JP2002507543A - Bicyclic compound, method for producing the same, and pharmaceutical composition containing them - Google Patents

Abstract

(57) [Summary] The present invention provides a novel anti-obesity and blood cholesterol-lowering compound, a derivative thereof, an analog thereof, a tautomer thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, The present invention relates to a pharmaceutically acceptable solvate and a pharmaceutically acceptable composition containing the same. In particular, the present invention relates to novel β-aryl-αoxy-substituted alkyl carboxylic acids of general formula (I), their derivatives, their analogs, their gohen isomers, their stereoisomers, their polymorphs, their pharmaceutically It relates to an acceptable salt, a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable composition containing the same.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION

The present invention relates to novel anti-obesity and anti-hypocholesterolemic compounds, their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphisms, their pharmaceutical properties. And pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable compositions containing them. In particular, the present invention relates to a novel β-aryl-α-oxy-substituted alkyl carboxylic acid of the general formula (I), its derivative, its analog, its tautomer, its stereoisomer, its polymorphism, its pharmaceutical And pharmaceutically acceptable solvates thereof, novel intermediates and methods for producing pharmaceutically acceptable compositions containing them.

[0002]

Embedded image The present invention also provides the above novel compounds, their analogs, their derivatives, their tautomers, their stereoisomers, their polymorphisms, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. And a method for producing pharmaceutically acceptable compositions containing them.

[0003] Compounds of the present invention lower total cholesterol (TC), increase high density lipoprotein (HDL) and lower low density lipoprotein (LDL), but these include coronary heart disease and atherosclerosis Has a beneficial effect on

The compounds of general formula (I) are useful for weight loss and for the treatment and / or prevention of hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular disease and. These diseases include treatment of familial hypercholesterolemia, hypertriglyceridemia, atherogenic lipoprotein, VLDL (very low density lipoprotein)
And LDL reduction. The compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis and glomerulosclerosis, nephrotic syndrome, hypertensive glomerulosclerosis, retinopathy and nephropathy. The compounds of general formula (I) are also useful in insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, hypertension, obesity, insulin resistance, coronary artery It is useful for treating and / or preventing diseases associated with Syndrome X, such as heart disease and other cardiovascular diseases. These compounds may also improve cognitive function in dementia, treat diabetic complications, diseases associated with endothelial cell activation, psoriasis,
It is also useful as an aldose reductase inhibitor for the treatment of hair cystic ovary syndrome (PCOS), inflammatory bowel disease, osteoporosis, muscular dystrophy, pancreatitis, atherosclerosis, xanthoma, and cancer. The compounds of the present invention may comprise one or more HMG CoA reductase inhibitors and / or hypolipidemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, or probucol. In combination / co-administration with a protein-lowering agent, it is useful for treating and / or preventing the above diseases.

[0005]

BACKGROUND OF THE INVENTION

Atherosclerosis and other peripheral vascular diseases are major causes affecting the quality of life of millions of people. Therefore, considerable attention has been paid to developing hypercholesterolemia and hyperlipidemia, as well as effective therapeutic guidelines.

[0006] Hypercholesterolemia is defined as a level of plasma cholesterol above an arbitrarily defined value called the "normal" level. Recently, "ideal" levels of cholesterol have been much lower than "normal" levels in the general population, and when cholesterol levels rise above this "ideal" (or "optimal") value, coronary artery disease ( It has been observed that the risk of CAD) increases. In particular, for individuals with multiple risk factors, the ring system of cause and effect between hypercholesterolemia and CAD is well defined. Most cholesterol is found in various lipoproteins such as low density lipoprotein (LDL), medium density lipoprotein (IDL), high density lipoprotein (HDL), and in part, very low density lipoprotein (VLDL). As such, it exists in an esterified form. The research is
An inverse relationship exists between CAD and atherosclerosis and serum HDL cholesterol levels (Stampfer et al., N. Engl. J. Med., 325 (1991), 373-381),
It clearly shows that the risk of CAD increases with increasing levels of LDL and VLDL.

[0007] In CAD, there is generally a "fatty layer" in the carotid, coronary and cerebral arteries, mainly free and esterified cholesterol. Miller et al., (Br. Med. J., 282 (1981), 1741-1744)
Increased particles reduce the number of stenotic sites in the human coronary arteries and also increase the level of HD
L cholesterol has been shown to be able to protect the progression of atherosclerosis. Picard
o et al., (Ateriosclerosis 6 (1986) 343-441) showed in vitro experiments that HDL can remove cholesterol from cells. They are HD
It has been suggested that L deprives cells of excess free cholesterol and transports it to the liver (Macikinnon et al., J. Biol. Chem. 261 (1986), 2548-2552). Therefore, agents that increase HDL cholesterol will have therapeutic value for the treatment of hypercholesterolemia and coronary heart disease (CHD).

[0008] Obesity is extremely common in wealthy societies and the developing world and is a major cause of illness and death. It is a condition of excessive body fat accumulation. It appears to be genetically derived or facilitated by the interaction between genotype and environment. Whatever the cause, the result is fat deposition due to an imbalance between energy intake and energy expenditure. Dieting, exercise and appetite suppression were part of obesity treatment. Because obesity results in coronary artery disease, disease, stroke, hyperlipidemia, gout, osteoporosis, osteoarthritis, reduced fertility, and many other physiological and social problems, There is a need for an efficient treatment.

[0009] Diabetes and insulin resistance are yet another problem that has a significant impact on the quality of life of many people worldwide. Insulin resistance is the diminished ability of insulin to biologically act over a wide range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this deficiency, and failure to do so will inevitably increase plasma glucose levels and develop diabetes. Diabetes is a common problem among developed countries, including obesity, hypertension, and hyperlipidemia (J. Clin.
Invest., (1985) 75: 809-817; N. Engl. J. Med. (1987) 317; 350-357; J. C.
lin. Endocrinol. Metab., (1988) 66: 580-583; J. Clin. Invest., (1975) 68:
957-969) and other renal complications (see patent application WO 95/21608). Currently, insulin resistance and relative hyperinsulinemia are obese,
It is increasingly recognized that it has a contributory role in hypertension, atherosclerosis and type 2 diabetes.

[0010] The complication of insulin resistance with obesity, hypertension and angina has been described as a syndrome with insulin resistance, as syndrome X at the central pathogenic link.

[0011] Hyperlipidemia is a major cause of cardiovascular disease (CVD) and other peripheral vascular diseases. The high risk of CVD is associated with high LDL (low density lipoprotein) and VLDL (very low density lipoprotein) found in hyperlipidemia. Patients with glucose intolerance / insulin resistance in addition to hyperlipidemia have a higher risk of gastric CVD. Many studies have shown that lowering plasma triglycerides and total cholesterol (particularly LDL and VLDL), as well as raising HDL cholesterol, help prevent cardiovascular disease.

[0012] Peroxyisomer growth factor activated receptors (PPARs) are members of the nuclear receptor superfamily. The gamma isoform of PPAR (PPAR-γ) regulates adipocyte differentiation (endo-crinology, (1994) 135: 798-800) and energy homeostasis (Cell, (1995) 83: 803-812), The alpha isoform of PPAR mediates the oxidation of fatty acids (Trend. Endocrin. Metab., (1993) 4:
291-296), which leads to a reduction in circulating free fatty acids in plasma. PPAR agonists have been found to be useful in treating obesity (WO 97/36579). It is disclosed that a molecule that is an agonist of both PPARα and PPARγ has a synergistic effect, and is suggested to be useful for treating syndrome X (
WO 97/25042). Similar synergy between insulin sensitizers (PPARγ agonists) and HMG CoA reductase inhibitors has been observed, which may be useful in the treatment of atherosclerosis and xanthoma (EP 0 753 298).

[0013] PPARγ is known to play an important role in adipocyte differentiation (Cell,
(1996) 87, 377-389). PPAR ligand activation is sufficient to cause complete terminal differentiation, including cell cycle arrest (Cell, (1994) 79, 1147-1156). PPAR
γ is constantly expressed in certain cells, and activation of the receptor by PPARγ agonists promotes terminal differentiation of adipocyte precursors, causing morphological and molecular changes characteristic of more differentiated and less malignant. (Molecular Cell, (1998), 465470; Carcinogenes
Natl. Acad. Sci., (1997) 94, 237-241) and also results in inhibition of prostate cancer tissue expression (Cancer Research (1998) 58: 3344-3352). ). This would be useful in the treatment of certain types of cancer that express PPARγ and could lead to completely non-toxic chemotherapy.

[0014] Leptin resistance refers to a condition in which a target cell cannot respond to a leptin signal. This results in obesity due to excessive food intake and reduced energy expenditure, and also results in impaired glucose tolerance, ie, type 2 diabetes, cardiovascular disease and other related complications. Kallen et al (Proc, Natl. Acad. Sci. (1996) 93
, 5793-5796, report insulin sensitization, probably due to PPAR agonists, and thus reduce plasma leptin levels. However, it has recently been disclosed that compounds having an insulin sensitizing ability also have a leptin sensitizing ability.
They reduce circulating plasma leptin levels by improving the response of target cells to leptin (W0 / 98/02159).

A small number of aryl-hydroxypropions and their derivatives and analogs have been reported to be useful in the treatment of hyperglycemia and hypercholesterolemia. Some of the compounds described in the prior art are outlined below.

I) US Pat. No. 5,306,726, WO 91/19702 describes certain 3-aryl-2-hydroxypropiones of formulas (IIa) and (IIb) as hyperlipidemic and hyperglycemic agents Disclosed are acid derivatives.

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Examples of these compounds are shown in the following formulas (IIc) and (IId).

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Ii) International patent applications WO 95/03038 and WO 96/04260 disclose compounds of the formula (IIe)

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Here, ^Ra represents 2-benzoxazolyl or 2-pyridyl, and ^Rb represents CF ₃ , CH ₂ OCH ₃ or CH ₃ . A typical example is (S) -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino] ethoxy] phenyl] -2- (2,2,2-tri Fluoroethoxy) propanoic acid (IIf).

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Iii) International Patent Applications WO 94/13650, WO 94101420 and WO 95/17394 discloses compounds of the following general formula (IIg):

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Here, A ¹ represents an aromatic hetero ring, A ² represents a substituted benzene ring, and A ³ represents a compound represented by the formula (C
H ₂ ) represents a moiety of _m— CH— (OR ¹ ), wherein R ¹ represents an alkyl group, and m is an integer;
X is substituted or unsubstituted N; Y is C = O or C = S; R ² represents OR ³ (where R ³ can be an alkyl, aralkyl or aryl group); 2-
It is an integer of 6. One example of these compounds is shown in (IIh).

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[0022]

SUMMARY OF THE INVENTION

Beneficial in the treatment and / or prevention of diseases associated with increased lipid levels, atherosclerosis, coronary artery disease, syndrome X, impaired glucose tolerance, insulin resistance, type 2 diabetes and insulin resistance leading to diabetic complications For the treatment of these diseases (insulin resistance is a pathophysiological mechanism), for the treatment of these diseases (insulin resistance is a pathophysiological mechanism), with higher efficacy, lower blood pressure, hypertension, atheroma With the aim of developing new compounds for treating sclerosis and coronary artery disease, we focused our work on research to develop new compounds that are effective in treating the above diseases. Efforts in this direction have led to compounds of general formula (I).

Accordingly, a primary object of the present invention is to provide novel -aryl--oxygen-substituted alkyl carboxylic acids, their derivatives, their analogs, their tautomers, their stereoisomers, their pharmaceutically acceptable It is to provide a pharmaceutical composition containing a salt, a pharmaceutically acceptable solvate thereof, or a mixture thereof.

Another object of the present invention is that it may have agonist activity on PPARα and / or PPARγ and, in addition to having agonist activity on PPARα and / or PPARγ, optionally inhibits HMG CoA reductase , A novel -aryl- -oxygen-substituted alkylcarboxylic acid, a derivative thereof, an analogue thereof, a tautomer thereof, a polymorph thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof It is to provide a possible solvate and a pharmaceutical composition containing this or a mixture thereof.

Another object of the invention is a novel -aryl-oxygen-substituted alkyl carboxylic acid, derivatives thereof, having enhanced effect, no toxic effect or reduced toxic effect, Pharmaceuticals containing the analogs, the tautomers, the stereoisomers, the polymorphs, the pharmaceutically acceptable salts, the pharmaceutically acceptable solvates, and the mixtures thereof To provide an objective composition.

Yet another object of the present invention is to provide a novel -aryl-oxy-substituted alkyl carboxylic acid of formula (I), its derivatives, its analogs, its tautomers, its stereoisomers,
It is to provide the polymorph, its pharmaceutically acceptable salt, and its pharmaceutically acceptable solvate.

[0027] Yet another object of the present invention is to provide novel -aryl of formula (I) in combination with suitable carriers, solvents, diluents and other media usually used in the manufacture of pharmaceutical compositions. -Provide a pharmaceutical composition containing an oxygen-substituted alkyl carboxylic acid, an analog, a derivative thereof, a tautomer thereof, a stereoisomer thereof, a polymorph thereof, a salt thereof, a solvate or a mixture thereof. That is.

Another object of the present invention is to provide novel intermediates and processes, as well as β-aryl-α-oxygen-substituted alkyl carboxylic acids of formula (I), analogs, tautomers, sterics It is an object of the present invention to provide isomers, polymorphs thereof, salts thereof, and their use as intermediates in processes for producing pharmaceutically acceptable solvates.

[0029]

DETAILED DESCRIPTION OF THE INVENTION

Oxygen-substituted propionic acids of the present invention having the general formula (I), derivatives and analogs thereof

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Here, R ¹ , R ² , R ³ , R ⁴ and groups R ⁵ and R ⁶ may be the same or different when bonded to a carbon atom, and may be hydrogen, halogen, hydroxy, nitro, cyano , Formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl , Amino, acylamino,
Alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl. Aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryl-oxycarbonylamino, An optionally substituted group selected from aralkoxycarbonylamino, a carboxylic acid or derivative thereof, or a sulfonic acid or derivative; R ⁵ and
One or both of R ⁶ may also represent an oxo group when attached to a carbon atom; R ⁵ and R ⁶ may be hydrogen, hydroxy, formyl, or alkyl, cycloalkyl, when attached to a nitrogen atom. Alkoxy, cyclo-alkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy , Heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl,
X represents an optionally substituted group selected from aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl group, carboxylic acid derivative or sulfonic acid derivative; X represents a heteroatom selected from oxygen, sulfur or NR ¹¹ ( Wherein R ¹¹ is selected from hydrogen or a group optionally substituted from alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl); Ar is optionally Represents a substituted divalent monocyclic or condensed aromatic or heterocyclic group; R ⁷ represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, optionally substituted aralkyl, or adjacent forms a bond together with R ^8; R ⁸ is hydrogen, hydroxy, alkoxy, halogen, lower Alkyl represents acyl, or an optionally substituted aralkyl, or R ⁸ forms a bond together with R ^7; R ⁹ is hydrogen or an alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl Represents an optionally substituted group selected from: alkylaminocarbonyl, aryl-aminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl; R ¹⁰ is hydrogen or alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclyl an aryl, or an optionally substituted group selected from heteroaralkyl; Y here represents oxygen or NR ¹² (, R ¹² is hydrogen, alkyl, aryl, hydroxy Al kill, aralkyl, heterocyclyl, heteroaryl, Other represents heteroaralkyl); R ¹⁰ and R ¹² are taken together the carbon atoms and optionally an oxygen atom, 5- or 6-membered ring containing one or more heteroatoms selected from oxygen, sulfur atom or nitrogen atom A linking group represented by-(CH ₂ ) _n- (O) _m- may be bonded via a nitrogen atom or a carbon atom; n is an integer from 1 to 4; It is 0 or 1.

R¹~ R^FourAnd a group represented by R^Five And R⁶ Is water when bonded to a carbon atom
Halogen atom such as chlorine, bromine or iodine; hydroxy, cyano, d
Toro, formyl; substituted or unsubstituted (C₁-C₁₂) Alkyl groups, especially linear or branched
(C₁-C₆) Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like;
Cyclo (C_Three-C₆) Alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like (the cycloalkyl groups may be substituted); _Three -C₆) Alkoxy groups such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like (wherein the cycloalkoxy group is
An aryl group such as phenyl or naphthyl (the aryl group may be
Aralkyl, benzyl or phenethyl, C₆H_FiveCH_TwoCH_TwoCH_Two Aralkyl such as naphthylmethyl, etc. (the aralkyl group may be substituted or unsubstituted)
And the substituted aralkyl is CH_ThreeC₆H_FourCH_Two, Hal-C₆H_FourCH_Two, CH_ThreeOC₆H_FourCH_Two, CH_ThreeOC₆H_FourCH _Two CH_TwoHeteroaryl groups such as pyridyl, thienyl, phenyl and the like.
Ryl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl
, Tetrazolyl, benzopyranyl, benzofuranyl and the like (the heteroaryl group is
A heterocyclyl group such as aziridinyl, pyrrolidinyl,
Rufolinyl, piperidinyl, piperazinyl and the like (the heterocyclyl group is substituted
Aralkoxy groups such as benzyloxy, phenethyloxy, naphthyl)
Methyloxy, phenylpropyloxy, etc. (even if the aralkoxy group is substituted
Good); heteroaralkyl groups such as furanmethyl, pyridinemethyl, oxazo
Methyl, oxazoleethyl, etc. (the heteroaralkyl group may be substituted
); An aralkylamino group such as C₆H_FiveCH_TwoNH, C₆H_FiveCH_TwoCH_TwoNH, C₆H_FiveCH_TwoNCH_ThreeEtc. (these may be substituted); alkoxycarbonyl groups such as ethoxycarbo
Aryloxy, ethoxycarbonyl and the like (these may be substituted);
Rubonyl groups such as optionally substituted phenoxycarnyl, naphthyloxycar
Bonyl and the like; an aralkoxycarbonyl group such as benzyloxycarbonyl,
Netyloxycarbonyl, naphthylmethoxycarbonyl, etc. (these are substituted
(C)₁-C₆A) alkylamino group such as NHCH_Three, NHC_TwoH_Five, NHC_ThreeH₇, NHC₆H₁₃ (These may be substituted); (C₁-C₆) Dialkylamino group such as N (CH_Three)_Two , NCH_Three(C_TwoH_Five), N (C_TwoH_Five)_TwoEtc. (these may be substituted); alkoxyalkyl
Groups such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl
And the like (they may be substituted); aryloxyalkyl groups such as C₆H_FiveOCH_Two , C₆H_FiveOCH_TwoCH_Two, Naphthyloxymethyl and the like (these may be substituted); aralkoxyalkyl groups such as C₆H_FiveCH_TwoOCH_Two, C₆H_FiveCH_TwoOCH_TwoCH_Two(Which may be substituted); heteroaryloxy and heteroaralkoxy (where
The aryl moiety is as defined above and may be substituted);
Cy groups such as phenoxy, naphthyloxy and the like (where the aryloxy group is substituted
Arylamino groups such as HNC₆H_Five, NCH_Three(C₆H_Five), NHC₆H_FourCH_Three, NHC₆H_Four-H
al and the like (they may be substituted); amino groups (they may be substituted);
Amino (C₁-C₆) Alkyl, which may be substituted; hydroxy (C1-C₆) Al
Kills (these may be substituted); (C₁-C₆) Alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.
Thio (C₁-C₆) Alkyl, which may be substituted; (C₁-C₆)
Alkylthio (which may be substituted); acyl groups such as acetyl, pro
Acylon or the like (the acyl group may be substituted); acylamino
Groups, such as NHCOCH_Three, NHCOC_TwoH_Five, NHCOC_ThreeH₇, NHCOC₆H_FiveAnd the like (they may be substituted); an aralkoxycarbonylamino group such as NHCOOCH_TwoC₆H_Five, NHCOOCH_TwoCH_TwoC ₆ H_Five, N (CH_Three) COOCH_TwoC₆H_Five, N (C_TwoH_Five) COOCH_TwoC₆H_Five, NHCOOCH_TwoC₆H_FourCH_Three, NHCOOCH_TwoC₆H_FourO
CH_Three(They may be substituted); aryloxycarbonylamino group, for example, NHCOOC₆H_Five, NHCOOC₆H_Five, NCH_ThreeCOOC₆H_Five, NC_TwoH_FiveCOOC₆H_Five, NHCOOC₆H_FourCH_Three, NHCOO
C₆H_FourOCH_ThreeEtc. (these may be substituted); alkoxycarbonyl-amino groups such as NHCOOC_TwoH_Five, NHCOOCH_Three(Which may be substituted); carboxylic acids or derivatives thereof, such as CONH_Two, CONHMe, CONMe_Two, CONHEt, CONEt_TwoAnd amides such as CONHPh (the carboxylic acid derivative may be substituted); acyloxy groups, for example,
OOCMe, OOCEt, OOCPh, etc. (these may be substituted); sulfonic acid or a derivative thereof such as SO_TwoNH_Two, SO_TwoNHMe, SO_TwoNMe_Two, SO_TwoNHCF_ThreeEtc. (the sulfonic acid derivative
May be substituted). Also, R^FiveAnd R⁶ One or both may represent an oxo group.

When the radicals R ^{1 to} R ⁴ and the radicals R ⁵ and R ⁶ when attached to a carbon atom are replaced, the substituent is halogen, hydroxy or nitro, or optionally Substituted groups such as alkyl, cycloalkyl, alkoxy, cycloalkoxy, aralkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, amino It is selected from an arbitrarily substituted group selected from alkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, and thioalkyl, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof. Substituents on R ¹ -R ⁶ are halogen atoms such as halogen atoms such as fluorine, chlorine, bromine;
Alkyl groups such as methyl, ethyl, isopropyl, n-propyl, n-butyl; cycloalkyl groups such as cyclopropyl; aryl groups such as phenyl; aralkyl groups such as benzyl; (C ₁ -C ₆ ) alkoxy It preferably represents a benzyloxy group, a hydroxy group, an acyl or an acyloxy group.

When attached to a nitrogen atom, suitable R ⁵ and R ⁶ are hydrogen, hydroxy, formyl; substituted or unsubstituted (C ₁ -C ₁₂ ) alkyl groups, especially linear or branched (C _1-
C ₆ ) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; cyclo (C _3-
C ₆ ) alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like (the cycloalkyl groups may be substituted); cyclo (C ₃ -C ₆ ) alkyloxy groups such as cyclopropyloxy, cyclobutyloxy , Cyclopentyloxy, cyclohexyloxy and the like (the cycloalkoxy group may be substituted); aryl group such as phenyl, naphthyl and the like (the aryl group may be substituted); aralkyl such as benzyl or phenethyl, C ₆ H ₅ CH ₂ CH ₂ CH ₂ , naphthylmethyl and the like (the aralkyl group may be substituted, and the substituted aralkyl is, for example, CH ₃ C ₆ H ₄ CH ₂ , Hal-C ₆ H ₄ CH ₂ , CH ₃ OC ₆ H ₄ CH ₂ , CH ₃ OC ₆ H ₄ CH ₂ CH ₂ ); heteroaryl groups such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl,
Thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and the like (the heteroaryl group may be substituted); heterocyclyl group such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and the like (the heterocyclyl group may be substituted) An aralkoxy group, for example, benzyloxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy, etc. (the aralkoxy group may be substituted); a heteroaralkyl group, for example, furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl, etc. Heteroaralkyl groups may be substituted); aralkylamino groups such as
C ₆ H ₅ CH ₂ NH, C ₆ H ₅ CH ₂ CH ₂ NH, C ₆ H ₅ CH ₂ NCH _{3 and the} like (these may be substituted); alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and the like (these are Aryloxycarbonyl groups such as optionally substituted phenoxycarbonyl, naphthyloxycarbonyl and the like; aralkoxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthyl
-Methoxycarbonyl and the like (which may be substituted); (C ₁ -C ₆ ) alkylamino groups such as NHCH ₃ , N (CH ₃ ) ₂ , NCH ₃ (C ₂ H ₅ ), NHC ₂ H ₅ , NHC ₃ H ₇ , NHC ₆ H _{13 and the} like (these may be substituted); alkoxyalkyl groups such as methoxy-methyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like (these may be substituted)
Aryloxyalkyl groups such as C ₆ H ₅ OCH ₂ , C ₆ H ₅ OCH ₂ CH ₂ , naphthyloxymethyl and the like (these may be substituted); aralkoxyalkyl groups such as C ₆ H ₅ CH ₂ OCH ₂ , C ₆ H ₅ CH ₂ OCH ₂ CH _2, etc., which may be substituted; heteroaryloxy and heteroaralkoxy, wherein the heteroaryl moiety is as defined above, An aryloxy group such as phenoxy, naphthyloxy and the like (the aryloxy group may be substituted); an arylamino group such as HNC ₆ H ₅ , NCH ₃ (C ₆ H ₅ ). NHC ₆ H ₄ CH ₃ , NHC ₆ H ₄ -Hal, etc. (these may be substituted); amino groups (they may be substituted); amino (C ₁ -C ₆ ) alkyl (they may be substituted) Hydroxy (C ₁ -C ₆ ) alkyl (which may be substituted); (C ₁ -C 6 ₆₎ alkoxy, such as methoxy, ethoxy, propyloxy, blanking yloxy, isopropyloxy, etc. (these may be substituted); thio (C ₁ -C ₆₎ alkyl (optionally they are substituted); (C ₁ -C ₆ ) alkylthio (which may be substituted); acyl groups such as acetyl, propionyl, benzoyl and the like (the acyl groups may be substituted); acylamino groups such as NHCOCH ₃ , NHCOC ₂ H ₅ , N
HCOC ₃ H ₇ , NHCOC ₆ H _{5 and the} like (these may be substituted); carboxylic acid derivatives, for example, amides such as CONH ₂ , CONHMe, CONMe ₂ , CONHEt, CONEt ₂ and CONHPh (the carboxylic acid Derivatives may be substituted); acyloxy groups such as OOCMe, OOCet, OO
CPh and the like (these may be substituted); sulfonic acid derivatives such as SO ₂ NH ₂ , SO ₂ NH
Me, SO ₂ NMe ₂ , SO ₂ NHCF _{3 and the} like (the sulfone derivative may be substituted). When the groups represented by R ⁵ and R ⁶ attached to the nitrogen atom are substituted, preferred substituents may be selected from fluorine, halogen such as chlorine; hydroxy, acyl, acyloxy, or amino groups. Suitable X includes oxygen, sulfur or the NR ¹¹ groups defined above, preferably oxygen and sulfur. Suitably, R ¹¹ is hydrogen, (Ct-C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, an aryl group such as phenyl or naphthyl, an aralkyl group such as benzyl or phenethyl; acetyl, propanoyl, butyroyl Acyl groups such as benzoyl, benzoyl and the like; (C) -C ₆ ) alkoxycarbonyl; aryloxycarbonyl, for example phenoxycarbonyl, CH ₃ OC ₆ H ₄ OCO, Hal-C ₆ H ₄ OCO, CH ₃ C ₆ H ₄ OCO
, Naphthyloxycarbonyl and the like; aralkoxycarbonyl, such as benzyl - represents O alkoxycarbonyl, phenethyl oxycarbonyl etc., groups represented by the R ¹¹ may be either non-substituted with a substituent. When the group represented by R ¹¹ is substituted, the substituent is selected from halogen, optionally halogenated lower alkyl, hydroxy, and optionally halogenated (C ₁ -C ₃ ) alkoxy.

