WO2008090356A1 - Thiazolidinone derivatives useful in the treatment of cancer and disorders caused by excess adiposity - Google Patents

Abstract

There is provided a compound of formula (I) wherein X, Y, T, W, A1, A2, R1, R5 and R6 have meanings given in the description. Such compounds are potentially useful in the treatment of cancer, such as breast cancer, and/or disorders or conditions caused by, linked to, or contributed to by, excess adiposity, such as hyperinsulinemia and type 2 diabetes.

Description

7HIAZOUDINONE DERIVATIVES USEFUL M THE TREATMENT OF CANCER AND DtSORDERS CAUSED BY EXCESS ADIPOSITY

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 cancer, and/or diabetes and associated conditions linked to excess adiposity and/or hyperinsulinemia and associated conditions.

Background

Excess adiposity is associated to different degrees with an increased risk of developing cancers, such as colorectal adenomas, breast cancer (postmenopausal), endometrial cancer, kidney cancer, oesophageal adenocarcinoma, ovarian cancer, prostate cancer, pancreatic cancer, gallbladder cancer, liver cancer and cervical cancer (CaIIe and Kaaks (2004), Nature Reviews Cancer, 4, 579-591).

Recent studies suggest that hyperinsulinemia is correlated among other things to the incidence of colon and lethal breast and prostate cancer. ,

Elevated plasma free fatty acids (FFAs) stimulate pancreatic β-cells and is one cause of hyperinsulinemia.

In prostate cancer, hyperinsulinemia has been shown to be prospective risk factor for death and data support that the insulin level could be used as a marker of prostate cancer prognosis (Hammarsten and Hδgstedt (2005) European Journal of Cancer, 41, 2887).

Several mechanisms may link hyperinsulinemia to the incidence and outcome of breast cancer. Firstly, chronic hyperinsulinemia results in increased production of ovarian testosterone and oestrogen and inhibition of hepatic production of sex hormone binding globulin, a sex-hormonal profile that is associated with breast cancer. Secondly, hyperinsulinemia suppresses hepatic production of insulin-like growth factor binding protein-1 (IGFBP-1 ), and thus increases circulating levels of IGF-1 , which has potent mitogenic effect on breast tissue. Thirdly, insulin itself may have a direct mitogenic effect on breast cancer cells.

The study by Hardy et al ((2005), J. Biol. Chem. 280, 13285) shows that FFAs directly stimulate the growth of breast cancer cells in a GPR40 dependent manner. Moreover, expression studies performed on tumor tissue isolated from 120 breast cancer patient shows a frequent expression of GPR40 emphasizing the clinical relevance of the findings of Hardy (see, for example, Ma et al, Cancer Cell (2004) 6, 445).

Another expression study on clinical material from colon cancer patients suggests that similar mechanisms could be relevant also in these malignancies (see http://www.ncbi. nlm.nih.gov/projects/geo/gds/gds_browse.cgi?gds=1263).

Cancer cells in general exhibit an aberrant metabolism compared to non- transformed cells. Neoplastic cells synthesise lipids to a much larger extent than their normal counterpart and metabolise glucose differently, it has been suggested that this aberrant metabolism constitutes a therapeutic target. By interfering with one or, preferably, several of the pathways controlling cellular metabolism, cancer cells would be more sensitive than non-transformed cells, thus creating a therapeutic window. Examples of pathways/targets include glycolysis interfering agents, lipid synthesis pathway, AMPK activating agents and agents affecting mitochondrial function.

Elevated FFAs and hyperinsulinemia (hypersecretion of insulin) also represent new targets for treatment of obesity-related disorders/metabolic syndrome.

The 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. It 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.

Over 300 million people worldwide suffer from obesity, with at least 1 billion people being regarded as overweight. Both problems are associated with elevated FFAs and hyperinsulinemia and can lead to increased insulin resistance and, in the worst case, the development of diabetes (approximately 80 percent of all adult diabetics are overweight), metabolic syndrome, fatty liver and/or other conditions or diseases.

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.

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.

Elevated plasma FFAs stimulate pancreatic β-cells and is one cause of hyperinsulinemia. A medicament that modulates (e.g. suppresses) the stimulatory effect by FFA on insulin secretion may therefore represent a novel therapeutic strategy to treat or prevent disorders caused by, linked to, or contributed to by, hyperinsulinemia.

A possible mechanism that may underpin the cause of the development of hyperinsulinemia after exposure of elevated plasma FFAs may be explained by Steneberg et a/ (2005), Cell Metabolism, 1, 245-258, which reports a study under high fat dietary conditions, and suggests that GPR40 may play a pivotal role in the pathogenic process leading to diabetes. A mouse mutant lacking the GPR40 receptor was protected from the disease.

Another FFA receptor, GPR120, is expressed abundantly in a variety of tissues, especially the intestinal tract. The stimulation of GPR120 by FFAs promotes the secretion of GLP-1 and increases circulating insulin (see Hirasawa ef a/ (2005), Nature Medicine, 11, 90-94).

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) α-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. For example, exenatide needs to be administered by subcutaneous injection and also has storage stability shortcomings.

Furthermore, 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. Patients may also become unresponsive to insulin secretagogues over time. Metformin and α- glucosidase inhibitors often lead to gastrointestinal problems and PPAR-γ agonists tend to cause increased weight gain and oedema. Exenatide is also reported to cause nausea and vomiting.

With the epidemic increase in obesity in western society there is an urgent unmet clinical need to develop novel innovative strategies with the aim to suppress the detrimental effects of excess adiposity and hyperinsulinemia without causing hyperglycemia and diabetes. Further, there is a clear need for new drugs with a superior effect and/or less side effects.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in the human, affecting approximately 10% of women of reproductive age. The syndrome is associated with a wide range of endocrine and metabolic abnormalities, including insulin resistance (see Ehrmann et al (2006), J Clin Endocrinol Metab, Jan 91(1), 48-53). PCOS patients are typically hyperinsulinemic and insulin resistant. Hyperinsulinemia may contribute to hyperandrogenic, anovulatory dysfunction Wa a multitude of ways. In vitro and in vivo studies suggest that insulin synergizes with LH to promote androgen production by thecal cells. Insulin inhibits hepatic synthesis of sex hormone binding globulin, thereby increasing the free pool of androgens (Nestler (1997), Hum Reprod., Oct 12, Suppl 1, 53-62).

In Alzheimer's disease (AD), longitudinal studies have established a strong association with hyperinsulinemia. Hyperinsulinemia is also related to a significant decline in memory-related cognitive scores, but not to decline in other cognitive domains. Thus, hyperinsulinemia is associated with a higher risk of AD and decline in memory.

insulin-degrading enzyme also appears to constitute a mechanistic link between hyperinsulinemia and AD (Wei and Folstein (2006), Neurobiology of Aging, 27, 190-198). This enzyme degrades both insulin and amyloid-β (Aβ) peptide, a short peptide found in excess in the AD brain. Evidence suggests that hyperinsulinemia may elevate Aβ through insulin's competition with the latter for insulin-degrading enzyme. Formation of neurofibrillary tangles, which contain hyperphosphorylated tau, represents a key step in the pathogenesis of neurodegenerative diseases. Promoting peripheral insulin stimulation, rapidly increased insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase and phosphatidylinositol (Pl) 3-kinase pathway activation, and dose- dependent tau phosphorylation at Ser(202) in the central nervous system in an insulin receptor-dependent manner. Thus, peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction, revealing an additional link between hyperinsulinemia and neurodegeneration.

Studies on patients suffering from Systemic Lupus Erythematosus (SLE) have shown that these patients have significantly higher fasting insulin levels compared to healthy controls. They also have increased risk of coronary heart disease (CHD) which is not fully explained by the . classic CHD risk factors, Magadmi et al (2006) J Rheumatol., Jan 33, 50-56. Thus, hyperinsulinemia may be a treatable risk factor in non-diabetic and diabetic SLE patients. Recent studies on metabolic syndrome in patients with chronic kidney disease suggest that insulin resistance and hyperinsulinemia are independently associated with an increased prevalence of the disease. Insulin per se can promote the proliferation of mesangial cells and the production of matrix proteins, and also stimulates the expression of growth factors such as IGF-1 and TGF-β, that are involved in mitogenic and fibrotic processes in nephropathy. Insulin also interferes with the systemic RAS and specifically increases the effect of angiotensin Il on mesangial cells. Hyperinsulinemia also increases levels of endothelin-1 and is associated with increased oxidative stress. In conclusion, reduction of hyperinsuiinemic levels may be of therapeutic value for patients with progressive renal disease (e.g. chronic renal failure; Sarafidis and Ruilope (2006), Am J Nephrol, 26, 232- 244).

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.

US 1293741 discloses inter alia thiazolidinones. However, there is no mention of the use of the compounds disclosed therein in the treatment of cancer or diabetes.

US 4,103,018 and US 4,665,083 disclose inter alia thiazolidinones. However, there is no mention or suggestion of the compounds disclosed in those documents in the treatment of cancer, nor (at all) of thiazolidinones that are substituted in the 5-position. WO 2005/051890 discloses inter alia thiazoiidinones (which are ultimately substituted with a cyclopropyl group) that may be useful in the treatment of diabetes. However, there is no mention or suggestion in this document of the use of the compounds in the treatment of cancer, nor of thiazoiidinones that are substituted in the 5-position with heterocyciyl, heteroaryl or, particularly, aryl group, either directly or via an alkylene linker group.

EP 1 535 915 discloses various furan and thiophene-based compounds. Cancer is mentioned as one of numerous indications.

EP 1 559 422 discloses a huge range of compounds for use in the treatment of inter alia cancer. However, this document does not appear to relate to thiazoiidinones.

US patent application US 2006/0089351 discloses various benzothiazole derivatives as neuropeptide Y receptor antagonists, and therefore of use in the treatment of eating disorders. International patent application WO 2006/020680 discloses a vast range of heterocyclic compounds as modulators of nuclear receptors. Further, US 6,353,006 discloses various heterocycles for use in modulating progesterone receptor mediated processes, and therefore of use in the treatment of e.g. diseases . relating to deficiencies in bone mineral density, such as osteopenia or osteoporosis. However, none of the above-mentioned documents specifically discloses any 1-oxo or 1 ,1-dioxo-derivatives of thiazoiidinones.

International patent applications WO 2005/075471 , WO 2005/1 16002 and WO 2007/061661 disclose inter alia thiazoiidinones and oxazolidinones as 11-β- hydroxysteroid dehydrogenase type 1 inhibitors. There is no mention or suggestion of the use of the disclosed compounds for the treatment of cancer, nor a teaching towards such thiazoiidinones that are each substituted at the 5- position with a heterocyclyl, heteroaryl or, particularly, aryl group, either directly or via an alkylene linker group. More particularly, there is no mention or suggestion of 1-oxo or 1,1-dioxo-derivaitves of thiazoiidinones.

International patent application WO 2006/040050 discloses certain quinazolinylmethylene thiazolinones as CDK1 inhibitors. Similarly, US patent application US 2006/0004045 discloses quinolinyimethylene thiazolinones. However, neither of these documents specifically discloses 1-oxo or 1 ,1-dioxo- derivativeε of thiazolidinones.

International patent applications WO 2007/010273 and WO 2007/010281 both disclose e.g. thiazolidin-4-one 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. There is no suggestion in either of these documents of 1-oxo- or 1,1-dioxo thiazolidin-4-one compounds.

Finally, international patent applications WO 2007/032028 discloses various heterocyclic compounds that may be useful in treating PTP-1B mediated diseases. However, there no mention of 1-oxo- or 1,1-dioxo thiazolidin-4-one compounds in this document.

Disclosure of the Invention

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

wherein

X represents -[C(R₈)(R₉)J_n-; n represents 0, 1 , 2 or 3;

Y represents -C(O)-, -S(O)₂- or =C(R₁₀)-; .

T represents -S(O)- or -S(O)₂- ;

W represents -NR₇-, -CR₇R₇-, -NR₇C(O)-, -NR₇S(O)₂-, -NR₇C(O)NR₇-,

-NR₇C(O)O- or a bond; one of Ai or A₂ represents a double bond and the other represents a single bond; when Ai represents a single bond, A₂ is a double bond and R₆ is absent; when A₂ represents a single bond, Ai is a double bond and, if present, one R₇

(which is attached α to the requisite ring of the. compound of formula I) is absent; R₁ represents -C(O)NR₃R₂, -NR₃R₂, -C(O)OR₂, -NR₄C(O)NR₃R₂, -NR₄C(O)OR₂, -OC(O)NR₃R₂, -NR₄C(O)R₂, -OC(O)R₂ , -OR₂, -SR₂, H, alkyl, cycloalkyl, heterocyciyl, benzyl, ary! or heteroaryl (which latter six groups are optionally substituted by one or more groups selected from B¹, B², B³, B⁴, B⁵ and B⁶, respectively);

R₂ and R₅ independently represent, on each occasion when used herein, hydrogen, alkyl, cycloalkyl, heterocyciyl, benzyl, aryl or heteroaryl (which latter six groups are optionally substituted by one or more groups selected from B⁷, B⁸, B⁹, B¹⁰, B¹¹ and B¹², respectively); R₃, R₄, R₆ and R₇ independently represent, on each occasion when used herein, hydrogen, alkyl, cycloalkyl, aryl or benzyl (which latter four groups are optionally substituted by one or more groups selected from B¹³, B¹⁴, B¹⁵ and B¹⁶, respectively), or heterocyciyl or heteroaryl (which latter two groups are optionally substituted by one or more groups selected from B¹⁴ and B¹⁵, respectively); R₈ and Rg are independently selected from hydrogen, alkyl and aryl (which latter two groups are optionally substituted by B^16a and B^16b, respectively); R-io represents hydrogen, alkyl or aryl (which latter two groups are optionally substituted by one or more groups selected from B¹⁷ and B¹⁸, respectively); B¹ to B¹⁸ independently represent cyano, -NO₂, halo, -OR₁-_I, -NR₁₂R₁₃, -SR₁₄, -Si(R₁₅)₃, -C(O)OR₁₆, -C(O)NR_16aRi₆b, -S(O)₂NR_16cR_16d, aryl or heteroaryl (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R₁₇); or, alternatively, B⁴, B⁵, B⁶, B¹⁰, B¹¹, B¹², B¹⁵, B¹⁶, B^16b or B¹⁸ independently represent R₁₇; R₁₁, R₁₂, Ri₃, Ri₄, Ri6, Ri6a. Ri6b_> R₁60 and R₁₆d independently represent H or R₁₇; and

R₁₅ and R₁₇ independently represent, on each occasion when used herein, C_1-6 alkyl optionally substituted by one or more halo atoms, 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, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids.

"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 I₁ provided that such prodrugs do not include compounds that are otherwise equivalent to compounds of formula I, but in which T represents -S-, rather than -S(O)- or -S(O)₂-.

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 1 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. 1-92, Elesevier, 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 contain double bonds and may thus exist as £ {entgegen) and Z {zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.

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. Specifically, tautomers exist when R⁶ represents H. Such compounds have different point of attachments of R⁶ accompanied by one or more double bond shifts.

Compounds of formula I may also 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/ Unless otherwise stated, the term "alkyl" refers to an unbranched or branched, cyclic, saturated or unsaturated (so forming, for example, an alkenyl or aikynyl) hydrocarbyl radical, which may be substituted or unsubstituted (with, for example, B¹, B², B⁷, B⁸, B¹³, B¹⁴, B^16a or B¹⁷). Where the term "alky!" refers to an acyciic group, it is preferably Ci--_I0 alkyl and, more preferably, C_1-6 alkyl (such as ethyl, propyl, (e.g. n-propyl or isopropyl), butyl (e.g. branched or unbranched butyl), pentyl or, more preferably, methyl). Where the term "aikyl" is a cyclic group (which may be where the group "cycloalkyl" is specified), it is preferably C_3-I2 cycloalkyl and, more preferably, C_5-10 (e.g. C_5-7) cycloalkyl.

When used herein, alkylene refers to Ci_i₀ (e.g. C_1-6) alkylene and, preferably C_1-3 alkylene, such as pentylene, butylene (branched or unbranched), preferably, propylene (n-propylene or isopropylene), ethylene or, more preferably, methylene (i.e. -CH₂-).

The term "halogen", when used herein, includes fluorine, chlorine, bromine and iodine.

Heterocyclyl groups that may be mentioned include non-aromatic monocyclic heterocyclyl groups in which one or more (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a het^'eroatom, which heteroatom is preferably selected from N, O and S), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C_2-q heterocycloalkenyl (where q is the upper limit of the range) or a C_3-q heterocycloalkynyl group. C_2-q heterocycloalkyl groups that may be mentioned include 7- azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]- octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1 ,3-dioxolanyl), dioxanyl (including 1 ,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyl (including 1 ,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6- oxabicyclo[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3- sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1 ,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloal^'kyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heterocycloalkyl groups may be Wa any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S- oxidised form. Preferred heterocyclyl groups include cyclic amino groups such as pyrrolidinyl, piperidyl, piperazinyl, morpholinyl or a cyclic ether such as tetrahydrofuranyl, monosaccharide.

The term "aryl" when used herein includes C_6-U (such as C_6-13 (e.g., C_6-10)) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. The point of attachment of aryl groups may be wa any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring. C_6-H aryl groups include phenyl, naphthyl and the like, such as 1 ,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. Most preferred aryl groups include phenyl.

The term "heteroaryl" when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group). Heteroaryl groups include those which have between 5 and 14 (e.g. 10) members and may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic. However, when heteroaryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring. Heterocyclic groups that may be mentioned include benzothiadiazolyl (including 2,1,3- benzothiadiazolyl), isothiochromanyl and, more preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3- benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2,1 ,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-1 ,4-. benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1 ,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1 ,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyi, isoindolyl, isoquinolinyi, isothiaziolyl, isoxazolyl, naphthyridinyl (including 1 ,6-naphthyridinyl or, preferably, 1 ,5-naphthyridinyl and 1 ,8-naphthyridinyI), oxadiazolyl (including 1 ,2,3- oxadiazolyl, 1 ,2,4-oxadiazolyl and 1 ,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1 ,2,3,4- tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl and 1 ,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1 ,2,4-triazolyl and 1 ,3,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heteroaryl groups may also be in the N- or S- oxidised form. Particularly preferred heteroaryl groups include pyridyl, pyrrolyl, quinoiinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl, thiophenetyl, pyranyl, carbazolyl, acridinyl, quinolinyl, benzoimidazolyl, benzthiazolyl, purinyl, cinnolinyl and pterdinyl.

