Derivatives of aryl carboxylic acids, methods for their preparing, pharmaceutical composition based on thereof, methods for treatment and prophylaxis of different diseases, intermediate compounds and methods for their preparing

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of aryl carboxylic acids and describes a compound of the formula (I):

, wherein groups R1, R2, R3, R4 and groups R5 and R6 when they are joined to carbon atom can be similar or different and mean hydrogen, halogen atom, hydroxy-group or optionally substituted group taken among alkyl, alkoxy-group, phenyl, carboxylic acid or sulfonic acid; one or both substitutes R5 and R6 can mean oxo-group also if they are joined to carbon atom; if R5 and R are joined to nitrogen atom then they mean hydrogen atom, hydroxy-group or optionally substituted alkyl or benzyl; X means heteroatom taken among oxygen and sulfur atom or NH; Ar means optionally substituted bivalent a single or condensed aromatic or heterocyclic group wherein aromatic ring represents phenyl, naphthyl and heterocyclic group represents furan; R7 means hydrogen, halogen atom, alkoxy-group, alkyl, or it forms a bond with the adjacent group R8; R8 means hydrogen atom, hydroxy-, alkoxy-group, alkyl or optionally substituted benzyl; or R8 forms a bond in common with R7; R9 means hydrogen atom or optionally substituted group taken among alkyl, phenyl or benzyl group; R10 means hydrogen atom or optionally substituted group taken among alkyl, phenyl or benzyl group; Y means oxygen atom or NR12 wherein R12 means hydrogen atom, alkyl or benzyl; R10 and R12 can form in common five- or six-membered cyclic structure comprising carbon atoms that involves optionally one or some heteroatoms taken among oxygen, sulfur or nitrogen atoms; a binding group represented by the formula: -(CH2)n-(O)m- can be joined through nitrogen atom or through carbon atom and wherein n means a whole number from 1 to 4; m means a whole number from 0 to 1 under condition that when a binding group is joined through carbon atom then R5 either R6 represents oxo-group; Y means oxygen atom; R9 doesn't mean hydrogen atom; or its derivatives, analogs, its tautomeric forms, its stereoisomers, its polymorphic forms, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates. Also, invention describes methods for preparing compounds of the general formula (I), intermediate compounds and methods for their preparing, a pharmaceutical composition eliciting activity with respect to hPPRα, hPPRγ and inhibitory activity with respect to HMG-CoA-reductase and involving compound of the formula (I). Also, invention relates to methods for prophylaxis and treatment of different diseases caused by above said activity, a method for reducing the total cholesterol level and a method for reducing the glucose level. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

27 cl, 64 ex

 

The technical field to which the invention relates.

The present invention relates to new compounds with preventing obesity and cholesterol-lowering properties, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate and a pharmaceutically acceptable compositions containing them. More specifically, the present invention relates to a new β-aryl-α-oxiclean alkalicarbonate acids of General formula (1), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate and a pharmaceutically acceptable compositions containing them.

The present invention relates also to a method for producing the above-mentioned novel compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate and a pharmaceutically acceptable compositions containing them.

Compounds of the present invention reduce the total cholesterol (TC); increase the level of high density lipoprotein (HDL) and decrease the level of low density lipoprotein (LDL), which have blugaria the impact on coronary heart disease and atherosclerosis.

Compounds of General formula (I) is applicable for weight loss and for the treatment and/or prevention of diseases such as hypertension, ischemic heart disease, atherosclerosis, stroke, lesions of peripheral vessels and related disorders. These compounds are applicable for the treatment of familial hypercholesterolemia, hypertriglyceridemia, reduced atherogenic lipoproteins, VLDL (lipoprotein very low density) and LDL. Compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, gipertenzivny nephrosclerosis, retinopathy and nephropathy. Compounds of General formula (I) are applicable also for the treatment and/or prophylaxis of insulin resistance (type 2 diabetes), latinboy resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary artery disease and other cardiovascular diseases. These compounds can also be used as inhibitors alsoreported, for improving cognitive functions in dementia, for the treatment of diabetic complications, complications associated with atively endothelial cell, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory disease the abdominal cavity, osteoporosis, muscular dystrophy, pancreatitis, arteriosclerosis, xanthoma and for the treatment of cancer. Compounds according to the present invention is applicable to treatment and/or prophylaxis of the aforementioned diseases in combination/joint application with one or more inhibitors of HMG-CoA [(DL-3-hydroxy-3-methylglutaryl)-coenzyme-A] and/or lipid/hypolipoproteinemia agents such as derivatives of fibrin acid, nicotinic acid, cholesterolemia, colestipol or probucol.

The level of technology

Atherosclerosis other peripheral vascular disease are the main cause affecting the quality of life of millions of people. Therefore, great attention is paid to understanding the etiology of hypercholesterolemia and hyperlipidemia and the creation of effective therapeutic strategies.

Hypercholesterolemia is defined as the level of cholesterol in plasma is greater than an arbitrarily set value, called the “normal” level. Recently it was accepted that the “ideal” levels of cholesterol in the plasma is much lower than “normal” cholesterol levels in the General population, and the risk of lesion of the coronary artery (CAD) increases with increasing the level of cholesterol above the “optimal” (or “ideal”values. There is a clear dependence of cause-effect between the ISU is cholesterolemia and CAD, especially for patients with multiple risk factors. Most cholesterol is present in esterified form with various lipoproteins, such as low-density lipoprotein (LDL), lipoprotein, intermediate density (IDL), high-density lipoprotein (HDL) and partly as lipoprotein very low density (VLDL). Research clearly indicates that there is an inverse correlation between CAD, atherosclerosis, and concentrations of HDL-cholesterol (Stampfer and others, N. Engl. J. Med. 325 (1991), 373-381), and the risk of CAD increases with increasing levels of LDL and VLDL.

When CAD in the carotid, coronary and cerebrally arteries usually are bold stripes, which initially are free and esterified cholesterol. Miller and others (Br. Med. J., 282 (1981), 1741-1744) showed that increasing the number of HDL particles can reduce the number of sites of stenosis in the coronary arteries of a human, and a high level of HDL-cholesterol may protect against the progression of atherosclerosis. Picardo and others (Arteriosclerosis, 6 (1986), 434-441) showed through experiments in vitro that HDL can remove cholesterol from cells. They suggested that HDL may deprive the tissues of excess cholesterol and carry it to the liver (Macikinnon etc., J. Biol. Chem., 261 (1986), 2548-2552). Therefore, compounds that increase the level of HDL-cholesterol, would be therapeutically important to ensure hypercholest is enemie and lesions of coronary artery disease (CAD).

Obesity is a disease common in affluent societies and in the developing world, and is the main cause of morbidity and mortality. Obesity is a condition of excessive accumulation of body fat. Causes of obesity is not clear. It is believed that they may be of genetic origin or be brought on by the interaction between genotype and environment. Regardless of the reason, the result is the deposition of fat due to the imbalance between energy absorption and energy expenditure. Diet, exercise, and appetite suppressant were part of the treatment of obesity. An effective therapy in order to defeat this disease, because 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 are another disease that has severe impact on the quality of life of many people in the world. Insulin resistance means reduced ability of insulin to exert its biological action in a wide range of concentrations. When insulin resistance to compensate for this defect, the body secretes abnormally high amounts of insulin; in the absence of the playing technique inevitably raises the level of glucose in plasma, leading to full-blown diabetes. For developed countries, diabetes is a common problem and is associated with various abnormalities, including obesity, hypertension, hyperlipidemia (J. din. 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 renal complications (see international patent application 95/21608). It is now becoming increasingly clear that insulin resistance and consequent hyperinsulinemia contribute to obesity, hypertension and diabetes mellitus type 2. The relationship of insulin resistance with obesity, hypertension and angina is described as a syndrome, including insulin resistance as a Central pathogenic link of syndrome X.

Hyperlipidemia is the primary cause of cardiovascular disease (CVD) and other peripheral vascular disease. High risk of CVD associated with higher levels of LDL (low density lipoprotein) and VLDL (lipoprotein very low density)observed in hyperlipidemia. Patients who, in addition to hyperlipidemia, observed glucose intolerance/insulin resistance have an increased risk of CVD. Numerous past studies have shown that reduced levels of plasma triglycerides and total cholesterol, in particular LDL and VLDL and increase HDL (high density lipoprotein) ways which contributes to prevention of cardiovascular diseases.

Peroxisomal proliferative activated receptor (PPAR) are members of the superfamily of nuclear receptors. Isoform γ (PPARγ) are involved in the regulation of differentiation of adipocytes (Endocrinology, (1994) 135:798-800) and energy homeostasis (Cell (1995) 83:803-812), whereas isoform α (PPARα) mediates the oxidation of fatty acids (Trend. Endocrin. Metab., (1993) 4:291-296), thereby leading to a reduction in the number of circulating plasma fatty acids (Current Biol., (1995) 5:618-621). It is shown that agonists of PPARα applicable for the treatment of obesity (international application WO 97/36579). Recently discovered information about the existence of synergies for molecules that are agonists as PPARαand PPARγand proposed their use for the treatment of syndrome X (international application WO 97/25042). Similar synergism was observed for insulin sensitizer (agonist of PPARγ) and an inhibitor of HMG-CoA-reductase, which can be used for the treatment of atherosclerosis and xanthoma (European patent 0753298).

It is known that PPARγ plays an important role in the differentiation of adipocytes (Cell (1996) 87, 377-389). Activation of PPAR by using ligand is sufficient to cause complete terminal differentiation (Cell (1994) 79, 1147-1156), including cell cycle arrest. Receptor PPARγ consistently expressed in some cells, and activation of this nuclear receptor by its agonist article which was mullerova if the terminal differentiation of the precursors of adipocytes and caused morphological and molecular changes characteristic of more differentiated, less malignant state (Molecular Cell, (1998), 465-470); Carcinogenesis, (1998), 1949-1953; Proc. Natl. Acad. Sci., (1997) 94, 237-241), and inhibited the expression of tissue prostate cancer (Cancer Research (1998), 58:3344-3352). This could find application in the treatment of certain types of cancer, which is expressed PPARγand to lead to a relatively non-toxic chemotherapy.

Latinova resistance is a condition in which target cells are not able to answer the leptin signal. This can lead to obesity due to excess of food absorbed and reduced power consumption and cause a violation glucose tolerance, type 2 diabetes, cardiovascular disease and other related complications. Kallen and others (Proc. Natl. Acad. Ci., (1996) 93, 5793-5796) reported that insulin sensitizers, which may be associated with the expression of PPAR agonists reduce as a consequence, the concentration of leptin in the plasma. However, it was recently reported that compounds with insulin-sensitizing property, have also leptin-sensitizing activity. They reduce the concentration of leptin circulating in the plasma, by improving the response of target cells to leptin (international application WO 98/02159).

Reported that some arylhydroxylamine acid, their derivatives and their analogs applicable to the treatment of the Oia hyperglycemia and hypercholesterolemia. Some of the methods in this field of knowledge of the connections below:

(i) U.S. patent 5306726, international application WO 91/19702 reveal several derivatives of 3-aryl-2-hydroxypropionic acids of General formula (IIA) and (IIb) as hypolipidemic and hypoglycemic agents.

Examples of such compounds represented by formulae (IIC) and (IId):

ii) international patent application WO 95/03038 and WO 96/04260 disclose compounds of the formula (IIE):

where Ramean 2-benzoxazolyl or 2-pyridyl, and Rbmeans trifluoromethyl, methoxymethyl or methyl. A typical example is (S)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-triptoreline)propanoic acid (IIf):

iii) international patent application WO 94/13650, WO 94/01420 disclose the compounds of General formula (IIg):

where a1means an aromatic heterocycle, And2mean benzene ring is replaced, and3means the residue of the formula (CH2)m-CH-(OR1), where R1means alkyl group, m means an integer; X is substituted or unsubstituted nitrogen atom; Y represents a carbonyl (C=O) or thiocarbonyl (C=S); R2OSN which includes OR 3where R3can be alkyl, aranceles or aryl group; n indicates an integer in the range of 2-6. An example of these compounds is represented by formula (IIh):

The invention

With the aim of creating new compounds to lower cholesterol and reduce the weight of the body with beneficial effects in the treatment and/or prevention of diseases associated with elevated levels of lipids, atherosclerosis, coronary artery lesions, syndrome X, impaired glucose tolerance, insulin resistance, insulin resistance leading to type 2 diabetes, and complications caused by diabetes, for treatment of diseases in which insulin resistance is the pathophysiological mechanism for the treatment of hypertension, atherosclerosis and damage the coronary arteries performed with greater efficiency and less toxicity, applicants have focused their efforts on creating new compounds effective in the treatment of the aforementioned diseases. Efforts in this direction have led to compounds having General formula (I).

Therefore, the main purpose of the present invention to provide a new arylacetamides alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate containing pharmaceutically acceptable compounds or mixtures thereof.

Another objective of the present invention is the provision of new arylacetamides alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate containing pharmaceutically acceptable compounds or their mixtures, which may have agonist activity against PPARα and/or PPARγ and possibly (not necessarily), to inhibit HMG-CoA-reductase along with agonistic activity against PPARα and/or PPARγ.

Another objective of the present invention is the provision of new arylacetamides alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate containing pharmaceutically acceptable compounds, or their mixtures having enhanced activity without toxicity or with reduced toxic effect.

Another objective of the present invention is a method of obtaining new arylacetamides alkylcarboxylic acids of the formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, apolinario, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvate.

Another objective of the present invention is to provide pharmaceutical compositions containing compounds of General formula (I), their analogs, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their salts, solvate, and other tools commonly used in the preparation of such compounds.

Another objective of the present invention is the provision of new intermediate compounds, the method of preparation and use of these intermediates in the processes of obtaining β-aryl-α-oxiclean alkylcarboxylic acids of the formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their salts and their pharmaceutically acceptable solvate.

Detailed description of the invention

α-Oxiclean propionic acid, their derivatives and analogues according to the present invention have the General formula (I)

where the group R1, R2, R3, R4group and R5and R6when they are attached to the carbon atom may be the same or different and mean hydrogen, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkene, aryl, aryloxy, aralkyl, Alcoxy,heterocyclyl, heteroaryl, heteroalkyl, heteroaromatic, heteroaromatic, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamines, aminoalkyl, alkoxycarbonyl, aryloxyalkyl, arylcarbamoyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, thioalkyl, alkoxycarbonyl, aryloxypropanolamine, alcoxycarbenium, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of the substituent R5and R6can also mean oxoprop, if they are attached to the carbon atom, R5and R6if they are attached to the nitrogen atom, denote hydrogen, hydroxy, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkene, aryl, aralkyl, heterocyclyl, heteroaryl, heteroalkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamines, aminoalkyl, aryloxy, Alcoxy, heteroaromatic, heteroaromatic, alkoxycarbonyl, aryloxyalkyl, arylcarbamoyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, thioalkyl, derivatives of carboxylic acids or sulfonic acid derivatives; x is the heteroatom selected from oxygen, sulfur or NR11where R11selected from hydrogen or optionally substituted groups, select the data from alkyl, cycloalkyl, aryl, Uralkaliy, acyl, alkoxycarbonyl, allamoxicillinpills or alcoxycarbenium groups; AG means optionally substituted divalent single or condensed aromatic or heterocyclic group; R7means a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, optionally substituted aracelio group or forms a bond together with the adjacent group, R8; R8means hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl or optionally substituted aralkyl or R8forms a bond together with R7; R9means hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, Uralkaliy, alkoxyalkyl, alkoxycarbonyl, aryloxyalkyl, alkylaminocarbonyl, allamericanheroes, acyl, heterocyclyl, heteroaryl or heteroalkyl group; R10means hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, Uralkaliy, heterocyclyl, heteroaryl or heteroalkyl groups; Y represents oxygen or NR12where R12means hydrogen, alkyl, aryl, hydroxyalkyl, Uralkaliy, heterocyclyl, heteroaryl or heteroalkyl group; R10and R12VM is the wall may form a five - or six-membered cyclic structure, containing carbon atoms, which optionally contains one or more heteroatoms selected from oxygen, sulfur or nitrogen; the linking group represented by formula -(CH2)n-(O)m-can be attached to or through the nitrogen atom or via a carbon atom, n is an integer indicates the number varying in the range of 1-4, and m means an integer from 0 to 1.

Suitable groups represented by R1-R4and the group R5and R6if they are attached to the carbon atom may be selected from a hydrogen atom, halogen atom, such as fluorine, chlorine, bromine or iodine; hydroxy, cyano, nitro, formyl; substituted or unsubstituted (C1-C12)-alkyl group, especially, linear or branched (C1-C6)-alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, hexyl and the like; cyclo(C3-C6)alkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, cycloalkyl group may be substituted; cyclo(C3-C6)alkoxygroup, such as cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy and the like, cycloalkanes may be substituted; aryl group such as phenyl or naphthyl, the aryl group may be substituted; aranceles group, tako is, as benzyl or penicilina,6H5CH2CH2CH2, naphthylmethyl and the like, kalkilya group may be substituted, and the substituted kalkilya group means a group as CH3C6H4CH2, l-C6H4CH2CH3OS6H4CH2CH3OS6H4CH2CH2and the like; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroaryl group may be substituted; heterocyclyl groups, such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinil and the like, heterocyclyl group may be substituted; urlcategory, such as benzyloxy, penetrate, naphthalenyloxy, phenylpropoxy and the like, urlcategory may be substituted, heteroalkyl groups, such as furanosyl, pyridylmethyl, oxazolyl, oxazolyl and the like, heteroalkyl group may be substituted; aralkylamines, such as6H5CH2NN, C6H5CH2CH2NH, C6H5CH2NCH3and the like, which may be substituted; alkoxycarbonyl such as methoxycarbonyl, etoxycarbonyl itomo such, which may be substituted; aryloxyalkyl groups, such as optionally substituted phenoxycarbonyl, naphthalocyanines and the like; alcoxycarbenium group, such as benzyloxycarbonyl, ventilatsioonil, naphthylenediamine and the like, which may be substituted; (C1-C6-alkylamino, such as N3, N2H5, N3H7, NHC6H13and the like, which may be substituted; and (C1-C6-dialkylamino, such as N(CH3)2, NCH3(C2H5), N(C2H5)2and the like, which may be substituted; alkoxyalkyl groups, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, which may be substituted; aryloxyalkyl group, such as6H5Och2With6H5Och2CH2naphthylacetyl and the like, which may be substituted; alcoxialchil group, such as6H5CH2Och2With6H5CH2Och2CH2and the like, which may be substituted; heteroaromatic, heteroaromatic, where the heteroaryl portion has the previous value and may be substituted; alloctype, such as phenoxy, naphthyloxy and things under the service, alloctype may be substituted; killingray, such as HNC6H5, NCH3(C6H5), N6H4-l and the like, which may be substituted; amino group which may be substituted; amino(C1-C6)-alkyl which may be substituted; hydroxy(C1-C6)-alkyl which may be substituted; and (C1-C6-alkoxygroup, such as methoxy, ethoxy, propyloxy, bucalossi, isopropoxy and the like, which may be substituted; thio(C1-C6)-alkyl which may be substituted; and (C1-C6)ancilliary, which may be substituted; acyl group such as acetyl, propionyl or benzoyl and the like, the acyl group may be substituted; alluminare, such as NHCOCH3, NHCOC2H5The N3H7, NHCOC6H5and the like, which may be substituted; alcoxycarboxylates, such as NH2With6H5, NHCOOCH2CH2C6H5N(CH3)SOON2With6H5N(C2H5)SOON2With6H5, NHCOOCH2C6H4CH3, NHCOOCH2C6H4OCH3and the like, which may be substituted; aryloxypropanolamine, such as the N6H5, NCH3COOC6 H5That NC2H5SOOS6H5The N6H4CH3, NH6H4Och3and the like, which may be substituted; alkoxycarbonylmethyl, such as NHCOOC2H5The N3and the like, which may be substituted; carboxylic acid or its derivatives such as amides, such CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHPh and the like, which may be substituted; alloctype, such as the Sooma, COOEt, COOPh, and the like, which may be substituted; sulfonic acid or its derivatives, such as SO2NH2, SO2NHMe, SO2NMe2, SO2NHCF3and the like, derivatives of sulfonic acids can be substituted. One or both of the substituent R5and R6can also be exography.

