WO2008069611A1

WO2008069611A1 - N-phenylamide derivative, process for the preparation thereof, and composition for preventing or treating ischemic diseases comprising same

Info

Publication number: WO2008069611A1
Application number: PCT/KR2007/006351
Authority: WO
Inventors: Jeehee Suh; Sung-Eun Yoo; Kyu Yang Yi; Nakjeong Kim; Eunhee Kim; Yong-Sam Jung; Yun-Suk Lee; Haeyoung Suh-Kim
Original assignee: Korea Research Institute Of Chemical Technology
Priority date: 2006-12-08
Filing date: 2007-12-07
Publication date: 2008-06-12

Abstract

The present invention relates to a compound of Formula I, a process for the preparation thereof, and a composition for preventing or treating an ischemic disease comprising a compound of Formula I' as an effective ingredient. Since the N-phenylamide derivatives of the present invention can significantly reduce ischemic cell death, they can be effectively used for preventing or treating ischemic diseases mediated by ischemic cell death, or for protecting organs.

Description

N-PHENYLAMIDE DERIVATIVE, PROCESS FOR THE PREPARATION

THEREOF, AND COMPOSITION FOR PREVENTING OR TREATING

ISCHEMIC DISEASES COMPRISING SAME

FIELD OF THE INVENTION

The present invention relates to a novel N-phenylamide derivative, a process for the preparation thereof, and a composition for preventing or treating ischemic diseases comprising same.

BACKGROUND OF THE INVENTION

Ischemia, a symptom of reduced blood supply to organs or tissues is caused by contraction or occlusion of the blood vessel. Once ischemia occurs, subsequent reperfusion causes various sequelae due to the damaged nerve cells. Ischemia is frequently associated with coronary artery diseases, cardiovascular diseases, angina pectoris, headache or other symptoms related to the blood vessel, and it ultimately leads to necrosis of cells or tissues.

Ischemic diseases such as myocardial infarction, arrhythmia or heart failure caused by the cell damage and cell dysfunction induced by ischemia-reperfusion are accompanied by high morbidity and mortality rates, and therefore, they have been the subject of extensive researches and clinic studies for the last fifty years [Wang, Q. D. et al., Cardiovasc. Res. 55:25-37, 2002]. As the ischemia-reperfusion injury also affects various physiological functions involving the change of metabolism, immune response and ion homeostasis, generation of oxygen free radicals and others, it has been subjected to various studies in the fields related to immune modulators, cell death suppressors, and ion channel modulators [Hearse, D. J. et al., MoI. Cell. Biochem. 186:177-184, 1998]. Based on the results of such studies, there have been developed a number of therapeutics and surgical operational procedures, but an effective technique for protecting cardiomyocytes injury caused by ischemia-reperfusion has not yet been commercialized. Therefore, there is a need for a new drug for preventing or treating ischemic heart diseases or for protecting heart, which can delay the progress of ischemic damage of cardiomyocytes and reduce reperfusion-induced injuries.

It has also been known that when ischemia is alleviated by restoring the blood supply, the generation of reactive oxygen species (ROS) becomes accelerated, which, in turns, induces a marked decrease in the glutathione level, to cause serious diseases similar to those observed when the blood supply stops or recovers during transplant surgery of such organs as heart, liver, lung, pancreas or blood vessel. Reactive oxygen species and reactive free radicals are assumed to cause such diseases, and they have been detected in the cytoplasm cell and organelle constructing tissues, especially in mitochondria which produces ATP as the main energy source of cells. Further, it has been observed that in mitochondria the above-mentioned reactive species are released mainly through the respiratory chain, and their concentrations significantly increase during ischemia-reperfusion.

Ischemia leads to cell death, especially after reperfusion, which is the main cause of various ischemic diseases involving brain ischemia, heart ischemia, diabetic cardiovascular disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis and ischemic acute renal failure.

