Novel formulations

Abstract

Provided are alkali metal salts of 4-chloro-N-[2-[(4-chlorphenyl) methyl]-3-oxo-1, 2, 4-thiadiazol-5-yl] benzamide and formulations thereof. Such salts are particularly useful in the treatment or prevention of disorders or conditions ameliorated by activation of AMPK.

Description

[0001] This application is a divisional application of an application with an application date of October 16, 2020, application number 202080072849.3, and invention name “New Formulation”. Technical Field

[0002] The present invention relates to alkali metal salts of specific pharmaceutical active ingredients and the use of such salts in medicine. In particular, the present invention relates to oral preparations comprising a milled alkali metal salt of the active ingredient. Background Art

[0003] AMP-activated protein kinase (AMPK) is a protein kinase that consists of three protein subunits and is activated by hormones, cytokines, exercise, and stress that reduces the energy status of the cell (e.g., glucose deprivation). Activation of AMPK increases processes that produce adenosine 5'-triphosphate (ATP), such as fatty acid oxidation, and inhibits other processes, such as fatty acid, glycerolipid, and protein synthesis, which consume ATP but are by no means necessary for survival. In contrast, when cells are presented with a sustained excess of glucose, AMPK activity decreases, while the synthesis of fatty acids, glycerolipids, and proteins increases. Therefore, AMPK is a protein kinase that plays an important role in cellular energy homeostasis. Therefore, the activation of AMPK is combined with the effects of lowering glucose and triggers several other biological effects, including inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, and reduction of hyperinsulinemia.

[0004] In view of the above, AMPK is a preferred target for treating metabolic syndrome, especially type 2 diabetes. AMPK is also involved in many pathways that are important for many different diseases (for example, AMPK is also involved in many pathways that are important for CNS disorders, fibrosis, osteoporosis, heart failure and sexual dysfunction).

[0005] AMPK is also involved in many pathways that are important for cancer. Several tumor suppressors are part of the AMPK pathway. AMPK acts as a negative regulator of the mammalian TOR (mTOR) and EF2 pathways, which are key regulators of cell growth and proliferation. Therefore, deregulation may be involved in diseases such as cancer (as well as diabetes). Therefore, AMPK activators may be used as anti-cancer drugs.

[0006] 4-Chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (ie, the compound of formula I) was first disclosed in WO 2011 / 004162 and has been shown to be an AMPK activator.

[0007]

[0008] As AMPK agonists (i.e., AMPK activators), compounds of Formula I can be used to treat disorders or conditions that are improved by activating AMPK. Such compounds can be used to treat cancer, diabetes, cardiovascular disease, hyperinsulinemia and related conditions, conditions / disorders in which fibrosis plays a role, sexual dysfunction, osteoporosis, and neurodegenerative diseases.

[0009] There is still 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 its effectiveness in medicine. The present inventors have now found that the use of a specific salt of a compound of formula I unexpectedly improves the bioavailability of the compound in vivo.

[0010] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an admission that the document is part of the current state of the art or is common general knowledge. DETAILED DESCRIPTION OF THE INVENTION

[0012] According to a first aspect of the present invention, there is provided an alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0013] "Alkali metals" are metals found in Group I of the periodic table along with hydrogen. Alkali metals are lithium, sodium, potassium, rubidium, cesium and francium. It is therefore understood that an "alkali metal salt" is a compound consisting of an aggregate of cations and associated anions of one or more alkali metals.

[0014] Thus, the term "alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide" refers to a compound comprising an alkali metal cation (e.g., lithium, rubidium, cesium, particularly sodium and potassium) and an anion of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. For example, an alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide may be referred to as a compound of formula II,

[0015]

[0016] Where X + represents an alkali metal (eg lithium, rubidium, cesium or in particular sodium or potassium) cation.

[0017] Those skilled in the art will recognize that alkali metal salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can dissociate into anionic and cationic components when dissolved in a suitable solvent, such as water.

[0018] Using the commercially available software package Autonom (a brand of nomenclature software provided as an add-on to the Symyx Draw 2.1 (TM) office suite sold by MDL Information Systems), the compound name 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide was obtained.

[0019] In this specification, the structure may or may not be represented by a chemical name. If any questions about nomenclature arise, the structure shall prevail. In the case where a compound may exist as a tautomer (e.g., in an alternative resonance form), the depicted structure represents one of the possible tautomeric forms, wherein the actual tautomeric form observed may vary according to environmental factors such as solvent, temperature, or pH value. 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:

[0020]

[0021] For the avoidance of doubt, the alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is solid at ambient conditions and the scope of the present invention therefore includes all amorphous, crystalline and partially crystalline forms thereof.

[0022] The alkali metal salts 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 an appropriate alkali metal hydroxide or alternative alkali metal base compound. Salt conversion techniques can also be used to convert one salt into another salt.

[0023] In the case where the commercial product 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. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be prepared according to the techniques described in international patent application WO 2011 / 004162, and all of its contents are incorporated herein by reference.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0025] In a specific embodiment, the alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is a sodium or potassium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. Preferably, the salt is the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. The sodium salt has been found to exhibit particularly enhanced bioavailability in vivo, as demonstrated by the data in the Examples, which show increased plasma exposure when the active ingredient is administered in this form.

[0026] For the avoidance of doubt, the skilled person will appreciate that references herein to a particular aspect of the invention (such as the first aspect of the invention) will include references to all embodiments and specific features thereof, which embodiments and specific features may be combined to form further embodiments and features of the invention.

[0027] The salts according to the first aspect of the present invention are referred to herein as "salts of the present invention".

[0028] Pharmaceutical preparations

[0029] As indicated herein, the salts of the present invention are useful as therapeutic agents to treat a variety of medical disorders or conditions. Typically, the salts of the present invention will be administered to a subject in need thereof in the form of a pharmaceutical formulation.

[0030] According to a second aspect of the present invention, there is provided a pharmaceutical formulation comprising an alkali metal salt (e.g., sodium salt) of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. Such formulations are referred to herein as formulations of the present invention. All embodiments described herein with respect to the first aspect of the present invention and their specific features are disclosed herein with respect to the second aspect of the present invention.

[0031] In a specific embodiment, the pharmaceutical formulation comprises a salt as defined in the first aspect of the invention, including all embodiments and special features thereof, wherein the salt has been milled.

[0032] As used herein, the term "milled" (which can be used interchangeably with other terms in the art such as "reduced size", "comminuted", "ground", and "pulverized") refers to a solid sample (e.g., particles) being subjected to mechanical energy (e.g., by grinding) to reduce the particle size of the solid sample. For example, coarse particles can be broken down into finer particles, thereby reducing the average particle size.

[0033] The phrase "the salt has been ground" will be understood to mean a salt of the invention (as defined in the first aspect of the invention) which has been obtained by any process involving the step of grinding said salt so that the average particle size of the solid salt product is smaller than the average particle size of the corresponding salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide which has been produced by methods known in the art but has not been treated to reduce its particle size.

[0034] Grinding is considered a 'top-down' method for producing fine particles. For example, a pharmaceutical solid can be cut by a sharp blade (e.g., a cutter mill), struck with a hammer, subjected to high-pressure homogenization, or crushed or compressed by applying pressure (e.g., a roller mill or pestle and mortar). Since a limited amount of energy is usually imparted, the particles produced by these methods remain relatively coarse. Technological advances in grinding equipment have enabled the production of ultrafine pharmaceutical particles to reach micron (i.e., μm unit range) or even submicron (e.g., nm unit range) sizes.

[0035] Certain milling processes can be characterized as dry milling processes. Such methods are preferred for processing the salts of the present invention.

