MXPA01008659A - Novel tricyclic compounds and their use in medicine;process for their preparation and pharmaceutical composition containing them - Google Patents

Abstract

The present invention relates to novel hypolipidemic, antihyperglycemic, antiobesity and hypocholesterolemic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel&bgr;-aryl-&agr;-oxysubstituted alkylcarboxylic acids of general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.

Description

NEW TRICICLIC COMPOUNDS AND THEIR USE IN MEDICINE: PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT THEY CONTAIN THEM FIELD OF THE INVENTION The present invention relates to novel hypolipidemic, anti-hyperglycemic, anti-obesity and hypocholesterolemic compounds, their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphic substances, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and compositions. pharmaceutically acceptable that contain them. More particularly, the present invention relates to novel β-aryl-α-oxy-substituted alkylcarboxylic acids of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphic substances, their pharmaceutically salts acceptable, their pharmaceutically acceptable solvates and the pharmaceutically acceptable compositions containing them.

IFF. The present invention also relates to a process for the preparation of the above novel compounds, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their polymorphic substances, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. . The present invention also relates to new intermediate compounds, processes for their preparation and their use in the preparation of the compounds of the formula (I). The compounds of the present invention decrease plasma glucose, triglycerides, total cholesterol (TC); they increase high-density lipoprotein (HDL) and decrease low-density lipoprotein (LDL), which have beneficial effects on coronary heart disease and atherosclerosis. The compounds of the general formula (I) are useful in reducing body weight and for the treatment and / or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. These compounds are useful for the treatment of familial hypercholesterolemia, hypertriglyceridemia, decreased atherogenic lipoproteins, VLDL and LDL. The compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. The compounds of the general formula (I) are also useful for the treatment and / or prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia and disorders related to syndrome X, such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders. These compounds may also be useful as aldose reductase inhibitors, to improve cognitive functions in dementia, the treatment of diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory diseases of the intestine, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, inflammation and for the treatment of cancer. The compounds of the present invention are useful in the treatment and / or prophylaxis of the above diseases in combination or concomitantly with one or more HMG-CoA reductase inhibitors, hypolipidemic / hypolipoproteinemic agents such as fibric acid derivatives, nicotinic, cholestyramine, colestipol, probucol.

BACKGROUND OF THE INVENTION Atherosclerosis and other peripheral vascular diseases are the main causes that affect the quality of life of millions of people. Therefore, considerable attention has been paid to the understanding of the etiology of hypercholesterolemia and hyperlipidemia and to the development of effective therapeutic strategies. Hypercholesterolemia has been defined as the level of plasma cholesterol that exceeds an arbitrarily defined value called the "normal" level. Recently, it has been accepted that the "ideal" plasma levels of cholesterol are much lower than the "normal" level of cholesterol in the general population and the increase in coronary artery disease (CAD) increases as the cholesterol level increases above the "optimal" (or "ideal") value. There is clearly a specific cause and an effect relationship between hypercholesterolemia and CAD, particularly for individuals with multiple risk factors. Most cholesterol is present in forms esterified with several lipoproteins such as low density lipoprotein (LDL), intermediate density lipoprotein (IDL), high density lipoprotein (HDL) and partially as very low density lipoprotein (VLDL). . Studies clearly indicate that there is an inverted relationship between CAD and atherosclerosis with serum HDL-cholesterol concentrations (Stampfer et al., N. Engl. J. Med., 325 (1991), 373-381) and the risk of CAD increase with increasing levels of LDL and VLDL. In CAD, in general the "fatty deposits" in the carotid, coronary and cerebral arteries are found to be mainly free and esterified cholesterol. Miller et al. , (Br. Med. J., 282 (1981), 1741-1744) has shown that the increase in HDL particles can decrease the number of sites of stenosis in the coronary arteries of humans, and the high level of HDL -cholesterol can protect against the progress of atherosclerosis. Picardo et al., (Arteriosclerosis 6 (1986) 434-441) has shown by experiment that HDL is capable of removing cholesterol from cells. They suggest that HDL can deplete excess free cholesterol tissues and transfer it to the liver (Macikinnon et al., J. Biol. Chem. 261 (1986), 2548-2552). Therefore, agents that increase HDL-cholesterol would have therapeutic significance for the treatment of hypercholesterolemia and coronary heart disease (CHD). Obesity is a highly prevalent disease in affluent societies and in the developing world and is the leading cause of morbidity and mortality. It is a state of accumulation in excess body fat. The causes of obesity are not clear. It is believed to be of genetic origin or is promoted by an interaction between the genotype and the environment. Despite the cause, the result is the deposit of fat due to the imbalance between the admission of energy against energy expenditure, diet, exercise and suppression of appetite have been part of the treatment against obesity. There is a need for efficient therapy to combat this disease, since it can lead to coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis, reduced fertility and many other psychological and social problems. Diabetes and insulin resistance is yet another disease that severely affects the quality of life of a large population in. the world. Insulin resistance is the diminished ability of insulin to exert its biological action through a broad aspect of concentrations. In insulin resistance, the body normally secretes high amounts of insulin to compensate for this defect, a failure that inevitably increases the plasma concentration of glucose and develops in diabetes. Among developed countries, diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75: 809-817.; N. Engl. J. Med. (1987) 317: 350-357; J. Clin. Endocrinol Metab., (1988) 66: 580-583; J. Clin. Invest., (1975) 68: 957-969) and other renal complications (see, Patent Application No. WO 95/21608). It is now increasingly recognized that insulin resistance and hyperinsulinemia have a contributing role in obesity, hypertension, atherosclerosis and type 2 diabetes mellitus. The association of insulin resistance with obesity, hypertension and angina has been described as a syndrome that has insulin resistance such as X syndrome, pathogenic, central. Hyperlipidemia is the main cause of cardiovascular diseases (CVD) and other peripheral vascular diseases. The high risk of CVD is related to higher concentrations of LDL (low density lipoproteins) and VLDL (very low density lipoprotein) seen in hyperlipidemia. Patients who have glucose intolerance / insulin resistance, in addition to hyperlipidemia, have a higher risk of CVD. Numerous studies in the past have shown that the decrease of plasma triglycerides and total cholesterol, in particular LDL and VLDL and the increase of HDL-cholesterol helps in the prevention of cardiovascular diseases. The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily. The gamma (?) Isoform of PPAR (PPAR?) Has been implicated in the regulation of adipocyte differentiation (Endocrinology, (1994) 135: 798-800) and energy homeostasis (Cell, (1995) 83: 803 -812), whereas the alpha (a) isoform of PPAR (PPARa) measured the oxidation of fatty acids (Trend, Endocrin, Metab., 1993) 4: 291-296) thereby resulting in acid reduction free fatty acid circulating in plasma (Current Biol. (1995) 5: 618-621). It has been found that PPARa agonists are useful for the treatment of obesity (WO 97/36579). It has recently been discovered that the hypolipidemic effect is improved when a molecule has PPARa and PPARα agonist activity. and it is suggested that it is useful for the treatment of syndrome X (WO 97/25042). Synergism has been observed between the insulin synthesizer (PPAR agonist?) And the HMG-CoA reductase inhibitor, which is useful for the treatment of atherosclerosis and xanthoma. (EP 0,753,298). It is known that PPAR? plays an important role in the differentiation of adipocytes (Cell. (1996) 87, 337-389), activation of the PPAR ligand is sufficient to cause a complete terminal differentiation (Cell, (1994) 79, 1147-1156) which includes the withdrawal of the cell cycle. The PPAR? is expressed consistently in certain cells and the activation of this nuclear receptor with the PPAR agonist? It will stimulate the terminal differentiation of adipocyte precursors and will cause morphological and molecular changes, characteristic of a more malignant, more differentiated state (Molecular Cell, (1998), 465-470, Carcinogenesis, (1998), 1949-53, Proc. Acad. Sci., (1997) 94, 237-241) and the inhibition of tissue expression of prostate cancer (Cancer Research (1998), 58; 3344-3352). This would be useful in the treatment of certain types of cancer, which express PPAR? and it could lead to a non-toxic, complete chemotherapy. Resistance to leptin is a condition in which the target cells are unable to respond to the leptin signal. This can cause obesity due to excessive intake of food and reduced energy expenditure and causes impaired tolerance to glucose, type 2 diabetes, cardiovascular diseases and other interrelated complications. Kallen et al., (Proc. Nati, Acad. Sci., (1996) 93, 5793-5796) has reported that insulin synthesizers that perhaps due to their PPAR agonist expression decrease the plasmatic concentrations of leptin. However, it has recently been described that compounds having insulin synthesis property also possess sensitization activity to leptin. Reduce the plasmatic concentrations of leptin in circulation by improving the response of the target cells to leptin (WO 98/02159) .. A few ß-aryl-α-hydroxy-propionic acids, its derivatives and other analogs have been reported to be useful in the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia. Some of these compounds described in the prior art are summarized below: i) U.S. Patent No. 5,306,726; WO 91/19702 describes various 3-aryl-2-hydroxypropionic acid derivatives of the general formula (lia) and (Ilb) as hypolipidemic and hypoglycemic agents.

Examples of these compounds are shown in the formula (lie) and (lid). ii) International patent applications, WO 95/03038 and WO 96/04260 describe compounds of the formula (He). wherein Ra represents 2-benzoxazolyl or 2-pyridyl and R represents CF3, CH2OCH3 or CH3. A typical example is (S) -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy] phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid (Hf) . iii) International Patent Applications WO 94/13650, WO 94/01420 and WO 95/17394 describe the compounds of the general formula (Hg).

A1-X- (CH2) n-O-A2-A3-Y. R2 (II g) wherein A1 represents aromatic heterocycle; A2 represents substituted benzene ring and A3 represents a portion of the formula (CH2) m-CH- (OR1), wherein R1 represents alkyl groups, m is an integer from 1 to 5; X represents N substituted or unsubstituted; Y represents C = 0 or C = S; R2 represents OR3, wherein R3 is an alkyl, aralkyl or aryl group and n is an integer in the range of 2-6. An example of these compounds is shown in the formula (Hh).

BRIEF DESCRIPTION OF THE INVENTION With the aim of developing new compounds for the treatment and / or prophylaxis of diseases related to increased levels of lipids, atherosclerosis, coronary arterial diseases, especially to treat hypertriglyceridemia and to decrease free fatty acids, for treatment and / or prophylaxis of diseases described as syndrome X that include hyperlipidemia, hyperinsulinemia, obesity, insulin resistance, insulin resistance leading to type 2 diabetes and diabetes complications thereof, for the treatment of diseases where resistance Insulin is the pathophysiological mechanism, for the treatment of hypertension, atherosclerosis and coronary arterial diseases with greater efficiency, potency and less toxicity, the search is focused on developing new effective compounds in the treatment of the aforementioned diseases. The effort in this direction has led to the compounds having the general formula (I). The main objective of the present invention is therefore to provide new ß-aryl-a-oxy-substituted alkylcarboxylic acids and their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphic substances, their pharmaceutically acceptable salts, their solvates pharmaceutically acceptable and pharmaceutical compositions containing them or their mixtures. Another object of the present invention is to provide novel β-aryl-a-oxy-substituted alkylcarboxylic acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphic substances, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions. which contain them or their mixtures which may have agonist activity against PPARa and / or PPAR ?, and optionally inhibit HMG-CoA reductase, in addition to the agonist activity against PPARa and / or PPAR ?. Another object of the present invention is to provide novel ß-aryl-a-oxy-substituted alkylcarboxylic acids and their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphic substances, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions which they contain them or their mixtures that have improved activities, without toxic effect or with a reduced toxic effect. Still another object of the present invention is to provide a process for the preparation of novel β-aryl-a-oxy-substituted alkylcarboxylic acids and their derivatives of the formula (I) as defined above, their analogues, their tautomeric forms, their stereoisomers, their polymorphic substances, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates. Still another object of the present invention is to provide pharmaceutical compositions containing the compounds of the general formula (I), their analogues, their derivatives, their tautomers, their stereoisomers, their polymorphic substances, their salts, their solvates or their mixtures in combination with suitable carriers, solvents, diluents and other means normally employed in the preparation of these compositions.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds having the general formula (I). wherein R1, R2, R3 and R4 may be the same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy , heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino , aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulphonic acid or its derivatives; ring A fused to the ring containing X and N represents a 5-6 member cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be replaced; Ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9, where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl; Ar represents a heterocyclic aromatic group, individual or fused, unsubstituted or substituted, divalent; R5 represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or an aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or unsubstituted or substituted aralkyl group or R6 forms a bond together with R5; R7 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen or NR 10, where R 10 represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R8 and R10 may together form a 5- or 6-membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; n is an integer ranging from 1-4 and m is an integer of 0 or 1. Suitable groups represented by R1-R4 include hydrogen, halogen atom such as fluorine, chlorine, bromine or iodine; hydroxy, cyano, nitro, formyl; alkyl group of 1 to 12 carbon atoms, substituted or unsubstituted, especially alkyl group of 1 to 6 carbon atoms, linear or branched, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; Cyclo (C3-C6) alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; Cyclo (Cs-Ce) alkoxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, the cycloalkoxy group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted, aralkyl such as benzyl, phenethyl, C6H5CH2CH2CH2, naphthylmethyl and the like, the aralkyl group may be substituted and the substituted aralkyl is a group such as CH3C6H4CH2, Hal-C6H4CH2 , CH3OC6H4CH2, CH3OC6H4CH2CH2 and the like; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuryl and the like, the heteroaryl group may be substituted; heterocyclyl groups such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and the like, the heterocyclic group may be substituted; Aralkoxy group such as benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy and the like, the aralkoxy group may be substituted; heteroaralkyl group such as furanmethyl, and pyridine-methyl, oxazolmethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted, aralkylamino group such as C6H5CH2NH, C6H5CH2CH2NH, C6H5CH2NCH3, and the like, which may be substituted; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, and the like, the alkoxycarbonyl group may be substituted; aryloxycarbonyl group such as phenoxycarbonyl, naphthyloxycarbonyl and the like, the aryloxycarbonyl group may be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may be substituted; monoalkylamino group such as NHCH3, NHC2H5, NHC3H7, NHC6H13 and the like, which may be substituted; dialkylamino group such as (N (CH 3) 2, NCH 3 (C 2 H 5) and the like, which may be substituted, alkoxyalkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, the alkoxyalkyl group may be substituted; aryloxyalkyl group such as C 6 H 5 OCH 2, C6H5OCH2CH2; naphthyloxymethyl and the like, which may be substituted: aralkoxyalkyl group such as C6H5CH2OCH2, C6H5CH2OCH2CH2 and the like, which may be substituted, heteroaryloxy and heteroaralkoxy, wherein the heteroaryl and heteroaralkyl moieties are as defined above and may be substituted; aryloxy group such such as phenoxy, naphthyloxy and the like, the aryloxy group can be substituted, arylamino group such as NHCßHs, NCH3 (C6H5), NHC6H4CH3, NHC6H4-Hal and the like, the arylamino group can be substituted, amino group, amino (C? ~ C6) alkyl, which may be substituted, hydroxy (Cx-C6) alkyl, which may be substituted, alkoxy of 1 to 6 carbon atoms such as methoxy, ethoxy, propyl oxy, butyloxy, iso-propyloxy and the like, which may be substituted; thio (Ci-Cß) alkyl, which may be substituted; (C? ~ C6) alkylthio, which may be substituted; acyl group such as acetyl, propionyl, benzoyl and the like, the acyl group may be substituted; acylamino groups such as NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC6H5 and the like, which may be substituted; aralkoxycarbonylamino group such as NHCOOCH2C6H5, NHCOOCH2CH2C6H5, N (CH3) COOCH2C6H5, N (C2H5) COOCH2C6H5, NHCOOCH2C6H4CH3, NHCOOCH2C6H4OCH3 and the like, the aralkoxycarbonylamino group may be substituted; aryloxycarbonylamino group such as NHCOOC6H5, NHCOOC6H5, NCH3COOC6H5, NC2H5COOC6H5, NHCOOC6H4CH3, NHCOOC6H4OCH3 and the like, the aryloxycarbonylamino group may be substituted, the alkoxycarbonylamino group such as NHCOOC2H5,, NHCOOCH3 and the like, the alkoxycarbonylamino group may be substituted, carboxylic acid or its derivatives such as amides, such as CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHPh and the like, the carboxylic acid derivatives may be substituted; acyloxy group such as OOCMe, OOCEt, OOCPh and the like, which may be substituted; sulfonic acid or its derivatives such as S02NH2, S02NHMe, S02NMe2, S02NHCF3 and the like, the sulfonic acid derivatives may be substituted. When the groups represented by Rx-R4 are substituted, the substituents may be selected from halogen, hydroxy, nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl groups, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl, alkylamino, alkylthio, thioalkyl, carboxylic acid or its derivatives, or sulphonic acid or its derivatives. The substituents are as defined above. Suitable ring A includes phenyl, naphthyl, cyclohexyl, cyclohexenyl, thienyl, furyl, pyrrolyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl, isoxazolyl, pyridyl, pyranyl, dihydropyranyl, pyridazyl, pyrimidinyl, and the like; which may be unsubstituted or substituted and the substituents are selected from the same group as that of R1-R4 and are defined as being for R1-R4. Preferred substituents are halogen, hydroxy, amino, formyl, alkyl of 1 to 6 carbon atoms optionally halogenated, alkoxy of 1 to 6 carbon atoms, (C3-C6) alkyl, (C3-C6) alkoxy, aryl, aralkyl, aralkoxy, heterocyclyl, acyl, acyloxy, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, acylamino, aralkoxycarbonylamino or aminocarbonyl groups. It is preferred that the cyclic structure represented by ring A be a phenyl or pyridyl ring. It is still more preferred that the cyclic structure represented by ring A be a phenyl ring. The right X includes oxygen, sulfur or a group NR9, preferably oxygen and sulfur. Suitably, R9 represents hydrogen, alkyl group of 1 to 6 carbon atoms such as methyl, ethyl, propyl and the like; cycloalkyl group of 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; aralkyl group such as benzyl, phenethyl and the like; acyl group such as acetyl, propanoyl, butanoyl, benzoyl and the like; alkoxycarbonyl group of 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl and the like; aryloxycarbonyl such as phenoxycarbonyl, CH3OC6H4OCO, Hal-C6H4OCO, CH3C6H4OCO, naphthyloxycarbonyl and the like; aralkoxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl and the like; the groups represented by R9 may be substituted or unsubstituted. When the groups represented by R9 are substituted, the substituents may be selected from halogen, optionally halogenated lower alkyl, hydroxy, optionally halogenated C1-C3 alkoxy groups. The group represented by Ar includes substituted or unsubstituted groups selected from divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, benzopyranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, dihydrobenzopyranyl, pyrazolyl and the like. The substituents in the group represented by Ar include straight or branched, optionally halogenated, C 1-6 alkyl, C 1 -C 3 alkoxy optionally halogenated, halogen, acyl, amino, acylamino, thio, carboxylic or sulphonic acids or Their derivatives. Substituents are defined as for R1-R4. It is more preferred that Ar represents a divalent, substituted or unsubstituted phenylene, naphthylene, benzofuranyl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl group. It is even more preferred that Ar represent phenylene or divalent benzofuranyl, which may be unsubstituted or substituted by methyl, halomethyl, methoxy or halomethoxy groups. Suitable R5 includes hydrogen, hydroxy, halogen atom, such as fluorine, chlorine, bromine or iodine; lower alkyl groups such as methyl, ethyl or propyl; alkoxy group of 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy and the like; aralkyl such as benzyl, phenethyl and the like, which may be unsubstituted or substituted by halogen, hydroxy, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, benzyloxy, acetyl, acetyloxy groups or R5 together with R6 represents a link. Suitable R6 can be hydrogen, hydroxy, halogen atom such as fluorine, chlorine, bromine or iodine; lower alkyl groups such as methyl, ethyl or propyl; alkoxy group of 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy and the like; acyloxy group of 2 to 10 straight or branched carbon atoms such as acetyl, propanoyl, butanoyl, pentanoyl, benzoyl and the like; aralkyl such as benzyl, phenethyl, which may be unsubstituted or substituted by halogen, hydroxy, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, benzyloxy, acetyl, acetyloxy groups or together with R5 forms a bond. It is preferred that R5 and R6 represent hydrogen atom or R5 and R6 together represent a bond. Suitable groups represented by R 7 can be selected from hydrogen, linear or branched alkyl of 1 to 16 carbon atoms, preferably, alkyl of 1 to 12 carbon atoms such as methyl, ethyl, n-propyl, iso- propyl, n-butyl, isobutyl, pentyl, hexyl, octyl and the like, the alkyl group may be substituted; cycloalkyl group of 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted, heteroaryl group such as pyridyl, thienyl, furyl and the like, the heteroaryl group may be substituted; heteroaralkyl group such as furanmethyl, pyridine-methyl, oxazole-methyl, oxazole-ethyl and the like; the heteroaralkyl group may be substituted; aralkyl group wherein the aryl group is as defined above and the alkyl portion may contain from 1 to 6 carbon atoms such as benzyl, phenethyl and the like, wherein the aralkyl group may be substituted; heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclic group may be substituted; group (C? -C6) alkoxy (Ci-C?) alkyl such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxypropyl and the like, the alkoxyalkyl group may be substituted; acyl group such as acetyl, propanoyl, butanoyl, benzoyl and the like, the acyl group may be substituted,; C 1-6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and the like, the alkoxycarbonyl group may be substituted; aryloxycarbonyl such as phenoxycarbonyl, naphthyloxycarbonyl and the like, the aryloxycarbonyl group may be substituted; (C? -C6) alkylaminocarbonyl, the alkyl group may be substituted; arylaminocarbonyl such as PhNHCO, naphthylaminocarbonyl, the aryl portion may be substituted. The substituents may be selected from halogen, hydroxy, nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfuric acid or its derivatives. These substituents are as defined above. Suitable groups represented by R 8 can be selected from hydrogen, linear or branched alkyl of 1 to 16 carbon atoms, preferably alkyl group of 1 to 12 carbon atoms such as methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like, the alkyl group may be substituted; cycloalkyl of 3 to 7 carbon atoms such as cyclopropyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; the aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; heteroaryl group such as pyridyl, thienyl, furyl and the like, the heteroaryl group may be substituted; heteroaralkyl group such as furanmethyl, pyridine-methyl, oxazole-methyl, oxazole-ethyl and the like, the heteroaralkyl group may be substituted; Aralkyl group such as benzyl, phenethyl and the like, the aralkyl group may be substituted; heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may be substituted. The substituents may be selected from halogen, hydroxy, formyl, nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaryl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkoxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulphonic acid or its derivatives. These substituents are as defined above. Suitable groups represented by R 10 can be selected from hydrogen, linear or branched alkyl of 1 to 16 carbon atoms, preferably alkyl of 1 to 12 carbon atoms; hydroxy (C6C6) alkyl; aryl group such as phenyl, naphthyl and the like; aralkyl group such as benzyl, phenethyl and the like; heterocyclyl group such as azi, aziridinyl, pyrrolidinyl, piperidinyl and the like; the heteroaryl group such as pyridyl, thienyl, furyl and the like; heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolmethyl, oxazolethyl and the like. Suitable ring structures formed by R8 and R10 together can be selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the like. Suitable m is an integer ranging from 0-1 it is preferred that when m = 0, Ar represents a benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, dihydrobenzofuryl, divalent dihydrobenzopyranyl groups, preferably a benzofuranyl group and when m = 1, Ar represents a phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, pyrazolyl, divalent group. It is preferred that when m = O, Ar represents a divalent benzofuranyl group, more preferably a benzofuran-2,5-diyl group, and when m = 1, Ar represents a phenylene group. Suitable n is an integer ranging from 1 to 4, preferably, n represents an integer, of 1 or 2. It is preferred that when m = 1, n represents 2. It is also preferred that when m 0, n represents 1. The pharmaceutically acceptable salts forming part of this invention include salts of the carboxylic acid moiety such as alkali metal salts, such as Li, Na and K salts.; alkaline earth metal salts such as Ca and Mg salts; salts of organic bases such as diethanolamine, choline and the like; chiral bases such as alkyl phenyl amine, phenyl glycinol and the like; natural amino acids such as lysine, arginine, guanidine and the like; non-natural amino acids such as D-isomers or substituted amino acids; ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate, sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthates, benzenesulfonates, ascorbates , glycerophosphates, ketoglutarates and the like. The pharmaceutically acceptable solvates may be hydrates or comprise other crystallization solvents such as alcohols.