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 and R² are both aryl groups substituted by one or more Ci_-6 alkyl groups, the alkyl groups in question may be the same or different.

For the avoidance of doubt, when a term such as "B¹ to B¹⁸" is employed herein, this will be understood by the skilled person to mean B¹, B², B³, B⁴, B⁵, B⁶, B⁷, B⁸, B⁹, B¹⁰, B¹¹, B¹², B¹³, B¹⁴, B¹⁵, B¹⁶, B^16a, B^16b, B¹⁷ and B¹⁸ inclusively.

For the avoidance of doubt, when the group 'benzyl' is substituted, then the substituents are preferably on the phenyl ring of the benzyl group, rather than on the methylene (-CH₂-) group. For the avoidance of doubt, when Y represents =C(R¹⁰)-, this refers to the following compound of formula Ia

As stated herein, compounds of the formula I, or pharmaceutically-acceptable salts, solvates, or pharmaceutically functional derivatives thereof, may be useful in the treatment of cancer and/or a disorder or condition caused by, linked to, or contributed to by, FFAs and, particularly, excess adiposity and/or hyperinsulinemia (hereinafter referred to together as ^!an excess adiposity/hyperinsuiinemia disorder'). Hence, compounds of the invention that may be mentioned include those that may find utility in the treatment of each of those disorders (i.e. cancer and an excess adiposity/hyperinsuiinemia disorder).

Preferred compounds of formula I (and particularly those that may be useful in the treatment of an excess adiposity/hyperinsuiinemia disorder) that may be mentioned include those in which:

Y represents =C(R₁₀)-, preferably, -S(O)₂- or, more preferably, -C(O)-; R₁₀ represents hydrogen;

W represents -NR₇C(O)NR₇-, -NR₇C(O)O-, preferably -NR₇S(O)₂-, -NR₇C(O)- or, more preferably, -NR₇-;

R₁ represents heterocyclyl, aryl or heteroaryl (which groups are optionally substituted by one or more groups selected from B³, B⁵ and B⁶, respectively); more preferably, R₁ represents optionally substituted heteroaryl or aryl (e.g. phenyl), both of which are optionally substituted as hereinbefore defined;

R₅ represents heterocyclyl or, more preferably, aryl or heteroaryl (which latter three groups are optionally substituted by one or more groups selected from B⁹,

B¹¹ and B¹², respectively); R₆ and R₇ independently represent hydrogen, alkyl, cycloalkyl or benzyl (which latter three groups are optionally substituted by one or more groups selected from

B¹³, B¹⁴ and B¹⁶, respectively). It is preferred that in compounds of formula I (and particularly those that may be useful in the treatment of an excess adiposity/hyperinsulinemia disorder), when Y represents -C(O)-, W represents -NR₇-, R₇ represents H, and: (i) R₅ represents bicyclo[2.2.1]hept-2-yl, then:

(a) when X represents a bond (e.g. when X represents -[CR₈Rg]_n- in which n represents 0), R₁ does not represent an unsubstituted phenyl group;

(b) when X represents -CH₂-, then Ri does not represent a 4- hydroxyphenyl group;

(ii) R₅ represents methyl substituted by cyclohexyl (i.e. a part-cyclic C₇ alkyl group) and X represents a bond, then Ri does not represent a 2-hydroxypheny! group;

(iii) R₅ represents cycloheptyl and X represents -CH₂-, then R₁ does not represent imidazol-4-yl, indol-3-yl, 4-hydroxyphenyl or 3-pyridyl;

(iv) R₅ represents cyclooctyl and X represents -CH₂-, then R-i does not represent

4-hydroxyphenyl;

(v) X represents a bond and Ri represents a 4-tetrahydropyranyl group, then R₅ does not represent a 2-fluoro-, 2-chloro- or 2-methylphenyl group; (vi) X represents a bond and R-i represents a 3-tetrahydrofuranyl group, then R₅ does not represent a 2-fluoro- or 2-chlorophenyl group;

(vii) X represents a bond and R-i represents a ferf-butyl-4-piperidinyl-1 - carboxylate group, then R₅ does not represent 2-chlorophenyl; (viii) X represents a bond and R₅ represents a tricyclo[3.3.1.1~3,7~]dec-1-yl group, then R-i does not represent an unsubstituted phenyl group;

(ix) X represents a bond and R₅ represents ethyl substituted at the 1 -position by B⁷ in which B⁷ represents 4-fluorophenyl;

(x) X represents -CH₂- and R₅ represents unsubstituted phenyl, then Ri does not represent benzimidazol-2-yl or 1-methylbenzimidazol-2-yl; and (xi) X represents -CH₂- and R₅ represents methyl substituted by cyclohexyl, then R₁ does not represent benzimidazol-2-yl.

It is also preferred that in compounds of formula I (and particularly those that may be useful in the treatment of an excess adiposity/hyperinsulinemia disorder), when Y represents -C(O)-, W represents -NR₇-, R₇ represents H, X represents -CH₂- and: (a) R₅ represents bicyc!o[2.2.1]hept-2-yl, then R-i does not represent 4- hydroxyphenyl;

(b) R₅ represents cycloheptyl, then R-i does not represent 3,4-dihydroxyphenyl;

(c) R₁ represents [5-(2-chlorophenyI)-1 ,3,4-oxadiazol-2-yl], then R₅ does not represent 2-fluorophenyl, tricyclo-[3.3.1.0~3,7~]non-3-y!, 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl or bicyclo[2.2.1]hept-2-yl;

(d) R₁ represents benzimidazol-2-yl, then R₅ does not represent cyclohexyl, cycloheptyl or bicyclo-[2.2.1]hept-2-yl;

(e) R₁ represents 1,3-benzoxazol-2-yl, then R₅ does not represent unsubstituted phenyl or cycloheptyl; and

(f) R₁ represents 1,3-benzothiazol-2-yl, then R₅ does not represent unsubstituted phenyl.

For instance for compounds of formula I in which R₅ represents heterocyclyl, aryl or heteroaryl (all of which are optionally substituted as hereinbefore defined), it is preferred that (particularly for those compounds that may be useful in the treatment of an excess adiposity/hyperinsuiinemia disorder), when Y represents

-C(O)-, W represents -NR₇-, R₇ represents H:

(i) n represents 0 and: (a) Ri represents a 4-tetrahydropyranyl group, then R₅ does not represent a 2-fluoro-, 2-chloro- or 2-methylphenyl group;

(b) Ri represents a 3-tetrahydrofuranyl group, then R₅ does not represent a 2-fluoro- or 2-chlorophenyl group;

(c) Ri represents a ferf-butyI-4-piperidinyl-i-carboxylate group, then R₅ does not represent 2-chlorophenyl; and

(ii) X represents -CH₂- and R₅ represents unsubstituted phenyl, then R₁ does not represent benzimidazol-2-yl or 1 -methylbenzimidazol-2-yl; (iii) when X represents -CH₂- and:

(a) R₅ represents unsubstituted phenyl, then R₁ does not represent 1 ,3- benzoxazol-2-yl or 1 ,3-benzothiazoI-2-yl; and

(b) R₅ represents 2-fluorophenyl, then R₁ does not represent [5-(2- chlorophenyl)-1 ,3,4-oxadlazol-2-yl].

It is preferred that, in compounds of formula I (and particularly those that may be useful in the treatment of cancer): when Y represents -C(O)-, W represents -NR₇-, R₇ represents H, n represents 0 and R₁ represents unsubstituted phenyl, then, for example when R₅ represents phenyl (e.g. 1-methyl-4-nitrophenyl), then R₆ does not represent alkyl (e.g. C_1-4 alkyl) such as butyl (e.g. isobutyl) or a part cyclic alkyl group (such as methyl or ethyl substituted by cycloalky], e.g. cyclohexyl); when W represents -NR₇-, R₇ represents H, and Y represents =C(Ri₀)-, then preferably, n represents 1 , 2 or 3, Ri does not represent hydrogen and/or R₆ does not represent alkyl or, particularly, cycloalkyl (such as C_5-10 cycloalkyl, e.g. cyclopenyl).

Further preferred compounds of formula I (e.g. compounds that may be useful in the treatment of cancer and/or an excess adiposity/hyperinsulinemia disorder) that may be mentioned include those in which:

X represents ~[C(R⁸)(R⁹)]_n-, in which n is 0 or, preferably, 1 , 2 or 3 (this is particularly so for compounds of formula 1 that may be useful in the treatment of cancer);

R₆ represents alkyl (optionally substituted by one or more B¹³ groups), preferably cycloalkyl (optionally substituted by one or more B¹⁴ groups), more preferably aryl or benzyl (which latter two groups are optionally substituted by one or more groups selected from B¹⁵ and B¹⁶, respectively), or, most preferably, R₆ represents hydrogen (especially when Y represents -C(O)-); when R₆ represents alkyl (e.g. C_1-6 alky! or, preferably, Ci_-3 alkyl, which alkyl groups are preferably not branched, i.e. are straight chain) or cycloalkyl (e.g. C_5-10 cycloalky!), such groups are optionally substituted by one or more B¹³ groups, but are preferably unsubstituted;

B¹ to B¹⁸ (e.g. B¹³ and B¹⁴) independently represent cyano, -NO₂, halo, -ORi₁, -NR₁₂R₁₃, -SR₁₄, -Si(R₁₅)_3l -C(O)OR₁₆, -C(O)NR_16aR₁₆b or -S(O)₂NR_1BcR_1sd; or, alternatively,

B⁴, B⁵, B⁶, B¹⁰, B¹¹, B¹², B¹⁵, B¹⁶, B^16b or B¹⁸ independently represent R₁₇; R₇ represents alkyl, cycloalkyl, aryl or benzyl (which latter four groups are optionally substituted by one or more groups selected from B¹³, B¹⁴, B¹⁵ and B¹⁶, respectively) or, most preferably, R₇ represents hydrogen.

Further compounds of formula I that may be mentioned (particularly those that may be useful in the treatment of an excess adiposity/hyperinsulinemia disorder) include those in which: n represents 2, 3 or, preferably, 1 ; W represents -NR₇-; one of R₈ and R₉ represents alkyl or aryl (both of which are optionally substituted as hereinbefore defined, and, e.g. in the case of aryl, is preferably substituted) and the other represents hydrogen or, alkyl or aryl as defined herein.

Yet further compounds of formula I that may be mentioned (particularly those that may be useful in the treatment of an excess adiposity/hyperinsulinemia disorder) include those in which: when R₁ represents heteroaryl, it is preferably monocyclic; when R₁ represents heteroaryl, it preferably contains less than 3 (e.g. 2 or, more preferably, 1) heteroatoms;

R₅ does not represent a cycloalkyl group (e.g. a C₆-io cycloalkyl group);

R-_I does not represent a heterocyclyl (such as a tetrahydropyranyl, tetrahydrofuranyl or piperidinyl) group;

R₅ does not represent alkyl substituted by B⁷ in which B⁷ represents optionally substituted aryl;

R₅ does not represent a part-cyclic alkyl group (e.g. methyl substituted by cyclohexyl); R-_I is preferably aryl.

Yet further compounds of formula I that may be mentioned (particularly those that may be useful in the treatment of an excess adiposity/hyperinsulinemia disorder) include those in which: R₅ does not represent H; when Y represents -C(O)- and n represents 1 or 2, when X represents -[CR₈Rg]-, then W represents -CR₇R₇-, -NR₇S(O)₂-, -NR₇C(O)NR₇- or -NR₇C(O)O- or a bond; when Y represents -C(O)-, W represents -NR₇, then R-i represents -C(O)NR₃R₂, -NR₃R₂, -C(O)OR₂, -NR₄C(O)NR₃R₂, -NR₄C(O)OR₂, -OC(O)NR₃R₂,

-NR₄C(O)R₂, -OC(O)R₂ , -OR₂ or -SR₂.

Compounds of formula I that may be mentioned (e.g. compounds that may be useful in the treatment of cancer and/or an excess adiposity/hyperinsulinemia disorder) include those in which: Y preferably represents -C(O)-; R₁ represents -C(O)NR₃R₂, -NR₃R₂, -C(O)OR₂, -NR₄C(O)NR₃R₂, -NR₄C(O)OR₂, -

OC(O)NR₃R₂₁ -NR₄C(O)R₂, -OC(O)R₂ , -OR₂, -SR₂, H, alkyl, haloalkyl cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl;

R₂ and R₅ independently represent, on each occasion when used herein, hydrogen, alky!, haloalkyl, cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl;

R₃. R₄, R₆ and R₇ independently represent, on each occasion when used herein, aryl or, more particularly, hydrogen, alkyl, haloalkyl, cycloalkyl or benzyl;

R₈ and R₉ are independently selected from hydrogen, alkyl and aryl;

R₁0 represents hydrogen, alkyl, haloalkyl or aryl.

Further compounds of formula I that may be mentioned (e.g. compounds that may be useful in the treatment of cancer and/or an excess adiposity/hyperinsulinemia disorder) include those in which:

B¹ to B¹⁸ independently represent halo, -OR₁₁, -NR₁₂Ri₃, -SR₁₄, -Si(R₁₅)₃, -C(O)OR₁₆ or aryl (which aryl group is itself optionally substituted by one or more groups selected from halo or R₁₇, or is preferably unsubstituted);

R₁₁, R₁₂, Ri₃, Ri₄ and R₁₆ independently represent R₁₇ or, more preferably, H.

B¹ to B¹⁸ may alternatively independently represent functional groups such as hydroxyl, amine, sulfide, silyl, carboxylic acid, halogen, aryl, etc.

Further compounds of formula I that may be mentioned (e.g. compounds that may be useful in the treatment of cancer and/or an excess adiposity/hyperinsulinemia disorder) include those in which: Y represents -C(O)-;

T represents -S(O)-; n represents 1 ;

W represents -N-;

A₂ represents a single bond and A₁ is a double bond; R₆ represents H;

R₁ and R₅ independently represent aryl or heteroaryl.

Further compounds of formula I that may be mentioned (e.g. compounds that may be useful in the treatment of cancer and/or an excess adiposity/hyperinsuiinemia disorder) include those in which: X is alkylene or a bond (i.e. when n represents O); T represents -S(O)-;

Y represents =C(H)- or, preferably -C(O)-; W represents -NR₇-;

A-i, A₂, R-_I, R₂ and R₅ are as hereinbefore defined; R₃, R₄ and R₆ independently represent hydrogen, alkyl (e.g. optionally substituted by one or more groups selected from B¹³), haloalkyl, cycloalkyl (e.g. optionally substituted by one or more groups selected from B¹⁴) or benzyl (e.g. optionally substituted by one or more groups selected from B¹⁶).

More preferred compounds of formula I (e.g. compounds that may be useful in the treatment of cancer and/or an excess adiposity/hyperinsulinemia disorder) include those in which:

X represents -CH₂-;

Y represents -C(O)-; Ri and R₂ independently represent aryl (e.g. phenyl) as hereinbefore defined (i.e.

Ri represents aryl optionally substituted by one or more B⁵ groups and R₂ represents aryl optionally substituted by one or more B¹¹ groups); when Ri and/or R₂ represent phenyl, it/they is/are substituted para relative to the point of attachment of the R₁ or R₂ group to X; B⁵ and B¹¹ independently represent halo;

R₅ represents heteroaryl (e.g. pyridyl).

More preferred compounds of formula I (e.g. compounds that may be useful in the treatment of cancer and/or an excess adiposity/hyperinsulinemia disorder) include those in which:

R₁ represents -C(O)NHR₂;

R₂ represents aryl (e.g. phenyl); when R₂ represents phenyl, it is substituted (i.e. with a B¹¹ substituent) at the para position (relative to the point of attachment of the R₂ group to the remainder of the compound of formula I);

B¹¹ represents C₁-C₆ alkyl.

In another preferred embodiment of the present invention: R₁ is -NHR₂; R₂ is aryl (e.g. phenyl); when R₂ represents phenyl, it is substituted (i.e. with a B¹¹ substituent) at the para position;

B¹¹ represents d-C₆ alkyl; Y represents =C(H)-; R₅ represents aryl (e.g. phenyl); when R₅ represents phenyl, it is either unsubstituted or substituted with a halogen (i.e. B¹¹ represents halo).

In a still another preferred embodiment of the present invention: R₅ represents aryl (e.g. phenyl); when R₅ represents phenyl, it is substituted (i.e. with a B¹¹ substituent) at the para position;

B¹¹ represents Ri₇;

Ri₇ represents Ci_-6 alkyl preferably substituted by one or more halo atoms (so forming a haloalkyl group).

In a still another preferred embodiment of the present invention; Y represents =C(H)-; R₅ represents aryl (e.g. phenyl); when R₅ represents phenyl, it is substituted (i.e. with a B¹¹ substituent) at the para position;

B¹¹ represents halo or R₁₇;

R₁₇ represents C_1-6 alkyl preferably substituted by one or more halo atoms (so forming a haloalkyl group).

In a still another preferred embodiment of the present invention:

X represents a single bond (i.e. n represents 0);

R₁ is -C(O)NHR₂;

R₂ is aryl (e.g. phenyl); when R₂ represents phenyl, it is substituted with B¹¹;

B¹¹ represents Ri₇;

R₁₇ represents C_rC₆ alkyl.