[0036] "Dry grinding" refers to the process of grinding a drug in its dry state, i.e., in the absence of a liquid medium (e.g., in the substantial absence of water). In the dry state, the drug may be ground alone or in the presence of one or more other components, such as a pharmaceutically acceptable excipient. Other grinding materials, such as salts, may be present during the grinding process to help reduce particle size. The mechanical energy imparted by dry grinding promotes interactions between drug particles (and other substances optionally present) through van der Waals forces or hydrogen bonding.

[0037] A review of pharmaceutical milling processes can be found in Loh et al., Asian Journal of Pharmaceutical Sciences, 10 (2015), 255-274. Excipients suitable for inclusion in drug particles are known in the art, for example described in the following literature: Peltonen et al., Handbook of Polymers for Pharmaceutical Technologies, Thakur and Thakur, ed., Wiley, Vol. 4, Chapter 3, 67-87, and Nekkanti et al., Drug Nanoparticles-An Overview, The Delivery of Nanoparticles, Intech Open. The contents of these documents are incorporated by reference.

[0038] It has been found that the salts and formulations of the present invention (as defined in the first and second aspects of the invention and all embodiments of these aspects) are surprisingly effective in improving (e.g. increasing) the in vivo bioavailability of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide compared to a pharmaceutical formulation comprising the free base form of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. Following administration of the pharmaceutical formulation to an animal, typically a mammal, the bioavailability of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be measured by measuring C max The improvement in bioavailability can be demonstrated by measuring the area under the curve (AUC). The salts and formulations of the present invention can be used in the treatments described herein for subjects in need of such treatment. Preferably, the subject is a human.

[0039] In the context of the present invention, the term "free base" refers to the form of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide that is not in the form of a salt. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is not in the form of an ion (e.g., anion) associated with one or more oppositely charged ions (e.g., cations). The free base 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be described as a compound of formula I,

[0040]

[0041] Those skilled in the art will fully understand that the term " max" and "AUC" refer herein to the peak plasma concentration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide after administration (e.g., to a human subject) and the integral of the concentration / time curve of the substance after administration of a salt or formulation of the invention, respectively.

[0042] It has been found that administration of a salt of the active ingredient surprisingly results in a significantly increased systemic exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide compared to administration of the compound in non-salt form, i.e. the free form of the compound.

[0043] Stabilizers, such as polymers and surfactants, are often used during the milling process to increase the repulsion between particles and inhibit aggregation. Aggregation of finely ground particles may occur during the micronization process, which ultimately slows down the dissolution process and affects bioavailability. It has been found that even without the addition of stabilizers, an increase in systemic exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide occurs after administration of dry-milled active ingredient salts. Therefore, in one embodiment, the pharmaceutical formulation does not contain any stabilizer.

[0044] Therefore, the formulation of the second aspect of the present invention is able to increase the bioavailability of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide compared to a pharmaceutical formulation comprising the free base form of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0045] When we say "capable of increasing the bioavailability of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide compared to a pharmaceutical formulation comprising the free base form of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide", we mean that administration of a formulation comprising a salt of the present 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 the body compared to administration of a formulation comprising free 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. The increase in the amount of systemically available 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide following administration of a formulation comprising a salt of the invention may 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) as compared to administration of a formulation comprising free 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0046] The improvement of bioavailability provided by the formulation of the present invention can be demonstrated using suitable methods known in the art. For example, the improvement of bioavailability can be demonstrated by comparing the pharmacokinetic data (e.g., AUC data) of a subject who has been administered a formulation comprising a salt of the present invention with the corresponding data of a subject who has been administered a pharmaceutical formulation comprising 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide in free base form.

[0047] Milling reduces the average size of the particles containing the alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. The extent and effectiveness of the milling can be determined by measuring the particle size distribution of the particles before and after the milling process.

[0048] The term "particle size distribution" refers to the relative number of particles present in a solid sample (e.g., powder, granular material) or particles dispersed in a fluid according to size. Particle size distribution affects the properties of solid samples (e.g., powders, etc.) in a variety of ways. We have found that a reduction in the average particle size results in a surprising improvement in the bioavailability of the resulting drug product.

[0049] 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 elutriation analysis, optical counting, resistance counting, sedimentation, laser shielding, and acoustic (e.g., ultrasonic attenuation) spectroscopy. Specific methods that can be mentioned for measuring the particle size distribution of the particles of the salt of the present invention are dynamic light scattering and laser diffraction.

[0050] The particle size distribution can also be determined based on the results of a sieve analysis. A sieve analysis presents the particle size information in the form of an S-curve of the cumulative mass retained on each sieve versus the size of the sieve opening. The most commonly used metric when describing a particle size distribution is a D value (e.g., D10, D50, and D90, which are the intercepts of 10%, 50%, and 90% of the cumulative mass, respectively). The particle size distribution of the present invention is preferably defined using one or more of these values. The D value essentially represents the diameter of a sphere that divides the mass of the sample into specified percentages when the particles are arranged in an increasing mass manner. For example, the D10 value is the diameter at which 10% of the sample mass is composed of particles having a diameter less than this value. The D50 value is the particle diameter at which 50% of the sample mass is less than and 50% of the sample mass is greater than.

[0051] The particles containing the salt of the present invention may have a particle size distribution defined by a D90 of less than about 10 μm (e.g., from about 5 μm to about 10 μm). The particles composed 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., from about 1 μm to about 6 μm). The particle size distribution of the particles composed of the salt of the present invention may be further defined by a D10 of less than about 2 μm (e.g., from about 0.5 μm to about 2 μm). In a specific embodiment, the formulation includes particles containing the salt of the present invention, the particles having a particle size distribution defined by a D90 of less than about 10 μm.

[0052] The above particle size distribution parameters may apply individually or in combination to any given salt, mixture or formulation. For example, in a particular embodiment, the formulation includes particles containing a salt of the invention having a particle size distribution defined by a D90 of less than about 10 μm and a D50 of greater than about 6 μm.

[0053] The particle size distribution of the particles comprising the salt of the present invention can be measured by laser diffraction, for example using a particle size analyzer (e.g. Shimadzu SALD-2300). When this method involves dispersing the substance to be analyzed in a liquid medium (e.g. water), a suitable amount of a dispersant, such as Tween 20 (polyethylene glycol dehydrated sorbitan monolaurate) can be used.

[0054] The present invention also encompasses pharmaceutical formulations comprising particles comprising a salt of the present invention having any particle size distribution as defined herein, irrespective of the method of preparing the particles.

[0055] Preferably, the pharmaceutical formulation of the second aspect of the invention comprises particles of a salt of the invention having any specific particle size distribution as described herein, wherein the particles are obtained by a process involving grinding of said salt.

[0056] The pharmaceutical formulations of the second aspect of the invention may be prepared according to standard and / or accepted pharmaceutical practice.

[0057] In an embodiment of the second aspect of the invention, the salt of the invention is the only active pharmaceutical ingredient present in the granules containing the salt. In another embodiment of the second aspect of the invention, the salt of the invention is present in a formulation with one or more other active pharmaceutical ingredients, or can be administered as part of a combination therapy with one or more other active pharmaceutical ingredients.

[0058] As described herein, for example, the formulation of the second aspect of the invention may comprise particles comprising a salt of the invention which has been milled such that the particles have a particle size distribution defined by a D90 of less than about 10 μm.

[0059] Thus, according to a third aspect of the present invention, there is provided a method of preparing a formulation as defined above (i.e. a formulation according to the second aspect of the present invention and all embodiments thereof), wherein the method comprises grinding a salt of the present invention, optionally together with one or more excipients, to produce particles having a particle size distribution defined by a D90 of less than about 10 μm.

[0060] In one embodiment of the third aspect of the invention, dry grinding is used to grind the particles. Dry grinding generally involves grinding a substance (i.e., a drug) in the substantial absence of other components (e.g., in the substantial absence of any other components of a pharmaceutical formulation). Thus, in one embodiment, the particles consist essentially of a salt of the invention and have a particle size distribution as defined herein. In another embodiment, the particles consist essentially of a salt of the invention and are obtained by dry grinding.