The group represented by Ar may be substituted or unsubstituted, and may be divalent phenylene, naph
Tylene, pyridyl, quinolinyl, benzofuranyl, dihydrobenzofuryl, ben
Zopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindo
Ril, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl
And the like. The substituents on the group represented by Ar may be straight-chain or branched and optionally halogenated (C₁-C₆) Alkyl, optionally halogenated (C₁-C ₆ ) Alkoxy, halogen, acyl, amino, acylamino, thioacid, carboxylic acid
Alternatively, it may be selected from sulfonic acids and their derivatives.

More preferably, Ar is a substituted or unsubstituted divalent phenylene, naphthylene,
Represents a benzofuranyl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl, or benzoxazolyl group.

More preferably, Ar represents a divalent phenylene or benzofuranyl, optionally substituted by a methyl, halomethyl, methoxy or halomethoxy group.

Suitable R ⁷ includes hydrogen, lower alkyl group (eg, methyl, ethyl or propyl); hydroxy, (C ₁ -C ₆ ) alkoxy; halogen atom (eg, fluorine, chlorine, bromine, iodine); Aralkyl (eg, benzyl, phenethyl)
Or R ⁷ together with R ⁸ represents a bond.

Appropriate R⁸ Is hydrogen, a lower alkyl group such as methyl, ethyl or propyl; hydroxy, (C₁-C₆) Alkoxy; halogen atoms (eg, fluorine, chlorine, bromine, iodine); linear or branched (C_Two-C_TenAn acyl group such as an acyl group (eg,
Acetyl, propanoyl, butanoyl, pentanoyl, benzoyl, etc.);
And aralkyls such as phenethyl, which may be optionally substituted.
Or R⁷Together with to form a bond. R⁹Suitable groups represented by are hydrogen; linear or branched (C₁-C₁₆) Alkyl, preferred
Or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
(C1-C such as methyl, hexyl, octyl, etc.₁₂) Alkyl groups; cyclopropyl,
(C such as cyclobutyl, cyclopentyl, cyclohexyl, etc._Three-C₇) Cycloalkyl groups (the cycloalkyl groups may be substituted); such as phenyl and naphthyl
Aryl groups (which may be substituted); pyridyl, thienyl,
A heteroaryl group such as furyl (the heteroaryl group may be substituted)
; Furan methyl, pyridine methyl, oxazole methyl, oxazole ethyl, etc.
A heteroaralkyl group such as (the heteroaralkyl group may be substituted);
Aralkyl groups such as benzyl and phenethyl, where the alkyl moiety is C₁-C ₆ And the aryl moiety may be substituted); aziridinyl, pyrrolyl
A heterocyclyl group such as dinyl, piperidinyl, etc. (the heterocyclyl group is substituted
Methoxymethyl, ethoxymethyl, methoxyethyl, ethoxy
(C such as xypropyl etc.₁-C₆) Alkoxy (C₁-C₆) Alkyl group (the alkoxyl
Alkyl groups may be substituted); acetyl, propanoyl, butanoyl,
Linear or branched (C) such as benzoyl, octanoyl, decanoyl, etc._Two-C₁₆A)
A sil group (which may be substituted); (C₁-C₆) Alkoxycarbonyl (the alkyl group of which may be substituted); phenoxycarbonyl, naphthyloxy
Aryloxycarbonyl such as -carbonyl and the like (the aryl group may be substituted); (C₁-C₆) Alkylamino-carbonyl wherein the alkyl group is substituted
Arylamino such as PhNHCO, naphthylaminocarbonyl, etc.
And no carbonyl (the aryl part of which may be substituted). Up
The substituent may be selected from halogen, hydroxy, or nitro;
Or alkyl, cycloalkyl, alkoxy, cyclo-alkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl,
Loaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylua
Mino, arylamino, aminoalkyl, aryl-oxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl,
Select from carboxylic acid or its derivative, or sulfonic acid or its derivative
What is necessary is just to select from the optionally substituted group.

Suitable groups represented by R ¹⁰ are hydrogen, linear or branched (C ₁ -C ₁₆ ) alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl ,
(C ₁ -C ₁₂ ) alkyl groups such as pentyl, hexyl, octyl, etc .; (C ₃ -C ₇ ) cycloalkyl groups, such as cyclopropyl, cyclopentyl, cyclohexyl (the cycloalkyl group may be substituted) Good); aryl groups such as phenyl, naphthyl and the like (the aryl group may be substituted); heteroaryl groups such as pyridyl, thienyl, furyl and the like (the heteroaryl group may be substituted) ;
Heteroaralkyl groups such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl (the heteroaralkyl groups may be substituted); aralkyl groups such as benzyl and phenethyl (the aralkyl groups are substituted); And a heterocyclyl group such as aziridinyl, pyrrolidinyl, piperidinyl and the like (the heterocyclyl group may be substituted). Substituents on R ¹⁰ may be selected from the same groups of R ¹ to R ^6.

Suitable groups represented by R ¹² are hydrogen, straight-chain or branched (C ₁ -C ₁₆ ) alkyl, preferably (C ₁ -C ₁₂ ) alkyl; hydroxy (C ₁ -C ₁₆ ) alkyl ₆ ) alkyl; aryl groups such as phenyl, naphthyl, etc .; aralkyl groups such as benzyl, phenethyl, etc .; heterocyclyl groups, such as aziridinyl, pyrrolidinyl, piperidinyl, etc .;
Heteroaryl groups such as thienyl, furyl and the like; and heteroaralkyl groups such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl and the like. The ring structure formed by R ¹⁰ and R ¹² together is selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and the like.

Suitable m is an integer from 0 to 1. When m = 0, Ar represents a divalent benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, indolinyl, dihydrobenzofuryl, or dihydrobenzopyranyl group, and when m = 1, Ar represents phenylene, naphthylene, Represents a substituted or unsubstituted divalent group selected from pyridyl, quinolinyl, benzofuranyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl, etc. preferable.

Suitable n is an integer from 1 to 4, preferably n represents 1 or 2.

When m = 1, n preferably represents 2.

When m = 0, n preferably represents 1.

Pharmaceutically acceptable salts forming part of the present invention include salts of the carboxylic acid moiety, eg
For example, alkali metal salts such as Li salt, Na salt and K salt, alkaline earth metal salts such as Ca salt and Mg salt, for example, lysine salt, arginine salt, guanidine salt, diethanolamine
Salts of organic bases such as min salts and choline salts, ammonium salts or substituted ammonium salts
Includes aluminum salts and aluminum salts. Where appropriate, the salts include acid addition salts
Can be This includes sulfates, nitrates, phosphates, perchlorates, borates, halogenates,
Acetate, tartrate, maleate, citrate, succinate, palmoate (pal
moates), methanesulfonate, benzoate, salicylate, hydroxynaphthoate, benzenesulfonate, ascorbate, glycerophosphate, ketogle
Tal's salt. Pharmaceutically acceptable solvates include hydrates, or alcohols.
May contain other crystallization solvents such as Particularly useful according to the invention
Compounds include: ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy)
] Phenyl] -2-ethoxypropenoic acid; (±) methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
] Phenyl] -2-ethoxypropanoic acid; (+) methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
Phenyl] -2-ethoxypropanoic acid; (-) methyl 3- [4- [2- (2,3-dihydro-1,4--benzoxazin-4-yl) ethoxy
] Phenyl] -2-ethoxypropanoic acid; ethyl (E / Z) -3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran-5-yl] -2- Ethoxypropenoic acid; Ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxypropenoic acid; (±) Methyl 3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran-5-yl] -2-ethoxypropanoate; (+) methyl 3- [2- (2, 3-dihydro-1,4-benzoxazin-4-yl) methylbenzo
Furan-5-yl] -2-ethoxypropanoic acid; (-) methyl 3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzo
Furan-5-yl] -2-ethoxypropanoic acid; (±) methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy J phenyl] -2- Ethoxypropanoic acid; (+) methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] f
Enyl] -2-ethoxypropanoic acid; (-) methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] f
Enyl] -2-ethoxypropanoic acid; (±) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl
) Ethoxy] phenyl] -2-ethoxypropanoic acid; (+) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl)
(Ethoxy) phenyl] -2-ethoxypropanoic acid; (-) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl)
(Ethoxy) phenyl] -2-ethoxypropanoic acid; (±) methyl 2- (2-fluorobenzyl) -3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) Ethoxy] phenyl] -2-ethoxypropanoic acid; (+) methyl 2- (2-fluorobenzyl) -3- [4- [2- (2,3-dihydro-1,4-benzoxy)
(Azin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid; (-) methyl 2- (2-fluorobenzyl) -3- [4- [2- (2,3-dihydro-1,4-benzoxy)
Sadin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid; ethyl (E / Z) -3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) Ethoxy]
Phenyl] -2-ethoxypropenoic acid; (±) methyl 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy]
Phenyl] -2-ethoxypropanoic acid; (+) methyl 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid; (-) Methyl 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy]
Ethyl phenyl] -2-ethoxypropanoate (E / Z) -3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy J naphthyl] -2-ethoxypropenoic acid (±) methyl 3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl] -2-ethoxypropanoic acid; (+) methyl 3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] na
(-) Methyl 3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl] -2-ethoxypropanoic acid; ethyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] fe
Nyl] -2-hydroxypropanoic acid; ethyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl
] -2-hydroxy-propanoic acid; ethyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] fe
Nyl] -2-benzyloxy-propanoic acid; ethyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] fe
Nyl] -2-butoxy-propanoic acid; ethyl 3- [4-12- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] fe
Nyl] -2-hexyloxy-propanoic acid; ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy
] Phenyl] -2-phenoxypropenoic acid; (±) methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
] Phenyl] -2-phenoxypropanoic acid; (+) methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
Phenyl] -2-phenoxypropanoic acid; (-) methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
Phenyl] -2-phenoxypropanoic acid; ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-phenoxypropene Acid; (±) methyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoic acid; (+) methyl 3- [4 -[2- (2,3-Dihydro-1,4-benzothiazin-4-yl) ethoxy] f
Enyl] -2-phenoxypropanoic acid; (-) methyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] f
Enyl] -2-phenoxypropanoic acid; ethyl (E / Z) -3- [4- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl
) Methoxyphenyl] -2-ethoxypropenoic acid; (±) methyl 3- [4- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl
) Methoxyphenyl] -2-ethoxypropanoic acid; (+) methyl 3- [4- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)
Methoxyphenyl] -2-ethoxypropanoic acid; (-) methyl 3- [4- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)
Methoxyphenyl] -2-ethoxypropanoic acid; ethyl (E / Z) -3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-i
L) methoxyphenyl] -2-ethoxypropenoic acid; (±) methyl 3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-i
) Methoxyphenyl] -2-ethoxypropanoic acid; (+) methyl 3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl]- 2-ethoxypropanoic acid; (-) methyl 3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid; (±) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl
] -2-ethoxy-propanoic acid and its salts; (+) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2- Ethoxy-propanoic acid and its salts; (-) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxy-propanoic acid and (±) 3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran
-5-yl] -2-ethoxypropanoic acid and its salts; (+) 3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran-
5-yl] -2-ethoxypropanoic acid and its salts; (-) 3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran-
5-yl] -2-ethoxypropanoic acid and its salts; (±) 3- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) methylbenzofuran-5
-Yl] -2-ethoxy-propanoic acid and its salts; (+) 3- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) methylbenzofuran-5-
Yl] -2-ethoxy-propanoic acid and its salts; (-) 3- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) methylbenzofuran-5-
Yl] -2-ethoxy-propanoic acid and salts thereof; (±) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl
] -2-ethoxypropanoic acid and its salts; (+) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl j-2-ethoxypropanoic acid and (-) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl]
2-ethoxypropanoic acid and its salts; (±) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl
] -2-ethoxypropanamide; (+) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl]
2-ethoxypropanamide; (-) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl]
2-ethoxypropanamide; (±) N-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy
] Phenyl] -2-ethoxy-propanamide; (+) N-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy]
Phenyl] -2-ethoxy-propanamide; (-) N-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy]
Phenyl] -2-ethoxy-propanamide; (±) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanamide ; (+) 3- [4-12- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanamide; (-) 3- [4- [ 2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanamide; (±) N-methyl-3- [4- [2- (2, 3-dihydro-1,4-benzoxazin-4-yl) ethoxy
[Phenyl] -2-ethoxy-propanamide; (+) N-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] 2-ethoxy-propanamide; (-) N-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxy -Propanamide; (±) N-benzyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoate
[Xy] phenyl] -2-ethoxy-propanamide; (+) N-benzyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] 2-ethoxy-propanamide; (-) N-benzyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxy -Propanamide; (±) N-benzyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy]
[Phenyl] -2-ethoxy-propanamide; (+) N-benzyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy]
[Phenyl] -2-ethoxy-propanamide; (-) N-benzyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl]- 2-ethoxy-propanamide; 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] f
Enyl] -2-ethoxy-propanoic acid and its salts; 2- (2-fluorobenzyl) -3- [4- [2- (2,3-dihydro-1,4-benzoxazine-4-i
L) ethoxy] phenyl] -2-ethoxypropanoic acid and its salts; (±) 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy] phenyl] 2-ethoxy-propanoic acid and its salts; (+) 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy] phenyl
] -2-ethoxy-propanoic acid and its salts; (-) 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy] phenyl
] -2-ethoxypropanoic acid and its salts; (±) 3- [4- [2- (3-oxo-2H-1,4-benzothiazin-4-yl) ethoxy] phenyl]
2-ethoxypropanoic acid and its salt; (+) 3- [4- [2- (3-oxo-2H-1,4-benzothiazin-4-yl) ethoxy] phenyl]-
2-ethoxy-propanoic acid and its salts; (-) 3- [4- [2- (3-oxo-2H-1,4-benzothiazin-4-yl) ethoxy] phenyl]-
2-ethoxypropanoic acid and its salts; (±) 3- [6- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] naphthy
] -2-ethoxypropanoic acid and its salts; (+) 3- [6- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] naphthyl] -2-ethoxy (-) 3- [6- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] naphthyl] -2-ethoxypropanoic acid and salts thereof; (±) 3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl] -2-ethoxypropanoic acid and its salt; (+) 3- [6 -[2- (2,3-Dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl
] -2-ethoxypropanoic acid and its salts; (-) 3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl] -2-ethoxypropanoic acid And its salts; (±) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl
2-hydroxypropanoic acid and its salt; (+) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-hydroxy (-) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-hydroxypropanoic acid and its salt; (±) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl
] -2-Hydroxypropanoic acid and its salts: (+) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl]
2-hydroxypropanoic acid and its salt; (-) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl]
2-hydroxypropanoic acid and its salts; (±) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl
] -2-benzyloxypropanoic acid and its salts; (+) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] 2 benzyloxy Propanoic acid and its salts; (-) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-benzyloxypropanoic acid and its salts (I) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-butoxypropanoic acid and salts thereof; (+) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-butoxypropanoic acid and its salt; (-) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-butoxypropanoic acid and salts thereof; (±) 3- [4- [2- (2,3-dihydro -1,4-benzoxazin-4-yl) ethoxy] phenyi
] -2-hexyloxypropanoic acid and its salts; (+) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2- Hexyloxypropanoic acid and salts thereof; (-) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid and (±) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl
] -2-phenoxypropanoic acid and its salts; (+) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxy (-) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and salts thereof; (±) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl
] -2-phenoxypropanoic acid and its salts; (+) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl]
-2-phenoxypropanoic acid and its salts; (-) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl]
2-phenoxypropanoic acid and salts thereof; (±) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl)
) Ethoxy] phenyl] -2-phenoxypropanoic acid; (+) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl)
Ethoxy] phenyl] -2-phenoxypropanoic acid; (-) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl)
(Ethoxy) phenyl] -2-phenoxypropanoic acid; (±) 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
[Phenyl] -2-phenoxypropanoic acid and its salt; (+) 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] Phenyl] -2-phenoxypropanoic acid and its salt; (-) 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] 2-phenoxypropanoic acid and its salt; (±) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2- Phenoxypropanoic acid; (+) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) e
Toxi] phenyl] -2-phenoxypropanoic acid; (-) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) e
Toxi] phenyl] -2-phenoxypropanoic acid; (±) 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy]
] Phenyl] -2-phenoxypropanoic acid and its salts; (+) 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy]
Phenyl] -2-phenoxypropanoic acid and its salt; (-) 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy]
(Phenyl) -2-phenoxypropanoic acid and a salt thereof; (±) 4-nitrophenyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl)
Ethoxy] phenyl] -2-ethoxypropanoic acid; (+) 4-nitrophenyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2- Ethoxypropanoic acid; (-) 4-nitrophenyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid; (±) 3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoate
(Phenyl) -2-ethoxypropanoic acid and its salt; (+) 3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2 -Ethoxypropanoic acid and salts thereof; (-) 3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid and (±) 4-nitrophenyl-3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid; (+) 4-nitrophenyl-3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid; and (- ) 4-Nitrophenyl-3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxa
Zin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid According to the invention, R⁷And R⁸Represents a bond together, Y represents an oxygen atom, R¹, R ^Two , R^Three, R^Four, R^Five, R⁶, R⁹, R^TenA compound of general formula (I) wherein X, n, m and Ar are as defined above can be prepared by any of the routes shown in Scheme I below.

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Scheme-I Route (1): With a compound of general formula (IIIa) where all symbols are as defined above, R ⁹ and R ¹⁰ are as defined above and R ¹⁴ is (C ₁ -C ₆ ) The reaction of reacting a compound of formula (IIIb :) representing alkyl to give a compound of general formula (I) wherein R ⁷ and R ⁸ together represent a bond and Y represents an oxygen atom comprises NaH carried out with a base neat in the presence of such as alkoxide or mixtures thereof, such as ^- or an alkali metal hydride such as KH, CH ₃ Li, organolithium such as BuLi or the like, NaOMe, NaOEt, K ⁺ BuO be able to. This reaction may be performed in the presence of a solvent such as THF, dioxane, DMF, DMSO, DME, or a mixture thereof. HMPA may be used as a co-solvent. Reaction temperature is -78 ℃
It may be carried out at a temperature of 50 ° C, preferably -10 ° C to 30 ° C. This reaction is more efficient under anhydrous conditions. The compound of the general formula (IIIb) may be prepared according to the method described in the literature (Annalen. Chemie, (1996) 53, 699).

Route (2): R ⁷ , R ⁸ together with a compound of general formula (IIIc), wherein all symbols are as defined above, wherein all symbols are as defined above L ¹ is a reaction of leaving a leaving group (for example, a halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate or the like, preferably a halogen atom) to obtain a compound of the general formula (I) by DMSO It may be carried out in the presence of a solvent such as, for example, DMF, DME, THF, dioxane, ether or the like, or a combination thereof. The reaction can be N ₂ , Ar, or
It may be performed in an inert atmosphere maintained using an inert gas such as He. The reaction may be an alkali such as sodium hydroxide or potassium hydroxide; an alkali metal carbonate such as sodium carbonate or potassium carbonate; a hydrogen or alkali such as hydrogen or sodium or hydrogen or potassium; an organic such as n-butyl lithium. The reaction may be performed in the presence of a metal base; an alkali metal amide such as sodamide, or a base such as a mixture thereof. The amount of base is from 1 to 5 based on the amount of compound of formula (IIIc).
The amount may be equivalent, and preferably the amount of the base is 1 to 3 equivalents. A phase transfer catalyst such as a tetraalkylammonium halide or hydroxide may be added. This reaction may be performed at a temperature of 0 ° C to 150 ° C, preferably 15 ° C to 100 ° C. The duration of the reaction may range from 0.25 to 48 hours, preferably from 0.25 to 12 hours.

Route (3): A compound of general formula (IIIe) in which all symbols are as defined above and a compound of formula (IIIf) wherein R ⁹ = R ¹⁰ and as defined above The reaction to give a compound of formula (I) in which R ⁷ and R ⁸ together represent a bond comprises an organolithium such as an alkali metal hydride such as NaH, KH, CH ₃ Li, BuLi, NaOMe , NaOEt, K ⁺ BuO ^- alkoxides such as or in the presence of a base as well as mixtures thereof, may be carried out neat. This reaction may be performed in an aprotic solvent such as THF, dioxane, DMF, DMSO, DME, etc., or a mixture thereof. HMPA may be used as a co-solvent. The reaction temperature may range from -78 ° C to 100 ° C, preferably from -10 ° C to 50 ° C.

Route (4): a compound of general formula (IIIa) wherein all symbols are as defined above, and R ⁸ represents a hydrogen atom and R ⁹ and R ¹⁰ are as defined above The reaction with the compound of the general formula (IIIg) may be performed in the presence of a base. The nature of the base is not important. Any base commonly used for aldol condensation may be used. For example, a metal hydride such as NaH Moshiku is ^{KH, NaOMe, K + BuO -} , or metal alkoxides such as NaOEt, LiNH _2, or LiN (ipr) may be a metal amide such as _2. THF,
You may use an aprotic good deprivation such as ether, or dioxane. The reaction may be performed in an inert atmosphere that can be maintained by using an inert gas such as as N2, Ar, or He, and is more efficient under anhydrous conditions. A temperature in the range of -80C to 35C may be used. The initially formed β-hydroxy product may be dehydrated under conventional dehydration conditions, such as treatment with PTSA in a solvent such as benzene or toluene. The nature of the solvent and the dehydrating agent are not critical. The reflux temperature of the solvent to be used may be used from 20 ° C to the reflux temperature of the solvent to be used. Preferably, the reflux temperature of the solvent is used while continuously removing water using a Dean-Stark water separator.

