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

Abstract

This invention provides the use of specific crystalline forms of compounds for the treatment of type 1 or type 2 diabetes. [Solution] The use of crystalline form A of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid ("Compound I") is provided.

Description

[Technical Field]

[0001] This disclosure relates to a) a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid ("Compound I" or "API"), b) a pharmaceutical composition comprising one or more crystalline forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid and optionally a pharmaceutically acceptable carrier, and c) a method for treating certain types of diabetes mellitus and other diseases by administering one or more crystalline forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid to a subject 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. Compound I, a hepatically selective agent, does not cause similar adverse effects. (Vella et al., Science Translational Medicine 16 Jan 2019).

[0004] Compound I is an orally administered small-molecule hepatic-selective glucokinase activator that improves glycemic control without inducing hypoglycemia, dyslipidemia, or pathological increases in hepatic glycogen or TG at therapeutically appropriate doses. (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 glucokinase, duration of glucokinase activation, oral bioavailability, tissue distribution, and stability (e.g., ability to be formulated or crystallized, shelf life). Favorable properties can lead to improved safety, tolerability, efficacy, therapeutic index, patient compliance, cost-effectiveness, and ease of manufacture.

[0006] Furthermore, there are many challenges in isolating and commercially preparing the crystalline form of compound I and the corresponding pharmaceutical formulations that possess acceptable physical properties (including chemical stability, thermal stability, solubility, hygroscopicity, and / or particle size), manufacturability of the compound (including yield, impurity removal rate during crystallization, filtration properties, drying properties, and grinding properties), and formulation feasibility (including stability with respect to pressure or compressive force during tableting). [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Vella et al., Science Translational Medicine 16 Jan 2019

Summary of the Invention

Problems to be Solved by the Invention

[0008] Therefore, there is a current need for one or more crystalline forms of Compound I that have an acceptable balance of these properties and can be used in the preparation of pharmaceutically acceptable solid dosage forms.

Means for Solving the Problems

[0009] In one aspect, the present disclosure relates to a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid. In one aspect, the crystalline form is anhydrous. In another aspect, the crystalline form is solvated.

[0010] In one aspect, the present disclosure relates to Compound I

[0011]

Chemical Formula

[0012] In one aspect, the present disclosure relates to a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid characterized by an XRPD pattern having peaks at 16.9±0.2, 17.4±0.2, and 20.1±0.2 degrees 2θ.

[0013] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is characterized by an endothermic peak having a starting point at about 160 °C, determined by DSC.

[0014] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is 1099.7±2.0, 1158.0 + 2.0, and 1313.2 + 2.0 cm -1Characterized by an IR pattern with a peak.

[0015] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is as shown in Figure 4. 13 The characteristics are substantially determined by solid-state NMR.

[0016] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid has a unit cell expressed exponentially as a simple monoclinic system. In another embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid has a unit cell with an a value of approximately 10.193 Å, a b value of approximately 12.256 Å, and a c value of approximately 18.991 Å. In yet another embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid has a unit cell with an a value of approximately 2370.9 Å 3 It has a unit cell with a volume of .

[0017] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is form A.

[0018] In one embodiment, the disclosure relates to a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido}-siazol-5-ylsulfanyl}acetic acid, characterized by an XRPD pattern having peaks at 11.0±0.2, 11.6±0.2, and 17.8±0.2 degrees 2θ.

[0019] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is characterized by an endothermic peak with an initiation point at approximately 166°C, as determined by DSC.

[0020] In one embodiment, the crystalline forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanyl}acetic acid are 1310.1±2.0, 1514.4±2.0, and 1661.3±2.0 cm². -1 Characterized by an IR pattern with a peak.

[0021] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is as shown in Figure 8. 13 It is substantially characterized by solid-state NMR.

[0022] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid has a unit cell expressed exponentially as a simple monoclinic system. In another embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid has a unit cell with an a value of approximately 11.028 Å, a b value of approximately 11.933 Å, and a c value of approximately 18.737 Å. In yet another embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid has a unit cell with an a value of approximately 2449.0 Å 3 It has a unit cell with a volume of .

[0023] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is form B.

[0024] In one embodiment, the disclosure relates to a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido}-siazol-5-ylsulfanyl}acetic acid, characterized by an XRPD pattern having peaks at 4.3±0.2, 17.4±0.2, and 21.6±0.2 degrees 2θ.

[0025] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is characterized by an endothermic peak with an initiation point at approximately 149°C, as determined by DSC.

[0026] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanyl}acetic acid is the dichloromethane solvate.

[0027] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid has a unit cell expressed exponentially as a simple monoclinic system. In another embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid has a unit cell with an a value of approximately 5.541 Å, a b value of approximately 13.040 Å, and a c value of approximately 40.818 Å. In yet another embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid has a unit cell with an a value of approximately 2947.6 Å 3 It has a unit cell with a volume of .

[0028] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is morphology C.

[0029] In one embodiment, the disclosure relates to a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido}thiazole-5-ylsulfanil}acetic acid, characterized by an XRPD pattern having peaks at 5.3±0.2, 8.7±0.2, and 26.4±0.2 degrees 2θ.

[0030] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is characterized by an endothermic peak with an initiation point at approximately 147°C, as determined by DSC.

[0031] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is as shown in Figure 13. 13 It is substantially characterized by solid-state NMR.

[0032] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is morphology D.

[0033] In one embodiment, the disclosure relates to a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido}-siazol-5-ylsulfanyl}acetic acid, characterized by an XRPD pattern having peaks at 5.8±0.2, 17.9±0.2, and 18.9±0.2 degrees 2θ.

[0034] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is characterized by an endothermic peak with an initiation point at approximately 171°C, as determined by DSC.

[0035] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is form E.

[0036] In one embodiment, the disclosure relates to a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido}-siazol-5-ylsulfanyl}acetic acid, characterized by an XRPD pattern having peaks at 3.8±0.2, 9.5±0.2, and 16.8±0.2 degrees 2θ.

[0037] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is morphology F.

[0038] In one embodiment, the disclosure relates to a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido}thiazole-5-ylsulfanil}acetic acid, characterized by an XRPD pattern having peaks at 3.4±0.2, 21.2±0.2, and 21.9±0.2 degrees 2θ.

[0039] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is form G.

[0040] In one embodiment, the disclosure relates to a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido}-siazol-5-ylsulfanyl}acetic acid, characterized by an XRPD pattern having peaks at 3.8±0.2, 5.3±0.2, and 8.5±0.2 degrees 2θ.

[0041] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is morph H.

[0042] In one embodiment, the disclosure relates to a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido}thiazole-5-ylsulfanil}acetic acid, characterized by an XRPD pattern having peaks at 5.0±0.2, 16.8±0.2, and 18.8±0.2 degrees 2θ.

[0043] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is form I.

[0044] In one embodiment, the disclosure relates to the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanyl}acetic acid, characterized by an XRPD pattern having peaks at 5.9±0.2, 17.4±0.2, and 18.8±0.2 degrees 2θ.

