4-Chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide for use in medicine

Abstract

The present invention relates to a novel method of activating 5' adenosine monophosphate-activated protein kinase (AMPK) for the treatment of certain diseases and disorders using salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in an administration-efficient manner. Diseases that may be treated in this manner include type 2 diabetes.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to the use of sodium salts of certain pharmacologic active ingredients in medicines in an administration-efficient manner by activating 5' adenosine monophosphate-activated protein kinase (AMPK) and thereby treating certain diseases. [Background technology]

[0002] BACKGROUND OF THEINVENTION AMP-activated protein kinase (AMPK) is a protein kinase enzyme consisting of three protein subunits, which is activated by hormones, cytokines, exercise, and stresses that decrease cellular energy status (e.g., glucose deprivation). Activation of AMPK increases processes that generate adenosine 5'-triphosphate (ATP) (e.g., fatty acid oxidation) and suppresses others, such as fatty acid, glycerolipid, and protein synthesis, that consume ATP but are not rapidly required for survival. Conversely, when cells are presented with a sustained excess of glucose, AMPK activity is decreased and fatty acid, glycerolipid, and protein synthesis are enhanced. Thus, AMPK is a protein kinase enzyme that plays a key role in cellular energy homeostasis. Thus, activation of AMPK is coupled with glucose-lowering effects and induces several other biological effects, including cholesterol synthesis, lipogenesis, inhibition of triglyceride synthesis, and reduction of hyperinsulinemia.

[0003] Considering the above, AMPK is a preferred target for the treatment of metabolic syndrome, especially type 2 diabetes. AMPK also participates in many pathways that are important for many different diseases (e.g., AMPK also participates in many pathways that are important in CNS disorders, inflammation (and the resulting fibrosis), osteoporosis, heart failure, and sexual dysfunction).

[0004] AMPK is also involved in many pathways that are important in cancer. Several tumor suppressors are part of the AMPK pathway. AMPK acts as a negative regulator of mammalian TOR (mTOR) and EF2 pathways, which are important regulators of cell growth and proliferation. Thus, deregulation can be associated with diseases such as cancer (as well as diabetes). Thus, AMPK activators can be useful as anticancer agents.

[0005] The effects of AMPK dysregulation in diseases such as obesity, inflammation, diabetes and cancer are described for example in Jeon SM, Experimental & Molecular Medicine (2016) 48, e245.

[0006] AMPK activators (e.g., metformin and 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (i.e., the compound of formula I below)) have been shown to be effective in treating pain. Das et al. report that post-injury treatment in mice with an AMPK activator reduces mechanical hypersensitivity after lumbar disc puncture (Das V, et al. Reg Anesth Pain Med 2019;0:1-5. doi:10.1136 / rapm-2019-100839). Similarly, Das and coworkers have reported that early treatment with AMPK activators reduces mechanical hypersensitivity in a postoperative pain model in mice (Das V, et al. Reg Anesth Pain Med 2019;0:1-6. doi:10.1136 / rapm-2019-100651). These drugs also normalize the AMPK pathway in the dorsal root ganglion. Thus, AMPK activators can be used to treat pain, especially postoperative pain.

[0007] It has also been shown that hepatic steatosis can be regulated by AMPK (Zhao et al. J. Biol. Chem. 2020 295: 12279- 12289). Activation of AMPK promotes fatty acid oxidation (β-oxidation) in the liver while inhibiting de novo lipogenesis. AMPK activation also reduces free fatty acid release from adipose tissue and prevents hepatic steatosis. Pharmacological activation of AMPK in the liver was reported to promote beneficial effects on multiple aspects of nonalcoholic fatty liver disease (NAFLD). For example, activation of AMPK was found to ameliorate nonalcoholic steatohepatitis (NASH) in both mouse and monkey animal models. Thus, AMPK activators may be useful for the treatment of NAFLD and NASH.

[0008] An example of an AMPK activator is 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (i.e., the compound of formula I), which was first disclosed in WO 2011 / 004162.

[0009] [ka]

[0010] As AMPK agonists (i.e., AMPK activators), the compounds of formula I are useful for treating disorders or conditions that are ameliorated by activation of AMPK. Such compounds may be useful for treating cardiovascular disease (such as heart failure), diabetic kidney disease, type 2 diabetes, insulin resistance, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, pain, opioid addiction, obesity, cancer, inflammation (including chronic inflammatory disease), autoimmune disease, osteoporosis, and intestinal disease.

[0011] There remains a need to improve the bioavailability of active ingredients such as 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in vivo to improve their effectiveness in medicine. The inventors have now surprisingly found a treatment that enhances the bioavailability of the compound of formula I in vivo.

[0012] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the prior art or is common general knowledge. Summary of the Invention

[0013] Detailed Description of the Invention According to a first aspect of the present invention, there is provided a method of activating 5' adenosine monophosphate-activated protein kinase (AMPK), comprising administering to a human subject about 200 to about 1000 mg / day of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in a pharmaceutical dosage form.

[0014] The method according to the first aspect of the invention is hereinafter referred to as "the method of the invention".

[0015] According to an alternative first aspect of the present invention there is provided about 200 to about 1000 mg / day of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in a pharmaceutical dosage form for use in activating AMPK.

[0016] According to a further alternative first aspect of the present invention there is provided the use of about 200 to about 1000 mg / day of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in a pharmaceutical dosage form in the manufacture of a medicament for treating a disease or disorder by activating AMPK.

[0017] It will be understood that a "sodium salt" is a compound consisting of a collection of sodium cations and associated anions. Thus, the term "sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide" refers to a compound that includes the sodium cation and the anion of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. For example, the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide refers to formula II:

[0018] [ka]

[0019] In the formula, Na + represents the sodium cation.

[0020] Those skilled in the art will recognize that when dissolved in an appropriate solvent (e.g., water), the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can dissociate into its anionic and cationic components.

[0021] Throughout this specification, structures may or may not be presented with chemical names. If any doubt arises regarding nomenclature, the structures shall prevail. If a compound can exist as a tautomer (e.g., in alternative resonance forms), the structure shown represents one of the possible tautomeric forms, and the actual tautomeric form observed may vary depending on environmental factors such as solvent, temperature, or pH. All tautomeric (and resonance) forms and mixtures thereof are included within the scope of the present invention. For example, the following tautomers are included within the scope of the present invention:

[0022] [ka]

[0023] For the avoidance of doubt, the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is a solid at ambient conditions and references herein to said salt include all amorphous, crystalline and partially crystalline forms thereof.

[0024] The sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be prepared according to techniques well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be reacted with sodium hydroxide or an alternative sodium base compound. Salt switching techniques can also be used to convert one salt to another.

[0025] When the salt is prepared from 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be prepared according to techniques well known to those skilled in the art, such as those described in International Patent Application WO 2011 / 004162. The contents of WO 2011 / 004162 are incorporated by reference.

[0026] The sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is referred to herein as the "salt of the invention."

[0027] The methods of the present invention have been found to be surprisingly effective in improving (e.g., increasing) the bioavailability of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in vivo as compared to methods involving administration of an equivalent amount of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in free base form. The improved bioavailability is measured by the C max Or it can be demonstrated by measuring the area under the curve (AUC). It has also been found that a comparable level of systemic exposure, e.g., comparable concentration, to 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in plasma in human subjects can be achieved by administering a significantly lower amount of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in the form of the sodium salt of the compound. The finding that administration of the sodium salt form can allow for a reduction in the dose required to achieve a certain level of systemic exposure is beneficial because use in a dose-efficient manner reduces the possibility of undesirable side effects. The salts of the present invention, and pharmaceutical dosage forms comprising said salts, are useful in the treatments described herein in subjects in need of such treatments.

[0028] In the context of the present invention, the term "free base" refers to a form of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide that is not in salt form. Free base 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be represented by formula I:

[0029] [ka]

[0030] "C maxIt will be appreciated by those skilled in the art that the terms " and "AUC" in this context refer respectively to the peak plasma concentration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide following administration (e.g., to a human subject) and the integral of the concentration / time curve for that substance following administration of a salt of the invention in a pharmaceutical dosage form.