Path (5): all symbols are as defined above and L¹ Is the elimination of halogen atoms, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, etc.
A compound of formula (IIIh)⁷And R⁸ Represent together a bond, and R⁹, R^Ten And Ar is reacted with a compound of formula (IIIi) as defined above to give a compound of formula (I) wherein m = 1 and the other symbols are as defined above, THF, DMF,
It may be carried out in an aprotic solvent such as DMSO, DME or a mixture thereof. The reaction is N_TwoInert maintained using an inert gas such as Ar, He, or He
What is necessary is just to carry out under a neutral atmosphere. This reaction is_TwoCO_Three, Na_TwoCO_Three Or NaH or it
What is necessary is just to carry out in the presence of a base like the mixture of these. Na_TwoCO_Three Or K_TwoCO_Three When is used as a base, acetone may be used as the solvent. The reaction temperature may be from 0 ° C to 120 ° C, preferably from 30 ° C to 100 ° C. The duration of the reaction may be in the range of 1 to 24 hours, preferably 2 to 12 hours. The compound of formula (IIIi) is benzyloxy
A hydroxy-protected aryl aldehyde such as an aryl aldehyde is represented by the formula (I
It can be produced according to a known method by a Wittig Horner reaction with the compound of IIb), followed by deprotection. Route (6): a compound of general formula (IIIj) wherein all symbols are as defined above, and R⁷And R⁸ Together represent a bond, and R⁹, R^Ten And reacting with a compound of general formula (IIIi) wherein Ar is as defined above, to obtain a compound of formula (I) wherein m = 1 and all other symbols are as defined above. The reaction is dicyclohexyl urea, PPh_Three/ DE
It may be performed using a suitable coupling agent such as a triaryl-phosphine / dialkylazadicarboxylate such as AD. This reaction is performed in THF, DME, CH _Two Cl_Two, CHCl_ThreeThe reaction may be performed in the presence of a solvent such as toluene, acetonitrile, carbon tetrachloride or the like. N_TwoBy using an inert gas such as, Ar, or He,
An active atmosphere may be maintained. This reaction may be performed in the presence of DMAP and HOBT.
These may be used in 0.05 to 2 equivalents, preferably 0.25 to 1 equivalent. The reaction temperature is between 0 ° C and 100 ° C, preferably between 20 ° C and 80 ° C. The duration of the reaction is 0.5 to 24 hours,
Preferably, it is 6 to 12 hours. In another embodiment of the present invention, there is provided a compound of general formula (I), wherein R¹, R^Two, R^Three, R^Four , R^Five, R⁶, R⁹, R^Ten, X, n, m, R⁷ Represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, an optionally substituted aralkyl group,⁸ Is hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl,
Compounds representing aralkyl, Ar as defined above, and Y representing oxygen can be prepared by one or more of the methods shown in Scheme II.

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Route 7: R ⁷ and R ⁸ together represent a bond, Y represents an oxygen atom, and all other symbols are as previously defined, as described above (Scheme I) Equation (
Reduction of the compound of the formula (IVa) corresponding to the compound of the formula (I) gives a compound of the formula (I) in which R ⁷ and R ⁸ each represent a hydrogen atom and all symbols are as defined above. The reaction may be performed in the presence of hydrogen gas and a catalyst such as Pd / C, Rh / C, Pt / C. Mixtures of catalysts may be used. In addition, this reaction may be performed in the presence of a solvent such as dioxane, acetic acid, and ethyl acetate. Pressures from atmospheric to 80 psi may be used. The catalyst is preferably 5-10% Pd / C and the amount of catalyst used is 50-300%.
It may be in the range of w / w. The reaction may also be performed by using a metal solvent reduction such as magnesium in alcohol, or sodium amalgam in alcohol (preferably methanol). In order to obtain an optically active compound of the formula (I), the hydrogenation may be carried out in the presence of a metal catalyst containing a chiral ligand. Metal catalysts include rhodium, ruthenium, indium and the like. The chiral ligand is preferably a chiral phosphine, such as (2S, 3S) -bis (diphenylphosphino) butane, 1,2-bis (diphenylphosphino) ethane, 1,2-bis (2-methoxyphenylphenylphosphino) ) Ethane, (-)-2,3-isopropylidene-2,3-dihydroxy-1
, 4-bis (diphenylphosphino) butane and the like. Any suitable chiral catalyst may be used and these will give the required optically pure product (1) (see Principles of Asymme Tri-c Synthesis, Tet. Org. Chem. Series Vol.
14, pp311-316. Ed. Baldwin. JE).

Route 8: a compound of formula (IVb) wherein all symbols are as defined above and L ² is halogen, and an alcohol of general formula (IVc) wherein R ⁹ is as defined above May be carried out in the presence of a solvent such as THF, DMF, DMSO, DME or a mixture thereof to obtain a compound of the formula (I) as defined above. The reaction may be performed in an inert atmosphere that can be maintained by using an inert gas such as N2, Ar, or He. This reaction may be performed in the presence of a base such as KOH, NaOH, NaOMe, NaOEt, K ⁺ BuO ^- or NaH or a mixture thereof. An interlayer transfer catalyst such as halogenated or tetraalkylammonium hydroxide may be used. Reaction temperature is 20 ° C ~
120 ° C., preferably in the range of 30 ° C. to 100 ° C. The duration of the reaction is 1 to 12 hours, preferably 2 to 6 hours. Compounds of general formula (IVb) and their preparation are disclosed in co-pending US patent application Ser. No. 08 / 982,910.

Route 9: A compound of formula (IIIh) as defined above, and a compound of formula (I) wherein all symbols are as defined above
The reaction of reacting a compound of formula IIi) to give a compound of formula (I) wherein m = 1 and all other symbols are as defined above is THF, DMF, DMSO, DME, etc. or a mixture thereof May be performed in the presence of a solvent such as This reaction may be performed in an inert atmosphere maintained by using an inert gas such as N2, Ar or He. This reaction may be performed in the presence of a base such as K ₂ CO ₃ , Na ₂ CO ₃ , NaH or a mixture thereof. When K ₂ CO ₃ or Na ₂ CO ₃ is used as a base, acetone may be used as a solvent. The reaction temperature ranges from 20 ° C to 120 ° C, preferably from 30 ° C to 80 ° C. The duration of the reaction is between 1 and 24 hours, preferably between 2 and 12 hours. The compound of formula (IIIi) is converted to a protected hydroxyaryl aldehyde with a compound of formula (IIIb).
It can be produced by the ttig Horner reaction, followed by reduction and deprotection of the double bond. Alternatively, compounds of formula (IIIi) may be prepared according to the method disclosed in WO 94/01420.

Route 10: reacting a compound of general formula (IIIj) as defined above with a compound of general formula (IIIi), wherein all symbols are as defined above, and m = 1 and other The reaction to obtain a compound of formula (I), in which all symbols are as defined above, is dicyclohexylurea, PPh ₃ / DEAD
And the like, using a suitable coupling agent such as triarylphosphine / dialkylazadicarboxylate. This reaction may be performed in the presence of a solvent such as THF, DME, CH ₂ Cl ₂ , CHCl ₃ , toluene, acetonitrile, carbon tetrachloride and the like. The inert atmosphere may be maintained by using N _2, Ar or an inert gas, such as the He,. This reaction may be performed in the presence of DMAP or HOBT,
It may be used in the range of 2 to 2 equivalents, preferably 0.25 to 1 equivalent. Reaction temperature is 0 ° C ~ 100
° C, preferably in the range of 20 ° C to 80 ° C. The duration of the reaction may range from 0.5 to 24 hours, preferably from 6 to 12 hours.

[0055] path 11: a compound of and R ⁹ represents a hydrogen atom and all other symbols have the reduction compounds of formula (I) as defined above formula (IVd), R ⁹ is above The reaction with the compound of the formula (IVe) as defined and L ² is a leaving group such as a halogen atom may be performed in the presence of a solvent such as THF, DMF, DMSO, DME and the like. The inert atmosphere may be maintained by using inert gases such as N _2, Ar or He. This reaction, KOH, NaOH, NaOMe, K + BuO ^{chromatography} may be performed in the presence of a base such as NaH. An interlayer transfer catalyst such as a halogenated or tetraalkylammonium hydroxide may be used. Reaction temperature is 20 ° C ~
It is in the range of 150 ° C, preferably 30 ° C to 100 ° C. The reaction duration ranges from 1 to 24 hours, preferably from 2 to 6 hours.

Route 12: The reaction of a compound of the general formula (IIIa) as defined above with a compound of the formula (IIIg), wherein R ⁸ , R ⁹ and R ¹⁰ are as defined above, takes place under conventional conditions You can do it below. The base is not critical. Any base usually used for the condensation reaction may be used. For example, NaH or metal hydride such as KH,; ^-; a metal amide such as LiNH ₂ or _{LiN (ipr) 2, NaOMe,} K + BuO, or metal alkoxides such as NaOEt. An aprotic solvent such as THF may be used. An inert atmosphere such as argon may be used, and the reaction is even more effective under anhydrous conditions. A temperature in the range of -80 ° C to 25 ° C may be used. The β-hydroxyaldol product may be conveniently dehydrated by conventional methods, ie, ionic hydrogenation techniques such as treatment with a trialkylsilane in the presence of an acid such as trifluoroacetic acid. A solvent such as CH ₂ Cl ₂ may be used. Preferably, the reaction proceeds at 25 ° C. If the reaction is slower, higher temperatures may be used.

Route 13: a compound of general formula (IIIc) wherein all symbols are as defined above, and L ¹ is a leaving group such as a halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and the like (Preferably L ¹ is a halogen atom), and reacting with a compound of the general formula (IIId) wherein all other symbols are as defined above, to form a compound of the general formula (I) The resulting reaction may be carried out in the presence of a solvent such as DMSO, DMF, DME, THF, dioxane, ether and the like, or a combination thereof. The reaction may be carried out in an inert atmosphere which is maintained by using N _2, Ar or an inert gas, such as the He,. The reaction includes an alkali such as sodium hydroxide or potassium hydroxide; an alkali metal carbonate such as sodium or potassium carbonate; an alkali metal hydride such as sodium or potassium hydride;
It may be carried out in the presence of a noble metal base such as n-butyl lithium; an alkali metal amide such as soda amide; or a base such as a mixture thereof. The amount of base is 1-5 equivalents, preferably 1-3 equivalents, based on the amount of compound of formula (IIIc). This reaction may be performed at a temperature of 0 ° C to 50 ° C, preferably 15 ° C to 100 ° C. The duration of the reaction is between 0.25 and 24 hours, preferably between 0.25 and 12 hours.

Route 14: The conversion of the compound of formula (I) from the compound of formula (IVf) may be performed in the presence of a base or acid, the choice of base and acid being immaterial. Any base commonly used for the hydrolysis of nitriles to acids may be used. For example, NaOH or KOH in an aqueous solvent. Alternatively, any acid commonly used for hydrolysis to nitrile esters may be used. For example, dry HCl in excess alcohol (methanol, ethanol, propanol, etc.). This reaction may be carried out at a temperature ranging from 0 ° C. to the reflux temperature of the solvent used, preferably from 25 ° C. to the reflux temperature of the solvent used. The duration of the reaction may be between 0.25 and 48 hours.

Route 15: reacting a compound of formula (IVg), wherein all symbols are as defined above, with a compound of formula (IVc), wherein R ⁹ is as defined above, to form a compound of formula (I) (By rhodium carbenoid-mediated insertion) is a reaction of rhodium (II) such as rhodium (II) acetate
It may be performed in the presence of a salt. This reaction is carried out in the presence of a solvent such as toluene, dioxane, ether, THF, or a combination thereof, or in the presence of R ⁹ OH as a solvent, generally at an elevated temperature such as the reflux temperature of the solvent. It may be performed at any temperature that provides a convenient rate of forming the article. An inert atmosphere may be maintained by using an inert gas such as N ₂ , Ar, or He. The duration of the reaction is 0.
It is 5 to 24 hours, preferably 0.5 to 6 hours.

Compounds of general formula (I) in which Y represents oxygen and R ¹⁰ is as defined above are suitable amines of the formula NHR ¹⁰ R ¹² in which R ¹⁰ and R ¹² are as defined above by reaction with, Y may also be converted to compounds of formula (I) representing the NR ^12. A suitable compound of formula (I) wherein YR ¹⁰ represents OH is reacted with a suitable reagent such as oxalyl chloride, thionyl chloride, and the like, followed by treatment with an amine to give an acid halide, preferably YR ¹⁰ = Cl. It may be converted. Alternatively, from compounds of formula (I) wherein YR ¹⁰ represents OH and all other symbols are as defined above, an acid such as acetyl chloride, acetyl bromide, pivaloyl chloride, dichloropivaloyl chloride, etc. A mixed acid anhydride may be prepared by treating with a halide. This reaction may be performed in the presence of a base such as pyridine, triethylamine, diisopropylethylamine and the like. Solvents such as hydrocarbons such as CHCl ₃ or CH ₂ Cl ₂ halogenated carbon; benzene, toluene, xylene and the like may be used. This reaction may be performed at a temperature in the range of -40C to 40C, preferably in the range of 0C to 20C. The mixed anhydride thus prepared may be further treated with a suitable amine.

In another preferred embodiment of the present invention there is provided a novel intermediate of formula (IVf), a process for its preparation and its use in the preparation of β-aryl-α-substituted hydroxyalkanoic acids.

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Here, the groups R ¹ , R ² , R ³ , R ⁴ and the groups R ⁵ and R ⁶ may be the same or different when bonded to a carbon atom and include hydrogen, halogen, hydroxy, nitro, cyano , Formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino , Alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, R ⁵ and R ⁶ represent a nitrogen atom; an alkoxycarbonylamino, an aryloxycarbonylamino, an aralkoxycarbonylamino, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof; When bonded to hydrogen, hydroxy, formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino , Aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl,
Represents an optionally substituted group selected from aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl group, carboxylic acid derivative, or sulfonic acid derivative; one of R ⁵ and R ⁶ or Both represent an oxo group when attached to a carbon atom; X is a heteroatom selected from oxygen, sulfur, or NR ¹¹ (R ¹¹ is hydrogen or alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, Ar represents an optionally substituted group selected from an aryloxycarbonyl group or an aralkoxycarbonyl group; Ar represents a monocyclic ring or an optionally substitutable divalent aromatic group or a heterocyclic group in a condensed relation; R ⁷ is a hydrogen atom, a substituted hydroxy, alkoxy, halogen, lower alkyl, or optionally, It represents an aralkyl group; R ⁸ represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl, or an optionally substituted aralkyl group,; R ⁹ is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy Represents an optionally substituted group selected from an alkyl, an alkoxycarbonyl, an aryloxycarbonyl, an alkylaminocarbonyl, an arylaminocarbonyl, an acyl, a heterocyclyl, a heteroaryl, or a heteroaralkyl group;-(CH ₂ ) _n- (O) _The linking group represented by _m- is bonded via a nitrogen atom or a carbon atom; n is an integer of 1 to 4, and m is 0 or 1.

Compounds of formula (IVf) wherein each of R ⁷ and R ⁸ is a hydrogen atom, and all other symbols are as defined above, are prepared by the method outlined in Scheme IIIni.

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Compounds of formula (IIIa) in which all symbols are as defined above and formula (IIIa) wherein R ⁹ is as defined above and Hal is a halogen atom (eg Cl, Br or I) The reaction with the compound of IVh) may be carried out under conventional conditions in the presence of a base. This base is not very important. Bases commonly used in Wittig reactions, i.e.Na
H or a metal hydride such as ^{KH,; - NaOMe, K +} BuO, or metallic alkoxides such as NaOEt; metal amides such as or LiNH _2, or LiN (ipr) ₂ may either can be used. Aprotic solvents such as THF, DMSO, dioxane, DME may be used. Mixtures of solvents may be used. HMPA may be used as a co-solvent. An inert atmosphere such as argon may be used and the reaction is more effective under anhydrous conditions. A temperature between -80 ° C and 100 ° C may be used.

Compounds of formula (IVi), wherein all symbols are as defined above, can be treated by treatment with an alcohol under anhydrous conditions in the presence of a strong acid anhydride, such as p-toluenesulphonic acid. R ⁷ and R ⁸ may be converted to a compound of formula (IVj) wherein R ⁷ and R ⁸ are hydrogen and all other symbols are as previously defined.

The compound of formula (IVj) as defined above, when treated with a trialkylsilyl cyanide such as trimethylsilyl cyanide, R ⁷ and R ⁸ represent a hydrogen atom, and all other symbols are The compound of formula (IVf) is obtained as defined in

In yet another embodiment of the present invention, there is provided a novel intermediate of formula (IVg), a process for its preparation, and its use in the preparation of β-aryl-α-substituted hydroxyalkanoic acids.

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Here, the groups R ¹ , R ² , R ³ , R ⁴ and the groups R ⁵ and R ⁶ may be the same or different when bonded to a carbon atom, and may be hydrogen, halogen, hydroxy, nitro , Cyano,
Formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy,
Aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy,
Acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, R ⁵ and R ⁶ also represent an optionally substituted group selected from thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; There represent an oxo group when attached to a carbon atom; R ⁵ and R ⁶ are hydrogen when attached to the nitrogen atom, hydroxy, formyl, or alkyl, cycloalkyl, alkoxy, Chloroalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy Si, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl group, represents an optionally substituted group selected from carboxylic acid derivatives, or sulfonic acid derivatives X is oxygen, sulfur or N
R ¹¹ (R ¹¹ is hydrogen or alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl chosen from carbonyl group) represents a heteroatom selected from; Ar is a single Represents an optionally substituted divalent aromatic or heterocyclic group of a ring system or a condensed ring system; R ⁷ represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or an optionally substituted aralkyl group ; R ¹⁰ is hydrogen or alkyl, cycloalkyl, the aryl, aralkyl, heterocyclyl, represents an optionally substituted group selected from heteroaryl or heteroaralkyl group,; Y is ;-( CH ₂ represent oxygen) _n - (O) _m - linking group represented by is coupled via a nitrogen atom or a carbon atom; n is an integer of 1 to 4, m is 0 or 1 A.

Compounds of formula (IVg), wherein all symbols are as defined above, are prepared by reacting a compound of formula (IVk) with a suitable diazotizing agent:

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Where R ⁸ is a hydrogen atom, and all other symbols are as previously defined.

This diazotization reaction is performed under conventional conditions. A suitable diazotizing agent is an alkyl nitrile such as isoamyl nitrile. This reaction may be performed in the presence of a solvent such as THF, dioxane, ether, benzene or the like or a combination thereof. A temperature of -50C to 80C may be used. This reaction can be performed with N ₂ , Ar or H
It may be performed in an inert atmosphere maintained by using an inert gas such as e. The duration of the reaction may be between 1 and 24 hours, preferably between 1 and 12 hours.

Compounds of formula (IVk) may also be prepared by reaction between a compound of formula (IIIh), wherein all symbols are as defined above, and a compound of formula (IVl).

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Where R ⁸ is a hydrogen atom, and all other symbols are as previously defined.

The reaction between a compound of formula (IIIh), where all symbols are as defined above, and a compound of formula (IVl), wherein all symbols are as defined above, comprises THF, DMF, The reaction may be performed in the presence of a solvent such as DMSO, DME, or a combination thereof. This reaction is carried out by N ₂ , Ar
Alternatively, it may be performed in an inert atmosphere maintained by using an inert gas such as He. This reaction may be performed in the presence of a base such as K ₂ CO ₃ , Na ₂ CO ₃ or NaH or a mixture thereof. When K ₂ CO ₃ or Na ₂ CO ₃ is used as a base, acetone may be used as a solvent. The reaction temperature may be in the range of 20 ° C to 120 ° C, preferably 30 ° C to 80 ° C. The duration of the reaction may range from 1 to 24 hours, preferably from 2 to 12 hours.

The term neat as used in this application means that the reaction is carried out without using a solvent. Pharmaceutically acceptable salts can be prepared by converting a compound of formula (I) from 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like. And, ether, TH
It is prepared by reacting in a solvent such as F, methanol, t-butanol, dioxane, isopropanol, ethanol and the like. Mixtures of solvents may be used. Also, organic bases such as lysine, arginine, diethanolamine, choline, guanidine and their derivatives may be used. Alternatively, whenever applicable, hydrochloric acid, bromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfone in a solvent such as ethyl acetate, ether, alcohol, acetone, THF, dioxane, etc. Acid, acetic acid, citric acid, maleic acid, salicylic acid,
Hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid,
An acid addition salt may be prepared by treating with an acid such as benzenesulfonic acid, tartaric acid and the like. Mixtures of solvents may be used.

The stereoisomers of the compounds forming part of the present invention can be prepared by using their single enantiomeric forms of reactants in the process, if possible, in the presence of reagents or catalysts in single enantiomeric form. It may be prepared by performing the reaction below or by resolving a mixture of stereoisomers in a conventional manner. Some preferred methods include microbial resolution, where applicable, chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, or chiral acids such as brucine, quince alkaloids and derivatives thereof, and the like. Includes resolving diastereomeric salts formed with bases. A commonly used method is "Enantiomers, Race
mates and Resolution "(Wiley Interscience, 1981).
Follow the steps in. More specifically, compounds of formula (I) wherein YR ¹⁰ represents OH are converted to a 1: 1 mixture of diastereomers of the amide by treatment with a chiral amine, amino acid, amino alcohol derived from the amino acid. Conventional reaction conditions may be used to convert the acid to the amide; the diastereomers may be separated by fractional crystallization or chromatography, and may be of the formula (I) The isomers may be prepared by hydrolyzing the pure diastereomer of the amide.

The various polymorphs of the compounds of the general formula (I) which form part of the invention may be prepared by crystallization of the compound of the formula (I) under different conditions. For example, different solvents or mixtures thereof commonly used for crystallization; crystallization at different temperatures; various cooling modes from rapid to slow cooling during crystallization. It may also be obtained by heating or melting the compound followed by gradual or rapid cooling. The presence of a polymorphism may be determined by solid-phase probe nmr spectra, ir spectra, manipulated differential thermal analysis, powder X-ray analysis, or other techniques.

Compounds of general formula (I) include insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, and hypertension, obesity, insulin resistance,
It is useful for treating and / or preventing diseases associated with Syndrome X, such as coronary heart disease and other cardiovascular disorders. These compounds also improve cognitive function in dementia, treat diabetes complications, treat diseases associated with endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), inflammatory bowel disease, and osteoporosis. It is also useful as an aldose reductase inhibitor for treating and for treating cancer. The compounds of the present invention may be used in combination with one or more HMG CoA reductase inhibitors, fibric acid derivatives, nicotinic acid, cholestyramine, colestipol or probucol in combination with a hypolipidemic / low proteinase agent such as atherosclerosis. And / or useful for the treatment and / or prevention of xanthomas. HMG CoA reductase inhibitors include lovastatin, provastatin, simvastatin, fluvastatin,
It may be selected from those for the treatment or use of hyperlipidemia, such as atorvastatin, cerivastatin, and analogs thereof. Suitable fibric acid derivatives include gemfibrozil, clofibrate (clofib
rate), fenofibrate, ciprofibrate
, Benzafibrate and their analogs.

The present invention also provides a compound of the general formula (I) as defined above, a tautomer, a stereoisomer, a polymorph, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a solvate which is acceptable in combination with a common pharmaceutically acceptable carrier, diluent and the like.

The pharmaceutical composition may be in any conventionally used form, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, and may be a suitable solid or liquid carrier or diluent, or an injectable solution. Alternatively, flavoring and sweetening agents may be contained in a suitable sterile medium to form a suspension. Such compositions typically contain 1-20%, preferably 1-10%, by weight of active compound, with the balance of the composition comprising a pharmaceutically acceptable carrier, diluent or solvent. It is.

The compounds of formula (I) as defined above are administered clinically to mammals, including humans, by the oral or parenteral route. Oral administration is more convenient and avoids injectable pain and irritation. However, parenteral administration of the drug is essential if the patient is unable to swallow the medication due to illness or other abnormalities, or if absorption after oral administration is impaired. With either route, the dosage will be from about 0.01 to about 50 mg / kg, preferably from about 0.01 to about 30 mg / kg per day, per body weight of the patient, and is administered in one or more divided doses. However, the optimal dose for the individual patient to be treated should be determined by the person responsible for the treatment,
Generally, small doses will be administered initially, then increasing to determine the optimal dose.

[0082] Suitable pharmaceutically acceptable carriers include solid fillers or diluents, and sterile aqueous or organic solutions. The active compound is present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage described above. Thus, for oral administration, the compounds are combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions, and the like. If desired, the pharmaceutical compositions may contain additional ingredients such as flavorings, sweeteners, excipients and the like. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. A solution of, for example, sesame or peanut oil, aqueous propylene glycol, and the like, together with an aqueous solution of a water-soluble pharmaceutically acceptable acid addition salt or a salt of the compound with a base can be used. Then, the injection solution thus prepared is intravenously,
Although it can be administered intraperitoneally, subcutaneously, or intramuscularly, intramuscular administration is preferred in humans.The invention is described in detail in the following examples, which are provided by way of example only Therefore, it should not be construed as limiting the scope of the invention.

Preparation Example 1 4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy] benzaldehyde

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2H-1,4-benzoxazin-3- (4H) -one (1.6 g, 10.7 mmol), 4- (2-bromoethoxy) benzaldehyde (2.95 g, 12.8 mmol) and potassium carbonate (5.93 g, 42.9
(7 mmol) in dry dimethylformamide (30 mL) was stirred at 80 ° C. for 10 hours.

