s] 34.92 Measurement temperature [℃] 25.00 K-alpha 1 [Å] 1.54 K-alpha 2 [Å] 1.54 K-beta [Å] 1.39 Rotation Yes 3. The composition of claim 1 or 2, wherein at least two X-ray diffraction peaks selected from 9.8±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 17.4±0.1, 18.9±0.1, 19.6±0.1, 22.1±0.1, 26.6±0.1, and 27.2±0.1 degrees two-theta (°θ) are observed when the composition is obtained using measurement conditions comprising:

[0191]

[0185] Embodiment 4. The composition described in embodiment 3, wherein X-ray diffraction peaks are observed at 9.8±0.1, 11.0±0.1, 17.4±0.1, 21.6±0.1, and 22.6±0.1 degrees two theta (°θ).

[0192]

[0186] Embodiment 5. A composition described in embodiment 3 or 4, wherein X-ray diffraction peaks are observed at 9.8±0.1, 11.0±0.1, 11.8±0.1, 15.0±0.1, 17.4±0.1, 21.6±0.1, 22.1±0.1, and 22.6±0.1 degrees two theta (°θ).

[0193]

[0187] A composition described in any one of embodiments 3 to 5, wherein X-ray diffraction peaks are observed at 9.8±0.1, 11.0±0.1, 11.4±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 15.0±0.1, 17.4±0.1, 18.9±0.1, 19.3±0.1, 19.6±0.1, 20.3±0.1, 21.6±0.1, 22.1±0.1, 22.6±0.1, 26.6±0.1, and 27.2±0.1 degrees two theta (°θ).

[0194]

[0188] Embodiment 7. The composition according to any one of embodiments 3 to 6, which exhibits X-ray diffraction peaks substantially as shown in FIG.

[0195]

[0189] Embodiment 8. Thermogravimetric analysis of a crystalline form is (a) equilibrating a sample of said crystalline form at 25° C. in a temperature controlled chamber; and (b) Using a thermogravimetric analyzer, increase the temperature to 250°C at a scan rate of approximately 10°C / min. 8. The composition of any one of embodiments 1-7, which, when obtained by, results in a thermogravimetric analysis profile substantially as shown in FIG.

[0196]

[0190] Embodiment 9. The dynamic vapor sorption profile of a crystalline form is (a) equilibrating a sample of said crystalline form at 25° C. and 50% relative humidity in a temperature and humidity controlled chamber until a mass variation of less than 0.002% per minute is obtained for 6 hours; (b) increasing the relative humidity from 50% to 90% at a rate of 10% per hour; (c) equilibrating the sample at 90% relative humidity until a mass variation of less than 0.002% per minute is obtained for 6 hours; (d) decreasing the relative humidity from 90% to 0% at a rate of 10% per hour; (e) equilibrating the sample at 0% relative humidity until a mass fluctuation of less than 0.002% per minute is observed for 6 hours; (f) increasing the relative humidity from 0% to 50% at a rate of 10% per hour; 9. The composition of any one of embodiments 1-8, which, when obtained by, results in a dynamic vapor sorption profile substantially as shown in FIG.

[0197]

[0191] Embodiment 10. A composition described in any one of embodiments 1 to 9, wherein the crystalline form is substantially anhydrous.

[0198]

[0192] Embodiment 11. A composition described in any one of embodiments 1 to 10, wherein the crystalline form comprises a population of particles, at least about 90% by weight of the particles having a diameter of about 20 microns or less.

[0199]

[0193] Embodiment 12. A composition described in any one of embodiments 1 to 10, wherein the crystalline form comprises a population of particles, at least about 50% by weight of the particles having a diameter of 10 microns or less.

[0200]

[0194] Embodiment 13. A composition described in any one of embodiments 1 to 10, wherein the crystalline form comprises a population of particles, at least about 50% by weight of the particles having a diameter of from about 6.9 microns to about 9.75 microns.

[0201]

[0195] Embodiment 14. A composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein the crystalline form has a T onset ) the composition.

[0202]

[0196] Embodiment 15. A composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein the crystalline form is characterized by an X-ray diffraction pattern including at least two X-ray diffraction peaks selected from 9.8±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 17.4±0.1, 18.9±0.1, 19.6±0.1, 22.1±0.1, 26.6±0.1, and 27.2±0.1 degrees two theta (°θ).

[0203]

[0197] Embodiment 16. A method for synthesizing a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, comprising: a. reacting 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or an ionized form thereof, with fumaric acid in the presence of isopropanol to produce a reaction mixture, wherein the reaction mixture includes a precipitate; isolating the precipitate from ba; washing the precipitate from cb with isopropanol; drying the precipitate from dc to obtain particles, the particles comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate; Including, The melting point of the crystalline form is between 201 and 203°C (T onset ) synthesis method that gives a melting point of

[0204]

[0198] The method described in embodiment 16, further comprising the step of cooling the reaction mixture produced in embodiment 17.(i) a., which is carried out prior to b.