[0031] Thus, the methods of the invention can increase the bioavailability of the compound of formula I in humans compared to methods involving administration of said compound in free base form. By this, we mean that administration of a pharmaceutical dosage form comprising a salt of the invention results in a greater systemically available fraction of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in vivo compared to administration of a pharmaceutical dosage form comprising the free base form of said compound. The increase in the amount of a compound of formula I systemically available following administration of a pharmaceutical dosage form comprising a salt of the invention compared to administration of a pharmaceutical dosage form comprising said compound in free base form can be at least about 10%, (at least) about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100% (i.e., 2-fold), about 150%, about 200% (i.e., 3-fold), about 250%, about 300% (i.e., 4-fold), about 350%, or about 400% (i.e., 5-fold).

[0032] Improved bioavailability at a given dose of a salt, or achievement of equivalent systemic exposure by administration of a reduced dose of the salt (compared to the dose of the non-salt form required to achieve that exposure), may be demonstrated using any suitable method known in the art. For example, pharmacokinetic data (e.g., C max By comparing the data from subjects administered a pharmaceutical dosage form containing the free base form of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide, changes in bioavailability and systemic exposure levels can be observed.

[0033] One of skill in the art will appreciate that the methods of the present invention include administering a total dosage of about 200 to about 1000 milligrams per day (mg / day) of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide using one or more of the pharmaceutical dosage forms described herein. In certain embodiments, the total dosage of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide administered to a human subject can range from about 200 to about 800 mg / day, about 200 to about 600 mg / day, or preferably about 200 to about 400 mg / day.

[0034] Advantageously, the salts of the invention (including pharmaceutical dosage forms comprising said salts) may be administered to a human subject in a single daily dose (e.g., via oral delivery). Alternatively, the total daily dose of the salts of the invention may be administered in divided doses two, three or four times daily (e.g., twice daily doses of 100 mg, 250 mg, or 500 mg, etc., with reference to the doses described herein). Furthermore, the methods of the invention may include administration less than once daily, for example, once every two days, once weekly or twice weekly. In such embodiments, the average daily dose received by the subject is still about 200 to about 1000 mg. In certain embodiments, the salts of the invention are administered no more than once daily. More specifically, the salts of the invention are administered once daily.

[0035] As shown by Example 3, the method of the present invention is particularly effective when the salt of the present invention is administered once a day for a duration of at least one week (e.g., at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days). In certain embodiments, the duration is at least two weeks. In further embodiments, the administration period is at least three weeks. In other embodiments, the salt of the present invention is administered once a day for at least a period sufficient to achieve a steady-state plasma concentration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. Longer periods of treatment are envisioned, including treatment that may be extended for months or years, as deemed appropriate by the prescribing physician under the circumstances. Such extended treatment is also contemplated as a method of the present invention.

[0036] The term "about" when referring to a measurable value, such as the amount of a compound, dosage, time, temperature, etc., refers to a variation of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the particular amount. In each case, it is contemplated that such terms may be replaced with notations such as "±10%" (or by indicating the variance of the particular amount calculated based on the relevant value). It is also contemplated that in each case, such terms may be omitted.

[0037] For the avoidance of doubt, in the context of the present invention, the dosage administered to a human subject should be sufficient to activate AMPK and thereby achieve therapeutic response in the subject over a reasonable time frame.Those skilled in the art will recognize that the selection of exact dosage and composition and most suitable delivery regimen will also be influenced by, among other things, the pharmacological properties of the dosage form, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, weight, sex and response of the subject being treated, and the stage / severity of the disease.In any case, a physician or other skilled in the art can routinely determine the actual dosage that is most suitable for each individual subject.

[0038] The methods of the present invention can be particularly advantageous in that they allow the clinician to achieve a desired peak plasma concentration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in a subject while administering a low dose of the active ingredient to the subject. In the study described in Example 2, repeated administration of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide resulted in a C of about 50 μg / ml. max In a previous study involving administration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in suspension, a similar C max was achieved only when subjects received substantially larger (approximately 5-fold larger) repeated doses.

[0039] In addition, as shown by the studies described in Example 3, it is possible to achieve peak plasma concentrations of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide of at least about 85 μg / ml after repeated administration of 212 mg of a salt of the invention in the form of a tablet, and of at least about 50 μg / ml after repeated administration of 200 mg of a salt of the invention in the form of a capsule.

[0040] Thus, the methods of the invention can achieve a peak plasma concentration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide of at least 40 μg / mL (e.g., after repeated administration of 200 mg of a salt of the invention daily for at least two weeks). In further embodiments, the methods of the invention achieve a peak plasma concentration of at least 50, 60, 70, 80, 90, 100, 110, 120 or 130 μg / mL.

[0041] The peak plasma concentration may be reached after administration of a sufficient number of doses to achieve a steady-state plasma concentration or to achieve a plasma concentration profile approaching a steady-state profile. In this context, a steady-state concentration is achieved when the fluctuation in the concentration of the test substance (analyte) in plasma (in this case, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide) remains within clinically acceptable boundaries over the period between successive administrations of the salt of the invention. Steady-state concentration is also known as C max It can be considered to be achieved when the fluctuation of remains within clinically acceptable boundaries after successive administration. Thus, in one embodiment, the peak plasma concentration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is reached after the steady-state concentration is achieved.

[0042] The time required to reach steady state varies between subjects. Steady state of a drug typically occurs within 4-5 half-lives (t 1 / 2 ) has elapsed. A person skilled in the art (i.e., a clinician) can understand when a steady state has been achieved by referring to a clinical evaluation of the subject's blood, for example, using the methods mentioned in Example 2 and Example 3. Typically, the steady state concentration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is obtained after about two weeks of repeated administration, but longer times may be required. For example, the peak plasma concentration may be reached after 15, 16, 17, or 18 days.

[0043] Unless otherwise defined, all technical and scientific terms used herein have their common meaning as understood by one of ordinary skill in the art to which this invention belongs.

[0044] For the avoidance of doubt, persons skilled in the art will understand that reference herein to a particular aspect of the invention (such as the first aspect of the invention) includes reference to all embodiments and particular features thereof, which embodiments and particular features may be taken in combination to form further embodiments and features of the invention.

[0045] [Pharmaceutical dosage form] As provided herein, the salts of the present invention are useful as therapeutic agents for activating AMPK and thereby treating various medical disorders and conditions. The salts of the present invention are administered to a human subject in need thereof in the form of a pharmaceutical formulation, also referred to herein as a pharmaceutical dosage form.

[0046] In one embodiment, the salt of the invention is the only active pharmaceutical ingredient (API) present in the dosage form. In a further embodiment, the salt of the invention (or a pharma- ceutically acceptable salt or solvate thereof) is present in the dosage form together with one or more other active pharmaceutical ingredients, or may be administered as part of a combination therapy with one or more other active pharmaceutical ingredients.

[0047] In certain embodiments, the method includes administration of a pharmaceutical dosage form of a salt of the invention, including all embodiments and particular features thereof, wherein the salt is provided in the form of particles having a particle size distribution defined by a D90 of less than about 10 μm (e.g., as measured using laser diffraction). Particle size is typically reduced by grinding larger particles of a given material.

[0048] The term "comminuted" (which may be used interchangeably with other terms in the art, such as "size reduce," "comminute," "grind," and "pulverize"), as used herein, refers to a process in which a solid sample (e.g., granules) is subjected to mechanical energy to reduce the particle size of the solid sample. For example, coarse particles may be broken down into finer particles such that the average particle size is reduced to meet desired parameters.

[0049] Milling is considered a "top-down" approach to the production of microparticles. For example, drug solids can be cut by sharp blades (e.g., cutter mills), impacted by hammers, subjected to high-pressure homogenization, or crushed or compressed by application of pressure (e.g., roller mills or pestle and mortar). Because a limited amount of energy is typically imparted, the particles produced by such methods remain relatively coarse. Technological advances in milling equipment have enabled the production of ultrafine drug particles down to micron (i.e., μm range) or submicron (e.g., nm range) dimensions.

