RS32404A - Benzoxazine and benzothiazine derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention relates to novel antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds of formula (I) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them, to a process for preparing such compounds. More particularly, the present invention relates to novel alkyl carboxylic acids of the general, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them, to a process for preparing such compounds. The present invention also relates to processes for the preparation of the compounds of formula (I), novel intermediates, processes for their preparation, their use in the preparation of the above said compounds and their use as antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds.

Description

BENZOXAZINE AND BENZOTHIAZINE DERIVATIVES AND PHARMACEUTICAL MIXTURES

WHICH CONTAIN THEM

Technical field

This invention relates to new anti-diabetic, hypolipidemic, anti-obesity and hypocholesterolemic compounds, to their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solutions and pharmaceutically acceptable mixtures containing them, and to the process for making such compounds. More precisely, this invention is brought to new alkyl carboxylic acids in general, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solutions and pharmaceutically acceptable mixtures containing them and to the process for making such compounds.

This invention also relates to new intermediates, processes for their preparation, their use in the preparation of the above-mentioned compounds and their use in the form of antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds.

The compounds of this invention lower plasma glucose, triglycerides, lower total cholesterol (TC) and increase high-density lipoprotein (HDL), and lower low-density lipoprotein (LDL), which favorably affects coronary heart disease and atherosclerosis.

The compounds of the present invention are useful in reducing body weight and for the treatment and/or prophylaxis of diseases such as atherosclerosis, stroke, peripheral vascular disease and related disorders. These compounds are useful in the treatment of hyperlipidemia, hyperglycemia, hypercholesterolemia, lowering atherogenic lipoproteins, VLDL (very low density lipoprotein) and LDL. The compounds of the present invention can be used to treat certain kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. Said compounds are also useful for the treatment and/or prophylaxis of leptin resistance, impaired glucose tolerance, disorders associated with syndrome X, such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders. These compounds may also be useful as aldolase reductase inhibitors, to improve cognitive function in dementia, to treat complications of diabetes, disorders related to endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), inflammatory bowel disease, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, eating disorders, inflammation, and to treat malignant diseases. The compounds of this invention are also useful in the treatment and/or prophylaxis of the aforementioned diseases in combination/simultaneously with one or more HMG CoA reductase inhibitors, hypolipidemic/hypo-lipoproteinemic agents, such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol and probucol; insulin, sulfonylurea, metformin.

State of the art

Atherosclerosis and other peripheral vascular diseases affect the quality of life of millions of people. For this reason, considerable attention is directed towards understanding the etiology of hypercholesterolemia and hyperlipidemia and the development of effective therapeutic strategies.

Hypercholesterolemia was defined as the level of plasma cholesterol, which exceeds an arbitrarily defined value, designated as "normal" concentration. Recently, it has been accepted that "ideal" plasma cholesterol levels are much lower than "normal" cholesterol concentrations in the general population, and the risk of coronary artery disease (CAD) increases as cholesterol levels rise above the "optimal" (or "ideal") concentration. There is a clear causal relationship between hypercholesterolemia and CAD, especially for individuals with multiple risk factors. Most of the cholesterol is present in esterified forms with different lipoproteins, such as: low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL), high-density lipoprotein (HDL) and partially, as very low-density lipoprotein (VLDL). Studies clearly show that there is an inverse correlation between CAD and atherosclerosis and serum HDL-cholesterol concentrations, (Stampferet al., N. Engl. J. Med., 325 (1991), 373-381) and that the risk of CAD increases with increasing levels of LDL and VLDL.

In CAD, "fatty streaks" are generally found in the carotid, coronary, and cerebral arteries, which are primarily free and esterified cholesterol. Milleret al, { No. Med. J., 282 (1981), 1741-1744) have shown that an increase in HDL particles can reduce the number of stenoses in human coronary arteries, and a high level of HDL-cholesterol can represent protection against the progression of atherosclerosis. Picardoet al, Arteriosclerosis 6

(1986) 434-441 showed in vitro experiments that HDL is able to remove cholesterol from cells. They suggest that HDL can rid tissues of excess free cholesterol and transport it to the liver, known as reverse cholesterol transport (Macikinnonet al., J. Biol. chem. 261 (1986), 2548-2552). Therefore, agents that increase HDL cholesterol would have therapeutic value for the treatment of hypercholesterolemia and coronary heart disease (CHD). Obesity is a disease, highly prevalent in rich societies, and in the developed world it is a significant cause of morbidity and mortality. It is a condition of excessive accumulation of fat in the body. The causes of obesity are unclear. It is believed to be genetic in origin or aided by the interaction between genotype and environment. Regardless of the cause, the consequence is fat storage, due to an imbalance between energy intake and energy expenditure. Diet, exercise and appetite suppression are part of obesity treatment. There is a need for effective therapy to control this disease since it can lead to coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis, reduced fertility, and many other psychological and social problems. Diabetes and insulin resistance represent another disease that seriously affects the quality of life of a large population in the world. Insulin resistance is a reduced ability of insulin to exert its biological effects across a wide range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this deficiency; otherwise, plasma glucose concentration inevitably increases and develops into diabetes. Among developed countries, diabetes mellitus is a general problem and is associated with various abnormalities, including obesity, hypertension, hyperlipidemia (J. Cl/ n. Invest, 75 (1985) 809-817; N. Engl. J. Med 317(1987) 350-357; J. Clin. Endocrinol. Metab., 66 (1988) 580-583; J. Clin. Inest, 68 (1975) 957-969) and other renal complications (Patent Publication No. WO 95/21608). Currently, knowledge is strengthening that insulin resistance and the corresponding hyperinsulinemia play an important role in obesity, hypertension, atherosclerosis and type 2 diabetes mellitus. The association of insulin resistance and obesity, hypertension and angina has been described as a syndrome of the existence of insulin resistance as a central pathogenic link with Syndrome X. Hyperlipidemia is the primary cause of cardiovascular (CVD) and other peripheral vascular diseases. High risk for CVD is associated with elevated LDL (low-density lipoprotein) and VLDL (very low-density lipoprotein), seen in hyperlipidemia. Patients who have intolerance

to glucose/insulin resistance, in addition to hyperlipidemia, have a higher risk of

e CVD. Numerous studies in the past have shown that lowering plasma triglycerides and total cholesterol, especially LDL and VLDL, and increasing HDL cholesterol help prevent cardiovascular disease.

Peroxisomal proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily. The gamma (y) isoform of PPAR (PPARγ) is involved in the regulation of adipocyte differentiation {Endocrinology,135 (1994) 798-800) and energy homeostasis (Cell,83 (1995) 803-812), while the alpha (a) isoform of PPAR (PPARα) mediates fatty acid oxidation {Trend. Endocrine. Metab.,4 (1993) 291-296), leading to a decrease in circulating free fatty acids in the plasma (Current Biol. 5

(1995) 618-621). PPARα agonists have been found to be useful in the treatment of obesity (WO 97/36579). Recently, compounds which are agonists of both PPARα and PPARγ have been proposed to be useful compounds in the treatment of syndrome X (WO 97/25042). A similar effect has been observed between insulin sensitizers (PPARy agonist) and HMG CoA reductase inhibitors, which may be useful in the treatment of atherosclerosis and xanthomas (EP 0 753 298).

It is known that PPARγ plays an important role in adipocyte differentiation {CeiI, 87 (1996) 377-389). Ligand activation of PPAR is sufficient to induce complete terminal differentiation {Cell, 79 (1994) 1147-1156), including cell cycle arrest. PPARγ is consistently expressed in certain cells, and activation of this nuclear receptor with PPARγ agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes, which are characteristic of a more differentiated, less malignant state {Molecular Cell,

(1998), 465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., 94

(1997) 237-241) and inhibition of expression of malignant prostate tissue {Cancer Research 58 (1998) 3344-3352). This would be useful in the treatment of certain types of cancer, which express PPARy and may lead to completely non-toxic chemotherapy.

Leptin resistance is a condition in which target cells are unable to respond to the leptin signal. This can cause obesity, due to excessive food intake and reduced energy expenditure, and cause impaired glucose tolerance, type 2 diabetes, cardiovascular disease and other such related complications. Kallenet al { Proc. Natl. Acad. Sci. (1996) 93, 5793-5796) have shown that insulin sensitizers, perhaps due to the expression of PPAR agonists, lower plasma insulin concentrations. However, compounds that have insulin-sensitizing properties have recently been shown to also possess leptin-sensitizing activity. They lower plasma concentrations of circulating leptin, improving target cell response to leptin (WO 98/02159).

Earlier techniques

Several alkyl carboxylic acids, their derivatives, and their analogs have been reported to be useful in the treatment of hyperglycemia and hypercholesterolemia. Some of such compounds, described in earlier professional works, are presented below: i). In our international publication No. WO 99/08501 disclosed are compounds with the general formula (lla)

in which the groups R1, R<2>, R<3>, R<4> and the groups R<5> and R<6>, when attached to a carbon atom, can be the same or different and represent: hydrogen, halogen, hydroxy, nitro, cyano, formyl or unsubstituted or substituted groups selected from: alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, aryloxy, aralkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaraloxy, acyl, acyloxy, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, araloxycarbonyl, alkylthio, alkoxycarbonylamino, aryloxycarbonylamino, araloxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R<5> and R<6> may also represent an oxo group when attached to a carbon atom; R<5> and R<6>, when attached to a nitrogen atom, represent hydrogen, hydroxy, formyl or unsubstituted or substituted groups selected from: alkyl, cycloalkyl,

alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aryloxy, aralkyl, heteroaryloxy, heteroaraloxy, alkoxycarbonyl, aryloxycarbonyl, aralkylthio, carboxylic acid derivative or sulfonic acid derivative; X represents a heteroatom, selected from oxygen, sulfur or NR<11>, where R11 represents hydrogen or unsubstituted or substituted groups, selected from: alkyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl group; Ar represents an unsubstituted or substituted divalent single or fused aromatic or heterocyclic group; R<7> represents: a hydrogen atom, hydroxy, alkoxy, halogen, lower alkyl, unsubstituted or substituted aralkyl group or forms a bond together with the neighboring group R<8>; R<8> represents: hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, unsubstituted or substituted aralkyl or R<8> forms a bond together with R<7>; R<9> represents hydrogen, unsubstituted or substituted groups, selected from alkyl, cycloalkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups; R<10> represents: hydrogen, unsubstituted or substituted groups, selected from: alkyl, cycloalkyl, aryl, aralkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl group; Y represents oxygen or NR<12>, where R<12> represents: hydrogen, alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl groups; R<10> and R<12> together can form a 5- or 6-membered cyclic structure, containing carbon atoms, at least one nitrogen atom and optionally containing one or more additional heteroatoms selected from oxygen, sulfur or nitrogen; the linking group represented by -(CH2)n-(0)m-, can be linked either through a nitrogen atom or through a carbon atom; n is an integer in the range 1-4 and m is an integer 0 or 1.

An example of these compounds is shown in formula (llb)

ii) International publication No. WO 00/64888 discloses compounds of general formula (llc)

wherein Ar<1> and Ar<2> are independently: aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylcyclenyl or fused heteroarylheterocyclyl; A is O, S, SO, SO2, NR<13>, C(O), NR<14>C(0), C(0)NR<14>, NR<14>C(0)N(R15), C(R<14>)=N; chemical bond and the like; B is O, S, NR<19>, a chemical bond, C(O), N^CCO) or CCOMR20); E is a chemical bond or ethylene group; a is 0-6; b is 0-4; c is 0-4; d is 0-6; g is 1-5; x is 1-4; R1, R<3>, R<5> and R<7> independently: hydrogen, halogen, alkyl, carbonyl, alkoxycarbonyl or aralkyl; R<2>, R4, R6 and R<8> are independently -(CH2)q-X; g is 0-3; X is: hydrogen, halogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkyl, heteroaralkyl, carbonyl,

alkoxycarbonyl, tetrazolyl, acyl, acylHNSO 2 and the like; Z is R<21>02C, R<21>OC, cyclo-imide: CN, R<21>02SHNCO, R<21>02SNH, R<21>NCO, R<21>0-2,4-thiazolidinonyl or tetrazolyl.

An example of these compounds is shown in formula (lld)

iii) International publications No. WO 95/03038 and WO 96/04260 disclose compounds of formula (II e) in which R<a>represents 2-benzoxazole or 2-pyridyl and R<b>represents CF 3 , CH 2 OCH 3 iii CH 3 . A typical example is (5)-3-[4-[2-[N-(2-benzoxazole)N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid (II f). iv) International publications No. WO 94/13650, WO 94/01420 and WO 95/17394 disclose compounds of general formula (II g)

in which A<1>represents an aromatic heterocycle, A<2>represents a substituted benzene ring, and A<3>represents a moiety with the formula (CH2)m-CH-(OR<1>), in which R<1>represents alkyl groups, m is an integer from 1-5; X represents substituted or unsubstituted N; Y represents C=0 or C=S, R<2>represents OR<3>, where R<3>can be: hydrogen, alkyl, aralkyl or aryl group, and n is an integer from 2-6.

An example of these compounds is shown in formula (II h)

c) International publication No. WO 00/49005 discloses compounds of general formula (II i) wherein Het is an optionally substituted, saturated, partially saturated or fully unsaturated 8 to 10 membered bicyclic ring, R<1> is optionally substituted aryl or optionally substituted heteroaryl, R<2> is hydrogen halogen, lower alkyl or lower alkoxy, L<1> is -R<3>-R<4>bond, where R<3>is alkylene, alkenylene or alkynylene, and R<4>is a direct bond, cycloalkylene, heterocycloalkylene, arylene, heteroarylidinyl, -C(=Z<2>)-NR<5>, NR<5->C(=Z<2>), -Z<2->, -C(=0), -C(=NOR<5>)-. NR<5->C(=Z<2>)-NR<5>, SO2-NR<5>NR<5->SO2, -0-C(=0)-, -C(=0)-0, -0-C(=0)-NR5,NR<5->C(=0)-0-; L<2>is an optionally substituted alkylene or alkenylene, Y is a carboxy or acidic bioisoster, and Z<1>is NR<5>and the corresponding N-oxides and their prodrugs and pharmaceutically acceptable salts and solvates. An example of these compounds is shown in formula (II j) vi) International publication No. WO 94/12181 discloses compounds of general formula (II k)

aryl is a 6-membered aromatic ring containing 0, 1, 2 or 3 nitrogen atoms and is substituted or unsubstituted by R<8> and R<9>; X represents NH2, NH-C(=NH)- and the like or a 4 to 10 membered mono or polycyclic aromatic or non-aromatic ring system and contains 0, 1, 2, 3 or 4 heteroatoms, selected from N, O or S, either unsubstituted or substituted; Y is selected from C^alkyl, C4.10cycloalkyl, C0.8alkyl-NR<3->CO-C0.8alkyl, C^alkyl-CONR^C^alkyl, C^alkyl-O-CMalkyl, CMalkyl^S(0)n-C„alkyl, (CH^arylHCH,)^, (CH2)^aryl-SO^, (CH^aryl-CO^CH,)^, (CH2)0.6aryl-SO2-(CH2)0.6-, (CH2)0.6NR<3->(CH2)0.6<-,>(CH2)Maryl-CH(OH)-(CH2)(,6-, (CH^-CONH-tCH^-, Cfr8alkyl-S02-NR<3->C0.alkyl, Co.alkyl-CO-CO. C0.aalkyl-CH(OH)-C0.8alkyl, wherein n is an integer of 0-2; Z and A are independently selected from: (CH2)m, (CH2)mO(CH2)n, (CH2)mNR<3>(C<H>2)n, (CH2)mNR<3>(CH2)n, (CH2)mCONR<11>(CH2)n, (CH2)mCO(CH2)n, (CH2)mCS(CH2)n, (C<H>2)mSO2(CH2)n, (CH2)m<S>(CH2)n, (C<H>2)mS02(CH2)n, (CH2)mSO(CH2)n, (CH2)m<S>02NR<3>(CH2)n, (C<H>2)mNR<3>S02(C<H>2)n, (C<H>2)m<C>R<3>=CR<4>(CHJn, (CH2)mC=C(CH2)n, (CH2)mCH(OH)(CH2)n; where m and n are each independently an integer up to 0 to 6; An aryl is a 6-membered aromatic ring system, which

contains 0, 1, 2, 3 or 4 N atoms and is unsubstituted or substituted by R<5>, provided that, when A is (CH2)m, the aryl ring linked by Z and A must contain at least one heteroatom;

B is

R<6>,R<7>,R<8>,R<9>,R10 and R11 are independently selected from: hydrogen, fluorine, (C^)alkyl, hydroxy, hydroxy(C1.6)alkyl, carboxy(C1.6)alkyl, (C^alkyloxy, aryl(Co.6)alkyloxy, (C^cycloalkyl, aryl(C^)alkyl, (C^alkylcarbonyloxy, (C^alkylamino) (C 1-6 )alkyl and the like;

An example of these compounds is shown in formula (II I)

vii) International publication No. WO 93/16697 and US Patent No. 5,227,400 discloses compounds of general formula (II m)

R<1>is selected from: hydrogen, C1-6alkyl, arylC1-10alkyl, aryl, carboxy, C1-6alkyloxy, carboxyC1-alkyl, carboxyC1-6alkyloxy, hydroxyC0-6alkyl, C1-6alkylsulfonylC0-6alkyl, C0-4alkylaminoC0-6alkyl, arylC0-10alkylaminoC0-6alkyl, C2-10acylaminoC0-6alkyl, C1.4carboalkoxyC0.6alkyl halogen, R<2> is independently selected from: hydrogen, halogen, hydroxy, C1-4 alkyl, wherein the alkyl group is substituted or unsubstituted, C1-4 alkyloxy, aryl C1-4 alkyl, aryl C1-4 alkyloxy and the like; R<3>hydrogen, C1-4 alkyl, arylC1-4 alkyl; Z is NR4R<5>or a 4-9 membered mono or bicyclic ring system, containing 1, 2 or 3 heteroatoms, selected from N, O or S, and is unsubstituted or substituted; Y is C 1-4 alkyl either unsubstituted or substituted, C 1-4 cycloalkyl, aryl, -C(=O)NH-, -NH(C=O)- and the like; X is O, SO, SO2, S, CO, -NR<4>CO-, CONR<4>, CH2 and the like;

An example of these compounds is shown in formula (II n)

Several (3-phenyl a-hydroxysubstituted propionic acid derivatives were disclosed, which were used as intermediates in the synthesis of target molecules. Some of such compounds, described in earlier professional works are listed below: i) European patent application EP0816316 discloses compounds with formula (lio)

The compound of formula (va) was further converted to the 1,2-ethanediol derivative of formula (llp)

These 1,2-ethanediol derivatives are useful intermediates for pharmaceutical preparations and agricultural chemicals.

ii) Japanese patent application JP 10017540 discloses a compound of formula (llq)

The compound of formula (llr) was further converted to the compound of formula (vd)

Presentation of the essence of the invention

With the aim of developing new compounds for the treatment and/or prophylaxis of diseases associated with elevated lipid levels, in particular for the treatment of hypertriglyceridemia and lowering of free fatty acids, for the treatment and/or prophylaxis of diseases described as Syndrome-X, which includes hyperlipidemia, hyperinsulinemia, obesity, insulin resistance, insulin resistance leading to type 2 diabetes and its diabetic complications, for the treatment of diseases in which insulin resistance is the pathophysiological mechanism, for the treatment of hypertension, atherosclerosis and coronary artery diseases, with better efficiency and power and less toxicity, we focused our research on the development of new compounds, which are effective in the treatment of the above-mentioned diseases.

The main objective of the present invention is, therefore, to provide new (3-aryl-α-oxysubstituted alkylcarboxylic acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical mixtures containing them, or their mixtures.

Another object of the present invention is to provide new (3-aryl-a-oxysubstituted alkyl carboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical mixtures, containing them, or mixtures thereof, which can have agonist activity towards PPARα and/or PPARγ and, optionally, inhibit HMG CoA reductase, in addition to agonist activity towards PPARα and/or PPARy.

Another objective of this invention is to provide new (3-aryl-a-oxysubstituted alkyl carboxylic acids and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical mixtures containing them, or their mixtures, which have enhanced activities, without toxic effects or with reduced toxic effects.

Another object of the present invention is to provide a process for the preparation of P-aryl-α-oxysubstituted alkyl carboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.

Another object of the present invention is to provide a pharmaceutical mixture of (3-aryl-a-oxysubstituted alkyl carboxylic acids, their analogs, their derivatives, their tautomers, their stereoisomers, their polymorphs, their salts, solvates or mixtures thereof in combination with suitable carriers, solvents, diluents and other media, commonly involved in the preparation of such mixtures.

Another objective of this invention is to provide new intermediates, a process for their production and the use of intermediates in the process for the production of p-aryl-a-oxysubstituted alkoxy carboxylic acids, their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their salts and their pharmaceutically acceptable solvates and their use in the form of antidiabetic, hypolipidemic, anti-obesity and hypocholesterolemic compounds.

Detailed description of the invention

(3-aryl-oc-oxy substituted propionic acids of the present invention having the general formula (I)

their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates in which R<1>, R<2> and R<3>, R<4> when attached to a carbon atom can be the same or different and represent: hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups, selected from: alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, aryloxy, aralkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, araloxycarbonyl, alkoxyalkyl, aryloxyalkyl, armethoxyalkyl, alkylthio, thioalkyl, Alkoxycarbonylamino, Aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives or sulfonic acid or its derivatives; one or both of R<3> and R<4> may represent an oxo or thioxo group when attached to a carbon atom; R<3> and R<4>, when attached to a nitrogen atom, represent: hydrogen, hydroxy, formine or substituted or unsubstituted groups selected from: alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkyl, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, aralkylcarbonyl, alkoxyalkyl, aryloxyalkyl, aralkyl, alkylthio, thioalkyl group, derivs.

carboxylic acids or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; W represents NR<12>, -C(=O)-(CR10R<11>)o-NR<12>, -O-aryl-(CR10R1<1>)o-NR<12>, where R<12> represents hydrogen or a substituted or unsubstituted group selected from alkyl, aryl or aralkyl groups; o is an integer in the range 0 - 6; R 10 and R 11 may be the same or different, and represent hydrogen or an unsubstituted or substituted group selected from: alkyl, alkoxy, aryl, or aralkyl groups; Ar represents a substituted or unsubstituted divalent single or fused aromatic or heterocyclic group; R<5> represents: a hydrogen atom, hydroxy, alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group or forms a bond together with the neighboring group R<6>; R<6> represents: hydrogen, hydroxy, alkoxy, halogen, alkyl group, acyl, substituted or unsubstituted aralkyl or R<6> forms a bond with R<5>; R<7> can be hydrogen or substituted or unsubstituted groups selected from: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl and heteroaralkyl groups; R<8> can be hydrogen or substituted or unsubstituted groups selected from: alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen, sulfur or NR<9>, where R<9> represents: hydrogen or substituted or unsubstituted groups, selected from: alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl group or NR<9> represents a chiral amine chiral amine alcohols, obtained from a chiral amino acid; R<8> and R<9> together may form a substituted or unsubstituted 5- or 6-membered cyclic structure containing carbon atoms and which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; m and n are integers in the range 0-6.

Suitable groups represented by R<1>, R<2>, R<3> and R<4> can be selected from hydrogen, halogen atoms, such as fluorine, chlorine, bromine or iodine; hydroxy, cyano, nitro, formyl, substituted or unsubstituted (C,-C12) alkyl groups, especially linear or branched (0,-0,0) alkyl groups, such as: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl and the like; cyclo (C3-C6) alkyl groups, such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and si., the cycloalkyl group may be substituted; (C₁CAlkoxy, such as: methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy, and the like, which may be substituted; cyclo(C3-C6) alkoxy group, such as: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like, the cycloalkoxy group may be substituted; the aryl group, such as phenyl, naphthyl, and the like, the aryl group may be substituted; aryloxy a group, such as phenoxy, naphthyloxy, and the like, an aralkyl group, such as benzyl, phenethyl, naphthylmethyl, and the like; an aralkyl group, such as: benzyloxy, phenethyloxy, phenylpropyloxy, and the like; a heterocyclyl group, such as aziridinyl, morpholinyl, piperidinyl, piperazinyl and si, the heterocyclyl group may be substituted; a heteroaryl group, such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuryl, and the like, the heteroaryl group may be substituted; a heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl and the like, the heteroaralkyl group may be substituted; heteroaryloxy and heteroaralkyl wherein the heteroaryl and heteroaralkyl moieties are as previously defined and may be substituted; acyl group, such as acetyl, propionyl, benzoyl, etc., the acyl group may be substituted; an acyloxy group, such as OOCMe, OOCEt, OOCPh and the like, which may be substituted; acylamino groups, such as: NHCOCH3, NHCOC2H5, NHCOC3H7, NHCOC6H5 and the like, which may be substituted; a monoalkylamino group, such as NHCH 3 , NHC 2 H 5 , NHC 3 H 7 , NHC 6 H 13 and the like, which may be substituted; a dialkylamino group, such as N(CH3)2, NCH3(C2H5), N(C2H5)2 and the like, which may be substituted; an arylamino group, such as HNC6H5, NCH3(C6H5), NHC6H4CH3, NHC6H4-Hal and the like, which may be substituted; an aralkylamino group, such as C6H5CH2NH, C6H5CH2CH2NH, C6H5CH2NCH3 and the like, which may be substituted; amino group; alkoxycarbonyl, such as: methoxycarbonyl, ethoxycarbonyl and the like, which may be substituted; aryloxycarbonyl group, such as phenoxycarbonyl, naphthyloxycarbonyl and the like, the aryloxycarbonyl group may be substituted; an aralkyloxycarbonyl group, such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may be substituted; an alkoxyalkyl group, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, and the like, the alkoxyalkyl group may be substituted; an aryloxyalkyl group, such as C6H5OCH2, C6H5OCH2CH2, naphthyloxymethyl, etc., which may be substituted; an aralkyl group, such as C6H5CH2OCH2, C6H5CH2OCH2CH2 and si., which may be substituted; hydroxy(C1-C6)alkyl, which may be substituted; thio(C1-C6)alkyl, which may be substituted; (C 1 -C 6 )alkylthio, which may be substituted; an alkoxycarbonylamino group, such as NHCOOC2H5, NHCOOCH3, and the like, which may be substituted; an aryloxycarbonylamino group such as: NHCOOC6H5, NCH3COOC6H5, NC2H5COOC6H5, NHCOOC6H4CH3, NHCOOC6H4OCH3 and the like, which may be substituted; aralkylamino group, such as: NHCOOCH2C6H5, NHCOOCH2CH2C6H5, N(CH3)COOCH2C6H5, N(C2H5)COOCH2C6H5, NHCOOCH2C6H4CH3, NHCOOCH2C6H4OCH3 and the like, which may be substituted; carboxylic acid or its derivatives, such as amides, such as: CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHPh, etc., carboxylic acid derivatives can be substituted; sulfonic acid or its derivatives, such as: SO2NH2, SO2NHMe, SO2NMe2, S02NHCF3i si., sulfonic acid derivatives can be substituted.

When the groups represented by R<1> to R<4> are substituted, the substituents may be selected from halogen, hydroxy, nitro, thio, or unsubstituted or unsubstituted groups selected from: alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryl, aralkyl, aryloxy, aralkyl, alkoxyalkyl, aryloxyalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl, alkylamino, alkylthio group, carboxylic acid or its derivatives or sulfonic acid or its derivatives. These groups are, as previously defined. It is preferable that the substituents on R<1> to R<4> represent a halogen atom, such as: fluorine, chlorine or bromine; an alkyl group, such as: methyl, ethyl, iso-propyl, n-propyl and n-butyl; a cycloalkyl group, such as cyclopropyl; an aryl group, such as phenyl; an aralkyl group such as a benzyl, (C 1 -C 6 -Alkoxy, benzyloxy, hydroxy, acyl or acyloxy group.