Water (100 mL) was added and extracted with ethyl acetate (2 × 75 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (2: 8) to give the title compound (2.9 g, 91%) as white crystals. ^{mp:. 75 -78 ℃ 1 H} NMR (CDCl 3, 200 MHz): 4.37 (s, 4H), 4.62 (s, 2H), 6.96-7.26 ( complex, 6H), 7.82 (d, J = 8.4 Hz, 2H), 9.89 (s, 1H). Preparation Example 2 6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] cyanonaphthalene

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2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethyl methanesulfonate (0
A mixture of .49 g, 1.82 mmol), 2-hydroxy-6-cyanonaphthalene (0.28, 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. Add water (50 mL) and add ethyl acetate (2 × 25 m
L). The combined ethyl acetate layers were washed with water (25 mL), brine (20 mL),
Dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (2: 8) to give the title compound (0.41 g, 72%) as a pale yellow solid. mp: 94-96
° C. ¹ H NMR (CDCl ₃ , 200 MHz): 3.05 (t, J = 5.21 Hz, 2H), 3.79-3.85 (complex,
4H), 4.31 (t, J = 5.82 Hz, 2H), 6.64-6.78 (composite, 2H), 6.97-7.25 (composite, 4H
), 7.53-7.80 (complex, 3H), 8.13 (s, 1H). Preparation Example 3 6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthaldehyde

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The 6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] cyano-naphthalene (8 g, 22.9 mmol) obtained in Preparation Example 2 in dry tetrahydrofuran (15 mL) Diisobutylaluminum hydride (93 mL, 20% in toluene) was added to the solution at -70 ° C.
Added over 1 hour. After this addition, the reaction mixture was stirred at 25 ° C for 16 hours. Thereafter, ethyl formate (20 mL) was added, and the mixture was stirred at 25 ° C for 1 hour. Saturated ammonium chloride solution (15 mL) was added. The reaction mixture was acidified with 10% sulfuric acid and extracted with ethyl acetate (2 × 75 mL). The combined ethyl acetate layers were washed with water (2 × 50 mL), brine (50 mL), dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel using a mixture of ethyl acetate and ether (10:90) to give the title compound (4.5 g, 56%) as a pale yellow solid. mp: 100-102 ° C. ¹ H NMR (CDCl ₃ , 200 MHz): 3.06 (t, J = 5.2 Hz, 2H), 3.72-3.86 (complex, 4H
), 4.33 (t, J = 5.67Hz, 2H), 6.60-6.79 (composite, 2H), 6.97-7.25 (composite, 4H),
7.74-7.93 (complex, 3H), 8.25 (s, 1H), 10.09 (s, 1H). Preparation Example 4 4- [4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2- Yl] methoxybenzaldehyde

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4-Methyl-3,4-dihydro-2H-1,4-benzoxazine-2-methanol (6.0 g, 33.5
1 mmol) in dichloromethane (20 mL) was added to triethylamine (10.15 g, 100
.5 mmol) was added at 25 ° C. under a nitrogen atmosphere. Methanesulfonyl chloride (5.7
(5 g, 50.25 mmol) was added to the above reaction mixture at 0 ° C. and stirring was continued at 25 ° C. for a further 10 hours. Water (50 mL) was added and extracted with chloroform (2 × 25 mL). The organic extracts were washed with water (50 mL), dried (Na ₂ SO _4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel using a mixture of ethyl acetate and hexane (2: 8) to give (4-methyl-3,4-dihydro-2
H-1,4-benzoxazin-2-yl) methyl methanesulfonate (3.7 g, 43%) was obtained as a syrup.

¹ H NMR (CDCl ₃ , 200 MHz): 2.88 (s, 3H), 3.07 (s, 3H), 3.13-3.31 (complex, 2H), 4.41 (d, J = 5.2 Hz, 2H), 4.53 -4.55 (composite, 1H), 6.81-6.89 (composite,
4H). (4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-4-yl) methyl methanesulfonate (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. Water (100 mL) was added and extracted with ethyl acetate (2 × 70 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (2: 8) to give the title compound (1.3 g, 32%) as a thick liquid.

¹ H NMR (CDCl ₃ , 200 MHz): 2.93 (s, 3H), 3.24-3.46 (complex, 2H), 4.14-4.
37 (Composite, 2H), 4.68-4.71 (Composite, 1H), 6.72-7.10 (Composite, 6H), 7.86 (d, J =
8.8 Hz, 2H), 9.92 (s, 1H). Preparation Example 5 4- [4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl] methoxybenzaldehyde

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4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-methanol (4.0 g, 1
5.68 mmol) and the title compound (3.2 g) in the same manner as described in Preparation Example 4.
, 80) as a pale yellow solid. ^{mp:. 92-94 ℃ 1 H NMR} (CDCl 3, 200 MHz): 3.38-3.43 ( complex, 2H), 4.14-4.32 (complex, 2H), 4.46 (d, J = 7.8 Hz, 2H), 4.60- 4.65 (composite, 1H), 6.65-6.89 (composite, 4H),
7.00 (d, J = 8.8 Hz, 2H), 7.32 (s, 5H), 7.83 (d, J = 8.8 Hz, 2H), 9.90 (
s, 1H). Example 1 Ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
Phenyl] -2-ethoxypropenoic acid

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Triethyl 2-ethoxyphosphonoacetic acid (W. Grell and H. Machleidt, Annalen
Chemie, 1960, 699, 53) (7.8 g, 29.1 mmol) in tetrahydrofuran (15 mL) was treated with sodium hydride (60% dispersion in oil) (1.39 g, 29.1 mmol) in dry tetrahydrofuran (5 mL). ) Was slowly added to the stirred ice-cooled suspension under a nitrogen atmosphere. After stirring the mixture at 0 ° C. for 30 minutes, 4- [2- (2,3-dihydro-1,4-dihydro-1,4-dihydro-1,4-dichloro-1,4-dichloro-1,4-dichloro-1,2) was prepared in tetrahydrofuran (20 mL) according to the method described in Preparation 1 of US patent application Ser. No. 08 / 982,910. 4-benzoxazin-4-yl) ethoxy] benzaldehyde (7.5 g, 26.5
(mmol). The reaction mixture was warmed to 25 ° C. and stirred for another 20 hours. The solvent was evaporated, the residue was suspended in water (100 mL) and ethyl acetate (2 × 75 m
L). The combined ethyl acetate layers were washed with water (75 mL), brine (50 mL),
Dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (2: 8) as eluent to give the title compound (8.0 g. 75%), ie 65: 5 of the geometric isomer. 35
Gum as a Z: E mixture (RA Aitken and GL Thom, Synthesis.1989, 9
58).

¹ H NMR (CDCl ₃ , 200 MHz): 1.18 and 1.36 (combined 6H, isomer OEt, triplet signal), 3.51 (t, J = 4.48 Hz, 2H), 3.71 (t, J = 5.39 Hz) , 2H), 3.89
-4.03 (complex, 2H), 4.10-4.34 (complex, 6H), 6.07 (s, 0.35H, E-olefin proton), 6.63-7.14 (complex, 6.65H), 7.73 (d, J = 8.72 Hz, 2H) Example 2 Methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid

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Ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropene obtained in Example 1 A mixture of the acid (8.0 g, 20.0 mmol) and magnesium shavings (9.64 g, 396.7 mmol) in dry methanol (50 mL) was added at 25 ° C.
Stir for 20 hours. Then, water (50 mL) was added, the pH was adjusted to about 7.0 using 10% hydrochloric acid versus solution, and the solution was extracted with ethyl acetate (2 × 10 mL). The organic extracts were washed with water (75 mL), washed with brine (75 mL), dried (Na ₂ SO _4), filtered and the solvent removed under reduced pressure. The residue was subjected to column chromatography on silica gel using a mixture of ethyl acetate and ether (2: 8) as eluent to give the title compound (5.0 g, 64%) as a gummy liquid.

¹ H NMR (CDCl ₃ , 200 MHz): 1.15 (t, J = 7.0 Hz, 3H), 2.93 (d, J = 6.64 H
z, 2H), 3.23-3.38 (composite, 1H), 3.43-3.72 (composite, 8H), 3.97 (t, J = 6.9 Hz,
1H), 4.14 (t, J = 5.81 Hz, 2H), 4.19 (t, J = 4.2 Hz, 2H), 6.55-6.83 (composite,
6H), 7.13 (d, J = 8.39 Hz, 2H) .Example 3 Ethyl (E / Z) -3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran- 5-yl] -2-ethoxypropenoic acid

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From 5-formyl-2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran (1.0 g, 3.41 mmol) in a manner analogous to that described in Example 1. , The title compound (0.8 g, 58%) was prepared as a gum.

¹ H NMR (CDCl ₃ , 200 MHz): 1.06 and 1.38 (6H, OCH ₂ CH ₃ and OCH ₂ CH ₃ , triplet signal), 3.48 (t, J = 4.98 Hz, 2H), 3.89-4.18 (Compound, 2H), 4.2
8-4.40 (complex, 4H), 4.54 and 4.56 (combined, 2H, -NCH ₂ -signal), 6.20 (0.5 H, E isomer of olefin proton), 6.52 and 6.59 (combined, 1H), 6.65-6.83 ( (Compound, 2.5 H), 7.08-7.11 (Compound, 1H), 7.32-7.44 (Compound, 2H), 7.69 (d, J = 8.3
Hz, 1H), 7.99 (s, 1H). Example 4 Ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl ] -2-ethoxypropenoic acid

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4- [2- (2,2) prepared according to the method described in Preparation Example 2 of US Patent Application
3-Dihydro-1,4-benzothiazin-4-yl) ethoxy] benzaldehyde (3.3 g, 11
From .03 mmol), by a similar method to that described in Example 1, a geometric isomer ratio 38: 62 ⁽¹ H
The title compound (3.2 g, 71%) was prepared as a gum (measured by NMR).

¹ H NMR (CDCl ₃ , 200 MHz): 1.14 and 1.35 (combined, 6H, isomeric-OCH ₂ CH ₃ triplet signals), 3.02 (t, J = 4.9 Hz, 2H), 3.69-3.88 (complex , 4H)
, 3.92-4.03 (complex 2H), 4.12-4.33 (complex 4H) 6.06 (s, 0.38 H, E-olefin proton), 6.61-7.14 (complex, 6.62 H), 7.73 (d, J = 8.81 Hz, 2H). Example 5 Methyl 3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran
-5-yl] -2-ethoxypropanoic acid

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Ethyl (E / Z) -3- [2- (2,3-dihydro-1,4-benzoxazine prepared in Example 3
-4-yl) methylbenzofuran-5-yl] -2-ethoxypropenoic acid (0.8 g, 1,96 mmol
) Was prepared in a similar manner as described in Example 2 to give the title compound (0.6 g, 78%) as a gum.

¹ H NMR (CDCl ₃ , 200 MHz): 1.15 (t, J = 7.0 Hz, 3H), 3.07 (d, J = 5.8 H
z, 2H), 3.28-3.67 (composite, 4H), 3.70 (s, 3H), 4.03 (t, J = 6.0 Hz, 1H), 4.2
8 (t, J = 4.47 Hz, 2H), 4.54 (s, 2H), 6.52 (s, 1H), 6.62-6.89 (composite, 4H), 7.10 (d, J = 7.05Hz, 1H), 7.35 (composite , 2H). Example 6 Methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl
] -2-ethoxypropanoic acid

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The ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) obtained in Example 4
) Ethoxy] phenyl] -2-ethoxypropenoic acid (3.1 g, 7.50 mmol) was prepared in a similar manner as described in Example 2 to give the title compound (2,3 g, 76%) as a gum. .

¹ H NMR (CDCl ₃ , 200 MHz): 1.15 (t, J = 7.01 Hz, 3H), 2.93 (d, J = 6.65
Hz, 2H), 3.03 (t, J = 5.21 Hz, 2H), 3.23-3.41 (composite, 1H), 3.52-3.80 (composite, 8H), 3.97 (t, J = 7.01 Hz, 1H), 4.14 (t , J = 5.81 Hz, 2H), 6.61-6.82 (composite, 4H), 6.92-7.05 (composite, 2H), 7.13 (d, J = 8.53 Hz, 2H) .Example 7 Methyl 2-methyl-3- [4 -[2- (2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid

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The methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoate obtained in Example 2 (0.6 g, To a solution of 1.5 mmol) in dry tetrahydrofuran (5 mL) was added lithium diisopropylamide (5.25 L, 0.5 mL solution in THF / hexane) at -78 ° C. After stirring at -78 ° C for 1 hour, methyl iodide (
(0.75 mL) was added and the reaction mixture was warmed to room temperature (about 25 ° C.) and stirred at the same temperature for another 20 hours. Water (20 mL) was added, acidified with 1 N aqueous hydrochloric acid, and ethyl acetate (2 × 25
mL). The combined ethyl acetate layers were washed with water (25 mL), brine (25 mL), dried (Na ₂ SO ₄ ), filtered, and the solvent was removed under reduced pressure to give the title compound (0.5 g, 80 g).
%) As an oil.

¹ H NMR (CDCl ₃ , 200 MHz): 1.21 (t, J = 6.97 Hz, 3H), 1.31 (s, 3H), 2.9
5 (s, 2H), 3.32-3.58 (composite, 4H), 3.62-3.84 (composite, 5H), 4.14 (t, J = 5.81
Hz, 2H), 4.22 (t, J = 4.25 Hz, 2H), 6.55-6.88 (composite, 6H), 7.08 (d, J = 8.
Example 8 Methyl 2- (2-fluorobenzyl) -3- [4- [2- (2,3-dihydro-1,4-benzoxazine)
-4-yl) ethoxy] phenyl] -2-ethoxypropenoic acid

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The methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoate obtained in Example 2 (0.6 g, From 1.5 mmol), the title compound (0.6 g, 78%) was prepared as a brown liquid by a method similar to that described in Example 7.

¹ H NMR (CDCl ₃ , 200 MHz): 1.22 (t, J = 6.96 Hz, 3H), 3.03-3.18 (complex,
4H), 3.51 (t, J = 4.2 Hz, 2H), 3.59-3.71 (composite, 7H), 4.14 (t, J = 5.81 Hz,
2H), 4.22 (t, J = 4.24 Hz, 2H), 6.42-6.85 (composite, 6H), 6.90-7.32 (composite 6H)
Example 9 Ethyl (E / Z) -3- [4- [2- (3-oxo-2H-1,4-benzoxazin J'-yl) ethoxy] phenyl] -2-ethoxypropenoic acid

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The 4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy] benzaldehyde (2.9 g, 9.7 mmol) obtained in Preparation Example 1 was used to explain the method described in Example 1. The title compound (3.9 g, 97%) with a 32:68 E: Z isomer ratio was prepared as a white solid. _{^{1 H NMR (CDCl 3, 200}} MHz): 1.13-1.43 ( complex, 6H), 3.88-4.02 (complex, 2H), 4.07-4.40 (complex, 6H), 4.60 (s, 2H), 6.05 (s, 0.32 H, E olefin proton), 6.76-7.32 (complex, 6.68 H), 7.71 (d, J = 8.72 Hz, 2H) .Example 10 Methyl 3- [4- [2- (3-oxo-2H-1,4 -Benzoxazin Jt-yl) ethoxy] phenyl l-2-ethoxypropanoate

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Ethyl (E / Z) -3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxy obtained from Example 9 The title compound (1.0 g, 51%) was prepared as a colorless syrup from propenoic acid (2.0 g, 4.8 mmol) by a method similar to that described in Example 2.

¹ H NMR (CDCl ₃ , 200 MHz): 1.14 (t, J = 7.0 Hz, 3H), 2.92 (d, J = 6.6 Hz, 2H), 3.25-3.41 (complex, 1H), 3.53-3.61 (Compound, 1H), 3.68 (s, 3H), 3.96 (t
, J = 7.0 Hz, 1H), 4.21-4.32 (composite, 4H), 4.68 (s, 2H), 6.77 (d, J = 8.63
Hz, 2H), 6.98-7.33 (complex, 6H). Example 11 Ethyl (E / Z) -3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] Naphthyl] -2-ethoxypropenoic acid

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From the 6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthaldehyde (1.5 g, 4.29 mmol) obtained in Preparation Example 3, The title compound as a 1: 1 E / Z isomer (1.74 g, 87%) was prepared as a brown syrup.

¹ H NMR (CDCl ₃ , 200 MHz): 0.99-1.47 (complex, 6H), 3.06 (t, J = 4.98 Hz,
2H), 3.79-3.95 (Composite, 4H), 3.99-4.18 (Composite, 2H), 4.25-4.37 (Composite, 4H), 6
.23 (s, 0.5 H, E olefmic proton), 6.59-6.79 (complex, 2H), 6.97-7.29 (complex, 4.5H), 7.57-7.95 (complex, 3H), 8.14 (s, 1H) .Example 12 Methyl 3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl
] -2-ethoxypropanoic acid

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The (E / Z) -3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl] -2-ethoxypropenoic acid obtained in Example 11 ( 1.7 g, 3.67 mmol) from the title compound (1.2
5g, 75%) was prepared as a colorless syrup.

¹ H NMR (CDCl ₃ , 200 MHz): 1.14 (t, J = 7.06 Hz, 3H), 3.06 (t, J = 5.21 H
z, 2H), 3.13 (d, J = 7.15 Hz, 2H), 3.29-3.37 (composite, 1H), 3.57-3.64 (composite, 1H), 3.70 (s, 3H), 3.77-3.83 (composite, 4H) , 4.09 (t, J = 7.2 Hz, 1H), 4.25
(t, J = 5.81Hz, 2H), 6.62-6.79 (composite, 2H), 6.96-7.36 (composite, 5H), 7.60-7.
Example 13 Ethyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin ~ t-yl) ethoxy] phenyl l-2-hydroxypropanoic acid 70 (complex, 3H).

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2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethyl methanesulfonate
(0.36 g, 1.42 mmol), potassium carbonate (0.80 g, 5.8 mmol) and ethyl 2-hydroxy-3- (4-hydroxyphenyl) propanoic acid (0.3 g, 1.42 mmol) as described in Preparation Example 2. The title compound (0.14 g, 32%) was prepared using conditions similar to.

¹ H NMR (CDCl ₃ , 200 MHz): 1.24 (t, J = 7.15 Hz, 3H), 2.71 (d, J = 6.23 Hz, 1H, D ₂ O exchangeability), 2.84-3.10 (complex, 2H), 3.50 (t, J = 4.47 Hz, 2H), 3.
67 (t, J = 5.48 Hz, 2H), 4.11-4.26 (composite, 6H), 4.37-4.39 (composite, 1H), 6.61
-6.86 (complex, 6H), 7.11 (d, J = 8.62 Hz, 2H). Example 14 Ethyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin Jt-yl) ethoxy] phenyl
] -2-Hydroxypropanoic acid

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2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethyl methanesulfonate (8
.,-g, 30.0 mmol), potassium carbonate (20.7 g, 150 mmol) and ethyl 2-hydroxy-3- (4-hydroxyphenyl) propanoic acid (6.3 g, 30.0 mmol). Using similar conditions as described above, the title compound (1.9 g, 17%) was prepared as a gummy liquid.

¹ H NMR (CDCl ₃ 200 MHz): 1.29 (t, J = 7.11 Hz, 3H), 2.70-2.80 (bs 1H, D ₂ O exchangeability), 2.82-3.15 (complex, 4H), 3.65 3.82 (Composite, 4H), 4.10-4.30 (Composite, 4H), 4.28-4.40 (Composite, 1H), 6.62-6.89 (Composite, 4H), 6.92-7.18 (Composite, 4H
Example 15 Ethyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-benzyloxypropanoic acid

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The ethyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-hydroxypropanoate obtained in Example 13 (0.5 g, A solution of 1.34 mmol) in dry dimethylformamide (5 mL) was treated under a nitrogen atmosphere with sodium hydride (
60% dispersion in oil) (0.08 g, 1.66 mmol) in dry dimethylformamide (3 mL)
Was added to the stirred ice-cold suspension. The reaction mixture was stirred at 0 ° C. for 30 minutes, followed by the addition of benzyl bromide (0.46 g, 2.69 mmol). The mixture was warmed to 25 ° C. and stirring was continued for another 18 hours. Water (25 mL) was added and extracted with ethyl acetate (2 × 50 mL). The combined organic layers with water (50 mL), washed with brine (50 mL), dried over Na ₂ SO _4, and filtered. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel using a mixture of ethyl acetate and ether (2: 8) as eluent to give benzyl 3- [4- [2- (2,3- The title compound (0.3 g) was obtained together with dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-benzoyloxypropanoic acid. This mixture (1: 1) is used in Example 47 without any separation.

¹ H NMR (CDCl ₃ , 200 MHz): 1.23 (t, J = 7.05 Hz, 1.5H), 2.99 (d, J = 7.
06Hz, 4H), 3.0-3.72 (Composite, 8H), 4.05-4.30 (Composite, 12H), 4.32-4.71 (Composite,
4H), 5.13 (s, 2H), 6.55-6.89 (complex, 12H), 7.05-7.36 (complex, 19H) .Example 16 ethyl 3- [4- [2- (2,3-dihydro-1,4- Benzoxazin-4-yl) ethoxy] phenyl] -2-butoxypropanoic acid

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Using conditions similar to those described in Preparation Example 2, 2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethyl methanesulfonate (0.46 g, 1.78 mmol), carbonic acid The title compound (0.4 g, 52%) was prepared as a gummy liquid from potassium (0.98 g, 7.12 mmol) and ethyl 2-butoxy-3- (4-hydroxyphenyl) propanoic acid (0.47 g, 1.78 mmol). .

¹ H NMR (CDCl ₃ , 200 MHz): 0.84 (t, J = 7.53 Hz, 3H), 1.19-1.34 (complex, 5
H), 1.43-1.55 (Composite, 2H), 2.92 (d, J = 6.32Hz, 2H), 3.22-3.36 (Composite, 1H)
, 3.48-3.59 (composite, 3H), 3.68 (t, J = 5.82Hz, 2H), 3.93 (t, J = 6.2Hz, 1H)
, 4.11-4.24 (complex, 6H), 6.61-6.86 (complex, 6H), 7.13 (d, J = 8.3 Hz, 2H) .Example 17 ethyl 3- [4- [2- (2,3-dihyd r0- 1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid

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2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethyl methanesulfonate
(0.35 g, 1.3 mmol), potassium carbonate (0.75 g, 5.4 mmol) and ethyl 2-hexyloxy-3- (4-hydroxyphenyl) propanoic acid (0.4 g, 1.3 mmol) as described in Preparation Example 2. The title compound (0.31 g, 50%) was prepared as a colorless syrup using conditions similar to.

¹ H NMR (CDCl ₃ , 200 MHz): 0.85 (t, J = 5.72 Hz, 3H), 1.20-1.34 (complex,
7H), 1.40-1.66 (composite, 4H), 2.93 (d, J = 6.0 Hz, 2H), 3.21-3.31 (composite, 1H
), 3.49-3.60 (composite, 3H), 3.68 (t, J = 5.72 Hz, 2H), 3.93 (t, J = 5.81 Hz,
1H), 4.11-4.24 (complex, 6H), 6.62-6.81 (complex, 5H), 7.09-7.16 (complex, 3H) .Example 18 Ethyl (E / Z) -3- [4- [2- (2, 3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl l-2-phenoxypropenoic acid

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4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] benzaldehyde (1.0 g, 3.0 mmol) and triethyl 2-phenoxyphosphonoacetic acid (AG Schu
The title compound (0.92 g, 58%) was obtained from ltz. et. al. J. Org. Chem., 1983, 48, 3408) (1.3 g, 4.0 mmol) by a method similar to that described in Example 1. Prepared as a syrupy liquid.

¹ H NMR (CDCl ₃ , 200 MHz): 1.06 and 1.18 (combined 3H, isomeric OCH ₂ C
H _3, triplets signal), 3.43-3.57 (complex, 2H), 3.64-3.75 (complex, 2H), 4
.06-4.28 (Composite, 6H), 6.60-6.90 (Composite, 8H), 6.94-7.12 (Composite, 2H), 7.22-7.
45 (complex, 3H), 7.64 (d, J = 8.72 Hz, 1H). Example 19 Methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] Phenyl] -2-phenoxypropanoic acid

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The ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzoxazine-4-) obtained in Example 18
The title compound (0.49 g, 57%) was prepared as a gum from yl) ethoxy] phenyl] -2-phenoxypropenoic acid (0.9 g, 2.0 mmol) by a method similar to that described in Example 2.

¹ H NMR (CDCl ₃ , 200 MHz): 3.17 (d, J = 6.2 Hz, 2H), 3.50 (t, J = 4.3 Hz
, 2H), 3.65-3.70 (composite, 5H), 4.14 (t, J = 5.76 Hz, 2H), 4.21 (t, J = 4.15H
z, 2H), 4.75 (t, J = 6.4 Hz, 1H), 6.61-6.98 (composite, 9H), 7.17-7.27 (composite,
4H). Example 20 Ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-phenoxypropenoic acid

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4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] benzaldehyde (4.0 g, 13.0 mmol) and triethyl 2-phenoxyphosphonoacetic acid (AG Schu
ltz, el. J. Org. Chem. 1983, 48, 3408) (5.07 g, 16.0 mmol) as an E: Z isomer mixture (35:65) by a method similar to that described in Example 1. The title compound (3.7 g, 60%) was prepared as a gum.

¹ H NMR (CDCl ₃ : 200 MHz): 1.05-1.36 (complex, 3H), 3.00-3.11 (complex, 2H), 3.64-3.85 (complex, 4H), 4.09-4.30 (complex, 4H), 6.58-7.13 (Composite, 8H), 7.20
-7.46 (complex, 4H), 7.65 (d, J = 8.7 Hz, 2H). Example 21 Methyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] Phenyl l-2-phenoxypropanoic acid

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Ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-phenoxypropeno obtained from Example 20 The title compound (2,3 g, 64%) was prepared as a gum from the ate (3.7 g, 8.0 mmol) by a method similar to that described in Example 2.