[0205]

[0199] Embodiment 18. The method of embodiment 16 or 17, further comprising a step of measuring the particle size of particles comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0206]

[0200] Embodiment 19. The method of any one of embodiments 16 to 18, further comprising a step of reducing the particle size of particles comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0207]

[0201] Embodiment 20. The method of embodiment 19, wherein the crystalline form comprises a population of particles, at least about 90% by weight of the particles having a diameter of about 20 microns or less.

[0208]

[0202] Embodiment 21. The method of embodiment 19, wherein the crystalline form comprises a population of particles, at least about 50% by weight of the particles having a diameter of about 10 microns or less.

[0209]

[0203] Embodiment 22. The method of embodiment 19, wherein the crystalline form comprises a population of particles, at least about 50% by weight of the particles comprising a diameter between about 6.9 microns and about 9.75 microns.

[0210]

[0204] Embodiment 23. 201 to 203°C (T onset 2. A method for the synthesis of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate having a melting point of a. reacting 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or an ionized form thereof, with fumaric acid in the presence of isopropanol to produce a reaction mixture, wherein the reaction mixture includes a precipitate; isolating the precipitate from ba; washing the precipitate from cb with isopropanol; drying the precipitate from dc to obtain particles, the particles comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate; A synthesis method comprising:

[0211]

[0205] Embodiment 24. A pharmaceutical composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate in unit dosage form, and a pharma- ceutically acceptable excipient, wherein the melting point of the crystalline form is (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature-controlled chamber to 250° C. at a scan rate of approximately 10° C. / min. If it is obtained by 201 to 203°C (T onset ) of the pharmaceutical composition.

[0212]

[0206] Embodiment 25. A pharmaceutical composition described in embodiment 24, wherein the unit dosage form is a solid dosage form.

[0213]

[0207] Embodiment 26. A pharmaceutical composition described in embodiment 24 or 25, wherein the unit dosage form is a tablet.

[0214]

[0208] Embodiment 27. A pharmaceutical composition described in embodiment 26, wherein the unit dosage form is a gastroresistant tablet.

[0215]

[0209] Embodiment 28. A pharmaceutical composition described in any one of embodiments 24 to 27, wherein the unit dosage form is suitable for oral administration.

[0216]

[0210] Embodiment 29. A pharmaceutical composition described in any one of embodiments 24 to 28, comprising from about 20 mg to about 200 mg of a crystalline form based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0217]

[0211] Embodiment 30. The pharmaceutical composition described in embodiment 29, comprising about 20 mg of the crystalline form, based on the mass of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

[0218]

[0212] Embodiment 31. A pharmaceutical composition described in any one of embodiments 24 to 28, comprising about 23.5 mg to about 235 mg of a crystalline form.

[0219]

[0213] Embodiment 32 The pharmaceutical composition described in embodiment 31, comprising about 23.5 mg of the crystalline form.

[0220]

[0214] Embodiment 33. A crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate in a unit dosage form, which is maintained at 201 to 203°C (T onset ) and a pharmaceutical composition comprising a crystalline form characterized by a melting point of 0.1 to 1.0 μg / ml.

[0221]

[0215] Embodiment 34. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein the crystalline form has a melting point of: (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature-controlled chamber at approximately 10°C / min to 250°C. If it is obtained by 201 to 203°C (T onset ) is obtained.

[0222]

[0216] Embodiment 35. The method of embodiment 34, wherein the condition is a cardiac condition.

[0223]

[0217] Embodiment 36. The method of embodiment 35, wherein the cardiac condition is characterized by an irregular heartbeat.

[0224]

[0218] Embodiment 37. The method of embodiment 35, wherein the cardiac condition is catecholamine-induced polymorphic ventricular tachycardia.

[0225]

[0219] Embodiment 38. The method of embodiment 35, wherein the cardiac condition is heart failure.

[0226]

[0220] Embodiment 39. The method of embodiment 38, wherein the heart failure is congestive heart failure.

[0227]

[0221] Embodiment 40. The method of embodiment 38, wherein the heart failure is chronic heart failure.

[0228]

[0222] Embodiment 41. The method of embodiment 38, wherein the heart failure is heart failure with reduced ejection fraction.

[0229]

[0223] Embodiment 42. The method of embodiment 38, wherein the heart failure is heart failure with preserved ejection fraction.

[0230]

[0224] Embodiment 43. The method of embodiment 38, wherein the subject is a heart failure patient with an implantable cardioverter defibrillator.