Suitable groups, represented by X, may be selected from oxygen or sulfur.

Suitable groups represented by Ar may be selected from substituted or unsubstituted groups selected from divalent phenylene, naphthylene, pyrrole, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl and the like. Substituents on the group represented by Ar may be selected from linear or branched, optionally halogenated (C₆C₆₆alkyl, optionally halogenated (C₆C₃)alkyl, halogen, acyl, amino, acylamino, thio, or carboxylic or sulfonic acids and their derivatives. Substituents are defined as defined for R'-R<4>.

It is more preferred that Ar represents substituted or unsubstituted divalent phenylene, naphthylene, benzofuryl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl groups.

Suitable groups represented by R<5> may be selected from: hydrogen, hydroxy, (C^C^alkyl groups, such as methyl, ethyl, propyl, etc.; (C^CgAlkoxy groups, such as: methoxy, ethoxy, propoxy, etc.); halogen atoms, such as: fluorine, chlorine, bromine, or iodine; aralkyl, such as benzyl, phenethyl, etc., which may be unsubstituted or substituted or R<5> together with R<6> represents a bond Substituents are selected from: halogen, hydroxy or alkyl groups.

Suitable groups represented by R<6> can be selected from: hydrogen, hydroxy, (C₂C₆Jalkyl group, such as methyl, ethyl, propyl and si; (C1-C3) alkoxy group, such as: methoxy, ethoxy, propoxy and si; halogen atom such as: fluorine, chlorine, bromine or iodine; (C2-C10)acyl group, such as acetyl, propanoyl, butanoyl, pentanoyl, benzoyl and si; aralkyl, such as benzyl, phenethyl and si., which may be unsubstituted or substituted or R<6> forms a bond. Substituents are selected from: halogen, hydroxy or alkyl groups.

Suitable groups represented by R<7> may be selected from hydrogen, linear or branched (CrC16) alkyl, preferably (C^-C^alkyl groups, such as: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like, the alkyl group may be substituted; (C3-C7) cycloalkyl groups, such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and si., a cycloalkyl group may be substituted; an aryl group, such as benzyl, phenethyl, and si., wherein the aryl portion may be substituted; a heteroaryl group, such as pyridyl, thienyl, furyl, and si., may be substituted which is furanmethyl, pyridinemethyl, oxazolemethyl, oxazoleethyl and the like, the heteroaralkyl group may be substituted; heterocyclyl groups, such as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may be substituted; linear or branched (C2-C16) acyl groups, such as acetyl, propionyl, butanoyl, benzoyl, octanoyl, decanoyl and the like, which may be substituted; (C^C^Alkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, etc., the alkoxycarbonyl group may be substituted; aryloxycarbonyl group, such as phenoxycarbonyl, naphthyloxycarbonyl, etc., the aryl group may be substituted; (C^C^alkylaminocarbonyl, the alkyl group may be substituted; arylaminocarbonyl, such as PhNHCO, naphthylaminocarbonyl, etc., aryl part may be substituted Substituents may be selected from halogen, hydroxy, nitro or unsubstituted or substituted groups selected from: alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkyloxyalkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkyl, alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylthio, thioalkyl, carboxylic acid or its derivatives or sulfonic acid or its derivatives. Substituents are as previously defined.

Suitable groups represented by R<8> can be selected from hydrogen, linear or branched (C^C^) alkyl, preferably (C^-C^ alkyl groups, such as: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like, the alkyl group may be substituted; (C3-C7) cycloalkyl such as: cyclopropyl, cyclopentyl, cyclohexyl, and si., cycloalkyl group, such as phenyl, naphthyl, and si, aryl group, such as pyridyl, thienyl, furyl, and si, heteroaryl group may be substituted, heteroaralkyl group, such as benzyl, phenethyl, and si si., the aralkyl group may be substituted with heterocyclyl; groups, such as aziridinyl, pyrrolidinyl, piperidinyl and the like, the heterocyclyl group may be substituted. Substituents on R<8> can be selected from halogen, hydroxy, nitro or unsubstituted or substituted groups selected from: alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkyl, alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl group, carboxylic acid or its derivatives or sulfonic acid or its derivatives. Substituents are as previously defined.

Suitable groups represented by R<9> can be selected from hydrogen, linear or branched (C^C^) alkyl, preferably (C-C-C^alkyl groups, such as: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, heptyl, octyl and the like; hydroxy(C1-C6)alkyl; aryl groups, such as phenyl, naphthyl and si; aralkyl groups, such as benzyl, phenethyl and si., heterocyclyl groups, such as pyrrolidinyl, and si., heteroaryl groups, such as furanmethyl, pyridinemethyl, oxazoleethyl, and si.

Suitable chiral amines represented by NR<9> can be selected from R(+)-α-ethylphenylamine, naphthylethylamine, S(+) phenylglycinol, cinchonidine, ephedrine, N-octylglucaramine, N-methylglucaramine and the like; chiral amine alcohols, such as phenyl glycinol, valine, tert-leucine and the like.

Suitable ring structures formed by R<8> and R<9> together may be selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl.

Suitable groups represented by R10 and R<11> can be selected from hydrogen, or substituted or unsubstituted linear or branched (C?-C?) alkyl groups, such as: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like; (C 1 -C 6 )alkoxy, such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may be substituted; aryl groups, such as phenyl, naphthyl and si, the aryl group may be substituted; aralkyl, such as benzyl, phenethyl, C6H5CH2CH2CH2, naphthylmethyl and si. Substituents may be selected from hydroxy, halogen, nitro or amino.

Suitable groups represented by R<12> may be selected from hydrogen, either substituted or unsubstituted linear or branched (C,-

C12) alkyl groups, such as: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like; aryl groups, such as phenyl, naphthyl and si, the aryl group may be substituted; aralkyl groups, such as benzyl, phenethyl, C6H5CH2CH2CH2, naphthylmethyl and si. Substituents may be selected from hydroxy, halogen, nitro or amino.

A suitable n is an integer in the range 0-6.

A suitable m is an integer in the range 0-6.

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases, such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases, such as: N,N'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, glycinol, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, adamentyl amine, diethanolamine, meglumine, ethylenediamine, N,N'-diphenylethylenediamine, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine and si; chiral bases such as: alkylphenylamine, phenyl glycinol and si, salts of natural amino acids, such as: glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; amino acids that do not occur in nature, such as D-isomers or substituted amino acids; guanidine, substituted guanidine in which the substituents are selected from: nitro, amino, alkyl, alkenyl, alkynyl, ammonium, or substituted ammonium salts and aluminum salts. Salts may include salts, which are formed by the addition of acid when appropriate, which are: sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates, and the like. Pharmaceutically acceptable solvates may be hydrates or contain other crystallization solvents, such as alcohols.

Particularly useful compounds in accordance with the present invention include: (±) ethyl 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (+) ethyl 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (-) ethyl 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (±) 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (±) ethyl 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate; (+) ethyl 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate; (-) ethyl 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate; (±) 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethyl-amino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethyl-amino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethyl-amino}phenyl]-2-ethoxypropanoic acid or its salts; (±) methyl 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate; (+) methyl 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate; (-) methyl 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate; (±) 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxo-ethyl)aminomethyl}phenyl]propanoic acid or its salts; (+) 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxo-ethyl)aminomethyl}phenyl]propanoic acid or its salts; (-) 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxo-ethyl)aminomethyl}phenyl]propanoic acid or its salts; (±) methyl 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentyl-amino}phenyl]-2-ethoxypropanoate; (+) methyl 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentyl-amino}phenyl]-2-ethoxypropanoate; (-) methyl 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentyl-amino}phenyl]-2-ethoxypropanoate; (±) 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-{5-(3,4-dihydro-2H-benz^ -2-ethoxypropanoic acid or its salts; (±) methyl 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (+) methyl 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (±) methyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (+) methyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (-) methyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (±) 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (±) methyl 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate; (+) methyl 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate; (-) methyl 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate; (±) methyl 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate; (+) methyl 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate; (-) methyl 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate; (±) 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid or its salts; (+) 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid or its salts; (-) 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid or its salts; (±) 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid or its salts; (+) 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid or its salts; (-) 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid or its salts; (±) ethyl 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoate; (+) ethyl 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenylpropanoate; (-) ethyl 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenylpropanoate; (±) 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoic acid or its salts; (+) 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoic acid or its salts; (-) 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoic acid or its salts; (±) ethyl 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoate; (+) ethyl 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenylpropanoate; (-) ethyl 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][l] ,4]oxazin-4-yl)ethylamino}phenylpropanoate; (±) 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4oxazin-4-yl)ethylamino}phenyl]propanoic acid or its salts; (+) 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4oxazin-4-yl)ethylamino}phenyl]propanoic acid or its salts; (-) 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[bJ[1,4oxazin-4-yl)ethylamino}phenyl]propanoic acid or its salts; (±) methyl 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy} phenylaminomethylphenylpropanoate; (+) methyl 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[bJ[1,4]oxazin-4-yl)ethoxy}phenylaminomethylphenylpropanoate; (-) methyl 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy} phenylaminomethyl]phenyl]propanoate; (±) 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenyl-aminomethyl]phenyl]propanoic acid or its salts; (+) 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenyl-aminomethyl]phenyl]propanoic acid or its salts; (-) 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenyl-aminomethyl]phenyl]propanoic acid or its salts; (±) ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (+) ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (-) ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (±) ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate; (+) ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate; (-) ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate; (±) 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid or its salts; (+) 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid or its salts; (-) 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid or its salts; (±) ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (+) ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (-) ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (±) 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoic acid or its salts; (±) ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (+) ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (-) ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (±) 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-{3-(2-methyl-3)4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4H1)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (±) ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (+) ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (-) ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (±) 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid or its salts; (+) 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid or its salts; (-) 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid or its salts; (±) ethyl 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (+) ethyl 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (-) ethyl 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (±) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (±) ethyl (2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate; (+) ethyl (2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate; (-) ethyl (2S)-3-[4-{3-(2-propN-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate; (±) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid and its salts; (+) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid and its salts; (-) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid and its salts; (±) ethyl 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoate; (+) ethyl 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoate; (-) ethyl 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoate; (±) 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoic acid and its salts; (+) 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoic acid and its salts; (-) 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoic acid and its salts; (±) ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (+) ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (-) ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (±) 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoic acid and its salts; (+) 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoic acid and its salts; (-) 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoic acid and its salts;

[2S,N(1/i)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b]

[1,4]oxazin-4-yl)propylamino}phenyl]propanamide;

[2/?,N(1/i)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b]

[1,4]oxazin-4-yl)propylamino}phenyl]propanamide;

25,N(1/t)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide;

[2/?,N(1 H ]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dibenzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide;

[2S,N(1/i)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b]

[1,4]oxazin-4-yl)propylamino}phenyl]propanamide hydrochloride salt;

[2^?,N(1^)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b]

[1,4]oxazin-4-yl)propylamino}phenyl]propanamide hydrochloride salt;

According to another embodiment of the present invention, a compound of general formula (I), wherein R<5> and R<6> together represent a bond; Y represents oxygen or sulfur and W represents NR<12>, -O-aryl-(CR10R1<1>)O-NR<12>; and all other symbols are, as defined above, may be produced by one or more of the processes shown in Scheme I below.

Route (1): Reaction of a compound of general formula (IIIa) in which L<1> is a leaving group, such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate, hydroxy and the like and all other symbols are, as defined above, with a compound of formula (lllb) in which W represents NR<12>, -O-aryl-(CR10R1<1>)o-NR<12>; and all other symbols are as defined above, in order to produce a compound of the general formula (I) in which all symbols are as defined above, can be carried out in the presence of a base, such as: metal carbonates, such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate and the like; metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, cesium bicarbonate and the like; metal hydrides such as NaH or KH; metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide and the like; alkoxides, such as NaOMe, NaOEt, K<+>BuO" and the like; organic bases, such as guanidine, triethyl amine, pyridine, N-methyl morpholine and the like or their mixtures. The reaction can be carried out in the presence of solvents, such as: THF, dioxane, DMF, DMSO, DME, toluene, benzene, acetone, dimethyl acetamide, acetonitrile and the like or their mixtures. A phase transfer catalyst can be used, such as tetraalkylammonium halides. The reaction temperature can be in the range of 0°C to 150°C. When L<1>represents a hydroxy group, the reaction can also be carried out using the reagents DEAD, DIAD and the like.

in which all symbols are, as defined earlier, with the compound formula

(IVd)

in which L<1> and all other symbols are as defined above.

Route 2: Reaction of a compound of general formula (III) in which all symbols are as defined above with a compound of formula (IIIld) in which L<1> is a leaving group such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate, hydroxy and the like and, in which all other symbols are as defined above, to produce a compound of general formula (I) in which all the symbols, as defined above, can be carried out in the presence of a base, such as: metal carbonates, such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate and the like; metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, cesium bicarbonate and the like; metal hydrides such as NaH or KH; metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide and the like; alkoxides, such as NaOMe, NaOEt, K<+>BuO" and the like; organic bases, such as guanidine, triethyl amine, pyridine, N-methyl morpholine and the like or their mixtures. The reaction can be carried out in the presence of solvents, such as: THF, dioxane, DMF, DMSO, DME, toluene, benzene, acetone, dimethyl acetamide, acetonitrile and the like or their mixtures. A phase transfer catalyst can be used, such as tetraalkylammonium halides or hydroxides.The reaction temperature can be in the range of 0°C to 150°C, preferably in the temperature range of 10°C to 100°C.When L<1>represents a hydroxy group, the reaction can also be carried out using Mitsunobu reagents using DEAD, DIAD and the like.

Route 3: The reaction of a compound of the general formula (Ila) in which all the symbols are as defined above with a compound of the formula (IIlf) in which R<13> represents a (C^CgJalkyl group and all other symbols are as previously defined) to produce a compound of the general formula (I) in which R<5> and R<6> together represent a bond and all other symbols are as defined above can be carried out in the presence of a base, such as: metallic hydrides such as NaH or KH; organolithiums such as CH3Li, BuLi and the like; alkoxides such as NaOMe, NaOEt, K<+>BuO" and the like or mixtures thereof. The reaction can be carried out in the presence of solvents such as: THF, dioxane, DMF, DME, dimethyl acetamide and the like or mixtures thereof. HMPA can be used as a co-solvent. The reaction temperature can be in the range of -78°C to 50°C, preference is given temperature range from -10°C to 30°C. The reaction is much more efficient under anhydrous conditions. The compound of general formula (IIlf) can be produced according to the procedure described in the literature (Annalen. Chemie, (1996) 53,699).

According to another embodiment of this invention, the compound of the general formula (I) in which R<5> represents: hydrogen atom, hydroxy, alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group; R<6> represents: hydrogen, hydroxy, alkoxy, halogen, alkyl group, acyl, substituted or unsubstituted and aralkyl; Y represents oxygen and W represents NR<12>, -O-aryl-(CR<10>R<11>)o-NR<12>; and all other symbols are, as defined above, may be produced by one or more of the procedures shown in Scheme-ll-below.

Route (4): Reduction of a compound of formula (IVa), which is a compound of formula (I) in which R<5> and R<6> represent a bond and Y represents an oxygen atom and all other symbols are, as previously defined, obtained as described earlier in Scheme-I, to give a compound of general formula (I) in which R<5> and R<6>, each, represent a hydrogen atom and all symbols are, as previously defined, can be carried out in the presence of a gas of hydrogen and catalysts, such as Pd/C, Rh/C, Pt/C, Ranev nickel and the like. Mixtures of catalysts may be used. The reaction can also be carried out in the presence of solvents, such as dioxane, acetic acid, ethyl acetate, methanol, ethanol, isopropanol and the like. Pressures from atmospheric to 80 psi can be used. High pressures can be used to reduce reaction time. 5-10% Pd/C is preferred as a catalyst and the amount of catalyst used can range from 1-50% w/w. The reaction can also be carried out using reduction with metal solvents, such as magnesium, samarium in alcohol or sodium amalgam in alcohol, preferably methanol. The hydrogenation can be carried out in the presence of metal catalysts containing chiral ligands to give the compound of formula (I) in an optically active form. Metal catalysts may include rhodium, ruthenium, indium, and the like. Chiral ligands can preferably be chiral phosphines, such as: (2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphenylphosphino)ethane, (-)-2,3-iso-propylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane and the like. Any suitable catalyst which will give the required optical purity of the product (I) can be used.

Route (5): Reaction of a compound of the general formula (lila) in which L<1>is a leaving group, such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate, hydroxy and the like and all other symbols are as defined above, with a compound of formula (IVb) in which R<5>represents hydrogen and all other symbols are as previously defined in order to produced a compound of the general formula (I) in which R<5> and R<6> represent a hydrogen atom and all other symbols are, as defined above, can be carried out in the presence of a base, such as: metal hydrides such as NaH or KH; organolithiums, such as CH3l_i, LiN(iPr)2, LiHMDS, LiN(Et)2, NaHMDS, KHMDS, BuLi and the like; alkoxides, such as NaOMe, NaOEt, t-BuO"K<+>and the like or their mixtures. The reaction can be carried out in the presence of solvents, such as: diethyl ether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide and the like or their mixtures. HMPA can be used as a co-solvent. The reaction temperature can be in the range of -78°C to 50°C, the temperature range of -10°C to 30° C. The reaction is much more efficient under anhydrous conditions.

According to another embodiment of the present invention, a compound of general formula (I) in which Y represents oxygen or sulfur and W represents -C(=O)-(CR<10>R<11>)o-NR<12->, where o is an integer in the range of 0-6 and all other symbols are as defined above, can be produced by a process, which includes:

reaction of compounds of formula (lllg)

wherein L<1> is a leaving group, such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate, hydroxy and the like and all other symbols are as defined above with a compound of formula (I I lb)

wherein W represents NR 12 , R< 12> represents hydrogen and all other symbols are as defined above in the presence of a base, such as: metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate and the like; metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, cesium bicarbonate and the like; metal hydrides such as NaH or

KH; metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like; alkoxides, such as NaOMe, NaOEt, K<+>BuO" and the like; organic bases, such as guanidine, triethyl amine, pyridine, N-methyl morpholine and the like or their mixtures. The reaction can be carried out in the presence of solvents, such as: THF, dioxane, DMF, DMSO, DME, toluene, benzene, acetone, dimethyl acetamide, acetonitrile and the like or their mixtures. A phase transfer catalyst can be used, such as tetraalkylammonium halides or hydroxides.The reaction temperature can be in the range of 0°C to 150°C, preferably in the temperature range of 10°C to 120°C.When L<1>represents a hydroxy group, the reaction can also be carried out using Mitsunobu reagents using DEAD, DIAD and the like.

According to another embodiment of the present invention, a compound of the general formula (I) in which Y represents oxygen and W represents -O-aryl-(CR10R11)o-NR<12>; and all other symbols are, as defined above, can be produced by a process, which includes: reacting a compound of the formula (lili)

wherein n and p are integers in the range 0-6, G<1>represents NH 2 or formyl and all other symbols are as defined above with a compound of formula (lllh)

wherein q is an integer in the range of 0-6, G<2> represents NH2 or formyl and all other symbols are as defined above using a solvent such as CH2CI2, CHCI3, chlorobenzene, benzene, THF, in the presence of a catalyst,

such as p-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH, BF3-OEt2 and the like. The reaction can also be performed using activated molecular sieves. The reaction temperature can be in the range of 10°C to 100°C, preferably in the range of 10°C to 60°C. The initially formed imine product can be reduced using Na(CN)BH3-HCl (ref: Hutchins, R.O. et al. J. Org. Chem. 1983, vol. 48, 3433-3428), H2-Pd/C, H2-Pt/C, H2-Ph/C and the like in solvents such as methanol, ethanol and the like.

A compound of formula (I) in which R<8> represents a hydrogen atom can be produced by hydrolyzing, using conventional procedures, a compound of formula (I) in which R<8> represents all previously defined groups except hydrogen. The hydrolysis can be carried out in the presence of a base, such as Na 2 CO 3 , and a suitable solvent, such as methanol, ethanol and the like or mixtures thereof. The reaction can be carried out at a temperature in the range of 20°C-40°C, preferably in the range of 25°C-30°C. The reaction time can be in the range from 2 to 12 h, preferably from 4 to 8 h.

A compound of the general formula (I) in which Y represents oxygen and R<8> represents hydrogen or a lower alkyl group can be converted into a compound of formula (I), in which Y represents NR<9>, by reaction with the corresponding amines of the formula NHR<8>R<9>, in which R<8> and R<9> are as defined earlier to obtain a compound of formula (I) in which Y represents NR<9> and all other symbols are as defined earlier. Alternatively, a compound of formula (I) in which YR<8>represents OH can be converted to an acid halide, preferably YR<8>=CI, by reaction with appropriate reagents, such as oxalyl chloride, thionyl chloride and the like, and then treatment with amines of the formula NHR8R<9>where R<8> and R<9> are as previously defined. Alternatively, mixed anhydrides can be produced from compounds of formula (I) wherein YR<8> represents OH and all other symbols are as previously defined by treatment with acidic halides, such as acetyl chloride, acetyl bromide, pivaloyl chloride, dichlorobenzoyl chloride and the like. The reaction can be carried out in the presence of a suitable base, such as pyridine, triethylamine, diisopropylethylamine and the like. Solvents such as halogenated hydrocarbons such as CHCl 3 or CH 2 Cl 2 may be used; hydrocarbons, such as benzene, toluene, xylene and the like. The reaction can be carried out at a temperature in the range of -40°C to 40°C, preferably at a temperature in the range of 0°C to 20°C. The acid halide or mixed anhydride thus produced may be further treated with appropriate amines of the formula NHR<8>R<9> wherein R<8> and R<9> are as previously defined to give a compound of formula (I) wherein Y is NR<9> and all other symbols are as previously defined.

In another embodiment of the present invention, a novel intermediate of formula (lllb)

their derivatives, their analogs, their tautomeric forms, their stereoisomers, their salts, their solutions, in which W represents NR<12>, R12 represents hydrogen, R10 and R<11> can be the same or different and represent hydrogen or a substituted or unsubstituted group, selected from: alkyl, alkoxy, aryl or aralkyl group; Ar represents a substituted or unsubstituted divalent single or fused aromatic or heterocyclic group; R<5> represents a hydrogen atom, hydroxy, alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group or forms a bond together with the neighboring group R<6>; R<6> represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, substituted or unsubstituted aralkyl or R<6> forms a bond together with R<5>; R<7> can be hydrogen or substituted or unsubstituted groups selected from: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl group; It can

be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen, sulfur or NR<13>, where R<13> represents hydrogen or substituted or unsubstituted groups selected from: alkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl or heteroaralkyl group; R<8> and R<13>, together, may form a substituted or unsubstituted 5- or 6-membered cyclic structure, containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; with the condition that m and n are integers 0-6.

A new intermediate of formula (lllb) in which m is 0 and all other symbols are as defined above can be produced by reduction of compounds of formula (lllj)

wherein R<7>, R<8> and Ar are as defined above in the presence of hydrogen gas and catalysts such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts can be used. The reaction can also be carried out in the presence of solvents, such as dioxane, acetic acid, ethyl acetate and the like. Pressures from atmospheric to 80 psi can be used. 5-10% Pd/C is preferred as a catalyst and the amount of catalyst used can range from 1-50% w/w. The reaction can also be carried out using reduction with metal solvents, such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol. The hydrogenation can be carried out in the presence of metal catalysts containing chiral ligands to give the compound of formula (I) in an optically active form. Metal catalysts may include rhodium, ruthenium, indium, and the like. Chiral ligands can,

preferably, be chiral phosphines, such as: (2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphenylphosphino)ethane, (-)-2,3-iso-propylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane and the like. (Ref: Principles of Asymmetric Synthesis, Tet. Org. Chem. Series Vol 14, pp311-316, Ed. Baldwin J.E.).

The compound of formula (lllj) can be produced by the reaction of the compound of formula (lllm)

wherein Ar is, as defined above, with a compound of formula (lllf) wherein R<13>represents a (C^C^alkyl group and all other symbols are as previously defined in the presence of a base, such as a metal hydride, such as NaH or KH; organolithiums, such as CH3Li, BuLi and the like; alkoxides, such as NaOMe, NaOEt, t-BuO"K<+>and the like or mixtures thereof. The reaction can be carried out in the presence of solvents such as: diethyl ether, DMF, DMSO, and the like. HMPA can be used as a co-solvent. The reaction temperature can be in the range of -10°C to 30°C. The reaction is more efficient under anhydrous conditions. described in the literature (Annalen. Chemie, (1996) 53, 699).

In yet another embodiment of the present invention, a compound of formula (IIIlb) wherein m is 0 and all other symbols are as defined above, can be prepared by diazotizing a compound of formula (III) to a compound of formula (III) and reducing a compound of formula (NN) to give a compound of formula (IIlb). The reaction is shown in Scheme-lll, below:

The diazotization of the compound of the formula (II) to obtain the compound of the formula (III) can be carried out using a diazotizing agent, such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite, and the like, under acidic conditions, using acids, such as: sulfuric acid, HCI, acetic acid, and the like, in an organic solvent, such as alcohols, such as methanol, ethanol, propanol, and the like; 1,4-dioxane, THF, acetone and the like. By etherification of the residue using alkyl sulfates, such as diethyl sulfate, dimethyl sulfate, and the like or alkyl halides, such as ethyl iodide, methyl iodide, and the like, in the presence of solvents, such as carbohydrates, such as toluene, benzene, and the like or DMF, DMSO, acetonitrile, THF, methyl isobutyl ketone (MIBK), and the like, in alkaline bases, such as sodium carbonate, potassium carbonate, sodium methoxide, sodium hydride, potassium hydride and the like.

Reduction of a compound of formula (INI) to give a compound of general formula (IIlb) can be carried out in the presence of hydrogen gas and catalysts such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts can be used. The reaction can also be carried out in the presence of solvents, such as dioxane, acetic acid, ethyl acetate and the like. Pressures from atmospheric to 80 psi can be used. 5-10% Pd/C is preferred as a catalyst and the amount of catalyst used can range from 1-50% w/w. The reaction can also be carried out using reduction with metal solvents, such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol. The hydrogenation can be carried out in the presence of metal catalysts containing chiral ligands to give the compound of formula (I) in an optically active form. The metal catalyst may include rhodium, ruthenium, indium, and the like. Chiral ligands can preferably be chiral phosphines, such as: (2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphenylphosphino)ethane, (-)-2,3-iso-propylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane and the like. (Ref: Principles of Asometric Synthesis, Tet. Org. Chem. Series Vol 14, pp311-316, Ed. Baldwin J.E.).

In yet another embodiment of the present invention, a compound of formula (lllb), wherein m is 1-6 and all other symbols are as defined above, may be prepared according to the procedure described in Scheme-IV, below:

The reaction of a compound of general formula (IIlf), defined above, with a compound of formula (IIIn) to give a compound of formula (IIlo) can be carried out in the presence of a base, such as a metal hydride, such as NaH or KH; organolithiums, such as CH3Li, BuLi and the like; alkoxides, such as NaOMe, NaOEt, t-BuO"K<+>and the like or their mixtures. The reaction can be carried out in the presence of solvents, such as: diethyl ether, THF, dioxane, DMF, DMSO, DME, dimethyl acetamide and the like or their mixtures. HMPA can be used as a co-solvent. The reaction temperature can be in the range of -78°C to 50°C, the temperature range of -10°C to 30°C.