The pharmaceutically acceptable salts forming part of this invention are found to have good solubility, which is one of the essential properties for pharmaceutical compounds. Particularly useful compounds according to the present invention include: ethyl (E / Z) -3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropenoate; (E) -3- [4- [2- (Fenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropeno-ethyl acetate; (Z) -3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropeno-ethyl ester; (E / Z) -3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropenoate ethyl; (E) -3- [2- (phenothiazin-10-yl) methylbenzof ran-5-yl] -2-ethoxypropenoate ethyl; (Z) -3- [2- (phenothiazin-10-y1) methylbenzofuran-5-yl] -2-ethoxypropenoate ethyl; (E / Z) -3- [4- [2- (phenoxazin-10-yl] ethoxy] phenyl] -2-ethoxypropenoate ethyl (E) -3- [4- [2- (phenoxazine-10-yl) ethyl) ethoxy] phenyl] -2-ethoxypropenoate; ethyl (Z) -3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropenoate; (±) methyl 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (+) Methyl 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanedioate; (-) methyl 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanedioate; (±) methyl 3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2- ethoxypropanoate; (+) Methyl 3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2- ethoxypropanoate; (-) methyl 3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2- ethoxypropanoate; (±) methyl 3- [4- [2- (phenovazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (+) Methyl 3- [4- [2- (phenovazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (-) methyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (±) ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (+) Ethyl 3- [- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (-) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (±) ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoate; (+) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoate; (-) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoate; (±) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoate; (+) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoate; (-) Ethyl 3- [4- [2- (phenovazin-10-yl) ethoxy] phenyl] -2-butoxypropanoate; (±) ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoate; (+) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoate; (-) ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoate; (±) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2- phenoxypropanoate; (+) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2- phenoxypropanoate; (-) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2- phenoxypropanoate; (±) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoate; (+) Methyl 3- [4- [2- (phenovazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoate; (-) methyl 3- [4- [2- (phenovazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoate; (±) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid and its salts; (+) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid and its salts; (-) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid and its salts; (±) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-methylpropanoic acid and its salts; (+) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-methylpropanoic acid and its salts; (-) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-methylpropanoic acid and its salts; (±) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and its salts; (+) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and its salts; (-) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and its salts; (±) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid and its salts; (+) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid and its salts; (-) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid and its salts; (±) 3- [2- (Phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoic acid and its salts; (+) 3- [2- (Phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoic acid and its salts; (-) 3- [2- (Phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2- ethoxypropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2- ethoxypropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2- ethoxypropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-meitylpropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-meitylpropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-meitylpropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid and its salts; [(2R) -N (1S)] -3 [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-1-phenyl-ethyl) propanamide; [(2S) -N (IS)] -3 [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-1-phenyl-ethyl) propanamide; [(2S) -N (IS)] -3 [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-l-phenyl-ethyl) propanamide and [ (2R) -N (IS)] -3 [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-1-phenyl-ethyl) propanamide.

According to a feature of the present invention, the compound of the general formula (III) wherein R1, R2, R3, R4, R7, R8, X, A, n, m, Ar are as defined above and can be prepared by any of the following routes shown in the Reaction Schedule cn - The orpueso cte the general formula (III) represents a compound of the general formula (I), wherein all the symbols are as defined above, R5 and R6 together represent a bond and Y represents an oxygen atom.

Scheme of Feacc? N I Route (1): The reaction of a compound of the general formula (Illa) where all the symbols are as defined above with a compound of the formula (IHb), where R11 can be a lower alkyl group and R7 and R8 are as is defined above excluding hydrogen, to produce a compound of the general formula (III) can be carried out in the presence of a base such as alkali metal hydrides such as NaH, KH or organolithiums such as CH3Li, BuLi and the like or alkoxides such as NaOMe, NaOEt, K + BuO "or mixtures thereof The reaction can be carried out in the presence of solvents such as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof. HMPA as the cosolvent The reaction temperature can vary from -78 ° C to 50 ° C, preferably at a temperature in the range of -10 ° C to 30 ° C. The compound of the general formula (IHb) is You can prepare according to the procedure described in the literature (Annalen Chemie, (1996) 53, 699). Alternatively, the compound of the formula (III) can be prepared by reacting the compound of the formula (Illa) where all the symbols are as defined above with Wittig reagents such as Hal-PH3P ~ CH- (OR7) C0R8 under similar reaction conditions as described above. Route (2): The reaction of a compound of the general formula (Illa) where all the symbols are as defined above with a compound of the formula (lile), where R6 represents a hydrogen atom and R7 and R8 are as defined above can be carried out in the presence of a base. The base is not critical. Any base normally used for the aldol condensation reaction can be used; the bases such as metal hydride such as NaH or KH; Metal alkoxides such as NaOMe, K + BuO "or NaOEt, metal amides such as LiNH2 or LiN (Ipr) 2 can be used.Approotic solvent such as THF, ether or dioxane can be used. in an inert atmosphere that can be maintained by using inert gases such as N2, Ar, He and the reaction is most effective under anhydrous conditions.The temperature of the range of -80 ° C to 35 ° C, can be used. of ß-hydroxy produced initially can be dehydrated under conventional dehydration conditions such as treatment with PTSA in solvents such as benzene or toluene.The nature of the solvent and the dehydrating agent is not critical.The temperature in the range of 20 ° C The reflux temperature of the solvent used can be used, preferably at a reflux temperature of the solvent, by continuous removal of water using a Dean-Stark water separator: Route (3): The reaction of the compound of the formula lile) don of L1 is a leaving group such as a halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like and other symbols are as defined above with a compound of the formula (Illd), wherein R7, R8 and Ar are as defined previously to produce a compound of the formula (III), it may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof. The reaction can be carried out in an inert atmosphere which can be maintained by using inert gases such as N2, Ar or He. The reaction can be carried out in the presence of a base such as K2CO3, Na2CO3 or NaH or a mixture thereof. Acetone can be used as a solvent when Na2C03 or K2C03 is used as a base. The reaction temperature can vary from 0 ° C-120 ° C, preferably at a temperature in the range of 30 ° C-100 ° C. The duration of the reaction can vary from 1 to 24 hours, preferably from 2 to 12 hours. The compound of the formula (IHd) can be prepared according to the known process by a Wittig-Horner reaction between the protected hydroxy-aryl aldehyde such as benzyloxyaryl aldehyde and the compound of the formula (IHb), followed by reduction of the double bond and deprotection. Route (4): The reaction of a compound of the general formula (IHg) where all symbols are as defined above with a compound of the general formula (IHf), where all the symbols are as defined above and L1 is a leaving group such as halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like, preferably a halogen atom to produce a compound of the general formula (III) can be carried out in the presence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like or a combination thereof. The reaction can be carried out in an inert atmosphere which can be maintained by using inert gases such as N2, Ar or He. The reaction can be carried out in the presence of a base such as sodium hydroxide-type alkali, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; organometallic bases such as n-butyl lithium; alkali metal amides such as sodamide or mixtures thereof. The amount of the base can vary from 1 to 5 equivalents, based on the amount of the compound of the formula (IHg), preferably the amount of the base varies from 1 to 3 equivalents. Base transfer catalysts such as tetraalkylammonium halide or hydroxide can also be used. The reaction can be carried out at a temperature in the range of 0 ° C to 150 ° C, preferably at a temperature in the range of 15 ° C to 100 ° C. The duration of the reaction can vary from 0.25 to 48 hours, preferably from 0.25 to 12 hours. Route (5): The reaction of the compound of the general formula (IHh), where all the symbols are as defined above with a compound of the general formula (IHd), where all the symbols are as defined above can be carried using suitable coupling agents such as dicyclohexyl urea, triarylphosphine / dialkylazicarboxylate such as PPI13 / DEAD and the like. The reaction can be carried out in the presence of solvents such as THF, DME, CH2C12, CHCl3, toluene, acetonitrile, carbon tetrachloride and the like. The inert atmosphere can be maintained by using inert gases such as -N2-, Ar or He. The reaction can be carried out in the presence of DMAP, HOBT and can be used in the range of 0.05 to 2 equivalents, preferably 0.25 to 1 equivalents. The reaction temperature can be in the range of 0 ° C to 100 ° C, preferably at a temperature in the range of 20 ° C to 80 ° C. The duration of the reaction can vary from 0.5 to 24 hours, preferably from 6 to 12 hours. Route (6): The reaction of a compound of the formula (lili), where all the symbols are as defined above with a compound of the formula (IIIj), where R7 = R8 and are as defined above excluding hydrogen, for producing a compound of formula (III), wherein all symbols are as defined above, can be carried out, pure in the presence of a base, such as alkali metal hydrides such as NaH or KH or organolithiums such as CH3LÍ , BuLi and the like or alkoxides such as NaOMe, NaOEt, K + BuO "and the like or mixtures thereof The reaction can be carried out in the presence of aprotic solvents such as THF, dioxane, DMF, DMSO, DME and mixtures. HMPA can be used as the co-solvent The reaction temperature can vary from -78 ° C to 100 ° C, preferably at a temperature in the range of -10 ° C to 50 ° C. according to another embodiment of the present invention, the compound of the general formula (I), wherein R5 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl or unsubstituted or substituted aralkyl group, R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl or unsubstituted or substituted aralkyl group, R1, R2, R3, R4, R7, R8, X, A, n, m, Ar as defined above and Y represents an oxygen atom, can be prepared by one or more of the processes shown in Reaction Scheme II.

Reaction Scheme II Route (7): The reduction of the compound of the formula (III) which represents a compound of the formula (I) wherein R5 and R6 together represent a bond and Y represents an oxygen atom and all other symbols are as defined above , can be obtained as described above in Scheme I, to produce a compound of the general formula (I), wherein R5 and R6 each represent a hydrogen atom and all symbols are as defined above, can be carried in the presence of gaseous hydrogen and a catalyst such as Pd / C, Rh / C, Pt / C, and the like. Mixtures of catalysts can be used. The reaction can also be carried out in the presence of solvents such as dioxane, acetic acid, ethyl acetate, ethanol and the like. The nature of the solvent is not critical. A pressure between atmospheric pressure and 5.62 kg / cm2 (80 psi) can be used. Higher pressures can be used to reduce the reaction time. The catalyst can be preferably Pd at 5-10% / C and the amount of catalyst used can vary from 1-50% w / w. The reaction can also be carried out by employing the reduction in metal solvent such as magnesium in alcohol or sodium amalgam in alcohol. The hydrogenation can be carried out in the presence of metal catalysts containing chiral ligands to obtain a compound of the formula (I) in an optically active form. The metal catalyst may contain rhodium, ruthenium, indium and the like. The chiral ligands may preferably be chiral phosphines such as (2S, 3S) - is (diphenylphosphino) butane, 1,2-bis (diphenylphosphino) ethane, 1,2-bis (2-methoxyphenylphosphino) ethane, (-) - 2, 3-isopropylidene-2,3-dihydroxy-l, 4-bis (diphenylphosphino) butane and the like. Any suitable chiral catalyst can be used which will give the required optical purity of the product (I) (Ref: Principies of Asymmetric Synthesis, Tet Org Chem. Series Vol. 14, pp 311-316, Ed. Baldwin J.E.). Route (8): The reaction of the compound of the formula (la), wherein R8 is as defined above excluding hydrogen and all other symbols are as defined above and L3 is a leaving group such as a halogen atom with an alcohol of the general formula (Ib), wherein R7 is as defined above excluding hydrogen to produce a compound of the formula (I) can be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures of the same. The reaction can be carried out in an inert atmosphere which can be maintained by using inert gases such as N2, Ar, or He. The reaction can be carried out in the presence of a base such as KOH, NaOH, NaOMe, NaOEt, K + BuO "or NaH or mixtures thereof Phase transfer catalysts such as tetraalkylammonium halides or hydroxides can be used. The reaction temperature can vary from 20 ° C-120 ° C, preferably at a temperature in the range of 30 ° C-100 ° C. The duration of the reaction can vary from 1 to 12 hours, preferably 2 hours. The compound of the formula (la) can be prepared according to the process described in International Patent Application No. US98 / 10612. Route (9): The reaction of the compound of the formula (Ule) defined above with the compound of the formula (le) wherein all the symbols are as defined above, to produce a compound of the formula (I) can be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof The reaction can be carried out in a an inert atmosphere that is maintained by using inert gases such as N2, Ar or He. The reaction can be carried out in the presence of a base such as K2C03, Na2C03 or NaH or mixtures thereof. Acetone can be used as a solvent when K2C03 or Na2C03 is used as a base. The reaction temperature can vary from 20 ° C-120 ° C, preferably at a temperature in the range of 30 ° C-80 ° C. The duration of the reaction can vary from 1 to 24 hours, preferably from 2 to 12 hours. The compound of the formula (le) can be prepared by Wittig-Horner reaction between the protected hydroxyaryl aldehyde and the compound of the formula (Illb) followed by reduction of the double bond and deprotection. Alternatively, the compound of the formula (le) can be prepared by following a procedure described in WO 94/01420.

