HK1084373A

HK1084373A - New compounds and their use in medicine, process for their preparation and pharmaceutical compositions containing them

Info

Publication number: HK1084373A
Application number: HK06104522.3A
Authority: HK
Inventors: D．布尼亚; S.K.达斯; G．R．迈德哈万; J．伊克巴勒; R．沙克拉巴蒂; R．K．维克拉马蒂斯彦
Original assignee: 雷迪实验室有限公司
Priority date: 2001-12-03
Filing date: 2002-12-02
Publication date: 2006-07-28

Description

Novel compounds and their use in medicine, processes for their preparation and pharmaceutical compositions containing them

Technical Field

The present invention relates to novel anti-diabetic, hypolipidemic, anti-obesity and hypocholesterolemic compounds of formula (I), their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.

More precisely, the invention relates to compounds of general formula (I), which are mainly PPAR-alpha agonists, their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them

Wherein R is¹Represents hydrogen, hydroxy, halogen, straight or branched chain (C)₁-C₁₂) Alkyl, straight or branched chain (C)₁-C₁₂) Alkoxy radicalSubstituted or unsubstituted arylalkyl or a group R adjacent thereto²Together form a key;

R²represents hydrogen, halogen, straight or branched chain (C)₁-C₁₂) Alkyl, straight or branched chain (C)₁-C₁₂) Alkoxy group, (C)₁-C₁₂) Alkanoyl, aroyl, arylalkanoyl, substituted or unsubstituted arylalkyl or with R¹Together form a key;

R³represents a hydrogen atom or a substituted or unsubstituted group selected from linear or branched (C)₁-C₁₂) Alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, (C)₁-C₁₂) Alkanoyl, aroyl, arylalkyl, arylalkanoyl, heterocyclyl, heteroaryl, heteroarylalkyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, or arylaminocarbonyl;

R⁴represents hydrogen or a substituted or unsubstituted radical selected from linear or branched (C)₁-C₁₂) Alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, or heteroarylalkyl;

y represents oxygen or NR⁷Or N (R)⁷) O, wherein R⁷Represents hydrogen or a substituted or unsubstituted radical selected from linear or branched (C)₁-C₁₂) Alkyl, aryl, arylalkyl, hydroxyalkyl, alkanoyl, aroyl, arylalkanoyl, heterocyclyl, heteroaryl, heteroarylalkyl, alkoxycarbonyl or arylalkoxycarbonyl;

R⁴and R⁷Together may form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms and one nitrogen atom, and may optionally contain one or more additional heteroatoms selected from oxygen, sulfur or nitrogen;

R⁵represents hydrogen or a substituted or unsubstituted group selected from alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, arylAlkyl, aroyl or aralkanoyl;

ar represents a substituted or unsubstituted group selected from divalent phenylene, naphthylene, pyridyl, quinolyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl, and the like;

x represents-C (═ O) -, -C (═ S) -O-, -C (═ O) -S-, -O- (CH) -, -O₂)_d-、-NH-(CH₂)_d-、-O-C(＝O)-、-C(O)CH₂-、-CR^a＝CR^b-CH₂-、-CR^a＝CR^b-CO-, wherein R^aAnd R^bMay be the same or different and represents hydrogen or (C)₁-C₆) Alkyl, d is an integer from 1 to 4, or X represents a bond;

R⁶represents a substituted or unsubstituted group selected from the group consisting of aryloxycarbonyl, arylalkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO₂R⁸、-OCONR⁸R⁹、NR⁸COOR⁹、-NR⁸COR⁹、-NR⁸SO₂R⁹、NR⁸CONR⁹R¹⁰、-NR⁸CSNR⁸R⁹、-SO₂R⁸、-SOR⁸、-SR⁸、-SO₂NR⁸R⁹、-SO₂OR⁸、-COOR⁹、-COR⁹or-CONR⁸R⁹Wherein R is⁸、R⁹And R¹⁰May be the same or different and independently represent hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; r⁸And R⁹When located on a nitrogen atom, together may form 5 or 5 containing carbon atoms and one or more heteroatoms selected from oxygen, sulfur or nitrogenA 6-membered cyclic structure; when R is¹³In the third position of the phenyl ring and not representing hydrogen, R⁶Is hydrogen;

R¹³represents hydrogen, halogen, nitro, cyano, amino, haloalkyl, hydroxyl or a substituted or unsubstituted radical selected from linear or branched (C)₁-C₁₂) Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, alkoxy, monoalkylamino, dialkylamino, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, aryloxy, arylalkoxy, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO₂R⁸、-OCONR⁸R⁹、NR⁸COOR⁹、-NR⁸COR⁹、-NR⁸R⁹、-NR⁸SO₂R⁹、NR⁸CONR⁹R¹⁰、-NR⁸CSNR⁸R⁹、-SO₂R⁸、-SOR⁸、-SR⁸、-SO₂NR⁸R⁹、-SO₂OR⁸、-COOR⁹、-COR⁹、-CONR⁸R⁹Wherein R is⁸、R⁹And R¹⁰May be the same or different and independently represent hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; r⁸And R⁹When located on a nitrogen atom, together may form a 5 or 6 membered cyclic structure containing carbon atoms and one or more heteroatoms selected from oxygen, sulfur or nitrogen;

m is an integer of 0 to 6, and n is an integer of 0 to 6.

The invention also relates to a preparation method of the compounds, the analogues, the derivatives, the tautomers, the stereoisomers, the polymorphs, the pharmaceutically acceptable salts, the pharmaceutically acceptable solvates and the compositions containing the compounds.

The invention also relates to novel intermediates, to a process for their preparation, to their use in the preparation of compounds of formula (I) and to their use as antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds.

The compounds of the present invention lower plasma glucose, triglycerides, insulin, lower Total Cholesterol (TC), increase High Density Lipoprotein (HDL), decrease Low Density Lipoprotein (LDL), which has beneficial effects on coronary heart disease and atherosclerosis.

The compounds of general formula (I) are useful for reducing body weight, for the treatment and/or prevention of diseases such as atherosclerosis, stroke, peripheral vascular disease and related disorders. These compounds are useful for treating hyperlipidemia, hyperglycemia, hypercholesterolemia, and lowering atherogenic lipoproteins, VLDL (very low density lipoprotein) and LDL. The compounds of the present invention can be used to treat certain renal diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. The compounds of general formula (I) may also be useful for the treatment and/or prevention of leptin resistance, impaired glucose tolerance, disorders related to syndrome X, such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders. These compounds may also be useful as aldose reductase inhibitors, for improving cognitive function in dementia, for treating diabetic complications, disorders involving endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), inflammatory bowel disease, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, eating disorders, inflammation, and for the treatment of cancer. The compounds of the invention may also be used in combination/concomitant with one or more HMG CoA reductase inhibitors; cholesterol absorption inhibitors; anti-obesity agents; a therapeutic agent for lipoprotein disorders; a hypoglycemic agent; insulin; a biguanide; a sulfonylurea; a thiazolidinedione; dual PPAR alpha and gamma agonists or mixtures thereof.

Background

Atherosclerosis and other peripheral vascular diseases affect the quality of life of millions of people. Therefore, considerable attention has been directed to understanding the etiology of hypercholesterolemia and hyperlipidemia and the development of effective therapeutic strategies.

Hypercholesterolaemia has been defined as plasma cholesterol levels exceeding any defined value, also referred to as "normal" levels. Recently, it has been accepted that "ideal" plasma cholesterol levels are much lower than "normal" cholesterol levels in the average population, and as cholesterol levels rise above "optimal" (or "ideal") values, the risk of Coronary Artery Disease (CAD) also increases. There is clearly a clear causal relationship between hypercholesterolemia and CAD, particularly for individuals with multiple risk factors. Most cholesterol exists in esterified forms of a variety of lipoproteins, such as Low Density Lipoprotein (LDL), medium density lipoprotein (IDL), High Density Lipoprotein (HDL), and Very Low Density Lipoprotein (VLDL). Studies have clearly shown that there is an inverse correlation between CAD and atherosclerosis and serum HDL-cholesterol concentration (Stampfer et al, n.engl.j.med., 325(1991), 373-381), and as levels of LDL and VLDL increase, the risk of CAD also increases.

In CAD, "fatty streaks" are commonly seen in the carotid, coronary, and cerebral arteries, which are primarily free and esterified cholesterol. Miller et al (Br. Med. J., 282(1981), 1741-1744) have shown that increased HDL-particles can reduce the number of stenotic sites in human coronary arteries, and that high levels of HDL-cholesterol can defend against the progression of atherosclerosis. Picardo et al, Arteriosclerosis 6(1986)434-441 have indicated that HDL is capable of removing cholesterol from cells in vitro experiments. They suggest that HDL can exclude excess free cholesterol from tissues and transfer to the liver, which is called reverse cholesterol transport (Macikinnon et al, j.biol.chem.261(1986), 2548-2552). Thus, agents that increase HDL cholesterol would be of therapeutic interest for the treatment of hypercholesterolemia and Coronary Heart Disease (CHD).

Obesity is a disease that is very common in the affluent society and developing world, and is a major cause of morbidity and mortality. It is a state of excess body fat accumulation. The cause of obesity is unclear. It is believed to be of genetic origin or facilitated by interactions between the genotype and the environment. Regardless of the cause, the result is fat deposition caused by an imbalance between energy intake and energy expenditure. Diet, exercise and appetite suppression have become part of the treatment of obesity. Effective therapy is needed to combat this disease because it can cause coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis, fertility decline and many other psychological and social problems.

Diabetes and/or insulin resistance is another disease that severely affects the quality of a large world population. Insulin resistance is the diminished ability of insulin to exert its biological effects over a wide range of concentrations. In insulin resistance, the body secretes abnormally large amounts of insulin to compensate for this deficiency; if not, the plasma glucose concentration inevitably rises, leading to the development of diabetes. Diabetes is a common problem in developed countries and is associated with a number of abnormalities, including obesity, hypertension, hyperlipidemia (j. clin. invest, 75(1985) 809-. It is now increasingly recognized that insulin resistance and associated hyperinsulinemia play a contributing role in obesity, hypertension, atherosclerosis, and type 2 diabetes. The association of insulin resistance with obesity, hypertension and angina has been described as a syndrome with insulin resistance as the central pathogenic link, syndrome X.

Hyperlipidemia is a major cause of cardiovascular disease (CVD) and other peripheral vascular diseases. High CVD risk involves higher LDL (low density lipoprotein) and VLDL (very low density lipoprotein) seen in hyperlipidemia. In addition to hyperlipidemia, patients with glucose intolerance/insulin resistance have a higher risk of CVD. Numerous studies in the past have shown that lowering plasma triglycerides and total cholesterol, particularly LDL and VLDL, and increasing HDL cholesterol may help prevent cardiovascular disease.

Peroxisome proliferator-activated receptors (PPARs) are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors (Wilson t.m. and Wahli w., curr. opin. chem.biol., 1997, vol.1, 235-241). Three mammalian peroxisome proliferator-activated receptors (PPARs) have been isolated, referred to as PPAR- α, PPAR- γ, and PPAR- δ. These PPARs regulate the expression of target genes by binding to DNA sequence elements.

Certain compounds that activate or interact with one or more PPARs have been implicated in the regulation of triglyceride and cholesterol levels in animal models (U.S. patent nos. 5,847,008, 5,859,051 and PCT publications WO 97/28149, WO 99/04815).

There is a wealth of information on the effect of PPAR-alpha agonists on cardiovascular risk, such as fibrates, which are weak PPAR-alpha agonists, correcting atherogenic dyslipidemias. Several angiographic intervention trials have demonstrated that these drugs have a beneficial effect on atherosclerotic lesion progression, with the results of primary and secondary prevention trials showing a reduced incidence of cardiovascular events (Ricote M.and Glass C.K.; trendsin pharmacological sciences; 2001; 22 (9); 441-.

Fibrates are weak PPAR-alpha activators that reduce plasma triglyceride levels while raising HDL-C levels, but nevertheless they are not the drug of choice because of low efficacy, high required doses, myositis and the opposite signs in patients with renal and hepatic insufficiency and pregnant and lactating women.

However, in addition to the conclusive beneficial effects on lipids, the understanding of the role of PPAR- α in different pathophysiological conditions has progressed rapidly. Inflammatory activation of aortic smooth muscle cells is a hallmark of atherosclerosis and increased PPAR- α activity appears to be inhibited (Vamecq J. and Latruffe N; Lancet; 1999; 354; 141-.

Recent evidence suggests a role for the PPAR-alpha receptor in improving insulin sensitivity. It has been demonstrated that PPAR-alpha ligands improve insulin sensitivity and obesity by lowering circulating and muscle lipids in insulin-resistant rodent models, such as obese Zucker rats, high fat-fed mice and sucrose-lard-fed rats. Furthermore, in addition to limited cholesterol availability, lipid lowering activity of statins is also associated with PPAR-alpha receptor communication (cross talk). The insulin sensitivity index has been shown to be increased in some clinical trials using fibrates (Guerre-Millo M, Rounalt C.and Poulan P; Diabetes; 2001; 50; 2809-.

Thus, there is interesting evidence for PPAR-alpha agonists for lipid control, even for insulin resistance according to recent evidence. The limitations of currently available drug therapies are related to the fact that the worldwide rise in lipid abnormalities necessitates the discovery of more potent and safer PPAR-alpha agonists. In an effort to meet this need, as our research work on PPAR agonists (U.S. Pat. Nos. 5,885,997; 6,054,453; 6,265,401; PCT application PCT/IB02/04275) continues, a series of compounds have been synthesized, which have been disclosed for the present invention.

Prior art technique

Several alkyl carboxylic acids, their derivatives and their analogs have been reported to be useful in the treatment of hyperglycemia and hypercholesterolemia. Description of the prior art some of these compounds are summarized below:

i) U.S. Pat. No.5,306,726, WO 91/19702 disclose several 3-aryl-2-hydroxypropionic acid derivatives of the general formulae (IIa) and (IIb) as hypolipidemic and hypoglycemic agents

Examples of these compounds are shown in the formulae (IIc) and (IId)

ii) International publications No. WO 95/03038 and WO 96/04260 disclose compounds of formula (IIe)

Examples of such compounds are shown in formula (IIf)

iii) International publications Nos. WO 94/13650, WO 94/01420 and WO 95/17394 disclose compounds of the general formula (IIg)

A¹-X-(CH₂)_n-O-A²-A³-Y.R² (IIg)

Examples of these compounds are shown in formula (IIh)

iv) International publication No. WO 00/49005 discloses compounds of the general formula (IIi)

Examples of these compounds are shown in formula (IIj)

v) International publication No. WO 94/12181 discloses compounds of the general formula (IIk)

X-Y-Z-Aryl-A-B (IIk)

Or

Examples of these compounds are shown in formula (II1)

vi) International publication No. WO 93/16697 and U.S. Pat. No.5,227,490 disclose compounds of the formula (IIm)

Examples of these compounds are shown in formula (IIn)

vii) International publication No. WO 99/62871 discloses a compound of the general formula (IIo)

Wherein A is in the ortho, meta or para position and represents

Or

Examples of such compounds are shown in formula (IIp)

viii) International publication No. WO 00/64888 discloses compounds of the general formula (IIq)

Examples of these compounds are shown in formula (IIr)

ix) International publication No. WO 99/62872 discloses compounds of formula (IIs)

x) International publication No. WO 00/63153 discloses compounds of formula (IIt)

Examples of these compounds are shown in formula (IIu)

xi) International publication No. WO 01/55085 discloses compounds of formula (IIv)

Examples of such compounds are shown in formula (IIw)

There are few reports of beta-phenyl alpha-hydroxy substituted propionic acid derivatives as synthetic intermediates for target molecules. Description of the prior art some of these compounds are summarized below:

i) european patent application EP 0816316 discloses compounds of formula (va)

The compound of formula (va) is further converted into a 1, 2-ethanediol derivative of formula (vb)

These 1, 2-ethanediol derivatives are useful intermediates for pharmaceuticals and agrochemicals.

ii) Japanese patent application JP 10017540 discloses compounds of the formula (vc)

Further conversion of the compound of formula (vc) to a compound of formula (vd)

Summary of The Invention

The object of the present invention is to provide novel compounds of general formula (I) which have mainly PPAR-alpha agonistic activity, significantly reduced toxicity associated with PPAR-gamma activation, useful for reducing blood glucose, lipid levels, cholesterol, weight, useful for the treatment and/or prevention of diseases involving increased lipid levels, atherosclerosis, coronary artery disease, X-syndrome, impaired glucose tolerance, insulin resistance leading to type 2 diabetes and diabetic complications, for the treatment of diseases in which insulin resistance is the pathophysiological mechanism, for the treatment of hypertension, and have better efficacy, potency and lower toxicity, and we focus on the development of novel compounds effective in the treatment of the above-mentioned diseases. The result of this effort has been to obtain compounds having the general formula (I).

The main object of the present invention is therefore to provide novel alkyl carboxylic acids of general formula (I), their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or mixtures thereof.

Another aspect of the present invention is to provide novel alkyl carboxylic acids, their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or mixtures thereof, which may have PPAR α and/or PPAR γ agonist activity, optionally inhibiting HMG CoA reductase in addition to PPAR α and/or PPAR γ agonist activity.

It is another object of the present invention to provide a process for preparing alkylcarboxylic acids of formula (I), their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.

It is another object of the present invention to provide pharmaceutical compositions comprising alkyl carboxylic acids of formula (I), their analogs, their derivatives, their tautomers, their stereoisomers, their polymorphs, their salts, solvates or mixtures thereof together with suitable carriers, solvents, diluents and other media commonly used in the preparation of such compositions.

It is another object of the present invention to provide novel intermediates, processes for their preparation and the use of these intermediates in a process for preparing alkylcarboxylic acids of formula (I), their derivatives, their analogs, their tautomers, their stereoisomers, and their use as antidiabetic, hypolipidemic, antiobesity and hypocholesterolemic compounds.

Detailed description of the invention

Novel beta-aryl alpha-oxy substituted propionic acids of general formula (I)

Their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein:

wherein R is¹Represents hydrogen, hydroxy, halogen, straight or branched chain (C)₁-C₁₂) Alkyl, straight or branched chain (C)₁-C₁₂) Alkoxy, substituted or unsubstituted arylalkyl or radicals R adjacent thereto²Together form a key;

R²represents hydrogen, halogen, straight or branched chain (C)₁-C₁₂) Alkyl, straight or branched chain (C)₁-C₁₂) Alkoxy group, (C)₁-C₁₂) Alkanoyl, aroyl, arylalkanoyl, substituted or unsubstituted arylalkyl or R²And R¹Together form a key;

R⁴represents hydrogen or a substituted or unsubstituted group selected from linear or branched (C)₁-C₁₂) Alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, or heteroarylalkyl;

y represents oxygen or NR⁷Or N (R)⁷) O, wherein R⁷Represents hydrogen or a substituted or unsubstituted group selected from linear or branched (C)₁-C₁₂) Alkyl, aryl, arylalkyl, hydroxyalkyl, alkanoyl, aroyl, arylalkanoyl, heterocyclyl, heteroaryl, heteroarylalkyl, alkoxycarbonyl or arylalkoxycarbonyl;

R⁸hydrogen or a substituted or unsubstituted group selected from alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aroyl or aralkanoyl;

n and m are integers from 0 to 6;

ar represents a substituted or unsubstituted group selected from divalent phenylene, naphthylene, pyridyl, quinolyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl, and the like; the substituents on the group represented by Ar are selected from linear or branched, optionally halogenated (C)₁-C₆) Alkyl, optionally halogenated (C)₁-C₃) Alkoxy, halogenAcyl radicals, e.g. acetyl, COC₂H₅Butyryl, pentanoyl, propionyl, benzoyl and the like, amino, acylamino, e.g. NHCOCH₃，NHCOC₂H₅，NHCOC₃H₇And NHCOC₆H₅Etc.; thio or carboxylic or sulfonic acids and derivatives thereof. Derivatives of carboxylic and sulfonic acids include amides, chlorides, esters and anhydrides of carboxylic and sulfonic acids.

R⁶represents a substituted or unsubstituted group selected from the group consisting of aryloxycarbonyl, arylalkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO₂R⁸、-OCONR⁸R⁹、NR⁸COOR⁹、-NR⁸COR⁹、-NR⁸SO₂R⁹、NR⁸CONR⁹R¹⁰、-NR⁸CSNR⁸R⁹、-SO₂R⁸、-SOR⁸、-SR⁸、-SO₂NR⁸R⁹、-SO₂OR⁸、-COOR⁹、-COR⁹or-CONR⁸R⁹Wherein R is⁸、R⁹And R¹⁰May be the same or different and independently represent hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; r⁸And R⁹When located on a nitrogen atom, together may form a 5-or 6-membered cyclic junction containing a carbon atom and one or more heteroatoms selected from oxygen, sulfur or nitrogenStructuring; when R is¹³In the third position of the phenyl ring and not representing hydrogen, R⁶Is hydrogen;

R¹³represents hydrogen, halogen, nitro, cyano, amino, haloalkyl, hydroxyl or a substituted or unsubstituted radical selected from linear or branched (C)₁-C₁₂) Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, alkoxy, monoalkylamino, dialkylamino, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, aryloxy, arylalkoxy, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO₂R⁸、-OCONR⁸R⁹、NR⁸COOR⁹、-NR⁸COR⁹、-NR⁸R⁹、-NR⁸SO₂R⁹、NR⁸CONR⁹R¹⁰、-NR⁸CSNR⁸R⁹、-SO₂R⁸、-SOR⁸、-SR⁸、-SO₂NR⁸R⁹、-SO₂OR⁸、-COOR⁹、-COR⁹、-CONR⁸R⁹Wherein R is⁸、R⁹And R¹⁰May be the same or different and independently represent hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; r⁸And R⁹When located on a nitrogen atom, together may form a 5 or 6 membered cyclic structure containing carbon atoms and one or more heteroatoms selected from oxygen, sulfur or nitrogen.

Suitably represented by R¹The groups represented may be selected from hydrogen; a hydroxyl group; halogen; straight or branched chain (C)₁-C₁₂) Alkyl, preferably (C)₁-C₆) Alkyl groups such as methyl, ethyl, propyl, isopropyl or tert-butyl; straight or branched chain (C)₁-C₁₂) Alkoxy, preferably straight-chain or branched (C)₁-C₆) Alkoxy radicals, e.g. methoxy, ethoxy, propoxy, isopropoxyA group, etc.; substituted or unsubstituted arylalkyl, e.g. benzyl, phenethyl, etc., or R¹And R²Together may form a key. The arylalkyl group may be represented by (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy or hydroxy.

Suitably represented by R²The groups represented may be selected from hydrogen; halogen; straight or branched chain (C)₁-C₁₂) Alkyl, preferably (C)₁-C₆) Alkyl groups such as methyl, ethyl, propyl, isopropyl or tert-butyl; straight or branched chain (C)₁-C₁₂) Alkoxy, preferably straight-chain or branched (C)₁-C₆) Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, and the like; (C)₁-C₁₂) Alkanoyl groups such as acetyl, propionyl, butyryl, valeryl and the like; aroyl groups such as benzoyl and the like; arylalkanoyl such as phenylacetyl, phenylpropionyl and the like; substituted or unsubstituted arylalkyl, e.g. benzyl, phenethyl, etc., or R²And R¹Together may form a key. The arylalkyl group may be represented by (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy or hydroxy.

Suitably represented by R³The groups represented may be selected from hydrogen; substituted or unsubstituted, straight or branched (C)₁-C₁₂) Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like; substituted or unsubstituted (C)₁-C₁₂) Alkanoyl radical, preferably (C)₂-C₈) Alkanoyl groups such as acetyl, propionyl, butyryl, valeryl and the like; aroyl, such as benzoyl, and the like, which may be substituted; an arylalkanoyl group such as phenylacetyl, phenylpropionyl and the like, which may be substituted; (C)₃-C₇) Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; (C)₃-C₇) Cycloalkylalkyl groups such as cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, and the like, which may be substituted; (C₃-C₇) Cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like, which may be substituted; aryl groups such as phenyl, naphthyl, and the like, which may be substituted; arylalkyl radicals, e.g. benzyl, phenethyl, C₆H₅CH₂CH₂CH₂Naphthylmethyl and the like, the arylalkyl group may be substituted; a heterocyclic group such as aziridinyl, pyrrolidinyl, piperidinyl and the like, which may be substituted; heteroaryl groups such as pyridyl, thienyl, furyl and the like, which heteroaryl groups may be substituted; heteroarylalkyl such as furylmethyl, pyridylmethyl, oxazolylmethyl, oxazolethyl, and the like, which may be substituted; (C)₁-C₆) Alkoxy (C)₁-C₆) An alkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxypropyl, etc., the alkoxyalkyl group may be substituted; (C)₁-C₆) Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like, which may be substituted; an aryloxycarbonyl group such as a phenoxycarbonyl group, a naphthyloxycarbonyl group and the like, which may be substituted; (C)₁-C₆) Alkylaminocarbonyl groups such as methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group and the like, which may be substituted; arylaminocarbonyl groups such as PhNHCO, naphthylaminocarbonyl group and the like, which may be substituted. From R³The substituents on the group represented may be selected from halogen, hydroxy, cyano, nitro or substituted or unsubstituted groups selected from alkyl; a cycloalkyl group; an alkoxy group; cycloalkoxy groups such as cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like; arylalkoxyalkyl, e.g. benzyloxy-CH₂-, benzyloxy-CH₂-CH₂-, naphthyloxy-CH₂-, 2-phenylethoxy-CH₂-and the like; an aryl group; an arylalkyl group; a heterocyclic group; a heteroaryl group; a heteroarylalkyl group; an acyl group; acyloxy groups such as OCOMe, OCOEt, OCOPh and the like; a hydroxyalkyl group; an amino group; acylamino, e.g. NHCOCH₃、NHCOC₂H₅Etc.; arylamino radicals, e.g. HNC₆H₅、NCH₃(C₆H₅)、NHC₆H₄CH₃、NHC₆H₄-Hal, etc.; an aminoalkyl group; an aryloxy group; an alkoxycarbonyl group; alkylamino radicals, e.g. NHCH₃、NHC₂H₅、NHC₃H₇、N(CH₃)₂、NCH₃(C₂H₅)、N(C₂H₅)₂Etc.; an alkoxyalkyl group; alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio and the like; thioalkyl groups such as thiomethyl, thioethyl, thiopropyl and the like; a carboxylic acid or derivative thereof; or a sulfonic acid or derivative thereof. Derivatives of carboxylic and sulfonic acids include amides, chlorides, esters, and anhydrides of carboxylic and sulfonic acids.