[0231]

[0225] Embodiment 44. The method of embodiment 38, wherein the heart failure is acute heart failure.

[0232]

[0226] Embodiment 45. The method of embodiment 38, wherein the subject is a heart failure patient requiring maintenance of cardiac function after myocardial infarction.

[0233]

[0227] Embodiment 46. The method of embodiment 35, wherein the cardiac condition is myocardial infarction.

[0234]

[0228] Embodiment 47. The method of embodiment 35, wherein the cardiac condition includes cardiac ischemia / reperfusion injury.

[0235]

[0229] Embodiment 48. The method of embodiment 34, wherein the condition is a musculoskeletal condition.

[0236]

[0230] Embodiment 49. The method of embodiment 48, wherein the musculoskeletal condition is a congenital myopathy.

[0237]

[0231] Embodiment 50. The method of embodiment 49, wherein the congenital myopathy is RYR1-associated myopathy.

[0238]

[0232] Embodiment 51. The method of embodiment 48, wherein the musculoskeletal condition is muscular dystrophy.

[0239]

[0233] Embodiment 52. The method of embodiment 51, wherein the muscular dystrophy is Duchenne muscular dystrophy.

[0240]

[0234] Embodiment 53. The method of embodiment 48, wherein the musculoskeletal condition is sarcopenia.

[0241]

[0235] Embodiment 54. The method of embodiment 34, wherein the condition is cancer-related muscle weakness.

[0242]

[0236] Embodiment 55. The method of embodiment 54, wherein the cancer-related muscle weakness is cancer cachexia.

[0243]

[0237] Embodiment 56. The method of embodiment 55, wherein the cancer cachexia is caused by a cancer having bone metastasis.

[0244]

[0238] Embodiment 57. The method of embodiment 34, wherein the condition is diabetes.

[0245]

[0239] Embodiment 58. The method of embodiment 34, wherein the condition is malignant hyperthermia.

[0246]

[0240] Embodiment 59. The method of any one of embodiments 34 to 58, wherein the therapeutically effective amount is from about 100 mg to about 200 mg per day.

[0247]

[0241] Embodiment 60. The method of any one of embodiments 34 to 58, wherein the therapeutically effective amount is about 120 mg per day.

[0248]

[0242] Embodiment 61. The method of any one of embodiments 34 to 58, wherein the therapeutically effective amount is about 200 mg per day.

[0249]

[0243] Embodiment 62. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein the crystalline form has a crystallinity of 201 to 203°C (T onset ) melting point of the compound.

[0250]

[0244] Embodiment 63. A composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate for use in a method of treating a medical condition, wherein the crystalline form has a melting point of: (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature-controlled chamber at approximately 10°C / min to 250°C. If it is obtained by 201 to 203°C (T onset ) the composition.

[0251]

[0245] Embodiment 64. A composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate for use in a method for treating a medical condition, wherein the crystalline form has a crystallinity of 201 to 203°C (T onset ) the composition.

[0252]

[0246] Embodiment 65. A composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein the melting point of the crystalline form is: (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature-controlled chamber at approximately 10°C / min to 250°C. If it is obtained by 208 to 210°C (T onset ) the composition.

[0253]

[0247] Embodiment 66. The composition described in embodiment 65, wherein the crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate is characterized by a differential scanning calorimetry profile substantially as shown in Figure 7.

[0254]

[0248] Embodiment 67. The X-ray diffraction pattern of the crystalline form is: Start position [°2θ] 3.00 End position [°2θ] 54.99 Step size [°2θ] 0.018 Scan step time [s] 34.92 Measurement temperature [℃] 25.00 K-alpha 1 [Å] 1.54 K-alpha 2 [Å] 1.54 K-beta [Å] 1.39 Rotation Yes 67. The composition of embodiment 65 or 66, wherein at least two X-ray diffraction peaks selected from 7.3±0.1, 13.2±0.1, 14.6±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two-theta (°θ) are observed when the composition is obtained using measurement conditions comprising:

[0255]

[0249] Embodiment 68. The composition described in embodiment 67, wherein X-ray diffraction peaks are observed at 7.3±0.1, 14.6±0.1, 18.0±0.1, 22.4±0.1, and 24.4±0.1 degrees two theta (°θ).

[0256]

[0250] Embodiment 69. A composition described in embodiment 67 or 68, wherein X-ray diffraction peaks are observed at 7.3±0.1, 11.1±0.1, 14.6±0.1, 18.0±0.1, 19.2±0.1, 22.4±0.1, 23.2±0.1, and 24.4±0.1 degrees two theta (°θ).