Route (10): The reaction of the compound of the general formula (Illh) defined above with a compound of the formula (le) where all the symbols are as defined above and can be carried out using suitable coupling agents such as dicyclohexyl -urea, triarylphosphine / dialkylazadicarboxylate such as PPh3 / DEAD and the like. The reaction can be carried out in the presence of solvents such as THF, DME, CH2C12, CHC13, toluene, acetonitrile, carbon tetrachloride and the like. The inert atmosphere can be maintained by using inert gases such as N2, Ar or He. The reaction can be carried out in the presence of DMAP, HOBT and can be used in the range of 0.05 to 2 equivalents, preferably 0.25 to 1 equivalents. The reaction temperature can be in the range of 0 ° C to 100 ° C, preferably at a temperature in the range of 20 ° C to 80 ° C. The duration of the reaction can vary from 0.5 to 24 hours, preferably from 6 to 12 hours. Route (11): The reaction of the compound of the formula (Id), which represents a compound of the formula (I), where all the symbols are as defined above, with a compound of the formula (le), where R7 represents unsubstituted or substituted groups selected from the groups alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl and Hal represents Cl, Br or I, to produce a compound of the formula ( I) can be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like. The inert atmosphere can be maintained by using inert gases such as N2, Ar or He. The reaction can be carried out in the presence of a base such as KOH, NaOH, NaOMe, K + BuO "or NaH and the like .. Phase transfer catalysts such as halides of tetraalkylammonium hydroxides can be used. vary from 20 ° C-150 ° C, preferably at a temperature in the range of 30 ° C-100 ° C. The duration of the reaction can vary from 1 to 24 hours, preferably from 2 to 12 hours The compound of the formula (Id) represents the compound of the formula (I), where R7 represents H and Y represents an oxygen atom Route (12): The reaction of a compound of the general formula (Illa) defined above with a compound of the formula (lile) where R6 is hydrogen, R7 and R8 are as defined above, it can be carried out under conventional conditions.The base is not critical.Any base normally used for the condensation reaction can be employed. of aldoles, such as hydrides of metals, such as NaH, KH and the like, metal alkoxides such as NaOMe, K + BuO ~, NaOEt and the like, metal amides such as LiNH2, LiN (ipr) 2 and the like. Aprotic solvent such as THF, ether, dioxane can be used. The reaction can be carried out in an inert atmosphere which can be maintained by using inert gases such as N2, Ar or He and the reaction is more effective under anhydrous conditions. The temperature can be used in the range of -80 ° C to 25 ° C. The β-hydroxy-aldol product can be dehydrolyzed using conventional methods, conveniently by ionic hydrogenation technique such as by treating with a trialkyl xylan in the presence of an acid such as trifluoroacetic acid. A solvent such as CH2C12 can be used. Favorably, the reaction proceeds at 25 ° C. Higher temperatures can be used if the reaction is slow. Route (13): The reaction of a compound of the general formula (Illg), where all the symbols are as defined above, with a compound of the general formula (If) where L1 is a leaving group such as a halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like, preferably a halogen atom and all other symbols are as defined above to produce a compound of the formula in General (I) can be carried out in the presence of such solvents as DMSO, DMF, DME, THF, dioxane, ether and the like or a combination thereof. The reaction can be carried out in an inert atmosphere which can be maintained by using inert gases such as N2, Ar or He. The reaction can be carried out in the presence of a base such as sodium hydroxide-type alkali, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; organometallic bases such as n-butyl lithium; alkali metal amides such as sodamide or mixtures thereof. The amount of base can vary from 1 to 5 equivalents, based on the amount of the compound of the formula (Illg), preferably the amount of base varies from 1 to 3 equivalents. The reaction can be carried out in the presence of phase transfer catalysts such as halides or tetraalkylammonium hydroxides. The reaction can be carried out at a temperature in the range of 0 ° C to 150 ° C, preferably at a temperature in the range of 15 ° C to 100 ° C. The duration of the reaction can vary from 0.25 to 24 hours, preferably from 0.25 to 12 hours. Route (14): The conversion of the compound of the formula (Ig), where all the symbols are as defined above, to a compound of the formula (I) where all the symbols are as defined above, can be carried out in either the presence of a base or acid and the selection of the base or acid is not critical. Any base normally used for the hydrolysis of nitrile to acid, hydroxides of metals such as NaOH or KOH in an aqueous solvent or any acid normally used for the hydrolysis of nitrile to ester can be employed, it can be employed, such as dry HCl in a excess of alcohol such as methanol, ethanol, propanol and the like. The reaction can be carried out at a temperature in the range of 0 ° C to reflux temperature of the solvent used, preferably at a temperature in the range of 25 ° C to the reflux temperature of the solvent used. The duration of the reaction can vary from 0.25 to 48 hours. Route (15): The reaction of the compound of the formula (Ih) wherein R8 is as defined above, excluding hydrogen atom, and all other symbols are as defined above, with a compound of the formula (Ib), where R7 is as defined above, excluding hydrogen, to produce a compound of the formula (I) (by a rhodium carbenoid-mediated insertion reaction) can be carried out in the presence of rhodium (II) salts such as acetate of rhodium (II). The reaction can be carried out in the presence of solvents such as benzene, toluene, dioxane, ether, THF and the like or a combination thereof or when practicable in the presence of ROH as a solvent at any temperature that provides a convenient rate of formation of the required product, in general at an elevated temperature, such as reflux temperature of the solvent. The inert atmosphere can be maintained by using inert gases such as N2, Ar or He. The duration of the reaction can vary from 0.5 to 24 hours, preferably from 0.5 to 6 hours. The compound of the formula (I), wherein R8 represents hydrogen atom can be prepared by hydrolyzing, using conventional methods, a compound of the formula (I), wherein R8 represents all the groups defined above, except hydrogen. The hydrolysis can be carried out in the presence of a base such as Na 2 CO 3 and a suitable solvent such as methanol, ethanol and the like, or mixtures thereof. The reaction can be carried out at a temperature in the range of 20 ° C-40 ° C, preferably at 25 ° C-30 ° C. The reaction time can vary from 2 to 12 hours, preferably from 4 to 8 hours. The compound of the general formula (I), wherein Y represents oxygen and R8 represents hydrogen or lower alkyl groups and all other symbols are as defined above, the compound of the formula (I) can be converted, wherein Y represents NR10 , by reaction with appropriate amines of the formula NHR8R10 where R8 and R10 are as defined above. Alternatively, the compound of the formula (I)wherein YR8 represents OH, it can be converted to the acid halide, preferably YR8 = Cl, by reacting with appropriate reagents such as oxalyl chloride, thionyl chloride and the like, followed by treatment with amides of the formula NHR8R10, where R8 and R10 are as defined above. Alternatively, mixed anhydrides of the compound of the formula (I) can be prepared, where YR8 represents OH and all other symbols are as defined above when dealing with acid halides such as acetyl chloride, acetyl bromide, hydrochloride pivaloyl, dichlorobenzoyl chloride and the like. The reaction can be carried out in the presence of a suitable base such as pyridine, triethylamine, diisopropylethylamine and the like. Solvents such as halogenated hydrocarbons such as CHC13, CH2C12, hydrocarbons such as benzene, toluene, xylene and the like, can be used. The reaction can be carried out at a temperature in the range of -40 ° C to 40 ° C, preferably 0 ° C to 20 ° C. The acid halide or mixed anhydride prepared in this manner can be further treated with appropriate amines of the formula NHR8R10 wherein R8 and R10 are as defined above. The processes for the preparation of the compounds of the general formula (Illa) have been described in International Application No. US 98/10612. As used herein, the term "pure" means that the reaction is carried out without the use of the solvent. In another embodiment of the present invention, the new intermediate compound of the formula (If). where Ar represents a heterocyclic, individual or fused, divalent, unsubstituted or substituted aromatic group; R5 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or unsubstituted or substituted aralkyl group or R6 forms a bond together with R5; R7 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; n is an integer that varies from 1-4; m is an integer of 0 or 1 and L1 is a leaving group such as halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like, preferably a halogen atom and a process is provided for its preparation and use in the preparation of β-aryl-a-substituted hydroxyalkanoic acids. The compound of the formula (If), where m = 0 and all other symbols are as defined above, can be prepared by reacting a compound of the formula (le). where R5, R6, R7, R8 and Ar are as defined above, with a compound of the formula (Ii). where L1 and L2 can be the same or different and represent a leaving group such as Cl, Br, I, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate and the like or L2 can also represent a hydroxy group or a protected hydroxy group which can be converted finally to a leaving group; n represents an entire group ranging from 1 to 4. The reaction of the compound of the formula (le) with a compound of the formula (Ii) to produce a compound of the formula (If) can be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof. The reaction can be carried out in an inert atmosphere, which can be maintained by using inert gases such as N2, Ar or He. The reaction can be carried out in the presence of a base such as K2C03, Na2CÜ3 or NaH or mixtures thereof. Acetone can be used as the solvent when Na 2 CO 3 or K 2 CO 3 is used as a base. The reaction temperature can vary from 20 ° C-120 ° C, preferably at a temperature in the range of 30 ° C-80 ° C. The duration of the reaction can vary from 1 to 24 hours, preferably from 2 to 12. Alternatively, the intermediate of the formula (If) can be prepared by reacting a compound of the formula (Ij). 1- (CH2) n- (0) m-Ar-CH0 (Ij) where L1 represents a leaving group such as Cl, Br, I, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate and the like and all other symbols are as defined above, with a compound of the formula (Illb). wherein R11 represents the lower alkyl group and R7, R8 are as described above, to produce a compound of the formula (Illf) which is further reduced to produce a compound of the formula (If). The compound of the formula (Illf) represents a compound of the formula (If), where R5 and R6 together represent a bond and all other symbols are as defined above. The reaction of the compound of the formula (Ij) with (Illb) can be carried out in the presence of a base such as alkali metal hydrides such as NaH, KH and the like, organolithiums such as CH3Li, BuLi and the like or alkoxides such as NaOMe, NaOEt, K'BuO "and the like or mixtures thereof The reaction can be carried out in the presence of solvents such as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof HMPA can be used as the co-solvent. reaction can vary from -78 ° C to 50 ° C, preferably at a temperature in the range of -10 ° C to 30 ° C. The reduction of the compound of the formula (Illf) can be carried out in the presence of gaseous hydrogen and a catalyst such as Pd / C, Rh / C, Pt / C, and the like. Mixtures of catalysts can be used. The reaction can also be carried out in the presence of solvents such as dioxane, ethyl acetate, acetic acid, ethyl acetate, ethanol and the like. The nature of the solvent is not critical. A pressure between atmospheric pressure and 5.62 kg / cm2 (80 psi) can be used. Higher pressures can be used to reduce the reaction time. The catalyst may be preferably Pd at 5-10% / C and the amount of the catalyst used may vary from 1-50% w / w. The reaction can also be carried out by employing reduction in metal solvent such as magnesium in alcohol or sodium amalgam in alcohol. In another embodiment of the present invention, a new intermediate of the formula dg is provided wherein R1, R2, R3 and R4 may be the same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl groups, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulphonic acid or its derivatives; Ring A fused to the ring containing X and N represents a cyclic structure of 5-6 members containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may be optionally substituted; Ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9, where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl groups; Ar represents an aromatic or heterocyclic group, individual or fused, divalent, unsubstituted or substituted; R5 represents hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, unsubstituted or substituted aralkyl, acyl or aralkyl group or R6 forms a bond together with R; R7 represents hydrogen or unsubstituted or substituted groups selected from the groups alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl; n is an integer ranging from 1-4 and m is an integer of 0 or 1, a process for its preparation and its use in the preparation of β-aryl-a-substituted hydroxyalkanoic acids. The compound of the formula (Ig) wherein R5 and R6 represent each hydrogen atom and all other symbols are as defined above, is prepared by a process outlined in reaction scheme III.

Reaction Scheme III The reaction of a compound of the formula (Illa), where all the symbols are as defined above, with a compound of the formula (Ik), wherein R7 is as defined above, excluding hydrogen, and Hal represents a halogen atom such as Cl, Br or I to produce a compound of the formula (II) can be carried out under conventional conditions in the presence of a base. The base is not critical. Any base normally employed for the Wittig reaction, metal hydride such as NaOH or KH, metal alkoxides such as NaOMe, K + BuO "or NaOEt, metal amides such as LiNH2 or LiN (iPr) 2 may be employed. it can use the aprotic solvent such as THF, DMSO, dioxane, DME and the like .. Mixtures of solvents can be used HMPA can be used as the cosolvent An inert atmosphere such as argon can be employed and the reaction is more effective under anhydrous conditions A temperature in the range of -80 ° C to 100 ° C can be used The compound of (II), where all symbols are as defined above, and R7 is as defined above, excluding hydrogen, can be converted to a compound of the formula (Im), wherein R 5 and R 6 represent hydrogen atom and all other symbols are as defined above, when dealing with an alcohol of the formula R 7 OH, wherein R 7 represents unsubstituted or substituted groups selected from alkyl, cycloa alkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl under anhydrous conditions in the presence of a strong anhydrous acid such as p-toluenesulfonic acid. The compound of the formula (Im) defined above in the treatment with trialkylsilyl cyanide such as trimethylsilyl cyanide produces a compound of the formula (Ig), where R 5 and R 6 represent hydrogen atom, R 7 is as defined above, excluding hydrogen , and all other symbols are as defined above. In still another embodiment of the present invention, the new intermediate compound of the formula (Ih). where R1, R2, R3 and R4 may be the same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulphonic acid or its derivatives; ring A fused to the ring containing X and N represents a cyclic structure of 5-6 members containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be replaced; Ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9, where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl groups; Ar represents an aromatic or heterocyclic group, individual or fused, divalent, unsubstituted or substituted; R5 represents hydrogen atoms, hydroxy, alkoxy, halogen, lower alkyl or aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, unsubstituted or substituted aralkyl or R6 forms a bond together with R5; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; n is an integer ranging from 1-4 and m is an integer of 0 or 1 and a process is provided for its preparation and its use in the preparation of β-aryl-a-substituted hydroxyalkanoic acids. The compound of the formula (Ih), where all other symbols are as defined above, can be prepared by reacting a compound of the formula (In). where all symbols are as defined above, with an appropriate diazotization agent. The diazotization reaction may be under conventional conditions. A suitable diazotization agent is an alkyl nitrile, such as iso-amyl nitrile. The reaction can be carried out in the presence of solvents such as THF, dioxane, ether, benzene and the like or a combination thereof. A temperature in the range of -50 ° C to 80 ° C can be used. The reaction can be carried out in an inert atmosphere which can be maintained by using inert gases such as N2, Ar or He. The duration of the reaction can vary from 1 to 24 hours, preferably from 1 to 12 hours. The compound of the formula (In) can be prepared by a reaction between (lile) where all the symbols are as defined above and a compound of the formula (lo). where R6 is a hydrogen atom and all other symbols are as defined above. The reaction of the compound of the formula (lile), where all the symbols are as defined above and a compound of the formula (lo), where all the symbols are as defined above, can be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof. The reaction can be carried out in an inert atmosphere which is maintained by using inert gases such as N2, Ar or He. The reaction can be carried out in the presence of a salt such as K2C03, Na2C03 or NaH, or mixtures thereof. Acetone can be used as a solvent when K2C03 or Na2C03 is used as a base. The reaction temperature can vary from 20 ° C-120 ° C, and preferably at a temperature in the range of 30 ° C-80 ° C. The duration of the reaction can vary from 1 to 24 hours, preferably from 2 to 12 hours. The pharmaceutically acceptable salts are prepared by reacting the compound of the formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, hydroxide of magnesium and the like, in solvents such as ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol, etc. Mixtures of solvents can be used. Organic bases such as diethanolamine, choline and the like; chiral bases such as alkyl phenyl amine, phenyl glycinol and the like; natural amino acids such as lysine, arginine, guanidine, and the like. Unnatural amino acids such as D-isomers or substituted amino acids; Ammonium or substituted ammonium salts and aluminum salts can also be used. Alternatively, the acid addition salts, wherever applicable, are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like, and solvents such as ethyl acetate, ether, alcohols, acetone, THF, dioxane , etc. Mixtures of solvents can also be used. The stereoisomers of the compounds forming part of this invention can be prepared by using reagents in their individual enantiomeric form in the process, wherever possible, or by carrying out the reaction in the presence of reactants or catalysts in their individual enantiomer or by solving the mixture of stereoisomers by conventional methods. Some of the preferred methods include the use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like, wherever applicable, or chiral bases such as brucine, alcolloids of cinchona and its derivatives and the like. The commonly used methods are compiled by Jaques et al., In "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More specifically, the compound of the formula (I), wherein YR9 represents OH can be converted to a 1: 1 mixture of diastereomeric amides by the treatment with chiral amines, amino acids, aminoalcohols derived from amino acids; conventional reaction conditions can be employed to convert the acid to an amide; the diastereomers can be separated either by fractional crystallization or chromatography and the stereoisomers of the compound of the formula (I) can be prepared by hydrolysing the pure, diastereomeric amide. The various polymorphic substances of the compound of the general formula (I) forming part of this invention can be prepared by crystallization of the compound of the formula (I) under different conditions. For example, using different commonly used solvents or their mixtures for recrystallization; crystallizations at different temperatures; several modes of cooling, the variation from a very fast cooling to very slow during the crystallizations. Polymorphous substances can also be obtained by heating or melting the compound followed by gradual or rapid cooling. The presence of polymorphic substances can be determined by NMR spectroscopy with solid probe, infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction or other techniques. The present invention provides pharmaceutical composition, which contains the compounds of the general formula (I) as defined above, their derivatives and their analogs, their tautomeric forms, their stereoisomers, their polymorphic substances, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with pharmaceutically employed carriers, diluents and the like, useful for the treatment and / or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. These compounds are useful for the treatment of familial hypercholesterolemia, hypertriglyceridemia, decreased atherogenic lipoproteins, VLDL and LDL. The compounds of the present invention can be used for the treatment of certain kidney diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. The compounds of the general formula (I) are also useful for the treatment / prophylaxis of insulin resistance (type II diabetes), resistance to leptin, impaired tolerance to glucose, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, Insulin resistance, coronary heart disease and other cardiovascular disorders. These compounds may also be useful as aldose reductase inhibitors, to improve cognitive functions in dementia, as anti-inflammatory agents, in the treatment of diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS). , inflammatory diseases of the intestine, osteoporosis, myotonic dystrophy, pancreatitis, retinopathy, arteriosclerosis, xanthoma and for the treatment of cancer. The compounds of the present invention are useful in the treatment and / or prophylaxis of the above diseases in combination / concomitantly with one or more inhibitors of HMG-CoA reductase, hypolipidemic / hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid , cholestyramine, colestipol, probucol or their combination. The compounds of the present invention in combination with the HMG-CoA reductase inhibitors, hypolipidemic / hypolipoproteinemic agents can be administered together, or in the space of a period to act synergistically. The HMG-CoA reductase inhibitors can be selected from those used for the treatment or prevention of hyperlipidemia such as lovastatin., provastatin, simvastatin, fluvastatin, atorvastatin, cerivastine and their analogues thereof. The suitable derivative of fibric acid may be gemfibrozil, clofibrate, fenofibrate, ciprofibrate, benzafibrate, and their analogues thereof. The present invention also provides a pharmaceutical composition, which contains the compounds of the general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphic substances, their pharmaceutically acceptable salts or their pharmaceutically solvates. acceptable and one or more inhibitors of HMG-CoA reductase, hypolipidemic / hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol in combination with the usual pharmaceutically employed carriers, diluents and the like. The pharmaceutical composition may be in forms normally used, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain seasoning agents, sweeteners, etc., solid or liquid importers or diluents, or in a suitable sterile medium. to form injectable solutions or suspensions. These compositions typically contain from 1 to 20%, preferably from 1 to 10% by weight of the active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents. Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile organic aqueous solutions. The active compound will be present in these pharmaceutical compositions in sufficient amounts to provide the desired dose in the range as described above. Thus, for oral administration, the compounds can be combined with a solid or liquid carrier or diluent, suitable for forming capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavorings, sweeteners, excipients and the like. For parenteral administration, the compounds can be combined with sterile, organic, aqueous media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of acid addition salts, pharmaceutically acceptable, water soluble or salts with base of the compounds. Injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, intramuscularly, with intramuscular administration which is most preferred in humans. The compounds of Formula (I) as defined above are administered clinically to mammals, including humans, via the oral or parenteral route. The administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of the injection. However, in circumstances where the patient can not ingest the medication, or absorption is damaged after oral administration, such as by disease or other abnormality, it is essential that the drug be administered parenterally. By any route, the dose is in the range of about 0.01 to about 100 mg / kg body weight of the subject per day preferably from about 0.01 to about 30 mg / kg of body weight per day administered individually or as a divided dose. However, the optimal dose for the individual subject to be treated will be determined by the person responsible for the treatment, the generally smaller doses that are administered initially and subsequently, the increments are made to determine the most appropriate dose. The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore, should not be considered as limiting the scope of the invention.