[0050] Certain grinding processes can be characterized as dry grinding processes, such methods being preferred for processing the salts of the invention.

[0051] "Dry milling" refers to a process in which a drug is milled in its dry state, i.e., in the absence of a liquid medium (e.g., substantially in the absence of water). In the dry state, the drug can be milled alone or in the presence of one or more other ingredients, such as pharma- ceutically acceptable excipients. Other abrasive materials, such as salts, can be present during the milling process to aid in particle size reduction. The mechanical energy imparted by dry milling promotes interactions between particles of the drug (and other substances optionally present) via van der Waals forces or hydrogen bonding.

[0052] A review of pharmaceutical milling processes can be found, for example, in Loh et al., Asian Journal of Pharmaceutical Sciences, 10 (2015), 255-274. Suitable excipients for inclusion in drug particles are described, for example, in Peltonen et al., in Handbook of Polymers for Pharmaceutical Technologies, ed. Thakur and Thakur, Wiley, volume 4, chapter 3, 67-87, and Nekkanti et al, in Drug Nanoparticles - An Overview, The Delivery of Nanoparticles, IntechOpen. The contents of these documents are incorporated by reference.

[0053] Stabilizers such as polymers and surfactants are often used during milling to increase the repulsion between particles and inhibit agglomeration. Agglomeration of milled particles may occur during milling, which may ultimately slow down the dissolution process and affect bioavailability. It has been found that an increase in the systemic exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide occurs after administration of the dry milled salt of the active ingredient, even without the addition of stabilizers.Therefore, in one embodiment, the pharmaceutical formulation does not contain any stabilizers.

[0054] Grinding reduces the average size of particles containing the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. The extent and effectiveness of grinding can be determined by measuring the particle size distribution of said particles before and after the grinding process by any suitable method. The term "particle size distribution" refers to the relative number of particles present according to size in a solid sample, such as a powder, a granular material, or particles dispersed in a fluid.

[0055] The particle size distribution of solid samples can be measured using techniques well known in the art.For example, the particle size distribution of solid samples can be measured by laser diffraction, dynamic light scattering, image analysis (e.g., dynamic image analysis), sieve analysis, air elution analysis, optical counting, electrical resistance counting, sedimentation, laser obscuration and acoustic (e.g., ultrasonic attenuation) spectroscopy.The specific methods that can be mentioned for measuring the particle size distribution of the salt particles of the present invention are dynamic light scattering and laser diffraction.

[0056] Particle size distribution can also be determined based on the results of sieve analysis. Sieve analysis provides particle size information in the form of an S-curve of cumulative mass retained on each sieve versus sieve mesh size. The most commonly used distance in describing particle size distribution is the D-value (e.g., D10, D50 and D90, which are the intercepts for 10%, 50% and 90% of cumulative mass, respectively). The particle size distribution of the present invention is preferably defined using one or more of such values. The D-value essentially represents the diameter of a sphere that divides the mass of the sample into a certain percentage when the particles are arranged based on the ascending mass. For example, the D10 value is the diameter such that 10% of the mass of the sample consists of particles with a diameter less than this value. The D50 value is the diameter such that 50% of the mass of the sample has a diameter smaller than this value and 50% of the mass of the sample has a diameter larger than this value.

[0057] In one embodiment, particles containing the salt of the present invention may have a particle size distribution defined by a D90 (e.g., measured using laser diffraction) of less than about 10 μm (e.g., about 5 μm to about 10 μm). Alternatively, the particle size distribution may be defined by a D90 of less than about 8 μm (e.g., about 5 μm to about 8 μm). In a further embodiment, particles comprised of the salt of the present invention may have a particle size distribution defined by a D50 of less than about 6 μm (e.g., about 0.5 μm to about 6 μm). In yet a further embodiment, the particle size distribution of particles comprised of the salt of the present invention may be further defined by a D10 of less than about 2 μm (e.g., about 0.2 μm to about 2 μm).

[0058] The above-mentioned particle size distribution parameters can be applied individually or in combination.For example, in certain embodiments, dosage form comprises particles containing the salt of the present invention, and said particles have a particle size distribution defined by D90 less than about 10 μm and D50 less than about 6 μm.Furthermore, said particles can have a particle size distribution defined by D90 less than 9 μm; D50 less than 6 μm or less than 5 μm; and D10 less than 2 μm or less than 1.5 μm.

[0059] The particle size distribution of particles containing the salt of the invention can be measured, for example, by laser diffraction using a commercially available particle size analyzer such as a Mastersizer 3000 from Malvern Instrument.

[0060] The invention also includes pharmaceutical dosage forms comprising particles containing a salt of the invention having any of the particle size distributions defined herein, regardless of the process by which the particles are manufactured.

[0061] Preferably the pharmaceutical dosage form comprises particles of a salt of the invention having any of the particular particle size distributions described herein, the particles being obtained by a process which comprises milling said salt.

[0062] Those skilled in the art will understand that the pharmaceutical dosage forms described herein may act systemically and therefore may be administered using suitable techniques known to those skilled in the art. The pharmaceutical dosage forms described herein are typically administered orally, i.e., as oral pharmaceutical dosage forms. Thus, in a second aspect of the present invention, there is provided an oral pharmaceutical dosage form comprising about 200 to about 1000 mg of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0063] In certain embodiments, the pharmaceutical dosage forms referred to in the first and second aspects of the invention may contain, for example, about 200 mg to about 800 mg, about 200 mg to about 600 mg, or about 200 mg to about 400 mg of the salt of the invention. Preferably, the pharmaceutical dosage form contains about 200 to about 400 mg of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0064] Dosage forms intended for oral administration may further comprise an enteric coating to prevent or minimize dissolution or disintegration in the stomach environment. Thus, an oral preparation (e.g., capsule or tablet) coated with an enteric coating may provide targeted release of the salt of the present invention in the small intestine. For example, the enteric coating may be present on the surface of the formulation (e.g., the surface of the tablet or capsule), or each of the particles containing the salt of the present invention may be coated with an enteric coating. Thus, in certain embodiments, the pharmaceutical dosage form used in the method of the present invention further comprises an enteric coating.

[0065] It may be desirable to minimize the dissolution or disintegration of oral pharmaceutical dosage forms (such as capsules or tablets) in the stomach environment and / or provide targeted release of active ingredients in the small intestine.Therefore, in certain embodiments, an enteric coating is present on the pharmaceutical dosage form of the present invention.For example, said coating can be provided as an outer layer on the pharmaceutical dosage form.

[0066] Alternatively, particles containing the salt of the invention may be individually coated with an enteric coating and the coated particles may be formulated into a pharmaceutical dosage form.Thus, in certain embodiments, the pharmaceutical dosage form contains particles comprising the salt of the invention, each particle being coated with an enteric coating.

[0067] The term "enteric coating" refers to a substance (e.g., a polymer) that is incorporated into an oral dosage form (e.g., applied onto the surface of a tablet, capsule, particle, or pellet) that inhibits the dissolution or disintegration of the dosage form in the gastric environment. Enteric coatings are typically stable at the highly acidic pH found in the stomach, but rapidly degrade at the relatively basic pH of the small intestine. Thus, enteric coatings prevent the release of the active ingredients in the dosage form until it reaches the small intestine.

[0068] Any enteric coating known to those skilled in the art can be used in the present invention.Specific enteric coating materials that can be mentioned include those that include beeswax, shellac, alkyl cellulose polymer resin (e.g., ethyl cellulose polymer, carboxymethyl ethyl cellulose, or hydroxypropyl methyl cellulose phthalate) or acrylic polymer resin (e.g., acrylic acid and methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, methacrylate copolymer, methacrylic acid copolymer, methacrylic acid copolymer, amino alkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkyl amide copolymer, poly(methyl methacrylate) (anhydride), polymethacrylate, methyl methacrylate copolymer, poly(methyl methacrylate) copolymer, polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymer), cellulose acetate phthalate, and polyvinyl acetate phthalate.

