WO2013108026A1

WO2013108026A1 - Thiadiazolone derivatives useful in the treatment of diabetes

Info

Publication number: WO2013108026A1
Application number: PCT/GB2013/050093
Authority: WO
Inventors: Jacob Westman; Björn Eriksson
Original assignee: Baltic Bio Ab
Priority date: 2012-01-17
Filing date: 2013-01-17
Publication date: 2013-07-25

Abstract

According to the invention there is provided a compound of formula I, wherein, R¹ to R⁴ have meanings given in the description, which compounds are useful in the treatment of diabetes.

Description

THIADIAZOLONE DERIVATIVES USEFUL IN THE TREATMENT OF DIABETES

Field of the Invention This invention relates to pharmaceutically-useful compounds. The invention also relates to the use of such compounds in the treatment of conditions ameliorated by the activation of AMPK, such as diabetes (especially type II diabetes).

Background AMP-activated protein kinase (AMPK) represents a new target for the treatment of several diseases, including metabolic syndrome. Hyperinsulinemia (hypersecretion of insulin) also represents a new target for the treatment of metabolic syndrome.

Metabolic syndrome has become increasingly common, and affects an estimated 47 million adults in the US alone. The syndrome is characterized by a combination of metabolic risk factors such as central obesity, atherogenic dyslipidemia, hypertension, insulin resistance or glucose intolerance. The syndrome is also characterised by hyperinsulinemia, a prothrombotic state in the blood, and a proinflammatory state. Underlying causes of metabolic syndrome include obesity, physical inactivity and genetic factors. Sufferers are at an increased risk of coronary heart disease and other diseases related to the build up of plaques in artery walls, for example stroke, peripheral vascular disease and type 2 diabetes. Diabetes is the most common metabolic disease with a high incidence in western countries, with more than 170 million people currently affected by type 2 diabetes. Type 2 diabetes is a chronic, presently incurable disease and sufferers have a high risk of developing life threatening complications as the disease progresses. The overall cost to society of diabetes and its complications is huge.

Thus, to a large extent, obesity, metabolic syndrome and diabetes are interrelated and there is a substantial need for better pharmacological treatment of patients with one or more of these conditions. When the above is coupled with the epidemic increase in obesity in western society, there is an urgent unmet clinical need to develop novel and innovative strategies leading to new drugs with a superior effect and/or less side effects. Insulin is both a potent hormone and growth factor. In addition to obesity, hyperinsulinemia is apparent in conditions such as impaired glucose tolerance, early or mild type 2 diabetes, polycystic ovary syndrome and Alzheimer's disease. Evidence is accumulating that hyperinsulinemia plays a major role in the development of these diseases.

A medicament that reduces insulin resistance and/or hyperinsulinemia may therefore represent an efficient therapeutic strategy to treat or prevent disorders caused by, linked to, or contributed to by insulin resistance and/or hyperinsulinemia or associated conditions.

No existing therapies for the different forms of diabetes appear to reduce hyperinsulinemia:

(a) insulin secretagogues, such as sulphonylureas stimulate only the insulin secretion step;

(b) metformin mainly acts on glucose production from the liver;

(c) peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, such as the thiazolidinediones, enhance insulin action; and

(d) a-glucosidase inhibitors interfere with gut glucose production.

All of these therapies fail to arrest progression of the disease and, over time, also fail to normalize glucose levels and/or to stop subsequent complications.

More recent therapies for the treatment of type 2 diabetes have limitations and/or side effects. For example, exenatide needs to be administered by subcutaneous injection, has storage stability shortcomings, is reported to cause nausea and vomiting and, more recently, has been shown to be coupled to several severe cases of acute pancreatitis.

Furthermore, other existing therapies for the treatment of type 2 diabetes are known to give rise to undesirable side effects. For example, insulin secretagogues and insulin injections may cause hypoglycaemia and weight gain and patients may also become unresponsive to insulin secretagogues over time. Metformin (an indirect AMPK activator) and a-glucosidase inhibitors often lead to gastrointestinal problems and PPAR-agonists tend to cause increased weight gain and oedema. Dipeptidyl peptidase-IV (DPP-IV) inhibitors belong to a new class of oral antidiabetic agents for the treatment of patients with type 2 diabetes. Inhibition of the enzyme DPP-IV results in prolonged activity of glucagon-like peptide-1 (GLP-1) and glucose- dependent insulinotropic peptide (GIP), the incretin hormones. Sitagliptin was the first DPP-IV inhibitor to be approved by FDA for treatment of type 2 diabetes and several other DPP-IV inhibitors are in late clinical phases. Several side-effects for DPP-IV inhibitors as a class may be expected, such as inflammation, allergic reactions and hypertension since many peptides, neuropeptides, and cytokines are cleaved by DPP-IV. Some of the reported side effects of certain DPP-IV inhibitors include anemia, thrombocytopenia, and splenomegaly.

Therefore, there is a substantial need for better pharmacological treatment of patients with type 2 diabetes. Recently, even more diseases have been found to be interrelated to common targets for type 2 diabetes.

AMP-activated protein kinase (AMPK) is a protein kinase enzyme that consists of three protein sub-units and is activated by hormones, cytokines, exercise, and stresses that diminish cellular energy state (e.g. glucose deprivation). Activation of AMPK increases processes that generate adenosine 5'-triphosphate (ATP) (e.g., fatty-acid oxidation) and restrains others such as fatty acid-, glycerolipid- and protein-synthesis that consume ATP, but are not acutely necessary for survival. Conversely, when cells are presented with a sustained excess of glucose, AMPK activity diminishes and fatty acid-, glycerolipid- and protein-synthesis are enhanced. AMPK thus is a protein kinase enzyme that plays an important role in cellular energy homeostasis. Therefore, the activation of AMPK is coupled to glucose lowering effects and triggers several other biological effects, including the inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, and the reduction of hyperinsulinemia.