¹ H NMR (CDCl ₃ , 200 MHz): 2.99 (t, J = 5.439 Hz, 2H), 3.15 (d, J = 5.9
9 Hz, 2H), 3.60-3.78 (composite, 7H), 4.13 (t, J = 5.4Hz, 2H), 4.74 (t, J = 6.2
3 Hz, 1H), 6.58-6.89 (Composite, 6H), 6.90-7.06 (Composite, 2H), 7.11-7.30 (Composite,
Example 22 Ethyl (E / Z) -3- [4- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)
Methoxy phenyl] -2-ethoxypropenoic acid

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4- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) obtained in Preparation Example 4
The title compound (0.4 g, 25%) of the E: Z isomer mixture (1: 1) was prepared as a brown liquid from methoxybenzaldehyde (1.2 g, 4.24 mmol) by a method similar to that described in Example 1. .

¹ H NMR (CDCl ₃ , 200 MHz): 1.36 (t, J = 7.IHz, 6H), 2.90 (s, 3H), 3.26
3.45 (composite, 2H), 3.99 (q, J = 7.2Hz, 2H), 4.10-4.38 (composite, 4H), 4.50-4.6
0 (composite, 1H), 6.70 (d, J = 7.47 Hz, 2H), 6.81-6.90 (composite, 5H), 7.75 (d, J
Example 23 Methyl 3- [4- (4-methyl-3,4-dihydro-2H-1,4-benzoxazine-2-y 1) methoxyphenyl] -2-ethoxypropanoic acid

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Ethyl (E / Z) -3- [4- (4-methyl-3,4-dihydro-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropene obtained in Example 22 The title compound (0.25 g, 65%) was prepared as a thick liquid from the acid (0.4 g, 1.0 mmol) by a method similar to that described in Example 2.

¹ H NMR (CDCl ₃ , 200 MHz): 1.16 (t, J = 7.0 Hz, 3H), 2.89 (s, 3H), 2.95 (d, J = 6.2 Hz, 2H), 3, 19-3.41 (Composite, 3H), 3.55-3.66 (Composite, 1H), 3.70
(s, 3H), 3.95-4.24 (complex, 3H), 4.60-4.64 (complex, 1H), 6.64-7.08 (complex, 6H
), 7.15 (d, J = 8.4 Hz, 2H) .Example 24 Ethyl (E / Z) -3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2- Il
) Methoxy phenyl] -2-ethoxypropenoic acid

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From the 4- [4-benzy] -3,4-dihydro-2H-1,4-benzoxazine-2-vl) methoxybenzaldehyde (3.0 g, 8.35 mmol) obtained in Preparation Example 5, By a method similar to that described, the title compound (3.0 g, 76%) of the E: Z isomer mixture (1: 1) was prepared as a syrupy liquid.

¹ H NMR (CDCl ₃ , 200 MHz): 1.33-1.40 (complex, 6H), 3.39-3.44 (complex, 2H), 3.99 (q, J = 7.0 Hz, 2H), 4.11-4.38 (complex, 4H), 4.46 (d, J = 5.0 Hz, 2
H), 4.52-4.66 (Compound, 1H), 6.60-6.97 (Compound, 7H), 7.28 (s, 5H), 7.75 (d, J
= 8.8 Hz, 2H). Example 25 Methyl 3- [4- (4- ~ enzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid

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The ethyl (E / Z) -3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-obtained in Example 24 Ethoxypropenoic acid (1.5 g, 3.17 mmol)
From the title compound (1.5 g, 100%) in a manner analogous to that described in Example 2.

¹ H NMR (CDCl ₃ , 200 MHz): 1.17 (t, J = 7.0 Hz, 3H), 2.96 (d, J = 6.6 Hz
, 2H), 3.3 1-3.57 (Composite, 3H), 3.60-3.70 (Composite, 1H), 3.71 (s, 3H), 3.97-4
.26 (composite, 3H), 4.47 (d, J = 4.0 Hz, 2H), 4.56-4.61 (composite, 1H), 6.68-6.9
0 (complex, 6H), 7.15 (d, J = 8.5 Hz, 2H), 7.29 (s, 5H) .Example 26 3- [4- [2- (2,3-dihydro-1,4-benzoxazine- 4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid

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The methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoate obtained in Example 2 (4.7 g, 12.2 mmol) of methanol (50
10 mL of an aqueous solution of sodium hydride (28 mL). The mixture was stirred at 25 ° C. for 3 hours. The solvent was removed under reduced pressure, the residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate (2 × 100 mL). The combined ethyl acetate layers were combined with water (75 mL), brine (50 mL).
mL), dried (Na ₂ SO ₄ ), filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate to prepare the title compound as a syrupy liquid (3.0 g, 66%).

¹ H NMR (CDCl ₃ , 200 MHz): 1.17 (t, J = 6.96 Hz, 3H), 2.85-3.12 (complex,
2H), 3.40-3.61 (composite, 4H), 3.69 (t, J = 5.72 Hz, 2H), 4.04 (dd, J = 7.38
and 4.27 Hz, 1H), 4.10-4.28 (composite, 4H), 6.52-6.85 (composite, 6H), 7.14 (d, J
= 8.6 Hz, 2H), COOH protons are not observed too broad.

Example 27 3- [4- [2- (2,3-Dihydro-1,4-benzoxazin-t-yl) ethoxy] phenyl] -2-ethoxypropanoic acid sodium salt

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3- [4- [2- (2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid obtained in Example 26 (0.15 g, 0.4 mmol ) And sodium methoxide (23.4 mg) in methanol (5 mL) were stirred at 25 ° C for 2 hours. The solvent was removed and the residue was triturated with dry ether (3 × 10 mL). The precipitated solid filtered filtration, dried over dry ether _{P 2 0 5 (2 × 5} mL) under vacuum, was the title compound as a colorless hygroscopic solid (0.12 g, 75%) was prepared.

¹ H NMR (DMSO-d ₆ , 200 MHz): δ 0.98 (t, J = 6.83 Hz, 3H), 2.60-2.69 (complex, 1H), 2.78-2.92 (complex, 1H), 3.05-3.21 (Composite, 2H), 3.41-3.75 (Composite, 5H
), 4.08-4.21 (complex, 4H), 6.49-6.85 (complex, 6H), 7.12 (d, J = 8.3 Hz, 2H) .Example 28 3- [2- (2,3-dihydro-1,4- Benzoxazin-4-yl) methylbenzofuran-5-yl
] -2-ethoxy-propanoic acid

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The methyl 3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran-5-yl] -2-ethoxy-propanoate obtained in Example 5 (0.6 g, 1.51 mmol) from Example 26
The title compound (0.5 g, 87%) was prepared as a gum by a method analogous to that described in (1).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.26 (t, J = 7.06 Hz, 3H), 3.05-3.28 (complex, 2H), 3.40-3.68 (complex, 4H), 4.09 (dd, J = 7.47 and 4.24 Hz, 1H), 4.28
(t, J = 4.15 Hz, 2H), 4.53 (s, 2H), 6.52 (s, 1H), 6.60-6.90 (composite, 4H),
7.13 (d, J = 8.7 Hz, 1H), 7.32-7.36 (complex, 2H), COOH protons are too broad to be observed Example 29 3- [4- [2- (2,3-dihydro-1,4- Benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxy-propanoic acid

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The methyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoate obtained in Example 6 (2.3 g, 5.73) mmol) from the title compound (1.4 g, 63%) as a gum in a manner analogous to that described in Example 26.

¹ H NMR (CDCl ₃ , 200 MHz) δ: 1.18 (t, J = 7.0 Hz, 3H), 2.82-3.15 (complex, 4H), 3.40-3.68 (complex, 2H), 3.70-3.81 (complex 4H), 4.05 (dd, J = 7.29, 4.
33 Hz, 1H), 4.16 (t, J = 5.72 Hz, 2H), 6.68-6.74 (composite, 2H), 6.81 (d, J =
8.5 Hz, 2H), 6.94-7.06 (complex, 2H), 7.14 (d, J = 8.5 Hz, 2H), COOH protons are not observed because they are too broad.Example 30 3- [4- [2- (2,3- Dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid sodium salt

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The 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid obtained in Example 29 (0.5 g, 1.30 mmol ) From the title compound (0.42 g, 81%) as a colorless solid by a method similar to that described in Example 27.

¹ H NMR (CDCl ₃ 200 MHz): δ 0.98 (t, J = 7.0 Hz, 3H), 2.72-3.25 (complex, 5H), 3.30-3.51 (complex, 1H), 3.61-3.73 (complex, 4H), 3.82-3.91 (composite, 1H), 4.04 (t, J = 5.72 Hz, 2H), 6.52-6.79 (composite, 4H), 6.91-7.03 (composite, 2H),
7.10 (d, J = 8.4 Hz, 2H). Example 31 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl l-2-ethoxy-propane Amide

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Oxalyl chloride (0.28 mL, 3.1 mmol) and 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2 obtained in Example 29. -Ethoxypropanoic acid (
A solution of 0.6 g (1.55 mmol) in dry dichloromethane (10 mL) was refluxed for 2 hours. The solvent and excess oxalyl chloride were 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 chloroform layers were washed with water (25 mL), dried (Na ₂ SO ₄ ), filtered and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (7: 3) as eluent to give the title compound (0.32 g, 54%) as a white solid. mp: 120-122 ° C. ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.15 (t, J = 6.96 Hz, 3H), 2.81-3.20 (complex, 4H), 3.38-3.58 (complex, 2H), 3.71 -3.90 (composite, 4H), 3.91 (dd, J = 7.38 an
d 3.73 Hz, 1H), 4.16 (t, J = 5.58 Hz, 2H), 5.54 (bs, D ₂ O exchangeable, 1H
), 6.44 (bs, D ₂ O exchange, 1H), 6.59-6.84 (complex, 4H), 6.92-7.19 (complex, 4H) .Example 32 N-methyl-3- [4- [2- (2, 3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxy-propanamide

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3- [4- [2- (2,3-Dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid obtained in Example 29 (0.3 g, 0.78 mmol) And triethylamine (0.
To an ice-cooled solution of 162 g (1.6 mmol) in dry dichloromethane (10 mL) was added pivaloyl chloride (0.10 g, 0.86 mmol) and stirring was continued at 0 ° C. for 30 minutes. Methylamine (40% solution) (0.124 mL) was added to the above reaction mixture at 25 ° C, and stirring was continued at 25 ° C for 1 hour. Water (20 mL) was added and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel using a mixture of ethyl acetate and petroleum ether (1: 1) as eluent to give the title compound as a colorless solid. mp: 80-82 ° C. ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.11 (t, J = 7.0 Hz, 3H), 2.76 (d, J = 4.
89Hz, 3H), 2.81-2.88 (Composite, 1H), 3.01-3.12 (Composite, 3H), 3.39-3.52 (Composite,
2H), 3.70-3.81 (composite, 4H), 3.86-3.91 (composite, 1H), 4.14 (t, J = 5.81 Hz, 2H
), 6.48 (bs, 1H), 6.61-6.81 (complex, 4H), 6.94-7.14 (complex, 4H) .Example 33 3- [4- [2- (2,3-dihydro-1,4-benzoxazine) -4-yl) ethoxy] phenyl] -2-ethoxy-propanamide

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3- [4- [2- (2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid obtained in Example 26 (0.25 g, 0.67 mmol ) And aqueous ammonia (4 mL
) From the title compound as a white solid (0.2 g, 8
0%) was prepared.

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.13 (t, J = 6.96 Hz 3H), 2.81-2.93 (complex, 1H), 3.03-3.19 (complex, 1H), 3.34-3.59 (complex, 4H), 3.69 (t, J = 5.53 Hz,
2H), 3.88 (dd, J = 7.43 and 3.7 Hz, 1H), 4.15 (t, J = 5.58 Hz, 2H), 4.28
(t, J = 4.24 Hz, 2H), 5.49 (bs, 1H, D 2 O exchangeable), 6.43 (bs, 1H, D 2 O exchangeable), 6.68-6.87 (complex, 6H), 7.15 (d, J = 8.49 Hz, 2H). Example 34 N-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxy-propane Amide

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3- [4- [2- (2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid obtained in Example 26 (0.3 g, 0.8 mmol) and methylamine (40% solution) (2 mL) to give the title compound (0.23 g, 74%) as a white solid by a method similar to that described in Example 32. mp: 97-99 ° C. ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.14 (t, J = 7.0 Hz, 3H), 2.76 (d, J = 4.9
8 Hz, 3H), 4.80-4.90 (Composite, 1H), 3.02-3.14 (Composite, 1H), 3.35-3.45 (Composite,
2H), 3.52 (t, J = 4.57 Hz, 2H), 3.68 (t, J = 5.81 Hz, 2H), 7.88 (dd, J = 7.
06 and 3.74 Hz, 1H), 4.14 (t, J = 5.72 Hz, 2H), 4.22 (t, J = 4.15 Hz, 2H),
6.50 (bs, 1H), 6.55-6.89 (complex, 6H), 7.11 (d, J = 8.3 Hz, 2H) .Example 35 N-benzyl-3- [4- [2- (2,3-dihydro-1) , 4-Benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxy-propanamide

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3- [4- [2- (2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid obtained in Example 26 (0.3 g, 0.8 mmol ) And benzylamine (0.
095 g (0.88 mmol) to give the title compound (0.25 g, 67%) as a white solid by a method similar to that described in Example 32. mp: 94-96 ° C. ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.11 (t, J = 7.0 Hz, 3H), 2.82-3.18 (complex, 2H), 3.40-3.55 (complex, 4H), 3.70 (t, J = 5.49Hz, 2H), 3.94-3.98 (composite, 1
H), 4.14 (t, J = 5.72 Hz, 2H), 4.23 (t, J = 4.24 Hz, 2H), 4.28-4.52 (composite,
2H), 6.60-6.87 (complex, 6H), 7.06-7.32 (complex, 7H). CONH proton too wide and not observed.Example 36 N-benzyl-3- [4- [2- (2,3-dihydro- 1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxy-propanamide

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3- [4- [2- (2,3-Dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid obtained in Example 29 (0.25 g, 0.65 mmol ) And benzylamine (0.0
The title compound (0.22 g, 74%) was prepared from 76 g (0.71 mmol) as a white solid by a method similar to that described in Example 32. mp: 92-93 ° C. ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.15 (t, J = 7.0 Hz, 3H), 2.88-3.20 (complex, 4H) 3.42-3.60 (complex, 2H), 3.73- 3.87 (composite, 4H), 3.98-4.06 (composite, 1H),
4.18 (t, J = 5.72 Hz, 2H), 4.30-4.56 (composite, 2H), 6.61-6.90 (composite, 4H), 7.
00-7.43 (complex, 9H), CONH proton is too broad to be observed Example 37 2-Methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy ] Phenyl] -2-ethoxy-propanoic acid

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Methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazine-4) obtained in Example 7
-Yl) ethoxy] phenyl] -2-ethoxypropanoic acid (0.5 g, 1.2 mmol) from Example 26
The title compound (0.3 g, 62%) was prepared as a gummy liquid by a method analogous to that described in (1).

¹ H NMR (CDCl ₃ , 200 MHz) δ: 1.24 (complex, 6H), 2.98, 3,04 (1H each, 2d
, J = 14.1 Hz each, 3.51 (t, J = 4.25 Hz, 2H), 3.49-3.71 (composite, 4H), 4.15 (
t, J = 5.63 Hz, 2H), 4.22 (t, J = 4.48 Hz, 2H), 6.60-6.87 (Composite, 6H), 7.07
(d, J = 8.67 Hz, 2H), COOH protons are too broad to be observedExample 38 2-Methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ) Ethoxy] phenyl] -2-ethoxy-propanoic acid, sodium salt

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2-Methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] pheny] -2-ethoxypropanoic acid obtained in Example 37 (0.22 g, 0.57 mmol) to give the title compound (0.12 g, 51%) as a white solid by a method similar to that described in Example 37.

¹ H NMR (DMSO-d ₆ , 200 MHz) δ: 0.96-1.08 (complex, 6H), 2.79 (s, 2H), 3.
28-3.52 (Composite, 4H), 3.64 (t, J = 5.3 Hz, 2H), 4.05-4.19 (Composite, 4H), 6.48-
6.59 (complex, 1H), 6,62-6.86 (complex, 4H), 7.03-7.28 (complex, 3H) .Example 39 2- (2-Fluorobenzyl) -3- [4- [2- (2,3 -di hyd ro-1,4-benzoxazin-4-yl) ethoxyl phenyl] -2-ethoxypropanoic acid

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Methyl 2- (2-fluorobenzyl) -3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2 obtained in Example 8 -Ethoxy-propanoic acid (0.6g, 1.2
mmol) from the title compound (0.25 g, 42%) as a gummy liquid by a method similar to that described in Example 26.

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.12 (t, J = 6.82 Hz, 3H), 1.65 (bs, 1H,
D ₂ O exchangeable), 3.11-3.42 (complex, 4H), 3.50 (t, J = 4.34 Hz, 2H), 3.68 (t, J =
5.67 Hz, 2H), 3.70-3.89 (composite, 2H), 4.14 (t, J = 5.67 Hz, 2H), 4.21 (t, J
= 4.15 Hz, 2H), 6.62-6.86 (complex, 6H), 7.03-7.12 (complex, 4H), 7.18-7.30 (complex, 2H) .Example 40 2- (2-Fluorobenzyl) 3- [4 [2 -(2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid sodium salt

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2- (2-Fluorobenzyl) -3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-obtained in Example 39 Ethoxy-propanoic acid (0.22 g, 0.45 mmol
) From the title compound (0.1%) as a white solid by a method analogous to that described in Example 27.
1 g, ¹ was 48%) was prepared _{H NMR (CDCl 3, 200 MHz} ): δ 1.02 (t, J = 6.65Hz, 3H), 2.75-2.92 ( complex, 4H), 3.39-3.58 (complex, 4H), 3.62 (bs, 2H), 4.04-4.20 (composite, 4H), 6.49-6
.82 (complex, 5H), 6.90-7.28 (complex, 6H), 7.49-7.13 (complex, 1H) .Example 41 3- [4- [2- (3-oxo-2H-1,4-benzoxazine- 4-yl) ethoxy 1-phenyl] -2-
Ethoxy-propanoic acid

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The methyl 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy] phenyl l-2-ethoxypropanoate obtained in Example 10 (1.0 g, 2.5 g mmol) was prepared as a white solid (0.75 g, 77%) by a method similar to that described in Example 26.
mp: 90-03 ° C. ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.18 (t, J = 6.96 Hz, 3H), 2.88-3.13 (complex, 2H), 3.41-3.63 (complex, 2H), 4.06 (dd, J = 7.43 and 4.33 Hz, 1H), 4.25
-4.52 (complex, 4H), 4.61 (s, 2H), 6.80 (d, J = 8.62 Hz, 2H), 7.00-7.34 (complex, 6H), COOH protons are too broad to be observed.Example 42 3- [4 -[2- (3-Oxo-2H-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid sodium salt

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3- [4- [2- (3oxo-2H-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid obtained in Example 41 (0.2 g, 0.51 mmol) From the title compound (0.12 g, 56%) was prepared in an analogous manner to that described in Example 27.

¹ H NMR (CDCl ₃ , 200 MHz): δ 0.99 (t, J = 6.97 Hz, 3H), 2.61-2.80 (complex, 2H), 3.32-3.57 (complex, 1H), 3.60-3.72 (complex , 1H), 3.65-3.70 (complex, 1H), 4.18 (bs, 2H), 4.30 (bs, 2H), 4.68 (s, 2H), 6.78 (d, J = 8.4 Hz, 2H),
7.03-7.14 (complex, 5H), 7.42 (d, J = 7.06 Hz, 1H). Example 43 3- [6- [2- (2,3-dihydro-1,4-benzothiazin A-yl) ethoxy] naphthyl ] -2-ethoxy-propanoic acid

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The methyl 3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl] -2-ethoxypropanoate obtained in Example 12 (1.2 g, 2.66 mmol) to give the title compound (0.8 g, 69%) as a white solid by a method similar to that described in Example 26. mp: 102-104 ° C. ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.15 (t, J = 7.01 Hz, 3H), 3.06 (t, J = 4.
98 Hz, 2H), 3.08-3.63 (composite, 4H), 3.77-3.83 (composite, 4H), 4.15 (dd, J = 4.
15 and 4.18 Hz, 1H), 4.28 (t, J = 5.95 Hz, 2H), 6.59-6.79 (composite, 2H), 6.9
6-7.36 (complex, 5H), 7.61-7.79 (complex, 3H), COOH protons are too wide to be observed Example 44 3- [6- [2- (2,3-dihydro-1,4-benzothiazine 4yl ) Ethoxy] naphthyl] -2-ethoxy-propanoic acid sodium salt

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3- [6- [2- (2,3-Dihydro-1,4-benzothiazi-4-yl) ethoxy] naphthyl] -2-ethoxypropanoic acid obtained in Example 43 (0.2 g, 0.457 mmol) to give the title compound (0.16 g, 76%) as a white solid in a manner analogous to that described in Example 27. mp: 138-140 ° C. ¹ H NMR (DMSO-d ₆ , 200 MHz): δ 0.98 (t, J = 7.06 Hz, 3H), 2.72-2.90 (composite, 1H), 2.92-3.21 (composite, 3H) , 3.32-3.54 (Compound, 2H), 3.6 1-3.91 (Compound, 5
H), 4.28 (bs, 2H), 6.56 (t, J = 7.00Hz, 1H), 6.73-7.00 (composite, 3H), 7.05-7
.30 (complex, 2H), 7.38 (d, J = 8.3 Hz, 1H), 7.60-7.82 (complex, 3H) .Example 45 3- [4- [2- (2,3-dihydro-1,4- Benzoxazin-4-yl) ethoxy] phenyl] -2-hydroxy-propanoic acid

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The ethyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-hydroxypropanoate obtained in Example 13 (0.15 g, 0.40 mmol) from the title compound as a brown syrupy liquid (0.06 g, 4
3%) was prepared.

¹ H NMR (CDCl ₃ , 200 MHz): δ 2.85-3.19 (complex, 2H), 3.43 (t, J = 4.15 H
z, 2H) 3.61 (t, J = 5.49 Hz, 2H), 4.07 (t, J = 5.40 Hz, 2H), 4.16 (t, J = 4.
48 Hz, 2H), 4.45 (bs, 1H), 6.50-6.82 (composite, 6H), 7.08 (d, J = 7.88 Hz, 2H
), COOH and OH protons are too broad to be observed Example 46 3- [4-12- (2,3-Dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-hydroxy-propanoic acid

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The ethyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-hydroxypropanoate obtained in Example 14 (1.7 g, 4.39) mmol) was prepared as a white solid (0.7 g, 46%) by a method similar to that described in Example 26. mp: 74-76 ° C. ¹ H NMR (CDCl ₃ , 200 MHz): δ 2.88-3.18 (complex, 4H), 3.69-3.79 (complex, 4
H), 4.15 (t, J = 5.72 Hz, 2H), 4.45 (dd, J = 6.73 and 4.79 Hz, 1H), 4.51-4
.97 (bs, D ₂ O exchangeability, 1H), 6.65-6.89 (complex, 4H), 6.94-7.17 (complex, 4H), COO
H proton is too broad to be observed Example 47 3- [4- [2- (2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-benzyloxy-propanoic acid

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The ethyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin JI: -yl) ethoxy] phenyl] -2-benzyloxypropanoate obtained in Example 15 (0.24 g, 0.52 mmol) from Example 26
The title compound (0.15 g, 67%) was prepared as a thick liquid by a method similar to that described in 1.

¹ H NMR (CDCl ₃ , 200 MHz): δ1.40-2.80 (br, 1H, D ₂ O exchangeability), 2.99-3.18
(Compound, 2H), 3.51 (t, J = 4.34 Hz, 2H), 3.70 (t, J = 5.82 Hz, 2H), 4.13-4.2
4 (composite, 5H), 4.51 (d, J = 17.0 Hz, 2H), 6.60-6.89 (composite, 6H), 7.10-7.37
(Compound, 7H). Example 48 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-b
enzyi oxy-propanoic acid sodium salt

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3- [4- [2- (2,3-Dihydro-1,4-benzoxazine-4-y 1) ethoxy] phenyl] -2-benzyloxy-propanoic acid obtained in Example 47 (0.13 g , 0.30 mmol) from the title compound (0.1 g, 73 g) as a cream colored hygroscopic solid by a method analogous to that described in Example 27.
%) Was prepared.

¹ H NMR (DMSO-d ₆ , 200 MHz): δ 2.62-2.74 (complex, 1H), 2.89-2.98 (complex, 1H), 3.48 (t, J = 4.2 Hz, 2H), 3.67 (t , J = 5.48Hz, 2H), 4.12-4.26 (Composite, 5H), 4.65 (d, J = 12.45Hz, 2H), 6.45-6.84 (Composite, 6H), 7.12-7.25 (Composite, 7H) .Example 49 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) etboxy] phenyl] -2-
Butoxypropanoic acid

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

¹ H NMR (CDCl ₃ , 200 MHz): δ 0.87 (t, J = 7.15 Hz, 3H), 1.25-1.40 (complex, 2H), 1.49-1.66 (complex, 2H), 2.95-3.15 ( Compound, 2H), 3.43-3.53 (Compound, 4H
), 3.68 (t, J = 5.49 Hz, 2H), 4.00-4.12 (composite, 1H), 4.14 (t, J = 5.65 Hz,
2H), 4.22 (t, J = 4.25 Hz, 2H), 6.60-6.89 (composite, 6H), 7.12 (d, J = 8.39 H
z, 2H), COOH protons are too broad to be observed Example 50 3- [4- [2- (2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-butoxypropane Acid sodium salt

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3- [4- [2- (2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-butoxypropanoic acid obtained in Example 49 (0.2 g, 0.5 mmol ) From the title compound (0.12 g, 57%) as a hygroscopic cream solid by a method similar to that described in Example 27.