If the groups denoted by R1-R4and the group R5and R6connected with the carbon atom and substituted, the substituents can be selected from halogen, hydroxy, or nitro or of the optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkane, Alcoxy, aryl, Uralkaliy, alcoxialchil, heterocyclyl, heteroaryl, heteroalkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, is alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.

Preferably, the substituents at R1-R6were halogen atom such as fluorine, chlorine, bromine; alkyl group such as methyl, ethyl, isopropyl, n-propyl, n-butyl; cycloalkyl group, such as cyclopropyl; aryl group such as phenyl; aranceles group, such as benzyl; and (C1-C3)-alkoxy, benzyloxy, hydroxy-group, acyl or allochrony.

Appropriate substituents R5and R6if they are attached to the nitrogen atom, selected from hydrogen, hydroxy, formyl; substituted or unsubstituted (C1-C12)-alkyl group, especially, linear or branched (C1-C6)-alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, n-pentyl, isopentyl, hexyl and the like; cyclo(C3-C6)-alkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, cycloalkyl group may be substituted; cyclo(C3-C6-alkoxygroup, such as cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy and the like, cycloalkanes may be substituted; aryl group such as phenyl, naphthyl, and things under the tion; the aryl group may be substituted; aranceles group, such as benzyl or phenethyl, C6H5CH2CH2CH2naphthylmethyl and the like, kalkilya group may be substituted, and the substituted kalkilya group means a group as CH3With6H4CH2Hal-C6H4CH2CH3OS6H4CH2CH3OS6H4CH2CH2and the like; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroaryl group may be substituted, heterocyclyl groups, such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinil and the like, heterocyclyl group may be substituted; urlcategory, such as benzyloxy, penetrate, naphthalenyloxy, phenylpropoxy and the like, urlcategory may be substituted; heteroaryl groups, such as furanosyl, pyridylmethyl, oxazolyl, oxazolyl and the like, heteroalkyl group may be substituted; aralkylamines, such as C6H5CH2NH2With6H5CH2CH2NH2C6H5CH2NCH3and the like, which can be replaced by the; alkoxycarbonyl such as methoxycarbonyl, etoxycarbonyl and the like, which may be substituted; aryloxyalkyl groups, such as optionally substituted phenoxycarbonyl, naphthalocyanines and the like; alcoxycarbenium groups, such as benzyloxycarbonyl, ventilatsioonil, naphthylenediamine and the like, which may be substituted; and (C1-C6-alkylamino, such as N3N(CH3)2, N3(C2H5), NHC2H5, NHC3H7, NHC6H13and the like, which may be substituted; alkoxyalkyl groups, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, which may be substituted; aryloxyalkyl group, such as6H5Och2With6H5Och2CH2naphthylacetyl and the like, which may be substituted; alcoxialchil group, such as6H5CH2Och2With6H5CH2Och2CH2and the like, which may be substituted; heteroaromatic, heteroaromatic, where the heteroaryl portion has the previous value and may be substituted; alloctype, such as phenoxy, naphthyloxy and the like, alloctype may be substituted; aryl is aminogruppy, such as N6H5, N3(C6H5), N6H4CH3, N6H4-Hl and the like, which may be substituted; amino group which may be substituted; amino(C1-C6)-alkyl which may be substituted; hydroxy(C1-C6)-alkyl which may be substituted; and (C1-C6-alkoxygroup, such as methoxy, ethoxy, propyloxy, bucalossi, isopropoxy and the like, which may be substituted, thio(C1-C6)-alkyl which may be substituted; and (C1-C6)ancilliary, which may be substituted; acyl group such as acetyl, propionyl, benzoyl and the like, the acyl group may be substituted; acylamino, such as NHCOCH3, NHCOC2H5, NHCOC3H7The N6H5and the like, which may be substituted; carboxylic acid derivatives such as amides, like CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHPh and the like, derivatives of carboxylic acids may be substituted; acyloxy groups, such as Oocme, OOCEt, OOCPh and the like, which may be substituted; sulfonic acid derivatives, such as the SO2NH2, SO2NHMe, SO2NMe2, SO2NHCF3and the like, derivatives of sulfonic acids can be for exename.

If the groups denoted by R5and R6connected to the nitrogen atom and are substituted, the preferred substituents may be selected from halogen, such as fluorine, chlorine; hydroxy, acyl, acyloxy or amino group.

The appropriate Deputy X comprises oxygen, sulfur or a group NR11indicated above, preferably oxygen and sulfur. The corresponding substituent R11means hydrogen, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, aryl group such as phenyl or naphthyl, aracelio group, such as benzyl or phenethyl; acyl group such as acetyl, propanol, butteroil, benzoyl and the like; and (C1-C6-alkoxycarbonyl; aryloxyalkyl, such as phenoxycarbonyl, CH3OS6H4CCA, l-C6H4OCO, CH3With6H4CCA, naphthalocyanines and the like; arelaxation, such as benzyloxycarbonyl, ventilatsioonil and the like; groups denoted by R11may be substituted or unsubstituted. If the groups denoted by R11are substituted, the substituents can be selected from halogen, optionally halogenated lower alkyl, hydroxy, and optionally halogenated (C1-C3)alkoxygroup.

Preferably, the group denoted by the r, was substituted or unsubstituted and selected from divalent phenylene, naphthylene, pyridyl, chinoline, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, dihydrobenzofuranyl, indolyl, indolinyl, isoindolyl, isoindoline, pyrazolyl, benzothiazolyl, benzoxazolyl and the like. The substituents in the group denoted by AG, can be selected from linear or branched optionally halogenated (C1-C6)-alkyl, optionally halogenated (C1-C3)-alkoxyl, halogen, acyl, amino, acylamino, tigroup or carboxylic or sulfonic acids or their derivatives.

More preferably, Ah meant a substituted or unsubstituted divalent fenelonov, Neftyanoy, benzofuranyl, indolenine, indolinyl, hyalinella, isoindolyl, isoindolyl, benzothiazolyl or benzoxazolyl group.

Even more preferably, Ah meant divalent fenelonov or benzofuranyl group, which is optionally substituted by methyl, kaleidotile, metaxylene or kaleidotile groups.

The corresponding R7includes hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, (C1-C3)-alkoxygroup; a halogen atom such as fluorine, chlorine, bromine, iodine; aralkyl, such as benzyl, f is Neil, which, optionally substituted, or R7together with R8means the connection.

The corresponding R8can be hydrogen, lower alkyl groups such as methyl, ethyl or propyl; hydroxy, (C1-C3-alkoxygroup; a halogen atom such as fluorine, chlorine, bromine, iodine; acyl group such as linear or branched (C2-C10)-acyl group such as acetyl, propanol, butanol, pentanol, benzoyl and the like; aralkyl, such as benzyl, phenethyl, which is optionally substituted, or together with R7makes a connection.

Appropriate groups denoted by R9can be selected from hydrogen, linear or branched (C1-C16)-alkyl, preferably (C1-C12)-alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, octyl and the like; and (C3-C7)-cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, cycloalkyl group may be substituted; aryl group such as phenyl, naphthyl, the aryl group may be substituted; heteroaryl group such as pyridyl, thienyl, furyl and the like, the heteroaryl group may be substituted; heteroaryl groups, such as furanosyl, pyridylmethyl, oxazolyl, oxazole the silt and the like, heteroalkyl group may be substituted; aranceles groups such as benzyl and phenethyl, and the like, where the alkyl part can contain 1-6 carbon atoms, where the aryl part can be substituted; heterocyclyl groups, such as aziridinyl, pyrrolidinyl, piperidinyl and the like, heterocyclyl group may be substituted; and (C1-C6)alkoxy(C1-C6)-alkyl groups, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxypropan and the like, alkoxyalkyl group may be substituted; a linear or branched (C2-C16)-acyl group such as acetyl, propanol, butanol, benzoyl, octanoyl, decanoyl and the like, which may be substituted; (C1-C6)-alkoxycarbonyl, the alkyl group may be substituted; aryloxyalkyl such as phenoxycarbonyl, naphthalocyanines and the like, the aryl group may be substituted; and (C1-C6)-alkylaminocarbonyl, the alkyl group may be substituted; arylenecarborane, such as PhNHCO, naphthaleneboronic and the like, aryl part can be substituted. The substituents can be selected from halogen, hydroxy-group or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkene, aryl, Uralkaliy, aralco alkylenes, heterocyclyl, heteroaryl, heteroalkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.

Appropriate groups denoted by R10can be selected from hydrogen, linear or branched (C1-C16)-alkyl, preferably (C1-C12)-alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, octyl and the like; and (C3-C7)-cycloalkyl groups, such as cyclopropyl, cyclopentyl, cyclohexyl and the like, cycloalkyl group may be substituted, aryl groups 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; heteroaryl groups, such as furanosyl, pyridylmethyl, oxazolyl, oxazolyl and the like, heteroalkyl group may be substituted; aranceles groups such as benzyl and phenethyl, and the like, kalkilya the group may be substituted, and heterocyclyl groups, such as aziridinyl, pyrrolidinyl, p is pyridinyl and the like, heterocyclyl group may be substituted. Substituents at R10can be selected from the same group that R1-R6.

Appropriate groups denoted by R12can be selected from hydrogen, linear or branched (C1-C16)-alkyl, preferably (C1-C12)-alkyl; hydroxy(C1-C6)-alkyl; aryl groups such as phenyl, naphthyl and the like; aranceles group, such as benzyl, phenethyl and the like; heterocyclyl groups, such as aziridinyl, pyrrolidinyl, piperidinyl and the like; heteroaryl group such as pyridyl, thienyl, furyl and the like, and heteroalkyl groups, such as furanosyl, pyridylmethyl, oxazolyl, oxazolyl and the like.

The corresponding ring structure formed by R10and R12together can be selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinil and the like.

The corresponding m is an integer varying in the interval 0-1. Preferably, when m=0 AG means the divalent benzofuranyl, benzoxazolyl, benzothiazolyl, indolenine, indolinyl, dihydrobenzofuranyl or dihydrobenzofuranyl group, and when m=1 AG means substituted or unsubstituted groups selected from divalent phenylene, naphthylene, pyrid the La, chinoline, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, dihydrobenzofuranyl, indolyl, indolinyl, isoindolyl, isoindoline, pyrazolyl, benzothiazolyl, benzoxazolyl and the like.

The corresponding n is a number varying in the range of 1 to 4, preferably n is 1 or 2.

Preferably, when m=1 n meant 2.

It is preferable that when m=0 n means 1.

Pharmaceutically acceptable salts forming part of this invention include the salts of the remaining carboxylic acid with alkali metals like lithium, sodium and potassium, alkaline earth metals, such as calcium and magnesium, with organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium, and salts with aluminum. In those cases, when possible, salts may also be formed by joining of the acid with the formation of sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartratami, malatov, citrates, succinates, palmoate, methansulfonate, benzoates, salicylates, hydroxynaphthoate, bansilalpet, ascorbate, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvate may be hydrates or include other solvents of crystallization, such as alcohols.

Particularly useful in the compounds of the present invention include:

ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate;

(±)methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

ethyl(E/Z)-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]methylbenzofuran-5-yl]-2-ethoxypropionate;

ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate;

(±)methyl-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol;

(+)methyl-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol;

(-)methyl-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol;

(±)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(±)methyl 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(±)methyl-2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy repeat;

(+)methyl-2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)methyl-2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

ethyl(E/Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate;

(±)methyl-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)methyl-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)methyl-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

ethyl(E/Z)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropionate;

(±)methyl-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol;

(+)methyl-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol;

(-)methyl-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol;

ethyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;

ethyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;

ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic;

ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan;

ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol;

ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(±)methyl-3-[4-[2-(2,3-dihydro-1,benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(+)methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(-)methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(±)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(+)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(-)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

ethyl(E/Z)-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropionate;

(±)methyl-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

(+)methyl-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

(-)methyl-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

ethyl(E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropionate;

(±)methyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

(+)methyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

(-)methyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ATOC and]phenyl]-2-ethoxypropanol acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(±)3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(+)3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(-)3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(±)3-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(+)3-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(-)3-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(-)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(±)N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(+)N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-this is sapropelic;

(-)N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(±)N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(+)N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(-)N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(±)N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(+)N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(-)N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(±)N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(+)N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane,

(-)N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(±)3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid is its salts;

(+)3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(-)3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(±)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(-)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(±)3-[6-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid and its salts;

(+)3-[6-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid and its salts;

(-)3-[6-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropionate acid and its salts;

(±)3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid and its salts;

(+)3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid and its salts;

(-)3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoyl acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoyl acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoyl acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin the-4-yl)ethoxy]phenyl]-2-hydroxypropanoyl acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoyl acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoyl acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(±)methyl 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(+)methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(-)methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(±)- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(+)- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(- )- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(±)methyl 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(+)methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(-)methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(±)- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salt,

(+)- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(- )- 2-methyl-3-[4-[2-(2,3-Digi the ro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(±)4-nitrophenyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol,

(+)4-nitrophenyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)4-nitrophenyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(±)3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol acid and its salts;

(+)3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol acid and its salts;

(-)3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol acid and its salts;

(±)4-nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

(+)4-nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

(-)4-nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol.

In accordance with the distinguishing feature of the present invention the compound of General formula (I), where R7and R8together form a bond, Y represents an oxygen atom, R1, R2, R3, R4, R5, R6, R9, R10, X, n, m and ar are as described earlier indicate, can be obtained by one of the following routes shown in scheme I.

Path (1): the reaction of compounds of General formula (IIIa)where all symbols designation is s earlier with the compound of the formula (IIIb), where R9, R10marked previously and R14means (C1-C6)-alkyl, with the formation of compounds of General formula (I), where R7, R8together denote a bond, Y represents an oxygen atom, can be effectively carried out in the presence of a base such as a hydride of an alkali metal as sodium hydride or potassium hydride, or organolithium compounds, as motility, utility and the like or alkoxides such as sodium methylate (NaOMe), sodium ethylate (NaOEt), butyl potassium (K+BuO-) or mixtures thereof. The reaction can be carried out in the presence of solvents, such as tetrahydrofuran (THF), dioxane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethoxyethane (DME) and the like, or mixtures thereof. As a co-solvent may be used hexamethylphosphoric (NMRA). The reaction temperature may range from -78°C to 50°C, preferably in the range from -10°C to 30°C. the Reaction is more effective in anhydrous conditions. The compound of General formula (IIIb) can be obtained according to the procedure described in the literature (Annalen Chemie, (1996) 53, 699).

Path (2): the reaction of compounds of General formula (S), where all symbols indicated earlier, with a compound of General formula (IIId)where R7, R8together denote a bond, and where all the characters indicated earlier, and L1OZNA the AET leaving group, such as a halogen atom, n-toluensulfonate, methanesulfonate, triftorbyenzola and the like, preferably a halogen atom, with the formation of compounds of General formula (I)above may be carried out in the presence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like, or mixtures thereof. The reaction may be carried out in an inert atmosphere, which can be installed using an inert gas, such as nitrogen, argon or helium. The reaction may be carried out in the presence of a base such as alkalis like sodium hydroxide, potassium hydroxide; carbonates of alkali metals as sodium carbonate or potassium carbonate; hydrides of alkali metals, such as sodium hydride or potassium hydride; ORGANOMETALLIC base such as n-utility; amides of alkaline metals, such as sodium amide, or mixtures thereof. The number can range from 1 to 5 equivalents based on the amount of compounds of formula (S), preferably the amount of base varies from 1 to 3 equivalents. Can be added to interphase catalysts, such as tetraalkylammonium or tetraalkylammonium. The reaction may be carried out at a temperature in the range from 0°C to 150°C, preferably at temperatures from 15°C to 100°C. the Duration of the reaction may vary within the interval is from 0.25 hours to 48 hours, preferably from 0.25 hours to 12 hours.

Path (3): the reaction of compounds of General formula (I), where all symbols previously defined, with a compound of formula (IIIf)where R9=R10and indicated earlier, with the formation of the compounds of formula (I), where R7and R8together denote a bond, can be carried out without solvent in the presence of bases, such as hydrides of alkali metals as sodium hydride, potassium hydride or organolithium compounds, as motility, utility and the like or alkoxides as sodium methylate, sodium ethylate, potassium butyl and the like, or mixtures thereof. The reaction may be carried out in the presence of aprotic solvents such as THF, dioxane, DMF, DMSO, DME and the like or mixtures thereof. As a co-solvent can be used, NMRA. The reaction temperature may range from -78°C to 100°C, preferably in the range from -10°C to 50°C.

Path (4): the reaction of compounds of General formula (IIIa)where all symbols previously defined, with a compound of formula (IIIg)where R8means a hydrogen atom, R9and R10indicated earlier, may be carried out in the presence of a base. The nature of the base is not essential. Can be used any basis, usually used in the aldol condensation; can be used such grounds as metal hydrides is, as sodium hydride or potassium hydride; alkoxides of metals such as sodium methylate, butyl potassium or sodium ethylate; amides of metals, such as lithium amide or diisopropylamide lithium. The reaction may be carried out in the presence of aprotic solvents such as THF, ether or dioxane. The reaction may be carried out in an inert atmosphere, which can be installed using an inert gas, such as nitrogen, argon or helium, and the reaction is more effective in anhydrous conditions. The temperature may be in the range from -80°C to 35°C. the Resulting original β-hydroxypropyl can be dehydration under normal conditions of dehydration, such as treatment with PTSA (n-toluensulfonate) in solvents such as benzene or toluene. The nature of the solvent and dehydrating agent is not essential. The reaction is carried out at a temperature in the range from 20°C to the boiling point of the solvent, preferably at the boiling temperature of the solvent with continuous removal of water using nozzles Dean-stark.

Path (5): the reaction of the compound (IIIh)where all symbols previously defined and L1means a leaving group such as halogen atom, n-toluensulfonate, methanesulfonate, triftorbyenzola and the like, with a compound of formula (IIIi)where R7and R8together denote a bond, and R9, R10and AG designation is s earlier with the formation of the compounds of formula (I), where m=1 and all other symbols are defined above, can be carried out in the presence of aprotic solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof. The reaction may be carried out in an inert atmosphere, which can be installed using an inert gas, such as nitrogen, argon or helium. The reaction can be carried out in the presence of a base such as potassium carbonate, sodium carbonate or sodium hydride, or mixtures thereof. Acetone can be used as a solvent, if sodium carbonate or potassium carbonate is used as the base. The reaction temperature can vary in the range from 0°C to 120°C, preferably in the range of 30-100°C. the Duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours. The compound of formula (IIIi) can be obtained in accordance with known procedure for the reaction of Wittig-Horner between protected by a hydroxy-group-arilaldegidov, such as benzyloxyacetaldehyde, and a compound of formula (IIIb) with the subsequent release.