[0069] The pharmaceutical dosage form referred to in the first and second aspects of the present invention can be provided in the form of a tablet or especially a capsule.For example, capsules such as soft gelatin capsules can be prepared to contain the salt of the present invention alone or together with a suitable vehicle, such as vegetable oil, fat, etc.Similarly, hard gelatin capsules can contain the salt of the present invention alone or in combination with solid powdered ingredients such as disaccharides (e.g. lactose or saccharose), alcohol sugars (e.g. sorbitol or mannitol), vegetable starches (e.g. potato starch or corn starch), polysaccharides (e.g. amylopectin or cellulose derivatives) or gelling agents (e.g. gelatin).

[0070] The pharmaceutical dosage forms described herein can be prepared according to standard and / or accepted pharmaceutical practice. The pharmaceutical dosage forms of the first and second aspects of the invention are generally provided as a mixture comprising the salt of the invention and one or more pharma- ceutically acceptable excipients. The one or more pharma-ceutically acceptable excipients can be selected according to standard pharmaceutical practice with due consideration to the intended route of administration. Such pharma-ceutically acceptable excipients are preferably chemically inert to the active compounds and preferably have no adverse side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations can be found, for example, in Remington The Science and Practice of Pharmacy, 19th ed, Mack Printing Company, Easton, Pennsylvania (1995). A brief review of methods of drug delivery can also be found, for example, in Langer, Science 249, 1527 (1990).

[0071] Thus, according to a particular embodiment, the pharmaceutical dosage form referred to in the first and second aspects of the present invention further comprises at least one pharma- ceutically acceptable excipient. In particular, the at least one pharma- ceutically acceptable excipient may be a lubricant, binder, filler, surfactant, diluent, anti-adherent, coating, flavoring agent, coloring agent, glidant, preservative, sweetener, disintegrant, adsorbent, buffer, antioxidant, chelating agent, dissolution promoter, dissolution retarder or wetting agent.

[0072] Specific pharma- ceutically acceptable excipients that may be mentioned include mannitol, PVP (polyvinylpyrrolidone) K30, lactose, saccharose, sorbitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as disintegrants and lubricants, such as sodium lauryl sulfate, nadocosate, magnesium stearate, calcium stearate, sodium stearyl fumarate, and polyethylene glycol wax. In preparing a pharmaceutical dosage form of the salt of the present invention for oral administration, particles (preferably milled) containing the salt of the present invention may be mixed together or separately with mannitol, PVP (polyvinylpyrrolidone) K30, and sodium lauryl sulfate.

[0073] In preparing pharmaceutical dosage forms for use in the methods of the invention, the salts of the invention may be mixed, together or separately, with one or more pharmaceutical excipients listed above, including basic excipients.

[0074] The mixture of the salt of the present invention and one or more pharma- ceutically acceptable excipients can be processed into pellets or granules or compressed into tablets. Thus, the pharmaceutical dosage form of the method of the present invention can be a tablet, mini-tablet, block, pellet, particle, granule or powder for oral administration.

[0075] [Medical Use] The efficient method of administration and pharmaceutical dosage forms of activating AMPK described herein are useful in medicine. 4-Chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is a known AMPK activator, and AMPK activation is known to be beneficial in the treatment of various diseases, as described in International Patent Applications WO 2011 / 004162 and WO 2020 / 095010.

[0076] Thus, according to a third aspect of the present invention there is provided the use of an oral pharmaceutical dosage form according to the second aspect of the present invention in the manufacture of a medicament for the treatment of a disease or disorder by activating AMPK, wherein about 200 to about 1000 mg / day of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is administered to a human subject.

[0077] Similarly, the method of activating AMPK according to the first aspect of the invention may be carried out to treat a disease or disorder that is ameliorated by AMPK activation in a human subject.

[0078] By "activates AMPK" we mean that the steady state level of phosphorylation of the Thr-172 portion of the AMPK-α (AMPK-alpha) subunit is increased compared to the steady state level of phosphorylation in the absence of a compound of Formula I. Alternatively or additionally, we mean that there is a higher steady state level of phosphorylation of any other protein downstream of AMPK, such as acetyl-CoA carboxylase (ACC).

[0079] Those skilled in the art are aware that diseases or disorders that can be treated by activating AMPK include cardiovascular disease (e.g., heart failure, e.g., heart failure with preserved ejection fraction), diabetic kidney disease, diabetes (e.g., type 2 diabetes), insulin resistance, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, pain, opioid addiction, obesity, cancer, inflammation (including chronic inflammatory disease), autoimmune disease, osteoporosis and intestinal disease.Other diseases or conditions that can be improved by activating AMPK include hyperinsulinemia and related conditions, conditions / disorders in which fibrosis plays a role, sexual dysfunction and neurodegenerative diseases.

[0080] The term "diabetes" (i.e., diabetes mellitus) is understood by those skilled in the art to refer to both type 1 (insulin-dependent) diabetes and type 2 (non-insulin-dependent) diabetes, both of which involve dysfunction of glucose homeostasis. The methods of the present invention are particularly suitable for the treatment of diabetes, i.e., type 1 diabetes and / or type 2 diabetes, particularly type 2 diabetes, which is described in detail in International Patent Application WO 2020 / 095010.

[0081] In addition to being useful for treating diabetes, the method of the present invention is also suitable for treating diabetic kidney disease (i.e., diabetic nephropathy). "Diabetic kidney disease" refers to kidney damage caused by diabetes and is a serious complication of type 1 and type 2 diabetes. Diabetic kidney disease affects the kidney's ability to remove waste products from the blood and excrete them in urine, which can lead to kidney failure.

[0082] The method of the present invention is also suitable for treating chronic kidney disease, including chronic kidney disease in the absence of type 2 diabetes.Chronic kidney disease is a condition characterized by the gradual loss of kidney function over time.Chronic kidney disease usually occurs as a result of one or more other diseases or conditions that affect the kidney, such as hypertension, diabetes, high cholesterol, kidney infection, glomerulonephritis, polycystic kidney disease, urinary tract obstruction in urine flow, and long-term drug use.

[0083] The term "hyperinsulinemia or related conditions" will be understood by those skilled in the art to include hyperinsulinemia, type 2 diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, childhood hyperinsulinemia, hypercholesterolemia, hypertension, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular conditions such as stroke, systemic lupus erythematosus, neurodegenerative diseases such as Alzheimer's disease, and polycystic ovarian syndrome. Other disease conditions include progressive renal diseases such as chronic renal failure.

[0084] In particular, the methods of the present invention are suitable for the treatment of obesity associated with hyperinsulinemia and / or cardiovascular disease associated with hyperinsulinemia.

[0085] The method of the present invention is also suitable for treating cardiovascular disease (e.g., heart failure), where the cardiovascular disease is not associated with hyperinsulinemia.Similarly, the method of the present invention is also suitable for use in treating obesity that is not associated with hyperinsulinemia.For the avoidance of doubt, the treatment of obesity and / or cardiovascular disease (such as heart failure) that AMPK activation can be beneficial is included within the scope of the present invention.In particular, the disease or disorder is heart failure, preferably heart failure with preserved ejection fraction (i.e., HFpEF).

[0086] The term "cancer" will be understood by those skilled in the art to include one or more diseases in a class of disorders characterized by the uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissues through invasion, proliferation, or by injection into distant sites by metastasis. By "proliferation", we include an increase in the number and / or size of cancer cells. By "metastasis", we mean the migration or migration (e.g., invasiveness) of cancer cells from a primary tumor site in the subject's body to one or more other areas in the subject's body (cells can then form secondary tumors).

