HK1089087A

HK1089087A - Amino acid phenoxy ethers

Info

Publication number: HK1089087A
Application number: HK06109552.5A
Authority: HK
Inventors: Bishwajit Nag; Abhijeet Nag; Debendranath Dey; Shiv Kumar Agarwal
Original assignee: Bexel Pharmaceuticals, Inc.
Priority date: 2003-01-17
Filing date: 2004-01-13
Publication date: 2006-11-24

Description

Amino acid phenoxy ethers

This application claims the benefit of U.S. provisional application No. 60/440,772, filed as early as 2003, month 1, day 17, which is incorporated herein by reference.

Technical Field

The present invention relates to novel amino acid phenyl ethers useful in the treatment of immunological disorders, inflammation, obesity, hyperlipidemia, hypertension, neurological disorders, and diabetes.

Background

The major elements of the immune system are macrophages or antigen presenting cells, T cells and B cells. The role of other immune cells such as NK cells, basophils, mast cells and dendritic cells is known, but their role in primary immune diseases is still uncertain. Macrophages are important mediators of both inflammation and "help" to provide stimulation and proliferation of T cells. Most importantly, macrophages can produce IL1, IL 12 and TNF- α, all of which are potent pro-inflammatory molecules and also provide help for T cells. In addition, activation of macrophages can lead to the induction of enzymes such as cyclooxygenase II (COX-2), Inducible Nitric Oxide Synthase (iNOS), and the like, and can lead to the production of free radicals that can damage normal cells. Many factors can activate macrophages, including bacterial products, superantigens, and interferon gamma (IFN γ). Phosphotyrosine kinase (PTK) and other unidentified cellular kinases are generally thought to be involved in the activation process.

Cytokines are molecules secreted by immune cells and are important in mediating immune responses. Production of cytokines can result in secretion of other cytokines, alteration of cell function, cell division or differentiation. Inflammation is the normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathological inflammatory processes can lead to morbidity and mortality. Tumor necrosis factor-alpha (TNF- α) among cytokines plays an important role in inflammatory responses and is targeted as an intervention point in inflammatory diseases. TNF- α is a polypeptide hormone that activates the release of macrophages and other cells. At low concentrations, TNF- α is involved in a protective inflammatory response by activating leukocytes and causing them to migrate to the periphery of inflamed vessels (Moser et al, J Clininvest, 83: 444-55, 1989). At higher concentrations, TNF- α acts as a potent pyrogen and induces the production of other proinflammatory cytokines (Haworth et al, Eur J Immunol, 21: 2575-79, 1991; Brennan et al, Lancet, 2: 244-7, 1989). TNF- α can also stimulate acute phase protein synthesis. In a chronic and progressive inflammatory disease, rheumatoid Arthritis, affecting approximately 1% of the adult population in the United states, TNF- α mediates a cytokine cascade that causes joint damage and destruction (Arend et al, Arthritis Rheum, 38: 151-60, 1995). Inhibitors of TNF- α, including the soluble TNF receptor (etanercept) (Goldenberg, Clin Ther, 21: 75-87, 1999) and anti-TNF- α antibodies (infliximab) (Luong et al, AnnPharmacother, 34: 743-60, 2000), have recently been approved by the U.S. Food and Drug Administration (FDA) as drugs for the treatment of rheumatoid arthritis.

Elevated levels of TNF- α can also cause a number of other diseases and conditions, including cachexia, septic shock syndrome, osteoarthritis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

Overproduction of IL-6 can also lead to several disease states, and there is an urgent need to develop compounds that inhibit IL-6 secretion.

The cytokine IL-1. beta. is also involved in inflammatory responses. It stimulates the proliferation of thymocytes, enhances fibroblast growth factor activity and increases prostaglandin release in synovial cells.

Elevated or uncontrolled levels of the cytokine IL-1 β are associated with a variety of inflammatory and other disease states, including but not limited to adult respiratory distress syndrome, allergies, Alzheimer's disease, and the like.

Since overproduction of IL-1 β is associated with a variety of disorders, there is a need to develop compounds that inhibit IL-1 β production or activity.

It is worth mentioning the previous research, as the large amount of research work previously done provides compounds for inhibiting e.g. TNF- α, IL-1, IL-6, COX-2 or other components which are believed to be responsible for the immune response, inflammation or inflammatory diseases such as arthritis, and there remains a need to find new or improved compounds which are effective in treating or inhibiting such diseases.

TNF-alpha appears to be associated with adipogenesis (obesity) and other metabolic disorders such as diabetes. Although the number of people diagnosed with diabetes worldwide has dramatically increased over the past 20 years [ Amos a., McCarty, d., Zimmet, P. (1997) diabetes med.14, S1-S85; king, H., Aubert, R., Herman, W. (1998) Diabetes Care, 21, 1414-1431], but relatively little progress has been made in new therapeutic approaches to Diabetes and its related disorders [ Moller, D.E (2001) Nature 414, 821-827 ]. There are two types of diabetes: insulin-dependent type I and non-insulin-dependent (insulin resistance) type II. Type II insulin resistant diabetes accounts for 90-95% of all diabetes. Metabolic disorders of this syndrome currently affect more than 1.5 million people worldwide, and are predicted to increase sharply to 3 billion by 2005 [ Amos, a., McCarty, d., Zimmet, P. (1997) Diabetic med.14, S1-S85; kopelman, P.G.Hitaman, G.A. (1998) Lancet, 352, SIV 5. The major driver contributing to the increased incidence of type II diabetes is the increase in obesity, a most important factor in the pathogenesis of type II diabetes [ Kopelman, p.g., Hitaman, G.A. (1998) Lancet, 352, SIV5 ].

Currently, the treatment of type II diabetes relies mainly on several therapies aimed at reducing hyperglycemia itself. They are: sulfonylureas and related insulin secretagogues known to release more insulin from pancreatic beta cells; metformin, which acts to reduce the production of glucose in the liver; peroxisome proliferator-activated receptor (PPAR) agonists that increase insulin action; alpha-glucosidase inhibitors that slow the absorption of glucose in the intestine; as well as insulin itself (summarized in table 1 below) which inhibits glucose production and increases glucose utilization. All of these therapies have limited efficacy, limited tolerability and significant mechanistic side effects. Of particular concern is the tendency of most treatments to increase body weight. Several current treatments for type II diabetes are associated with the onset of hypoglycemia, and few of the current treatments adequately address potential drawbacks, such as obesity and the phenomenon known as insulin resistance. Of these oral drugs, sulfonylureas represent the oldest most widely used form of treatment. Over time, many patients who initially respond to sulfonylureas become refractory to treatment (secondary failure). In addition to glucose levels and obesity, type II diabetes is now associated with high levels of triglycerides and cholesterol. Therefore, a new class of drugs is required to be sought to solve the problems of metabolic defects (increasingly referred to as Syndrome X), such as obesity, hyperglycemia and hyperlipidemia, to solve type II diabetes and its related disorders.