Path (6): the reaction of compounds of General formula (IIIj)where all symbols previously defined, with a compound of General formula (IIIi)where R7and R8together denote a bond, and R9, R10and AG indicated earlier, with the formation of the compounds of formula (I), g is e m=1, and all other symbols are defined above, can be carried out using appropriate condensing agents, such as dicyclohexylamine, triarylphosphine/dialkyldithiocarbamate, such as triphenylphosphine/diethylazodicarboxylate, and the like. The reaction can be carried out in the presence of solvents such as THF, DME, methylene chloride, chloroform, toluene, acetonitrile, carbon tetrachloride and the like. The inert atmosphere can be installed using an inert gas, such as nitrogen, argon or helium. The reaction may be carried out in the presence of DMAP (dimethylaminopyridine), NOT (hydroxybenzotriazole)that can be used in amounts of from 0.05 to 2 equivalents, preferably from 0.25 to 1 equivalent. The reaction temperature can vary in the range from 0°C to 100°C, preferably in the range from 20°C to 80°C. the Duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.

In yet another variant embodiment of the present invention the compound of General formula (I), where R1, R2, R3, R4, R5, R6, R9, R10, X, n, m are defined above, R7means a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, optionally substituted aracelio group, R8means a hydrogen atom, hydroxy, alkoxy, g is laid, lower alkyl group, acyl or optionally substituted aralkyl, and AG indicated earlier, and Y represents an oxygen atom, can be obtained by using one or more of the processes shown in scheme II:

Path 7: restore the compounds of formula (IVa), which is a compound of formula (I), where R7and R8together denote a bond, Y represents an oxygen atom and all other symbols are defined previously obtained as described previously (scheme I), with the formation of compounds of General formula (I), where R7and R8each means hydrogen atom and all symbols are defined earlier may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, and the like. You can apply a mixture of catalysts. The reaction may also be carried out in the presence of solvents such as dioxane, acetic acid, ethyl acetate, and the like. Use a pressure between atmospheric and 551,6 kPa (80 psi). Preferably the catalyst is 5-10% Pd/C, and the amount of catalyst may vary in the range 50-300% by weight. The reduction can also be carried out using metal in a solvent, such as magnesium in alcohol or sodium amalgam in alcohol, preferably in methanol. To obtain the compounds of formula (I) in optically active form is gidrirovanie can be carried out in the presence of a metal catalyst, containing a chiral ligand. The metal catalyst may contain rhodium, ruthenium, indium, and the like. Chiral ligands preferably can be chiral phosphines, such as (2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylpiperazine)ethane, (-)-2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane and the like. You can use any appropriate chiral catalyst, which will provide the optical purity of the product (I) (Principles of Asymmetric Synthesis, Tet. Org. Chem. Series, 14, 311-316, Ed. Baldwin J.E.).

Path 8: reaction of compounds of formula (IVb), where all symbols previously defined, and L2means a leaving group such as halogen atom, with an alcohol of General formula (IVc), where R9previously defined, to obtain the compounds of formula (I)defined earlier may be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like, and mixtures thereof. The reaction may be carried out in an inert atmosphere, which can be installed by using inert gases such as nitrogen, argon or helium. The reaction may be carried out in the presence of a base such as potassium hydroxide, sodium hydroxide, sodium methylate, sodium ethylate, butyl potassium or sodium hydride, or mixtures thereof. You can use a phase transfer catalyst, such as tetraalkylammonium or Tetra kilmonivaig. The reaction temperature can vary in the range from 20°C to 120°C, preferably in the range of 30-100°C. the Duration of the reaction may range from 1 to 12 hours, preferably from 2 to 6 hours. The compound of General formula (IVb) and its getting disclosed in concurrently pending application, U.S. 08/982910.

Path 9: reaction of compounds of formula (IIIh)defined earlier with a compound of formula (IIIi)where all symbols defined previously, with the formation of the compounds of formula (I), where m=1, and all other symbols are 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 may be carried out in an inert atmosphere, which is established by using inert gases such as nitrogen, argon or helium. The reaction may be carried out in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydride or mixtures thereof. Acetone can be used as a solvent, if the potassium carbonate or sodium carbonate is used as the base. The reaction temperature can vary in the range from 20°C to 120°C, preferably in the range of 30-80°C. the Duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours. The compound of formula (IIIi) can be obtained by the reaction of the Wittig-Horner between protected hydroxyaryl what idigicon and the compound of the formula (IIIb), followed by reduction of the double bond and release. Alternatively, the compound of formula (IIIi) can be obtained using the following procedures disclosed in international application WO 94/01420.

Path 10: reaction of compounds of General formula (IIIj)defined earlier with a compound of General formula (IIIi)where all symbols defined previously, with the formation of the compounds of formula (I), where m=1 and all other symbols are defined above, can be carried out with appropriate condensing agents, such as dicyclohexylamine, triarylphosphine/dealkylase, in primary forms, such as triphenylphosphine/diethylazodicarboxylate, and the like. The reaction can be carried out in the presence of solvents such as THF, DME, methylene chloride, chloroform, toluene, acetonitrile, carbon tetrachloride and the like. The inert atmosphere can be installed using inert gases such as nitrogen, argon or helium. The reaction may be carried out in the presence of DMAP, HOBT, and they can be used in amounts of from 0.05 to 2 equivalents, preferably from 0.25 to 1 equivalent. The reaction temperature can vary in the range from 0°C to 100°C, preferably in the range of 20-80°C. the Duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.

Path 11: reaction of compounds of formula (IVd), which is a compound of formula (I), where R9who appoints a hydrogen atom, and all other symbols previously defined, with a compound of formula (IVe), where R9previously defined, and L2means a leaving group such as halogen atom, can be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like. The inert atmosphere can be installed using inert gases such as nitrogen, argon or helium. The reaction may be carried out in the presence of a base such as potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium methylate (NaOMe), butyl potassium (K+BuO-), sodium hydride (NaH), and the like. Can be used phase transfer catalyst, such as tetraalkylammonium or tetraalkylammonium. The reaction temperature can vary in the range from 20°C to 150°C, preferably in the range of 30-100°C. the Duration of the reaction may range from 1 to 24 hours, preferably from 2 to 6 hours.

Path 12: reaction of compounds of General formula (IIIa), defined above, with a compound of formula (IIIg)where R8, R9and R10defined earlier may be carried out under normal conditions. The nature of the base is not essential. Can be used any base used in the aldol condensation, metal hydride such as sodium hydride or potassium hydride; alkoxides of metals such as sodium methylate, potassium butyl or ethylate n is sodium; amides of metals, such as lithium amide or diisopropylamide lithium. Can be used aprotic solvent, such as THF. Can be used an inert atmosphere, such as argon, and the reaction is more effective in anhydrous conditions. The reaction temperature may be in the range from -80°C to 25°N β-Hydroxyindole product can be dehydrosilybin using well-known methods, typically by ionic hydrogenation, such as treatment with trialkylsilanes in the presence of acid, such as triperoxonane acid. You can use a solvent such as methylene chloride. It is convenient that the reaction was held at 25°C. Can be used in higher temperature, if the reaction proceeds slowly.

Path 13: reaction of compounds of General formula (S), where all symbols previously defined, with a compound of General formula (IIId), where L1means a leaving group such as halogen atom, n-toluensulfonate, methanesulfonate, triftorbyenzola and the like, preferably L1means a halogen atom and all other symbols are defined previously, with the formation of compounds of General formula (I) can be carried out in the presence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like, or mixtures thereof. The reaction may be carried out in an inert atmosphere, which can be installed to use the using inert gases, such as nitrogen, argon or helium. The reaction may be carried out in the presence of a base such as alkalis like sodium hydroxide or potassium hydroxide, carbonates of alkali metals as sodium carbonate or potassium carbonate; hydrides of alkali metals, such as sodium hydride or potassium hydride; ORGANOMETALLIC bases like n-utility, amides of alkali metals as sodium amide, or mixtures thereof. The number can range from 1 to 5 equivalents based on the amount of compounds of formula (S), preferably the amount of base is changed in the range from 1 to 3 equivalents. The reaction may be conducted at a temperature in the range from 0°C to 150°C, preferably at a temperature in the range from 15°C to 100°C. the Duration of the reaction may range from 0.25 to 24 hours, preferably from 0.25 to 12 hours.

Path 14: conversion of the compounds of formula (IVf) in the compound of formula (I) can be performed either in the presence of a base, or in the presence of acid, and the choice of acid or base is not essential. Can be used any base used for hydrolysis of the nitrile to the acid, such as a metal hydroxide, such as sodium hydroxide or potassium hydroxide, in aqueous solution, or can be used any acid commonly used for hydrolysis of the nitrile in e is R & d such as a solution of dry hydrogen chloride in excess of alcohol, such as methanol, ethanol, propanol, etc. the Reaction can be carried out at a temperature in the range from 0°C to the boiling point of the solvent, preferably at a temperature in the range from 25°C to the boiling point of the used solvent. The duration of the reaction may range from 0.25 hours to 48 hours.

Way 15: reaction of compounds of formula (IVg), where all symbols previously defined, with a compound of formula (IVc), where R9previously defined, to obtain the compounds of formula (I) by using the reaction activation mediated by carbenoid rhodium) can be carried out in the presence of salts of rhodium(II), such as acetate, rhodium(II). The reaction can be carried out in the presence of solvents, such as benzene, toluene, dioxane, ether, THF and the like, or combinations thereof, or, when feasible, in the presence of R9OH as solvent at any temperature providing a sufficient rate of formation of the required product, generally at an elevated temperature, such as the boiling point of the solvent. The inert atmosphere can be installed using inert gases such as nitrogen, argon or helium. The duration of the reaction may vary from 0.5 hours to 24 hours, preferably from 0.5 hours to 6 hours.

Soy is inania General formula (I), where Y represents an oxygen atom and R10previously defined, may be converted into a compound of formula (I)where Y represents NR12by reaction with the corresponding amines of the formula with other10R12where R10and R12defined previously. Accordingly, the compound of formula (I), where YR10means a hydroxyl group, can be converted into galoyanized acid, preferably YR10=Cl, by reaction with appropriate reagents, such as oxacillin, thionyl chloride and the like, followed by treatment of amines. Alternatively, mixed anhydrides can be obtained from compounds of formula (I), where YR10means a hydroxyl group and all other symbols are defined previously, when processing the anhydrides of the acids, such as acetylchloride, acetylmuramic, pivaloyloxy, dichlorobenzophenone and the like. The reaction may be carried out in the presence of an appropriate base, such as pyridine, triethylamine, diisopropylethylamine and the like. Can be used solvents such as halogenated hydrocarbons as chloroform or methylene chloride, hydrocarbons such as benzene, toluene, xylene and the like. The reaction may be carried out at a temperature in the range from -40°C to 40°C, preferably at a temperature in the range from 0°C to 20°C. Obtained is thus the acid chloride or mixed anhydride can be further processed corresponding amines.

In another embodiment, the present invention provides a new intermediate compound of formula (IVf)

where the group R1, R2, R3, R4group and R5and R6when they are attached to the carbon atom may be the same or different and mean a hydrogen atom, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkene, aryl, aryloxy, aralkyl, Alcoxy, heterocyclyl, heteroaryl, heteroalkyl, heteroaromatic, heteroaromatic, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamines, aminoalkyl, alkoxycarbonyl, aryloxyalkyl, arylcarbamoyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, thioalkyl, alkoxycarbonyl, aryloxypropanolamine, alcoxycarbenium, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; R5and R6when they are attached to the nitrogen atom, denote hydrogen, hydroxy, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkene, aryl, Uralkaliy, heterocyclyl, heteroaryl, heteroalkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino is, arylamino, aralkylamines, aminoalkyl, aryloxy, Alcoxy, heteroaromatic, heteroaromatic, alkoxycarbonyl, aryloxyalkyl, alcoxycarbenium, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, thioalkyl groups, derivatives of carboxylic acid or sulfonic acid; one or both of the substituent R5and R6can also mean oxoprop, if they are attached to the carbon atom, x is the heteroatom chosen from oxygen, sulphur or the group NR11where R11selected from hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, Uralkaliy, acyl, alkoxycarbonyl, aryloxyalkyl or alcoxycarbenium groups; AG means optionally substituted divalent monocyclic or condensed aromatic or heterocyclic group; R7means a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or optionally substituted aracelio group; R8means hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, optionally substituted aracelio group; R9means hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, Uralkaliy, alkoxyalkyl, alkoxycarbonyl, aryloxyalkyl alkylaminocarbonyl, allamericanheroes, acyl, heterocyclyl, heteroaryl or heteroalkyl groups; the linking group represented by -(CH2)n-(O)m-can be attached to or through the nitrogen atom or via a carbon atom; n denotes an integer in the range of 1-4, and m means an integer from 0 to 1; and the method of its production and its use to obtain β-aryl-α-substituted hydroxyalkanoate acids.

The compound of formula (IVf), where R7and R8each means a hydrogen atom and all other symbols are defined previously, receive, shown in scheme III:

The reaction of the compound of formula (IIIa)where all symbols previously defined, with a compound of formula (IVh), where R9previously defined, and Hal means a halogen atom such as chlorine, bromine or iodine, can be carried out under normal conditions in the presence of a base. The nature of the base is not essential. Can be used any base commonly used in the Wittig reaction, a metal hydride such as sodium hydride or potassium hydride; alkoxides of metals such as sodium methylate, tert.-butyl potassium or sodium ethylate; or amides of metals, such as lithium amide or diisopropylamide lithium. Can be used aprotic solvents, such as THF, DMSO, dioxane, DME and the like. Can primantis the solvent mixture. As a co-solvent can be used, NMRA. Can be used an inert atmosphere, such as argon, and the reaction is more effective in anhydrous conditions. The temperature can vary in the range from -80°C to 100°C.

Connection (IVi), where all symbols defined previously, can be converted into a compound of formula (IVj), where R7and R8mean hydrogen atoms and all other symbols previously defined, by treatment with alcohol in anhydrous conditions in the presence of absolutely anhydrous acid, such as n-toluensulfonate.

The compound of formula (IVj), above, when processing with trialkylsilanes, such as trimethylsilane, forms a compound of formula (IVf), where R7and R8mean hydrogen atoms, and all other symbols are defined above.

In another variant embodiment of the present invention provides a new intermediate compound of formula (IVg)

where the group R1, R2, R3, R4group and R5and R6when they are attached to the carbon atom may be the same or different and mean a hydrogen atom, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkene, aryl, aryloxy, aralkyl, Alcoxy, heterocyclyl, heteroaryl is, heteroalkyl, heteroaromatic, heteroaromatic, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamines, aminoalkyl, alkoxycarbonyl, aryloxyalkyl, arylcarbamoyl, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, thioalkyl, alkoxycarbonyl, aryloxypropanolamine, alcoxycarbenium, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of the substituent R5and R6when they are attached to the carbon atom, can also be oxopropoxy; R5and R6when they are attached to the nitrogen atom, denote hydrogen, hydroxy, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkene, aryl, Uralkaliy, heterocyclyl, heteroaryl, heteroalkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamines, aminoalkyl, aryloxy, Alcoxy, heteroaromatic, heteroaromatic, alkoxycarbonyl, aryloxyalkyl, alcoxycarbenium, alkoxyalkyl, aryloxyalkyl, alcoxialchil, alkylthio, thioalkyl groups, derivatives of carboxylic acid or sulfonic acid; X represents heteroatom selected from oxygen, sulphur or the group NR11where R11choose from ogorodili optionally substituted groups, selected from alkyl, cycloalkyl, aryl, Uralkaliy, acyl, alkoxycarbonyl, aryloxyalkyl or alcoxycarbenium groups; AG means optionally substituted divalent monocyclic or condensed aromatic or heterocyclic group; R7means a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl or optionally substituted aracelio group; R10means hydrogen or optionally substituted groups selected from alkyl, cycloalkyl, aryl, Uralkaliy, heterocyclyl, heteroaryl or heteroalkyl groups; Y represents oxygen; the linking group represented by -(CH2)n-(O)m-can be attached to or through the nitrogen atom or via a carbon atom; n denotes an integer in the range of 1-4, and m means an integer from 0 to 1; and the method of its production and its use to obtain β-aryl-α-substituted hydroxyalkanoate acids.

The compound of formula (IVg), where all symbols defined previously, can be obtained by reaction of compounds of formula (IVk)

where R8means a hydrogen atom and all other symbols are defined previously, with a corresponding diastereomer agent.

The reaction of diazotization can be carried out under normal conditions. Suitable diastereomer AG is ntom is alkynylaryl, such as isoamylase. The reaction may be carried out in the presence of a solvent, such as THF, dioxane, ether, benzene and the like, or mixtures thereof. The temperature may be in the range from -50°C up to 80°C. the Reaction can be carried out in an inert atmosphere, which can be installed using inert gases such as nitrogen, argon or helium. The duration of the reaction may range from 1 to 24 hours, preferably from 1 to 12 hours.

The compound of formula (IVk) can also be obtained by the reaction between the compound of formula (IIIh)where all symbols are defined previously, and the connection

where R8means a hydrogen atom and all other symbols are defined above.

The reaction between the compound of formula (IIIh)where all symbols are defined previously, and a compound of formula (IV1), where all symbols are defined earlier may be carried out in the presence of solvents such as THF, DMF, DMSO and the like, or mixtures thereof. The reaction may be carried out in an inert atmosphere, which is established by using inert gases such as nitrogen, argon or helium. The reaction may be carried out in the presence of a base such as potassium carbonate, sodium carbonate or sodium hydride, or mixtures thereof. Acetone can be used as a solvent, if carbonate or potassium carbonate nationpolitics as a base. The reaction temperature can vary in the range from 20°C to 120°C, preferably in the range 30°C-80°C. the Duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours.

The term “without dilution (undiluted)as used in this application, means that the reaction is carried out without using solvent. Pharmaceutically acceptable salts are obtained by interaction of the compounds of formula (I) with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methylate, sodium hydride, tert.-butyl potassium, calcium hydroxide, magnesium hydroxide and the like, in solvents such as ether, THF, methanol, tert.-butanol, dioxane, isopropanol, ethanol, etc. May be used a mixture of solvents. Such organic bases as lysine, arginine, diethanolamine, choline, guanidine, derivatives thereof, etc. may also be used. In the alternative, formed by the joining of acid salts, wherever they are applicable, are obtained by treatment with acids such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, n-toluensulfonate, methanesulfonate acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic to the slot, succinic acid, benzoic acid, benzolsulfonat acid, tartaric acid and the like, in solvents such as ethyl acetate, ether, alcohols, acetone, THF, dioxane, etc. the Mixture of solvents can also be used.

The stereoisomers of the compounds forming part of the present invention can be obtained by using in the process of reagents in one enantiomeric form, if possible, or by conducting the reaction in the presence of reagents or catalysts in one enantiomeric form, or by separating a mixture of stereoisomers using well-known methods. Some of the preferred methods include microbial separation, separation of the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like, wherever they are applicable, or with chiral bases such as brucine, Tikhonova alkaloids and their derivatives and the like. Applied methods typically collected Jaques and others in “Enantiomers, Racemates and Resolution” (Wiley Interscience, 1981). More specifically, the compound of formula (I), where YR10means a hydroxyl group, can be converted into a mixture of diastereomeric amides (1:1) by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; to turn to the slots in the amide can be applied normal conditions; the diastereomers can be separated or fractional crystallization or chromatography and the stereoisomers of the compounds of formula (I) can be obtained by hydrolysis of pure diastereomeric amide.