Preparation 1 ethyl (E / Z) -3- [4-benzyloxyphenyl] -2-ethoxypropenoate: A solution of triethyl 2-ethoxyphosphonoacetate prepared by the method of Grell and Machleidt; Annalen Chemie, 1996, 699, 53 (3.53 g, 13.2 mmol) in dry tetrahydrofuran (10 mL) was added slowly to an ice-cooled, stirred suspension of sodium hydride. (dispersion at 60% oil) (0.62 g, 25.94 mmol) in dry tetrahydrofuran (5 mL), under nitrogen atmosphere.

The mixture was stirred at 0 ° C for 30 minutes before the addition of 4-benzyloxybenzaldehyde (2.5 g, 11.79 mmol) in dry tetrahydrofuran (20 mL). The mixture was allowed to warm to room temperature and was stirred at this temperature for an additional 20 hours. The solvent was evaporated, water (100 mL) was added and extracted with ethyl acetate (2 x 75 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (2: 8) as an eluent to give the title compound (3.84 g, quantitative) as an oil. The 1 H NMR of the product suggests a mixture (76:24 = Z: E) of the geometric isomers (R. A. Aitken and G. L. Thom, Synthesis, 1989, 958).

AH NMR (CDC13, 200 MHz): d 1.25-1.50 (6H complex), 3.85- 4.03 (complex, 2H), 4.28 (q, J = 7.0 Hz, 2H), 5.05, 5.09 (2s, 2H, benzyloxy CH2), 6.08 (s, 0.24H, E isomer of olefinic proton), 6.85-6.90 (complex, 2H), 6.99 (s, 0. 76Hm, Z isomer) 7.33-7.45 (complex, 5H), 7.75 (d, J = 8.72 Hz, 2H).

Preparation 2 Methyl 3- (4-benzyloxyphenyl) -2-ethoxypropanoate: A mixture of ethyl (E / Z) -3- (4-benzyloxyphenyl) -2-ethoxypropanoate (3.84 g, 11.79 mmol obtained in preparation 1) and magnesium swarf (5.09 g, 0.21 mol) in dry methanol (40 g) was added. mL) was stirred at 25 ° C for 1 hour. Water (80 mL) was added and the pH of the solution was adjusted to 6.5-7.5 with 2N hydrochloric acid. The solution was extracted with ethyl acetate (3 x 75 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and filtered. The solvent was evaporated under reduced pressure to give the title compound (3.7g, quantitative yield) as an oil.

NMR? (CDCI3, 200 MHz): d 1.16 (t, J = 6.97 Hz, 3H), 2.95 (d, J = 6.55 Hz, 2H), 3.30-3.38 (complex, ÍH), 3.55-3.67 (complex, ÍH), 3.69 (s, 3H), 3.99 (t, J = 6.64 Hz, ÍH), . 04 (s, 2H), 6.89 (d, J = 8.63 Hz, 2H), 7.15 (d, J = 8.62 Hz, 2H), 7.31-7.41 (complex, 5H).

Preparation 3 Methyl 3- (4-hydroxyphenyl) -2-ethoxypropanoate: A suspension of methyl 3- (4-benzyloxyphenyl) -2-ethoxypropanoate (3.7 g, 11.78 mmol, obtained in preparation 2) and 10% Pd-C (0.37 g) in ethyl acetate (50 mL) was stirred at 25 ° C under 4.21 kg / cm2 (60 psi) of hydrogen pressure for 24 hours. The catalyst was filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (2: 8) as an eluent to give the title compound (2: 2g, 84%) as an oil.

X H NMR (CDCl 3, 200 MHz): d 1.21 (t, J = 6.97 Hz, 3H), 2.99 (d, J = 6.37 Hz, 2H), 3.32-3.49 (complex, HH), 3.57-3.5 (Complex, HH), 3.76 (s, 3H), 4.05 (t, J = 6.64 Hz, HH), . 19-5.40 (bs, ÍH, interchangeable D20), 6.80 (d, J = 8.44 Hz, 2H), 7.14 (d, J 0 8.39 Hz, 2H).

Preparation 4 Ethyl 3- (4-hydroxyphenyl) -2-ethoxypropanoate: The title compound (1.73 g, 61%) was prepared as a colorless oil from ethyl (E / Z) -3- (4-benzyloxyphenyl) -2-ethoxypropenoate (3.85 g, 11.80 mmol) obtained in Preparation 1 by the hydrogenation process described in Preparation 3.

X H NMR (CDCl 3, 200 MHz): d 1.12-1.29 (complex, 6H), 2.93 (d, J = 6.55 Hz, 2H), 3.28-3.45 (complex, HH), 3.51-3.68 (complex, HH), 3.98 (t, J = 6.55 Hz, ÍH), 4.16 (q, J = 7.15 Hz, 2H), 5.40 (s, ÍH, interchangeable D20), 6.73 (d, J = 8.39 Hz, 2H), 7.08 (d, J = 8.53 Hz, 2H).

Preparation 5 Ethyl 3- (4-benzyloxyphenyl) -2-butoxypropanoate: A solution of ethyl 3- (4-benzyloxyphenyl) -2-hydroxypropanoate (5.0 g, 16.6 mmol) (prepared in a similar manner as described in reference: WO 95/18125) in dry dimethylformamide (5 mL) was added to a sodium hydride suspension (0.1 g, 41.6 mmol) (60% dispersion in oil) in dry dimethylformamide (3 mL) at 0 ° C and stirred for 1 hour. To the above reaction mixture was added n-butyl bromide (3.4 g, 24.0 mmol) at 0 ° C and stirring was continued for 10 hours at about 25 ° C. Water (30 mL) was added and extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate layer was washed with water (50 mL), brine (25 mL), dried (Na2SO), filtered and the solvent was evaporated. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (1: 9) as an eluent to give the title compound (0.7 g, 20%) as an oil.

XR NMR (CDCl3, 200 MHz): d 0.85 (t, J = 7.38 Hz, 3H), 1.18-1.40 (complex, 5H), 1.49-1.58 (complex, 2H), 2.94 (d, J = 6.74 Hz, 2H ), 3.20-3.33 (complex, ÍH), 3.46-3.61 (complex, ÍH), 3.94 (t, J - 6.37 Hz, ÍH), 4.16 (q, J = 7.0 Hz, 2H), 5.04 (s, 2H) 6.89 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.48 Hz, 2H), 7.30-7.44 (complex, 5H).

Preparation 6 Ethyl 3- (4-hydroxyphenyl) -2-butoxypropanoate: The title compound (0.475 g, 75%) was prepared as an oil from ethyl 3- (4-benzyloxyphenyl) -2-butoxypropanoate (0.85 g, 2.38 mmol) obtained in preparation 5 by a procedure analogous to that described in preparation 3.

XR NMR (CDCl3, 200 MHz): d 0.85 (t, J = 7.24 Hz, 3H), 1.19-1.38 (complex, 5H), 1.44-1.58 (complex, 2H), 2.94 (d, J = 6.55 Hz) , 2H), 3.21-3.32 (complex, ÍH), 3.49-3.62 (complex, ÍH), 3.94 (t, J = 6.88 Hz, ÍH), 4.16 (q, J = 7.1 Hz, 2H), 4.99 (s, ÍH, interchangeable D20), 6.73 (d, J = 8. 53 Hz, 2H), 7. 09 (d, J = 8, 44 Hz, 2H).

Preparation 7 Ethyl 3- (4-benzyloxyphenyl) -2-hexyloxypropanoate: The title compound (1.2 g, 22%) was prepared as an oil from ethyl 3- (4-benzyloxyphenyl) -2-hydroxypropanoate (4.2 g, 14.0 mmol), and 1-bromohexane (3.4 g, 21.0 mmol). ) by a procedure analogous to that described in Preparation 5.

XH NMR (CDC13, 200 MHz): d 0.86 (t, J = 5.9 Hz, 3H), 1.18-1.37 (complex, 7H), 1.45-1.66 (complex, 4H), 2.94 (d, J = 6.55 Hz, 2H ), 3.22-3.33 (complex, 1H), 3.52-3.64 (complex, ÍH), 3.94 (t, J = 6.9 Hz, ÍH), 4.16 (q, J = 7.06 Hz, 2H), 5.03 (s, 2H) , 6.89 (d, J = 8.63 Hz, 2H), 7.15 (d, J = 8.63 Hz, 2H), 7.31-7.44 (complex, 5H).

Preparation 8 Ethyl 3- (4-hydroxyphenyl) -2-hexyloxypropanoate: The title compound (0.7 g, 76%) was prepared as an oil from ethyl 3- (4-benzyloxyphenyl) -2-hexyloxypropanoate (1.2 g, 3.1 mmol) obtained in Preparation 7 by a procedure analogous to that described in Preparation 3.

NMR I (CDC13, 200 MHz): d 0.85 (t, J = 5.81 Hz, 3H), 1.19-1.39 (complex, 7H), 1.48-1.68 (complex, 4H), 2.92 (d, J = 6.74 Hz, 2H ), 3.18-3.39 (complex, ÍH), 3.48-3.62 (complex, ÍH), 3.93 (t, J = 7.0 Hz, ÍH), 4.16 (q, J = 7.06 Hz, 2H), 4.85 (s, ÍH, Interchangeable D20), 6.73 (d, J = 8.53 Hz, 2H), 7.10 (d, J = 8.31 Hz, 2H).

Preparation 9 (E / Z) -3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropanoate ethyl: The title compound (4.0 g, 66%) was prepared as an oil in a 45:55 ratio of the E: Z isomers (as measured by 1 H NMR) from 4- (2-bromoethoxy) benzaldehyde (4.0 g, 17.4 mmol) and triethyl 2-ethoxyphosphonoacetate (5.61 g, 20.89 mmol) by an analogous procedure to that described in Preparation 1 .

XH NMR (CDC13, 200 MHz): d 1.17 and 1.42 (6H, E and Z triplet, isomeric OCH2CH3 and COH2-CH3), 3.62-3.72 (complex, 2H), 3.90-4.28 (complex, 2H), 4.30-4.37 (complex, 4H), 6.09 (s, 0.45H, olefinic proton of the E isomers) 6.85 and 6.92 (2H, d, and d, J = 8.67 and 8.7 Hz), 6.98 (s, 0.55H, Z isomer of the olefinic proton), 1. 16 and 1. 18 (d and d, combined 2H, J = 8.63 Hz and 8.72 Hz).

Preparation 10 Ethyl 3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropanoate: The title compound (4.0g, 80%) was prepared as a colorless oil from ethyl (E / Z) -3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropenoate (5.0 g, 14.5 mmol ) obtained in Preparation 9 using 10% H2 / Pd-C (4g) in dioxane as a solvent by a procedure analogous to that described in Preparation 3.

Zn-NMR (CDCl 3, 200 MHz): d 1.12-1.30 (complex, 6H), 2.95 (d, J = 6.64 Hz, 2H), 3.25-3.45 (complex, 1H), 3.56-3.68 (complex, 3H), 3.96. (t, J = 6.65 Hz, ÍH), 4.16 (q, J = 7.1 Hz, 2H), 4.27 (t, J = 6.3 Hz, 2H), 6.81 (d, J = 8.67 Hz, 2H), 7.16 (d , J = 8.63 Hz, 2H).

Example 1 (E / Z) -3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropenoate ethyl: The title compound was obtained as E: Z isomers 1: 1 (1.46 g, quantitative) as a caramelized liquid from 4- [2- (phenothiazin-10-yl) ethoxy] benzaldehyde (1.08 g, 3.11 mmol) and Triethyl triethyl-2-ethoxyphosphonoacetate (W. Grell &H. Machleidt, Annalen chemie, 1966, 699, 53) (1.0 g, 3.73 mmol) by a procedure analogous to that described in Preparation 1.

X H NMR (CDCl 3, 200 MHz): d 1.15-1.43 (complex, 6H), 3.89-4.03 (complex, 2H), 4.11-4.17 (complex, 2H), 4.30, 4.33 (combined, 4H), -CH2CH2-simple ), 6.07 (s, 0.5H, olefinic proton of the E isomers), 6.80-7.10 (complex, 6.5H), 7.14-7.20 (complex, 4H), 7.73 (d, J = 8.39-Hz, 2H).

Example 2 (E / Z) -3- [2- (phenothiazin-10-yl) methylbenzofuan-5-yl] -2-ethoxypropenoate ethyl: The title compound was obtained as isomers E: Z (38:62) (measured as NMR? E) (1.5 g, 100%) as a colorless liquid from 5-formyl-2- (phenothiazin-10-yl) -methylbenzofuran (1.14 g, 3.2 mmol ) by a procedure normal to that described in Preparation 1.

NMR? H (CDCl.sub.3, 200 MHz): d 1.23-1.45 (complex, 6H), 3.55-3.78 (complex, IH), 3.88-4.19 (complex, IH), 4.22-4.35 (complex, 2H), 5.14 (s) , 2H) 6.18 (s, 0.38H, olefinic proton of the E-isomers), 6.47 and 6.54 (combined, IH), 6.78-7.12 (complex, 8.62H), 7.37-7.48 (complex, IH), 7.71 (d, J = 7.57 Hz, ÍH), 7.95 (s, ÍH).

Example 3 (E / Z) -3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropenoate ethyl: The title compound (14.4 g, 76%) was obtained as E: Z isomer (36:64) (as measured by 1 H NMR) as a white solid from 4- [2- (phenoxazine-10-yl) ethoxy] benzaldehyde (14.0 g, 42.3 mmol) by a procedure analogous to that described in Preparation 1. mp: 110-112 ° C.

NMR? E (CDC13, 200 MHz): d 1.16 and 1.38 (combined, 6H, isomeric -OCH2CH3 triple signals), 3.89-4.05 (complex, 4H), 4.14-4.31 (complex, 4H), 6.06 (s, 0.36H) , olefinic proton of the E isomers), 6.66-6.95 (complex, 10.64H), 7.75 (d, J = 8.76Hz, 2H).

Example 4 (±) methyl 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate: The title compound (1.3 g, 94%) was prepared as a gummy liquid from (E / Z) -3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropenoate of ethyl (1.43 g, 3.10 mmol) obtained in Example 1 by a procedure analogous to that described in Preparation 2.

XH NMR (CDC13, 200 MHz): d 1.15 (t, J = 7.00 Hz, 3H), 2.93 (d, J = 6.64 Hz, 2H), 3.33-3.42 (complex, 1H), 3.52-3.63 (complex, 1H). ), 3.69 (s, 3H), 3.97 (t, J = 6.20Hz), 4.29 (s, 4H), 6.81 (d, J = 8.62 Hz, 2H), 6.92-6.96 (complex, 4H), 7.12- 7.22 (complex, 6H).