[0087] Thus, the method of the present invention is suitable for the treatment of any type of cancer, including all tumors (non-solid and preferably solid tumors, e.g. carcinoma, adenoma, adenocarcinoma, regardless of organ, blood cancer). For example, the cancer cells can be selected from the group consisting of breast, bile duct, brain, colon, stomach, reproductive organs, thyroid, hematopoietic system, lung and airway, skin, gallbladder, liver, nasopharynx, neuronal cells, kidney, prostate, lymphatic gland and gastrointestinal tract cancer cells. Preferably, the cancer is selected from the group consisting of colon cancer (including colorectal adenoma), breast cancer (e.g. postmenopausal breast cancer), endometrial cancer, hematopoietic system cancer (e.g. leukemia, lymphoma, etc.), thyroid cancer, kidney cancer, esophageal adenocarcinoma, ovarian cancer, prostate cancer, pancreatic cancer, gallbladder cancer, liver cancer and cervical cancer. More preferably, the cancer is selected from the group consisting of colon, prostate, and especially breast cancer. When the cancer is a non-solid tumor, it is preferably a hematopoietic tumor, such as leukemia (e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), or chronic lymphocytic leukemia (CLL)). Preferably, the cancer cell is a breast cancer cell.

[0088] Conditions / disorders in which fibrosis plays a role include, but are not limited to, scar healing, keloids, scleroderma, pulmonary fibrosis (including idiopathic pulmonary fibrosis), nephrogenic systemic fibrosis, and cardiovascular fibrosis (including endomyocardial fibrosis), systemic sclerosis, liver cirrhosis, ocular macular degeneration, retinal and vitreoretinopathy, Crohn's disease / inflammatory bowel disease, surgical scar tissue formation, radiation and chemotherapy induced fibrosis, and cardiovascular fibrosis.

[0089] The method of the present invention is also suitable for the treatment of sexual dysfunction (eg, the treatment of erectile dysfunction). The method of the present invention may also be suitable for the treatment of inflammation.

[0090] Neurodegenerative diseases that may be mentioned include Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, polyglutamine disorders such as spinal and bulbar muscular atrophy (SBMA), dentate and pallidoluysian atrophy (DRPLA), and some spinocerebellar ataxias (SCAs).

[0091] The methods of the present invention are suitable for the treatment of non-alcoholic fatty liver disease (NAFLD).

[0092] Nonalcoholic fatty liver disease (NAFLD) is defined by excess fat accumulation in the form of triglycerides (steatosis) in the liver (histologically referred to as accumulation in more than 5% of liver cells). It is the most common liver disorder in developed countries (e.g., affecting about 30% of US adults), and most patients are asymptomatic. If left untreated, the condition can progressively worsen and eventually lead to cirrhosis. NAFLD is particularly common in obese patients, with about 80% thought to have the disease.

[0093] NAFLD can be diagnosed when a patient's alcohol intake is not considered to be a major causative factor. Typical thresholds for diagnosing fatty liver disease as "non-alcohol related" are daily intakes of less than 20 g for female subjects and less than 30 g for male subjects.

[0094] Specific diseases or conditions associated with NAFLD include metabolic conditions such as diabetes, hypertension, obesity, dyslipidemia, dyslipidemia, glycogen storage disease, Weber-Christian disease, acute fatty liver of pregnancy, and lipodystrophy. Other non-alcohol related factors associated with fatty liver disease include malnutrition, total parenteral nutrition, severe weight loss, refeeding syndrome, jejunal oil film bypass, gastric bypass, polycystic ovary syndrome, and diverticulosis.

[0095] Nonalcoholic steatohepatitis (NASH) is the most aggressive form of NAFLD, a condition in which excess fat accumulation (steatosis) is accompanied by inflammation of the liver. When advanced, NASH can lead to the development of scar tissue in the liver (fibrosis), and ultimately to cirrhosis. As mentioned above, compounds that activate AMPK have been found to be useful in treating NAFLD and inflammation. Thus, the method of the present invention is also useful in treating NASH. Thus, in a further embodiment, the treatment is the treatment of nonalcoholic steatohepatitis (NASH).

[0096] AMPK activator compounds (e.g., 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (i.e., compound of formula I)) can treat pain (Das V, et al. Reg Anesth Pain Med 2019;0:1-5doi:10.1136 / rapm-2019-100839 and Das V, et al. Reg Anesth Pain Med 2019;0:1-6doi:10.1136 / rapm-2019-100651), and such compounds are analgesics. Thus, since the method of the present invention increases the bioavailability of known AMPK activator compounds, the method of the present invention may be suitable for treating pain. In particular, the method of the present invention may be suitable for treating patients with severe pain, chronic pain, or may be useful for managing postoperative pain.

[0097] Opioid-based treatments, such as opioid analgesics, are used to treat severe chronic cancer pain, acute pain (e.g., surgery recovery and sudden pain), and their use is increasing in the management of chronic non-malignant pain.However, the increased use of opioid-based therapy to treat pain has led to an increase in opioid dependence (e.g., opioid addiction).By providing a known AMPK activator, the method of the present invention can be used to treat pain instead of opioid-based treatments, as known to those skilled in the art.Therefore, the method of the present invention is suitable for treating opioid dependence.

[0098] Specific autoimmune diseases known to those skilled in the art include Crohn's disease / inflammatory bowel disease, systemic lupus erythematosus and type 1 diabetes.

[0099] Specific bowel diseases to mention include Crohn's disease / inflammatory bowel disease and cancer of the gastrointestinal tract.

[0100] Those skilled in the art will understand that references to "treatment" of a particular condition (or, equivalently, "treatment" of that condition) take their ordinary meaning in the medical arts. In particular, the term can refer to achieving a reduction in the severity and / or frequency of occurrence of one or more clinical symptoms associated with the condition, as judged by the attending physician of a subject having or susceptible to such a condition.

[0101] Those skilled in the art will understand that such treatment is carried out in a subject in need thereof. The need for such a subject for treatment can be evaluated by those skilled in the art using routine techniques. In the context of the present invention, the "subject in need" of the method of the present invention includes a subject suffering from a disorder or condition that is improved by the activation of AMPK. As used herein, the terms "disease" and "disorder" (as well as the terms "condition", "disease", "medical problem", etc.) can be used interchangeably.

[0102] Without wishing to be bound by theory, it is believed that administration of reduced amounts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide to human subjects can still result in clinically useful concentrations of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in the systemic circulation when the active ingredient is administered in the form of the sodium salt of the compound. Repeated administration of a salt of the invention in an amount of 200-1000 mg / day has been shown to result in plasma concentrations of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide that are approximately 5-fold higher than concentrations obtained following repeated administration of the same amount of the free base form of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0103] [Combination therapy] One of skill in the art will appreciate that the methods of the present invention may include (ie, be combined with) additional treatment(s) for the same condition.

[0104] In particular, when treating a disease or disorder that is ameliorated by activating AMPK, the salts of the invention may be administered in combination with one or more other (i.e., different) therapeutic agents that are useful in treating the disease or disorder.

[0105] Such combination treatment may include administering to a subject a salt of the invention in conjunction with a different therapeutic agent (i.e., sequentially or simultaneously) in the same formulation or, preferably, in separate formulations. By "co-administration" (and similarly "co-administration"), we include that each active ingredient is administered sequentially or simultaneously as part of a medical intervention directed to the treatment of the relevant condition. At the same time, we mean that the salt of the invention and the different therapeutic agent are administered together with each other, either in a single pharmaceutical dosage form containing both active ingredients or in separate dosage forms that are administered simultaneously.

[0106] Thus, in the context of the present invention, the term "co-administration" (and similarly "co-administration") includes the administration of a salt of the invention and a different therapeutic agent together, or sufficiently close in time, to permit a greater beneficial effect on the patient over the course of treatment of the relevant condition than if either agent were administered alone in the absence of the other component over the same course of treatment. The determination of whether a combination provides a greater beneficial effect with respect to and over the course of treatment of a particular condition will depend on the condition to be treated, but can be routinely accomplished by one of ordinary skill in the art.