Given the above, AMPK is a preferred target for the treatment of the metabolic syndrome and especially type 2 diabetes. AMPK is also involved in a number of pathways that are important for many different diseases (e.g. AMPK is also involved in a number of pathways that are important in CNS disorders, fibrosis, osteoporosis, heart failure and sexual dysfunction). Current anti-diabetic drugs (e.g. metformin, glitazones) are known to not be significantly potent AMPK activators, but only activate AMPK indirectly and with low efficacy. However, due to the biological effects of AMPK activation at the cell level, compounds that are AMPK activators, and preferably direct activators of AMPK, may find utility as anti-cancer drugs, as well as for the treatment of many other diseases. 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 state of the art or is common general knowledge.

Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains. Keilen et a/., Acta Chem. Scand. 1988, B42, 362-366 describe the formation of 1 ,2,4-thiadiazolo activated pyrimidinones. There is also disclosed a specific 1 ,2,4-thiadiazolo-3-ones. However, the document does not disclose any biological effects associated with the disclosed compounds, nor does it disclose 1 ,2,4-thiadiazolo- 3-ones substituted at the 5-position with an amide or amine derivative bearing at least one substituted aromatic ring.

Kaugars er a/., J. Org. Chem. 1979, 44(22), 3840-3843 describe 5-phenyl- and 5-methyl-substituted phenyl urea derivatives of 1 ,2,4, thiadiazol-3-one that are substituted in the 2-position with a methyl group. There is no mention of any biological effects associated with the disclosed compounds.

Cho et al J. Heterocyclic Chem. 1991 , 28, 1645-1649 discloses various 1 ,2,4-thiadiazol-3-ones. However, there is no disclosure of such 1 ,2,4-thiadiazol-3-ones, in which the 2-position and 5-position contain substituents bearing an aromatic ring.

US patent 4,093,624 describes 1 ,2,4 thiadiazolidin-3-one compounds, described as having antimicrobial activity, which are substituted by a -NH₂ or -NHAc in the 5-position and H or ribofuranosyls in the 2-position. There is no disclosure of 1 ,2,4-thiadiazol-3-ones in which the 2-position and 5-position contain substituents bearing an aromatic ring. Castro et al., Bioorg. Med. Chem. 2008, 16, 495-510 describes thiadiazolidinone derivates as GSK-3 inhibitors that are potentially useful for the treatment of Alzheimer's disease. There is no mention that such compounds may be useful as AMPK activators. Further, there is no mention of 1 ,2,4-thiadiazol-3-ones substituted at the 5-position with an amide or amine derivative bearing at least one substituted aromatic ring.

Martinez et al. Bioorg. Med. Chem. 1997, 7, 1275-1283 describes arylimino-1 ,2,4- thiadiazolidinone derivatives as potassium channel openers that are potentially useful for the treatment of diseases involving smooth muscle contraction (e.g. hypertension). However, there is no disclosure of such thiadiazolidinones substituted at the 2-position with an aromatic group.

US patent application publication number 2003/0195238 describes thiadiazolidine derivates as GSK-3 inhibitors that are potentially useful for the treatment of Alzheimer's disease. However, this document mainly relates to thiadiazoiidines substituted by two carbonyl/thiocarbonyl groups (thereby forming e.g. a 3,5-dioxo-thiadiazolidine or a 3-thioxo-5-oxo-thiadiazolidine). Further, it mainly relates to compounds in which both nitrogen atoms of the thiadiazolidine are substituted. The document does not relate to thiadiazoiidines substituted at the 2-position with a group bearing an aromatic group and at the 5-position with an amino or amido derivative bearing an aromatic group.

International patent applications WO 2007/010273 and WO 2007/010281 both disclose e.g. thiazolidin-4-one and 1 ,1-dioxo-1 ,5-dihydro-[1 ,4,2]dithiazole compounds that are able to antagonize the stimulatory effect of FFAs on cell proliferation when tested in an assay using a human breast cancer cell line (MDA-MB-231). Such compounds are thus indicated in the treatment of cancer and/or as modulators of FFAs. However, these documents do not disclose or suggest thiadiazolidinones.

International patent application no. WO 2011/004162 discloses 1 ,2,4-thiadiazolidine-3-one and 1 ,2,4-thiadiazol-3-one compounds that are able to stimulate the phosphorylation of AMPK and increase production of phosphorylated acetyl co-enzyme A (a substrate of AMPK), and that are therefore potentially useful for the treatment of cancer. Disclosure of the Invention

According to embodiments of the invention, there is provided a compound of formula I,

wherein:

(a) R¹ represents a -CF₃ group;

R² represents H;

R³ represents a substituent selected from the group consisting of chloro, fluoro, and -CF₃; and

R⁴ represents a substituent selected from the group consisting of hydrogen and chloro; or

(b) each of R¹ to R³ represents a substituent independently selected from the group consisting of chloro and fluoro; and

R⁴ represents hydrogen, chloro or fluoro;

provided that when R and R² both represent fluoro and R³ represents chloro, R⁴ is not hydrogen; or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.

Pharmaceutically-acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. Examples of pharmaceutically acceptable addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulphonic acids; and from metals such as sodium, magnesium, or preferably, potassium and calcium.

"Pharmaceutically functional derivatives" of compounds of formula I as defined herein includes ester derivatives and/or derivatives that have, or provide for, the same biological function and/or activity as any relevant compound. Thus, for the purposes of this invention, the term also includes prodrugs of compounds of formula I.

The term "prodrug" of a relevant compound of formula I includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration.

