Salt or cocrystal of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid and its use

Abstract

This provides a drug form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid that has properties suitable for large-scale production and formulation. [Solution] A crystalline form of the 1:1 sodium salt of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is provided, characterized by an XRPD pattern having peaks at 4.4±0.2, 9.4±0.2, and 20.0±0.2 degrees 2θ when measured using Cu, Kα radiation.

Description

[Technical Field]

[0001] This disclosure relates to a) a salt or cocrystal of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid ("Compound 1" or "API"), b) crystalline form of a salt or cocrystal of Compound 1, c) a pharmaceutical composition comprising one or more salts or cocrystals of Compound 1 and optionally a pharmaceutically acceptable carrier, and d) a method for treating certain types of diabetes mellitus and other diseases by administering one or more salts or cocrystals of Compound 1 to a patient in need of treatment. [Background technology]

[0002] Glucokinase (GK) is an important regulator of glucose homeostasis, functioning as a physiological glucose sensor that changes its structure, activity, and / or intracellular location in parallel with changes in glucose concentration. GK has two key characteristic properties that make it suitable for blood glucose control. First, its expression is almost exclusively limited to tissues that require glucose sensing (mainly β-cells of the liver and pancreas). Second, GK can sense changes in serum glucose levels, regulate changes in hepatic glucose metabolism to balance hepatic glucose production (HGP) and glucose consumption, and regulate changes in insulin secretion by β-cells. The idea of ​​GK activation for diabetes treatment is attractive because it works through a completely different mechanism than currently available antidiabetic therapies, and has been proven to effectively and safely normalize blood glucose in animal models of type 1 and type 2 diabetes.

[0003] Although several GK small molecule activators have been clinically developed, their initial therapeutic prospects are limited due to the occurrence of hypoglycemia, elevated triglyceride (TG) levels, and loss of effect over time. These adverse events (AEs) were associated with progressive β-cell activation.

[0004] Compound 1 is an orally administered small-molecule hepatic-selective glucokinase activator that improves glycemic control and does not induce hypoglycemia, dyslipidemia, or pathological increases in hepatic glycogen or TG at therapeutically appropriate doses. Compound 1 does not cause similar adverse effects (Vella et al., Science Translational Medicine 16 Jan 2019).

[0005] Not all compounds that are GK activators possess the properties that best give them the potential to become useful therapeutic agents. Some of these properties include high affinity for GK, duration of GK inactivation, oral bioavailability, tissue distribution, and stability (e.g., ability to formulate or crystallize, shelf life). Favorable properties can lead to improved safety, tolerability, efficacy, therapeutic index, patient compliance, cost-effectiveness, and ease of manufacture.

[0006] Furthermore, salts or cocrystals of a given compound may differ from one another with respect to one or more physical properties such as solubility and dissociation, true density, melting point, crystal shape, compressibility, flow properties, and / or solid stability. These differences affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (an important factor in determining bioavailability). While U.S. Patent No. 7,598,391 discloses compound 1 as a free acid, there is a need for additional drug forms that are useful for activating GK activity in vitro and in vivo and possess properties suitable for large-scale production and formulation. Provided herein are novel salt or cocrystal forms of compound 1, and methods for treating diabetes mellitus by using these novel salt or cocrystal forms of compound 1. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Vella et al., Science Translational Medicine 16 Jan 2019 [Overview of the project] [Means for solving the problem]

[0008] In one embodiment, the disclosure provides a salt or cocrystal of compound 1. In one embodiment, the disclosure provides a crystalline form of the salt or cocrystal of compound 1. In one embodiment, the salt or cocrystal of compound 1 is an anhydrous, hydrate, or solvate.

[0009] In one embodiment, this disclosure, Equation (I)

[0010] [ka] The component (a) is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid, (b) A component selected from the group consisting of sodium, piperazine, and hydrochloride The present invention provides a salt or cocrystal containing the present material.

[0011] In one embodiment, the disclosure specifies that component (b) of the salt or cocrystal is sodium. In one embodiment, the disclosure specifies that the molar ratio of component (a) to component (b) sodium of the salt or cocrystal is about 1:1.

[0012] In one embodiment, the sodium salt of compound 1 is a crystalline form characterized by an XRPD pattern having peaks at 4.4±0.2, 9.4±0.2, and 20.0±0.2 degrees 2θ.

[0013] In one embodiment, the crystalline form of the sodium salt is substantially characterized by the TGA profile shown in Figure 2.

[0014] In one aspect, the crystal form of the sodium salt is substantially characterized by the DSC profile shown in FIG. 3.

[0015] In one aspect, the crystal form of the sodium salt is characterized by an IR pattern having peaks at 1358.3 ± 2.0, 1606.1 ± 2.0, and 1649.0 ± 2.0 cm -1 -1.

[0016] In one aspect, the crystal form of the sodium salt is Form A.

[0017] In one aspect, the crystal form of the sodium salt substantially does not contain other polymorphs. In one aspect, the crystal form of the sodium salt has a polymorph purity of at least 90%. In one aspect, the crystal form of the sodium salt has a polymorph purity of at least 99%.

[0018] In one aspect, the present disclosure provides that component (b) of the salt or co-crystal is piperazine.

[0019] In one aspect, the present disclosure provides that the molar ratio of component (a) to component (b) piperazine is about 2:1.

[0020] In one aspect, the piperazine salt or co-crystal of Compound 1 is a) a crystal form characterized by an XRPD pattern having peaks at 4.9 ± 0.2, 12.5 ± 0.2, and 14.9 ± 0.2 degrees 2θ, b) a crystal form characterized by an XRPD pattern having peaks at 5.1 ± 0.2, 13.6 ± 0.2, and 20.5 ± 0.2 degrees 2θ, and c) a crystal form characterized by an XRPD pattern having peaks at 5.5 ± 0.2, 16.7 ± 0.2, and 19.9 ± 0.2 degrees 2θ selected from the group consisting of.

[0021] In one embodiment, the crystalline form of the piperazine salt or cocrystal is characterized by an XRPD pattern having peaks at 4.9±0.2, 12.5±0.2, and 14.9±0.2 θ.

[0022] In one embodiment, the crystalline form of the piperazine salt or cocrystal is substantially characterized by the TGA profile shown in Figure 6.

[0023] In one embodiment, the crystalline form of the piperazine salt or cocrystal is characterized by an endothermic peak with an initiation point at approximately 226°C, determined by DSC.

[0024] In one embodiment, the crystalline form of the piperazine salt or cocrystal is shown in Figure 8. 13 It is substantially characterized by 13C NMR.

[0025] In one embodiment, the crystalline form of the piperazine salt or cocrystal is a hydrate.

[0026] In one embodiment, the crystalline form of the piperazine salt or cocrystal is morphology B.

[0027] In one embodiment, the crystalline form of the piperazine salt or cocrystal is characterized by an XRPD pattern having peaks at 5.1±0.2, 13.6±0.2, and 20.5±0.2 degrees 2θ.

[0028] In one embodiment, the crystalline form of the piperazine salt or cocrystal is substantially characterized by the TGA profile shown in Figure 10.

[0029] In one embodiment, the crystalline form of the piperazine salt or cocrystal is substantially characterized by the DSC profile shown in Figure 11.

[0030] In one embodiment, the crystalline form of the piperazine salt or cocrystal is morphology C.

[0031] In one embodiment, the crystalline form of the piperazine salt or cocrystal is characterized by an XRPD pattern having peaks at 5.5±0.2, 16.7±0.2, and 19.9±0.2 degrees 2θ.

[0032] In one embodiment, the crystalline form of the piperazine salt or cocrystal is morphology D.

[0033] In one embodiment, the disclosure specifies that the molar ratio of component (a) to component (b) piperazine is approximately 1:1.

[0034] In one embodiment, the piperazine salt or cocrystal of compound 1 is a crystalline form characterized by an XRPD pattern having peaks at 4.9±0.2, 12.5±0.2, and 18.3±0.2 degrees 2θ.

[0035] In one embodiment, the crystalline form of the piperazine salt or cocrystal is substantially characterized by the TGA profile shown in Figure 14.

[0036] In one embodiment, the crystalline form of the piperazine salt or cocrystal is substantially characterized by the DSC profile shown in Figure 15.

[0037] In one embodiment, the crystalline form of the piperazine salt or cocrystal is morphology E.

[0038] In one embodiment, the crystalline form of the piperazine salt or cocrystal is substantially free of other polymorphs. In one embodiment, the crystalline form of the piperazine salt or cocrystal has a polymorphic purity of at least 90%. In one embodiment, the crystalline form of the piperazine salt or cocrystal has a polymorphic purity of at least 99%.

