FIELD OF THE INVENTION

The present invention relates to the use of some heterocyclic compounds, having a thiadiazolidine core, which act as peroxisome proliferator-activated receptor (PPAR) ligands, in particular gamma receptors (PPAR -gamma), thus being useful in the treatment of numerous diseases and conditions.

BACKGROUND OF THE INVENTION

Peroxisome proliferator-activated receptors, PPARs, are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. They were first recognized for their roles in peroxisome synthesis, to which they owe their name. Their normal ligands are fatty acids or fatty acid derivatives, but they can also bind synthetic agonists and can be activated in the laboratory by genetic manipulation. So far three types of PPARs of this nuclear receptor superfamily have been described: PPAR-alpha, PPAR- gamma and PPAR-delta. Each one is coded by a different gene, and has different properties. They act in the nucleus by forming heterodimers with another nuclear receptor, RXR (retinoid X receptor), binding to regulatory regions of DNA near the genes under their control and changing the rate of transcription of those genes. PPAR- gamma, which is the most studied sub-type, is known to be expressed primarily in adipose tissue, spleen, colon and macrophages, but much less in liver, skeletal muscle, heart and pancreas; it is involved in turning on genes necessary to the differentiation of fibroblasts into adipocytes and genes that encode proteins required for lipid synthesis and storage in adipocytes, thus performing key functions in the regulation of the lipidic metabolism, in the glucose homeostasis, as well as in cell differentiation.

Recent research has proved that PPAR-gamma is involved in some types of cancer, in cardiovascular diseases, metabolic alterations like obesity and diabetes, and different inflammatory processes, including CNS (central nervous system)

inflammations. The multiple implications which have been found for PPAR-gamma, and their mechanism of action and that of their ligands, have turned them into attractive therapeutic targets of the synthesis and design of new molecules with potential activity for the treatment of the above-mentioned diseases and metabolic alterations.

Metabolic syndrome, obesity and diabetes

Type II diabetes is a common metabolic disorder which has no effective treatment, and involves a subnormal or inadequate amount of circulating endogenous insulin. PPAR-gamma agonists, especially a family of compounds known as thiazolidinedione (TZD) derivatives have shown their clinical efficiency, causing an important decrease of the plasmatic levels of glucose, insulin, triglycerides and fatty acids (see for example "Experimental Approaches to Study PPAR-gamma Agonists as Antidiabetic Drugs", Methods Find Exp CHn Pharmacol 2002, 24(8): 515-523, Vazquez et al.; US 6,787,556 Bl and US 6,716,514 Bl). The first TZD used in therapeutics was the troglitazone; another two TZD, rosiglitazone and pioglitazone, are used since 1999 for the treatment of diabetes II. These compounds are PPAR-gamma agonists and their action is due mainly to the activation of said receptor. It has been shown that there is a clear correlation between affinity towards PPAR-gamma and clinical efficiency (Plutzky J., 2003, "The potential role of PPARs on inflammation in type 2 diabetes mellitus and atherosclerosis". Am J Cardiol. 92: 34J-41J). Through TZD it has been possible to show that the stimulation of PPAR-gamma increases the sensibilization towards insulin and the adipogenesis; said activation conducts to biochemical and metabolic changes related to an increase in the sensibility towards insulin.

Further, for years researchers have studied a mysterious disease known as "Syndrome X", also known as "methabolic syndrome". Afflicted people have insulin inefficiency or resistance to insulin in the liver, adipose tissue, and skeletal muscle. It is generally associated to the compensatory hypersecretion of insulin and, in the long run, to a progressive deterioration of the beta cells in the pancreas. This culminates in unhealthy cholesterol levels, high blood sugar levels and inflamed arteries; all these symptoms increase the likelihood of having a heart attack or a stroke. The syndrome seems to be originated both in genetic factors and environmental factors (obesity, sedentary way of life, etc.).