Suitably represented by R⁴The groups represented may be selected from hydrogen; substituted or unsubstituted, straight or branched (C)₁-C₁₂) Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, heptyl, octyl and the like; (C)₃-C₇) Cycloalkyl groups such as cyclopropyl, cyclopentyl, cyclohexyl, and the like, which may be substituted; aryl groups such as phenyl, naphthyl, and the like, which may be substituted; arylalkyl groups, such as benzyl and phenethyl, which arylalkyl groups may be substituted; a heterocyclic group such as aziridinyl, pyrrolidinyl, piperidinyl and the like, which may be substituted; heteroaryl groups such as pyridyl, thienyl, furyl and the like, which heteroaryl groups may be substituted; heteroarylalkyl groups such as furylmethyl, pyridylmethyl, oxazolylmethyl, oxazolethyl, and the like, which may be substituted. From R⁴The substituents on the group represented may be selected from cycloalkoxy groups such as cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like; arylalkoxyalkyl, e.g. benzyloxy-CH₂-, benzyloxy-CH₂-CH₂-, naphthyloxy-CH₂-, 2-phenylethoxy-CH₂-and the like; an aryl group; an arylalkyl group; a heterocyclic group; a heteroaryl group; a heteroarylalkyl group; an acyl group; acyloxy groups such as OCOMe, OCOEt, OCOPh and the like; a hydroxyalkyl group; an amino group; acylamino, e.g. NHCOCH₃、NHCOC₂H₅Etc.; (ii) an arylamino group,such as HNC₆H₅、NCH₃(C₆H₅)、NHC₆H₄CH₃、NHC₆H₄-Hal, etc.; an aminoalkyl group; an aryloxy group; an alkoxycarbonyl group; alkylamino radicals, e.g. NHCH₃、NHC₂H₅、NHC₃H₇、N(CH₃)₂、NCH₃(C₂H₅)、N(C₂H₅)₂Etc.; an alkoxyalkyl group; alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio and the like; thioalkyl groups such as thiomethyl, thioethyl, thiopropyl and the like; a carboxylic acid or derivative thereof; or a sulfonic acid or derivative thereof.

Suitably represented by R⁵The groups represented may be selected from hydrogen; substituted or unsubstituted, straight or branched (C)₁-C₁₆) Alkyl, preferably (C)₁-C₁₂) Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, heptyl, octyl and the like; substituted or unsubstituted, straight or branched (C)₂-C₈) Alkenyl groups such as vinyl, n-propenyl, n-butenyl, isobutenyl, n-pentenyl, hexenyl, heptenyl and the like; (C)₃-C₇) Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, which may be substituted; (C)₃-C₇) Cycloalkyl (C)₁-C₁₀) Alkyl groups such as cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl and the like, which may be substituted; aryl groups such as phenyl, naphthyl, and the like, which may be substituted; arylalkyl radicals, e.g. benzyl, phenethyl, C₆H₅CH₂CH₂CH₂Naphthylmethyl and the like, the arylalkyl group may be substituted; aroyl, such as benzoyl, and the like, which may be substituted; aralkanoyl group such as phenylacetyl group, phenylpropionyl group and the like, which may be substituted. From R⁵The substituents on the group represented may be selected from halogen; a hydroxyl group; a nitro group; an alkyl group; a cycloalkyl group; an alkoxy group; an aryl group; an arylalkyl group; arylalkoxyalkyl radicals, e.g. C₆H₅CH₂OCH₂-、C₆H₅CH₂OCH₂CH₂-、C₆H₅CH₂CH₂OCH₂CH₂-、C₆H₅CH₂CH₂OCH₂-and the like; a heterocyclic group; a heteroaryl group; and an amino group.

Suitably represented by R⁶The group represented may be selected from unsubstituted or substituted aryloxycarbonyl groups such as phenoxycarbonyl, naphthyloxycarbonyl, and the like; arylalkoxycarbonyl, such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may be substituted; alkylcarbonyloxy group such as methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy and the like, which may be substituted; alkoxycarbonylamino group such as methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, butoxycarbonylamino group, tert-butoxycarbonylamino group and the like, which may be substituted; aryloxycarbonylamino, e.g. NHCOOC₆H₅、N(CH₃)COOC₆H₅、N(C₂H₅)COOC₆H₅、NHCOOC₆H₄CH₃、NHCOOC₆H₄OCH₃Etc., which may be substituted; arylalkoxycarbonylamino, e.g. NHCOOCH₂C₆H₅，NHCOOCH₂CH₂C₆H₅，N(CH₃)COOCH₂C₆H₅，N(C₂H₅)COOCH₂C₆H₅，NHCOOCH₂C₆H₄CH₃，NHCOOCH₂C₆H₄OCH₃Etc., which may be substituted; fluorenylmethoxycarbonyl (Fmoc); fluorenylmethoxycarbonylamino (N-Fmoc); -OSO₂R⁸；-OCONR⁸R⁹；NR⁸COOR⁹；-NR⁸COR⁹；-NR⁸SO₂R⁹；NR⁸CONR⁹R¹⁰；-NR⁸CSNR⁸R⁹；-SO₂R⁸；-SOR⁸；-SR⁸；-SO₂NR⁸R⁹；-SO₂OR⁸；-COOR⁹；-COR⁹or-CONR⁸R⁹. When R is¹³In the third position of the phenyl ring and not representing hydrogen, R⁶Is hydrogen.

When represented by R⁶When the groups represented are substituted, the substituents may be selected from halogen, hydroxy, nitro, alkyl, cycloalkyl, alkoxy, aryl, arylalkyl or amino.

Suitably represented by R¹³The groups represented may be selected from hydrogen; a halogen atom such as fluorine, chlorine, bromine or iodine; a hydroxyl group; an amino group; a nitro group; a cyano group; or substituted or unsubstituted, straight or branched (C)₁-C₁₂) Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like; haloalkyl groups such as trifluoromethyl and the like; (C)₁-C₆) Alkoxy groups such as methoxy, ethoxy, propoxy, and the like, which may be substituted; aryl groups such as phenyl, naphthyl, and the like, which may be substituted; arylalkyl radicals, e.g. benzyl, phenethyl, C₆H₅CH₂CH₂CH₂Naphthylmethyl and the like, the arylalkyl group may be substituted; heteroaryl groups such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl, and the like, which heteroaryl groups may be substituted; heteroarylalkyl such as furylmethyl, pyridylmethyl, oxazolylmethyl, oxazolethyl, and the like, which may be substituted; a heterocyclic group such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and the like, which may be substituted; monoalkylamino radicals, e.g. NHCH₃、NHC₂H₅、NHC₃H₇、NHC₆H₁₃Etc., which may be substituted; dialkylamino radicals, e.g. N (CH)₃)₂、NCH₃(C₂H₅)、N(C₂H₅)₂Etc., which may be substituted; alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxyCarbonyl, tert-butoxycarbonyl and the like, which may be substituted; an aryloxycarbonyl group such as a phenoxycarbonyl group, a naphthyloxycarbonyl group and the like, which may be substituted; arylalkoxycarbonyl, such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, which may be substituted; aryloxy groups such as phenoxy, naphthoxy and the like, which may be substituted; arylalkoxy groups, such as benzyloxy, phenethyloxy, naphthylmethoxy, phenylpropoxy, and the like, which may be substituted; alkylcarbonyloxy group such as methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy and the like, which may be substituted; alkoxycarbonylamino group such as methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, butoxycarbonylamino group, tert-butoxycarbonylamino group and the like, which may be substituted; aryloxycarbonylamino, e.g. NHCOOC₆H₅、N(CH₃)COOC₆H₅、N(C₂H₅)COOC₆H₅、NHCOOC₆H₄CH₃、NHCOOC₆H₄OCH₃Etc., which may be substituted; arylalkoxycarbonylamino, e.g. NHCOOCH₂C₆H₅、NHCOOCH₂CH₂C₆H₅、N(CH₃)COOCH₂C₆H₅、N(C₂H₅)COOCH₂C₆H₅、NHCOOCH₂C₆H₄CH₃、NHCOOCH₂C₆H₄OCH₃Etc., which may be substituted; fluorenylmethoxycarbonyl (Fmoc); fluorenylmethoxycarbonylamino (N-Fmoc); -OSO₂R⁸；-OCONR⁸R⁹；NR⁸COOR⁹；-NR⁸COR⁹；-NR⁸R⁹；-NR⁸SO₂R⁹；NR⁸CONR⁹R¹⁰；-NR⁸CSNR⁸R⁹；-SO₂R⁸；-SOR⁸；-SR⁸；-SO₂NR⁸R⁹；-SO₂OR⁸；-COOR⁹；-COR⁹；-CONR⁸R⁹。

When represented by R¹³When the groups represented are substituted, the substituents may be selected from halogen, hydroxy, nitro, alkyl, cycloalkyl, alkoxy, aryl, arylalkyl or amino.

Suitably represented by R⁸、R⁹、R¹⁰The groups represented may be selected from hydrogen; unsubstituted straight or branched chain (C)₁-C₁₂) Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl and the like; aryl groups such as phenyl, naphthyl, and the like, which may be substituted; arylalkyl radicals, e.g. benzyl, phenethyl, C₆H₅CH₂CH₂CH₂Naphthylmethyl and the like, the arylalkyl group may be substituted; alkoxycarbonyl such as tert-Butoxycarbonyl (BOC), etc.; arylalkoxycarbonyl, such as benzyloxycarbonyl (CBZ), and the like. R⁸And R⁹When located on a nitrogen atom, together may form a 5-or 6-membered cyclic ring system containing carbon atoms, at least one nitrogen and optionally one or more heteroatoms selected from oxygen, sulphur or nitrogen, which may contain one or two double bonds or which may be aromatic. From R⁸、R⁹And R¹⁰The substituents on the groups represented may be selected from halogen, hydroxy, alkoxy, cyano, nitro, alkyl, cycloalkyl, aryl, arylalkyl, acyl, acyloxy, hydroxyalkyl, amino, aryloxy, alkylthio or thioalkyl.

Suitably represented by R⁷The group represented may be selected from hydrogen or substituted or unsubstituted straight or branched (C)₁-C₁₂) An alkyl group; aryl groups such as phenyl, naphthyl, and the like, which may be substituted; hydroxy (C)₁-C₆) Alkyl, which may be substituted; arylalkyl groups such as benzyl and phenethyl, and the like, which may be substituted; heterocyclic groups such as aziridinyl, pyrrolidinyl, piperidinyl and the like, which may be substituted; heteroaryl, such as pyridyl, thienyl, furyl, and the like, which may be substituted; heteroarylalkyl groups such as furylmethyl, pyridylmethyl, oxazolylmethyl, oxazolethyl and the like,it may be substituted; straight or branched chain (C)₂-C₈) Alkanoyl groups such as acetyl, propionyl, butyryl, valeryl and the like, which may be substituted; aroyl, such as benzoyl, and the like, which may be substituted; an arylalkanoyl group such as phenylacetyl, phenylpropionyl and the like, which may be substituted; alkoxycarbonyl such as tert-butoxycarbonyl and the like; arylalkoxycarbonyl, such as benzyloxycarbonyl, and the like. From R⁷The substituents on the groups represented may be selected from halogen, hydroxy, alkoxy, cyano, nitro, alkyl, cycloalkyl, aryl, arylalkyl, acyl, acyloxy, hydroxyalkyl, amino, aryloxy, alkylthio or thioalkyl.

Suitably represented by R⁴And R⁷The ring structures that together may be selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolinyl, and the like. Suitably represented by R⁴And R⁷The substituents on the ring structures that are formed together may be selected from hydroxy, alkyl, oxo, arylalkyl, and the like.

The groups suitably represented by Ar may be selected from substituted or unsubstituted divalent phenylene, naphthylene, benzofuranyl, indolyl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl groups, which may be unsubstituted or substituted with alkyl, haloalkyl, methoxy or haloalkoxy groups.

Suitable n and m are integers from 0 to 6.

Suitable X represents-C (═ O) -, -O (CH)₂)_d(wherein d is an integer of 1 to 4), -C (═ S) -, O-C (═ O) -, -C (O) CH₂-、-CH＝CH-CH₂-, -CH ═ CH-CO-or X represents a bond.

Preferred compounds of the invention are those of formula (I) wherein:

R¹is hydrogen, straight-chain or branched (C)₁-C₆) Alkyl or with R²Forming a key;

R²is hydrogen, straight chainOr branched (C)₁-C₆) Alkyl or with R¹Forming a key;

R³is hydrogen, straight-chain or branched (C)₁-C₁₂) Alkyl, (C)₃-C₇) Cycloalkyl, aryl (e.g., phenyl, naphthyl), or arylalkyl;

R⁴is hydrogen, straight-chain or branched (C)₁-C₁₂) Alkyl, (C)₃-C₇) Cycloalkyl, aryl (e.g., phenyl, naphthyl), or arylalkyl;

R⁵is hydrogen, (C)₁-C₁₂) Alkyl or (C)₃-C₇) A cycloalkyl group;

R⁶is fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO₂R⁸、-OCONR⁸R⁹、-NR⁸COOR⁹、-NR⁸COR⁹or-NR⁸SO₂R⁹；

R⁸Is hydrogen, straight-chain or branched (C)₁-C₆) Alkyl or aryl, which may be substituted;

R⁹is hydrogen, straight-chain or branched (C)₁-C₆) Alkyl, tert-butoxycarbonyl or benzyloxycarbonyl;

R¹³is hydrogen or-OSO₂R⁸；

X is-C (═ O) -, O-C (═ O) -, -O (CH)₂)_d(wherein d is an integer of 1 to 4), -C (═ S) -, -CH ═ CH-CH₂-, -CH ═ CH-CO-or X represents a bond;

y is oxygen or NR⁷；

R⁷Is hydrogen, substituted or unsubstituted straight or branched chain (C)₁-C₁₂) Alkyl or aryl, which aryl may be substituted;

d is an integer from 1 to 4;

m is an integer from 0 to 1;

n is an integer from 0 to 2.

Even more preferred compounds of the invention are those of formula (I) wherein:

R¹is hydrogen or with R²Forming a key;

R²is hydrogen or with R¹Forming a key;

R³is hydrogen, straight-chain or branched (C)₁-C₁₂) An alkyl group;

R⁴is hydrogen, straight-chain or branched (C)₁-C₁₂) An alkyl group;

R⁵is hydrogen or (C)₁-C₁₂) An alkyl group;

R⁶is-OSO₂R⁸or-NR⁸SO₂R⁹；

R⁸Is straight-chain or branched (C)₁-C₆) Alkyl or substituted aryl, wherein the substituent is straight or branched (C)₁-C₆) An alkyl group;

R⁹is straight-chain or branched (C)₁-C₆) Alkyl, tert-butoxycarbonyl or benzyloxycarbonyl;

R¹³is hydrogen or-OSO₂R⁸；

X is-C (═ O) -, O-C (═ O) -, -O (CH)₂)_d(d is 1 to 4), -CH-CH₂-, -CH ═ CH-CO-or X represents a bond;

y is oxygen.

Pharmaceutically acceptable salts forming part of the invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, 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, theobromine, valinol, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, amantadine, diethanolamine, meglumine, ethylenediamine, N' -diphenylethylenediamine, N, n' -dibenzylethylenediamine, N-benzylphenethylamine, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, spermidine, and the like; salts of chiral bases such as alkylanilines, glycinol, phenylglycinol, and the like; salts of natural amino acids, such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; salts of unnatural amino acids, amino acids such as D-isomers or substituted amino acids; salts of acidic amino acids, such as aspartic acid, glutamic acid; a guanidine salt; a substituted guanidinium salt wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium and aluminum salts. Salts may include acid addition salts, suitably sulphate, nitrate, phosphate, perchlorate, borate, hydrohalide (HCl, HBr, HI), acetate, tartrate, maleate, citrate, succinate, pamoate, methanesulphonate, benzoate, salicylate, hydroxynaphthoate, benzenesulphonate, ascorbate, glycerophosphate, ketoglutarate and the like. The pharmaceutically acceptable solvate may be a hydrate or comprise other crystallization solvents, such as alcohols.

Particularly useful compounds according to the invention include:

ethyl 2-methoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoate or salts thereof in its single enantiomeric form or as a racemate;

ethyl 2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoate or salts thereof in its single enantiomeric form or as a racemate;

ethyl 2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propoxycarbonylamino } phenyl ] propanoate or salts thereof, in its single enantiomeric form or as a racemate;

ethyl 2-ethoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoate or a salt thereof, in its single enantiomeric form or as a racemate;

ethyl 2-ethoxy-3- [4- {3- (4- (toluene-4-sulfonyloxy) phenyl) propylamino } phenyl ] propanoate or salts thereof, in its single enantiomeric form or as a racemate;

ethyl 2-ethoxy-3- [3- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoate or salts thereof in its single enantiomeric form or as a racemate;

ethyl 2-isopropoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoate or a salt thereof, in its single enantiomeric form or as a racemate;

ethyl 2-ethoxy-3- [4- (4-methanesulfonyloxyphenethylamino) phenyl ] propanoate or salts thereof, in its single enantiomeric form or as a racemate;

ethyl 2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino ] phenyl } propanoate or salts thereof, in its single enantiomeric form or as a racemate;

methyl 2-ethoxy-3- [4- (4-methanesulfonyloxybenzylamino) phenyl ] propanoate or salts thereof, in its single enantiomeric form or as a racemate;

2-methoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid or a salt thereof in its single enantiomeric form or as a racemate;

2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid or a salt thereof, in its single enantiomeric form or as a racemate;

2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propoxycarbonylamino } phenyl ] propanoic acid or a salt thereof, in its single enantiomeric form or as a racemate;

2-ethoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid or a salt thereof, in its single enantiomeric form or as a racemate;

2-ethoxy-3- [4- {3- (4- (toluene-4-sulfonyloxy) phenyl) propylamino } phenyl ] propanoate or a salt thereof, in its single enantiomeric form or as a racemate;

2-ethoxy-3- [3- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid or a salt thereof in its single enantiomeric form or as a racemate;

2-isopropoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl } propanoic acid or a salt thereof, in its single enantiomeric form or as a racemate;

2-ethoxy-3- [4- (4-methanesulfonyloxybenzylamino) phenyl ] propionic acid or a salt thereof, in its single enantiomeric form or as a racemate;

2-ethoxy-3- [4- (4-methanesulfonyloxyphenethylamino) phenyl ] propionic acid or a salt thereof, in its single enantiomeric form or as a racemate;

2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino ] phenyl } propanoic acid or a salt thereof, in its single enantiomeric form or as a racemate;

ethyl 2-ethoxy-3- [4- (4-methanesulfonyloxybenzylcarboxamido) phenyl ] propanoate or salts thereof, in its single enantiomeric form or as a racemate;

2-ethoxy-3- [4- (4-methanesulfonyloxybenzylcarboxamido) phenyl ] propionic acid or salts thereof, in its single enantiomeric form or as racemate;

ethyl 2-ethoxy-3- [4- {3- (4-tert-butoxy-4-methylsulfonylaminophenyl) propylamino } phenyl ] propanoate or salts thereof, in its single enantiomeric form or as a racemate;

2-ethoxy-3- [4- {3- (4-tert-butoxy-4-methylsulfonylaminophenyl) propylamino } -phenyl ] propionic acid or a salt thereof, in its single enantiomeric form or as a racemate;

ethyl 2-ethoxy-3- {4- [ (E) -2- (4-methanesulfonyloxyphenyl) -1-vinylformamido ] phenyl } propanoate or salts thereof, in its single enantiomeric form or as a racemate;

2-ethoxy-3- {4- [ (E) -2- (4-methanesulfonyloxyphenyl) -1-vinylformamido ] -phenyl } propanoic acid or a salt thereof, in its single enantiomeric form or as a racemate;

2-ethoxy-3- [4- (4-methanesulfonyloxybenzylcarboxamido) phenyl ] propionic acid or a salt thereof, in its single enantiomeric form or as a racemate;

ethyl 2-methoxy-3- [4- { (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino } phenyl ] propanoate or salts thereof, in its single enantiomeric form or as a racemate;

2-methoxy-3- [4- { (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino } phenyl ] propanoic acid or a salt thereof, in its single enantiomeric form or as a racemate;

ethyl 2-methoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoate or salts thereof in its single enantiomeric form or as a racemate;

2-methoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid or a salt thereof in its single enantiomeric form or as a racemate;

ethyl 2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoate or salts thereof, in its single enantiomeric form or as a racemate;

2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoic acid or salts thereof, in its single enantiomeric form or as a racemate;

methyl 2-methoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoate or salts thereof, in its single enantiomeric form or as a racemate;

2-methoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoic acid or salts thereof, in its single enantiomeric form or as a racemate.

According to a characteristic of the invention, the compounds of formula (I) in which R¹、R²、R³、R⁴、R⁵、R⁶、R¹³X, Y, n, m and Ar are as defined above-and can be prepared by any of the routes shown in scheme-I below.

Scheme I

Route 1: a compound of formula (IIIa), wherein all symbols are as defined above, and a compound of formula (IIIb), wherein Y is as defined above, with the exception of NH, R¹¹Represents a straight chain or branched chain (C)₁-C₆) Alkyl, all other symbols being as defined above, to a compound of general formula (I) wherein Y is as defined above, except NH, and all other symbols are as defined above, which reaction may be carried out in the presence of a base, for example an alkali metal hydride, like NaH or KH; organic lithium, e.g. CH₃Li, BuLi, LDA, TMEDA, etc.; alkoxides, e.g. NaOMe, NaOEt, K⁺BuO^-And the like or mixtures thereof. The reaction may be in solutionIn the presence of an agent, such as diethyl ether, THF, dioxane, DMF, DMSO, DME, toluene, benzene, and the like, or a mixture thereof. HMPA may be used as a co-solvent. The reaction temperature may be from-78 to 50 deg.C, preferably-10 deg.C to 30 deg.C. The reaction is more efficient under anhydrous conditions. The compounds of formula (IIIb) can be prepared by means of the Arbuzov reaction (Annalen. Chemie, 1996, 53, 699).

Alternatively, the compounds of formula (I) may be prepared by reacting a compound of formula (IIIa), wherein all symbols are as defined above, with a Wittig reagent, for example Hal, under similar reaction conditions as described above^-Ph₃P⁺CH-(OR³)CO₂R⁴Wherein R is³And R⁴As defined above.

Route 2: a compound of formula (IIId) -wherein R⁶Is as defined above, NR⁸R⁹Y is as defined above, with the exception of NH, all other symbols being as defined above, and a compound of formula (IIIc) wherein R³Is as defined above, except that hydrogen, L¹Is a leaving group, such as a halogen atom, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, etc., to produce a compound of formula (I), which may be carried out in the presence of a solvent, such as diethyl ether, THF, DMF, DMSO, DME, toluene, benzene, etc. The inert atmosphere can be maintained by means of an inert gas, e.g. N₂Ar, He, etc. The reaction can be carried out in the presence of a base, such as KOH, NaOH, NaOMe, t-BuO^-K⁺、NaH、KH、LDA、NaHMDS、K₂CO₃、Na₂CO₃And the like. Phase transfer catalysts, such as tetraalkylammonium halides or hydroxides or bisulfates, may be employed. The reaction temperature may be from-20 ℃ to 200 ℃, preferably from 0 to 150 ℃. The reaction time may be from 1 to 72 hours, preferably from 1 to 12 hours. The reaction can also be carried out using alkylating agents, such as dialkyl sulfates like diethyl sulfate or dimethyl sulfate; alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, and the like.

Route 3: a compound of the general formula (IIIa) —Wherein all symbols are as defined above, with a compound of formula (IIIe) wherein R²The reaction, which represents a hydrogen atom, Y being as defined above, with the exception of NH, and all other symbols being as defined above, can be carried out in the presence of a base. The nature of the base is not critical. Any base commonly used in aldol condensation reactions can be used; metal hydrides, such as NaH, KH, metal alkoxides, such as NaOMe, t-BuO, may be used^-K⁺NaOEt, metal amides, e.g. LiNH₂、LiN(ipr)₂. Aprotic solvents such as THF, diethyl ether, dioxane may be used. The reaction may be carried out in an inert atmosphere, which may be maintained with an inert gas, such as N₂Ar or He, the reaction is more efficient under anhydrous conditions. The temperature may be from-80 ℃ to 35 ℃. The initially formed β -hydroxy product may be dehydrated under conventional dehydration conditions, for example by treatment with p-TSA in a solvent such as benzene or toluene. The nature of the solvent and dehydrating agent is not critical. The temperature can be from 20 ℃ to the reflux temperature of the solvent, preferably at the reflux temperature of the solvent, with continuous removal of water using a Dean-Stark water separator.

Route 4: a compound of formula (IIIg) — wherein R⁶、R¹³X, n is as defined above, L¹Represents a leaving group, e.g. a halogen atom, such as chlorine or bromine or iodine, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, etc., preferably a halogen atom, with a compound of the formula (IIIf) in which R is¹And R²Together represent a bond and all other symbols are as defined above-the reaction yields a compound of formula (I) as defined above, which may be carried out in the presence of an aprotic solvent, such as diethyl ether, THF, DMF, DMSO, DME, toluene, benzene, acetone, acetonitrile and the like or mixtures thereof. The reaction may be carried out in an inert atmosphere, which may be maintained with an inert gas, such as N₂Ar, He, etc. The reaction can be carried out in the presence of a base, e.g. K₂CO₃、Na₂CO₃Or NaH or mixtures thereof. The reaction temperature may be from-20 ℃ to 120 ℃, preferably from 0 ℃ to 120 ℃. The reaction time may be from 1 to 48 hours. Can adopt phase inversionA cocatalyst, for example a tetraalkylammonium halide or hydroxide or hydrogen sulfate.

Route 5: a compound of the general formula (IIIh): wherein R⁶、R¹³X, n is as defined above with a compound of the formula (IIIf) in which R¹And R²Together represent a bond, R⁵Is hydrogen, all other symbols being as defined above-can be carried out using a suitable coupling agent, for example isobutyl chloroformate or ethyl chloroformate/Et₃N, pivaloyl chloride/Et₃N, dicyclohexylurea, triarylphosphines/dialkyl azodicarboxylates, e.g. PPh₃DEAD and the like. The reaction may be carried out in the presence of a solvent, e.g. THF, DME, CH₂Cl₂、CHCl₃Toluene, acetonitrile, carbon tetrachloride, and the like. The inert atmosphere can be maintained by means of an inert gas, e.g. N₂Ar, He, etc. The reaction can be carried out in the presence of DMAP, HOBt and they can be used in an amount of 0.05 to 2 equivalents, preferably 0.25 to 1 equivalent. The reaction temperature may be 0 ℃ to 100 ℃, preferably 20 ℃ to 80 ℃. The reaction time may be from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

Route 6: a compound of formula (IIIi), wherein all symbols are as defined above, and a compound of formula (IIIj), wherein Y represents oxygen, R³＝R⁴And is as defined hereinbefore, except that hydrogen, to produce a compound of formula (I) wherein R is¹And R²Together representing a bond and Y represents an oxygen atom, which can be carried out neat in the presence of a base, e.g. an alkali metal hydride, such as NaH, KH, or an organolithium, such as CH₃Li, BuLi, etc., or alkoxides, e.g. NaOMe, NaOEt, t-BuO^-K⁺And the like or mixtures thereof. The reaction may be carried out in the presence of an aprotic solvent, such as THF, dioxane, DMF, DMSO, DME, and the like, or a mixture thereof. HMPA may be used as a co-solvent. The reaction temperature may be from-78 to 100 deg.C, preferably-10 deg.C to 50 deg.C. The reaction time may be from 1 to 48 hours.

In another embodiment of the invention, the compounds of formula (I) wherein R¹Represents a hydrogen atom, a hydroxyl group, an alkoxy group, a halogen, a lower alkyl group, a substituted or unsubstituted arylalkyl group, R²Represents hydrogen, halogen, lower alkyl, alkanoyl, aroyl, arylalkanoyl, substituted or unsubstituted arylalkyl, R³、R⁴、R⁵、R⁶、R¹³X, Y, Ar, m and n are as defined above-can be prepared by one or more of the procedures shown in scheme-II below.