[0045] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is characterized by an endothermic peak with an onset point at approximately 164°C, as determined by DSC.

[0046] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is morphology J.

[0047] In some embodiments, the crystalline form is substantially free of other polymorphs. In some embodiments, the crystalline form has a polymorphic purity of at least about 80%.

[0048] In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is selected from the group consisting of morphology A, morphology B, morphology C, morphology D, morphology E, morphology F, morphology G, morphology H, morphology I and morphology J. In one embodiment, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid is morphology A.

[0049] In some embodiments, the disclosure relates to a pharmaceutical composition comprising one or more of the crystalline forms described above and a pharmaceutically acceptable carrier, diluent, excipient, or mixture thereof.

[0050] In some embodiments, the present disclosure relates to a method for treating a particular type of diabetes mellitus or other disease, comprising administering the above-described pharmaceutical composition to a patient in need of treatment. In some embodiments, the type of diabetes mellitus is type 1 diabetes mellitus. In some embodiments, the type of diabetes mellitus is type 2 diabetes mellitus.

[0051] In some embodiments, the pharmaceutical composition is administered orally. In some embodiments, the pharmaceutical composition is administered as a tablet. In some embodiments, the patient is administered up to approximately 2000 mg of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid daily.

[0052] In some embodiments, the present disclosure provides a method for producing crystalline forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-yldusphanyl}acetic acid, selected from the group consisting of forms A, B, C, D, E, F, G, H, I, and J. [Brief explanation of the drawing]

[0053] [Figure 1] This is the powder X-ray diffraction pattern ("XRPD") corresponding to crystal form A. [Figure 2A] This is a differential scanning calorimetry thermogram ("DSC") corresponding to crystal form A. [Figure 2B] This is a thermogravimetric thermogram ("TGA") corresponding to crystal form A. [Figure 3] This is the infrared ("IR") spectrum corresponding to crystal form A. [Figure 4] This is a 13C solid-state NMR spectrum corresponding to crystal form A. [Figure 5] This is the XRPD corresponding to crystal form B. [Figure 6A] This is a DSC corresponding to crystal form B. [Figure 6B] This is the TGA corresponding to crystal form B. [Figure 7] This is the IR spectrum corresponding to crystal form B. [Figure 8] This is a 13C solid-state NMR spectrum corresponding to crystal form B. [Figure 9] This is an XRPD corresponding to crystal form C. [Figure 10A] This is a DSC corresponding to crystal form C. [Figure 10B] This is the TGA corresponding to crystal form C. [Figure 11] This is an XRPD corresponding to crystal form D. [Figure 12A] This is a DSC corresponding to crystal form D. [Figure 12B] This is the TGA corresponding to crystal form D. [Figure 13] This is a 13C solid-state NMR spectrum corresponding to crystal form D. [Figure 14] This is an XRPD corresponding to crystal form E. [Figure 15A] This is a DSC corresponding to crystal form E. [Figure 15B] This is the TGA corresponding to crystal form E. [Figure 16] This is an XRPD corresponding to crystal form F. [Figure 17]This is an XRPD corresponding to crystal form G. [Figure 18] This is the XRPD corresponding to crystal form H. [Figure 19] This is an XRPD corresponding to crystal form I. [Figure 20] This is the XRPD corresponding to crystal form J. [Figure 21A] This is a DSC corresponding to crystal form J. [Figure 21B] This is the TGA corresponding to crystal form J. [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 I" refers to 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 the cause of the disease, illness, or condition itself.

[0061] The terms “pharmaceutically acceptable carrier,” “pharmaceutically acceptable diluent,” or “pharmaceutically acceptable excipient” refer to 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).

[0062] 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.

[0063] 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 condition, disease, or illness. As used herein, “active ingredient” and “active substance” may be optically active isomers of the compounds described herein.

[0064] The terms “solvate” or “solvated” mean a compound or salt thereof provided herein that further comprises 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.

[0065] 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).

[0066] Crystal forms are most commonly characterized by X-ray powder diffraction (XRPD). The XRPD pattern of reflections (peaks typically represented by the angle 2θ) is generally considered the fingerprint of a particular crystal form. The relative intensities of XRPD peaks can vary significantly, particularly depending on the sample preparation technique, crystal size distribution, filters, sample positioning procedure, and the specific apparatus used. In some cases, new peaks may be observed or existing peaks may disappear depending on the type or settings of the apparatus. In some cases, any given peak within an XRPD pattern may appear as a singlet, doublet, triplet, quartet, 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 given peak in XRPD may appear with a symmetric shape or an asymmetric shape, such as a shape with a shoulder. Additionally, instrument variations and other factors can affect the 2θ value. Those skilled in the art who understand these variations can use XRPD, as well as other known physicochemical techniques, to identify or confirm the explicit features or characteristics of a particular crystal form.

[0067] The term "anhydrous" or "anhydrate" as applied to a compound refers to a solid state in which the compound does not contain water of crystallization within the crystal lattice.

[0068] Unless the context requires otherwise, the terms "comprise", "comprises", and "comprising" are to be construed inclusively rather than exclusively, and are used on the basis of and with the clear understanding that the applicant intends each of those terms to be construed in that way in the interpretation of this patent, including the following claims.

[0069] For all embodiments disclosed herein, peak position reproducibility is at degrees 2θ (XRPD), ppm ( 13 C solid NMR), and -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.

[0070] 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.

[0071] II. Crystal Form In one embodiment, the disclosure relates to the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid. In one embodiment, the crystalline form is 1 It is anhydrous, as determined by 1H NMR. In another embodiment, the crystal form is 1 It is solvated as determined by 1H NMR.

[0072] In one embodiment, this disclosure relates to formula (I)

[0073] [ka] The crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid, a) Crystal form characterized by an XRPD pattern having peaks at 16.9±0.2, 17.4±0.2, and 20.1±0.2 degrees 2θ. b) Crystal form characterized by an XRPD pattern having peaks at 11.0±0.2, 11.6±0.2, and 17.8±0.2 degrees 2θ. c) Crystal form characterized by an XRPD pattern with peaks at 4.3±0.2, 17.4±0.2, and 21.6±0.2 degrees 2θ. d) Crystal form characterized by an XRPD pattern having peaks at 5.3±0.2, 8.7±0.2, and 26.4±0.2 degrees 2θ. e) Crystal form characterized by an XRPD pattern with peaks at 5.8±0.2, 17.9±0.2, and 18.9±0.2 degrees 2θ. f) Crystal form characterized by an XRPD pattern with peaks at 3.8±0.2, 9.5±0.2, and 16.8±0.2 degrees 2θ. g) Crystal form characterized by an XRPD pattern with peaks at 3.4±0.2, 21.2±0.2, and 21.9±0.2 degrees 2θ. h) Crystal form characterized by an XRPD pattern with peaks at 3.8±0.2, 5.3±0.2, and 8.5±0.2 degrees 2θ. i) Crystal form characterized by an XRPD pattern having peaks at 5.0±0.2, 16.8±0.2, and 18.8±0.2 degrees 2θ, and j) Crystal shape characterized by an XRPD pattern with peaks at 5.9±0.2, 17.4±0.2, and 18.8±0.2 degrees 2θ This relates to crystal forms selected from the group consisting of the following.