Table 1: common therapeutic agent for type II diabetes

Kind of drug	Administration of drugs	Molecule	Target of action	Side effects
Kind of drug	Administration of drugs	Molecule	Target of action	Side effects	Insulin sulfonylurea (glibenclamide) (repaglinide) (nateglinide) metformin (biguanide) alpha-glucosidase inhibitor (acarbose) PPAR-agonist (rosiglitazone) (pioglitazone)	Intramuscular oral administration	Insulin receptor SU receptor K +/ATP channel unknown alpha-glucosidase PPAR-γ	Liver, muscle, fatty pancreas beta cell liver (muscle) intestinal fat, muscle, liver	Weight gain for hypoglycemia gastrointestinal discomfort lactic acidosis and gastrointestinal discomfort weight gain for anemia edema

Summary of The Invention

The present invention relates to novel amino acid phenyl ethers of the following formula (I), derivatives thereof, analogues thereof, tautomers thereof, stereoisomers thereof, polymorphs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof:

wherein- - -represents an optional double bond; y represents oxygen, sulphur or NR, wherein R represents hydrogen or alkyl; z represents oxygen or sulfur; r₁、R₂、R₃And R₄May be the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, alkoxy; a represents a bond or a substituted or unsubstituted aryl, heterocyclic or heteroaromatic ring; x represents an alpha-aminocarboxylic acid or a derivative thereof bonded to A or Y through its alpha side chain.

The present invention also relates to processes for the preparation of the aforementioned novel compounds, their analogs, their derivatives, their tautomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, novel intermediates and pharmaceutical compositions containing them. Tautomers are isomers that can exist in equilibrium by reacting according to either form. Stereoisomers include configurational isomers, such as cis and trans double bonds, and optical isomers whose atoms have different spatial arrangements. Polymorphs are molecules that can crystallize in two or more crystal forms. Solvates are molecular complexes or ionic complexes of molecules or ions of a solvent and molecules or ions of a solute. Alpha-amino carboxylic acids include, but are not limited to, naturally occurring amino acids. The alpha side chain is a group that includes a hydrogen and can be covalently bonded to the alpha carbon of an alpha-amino carboxylic acid. Analogs include those compounds that differ in the position of an oxygen, sulfur, nitrogen or carbon atom by substitution with an oxygen, sulfur, nitrogen or carbon atom. Analogs also include atoms of the same group of the periodic Table, such As F, Cl, Br, I, As. Derivatives include compounds formed by conventional functionalization of atoms, for example, by protecting amino or carboxyl groups by carboxylation or esterification, respectively.

The compounds of the present invention are effective in lowering blood glucose, serum insulin, free fatty acids, cholesterol and triglyceride levels and are therefore useful in the treatment and/or prevention of diabetes. The compounds of the present invention are useful in the treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Unexpectedly, these compounds increase leptin levels and are not hepatotoxic.

In addition, the compounds of the present invention are useful in the treatment of diseases associated with insulin resistance, such as polycystic ovary syndrome, as well as hyperlipidemia, coronary artery disease and peripheral vascular disease, and in the treatment of inflammatory and immune disorders, particularly those mediated by cytokines such as TNF- α, IL-1, IL-6, IL-1 β, and cyclooxygenase such as COX-2.

Brief Description of Drawings

Figure 1 shows that the compound of example 1 reduces pro-inflammatory cytokines in human macrophages.

Figure 2 shows the efficacy of compound 2 in example 1 in an animal model of inflammation.

Figure 3 shows the efficacy of compound 1 and compound 2 in example 1 in an autoimmune animal model.

Figure 4 shows a schematic of different cytokines and their role in controlling various inflammatory and autoimmune diseases.

Figure 5 is a schematic diagram of how TNF-alpha is associated with different metabolic diseases in addition to its inflammatory and autoimmune properties.

FIG. 6 shows the blood glucose lowering effect of the compound of example 1 on ob/ob and db/db mice.

Fig. 7 shows the reduction of body weight gain of the animal model of obesity by compound 1 and compound 2 in example 1.

FIG. 8 shows the effect of Compound 2 in example 1 on insulin sensitization and lipid lowering activity.

FIG. 9 shows the effect of treatment with different doses of a compound of the invention on human pre-adipocyte lipid accumulation compared to rosiglitazone.

Detailed Description

In one embodiment of the invention, R is substituted with one or more substituents selected from the group consisting of₁、R₂、R₃And R₄The group represented is selected from: hydrogen, halogen, such as fluorine, chlorine, bromine or iodine; hydroxy, nitro, cyano, formyl, amino, straight or branched, substituted or unsubstituted (C)₁-C₁₂) Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, nonyl, and the like; substituted or unsubstituted (C)₁-C₁₂) Alkoxy groups such as methoxy, ethoxy, propoxy, butoxy, and the like.

In one embodiment of the invention, the group represented by a is selected from: aryl groups such as phenyl, naphthyl, and the like; heteroaromatic rings such as pyridyl, pyrrolyl, thiazolyl, indolyl, imidazolyl, furyl and the like; heterocycles, such as piperazine, morpholine, piperidine, pyrrolidine, and the like. The group a may be mono-, di-, or tri-substituted, and the substituents are selected from halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, and the like.

In one embodiment of the present invention, the amino acid represented by X, X-a or X-a-Y and the side chain are selected from alanine, glycine, arginine, asparagine, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, ornithine, proline, serine, threonine, tryptophan, tyrosine, and the like, wherein the amino acid may be substituted or unsubstituted; and derivatives of said amino acids, such as carboxylic acid esters and carboxylic acid amides. Preferably, the substituents are selected from halogen, alkyl, alkoxy, aryl, heteroaryl, amino, and the like.

The amino acids X-a-Y preferably represent substituted or unsubstituted arginine, asparagine, cysteine, glutamine, histidine, lysine, methionine, ornithine, proline, serine, threonine, tryptophan, tyrosine and derivatives thereof. The radical X-A also preferably represents alanine, glycine, isoleucine, leucine and derivatives thereof. In another embodiment, a represents a substituted or unsubstituted alkyl, heterocyclic or heteroaromatic ring.

In another embodiment, Z is sulfur and Y is oxygen. Preferably R₁To R₄Is hydrogen.

Pharmaceutically acceptable salts forming part of the invention include base addition salts such as alkali metal salts (e.g. lithium, sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts), salts with organic bases (e.g. lysine, arginine, guanidine, diethanolamine, choline and the like), ammonium or substituted ammonium salts. Salts may include acid addition salts, among which are sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmitates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates, and the like. The pharmaceutically acceptable solvate may be a hydrate or other solvent comprising crystallization, such as ethanol.

Preferably, the present invention relates to novel amino acid phenyl ethers of the following formula (I), derivatives thereof, analogs thereof, tautomers thereof, stereoisomers thereof, polymorphs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof:

wherein- - -represents an optional double bond; y represents oxygen, sulphur or NR, wherein R represents hydrogen or alkyl; z represents oxygen or sulfur; r₁、R₂、R₃And R₄May be the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy; a represents a substituted or unsubstituted aryl group; x represents an alpha-aminocarboxylic acid or a derivative thereof bonded to A through its alpha side chain.