It has been reported that in the case of brain ischemia, the depletion of the energy supply caused by reduced blood supply induces ischemic cell death, which excessively activates cell membrane receptors, leading to various biochemical alterations including accumulation of glutamic acid on the outside, and calcium on the inside, of cells, to injure the brain tissue [Liu, P. K., J Biomed. Sd. 10:4-13, 2003; Lipton, P.,

Physiol. Rev. 79: 1431-1568, 1999; and Renolleau, S. et al., Stroke 29:1454-1460, 1998]. hi case of heart ischemia, it has been reported that myocardial infarction, heart failure and arrhythmia are linked to ischemic cell death caused by the activation of lipid enzymes, leading to damaged cell membranes among others [Ferrari, R. Rev. Port. Cardiol. 5:7-20, 2000; Webster, K. A. et al., J. Clin. Invest. 104:239-252, 1999; Katz, A. M. et al., J. MoI Cell. Cardiol. 2:11-20, 1985; and Vandeplassche, G. et al., Basic Res. Cardiol. 85:384-391, 1990]. The retinal ischemia has been reported to be caused by cell death of retinal cells mediated by glutamate salt in combination with ischemic cell death [Napper, G. A. et al., Vis. Neurosci. 16:149-158, 1999]. Insufficient blood supply to the colon results in ischemic cell death, causing occlusive artery injuries and hemodynamic disorders, and ultimately ischemic colitis[Saegesser, F. et al., Pathobiol. Annu. 9:303-337, 1979]. Minocycline, a tetracycline antibiotic for inhibiting ischemic cell death, has been known to be effective in treating ischemic diseases such as cerebral infarction [Yrjanheikki, J. et al., Proc. Natl. Acad. ScL USA 96:13496-13500, 1999], myocardial infarction [Scarabelli, T. M. et al., J. Am. Coll. Cardiol. 43:865-874, 2004], and ischemic acute renal failure [Wang, J. et al., J. Biol. Chem. 279:19948-19954, 2004], which suggests that the above- mentioned diseases are caused by ischemic cell death.

It has also been elucidated that nerve cells damage or death induced by ischemia is involved in various nerve diseases such as stroke, head trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma or diabetic neuropathy [G. J. Zoppo et al., Drugs 54, 9 (1997); I. Sziraki et al., Neurosci. 85, 1101 (1998)]. The present inventors have conducted an extensive research to develop a compound effective in treating ischemic diseases and discovered that a novel N- phenylamide derivative inhibits ischemic cell death, and thus, can be used for preventing and treating ischemic diseases such as brain ischemia, heart ischemia, diabetic cardiovascular disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, head trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma and diabetic neuropathy, and for protecting organs.

SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide a novel N- phenylamide derivative and a process for the preparation thereof.

It is another object of the present invention to provide a composition for preventing or treating ischemic diseases comprising the N-phenylamide derivative or a pharmaceutically acceptable salt thereof.

It is a further object of the present invention to provide a composition for protecting organs comprising the N-phenylamide derivative or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWING

The above and other objects and features of the present invention will become apparent from the following description of the invention, when taken in conjunction with the accompanying drawings which respectively show:

FIG. 1: inhibitory effects of the N-phenylamide derivatives of the present invention against hypoxemia-induced ischemic cell death, and

FIG. 2: inhibitory effects against cerebral ischemia-induced cerebral infarction.

DETAILED DESCRIPTION OF THE INVENTION

hi accordance with one aspect of the present invention, there is provided a compound of Formula I or a pharmaceutically acceptable salt thereof:

wherein:

R¹ is H₃ -CO₂R⁵, -CH₂OR⁵, -CONR⁵R⁶ or

R⁵ and R⁶ being each independently H, or C₁-C₆ alkyl which optionally have one or more halogen substituents; R², R³ and R⁴ are each independently H, hydroxyl, C₁-C₃ alkyl, C₁-C₃ alkoxy, or halogen;

B is H, or phenyl having one or more optional C_1-3 alkyl or halogen substituents; Y is S, 0, SO, or SO₂;

Z is H, halogen, hydroxyl, or C₁-C₃ alkoxyl; and A is CH or N₅ n is 0, 1 or 2; with the proviso that when n is O, B is phenyl having one or more optional C₁-C₃ alkyl or halogen substituents, and when n is 1 , A is N

In accordance with another aspect of the present invention, there is provided a process for preparing the compound of Formula I or the pharmaceutically acceptable salt thereof.