[0061] Optionally, dry milling comprises jet milling. Jet milling is a milling process that involves a high velocity compressed air stream to reduce the size of drug particles, typically from a range of 20 to 100 μm to less than 10 μm. Particle size reduction is achieved by a combination of impact (impact between particles or against the walls of the milling chamber) and abrasion (as particles move relative to each other). The skilled artisan will appreciate that control of particle size can be achieved by varying milling conditions according to methods known in the art.

[0062] In a specific embodiment of the method of the third aspect of the invention, after grinding the salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide, the salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is mixed with one or more excipients.

[0063] In other embodiments of the method of the third aspect of the present invention, an enteric coating may be introduced into the preparation at any time point, provided that the salt of the present invention in the resulting preparation is encapsulated in the enteric coating. For example, when the pharmaceutical preparation is provided in the form of a capsule or tablet, the method may further include the step of coating the capsule or tablet with an enteric coating before or after (preferably after) the ground 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide salt has been incorporated into the capsule or tablet. Alternatively, the method may further include the step of applying an enteric coating to the ground 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide salt before the granules are incorporated into the capsule or tablet.

[0064] Dry grinding can be used to produce particles that are generally larger in size than those obtained with wet grinding. Specific particle size distributions that may be mentioned herein include those having a D90 of less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, or less than about 6 μm.

[0065] More specifically, the particles containing the salt of the invention present in the formulations defined herein may have a particle size distribution defined by a D90 of about 5 μm, about 5.5 μm, about 6 μm, about 6.5 μm, about 7 μm, about 7.5 μm, about 8 μm, about 8.5 μm, about 9 μm, about 9.5 μm or about 10 μm. The particle size distribution preferably relates to particles consisting essentially of the salt of the invention.

[0066] Preferably, particles containing the salt of the present invention have a particle size distribution defined by a D50 of less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, or less than about 2 μm.

[0067] The particle size distribution of particles containing the salt of the present invention can also be defined by a D50 of about 1 μm, about 1.5 μm, about 2 μm, about 2.5 μm, about 3 μm, about 3.5 μm, about 4 μm, about 4.5 μm, about 5, about 5.5, or about 6 μm.

[0068] Still further, particles containing the salt of the present invention may have a particle size distribution defined by a D10 of less than about 2 μm, less than about 1.5 μm, or less than about 1 μm.

[0069] The particle size distribution of particles containing the salt of the present invention may also be defined by a D10 of about 0.5 μm, about 1 μm, about 1.5 μm, or about 2 μm.

[0070] Thus, in a particular embodiment of the formulation (i.e., a formulation according to any embodiment of the second aspect of the invention), the particles containing the salt of the invention have a particle size distribution defined by a D90 of less than 9 μm; a D50 of less than 6 μm; a D50 of less than 5 μm; a D10 of less than 2 μm; or a D10 of less than 1.5 μm.

[0071] The preparation of the second aspect of the present invention is generally provided as a mixture comprising a salt of the present invention and one or more pharmaceutically acceptable excipients. One or more pharmaceutically acceptable excipients can be selected according to standard pharmaceutical practice with due consideration of the intended route of administration. Such pharmaceutically acceptable excipients are preferably chemically inert to the active compound and preferably do not have harmful side effects or toxicity under the conditions of use. Suitable pharmaceutical preparations can be found in, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). A brief review of drug delivery methods can also be found in, for example, Langer, Science 249, 1527 (1990).

[0072] It has been found that pH adjusting excipients are particularly advantageous in the formulations of the present invention. pH adjusting excipients are those that significantly change the pH of the formulation aqueous solution compared to the pH of the aqueous solution of the same formulation not comprising the excipient. The pH adjusting excipient can increase (or decrease) the pH of the formulation aqueous solution (e.g., to a pH of 8 or higher) compared to the aqueous solution of the same formulation not comprising the excipient. Such excipients can be used to increase (i.e., improve) the water solubility and / or stability of the compounds of the present invention in the formulation.

[0073] In the formulations of the present invention, it has been found that basic excipients can be combined with the salts of the present invention and lead to improved solubility of the compound. Thus, in a particular embodiment of the second aspect of the present invention, at least one pharmaceutically acceptable excipient is a basic excipient.

[0074] As used herein, the term "alkaline excipient" refers to a pharmaceutically acceptable excipient that increases the pH of the microenvironment of the formulation. It has been found that adjusting the microenvironment pH of the formulation can improve the solubility of the active ingredient in the formulation, which in turn may lead to enhanced oral absorption of the active ingredient. Specific alkaline excipients that may be mentioned include magnesium oxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, magnesium carbonate and calcium carbonate. In a specific embodiment, the alkaline excipient is magnesium oxide.

[0075] Therefore, according to a specific embodiment, the formulation further comprises at least one pharmaceutically acceptable excipient. In particular, at least one pharmaceutically acceptable excipient can be a lubricant, a binder, a filler, a surfactant, a diluent, an antiadherent, a coating, a flavoring agent, a colorant, a glidant, a preservative, a sweetener, a disintegrant, an adsorbent, a buffer, an antioxidant, a chelating agent, a dissolution promoter, a dissolution delay agent or a wetting agent.

[0076] Specific pharmaceutically acceptable excipients that may be mentioned include mannitol, PVP (polyvinyl pyrrolidone) K30, lactose, sucrose, sorbitol, starch, pullulan, cellulose derivatives, gelatin or other suitable ingredients, as well as disintegrants and lubricants, such as docusate sodium, magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol wax. In the preparation of pharmaceutical preparations of the salts of the present invention for oral administration, the salts of the present invention (preferably after grinding) may be mixed with mannitol, PVP (polyvinyl pyrrolidone) K30 and docusate sodium together or separately. Therefore, in a specific embodiment, the preparation of the present invention comprises PVP K30, docusate sodium and mannitol.

[0077] Such mixtures may then be processed into pellets or granules or compressed into tablets. Thus, the pharmaceutical formulations of the present invention include formulations for oral administration provided in the form of tablets, mini-tablets, blocks, pellets, particles, granules or powders.

[0078] The skilled person will appreciate that the preparations described herein can act systemically and therefore can be administered accordingly using suitable techniques known to those skilled in the art. The preparations described herein are generally administered orally in a pharmaceutically acceptable dosage form. Therefore, the pharmaceutical preparation of the second aspect of the present invention is preferably an oral pharmaceutical preparation.

[0079] The preparation of the present invention can be prepared into capsule form for oral administration. For example, capsules such as soft gelatin capsules can be prepared, which contain the salt of the present invention alone, or together with suitable carriers such as vegetable oils, fats, etc. Similarly, hard gelatin capsules can contain the salt of the present invention alone, or in combination with solid powder ingredients such as disaccharides (e.g. lactose or sucrose), alcohol sugars (e.g. sorbitol or mannitol), plant starches (e.g. potato starch or corn starch), polysaccharides (e.g. amylopectin or cellulose derivatives) or gelling agents (e.g. gelatin).

[0080] Thus, the pharmaceutical formulations of the present invention include formulations provided in capsule or tablet form, for example, for oral administration.

[0081] Preparations for oral administration may also include enteric coatings to prevent or minimize dissolution or disintegration in the gastric environment. Therefore, oral preparations (e.g., capsules or tablets) coated with enteric coatings may provide targeted release of the salt of the present invention in the small intestine. For example, enteric coatings may be present on the surface of the preparation (e.g., the surface of a tablet or capsule), or each particle containing the salt of the present invention may be coated with an enteric coating. Therefore, in a particular embodiment, the preparation also includes an enteric coating.

