Title of Invention

COMPOUNDS AND THEIR SALT SPECIFIC TO THE PPAR RECEPTORS AND THE EGF RECEPTORS AND THEIR USE IN THE MEDICAL FIELD

Abstract

The present invention relates to compounds comprising the general formula (I), in which R1and R2, which may be identical or different, are selected from the group comprising -H or a linear or branched alkyl group having from 1 to 6 carbon atoms or together form an aromatic or aliphatic ring with 5 or 6 atoms; Y and Z, which may be identical or different, are selected from the group comprising -H, -OH, -COOH, -OR3, -CH(OR3)COOH, in which R3 is selected from H, phenyl, benzyl, -CF3 or -CF2CF3, vinyl, allyl and a linear or branched alkyl group having from 1 to 6 carbon atoms.

Full Text

FIELD OF THE INVENTION The present invention relates to compounds and their salts specific to the PPAR receptors and the EGF receptors and their use in the medical field. OBJECT OF THE INVENTION In particular, the compounds and their salts according to the present invention can be used advantageously for the prevention and treatment of tumours expressing the PPARy receptors (Peroxisome Proliferator-Activated Receptors) and the EGF receptors (Epidermal Growth Factor receptors) such as tumours of the: oesophagus, stomach, pancreas, colon, prostate, breast, uterus and appendages, kidneys and lungs. Moreover, the compounds and their salts according to the invention can be used for the treatment of chronic inflammatory diseases, in particular chronic intestinal diseases, such as Crohn's disease and ulcerative rectocolitis. BACKGROUND TO THE INVENTION The PPARy receptors are nuclear receptors (group of approx. 50 transcription factors) which control the expression of many genes that are important for the regulation of lipid metabolism, the synthesis of insulin and the processes of carcinogenesis and inflammation. (Bull AW, Arch Pathol Lab Med 2003;127: 1121-1123) (Koeffler HP, Clin Cancer Res 2303; 9: 1-9) (Youssef J et a/., J Biomed Biotec 2004; 3: 156-166). There are various natural and synthetic agonists which bind to the PPARy receptors and alter their conformation, giving rise to activation. Natural and synthetic ligands are described in The Lancet 2002; 360:1410-1418. Recent studies have shown that treatment of tumour cells with ligands of the PPARy receptors induces a decrease in cellular proliferation, cell differentiation and apoptosis, suggesting potential application of such compounds as agents for preventing carcinogenesis (Osawa E etal, Gastroenterology 2003; 124:361-367). Other studies have shown that ligands of the PPARy receptors (e.g. troglitazone) have anti-inflammatory effects and inhibit the mucosal inflammatory response in animal models of IBD (Tanaka T ef al., Cancer Res 2001; 61: 2424-2428). Moreover, evidence has been published very recently that the intestinal anti- inflammatory activity of 5-ASA, the gold standard in the treatment of IBD, is dependent on binding, and consequent activation, of the PPARy receptors (Rousseaux C er al., J Exp Med 2005; 201: 1205-1215). The transmembrane receptor with tyrosine-kinase EGF activity is expressed to a very high degree in activated form in various types of neoplasms (Mendelsohn J, Endocr Relat Cancer 2001; 8: 3-9) (Harari PM, Endocr Relat Cancer 2004; 11: 689-708). Overexpression of the receptor is also related to potential ability of carcinomatous cells to metastasize. In connection to this, it has been demonstrated that EGF promotes the migration and invasiveness of various cell types connected with lesions at the level of interactions with the extracellular matrix (Brunton et al., Oncogene 1997; 14: 283-293). Numerous studies performed both on experimental animals and in humans have established the efficacy of inhibitors of the EGF receptor in controlling proliferation and the spread of tumours (Mendelsohn J, Endocr Relat Cancer 2001; 8: 3-9) (Harari PM, Endocr Relat Cancer 2004; 11: 689-708). There is no doubt that the intracellular signals triggered by activation of the EGF receptor facilitate the growth and survival of neoplastic cells, contributing to the development of the pathology, and that such signals are essential in determining the ability of tumour ceils to spread and colonize remote organs.- (Mendelsohn J, Endocr Relat Cancer 2001; 8: 3-9) (Kari C et al., Cancer Res 2003; 63: 1-5). From the foregoing and bearing in mind, moreover, that from the biological standpoint, chronic inflammatory processes play a part in carcinogenesis, it becomes clear that there is a real need for innovative research into new chemical entities which, by their complementary action both on the PPARy receptors and on the EGF receptors, are able to exert anti-inflammatory and anti-tumour action, of the chemo-preventive, anti- proliferative and anti-metastatic type. The present invention provides a novel class of compounds that are suitable for the prevention and treatment of cancer and of chronic inflammation by the modulation of specific receptors such as the PPARy receptors and the EGF receptors. SUMMARY OF THE INVENTION The present invention relates to novel and inventive medical and therapeutic uses of a series of compounds In so far as any of these compounds are not known, the invention also relates to these compounds. The present invention relates to compounds comprising the general formula (I) in which R1 and R2, which may be identical or different, are selected from the group comprising - H or a linear or branched alkyl group having from 1 to 6 carbon atoms or together form an aromatic or aliphatic ring with 5 or 6 atoms; Y and Z, which may be identical or different, are selected from the group comprising - H, -OH, -COOH, -OR3, -CH(OR3)COOH, in which R3 is selected from H, phenyl, benzyl , -CF3 or -CF2CF3, vinyl^aiiyl and a linear or branched alkyl group having from 1 to 6 carbon atoms. The present invention also relates to a subgroup of compounds, of general formula (la) in which R1 and R2, which may be identical or different, are selected from the group comprising - H or a linear or branched alkyl group having from 1 to 6 carbon atoms Y and Z, which may be identical or different, are selected from the group comprising - H, -OH, -COOH, -OR3, -CH(OR3)COOH, in which R3 is selected from -H and a linear or branched alkyl group having from 1 to 6 carbon atoms. In some embodiments of the invention, Z and Y are different. In some embodiments of the invention, at least one of Y or Z terminates in -COOH. Therefore, in some embodiments of the invention, Y or Z (and in some embodiments at least one of Y or Z, and in some embodiments, only one of Y or Z) is -COOH. In some embodiments of the invention, Y or Z (and in some embodiments at least one of Y or Z, and in some embodiments, only one of Y or Z) is -CH(OR3)COOH. The present invention also relates to compounds according to both formula (I) and (la), except wherein Y and Z, which may be identical or different, are selected from the group comprising -H, -COOH, -OR3l -CH(OR3)COOH. Therefore, in some embodiments of the invention, Z or Y may not be -OH. In such embodiments of the invention, compounds 10 and 11 are excluded. In some embodiments of the invention, when Y is -H and Z is -CH(OH)COOH, the group NR1R2 is connected at the 3' position. Thus, in some embodiments of the invention, compound 21 is excluded: In other embodiments of the invention, when Z is -OCH3 and Y is -COOH, the group NR1R2 is connected at the 4' position. Thus, in some embodiments of the invention, the compound 22 is excluded. In some embodiments of the invention, when Y is -H and Z is -CH(OCH3)COOH, the group NR1R2 is connected at the 4' position. Thus, in some embodiments of the invention, compound 35 is excluded: In particular, the aforementioned linear or branched alkyl group having from 1 to 6 carbon atoms can be selected from -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CnH2n-1. The compounds of formula (I) and (la) can be selected from the group comprising 3-(3'-aminophenyl)2-hydroxypropanoic acid (compound 20) 2-(4-aminophenyl)2-methoxyacetic acid (compound 