Different polymorphic forms of the compounds of General formula (I), forming part of this invention, can be obtained by crystallization of the compounds of formula (I) in various conditions. For example, by using for recrystallization, various commonly used solvents or their mixtures; by crystallization at different temperatures; various methods of cooling during crystallization, varying from very fast to very slow cooling. Polymorphic forms can also be obtained by heating or melting compounds, accompanied by gradual or fast cooling. The presence of polymorphic forms can be determined using NMR spectroscopy solid sample, IR spectroscopy, differential scanning calorimetry, x-ray structural analysis on the powder or other similar methods.

Compounds of General formula (I) applicable for treatment and/or prophylaxis of insulin resistance (type II diabetes), latinboy resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insul the new resistance, coronary heart disease and other cardiovascular disorders. These compounds can also be used as inhibitors alsoreported to improve cognitive abilities in dementia, treatment of complications of diabetes, disorders associated with activation of endothelial cells, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory diseases of the abdominal cavity, osteoporosis and cancer. Compounds of the present invention in combination with one or more inhibitors of HMG-CoA reductase inhibitors, hypolipidemic/hypolipoproteinemia agents, such as derivatives fibre acid, nicotinic acid, cholestyramine, or probucol applicable for the treatment and/or prevention of atherosclerosis and/or xanthomas. Compounds of the present invention in combination with inhibitors of HMG-CoA reductase inhibitor and/or lipid-lowering or hypolipoproteinemia agents can be administered together or within such a period of time when provided the synergy of their actions. Inhibitors of HMG-CoA reductase inhibitor can be selected from those compounds, which are used for treatment or prevention of hyperlipidemia, such as lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, tseriwastatina and their analogues. Respective derivatives fibre acid can serve as gemfibrozil, clofe the rat, fenofibrate, ciprofibrate, bezafibrate and their equivalents.

The present invention also provides pharmaceutical compositions containing compounds of General formula (I)described above, their tautomeric forms, their stereoisomers, their polymorphic forms, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvate in combination with commonly used pharmaceutical excipients, diluents and the like.

The pharmaceutical compositions can be in the form of commonly used forms, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavoring agents, sweeteners, etc. in the appropriate solid or liquid fillers or diluents, or in an appropriate sterile environment when receiving injectable solutions or suspensions. Such compositions typically contain from 1 to 20%, preferably from 1 to 10% by weight of active compounds, and the remainder of the composition is pharmaceutically acceptable excipients, diluents or solvents.

The compound of formula (I)described above, in the clinical setting introduced mammals, including humans, orally or parenterally.

It is preferable to oral administration because it is more convenient and avoids possible with injection pain and annoyed at what I do. However, under circumstances when the patient is unable to swallow medication, or in violation of the absorption after injection, as in the case of illness or other anomalies, it is important that the drug was introduced parenterally. Any method of administration the dose is in the range of from about 0.01 to about 50 mg/kg body weight of the patient per day or preferably from about 0.01 to about 30 mg/kg of body weight per day administered once or in divided doses. However, the optimal dose for each patient treatment will be determined by the person responsible for treatment, usually smaller doses entered in the first and subsequent times, allow us to determine the most appropriate dose.

Appropriate pharmaceutically acceptable fillers include particulate fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in effective amounts sufficient to provide the required dose in the range described above. Thus, for oral administration, the compound can be connected with the corresponding solid, liquid filler or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. Optionally, the pharmaceutical composition may contain additional components, the hat, as flavorings, sweeteners, fillers, and the like. For parenteral administration the compounds can be combined with sterile aqueous or organic medium to form a solution or suspension for injection. For example, can be used solutions in sesame or peanut oil, aqueous propylene glycol and the like, as well as aqueous solutions of water-soluble pharmaceutically acceptable salts formed by the addition of acid, or salts with bases. Thus obtained injectable solutions can then be administered intravenously, intraperitoneally, subcutaneously or intramuscularly, preferably by the introduction of man is intramuscular.

Information confirming the possibility of carrying out the invention

The invention is explained in detail in the following examples which are only illustrative and should not be construed as limiting the scope of the invention.

Method 1

4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]benzaldehyde

A mixture of 2H-1,4-benzoxazin-3-(4H)-she (1.6 g, 10.7 mmol), 4-(2-bromoethoxy)benzaldehyde (2.95 g, 12.8 mmol) and potassium carbonate (5,93 g, 42.97 mmol) in dry dimethylformamide (30 ml) was stirred at 80°C for 10 hours. Was added water (100 ml) and extragere the Ali ethyl acetate (2× 75 ml).

The combined organic layers were washed with water (50 ml), brine (50 ml), dried over sodium sulfate, filtered and evaporated the solvent. The residue was chromatographically on silica gel using a mixture of ethyl acetate-petroleum ether (2:8) and obtaining the target compound (2.9 g, 91%) as a colourless solid, TPL 75-78°C.

1H-NMR (Dl3, 200 MHz): 4.37 (s, 4H), 4.62 (s, 2H), 6.96-7.26 (m, 6N), of 7.82 (d, 2H, J=8.4 Hz), 9.89 (s, 1H).

Method 2

6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]cyanonaphthalene

A mixture of 2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethylmethanesulfonate (0.49 g, 1.82 mmol), 2-hydroxy-6-cyanonaphthalene (0.28 g, 1.65 mmol) and potassium carbonate (1.15 g, 8.28 mmol) in dry dimethylformamide (15 ml)was stirred at 80°C for 12 hours. Was added water (50 ml) and was extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with water (25 ml), brine (20 ml), dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was chromatographically on silica gel using a mixture of ethyl acetate-petroleum ether and obtaining the target compound (0.41 g, 72%) as a pale yellow solid, TPL 94-96°C.

1H-NMR (CDCl3, 200 MHz): 3.05 (t, 2H, J=5.21 Hz), 3.79-3.85 (m, 4H), 4.31 (t, 2H, J=5.82 Hz), 6.64-6.78 (m, 2H), 6.97-7.25 (m, 4H), 7,53-7.80 (m 3 is), 8.13 (s, 1H).

Method 3

6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthaldehyde

To a solution of 6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]cyanonaphthalene (8 g, 22.9 mmol)obtained according to method 2, in dry tetrahydrofuran (15 ml) were added diisobutylaluminium (93 ml, 20% in toluene) at -70°C for 1 hour. After addition, the reaction mixture was stirred at 25°C. for 16 hours. At the end of this period were added ethylformate (20 ml) and was stirred for 1 hour at 25°C. was Added a saturated solution of ammonium chloride (15 ml). The reaction mixture was acidified with 10% sulfuric acid and was extracted with ethyl acetate (2×75 ml). The combined organic extracts were washed with water (2×50 ml), brine (50 ml), dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure.

The residue was chromatographically on silica gel using a mixture of ethyl acetate-petroleum ether (10:90)received the target compound (4.5 g, 56%) as a pale yellow solid, TPL 100-102°C.

1H-NMR (Dl3, 200 MHz): 3.06 (t, 2H, J=5.2 Hz), 3.72-3.86 (m, 4H), 4.33 (t, 2H, J=5.67 Hz), 6.60-6.79 (m, 2H), 6.97-7.25 (m, 4H), 7.74-7.93 (m, 3H), 8.25 (s, 1H), 10.09 (s, 1H).

Method 4

4-[4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methoxybenzaldehyde

To a solution of 4-methyl-3,4-dihydro-2H-14-benzoxazin-2-methanol (6.0 g, 33.51 mmol) in dichloromethane (20 ml) were added triethylamine (10.15 g, 100.5 mmol) under nitrogen atmosphere at 25°C. To the reaction mixture were added at 0°C methanesulfonanilide (5.75 g, 50.25 mmol) and continued stirring the next 10 hours at 25°C. was Added water (50 ml) and was extracted with chloroform (2×25 ml). The combined organic attracti washed with water (50 ml), dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was chromatographically on silica gel using a mixture of ethyl acetate-hexane (2:8), was obtained (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methylmethanesulfonate (3.7 g, 43%) as syrup.

1H-NMR (CDCl3, 200 MHz): 2.88 (s, 3H), 3.07 (s, 3H), 3.13-3.31 (m, 2H), 4.41 (d, 2H, J=5.2 Hz), 4.53-4.55 (m, 1H), 6.81-6.89 (m, 4H). A mixture of (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methylmethanesulfonate (3.7 g, 14.39 mmol), 4-hydroxybenzaldehyde (2.6 g, 21.29 mmol) and potassium carbonate (5.9 g, 42.7 mmol) in dry dimethylformamide (30 ml) was stirred at 80°C for 10 hours. Was added water (100 ml) and was extracted with ethyl acetate (2×70 ml). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was chromatographically on silica gel using a mixture of ethyl acetate-petroleum ether (2:8) and receiving the target link is (1.3 g, 32%) as a thick liquid,

1H-NMR (CDCl3, 200 MHz): 2.93 (s, 3H), 3.24-3.46 (m, 2H), 4.14-4.37 (m, 2H), 4.68-4.71 (m, 1H), 6.72-7.10 (m, 6N), 7.86 (d, 2H, J=8.8 Hz), 9.92 (s, 1H).

Method 5

4-[4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methoxybenzaldehyde

The target compound (3.2 g, 80%) was obtained as a pale yellow solid from 4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-methanol (4.0 g, 15.68 mmol) in a manner similar to that described in method 4, TPL 92-94°C.

1H-NMR (Dl3, 200 MHz): 3.38-3.43 (m, 2H), 4.14-4.32 (m, 2H), 4.46 (d, 2H, J=7.8 Hz), 4.60-4.65 (m, 1H), 6.65-6.89 (m, 4H), 7.00 (d, 2H, J=8.8 Hz). to 7.32 (s, 5H), 7.83 (d, 2H, J=8.8 Hz), 9.90 (s, 1H).

Example 1

Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate

A solution of triethyl-2-ethoxypropionate (W.Grell, H.Machleidt, Annalen Chemie, 1960, 699, 53) (7.8 g, 29.1 mmol) in dry tetrahydrofuran (15 ml) was slowly added to a stirred and cooled with ice suspension of sodium hydride (60% dispersion oil) (1.39 g, 29.1 mmol) in dry tetrahydrofuran (5 ml) under nitrogen atmosphere. The mixture was stirred at 0°C for 30 minutes followed by addition of a solution of 4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]benzaldehyde (7.5 g, 26.5 mmol), which was obtained in accordance with the process described in method 1, disclosed in application for U.S. patent 08/982910, dry Tetra is drofuran (20 ml). The mixture was allowed to warm to 25°C. and stirred further for 20 hours. The solvent was evaporated, the residue suspended in water (100 ml) and was extracted with ethyl acetate (2×75 ml). The combined organic layers were washed with water (75 ml), brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was chromatographically on silica gel using a mixture of ethyl acetate-petroleum ether (2:8) as eluent, received the target compound (8.0 g, 75%) as a resinous substance in the form of a mixture of geometrical isomers in the ratio of Z:E=65:35 (R.A.Aitken, G.L.Thom, Synthesis, 1989, 958).

1H-NMR (CDCl3, 200 MHz): 1.18, 1.36 (2T, blocked, 6N, isomeric OEt, signals triplet), 3.51 (t, 2H, J=4.48 Hz), 3,71 (t, 2H, J=5.39 Hz), 3.89-4-03 (m, 2H), 4.10-4.34 (m, 6N), 6.07 (s, S, olefinic proton isomer (E), 6.63-7.14 (m, N), 7.73 (d, 2H, J=8.72 Hz).

Example 2

Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol

The mixture obtained in example 1 ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate (8.0 g, 20.0 mmol) and magnesium turnings (9.64 g, 396.7 mmol) in dry methanol (50 ml) was stirred at 25°C. for 20 hours. At the end of this period, was added water (50 ml) and brought the pH to about 7.0 using 10% aqueous hydrochloric acid, the solution was extracted with ethylacetate is (2× 10 ml). The combined organic extract was washed with water (75 ml), brine (75 ml), dried over sodium sulfate, filtered and solvent was removed under reduced pressure. The residue was chromatographically on silica gel using a mixture of ethyl acetate-petroleum ether (2:8) as eluent, received the target compound (5.0 g, 64%) as a viscous liquid.

1H-NMR (CDCl3, 200 MHz): 1.15 (t, 3H, J=7.0 Hz), 2.93 (d, 2H, J=6.64 Hz), 3.23-3.38 (m, 1H), 3.43-3.72 (m,8H), 3.97 (t, 1H, J=6.9 Hz), 4.14 (t, 2H, J=5.81 Hz), 4.19 (t, 2H, J=4.2 Hz), 6.55-6.83 (m, 6N), 7.13 (d, 2H, J=8.39 Hz).

Example 3

Ethyl(E/Z)-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropionate

The target compound (0.8 g, 58%) was obtained in the form of a resinous substance of 5-formyl-2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran (1.0 g, 3.41 mmol) by the method similar to that described in example 1.

1H-NMR (Dl3, 200 MHz): 1.06, 1.38 (2T, 6N, 2Et), 3.48 (t, 2H, J=4.98 Hz), 3.89-4.18 (m, 2H), 4.28-4.40 (m, 4H), 4.54, 4.56 (overlapped. 2H, NCH2), 6.20 (S, olefinic proton isomer (E), 6.52, 6.59 (overlapped, 1H), 6.65-6.83 (m, N), 7.08-7.11 (m, 1 H), 7.32-7.44 (m, 2H), 7.69 (d, 1H, J=8.3 Hz), 7.99 (s, 1H).

Example 4

Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate

The target compound was obtained as a mixture of geometric isomers in a ratio of 38:62 (data 1H-NMR) (3.2 g, 71%) as a resinous substance from 4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]benzaldehyde (3.3 g, 11.03 mmol), obtained in accordance with the process described in method 2, disclosed in the patent application 08/982910, according to the method similar to that described in example 1.

1H-NMR (CDCl3, 200 MHz): 1.14, 1.35 (2T, blocked, 6N, 2OEt), 3.02 (t, 2H, J=4.9 Hz), 3.69-3.88 (m, 4H), 3.92-4.03 (m, 2H), 4.12-4.33 (m, 4H), 6.06 (s, S, olefinic proton isomer (E), 6.61-7.14 (m, N), 7.73 (d, 2H, J=8.81 Hz).

Example 5

Methyl-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol

The target compound (0.6 g, 78%) was obtained in the form of a resinous substance obtained from example 3 ethyl(E/Z)-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropionate (0.8 g, 1.96 mmol) by the method similar to that described in example 2.

1H-NMR (CDCl3, 200 MHz): 1.15 (t, 3H, J=7.0 Hz). 3.07 (d, 2H, J=5.8 Hz), 3.28-to 3.67 (m, 4H), 3.70 (s, 3H), 4.03 (t, 1H, J=6.0 Hz), 4.28 (t, 2H, J=4.47 Hz), 4.54 (s, 2H), 6.52 (s, 1H), 6.62-6.89 (m, 4H), 7.10 (d, 1H, J=7.05 Hz), 7.35 (m, 2H).

Example 6

Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol

The target compound (2.3 g, 76%) was obtained as a viscous liquid obtained in example 4 ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate (3.1 g, 7.50 mmol) according to the method, anal is the same as described in example 2.

1H-NMR (CDCl3200 MHz): 1.15 (t, 3H, J=7.01 Hz), 2.93 (d, 2H, J=6.65 Hz), 3.03 (t, 2H, J=5.21 Hz), 3.23-3.41 (m, 1H), 3.52-3.80 (m, 8H), 3.97 (t, 1H, J=7.01 Hz), 4,14 (t, 2H, J=5.81 Hz), 6.61-6.82 (m, 4H), 6,92-7.05 (m, 2H), 7.13 (d, 2H, J=8.53 Hz).

Example 7

Methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol

To the solution obtained in example 2 methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate (0.6 g, 1.5 mmol) in dry tetrahydrofuran (5 ml) were added diisopropylamide lithium (0.5 ml solution in THF/hexane) at -78°C. After stirring for 1 hour at -78°C was added modesty methyl (0.75 ml), the reaction mixture was allowed to warm to room temperature (approximately 25°C.) and stirred at this temperature the next 20 hours. Was added water (20 ml), acidified 1 N. hydrochloric acid and was extracted with ethyl acetate (2×25 ml). The combined organic layer was washed with water (25 ml), brine (25 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure, obtaining the target compound (0.5 g, 80%) as oil.

1H-NMR (CDCl3, 200 MHz): 1.21 (t, 3H, J=6,97 Hz), 1.31 (s, 3H), 2.95 (s, 2H), 3.32-3.58 (m, 4H), 3.62-3.84 (m, 5H), 4.14 (t, 2H, J=5.81 Hz), 4.22 (t, 2H, J=4.25), 6.55-6.88 (m, 6N), 7.08 (d, 2H, J=8.63).

Example 8

Methyl-2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl]ethoxy]phenyl]-2-ethoxypropanol

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The target compound (0.6 g, 78%) was obtained as a brown liquid obtained from example 2 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate (0.6 g, 1.5 mmol) by the method similar to that described in example 7.

1H-NMR (Dl3, 200 MHz): 1.22 (t, 3H, J=6.96 Hz), 3.03-3.18 (m, 4H), 3.51 (t, 2H, J=4.2 Hz), 3.59-3.71 (m, 7H), 4.14 (t, 2H, J=5.81 Hz), 4.22 (t, 2H, J=4.24 Hz), 6.42 per-6.85 (m, 6N), 6.90-7.32 (m, 6N).

Example 9

Ethyl(E/Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate

The target compound (3.9 g, 97%) was obtained as a mixture of isomers E/Z ratio of 32:68 in the form of a white solid of the obtained by the method 1 4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]benzaldehyde (2.9 g, 9.7 mmol) by the method similar to that described in example 1, TPL 92-95°C.

1H-NMR (CDCl3, 200 MHz): 1.13 was 1.43 (m, 6N), 3.88-4.02 (m, 2H), 4.07-4.40 (m, 6N), 4,60 (s, 2H), 6.05 (s, S, olefinic proton isomer (E), 6.76-7.32 (m, N), 7.71 (d, 2H, J=8.72 Hz).

Example 10

Methyl-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol

The target compound (1.0 g, 51%) was obtained as colorless syrup obtained in example 9 ethyl(E/Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate (2.0 g, 4.8 mmol) by the method similar to that described in example 2.

1H-NMR (CDCl3, 200 MHz): 1.14 (t, 3H, =7.0 Hz), 2.92 (doctor 2H, J=6.6 Hz), 3.25-3.41 (m, 1H), 3.53-3.61 (m, 1H), 3.68 (s, 3H), 3.96 (t, 1H, J=7.0 Hz), 4.21-4.32 (m, 4H), 4.68 (s, 2H), 6.77 (d, 2H, J=8.63 Hz), 6.98-7.33 (m, 6N).

Example 11

Ethyl(E/Z)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropionate

The target compound in the form of a mixture of isomers E/Z ratio of 1:1 (1.74 g, 87%) was obtained as a brown syrup as described in method 3 of 6-[2-(2.3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthaldehyde (1.5 g, 4.29 mmol) by the method described in example 1.