Preferred compounds of formula I (e.g. compounds that may be useful in the treatment of cancer and/or an excess adiposity/hyperinsulinemia disorder) include those in which: T represents -S(O)-;

Y represents =C(R₁₀)-, preferably, -S(O)₂- or, more preferably, -C(O)-; R₁₀ represents H or, more preferably, alkyl (e.g. methyl or trifluoromethyl); W represents -CR₇R₇-, a bond, or, more preferably, -NR₇-, -NR₇C(O)-, -NR₇C(O)O-, -NR₇C(O)NR₇- or -NR₇S(O)₂-;

R₅ represents optionally substituted (i.e. by B⁷) alkyl (such as C-_I-3 alkyl, e.g. propylene or, preferably, isopropyl or methyl; so forming, for example, a benzyl group), cycloalkyl (e.g. cyclohexyl) or, more preferably represents optionally substituted (i.e. by B¹¹) aryl (e.g. phenyl) or optionally substituted (i.e. by B¹²) heteroaryl (e.g. 2-pyridyl); n represents 3 or O or, more preferably, 1 or 2;

R₈ and R₉ independently represent C₁-₃ (e.g. Ci_-2) alkyl (e.g. methyl) or, more preferably, H;

R₁ represents (e.g. when n represents 1) alkyl or, more preferably -NR₃R₂, -OR₂, -SR₂, -NR₄C(O)R₂, -NR₄C(O)NR₃R₂, -NR₄C(O)OR₂, particularly -C(O)NR₃R₂, -C(O)OR₂, more particularly, optionally substituted (i.e. by B⁶) heteroaryl (e.g. furanyl, such as furan-2-yl or thienyl, such as thien-2-yl) or, especially, optionally substituted (i.e. by B⁵) aryl (e.g. phenyl); when n represents O, then R₁ preferably represents alkyl, such as C_1-3 alkyl (e.g. propyl or methyl), which group is saturated or unsaturated (e.g. contains one or two double bonds, one of which is, for example, directly attached to the requisite 5-membered ring of formula I) so forming, for example, a methenyl (i.e. a =CH₂) or a propdienyl (i.e. =CH-CH=CH-) group, and which group is unsubstituted or, preferably, substituted (e.g. at the terminal position) by one or more (e.g. one) B¹ group (so forming, for example, a -C(OH)(H)- or, preferably, a benzyl group); R₄ represents Ci_-3 (e.g. C_1-2) alkyl (e.g. methyl) or H; R₃ represents Ci_-3 (e.g. Ci_-2) alkyl (e.g. methyl) or, preferably, H; R₂ represents optionally substituted (i.e. by B⁷) alkyl (such as Ci_-3 alkyl, e.g. ethyl or, preferably, methyl; so forming, for example, a benzyl group) or, preferably, optionally substituted (i.e. by B¹¹) aryl (e.g. phenyl) or (e.g. when R₁ represents -C(O)OR₂) H; when W represents -NR₇- and R₇ is absent, then R₆ represents alkyl such as C_1-6 (e.g. C_1-3) alkyl (e.g. methyl) or aryl (e.g. phenyl), both of which may be substituted by one or more of B¹³ or B¹⁵, respectively, or are more preferably unsubstituted, or, more preferably Re represents H; when W represents -NR₇- and R₆ is absent, then R₇ represents C_1-3 (e.g. C_1-2) alky! (e.g. methyl), aryl (e.g. phenyl) or benzyl, all of which may be substituted by one or more B¹³, B¹⁵ and B¹⁶, respectively, or, are more preferably unsubstituted; when W represents -CR₇R₇-, then A₂ represents a double bond; when W represents -CR₇R₇-, then each R₇ independently represents, at each occurrence, Ci_-3 (e.g. C_1-2) alkyl or H;

B¹ to B¹⁸ (and, in particular, B⁵, B⁶, B¹¹ and B¹²) independently represent cyano, HO₂, halo (e.g. chloro, fluoro or bromo), -OR₁₁, -C(O)ORi₆, -C(O)NR_16aRi6b or -S(O)₂NR_16cR_16d; and/or B⁴ to B⁶, B¹⁰ to B¹², B¹⁵, B¹⁶ and B¹⁸ (and, in particular, B⁵, B¹¹ and B¹²) represents R₁₇; and/or

B¹ to B¹⁸ (and, in particular, B¹³ and B¹⁴) independently represent -OR₁₁, -C(O)OR₁₆ or, preferably, halo (e.g. chloro, fluoro or bromo); and/or B¹ to B¹⁸ (and, in particular, B¹ and B⁷) independently represent heteroaryl (e.g. furanyl, such as furan-2-yl or thienyl, such as thien-2-yl) or, preferably, aryl (e.g. phenyl), both of which may be substituted by one or more groups selected from halo (e.g. fluoro) or R₁₇;

R₁₁ represents C_1-3 (e.g. C_1-2) alkyl (e.g. methyl or ethyl) or H; R-₁₆ represents H or C_1-3 (e.g. Ci_-2) alkyl (e.g. ethyl); Ri₆a, R-ieb, Ri_6c and Ri_6d independently represent C_1-2 alkyl or, more preferably, H; Ri₇ represents C_1-4 (e.g. Ci_-3) alkyl (e.g. methyl or isopropyl) optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a trifluoromethyl group).

Most preferably, compounds of the formula I (e.g. compounds that may be useful in the treatment of cancer and/or an excess adiposity/hyperinsulinemia disorder) include those in which:

W represents -NR₇-, -NR₇C(O)- or -NR₇S(O)₂-;

R₁ represents phenyl optionally substituted by B⁵; R₅ represents phenyl optionally substituted by B¹¹;

R_& and R₇ (if present) independently represent hydrogen;

B⁵ represents halo or, preferably, Ri₇;

B¹¹ represents R₁₇ or, preferably, halo (e.g. chloro);

Ri₇ represents Ci_-3 alkyl (e.g. methyl) optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a trifluoromethyl group); when R₁ represent an optionally substituted phenyl group, then it is preferably a trifluoromethylphenyl group (e.g. 3-trifluoromethylphenyl); when R₅ represents an optionally substituted phenyl group, then it is preferably a haiophenyl group (i.e. one in which the phenyl group is substituted with one or more halo substituents), such as monochlorophenyl (e.g. 2-chlorophenyl, 3- chloropheny! or, preferably, 4-chlorophenyl) or dichlorophenyl (e.g. 3,4- dichlorophenyl).

It preferred that: R₁₀ does not represent H; when Y represents =C(R_1Q)-, W does not represent -N(R₇)C(O)-; n represents 1 , 2 or 3;

R₃. R₄, Re and R₇ independently represent, on each occasion when used herein, hydrogen, alky!, cycioalkyl, aryl or benzyl (which latter four groups are optionally substituted by one or more groups selected from B¹³, B¹⁴, B¹⁵ and B¹⁶, respectively;

R-i does not represent H or alkyl as hereinbefore defined;

R₅ does not represent H.

Preferred compounds of formula I (e.g. compounds that may be useful in the treatment of cancer and/or an excess adiposity/hyperinsulinemia disorder) include those in which: when X represents a single bond (i.e. n represents 0) and R₁ represents an optionally substituted alkyl group, then it is preferably saturated; when X does not represent a single bond (i.e. n does not represent 0), then R-i does not represent -NR₃R₂, -OR₂, -SR₃, -NR₄C(O)R₂, -NR₄C(O)NR₃R₂ or

-NR₄C(O)OR₂; when X represents -CH₂-, R₁ represents optionally substituted aryl, W represents

-NR₇-, then: (i) R₅ does not represent alkyl or cycloaikyl; or

(ii) R₅ does not represent hydrogen; when X represents a single bond (i.e. n represents 0) and R₅ represents optionally substituted aryl, then R₁ does not represent an optionally substituted alkyl group or hydrogen; when X represents -CH₂- and R₅ represents optionally substituted aryl, then R₁ does not represent -C(O)NR₃R₂; when X represents -CH₂- and R₅ represents optionally substituted alkyl or aryl, then Ri does not represent -C(O)NRaRa.

Compounds of formula I (e.g. compounds that may be useful in the treatment of cancer) that may be mentioned include those in which: n represents 2 or preferably 1 ; R₈ and R₉ both represent H;

Ri represents aryl (e.g. phenyl) optionally and/or preferably substituted by B⁵; B⁵ represents R-_I7; R₁₇ represents Ci_-4 (e.g. Ci_-3) alkyl (e.g. methyl) optionally and/or preferably substituted by one or more halo (e.g. fluoro) atoms; T represents -S(O)₂- or, preferably, -S(O)-; R₆ represents H.

More preferred compounds of formula I (e.g. compounds that may be useful in the treatment of cancer and/or an excess adiposity/hyperinsulinemia disorder) include: i-oxo-S-fS-^rifluoromethyObenzyO^S^-dichlorophenyOsulfonyliminothiazol-iciin- 4-one; 1 ,1 -dioxo-5-(3-(trifluoromethyl)benzyl)-2-(3,4-dichlorophenyl)sulfonyliminothiazol- idin-4-one;

2-chlorophenyl 1-oxo-5-(3-(trifluoromethyl)benzyl)-4-oxothiazolidin-2~ylidenecarb- amate;

2-chlorophenyl 1 , 1 ,-dioxo-5-(3-(trifluoromethyl)benzyI)-4-oxothiazolidin-2-ylidene- carbamate; and, preferably,

1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(3,4-dichlorophenylimino)-1λ⁴-thiazoiidin-4- one;

1 ,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(3,4-dichlorophenylimino)-1λ⁶-thiazol- idin-4-one; [5-(3-trifluoromethylbenzyl)-1 , 1,4-trioxo-1λ⁶-4λ⁴-[1 ,4_J2]dithiazolidin-3-ylidene]-(3,4- dichloro)phenyl-2-amine;

[5-(3-trifluoromethylbenzyl)-1 , 1 ,4,4-tetraoxo-1 λ⁶-4λ⁶-[1 ,4,2]dithiazolidin-3-ylidene]- (3,4-dichloro)pheny!-2-amine;

[5-(3-trifluoromethylbenzyl)-1 , 1 ,4-trioxo-1 λ^δ-4λ⁴-[1 ,4,2]dithiazolidin-3-ylidene]-(4- chloro)phenyl-2-amine; [5-(3-trifluoromethylbenzyf}-1 ,1 ,4,4-tetraoxo-1λ⁶-4λ⁶-[1 ,4,2]dithiazolidin-3-ylidene]- (4-ch)oro)phenyl-2-amine; and, more preferably; 1-oxo-5-(4-fluorobenzyl)-2-(pyridin~2-ylirnino)thiazolidin-4-one; 1 ,1-dioxo-5-(4-fluorobenzyI)-2-(pyridin-2-yIimino)thia2olidin-4-one; 1-oxo-5-(4-methylbenzyl)-2-(4-chlorophenylimino)thiazolidin-4-one; 1 , 1 -dioxo-5-(4-methylbenzyl)-2-(4-chlorophenylimino)thiazolidin-4-one; 1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(p-tolylimino)thiazolidin-4-one; 1,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(p-tolylimino)thiazolidin-4-one; 1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenylimino)thiazolidin-4-one; 1,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenylimino)thiazolidin-4-one; 1-oxo-5-(3-(trifluoromethyl)benzyI)-2-(4-isopropylphenylimino)thiazolidin-4-one; 1 ,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(4-isopropylphenylimino)thiazolidin-4- one;

1-oxo-5-(3-(trifluoromethyI)benzyl)-2-(4-methoxyphenylimino)thiazolidin-4-one; 1 ,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(4-methoxyphenylimiπo)thiazolidin-4- one;

1-oxo-5-(3-(trifluoromethyl)benzy!)-2-(phenylimino)thiazolidin-4-one; 1 , 1 -dioxo-δ^S-^rifiuoromethyObenzyO^-CphenyliminoJthiazolidin^-one; i-oxo^S^-dichlorophenylimino^δ^S-^rifluoromethyObenzyOthiazolidin^-one; i .i-dioxo^S^-dichlorophenyliminoJ-S^S-CtrifluoromethyObenzylJthiazolidin^- one;

1-oxo-2-(2,4-dich!orophenylimino)-5-(3-(trifluoromethyl)benzyl)thiazolidin-4-one; 1 , 1 -dioxo-2-(2,4-dichlorophenylimino)-5-(3-(trifluoromethyl)benzy!)thiazolidin-4- one; 1-oxo-5-(3-(trifluoromethyl)benzyI)-2-(p-tolylimino)-3-methylthiazolidin-4-one; 1 , 1 -dioxo-5-(3-(trifluoromethyl)benzyi)-2-(p-tolylimino)-3-methylthiazolidin-4-one; 1-oxo-N-(5-(3-(trifluoromethyl)benzyl)-4-oxothiazolidin-2-yIidene)-4-chlorobenz- amide;

1 , 1 -dioxo-N-(5-(3-(trifluoromethyI)benzyl)-4-oxothiazoIidin-2-ylidene)-4-chloro- benzamide;

1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenyl)sulfonyliminothiazolidin-4- one;

1,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenyl)suIfonyliminothiazolidin- 4-one; phenyl 5-(3-(trifluoromethyl)benzyl)-1 ,4-dioxothiazolidin-2-ylidenecarbamate; phenyl 5-(3-(trifluoromethyl)benzyl)-1 , 1 ,4-trioxothiazolidin-2-ylidenecarbamate; 1-oxo-5-(4-methoxyphenethyl)-2-(p~toIyiimino)thiazoiidin-4-one; 1 , 1 -dioxo-5-(4-methoxyphenethyI)-2-(p-to)ylimino)thiazolidin-4-one; 1-oxo-5-(4-methoxyphenethyl)-2-(phenylimino)thiazolidin-4-one; 1 ,1-dioxo-5-(4-methoxyphenethyl)-2-(phenylimino)thiazoIidin-4-one; 1 -oxo-2-(p-tolylimino)-5-phenethylthiazolidin-4-one; 1 ,1-dioxo-2-(p-tolyiimino)-5-phenethylthiazolidin-4-one.

Particularly preferred compounds of formula I include:

1-oxo-5-(3-(trifluoromethyl)benzyI)-2-(3,4-dichloropheny!)su!fonyliminothiazol-idin- 4-one;

1 ,1-dioxo-5-(3-(tπfluoromethyl)benzyl)-2-(3,4-dichlorophenyl)sulfonyliminothi- azolidin-4-one;

2-chlorophenyl 1-oxo-5-(3-(trifluoromethyl)benzyl)-4-oxothiazolidin-2-ylidene- carbamate; 2-chlorophenyl 1 ,1,-dioxo-5-(3-(trifluoromethyl)benzy[)-4-oxothiazolidin-2-ylidene- carbamate; and, particularly,

1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenyl)sulfonyliminothiazolidin-4- one;

1 ,1-dioxo-5-(3-(trifluoromethyl)benzyI)-2-(4-chlorophenyl)sulfonyliminothiazolidin- 4-one;

1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(3,4-dichlorophenylimino)-1λ⁴-thiazolidin-4- one; i .i-dioxo-δ^S-^rifluoromethyObenzyO^-CS^-dichlorophenylimino^iλ^thiazol- idin-4-one; [5-(3-trifluoromethylbenzyl)-1,1 ₎4-trioxo-1λ⁶-4λ⁴-[1 ,4,2]dithiazolidin-3-ylidene]-(3,4- dichloro)phenyl-2-amine;

[5-(3-trifluoromethylbenzyl)-1 , 1 ,4,4-tetraoxo-1λ⁶-4λ⁶-[1 ,4,2]dithiazolidin-3-ylidene]- (3,4-dichloro)phenyl-2-amine;

[5-(3-trifluoromethylbenzyl)-1 ,1 ,4-trioxo-1λ⁶-4λ⁴-[1 ,4,2]dithiazolidin-3-ylidene]-(4- chloro)phenyl-2-amine;

[5-(34rifluoromethylbenzyl)-1 ,1 ,4,4-tetraoxo-1λ⁶-4λ⁶-[1 ,4,2]dithiazolidin-3-ylidene]- (4-chloro)phenyl-2-amine; and, more particularly, 1-oxo-5-(4-fluorobenzyl)-2-(pyridin-2-ylimino)thiazolidin-4-one; 1 , 1 -dioxo-5-(4-fluorobenzyl)-2-(pyridin-2-ylimino)thiazolidin-4-one; 1-oxo-5-(3-(trifluoromethyl)benzyI)-2-(4-chlorophenylimino)thiazolidin-4-one; 1 ,1-dioxo-5-(3-(thfluoromethyl)benzyl)-2-(4-chlorophenylimino)thiazolidin-4-one; 1-oxo-5-(3-(trifiuoromethyl)benzyI)-2-(p-tolylimino)thiazolidin-4-one; 1 , 1 -dioxo-5-(3-(trifluoromethyl)benzyl)-2-(p-tolylimino)thiazolidin-4-one 1-oxo-5-(4-methoxyphenethyl)-2-(p-tolyiimino)thiazolidin-4-one; 1 , 1 -dioxo-5-(4-methoxyphenethyl)-2-(p-tolylimino)thiazolidin-4-one; 1-oxo-5-(4-methoxyphenethyI)-2-(phenylimino)thiazolidin-4-one; 1 , 1 -dioxo-5-(4-methoxyphenethyl)-2-(phenylimino)thiazolidin-4-one 1-oxo-2-(p-tolylimino)-5-phenethylthiazolidin-4-one; and 1 , 1 -dioxo-2-(p-tolylimino)-5-phenethylthiazolidin-4-one.

Especially preferred compounds of formula I include:

1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenyl)sulfonyliminothiazolidin-4- one;

1 , 1 -dioxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenyl)sulfonyliminothiazolidin- 4-one; 2-chlorophenyl 1 -oxo-δ-CS-CtrifluoromethyObenzyO^-oxothiazolidin^-ylidene- carbamate;

2-chlorophenyl 1 ,1,-dioxo-5-(3-(trifluoromethyl)benzyl)-4-oxothiazolidin-2-ylidene- carbamate;

1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(3,4-dichlorophenylimino)-1λ⁴-thiazolidin-4- one;

1 ,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(3,4-dichlorophenylimino)-1λ⁶-thiazol- idin-4-one;

[5-(3-trifluoromethylbenzyl)-1 , 1 ,4-trioxo-i λ⁶-4λ⁴-[1 ,4,2]dithiazolidin-3-ylidene]-(3,4- dichloro)phenyl-2-amine; [5-(3-trifluoromethylbenzyl)-1,1,4,4-tetraoxo-1λ⁶-4λ⁶-[1 ,4,2]dithiazolidin-3-ylidene]- (3,4-dichloro)phenyl-2-amine;

[5-(3-trifluoromethylbenzyl)-1 ,1 ,4-trioxo-1λ⁶-4λ⁴-[1 ,4,2]dithiazolidin-3-ylidene]-(4- chloro)phenyl-2-amine;

[5-(3-trifluoromethylbenzyl)-1,1,4,4-tetraoxo-1λ⁶-4λ⁶-[1 ,4₎2]dithiazolidin-3-ylidene]- (4-chloro)phenyl-2-amine; i-oxo-δ^S-^rifluoromethyObenzyO^S^-dichlorophenyOsulfonyliminothiazolidin- 4-one; i .i-dioxo-δ^S-^rifluoromethyObenzyl^^S^-dichlorophenyOsulfonyliminothiazol- idin-4-one; and, more particularly, 1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenylimino)thiazolidin-4-one; and 1,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenylimino)thiazolidin-4-one. Compounds of formula I may be prepared from compounds corresponding to compounds of formula I in which T represents -S- rather than -S(O)- or -S(O)₂-, for example by oxidation in the presence of an appropriate amount of a suitable oxidising agent (e.g. mCPBA, hydrogen peroxide, potassium permanganate or potassium peroxymonosulfate) and an appropriate organic solvent (e.g. CH₂CI₂, methanol, water or mixtures thereof), optionally in the presence of a suitable protic acid (e.g. acetic acid), and optionally in an inert atmosphere (e.g. under nitrogen).