The main target that is envisaged to treat this syndrome are PPARs, as it has been observed that the pharmacological activation of PPAR-gamma increases significantly the sensibility towards insulin of the peripheric tissues. Drugs of the thiazolidinedione class (TZD) have also here clearly shown their clinical efficiency causing an important decrease of the plasmatic levels of glucose, insulin, triglycerides and fatty acids.

Inflammation

It has been shown that PPAR can participate in the regulation of inflammatory responses and can modulate the intensity, duration and consequences of inflammatory events. See for example Nature 391, 82-86 (1998), "PPAR-gamma agonists inhibit the production of monocyte inflammatory cytokines", Jiang et al.

PPAR-gamma specific ligands have been shown to have potent anti¬ inflammatory effects, as they inhibit the production of many inflammatory cytokines (such as tumour-necrosis factor (TNF), interleukin-lβ (IL- lβ) and IL-6), the inducible nitric oxide synthase (iNOS), cyclooxygenase type 2 (COX2), and the expression of matrix metalloproteinase 9 (MMP9) and macrophage scavenger receptor 1 (MSRl) on various cell types, including monocytes, macrophages and epithelial cells.

Of relevance to CNS diseases is that PPAR-gamma agonists have been demonstrated to have similar anti-inflammatory effects on astrocytes and microglial cells (review in Kielian and Drew, 2003, "Effects of peroxisome proliferator-activated receptor-gamma agonists on central nervous system inflammation". J Neurosci Res

71:315-325).

Inflammatory activation of neuronal, as well as glial cells is believed to contribute to cell death and damage during neurological disease. One of the hallmarks of neurodegenerative and inflammatory pathologies is the increased number of activated astrocytes and microglia in response to the pathological stimulus (Arvin et al., 1996,

"The role of inflammation and cytokines in brain injury". Neurosci Biobehav Rev

20:445-452.; Sheng et al., 1997, "Neuritic plaque evolution in Alzheimer's disease is accompanied by transition of activated microglia from primed to enlarged to phagocytic forms". Acta Neuropathol (Berl) 94:1-5.). Under normal conditions, brain microglia are

involved in immune surveillance and host defense against infectious agents (Gehrmann et al., 1995, "Microglia: intrinsic immuneffector cell of the brain". Brain Res Brain Res Rev 20:269-287). However, in response to brain injury, infection, or inflammation, microglia readily become activated in a way similar to peripheral tissue macrophages. Now, there is a growing evidence that toxic mediators, including tumour necrosis factor (TNF)-α, IL-6, and nitric oxide (NO), produced by activated microglial cells might be involved in the pathogenesis of various neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, and the AIDS dementia (McGeer and McGeer, 1995, "The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases". Brain Res Brain Res Rev 21 :195-218; Minghetti and Levi, 1998, "Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide". Prog Neurobiol 54:99-125; Gonzalez-Scarano and Baltuch, 1999, "Microglia as mediators of inflammatory and degenerative diseases". Annu Rev Neurosci 22:219-240). Astrocytes, which are responsible for maintaining the homeostasis of the brain tissue, also participate to a large extend in the neuroimmune responses (Genis et al., 1992, "Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HΙV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease". J Exp Med 176:1703-1718; Lassmann et al., 1994, "Differential role of hematogenous macrophages, resident microglia and astrocytes in antigen presentation and tissue damage during autoimmune encephalomyelitis". Neuropathol Appl Neurobiol 20:195-196.). Hence, it is of great interest to find a means to modulate microglial activation in CNS inflammatory responses for the therapeutic intervention against these neurodegenerative diseases.