[0082] It may be desirable to minimize dissolution or disintegration of a capsule or tablet (etc.) in the gastric environment and / or to provide targeted release of the active ingredient in the small intestine. Thus, in certain embodiments, an enteric coating is present on the capsule or tablet. For example, the coating may be provided as an outer layer on the capsule or tablet.

[0083] Alternatively, the granules containing the salt of the present invention can be individually coated with an enteric coating, and the coated granules can be encapsulated or compressed into tablets. Thus, in a specific embodiment, a capsule or tablet contains granules comprising a salt of the present invention and each granule is enteric coated.

[0084] The term "enteric coating" refers to a substance (e.g., a polymer) that is incorporated into an oral drug (e.g., applied to the surface of a tablet, capsule, granule, or pill) and inhibits the drug from dissolving or disintegrating in the gastric environment. Enteric coatings are generally stable at the highly acidic pH of the stomach, but rapidly decompose at the relatively alkaline pH of the small intestine. Thus, enteric coatings prevent the release of the active ingredient in the drug until it reaches the small intestine.

[0085] Any enteric coating known to those skilled in the art can be used in the present invention. Specific enteric coating materials that may be mentioned include those containing beeswax, shellac, alkylcellulose polymer resins (e.g., ethylcellulose polymers, carboxymethylethylcellulose or hydroxypropylmethylcellulose phthalate) or acrylic polymer resins (e.g., acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylate copolymers, methacrylic acid ester copolymers, methacrylic acid copolymers, aminoalkyl methacrylate copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymers, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, methyl methacrylate copolymers, poly(methyl methacrylate), poly(methyl methacrylate) copolymers, polyacrylamide, aminoalkyl methacrylate copolymers, poly(methacrylic anhydride), glycidyl methacrylate copolymers), cellulose acetate phthalate and polyvinyl acetate phthalate). A specific polyacrylic acid resin that may be mentioned is polyacrylic acid resin HB-50.

[0086] Preferably, the pharmaceutical formulation of the second aspect of the invention comprises milled particles of a salt of the invention, said particles having any of the specific particle size distributions described herein, and wherein the formulation further comprises an enteric coating. Thus, in a specific embodiment, in the pharmaceutical formulation of the second aspect of the invention, the salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide has been milled so that the particles containing the salt have a particle size distribution defined by a D90 of less than 10 μm, and the formulation further comprises an enteric coating.

[0087] Pharmaceutical preparations that may be mentioned include those in which the salt of the invention is present in a total amount of at least 1% by weight (or at least 10%, at least 30% by weight or at least 50% by weight) of the preparation. That is, the weight ratio of the salt of the invention to all components of the pharmaceutical preparation (i.e. the salt of the invention and all pharmaceutical excipients, such as adjuvants, diluents and carriers) is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50).

[0088] As used herein, "therapeutically effective amount", "effective amount" or "dose" refers to the amount of the salt of the present invention sufficient to produce the desired effect, which can be a therapeutic and / or beneficial effect. The effective amount or dosage will vary with the age or general condition of the subject (e.g., human), the severity of the condition being treated, the specific agent administered, the duration of treatment, the nature of any concurrent treatment, the pharmaceutically acceptable carrier used, and similar factors within the knowledge and expertise of those skilled in the art. As appropriate, in any individual case, a "therapeutically effective amount", "effective amount" or "dose" can be determined by those skilled in the art by reference to relevant texts and literature and / or by using routine experiments. It will be understood by those skilled in the art that the therapeutic effect does not have to be complete or curative, as long as some benefit is provided to the subject.

[0089] It will be appreciated by the skilled person that the preparations of the present invention can be administered at different doses (e.g., by one or more preparations as described herein), wherein the appropriate dosage is easily determined by the skilled person in the art. The total dosage range of the salt of the present invention administered to a subject in need thereof can be from about 0.01 to about 2000 mg / kg body weight (mg / kg / day), from about 0.1 to about 500 mg / kg / day, or from about 1 to about 100 mg / kg / day per day. Such dosage can be, for example, the oral dosage of the preparation of the second aspect of the present invention.

[0090] When administered orally, treatment with such preparations (including capsules containing such preparations) may include administering a unit dose formulation containing about 0.01 mg to about 3000 mg of a salt of the present invention, such as about 0.1 mg to about 2000 mg or about 1 mg to about 1000 mg (e.g., about 10 mg to about 500 mg) of a salt of the present invention. Advantageously, treatment may include administering a salt of the present invention (including capsules containing the preparation) using a single daily dose. Alternatively, the total daily dose of the salt of the present invention may be administered in divided doses, twice, three times, or four times a day (e.g., with reference to dosages described herein, twice a day, such as 100 mg, 250 mg, 500 mg, or 1000 mg, twice a day). A skilled physician will recognize that dosage varies from subject to subject.

[0091] In a specific embodiment, the daily dosage of the salt of the invention administered to a subject is in the range of about 1 to about 3000 mg, preferably about 1 to about 1000 mg.

[0092] As used herein, the term "about" refers to a measurable value, such as an amount of a compound, a dosage, a time, a temperature, etc., and refers to a variation of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. It is contemplated that, in each case, such terms may be replaced with the notation "±10%" or the like (or by indicating the variance of a particular amount calculated based on the relevant value). It is also contemplated that, in each case, such terms may be deleted.

[0093] For the avoidance of doubt, in the context of the present invention, the dose administered to a subject, particularly a human subject, should be sufficient to produce a therapeutic response in the subject within a reasonable time frame. Those skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by, among other things, the pharmacological properties of the formulation, the nature and severity of the condition being treated, the physical condition and mental acuity of the recipient, and the potency of the specific compound, the age, condition, weight, sex and response of the subject to be treated, and the stage / severity of the disease.

[0094] In any case, a medical practitioner or other technical personnel will be able to routinely determine the actual dosage that is most suitable for an individual subject. The dosages mentioned above are exemplary in general; of course, in individual cases, higher or lower dosage ranges may be required, and such dosage ranges are within the scope of the present invention.

[0095] Medical Uses

[0096] The salts of the present invention and their preparations can be used as medicines.

[0097] The salts of the present invention (i.e., the salts as defined in the first aspect of the present invention, including all its embodiments and its specific features) and their preparations (i.e., the preparations as defined in the second aspect of the present invention, including all its embodiments and its specific features)) may be particularly useful for treating disorders or conditions improved by activating AMP-activated protein kinase (AMPK). Therefore, in a fourth aspect of the present invention, there is provided a use of the salts of the present invention or preparations comprising the salts as defined herein for the preparation of a medicament for treating disorders or conditions improved by activating AMPK.

[0098] Similarly, a method for treating a disease or condition improved by activating AMPK is provided, comprising administering a therapeutically effective amount of a salt of the present invention or a preparation comprising the salt to a subject (e.g., a person) in need thereof. Likewise, a salt of the present invention (or a preparation comprising the salt) is provided for use in treating a disease or condition improved by activating AMPK.

[0099] By 'activation of AMPK' we mean that the steady state phosphorylation level of the Thr-172 portion of the AMPK-alpha subunit is increased compared to the steady state phosphorylation level in the absence of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. Alternatively, or additionally, we mean that the steady state phosphorylation level of any other protein downstream of AMPK, such as acetyl CoA carboxylase (ACC), is higher.

[0100] One skilled in the art will understand that the term "disorder or condition improved by activation of AMPK" includes cancer, diabetes, cardiovascular disease, hyperinsulinemia and related conditions, conditions / disorders in which fibrosis plays a role, sexual dysfunction, osteoporosis, and neurodegenerative diseases.