Prodrugs of compounds of formula I may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds of formula I wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs" p. I-92, Elsevier, New York-Oxford (1985).

Compounds of formula I, as well as pharmaceutically-acceptable salts, solvates and pharmaceutically functional derivatives of such compounds are, for the sake of brevity, hereinafter referred to together as the "compounds of formula I". Compounds of formula I may exist as regioisomers and may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. For example, the following tautomers are included within the scope of the invention:

Compounds of formula I may contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.

The term "halogen", when used herein, includes fluorine, chlorine, bromine and iodine. For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of formula I may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which R¹, R², R³ and R⁴ independently represent one of a selection of substituents then those substituents may be the same or different.

For the avoidance of doubt, when a term such as "R¹ to R⁴" is employed herein, this will be understood by the skilled person to mean any of (i.e. some or all, as applicable) R¹, R², R³ and R⁴ inclusively. Ail individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).

In a first embodiment of the invention, there is provided a compound of formula I, wherein:

(a) R¹ represents a -CF₃ group;

R² represents H;

(b) each of R to R³ represents a substituent independently selected from the group consisting of chloro and fluoro; and

R⁴ represents hydrogen, chloro or fluoro;

provided that when R¹ and R² both represent fluoro, R⁴ is not hydrogen.

In a second embodiment of the invention, there is provided a compound of formula I, wherein:

(a) R represents a -CF₃ group;

R² represents H;

(b) each of R to R⁴ represents a substituent independently selected from the group consisting of chloro and fluoro. In a further embodiment of the invention, there is provided a compound of formula I wherein:

when R¹ to R³ are independently selected from the group consisting of chloro and fluoro, then either, or preferably both, of R² and R⁴ are fluoro. In a further embodiment of the invention, there is provided a compound of formula I wherein: when R¹ to R⁴ are independently selected from the group consisting of chloro and fluoro, then either, or preferably both, of R² and R⁴ are fluoro.

More preferred compounds of formula I include those of the examples described hereinafter.

Preferred compounds of formula I include:

3,4-dichloro-N-[2-(4-trifluoromethyl-benzyl)-3-oxo-2,3-dihydro-[1,2,4]thiadiazol-5-yl]- benzamide;

4-trifluoromethyl-N-[2-(4-trifluoromethyl-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]- benzamide;

4-chloro-N-[2-(4-chloro-3-fluoro-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]-3-fluoro- benzamide;

N-[2-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]-3,4-difluoro- benzamide;

4-chloro-N-[2-(4-trifluoromethyl-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]- benzamide;

4-fluoro-N-[2-(4-trifluoromethyl-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]- benzamide; and

4-chloro-N-[2-[(3,4-dichlorophenyl)methyl]-3-oxo-1 ,2,4-thiadiazol-5-yl]benzamide.

Compound names were derived using the commercially available software package Autonom (brand of nomenclature software provided as an add-on for use in the Symyx Draw 2.1 (TM) office suite marketed by MDL Information Systems).

Throughout this specification, structures may or may not be presented with chemical names. Where any question arises as to nomenclature, the structure prevails. Where it is possible for a compound to exist as a tautomer the depicted structure represents one of the possible tautomeric forms, wherein the actual tautomeric form(s) observed may vary depending on environmental factors such as solvent, temperature or pH.

Compounds of formula I may be prepared in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter. According to a further embodiment of the invention there is provided a process for the preparation of a compound of formula I, which process comprises cyclisation of a compound of formula II,

wherein R to R⁴ are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable bromine source (e.g. N-bromo succinimide or bromine) and a suitable solvent (e.g. methanol, ethanol, ethyl acetate) and at a suitable temperature (e.g. -10^°C to 80^°C) as described in Castro et al. (Bioorganic. Med. Chem. 2008, 16, 495-510) or Kaugars et al. (J. Org. Chem. 1979, 44(22), 3840-3843), or in the presence of a suitable base (e.g. sodium hydroxide) in a suitable solvent (e.g. water containing hydrogen peroxide (e.g. a 30% H₂0₂ solution in water)) and at a suitable temperature (e.g. -10^°C to 100^°C) as described in Castro et al. {ibid), Cho et al. (J. Heterocyclic Chem. 1991 , 28, 1645-1649) and Encinas et al. (Eur. J. Org. Chem. 2007, 5603-5608).

Compounds of formulae II are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein (or processes described in references contained herein), or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. They may also be obtained by analogy with the processes described in international patent application no. WO 2011/004162. Compounds of formula I may be isolated from their reaction mixtures using conventional techniques.

It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.

The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes. Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.

The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in ''Protective Groups in Organic Chemistry, edited by J W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3^rd edition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999).

As used herein, the term "functional groups" means, in the case of unprotected functional groups, hydroxy-, thiolo-, aminof unction, carboxylic acid and, in the case of protected functional groups, lower alkoxy, N-, 0-, S- acetyl, carboxylic acid ester.

Medical and Pharmaceutical Uses Compounds of formula I are indicated as pharmaceuticals. According to a further embodiment of the invention there is provided a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for use as a pharmaceutical. Advantageously, compounds of formula I may be AMPK agonists, i.e. they may activate AMPK. By 'activate AMPK', we mean that the steady state level of phosphorylation of the Thr-172 moiety of the AMPK- subunit is increased compared to the steady state level of phosphorylation in the absence of the agonist. Alternatively, or in addition, we mean that there is a higher steady state level of phosphorylation of any other proteins downstream of AMPK, such as acetyl-CoA carboxylase (ACC).

As the compounds of formula I may be AMPK activators, they may therefore be useful in the treatment of diseases such as those described herein, especially diabetes (e.g. type II diabetes). Compounds of formula I are therefore indicated for use in the treatment of a disorder or condition ameliorated by the activation of AMPK.