[0257]

[0251] Embodiment 70. A composition described in any one of embodiments 67 to 69, wherein X-ray diffraction peaks are observed at 7.3±0.1, 11.0±0.1, 11.1±0.1, 11.5±0.1, 13.2±0.1, 14.6±0.1, 15.2±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 19.2±0.1, 20.2±0.1, 21.4±0.1, 22.4±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two theta (°θ).

[0258]

[0252] Embodiment 71. A composition described in any one of embodiments 67 to 70, which exhibits an X-ray diffraction peak substantially as shown in FIG. 6.

[0259]

[0253] Embodiment 72. Thermogravimetric analysis of the crystalline form is (a) equilibrating a sample of said crystalline form at 25° C. in a temperature controlled chamber; and (b) Using a thermogravimetric analyzer, increase the temperature to 250°C at a scan rate of approximately 10°C / min. 72. The composition of any one of embodiments 65-71, which, when obtained by, results in a thermogravimetric analysis profile substantially as shown in FIG.

[0260]

[0254] Embodiment 73. The dynamic vapor sorption profile of the crystalline form is (a) equilibrating a sample of said crystalline form at 25° C. and 50% relative humidity in a temperature and humidity controlled chamber until the mass fluctuation is less than 0.002% per minute for 6 hours; (b) increasing the relative humidity from 50% to 90% at a rate of 10% per hour; (c) equilibrating the sample at 90% relative humidity until a mass fluctuation of less than 0.002% per minute is observed for 6 hours; (d) decreasing the relative humidity from 90% to 0% at a rate of 10% per hour; (e) equilibrating the sample at 0% relative humidity until a mass fluctuation of less than 0.002% per minute is observed for 6 hours; (f) increasing the relative humidity from 0% to 50% at a rate of 10% per hour; 73. The composition of any one of embodiments 65-72, which, when obtained by, results in a dynamic vapor sorption profile substantially as shown in FIG.

[0261]

[0255] Embodiment 74. A composition described in any one of embodiments 65 to 73, wherein the crystalline form is substantially anhydrous.

[0262]

[0256] Embodiment 75. A composition described in any one of embodiments 65 to 74, wherein the crystalline form comprises a population of particles, at least about 90% by weight of the particles having a diameter of about 90 microns or less.

[0263]

[0257] Embodiment 76. A composition described in any one of embodiments 65 to 74, wherein the crystalline form comprises a population of particles, at least about 50% by weight of the particles having a diameter of 30 microns or less.

[0264]

[0258] Embodiment 77. A composition described in any one of embodiments 65 to 74, wherein the crystalline form comprises a population of particles, at least about 50% by weight of the particles having a diameter of about 10 microns to about 30 microns.

[0265]

[0259] Embodiment 78. A composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein the crystalline form is at a temperature between 208 and 210°C (T onset ) the composition.

[0266]

[0260] Embodiment 79. A composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein the crystalline form is characterized by an X-ray diffraction pattern including at least two X-ray diffraction peaks selected from 7.3±0.1, 13.2±0.1, 14.6±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two theta (°θ).

[0267]

[0261] Embodiment 80. A method for synthesizing a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, comprising: a. reacting 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or an ionized form thereof, with fumaric acid in the presence of a mixture of dimethylsulfoxide (DMSO) and water to produce a reaction mixture, the reaction mixture including a precipitate; isolating the precipitate from ba; washing the precipitate from cb with water and acetone; drying the precipitate from dc to obtain particles, the particles comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate; Including, The melting point of the crystalline form is between 208 and 210°C (T onset ) synthesis method that gives a melting point of

[0268]

[0262] The method of embodiment 81. (i) The method of embodiment 80, further comprising a step of cooling the reaction mixture produced in a., the step being carried out prior to b.

[0269]

[0263] Embodiment 82. The method of embodiment 80 or 81, further comprising a step of measuring the particle size of particles comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0270]

[0264] Embodiment 83. The method of any one of embodiments 80 to 82, further comprising a step of reducing the particle size of the crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate.

[0271]

[0265] Embodiment 84. The method of embodiment 83, wherein the crystalline form comprises a population of particles, at least about 90% by weight of the particles having a diameter of about 90 microns or less.

[0272]

[0266] Embodiment 85. The method of embodiment 83, wherein the crystalline form comprises a population of particles, at least about 50% by weight of the particles having a diameter of about 30 microns or less.

[0273]

[0267] Embodiment 86. The method of embodiment 83, wherein the crystalline form comprises a population of particles, at least about 50% by weight of the particles comprising a diameter of about 10 microns to about 30 microns.