1H-NMR (CDCl3, 200 MHz): 0.99-1.47 (m, 6N), 3.06 (t, 2H, J=4.98 Hz), 3.79-3.95 (m, 4H), 3.99-4.18 (m, 2H), 4.25-4.37 (m, 4H), 6.23 (s, S, olefinic proton isomer (E), 6.59-6.79 (m, 2H), 6.97-7.29 (m, N), 7.57-7.95 (m, 3H), 8.14 (s, 1H).

Example 12

Methyl-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol

The target compound (1.25 g, 75%) was obtained as colorless syrup obtained in example 11 ethyl(E/Z)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropionate (1.7 g, 3.67 mmol) by the method similar to that described in example 2,

1H-NMR (CDCl3, 200 MHz): 1.14 (t, 3H, J=7.06 Hz), 3.06 (t, 2H, J=5.21 Hz), 3.13 (d, 2H, J=7.15 Hz), 3.29-3.37 (m, 1H), 3.57-3.64 (m, 1H), 3.70 (s, 3H), 3.77-3.83 (m, 4H), 4.09 (t, 1H, J=7.2 Hz), 4.25 (t, 2H, J=5.81 Hz), 6.62-6.79 (m, 2H), 6.96-7.36 (m, 5H), 7.60-7.70 (m, 3H).

Example 13

Ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate

The target compound (0.14 g, 32%) was obtained as a viscous liquid of 2-(2,3-dihydro-1.4-benzoxazin-4-yl)ethylmethanesulfonate (0.36 g, 1.42 mmol), potassium carbonate (0.80 g, 5.8 mmol) and ethyl-2-hydroxy-3-(4-hydroxyphenyl)propanoate (0.3 g, 1.42 mmol), using conditions similar to those described in method 2.

1H-NMR (CDCl3, 200 MHz): 1.24 (t, ZN, J=7.15 Hz), 2.71 (d, 1H, J=6.23 Hz, exchanged with D2Oh), 2.84-3.10 (m, 2H), 3.50 (t, 2H, J=4.47 Hz), 3.67 (t, 2H, J=5.48 Hz), 4.11-4.26 (m, 6N), 4,37-4.39 (m, 1H), 6.61-6.86 (m, 6N), 7.11 (d, 2H, J=at 8.62 Hz).

Example 14

Ethyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate

The target compound (1.9 g, 17%) was obtained as a viscous liquid of 2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethylmethanesulfonate (8.2 g, 30.0 mmol), potassium carbonate (20.7 g, 150 mmol) and ethyl-2-hydroxy-3-(4-hydroxyphenyl)propanoate (6.3 g, 30.0 mmol), using conditions similar to those described in method 2.

1H-NMR (CDCl3, 200 MHz): 1.29 (t, 3H, J=7.11 Hz), 2.70-2.80 (ush. s, 1H, exchanges with D2O), 2.82-3.15 (m, 4H), 3.65-3.82 (m, 4H), 4.10-4.30 (m, 4H), 4.28-4.40 (m, 1H), 6.62-6.89 (m, 4H), 6.92-7.18 (m, 4H).

Example 15

Ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic

A solution of ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate (0.5 g, 1.34 mmol)obtained in example 13, in a dry di is ethylformate (5 ml) was added to a stirred and cooled with ice suspension of sodium hydride (60% dispersion in oil) (0.08 g, 1.66 mmol) in dry dimethylformamide (3 ml) under nitrogen atmosphere. The reaction mixture was stirred at 0°C for 30 minutes followed by the addition of benzylbromide (0.46 g, 2.69 mmol). The mixture was allowed to warm to 25°C. and continued stirring the next 18 hours. Was added water (25 ml) and was extracted with ethyl acetate (2×50 ml). The combined organic layer was washed with water (50 ml), brine (50 ml), dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was chromatographically on silica gel using a mixture of ethyl acetate-petroleum ether (2:8) as eluent, received the target compound (0.3 g) with benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic. This mixture (1:1) without separation used in example 47.

1H-NMR (CDCl3, 200 MHz): 1.23 (t, N, J=7.05 Hz), 2.99 (d, 4H, J=7.06 Hz), 3.10-3.72 (m, 8H), 4.05-4.30 (m, N), 4.32-4.71 (m, 4H), 5.13 (s, 2H), 6.55-6.89 (m, N), 7.05-7.36 (m, N).

Example 16

Ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan

The target compound (0.4 g, 52%) was obtained as a viscous liquid of 2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethylmethanesulfonate (0.46 g, 1.78 mmol), potassium carbonate (0.98 g, 7.12 mmol) and ethyl-2-butoxy-3-(4-hydroxyphenyl)propanoate (0.47 g, 1.78 mmol), using conditions similar to those outlined in the methodology 2.

1H-NMR (CDCl3, 200 MHz): 0.84 (t, 3H, J=7.53 Hz), 1.19-1.34 (m, 5H), 1.43-1.55 (m, 2H), 2.92 (d, 2H, J=6.32 Hz), 3.22-3.36 (m, 1H), 3.48-3.59 (m, 3H), 3.68 (t, 2H, J=5.82 Hz), 3.93 (t, 1H, J=6.2 Hz), 4.11-4.24 (m, 6N), 6.61-6.86 (m, 6N), 7.13 (d, 2H, J 8.3 Hz).

Example 17

Ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol

The target compound (0.31 g, 50%) was obtained as colorless syrup of 2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethylmethanesulfonate (0.35 g, 1.3 mmol), potassium carbonate (0.75 g, 5.4 mmol) and ethyl-2-hexyloxy-3-(4-hydroxyphenyl)propanoate (0.4 g, 1.3 mmol), using conditions similar to those described in method 2.

1H-NMR (Dl3, 200 MHz): 0.85 (t, 3H, J=5.72 Hz), 1.20-1.34 (m, 7H), 1.40-1.66 (m, 4H), 2.93 (d, 2H, J=6.0 Hz), 3.21-3.31 (m, 1H), 3.49-3.60 (m, 3H), 3.68 (t, 2H, J=5.72 Hz), 3.93 (t, 1H, J=5.81 Hz), 4.11-4.24 (m, 6N), 6.62-6.81 (m, 5H), 7.09-7.16 (m, 3H).

Example 18

Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropionate

The target compound (0.92 g, 58%) was obtained as a mixture of isomers E/Z (40:60) as a syrupy liquid from 4-[2-(2,3-dihydro-1.4-benzoxazin-4-yl)ethoxy]benzaldehyde (1.0 g, 3.0 mmol) and triethyl-2-phenoxypropionate (A.G.Schultz, etc., J. Org. Chem., 1983, 48, 3408) (1.3 g, 4.0 mmol) by the method similar to that described in example 1.

1H-NMR (CDCl3, 200 MHz): 1.06, 1.18 (2T, overlap, 3H, isomeric OEt), 3.43-3.57 (m, 2H), 3.64-3.75 (m, 2H, 4.06-4.28 (m, 6N), 6.60-6.90 (m, 8H), 6.94-7.12 (m, 2H), 7.22-7.45 (m, 3H), 7.64 (d, 1H, J=8.72 Hz).

Example 19

Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol

The target compound (0.49 g, 57%) was obtained as a resinous substance obtained from example 18 ethyl-(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropionate (0.9 g, 2.0 mmol) by the method similar to that described in example 2.

1H-NMR (CDCl3, 200 MHz): 3.17 (d, 2H, J=6.2 Hz), 3.50(t, 2H, J=4.3 Hz), 3.65-3.70 (m, 5H), 4.14 (t, 2H, J=5.76 Hz), 4.21 (t, 2H, J=4.15 Hz), 4.75 (t, 1H, J=6.4 Hz), 6.61-6.98 (m, N), 7.17-7.27 (m, 4H).

Example 20

Ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropionate

The target compound (3.7 g, 60%) was obtained as a mixture of isomers E/Z (35:65) as a syrupy substance of 4-[2-(2,3-dihydro-1.4-benzothiazin-4-yl)ethoxy]benzaldehyde (4.0 g, 13.0 mmol) and triethyl-2-phenoxypropionate (A.G. Schultz, and others, J. Org. Chem., 1983, 48, 3408) (5.07 g, 16.0 mmol) by the method similar to that described in example 1.

1H-NMR (Dl3, 200 MHz): 1.05-1.36 (m, 3H), 3.00-3.11 (m, 2H), 3.64-3.85 (m, 4H), 4.09-4.30 (m, 4H), 6.58-7.13 (m, 8H), 7.20-7.46 (m, 4H), 7.65 (d, 2H, J=8.7 Hz).

Example 21

Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol

The target compound (2.3 g, 64%) was obtained as smolorz the CSOs substances from the obtained in example 20 ethyl-(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropionate (3.7 g, 8.0 mmol) by the method similar to that described in example 2.

1H-NMR (CDCl3, 200 MHz): 2.99 (t, 2H, J=5.439 Hz), 3.15 (d, 2H, J=5.99 Hz), 3.60-3.78 (m, 7H), 4.13 (t, 2H. J=5.4 Hz), 4,74 (t, 1H, J=6.23 Hz), 6.58-6.89 (m, 6N), 6.90-7.06 (m,2H), 7.11-7.30 (m, 5H).

Example 22

Ethyl(E/Z)-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropionate

The target compound (0.4 g, 25%) was obtained as a mixture of isomers E/Z (1:1) in the form of a brown liquid obtained by the method 4 4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxybenzaldehyde (1.2 g, 4.24 mmol) by the method similar to that described in example 1.

1H-NMR (CDCl3, 200 MHz): 1.36 (t, 6N, J=7.1 Hz), 2.90 (s, 3H), 3.26-3.45 (m, 2H), 3.99 (K, 2H, J=7.2 Hz), 4.10-4.38 (m, 4H), 4.50-4,60 (m, 1H), 6.70 (d, 2H, J=7.47 Hz), 6.81-6.90 (m, 5H), 7.75 (d, 2H, J=8.8 Hz).

Example 23

Methyl-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol

The target compound (0.25 g, 65%) was obtained as a thick liquid obtained in example 22 ethyl(E/Z)-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropionate (0.4 g, 1.0 mmol) by a method similar to that described in example 2.

1H-NMR (CDCl3, 200 MHz): 1.16 (t, 3H, J=7.0 Hz), 2.89 (s, 3H), 2.95 (d, 2H, J=6.2 Hz), 3.19-3.41 (m, 3H), 3.55-3.66 (m, 1H), 3.70 (s, 3H), 3.95-4.24 (m, 3H), 4.60-4.64 (m, 1H), 6.64-7.08 (m, 6N), 7.15 (d, 2H, J=8.4 Hz).

Example 24

Ethyl(E/Z)-3-[4-(4-benzyl-3,4-dig the DRO-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropionate

The target compound (3.0 g, 76%) was obtained as a mixture of isomers E/Z (1:1) in the form of a syrupy liquid obtained from the method 5 4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxybenzaldehyde (3.0 g, 8.35 mmol) by the method similar to that described in example 1.

1H-NMR (CDCl3, 200 MHz): of 1.33-1.40 (m, 6N), 3.39-3.44 (m, 2H), 3.99 (K, 2H, J=7.0 Hz), 4.11-4.38 (m, 4H), 4.46 (d, 2H, J=5.0 Hz), 4.52-4.66 (m, 1H), 6.60-6.97 (m, 7H), 7.28 (s, 5H), of 7.75 (d, 2H, J=8.8 Hz).

Example 25

Methyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol

The target compound (1.5 g, 100%) was obtained from synthesized in example 24 ethyl-(E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropionate (1.5 g, 3.17 mmol) by the method similar to that described in example 2.

1H-NMR (CDCl3, 200 MHz): 1.17 (t, 3H, J=7.0 Hz), 2.96 (d, 2H, J=6.6 Hz), 3.31-3.57 (m, 3H), 3.60-3.70 (m, 1H), 3.71 (s, 3H), 3.97-4.26 (m, 3H), 4.47 (d, 2H, J=4.0 Hz), 4.56-4.61 (m, 1H), 6.68-6.90 (m, 6N), 7.15 (d, 2H, J=8.5 Hz), 7.29 (s, 5H).

Example 26

3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid

To a solution of methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate (4.7 g, 12.2 mmol)obtained in example 2 in methanol (50 ml) was added aqueous 10% sodium hydroxide (28 ml). The mixture was stirred at 25°C. in those who tell 3 hours. The solvent was removed under reduced pressure, the residue was acidified using 2 N. hydrochloric acid, was extracted with utilitatem (2×100 ml). The combined organic layers were washed with water (75 ml), brine (50 ml), dried over sodium sulfate, filtered, the solvent was evaporated under reduced pressure. The residue was chomatography on silica gel, using ethyl acetate, was obtained target compound (3.0 g, 66%) as a viscous liquid.

1H-NMR (CDCl3, 200 MHz): 1.17 (t, 3H, J=6.96 Hz), 2.85-3.12 (m, 2H), 3.40-3.61 (m, 4H), 3.69 (t, 2H, J=5.72 Hz), 4.04 (DD, 1H, J=7.38 and 4.27 Hz), proton group of COOH was not observed due to broadening.

Example 27

3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid, sodium salt

A mixture of 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.15 g, 0.4 mmol)obtained in example 26, and sodium methylate (23.4 mg) in methanol (5 ml), stirred at 25°C for 2 hours. The solvent was removed, the residue was treated with dry ether (3×10 ml). The formed precipitation was filtered, washed with dry ether (2×5 ml) and dried over pjatiokisi phosphorus in vacuum, obtaining the target compound (0.12 g, 75%) as a colorless hygroscopic solid.

1H-NMR (DMSO-d6, 200 MHz): 0.98 (t, 3H, J=6.83 Hz), 2.60-2.69 (m, 1H), 2.78-2.92 (m, 1H), 3.5-3.21 (m, 2H), 3.41-3.75 (m, 5H), 4.08-4.21 (m, 4H), 6.49-6.85 (m,6N), 7.12 (d,2H, J=Hz).

Example 28

3-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid

The target compound (0.5 g, 87%) was obtained as a resinous substance obtained from example 5 methyl-3-[2-(2,3-dihydro-1.4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropionate (0.6 g, 1.5 mmol) by the method similar to that described in example 26.

1H-NMR (CDCl3, 200 MHz): 1.26 (t, 3H, J=7.06 Hz), 3.05-3.28 (m, 2H), 3.40-3.68 (m, 4H), 4.09 (DD, 1H, J=7.47 and 4.24 Hz), 4.28 (t, 2H, J=4.15 Hz), 4.53 (s, 2H), 6.52 (s, 1H), 6.60-6.90 (m, 4H), 7.13 (d, 1H, J=8.7 Hz), 7.32-7.36 (m, 2H), COOH proton is not observed due to broadening.

Example 29

3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid

The target compound (1.4 g, 63%) was obtained as a resinous substance obtained from example 6 methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate (2.3 g, 5.73 mmol)by the method similar to that described in example 26.

1H-NMR (CDCl3, 200 MHz): 1.18 (t, 3H, J=7.0 Hz), 2.82-3.15 (m, 4H), 3.40-3.68 (m, 2H), 3.70-3.81 (m, 4H), 4.05 (DD, 1H, J=7.29 and 4.33 Hz), 4.16 (t, 2H, J=5.72 Hz), 6.68-6.74 (m, 2H), 6.81 (d, 2H, J=8.5 Hz), 6.94-7.06 (m, 2H), 7.14 (d, 2H, J=8.5 Hz), COOH proton is not observed due to broadening.

Example 30

3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol the I acid, sodium salt

The target compound (0.42 g, 81%) was obtained from the obtained in example 29 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.5 g, 1.30 mmol) by the method similar to that described in example 27.

1H-NMR (CDCl3, 200 MHz): 0.98 (t, 3H, J=7.0 Hz). 2.72-3.25 (m, 5H), 3.30-3.51 (m, 1H), 3.61-3.73 (m, 4H), 3.82-3.91 (m, 1H), 4.04 (t, 2H, J=5.72 Hz), 6.52-6.79 (m, 4H), 6.91-7.03 (m, 2H), 7.10 (d, 2H, J=8.4 Hz).

Example 31

3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane

The solution oxalicacid (0.28 g, 3.1 mmol) and 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.6 g, 1.55 mmol)obtained in example 29, in dry dichloromethane (10 ml) was heated at boiling for 2 hours. The solvent and excess oxalicacid was removed under reduced pressure. The residue was dissolved in dichloromethane and stirred with aqueous ammonia (5 ml) for 30 minutes. The reaction mixture was extracted with chloroform (2×25 ml). The combined organic layers were washed with water (25 ml), dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was chromatographically on silica gel using a mixture of ethyl acetate-petroleum ether (7:3) as eluent, received the target compound (0.32 g, 54%) as a white solid, TPL 120-12°C.

1H-NMR (CDCl3, 200 MHz): 1.15 (t, 3H, J=6.96 Hz), 2.81-3.20 (m, 4H), 3.38-3.58 (m, 2H), 3.71-3.90 (m, 4H), 3.91 (DD, 1H, J=7.38 and 3.73 Hz), 4.16 (t, 2H, J=5.58 Hz), 5.54 (USS, 1H, exchanges with D2O), 6.44 (USS, 1H, exchanges with D2Oh), 6.59-6.84 (m, 4H), 6.92-7.19 (m, 4H).

Example 32

N-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane

It chilled with ice to a solution of 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.3 g, 0.78 mmol)obtained in example 29, and triethylamine (0.162 g, 1.6 mmol) in dry chloromethane (10 ml) were added pivaloate (0.10 g, 0.86 mmol)and continued stirring for 30 minutes at 0°C. To the above reaction mixture was added methylamine (40% solution) (0.124 ml) at 25°C. and continued stirring for 1 hour at 25°C. was Added water (20 ml) and was extracted with ethyl acetate (2×20 ml). The combined organic extract was washed with water (10 ml), brine (10 ml), dried over sodium sulfate, filtered and the solvent was evaporated in vacuum under reduced pressure. The residue was chromatographically on silica gel using a mixture of ethyl acetate-petroleum ether (1:1)were the target compound as a colourless solid, TPL 80-82°C.

1H-NMR (CDCl3, 200 MHz): 1.11 (t, 3H, J=7.0 Hz), 2.76 (d, 3H, J=4.89 Hz), 2.81-2.88 (m, 1H), 3.01-3.12 (m, 3H), 3.39-3.52 (m, N), 3.70-3.81 (m, 4H), 3.86-3.91 (m, 1H), 4.14 (t, 2H, J=5.81 Hz), 6.48 (ush. s, 1H), 6.61-6.81 (m, 4H), 6.94-7.14 (m, 4H).

Example 33

3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane

The target compound (0.2 g, 80%) was obtained as a white solid from the obtained in example 26 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.25 g, 0.67 mmol) and aqueous ammonia (4 ml) by the method similar to that described in example 31, TPL 107-109°C.

1H-NMR (CDCl3, 200 MHz): 1.13 (t, 3H, J=6.96 Hz), 2.81-2.93 (m, 1H), 3.03-3.19(m, 1H), 3.34-3.59 (m, 4H), 3.69 (t, 2H, J=5.53 Hz), 3.88 (DD, 1H, J=7.43 and 3.7 Hz), 4.15 (t, 2H, J=5.58 Hz), 4.28 (t, 2H, J=4.24 Hz), 5.49 (USS, 1H, exchanges in D2O), 6.43 (USS, 1H, exchanges with D2O), 6.68-6.87 (m, 6N), 7.15 (d, 2H, J=8.49 Hz).