The terms "disorder or condition ameliorated by the activation of AMPK" will be understood by those skilled in the art to include lung disease, obesity, dry-type age-related macular degeneration, cardioprotection or, preferably, diabetes, hyperinsulinemia and associated conditions, cancer, a condition/disorder where fibrosis plays a role, sexual dysfunction, osteoporosis, inflammation, heart failure and neurodegenerative diseases.

Compounds of formula I may also be indicated for use in the treatment of a disorder or a condition caused by, linked to, or contributed to by, hyperinsulinemia.

According to a further embodiment of the invention, there is provided the use of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof for the manufacture of a medicament for the treatment of a disorder or condition ameliorated by the activation of AMPK. The terms "disorder or condition caused by, linked to, or contributed to by, hyperinsulinemia" or "treatment of hyperinsulinemia or an associated condition" will be understood by those skilled in the art to include hyperinsulinemia and associated conditions, such as cardiovascular disease or, preferably, type 2 diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, hyperinsulinism in childhood, hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, 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.

Preferred disorders include hyperinsulinemia and, particularly, type 2 diabetes.

Certain compounds of formula I may also have the additional advantage that they exhibit partial agonist activity and may therefore be useful in conditions, such as late type 2 diabetes, in which stimulation of the production of insulin is required. By "agonist activity", we include direct and indirect-acting agonists.

According to a further aspect of the invention there is provided a method of treatment of a disorder or condition ameliorated by the activation of AMPK, which method comprises the administration of an effective amount of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, to a patient in need of such treatment. Compounds of formula I may also be of use in the treatment of a disorder or condition ameliorated by the activation of AMPK.

According to a further embodiment of the invention, there is provided the use of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for the manufacture of a medicament for the treatment of a disorder or condition ameliorated by the activation of AMPK.

The terms "disorder or condition ameliorated by the activation of AMPK" will be understood by those skilled in the art to include, in addition to diabetes, hyperinsulinemia and associated conditions, a condition/disorder where fibrosis plays a role, sexual dysfunction, osteoporosis, neurodegenerative diseases and cancer.

Compounds of formula I may thus also be indicated for use in the treatment of a disorder or a condition caused by, linked to, or contributed to by, hyperinsulinemia.

The terms "disorder or condition caused by, linked to, or contributed to by, hyperinsulinemia" or "treatment of hyperinsulinemia or an associated condition" will be understood by those skilled in the art to include hyperinsulinemia and associated conditions, such as type 2 diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, hyperinsulinism in childhood, hypercholesterolemia, high blood pressure, 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. Preferred disorders include hyperinsulinemia and, particularly, type 2 diabetes. Certain compounds of formula I may also have the additional advantage that they exhibit partial agonist activity and may therefore be useful in conditions, such as late type 2 diabetes, in which stimulation of the production of insulin is required. By "agonist activity", we include direct and indirect-acting agonists.

According to a further embodiment of the invention there is provided a method of treatment of a disorder or condition ameliorated by the activation of AMPK, which method comprises the administration of an effective amount of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, to a patient in need of such treatment. An effective amount can be determined by a physician and will be determined for a specific patient by assessment of the patient's clinical parameters including, but not limited to the stage of disease, age, gender and histology.

Preferebaly, compounds of formula I can be used in the treatment of diabetes, a disorder or condition where fibrosis plays a role, and hyperinsulinemia and associated conditions.

For the avoidance of doubt, in the context of the present invention, the terms "treatment", "therapy" and "therapy method" include the therapeutic, or palliative, treatment of patients in need of, as well as the prophylactic treatment and/or diagnosis of patients which are susceptible to, the relevant disease states.

"Patients" include mammalian (including human) patients.

The term "effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated patient (e.g. sufficient to treat or prevent the disease). The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).

In accordance with the invention, compounds of formula I may be administered alone, but are preferably administered orally, intravenously, intramuscularly, cutaneously, subcutaneously, transmucosally (e.g. sublingually or buccally), rectally, transdermally, nasally, pulmonarily (e.g. tracheally or bronchially), topically, by any other parenteral route, in the form of a pharmaceutical preparation comprising the compound in a pharmaceutically acceptable dosage form. Preferred modes of delivery include oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal delivery.

Compounds of formula I will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations may be found in, for example, Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). For parenteral administration, a parenterally acceptable aqueous solution may be employed, which is pyrogen free and has requisite pH, isotonicity, and stability. Suitable solutions will be well known to the skilled person, with numerous methods being described in the literature. A brief review of methods of drug delivery may also be found in e.g. Langer, Science, 249, 1527 (1990).

Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques and/or in accordance with standard and/or accepted pharmaceutical practice.

Another aspect of the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in combination with a pharmaceutically acceptable excipient, such as an adjuvant, diluent or carrier.

The amount of compound of formula I in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.

Depending on the disorder, and the patient, to be treated, as well as the route of administration, compounds of formula I may be administered at varying therapeutically effective doses to a patient in need thereof. However, the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe. One 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 inter alia the pharmacological properties of the formulation, 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, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.