¹ H NMR (DMSO-d ₆ , 200 MHz): δ 0.78 (t, J = 7.06 Hz, 3H), 1.16-1.56 (complex, 4H), 2.52-2.64 (complex, 1H), 2.79-2.87 (Compound, 1H), 2.99-3.18 (Compound, 2H
), 3.40 (bs, 2H), 3.66 (t, J = 5.31 Hz, 2H), 4.10-4.25 (composite, 5H), 6.52-6.
90 (complex, 6H), 7.12 (d, J = 8.3 Hz, 2H). Example 51 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl ] -2-Hexyloxy-propanoic acid

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The ethyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-hexyloxypropanoate obtained in Example 17 (0.3 g , 0.65 mmol) as a greenish liquid by a method analogous to that described in Example 26 (0.17 g, 6
0%) was prepared.

¹ H NMR (CDCl ₃ , 200 MHz): δ 0.86 (t, J = 5.72 Hz, 3H), 1.25-1.33 (complex, 4H), 1.41-1.75 (complex, 4H), 2.94-3.06 (t (Compound, 2H), 3.36-3.58 (Compound, 4H
), 3.68 (t, J = 5.49 Hz, 2H), 4.01-4.06 (composite, 1H), 4.14 (t, J = 5.7 Hz, 2
H), 4.22 (t, J = 4.15 Hz, 2H), 6.71-7.08 (complex, 6H), 7.12 (d, J = 8.4 Hz, 2H), COOH protons are too wide to be observed.Example 52 3- [4 -[2- (2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid sodium salt

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3- [4- [2- (2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-hexyloxypropanoic acid obtained in Example 51 (0.18 g, 0.42 mmol) was prepared the title compound (0.1 g, 52%) as a white hygroscopic solid by a method similar to that described in Example 27.

¹ H NMR (DMSO-d ₆ , 200 MHz): δ 0.82 (t, J = 5.72 Hz, 3H), 1.10-1.45 (complex, 8H), 2.75-2.96 (complex, 2H), 3.35-3.56 (Composite, 4H), 3.67 (t, J = 5.3Hz,
2H), 4,08-4.21 (Composite, 5H), 6.50-6.82 (Composite, 6H), 7.12 (d, J = 8.0Hz, 2H)
Example 53 3- [4- [2- (2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-
Phenoxypropanoic acid

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The methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoate obtained in Example 19 (0.2 g, 0.461 mmol) from the title compound (0.1 g, 53%) as a colorless liquid by a method analogous to that described in Example 26.
Was prepared.

¹ H NMR (CDCl ₃ , 200 MHz): δ 2.40-2.80 (bs, 1H, D ₂ O exchangeable), 3.
22 (d, J = 5.8 Hz, 2H), 3.49 (t, J = 4.25 Hz, 2H), 3.67 (t, J = 5.81 Hz, 2
H), 4.14 (t, J = 5.81 Hz, 2H), 4.21 (t, J = 4.16 Hz, 2H), 4.82 (t, J = 5.9
Hz, 1H), 6.61-7.02 (complex, 8H), 7.17-7.30 (complex, 5H) Example 54 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy) ] Phenyl] -2-phenoxypropanoic acid

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

¹ H NMR (CDCl ₃ , 200 MHz): δ 3.02 (t, J = 5.0 Hz, 2H), 3.22 (d, J = 6.2
5Hz, 2H), 3.68-3.78 (composite, 4H), 4.14 (t, J = 5.81Hz, 2H), 4.50 (t, J = 6.1
9 Hz, 1H), 4.90-5.40 (b, 1H, D ₂ O exchangeability), 6.58-6.86 (complex, 7H), 6.94-7.07 (complex, 2H), 7.18-7.29 (complex, 4H) .Example 55 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoic acid sodium salt

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3- [4- [2- (2,3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoic acid obtained in Example 53 (0.1 g, 0.24 mmol ) Was prepared the title compound (0.05 g, 48%) as a water-absorbing solid by a method similar to that described in Example 27.

¹ H NMR (DMSO-d ₆ , 200 MHz): δ 2.81-3.09 (complex, 2H), 3.42 (bs, 2H), 3
.65 (t, J = 4.5Hz, 2H), 4.12 (bs, 4H), 4.22-4.32 (composite, 1H), 6.50-6.92 (composite, 8H), 7.10-7.33 (composite, 5H) .Example 56 methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoic acid

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The methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoate obtained in Example 19 (0.3 g, 0.69 mmol) to give the title compound (0.27 g, 87%) as a syrupy liquid in a manner analogous to that described in Example 7.

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.39 (s, 3H), 3.09, 3.26 (1H each, 2d, J
= 13.7 Hz each), 3.51 (t, J = 4.3 Hz, 2H), 3.66-3.73 (composite, 5H), 4.15 (t, J = 5.5 Hz, 2H), 4.22 (t, J = 4.24 Hz, 2H) , 6.61-7.01 (composite, 9H), 7.12-7.
22 (complex, 4H). Example 57 2-Methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoic acid

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Methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazine-4) obtained in Example 56
From the -yl) ethoxy] phenyl] -2-phenoxypropanoic acid (0.27 g, 0.60 mmol) by a method analogous to that described in Example 26, the title compound (0.13 g, 50%) as a pale yellow water-absorbing solid. Was prepared.

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.42 (s, 3H), 3.12, 3.29 (1H, 2d, J = 14.1 Hz, respectively), 3.50 (t, J = 4.5 Hz, 2H), 3.69 (t, J = 5.6 Hz, 2H), 4.16 (
t, J = 5.81 Hz, 2H), 4.22 (t, J = 4.5 Hz, 2H), 6.62-7.17 (composite, 9H), 7.21-
7.30 (complex, 4H), COOH too wide to be observed Example 58 2-Methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] 2-phenoxypropanoic acid sodium salt

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The 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoic acid obtained in Example 57 (0.13 g, 0.28 mmol) from the title compound (0.055 g,
46%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.15 (s, 3H), 2.99-3.21 (complex, 2H), 3.47 (bs, 2H), 3.67 (bs, 2H), 4.14 (bs, 4H ), 6.53-6.9 (Composite, 9H), 7.08-7.30
(Complex, 4H). Example 59 Methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy]
] Phenyl l-2-phenoxypropanoic acid

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

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.40 (s, 3H), 3.03 (t, J = 4.9 Hz, 2H), 3
.09, 3.27 (1H each, 2d, J = 13.7 Hz each), 3.70-3.85 (composite, 7H), 4.16 (t
, J = 5.81 Hz, 2H), 6.60-6.89 (complex, 6H), 6.96-7.30 (complex, 7H) .Example 60 2-methyl-3- [4- [2- (2,3-dihydro-1, 4-benzothiazin-4-yl) ethoxy] phenyl l-2-phenoxypropanoic acid

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The methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoate obtained in Example 59 (0.96 g, 2.00 mmol) from the title compound (syrupy liquid) by a method analogous to that described in Example 26.
0.6 g, 65%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.42 (s, 3H), 3.03 (t, J = 5.0 Hz, 2H), 3
.12, 3.30 (1H each, 2d, J = 13.8 Hz each), 3.70-3.80 (composite, 4H), 4.15 (t
, J = 5.5 Hz, 2H), 6.58-7.08 (complex, 8H), 7.18-7.30 (complex, 5H), COOH protons are not observed because they are too broad.Example 61 4-Nitrophenyl 3- [4- [2- (2,3-Dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid:

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The 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid obtained in Example 29 (0.3 g, 0.77 mmol ) And 4-nitrophenol as a yellow liquid by a method similar to that described in Example 32 (0.15
g, 38%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.24 (t, J = 6.92 Hz, 3H), 3.04 (t, J = 5.
16 Hz, 2H), 3.12 (d, J = 6.63 Hz, 2H), 3.46-3.65 (composite, 1H), 3.70-3.86 (
Compound, 5H), 4.16 (t, J = 5.23 Hz, 2H), 4.26 (t, J = 5.5 Hz, 1H), 6.62-6.74
(Compound, 2H), 6.84 (d, J = 8.62 Hz, 2H), 6.94-7.22 (Compound, 6H), 8.23 (d, J
= 9.0 Hz, 2H). Example 62 3- [4- (4-Benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxy-propanoic acid

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The methyl 3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazine obtained in Example 26
-2-yl) methoxyphenyl] -2-ethoxypropanoic acid (0.8 g, 2.16 mmol) as a syrupy liquid from the title compound (0.
4 g, 57%).

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.17 (t, J = 7.0 Hz, 3H), 2.99-3.13 (complex, 2H), 3.31-3.65 (complex, 4H), 4.01-4.24 (complex , 3H), 4.45 (d, J = 3.4 Hz,
2H), 4.52-4.59 (composite, 1H), 6.62-6.68 (composite, 6H), 7.14 (d, J = 8.6Hz, 2H)
, 7.27 (s, 5H), COOH protons are too broad to be observed Example 63 3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] 2-ethoxy-propanoic acid sodium salt

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The 3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl obtained in Example 62
) Methoxyphenyl] -2-ethoxy-propanoic acid (0.2 g, 0.44 mmol) to give the title compound (0.15 g, 75%) as a colorless hygroscopic solid by a method similar to that described in Example 27. .

¹ H NMR (DMSO-d ₆ , 200 MHz): δ 0.99 (t, J = 6.97 Hz, 3H), 2.60-2.90 (complex, 2H), 3.30-3.65 (complex, 5H), 4,16 (d, J = 5.0 Hz, 2H), 4.40-4.65 (composite, 3H), 6.55-6.89 (composite, 6H), 7.14 (d, J = 8.5 Hz, 2H), 7.32 (s, 5H) .Example 64 4-nitrophenyl-3-14- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2
-Yl) methoxyphenyl] -2-ethoxypropanoic acid

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The 3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl obtained in Example 62
) Methoxyphenyl] -2-ethoxypropanoic acid (0.5 g, 1.34 mmol) and 4-nitrophenol to give the title compound (0.6 g, 100%) as a dark brown liquid by a method similar to that described in Example 32. Prepared.

¹ H NMR (CDCl ₃ , 200 MHz): δ 1.25 (t, J = 7.0 Hz, 3H), 3.14 (d, J = 6.6
Hz, 2H), 3.33-3.55 (composite, 3H), 3.69-3.77 (complex, 1H), 4.05-4.31 (complex, 3
H), 4.46 (d, J = 3.4 Hz, 2H), 4.55-4.61 (composite, 1H), 6.63-6.68 (composite, 6H)
, 7.11-7.28 (composite, 7H), 7.52 (d, J = 7.6 Hz, 2H), 8.23 (d, J = 9.0 Hz, 2
H). The compounds of the present invention may be used in blood glucose levels, triglycerides, total cholesterol, LDL, V
LDL was reduced randomly and HDL was increased. This has been demonstrated by in vitro experiments as well as in vivo animal experiments.

Demonstration of Compound Efficacy A) In vitro: a) Measurement of hPPARα activity The ligand binding domain of hPPARα was fused to the DNA binding domain of the yeast transcription factor GAL4 in a eukaryotic expression vector. Using Superfect (Qiagen, Germany) as a transfection reagent, HEK-293 cells were treated with the plasmid and GAL.
Transfections were made with a reporter plasmid having a luciferase gene driven by a 4 specific promoter. Compounds were added at different concentrations 42 hours after transfection and incubated overnight. Luciferase activity was measured in TopCount as an indicator of the PPARα binding / activation ability of the compound using the Packard Luclite kit (Packard, USA) (Top Count, Ivan Sadowski, Bredan Bell, Peter Broag) and Melv
yn Hollis. Gene. 1992, 118: 137-141; Superfect Transfection Reagent Handboo
k.February, 1997. Qiagen, Germany).

B) Measurement of hPPARγ activity The ligand binding domain of hPPARγ1 was fused to the DNA binding domain of the yeast transcription factor GAL4 in a eukaryotic expression vector. Using lipofectamine (Gibco BRL, USA) as a transfection reagent, HEK-293 cells were transfected with the plasmid and a reporter plasmid carrying a luciferase gene driven by a GAL4 specific promoter. 48 hours after transfection, compounds were added at a concentration of 1 μM and incubated overnight. Using the Packard Lucrite Kit (Packard, USA), luciferase activity was measured as an indicator of the ability of the drug to bind / activate PPARγ1, using Packard Top Count.
(Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis
. Gene. 1992. 118: 137-141; Guide to Eukaryotic Transfections with Catio.
nic Lipid Reagents. Life Technologies, GIBCO BRL, USA).

C) Measurement of HMG CoA reductase inhibitory activity Reductase bound to liver microsomes was prepared from rats fed 2% cholestiamine in a Mid-Dark cycle. 100mM KH ₂ PO ₄ , 4mM
Spectrophotometric assays were performed in DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 μg of liver microsomal enzymes. The total volume of the reaction mixture was kept at 1 mL. The reaction was started by adding HMG CoA. The reaction mixture was incubated at 37 ° C. for 30 minutes and the decrease in absorbance at 340 nm was recorded. The reaction mixture without substrate was used as a blank (Goldstein, J. L and Brown, MS 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 test compound inhibited the HMG CoA reductase enzyme.

B) In vivo a) Effects in genetic models Mutations in experimental animal colonies and variable susceptibility to diet have non-insulin dependent diabetes mellitus and hyperlipidemia with obesity and insulin resistance Developed animal models. db / db and ob / ob mice (Diabetes, (1982
Genetic models such as 31 (1): 1-6) and Zucker fa / fa rats have been developed by various laboratories to understand the pathophysiology of the disease and to test the efficacy of novel antidiabetic compounds. (Diabetes, (1983) 32: 830-838; Annu.Rep.Sankyo Res.Lab. (1
994). 46: 1-57). A homozygous animal, C57 BL / KsJ-db / db mouse, developed by Jackson Laboratory in the United States, is used for obesity, hyperglycemia, hyperinsulinemia,
And insulin resistance (J. Clin. Invest., (1990) 85: 962-9
67), Heterozygotes are lean and have normal blood glucose levels. In the db / db model, mice progressively develop insulin deficiency with aging, a feature commonly observed in late stages of human type II diabetes when blood glucose levels are poorly regulated . Pancreatic stages and their course vary from model to model. Since this model mimics type II diabetes, compounds of the invention were tested for blood glucose and triglyceride lowering activity.

8-14 week old male C57BL / Ks-db / db mice weighing 35-60 grams and bred in a DRF (Dr. Reddy's Research Foundation) animal room were used for the experiments. . Mice receive standard feed (National Institute of Nutrition (NIN), Hyderabad
, India) and acid water. Animals with blood glucose above 350 mg / dL were used for the test. The number of animals in each group was four.

The test compound was suspended in 0.25% carboxymethylcellulose and administered to the test group by gavage daily for 6 days at a dose of 0.1-30 mg / kg. The control group received vehicle (dose 10 mL / kg). On day 6, one hour after administration of test compound / vehicle, a blood sample was taken to assess biological activity.

Random blood glucose and triglyceride levels were measured by collecting blood (100 μL) from the orbital sinus using heparinized capillaries in tubes containing EDTA that were centrifuged to obtain plasma. Plasma glucose and triglyceride levels, respectively glucose oxidase and glycerol -3-PO ₄ oxidase / peroxidase enzyme (Dr. Reddy's Lab Diagnostic Division Kits , Hy
derabad India) method.

The blood glucose and triglyceride lowering activity of the test compound was calculated according to the formula.

In the above tests, no adverse effects were observed for any of the indicated compounds of the present invention.

[0219]

[Table 1]

[0220] Ob / ob mice, 5 weeks old, were obtained from Bomholtgard, Denmark, and used at 8 weeks of age. 10-week-old Zuck from IffaCredo, France
er fa / fa fatty rats were obtained and used at 13 weeks of age. Animals were housed at 25 ± 1 ° C. under a 12-hour light-dark cycle. Animals receive standard laboratory chow (NIN,
Hyderabad, India) and water (Fujiwara, T., Yoshioka, S., Yoshiok
a, T. Ushiyama, I and Horikoshi, H. Characterization of new oral antidia
betic agent CS-045.Studies in KK and ob / ob mice and Zucker fatty rats.
Diabetes. 1988. 37: 1549-1558).

The test compound was administered at a dose of 0.1-30 mg / kg / day for 9 days. Control animals received vehicle by oral gavage (0.25% carboxymethylcellulose, dose 10
mL / kg).

On days 0 and 9 of treatment, one hour after drug administration, blood samples were taken in the fed state. Blood was collected from the retro-orbital sinus through heparinized capillaries in tubes containing EDTA. After centrifugation, triglycerides, glucose, free fatty acids, and total cholesterol in the plasma sample were separated, and insulin was quantified. Plasma triglyceride, glucose and total cholesterol were measured using a commercially available kit (Dr. Reddy's Laboratory, Diagnostic Division, India). Plasma free fatty acids were measured using a commercial kit from Boehringer Mannheim, Germany. Plasma insulin was measured using a RIA kit (BARC, India). The reduction of the various parameters examined was calculated according to the following formula:

Nine days after the treatment, an oral glucose tolerance test was performed on ob / ob mice.

The mice were fasted for 5 hours and administered 3 gm / kg glucose orally by gavage. Blood samples were taken at 0, 15, 30, 60, and 120 minutes to assess plasma glucose levels.

As known from the literature, such diseases are interconnected,
Experimental data from db / db mice, ob / ob mice, and Zucker fa / fa rats indicate that the novel compounds of the present invention are useful for the treatment of cardiovascular diseases such as diabetes, obesity, hypertension, hyperlipidemia, and other diseases. It also suggests that it has therapeutic utility as prophylactic or routine treatment.

At doses above 10 mg / kg, blood glucose levels and triglycerides are also reduced. Usually, the amount of reduction is dose-dependent and reaches a plateau at certain doses.

B) Plasma triglyceride and cholesterol lowering activity in a hypercholesterolemic rat model Male SD rats (NIN strain) were housed in a DRF animal room. Animals were housed at 25 ± 1 ° C. under a 12-hour LD cycle. Rats in the 180-200 g body weight range were used for the experiments. Animals were rendered hypercholesterolemic by feeding a standard laboratory diet containing 2% cholesterol and 1% sodium cholate [National Nutrition Research Institute (NIN), Hyderabad, India] for 6 days. Throughout the experiment, animals were fed the same diet (Petit, D., Bonnefis, MT, Rey, C and Infante, R. Effects of
ciprofibrate on liver lipids and lipoprotein synthesis in normo- and hyp
erlipidemic rats. Atherosclerosis 1988. 74: 215-225).

The test compound was administered orally at a dose of 0.1 to 30 mg / kg / day for 3 days. The control group was treated with vehicle only (0.25% carboxymethylcellulose; dose 10 mL / kg).

On days 0 and 3 of compound treatment, one hour after drug administration, blood samples were collected in the fed state. Blood was collected from the retro-orbital sinus through heparinized capillaries in tubes containing EDTA. After centrifugation, the plasma sample was
HDL and triglyceride were separated and evaluated. Measurement of plasma triglyceride, total cholesterol, and HDL was performed using a commercially available kit (Dr. Reddy's Laboratory, Diagnos
tic Division, India). LDL and VLDL cholesterol were calculated from data obtained for total cholesterol, HDL, and triglycerides. The measured reduction of the various parameters is calculated according to the formula.

[0230]

FIG. 2

C) Plasma triglyceride and total cholesterol lowering activity in Swiss Albino mice and guinea pigs Male Swiss Albino mice (SAM) and male guinea pigs were obtained from NIN and housed in a DRF animal rearing room. All these animals were housed at 25 ± 1 ° C. under a 12 hour LD cycle. Animals were fed standard laboratory chow (NIN, Hyderabad, India) and water ad libitum. SAMs in the 20-25 g body weight range and guinea pigs in the 500-700 g body weight range were used (Oliver, P., Plancke, MO, Marzin, D., Clavey, V., Sauzieres, J and F.
uchart, JC Effects of fenofibrate, gemfibrozil and nicotinic acid on p
lasma lipoprotein levels in normal and hyperlimidemic mice.Atherosclero
sis. 1988. 70: 107-114).

The test compound was orally administered to Swiss Albino mice at a dose of 0.3-30 mg / kg / day for 6 days. Control mice received vehicle (0.25% carboxymethylcellulose; dose
10 mL / kg). The test compound was orally administered to guinea pigs at a dose of 0.3 to 30 mg / kg / day for 6 days. Control animals were treated with vehicle (0.25% carboxymethylcellulose; dose 5 mL / kg).

On days 0 and 6 of treatment, one hour after drug administration, blood samples were taken in the fed state. Blood was collected from the retro-orbital sinus through heparinized capillaries in tubes containing EDTA. After centrifugation, the plasma samples were separated into triglycerides and total cholesterol, and the plasma samples were separated to determine (Wieland, O.
Methods of Enzymatic analysis: Bergermeyer, HO, Ed., 1963. 211-214; T
rinder, P. Ann. Clin. Biochem. 1969, 6: 24-27). Measurements of plasma triglyceride, total cholesterol, and HDL were performed using a commercially available kit (Dr. Reddy's D
iagnostic Division, Hyderabad, India).

[0234]

[Table 3]

C) Weight loss effect in cholesterol-loaded hamsters: Male Syrian hamsters were obtained from NIN (Hyderabed, India). Animals were housed in a DRF animal room at 15 ± 1 ° C. under a 12 hour light / dark cycle with free access to food and water. Animals received standard laboratory chow (NIN) containing 1% cholesterol from the day of treatment.

Test compounds were administered orally at doses of 1 to 30 mg / kg / day for 15 days. Animals in the control group were treated with vehicle (Mill Q water, 10 ml / kg / day). Body weight was measured every third day.

[0237]

[Table 4]

Formula: 1.% reduction in blood glucose / triglyceride / total cholesterol / body weight is calculated by the formula:% reduction (%) = 1- TT / OT × 100 TC / OC OC = value of control group on day 0 OT = Value of treatment group on day 0 TC = value of control group on test day TT = value of treatment group on test day

2. LDL and VLDL cholesterol levels are calculated by the formula: [LDL cholesterol (mg / dL)] = (total cholesterol) − (HDL cholesterol) − (triglyceride) 5 [VLDL cholesterol (mg / dL)] = (total Calculated according to (cholesterol)-(HDL cholesterol)-(LDL cholesterol).

[Procedure amendment]

[Submission date] October 18, 2001 (2001.10.18)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded image Here, the groups R ¹ , R ² , R ³ , R ⁴ , and the groups R ⁵ and R ⁶ may be the same or different when bonded to a carbon atom, and may be hydrogen, halogen, hydroxy, nitro, cyano, Formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, Alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxy Represents an optionally substituted group selected from carbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; one or both of R ⁵ and R ⁶ are carbon atoms R ⁵ and R ⁶ may be hydrogen, hydroxy, formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl when bonded to a nitrogen atom when attached to an atom; , Heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, al Alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,
X represents an optionally substituted group selected from sulfonic acid derivatives; X represents oxygen, sulfur or a heteroatom selected from NR ¹¹ (where R ¹¹ is hydrogen, or an optionally substituted alkyl, cycloalkyl Represents an aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl group); Ar is an optionally substituted monocyclic or condensed divalent aromatic or heterocyclic group R ⁷ represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, an optionally substituted aralkyl group or forms a bond with an adjacent group R ⁸ ; R ⁸ represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or or represents optionally substituted aralkyl, or R ⁸ forms a bond together with R ^7; R ⁹ is Or an optionally substituted group selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl R ¹⁰ represents hydrogen or an optionally substituted group selected from an alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl group; and Y represents oxygen or NR ¹² (wherein R ¹² represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl); R ¹⁰ and R ^{12 taken} together are a 5- or 6-membered containing carbon atom Ring structure ( Re is optionally oxygen, ;-( CH ₂ may be formed comprising one or more heteroatoms selected from oxygen, sulfur or nitrogen)) n- (O) of the linking group represented by m- nitrogen atom or a carbon May be linked via an atom; n is an integer from 1 to 4 and m is 0 or 1.