Example 34

N-Methyl-3-[4-[2-(2,3-dihydro-1.4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane

The target compound (0.23 g, 74%) was obtained as a white solid from the obtained in example 26 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.3 g, 0.8 mmol) and methylamine (40% solution) (2 ml) by the method similar to that described in example 32, TPL 97-99°C.

1H-NMR (CDCl3, 200 MHz): 1.14 (t, 3H, J=7.0 Hz), 2.76 (d, 3H, J=4.98 Hz), 4.80-4.90 (m, 1H), 3.02-3.14 (m, 1H), 3.35-3.45 (m, 2H), 3.52 (t, 2H, J=4.57 Hz), 3.68 (t, 2H, J=5.81 Hz), 7.88 (DD, 1H, J=7.06 and 3.74 Hz), 4.14 (t, 2H, J=5.72 Hz), 4.22 (t, 2H, J=4.15 Hz), 650 (USS, 1H), 6.55-6.89 (m, 6N), 7.11 (d, 2H, J=8.3 Hz).

Example 35

N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane

The target compound (0.25 g, 67%) was obtained as a white solid from the obtained in example 26 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.3 g, 0.8 mmol) and benzylamine (0.095 g, 0.88 mmol) by the method similar to that described in example 32, TPL 94-96°C.

1H-NMR (Dl3, 200 MHz): 1.11 (t, 3H, J=7.0 Hz), 2.82-3.18 (m, 2H), 3.40-3.55 (m, 4H), 3.70 (t, 2H, J=5.49 Hz), 3.94-3.98 (m, 1H), 4.14 (t, 2H, J=5.72 Hz), 4.23 (t, 2H, J=4.24 Hz), 4.28-4.52 (m, 2H), 6.60-6.87 (m, 6N), 7.06-7.32 (m, 7H), proton CONH not observed due to broadening.

Example 36

N-Benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane

The target compound (0.22 g, 74%) was obtained as a white solid from the obtained in example 29 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.25 g, 0.65 mmol) and benzylamine (0.076 g, 0.71 mmol) by the method similar to that described in example 32, so pl. 92-93°C.

1H-NMR (CDCl3, 200 MHz): 1.15 (t, 3H, J=7.0 Hz), 2.88-3.20 (m, 4H), 3.42-3.60 (m, 2H), 3.73-3.87 (m, 4H), 3.98-4.06 (m, 1H), 4.18 (t, 2H, J=5.72), 4.30-4.56 (m, 2H), 6,61-6.90 (m, 4H), 7.00-7.43 (m, N), proton CONH not observed due to broadening.

Example 37

2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-the l)ethoxy]phenyl]-2-ethoxypropanol acid

The target compound (0.3 g, 62%) was obtained as a viscous liquid obtained in example 7 methyl 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate (0.5 g, 1.2 mmol) by the method similar to that described in example 26.

1H-NMR (CDCl3, 200 MHz): 1.24 (m, 6N), 2.98, 3.04 (2D, 2H, J=14.1 Hz), 3.51 (t, 2H, J=4.25 Hz), 3.49-3,71 (m, 4H), 4.15 (t, 2H, J=5.63 Hz), 4.22 (t, 2H, J=4.48 Hz), 6.60-6.87 (m, 6N), 7.07 (d, 2H, J=8.67 Hz), COOH proton is not observed due to broadening.

Example 38

2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid, sodium salt

The target compound (0.12 g, 51%) was obtained as a white solid from the obtained in example 37 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.22 g, 0.57 mmol) by the method similar to that described in example 27.

1H-NMR (CDCl3, 200 MHz): 0.96-1.08 (m, 6N), 2.79 (s, 2H), 3.28-3.52 (m, 4H), 3.64 (t, 2H, J=5.3 Hz), 4.05-4.19 (m, 4H), 6.48-6.59 (m, 1H), 6.62-6.86 (m, 4H), 7.03-7.28 (m, 3H).

Example 39

2-(2-Terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid

The target compound (0.25 g, 42%) was obtained as a viscous liquid obtained in example 8 methyl-2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol is (0.6 g, 1.2 mmol) by the method similar to that described in example 26.

1H-NMR (CDCl3, 200 MHz): 1.12 (t, 3H, J=6.82), 1.65 (ush. s, 1H, exchanges with D2O), 3.11-3.42 (m, 4H), 3.50 (t, 2H, J=4.34 Hz), 3.68 (t, 2H, J=5.67 Hz), 3.70-3.89 (m, 2H), 4.14 (t, 2H, J=5.67 Hz), 4.21 (t, 2H, J-4.15 Hz), 6.62-6.86 (m, 6N), 7.03-7.12 (m, 4H), 7.18-7.30 (m, 2H).

Example 40

2-(2-Terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid, sodium salt

The target compound (0.11 g, 48%) was obtained as a white solid from the obtained in example 39 2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.22 g, 0.45 mmol) by the method similar to that described in example 27.

1H-NMR (CDCl3, 200 MHz): 1.02 (t, 3H, J=6.65 Hz), 2.75-2.92 (m, 4H), 3.39-3.58 (m, 4H), 3.62 (USS, 2H), 4.04-4.20 (m, 4H), 6.49-6.82 (m, 5H), 6.90-7.28 (m, 6N), 7.49-7.13 (m, 1H).

Example 41

3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid

The target compound (0.75 g, 77%) was obtained as a white solid from the obtained in example 10 methyl-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate (1.0 g, 2.5 mmol) by the method similar to that described in example 26, TPL 90-93°C.

1H-NMR (DCl3, 200 MHz): 1.18 (t, 3H, J=6.96 Hz), 2.88-3.13 (m, 2H), 3,41-3.63 (m, 2H), 4.06 (DD, 1H, J=7.43 and 4.33 Hz), 4.25-4.52 (m, 4H), 4.61 (s, 2H), 6.80 (d, 2H, J=at 8.62 G is), 7.00-7.34 (m, 6N), the COOH proton is not observed due to broadening.

Example 42

3-[4-[2-(3-Oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid, sodium salt

The target compound (0.12 g, 56%) was obtained as a white solid from the obtained in example 41 3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.2 g, 0.51 mmol) by the method similar to that described in example 27.

1H-NMR (CDCl3, 200 MHz): 0.99 (t, 3H, J=6.97 Hz), 2.61-2.80 (m, 2H), 3.32-3.57 (m, 1H), 3.60-3.72 (m, 1H), 3.65-3.70 (m, 1H), 4.18 (USS, 2H), 4.30 (USS, 2H), 4.68 (s, 2H), 6.78 (d, 2H, J=8.4 Hz), 7.03-7.14 (m, 5H), 7.42 (d, 1H, J=7.06 Hz).

Example 43

3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid

The target compound (0.8 g, 69%) was obtained as a white solid from the obtained in example 12 methyl-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropionate (1.2 g, 2.66 mmol) by the method similar to that described in example 26, so pl. 102-104°C.

1H-NMR (CDCl3, 200 MHz): 1.15 (t, 3H, J=7.01 Hz), 3.06 (t, 2H, J=4.98 Hz), 3.08-3.63 (m, 4H), 3.77-3.83 (m, 4H), 4.15 (DD, 1H, J=4.15 and 4.18 Hz), 4.28 (t, 2H, J=5.95 Hz), 6.59-6.79 (m, 2H), 6.96-7.36 (m, 5H), 7.61-7.79 (m, 3H), the COOH proton is not observed due to broadening.

Example 44

3-[6-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid, sodium Sol is

The target compound (0.16 g, 76%) was obtained as a white solid from the obtained in example 43 3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid (0.2 g, 0.457 mmol) by the method similar to that described in example 27, TPL 138-140°C.

1H-NMR (DMSO-d6, 200 MHz): 0.98 (t, 3H, J=7.06 Hz), 2.72-2.90 (m, 1H), 2.92-3.21 (m, 3H), 3.32-3.54 (m, 2H), 3.61-3.91 (m, 5H), 4.28 (USS, 2H), 6.56 (t, 1H, J=7.00 Hz), 6.73-7.00 (m, 3H), 7,05-7.30 (m, 2H), 7.38 (d, 1H, J=8.3 Hz), 7.60-7.82 (m, 3H).

Example 45

3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic acid

The target compound (0.06 g, 43%) was obtained as a brown viscous liquid obtained in example 13 ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate (0.15 g, 0.40 mmol) by the method similar to that described in example 26.

1H-NMR (Dl3, 200 MHz): 2.85-3.19 (m, 2H), 3.43 (t, 2H, J=4.15 Hz), 3.61 (t, 2H, J=5.49 Hz), 4.07 (t, 2H, J=5.40 Hz), 4.16 (t, 2H, J=4.48 Hz), 4.45 (ush. s, 1H), 6.50-6.82 (m, 6N), 7.08 (d, 2H, J=7.88 Hz), COOH protons and IT is not observed due to broadening.

Example 46

3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic acid

The target compound (0.7 g, 46%) was obtained as a white solid from the obtained in example 14 ethyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ATOC and]phenyl]-2-hydroxypropanoate (1.7 g, 4.39 mmol) by the method similar to that described in example 26, TPL 74-76°C.

1H-NMR (CDCl3, 200 MHz): 2.88-3,18 (m, 4H), 3.69-3.79 (m, 4H), 4.15 (t, 2H, J=5.72 Hz), 4.45 (DD, 1H, J=6.73 and 4.79 Hz), 4.51-4.97 (USS, 1H, exchanges with D2o), 6.65-6.89 (m, 4H), 6.94-7.17 (m, 4H), COOH proton is not observed due to broadening.

Example 47

3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic acid

The target compound (0.15 g, 67%) was obtained as a thick liquid obtained in example 15 ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic (0.24 g, 0.52 mmol) by the method similar to that described in example 26.

1H-NMR (CDCl3, 200 MHz): 1.40-2.80 (USS, 1H, exchanges with D2O), 2.99-3.18 (m, 2H), 3.51 (t, 2H, J=4.34 Hz), 3.70 (t, 2H, J=5.82 Hz), 4.13-4.24 (m, 5H), 4.51 (d, 2H, J=17.0 Hz), 6,60-6,89 (m, 6N), 7.10-7.37 (m, 7H).

Example 48

3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic acid, sodium salt

The target compound (0.1 g, 73%) was obtained as a hygroscopic solid cream color of the data obtained in example 47 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic acid (0.13 g, 0.30 mmol) by the method similar to that described in example 27.

1H-NMR (DMSO-d6, 200 MHz): 2.62-2.74 (m, 1H), 2.89-2.98 (m, 1H), 3.48 (t, 2H, J=4.2 Hz), 3.67 (t, N, J=5.48 Hz), 4.12-4.26 (m, 5H), 4.65 (d, 2H, J=12.45 Hz), 6.45-6.84 (m, 6N), 7.12-7.25 (m, 7H).

Example 49

3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan acid

The target compound (0.25 g, 67%) was obtained as a viscous liquid obtained in example 16 ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan (0.4 g, 0.93 mmol) by the method similar to that described in example 26.

1H-NMR (CDCl3, 200 MHz): 0.87 (t, 3H, J=7.15 Hz), 1.25-1.40 (m, 2H), 1.49-1.66 (m, 2H), 2.95-3.15 (m, 2H), 3.43-3.53 (m, 4H), 3.68 (t, 2H, J=5,49 Hz), 4.00-4.12 (m, 1H), 4.14 (t, 2H, J=5.65 Hz), 4.22 (t, 2H, J=4.25 Hz), 6.60-6,89 (m, 6N), 7.12 (d, 2H, J=8.39 Hz), COOH proton is not observed due to broadening.

Example 50

3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan acid, sodium salt

The target compound (0.12 g, 57%) was obtained as a hygroscopic solid cream color of the data obtained in example 49 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan acid (0.2 g, 0.5 mmol) by the method similar to that described in example 27.

1H-NMR (DMSO-d6, 200 MHz): 0.78 (t, 3H, J=7.06 Hz), 1.16-1.56 (m, 4H), 2.52-2.64 (m, 1H), 2.79-2.87 (m, 1H), 2.99-3,18 (m, 2H), 3.40 (USS, 2H), 3.66 (t, 2H, J=5.31 Hz), 4.10-4.25 (m, 5H), 6.52-6.90 (m, 6N), 7.12 (d, 2H, J=8.3 Hz).

Example 51

3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol Isleta

The target compound (0.17 g, 60%) was obtained as a greenish liquid from the obtained in example 17 ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol (0.3 g, 0.65 mmol) by the method similar to that described in example 26.

1H-NMR (CDCl3, 200 MHz): 0.86 (t, 3H, J=5.72 Hz), 1.25-1.33 (m, 4H), 1.41-1.75 (m, 4H), 2.94-3.06 (m, 2H), 3.36-3.58 (m, 4H), 3.68 (t, 2H, J=5.49 Hz), 4.01-4.06 (m, 1H), 4.14 (t, 2H, J=5.7 Hz), 4.22 (t, 2H, J=4.15 Hz), 6.71-7.08 (m, 6N), 7.12 (d, 2H, J=8.4 Hz), COOH proton is not observed due to broadening.

Example 52

3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol acid, sodium salt

The target compound (0.1 g, 52%) was obtained as a white hygroscopic solid from the obtained in example 51 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol acid (0.18 g, 0.42 mmol) by the method similar to that described in example 27.

1H-NMR (DMSO-d6, 200 MHz): 0.82 (t, 3H, J=5.72 Hz), 1.10-1.45 (m, 8H), 2.75-2.96 (m, 2H), 3.35-3.56 (m, 4H), 3.67 (t, 2H, J=5.3 Hz), 4.08-4.21 (m, 5H), 6.50-6.82 (m, 6N), 7.12 (d, 2H, J=8.0 Hz).

Example 53

3-[4-[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid

The target compound (0.1 g, 53%) was obtained as colourless liquid obtained in example 19 methyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-the l)ethoxy]phenyl]-2-phenoxypropionate (0.2 g, 0.461 mmol) by the method similar to that described in example 26.

1H-NMR (CDCl3, 200 MHz): 2.40-2.80 (USS, 1H, exchanges with D2O), 3.22 (d, 2H, J=5.8 Hz), 3.49 (t, 2H, J=4.25 Hz), 3.67 (t, 2H, J=5.81 Hz), 4.14 (t, 2H, J=5.81 Hz), 4.21 (t, 2H, J=4.16 Hz), 4.82 (t, 1H, J=5.9 Hz), 6.61-7.02 (m, 8H), 7.17-7.30 (m, 5H).

Example 54

3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid

The target compound (0.2 g, 51%) was obtained as a resinous solid matter from the obtained in example 21 methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropionate (0.4 g, 0.9 mmol) by the method similar to that described in example 26.

1H-NMR (CDCl3, 200 MHz): 3.02 (t, 2H, J=5.0 Hz), 3.22 (d, 2H, J=6.25 Hz), 3.68-3.78 (m, 4H), 4,14 (t, 2H, J=5.81 Hz), 4.50 (t, 1H, J=6.19 Hz), 4.90-5.40 (USS, 1H, exchanges with D2Oh), 6.58-6.86 (m, 7H), 6.94-7.07 (m, 2H), 7.18-7.29 (m, 4H).

Example 55

3-[4-[2-(2,3-Dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid, sodium salt

The target compound (0.05 g, 48%) was obtained as a hygroscopic solid from the obtained in example 53 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid (0.1 g, 0.24 mmol) by the method similar to that described in example 27.

1H-NMR (DMSO-d6, 200 MHz): 2.81-3.09 (m, 2H), 3.42 (USS, 2H), 3.65 (t, 2H, J=4.5 Hz), 4.12 (USS, 4H), 4.22-4.32 (m, 1H), 6.50-6.92 (m, N), 7.10-7.33 (m, 5H).

Example 56

Methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol

The target compound (0.27 g, 87%) was obtained as a viscous liquid obtained in example 19 methyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropionate (0.3 g, 0.69 mmol) by the method similar to that described in example 7.

1H-NMR (CDCl3, 200 MHz): 1.39 (s, 3H), 3.09, 3.26 (2D, 2H, J=13.7 Hz), 3.51 (t, 2H, J=4.3 Hz), 3.66-3.73 (m, 5H), 4.15 (t, 2H, J=5.5 Hz), 4.22 (t, 2H, J=4.24 Hz), 6.61-7.01 (m, N), 7.12-7.22 (m, 4H).

Example 57

2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid

The target compound (0.13 g, 50%) was obtained as a pale yellow hygroscopic solid from the obtained in example 56 methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropionate (0.27 g, 0.60 mmol) by the method similar to that described in example 26.

1H-NMR (Dl3, 200 MHz): 1.42 (s, 3H), 3.12-3.29 (2D, 2H, J=14.1 Hz), 3.50 (t, 2H, J=4.5 Hz), 3.69 (t, 2H, J=5.6 Hz), 4.16 (t, 2H, J=5.81 Hz), 4.22 (t, 2H, J=4.5 Hz), 6.62-7.17 (m, N), 7.21-7.30 (m, 4H), COOH proton is not observed due to broadening.

Example 58

2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid, sodium salt

The target compound (0.055 g, 46%) gender is made in the form of a pale yellow hygroscopic powder obtained in example 57 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid (0.13 g, 0.28 mmol) by the method similar to that described in example 27.

1H-NMR (Dl3, 200 MHz): 1.15 (s, 3H), 2.99-3.21 (m, 2H), 3.47 (ush. s, 2H), 3.67 (ush. s, 2H), 4.14 (ush. s, 4H), 6.53-6.9 (m, N), 7.08-7.30 (m, 4H).

Example 59

Methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol

The target compound (0.96 g, 93%) was obtained as a pale yellow liquid obtained in example 21 methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropionate (1.0 g, 2.22 mmol) by the method similar to that described in example 7.

1H-NMR (CDCl3, 200 MHz): 1.40 (s, 3H), 3.03 (t, 2H, J=4.9 Hz), 3.09, 3.27 (2D, 2H, J=13.7 Hz), 3.70-3.85 (m, 7H), 4.16 (t, 2H, J=5.81 Hz), 6.60-6.89 (m, 6N), 6.96-7.30 (m, 7H).

Example 60

2-Methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid

The target compound (0.6 g, 65%) was obtained as a viscous liquid obtained in example 59 methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropionate (0.96 g, 2.00 mmol) by the method similar to that described in example 26.

1H-NMR (CDCl3, 200 MHz): 1.42 (s, 3H), 3.03 (t, 2H, J=5.0 Hz), 3.12, 3.30 (2D, 2H, J=13.8 Hz), 3.70-3.80 (m, 4H), 4.15 (t, 2H, J=5.5 Hz), 6.58-7.08 (m, 8H), 7.18-7.30 (m, 5H), COOH proton is not observed due to broadening.

Example 61

4-Nitrophenyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ataxia anout

The target compound (0.15 g, 38%) was obtained as a yellow liquid obtained from example 29 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid (0.3 g, 0.77 mmol) and 4-NITROPHENOL by method similar to that described in example 32.

1H-NMR (CDCl3, 200 MHz): 1.24 (t, 3H, J=6.92 Hz), 3.04 (t, 2H, J=5.16 Hz), 3.12 (d, 2H, J=6.63 Hz), 3.46-3.65 (m, 1H), 3.70-3.86 (m, 5H), 4.16 (t, 2H, J=5.23 Hz), 4.26 (t, 1H, J=5.5 Hz), 6.62-6.74 (m, 2H), 6.84 (d, 2H, J=At 8.62 Hz), 6.94-7.22 (m, 6N), 8.23 (d, 2H, J=9.0 Hz).