[0274]

[0268] Embodiment 87. 208 to 210°C (T onset 2. A method for the synthesis of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate having a melting point of a. reacting 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid, or an ionized form thereof, with fumaric acid in the presence of a mixture of dimethylsulfoxide (DMSO) and water to produce a reaction mixture, the reaction mixture including a precipitate; isolating the precipitate from ba; washing the precipitate from cb with water and acetone; drying the precipitate from dc to obtain particles, the particles comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate; A synthesis method comprising:

[0275]

[0269] Embodiment 88. A pharmaceutical composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate in unit dosage form, and a pharma- ceutically acceptable excipient, wherein the melting point of the crystalline form is (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature-controlled chamber at 10°C / min to 250°C. If it is obtained by 208 to 210°C (T onset ) of the pharmaceutical composition.

[0276]

[0270] Embodiment 89. A pharmaceutical composition described in embodiment 88, wherein the unit dosage form is a solid dosage form.

[0277]

[0271] Embodiment 90. A pharmaceutical composition described in embodiment 88 or 89, wherein the unit dosage form is a tablet.

[0278]

[0272] Embodiment 91. A pharmaceutical composition described in embodiment 90, wherein the unit dosage form is a gastroresistant tablet.

[0279]

[0273] Embodiment 92. A pharmaceutical composition described in any one of embodiments 88 to 91, wherein the unit dosage form is suitable for oral administration.

[0280]

[0274] Embodiment 93. A pharmaceutical composition described in any one of embodiments 88 to 92, comprising from about 20 mg to about 200 mg of a crystalline form.

[0281]

[0275] Embodiment 94. A pharmaceutical composition described in embodiment 93, comprising about 20 mg of the crystalline form.

[0282]

[0276] Embodiment 95. A pharmaceutical composition described in any one of embodiments 88 to 92, comprising about 23.5 mg to about 235 mg of crystals.

[0283]

[0277] Embodiment 96. A pharmaceutical composition described in embodiment 95, comprising about 23.5 mg of the crystalline form.

[0284]

[0278] Embodiment 97. A crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate in a unit dosage form, which is maintained at 208 to 210°C (T onset ) and a pharmaceutical composition comprising a crystalline form characterized by a melting point of 0.1 to 1.0 μg / ml.

[0285]

[0279] Embodiment 98. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein the crystalline form has a melting point of: (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature-controlled chamber to 250° C. at a scan rate of approximately 10° C. / min. If it is obtained by 208 to 210°C (T onset ) is obtained.

[0286]

[0280] Embodiment 99. The method of embodiment 98, wherein the condition is a cardiac condition.

[0287]

[0281] Embodiment 100. The method of embodiment 99, wherein the cardiac condition is characterized by an irregular heartbeat.

[0288]

[0282] Embodiment 101. The method of embodiment 99, wherein the cardiac condition is catecholamine-induced polymorphic ventricular tachycardia.

[0289]

[0283] Embodiment 102. The method of embodiment 99, wherein the cardiac condition is heart failure.

[0290]

[0284] Embodiment 103. The method of embodiment 102, wherein the heart failure is congestive heart failure.

[0291]

[0285] Embodiment 104. The method of embodiment 102, wherein the heart failure is chronic heart failure.

[0292]

[0286] Embodiment 105. The method of embodiment 102, wherein the heart failure is heart failure with reduced ejection fraction.

[0293]

[0287] Embodiment 106. The method of embodiment 102, wherein the heart failure is heart failure with preserved ejection fraction.

[0294]

[0288] Embodiment 107. The method described in embodiment 102, wherein the subject is a heart failure patient having an implantable cardioverter defibrillator.

[0295]

[0289] Embodiment 108. The method of embodiment 102, wherein the heart failure is acute heart failure.

[0296]

[0290] Embodiment 109. The method described in embodiment 102, wherein the subject is a heart failure patient requiring maintenance of cardiac function after myocardial infarction.

[0297]

[0291] Embodiment 110. The method of embodiment 99, wherein the cardiac condition is myocardial infarction.

[0298]

[0292] Embodiment 111. The method of embodiment 99, wherein the cardiac condition includes cardiac ischemia / reperfusion injury.

[0299]

[0293] Embodiment 112. The method of embodiment 98, wherein the condition is a musculoskeletal condition.

[0300]

[0294] Embodiment 113. The method of embodiment 112, wherein the musculoskeletal condition is a congenital myopathy.

[0301]

[0295] Embodiment 114. The method of embodiment 113, wherein the congenital myopathy is RYR1-associated myopathy.

[0302]

[0296] Embodiment 115. The method of embodiment 112, wherein the musculoskeletal condition is muscular dystrophy.

[0303]

[0297] Embodiment 116. The method of embodiment 115, wherein the muscular dystrophy is Duchenne muscular dystrophy.

[0304]

[0298] Embodiment 117. The method of embodiment 112, wherein the musculoskeletal condition is sarcopenia.

[0305]

[0299] Embodiment 118. The method of embodiment 98, wherein the condition is cancer-related muscle weakness.