[0039] In one embodiment, the disclosure specifies that component (b) of the salt or cocrystal is a hydrochloride salt. In one embodiment, the disclosure specifies that the molar ratio of component (a) to component (b) hydrochloride salt of the salt or cocrystal is about 1:1.

[0040] In one embodiment, the hydrochloride salt of compound 1 is a crystalline form characterized by an XRPD pattern having peaks at 4.6±0.2, 7.2°±0.2, and 17.7°±0.2 degrees 2θ.

[0041] In one embodiment, the crystalline form of the hydrochloride is substantially characterized by the TGA profile shown in Figure 17.

[0042] In one embodiment, the crystalline form of the hydrochloride salt is substantially characterized by the DSC profile shown in Figure 18.

[0043] In one embodiment, the crystalline forms of the hydrochloride salt are 1119.0±2.0, 1540.2±2.0, and 1667.5±2.0 cm². -1 Characterized by an IR pattern with a peak.

[0044] In one embodiment, the crystalline form of the hydrochloride salt is morphology F.

[0045] In one embodiment, the crystalline form of the hydrochloride salt is substantially free of other polymorphs. In one embodiment, the crystalline form of the hydrochloride salt has a polymorphic purity of at least 90%. In one embodiment, the crystalline form of the hydrochloride salt has a polymorphic purity of at least 99%.

[0046] In one embodiment, the present disclosure provides a pharmaceutical composition comprising one or more salts or cocrystals of Compound 1 disclosed herein and a pharmaceutically acceptable carrier, diluent, excipient, or mixture thereof.

[0047] In one embodiment, the present disclosure provides a method for treating a particular type of diabetes mellitus or other disease, comprising administering a pharmaceutical composition disclosed herein to a patient in need thereof. In some embodiments, the type of diabetes is type 1 diabetes mellitus. In some embodiments, the type of diabetes is type 2 diabetes mellitus.

[0048] In one embodiment, the pharmaceutical composition is administered orally. In another embodiment, the pharmaceutical composition is administered as a tablet.

[0049] In one embodiment, the patient is administered up to approximately 2000 mg of {2-[3-cyclohexyl-3-(trans-4-propoxycyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid daily.

[0050] In one embodiment, the present disclosure provides a method for producing one or more salts or cocrystals of compound 1 disclosed herein.

[0051] In one embodiment, the disclosure provides the use of the pharmaceutical compositions disclosed herein for the manufacture of a medicament for treating a particular type of diabetes mellitus or other disease. In one embodiment, the use is for the treatment of type 1 diabetes mellitus. In one embodiment, the use is for the treatment of type 2 diabetes mellitus.

[0052] In one embodiment, the present disclosure provides a pharmaceutical composition disclosed herein for use in a method for treating a particular type of diabetes or other disease. In one embodiment, the use is for the treatment of type 1 diabetes mellitus. In one embodiment, the use is for the treatment of type 2 diabetes mellitus. [Brief explanation of the drawing]

[0053] [Figure 1] This is the powder X-ray diffraction pattern ("XRPD") corresponding to form A, which is the sodium salt of compound 1. [Figure 2] This is a thermogravimetric thermogram (hereinafter referred to as "TGA") corresponding to form A, which is the sodium salt of compound 1. [Figure 3] This is a differential scanning calorimetry thermogram ("DSC") corresponding to form A, which is the sodium salt of compound 1. [Figure 4] This is the infrared spectrum ("IR") of form A, which is the sodium salt of compound 1. [Figure 5]This is the XRPD corresponding to form B, which is the piperazine salt or cocrystal of compound 1. [Figure 6] This TGA corresponds to form B, which is the piperazine salt or cocrystal of compound 1. [Figure 7] This is a DSC corresponding to form B, which is the piperazine salt or cocrystal of compound 1. [Figure 8] This is the carbon-13 solid-state nuclear magnetic resonance (13C NMR) spectrum corresponding to form B, which is either the piperazine salt or a cocrystal of compound 1. [Figure 9] This is the XRPD corresponding to form C, which is the piperazine salt or cocrystal of compound 1. [Figure 10] This TGA corresponds to form C, which is the piperazine salt or cocrystal of compound 1. [Figure 11] This is a DSC corresponding to form C, which is the piperazine salt or cocrystal of compound 1. [Figure 12] This is the XRPD corresponding to form D, which is the piperazine salt or cocrystal of compound 1. [Figure 13] This is the XRPD corresponding to form E, which is the piperazine salt or cocrystal of compound 1. [Figure 14] This TGA corresponds to form E, which is the piperazine salt or cocrystal of compound 1. [Figure 15] This is a DSC corresponding to form E, which is the piperazine salt or cocrystal of compound 1. [Figure 16] This is the XRPD corresponding to form F, which is the hydrochloride salt or cocrystal of compound 1. [Figure 17] This TGA corresponds to form F, which is the hydrochloride salt or cocrystal of compound 1. [Figure 18] This DSC corresponds to form F, which is the hydrochloride salt or cocrystal of compound 1. [Figure 19] This is the IR of form F, which is the sodium salt of compound 1. [Modes for carrying out the invention]

[0054] I. Definition To facilitate understanding of the disclosures contained herein, several terms are defined below.

[0055] In general, the nomenclature used herein, and the organic chemistry, medicinal chemistry, and pharmacology test procedures described herein, are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which this disclosure belongs.

[0056] In this specification and the appended claims, the singular forms “a,” “an,” and “the” refer to multiple subjects unless the context clearly indicates otherwise. The terms “a” (or “an”), as well as “one or more” and “at least one,” may be used interchangeably in this specification. In certain embodiments, the terms “a” or “an” mean “single.” In other embodiments, the terms “a” or “an” include “two or more” or “plural.”

[0057] Furthermore, as used herein, “and / or” is to be interpreted as expressing that each of the two specified features or components may or may not be accompanied by the other. Accordingly, as used herein in phrases such as “A and / or B,” the term “and / or” is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Similarly, as used in phrases such as “A, B, and / or C,” the term “and / or” is intended to include each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0058] The term "compound 1" refers to the compound {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid.

[0059] The term “subject” refers to animals including, but not limited to, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms “subject” and “patient” are used interchangeably herein to refer to mammalian subjects, such as human subjects.

[0060] The terms “treat,” “treating,” and “treatment” are intended to include alleviating or suppressing one or more symptoms of a disease, illness, or condition, or of a disease, illness, or condition; or alleviating or eliminating the cause of the disease, illness, or condition itself.

[0061] The term “therapeutic dose” means the amount of a compound that, when administered, is sufficient to prevent or, to some extent, alleviate the onset of one or more symptoms of the disease, illness, or condition being treated. The term “therapeutic dose” also means the amount of a compound that is sufficient to elicit a biological or medical response in a cell, tissue, system, animal, or human, as sought by researchers, veterinarians, physicians, and clinicians.

[0062] The terms “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” and “pharmaceutically acceptable diluent” mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of a pharmaceutical formulation, has a reasonable benefit-risk ratio, and is suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications. See Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th edition, Rowe et al., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd edition, Ash and Ash, Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0063] The term "cocrystal" means a molecular complex of a compound disclosed herein with one or more non-ionized cocrystal-forming agents linked via non-covalent interactions. In one embodiment, the cocrystal disclosed herein may comprise a non-ionized form of compound 1 (e.g., a free acid of compound 1) and one or more non-ionized cocrystal-forming agents, where the non-ionized compound 1 and the cocrystal-forming agents are linked via non-covalent interactions. In another embodiment, the cocrystal disclosed herein may comprise an ionized form of compound 1 (e.g., a salt of compound 1) and one or more non-ionized cocrystal-forming agents, where the ionized compound 1 and the cocrystal-forming agents are linked via non-covalent interactions. The cocrystal may further exist in an anhydrous, solvated, or hydrated form. In certain cases, the cocrystal may have improved properties compared to the parent form (i.e., a free molecule, zwitterion, etc.) or a salt of the parent compound. Improved properties may include increased solubility, increased dissolution, increased bioavailability, increased dose-response, decreased hygroscopicity, crystalline form of compounds that are normally amorphous, crystalline form of compounds that are difficult or non-precipitation-prone, reduced morphological diversity, and more desirable morphology.

[0064] The terms "cocrystal-forming agent" or "co-forming agent" refer to a base or acid disclosed herein in conjunction with Compound 1 or any other compound disclosed herein.

[0065] The terms “about” or “approximately” mean a tolerance for a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the terms “about” or “approximately” mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms “about” or “approximately” mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0066] The terms “active ingredient” and “active substance” refer to compounds administered to a subject, either alone or in combination with one or more pharmaceutically acceptable excipients, to treat, delay, or improve one or more symptoms of a pathological condition, disease, or illness. As used herein, “active ingredient” and “active substance” may be optically active isomers of the compounds described herein.