Example 5 (±) methyl 3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoate: The title compound (1.0 g, 68%) was prepared as a gum, from ethyl (E / Z) -3- [2- (phenothiazin-10-methylbenzofuran-5-yl) -2-ethoxypropenoate (1.5 g, 3. 0 mmol) obtained in Example 2 by a procedure analogous to that described in Preparation 2.

NMR? E (CDCl3, 200 MHz): d 1.16 (t, J = 7.00 Hz, 3H), 3.07 (d, J = 6.55 Hz, 2H), 3.30-3.49 (complex, IH), 3.56-3.68 (complex, ÍH), 3.70 (s, 3H), 4.05 (t, J = 6.3 Hz, ÍH), 5.13 (s, 2H), 6.48 (s, ÍH), 6.79-7.48 (complex, 11H).

Example 6 (±) methyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate Method A The title compound (0.68 g, 52%) was prepared as a white solid, from (E / Z) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2- ethyl ethoxypropenoate (1.3 g, 2.9 m ol) obtained in Example 3 by a procedure similar to that described in Preparation 2, mp: 88-90 ° C.

XH NMR (CDC13, 200 MHz): d 1.16 (t, J = 6.92 Hz, 3H), _ 2.96 (d, J = 6.64 Hz, 2H), 3.22-3.40 (complex, ÍH), 3.51-3.66, (complex, ÍH), 3.68 (s, 3H), 4.00 (t, J = 7.0 Hz, ÍH), 4. 18 (complex, 4H), 6.55-6.89 (complex, 10H), 7.12 (d, J = 8.63 Hz, 2H).

Method B A mixture of 2- (phenoxazin-10-yl) ethyl methanesulfonate (1.75 g, 5.0 mmol), methyl 3- (4-hydroxyphenyl) -2-ethoxypropanoate (1.5 g, 0.68 mmol) obtained in Preparation 3 and potassium carbonate (3.16 g), in dry dimethylformamide (20 mL) was stirred for 12 hours at 80 ° C. The reaction mixture was cooled to room temperature (approximately 25 ° C). Water (30 mL) was added and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4) and evaporated. The residue was chromatographed using a mixture of ethyl acetate and petroleum ether (1: 9) to give the title compound (1.15 g, 47%) as a white solid. p.f. 89-90 ° C. The data from XH NMR corresponds to the desired product (see above).

Example 7 (±) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate Method AA a solution of ethyl (E / Z) -3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropenoate (1.Og, 2.24 mmol) obtained in Example 3 in dioxane (50 mL) was added Pd at 10% -C (0.25 g) and stirred at 25 ° C under a hydrogen pressure of 4.21 kg / cm2 (60 lb / in2) for 24 hours. At the end of this time, the reaction mixture was filtered and the solvent was evaporated under reduced pressure. The residue was triturated with petroleum ether to give the title compound (0.96 g, 96%) as a white solid. p.f. 51-53 ° C.

X H NMR (CDCl 3, 200 MHz): d 1.12-1.27 (complex, 6.H), 2.94 (d, J = 6.31 Hz, 2H), 3.26-3.41 (complex, ÍH), 3.52-3.75 (complex, ÍH), 3.96 (t, J = 6.64 Hz, 2H), 4.10-4.28 (complex, 5H), 6.55-6.92 (complex, 10H), 7.16 (d, J = 8. 39 Hz, 2H).

Method B The title compound (0.55g 75%) was repaired as a white solid from 2- (phenoxazin-10-yl) ethyl methanesulfonate (0.5 g, 1.63 mmol) and 3- (4-hydroxyphenyl) -2 ethyl ethoxypropanoate (0.46 g, 1.9 mmol) obtained in Preparation 4 by a procedure similar to that described in Example 6 (Method B). p.f. 52-53 ° C. The 1 H NMR data corresponds to the desired product (see above).

Method CA a suspension of sodium hydride (60% dispersion in oil) (0.098 g, 4.0 mmol) in dry dimethylformamide (3 mL) was added a solution of phenoxazine (0.3 g, 1.6 mmol) in dry dimethylformamide (5 mL) at 0 ° C under nitrogen atmosphere and stirred for 30 minutes at about 25 ° C. A solution of ethyl 3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropanoate (0.85 g, 2.4 mmol) obtained in Preparation 10 in dry dimethylformamide was added to the above reaction mixture at 0 ° C. mL) at 0 ° C and stirring was continued for an additional 10 hours at about 25 ° C. Water (40 mL) was added and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried (Na2SO4), filtered and evaporated. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (1: 9) as an eluent to give the title compound (0.3 g, 40%) as a colorless solid. p.f. 52-53 ° C. The 1 H NMR data corresponds to the desired product (see above).

Example 8 (±) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropane-noate: The title compound (1.06 g, 43%) was prepared as a pale yellow liquid from 2- (phenoxazin-10-yl) ethyl methanesulfonate (1.8 g, 5.9 mmol) and 3- (4-hydroxyphenyl) -2 ethylhydroxypropanoate (1.36 g, 6.49 mmol) by a procedure analogous to that described in Example 6 (Method B).

XH NMR (CDC13, 200 MHz): d 1.29 (t, J = 6.96 Hz 3H), 2.85-3.12 (complex, 2H), 3.92 (bs, 2H), 4.10-4.27 (complex, 4H), 4.39 (t, J = 6.1 Hz, ÍH), 6.68-6.89 (complex, 10H), 7. 13 (d, J = 8.39 Hz, 2H), the OH proton is too broad to be observed.

Example 9 (±) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoate The title compound (0.25 g, 53%) was prepared as a colorless liquid from 2- (phenoxazin-1-yl) ethyl methanesulfonate (0.3 g, 0.98 mmol) and 3- (4-hydroxyphenyl) -2 ethyl -butoxypropanoate (0.26 g, 0.97 mmol) obtained in Preparation 6 by a procedure analogous to that described in Example 6 (Method B).

NMR? E (CDCl3, 200 MHz): d 0.92 (t, J = 6.40 Hz, H), 1.21-1.39 (complex, 5H), 1.45-1.58 (complex, 2H), 2.94 (d, J = 6.32 Hz, 2H), 3.24-3.31 (complex, ÍH), 3.50-3.57 (complex, ÍH), 3.94 (t, J = 6.13 Hz, ÍH), 4.13-4.23 (complex, 6H), 6.61-6.84 (complex, 10H) , 7.16 (d, J = 8.3 Hz, 2H).

Example 10 (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropaxy-ethyl ester The title compound (0.52 g, 53%) was prepared as a pale yellow oil from 2- (phenoxazin-10-yl) ethyl methanesulfonate (0.6 g and 1.97 mmol) and 3- (4-hydroxyphenyl) -2- ethyl hexyloxypropanoate (0.70 g, 2.4 mmol) obtained in Preparation 8 by a procedure analogous to that described in Example 6 (Method B).

NMR I (CDCI3) 200 MHz): d 0.85 (t, J = 6.00 Hz, 3H), 1.20-1.27 (complex, 7H), 1.48-1.57 (complex, 4H), 2.94 (d, J = 6.00 Hz, 2H ), 3.21-3.30 (complex, IH), 3.52-3.56 (complex, IH), 3.90-3.99 (complex, 3H), 4.13-4.22 (complex, 4H), 6.60-6.83 (complex, 10H), 7.15 (d , J = 8.62 Hz, 2H).

Example 11 (±) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid A solution of methyl (±) 3-f4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate (7.5 g, 16.70 mmol) obtained in Example 4 in ethanol (50 mL) was added 10% aqueous sodium hydroxide (20 mL). The reaction mixture was stirred at about 25 ° C for 3 hours. The solvent was removed under reduced pressure and the residue was acidified with 2N hydrochloric acid, extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate extract was washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel using a mixture of dichloromethane and methanol (9: 1) as an eluent to give the title compound (6.0 g, 83%) as a white solid, m.p. 79-82 ° C.

XH NMR (CDC13, 200 MHz): d 1.18 (t, J = 6.80 Hz, 3H), 2.88-3.11 (complex, 2H), 3.39-3.64 (complex, 2H), 4.06 (dd, J = 9.2 and 4.3 Hz , ÍH), 4.30 (s, 4H), 5.30-5.98 (bs, ÍH, interchangeable D20), 6.80-7.02 (complex, 6H), 7.12-7.21 (complex, 6H).

Example 12 Sodium salt of (±) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid A mixture of (±) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid (0.3 g, 0.689 mmol) obtained in Example 11 and sodium methoxide (0.041 g, 0.758 mmol) in methanol (5 mL) was stirred at about 25 ° C for 2 hours. The solvent was removed under reduced pressure and the residue was triturated with dry ether (3 x 10 mL). The separated solid was filtered, washed with dry ether (2 x 5 mL) and dried over P205 under reduced pressure to give the title compound (0.25 g, 89%) as a white solid, m.p. 188-191 ° C.

X H NMR (DMS0-d 6, 200 MHz): d 1.04 (t, J = 6.90 Hz, 3H), 2.71-2.89 (complex, HH), 2.90-3.06 (complex, HH), 3.16-3.30 (complex, HH) , 3.36-3.54 (complex, ÍH), 3.88-3.91 (complex, ÍH), 4.21 (s, 4H), 6.72 (d, J = 8.3 Hz, 2H), 6.89-6.99 (complex, 4H), 7.05- 7.21 (complex, 6H).

Example 13 (±) 3- [2- (Phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoic acid The title compound (0.8 g, 83%) was prepared as a white solid from methyl (±) 3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoate (1.0 g , 2.0 mmol) obtained in Example 5 by a procedure analogous to that described in Example 11. pf 120-121 ° C. The COOH proton is too broad to be observed.

XH NMR (CDC13, 200 MHz): d 1.15 (t, J = 6.95 Hz, 3H), 3.00-3.26 (complex, 2H), 3.40-3.68 (complex, 2H), 4.08 (t, J = 4.47 Hz, ), 5.11 (s, 2H), 6.46 (s, ÍH), 6.77-7.40 (complex, 11H).

EXAMPLE 14 Sodium salt of (±) 3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoic acid The title compound (0.12 g, 67%) was prepared as a white solid from (±) 3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoic acid (0.16 g, 0.38 mmbl) obtained in Example 13 by a procedure analogous to that described in Example 12. p.f. 258-261 ° C.

NMR t (CDCl 3, 200 MHz): d 0.95 (t, J = 6.97 Hz, 3H), 2.62-2.80 (complex, HH), 2.89-3.02 (complex, HH), 3.06-3.18 (complex, 1H), 3.22. -3.31 (complex, ÍH), 3.50-3.61 (complex, ÍH), 5.25 (s, 2H), 6.64 (s, ÍH), 6.90-7.39 (complex, 11H).

Example 15 (±) 3- [4- [2- (Phenothiazin-1-yl) -ethoxy] phenyl] -2-ethoxypropanoic acid The title compound (5.4 g, 77%) was prepared as a white solid from methyl (±) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate (7.5 g, 16.8 mmol) obtained in Example 6 by a procedure similar to that described in Example 11. pf 90-92 ° C. X H NMR (CDCl 3, 200 MHz): d 1.19 (t, J = 7.00 Hz, 3H), 2.90-3.18 (complex, 2H), 3.41-3.62 (complex, 2H), 3.90-4.10 (complex, 3H), 4.18 (t, J = 6.20 Hz, 2H), 6.58-6.89 (complex, 10H), 7.16 (d, J = 8.40 Hz, 2H). The COOH proton is too broad to be observed.

Example 16 Sodium salt of (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid: The title compound (0.27 g, 85%) was prepared as a white solid from (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid (0.3 g) , 0.72 mmol) obtained in Example 15 by a procedure analogous to that described in Example 12. pf 194-202 ° C. X H NMR (CDCl 3, 200 MHz): d 0.92 (t, J = 6.97 Hz, 3H), 2.65-2.82 (complex, 1H), 2.96-3.14 (complex, 2H), 3.31-3.41 (complex, 1H), 3.70 -3.90 (complex, 3H), 3.94-4.04 (complex, 2H), 6.47-6.74 (complex, 10H), 7.05 (d, J = 8.30 Hz, 2H).

Example 17 (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoic acid: The title compound (0.40 g, 72%) was prepared as a brown liquid from ethyl (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoate (0.6 g, 1.43 mmol) obtained in Example 8 by a procedure analogous to that described in Example 11.

XH NMR (CDC13, 200 MHz): d 2.75 (bs, ÍH, interchangeable D20), 2.86-3.23 (complex, 2H), 3.85 (t, J = 6.0 Hz, 2H), 4.18 (t, J = 5.90 Hz, 2H), 4.47 (complex, ÍH), 6.58-6.89 (complex, 10H), 7.17 (d, J = 8.63 Hz, 2H). The COOH proton is too broad to be observed.

Example 18 (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoic acid: The title compound (0.13 g, 69%) was prepared as a cream solid from ethyl (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoate ( 0.2 g, 0.42 mmol) obtained in Example 9 by a procedure analogous to that described in Example 11. pf 84 - 88 ° C.

XH NMR (CDC13 200 MHz): d 0.88 (t, J = 7.50 Hz, 3H), 1.26 -1.47 (complex, 2H), 1.47-1.66 (complex, 2H), 2.87 -3.16 (complex, 2H), 3.35- 3.58 (complex, 2H), 3.88 -4.08 (complex, 3H), 4.15 (t, J = 6.4 Hz, 2H), 6.65-6.86 (complex 10H), 7.15 (d, J = 8.63 Hz, 2H). The COOH proton is too broad to be observed.

Example 19 Sodium salt of (±) 3- [44- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoic acid The title compound (0.07 g, 83%) was prepared as a creamy hygroscopic solid from (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoic acid ( 0.08 g, 0.178 mmol) obtained in Example 18 by a procedure similar to that described in Example 12.

X H NMR (DMSO-d 6, 200 MHz): d 0.78 (t, J = 7.28 Hz, 3H), 1.19-1.52 (complex, 4H), 2.72-3.02 (complex, 2H), 3.45-3.67 (complex, 2H) , 4.01 (bs, 3H), 4.18 (bs, 2H), 6.61-6.89 (complex, 8H), 7.10 - 7.24 (complex, 4H).

Example 20 (±) 3- [4 - [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid: The title compound (0.10 g, 23%) was obtained as a caramelized liquid from ethyl (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoate (0.46) g, 0.96 mmol) obtained from Example 10 by a procedure analogous to that described in Example 11.

NMR? H (200 MHz CDCI3): d 0.86 (t, J = 0.86 (t, J = 6.00 Hz, 3H), 1.18-1.30 (complex, 4H), 1.42-1.80 (complex, 4H), 2.88-3.18 ( complex 2H), 3.32 - 3.60 (complex, 2H), 3.89 - 4.09 (complex, 3H), 4.16 (t, J = 6.0 Hz, 2H), 6.58 - 6.89 (complex, 10H), 7.14 (d, J = 8.63 Hz, 2H) .COOH is too wide to be observed.

Example 21 [(2R) -N (1S)] -3- [4- [2-phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-1-phenylethyl) propanamide (21a ) 21a [(2S) -N (1S)] -3- [4- [2-phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-1-phenylethyl) propanamide (21b) 21b To an ice-cooled solution of the (+) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid (1.2 g, 2.9 mmol) obtained in Example 15 and triethylamine (0.48) g, 5.8 mmol) in dry dichloromethane (25 mL) was added pivaloyl chloride (0.38 g, 3.19 mmol) and stirred for 30 minutes at 0 ° C. A mixture of (S) -2-phenylglycinol (0.39 g, 2.9 mmol) and triethylamine (0.58 g, 5.8 mmol) in dichloromethane (20 mL) was added to the above reaction mixture at 0 ° C and stirring was continued for 2 additional hours of 25 ° C. Water (50 mL) was added and extracted with dichloromethane (2 x 50 mL). The organic extracts were washed with water (2 x 25 mL), brine (25 mL), dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel using a gradient of 40-60% ethyl acetate in petroleum ether as an eluent to give first a diastereomer tentatively assigned to [2R, N (lS)] - 3- [4- [2-phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-1-phenylethyl) propanamide (0.55 g, 35%), (21 a) followed by [2S-N (IS )] -3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-l-phenylethyl) propanamide (0.5 g, 32%) (21b). 21a: p.f: 126-128 ° C. [a] D25 = + 24.6 (c = 1.0%, CHC13). XH NMR (CDC13 200 MHz): d 1.16 (t, J = 7.20 Hz, 3H), 2.50 (bs, ÍH, exchangeable D20), 2.92 - 3.20 (complex, 2H), 3. 52 (q, J = 7.05 Hz, 2H), 3.72 (bs, 2H), 3.99 (complex, 3H), 4.21 (t, J = 6.64 Hz, 2H), 4.98 - 5.01 (complex, ÍH), 6. 64-6.70 (complex, 5H), 6.73-6.89 (complex, 4H), 7. 03 (d, J = 7.15 Hz, ÍH), 7.18 - 7.29 (complex, 4H), (J = 7. 32-7.39 complex, 3H). CONH is too broad to be observed. 21b: p.f. : 139 - 141 ° C. [α] D 5 = -13.3 (c, 1.00%, CHC13) XH-NMR (CDC13 200 MHz): d 1.18 (t, J = 6.96 Hz, 3H), 2.05 (bs, ÍH, interchangeable D20), 2.80 - 3.14 (complex, 2H), 3.54 (q, J = 7.00 Hz, 2H), 3.85 (bs, 2H), 3.97 (complex, 3H), 4.14 (t, J = 6.23 Hz, 2H), 4.92 - 5.01 (complex, ÍH), 6.62 - 6.85 (complex, 9H), 7.02 - 7.20 (complex, 5H), 7.26 - 7.30 (complex, 3H), CONH is too broad to be observed.