In accordance with a further aspect of the present invention, there is provided a composition for preventing or treating ischemic diseases, comprising the compound of Formula F or the pharmaceutically acceptable salt thereof:

wherein:

R¹ is H, -CO₂R⁵, -CH₂OR⁵, -CONR⁵R⁶ or -^V, R⁵ and R⁶ being each independently H or C₁-C₆ alkyl having one or more optional halogen substituents;

R², R³ and R⁴ are each independently H, hydroxyl, C₁-C₃ alkyl, C₁-C₃ alkoxy, or halogen;

B is H, or phenyl having one or more optional C₁-C₃ alkyl or halogen substituents; n is 0, 1 or 2;

Y is S, O, SO, or SO₂;

Z is H, halogen, hydroxyl, or C₁-C₃ alkoxyl; and

A is CH or N.

In accordance with a still further aspect of the present invention, there is provided a composition for protecting organs, comprising the compound of Formula F or the pharmaceutically acceptable salt thereof.

Preferably, the present invention provides the compound of Formula I, wherein:

R¹ is -CO₂R⁵, -CH₂OR⁵, or ^o , R⁵ and R⁶ being each independently H or methyl; R², R³ and R⁴ are each independently H, hydroxyl, C₁-C₃ alkyl, C₁-C₃ alkoxy, or halogen;

B is H, or phenyl having one or more optional C₁-C₃ alkyl or halogen substituents; n is 0 or 1; Y is S;

Z is H or halogen;

A is CH or N; with the proviso that when n is 0, B is phenyl having one or more optional C₁-C₃ alkyl or halogen substituents, and when n is 1, A is N.

More Preferably, the compound of Formula I are:

Methyl 2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

Methyl 5-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

Methyl 4-chloro-2-[3-(pvridin-2-ylsulfanyl)-propionylamino]-benzoate; Methyl 3,5-dibromo-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

Methyl 4,5-dimethoxy-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

Methyl 3,4,5-trimethoxy-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

2-[3-(pyridin-2-ylsulfanyl)-proρionylamino]-benzoic acid;

5-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid; 4-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

4,5-dimethoxy-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

3,5-dibromo-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

3,4,5-trimethoxy-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

N-(2-hydroxymethyl-phenyl)-3-(pyridin-2-ylsulfanyl)-propionylamide; Methyl 2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-5-chloro-benzoate;

Methyl 3, 5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-benzoate;

2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-5-chloro-benzoic acid;

3,5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-benzoic acid;

N-[2-(4,5-dihydro-oxazol-2-yl)-phenyl]-3-(pyridin-2-ylsulfanyl)-propionamide; N-[4-chloro-2-(4,5-dihydro-oxazol-2-yl)-phenyl]-3-(pyridin-2-ylsulfanyl)-propionamide;

N-[5-chloro-2-(4,5-dihydro-oxazol-2-yl)-phenyl]-3-(pyridin-2-ylsulfanyl)-propionamide; and

N-[2-(4,5-dihydro-oxazol-2-yl)-4,5-dimethoxy-phenyl]-3-(pyridin-2-ylsulfanyl)- propionamide. The N-phenylamide derivative of the present invention may exist in the form of a pharmaceutically acceptable salt, a solvate or an enantiomers thereof.

The pharmaceutically acceptable salt of the N-phenylamide derivative of the present invention may be an acid addition salt formed with a pharmaceutically acceptable free acids, an inorganic acid or an organic acid. Examples of the organic acid include citric acid, maleic acid, fumaric acid, gluconic acid, methane sulfonic acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid and aspartic acid, while the inorganic acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid or phosphoric acid, preferably methane sulfonic acid and hydrochloric acid.

The acid addition salt of the present invention may be prepared by a conventional method, for example, by dissolving the N-phenylamide derivative in a water-miscible organic solvent such as acetone, methanol, ethanol and acetonitrile, adding thereto an excess amount of the organic acid or an aqueous solution of the inorganic acid, to induce the precipitation of the salt from the resulting mixture, removing the solvent or remaining acid therefrom, and isolating the precipitated salts.

Also, the present invention provides a process for the preparation of the compound of Formula I.

Specifically, the compound of Formula I may be prepared by allowing a compound of Formula II to react with a compound of Formula III in the presence of a solvent and a base.

wherein: R¹, R², R³, R⁴, B, n, Y, Z and A are the same as defined in Formula I, and

L is a leaving group selected from the group consisting of halogen, methanesulfonyloxy, and toluenesulfonyloxy.