Reduction of the compound of formula (Ilio) to give the compound of formula (IIlp) can be carried out in the presence of hydrogen gas and catalysts such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts can be used. The reaction can also be carried out in the presence of solvents, such as dioxane, acetic acid, ethyl acetate and the like. Pressures from atmospheric to 80 psi can be used. 5-10% Pd/C is preferred as a catalyst and the amount of catalyst used can range from 1-50% w/w. The reaction can also be carried out using reduction with metal solvents, such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol. The hydrogenation can be carried out in the presence of metal catalysts containing chiral ligands to give the compound of formula (I) in an optically active form. The metal catalyst may include rhodium, ruthenium, indium, and the like. Chiral Ugandans may preferably be chiral phosphines, such as: (2S,3S)-bis(diphenylphosphino)butane, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(2-methoxyphenylphenylphosphino)ethane, (-)-2,3-iso-propylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane and the like.

The reaction of the compound of the general formula (lllp) with the compound of the formula (lllq) can be carried out using a solvent, such as CH2CI2, CHCl3, chlorobenzene, benzene, THF, in the presence of a catalyst, such as p-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH, BF3-OEt2 and the like. The reaction can also be performed using activated molecular sieves. The reaction temperature can be in the range of 10°C to 100°C, preferably in the range of 10°C to 60°C. The initially formed imine product can be reduced using Na(CN)BH3-HCl (ref: Hutchins, R.O. et al. J. Org. Chem. 1983, vol. 48, 3433-3428), H2-Pd/C, H2-Pt/C, H2-Ph/C and the like in solvents such as methanol, ethanol and the like.

In another embodiment of the present invention, a compound of formula (lllb) wherein m is 0 or 1 and all other symbols are as defined above can be prepared by diazotizing a compound of formula (lllk) to a compound of formula (Va), decomposing a compound of formula (Va) to a compound of formula (MH) in the presence of an alcohol, such as R<7>OH and reducing a compound of formula (lli) to give a compound of formula (lllb). The sequence of reactions is shown in Scheme-V, below:

Diazotization of a compound of formula (IIIlk) wherein m is 0, R<6> is hydrogen and all other symbols are as defined above to give a compound of formula (Va) can be carried out using a diazotizing agent such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite and the like in the presence of a catalytic amount of a carboxylic acid such as acetic acid, propionic acid and the like in a suitable solvent such as chloroform. chlorobenzene, dichloroethane and the like or a mixture thereof, at a temperature ranging from room temperature to the reflux temperature of the solvent used, for a period ranging from 0.5 to 16 h.

Decomposition of an arylalkyl diazo acetate of formula (Va) to give a compound of formula (IIII) wherein R<7> is as defined above excluding hydrogen and all other symbols are as defined above can be promoted by a suitable catalyst, such as Rh(II) acetate, salt/complex of Cu(I) or Rh(II) and the like {Bio. Org. Med. Chem. Leti., 1996, 2121-2126), in the presence of alcohol of formula R<7>OH.

Reduction of a compound of formula (INI) to give a compound of general formula (lllb) wherein all the symbols are as previously defined can be carried out in the presence of hydrogen gas and catalysts such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Mixtures of catalysts can be used. The reaction can also be carried out in the presence of solvents, such as dioxane, acetic acid, ethyl acetate and the like. Pressures from atmospheric to 80 psi can be used. 5-10% Pd/C is preferred as a catalyst and the amount of catalyst used can range from 1-50% w/w. The reaction can also be carried out using reduction with metal solvents, such as magnesium, iron, tin, samarium in alcohol or sodium amalgam in alcohol, preferably methanol. Hydrogenation can be performed using ammonium formate, hydrogen donor type cyclohex-1,4-diene under pd/c conditions, using solvents such as methanol, ethanol, ethyl acetate and the like.

However, in another embodiment of the present invention, the compound of formula (lllb) in its enantiomerically pure form, where m is 0, R<5>=R<6>=H and all other symbols are as defined above, can be prepared according to the following procedure, described in Scheme-VI, below:

Diazotization of a compound of formula (Via) wherein all symbols are as defined above to obtain a compound of formula (Vlb) can be carried out using a diazotizing agent, such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite and the like, under aqueous acidic conditions using acids such as: sulfuric acid, HCl, acetic acid and the like, in an organic solvent such as: alcohols such as methanol, ethanol, propanol and the like similar; 1,4-dioxane, THF, acetone and the like.

One-pot esterification and etherification of a compound of the general formula (Vlb) to a compound of the general formula (Vic) can be performed by initial dideprotonation (Vlb) using a suitable base, such as: NaH, KH, KOH or the like, in a suitable solvent, such as toluene, benzene, diethyl ether, THF, DMF, DME, HMPA and the like, and then, treatment with an alkyl halide such as ethyl iodide or methyl iodide and the like. Other alkylating agents can also be used, such as: Et30<+>BF4~, Me30<+>BF4~, dialkylsulfate. The reaction temperature can vary from 0°C to 100°C.

Nitration of compounds of formula (Vic) to compounds of formula (Vid) where n is 0 and all other symbols are as defined above can be carried out using nitrating agents such as: fuming nitric acid, N 2 O 5 , a mixture of conc. of nitric acid and conc. sulfuric acid or a mixture of nitric acid and acetic anhydride in the presence of a solvent or under clean conditions, at a temperature ranging from -10°C to room temperature, for a period ranging from 0.5 to 4 h (Ref: Org. Svnth. Col.

Vol. I, 396)

The reduction of the compound of formula (Vid) to the compound of formula (lllb) can be carried out in the presence of hydrogen gas or hydrogen donors, such as ammonium formate, cyclohex-1,4-diene and the like and catalysts such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Catalyst mixtures can be used in the presence of solvents, such as: methanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. Pressures from atmospheric to 80 psi can be used. 5-10% Pd/C is preferred as a catalyst and the amount of catalyst used can range from 1-50% w/w. Alternatively, the reaction can also be carried out using reduction with metal solvents such as magnesium, iron, tin, samarium, indium, sodium amalgam in alcohol or other suitable solvents, methanol being preferred.

In another embodiment of the present invention, a compound of formula (lllb) in its enantiomerically pure form, where m is 0, R<5>=R<6>=H and all other symbols are as defined above, can be produced according to the process described in Scheme-VII below:

Diazotization of a compound of formula (VIa) wherein all symbols are as defined above to obtain a compound of formula (VIlb) can be carried out using diazotizing agents, such as: sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite, and the like, under aqueous acidic conditions using acids, such as: sulfuric acid, hydrochloric acid, acetic acid, and the like, in the presence of an optional cosolvent, such as alcohols, such as methanol, ethanol, propanol and the like; or ethers, such as 1,4-dioxane, THF and the like; or ketones, such as acetone, methyl ethyl ketone and the like.

Esterification of compounds of formula (Vllb) to compounds of formula (Ville) can be done using the appropriate alcohol of the formula R<8>OH, where R<8> represents lower alkyl groups, such as: methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and the like, in the presence of a suitable catalyst, as conc. sulfuric acid, dry HCI, BF3-OEt2 and the like. The reaction can be carried out at the reflux temperature of the alcohol used. Alternatively, diazotomethane or Et30+BF4 or Me30<+>BF4" and the like can also be used for esterification.

Selective O-alkylation of a compound of formula (VII) to a compound of formula (Vlld) can be carried out using alkyl sulfates such as diethyl sulfate, dimethyl sulfate and the like or alkyl halides such as ethyl iodide, methyl iodide, n-propyl iodide, n-propyl bromide, isopropyl iodide and the like, in solvents such as hydrocarbons such as toluene, benzene and the like or acetonitrile, tetrahydrofuran, dimethyl formamides, dimethyl sulfoxide and the like, in the presence of molecular sieves and alkaline bases, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium hydride, potassium hydride, sodium or potassium hydroxide and the like. Heavy metal oxides such as Ag 2 O, PbO, HgO and the like may be particularly useful for performing alkylation when alkyl halides are used as alkylation reagents. Also, phase transfer catalysts can be used, such as tetraalkylammonium hydroxide or tetraalkylammonium halides, such as tetrabutylammonium chloride, tetrabutylammonium bromide and the like.

The reduction of the compound of formula (VIId) to the compound of formula (lllb) can be carried out in the presence of hydrogen gas or hydrogen donors, such as ammonium formate, cyclohex-1,4-diene and the like and catalysts such as Pd/C, Rh/C, R/C, Raney nickel and the like. Catalyst mixtures can be used in the presence of solvents, such as: methanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. Pressures from atmospheric to 80 psi can be used. 5-10% Pd/C is preferred as a catalyst and the amount of catalyst used can range from 1-50% w/w. Alternatively, the reaction can also be carried out using reduction with metal solvents such as magnesium, iron, tin, samarium, indium, sodium amalgam in alcohol or other suitable solvents, methanol being preferred.

In another embodiment of the present invention, the compound of formula (lllb) in its enantiomerically pure form, where m is 0, R<5>=R<6>=H and all other symbols are as defined above, can be produced according to the process described in Scheme-VIII below:

The diazotization of a compound of formula (VIa) wherein all symbols are as defined above to obtain a compound of formula (VIlb) can be carried out using diazotizing agents such as: sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite and the like, under aqueous acidic conditions using acids such as: sulfuric acid, hydrochloric acid, acetic acid and the like, in the presence of an optional co-solvent such as alcohols such as methanol, ethanol, propanol and the like; or ethers, such as 1,4-dioxane, THF and the like; or ketones, such as acetone, methyl ethyl ketone and the like.

Esterification of compounds of formula (Vllb) to compounds of formula (VIIc) can be done using the appropriate alcohol of the formula R<8>OH, where R<8> represents lower alkyl groups, such as: methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and the like, in the presence of a suitable catalyst, as conc. sulfuric acid, dry HCI, BF3-OEt2 and the like. The reaction can be carried out at the reflux temperature of the alcohol used. Alternatively, diazotomethane or Et30<+>BF4" or Me30<+>BF4~ and the like can also be used for esterification.

The reduction of the compound of formula (VIIc) to the compound of formula (VIMa) can be carried out in the presence of gaseous hydrogen or hydrogen donors, such as ammonium formate, cyclohex-1,4-diene and the like and catalysts such as Pd/C, Rh/C, Pt/C, Raney nickel and the like. Catalyst mixtures can be used in the presence of solvents, such as: methanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. Pressures from atmospheric to 80 psi can be used. 5-10% Pd/C is preferred as a catalyst and the amount of catalyst used can range from 1-50% w/w. Alternatively, the reaction can also be carried out using reduction with metal solvents such as magnesium, iron, tin, samarium, indium, sodium amalgam in alcohol or other suitable solvents, methanol being preferred.

The N,N-dibenzylation of the compound of formula (VIlla) to the compound of formula (VIllb) can be carried out using benzyl halides such as benzyl bromide, benzyl chloride and the like, in solvents such as hydrocarbons such as toluene, benzene and the like or acetonitrile, tetrahydrofuran, dimethyl formamide, dimethyl sulfoxide and the like, in the presence of alkaline bases such as sodium carbonate, potassium carbonate, sodium or potassium hydroxide and the like. Also, phase transfer catalysts can be used, such as tetraalkylammonium hydroxide or tetraalkylammonium halides, such as tetrabutylammonium chloride, tetrabutylammonium bromide, and the like. The reaction can be carried out in the range from room temperature to the reflux temperature of the solvent used.

Hydrolysis of the compound of formula (Vlllb) to the compound of formula (Vlllc) using aqueous alkali metal bases, such as lithium carbonate, sodium carbonate, potassium carbonate or potassium bicarbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide and the like, in suitable co-solvents, such as methanol, ethanol, THF and the like or mixtures thereof. The reaction time can range from 0.5 h to 24 h, preferably 0.5 h to 3-4 h and the reaction temperature can be in the range from 0°C to 80°C.

Esterification and etherification in one vessel, compounds of formula (Vlllc) to compounds of formula (Vllld), where R<5>= R<6>, can be carried out by treatment with bases, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and the like, in solvents, such as hydrocarbons, such as toluene, benzene, and the like, dialkyl ethers, such as diethyl ether, tetrahydrofuran, and the like. or dimethyl formamide, HM PA, and then, by treatment with alkyl halides, such as ethyl iodide, methyl iodide, n-propyl iodide, n-propyl bromide, isopropyl iodide and so on. or alkyl sulfates, such as diethyl sulfate, dimethyl sulfate, etc. or alkylating agents, such as Et30<+>BF4", Me30+BF4" and the like. The reaction time can be in the range of 2 h to 20 h and the reaction temperature can be in the range of 0°C to 80°C.

The debenzylation of the compound of formula (VIIId) to the compound of formula (lllb) can be carried out in the presence of hydrogen gas or a hydrogen donor such as ammonium formate, cyclohex-1,4-diene and the like and catalysts such as Pd/C, Rh/C, R/C, Raney nickel and the like. Catalyst mixtures can be used in the presence of solvents, such as: methanol, ethanol, dioxane, acetic acid, ethyl acetate and the like. Pressures from atmospheric to 80 psi can be used. 5-10% Pd/C is preferred as a catalyst and the amount of catalyst used can range from 1-50% w/w.

A new intermediate of the formula (lllb) where W represents NR<12> and R<12> represents hydrogen, and which can be used for the preparation of the compounds of this invention and the process for the preparation of the intermediate (lllb), is described and claimed in our PCT application entitled "New pMenyl-ct-oxysubstituted propion derivatives: process for their preparation and their use in the preparation of pharmaceutically important compounds", filed on the same day as this application.

In another embodiment of the present invention, a new intermediate of the formula (llld)

its derivatives, its analogs, its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, in which L<1> is a leaving group, such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate

p-nitrobenzenesulfonate, acetate, sulfate, phosphate or hydroxy; W represents NR<12>, -C(=O)-(CR<10>R<n>)o-NR<1>2, -O-aryl-(CR<10>R<1>')o-NR<12>, where R<12> represents hydrogen or a substituted or unsubstituted group selected from alkyl, aryl or aralkyl groups; o is an integer in the range 0-4; R<10> and R<n> can be the same or different, and represent hydrogen or an unsubstituted or unsubstituted group, which is selected from: alkyl, alkoxy, aryl or aralkyl group; Ar represents a substituted or unsubstituted divalent single or fused aromatic or heterocyclic group; R<5> represents: a hydrogen atom, hydroxy, alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group, or forms a bond together with the neighboring group R<6>; R<6> represents: hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, substituted or unsubstituted aralkyl or R<6> forms a bond together with R<5>; R<7> can be hydrogen or substituted or unsubstituted groups selected from: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl group; R<8> can be hydrogen or substituted or unsubstituted groups selected from: alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen, sulfur or NR<9>, where R<9> represents hydrogen or substituted or unsubstituted groups selected from: alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl group; R<8> and R<9> together can form a substituted or unsubstituted cyclic structure with 5 or 6 members, containing carbon atoms, which can optionally contain one or more heteroatoms, selected from oxygen, sulfur or nitrogen; m and n are integers in the range 0-6.

In another embodiment of this invention, there is provided a new intermediate of formula (lllg) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, in which R1,R<2> and R<3>,R<4>, when attached to a carbon atom, can be the same or different and represent: hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups selected from: alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, armethoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkylalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R<3> and R<4> may represent an oxo or thioxo group when attached to a carbon atom; R<3> and R<4>, when attached to a nitrogen atom, represent: hydrogen, hydroxy, formyl or optionally substituted groups selected from: alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkyl, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, araloxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; R<10> and R11 may be the same or different and represent hydrogen or a substituted or unsubstituted group selected from: alkyl, alkoxy, aryl or aralkyl groups; L<1>is a leaving group, such as: a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate or hydroxy; n and o are integers in the range 0-6.

In another embodiment of the present invention, a novel intermediate of formula (lili) is provided

their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, in which R1, R<2> and R<3>, R<4>, when attached to a carbon atom, can be the same or different and represent: hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups, selected from: alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, aryloxy, aralkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, araloxycarbonyl, alkoxyalkyl, aryloxyalkyl, armethoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R<3> and R<4> may represent an oxo or thioxo group when attached to a carbon atom; R<3> and R<4>, when attached to a nitrogen atom, represent: hydrogen, hydroxy, formyl or optionally substituted groups selected from: alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl,

acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, araloxycarbonyl, alkoxyalkyl, aryloxyalkyl, araloxyalkyl, alkylthio, thioalkyl group, carboxylic acid derivative or sulfonic acid derivative; X represents a heteroatom selected from oxygen or sulfur; R<10> and R11 may be the same or different and represent hydrogen or a substituted or unsubstituted group selected from: alkyl, alkoxy, aryl or aralkyl groups; G<1> is CHO or NH2 and p and m are integers in the range 0-6.

It is appreciated that in any of the above-mentioned reactions, each reactive group in the substrate molecule can be protected according to common chemical practice. Suitable protecting groups in any of the above reactions are: tertiary butyl dimethyl silyl chloride, methoxymethyl chloride, etc., to protect the hydroxyl group, N-Boc, N-Cbz, N-Fmoc, etc., to protect the amino group, acetal protection for aldehyde, ketal protection for ketone, and the like. Procedures for formation and removal of such protecting groups are conventional procedures suitable for the molecule to be protected.

Pharmaceutically acceptable salts are prepared by reacting a compound of formula (I) with 1 to 4 equivalents of a base, such as sodium hydroxide, sodium methoxide, sodium hydride, potassium hydroxide, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents such as: ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol, toluene, etc. Mixtures of solvents may also be used. Also, organic bases can be used, such as: lysine, arginine, diethanolamine, choline, guanidine, adamentyl amine, their derivatives, etc. Alternatively, acid addition salts, whenever practicable, are prepared by treatment with acids such as: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthenic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like, in solvents such as: ethyl acetate, ether, alcohols, acetone, THF, dioxane and the like. Also, solvent mixtures may be used.

Stereoisomers, which form part of this invention, can be prepared by using the reactants in their single enantiomeric form in the process, whenever possible, or by performing the reaction in the presence of reagents or catalysts in their single enantiomeric form or by separating the mixture of stereoisomers by conventional methods. Some of the preferred methods include: the use of microbial resolution, the resolution of diastereomer salts, which are formed with chiral acids such as: mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like, whenever feasible, or with chiral bases such as: brucine, quinine alkaloids, their derivatives and the like. Commonly used procedures are summarized in "Enantiomers, Racemates and Resolution" by Jaques et al.

(Wiley Interscience, 1981). More specifically, the compound of formula (I), where YR<8> represents OH, can be converted into a mixture of diastereomeric amides, in a ratio of 1:1, by treatment with chiral amines, amino acids, amino alcohols derived from amino acids; to convert the acid to the amide, the usual reaction conditions can be used; diastereomers can be separated either by fractional crystallization or chromatography, and stereoisomers of compounds of formula (I) can be prepared by hydrolysis of the pure diastereomeric amide.

Pharmaceutically acceptable solvates of compounds of formula (I), which form part of this invention, can be prepared by conventional methods, such as dissolving compounds of formula (I) in solvents, such as: water, methanol, ethanol and the like, preferably water and, by recrystallization, using various crystallization techniques.

Various polymorphs of compounds of general formula (I), which form part of the present invention, can be prepared by crystallizing compounds of formula (I) under different conditions. For example, using different, commonly used solvents or their mixtures for recrystallization; by crystallization at different temperatures; by various methods of cooling, ranging from very fast to very slow cooling, during crystallization. Polymorphs can also be obtained by heating or melting the compound, followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid-state NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, X-ray powder diffraction, or other similar techniques.

This invention provides a pharmaceutical mixture, which contains compounds of the general formula (I), as previously defined, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates, in combination with the usual pharmaceutically used carriers, diluents and the like, useful for the treatment and/or prophylaxis of diseases, such as: hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. These compounds are useful in the treatment of hyperlipidemia, hyperglycemia, familial hypercholesterolemia, hypertriglyceridemia, lowering atherogenic lipoproteins, VLDL and LDL. The compounds of the present invention can be used to treat certain kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. The compounds of general formula (I) are also useful for the treatment/prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, disorders associated with syndrome X, such as: hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders. These compounds may also be useful as aldolase reductase inhibitors, to improve cognitive function in dementia, to treat complications of diabetes, disorders related to endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), inflammatory bowel disease, osteoporosis, myotonic dystrophy, pancreatitis, retinopathy, arteriosclerosis, xanthoma, inflammation, and to treat malignant diseases. The compounds of the present invention are also useful in the treatment and/or prophylaxis of the above-mentioned diseases in combination/simultaneously with one or more HMG CoA reductase inhibitors; cholesterol absorption inhibitors; anti-obesity drugs; drugs for the treatment of lipoprotein disorders; hypoglycemic agents; insulinoma; biguanides; sulfonylureas; thiazolidinediones; double PPARα and γ or their mixtures. The compounds of this invention in combination with HMG CoA reductase inhibitors, cholesterol absorption inhibitors, anti-obesity drugs, hypoglycemic agents, can be administered together or within such a time period in which they will act synergistically.

This invention also provides a pharmaceutical composition containing compounds of the general formula (I), as previously defined, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates and one or more HMG CoA reductase inhibitors; cholesterol absorption inhibitors; anti-obesity drugs; drugs for the treatment of lipoprotein disorders; hypoglycemic agents; insulin; biguanides; sulfonylureas; thiazolidinediones; double PPARa and y or their mixtures, in combination with, in pharmacy, commonly used, carriers, diluents and the like.

The pharmaceutical composition may be in commonly used forms, such as tablets, capsules, powders, syrups, solutions, suspensions, and the like, and may contain flavoring agents, sweeteners, etc., in suitable solid or liquid carriers or diluents, or in suitable sterile media, to form injectable solutions or suspensions. Such mixtures usually contain from 1 to 20%, preferably 1 to 10%, by weight, of the active ingredient, with the remainder of the mixture being pharmaceutically acceptable carriers, diluents or solvents.

Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active ingredient may be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage range, as described above. Therefore, for oral administration, a compound of formula (I) may be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. Pharmaceutical mixtures may, if desired, contain additional components, such as: flavoring agents, sweeteners, excipients and the like. For parenteral administration, the polymorph form may be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble, pharmaceutically acceptable, acid-formation salts or base-formation salts of compounds. For injection solutions, aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil can also be used. Injectable solutions prepared in this manner may then be administered intravenously, intraperitoneally, subcutaneously or intramuscularly, with intramuscular administration being preferred in humans.

For nasal administration, the preparations may contain polymorphic forms of the present invention, dissolved or suspended in a liquid carrier, especially an aqueous carrier, for aerosol administration. The carrier may contain additives such as solubilizing agents such as propylene glycol, surfactants, absorption enhancing agents such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabens.

Tablets, dragees or capsules, having a binding agent, carrying talc and/or carbohydrate, or the like, are particularly suitable for any oral administration. Preferably, carriers for tablets, dragees or capsules include: lactose, corn starch and/or potato starch. In cases where a sweetening agent can be used, a syrup or elixir can be used.

A typical tablet manufacturing process is shown below:

Ingredients 1 to 3 were uniformly mixed with water and granulated after drying under reduced pressure. Ingredients 4 and 5 were well mixed with the granules and compressed using a tableting machine to prepare 1000 tablets, each containing 30 mg of active ingredient.

Ingredients 1 to 4 are uniformly moistened with aqueous solution 5 and are granulated after drying under reduced pressure. Ingredient 6 was added and the granules were compressed using a tableting machine to prepare 1000 tablets, each containing 30 mg of Ingredient 1.

A compound of formula (I), as defined above, has been clinically administered to mammals, including humans, orally, nasally, pulmonaryly, transdermally or parenterally, rectally, as a depot preparation, subcutaneously, intravenously, intraurethrally, intramuscularly, intranasally, via ophthalmic solution or ointment. Oral administration is preferred, which is more convenient and avoids possible pain and irritation as a result of injection. However, in circumstances where the patient cannot swallow the drug, or the absorption following oral administration is impaired, due to disease or other abnormality, it is necessary to administer the drug parenterally. Regardless of the route of administration, the dose is in the range of about 0.01 to about 100 mg/kg body weight of the subject per day, or preferably, about 0.01 to about 30 mg/kg body weight per day administered at once or in divided doses. However, the optimal dosage for the individual subject to be treated will be determined by the person responsible for the treatment, generally using lower doses at first, and then increasing the dose to determine the most suitable dose.

The invention is explained in detail in the examples, given below, which are presented by way of illustration only and therefore should not be construed as limiting the scope of the invention.

Production 1

Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate

Namely, the salt of triethyl 2-ethoxyphosphonoacetate (26.5 g, 1.5 eq, 99.3 mmol) and NaH (50% in oil) (5.3 g, 2 eq, 132.4 mmol) was prepared in THF (350 ml) at 0°C. To this solid, 4-nitrobenzaldehyde (10 g, 1 eq, 66.2 mmol) was added in portions at 0°C and the resulting solution was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate and washed with aqueous NH 4 Cl. The crude product contains ethyl 4-nitro-2-ethoxycinnamate in both Z and E stereoisomers (11 g).

Step (ii)

Ethyl 4-nitro-2-ethoxycinnamate obtained in step (i) was hydrogenated using Pd(10%)/C-H2(60 psi) (11 g) in ethyl acetate (150 ml) at RT and chromatographed using ethyl acetate/hexanes to give the title compound as a viscous oil (9.41 g, 60% yield).

1H NMR (200 MHz, CDCl3) δ: 1.16 (t, J=7.0Hz, 3H), 1.22 (t, J=7.0Hz, 3H), 2.90 (d, J=6.3Hz, 2H), 3.30 (bs, 2H, NH2), 3.35 (m, 1H), 3.55 (m, 1H), 3.94 (t, J=6.3Hz, 1H), 4.15 (q, J=7.0Hz, 2H), 6.62 (d, J=8.3Hz, 2H), 7.03 (d, J=8.0Hz, 2H).

IR (neat) cm'<1>: 3372.1738.

Mass. m/z (Cl): 238 (M+1), 192 (M-OC 2 H 5 ).

Production 2

3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide

A mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (3.0 g, 1 eq, 22.2 mmol), 1,3-dibromopropane (22.5 ml, 10 eq, 222 mmol) and anhydrous sodium carbonate (7.05 g, 3 eq, 66.6 mmol) in dry DMF (200 ml) was heated at 70°C for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to give the title compound as a liquid (2.6 g, 47%).

<1>H NMR (200 MHz, CDCl3) δ: 2.10-2.30 (m, 2H), 3.37 (t, J=4.4Hz, 2H), 3.40-3.56 (m, 4H), 4.25 (d, J=4.3Hz, 2H), 6.60-6.90 (m, aromatics, 4H).

Mass. m/z (Cl): 255 (M(<79>Br)), 256 (MfBrJ+1), 257 (M(Br<81>)), 258 (M(Br<81>)+1).

Production 3

Ethyl 2-ethoxy-3-[4-{N-heptyl-N-(2'-bromoethyl)}aminophenyl]propanoate

A mixture of ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (5 g, 1 eq, 21 mmol), obtained from preparation 1, heptyl bromide (18.8 g, 5 eq, 105 mmol) and anhydrous K 2 CO 3 (14.5 g, 5 eq, 105 mmol) was heated at 70 °C in DMF (100 mL) for 16 h. h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using a mixture of ethyl acetate and hexane as diluent to give the monoheptylated product as a thick liquid (3.85 gm, 55% yield).

<1>H NMR (200 MHz, CDCl3) δ: 0.88 (bt, J=6.3Hz, 3H), 1.05-1.42 (m, 15H), 1.42-1.68 (m, 2H), 2.90 (d, J=6.6Hz, 2H), 3.08 (t, J=6.8Hz, 2H), 3.22-2.42 (m, 1H), 3.44-3.64 (m, 1H), 3.94 (t, J=6.8Hz, 1H), 4.1 (q, J=7.0Hz, 2H), 6.55 (d, J=8.3Hz, 2H), 7.04 (d, J=8.3Hz, 2H).