[0101] Those skilled in the art will understand that the term "cancer" includes one or more diseases belonging to a classification of disorders characterized by the uncontrolled division of cells and the ability of these cells to invade other tissues by invasion, proliferation, direct growth into adjacent tissues, or implantation 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 movement or migration (e.g., invasiveness) of cancer cells from a primary tumor site in a subject's body to one or more other areas in the subject's body (where the cells can then form secondary tumors). 4-Chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is capable of inhibiting the proliferation of cancer cells and the metastasis of cancer cells.

[0102] Therefore, the preparation of the present invention can be suitable for treating any cancer type, including all tumors (non-solid and preferably solid tumors, such as carcinomas, adenomas, adenocarcinomas, blood cancers, regardless of the organ). For example, the cancer cells can be selected from cancer cells of the breast, bile duct, brain, colon, stomach, reproductive organs, thyroid, hematopoietic system, lung and airway, skin, gallbladder, liver, nasopharynx, nerve cells, kidney, prostate, lymph nodes and gastrointestinal tract. Preferably, the cancer is selected from colon cancer (including colorectal adenomas), breast cancer (such as postmenopausal breast cancer), endometrial cancer, hematopoietic cancer (such as 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 colon cancer, prostate cancer, in particular breast cancer. In case the cancer is a non-solid tumor, it is preferably a hematopoietic tumor, such as a leukemia (e.g. acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL)). Preferably, the cancer cell is a breast cancer cell.

[0103] Those skilled in the art will appreciate that the term "diabetes" (i.e., diabetes mellitus) refers to type 1 (insulin-dependent) diabetes and type 2 (insulin-independent) diabetes, both of which involve dysfunction of glucose homeostasis. The salts of the present invention and their preparations may be particularly useful in treating type 1 diabetes and / or type 2 diabetes.

[0104] Those skilled in the art will appreciate that the term "hyperinsulinemia or related conditions" includes 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 ovary syndrome. Other disease states include progressive renal disease, such as chronic renal failure.

[0105] In particular, the salts and preparations thereof of the present invention are useful for treating obesity associated with hyperinsulinemia and / or cardiovascular diseases associated with hyperinsulinemia.

[0106] The salts and preparations thereof of the present invention may also be applicable to the treatment of cardiovascular diseases, such as heart failure, wherein the cardiovascular diseases are unrelated to hyperinsulinemia. Similarly, the salts and preparations thereof of the present invention may also be applicable to the treatment of obesity unrelated to hyperinsulinemia. For the avoidance of doubt, the treatment of obesity and / or cardiovascular diseases (e.g., heart failure) to which AMPK activation may be beneficial is included within the scope of the present invention.

[0107] 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, cirrhosis of the liver, ocular macular degeneration, retinal and vitreoretinopathy, Crohn's disease / inflammatory bowel disease, post-operative scar tissue formation, radiation and chemotherapeutic drug-induced fibrosis, and cardiovascular fibrosis.

[0108] The salts of the invention may also be used to treat sexual dysfunction (eg, to treat erectile dysfunction). The salts of the invention may also be used to treat inflammation.

[0109] Neurodegenerative diseases that may be mentioned include Alzheimer's disease, Parkinson's disease and Huntington's disease, amyotrophic lateral sclerosis, polyglutamine diseases such as spinal and bulbar muscular atrophy (SBMA), dentary and pallidum atrophy (DRPLA), and various spinocerebellar ataxias (SCA).

[0110] The skilled artisan will understand that reference to "treatment" of a particular condition (or similarly, "treating" the condition) will have its normal meaning in the medical arts. Specifically, the term may refer to achieving a reduction in the severity and / or frequency of occurrence of one or more clinical symptoms associated with the condition, as determined by a physician treating a subject suffering from or susceptible to such symptoms.

[0111] As used herein, reference to a subject (or subjects) refers to a living subject, including a mammalian (eg, human) subject, who is being treated or receiving a prophylactic drug. In particular, reference to a subject refers to a human subject.

[0112] The skilled person will understand that such treatment or prevention will be performed in a subject in need thereof. The skilled person can assess the need for such treatment or prevention in a subject using routine techniques.

[0113] In the context of the present invention, a "subject in need thereof" of the salts of the present invention includes a subject suffering from a disorder or condition that is ameliorated by activation of AMPK.

[0114] As used herein, the terms "disease" and "disorder" (and similarly, the terms condition, illness, medical problem, etc.) are used interchangeably.

[0115] Without wishing to be bound by theory, it is believed that administration of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in the form of a salt of the present invention increases the bioavailability of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide in systemic circulation. Formulations containing the salts of the present invention have been shown to increase the bioavailability of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide by about two-fold in some cases compared to formulations containing the free base form of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0116] The salts of the present invention (and their preparations) may have the following advantages: they may be more effective, less toxic, longer acting, more potent, produce fewer side effects, be more easily absorbed and / or have better pharmacokinetic characteristics (e.g., higher oral bioavailability and / or lower clearance) and / or have other useful pharmacological, physical or chemical properties, whether or not used or otherwise for the indications described above. Specifically, the preparations of the present invention may have the following advantages: they are more effective and / or exhibit favorable properties in vivo. BRIEF DESCRIPTION OF THE DRAWINGS

[0117] The following drawings are provided to illustrate various aspects of the inventive concept and are not intended to limit the scope of the present invention unless specifically specified herein.

[0118] Figure 1 Comparative results of oral pharmacokinetic studies using 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (Compound 1) in suspension and uncoated capsules, and 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide sodium salt (Compound 2) and 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide potassium salt (Compound 3), respectively, in uncoated capsules are shown.

[0119] Figure 2 Comparative results of oral pharmacokinetic studies using Compound 1 in suspension and enteric coated capsules, and Compound 2 and Compound 3, respectively, in enteric coated capsules are shown.

[0120] Figure 3 and Figure 4 The absolute and relative C values ​​of the formulations of compound 1 as a suspension and uncoated capsules and the formulations of compound 2 and compound 3 in uncoated capsules are shown. max result.

[0121] Figure 5 and Figure 6 Absolute and relative AUC results are shown for formulations of Compound 1 as a suspension and uncoated capsules, and formulations of Compound 2 and Compound 3, respectively, in uncoated capsules.

[0122] Figure 7 and Figure 8 The absolute and relative C values ​​for the formulations of compound 1 as a suspension and enteric coated capsules and the formulations of compound 2 and compound 3 in enteric coated capsules are shown. max result.

[0123] Fig. 9 and Fig.10 Absolute and relative AUC results are shown for formulations of Compound 1 as a suspension and in enteric coated capsules, and formulations of Compound 2 and Compound 3, respectively, in enteric coated capsules. Example

[0124] Abbreviations

[0125] AUC 0-t : Area under the concentration-time curve from time zero to the last quantifiable concentration

[0126] AUC 0-∞ : Area under the concentration-time curve from time zero to infinity

[0127] bw: weight

[0128] CE: Collision Energy

[0129] CL: Clearance

[0130] C max : Peak plasma concentration.

[0131] CXP: Collision cell exit potential

[0132] DLS: Dynamic Light Scattering

[0133] DP: Declustering Potential

[0134] EP: Entry Potential

[0135] h: hours

[0136] HPLC: High Performance Liquid Chromatography

[0137] ISD: Internal Standard

[0138] K2EDTA Potassium Ethylenediaminetetraacetate

[0139] LC: Liquid chromatography

[0140] LC-MS / MS: Liquid chromatography-(tandem) mass spectrometry

[0141] LS: Light Scattering

[0142] MRT: mean residence time.

[0143] min: minutes

[0144] PVP K30: Polyvinylpyrrolidone K30

[0145] rpm: revolutions per minute

[0146] RT: Room temperature

[0147] T 1 / 2 : half life

[0148] T max : Time to peak plasma concentration

[0149] v / v: volume / volume

[0150] w / v: weight / volume

[0151] The present invention will be further described by reference to the following examples, which are not intended to limit the scope of the present invention.