[0067] The term "solvate" means a compound or salt thereof provided herein, further comprising a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate. When the solvent contains ethanol, the compound may be an ethanol solvate.

[0068] As used herein, the term “polymorph” refers to a crystalline form of a compound or its salt, hydrate, or solvate in a particular crystalline packing arrangement. All polymorphs have the same elemental composition. As used herein, the term “crystalline” refers to a solid state form consisting of orderly arranged structural units. Different crystalline forms of the same compound, or its salt, hydrate, or solvate, arise from differences in molecular packing in the solid state, resulting in different crystalline symmetries and / or unit cell parameters. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. See, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton PA, 173 (1990); The United States Pharmacopeia, 23rd edition, pp. 1843-1844 (1995) (incorporated herein by reference).

[0069] Crystal forms are most commonly characterized by X-ray powder diffraction (XRPD). The XRPD pattern of reflections (typically peaks represented by an angle of 2θ) is generally considered a fingerprint of a particular crystal form. The relative intensity of XRPD peaks can vary considerably, particularly depending on sample preparation techniques, crystal size distribution, filters, sample placement procedures, and the specific instrument used. In some cases, new peaks may be observed or existing peaks may disappear depending on the type or settings of the instrument. In some cases, any particular peak in the XRPD pattern may appear as a singlet, doublet, triplet, quadrant, or multiplet, depending on the type and settings of the instrument, the sensitivity of the instrument, the measurement conditions, and / or the purity of the crystal form. In some cases, any particular peak in XRPD may appear as a symmetrical shape or asymmetrical shape, such as a shape with shoulders. Furthermore, instrument variability and other factors can affect the 2θ value. Those skilled in the art who understand these variability can use XRPD, as with other known physicochemical methods, to identify or confirm the explicit features or properties of a particular crystal form.

[0070] The term "anhydrous" applied to compounds refers to a solid state in which the compound does not contain structural water within its crystal lattice.

[0071] Unless otherwise required by context, the terms “comprise,” “comprises,” and “comprising” are used on the basis and with a clear understanding that they are to be interpreted comprehensively, not exclusively, and that the applicant intends to interpret each of these terms in that way in the interpretation of this Patent, including the following claims.

[0072] For all embodiments disclosed herein, the peak position reproducibility is in degrees 2θ (XRPD), ppm( 13 (1C solid-state NMR), and cm -1This is associated with the (IR) value. Therefore, it will be understood that all peaks disclosed herein have peak position reproducibility associated with the disclosed value ± each analytical method. The XRPD peak position reproducibility is ±0.2, expressed in degrees 2θ. 13 The peak position reproducibility of 13C NMR is ±0.2 ppm. The IR peak position reproducibility is ±2 cm. -1 That is the case.

[0073] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in the field to which this disclosure pertains. In case of any conflict, the application containing the definition shall prevail. Unless otherwise required by context, singular terms shall include plural forms, and plural terms shall include singular forms. All publications, patents, and other references described herein are incorporated by reference in their entirety for all purposes, as each individual publication or patent application is specifically and individually indicated to be incorporated by reference.

[0074] II. Salts or cocrystals In one embodiment, the present disclosure provides a salt or cocrystal of compound 1.

[0075] In one embodiment, the salt or cocrystal of compound 1 is in crystalline form. In one embodiment, the salt or cocrystal of compound 1 is an anhydrous, hydrate, or solvate. Hydrates include, for example, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, and sesquihydrate.

[0076] In one embodiment, a salt or cocrystal of compound 1 is Equation (I)

[0077] [ka] The component (a) is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid, (b) A component selected from the group consisting of sodium, piperazine, and hydrochloride Includes.

[0078] In one embodiment, the disclosure specifies that component (b) of the salt or cocrystal is sodium. In one embodiment, the disclosure specifies that the molar ratio of component (a) to component (b) sodium of the salt or cocrystal is about 1:1.

[0079] In one embodiment, the disclosure specifies that component (b) of the salt or cocrystal is piperazine. In one embodiment, the disclosure specifies that the molar ratio of component (a) to component (b) piperazine is about 2:1 or about 1:1.

[0080] In one embodiment, the disclosure specifies that component (b) of the salt or cocrystal is a hydrochloride salt. In one embodiment, the disclosure specifies that the molar ratio of component (a) to component (b) piperazine is about 1:1.

[0081] III. Crystal form of salt or cocrystal A. Compound monosodium salt In one embodiment, the sodium salt of compound 1 is a crystalline form in which the molar ratio of compound 1 to sodium is approximately 1:1.

[0082] In one embodiment, the sodium salt of compound 1 is crystalline and characterized by an XRPD pattern having peaks at 4.4±0.2, 9.4±0.2, and 20.0±0.2 degrees 2θ. In one embodiment, the sodium salt of compound 1 is crystalline and characterized by an XRPD pattern having peaks at 4.4±0.2, 9.4±0.2, 10.1±0.2, 15.1±0.2, 17.4±0.2, and 20.0±0.2 degrees 2θ. In one embodiment, the sodium salt of compound 1 is crystalline and substantially characterized by the XRPD pattern shown in Figure 1.

[0083] In one aspect, the sodium salt of Compound 1 is crystalline and has a TGA profile showing a weight loss of about 3.6% by weight at about 50 °C to about 150 °C. In one aspect, the sodium salt of Compound 1 is crystalline and is substantially characterized by the TGA profile shown in Figure 2.

[0084] In one aspect, the sodium salt of Compound 1 is crystalline and is characterized by an endothermic peak having a starting point at 216 °C ± 2 °C, determined by DSC. In one aspect, the sodium salt of Compound 1 is crystalline and is substantially according to the DSC profile shown in Figure 3.

[0085] In one aspect, the sodium salt of Compound 1 is crystalline and is characterized by the following XRPD pattern in Table 1 expressed based on degree 2θ and relative intensity.

[0086]

Table 1-1

[0087]

Table 1-2

[0088] In one aspect, the sodium salt of Compound 1 is crystalline and is characterized by an IR pattern having peaks at 1358.3 ± 2.0, 1606.1 ± 2.0, and 1649.0 ± 2.0 cm -1 In one aspect, the sodium salt of Compound 1 is crystalline and is characterized by an IR pattern having peaks at 1307.4 ± 2.0, 1358.3 ± 2.0, 1606.1 ± 2.0, and 1649.0 ± 2.0 cm -1 In one aspect, the sodium salt of Compound 1 is crystalline and is characterized by the following IR peaks in Table 2.

[0089]

Table 2

[0090] In one embodiment, the sodium salt of compound 1 is crystalline and is substantially characterized by the IR pattern shown in Figure 4.

[0091] In one embodiment, the sodium salt of compound 1 is crystalline and is characterized by at least two of the following features (Ii) to (I-iv). (Ii) XRPD pattern with peaks at 4.4±0.2, 9.4±0.2, and 20.0±0.2 degrees 2θ. (I-ii) TGA profile shown in Figure 2, (I-iii) DSC profile shown in Figure 3, or (I-iv) IR patterns with peaks as described in Table 2.

[0092] In one embodiment, the sodium salt of compound 1 is crystalline and has aqueous solubility greater than 38 mg / mL.

[0093] In one embodiment, the sodium salt of compound 1 is crystalline and has form A.

[0094] In one embodiment, the sodium salt of compound 1 is crystalline and substantially free of other polymorphs. In one embodiment, the sodium salt of compound 1 is crystalline and has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0095] B. Compound 1: Piperazine salt or cocrystal In one embodiment, the piperazine salt or cocrystal of compound 1 is a crystalline form in which the molar ratio of compound 1 to piperazine is approximately 2:1.

[0096] In one embodiment, the piperazine salt or cocrystal of compound 1 is a) Crystal form characterized by an XRPD pattern having peaks at 4.9±0.2, 12.5±0.2, and 14.9±0.2 degrees 2θ. b) Crystal form characterized by an XRPD pattern having peaks at 5.1±0.2, 13.6±0.2, and 20.5±0.2 degrees 2θ, and c) Crystal shape characterized by an XRPD pattern with peaks at 5.5±0.2, 16.7±0.2, and 19.9±0.2 degrees 2θ. It is a crystal form selected from the group consisting of the following.

[0097] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and characterized by an XRPD pattern having peaks at 4.9±0.2, 12.5±0.2, and 14.9±0.2 degrees 2θ. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and characterized by an XRPD pattern having peaks at 4.9±0.2, 12.5±0.2, 14.9±0.2, and 16.2±0.2 degrees 2θ. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and substantially characterized by the XRPD pattern shown in Figure 5.