[0074] A. Crystal form A In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 16.9±0.2, 17.4±0.2, and 20.1±0.2 degrees 2θ. In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 8.7±0.2, 16.9±0.2, 17.4±0.2, and 20.1±0.2 degrees 2θ. In one embodiment, the crystalline form of compound I is substantially characterized by the XRPD pattern shown in Figure 1.

[0075] In one embodiment, the crystalline form of compound I is characterized by the XRPD pattern shown in Table 1 below, based on the degree 2θ and relative intensity.

[0076] [Table 1]

[0077] In one embodiment, the crystalline form of compound I is characterized by an endothermic peak with an initiation point at approximately 160°C, determined by DSC. In one embodiment, the crystalline form of compound I is substantially characterized by the DSC profile shown in Figure 2A. In one embodiment, the crystalline form of compound I is substantially characterized by the TGA profile shown in Figure 2B.

[0078] In one embodiment, the crystalline forms of compound I are 1099.7±2.0, 1158.0±2.0 cm², and 1313.2±2.0 cm². -1 Characterization is determined by an IR pattern having a peak. In one embodiment, the crystal form of compound I is 1099.7±2.0, 1158.0±2.0, 1238.7±2.0, and 1313.2±2.0 cm. -1 The characteristics are determined by the IR pattern having peaks. In one embodiment, the crystalline form of compound I is characterized by the IR peaks in Table 2 below.

[0079] [Table 2]

[0080] In one embodiment, the crystalline form of compound I is substantially characterized by the IR pattern shown in Figure 3.

[0081] In one embodiment, the crystalline form of compound I is shown in Figure 4. 13 It is substantially characterized by solid-state NMR.

[0082] In one embodiment, the crystal form is, 1 It is anhydrous, as determined by 1H NMR.

[0083] In one embodiment, the crystalline form of compound I has a unit cell expressed exponentially as a simple monoclinic system. In another embodiment, the crystalline form of compound I has a unit cell with an a value of approximately 10.193 Å, a b value of approximately 12.256 Å, and a c value of approximately 18.991 Å. In yet another embodiment, the crystalline form of compound I has a unit cell of approximately 2370.9 Å 3 It has a unit cell with a volume of .

[0084] In one embodiment, the crystalline form of compound I is morphology A.

[0085] B. Crystal form B In one embodiment, the disclosure relates to a crystalline form of compound I, characterized by an XRPD pattern having peaks at 11.0±0.2, 11.6±0.2, and 17.8±0.2 degrees 2θ. In one embodiment, the disclosure relates to a crystalline form of compound I, characterized by an XRPD pattern having peaks at 11.0±0.2, 11.6±0.2, 17.8±0.2, and 21.1±0.2 degrees 2θ.

[0086] In one embodiment, the crystalline form of compound I is substantially characterized by the XRPD pattern shown in Figure 5.

[0087] In one embodiment, the crystalline form of compound I is characterized by the XRPD patterns in Table 3 below, based on the degree 2θ and relative intensity.

[0088] [Table 3]

[0089] In one embodiment, the crystalline form of compound I is characterized by an endothermic peak with an initiation point at approximately 166°C, determined by DSC. In one embodiment, the crystalline form of compound I is substantially characterized by the DSC profile shown in Figure 6A. In one embodiment, the crystalline form of compound I is substantially characterized by the TGA profile shown in Figure 6B.

[0090] In one embodiment, the crystalline forms of compound I are 1310.1±2.0, 1514.4±2.0, and 1661.3±2.0 cm². -1 Characterization is determined by an IR pattern having a peak. In one embodiment, the crystal form of compound I is 1097.3±2.0, 1310.1±2.0, 1541.4±2.0, and 1661.3±2.0 cm. -1 The characteristics are determined by the IR pattern having peaks. In one embodiment, the crystalline form of compound I is characterized by the IR peaks in Table 4 below.

[0091] [Table 4]

[0092] In one embodiment, the crystalline form of compound I is substantially characterized by the IR pattern shown in Figure 7.

[0093] In one embodiment, the crystalline form of compound I is shown in Figure 8. 13 It is substantially characterized by solid-state NMR.

[0094] In one embodiment, the crystal form is, 1 It is anhydrous, as determined by 1H NMR.

[0095] In one embodiment, the crystalline form of compound I has a unit cell expressed exponentially as a simple monoclinic system. In another embodiment, the crystalline form of compound I has a unit cell with an a value of approximately 11.028 A, a b value of approximately 11.933 A, and a c value of approximately 18.737 A. In yet another embodiment, the crystalline form of compound I has a unit cell of approximately 2449.0 Å 3 It has a unit cell with a volume of .

[0096] In one embodiment, the crystalline form of compound I is morphology B.

[0097] C.Crystal form C In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 4.3±0.2, 17.4±0.2, and 21.6±0.2 degrees 2θ. In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 4.3±0.2, 8.0±0.2, 17.4±0.2, and about 21.6±0.2 degrees 2θ.

[0098] In one embodiment, the crystalline form of compound I is substantially characterized by the XRPD pattern shown in Figure 9.

[0099] In one embodiment, the crystalline form of compound I is characterized by the XRPD pattern shown in Table 5 below, based on the degree 2θ and relative intensity.

[0100] [Table 5-1]

[0101] [Table 5-2]

[0102] In one embodiment, the crystalline form of compound I is characterized by an endothermic peak with an initiation point at approximately 149°C, determined by DSC. In one embodiment, the crystalline form of compound I is substantially characterized by the DSC profile shown in Figure 10A. In one embodiment, the crystalline form of compound I is substantially characterized by the TGA profile shown in Figure 10B.

[0103] In one embodiment, the crystal form is, 1 It is a solvate determined by 1H NMR. In one embodiment, the crystalline form of compound I is the dichloromethane solvate.

[0104] In one embodiment, the crystalline form of compound I has a unit cell expressed exponentially as a simple monoclinic system. In another embodiment, the crystalline form of compound I has a unit cell with an a value of approximately 5.541 Å, a b value of approximately 13.040 Å, and a c value of approximately 40.818 Å. In yet another embodiment, the crystalline form of compound I has a unit cell with an a value of approximately 2947.6 Å 3 It has a unit cell with a volume of .

[0105] In one embodiment, the crystalline form of compound I is morphology C.

[0106] D. Crystal form D In one embodiment, the disclosure relates to a crystalline form of compound I, characterized by an XRPD pattern having peaks at 5.3±0.2, 8.7±0.2, and 26.4±0.2 degrees 2θ.

[0107] In one embodiment, the crystalline form of compound I is substantially characterized by the XRPD pattern shown in Figure 11.