More preferably, the present invention relates to novel amino acid phenyl ethers of the following formula (I), derivatives thereof, analogs thereof, tautomers thereof, stereoisomers thereof, polymorphs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof:

wherein- - -represents an optional double bond; y represents oxygen, sulphur or NR, wherein R represents hydrogen or alkyl; z represents oxygen or sulfur; r₁、R₂、R₃And R₄May be the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy; a represents a substituted or unsubstituted phenyl group; x represents alanine or a derivative thereof bonded to A through its alpha-methyl group.

Particularly useful compounds according to the present invention include:

1)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

2)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

3)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

4)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

5)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

6)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

7)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

8)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

9)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2, 6-difluorobenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

10)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2, 6-difluorobenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

11)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2, 6-difluorobenzyl ] oxazolidine-2, 4-dione or a salt thereof;

12)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2, 6-difluorobenzyl ] oxazolidine-2, 4-dione or a salt thereof;

13)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2, 6-difluorobenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

14)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2, 6-difluorobenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

15)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2, 6-difluorobenzyl ] thiazolidine-2, 4-dione or a salt thereof;

16)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2, 6-difluorobenzyl ] thiazolidine-2, 4-dione or a salt thereof;

17)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2, 3-difluorobenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

18)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2, 3-difluorobenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

19)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2, 3-difluorobenzyl ] thiazolidine-2, 4-dione or a salt thereof;

20)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2, 3-difluorobenzyl ] thiazolidine-2, 4-dione or a salt thereof;

21)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2, 3-difluorobenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

22)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2, 3-difluorobenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

23)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2, 3-difluorobenzyl ] oxazolidine-2, 4-dione or a salt thereof;

24)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2, 3-difluorobenzyl ] oxazolidine-2, 4-dione or a salt thereof;

25)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-methylbenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

26)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-methylbenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

27)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-methylbenzyl ] oxazolidine-2, 4-dione or a salt thereof;

28)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-methylbenzyl ] oxazolidine-2, 4-dione or a salt thereof;

29)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-methylbenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

30)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-methylbenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

31)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-methylbenzyl ] thiazolidine-2, 4-dione or a salt thereof;

32)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-methylbenzyl ] thiazolidine-2, 4-dione or a salt thereof;

33)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-nitrobenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

34)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-nitrobenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

35)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-nitrobenzyl ] thiazolidine-2, 4-dione or a salt thereof;

36)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-nitrobenzyl ] thiazolidine-2, 4-dione or a salt thereof;

37)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-nitrobenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

38)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-nitrobenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

39)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-nitrobenzyl ] oxazolidine-2, 4-dione or a salt thereof;

40)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-nitrobenzyl ] oxazolidine-2, 4-dione or a salt thereof;

41)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-aminobenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

42)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-aminobenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

43)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-aminobenzyl ] thiazolidine-2, 4-dione or a salt thereof;

44)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-aminobenzyl ] thiazolidine-2, 4-dione or a salt thereof;

45)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-aminobenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

46)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-aminobenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

47)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-aminobenzyl ] oxazolidine-2, 4-dione or a salt thereof;

48)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-aminobenzyl ] oxazolidine-2, 4-dione or a salt thereof;

49)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-fluorobenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

50)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-fluorobenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

51)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-fluorobenzyl ] thiazolidine-2, 4-dione or a salt thereof;

52)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-fluorobenzyl ] thiazolidine-2, 4-dione or a salt thereof;

53)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-fluorobenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

54)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-fluorobenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

55)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-fluorobenzyl ] oxazolidine-2, 4-dione or a salt thereof;

56)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-fluorobenzyl ] oxazolidine-2, 4-dione or a salt thereof;

57)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-fluorobenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

58)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-fluorobenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

59)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-fluorobenzyl ] thiazolidine-2, 4-dione or a salt thereof;

60)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-fluorobenzyl ] thiazolidine-2, 4-dione or a salt thereof;

61)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-fluorobenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

62)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-fluorobenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

63)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-fluorobenzyl ] oxazolidine-2, 4-dione or a salt thereof;

64)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-fluorobenzyl ] oxazolidine-2, 4-dione or a salt thereof;

65)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-trifluoromethylbenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

66)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-trifluoromethylbenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

67)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-trifluoromethylbenzyl ] thiazolidine-2, 4-dione or a salt thereof;

68)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-trifluoromethylbenzyl ] thiazolidine-2, 4-dione or a salt thereof;

69)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-trifluoromethylbenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

70)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-trifluoromethylbenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

71)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -2-trifluoromethylbenzyl ] oxazolidine-2, 4-dione or a salt thereof;

72)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -2-trifluoromethylbenzyl ] oxazolidine-2, 4-dione or a salt thereof;

73)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-trifluoromethylbenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

74)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzylidene ] thiazolidine-2, 4-dione or a salt thereof;

75)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-trifluoromethylbenzyl ] thiazolidine-2, 4-dione or a salt thereof;

76)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzyl ] thiazolidine-2, 4-dione or a salt thereof;

77)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-trifluoromethylbenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

78)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzylidene ] oxazolidine-2, 4-dione or salt thereof

79)5- [4- (4- (2-amino-2-carboxyethyl) phenoxy) -3-trifluoromethylbenzyl ] oxazolidine-2, 4-dione or a salt thereof;

80)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzyl ] oxazolidine-2, 4-dione or a salt thereof;

81)5- [4- (4- (2-amino-2-carboxyethyl) -2, 6-difluorophenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

82)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2, 6-difluorophenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

83)5- [4- (4- (2-amino-2-carboxyethyl) -2, 6-difluorophenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

84)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2, 6-difluorophenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

85)5- [4- (4- (2-amino-2-carboxyethyl) -2, 6-difluorophenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

86)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2, 6-difluorophenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

87)5- [4- (4- (2-amino-2-carboxyethyl) -2, 6-difluorophenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

88)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2, 6-difluorophenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

89)5- [4- (4- (2-amino-2-carboxyethyl) -2, 3-difluorophenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

90)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2, 3-difluorophenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

91)5- [4- (4- (2-amino-2-carboxyethyl) -2, 3-difluorophenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

92)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2, 3-difluorophenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

93)5- [4- (4- (2-amino-2-carboxyethyl) -2, 3-difluorophenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

94)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2, 3-difluorophenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

95)5- [4- (4- (2-amino-2-carboxyethyl) -2, 3-difluorophenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

96)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2, 3-difluorophenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

97)5- [4- (4- (2-amino-2-carboxyethyl) -3-methylphenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

98)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-methylphenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

99)5- [4- (4- (2-amino-2-carboxyethyl) -3-methylphenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

100)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-methylphenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

101)5- [4- (4- (2-amino-2-carboxyethyl) -3-methylphenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

102)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-methylphenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

103)5- [4- (4- (2-amino-2-carboxyethyl) -3-methylphenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

104)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-methylphenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

105)5- [4- (4- (2-amino-2-carboxyethyl) -3-nitrophenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

106)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-nitrophenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