In this reaction, the base, which may be an organic base such as pyridine, triethylamine, N,N-diisopropylethylamine, 1 ,8-diazabicyclo[5,4,0]-unde-7-cene(DBU), or an inorganic base such as NaOH, Na₂CO₃, K₂CO₃ or Cs₂CO₃ is used in an amount equivalent or more based on the compound of formula F. The solvent used in the above reaction may be tetrahydrofuran, dioxane, 1,2-dimethoxyethane, dichloromethane, dimethylformamide(DMF), dimethylsulfoxide, or a mixture thereof. The reaction may be conducted at a temperature ranging from O ^°C to the boiling point of the solvent used.

Meanwhile, a compound of Formula Ha, which is the compound of Formula II in case of that R¹ is alkoxycarbonyl may be prepared by amidation of a commercially available compound of Formula TV, as illustrated in Reaction Scheme I.

wherein:

R², R³, R⁴, n and B are the same as defined in Formula I; L is a leaving group selected from the group consisting of a halogen, methanesulfonyloxy, and tolunenesulfonyloxy; and D is OH, Br, or Cl.

In the Reaction Scheme I, when D is Br or Cl, the amidation may be conducted in the presence of a base in a manner similar to that described for the preparation of the compound of Formula I. When D is hydroxyl, the amidation may be conducted in the presence of a condensation agent such as l,3-dicyclohexylcarbodiimide(DCC), 1,3- diisopropylcarbodiimide(DIC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDC) and 1,1-carbonyldiimidazole (CDI), in a solvent such as dichloromethane, chloroform, tetrahydrofuran and DMF, at a temperature in the range of room temperature to the boiling point of the solvent used.

Also, the compound of Formula I, in which n is 1 may be prepared by 1,4-addition reaction of the compound of Formula V with an equivalent or excess amount of a compound of Formula III in the presence of a suitable solvent and a base, as illustrated in Reaction Scheme II. The base and the reaction conditions are the same as those used in the preparation of the compound of Formula F.

wherein:

R¹, R², R³, R⁴, Y, Z, A and B are as defined in Formula I.

The compound of Formula V used in the Reaction Scheme II may be prepared by treating the compound of Formula II in which n is 1 with an equivalent or excess amount of a base to induce 1,2-elimination reaction to remove the leaving group L as the J3 - hydrogen atom from the compound of Formula II in a conventional way, or alternatively by subjecting the compound of formula TV in Reaction Scheme I to the amidation reaction with an acryloyl halide. In addition, other N-phenylamide derivative according to the subject invention may be prepared from the N-methylamide derivatives of Formula I in which R¹ is alkoxycarbonyl, as depicted in Reaction Scheme III.

wherein: R², R³, R⁴, R^s, Y, Z, A and B are the same as defined in Formula I.

As illustrated in Reaction Scheme IH, the earboxylic acid derivatives of Formula Ib is prepared by hydrolyzing the ester group of the compound of Formula Ia using 1 to 5 equivalent amount of a base in a solvent which may be an alcohol such as methanol, an ether such as tetrahydrofuran and dioxane, or a mixture thereof. The base used in the above reaction is preferably sodium hydroxide or potassium hydroxide, and the reaction is conducted at a temperature in the range of 0^°C to the boiling point of the solvent used.

The compound of Formula Ic is prepared by the treating the compound of Formula

Ib with a condensation agent, which may be l,3-dicyclohexylcarbodiimide(DCC), 1,3- diisopropylcarbodiimide(DIC), l-(3-dimethylaminopropyl)-3-ethylcarbodϋmide(EDC) or l,l-carbonyldiimidazole(CDi), and then with 2-chloroethylamine in the presence of an equivalent or excess amount of a base to allow the condensation reactant to proceed. The solvents which can be used in this reaction may be an ether such as tetrahydrofuran, dioxane, and 1,2-dimethoxyethane, and dimethylformamide (DMF), dichloromethane, dimethylsulfoxide, or a mixture thereof, and the base may be an organic base such as pyridine, triethylamine, IS^N-diisopropylethylarnine, and DBU(1, 8-diazabicyclo[5 ,4,0]- unde-7-cene) or an inorganic base such as NaOH₅ Na₂CO₃, K₂CO₃, and Cs₂CO₃. The reaction is conducted at a temperature in the range of O "C to the boiling point of the solvent used.

The compound of Formula Id is prepared by subjecting the compound of Formula Ic to an oxazolidine heterocycle formation reaction in the presence of a base such as DBU in a solvent such as tetrahydrofurane, benzene and toluene, at a temperature in the range of 0^°C to the boiling point of the solvent used.