Scheme II

Route 7: reduction of a compound of formula (IVa) which represents a compound of formula (I) wherein R¹And R²Together represent a bond, Y represents an oxygen atom and all other symbols are as defined above, are obtained as described above (scheme-I) -yielding a compound of general formula (I), wherein R represents¹And R²Each represents a hydrogen atom, all symbols being as defined above, which can be carried out in the presence of gaseous hydrogen and a catalyst, such as Pd/C, Rh/C, Pt/C and the like. Mixtures of catalysts may be used. The reaction may also be carried out in the presence of a solvent, such as dioxane, acetic acid, ethyl acetate, alcohols, such as methanol, ethanol, and the like. Pressures between atmospheric and 40 to 80psi may be employed. The catalyst may preferably be 5-10% Pd/C and the amount of catalyst may be 5-100% w/w. The reaction can also be carried out using a metal solvent reduction, such as magnesium or samarium/alcohol or sodium amalgam/alcohol, the alcohol preferably being methanol. The hydrogenation may be carried out in the presence of a metal catalyst containing a chiral ligand to give the compound of formula (I) in an optically active form. The metal catalyst may contain rhodium, ruthenium, indium, or the like. The chiral ligand may preferably be a chiral phosphine, such as an optically pure enantiomer of 2, 3-bis (diphenylphosphino) butane, 2, 3-isopropylidene-2, 3-dihydroxy-1, 4-bis (diphenylphosphino) butane, or the like. Any suitable chiral catalyst may be employed which will give the desired optical purityProduct (I) (Ref: Principles of asymmetry Synthesis, Tetrahedron Series Vol 14, pp 311-316, Ed. Baldwin J. E.).

Route 8: a compound of formula (IVb) — wherein R⁶Is as defined above, R⁴Is as defined above, except for hydrogen, all other symbols are as defined above, L¹Is a leaving group, e.g. a halogen atom, such as chlorine, bromine or iodine, a mesylate, p-tosylate, triflate, with an alcohol of the formula (IVc) wherein R is³Is as defined above except hydrogen, which reaction produces a compound of formula (I) as defined above, which may be carried out in the presence of a solvent, such as diethyl ether, THF, DMF, DMSO, DME, diethyl ether, toluene, benzene, and the like, or mixtures thereof. The reaction may be carried out in an inert atmosphere, which may be maintained with an inert gas, such as N₂Ar, He, etc. The reaction can be carried out in the presence of a base, such as KOH, NaOH, NaOMe, NaOEt, t-BuO^-K⁺NaH, KH or mixtures thereof. Phase transfer catalysts such as tetraalkylammonium halides, bisulfates, or hydroxides may be employed. The reaction temperature may be from-20 ℃ to 120 ℃, preferably from 0 ℃ to 100 ℃. The reaction time may be from 1 to 48 hours, preferably from 1 to 24 hours.

Route 9: the reaction of a compound of formula (IIIg) as defined above with a compound of formula (IIIf), wherein all symbols are as defined above, gives a compound of formula (I) as defined above, which may be carried out in the presence of a solvent, such as diethyl ether, THF, DMF, DMSO, DME, toluene, benzene, acetone, acetonitrile and the like or mixtures thereof. The reaction may be carried out in an inert atmosphere, which may be maintained with an inert gas, such as N₂Ar, He, etc. The reaction can be carried out in the presence of a base, e.g. K₂CO₃、Na₂CO₃NaH, and the like or mixtures thereof. The reaction temperature may be from-20 ℃ to 120 ℃, preferably from 0 ℃ to 120 ℃. The reaction time may be from 1 to 48 hours, preferably from 1 to 24 hours. Phase transfer catalysts, such as tetraalkylammonium halides or hydroxides, may be employed.

Route 10: the reaction of a compound of formula (IIIh) with a compound of formula (IIIf) as defined above, wherein all symbols are as defined above, may be carried out using a suitable coupling agent, for example isobutyl chloroformate, ethyl chloroformate/Et₃N, pivaloyl chloride/Et₃N, dicyclohexylurea, triarylphosphines/dialkyl azodicarboxylates, e.g. PPh₃DEAD and the like. The reaction may be carried out in the presence of a solvent, e.g. THF, DME, CH₂Cl₂、CHCl₃Toluene, acetonitrile, carbon tetrachloride, and the like. The inert atmosphere can be maintained by means of an inert gas, e.g. N₂Ar, He, etc. The reaction can be carried out in the presence of DMAP, HOBt and they can be used in an amount of 0.05 to 2 equivalents, preferably 0.25 to 1 equivalent. The reaction temperature may be 0 ℃ to 100 ℃, preferably 20 ℃ to 80 ℃. The reaction time may be from 0.5 to 48 hours, preferably 6 to 24 hours.

Route 11: a compound of formula (IIId), which represents a compound of formula (I) wherein all symbols are as defined above, and a compound of formula (IIIc) wherein R³Is as defined above, except that hydrogen, L¹The reaction which is a leaving group, for example a halogen atom such as chlorine, bromine or iodine, mesylate, p-tosylate, triflate and the like-can be carried out in the presence of a solvent such as diethyl ether, THF, DMF, DMSO, DME, toluene, benzene, acetone, acetonitrile and the like. The inert atmosphere can be maintained by means of an inert gas, e.g. N₂Ar, He, etc. The reaction can be carried out in the presence of a base, such as KOH, NaOH, NaOMe, t-BuO^-K⁺、NaH、KH、LDA、NaHMDS、K₂CO₃、Na₂CO₃And the like. Phase transfer catalysts, such as tetraalkylammonium halides or hydroxides or bisulfates, may be employed. The reaction temperature may be from-20 ℃ to 200 ℃, preferably from 0 to 150 ℃. The reaction time may be from 1 to 72 hours, preferably from 1 to 12 hours. The reaction can also be carried out using alkylating agents, such as dialkyl sulfates like diethyl sulfate or dimethyl sulfate; alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, and the like.

Route 12:a compound of formula (IIIa) and a compound of formula (IIIe) as defined hereinbefore wherein R²The reaction, which represents a hydrogen atom, Y being as defined above, with the exception of NH, and all other symbols being as defined above, can be carried out under conventional conditions. Any base commonly used in aldol condensation reactions can be used, including metal hydrides such as NaH or KH; metal alkoxides, e.g. NaOMe, t-BuO^-K⁺Or NaOEt; metal amides, e.g. LiNH₂、LiN(iPr)₂. Aprotic solvents such as THF, DMF or diethyl ether may be used. An inert atmosphere, such as argon, may be used, the reaction being more efficient under anhydrous conditions. The temperature may be from-80 ℃ to 25 ℃. The β -hydroxyaldehyde product can be dehydroxylated by conventional means, suitably by means of ionic hydrogenation techniques, for example by treatment with a trialkylsilane in the presence of an acid, for example trifluoroacetic acid. Solvents may be used, for example CH₂Cl₂. Desirably, the reaction is carried out at 25 ℃. If the reaction is slow, higher temperatures may be used. Dehydroxylation can also be performed using the Barton deoxygenation method (Ref. D. H. R. Barton et al J. Chez. Soc., Perkin Trans I, 1975, 1574; F.S. Martin et al Tetrahedron Lett., 1992, 33, 1839).

Route 13: the conversion of a compound of formula (IVd), wherein all symbols are as defined above, to a compound of formula (I), wherein Y represents an oxygen atom and all other symbols are as defined above, may be carried out in the presence of a base or an acid, the choice of base or acid not being critical. Any base commonly used for the hydrolysis of nitriles to acids can be used, metal hydroxides such as NaOH or KOH in aqueous solvents, or any acid commonly used for the hydrolysis of nitriles to esters can be used, such as HCl in an excess of alcohol, such as methanol, ethanol, propanol, and the like. The reaction may be carried out at a temperature in the range of 0 ℃ to the reflux temperature of the solvent used, preferably 25 ℃ to the reflux temperature of the solvent used. The reaction time may be from 0.25 to 48 hours.

Route 14: a compound of formula (IVe) — wherein R⁴Is as defined above, except for hydrogen, all symbols are as defined aboveWith a compound of formula (IVc) in which R³As defined above, except for hydrogen-the reaction produces a compound of formula (I) (via insertion mediated by rhodium-based carbenoids), which may be carried out in the presence of a rhodium (II) salt, for example rhodium (II) acetate. The reaction may be carried out in the presence of a solvent, such as benzene, toluene, dioxane, diethyl ether, THF, and the like, or combinations thereof, or where feasible at R³OH as a solvent, at any reaction temperature that provides a suitable rate of formation of the desired product, typically at elevated temperatures, such as the reflux temperature of the solvent. The inert atmosphere can be maintained by means of an inert gas, e.g. N₂Ar, He, etc. The reaction time may be from 0.5 to 24 hours, preferably from 0.5 to 6 hours.

Route 15: compounds of formula (IVg) and compounds of formula (IVf) -wherein G¹And G²Is different and independently represents NH₂Or CHO, q is an integer from 0 to 6 and all other symbols are as defined above to give a compound of formula (I) wherein R is⁵Represents hydrogen and all other symbols are as defined above, which can be carried out in two steps, the first step being imine formation followed by reduction. Imine formation can be carried out in a solvent such as MeOH, EtOH, i-PrOH, and the like. The reaction may be carried out in the presence of a base, such as NaOAc, KOAc, and the like, or mixtures thereof. The reaction temperature may range from room temperature to the reflux temperature of the solvent used. The reaction time may be 2 hours to 24 hours, preferably 2 hours to 12 hours.

Imines may also be obtained by using solvents, e.g. CH₂Cl₂、CHCl₃Chlorobenzene, benzene, THF in the presence of catalysts, e.g. p-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH, BF₃-OEt₂Etc. reacting a compound of formula (IVg) with a compound of formula (IVf), wherein G¹And G²Is different and independently represents NH₂Or CHO, q is an integer from 0 to 6, and all other symbols are as defined above. The reaction may also be carried out in the presence of a reactive molecular sieve. The reaction temperature may be in the range of 10 ℃ to 100 ℃, preferably 10 ℃ to 60 ℃. The reaction time may be from 1 hour to 48 hours.

The imine product obtained as above can be used with Na (CN) BH₃-HCl(ref：Hutchins，R.O.et al.J.Org.Chem.1983，48，3433)、NaBH₄、H₂-Pd/C、H₂-Pt/C、H₂Rh/C, etc., in solvents such as methanol, ethanol, etc.

Wherein R is⁵The compounds of formula (I) representing hydrogen can also be prepared by a single-step process using compounds of formulae (IVg) and (IVf), wherein all symbols are as defined above, and reductive amination using hydrogen as reducing agent. The compounds of formula (IVg) and (IVf) can be condensed in the presence of hydrogen under pressure to give the compounds of formula (I). The pressure may vary from 10 to 90psi, preferably between 20 and 60 psi. The solvent may be selected from MeOH, EtOH, EtOAc, dioxane, toluene, and the like. The temperature may be from RT to 50 ℃, preferably RT to 40 ℃. Catalysts such as Pd/C, Rh/C, Pt/C and the like may be used.

Wherein R is⁴Compounds of the general formula (I) which represent a hydrogen atom, in which R is hydrogen, can be prepared by hydrolysis of compounds of the formula (I) in which R is hydrogen⁴Represents all groups as defined above except hydrogen. The hydrolysis may be carried out in the presence of a base, such as Na, and a suitable solvent₂CO₃、K₂CO₃NaOH, KOH, LiOH, etc., solvents such as methanol, ethanol, water, etc., or mixtures thereof. The reaction may be carried out at a temperature of 20-120 ℃. The reaction time may be from 2 to 48 hours, preferably from 2 to 12 hours.

A compound of the general formula (I) wherein Y represents oxygen, R⁴Represents hydrogen or lower alkyl-optionally with the appropriate formula NHR⁴R⁷Amine-wherein R⁴And R⁷Is as defined above-into a compound of formula (I) wherein Y represents NR⁷To give a compound of formula (I) wherein Y represents NR⁷All other symbols are as defined above. Alternatively, compounds of formula (I) wherein YR⁴Represents OH-may be so converted to an acid halide, preferably YR⁴With appropriate reagents, e.g. oxalyl chloride,Thionyl chloride, etc., followed by NHR⁴R⁷Amine treatment of R⁴And R⁷As previously defined. Alternatively, a compound of formula (I): wherein YR⁴Represents OH, all other symbols are as defined above-treatment with an acid halide, such as acetyl chloride, acetyl bromide, pivaloyl chloride, dichlorobenzoyl chloride, and the like, may prepare a mixed anhydride. The reaction may be carried out in the presence of pyridine, triethylamine, diisopropylethylamine, or the like. Acids can also be activated using coupling reagents such as DCC/DMAP, DCC/HOBt, EDCI/HOBT, ethyl chloroformate, isobutyl chloroformate. Solvents may be used, for example halogenated hydrocarbons, like CHCl₃Or CH₂Cl₂(ii) a Hydrocarbons such as benzene, toluene, xylene, and the like. The reaction may be carried out at a temperature of-40 ℃ to 40 ℃, preferably 0 ℃ to 20 ℃. The acid halide or mixed anhydride or activated acid prepared with the above coupling reagent may be further reacted with an appropriate NHR of the formula⁴R⁷Amine treatment of R⁴And R⁷Is as defined hereinbefore, to produce a compound of formula (I) wherein Y represents NR⁷All other symbols are as defined above.

In another embodiment of the present invention, there are provided novel intermediates of formula (IIIa)

Their derivatives, their analogs, their tautomers, their stereoisomers, their salts, their solvates wherein R⁵Represents hydrogen or a substituted or unsubstituted group selected from alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; n and m are integers from 0 to 6; ar represents a substituted or unsubstituted group selected from the group consisting of divalent phenylene, naphthylene, pyridyl, quinolyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolylEtc.; x represents C-O, C-S-C (O) CH₂-、-CH＝CH-CH₂-, -CH ═ CH-CO-, or X represents a bond; r⁶Represents a substituted or unsubstituted group selected from the group consisting of aryloxycarbonyl, arylalkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO₂R⁸、-OCONR⁸R⁹、NR⁸COOR⁹、-NR⁸COR⁹、-NR⁸SO₂R⁹、NR⁸CONR⁹R¹⁰、-NR⁸CSNR⁸R⁹、-SO₂R⁸、-SOR⁸、-SR⁸、-SO₂NR⁸R⁹、-SO₂OR⁸、-COOR⁹、-COR⁹or-CONR⁸R⁹Wherein R is⁸、R⁹And R¹⁰May be the same or different and independently represent hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; r⁸And R⁹When located on a nitrogen atom, may together form a 5-or 6-membered cyclic structure containing carbon atoms and one or more heteroatoms selected from oxygen, sulfur or nitrogen; or when R is¹³In the third position of the phenyl ring and not representing hydrogen, R⁶Is hydrogen;

R¹³represents hydrogen, halogen, nitro, cyano, amino, haloalkyl, hydroxy or a substituted or unsubstituted radical selected from linear or branched (C)₁-C₁₂) Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, alkoxy, monoalkylamino, dialkylamino, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, aryloxy, arylalkoxy, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO₂R⁸、-OCONR⁸R⁹、NR⁸COOR⁹、-NR⁸COR⁹、-NR⁸R⁹、-NR⁸SO₂R⁹、NR⁸CONR⁹R¹⁰、-NR⁸CSNR⁸R⁹、-SO₂R⁸、-SOR⁸、-SR⁸、-SO₂NR⁸R⁹、-SO₂OR⁸、-COOR⁹、-COR⁹、-CONR⁸R⁹Wherein R is⁸、R⁹And R¹⁰May be the same or different and independently represent hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; r⁸And R⁹When located on a nitrogen atom, together may form a 5 or 6 membered cyclic structure containing carbon atoms and one or more heteroatoms selected from oxygen, sulfur or nitrogen.

From Ar, R⁵、R⁶、R⁸、R⁹、R¹⁰And R¹³The substituents of the groups represented are as defined for the compounds of formula (I).

m is an integer of 0 to 6, and n is an integer of 0 to 6.

In another embodiment of the invention, the compound of formula (IIIa) -wherein R⁵Represents hydrogen, X represents C (O) CH₂-、-CH＝CH-CH₂Or X represents a bond, m is 0, Ar represents phenyl, all other symbols are as defined above-can be prepared by the procedure described in scheme-III below.

Scheme III

A compound of formula (IIIk), wherein all symbols are as defined above, with a compound of formula (III1), wherein R¹²Represents hydrogen or (C)₁-C₆) Alkyl-reaction to give compounds of the formula (IIIm) in which all the symbols are as defined above, which can be carried out in two stepsIn the first step, imine formation is followed by reduction. Imine formation can be carried out in a solvent such as MeOH, EtOH, i-PrOH, and the like. The reaction may be carried out in the presence of a promoter, such as NaOAc, KOAc, and the like, or mixtures thereof. The reaction temperature may range from room temperature to the reflux temperature of the solvent used. The reaction time may be 2 hours to 24 hours, preferably 2 hours to 12 hours.

Imines may also be obtained by using solvents, e.g. CH₂Cl₂、CHCl₃Chlorobenzene, benzene, THF in the presence of catalysts, e.g. p-toluenesulfonic acid, methanesulfonic acid, TFA, TfOH, BF₃-OEt₂And the like, reacting the compound of formula (IIIk) with the compound of formula (IIIl). The reaction may also be carried out in the presence of a reactive molecular sieve. The reaction temperature may be from 10 ℃ to 100 ℃, preferably from 10 ℃ to 60 ℃. The reaction time may be 1 hour to 48 hours.

Hydrolysis of a compound of formula (IIIm), wherein all symbols are as defined above, to produce a compound of formula (IIIa), may be carried out in the presence of a base or acid, the choice of base or acid not being critical. Using bases, e.g. metal hydroxides, such as NaOH or KOH, in aqueous solvents, or acids in solvents, e.g. CH₂Cl₂THF, acetone, methanol, ethanol, propanol, water, and the like, acids such as aqueous HCl or TFA. The reaction may be carried out at a temperature in the range of 0 ℃ to the reflux temperature of the solvent used, preferably 0 ℃ to the reflux temperature of the solvent used. The reaction time may be from 0.25 to 48 hours.

In another embodiment of the invention, the compound of formula (IIIa) -wherein R⁵Represents hydrogen or alkyl, m is 0 and all other symbols are as defined above-can be prepared by a process which comprises reacting a compound of formula (IIIg)

Wherein all symbols are as defined above,

with a compound of formula (IIIn),

wherein R is¹²Represents hydrogen or alkyl, R⁵As defined above, m is an integer from 0 to 6.

The reaction of the compound of formula (IIIg) with the compound of formula (IIIn) may be carried out in the presence of a solvent, such as THF, DMF, DMSO, DME, toluene, benzene, acetone, acetonitrile, etc., or a mixture thereof. The reaction may be carried out in an inert atmosphere, which may be maintained with an inert gas, such as N₂Ar, He, etc. The reaction can be carried out in the presence of a base, e.g. K₂CO₃、Na₂CO₃NaH, and the like or mixtures thereof. The reaction temperature may be from 20 ℃ to 120 ℃, preferably from 30 ℃ to 80 ℃. The reaction time may be from 1 to 24 hours, preferably from 1 to 12 hours.

The intermediates (IIIf) of the present invention and their preparation have been the subject of our PCT application No. PCT/IB 02/04274.

It will be appreciated that in any of the above reactions, any reactive group in the substrate molecule may be protected in accordance with conventional chemical practice. Suitable protecting groups in any of the above reactions are t-butyldimethylsilyl, methoxymethyl, triphenylmethyl, benzyloxycarbonyl, THP, etc., for protecting a hydroxyl group or a phenolic hydroxyl group; N-Boc, N-Cbz, N-Fmoc, benzophenone imine and the like for protecting amino or phenylamino; acetals for protecting aldehydes; ketals, for protecting ketones, and the like. The generation and removal of such protecting groups is a routine procedure 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 tert-butoxide, calcium hydroxide, magnesium hydroxide, and the like, and a solvent such as diethyl ether, THF, methanol, tert-butanol, dioxane, isopropanol, ethanol, toluene, and the like. Mixtures of solvents may be used. Organic bases such as lysine, arginine, diethanolamine, choline, guanidine, tromethamine and their derivatives and the like may also be used. Alternatively, acid addition salts are prepared, where applicable, by treatment with an acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, pamoic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, and the like in a solvent such as ethyl acetate, diethyl ether, alcohol, acetone, THF, dioxane, and the like. Mixtures of solvents may also be used.

Stereoisomers of compounds forming part of the invention may be prepared by using the individual enantiomeric forms of the reactants, if possible, in the process, or by reacting in the presence of individual enantiomeric forms of the reagents or catalysts, or by resolving mixtures of stereoisomers by conventional methods. Some preferred methods include the use of microbial resolution, resolution of the resulting diastereomeric salts with an appropriate chiral acid or chiral base, such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like, bases such as brucine, cinchona alkaloid and their derivatives and the like. A commonly used method is compiled by Jaques et al in "Enantiomers, racemes and Resolution" (Wiley Interscience, 1981). More specifically, wherein YR¹⁰The compounds of formula (I) representing OH can be converted into a 1: 1 mixture of diastereoisomeric amides by treatment with a chiral amine, an amino acid, an amino alcohol derived from an amino acid; conventional reaction conditions may be employed to convert the acid to the amide; the stereoisomers of the compounds of formula (I) may be prepared by hydrolysis of the pure diastereomeric amides by fractional crystallization or chromatographic separation.

The various polymorphic forms of the compound of formula (I) which form part of the present invention may be prepared by crystallisation of the compound of formula (I) under different conditions. For example, use is made of different solvents or mixtures thereof, which are customarily used for recrystallization; crystallization at different temperatures; the various cooling means during crystallization range from very fast to very slow. Polymorphs can also be obtained by heating or melting the compound, followed by gradual or rapid cooling. The presence of polymorphic forms can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or other techniques.

The present invention provides pharmaceutical compositions comprising a combination of a compound of general formula (I), their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates as defined above, together with pharmaceutically usual carriers, diluents and the like, useful for the treatment and/or prevention of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular disease and related disorders. These compounds are useful for treating familial hypercholesterolemia, hypertriglyceridemia, and lowering atherogenic lipoproteins VLDL and LDL.

The compounds of the present invention can be used for the treatment of certain renal diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathies. The compounds of general formula (I) may also be useful in the treatment/prevention of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X, such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders.

The compounds of the invention may also be useful as aldose reductase inhibitors, for improving cognitive function in dementia, as anti-inflammatory agents, in the treatment of diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), inflammatory bowel disease, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, and in the treatment of cancer.

The compounds of the invention may also be used in combination/concomitantly with one or more HMG CoA reductase inhibitors; cholesterol absorption inhibitors; anti-obesity agents; a therapeutic agent for lipoprotein disorders; hypoglycemic agents: insulin, biguanides, sulfonylureas, thiazolidinediones, dual PPAR alpha and gamma agonists, or mixtures thereof. Combinations of the compounds of the present invention with HMG CoA reductase inhibitors, cholesterol absorption inhibitors, anti-obesity agents, hypoglycemic agents may be administered together or at certain stages to exert a synergistic effect.

The present invention also provides pharmaceutical compositions comprising a compound of general formula (I), their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates as defined above, together with one or more HMG CoA reductase inhibitors; cholesterol absorption inhibitors; anti-obesity agents; hypoglycemic agents: insulin, biguanides, sulfonylureas, thiazolidinediones, dual PPAR α and γ agonists or mixtures thereof in combination with pharmaceutically common carriers, diluents and the like.

The pharmaceutical compositions may be in conventional dosage forms, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, and may contain flavoring agents, sweeteners and the like in suitable solid or liquid carriers or diluents or in suitable sterile media for the formation of injectable solutions or suspensions. Such compositions typically contain from 1 to 20%, preferably from 1 to 10% by weight of the active compound, the remainder being pharmaceutically acceptable carriers, diluents or solvents.

Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The amount of active ingredient in such pharmaceutical compositions will be sufficient to provide the desired dosage within the above-described ranges. Thus, for oral administration, the compounds of formula (I) may be combined with suitable solid or liquid carriers or diluents to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may contain additional ingredients, such as flavoring agents, sweeteners, excipients, and the like, if desired. For parenteral administration, the compounds may be combined with a sterile aqueous or organic medium to form an injectable solution or suspension. For example, solutions of the compounds in sesame or peanut oil, aqueous propylene glycol, and the like, as well as aqueous solutions of water-soluble pharmaceutically acceptable acid addition or base salts, may be employed. Aqueous solutions of the active ingredient dissolved in polyhydroxylated castor oil may also be used as injectable solutions. Injectable solutions prepared in this manner may be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.

For nasal administration, the preparations may contain a compound of the invention dissolved or suspended in a liquid carrier, especially an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizers, e.g., propylene glycol; a surfactant; absorption enhancers, such as lecithin (phosphatidylcholine) or cyclodextrin; or preservatives, such as parabens.

Tablets, lozenges or capsules containing talc and/or carbohydrate binders and the like are particularly suitable for any oral use. Preferably, the carrier for the tablet, lozenge or capsule comprises lactose, corn starch and/or potato starch. In the case where sweeteners may be used, syrups or elixirs may be used.

The compounds of formula (I) as defined above are administered clinically to mammals, including humans, via oral or parenteral routes. Administration by the oral route is preferred and more suitable, avoiding the pain and irritation that may be caused by injection. However, parenteral administration of a drug is necessary in an environment where patients cannot swallow the drug or absorption after oral administration is poor due to diseases or other abnormalities. Regardless of the route, the dosage is from about 0.01 to about 100mg/kg body weight of the subject per day or preferably from about 0.01 to about 50mg/kg body weight per day, administered in single or divided doses. However, the optimal dosage for an individual subject will be determined by the person responsible for the treatment, and typically a smaller dosage will be administered initially and then escalated to determine the most appropriate dosage.

The compounds of the invention lower random blood glucose levels, triglycerides, total cholesterol, LDL, VLDL, and increase HDL through an agonistic mechanism. This can be demonstrated by means of in vitro as well as in vivo animal experiments.

The invention is explained in detail in the following examples, which are provided for illustration only and thus should not be construed as limiting the scope of the invention.

Preparation example 1

4- (3-Methanesulfonyloxypropyl) phenylmethanesulfonate

Step (i)

To a suspension of LAH (22.1g, 2.5eq, 583mmol) in dry THF (1.0L) at RT was added dropwise a solution of methyl 3- (4-hydroxyphenyl) propionate (21g, 1.0eq, 116mmol) in THF (50 ml). The reaction mixture was refluxed for 4-5 hours. Quench with excess ethyl acetate, followed by addition of water (23ml), 15% aq. NaOH (23ml) and water (70ml), stirring was controlled and the RT maintained. To the mixture was added concentrated HCl to adjust the pH to 7.0. Then filtered through celite, washing with ethyl acetate. The filtrates were combined and dried (Na)₂SO₄) And (4) concentrating. The resulting residue was chromatographed (ethyl acetate/hexane) to give 3- (4-hydroxyphenyl) propanol (17g, 100%) as a white solid.

Mp：52-54℃.

¹H NMR(CDCl₃，200MHzδ：1.78-1.86(m，2H)；2.63(t，J＝7.9Hz，2H)；3.67(t，J＝6.3Hz，2H)；6.74(d，J＝8.8Hz，2H)；7.05(d，J＝8.8Hz，2H).

IR(neat)cm^-1：3485，3029，2940，1505.

Mass m/z(CI)：152[M+1].

Step (ii)

Methanesulfonyl chloride (26ml, 3.0eq, 335.4mmol) was added dropwise to a solution of 3- (4-hydroxyphenyl) propanol (17g, 1.0eq, 111.8mmol) from step (i) and triethylamine (93.3ml, 6.0eq, 670.8mmol) in DCM (550ml) at 0 deg.C. The reaction mixture was stirred at RT for 16 h, then diluted with excess DCM and the organic layer was washed with dilute HCl, water and brine. The organic layer was dried (Na)₂SO₄) And (4) concentrating. The crude product was recrystallized from diisopropyl ether and the desired product was purified. The remaining mother liquor was concentrated and chromatographed (ethyl acetate/hexane) to give additional desired compound (total yield 20.8g, 61%) as a white solid.