[0107] Furthermore, in the context of the present invention, the term "in conjunction with" includes that one or the other of the two active ingredients may be administered before, after, and / or simultaneously with the administration of the other (optionally repeatedly). As used in this context, the terms "administered simultaneously" and "administered at the same time" include cases where individual doses of a salt of the invention and a different therapeutic agent are administered within 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes or 10 minutes of each other.

[0108] Other therapeutic agents useful for treating diseases or disorders ameliorated by activating AMPK (e.g., heart failure, diabetic kidney disease, diabetes, etc., as described herein) are well known to those skilled in the art. Preferably, the other therapeutic agent is a sodium-glucose transport protein 2 (SGLT2) inhibitor, or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, the combination of which is useful for treating diseases such as type 2 diabetes. In a further embodiment, the method of the present invention comprises the sequential or simultaneous administration of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide and an SGLT2 inhibitor.

[0109] Those skilled in the art will understand that a sodium-glucose transport protein 2 inhibitor is a substance or agent that induces a decrease in one or more functions of sodium-glucose transport protein 2, and by "decrease in function of sodium-glucose transport protein 2" it includes stopping one or more functions, or slowing down the rate of a particular function, of sodium-glucose transport protein 2. A particular function that may be fully or partially inhibited is the ability of sodium-glucose transport protein 2 to act as a glucose transporter.

[0110] In certain embodiments, the sodium-glucose transport protein 2 inhibitor is gliflozin. Gliflozin is a known class of small molecule sodium-glucose transport protein 2 inhibitor. Hawley et al (Diabetes, 2016, 65, 2784-2794) and Villani et al (Molecular Metabolism, 2016, 5, 1048-1056) have recently discussed the possible mechanism of action of certain gliflozins. Specific gliflozins that can be mentioned include dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, tofogliflozin, sergliflozin (such as sergliflozin etabonate), remogliflozin (such as remogliflozin etabonate), ertugliflozin and sotagliflozin. In further specific embodiments, the sodium-glucose transport protein 2 inhibitor is dapagliflozin.

[0111] In certain embodiments, the sodium-glucose transport protein 2 inhibitor is a pharmaceutically acceptable salt of gliflozin.For example, the additional active ingredient may be a pharmaceutically acceptable salt of dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, tofogliflozin, sergliflozin (such as sergliflozin etabonate), remogliflozin (such as remogliflozin etabonate), ertugliflozin or sotagliflozin.

[0112] In a further embodiment, the sodium-glucose transport protein 2 inhibitor is a solvate of gliflozin.For example, the further active ingredient may be a solvate of dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, tofogliflozin, sergliflozin (such as sergliflozin etabonate), remogliflozin (such as remogliflozin etabonate), ertugliflozin or sotagliflozin.

[0113] In yet another embodiment, the sodium-glucose transport protein 2 inhibitor is a prodrug of gliflozin.For example, the further active ingredient may be a prodrug of dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, tofogliflozin, sergliflozin (such as sergliflozin etabonate), remogliflozin (such as remogliflozin etabonate), ertugliflozin or sotagliflozin.

[0114] The methods of the invention disclosed herein (and oral dosage forms used in such methods) may also have the advantage that the dose-efficient methods using the salts of the invention, whether or not used for the indications described above, may be more effective, less toxic, longer acting, more potent, have fewer side effects, are more easily absorbed, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance) than other treatments known in the prior art. In particular, the methods of the invention may have the advantage of exhibiting advantageous properties in vivo, such as more efficacy and / or fewer side effects, as a result of the dose-efficient characteristics of the salts of the invention.

[0115] 〔figure〕 The following drawings are provided to illustrate various aspects of the inventive concept and are not intended to limit the scope of the invention unless otherwise specified herein. [Brief description of the drawings]

[0116] [Figure 1] FIG. 1 shows comparative results of an oral pharmacokinetic study (days 1 and 18) using doses of 200, 400 and 800 mg of a salt of the invention. [Diagram 2] FIG. 2 shows comparative results of an oral pharmacokinetic study (days 16-19 and 25) using doses of 200, 400 and 800 mg of a salt of the invention. [Diagram 3]Comparative results of an oral pharmacokinetic study (day 21) using 212.12 and 424.24 mg doses of a salt of the invention are shown, which correspond to 200 mg and 400 mg of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide, respectively. EXAMPLES

[0117] [Abbreviation] AUC 0-24 : Area under the plasma concentration-time curve from days 0 to 24 AUC last : Area under the plasma concentration-time curve from time zero to the last quantifiable concentration AUC ss : Area under the steady-state plasma concentration-time curve AUC t : Area under the plasma concentration-time curve from time zero to time t AUC tau : Area under the plasma concentration-time curve during the dosing interval (τ): τ=tau C max : Maximum plasma concentration C trough : Minimum plasma concentration IMP: Investigational Product (Preparation) T max : Time to reach peak plasma concentration.

[0118] The present invention is further illustrated by reference to the following examples, which are not intended to limit the scope of the invention.

[0119] Example 1 Preparation of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide sodium salt [Scheme:]

[0120] [ka]

[0121] 〔procedure:〕 To a suspension of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (100 g, 0.2629 mol) in isopropanol (1.0 L) was slowly added a solution of sodium hydroxide (11.56 g, 0.2891 mol) in water (100 mL) at 25±5°C. The mass was stirred at 25±5°C for 3 hours and cooled to 5±5°C. The mass was stirred at 5±5°C for 3 hours and filtered to collect the solid. The solid was washed with isopropanol (300 mL) and dried under reduced pressure at 35±5°C for 8 hours. The dried solid was separated by filtration under a primary pressure of 4.0 kg / cm. 2 , secondary pressure 7.0kg / cm 2 The desired sodium salt was isolated as a white solid (50 g, 48%) by pulverizing twice using an air jet mill with a 100 rpm displacement and a screw feeder with 8 RPM.

[0122] 4.0kg / cm 2 Primary pressure up to 7.0kg / cm 2 Repeated dry grinding using a jet mill under argon at a secondary pressure of up to 1000 nm was used to obtain a particle size distribution with a D10 value of 0.3 μm, a D50 value of 1.9 μm and a D90 value of 7.1 μm (measured by laser diffraction (Malvern Instrument, Mastersizer 3000)).

[0123] Example 2: Pharmacokinetic study in humans The test material used in Example 2 was the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. Hereinafter, this substance will be referred to as "test material" etc. The test material used in the test was synthesized and purified by Anthem Bioscience Pvt. Ltd. (Bangalore, India). Formulations containing the test material were manufactured by RISE (Sodertalje, Sweden) of Betagenon AB (Umea, Sweden).

[0124] 〔method〕 [Clinical trial design] An open-label, randomized, parallel-group study was conducted in healthy volunteers (HVs) to assess the exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide sodium salt after single and repeated administration of three dose levels, and in combination with dapagliflozin at steady state.

[0125] Main inclusion criteria: Body mass index (BMI) ≥ 18.0 and ≤ 30.0 kg / m 2 Healthy male and female subjects, aged 18-65 years, of non-childbearing potential, with gestational age 18-65 years.

[0126] Main Exclusion Criteria: Subjects with a history of clinically significant disease or disorder that, in the opinion of the investigator, would endanger the subject or affect the outcome or the subject's ability to participate in the trial.

[0127] [Clinical trial compounds] Good manufacturing practice (GMP) 1 kg batches of test material were manufactured following a method similar to that of Example 1. The compound was provided in the form of a white to off-white crystalline powder with a D90<8 μm as measured by laser diffraction (Malvern Instrument, Mastersizer 3000).

[0128] For the study, size 0 Vcaps enteric capsules were individually filled with 200 mg of milled test material along with 2 mg of docusate sodium, 125 mg of mannitol, and 6.5 mg of sodium lauryl sulfate.

[0129] A commercially available oral tablet of 10 mg dapagliflozin was provided.

[0130] [Clinical methodology] Twenty-four subjects were randomized (1:1:1) to receive 200 mg (one 200 mg capsule), 400 mg (two 200 mg capsules), or 800 mg (four 200 mg capsules) of test material.