23) 2-(3-aminophenyl)2-ethoxyacetic acid (compound 32) 2-(4-aminophenyl)2-ethoxyacetic acid (compound 33) 3-(4'-aminophenyl)2-methoxypropionic acid (compound 34) 3-(4'-aminophenyl)2-ethoxypropionic acid (compound 39) 3-(3'-aminophenyl)2-ethoxypropionic acid (compound 40). The above compound names can also be written in standard chemical nomenclature as follows (which nomenclature will be used throughout the text): (±)-2-hydroxy-3-(3'-aminophenyl) propionic acid (compound 20) (+)-2-methoxy-2-(4'-aminophenyl) acetic acid (compound 23) (±)-2-ethoxy-2-(3'-aminophenyl) acetic acid (compound 32) (±)-2-ethoxy-2-(4'-aminophenyl) acetic acid (compound 33) (±)-2-methoxy-3-(4'-aminophenyl) propionic acid (compound 34) (±)-2-ethoxy-3-(4'-aminophenyl) propionic acid (compound 39) (±)-2-ethoxy-3-(3'-aminophenyl) propionic acid (compound 40). The compounds according to the present invention can be used advantageously in the medical field. Therefore the present invention relates to a pharmaceutical composition comprising one or more compounds as defined above as active principles in combination with one or more pharmaceutically acceptable excipients or adjuvants. The present invention relates, moreover, to the use of the compounds as defined above for the preparation of a medicinal product for the prevention and treatment of tumours expressing the PPARy receptors and the EGF receptors such as, for example, tumour of the oesophagus, stomach, pancreas, colon, prostate, breast, of the uterus and its appendages, of the kidneys and of the lungs. Moreover, theinvention relates to the use of the compounds according to the invention for the preparation of a medicinal product for the treatment of chronic inflammatory diseases such as, for example, Crohn's disease and ulcerative rectocolitis. In particular, the compounds according to the invention that can be used in the aforementioned applications, apart from those already described, can be as follows: (R,S)-2-hydroxy-2-(3-aminophenyl)acetic acid (compound 10) (R,S)-2-hydroxy-2-(4-aminophenyl)acetic acid (compound 11) (R,S)-2-hydroxy-3-(4'-aminophenyl)propionic acid (compound 21) (R,S)-2-methoxy-3-(3'-aminophenyl)propionic acid (compound 35) (R,S)-2-methoxy-3-(3-aminophenyl)propionic acid(compound 34). The above compound names can also be written in standard chemical nomenclature as follows (which nomenclature will be used throughout the text): (±)-2-hydroxy-2-(3'-aminophenyl)acetic acid (compound 10) (±)-2-hydroxy-2-(4'-aminophenyl)acetic acid (compound 11) (±)-2-hydroxy-3-(4'-aminophenyl)propionic acid (compound 21) (±)-2-methoxy-3-(3'-aminophenyl)propionic acid (compound 35) (±)-2-methoxy-3-(4'-aminophenyl)propionic acid(compound 34). According to one embodiment, R3 of the compounds of formula (I) can be H according to the following formula (II) while R1, R2, X and Y are defined above. According to another embodiment, R3 of the compounds of formula (I) can be -CH3 according to the following formula (III) while R1,R2, X and Y are defined above. According to another embodiment, R3 of the compounds of formula (I) can be -CH2CH3 according to the following formula (IV) while R1, R2, X and Y are defined above. According to another embodiment, R3 of the compounds of formula (I) can be -CH2CH3 according to the following formula (V) while R1, R2 X and Y are defined above. According to another embodiment, R3 of the compounds of formula (I) can be -CH3 according to the following formula (VI) while R1, R2, X and Y are defined above. According to another embodiment, R3 of the compounds of formula (I) can be -CH3 according to the following formula (VI) while R1, R2| X and Y are defined above. According to another embodiment, R3 of the compounds of formula (!) can be-CH2CH3 according to the following formula (VII) while R1, R2, X and Y are defined above. According to another embodiment, R3 of the compounds of formula (I) can be -CH2CH3 according to the following formula (VIII) while R1, R2, X and Y are defined above. According to another embodiment, R3 of the compounds of formula (I) can be -CH3 according to the following formula (IX) while R1, R2, X and Y are defined above. Preferably, the compounds of formula (I) can be selected from the group comprising (±)-2-hydroxy-3-(3'-aminophenyl) propionic acid (compound 20) (±)-2-methoxy-2-(4'-aminophenyl) acetic acid (compound 23) (±)-2-ethoxy-2-(3'-aminophenyl) acetic acid (compound 32) (±)-2-ethoxy-2-(4'-aminophenyl) acetic acid (compound 33) (±)-2-methoxy-3-(4-aminopheny!) propionic acid (compound 34) (±)-2-ethoxy-3-(4'-aminophenyl) propionic acid (compound 39) (±)-2-ethoxy-3-(3'-aminophenyl) propionic acid (compound 40). The compounds according to the present invention can be used advantageously in the medical field. Therefore the present invention relates to a pharmaceutical composition comprising one or more compounds as defined above as active principles in combination with one or more pharmaceutically acceptable excipients or adjuvants. The present invention relates, moreover, to the use of the compounds as defined above for the preparation of a medicinal product for the prevention and treatment of tumours expressing the PPARy receptors and the EGF receptors such as, for example, tumour of the oesophagus, stomach, pancreas, colon, prostate, breast, of the uterus and its appendages, of the kidneys and of the lungs. Moreover, the invention relates to the use of the compounds according to the invention for the preparation of a medicinal product for the treatment of chronic inflammatory diseases such as, for example, Crohn's disease and ulcerative rectocolitis. The present invention also relates to methods of treatment of humans and/or mammals (including rodents, farm animals, domestic pets, mice, rats, hamsters, rabbits, dogs, cats, pigs, sheep, cows, horses), In particular, the compounds according to the invention that can be used in the aforementioned applications, apart from those already described, can be as follows: (±)-2-hydroxy-2-(3-aminophenyl)acetic acid (compound 10) (±)~2-hydroxy-2-(4-aminophenyl)acetic acid (compound 11) (±)-2-hydroxy-3-(4'-aminophenyl)propionic acid (compound 21) (+)-2-methoxy-3-(3'-aminophenyl)propionic acid (compound 35) (±)-2-methoxy-3-(4'-aminophenyl)propionic acid, (compound 34) The uses of the compounds described is not restricted to their use in the racemic form. This invention extends to the use of any described compounds in the enantiomerically pure R or S forms, or any mixture in which one enantiomer is in excess of the other, in any proportion. In fact, docking studies performed indicate that the S enantiomer to be more active than the R enantiomer, although the pure R enantiomer does show activity. The molecules of the present invention were derived from molecular modeling work using mesalazine as a basis and all chemically feasible variations were evaluated in order to achieve the best score (affinity and activation of the receptor) in computer docking experiments. Consequently, it is believed that the compounds of the present invention that show comparable function and/or activity to mesalazine do so through similar biological pathways. It is believed that similar characteristics to mesalazine inherent in the molecules of the invention confer upon the molecules a similar activity in relation to the EGF pathway. The examples provided herein are useful models for use in the prediction of the use of the compounds in the various medical fields already discussed. The models therefore provide valuable and meaningful results regardless of their mechanism of action. In addition to the above mentioned compounds, the present invention provides for the use of the following compounds: 2_10 2_11 (R,S) 2-hydroxy-2-(3-aminophenyl) (R,s) 2-hydroxy-2-(4-aminophenyl) acetic acid acetic acid 2_21 2_ 22 (R,S) 2-hydroxy-3-(4'-aminophenyl) propionic acid (R,S) 2-methoxy-2-(3-aminophenyl) acetic acid The present invention will now be described for purposes of illustration, but without limiting it, according to its preferred embodiments, with particular reference to the