Mp：60-62℃.

¹H NMR(CDCl₃，200MHz：δ2.00-2.18(m，2H)；2.77(t，J＝7.8Hz，2H)；3.00(s，3H)；3.13(s，3H)；4.23(t，J＝6.3Hz，2H)；7.22(aromatics，4H).

IR(neat)cm^-1：3029，2935，1504.

Mass m/z(CI)：309[M+1].

Note: the appearance of "aromatics" in the spectral data is "aromatic" and "neat" in the spectral data, the same applies below.

Preparation example 2

3- (3-Methanesulfonyloxypropyl) phenylmethanesulfonate

Prepared according to the typical method of preparation example 1.

Step (i)

From methyl 3-hydroxyphenylpropionate, 3- (3-hydroxyphenyl) propanol was obtained as a liquid (100%).

¹H NMR(CDCl₃，200MHz：δ1.80-1.88(m，2H)；2.64(t，J＝7.9Hz，2H)；3.49(bs，-OH)；3.67(t，J＝6.5Hz，2H)；6.65-6.76(aromatics，3H)；7.09-7.17(aromatics，1H).

IR(neat)cm^-1：3353，2932，2859，1590.

Massm/z(CI)：152[M+1].

Step (ii)

From the 3- (3-hydroxyphenyl) propanol obtained in step (i) (900mg, 1.0eq, 5.92mmol), 3- (3-methanesulfonyloxypropyl) phenylmethanesulfonate was obtained (52%) as a white solid.

Mp：60-62℃.

¹H NMR(CDCl₃，200MHz：δ2.00-2.18(m，2H)；2.79(t，J＝7.8Hz，2H)；3.00(s，3H)；3.15(s，3H)；4.22(t，J＝6.4Hz，2H)；7.10-7.20(aromatics，3H)；7.21-7.40(m，1H).

IR(neat)cm^-1：3030，2941，1586.

Mass m/z(CI)：309[M+1].

Preparation example 3

4- (3- (toluene-4-sulfonyloxy) propyl) phenyl toluene-4-sulfonate

To a solution of 3- (4-hydroxyphenyl) propanol (2.5g, 1.0eq, 16.44mmol) from preparation 1, step (i), in DCM (82ml) and triethylamine (11.4ml, 5.0eq, 82.2mmol) was added toluene-4-sulfonyl chloride (9.4g, 3.0eq, 49.3mmol) dropwise at 0 ℃. The reaction mixture was stirred at RT for 16 h, then diluted with excess DCM and the organic layer washed with water and brine. Drying (Na)₂SO₄) And after concentration, the resulting crude residue was subjected to chromatography (ethyl acetate/hexane) to give the desired compound (5.1g, 67.7%) as a thick liquid。

¹H NMR(CDCl₃，200MHz：δ1.90(quintet，J＝7.9Hz，2H)；2.44(s，6H)；2.61(t，J＝6.8Hz，2H)；3.98(t，J＝6.3Hz，2H)；6.83(d，J＝8.8Hz，2H)；6.97(d，J＝8.8Hz，2H)；7.32(t，J＝7.5Hz，2H)；7.67(d，J＝8.3Hz，2H)；7.76(d，J＝8.3Hz，2H).

IR(neat)cm^-1：2926，1597，1502，1364.

Massm/z(CI)：461[M+1].

Preparation example 4

2- (4-Nitrophenoxy) ethyl bromide

4-nitrophenol (1.0g, 1.0eq, 7.19mmol), 1, 2-dibromoethane (3.85ml, 6.0eq, 43.1mmol) and anhydrous K₂CO₃A mixture of (3.0g, 3eq, 21.5mmol) in anhydrous acetone (36ml) was stirred at RT for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The concentrate was again dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried (Na)₂SO₄) Concentrated, and the residue chromatographed using ethyl acetate and hexane to give the title compound as a solid (540mg, 32%).

Mp：168℃

¹H NMR(CDCl₃，200MHz)：δ3.67(t，J＝6.1Hz，2H)；4.38(t，J＝6.1Hz，2H)；6.97(d，J＝8.7Hz，2H)；8.20(d，J＝8.7Hz，2H).

IR(neat)cm^-1：2925，1592，1511，1330.

Mass m/z(CI)：245[M(⁷⁹Br)]，246[M(⁷⁹Br+1]，247[M(⁸¹Br)]，248[M(⁸¹Br)+1].

Preparation 5

2-ethoxy-3- (4-aminophenyl) propionic acid ethyl ester

Step (i)

Wittig salts were prepared from triethyl 2-ethoxyphosphonoacetate (26.5g, 1.5eq, 99.3mmol) and NaH (50% in oil) in THF (350ml) at 0 deg.C. To this solid was added 4-nitrobenzaldehyde (10g, 1eq, 66.2mmol) portionwise at 0 ℃ and the resulting solution was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate and washed with aqueous NH₄And (5) washing with Cl. The crude product contained ethyl p-nitro-2-ethoxycinnamate as Z and E stereoisomers (11 g).

Step (ii)

(ii) Ethyl p-nitro-2-ethoxycinnamate obtained in step (i) was used in 10% Pd-C-H in ethyl acetate (150ml) at room temperature₂(60psi) (11g) hydrogenation, chromatography eluting with ethyl acetate/hexanes afforded the title compound as a viscous oil (9.41g, 60%).

¹H NMR(CDCl₃，200MHz)：δ1.16(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(CI)：238(M+1)，192(M-OC₂H₅).

Preparation example 6

2-ethoxy-3- (4-aminophenyl) propionic acid methyl ester

Step (i)

Wittig salt (6.28g, 2eq, 132mmol) was prepared from triethyl 2-ethoxyphosphonoacetate (34.3ml, 2eq, 132mmol) and NaH (50% in oil) in THF (350ml) at 0 deg.C. P-nitrobenzaldehyde (10g, 1eq, 66mmol) was added portionwise to the solid at 0 ℃ and the resulting solution was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate and washed with aqueous NH₄And (5) washing with Cl. The crude product contained ethyl p-nitro-2-ethoxycinnamate as Z and E stereoisomers (15g, 86%).

Step (ii)

The crude compound obtained in step (i) (15g, 1eq, 56.6mmol) was dissolved in methanol (250 ml). Ammonium formate (35.6g, 10eq, 566mmol) and 10% Pd-C (40g) were added thereto and the reaction mixture was stirred at RT for 16 hours. The catalyst is filtered off and the filtrate is concentrated on a rotary evaporator. The residue was diluted with ethyl acetate, washed with water and brine. The crude product was chromatographed to give ethyl 2-ethoxy-p-aminocinnamate as (E) and (Z) isomers (10g, 75%).

Step (iii)

The ethyl 2-ethoxy-p-aminocinnamate (10g, 1eq, 42.5mmol) obtained in step (ii) was treated with magnesium (20.4g, 20eq, 850mmol) and dry methanol (500 ml). The reaction mixture was refluxed for 2-3 hours and stirred at room temperature for 16 hours. 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, eluting with ethyl acetate and hexanes to give the title compound as a viscous liquid (8.06g, 80%).

¹H NMR(200MHz，CDCl₃)：δ1.64(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(neat)cm^-1：3350(br)，1735.

Mass m/z(CI)：224[M+1].

Preparation example 7

2-ethoxy-3- (3-aminophenyl) propionic acid ethyl ester

Starting from 3-nitrobenzaldehyde, following a typical procedure as in preparation 5, the title compound was obtained as a thick oil (60%, two steps).

¹NMR(200MHz，CDCl₃)：δ1.17(t，J＝7Hz，3H)；1.22(t，J＝7Hz，3H)；2.91(d，J＝6.7Hz，2H)；3.30-3.48(m，1H)；3.48-3.62(m，lH)；4.00(t，J＝6.7Hz，1H)；4.17(q，J＝7Hz，2H)；6.50-6.70(aromatics，3H)；7.06(t，J＝7.5Hz，1H).

IR(neat)cm^-1：3374，2978，1738，1606

Mass m/z(CI)：238[M+1]

Preparation example 8

2-Isopropoxy-3- (4-nitrophenyl) propionic acid ethyl ester

Step (i)

4-Nitrophenylalanine (5g, 1eq, mmol) was added portionwise to a solution of anhydrous ethanol (50ml) and thionyl chloride (5ml) at-5 ℃. Stirring was continued at this temperature for a further 1 hour, followed by stirring at RT for 16 hours. The reaction mixture was concentrated on a rotary evaporator, azeotroped with toluene, and then dried on a high vacuum pump to give 4-nitrophenylalanine ethyl ester hydrochloride as a white solid (quantitative yield).

Step (ii)

The ethyl 4-nitrophenylalaninate hydrochloride obtained in step (i) (2g, 1.0eq, 7.28mmol) was dissolved in ethyl acetate (150 ml). Adding Na thereto₂CO₃(386mg, 0.5eq, 3.64mmol) and stirred for 15 min. NaHCO for reaction mixture₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Concentration gave 4-nitrophenylalanine ethyl ester as a thick oil (1.55g, 89%).

Step (iii)

The ethyl 4-nitrophenylalaninate obtained in step (ii) (1.55g, 1.0eq, 6.51mmol) was dissolved in chloroform (33 ml). Glacial acetic acid (20. mu.l, 0.05eq, 0.33mmol) and isovaleronitrile (958. mu.l, 1.1eq, 7.16mmol) were added to it and the reaction mixture was heated at reflux for 30 min. The reaction mixture was diluted with chloroform and NaHCO₃And (4) washing with an aqueous solution. The organic layer was dried (Na)₂SO₄) Concentrate (caution!) to a yellow liquid.

Step (iv)

(iv) the liquid obtained in step (iii) (1.54g, 1.0eq, 6.18mmol) was dissolved in anhydrous isopropanol (31ml) and Rh was added thereto in a catalytic amount₂(OAc)₄.2H₂O (38mg, 0.02eq, 0.12mmol), the reaction mixture was stirred at room temperature for 16 h. The isopropanol was concentrated and the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and brine and dried (Na)₂SO₄) And (4) concentrating. Column chromatography eluting with ethyl acetate and hexanes afforded the desired compound, ethyl 2-isopropoxy-3- (4-nitrophenyl) propionate (1.25g, 61% total).

¹H NMR(200MHz，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(neat)cm^-1：2975，1747，1602，1522，1347.

Mass m/z(CI)：282[M+1]

Note: wherein the "guinet" appearing in the spectral data is "quintuple", as follows.

Preparation example 9

2-Isopropoxy-3- (4-aminophenyl) propionic acid ethyl ester

Ethyl 2-isopropoxy-3- (4-nitrophenyl) propionate obtained in preparation example 8 (1.52g, 5.4mmol) was hydrogenated under a molecular hydrogen pressure of 10psi for 3-4 hours in ethyl acetate (200ml) at room temperature, using 10% Pd/C (700mg) as a catalyst. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the desired product was isolated. The crude product was subjected to column chromatography, eluting with ethyl acetate and hexane, to give the desired compound ethyl 2-isopropoxy-3- (4-aminophenyl) propionate (1.16g, 86% in total).

¹H NMR(200MHz，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(CI)：252[M+1]

Preparation example 10

4-methanesulfonyloxybenzaldehyde

4-hydroxybenzaldehyde (5.0gm, 1.0eq, 40.98mmol), anhydrous K₂CO₃A mixture of (17g, 3eq, 123mmol) and methanesulfonamide (4.76ml, 1.5eq, 61.37mmol) in anhydrous DMF (200ml) was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (200ml), which was washed with water and brine. The organic layer was dried (Na)₂SO₄) Concentrated and the resulting residue chromatographed, eluting with ethyl acetate and hexanes to give the title compound as a white solid (2.0g, 25%).

Mp：60-62℃.

¹H NMR(CDCl₃，200MHz)δ：3.21(s，3H)；7.45(d，J＝8.8Hz，2H)；7.95(d，J＝8.8Hz，2H)；10.01(s，1H).

IR(neat)cm^-1：3024，2932，1701，1591，1502.

Mass m/z(CI)：201[M+1].

Preparation example 11

2- (4-hydroxyphenyl) -1-ethanol

A solution of methyl 2- (4-hydroxyphenyl) acetate (3.0g, 18.07mmol) in THF (20ml) was added to a stirred suspension of LAH (0.89g, 23.49mmol) in THF (20ml) at 0 deg.C. Stirring was continued at RT for 4 hours. Excess LAH with saturated Na₂SO₄The solution was quenched and the precipitate formed was filtered off. The filtrate was extracted with ethyl acetate, the organic extracts washed with brine and dried (Na)₂SO₄) And evaporating to dryness. Purification by column eluting with 50% ethyl acetate-petroleum ether gave the title compound (1.1g, 44%) as a white solid.

Mp：88-92℃.

¹H NMR(200MHz，CDCl₃+DMSO-d₆)：δ2.75(t，J＝7.1Hz，2H)；3.75(t，J＝6.3Hz，2H)；6.75(d，J＝8.3Hz，2H)；7.03(d，J＝8.3Hz，2H).

Mass m/z(CI)：138[M].

Preparation example 12

4- (2-Methanesulfonyloxyethyl) phenylmethanesulfonate

According to a similar manner to that described in preparation example 1 step (ii), 2- (4-hydroxyphenyl) -1-ethanol (1.0g, 7.25mmol) obtained in preparation example 11 was treated with triethylamine (2.52ml, 16.1mmol) and methanesulfonyl chloride (0.83ml, 15.9mmol) in DCM (20ml) at room temperature for 2 hours to give the title compound (2g, 94%).

¹H NMR(200MHz，CDCl₃)：δ2.91(s，3H)；3.08(t，J＝6.8Hz，2H)；3.15(s，3H)；4.42(t，J＝6.8Hz，2H)；7.20-7.34(m，4H).

Mass m/z(CI)：199[M-OSO₂Me].

Preparation example 13

2- (4-Methanesulfonyloxyphenyl) acetic acid methyl ester

According to a similar manner to that described in preparation example 1 step (ii), methyl 2- (4-hydroxyphenyl) acetate (1.5g, 9.04mmol) was treated with triethylamine (3.14ml, 22.59mmol) and methanesulfonyl chloride (0.84ml, 10.84mmol) in DCM (20ml) at room temperature for 2 hours to give the title compound (1.7g, 77%).

¹H NMR(200MHz，CDCl₃)：δ3.14(s，3H)；3.64(s，2H)；3.71(s，3H)；7.24(d，J＝8.8Hz，2H)；7.34(d，J＝8.8Hz，2H).

Mass m/z：244[M].

Preparation example 14

2- (4-Methanesulfonyloxyphenyl) acetic acid

To a solution of methyl 2- (4-methanesulfonyloxyphenyl) acetate (0.95g, 3.89mmol) obtained in preparation example 13 in methanol (10ml) was added Na₂CO₃(2.06g, 19.48mmol) in water (5ml) and the reaction mixture was stirred at RT for 24 h. The methanol was evaporated and the residue was dissolved in water and washed with ethyl acetate until free of impurities, if any. The aqueous layer was acidified to pH about 2 and the title compound (0.55g, 61.4%) was isolated as a white solid.

Mp：158-162℃.

¹H NMR(200MHz，DMSO-d₆)：δ3.32(s，3H)；3.62(s，2H)；7.28(d，J＝8.9Hz，2H)；7.37(d，J＝8.6Hz，2H).

Mass m/z(CI)：231[M+1]；230[M].

Preparation example 15

4-Nitrocinnamic acid methyl ester

A solution of 4-nitrocinnamic acid (3g, 15.54mmol) in methanol (50ml) was cooled to 10 ℃ and concentrated H was slowly added₂SO₄(1ml) and then refluxed for 30 hours. Methanol was evaporated under reduced pressure. Ethyl acetate (150ml) was added to the residue and the solution was taken up in water and saturated NaHCO respectively₃The solution, water and brine were washed. The organic layer was dried (Na)₂SO₄) Evaporation gave the title compound (3g, 93%) as an off-white solid.

Mp：158-160℃.

¹H NMR(200MHz，CDCl₃)：δ3.84(s，3H)；6.56(d，J＝15.9Hz，1H)；7.64-7.78(m，3H)；8.25(d，J＝8.9Hz，2H).

Mass m/z(CI)：208[M+1]；194[M-CH₃].

Preparation example 16

3- (4-aminophenyl) propionic acid methyl ester

To a solution of methyl 4-nitrocinnamate (1.5g, 7.25mmol) obtained in preparation example 15 in dioxane (25ml) was added 10% Pd-C (0.6g), and the mixture was hydrogenated at 60psi for 20 hours at room temperature. The reaction mixture was filtered through celite and concentrated under reduced pressure. The crude residue was purified by column chromatography eluting with 50% EtOAc-petroleum ether to give the pure title compound (1.07g, 82.5%) as an off-white solid.

Mp：142-144℃.

¹H NMR(200MHz，CDCl₃)：δ2.57(t，J＝7.5Hz，2H)；2.85(t，J＝7.8Hz，2H)；3.66(s，3H)；6.64(d，J＝8.3Hz，2H)；7.00(d，J＝8.3Hz，2H).

Mass m/z(CI)：180[M+1].

Preparation example 17

3- (4-aminophenyl) -1-propanol

A cold solution of methyl 3- (4-aminophenyl) propionate (0.48g, 2.7mmol) from preparation 16 in THF (10ml) was added dropwise slowly to a suspension of LAH (132mg, 3.49mmol) in THF (10ml) at 0 ℃ and stirred at room temperature overnight. Unreacted LAH is saturated with Na₂SO₄The solution was quenched, filtered through celite, and the filter bed was washed thoroughly with ethyl acetate. The filtrate and washings were combined and the organic layer was dried (Na)₂SO₄) And (4) evaporating. The residue was purified to give the title compound (0.27g, 66.7%) as a yellow solid.

Mp：54-56℃.

¹H NMR(200MHz，CDCl₃)：δ1.88-1.92(m，2H)；2.60(t，J＝7.5Hz，2H)；3.66(t，J＝6.3Hz，2H)；6.63(d，J＝8.1Hz，2H)；6.99(d，J＝8.1Hz，2H).

Mass m/z(CI)：152[M+1].

Preparation example 18

3- (4-amino-4-tert-butoxyphenyl) -1-propanol

To a cold (0 ℃ C.) solution of 3- (4-aminophenyl) -1-propanol (0.5g, 3.3mmol) obtained in preparation example 17 in methylene chloride (15ml) was added Et₃N (1.4ml), followed by addition of Boc-anhydride (0.84ml, 3.64mmol), the mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with DCM (50ml), the organic layer washed with water and brine and dried (Na)₂SO₄) And evaporating to dryness. The residue was subjected to column chromatography to give the title compound (0.4g, 48%) as a colorless oil.

¹H NMR(200MHz，CDCl₃)：δ1.44-1.53(m，9H)；1.78-1.93(m，2H)；2.64(t，J＝7.6Hz，2H)；3.64(t，J＝6.6Hz，2H)；6.41(bs，1H，D₂O exchangeable)；7.10(d，J＝8.3Hz，2H)；7.25(d，J＝8.3Hz，2H).

Mass m/z(CI)：252[M+1]；152[M-Boc].

Preparation example 19

3- (4-tert-butoxy-4-methanesulfonamidophenyl) propyl methanesulfonate

To a cold (0 ℃ C.) solution of 3- (4-amino-4-tert-butoxyphenyl) -1-propanol (0.5g, 3.3mmol) obtained in preparation example 18 in dichloromethane (10ml) was added Et₃N (1.4ml) followed by addition of methanesulfonyl chloride (0.27ml, 3.5mmol) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM (50ml), the organic layer washed with water and brine and dried (Na)₂SO₄) Evaporated to dryness to give the title compound (0.61g, 94%).

¹H NMR(200MHz，CDCl₃)：δ1.50(s，9H)；1.95-2.10(m，2H)；2.68(t，J＝7.5Hz，2H)；2.97(s，3H)；3.13(s，1H)；3.66(s，2H)；4.19(t，J＝6.3Hz，2H)；7.08(d，J＝8.3Hz，2H)；7.27(d，J＝8.3Hz，2H).

Mass m/z(CI)：329[M-SO₂Me].

Preparation example 20

4-Hydroxycinnamic acid methyl ester

4-Hydroxycinnamic acid (2g, 12.18mmol) was reacted with methanol (25ml) and concentrated H in the same manner as described in preparation example 15₂SO₄(0.8ml) for 20 h to give the title compound as a brown solid.

Mp：144-146℃.

¹H NMR(200MHz，CDCl₃)：δ3.8o(s，3H)；5.69(bs，D₂O exchangeable)；6.30(d，J＝15.8Hz，1H)；6.85(d，J＝8.6Hz，2H)；7.43(d，J＝8.6Hz，2H)；7.64(d，J＝16.1Hz，1H).

Mass m/z(CI)：179[M+1].

Preparation example 21

(E) -3- (4-hydroxyphenyl) -2-propen-1-ol

A THF (15ml) solution of methyl 4-hydroxycinnamate (1.5g, 8.43mmol) from preparation 20 was added dropwise to a suspension of LAH (416mg) in anhydrous THF (10ml) at 0 ℃ and the reaction mixture was stirred at room temperature for 2 hours. Filtration of LAH with saturated Na₂SO₄The solution was quenched. Filtered through a bed of celite and the filtrate dried (Na)₂SO₄) And evaporating to dryness. The residue was purified by column chromatography eluting with 20% EtOAc in petroleum ether to give the title compound (0.4g, 31.6%) as an off-white solid.

Mp：116-118℃.

¹H NMR(200MHz，CD₃OD)δ：4.17(d，J＝5.9Hz，2H)；6.15(td，J＝5.9 and 15.8Hz，1H)；6.50(d，J＝5.9Hz，1H)；6.71(d，J＝8.3Hz，2H)；7.23(d，J＝8.6Hz，2H)

Mass m/z(CI)：151[M+1]

Preparation example 22

4- [ (E) -3-chloro-1-propenyl ] phenylmethanesulfonate

(E) -3- (4-hydroxyphenyl) -2-propen-1-ol (0.36g, 2.4mmol), DCM (10ml), Et obtained from preparation 21 in the same manner as described in preparation 19₃N (0.83ml) and methanesulfonyl chloride (0.41ml) gave the title compound (0.47g, 64%).

¹H NMR(200MHz，CDCl₃)：δ3.14(s，3H)；4.24(d，J＝7.0Hz，2H)；6.21-6.4(m，1H)；6.65(d，J＝15.8Hz，1H)；7.25(d，J＝8.6Hz，2H)；7.43(d，J＝8.8Hz，2H).

Mass m/z(CI)：247[M+1].

Preparation example 23

(E) -3- (4-methanesulfonyloxyphenyl) -2-propenoic acid

From (E) -4-hydroxycinnamic acid (1.0g, 6.1mmol), DCM (20ml), Et in the same manner as described in preparation 19₃N (2.12ml, 15.24mmol) and methanesulfonyl chloride (0.57ml, 7.32mmol) gave the title compound (0.53g, 36%).

¹H NMR(200MHz，CDCl₃)：δ3.20(s，3H)；6.51(d，J＝15.8Hz，1H)；7.36(d，J＝8.62H)；7.64(d，J＝8.3Hz，2H)；7.81(d，J＝15.8Hz，1H).

Mass m/z(CI)：243[M+1].

Preparation example 24

3- (4-Methanesulfonyloxyphenyl) propionic acid

Prepared in the same manner as described in preparation 19 from 3- (4-hydroxyphenyl) propionic acid (1.0g, 6.02mmol), DCM (15ml), Et₃N (2.1ml, 15.06mmol) and methanesulfonyl chloride (0.56ml, 7.23mmol) gave the title compound (1.02g, 69.4%).

¹H NMR(200MHz，CDCl₃)：δ2.74(t，J＝7.4Hz，2H)；3.00-3.09(m，2H)；3.14(s，3H)；7.14-7.37(m，4H).

Mass m/z(CI)：245[M+1].

Preparation example 25

(2S) -3- (4-aminophenyl) -2-ethoxypropionic acid ethyl ester and (2R) -3- (4-aminophenyl) -2-ethoxypropionic acid ethyl ester

Step (i): 3- (4-dibenzylaminophenyl) -2-ethoxypropionic acid ethyl ester

To a cold solution of ethyl 2-ethoxy-3- (4-aminophenyl) propionate (2.0g, 8.44mmol) obtained in preparation example 5 in anhydrous DMF (30ml) was added Na₂CO₃(2.68g, 25.3mmol), and stirred for 15 minutes. To this solution was then added benzyl bromide (2.0ml, 16.88mmol) dropwise and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (50ml) and extracted with ethyl acetate (3X 50 ml). The combined organic layers were washed with brine and dried (Na)₂SO₄) Evaporated to dryness to give the title compound as a yellow oil (3.42g, 97%) which was used in the next step without purification.

¹H NMR(200MHz，CDCl₃)：δ1.06-1.32(m，6H)；2.89(d，J＝6.4Hz，2H)；3.28-3.48(m，1H)；3.52-3.70(m，1H)；3.95(t，J＝6.6Hz，1H)；4.12(q，J＝7.0Hz，2H)；4.63(s，4H)；6.67(d，J＝7.0Hz，2H)；7.03(d，J＝8.3Hz，2H)；7.15-7.43(m，10H).

Mass m/z(CI)：418[M+1].

Step (ii): 3- (4-dibenzylaminophenyl) -2-ethoxypropionic acid

(ii) conversion to step (i)A solution of the compound (0.5g, 1.2mmol) in methanol (10ml) was added Na₂CO₃(380mg, 3.6mmol) in water (2ml) and the reaction mixture was stirred at RT for 3 days. The methanol was then removed and the reaction mixture was diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate to remove any undesirable non-polar impurities. The aqueous layer was then acidified to pH about 4 with 2N HCl solution and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with brine (3X 10ml), dried (Na)₂SO₄) And concentrated to give the title compound (0.340g, 74%).

¹H NMR(200MHz，CDCl₃)：δ1.17(t，J＝7.1Hz，3H)；2.82-3.05(m，2H)；3.29-3.67(m，2H)；3.97-4.09(m，1H)；4.63(s，4H)；6.67(d，J＝8.8Hz，2H)；7.03(d，J＝8.3Hz，2H)；7.13-7.42(m，10H).

Mass m/z(CI)：390[M+1].

Step (iii): n1- [ (1S) -1-phenylpropyl ] - (2S) -3- (4-dibenzylaminophenyl) -2-ethoxypropionamide (iiia) and N1- [ (1S) -1-phenylpropyl ] - (2R) -3- (4-dibenzylaminophenyl) -2-ethoxypropionamide (iiib)

To a cold solution of the compound obtained in step (ii) (1.0g, 2.57mmol) in anhydrous DCM were added 5-hydroxybenzotriazole (172mg, 1.286mmol) and EDCI (592mg, 3.08mmol) and the reaction mixture was stirred at 0 deg.C for 30 min (until it became a clear solution). To this solution was added 2-L-phenylglycinol (0.37g, 2.69mmol) and stirred at RT for 16 h. The reaction mixture was diluted with DCM (25ml), washed with water (3X 25ml) and dried (Na)₂SO₄) And (4) concentrating. The diastereomers were separated on a silica gel column, eluting with 10-45% ethyl acetate in petroleum ether.

Yield of iiia: 420mg (32%); white solid, mp: 110 ℃ and 112 ℃.