[0098] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and has a TGA profile showing a weight loss of about 9.5% at about 40°C to about 150°C. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and is substantially characterized by the TGA profile shown in Figure 6.

[0099] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and characterized by an endothermic peak with an initiation point at approximately 226°C, as determined by DSC. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and substantially characterized by the DSC profile shown in Figure 7.

[0100] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and is characterized by the XRPD pattern shown in Table 3 below, expressed on a basis of degree 2θ and relative intensity.

[0101] [Table 3]

[0102] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline, as shown in Figure 8. 13 It is substantially characterized by 13C NMR.

[0103] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and is characterized by at least two of the following features (Ii) to (I-iv). (Ii) XRPD pattern with peaks at 4.9±0.2, 12.5±0.2, and 14.9±0.2 degrees 2θ. (I-ii) TGA profile shown in Figure 6, (I-iii) DSC profile shown in Figure 7, or (I-iv) Essentially shown in Figure 8 13 13C NMR.

[0104] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and hydrated.

[0105] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and has form B.

[0106] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and characterized by an XRPD pattern having peaks at 5.1±0.2, 13.6±0.2, and 20.5±0.2 degrees 2θ. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and characterized by an XRPD pattern having peaks at 5.1±0.2, 13.6±0.2, 15.9±0.2, 17.0±0.2, 19.6±0.2, and 20.5±0.2 degrees 2θ. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and substantially characterized by the XRPD pattern shown in Figure 9.

[0107] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and has a TGA profile showing a first weight loss of about 0.9 wt% from about 38°C to about 100°C and a second weight loss of about 2.1 wt% from about 100°C to about 160°C. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and is substantially characterized by the TGA profile shown in Figure 10.

[0108] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and characterized by an endothermic peak with an onset point at approximately 214°C, determined by DSC. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and substantially characterized by the DSC profile shown in Figure 11.

[0109] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and is characterized by the XRPD pattern shown in Table 4 below, expressed on a basis of degree 2θ and relative intensity.

[0110] [Table 4]

[0111] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and is characterized by at least two of the following features (Ii) to (I-iii). (Ii) XRPD pattern with peaks at 5.1±0.2, 13.6±0.2, and 20.5±0.2 degrees 2θ. (I-ii) The TGA profile shown in Figure 10, or (I-iii) DSC profile shown in Figure 11.

[0112] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and has morphology C.

[0113] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and characterized by an XRPD pattern having peaks at 5.5±0.2, 16.7±0.2, and 19.9±0.2 degrees 2θ. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and characterized by an XRPD pattern having peaks at 5.5±0.2, 16.7±0.2, 19.9±0.2, and 21.8±0.2 degrees 2θ. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and substantially characterized by the XRPD pattern shown in Figure 12.

[0114] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and is characterized by the XRPD pattern shown in Table 5 below, expressed on a basis of degree 2θ and relative intensity.

[0115] [Table 5]

[0116] In one embodiment, the piperazine salt of compound 1 is crystalline and has morphology D.

[0117] In one embodiment, the piperazine salt or cocrystal of compound 1 is a crystalline form in which the molar ratio of compound 1 to piperazine is approximately 1:1.

[0118] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and characterized by an XRPD pattern having peaks at 4.9±0.2, 12.5±0.2, and 18.3±0.2 degrees 2θ. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and characterized by an XRPD pattern having peaks at 4.9±0.2, 12.5±0.2, 13.6±0.2, and 18.3±0.2 degrees 2θ. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and substantially characterized by the XRPD pattern shown in Figure 13.

[0119] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and has a TGA profile showing a weight loss of about 11.2% at about 45°C to about 150°C. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and is substantially characterized by the TGA profile shown in Figure 14.

[0120] In one embodiment, the crystalline form of the piperazine salt or cocrystal is characterized by an endothermic peak with an initiation point at approximately 221°C, determined by DSC. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and substantially characterized by the DSC profile shown in Figure 15.

[0121] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and is characterized by the XRPD pattern shown in Table 6 below, expressed on a basis of degree 2θ and relative intensity.

[0122] [Table 6]

[0123] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and is characterized by at least two of the following features (Ii) to (I-iii). (Ii) XRPD pattern with peaks at 4.9±0.2, 12.5±0.2, and 18.3±0.2 degrees 2θ. (I-ii) The TGA profile shown in Figure 12, or (I-iii) DSC profile shown in Figure 13.

[0124] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and has morphology E.

[0125] In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and substantially free of other polymorphs. In one embodiment, the piperazine salt or cocrystal of compound 1 is crystalline and has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0126] C. Compound 1 Hydrochloride In one embodiment, the hydrochloride salt of compound 1 is a crystalline form in which the molar ratio of compound 1 to the hydrochloride salt is approximately 1:1.

[0127] In one embodiment, the hydrochloride salt of compound 1 is crystalline and characterized by an XRPD pattern having peaks at 4.6±0.2, 7.2°±0.2, and 17.7°±0.2 degrees 2θ. In one embodiment, the hydrochloride salt of compound 1 is crystalline and characterized by an XRPD pattern having peaks at 4.6±0.2, 15.2±0.2, 7.2°±0.2, and 17.7°±0.2 degrees 2θ. In one embodiment, the hydrochloride salt of compound 1 is crystalline and substantially characterized by the XRPD pattern shown in Figure 16.

[0128] In one embodiment, the hydrochloride salt of compound 1 is crystalline and has a TGA profile showing a weight loss of about 3.2% by weight at about 40°C to about 120°C. In another embodiment, the hydrochloride salt of compound 1 is crystalline and has a TGA profile showing a weight loss of about 5.5% by weight at about 120°C to about 165°C. In another embodiment, the hydrochloride salt of compound 1 is crystalline and is substantially characterized by the TGA profile shown in Figure 17.

[0129] In one embodiment, the hydrochloride salt of compound 1 is crystalline and characterized by an endothermic peak with an onset at approximately 100°C and an exothermic line with an onset at approximately 138°C, as determined by DSC. In one embodiment, the hydrochloride salt of compound 1 is crystalline and substantially as shown by the DSC profile in Figure 18.

[0130] In one embodiment, the sodium salt of compound 1 is crystalline and is characterized by the XRPD pattern shown in Table 7 below, expressed on a basis of degree 2θ and relative intensity.

[0131] [Table 7-1]

[0132] [Table 7-2]

[0133] In one embodiment, the hydrochloride salt of compound 1 is a hydrochloride salt with values ​​of 1119.0±2.0, 1540.2±2.0, and 1667.5±2.0 cm. -1 Characterization is determined by an IR pattern having a peak at . In one embodiment, the hydrochloride salt of compound 1 is crystalline and has 1119.0±2.0, 1540.2±2.0, 1573.5±2.0, 1606.1±2.0, and 1667.5±2.0 cm -1 The compound is characterized by an IR pattern with a peak. In one embodiment, the hydrochloride salt of compound 1 is crystalline and is characterized by the IR peaks shown in Table 8 below.

[0134] [Table 8-1]

[0135] [Table 8-2]

[0136] In one embodiment, the hydrochloride salt of compound 1 is crystalline and is substantially characterized by the IR pattern shown in Figure 19.

[0137] In one embodiment, the hydrochloride salt of compound 1 is crystalline and is characterized by at least two of the following features (Ii) to (Iv). (Ii) XRPD pattern with peaks at 4.6±0.2, 7.2±0.2, and 17.7±0.2 degrees 2θ. (I-ii) TGA profile shown in Figure 17, (I-iii) DSC profile shown in Figure 18, or (I-iv) IR patterns with peaks as described in Table 8.

[0138] In one embodiment, the hydrochloride salt of compound 1 is crystalline and has form F.

[0139] In one embodiment, the hydrochloride salt of compound 1 is crystalline and substantially free of other polymorphs. In one embodiment, the hydrochloride salt of compound 1 is crystalline and has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

[0140] In one embodiment, a salt or cocrystal of compound 1 disclosed herein contains a detectable amount of the crystalline form of compound 1 as a free acid. In several embodiments, a salt or cocrystal of compound 1 disclosed herein contains a detectable amount of the crystalline form of compound 1 as a free acid, where the free acid is in crystalline form.

[0141] IV. Pharmaceutical Compositions In one embodiment, the present disclosure provides a pharmaceutical composition comprising one or more salts or cocrystals of Compound 1 disclosed herein.

[0142] In one embodiment, the pharmaceutical composition comprises a crystalline form of a salt or cocrystal of compound 1. In one embodiment, the pharmaceutical composition comprises a salt or cocrystal of compound 1, which is an anhydrous, hydrate, or solvate. In one embodiment, the pharmaceutical composition comprises a salt or cocrystal of compound 1 as described herein.