107)5- [4- (4- (2-amino-2-carboxyethyl) -3-nitrophenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

108)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-nitrophenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

109)5- [4- (4- (2-amino-2-carboxyethyl) -3-nitrophenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

110)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-nitrophenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

111)5- [4- (4- (2-amino-2-carboxyethyl) -3-nitrophenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

112)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-nitrophenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

113)5- [4- (4- (2-amino-2-carboxyethyl) -3-aminophenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

114)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-aminophenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

115)5- [4- (4- (2-amino-2-carboxyethyl) -3-aminophenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

116)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-aminophenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

117)5- [4- (4- (2-amino-2-carboxyethyl) -3-aminophenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

118)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-aminophenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

119)5- [4- (4- (2-amino-2-carboxyethyl) -3-aminophenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

120)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-aminophenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

121)5- [4- (4- (2-amino-2-carboxyethyl) -2-fluorophenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

122)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-fluorophenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

123)5- [4- (4- (2-amino-2-carboxyethyl) -2-fluorophenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

124)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-fluorophenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

125)5- [4- (4- (2-amino-2-carboxyethyl) -2-fluorophenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

126)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-fluorophenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

127)5- [4- (4- (2-amino-2-carboxyethyl) -2-fluorophenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

128)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-fluorophenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

129)5- [4- (4- (2-amino-2-carboxyethyl) -3-fluorophenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

130)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-fluorophenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

131)5- [4- (4- (2-amino-2-carboxyethyl) -3-fluorophenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

132)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-fluorophenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

133)5- [4- (4- (2-amino-2-carboxyethyl) -3-fluorophenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

134)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-fluorophenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

135)5- [4- (4- (2-amino-2-carboxyethyl) -3-fluorophenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

136)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-fluorophenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

137)5- [4- (4- (2-amino-2-carboxyethyl) -2-trifluoromethylphenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

138)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-trifluoromethylphenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

139)5- [4- (4- (2-amino-2-carboxyethyl) -2-trifluoromethylphenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

140)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-trifluoromethylphenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

141)5- [4- (4- (2-amino-2-carboxyethyl) -2-trifluoromethylphenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

142)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-trifluoromethylphenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

143)5- [4- (4- (2-amino-2-carboxyethyl) -2-trifluoromethylphenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

144)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -2-trifluoromethylphenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

145)5- [4- (4- (2-amino-2-carboxyethyl) -3-trifluoromethylphenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

146)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-trifluoromethylphenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

147)5- [4- (4- (2-amino-2-carboxyethyl) -3-trifluoromethylphenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

148)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-trifluoromethylphenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

149)5- [4- (4- (2-amino-2-carboxyethyl) -3-trifluoromethylphenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

150)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-trifluoromethylphenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

151)5- [4- (4- (2-amino-2-carboxyethyl) -3-trifluoromethylphenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

152)5- [4- (4- (2-amino-2-methoxycarbonylethyl) -3-trifluoromethylphenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

153)5- [4- (4- (2-tert-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

154)5- [4- (4- (2-tert-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

155)5- [4- (4- (2-tert-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof;

156)5- [4- (4- (2-tert-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof;

157)5- [4- (4- (2-tert-butoxycarbonylamino-2-carboxyethyl) phenoxy) benzylidene ] thiazolidine-2, 4-dione or a salt thereof;

158)5- [4- (4- (2-tert-butoxycarbonylamino-2-carboxyethyl) phenoxy) benzyl ] thiazolidine-2, 4-dione or a salt thereof;

159)5- [4- (4- (2-tert-butoxycarbonylamino-2-carboxyethyl) phenoxy) benzylidene ] oxazolidine-2, 4-dione or a salt thereof; and

160)5- [4- (4- (2-tert-butoxycarbonylamino-2-carboxyethyl) phenoxy) benzyl ] oxazolidine-2, 4-dione or a salt thereof.

The salt of the compound in the above table is preferably the hydrochloride, hydrobromide, sodium, potassium or magnesium salt.

According to another feature of the present invention, there is provided a process for the preparation of a compound of formula (I) wherein- - -represents a bond and all other symbols are as defined above, as illustrated in scheme-I.

Scheme I

The compound of formula (IIIa) can be reacted with the compound of formula (IIIb) in the presence of a solvent such as THF, DMF, DMSO, DME, or the like, or a mixture of solvents can be used, to give the compound of formula (IIIc), wherein X in formula (IIIa)₁Represents a protected α aminocarboxylic acid group, all other symbols being as defined above; in formula (IIIb) L represents a nucleophilic aromatic-substituted leaving group, all other symbols being as defined above. The reaction can be carried out under an inert atmosphere, which can be achieved by using, for example, N₂Ar or He, etc. Can be in the presence of a base such as K₂CO₃、Na₂CO₃The reaction is completed in the presence of NaH or a mixture thereof. The reaction temperature may range from 20 ℃ to 150 ℃, preferably from 30 ℃ to 100 ℃. The duration of the reaction may range from 1 to 24 hours, preferably from 2 to 6 hours.

Commonly used protecting groups are those that are easily removed and are selected from t-Boc, CBz, F-moc, and the like.

The compound of formula (IIIc) may be reacted with 2, 4-thiazolidinedione or 2, 4-oxazolidinedione in the absence of a solvent, either in the presence of sodium acetate or in the presence of a solvent such as benzene, toluene, methoxyethanol or mixtures thereof, to give the compound of formula (IIId). When the reaction is carried out in the presence of neat sodium acetate, the reaction temperature may range from 80 ℃ to 180 ℃. Suitable catalysts may also be used, for example piperidinium acetate or benzoate, sodium acetate or mixtures of catalysts. Sodium acetate may be used in the presence of a solvent, but it is preferred to use neat sodium acetate. The water produced in the reaction can be removed, for example, using a Dean Stark dehydrator or using a water absorbent such as a molecular sieve.

Deprotection of the amino acid group in formula (IIId) can be carried out in the presence of a solvent such as DCM, ethyl acetate, water, and the like, or mixtures thereof, using an acid such as HCl, sulfuric acid, acetic acid, and the like, at a temperature in the range of-10 ℃ to 50 ℃ to give compounds of formula (I).

In another embodiment of the invention, compounds of general formula (I) wherein Z represents sulfur and- - -represents no chemical bond, can be prepared by reacting a compound of formula (IIIe) with thiourea and then treating with an acid,

wherein J is a halogen atom, e.g. chlorine, bromine or iodine, R₅Is a lower alkyl group.

The reaction of the compound of the general formula (IIIe) with thiourea may be carried out in the presence of an alcohol solvent such as methanol, ethanol, propanol, isobutanol, 2-methoxybutanol, or the like, or DMSO or sulfolane. The reaction can be carried out at a temperature in the range of 20 ℃ and the reflux temperature of the solvent used. Bases such as NaOAc, KOAc, NaOMe, NaOEt, etc. can be used.