Administration may be continuous or intermittent (e.g. by bolus injection). The dosage may also be determined by the timing and frequency of administration. In the case of oral or parenteral administration the dosage can vary from about 0.01 mg to about 1000 mg per day of a compound of formula I (or, if employed, a corresponding amount of a pharmaceutically acceptable salt or prodrug thereof). In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

The compounds of formula I may be used or administered in combination with one or more additional drugs useful in the treatment of a disorder or condition ameliorated by the activation of AMPK, in combination therapy. According to a further embodiment of the invention, there is provided a combination product comprising:

(A) a compound of formula I; and

(B) another therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK,

wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

Other therapeutic agents useful in the treatment of a disorder or condition ameliorated by the activation of AMPK will be well known to those skilled in the art and include biguanides, glitazones (i.e. thiazolidinediones), oligomycins, AICAR (aminoimidazole carboxamide ribonucleotide), insulin, insulin secretagogues (such as sulphonylureas), peroxisome proliferator-activated receptor (PPAR) agonists (which also include thiazolidinediones), a-glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, exenatide, inhibitors of 1 -β hydroxysteroid dehydrogenase type 1, inhibitors of stearoyl-CoA desaturase 1 (SCD-1), A-769662, D942 (5-(3-(4-(2-(4-Fluorophenyl)ethoxy)-phenyl)propyl)furan-2-carboxylic acid), cilostazol, AM251 (a CB₁ receptor antagonist), SIRT1 activators (e.g. resveratrol) and salidroside. By "agonist" we include direct and indirect-acting agonists. By "agonist" we include direct and indirect-acting agonists. In one embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a biguanide. For example, the agent may be selected from the group consisting of phenformin, buformin, and, most preferably, metformin. In an alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise glitazones. For example, the agent may be selected from the group consisting of troglitazone, pioglitazone and rosiglitazone. In an alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise an oligomycin. For example, the agent may be selected from the group consisting of oligomycin A, oligomycin B, oligomycin C, oligomycin D (rutamycin A), oligomycin E, oligomycin F, rutamycin B, 44-homooligomycin A and 44-homooligomycin B.

In an alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise AICAR.

In one embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise GLP-1 or a biologically active fragment, variant, fusion of derivative thereof. For example, the agent may be selected from the group consisting of Exendin-4 (exenatide; Byetta), exenatide long acting release (LAR), exenatide derivatives (such as ZP10 developed by Zealand Pharmaceuticals), native GLP-1 , human GLP-1 derivatives (such as BIM51077 (Ipsen and Roche)), DPP-IV resistant GLP-1 analogues (for example LY315902 and LY30761 SR (Lilly)), long acting GLP-1 derivatives (such as NN2211 (Liraglutide; Novo Nordisk)) and complex proteins (such as the GLP-1 -albumin complex CJC-1131).

In an alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a dipeptidyl peptidase IV (DPP-IV) inhibitor. For example, the agent may be selected from the group consisting of Vildagliptin (LAF237), MK-0431-Sitagliptin and Saxagliptin.

In a further alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise gastric inhibitory polypeptide (GIP), or a biologically active fragment, variant, fusion of derivative thereof. GIP, also known as glucose-dependent insulinotropic polypeptide, is a 42-amino acid peptide hormone synthesised in and secreted from K cells in the intestinal epithelium. An important determinant of GIP action is the N-terminal cleavage of the peptide to the inactive GIP (3-42). The enzyme DPP-4, which also cleaves GLP-1 and GLP-2, rapidly inactivates GIP both in vitro and in vivo. Hence, it may be desirable to administer GIP in combination with a DPP-4 inhibitor.

In a further alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a selective inhibitor of 11-β hydroxysteroid dehydrogenase type 1 (Ι ΐ β-HSDI), an enzyme associated with conversion of cortisone to Cortisol in the liver and adipose tissue. Examples of suitable Ι ΐ β-HSDI inhibitors/antagonists include AMG221 (developed by Amgen) and BVT83370 (developed by Biovitrum).

In one embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise an inhibitor of stearoyl-CoA desaturase 1 (SCD-1 ). Examples of suitable SCD-1 inhibitors include those described in US 2005/0019251 (e.g. 6-[4-(2-bromo-4-methoxy-benzoyl)-piperazin- 1-yl]-N-(3-phenyl-propyl)-nicotinamide), those described in WO 2006/130986 (e.g. 2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-thiazole-5-carboxylic acid amide), those described in WO 2008/029266 and WO 2008/062276 (e.g. GRC 9332), those described in Freeman, J. et al. (2007) Discovery of phenoxypiperidines as novel Stearoyl-CoA desaturase inhibitors: From Assay Validation to Lead Development, 233rd ACS National Meeting, 25-29 March 2007, Chicago, IL, USA (MEDI-383) (e.g. 4-(2-chloro-5-fluoro- phenoxy)-1-(5-methyl-[1 ,3,4]oxadiazol-2-yl)-piperidine), those described in Xin ef al. Bioorg. Med. Chem. Lett. (2008), 18(15), 4298-4302 (e.g. 4-(2-chlorophenoxy)-/V-[3- (methylcarbamoyl)phenyl]piperidine-1-carboxamide) and those described in Liu et al. J. Med. Chem. (2007), 50(13), 3086-3100. Without wishing to be bound by theory, it is proposed that inhibition of SCD-1 results in the activation of AMPK (Dobrzyn et al. Proceedings of the National Academy of Sciences (2004), 101(17), 6409-6414.

In yet a further alternative embodiment, the other therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK may comprise a SIRT1 (also known as sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)) activator. Examples of suitable SIRT1 activators include resveratrol and SRT- 720 (N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1 ,3]thiazol-6-yl]phenyl]quinoxal- ine-2-carboxamide).

Combination products as described herein provide for the administration of compound of formula I in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises compound of formula I, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including compound of formula I and the other therapeutic agent).

Thus, there is further provided:

(1) pharmaceutical formulations including a compound of formula I; another therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK; and a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(2) kits of parts comprising components:

(a) a pharmaceutical formulation including a compound of formula I, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including another therapeutic agent useful in the treatment of a disorder or condition ameliorated by the activation of AMPK, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other. Components (a) and (b) of the kits of parts described herein may be administered simultaneously or sequentially.

According to a further embodiment of the invention, there is provided a method of making a kit of parts as defined above, which method comprises bringing component (a), as defined above, into association with a component (b), as defined above, thus rendering the two components suitable for administration in conjunction with each other.