diagrams in the appended drawings. BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS AND TABLE Table 1. Percentages of DLD-1 cell inhibition by graded doses (0.5-10 mM) of the specified compounds. Cells were cultured in the presence or absence of the compounds, and cell growth was then assessed by the colorimetric (BrdU) assay after 48 hours culture. Figure 1 shows the structures of compounds 20, 23, 32, 33, 34, 35, 39 and 40. Figure 2: PPARy activity by treatment with compounds. Figures 3-4: Effect of the specified substances on the proliferation of human colon carcinoma cell lines (i.e. HT29, HT115 and DLD1). Cells were treated with increasing concentrations of substances (0.5-10 mM)) for 48 hours and the proliferation was determined by using a colorimetric assay for the measurement of BrdU incorporation. Optical density (OD) was determined at 450 nm using an ELISA reader. Data indicate the mean ± SD of 3 separate experiments. Figure 5: Docking of (R) Compound 34 to PPAPy receptor (amino acid residues labeling and hydrogen bonding is shown). Figure 6: Docking of (S) Compound 34 to PPAPy receptor (amino acid residues labeling and hydrogen bonding is shown). Figure 7: Docking of (R) Compound 35 to PPAPy receptor (amino acid residues labeling and hydrogen bonding is shown). Figure 8: Docking of (S) Compound 35 to PPAPy receptor (amino acid residues labeling and hydrogen bonding is shown). Figure 9: Docking of (R) Compound 39 to PPAPy receptor (amino acid residues labeling and hydrogen bonding is shown). Figure 10: Docking of (S) Compound 39 to PPAPy receptor (amino acid residues labeling and hydrogen bonding is shown). Figure 11: Docking of mesalamine to PPAPy receptor (amino acid residues labeling and hydrogen bonding is shown). Figure 12: Schematic Synthesis and Subsequent Resolution of Compound 39. EXAMPLE 1 Method of preparing (+)-2-hydroxy-3-(3'-aminophenyl)-propanoic acid (Compound 20) Step 1 3-Nitrobenzaldehyde (45.3g, 0.3mol), N-acetylglycine (42.1g, 0.36mol) and sodium acetate (32g, 0.39mol) were mixed with acetic anhydride (142ml, 1.5mol) and the resulting mixture heated with stirring to 120°C for 6 hrs, giving a dark solution. The mixture was then cooled to RT overnight, resulting in the formation of a precipitated solid. The reaction mixture was poured into ice-water (130g) and the resulting suspended solid was collected by filtration. The crude solid product (72g) was washed with acetone (80ml) then recrystallized from hot acetone (320mi) io give a crystalline solid that was washed with 50% aqueous ethanol, then dried at 40°C/40mmHg to give 2-methyl-4-(3-nitrobenzy!idene)oxazo!-5(4H)-one (49.0g, 78%) as pale yellow needles. 1H NMR (δ, 250MHz, CDCI3) = 2.47 (3H, s), 7.15 (1H, s), 7.63 (1H, dd, 8.2 & 7.6Hz), 8.27 (1H, d, 8.2Hz), 8.34 (1H, d, 7.6Hz), 9.02 (1H, s). Step 2 2-Methyl-4-(3-nitrobenzylidene)oxazol-5(4H)-one (52.0g, 0.224mol) was mixed with 3M hydrochloric acid (1.3L) and the suspension stirred at 100°C for 6h. The resulting suspension was stirred at RT overnight then the suspended solid was collected by filtration, washed with water (2 x 40ml), then dried in vacuo to give 2-hydroxy-3-(3- nitrophenyl)acrylic acid (29.3g). The combined filtrate and washes were extracted with ethyl acetate (4 x 0.5L), then the combined organic extracts were dried over sodium sulfate and concentrated to dryness to give a further crop of 2-hydroxy-3-(3- nitrophenyl)acrylic acid (12.Og). The total yield of 2-hydroxy-3-(3-nitrophenyl)acrylic acid was 41.3g (88%). 1H NMR (δ, 250MHz, DMSO-d6) = 6.56 (1H, s), 7.64 (1H, t, 8Hz), 8.0-8.1 (2H, m), 8.78 (1H, s), 9.95 (1H, brs), 12.80 (1H, brs). Step 3 Sodium ethoxide (1.8g, 26.4mmol) was added portionwise at 0°C to a stirred solution of 2-hydroxy-3~(3-nitrophenyl)acrylic acid (5.25g, 25.0mmol) in methanol (131ml) to form a clear, pale yellow solution. Sodium borohydride (1g, 26.4mmol) was then carefully added in two portions and the mixture stirred at 5-10°C for 30mins. A small amount of water was then added to quench the reaction and destroy any excess NaBH4. The methanol was removed in vacuo to give a solid residue, which was ground with a 5:2 mixture of ethyl acetate and heptane (21ml) then further ground with 3% aqueous methanol. The resulting solid was collected by filtration and dried in vacuo to give 2- hydroxy-3-(3-nitrophenyl)propionic acid (3.0g, 57%). 1H NMR (δ, 250MHz, DMSO-d6) = 2.97 (1H, dd, 14 & 8.2Hz), 3.15 (1H, dd, 14 & 4.2Hz), 4.23 (1H, dd, 8.2 8, 4.2Hz), 7.58 (1H, t, 8Hz), 7.70 (1H, d, 8Hz), 8.0-8.15 (2H, m). Step 4 A mixture of 2-hydroxy-3-(3-nitrophenyl)propionic acid (3.0g, 14.2mmol), methanol (129ml) and 5% palladium on activated charcoal (600mg, 2 mol%) was hydrogenated at 10psi H2 atmosphere for 1hr. The mixture was then filtered through celite, the filter cake was washed with methanol and the filtrates concentrated at 40°C under high vacuum to give the product as a foamy solid. This was dissolved in water and the solution freeze-dried to give (±)-2-hydroxy-3-(3'-aminophenyl)-propanoic acid (2.6g, 100%) as a white solid. 1H NMR (6, 250MHz, DMSO-d6) = 2.61 (1H, dd, 13.6 & 8.3Hz), 2.81 (1H, dd, 13.6 & 4.6Hz), 4.09 (1H, dd, 8.25 & 4.6Hz), 6.35-6.43 (2H, m), 6.45 (1H, d, 1Hz), 6.90 (1H, t, 7.6Hz). EXAMPLE 2 Method of preparing (±)-2-methoxy-2-(4'-aminophenyl)-acetic acid (Compound 23) Step 1 A solution of potassium hydroxide (6.72g, 0.12mol) in methanol (25rnl) was added to a cooled (-7°C) solution of 4-acetamidobenzaldehyde (24.5g, 0.15mol) and chloroform (40.1g, 0.33moL) in DMF (100ml) at such a rate as to keep the temperature below - 5°C. The mixture was allowed to warm to 2°C over 5.5h then it was added to a mixture of 1M aq. HCI (200ml) and toluene (200ml) and stirred overnight. The resulting 2-(4- acetamidophenyl)-trichlorocarbinol was collected by filtration (29g) and suction dried. Step 2 Solutions of 2-(4-acetamidophenyl)-trichlorocarbinol (14.Og, 49.5mmol) in methanol (330ml) and potassium hydroxide (13.8g, 250mmol) in methanol (150ml) were combined and the mixture heated to 70-80°C for 3hr. After cooling, the KCI by-product was removed by filtration then concentration of the filtrate in vacuo gave 2-(4- acetamidophenyl)-2-methoxyacetic acid (14g) as a white solid. Step 3 2-(4-Acetamidophenyl)-2-methoxyacetic acid (7.1g, 31.8mmol) was heated with hydrazine monohydrate (40ml) for 16hr, cooled and concentrated in vacuo. The resulting residual oil was purified by silica gel column chromatography (eluent 20-40% methanol in CH2CI2) to give 2.6g (45%) of (±)-2-methoxy-2-(4'-aminophenyl)-acetic acid 1H NMR (δ, 250MHz, CD3OD): 3.27 (3H, s), 4.43 (1H, s), 6.66 (2H, d, 8.5Hz), 7.18 (2H, d, 8.2Hz). EXAMPLE 3 Method of preparing (±)-2~ethoxy- 2-(3'-aminophenyl)-acetic acid (Compound 32) Step 1 3-Nitrobenzaldehyde (25g, 165mmol) and chloroform (30ml, 375mmol) were dissolved in DMF (100ml) and the solution cooled to between -5 °C and -10 °C. A fresh solution of potassium hydroxide (7.5g, 134mmoi) in methanol (22.5ml) was added slowly so as maintain the internal temperature and then quenched with a cooled mixture of aqueous hydrochloric acid (225ml) in toluene (225 ml). The solution was allowed to warm slowly to room temperature overnight in the ice bath. After this time the toluene layer was separated and the aqueous layer further extracted with toluene. The combined organic layers were washed with water (2 x 225ml), 5% sodium bicarbonate solution (225ml) and water (225ml). The solution was dried (MgSO4), filtered, and concentrated in vacuo to give 2- (3-nitrophenyl)-trichlorocarbinol as an orange solid (42g, 155mmol, 94 %). 1H NMR (δ, 250MHz, CDCI3): 3.7 (br. s, 1H), 5.4 (s, 1H), 7.6 (t, 1H, 8.0Hz), 8.0 (d, 1H, 8.0Hz), 8.3 (d; 1H, 8.0Hz), 8.5 (s, 1H). Step 2 2-(3-Nitrophenyl)-trichlorocarbinol (20g, 74mmol) was dissolved in absolute ethanol (74ml) and a solution of potassium hydroxide (20.7g, 369mmol) in absolute ethanol (150ml) was added slowly. The solution was heated at reflux for 4hr, allowed to cool and then concentrated in vacuo. The residue was acidified with dilute hydrochloric acid and the product extracted in ethyl acetate (x 3). The combined organic layers were dried (MgSCU), filtered, and concentrated in vacuo to give 2-ethoxy-2-(3- nitrophenyl)acetic acid as a brown solid (6.4g, 28.4mmol, 38%). 