Compounds corresponding to compounds of formula I in which T represent -S- may be known and/or may be commercially available. Other such compounds (e.g. those that are not commercially available) may be prepared in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.

For example:

(i) for such compounds in which Y represents -C(O)-, W represents -NR₇, and Ai represents a double bond (and R₇ is therefore absent), reaction of either:

(A) a compound of formula II,

(B) a compound of formula III,

wherein R^a represents Ci_-6 alkyl (e.g. methyl or, preferably, ethyl; so forming an ester group), L¹ represents a suitable leaving group, such as a sulfonate group (e.g. mesylate or, preferably, tosylate) or, for example preferably, halo (e.g. bromo or chloro); or

(C) a compound of formula IV,

wherein, in all cases, X and R₁ are as hereinbefore defined,

with, in each case, a compound of formula V₁

wherein T^a represents S and R₅ and R_& are as hereinbefore defined, under reaction conditions known to those skilled in the art, for example for reaction (A) above conditions such as those described in Blanchet et al, Tetrahedron Letters, 2004, 45, 4449-4452; for reaction (B) above, conditions such as those described in St. Laurent et al, Tetrahedron Letters, 2004, 45, 1907-1910; K. Arakawa et al., Chem. Pharm. Bull. 1997, 45, 1984-1993; A. Mustafa, W. Musker, A.F.A.M. Shalaby, A.H. Harhash, R. Daguer, Tetrahedron 1964, 20; 25-31 ; or P. Herold, A. F. Indolese, M. Studer, H. P. Jalett, U. Siegrist, H. U. Blaser, Tetrahedron 2000, 56, 6497-6499 and for reaction (C) above, conditions such as those described in Le Martchalal et al, Tetrahedron 1990, 46, 453-464;

(ii) for such compounds in which Y represents -S(O)₂-, W represents -NR₇-, and A₁ represents a double bond (and R₇ is therefore absent), X represents -[RsRg]_n- in which n represents 0 and R-i represents H, reaction of a compound of formula Vl,

wherein L² represents a suitable leaving group, such as halo (e.g. chloro), with a compound of formula VII,

R₅-N=C=T³ VII

wherein T is as hereinbefore defined and R₅ is as hereinbefore defined under conditions known to those skilled in the art, for example such as those described in Zbirovsky and Seifert, Coll. Czech. Chem. Commun. 1977, 42, 2672-2679 or Von Zaki El-Heweri, Franz Runge, Journal fur praktische Chemie, 4, Band 16, 1962, e.g. in the presence of base (e.g. an aqueous solution of NaOH) in an appropriate solvent (e.g. acetone), for example at elevated temperature (e.g. 50°);

(iii) for such compounds in which A₁ represents a double bond (and R₇ is therefore absent), X represents -[RsRg]_n- in which n represents 1, 2 or 3 and Ri is as hereinbefore defined and, preferably, Y represents -S(O)₂- and/or W represents -NR₇-, reaction of a corresponding compound in which n represents 0 and R₁ represents hydrogen, with a compound of formula VIII,

R_1a-X^a-L³ VIII

wherein X^a represents -[R₈Rg]_n- in which n represents 1, 2 or 3 and R_{1 a} represents R₁ as hereinbefore defined, or n represent 0 and R_1a represents R₁ as hereinbefore defined provided that it does not represent hydrogen, aryl or heteroaryl, and L³ represents a suitable leaving group (e.g. a halo, such as chloro, iodo or, preferably, bromo, or a sulfonate group), under reaction conditions known to those skilled in the art, for example, in the presence of a suitable base (e.g. an organometallic base (e.g. an organolithium), an alkali metal base (e.g. sodium hydride) or an amide salt (e.g. (Me₃Si)₂NNa) and the like) and a suitable solvent (e.g. tetrhydrofuran, dimethylformamide, dimethlysulfoxide or the like) at room temperature or below (such as at sub-zero temperatures (e.g. -78⁰C)). For example, for the synthesis of such compounds in which Y represents -S(O)₂- and/or W represents -NR₇, reaction conditions include those described in the journal article mentioned in respect of process step (ii) above;

(iv) for such compounds in which n represents 0 and R₁ represents alkenyl optionally substituted as hereinbefore defined (i.e. by B¹) in which one double bond of the alkenyl group is directly attached to the requisite ring or Ri represents alkyl substituted with a -OH group α to the point of attachment of the said alkyl group to the requisite ring and which alkyl group is optionally further substituted as hereinbefore defined (i.e. by B¹) and, in both cases, W represents -NR₇C(O)-, -NR₇S(O)₂-, -NR₇C(O)NR₇-, -NR₇C(O)O- or -NR₇-, -CR₇R₇- or a bond, reaction of a corresponding compound in which n represents O and R-i represents H with a compound of formula IX₁

R_1b=0 IX

wherein Ri_b represents alkyl optionally substituted by B¹ as hereinbefore defined, under standard reactions conditions known to those skilled in the art. For example for the preparation of compounds in which Ri represents alkenyl as defined above, under standard dehydration conditions, e.g. in the presence of a suitable base (such as NaOAc or an appropriate base described hereinafter in respect of process step (vii)) in the presence of a suitable solvent (e.g. glacial acetic acid), e.g. as described in A. Mustafa, W. Musker, A.F.A.M. Shalaby, A.H. Harhash, R. Daguer, Tetrahedron 1964, 20, 25-31. For the preparation of compounds in which R₁ represents alkyl substituted by -OH as defined above, reaction in the presence of a suitable base (e.g. lithium diisopropylamide or another suitable base described in process step (vii) below) in the presence of an appropriate solvent (e.g. anhydrous THF) at room temperature or below (e.g. about O⁰C) under an inert atmosphere. The skilled person will appreciate that for preparation of compounds in which R-i represents optionally substituted alkenyl as described above, this may involve an intermediate which is the above- mentioned compound in which R-i represents alkyl substituted by -OH as defined above (which intermediate may be isolable), which intermediate may need to be transformed to the alkenyl group separately, for example by converting the -OH group to a better leaving group, for example by reaction with trifluoroacetic anhydride or the like optionally in the presence of a suitable base (e.g. triethylamine) and a catalyst (e.g. DMAP) in an appropriate solvent (e.g. dichloromethane) at below room temperature (such as at about 0°C) e.g. employing conditions described in Zbirovsky and Seifert, Coll. Czech. Chem. Commun. 1977, 42, 2672-2679;

(v) for such compounds in which n represents 0 and R-] represents saturated alky! optionally substituted (i.e. by B¹) as hereinbefore defined, Y represents -S(O)₂ or, preferably, -C(O)- or =C(R₁₀)- as hereinbefore defined, reduction of a corresponding compound in which Ri represents optionally substituted unsaturated alkyl, under standard reaction conditions, for example in the presence of a suitable (e.g. chemoselective) reducing agent such as LiBH₄ or NaBH₄ optionally in the presence of a suitable solvent such as a THF or pyridine (or a mixture thereof, e.g. as described in R.G. Giles, N.J. Lewis, J. K. Quick, M.J. Sasse, M.W.J. Urquhart, L. Youssef, Tetrahedron 2000; 56, 4531-4537). The skilled person will appreciate that the choice of the reducing agent is important in order to achieve the desired reduction selectively (i.e. whilst not reducing other functional groups, such as carbonyl groups, in the relevant compound). Alternative methods include reduction by hydrogenation under standard conditions, for example in the presence of hydrogen gas or nascent hydrogen, an appropriate solvent (e.g. an alcoholic solvent) and catalyst (e.g. Pd/C);

(vi) for such compounds in which R₆ is alkyl, cycloalkyl or benzyl, all of which are optionally substituted as hereinbefore defined, reaction of a corresponding compound in which R₆ represents H, with a compound of formula X,

R₆₃L⁴ X

wherein R_6a represents alkyl, cycloalkyl or benzyl (e.g. which are optionally substituted by one or more groups selected from B¹³, B¹⁴ or B¹⁶, respectively) and L⁴ represents a suitable leaving group such as halo (e.g. iodo or bromo) or a sulfonate group, under standard reaction conditions, for example at around room temperature, in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1 ,8- diazabicyc!o[5.4.0]undec-7-ene, sodium hydroxide, or mixtures thereof), an appropriate solvent (e.g. pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, triethylamine, dimethylsulfoxide, water or mixtures thereof) and, in the case of Diphasic reaction conditions, optionally in the presence of a phase transfer catalyst;

(vii) for such compounds that are substituted with at least one of B¹ to B¹⁸ that represents a -C(O)NR_16aR_16b group, reaction of a corresponding compound in which that/those (as appropriate) B¹ to B¹⁸ substituents represent -C(O)ORi₆, with a compound of formula Xl,

or a protected derivative (e.g. a salt) thereof, wherein Ri_6a and R-iβb . are as hereinbefore defined, for example under standard coupling reaction conditions. For example, in the case where Ri₆ represents H, in the presence of a suitable coupling reagent (e.g. 1,1'-carbonyldiimidazole, Λ/,Λ/'-dicyclohexylcarbodiimide, 1- (3-dimethylamino-propyl)-3-ethylcarbodiimide (or hydrochloride thereof), Λ/.Λ/¹- disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 2-(1/-/-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexa- fluorophosphate, benzotriazo!-1 -yioxytris-pyrrolidinophosphonium hexafluoro- phosphate, bromo-tris-pyrrolidinophosponium hexafluorophosphate, 2-(1H- benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetra-fluorocarbonate) or ^"1- cyclohexylcarbodiimide-3-propyloxymethyl polystyrene, a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, N- ethyldiisopropylamine, Λ/-(methylpolystyrene)-4-(methylamino)pyridine, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium te/f-butoxide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine or mixtures thereof) and an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichioromethane, chloroform, acetonitrile or dimethylformamide). Alternatively, for example in the case where R₁₆ is other than H (i.e. -C(O)ORi₆ represents an ester group), the reaction may be performed in the presence of an appropriate reagent (e.g. trimethylaluminium) in the presence of a suitable solvent (e.g. benzene), for example at elevated temperature (e.g. about 60⁰C), e.g. as described in Hwang, K.-J.; O'Neil, J. -P.; Katzenellenbogen, J. A. J. Org. Chem. 1992, 57, 1262; (viii) for such compounds in which W represents -NR₇C(O)-, -NR₇S(O)₂-, -NR₇C(O)NR₇- or -NR₇C(O)O-, reaction of a corresponding compound in which W represents -NR₇- and R₅ represents H, with a compound of formula XII,

L⁵WR₅ XII

wherein W^x represents -C(O)-, -S(O)₂, -C(O)NR₇- or -C(O)O-, L⁵ represents a suitable leaving group such as halo (e.g. chloro) and R₅ is as hereinbefore defined, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (e.g. NaH, NaOH, triethylamine, pyridine, another suitable base mentioned at process step (vii) above or mixtures thereof) and solvent (e.g. pyridine (which may serve as the base and solvent) DMF or dichloromethane (e.g. further in the presence of water and, optionally, a phase transfer catalyst)) for example at room temperature e.g. as described in Hurst, D. T.; Stacey, A. D., Nethercleft, M., Rahim, A., Harnden, M. R. Aust. J. Chem. 1998, 41, 1221; or

(ix) for such compounds in which W represents -NR₇C(O)NH-, reaction of a corresponding compound in which W represents -NR₇- and R₅ represents H, with a compound of formula XIII,

R₅-N=C=O XIII

wherein R₅ is as hereinbefore defined, under standard conditions, for example, in the presence of a suitable solvent (e.g. a polar aprotic solvent such as toluene) and at elevated temperature (e.g. reflux), for example as described in the journal article mentioned in respect of process (viii) above.

Compounds of formula Il may be prepared by reaction of a compound of formula XIV,

R₁-X-C(O)H XIV

wherein R₁ and X are as hereinbefore defined, with trichloroacetic acid under standard conditions known to those skilled in the art, for example such as those described in the journal article mentioned in respect of process step (i) (part (A)) above.

Compounds of formula ill may be commercially available, prepared under standard conditions or, for those compounds in which X represents -CH₂-, Ri represents aryl or heteroaryl optionally substituted as hereinbefore defined and L¹ represents a halo group, reaction of a compound of formula XV,

R₁₀NH₂ XV

wherein R_{1 c} represents aryl or heteroaryl (e.g. optionally substituted by B⁵ and B⁶) to form the corresponding diazonium salt (for example by reaction with sodium nitrite at low temperatures such as at about 0⁰C) followed by reaction with a compound of formula XVI,

R^a-OC(O)CH=CH₂ XVI

wherein R^a is as defined above, in the presence of a suitable solvent (e.g. acetone) and a hydrohalic acid which is preferably concentrated (e.g. in the case where L¹ represents chloro, concentrated hydrochloric acid) optionally in the presence of an agent that aids the Michael addition of the halide onto the acrylafe/enone such as cuprous oxide.

Compounds of formula ill in which L¹ represents a sulfonate group (e.g. a toslyate or mesylate) may be prepared by reaction of a compound corresponding to a compound of formula III but in which L¹ represents -OH with an appropriate sulfonyl chloride (e.g. tosyl chloride or mesyl chloride) under standard conditions known to those skilled in the art, such as those described in respect of preparation of the precursors to compounds of formula I above (process step (vi) above).

Compounds of formula Vl may be prepared by reaction of a compound of formula XVII,

wherein L⁶ represents a suitable leaving group such as halo (e.g. chloro) and L² is as hereinbefore defined, with ammonia (e.g. in gaseous or other form) for example under standard conditions known to those skilled in the art, such as those described in respect of preparation of the precursors to compounds of formula I above (process step (vi) above) or, preferably, in the presence of diethyl ether at low temperature (e.g. about 0⁰C) in which case the skilled person will appreciate that the ammonia additionally serves as a base.

Compounds of formulae IV, V, VII, VIII, IX, X, Xl, XII, XIII, XIV₁ XV, XVI and XVII (and also certain compounds of formulae II, III and Vl) 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.

Substituents, such as R-,, R₅, R₆, X, W and Y in final compounds of formula I (or precursors thereto and other relevant intermediates) may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, and etherifications. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.

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 Chemistrf, 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-, aminofunction, carboxylic acid and, in the case of protected functional groups, lower alkoxy, N-, O-, S- acetyl, carboxylic acid ester.

Medical and Pharmaceutical Uses

Compounds of formula I are indicated as pharmaceuticals. According to a further aspect 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. Furthermore, 2-chlorophenyl 5- (3-(trifluoromethyl)benzyl)-4-oxothiazolidin-2-ylidenecarbamate (Compound 23), described hereinafter as an intermediate to certain compounds of formula I may also be useful itself as a pharmaceutical. Hence, according to a further aspect of the invention, there is provided Compound 23, as defined hereinafter, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for use as a pharmaceutical. Compounds of formula I (and Compound 23) may reduce the rate of cell proliferation (e.g. they may modulate (e.g. antagonize) the stimulatory effect of FFAs on cell proliferation) when tested in an assay using a human breast cancer cell line (e.g. MDA-MB-231 ). The compounds may thus possess a beneficial inhibitory effect on the ability of tumors of this type, and of cancers generally, to survive. Also, as the assay may be conducted in the presence of linolenic acid, the compounds may act as FFA modulators.

Such compounds are therefore indicated for use in the treatment of cancer, and/or a disorder or a condition caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity and/or hyperinsulinemia.

According to a further aspect of the invention, there is provided the use of a compound of formula I (or Compound 23), or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for the manufacture of a medicament for the treatment of cancer, and/or a disorder or condition caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity and/or hyperinsulinemia.

The term "cancer" will be understood by those skilled in the art to include one or more diseases in the class of disorders that is characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion, proliferation or by implantation into distant sites by metastasis.

In a preferred embodiment, compounds of formula I (or Compound 23) are capable of inhibiting the proliferation of cancer cells. By "proliferation" we include an increase in the number and/or size of cancer cells.

Alternatively, or preferably in addition, such compounds are capable of inhibiting metastasis of cancer cells.

By "metastasis" we mean the movement or migration (e.g. invasiveness) of cancer cells from a primary tumour site in the body of a subject to one or more other areas within the subject's body (where the cells can then form secondary tumours). Thus, in one embodiment the invention provides compounds and methods for inhibiting, in whole or in part, the formation of secondary tumours in a subject with cancer. It will be appreciated by skilled persons that the effect of a compound of formula I on "metastasis" is distinct from any effect such a compound may or may not have on cancer cell proliferation.

Advantageously, compounds of formula I (or Compound 23) may be capable of inhibiting the proliferation and/or metastasis of cancer cells selectively.

By "selectively" we mean that the combination product inhibits the proliferation and/or metastasis of cancer cells to a greater extent than it modulates the function (e.g. proliferation) of non-cancer cells. Preferably, the compound inhibits the proliferation and/or metastasis of cancer cells only.

Compounds of formula I (or Compound 23) may be suitable for use in the treatment of any cancer type, including all solid tumors. For example, the cancer cells may be selected from the group consisting of cancer cells of the breast, bile duct, brain, colon, stomach, reproductive organs, thyroid, hematopoetic system, lung and airways, skin, gallbladder, liver, nasopharynx, nerve cells, kidney, prostate, lymph glands and gastrointestinal tract. Preferably, the cancer is selected from the group of colon cancer (including colorectal adenomas), breast cancer (e.g. postmenopausal breast cancer), endometrial cancer, cancers of the hematopoetic system (e.g. leukemia, lymphoma, etc), thyroid cancer, kidney cancer, oesophageal adenocarcinoma, ovarian cancer, prostate cancer, pancreatic cancer, gallbladder cancer, liver cancer and cervical cancer. More preferably, the cancer is selected from the group of colon, prostate and, particularly, breast cancer.

Preferably, the cancer cells are breast cancer cells.

The term "disorder or condition caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity and/or hyperinsulinemia" 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 renat failure.

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

Certain compounds of formula I (or Compound 23) 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 cancer, and/or a disorder or a condition caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity and/or hyperinsulinemia, which method comprises the administration of an effective amount of a compound of formula I (or Compound 23), or a pharmaceutically- acceptable salt or solvate, or a pharmaceutically functional derivative thereof, to a patient in need of such treatment.

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, cancer, and/or disorders or conditions caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity and/or hyperinsulinemia.