[0131] A screening visit (Visit 1) took place within 28 days prior to randomization and initiation of IMP dosing. Subjects were confined to the study clinic the evening before Day 1 (Visit 2; Day -1). Subjects were randomized on Day 1 to one of three parallel arms of IMP: 200, 400, or 800 mg once daily (1:1:1).

[0132] Pre-dose safety assessments and pre- and post-dose PK assessments were performed. Subjects left the clinic after the final PK sample on Day 1 and returned for a 24-hour PK sample and dosing on Day 2 (Visit 3).

[0133] Subjects self-administered study material at home from Day 3 through Day 15. A telephone visit to verify compliance, adverse event (AE) status, and concomitant medication use will be conducted on Day 8 (Visit 4).

[0134] Subjects returned to the clinic on days 16 and 17 (Visits 5 and 6) for PK sampling and AE assessments. Visit 6 continued in the evening of day 17 and kept subjects in the clinic until day 18. Pre- and post-dose PK and safety assessments were performed on day 18. Subjects left the clinic after the last PK sample on day 18 and returned for a 24-hour PK sample and dosing on day 19 (Visit 7).

[0135] On Day 19 (Visit 7), subjects began coadministration of test material and dapagliflozin (Forxiga) at 10 mg per day for 7 days (Days 19-25). Subjects returned to the clinic on Day 25 (Visit 8) for final dosing, PK, and safety assessments. A final end-of-study visit (Visit 9) for follow-up safety assessments occurred 28 days (+14 days) after Visit 8 or early discontinuation.

[0136] Venous blood samples (approximately 5 mL) for measuring plasma concentrations of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide after administration of the test material were collected via an indwelling venous catheter on days 1, 2, 16-19, and 25.

[0137] Blood samples were collected in pre-labeled Li-heparin tubes. All collected blood samples were centrifuged at 1500G for 10 minutes to separate plasma within 60 minutes from the sample. Plasma separated from each blood sample was divided into two aliquots in pre-labeled polypropylene cryotubes (A and B samples, approximately 750 μL in each tube) and frozen at <-70°C. On day 25, plasma was divided into three aliquots of at least 500 μL (A and B samples for test material, and one sample for potential future analysis of dapagliflozin).

[0138] Samples for determining plasma concentrations of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide were analyzed by means of a validated LS-MS / MS method by Lablytica Life Science AB, Uppsala, Sweden.

[0139] [Data Analysis] The plasma concentration data of the test substance (4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide) up to each time point were used for pharmacokinetic analysis. Pharmacokinetic analysis was performed using the noncompartmental analysis (NCA) module of Phoenix WinNonlin 8.1 software, and the following pharmacokinetic parameters were determined.

[0140] After a single dose of test material: AUC 0-24 , C max , T max and dose proportionality (AUC0-24 and C. max (based on secondary endpoint).

[0141] After repeated administration of test material: AUC at steady state (primary endpoint) tau and C max AUC t , AUC ss , T max (Secondary endpoint) Steady-state AUC (AUC ss ) and C max Dose proportionality after repeated dosing based on (secondary endpoint) C on days 16 and 17 trough Before administration (secondary endpoint) Accumulation rate (secondary outcome).

[0142] 〔result〕 The results of the repeated-dose oral pharmacokinetic study in humans are summarized in Tables 1 to 4 below and are graphically depicted in Figures 1 and 2.

[0143] The results show substantial accumulation of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in plasma after repeated dosing. Trough concentrations were similar on days 16-25, suggesting that steady-state conditions (or at least near-steady-state conditions) were established before day 18. On day 18, there was very little fluctuation in plasma concentrations, indicating a significant increase in C, compared with previous Phase I and IIa pharmacokinetic studies conducted with 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in suspension. max There has been a significant increase in

[0144] In a previous phase IIa study of patients with type 2 diabetes treated with 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide administered as a suspension at 1000 mg / day, the mean C maxThe mean mean plasma glucose concentration was 55 μg / ml. This was a randomized, parallel-group, double-blind, placebo-controlled, phase IIa 28-day study (TELLUS) conducted in 65 patients who had been using metformin for at least 3 months. TELLUS is listed in the EudraCT database protocol number 2016-002183-13.

[0145] When compared with a standard suspension of the active ingredient, there was a surprising and substantial (up to 5-fold) increase in systemic exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide when subjects were administered 200 mg of the sodium salt of the active ingredient.

[0146] [Table 1]

[0147] [Table 2]

[0148] [Table 3]

[0149] [Table 4]

[0150] Example 3: Pharmacokinetic study in humans using a new tablet formulation of O304Na salt The test material used in Example 3 was the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. The free base form of this material (i.e., 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide) is hereinafter referred to as the "test material", IMP, etc. The drug substance of the test material used in the study was synthesized by Anthem BioSciences (Bangalore, India) and the tablets (formulation) were manufactured by Recipharm Pharmaservices Pvt. Ltd. of Betagenon Bio AB (Umea, Sweden).

[0151] 〔method〕 [Clinical trial design] An open-label, randomized, parallel-group study was conducted to evaluate the exposure and safety of healthy volunteers (hereafter referred to as subjects) at steady-state doses of 212.12 mg and 424.24 mg of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide sodium salt tablets (equivalent to 200 mg and 400 mg doses of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide).

[0152] Main inclusion criteria: Body mass index (BMI) ≥ 18.0 and ≤ 30.0 kg / m 2 Healthy male and female subjects, aged 18-65 years, of non-childbearing potential, with gestational age 18-65 years.

[0153] Main Exclusion Criteria: Subjects with a history of clinically significant disease or disorder that, in the opinion of the investigator, would endanger the subject or affect the outcome or the subject's ability to participate in the trial.

[0154] [Clinical trial compounds] Each "400 mg" tablet contains 424.24 mg of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (compound of formula II), which corresponds to 400 mg of the parent compound 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0155] Formulation details for the "400 mg" tablet are shown in Table 5 below.

[0156] [Table 5]

[0157] Each tablet had a score line that allowed the tablet to be split into two for administration of lower doses of 200 mg of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0158] [Clinical methodology] Twenty subjects were randomized (1:1) to receive either 200 mg (one 200 mg tablet) or 400 mg (one 400 mg tablet) of test article.

[0159] A screening visit (Visit 1) occurred within 28 days prior to randomization and initiation of IMP dosing. Subjects arrived at the study clinic on Day 1 (Visit 2), were randomized, and received their first dose of study article (randomized 200 mg or 400 mg).

[0160] Subjects returned to the clinic in the morning of Day 2 (Visit 3) for pre-dose PK sampling and subsequent administration of study article.

[0161] Prior to discharge, subjects self-administered the test substance once daily at home for 18 days (days 3-20).

[0162] In addition, subjects were instructed on how to use the electronic diary in which daily intake of the study substance was registered. Subjects were contacted by telephone on Day 11 ± 1 (Visit 4) regarding adverse events (AEs), concomitant medication use, and IMP accountability. Site personnel contacted subjects who did not regularly register their IMP intake in the electronic diary.

[0163] After 18 days of home-based self-administration of test article, subjects returned to the clinic on the morning of Day 21 (Visit 5) for pre-dose PK sampling followed by administration of the final dose of test article. Subjects remained in the clinic for at least 8 hours post-dose for safety assessments and additional PK sampling. In the morning of Day 22 (Visit 6), subjects made a final visit to the clinic for a final PK sample 24 hours after the final dose.

[0164] The final telephone-based end-of-study visit (Visit 7) occurred approximately 2 weeks after the last dose, on Day 35 ± 3.

[0165] Venous blood samples (approximately 5 mL) for measuring plasma concentrations of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide after administration of the test article were collected via an indwelling venous catheter on days 2, 21, and 22.

[0166] Blood samples were collected in pre-labeled Li-heparin tubes. All collected blood samples were centrifuged at 1500G for 10 minutes to separate plasma within 60 minutes from the sample. The separated plasma from each blood sample was divided into two aliquots in pre-labeled polypropylene cryotubes (A and B samples, approximately 750 μL in each tube) and frozen at <-70°C.