1H NMR (δ, 250MHz, CD3OD): 1.0 (t, 3H, 7.0Hz), 3.6 (m, 1H), 3.7 (m, 1H), 5.1 (s, 1H), 7.7 (t, 1H, 7.8Hz), 7.9 (a, 1H, 7.8Hz), 8.3 (d, 1H, 7.8Hz), 8.4 (s, 1H). Step 3 2-Ethoxy-2-(3-nitrophenyl)acetic acid (6.4g, 28.4mmol) was dissolved in absolute ethanol (500m), 5% palladium on carbon (wet) (1.5g) added and the mixture 5 hydrogenated at 60psi overnight. The suspension was filtered through celite and the filtrate concentrated to give (±)-2-ethoxy- 2-(3'-aminophenyl)-acetic acid (3.0g, 15.3mmol, 54%) as a brown solid. 1H NMR (δ, 250MHz, CD3OD): 1.2 (t, 3 H, J = 6.9 Hz), 3.5 (m, 1 H), 3.6 (m, 1 H), 4.6 (s, 1 H), 6.7 (d, 1 H, J = 7.6 Hz), 6.9 (m, 2 H), 7.0 (t, 1 H, J = 7.6 Hz). 10 EXAMPLE 4 Method of pre paring (±)-2-ethoxy-2-(4'-aminophenyl)-acetic acid (Compound 33) Step 1 See "Compound 23 step 1" Step 2 Solutions of 2-(4-acetamidophenyl)-trichlorocarbinol (14.0g, 49.5mmol) in ethanol (400ml) and potassium hydroxide (13.8g, 250mmol) in ethanol (150ml) were combined and the mixture heated at 70-80°C for 2.5hr. The mixture was cooled, filtered to remove the KG by-product, and concentrated in vacuo to give 2-(4-acetamidophenyl)~ 2-ethoxyacetic acid (I4g) as a yellow solid. Step 3 2-(4-Acetamidophenyl)-2-ethoxyaceticacid (7.54g, 31.8mmol) was heated with hydrazine monohydrate (40ml) for 16hr, the mixture cooled then concentrated in vacuo. The residual oil was then purified by silica column chromatography (20-40% methanol in CH2CI2 eluent) to give (±)-2-ethoxy-2-(4'-aminopheny!)-acetic acid (2.3g, 37%) as a white foam. 1H NMR (δ, 250MHz, CD3OD): 1.18 (3H, t, 7.0Hz), 4.42 (1H, qd, 7.3, 2.4Hz), 4.56 (2H, s), 5.50 (1H, qd, 7.0, 2.1Hz), 6.66 (2H, d, 8.7Hz), 7.20 (2H, d, 8.5Hz) EXAMPLE 5 Method of preparing (±)-2-methoxy-3-(4'-aminophenyl)-propionic acid (Compound 34) Step 1 4-Nitrobenzaldehyde (53,7g, 0.356mol), N-acetylglycine (49.9g, 0.427mol) and sodium acetate (37.9g, 0.463mol) were mixed with acetic anhydride (168g, 1.78mol) and the resulting mixture heated with stirring to 120°C for 6 hrs, giving a dark suspension. The mixture was then cooled to RT overnight, resulting in the formation of a precipitated solid. The reaction mixture was poured into ice-water (150g) and the resulting suspended solid was collected by filtration. The crude solid product was washed with acetone (100ml) then recrysiaiiized from hot acetone (650ml) to give a crystalline solid that was washed with 50% aqueous ethanol, then dried in vacuo to give 2-methyl-4-(4- nitrobenzylidene)oxazol-5(4H)-one (55.Og, 66%) as pale yellow needles. The crystallisation mother liquors and washes were combined and evaporated to give a solid residue that was recrystallized from acetone to give a second crop of 2-methyl-4- (4-nitrobenzylidene)oxazol-5(4H)-one (8g, 10%). The combined yield of 2-methyl-4-(4- nitrobenzylidene)oxazol-5(4H)-one was 63g (76%) 1H NMR (δ, 250MHz, CDCI3) = 2.47 (3H, s), 7.14 (1H, s), 8.28 (4H, m). Step 2 2-Methyl-4-(4-nitrobenzylidene)oxazol-5(4H)-one (63.0g, 0.272mol)was mixed with 3M hydrochloric acid (1.2L) and the suspension was stirred at 100°C for 6h. The resulting suspension was stirred at RT overnight then the suspended solid was collected by filtration, washed with water (2 x 50ml), then dried in vacuo to give 2-hydroxy-3-(4- nitrophenyhacrylic acid (46.6g, 81%). The combined filtrate and washes were extracted with ethyl acetate (4 x 0.5L), then the combined organic extracts were dried over sodium sulfate and concentrated to dryness to get a further crop of 2-hydroxy-3-(4- nitrophenyl)acrylic acid (0.8g, 1%). The total yield of 2-hydroxy-3-(4-nitrophenyl) acrylic acid was 47.4g (82%). 1H NMR (δ, 250MHz, DMSO-d6) = 6.52 (1H, s), 8.01 (2H, d, 8.5Hz), 8.22 (2H, d, 8.5Hz). Step 3 A mixture of 2-hydroxy-3-(4-nitrophenyl)acrylic acid (15g, 71.7mmol), cesium carbonate (56g, 172.1 mmol) and dimethyl sulphate (14.2ml, 150.6mmol) in DMF (270ml) was stirred at RT for 18hr. Water (220ml) and ethyl acetate (150ml) were added and the layers separated. The aqueous layer was further extracted with ethyl acetate (4 x 100ml) then the combined organics were washed with water (6 x 100ml), brine (2 x 120ml) and concentrated to half volume. Heptane was added (70ml) and the mixture concentrated to 200ml volume. The resulting precipitated solid was collected by filtration, washed with heptane (2 x 100ml) and suction dried on the filter to afford methyl 2-methoxy-3-(4~nitrophenyl)acrylate as a tan solid (9.2g, 54% yield) containing a trace of heptane. 1H NMR (δ, 250MHz, DMSO-d6): 3.82 (s, 3-H, OMe), 3.84 (s, 3-H, OMe), 7.02 (s, 1-H, CH=), 8.04 (d, 2-H, CHaromatic), 8.26 (d, 2-H, CHaromatic). Step 4 Methyl 2-methoxy-3-(4-nitrophenyl)acrylate (7.8g, 32.8mmol) was dissolved in IMS (156ml). A solution of NaOH (1.44g, 36.1 mmol) in water (78ml) was added and the mixture stirred at ambient temperature (18°C) for 18hr. The reaction mixture was acidified with 1M HCI (120ml) and the resulting precipitated solid was collected by filtration, washed with water (2 x 100ml) and partially suction dried on the filter for 30 mins, followed by vacuum oven drying at 18°C for 18hr. Thus 2-methoxy-3-(4- nitrophenyl)acrylic acid was afforded as a tan solid containing some water of crystallisation (6.7g, 91%). 1H NMR (δ, 250MHz, DMSO-d6): 3.83 (s, 3-H, OMe), 6.97 (s, 1-H, CH=), 8.02 (d, 2-H, CHaromatic), 8.25 (d, 2-H, CHaromatic). Step 5 2-Methoxy-3-(4-nitrophenyl)acrylic acid (6.7g, 30mmol) was taken up in methanol (700ml) and THF (300ml) and 10% Pd on C (wet basis) (0.67g) was added. The mixture was hydrogenated at 45psi for 43mins, followed by repeated refills to 45-48psi every hour for 3hr and finally 48psi for 18hr. The resulting suspension was filtered through GF/F filter paper and the filter residue washed with MeOH (200ml). The filtrates were concentrated to an off-white solid. The solid was slurried in IMS (75ml) at 20°C for 1.5hr, filtered, and washed with IMS/heptane (1:2) (20ml) and dried on the filter for 1 hr to afford (±)-2-methoxy-3-(4'-aminophenyl)-propionic acid as an off-white solid (5.1g, 88% yield) 1H NMR (δ, 250MHz, DMSO-d6): 2.74 (m, 2-H), 3.23 (s, 3-H, CH3), 3,80 (dd, 1-H, CH), 6.47 (d, 2-H, aromatic), 6.87 (d, 2-H, aromatic). EXAMPLE 5 Method of preparing (±)-2-methoxy-3-(3'-aminophenyl)- propionic acid (Compound 35) Steps 1 & 2 As per compound 20 Step 3 Dimethyl sulfate (13.23g, 105mmol) was added to a stirred mixture of 2-hydroxy-3-(3- nitrophenyl)acrylic acid (10.5g, 50.0mmol) and caesium carbonate (39.1g, 120mmol) in DMF (105ml) to form a clear, pale yellow mixture, which was stirred at RT overnight. The resulting dark red suspension was concentrated in vacuo and the residue partitioned between water (100ml) and dichloromethane (150ml). The organic layer was separated, further washed with water (2 x 100ml), dried over sodium sulphate and filtered through silica gel. The resulting yellow solution was evaporated to dryness in vacuo to give methyl 2-methoxy-3-(3-nitrophenyl)acrylate as a yellow solid (8.1g, 67%). 1H NMR (δ, 250MHz, DMSO-d6) = 3.81 (3H, s), 3.83 (3H, s), 7.08 (1H, s), 7.71 (1H, dd, 7.9 & 8.2Hz), 8.10-8.22 (2H, m), 8.66 (1H, s). Step 4 A solution of potassium hydroxide (2.0g, 35.9mol) in water (25ml) was added to a stirred solution of methyl 2-methoxy-3-(3-nitrophenyl)acrylate (8.1g, 34.2mmol) in methanol (150ml) and the resulting mixture was stirred at RT overnight. A further quantity of KOH (0.5g, 8.9mmol) in water (10ml) was added and the mixture heated to 80°C for 1hr. The methanol was then evaporated in vacuo and the residue diluted with water (200ml). The solution was washed with dichloromethane (2 x 100ml), filtered through a pad of celite and then acidified by the addition of 3M HCI to pH 3. The mixture was refrigerated for 18h then the precipitated solid was collected by filtration, washed with water (3 x 30ml) and dried in vacuo at 40°C to give 2-methoxy-3-(3- nitrophenyl)acrylic acid as a yellow solid (6.4g, 84%). 