[0108] In one embodiment, the crystalline form of compound I is characterized by the XRPD patterns in Table 6 below, based on the degree 2θ and relative intensity.

[0109] [Table 6]

[0110] In one embodiment, the crystalline form of compound I is characterized by an endothermic peak with an initiation point at approximately 147°C, determined by DSC. In one embodiment, the crystalline form of compound I is substantially characterized by the DSC profile shown in Figure 12A. In one embodiment, the crystalline form of compound I is substantially characterized by the TGA profile shown in Figure 12B.

[0111] In one embodiment, the crystalline form of compound I is shown in Figure 13. 13 It is substantially characterized by solid-state NMR.

[0112] In one embodiment, the crystalline form of compound I is morphology D.

[0113] E. Crystal form E In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 5.8±0.2, 17.9±0.2, and 18.9±0.2 degrees 2θ. In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 5.8±0.2, 17.9±0.2, 18.9±0.2, and 20.7±0.2 degrees 2θ.

[0114] In one embodiment, the crystalline form of compound I is substantially characterized by the XRPD pattern shown in Figure 14.

[0115] In one embodiment, the crystalline form of compound I is characterized by the XRPD pattern shown in Table 7 below, based on the degree 2θ and relative intensity.

[0116] [Table 7]

[0117] In one embodiment, the crystalline form of compound I is characterized by an endothermic peak with an initiation point at approximately 171°C, determined by DSC. In one embodiment, the crystalline form of compound I is substantially characterized by the DSC profile shown in Figure 15A. In one embodiment, the crystalline form of compound I is substantially characterized by the TGA profile shown in Figure 15B.

[0118] In one embodiment, the crystalline form of compound I is morphology E.

[0119] F. Crystal form F In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 3.8±0.2, 9.5±0.2, and 16.8±0.2 degrees 2θ. In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 3.8±0.2, 9.5±0.2, 16.8±0.2, and 17.9±0.2 degrees 2θ.

[0120] In one embodiment, the crystalline form of compound I is substantially characterized by the XRPD pattern shown in Figure 16.

[0121] In one embodiment, the crystalline form of compound I is characterized by the XRPD pattern shown in Table 8 below, based on the degree 2θ and relative intensity.

[0122] [Table 8]

[0123] In one embodiment, the crystalline form of compound I is morphology F.

[0124] G. Crystal form G In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 3.4±0.2, 21.2±0.2, and 21.9±0.2 degrees 2θ. In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 3.4±0.2, 21.2±0.2, 21.9±0.2, and 22.4±0.2 degrees 2θ.

[0125] In one embodiment, the crystalline form of compound I is substantially characterized by the XRPD pattern shown in Figure 17.

[0126] In one embodiment, the crystalline form of compound I is characterized by the XRPD pattern shown in Table 9 below, based on the degree 2θ and relative intensity.

[0127] [Table 9]

[0128] In one embodiment, the crystalline form of compound I is morphology G.

[0129] H. Crystal form H In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 3.8±0.2, 5.3±0.2, and 8.5±0.2 degrees 2θ. In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 3.8±0.2, 5.3±0.2, 8.5±0.2, and 15.9±0.2 degrees 2θ.

[0130] In one embodiment, the crystalline form of compound I is substantially characterized by the XRPD pattern shown in Figure 18.

[0131] In one embodiment, the crystalline form of compound I is characterized by the XRPD patterns in Table 10 below, based on the degree 2θ and relative intensity.

[0132] [Table 10]

[0133] In one embodiment, the crystalline form of compound I is morphology H.

[0134] I. Crystal Form I In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 5.0±0.2, 16.8±0.2, and 18.8±0.2 degrees 2θ. In one embodiment, the disclosure relates to a crystalline form of compound I characterized by an XRPD pattern having peaks at 5.0±0.2, 15.9±0.2, 16.8±0.2, and 18.8±0.2 degrees 2θ.

[0135] In one embodiment, the crystalline form of compound I is substantially characterized by the XRPD pattern shown in Figure 19.

[0136] In one embodiment, the crystalline form of compound I is characterized by the XRPD pattern shown in Table 11 below, based on the degree 2θ and relative intensity.

[0137] [Table 11]

[0138] In one embodiment, the crystalline form of compound I is morphology I.

[0139] J. Crystal form J In one embodiment, the disclosure relates to a crystalline form of compound I, characterized by an XRPD pattern having peaks at 5.9±0.2, 17.4±0.2, and 18.8±0.2 degrees 2θ. In one embodiment, the disclosure relates to a crystalline form of compound I, characterized by an XRPD pattern having peaks at 5.9±0.2, 12.7±0.2, 17.4±0.2, and 18.8±0.2 degrees 2θ.

[0140] In one embodiment, the crystalline form of compound I is substantially characterized by the XRPD pattern shown in Figure 20.

[0141] In one embodiment, the crystalline form of compound I is characterized by an endothermic peak with an initiation point at approximately 164°C, determined by DSC. In one embodiment, the crystalline form of compound I is substantially characterized by the DSC profile shown in Figure 21A. In one embodiment, the crystalline form of compound I is substantially characterized by the TGA profile shown in Figure 21B.

[0142] In one embodiment, the crystalline form of compound I is characterized by the XRPD patterns in Table 12 below, based on the degree 2θ and relative intensity.

[0143] [Table 12]

[0144] In one embodiment, the crystalline form of compound I is morphology J.

[0145] In some embodiments, any one of the above-described crystalline forms substantially contains no other polymorphs. In some embodiments, the crystalline forms have a polymorphic purity of at least about 80%. In some embodiments, the crystalline forms have a polymorphic purity of at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0146] In one embodiment, the crystalline form of compound I is selected from the group consisting of morphology A, morphology B, morphology C, morphology D, morphology E, morphology F, morphology G, morphology H, morphology I, and morphology J. In one embodiment, the crystalline form of compound I is morphology A.

[0147] In one embodiment, the crystalline form of compound I is a mixture of two or more forms selected from the group consisting of forms A, B, C, D, E, F, G, H, I, and J. In another embodiment, the crystalline form of compound I is a mixture of two or more forms selected from the group consisting of forms A, B, and C. In yet another embodiment, the crystalline form of compound I is a mixture of forms A and B, where form B is the more abundant form and form A is the less abundant form.

[0148] In some embodiments, this disclosure provides methods for preparing crystalline forms of compound I, selected from the group consisting of morphology A, morphology B, morphology C, morphology D, morphology E, morphology F, morphology G, morphology H, morphology I, and morphology J. One or more methods for preparing morphology A to J are described in the Experimental section of this specification.

[0149] Mai. Pharmaceutical composition This disclosure relates to a pharmaceutical composition comprising one crystalline form of compound I (A to J) and a pharmaceutically acceptable carrier, diluent, or excipient, or a mixture thereof.

[0150] In one embodiment, the pharmaceutical composition comprises one crystalline form of compound I, any one of forms A to J.