"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 (or Compound 23) may be administered alone, but are preferably administered orally, intravenously, intramuscularly, cutaneously, subcutaneously, transmucosally (e.g. sublingually or buccally), rectally, transdermal^, 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 (or Compound 23) 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 Compound 23), 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 (or Compound 23) 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 (or Compound 23) 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 I₁ or Compound 23, (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 (or Compound 23) may be used or administered in combination with one or more additional drugs useful in the treatment of cancer, in combination therapy. According to a further aspect of the invention, there is provided a combination product comprising:

(A) a compound of formula I (or Compound 23); and

(B) another therapeutic agent useful in the treatment of cancer, 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 cancer include standard cancer therapies, such as cytostatica, irradiation, photodynamic therapy, etc.

It is preferred that the other therapeutic agent is a cytostatic (such as a taxane (e.g. docetaxel and, particularly, paclitaxel) or preferably, a platin (e.g. cisplatin and carboplatin) or an anthracycline (e.g. doxorubicin)) or an angiogenesis inhibitor, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative of either of these. However, the other therapeutic agent may also be selected from:

(i) tamoxifen, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;

(ii) an aromatase inhibitor (i.e. a compound that blocks the production of estrogen from adrenal androgens via the aromatase pathway in peripheral tissues), or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof. Preferred AIs include anastrozole, letrozole and exemastane;

(iii) trastuzumab (Herceptin), or another antibody that is useful in the treatment of cancer, such as bevacizumab, cetuximab or panitumumab;

(iv) a tyrosine kinase inhibitor (i.e. a compound that blocks (or is capable of blocking), to a measurable degree, the autophosphorylation of tyrosine residues, thereby preventing activation of the intracellular signalling pathways in tumor cells), or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof. Preferred TKIs include inhibitors of the vascular endothelial growth factor (VEGF) family, and/or the HER-family of TKs, such as HER-1/Human Epidermal Growth Factor (EGFR; erbB1 ), HER3 (erbB3), HER4 (erbB4) and, more particularly, HER2 (erbB2). Preferred TKIs thus include imatinib, gefitinib, erlotinib, canertinib, sunitinib, zactima, vatalanib, sorafenib, leflunomide and, particularly, lapatinib; (v) a glitazone (such as rosiglitazone), or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (vi) metformin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (vii) a statin, such as fluvastatin, simvastatin, rosuvastatin, pravastatin, atorvastatin and, particularly, lovastatin, or a pharmaceutically- acceptable salt, solvate or pharmaceutically functional derivative thereof; and/or

(viii) an inhibitor of activity of the mammalian target of rapamycin (mTOR), such as rapamycin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof.

It has recently been suggested in the literature (see, for example, MoI. Cancer Then, 5, 430 (2006), Cancer Res., 66, 10269 (2006) and Int. J. Cancer, 118, 773 (2006)) that the above mentioned compound classes (v) to (vii) may be used in the treatment of cancer, as described herein.

When the other therapeutic agent is (particularly) in category (i) or (ii) above, combination products according to the invention are particularly useful in the treatment of ER-positive cancers and/or early-stage breast cancers, for example in adjuvant therapy (i.e. reducing the risk of the cancer coming back after surgery), in neo-adjuvant therapy (before surgery, to shrink a large breast cancer so that a lumpectomy is possible), in the control of breast cancers that have come back after initial treatment, or in the control of breast cancers that cannot be removed when first diagnosed. Such combination products according to the invention are also particularly useful in the treatment of patients at a high risk of breast cancer.

When the other therapeutic agent is (particularly) in category (iii) or (iv) above, combination products according to the invention are particularly useful in the treatment of HER2-positive cancers.

Pharmaceutically-acceptable salts, solvates or pharmaceutically functional derivatives of any of the. compounds listed in categories (i), (ii) and (iv) to (viii) above are as described hereinbefore. In particular, when the other therapeutic agent is tamoxifen, preferred pharmaceutically-acceptable salts include those of citric acid, when the other therapeutic agent is imatinib, preferred pharmaceutically-acceptable salts include mesylate salts and when the other therapeutic agent is sunitinib, preferred pharmaceutically-acceptable salts include maleate salts.

The compounds of formula I (or Compound 23) may also be used or administered in combination with one or more additional drugs useful in the treatment of disorders or conditions caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity and/or hyperinsulinemia, in combination therapy.

According to a further aspect of the invention, there is provided a combination product comprising:

(A) a compound of formula I (or Compound 23); and

(B) another therapeutic agent useful in the treatment of a disorder or a condition caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity and/or hyperinsulinemia, 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 disorders or conditions caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity (such as hyperinsulinemia and type 2 diabetes) will be well known to those skilled in the art and include insulin, insulin secretagogues (such as sulphonylureas), metformin, peroxisome proliferator-activated receptor (PPAR) agonists (such as thiazolidinediones), α-glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, exenatide, and inhibitors of 11-β hydroxysteroid dehydrogenase type 1. By "agonist" we include direct and indirect-acting agonists.

In one embodiment, the other therapeutic agent useful in the treatment of useful in the treatment of a disorder or a condition caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity (such as hyperinsulinemia and type

2 diabetes) 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 BJM51077 (Ipsen and Roche)), DPP-IV resistant GLP-1 analogues (for example LY315902 and LY30761 SR (Lilly)), long acting GLP-1 derivatives (such as NN2211 (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 a condition caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity (such as hyperinsulinemia and type 2 diabetes) may comprise a dipeptidyl peptidase IV (DPP-(V) inhibitor. For example, the agent may be selected from the group consisting of Vildagliptin (LAF237), MK- 0431-Sitagiiptin and Saxagliptin.

In a further alternative embodiment, the other therapeutic agent useful in the treatment of useful in the treatment of a disorder or a condition caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity (such as hyperinsulinemia and type 2 diabetes) 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 GlP (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 useful in the treatment of a disorder or a conditions caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity (such as hyperinsulinemia and type 2 diabetes) may comprise a selective inhibitor of 11 -β hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme associated with conversion of cortisone to Cortisol in the liver and adipose tissue. Examples of suitable 11β-HSD1 inhibitors/antagonists include AMG221 (developed by Amgen) and BVT83370 (developed by Biovitrum).

Combination products as described herein provide for the administration of compound of formula I (or Compound 23) 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 (or Compound 23), 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 (or Compound 23) and the other therapeutic agent).

Thus, there is further provided:

(1) pharmaceutical formulations including a compound of formula I (or Compound 23); another therapeutic agent useful in the treatment of cancer, and/or in the treatment of a disorder or a condition caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity and/or hyperinsulinemia; 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 (or Compound 23) in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation including another therapeutic agent useful in the treatment of cancer, and/or in the treatment of a disorder or a condition caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity and/or hyperinsulinemia, 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 aspect 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 (or Compound

23) 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 (or Compound 23) 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 the invention, the term "administration in conjunction with" includes that the two components of the combination product (compound of formula I (or Compound 23) 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 Compound 23), 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 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 (or Compound 23) 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 cancer, and/or disorders or conditions caused by, linked to, or contributed to by, FFAs and, in particular, excess adiposity and/or hyperinsulinemia, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, 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 and WO 2007/010281.

Examples

The invention is illustrated by the following examples, in which the following abbreviations may be employed:

DMF dimethylformamide

ES electro spray

EtOAc ethyl acetate

LC liquid chromatography m-CPBA mefø-chloroperbenzoic acid MS mass spectrometry

NMR nuclear magnetic resonance THF tetrahydrofuran tic thin layer chromatography

Where no preparative routes are includes, 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 mL/min. Two gradient systems of acetonitrile in water (with 0.1% TFA) were 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.

Intermediates

Compound 1

5-(4-Methylbenzyl)-2-(4-chlorophenylimino)thiazolidin-4-one

Compound 2 5-(3-(Trifluoromethyl)benzyl)-2-(p-tolylimino)thiazolidin-4-one

(a) Methyl 2-chloro-3-(3-(trifluoromethy0phenyl)propanoate A solution of sodium nitrite (0.47 g, 6.82 mmol) in water (1.4 mL) was added drop-wise to a solution of 3-trifluoromethylaniline (0.77 mL, 6.21 mmol) in concentrated hydrochloric acid and acetone (14 mL), which mixture was prior cooled under an ice-water bath. The mixture was stirred at O⁰C for 10 min. After addition of methyl acrylate (3.37 mL, 37.4 mmol), cuprous oxide (40 mg) was added portionwise to the mixture at 40⁰C. The mixture was stirred at 35⁰C for 20 min and then washed twice with equal amounts of water and ethyl acetate (50 mL). The organic layer was dried with MgSO₄, filtered and concentrated. The crude oil was purified by silica gel chromatography using chloroform as eluent to give the sub-title compound (1.22 g, 4.58 mmol, 74%) as yellow oil. ES-MS m/z 289.1 (MNa+). ¹H NMR: S(CDCI₃): 3.24 (dd, 1 H), 3.43 (dd, 1 H), 3.76 (s, 3H)₁ 4.46 (dd, 1H), 7.4-7.6 (m, 4H).

(b) 5-(3-(Trifluoromethyl)ben2yl)-2-(p-tolylimino)thiazolidin-4-one A mixture of methyl 2-chloro-3-(3-(trifluoromethyl)phenyl)propanoate (0.61 g, 2.29 mmol; see step (a) above), Λ/-(p-methylphenyl) thiourea (698 mg, 4.2 mmol) and sodium acetate (212 mg, 2.54 mmol) in ethanol (5.OmL) was refluxed for 8 hours and then concentrated. The crude product was purified by silica gel chromatography using toluene:ethyl acetate (3:2) as eluent followed by re- crystallisation from hot methanol to give the title compound (170mg, 0.47 mmol,

21%) as a white solid. LC-MS (A) t_R: 6.26 min, m/z 365.2 (MH+). ¹H NMR: δ(DMSO-c/₆): 2.27 (s, 3H), 3.14 (nr, 1 H), 3.46 (dd, 1 H), 4.75 (nr, 1 H)₁ 6.80 (nr,

1H)₁ 7.12 (m, 2H), 7.56 (m, 5H).

Compound 3

5-(3-fTnfluoromethyl)benzyl)-2-(^'4-isopropylphenylimino)thiazolidin-4-one The title compound was prepared in accordance with the procedure described above in respect of Compound 2. The title compound was purified by flash chromatography and recrystallised from hot methanol to give 167 mg as a white solid. LC-MS (A) t_R: 7.03 min, m/z 393.4 (MH+). ¹H NMR: δ(DMSO-c/₆): 1.15 (d, 6H), 2.83 (m, 1H), 3.15 (m, 1 H), 3.45 (ddd, 1 H), 4.75 (m, 1 H), 6.83 (d, 1 H), 7.30 (dd, 2H), 7.45-7.65 (m, 5H).

Compound 4 5-(3-(Trifluoromethyπbenzyl)-2-(4-chlorophenylimino)thiazolidin-4-one

The title compound was prepared in accordance with the procedure described above in respect of Compound 2. The title compound was purified by flash chromatography and recrystallised from hot methanol to give 271 mg of the title compound as a white solid. LC-MS (A) i_R: 6.9 min, m/z 385.4 (MH+). ¹H NMR: δ(DMSO-cy₆): 3.2 (m, 1 H), 3.6 (big HDO signal), 4.8 (nr, 1H), 6.85 (d, 1H)₁ 7.4 (dd, 2H), 7.5-7.7 (m, 6H).

Compound 5

5-(3-fTrifluoromethyl)ben2yl)-2-f4-methoxyphenylimino)thiazolidin-4-one The title compound was prepared in accordance with the procedure described above in respect of Compound 2. The title compound was purified by flash' chromatography and recrystallised from hot methanol to give 137mg of the title compound as a white solid. LC-MS (A) ϊ_R: 6.25 min, m/z 381.2 (MH+). ¹H NMR: δ(DMSO-d₆): 3.12 (dd, 1 H), 3.45 (ddd, 1H), 4.74 (dd, 1 H), 6.86-6.95 (m, 3H), 7.50-7.63 (m, 5H).

Compound 6

5-f3-fTrifluoromethyl)benzyl)-2-(phenylimino)thiazolidin-4-one The title compound was prepared in accordance with the procedure described above in respect of Compound 2. The title compound was purified by flash chromatography and recrystallised from hot methanol to give 289 mg of the title compound as a white solid. LC-MS (A) t_R: 6.42 min, m/z 351.4 (MH+). ¹H NMR: §(DMSO-cf_β): 3.1-3.5 (m, 2H), 4.76 (dd, 1 H), 6.86 (d, 1 H), 7.11 (m, 1 H), 7.23 (m, 2H), 7.57 (m, 5H).

Compound 7

2-(3,4-Dichlorophenylimino)-5-(3-(trifluoromethyl)benzyl)thiazolidin-4-one The title compound was prepared in accordance with the procedure described above in respect of Compound 2. The title compound was purified by flash chromatography and recrystallised from hot methanol to give 67 mg of the title compound as a white powder. LC-MS (A) t_R: 9.14 min. ES-MS m/z: 369.0 (MH+). 1H NMR: δ(DMSO-c/₆): 3.15 (app. t, 1H), 3.45 (m, 1H), 4.80 (m, 1 H), 6.85 (d, 1 H), 7.10 (s, 1 H), 7.50-7.70 (5H), 8.10 (m, 1 H).

Compound 8 2-(2,4-Dichlorophenylimino)-5-(3-(trifluoromethyl)benzvπthiazolidin-4-one

The title compound was prepared in accordance with the procedure described above in respect of Compound 2. The title compound was purified by flash chromatography and recrystallised from hot methanol to give 68 mg of the title compound as an off-white powder. LC-MS (A) t_R: 9.52 min. ES-MS m/z: 419.0 (MH+). ¹H NMR: δ(DMSO-c/₆): 3.20 (m, 1 H), 3.40 (dd, 1 H), 4.80 (dd, 1 H), 6.95 (d, 1H), 7.35 (d, 1H), 7.50-7.65 (m, 4H).

Compound 9

5-(3-(^rTrifluoromethyl)benzyl)-2-(p-tolylimino)-3-methylthiazolidin-4-one A mixture of 5-(3-(trifluoromethyl)benzyl)-2-(p-tolylimino)thiazolidin-4-one (250 mg, 0.686 mmol), sodium carbonate (145 mg, 1 ,37 mmol) and methyl iodide (127 μl_, 1.37 mmo!) in DMF (2.5 mL) was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried with MgSO₄, filtered and concentrated. The crude product was purified by silica gel chromatography using toluene:ethyl acetate (2:1) as eluent to yield the title compound (99 mg, 0.262 mmol, 38%). LC-MS (B) t_R: 0.98 min (256 nm). ¹H NMR: δ(DMSO-c/₆): 2.42 (s, 3H), 3.11 (d, 1H), 3.28 (s, 3H), 3.33 (dd, 2H), 7.20-7.33 (m, 6H), 7.38 (t, 1 H), 7.53 (d, 1 H).

Compound 10 5-(4-MethoxyphenethyO-2-(p-tolylimino)thiazolidin-4-one

(a) Ethyl 2-hvdroxy-4-(4-methoxyphenyl)-4-oxobutanoate

Ethyl glyoxylate (50% in toluene, 6 mL, 29.39mmol) and 4-methoxy acetophenone (4400mg, 29.39mmol) were stirred at 135⁰C in an open flask for 2Oh. The crude reaction mixture was purified by silica gel column chromatography using toluene.ΕtOAc 2:1 as eluent yielding the title compound as a thick yellowish oil which solidified upon standing (4000mg, 54%). ¹H NMR: 5(CDCI₃): 1.40 (t, 3H)₁ 3.45 (dt, 2H), 3.90 (s, 3H), 4.25 (q, 2H), 4.65 (t, 1 H)₁ 6.95 (d, 2H), 7.95 (d, 2H).

(b) Ethyl 2-hydroxy-4-(4-methoxyphenyl)butanoate

To a solution of ethyl 2-hydroxy-4-(4-methoxyphenyl)~4-oxobutanoate (500mg, 1.98mmol; see step (a) above) in ethanolic HCI (1 M, 2OmL), 10% Pd/C (40mg) was added. The reaction mixture was flushed with H₂ gas and hydrogenated for 6 hours at 1 atm. using a balloon filled with H₂ gas. After stirring for 6h, the palladium catalyst was filtered off and the solvent and HCI were evaporated yielding the sub-title compound (470mg, 100%) that was used without purification. ¹H NMR: 5(CDCI₃): 1.30 (t, 3H), 1.95 (m, 1 H), 2.10 (m, 1 H), 2.75 (m, 2H), 3.80 (s, 3H), 4.25 (q, 2H), 6.85 (d, 2H), 7.15 (d, 2H).

(c) 1-(Ethoxycarbonyl)-3-(4-methoxypheny0propyl 4-methylbenzenesulfonate To a solution of ethyl 2-hydroxy-4-(4~methoxyphenyl)butanoate (470mg, 2.0mmol; see step (b) above) in pyridine (5mL), tosyl chloride (497mg, 2.6mmol) was added in portions at room temperature. The reaction mixture was stirred overnight, diluted with toluene and washed with water (3x). The organic phase was dried (MgSO₄) and concentrated, and the crude product was purified by silica gel chromatography using toluene:EtOAc 20:1 as eluent affording the sub-title compound as a reddish oil (322mg, 41 %). ¹H NMR: 5(CDCI₃): 1.20 (t, 3H), 2.15 (m, 1H)₁ 2.45 (s, 3H), 2.55-2.70 (m, 2H), 8.85 (S.3H), 4.15 (t, 2H), 5.90 (m, 1 H), 6.85 (d, 2H), 7.10 (d, 2H), 7.40 (d, 2H)₁ 7.90 (d, 2H).

(d) 5-(4-MethoxyphenethyO-2-(p-tolylimino)thiazolidin-4-one

1-(Ethoxycarbonyl)-3-(4-methoxyphenyl)propyl 4-methylbenzenesulfonate

(155mg, 0.40mmol; see step (c) above), p-tolyl thiourea (67mg, 0.40mmol) and

NaOAc (36mg, 0.44mmol) were dissolved in 1.0 mL 95% EtOH. The reaction mixture was refluxed for 16h, concentrated in vacuum and partitioned between

EtOAc and water. After three extractions with EtOAc, the combined organic phases were dried (MgSO₄) and concentrated, and the crude product was purified by silica gel column chromatography using toluene:EtOAc 2:1 as eluent.

Further purification by recrystallisation from hot MeOH yielded the title compound as a beige-brown powder (42mg, 31 %). LC-MS (A) t_R: 8.50 min. ES-MS m/z:

341.2 (MH+). ¹H NMR: δ(DMSO-d₆): 1.80-2.00 (m, 1 H), 2.20-2.40 (s, 3H overlap with m, 1 H), 2.60 (m, 1H), 2.75 (m, 1 H), 3.70 (s, 3H), 4.15-4.25 (m, 1 H), 6.80-

6.90 (m, 2H), 6.95 (m, 1H), 7.05-7.20 (m, 4H), 7.60 (d, 1 H).