Example 62

3-[4-(4-Benzyl-3,4-dihydro-2H-1,4-benzothiazin-2-yl)methoxyphenyl]-2-ethoxypropanol acid

The target compound (0.4 g, 57%) was obtained as a viscous liquid obtained in example 25 methyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropionate (0.8 g, 2.16 mmol) by the method similar to that described in example 26.

1H-NMR (CDCl3, 200 MHz): 1.17 (t, 3H, J=7.0 Hz), 2.99-3.13 (m, 2H), 3.31-3.65 (m, 4H), 4.01-4.24 (m, 3H), 4.45 (d, 2H, J=3.4 Hz), 4.52-4.59 (m, 1H), 6.62-6.68 (m, 6N), 7.14 (d, 2H, J=8.6 Hz), 7.27 (s, 5H), COOH proton is not observed due to broadening.

Example 63

3-[4-(4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol acid, sodium salt

The target compound (0.15 g, 75%) was obtained as a colorless hygroscopic solid substance resulting from the use of the e 62 3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-4-yl)methoxyphenyl]-2-ethoxypropanol acid (0.2 g, 0.44 mmol) by the method similar to that described in example 27.

1H-NMR (DMSO-d6, 200 MHz): 0.99 (t, 3H, J=6.97 Hz), 2.60-2.90 (m, 2H), 3.30-3.65 (m, 5H), 4.16 (d, 2H, J=5.0 Hz), 4.40-4.65 (m, 3H), 6.55-6.89 (m, 6N), 7.14 (d, 2H, J=8.5 Hz), 7.32 (s, 5H).

Example 64

4-Nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol

The target compound (0.6 g, 100%) was obtained as a dark brown liquid obtained in example 62 3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol acid (0.5 g, 1.34 mmol) and 4-NITROPHENOL by method similar to that described in example 32.

1H-NMR (CDCl3, 200 MHz): 1.25 (t, 3H, J=7.0 Hz), 3.14 (d, 2H, J=6.6 Hz), 3.33-3.55 (m, 3H), 3.69-3.77 (m, 1H), 4.05-4.31 (m, 3H), 4.46 (d, 2H, J=3.4 Hz), 4.55-4.61 (m, 1H), 6.63-6.68 (m, 6N), 7.11-7.28 (m, 7H), 7.52 (d, 2H, J=7.6 Hz), 8.23 (d, 2H, J=9.0 Hz).

Compounds of the present invention reduced arbitrarily chosen level of blood sugar, triglycerides, total cholesterol, LDL, VLDL and increased level of HDL. This was demonstrated in experiments in vitro and in vivo.

To demonstrate the efficiency of connections

A) In vitro

a) Determination of the activity of hPPRα

A ligand-binding domain hPPRα combined with the yeast transcription factor GAL4 in a eukaryotic expression vector. Using superfect (Quiagen, Germany) as transfairusa reagent cell line SOME 293 was transfusional this plasmid and reporter plasmid, carrying luciferase gene controlled by specific GAL4 promoter. The compound was added at different concentrations after 24 hours of transfection and incubated overnight. Luciferase activity was measured as a function of the link connection/activation ability PPRαusing the set of Packard Luclite (Packard company, USA) in the counter Top Count (I.Sadowski, .Bell, P.Broag, M.Hollis. Gene, 1992, 118:137-141; Superfect Transfection Reagent Handbook. February, 1997. Quiagen, Germany).

b) determining the activity hPPRγ

A ligand-binding domain hPPRγ combined with the yeast transcription factor GAL4 in a eukaryotic expression vector. Using lipofectamine (Gibco BRL, USA) as transfairusa reagent cell line SOME 293 was transfusional this plasmid and a reporter plasmid carrying the gene luciferase controlled by specific GAL4 promoter. The compound was added at a concentration of 1 μm at 48 hours after transfection and incubated overnight, Luciferase activity was measured as a function of the binding of the drug/activation ability PPRγusing the set of Packard Luclite (Packard company, USA) in the counter Packard Top Count (I.Sadowski, B.Bell, P.Broag, M.Hollis. Gene, 1992, 118:137-141; Guide to Eukaryotic Transfections with Cationic Lipid Reagents. Life Technologies, GIBCO BRL, USA).

C) Determination of inhibitory activity against HMG-CoA reductase inhibitor

Reductase-related liver microsomes were obtained from rats fed with feed 2% cholestyramine with medium-dark cycle. Spectrophotometric measurements were carried out in a mixture consisting of 10 mm KN2RHO4, 4 mm DTT, 0.2 mm NADPH, 0.3 mm HMG-CoA and 125 μg of the enzyme from liver microsomes. The total volume of the reaction mixture was 1 ml Reaction was started by addition of HMG-CoA. The reaction mixture was incubated at 37°C for 30 minutes and record the decrease in absorption at 340 nm. The reaction mixture without substrate was used as blind samples (J.L, Goldstein, M.S. Brown. “Progress in understanding the LDL receptor and HMG-CoA-reductase, two membrane proteins that regulate the plasma cholesterol” J. lipid Res. 1984, 25:1450-1461). The compounds inhibit the enzyme HMG-CoA-reductase.

B) In vivo

a) Effectiveness in animal models of

Mutations in colonies of laboratory animals and different sensitivity to food regimes has led to the creation of animal models of non-insulin-dependent diabetes and hyperlipidemia associated with obesity and possible insulin resistance. In different laboratories were established genetic models, such as mice db/db and ob/ob (Diabetes, 1982, 31(1):1-6) and rats Zucker fa/fa, for understanding the pathophysiology of the disease and determine the effectiveness of new anti-diabetic compounds (Diabetes, 1983, 32:830-838; Ann. Rep, Sankyo Res. Lab., 1994, 46:1-57). Homozygous animals, mice C57BL/KsJ-db/db obtained in the Jackson Laboratory, USA, characterized by obesity, hyperglycemia, hyperinsulinemia and insulin resistance J. Clin. Inest., 1990, 85:962-967), whereas heterozygotes are characterized by thinness and normal glycemia. Model db/db mice with progressive age evolves insulinopenia, a characteristic that is usually observed at the late stage of type II diabetes in humans, when blood sugar levels are controlled is not enough. The condition of the pancreas and its function changes depending on the model. Because this model is reminiscent of diabetes mellitus type II, the compounds of the present invention were tested for activity associated with reduced sugar and triglycerides in the blood.

In the experiment used mice male C57BL/KsJ-db/db in age from 8 to 14 weeks, with a weight in the range from 35 to 60 g, bred in the kennel Dr. Reddy's Research Foundation (DRF). Mice received standard feed (from the National Institute of nutrition (NIN), Hyderabad, India) and acidified water at the contractor's discretion. For studies used animals with more than 350 mg/gave blood sugar. Each group consisted of 4 animals.

The compounds suspended in 0.25% carboxymethylcellulose and introduced the study group in a dose of from 0.1 mg/kg to 30 mg/kg via oral probe daily for 6 days. The control group received the filler (in a dose of 10 ml/kg). On the sixth day, one hour after administration of the compounds or filler took blood samples for cancerologia activity.

Random blood sugar levels and triglyceride levels were measured by taking blood (100 μl) via the orbital sinus using heparinized capillary, in tubes containing EDTA, which was centrifuged to obtain plasma. The levels of glucose and triglycerides in plasma were determined spectrophotometrically by glucose oxidase and glycerol-3-phosphokinase/peroxidase (sets Dr. Reddy's Laboratory, Diagnostic Division, Hyderabad, India).

The activity of the compounds in reducing blood sugar levels and triglyceride levels was calculated by the formula.

In the above experience was not observed any side effects for any of the aforementioned compounds according to the invention.

ConnectionDose (mg/kg)Reducing the level of glucose in the blood (%)Reduction of triglycerides(%)
Example 4135327
Example 5034523
Example 44104774

Mice ob/ob received five weeks of age from the company Bomholtgard (Denmark) and used at the age of 8 weeks. Fatty rats Zucker fa/fa received from the company IffaCredo (France) at ten weeks of age and used in age is 13 weeks. Animals were kept under 12-hour light-dark cycle at 25±1°C. Animals were given standard laboratory feed (NIN, Hyderabad, India) and water at the discretion of the contractor (.Fujiwara, S.Yoshioka, .Yoshioka, I.Ushiyama, H.Horikoshi. “Characterization of new oral antidiabeticagent CS-045”. Research on the KK mice and ob/ob and fatty Zucker rats.” Diabetes, 1988, 37:1549-1558).

The investigated compounds were administered at a dose of 0.1-30 mg/kg/day for 9 days. Control animals received the filler (0.25% CMC, 10 ml/kg) via oral probe.

Blood samples were taken from well-fed animals after 1 hour after drug administration on zero and the ninth day of treatment. Blood was taken from the retro-orbital sinus through heparinised capillary in tubes containing EDTA. After centrifugation, the plasma samples were divided into parts to determine triglycerides, glucose, free fatty acids, total cholesterol and insulin. Measurement of plasma triglycerides, glucose, total cholesterol was performed using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, Hyderabad, India). The free fatty acid in plasma was determined using a commercial kit from the company, Boehringer Mannheim, Germany. Insulin in plasma was determined using kit RIA (radioimmunoassay) (BARC, India). The reduction of the investigated parameters was calculated by the formula below.

In mice ob|ob test the endurance of the input oral glucose was carried out in 9 days of treatment. Mice were subjected to a five-hour starvation and were loaded with 3 mg/kg oral glucose. After 0, 15, 30, 60 and 120 minutes took blood samples to determine the levels of glucose in plasma.

Results of experiments with mice, db/db, ob|ob rats and Zucker fa/fa anticipate that the new compounds of the present invention also have therapeutic applications for the prevention or regular treatment of diabetes, obesity, cardiovascular disorders such as hypertension, hyperlipidemia and other diseases; from literature it is known that these diseases are interrelated.

The levels of blood glucose and triglyceride levels also reduced at doses above 10 mg/kg Usually decrease curve is partially dose-dependent and at a certain dose enters the plateau.

b) Activity to reduce levels of plasma triglycerides and cholesterol on hypercholesterinemia rat models

Rats-males line Sprague Dawley (NIN) were bred in the kennel DRF. Animals were kept under 12-hour light-dark cycle at 25±1°C. In the experiments used rats weighing 180-200 g In animals caused hypercholesterolemia, by feeding them with 2% cholesterol and 1% Holt sodium, mixed with standard laboratory food (national Institute of nutrition (NIN), Hyderabad, ind is I) within 6 days. Throughout the experiment the animals were kept on the same diet (D.Petit, V.N.Bonnefis, .Rey, R.Inflante. “Effects of ciprofibrate on liver lipids and lipoprotein synthesis in normo - and hyperlipidemic rats”. Atherosclerosis. 1988, 74:215-225).

The compounds were administered orally at a dose of 0.1-30 mg/kg/day for 3 days. The control group received only the filler (0.25% carboximetilzellulozu; dose 10 ml/kg).

Blood samples were taken from well-fed animals after 1 hour after drug administration on zero and the third day of treatment. Blood was taken from the retro-orbital sinus through heparinised capillary in tubes containing EDTA. After centrifugation, the plasma samples were divided into parts to determine total cholesterol, HDL and triglycerides. Measurement of plasma triglycerides, total cholesterol and HDL was performed using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, Hyderabad, India). Cholesterol LDL and VLDL was calculated on the basis of the data obtained for total cholesterol, HDL and triglycerides. The reduction of the different studied parameters was calculated by the formula.

Example No.Dose mg/kgTriglyceride (%) ↓Total cholesterol (%) ↓HDL (%) ↑LDL (%) ↓VLDL (%) ↓
Example 27157375879
Example 4415042464453
↓ - decrease; ↑ - increase

in) Activity decreased levels of plasma triglycerides and total cholesterol in mice Swiss albino and Guinea pigs

Of male mice of the line Swiss albino (SAM) and Guinea pigs (males) were obtained from NIN and were kept in a vivarium DRF. All these animals were kept under 12-hour light-dark cycle at 25±1°C. Animals were given standard laboratory feed (NIN, Hyderabad, India) and water at the contractor's discretion. Used SAM weighing 20-25 g and Guinea pigs weighing 500-700 g (.Oliver, M.O.Plancke, D.Marzin, V.Clavey, J.Sauzieres, J.C.Fruchart. “Effects of fenofibrate, gemfibrozil and nicotinic and on plasma lipoprotein levels in normal and hyperlipidemic mice”. Atherosclerosis. 1988, 70:107-114).

The compounds were administered orally to mice Swiss albino dose of 0.3-30 mg/kg/day for 6 days. The control group received only the filler (0.25% carboxymethylcellulose; a dose of 10 ml/kg). The compounds were administered orally Guinea pigs at a dose of 0.3-30 mg/kg/day for 6 days. The control group received only the filler (0.25% carboxymethylcellulose; dose 5 ml/kg).

Blood samples were taken from well-fed animal is x 1 hour after drug administration on zero and the sixth day of treatment. Blood was taken from the retro-orbital sinus through heparinised capillary in tubes containing EDTA. After centrifugation, the plasma samples were divided into parts to determine triglycerides, and total cholesterol (O. Wieland. “Methods of Enzymatic analysis”. The CONCENTRATION Bergermeyer, Ed., 1963, 211-214; P.Trinder, Ann. Clin. Biochem., 1969, 6:24-27). Measurement of plasma triglycerides, total cholesterol and HDL was performed using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, Hyderabad, India).

ConnectionDose (mg/kg)The decrease in triglycerides (%)
Example 33355
Example 411054
Example 43349
Example 63357

g) the Effect of reducing body weight in hamsters fed cholesterol

Syrian hamsters-males were obtained from NIN, Hyderabad, India. Animals were kept in a vivarium DRF with 12-hour light-dark cycle at 25±1°C with free access to feed and water. From the first day of the experience, the animals received standard laboratory feed (NIN)containing 1% cholesterol.

The compounds were administered orally at a dose of 1-30 mg/kg/day for 15 days. The control group received only the filler (in the near Mill Q; the dose of 10 ml/kg/day). Body weight was measured every third day.

# exampleDose (mg/kg/day)The decrease in body weight (%)
Example 271012
Example 301018

Formula for calculation:

1. The percentage reduction in blood sugar/triglycerides/cholesterol/body weight was calculated by the formula:

OS - the value of the control group in the zero day

FROM - value of the treated group in the zero day

TC - value of the control group on the day of the experience

TT - value of the treated group at day experience

2. The levels of LDL cholesterol and VLDL was calculated by the formula:

The VLDL cholesterol in mg/dal = total cholesterol - HDL cholesterol - LDL cholesterol.

1. The compound of formula (I)

where the group R1, R2, R3, R4group and R5and R6when they are attached to the carbon atom may be the same or different and mean hydrogen, halogen, hydroxy or optionally substituted group selected from alkyl, alkoxy, phenyl, carboxylic acid or sulfonic acid; one or both of the substituent R5and R6could the t also mean oxoprop, if they are attached to the carbon atom; R5and R6if they are attached to the nitrogen atom, denote a hydrogen, hydroxy or optionally substituted alkyl or benzyl; x is the heteroatom selected from oxygen, sulfur or NH; AG means optionally substituted divalent single or condensed aromatic or heterocyclic group in which the aromatic ring is a phenyl, naphthyl, and heterocyclic group represents a furan; R7means hydrogen, halogen, alkoxy, alkyl, or forms a bond together with the adjacent group, R8; R8means hydrogen, hydroxy, alkoxy, alkyl or optionally substituted benzyl, or R8forms a bond together with R7; R9means hydrogen or optionally substituted group selected from alkyl, phenyl or benzyl groups; R10means hydrogen or optionally substituted group selected from alkyl, phenyl or benzyl groups; Y represents oxygen or NR12where R12means hydrogen, alkyl or benzyl; R10and R12together may form a five - or six-membered cyclic structure containing carbon atoms, which optionally contains one or more heteroatoms selected from oxygen, sulfur or nitrogen; the linking group represented by formula (CH 2)n-(O)m-can be attached to or through the nitrogen atom or via a carbon atom, n indicates an integer variable in the range of 1-4, and m means an integer from 0 to 1; provided that when linking group attached through a carbon atom and either R5or R6is oxoprop, a Y represents oxygen, R9is not hydrogen, or its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphic forms, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvate.

2. The compound according to claim 1, where if the groups denoted by R1-R4and the group R5and R6,United with the carbon atom are substituted, the substituents can be selected from halogen, hydroxy, alkyl or alkoxy.

3. The compound according to claim 1, where if the group R5and R6connected to the nitrogen atom are substituted, the substituents are selected from halogen, hydroxyl, acyl, or amino group.

4. The compound according to claim 1, where the substituents for the group denoted by R9choose from halogen, hydroxy, alkoxy, alkyl, aryl, heterocyclyl, heteroaryl or amino.

5. The method of obtaining the compounds of formula (I)

where R1, R2, R3, R4, R5, R6, n, m, AG, X, R 9and R10have the meanings given in claim 1; R7and R8together denote a bond; Y represents oxygen; the linking group represented by formula -(CH2)n-(O)m-can be attached to or through the nitrogen atom or via a carbon atom, provided that when linking group attached through a carbon atom and either R5or R6represents an oxo group, R9is not hydrogen, including

a) interaction of the compounds of formula (IIIA)

where all symbols are defined above,

with the compound of the formula (IIIb)

where R9and R10defined above

and R14means (C1-C6)-alkyl,

with the formation of the compounds of formula (I), above; and optional

b) the conversion of the compounds of formula (I) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

6. The method of obtaining the compounds of formula (I)

where R1, R2, R3, R4, R5, R6, n, AG, X, R9and R10have the meanings given in claim 1; R7and R8together denote a bond; Y represents oxygen; the linking group represented by the formula is y -(CH 2)n-(O)m-can be attached to or through the nitrogen atom or via a carbon atom and m is 1, provided that when linking group attached through a carbon atom and either R5or R6is oxoprop, R9is not hydrogen, including

a) interaction of the compounds of formula (IIIh)

where all symbols previously defined, and L1means a leaving group,

with the compound of the formula (IIIi)

where R7and R8together denote a bond, R9, R10and ar have the previously indicated meanings,

with the formation of the compounds of formula (I), above; and optional

b) the conversion of the compounds of formula (I) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

7. The method of obtaining the compounds of formula (I)

where R1, R2, R3, R4, R5, R6, n, Ar, X, R9and R10have the meanings given in claim 1; R7and R8together denote a bond; Y represents oxygen; the linking group represented by formula -(CH2)n-(O)m-can be attached to or through the nitrogen atom or via a carbon atom, and m means 1At condition, when linking group attached through a carbon atom and either R5or R6represents an oxo group, R9is not hydrogen

including

a) interaction of the compounds of formula (IIIj)

where all symbols are defined above,

with the compound of the formula (IIIi)

where R7and R8together denote a bond, R9, R10and ar have the previously indicated meanings,

with the formation of the compounds of formula (I), above; and, optionally,

b) the conversion of the compounds of formula (I) into a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

8. The method of obtaining the compounds of formula (I)

where R1, R2, R3, R4, R5, R6, n, m, Ar, X, R9and R10have the meanings given in claim 1; R7and R8mean hydrogen; Y represents oxygen; the linking group represented by formula -(CH2)n-(O)m-can be attached to or through the nitrogen atom or via a carbon atom, provided that when linking group attached through a carbon atom, or R5or R6is oxoprop, R9is not the water is born

including:

a) restoring the compounds of formula (IVa)

which means the compound of formula (I), where R7and R8together denote a bond, Y represents oxygen, and all other symbols are defined above,

received via any of the methods described in pp.5-7, with the formation of the compounds of formula (I), where R7and R8each means hydrogen and all other symbols are defined above; and, optionally,

b) separation of the compounds of formula (I), its stereoisomers, and,optionally,

C) convert the compounds of formula (I) or its stereoisomers in pharmaceutically acceptable salt or pharmaceutically acceptable MES.