[0143] A pharmaceutical composition comprising one or more salts or cocrystals of compound 1 may be in a form suitable for oral use, such as tablets, lozenges, dispersible powders or granules, or hard or soft capsules. Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives for pharmaceutically refined and acceptable preparations.

[0144] In one embodiment, the pharmaceutical composition contains approximately 100 mg to approximately 1500 mg, approximately 100 mg to approximately 1400 mg, approximately 100 mg to approximately 1300 mg, approximately 100 mg to approximately 1200 mg, approximately 100 mg to approximately 1100 mg, approximately 100 mg to approximately 1000 mg, approximately 100 mg to approximately 900 mg, approximately 100 mg to approximately 800 mg, approximately 100 mg to approximately 700 mg, approximately 100 mg to approximately 600 mg, approximately 100 mg to approximately 500 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 200 mg, or approximately 100 mg to approximately 150 mg of one or more salts or cocrystals of Compound 1 disclosed herein. In one embodiment, the pharmaceutical composition comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg of one or more salts or cocrystals of Compound 1 disclosed herein.

[0145] In some embodiments, the pharmaceutical composition is an oral tablet. In some embodiments, the oral tablet contains about 0.1 mg to 2000 mg of a salt or cocrystal of Compound 1 disclosed herein. In some embodiments, the oral tablet contains about 1 mg to about 2000 mg of a salt or cocrystal of Compound 1 disclosed herein. In some embodiments, the oral tablet contains about 1 mg to about 1000 mg of a salt or cocrystal of Compound 1 disclosed herein. In some embodiments, the oral tablet contains about 100 mg to about 800 mg of a salt or cocrystal of Compound 1 disclosed herein. In some embodiments, the oral tablet contains about 50 mg to about 400 mg of a salt or cocrystal of Compound 1 disclosed herein. In some embodiments, the oral tablet contains about 100 mg to about 400 mg of a salt or cocrystal of Compound 1 disclosed herein. In some embodiments, the oral tablet contains about 100 mg to about 300 mg of a salt or cocrystal of Compound 1 disclosed herein. In some embodiments, the oral tablets contain about 500 mg to about 1000 mg of a salt or cocrystal of Compound 1 disclosed herein. In some embodiments, the oral tablets contain about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg g comprises a salt or cocrystal of Compound 1 disclosed herein, approximately 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, or 2000 mg.In some embodiments, the oral tablet contains 800 mg of a salt or cocrystal of Compound 1 disclosed herein. In some embodiments, the oral tablet contains 400 mg of a salt or cocrystal of Compound 1 disclosed herein. In some embodiments, the oral tablet contains 300 mg of a salt or cocrystal of Compound 1 disclosed herein. In some embodiments, the oral tablet contains about 200 mg of a salt or cocrystal of Compound 1 disclosed herein.

[0146] V. Treatment method In another embodiment, the Disclosure provides a method for treating a particular type of diabetes mellitus, comprising administering a pharmaceutically acceptable composition disclosed herein to a patient in need thereof. The method may comprise administering a pharmaceutical composition comprising a therapeutically effective amount of one or more salts or cocrystals of Compound 1 disclosed herein to a patient in need thereof.

[0147] In one embodiment, the patient has type 1 diabetes mellitus. In another embodiment, the patient has type 2 diabetes mellitus.

[0148] In some embodiments, the patient is treated with insulin therapy. In some embodiments, insulin therapy is continuous insulin infusion. In some embodiments, insulin therapy is continuous subcutaneous insulin infusion. In some embodiments, insulin therapy is multiple daily administrations of insulin.

[0149] In another embodiment, the Disclosure provides a method for treating a condition or disease mediated by glucokinase deficiency, or a condition that benefits from increased glucokinase activity, comprising administering a compound or pharmaceutical composition of the Disclosure to a subject in need thereof.

[0150] In another embodiment, the Disclosure provides a method for treating metabolic disorders, lowering blood glucose, treating hyperglycemia, treating hypoglycemia, treating impaired glucose tolerance (IGT), treating syndrome X, treating impaired fasting glucose (IFG), delaying the progression from impaired glucose tolerance (IGT) to type 2 diabetes, delaying the progression from non-insulin-requiring type 2 diabetes to insulin-requiring type 2 diabetes, treating dyslipidemia, treating hyperlipidemia, treating hypertension, reducing food intake, regulating appetite, treating obesity, regulating eating behavior, or promoting the secretion of enteroincretins, comprising administering a compound or pharmaceutical composition of the Disclosure to a subject in need of these treatments.

[0151] In another embodiment, the present disclosure provides a method for preserving beta cell quantity and function, comprising administering a compound or pharmaceutical composition of the present disclosure to a subject in need of such treatment.

[0152] In another embodiment, the present disclosure provides a method for preserving and / or increasing the mass and function of beta cells in a subject who has undergone islet transplantation, the method comprising administering a compound or pharmaceutical composition of the present disclosure to a subject in need of such treatment.

[0153] In another embodiment, the Disclosure provides a method for improving liver function and / or survival in a liver transplant subject, comprising administering a compound or pharmaceutical composition of the Disclosure to a subject in need of such treatment. In a further embodiment, the administration is performed pre-transplant, during transplant, post-transplant, or any combination thereof.

[0154] In another embodiment, the Disclosure provides a method for preventing diabetic ketoacidosis in a subject or reducing the occurrence of diabetic ketoacidosis events, comprising administering a compound or pharmaceutical composition of the Disclosure to a subject in need of such treatment.

[0155] Depending on the condition, disease, or illness being treated and the condition of the subject, the pharmaceutical compositions provided herein may be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous or intra-arterial (e.g., via catheter), ICV, intracisterna magna injection or infusion, subcutaneous injection, or implantation), inhaled, nasal, vaginal, rectal, sublingual, and / or locally (e.g., perdermal or topical) by any route of administration, and may be formulated alone or with pharmaceutically acceptable vehicles, carriers, diluents, excipients, or mixtures thereof suitable for each route of administration, into suitable dosage units. In one embodiment, the pharmaceutical composition is administered orally.

[0156] For oral administration, the pharmaceutical compositions provided herein may be provided in solid, semi-solid, or liquid dosage forms for oral administration. When used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, lozenges, sachets, granules, medicinal chewing gum, granules, active ingredient powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions (e.g., aqueous or oily suspensions), wafers, powders, elixirs, syrups, pills, poultices, or pastes. In one embodiment, the pharmaceutical composition is administered as a tablet.

[0157] The dose may be in the form of one, two, three, four, five, six, or more subdivided doses administered at appropriate intervals per day. The dose or subdivided dose may be administered in the form of dose units containing compound 1, with a dose of approximately 1 mg to approximately 2000 mg, approximately 10 mg to approximately 2000 mg, approximately 100 mg to approximately 1500 mg, approximately 200 mg to approximately 1500 mg, approximately 300 mg to approximately 1500 mg, approximately 400 mg to approximately 1500 mg, approximately 500 mg to approximately 1500 mg, approximately 500 mg to approximately 1000 mg, or approximately 500 mg to approximately 800 mg per drug unit. For example, doses or sub-doses may be administered in the form of dosing units containing one or more salts or cocrystals of Compound 1 disclosed herein, in amounts of approximately 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg.

[0158] In one embodiment, a patient is administered one or more salts or cocrystals of Compound 1 disclosed herein, in amounts of approximately 2000 mg, approximately 1500 mg, approximately 1000 mg, approximately 800 mg, approximately 500 mg, approximately 300 mg, or approximately 100 mg, once daily.

[0159] In one embodiment, a patient is administered once daily one or more salts or cocrystals of Compound 1 disclosed herein, in amounts of 100 mg to approximately 1500 mg, approximately 200 mg to approximately 1500 mg, 300 mg to approximately 1500 mg, 400 mg to approximately 1500 mg, approximately 500 mg to approximately 1500 mg, approximately 500 mg to approximately 1000 mg, or approximately 500 mg to approximately 800 mg.