IR (pure) cm"<1>: 3396.1747.

Mass. m/z (Cl): 335 (M+1), 290 (M-OC 2 H 5 ).

Step (ii)

The monoheptylated product (3g, 1 eq, 8.98 mmol), obtained in step (i) was treated with an excess of dibromoethane (10 eq) in the presence of anhydrous K 2COa (3.72 g, 3 eq, 27 mmol), in DMF (40 ml) and heated at 70°C for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using a mixture of ethyl acetate and hexane as diluent to give ethyl 2-ethoxy-3-[4-{N-heptyl-N-(2'-bromoethyl)}aminophenyl]propanoate as a thick liquid (1.98 g, 50% yield).

<1>H NMR (200 MHz, CDCl3) δ: 0.88 (bt, J=6.3Hz, 3H), 1.05-1.42 (m, 14H), 1.42-1.68 (m, 2H), 2.90 (d, J=6.6Hz, 2H), 3.28 (t, J=7.3Hz, 2H), 3.30-3.45 (m, 3H), 3.50-3.70 (m, 3H), 3.96 (t, J=6.8Hz, 1H), 4.17 (q, J=7.0Hz, 2H), 6.57 (d, J=8.3Hz, 2H), 7.09 (d, J=8.3Hz, 2H).

IR (pure) cm": 1747.

Mass. m/z (Cl): 442 (M(<79>Br)+1), 444 (M(Br<8>,)+1).

Production 4

2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)carboxymethyl chloride

3,4-Dihydro-2H-benzo[b][1,4]oxazine (1.52 g, 1 eq, 11.3 mmol), triethylamine (4.73 ml, 3 eq, 33.9 mmol) and a catalytic amount of DMAP were placed in DCM (50 ml). To this mixture was added 2-chloroacetyl chloride (1.8 ml, 2 eq, 22.6 mmol) at 0 °C and the reaction mixture was stirred at 0 °C for 4 h. The reaction mixture was diluted with DCM and washed with dilute aqueous HCl followed by NaHCO 3 and brine. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated on a rotary evaporator. The crude compound was chromatographed using ethyl acetate and hexane to afford the title compound as a waxy solid (1.54 g, 65% yield).

<1>H NMR (200 MHz, CDCIg) δ: 3.98 (t, J=4.4Hz, 2H), 4.25-4.40 (m, 4H), 6.90-7.20 (aromatics, 4H).

IR (pure) cm"<1>:1655.

Mass. m/z (Cl): 212 (MfCl)<*>1), 214 (M(Cl<37>)+1).

Production 5

Methyl 3-[4-formylphenyl]-2-ethoxypropanoate

Namely, the salt of triethyl 2-ethoxyphosphonoacetate (25.6 g, 2.0 eq, 96 mmol) and NaH (3.84 g, 2 eq, 96 mmol) was prepared in THF (240 ml) at 0°C. To this was added dropwise, at 0°C, terephthalaldehyde monodiethylacetal (10 g, 1 eq, 48 mmol). The resulting solution was stirred at RT for 24 h. The reaction mixture was diluted with ethyl acetate and washed with aqueous NH 4 Cl. The residue was chromatographed (ethyl acetate and hexane) to give 4'-(diethoxymethyl)-2-ethoxycinnamate in both Z and E stereoisomers (13.9 g, 90% yield).

Step (ii)

A dry methanol (20 ml) solution of ethyl 4'-(diethoxymethyl)-2-ethoxycinnamate (5 g, 1 eq, 15.5 mmol) obtained in step (i) was added to a dry methanol solution (60 ml) containing activated magnesium filings (7.44 g, 20 eq, 310 mmol) and allowed to stir. Eventually, the reaction mixture becomes turbulent requiring a reflux condenser. Once the magnesium is consumed to produce Mg(OMe)2 (takes 3-4 h), it is stirred at RT for 16 h. The reaction mixture was acidified carefully with conc. HCl, stirred for 2 h at RT. Finally, ethyl acetate was added and the organic layer was carefully washed with water and brine and dried over anhydrous Na 2 SO 4 . The residue was chromatographed (EtOAc/hexane) to give the title compound as a viscous oil (2.92 g, 80% yield).

<1>H NMR (200 MHz, CDCIg) δ: 1.14 (t,«£6.8Hz, 3H), 3.00-3.20 (m, 2H), 3.22-3.41 (m, 1H), 3.48-3.67 (m, 1H), 3.73 (S, 3H), 4.06 (dd, ^7.8, 1^5.4Hz, 1H), 6.40 (d, J=8.3Hz, 2H), 7.81 (d,ufc8.3Hz, 2H), 9.99 (S, 1H).

IR (pure) cm*1: 1751, 1701.

Mass m/z (Cl): 237 [M+1].

Production 6

Methyl 2-ethoxy-3-[4-(N-heptylaminomethyl)phenyl]propanoate

Methyl 3-[4-formylphenyl]-2-ethoxypropanoate (2 g, 1 eq, 8.51 mmol), obtained by preparation of 5, heptylamine (978 mg, 1 eq, 8.51 mmol) and cat. amount of p-TsOH.H 2 O) were placed in DCM (40 ml), together with several pieces of activated molecular sieves (4 A). The reaction mixture was filtered through celite after 24 h at RT and the filtrate was diluted with DCM and washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate to give crude methyl 2-ethoxy-3-[4-(N-heptyliminomethyl)phenyl]propanoate.

Step (ii)

The crude 2-ethoxy-3-[4-(N-heptyliminomethyl)phenyl]propanoate obtained in step (i) above (2.95 g) was dissolved in methanol (40 ml) and treated with conc. HCl (850 uJ, 1 eq, 8.51 mmol) and sodium cyanoborohydride (535 mg, 1 eq, 8.51 mmol) at 0°C. The progress of the reaction was monitored by TLC. After 2-3 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The residue was chromatographed using methanol and chloroform to give the title compound (1.71 g, 60% yield) as a viscous liquid.

■H NMR (200 MHz, CDCl3) δ: 0.86 (bt, J=6.3Hz, 3H), 1.14 (t, J=6.8Hz, 3H), 1.20-1.40 (m, 9H), 1.50-1.70 (m, 2H), 2.60 (t, J=7.4Hz, 2H), 2.98 (d, J=6.3Hz, 2H), 3.22-3.41 (m, 1H), 3.48-3.67 (m, 1H), 3.71 (s, 3H), 3.89 (s, 2H), 4.02 (t, J=6.3Hz, 1H), 7.23 (d, J=7.8Hz, 2H), 7.30 (d, J=7.8Hz, 2H).

IR (pure) black': 3500 (br), 1748.

Mass m/z (Cl): 336 [M+1].

Production 7

Methyl 2-ethoxy-3-(4-aminophenyl)propanoate

Ethyl 4-nitro-2-ethoxycinnamate (10 g, 1 eq, 37.7 mmol), obtained in step (i) of Preparation 1, was treated with activated magnesium filings (18 g, 20 eq, 754 mmol) in dry methanol (400 mL). The reaction mixture was refluxed for 2-3 h, allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and quenched with cold aqueous ammonium chloride. The organic layer was washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to give the title compound as a liquid (6 g, 72% yield).

<1>H NMR (200 MHz, CDCl3) 6: 1.64 (t, J=6.8Hz, 3H), 2.90 (d, J=6.3Hz, 2H), 3.22-3.42 (m, 1H), 3.42-3.65 (m, 2H), 3.70 (S, 3H), 3.96 (t, J=6.8Hz, 1H), 6.61 (d, J=8.3Hz, 2H), 7.00 (d, J=8.3Hz, 2H).

IR (pure) black': 3350 (br), 1735.

Mass m/z (Cl): 224 [M+1].

Production 8

5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentyl bromide

Step(s)

To a mixture of 5-bromo pentanoic acid (4.63 g, 1 eq, 25.6 mmol) and oxalyl chloride (11.2 ml, 5 eq, 128 mmol) in hexane (5 ml) was added DMF (10 µJ) and the reaction mixture was heated to 70°C for 3 h. Excess oxalyl chloride and hexane were removed by distillation and the residue was distilled under high vacuum to give 5-bromo pentanoyl chloride as a bright yellow liquid (2.1 g, 41% yield).

Step (ii)

To a solution of 3,4-dihydro-2H-benzo[b]oxazine (500 mg, 1 eq, 3.7 mmol), triethylamine (1.54 ml, 3 eq, 11.1 mmol) and a catalytic amount of DMAP in dry DCM (20 ml) was added 5-bromopentanoyl chloride (870 ml, 2 eq, 7.40 mmol) at 0°C. The reaction mixture was stirred at 0°C for 4 h and then diluted with excess ethyl acetate. The ethyl acetate layer was washed with diln. HCI, water and then brine. The residue was chromatographed with ethyl acetate and hexane to give a liquid of the title compound (535 mg, 53% yield) as a viscous liquid.

1H NMR (200 MHz, CDCl3) δ: 1.70-2.00 (m, 4H), 2.63 (bt, J=5.9Hz, 2H), 3.39 (t, J=5.8Hz, major rotamer 1.2H), 3.53 (t, J=6.3Hz, minor rotamer 0.8H), 3.94 (t, J=4.4Hz, 2H), 4.29 (t, J=4.9Hz, 2H), 6.80-7.20 (aromatics, 4H).

IR (pure) cm"<1>:2936, 1660.

Mass. m/z (Cl): 298 [M(<7>9Br)+1], 300 [M(<81>Br)+1].

Production 9

Methyl 2-ethoxy-3-(3-aminophenyl)propanoate

Step(s)

Namely, a salt of triethyl 2-ethoxyphosphonoacetate (34.3 ml, 2 eq, 132 mmol) and NaH (50% in oil) (6.28 g, 2 eq, 132 mmol) was prepared in THF (350 ml) at 0°C. To this solid was added 3-nitrobenzaldehyde (10 g, 1 eq, 66 mmol) in portions at 0°C. The resulting solution was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate and washed with aqueous NH 4 Cl. The crude product contains ethyl 4-nitro-2-ethoxycinnamate in both Z and E stereoisomers (15 g, 86% yield).

Step (ii)

The crude compound (15 g, 1 eq, 56.6 mmol) obtained in step (i) was dissolved in methanol (250 ml). To this was added ammonium formate (35.6 g, 10 eq, 566 mmol) and 10% Pd/C (40 g) and the reaction mixture was stirred at RT for 16 h. The catalyst was filtered off and the methanol condensed on a rotary evaporator. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was subjected to chromatography to give methyl 2-ethoxy meta amino cinnamate as (E) and (Z) isomers (10 g, 75% yield).

Step (iii)

Methyl 2-ethoxy meta amino cinnamate (10 g, 1 eq, 42.5 mmol), obtained in step (ii) was treated with magnesium (20.4 g, 20 eq, 850 mmol) and dry methanol (500 ml). The reaction mixture was refluxed for 2-3 h and allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and quenched with cold aqueous ammonium chloride. The organic layer was washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to give the title compound as a viscous liquid (8.06 g, 80% yield).

<1>H NMR (200 MHz, CDCl3) δ: 1.15 (t, J=6.8Hz, 3H), 2.96 (d, J=6.9Hz, 2H), 3.22-3.42 (m, 1H), 3.42-3.65 (m, 2H), 3.70 (S, 3H), 4.01 (t, J=6.4Hz, 1H), 6.50-6.62 (aromatics, 3H), 7.06 (t, J=7.8Hz, 1H).

IR (pure) cm<1>: 3360, 1738.

Mass m/z (Cl): 224 (M+1).

Production 10

3-(7-Fluoro-3,4-dihydro-2H-benzo[b]ri,43oxazin-4-yl)propyl bromide

Step(s)

Anhydrous potassium carbonate (8.7 g, 2 eq, 63.2 mmol) was added to a solution of 2-nitro-5-fluorophenol (5 g, 1 eq, 31.6 mmol) and ethyl 2-bromoacetate (3.8 ml, 1.1 eq, 34.8 mmol) in dry acetone (160 ml) and stirred at RT for 16 h. The reaction mixture was filtered through celite and then condensed on a rota-evaporator. The residue was diluted with ethyl acetate and washed with water and brine to give the crude compound (6 g, 78% yield), which was used in step (ii).

Step (ii)

The crude compound obtained in step (i) (6 g, 1 eq, 28.8 mmol) was taken up in dry methanol (150 ml). To this iron powder (8.06 g, 5 eq, 144 mmol) was added glacial acetic acid (25 ml, 15 eq, 432 mmol) and heated to 110°C for 4 h. Solvents were removed from the reaction mixture and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous ammonium chloride, water, and brine. The residue was subjected to chromatography to give 3-oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine as a solid (2.2 g, mp: 204-206°C, 46% yield).

<1>H NMR (200 MHz, CDCl3+DMSO-d6) δ: 4.52 (s, 2H), 6.60-6.70 (m, 2H), 6.88 (dd, J=8.3 and 5.8Hz, 1H), 10.63 (bs, 1H).

IR (KBr) cm<1>: 1677, 1622.

Mass m/z (Cl): 168 (M+1).

Step (iii)

3-oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (2.2 g, 1 eq, 13.1 mmol), obtained in step (ii) in dry THF (10 ml) was added dropwise to refluxing THF (60 ml) containing LAH (1.5 g, 3 eq, 39.5 mmol). Reflux was then continued for 3 h and quenched with ethyl acetate. To this water (1.5 ml), 15% sodium hydroxide (1.5 ml) and water (4.5 ml) were added in turn. Once Al(OH) 3 .H 2 O is precipitated, it is filtered through celite. The filtrate was condensed on a rotary evaporator and chromatographed (ethyl acetate and hexanes) to give 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.3 g, 65% yield) as a yellow oil.

<1>H NMR (200 MHz, CDCl3) δ: 2.80 (bs, 1H), 3.38 (t, J=4.4Hz, 2H), 4.24 (t, J=4.4Hz, 2H), 6.48-6.56 (aromatics, 3H).

IR (pure) cm<1>: 3395 (br), 2957, 1606.

Mass m/z (Cl): 154 (M+1).

Step (iv)

A mixture of 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.3 g, 1 eq, 8.49 mmol), obtained in step (ii), above, 1,3-dibromopropane (8.6 ml, 10 eq, 84.9 mmol) and anhydrous sodium carbonate (2.7 g, 3 eq, 25.4 mmol) in dry DMF. (85 ml) was heated at 70°C for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to give the title compound (1.1 g, 47% yield) as a viscous oil.

<1>H NMR (200 MHz, CDCl3) δ: 2.10-2.28 (m, 2H), 3.30 (t, J=4.4Hz, 2H), 3.38 (t, J=6.7Hz, 2H), 3.49 (t, J=6.2Hz, 2H), 4.24 (t, J=4.4Hz, 2H), 6.50-6.70 (aromatics, 3H). Mass. m/z (Cl): 274 [M(<79>Br)+1], 276 [M(<81>Br)+1].

Production 11

N-{(3,4-dihydro-2H-benzo[b]oxazin-4-ylpropyl}benzylamine

Cesium hydroxide monohydrate (288 g, 1.1 eq, 1.72 mmol) and crushed molecular sieves 4A (500 mg) were stirred at RT in dry DMF (7 mL) for 15 min. To this was added benzylamine (510 µl, 3 eq, 4.68 mmol) and then stirred for another 30 min. Finally, 3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (400 mg, 1 eq, 1.50 mmol), obtained from Preparation 2, in DMF (3 mL) was added. After stirring for 16 h at RT, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was condensed and chromatographed using chloroform/methanol to give the title compound as a viscous oil (307 mg, 70% yield).

H NMR (200 MHz, CDCl3) δ: 1.77 (q, J=6.8Hz, 2H), 2.00 (bs, 1H), 2.67 (t, J=7.3Hz, 2H), 3.20-3.28 (m, 4H), 3.76 (s, 2H), 4.16 (t, J=4.4Hz, 2H), 6.50-6.82 (aromatics, 4H), 7.18-7.38 (aromatics, 5H).

IR (pure) cm"<1>: 3311 (br), 2931, 1669.

Mass m/z (Cl): 283 (M+1).

Production 12

Methyl 2-ethoxy-3-{4-(4-hydroxybenzyl)aminophenyl}propanoate

Methyl 2-ethoxy-3-(4-aminophenyl)propanoate (500 mg, 1 eq, 2.24 mmol), obtained from the preparation of 7,4-hydroxybenzaldehyde (273 mg, 1 eq, 2.24 mmol) and a catalytic amount of p-TsOH were dissolved in DCM (5 ml) along with several pieces of molecular sieves (4A). The reaction mixture was stirred at RT for 24 h, diluted with excess ethyl acetate and washed with aqueous sodium bicarbonate. The EtOAc layer was dried over anhydrous sodium sulfate and then condensed on a rotary evaporator. The crude product was dissolved in methanol (10 mL) and treated with Na(CN)BH3 (166 mg, 1.2 eq, 2.64 mmol) in the presence of conc. HCl (220 mL) at 0°C and stirred for 2 h. The reaction mixture was diluted with excess ethyl acetate, washed with water and brine. The EtOAc layer was dried over anhydrous sodium sulfate and then condensed on a rotary evaporator. The residue was chromatographed using EtOAc/hexanes to give the title compound as a solid (405 mg, 55% yield, mp: 109-110°C).

<1>H NMR (200 MHz, CDCl3) δ: 1.17 (t,ofc6.9Hz, 3H), 2.89 (d,ofc6.4Hz, 2H), 3.22-3.42 (m, 1H), 3.50-3.65 (m, 1H), 3.70 (bs, 5H, CO2Me, -OH, -NH-), 3.98 (t, jb6.8Hz, 1H), 4.20 (s, 2H), 6.56 (d,J±8. 3Hz,2H), 6.78 (d,ufc8.3Hz, 2H), 7.03 (d, j!=8.3Hz, 2H), 7.21 (d, ofc8.3Hz, 2H).

IR (KBr) cm"1: 3369 (br), 1680.

Mass m/z (Cl): 330 [M+1].

A mixture of 3,4-dihydro-2H-benzo[b][1,4]thiazine (2.0 g, 1 eq, 13.24 mmol), 1,3-dibromopropane (14 ml, 10 eq, 132.4 mmol) and anhydrous Na 2 CO 3 (4.21 g, 3.0 eq, 39.7 mmol) in dry DMF (130 ml) was heated at 70°C for 16 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water and brine. The organic layer was dried (Na 2 SO 4 ), condensed and the residue was chromatographed using ethyl acetate and hexane to give the title compound as a yellow oil (2.13 g, 59% yield).

<1>H NMR (200 MHz, CDCl3) 6: 2.11-2.25 (m, 2H), 3.02 (t, J=4.4Hz, 2H), 3.20-3.28 (m, 4H), 3.62 (t, J=4.4Hz, 2H), 6.60-6.72 (aromatics, 2H), 6.90-7.20 (aromatics, 2H).

Mass. m/z (Cl): 271 [M(<79>Br)], 272 [M(<79>Br)+1], 273 [M(<81>Br)], 271 [M(<81>Br)+1],

Production 15

2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethyl bromide

A mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (1.5 g, 1.0 eq, 11.12 mmol), 1,3-dibromoethane (10 ml, 10 eq, 111.2 mmol) and anhydrous K20O3 (4.6 g, 3.0 eq, 33.36 mmol) in dry DMF (110 ml) was heated at 70°C for 16 h. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water and brine. The organic layer was dried (Na 2 SO 4 ), condensed and the residue was chromatographed using ethyl acetate and hexane to give the title compound as a yellow oil (940 g, 34%).

1H NMR (200 MHz, CDCl3) δ: 3.45 (t, J=4.4Hz, 2H), 3.50-3.72 (m, 4H), 4.24 (t, J=4.4Hz, 2H), 6.65 (t, J=7.8Hz, 2H), 6.78-6.90 (aromatics, 2H).

Mass. m/z (Cl): 241 [M(79Br)], 242 [M(<79>Br)+1], 243 [M(<81>Br)], 244 [M(<fl1>Br)+1],

Production 16

4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}aniline

Step(s)

A mixture of 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethyl bromide (500 mg, 1.0 eq, 2.07 mmol), prepared from 15, 4-nitrophenol (288 mg, 1 eq, 2.07 mmol) and anhydrous K2CO3 (857 mg, 3.0 eq, 6.21 mmol) in dry acetone (12 ml) was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (200 ml), washed with water and brine. The organic layer was dried (Na2SO4), condensed. The crude mass was used for step (ii).

Step (ii)

A methanolic solution (10 ml) of the crude product (600 mg, 1 eq, 2.0 mmol) obtained in step (i) was hydrogenated at RT under atmospheric pressure using ammonium formate (2.6 g, 20 eq, 40 mmol) and 10% Pd/C as catalyst (500 mg). After 6 h of stirring, TLC showed the absence of starting material. The reaction mixture was filtered through celite and condensed. The residue was chromatographed using acetate and hexane to give the title compound as a viscous liquid (355 mg, 66%).

<1>H NMR (200 MHz, CDCl3) δ: 3.40 (bs, -NH2), 3.51 (t, J=4.4Hz, 2H), 3.65 (t, J=5.8Hz, 2H), 4.10 (t, J=5.6Hz, 2H), 4.23 (t, J=4.4Hz, 2H), 6.50-6.90 (aromatics, 4H). Mass. m/z (Cl): 270 [M], 271 [M+1].

Production 17

3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide

Step(s)

To a solution of 2-nitro-5-fluorophenol (1.0 g, 1 eq, 6.36 mmol) and ethyl 2-bromopropionate (0.91 ml, 1.1 eq, 6.99 mmol) in dry acetone (32 ml) was added anhydrous potassium carbonate (2.63 g, 3 eq, 19.08 mmol) and the reaction mixture was refluxed for 16 h. The reaction mixture was filtered through celite and then condensed on a rota-evaporator. The residue was diluted with ethyl acetate and washed with water and brine to give 2-(2-nitro-5-fluorophenoxy)propanoate as the crude compound (1.6 g, yield 98%), which was used in step (ii).

Step (ii)

The crude compound obtained in step (i) (1.6 g, 1 eq, 6.22 mmol) was taken up in dry methanol (150 ml). To this was added iron powder (5.23 g, 15 eq, 93.37 mmol) and glacial acetic acid (5.6 ml, 15 eq, 93.37 mmol) and heated to 110°C for 4 h. The solvents were removed from the reaction mixture and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous ammonium chloride, water, and brine. The residue was subjected to chromatography to give 2-methyl-3-oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine as a solid (1.0 g, 88% yield).

Mp: 166-168°C

<1>H NMR (200 MHz, CDCl3) δ: 1.59 (d, J=6.9Hz, 3H); 4.67 (q, J=6.9Hz, 1H), 6.60-6.80 (aromatics, 3H), 8.61 (bs, 1H).

IR (KBr)cm<1>: 1677, 1610.

Mass m/z (Cl): 182 (M+1).

Step (iii)

2-Methyl-3-oxo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.8 g, 1 eq, 26.5 mmol), obtained in step (ii) in dry THF (60 ml) was added dropwise to refluxing THF (200 ml) containing LAH (6.05 g, 6 eq, 159.1 mmol). Reflux was maintained for the next 3 h, and then the reaction was quenched with ethyl acetate and hydrolysis was carried out with saturated water. sodium sulfate. Once Al(OH) 3 .H 2 O had precipitated, it was filtered through celite. The filtrate was condensed on a rotary evaporator and chromatographed (ethyl acetate and hexane) to give 2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.3 g, 97% yield) as a yellow oil. The crude product was used for the next reaction.

<1>H NMR (200 MHz, CDCl3) δ: 1.36 (d, J=6.5Hz, 3H); 3.05 (dd, J=11.3, 8.0Hz, 1H); 3.32 (d, J=11.8Hz, 1H); 3.60 (bs, 1H, N-H); 4.18-4.30 (m, 1H), 6.40-6.60 (aromatics, 3H).

IR (KBr)cm<1>: 3387, 2977, 2933, 1605, 1510.

Mass m/z (Cl): 168 (M+1).

Step (iv)

A mixture of 2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][l,4]oxazine (4.3 g, 1 eq, 25.74 mmol), obtained in step (iii) above, 1,3-dibromopropane (26.1 ml, 10 eq, 257 mmol) and anhydrous sodium carbonate (8.2 g, 3 eq, 77.2 mmol) in dry DMF (260 ml) was heated at 70°C for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to give the title compound (3.5 g, 48% yield) as a viscous oil.

1H NMR (200 MHz, CDCl3) δ: 1.35 (d, J=6.7Hz, 3H); 2.02-2.22 (m, 2H); 3.01 (dd, J=11 -3, 8.3Hz, 1H); 3.32 (dd, J=11.6, 2.3Hz, 1H); 3.22-3.58 (m, 4H); 4.18-4.35 (m, 1H), 6.42-6.62 (aromatics, 3H).

Mass. m/z (Cl): 288 [M(<79>Br)+1], 290 [M(<81>Br)+1].

Production 18

3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide

Step(s)

Starting from 2-nitrophenol (10 g, 1 eq, 71.9 mmol) and ethyl 2-bromo-propionate (10.2 ml, 1.1 eq, 79.09 mmol), the procedure of Step (i) of Preparation 17 was followed to give crude ethyl 2-(2-nitrophenoxy)propanoate (16 g), which was used for step (ii).

Step (ii)

The crude compound obtained in step (i) (16 g, 1 eq, 62.2 mmol) was converted to 2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine as a solid (10.0 g, 98% yield) according to the procedure of step (ii), Preparation 17.

Mp: 164-166°C

<1>H NMR (200 MHz, CDCl3) δ: 1.59 (d, J=6.7Hz, 3H); 4.67 (q, J=6.7Hz, 1H), 6.80-7.00 (aromatics, 4H), 9.45 (bs, 1H).

IR (KBr)cm-': 3500, 3198, 2917, 1675, 1608, 1501.

Mass m/z (Cl): 164 (M+1).

Step (iii)

2-Methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine (5.0 g, 1 eq, 30.6 mmol), obtained in step (ii) was reduced to 2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.3 g, yield 90%) as a yellow oil, according to the procedure of step (iii), preparation 17.

<1>H NMR (200 MHz, CDCl3) δ: 1.37 (d, J=6.1Hz, 3H); 3.10 (dd, J=11.3, 8.1Hz, 1H); 3.34 (d, J=11.6, 2.5Hz, 1H); 3.60 (bs, 1H, N-H); 4.18-4.30 (m, 1H), 6.50-6.80 (aromatics, 4H).

IR (KBr)cm<1>: 3389, 2977, 2976, 1608, 1503.

Mass m/z (Cl): 150 (M+1).

Step (iv)

From 2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.5 g, 1 eq, 30.2 mmol), obtained in the above step (iii) and 1,3-dibromopropane (30 ml, 10 eq, 300 mmol) and according to the procedure of step (iv), preparation 17, the titled compound (3.5 g, yield 48%) was obtained in the form of a viscous oil.

1H NMR (200 MHz, CDCl3) δ: 1.29 (d, J=6.4Hz, 3H); 2.05-2.25 (m, 2H); 3.07 (dd, J=11.3, 8.3Hz, 1H); 3.24 (dd, J=11.6, 2.3Hz, 1H); 3.30-3.58 (m, 4H); 4.18-4.35 (m, 1H), 6.50-6.82 (aromatics, 4H).

Mass. m/z (Cl): 270 [M(79Br)+1], 272 [M(<81>Br)+1].