[0151] A pharmaceutical composition comprising any one crystalline form A to J of compound I may be in a form suitable for oral use, such as a tablet, lozenge, dispersible powder or granule, or hard or soft capsule. A composition intended for oral use may be prepared according to any known method, and such a composition may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives for a pharmaceutically refined and acceptable preparation.

[0152] In some embodiments, the pharmaceutical composition may be administered to a subject via oral, parenteral (e.g., subcutaneous, intravenous, intramuscular, intrasternal, and injectable techniques), rectal, intranasal, topical, or transdermal (e.g., via the use of a patch) routes.

[0153] 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 any one crystalline form A to J of compound I 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 any one crystalline form A to J of Compound I disclosed herein.

[0154] 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 2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid in one crystalline form of any of forms A to J. In some embodiments, the oral tablet contains about 1 mg to about 2000 mg of one crystalline form of compound I in any of forms A to J. In some embodiments, the oral tablet contains about 1 mg to about 1000 mg of one crystalline form of compound I in any of forms A to J. In some embodiments, the oral tablet contains about 100 mg to about 800 mg of one crystalline form of compound I in any of forms A to J. In some embodiments, the oral tablet contains about 50 mg to about 400 mg of one crystalline form of compound I in any of forms A to J. In some embodiments, the oral tablet contains about 100 mg to about 400 mg of one crystalline form of compound I from A to J. In some embodiments, the oral tablet contains about 100 mg to about 300 mg of one crystalline form of compound I from A to J. In some embodiments, the oral tablet contains about 500 mg to about 1000 mg of one crystalline form of compound I from A to J.In some cases, oral tablets are available in doses of 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, 475 mg, 500 mg, 550 mg, 600 mg, and 650 mg. g contains one crystalline form of Compound I, forms A to J, in amounts of 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 one crystalline form of Compound I, forms A to J. In some embodiments, the oral tablet contains 400 mg of one crystalline form of Compound I, forms A to J. In some embodiments, the oral tablet contains 300 mg of one crystalline form of compound I, forms A to J. In some embodiments, the oral tablet contains about 200 mg of one crystalline form of compound I, forms A to J.

[0155] IV. Treatment method In some embodiments, the present disclosure relates to a method for treating a particular type of diabetes, comprising administering the above-described pharmaceutical composition to a patient in need of treatment. The method may comprise administering a therapeutically effective amount of the pharmaceutical composition comprising one crystalline form of any one of forms A to J of compound I. In some embodiments, the type of diabetes mellitus is type 1 diabetes mellitus. In some embodiments, the type of diabetes mellitus is type 2 diabetes mellitus. In some embodiments, the type of diabetes mellitus is one or two of type 1 and type 2 diabetes mellitus.

[0156] 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.

[0157] 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, the method comprising administering a compound or pharmaceutical composition of the Disclosure to a subject in need of treatment.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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 one of the crystalline forms A to J, with each drug unit containing 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. For example, doses or sub-doses may be administered in the form of dosing units containing any one of the crystalline forms A to J 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.

[0166] In some embodiments, the patient is administered approximately 0.1 mg to approximately 2000 mg of one crystalline form of Compound I (A-J) daily. In some embodiments, the patient is administered approximately 1 mg to approximately 2000 mg of one crystalline form of Compound I (A-J) daily. In some embodiments, the patient is administered approximately 100 mg to approximately 800 mg of one crystalline form of Compound I (A-J) daily. In some embodiments, the patient is administered approximately 50 mg to approximately 400 mg of one crystalline form of Compound I (A-J) daily. In some embodiments, the patient is administered approximately 100 mg to approximately 400 mg of one crystalline form of Compound I (A-J) daily. In some embodiments, the patient is administered approximately 100 mg to approximately 300 mg of one crystalline form of Compound I (A-J) daily. In some embodiments, the patient is administered approximately 500 mg to approximately 1000 mg of one crystalline form of Compound I (A-J) daily. 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 5 mg. The patient is administered 50 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 of one crystalline form of Compound I, A to J, once daily. In some embodiments, the patient is administered approximately 800 mg of one crystalline form of Compound I, A to J, once daily. In some embodiments, the patient is administered approximately 400 mg of one crystalline form of Compound I, A to J, once daily.In some embodiments, the patient is administered approximately 300 mg of one crystalline form of compound I, forms A to J, once daily. In some embodiments, the patient is administered approximately 200 mg of one crystalline form of compound I, forms A to J, once daily. In some embodiments, the patient is administered approximately 100 mg of one crystalline form of compound I, forms A to J, once daily. [Examples]

[0167] A. Abbreviations and acronyms

[0168] [Table 13-1]

[0169] [Table 13-2]

[0170] B. Test Method

[0171] Example 1: Stable form and hydrate screen via slurry polishing test The slurry mixing test targets stable forms, including stable solvates and hydrates.

[0172] Slurry mixing tests were performed by stirring the solid compound I in specified solvents and solvent mixtures at various temperatures for 7 days (heated) or 14-18 days (at and below ambient temperature). The test conditions and a summary of the results are detailed in Table 13.

[0173] [Table 14-1]

[0174] [Table 14-2]

[0175] Example 2: Polymorphic Screen Unless otherwise specified, the solid form of compound I was used as the starting material. The materials produced in the research were used in the selected tests.

[0176] Method a: Evaporation test The starting material solution was partially evaporated or evaporated to dry at ambient temperature or high temperature, either from an open vial for fast evaporation (FE) or from a vial covered with pinhole aluminum foil for slow evaporation (SE). Prior to evaporation, the solution was filtered at ambient temperature or high temperature using a 0.2 μm nylon filter.

[0177] Method b: Cooling test The starting material solution was prepared in the specified solvent at a high temperature using a hot plate for heating. These solutions were typically passed through a 0.2 μm nylon filter and then through a hot filter, and placed in a warm receiving vial. For rapid cooling (CC), the vial was quickly transferred to a bath below ambient temperature (usually dry ice / acetone), for fast cooling (FC), the vial was removed from the high-temperature location, or for slow cooling (SC), heating was stopped. If solid material precipitated, it was separated at low temperature by vacuum filtration. If the solution remained clear, the sample was kept below ambient temperature, or further crystallization techniques were applied.

[0178] Method c: Slurry test The solid material was suspended in a specific solvent. Next, the suspension was stirred at ambient temperature or a set temperature. After a certain period of time, the solid material was separated.

[0179] Method d: Solvent / antisolvent precipitation Solutions of the starting materials were prepared at ambient temperature or high temperature and filtered using a 0.2 μm nylon filter. These solutions were then mixed with a suitable reverse solvent at high temperature. If no solid material was observed, the sample was cooled to ambient temperature or below, or other crystallization techniques were applied.

[0180] Polymorph screening was performed using various solvent-based methods, including evaporation, cooling, slurrying, solvent / reverse solvent addition, and combinations thereof. Detailed test conditions, findings, and XRPD results are summarized in Table 14.

[0181] [Table 15-1]

[0182] [Table 15-2]

[0183] [Table 15-3]

[0184] Example 3: Preparation of selected materials Table 15 summarizes the preparation conditions for the selected materials.