Compound 11

5-f4-Methoxyphenethyl)-2-(phenylimino)thiazolidin-4-one

The title compound was prepared in accordance with the procedure described above in respect of Compound 10, purified by flash chromatography and recrystallised from hot methanol to give 35 mg of the title compound as an off- white powder. LC-MS (A) t_R: 8.58 min. ES-MS m/z: 327.0 (MH+). ¹H NMR: δ(DMSO-d₆): 1.95 (m, 1H), 2.20-2.40 (m, 1 H), 2.65 (m, 1 H), 2.70 (m, 1 H), 3.70 (s, 3H), 4.25 (m, 1H), 6.85 (m, 2H), 6.95-7.20 (m, 4H), 7.40 (m, 2H), 7.70 (d, 1 H).

Compound 12 2-(p-Tolylimino)-5-phenethylthiazolidin-4-one

The title compound was prepared in accordance with the procedure described above in respect of Compound 10, purified by flash chromatography and recrystallised from hot methanol to give 96 mg of the title compound. LC-MS (B) t_R: 1.75 min, m/z 310.9 (MH+). ¹H NMR: δ.(DMSO-d₆): 2.00 (m, 1 H), 2.30 (s, 3H), 2.36 (m, 1 H), 2.61 (m, 1H), 2.75 (m, 1 H), 4.21 (dm, 1H), 6.91 (m, 1 H), 7.19 (m,

5H), 7.29 (m, 2H), 7.58 (d, 2H). Compound 13 5-(4-Fluorobenzyl)-2-(pyridin-2-ylimino)thiazolidin-4-one

Compound 14

/V-(5-(3-(Trifluoromethyl)benzvO-4-oxothiazolidin-2-ylidene)benzamide

To a suspension of 5-(3-(trifluoromethyl)benzyl)-2-aminothiazol-4(5H)-one (100 mg, 0.36 mmol, prepared in accordance with the procedures described in respect of Compound 2) and triethylamine (76 μL, 0.55 mmol) in CH₂CI₂ (3 ml), benzoyl chloride (50 μL, 0.40 mmol) was dropwise added. The reaction mixture was stirred at room temperature overnight and poured into a saturated solution of

NaHCO₃ in water. The water phase was extracted with CH₂CI₂, and the organic phase was dried with MgSO₄, filtered and concentrated in vacuum. The crude material was purified by column chromatography using a gradient of CH₂CI₂/Me0H (0-1%) as eluent to give 38 mg (0.10 mmol, 28 %) of the title compound as colourless oil. Recrystallisation from CH₂CI₂//so-hexane gave 22 mg of the title compound as white solid. LC-MS (A) t_R: 8.72 min. ES-MS m/z

379.0 (MH+). ¹H NMR: δ(400 MHz) -(CDCI₃): 3.23 (dd, 1 H), 3.64 (dd, 1H), 4.34

(dd, 1 H), 7.46-7.61 (m, 7H), 8.12 (d, 2H) ppm.

Compound 15

Λ/-(5-(3-(Trifluoromethyl)benzyl)-4-oxothiazolidin-2-ylidene)-4-chlorobenzamide The title compound was prepared in accordance with the procedure described above in respect of Compound 14, purified by flash chromatography (83 mg, colourless oil) and recrystallised from CH₂CI₂//so-hexane to give 72 mg of the title compound as white solid. LC-MS (A) t_R: 8.92 min. ES-MS m/z 413.2 (MH+). ¹H NMR: δ(400 MHz) .(CDCI₃): 3.22 (dd, 1 H), 3.61 (dd, 1 H), 4.34 (dd, 1 H), 7.42-7.49 (m, 4H), 7.52-7.59 (m, 2H), 8.12 (d, 2H)ppm.

Compound 16

Phenyl 5-(3-ftrifluoromethyl)benzyl)-4-oxothiazolidin-2-ylidenecarbamate The title compound was prepared in accordance with the procedure described above in respect of Compound 14, purified by flash chromatography (88 mg, colourless oil) and recrystallised from CH₂CI₂//so-hexane to give 74 mg of the title compound as white solid. LC-MS (A) t_R: 8.73 min. ES-MS m/z 395.0 (MH+). ¹H NMR: δ(400 MHz) (CDCI₃): 3.22 (dd, 1H), 3.61 (dd, 1H), 4.37 (dd, 1H), 7.21-7.28 (m, 3H), 7.37-7.58 (m, 6H) ppm.

Compound 17 5-f3-fTrifluoromethy[)benzyl)-2-tosyliminothiazolidin-4-one

5-(3-(Trifluoromethyl)benzyl)-2-amiπothiazol-4(5H)-one (100 mg, 0.36 mrnol, prepared in accordance with the procedure described above in respect of Compound 2) was dissolved in pyridine (3 ml_), and tosyl chloride (77 mg, 0.40 mmol) was added. The reaction mixture was stirred at room temperature overnight and poured into a saturated solution of NaHCO₃ in water. The water phase was extracted with CH₂CI₂, and the organic phase was dried with MgSO₄, filtered and concentrated in vacuum. The crude material was purified by column chromatography using a gradient of CH₂CI₂/Me0H (0-1 %) as eluent to give 55 mg. (0.13 mmol, 36%) of the title compound as colourless oil. Recrystallisation from CH₂CI₂//so-hexane yielded 34 mg of a white solid. LC-MS (A) t_R: 8.53 min. ES-MS m/z 429.2 (MH+). ¹H NMR: δ(400 MHz) (CDCI₃): 2.44 (s, 3H), 3.22 (dd, 1 H), 3.58 (dd, 1 H), 4.40 (dd, 1 H), 7.33 (d, 2H), 7.42-7.51 (m, 3H), 7.58 (d, 1 H), 7.78 (d, 2H) ppm.

Compound 18

5-f3-fTrifluoromethyl)benzyl)-2-(4-chlorophenyπsulfonyliminothiazolidin-4-one The title compound was prepared in accordance with the procedure described above in respect of Compound 17, purified by flash chromatography (43 mg, colourless oil) and recrystallised from CH₂CI₂//so-hexane to give 20 mg of the title compound as a white solid. LC-MS (A) t_R: 8.78 min. ES-MS m/z 449.2 (MH+). ¹H NMR: 5(400 MHz)-(CDCI₃): 3.35 (dd, 1 H)₁ 3.57 (dd, 1 H), 4.40 (dd, 1 H), 7.41-7.45 (m, 5H), 7.59 (d, 1H), 7.83 (d, 2H) ppm.

Compound 19 5-(3-(Trifluoromethyl)benzyl)-2-(3,4-dichlorophenylimino)thiazolidin-4-one

Methyl 2-chloro-3-(3-(trifluoromethyl)phenyl)propanoate (see Compound 2 (a) above; 200 mg, 0.75 mmol), 3,4-dichlorophenyl thiourea (166 mg, 0.75 mmol), and NaOAc (68 mg, 0.83 mmol) were dissolved in 2.OmL 95% EtOH. The mixture was heated at reflux for 21 h and the EtOH was evaporated. EtOAc and water were subsequently added and three portions of EtOAc were used for extraction. After drying the combined organic phases with MgSO₄, the crude product was purified on silica gel column using toluene.ΕtOAc 2:1 as eluent, followed by recrystalfisation from MeOH. This yielded the title compound as a white powder (159 mg, 50.6%). Alternatively, the solid crude product may be purified by washing it in the presence of hexane (which should remove any residual propanoate starting material), dissolving the solid product with EtOAc and then filtering (which should remove the urea and the any salts, as they should not be soluble therein), followed by recrystallisation from MeOH. LC-MS t_R: 9.14 min. ES-MS m/z: 419.0 (MH+). ¹H NMR: 6(DMSO-CZ₆): 3.20 (m, 1 H), 3.40 (dd, 1H), 4.80 (dd, 1H), 6.95 (d, 1H), 7.35 (dd, 2H), 7.50-7.75 (m, 4H).

Compound 20 f5-f3-Trifluoromethylbenzyl)-1 ,1-dioxo-1λ⁶-π.4,21dithiazolidin-3-ylidene1-(3,4- dichloro)phenyl-2-amine

(a) 2-Chloromethanesulfonamide

Ammonia gas was bubbled through a solution of chloromethanesulfonyl chloride (5.0 g, 34 mmol) in Et₂O (50 mL) at O⁰C. The reaction mixture was stirred at ambient temperature for 2 hours. The precipitate (ammonium chloride) was filtered off and washed with EtOAc (3x). The combined organic phases were dried (Na₂SO₄) and concentrated to give 2.96 g (67%) of the crude sub-title compound as a white solid. The compound was used without further purification. 1H NMR: δ(DMSO-c/₆): 5.74 (s, 2H), 7.33 (s, 2H).

(b) 1 ,1-Dioxo-1λ⁶-H.4,21dithiazolidin-3-ylideneH3.4-dichloro)phenyl-2-amine An aqueous solution of NaOH (18 M, 1.38 mL, 25 mmol) was added over 30 minutes to a solution of crude 2-chloromethanesulfonamide (3.4 g, -26 mmol) and 3,4-dichlorophenyl isothiocyanate (5.3 g, 26.0 mmol) in acetone (16 mL) at

50 ⁰C. The resulting mixture was stirred over night at ambient temperature. The reaction mixture was acidified with hydrochloric acid (1 M) and the organic solvent was evaporated in vacuo. Water and EtOAc were added and the water phase was extracted with EtOAc (x3). The combined organic phases were dried

(Na₂SO₄) and the solvent was removed in vacuo. The crude product was purified on a silica gel column (toluene : EtOAc 8:1 to 2:1 ) to give 3.8 g (49.2% yield) of the title compound as a pale white solid. ES-MS m/z: 298.1 (MH+). ¹H NMR: 5(CDCI₃): 5.78 (s, 2H), 7.51 (d, 2H), 7.65 (d, 1 H). (c) r5-f3-Thfluoronnethylbenzvπ-1.1-ciioxo-1λ⁶-ri ,4.21dithia2θlidin-3-ylideneK3,4- dichloro)phenyl-2 -amine

Sodium bis(t!Ϊmethylsilyl)amide (0.6M, 5.85 ml_, 3.51 mmol) was added drop-wise to a solution of 1 ,1-dioxo-1λ⁶-[1 ,4,2]dithiazolidin-3-yiidene]-(3,4-dichloro)phenyl-2- amine (531 mg, 1.78 mmol; see step (b) above) in dry THF (8 mL) at -78⁰C under nitrogen. The reaction mixture was stirred at this temperature for 1 h, after which a solution of 3-trifluorobenzylbromide (272 μl_, 1.778 mmol) in dry THF (0.5 mL) was added drop-wise. The reaction temperature was maintained at -78⁰C for 5 h and the resulting mixture was quenched by the addition of hydrochloric acid. EtOAc was added and the water phase was extracted with EtOAc (x3). The combined organic phases were dried (Na₂SO₄) and the solvent was removed in vacuo. The crude product was purified on a silica gel column (toluene: EtOAc 100:0 to 2:1) to give 200 mg (24% yield) of the title compound. ES-MS m/z: (MH+Na) 479, (M-H) 453.6. ¹H NMR: δ(Acetone-tf₆): 3.55 (dd, 1 H), 3.7 (dd, 1 H), 5.4 (dd, 1 H), 7.5-7.78 (m, 5H), 7.8 (d, 1 H), 7.9 (s, 1 H).

Compound 21

[5-(3-Trifluoromethylbenzyl)-1.1-dioxo-1Λ⁶-π ,4,21dithiazolidin-3-ylidene1-(4- chloro)phenyl-2-amine Sodium bis(trimethylsilyl)amide (0.6M, 1.06 mL, 0.63 mmol) was added dropwise to a solution of 1 ,1-dioxo-1λ⁶-[1,4,2]dithiazolidin-3-ylidene]-p-chlorophenyl-amine (33 mg, 0.12 mmol; which was prepared in accordance with the procedures described in respect of Compound 20 above) in dry THF (2 mL) at -78⁰C under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 1 hour, before a solution of 3-trifluorobenzyl bromide (75 μL, 0.63 mmol) in dry THF (0.5 mL) was dropwise added. The temperature was kept at -78⁰C for 5h, and the reaction was quenched by addition of hydrochloric acid and EtOAc. The water phase was extracted with EtOAc (x3), and the combined organic phases were dried with Na₂SO₄, filtered and concentrated. The crude product was purified by silica gel ζ(DMSO-c/₆): 3.2 (dd, 1 H), 3.6 (dd, 1H), 5.5 (dd, 1H), 7.4-7.5.(m, 2H), 7.6-7.7-. (m, column chromatography (toluene:EtOAc 100:0 to 2:1 ) to give 15 mg of the title compound. LC-MS (A) t_R: 10.89 min. ES-MS m/z: 421.2 (MH+). ¹H NMR: 4H), 7.7-7.8 (d, 1 H), 7.8 (s, 1 H). Compound 22 5-f3-fTrifluoromethyl)ben2yl)-2-(3,4-dichlorophenyl)sulfonyliminothiazolidin-4-one

(a) 5-(3-(Trifluoromethyl)benzvπ-2-aminothiazol-4(^'5H)-one Methyl 2-chloro-3-(3-(trifluoromethyl)phenyl)propanoate (2.44 g, 9,16 mmol; see Compound 2 (a) above), thiourea (697 mg, 9.16 mmol), and NaOAc (848 mg, 10.13 mmol) were dissolved in 95% EtOH (20.0 mL). The mixture was heated at reflux for 20 h, after which the EtOH was evaporated. The crude product was washed with H₂O / CH₂CI₂, and the solid separated was collected to give sub-title compound (1.5 g). The organic phase was dried, concentrated and triturated with isohexane to give more of the sub-title compound (0.5g). The total mass of the crude sub-title compound was 2 g (7.29 mol, 80 %). ES-MS m/z: 275 (MH+). The product was used for the next step without further purification.

(b) [5-(3-(Trifluoromethvnbenzyl)-2-(3,4-dichlorophenyl)sulfonyliminothiazolid-in- 4-one

To 5-(3-(trifluoromethyl)benzyl)-2-aminothiazol-4(5H)-one (1100 mg, 4.01 mmol) in dichloromethane (10 mL), was successively added pyridine (0.317 mL, 4.01 mmol) and 3,4-dichlorobenzenesulfonyl chloride (0.984 mg, 0.626 mL, 4.01 mmol). The reaction mixture was stirred at room temperature overnight and poured into a saturated aqueous solution of NaHCO₃. The water phase was extracted with CH₂CI₂, and the organic phase was dried with MgSO₄, filtered and concentrated in vacuo. The crude material was purified by column chromatography using a gradient of CH₂CI₂/Me0H (0-1%) as elueπt to give 450 mg (0.931 mmol, 23.3%) of the title compound as colourless oil. Recrystallisation from CH₂CI₂ / /so-hexane yielded 360 mg of a white-yellow solid. ES-MS: 506 (M+HNa) 481.0 (M-H). ¹H NMR: δ(400 MHz) Acetone d₆): 3.25 {dd, 1 H), 3.62 (CfQf₁ 1 H), 4.82 (eld, 1 H), 7.60-7.70 (m, 4H), 7.72-7.88 (m, 2H), 7.92 (d, 1 H).

Compound 23

2-Chlorophenyl 5-(3-(trifluoromethyl)benzyl)-4-oxothiazolidin-2-ylidenecarbamate To 5-(3-(trifluoromethyl)benzyl)-2-aminothiazol-4(5H)-one (see Compound 22 (a)) in dichloromethane, is successively added either pyridine or triethylamine and 2- chlorophenyl chioroformate. The reaction mixture is stirred at room temperature overnight and is then poured into a saturated aqueous solution of NaHCO₃. The water phase is extracted with CH₂CI₂, and the organic phase is dried with MgSO₄, filtered and concentrated in vacuo. The crude material is purified by column chromatography and/or by recrystallisation to afford the title compound.

Compounds of the Invention

General Procedure for the Synthesis of Compounds of the Invention

To a solution of the intermediate sulfide in CH₂CI₂ was added m-CPBA (1.1 equivalents; 70%, Fluka) portion-wise at O⁰C under N₂. The reaction was monitored by tic, and after 6 hours, tic indicated that no started material was left in the reaction mixture. The reaction mixture was then neutralised with a saturated aqueous solution of NaHCO₃ and extracted with EtOAc (3 x 5m!_). The organic extract was dried with anhydrous MgSO₄, solvent was removed and the resulting residue was purified by flash column chromatography (1 % MeOH/CH₂Ci₂).

Example 1 i-Oxo-δ-O-ftrifluoromethvπbenzvπ-Σ-fSΛ-dichlorophenyliminoViλMhiazolidin-^ one To a solution of 5-(3-(trifluoromethyl)benzy!)-2-(3,4-dichlorophenylimino)- thiazolidin-4-one (50 mg, 0.119 mmol; see Compound 19 above) in CH₂CI₂ was added /π-CPBA (31.4 mg, 0.131 mmol, 70%, Fluka), portion-wise at O⁰C under N₂. The reaction was monitored by tic, and after 6 h, tic indicated that no started material was left in the reaction mixture. The reaction mixture was then neutralised with saturated aqueous solution of NaHCO₃ and extracted with EtOAc (3 x 5mL). The organic extract was dried with anhydrous MgSO₄, solvent was removed and the resulting residue was purified by flash column chromatography (1% MeOH / CH₂CI₂) to yield the title compound (24 mg, 47%) in an impure form (due to some residual starting material remaining, as well as other bi-products including 1,1 -dioxo-derivatives). ES-MS m/z: 457 (MH+Na), 434 (M-H). ¹H NMR: δ(Acetone-d₆): 3.40 (m, 1 H), 3.60 (dd, 1H), 4.85 (dd, 1 H), 6.95 (d, 1 H), 7.35 (dd, 2H), 7.50-7.75 (m, 4H). These data apparently relate to the title compound. However, given that this oxidation step may generate a large number of compounds (and was not isolated in pure form), some of these data and/or additional data may correlate to starting material and/or any bi-products produced. Example 2 f5-(3-Trif[uoromethylbenzvn-f 1 ,1 ,4-thoxoV1λ⁶-4λ⁴-π .4,21dithiazolidin-3-ylid-ene1- (3,4-dichloro)phenyl-2-amine To a solution of ^-(S-trifluoromethyibenzyO-i .i-dioxo-U^CI ^^Jdithiazolidin-S- ylidene]-(3,4-dichloro)phenyl-2-amine (50 mg, 0.110 mmol; see Compound 20 above) in CH₂CI₂ was added m-CPBA (28.5 mg, 0.120 mmol, 70%, Fluka), portion-wise at O⁰C under N₂. The reaction was monitored by tic, and after 6 h, tic indicated that no started material was left in the reaction mixture. The reaction mixture was then neutralised with saturated aqueous solution of NaHCO₃ and extracted with EtOAc (3 x 5mL). The organic extract was dried with anhydrous MgSO₄, solvent was removed and the resulting residue was purified by flash column chromatography (1 % MeOH /CH₂CI₂) to yield the title compound (20mg, 38%). ES-MS m/z: (M-H⁺) 470 (M-H). ¹H NMR: δ(Acetone-cf₆): 3.6-3.8 (q, 2H), 4.9 (t, 1 H), 7.62 (m, 3H), 7.8 (d, 1H), 7.85 (s, 1 H), 7.92 (d, 1H), 8.1 (d, 1 H).