Yield of iiib: 380mg (29%).

iiia：¹H NMR(200MHz，CDCl₃)：δ1.18(t，J＝7.1Hz，3H)；2.74-3.12(m，2H)；3.46-3.64(m，2H)；3.87(d，J＝5.4Hz，2H)；3.98(dd，J＝6.9 and 3.7Hz，1H)；4.64(s，4H)；4.93-5.05(m，1H)；6.64(d，J＝8.4Hz，2H)；7.02(d，J＝8.3Hz，2H)；7.12-7.46(m，15H).

Mass m/z(CI)：509[M+1].

iiib：¹H NMR(200MHz，CDCl₃)：δ1.13(t，J＝7.6Hz，3H)；2.80-3.16(m，2H)；3.39-3.68(m，4H)；3.96(dd，J＝3.9 and 5.5Hz，1H)；4.64(s，4H)；4.85-5.00(m，1H)；6.67(d，J＝6.8Hz，2H)；6.97(d，J＝6.8Hz，2H)；7.06(d，J＝8.3Hz，2H)；7.12-7.42(m，13H).

Mass m/z(CI)：509[M+1].

Step (iv): (2S) -3- (4-dibenzylaminophenyl) -2-ethoxypropionic acid (iva)

To a solution of compound iiia (410mg, 0.8mmol) in dioxane (6ml) was added 1MH₂SO₄(4ml), the reaction mixture was refluxed for 24 hours. Dioxane was removed under reduced pressure and the residue was diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate (3X 25ml), the organic layers were combined, washed with brine and dried (Na)₂SO₄) And evaporating to dryness. The crude product was purified on silica gel, eluting with 40% ethyl acetate in petroleum ether to give the title compound (180mg, 58%).

[α]_D ²⁵＝1.8°(c0.5，MeOH).

¹H NMR(200MHz，CDCl₃)：δ1.16(t，J＝7.6Hz，3H)；2.80-3.07(m，2H)；3.43-3.68(m，2H)；4.16(dd，J＝7.3 and 4.4Hz，1H)；4.61(s，4H)；6.65(d，J＝8.3Hz，2H)；7.04(d，J＝8.8Hz，2H)；7.12-7.39(m，10H).

Mass m/z(CI)：390[M+1].

(2R) -3- (4-dibenzylaminophenyl) -2-ethoxypropionic acid (ivb)

Following the same procedure as described for the preparation of compound iva, compound iiib (0.5g, 0.98mmol) and 1M H were reacted₂SO₄(5ml) refluxing in dioxane for 24 h gave compound ivb (152mg, 60%).

¹H NMR(200MHz，CDCl₃)：δ1.18(t，J＝7.0Hz，3H)；2.83-3.05(m，2H)；3.40-3.67(m，2H)；4.03(dd，J＝7.3 and 4.3Hz，1H)；4.63(s，4H)；6.67(d，J＝8.6Hz，2H)；7.03(d，J＝8.6Hz，2H)；7.15-7.40(m，10H).

Mass m/z(CI)：390[M+1].

Step (v): (2S) -3- (4-dibenzylaminophenyl) -2-ethoxypropionic acid ethyl ester (va)

To a cooled solution of compound iva (1.2g, 3.08mmol) in anhydrous DMF (30ml) was added K₂CO₃(1.277g, 9.25mmol), and stirred at low temperature for 15 minutes. Ethyl iodide (0.75ml, 9.25mmol) was added and the reaction mixture was stirred at RT for 3 h. Water was added to the reaction mixture, which was extracted with ethyl acetate (3X 30 ml). The combined organic layers were washed (brine) and dried (Na)₂SO₄) Concentration gave the title compound (1.1g, 85%).

¹H NMR(200MHz，CDCl₃)：δ1.09-1.30(m，6H)；2.90(d，J＝6.5Hz，2H)；3.27-3.67(m，2H)；3.96(t，J＝6.7Hz，1H)；4.14(q，J＝7.3Hz，2H)；4.63(s，4H)；6.65(d，J＝8.6Hz，2H)；7.03(d，J＝8.3Hz，2H)；7.15-7.42(m，10H).

Mass m/z(CI)：418[M+1].

(2R) -3- (4-dibenzylaminophenyl) -2-ethoxypropionic acid ethyl ester (vb)

The same procedure as described for the preparation of va was followed from compound ivb (150mg, 0.39mmol), K in anhydrous DMF₂CO₃(156mg, 1.17mmol), ethyl iodide (0.09ml, 1.17mmol) gave compound vb (120mg, 74%).

¹H NMR(200MHz，CDCl₃)：δ1.08-1.30(m，6H)；2.89(d，J＝6.4Hz，2H)；3.28-3.67(m，2H)；3.95(t，J＝10Hz，1H)；4.13(q，J＝7.0Hz，2H)；4.62(s，4H)；6.64(d，J＝8.6Hz，2H)；7.02(d，J＝8.6Hz，2H)；7.19-7.40(m，10H).

Mass m/z(CI)：418[M+1].

Step (vi): (2S) -3- (4-aminophenyl) -2-ethoxypropionic acid ethyl ester (via)

To a solution of va (1.0g, 2.4mmol) in methanol (20ml) was added 10% Pd-C (0.2g, 20% w/w) and the mixture was hydrogenated on a parr hydrogenator at 60psi and RT for 24 h. The reaction mixture was filtered through celite and the filter bed was washed with methanol. The layers were combined, evaporated to dryness and the residue was purified on silica gel eluting with 20% EtOAc in petroleum ether to give the title compound (300mg, 53%).¹H NMR(200MHz，CDCl₃)：δ1.17(t，J＝6.8Hz，3H)；1.23(t，J＝7.0Hz，3H)；2.91(d，J＝6.8Hz，2H)；3.25-3.79(m，2H)；3.95(t，J＝6.8Hz，1H)；4.13(q，J＝7.6Hz，2H)；6.62(d，J＝8.3Hz，2H)；7.03(d，J＝8.3Hz，2H).

Mass m/z(CI)：238[M+1].

(2R) -3- (4-aminophenyl) -2-ethoxypropionic acid ethyl ester (vib)

According to the same method as described for the preparation of compound via, compound vb (1.6g, 3.89mmol) was treated with 10% Pd-C (0.32g, 20% w/w) in methanol (20ml) for 24 h to give compound vib (1.6g, 84%).

¹H NMR(200MHz，CDCl₃)：δ1.17(t，J＝7.0Hz，3H)；1.23(t，J＝7.0Hz，3H)；2.90(d，J＝6.7Hz，2H)；3.25-3.80(m，2H)；3.94(t，J＝6.7Hz，1H)；4.16(q，J＝7.1Hz，2H)；6.61(d，J＝8.3Hz，2H)；7.03(d，J＝8.1Hz，2H).

Mass m/z(CI)：238[M+1].

Preparation example 26

(S) -2-ethoxy-3- (4-aminophenyl) propionic acid ethyl ester

Step (i)

(S) - (4-Nitrophenyl) glycine (10g, 47.6mmol) in water (50ml), H was added over 30 minutes at-5 ℃ with stirring₂SO₄A solution of a mixture of (1M, 60ml) and acetone (150ml) was added dropwise to a solution of sodium nitrite (9.85g, 142.8mmol) in water (40 ml). The reaction mixture was stirred at-5 to 0 ℃ for an additional 1.5 hours, followed by stirring at room temperature for 16 hours. The acetone was removed and the reaction mixture was diluted with 500ml ethyl acetate. The organic layer was washed with brine, over anhydrous Na₂SO₄Drying and concentrating. The crude product is recovered from isopropyl acetateCrystals were purified (9.0g, 96%).

Mp：134-136℃

[α]_D：-25°(c1.0，MeOH)

¹H NMR(CDCl₃)：δ3.04(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(neat)cm^-1：3485，3180，2927，1715，1515，1343.

Mass m/z(CI)：212(M+1).

Step (ii)

(S) -2-hydroxy-3- (4-nitrophenyl) propionic acid (9.0g, 42.6mmol) obtained in step (i) above was dissolved in anhydrous EtOH (300 ml). To this solution was added concentrated H₂SO₄(326. mu.l, 5.9mmol) and refluxed for 5 to 6 hours. The reaction mixture was neutralized with aqueous sodium bicarbonate. The ethanol was concentrated on a rotary evaporator and the residue was dissolved in ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate, water, brine, then over anhydrous Na₂SO₄Drying and concentrating. The crude product was crystallized from diisopropyl ether to give the desired product (8.0g, 78.5%).

Mp：74-76℃.

[α]_D：-13°(c1.0，MeOH)

¹H NMR(CDCl₃)：δ1.30(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＝7，4.3Hz，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(CI)：240(M+1).

Step (iii)

(S) -ethyl 2-hydroxy-3- (4-nitrophenyl) propionate obtained in step (ii) above (4.77g, 19.95mmol), molecular sieves (4A) (5.0g) and powdered Ag at room temperature₂A mixture of O (13.8g, 59.8mmol) in dry acetonitrile (100ml) was added ethyl iodide (6.4ml, 79.8 mmol). The reaction mixture was heated at 60 ℃ for 16 hours. The reaction mixture was filtered through celite and concentrated. The crude product was chromatographed, eluting with ethyl acetate and hexanes to give the desired product as a viscous liquid (3.5g, isolated yield 67%). Unreacted starting material (900mg) was recovered and it was reused.

[α]_D：-26°(c1.0，MeOH)

¹H NMR(CDCl₃)：δ1.15(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(neat)cm^-1：2980，1747，1604，1521，1347.

Mass m/z(CI)：268(M+1).

Step (iv)

(S) -ethyl 2-ethoxy-3- (4-nitrophenyl) propionate obtained in (iii) above (6.0, 25.3mmol) was dissolved in anhydrous methanol (100 ml). To this solution was added 10% Pd/C (2.0g) and hydrogenated with hydrogen (20psi) for 3-4 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated to give a syrup. The product was obtained in quantitative yield.

[α]_D：-14.2°(c1.0，MeOH).

Chiral HPLC：＞98％ ee.

¹H NMR(CDCl₃)：δ1.16(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(neat)cm^-1：3372，1738.

Mass m/z(CI)：238(M+1)，192(M-OC₂H₅).

Preparation example 27

(S) -2-methoxy-3- (4-aminophenyl) propionic acid ethyl ester

Step (i)

To the ethyl (S) -2-hydroxy-3- (4-nitrophenyl) propionate obtained in preparation 26 step (ii) (12.5g, 52.3mmol) and powdered Ag at room temperature₂A mixture of O (36.3g, 157mmol) in dry acetonitrile (260ml) was added methyl iodide (13ml, 209.2 mmol). Activated molecular sieve (4A) (12.5g) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite and concentrated. The crude product was chromatographed, eluting with ethyl acetate and hexanes to give the desired product as a viscous liquid (10.0g, 75%).

[α]_D：-30.1°(c1.0，MeOH)

¹H NMR(CDCl₃)：δ1.24(t，J＝7.1Hz，3H)；3.09(d，J＝5.4Hz，1H)；3.12(d，J＝2.7Hz，1H)；3.35(s，3H)；3.96(dd，J＝7.5，5.1Hz，1H)；4.19(q，J＝7.1Hz，2H)；7.39(d，J＝8.6Hz，2H)；8.13(d，J＝8.6Hz，2H).

IR(neat)cm^-1：2995，1747，1604，1521，1343.

Mass m/z(CI)：254(M+1).

Step (ii)

(S) -ethyl 2-methoxy-3- (4-nitrophenyl) propionate obtained in (i) above (8.0, 31.6mmol) was dissolved in anhydrous methanol (200 ml). To this solution was added 10% Pd/C (2.5g) and hydrogenated with hydrogen (20psi) for 3-4 hours. The reaction mixture was filtered through celite and concentrated to a slurry. The desired product was isolated by column chromatography eluting with ethyl acetate/hexanes as a thick liquid (7.0g, quant.).

[α]_D：-14.1°(c1.0，MeOH).

Chiral HPLC：＞98％ee.

¹H NMR(CDCl₃)：δ1.23(t，J＝7.2Hz，3H)，2.91(d，J＝6.1Hz，2H)，3.30(bs，2H，NH₂)，3.34(s，3H)，3.88(t，J＝6.2Hz，1H)，4.17(q，J＝7.2Hz，2H)，6.62(d，J＝8.3Hz，2H)，7.01(d，J＝8.1Hz，2H).

IR(neat)cm^-1：3372，2985，2932，1739，1627，1519.

Mass m/z(CI)：223(M)，234(M+1)，192(M-OMe).

Preparation example 28

(S) -2-ethoxy-3- (4-aminophenyl) propionic acid ethyl ester

Step (i)

Ethyl (S) -2-hydroxy-3- (4-nitrophenyl) propionate obtained in preparation 26 step (ii) (9.6g, 40.1mmol) was dissolved in ethyl acetate (250 ml). To this solution was added 10% Pd/C (7.0g) and hydrogenated with hydrogen (20psi) for 3-4 hours. The reaction mixture was filtered through celite and concentrated to a syrup. The desired product was isolated by column chromatography eluting with ethyl acetate/hexanes as a thick liquid (6.1g, 72%).

[α]_D：+6.5°(c1.0，MeOH)

¹H NMR(CDCl₃)：δ1.25(t，J＝7.2Hz，3H)，2.83(dd，J＝14，6.5，Hz，1H)，2.98(dd，J＝14，4.6，Hz，1H)，3.35(bs，2H，NH₂)，4.17(q，J＝7.2Hz，2H)，4.33(dd，J＝6.5，4.6Hz，1H)，6.58(d，J＝8.4Hz，2H)，6.97(d，J＝8.1Hz，2H).

IR(neat)cm^-1：3372，2985，2932，1739，1627，1519.

Mass m/z(CI)：209[M]，210[M+1].

Step (ii)

(S) -ethyl 2-hydroxy-3- (4-aminophenyl) propionate obtained in the above step (i) (4.0g, 19.1mmol), benzyl bromide (4.7ml, 40.19mmol) and anhydrous Na₂CO₃A mixture of (6.07g, 57.3mmol) in anhydrous DMF (100ml) was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (300ml), washed with 10% aqueous citric acid and dried over anhydrous Na₂SO₄Drying and concentrating. The desired product was isolated by column chromatography eluting with ethyl acetate/hexanes as a thick liquid (4.5g, 61%).

[α]_D：-12°(c0.1，MeOH)

¹H NMR(CDCl₃)：δ1.25(t，J＝7.2Hz，3H)，2.16(s，OH)；2.84(dd，J＝14，6.5，Hz，1H)，2.99(dd，J＝14，4.6，Hz，1H)，4.19(q，J＝7.2Hz，2H)，4.31-4.37(m，1H)，4.62(s，4H)；6.66(d，J＝8.8Hz，2H)，7.01(d，J＝8.8Hz，2H)；7.21-7.35(aromatics，10H).

IR(neat)cm^-1：3497，3062，3028，1733，1615，1521.

Mass m/z(CI)：390[M+1].

Step (iii)

(S) -ethyl 2-hydroxy-3- (4-dibenzylaminophenyl) propionate obtained in step (ii) (4.5g, 1.0eq, 11.57mmol) was taken up in LiOH.H. in MeOH-THF-water at room temperature₂O (972mg, 2eq, 23.1mmol) was hydrolyzed. The reaction mixture was concentrated and the pH was adjusted to 3. The desired acid precipitated out and was then filtered (4.0g,96% yield).

Mp：114-116℃.

¹H NMR(CDCl₃)：δ2.83(dd，J＝14，7Hz，1H)；3.09(dd，J＝14，3.5Hz，1H)，4.35-4.44(m，1H)，4.62(s，4H)；6.68(d，J＝8.3Hz，2H)，7.03(d，J＝8.3Hz，2H)；7.21-7.35(aromatics，10H).

IR(neat)cm^-1：3450，3028，2923，1725，1615，1521.

Mass m/z(CI)：362[M+1].

Step (iv)

To a solution of (S) -2-hydroxy-3- (4-dibenzylaminophenyl) propionic acid (4.0g, 11.1mmol) obtained in step (iii) in anhydrous DMF (56ml) was added NaH (60% oil, 886mg, 22.2mmol) portionwise at room temperature. The resulting mixture was stirred at 50 ℃ for 2 hours. The reaction mixture was allowed to return to room temperature again and ethyl iodide (2.67ml, 33.3mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine. Subjecting the organic layer to anhydrous Na₂SO₄Drying and concentrating. The residue was purified by column chromatography eluting with ethyl acetate/hexanes to give the desired product as a viscous liquid (2.65g, 57% yield).

[α]_D：-3.5°(c.1，MeOH).

¹H NMR(CDCl₃)：δ1.18(t，J＝7.0Hz，3H)，1.20(t，J＝7.3Hz，3H)，2.91(d，J＝6.7Hz，2H)，3.30-3.48(m，1H)，3.52-3.70(m，1H)，3.97(t，J＝6.7Hz，1H)，4.15(q，J＝7.2Hz，2H)，4.62(s，4H)，6.67(d，J＝8.3Hz，2H)，7.04(d，J＝8.0Hz，2H)，7.23-7.36(aromatics，10H).

IR(neat)cm^-1：3027，2978，1744，1616，1521.

Mass m/z(CI)：418(M+1).

Step (v)

The ethyl (S) -2-ethoxy-3- (4-dibenzylaminophenyl) propionate obtained in the above step (iv) was hydrogenated with Pd/C (10%) and hydrogen (20-30psi) in an ethyl acetate solvent for 3-4 hours. The catalyst is filtered off and the filtrate is concentrated to give the desired product from the reaction mixture.

[α]_D：-14.2°(c1.0，MeOH).

Chiral HPLC：＞98％ ee.

IR(neat)cm^-1：3372，1738.

Mass m/z(CI)：238(M+1)，192(M-OC₂H₅).

Example 1

(S) -2-methoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid ethyl ester

4- (3-Methanesulfonyloxypropyl) phenylmethanesulfonate (5.5g, 1.0eq, 17.9mmol) from preparation 1, ethyl (S) -2-methoxy-3- (4-aminophenyl) propionate (4.0g, 1.0eq, 17.9mmol) from preparation 27, tetrabutylammonium bromide (2.8g, 0.5eq, 9.0mmol) and anhydrous K₂CO₃A mixture of (7.4g, 3.0eq, 53.7mmol) in dry toluene (90ml) was heated at 90 ℃ for 7-9 hours with stirring. The reaction mixture was diluted with ethyl acetate (300ml), which was washed with water and brine. The organic layer was dried (Na)₂SO₄) Concentrated and the residue chromatographed using ethyl acetate and hexane to give the title compound asViscous liquid (3.4g, 44%).

[α]25_D：-6.5°(c1.0，MeOH).

¹H NMR(CDCl₃，200MHz)：δ1.26(t，J＝7.0Hz，3H)；1.98(quintet，J＝7.2Hz，2H)；2.75(t，J＝7.6Hz，2H)；2.93(d，J＝5.9Hz，2H)；3.02-3.22(m，5H)；3.37(s，3H)；3.91(t，J＝6.4Hz，1H)；4.20(q，J＝7.0Hz，2H)；6.65(d，J＝8.0Hz，2H)；7.08(d，J＝8.3Hz，2H)；7.15-7.3(aromatics，4H).

IR(neat)cm^-1：3405，2934，2934，1739，1617，1522，1367.

Mass m/z(CI)：435[M]，436[M+1].

Example 2

2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid ethyl ester

The title compound was obtained as a viscous liquid (40% yield) according to the method of example 1 from 4- (3-methanesulfonyloxypropyl) phenylmethanesulfonate obtained in preparation 1 and ethyl 2-ethoxy-3- (4-aminophenyl) propionate obtained in preparation 5.

¹H NMR(CDCl₃，200MHz)：δ1.16(t，J＝5.8Hz，3H)；1.21(t，J＝5.8Hz，3H)；1.91(quintet，J＝7.2Hz，2H)；2.72(t，J＝7.3Hz，2H)；2.88(d，J＝6.3Hz，2H)；3.02-3.18(m，5H)；3.22-3.42(m，1H)；3.42-3.62(m，1H)；3.93(t，J＝6.5Hz，1H)；4.15(q，J＝7.3Hz.2H)；6.51(d，J＝8.3Hz，2H)；7.10(d，J＝8.3Hz，2H)；7.15-7.24(aromatics，4H).

IR(neat)cm^-1：3400，2978，2934，1738，1616，1502.

Mass m/z(CI)：449[M]，450[M+1].

Example 3

(S) -2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid ethyl ester

The title compound was obtained from 4- (3-methanesulfonyloxypropyl) phenylmethanesulfonate obtained in preparation 1 and ethyl (S) -2-ethoxy-3- (4-aminophenyl) propionate obtained in preparation 26 by the method of example 1.

[α]25_D：-6.3°(1.0，MeOH).

¹H NMR(CDCl₃，200MHz)：δ1.16(t，J＝5.8Hz，3H)；1.21(t，J＝5.8Hz，3H)；1.91(quintet，7.2Hz，2H)；2.72(t，J＝7.3Hz，2H)；2.88(d，J＝6.3Hz，2H)；3.02-3.18(m，5H)；3.22-3.42(m，1H)；3.42-3.62(m，1H)；3.93(t，J＝6.5Hz，1H)；4.15(q，J＝7.3Hz，2H)；6.51(d，J＝8.3Hz，2H)；7.10(d，J＝8.3Hz，2H)；7.15-7.24(aromatics，4H).

IR(neat)cm^-1：3400，2978，2934，1738，1616，1502.

Mass m/z(CI)：449[M]，450[M+1].

Example 4

2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propoxycarbonylamino } phenyl ] propanoic acid ethyl ester

The title compound was obtained as a by-product during the synthesis of example 2 (20% yield).

¹H NMR(CDCl₃，200MHz)：δ1.14(t，J＝7Hz，3H)；1.22(t，J＝7Hz，3H)；1.98(quintet，J＝7Hz，2H)；2.72(t，J＝8Hz，2H)；2.95(d，J＝6.1Hz，2H)；3.10(s，3H)；3.25-3.45(m，1H)；3.50-3.70(m，1H)；3.97(t，J＝6.4Hz，1H)；4.05-4.24(m，4H)；6.68(s，NH)；7.10-7.30(aromatics，8H)；

IR(neat)cm^-1：3357，2978，1730，1530

Mass m/z(CI)：494[M+1]

Example 5

2-ethoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid ethyl ester

The title compound was obtained as a viscous liquid (44%) according to the method of example 1 from 3- (3-methanesulfonyloxypropyl) phenylmethanesulfonate obtained in preparation 2 and ethyl 2-ethoxy-3- (4-aminophenyl) propionate obtained in preparation 5.

¹H NMR(CDCl₃，200MHz)：δ1.19(t，J＝7.0Hz，3H)；1.25(t，J＝7.0Hz，3H)；1.91(quintet，J＝7.3Hz，2H)；2.78(t，J＝7.8Hz，2H)；2.92(d，J＝6.7Hz，2H)；3.02-3.20(m，5H)；3.22-3.42(m，1H)；3.42-3.62(m，1H)；3.97(t，J＝6.7Hz，1H)；4.19(q，J＝7.2Hz，2H)；6.58(d，J＝8.4Hz，2H)；6.64(d，J＝8.4Hz，2H)；7.00-7.20(aromatics，3H)；7.22-7.40(aromatics，1H).

IR(neat)cm^-1：3379，2978，2934，1739，1616，1521.

Mass m/z(CI)：449[M]，450[M+1].

Example 6

2-ethoxy-3- [4- {3- (4- (toluene-4-sulfonyloxy) phenyl) propylamino } phenyl ] propanoic acid ethyl ester

The title compound was obtained as a viscous liquid (77%) according to the method of example 1 from 4- (3- (toluene-4-sulfonyloxy) propyl) phenyltoluene-4-sulfonate obtained in preparation example 3 and ethyl 2-ethoxy-3- (4-aminophenyl) propionate obtained in preparation example 5.

¹H MR(CDCl₃，200MHz)：δ1.16(t，J＝7.0Hz，3H)；1.22(t，J＝7.2Hz，3H)；1.88(quintet，J＝7.3Hz，2H)；2.43(s，3H)；2.67(t，J＝7.4Hz，2H)；2.89(d，J＝6.4Hz，2H)；3.08(t，J＝7.0Hz，2H)；3.25-3.45(m，1H)；3.45-3.65(m，1H)；3.94(t，J＝6.7Hz，1H)；4.15(t，J＝7.2Hz，2H)；6.48(d，J＝8.3Hz，2H)；6.87(d，J＝8.3Hz，2H)；6.95-7.15(aromatics，4H)；7.28(d，J＝8.3Hz，2H)；7.68(d，J＝8.3Hz，2H).

IR(neat)cm^-1：3407，2927，1741，1616，1521，1502.

Mass m/z(CI)：526[M+1].

Example 7

2-ethoxy-3- [3- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid ethyl ester

The title compound was obtained as a viscous liquid (35%) according to the method of example 1 from 4- (3-methanesulfonyloxypropyl) phenylmethanesulfonate obtained in preparation 1 and ethyl 2-ethoxy-3- (3-aminophenyl) propionate obtained in preparation 7.

¹H NMR(CDCl₃，200MHz)：δ1.16(t，J＝7.0Hz，3H)；1.22(t，J＝7.0Hz，3H)；1.92(quintet，J＝7.3Hz，2H)；2.73(t，J＝7.6Hz，2H)；2.92(d，J＝6.5Hz，2H)；3.02-3.22(m，5H)；3.22-3.42(m，1H)；3.42-3.62(m，1H)；4.00(t，J＝6.5Hz，1H)；4.16(q，J＝7.0Hz，2H)；6.40-6.62(aromatics，3H)；7.00-7.30(aromatics，5H).

IR(neat)cm^-1：3406，2978，2934，1740，1606，1503.

Mass m/z(CI)：450[M+1]，449[M].

Example 8

2-Isopropoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid ethyl ester

The title compound was obtained as a viscous liquid (47%) according to the method of example 1 from 4- (3-methanesulfonyloxypropyl) phenylmethanesulfonate obtained in preparation 1 and ethyl 2-isopropoxy-3- (4-aminophenyl) propionate obtained in preparation 9.

¹H NMR(CDCl₃，200MHz)：δ0.99(d，J＝6.0Hz，3H)；1.16(d，J＝6.3Hz，3H)；1.24(t，J＝7.3Hz，3H)；1.93(quintet，J＝7.3Hz，2H)；2.74(t，J＝7.8Hz，2H)；2.80-2.90(m，2H)；3.02-3.20(m，5H)；3.50(apparent quintet，J＝6.0Hz，1H)；3.99(dd，J＝7.8 and 5.3Hz，1H)；4.17(q，J＝7.3Hz，2H)；6.52(d，J＝8.3Hz，2H)；7.05(d，J＝8.3Hz，2H).

IR(neat)cm^-1：3406，2974，2939，1739，1616，1522.

Mass m/z(CI)：464[M+1].

Example 9

2-ethoxy-3- [4- (4-methanesulfonyloxyphenethylamino) phenyl ] propanoic acid ethyl ester

A mixture of ethyl 2-ethoxy-3- (4-aminophenyl) propionate (obtained in preparation 5) (0.3g, 1.27mmol) and anhydrous potassium carbonate (0.437g, 3.16mmol) in toluene (10ml) was stirred at RT for 30 minutes. A solution of 4- (2-methanesulfonyloxyethyl) phenylmethanesulfonate (0.484g, 1.65mmol) obtained in preparation example 12 in toluene (5ml) was added dropwise to the above reaction mixture, followed by addition of tetrabutylammonium bromide (81mg, 0.25 mmol). The reaction mixture was stirred at 90 ℃ for 30 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate (50ml) and washed with water. The aqueous layer was extracted with ethyl acetate (2X 50 ml). The combined organic layers were washed with brine and dried (Na)₂SO₄) And (4) concentrating. The residue was purified by column on silica gel eluting with 20% ethyl acetate in petroleum ether to give the title compound (0.24g, 44%) as a pale yellow oil.