[0185] [Table 16]

[0186] Table 16 summarizes the drying conditions for the selected materials.

[0187] [Table 17]

[0188] Example 4: Competitive Slurry Test To identify the thermodynamically most stable anhydrous form among forms A, D, B, and E, competitive slurries were prepared in acetone at 2–8°C, ambient temperature, and 45°C.

[0189] Under each condition, equal amounts of solids obtained from four different forms / materials were slurryed in a pre-saturated solution at the test temperature for 7 days. The solids were then separated and wet-analyzed by XRPD. Detailed test conditions and XRPD results are summarized in Table 17.

[0190] [Table 18]

[0191] X-ray powder diffraction (XRPD) XRPD patterns were collected using a PANalytical X'Pert PRO MPD or 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.

[0192] Thermogravimetric analysis and differential scanning calorimetry combined analysis (TGA / DSC) 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.

[0193] Dynamic vapor sorption (DVS) Moisture sorption / desorption data was collected using the DVS Intrinsic surface measurement system. Samples were not dried before analysis. For incoming lots, sorption 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% in 5 minutes, with a maximum equilibrium time of 3 hours. The data were not corrected for the initial moisture content of the samples.

[0194] Hot stage microscopy (HSM) A Leica DM LP microscope equipped with a SPOT Insight® color digital camera was fitted with a Linkam FTIR 600 hot stage for hot stage microscopy. 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, and a 0.40 NA. Images were captured using SPOT software (v.4.5.9).

[0195] Polarized light microscopy (PLM) PLM was performed using a Leica DM LP microscope equipped with a Spot Insight color camera. Cross-polarized light was used with a primary red corrector. Various objective lenses were used to observe the samples. The samples were suspended in mineral oil or a dispersant selected for the method. Images were acquired at room temperature using Spot Advanced software (v.4.5.9). A micrometer bar was inserted into the images as a size reference. Particle size was measured using an eyepiece reticle scale calibrated with a NIST traceable stage micrometer.

[0196] Proton solution nuclear magnetic resonance (MMU) 1 (H NMR) Solution NMR spectra were acquired using a Bruker AVANCE 600MHz spectrometer with DMSO-d6.

[0197] Carbon-13 solid-state nuclear magnetic resonance spectroscopy ( 13 C solid state NMR) Agilent DD2-400 spectrometer (Larmor frequency: 13 C = 100.549 MHz, 1 Using H=399.812MHz, 13 Solid-C64 cross-polarized magic-angle rotation (CP / MAS) NMR spectra were acquired at ambient temperature. The sample was packed into a 4 mm PENCIL-type zirconia rotor and rotated at 12 kHz with a magic angle. 1 With an H pulse width of 2.6 μs (90°), a gradient amplitude cross-polarization contact time of 5 ms, an acquisition time of 30 ms, an inter-scan delay of 10 seconds, a spectral width of 45 kHz, 2678 data points, and 1600 simultaneous additional scans, phase modulation (SPINAL-64) high power was performed during the acquisition time. 1 H decoupling was performed and spectra were acquired. Using Agilent VnmrJ 3.2A software, free induction decay (FID) was processed at 65,536 points, and the exponential linewidthing factor was set to 10 Hz to improve the signal-to-noise ratio. The first three data points of the FID were inversely predicted using the VNMR linear prediction algorithm to generate a flat baseline. The chemical shifts of the spectral peaks were externally referenced to the carbonyl carbon resonance of glycine at 176.5 ppm.

[0198] 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 obtained using a clean Ge crystal. By taking the ratio of these two datasets, a logarithmic 1 / R (R = reflectance) spectrum was obtained.

[0199] XRPD Index In this study, the high-resolution XRPD pattern of compound I was indexed using X'Pert High Score Plus 2.2a (2.2.1). Indexing and structural refinement were performed using computer simulations. The agreement between the observed peaks and the acceptable peak positions indicated by the red bars demonstrates a consistent unit cell determination. The successful indexing of the pattern indicates that the sample is mainly composed of single-crystal phases. The assigned quenching symbols, unit cell parameters, and space groups consistent with the derived quantities are shown in a table, with the provisional indexing solution shown below each figure. To confirm the provisional indexing solution, it is necessary to determine the molecular packing motifs within the crystallographic unit cell. No attempt was made to determine molecular packing.

[0200] conclusion In this study, multiple crystalline forms of compound I, including forms A to J, were observed.

[0201] Forms A, B, D, and E are anhydrous forms of compound I. Of these, form A is considered to be the most stable form in the temperature range of 2–8°C to 45°C, based on the results from competitive slurries.

[0202] Form C is thought to be a DCM solvate that undergoes desolvation to form D. Form F is also a solvate and converts to form D upon drying.

[0203] Form I may be an isosolvate. Form I dries to form E or a solid similar to form E.

[0204] G and H are disordered crystalline substances and may be solvates. They become disordered upon drying.

[0205] While the present invention has been described in relation to its particular aspects, it is understood that further modifications are possible, and this application is intended to cover any modifications, uses, or adaptations, including deviations from the disclosure, that generally follow the present principles, are within the scope of prior art or common practice in which the present invention pertains, are applicable to the essential features described herein, and are subject to the claims.

Claims

1. Equation (I) 【Chemistry 1】 The crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid, a) Crystal form characterized by an XRPD pattern having peaks at 16.9±0.2, 17.4±0.2, and 20.1±0.2 degrees 2θ, b) Crystal form characterized by an XRPD pattern having peaks at 11.0±0.2, 11.6±0.2, and 17.8±0.2 degrees 2θ, c) Crystal form characterized by an XRPD pattern having peaks at 4.3±0.2, 17.4±0.2, and 21.6±0.2 degrees 2θ. d) Crystal form characterized by an XRPD pattern having peaks at 5.3±0.2, 8.7±0.2, and 26.4±0.2 degrees 2θ. e) Crystal form characterized by an XRPD pattern having peaks at 5.8±0.2, 17.9±0.2, and 18.9±0.2 degrees 2θ, f) Crystal form characterized by an XRPD pattern having peaks at 3.8±0.2, 9.5±0.2, and 16.8±0.2 degrees 2θ. g) Crystal form characterized by an XRPD pattern having peaks at 3.4±0.2, 21.2±0.2, and 21.9±0.2 degrees 2θ, h) Crystal form characterized by an XRPD pattern having peaks at 3.8±0.2, 5.3±0.2, and 8.5±0.2 degrees 2θ. i) Crystal forms characterized by XRPD patterns having peaks at 5.0±0.2, 16.8±0.2, and 18.8±0.2 degrees 2θ, and j) Crystal form characterized by an XRPD pattern with peaks at 5.9±0.2, 17.4±0.2, and 18.8±0.2 degrees 2θ A crystal form selected from the group consisting of the following.

2. The crystal form according to claim 1, wherein the crystal form is characterized by an XRPD pattern having peaks at 16.9±0.2, 17.4±0.2, and 20.1±0.2 degrees 2θ.