[0152] Material

[0153] 4-Chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide (Compound 1), 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide sodium salt (Compound 2) and 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide potassium salt (Compound 3) were prepared by Anthem Biosciences.

[0154] Docusate sodium, PVP K30, and mannitol were provided by Sigma-Aldrich.

[0155] Preparation of sodium 1-4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide Salt (Compound 2)

[0156] plan:

[0157]

[0158] program:

[0159] 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), a solution of sodium hydroxide (11.56 g, 0.2891 mol) in water (100 mL) was slowly added at 25 ± 5 ° C. The substance was stirred at 25 ± 5 ° C for 3 hours and cooled to 5 ± 5 ° C. The substance 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 at 35 ± 5 ° C under reduced pressure for 8 hours. A column having a mass of 4.0 kg / cm 2 Primary pressure, 7.0kg / cm 2The dried solid was micronized twice with secondary pressure and air jet milling with an 8 RPM screw feeder to isolate the desired sodium salt as a white solid (50 g, 48%).

[0160] Preparation of potassium 2-4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide Salt (Compound 3)

[0161] plan:

[0162]

[0163] program:

[0164] 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), a solution of potassium hydroxide (16.22 g, 0.2891 mol) in water (100 mL) was slowly added at 25 ± 5 ° C. The substance was stirred at 25 ± 5 ° C for 3 hours and cooled to 5 ± 5 ° C. The substance 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 at 35 ± 5 ° C under reduced pressure for 8 hours. A 4.0 kg / cm 2 Primary pressure, 7.0kg / cm 2 The dried solid was micronized twice with secondary pressure and air jet milling with an 8 RPM screw feeder to isolate the desired potassium salt as a white solid (55 g, 50%).

[0165] Example 1 - Ground product

[0166] Examples 1a to 1c were milled using an air jet mill (equipment code: CP-AJM-01; Promas engineers) with the following parameters:

[0167] parameter value Primary pressure (argon / nitrogen) <![CDATA[4.0kg / cm 2 <!-- 14 -->]]> Secondary pressure (argon / nitrogen) <![CDATA[7.0kg / cm 2 ]]> Screw Feeder RPM 8

[0168] In all examples the micronization was repeated by a second air jet milling using the same parameters. This resulted in a reduction of the particle size D90 to less than 10 μm.

[0169] Particle size analysis

[0170] Reagents

[0171] name grade water HPLC Twain 20 Laboratory Reagents

[0172] instrument

[0173] Balance Analytical Balance Particle size analyzer Shimadzu SALD-2300

[0174] Method Parameters

[0175] Dispersion method Flow cell measurement technology with sampler Refractive Index 3.00-0.20i (almost equal to Fraunhofer) Dispersants Twain 20 Pump speed 5.0 Ultrasonic treatment time 10 blank 4 drops of Tween 20 in 25 mL of water

[0176] preparation

[0177] Four drops of Tween 20 were added to 25 mL of water, and the mixture was sonicated for 3 minutes to form a dispersant solution.

[0178] 0.05 g of the ground material was transferred to a 250 mL glass beaker. 25 mL of dispersant solution (Tween 20 / water mixture) was added to the beaker while vortexing continuously for 2 to 3 minutes. The suspension was transferred to a measuring cell and the particle size distribution was measured in triplicate.

[0179]

[0180] Table 1: Average particle size results of dry-milled products

[0181] Examples 2 to 8 - Single-dose oral pharmacokinetic studies in rabbits

[0182] The studies detailed below (and referred to as Examples 2 to 8) were conducted in male New Zealand White rabbits using uncoated and enteric coated capsules to provide comparative single dose oral pharmacokinetic data for Compound 1 and the sodium and potassium salts of that compound.

[0183] Preparation

[0184] 1. Capsules

[0185] Ready-to-use enteric coated and uncoated capsules were used. Capsules were obtained from CapsulCN International Co., Ltd.

[0186] Compound 1 was prepared using the process described in WO 2011 / 004162 and ground as described in Example 1c. Uncoated or enteric coated gelatin capsules were filled with 180 mg of dry ground Compound 1 and the accompanying excipients indicated. Both capsule types were filled with Compound 1 and 1.8 mg of docusate sodium, 0.18 mg of PVP K30 and 9 mg of mannitol.

[0187] Similarly, Compound 2, uncoated or enteric coated gelatin capsules were filled with 180 mg of dry-milled Compound 2 (as obtained in Example 1f) and 1.8 mg of docusate sodium, 0.18 mg of PVP K30 and 9 mg of mannitol, respectively.

[0188] For Compound 3, uncoated or enteric coated gelatin capsules were filled with 90 mg of dry-milled Compound 3 (as obtained in Example 1i) and 0.90 mg of docusate sodium, 0.09 mg of PVP K30 and 4.50 mg of mannitol, respectively.

[0189] After preparation, the capsules were stored in a desiccator at 19 to 25°C prior to administration to animals.

[0190] The details of the formulations are summarized in Table 2.

[0191] 2. Suspension

[0192] Compound 1 was prepared using the method described in WO 2011 / 004162.

[0193] A 2% w / v methylcellulose solution was prepared in 4 mM phosphate buffer pH 7.4.

[0194] 40 mL of 2% w / v methylcellulose solution was added to a 250 mL conical flask along with 10 g of 2 mm glass beads and stirred vigorously. Compound 1 (720 mg) was slowly added to the solution and the mixture was stirred continuously for 1 h. The homogenate was transferred to a separate flask and its pH was recorded. The suspension formulation was prepared before administration to the animal.

[0195] Animal husbandry

[0196] Rabbits (New Zealand White rabbits; male) were housed under standard laboratory conditions in an environmentally monitored air-conditioned room with adequate fresh air supply (10-15 air changes per hour), room temperature (22±3°C) and relative humidity of 30-70%, with a 12-hour light and 12-hour dark cycle. Temperature and relative humidity were recorded once a day.

[0197] Each animal was housed in a standard stainless steel rabbit cage SS-304 (dimensions: L 24” x B 18” x H 18”) with a stainless steel mesh and a removable bottom tray for waste disposal, a food hopper to hold pelleted food, a holder for a drinking water bottle, and a siphon and label holder. Clean, sterilized corn cobs were provided as bedding.

[0198] The animals were fed Krishna Valley Agrotech rabbit chow ad libitum throughout the acclimation and experimental periods.

[0199] Water was provided ad libitum throughout the acclimation period and during the experiment. Water from an Aqua Guard water filter-cum-purifier was autoclaved and provided in polypropylene water bottles with stainless steel straws.

[0200] Adapting to the environment

[0201] The animals were acclimatized to the facility room conditions for at least 1 week (7 days) and observed daily for clinical signs. All animals were examined by a veterinarian on the day of receipt, daily, and on the day of randomization.

[0202] Grouping

[0203] Animal grouping was performed by weight stratification and randomization. The animals selected for the study were weighed and grouped into weight ranges. If possible, these weight stratified rabbits were assigned to all study groups in equal numbers so that the weight variation of the animals used did not exceed ±20% of the mean body weight. Grouping was performed one day before the start of treatment.

[0204]

[0205] Dosage Administration

[0206] After acclimatization for 7 days, adult healthy male New Zealand white rabbits, approximately 2-3 months old, were used for the experiment.

[0207] 1. Capsules

[0208] To administer the filled capsule, use a soft plastic dosing tube. Insert the filled capsule into the dosing tube so that the short end of the capsule protrudes slightly from the tip of the tube. Dip the tip of the capsule in mineral oil to aid swallowing.

[0209] Hold the head firmly with one hand around the maxilla. Insert the dosing tube containing the capsule behind the front teeth. Slide the dosing tube directly into the back of the mouth. Eject the capsule by pushing the plunger on the dosing tube. Remove the dosing tube and close the rabbit's mouth. Gently stroke the neck to facilitate swallowing.