Production 19

3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide

Step(s)

Starting from 2-nitrophenol (1.0 g, 1 eq, 7.19 mmol) and ethyl 2-bromo-pentanoate (2.97 ml, 3.0 eq, 21.54 mmol), the procedure of Step (i) of Preparation 17 was followed to give crude ethyl 2-(2-nitrophenoxy)pentanoate (2.0 g), which was used for step (ii).

Step (ii)

The crude compound obtained in step (i) (1.7 g, 1 eq, 6.36 mmol) was converted to 2-propyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine as a solid (1.2 g, 87% yield over 2 steps), following the procedure of step (ii), preparation 17.

Mp: 172-174°C

<*>H NMR (200 MHz, CDCl3) δ: 0.98 (d, J=7.0Hz, 3H); 1.40-1.70(m, 2H); 1.70-1.98 (m, 2H); 4.59 (t, J=6.4Hz, 1H), 6.84-7.00 (aromatics, 4H), 9.00 (bs, 1H).

IR (KBr) cm': 3198, 2917, 1677, 1611, 1502.

Mass m/z (Cl): 192 (M+1).

Step (iii)

2-propyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine (2.0 g, 1 eq, 10.4 mmol), obtained in step (ii) was reduced to 2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.65 g, yield 90%) as a crude product, according to the procedure of step (iii), preparation 17 and passed for the next reaction.

Mass m/z (Cl): 178 (M+1).

Step (iv)

From 2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.65 g, 1 eq, 9.3 mmol), obtained in the above step (iii) and 1,3-dibromopropane (9.4 ml, 10 eq, 93 mmol) and according to the procedure of step (iv), preparation 17, the titled compound (915 mg, yield 33%) was obtained in the form of a viscous oil.

<1>H NMR (200 MHz, CDCl3) δ: 0.97 (t, J=7.0Hz, 3H); 1.40-1.80 (m, 4H); 200-2.25 (m, 2H); 3.10 (dd, J=11.6, 8.0Hz, 1H); 3.27 (dd, J=11.6, 2.4Hz, 1H); 3.35-3.58 (m, 4H); 4.00-4.18 (m, 1H), 6.50-6.90 (aromatics, 4H).

Mass. m/z (Cl): 298 [M(<79>Br)+1], 300 [M(<81>Br)+1].

Production 20

(S)-Ethyl 2-ethoxy-3-(4-aminophenyl)propionate

Step(s)

To a solution of (S)-(4-nitrophenyl)alanine (10 g, 47.6 mmol) in a mixture of water (50 ml_), H2SO4(1M, 60 ml_) and acetone (150 ml_), at -5°C, a solution of sodium nitrite (9.85 g, 142.8 mmol) in water (40 ml_) was added dropwise over a period of 30 minutes with stirring. The reaction mixture was stirred at

-5 to 0°C for another 1.5 h, and then it was stirred at room temperature for 16 h. The acetone was removed and the reaction mixture was diluted with 500 ml of ethyl

of acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude mass was purified by crystallization from isopropyl acetate (9.0 g, 96%).

Mp: 134-136°C

1 H NMR (CDCl 3 ) δ: 3.04 (dd, J=14, 7.8Hz, 1H); 3.24 (dd, J=14, 4, Hz, 1H); 4.39 (dd, J=7.3, 4.1Hz, 1H); 7.42 (d, J=8.7Hz, 2H); 8.16 (d, J=8.7Hz, 2H).

IR (pure) cm<1>:3485, 3180, 2927, 1715, 1515, 1343.

Mass m/z (Cl): 212 (M+1).

Step (ii)

(S)-2-Hydroxy-3-(4-nitrophenyl)propionic acid (9.0 g, 42.6 mmol), obtained from step (i) above, was dissolved in dry EtOH (300 ml_). To this solution was added conc. H 2 SO 4 (326 ml_, 5.9 mmol) and refluxed for 5 to 6 h. The reaction mixture was neutralized with aqueous sodium bicarbonate. Ethanol was condensed on a rotary evaporator and the residue was dissolved in ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate, water, brine and then dried over anhydrous Na 2 SO 4 and concentrated. The desired product was obtained from the crude mass by crystallization from diisopropyl ether (8.0 g, 78.5%).

Mp: 74-76°C

[α]D: -13° (c 1.0, MeOH)

<1>H NMR (CDCl3) δ: 1.30 (t, J=7Hz, 3H); 3.06 (dd, J=14, 7, Hz, 1H); 3.25 (dd, J=14, 4.3, Hz, 1H); 4.25 (q, J=7Hz, 2H); 4.25 (dd, J=7, 4.3 Hz, 1H), 7.42 (d, J=8.7Hz, 2H), 8.16 (d, J=8.7Hz, 2H).

IR (neat) cm<1>: 3432, 2924, 1736, 1518, 1347.

Mass m/z (Cl): 240 (M+1).

Step (iii)

To a mixture of (S)-ethyl 2-hydroxy-3-(4-nitrophenyl)propionate (4.77 g, 19.95 mmol), obtained in step (ii) above, molecular sieves (4A) (5.0 g) and powdered Ag2O (13.8 g, 59.8 mmol) in dry acetonitrile (100 mL) was added ethyl iodide (6.4 mL_, 79.8 mmol) at room temperature. The reaction mixture was heated at 60°C for 16 h. The reaction mixture was filtered through celite and concentrated. The crude mass was subjected to chromatography using ethyl acetate and hexane to give the desired product as a viscous liquid (3.5 g, 67% isolated yield). The unreacted starting material was recovered (900 mg) and could be reused.

[α]D: -26° (c 1.0, MeOH)

<1>H NMR (CDCl3) δ: 1.15 (t, J=7Hz, 3H); 1.26 (t, J=7.1Hz, 3H); 3.10 (d, J=3.8Hz, 1H); 3.13 (s, 1H); 3.16-3.35 (m, 1H); 3.45-3.65 (m, 1H); 4.03 (dd, J=7.5, 5.4Hz, 1H); 4.21 (q, J=7.2Hz, 2H), 7.43 (d, J=8.6Hz, 2H), 8.15 (d, J=8.6Hz, 2H).

IR (Pure) cm"1: 2980, 1747, 1604, 1521, 1347.

Mass m/z (Cl): 268 (M+1).

Step (iv)

(S)-Ethyl 2-ethoxy-3-(4-nitrophenyl)propionate (6.0, 25.3 mmol) obtained in step (iii) above was dissolved in dry methanol (100 ml_). To this solution was added 10%Pd/C (2.0 g) and subjected to hydrogenation using hydrogen gas (20 psi) for 3-4 h. The reaction mixture was filtered through celite and the filtrate concentrated to provide a syrupy mass. The product was obtained in quantitative yield.

[α]D: -14.2° (c 1.0, MeOH)

<1>H NMR (CDCl3) δ: 1.16 (t, J=7.0Hz, 3H); 1.22 (t, J=7.0Hz, 3H); 2.90 (d, J=6.3Hz, 2H); 3.30 (bs, 2H, NH2); 3.24-3.42 (m, 1H); 3.50-3.70 (m, 1H); 3.94 (t, J=6.3Hz, 1H); 4.15 (q, J=7.0Hz, 2H), 6.62 (d, J=8.3Hz, 2H), 7.03 (d, J=8.0Hz, 2H).

IR (pure) cm"': 3372, 1738.

Mass. m/z (Cl): 238 (M+1), 192 (M-OC 2 H 5 ).

Production 21

(S)-Ethyl 2-methoxy-3-(4-aminophenyl)propionate

Production 22

Ethyl 2-isopropoxy-3-(4-aminophenyl)propionate

C02Et

Step(s):

4-Nitrophenylalanine (5 g, 1 eq, mmol) was gradually added to a solution of dry ethanol (mL) and thionyl chloride (mL_) at -5°C. It was stirred at that temperature for another hour, and then the stirring was continued at RT for 16 h. The reaction mixture was condensed on a rota-evaporator, azeotroped with toluene and then dried via a high vacuum pump to give 4-nitrophenylalanine hydrochloride ethyl ester as a white solid (quantitative yield).

Step (ii):

The ethyl ester of 4-nitrophenylalanine hydrochloride (2 g, 1.0 eq, 7.28 mmol), obtained in step (i) was dissolved in ethyl acetate (150 mL). To this, Na 2 CO 3 (386 mg, 0.5 eq, 3.64 mmol) was added and stirred for 15 min. The reaction mixture was washed with water. NaHCO3. The organic layer was dried (Na2SO4) and condensed to give 4-nitrophenylalanine ethyl ester as a thick oil (1.55 g, 89%).

Step (iii):

4-Nitrophenylalanine ethyl ester (1.55 g, 1.0 eq, 6.51 mmol), obtained in step (ii) above, was dissolved in chloroform (33 mL). To this was added glacial acetic acid (20 µL, 0.05 eq, 0.33 mmol) and isoamyl nitrite (958 µL, 1.1 eq, 7.16 mmol), the reaction mixture was heated at reflux for 30 min. The reaction mixture was diluted with chloroform and washed with aq. NaHCO3. The organic layer was dried (Na2SO4) and condensed (caution!) to a yellowish liquid.

Step (iv):

The liquid (1.54 g, 1.0 eq, 6.18 mmol) thus obtained in step (iii) was dissolved in dry isopropanol (31 mL) and a catalytic amount of Rh2(OAc)4.2H20 (38 mg, 0.02 eq, 0.12 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Isopropanol was condensed and the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography using ethyl acetate and hexane provided the desired compound: ethyl 2-isopropoxy-3-(4-nitrophenyl)propionate (1.25 g, 61% total).

<1>H NMR (200 MHz, CDCl3) δ: 0.92 (d, J=5.8Hz, 3H), 1.16 (d, J=5.8Hz, 3H), 1.27 (t, J=7.4Hz, 3H), 3.00-3.10 (m, 2H), 3.52 (quintet, 1H); 4.08 (dd, J=8.7 and 4.8Hz, 1H), 4.21 (q, J=7.4Hz, 2H), 7.43 (d, J=8.7Hz, 2H), 8.16 (d, J=8.7Hz, 2H).

IR (Clear) cm"<1>: 2975, 1747, 1602, 1522, 1347.

Mass m/z (Cl): 282 [M+1].

Step (v):

Ethyl 2-isopropoxy-3-(4-nitrophenyl)propionate (1.52 g, 5.4 mmol), obtained in step (v) was hydrogenated under 10 psi molecular hydrogen using 10% Pd/C (700 mg) as catalyst in ethyl acetate (200 mL) at room temperature for 3-4 h. The desired product was isolated after filtering the reaction mixture and concentrating the filtrate under reduced pressure. Column chromatography of the crude mass using ethyl acetate and hexane provided the desired compound ethyl 2-isopropoxy-3-(4-aminophenyl)propionate (1.16 g, 86% overall).

<1>H NMR (200 MHz, CDCl3) δ: 0.97 (d, J=5.8Hz, 3H), 1.15 (d, J=5.8Hz, 3H), 1.23 (t, J=7.0Hz, 3H), 2.80-2.95 (m, 2H), 3.49 (quintet, 1H); 3.98 (dd, J=8.1 and 5.7Hz, 1H), 4.16 (q, J=7.0Hz, 2H), 6.61 (d, J=8.3Hz, 2H), 7.03 (d, J=8.3Hz, 2H).

IR (neat) cm<1>: 3455, 3371, 2975, 2929, 1737, 1626, 1519.

Mass m/z (Cl): 252 [M+1].

Example 1

Ethyl 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate

Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (2 g, 1 eq, 8.4 mmol), obtained in preparation 1, 3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (2.36 g, 1.1 eq, 9.3 mmol), obtained in preparation 2 and anhydrous K2CO3 (3.5 g, 3 eq, 25 mmol), were heated at 70°C in DMF (40 ml) for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The residue was chromatographed using a mixture of ethyl acetate and hexane as eluent to give the title compound as a viscous liquid (1.04 g, 30% yield).

<1>H NMR (200 MHz, CDCl3) δ: 1.17 (t, J=7.0Hz, 3H), 1.23 (t, J=7.0Hz, 3H), 1.92 (q, J=7.0Hz, 2H), 2.90 (d, J=6.8Hz, 2H), 3.20 (t, J=7.0Hz, 2H); 3.22-3.41 (m, 5H), 3.45-3.62 (m, 1H), 3.95 (t, J=6.4Hz, 1H), 4.05-4.37 (m, 4H), 6.65 (d, J=8.3Hz, 2H), 6.61-6.85 (m, 4H), 7.05 (d, J=8.3Hz, 2H).

IR (clear) cm"<1>: 3396 (br), 1740.

Mass m/z (Cl): 413 (M+1).

Example 2

3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid

Ethyl 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate (700 mg, 0.98 mmol), obtained in Example 1, was hydrolyzed using lithium hydroxide monohydrate (123 mg, 2.9 mmol) in methanol-water at RT until all starting material was consumed (4 to 5 h). The reaction mixture was diluted with water, acidified diln. HCl to adjust the pH to ~4-5 and then extracted with ethyl acetate. The ethyl acetate layer was dried over Na 2 SO 4 and concentrated on a rotary evaporator. The residue was chromatographed using methanol and chloroform to give the title compound as a viscous liquid (256 mg, 68% yield).

1H NMR (200 MHz, CDCl3) δ: 1.19 (t, J=7.4Hz, 3H), 1.94 (q, J=7.4Hz, 2H), 2.90 (dd, J=14.0 and 7.0Hz, 1H), 3.05 (dd, J=14.0 and 4.9Hz, 1H), 3.21 (t, J=6.8Hz, 2H), 3.25-3.40 (m, 5H), 3.40-3.62 (m, 1H), 4.00-4.17 (m, 1H), 4.18-4.22 (m, 2H), 6.59 (d, J=8.3Hz. 2H), 6.65-6.85 (m, 4H), 7.06 (d, J=8.3Hz, 2H).

IR (pure) cm<1>: 3500. 1725.

Mass m/z (Cl): 385 (M+1).

Example 3

Arginine salt of 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid

L-arginine (90.5 mg, 1 eq, 0.52) was added to a solution of 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid (200 mg, 1 eq, 0.52 mmol), obtained in Example 2, in a mixture of dry methane-dichloroethane (10:1) (5 ml). mmol) and allowed to stir for 3-4 h. The solvent was removed on a rotavapor, followed by an azeotropic procedure with benzene. The residue was dried under high vacuum to give the title compound as a free-flowing solid (yield 100%), mp: 92-94°C

DSC: endotherm (weak and broad): 66.6°C

XRD: amorphous.

Example 4

Ethyl 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethyl-amino}phenyl]-2-ethoxypropanoate

3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine (185 mg, 1.24 mmol), ethyl 2-ethoxy-3-[4-{N-heptyl-N-(2'-bromoethyl)}aminophenyl]propanoate (500 mg, 1 eq, 1.13 mmol), obtained in preparation 3 and anhydrous K2CO3 (468 mg, 3 eq, 3.39 mmol) were heated at 70°C in DMF (6 ml) for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using a mixture of ethyl acetate and hexane as eluent to give the title compound as a thick liquid (363 mg, 63% yield).

<1>H NMR (200 MHz, CDCl3) δ: 0.88 (bt, J=6.3 Hz, 3H), 1.05-1.42 (m, 14H). 1.42-1.68 (m, 2H), 2.92 (d, J=6.8Hz, 2H), 3.25 (t, J=7.3 Hz, 2H), 3.30-3.45 (m, 1H), 3.50-3.70 (m, 3H), 3.97 (t, J=6.6 Hz, 1H), 4.08 (t, J=7.3 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 4.57 (s, 2H), 6.57 (d, J=8.3Hz, 2H), 6.99 (s, 4H), 7.10 (d, J=8.0Hz, 2H).

IR (neat)cm<1>:1747.

Mass m/z (Cl): 511 (M+1).

Example 5

3-f4-N-heptyl-N-{2-(3-oxo-3,4<lihydro-2H-benzo[b|[1,4loxazin-4-yl)ethylamino} phenyl]-2-ethoxypropanoic acid

3- [4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}

phenyl]-2-ethoxypropanoate (350 mg, 1 eq, 0.68 mmol), obtained in Example 4, was hydrolyzed using lithium hydroxide monohydrate (86 mg, 3 eq, 2.04 mmol) in methanol-water, at RT, until all the starting material was consumed (4 to 5 h). The reaction mixture was diluted with water, acidified with dilute HCl to pH 2-3, and then extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated on a rotary evaporator. The residue was chromatographed using methanol and chloroform to give the title compound as a sticky mass (197 mg, 60% yield).

1H NMR (200 MHz, CDCl3) δ: 0.88 (bt, J=6.3Hz, 3H), 1.05-1.42 (m, 11H), 1.42-1.68 (m, 2H), 2.82-3.10 (m, 2H), 3.25 (t, J=7.3 Hz, 2H), 3.40-3.70 (m, 4H), 3.98-4.15 (m, 3H), 4.56 (s, 2H), 6.67 (d, J=8.3Hz, 2H). 6.98 (s, 4H), 7.10 (d, J=8.0Hz, 2H).

IR (clean) cm<1>: 3500 (br), 1687.

Mass m/z (Cl): 483 (M+1).

Example 6

Arginine salt of 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoic acid

3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-bene

phenyl]-2-ethoxypropanoic acid (150 mg, 1 eq, 0.31 mmol), obtained in Example 5, and L-arginine (54 mg, 1 eq, 0.31 mmol) were placed in dry methanol (2 ml) and stirred at RT for 2-3 h. The solvent was removed on a rotary evaporator, followed by benzene azeotropy. The residue was dried under high vacuum to give the title compound as a free-flowing solid (yield 100%), mp: 118-120°C

Example 7

Methyl 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxo-ethyl)aminomethyl}phenyl]propanoate

2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)carboxymethyl chloride (208 mg, 1 eq, 0.98 mmol), obtained in preparation 4 and methyl 2-ethoxy-3-[4-(N-heptylaminomethyl) phenylpropanoate (300 mg, 1 eq, 0.89 mmol), obtained in preparation 6, were treated with acetonitrile (5 mL) with anhydrous sodium carbonate (285 mg, 3 eq, 2.68 mmol). The reaction mixture was stirred at 80°C for 4 h. TLC showed the absence of starting material. The reaction mixture was diluted

ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed using ethyl acetate and hexane to give the title compound (250 mg, 55% yield) as a viscous liquid.

<1>H NMR (200 MHz, CDCIg) δ: 0.86 (bt, J=6.3 Hz, 3H), 1.14 (t, J=6.8 Hz, 3H), 1.20-1.40 (m, 8H), 1.50-1.70 (m, 2H), 2.57 (t, J=7.0 Hz, 2H), 2.99 (d, J=6 Hz, 2H), 3.22-4.40 (m, 11H), 3.67 (s, 3H), 6.80-7.26 (aromatics, 8H).

IR (pure) cm<1>: 1752, 1683.

Mass m/z (Cl): 511 [M+1].

Example 8

2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoic acid

Methyl 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxo-ethyl)aminomethyl}phenyl]propanoate (240 mg, 1 eq, 0.47 mmol), obtained in Example 7, was hydrolyzed using lithium hydroxide monohydrate (99 mg, 5 eq, 2.35 mmol) in methanol-water. (lasts 4 to 5 hours). The reaction mixture was acidified with aqueous HCl, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed (ethyl acetate and hexane-»methanol/chloroform) to give the title compound (130 mg, 56% yield) as a viscous liquid.

<1>H NMR (200 MHz, CDCl3) δ: 0.86 (bt, J=6.3Hz, 3H), 1.10-1.40 (m, 11H). 1.40-1.60 (m, 2H), 2.79 (t, J=7.5 Hz, 2H), 2.90-4.22 (m, 13H), 6.80-7.26 (aromatics, 8H).

Mass m/z (Cl): 497 [M+1],

Example 9

Arginine salt of 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoic acid

2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoic acid (90 mg, 0.18 mmol), obtained in Example 8 and L-arginine (32 mg, 0.18 mmol) were introduced into dry methanol (2 ml) and stirred at RT for 2-3 h. The solvent was removed on a rotavapor, followed by benzene azeotropy. The residue was dried under high vacuum to give the title compound as a free-flowing solid (100% yield), mp: 118-120°C.

Example 10

Methyl 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino} phenyl]-2-ethoxypropanoate

A solution of methyl 2-ethoxy-3-(4-aminophenyl)propanoate (337 mg, 1 eq, 1.51 mmol), obtained in Preparation 7 and 5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentyl bromide (450 mg, 1 eq, 1.51 mmol), obtained in Preparation 8, in DMF (6 mL). were treated with anhydrous potassium carbonate (627 mg, 3 eq, 4.54 mmol) and the reaction mixture was stirred at 70°C for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed using ethyl acetate and hexane to give the title compound as a viscous liquid (179 mg, 27% yield).

<1>H NMR (200 MHz, CDCl3) δ: 1.16 (t,J=7.0Hz, 3H), 1.50-1.70 (m, 2H), 1.70-1.90 (m, 2H), 2.64 (t,J=7.0Hz, 2H), 2.89 (d,J=6.QHz, 2H), 3.08 (t,J=6. 7Hz, 2H), 3.22-3.42 (m, 1H), 3.42-3.62 (m, 2H), 3.68 (s, 3H), 3.88-4.00 (m, 3H), 4.26 (t,J=4. 8,2H), 6.50 (d,J=7. 8Hz, 2H, aromatics), 6.82-7.10 (aromatics, 4H), 7.04 (d, J=7.8Hz, 2H, aromatics).

IR (KBr) cm': 3408, 1739, 1683.

Mass m/z (Cl): 441 [M+1].

Example 11

3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic acid

Methyl 3-[4-{5-(3,4<lihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamine phenyl]-2-ethoxypropanoate (211 mg, 1 eq, 0.48 mmol), obtained in Example 10, was hydrolyzed using lithium hydroxide monohydrate (60 mg, 3 eq, 1.44 mmol) in methanol-water at RT (continued 4-5 hours). The reaction mixture was diluted with water, acidified (pH 3-4) with aqueous HCl, and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was subjected to chromatography (ethyl acetate and hexane -> methanol/chloroform) to give the title compound (139 mg, 68% yield) as a viscous liquid.

<1>HNMR(200 MHz, CDCl,) 8: 1.14 (t, J=7.0 Hz, 3H), 1.50-1.90 (m, 2H), 2.62 (t, J=6.8 Hz, 2H), 2.80-3.15 (m, 4H), 3.22-3.42 (m, 1H), 3.42-3.62 (m, 1H), 3.82-4.00 (m, 3H), 4.25 (t, J=4.9, 2H), 6.40-7.30 (br bulge, N-H, CO2H), 6.55 (d, J=7.8Hz, 2H, aromatics), 6.82-7.10 (aromatics, 4H), 7.04 (d, J=7.8 Hz, 2H, aromatics).

IR (KBr) cm"<1>: 3408, 1719, 1680.

Mass m/z (Cl): 427 [M+1].

Example 12

Arginine salt of 3-[4-{5-(3,4-dihydro-2H-benzo[b] [1,4]oxazin-4-yl)-5-oxopentyl-amino}phenyl]-2-ethoxypropanoic acid

3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic acid (120 mg, 1 eq, 0.28 mmol), obtained in Example 11 and L-arginine (49 mg, 1 eq, 0.28 mmol) were introduced into dry methanol (3 mL) and stirred at RT during 2-3 hours. The solvent was removed on a rotavapor, followed by benzene azeotropy. The rest is dried under a pump with

under high vacuum to afford the title compound as a free-flowing solid (100% yield), mp: 137-139°C.

Example 13

Methyl 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate

Methyl 2-ethoxy-3-(3-aminophenyl)propanoate (200 mg, 1 eq, 0.89 mmol), obtained in preparation 9, 3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (253 mg, 1.1 eq, 0.98 mmol), obtained in preparation 2 and anhydrous Na2CO3 (285 mg, 3 eq, 2.68 mmol) were heated at 70°C in DMF (5 ml) for 24 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to give the title compound (304 mg, 86% yield) as a viscous liquid.

<1>H NMR (200 MHz, CDCIg) δ: 1.17 (t, J=7 Hz, 3H), 1.98 (q, J=7 Hz, 2H), 2.92 (d, J=6.8 Hz, 2H), 3.19 (t, J=7Hz, 2H). 3.22-3.41 (m, 5H), 3.45-3.62 (m, 1H), 3.70 (s, 3H), 4.02 (t, J=6.4Hz, 1H), 4.22 (t, J=4.3 Hz, 2H), 6.40-6.82 (m, aromatics, 6H), 6.75 (d,J=7.&Hz.1H). 7.08 (t. J=7.8 Hz, 1H).

IR (pure) cm"<1>: 3380 (br), 1743, 1680.

Mass m/z (Cl): 399 (M+1).

Example 14

3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4Yoxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid

Methyl 3-[3-{3-(3,4<lihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate (350 mg, 1 eq, 0.87 mmol), obtained in Example 13 was hydrolyzed using lithium hydroxide monohydrate (110 mg, 3 eq, 2.64 mmol) in methanol-water, at RT, until all the starting material was consumed. (4 to 5 hours). The reaction mixture was diluted with water and acidified (pH~4-5) with dilute HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed using methanol and chloroform to give the title compound (203 mg, 61% yield) as a viscous oil.

<1>H NMR (200 MHz, CDCL,) δ: 1.19 (t, J=7.4 Hz, 3H), 1.94 (q, J=7.4 Hz, 2H), 2.85-3.60 (m, 10H), 4.00-4.17 (m, 1H), 4.23 (t, J=4.4 Hz, 2H), 4.95 (bs, NH, COgH), 6.42-7.20 (aromatics, 8H).

IR (clean) cm"<1>: 3500 (br), 1727.

Mass m/z (Cl): 385 (M+1).

Example 15

Arginine salt of 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid

3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid (90 mg, 1 eq, 0.23 mmol), obtained in Example 14 and L-

arginine (40.8 mg, 1 eq, 0.23 mmol) were placed in dry methanol (5 ml) and stirred at RT for 2-3 h. The solvent was removed on a rotavapor, followed by an azeotropy procedure with benzene. The residue was dried under high vacuum to give the title compound as a free-flowing solid (yield 100%), mp: 178-180°C.

Example 16

Methyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoate

Methyl 2-ethoxy-3-(4-aminophenyl)propanoate (405.8 mg, 1 eq, 1.82 mmol), obtained in preparation 7, 3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (500 mg, 1 eq, 1.82 mmol), obtained in preparation 10 and anhydrous Na 2 CO 3 (572 mg, 3 eq, 5.4 mmol) were heated at 70°C in acetonitrile for 24 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to give the title compound (333 mg, 44% yield) as a viscous liquid.

1H NMR (200 MHz, CDCl3) δ: 1.17 (t, J=7 Hz, 3H), 1.88 (q, J=7 Hz, 2H), 2.91 (d, J=6.8 Hz, 2H), 3.10-3.42 (m, 7H), 3.45-3.65 (m,1H), 3.69 (s, 3H), 3.98 (t, J=6.3 Hz, 1H), 4.22 (t, J=3.9 Hz, 2H), 6.40-6.70 (m, aromatics, 5H), 7.04 (d, J=8.3Hz, 2H).

IR (pure) cm"<1>: 3382 (br), 1746, 1616.

Mass m/z (Cl): 417 (M+1).

Example 17

3-(4-{3-(7-fluoro-3,4Clihydro-2H-benzo[b][1,4|oxazin-4-yl)propylamino}phenylJ-2-ethoxypropanoic acid

Methyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoate (180 mg, 1 eq, 0.43 mmol), obtained in Example 16 was hydrolyzed using lithium hydroxide monohydrate (55 mg, 3 eq, 1.2 mmol) in methanol-water at RT, while all the starting material not consumed (4 to 5 h). The reaction mixture was diluted with water, acidified (pH~4-5) with dilute HCl, and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed using ethyl acetate and hexanes-»methanol and chloroform to give the title compound (121 mg, 70% yield) as a viscous liquid.