Embedded image Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , n, m, Ar, X, R ⁹ and R ¹⁰ are as defined in claim 1 ; R ⁷ and R ⁸ Together represent a bond; Y represents oxygen;-(C
The linking group represented by H ₂ ) _n- (O) _m- may be bonded via a nitrogen atom or a carbon atom; a) reacting the compound of the formula (IIIa) with the compound of the formula (IIIb) And the formula (I
))

Embedded image Wherein all symbols are as defined above;

Embedded image Where R ⁹ and R ¹⁰ are as defined above, and R ¹⁴ is (C ₁ -C ₆ ) alkyl. b) reacting a compound of formula (IIIc) with a compound of formula (IIId) to give a compound of formula (I
))

Embedded image Wherein all symbols are as defined above;

Embedded image Here, R ⁷ and R ⁸ together form a bond, all other symbols are as defined above, and L ¹ is a leaving group. c) reacting a compound of formula (IIIe) with a compound of formula (IIIf) to give a compound of formula (I
))

Embedded image Wherein all symbols are as defined above;

Embedded image Here, R ⁹ = R ¹⁰ , as defined above. d) reacting a compound of formula (IIIa) with a compound of formula (IIIg) to obtain, after dehydration, a compound of formula (I) as defined above;

Embedded image Wherein all symbols are as defined above;

Embedded image Here, R ⁸ , R ⁹ and R ¹⁰ are as defined above. e) reacting a compound of formula (IIIh) with a compound of formula (IIIi) to form a compound of formula (I) wherein m is 1 and all other symbols are as defined above. Get)

Embedded image Wherein all symbols are as previously defined and L ¹ represents a leaving group;

Embedded image Here, R ⁷ and R ⁸ together represent a bond, and R ⁹ , R ¹⁰ and Ar are as defined above. f) reacting a compound of formula (IIIj) with a compound of formula (IIIi) to give a compound of formula (I) wherein m is
1 representing all other symbols are as defined above);

Embedded image Wherein all symbols are as defined above;

Embedded image Wherein R ⁷ and R ⁸ together form a bond, and R ⁹ , R ¹⁰ and Ar are as defined above; and, optionally, g) by any of the methods described above. Converting the obtained compound of formula (I) to a pharmaceutically acceptable salt or pharmaceutically acceptable solvate. .

Embedded image Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , n, m, Ar, X, R ⁹ and R ¹⁰ are as defined in claim 1 ; R ⁷ is a hydrogen atom R ⁸ represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl, or optionally substituted aralkyl; Y represents A linking group represented by-(CH ₂ ) _n- (O) _m- may be bonded via a nitrogen atom or a carbon atom; a) reducing a compound of the formula (IVa) To obtain a compound of formula (I), wherein R ⁷ and R ⁸ each represent a hydrogen atom, and all other symbols are as defined above;

Embedded imageThis is a compound of formula (I), prepared according to any of the methods of claim 6, ⁷ And R⁸Together represent a bond, Y represents an oxygen atom, and all other symbols are
B) reacting a compound of formula (IVb) with an alcohol of formula (IVc) to form a compound as defined above
Obtaining the compound of (I);

Embedded image Wherein all symbols are as defined above, and L ² is a leaving group;

Embedded image Here, R ⁹ is an optionally substituted alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl group C) reacting a compound of formula (IIIh) with a compound of formula (IIIi) to form a compound of formula (I) wherein m represents 1 and all other symbols are as defined above. As defined);

Embedded image Wherein all symbols are as defined above, and L ¹ is a leaving group

Embedded image Wherein all symbols are as defined above; d) reacting a compound of formula (IIIj) with a compound of formula (IIIi) to form a compound of formula (I) wherein m represents 1 , All other symbols are as defined above).

Embedded image Wherein all symbols are as defined above;

Embedded image Here, all symbols are as defined above. e) reacting a compound of formula (IVd) with a compound of formula (IVe) to obtain a compound of formula (I) as defined above;

Embedded image This is because of the formula ( ⁹⁾ where R ⁹ represents a hydrogen atom and all other symbols are as defined above.
Represents a compound of I);

Embedded image Here, R ⁹ is an optionally substituted alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl group L ² represents a halogen atom. f) reacting a compound of formula (IIIa) with a compound of formula (IIIg) to obtain a compound of formula (I) after dehydroxylation;

Embedded image Wherein all symbols are as defined above;

Embedded image Here, R ⁸ , R ⁹ and R ¹⁰ are as defined above. g) reacting a compound of formula (IIIc) with a compound of formula (IIId) to give a compound of formula (I
))

Embedded image Wherein all symbols are as defined above;

Embedded image Wherein L ¹ is a leaving group, and all other symbols are as defined above. h) converting a compound of formula (IVf) to a compound of formula (I) as defined above;

Embedded image Wherein all symbols are as defined above; i) reacting the compound of (IVg) with the compound of (IVc) to obtain a compound of formula (I);

Embedded image Wherein all symbols are as defined above;

Embedded image Here, R ⁹ is an optionally substituted alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl group J) splitting the compound of formula (I) obtained by any of the above methods into its stereoisomers; and, optionally, k) obtaining by any of the above methods. Converting the compound of formula (I) or a stereoisomer thereof into a pharmaceutically acceptable salt or pharmaceutically acceptable solvate.

Embedded image Where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , n, m, Ar, X, R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined in claim 1 Y represents NR ¹² wherein R ¹² represents a hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl group; R ¹⁰ and R ^{12 taken} together form a carbon atom A 5- or 6-membered ring structure (optionally containing one or more heteroatoms selected from oxygen, sulfur or nitrogen atoms);-(CH ₂ ) _n- (O) _m- The linking group represented by may be bonded via a nitrogen atom or a carbon atom; a) converting a compound of formula (I) to a compound of formula NHR ¹⁰ R ¹² (R ¹⁰ and R ¹² are as defined above) ) With the appropriate amine of

Embedded image Wherein all symbols are as defined above, and Y represents oxygen or COY
R ¹⁰ represents a mixed anhydride; b) resolving the compound of formula (I) obtained above into stereoisomers; and, optionally, c) converting the compound of formula (I) obtained above into a pharmaceutical compound. Converting to a chemically acceptable salt or a pharmaceutically acceptable solvate.

Embedded image Here, the groups R ¹ , R ² , R ³ , R ⁴ and the groups R ⁵ and R ⁶ may be the same or different when bonded to a carbon atom, and may be hydrogen, halogen, hydroxy, nitro, cyano, formyl. Or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkyl Amino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxy Ruboniruamino, aryloxycarbonylamino, aralkoxycarbonyl amino, carboxylic acid or a derivative thereof, also represents a group optionally substituted selected from a sulfonic acid or a derivative thereof; one or both of R ⁵ and R ^6, carbon R ⁵ and R ⁶ may be hydrogen, hydroxy, formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl when attached to a nitrogen atom; Heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxy X represents an optionally substituted group selected from a carbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl group, carboxylic acid derivative, or sulfonic acid derivative; oxygen, sulfur or represents a hetero atom selected from NR ^11, wherein the alkyl R ¹¹ is substituted with hydrogen or optionally, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or Ararukoki, Ar represents an optionally substituted monocyclic or condensed divalent aromatic or heterocyclic group; R ⁷ is a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or an optionally substituted aralkyl group; R ⁸ is hydrogen Hydroxy, alkoxy, halogen, lower alkyl group, acyl or optionally substituted aralkyl,; R ⁹ is hydrogen or alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylamino A carbonyl, an arylaminocarbonyl, an acyl, a heterocyclyl, a heteroaryl, or an optionally substituted group selected from a heteroaralkyl group; a linking group represented by-(CH ₂ ) _n- (O) _m- It may be attached via an atom or a carbon atom; n is an integer from 1 to 4 and m is 0 or 1.

Embedded image Wherein all symbols are as defined above;

Embedded image Here, R ⁹ is an optionally substituted alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl group. Hal represents a halogen atom;

Embedded image Wherein all symbols are as defined above; b) reacting the compound of formula (IVi) with an alcohol of formula R ⁹ OH, where R ⁹ is as defined above, Obtaining a compound of formula (IVj)

Embedded image Wherein all symbols are as defined above; c) reacting the compound of formula (IVj) obtained above with trialkylsilyl cyanide to give a compound of formula (IVf) (all symbols are (As defined above).

Embedded image Here, the groups R ¹ , R ² , R ³ , R ⁴ and the groups R ⁵ and R ⁶ may be the same or different when bonded to a carbon atom, and may be hydrogen, halogen, hydroxy, nitro, cyano, formyl. Or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkyl Amino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxyca Ruboniruamino, aryloxycarbonylamino, aralkoxycarbonyl amino, represents a carboxylic acid or a derivative thereof or a sulfonic acid or an optionally substituted group selected from derivatives thereof,; R ⁵ and R ⁶ are attached to a carbon atom Represents an oxo group; R ⁵ and R ⁶ are hydrogen, hydroxy, formyl, or alkyl, cycloalkyl, alkoxy,
Cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl,
Heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxy selected from X is oxygen, sulfur or NR ^11; carbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, represents alkylthio, thioalkyl groups, carboxylic acid derivative or an optionally substituted group selected from sulfonic acid derivatives, It represents a hetero atom, wherein R ¹¹ is hydrogen or optionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl addition, Selected from aralkoxycarbonyl groups; Ar is represents a divalent aromatic or heterocyclic group monocyclic or fused ring system which is optionally substituted; R ⁷ is a hydrogen atom, hydroxy, alkoxy, halogen, lower Represents an alkyl or an optionally substituted aralkyl group; R ¹⁰ represents hydrogen or an optionally substituted group selected from an alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl group. Y represents oxygen; the linking group represented by-(CH ₂ ) _n- (O) _m- may be bonded through a nitrogen atom or a carbon atom; n is an integer of 1 to 4; , M is 0 or 1.

Embedded image Wherein L ¹ is a leaving group, and all other symbols are as defined in claim 11 ;

Embedded image Wherein R ⁸ is a hydrogen atom, and all other symbols are as defined in claim 11 ;

Embedded image Wherein R ⁸ is a hydrogen atom, and all other symbols are as defined above; b) reacting the compound of formula (IVk) obtained above with a diazotizing agent Method.

Embedded image

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 9/48 A61K 9/48 31/538 31/538 31/5415 31/5415 A61P 3/04 A61P 3 / 04 3/06 3/06 3/10 3/10 9/10 101 9/10 101 103 103 103 13/12 13/12 17/06 17/06 19/10 19/10 25/28 25/28 C07D 279 / 16 C07D 279/16 413/06 413/06 // (A61K 31/538 (A61K 31/538 45:00) 45:00) (A61K 31/5415 (A61K 31/5415 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE) LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Lorai, Bly Boushan India, Hyderabad, Andhra Pradesh, 500 016 , Amarpet, 7-1-27 (72) Inventor Lorai, Diya Boushan India, Hyderabad, Andhra Pradesh, 500 016, Amarpet, 7-1-27 (72) Inventor Bazi, Ashok Chanabylappa India, Hyderabad, Andhra Pradesh, 500 016, Amar Pet, 7-1-27 (72) Inventor's culture, Sibara Maya India, Hyderabad, Andhra Pradesh, 500 016, Amarpet, 7-1-27 (72) Inventor Ramanu Jam, Rajagoparan India, Hyderabad, Andorra・ Pradesh, 500 016, Amarpet, 7-1-27 (72) Inventor Chakrabati, Ranjan India, Hyderabad, Andhra Pradesh, 500 016, Amarpet, 7-1-27 F Term (Reference) 4C036 AA02 AA05 AA12 AA17 AA18 AA20 4C056 EA02 EA07 EB01 EB03 EC02 EC03 EC08 ED01 4C063 AA01 BB03 CC76 DD54 EE01 4C0 76 AA11 AA22 AA29 AA36 AA54 BB01 CC21 4C086 AA01 AA02 AA03 BC74 BC89 GA02 MA01 MA04 NA14 ZA15 ZA42 ZA45 ZA70 ZA81 ZA89 ZA97 ZB22 ZB26 ZC33 ZC35

Claims (25)