By bringing the two components "into association with" each other, we include that components (a) and (b) of the kit of parts may be:

(i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or

(ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.

Thus, there is further provided a kit of parts comprising:

(I) one of components (a) and (b) as defined herein; together with

(II) instructions to use that component in conjunction with the other of the two components.

The kits of parts described herein may comprise more than one formulation including an appropriate quantity/dose of compound of formula I, and/or more than one formulation including an appropriate quantity/dose of the other therapeutic agent, in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of either compound, chemical composition(s) and/or physical form(s).

With respect to the kits of parts as described herein, by "administration in conjunction with", we include that respective formulations comprising compound of formula I and the other therapeutic agent are administered, sequentially, separately and/or simultaneously, over the course of treatment of the relevant condition.

Thus, in respect of the combination product according to embodiments of the invention, the term "administration in conjunction with" includes that the two components of the combination product (compound of formula I and the other therapeutic agent) are administered (optionally repeatedly), either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either a formulation comprising compound of formula I, or a formulation comprising the other therapeutic agent, are administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition will depend upon the condition to be treated or prevented, but may be achieved routinely by the skilled person.

Further, in the context of a kit of parts according to embodiments of the invention, the term "in conjunction with" includes that one or other of the two formulations may be administered (optionally repeatedly) prior to, after, and/or at the same time as, administration with the other component. When used in this context, the terms "administered simultaneously" and "administered at the same time as" include that individual doses of compound of formula I and the other therapeutic agent are administered within 48 hours (e.g. 24 hours) of each other.

The compounds/combinations/methods/uses described herein may have the advantage that, in the treatment of the conditions described herein, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have better selectivity, have a broader range of activity than, be more potent than, produce fewer side effects than, or may have other useful pharmacological properties over, similar compounds, combinations, methods (treatments) or uses known in the prior art for use in the treatment of those conditions or otherwise, for example over the compounds disclosed in international patent applications WO 2007/010273, WO 2007/010281 and/or WO 2011/004162.

Advantageously, the compounds of the invention are proven to be efficacious in the treatment of diabetes (e.g. type 2-diabetes), for instance as evidenced by the biological test discussed hereinafter. For instance, any one of the compounds of the invention (e.g. as exemplified herein) may have the advantage that they each have a greater ability to confer insulin independent glucose uptake, as compared to other known compounds of the prior art (e.g. other known diabetes compounds). Further, such advantages may stem from the compounds of formula I being AMPK activators (e.g. especially where it is stated that the compounds described herein may have better selectivity, and may produce fewer side effects, e.g. gastrointestinal side effects).

Preferred, non-limiting examples which embody certain aspects of the invention will now be described, with reference to the following figures:

Figure 1, which shows the effect of the compounds of Examples 1 and 2a to 2d on glucose uptake in muscle cells. Glucose uptake in L6 derived myotube cultures is shown as a percentage of the vehicle control. The compounds tested all display the ability to confer insulin independent glucose uptake.

Figure 2, which shows the effect of the compound of Example 2f on glucose uptake in muscle cells. Glucose uptake in L6 derived myotube cultures is shown as a percentage of vehicle control. The compound tested displays the ability to confer insulin independent glucose uptake.

Examples

The invention is illustrated by the following examples, in which the following abbreviations may be employed: nBuLi N-butyl lithium

DCM dichloromethane

DMF dimethylformamide

DMSO dimethylsulfoxide

ES electro spray

Et₂0 diethyl ether

EtOAc ethyl acetate

EtOH ethanol

LC liquid chromatography

MeOH methanol

MS mass spectrometry

MTBE methyl tert-butyl ether

NMR nuclear magnetic resonance THF tetrahydrofuran

Where no preparative routes are included, the relevant intermediate is commercially available (e.g. from Chemical Diversity, San Diego, CA, USA or other available commercial sources).

General Procedures

LC-MS was performed on a Sciex API 150 LC/ES-MS equipped with an ACE 3 C8 column (30 x 3.0 mm) using a flow of 1 mUmin. Two gradient systems of acetonitrile in water (with 0.1% TFA) are used for elution: A) 5-100% under 10 min, then 2 min 100% isocratic; or B) 90-100% under 2 min, then 2 min 100% isocratic. Direct inlet ES-MS was also performed on a Bruker Esquire LC/ES-MS. ¹H nuclear magnetic resonance was recorded on a Bruker Avance DRX 400 spectrometer at 400.01 MHz using residual solvent as internal standard.

Example 1

3,4-dichloro-N-[2-(4-trifluoromethyl-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]- benzamide

(i) [4-Trifluoromethyl-benzyl]urea

To a solution of benzyl amine, 1 (4.9 g, 0.028mol) in water (52ml) was added cone. HCI (2.8ml) over a period of 30 min at 25°C. A solution of potassium cyanate (4.58g, 0.056mol) in water (16ml) was then added slowly at room temperature over a period of 15 min. The reaction mixture was stirred at 90°C for 4 h and then slowly cooled to 25°C The solids were filtered and washed with water (100 ml) before being dried at 65°C in a vacuum tray drier for 6 h to afford 5g (0.023mol of the product, lnt-2.

Appearance: White Solid. (ii) 3,4-Dichloro-N-[3-{4-trifluoromethyl-benzyl)-ureidocarbothioyl]-benzamide

To a solution of benzoylchoride, 3 (4.8g, 0.023 mol) in acetone (80ml) was added potassium thiocyanate (2.67g, 0.027mol) at 25°C. The reaction mixture was refluxed for 1 h. Urea derivative, lnt-2 (1 equiv.) was added at 25°C. The reaction mixture was refluxed for 4 to 16 h and then cooled to room temperature. 150 ml of water was added and the resulting mixture was stirred for 2 h. The solids were filtered and washed with water (100 ml), before being dried at 60°C under high vacuum for 4 h to afford 4.4 g (9.8mmol) of the product, 4.