Cardiovascular disease

Previous works using a pre-macrophage cell line have showed that activation of PPAR-gamma-signalling enhanced macrophage differentiation, inducing expression of CD36, which is one of the cell's "scavenger" receptors for the atherogenic low- density lipoprotein (LDL). It is postulated that increased CD36 expression leads to an intracellular accumulation of cholesterol and to the production of natural PPAR-gamma , ligands. This would conduct to additional activation of PPAR-gamma, thus creating a vicious cycle of ever-increasing lipid accumulation and conversion of macrophages,

into atherogenic foam cells. Additionally, PPAR-gamma ligands have also shown to reduce inflammatory cytokine production by macrophages, an effect which is anti¬ atherogenic. Actually, it has been shown that atherosclerosis is reduced in rodents and also in patients, which have been treated with PPAR-gamma ligands. (Mitchell A. Lazar, "Progress in cardiovascular biology: PPAR for the course", Nature Medicine, January 2001 vol. 7, NoI).

Cancer

In vitro and in vivo studies show the importance of specific PPAR-gamma ligands as cell-cycle modulators (see for example "Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators", Cancer Treatment Reviews, Volume

30, Issue 6, Pages 545 - 554, Theocharis et al.), and their role as cell-cycle modulators as well as their role in cell proliferation, apoptosis and cancer.

It has also been disclosed that peroxisome proliferator-activated receptor- gamma (PPAR-gamma) ligands inhibit the growth of PPAR-gamma expressing cancer cells through terminal differentiation (see Int J Oncol. 2004 Sep; 25(3):631-9, "Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation- promoting effects"; and US 6,756,399 B2). The authors of the above mentioned article have developed a rectal cancer xenograft animal model in which anti-tumour and anti- metastatic efficacy of agents can be evaluated. The study was designed to examine whether thiazolidinedione (TZD) could inhibit growth and metastasis of PPAR-gamma positive HT-29 human colon cancer cells through the induction of terminal differentiation. TZD caused Gl arrest in association with a marked increase in p21Waf- 1, Drg-1, and E-cadherin expression. In untreated cancer cells, fluorescence immunostaining demonstrated beta-catenin in the nucleus and/or cytoplasm; in TZD- treated cancer cells, beta-catenin localization shifted to the plasma membrane, in association with increased E-cadherin at this site and reduced tyrosine phosphorylation of beta-catenin. In addition, TZD completely inhibited lymph node and lung metastasis in the xenograft animal model, and TZD inhibited growth of primary xenografts by 40%. The results suggest that TZD can function as a cytostatic anti-cancer agent to inhibit growth and metastasis of HT-29 colon cancer cells through differentiation-

promoting effects. These effects seem to involve not only modulation of the E- cadherin/beta-catenin system, but also up-regulation of Drg-1 gene expression.

Similar results have also been published for pituitary tumours, which cause considerable morbidity due to local invasion, hypopituitarism, or hormone hypersecretion. (J Clin Invest. 2003 May; 11 1(9): 1381 -8, "PPAR-gamma receptor ligands: novel therapy for pituitary adenomas", Heaney et al.) The authors show abundant expression of nuclear hormone receptor PPAR-gamma in all of 39 human pituitary tumours. PPAR-gamma activating thiazolidinediones (TZDs) rosiglitazone and troglitazone induced G(O)-G(I) cell-cycle arrest and apoptosis in human, rat somatolactotroph, and murine gonadotroph pituitary tumour cells, and suppressed in vitro hormone secretion. In vivo development and growth of murine somatolactotroph and gonadotroph tumours, generated by subcutaneous injection of prolactin-secreting (PRL-secreting) and growth hormone-secreting (GH-secreting) GH3 cells, luteinizing hormone-secreting (LH-secreting) LbetaT2 cells, and alpha-T3 cells, was markedly suppressed in rosiglitazone-treated mice, and serum GH, PRL, and LH levels were attenuated in all treated animals (P < 0.009). The results demonstrate that PPAR-gamma is an important molecular target in pituitary adenoma cells and PPAR-gamma ligands inhibit tumour cell growth and GH, PRL, and LH secretion in vitro and in vivo.