¹H NMR(200MHz，CDCl₃)：δ1.17(t，J＝7.1Hz，3H)；1.24(t，J＝6.4Hz，3H)；2.91(d，J＝6.8Hz，2H)；2.93(t，J＝7.1Hz，2H)；3.15(s，3H)；3.32-3.3.44(m，3H)；3.50-3.67(m，1H)；3.96(t，J＝6.6Hz，1H)；4.18(q，J＝7.3Hz，2H)；6.59(d，J＝8.3Hz，2H)；7.08(d，J＝8.3Hz，2H)；7.19-7.30(m，4H).

Mass m/z(CI)：436[M+1].

Example 10

(S) -2-ethoxy-3- [4- (4-methanesulfonyloxyphenethylamino) phenyl ] propanoic acid ethyl ester

A mixture of ethyl (S) -2-ethoxy-3- (4-aminophenyl) propionate obtained in preparation 26 (2.5g, 10.55mmol) and anhydrous potassium carbonate (4.37g, 31.65mmol) was stirred in RT toluene (20ml) for 30 minutes. A solution of 4- (2-methanesulfonyloxyethyl) phenylmethanesulfonate (4.03g, 13.71mmol) obtained in preparation example 12 in toluene (10ml) was added dropwise to the above reaction mixture, followed by addition of tetrabutylammonium bromide (0.34g, 1.055 mmol).The reaction mixture was stirred at 90-100 ℃ for 30 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate (100ml) and washed with water. The aqueous layer was extracted with ethyl acetate (2X 50 ml). The combined organic layers were washed with brine and dried (Na)₂SO₄) And (4) concentrating. The residue was purified on a silica gel column, eluting with 20% ethyl acetate in petroleum ether, to give the title compound (0.31g, 6.7%) as a yellow oil.

¹H NMR(200MHz，CDCl₃)：δ1.17(t，J＝6.8Hz，3H)；1.26(t，J＝7.0Hz，3H)；2.88-3.02(m，4H)；3.15(s，3H)；3.28-3.3.45(m，3H)；3.50-3.70(m，1H)；3.95(t，J＝6.6Hz，1H)；4.17(q，J＝7.2Hz，2H)；6.67(d，J＝8.3Hz，2H)；7.10(d，J＝8.0Hz，2H)；7.18-7.30(m，4H).

Mass m/z(CI)：436[M+1].

Example 11

2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino ] phenyl } propanoic acid ethyl ester

According to the same method as described in example 9, 4- [ (E) -3-chloro-1-propenyl ] phenylmethanesulfonate (0.43g, 1.41mmol) obtained in preparation 22 and ethyl 2-ethoxy-3- (4-aminophenyl) propionate (0.28g, 1.18mmol) obtained in preparation 5 were treated with potassium carbonate (489mg, 3.54mmol), tetrabutylammonium bromide (38mg, 0.118mmol) and toluene (25ml) for 30 hours to give the title compound (150mg, 28.4%).

¹H NMR(200MHz，CDCl₃)：δ1.17(t，J＝7.1Hz，3H)；1.22(t，J＝7.1Hz，3H)；2.91(d，J＝6.3Hz，2H)；3.14(s，3H)；3.26-3.44(m，1H)；3.51-3.68(m，1H)；3.93(d，J＝6.3Hz，2H)；3.95(t，J＝6.6Hz，1H)；4.16(q，J＝7.1Hz，2H)；6.23-6.39(m，1H)；6.56-6.64(m，3H)；7.07(d，J＝8.3Hz，2H)；7.22(d，J＝8.3Hz，2H)；7.40(d，J＝8.3Hz，2H).

Mass m/z(CI)：402[M+1-OEt].

Example 12

(S) -2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino ] phenyl } propanoic acid ethyl ester

According to the same method as described in example 10, 4- [ (E) -3-chloro-1-propenyl ] phenylmethanesulfonate (15.90g, 52.1mmol) obtained in preparation 22 and ethyl (S) -2-ethoxy-3- (4-aminophenyl) propionate (9.5g, 40.1mmol) obtained in preparation 26 were treated with potassium carbonate (16.6g, 120.25mmol), tetrabutylammonium bromide (1.29g, 4.01mmol) and toluene (150ml) for 24 hours to give the title compound (5.2g, 31.8%).

¹H NMR(200MHz，CDCl₃)：δ1.17(t，J＝7.2Hz，3H)；1.22(t，J＝7.3Hz，3H)；2.90(d，J＝6.4Hz，2H)；3.13(s，3H)；3.26-3.44(m，1H)；3.51-3.68(m，1H)；3.90-4.00(m，3H)；4.16(q，J＝7.2Hz，2H)；6.28(td，J＝5.4 and 16.1Hz，1H)；6.57-6.64(m，3H)；7.06(d，J＝8.3Hz，2H)；7.21(d，J＝8.6Hz，2H)；7.39(d，J＝8.6Hz，2H).

Mass m/z(CI)：448[M⁺+1]；402[M+1-OEt].

Example 13

2-ethoxy-3- [4- (4-methanesulfonyloxybenzylamino) phenyl ] propionic acid methyl ester

4-Methylsulfonyloxybenzaldehyde (500mg, 1eq, 2.5mmol) obtained in production example 10, methyl 2-ethoxy-3- (4-aminophenyl) propionate (557mg, 1eq, 2.5mmol) obtained in production example 6, and,A mixture of active molecular sieve (4A) and p-TsOH (43mg, 0.1eq, 0.25mmol) in dry DCM (15ml) was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (100ml), washed with aqueous sodium bicarbonate and dried (Na)₂SO₄) Concentrated (rotary evaporator), dried under high vacuum. The crude product was dissolved in anhydrous methanol (15ml) and concentrated HCl (250 μ l) was added at 0 ℃ followed by addition of NaB (CN) H in portions₃(188mg, 1.2eq, 3.0 mmol). The reaction mixture was stirred at 0 ℃ for 3 hours, then diluted with ethyl acetate (100 ml). The organic layer was washed with aqueous sodium bicarbonate and dried (Na)₂SO₄) And (4) concentrating. The residue was chromatographed using ethyl acetate and hexanes to give the title compound as a thick oil (950mg, 37%).

¹H NMR(CDCl₃，200MHz)：δ1.16(t，J＝6.9Hz，3H)；2.90(d，J＝6.8Hz，2H)；3.14(s，3H)；3.22-3.41(m，1H)；3.44-3.62(m，1H)；3.70(s，3H)；3.97(t，J＝6.6Hz，1H)；4.33(s，2H)；6.54(d，J＝8.3Hz，2H)；7.04(d，J＝8.3Hz，2H)；7.25(d，J＝8.3Hz，2H)；7.41(d，J＝8.3Hz，2H).

IR(neat)cm^-1：3412，2932，1744，1616，1522，1503.

Mass m/z(CI)：408[M+1]，407[M].

Example 14

(S) -2-methoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid

(S) -2-methoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl obtained in example 1 was added to a mixture of MeOH-THF-water solvent at RT]Ethyl propionate (3.4g, 1.0eq, 7.8mmol) in LiOH₂O (492mg, 1.5eq, 11.7mmol) was treated for 3-4 hours for hydrolysis. The reaction mixture was concentrated, diluted with water, and concentrated with aqueous HClAcidification (pH 3). The desired acid precipitated from the aqueous layer and was then filtered off. If the acid precipitated according to TLC is not sufficiently pure, it is chromatographed using MeOH and CHCl₃As eluent, pure acid was obtained as a white solid (2.5g, 79%).

Mp：90-92℃.

[α]d：-16°(c1.0，MeOH).

¹H NMR(CDCl₃，200MHz)：δ1.25(s，1H，N-H)；1.94(quintet，7.2Hz，2H)；2.72(t，J＝7.8Hz，2H)；2.82-3.02(m，2H)；3.02-3.18(m，5H)；3.38(s，3H)；3.97(t，J＝4.8Hz，1H)；4.90(bs，CO₂H))；6.58(d，J＝8.1Hz，2H)；7.05(d，J＝8.3Hz，2H)；7.15-7.24(aromatics，4H).

¹³C NMR(CDCl₃，50MHz)δ：29.53，32.34，37.15(2C)，46.48，57.58，82.07，116.31，121.90，129.75，130.39，140.57，142.48，147.33，175.87.

IR(neat)cm^-1：3046，2932，1732，1615，1520，1365.

Mass m/z(CI)：408[M+1]，407[M].

Example 15

2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid

The procedure is as described in example 14, using LiOH₂O hydrolysis of 2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl obtained in example 2]Ethyl propionate to give the title compound.

Mp：120-122℃.

¹H NMR(CDCl₃，200MHz)：δ1.18(t，J＝7.1Hz，3H)；1.25(s，1H，N-H)；1.93(quintet，6.9Hz，2H)；2.74(t，J＝7.5Hz，2H)；2.80-3.02(m，2H)；3.02-3.18(m，5H)；3.40-3.62(m，2H)；4.03(dd，J＝6.9，4.4Hz，1H)；4.07(bs，CO₂H))；7.05(d，J＝8.3Hz，2H)；7.22(d，J＝8.3Hz，2H)；7.15-7.24(aromatics，4H).

IR(neat)cm^-1：3389，2925，1616，1502.

Mass m/z(CI)：422[M+1].

Example 16

2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propoxycarbonylamino } phenyl ] propanoic acid

The procedure is as described in example 14, using LiOH₂O hydrolysis of 2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propoxycarbonylamino } phenyl obtained in example 4]Ethyl propionate to give the title compound as a thick liquid.

¹H NMR(CDCl₃，200MHz)：δ1.19(t，J＝7Hz，3H；2.01(q，J＝7Hz，2H；2.75(t，J＝7.5Hz，2H；2.90-3.10(m，2H)；3.13(s，3H)；3.35-3.55(m，1H)；3.55-3.75(m，1H)；4.08(dd，J＝7，4.8Hz，1H)；4.21(t，J＝6.3Hz，2H)；6.85(bs，NH)；7.10-7.35(aromatics，8H)；8.4(bs，-COOH).

IR(neat)cm^-1：3334，3021，2935，1723，1528；

Example 17

(S) -2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid

The procedure is as described in example 14, using LiOH₂O hydrolysis (S) -2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl group obtained in example 3]Ethyl propionate synthesized the desired compound.

[α]_D ²⁵：-16°(1.0，MeOH).

IR(neat)cm^-1：3389，2925，1616，1502.

Mass m/z(CI)：422[M+1].

Example 18

2-ethoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid

The procedure is as described in example 14, using LiOH₂O hydrolysis 2-ethoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl group obtained in example 5]Ethyl propionate (245mg, 1.0eq, 0.54mmol) gave the title compound as a thick liquid (73%).

¹H NMR(CDCl₃，200MHz)：δ1.19(t，J＝7.1Hz，3H)；1.25(s，1H，N-H)；1.90-2.02(quintet，6.9Hz，2H)；2.76(t，J＝7.9Hz，2H)；2.80-3.05(m，2H)；3.05-3.20(m，5H)；3.40-3.62(m，2H)；4.03(dd，J＝6.9 and 4.4Hz，1H)；4.60(bs，CO₂H)；6.58(d，J＝8.3Hz，2H)；7.00-7.20(aromatics，5H)；7.22-7.29(aromatics，1H).

IR(neat)cm^-1：3406，2931，1613，1521.

Mass m/z(CI)：422[M+1].

Example 19

2-ethoxy-3- [4- {3- (4- (toluene-4-sulfonyloxy) phenyl) propylamino } phenyl ] propanoate

The procedure is as described in example 14, using LiOH₂O hydrolysis 2-ethoxy-3- [4- {3- (4- (toluene-4-sulfonyloxy) phenyl) propylamino } phenyl obtained in example 6]Ethyl propionate (450mg, 1.0eq, 0.85mmol) to give the title compound as a white solid (310mg, 72%).

Mp：98-100℃.

¹H NMR(CDCl₃，200MHz)δ：1.16(t，J＝6.8Hz，3H)；1.88(quintet，J＝7.3Hz，2H)；2.42(s，3H)；2.66(t，J＝6.9Hz，2H)；2.80-3.30(m，4H)；3.35-3.65(m，2H)；4.01(dd，J＝7.1，4.4Hz，1H)；4.40(bs，OH，NH)；6.53(d，J＝8.3Hz，2H)；6.86(d，J＝8.3Hz，2H)；7.00-7.10(aromatics，4H)；7.28(d，J＝8.3Hz，2H)；7.68(d，J＝8.3Hz，2H).

IR(neat)cm^-1：3411，2925，1731，1618，1525，1502.

Mass m/z(CI)：498[M+1].

Example 20

2-ethoxy-3- [3- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid

The procedure is as described in example 14, using LiOH₂O hydrolysis 2-ethoxy-3- [3- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl group obtained in example 7]Ethyl propionate (800mg, 1.0eq, 1.78mmol) gave the title compound as a thick liquid (500mg, 67%).

¹H NMR(CDCl₃，200MHz)δ：1.16(t，J＝7.0Hz，3H)；1.92(quintet，7.3Hz，2H)；2.73(t，J＝7.6Hz，2H)；2.90(dd，J＝14 and 7.5Hz，1H)；3.08(dd；J＝14，4.3Hz，1H)；3.02-3.20(m，5H)；3.32-3.50(m，1H)；3.50-3.68(m，1H)；4.07(dd，J＝7.5，4.3Hz，1H)；4.16(q，J＝7.0Hz，2H)；6.42-6.62(aromatics，3H)；7.00-7.30(aromatics，5H).

IR(neat)cm^-1：3500，3021，2936，1723，1607，1504.

Mass m/z(CI)：422[M+1].

Example 21

2-isopropoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid

The procedure is as described in example 14, using LiOH₂O hydrolysis 2-Isopropoxy-3- [4- {3- (4-Methanesulfonyloxyphenyl) propylamino } phenyl group from example 8]Ethyl propionate (300mg, 1.0eq, 0.65mmol) gave the title compound as a white solid (74%).

Mp：143-145℃

¹H NMR(CDCl₃，200MHz)δ：1.04(d，J＝6.3Hz，3H)；1.16(d，J＝6.0Hz，3H)；1.25(s，1H，NH)；1.93(quintet，7.3Hz，2H)；2.74(t，J＝7.8Hz，2H)；2.87(dd，J＝14.2 and 7.9Hz，1H)；3.01(dd，J＝14.1，3.4Hz，1H)；3.05-3.20(m，5H)；3.55(apparent quintet，J＝6.0Hz，1H)；4.07(dd，J＝7.9 and 3.4Hz，1H)；4.17(q，J＝7.3Hz，2H)；4.90(bs，CO₂H)；6.52(d，J＝8.3Hz，2H)；7.04(d，J＝8.3Hz，2H).

IR(neat)cm^-1：3406，2974，2939，1739，1616，1522.

Mass m/z(CI)：436[M+1].

Note: wherein the "apparent quintet" appears in the spectral data.

Example 22

2-ethoxy-3- [4- (4-methanesulfonyloxy-benzylamino) phenyl ] propionic acid

The procedure is as described in example 14, using LiOH₂O hydrolysis 2-ethoxy-3- [4- (4-methanesulfonyloxybenzylamino) phenyl ] obtained from example 13]Methyl propionate (500mg, 1.0eq, 1.2mmol) gave the title compound as a viscous liquid (400mg, 83%).

¹H NMR(CDCl₃，200MHz)：δ1.16(t，J＝6.8Hz，3H)；2.87(dd，J＝14.1 and 7.3Hz，1H)；2.99(dd，J＝14.1 and 4.4Hz，1H)；3.11(s，3H)；3.28-3.62(m，2H)；4.00(dd，J＝7.3，4.4Hz，1H)；4.30(s，2H)；5.23(bs，NH)；6.53(d，J＝8.3Hz，2H)；7.03(d，J＝8.3Hz，2H)；7.22(d，J＝8.3Hz，2H)；7.39(d，J＝8.3Hz，2H).

IR(neat)cm^-1：3397，2977，2932，1730，1615，1522，1503.

Mass m/z：393[M].

Example 23

2-ethoxy-3- [4- (4-methanesulfonyloxyphenethylamino) phenyl ] propanoic acid

To the 2-ethoxy-3- [4- (4-methanesulfonyloxyphenethylamino) -phenyl ] obtained in example 9 at RT]Ethyl propionate (0.22g, 0.51mmol) in methanol (10ml) was added to a solution of sodium carbonate (268mg, 2.53mmol) in water (5ml) and stirred at RT for 36 h. Methanol was evaporated under reduced pressure and the residue was diluted with water (20 ml). The aqueous layer was washed with ethyl acetate (50 ml). The aqueous layer was acidified to pH about 4 with 2N HCl and extracted with ethyl acetate (2X 50 ml). The organic layer was washed with brine and dried (Na)₂SO₄) And (4) concentrating. The residue was purified by column chromatography, eluting with 50% ethyl acetate in petroleum ether, to give the title compound (80mg, 39%).

¹H NMR(200MHz，CDCl₃)：δ1.19(t，J＝6.8Hz，3H)；2.82-3.05(m，4H)；3.15(s，3H)；3.40(t，J＝7.2Hz，3H)；3.45-3.62(m，1H)；4.01-4.10(m，1H)；6.63(d，J＝8.3Hz，2H)；7.08(d，J＝8.4Hz，2H)；7.18-7.30(m，4H).

Mass m/z(CI)：408[M+1].

Example 24

(S) -2-ethoxy-3- [4- (4-methanesulfonyloxyphenethylamino) phenyl ] propanoic acid

According to the same method as described in example 23, ethyl (S) -2-ethoxy-3- [4- (4-methanesulfonyloxyphenethylamino) phenyl ] propionate (0.34g, 0.78mmol) obtained in example 10 was hydrolyzed in methanol (5ml) with a solution of sodium carbonate (414mg, 3.91mmol) in water (5ml) at RT for 24 hours to give the title compound (180mg, 56.6%).

¹H NMR(200MHz，CDCl₃)：δ1.19(t，J＝7.0Hz，3H)；2.84-3.03(m，4H)；3.14(s，3H)；3.39(t，J＝7.0Hz，3H)；3.42-3.61(m，2H)；4.04(dd，J＝4.4 and 7.1Hz，1H)；6.55(d，J＝8.3Hz，2H)；7.05(d，J＝8.3Hz，2H)；7.22-7.27(m，4H)

Mass m/z(CI)：408[M+1].

Example 25

(S) -2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino ] phenyl } propanoic acid

The title compound (1.2g, 32%) was synthesized by hydrolyzing the ethyl (S) -2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino ] phenyl } propanoate (4g, 8.95mmol) obtained in example 12 with lithium hydroxide (563mg, 13.42mmol) in methanol-THF-water (45: 4: 9, 58ml) according to the same method as described in example 14.

[α]_D ²⁵＝-18°(c0.1，MeOH)

Mp：156-158℃.

¹H NMR(CD₃OD，200MHz)：δ1.11(t，J＝6.8Hz，2H)；2.74-2.98(m，2H)；3.19(s，3H)；3.25-3.70(m，2H)；3.88-4.02(m，3H)；6.36(td，J＝16.1 and 5.4Hz，1H)；6.62-6.75(m，3H)；7.02(d，J＝7.8Hz，2H)；7.24(d，J＝8.3Hz，2H)；7.45(d，J＝8.8Hz，2H).Mass m/z(ES)：420[M+1].

Example 26

2-ethoxy-3- [4- (4-methanesulfonyloxy-benzylcarboxamido) phenyl ] propanoic acid ethyl ester

To a cooled solution of 2- (4-methanesulfonyloxyphenyl) acetic acid (0.53g, 2.3mmol) from preparation 14 in DCM (25ml) was added HOBt (311mg, 2.30mmol) slowly, followed by EDC (442mg, 2.30mmol) and the mixture stirredStirring for 10 minutes. To the above reaction mixture was added a solution of ethyl 2-ethoxy-3- (4-aminophenyl) propionate (601mg, 2.535mmol) obtained in preparation example 5 in DCM (5ml), and the mixture was stirred at RT for 18 hours. The reaction mixture was diluted with DCM and saturated NaHCO₃The solution, water and brine were washed and dried (Na)₂SO₄) And (4) concentrating. The residue was purified by column chromatography, eluting with ethyl acetate-petroleum ether (1: 3), to give the title compound (710mg, 69%).

¹H NMR(200MHz，CDCl₃)：δ1.13(t，J＝7.1Hz，3H)；1.23(t，J＝7.1Hz，3H)；2.95(d，J＝5.9Hz，2H)；3.16(s，3H)；3.21-3.41(m，1H)；3.51-3.67(m，1H)；3.71(s，2H)；3.95(t，J＝6.6Hz，1H)；4.16(q，J＝6.8Hz，2H)；7.09-7.43(m，8H).

Mass m/z(CI)：450[M+1].

Example 27

2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino ] phenyl } propanoic acid

The title compound (40mg, 30.5%) was synthesized by hydrolyzing ethyl 2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino ] phenyl } propanoate (140mg, 0.313mmol) obtained in example 11 with lithium hydroxide (17mg, 0.407mmol) in methanol-water (2: 1, 6ml) according to the same method as described in example 14.

Mp：146-148℃.

¹H NMR(200MHz，CDCl₃)：δ1.12(t，J＝6.6Hz，3H)；2.72-3.00(m，2H)；3.20(s，3H)；3.25-3.42(m，2H)；3.50-3.68(m，1H)；3.88-4.00(m，2H)；6.30-6.48(m，1H)；6.60-6.70(m，3H)；7.04(d，J＝7.3Hz，2H)；7.25(d，J＝7.8Hz，2H)；7.47(d，J＝8.3Hz，2H).

Example 28

2-ethoxy-3- [4- (4-methanesulfonyloxy-benzylcarboxamido) phenyl ] propanoic acid

Ethyl 2-ethoxy-3- [4- (4-methanesulfonyloxybenzylcarboxamido) phenyl ] propionate obtained in example 26 (0.7g, 1.56mmol) was hydrolyzed with sodium carbonate in methanol-water (3: 1, 20ml) at room temperature for 60 hours as described in example 23 to give the title compound (220mg, 33.5%) as a white solid.

Mp：162-164℃.

¹H NMR(200MHz，CDCl₃+DMSO-d₆)：δ1.14(t，J＝7.0Hz，3H)；2.84-3.10(m，2H)；3.15(s，3H)；3.25-3.40(m，1H)；3.55-3.67(m，1H)；3.70(s，2H)；3.95(dd，J＝4.7 and 7.9Hz，1H)；7.18-7.52(m，8H).

Mass m/z(CI)：422[M+1].

Example 29

2-ethoxy-3- [4- {3- (4-tert-butoxy-4-methanesulfonylaminophenyl) propylamino } phenyl ] propanoic acid ethyl ester

Ethyl 2-ethoxy-3- (4-aminophenyl) propionate (0.29g, 1.22mmol) obtained in preparation example 5 and potassium carbonate (506mg, 3.67mmol) were stirred in toluene (20ml) at room temperature for 30 minutes. A solution of 3- (4-tert-butoxy-4-methanesulfonamidophenyl) propyl methanesulfonate (0.6g, 1.47mmol) obtained in preparation example 19 in toluene (10ml) was added dropwise, followed by addition of tetrabutylammonium bromide (39mg, 0.122 mmol). The reaction mixture was stirred at 90-100 ℃ for 40 hours. The reaction mixture was cooled to RT, diluted with EtOAc (100ml) and washed with water. Extracting the aqueous layer with ethyl acetate, combining the organic layers, and adding brineWashed and dried (Na)₂SO₄) And (4) evaporating. The residue was purified on silica gel to give the title compound (190mg, 28.3%).

¹H NMR(200MHz，CDCl₃)：δ1.16(t，J＝6.8Hz，3H)；1.26(t，J＝7.2Hz，3H)；1.50(s，9H)；1.64-1.82(m，2H)；2.59(t，J＝7.6H，2H)；2.84(s，3H)；3.02(d，J＝6.7Hz，2H)；3.26-3.42(m，1H)；3.55-3.70(m，3H)；4.02(t，J＝6.6Hz，1H)；4.19(q，J＝6.2Hz，2H)；6.39(bs，1H，D₂O exchangeable)；7.00(d，J＝8.3Hz，2H)；7.20-7.34(m，6H).

Mass m/z (CI)：548[M].

Example 30

2-ethoxy-3- [4- {3- (4-tert-butoxy-4-methylsulfonylaminophenyl) propylamino } phenyl ] propanoic acid

2-ethoxy-3- [4- {3- (4-tert-butoxy-4-methanesulfonamidophenyl) propylamino } phenyl obtained in example 29 was dissolved in MeOH-water (2: 1) solvent mixture (6ml) at RT]Ethyl propionate (180mg, 0.33mmol) in LiOH₂O (18mg, 0.43mmol) was treated overnight and hydrolyzed. The reaction mixture was concentrated, diluted with water, and acidified with aqueous HCl to a pH of about 4. Finally, the crude acid was extracted with ethyl acetate. The ethyl acetate layer was dried (Na)₂SO₄) Concentrated and chromatographed using ethyl acetate-petroleum ether (1: 1) to give the desired compound (140mg 82%) as a white solid.

Mp：78-80℃.

¹H NMR(200MHz，CDCl₃)：δ1.21(t，J＝6.8Hz，3H)；1.51(s，9H)；1.70-1.88(m，2H)；2.60(t，J＝7.3H，2H)；2.85(s，3H)；3.00-3.22(m，2H)；3.38-3.70(m，4H)；4.08-4.20(m，1H)；6.48(bs，1H，D₂O Changeable); 7.97(d, J ═ 8.3Hz, 2H); 7.20-7.35(m, 6H). Note: where "exchangeable" appears in the spectral data is "exchangeable", the same applies below.

Example 31

2-ethoxy-3- {4- [ (E) -2- (4-methanesulfonyloxyphenyl) -1-vinylformamido ] phenyl } propanoic acid ethyl ester

The title compound (0.24g, 25.2%) was prepared by reacting (E) -3- (4-methanesulfonyloxyphenyl) -2-propenoic acid (0.5g, 2.07mmol) obtained in preparation 23, HOBt (279mg, 2.07mmol), EDC (396mg, 2.07mmol) and ethyl 2-ethoxy-3- (4-aminophenyl) propionate (539mg, 2.273mmol) obtained in preparation 5 at RT for 48 hours using DCM (25ml) as described in example 26.

¹H NMR(200MHz，CDCl₃)：δ1.17(t，J＝7.0Hz，3H)；1.27(t，J＝7.1Hz，3H)；3.00(d，J＝6.2Hz，2H)；3.19(s，3H)；3.28-3.45(m，1H)；3.55-3.70(m，1H)；4.01(t，J＝6.6Hz，1H)；4.16(q，J＝6.3Hz，2H)；6.54(d，J＝15.3Hz，1H)；7.20-7.35(m，4H)；7.50-7.60(m，4H)；7.72(d，J＝15.6Hz，1H).

Mass m/z(CI)：462[M+1].