Example 22 (±) 3- [4- [2- (Phenoxazin-1-yl) ethoxy] phenyl] -2-ethoxypropanoic acid: A solution of [2R diastereomer, N (lS)] - 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-l-phenylethyl) propanamide ( 0.45 g, 0.84 mmol) obtained in Example 21a in mixture with 1M sulfuric acid (17 mL) and dioxane / water (1: 1, 39 mL) was heated at 90 ° C for 88 hours. The pH of the mixture was adjusted to 3.0 by the addition of an aqueous solution of sodium acid carbonate. The mixture was extracted with ethyl acetate (2 x 25 mL), and the organic extract was washed with water (50 mL), brine (25 mL), dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel using a gradient of 50-75% ethyl acetate in petroleum ether to give the title compound (0.2 g, 57%) as a white solid, m.p .: 77-78 ° C. [a] D25 = '+ 12.1 (c = 1.0%, CHC13) XH-NMR (CDC13 200 MHz): d 1.16 (t, J = 7.0 Hz, 3H), 1.43 -1.85 (bs, ÍH, interchangeable D20), 2.86 - 3.14 (complex, 2H), 3.40 - 3.67 (complex, 2H, 3.90 - 4.08 (complex, 3H), 4.15 (t, J = 6.65 Hz, 2H), 6.59 - 6.83 (complex, 10 H), 7.13 ( d, J = 8.4 Hz, 2H).

Example 23 (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid The title compound (0.19 g, 54%) was prepared as a white solid from the diastereomer [(2S-N (IS)] -3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-1-phenylethyl) propanamide (0.45 g, 0.84 mmol) obtained in Example 21b by a procedure analogous to that described in Example 22, mp: 89-90 ° C. a] D25 = 12.6 (c = 1.0%, CHC13) XH-NMR (CDC13 200 MHz): d 1.16 (t, J = 7.02 Hz, 3H), 1.42 -1.91 (bs, ÍH, interchangeable D20), 2.94 - 3.15 ( complex, 2H), 3.40 - 3.65 (complex, 2H), 3.86 - 4.06 (complex, 3H), 4.15 (t, J = 6.65 Hz, 2H), 6.63 - 6.83 (complex, 10H), 7.13 (d, J = 8.54 Hz, 2H).

Example 24 Potassium salt of (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid: A mixture of (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid (0.3 g, 0.72 mmol) obtained from example 15 and potassium tert-butoxide (88 mg) , 0.72 mmol) in methanol (5 ml) was stirred at about 25 ° C for 2 hours. The solvent was removed under reduced pressure and the residue was triturated with dry ether (3 x 3 mL). The supernatant solvent was decanted and the additional traces of ether were removed and dried under reduced pressure to give the title compound (0.25 g, 76%) as a hygroscopic solid.

XH NMR (CDCl3 200 MHz): d 0.96 - 1.03 (t, J = 6.82 Hz, 3H), 2.55 - 2.65 (m, 3H), 2.81 - 2.90 (m, ÍH), 3.10 - 3.40 (t, J = 7.05 Hz, ÍH), 4.01 - 4.07 (t, J = 5.30 Hz, 2H), 4.18 -4.23 (t, J = 5.30 Hz, 2H), 6.60 - 7.00 (m, 10 H), 7.1 (d, J = 8.30 Hz, 2H).

Example 25 Magnesium salt of the (-) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid: To a solution of the (-) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid (0.3 g, 0.72 mmol) obtained in Example 23 in methanol (10 mL) was added magnesium hydroxide (20 mg, 0.345 mmol). The reaction mixture was stirred at room temperature at about 25 ° C for 72 hours. The solvent was removed and the residue was triturated with diethyl ether and decanted to yield the title compound as a white solid (280 mg, 90%). p.f .: 300 ° C (decomposition). [α] D25 = -31.0 (c = 1.0%, CHC13) XH-NMR (CDC13 200 MHz): d 1.10 (t, J = 7.00 Hz, 3H), 2.80 (dd, J = 8.39 Hz, 14Hz, ÍH), 3.0 (dd, J = 3.83 Hz, ÍH), 3.20 - 3.40 (m, ÍH), 3.50 - 3.70 (m, ÍH), 3.80-3.90 (m, ÍH), 3.99 (t, J = 5.90 Hz, 2H) , 4.20 (t, J = 5.90 Hz, 2H), 6.54-6.90 (m, 6H), 7.16 (d, J = 8.50 Hz, 2H).

Example 26 Arginine salt of (±) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid: A mixture of the (±) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid (50 mg, 0.115 mmol) obtained in Example 11 and L-arginine (20 mg, 0.115 mmol) in methanol (3.0 mL) was stirred for 14 hours at 30 ° C. The methanol was removed under reduced pressure and the residual mass was triturated with ether to give the title compound as a white solid (62 mg, 88%). p.f. 178 ° C.

NMR tE (DMSO-d6, 200 MHz): d 1.08 (t, J = 6.90 Hz, 3H), 1.72 - 1.84 (m, 4H), 2.86 - 2.90 (m; 2H), 3.16 - 3.30 (m, 4H) , 3.52 - 3.56 (m, 2H), 3.68 - 3.91 - (m, 2H), 4.28 (s, 4H), 6.70 (d, J = 8.66 Hz, 2H), 6.74 - 6.96 (m, 2H), 7.00 - 7.23 (m, 8H).

Example 27 Arginine salt of the (+) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid A solution of L-arginine (41.5 mg, 0.23 mmol) in water (0.25 mL) was added to a stirred solution of (+) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] - 2-ethoxypropanoic acid (100 mg, 0.23 mmol) obtained in Example 22 in ethanol (1 mL) at room temperature at about 25 ° C. The reaction mixture was stirred vigorously for 16 hours at the same temperature. The precipitated solid was filtered and dried under reduced pressure to yield the title compound (110 mg, 78%). p.f .: 196-198 ° C. [a] D25 = +24.0 (c = 0.5% CHC13 NMR XH (CD3OD, 200 MHz): d 1.04-1.11 (t, J = 7.06 Hz, 3H), 1.71-1.87 (m, 4H), 2.78-2.90 ( m, 2H), 3.18 - 3.26 (m, 3H), 3.54 - 3.58 (m, 2H), 3.75 - 3.85 (m, ÍH), 3.96 - 4.01 (t, J = 5.81 Hz, 2H), 4.17 - 4.23 (t, J = 5.82 Hz, 2H), 6.60-6.82 (m, 10H), 7.15 - 7.19 (d, J = 8.40 Hz, 2H).

Example 28 Arginine salt of the (-) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid: A mixture of the (-) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid obtained in Example 23 (104.3 mg, 0.24 mmol) and L-arginine (43.3 mg, 0.25 mmol) in a mixture of ethanol (2.5 mL) and water (0.15 mL) was stirred for 24 hours at room temperature. The white precipitate formed was filtered and the solid was washed with dry ether (10-15 mL) to yield the title compound as a white solid (100 mg, 67.7%). p.f .: 145-147 ° C. [a] D25 = -24 (C = 0.545%, MeOH) XH NMR (DMSO-D6): d 1.10 (t, J = 7.06 Hz, 3H), 1.72-1.86 (m, 4H), 2.81-2.92 (m , 2H), 3.19-3.25 (m, 3H), 3.56 -3.60 (m, 2H), 3.75 - 3.85 (m, ÍH), 3.97 - 4.03 (t, J = 5.72 Hz, 2H), 4.19 - 4.25 (t , J = 5-82 Hz, 2H), 6.58-6.84 (m, 10H), 7.17 - 7.21 (d, J = 8.27 Hz, 2H).

EXAMPLE 29 Lysine salt of the (-) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid A mixture of the (-) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid (50 mg, 0.119 mmol) obtained in Example 23 and lysine (17.5 mg, 0.119 mmol ) in methanol (3.0 mL) was stirred for 36 hours at room temperature at about 25 ° C under nitrogen atmosphere. The methanol was removed under reduced pressure and the residual mass was triturated with ether to give the title compound as a white solid (65 mg, 96.4%) m.p .: 153-155 ° C. [a] D25 = -14.0 (c = 0.5%, CHC13) XH NMR (CD3OD, 200 MHz): 8 1.11 (t, J = 7.01 Hz,, 3H), 1.42 - 1.92 (m, 6H), 2.79 ( q, J = 7.05 Hz, 2H), 2.95 (dd, J = 4.00, 12.6 Hz, ÍH), 3.15 - 3.45 (m, 2H), 3.48 - 3.70 (m, ÍH), 3.78 (dd, J = 8.97, 4.00 Hz, HH), 4.02 (t, J = 5.80 Hz, 2H), 4.23 (t, J = 5.85 Hz, 2H), 6.59-6.90 (m, 10H), 7.22 (d, J = 8.73 Hz, 2H) .

EXAMPLE 30 Sodium salt of (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid: To a solution of (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-methyl-2-phenoxypropanoic acid (210 mg, 0.43 mmol) in dry methanol (4 mL) was added freshly prepared sodium methoxide (23 mg, 0.42 mmol) and allowed to stir the reaction mixture at 30 ° C for 2 hours. Methanol was removed under reduced pressure and the residue was triturated with dry ether (3 x 5 mL) to give the title compound as a hygroscopic solid (200 mg, 91%).

X H NMR (DMSO, 200 MHz): d 1.1 (s, 3 H), 3.00 - 3.10 (dd, J = 13.7 Hz, 2 H), 3.90 (d, J = 5.00 Hz, 2 H), 4.18 (d, J = 5.30) Hz, 6.60-6.90 (m, 8H), 7.10-7.30 (m, 4H).

Example 31 Arginine salt of the (-) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid: A mixture of (-) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid (78 mg, 0.23 mmol) and L-arginine (34 mg, 0.23 mmol) in methanol (3 mL) was stirred for 14 hours at 30 ° C. The solvent was removed and the residue triturated with ether to yield the title compound as a white solid (70 mg, 64%), m.p. 194 ° C.

NMR? E (DMSO-D6): d 1.08 (t, J = 6.90 Hz, 3H), 1.73 - 1.84 (m, 4H), 2.83 - 2.90 (m, 2H), 3.15 - 3.31 (m, 4H), 3.53 -3.55 (m, 2H), 3.70 - 3.90 (m, 2H), 4.28 (s, 4H), 6.79 (d, J = 8.60 Hz, 2H), 6.76 - 6.98 (m, 2H), 7.01 - 7.21 (m , 8H).

EXAMPLE 32 Lysine salt of (-) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid: A mixture of (-) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid (50 mg, 0.1079 mmol) and L-lysine (18 mg, 0.1079 mmol) in methanol (1 mL) was stirred for 14 hours at room temperature. The solvent was removed and the residue was treated with dry ether (5 ml x 2). The gummy mass was struck when a pale solid separated from the ether layer. The ether layer was decanted to yield the title compound (55 mg, 83%) m.p .: 138-140 ° C. [a] D25 = -1.28 (C = 0.5% MeOH) XH NMR (CDC13 200 MHz): d 1.07 (t, J = 6.95 Hz, 3H), 1.51 -1.89 (m, 4H), 2.87-2.94 (m, 2H), 3.29 - 3.30 (m, 5H), 3.50 - 3.53 (m, 2H), 3.71 - 3.80 (m, ÍH), 4.28 (s, 4H), 6.76 '- 6.80 (m, 2H), 6.92 - 6.95 (m, 2H), 7.01 - 7.21 (m, 8 H).

Example 33 Sodium salt of (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoic acid: The title compound (80 mg, 47.33%) was prepared from (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoic acid (160 mg, 0.49 mmol) obtained from example 17 by a procedure analogous to that described in example 12 pf : > 280 ° C.

X H NMR (DMSO-D6, 200 MHz): d 2.88 - 2.96 (m, 2H), 4.01 - 4.04 (d, J = 5.31 Hz, 2H), 4.15 - 4.18 (d, J = 5.07 Hz, 2H), 6.60 - 6.90 (m, 10H), 7.10 - 7.20 (d, J = 8.54 Hz, 2H).

Example 34 (±) methyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoate: A solution of diethylphosphino-phenoxyethyl acetate in dry THF was added slowly to a stirred, ice-cooled suspension of sodium hydride in dry THF under nitrogen atmosphere. The mixture was stirred at 0 ° C for 30 minutes and a solution of 4- [2- (phenoxazin-10-yl) ethoxy] benzaldehyde in dry THF was added dropwise at room temperature. The mixture was allowed to warm to room temperature - and stirred overnight. The solvent was evaporated under reduced pressure, the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and concentrated. The residue was chromatographed with 10% ethyl acetate in petroleum ether as an eluent to give ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropenoate (59%). like a thick liquid. Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropenoate (3.5 gm) and magnesium turnings in dry methanol was stirred at room temperature for 12 hours. The methanol was evaporated and the residue was taken up in water, acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed with water, brine, evaporated and chromatographed with 10% ethyl acetate in petroleum ether to yield the title compound (2.9 g, 85%). p.f .: 106-110 ° C.

XH NMR (CDC13 200 MHz): d 3.16 - 3.10 (d, J = 6.23 Hz, 2H), 3.70 (s, 3H), 4.16 (m, 4H), 4.72 - 4.79 (t, J = 6.32 Hz, 6.63 - 7.27 (m, 17H).

Example 35 (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid: To a solution of methyl (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoate (300 mg, 0.6 mmol) obtained in Example 34 in methanol (15 mL) 10% NaOH solution (5 mL) was added. The reaction was stirred at room temperature for 10 hours. The methanol was removed and the residue was acidified with 2N HCl, extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with water, brine, dried and concentrated. The residue was chromatographed using 30% ethyl acetate: petroleum ether to produce a thick liquid which was triturated with petroleum ether to yield the title compound as a title compound (192 mg, 66%). p.f .: 119-120 ° C.

NMR? E (CDC13 200 MHz): d 3.23 - 3.26 (d, J = 5.81 Hz, 2H), 3.94 - 4.00 (t, J = 6.23 Hz, 2H), 4.14 - 4.20 (t, J = 6.64 Hz, 2H ), 4.81 - 4.87 (t, J = 6.23 Hz, ÍH). 6.61-6.89 (m, 12H), (m, 12H), 6.96-7.044 (t, J = 7.31 Hz, ÍH), 7.21-7.32 (m, 4H).

The compounds of the present invention decreased the random, blood, sugar, triglyceride, total cholesterol, LDL, VLDL level and increased HDL. This was demonstrated by in vitro experiments as well as in vivo in animals.

Demonstration of Efficiency of the Compounds: A) In vitro: a) Determination of the hPPARa activity: The ligand-binding domain of hPPARa was fused to the DNA binding domain of the yeast transcription factor GAL4 in the expression vector eukaryotic Using superfect (Qiagen, Germany) as the reagent to transfect, HEK-293 cells were transfected with this plasmid, and a reporter plasmid having the luciferase gene driven by a GAL4 specific promoter. The compound was added at different concentrations after 42 hours of transfection and incubated overnight. Luciferase activity as a function of the binding / activating capacity of the PPARa compound was measured using the Packard Luclite kit (Packard, USA) in the Top Count "Top Count (Ivan Sado ski, Brendan beil, Peter Broag and Melvyn Hollis, Gene. 1992. 118: 137-141; Superfect Transfection Reagent Handbook, February 1997, Qiagen, Germany). b) Determination of hPPAR activity: The ligand binding domain of hPPAR? l was fused to the DNA binding domain of the yeast transcription factor GAL4 in the eukaryotic expression vector. Using lipofectamine (Gibco BRL, USA) as the reagent to be transfected, HEK-293 cells were transfected with this plasmid and a reporter plasmid having the luciferase gene driven by a GAL4 specific promoter. The compound was added at a concentration of 1 μM after 48 hours of transfection and incubated overnight. Luciferase activity as a function of the drug binding / activating capacity of PPARγ was measured using the Packard Luclite kit (Packard, USA) in the Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis). Gene. 1992. 118: 137-141; Guide to Eukaryotic Transfections with Cationic Lipid Reagents, Life Technologies, GIBCO BRL, USA). e) Determination of HMG-CoA reductase inhibition activity: Liver microsome-bound reductase was prepared from rats fed with 2% cholestyramine in a medium darkness cycle. Spectrophotometric assays were carried out on KH2P0, 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG-CoA and 125 μg of liver microsomal enzyme. The total volume of the reaction mixture was kept at 1 mL. The reaction was initiated by the addition of HMG-CoA. The reaction mixture was incubated at 37 ° C for 30 minutes and the decrease in absorbance at 340 nm was recorded. The reaction mixture without the substrate was used as the blank value (Goldstein; J, L and Brown, MS Progress in understanding of the LDL receptor and HMG CoA reductase, two membrane proteins that regulate the plasma cholesterol. J. Lipid Res 1984, 25: 1450-1461). The test compounds inhibited the enzyme HMG-CoA reductase.

B) In vivo: a) Efficiency in genetic models: Mutation in laboratory animal colonies and different sensitivities to dietary regimens has made possible the development of animal models with non-insulin-dependent diabetes and hyperlipidemia associated with obesity and insulin resistance . Genetic models such as db / db and ob / ob mice (Diabetes, (1982) 31 (1): 1-6) and fa / fa zucker rats have been developed by various laboratories for the understanding of the pathophysiology of the disease and the test of the efficiency of the new antidiabetic compounds (Diabetes, (1983) 32: 830-838; Annu. Rep Sankyo Res. Lab. (1994). 46: 1-57). The homozygous C57 BL / KsJ-db / db mice developed by Jackson Laboratory, USA are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85: 962-967), whereas heterozygotes are thin and normoglycemic. In the db / db model, the mouse progressively develops insulinopenia with age, a characteristic commonly observed in the late stages of human type II diabetes when blood sugar levels are insufficiently controlled. The state of the pancreas and its course vary according to the models. Since this model resembles that of type II diabetes mellitus, the compounds of the present invention were tested for triglyceride and blood sugar lowering activities. Male mice C57BL / KsJ-db / db from 8 to 14 weeks of age, having a body weight range of 35 to 60 grams, reared in the animal house of the Dr. Freddy Research Foundation "Dr. Freddy Research Foundation (DRF) "were used in the experiment. Mice were provided with normal diet (National Institute of Nutrition (NIN), Hyderabad, India) and acidified water, ad libitum. Animals that have more than 350 mg / dl of blood sugar were used for the test. The number of animals in each group was 4. The test compounds were suspected at 0.25% carboxymethylcellulose and administered to the test group at a dose of 0.1 mg to 30 mg / kg through oral priming daily for 6 days. The control group received vehicle (dose of 10 mL / kg). The sixth day, blood samples were collected one hour after administration of the test / vehicle compounds to assess the biological activity. Random blood sugar and triglyceride levels were measured by collecting blood (100 μl) through the orbital sinus, using the capillary vein treated with heparin in tubes containing EDTA which was centrifuged to obtain plasma. Plasma levels of glucose and triglycerides were measured spectrometrically, by the methods of the above glucose oxidase and glycerol-3-P04 oxidase / peroxidase (Dr. Readdy Lab. Diagnostic Division Kits, Hyderabad, India), respectively. The blood sugar lowering and triglyceride activities of the test compound were calculated according to the formula. No adverse effects were observed for any of the mentioned compounds of the invention in the previous test.