3. The crystal form according to claim 2, wherein the crystal form is characterized by an XRPD pattern having peaks at 8.7±0.2, 16.9±0.2, 17.4±0.2, and 20.1±0.2 degrees 2θ.

4. The crystal form according to claim 2 or 3, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 1.

5. The crystal form according to any one of claims 2 to 4, wherein the crystal form is characterized by an endothermic peak having an initiation point at approximately 160°C, determined by DSC.

6. The crystal form according to any one of claims 2 to 5, wherein the crystal form is substantially characterized by the DSC profile shown in Figure 2A.

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

8. The aforementioned crystal forms are 1099.7±2.0, 1158.0±2.0, and 1313.2±2.0 cm. －１ The crystal form according to any one of claims 2 to 7, characterized by an IR pattern having a peak.

9. The aforementioned crystal forms are 1099.7±2.0, 1158.0±2.0, 1238.7±2.0, and 1313.2±2.0 cm. －１ The crystal form according to any one of claims 2 to 8, characterized by an IR pattern having a peak.

10. The crystal form according to any one of claims 2 to 9, wherein the crystal form is substantially characterized by the IR pattern shown in Figure 3.

11. The aforementioned crystal form is shown in Figure 4. １３ A crystalline form according to any one of claims 2 to 10, substantially characterized by solid-state NMR.

12. The crystal form according to any one of claims 2 to 11, wherein the crystal form is anhydrous.

13. The crystal form according to any one of claims 2 to 12, wherein the crystal form has a unit cell that is expressed exponentially as a simple monoclinic system.

14. The crystal form according to any one of claims 2 to 13, wherein the crystal form has a unit cell having an a value of about 10.193 Å, a b value of about 12.256 Å, and a c value of about 18.991 Å.

15. The aforementioned crystal form is approximately 2370.9 Å. ３ A crystal form according to any one of claims 2 to 14, having a unit cell having a volume of .

16. The crystal form according to any one of claims 2 to 15, wherein the aforementioned crystal form is form A.

17. The crystal form according to claim 1, wherein the crystal form is characterized by an XRPD pattern having peaks at 11.0 ± 0.2, 11.6 ± 0.2, and 17.8 ± 0.2 degrees 2θ.

18. The crystal form according to claim 17, wherein the crystal form is characterized by an XRPD pattern having peaks at 11.0±0.2, 11.6±0.2, 17.8±0.2, and 21.1±0.2 degrees 2θ.

19. The crystal form according to claim 17 or claim 18, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 5.

20. The crystal form according to any one of claims 17 to 19, wherein the crystal form is characterized by an endothermic peak having an initiation point at approximately 166°C, determined by DSC.

21. The crystal form according to any one of claims 17 to 20, wherein the crystal form is substantially characterized by the DSC profile shown in Figure 6A.

22. The crystal form according to any one of claims 17 to 21, wherein the crystal form is substantially characterized by the TGA profile shown in Figure 6B.

23. The aforementioned crystal forms are 1310.1±2.0 cm, 1514.4±2.0 cm, and 1661.3±2.0 cm. －１ The crystal form according to any one of claims 17 to 22, characterized by an IR pattern having a peak.

24. The aforementioned crystal forms are 1097.3±2.0, 1310.1±2.0, 1541.4±2.0, and 1661.3±2.0 cm. －１ The crystal form according to any one of claims 17 to 23, characterized by an IR pattern having a peak.

25. The crystal form according to any one of claims 17 to 24, wherein the crystal form is substantially characterized by the IR pattern shown in Figure 7.

26. The aforementioned crystal form is shown in Figure 8. １３ A crystalline form according to any one of claims 17 to 25, substantially characterized by solid-state NMR.

27. The crystal form according to any one of claims 17 to 26, wherein the crystal form is anhydrous.

28. The crystal form according to any one of claims 17 to 27, wherein the crystal form has a unit cell that is expressed exponentially as a simple monoclinic system.

29. The crystal form according to any one of claims 17 to 28, wherein the crystal form has a unit cell having an a value of about 11.028 Å, a b value of about 11.933 Å, and a c value of about 18.737 Å.

30. The aforementioned crystal form is approximately 2449.0 Å. ３ A crystal form according to any one of claims 17 to 29, having a unit cell having a volume of .

31. The crystal form according to any one of claims 17 to 30, wherein the aforementioned crystal form is form B.

32. The crystal form according to claim 1, wherein the crystal form is characterized by an XRPD pattern having peaks at 4.3±0.2, 17.4±0.2, and 21.6±0.2 degrees 2θ.

33. The crystal form according to claim 32, wherein the crystal form is characterized by an XRPD pattern having peaks at 4.3±0.2, 8.0±0.2, 17.4±0.2, and approximately 21.6±0.2 degrees 2θ.

34. The crystal form according to claim 32 or claim 33, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 9.

35. The crystal form according to any one of claims 32 to 34, wherein the crystal form is characterized by an endothermic peak having an initiation point at approximately 149°C, determined by DSC.

36. The crystal form according to any one of claims 32 to 35, wherein the crystal form is substantially characterized by the DSC profile shown in Figure 10A.

37. The crystal form according to any one of claims 32 to 36, wherein the crystal form is substantially characterized by the TGA profile shown in Figure 10B.

38. The crystalline form according to any one of claims 32 to 37, wherein the crystalline form is a dichloromethane solvate.

39. The crystal form according to any one of claims 32 to 38, wherein the crystal form has a unit cell that is expressed exponentially as a simple monoclinic crystal system.

40. The crystal form according to any one of claims 32 to 39, wherein the crystal form has a unit cell having an a value of about 5.541 Å, a b value of about 13.040 Å, and a c value of about 40.818 Å.

41. The crystalline form has a unit cell having a volume of about 2947.6 Å ３ The crystalline form according to any one of claims 32 to 40, which has a unit cell having a volume of ３ .

42. The crystal form according to any one of claims 32 to 41, wherein the crystal form is morphology C.

43. The crystal form according to claim 1, wherein the crystal form is characterized by an XRPD pattern having peaks at 5.3±0.2, 8.7±0.2, and 26.4±0.2 degrees 2θ.

44. The crystal form according to claim 43, wherein the crystal form is characterized by an XRPD pattern having peaks at 5.3±0.2, 8.7±0.2, 18.2±0.2, and 26.4±0.2 degrees 2θ.

45. The crystalline form according to claim 43 or claim 44, substantially characterized by the XRPD pattern shown in Figure 11.

46. The crystal form according to any one of claims 43 to 45, wherein the crystal form is characterized by an endothermic peak having an initiation point at approximately 147°C, determined by DSC.

47. The crystal form according to any one of claims 43 to 46, wherein the crystal form is substantially characterized by the DSC profile shown in Figure 12A.

48. The crystal form according to any one of claims 43 to 47, wherein the crystal form is substantially characterized by the TGA profile shown in Figure 12B.