[0210] 2. Suspension

[0211] To administer the suspension, an infant feeding tube was used. The feeding tube was inserted through the rabbit's mouth into the esophagus and stomach, and it was determined that it was not placed in the trachea prior to dosing the animal. The suspension of Compound 1 was administered via the feeding tube. After administration of the suspension, approximately 2.0-2.5 mL of drinking water was administered to flush the contents of the feeding tube.

[0212] Blood collection

[0213] Animals were restrained in rabbit restrainers and blood samples (400-500 μL / time point) were collected via the middle ear artery at 0.16, 0.25, 0.50, 1.0, 2.0, 4.0, 6.0, 8.0, 24.0, 48.0 and 72 hours after dosing. The collected blood samples were centrifuged at 4000 or 6000 rpm for 10 minutes at 4°C, and plasma samples were separated and stored at -80°C until analysis.

[0214] Biological analysis

[0215] The concentration of the analyte of Compound 1 in New Zealand White rabbits was determined using an API 3200Q-trap LC-MS / MS system.

[0216] Method Overview

[0217] Chromatographic separation was achieved on a Zorbax C18, 50 x 4.6 mm, 5 μm column with methanol-0.1% formic acid as the mobile phase and gradient elution. The flow rate was set at 1.0 mL min -1 . Detection was performed by a triple quadrupole tandem mass spectrometer in a multiple reaction monitoring (MRM) scan with an electrospray ionization source, applied in positive mode. The optimized mass transition ion pairs for quantification were m / z 379.999→125.000 for compound 1 and m / z 376.165→165.00 for ISD (haloperidol). The calibration curve was linear in the range of 11.062 to 20594.820 ng / mL.

[0218] Buffer (0.1% formic acid)

[0219] Prepare the buffer by adding approximately 1.0 mL of formic acid to 999 mL of Type 1 ultrapure water. Store the solution at room temperature and use within two days of preparation.

[0220] Dilution solvent (methanol: water, 80:20% v / v)

[0221] Add exactly 800 mL of methanol and 200 mL of Type 1 ultrapure water to the reagent bottle, mix thoroughly, and then sonicate. The solution should be stored at room temperature and used within seven days of preparation.

[0222] Washing solvent (methanol: water, 50:50% v / v)

[0223] Add exactly 500 mL of methanol and 500 mL of Type 1 ultrapure water to the reagent bottle, mix thoroughly, and then sonicate. The solution should be stored at room temperature and used within three days from the date of preparation.

[0224] Preparation of stock solution of compound 1

[0225] Weigh 3.044 mg of compound 1, transfer to a 5.0 mL volumetric flask, and dissolve in 5 mL of methanol to obtain a 605.756 μg / mL stock solution. The final concentration of compound 1 was corrected based on the potency of the standard and the actual amount weighed.

[0226] Internal standard stock solution

[0227] Weigh approximately 2.00 mg of haloperidol (Sigma-Aldrich), transfer to a 5.0 mL volumetric flask, and dissolve in methanol to obtain a 400 μg / mL internal standard stock solution. The final concentration of haloperidol was calibrated based on the potency of the standard.

[0228] Preparation of internal standard (haloperidol) working solution

[0229] About 0.250 mL of the internal standard stock solution was diluted to 10 mL using dilution solvent (methanol / water, 80:20) to obtain a solution of about 10 μg / mL.

[0230] Preparation of calibration curve of compound 1 in plasma

[0231] Calibration curve standards were prepared by spiking blank plasma with aqueous analyte standards ranging from 11.062–20594.820 ng / mL in plasma (prepared concentrations: 11.062, 20.112, 40.224, 80.449, 160.897, 321.794, 643.588, 1287.176, 2574.353, 5148.705, 10297.410, and 20594.820 ng / mL).

[0232] Quality control samples LQC, MQC and HQC were prepared within the calibration curve range for Compound 1 in plasma (prepared concentrations: 40.224, 5148.705 and 10297.410 ng / mL) by spiking blank plasma with appropriate aqueous analyte standards.

[0233] Liquid-Liquid Extraction of Plasma Samples

[0234] - Add 10 μL of ISD working solution (approximately 10 μg / mL) to the RIA vial.

[0235] • Add 50 μL of rabbit plasma from the polypropylene cap tube / vial to the RIA vial and vortex for 30-40 seconds.

[0236] • Add 2.5 mL of TBME to the RIA vial and vortex for 10 minutes at 2000 rpm using a vibramax shaker.

[0237] • Centrifuge the samples at 4000 rpm for 10 minutes at 4°C.

[0238] • Separate 2 mL of the organic layer and evaporate to dryness using a turbo evaporator at 50 °C for 20 minutes.

[0239] • Reconstitute the sample residue with 200 μL of reconstitution solvent (methanol).

[0240] • The reconstituted sample was then transferred to an autosampler vial.

[0241] · Inject 10 μL of the reconstituted sample into the API 3200Q Trap LC-MS / MS system.

[0242] Instrument conditions

[0243] LC parameters

[0244] Column: Zorbax C18, 50 x 4.6 mm, 5 μm

[0245] Mobile phase: Methanol (A): 0.1% formic acid (B)

[0246] Separation mode: Gradient mode

[0247] Flow rate: 1.0mL / min

[0248] Injection volume: 10μL

[0249] Autosampler temperature: 10°C

[0250] Column oven temperature: 40°C

[0251] LC-MS / MS API 3200QTRAP

[0252] Source Turbine ion spray

[0253] Polarity Positive

[0254] Scan TypeMRM

[0255] Analyte (Compound 1) m / z [M+1] 379.999 / 125.000

[0256] m / z[M+1] of internal standard (haloperidol) 376.165 / 165.000

[0257] Ion spray voltage (IS) 5500

[0258] Temperature (TEM) 500

[0259] Compound Name DP CE EP CXP Compound 1 66 25 4.5 16 Haloperidol 21 33 7 20.676

[0260] Data analysis

[0261] The plasma concentration data of the analyte compound 1 at each time point were used for pharmacokinetic analysis. The pharmacokinetic analysis was performed using the non-compartmental analysis (NCA) module of Phoenix WinNonlin 6.3 software to determine the following pharmacokinetic parameters:

[0262] ·C max

[0263] ·T max

[0264] AUC 0-t

[0265] AUC 0-∞

[0266] ·T1 / 2:

[0267] ·MRT

[0268] The chromatograms of the data collected using Analyst software version 1.6.1 were processed by the peak area ratio method. 1 / x2 was used as the weighting factor. The concentration of the unknown was calculated by the following formula.

[0269] y=mx+c

[0270] Where x = drug concentration;

[0271] m = slope of the calibration curve;

[0272] y = peak area ratio; and

[0273] c = intercept of the calibration curve.

[0274] result

[0275] The results of the single-dose oral pharmacokinetic study in rabbits are presented in Tables 3 to 8 below and are shown graphically in Figures 1 to 10 middle.

[0276] The results show that the systemic exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is increased by 50% to 100% when administered as the dry-milled sodium salt (Compound 2) compared to the free base active ingredient (Compound 1) - compare Examples 2 and 3, also compare Examples 5 and 6; Figures 3 to 10 The dry-milled potassium salt (Compound 3) gave a more modest improvement compared to the milled free base active ingredient - compare Examples 2 and 4, and also compare Examples 5 and 7; Figures 3 to 10 .

[0277] The systemic exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl)]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide was unexpectedly and significantly increased (up to six-fold) when the active ingredient was administered as a dry-milled sodium salt (Compound 2) in uncoated or enteric-coated capsules when compared to a standard suspension of the active ingredient (Example 8).

[0278] Thus, the systemic exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl)]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide was increased by administering the compound in alkali metal salt form. The greatest increase in systemic exposure was observed when the drug was administered in sodium salt form.