Another study ("Therapeutic potential of thiazolidinediones as anticancer agents", Expert Opin. Investig. Drugs. 2003 Dec; 12(12):1925-37; Panigrahy et al) focuses on the PPAR-gamma ligand rosiglitazone, a compound widely used in the treatment of type II diabetes, as mentioned above. It is demonstrated that PPAR-gamma is highly expressed in tumour endothelium and is activated by rosiglitazone in cultured endothelial cells. Furthermore, it is shown that rosiglitazone suppresses primary tumour growth and metastasis by both direct and indirect antiangiogenic effects. Rosiglitazone inhibits bovine capillary endothelial cell but not tumour cell proliferation at low doses in vitro and decreases VEGF production by tumor cells. In in vivo studies, rosiglitazone suppressed angiogenesis in the chick chorioallantoic membrane, in the avascular cornea, and in a variety of primary tumours. The results show that PPAR-gamma ligands may be useful in treating angiogenic diseases such as cancer by inhibiting angiogenesis.

Asthma and allergies

Moreover, it has been found (see, for example, US 2004/0122059 Al), that ligands for PPAR-gamma significantly reduce the immunological symptoms of allergic asthma.

According to all the above, it is evident that a need for synthesis and design of new molecules that are selective PPAR ligands and therefore with potential activity for the treatment of the above-mentioned diseases and conditions exists.

SUMMARY OF THE INVENTION We have found a family of structurally distinct compounds having a thiadiazolidine heterocycle core which are potent PPAR ligands and have good pharmacological properties.

According to one aspect the invention is directed to the use of a compound of general formula (I)

wherein:

R ^a and R ^b are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, -COR ¹ , -C(O)OR ¹ , -C(O)NR ¹ R ² , -C=NR ¹ , -CN, -OR ¹ , -OC(O)R ¹ , - S(O) ₁ -R ¹ , or halogen, t is selected from 0, 1, 2, or 3;

X and Y are independently selected from =0, =S, =N(R'), =C(R')(R ² ) or two H;

R ¹ and R ² are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy or halogen; in the preparation of a medicament for the treatment of a PPAR mediated disease or condition or a disease or condition requiring activation of PPAR.

Preferably, in the compound of formula (I), R ^a and R ^b are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, and -(CH ₂ ) _n -

C(O)OR ¹ wherein R ¹ is as defined in claim 1 and n is selected from 1, 2, 3, 4, 5, 6, 7 or

8.

In another preferred variant of the invention at least one of R ^a or R ^b contains an aromatic group.

In another preferred embodiment the sustituents R ^a and R ^b in the compounds of formula (I) are independently selected from methyl, ethyl, propyl, isopropil, adamantyl and -CH ₂ -CO ₂ -ethyl, or from benzyl, phenyl, naphthyl, phenylethyl, diphenylmethyl, 2- benzyl-phenyl or phenoxyphenyl optionally substituted with a group selected from methyl, ethyl, terbutyl, fluoro, chloro, bromo methoxy or methylendioxy.

Good PPAR activation properties have been obtained when R ^a in the compound of formula (I) is independently selected from phenyl, benzyl or -CH ₂ -CO ₂ EtIIyI.

In another embodiment it is preferred that X and Y in positions 3 and 4 of the thiadiazolidine heterocycle are independently selected from =0, =S and =NR ^! , wherein R ¹ is heterocyclyl or aryl. Preferably X is =0, most preferably X is =0 and Y is =0.

In another preferred embodiment a class of compounds which is especially preferred is that wherein R ^a is independently selected from phenyl, benzyl or -CH ₂ - CO ₂ EAyI, X is =0; and Y is =0.

In another aspect the invention is directed to a use as defined above wherein the disease or condition is selected from diabetes, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia,

Huntingdon's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis acute stroke, schizophrenia and bipolar disorders, cerebral bleeding due to solitary cerebral amyloid angiopathy, ischaemia, traumatic brain injury, neurogenic pain, cancer, atheriosclerosis, infarction, obesity, Syndrome X, inflammatory diseases, hyperplasias, immunodeficiency, asthma or allergies.