[0167] Samples for determining plasma concentrations of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide were analyzed by means of a validated LS-MS / MS method by Lablytica Life Science AB, Uppsala, Sweden.

[0168] [Data Analysis] The plasma concentration data of the test substance (4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide) up to each time point were used for pharmacokinetic analysis. Pharmacokinetic analysis was performed using the noncompartmental analysis (NCA) module of Phoenix WinNonlin 8.1 software to determine the following pharmacokinetic parameters after repeated administration of the test substance:

[0169] Primary endpoint: C at steady state on day 21 for each treatment group max , AUC 0-last , T max .

[0170] Secondary endpoints: Accumulation ratio based on plasma concentrations 24 hours after the first and last doses. C at steady state on day 21 max and AUC 0-last Dosage normalization.

[0171] 〔result〕 The results of the repeated dose oral pharmacokinetic studies in humans are summarized in Tables 6 to 9 below and are presented graphically in FIG.

[0172] The results again show substantial accumulation of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in plasma following repeated dosing.

[0173] Additionally, when subjects were administered 212 mg of the sodium salt of the active ingredient in tablet form, there was a surprising and substantial (approximately 7-fold) increase in total body accumulation of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide from days 1 to 21. An approximately 5-fold increase in total body accumulation of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide from days 1 to 21 was observed for subjects administered 424 mg of the sodium salt of the active ingredient in tablet form.

[0174] There was a significant (up to 2-fold) increase in systemic exposure to 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide when subjects were administered 212 mg of the sodium salt of the active ingredient in tablet form compared to a capsule containing 200 mg of the sodium salt of the active ingredient.

[0175] Furthermore, both tablets and capsules containing the sodium salt of the active ingredient resulted in surprisingly high dose-normalized plasma exposures of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide compared to multiple-administered doses of the free base of the active ingredient in suspension.

[0176] [Table 6]

[0177] [Table 7]

[0178] [Table 8]

[0179] [Table 9]

[0180] [References] 1. Hardie D.G, AMPK-activated protein kinase - an energy sensor that regulates all aspects of cell function. Genes Dev. 25, 1895 - 1908, 2011 2. Schulz E, et al., When Metabolism Rules Perfusion, AMPK-Mediated Endothelial Nitric Oxide Synthase Activation. Circulation Research. 104, 422 - 424, 2009 3. Hardie D.G, et. al., AMP-activated protein kinase: A Target for Drugs both Ancient and Modern. Chemistry & Biology 19, 1222 - 1236, 2012 4. Myers R. W, et al., Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy. Science 357, 507 - 511, 2017 5. Cokorinos E.C, et al., Activation of Skeletal Muscle AMPK Promotes Glucose Disposal and Glucose Lowering in Non-human Primates and Mice. Cell Metab. 2017;25(5):1147 - 1159, 2017 6. Steneberg P, et al., PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients. JCI Insight. 3(12):e99114, 2018 7. National Cancer Institute Cancer Therapy Evaluation Program. Common terminology criteria for adverse events, CTCAE v5.0 (2017) 8. World Medical Association, WMA Declaration of Helsinki - Ethical principles for medical research involving human subjects [website], https: / / www.wma.net / policiespost / wma-declaration-of-helsinki-ethical-principles-for-medical-research-involvinghuman-subjects / , (accessed 16 April 2020)

Claims

1. An oral pharmaceutical dosage form comprising about 200 to about 1000 mg of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

2. 2. The oral pharmaceutical dosage form of claim 1, characterized in that the oral pharmaceutical dosage form comprises about 200 to about 800 mg, or about 200 to about 400 mg, or about 400 to about 1000 mg, or about 800 to about 1000 mg, or about 400 mg, or about 800 mg, or about 1000 mg of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

3. 3. The oral pharmaceutical dosage form according to claim 1 or 2, characterized in that the oral pharmaceutical dosage form comprises an enteric coating, preferably the enteric coating comprises beeswax, shellac, alkyl cellulose polymer resin, acrylic polymer resin, cellulose acetate phthalate or polyvinyl acetate phthalate.

4. 4. The oral pharmaceutical dosage form according to any one of claims 1 to 3, characterized in that the oral pharmaceutical dosage form further comprises at least one pharma- ceutically acceptable excipient selected from the group consisting of lubricants, binders, fillers, surfactants, diluents, anti-adherents, coatings, flavoring agents, coloring agents, glidants, preservatives, sweetening agents, disintegrants, adsorbents, buffers, antioxidants, chelating agents, dissolution enhancers, dissolution retarders and wetting agents.

5. 5. The oral pharmaceutical dosage form according to any one of claims 1 to 4, characterized in that the oral pharmaceutical dosage form is a capsule or a tablet.

6. 6. An oral pharmaceutical dosage form according to any one of claims 1 to 5, characterized in that the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is provided in the form of particles having a particle size distribution defined by a D90 of less than about 10 μm.

7. Use of an oral pharmaceutical dosage form according to any one of claims 1 to 6 in the manufacture of a medicament for treating a disease or disorder by activating 5' adenosine monophosphate-activated protein kinase (AMPK), comprising:

20. The method of claim 1, wherein about 200 to about 1000 mg / day of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is administered to a human subject.

8. 8. The use according to claim 7, characterized in that about 200 to about 800 mg / day, or about 200 to about 400 mg / day, or about 400 to about 1000 mg / day, or about 800 to about 1000 mg / day, or about 400 mg / day, or about 800 mg / day, or about 1000 mg / day of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is administered to a human subject.

9. 9. The use according to claim 7 or 8, characterized in that the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is administered daily to a human subject to achieve a peak plasma concentration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide of at least 40, 50, 60, 70, 80, 90, 100, 110, 120 or 130 μg / mL.

10. 10. The use according to claim 9, characterized in that the maximum plasma concentration is reached after a steady state concentration has been achieved.

11. 10. The use according to claim 9, characterized in that the maximum plasma concentration is reached after 15, 16, 17 or 18 days.

12. Use according to any one of claims 7 to 11, characterised in that the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is provided in the form of particles having a particle size distribution defined by a D90 of less than about 10 µm.

13. 13. The use according to any one of claims 7 to 12, characterized in that the disease or disorder is heart failure.

14. 13. The use according to any one of claims 7 to 12, characterized in that the disease or disorder is diabetic kidney disease.

15. 13. The use according to any one of claims 7 to 12, characterized in that the disease or disorder is diabetes.

16. The use according to any one of claims 7 to 12, characterized in that the disease or disorder is obesity.

17. further comprising administering to the human subject a sodium-glucose transport protein 2 (SGLT2) inhibitor, or a pharma- ceutically acceptable salt, solvate or prodrug thereof; 17. The use according to any one of claims 7 to 16, optionally characterized in that the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide and said SGLT2 inhibitor are administered sequentially or simultaneously to a human subject.

18. 18. The use according to claim 17, characterized in that the SGLT2 inhibitor is dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin or sotagliflozin.

19. 19. Use according to any one of claims 7 to 18, characterized in that the oral pharmaceutical dosage form comprises an enteric coating, optionally comprising beeswax, shellac, alkyl cellulose polymer resin, acrylic polymer resin, cellulose acetate phthalate or polyvinyl acetate phthalate.

20. 20. The use according to any one of claims 7 to 19, characterized in that the oral pharmaceutical dosage form comprising the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide further comprises at least one pharma- ceutically acceptable excipient selected from the group consisting of lubricants, binders, fillers, surfactants, diluents, antiadherents, coatings, flavourings, colourings, glidants, preservatives, sweeteners, disintegrants, adsorbents, buffers, antioxidants, chelating agents, dissolution enhancers, dissolution retarders and wetting agents.

21. 21. Use according to any one of claims 7 to 20, characterized in that the oral pharmaceutical dosage form is a capsule or a tablet.

Images