[Claims] 1. A compound of formula (I), a derivative thereof, an analog thereof, a tautomer thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof. Solvate acceptable for: Here, the groups R ¹ , R ² , R ³ , R ⁴ , and the groups R ⁵ and R ⁶ may be the same or different when bonded to a carbon atom, and may be hydrogen, halogen, hydroxy, nitro, cyano, Formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, Alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxy Represents an optionally substituted group selected from carbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; one or both of R ⁵ and R ⁶ are carbon atoms R ⁵ and R ⁶ may be hydrogen, hydroxy, formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl when bonded to a nitrogen atom when attached to an atom; , Heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, al Alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,
X represents an optionally substituted group selected from sulfonic acid derivatives; X represents oxygen, sulfur or a heteroatom selected from NR ¹¹ (where R ¹¹ is hydrogen, or an optionally substituted alkyl, cycloalkyl Represents an aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl group); Ar is an optionally substituted monocyclic or condensed divalent aromatic or heterocyclic group R ⁷ represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, an optionally substituted aralkyl group or forms a bond with an adjacent group R ⁸ ; R ⁸ represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or or represents optionally substituted aralkyl, or R ⁸ forms a bond together with R ^7; R ⁹ is Or an optionally substituted group selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl R ¹⁰ represents hydrogen or an optionally substituted group selected from an alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl group; and Y represents oxygen or NR ¹² (wherein R ¹² represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl); R ¹⁰ and R ^{12 taken} together are a 5- or 6-membered containing carbon atom Ring structure ( Re is optionally oxygen, ;-( CH ₂ may be formed comprising one or more heteroatoms selected from oxygen, sulfur or nitrogen)) n- (O) of the linking group represented by m- nitrogen atom or a carbon May be linked via an atom; n is an integer from 1 to 4 and m is 0 or 1. 2. The compound according to claim 1, wherein when the groups represented by R ^{1 to} R ⁴ and the groups R ⁵ and R ⁶ when bonded to a carbon atom are substituted, the substituent is substituted. Is halogen, hydroxy, or nitro, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, Aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl,
A compound representing an optionally substituted group selected from alkylthio, thioalkyl, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof. 3. The compound according to claim 1, wherein when the groups R ⁵ and R ⁶ bonded to the nitrogen atom are substituted, the substituent is a halogen atom, hydroxy, acyl,
Compounds selected from acyloxy or amino groups. 4. The compound of claim 1, wherein Ar is an optionally substituted divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuranyl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl. Or a azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, or oxazolyl group. 5. The compound according to claim 1, wherein the substituent on the group represented by R ⁹ is halogen, hydroxy, or nitro, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl. , Aralkoxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl group, carboxylic acid Or a derivative or a compound representing an arbitrarily substituted group selected from sulfonic acid or a derivative thereof. 6. A compound of formula (I), a derivative thereof, an analog thereof, a tautomer thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof. A process for preparing a solvate which is acceptable to Here, the groups R ¹ , R ² , R ³ , R ⁴ , and the groups R ⁵ and R ⁶ may be the same or different when bonded to a carbon atom, and may be hydrogen, halogen, hydroxy, nitro, cyano, Formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, Alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxy Represents an optionally substituted group selected from carbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; one or both of R ⁵ and R ⁶ are carbon atoms R ⁵ and R ⁶ may be hydrogen, hydroxy, formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl when bonded to a nitrogen atom when attached to an atom; , Heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, al Alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,
X represents an optionally substituted group selected from sulfonic acid derivatives; X represents oxygen, sulfur or a heteroatom selected from NR ¹¹ (where R ¹¹ is hydrogen, or an optionally substituted alkyl, cycloalkyl Represents an aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl group); Ar is an optionally substituted monocyclic or condensed divalent aromatic or heterocyclic group R ⁷ represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, an optionally substituted aralkyl group or forms a bond with an adjacent group R ⁸ ; R ⁸ represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or or represents optionally substituted aralkyl, or R ⁸ forms a bond together with R ^7; R ⁹ is Or an optionally substituted group selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl R ¹⁰ represents hydrogen or an optionally substituted group selected from an alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl group; and Y represents oxygen or NR ¹² (wherein R ¹² represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl); R ¹⁰ and R ^{12 taken} together are a 5- or 6-membered containing carbon atom Ring structure ( Re is optionally oxygen, ;-( CH ₂ may be formed comprising one or more heteroatoms selected from oxygen, sulfur or nitrogen)) n- (O) of the linking group represented by m- nitrogen atom or a carbon N may be an integer from 1 to 4 and m is 0 or 1. a) reacting a compound of formula (IIIa) with a compound of formula (IIIb) The defined expression (I
To obtain a compound of the formula: Wherein all symbols are as defined above; Where R ⁹ and R ¹⁰ are as defined above, and R ¹⁴ is (C ₁ -C ₆ ) alkyl. b) reacting a compound of formula (IIIc) with a compound of formula (IIId) to give a compound of formula (I
To obtain a compound of the formula: Wherein all symbols are as defined above; Here, R ⁷ and R ⁸ together form a bond, all other symbols are as defined above, and L ¹ is a leaving group. c) reacting a compound of formula (IIIe) with a compound of formula (IIIf) to give a compound of formula (I
To obtain a compound of the formula: Wherein all symbols are as defined above; Here, R ⁹ = R ¹⁰ , as defined above. d) reacting a compound of formula (IIIa) with a compound of formula (IIIg) to obtain, after dehydration, a compound of formula (I) as defined above; Wherein all symbols are as defined above; Here, R ⁸ , R ⁹ and R ¹⁰ are as defined above. e) reacting a compound of formula (IIIh) with a compound of formula (IIIi) to form a compound of formula (I) wherein m is 1 and all other symbols are as defined above. ); Wherein all symbols are as previously defined and L ¹ represents a leaving group; Here, R ⁷ and R ⁸ together represent a bond, and R ⁹ , R ¹⁰ and Ar are as defined above. f) reacting a compound of formula (IIIj) with a compound of formula (IIIi) to give a compound of formula (I) wherein m is
1 and all other symbols are as defined above). Wherein all symbols are as defined above; Wherein R ⁷ and R ⁸ together form a bond, and R ⁹ , R ¹⁰ and Ar are as defined above; and, optionally, g) by any of the methods described above. Converting the obtained compound of formula (I) to a pharmaceutically acceptable salt or pharmaceutically acceptable solvate. . 7. A compound of the formula (I), a derivative thereof, an analogue thereof, a tautomer thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical thereof.
A process for preparing a chemically acceptable solvate, comprising:Where the group R¹, R^Two, R^Three, R^Four, And the group R^FiveAnd R⁶Is when bonded to a carbon atom
May be the same or different and include hydrogen, halogen, hydroxy, nitro, cyano, e
Rumyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy,
Reel, aryloxy, aralkyl, aralkoxy, heterocyclyl, hetero
Aryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, a
Sil, acyloxy, hydroxyalkyl, amino, acylamino, alkyla
Mino, arylamino, aralkylamino, aminoalkyl, alkoxycarbo
Nil, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl
, Aryloxyalkyl, aralkoxyalkyl, alkylthio, thioal
Kill, alkoxycarbonylamino, aryloxycarbonylamino, aral
Coxycarbonylamino, carboxylic acid or its derivative, or sulfonic acid also
Or an optionally substituted group selected from its derivatives;^FiveAnd R⁶One side of
Or both may represent an oxo group when attached to a carbon atom;^FiveAnd R⁶Is
Hydrogen, hydroxy, formyl, or alkyl,
Chloroalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, hetero
Cyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydro
Xyalkyl, amino, acylamino, alkylamino, arylamino, ara
Alkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryl
Ruoxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbo
Nil, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl
, Aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,
Or an optionally substituted group selected from sulfonic acid derivatives; X is oxygen, sulfur or NR¹¹Represents a heteroatom selected from (where R¹¹Is hydrogen or an optionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl,
Coxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl
Ar represents an optionally substituted monocyclic or condensed divalent aromatic group or
Represents a heterocyclic group; R⁷Is a hydrogen atom, hydroxy, alkoxy, halogen, lower
Alkyl represents an optionally substituted aralkyl group, or an adjacent group R⁸With
To form a bond to R⁸Is hydrogen, hydroxy, alkoxy, halogen, lower alkyl
Represents a group, acyl, or an optionally substituted aralkyl, or R⁸Is R⁷With
To form a bond to R⁹Is hydrogen, or alkyl, cycloalkyl, aryl, ara
Alkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarboni
, Alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocy
An optionally substituted one selected from a cryl, heteroaryl, or heteroaralkyl group
Represents a substituted group; R^TenIs selected from hydrogen or an alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl group
Y represents oxygen or NR¹²(Where R¹²Is hydrogen, al
Kill, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroa
A reel or a heteroaralkyl group); R^TenAnd R¹²Are together
A 5- or 6-membered ring structure containing carbon atoms (optionally oxygen, sulfur or nitrogen
(Including one or more heteroatoms selected from hydrogen);-(CH_Twoa) a linking group represented by n- (O) m- may be bonded via a nitrogen atom or a carbon atom; n is an integer from 1 to 4, and m is 0 or 1; The compound of formula (IVa) is reduced to give a compound of formula (I) wherein R⁷And R⁸But each
Which represents a hydrogen atom and all other symbols are as defined above);This is a compound of formula (I), prepared according to any of the methods of claim 6, ⁷ And R⁸Together represent a bond, Y represents an oxygen atom, and all other symbols are
A) reacting a compound of formula (IVb) with an alcohol of formula (IVc) to form a compound as defined above
Obtaining a compound of formula (I);Where all symbols are as defined above and L^TwoIs a leaving group;Where R⁹Is alkyl, cycloalkyl, aryl, aralkyl, alkoxya
Alkyl, alkoxycarbonyl, aryloxycarbonyl, alkylamino
Rubonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl
B) represents an optionally substituted group selected from a heteroaralkyl group; b) reacting a compound of the formula (IIIh) with a compound of the formula (IIIi) to form a compound of the formula (I) wherein m is Represents 1 and all other symbols are as defined above)
Embedded imageWhere all symbols are as defined above and L¹Is a leaving groupWherein all symbols are as defined above; c) reacting a compound of formula (IIIj) with a compound of formula (IIIi) to form a compound of formula (I) wherein m represents 1 , All other symbols are as defined above)
Embedded imageWherein all symbols are as defined above;Here, all symbols are as defined above. d) reacting a compound of formula (IVd) with a compound of formula (IVe) to obtain a compound of formula (I) as defined above;This is R⁹ Represents a hydrogen atom, and all other symbols are as defined above.
Represents a compound of the formula (I);Where R⁹Is alkyl, cycloalkyl, aryl, aralkyl, alkoxya
Alkyl, alkoxycarbonyl, aryloxycarbonyl, alkylamino
Rubonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl
Or an optionally substituted group selected from heteroaralkyl groups,^TwoHa
Represents a logen atom. f) reacting a compound of formula (IIIa) with a compound of formula (IIIg)
Later obtaining a compound of formula (I);Wherein all symbols are as defined above;Where R⁸, R⁹, R^TenIs as defined above. g) reacting a compound of formula (IIIc) with a compound of formula (IIId) to give a compound of formula (I
To obtain a compound of the formula:Wherein all symbols are as defined above;Where L¹Is a leaving group, and all other symbols are as defined above. h) converting a compound of formula (IVf) to a compound of formula (I) as defined above;Wherein all symbols are as defined above; i) reacting the compound of (IVg) with the compound of (IVc) to give a compound of formula (I)
That;Wherein all symbols are as defined above;Where R⁹Is alkyl, cycloalkyl, aryl, aralkyl, alkoxya
Alkyl, alkoxycarbonyl, aryloxycarbonyl, alkylamino
Rubonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl
Or an optionally substituted group selected from heteroaralkyl groups; optionally, j) resolving the compound of formula (I) obtained by any of the above methods into its stereoisomers; Optionally, k) converting the compound of formula (I) or a stereoisomer thereof obtained by any of the above methods into a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate. Method. 8. A compound of formula (I), a derivative thereof, an analog thereof, a tautomer thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof. A process for preparing a solvate which is acceptable for: Here, the groups R ¹ , R ² , R ³ , R ⁴ , and the groups R ⁵ and R ⁶ may be the same or different when bonded to a carbon atom, and may be hydrogen, halogen, hydroxy, nitro, cyano, Formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, Alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxy Represents an optionally substituted group selected from carbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; one or both of R ⁵ and R ⁶ are carbon atoms R ⁵ and R ⁶ may be hydrogen, hydroxy, formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl when bonded to a nitrogen atom when attached to an atom; , Heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, al Alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,
X represents an optionally substituted group selected from sulfonic acid derivatives; X represents oxygen, sulfur or a heteroatom selected from NR ¹¹ (where R ¹¹ is hydrogen, or an optionally substituted alkyl, cycloalkyl Represents an aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl group); Ar is an optionally substituted monocyclic or condensed divalent aromatic or heterocyclic group R ⁷ represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, an optionally substituted aralkyl group or forms a bond with an adjacent group R ⁸ ; R ⁸ represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or or represents optionally substituted aralkyl, or R ⁸ forms a bond together with R ^7; R ⁹ is Or an optionally substituted group selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl R ¹⁰ represents hydrogen or an optionally substituted group selected from an alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl group; and Y represents oxygen or NR ¹² (wherein R ¹² represents hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl); R ¹⁰ and R ^{12 taken} together are a 5- or 6-membered containing carbon atom Ring structure ( Re is optionally oxygen, ;-( CH ₂ may be formed comprising one or more heteroatoms selected from oxygen, sulfur or nitrogen)) n- (O) of the linking group represented by m- nitrogen atom or a carbon may be bonded via an atom; n is an integer from 1 to 4, m is 0 or 1; a) reacting a compound of formula (I), formula NHR ¹⁰ R ¹² (R ¹⁰ and R ¹² Reacting with the appropriate amine (as defined above); Wherein all symbols are as defined above, and Y represents oxygen or COY
R ¹⁰ represents a mixed anhydride; b) resolving the compound of formula (I) obtained above into stereoisomers; and, optionally, c) converting the compound of formula (I) obtained above into a pharmaceutical compound. Converting to a chemically acceptable salt or a pharmaceutically acceptable solvate. 9. A compound of the formula (I) produced by the method according to claim 6, a derivative thereof, an analog thereof, a tautomer thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutical thereof. Or a pharmaceutically acceptable solvate thereof: Wherein the groups R ¹ , R ² , R ³ , R ⁴ and the groups R ⁵ and R ⁶ may be the same or different when attached to a carbon atom, hydrogen, halogen, hydroxy, nitro, Cyano, formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, Acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alcohol Represents an optionally substituted group selected from xycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; one or both of R ⁵ and R ⁶ are R ⁵ and R ⁶ may be hydrogen, hydroxy, formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl when bonded to a nitrogen atom when attached to a carbon atom; , Heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, al Alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives,
Or X represents an optionally substituted group selected from sulfonic acid derivatives; X represents a heteroatom selected from oxygen, sulfur, or NR ¹¹ , wherein R ¹¹ is hydrogen, or an optionally substituted alkyl, cycloalkyl Selected from aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, and aralkoxycarbonyl; Ar is an optionally substituted monocyclic or condensed divalent aromatic or heterocyclic group R ⁷ and R ⁸ together represent a bond; R ⁹ is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl , Heterocyclyl, heteroaryl, or heteroaralkyl groups It represents an optionally substituted group; R ¹⁰ represents hydrogen, or A alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, an optionally substituted group selected from heteroaryl or heteroaralkyl group,; Y is oxygen A linking group represented by-(CH ₂ ) _n- (O) _m- may be bonded via a nitrogen atom or a carbon atom; n is an integer of 1 to 4, and m is It is 0 or 1. 10. A compound of the formula (I) produced by the method according to claim 7, a derivative thereof, an analog thereof, a tautomer thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof. Acceptable salts, pharmaceutically acceptable solvates thereof: Wherein the groups R ¹ , R ² , R ³ , R ⁴ , and the groups R ⁵ and R ⁶ may be the same or different when attached to a carbon atom, hydrogen, halogen, hydroxy, nitro, cyano, Formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, Alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxy Represents an optionally substituted group selected from carbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; one or both of R ⁵ and R ⁶ are carbon atoms R ⁵ and R ⁶ may represent hydrogen, hydroxy, formyl, or alkyl when attached to a nitrogen atom, when attached to an atom;
Cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryl Oxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, carboxylic acid derivative, or sulfonic acid derivative It represents radicals; X is oxygen, represents a heteroatom selected from oxygen, sulfur or NR ^11, wherein the alkyl R ¹¹ is substituted hydrogen, or optionally Selected from cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, and aralkoxycarbonyl groups; an optionally substituted monocyclic or condensed divalent aromatic or heterocyclic group R ⁷ represents a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or an optionally substituted aralkyl group; R ⁸ represents hydrogen, hydroxy,
R ⁹ represents hydrogen, or alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, aryl; alkoxy, halogen, lower alkyl, acyl, or optionally substituted aralkyl; Represents an optionally substituted machine selected from an aminocarbonyl, acyl, heterocyclyl, heteroaryl, or heteroaralkyl group; R ¹⁰ is hydrogen or an alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl Y represents oxygen; a linking group represented by — (CH ₂ ) _n — (O) _m — is bonded through a nitrogen atom or a carbon atom; n is an integer from 1 to 4, and m is 0 or 1. 11. A compound of the formula (I) produced by the method according to claim 8, a derivative thereof, an analog thereof, a tautomer thereof, a stereoisomer thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof. Acceptable salts, pharmaceutically acceptable solvates thereof: Here, the groups R ¹ , R ² , R ³ , R ⁴ and the groups R ⁵ and R ⁶ may be the same or different when bonded to a carbon atom, and may be hydrogen, halogen, hydroxy, nitro, cyano, formyl. Or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkyl Amino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxyca Represents an optionally substituted group selected from rubonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; one or both of R ⁵ and R ⁶ are carbon atoms R ⁵ and R ⁶ when attached to a nitrogen atom represent hydrogen, hydroxy, formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, when attached to an atom;
Heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy,
Heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl group, carboxylic acid derivative, or sulfonic acid derivative optionally substituted X represents a heteroatom selected from oxygen, sulfur or NR ¹¹ , wherein R ¹¹ is hydrogen or an optionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl Or an aralkoxycarbonyl group; Ar is an optionally substituted monocyclic or condensed divalent aromatic or heterocyclic group; R ⁷ is a hydrogen atom, hydroxy, alkoxy, halogen, lower Alkyl or optionally substituted aralkyl It represents a group, or form a bond together with the adjacent group R ^8; R ⁸ represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl, acyl or optionally substituted aralkyl, or R ⁸ together with R ⁷ forms a bond; R ⁹ is hydrogen or alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl,
Represents an optionally substituted group selected from an alkylaminocarbonyl, an arylaminocarbonyl, an acyl, a heterocyclyl, a heteroaryl, or a heteroaralkyl group; R ¹⁰ is hydrogen or an alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl Represents an optionally substituted group selected from an aryl or heteroaralkyl group; Y represents NR ¹² , wherein R ¹² is a hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl group Represents; R ¹⁰ and R ¹² together comprise a carbon atom
5-membered or 6-membered ring structure ;-( CH ₂ may be formed (optionally oxygen, which may include one or more heteroatoms selected from oxygen, sulfur or nitrogen _{atom)) n - (O) m} - in The linking group represented may be linked via a nitrogen or carbon atom; n is an integer from 1 to 4 and m is 0 or 1. 12. An intermediate of formula (IVf): Here, the groups R ¹ , R ² , R ³ , R ⁴ and the groups R ⁵ and R ⁶ may be the same or different when bonded to a carbon atom, and may be hydrogen, halogen, hydroxy, nitro, cyano, formyl. Or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkyl Amino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxy Ruboniruamino, aryloxycarbonylamino, aralkoxycarbonyl amino, carboxylic acid or a derivative thereof, also represents a group optionally substituted selected from a sulfonic acid or a derivative thereof; one or both of R ⁵ and R ^6, carbon R ⁵ and R ⁶ may be hydrogen, hydroxy, formyl, or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl when attached to a nitrogen atom; Heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxy X represents an optionally substituted group selected from a carbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl group, carboxylic acid derivative, or sulfonic acid derivative; oxygen, sulfur or represents a hetero atom selected from NR ^11, wherein the alkyl R ¹¹ is substituted with hydrogen or optionally, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or Ararukoki, Ar represents an optionally substituted monocyclic or condensed divalent aromatic or heterocyclic group; R ⁷ is a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, or an optionally substituted aralkyl group; R ⁸ is hydrogen Hydroxy, alkoxy, halogen, lower alkyl group, acyl or optionally substituted aralkyl,; R ⁹ is hydrogen or alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylamino A carbonyl, an arylaminocarbonyl, an acyl, a heterocyclyl, a heteroaryl, or an optionally substituted group selected from a heteroaralkyl group; a linking group represented by-(CH ₂ ) _n- (O) _m- It may be attached via an atom or a carbon atom; n is an integer from 1 to 4 and m is 0 or 1. 13. The compound of formula (IVf) according to claim 12, wherein R⁷And R ⁸ Represents a hydrogen atom, and all other symbols are as defined in claim 12): a) reacting a compound of formula (IIIa) with a compound of (Ivh) With the compound of formula (Ivi)
And obtaining;Wherein all symbols are as defined above;Where R⁹Is alkyl, cycloalkyl, aryl, aralkyl, alkoxya
Alkyl, alkoxycarbonyl, aryloxycarbonyl, alkylamino
Rubonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl
And Hal represents an optionally substituted group selected from a heteroaralkyl group, and Hal represents a halogen atom;Wherein all symbols are as defined above; b) converting a compound of formula (IVi) to a compound of formula R⁹OH (where R⁹Reacting with an alcohol as defined above) to give a compound of formula (IVj)Wherein all symbols are as defined above; c) reacting the compound of formula (IVj) obtained above with trialkylsilyl cyanide to give a compound of formula (IVf) (all symbols are (As defined above). 14. An intermediate of formula (IVg) Here, the groups R ¹ , R ² , R ³ , R ⁴ and the groups R ⁵ and R ⁶ may be the same or different when bonded to a carbon atom, and may be hydrogen, halogen, hydroxy, nitro, cyano, formyl. Or alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkyl Amino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxyca Ruboniruamino, aryloxycarbonylamino, aralkoxycarbonyl amino, represents a carboxylic acid or a derivative thereof or a sulfonic acid or an optionally substituted group selected from derivatives thereof,; R ⁵ and R ⁶ are attached to a carbon atom Represents an oxo group; R ⁵ and R ⁶ are hydrogen, hydroxy, formyl, or alkyl, cycloalkyl, alkoxy,
Cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl,
Heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxy selected from X is oxygen, sulfur or NR ^11; carbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, represents alkylthio, thioalkyl groups, carboxylic acid derivative or an optionally substituted group selected from sulfonic acid derivatives, It represents a hetero atom, wherein R ¹¹ is hydrogen or optionally substituted alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl addition, Selected from aralkoxycarbonyl groups; Ar is represents a divalent aromatic or heterocyclic group monocyclic or fused ring system which is optionally substituted; R ⁷ is a hydrogen atom, hydroxy, alkoxy, halogen, lower Represents an alkyl or an optionally substituted aralkyl group; R ¹⁰ represents hydrogen or an optionally substituted group selected from an alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl group. Y represents oxygen; the linking group represented by-(CH ₂ ) _n- (O) _m- may be bonded through a nitrogen atom or a carbon atom; n is an integer of 1 to 4; , M is 0 or 1. 15. A process for preparing a compound of formula (IVg) according to claim 14, comprising: a) reacting a compound of formula (IIIh) with a compound of formula (IVl) to form a compound of formula (IVk) Obtaining a compound of the formula: Wherein L ¹ is a leaving group and all other symbols are as defined in claim 14; Wherein R ⁸ is a hydrogen atom, and all other symbols are as defined in claim 14; Wherein R ⁸ is a hydrogen atom, and all other symbols are as defined above; b) reacting the compound of formula (IVk) obtained above with a diazotizing agent Method. 16. The compound according to claim 1, wherein the compound is selected from the group consisting of: ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1, 4-benzoxazin-4-yl) ethoxy
] Phenyl] -2-ethoxypropenoic acid; (±) methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
] Phenyl-2-ethoxypropanoic acid; (+) methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
Phenyl] -2-ethoxypropanoic acid; (-) methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
Phenyl-2-ethoxypropanoic acid; ethyl (E / Z) -3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran-5-yl] -2-ethoxypropene Acid; ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-2-ethoxypropenoic acid; (±) methyl 3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran-5-yl] -2-ethoxypropanoic acid; (+) methyl 3- [2- (2,3-dihydro -1,4-benzoxazin-4-yl) methylbenzofuran-5-yl] -2-ethoxypropanoic acid; (-) methyl 3- [2- (2,3-dihydro-1,4-benzoxazine-4 -Yl) methylbenzofuran-5-yl] -2-ethoxypropanoic acid; (±) methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl 2-ethoxypropanoic acid; (+) methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] fe (-2-) methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid; (-) methyl-2-ethoxypropanoic acid; ±) Methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl
) Ethoxy] phenyl] -2-ethoxypropanoic acid; (+) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl)
(Ethoxy) phenyl] -2-ethoxypropanoic acid; (-) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl)
(Ethoxy) phenyl] -2-ethoxypropanoic acid; (±) methyl 2- (2-fluorobenzyl) -3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) (Ethoxy) phenyl] -2-ethoxypropanoic acid; (+) methyl 2- (2-fluorobenzyl) -3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) (Ethoxy) phenyl] -2-ethoxypropanoic acid; (-) methyl 2- (2-fluorobenzyl) -3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) Ethoxy] phenyl] -2-ethoxypropanoic acid; ethyl (E / Z) -3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy]
Phenyl] -2-ethoxy-propenoic acid; (±) methyl 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy]
Phenyl-2-ethoxy-propanoic acid; (+) methyl 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-ethoxy-propanoic acid; (-) Methyl 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxy-propanoic acid; ethyl (E / Z) -3 -[6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl] -2-ethoxypropenoic acid; (±) methyl 3- [6- [2- (2, 3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl] -2-ethoxypropanoic acid; (+) methyl 3- [6- [2- (2,3-dihydro-1,4-benzothiazine- 4-yl) ethoxy] naphthyl] -2-ethoxypropanoic acid; (-) methyl 3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl] -2 -Ethoxypropanoic acid; Ethyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-hydroxy-propanoic acid Ethyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-hydroxy-propanoic acid; ethyl 3- [4- [2- (2 , 3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-benzyloxy-propanoic acid; ethyl 3- [4- [2- (2,3-dihydro-1,4-benz) Oxazin-4-yl) ethoxy] phenyl] -2-butoxypropanoic acid; ethyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2- Hexyloxypropanoic acid; ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy
] Phenyl-2-phenoxypropenoic acid; (±) methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
] Phenyl-2-phenoxypropanoic acid; (+) methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
Phenyl-2-phenoxypropanoic acid; (-) methyl 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy]
Phenyl-2-phenoxypropanoic acid; ethyl (E / Z) -3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-phenoxypropenoic acid (±) methyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-2-phenoxypropanoic acid; (+) methyl 3- [4- [ 2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-2-phenoxypropanoic acid; (-) methyl 3- [4- [2- (2,3-dihydro-1, 4-benzothiazin-4-yl) ethoxy] phenyl-2-phenoxypropanoic acid; ethyl (E / Z) -3- [4- (4-methyl-3,4-dihydro-2H-1,4-benzoxazine- 2-Il
) Methoxyphenyl] -2-ethoxypropenoic acid; (±) methyl 3- [4- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl
) Methoxyphenyl] -2-ethoxypropanoic acid; (+) methyl 3- [4- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)
Methoxyphenyl] -2-ethoxypropanoic acid; (-) methyl 3- [4- (4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)
Methoxyphenyl] -2-ethoxypropanoic acid; ethyl (E / Z) -3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl]- 2-ethoxypropenoic acid; (±) methyl 3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid; ( +) Methyl 3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoate; (-) methyl 3- [ 4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid; (±) 3- [4- [2- (2 , 3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid and its salts; (+) 3- [4- [2- (2,3-dihydro-1, 4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid and its salts; (-) 3- [4- [2- (2,3-dihydro-1,4- Nzuokisajin 4-yl) ethoxy] phenylcarbamoyl] -2- ethoxy propanoic acid and its salts; (±) 3- [2- (2,3- dihydro-1,4-benzoxazin-4-yl) methylbenzofuran
-5-yl] -2-ethoxypropanoic acid and its salts; (+) 3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran-
5-yl] -2-ethoxy-propanoic acid and its salts; (-) 3- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) methylbenzofuran-
5-yl] -2-ethoxy-propanoic acid and its salts; (±) 3- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) methylbenzofuran-5
-Yl] -2-ethoxy-propanoic acid and its salts; (+) 3- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) methylbenzofuran-5-
Yl] -2-ethoxy-propanoic acid and salts thereof; (-) 3- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) methylbenzofuran-5-
Yl] -2-ethoxy-propanoic acid and salts thereof; (±) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl
] -2-ethoxy-propanoic acid and its salts; (+) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-
2-ethoxy-propanoic acid and its salts; (-) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-
2-ethoxy-propanoic acid and its salts; (±) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl
2-ethoxy-propanamide; (+) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-
2-ethoxy-propanamide; (-) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-
2-ethoxy-propanamide; (±) N-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy
] Phenyl] -2-ethoxypropanamide; (+) N-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy]
Phenyl-2-ethoxypropanamide; (-) N-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy]
(Phenyl) -2-ethoxypropanamide; (±) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-ethoxy-propanamide; ( +) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-ethoxy-propanamide; (-) 3- [4- [2 -(2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-ethoxy-propanamide; (±) N-methyl-3- [4- [2- (2,3 -Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-ethoxypropanamide; (+) N-methyl-3- [4- [2- (2,3-dihydro-1,4- (Benzoxazin-4-yl) ethoxy] phenyl-2-ethoxypropanamide; (-) N-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ) Ethoxy] phenyl-2-ethoxypropanamide; (±) N-benzyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] fe ] -2-ethoxypropanamide; (+) N-benzyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2- (-) N-benzyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-ethoxypropanamide; ( ±) N-benzyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-2-ethoxypropanamide; (+) N-benzyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-2-ethoxypropanamide; (-) N-benzyl-3- [4- [2- ( 2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-2-ethoxypropanamide; 2-methyl-3- [4- [2- (2,3-dihydro-1,4- Benzoxazin-4-yl) ethoxy] phenyl-2-ethoxy-propanoic acid and its salts; 2- (2-fluorobenzyl) -3- [4- [2- (2,3-dihydro-1,4- (Noxaxazin-4-yl) ethoxy] phenyl-2-ethoxypropanoic acid and its salts; (±) 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy ] Phenyl-2-ethoxypropanoic acid and its salts; (+) 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy] phenyl
2-ethoxypropanoic acid and salts thereof; (-) 3- [4- [2- (3-oxo-2H-1,4-benzoxazin-4-yl) ethoxy] phenyl
2-ethoxypropanoic acid and its salt; (±) 3- [4- [2- (3-oxo-2H-1,4-benzothiazin-4-yl) ethoxy] phenyl-
2-ethoxypropanoic acid and salts thereof; (+) 3- [4- [2- (3-oxo-2H-1,4-benzothiazin-4-yl) ethoxy] phenyl-2
-Ethoxypropanoic acid and its salts; (-) 3- [4- [2- (3-oxo-2H-1,4-benzothiazin-4-yl) ethoxy] phenyl]-
2-ethoxy-propanoic acid and its salts; (±) 3- [6- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] naphthyl] -2-ethoxy-propanoic acid (+) 3- [6- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] naphthyl] -2-ethoxy-propanoic acid and salts thereof; -) 3- [6- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] naphthyl] -2-ethoxy-propanoic acid and salts thereof; (±) 3- [ 6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl
] -2-ethoxy-propanoic acid and its salts; (+) 3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl]
2-ethoxy-propanoic acid and its salts; (-) 3- [6- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] naphthyl]
2-Ethoxy-propanoic acid and its salts; (±) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-hydroxy-propanoic acid (+) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-hydroxy-propanoic acid and salts thereof; -) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-hydroxy-propanoic acid and salts thereof; (±) 3- [4 -[2- (2,3-Dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl
2-hydroxy-propanoic acid and its salts; (+) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-
2-hydroxy-propanoic acid and its salts; (-) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-
2-hydroxy-propanoic acid and salts thereof; (±) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-benzyloxy-propanoic acid (+) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-benzyloxy-propanoic acid and salts thereof; (-) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-benzyloxy-propanoic acid and salts thereof; (±) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-butoxypropanoic acid and salts thereof; (+) 3- [4- [2- (2 , 3-Dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-butoxypropanoic acid and salts thereof; (-) 3- [4- [2- (2,3-dihydro-1) , 4-benzoxazin-4-yl) ethoxy] phenyl-2-butoxypropanoic acid and its salts; (±) 3- [4- [2- (2,3-dihydro-1,4- Benzoxazin-4-yl) ethoxy] phenyl-2-hexyloxypropanoic acid and its salts; (+) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) [Ethoxy] phenyl] -2-hexyloxypropanoic acid and its salts; (-) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] 2- (hexyloxy-propanoic acid and its salt; (±) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxypropane (+) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and salts thereof; -) 3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-phenoxypropanoic acid and salts thereof; (±) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl
2-phenoxypropanoic acid and salts thereof; (+) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-
2-phenoxypropanoic acid and its salt; (-) 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-
2-phenoxypropanoic acid and its salts; (±) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl)
) Ethoxy] phenyl-2-phenoxypropanoic acid; (+) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl)
Ethoxy] phenyl-2-phenoxypropanoic acid; (-) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl)
(Ethoxy) phenyl-2-phenoxypropanoic acid; (±) 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl-2-phenoxy Propanoic acid and its salts; (+) 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoic acid (-) 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzoxazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoic acid and salts thereof Salt; (±) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoic acid; (+) methyl 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-2-phenoxypropanoic acid; (-) methyl 2-methyl-3- [ 4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-phenoxypropanoic acid; ( ±) 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy
] Phenyl] -2-phenoxypropanoic acid and its salts; (+) 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy]
Phenyl] -2-phenoxypropanoic acid and its salt; (-) 2-methyl-3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy]
Phenyl-2-phenoxypropanoic acid and its salts; (±) 4-nitrophenyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl)
Ethoxy] phenyl] -2-ethoxypropanoic acid; (+) 4-nitrophenyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl-2-ethoxy (-) 4-nitrophenyl 3- [4- [2- (2,3-dihydro-1,4-benzothiazin-4-yl) ethoxy] phenyl] -2-ethoxypropanoic acid; (±) 3 -[4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid and salts thereof; (+) 3- [4- ( 4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid and salts thereof; (-) 3- [4- (4-benzyl-3) , 4-Dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid and its salts; (±) 4-nitrophenyl-3- [4- (4-benzyl-3) , 4-Dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypro Acid; (+) 4-nitrophenyl-3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid; And (-) 4-nitrophenyl-3- [4- (4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl) methoxyphenyl] -2-ethoxypropanoic acid. 17. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or 16 and a pharmaceutically acceptable carrier, diluent, excipient or solvate: 46] 18. The pharmaceutical composition according to claim 19, which is in the form of a tablet, capsule, powder, syrup, solution or suspension. 19. A hyperlipidemia, hyperglycemia, osteoporosis, obesity, glucose intolerance, insulin resistance, or a disease with a beneficial effect on diseases in which the underlying pathological mechanism is insulin resistance. A method for preventing or treating cholesterolemia, obesity, comprising the formula (I) as defined in any one of claims 1 to 5, 9 to 11, or 16.
Or a pharmaceutical composition according to claim 17 or 18 and a pharmaceutically acceptable carrier, diluent, solvate or excipient, in need of such prevention or treatment. Administering to the subject. 20. The method of claim 19, wherein the disease is type II diabetes, impaired glucose tolerance, dyslipidemia, or hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidemia. Diseases associated with syndrome X, including coronary artery disease and other cardiovascular diseases; glomerulonephritis, glomerulosclerosis, nephrotic syndrome,
Renal diseases including hypertensive glomerulosclerosis; methods that are psoriasis, ovarian syndrome (PCOS), dementia, diabetic complications and osteoporosis. 21. A method for reducing total cholesterol, body weight, plasma glucose, triglycerides, LDL, VLDL, and free fatty acids in plasma, comprising: 20. A method comprising administering a compound of formula (I) as defined above, or a pharmaceutical composition according to claim 17 or 18, to a patient in need of such a method. 22. Hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis,
A method of preventing or treating obesity, glucose intolerance, leptin resistance, insulin resistance, or a disease in which the underlying pathological mechanism is insulin resistance, comprising: 1 to 5, 5 to 9 or An HMG CoA reductase inhibitor wherein the compound of formula (I) as defined in any one of claims 16 or the pharmaceutical composition according to claims 17 or 18 is administered together or within a synergistic time. , Fibrate, nicotinic acid, cholestyramine, colestipol or probucol in combination / concurrently with a patient in need of such a method. 23. The method of claim 22, wherein the diabetes is type II diabetes, impaired glucose tolerance, dyslipidemia, hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery disease, and others. Disease associated with Syndrome X, such as cardiovascular disease, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive glomerulosclerosis, diseases associated with retinopathy endothelial cell activation, and nephropathy Certain renal diseases, psoriasis, follicular ovarian syndrome (PCOS), improved cognitive function in dementia, treatment for diabetic complications, diseases associated with endothelial cell activation, psoriasis, follicular ovarian syndrome (PCOS)
A method that is useful as an aldose reductase inhibitor for the treatment of inflammatory bowel disease, osteoporosis, muscular dystrophy, pancreatitis, atherosclerosis, xanthomas, and cancer. 24. A method according to claim 23 for treating or preventing a disease associated with Syndrome X, wherein the compounds of formula (I) are administered together or within a time acting synergistically. HMG CoA
A method comprising administering to a patient in need of such a method in combination / concurrent with a reductase inhibitor, fibrate, nicotinic acid, cholestyramine, colestipol or probucol. 25. Plasma glucose, triglyceride, total cholesterol, LD
A method for reducing L, VLDL and free fatty acids in plasma, comprising: a compound of formula (I) according to any one of claims 1 to 5, 9 to 11 or 16; 18. A pharmaceutical composition according to item 18, wherein the pharmaceutical composition is administered in combination / simultaneously with a HMG CoA reductase inhibitor, fibrate, nicotinic acid, cholestyramine, colestipol or probucol administered together or within a synergistic time. Administering to a patient in need thereof.