Example 32

2-ethoxy-3- {4- [ (E) -2- (4-methanesulfonyloxyphenyl) -1-vinylformamido ] phenyl } propanoic acid

According to the same method as described in example 23, ethyl 2-ethoxy-3- {4- [ (E) -2- (4-methanesulfonyloxyphenyl) -1-vinylformamido ] phenyl } propanoate obtained in example 31 was hydrolyzed in RT methanol (10ml) with a solution of sodium carbonate (230mg, 2.17mmol) in water (5ml) for 48 hours to give the title compound as a white solid (35mg, 18.6%), mp: 178 ℃ and 180 ℃.

¹H NMR(200MHz，CDCl₃)：δ1.15(t，J＝7.0Hz，3H)；2.84-3.10(m，2H)；3.22(s，3H)；3.22-3.42(m，1H)；3.55-3.72(m，1H)；3.97(dd，J＝4.8 and 8.0Hz，1H)；6.80(d，J＝15.6Hz，1H)；7.20-7.35(m，4H)；7.50-7.70(m，5H).

Mass m/z(CI)：434[M+1].

Example 33

2-ethoxy-3- [4- (4-methanesulfonyloxy-phenethylcarboxamido) phenyl ] propanoic acid ethyl ester

The title compound (0.5g, 52.7%) was prepared by reacting 3- (4-methanesulfonyloxyphenyl) propionic acid (0.5g, 2.049mmol) obtained in preparation 24, HOBt (277mg, 2.049mmol), EDC (393mg, 2.049mmol) and ethyl 2-ethoxy-3- (4-aminophenyl) propionate (534mg, 2.254mmol) obtained in preparation 5 with DCM (25ml) for 20 hours at RT according to the same method as described in example 26: 90-92 ℃.

¹H NMR(200MHz，CDCl₃)：δ1.15(t，J＝7.0Hz，3H)；1.24(t，J＝7.5Hz，3H)；2.64(t，J＝7.5Hz，2H)；2.96(d，J＝6.4Hz，2H)；3.07(t，J＝7.5Hz，2H)；3.12(s，3H)；3.25-3.42(m，1H)；3.52-3.66(m，1H)；3.97(t，J＝6.4Hz，1H)；4.17(q，J＝7.2Hz，2H)；7.18-7.42(m，8H).

Mass m/z(CI)：464[M+1].

Example 34

2-ethoxy-3- [4- (4-methanesulfonyloxy-phenethylcarboxamido) phenyl ] propionic acid

According to the same method as described in example 23, ethyl 2-ethoxy-3- [4- (4-methanesulfonyloxybenzylcarboxamido) phenyl ] propionate obtained in example 33 was hydrolyzed with a solution of sodium carbonate (372mg, 3.51mmol) in water (5ml) for 24 hours in RT methanol (10ml) to give the title compound as a white solid (70mg, 23%), mp: 164 ℃ and 166 ℃.

¹H NMR(200MHz，CDCl₃)：δ1.13(t，J＝7.1Hz，3H)；2.54-2.70(m，2H)；2.88-3.10(m，4H)；3.12(s，3H)；3.22-3.40(m，1H)；3.52-3.72(m，1H)；3.94(dd，J＝4.9 and 7.8Hz，1H)；7.12-7.50(m，8H).

Example 35

2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid arginine salt

2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid (100mg, 1eq, 0.237mmol) obtained in example 15 and L-arginine (41.2mg, 1eq, 0.237mmol) were dissolved in anhydrous methanol (3ml) and stirred at RT for 2 to 3 hours. The solvent was removed on a rotary evaporator followed by benzene azeotropes. The residue was dried under high vacuum pump to give the title compound as a free flowing solid (yield 100%).

Mp：85-87℃.

¹H NMR(DMSO-d₆，200MHz)：δ1.02(t，J＝6.8Hz，3H)；1.24(s，1H，N-H)；1.50-1.90(m，6H)；2.55-3.22(m，10H)；3.32(s，3H)；3.42-3.65(m，2H)；6.43(d，J＝8.1Hz，2H)；6.92(d，J＝8.1Hz，2H)；7.24(d，J＝8.6Hz，2H)；7.32(d，J＝8.6Hz，2H)；8.18(bs，D₂Oexchangeable).

Example 36

2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propoxycarbonylamino } phenyl ] propanoic acid arginine salt

The title compound was obtained from 2-ethoxy-3- [4- {3- (4-methanesulfonyloxyphenyl) propoxycarbonylamino } phenyl ] propanoic acid and L-arginine obtained in example 16 by the method of example 35.

Mp：180-82℃

Example 37

2-ethoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid arginine salt

The title compound was obtained as a free-flowing solid (100%) from 2-ethoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid (95mg, 0.22mmol) and L-arginine (39.3mg, 0.22mmol) obtained in example 18 according to the procedure of example 35. And Mp: 80-82 ℃.

¹H NMR(DMSO-d₆，200MHz)：δ0.99(t，J＝6.8Hz，3H)；1.50-1.90(m，7H)；2.55-3.30(m，10H)；3.35(s，3H)；3.42-3.65(m，2H)；5.36(bs，D₂O-exchangable)；6.43(d，J＝8.1Hz，2H)；6.92(d，J＝8.1Hz，2H)；7.10-7.30(aromatics，3H)；7.30-7.40(aromatics，1H)；8.18(bs，D₂O exchangeable).

Example 38

2-ethoxy-3- [4- (4-methanesulfonyloxybenzylamino) phenyl ] propanoic acid arginine salt

The title compound was obtained as a free-flowing solid (yield 100%) from 2-ethoxy-3- [4- (4-methanesulfonyloxybenzylamino) phenyl ] propionic acid (140mg, 0.35mmol) and L-arginine (68mg, 0.35mmol) obtained in example 22 according to the procedure of example 35.

Mp：138-140℃.

¹H NMR(DMSO-d₆，200MHz)：δ0.98(t，J＝6.7Hz，3H)；1.42-1.82(m，4H)；2.55-3.60(m，8H)；3.34(s，3H)；4.23(s，1H)；4.26(s，1H)；6.06(bs，1H)；6.45(d，J＝8Hz，2H)；6.90(d，J＝8.1Hz，2H)；7.28(d，J＝8.6Hz，2H)；7.45(d，J＝8.6Hz，2H)；8.18(bs，D₂Oexchangeable).

Example 39

2-ethoxy-3- [3- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid arginine salt

From 2-ethoxy-3- [3- {3- (4-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid (200mg, 0.475mmol) and L-arginine (83mg, 0.475mmol) obtained in example 20 according to the procedure of example 35, the title compound was obtained as a free-flowing solid (yield 100%).

Mp：162-164℃

Example 40

Magnesium salt of 2-ethoxy-3- [4- (4-methanesulfonyloxyphenethylamino) -phenyl ] propionic acid

To 2-ethane obtained in example 23Oxy-3- [4- (4-methanesulfonyloxyphenethylamino) phenyl]Propionic acid (70mg, 171. mu. mol) in methanol (5m) Mg (OH) was added₂(5mg) and refluxed for 24 hours. Methanol was removed by evaporation and the residue was washed with toluene to give the title compound (50mg, 68%) as a white solid.

Mp：130-134℃.

¹H NMR(200MHz，CD₃OD)：δ1.10(t，J＝6.8Hz，3H)；2.70-2.96(m，4H)；3.18(s，3H)；3.22-3.40(m，3H)；3.50-3.66(m，1H)；3.78-3.91(m，1H)；6.58(d，J＝8.3Hz，2H)；7.05(d，J＝8.3Hz，2H)；7.23(d，J＝8.8Hz，2H)；7.32(d，J＝8.3Hz，2H).

EXAMPLE 41

Magnesium salt of (S) -2-ethoxy-3- [4- (4-methanesulfonyloxyphenethylamino) -phenyl ] propionic acid

To the (S) -2-ethoxy-3- [4- (4-methanesulfonyloxyphenethylamino) phenyl group obtained in example 24]Propionic acid (170mg, 418. mu. mol) in methanol (10m) Mg (OH) was added₂(12mg) and refluxed for 20 hours. Methanol was removed by evaporation and the residue was washed with toluene to give the title compound (135mg) as a white solid.

Mp：134-138℃.

[α]_D ²⁵＝-26.8°(c0.5，MeOH)

¹H NMR(200MHz，CD₃OD)：δ1.10(t，J＝7.0Hz，3H)；2.70-2.95(m，4H)；3.18(s，3H)；3.22-3.40(m，3H)；3.50-3.70(m，1H)；3.78-3.90(m，1H)；6.57(d，J＝8.1Hz，2H)；7.05(d，J＝8.3Hz，2H)；7.23(d，J＝8.6Hz，2H)；7.32(d，J＝8.3Hz，2H).

Mass m/z(ES)：837.2[M+1].

Example 42

(S) -2-methoxy-3- [4- { (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino } phenyl ] propanoic acid ethyl ester

The compound (892mg, 2.91mmol) obtained in preparation 22 and ethyl (S) -2-methoxy-3- (4-aminophenyl) propionate (500mg, 2.24mmol) obtained in preparation 27 were reacted by the method of example 9, using K₂CO₃(928mg, 6.72mmol) and tetrabutylammonium bromide (72mg, 0.22mmol) were heated in toluene for 16 hours to give the title compound (yield 300mg, 31%).

¹H NMR(200MHz，CDCl₃)：δ1.23(t，J＝7.2Hz，3H)；2.91(d，J＝6.4Hz，2H)；3.13(s，3H)；3.52(s，3H)；3.82-3.98(m，2H)；4.03-4.21(m，3H)；6.30(td，J＝5.4 and 15.8Hz，1H；6.54-6.65(m，3H)；7.05(d，J＝8.3Hz，2H)；7.22(d，J＝8.9Hz，2H)；7.40(d，J＝8.6Hz，2H).

Mass m/z(CI)：434[M+1].

Example 43

(S) -2-methoxy-3- [4- { (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino } phenyl ] propanoic acid

The compound (300mg, 0.69mmol) obtained in example 42 was reacted with LiOH. H in methanol-water (3.5ml) at room temperature as described in example 14₂O (44mg, 1.04mmol) for 5 h to give the title compound as a pale yellow solid (620mg, 51%).

Mp：116-118℃

¹H NMR(200MHz，DMSO d₆)：δ2.75(t，J＝7.3Hz，2H)；3.20(s，3H)；3.34(s，3H)；3.75-3.92(m，3H)；6.40-6.63(m，4H)；6.92(d，J＝8.3Hz，2H)；7.28(d，J＝8.6Hz，2H)；7.51(d，J＝8.6Hz，2H).

Mass m/z(ES)：406[M+1].

Example 44

(S) -2-methoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid ethyl ester

The title compound was obtained as a thick liquid (220mg, 35%) by the method described in example 1 starting from 3- (3-methanesulfonyloxypropyl) phenylmethanesulfonate (911mg, 2.95mmol, 1.1eq) obtained in preparation 2 and ethyl (S) -2-methoxy-3- (4-aminophenyl) propionate (600mg, 2.69mmol, 1.0eq) obtained in preparation 27.

¹H NMR(CDCl₃，200MHz)：δ1.23(t，J＝7.2Hz，3H)；1.92(quintet，7.0Hz，2H)；2.75(t，J＝7.0Hz，2H)；2.90(d，J＝6.7Hz，2H)；3.02-3.20(m，5H)；3.34(s，3H)；3.89(t，J＝6.7Hz，1H)；4.17(q，J＝7.2Hz，2H)；6.50(d，J＝8.3Hz，2H)；7.02(d，J＝8.3Hz，2H)；7.10-7.40(aromatics，4H).

IR(neat)cm^-1：3405，2935，1739，1615，1376.

Mass m/z(CI)：436[M+1].

Example 45

(S) -2-methoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid

Ethyl (S) -2-methoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl ] propionate obtained in example 44 (220mg, 1.0eq, 0.50mmol) was hydrolyzed according to the procedure of example 14 to give the desired acid (170mg, 83%) as a thick liquid after purification by column chromatography.

¹H NMR(CDCl₃，400MHz)：δ1.94(quintet，7.0Hz，2H)；2.75(t，J＝7.0Hz，2H)；2.92(dd，J＝14，7.3Hz，1H)；3.03(dd，J＝14，4.3Hz，1H)；3.10-3.18(m，5H)；3.40(s，3H)；3.96(dd，J＝7.3，4.3Hz，1H)；4.40(bs，NH，CO₂H))；6.53(d，J＝8.3Hz，2H)；7.04(d，J＝8.3Hz，2H)；7.11-7.35(aromatics，4H).

IR(neat)cm^-1：3380，2924，1739，1611，1522，1364.

Mass m/z(ES)：408[M+1]，430[M+Na⁺]，815[M₂+1].

Example 46

Arginine salt of (S) -2-methoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl } propanoic acid

The title compound was obtained as a free-flowing solid (yield 100%) from (S) -2-methoxy-3- [4- {3- (3-methanesulfonyloxyphenyl) propylamino } phenyl ] propanoic acid (170mg, 1eq, 0.41mmol) and L-arginine (73mg, 1eq, 0.41mmol) obtained in example 45 according to the procedure described in example 35.

Mp：110-112℃

Example 47

(S) -2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoic acid ethyl ester

To a solution of ethyl (S) -2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino ] phenyl } propanoate, obtained in example 12, (0.2g, 0.447mmol) and potassium carbonate (0.185g, 1.34mmol) in anhydrous DMF (3ml) was added benzoyl chloride (62. mu.l, 0.537mmol) dropwise at RT and stirred for 20 h. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with 20% ethyl acetate-petroleum ether, to give the title compound (0.2g, 81%).

¹H NMR[200MHz，CDCl₃]：δ7.41-7.05(m，11H)，6.94(d，J＝8.3Hz，2H)，6.45-6.34(m，2H)，4.65(d，J＝5.4Hz，2H)，4.11(q，J＝6.8Hz，2H)，3.89(dd，J＝5.2 and 7.9Hz，1H)，3.68-3.46(m，1H)，3.35-3.19(m，1H)，3.13(s，3H)，3.02-2.85(m，2H)，1.18(t，J＝7.2Hz，3H)，1.06(t，J＝7.0Hz，3H).

Mass：m/z(CI)：552(M⁺+1，100).

Example 48

(S) -2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoic acid

To a solution of ethyl (S) -2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoate obtained in example 47 (0.2g, 0.363mmol) in methanol (4ml) was added dropwise a solution of sodium carbonate (0.192g, 1.82mmol) in water (2ml) and stirred at RT for 72 hours. Methanol was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The aqueous layer was cooled to 0 ℃, acidified to pH about 2 with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The crude product was chromatographed on silica gel eluting with 2% methanol-chloroform to give the title compound (100mg, 53%).

¹H NMR[200MHz，CDCl₃]：δ7.40-7.04(m，11H)，6.96(d，J＝8.3Hz，2H)，6.46-6.37(m，2H)，4.66(d，J＝5.6Hz，2H)，4.02-3.92(m，1H)，3.60-3.41(m，1H)，3.39-3.20(m，1H)，3.13(s，3H)，3.05-2.80(m，2H)，1.06(t，J＝7.0Hz，3H).

Example 49

Magnesium salt of (S) -2-ethoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoic acid

To a solution of (S) -2-ethoxy-3- (4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoic acid (70mg, 0.134mmol) obtained in example 48 in methanol (5ml) was added magnesium hydroxide (4mg, 0.065mmol) and the mixture refluxed overnight methanol was evaporated under reduced pressure, washed twice with toluene and triturated with petroleum ether to give the product as a solid (65mg, 89%) mp > 250 ℃.

¹H NMR[200MHz，CD₃OD]：δ7.44(d，J＝8.6Hz，2H)，7.35-7.10(m，9H)，7.04(d，J＝8.1Hz，2H)，6.50-6.39(m，2H)，4.66(d，J＝5.4Hz，2H)，3.78-3.68(m，1H)，3.60-3.40(m，1H)，3.19(s，3H)，3.18-02(m，1H)，3.00-2.84(m，1H)，2.82-2.65(m，1H)，0.94(t，J＝7.0Hz，3H).

Mass：m/z(ES)：1069(M⁺，24)，

Example 50

(S) -2-methoxy-3- {4- [ (E) -3- (4-methyl-sulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoic acid methyl ester

A solution of ethyl (S) -2-methoxy-3- [4- { (E) -3- (4-methanesulfonyloxyphenyl) -2-propenylamino } phenyl ] propanoate (0.650g, 1.50mmol) obtained in example 42 and potassium carbonate (0.621g, 4.50mmol) in dry DMF (10ml) was stirred at RT for 20 min. Benzoyl chloride (0.21ml, 1.80mmol) was added dropwise and stirred at RT for 16 h. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate and rotary evaporated to dryness. The residue was chromatographed on silica gel, eluting with 20% ethyl acetate-petroleum ether, to give the title compound (372mg, 47%).

¹H NMR[200MHz，CDCl₃]：δ7.48-7.18(m，9H)，7.10(d，J＝8.3Hz，2H)，6.98(d，J＝8.3Hz，2H)，6.52-6.32(m，2H)，4.69(d，J＝5.4Hz，2H)，3.91(t，J＝6.4Hz，1H)，3.65(s，3H)，3.32(s，3H)，3.16(s，3H)，3.02-2.88(m，2H).

Mass：m/z(CI)：524(M⁺+1).

Example 51

(S) -2-methoxy-3- {4- [ (E) -3- (4-methyl-sulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoic acid

To a solution of methyl (S) -2-methoxy-3- {4- [ (E) -3- (4-methyl-sulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoate (0.318g, 0.608mmol) obtained in example 50 in methanol (5ml) was added dropwise a solution of sodium carbonate (0.322g, 3.04mmol) in water (1ml) and stirred at RT for 18 hours. The methanol was removed under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The aqueous layer was cooled to 0 ℃, acidified to pH about 2 with 2N HCl and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel eluting with 40% ethyl acetate-petroleum ether to give the title compound (220mg, 73%).

¹H NMR[200MHz，CDCl₃]：δ7.44-7.20(m，7H)，7.16(d，J＝7.5Hz，2H)，7.08(d，J＝8.3Hz，2H)，6.96(d，J＝8.1Hz，2H)，6.50-6.28(m，2H)，4.66(d，J＝5.6Hz，2H)，3.92(dd，J＝4.2 and 7.4Hz，1H)，3.31(s，3H)，3.13(s，3H)，3.10-2.85(m，2H).

Mass：m/z(CI)：510(M⁺+1).

Example 52

Magnesium salt of (S) -2-methoxy-3- {4- [ (E) -3- (4-methyl-sulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoic acid

To a solution of (S) -2-methoxy-3- {4- [ (E) -3- (4-methanesulfonyloxyphenyl) -2-propenyl (phenyl) carboxamido ] phenyl } propanoic acid (0.175g, 0.354mmol) obtained in example 51 in methanol (3ml) was added magnesium hydroxide (10mg, 0.175mmol), and the mixture was refluxed for 16 hours. Methanol was removed under reduced pressure, rinsed twice with toluene and the residue triturated with petroleum ether to give the product (180mg, 99%) mp > 250 ℃.

¹H NMR[200MHz，CD₃OD]：δ7.40(d，J＝8.8Hz，2H)，7.36-6.96(m，11H)，6.44-6.24(m，2H)，4.62(d，J＝5.4Hz，2H)，3.27(s，3H)，3.16(s，3H)，3.12-2.99(m，2H).

Mass：m/z(ES)：1041(M⁺+1).

Demonstration of the efficacy of Compounds

A) In vitro

a) Determination of hPPAR alpha Activity

The ligand binding domain of hPPAR α is fused to the DNA binding domain of the yeast transcription factor Gal4 in a eukaryotic expression vector. HEK-293 cells were transfected with this plasmid and a reporter plasmid that harbors the luciferase gene driven by a GAL 4-specific promoter using superfect (Qiagen, Germany) as a transfection reagent. Compounds at various concentrations can be added 42 hours after transfection and incubated overnight. Luciferase activity was measured in a Top Count using the Packard Luclite kit (Packard, USA) as a function of the PPAR α binding/activating ability of the compound (Ivan Sadowski, Bredan Bell, Peter Broag and Melvyn Hollis. Gene. 1992.118: 137-141; Superfect TransfectionReagent handbook. February 1997.Qiagen, Germany).

b) Determination of hPPAR gamma Activity

The ligand binding domain of hPPAR γ 1 is fused to the DNA binding domain of the yeast transcription factor GAL4 in a eukaryotic expression vector. HEK-293 cells were transfected with this plasmid and a reporter plasmid that harbors the luciferase gene driven by a GAL 4-specific promoter using lipofectamine (Gibco BRL, USA) as a transfection reagent. Compounds at a concentration of 1. mu.M can be added 48 hours after transfection and incubated overnight. Luciferase activity was measured in a Packard Top Count using the Packard Luclite kit (Packard, USA) as a function of the PPAR γ 1 binding/activating capacity of the drug (Ivan Sadowski, Bredan Bell, PeterBroag and Melvyn Hollis. Gene. 1992.118: 137-141; Guide to Eurocaretic transformations with Cationic reagents. Life technologies, GIBCO BRL, USA).

Example No.	Concentration of	PPARα	Concentration of	PPARγ
Example No.	Concentration of	PPARα	Concentration of	PPARγ	Example 14	50μM	9.4	1μM	0.7
Example 15	50μM	6.1	1μM	0.7	Example 14	50μM	9.4	1μM	0.7
Example 15	50μM	6.1	1μM	0.7	Example 27	50μM	8.5	1μM	0.8

c) Assay of HMG CoA reductase inhibitory Activity

Liver microsome-bound reductase was prepared from mid-dark-cycle (mid-dark cycle) rats fed with 2% cholestyramine. At 100mM KH₂PO₄Spectrophotometric assay was performed in 4mM DTT, 0.2mM NADPH, 0.3mM MHMG CoA and 125. mu.g liver microsomal enzyme. The total reaction volume was kept at 1 ml. HMG CoA was added to initiate the reaction. The reaction mixture was incubated at 37 ℃ for 30 minutes and the decrease in absorbance at 340nm was recorded. A reaction mixture without substrate was used as a blank (Goldstein, J.L.and Brown, M.S.progress in understating the LDL-receiver and HMG CoA reductase, two membrane proteins with a catalyst regulation the plasma cholesterol. J.Lipid Res.1984, 25: 1450-. The test compounds will inhibit HMG CoA reductase.

B) In vivo

a) Efficacy in genetic models

Non-insulin dependent diabetes and hyperlipidemic animal models that may be associated with obesity and insulin resistance have been developed using mutations in the laboratory animal community and different sensitivities to the diet regime. Genetic models have been developed in various laboratories, such as db/db and ob/ob mice (Diabetes, (1982)31 (1): 1-6) and zucker fa/fa rats, for understanding the pathophysiology of disease, testing the efficacy of novel antidiabetic compounds (Diabetes, (1983) 32: 830-. Homozygous animals developed by Jackson laboratory, US C57BL/KsJ-db/db mice are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J.Clin.invest., (1990) 85: 962-. In the db/db model, mice develop progressively with age a decrease in insulin secretion, a feature commonly seen in the later stages of human type II diabetes when blood glucose levels are poorly controlled. The state of the pancreas and its course varies from model to model. Since this model is similar to type II diabetes, the compounds of the present invention will be tested for hypoglycemic activity against blood glucose and triglycerides.

Male C57BL/KsJ-db/db mice, 8 to 14 weeks old, weighing 35 to 60 grams, were used in experiments and fed in Dr.Reddy's Research Foundation (DRF) animal cages. The mice were provided with sufficient standard feed (National Institute of Nutrition (NIN), hyderapad, India) and acidified water. Animals with blood glucose above 350mg/dl will be tested. The number of animals per group was 4.

Test compounds were suspended on 0.25% carboxymethylcellulose and administered to the test groups daily by oral gavage at a dose of 0.1mg to 30mg/kg for 6 days. The control group received vehicle at a dose of 10 ml/kg. On day 6, blood samples were collected 1 hour after test compound/vehicle administration for evaluation of biological activity.

In order to measure random blood glucose and triglyceride levels,blood (100 μ l) can be collected in tubes containing EDTA through the orbital sinus using heparinized capillaries and centrifuged to obtain plasma. With the aid of glucose oxidase and glycerol-3-PO, respectively₄Oxidase/peroxidase methods, which can spectroscopically measure plasma glucose and triglyceride levels (dr. heavy's lab. diagnostic division kits, hyderapad, India).

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

Compound (I)	Dosage (mg/kg)	Reduction in blood glucose level (%)	Reduction of triglyceride (%)
Compound (I)	Dosage (mg/kg)	Reduction in blood glucose level (%)	Reduction of triglyceride (%)	Example 16	3	15	39
Example 39	3	56	36	Example 16	3	15	39
Example 39	3	56	36	Example 42	3	63	56

Results after 6 days

b) Plasma triglyceride and cholesterol lowering activity in a hypercholesterolemic rat model

Male Sprague Dawley rats (NIN stock) were fed in DRF animal cages. Animals were maintained at 25 + -1 ℃ for a 12 hour light and dark cycle. Rats weighing 180-. Animals were hypercholesterolaemic by feeding them for 6 days with standard laboratory feed (national institute of Nutrition (NIN), hyderapad, India) containing 2% cholesterol and 1% sodium cholate. Animals were maintained on the same diet throughout the experiment (Petit, D., Bonnefis, M.T., Rey, C.and Infante, R.Effect of bioprosthen over peptides and lipoprotein synthesis in non-homo-and dhyperlipidemic rates. Atherosclerosis. 1988.74: 215-.

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

Blood samples were taken on days 0 and 3 of compound treatment at a feeding state of 1 hour after drug administration. Blood was collected from the retro-orbital sinus through heparinized capillaries in tubes containing EDTA. After centrifugation, plasma was separated for estimation of total cholesterol, HDL and triglycerides. Measurements of plasma triglycerides, total cholesterol and HDL were performed using a commercial kit (dr. red's Laboratory, Diagnostic Division, India). LDL and VLDL cholesterol were calculated from the data obtained for total cholesterol, HDL and triglycerides. The decrease in the various parameters examined is calculated according to a formula.

Compound (I)	Dosage mg/kg	Reduction of Total Cholesterol (%)	Triglyceride reduction (%)	High density lipoprotein increase (%)	Low density lipoprotein reduction (%)
Compound (I)	Dosage mg/kg	Reduction of Total Cholesterol (%)	Triglyceride reduction (%)	High density lipoprotein increase (%)	Low density lipoprotein reduction (%)	Example 43	1	53	55	77	56

Results after 3 days

c) Plasma triglyceride and total cholesterol lowering activity in swiss albino mice

Male Swiss Albino Mice (SAM) were obtained from NIN and fed in DRF animal cages. All of these animals were maintained at 25. + -. 1 ℃ for a 12 hour light and dark cycle. Animals were given sufficient standard laboratory feed (NIN, hyderapad, India) and water. SAM weighing 20-25g and guinea pigs weighing 500-700g (Oliver, P., Plancke, M.O., Marzin, D., Clavey, V., Sauziers, J.and Fruchart, J.C.Effects of fenofibrate, gemfibrozil and nicotinic acid on plamiphereoprotein levels in normals and hyperlipidemics of atherocross.1988.70: 107-114) were used.

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

Blood samples were taken on days 0 and 6 of the treatment at a feeding state of 1 hour after drug administration. Blood was collected from the retro-orbital sinus through heparinized capillaries in tubes containing EDTA. After centrifugation, plasma was separated for estimation of triglycerides (Wieland, O.methods of enzymic analysis. Bergermeyer, H.O., Ed., 1963.211-214; Trinder, P.Ann.Clin.biochem.1969.6: 24-27). Measurement of plasma triglycerides was performed using a commercial kit (dr. heavy's Diagnostic Division, hyderapad, India).