1H NMR (δ, 250MHz, DMSO-d6) = 3.82 (3H, s), 7.02 (1H, s), 7.70 (1H, t, 7.93Hz), 8.10- 8.22 (2H,m), 8.65 (1H,s). Step 5 A mixture of 2-methoxy-3-(3-nitrophenyl)acrylic acid (3.4g, 15.25mmol), methanol (340ml) and 5% palladium on activated charcoal (1.36g, 4 mol%) was hydrogenated at 12-36psi H2 atmosphere for 1.5hr. The mixture was then filtered through celite, the filter cake washed with methanol and the filtrates concentrated at 40°C under vacuum to give the prodcrct as a foamy solid. This was dissolved in water (100ml) and the solution freeze-dried to give (±)-2-methoxy-3-(3'-aminophenyl)-propionic acid (2.6g, 100%) as an off-white solid. 1H NMR (δ, 250MHz, DMSO-dB) = 2.68 (1H, dd, 13.9 & 8Hz), 2.80 (1H, dd, 13.9 & 4.6Hz), 3.21 (3H, s), 3.84 (1H, dd, 8.25 & 4.6Hz), 6.36-6.44 (3H, m), 6.91 (1H, dd, 7.6Hz). EXAMPLE 7 Method of preparing (±)-2-ethoxy 3-(4'-aminophenyl)-propionic acid (Compound 39). Enantiomeric Resolution (Figure 12). Steps 1 & 2 As per compound 34 steps 1 & 2. Step 3 2-Hydroxy-3-(4-nitrophenyl)acrylic acid (20g, 95.6mmol) was suspended in DMF (200ml). Cs2CO3 (74.9g, 229.9mmol) and diethyl sulphate (26.3ml, 201mmol) were added and dissolution was observed, After stirring for 18hr at 18°C water (350ml) and ethyl acetate (250ml) were added and the layers separated. The aqueous layer was further extracted with ethyl acetate (5 x 200ml) then the combined organics were washed with water (2 x 200ml), brine (2 x 200ml) and dried over magnesium sulfate. The organics were concentrated to dryness to obtain ethyl 2-ethoxy-3-(4-nitrophenyl)- acrylate as an orange solid containing 3.6% by mass DMF (27.6g wet, >100% yield). 1H NMR (δ, 250MHz, DMSO-d6): 1.32 (t, 6-H, 2 x CH2CH3), 4.13 (q, 2-H, CH2CH3), 4,30 (q, 2-H, CH2CH3), 6.99 (s, 1-H, CH=), 8.06 (d, 2-H, CHaromatic), 8.26 (d, 2-H, CHaromatic). Step 4 Ethyl 2-ethoxy-3-(4-nitrophenyl)acrylate containing 3.6wt% DMF (26.07g corrected, 98.3mmol) was dissolved in IMS (500ml) and a solution of NaOH (1.44g, 36.1mmol) in water (260ml) was added. The resulting mixture was stirred at ambient temperature for 18hr then acidified with 1M HCI (120ml) and the resulting solid collected by filtration, washed with water (2 x 100ml) and suction dried on the filter for 30mins, followed by vacuum oven drying at 18°C for 18hr, 2-Ethoxy-3-(4-nitrophenyl)acrylic acid was thus obtained as an orange solid containing water of crystallisation (18.4g, 79%). 1H NMR (δ, 250MHz, DMSO-d6): 1.31 (t, 3-H, Me), 4.11 (q, 2-H, CH2), 6.98 (s, 1-H, CH=), 8.05 (d, 2-H, CHaromatic), 8.25 (d, 2-H, CHaromatic). Step 5 2-Ethoxy-3-(4-nitrophenyl)acrylic acid (18.4g wet, approx. 77.5mmol) was dissolved in MeOH (1.1L) and 10% Pd on C (wet basis) (1.84g) was added. The mixture was hydrogenated at 12psi for 10mins, followed by repeated refill to 20-28psi every 10- 20mins for 5hr then 46psi for 18hr. The mixture was filtered through GF/F paper and the residue was slurried in IMS (100ml), filtered, washed with heptane (100ml), and suction dried on the filter. Thus (±)-2-ethoxy 3-(4'-Aminophenyl)-propionic acid was obtained as an off-white solid (11.2g, 69%). 1H NMR (δ, 250MHz, DMSO-d6): 1.03 (t, 3-H, CH3), 2.73 (m, 2-H,), 3.29 (m, 1H), 3.46 (m, 1H), 3.80 (dd, 1-H), 6.50 (d, 2-H), 6.87 (d, 2-H). EXAMPLE 8 Method of preparing (±)-2-ethoxy-3-(3'-aminophenyl)- propanoic acid (Compound 40) Steps 1 & 2 As per compound 20 steps 1 & 2. Step 3 Diethyl sulfate (12g, 78.2mmol) was added to a stirred mixture of 2-hydroxy-3-(3- nitrophenyl)acrylic acid (6.1g, 30.0mmol) and caesium carbonate (29.3g, 90mmol) in DMF (61 ml) to form a clear, pale yellow mixture, which was stirred at RT overnight. The resulting dark red suspension was heated to 50°C for 4h then concentrated in vacuo and the residue partitioned between water (100ml) and dichloromethane (150ml). The organic layer was separated, further washed with water (2 x 100ml), dried over sodium sulphate and filtered through a silica gel pad. The resulting yellow solution was evaporated to dryness in vacuo to give ethyl 2-ethoxy-3-(3-nitrophenyl)acrylate as a yellow solid (5.6g, 72%). Step 4 A solution of potassium hydroxide (1.3g, 22.2mol) in water (20ml) was added to a stirred solution of ethyl 2-ethoxy-3-(3-nitrophenyl)acrylate (5.6g, 21.1mmol) in methanol (100ml) and the resulting mixture heated to reflux overnight. The methanol was then evaporated in vacuo and the residue diluted with water (150ml). The solution was washed with dichloromethane (2 x 80ml), filtered through a pad of celite and then acidified by the addition of 3M HCI to pH 3. The mixture was refrigerated for 18h then the precipitated solid was collected by filtration, washed with water (3 x 30ml) and dried in vacuo at 40°C. The resulting solid was recrystallized from ethyl acetate and heptane to give 2-ethoxy-3-(3-nitrophenyl)acrylic acid as a yellow solid (3.06g, 61%). 1H NMR (δ, 250MHz, DMSO-d6) = 1.34 (3H, t, 7Hz), 4.10 (2H, q, 7Hz), 7.04 (1H, s), 7.69 (1H, t, 7.93Hz), 8.07-8.22 (2H, m), 8.80 (1H, m), 13.25 (1H, brs). Step 5 A mixture of 2-ethoxy-3-(3-nitrophenyl)acrylic acid (3.06g, 12.9mmol), methanol (150ml) and 5% palladium on activated charcoal (0.60g, 2 mol%) was hydrogenated at 12-30psi H2 atmosphere for 2hr. The mixture was then filtered through celite, the filter cake washed with methanol and the filtrates concentrated at 40°C under vacuum to give the product as a foamy solid. This was dissolved in water (100ml) and the solution freeze-dried to give (±)-2-ethoxy-3-(3'-aminophenyl)- propanoic acid (2.7g, 100%) as an off-white solid. 1H NMR (δ, 250MHz, DMSO-d6) = 1.07 (3H, t, 7Hz), 2.6-2.85 (2H, m), 3.20-3.38 (1H, m), 3.40-3.60 (1H, m), 3.92 (1H, dd, 5 & 7.7Hz), 6.3-6.45 (3H, m), 7.01 (1H, t, 7.6Hz). EXAMPLE 9 Molecular modelling Molecular modelling studies were performed using SYBYL software version 6.9.1 (Tripos Associates Inc, St Louis, MO) running on Silicon Graphics workstations. Three- dimensional model of the zwitterion form of 5-ASA was built from a standard fragments library, and its geometry was subsequently optimized using the Tripos force field (3) As the pKa of compounds are still unknown, the SPARC online calculator was used to determine the species occurring at physiological pH (7.4)(http://ibmlc2.chem.uga.edu/sparc/index.cfm). Three-dimensional model of ionized compounds were built from a standard fragments library, and their geometry was subsequently optimized using the Tripos force field (3) including the electrostatic term calculated from Gasteiger and Huckel atomic charges. The method of Powell available in Maximin2 procedure was used for energy minimization until the gradient value was smaller than 0.001 kcal/mol.A. The structure of the human PPARy ligand-binding domain was obtained from its complexed X-Ray crystal structure with the tesaglitazar (AZ 242) available in the RCSB Protein Data Bank (117I) (4,5). Flexible docking of the compounds into the receptor active site was performed using GOLD software (6). The most stable docking models were selected according to the best scored conformation predicted by the GoldScore (6) and X-Score scoring functions (7). The complexes were energy-minimized using the Powell method available in Maximin2 procedure with the Tripos force field and a dielectric constant of 4.0 until the gradient value reached 0.01 kcal/mol.A. The anneal function was used defining around the ligand a hot region (10 A) and an interesting region (15 A). RESULTS The molecular modelling receptor docking studies predicted that, in general, the S enantiomer is more active that the R enantiomer, even though R enantiomer does show activity also. This phenomenon of one enantiomer being more biologically active is well known. As a consequence, the present invention provides a method to resolve the compounds into enantiomers. The resolution method for compound 32 is shown schematically in Figure 11. While not wishing to be bound by theory, it is believed that the S-enantiomers of the compounds will afford higher activity. The results of the docking studies are shown in Figures 5-10. EXAMPLE 7 Method of preparing (±)-2-ethoxy 3-(4'-aminophenyl)-propionic acid (Compound 39). Enantiomeric Resolution (Figure 12). Steps 1 & 2 As per compound 34 steps 1 & 2. Step 3 2-Hydroxy-3-(4-nitrophenyl)acrylic acid (20g, 95.6mmol) was suspended in DMF (200ml). Cs2CO3 (74.9g, 229.9mmol) and diethyl sulphate (26.3ml, 201mmol) were added and dissolution was observed. After stirring for 18hr at 18°C water (350ml) and ethyl acetate (250ml) were added and the layers separated, The aqueous layer was further extracted with ethyl acetate (5 x 2Q0ml) then the combined organics were washed with water (2 x 200ml), brine (2 x 200ml) and dried over magnesium sulfate. The organics were concentrated to dryness to obtain ethyl 2-ethoxy-3-(4-nitrophenyl)- acrylate as an orange solid containing 3.6% by mass DME (27.6g wet, >100% yield). 