<1>H NMR (200 MHz, CDCl3) δ: 1.19 (t, J=7.4 Hz, 3H), 1.94 (quintet J=7.4Hz, 2H), 2.85-3.10 (m, 2H), 3.10-3.20 (m, 6H), 3.40-3.70 (m, 2H), 3.90-4.10 (m, 1H), 4.10-4.30 (m, 2H), 6.20 (bs, CO 2 H). 6.42-6.70 (m, aromatics, 5H), 7.07 (d, J=8.3 Hz, 2H).

IR (KBr) cm<1>: 3394, 1725, 1619.

Mass m/z (Cl): 403 (M+1).

Example 18

Arginine salt of 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoic acid "00 fv-Yco>H NH2-r^^_NH2

L???L? OEt C02H |!|H

H

344-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phene

ethoxypropanoic acid (120 mg, 1 eq, 0.298 mmol), obtained in Example 17 and L-arginine (52 mg, 1 eq, 0.298 mmol) were placed in dry methanol (2 ml) and stirred at RT for 2-3 h. The solvent was removed on a rotavapor, followed by benzene azeotropy. The residue was dried under high vacuum to give the title compound as a free-flowing solid (yield 100%), mp: 158-160°C.

Example 19

Methyl 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate

A mixture of methyl 2-ethoxy-3-{4-(4-hydroxybenzyl)aminophenyl}propanoate (600 mg, 1 eq, 1.82 mmol), obtained in the preparation of 12, 3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (467 mg, 1 eq, 1.82 mmol), obtained in the preparation of 2 and anhydrous K 2 CO 3 (755 mg, 3 eq, 5.46 mmol) in DMF (10 mL) was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed using EtOAc/hexanes to afford the title compound (520 mg, 56% yield) as a thick liquid.

<1>H NMR (CDCl3, 200 MHz) δ: 1.19 (t,J=7.QHz, 3H), 2.00-2.20 (m, 2H), 2.90 (d, J=6.3Hz, 2H), 3.30-3.60 (m, 6H), 3.70 (bs, 3H), 3.80-4.10 (m, 3H+NH), 4.10-4.25 (m, 4H), 6.57 (d, J=Q. 3 Hz, 2H), 6.60-6.90 (m, 6H), 7.04 (d, J=S3Hz, 2H). 7.28 (d, .£=8.3 Hz, 2H).

IR (pure) cm<1>: 3401 (br), 1742, 1614.

Mass m/z (Cl): 504 [M], 505 [M+1].

Example 20

Methyl 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate

The title compound was prepared (340 mg, yield 90%) as a viscous liquid from a mixture of methyl 2-ethoxy-3-{3-(4-hydroxybenzyl)aminophenyl} propanoate (250 mg, 1 eq, 0.75 mmol), obtained in preparation 13 and 3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (192 mg, 1 eq, 0.75 mmol), obtained in Preparation 2, following a similar procedure as described in Example 19.

1H NMR (200 MHz, CDCy 5 : 1.19 (t,J=7.0Hz, 3H), 1.95-2.18 (m, 2H), 2.90 (d,c/=6.3 Hz, 2H), 3.22-3.60 (m, 6H), 3.70 (bs, 3H), 3.90-4.10 (m, 3H), 4.10-4.25 (m, 4H), 6.42-6.90 (aromatics, 8H), 7.05 (t, J=7.8 Hz, 1H), 7.20-7.30 (m, aromatics, 3H).

IR (clean) cm': 3407 (br), 1742, 1607.

Mass m/z (Cl): 504 [M], 505 [M+1].

Example 21

2-ethoxy-3-14-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benz aminophenylpropanoic acid

Methyl 2-ethoxy-3-[4- {4-(3-(3,4-dihydro-2H-benzo[b] [1,4]oxazin-4-yl)propyloxy} benzyl}aminophenyl]propanoate (510 mg, 1 eq, 1.01 mmol), obtained in Example 19 was hydrolyzed using lithium hydroxide monohydrate (127 mg, 3 eq, 3.03 mmol) in methanol-water at RT, while all starting material was not consumed (4 to 5 h). The reaction mixture was diluted with water, acidified (pH~3-4) with dilute HCl. The residue was chromatographed using ethyl acetate/hexanes to give the title compound as a sticky liquid (250 mg, 51%).

<1>H NMR (200 MHz. CDCy 6: 1.18 (t,J=6. 9Hz, 3H), 1.26 (t,J=7. 3Hz, 1H, N-H), 1.98-2.18 (m, 2H), 2.90 (dd, .£=14.1, 7.4 Hz, 1H), 3.04 (dd, JM4.1. 4.4 Hz, 1H), 3.35 (t,J=4. 2Hz, 2H), 3.40-3.64 (m. 3H), 4.10-4.25 (m. 4H), 6.57 (d. J=8. 3Hz, 2H), 6.60-6.82 (m. 4H), 6.88 (d,J=8.3Hz, 2H), 7.05 (d,£=8.3Hz, 2H), 7.28 (d,£=8.3Hz, 2H).

IR (neat) cm"': 3407, 1723, 1610.

Mass m/z (Cl): 490 [M], 491 [M+1].

Example 22

2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4Yoxazin-4-yl)propyloxy)benzyl}aminophenylpropanoic acid

The title compound was prepared (220 mg, yield 53%) as a viscous liquid from methyl 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate (420 mg, 0.83 mmol), obtained in Example 20, following the same procedure as that described in Example 21. •H NMR (200 MHz, CDCU 6: 1.15 (t, .£=6.9 Hz, 3H), 1.26 (t,J=7. 3Hz, 1H, N-H), 1.98-2.18 (m, 2H), 2.90 (dd, c/=14.1, 7.8 Hz, 1H), 3.05 (dd, .£=13.7, 3.9 Hz, 1H), 3.30-3.60 (m, 6H), 3.70 (bs. 3H), 4.00-4.10 (m, 3H), 4.10-4.25 (m. 4H). 6.42-6.90 (m, aromatics, 8H), 7.09 (t, .£=7.8, 1H), 7.20-7.30 (m, aromatics, 3H).

IR (clean) cm"<1>: 3407 (no). 1725, 1606.

Mass m/z (Cl): 491 [M+1].

Example 23

Arginine salt of 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid

2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}

aminophenylpropanoic acid (250 mg, 1 eq, 0.5 mmol), obtained in Example 21 and L-arginine (88.7 mg, 1 eq, 0.51 mmol) were stirred in dry methanol (3 ml) for 3-4 h at RT. The solvent was condensed on a rotavapor, after

followed by benzene azeotropy. The residue was dried under high vacuum to give the title compound as a solid (100% yield), mp: 141-142°C.

Example 24

Arginine salt of 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid

2-Ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid (140 mg, 1 eq, 0.28 mmol), obtained in Example 22 and L-arginine (50 mg, 1 eq, 0.28 mmol) were stirred in dry methanol (3 mL) for 3-4 h. h, on RT. The solvent is condensed on a rotavapor, followed by benzene azeotropy. The residue was dried under high vacuum to give the title compound as a solid (100% yield), mp: 152-154°C.

Example 25

Ethyl 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoate

A mixture of 3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propyl bromide (1.76 g, 1.1 eq, 6.5 mmol), obtained in Example 14, ethyl 2-ethoxy-3-(4-aminophenyl) propanoate (1.4 g, 1.0 eq, 5.9 mmol), obtained in preparation 1 and anhydrous K 2 CO 3 (2.45 g, 3.0 eq, 17.7 mmol) in dry DMF (30 mL) was stirred at RT for 2 days. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water and brine. The organic layer was dried (Na 2 SO 4 ) and condensed, and the residue was chromatographed using ethyl acetate and hexane to give the title compound as a viscous liquid (500 mg, 20% yield).

<1>H NMR (200 MHz, CDCl,) δ: 1.17 (t, J=6.8 Hz, 3H), 1.23 (t, J=6.6 Hz, 3H), 1.27 (bs, 1H, N-H), 1.94 (quintet, 6.8 Hz, 2H), 2.90 (d, J=6.9 Hz, 2H), 3.03 (t, J=4.8 Hz, 2H), 3.20 (t. J=6.9Hz, 2H), 3.20-3.45 (m, 3H), 3.45-3.64 (m, 3H), 3.95 (t, J=6.4 Hz, 1H), 4.16 (q, J=6.9 Hz, 2H), 6.50-6.72 (aromatics, 4H), 6.90-7.10 (aromatics, 4H).

IR (pure) cm': 3398, 2926, 1742, 1616.

Mass m/z (Cl): 428 [M], 429 [M+1].

Example 26

2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoic acid

Ethyl 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenyl]propanoate (250 mg, 1.0 eq, 0.58 mmol), obtained in Example 25, was hydrolyzed by treatment with LiOH.H2O (74 mg, 3 eq, 1.75 mmol) in a solvent mixture. MeOH-THF-water, at RT, for 3-4 h. The reaction mixture was condensed, diluted with water and acidified (pH to 4) with aqueous HCl. Finally, the crude acid was extracted with ethyl acetate. The ethyl acetate layer was dried (Na 2 SO 4 ), condensed and chromatographed using MeOH and CHCl 3 as eluent to give the title compound as a thick liquid (152 mg, 68% yield).

<1>H NMR (200 MHz, CDCIg) δ: 1.17 (t, J=6.9 Hz, 3H), 1.26 (bs, 1H, N-H); 1.93 (quintet, 6.9 Hz, 2H), 2.85-3.10 (m, 4H), 3.02 (t, J=5.1 Hz, 2H), 3.19 (t, J=6.9Hz, 2H), 3.20-3.65 (m, 4H), 4.02 (dd, J=6.9, 4.4 Hz, 1H), 4.70 (bs, 1H, CO2H), 6.50-6.72 (aromatics, 4H), 6.90-7.10 (aromatics, 4H).

IR (pure) cm1: 3411, 2929. 1726, 1616.

Mass m/z (Cl): 400 [M], 401 [M+1].

Example 27

Arginine salt of 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propyl-amino}phenyl]propanoic acid

A mixture of 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino} phenypropanoic acid (110 mg, 1 eq, 0.27 mmol), obtained in Example 26 and L-arginine (47.9 mg, 1 eq, 0.27 mmol) was placed in dry MeOH (2.0 mL) and stirred at RT. for 2 h to obtain a clear solution. The solvent was condensed, the residue was azeotroped with dry benzene and dried via a vacuum pump to give the title compound as a solid (100% yield), mp: 142-144°C.

Example 28

Ethyl 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoate

A mixture of 2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethyl bromide (940 mg, 1 eq, 3.8 mmol), obtained in preparation 15, ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (1.0 g, 1.1 eq, 4.2 mmol), obtained in preparation 1, anhydrous K2CO3 (1.6 g, 3 eq, 10.8 mmol) and tetrabutylammonium bromide (265 mg, 0.2 eq, 0.8 mmol) in dry toluene (20 ml) was heated at 90°C for 24 h. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and brine, then dried (Na 2 O and condensed. The residue was chromatographed with ethyl acetate and hexanes as eluants to give the desired product as a thick liquid (960 mg, 60%).

<1>H NMR (200 MHz, CDCl3) δ: 1.17 (t, J=6.9 Hz, 3H), 1.23 (t, J=6.6 Hz, 3H), 1.27 (bs, 1H, N-H), 2.90 (d. J=6.4 Hz, 2H), 3.20-3.65 (m, 8H). 3.95 (t, J=6.4 Hz, 1H), 4.05-4.25 (m, 4H), 6.56 (d, J=8.3 Hz, 2H), 6.60-6.85 (aromatics, 4H), 7.06 (d, J=8.3 Hz, 2H).

IR (pure) cm"<1>: 3395, 2977, 1740, 1616.

Mass m/z (Cl): 398 [M], 399 [M+1].

Example 29

2-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[bj[1,4]oxazin-4-yl)ethylamino}phenyl]propanoic acid

Ethyl 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoate (960 mg, 1.0 eq, 2.41 mmol), obtained in Example 28, was hydrolyzed by treatment with LiOH.H 2 O (350 mg, 3 eq, 7.2 mmol) in a solvent mixture. MeOH-THF-water, at RT, for 3-4 h. The reaction mixture was condensed, diluted with water and acidified (pH to 4-5) with aqueous HCl. Finally, the crude acid was extracted with ethyl acetate. The ethyl acetate layer was dried (Na 2 SO 4 ), condensed and chromatographed using MeOH and CHCl 3 as eluents to give the desired compound as a thick liquid (370 mg, 42%).

<1>H NMR (200 MHz, CDCy 8: 1.17 (t, J=6.8 Hz, 3H), 1.21 (bs, 1H, N-H), 2.90 (dd, J=14, 8 Hz, 1H), 3.03 (dd. J=14, 4.3 Hz. 1H), 3.20-3.65 (m. 8H), 4.02 (dd, J=6.49, 4.4 Hz, 1H), 4.21 (t. J=4.4Hz. 2H), 5.00 (bs, CO2H), 6.58 (d. J=8.3Hz. 2H), 6.60-6.85 (aromatics, 4H), 7.06 (d, J=8.3 Hz, 2H).

IR (pure) cm"<1>: 3383 (br), 2927, 1727, 1607.

Mass m/z (Cl): 371 [M+1].

Example 30

Arginine salt of 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethyl-amino}phenyl]propanoic acid

The title compound was prepared as a free flowing solid (mp: i42-i44°c) from 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]propanoic acid, obtained in Example 29 and L-arginine, following a similar procedure as described in Example 27.

Example 31

Methyl 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b] [1,4]oxazin-4-yl)ethoxy}phenyl-aminomethyl]phenyl]propanoate

A mixture of 4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy} aniline (305 mg, 1 eq, 1.13 mmol), obtained in the preparation of 16, methyl 2-ethoxy-3-(4-formylphenyl)propanoate (267 mg, 1 eq, 1.13 mmol), obtained in the preparation of 5, activated molecular sieves (4). A) and p-TsOH (21 mg, 0.1 eq, 0.11 mmol) in dry DCM (4 ml) was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with aqueous sodium bicarbonate, dried (Na 2 O 4 ) and condensed. The crude mass was dissolved in dry methanol (6 mL) and conc. HCl (125 µL) was added, at 0 °C, followed by portionwise addition of NaB(CN)H3 (118 mg, 1.5 eq, 1.87 mmol). The reaction mixture was stirred at 0 °C for 3 h, after which it was diluted with ethyl acetate (100 ml). The organic layer was washed with aqueous sodium bicarbonate, dried (Na 2 SO 4 ) and condensed. The residue was chromatographed using ethyl acetate and hexanes to give the title compound as a thick oil (525 mg, 85%).

'H NMR (200 MHz. CDCU 5: 1.16 (t, J=6.9Hz, 3H), 1.25 (bs. -NH-), 3.00 (d. J=6.8Hz,

2H), 3.22-3.42 (m, 1H), 3.49 (t, J=4.4 Hz, 2H), 3.55-3.75 (m. 3H). 3.71 (s, 3H). 3.99-4.12 (m, 3H), 4.15-4.24 (m, 4H), 6.50-6.90 (aromatics, 8H), 7.19 (d, J=7.8Hz, 2H), 7.28

(d, J=8.0, 2H).

IR (pure) cm<1>: 3405 (no). 2927, 1746. 1606.

Mass m/z (Cl): 490 [M], 491 [M+1].

Example 32

2-ethoxy-3-[4-[4-{2-(3,4Clhydro-2H-benzo[b][1)4]oxazin-4-yl)ethoxy}phenylamino-methyl]phenyl]propanoic acid

Methyl 2-ethoxy-3-[444-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoate (520 mg, 1.0 eq, 1.06 mmol), obtained in Example 31, was hydrolyzed by treatment with LiOH.H2O (134 mg, 3 eq, 3.18 mmol) in to the solvent mixture MeOH-THF-water, at RT, for 3-4 h. The reaction mixture was condensed, diluted with water and acidified (pH to 4) with aqueous HCl. Finally, the crude acid was extracted with ethyl acetate. The ethyl acetate layer was dried (Na 2 SO 3 ), condensed and chromatographed using MeOH and CHCl 3 as eluents to give the desired compound as a thick liquid (150 mg, 30%).

<1>H NMR (200 MHz, CDCl,) δ: 1.18 (t, J=6.9Hz, 3H), 1.29 (bs, -NH-), 2.90-3.20 (m, 2H), 3.22-3.75 (m, 6H), 4.00-4.18 (m, 3H), 4.20-4.25 (m, 4H), 6.00 (bs, CO^), 6.60-6.90 (aromatics, 8H), 7.24 (d, J=8.3, 2H), 7.29 (d, J=8.3, 2H).

IR (pure) cm"<1>: 3390 (br), 2927, 1725, 1605.

Mass m/z (Cl): 476 [M], 477 [M+1].

Example 33

Arginine salt of 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenylaminomethyl]phenyl]propanoic acid

A mixture of 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy} phenylaminomethyl]phenyl]propanoic acid (110 mg, 1 eq, 0.23 mmol), obtained in Example 32 and L-arginine (40 mg, 1 eq, 0.23 mmol) was introduced into dry MeOH (2 mL) and was stirred at RT for 2 h to obtain a clear solution. The solvent was condensed, the residue was azeotroped with dry benzene and dried via a vacuum pump to give a solid (100% yield), mp:154-156°C.

Example 34

[2S,N(1/^]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b]

[1,4oxazin-4-yl)propylamino}phenyl]propanamide

To a solution of racemic 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoic acid (2.0 g, 1.0 eq, 5.20 mmol), obtained in Example 2, in DCM (26 mL) and triethylamine (3.61 mL, 5 eq, 26 mmol) was added dropwise. dropwise, at 0°C, isobutylchloroformate (1.35 ml, 2 eq, 10.4 mmol). The reaction mixture was stirred at RT for 30 min, followed by the addition of (β)-phenylglycinol (1.42 g, 2 eq, 10.4 mmol). The reaction mixture was further stirred at RT for 16 h and then diluted with DCM, washed with water and brine, dried (Na 2 O, and condensed. The residue was chromatographed using ethyl acetate and hexane to give the title compound as the (S./^-diastereomer (620 mg, 23.7% yield)), which is faster moving, followed by the (/^/^-diastereomer (630 mg, 24% yield), which is relatively slower moving, both as a viscous liquid The characterization of the (/?,/5)-diastereomer is described in Example 35.

<1>H NMR (200 MHz, CDCL,) δ: 1.14 (t, J=6.8 Hz, 3H). 1.24 (s, 1H), 1.91 (quintet, J=6.8 Hz, 2H), 2.90 (dd, J=12 and 5.8 Hz, 1H), 3.06 (dd, J=12 and 3.9 Hz, 1H), 3.19 (t, J=6.8 Hz, 2H), 3.25-3.60 (m, 6H), 3.60-3.70 (m, 2H), 3.97 (dd, J=5.8 and 3.9 Hz, 1H), 4.22 (t, J=4.4 Hz, 2H), 4.88-5.00 (m, 1H), 6.50-7.40 (aromatic and amide-NH, 14H).

IR (pure) cm': 3393 (br), 2927, 1660.

Mass/z(Cl): 503 [M], 504 [M+1].

Example 35

[2/?,N(1/5)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihyde [1,4]oxazin-4-yl)propylamino}phenyl]propanamide

The title compound was obtained following a procedure similar to that described in Example 34.

<1>H NMR (200 MHz, CDCy 5: 1.16 (t, J=6.8 Hz, 3H), 1.24 (s, 1H), 1.91 (quintet, J=6.8Hz, 2H), 2.80 (dd, J=14, 7.5 Hz, 1H), 3.06 (dd, J=14, 3.9 Hz, 1H), 3.17 (t, J=6.8 Hz, 2H), 3.25-3.60 (m, 6H), 3.78-3.90 (m, 2H), 3.89 (dd, J=7.5, 3.9 Hz, 1H), 4.22 (t, J=4.4 Hz, 2H), 4.88-5.00 (m, 1H), 6.45-7.35 (aromatics and amide-NH, 14H).

IR (pure) cm1: 3399 (br), 2927, 1660.

Mass m/z (Cl): 503 [M], 504 [M+1].

Example 36

Hydrochloride salt of [2S,N(1 /?)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide

[2S,N(1Ar)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]propanamide (95 mg, 0.19 mmol), obtained in Example 34, obtained in Example 34, was added to a dry methanolic HCl solution (2 ml) and the mixture was stirred at RT for 5 min. The reaction mixture was then condensed and azeotroped using dry benzene on a rotary evaporator. The residue was dried under high vacuum to give the title compound as a brown solid (100% yield, mp: 74-75°C).

Example 37

Hydrochloride salt of [2/?,N(1 /?)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide

[2/?,N(1/"")]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]propanamide (95 mg, 0.19 mmol), obtained in Example 35, obtained in Example 35, was added to a dry methanolic HCl solution (2 ml) and the mixture was stirred at RT for 5 minutes. The reaction mixture was then condensed and azeotroped using dry benzene on a rotary evaporator. The residue was dried under high vacuum to give the title compound as a brown solid (100% yield, mp: 69-70°C).

Example 38

Magnesium salt of 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo|b|[1,4|oxazin-4-yl)propylamino}phenyl]propanoic acid

A mixture of a methanolic solution (2 ml) of 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoic acid (75 mg, 1 eq, 0.19 mmol), obtained in Example 2, and magnesium hydroxide (5.6 mg, 0.5 eq, 0.095 mmol) was heated to 50°C. during 5 h. The resulting solution was condensed, azeotroped with benzene and then finally dried on a high vacuum pump to give the title compound as a free flowing solid (100% yield, mp: 132-134°C).

Example 39

[25,N(1/i)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b] [1,4]oxazin-4-yl)propylamino}phenyl]propanamide

To a solution of racemic 2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoic acid (1.8 g, 1.0 eq, 4.48 mmol), obtained in Example 17, in DCM (25 mL) and triethylamine (2.49 mL, 4 eq, 17.92 mmol), isobutylchloroformate (875 u.L, 1.5 eq, 6.72 mmol) was added dropwise at 0°C. The reaction mixture was stirred at RT for 30 min, followed by the addition of (/T)-phenylglycinol (1.23 g, 2 eq, 8.96 mmol). The reaction mixture was further stirred at RT for 16 h, then diluted with DCM, washed with water and brine, dried (Na 2 SO 4 , and condensed. The residue was chromatographed using ethyl acetate and hexane to give the title compound as the ( S , R )-diastereomer (370 mg, 32% yield), which is fast moving, followed by the (/7,/i)-diastereomer (370 mg, 32% yield), which is relatively slower moving, both as a viscous liquid The characterization of the (/?,/T)-diastereomer is described in Example 40 (next example).

[α]D: -7.0° (c,1.0 CHCl3).

'H NMR (200 MHz, CDCy 8: 1.16 (t. J=6.8Hz, 3H), 1.92 (quintet, J=6.8Hz, 2H), 2.92 (dd, J=14, 5.6 Hz, 1H), 3.08 (dd, J=14, 3.5 Hz, 1H), 3.22 (t, J=6.4 Hz). 2H), 3.20-3.40 (m, 4H), 3.99 (t, J=5.2 Hz, 1H), 4.88-5.02 (m, 1H), 6.40-6.60 and 6.90-7.40 (aromatics amide-NH, 13H).

IR (pure) cm-': 3405 (no), 2933, 1660, 1615, 1514.

Mass m/z (Cl): 521 [M], 522 [M+1].

Example 40

[2/?,N(1/?)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b] [1,4]oxazin-4-yl)propylamino}phenyl]propanamide

The title compound was obtained during the synthesis of Example 39, as the second diastereomer (R, R).

[α]D: 17.4° (c, 1.0 CHCl3).

1H NMR (200 MHz, CDCl3) δ: 1.18 (t, J=6.8 Hz, 3H), 1.91 (quintet, J=6.8 Hz, 2H), 2.51 (bs, NH, OH); 2.82 (dd, J=14.2 and 7.3 Hz, 1H), 3.04 (dd. J=14.2 and 3.4 Hz, 1H), 3.20 (t, J=6.4 Hz, 2H), 3.25-3.40 (m, 4H), 3.42-3.70 (m, 2H), 3.80-3.90 (m, 2H); 3.98 (dd, J-7.3 and 4.0 Hz. 1H), 4.24 (t, J=4.8 Hz, 2H), 4.88-5.2 (m, 1H), 6.4-6.60 and 7.00-7.40 (aromatics and amide-NH, 13H).

IR (clean) cm1: 3398 (no), 2929, 1660, 1616, 1513.

Mass m/z (Cl): 521 [M], 522 [M+1].

Example 41

Hydrochloride salt of [2S,N(1 /?)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide

[2S,N(1/i)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenylpropanamide (95 mg, 0.19 mmol), obtained in Example 34, obtained in Example 34, was added to a dry methanolic solution of HCl (2 ml) and the mixture was stirred at RT for 5 minutes. The reaction mixture was then condensed and azeotroped using dry benzene on a rotary evaporator. The residue was dried under high vacuum to give the title compound as a brown solid (100% yield, mp: 74-75°C).

Example 42

Hydrochloride salt of [2/7,N(1 /?)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide

[2/7,N(1/i)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenylpropanamide (95 mg, 0.19 mmol), obtained in Example 35, obtained in Example 35 was added to dry methanolic solution of HCl (2 ml) and the mixture was stirred at RT for 5 minutes. The reaction mixture was then condensed and azeotroped using dry benzene on a rotary evaporator. The residue was dried under high vacuum to give the title compound as a brown solid (100% yield, mp: 69-70°C).

Example 43

(-)-(S)-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid

[α]D: -17° (c, 1.0 MeOH).

1H NMR (200 MHz, CDCy 8: 1.19 (t. J=7.4 Hz, 3H), 1.94 (q, J=7.4 Hz, 2H). 2.90 (dd, J=14.0 and 7.0 Hz, 1H), 3.05 (dd. J=14.0 and 4.9 Hz, 1H), 3.21 (t. J=6.8 Hz. 2H), 3.25-3.40 (m, 5H), 3.40-3.62 (m, 1H), 4.00-4.17 (m, 1H), 4.18-4.22 (m, 2H), 6.59 (d, J=8.3 Hz, 2H), 6.65-6.85 (m, 4H). J=8.3 Hz, 2H).

IR (pure) cm"<1>: 3500, 1725.

Mass m/z (Cl): 385 (M+1).

Example 44

(+)-(/^-3-[4-{3-(3,4<lihydro-2H-benzolb][1,4|oxazin-4-yl)propylamino}phenylJ-2-ethoxypropanoic acid

[α]D: 16.8° (c, 1.0 MeOH).

1H NMR (200 MHz, CDCy 5: 1.19 (t, J=7.4 Hz. 3H), 1.94 (q, J=7.4 Hz. 2H), 2.90 (dd, J-14.0 and 7.0 Hz. 1H), 3.05 (dd. J=14.0 and 4.9 Hz. 1H), 3.21 (t, J=6.8 Hz. 2H). 3.25-3.40 (m. 5H), 3.40-3.62 (m, 1H), 4.18-4.22 (m, 2H). 6.59 (d. J=8.3 Hz, 2H), 7.06 (d, J=8.3 Hz, 2H).

IR (pure) cm<1>: 3500, 1725.

Mass m/z (Cl): 385 (M+1).