In another embodiment the invention is directed to a method of treating diabetes, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia, Huntingdon's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis acute stroke, schizophrenia and bipolar disorders, cerebral bleeding due to solitary cerebral amyloid angiopathy, ischaemia, traumatic brain injury, neurogenic pain, cancer, atheriosclerosis, infarction, obesity, Syndrome X, inflammatory diseases, hyperplasias, immunodeficiency, asthma or allergies comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined above or or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

DESCRIPTION OF THE INVENTION

Heterocyclic compounds having among others a core thiadiazolidine, in particular thiadiazolidindiones (TDZD) and other heterocyclic compounds, were initially described as the first non-ATP competitive inhibitors of glycogen synthase kinase-3 beta (GSK-3β) (see WO 01/85685). These thiadiazolidines and derivatives are small molecules with favourable ADME-Tox drugable properties, such as oral bioavailability and blood-brain barrier penetration.

Surprisingly it has now been found that the heterocyclic compounds of general formula (I) as defined above do exhibit PPAR-gamma activating properties.

In the above definitions, unless specified to the contrary, the following terms have the meaning indicated:

"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having one to 12 carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc. Alkyl radicals may be optionally substituted by one or more substituents such as a aryl, halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, alkylthio, etc. If substituted by aryl we have an "Aralkyl" radical, such as benzyl and phenethyl.

"Alkenyl" refers to an alkyl radical having at least 2 C atoms and having one or more unsaturated bonds. "Cycloalkyl" refers to a stable 3-to 10-membered monocyclic or bicyclic radical which is saturated or partially saturated, and which consist solely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl. Unless otherwise stated specifically in the specification, the term"cycloalkyl" is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy, alkoxycarbonyl, etc.

"Aryl" refers to single and multiple ring radicals, including multiple ring radicals that contain separate and/or fused aryl groups. Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms, such as phenyl, naphthyl, indenyl, fenanthryl or anthracyl radical. The aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl, alkoxycarbonyl, etc.

"Aralkyl" refers to an aryl group linked to an alkyl group. Preferred examples include benzyl and phenethyl.

"Heterocyclyl" refers to a stable 3-to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, preferably a 4-to 8-membered ring with one or more heteroatoms, more preferably a 5-or 6-membered ring with one or more heteroatoms.

For the purposes of this invention, the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quaternized ; and the heterocyclyl radical may be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, coumarine, morpholine; pyrrole, pyrazole, oxazole, isoxazole, triazole, imidazole, etc.

"Alkoxy" refers to a radical of the formula -OR ^a where R ^a is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc.

"Alkoxycarbonyl" refers to a radical of the formula-C (O) OR ^a where R ^a is an alkyl radical as defined above, e. g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.

"Alkylthio" refers to a radical of the formula-SR ^a where R ^a is an alkyl radical as defined above, e. g., methylthio, ethylthio, propylthio, etc.

"Amino" refers to a radical of the formula-NH ₂ , -NHR ^a or -NR ^a R ^b , optionally quaternized.

"Halo" or "hal" refers to bromo, chloro, iodo or fluoro.

References herein to substituted groups in the compounds of the present invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups, e. g., halogen such as fluoro, chloro, bromo and iodo ; cyano; hydroxyl ; nitro ; azido ; alkanoyl such as a C 1-6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon

atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms ; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; carbocylic aryl having 6 or more carbons, particularly phenyl or naphthyl and aralkyl such as benzyl. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.

Particular individual compounds of the invention include the compounds 1-24 in the examples, either as salts or as free bases.