In addition, an alcohol derivative of Formula Ie may be prepared by reducing the ester group of the compound of Formula Ia with an equivalent or excess amount of a reducing agent such as sodium borohydride in an alcohol such as methanol or lithium borohydride in tetrahydrofuran at a temperature in the range of 0 ^°C to the boiling point of the solvent used.

The present invention provides a composition of the subject invention, comprising the compound of Formula I or a pharmaceutically acceptable salt thereof:

wherein:

R¹ is H, -CO₂R⁵, -CH₂OR⁵, -CONR⁵R⁶ or

R⁵ and R⁶ being each independently H or C₁-C₆ alkyl having one or more optional halogen substituents;

R², R³ and R⁴ are each independently H, hydroxyl, C₁-C₃ alkyl, C₁-C₃ alkoxy, or halogen; B is H, or phenyl having one or more optional C₁-C₃ alkyl or halogen substituents; n is O, 1 or 2;

Y is S, O, SO, or SO₂;

Z is H, halogen, hydroxyl, or C₁-C₃ alkoxyl; and

A is CH or N.

Preferably, the present invention provides the composition comprising the

compound of Formula F, wherein R¹ is H, -CO₂R⁵, -CH₂OR⁵, -CONR⁵R⁶ or ^° , R⁵ and R⁶ being each independently H or methyl; R², R³ and R⁴ are each independently H, hydroxyl, C₁-C₃ alkyl, C₁-C₃ alkoxy, or halogen; B is H, or phenyl having one or more optional C₁-C₃ alkyl or halogen substituents; n is O or 1; Y is S, O, SO, or SO₂; Z is H, halogen, hydroxyl, or C₁-C₃ alkoxyl; and A is CH or N. More preferably, the present invention provides the composition comprising the compound selected from the group consisting of

1) methyl 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-benzoate;

2) methyl 2-(2-phenylsulfanyl-acetylamino)-benzoate; 3) methyl 2-[2-(pyridin-2-ylsulfanyl)-acetylamino]-benzoate;

4) methyl 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-5-chloro-benzoate;

5) methyl 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-4-chloro-benzoate; 6) 2-(4-bromo-ρhenylsulfanyl)-N-(3,4-dimethyl-phenyl)-acetamide; 7) N-(3,4-dimethyl-phenyl)-2-phenylsulfanyl-acetamide; 8) methyl 3,5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-benzoate;

9) methyl 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-4,5-dimethoxy-benzoate;

10) methyl 4,5-dimethoxy-2-[2-phenylsulfanyl-acetylamino]-benzoate;

11) methyl 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-3,4,5-trimethoxy-benzoate;

12) methyl 2-[3-(4-bromo-phenylsulfanyl)-propionylamino]-benzoate; 13) methyl 2-(3-phenylsulfanyl-propionylamino)-benzoate;

14) methyl 2- [3 -(4-methoxy-phenylsulfanyl)-propionylamino] -benzoate;

15) methyl 2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

16) methyl 5-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

17) methyl 4-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate; 18) methyl 3,5-dibromo-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

19) methyl 4,5-dimethoxy-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

20) methyl 3,4,5-trimethoxy-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

21) 2- [2-(4-bromo-phenylsulfanyl)-acetylamino] -benzoic acid;

22) 2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid; 23) 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-4-chloro-benzoic acid;

24) 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-4,5-dimethoxy-benzoic acid;

25) 4,5-dimethoxy-2-(2-phenylsulfanyl-acetylamino)-benzoic acid;

26) 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-5-chloro-benzoic acid;

27) 3,5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-benzoic acid; 28) 5-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

29) 4-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

30) 4, 5-dimethoxy-2- [3 -(pyridm-2-ylsulfanyl)-propionylamino] -benzoic acid;

31) 3,5-dibromo-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

32) 3,4,5-trimethoxy-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid; 33) 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-3,4,5-trimethoxy-benzoic acid;

34) N-(2-hydroxymethyl-phenyl)-3-(pyridin-2-ylsulfanyl)-propionylamide;

35) phenyl 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-5-chloro-benzoate;

36) methyl 2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino] -5-chloro- benzoate; 37) methyl 3,5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]- benzoate; 38) 2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-5-chloro-benzoic acid;

39) 3,5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-benzoic acid;