1H NMR (δ, 250MHz, DMSO-d6): 1.32 (t, 6-H, 2 x CH2CH3), 4.13 (q, 2-H, CH2CH3), 4.30 (q, 2-H, CH2CH3), 6.99 (s, 1-H, CH=), 8.06 (d, 2-H, CHaromatic), 8.26 (d, 2-H, CHaromatic). Step 4 Ethyl 2-ethoxy-3-(4-nitrophenyl)acrylate containing 3.6wt% DMF (26.07g corrected, 98.3mmol) was dissolved in IMS (500ml) and a solution of NaOH (1.44g, 36.1mmol) in water (260ml) was added. The resulting mixture was stirred at ambient temperature for 18hr then acidified with 1M HCI (120ml) and the resulting solid collected by filtration, washed with water (2 x 100ml) and suction dried on the filter for 30mins, followed by RESULTS Activation of PPARy results in a cascade of reactions leading to a binding to specific DNA sequence elements termed peroxisome proliferator response elements (PPRE) (7-9). We investigated PPARy transcriptional activity by transient transfections of epithelial cells with the renilla luciferase and PPRE plamids. To evaluate if the new molecules have more efficacy than 5-ASA to stimulate PPARy activation, we tested these molecules at a concentration of 1mM. Effect of the new molecules at a concentration of 1 mM was compared to 5-ASA and rosiglitazone, used as positive controls at optima! concentrations of 30mM and 10-5 M respectively. Cells were stimulated with the different molecules during 24 hours. Analysis of PPARy activity in transfected HT-29 cells showed that the new molecules 34, 39, 35 and 40 at 1mM increased the reporter gene activity by 4.8±0.71; 2.73+0.31; 2.64±0.46; 3.4±0.97 fold respectively, thereby displaying an activity similar or superior to 5-ASA at 30mM (2.8+0.7 ) and rosiglitazone at 10¬5M (3.17+0.29). Figure 2 represents all the results obtained for each molecule assessed in 2 or 3 experiments done in triplicate. Reproducibility between the different experiments is good and similar to data described in the literature. This study allowed us to identify 4 new molecules having 30 to 50 times more efficacy than 5-ASA to activate PPARy. EXAMPLE 11 Colon cancer cell growth The following substances (i.e. 20, 34, 35, 39 and 40) were tested for their ability to modulate colon cancer cell growth. For this purpose, three human colon carcinoma cell lines (i.e. HT-29, HT-115 and DLD-1) were used. These cell types were selected on the basis of the cyclooxigenase-2 (COX-2) expression. Indeed, HT-115 cells express a biologically active COX-2, HT-29 cells express a non-functional COX-2 isoform, and DLD-1 are COX-2-deficient cells. It is believed that these molecules are also active on cells that do not express COX-, and thus the molecules of the present invention may be used in cells which do not express COX-2 for the purposes of treating tumours and other applications as herein described. HT-29 and DLD-1 cells were cultured in McCoy and RPMI1640 media respectively, supplemented with 10% fetal bovine serum (FBS), 1% penicillin/streptomycin (P/S) and 50mg/ml gentamycin. HT-115 were cultured in DMEM medium supplemented with 15% FBS and 1% P/S. Cells were maintained in a humidified incubator at 37°C, in the presence of 5% CO2. For cell growth assays, single-cell suspensions were plated at 2 x 103 cells/well (4 x 103 cells/well for HT 115) in 96-well culture dishes in medium containing 0.5% FBS and allowed to adhere. The non-adherent cells were then removed, and fresh medium containing 0.5% FBS was added into each well. Cells were cultured in the presence or absence of the specified substances. Each substance was dissolved as a 25 mM stock solution in culture medium containing 0.5% FBS, and the pH of each stock solution was adjusted to 7.4, if necessary, with NaOH. Substances were used at a final concentration ranging from 0.5 to 10 mM. Cell proliferation was determined by measuring the incorporation of 5-bromo-2'- deoxyuridine (BrdU) into DNA using a commercially available cell proliferation kit (Roche Diagnostics, Monza, Italy). BrdU was added to the cell cultures during the last 6 hours of incubation, and the level of BrdU-positive cells was assessed after 48 h culture by enzyme-linked immunosorbent assay (ELISA). Optical density (OD) was determined at 450 nm using an ELISA reader. Experiments were performed in triplicate and the results are reported as the mean + standard deviation (SD). RESULTS The compounds differed in their ability to inhibit colon cancer cell growth. Results are summarized in Table 1 where the percentage of inhibition of growth of DLD-1 cells by the specified compounds is shown. The substance 20, exhibits a marked anti- proliferative effect in a dose-dependent fashion, in each of the three cell lines tested (Figures 3 & 4). More than 90% of cell growth inhibition was seen when compounds were used at a final concentration of 10 mM. The ability of the compound 20 to significantly inhibit cell growth was seen when used at a final concentration of 5 or 10 mM. The compounds 34 and 39 slightly reduced the cell growth when used at high doses (10 mM) (Figure 4), but differences among groups were not statistically significant. Similarly, no inhibition in cell growth was seen in cultures added with the substances 35, and 40 (see Table 1). CONCLUSIONS This first set of examples of the invention (Example 10) shows the ability of four optimized molecules 34, 39, 35 and 40 at concentration of 1mM, to increase the PPARy activity in transfected HT-29 cells, displaying an activity similar or superior to 5- ASA at 30mM and rosiglitazone at 10"5M. The second set examples of the invention (Example 11) shows that the compounds affect the inhibition of the growth of the colon cancer cell lines, HT-29, HT-115 and DLD1 to varying degrees. The compounds differed in their ability to inhibit colon cancer cell growth. The substance 20, exhibits a marked antiproliferative effect on cell lines tested. These molecules of the present invention are also active on cells that do not express COX-2, and thus the molecules of the present invention may be used in cells which do not express COX-2 for the purposes of treating tumours and other applications as herein described. OVERALL CONCLUSIONS The synthesized highest ranking compounds, indicated from modelling studies, all show an activity similar/superior to that of mesalazine. REFERENCES 1. Dubuquoy, L, E.A. Jansson, S. Deeb, S. Rakotobe, M. Karoui, J.F. Colombel, J. Auwerx, S. Pettersson, and P. Desreumaux, 2003. Impaired expression of peroxisome proiiferator-activated receptor gamma in ulcerative colitis. Gastroenterology 124:1255-1276. 2. Rousseaux C, Lefebvre B, Dubuquoy L, Lefebvre P, Romano 0, Auwerx J, Metzger D, Wahli W, Desvergne B, Naccari GC, Chavatte P, Farce A, Bulois P, Cortot A, Colombel JF, Desreumaux P. Intestinal anti-inflammatory effect of 5- amino salicylic acid is dependent on PPARy. J Exp Med 2005; 201: 1205-15. 3. Clark, M.C.R.D.I.V.O., N. 1989. Validation of the General Purpose Tripos 5.2 Field. J. Comput Chem. 10:982-1012. 4. Gampe, R.T., Jr., V.G. Montana, M.H. Lambert, A.B. Miller, R.K. Bledsoe, M.V. Milburn, S.A. Kliewer, T.M. Wilison, and H.E. Xu. 2000. Asymmetry in the PPARy/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell 5:545-555, 5. Jones, G., P. Willett, R.C. Glen, A.R. Leach, and R. Taylor. 1997. Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267:727- 748. 