In a further embodiment of the invention, it is also possible to prepare compounds of the general formula (I) in which- - -represents a chemical bond and all other symbols are as defined above, by a process which comprises reacting a compound of the formula (IIIf) with a compound of the formula (IIIg):

wherein L is a nucleophilic leaving group, for example a halogen atom, such as chlorine, bromine or iodine; methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate and the like.

The reaction of the compound of formula (IIIf) with the compound of formula (IIIg) to form the compound of formula (I) may be carried out in the presence of a solvent such as THF, DMF, DMSO, DME, and the like, or a mixture thereof. The reaction can be carried out under an inert atmosphere, which can be achieved by using, for example, N₂Ar or He, etc. The reaction may be carried out in the presence of a base, such as a base like sodium hydroxide or potassium hydroxide; alkali metal carbonates such as sodium carbonate or potassium carbonate; hydrogenated alkali metals such as sodium hydride; organometallic bases such as n-butyllithium; alkali metal amides such as sodium amide; or mixtures thereof. A variety of solvents and a variety of bases may be used. The amount of base ranges from 1 to 5 equivalents, preferably from 1 to 3 equivalents. The reaction temperature may range from 0 ℃ to 120 ℃, preferably from 20 ℃ to 100 ℃. The duration of the reaction may range from 0.5 to 24 hours, preferably from 0.5 to 6 hours.

In a further embodiment of the invention, it is also possible to prepare compounds of the general formula (I) in which- - -represents a chemical bond and all other symbols are as defined above, by a process which comprises reacting a compound of the formula (IIIh) with a compound of the formula (IIIg):

wherein A and X are as defined above.

THE reaction of THE compound of formula (IIIh) with THE compound of formula (IIIg) to form THE compound of formula (I) may be carried out in THE presence of a solvent such as THE, DMF, DMSO, DME and THE like or mixtures thereof. The reaction can be carried out under an inert atmosphere, which can be achieved by using, for example, N₂Ar or He, etc. The reaction may be carried out in the presence of a base, such as a base like sodium hydroxide or potassium hydroxide; alkali metal carbonates such as sodium carbonate or potassium carbonate; hydrogenated alkali metals such as sodium hydride; organometallic bases such as n-butyllithium; alkali metal amides such as sodium amide; or mixtures thereof. A variety of solvents and a variety of bases may be used. The amount of base ranges from 1 to 5 equivalents, preferably from 1 to 3 equivalents. The reaction temperature may range from 0 ℃ to 120 ℃, preferably from 20 ℃ to 100 ℃. The duration of the reaction may range from 0.5 to 24 hours, preferably from 0.5 to 6 hours.

In another embodiment of the invention, there is provided a process for the preparation of a compound of formula (I) representing no chemical bond by reduction of a compound of formula (I) representing a chemical bond, wherein all other symbols are as defined above. The reduction may be carried out in the presence of gaseous hydrogen and a catalyst such as Pd/C, Rh/C, Pt/C, Raney nickel, etc. Mixtures of catalysts may also be used. The reaction may be carried out in the presence of a solvent such as dioxane, acetic acid, ethyl acetate, and the like. Mixtures of solvents may also be used. Pressures from atmospheric to 100psi can be used. The catalyst can be 5-10% Pd/C and the amount of catalyst can range from 50-300% (wt./wt.). The reaction can also be carried out by reduction using a metal solvent, such as magnesium in methanol or sodium amalgam in methanol. Also useful are, for example, LiBH₄、NaBH₄、KBH₄In the presence of alkali metal borohydrides such as CoCl₂And a ligand, preferably a bidentate ligand, such as 2, 2' -bipyridyl, 1, 10-phenanthroline, bisoximes, etc.

In yet another embodiment of the present invention, there is provided an intermediate of formula (IIIc) below, derivatives thereof, analogs thereof, tautomers thereof, stereoisomers thereof, polymorphs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof:

wherein Y represents oxygen, sulfur or NR, wherein R represents hydrogen or an alkyl group; r₁、R₂、R₃And R₄May be the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy; a represents a substituted or unsubstituted aryl group; x represents an alpha-aminocarboxylic acid or a derivative thereof bonded to A through its alpha side chain.

In yet another embodiment of the present invention, there is provided an intermediate of formula (IIIe) below, derivatives thereof, analogs thereof, tautomers thereof, stereoisomers thereof, polymorphs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof:

wherein Y represents oxygen, sulfur or NR, wherein R represents hydrogen or an alkyl group; r₁、R₂、R₃And R₄May be the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy; a represents a substituted or unsubstituted aryl group; x represents an alpha-aminocarboxylic acid or a derivative thereof bonded to A through its alpha side chain; j represents a halogen atom, R₅Represents a lower alkyl group.

It was unexpectedly found that the compounds of the present invention, unlike other thiazolidine compounds (TZD molecules), do not exhibit adipocyte differentiation activity. It has also been unexpectedly found that administration reduces the increase in body weight. Finally, the compounds of the present invention appear to have no affinity for PPAR-g. These three characteristics of the compounds are different from those of the known TZD molecules, which have typical adipocyte differentiation activity, increase body weight and are PPAR-g agonists. In addition, the compounds of the present invention have anti-inflammatory properties. For example, the compounds inhibit TNF α, IL-6 and IL1 β.

The compounds according to the invention can be mixed with physiologically acceptable excipients to form pharmaceutical compositions. Particularly preferred compositions are in the form of oral capsules, or solutions of the compounds dissolved in water, saline or phosphate buffer, or lyophilized powders in the form of tablets or capsules further comprising various fillers and binders. Effective dosages of the compounds in the compositions will be selected by one of ordinary skill in the art and can be determined empirically.

The compounds of the invention are useful for the treatment of inflammation, autoimmune diseases such as multiple sclerosis, IBD, obesity, neurological diseases, hypertension and diseases such as diabetes characterized by elevated blood glucose levels, i.e., hyperglycemia such as diabetes, including both type I and type II diabetes as well as other hyperglycemia-related diseases such as hyperlipidemia, kidney-related diseases, and the like.

By "treating" is meant administering the compound to at least reduce inflammation, hypertension, obesity, blood lipid levels, blood glucose levels, or symptoms of a disease associated with an autoimmune or neurological disorder in a subject. The compound is administered in a sufficient amount to lower, for example, blood glucose levels to an acceptable range, where an acceptable range refers to +/-10%, typically +/-8%, more typically +/-5% of the subject's normal mean blood glucose level. Various subjects such as domestic animals, rare and rare animals, pets and humans can also be treated with the compounds. The compounds can be administered to a subject using convenient administration techniques, including intravenous, intradermal, intramuscular, subcutaneous, oral administration, and the like. However, the oral route of administration is particularly preferred. The dose to be administered to the host depends naturally on the route of administration of the compound, but is generally in the range of 5 to 500mg/70kg body weight of a human.

The present invention is illustrated in detail by the following examples, which are illustrative only and therefore should not be construed as limiting the scope of the present invention.