Example 45

Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoate

(S)-Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (2.20 g, 1 eq, 9.28 mmol), obtained in preparation 20, 3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (3.30 g, 1.3 eq, 12.06 mmol), obtained in preparation 10, anhydrous K 2 CO 3 (3.84 g, 3 eq, 27.84 mmol) and tetrabutyl ammonium bromide (597 mg, 0.2 eq, 1.85 mmol) were heated at 90°C, in dry toluene (47 mL), for 20 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine

solution. The residue was chromatographed with ethyl acetate and hexane to give the title compound (1.78 g, 44.5% yield) as a viscous liquid.

[α]D: -9.2° (c1.0, MeOH).

<1>H NMR (200 MHz, CDCl, ) δ: 1.17 (t, J=7 Hz, 3H), 1.23 (t, J=7 Hz, 3H). 1.89 (q, J=6.8 Hz, 2H), 2.90 (d, J=6.5 Hz, 2H), 3.10-3.42 (m, 7H). 3.45-3.65 (m, 1H), 3.95 (t, J=6.7 Hz. 1H), 4.10-4.30 (m, 4H), 6.40-6.70 (m, aromatics, 5H), 7.05 (d, J=8.4 Hz, 2H).

IR (clean) cm"': 3394 (no), 2978, 1740. 1617, 1514.

Mass m/z (Cl): 431 (M+1).

Example 46

(S)-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid

(5)-Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoate (1.7 g, 1 eq, 3.95 mmol), obtained in Example 45, was hydrolyzed using lithium hydroxide monohydrate (249 mg, 1.5 eq, 5.93 mmol) in a mixture methanol-THF-water, at RT, until all the starting material is consumed (4 to 5 h). The reaction mixture was diluted with water and acidified (pH~4-5) with dilute HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed using ethyl acetate and hexanes -> methanol and chloroform to give the title compound (1.5 g, 94% yield) as a viscous liquid.

[α]D: -16.1° (c 1.0, MeOH).

Chiral HPLC:>98% ee.

<1>H NMR (200 MHz, CDCl3) δ: 1.19 (t, J=7.4Hz, 3H), 1.94 (quintet, J=7.4 Hz, 2H), 2.85-3.10 (m, 2H), 3.10-3.20 (m, 6H), 3.40-3.70 (m, 2H), 3.90-4.10 (m, 1H), 4.10-4.30 (m, 2H), 6.20 (bs, NH, COjH), 6.42-6.70 (m, aromatics, 5H), 7.07 (d, J=8.3 Hz, 2H).

IR (KBr) cm<1>: 3394, 1725, 1619.

Mass m/z (Cl): 403 (M+1).

Example 47

L-arginine salt of (5)-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid

(^-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}

phenyl]-2-ethoxypropanoic acid (300 mg, 1 eq, 0.74 mmol), obtained in Example 46 and L-arginine (130 mg, 1 eq, 0.74 mmol) were placed in dry methanol (4 ml) and stirred at RT for 2-3 h. The solvent was removed on a rotavapor, followed by benzene azeotropy. The residue was dried under a high-vacuum pump to give the title compound as a free-flowing solid (100% yield).

Mp: 114-116°C.

Example 48

Magnesium salt of (S)-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid

(S)-344-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylam

phenyl]-2-ethoxypropanoic acid (1.13 g, 1.0 eq, 2.81 mmol), obtained in Example 46, in dry methanol (15 mL) was treated with Mg(OMe) 2 (121 mg, 0.5 eq, 1.4 mmol). The resulting mixture was heated to 55-60°C for 7-8 hours. The reaction mixture was condensed on a rotavapor, azeotroped with benzene and, finally, dried on a high vacuum pump. The sticky mass was triturated with hexanes to give the desired salt as a powdery solid (quantitative yield).

Mp: 240-242°C (dec.).

Example 49

Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,41oxazin-4-yl)propylamino} phenyl]-2-methoxypropanoate

(S)-Ethyl 2-methoxy-3-(4-aminophenyl)propanoate (800 mg, 1.0 eq, 3.58 mmol), obtained in preparation 21, 3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl) propyl bromide (1.27 g, 1.3 eq, 4.65 mmol), obtained in preparation 10, anhydrous K 2 CO 3 (1.48 g, 3 eq, 10.79 mmol) and tetrabutyl ammonium bromide (576 mg, 0.5 eq, 1.79 mmol) were heated at 90 °C, in dry toluene (20 mL), for 9 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to give the title compound (1.1 g, 73% yield) as a viscous liquid.

[α]D: -4.0° (c1.0, MeOH).

<1>H NMR (200 MHz, CDCIg) δ: 1.25 (t.J=7.3Hz, 3H), 1.89 (q, J=7.0Hz, 2H), 2.91 (d, J=6.0 Hz, 2H), 3.05-3.42 (m, 6H), 3.36 (s, 3H); 3.90 (t, J=6.4 Hz, 1H), 4.10-4.30 (m, 4H), 6.40-6.70 (m, aromatics, 5H), 7.05 (aromatics, 2H).

IR (clean) cm"<1>: 3385 (br), 2934. 1741, 1617, 1514.

Mass m/z (Cl): 417 (M+1).

Example 50

(S)-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid

(S)-Ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]-2-methoxypropanoate (1.0 g, 1 eq, 2.4 mmol), obtained in Example 49, was hydrolyzed using lithium hydroxide monohydrate (151 mg, 1.5 eq, 3.6 mmol) in a mixture of methanol-THF-water, at RT, until all starting material is consumed (4 to 5 h). The reaction mixture was diluted with water and acidified (pH~4-5) with dilute HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed using ethyl acetate and hexanes -> methanol and chloroform to give

gave the title compound (650 mg, yield 70%) as a viscous liquid.

[α]D: -14.2° (c1.0, MeOH).

Chiral HPLC>98% ee.

<1>H NMR (200 MHz, CDCL,) δ: 1.9 (quintet. J=7.4 Hz. 2H). 2.85-3.10 (m. 2H), 3.10-3.38 (m, 6H), 3.40 (s, 3H); 3.90-4.05 (m, 1H), 4.24 (t, J=4.2 Hz, 2H); 6.42-6.70 (m, aromatics, 5H); 7.05 (d. J=8.0 Hz. 2H).

IR (neat) cm"': 3396, 2936, 1727, 1614, 1513.

Mass m/z (Cl): 389 (M+1).

Example 51

Magnesium salt of (S)-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid

(S)-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}

phenyl]-2-methoxypropanoic acid (400 g, 1.0 eq, 1.03 mmol), obtained in Example 50, in dry methanol (5 mL) was treated with Mg(OMe) 2 (44.3 mg, 0.5 eq, 0.51 mmol). The resulting mixture was heated to 55-60°C for 7-8 hours. The reaction mixture was condensed on a rotavapor, azeotroped with benzene and, finally, dried on a high vacuum pump. The sticky mass was triturated with hexanes to obtain the desired salt as a powdery solid (quantitative yield).

Mp: 210-212°C (dec.).

Example 52

Ethyl 344-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b)(1,4|oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate

Ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (500 mg, 1 eq, 2.11 mmol), obtained in preparation 1, 3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (670 mg, 1.1 eq, 2.32 mmol), obtained in preparation 17, anhydrous K 2 CO 3 (875 mg, 3 eq, 6.33 mmol) and tetrabutyl ammonium bromide (340 mg, 0.5 eq, 1.05 mmol) were heated at 90 °C, in dry toluene (11 mL), for 12 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to give the title compound (320 mg, 32% yield) as a mixture of diastereomers as a viscous liquid.

<1>H NMR (200 MHz, CDCIg) δ: 1.10-1.25 (m, 9H), 1.80-2.00 (m, 2H), 2.82-3.02 (m, 2H), 3.10-3.50 (m, 2H), 3.28-3.44 (m, 3H). 3.50-3.65 (m, 1H); 3.90^.00 (m. 1H). 4.10-4.30 (m, 3H), 6.40-6.80 (aromatics, 5H), 7.00-7.20 (aromatics, 2H).

IR (clean) cm"<1>: 3389 (br), 2929, 1740, 1617, 1515.

Mass nilz(Cl): 445 (M+1).

Example 53

3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid

Ethyl 344-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate (320 mg, 1 eq, 0.72 mmol), obtained in Example 52, was hydrolyzed using lithium hydroxide monohydrate (46 mg, 1.5 eq, 1.08 mmol) in a mixture of methanol-THF-water, at RT, until all starting material is consumed (4 to 5 h). The reaction mixture was diluted with water and acidified (pH~4-5) with dilute HCl and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue was chromatographed using methanol and chloroform to give the title compound (190 mg, 64% yield) as a viscous liquid.

<1>H NMR (200 MHz, CDCl,) δ: 1.21 (t, J=7.1 Hz, 3H), 1.36 (d, J=6.4Hz, 3H), 1.92 (quintet, J=6.8 Hz, 2H), 2.90-3.10 (m, 2H), 3.10-3.40 (m, 6H), 3.42-3.60 (m, 2H); 4.06 (dd, J=6.8, 3.9 Hz, 1H), 4.20-4.35 (m, 1H); 6.50-6.62 (aromatics, 5H), 7.07 (d, J=8.3Hz, 2H).

IR (KBr) cm"<1>: 3387, 2927, 1726, 1615. 1514.

Mass m/z (Cl): 417 (M+1).

Example 54

3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid magnesium salt

3-[4-{3-(2-methyl-74fluoro-3,4<lihydro-2H-benzo[b][1,4]oxazin-4-io

phenyl]-2-ethoxypropanoic acid (170 mg, 1.0 eq, 0.41 mmol), obtained in Example 53, in dry methanol (5 mL) was treated with Mg(OMe) 2 (17.6 mg, 0.5 eq, 0.21 mmol). The resulting mixture was heated to 55-60°C for 7-8 h. The reaction mixture was condensed on a rotavapor, azeotroped with benzene and, finally, dried on a high vacuum pump. The sticky mass was triturated with hexanes to obtain the desired salt as a powdery solid (quantitative yield).

Mp: 110-112°C.

Example 55

Ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate

Starting from ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (438 mg, 1 eq, 1.85 mmol), obtained in preparation 1 and 3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (550 mg, 1.1 eq, 2.32 mmol), obtained in preparation 18, and following the procedure from Example 52, the title compound was obtained (300 mg, yield 35%) as a mixture of diastereomers, as a viscous liquid.

<1>H NMR (200 MHz, CDCl3) δ: 1.17 (t, J=7.0 Hz, 3H); 1.23 (t, J=7.0 Hz, 3H); 1.35 (d, J=6.4 Hz, 3H); 1.80-2.00 (m, 2H), 2.91 (d, J=6.7 Hz, 2H); 3.00-3.42 (m, 7H); 3.45-3.65 (m, 1H); 3.95 (t, J=6.7 Hz, 1H), 4.10-4.30 (m, 3H), 6.53 (d. J=8.3 Hz, 2H); 6.65 (t, J=7.8 Hz, 2H); 6.79 (d, J=7.8 Hz, 2H); 7.06 (d, J=8.3 Hz, 2H).

IR (clean) cm': 3400 (no), 2976. 1741. 1616, 1520.

Mass m/z (Cl): 427 (M+1).

Example 56

3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid

Ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate (300 mg, 1 eq, 0.72 mmol), obtained in Example 55, was hydrolyzed following the procedure of Example 53 to give the title compound (170 mg, 61% yield) as a viscous liquid.

1H NMR (200 MHz, CDCy 5: 1.17 (t, J=7.0 Hz, 3H); 1.34 (d. J=6.1 Hz, 3H); 1.80-2.00 (m, 2H), 2.80-3.70 (m, 10H); 4.02 (dd, J=7.3, 4.5 Hz, 1H); 4.10-4.30 (bs, 2H, NH); 6.64 (t, J=7.8 Hz, 2H); 7.06 (d, J=8.3Hz).

IR (KBr) cm<1>: 3393, 2974, 1726, 1617, 1503.

Mass m/z (Cl): 399 (M+1).

Example 57

3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[bJ[1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid magnesium salt

From 344-{3-(2-methyl-3,4<lihydro-2H-benzo[b][1,4]oxazin-4-yl)propylam 2-ethoxypropanoic acid (155 mg, 1.0 eq, 0.39 mmol), obtained in Example 56 and Mg(OMe)2 (16.5 mg, 0.5 eq, 0.20 mmol), the desired salt was obtained as a powdery solid. (quantitative yield), following the procedure from Example 54.

Mp: 102-104°C.

Example 58

Ethyl (2S)-3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b] [1,4]oxazin-4-yl)propylamino} phenyl]-2-methoxypropanoate

Starting from ethyl (S)-2-methoxy-3-(4-aminophenyl)propanoate (500 mg, 1 eq, 2.24 mmol), obtained in preparation 21 and 3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (666 mg, 1.1 eq, 2.47 mmol), obtained in preparation 18, and the following procedure from Example 52, the title compound was obtained (340 mg, yield 38%) as a mixture of diastereomers, as a viscous liquid.

<1>H NMR (200 MHz, CDCl3) δ: 1.25 (t, J=7.2Hz. 3H); 1.36 (d. J=6.4Hz. 3H); 1.80-2.00 (m, 2H), 2.92 (d, J=6.2Hz, 2H); 3.02-3.50 (m, 9H); 3.90 (t, J=6.2Hz, 1H), 4.10-4.30 (m. 3H), 6.54 (d, J=8.3 Hz, 2H); 6.65 (t, J=7.2 Hz, 2H); 6.80 (d, J=7.2 Hz, 2H); 7.05 (d. J=8.3 Hz. 2H).

IR (pure) cm"': 3398 (no), 2928, 1741, 1613, 1520.

Mass m/z (Cl): 413 (M+1).

Example 59

(2S)-3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid

Ethyl (2S)-3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]-2-methoxypropanoate (170 mg, 1 eq, 0.413 mmol), obtained in Example 58, was hydrolyzed following the procedure of Example 53 to give the title compound (100 mg, 63% yield) in in the form of a viscous liquid.

<1>H NMR (200 MHz, CDCl3) δ: 1.35 (d, J=6.5Hz, 3H); 1.80-2.00 (m, 2H), 2.85-3.60 (m, 11H); 3.98 (dd, J=7.0, 4.3 Hz, 1H), 4.15-4.30 (m, 1H), 6.55 (d, J=8.3 Hz, 2H); 6.65 (t, J=7.2 Hz, 2H); 6.79 (d, J=7.2Hz, 2H); 7.05 (d, J=8.3Hz, 2H).

IR (KBr) cm"<1>: 3391, 2930, 1727, 1608, 1506.

Mass m/z (Cl): 385 (M+1).

Example 60

Magnesium salt of (25)-3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid

From (2S)-344-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylam phenyl]-2-ethoxypropanoic acid (90 mg, 1.0 eq, 0.23 mmol), obtained in Example 59 and Mg(OMe)2 (10.1 mg, 0.5 eq, 0.12 mmol) gave the desired salt in in the form of a powdery solid mass (quantitative yield), following the procedure from example 54.

Mp: 160-162°C.

Example 61

Ethyl 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoate

Starting from ethyl 2-ethoxy-3-(4-aminophenyl)propanoate (325 mg, 1 eq, 1.37 mmol), obtained in preparation 1 and 3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (450 mg, 1.1 eq, 1.51 mmol), obtained in preparation 19 and following the procedure from example 52, the title compound was obtained (343 mg, yield 69%) as a mixture of diastereomers, as a viscous liquid.

<1>H NMR (200 MHz, CDCL,) δ: 0.97 (t, J=7.0 Hz, 3H); 1.17 (t, J=7.2 Hz, 3H); 1.22 (t, J=7.3 Hz, 3H); 1.40-1.80 (m, 4H); 1.91 (quintet, J=6.7 Hz, 2H), 2.90 (d, J=6.4 Hz, 2H); 3.00-3.42 (m, 7H); 3.45-3.65 (m. 1H); 3.94 (t, J=6.4 Hz, 1H), 4.00-4.22 (m. 3H), 6.52 (d, J=8.3 Hz, 2H); 6.64 (t. J=7.0 Hz, 2H); 6.78 (d. J=7.2 Hz, 2H); 7.05 (d, J=8.3 Hz. 2H). IR (pure) cr<n1>: 3400 (br). 2959, 1741. 1616. 1520.

Mass m/z (Cl): 455 (M+1).

Example 62

3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl|-2-ethoxypropanoic acid

Ethyl 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoate (305 mg, 1 eq, 0.67 mmol), obtained in Example 61, was hydrolyzed following the procedure of Example 53 to give the title compound (177 mg, 62% yield) as a viscous liquid.

1 H NMR (200 MHz, CDCl 3 ) δ: 0.97 (t, J=7.0 Hz, 3H); 1.18 (t, J=7.2 Hz, 3H); 1.40-1.80 (m, 4H); 1.92 (quintet, J=6.7 Hz, 2H), 2.80-3.62 (m, 10H); 3.95-4.15 (m, 2H); 4.60 (bs, 2H); 6.55 (d, J=8.3 Hz, 2H); 6.64 (t, J=7.0 Hz, 2H); 6.79 (d, J-7.2 Hz, 2H); 7.06 (d. J=8.3 Hz, 2H).

IR (KBr) cm"<1>: 3500, 2931, 1724, 1606, 1504.

Mass m/z (Cl): 427 (M+1), 853 (M2+1).

Example 63

3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid magnesium salt

From 3-[4-{3-(2-propyl-7-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino} phenyl]-2-ethoxypropanoic acid (164 mg, 1.0 eq, 0.39 mmol), obtained in Example 62 and Mg(OMe)2 (16.5 mg, 0.5 eq, 0.20 mmol) gave the desired salt in in the form of a powdery solid mass (quantitative yield), following the procedure from example 54.

Mp: 104-106°C.

Example 64

Ethyl (2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b] [1,4]oxazin-4-yl)propylamino} phenyl]-2-methoxypropanoate

Starting from ethyl (S)-2-methoxy-3-(4-aminophenyl)propanoate (312 mg, 1 eq, 1.1.40 mmol), obtained in preparation 21 and 3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (460 mg, 1.1 eq, 1.54 mmol), obtained in preparation 19 and the following procedure from Example 52, the title compound was obtained (255 mg, yield 69%) as a mixture of diastereomers, as a viscous liquid.

<1>H NMR (400 MHz, CDCL,) δ: 0.99 (t, J=6.8 Hz, 3H); 1.26 (t, J=7.2 Hz, 3H); 1.47-1.61 (m, 3H); 1.69-1.74 (m, 1H); 1.89-1.97 (m, 2H), 2.92 (d, J=4.0 Hz, 1H); 2.93 (d, J=2.0 Hz, 1H); 3.09 (dd, J=11.2, 7.8 Hz, 1H); 3.18-3.30 (m, 3H); 3.36 (s, 3H); 3.31-3.48 (m, 2H); 3.90 (t, J=6.0 Hz, 1H), 4.06-4.10 (m, 1H), 4.19 (q, J=7.2 Hz, 2H); 6.54 (d, J=8.8 Hz, 2H); 6.55-6.65 (aromatics. 2H); 6.79 (d, J=7.2 Hz, 2H); 7.04 (d, J=8.8 Hz, 2H).

IR (pure) cm"<1>: 3396 (br), 2930, 1741, 1613, 1518.

Mass m/z (Cl): 441 (M+1).

Example 65

(2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4|oxazin-4-yl)propylamino} phenyl]-2-methoxypropanoic acid

Ethyl (2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate (240 mg, 1 eq, 0.55 mmol), obtained in Example 64, was hydrolyzed following the procedure of Example 53 to give the title compound (164 mg, 73% yield) as viscous liquids.

<1>H NMR (200 MHz, CDCIg) δ: 0.96 (t, J=7.0 Hz, 3H); 1.44-1.67 (m, 4H); 1.91 (quintet, J=7.0 Hz, 2H), 2.90-3.33 (m, 8H); 3.38 (s, 3H); 3.92-4.06 (m, 2H); 4.60 (bs, 2H); 6.55-6.66 (aromatics, 4H); 6.78 (d, J=7.4 Hz, 2H); 7.06 (d, J=8.2 Hz. 2H).

IR (KBr) cm"<1>: 3397.2930. 1727, 1606, 1504.

Mass m/z (ES): 413 (M+1), 825 (M2+1), 1237 (M3+1).

Example 66

Magnesium salt of (S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid

From (25)-3-[4-{3-(2-propyl-7-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoic acid (140 mg, 1.0 eq, 0.34 mmol), obtained in Example 65 and Mg(OMe)2 (14.5 mg, 0.5 eq, 0.17 mmol) was obtained the desired salt, in the form of a powdery solid mass (quantitative yield), following the procedure from example 54.

Mp: 172-174°C.

Example 67

Ethyl 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoate

Starting from ethyl 2-isopropoxy-3-(4-aminophenyl)propanoate (650 mg, 1 eq, 2.59 mmol), obtained in preparation 22 and 3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (781 mg, 1.1 eq, 2.85 mmol), obtained in preparation 10 and the following procedure from Example 52, the title compound was obtained (700 mg, yield 61%) as a viscous liquid.

1 H NMR (200 MHz, CDCIg) δ: 0.98 (d, J=6.2 Hz, 3H); 1.16 (d, J=6.2Hz, 3H); 1.23 (t, J=7.2 Hz, 3H); 1.81-1.88 (m, 2H); 2.85-2.89 (m, 2H); 3.17-3.24 (m, 4H); 3.33 (t, J=7.3 Hz, 2H); 3.40-3.60 (m, 1H); 3.99 (t, J=6.0Hz, 1H), 4.11-4.23 (m, 4H), 6.48-6.55 (aromatics, 3H); 6.63 (d. J=8.3 Hz. 2H); 7.08 (d, J=8.3Hz, 2H).

IR (pure) cm"': 3396 (no). 2939, 1729, 1615, 1514.

Mass m/z (Cl): 445 (M+1).

Example 68

2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[bJ[1,4]oxazin-4-yl)propylamino}phenyl]propanoic acid

Ethyl 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoate (600 mg, 1 eq, 1.35 mmol), obtained in Example 64, was hydrolyzed following the procedure of Example 53 to give the title compound (240 mg, 43% yield) as a viscous liquids.

<1>H NMR (200 MHz, CDCl3) δ: 1.01 (t, J=6.2 Hz, 3H); 1.16 (d, J=6.2Hz, 3H); 1.91 (quintet, J=6.7Hz, 2H), 2.84 (dd, J=14, 8.1Hz, 1H); 3.00 (dd, J=14, 4.2Hz, 1H); 3.16-3.34 (m, 6H); 3.42-3.60 (m, 1H); 4.06 (dd, J=8.1, 4.2Hz, 1H), 4.20-4.25 (m, 2H), 6.09 (bs, 2H); 6.47-6.58 (aromatics, 5H); 7.06 (d, J=8.3Hz, 2H).

IR (pure) cm<1>: 3388 (br), 2932, 1722, 1616, 1513.

Mass m/z (Cl): 417 (M+1).

Example 69

Magnesium salt of 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b]

[1,4]oxazin-4-yl)propylamino}phenyl]propanoic acid

From 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]propanoic acid (240 mg, 1.0 eq, 0.57 mmol), obtained in Example 68 and Mg(OMe)2 (25 mg, 0.5 eq, 0.29 mmol) the desired salt was obtained, in the form powdery solids (quantitative yield), following DELIVERY from Drimer 54.

Mp: 110°C.

Example 70

Ethyl (2S)-3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate

Starting from ethyl (S)-2-methoxy-3-(4-aminophenyl)propanoate (500 mg, 1 eq, 2.24 mmol), obtained in the preparation of 21 and 3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl bromide (711 mg, 1.1 eq, 2.47 mmol), obtained in the preparation of 17 and following the procedure of Example 52, the title compound was obtained (380 mg, yield 40%) in the form of a mixture of diastereomers and as a viscous liquid.

<1>H NMR (200 MHz, CDCl 3 ) δ: 1.20-1.40 (m, 6H); 1.80-2.00 (m, 2H), 2.90-3.02 (m, 2H); 3.02-3.40 (m, 9H); 3.90 (t, J=6.3Hz, 1H), 4.10-4.30 (m, 3H), 6.40-6.60 (aromatics, 5H); 7.05 (d, J=8.3Hz, 2H).

IR (pure) cm"<1>: 3450 (br), 2926, 1740, 1617, 1515.

Mass m/z (Cl): 431 (M+1).

Example 71

(2S)-3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid

Ethyl (2S)-3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate (380 mg, 1 eq, 0.88 mmol), obtained in Example 70, was hydrolyzed following the procedure of Example 53 to give the title compound (150 mg, yield 43%) in the form of a viscous liquid.

1 H NMR (200 MHz, CDCl 3 ) δ: 1.37 (d, J=6.2 Hz, 3H); 1.80-2.00 (m, 2H); 2.90-3.60 (m, 13H); 3.98 (dd, J=7.0, 4.3Hz, 1H), 4.18-4.35 (m, 1H); 6.55-6.70 (aromatics, 5H); 7.10 (d, J=8.0Hz, 2H).

IR (KBr) cm'1: 3400 (br), 2930, 1729, 1614, 1513.

Mass m/z (ES): 403.3 (M+1), 805.5 (M2+1).

Example 72

Magnesium salt (2S)-3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b]

[1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid

From (2S)-3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid (150 mg, 1.0 eq, 0.37 mmol), obtained in Example 71 and Mg(OMe)2 (16 mg, 0.5 eq, 0.185 mmol) obtained is the desired salt, in the form of a brittle solid mass (quantitative yield), following the procedure from Example 54.

Mp: 208-210°C.

The compounds of the present invention lower random blood sugar, triglycerides, total cholesterol, LDL, VLDL and increase HDL. This has been shown in vitro as well as in vivo in animal experiments.

Demonstration of compound activity

A) In vitro:

a) Determination of hPPARa activity

The ligand binding domain of hPPARα is fused to the domain

of DNA binding of the yeast transcription factor Gal 4 in a eukaryotic expression vector. Using superfect (Oiagen, Germanv) as a transfection reagent, HEK-293 cells were transfected with this plasmid and displayed a plasmid protecting the luciferase gene driven by a GAL4 specific promoter. The compound can be added at different concentrations after 42 hours of transfection and incubated overnight. Luciferase activity, as a function of the PPARα binding/activation capacity of the compound will be measured using the Packard Luclite kit (Packard, USA) in Top Count (Ivan Sadovski, Brendan Bell, Peter Broag and Melvyn Hollis. Gene. 1992. 118: 137-141; Superfect Transfection Reagent Handbook. February 1997. Oiagen, Germany).

b) Determination of hPPARct activity

The ligand binding domain of hPPARy1 is fused to the domain

of DNA binding of the yeast transcription factor Gal 4 in a eukaryotic expression vector. Using lipofectamine (Gibco BRL, USA) as a transfection reagent, HEK-293 cells were transfected with this plasmid and displayed a plasmid protecting the luciferase gene driven by a GAL4 specific promoter. The compound can be added at a concentration of 1u.M after 48 hours of transfection and incubated overnight. Luciferase activity, as a function of the PPARγ1 binding/activation capacity of the compound will be measured using the Packard Luclite kit (Packard, USA) in the Packard Top Count (Ivan Sadovski, Brendan Bell, Peter Broag and Melvyn Hollis. Gene. 1992. 118: 137-141; Guide to Eukarvotic Transfection with Cationic Lipid Reagents. Life Technologies, GIBCO

BRL, USA).

c) Determination of HMG CoA reductase inhibitory activity

Liver microsomal bound reductase was prepared from

of rats fed 2% cholestyramine in the middle of the dark cycle. Spectrophotometric assays were performed in 100 mM KH2PO4, 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 µg liver microsomal enzyme. The total volume of the reaction mixture was taken as 1 ml. The reaction was initiated by the addition of HMG CoA. The reaction mixture was incubated at 37°C for 30 min and the decrease in absorbance at 340 nm was recorded. A substrate-free reaction mixture was used as a float (Goldstein, J.L. and Brown, M.S. Advances in understanding the LDL receptor and HMG CoA reductase, two membrane proteins that regulate plasma cholesterol. J. Lipid Res. 1984, 25: 1450-1461). The test compound will inhibit the enzyme HMG CoA reductase.