6. Wang, R., L. Lai, and S. Wang. 2002. Further development and validation of empirical scoring functions for structure-based binding affinity prediction. J Comput Aided Mol Des 16:11 -26. 7. Westin, S., R. Kurokawa, R.T. Nolte, G.B. Wisely, E.M. Mclnemey, D.W. Rose, M.V. Milburn, M.G. Rosenfeld, and C.K. Glass. 1998. Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators. Nature 395:199-202. 8. Mangelsdorf, D.J., C. Thummel, M, Beato, P. Herrlich, G. Schutz, K. Umesono, B. Blumberg, P. Kastner, M. Mark, P. Chambon, and et al. 1995. The nuclear receptor superfamily: the second decade. Cell 83:835-839. 9. Misra, P., E.D. Owuor, W. Li, S. Yu, C. Qi, K. Meyer, Y.J. Zhu, M.S. Rao, A.N. Kong, and J.K. Reddy. 2002. Phosphorylation of transcriptional coactivator peroxisome proiiferator-activated receptor (PPAR)-binding protein (PBP). Stimulation of transcriptional regulation by nitogen-activated protein kinase. J Biol Chem 277:48745-48754. Epub 42002 Sep 48727. WE CLAIM : 1. A compound of the general formula (I), and salts thereof: in which R1 and R2, which may be identical or different, are selected from the group consisting of: -H and a linear or branched alkyl group having from 1 to 6 carbon atoms or together form an aromatic or aliphatic ring with 5 or 6 atoms; Y is selected from the group consisting of: -H, -OH, -COOH, -OR3, -CH(OR3)COOH; wherein R3 is selected from phenyl, benzyl, -CF3 or -CF2CF3, vinyl, allyl, and a linear or branched alkyl group having from 1 to 6 carbon atoms; and Z is -CH(OR3)COOH; wherein R3 is selected from the group consisting of: phenyl, benzyl, -CF3 or -CF2CF3, vinyl, allyl and a linear or branched alkyl group having from 1 to 6 carbon atoms;. wherein -NR1R2 is at the 3' or the 4' position, and the compound is not 2-methoxy- 3-(3'-aminophenyl)-propionic acid. 2. The compound as claimed in claim 1 wherein R1 and R2, which may be identical or different, are selected from the group consisting of: -H and a linear or branched alkyl group having from 1 to 6 carbon atoms; Y is selected from the group consisting of: -H, -OH, -COOH, -ORs, -CH(OR3)COOH, in which R3 is selected from -H and a linear or branched alkyl group having from 1 to 6 carbon atoms; andZ is -CH(OR3)COOH, in which R3 is selected from a linear or branched alkyl group having from 1 to 6 carbon atoms. 3. The compound as claimed in claim 1 or 2 wherein R1 and R2, which may be identical or different are selected from -H, Me or Et; Y is selected from the group consisting of: -H, -OH, -COOH, -OR3, -CH(OR3)COOH; and Z is CH(OR3)COOH, in which R3 is selected from a linear or branched alkyl group having from 1 to 6 carbon atoms. 4. A compound of the general formula (I), and salts thereof: in which: R1 and R2 are -H or Me; Y is COOH; and Z is -OR3; or R1 and R2 are -H or Me; Y is H; and Z is -CH(OR3)COOH; in which, R3 is selected from a linear or branched alkyl group selected from -CH3 or -CH2CH3, -CH2CH2CH3, or-CH(CH3)2; with the proviso that: when Y is -H and Z is -CH(OCH3)COOH the -NR,R2 is at the 4' position; or when Y is -COOH and Z is -OCH3 then -NRiR2 is at the 4' position. 5. A compound of the general formula (I) in which: -NR1R2 is bonded to the phenyl ring at the 3-position; R1 and R2, which may be identical or different, are selected from the group consisting of H or a linear or branched alkyl group having from 1 to 6 carbon atoms or together form an aromatic or aliphatic ring with 5 or 6 atoms; Y is selected from the group consisting of H, COOH, and -CH(OR3)COOH; Z is-CH(OR3)COOH;and R3 is H. 6. The compound as claimed in any one of claims 1 to 5 in which R1 and R2 are -H. 7. The compound as claimed in any one of claims 1 to 6 wherein the linear or branched alkyl group having from 1 to 6 carbon atoms is selected from the group consisting of: -CH3, -CH2CH3, - CH(CH3)2, and -CH2CH2CH3. 8. The compound as claimed in any one of claims 1 to 4 wherein Y is -H, and Z is -CH3(OR3)COOH, wherein R3 is -CH3 or-CH2CH3. 9. A compound as claimed in any one of claims 1 to 6 having the following formula: 10. A compound as claimed in any one of claims 1 to 6 having the following formula: 11. A compound as claimed in any one of claims 1 to 6 having the following formula: 12. A compound as claimed in any one of claims 1 to 6 having the following formula: 13. A compound as claimed in any one of claims 1 to 6 having the following formula: 14. A compound as claimed in any one of claims 1 to 6 having the following formula: 15. A compound as claimed in any one of claims 1 to 6 having the following formula (II) 16. The compound as claimed in any preceding claim, wherein the compound is in enantiomerically pure R or S form. 17. A pharmaceutical composition comprising one or more compounds as defined in any one of claims 1 to 16 as active principles in combination with one or more pharmaceutically acceptable excipients or adjuvants, such as herein described. 18. A pharmaceutical composition as claimed in claim 17 wherein the compound is in a mixture in which one enantiomer is in excess of the other, in any proportion. 19. Compound of the general formula (I), and salts thereof: in which: R1 and R2, which may be identical or different, are selected from the group consisting of: H and a linear or branched alkyl group having from 1 to 6 carbon atoms or together form an aromatic or aliphatic ring with 5 or 6 atoms; Y is selected from the group consisting of: H, -OH, -COOH, -OR3 and -CH(OR3)COOH; Z is -CH(OR3)COOH, wherein R3 is selected from the group consisting of: phenyl, benzyl, - CF3 or -CF2CF3, vinyl, allyl and a linear or branched alkyl group having from 1 to 6 carbon atoms, wherein -NR1R2 is at the 3' or 4' position, for use as a medicament. 20. Compound of the general formula (I), and salts thereof: in which: R1 and R2 are -H or Me; Y is COOH; and Z is -OR3; or R1 and R2 are -H or Me; Y is H; and Z is -CH(OR3)COOH; in which R3 is selected from a linear or branched alkyl group selected from -CH3 or- CH2CH3,-CH2CH2CH3, or-CH(CH3)2; with the proviso that: when Y is -H and Z is -CH(OCH3)COOH the -NR,R2 is at the 4' position; or when Y is -COOH and Z is -OCH3 then -NR1R2 is at the 4' position, for use as a medicament. 21. Compound of the general formula (I) in which: -NR1R2 is bonded to the phenyl ring at the 3-position; R1 and R2, which may be identical or different, are selected from the group consisting of H or a linear or branched alkyl group having from 1 to 6 carbon atoms or together form an aromatic or aliphatic ring with 5 or 6 atoms; Y is selected from the group consisting of H, COOH, and -CH(OR3)COOH; Z is-CH(OR3)COOH;and R3 is H, for use as a medicament. 22. Compound as claimed in any one of claim 1-16 for the prevention and treatment of tumours expressing the PPARY receptors and the EGF receptors. 23. Compound as claimed in claim 22, wherein the tumours are selected from the group comprising tumour of the oesophagus, of the stomach, of the pancreas, of the colon, of the prostate, of the breast, of the uterus and appendages, of the kidneys and of the lungs. 24. Compound as claimed in any one of claim 1-16 for the preparation of a medicinal product for the treatment of chronic inflammatory diseases. 25. Compound as claimed in claim 24, wherein the chronic inflammatory diseases are selected from the group comprising Crohn's disease and ulcerative rectocolitis. (54) Title: COMPOUNDS AND THEIR SALTS SPECIFIC TO THE PPAR RECEPTORS AND THE EGF RECEPTORS AND THEIR USE IN THE MEDICAL FIELD (57) Abstract: The present invention relates to compounds comprising the general formula (I), in which R1and R2, which may be identical or different, are selected from the group comprising -H or a linear or branched alkyl group having from 1 to 6 carbon atoms or together form an aromatic or aliphatic ring with 5 or 6 atoms; Y and Z, which may be identical or different, are selected from the group comprising -H, -OH, -COOH, -OR3, -CH(OR3)COOH, in which R3 is selected from H, phenyl, benzyl, -CF3 or -CF2CF3, vinyl, allyl and a linear or branched alkyl group having from 1 to 6 carbon atoms.