[0306]

[0300] Embodiment 119. The method of embodiment 118, wherein the cancer-related muscle weakness is cancer cachexia.

[0307]

[0301] Embodiment 120. The method of embodiment 119, wherein the cancer cachexia is caused by a cancer having bone metastasis.

[0308]

[0302] Embodiment 121. The method of embodiment 98, wherein the condition is diabetes.

[0309]

[0303] Embodiment 122. The method of embodiment 98, wherein the condition is malignant hyperthermia.

[0310]

[0304] Embodiment 123. The method of any one of embodiments 98 to 122, wherein the therapeutically effective amount is from about 100 mg to about 200 mg per day.

[0311]

[0305] Embodiment 124. The method of any one of embodiments 98 to 122, wherein the therapeutically effective amount is about 120 mg per day.

[0312]

[0306] Embodiment 125. The method of any one of embodiments 98 to 122, wherein the therapeutically effective amount is about 200 mg per day.

[0313]

[0307] Embodiment 126. A method of treating a medical condition, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, wherein the crystalline form is at a temperature between 208 and 210°C (T onset ) melting point of the compound.

[0314]

[0308] Embodiment 127. A composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate for use in treating a medical condition, wherein the crystalline form has a melting point of: (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature-controlled chamber at 10°C / min to 250°C. If it is obtained by 208 to 210°C (T onset ) the composition.

[0315]

[0309] Embodiment 128. A composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate for use in a method for treating a medical condition, wherein the crystalline form is at a temperature between 208 and 210°C (T onset ) the composition.

[0316]

[0310] Embodiment 129. A pharmaceutical composition comprising a gastroresistant tablet, the gastroresistant tablet comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate as an active ingredient, and a pharma- ceutically acceptable carrier, wherein the melting point of the crystalline form is (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature-controlled chamber at 10°C / min to 250°C. If it is obtained by 208 to 210°C (T onset ) of the pharmaceutical composition.

[0317]

[0311] Embodiment 130. A method of treating an RYR1-associated myopathy, comprising administering to a subject in need thereof a pharmaceutical composition, the composition comprising a gastroresistant tablet, the gastroresistant tablet comprising a therapeutically effective amount of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, the melting point of the crystalline form being: (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature-controlled chamber at 10°C / min to 250°C. If it is obtained by 208 to 210°C (T onset ) is obtained.

[0318]

[0312] Embodiment 131. The method of embodiment 130, wherein the therapeutically effective amount is about 100 mg to about 200 mg per day.

[0319]

[0313] Embodiment 132. The method of embodiment 130 or 131, wherein the therapeutically effective amount is about 120 mg per day.

[0320]

[0314] Embodiment 133. The method of embodiment 130 or 131, wherein the therapeutically effective amount is about 200 mg per day.

[0321]

[0315] Embodiment 134. A method for treating catecholamine-induced polymorphic ventricular tachycardia, comprising administering to a subject in need thereof a pharmaceutical composition, the pharmaceutical composition comprising a gastroresistant tablet, the gastroresistant tablet comprising a therapeutically effective amount of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, the melting point of the crystalline form being: (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature-controlled chamber at 10°C / min to 250°C. If it is obtained by 208 to 210°C (T onset ) is obtained.

[0322]

[0316] Embodiment 135. The method of embodiment 134, wherein the therapeutically effective amount is about 100 mg to about 200 mg per day.

[0323]

[0317] Embodiment 136. The method of embodiment 134 or 135, wherein the therapeutically effective amount is about 120 mg per day.

[0324]

[0318] Embodiment 137. The method of embodiment 134 or 135, wherein the therapeutically effective amount is about 200 mg per day.

[0325]

[0319] Embodiment 138. A pharmaceutical composition comprising a gastroresistant tablet, the gastroresistant tablet comprising a therapeutically effective amount of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate in crystalline form as an active ingredient, the crystalline form being stable at 208 to 210°C (T onset ) and a pharma- ceutically acceptable carrier.

[0326]

[0320] Embodiment 139. A method for treating RYR1-associated myopathy, comprising administering a pharmaceutical composition to a subject in need thereof, the pharmaceutical composition comprising a gastroresistant tablet, the gastroresistant tablet comprising a therapeutically effective amount of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, the crystalline form being stable at 208 to 210°C (T onset ) melting point of the compound.

[0327]

[0321] Embodiment 140. A method for treating catecholamine-induced polymorphic ventricular tachycardia, comprising administering to a subject in need thereof a pharmaceutical composition, the pharmaceutical composition comprising a gastroresistant tablet, the gastroresistant tablet comprising a therapeutically effective amount of a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, the crystalline form being stable at 208 to 210°C (T onset ) melting point of the compound.