B)In vivo

a) Action in genetic models

Mutating in colonies of laboratory animals and different

sensitivity to dietary regimens have developed animal models with insulin-independent diabetes and hyperlipidemia associated with obesity, as well as the possibility of insulin resistance. Genetic models, such as db/db and ob/ob (Diabetes, (1982) 31(1): 1-6) mice and "zucker" fa/fa rats, have been developed in numerous laboratories to elucidate the pathophysiology of the disease and to test the action of new antidiabetic drugs (Diabetes,

(1983) 32:830-838; Annu. Rep. Sanquo Res. Lab. (1994). 46:1-57). Homozygous animals, C57 BL/KsJ-db/db mice, developed by the Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85:962-967), while heterozygotes are lean and normoglycemic. In the db/db model, the mouse progressively develops insulinopenia with aging, a feature commonly seen in the later stages of human type II diabetes, when blood sugar levels are not satisfactorily controlled. The state of the pancreas and its course vary by model. Since this model resembles type II diabetes mellitus, compounds of the present invention will be tested for blood sugar and triglyceride lowering activities.

The experiment used male C57BL/KsJ-db/db mice, aged 8 to 14 weeks, with a body weight range of 35 to 60 grams, raised in the animal house of Dr. Reddy Research Foundation (DRF). Mice were fed standard chow (National Institute of Nutrition (NIN), Hyderabad, India) and acidified water ad libitum. Animals that have more than 350 mg/dl blood sugar will be used for testing. The number of animals in each group was 4.

The test compounds are suspended on 0.25% carboxymethyl cellulose and administered to the test group in a dose of 0.1 mg to 30 mg/kg via oral administration, daily for 6 days. The control group received the vehicle (dose 10 ml/kg). On day 6, blood samples will be collected one hour after administration of the test compound / vehicle for testing biological activity.

Random blood sugar and triglyceride levels can be measured by collecting blood (100 uJ) via the orbital sinus using a heparinized capillary, into tubes containing EDTA and centrifuged to obtain plasma. Plasma glucose and triglyceride levels can be measured spectrophotometrically, individually, using glucose oxidase and glycerol-3-PO4 oxidase/peroxidase enzyme methods (Dr. Redd's Lab. Diagnostic Division Kits, Hyderabad, India).

The blood sugar and triglyceride lowering activities of the test compounds were calculated according to the formula.

In the above test, no side effects were observed with any of the mentioned compounds of the invention.

Ob/ob mice, 5 weeks of age, were obtained from Bomholtgard, Denmark and used at 8 weeks of age. Zucker fa/fa fattened rats were obtained from IffaCredo, France at 10 weeks of age and used at 13 weeks of age. The animals were kept at 25 ± 1°C, under a 12-hour light/dark cycle. Animals were provided with standard laboratory food (NIN, Hyderabad, India) and water, ad libitum (Fujivvara, T., Yoshioka, S., Yoshioka, I., Ushivama, I and Horikoshi, H. Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes. 1988. 37:1549-1558).

The test compounds were administered at a dose of 0.1 to 30 mg/kg for 9 days. Control animals received vehicle (0.25% carboxymethylcellulose, dose 10 ml/kg) via oral administration.

Blood samples were collected in a saturated state, 1 hour after drug administration on days 0 and 9 of treatment. Blood was collected from the retro-orbital sinus through a heparinized capillary into EDTA tubes. After centrifugation, plasma samples were separated for determination of: glucose, free fatty acids, total cholesterol and insulin. Measurements of plasma triglycerides, glucose and total cholesterol were performed using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India). Plasma free fatty acid was measured using a commercial kit from Boehringer Mannheim, Germany. Plasma insulin was measured using an RIA kit (BARC, India). The investigated reduction of various parameters was calculated according to the formula, which is given below.

An oral glucose tolerance test was performed on ob/ob mice after 9 days of treatment. Mice were fasted for 5 hours and then given 3 gm/kg glucose orally. Blood samples for determination of plasma glucose levels were collected at 0, 15, 30, 60 and 120 minutes.

Experimental results for db/db mice, ob/ob mice, Zucker fa/fa rats indicate that the new compounds of this invention also have therapeutic utility for the prophylaxis or regular treatment of diabetes, obesity, cardiovascular disorders, such as hypertension, hyperlipidemia and other diseases; since it is known from the literature that such diseases are interconnected with each other.

The level of glucose and triglycerides in the blood were also reduced at doses higher than 10 mg/kg. Normally, the decrease is dose-dependent and a plateau occurs at a certain dose.

b) Plasma triglyceride and cholesterol lowering activity in models

hypercholesterolemic rats

Male Sprague Dawley rats (NIN stored) were bred in the DRF animal house. The animals were kept under a 12-hour light/dark cycle at 25±1°C. Rats with a body weight of 180-200 grams were used for the experiment. Animals were rendered hypercholesterolemic by feeding 2% cholesterol and 1% sodium cholate mixed with standard laboratory chow [National Institute of Nutrition (NIN), Hyderabad, India] for 6 days. During the period of the experiment, the animals were on the same diet (Petit, D., Bonnefis, M.T., Rey, C and Infante, R. Effects of ciprofibrate on liver lipids and lipoprotein synthesis in normo-and hyperlipidemic rats. Atherosclerosis. 1988. 74:215-225).

Test compounds can be administered orally at a dose of 0.1 to 30 mg/kg/day for 3 days. The control group was treated with the vehicle itself (0.25% carboxymethylcellulose; dose 10 ml/kg).

Blood samples were collected in a saturated state, 1 hour after drug administration, on days 0 and 3 of compound treatment. Blood was taken from the retro-orbital sinus through a heparinized capillary into EDTA tubes. After centrifugation, plasma samples are separated for determination of total cholesterol, HDL and triglycerides. Measurements of plasma triglycerides, total cholesterol, and HDL were performed using commercial kits (Dr. Redd's Laboratory, Diagnostic Division, India). LDL and VLDL cholesterol were calculated from data obtained for total cholesterol, HDL and triglycerides. The reduction of various tested parameters was calculated according to the formula.

c) The activity of lowering plasma triglycerides and total cholesterol in

Swiss albino mice and guinea pigs

Male Swiss albino mice (SAM) and male guinea pigs (Guinea pigs) were obtained from NIN and kept in the DRF animal house. All these animals were kept under a 12-hour light/dark cycle, at 25±1°C. The animals were provided with standard laboratory chow (NIN, Hyderabad, India) and water, ad libitum. SAM of 20-25 g body weight range and guinea pigs of 500-700 g body weight range were used (Oliver, P., Plancke, M.O., Marzin, D., Clavev, V., Sauzieres, J and Fruchart, J.C. Effects of fenofibrate, gemfibrozil and nicotinic acid on plasma lipoprotein levels in normal and hyperlipidemic mice. Atherosclerosis 1988. 70:107-114).

The test compounds were administered orally to Swiss albino mice in a dose of 0.3 to 30 mg/kg/day, during 6 days. Control mice were treated with vehicle (0.25% carboxymethylcellulose; dose 10 ml/kg). Test compounds were administered orally to guinea pigs in a dose of 0.3 to 30 mg/kg/day, during 6 days. Control animals were treated with vehicle (0.25% carboxymethylcellulose; dose 5 ml/kg).

Blood samples were collected in a saturated state, 1 hour after drug administration, on days 0 and 6 of compound treatment. Blood was taken from the retro-orbital sinus through a heparinized capillary into EDTA tubes. After centrifugation, plasma samples were separated for determination of triglycerides and total cholesterol (Vieland, O. Methods of Enzymatic analvsis. Bergermever, H.O., Ed., 1963. 211-214; Trinder, P. Ann. Clin. Biochem. 1969. 6:24-27). Measurement of plasma triglycerides was done using commercial kits (Dr. Redd's Diagnostic Division, Hyderabad, India).

d) Effect of body weight reduction on cholesterol-fed hamsters: Male Syrian hamsters were obtained from NIN, Hyderabad,

India. The animals were kept in the DRF animal house under a 12-h light/dark cycle, at 25±1°C with free access to food and water. Animals were fed standard laboratory chow (NIN) with 1% cholesterol from the start of treatment.

Test compounds can be administered orally at a dose of 1 to 30 mg/kg/day for 15 days. A control group of animals was treated with vehicle (Mili Q water, dose 10 ml/kg/day). Body weights are measured every third day.

Calculation formula:

1. The percentage reduction of sugar / triglycerides / total cholesterol in the blood will be calculated according to the formula:

OC = control group value on day zero

OT = treated group value on day zero

TC = value of the control group on the test day

TT = value of the treated group on the test day

2. LDL and VLDL cholesterol levels are calculated according to the formula:

Claims (16)

1. New compounds of formula (I) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates in which R1,R<2>and R<3>,R<4>when attached to a carbon atom can be the same or different and represent: hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups, selected from: alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroarlkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkyl, alkoxyalkyl, aryloxyalkyl, aralkyl, alkylthio, thioalkyl, Alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives or sulfonic acid or its derivatives; one or both of R<3> and R<4> may represent an oxo or thioxo group when attached to a carbon atom; R<3> and R<4>, when attached to a nitrogen atom, represent: hydrogen, hydroxy, formyl or substituted or unsubstituted groups, selected from: alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkyl, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, araloxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; W represents NR<12>, -C(=O)-(CR<1>0R11)o-NR<12>, -O-aryl-(CR,<0>R<11>)o-NR<12>, where R12 represents hydrogen or a substituted or unsubstituted group selected from alkyl, aryl or aralkyl groups; o is an integer in the range of 0-6; R10 and R<11> can be the same or different, and represent hydrogen or an unsubstituted or substituted group selected from: alkyl, alkoxy, aryl, or aralkyl groups; Ar represents a substituted or unsubstituted divalent single or fused aromatic or heterocyclic group selected from divalent phenylene, naphthylene, pyrrolyl, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl or benzoxazolyl groups; R<5> represents: a hydrogen atom, hydroxy, alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group or forms a bond together with the neighboring group R<6>; R<6> represents: hydrogen, hydroxy, alkoxy, halogen, alkyl group, acyl, substituted or unsubstituted aralkyl or R<6> forms a bond with R<5>; R<7>represents hydrogen or substituted or unsubstituted groups selected from: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl and heteroaralkyl groups; R<8>represents hydrogen or substituted or unsubstituted groups selected from: an alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl group; Y represents oxygen, sulfur or NR<9>, where R<9> represents: hydrogen or substituted or unsubstituted groups, selected from: alkyl, aryl, hydroxyalkyl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl group or NR<9> represents a chiral amine chiral amine alcohols, obtained from a chiral amino acid; R<8> and R<9> together may form a substituted or unsubstituted 5- or 6-membered cyclic structure containing carbon atoms and which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; m and n are integers in the range 0-6. 2. A compound, as in claim 1, characterized in that the substituents on R<1> to R<4> are selected from: halogen, hydroxyl, nitro, thio, or unsubstituted or unsubstituted groups selected from: alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, aryloxy, aralkyl, alkoxyalkyl, aryloxyalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, alkoxycarbonyl, alkylamino, alkylthio group, carboxylic acid or its derivatives or sulfonic acid or its derivatives; Substituents on R<7> are selected from: alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, aralkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, aralkyl, alkoxycarbonyl, alkylamino, alkoxyalkyl, aryloxyalkyl, alkylthio, thioalkyl, carboxylic acid or its derivatives or sulfonic acid or its derivatives. 3. A compound, as in claim 1, characterized in that R<1>, R<2> and R<3>, R<4> when attached to a carbon atom are the same or different and represent: hydrogen, halogen or alkyl; one or both of R<3> and R<4> represent an oxo or thioxo group when attached to a carbon atom; R<3> and R<4> when attached to a nitrogen atom represent hydrogen or alkyl; R<5>represents a hydrogen atom or forms a bond together with an adjacent group R<6>; R<6>represents hydrogen or forms a bond together with R<5>; R<7> represents hydrogen or substituted or unsubstituted alkyl, aryl or aralkyl; R<8> represents hydrogen or a substituted or unsubstituted group selected from: alkyl, aryl or aralkyl; m and n are integers in the range 0-2. 4. A compound, as in claims 1-3, selected from: (±) ethyl 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (+) ethyl 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (-) ethyl 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (±) 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (-) S-^S^S^-dihydro^H-benzofbJIl^loxazine^-ylJpropylaminoJphenyl]^-ethoxypropanoic acid or its salts; (±) ethyl 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate; (+) ethyl 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate; (-) ethyl 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino}phenyl]-2-ethoxypropanoate; (±) 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethyl-amino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethyl-amino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-N-heptyl-N-{2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethyl-amino}phenyl]-2-ethoxypropanoic acid or its salts; (±) methyl 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate; (+) methyl 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate; (-) methyl 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxoethyl)aminomethyl}phenyl]propanoate; (±) 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxo-ethyl)aminomethyl}phenyl]propanoic acid or its salts; (+) 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxo-ethyl)aminomethyl}phenyl]propanoic acid or its salts; (-) 2-ethoxy-3-[4-{N-heptyl-N-(2-(3,4-dihydro-2H-benzo[b]oxazin-4-yl)-2-oxo-ethyl)aminomethyl}phenyl]propanoic acid or its salts; (±) methyl 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentyl-amino}phenyl]-2-ethoxypropanoate; (+) methyl 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentyl-amino}phenyl]-2-ethoxypropanoate; (-) methyl 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentyl-amino}phenyl]-2-ethoxypropanoate; (±) 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-{5-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-5-oxopentylamino}phenyl]-2-ethoxypropanoic acid or its salts; (±) methyl 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (+) methyl 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (-) methyl 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (±) 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamine ethoxypropanoic acid or its salts; (+) 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[3-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (±) methyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (+) methyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (-) methyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (±) 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (±) methyl 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate; (+) methyl 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate; (-) methyl 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate; (±) methyl 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate; (+) methyl 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate; (-) methyl 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoate; (±) 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid or its salts; (+) 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid or its salts; (-) 2-ethoxy-3-[4-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid or its salts; (±) 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid or its salts; (+) 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid or its salts; (-) 2-ethoxy-3-[3-{4-(3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyloxy)benzyl}aminophenyl]propanoic acid or its salts; (±) ethyl 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenylpropanoate; (+) ethyl 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenylpropanoate; (-) ethyl 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl)propylamino}phenylpropanoate; (±) 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4-thiazin-4-yl)propylamino}phenyl]propanoic acid or its salts; (+) 2-Ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[bJ[1,4]thiazin-4-yl)propylamino}phenyl]propanoic acid or its salts; (-) 2-Ethoethyl-3-[4-{3-(3,4-dihydro propanoic acid or its salts; (±) ethyl 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino} phenylpropanoate; (+) ethyl 2-Ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethylamino} phenylpropanoate; 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4oxazin-4-yl)ethylamino}phenyl] propanoic acid or its salts; 2-ethoxy-3-[4-{2-(314-dihydro-2H-benzo[b[1,4]oxazin-4-yl)ethylamino}phenyl]propanoic acid or its salts; (-) 2-ethoxy-3-[4-{2-(3,4-dihydro-2H-benzo[b][1,4oxazin-4-yl)ethylamino}phenyl]propanoic acid or its salts; (±) methyl 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[bJ[1,4]oxazin-4-yl)ethoxy} phenylaminomethylphenylpropanoate; (+) methyl 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[bJ[1,4]oxazin-4-yl)ethoxy} phenylaminomethylphenylpropanoate; (-) methyl 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4oxazin-4-yl)ethoxy}phenylaminomethylphenylpropanoate; (±) 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)ethoxy}phenyl-aminomethylphenylpropanoic acid or its salts; (+) 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[bJ[1,4]oxazin-4-yl)ethoxy}phenyl-aminomethyl-phenyl-propanoic acid or its salts; (-) 2-ethoxy-3-[4-[4-{2-(3,4-dihydro-2H-benzo[b][1,4oxazin-4-yl)ethoxy}phenyl-aminomethylphenyl]propanoic acid or its salts; (±) ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (+) ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (-) ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (±) ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate; (+) ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate; (-) ethyl 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate; (±) 3-[4-{3-(74fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid or its salts; (+) 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid or its salts; (-) 3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid or its salts; (±) ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (+) ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (-) ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (±) 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoic acid or its salts; (±) ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (+) ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (-) ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoate; (±) 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (±) ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (+) ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (-) ethyl 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (±) 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid or its salts; (+) 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid or its salts; (-) 3-[4-{3-(2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4H1)propylamino}phenyl]-2-methoxypropanoic acid or its salts; (±) ethyl 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (+) ethyl 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (-) ethyl 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-ethoxypropanoate; (±) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (+) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (-) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-ethoxypropanoic acid or its salts; (±) ethyl (25)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate; (+) ethyl (2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate; (-) ethyl (2S)-3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoate; (±) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid and its salts; (+) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid and its salts; (-) 3-[4-{3-(2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoic acid and its salts; (±) ethyl 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoate; (+) ethyl 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoate; (-) ethyl 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoate; (±) 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoic acid and its salts; (+) 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoic acid and its salts; (-) 2-isopropoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoic acid and its salts; (±) ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (+) ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (-) ethyl 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]-2-methoxypropanoate; (±) 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoic acid and its salts; (+) 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoic acid and its salts; (-) 3-[4-{3-(2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propyl-amino}phenyl]-2-methoxypropanoic acid and its salts; [2S,N(1^]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b] [1,4]oxazin-4-yl)propylamino}phenyl]propanamide; [2/9,N(1A^]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dih [1,4]oxazin-4-yl)propylamino}phenyl]propanamide; 25,N(1/^]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide; [2A7,N(1/i)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanamide; [2S,N(1 H ]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b] [1,4]oxazin-4-yl)propylamino}phenyl]propanamide hydrochloride salt; [2A?,N(1/i)]-N-(2-hydroxy-1-phenylethyl)-2-ethoxy-3-[4-{3-(3l4-dihydro-2H-benzo[b] [1,4]oxazin-4-yl)propylamino}phenyl]propanamide hydrochloride salt; 5. A compound, as in claim 1, characterized in that it is a pharmaceutically acceptable salt of: Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; N,N'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methy Iglu kamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N,N'-diphenylethylenediamine, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, spermidine; alkylphenylamine, glycinol, phenyl glycinol; glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; amino acids that do not occur in nature; D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from: nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts; sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, cypherates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates; ammonium or substituted ammonium salts or aluminum salts. 6. Procedure for making compounds of formula (I) as defined in claim 1, comprising a. reaction of compounds of formula (lila) in which L<1> is a leaving group and all other symbols are as defined above with a compound of formula (lllb) wherein W represents NR<12> or -O-aryl-(CR<10>R<11>)o-NR<12> and all other symbols are as defined above to obtain a compound of formula (I), defined above; or b. the reaction of a compound of formula (lila) in which all symbols are defined above, with a compound of formula (llld) wherein L<1> is a leaving group and W represents NR<12> or -O-aryl-(CR10R1<1>)o-NR<12> and all other symbols are as defined above to produce a compound of formula (I) as defined above; c. reaction of compounds of the formula (lila) where WV represents NR<12> or -O-aryl-(CR<10>R11)o-NR<12> and all other symbols are as defined above with a compound of formula (lllf) where R < 13> represents (C 1 -C 4 alkyl and all other symbols are as defined above to obtain a compound of formula (I) as defined above. and optionally, by converting the compound of formula (I) obtained in any of the processes described above into pharmaceutically acceptable salts or pharmaceutically acceptable solvates; which represents a compound of formula (I), in which R<5> and R<6> together represent a bond and Y represents an oxygen atom and all other symbols are as defined above, produced according to any of the processes, as in claim 5, to obtain a compound of formula (I) in which R<5> and R<6>, each represent a hydrogen atom and all other symbols are as previously defined; e. reaction of compounds of the formula (lila) where W represents NR<12> or -O-aryl-(CR<1>0R11)o-NR<12> and all other symbols are as defined above with the compound of formula (IVb) wherein R<5>represents hydrogen and any other symbols as defined above to provide a compound of formula (I) as defined above; or f. the reaction of a compound of formula (lllg) in which L<1> is a leaving group, n and o are integers in the range 0-6 and all other symbols are as defined above with a compound of formula (lllb) wherein W represents NR<12> and all other symbols are as defined above to give a compound of formula (I) wherein W represents -C(=O)-(CR<10>R<11>)0-NR<12> and all other symbols are as defined above; Mr. reaction of compounds of the formula (lily) wherein n and p are integers in the range 0-6, G<1>represents NH2 and all other symbols are as defined above with a compound of formula (lllh) wherein q is an integer in the range of 0-6, G<2>represents CHO or NH2 and all other symbols are as defined above to give a compound of formula (I) wherein W is -O-aryl-(CR<1>0R11)o-NR1<2>and all other symbols are as previously defined; or h. reaction of compounds of formula (I) wherein all symbols are as defined above and Y represents oxygen or YR<8>represents a halogen atom or COYR<8>represents a mixed anhydride group and all other symbols are as defined above with an amine of the formula NHR<8>R<9>wherein R<8>and R<9> are as defined above and optional; ii. separation of compounds of formula (I), obtained above in stereoisomers; and. hydrolysis of compounds of formula (I) in which R<8> represents unsubstituted or substituted groups, selected from: alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl group and all other symbols are as defined above in the compound of formula (I) in which R<8> represents hydrogen. optionally converting the compound of formula (I) obtained by any of the methods described above into pharmaceutically acceptable salts or pharmaceutically acceptable solvates. 7. New intermediate formula (llld) their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, in which L<1> represents a leaving group, such as a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate or hydroxy; W represents NR<12>, -O-C(=O)-(CR<1>0R11)o-NR<12>, -O-aryl-(CR10R1<1>)0-NR<12>, where R<12> represents hydrogen, or a substituted or unsubstituted group selected from: alkyl, aryl or aralkyl group; o is an integer in the range 0-4; R<10> and R11 may be the same or different and represent hydrogen or an unsubstituted or unsubstituted group selected from: alkyl, alkoxy, aryl or aralkyl groups; Ar represents a substituted or unsubstituted divalent single or fused aromatic or heterocyclic group; R<5> represents a hydrogen atom, hydroxy, alkoxy, halogen, alkyl, substituted or unsubstituted aralkyl group or forms a bond together with the neighboring group R<6>; R<6> represents hydrogen, hydroxy, alkoxy, halogen, lower alkyl group, acyl, substituted or unsubstituted aralkyl or R<6> forms a bond together with R<5>; R<7> can be hydrogen or substituted or unsubstituted groups selected from: alkyl, cycloalkyl, aryl, aralkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl, heteroaralkyl group; R<8> can be hydrogen or substituted or unsubstituted groups selected from alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl or heteroaralkyl groups; Y represents oxygen, sulfur or NR<9>, where R<9> represents hydrogen or substituted or unsubstituted groups selected from: alkyl, aryl, hydroxyalkyl, aralkyl heterocyclyl, heteroaryl or heteroaralkyl group; R<8> and R<9>, together, may form a substituted or unsubstituted 5- or 6-membered cyclic structure, containing carbon atoms, which may optionally contain one or more heteroatoms selected from oxygen, sulfur or nitrogen; m and n integers in the range 0-6. 8. New intermediate formula (lllg) their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, in which R<1>, R2 and R<3>, R<4>, when attached to a carbon atom, can be the same or different and represent: hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups, selected from: alkyl, cycloalkyl, alkoxy, cycloalkyl, aryl, aryloxy, aralkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, araloxycarbonyl, alkoxyalkyl, aryloxyalkyl, armethoxyalkyl, alkylthio, thioalkyl, Alkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R<3> and R<4> may represent an oxo or thioxo group when attached to a carbon atom; R<3> and R<4>, when attached to a nitrogen atom, represent: hydrogen, hydroxy, formyl or optionally substituted groups selected from: alkyl, cycloalkyl, alkoxy, cycloalkyloxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkyl, heteroaryloxy, heteroaralkoxy, alkoxycarbonyl, aryloxycarbonyl, araloxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkyl, alkylthio, thioalkyl groups, carboxylic acid derivatives or sulfonic acid derivatives; X represents a heteroatom selected from oxygen or sulfur; R<10> and R<11> can be the same or different and represent hydrogen or a substituted or unsubstituted group, selected from: alkyl, alkoxy, aryl or aralkyl groups; L<1>is a leaving group, such as: a halogen atom, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, p-nitrobenzenesulfonate, acetate, sulfate, phosphate or hydroxy; n and o are integers in the range 0-6. 9. New formula intermediate (lily) their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, in which R\ R<2> and R<3>, R\ when attached to a carbon atom, can be the same or different and represent: hydrogen, halogen, hydroxy, nitro, cyano, formyl or substituted or unsubstituted groups, selected from: alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroarlkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkyl, alkoxyalkyl, aryloxyalkyl, aralkyl, alkylthio, thioalkyl, Alkoxy-carbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; one or both of R<3> and R<4> may represent an oxo or thioxo group when attached to a carbon atom; R<3> and R<4>, when attached to a nitrogen atom, represent: hydrogen, hydroxy, formyl or optionally substituted groups selected from: alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, aminoalkyl, aryloxy, aralkyl, heteroaryloxy, heteroarloxy, alkoxycarbonyl, aryloxycarbonyl, aralkyl, aryloxyalkyl, aralkyl, alkylthio, thioalkyl group, carboxylic acid derivative or sulfonic acid derivative; X represents a heteroatom selected from oxygen or sulfur; R10 and R<11> can be the same or different and represent hydrogen or a substituted or unsubstituted group selected from: alkyl, alkoxy, aryl or aralkyl groups; G<1> is CHO or NH2 and n and p are integers in the range 0-6. 10. A pharmaceutical composition comprising a compound of formula (I) as defined in claims 1-5 and a pharmaceutically acceptable carrier, diluent, carrier or solvate. 11. Pharmaceutical mixture, which includes a compound of formula (I), as defined in claims 1-5 and an inhibitor of HMG CoA reductase; fibrate; nicotinic acid; cholestyramine; cholestipol; probucol or a combination thereof and a pharmaceutically acceptable carrier, diluent, carrier or solvate. 12. Pharmaceutical mixture, as in claims 10 or 11, characterized in that it is in the form of tablets, capsules, powder, syrup, solution or suspension. 13. A method for the prevention or treatment of hyperlipemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases in which insulin resistance is the main pathophysiological mechanism, and which includes the administration of the compound of formula (I), as defined in patent claims 1-5 or a pharmaceutical mixture, as in patent claims 10 or 11 to a patient who needs it. 14. The method, as in claim 13, characterized in that the disease is: type II diabetes, impaired glucose tolerance, dyslipidemia, disorders related to Syndrome X, including hypertension, obesity, insulin resistance, coronary artery disease and other, cardiovascular disorders; kidney disease, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy, disorders associated with endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), dementia, complications of diabetes, inflammatory bowel disease, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer or osteoporosis or as anti-inflammatory agents. 15. The method, as in patent claim 13, characterized in that it is for the treatment and/or prophylaxis of disorders associated with Syndrome X, which includes the administration of PPARa and/or PPARy agonists of formula (I), as defined in patent claims 1-5 or pharmaceutical mixtures, as in patent claims 10 or 11, to a patient who needs it. 16. A method for lowering total cholesterol, body weight, plasma glucose, triglycerides, LDL, VLDL or free fatty acids or increasing HDL in plasma, which includes the administration of a compound of formula (I), as defined in patent claims 1-5 or a pharmaceutical mixture, as in patent claims 10 or 11, to a patient who needs it.