Example 3 r5-(3-Trifluoromethylbenzyl)-(1 ,1 ,4-trioxo)-1λ⁶-4λ⁴-F1 ,4,21dithia-zolidin-3-ylid-ene1-

(4-chloro)phenyl-2-amine To a solution of [5-(3-trifluoromethylbenzyl)-1,1-dioxo-1λ⁶-[1 ,4,2]dithiazolidin-3- ylidene]-(4-chloro)phenyl-2-amine (46 mg, 0.109 mmol; see Compound 21 ) in CH₂CI₂ was added m-CPBA (29 mg, 0.122 mmol, 70%, Fluka), portion-wise at O⁰C under N₂. The reaction was monitored by tic, and after 6 h, tic indicated that no started material was left in the reaction mixture. The reaction mixture was then neutralised with saturated aqueous solution of NaHCO₃ and extracted with EtOAc (3 x 5ml_). The organic extract was dried with anhydrous MgSO₄, solvent was removed and the resulting residue was purified by flash column chromatography (1% MeOH /CH₂CI₂) to yield the title compound (21 mg, 51 %). ES-MS m/z: 435 (M-H+). ¹H NMR: δ(Acetone-d₆): 3.82 (q, 2H), 4.9 (t, 1 H), 7.5 (d, 2H), 7.7 (d, 2H), 7.8 (m, 3H), 7.9(s, 1H).

Example 4

1-Oxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenyl)sulfonyliminothiazolidin-4- one To a solution of 5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenyI)suIfonyi- iminothiazolidin-4-one (50 mg, 0.1113 mmol; see Compound 18) in CH₂CI₂ was added m-CPBA (30 mg, 0.1225 mmol, 70%, Fluka), portion-wise at O⁰C under N₂. The reaction was monitored by tic, and after 6 h, tic indicated that no started material was left in the reaction mixture. The reaction mixture was then neutralised with saturated aqueous solution of NaHCO₃ and extracted with EtOAc (3 x 5mL). The organic extract was dried with anhydrous MgSO₄, solvent was removed and the resulting residue was purified by flash column chromatography (1 % MeOH /CH₂CI₂) to yield the title compound.

Example 5 The following compounds of the invention are prepared by oxidation of the corresponding intermediate compounds under oxidation conditions such as those described hereinbefore:

1-oxo-5-(4-fluorobenzyl)-2-(pyridin-2-ylimino)thiazolidin~4-one; and 1 ,1-dioxo-5-(4-fluorobenzyl)-2-(pyridin-2-ylimino)thia2olidin-4-one (from Compound 13);

1-oxo-5-(4-methylbenzyl)-2-(4-chlorophenyiimino)thiazolidin-4-one; and 1 ,1-dioxo-5-(4-methylbenzyl)-2-(4-chlorophenylimino)thiazolidin-4-one (from Compound 1 );

1-oxo-5-(3-(trifluoromethyI)benzyl)-2-(p-tolylimino)thiazolidin-4-one; and 1 ,1 -dioxo-5-(3-(trifluoromethyI)benzyl)-2-(p-tolylimino)thiazolidin-4-one (from Compound 2);

1-oxo-5-(3-(thfiuoromethyl)benzyl)-2-(4-chlorophenylimino)thiazolidin-4-one; and 1 , 1 -dioxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenylimino)thiazolidin-4-one (from Compound 4); 1-oxo-5-(3-(trifluoromethy[)benzyl)-2-(4-isopropylphenylimino)thiazolidin-4-one; and

1 , 1 -dioxo-5-(3-(trifluoromethyl)benzyl)-2-(4-isopropylphenylimino)thiazolidin-4-one (from Compound 3);

1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(4-methoxyphenylimino)thiazoIidin-4-one; and

1,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(4-methoxyphenylimino)thiazolidin-4-one (from Compound 5); 1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(phenylimino)thiazolidin-4-one ; and

1 , 1 -dioxo-5-(3-(trifluoromethyl)benzyl)-2-(phenylimino)thiazolidin-4-one (from Compound 6); 1-oxo-2-(3,4-dichlorophenylimino)-5-(3-(trifluoromethyl)benzyl)thiazolidin-4-one; and

1 ,1-dioxo-2-(3,4-dichlorophenylimino)-5-(3-(trifluoromethyl)benzyl)thiazolidin-4- one (from Compound 7);

1-oxo-2-(2_l4-dichlorophenylimino)-5-(3-(trifluoromethyl)benzyl)thiazolidin-4-one; and

1,1-dioxo-2-(2,4-dichlorophenylimino)-5-(3-(trifluoromethyl)benzyl)thiazolidin-4- one (from Compound 8);

1-oxo-5-(3-(trifluoromethy!)benzyI)-2-(p-to)ylimino)-3-methylthiazolidin-4-one; and 1 , 1 -dioxo-5-(3-(trifluoromethyl)benzyl)-2-(p-tolylimino)-3-methylthiazolidin-4-one (from Compound 9);

1-oxo-N-(5-(3-(trifluoromethyl)benzyl)-4-oxothiazolidin-2-ylidene)-4- chlorobenzamide; and

1 , 1 -dioxo-N-(5-(3-(trifluoromethyl)benzyl)-4-oxothiazolidin-2-yiidene)-4- chlorobenzamide (from Compound 15);

1 ,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenyI)sulfonyliminothiazolidin- 4-one (from Compound 18 or Example 4); phenyl 5-(3-(trifluoromethyl)benzyl)-1 ,4-dioxothiazolidin-2-ylidenecarbamate; and phenyl 5-(3-(trifluoromethyl)benzyl)-1,1 ,4-trioxothiazolidin-2-ylidenecarbamate from Compound 16);

1-oxo-5-(4-methoxyphenethyI)-2-(p-tolylimino)thiazolidin-4-one; and 1 ,1 -dioxo-5-(4-methoxyphenethy!)-2-(p-tolylimino)thiazolidin-4-one (from Compound 10);

1-oxo-5-(4-methoxyphenethyl)-2-(phenylimino)thiazolidin-4-one; and; 1 , 1 -dioxo-5-(4-methoxyphenethyl)-2-(phenylimino)thiazolidin-4-one (from Compound 11); 1-oxo-2-(p-toly!imino)-5-phenethylthiazo!idin-4-one; and 1 , 1 -dioxo-2-(p-tolylimino)-5-phenethylthiazolidin-4-one (from Compound 12);

1 ,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(3,4-dichlorophenylimino)-1λ⁶-thiazol- idin-4-one (from Compound 19 or Example 1 ); [5-(3-trifluoromethylbenzyl)-1_J1,4,4-tetraoxo-1λ⁶-4λ⁶-[1 ,4,2]dithiazolidin-3-ylidene]- (3,4-dichloro)phenyl-2-amine (from Compound 20 or Example 2); [5-(3-trifluoromethylbenzyl)-1 , 1 ,4,4-tetraoxo-1 λ⁶-4λ⁶-[1 ,4,2]dithiazolidin-3-ylidene]- (4-chloro)phenyl-2-amine (from Compound 21 or Example 3); i-oxo-δ^S-CtrifluoromethyObenzyO-^-CS^-dichlorophenyOsulfonyliminothiazolidin- 4-one; and i .i-dioxo-δ^S-^rifluoromethyObenzyO^-CS^-dichlorophenyOsulfonyliminothi- azoiidin-4-one (from Compound 22);

2-Chlorophenyl 1-oxo-5~(3-(trifluoromethyl)benzyI)-4-oxothiazolidin-2-ylidene- carbamate; and 2-Chlorophenyl 1 ,1 ,-dioxo-5-(3-(trifluoromethyl)benzyl)-4-oxothiazolidin-2-yli- denecarbamate (from Compound 23).

Biological Tests

Test A

Cell Proliferation Assay

Reagents Dulbecco's modified Eagle's medium (D-MEM) +1000mg/L Glucose +GlutaMAX™1 + Pyruvate (Gibco #21885-025) V/V Foetal Bovine Serum (Gibco 10500-064) 5-bromo-2-deoxyuridine (BrdU) Dimethyl sulfoxide (DMSO)

MDA-MB-231 Human breast cancer cell line was propagated in D-MEM (Gibco 21885) supplemented with 10% Foetal calf serum. 15000 cellS per well were seeded in 96 well plates and incubated overnight. The culture media was changed to serum-free D-MEM for 24 h. The culture media was then changed to serum free D-MEM containing either 0.2 % DMSO as vehicle control or 10, 5, 1 , 0.1 μM of the compound of Example 1 in 0.2% DMSO in quadruplicate. After 18 h incubation, BrdU was added according to manufacturer's recommendations. After 6 h incubation in the presence of BrdU, the culture media was removed and BrdU incorporation was measured using "Cell Proliferation EUSA, BrdU colorimetric" Roche (11647229001 ) according to manufacturer's recommendations. Results

Proliferation rate of MDA-MB-231 cells are reduced by relevant concentrations of the test compounds as measured by BrdLJ incorporation (see figure 1 ).

In the above assay, relative to a vehicle control (which displays a BrdU incorporation of 1 unit), title compounds of the examples (or Compound 23) display less than one unit of BrdU incorporation at concentrations of between 10 μM and 0.1 μM. For example, the (impure) compound of Example 1 displayed the following (approximate) units of BrdU incorporations at different concentrations:

10 μM: 0

5 μM: 0.1

1 μM: 0.5

These results are depicted in Figure 1.

Test B

In vivo Mouse Model

5 week old Athymic BALB/cA nude mice are delivered from Taconic (Denmark) and kept under barrier conditions for 1 week acclimatisation. At 6 weeks, 17 mice are injected subcutaneously on the flank with 1.8 x 10⁶ MDA-MB-231 human breast cancer cells (LGC Promochem-ATCC) in a 50/50 v/v solution of phosphate buffered saline (PBS) (Gibco 10010-015, Invitrogen) Matrigel HC (BD Biosciences).

After 11 days, palpable tumors are observed in 16 mice. 2 mice are sacrificed and the tumors dissected and examined. 2 groups of 7 mice each are treated once daily by intraperitoneal injections of 1-10 mg/kg bodyweight of test compound in 79% PBS/20% Solutol HS 15(BASF)/1 % DMSO or vehicle control respectively for 5-30 days. The mice are sacrificed by cervical dislocation and tumors are dissected. Histology

The tumor tissue are fixated overnight in PBS (containing 4% w/v paraformaldehyde (Scharlau PA0095, Sharlau Chemie SA, Spain) at +4⁰C. The tumor tissue is then cryopreserved by 24 hour incubation in PBS containing 30% w/v sucrose (BDH #102745C (www.vwr.com) at +4°C and embedded in Tissue-

Tek embedding media (Sakura Finetek Europa BV, Netherlands). 10 μm cryosections are generated and stained with Mayers Hematoxylin (Dako) for 5 minutes and destained for 3 x 10 minutes in tap water. Slides are mounted using

Dako faramount aqueous mounting medium and examined using a Nikon Eclipse TS 100 microscope documented using a Nikon coolpix 4500.

Results

The tumors from mice treated with test compound and vehicle are analyzed for morphology by microscopic examination of hematoxylin stained cryosections.

Hematoxylin stained sections from tumors dissected from mice show that the cell- density in the interior of the tumors is reduced in tumors dissected from test compound treated mice as compared to tumors from vehicle treated mice, showing a correlation between treatment with test compound and reduction of cancer cells in xenograft tumors.

Test C

Insulin Measurement Study in Diabetic Ob/Ob Mice

Reagents

Ultra sensitive rat insulin ELISA kit (Crystal Chen inc) according to manufacturer's recommendations.

Serum insulin measurements on 8-9 week old Ob/Ob mice (Taconic) fasted for 4h/unfasted/ day after 4h fast was performed. Mice are distributed to a vehicle control group (VC) or a test compound treatment group, so that mean s-insulin is equal between the groups. 1-20 mg/kg bodyweight of test compound in vehicle and VC groups are injected intraperitoneally or subjected to oral gavage once/twice daily for 2-4 weeks, after which serum insulin levels are measured as described above. Results

Test compound attenuates hyperinsulinemia in Ob/Ob mice. The hyperinsuiinemia observed in Ob/Ob mice is generally believed to be a consequence of obesity and perturbed lipid metabolism leading to insulin resistance. We interpret the activity of the test compound in Ob/Ob mice as attenuating the insulin resistance.

Test D

Blood glucose measurement study in diabetic Ob/Ob Mice

Reagents

Ascensia Elit XL (Bayer diagnostic) hand held glucometer.

Blood glucose measurements on 8-9 week old Ob/Ob mice (Taconic) fasted for 4h/unfasted/ day after 4h fast was performed. Mice are distributed to a vehicle control group (VC) or a test compound treatment group, so that mean blood glucose is equal between the groups. 1-20mg/kg bodyweight of test compound in vehicle and VC groups are injected intraperitoneally or subjected ϊo oral gavage once/twice daily for 2-4 weeks, after which blood glucose levels are measured as described above.

Results

Blood glucose levels are attenuated by treatment with the test compounds.

Test E

Serum triglyceride measurements study in diabetic Ob/Ob Mice.

Reagents

Serum Triglyceride Determination Kit TR0100 (sigma).

Serum Triglyceride measurements on 8-9 week old Ob/Ob mice (Taconic) fasted for 4h/unfasted/ day after 4h fast was performed. Mice are distributed to a vehicle control group (VC) or a test compound treatment group, so that mean serum triglyceride is equal between the groups. 1-20mg/kg bodyweight of test compound in vehicle and VC groups are injected intraperitoneally or subjected to oral gavage once/twice daily for 2-4 weeks, after which serum triglyceride levels are measured as described above.

Results Serum triglyceride levels are attenuated by treatment with the test compounds.

Claims

Claims

1. A compound of formula I,

wherein

X represents -[C(R₈)(R₉)I_n-; n represents 0, 1 , 2 or 3; Y represents -C(O)-, -S(O)₂- or =C(R₁₀)-; T represents -S(O)- or -S(O)₂- ;

W represents -NR₇-, -CR₇R₇-, -NR₇C(O)-, -NR₇S(O)₂- -NR₇C(O)NR₇-, -NR₇C(O)O- or a bond; one of A-_I or A₂ represents a double bond and the other represents a single bond; when A₁ represents a single bond, A₂ is a double bond and R₆ is absent; when A₂ represents a single bond, A₁ is a double bond and, if present, one R₇ (which is attached α to the requisite ring of the compound of formula I) is absent; R₁ represents -C(O)NR₃R₂, -NR₃R₂, -C(O)OR₂, -NR₄C(O)NR₃R₂, -NR₄C(O)OR₂, -OC(O)NR₃R₂, -NR₄C(O)R₂, -OC(O)R₂ , -OR₂, -SR₂, H, alkyl, cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl (which latter six groups are optionally substituted by one or more groups selected from B¹, B², B³, B⁴, B⁵ and B⁶, respectively);

R₂ and R₅ independently represent hydrogen, alkyl, cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl (which latter six groups are optionally substituted by one or more groups selected from B⁷, B⁸, B⁹, B¹⁰, B¹¹ and B¹², respectively); R₃, R₄, R₆ and R₇ independently represent hydrogen, alkyl, cycloalkyl, aryl or benzyl (which latter four groups are optionally substituted by one or more groups selected from B¹³, B¹⁴, B¹⁵ and B¹⁶, respectively), or heterocyclyl or heteroaryl (which latter two groups are optionally substituted by one or more groups selected from B¹⁴ and B¹⁵, respectively); R₈ and R₉ are independently selected from hydrogen, alkyl and aryl (which latter two groups are optionally substituted by B^16a and B^16b, respectively); R₁₀ represents hydrogen, alkyl or aryl (which latter two groups are optionally substituted by one or more groups selected from B¹⁷ and B¹⁸, respectively); B¹ to B¹⁸ independently represent cyano, -NO₂, halo, -OR₁₁, -NR₁₂Ri₃, -SR₁₄, -Si(R₁₅)_3l -C(O)OR₁₆, -C(O)NR_16aR₁₆b, -S(O)₂NR_16cRi₆d, aryl or heteroary! (which aryl and heteroaryl groups are themselves optionally and independently substituted by one or more groups selected from halo and R₁₇); or, alternatively, B⁴, B⁵, B⁶, B¹⁰, B¹¹, B¹², B¹⁵, B¹⁶, B^16b or B¹⁸ independently represent R₁₇;

Rn, R₁₂, Ri3, Ri₄, Ri6, Ri6a, Ri6b, Rise and R_16d independently represent H or R₁₇; and

R₁₅ and R₁₇ independently represent C_1-6 alkyl optionally substituted by one or more halo atoms, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof.

2. A compound as claimed in Claim 1 wherein T represents -S(O)-.

3. A compound as claimed in Claim 1 or Claim 2 wherein Y represents -C(O)-.

4. A compound as claimed in any one of the preceding claims wherein Ri₀ represents H or alkyl.

5. A compound as claimed in Claim 4 wherein Ri₀ represents hydrogen.

6. A compound as claimed in any one of the preceding claims wherein W represents -NR₇-, -NR₇C(O)-, -NR₇C(O)O-, -NR₇C(O)NR₇- or -NR₇S(O)₂-.

7. A compound as claimed in Claim 6 wherein W represents -NR₇-.

8. A compound as claimed in any one of the preceding claims wherein R₅ represents heterocyclyl, aryl or heteroaryl (which latter three groups are optionally substituted by one or more groups selected from B⁹, B¹¹ and B¹², respectively).

9. A compound as claimed in any one of Claims 1 to 7 wherein R₅ represents optionally substituted C_1-3 alkyl, cycloalkyl or optionally substituted phenyl or optionally substituted heteroaryl.