Appearance: Pale yellow solid.

(iii) 3,4-dichloro-N-[2-(4-trlfluoromethyl-benzyl)-3-oxo-2,3-dihydro-[1,2,4]thiadiazol- 5-yl]-benzamide

To a slurry of compound 4 (4.4g, 9.8mmol) in methanol (90ml) was added N-bromo succinimide (2.56g, 14mmol) at room temperature portionwise over a period of 30 min. The reaction mixture was then refluxed for 3 to 12 h. Reaction progress was monitored by TLC. The reaction mixture was cooled to RT and stirred for 45 min, then filtered and washed with methanol (50 ml). The solids were dried under high vacuum at 60°C for 6 h, yielding 3.3g (7.36mmol) of compound-5.

Appearance: Off-White Solid.

MS: [M+H]: 448.1; HPLC purity: 98.3 %; yield: 75%; 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.25 (d, 1 H) 8.03 (dd, 1 H) 7.85 (d, 1 H) 7.76 (d, 2 H) 7.57 (d, 2 H) 4.91 (s, 2 H).

Example 2

The following compounds were produced using the general protocol described above. a) 4-trifluoromethyl-N-[2-(4-trifluoromethyl-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5- yl]-benzamide

MS: [M+H]: 448.1 ; HPLC purity: 99.9 %; yield: 54%;

1H NMR (300 MHz, DMSO-d6) δ ppm: 8.29 (d, 2 H) 7.94 (d, 2 H) 7.76 (d, 2 H) 7.58 (d, 2 H) 4.92 (s, 2 H); b) 4-chloro-N-[2-(4-chloro-3-fluoro-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]-3- fluoro-benzamide

MS: [M+H]: 416.4; HPLC purity: 100 %; yield: 72%;

1 H NMR (300 MHz, DMSO-d6) δ ppm: 7.98 (m, 2 H) 7.81 (t, 1 H) 7.61 (t, 1 H) 7.45 (d, 1 H) 7.22 (d, 1 h) 4.82 (s, 2 H); c) N-[2-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]-3,4-difluoro- benzamide

MS: [M+H]: 384.3; HPLC purity: 98.9 %; yield: 70%;

1H NMR (300 MHz, DMS0-d6) δ ppm: 8.01 (m, 2 H) 7.61 (dd, 1 H) 7.45 (m, 2 H) 7.22 (m, 1 H) 4.78 (s, 2 H); d) 4-chloro-N-[2-(4-trifluoromethyl-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]- benzamide

MS: [M+H]: 414; HPLC purity: 99.8 %; yield: 77%;

1H NMR (300 MHz, DMS0-d6) δ ppm: 8.11 (d, 2 H) 7.75 (d, 2 H) 7.63 (d, 2 H) 7.57 (d, 2 H) 4.91 (s, 2 H); e) 4-fluoro-N-[2-(4-trifluoromethyl-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]- benzamide

MS: [M+H]: 398; HPLC purity: 99.3 %; yield: 75%;

1 H NMR (300 MHz, DMS0-d6) δ ppm: 8.18 (m, 2 H) 7.75 (d, 2 H) 7.57 (d, 2 H) 7.37 (d, 2 H) 4.90 (s, 2 H). f) 4-chloro-N-[2-[(3,4-dichlorophenyl)methyl]-3-oxo-1 ,2,4-thiadiazol-5-yl]benzamide

MS: [M+H]: 415.9 ; HPLC purity: 97.8 %;

1 H NMR (300 MHz, DMSO-d6) δ ppm: 8.11 (m, 2 H) 77.6 (m, 4 H) 7.34 (dd, 1 H) 4.80 (s, 2 H). Biological Tests Test A

Glucose uptake in L6 myotubes.

Rat L6 skeletal muscle cells were seeded in 6-well plates (#83.1839, Sarstedt) and differentiated in Dulbecco's Modified Eagle Medium (DMEM GlutaMAX™-ll, #31965, Gibco) containing 4.5g/L D-glucose 2% FCS, (#10500-064, Gibco) 25 pg/mL gentamicin for 14-15 days. Each well was examined by phase contrast microscopy for the presence of myotubes. The myotube cultures were incubated in serum free DMEM (DMEM GlutaMAX™-!, #21885, Gibco) containing 1g/L D-glucose with test compounds at the indicated final concentration or vehicle control, DMSO (Dimethyl Sulphoxide (DMSO) HYBRI-MAX® D2650, Sigma). After 2h incubation, the media was changed to serum free DMEM without glucose (DMEM #11966, Gibco), containing the indicated concentrations of test compound and vehicle control respectively. After 20 min incubation, 1 pCi of Deoxy-D-glucose, 2-[1 ,2-³H(N)] (NET549A250UC, Perkin Elmer) was added. After 10 min incubation, the wells were rinsed with serum free DMEM without glucose 3 times after which the cells were lysed in 1 ml. RIPA lysis buffer and 300 pl_ were transferred to scintillation tubes containing 4 ml_ liquid scintillation cocktail (Optiphase Hisafe 2, 1200-436, Perkin Elmer). Samples were counted for 1 min in a Wallac 1414 beta counter. CPM was converted to arbitrary units by setting the vehicle control to 1.