Ob / ob mice were obtained at 5 wk of age from Bomholtgard, Denmark and were used at 8 wk of age. Fat Fa / Fa Zucker rats were obtained from IffaCredo, France at 10 weeks of age and used at 13 weeks of age. The animals were kept under a cycle of 12 hours of light and dark at 25 ± 1 ° C. The animals were given normal laboratory food (NIN, Hyderabad, India) and water, ad libitum (Fujiwara, T., Yoshioka S., Yoshioka, T., Ushiyama, I and Horikoshi, H. Characterization of new oral antidiabetic agent CS-045, Studies in KK and ob / ob mice and Zucket fatty rats, Diabetes, 1988, 37: 1549-1558). The test compounds were administered at a dose of 0.1 to 30 mg / kg / day for 9 days. The control animals received the vehicle (0.25% carboxymethylcellulose, 10 mL / kg dose) through oral priming. The blood samples were collected in the feeding state, one hour after the administration of the drug on day 0 and 9 of the treatment. Blood was collected from the retro-orbital sinus through capillary vein treated with heparin in tubes containing EDTA. After centrifugation, the plasma sample was separated for estimates of triglycerides, glucose, free fatty acids, total cholesterol and insulin. Measurements of plasma triglycerides, glucose, total cholesterol were made using commercial equipment (Dr. Reddy's Laboratory, Diagnostic Division, India). The free fatty acid in plasmas was measured using a commercial kit from Boehringer Mannheim, Germany. Plasma insulin was measured using a RIA Kit kit (BARC, India). The reduction of the various parameters examined was calculated according to the formula. In ob / ob mice the oral glucose tolerance test was performed after 9 days of treatment. The mice were fasted for 5 hours and stimulated with 3 mg / kg of glucose orally. Blood samples were collected at 0, 15, 30, 60 and 120 minutes for the estimation of plasma glucose levels. The experimental results of the db / db mice, ob / ob mice, fau / fa Zucker rats suggested that the novel compounds of the present invention also possess therapeutic utility as a regular prophylactic treatment for diabetes, obesity, cardiovascular disorders such as hypertension. , hyperlipidemia and other diseases, as it is known from the literature that these diseases are interrelated. The blood level of glucose and triglycerides was also decreased at doses higher than 10 mg / kg. Normally, the amount of reduction is dependent on the dose and reaches a plateau at a certain dose. b) Cholesterol lowering activity in models with hypercholesterolemic rats: Male Sprague Dawley rats (NIN breed) were created in a DRF animal house. The animals were kept under a cycle of 12 hours of light and dark at 25 ± 1 ° C. Rats of 180-200 grams of body weight range were used for the experiment. The animals were made hypercholesterolemic by feeding with 2% cholesterol and 1% sodium cholate and mixed with normal laboratory food [National Institute of Nutrition (NIN), Hyderabad, India] for 6 days. Throughout the experimental period, the animals were kept on the same diet (Petit, D., Bonnefis, MT, King, C and Infante, R. Effects of ciprofibrate on liver lipids and lipoprotein synthesis in normo- and hyperlipidemic rats. Atherosclerosis, 1988. 74: 215-225). The test compounds were administered orally at a dose of 0.1 to 30 mg / kg / day for 3 days. The control group was treated only with vehicle (0.25% carboxymethylcellulose, 10 mL / kg dose). Blood samples were collected in the feeding state, at 1 hour after administration of the drug on day 0 and 3 of treatment with the compound. Blood was collected from the retroviral sinus through the capillary vein treated with heparin in tubes containing EDTA. After centrifugation, the plasma sample was separated for total cholesterol, HDL and triglyceride estimations. The measurement of plasma triglycerides, total cholesterol and HDL was performed using commercial equipment (Dr. Reddy's laboratory, Diagnostic Division, India). The LDL and VLDL cholesterol was calculated from the data obtained from total cholesterol, HDL and triglycerides. The reduction of the various parameters examined is calculated according to the formula c) Activity of decrease of total cholesterol and triglycerides in plasma in Swiss albino mice and Guinea pigs: Swiss albino mice, males (SAM) and male guinea pigs were obtained from NIN and housed in a DRF animal house. All these animals were kept under a cycle of 12 hours of light and darkness at 25 ± 1 ° C. The animals were given normal laboratory food (NIN Hyderabad, India) and water, ad libitum. SAM of 20 - 25 ga range of body weight and guinea pigs of 500 - 700 g of body weight interval were used (Oliver, P., Plancke, MO, Marzin, D., Clavey, V., Sanzieres, J and Fruchart, JC Effects of fenofibrate, gemfibrozil and nicotinic acid on plasma lipoprotein levéis in normal and hyperlipidemic mice, Atherosclerosis, 1988. 70: 107-114). The test compounds were orally administered to Swiss albino mice at a dose of 0.3 to 30 mg / kg / day for 6 days. The control mice were treated with vehicle (0.25% Carboxymethylcellulose, 5 mL / kg dose). The test compounds were orally administered to Cobayos at a dose of 0.3 to 30 mg / kg / day for 6 days. The control animals were treated with vehicle (Carboxymethylcellulose at 0.25%, dose of 5 mL / kg). The blood samples were collected in the feeding state, 1 hour after the administration of the drug on day 0 and 6 of treatment. Blood was collected from the retroviral sinus through the capillary vein treated with heparin in tubes containing EDTA. After centrifugation, the plasma sample for triglycerides and total cholesterol was separated (Wieland, O. Methods of Enzymatic Analysis, Bergermeyer, HO, Ed., 1963. 211-214; Trinder, P. Ann Clin Biochem 1969. 6: 24 27). Measurements of plasma triglycerides, total cholesterol and HDL were made using commercial equipment (Dr. Reddy's Diagnostic Division, Hyderabad, India).

Formulas for calculation: 1. Percent. of reduction in blood sugar / triglycerides / total cholesterol was calculated according to the formula: Percent reduction (X 100 OC = Value of control group on day zero OT = Value of group treated on day zero TC = Value of control group on test day TT = Value of group treatment on the day of proof 2. The LDL and VLDL cholesterol levels were calculated according to the formula: LDL cholesterol in mg / l = [Total cholesterol - HDL cholesterol-triglyceride / 5] mg / dl VLDL cholesterol in mg / dl = [Total cholesterol-HDL-cholesterol -LDL-cholesterol] mg / dl It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention.