Especially preferred are 2,4-dibenzyl-[l,2,4]thiadiazolidine-3,5-dione, 4-benzyl- 2-naphthyl-[ 1 ,2,4]thiadiazolidine-3,5-dione, 2-ethyl-4-phenyl-[ 1 ,2,4]thiadiazolidine- 3,5-dione, 2,4-di(ethoxycarbonylmethyl)-[l,2,4]thiadiazolidine-3,5-dion e or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

The term "pharmaceutically acceptable salts, solvates, prodrugs" refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as described herein. However, it will be appreciated that non- pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts, prodrugs and derivatives can be carried out by methods known in the art.

For instance, pharmaceutically acceptable salts of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.

Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of the acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p-toluenesulphonate. Examples of the alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glucamine and basic aminoacids salts.

Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

The compounds of formula (I) are also mean to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a ¹³ C- or ¹⁴ C- enriched carbon or

¹⁵ N-enriched nitrogen are within the scope of this invention.

Any compound that is a prodrug of a compound of formula (I) is within the scope of the invention. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al. "Textbook of Drug design and Discovery" Taylor & Francis (april 2002).

The compounds of the invention may be in crystalline form either as free compounds or as solvates and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate.

The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts, solvates or prodrugs.

The compounds of the present invention represented by the above described formula (I) may include enantiomers depending on the presence of chiral centres or isomers depending on the presence of multiple bonds (e.g. Z, E). The single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.

The compounds of formula (I) defined above can be obtained by available synthetic procedures. For examples the procedures disclosed in WO 01/85685 or US 2003/0195238 as well as our copending EP04 075 597.9 and references therein. The content of these documents is incorporated herein by reference in its entirety.

For example, the following procedure can be used to produce 4-N-benzyl substituted thiadiazolidindiones:

The general experimental procedure of Scheme 1 is described for example in Slomczynska, U.; Barany, G., "Efficient Synthesis of l,2,4-Dithiazolidine-3,5-diones (Dithiasuccinoyl-amines) and observations on formation of l,2,4-Thiadiazolidine-3,5- dione by related Chemistry", J. Heterocyclic Chem., 1984, 21, 241-246..

For example, sulfuryl chloride is added dropwise with stirring, under nitrogen atmosphere, at low temperature, preferably at about 5 ⁰ C, to a solution of benzyl isothiocyanate and the isocyanate indicated in each case, in a suitable solvent such as hexane, eter or THF. When the addition is finished, the mixture is left to react, for example by stirring for 20 hours at room temperature. After this time, the resulting product is isolated by conventional methods such as suction filtration or solvent evaporation and then, the purification is performed (e.g. by recristallization or silica gel column chromatography using the appropriate eluent).

Other alternative procedures will be apparent for the person skilled in the art, such as the use of any other chlorinating agent instead of sulfuryl chloride, variations in the order of addition of the reactants and reaction conditions (solvents, temperature, etc).

The reaction products may, if desired, be purified by conventional methods, such as crystallisation, chromatography and trituration.

The compounds used in the invention are useful for treating diseases and conditions wherein an activation of PPAR-gamma is required. This encompasses any disease or other deleterious condition or state wherein PPAR-gamma is known to play a role. Such diseases or conditions include, without limitation, diabetes, especially

diabetes of type II, and conditions associated with diabetes; neurodegenerative conditions including dementias, especially those wherein an inflammatory process is involved, such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, fronto temporal dementia, Huntingdon's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding (for example, due to solitary cerebral amyloid angiopathy), ischaemia and traumatic brain injury; neurogenic pain; oncological conditions, such as cancer; cardiovascular conditions, such as atheriosclerosis and infarction; and other conditions such as obesity, Syndrome X, inflammations and inflammatory diseases of any type and hyperproliferative diseases such as hyperplasias and immunodeficiency, and asthma and allergies.

The utility of the compounds of the present invention, their prodrugs and the salts of such compounds and prodrugs as medical agents in the treatment of the above described disease/conditions in mammals, preferably humans (male or female) is demonstrated by the activity of the compounds of the present invention in one or more of the conventional assays and in vivo assays described below.