[0160] In some embodiments, the patient is administered daily in amounts ranging from about 0.1 mg to about 2000 mg of a salt or cocrystal of compound 1 disclosed herein. In some embodiments, the patient is administered daily in amounts ranging from about 1 mg to about 2000 mg of a salt or cocrystal of compound 1 disclosed herein. In some embodiments, the patient is administered daily in amounts ranging from about 100 mg to about 800 mg of a salt or cocrystal of compound 1 disclosed herein. In some embodiments, the patient is administered daily in amounts ranging from about 50 mg to about 400 mg of a salt or cocrystal of compound 1 disclosed herein. In some embodiments, the patient is administered daily in amounts ranging from about 100 mg to about 400 mg of a salt or cocrystal of compound 1 disclosed herein. In some embodiments, the patient is administered daily in amounts ranging from about 100 mg to about 300 mg of a salt or cocrystal of compound 1 disclosed herein. In some embodiments, the patient is administered daily in amounts ranging from about 500 mg to about 1000 mg of a salt or cocrystal of compound 1 disclosed herein. In some cases, patients take approximately 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 500 mg, and 55 mg. A salt or cocrystal of Compound 1 disclosed herein is administered once daily in amounts of 0 mg, approximately 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1200 mg, approximately 1250 mg, approximately 1300 mg, approximately 1350 mg, approximately 1400 mg, approximately 1450 mg, approximately 1500 mg, approximately 1550 mg, approximately 1600 mg, approximately 1650 mg, approximately 1700 mg, approximately 1750 mg, approximately 1800 mg, approximately 1850 mg, approximately 1900 mg, approximately 1950 mg, or approximately 2000 mg. In some embodiments, the patient is administered approximately 800 mg of a salt or cocrystal of Compound 1 disclosed herein once daily. In some embodiments, the patient is administered approximately 400 mg of a salt or cocrystal of Compound 1 disclosed herein once daily.In some embodiments, the patient is administered about 300 mg of a salt or cocrystal of compound 1 disclosed herein once daily. In some embodiments, the patient is administered about 200 mg of a salt or cocrystal of compound 1 disclosed herein once daily. In some embodiments, the patient is administered about 100 mg of a salt or cocrystal of compound 1 disclosed herein once daily. [Examples]

[0161] A. Abbreviations and initials i.Analysis technology

[0162] [Table 9]

[0163] ii. Solvents and Reagents

[0164] [Table 10]

[0165] iii. Others

[0166] [Table 11]

[0167] B. General Test Methods i. Fast evaporation A solution containing compound 1 and a specific guest was prepared in a clean glass vial in a selected solvent and evaporated from the open vial at ambient temperature.

[0168] ii. Vacuum filtration The suspension was vacuum filtered on a 0.45 μm nylon filter membrane using a water aspirator.

[0169] iii. Relative humidity (RH) stress The specific solid was placed in a clean, capless glass vial, the vial was covered with aluminum foil, and the sealed jar was placed under controlled RH conditions maintained by a saturated solution of KNO3, with the specific solid being kept under 94% RH conditions. The sealed jar was kept at ambient temperature.

[0170] C. Measurement Technology iX-ray powder diffraction (XRPD) Method a: Transparent Geometry XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer or a PANalytical Empyrean diffractometer with an incident beam of Cu radiation generated by an Optix long-length fine-focus light source. An ellipsoidal multilayer mirror was used to focus the Cu Kα X-rays onto the detector via the sample. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to confirm that the observed Si(111) peak position matched the NIST-certified position. The sample was sandwiched between 3 μm thick films and analyzed by transmission geometry. Background caused by the atmosphere was minimized using a beam stop, a short scatter removal extension, and a scatter removal knife edge. Broadening from axial divergence was minimized using solar slits for the incident and diffracted beams. Diffraction patterns were collected using a scanning position detector (X'Celerator) and Data Collector software v.5.5, positioned 240 mm from the sample.

[0171] Method B: Reflection XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu Kα radiation generated by an Optix long-length fine-focus light source. The diffractometer was constructed based on symmetric Bragg-Brentano geometry. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to confirm that the observed Si 111 peak position matched the NIST-certified position. The sample was prepared as a thin, circular layer centered on a silicon zero-background substrate. A scatter-removal slit (SS) was used to minimize background generated by air. Solar slits were used for the incident and diffracted beams to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position detector (X'Celerator) and Data Collector software v.2.2b, placed 240 mm away from the sample.

[0172] ii. TGA / DSC combined analysis TGA / DSC combined analysis was performed using a Mettler Toledo TGA / DSC3+ analyzer. Temperature and enthalpy were adjusted using indium, tin, and zinc, and then verified with indium. The balance was verified with calcium oxalate. The sample was placed in an aluminum dish. The dish was sealed, a hole was made in the lid, and then placed in the TG furnace. The weighed aluminum dish, configured as the sample dish, was placed on the control stage. The furnace was heated under nitrogen.

[0173] iii. Differential scanning calorimeter DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Isothermal or gradient temperatures were superimposed on time series of random temperature pulses of different durations using TOPEM®. Taulag adjustment was performed with indium, tin, and zinc. Temperature and enthalpy were adjusted with octane, phenyl salicylate, indium, tin, and zinc. Then, the adjustment was confirmed with octane, phenyl salicylate, indium, tin, and zinc. The sample was placed in a sealed aluminum DSC dish and its weight was accurately recorded. A hole was made in the lid of the dish, and then it was inserted into the DSC cell. The weighing aluminum dish configured as the sample dish was placed on the reference side of the cell. Data was collected at a heating rate of 10°C / min from -30°C to 140°C.

[0174] iv. Hot Stage Microscopy (HSM) Hot stage microscopy was performed using a Leica DM LP microscope equipped with a SPOT Insight® color digital camera and a Linkam FTIR 600 hot stage. Temperature calibration was performed using a USP melting point standard. The sample was placed on a coverslip, and another coverslip was placed on top of that. While the stage was heated, each sample was visually observed using a 20x objective lens with a cross-polarizer and primary red corrector, 0.40 NA, or a 10x objective lens with a 0.22 NA. Images were captured using SPOT software (v.4.5.9).

[0175] v. Dynamic vapor deposition (DVS) Moisture sorption / desorption data were collected using the DVS Intrinsic surface measurement system. Samples were not dried before analysis. Acsorption and desorption data were collected in 10% RH increments within the range of 5% to 95% RH. The equilibrium criterion used for analysis was a weight change of less than 0.0100% over 5 minutes, with a maximum equilibrium time of 3 hours. The data were not corrected for the initial moisture content of the samples.

[0176] vi. Infrared spectroscopy (IR) IR spectra were acquired using a Nicolet 6700 Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid-far infrared light source, potassium bromide (KBr) beam splitter, and deuterated triglycine sulfate (DTGS) detector. Wavelength validation was performed using NIST SRM1921b (polystyrene). A damped total internal reflection (ATR) accessory (Thunderdome®, Thermo Spectra-Tech) with a germanium (Ge) crystal was used for data acquisition. This spectrum was obtained at 4 cm. -1 This represents 256 simultaneous addition scans collected with a spectral resolution of [specify spectral resolution]. A background dataset was acquired using a clean Ge crystal. By taking the ratio of these two datasets, a logarithmic 1 / R (R = reflectance) spectrum was obtained.

[0177] vii. Ion chromatography The sodium content (cation) of a sample of compound 1 was analyzed using an unverified IC technique capable of quantifying multiple anions and cations. Sigma-Aldrich Multielement Cation Standard (cation part number 89316, 10.0 mg / kg) was diluted 10-fold with water to a practical concentration of 1000 μg / L. System compatibility was established based on scientific judgment using this standard reagent.

[0178] IC analysis was performed using a Dionex ICS-5000+ series ion chromatograph. The ICS-5000+ consists of two chromatography systems sharing an autosampler. The anion detection system was equipped with a gradient pump, eluent generation module, conductivity detector, and suppressor (AERS 500 4mm). A Dionex UTAC-ULP1 5x23mm concentration column was installed in place of the sample loop. A Dionex IonPac® AG19 4x50mm guard column and a Dionex IonPac® AS19 4x250mm analytical column were installed. The system used for cation detection was equipped with a non-gradient pump, eluent generation module, conductivity detector, and suppressor (CERS 500 4mm). A Dionex TCC-UP1 concentration column was installed in place of the sample loop. A Dionex IonPac® CG12A-5μm 3x30mm guard column and a Dionex IonPac® CS12A-5μm 3x150mm analytical column were installed.

[0179] Water (18.2 MΩ, supplied from ELGA Purelab Flex 2) was used to fill the eluent reservoir, prepare standard samples, and clean the autosampler. DMSO was used for sample preparation and associated blank injection.

[0180] viii. Solution proton nuclear magnetic resonance spectroscopy ( 1 (H NMR) Using deuterated DMSO, the proton NMR spectrum of the solution was acquired using an Avance 600 MHz NMR spectrometer.

[0181] ix. Solid-state carbon nuclear magnetic resonance ( 13 C solid state NMR) solid 13 C-cross-polarized magic angle rotation (CP / MAS) NMR spectrum obtained using an Agilent DD2-400 spectrometer (Larmor frequency: 13Spectra were acquired at C=100.549MHz, 1H=399.819MHz. The sample was packed into a 4mm PENCIL-type zirconia and rotated at a magic angle of 12kHz. During acquisition, the spectrum was acquired at ambient temperature with phase modulation (SPINAL-64) high-power 1H decoupling, lamp amplitude cross-polarization contact time 5ms, acquisition time 30ms, inter-scan delay 15 seconds, spectral width 45kHz, 2678 data points, and 400 core scans. Free induction decay (FID) was processed at the 2678 points using Agilent VnmrJ3.2A software, and the exponential linewidth coefficient was set to 10Hz to improve the signal-to-noise ratio. The first three FID data points were inversely predicted using the VNMR linear prediction algorithm to generate a flat baseline. The chemical shift of the spectral peaks was externally referenced to the carbonyl carbon resonance of glycine at 176.5ppm.