Claims (64)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula (I) its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphic substances, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, characterized in that R1 R2, R3 and R4 can be the same or different and represent hydrogen, halogen, hydroxy, nitro , cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino , arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulphonic acid or its derivatives; ring A fused to the ring containing X and N represents a 5-6 member cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be replaced; Ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9, where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl; Ar represents a heterocyclic aromatic group, individual or fused, unsubstituted or substituted, divalent; R5 represents a hydrogen, hydroxy, alkoxy, halogen, lower alkyl or an aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or unsubstituted or substituted aralkyl group or R6 forms a bond together with R5; R7 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen or NR 10, where R 10 represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R8 and R10 may together form a 5 or 6 membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; n is an integer ranging from 1-4 and m is an integer of 0 or 1.
2. 2. A compound according to claim 1, characterized in that the substituents on R1-R4 are selected from halogen, hydroxy, nitro or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino groups, aminoalkyl, alkoxycarbonyl, alkylamino, alkylthio, thioalkyl, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.
3. 3. A compound according to claim 1 and 2, characterized in that the cyclic structure A represents phenyl or pyridyl rings.
4. 4. A compound according to claims 1 to 3, characterized in that Ar represents an unsubstituted or substituted, divalent group of phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, benzopyranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, dihydrobenzopyranyl or pyrazolyl.
5. A compound according to claim 4, characterized in that the substituents in the group represented by Ar are selected from alkyl of 1 to 6 carbon atoms, linear or branched, optionally halogenated, alkoxy of 1 to 3 carbon atoms , optionally halogenated, halogen, acyl, amino, acylamino, thio, carboxylic acid or sulphonic acids or their derivatives.
6. 6. A compound according to claims 1 to 5, characterized in that when m = O, Ar represents a divalent group of benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, dihydrobenzofuryl or dihydrobenzopyranyl.
7. 7. A compound according to claims 1 to 6, characterized in that when m = 1, Ar represents a divalent group of phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, azaindolyl, azaindolinyl, indenyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl or pyrazolyl.
8. 8. A compound according to claim 1, characterized in that the pharmaceutically acceptable salt is Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium salts or aluminum salts.
9. 9. A compound according to claim 1, characterized in that it is selected from: (E / Z) -3- [4- [2- (Fenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropenoate ethyl; (E) -3- [4- [2- (Fenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropeno-ethyl acetate; (Z) -3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropeno-ethyl ester; (E / Z) -3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropenoate ethyl; (E) -3- [2- (Fenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropenoate ethyl; (Z) -3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropenoate ethyl; (E / Z) -3- [4- [2- (phenoxazin-10-yl] ethoxy] phenyl] -2-ethoxypropenoate ethyl (E) -3- [4- [2- (phenoxazine-10-yl) ethyl) ethoxy] phenyl] -2-ethoxypropenoate; ethyl (Z) -3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropenoate; (±) methyl 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (+) Methyl 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (-) methyl 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (±) methyl 3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoate; (+) Methyl 3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoate; (-) methyl 3- [2- (phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoate; (±) methyl 3- [4- [2- (phenovazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (+) Methyl 3- [4- [2- (phenovazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (-) methyl 3- [4- [2- (phenovazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (±) ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (+) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (-) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoate; (±) ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoate; (+) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoate; (-) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoate; (±) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoate; (+) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoate; (-) ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoate; (±) ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoate; (+) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoate; (-) ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoate; (±) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoate; (+) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoate; (-) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoate; (±) Ethyl 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoate; (+) Methyl 3- [4- [2- (phenovazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoate; (-) methyl 3- [4- [2- (phenovazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoate; (±) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid and its salts; (+) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid and its salts; (-) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid and its salts; (±) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-methylpropanoic acid and its salts; (+) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-methylpropanoic acid and its salts; (-) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-methylpropanoic acid and its salts; (±) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and its salts; (+) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and its salts; (-) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and its salts; (±) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid and its salts; (+) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid and its salts; (-) 3- [4- [2- (Phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid and its salts; (±) 3- [2- (Phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoic acid and its salts; (+) 3- [2- (Phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoic acid and its salts; (-) 3- [2- (Phenothiazin-10-yl) methylbenzofuran-5-yl] -2-ethoxypropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-meitylpropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-meitylpropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-meitylpropanoic acid and its salts; * - * (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoic acid and its salts; (±) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid and its salts; (+) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid and its salts; (-) 3- [4- [2- (Phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid and its salts; [(2 R) - (S S)] -3 [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-1-phenyl-ethyl) propanamide; [(2S) -N (IS)] -3 [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-1-phenyl-ethyl) propanamide; [(2S) -N (1S)] -3 [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-1-phenyl-ethyl) propanamide and [ (2R) -N (IS)] -3 [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxy-N- (2-hydroxy-1-phenyl-ethyl) propanamide.
10. 10. A compound according to claims 1 and 9, characterized in that it is selected from: salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (±) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (-) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-ethoxy-methylpropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-methylpropanoic; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (-) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-methylpropanoic; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (±) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (-) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (±) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (-) 3- [4- [2- (phenothiazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (±) 3- [4- [2- (phenothiazin-10-yl) methylbenzofuran- 5-yl] -2-ethoxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenothiazin-10-yl) methylbenzofuran- 5-yl] -2-ethoxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (-) 3- [4- [2- (phenothiazin-10-yl) methylbenzofuran- 5-yl] -2-ethoxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (-) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxypropanoic; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-methylpropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-methylpropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (-) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-ethoxy-2-methylpropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (-) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (-) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-phenoxy-2-methylpropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts _ of (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] ] phenyl] -2-butoxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (-) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-butoxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (-) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (±) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoic; salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (+) 3- [4- [2- (phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoic, and salts of Li, Na, K, Mg, lysine, arginine, guanidine, diethanolamine, choline, ammonium, substituted ammonium or aluminum salts of (-) 3- [4- [2- ( phenoxazin-10-yl) ethoxy] phenyl] -2-hydroxypropanoic acid.
11. 11. A pharmaceutical composition characterized in that it comprises a compound of the formula (I) as defined in claims 1 to 10 and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
12. 12. A pharmaceutical composition, characterized in that it comprises a compound of the formula (I) as defined in claims 1 to 10 and inhibitors of HMG-CoA reductase, fibrates, nicotinic acid, cholesteramine, colestipol. probucol or its combination, and a pharmaceutically acceptable carrier, diluent, excipient or solvate.
13. 13. A pharmaceutical composition according to claims 11 and 12, characterized in that it is in the form of a tablet, capsule, powder, syrup, solution or suspension.
14. 14. A pharmaceutical composition according to claims 11 and 12, characterized in that it is for the treatment and / or prevention of type II diabetes, impaired tolerance to glucose, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia , coronary artery disease and other cardiovascular disorders, certain kidney diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to the activation of endothelial cells, psoriasis, polycystic ovarian syndrome (PCOS), dementia , such as inflammatory agents and diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
15. 15. A method for preventing or treating hyperlipidemia hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, resistance to leptin, insulin resistance, or diseases in which insulin resistance is the pathophysiological mechanism, characterized in that it comprises administering a compound of the formula (I) as defined in claims 1 to 10 or a pharmaceutical composition as claimed in claim 11 to a patient in need thereof.
16. 16. A method according to claim 15, characterized in that the disease is type II diabetes, impaired tolerance to glucose, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other disorders cardiovascular diseases, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to the activation of endothelial cells, psoriasis, polycystic ovarian syndrome (PCOS), dementia, such as inflammatory agents and diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
17. 17. A method according to claim 15, for the treatment and / or prophylaxis of disorders related to Syndrome X, characterized in that it comprises administering a PPARa and / or PPARα agonist. of the formula (I) as claimed in claims 1 to 10 or a pharmaceutical composition as claimed in claim 11 to a patient in need thereof.
18. 18. A method for reducing blood plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in plasma, characterized in that it comprises administering a compound of formula (I) as defined in claims 1 to 10 or a pharmaceutical composition as claimed in claim 11 to a patient in need thereof.
19. 19. A method for preventing or treating hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, resistance to leptin, insulin resistance, or diseases in which insulin resistance is the basic pathophysiological mechanism, characterized in that it comprises administering to a patient in need thereof a pharmaceutical composition as claimed in claim 12.
20. 20. A method for preventing or treating hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases wherein insulin resistance is the basic pathophysiological mechanism, characterized in that it comprises administering to a patient in need thereof an effective amount of a compound of the formula (I) as defined in claims 1 to 10 or a pharmaceutical composition such as claimed in claim 11 and inhibitors of HMG-CoA- reductase, fibrates, nicotinic acid, cholesteramine, colestipol or probucol or their combination within a period to act synergistically.
21. 21. A method according to claims 19 and 20, characterized in that the disease is type II diabetes, impaired tolerance to glucose, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain kidney diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to the activation of endothelial cells, psoriasis, polycystic ovarian syndrome (PCOS), dementia, such as inflammatory agents and complications diabetics, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
22. 22. A method according to claim 19 for the treatment and / or prophylaxis of disorders related to Syndrome X, characterized in that it comprises administering to a patient in need thereof a. PPARa agonist and / or PPAR? of the formula (I) as a pharmaceutical composition claimed in claim 12.
23. 23. A method according to claim 20 for the treatment and / or prophylaxis of disorders related to Syndrome X, characterized in that it comprises administering to a patient in need of same a PPARa and / or PPAR agonist? of the formula (I) as defined in claims 1 to 10 and a pharmaceutical composition as claimed in claim 11 and with inhibitors of HMG-CoA reductase, fibrates, nicotinic acid, cholesteramine, colestipol or probucol or their combination within a period to act synergistically.
24. 24. A method for producing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in plasma, characterized in that it comprises administering to a patient in need thereof a pharmaceutical composition of claim 12.
25. 25. A method to reduce plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma, characterized in that it comprises administering a compound of the formula (I) claimed in any of claims 1 to 10 or a pharmaceutical composition as claimed in claim 11 in combination / concomitantly with inhibitors of HMG-CoA reductase, fibrates, nicotinic acid, cholesteramine, colestipol or probucol or their combination within a period to act synergistically together, to a patient in need thereof.
26. 26. A process for the preparation of a compound of the formula (III) its derivatives, its analogues, its tautomeric forms, its stereoisomers, its polymorph substances, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, wherein R 1, R 2, R 3 and R 4 can be the same or different and represent hydrogen, halogen, hydroxy, Nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulphonic acid or its derivatives; ring A fused to the ring containing X and N represents a 5-6 member cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be replaced; Ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9, where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl; Ar represents a heterocyclic aromatic group, individual or fused, unsubstituted or substituted, divalent; R7 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; n is an integer that varies from 1-4 and m is an integer of 0 or 1; characterized in that it comprises: a) reacting a compound of the general formula (Illa) where all the symbols are as defined above with a compound of the formula (Illb) wherein R7 and R8 are as defined above excluding hydrogen atom and R11 may be an alkyl group of 1 to 6 carbon atoms to produce a compound of formula (III) defined above; or b) reacting a compound of the general formula (Illa) where all symbols are as defined above with Wittig reagents; or c) reacting a compound of the general formula (Illa) where all the symbols are as defined above with a compound of the formula (lile) where R6 represents the hydrogen atom and R7, R8 are as defined above to produce a compound of the formula (III); or d) reacting a compound of the formula (Ule) where L1 represents a leaving group and all other symbols are as defined above with a compound of the formula (Illd) wherein R7, R8 and Ar are as defined above to produce a compound of the formula (III) wherein all the symbols are as defined above; or e) reacting a compound of the general formula (Illg) where all symbols are as defined above with a compound of the general formula (Illf) wherein all symbols are as defined above and L1 is a leaving group to produce a compound of formula (III) defined above; or f) reacting a compound of the general formula (Illh) where all symbols are as defined above with a compound of the general formula (Illd) wherein all symbols are as defined above to produce a compound of formula (III) defined above; or g) reacting a compound of the formula (lili) where all the symbols are as defined above with a compound of the formula (IIIj) where R7 = R8 and are as defined above, excluding hydrogen, to produce a compound of the formula (III) and if desired, convert the compounds of the formula (III) obtained in any of the processes described above to pharmaceutically acceptable salts , or pharmaceutically acceptable solvates.
27. 27. A process for the preparation of the compounds of the formula (I) its derivatives, its analogues, its tautomeric forms, its stereoisomers, its polymorph substances, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, wherein R 1, R 2, R 3 and R 4 can be the same or different and represent hydrogen, halogen, hydroxy, Nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulphonic acid or its derivatives; ring A fused to the ring containing X and N represents a 5-6 member cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be replaced; Ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9, where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl; Ar represents a heterocyclic aromatic group, individual or fused, unsubstituted or substituted, divalent; R5 represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or an aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or unsubstituted or substituted aralkyl group or R6 forms a bond together with R5; R7 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; And represents oxygen; n is an integer that varies from 1-4 and m is an integer of 0 or 1; characterized in that it comprises: a) reducing a compound of the formula (III) which represents a compound of the formula (I) wherein R5 and R6 represents a bond and Y represents oxygen atom and all other symbols are as defined above, to produce a compound of the general formula (I) wherein R5 and R6 represent each hydrogen atom and all other symbols are as defined above; or b) reacting a compound of the formula (la] where all the symbols are as defined above, R8 is as defined above, excluding hydrogen, and L3 is a leaving group with an alcohol of the general formula (Ib) R7-OH (Ib) where R7 represents selected unsubstituted or substituted groups from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups to produce a compound of formula (I) wherein all groups are as defined above; or c) reacting a compound of the formula (Ule) wherein L1 is a leaving group and all other symbols are as defined above with a compound of the formula (le) where all the symbols are as defined above, to produce a compound of the formula (I) where all the symbols are as defined above, or d) reacting a compound of the general formula (Illh) where all symbols are as defined above with a compound of the formula (le) wherein all symbols are as defined above to produce a compound of formula (I) defined above; or e) reacting a compound of the formula (Id) which represents a compound of the formula (I), wherein R7 represents a hydrogen atom and all other symbols are as defined above with a compound of the formula (le) R-Hal (le) where R7 represents selected unsubstituted or substituted groups from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups and Hal represents halogen atom, to produce a compound of the formula (I) wherein all the symbols they are as defined above; or f) reacting a compound of the formula (Illa) where all the symbols are as defined above with a compound of the formula (lile) wherein R6 is hydrogen and R7, R8 are as defined above to produce a compound of the formula (I), wherein all symbols are as defined above; or g) reacts a compound of the general formula (Illg) where all symbols are as defined above, with a compound of the general formula (If) where L is a leaving group and all other symbols are as defined above, to produce a compound of the formula (I), where all the symbols are as defined above; or h) converting a compound of the formula (Ig) where all the symbols are as defined above to a compound of the formula (I), where all the symbols are as defined above; or i) reacting a compound of the formula (Ih) where R8 is as defined above, excluding hydrogen, and all other symbols are as defined above, with a compound of the formula (Ib) R7-OH (Ib) where R7 represents unsubstituted or substituted groups selected from alkyl groups , cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups to produce a compound of the formula (I) wherein all the symbols are as defined above, and if one wishes to convert the compounds of the formula (I) obtained in any of the processes described above in pharmaceutically acceptable salts or pharmaceutically acceptable solvates.
28. 28. A process for the preparation of the compound of the formula (I) their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphic substances, their pharmaceutically acceptable salts, their pharmaceutically acceptable sorbates, wherein R 1, R 2, R 3 and R 4 may be the same or different and represent hydrogen, halogen, hydroxy, Nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulphonic acid or its derivatives; ring A fused to the ring containing X and N represents a 5-6 member cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be replaced; Ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9, where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl; Ar represents a heterocyclic aromatic group, individual or fused, unsubstituted or substituted, divalent; R5 represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or an aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or unsubstituted or substituted aralkyl group or R6 forms a bond together with R5; R7 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen or NR 10, where R 10 represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R8 and R10 may together form a 5 or 6 membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; n is an integer that varies from 1-4 and m is an integer of 0 or 1; characterized in that it comprises reacting a compound of the formula (I) wherein all the symbols are as defined above and Y represents oxygen with appropriate amines of the formula NHR8R10, wherein R8 and R10 are as defined above and if the compounds need to be converted of formula (I) obtained above in pharmaceutically acceptable salts or pharmaceutically acceptable solvates.
29. 29. A compound of the formula (III) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs substances, their pharmaceutically acceptable salts, sorbate pharmaceutically acceptable, wherein R1, R2, R3 and R4 may be the same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted groups or substituted selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; ring A 'fused to the ring containing X and N represents a 5-6 member cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may be optionally substituted; Ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9, where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl; Ar represents a heterocyclic aromatic group, individual or fused, unsubstituted or substituted, divalent; R5 represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or an aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or unsubstituted or substituted aralkyl group or R6 forms a bond together with R5; R7 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; And represents oxygen; n is an integer ranging from 1-4 and m is an integer of 0 or 1, characterized in that it is prepared according to the process of claim 26.
30. 30. A compound of the formula (I) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs substances, their pharmaceutically acceptable salts, sorbate pharmaceutically acceptable, wherein R1, R2, R3 and R4 may be the same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted groups or substituted selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; ring A fused to the ring containing X and N represents a 5-6 member cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be replaced; Ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9, where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl; Ar represents a heterocyclic aromatic group, individual or fused, unsubstituted or substituted, divalent; R5 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl or an aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or unsubstituted or substituted aralkyl group or R6 forms a bond together with R5; R7 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; And represents oxygen; n is an ier ranging from 1-4 and m is an ier of 0 or 1, characterized in that it is prepared according to the process of claim 27.
31. 31. A compound of the formula (I) their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphic substances, their pharmaceutically acceptable salts, their pharmaceutically acceptable sorbates, wherein R 1, R 2, R 3 and R 4 may be the same or different and represent hydrogen, halogen, hydroxy, Nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulphonic acid or its derivatives; ring A fused to the ring containing X and N represents a 5-6 member cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be replaced; Ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9, where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl; Ar represents a heterocyclic aromatic group, individual or fused, unsubstituted or substituted, divalent; R5 represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or an aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or unsubstituted or substituted aralkyl group or R6 forms a bond together with R5; R7 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen or NR 10, where R 10 represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R8 and R10 may together form a 5 or 6 membered cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; n is an integer ranging from 1-4 and m is an integer of 0 or 1, characterized in that it is prepared according to the process of claim 28.
32. 32. An intermediate of the formula (If) L1- (CH2) "? O -Ar? R £ (i) OR 'characterized in that Ar represents a heterocyclic aromatic group, individual or fused, unsubstituted or substituted, divalent; R5 represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or an aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or unsubstituted or substituted aralkyl group or R6 forms a bond together with R5; R7 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; n is an integer that varies from 1-4 and m is an integer of 0 or 1 and L1 is a leaving group.
33. 33. A process for the preparation of a compound of the formula (If) described in claim 32, characterized in that it comprises: a) reacting a compound of the formula (le) wherein R5, R6, R7, R8 and Ar are as defined in claim 32, with a compound of the formula (Ii) cHz J n-L2 (Ii) where L1 and L2 are the same or different and represent a leaving group or L2 may also represent a hydroxy group or a protected hydroxy group which is further converted to a leaving group, n represents an integer 1-4; or b) reacting a compound of the formula (Ij) L CHzJn-ÍOJm-Ar-CHO (Ij) wherein L1 represents a leaving group and all other symbols are as defined above, with a compound of the formula (Illb) wherein R11 is a lower alkyl group and R7, R8 are as defined in claim 32, to produce a compound of the formula (Illf) where all the symbols are as defined above and L1 is a leaving group, which is further reduced to produce a compound of the formula (If).
34. 34. An intermediate of the formula (Ig) characterized in that R1, R2, R3 and R4 can be the same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy , heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino , aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulphonic acid or its derivatives; ring A fused to the ring containing X and N represents a 5-6 member cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be replaced; Ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9, where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl; Ar represents a heterocyclic aromatic group, individual or fused, unsubstituted or substituted, divalent; R5 represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or an aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or unsubstituted or substituted aralkyl group or R6 forms a bond together with R5; R7 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroarylalkyl groups; n is an integer ranging from 1-4 and m is an integer of 0 or 1.
35. 35. A process for the preparation of the compound of the formula (Ig) defined in claim 34, wherein R5 and R6 represent hydrogen, characterized because it comprises a) reacting a compound of the formula (Illa) wherein all the symbols are as defined in claim 34 with a compound of the formula (Ik) R7OCH2P + PPh3"Hal (Ik) wherein R7 represents unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl and Hal represents a halogen atom, to produce a compound of the formula (II) wherein all the symbols are as defined above b) reacting a compound of the formula (II) with an alcohol of the formula R7OH, wherein R7 represents unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl to produce a compound of the formula (Im) wherein all the symbols are as defined above, and c) reacting a compound of the formula (Im) obtained above, wherein all the symbols are as defined above, with trialkylsilyl cyanide to produce a compound of the formula (Ig) where all symbols are as defined above.
36. 36. An intermediate of the formula (Ih) characterized in that R, R, R3 and R can be the same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy , heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino , aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulphonic acid or its derivatives; ring A fused to the ring containing X and N represents a 5-6 member cyclic structure containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms, which may optionally be replaced; Ring A may be saturated or contain one or more double bonds or may be aromatic; X represents a heteroatom selected from oxygen, sulfur or NR9, where R9 is hydrogen, alkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl; Ar represents a heterocyclic aromatic group, individual or fused, unsubstituted or substituted, divalent; R5 represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or an aralkyl group unsubstituted or substituted or forms a bond together with the adjacent group R6; R6 represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or unsubstituted or substituted aralkyl group or R6 forms a bond together with Rs; R8 represents hydrogen or unsubstituted or substituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; n is an integer ranging from 1-4 and m is an integer of 0 or 1.
37. 37. A process for the preparation of the compound of the formula (Ih) defined in claim 36, characterized in that it comprises a) reacting a compound of the formula (Ule) where L1 is a leaving group, and all other symbols are as defined above with a compound of the formula (lo) where R6 is hydrogen and all symbols are as defined above, to produce a compound of the formula (In) where all the symbols are as defined above, and b) reacting a compound of the formula (In) obtained above, with an appropriate diazotization agent.
38. 38. A medicine for preventing or treating hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, resistance to leptin, insulin resistance, or diseases in which insulin resistance is the basic pathophysiological mechanism, characterized in that it comprises a effective amount of a compound of the formula (I) as defined in claims 1 to 10 or a pharmaceutical composition according to claim 11.
39. 39. A medicine according to claim 38, characterized in that the disease is type II diabetes, impaired tolerance to glucose, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain kidney diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to the activation of endothelial cells, psoriasis, polycystic ovary syndrome (PCOS), dementia, such as inflammatory agents and diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
40. 40. A medicine according to claim 38 for the treatment and / or prophylaxis of disorders related to Syndrome X, characterized in that it comprises an effective amount of a PPARa agonist and / or PPAR? of the formula (I) as defined in claims 1 to 10 or a pharmaceutical composition according to claim 11.
41. 41. A medicine for reducing glucose in blood plasma, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in plasma, characterized in that it comprises an effective amount of a compound of the formula (I), as defined in claims 1 to 10, or a pharmaceutical composition as claimed in claim 11.
42. 42. A medicine for preventing or treating the hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, resistance to leptin, insulin resistance, or diseases in which insulin resistance is the pathophysiological basis mechanism, characterized in that it comprises a pharmaceutical composition as claimed in claim 12
43. 43. A medicine to prevent or treat hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose tolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the pathophysiological basis mechanism characterized in that it comprises an effective amount of a compound of the formula (I) as defined in claims 1 to 10 , or a pharmaceutical composition as claimed in claim 11 and inhibitors of HMG-CoA reductase, fibrates, nicotinic acid, cholesteramine, colestipol or probucol or their combination within a period to act synergistically.
44. 44. A medicine according to claims 42 and 43, characterized in that the disease is type II diabetes, impaired tolerance to glucose, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain kidney diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to the activation of endothelial cells, psoriasis, polycystic ovarian syndrome (PCOS), dementia, such as inflammatory agents and complications diabetics, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
45. 45. A medicine according to claim 42 for the treatment and / or prophylaxis of disorders related to syndrome X, characterized in that it comprises a PPARa and / or PPARα agonist. of the formula (I) as a pharmaceutical composition claimed in claim 12.
46. 46. A method according to claim 43, for the treatment and / or prophylaxis of disorders related to Syndrome X, characterized in that it comprises a PPARa agonist and / or PPAR? of formula (I) as claimed in claims 1 to 10 and a pharmaceutical composition as claimed in claim 11 claimed and with HMG-CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol or their combination within a period to act synergistically.
47. 47. A medicine to reduce plasma glucose, triglycerides, total cholesterol. LDL, VLDL and free plasma grases acids, wherein cprprarde carpasicicn a pharmaceutical as claimed in claim 12.
48. 48. A medicine for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in plasma , characterized in that it comprises an effective amount of a compound of the formula (I) claimed in any of claims 1 to 10 or a pharmaceutical composition as claimed in claim 11 in combination / concomitantly with HMG-CoA reductase inhibitors. , fibrates, nicotinic acid, cholesteramine, colestipol or probucol or their combination within a period to act synergistically together with a patient in need of it.
49. 49. The use of a compound of formula (I) as defined in any of claims 1 to 10 or a pharmaceutical composition as claimed in claim 11 for preventing or treating hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, intolerance to glucose, resistance to leptin, insulin resistance, or diseases in which insulin resistance is the basic pathophysiological mechanism.
50. 50. The use according to claim 49, wherein the disease is type II diabetes, impaired glucose tolerance to, dyslipidemia, Syndrome X related as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, related to activation of endothelial cells disorders, psoriasis, polycystic ovary syndrome (PCOS), dementia, as inflammatory agents and diabetic complications, osteoporosis, diseases inflammatory bowel, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
51. 51. The use of a compound of formula (I) according to claims 1 to 10, or a pharmaceutical composition as claimed in claim 11 for reducing glucose in blood plasma, triglycerides, total cholesterol, LDL, VLDL and fatty acids free in the plasma.
52. 52. The use of a compound of the formula (I) according to claim 12 for preventing or treating hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which the Insulin resistance is the basic pathophysiological mechanism.
53. 53. The use of a compound of the formula (I) according to claims 1 to 10, or a pharmaceutical composition as claimed in claim 11 and inhibitors of HMG-CoA reductase, fibrates, nicotinic acid, cholesteramine, colestipol or probucol or combination within a period to act synergistically to prevent or treat hyperlipidemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance, resistance to leptin, insulin resistance, or diseases in which insulin resistance is the pathophysiological mechanism base.
54. 54. The use of a compound of the formula (I) according to claims 52 and 53, where the disease is type II diabetes, impaired glucose tolerance, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain kidney diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to the activation of endothelial cells, psoriasis, polycystic ovary syndrome (PCOS), dementia, such as inflammatory agents and diabetic complications, osteoporosis, inflammatory bowel diseases, dystrophy myotonic, pancreatitis, arteriosclerosis, xanthoma or cancer.
55. 55. The use of a compound of formula (I) according to claim 12, for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in plasma.
56. 56. The use of a compound of the formula (I) according to any of claims 1 to 10 or a pharmaceutical composition according to claim 11, in combination / concomitantly with inhibitors of HMG-CoA reductase, fibrates, nicotinic acid, cholesteramine, colestipol or probucol or their combination within a period to act synergistically together to reduce plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma.
57. 57. The use of a compound of the formula (I) according to any of claims 1 to 10 or a pharmaceutical composition according to claim 11, for preparing a medicament for preventing or treating hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, intolerance to glucose, resistance to leptin, insulin resistance or diseases in which insulin resistance is the basic pathophysiological mechanism.
58. 58. The use according to claim 57, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other cardiovascular disorders, certain kidney diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to the activation of endothelial cells, psoriasis, polycystic ovarian syndrome (PCOS), dementia, such as inflammatory agents and diabetic complications, osteoporosis, diseases inflammatory bowel, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
59. 59. The use of a compound of formula (I) according to claims 1 to 10 or a pharmaceutical composition as claimed in claim 11 for preparing a medicament for reducing glucose in blood plasma, triglycerides, total cholesterol, LDL, VLDL and acids free fatty acids in the plasma.
60. 60. The use of a compound of the formula (I) according to claim 12 to prepare a medicament for preventing or treating hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance, insulin resistance, or diseases in which insulin resistance is the basic pathophysiological mechanism.
61. 61. The use of a compound of the formula (I) according to claims 1 to 10 or a pharmaceutical composition according to claim 11 and inhibitors of HMG-CoA reductase, fibrates, nicotinic acid, cholesteramine, colestipol or probucol or their combination within a period to act in a synergistic manner, to prepare a medicament or to prevent or treat hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, resistance to leptin, insulin resistance, or diseases in which resistance Insulin is the basic pathophysiological mechanism.
62. 62. The use of a compound of formula (I) according to claims 60 and 61, wherein the disease is type II diabetes, impaired tolerance to glucose, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia, disease of the coronary arteries and other cardiovascular disorders, certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to the activation of endothelial cells, psoriasis, polycystic ovary syndrome (PCOS), dementia, as inflammatory agents and diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
63. 63. The use of a compound of the formula (I) according to claim 12 for preparing a medicament for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in the plasma.
64. 64. The use of a compound of the formula (I) according to any of claims 1 to 10, or a pharmaceutical composition as claimed in claim 11, for preparing a medicament in combination / concomitantly with HMG-CoA inhibitors. -reductase fibrates, nicotinic acid, cholesteramine, colestipol or probucol or their combination within a period to act synergistically together to reduce plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in plasma.