[0279] Example 2 5 8 Compound No. 1 1 1 Carrier Uncoated capsules Enteric coated capsules Suspension Dosage (mg / kg b.w.) 90 90 90 <![CDATA[C max (μg / mL)]]> 63.70±3.79 60.8±15.7 31.2±11.5 <![CDATA[T max (h)]]> 32.00±13.86 40.00±13.86 19±9 <![CDATA[AUC last (h*μg / mL)]]> 3448±405.1 2988±665.8 952±175 <![CDATA[AUC inf (h*μg / mL)]]> 7394±3873 18639±12808 1123±259.1 <![CDATA[AUC extrap (%)]]> 46.71±19.06 82.44±9.84 14±9 <![CDATA[T 1 / 2 (h)]]> 68.17±43.03 252.2±133.0 36±8 <![CDATA[MRT last (h)]]> 36.86±2.56 45.17±2.54 25±5

[0280] Table 3. Mean plasma pharmacokinetic parameters of compound 1 (4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide)

[0281]

[0282] Table 4. Plasma concentrations of compound 1 (4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide)

[0283] Example 3 6 Compound No. 2 2 Carrier Uncoated capsules Enteric coated capsules Dosage (mg / kg b.w.) 90 90 <![CDATA[C max (μg / mL)]]> 98.97±34.56 101.4±17.04 <![CDATA[T max (h)]]> 32.00±13.86 32.00±13.86 <![CDATA[AUC last (h*μg / mL)]]> 5985±2274 5708±1142 <![CDATA[AUC inf (h*μg / mL)]]> 38101±34673 55694±22737 <![CDATA[AUC extrap (%)]]> 79.01±8.87 88.81±3.497 <![CDATA[T 1 / 2 (h)]]> 226.7±139.9 367.6±109.2 <![CDATA[MRT last (h)]]> 38.79±1.20 42.99±1.59

[0284] Table 5. Mean plasma pharmacokinetic parameters of dry-milled Compound 2 (4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide sodium salt)

[0285]

[0286] Table 6. Plasma concentrations of dry-milled Compound 2 (4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide sodium salt)

[0287] Example 4 7 Compound No. 3 3 Carrier Uncoated capsules Enteric coated capsules Dosage (mg / kg b.w.) 90 90 <![CDATA[C max (μg / mL)]]> 81.90±10.4 79.47±5.43 <![CDATA[T max (h)]]> 40.00±13.86 48.00±0.00 <![CDATA[AUC last (h*μg / mL)]]> 4526±589.4 3993±43.27 <![CDATA[AUC inf (h*μg / mL)]]> 9370±3377 18614±13840 <![CDATA[AUC extrap (%)]]> 52.23±10.63 69.48±19.80 <![CDATA[T 1 / 2 (h)]]> 71.56±22.63 188.57±158.39 <![CDATA[MRT last (h)]]> 39.563±3.879 41.971±0.696

[0288] Table 7. Mean plasma pharmacokinetic parameters of dry-milled compound 3 (4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide potassium salt)

[0289]

[0290] Table 8. Plasma concentrations of dry-milled compound 3 (4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide potassium salt)

[0291] Examples 9 and 10

[0292] The following studies (referred to as Examples 9 and 10) provide comparative single-dose oral pharmacokinetic data for Compound 2 (sodium salt of Compound 1) in male New Zealand white rabbits using enteric-coated capsules in the presence of a pH adjuster (magnesium oxide). The studies were conducted using the methods described above for Examples 2 to 8, with the exceptions noted below.

[0293] Enteric coated gelatin capsules are filled with the following substances:

[0294] Example 9: Compound 2 (62.5 mg), docusate sodium (6.25 mg), PVP K30 (0.625 mg) and magnesium oxide (125 mg).

[0295] Example 10: Compound 2 (62.5 mg), docusate sodium (6.25 mg), PVP K30 (0.625 mg) and mannitol (125 mg).

[0296] Animals received Compound 2 at 25 mg / kg bw as a single dose.

[0297] result

[0298] The results of the single-dose oral pharmacokinetic study in rabbits are listed in Table 9 below.

[0299] The results showed that when Compound 2 was formulated with a basic excipient, the systemic exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide was increased compared to the formulation without a basic excipient.

[0300] Example 9 10 Compound No. 2 2 Carrier Enteric coated capsules with MgO Enteric coated capsules with mannitol Dosage (mg / kg b.w.) 25 25 <![CDATA[C max (μg / mL)]]> 49.60±4.80 47.43±7.06 <![CDATA[T max (h)]]> 24.00±0.00 32.00±13.86 <![CDATA[AUC last (h*μg / mL)]]> 1703.93±247.60 1472.50±78.72 <![CDATA[MRT last (h)]]> 27.67±0.11 29.98±1.73

[0301] Table 9. Mean plasma pharmacokinetic parameters of Compound 2 co-formulated with basic excipients

[0302] Embodiment 11

[0303] The following study is a single dose oral pharmacokinetic study of Compound 2 in male New Zealand white rabbits using enteric coated capsules in the presence of a pH adjuster (magnesium oxide). The study was conducted using the methods described above for Examples 2 to 8, with the differences noted below.

[0304] Enteric coated gelatin capsules were filled with Compound 2 (106 mg, as obtained in Example 1f), docusate sodium (10.6 mg), PVP K30 (1.1 mg) and magnesium oxide (100 mg), respectively.

[0305] Animals received 53 mg / kg bw of Compound 2 (equivalent to 50 mg / kg of Compound 1) as a single dose.

[0306] result

[0307] The results of the single-dose oral pharmacokinetic study in rabbits are listed in Table 10 below.

[0308] The results indicate that when Compound 2 is formulated with a basic excipient, there is a significant amount of systemic exposure of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0309]

[0310] Table 10. Mean plasma pharmacokinetic parameters of Compound 2 co-formulated with basic excipients

[0311] Example 12

[0312] Representative pharmaceutical tablet dosage forms containing Compound 2 for human therapeutic or prophylactic use are exemplified below:

[0313] Element Amount (mg) quantity(%) Compound 2 106.06 30.30 Microcrystalline Cellulose 66.15 18.9 Lactose monohydrate 132.29 37.8 Sodium starch glycolate 26.25 7.5 Colloidal Silica 8.75 2.5 Magnesium Stearate 10.50 3 total 350 100

[0314] Element Amount (mg) quantity(%) Compound 2 106.06 30.30 Microcrystalline Cellulose 63.81 18.23 Lactose monohydrate 127.63 36.47 Sodium starch glycolate 26.25 7.5 Colloidal Silica 8.75 2.5 Sodium stearyl fumarate 17.50 5 total 350 100

[0315] These preparations can be obtained by conventional methods well known in the pharmaceutical art.Tablets may also be enteric-coated in a conventional manner, for example to provide a polymethacrylate coating.

Claims

1. An oral unit dosage formulation comprising from about 10 mg 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. The formulation of claim 1, comprising about 10 mg to about 500 mg of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

3. The formulation of claim 1, comprising about 200 mg 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.

4. The formulation of claim 1, comprising about 200 mg to about 500 mg of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

5. The formulation of claim 1, comprising about 500 mg 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.

6. The preparation according to any one of claims 1 to 5, wherein the preparation is a tablet or a capsule.

7. Use of a formulation according to any one of claims 1 to 6 in the manufacture of a medicament for treating a disorder or condition improved by activation of AMPK.

8. The use according to claim 7, wherein the disorder or condition improved by activating AMPK is diabetes.

9. The use according to claim 7, wherein the disorder or condition improved by activating AMPK is type 2 diabetes.

10. The use according to claim 7, wherein the disorder or condition improved by activating AMPK is obesity.

11. The use according to claim 7, wherein the disorder or condition improved by activating AMPK is cardiovascular disease.

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