Compound (I)	Dosage (mg/kg)	Triglyceride reduction (%)
Compound (I)	Dosage (mg/kg)	Triglyceride reduction (%)	Example 19	1	39
Example 30	3	41	Example 19	1	39
Example 30	3	41	Example 38	1	41

Results after 6 days

d) Weight reduction effect in Cholesterol fed hamster

The male syrian hamster is from NIN, hyderapad, India. Animals were kept in DRF animal cages with free access to food and water for 12 hours light and dark cycles at 25 + -1 deg.C. From the day of treatment, animals were fed standard laboratory feed (NIN) containing 1% cholesterol.

The test compound may be administered orally at a dose of 1 to 30 mg/kg/day for 15 days. Control animals were treated with vehicle (Mill Q water, dose 10 ml/kg/day). Body weight was measured once every 3 days.

Compound (I)	Dosage mg/kg	Reduction of Total Cholesterol (%)	Triglyceride reduction (%)	Weight loss (%)
Compound (I)	Dosage mg/kg	Reduction of Total Cholesterol (%)	Triglyceride reduction (%)	Weight loss (%)	Example 16	3	63	77	19

Calculating the formula:

1. the percent reduction in blood glucose/triglycerides/total cholesterol was calculated according to the following formula:

control group on day zero OC

OT-day zero treatment group value

TC-control group value on test day

TT-handling group value on test day

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

LDL Cholesterol (mg/dl) ═ Total Cholesterol-HDL Cholesterol-Triglycerides/5 ] mg/dl

VLDL cholesterol (mg/dl) ═ total cholesterol-HDL cholesterol-LDL cholesterol ] mg/dl

Claims

1. A compound of formula (I)

Its derivative, its analog, its tautomer, its stereoisomer, its polymorph, its pharmaceutically acceptable salt, their pharmaceutically acceptable solvate,

wherein R is¹Represents hydrogen, hydroxy, halogen, straight or branched chain (C)₁-C₁₂) Alkyl, straight-chain or branchedChain (C)₁-C₁₂) Alkoxy, substituted or unsubstituted arylalkyl or radicals R adjacent thereto²Together form a key;

y represents oxygen, NR⁷Or N (R)⁷) O, wherein R⁷Represents hydrogen or a substituted or unsubstituted group selected from (C)₁-C₁₂) Alkyl, aryl, arylalkyl, hydroxyalkyl, alkanoyl, aroyl, arylalkanoyl, heterocyclyl, heteroaryl, heteroarylalkyl, alkoxycarbonyl or arylalkoxycarbonyl;

or R⁴And R⁷Together may form a substituted or unsubstituted 5 or 6 membered cyclic structure containing carbon atoms and one nitrogen atom, and which optionally contains one or more additional heteroatoms selected from oxygen, sulphur or nitrogen;

R⁵represents hydrogen or a substituted or unsubstituted group selected from alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl;

ar represents a substituted or unsubstituted group selected from the group consisting of divalent phenylene, naphthylene, pyridyl, quinolyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl;

x represents-C (═ O) -, -C (═ S) -O, -C (═ O) -O-, -C (═ O) -S-, -C (═ S) -O-, -O- (CH) -₂)_d-、-NH-(CH₂)_d-, where d is an integer from 1 to 4, -O-C (═ O) -, -C (O) CH₂-、-CR^a＝CR^b-CH₂-、-CR^a＝CR^b-CO-, wherein R^aAnd R^bMay be the same or different and represents hydrogen or (C)₁-C₆) Alkyl, or X represents a bond;

R⁶represents a substituted or unsubstituted group selected from the group consisting of aryloxycarbonyl, arylalkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO₂R⁸、-OCONR⁸R⁹、NR⁸COOR⁹、-NR⁸COR⁹、-NR⁸SO₂R⁹、NR⁸CONR⁹R¹⁰、-NR⁸CSNR⁸R⁹、-SO₂R⁸、-SOR⁸、-SR⁸、-SO₂NR⁸R⁹、-SO₂OR⁸、-COOR⁹、-COR⁹or-CONR⁸R⁹Wherein R is⁸、R⁹And R¹⁰May be the same or different and independently represent hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; r⁸And R⁹When located on a nitrogen atom, may together form a 5-or 6-membered cyclic structure containing carbon atoms and one or more heteroatoms selected from oxygen, sulfur or nitrogen; or when R is¹³In the third position of the phenyl ring and not representing hydrogen, R⁶Is hydrogen;

R¹³representsHydrogen, halogen, nitro, cyano, amino, haloalkyl, hydroxy or a substituted or unsubstituted radical selected from linear or branched (C)₁-C₁₂) Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, alkoxy, monoalkylamino, dialkylamino, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, aryloxy, arylalkoxy, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO₂R⁸、-OCONR⁸R⁹、NR⁸COOR⁹、-NR⁸R⁹、-NR⁸COR⁹、-NR⁸SO₂R⁹、NR⁸CONR⁹R¹⁰、-NR⁸CSNR⁸R⁹、-SO₂R⁸、-SOR⁸、-SR⁸、-SO₂NR⁸R⁹、-SO₂OR⁸、-COOR⁹、-COR⁹、-CONR⁸R⁹Wherein R is⁸、R⁹And R¹⁰May be the same or different and independently represent hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; r⁸And R⁹When located on a nitrogen atom may together form a 5 or 6 membered cyclic structure containing carbon atoms and one or more heteroatoms selected from oxygen, sulfur or nitrogen;

n is 1 to 6 and m is 0 to 6.

2. A compound of formula (I) as claimed in claim 1 wherein

R²is hydrogen, straight-chain or branched (C)₁-C₆) Alkyl or with R¹Forming a key;

R³is hydrogen, straight-chain or branched (C)₁-C₁₂) Alkyl, (C)₃-C₇) Cycloalkyl, aryl or arylalkyl;

R⁴is hydrogen, straight-chain or branched (C)₁-C₁₂) Alkyl, (C)₃-C₇) Cycloalkyl, aryl or arylalkyl;

R⁵is hydrogen, (C)₁-C₁₂) Alkyl or (C)₃-C₇) A cycloalkyl group;

R⁸Is hydrogen, straight-chain or branched (C)₁-C₆) Alkyl or substituted or unsubstituted aryl;

R¹³is hydrogen or-OSO₂R⁸；

X is-C (O) -, -C (S), -C (O) CH₂-、O-C(＝O)-、-O(CH₂)_d、-CH＝CH-CH₂-, -CH ═ CH-CO-or X represents a bond;

y is oxygen;

d is an integer from 1 to 4;

m is an integer from 0 to 1; and is

n is an integer from 0 to 2.

3. A compound of formula (I) as claimed in claim 2 wherein

R¹Is hydrogen or with R²Forming a key;

R²is hydrogen or with R¹Forming a key;

R³is hydrogen, or straight or branched (C)₁-C₁₂) An alkyl group;

R⁴is hydrogen, or straight or branched (C)₁-C₁₂) An alkyl group;

R⁵is hydrogen or (C)₁-C₁₂) An alkyl group;

R⁶is-OSO₂R⁸or-NR⁸SO₂R⁹；

R¹³is hydrogen or-OSO₂R⁸；

X is-C (═ O) -, O-C (═ O) -, -O (CH)₂)_d、-CH＝CH-CH₂-, -CH ═ CH-CO-or X represents a bond;

y is oxygen.

4. A compound according to claims 1-3 selected from:

5. The compound according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn; n, N ' -diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, theobromine, valinol, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, amantadine, diethanolamine, meglumine, ethylenediamine, N ' -diphenylethylenediamine, N ' -dibenzylethylenediamine, N-benzylphenethylamine, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, spermidine; alkylanilines, glycinol, phenylglycinol; glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; a non-natural amino acid; d-isomer or substituted amino acid; a salt of an acidic amino acid selected from aspartic acid or glutamic acid; guanidine, substituted guanidines, wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl; an ammonium or substituted ammonium salt; sulfate, nitrate, phosphate, perchlorate, borate, hydrohalic acid (HCl, HBr, HI) salt, acetate, tartrate, maleate, citrate, succinate, pamoate, mesylate, benzoate, salicylate, hydroxynaphthoate, benzenesulfonate, ascorbate, glycerophosphate, or ketoglutarate.

6. Preparation of a compound of formula (I) according to claim 1

A process for the preparation of its derivatives, its analogs, its tautomers, its stereoisomers, its pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein all symbols are as defined above, which process comprises

a) Reacting a compound of formula (IIIa)

Wherein R is⁵、R⁶、R¹³X, m and n are as defined in claim 1,

with a compound of formula (IIIb),

wherein Y is as defined in claim 1, except NH, R¹¹Represents a straight chain or branched chain (C)₁-C₆) Alkyl, all other symbols being as defined in claim 1，

To produce a compound of formula (I) wherein Y is as defined above, except NH, and all other symbols are as defined above;

or

b) Reacting a compound of formula (IIId)

Wherein R is⁶、R¹³Is as defined above, NR⁸R⁹With the exception that Y is as defined in claim 1, with the exception of NH, all other symbols being as defined above,

with compounds of the formula (IIIc)

R³-L¹ (IIIc)

Wherein R is³Is as defined in claim 1, except for hydrogen, and L¹Is a leaving group to produce a compound of formula (I) wherein Y is as defined above, except NH, all other symbols are as defined above;

or

c) Reacting a compound of formula (IIIa), wherein all symbols are as defined above, with a compound of formula (IIIe),

wherein R is²Represents a hydrogen atom, Y is as defined above, except NH, and all other symbols are as defined above,

or

d) Reacting a compound of formula (IIIg)

Wherein R is⁶、R¹³X and n are as defined in claim 1, L¹Represents a leaving group, with a compound of formula (IIIf),

wherein R is¹And R²Together represent a bond and all other symbols are as defined above, to yield a compound of formula (I);

or

e) Reacting a compound of formula (IIIh)

Wherein R is⁶、R¹³X and n are as defined in claim 1,

with a compound of formula (IIIf) wherein R¹And R²Together represent a bond and all other symbols are as defined above, to yield a compound of formula (I);

or

f) Reacting a compound of formula (IIIi)

Wherein all the symbols are as defined above,

with a compound of formula (IIIj),

wherein Y represents oxygen, R³＝R⁴And as defined above, except for hydrogen,

to produce a compound of formula (I) wherein R¹And R²Together represent a bond, Y represents an oxygen atom, all other symbols being as defined above;

or

g) Reduction of a compound of formula (IVa)

It represents a compound of formula (I) wherein R¹And R²Together represent a bond, Y represents an oxygen atom and all other symbols are as defined aboveAs defined, to produce a compound of formula (I) wherein R¹And R²Each represents hydrogen, all symbols are as defined above;

or

h) Reacting a compound of formula (IVb)

Wherein R is⁴As defined above, except for hydrogen, L¹Is a leaving group, all other symbols are as defined above,

with a compound of the formula (IVc),

R³-OH (IVc)

wherein R is³As defined above, except for hydrogen,

to produce a compound of formula (I);

or

i) Reacting a compound of formula (IIIg)

Wherein all the symbols are as defined above,

with a compound of formula (IIIf),

wherein all the symbols are as defined above,

to produce a compound of formula (I) wherein all symbols are as defined above;

or

j) Reacting a compound of formula (IIIh)

Wherein all the symbols are as defined above,

with a compound of formula (IIIf),

wherein all the symbols are as defined above,

to produce a compound of formula (I) wherein all symbols are as defined above;

or

k) Reacting a compound of formula (IIId)

Wherein all the symbols are as defined above,

with a compound of the formula (IIIc),

R³-L¹ (IIIc)

wherein R is³As defined above, except for hydrogen, L¹Is a leaving group which is a substituent of the group,

to produce a compound of formula (I) wherein all symbols are as defined above;

or

1) Reacting a compound of formula (IIIa)

Wherein all the symbols are as defined above,

with a compound of formula (IIIe),

to produce a compound of formula (I) wherein R²Represents a hydrogen atom, Y is as defined above, with the exception of NH, and all other symbols are as defined above;

or

m) converting the compound of formula (IVd) in the presence of an acid or a base

Wherein all the symbols are as defined above,

to obtain a compound of formula (I) wherein Y represents an oxygen atom and all other symbols are as defined above;

or

n) reacting a compound of formula (IVe)

Wherein R is⁴As defined above, except for hydrogen, all symbols are as defined above,

with a compound of the formula (IVc),

R³-OH (IVc)

wherein R is³As defined above, except for hydrogen,

to produce a compound of formula (I) wherein R³And R⁴As defined above, except for hydrogen, all other symbols are as defined above;

or

o) reacting a compound of formula (IVg)

Wherein G is²Represents NH₂or-CHO, all other symbols being as defined above,

with a compound of formula (IVf),

wherein when G²When is-CHO, G¹Is NH₂Or when G is²Is NH₂When, G¹is-CHO, q is 0 to 6, all other symbols are as defined above,

to produce a compound of formula (I) wherein R⁵Represents hydrogen and all other symbols are as defined above.

7. Intermediate of formula (IIIa)

They are used forTheir analogs, their tautomers, their stereoisomers, their salts, their solvates, wherein R is⁵Represents hydrogen or a substituted or unsubstituted group selected from alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; n and m are integers from 0 to 6; ar represents a substituted or unsubstituted group selected from divalent phenylene, naphthylene, pyridyl, quinolyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, dihydrobenzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl, and the like; the substituents on the group represented by Ar are selected from linear or branched, optionally halogenated (C)₁-C₆) Alkyl, optionally halogenated (C)₁-C₃) Alkoxy, halogen, acyl, amino, amido, thio or carboxylic or sulfonic acids and derivatives thereof; x represents C-O, C-S-C (O) CH₂-、-CH＝CH-CH₂-, -CH ═ CH-CO-, or X represents a bond; r⁶Represents a substituted or unsubstituted group selected from the group consisting of aryloxycarbonyl, arylalkoxycarbonyl, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO₂R⁸、-OCONR⁸R⁹、NR⁸COOR⁹、-NR⁸COR⁹、-NR⁸SO₂R⁹、NR⁸CONR⁹R¹⁰、-NR⁸CSNR⁸R⁹、-SO₂R⁸、-SOR⁸、-SR⁸、-SO₂NR⁸R⁹、-SO₂OR⁸、-COOR⁹、-COR⁹or-CONR⁸R⁹Wherein R is⁸、R⁹And R¹⁰May be the same or different and independently represent hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; r⁸And R⁹When located on a nitrogen atom may together be composed of carbon atoms and one or moreA 5 or 6 membered cyclic structure of a heteroatom selected from oxygen, sulfur or nitrogen; or when R is¹³In the third position of the phenyl ring and not representing hydrogen, R⁶Is hydrogen; r¹³Represents hydrogen, halogen, nitro, cyano, amino, haloalkyl, hydroxyl or a substituted or unsubstituted radical selected from linear or branched (C)₁-C₁₂) Alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, alkoxy, monoalkylamino, dialkylamino, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, aryloxy, arylalkoxy, alkylcarbonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, arylalkoxycarbonylamino, fluorenylmethoxycarbonyl (Fmoc), fluorenylmethoxycarbonylamino (N-Fmoc), -OSO₂R⁸、-OCONR⁸R⁹、NR⁸COOR⁹、-NR⁸COR⁹、-NR⁸R⁹、-NR⁸SO₂R⁹、NR⁸CONR⁹R¹⁰、-NR⁸CSNR⁸R⁹、-SO₂R⁸、-SOR⁸、-SR⁸、-SO₂NR⁸R⁹、-SO₂OR⁸、-COOR⁹、-COR⁹、-CONR⁸R⁹Wherein R is⁸、R⁹And R¹⁰May be the same or different and independently represent hydrogen or a substituted or unsubstituted alkyl, aryl, arylalkyl, alkoxycarbonyl or arylalkoxycarbonyl group; r⁸And R⁹When located on a nitrogen atom, may together form a 5-or 6-membered cyclic structure containing carbon atoms and one or more heteroatoms selected from oxygen, sulfur or nitrogen.

8. Preparation of a compound of formula (IIIa) as defined in claim 7

A process for their derivatives, their analogs, their tautomers, their stereoisomers, comprising:

a) i) reacting a compound of formula (IIIk)

Wherein X represents C (O) CH₂-、-CH＝CH-CH₂-or X represents a bond, and R⁶And R¹³As defined in claim 6, is that,

with a compound of formula (IIIl),

wherein R is¹²Represents hydrogen or (C)₁-C₆) Alkyl, m being as defined above, to give a compound of formula (IIIm)

Wherein all symbols are as defined above;

ii) converting the compound of formula (IIIm) to a compound of formula (IIIa) in the presence of an acid or base, wherein R⁵Represents hydrogen, X represents C (O) CH₂-、-CH＝CH-CH₂-or X represents a bond, m is 0, Ar represents phenyl, all other symbols are as defined above;

or

b) Reacting a compound of formula (IIIg)

Wherein all symbols are as defined above,

with a compound of formula (IIIn),

wherein R is¹²Represents hydrogen or alkyl, m is an integer from 0 to 6, R⁵As defined above, the above-mentioned,

to produce a compound of formula (IIIa), wherein R⁵Represents hydrogen orAlkyl, m is 0 or 1, and all other symbols are as defined above.

9. A composition comprising a compound of formula (I) as defined in any one of claims 1 to 5

And a pharmaceutically acceptable carrier, diluent, excipient or solvate.

10. A composition comprising a compound of formula (I) as defined in claims 1 to 5 and an HMGCoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, a lipoprotein disorder therapeutic agent, a hypoglycemic agent, insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR α and γ agonist or a mixture thereof together with a pharmaceutically acceptable carrier, diluent, excipient or solvate.

11. A pharmaceutical composition as claimed in claim 9 or 10 in the form of a tablet, capsule, powder, syrup, solution or suspension.

12. A method for the treatment and/or prophylaxis of diabetes mellitus which is caused by insulin resistance or impaired glucose tolerance, which comprises administering a compound of formula (I) as defined in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 to a patient in need thereof.

13. A method for the treatment and/or prophylaxis of diabetes or diabetic complications caused by insulin resistance or impaired glucose tolerance, wherein the complication is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary artery disease, cardiovascular disease, renal disease, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy, retinopathy, disorders involving endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel disease, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer or osteoporosis, or as an aldose reductase inhibitor or an anti-inflammatory agent, comprising administering to a patient in need thereof a compound of formula (I) as defined in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10.

14. A method for the treatment and/or prophylaxis of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases in which insulin resistance is the pathophysiological mechanism, which comprises administering a compound of the formula (I) as defined in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 to a patient in need thereof.

15. A method of treatment and/or prophylaxis of disorders related to syndrome X, which method comprises administering to a patient in need thereof a PPAR agonist of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10.

16. The method according to claim 15, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease or cardiovascular disease.

17. Reducing total cholesterol, body weight, plasma glucose, insulin, HbA_1CA triglyceride, LDL, VLDL or free fatty acid or increasing HDL in plasma comprising administering to a patient in need thereof a compound of formula (I) as defined in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10.

18. A method for the treatment and/or prophylaxis of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases in which insulin resistance is the pathophysiological mechanism, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as defined in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 over a period of time in combination/concomitant with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity drug, a lipoprotein disorder therapeutic agent, a hypoglycemic agent, insulin, biguanide, sulfonylurea, thiazolidinedione, dual PPAR α and γ agonists or mixtures thereof or combinations thereof, in order to exert a synergistic and/or additive effect.

19. A method for the treatment and/or prophylaxis of diabetes mellitus or a complication of diabetes mellitus resulting from insulin resistance or impaired glucose tolerance, wherein the complication is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary artery disease, cardiovascular disease, kidney disease, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy, retinopathy, disorders involving endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel disease, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer or osteoporosis, or as an aldose reductase inhibitor or anti-inflammatory agent, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as defined in claims 1 to 5 or according to claim 9 or 10 over a period of time A pharmaceutical composition in combination/concommittance with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, a therapeutic agent for lipoprotein disorders, a hypoglycemic agent, insulin, biguanide, sulfonylurea, thiazolidinedione, dual PPAR α and γ agonists or a mixture thereof or a combination thereof so as to exert a synergistic and/or additive effect.

20. A method of treatment and/or prophylaxis of disorders related to syndrome X, which method comprises administering to a patient in need thereof an effective amount of a PPAR agonist of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 in combination/concomitantly with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, a lipoprotein disorder treating agent, a hypoglycaemic agent, insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR α and γ agonist or a mixture thereof or a combination thereof, so as to exert a synergistic and/or additive effect.

21. The method according to claim 20, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease or cardiovascular disease.

22. Reducing total cholesterol, body weight, plasma glucose, insulin, HbA_1CA method of treating or preventing a disease or condition associated with an increase in plasma HDL comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10, in combination/concomittant with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, a lipoprotein disorder treating agent, a hypoglycemic agent, insulin, biguanide, sulfonylurea, thiazolidinedione, dual PPAR α and γ agonists or mixtures thereof or combinations thereof, for a period of time so as to exert a synergistic and/or additive effect.

23. Use of a compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prophylaxis of diabetes mellitus which is caused by insulin resistance or impaired glucose tolerance.

24. The use of a compound of the formula (I) as claimed in claims 1 to 5 or of a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prophylaxis of diabetes or diabetic complications resulting from insulin resistance or impaired glucose tolerance, wherein the complications are dyslipidemia, stroke, hyperlipidemia, hypercholesteremia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary artery disease, cardiovascular disease, kidney disease, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy, retinopathy, disorders involving endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel disease, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer or osteoporosis, or as aldose reductase inhibitors or anti-inflammatory agents.

25. The use of a compound of the formula (I) as claimed in claims 1 to 5 or of a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prophylaxis of hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases in which insulin resistance is the pathophysiological mechanism.

26. Use of a compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prevention of disorders related to syndrome X, which comprises the administration of a PPAR α and/or PPAR γ agonist.

27. Use according to claim 26, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease or cardiovascular disease.

28. A compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 for use in reducing total cholesterol, body weight, plasma glucose, insulin, HbA_1CTriglyceride, LDL, VLDL or free fatty acids or increasing HDL in plasma.

29. Use of a compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 in combination/concomitance with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, a therapeutic agent for lipoprotein disorders, a hypoglycemic agent, insulin, biguanide, sulfonylurea, thiazolidinedione, dual PPAR α and γ agonists or a combination thereof for a period of time so as to exert a synergistic and/or additive effect for the treatment and/or prevention of hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases in which insulin resistance is the pathophysiological mechanism, which comprises administering to a patient in need thereof.

30. The use of a compound of the formula (I) as claimed in claims 1 to 5 or of a pharmaceutical composition according to claim 9 or 10 for the treatment and/or prophylaxis of diabetes or diabetic complications resulting from insulin resistance or impaired glucose tolerance, wherein the complications are dyslipidemia, stroke, hyperlipidemia, hypercholesteremia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary artery disease, cardiovascular disease, kidney disease, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy, retinopathy, disorders related to endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel disease, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer or osteoporosis, or as aldose reductase inhibitors or anti-inflammatory agents.

31. Use of a compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claims 9 or 10 in combination/concomitance with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, a therapeutic agent for lipoprotein disorders, a hypoglycemic agent, insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR α and γ agonist or a combination thereof for a period of time so as to exert a synergistic and/or additive effect for the treatment and/or prevention of disorders related to syndrome X, comprising administering a PPAR α and/or PPAR γ agonist to a patient in need thereof.

32. Use according to claim 31, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease or cardiovascular disease.

33. A compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claims 9 or 10 in combination/concomitance with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, a therapeutic agent for lipoprotein disorders, a hypoglycemic agent, insulin, biguanide, sulfonylurea, thiazolidinedione, dual PPAR α and γ agonists or mixtures thereof for reducing total cholesterol, body weight, plasma glucose, insulin, HbA_1CTriglyceride, LDL, VLDL or free fatty acids or increasing HDL in plasma.

34. A medicament for the treatment and/or prophylaxis of diabetes mellitus which is caused by insulin resistance or impaired glucose tolerance which comprises administering to a patient in need thereof a compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10.

35. A medicament for treating and/or preventing diabetes or diabetic complications caused by insulin resistance or impaired glucose tolerance, wherein the complication is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary artery disease, cardiovascular disease, renal disease, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy, retinopathy, disorders involving endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel disease, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer or osteoporosis, or as an aldose reductase inhibitor or an anti-inflammatory agent, comprising administering to a patient in need thereof a compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10.

36. Medicament for the treatment and/or prophylaxis of hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases in which insulin resistance is the pathophysiological mechanism, comprising administering a compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 to a patient in need thereof.

37. A medicament for the treatment and/or prevention of disorders related to syndrome X, comprising administering to a patient in need thereof a PPAR α and/or PPAR γ agonist of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10.

38. A medicament according to claim 37, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease or cardiovascular disease.

39. Reducing total cholesterol, body weight, plasma glucose, insulin, HbA_1CTriglyceride, LDL, VLDL or free fatty acids or an agent increasing HDL in plasma comprising administering to a patient in need thereof a compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10.

40. Medicament for the treatment and/or prophylaxis of hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis, obesity, impaired glucose tolerance, atherosclerosis, leptin resistance, insulin resistance or diseases in which insulin resistance is the pathophysiological mechanism, comprising an effective amount of a compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 in combination/concomitantly with HMG CoA reductase inhibitors, cholesterol absorption inhibitors, anti-obesity agents, lipoprotein disorder remedies, hypoglycaemic agents, insulin, biguanides, sulfonylureas, thiazolidinediones, dual PPAR α and β agonists or combinations thereof, for a period of time, for the administration to a patient in need thereof, in order to exert a synergistic and/or additive effect.

41. A medicament for treating and/or preventing diabetes or diabetic complications caused by insulin resistance or impaired glucose tolerance, wherein the complication is dyslipidemia, stroke, hyperlipidemia, hypercholesterolemia, hyperglycemia, osteoporosis, atherosclerosis, leptin resistance, hypertension, obesity, coronary artery disease, cardiovascular disease, renal disease, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy, retinopathy, disorders involving endothelial cell activation, psoriasis, polycystic ovary syndrome (PCOS), dementia, inflammatory bowel disease, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma, eating disorders, cancer or osteoporosis, or as an aldose reductase inhibitor or an anti-inflammatory agent, comprising administering to a patient in need thereof a compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10.

42. A medicament for the treatment and/or prevention of disorders related to syndrome X comprising administering to a patient in need thereof an effective amount of a PPAR α and/or PPAR γ agonist of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 and an HMGCoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, a lipoprotein disorder therapeutic agent, a hypoglycemic agent, insulin, biguanide, sulfonylurea, thiazolidinedione, dual PPAR α and β agonists or a combination thereof over a period of time so as to exert a synergistic and/or additive effect.

43. A medicament according to claim 42, wherein the disorder is hypertension, obesity, insulin resistance, atherosclerosis, coronary artery disease or cardiovascular disease.

44. Reducing total cholesterol, body weight, plasma glucose, insulin, HbA_1CMedicine for treating diabetesAn agent for the treatment of triglycerides, LDL, VLDL or free fatty acids or for increasing HDL in the plasma comprising administering to a patient in need thereof a compound of formula (I) as claimed in claims 1 to 5 or a pharmaceutical composition according to claim 9 or 10 in combination/concomitantly with an HMG CoA reductase inhibitor, a cholesterol absorption inhibitor, an anti-obesity agent, a therapeutic agent for lipoprotein disorders, a hypoglycemic agent, insulin, a biguanide, a sulfonylurea, a thiazolidinedione, a dual PPAR α and β agonist or a mixture thereof, either together or within a period of time that exerts a synergistic and/or additive effect.