Example 1

Preparation of 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzyl ] -thiazolidine-2, 4-dione hydrochloride

Step (i)

Preparation of methyl 2- [ (tert-butoxycarbonyl) amino ] -3[ - (4-formylphenoxy) phenyl ] propanoate

To a suspension of freshly prepared sodium hydride (0.813g, 33.9mmol) in anhydrous DMF (20ml) under nitrogen was slowly added a solution of methyl 2- [ (tert-butoxycarbonyl) amino ] -3- (4-hydroxyphenyl) propionate (10g, 33.9mmol) in DMF (20 ml). The mixture was stirred for 15 minutes. 4-fluorobenzaldehyde (4.20g, 33.9mmol) was added and the mixture was heated to 80 ℃. After completion of the reaction, the solvent was removed by high vacuum and the mixture was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (3X 50 ml). After washing with brine, drying over anhydrous sodium sulfate, evaporation of the solvent and purification of the product on flash column eluting with hexane/ether (12/30 to 12/22) the title compound was obtained as an oil (yield 11.5g, 85.0%).

¹H NMR(CDCl₃360MHz,): δ 9.92(s, 1H), 7.83(d, 2H), 7.19(d, 2H), 7.05(d, 2H), 7.03(d, 2H), 4.60(t, 1H), 3.72(s, 3H), 3.09(d, 2H), 1.42(s, 9H). The structure was confirmed by mass spectrometry. Calculated value (M +1) 400.4; found 400.3.

Step (ii)

Preparation of 5- [4- (4- (2-tert-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzylidene ] thiazolidine-2, 4-dione

To a solution of methyl 2- [ (tert-butoxycarbonyl) amino ] -3- [ - (4-formylphenoxy) phenyl ] propionate obtained in the above step (i) in anhydrous toluene (10g, 25mmol) was added 2, 4-thiazolidinedione (3.53g, 30mmol), followed by benzoic acid (0.46g, 3.75mmol) and piperidine (0.28g, 3.25 mmol). The solution was heated to reflux at 145-155 ℃ for 5 hours while continuing to remove water using a dean-Stark apparatus. The solution was cooled to room temperature and a yellow solid precipitated to give the title compound (yield 11.9g, 96%, HPLC purity 96.5%, mp: 160-.

¹H NMR(CDCl₃360MHz,): 7.82(s, 1H), 7.47(d, 2H); 7.05(d, 2H), 7.00(d, 2H); 6.75(d, 2H), 5.18(m, 1H), 4.54(m, 1H), 3.71(s, 3H); 3.02(m, 2H), 3.00(m, 2H), 1.42(s, 9H). The structure was confirmed by mass spectrometry. Calculated value (M +1) 498.5; found 498.5.

Step (iii)

Preparation of 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzylidene ] thiazolidine-2, 4-dione

To 5- [4- (4- (2-tert-butoxycarbonylamino-2-methoxycarbonylethyl) phenoxy) benzylidene at 0 ℃ in the presence of a catalyst]HCl gas was bubbled through a solution of thiazolidine-2, 4-dione (2g, 4.0mmol) in DCM (100 ml). After stirring for 1 hour, the yellow precipitate was filtered and 1.7g (3.9mmol) of HCl-Tyr (C) were collected₆H₄-CH ═ TDZ) -OMe, yield 97.5%, mp: 187-190 ℃. The HPLC purity of the product was 94.5%. This is compound 1.

¹H NMR (D2O, 360MHz,): 7.46(s, NH, 1H); 7.24(d, 2H); 7.16(d, 2H); 6.94(d, 2H); 6.78(d, 2H); 4.80(s, NH3, 3H); 4.40(m, C α -H, 1H); 3.80(s, OMe). The structure was confirmed by mass spectrometry. Calculated (M +1) 501.5; measured value501.5。

Step (iv)

Preparation of 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzyl ] thiazolidine-2, 4-dione

To a solution of 5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) benzylidene ] thiazolidine-2, 4-dione (0.7g, 1.6mmol) in methanol (20ml) was added anhydrous Pd/C (0.15 g). After hydrogenation at 60psi and 40 deg.C overnight, the solution was filtered through Celite (Celite) and evaporated under reduced pressure to give quantitative title compound. The compound showed no melting in DSC, but turned black in the capillary and shrunk at 97-133 ℃. This is compound 2.

The pharmaceutically acceptable salts can be prepared as follows: the compound of formula (I) is reacted with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium tert-butoxide, calcium hydroxide, magnesium hydroxide, etc., in a solvent such as diethyl ether, THF, methanol, tert-butanol, dioxane, isopropanol, hexanol, etc. Mixtures of solvents may also be used. Organic bases such as lysine, arginine, diethanolamine, choline, guanidine and their derivatives can also be used. On the other hand, acid addition salts are prepared by treatment with the following acids in solvents such as ethyl acetate, diethyl ether, ethanol, acetone, THF, dioxane, etc.: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, and the like. Mixtures of solvents may also be used.

The present invention also provides a pharmaceutical composition comprising one or more compounds of the general formula (I) as defined above, its tautomers, its derivatives, its analogs, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates and conventional pharmaceutical carriers, diluents and the like.

The pharmaceutical compositions may be in the usual form, for example, 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 may be in the form of injectable solutions or suspensions in suitable sterile media. Such compositions will generally contain from 1 to 25% by weight, preferably from 1 to 15% by weight, of the active compound, with the remainder of the composition being in a pharmaceutically acceptable carrier, diluent, excipient or solvent.

Suitable pharmaceutically acceptable carriers include solid fillers or diluents, as well as sterile aqueous or organic solutions. The active compound is present in the pharmaceutical composition in an amount sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds may be combined with suitable solid or liquid carriers or diluents and formulated into capsules, tablets, powders, syrups, solutions, suspensions and the like. If desired, the pharmaceutical compositions may contain additional ingredients such as flavoring agents, sweeteners, excipients, and the like. For parenteral administration, the compounds may be mixed with sterile aqueous or organic media and formulated as solutions or suspensions for injection. For example, sesame or peanut oil solutions, aqueous propylene glycol solutions and the like may be used, and aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts or alkali metal or alkaline earth metal salts of the compounds may also be used. The injection solution prepared in this way can then be administered intravenously, intraperitoneally, subcutaneously or intramuscularly, preferably intramuscularly, to the human body.

The pharmaceutical compositions of the present invention are particularly effective in reducing blood glucose, serum insulin and triglyceride levels in animal models of type II diabetes. The pharmaceutical composition of the present invention is also effective for treating obesity, inflammation, and autoimmune diseases. In addition, the pharmaceutical compositions of the present invention are useful in the treatment of disorders associated with insulin resistance, such as polycystic ovary syndrome, as well as hyperlipidemia, coronary artery disease and peripheral vascular disease, and in the treatment of inflammatory and immune disorders, particularly those mediated by cytokines such as TNF- α, IL-1, IL-6, and cyclooxygenase such as COX-2.

Protocol for biological experiments

The compounds of the present invention have been tested for their biological activity in reducing inflammatory cytokine levels, chemically induced inflammation, obesity and blood glucose, and in different models. Figures 1-9 show the activity profile of representative compounds.