10. A compound as claimed in any one of the preceding claims wherein n represents 1 , 2 or 3.

11. A compound as claimed in Claim 10 wherein n represents 1.

12. A compound as claimed in any one of the preceding claims wherein R₈ and R₉ independently represent Ci_-3 aikyl or H.

13. A compound as claimed in Claim 12 wherein R₈ and R₉ both represent H.

14. A compound as claimed in any one of the preceding claims wherein R-i represents heterocyclyl, aryl or heteroaryl (which groups are optionally substituted by one or more groups selected from B³, B⁵ and B⁶, respectively).

15. A compound as claimed in any one of Claims 1 to 13 wherein R₁ represents alkyl, -NR₃R₂, -OR₂, -SR₂, -NR₄C(O)R₂, -NR₄C(O)NR₃R₂, -NR₄C(O)OR₂, -C(O)NR₃R₂, -C(O)OR₂, optionally substituted heteroaryl or optionally substituted phenyl.

16. A compound as claimed in Claim 14 or Claim 15 wherein R-i represents optionally substituted heteroaryl or optionally substituted phenyl.

17. A compound as claimed in Claim 14 or Claim 15 wherein R₁ represents aryl optionally substituted by B⁵.

18. A compound as claimed in any one of Claims 14 to 17 wherein R-i represents phenyl optionally substituted by B⁵.

19. A compound as claimed in any one of Claims 14 to 16 wherein Ri represents optionally substituted furanyl, thienyl or phenyl.

20. A compound as claimed in any one of the preceding claims wherein R₄ or R₃ independently represent C_1-3 alkyl or H.

21. A compound as claimed in any one of the preceding claims wherein R₂ represents optionally substituted Ci_-3 alkyl, optionally substituted phenyl or H.

22. A compound as claimed in any one of the preceding claims wherein R₆ represents hydrogen.

23. A compound as claimed in any one of the preceding claims wherein, when W represents -NR₇- and R₇ is absent, then R₆ represents H, C_1-6 alkyl or phenyl, which latter two groups may be substitutued by one or more of B¹³ and B¹⁵, respectively.

24. A compound as claimed in any one of Claims 1 to 22 wherein, when W represents -NR₇- and R₆ is absent, then R₇ represents C_1-3 alkyl, phenyl or benzyl, all of which may be substituted by one or more B¹³, B¹⁵ and B¹⁶, respectively.

25. A compound as claimed in any one of Claims 1 to 22 wherein, when W represents -CR₇R₇-, then A₂ represents a double bond.

26. A compound as claimed in any one of Claims 1 to 22 wherein, when W represents -CR₇R₇-, then each R₇ independently represents Ci_-3 alkyl or H.

27. A compound as claimed in any one of the preceding claims wherein B¹ to B¹⁸ independently represent cyano, NO₂, halo, -OR₁₁, -C(O)OR₁₆, -C(O)NR_16aR_16b or -S(O)₂NR_16cR_16d; and/or B⁴ to B⁶, B¹⁰ to B¹², B¹⁵, B¹⁶ and B¹⁸ independently represent R₁₇; and/or B¹ to B¹⁸ independently represent heteroary! or phenyl, both of which may be substituted by one or more groups selected from halo or R₁₇.

28. A compound as claimed in Claim 27 wherein B⁵ represents R₁₇.

29. A compound as claimed in any one of the preceding claims wherein Ri₁ represents C_1-3 alkyl or H.

30. A compound as claimed in any one of the preceding claims wherein Ri₆ represents H or Ci_₃ alkyl.

31. A compound as claimed in any one of the preceding claims wherein Ri_Ba, R_16b, R_16c and R_16d independently represent C_1-2 alkyl or H.

32. A compound as claimed in any one of the preceding claims wherein R₁₇ represents C_1-4 alkyl optionally substituted by one or more halo atoms.

33. A compound as claimed in Claim 32 wherein R₁₇ represents methyl optionally substituted by one or more fluoro atoms.

34. A compound as claimed in any one of the preceding claims selected from: 1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(3,4-dichlorophenylimino)-1λ⁴-thiazolidin-4- one; i.i-dioxo-δ^S-ftrifluoromethyObenzyO^S.Λ-dichlorophenyliminoJ-iλ^thiazol- idin-4-one;

[5-(3-trifluoromethylbenzyl)-1,1,4-trioxo-1λ⁶-4λ⁴-[1,4,2]dithiazolidin-3-ylidene]-(3,4- dichloro)phenyl-2-amine;

,1 _I4Λtetraoxo-1λ^β-4λ^β-[1_f4,2]clithiazolidin-3-ylidenθ]- (3,4-dichloro)pheny!-2-amine;

[5-(3-trifluoromethylbenzyl)-1 ,1 ,4-trioxo-1λ⁶-4λ⁴-[1 ,4,2]dithiazolidin-3-ylidene]-(4- chloro)phenyl-2-amine;

[5-(3-trifluoromethylbenzyl)-1 ,1,4,4-tetraoxo-1λ⁶-4λ⁶-[1,4,2]dithiazolidin-3-ylidene]- (4-chloro)phenyl-2-amine; 2-chlorophenyl 1 -oxo-δ-^-^rifluoromethyObenzyO^-oxothiazolidin^-ylidenecarb- amate;

2-chiorophenyl 1 , 1 ,-dioxo-5-(3-(trifluoromethyl)benzyl)-4-oxothiazolidin-2-ylidene- carbamate;

1-oxo-5-(4-fluorobenzyl)-2-(pyridin-2-ylimino)thiazolidin-4-one; 1,1 -dioxo-5-(4-fluorobenzyl)-2-(pyridin-2-ylimino)thiazolidin-4-one; 1-oχo-5-(4-methylbenzyl)-2-(4-chlorophenylimino)thiazolidin-4-one; 1,1-dioxo-5-(4-methylbenzyl)-2-(4-chlorophenylimino)thiazolidin-4-one; 1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(p-tolylimino)thiazolidin-4-one; 1,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(p-tolylimino)thiazolidin-4-one; 1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenylimino)thiazolidin-4-one;

1,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenylimino)thiazolidin-4-one; 1-oxo-5-(3-(trifluoromethyl)benzyI)-2-(4-isopropylphenylimino)thiazolidin-4-one; 1,1-dioxo-5-(3-(trifluoromethyl)benzyl)-2-(4-isopropylphenylimino)thiazolidin-4- one; 1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(4-methoxyphenylimino)thiazolidin-4-one; 1 ,1-dioxo-5-(3-(trifluoromethy[)benzyl)-2-(4-methoxypheπylimino)thiazoiidin-4- one;

1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(phenylimino)thiazolidin-4-one; 1 , 1 -dioxo-5-(3-(trifluoromethyl)benzyl)-2-(phenylimino)thiazolidin-4-one; 1-oxo-2-(3,4-dichlorophenylimino)-5-(3-(trifluoromethyl)benzyl)thiazolidin-4-one; 1 , 1 -dioxo-2-(3,4-dichlorophenylimino)-5-(3-(trifluoromethyl)benzyI)thiazolidin-4- one;

1-oxo-2-(2,4-dichlorophenylimino)~5-(3-(trifluoromethyl)benzyl)thiazolidin-4-one; 1 ,1-dioxo-2-(2,4-dichlorophenylimino)-5-(3-(trifluoromethyl)benzyl)thiazolidin-4- one;

1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(p-tolylimino)-3-methylthiazolidin-4-one; 1 ₎1-dioxo-5-(3-(trifluororτiethyl)benzyl)-2-(p-tolylimino)-3-methylthiazolidin-4-one; 1-oxo-N~(5-(3-(trifluoromethyl)benzyl)-4-oxothiazolidin-2-ylidene)-4- chlorobenzamide; 1 ,1 -dioxo-N-(5-(3-(trifluoromethyl)benzyl)-4-oxothiazolidin-2-ylidene)~4- chbrobenzamide;

1-oxo-5-(3-(trifluoromethyl)benzyI)-2-(4-chlorophenyl)sulfonyliminothiazolidin-4- one;

1,1-dioxo-5-(3-(trifluoromethyl)ben2yl)-2-(4-chlorophenyl)sulfonyliminothiazolidin- 4-one; phenyl 5-(3-(trifluoromethyl)benzyl)-1 ,4-dioxothiazolidin-2-ylidenecarbamate; phenyl 5-(3-(trifluoromethyl)benzy!)-1 , 1 ,4-trioxothiazoIidin-2-ylidenecarbamate; 1-oxo-5-(4-methoxyphenethy[)-2-(p-to!ylimino)thiazolidin-4-one; 1 , 1 -dioxo-5-(4-methoxyphenethyl)-2-(p-tolylimino)thiazolidin-4-one; 1-oxo-5-(4-methoxyphenethyI)-2-(phenylimino)thiazolidin-4-one; 1 , 1 -dioxo-5-(4-methoxyphenethyl)-2-(phenylimino)thiazoiidin-4-one; 1 -oxo-2-(p-tolylimino)-5-phenethylthiazolidin-4-one; and 1 , 1 -dioxo-2-(p-tolylimino)-5-phenethylthiazolidin-4-one.

35. A compound as claimed in Claim 34 wherein the compound is:

1-oxo-5-(3-(trifluoromethy[)benzyI)-2-(4-chlorophenyl)sulfonyliminothiazolidin-4- one; i .i-dioxo-δ-CS-CtrifluoromethyObenzyl^^-chlorophenyOsulfonyliminothiazolidin-

4-one; i-oxo-δ-CS^trifluoromethyObenzyO^S^-dichlorophenylimino^iλ^thiazolidin^- one; i . i-dioxo-δ^S-CtrifluoromethyObenzyO^S^-dichloropheπylimino^iλMhiazo!- idin-4-one;

[5-(3-trifluoromethylbeπzy!)-1 , 1 ,4-trioxo-1λ⁶-4λ⁴-[1 ,4₁2]dithiazolidin-3-ylidene]-(3,4- dichloro)phenyl-2-amine; [5-(3-trifluoromethy!benzyi)-1 ,1 ,4,4-tetraoxo-1λ⁶-4λ⁶-[1 ,4,2]dithiazolidin-3-yiidene]-

(3,4-dichloro)phenyl-2-amine;

[5-(3-trifluoromethylbenzyl)-1 ,1 ,4-trioxo-1λ⁶-4λ⁴-[1 ,4,2]dithiazolidin-3-ylidene]-(4- chloro)phenyl-2-amine;

^-(S-trifluoromethylbenzylhti ^^-tetraoxo-iλ^λ^fi ^^Jdithiazolidin-S-yiidene]- (4-chloro)phenyl-2-amine;

2-chlorophenyI 1-oxo-5-(3-(trifluoromethyl)benzyl)-4-oxothiazolidiπ-2-ylidene- carbamate;

2-chlorophenyl 1 , 1 ,-dioxo-5-(3~(trifluoromethyl)benzyl)-4-oxothiazolidin-2-yli- denecarbamate; 1-oxo-5-(3-(trifluoromethyl)benzyl)-2-(4-chlorophenylimino)thiazolidin-4-one; or

1 ,1-dioxo-5-(3-(trifluoromethyI)benzyl)-2-(4-chiorophenylimino)trιiazolidin-4-one.

36. A compound as defined in any one of the preceding claims, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for use as a pharmaceutical.

37. A pharmaceutical formulation including a compound as defined in any one of Claims 1 to 35, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

38. A combination product comprising:

(A) a compound of formula I as defined in any one of Claims 1 to 35, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; and

(B) another therapeutic agent useful in the treatment of cancer, wherein each of components (A) and (B) is formulated in admixture . with a pharmaceutically-acceptable adjuvant, diluent or carrier.

39. A combination product as claimed in Claim 38 which comprises a pharmaceutical formulation including a compound of formula I as defined in any one of Claims 1 to 35, or a pharrmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; another therapeutic agent useful in the treatment of cancer; and a pharmaceutically-acceptable adjuvant, diluent or carrier.

40. A combination product as claimed in Claim 38, 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 35, 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 cancer 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.

41. A kit of parts as claimed in Claim 40, wherein components (A) and (B) are suitable for sequential, separate and/or simultaneous use in the treatment of cancer.

42. A combination product as claimed in any one of Claims 38 to 41, wherein the other therapeutic agent is selected from: (i) a cytostatic, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (ii) an angiogenesis inhibitor, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;

(iii) tamoxifen, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof;

(iv) an aromatase inhibitor, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (v) trastuzumab, bevacizumab, cetuximab or panitumumab; (vi) a tyrosine kinase inhibitor, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (vii) a glitazone, or a pharmaceutically-acceptable salt,, solvate or pharmaceutically functional derivative thereof; (viii) metformin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; (ix) a statin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof; and/or (x) an inhibitor of activity of the mammalian target of rapamycin, or a pharmaceutically-acceptable salt, solvate or pharmaceutically functional derivative thereof.

43. A combination product as claimed in Claim 42, wherein the other therapeutic agent is selected from cisplatin, doxorubicin, tamoxifen, anastrozole, letrozole, exemastane, herceptin, imatinib, gefitinib, erlotinib, canertinib, sunitinib, zactima, vatalanib, sorafenib, leflunomide, lapatinib, rosiglitazone, metformin, fluvastatin, simvastatin, rosuvastatin, pravastatin, atorvastatin, lovastatin and rapamycin.

44. A combination product as claimed in Claim 43, wherein the other therapeutic agent is selected from cisplatin, doxorubicin, tamoxifen and herceptin.

45. The use of a compound of formula I as defined in any one of Claims 1 to 35, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, or a combination product as defined in any one of Claims 38 to 44, for the manufacture of a medicament for the treatment of cancer.

46. A compound as defined in any one of Claims 1 to 35, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, or a combination product as defined in any one of Claims 38 to 44, for use in the treatment of cancer.

47. A method of treatment of cancer, which method comprises the administration of an effective amount of a compound of formula I as defined in any one of Claims 1 to 35, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, or a combination product as defined in any one of Claims 38 to 44, to a patient in need of such treatment.

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48. A kit of parts as claimed in Claim 41 , a use as claimed in Claim 45, a compound as claimed in Claim 46, a combination product as claimed in. Claim 45 or Claim 46, or a method as claimed in Claim 47, wherein the cancer is of the colon, the breast or the prostate.

49. A kit of parts, use, compound, combination or method as claimed in Claim 48, wherein the cancer is of the breast.

50. A combination product comprising: (A) a compound of formula I as defined in any one of Claims 1 to 35, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; and

(B) another therapeutic agent useful in the treatment of a disorder or a condition caused by, linked to, or contributed to by, excess adiposity and/or hyperinsuϋnemia, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

51. A combination product as claimed in Claim 50 which comprises a pharmaceutical formulation including a compound of formula I as defined in any one of Claims 1 to 35, or a pharmaceutically-acceptable salt or solvate, or a pharmaceutically functional derivative thereof; another therapeutic agent useful in the treatment of a disorder or a condition caused by, linked to, or contributed to by, excess adiposity and/or hyperinsulinemia; and a pharmaceutically-acceptable adjuvant, diluent or carrier.

52. A combination product as claimed in Claim 50, 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 35, 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 a disorder or a condition caused by, linked to, or contributed to by, excess adiposity and/or hyperinsulinemia in admixture with a pharmaceuticaliy-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.

53. A kit of parts as claimed in Claim 52, wherein components (A) and (B) are suitable for sequential, separate and/or simultaneous use in the treatment of a disorder or a condition caused by, linked to, or contributed to by, excess adiposity and/or hyperinsuiinemia.

54. A combination product as claimed in any one of Claims 50 to 53, wherein the other therapeutic agent is selected from insulin, an insulin secretagogue, metformin, a peroxisome proliferator-activated receptor agonist, an α-glucosidase inhibitor, a GLP-1 receptor agonist, a DPP-IV inhibitor, exenatide, an inhibitor of 11 -beta hydroxysteroid dehydrogenase type 1 , an enzyme associated with conversion of cortisone to Cortisol in the liver and adipose tissue, and GLP-1 or gastric inhibitory polypeptide, or a biologically active fragment, variant, fusion or derivative of either of these peptides.

55. The use of a compound of formula I as defined in any one of Claims 1 to 35, or a pharmaceuticaliy-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, or a combination product as defined in any one of Claims 50 to 54, for the manufacture of a medicament for the treatment of a disorder or a condition caused by, linked to, or contributed to by, excess adiposity and/or hyperinsulinemia.

56. A compound as defined in any one of Claims 1 to 35, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, or a combination product as defined in any one of Claims 50 to 54, for use in the treatment of a disorder or a condition caused by, linked to, or contributed to by, excess adiposity and/or hyperinsulinemia.

57. A method of treatment of a disorder or a condition caused by, linked to, or contributed to by, excess adiposity and/or hyperinsulinemia, which method comprises the administration of an effective amount of a compound of formula I as defined in any one of Claims 1 to 35, or a pharmaceuticaliy-acceptable salt or solvate, or a pharmaceutically functional derivative thereof, or a combination product as defined in any one of Claims 50 to 54, to a patient in need of such treatment.

58. A kit of parts as claimed in Claim 53, a use as claimed in Claim 55, a compound as claimed in Claim 56, a combination product as claimed in Claim 55 or Claim 56, or a method as claimed in Claim 57, wherein the disorder or condition is hyperinsulinemia or an associated condition.

59. A kit of parts, use, compound, combination or method as claimed in Claim 58, wherein the condition is selected from hyperinsulinemia, type 2 diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, hyperinsulinism in childhood, hypercholesterolemia, high blood pressure, obesity, a fatty liver condition, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, a cardiovascular disease, atherosclerosis, a cerebrovascular condition, stroke, systemic lupus erythematosus, a neurodegenerative disease, Alzheimer's disease, polycystic ovary syndrome, progressive renal disease and chronic renal failure.

60. A kit of parts, use or method as claimed in Claim 59, wherein the condition is hyperinsulinemia or type 2 diabetes.

61. A kit of parts comprising:

(I) one of components (a) and (b) as defined in Claim 40, any one of Claims 41 to 44, 48 or 49 (as dependent on Claim 40), Claim 52, or any one of Claims 53, 54 or 58 to 60 (as dependent on Claim 52); together with

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

62. A method of making a kit of parts as defined in Claim 40, any one of Claims 41 to 44, 48 or 49 (as dependent on Claim 40), Claim 52, or any one of Claims 53, 54 or 58 to 60 (as dependent on Claim 52), 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.

63. A process for the preparation of a compound of formula I as defined in any one of Claims 1 to 35, which process comprises oxidation of a compound corresponding to a compound of formula I, in which T represents -S-.