[0182] D. Exam Example 1: Preparation of Compound 1 Sodium Form A Compound 1 (62.3 mg) and sodium benzoate (22.3 mg, 1:1.1, API: Na+, mol / mol) were placed in a 20 mL glass scintillation vial with dioxane (15 mL). The sample was stirred under ambient conditions for 8 days to obtain a turbid suspension. The suspension was frozen by maintaining it at a temperature below ambient temperature (2–8°C). After 10 days, the sample was warmed to ambient temperature and then stirred for another day under ambient conditions to obtain a white suspension, which was isolated by vacuum filtration using a nylon membrane filter (pore size 0.45 μm). The solid is a white powder composed of needle-like structures that exhibit birefringence and quenching under a polarizing microscope.

[0183] Example 2a: Preparation of compound 1 piperazine form B Piperazine (15.8 mg) and acetonitrile (1 mL) were packed into a 2dram glass vial, and the mixture was briefly sonicated to obtain a clear solution. The solution was transferred to a 20 mL glass scintillation vial containing compound 1 (80.7 mg, 1:1 API: piperazine, mol / mol). Additional acetonitrile (6 mL) was added to obtain a turbid slurry containing a white solid. This sample was stirred under ambient conditions for 1 day, then additional acetonitrile (7 mL) was added, the sample was vortexed for approximately 2 minutes, and then stirred under ambient conditions for 5 days. The sample was protected from light during the test. The solid was isolated by vacuum filtration using a paper filter. The obtained solid was a white flake with off-white solid aggregates exhibiting birefringence and quenching under a polarizing microscope.

[0184] Example 2b: Preparation of compound 1 piperazine form B Piperazine (69.4 mg) was dissolved in acetonitrile (3 mL), and then added to compound 1 (82.3 mg, piperazine excess ratio) in two drum vials along with an additional acetonitrile (3 mL). The suspension was briefly sonicated and stirred under ambient conditions for two days to obtain a thick white paste. The solid was isolated by vacuum filtration using a nylon membrane filter (pore size 0.45 μm) and washed with an arbitrary amount of fresh acetonitrile. The solid was white and showed birefringence and quenching under a polarizing microscope.

[0185] Example 3a: Preparation of compound 1 piperazine form C Piperazine (16.3 mg) was dissolved in dichloromethane (2 mL), and the solution was added to two glass vials containing compound 1 (77.8 mg, APP:piperidine, mol / mol at a 1:1.1 ratio). After stirring for approximately 30 seconds under ambient conditions, the sample became a clear solution. When heptane (5 mL) was added to the solution, a white solid precipitated. The resulting white suspension was stirred under ambient conditions for 3 days, and the solid was isolated by vacuum filtration using a nylon membrane filter (pore size 0.45 μm), yielding a static white solid exhibiting birefringence and quenching under a polarizing microscope.

[0186] Example 3b: Preparation of compound 1 piperazine form C Piperazine (10.3 mg) was dissolved in dichloromethane (2.5 mL), and the solution was transferred to a 2 dram vial containing compound 1 (100.6 mg, APP:piperazine, mol / mol at a ratio of 2:1.1). A clear solution was obtained after approximately 1 minute. The solution was stirred under ambient conditions for approximately 25 minutes, and when heptane (6.5 mL) was added, a viscous white solid was immediately formed. The sample became a homogeneous, concentrated white suspension upon shaking and was stirred for 3 days. Next, the sample was centrifuged, and the liquid was decanted to obtain a wet white solid.

[0187] Example 3c: Preparation of compound 1 piperazine form C Piperazine (9.5 mg) was dissolved in acetone (5 mL). The solution was transferred to two glass vials containing compound 1 (102.5 mg, APP:piperazine in a 2:1 ratio, mol / mol), and the sample was stirred under ambient conditions for 24 days. The resulting concentrated white suspension was centrifuged, and the liquid was decanted from the sample to obtain a white solid.

[0188] Example 4: Preparation of compound 1 piperazine form D Compound 1-piperazine form D was produced from piperazine form B by drying the solid in a vacuum oven at room temperature for one day.

[0189] Example 5: Preparation of compound 1 piperazine form E Piperazine (67.9 mg) was dissolved in dichloromethane (3 mL), and the solution was transferred to a 20 mL glass scintillation vial containing TPP399 (80.0 mg, piperazine excess ratio). A clear solution was immediately obtained, to which heptane (7.5 mL) was added to produce a milky white suspension. The suspension was stirred under ambient conditions for 2 days. The solid was isolated by vacuum filtration using a nylon membrane filter (pore size 0.45 μm), washed with an arbitrary amount of acetonitrile, and a white powder exhibiting birefringence and quenching under a polarizing microscope was obtained.

[0190] Example 6: Preparation of Compound 1 Hydrochloride Form F

[0191] [Table 12]

[0192] Various embodiments for achieving various objectives of the present invention have been described. It should be recognized that these embodiments are merely illustrative of the principles of the present invention. Numerous changes and modifications will be readily apparent to those skilled in the art without departing from the spirit and scope of the invention.

Claims

1. Equation (I) 【Chemistry 1】 The component (a) is {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid, (b) A component selected from the group consisting of sodium, piperazine, and hydrochloride A salt or cocrystal containing this material.

2. The salt or cocrystal according to claim 1, wherein component (b) is sodium.

3. The salt or cocrystal according to claim 2, wherein the molar ratio of component (a) to component (b) is approximately 1:

1.

4. The salt or cocrystal according to claim 3, wherein the salt or cocrystal is a crystalline form characterized by an XRPD pattern having peaks at 4.4±0.2, 9.4±0.2, and 20.0±0.2 degrees 2θ.

5. The crystal form according to claim 4, wherein the crystal form is characterized by an XRPD pattern having peaks at 4.4±0.2, 9.4±0.2, 10.1±0.2, 15.1±0.2, 17.4±0.2, and 20.0±0.2 degrees 2θ.

6. The crystal form according to claim 4 or 5, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 1.

7. The crystal form according to any one of claims 4 to 6, wherein the crystal form is substantially characterized by the TGA profile shown in Figure 2.

8. The crystal form according to any one of claims 4 to 7, wherein the crystal form is characterized by an endothermic peak having a starting point at 216°C ± 2°C, determined by DSC.

9. The crystal form according to any one of claims 4 to 8, wherein the crystal form is substantially characterized by the DSC profile shown in Figure 3.

10. The aforementioned crystal forms are 1358.3 ± 2.0 cm, 1606.1 ± 2.0 cm, and 1649.0 ± 2.0 cm. －１ The crystal form according to any one of claims 4 to 9, characterized by an IR pattern having a peak.

11. The aforementioned crystal forms are 1307.4±2.0, 1358.3±2.0, 1606.1±2.0, and 1649.0±2.0 cm. －１ The crystal form according to any one of claims 4 to 10, characterized by an IR pattern having a peak.

12. The crystal form according to any one of claims 4 to 11, wherein the crystal form is substantially characterized by the IR pattern shown in Figure 4.

13. The crystal form according to any one of claims 4 to 12, wherein the crystal form is morphology A.

14. The crystal form according to any one of claims 4 to 13, wherein the crystal form substantially does not contain other polymorphs.

15. The crystal form according to any one of claims 4 to 13, wherein the crystal form has a polymorphic purity of at least 90%.

16. The crystal form according to any one of claims 4 to 13, wherein the crystal form has a polymorphic purity of at least 99%.

17. The salt or cocrystal according to claim 1, wherein component (b) is piperazine.

18. The salt or cocrystal according to claim 17, wherein the molar ratio of component (a) to component (b) is approximately 2:

1.

19. The aforementioned salt or cocrystal a) Crystal form characterized by an XRPD pattern having peaks at 4.9±0.2, 12.5±0.2, and 14.9±0.2 degrees 2θ, b) Crystal forms characterized by XRPD patterns having peaks at 5.1±0.2, 13.6±0.2, and 20.5±0.2 degrees 2θ, and c) Crystalline form characterized by an XRPD pattern with peaks at 5.5±0.2, 16.7±0.2, and 19.9±0.2 degrees 2θ The salt or cocrystal according to claim 18, which is a crystal form selected from the group consisting of the above.