Results

Glucose uptake in L6 derived myotube cultures is shown in Figure 1 as a percentage of the vehicle control, and the results are indicated in Table 1 , below. The compounds tested all display the ability to confer insulin independent glucose uptake. Table 1

Glucose uptake (expressed

Test material Concentration

relative to vehicle control)

Vehicle - 100.0 %

1.25 μΜ 126.7 %

2.5 μΜ 146.8 %

Ex.1

5.0 μΜ 137.5%

10 μΜ 101.4%

2.5 μΜ 118.8%

Ex.2a 5.0 μΜ 141.1 %

10 μ 152.3%

1.25 μΜ 116.0%

2.5 μΜ 144.9 %

Ex.2b

5.0 μΜ 166.2 %

10 μΜ 96.2 %

1.25 μΜ 112.5%

2.5 μΜ 105.7%

Ex.2c

5.0 μΜ 132.5%

10 μΜ 129.5%

1.25 μΜ 105.8%

2.5 μΜ 17.9%

Ex.2d

5.0 μΜ 128.8%

10 μΜ 140.4 %

1.25 μΜ 112%

2.5 μΜ 124%

Ex.2f

5.0 μΜ 158%

10 μΜ 131 %

Claims

1. A compound of formula I,

wherein:

(a) R represents a -CF₃ group;

R² represents H;

R³ represents a substituent selected from the group consisting of chioro, fluoro, and -CF₃; and

R⁴ represents a substituent selected from the group consisting of hydrogen and chioro; or

(b) each of R¹ to R³ represents a substituent independently selected from the group consisting of chioro and fluoro; and

R⁴ represents hydrogen, chioro and fluoro;

provided that when R¹ and R² both represent fluoro and R³ represents chioro, R⁴ is not hydrogen; or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.

2. A compound as claimed in Claim 1 , wherein wherein:

when R to R³ are independently selected from the group consisting of chioro and fluoro, then either, or preferably both, of R² and R⁴ are fluoro.

3. A compound as claimed in Claim 1 , which is selected from the group:

i) 3,4-dichloro-N-[2-(4-trifluoromethyl-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5- yl]-benzamide;

ii) 4-trifluoromethyl-N-[2-(4-trifluoromethyl-benzyl)-3-oxo-2,3-dihydro- [1 ,2,4]thiadiazol-5-yl]-benzamide;

iii) 4-chloro-N-[2-(4-chloro-3-fluoro-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]- 3-fluoro-benzamide; iv) N-[2-(3,4-difluoro-benzyl)-3-oxo-2,3-dihydro-[1,2,4]thiadiazol-5-yl]-3,4-difluoro- benzamide;

v) 4-chloro-N-[2-(4-trifluoromethyl-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]- benzamide;

vi) 4-fluoro-N-[2-(4-trifluoromethyl-benzyl)-3-oxo-2,3-dihydro-[1 ,2,4]thiadiazol-5-yl]- benzamide; and

vii) 4-chloro-N-[2-[(3,4-dichlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

4. A compound as defined in any one of Claims 1 to 3, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for use as a pharmaceutical.

5. A pharmaceutical formulation including a compound as defined in any one of Claims 1 to 3, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

6. A combination product comprising:

(A) a compound of formula I as defined in any one of Claims 1 to 3, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; and

(B) another therapeutic agent useful in the treatment of diabetes,

7. A combination product as claimed in Claim 6 which comprises a pharmaceutical formulation including a compound of formula I as defined in any one of Claims 1 to 3, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; another therapeutic agent useful in the treatment of diabetes; and a pharmaceutically-acceptable adjuvant, diluent or carrier.

8. A combination product as claimed in Claim 6, which comprises a kit of parts comprising components:

(a) a pharmaceutical formulation including a compound of formula I as defined in any one of Claims 1 to 3, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including another therapeutic agent useful in the treatment of diabetes in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier,

which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

9. A kit of parts as claimed in Claim 8, wherein components (a) and (b) are suitable for sequential, separate and/or simultaneous use in the treatment of diabetes.

10. A combination product as claimed in any one of Claims 6 to 9, wherein the other therapeutic agent is selected from biguanides, glitazones, oligomycins, AICAR, insulin, insulin secretagogues, peroxisome proliferator-activated receptor agonists, a-glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, exenatide, inhibitors of 11-β hydroxysteroid dehydrogenase type 1 , inhibitors of stearoyl-CoA desaturase 1 , A-769662, D942, cilostazol, AM251 , SIRT1 activators and salidroside.

11. The use of a compound of formula I as defined in any one of Claims 1 to 3, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, or a combination product as defined in any one of Claims 6 to 10, for the manufacture of a medicament for the treatment of diabetes.

12. A compound as defined in any one of Claims 1 to 3, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, or a combination product as defined in any one of Claims 6 to 10, for use in the treatment of diabetes.

13. A method of treatment of diabetes, which method comprises the administration of an effective amount of a compound of formula I as defined in any one of Claims 1 to 3, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, or a combination product as defined in any one of Claims 6 to 10, to a patient in need of such treatment.

14. A kit of parts comprising:

(I) one of components (a) and (b) as defined in any one of Claims 8 to 10; together with (II) instructions to use that component in conjunction with the other of the two components.

15. A method of making a kit of parts as defined in any one of Claims 8 to 10, which method comprises bringing a component (a) into association with a component (b), thus rendering the two components suitable for administration in conjunction with each other.

16. A process for the preparation of a compound of formula I as defined in any one of Claims 1 to 3, which process comprises cyclisation of a compound of formula II,

wherein R to R⁴ are as defined in Claim 1.

17. A process for the preparation of a pharmaceutical formulation as defined in Claim 5, which process comprises bringing into association a compound of formula I, as defined in any one of Claims 1 to 3, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.

18. A process for the preparation of a combination product as defined in any one of Claims 6 to 10, which process comprises bringing into association a compound of formula I, as defined in any one of Claims 1 to 3, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof with the other therapeutic agent that is useful in the treatment of diabetes.