Claims

1. A crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, The X-ray diffraction pattern of the crystalline form is Starting position [°2θ] 3.00 End position [°2θ] 54.99 Step size [°2θ] 0.018 Scan step time [s] 34.92 Measurement temperature [℃] 25.00 K-alpha 1 [Å] 1.54 K-alpha2 [Å] 1.54 K-beta [Å] 1.39 Rotation Yes and wherein at least four X-ray diffraction peaks selected from 7.3±0.1, 13.2±0.1, 14.6±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two-theta (°θ) are observed when the crystalline form is obtained using measurement conditions comprising:

2. 2. The crystalline form of claim 1, wherein X-ray diffraction peaks are observed at 7.3±0.1, 14.6±0.1, 18.0±0.1, 22.4±0.1, and 24.4±0.1 degrees two theta (°θ).

3. 3. The crystalline form of claim 1 or 2, wherein X-ray diffraction peaks are observed at 7.3±0.1, 11.1±0.1, 14.6±0.1, 18.0±0.1, 19.2±0.1, 22.4±0.1, 23.2±0.1, and 24.4±0.1 degrees two-theta (°θ).

4. 4. The crystalline form of any one of claims 1 to 3, wherein X-ray diffraction peaks at 7.3±0.1, 11.0±0.1, 11.1±0.1, 11.5±0.1, 13.2±0.1, 14.6±0.1, 15.2±0.1, 17.1±0.1, 18.0±0.1, 18.3±0.1, 19.2±0.1, 20.2±0.1, 21.4±0.1, 22.4±0.1, 23.2±0.1, 23.9±0.1, 24.4±0.1, and 28.6±0.1 degrees two theta (°θ) are observed.

5. The crystalline form of any one of claims 1 to 4, wherein the crystalline form exhibits X-ray diffraction peaks substantially as shown in Figure 6.

6. Thermogravimetric analysis of the crystalline form (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at 25° C.; and (b) Using a thermogravimetric analyzer, increase the temperature to 250° C. at a scan rate of about 10° C. / min.

6. The crystalline form of any one of claims 1 to 5, which, when obtained by

7. The dynamic vapor sorption profile of the crystalline form is (a) equilibrating a sample of said crystalline form at 25° C. and 50% relative humidity in a temperature and humidity controlled chamber until the mass fluctuation is less than 0.002% per minute for 6 hours; (b) increasing the relative humidity from 50% to 90% at a rate of 10% per hour; (c) Equilibrating the sample at 90% relative humidity until less than 0.002% mass variation per minute is observed for 6 hours; (d) decreasing the relative humidity from 90% to 0% at a rate of 10% per hour; (e) Equilibrating the sample at 0% relative humidity until a mass fluctuation of less than 0.002% per minute is observed for 6 hours; (f) increasing the relative humidity from 0% to 50% at a rate of 10% per hour; 7. The crystalline form of any one of claims 1 to 6, which, when obtained by:

8. The melting point of the crystalline form is (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature controlled chamber at about 10° C. / min to 250° C. The crystalline form of any one of claims 1 to 7, when obtained by: obtaining a melting point of 208-210°C (T onset ).

9. The crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate salt according to any one of claims 1 to 8, characterized by a differential scanning calorimetry profile substantially as shown in Figure 7.

10. 10. The crystalline form of any one of claims 1 to 9, wherein the crystalline form comprises a population of particles, at least about 90% by weight of the particles comprising a diameter of about 90 microns or less.

11. 10. The crystalline form of any one of claims 1 to 9, wherein the crystalline form comprises a population of particles, at least about 50% by weight of the particles having a diameter of 30 microns or less.

12. 10. The crystalline form of any one of claims 1 to 9, wherein the crystalline form comprises a population of particles, at least about 50% by weight of the particles comprising a diameter of from about 10 microns to about 30 microns.

13. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 12 in unit dosage form, and at least one pharma- ceutically acceptable excipient.

14. 14. The pharmaceutical composition according to claim 13, wherein the unit dosage form is a gastroresistant tablet.

15. 14. The pharmaceutical composition of claim 13, comprising an amount of the crystalline form equivalent to about 20 mg to about 200 mg of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid.

16. A pharmaceutical composition according to any one of claims 13 to 15 for use in treating a medical condition.

17. The pharmaceutical composition described in claim 16, wherein the condition is associated with leaky ryanodine receptors.

18. 17. The pharmaceutical composition of claim 16, wherein the condition is a cardiac condition.

19. 20. The pharmaceutical composition of claim 18, wherein the cardiac condition is characterized by an irregular heartbeat.

20. 19. The pharmaceutical composition of claim 18, wherein the cardiac condition is catecholaminergic polymorphic ventricular tachycardia.

21. 19. The pharmaceutical composition of claim 18, wherein the cardiac condition is heart failure.