40) N-[2-(4,5-dihydro-oxazol-2-yl)-phenyl]-3-(pyridin-2-ylsulfanyl)-propionamide; 41) 2-(4-bromo-phenylsulfanyl)-N-[5-chloro-2-(4,5-dihydro-oxazol-2-yl)-phenyl]- acetamide;

42) 2-(4-bromo-phenylsulfanyl)-N-[2-(4,5-dihydro-oxazol-2-yl)-4,5-dimethoxy- phenyl] -acetamide;

43) 2-(4-bromo-phenylsulfanyl)-N-[4-chloro-2-(4,5-dihydro-oxazol-2-yl)-phenyl]- acetamide;

44) N-[2-(4,5-dihydro-oxazol-2-yl)-4,5-dimethoxy-phenyl]-2-phenylsulfanyl- acetamide;

45) N-[4-chloro-2-(4,5-dihydro-oxazol-2-yl)-phenyl]-3-(pyridin-2-ylsulfanyl)- propionamide; 46) N-[5-chloro-2-(4,5-dihydro-oxazol-2-yl)-phenyl]-3-(pyridin-2-ylsulfanyl)- propionaraide;

47) N-[2-(4, 5 -dihydro-oxazol-2-yl)-4,5 -dimethoxy-phenyl] -3 -(pyridin-2-ylsulfanyl)- propionamide;

48) 3-(4-bronio-phenylsulfanyl)-N-[6-(4,5-dihydro-oxazol-2-yl)-2,3,4-trimethoxy- phenyl] -propionamide;

49) 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-N-(2-chloro-ethyl)-4,5-dimethoxy- benzamide;

50) N-(2-chloro-ethyl)-4,5-dimethoxy-2-(2-phenylsulfanyl-acetylamino)-benzamide.

Further, the respective structures of the compounds listed above are shown in Table

1:

In this regards, the compound of Formula Y may be prepared by the same manners of the preparation of the compound of Formula I.

The compound of Formula F or a its salt is effective in inhibition of the ischemic cell death. Accordingly, the composition of the present invention can be used for the prevention or treatment of ischemic diseases mediated by the ischemic cell death induced by hypoxemia, for example, brain ischemia, heart ischemia, diabetic cardiovascular disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, head trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma or for diabetic neuropathy, or for protecting organs.

The inventive pharmaceutical composition may be administered in oral or parentally and formulated with a diluent or excipient such as a filler, a thickening agent, a binder, a wetting agent, a disintegrant or a surfactant, etc. in accordance with any of the conventional method.

Solid formulations for oral administration may be prepared by mixing at least one of N-phenylamide derivatives of the present invention with at least one of excipients such as starch, calcium carbonate, sucrose, lactose or gelatine. Besides, a lubricant such as magnesium stearate, talc, and the like maybe added, as well.

Liquid formulations for oral administration include suspensions, internal use solutions, emulsion, syrups, and the like. In addition to a diluent such as water or liquid paraffin, various excipients, such as wetting agents, sweetening agents, aromatics, preservatives, and the like maybe used.

For parentally administration, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyopphilics, suppositories, and the like may be used. Injectable vegetable oil such as propylene glycol, polyethylene glycol or olive oil and ester such as ethyl olate may be suitable for non-aqueous solvents and suspensions. The base materials for suppositories include witepsol, macro gol, tween 61, cacao butter, laurin better, glycerol and gelatine. Depending on the conditions of the subject to be treated, including age, body weight, sex, administration route, health state, and disease severity, the dosage of N-phenylamide of the subject invention may vary. Typically, the active ingredient of the present invention is administered at a dose from 0.1 to 1,000 mg per day for an adult weighing 70 kg, preferably at a dose from 1 to 500 mg per day, in a single dose or in divided doses per day.

The present invention is further described particularly by the following examples which are set forth to illustrate, but are not to be construed as the limit of the present invention.

In the subject application, molecular structures of the compounds were determined by infrared spectroscopy, NMR spectroscopy, mass spectroscopy, liquid chromatography, X-ray crystallography, optical rotation spectroscopy, or elemental analysis for comparing calculated values of the compound with experimentally observed values thereof.