FIG. 1. Compounds 1 and 2 of example 1 inhibit the major proinflammatory cytokines in human monocytes

Human THP-1 monocytes were cultured and incubated with different concentrations of the two compounds of example 1. The cells were then challenged with Lipopolysaccharide (LPS) at a concentration of 1 microgram/ml for 24 hours. Then, cell supernatants were analyzed for the levels of cytokines such as TNF α, IL1 β and IL-6 by antibody directed enzyme immunoassay. As shown in figure 1, the compounds of this example inhibited the production of these three major pro-inflammatory cytokines in a dose-dependent manner. No significant change in cell viability was observed by incubating the cells in the presence of the highest concentration of the compound. These results strongly suggest that the compound of example 1 is very effective in reducing the production of proinflammatory cytokines.

FIG. 2 Compound 2 of example 1 reduces carrageenan-induced inflammation in rats

Spegue-Dowley rats having an average body weight of 250g (6-7 weeks old) were randomly divided into three groups and administered an oral dose of 50mg/kg of the compound of example 1. After 30 minutes, carrageenan was administered in the subplantar (sub-planer) area of the right hind paw. The control group received the same volume of water without any compound. The volume of the paw was measured after 2 hours and 3 hours. In this experiment, a ground based methasone with a concentration of 5mg/kg was used as a positive control. As shown in fig. 2, the compound of example 1 significantly reduced carrageenan-induced inflammation. At hour 3, the compound of example 1 was as effective as dexamethasone, a known anti-inflammatory agent that works by a different mechanistic route.

FIG. 3 prevention of EAE in mice by Compound 1 and Compound 2 of example 1 (multiple sclerosis model)

Multiple Sclerosis (MS) is an autoimmune disease and is regulated by cytokine levels. To test the effect of the compound of example 1 in the MS model, Experimental Allergic Encephalomyelitis (EAE) was induced in SJL/J mice. EAE is an autoimmune inflammatory disease of the Central Nervous System (CNS). The disease shares many similarities with human MS and is therefore a model for testing the potential efficacy of new drugs for MS. EAE was induced by injecting spinal cord homogenates into animals treated with the compounds of the examples. The severity of EAE was determined by clinical scores of paralysis. As shown in fig. 3, the new compound treatment group showed complete prevention of EAE. These results demonstrate the utility of the compounds of the examples in the treatment of MS and other neurological disorders.

FIG. 4 schematic representation of cytokine modulation and immune disorders

Upon stimulation by mitogens and other unknown factors, macrophages produce various cytokines. A few of these key cytokines are known to be involved in various immunological diseases, including many autoimmune diseases.

FIG. 5 direct and indirect association of TNF α in metabolic disorders

It has been well established that TNF α plays a major role in inflammatory and autoimmune diseases, and thus anti-TNF α antibodies can be used to treat rheumatoid arthritis. In addition, several studies have recently predicted the possible role of TNF α in fat biology, as well as metabolic diseases such as diabetes, obesity, hyperlipidemia, and vascular complications. The schematic shows how modulation of TNF α can have an impact on a variety of metabolic diseases, which opens up different avenues for treating these diseases.

FIG. 6 Compound 2 of example 1 significantly ameliorates hyperglycemia in diabetic mice

The hypoglycemic effect of the compounds was studied in two spontaneous animal models of diabetes (ob/ob mice and db/db mice). ob/ob mice lack the leptin gene and are also considered to be a typical model of obesity. db/db mice have deficient leptin receptors and exhibit hyperglycemia with a significant weight gain. The compounds were administered orally to these animals at doses of 5mg/kg, 10mg/kg and 50mg/kg body weight over a period of 15-21 days. The treatment results of two diabetic animals, ob/ob and db/db, show that the symptoms of hyperglycemia are remarkably improved. The results for compound 1 were essentially the same.

FIG. 7 Compound 1 and Compound 2 of example 1 reduce weight gain in an obese animal model

Leptin knockout mice (ob/ob) are considered suitable models of obesity, in addition to diabetes. To test the efficacy of these compounds on obesity, ob/ob mice were treated with the compounds for 21 days. As shown in figure 7, daily treatment of ob/ob mice with a single dose of the compound resulted in a 35% improvement in body weight gain, demonstrating the utility of these compounds for the treatment of obesity. This finding is contrary to the results of using other thiazolidines, which typically increase body weight.

FIG. 8 Compound 2 of example 1 improves insulin resistance and lipid homeostasis

Leptin knock-out ob/ob mice are also considered a good model for insulin resistance. Treatment of these animals with compound 2 reduced serum insulin concentrations > 70%. Also, a 48% reduction in triglyceride levels and > 50% reduction in serum cholesterol concentrations was observed in the 15-day treatment study. These results indicate that the compounds have potent antilipidemic properties and improve insulin sensitivity.

In a separate study, it was also unexpectedly observed that, in contrast to other known thiazolidinediones, these compounds are non-adipogenic and exhibit little or no affinity for the peroxisome proliferator-activated receptor-gamma (PPAR- γ). All of these biological findings suggest that the compounds possess a number of novel properties and act by very different mechanisms of action than PPAR- γ binding.

FIG. 9. the PPAR-g agonist rosiglitazone is known to be a adipogenic agent, while Compound 2 is not an adipogenic agent

Human subcutaneous preadipocytes were cultured in 96-well plates for 13 days in the presence of vehicle or different doses (0.01 micromolar, 0.1 micromolar, 1.0 micromolar and 10 micromolar) of rosiglitazone (BRL) or compound 2 (BLX). The medium was replaced with the freshly prepared compound every 72 hours. TNF, because it inhibits the adipogenesis process, was used as a negative control in this experiment, where co-incubation with rosiglitazone showed a significant reduction in adipogenesis compared to rosiglitazone alone incubation. On day 13, cells were fixed and lipid (triglyceride) accumulation was measured by staining with oil red O and photographs taken under a microscope. To obtain more quantitative data, oil red O was extracted by addition of isopropanol and measured spectrophotometrically at 540nM (as shown in the bar graph). It was observed that compound 2 did not cause lipid accumulation regardless of the dose. Rosiglitazone showed an increase in lipid formation with dose, but its lipid formation could be inhibited by the addition of TNF α.

Claims

1. A compound of formula (I), tautomers thereof, stereoisomers thereof, polymorphs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof:

wherein- - -represents an optional double bond; y represents oxygen, sulphur or NR, wherein R represents hydrogen or alkyl; z represents oxygen or sulfur; r₁、R₂、R₃And R₄May be the same orDifferent and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy; a represents a bond or a substituted or unsubstituted aryl, heterocyclic or heteroaromatic ring; x represents an alpha-aminocarboxylic acid or an alpha-aminocarboxylic acid derivative bonded to A or Y through its alpha side chain.

2. A compound of formula (I) according to claim 1, wherein X-a-Y-represents an amino acid selected from: substituted or unsubstituted arginine, asparagine, cysteine, glutamine, histidine, lysine, methionine, ornithine, proline, serine, threonine, tryptophan, tyrosine, and derivatives thereof.