The use of the compounds of formula (I) may be performed through pharmaceutical compositions comprising a compound of formula (I), a pharmaceutically acceptable salts, derivatives, prodrugs or stereoisomers thereof with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration. The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US

Pharmacopoeias and similar reference texts.

The use of the compounds of formula (I) may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated.

Generally the use of the compounds in an effective administered amount will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer. However, active compounds will typically be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.

The compounds and compositions of this invention may be used with other drugs to provide a combination therapy. The other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.

Preferably, the compounds of general formula (I) are used for the treatment of a neurodegenerative disease, preferably selected from Alzheimer's Disease, Parkinson's Disease, stroke and ischemia.

According to further embodiments, but not limited to, the compounds of formula (I) are used for the treatment of any of diabetes, metabolic syndrome, obesity, and any cardiovascular disease.

In the following, the present invention will be further illustrated by a series of examples, which in no case should be interpreted as limitative to the scope of the present invention.

EXAMPLES

In order to determine the PPAR-gamma activation properties of the compounds of formula (I) according to the present invention, the following assay was performed:

PPAR-gamma activation was measured as an increase in light intensity after transfection of CHO cells with plasmid p(A-Ox ₃ )-TKSL, containing PPAR-gamma consensus binding sites (PPRE) linked to tk-luciferase as a reporter gene (for details, see Tugwood JD et al., EMBO J. 1992, 11 : 433-9).

CHO-Kl cells (ATCC # CCL-61) were maintained in Ham's Fl 2 Medium (Invitrogen) containing 10% Fetal Bovine Serum (FBS), 2mM glutamine and Penicillin: Streptomycin (100 U/ml : 100 μ/ml) at 37 ⁰ C with 5% CO ₂ .

Transient transfections were carried out with Lipofectamine 2000 (Invitrogen) following manufacturer's instructions.

Briefly, cells were plated (96 well-plates) in antibiotic-free medium the day before transfection. DNA:Lipofectamine complexes were added to cells and incubated at 37 ⁰ C. After 12 hours, cells were washed and different assays were performed: in the wells either a compound of formula (I) at concentrations ranging from 0.1-100 μM, or an internal control of the assay (which are known PPAR-gamma activators; see below) was added, in serum-free medium. 24 hours later luciferase activity was measured with Steady Lite HTS reactive (Perkin Elmer, MA, USA) and processed in a Wallac, Trilux 1450 Microbeta (Perkin Elmer, MA, USA) reader. As internal controls for PPAR- gamma activation two different molecules were used:

1) 15-Deoxy-Δ ^12>I4 -prostaglandin J ₂ (10 μM) (Calbiochem, San Diego, CA, USA), as a natural ligand for PPAR-gamma.

2) Rosiglitazone (30 μM) (Calbiochem, CA, USA) described as a selective activator of the peroxisome receptor.

As a control of inhibition the PPAR-gamma antagonist GW 9662 (30 μM) (Cayman Chemical, MI, USA) was also used.

All the assays were performed at least three times in triplicate.

Moreover, as a control of cellular viability, i.e., to determine the compounds' toxicity, Lactate Dehydrogenase (LDH, Citotoxicity Detection Kit Roche,

Mannheim, Germany) released from the cytosol of damaged cells into the supernatant was measured in parallel.

24 different compounds of formula (I) were tested in the conditions above described. The results obtained are shown in table 1. Cell viability in all cases was higher than 80%, so that the compounds were considered non-toxic.

The criteria used to determine whether a compound acted as a PPAR-gamma activator was the following: compounds for which the luminescence increased compared to the basal value (that is, when no PPAR-gamma activator was added), were considered as PPAR-gamma activators; compounds for which the luminescence was equal or below the basal value, were considered as not activating PPAR-gamma.

As shown in table 1, the compounds tested are considered as activators of PPAR-gamma (shown with + symbol in the table), at the concentration written within brackets behind the symbol.