20. The crystal form according to claim 19, wherein the crystal form is characterized by an XRPD pattern having peaks at 4.9±0.2, 12.5±0.2, and 14.9±0.2 degrees 2θ.

21. The crystal form according to claim 20, wherein the crystal form is characterized by an XRPD pattern having peaks at 4.9±0.2, 12.5±0.2, 14.9±0.2, and 16.2±0.2 degrees 2θ.

22. The crystal form according to claim 20 or 21, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 5.

23. The crystal form according to any one of claims 20 to 22, wherein the crystal form is substantially characterized by the TGA profile shown in Figure 6.

24. The crystal form according to any one of claims 20 to 23, wherein the crystal form is characterized by an endothermic peak having an initiation point at approximately 226°C, determined by DSC.

25. The crystal form according to any one of claims 20 to 24, wherein the crystal form is substantially characterized by the DSC profile shown in Figure 7.

26. The aforementioned crystal form is shown in Figure 8. １３ A crystalline form according to any one of claims 20 to 25, substantially characterized by 13C NMR.

27. The crystalline form according to any one of claims 20 to 26, wherein the crystalline form is a hydrate.

28. The crystal form according to any one of claims 20 to 27, wherein the aforementioned crystal form is form B.

29. The crystal form according to claim 19, wherein the crystal form is characterized by an XRPD pattern having peaks at 5.1±0.2, 13.6±0.2, and 20.5±0.2 degrees 2θ.

30. The crystal form according to claim 29, wherein the crystal form is characterized by an XRPD pattern having peaks at 5.1±0.2, 13.6±0.2, 15.9±0.2, 17.0±0.2, 19.6±0.2, and 20.5±0.2 degrees 2θ.

31. The crystal form according to claim 29 or 30, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 9.

32. The crystal form according to any one of claims 29 to 31, wherein the crystal form is substantially characterized by the TGA profile shown in Figure 10.

33. The crystal form according to any one of claims 29 to 32, wherein the crystal form is characterized by an endothermic peak having an initiation point at approximately 214°C, determined by DSC.

34. The crystal form according to any one of claims 29 to 33, wherein the crystal form is substantially characterized by the DSC profile shown in Figure 11.

35. The crystal form according to any one of claims 29 to 34, wherein the crystal form is morphology C.

36. The crystal form according to claim 19, wherein the crystal form is characterized by an XRPD pattern having peaks at 5.5±0.2, 16.7±0.2, and 19.9±0.2 degrees 2θ.

37. The crystal form according to claim 35, wherein the crystal form is characterized by an XRPD pattern having peaks at 5.5±0.2, 16.7±0.2, 19.9±0.2, and 21.8±0.2 degrees 2θ.

38. The crystal form according to any one of claims 36 and 37, wherein the crystal form is substantially characterized by an XRPD pattern as shown in Figure 12.

39. The salt or cocrystal according to any one of claims 36 to 38, wherein the molar ratio of component (a) to component (b) is approximately 1:

1.

40. The salt or cocrystal according to claim 19, wherein the salt or cocrystal is a crystalline form characterized by an XRPD pattern having peaks at 4.9±0.2, 12.5±0.2, and 18.3±0.2 degrees 2θ.

41. The crystal form according to claim 40, wherein the crystal form is characterized by an XRPD pattern having peaks at 4.9±0.2, 12.5±0.2, 13.6±0.2, and 18.3±0.2 degrees 2θ.

42. The crystal form according to claim 40 or claim 41, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 13.

43. The crystal form according to any one of claims 40 to 42, wherein the crystal form is substantially characterized by the TGA profile shown in Figure 14.

44. The crystal form according to any one of claims 40 to 43, wherein the crystal form is characterized by an endothermic peak having an initiation point at approximately 221°C, determined by DSC.

45. The crystal form according to any one of claims 40 to 44, wherein the crystal form is substantially characterized by the DSC profile shown in Figure 15.

46. The crystal form according to any one of claims 40 to 45, wherein the crystal form is form E.

47. The crystalline form according to any one of claims 19 to 46, wherein the crystalline form substantially does not contain other polymorphs.

48. The crystal form according to any one of claims 19 to 46, wherein the crystal form has a polymorphic purity of at least 90%.

49. The crystal form according to any one of claims 19 to 46, wherein the crystal form has a polymorphic purity of at least 99%.

50. The salt or cocrystal according to claim 1, wherein component (b) is a hydrochloride salt.

51. The salt or cocrystal according to claim 50, wherein the molar ratio of component (a) to component (b) is approximately 1:

1.

52. The salt or cocrystal according to claim 51, wherein the salt or cocrystal is a crystalline form characterized by an XRPD pattern having peaks at 4.6 ± 0.2°, 7.2° ± 0.2°, and 17.7° ± 0.2° 2θ.

53. The crystal form according to claim 52, wherein the crystal form is characterized by an XRPD pattern having peaks at 4.6 ± 0.2, 15.2 ± 0.2, 7.2° ± 0.2, and 17.7° ± 0.2 degrees 2θ.

54. The crystal form according to claim 52 or claim 53, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 16.

55. The crystal form according to any one of claims 52 to 54, wherein the crystal form is substantially characterized by the TGA profile shown in Figure 17.

56. The crystal form according to any one of claims 52 to 54, wherein the crystal form is characterized by an endothermic peak having an initiation point at about 100°C and an exothermic line having an initiation point at about 138°C, determined by DSC.

57. The crystal form according to any one of claims 52 to 54, wherein the crystal form is substantially characterized by the DSC profile shown in Figure 18.

58. The aforementioned crystal forms are 1119.0 ± 2.0 cm, 1540.2 ± 2.0 cm, and 1667.5 ± 2.0 cm. －１ The crystalline form according to any one of claims 52 to 57, characterized by an IR pattern having a peak.

59. The aforementioned crystal forms are 1119.0±2.0, 1540.2±2.0, 1573.5±2.0, 1606.1±2.0, and 1667.5±2.0 cm. －１ The crystal form according to any one of claims 52 to 58, characterized by an IR pattern having a peak.

60. The crystal form according to any one of claims 52 to 59, wherein the crystal form is substantially characterized by the IR pattern shown in Figure 19.

61. The crystal form according to any one of claims 52 to 60, wherein the crystal form is morphology F.

62. The crystal form according to any one of claims 52 to 61, wherein the crystal form substantially does not contain other polymorphs.

63. The crystal form according to any one of claims 52 to 61, wherein the crystal form has a polymorphic purity of at least about 90%.

64. The crystal form according to any one of claims 52 to 61, wherein the crystal form has a polymorphic purity of at least about 99%.

65. A pharmaceutical composition comprising a salt or cocrystal according to any one of claims 1 to 64, and a pharmaceutically acceptable carrier, diluent, excipient, or mixture thereof.

66. A method for treating a specific type of diabetes mellitus, comprising administering the pharmaceutical composition according to claim 65 to a patient in need of treatment.

67. The method according to claim 66, wherein the type of diabetes is type 1 diabetes mellitus.

68. The method according to claim 66, wherein the type of diabetes is type 2 diabetes mellitus.

69. The method according to any one of claims 66 to 68, wherein the pharmaceutical composition is administered orally.

70. The method according to any one of claims 66 to 69, wherein the pharmaceutical composition is administered as a tablet.

71. The method according to any one of claims 66 to 70, wherein the patient is administered up to approximately 2000 mg of {2-[3-cyclohexyl-3-(trans-4-propoxycyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid once daily.

72. The method according to any one of claims 66 to 70, wherein the patient is administered approximately 100 mg to approximately 1500 mg of {2-[3-cyclohexyl-3-(trans-4-propoxycyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid once daily.

73. The method according to any one of claims 66 to 70, wherein the patient is administered approximately 500 mg to approximately 1000 mg of {2-[3-cyclohexyl-3-(trans-4-propoxycyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid once daily.

74. The method according to any one of claims 66 to 70, wherein the patient is administered approximately 800 mg of {2-[3-cyclohexyl-3-(trans-4-propoxycyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid once daily.

75. The method according to any one of claims 66 to 70, wherein the patient is administered less than 800 mg of {2-[3-cyclohexyl-3-(trans-4-propoxycyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid once daily.

76. The method according to any one of claims 66 to 70, wherein the patient is administered approximately 500 mg of {2-[3-cyclohexyl-3-(trans-4-propoxycyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid once daily.

77. The method according to any one of claims 66 to 70, wherein the patient is administered approximately 300 mg of {2-[3-cyclohexyl-3-(trans-4-propoxycyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid once daily.

78. The method according to any one of claims 66 to 70, wherein the patient is administered about 100 mg of {2-[3-cyclohexyl-3-(trans-4-propoxycyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid once daily.

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