3. A compound according to claim 1, wherein a represents a substituted or unsubstituted alkyl, heterocyclic or heteroaromatic ring.

4. A compound according to claim 1, wherein X-a-represents an amino acid selected from: alanine, glycine, isoleucine and leucine and their derivatives.

5. A compound according to claim 1, wherein a represents a bond.

6. The compound of any one of claims 1-5, wherein Z is sulfur and Y is oxygen.

7. The compound of any one of claims 1-5, wherein R₁To R₄Is hydrogen.

8. The compound of any one of claims 1-5 wherein the- - -double bond is present.

9. The compound of any one of claims 1-5 wherein the- - -double bond is absent.

10. The compound of claim 2, wherein X-a-Y-comprises tyrosine.

11. The compound of claim 2, wherein X-a-Y comprises a tyrosine derivative.

12. The compound of claim 11, wherein the derivative comprises an alkyl ester of tyrosine.

13. The compound of claim 12, wherein the ester is a methyl ester.

14. The compound of claim 10 or 11, wherein R₁、R₂、R₃And R₄Is hydrogen and Z is sulfur.

15. The compound of claim 14 wherein said — double bond is present.

16. The compound of claim 14 wherein the — double bond is absent.

17. The compound of claim 1 selected from the group consisting of:

78)5- [4- (4- (2-amino-2-methoxycarbonylethyl) phenoxy) -3-trifluoromethylbenzylidene ] oxazolidine-2, 4-dione or a salt thereof;

18. A process for the preparation of an amino acid phenyl ether of the following formula (I), its derivatives, its analogs, its tautomers, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates:

wherein- - -represents a chemical bond; y represents oxygen, sulphur or NR, wherein R represents hydrogen or alkyl; z represents oxygen or sulfur; r₁、R₂、R₃And R₄May be the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy; a represents a bond or a substituted or unsubstituted aryl, heterocyclic or heteroaromatic ring; x represents an alpha-aminocarboxylic acid or derivative thereof bonded to A or Y through its alpha side chain, said method comprising:

i) reacting a compound of formula (IIIa) with a compound of formula (IIIb) to give a compound of formula (IIIc);

wherein the compound of formula (IIIa) represents a protected amino acid and all other symbols are as defined above, and wherein in the compound of formula (IIIb) L represents a nucleophilic aromatic-substituted leaving group and R₁、R₂And R₃The definition of (1) is as above;

reacting the compound of formula (IIIc) with 2, 4-thiazolidinedione or 2, 4-oxazolidinedione to give a compound of formula (IIId);

deprotecting the amino acid group of formula (IIId) to give a compound of formula (I).

19. A process for the preparation of an amino acid phenyl ether of the following formula (I), its derivatives, its analogs, its tautomers, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates:

wherein- - -represents no chemical bond; y represents oxygen, sulphur or NR, wherein R represents hydrogen or alkyl;

z represents sulfur; r₁、R₂、R₃And R₄May be the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy; a represents a bond or a substituted or unsubstituted aryl, heterocyclic or heteroaromatic ring; x represents an alpha-aminocarboxylic acid or a derivative thereof bonded to A or Y through its alpha side chain, which comprises reacting a compound of the following formula (IIIe) with thiourea and then treating with an acid,

wherein J is a halogen atom and R is a lower alkyl group.

20. A process for the preparation of an amino acid phenyl ether of the following formula (I), its derivatives, its analogs, its tautomers, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates:

wherein- - -represents a chemical bond; y represents oxygen, sulphur or NR, wherein R represents hydrogen or alkyl; z represents oxygen or sulfur; r₁、R₂、R₃And R₄May be the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy; a represents a bond or a substituted or unsubstituted aryl, heterocyclic or heteroaromatic ring; x represents an alpha-aminocarboxylic acid or derivative thereof bonded to A through its alpha side chain, said process comprising reacting a compound of formula (IIIf) with a compound of formula (IIIg):

wherein L is a nucleophilic leaving group.

21. A process for the preparation of an amino acid phenyl ether of the following formula (I), its derivatives, its analogs, its tautomers, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates:

wherein- - -represents a chemical bond; y represents oxygen, sulphur or NR, wherein R represents hydrogen or alkyl; z represents oxygen or sulfur; r₁、R₂、R₃And R₄May be the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy; a represents a bond or a substituted or unsubstituted aryl, heterocyclic or heteroaromatic ring; x represents an alpha-aminocarboxylic acid or derivative thereof bonded to A through its alpha side chain, said process comprising reacting a compound of formula (IIIh) with a compound of formula (IIIg):

wherein A and X are as defined above.

22. A process for the preparation of a compound of formula (I) wherein "- - -" denotes no chemical bond:

said process comprising reducing a compound of formula (I) wherein "- -" denotes a bond, wherein all other symbols are as defined in claim 1.

23. A pharmaceutical composition comprising a pharmaceutically effective amount of an amino acid phenyl ether of formula (I) as defined in claim 1 and a pharmaceutically acceptable carrier, diluent, excipient or solvate:

24. a method for reducing glucose in plasma, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as defined in claim 1.

25. A method for reducing free fatty acids in plasma, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as defined in claim 1.

26. A method for lowering cholesterol in plasma, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as defined in claim 1.

27. A method for lowering triglyceride levels in plasma, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as defined in claim 1.

28. A method for the treatment of obesity, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as defined in claim 1.

29. A method for the treatment of an autoimmune disease, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as defined in claim 1.

30. A method for the treatment of inflammation, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as defined in claim 1.

31. A method for the treatment of immunological diseases which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as defined in claim 1.

32. The method of claim 29, wherein the autoimmune disease is multiple sclerosis.

33. The method of claim 29, wherein the autoimmune disease is rheumatoid arthritis.

34. The method of claim 30, wherein the inflammation is mediated by cyclooxygenase.

35. The method of claim 31, wherein the immune disease is mediated by a cytokine.

36. A method for the treatment of diseases associated with insulin resistance, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as defined in claim 1.

37. An intermediate of formula (IIIc) below, derivatives thereof, analogs thereof, tautomers thereof, stereoisomers thereof, polymorphs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof:

wherein Y represents oxygen, sulfur or NR, wherein R represents hydrogen or an alkyl group; r₁、R₂、R₃And R₄May be the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy; a represents a substituted or unsubstituted aryl group; x represents an alpha-aminocarboxylic acid or derivative thereof bonded to A through its alpha-amino side chain.

38. An intermediate of formula (IIIe) below, derivatives thereof, analogs thereof, tautomers thereof, stereoisomers thereof, polymorphs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof:

wherein Y represents oxygen, sulfur or NR, wherein R represents hydrogen or an alkyl group; r₁、R₂、R₃And R₄May be the same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl or alkoxy; a represents a substituted or unsubstituted aryl group; x represents an alpha-aminocarboxylic acid or derivative thereof bonded to A through its alpha-amino side chain; j represents a halogen atom, R₅Represents a lower alkyl group.

39. The compound of claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of a hydrochloride, hydrobromide, sodium, potassium or magnesium salt.