49. The aforementioned crystal form is shown in Figure 13. １３ A crystalline form according to any one of claims 43 to 48, substantially characterized by solid-state NMR.

50. The crystal form according to any one of claims 43 to 49, wherein the crystal form is anhydrous.

51. The crystal form according to any one of claims 43 to 50, wherein the crystal form is morphology D.

52. The crystal form according to claim 1, wherein the crystal form is characterized by an XRPD pattern having peaks at 5.8±0.2, 17.9±0.2, and 18.9±0.2 degrees 2θ.

53. The crystal form according to claim 52, wherein the crystal form is characterized by an XRPD pattern having peaks at 5.8±0.2, 17.9±0.2, 18.9±0.2, and 20.7±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 14.

55. 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 approximately 171°C, determined by DSC.

56. The crystal form according to any one of claims 52 to 55, wherein the crystal form is substantially characterized by the DSC profile shown in Figure 15A.

57. The crystal form according to any one of claims 52 to 56, wherein the crystal form is substantially characterized by the TGA profile shown in Figure 15B.

58. The crystal form according to any one of claims 52 to 57, wherein the crystal form is anhydrous.

59. The crystal form according to any one of claims 52 to 58, wherein the crystal form is form E.

60. The crystal form according to claim 1, wherein the crystal form is characterized by an XRPD pattern having peaks at 3.8±0.2, 9.5±0.2, and 16.8±0.2 degrees 2θ.

61. The crystal form according to claim 60, wherein the crystal form is characterized by an XRPD pattern having peaks at 3.8±0.2, 9.5±0.2, 16.8±0.2, and 17.9±0.2 degrees 2θ.

62. The crystal form according to claim 60 or claim 61, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 16.

63. The crystalline form according to any one of claims 60 to 62, wherein the crystalline form is a solvate.

64. The crystal form according to any one of claims 60 to 63, wherein the crystal form is morphology F.

65. The crystal form according to claim 1, wherein the crystal form is characterized by an XRPD pattern having peaks at 3.4±0.2, 21.2±0.2, and 21.9±0.2 degrees 2θ.

66. The crystal form according to claim 65, wherein the crystal form is characterized by an XRPD pattern having peaks at 3.4±0.2, 21.2±0.2, 21.9±0.2, and 22.4±0.2 degrees 2θ.

67. The crystal form according to claim 65 or claim 66, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 17.

68. The crystalline form according to any one of claims 65 to 67, wherein the crystalline form is a solvate.

69. The crystal form according to any one of claims 65 to 68, wherein the crystal form is morphology G.

70. The crystal form according to claim 1, wherein the crystal form is characterized by an XRPD pattern having peaks at 3.8±0.2, 5.3±0.2, and 8.5±0.2 degrees 2θ.

71. The crystal form according to claim 70, wherein the crystal form is characterized by an XRPD pattern having peaks at 3.8±0.2, 5.3±0.2, 8.5±0.2, and 15.9±0.2 degrees 2θ.

72. The crystal form according to claim 70 or claim 71, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 18.

73. The crystalline form according to any one of claims 70 to 72, wherein the crystalline form is a solvate.

74. The crystal form according to any one of claims 70 to 73, wherein the crystal form is morphology H.

75. The crystal form according to claim 1, wherein the crystal form is characterized by an XRPD pattern having peaks at 5.0 ± 0.2, 16.8 ± 0.2, and 18.8 ± 0.2 degrees 2θ.

76. The crystal form according to claim 75, wherein the crystal form is characterized by an XRPD pattern having peaks at 5.0±0.2, 15.9±0.2, 16.8±0.2, and 18.8±0.2 degrees 2θ.

77. The crystal form according to claim 75 or claim 76, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 19.

78. The crystalline form according to any one of claims 75 to 77, wherein the crystalline form is a solvate.

79. The crystal form according to any one of claims 75 to 78, wherein the aforementioned crystal form is form I.

80. The crystal form according to claim 1, wherein the crystal form is characterized by an XRPD pattern having peaks at 5.9±0.2, 17.4±0.2, and 18.8±0.2 degrees 2θ.

81. The crystal form according to claim 80, wherein the crystal form is characterized by an XRPD pattern having peaks at 5.9±0.2, 12.7±0.2, 17.4±0.2, and 18.8±0.2 degrees 2θ.

82. The crystal form according to claim 80 or claim 81, wherein the crystal form is substantially characterized by the XRPD pattern shown in Figure 20.

83. The crystal form according to any one of claims 80 to 82, wherein the crystal form is characterized by an endothermic peak having an initiation point at approximately 164°C, determined by DSC.

84. The crystal form according to any one of claims 80 to 83, wherein the crystal form is substantially characterized by the DSC profile shown in Figure 21A.

85. The crystal form according to any one of claims 80 to 84, wherein the crystal form is substantially characterized by the TGA profile shown in Figure 21B.

86. The crystal form according to any one of claims 80 to 85, wherein the crystal form is morphology J.

87. The crystal form according to any one of claims 1 to 86, wherein the crystal form substantially does not contain other polymorphs.

88. The crystal form according to any one of claims 1 to 86, wherein the crystal form has a polymorphic purity of at least about 80%.

89. The crystal form according to any one of claims 1 to 86, wherein the crystal form has a polymorphic purity of at least about 90%.

90. The crystal form according to any one of claims 1 to 86, wherein the crystal form has a polymorphic purity of at least about 95%.

91. The crystal form according to any one of claims 1 to 86, wherein the crystal form has a polymorphic purity of at least about 99%.

92. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 91, and a pharmaceutically acceptable carrier, diluent, or excipient, or a mixture thereof.

93. A method for treating a particular type of diabetes, comprising administering the pharmaceutical composition described in claim 92 to a patient in need of treatment.

94. The method according to claim 93, wherein the type of diabetes mellitus is type 1 diabetes mellitus.

95. The method according to claim 93, wherein the type of diabetes mellitus is type 2 diabetes mellitus.

96. The method according to any one of claims 93 to 95, wherein the pharmaceutical composition is administered orally.

97. The method according to any one of claims 93 to 96, wherein the pharmaceutical composition is administered as a tablet.

98. The method according to any one of claims 93 to 97, 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.

99. The method according to any one of claims 93 to 97, 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.

100. The method according to any one of claims 93 to 97, 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.

101. The method according to any one of claims 93 to 97, wherein the patient is administered approximately 800 mg of {2-[3-cyclohexyl-3-(trans-4-propoxycyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid once daily.

102. The method according to any one of claims 93 to 97, 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.

103. The method according to any one of claims 93 to 97, wherein the patient is administered approximately 500 mg of {2-[3-cyclohexyl-3-(trans-4-propoxycyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid once daily.

104. The method according to any one of claims 93 to 97, wherein the patient is administered approximately 300 mg of {2-[3-cyclohexyl-3-(trans-4-propoxycyclohexyl)-ureido]-thiazole-5-ylsulfanil}acetic acid once daily.

105. The method according to any one of claims 93 to 97, 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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