22. 17. The pharmaceutical composition of claim 16, wherein the condition is a musculoskeletal condition.

23. The pharmaceutical composition of claim 16, wherein the condition is RYR1-associated myopathy.

24. The pharmaceutical composition described in claim 16, wherein the condition is Duchenne muscular dystrophy.

25. The pharmaceutical composition described in claim 16, wherein the condition is sarcopenia.

26. The pharmaceutical composition of any one of claims 16 to 25, wherein the crystalline form is administered in a therapeutically effective amount, the therapeutically effective amount being about 200 mg per day.

27. The pharmaceutical composition of any one of claims 16 to 25, wherein the crystalline form is administered in a therapeutically effective amount, the therapeutically effective amount being about 300 mg per day.

28. The pharmaceutical composition of any one of claims 16 to 25, wherein the crystalline form is administered in a therapeutically effective amount, the therapeutically effective amount being about 400 mg per day.

29. A crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate, The X-ray diffraction pattern of the crystalline form is Starting position [°2θ] 3.00 End position [°2θ] 54.99 Step size [°2θ] 0.018 Scan step time [s] 34.92 Measurement temperature [℃] 25.00 K-alpha 1 [Å] 1.54 K-alpha2 [Å] 1.54 K-beta [Å] 1.39 Rotation Yes and wherein at least four X-ray diffraction peaks selected from 9.8±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 17.4±0.1, 18.9±0.1, 19.6±0.1, 22.1±0.1, 26.6±0.1, and 27.2±0.1 degrees two-theta (°θ) are observed when the A crystalline form comprising a population of particles, at least about 90% by weight of the particles comprising a diameter of about 20 microns or less.

30. 30. The crystalline form of claim 29, wherein X-ray diffraction peaks are observed at 9.8±0.1, 11.0±0.1, 11.4±0.1, 11.8±0.1, 13.5±0.1, 14.0±0.1, 14.3±0.1, 15.0±0.1, 17.4±0.1, 18.9±0.1, 19.3±0.1, 19.6±0.1, 20.3±0.1, 21.6±0.1, 22.1±0.1, 22.6±0.1, 26.6±0.1, and 27.2±0.1 degrees two-theta (°θ).

31. Thermogravimetric analysis of the crystalline form (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at 25° C.; and (b) Using a thermogravimetric analyzer, increase the temperature to 250° C. at a scan rate of about 10° C. / min.

31. The crystalline form of claim 29 or 30, which, when obtained by:

32. The dynamic vapor sorption profile of the crystalline form is (a) equilibrating a sample of said crystalline form at 25° C. and 50% relative humidity in a temperature and humidity controlled chamber until a mass variation of less than 0.002% per minute is obtained for 6 hours; (b) increasing the relative humidity from 50% to 90% at a rate of 10% per hour; (c) equilibrating the sample at 90% relative humidity until a mass variation of less than 0.002% per minute is obtained for 6 hours; (d) decreasing the relative humidity from 90% to 0% at a rate of 10% per hour; (e) Equilibrating the sample at 0% relative humidity until a mass fluctuation of less than 0.002% per minute is observed for 6 hours; (f) increasing the relative humidity from 0% to 50% at a rate of 10% per hour; 32. The crystalline form of any one of claims 29 to 31, which, when obtained by:

33. The crystalline form of any one of claims 29 to 32, When the melting point of the crystalline form is obtained by (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C., and (b) increasing the temperature of the temperature controlled chamber at about 10° C. / min to 250° C. using a differential scanning calorimeter instrument, a melting point of 201-203° C. (T onset ) is obtained; A crystalline form comprising a population of particles, at least about 90% by weight of the particles comprising a diameter of about 20 microns or less.

34. A pharmaceutical composition comprising the crystalline form of any one of claims 29 to 33 in unit dosage form, and at least one pharma- ceutically acceptable excipient.

35. 35. The pharmaceutical composition of claim 34, wherein the unit dosage form is a gastroresistant tablet.

36. 36. A pharmaceutical composition according to claim 34 or 35 for use in treating a medical condition.

37. The pharmaceutical composition described in claim 36, wherein the condition is associated with leaky ryanodine receptors.

38. A pharmaceutical composition comprising a crystalline form of 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)yl)methyl]benzoic acid hemifumarate in unit dosage form, wherein the melting point of the crystalline form is (a) equilibrating a sample of said crystalline form in a temperature controlled chamber at a temperature of about 20° C.; and (b) Using a differential scanning calorimeter, increase the temperature of the temperature controlled chamber at about 10° C. / min to 250° C. When the temperature is 201 to 203° C. (T ｏｎｓｅｔ ) melting point is obtained, A pharmaceutical composition, wherein the unit dosage form is a gastroresistant tablet.

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