Documents:

00567-kolnp-2008-abstract.pdf

00567-kolnp-2008-claims.pdf

00567-kolnp-2008-correspondence others.pdf

00567-kolnp-2008-description complete.pdf

00567-kolnp-2008-drawings.pdf

00567-kolnp-2008-form 1.pdf

00567-kolnp-2008-form 3.pdf

00567-kolnp-2008-form 5.pdf

00567-kolnp-2008-international publication.pdf

00567-kolnp-2008-international search report.pdf

567-KOLNP-2008-(14-02-2013)-ANNEXURE TO FORM-3.pdf

567-KOLNP-2008-(14-02-2013)-CLAIMS.pdf

567-KOLNP-2008-(14-02-2013)-CORRESPONDENCE.pdf

567-KOLNP-2008-(14-02-2013)-PETITION UNDER RULE 137.pdf

567-KOLNP-2008-(23-01-2013)-CORRESPONDENCE.pdf

567-KOLNP-2008-(23-01-2013)-OTHERS.pdf

567-KOLNP-2008-(29-11-2012)-ABSTRACT.pdf

567-KOLNP-2008-(29-11-2012)-AMANDED PAGES OF SPECIFICATION.pdf

567-KOLNP-2008-(29-11-2012)-ANNEXURE TO FORM 3.pdf

567-KOLNP-2008-(29-11-2012)-CLAIMS.pdf

567-KOLNP-2008-(29-11-2012)-CORRESPONDENCE.pdf

567-KOLNP-2008-(29-11-2012)-DESCRIPTION (COMPLETE).pdf

567-KOLNP-2008-(29-11-2012)-DRAWINGS.pdf

567-KOLNP-2008-(29-11-2012)-FORM-1.pdf

567-KOLNP-2008-(29-11-2012)-FORM-13.pdf

567-KOLNP-2008-(29-11-2012)-FORM-2.pdf

567-KOLNP-2008-(29-11-2012)-OTHERS-1.pdf

567-KOLNP-2008-(29-11-2012)-OTHERS.pdf

567-KOLNP-2008-(29-11-2012)-PETITION UNDER RULE 137.pdf

567-KOLNP-2008-ASSIGNMENT 1.1.pdf

567-KOLNP-2008-ASSIGNMENT.pdf

567-KOLNP-2008-CORRESPONDENCE 1.2.pdf

567-KOLNP-2008-CORRESPONDENCE 1.3.pdf

567-KOLNP-2008-CORRESPONDENCE OTHERS-1.1.pdf

567-KOLNP-2008-EXAMINATION REPORT.pdf

567-KOLNP-2008-FORM 13.pdf

567-KOLNP-2008-FORM 18 1.1.pdf

567-kolnp-2008-form 18.pdf

567-KOLNP-2008-FORM 3-1.1.pdf

567-KOLNP-2008-GPA.pdf

567-KOLNP-2008-GRANTED-ABSTRACT.pdf

567-KOLNP-2008-GRANTED-CLAIMS.pdf

567-KOLNP-2008-GRANTED-DESCRIPTION (COMPLETE).pdf

567-KOLNP-2008-GRANTED-DRAWINGS.pdf

567-KOLNP-2008-GRANTED-FORM 1.pdf

567-KOLNP-2008-GRANTED-FORM 2.pdf

567-KOLNP-2008-GRANTED-FORM 3.pdf

567-KOLNP-2008-GRANTED-FORM 5.pdf

567-KOLNP-2008-GRANTED-SPECIFICATION-COMPLETE.pdf

567-KOLNP-2008-PA.pdf

567-KOLNP-2008-PCT PRIORITY DOCUMENT NOTIFICATION.pdf

567-KOLNP-2008-PETITION UNDER RULE 137.pdf

567-KOLNP-2008-REPLY TO EXAMINATION REPORT.pdf

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