9. The method of obtaining the compounds of formula (I)

where the group R1, R2, R3, R4, R5, R6, R7, R8, R9, n, m, Ar and X have the meanings given in paragraph 1; Y represents NR12where R12means hydrogen, alkyl or benzyl, R10and R12together may form a five - or six-membered cyclic structure containing carbon atoms, which optionally contains one or more heteroatoms selected from oxygen, sulfur or nitrogen; and linking group, a represents the formula -(CH 2)n-(O)m-can be attached to or through the nitrogen atom or via a carbon atom; including

a) interaction of the compounds of formula (I)

where all symbols are defined above, Y represents an oxygen atom, YR10means halogen or COYR10means anhydrite mixed group with an appropriate amine of the formula with other10R12where R10and R12defined above; and, optionally,

b) separation of the compounds of formula (I)obtained above, stereoisomers and, optionally,

C) the conversion of compounds of formula (I), obtained above, in a pharmaceutically acceptable salt or pharmaceutically acceptable MES.

10. The intermediate compound of formula (IVf)

where the group R1, R2, R3, R4group and R5and R6when they are attached to the carbon atom may be the same or different and mean hydrogen, halogen, hydroxy or optionally substituted group selected from alkyl, alkoxy, phenyl, carboxylic acid or sulfonic acid; one or both of the substituent R5and R6can also mean oxoprop, if they are attached to the carbon atom; R5and R6if they are attached to the nitrogen atom, denote hydrogen, g is droxy or optionally substituted alkyl or benzyl; x is the heteroatom selected from oxygen, sulfur or NH; AG means optionally substituted divalent single or condensed aromatic or heterocyclic group in which the aromatic ring is a phenyl, naphthyl, and heterocyclic group represents a furan; R7means hydrogen, halogen, alkoxy, alkyl, or forms a bond together with the adjacent group, R8; R8means hydrogen, hydroxy, alkoxy, alkyl or optionally substituted benzyl, or R8forms a bond together with R7; R9means hydrogen or optionally substituted group selected from alkyl, phenyl or benzyl groups; the linking group represented by formula -(CH2)n-(O)m-can be attached to or through the nitrogen atom or via a carbon atom, n indicates an integer variable in the range of 1-4, and m means an integer from 0 to 1.

11. The method of obtaining the compounds of formula (IVf), as described in paragraph 10, where R7and R8mean hydrogen and all other symbols have the meanings defined in claim 10, including

a) interaction of the compounds of formula (IIIA)

where all symbols are defined above,

with a compound of formula (IVh)

R9 OCH2P+Ph3Hal-,(IVh)

where R9means optionally substituted group selected from alkyl, phenyl or benzyl group, and Hal means halogen,

with the formation of the compounds of formula (IVi)

where all symbols are defined above;

b) interaction of the compounds of formula (IVi) with an alcohol of formula R9OH, where R9defined above,

with the formation of the compounds of formula (IVj)

where all symbols are defined above;

C) the interaction of the compounds of formula (IVj), obtained above, where all symbols defined previously, with trialkylsilanes with the formation of the compounds of formula (IVf), where all symbols are defined above.

12. The intermediate compound of formula (IVg)

where the group R1, R2, R3, R4group and R5and R6when they are attached to the carbon atom may be the same or different and mean hydrogen, halogen, hydroxy or optionally substituted group selected from alkyl, alkoxy, phenyl, carboxylic acid or sulfonic acid; one or both of the substituent R5and R6can also mean oxoprop, if they are attached to the carbon atom; R5and R6 if they are attached to the nitrogen atom, denote a hydrogen, hydroxy or optionally substituted alkyl or benzyl; x is the heteroatom selected from oxygen, sulfur or NH; AG means optionally substituted divalent single or condensed aromatic or heterocyclic group in which the aromatic ring is a phenyl, naphthyl, and heterocyclic group represents a furan; R7means hydrogen, halogen, alkoxy, alkyl; R10means hydrogen or optionally substituted group selected from alkyl, phenyl or benzyl groups; the linking group represented by formula -(CH2)n-(O)m-can be attached to or through the nitrogen atom or via a carbon atom, n indicates an integer variable in the range of 1-4, and m means an integer from 0 to 1.

13. The method of obtaining the compounds of formula (IVg), described in item 12, including:

a) interaction of the compounds of formula (IIIh)

where L1means a leaving group and all other symbols are defined in paragraph 10, with the compound of formula (IVl)

where R8means hydrogen and all other symbols are defined in paragraph 10, with the formation of the compounds of formula (IVk)

where R8means hydrogen and all other symbols are defined above;

b) interaction of the compounds of formula (IVk), obtained above, with diasterous agent.

14. The compound according to claim 1, which is selected from the group including

ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate;

(±)methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

ethyl(E/Z)-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropionate;

ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate;

(±)methyl-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol;

(+)methyl-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol;

(-)methyl-3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol;

(±)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(±)methyl 2-methyl-3-[4-[2-(2,3-dig the draw-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(±)methyl-2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)methyl-2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)methyl-2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy] phenyl] -2-ethoxypropanol;

ethyl(E/Z)-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropionate;

(±)methyl-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)methyl-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)methyl-3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

ethyl(E/Z)-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropionate;

(±)methyl-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol;

(+)methyl-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol;

(-)methyl-3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol;

(±)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(+)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropy the oat;

(-)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(±)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(+)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(-)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate;

(±)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic;

(+)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic;

(-)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic;

(±)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan;

(+)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan;

(-)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan;

(±)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol;

(+)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol;

(-)ethyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol;

ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(±)methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(+)methyl-3-[4-[2-(2,3-di is Idro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(-)methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

ethyl(E/Z)-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(±)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(+)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(-)methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

ethyl(E/Z)-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropionate;

(±)methyl-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl] -2-ethoxypropanol;

(+)methyl-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

(-)methyl-3-[4-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyp enyl]-2-ethoxypropanol;

ethyl(E/Z)-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropionate;

(±)methyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

(+)methyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

(-)methyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)who toxi]phenyl]-2-ethoxypropanol acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid;

(±)3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(+)3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(-)3-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(±)3-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(+)3-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(-)3-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)methylbenzofuran-5-yl]-2-ethoxypropanol acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(-)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(±)N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane is;

(+)N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(-)N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(±)N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(+)N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(-)N-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(±)N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(+)N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(-)N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(±)N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(+)N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(-)N-benzyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropane;

(±)- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)- 2-methyl-3-[4-[2-(2,-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(- )- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(±)2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(-)2-(2-terbisil)-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(±)3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(-)3-[4-[2-(3-oxo-2H-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(±)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(+)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(-)3-[4-[2-(3-oxo-2H-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol acid and its salts;

(±)3-[6-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid and its salts;

(+)3-[6-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid and its salts;

(-)3-[6-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid and its salts;

(±)3-[6-[2-(,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid and its salts;

(+)3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid and its salts;

(-)3-[6-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]naphthyl]-2-ethoxypropanol acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoyl acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoyl acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoyl acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoyl acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoyl acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoyl acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-benzyloxypropionic acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,-benzoxazin-4-yl)ethoxy]phenyl]-2-butoxypropan acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-hexyloxyphenol acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(±)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(+)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(-)3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(±)methyl 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(+)methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(-)methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(±)- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(+)- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzac Azin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(- )- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(±)methyl 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(+)methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2 - phenoxypropanol;

(-)methyl-2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol;

(±)- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(+)- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(- )- 2-methyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-phenoxypropanol acid and its salts;

(±)4-nitrophenyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(+)4-nitrophenyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(-)4-nitrophenyl-3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanol;

(±)3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol acid and its salts;

(+)3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol acid and its salts;

(-)3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol acid and its salts;

(±)4-nitrophenyl-3-[4-(benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl] -2-ethoxypropanol;

(+)4-nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol;

(-)4-nitrophenyl-3-[4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxyphenyl]-2-ethoxypropanol.

15. Pharmaceutical composition having activity against hPPRα, hPPRγ and inhibitory activity against HMG-CoA reductase inhibitor, comprising the compound of formula (I)

according to any one of claims 1 to 4 or 14 and a pharmaceutically acceptable carrier, diluent, filler or MES.

16. The pharmaceutical composition according to item 15 in the form of tablets, capsules, powder, syrup, solution or suspension.

17. The pharmaceutical composition according to item 15 or 16 for the prevention or treatment of hypercholesterolemia, hyperlipemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, latinboy resistance, insulin resistance or diseases in which insulin resistance is the main pathophysiological mechanism.

18. The pharmaceutical composition according to item 15 or 16 to reduce total cholesterol, glucose in blood plasma, triglyceride, LDL, VLDL and free fatty acids in plasma.

19. The pharmaceutical composition according to item 15 or 16 for the prevention or treatment of type II diabetes, impaired glucose tolerance, dyslipidemia, disorders svyazannyhs syndrome X, such as hypertension, obesity, atherosclerosis, hyperlipidemia, damage to the coronary arteries and other cardiovascular disorders, certain kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders associated with activation of endothelial cells, psoriasis, polycystic ovarian syndrome (PCOS), are useful for inhibiting alsoreported, for improving cognitive functions in dementia and treatment of complications of diabetes, osteoporosis, inflammatory diseases of the abdominal cavity, motonishi dystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.

20. The method of prevention or treatment of hypercholesterolemia, hyperlipemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, latinboy resistance, insulin resistance or diseases in which insulin resistance is the main pathophysiological mechanism involving the introduction of the compounds of formula (I), as defined according to any one of claims 1 to 4 or 14, or a pharmaceutical composition according to item 15 or 16, and a pharmaceutically acceptable carrier, diluent, MES or excipient to a patient in need of such introduction.

21. The way to reduce total cholesterol, glucose in blood plasma, triglyceride, LDL, VLDL and free jirnexxilu plasma, including the introduction of the compounds of formula (I), as defined according to any one of claims 1 to 4 or 14, or a pharmaceutical composition according to item 15 or 16 to a patient in need of such introduction.

22. The method of prevention or treatment of hyperlipemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, latinboy resistance, insulin resistance or diseases in which insulin resistance is the main pathophysiological mechanism involving the introduction of the compounds of formula (I), as defined according to any one of claims 1 to 4 or 14, or a pharmaceutical composition according to item 15 or 16, in combination with/the company with inhibitors of HMG-CoA reductase inhibitor, fibrate, nicotinic acid, cholestyramine, colestipol or probucol that can be administered together or within such a period of time to the combined effect was synergistic, the patient in need of such introduction.

23. The way to reduce levels of glucose, triglycerides, total cholesterol, LDL, VLDL and free fatty acids in plasma, including the introduction of the compounds of formula (I) according to any one of claims 1 to 4 or 14 or a pharmaceutical composition according to item 15 or 16 in combination/the company with inhibitors of HMG-CoA reductase inhibitor, fibrate, nicotinic acid, cholestyramine, colestipol or probucol that can be administered together or within such a period is and time, to the combined effect was synergistic, to a patient in need of such introduction.

24. The method according to claim 20 or 22, where the disease is type II diabetes, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, atherosclerose, hyperlipidemia, damage to the coronary arteries and other cardiovascular disorders, some kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders associated with activation of endothelial cells, psoriasis, polycystic ovarian syndrome (PCOS), are useful for inhibiting alsoreported, for improving cognitive functions in dementia and treatment of complications of diabetes, osteoporosis inflammatory diseases of the abdominal cavity, motonishi dystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.

25. The method according to paragraph 24 of treatment or prevention of disorders related to syndrome X, which includes the introduction of the compounds of formula (I) in combination with inhibitors of HMG-COA reductase inhibitor, fibrate, nicotinic acid, cholestyramine, colestipol or probucol that can be administered together or within such a period of time to the combined effect was synergistic.

26. The compound of formula (IIIj)

where the group R1, R2, R3, R4group and R5and R6when they are attached to the carbon atom may be the same or different and mean hydrogen, halogen, hydroxy or optionally substituted group selected from alkyl, alkoxy, phenyl, carboxylic acid or sulfonic acid; one or both of the substituent R5and R6can also mean oxoprop, if they are attached to the carbon atom; R5and R6if they are attached to the nitrogen atom, denote a hydrogen, hydroxy or optionally substituted alkyl or benzyl; x is the heteroatom selected from oxygen, sulfur or NH; the linking group represented by formula -(CH2)nis attached via the nitrogen atom, n indicates an integer variable in the range 1-4.

27. The compound of formula (IIIh)

where the group R1, R2, R3, R4group and R5and R6when they are attached to the carbon atom may be the same or different and mean hydrogen, halogen, hydroxy or optionally substituted group selected from alkyl, alkoxy, phenyl, carboxylic acid or sulfonic acid; one or both of the substituent R5and R6can also mean oxoprop, if they are attached to the carbon atom; R5The R 6if they are attached to the nitrogen atom, denote a hydrogen, hydroxy or optionally substituted alkyl or benzyl; x is the heteroatom selected from oxygen, sulfur or NH; the linking group represented by formula -(CH2)nis attached via the nitrogen atom, n indicates an integer variable in the range of 1-4, and L1means a leaving group.



 

Same patents:

The invention relates to a derivative of methotrexate, more specifically, to novel derivatives of methotrexate suitable as an Antirheumatic agent, agent, healing psoriasis, and cancerostatic agent

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

The invention relates to new benzoxazine and piridokshinom compounds of formula I, where part of the Q - condensed phenyl, or condensed pyridyl; Z1is hydrogen, halogen, C1-C6alkyl, phenyl, nitro, sulfonylamino or trifluoromethyl; Z2is hydrogen or halogen; X is hydrogen or oxygen; And - C1-C6-alkyl, C1-C6-alkylaryl or C1-C6-Alkylglucoside, where aryl and heterocyclyl described in the claims, n = 0 to 3; Y is the portion described in the claims, and their pharmaceutically acceptable salts, esters and proletarienne forms

The invention relates to the derivatives of colchicine formula (I), where R denotes methoxy or methylthiourea; R1means a linear or branched C1- C6alkyl, provided that when R is methoxy, R1cannot be methyl; and compounds of formula II, where R is methylthio; R1means a linear or branched C1- C6-alkyl

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: invention proposes applying false flax plant oil as a hypoglycemic agent and agent that exerts the normalizing effect on lipid fraction of alpha-lipoproteins (high density lipoproteins; HDLP) and used in treatment of cardiovascular and endocrine diseases, and a method for it applying. This agent is known early as an antioxidant and a hypolipidemic preparation. Detection of new properties allows expanding application of this agent in clinics for treatment of patients with heart ischemic disease, stenocardia, hypertension and diabetes mellitus. The preparation reduces risk for development of atherosclerosis and allows significant reducing doses of basic drugs.

EFFECT: valuable medicinal properties of agent, enhanced effectiveness of treatment.

4 cl, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition as a capsule for oral administration that comprises testosterone undecanoate as an active component dissolved in pharmaceutically acceptable liquid carrier wherein liquid carrier involves at least 50 wt.-% of castor oil. Using castor oil as a liquid carrier in combination with testosterone undecanoate as androgen provides preparing a solution that can contain about 200-250 mg of testosterone undecanoate/ml that represents the new achievement for testosterone solution for oral administration. Solution can contain lipophilic surface-active substance, such as lauryl glycol also. The composition shows good absorption in human body and elicits higher activity as compared with the known composition of undecanoate.

EFFECT: improved and valuable properties of composition.

7 cl, 1 ex

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention relates to a new type of selective estrogens comprising steroid structure of the general formula (I) with nonaromatic ring A and free of bound hydroxyl group at carbon atom 3 wherein R1 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R2 means hydrogen atom (H), α-(C1-C4)-alkyl, α-(C2-C4)-alkenyl or α-(C2-C4)-alkynyl; R3 means hydrogen atom (H) or (C1-C4)-alkyl at position 16 of steroid structure; R4 means ethynyl; R5 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R6 means (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl being each of that is substituted optionally with chlorine or fluorine atom; dotted line means the optional double bond. Compounds of the formula (I) elicit the selective affinity to ERα-receptors.

EFFECT: valuable properties of compounds and composition.

4 cl, 3 sch, 1 tbl, 8 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

17 cl, 70 ex

FIELD: medicine, gynecology.

SUBSTANCE: the present innovation deals with carrying out hormone-substitution therapy in women during menopause period or in sterilized women. For this purpose the above-mentioned therapy consists of the phase of relative dominant estrogen activity including three daytime dosages of a substance inducing estrogen activity being equivalent to approximately to 1 mg 17beta-estradiol daily, and the phase of relative dominant progestogen activity including combination of a substance inducing estrogen activity being equivalent to approximately 1 mg 17beta-estradiol daily and a substance that demonstrates progestogen activity being equivalent to approximately 90 mcg norgestimate daily. To fulfill such a therapy a pharmaceutical preparation is, also, suggested and a set of mentioned preparations. The innovation provides maximal weakening the symptoms of the disease, in particular, congestions along the safety of application due to decreased risk of known complications of estrogen therapy.

EFFECT: higher efficiency of therapy.

31 cl, 1 dwg, 1 ex, 2 tbl

FIELD: medicine, endocrinology.

SUBSTANCE: the present innovation deals with preventing diabetes mellitus and its aftereffects. It is suggested to apply sibutramin and its analogs to decrease non-susceptibility to insulin in diabetes-free patients, prevent decreased tolerance to glucose and decrease the quantity of introduced insulin in diabetes-suffering patients and normalize body weight, as well.

EFFECT: higher efficiency of application.

28 cl, 3 dwg, 1 tbl

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention describes unsaturated 14,15-cyclopropanoandrostanes of the general formula (I):

wherein R1 means hydrogen atom (H), hydroxy-group (OH); R2 means hydroxy-group (OH), hydrogen atom (H); R3 means hydrogen atom (H), (C1-C10)-alkyl at α- or β-position; R4 means halogen atom (F, Cl, Br) or pseudohalogen group (azide, rhodanide), hydroxy-group (OH), perfluoroalkyl; R5 means (C1-C4)-alkyl; if double bond is at 1,2-position then R4 can mean hydrogen atom (H). Also, invention relates to a method for preparing these compounds and pharmaceutical compositions containing these compounds. Compounds of the formula (I) are compounds eliciting gestagenic and/or androgenic effect.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 1 tbl, 9 ex

The invention relates to pharmaceutical industry and relates to inhibitors lks-channel simultaneous action as inhibitors KQT1 channel to obtain drugs for the treatment of diseases caused by helminths and ectoparasites, while inhibitors KQT1 channel have high selectivity and are non-toxic to warm-blooded animals and humans

The invention relates to medicine, namely to surgery, and is designed to handle surgical suture material
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