Examples

Preparative Example 1: Synthesis of methyl 2-(2-bromo-acetylamino)-benzoate

0.86 ml (6.62 mmol) of methyl 2-aminobenzoate was dissolved in 5 ml of tetrahydrofuran, to which 0.69 ml (7.97 mmol) of bromoacetyl bromide and 1.38 ml (9.93 mmol) of triethylarnine were added dropwise. The resulting mixture was stirred under a nitrogen atmosphere for one day, the solvent was removed under a reduced pressure, and the residue was shaken with a mixture of ethyl acetate and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and then distilled under a reduced pressure, to obtain a crude product, which was purified by column chromatography (hexane:ethyl acetate = 6:1), to obtain 1.31 g of the title compound(yield: 73%).

¹H NMR(300MHz, CDCl₃): δ 3.96(s, 3H), 4.03(s, 2H), 7.13(t, IH), 7.55(t, IH), 8.06(dd, IH), 8.67(d, IH), 11.72(br, NH); MS (m/e, M⁺): 272.

Preparative Example 2: Synthesis of methyl 2-(2-bromo-acetylamino)-4-chloro-benzoate

The same procedure as described in the Preparative Example 1 was repeated except that 0.50 g (2.69 mmol) of methyl 2-amino-4-chloro-benzoate was used as a starting material and n-hexane: ethyl acetate=10:l was used as an eluent, respectively, to obtain 0.60 g of the title compound(yield: 72 %). ¹H NMR(300MHz, CDCl₃): δ 3.96(s, 3H), 4.03(s, 2H), 7.11(dd, IH), 7.98(d, IH), 8.78(d, IH), 11.76(br, NH); MS(m/e, M⁺): 307.

Preparative Example 3: Synthesis of methyl 2-C2-bromo-acetylammo)-5-chloro-benzoate

The same procedure as described in the Preparative Example 1 was repeated except that 0.20 g (1.08 mmol) of methyl 2-amino-5-chloro-benzoate was used as a starting material and n-hexane:ethyl acetate=7:l was used as an eluent, respectively, to obtain 0.32 g of the title compound(yield: 96%).

¹H NMR(300 MHz, CDCl₃): δ 3.97-4.03(m, 5H), 7.51(dd, J = 9.0, 2.7 Hz, IH), 8.01(s, IH), 8.66(d, J= 9.0 Hz, IH), 11.63(brs, IH)

MS(m/e, M^""): 307, 185, 166, 153, 63.

Preparative Example 4: Synthesis of 2-bromo-N-(3,4-dimethylphenvO acetamide

0.2 g (1.65 mmol) of 3,4-dimethylaniline compound was dissolved in 5 ml of tetrahydrofuran, to which 0.45 g(3.30 mmol) of bromo acetic acid and 0.51 ml(3.30 mmol) of 1,3-diisopropylcarbodiimide were added. The resulting mixture was stirred for 2 hours under a nitrogen atmosphere, the solvent was removed under a reduced pressure, and the residue was shaken with a mixture of ethyl acetate and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure, to obtain a crude product. The crude product was purified by column chromatography(hexane:ethylacetate=4:l) to obtain 0.38 g of the title compound(yield: 97%) .

1H NMR(300MHz, DMSOd₆): δ 2.17(s, 3H), 2.19(s, 3H), 4.00(s, 2H), 7.06(d, IH), 7.30(d, IH), 7.34(s, IH), 10.20(s, IH); MS(m/e, M⁴): 243, 241, 121, 106.

Preparative Example 5: Synthesis of methyl 3,5-dibromo-2-(2-bromo-acetylamino)- benzoate

The same procedure as described in the Preparative Example 1 was repeated except that 0.20 g (0.65 mmol) of methyl 2-amino-3,5-dibromo-benzoate was used as a starting material and n-hexane: ethyl acetate=4:l was used as an eluent, respectively, to obtain 0.25 g of the title comρound(yield: 89%).

¹H NMR (300 MHz, CDCl₃): δ 3.91 (s, 3H), 4.03 (s, 2H), 7.93 (d, J= 2.1 Hz, IH), 7.99 (d, J= 2.1 Hz, IH), 8.91 (brs, IH).

Preparative Example 6: Synthesis of methyl 2-f2-bromo-acetylaminoV4,5-dimethoxy- benzoate The same procedure as described in the Preparative Example 1 was repeated except that 0.5 g (2.37 mmol) of methyl 2-amino-3,4-dimethoxy-benzoate was used as a starting material and n-hexane:ethyl acetate=4:l was used as an eluent, respectively, to obtain 0.78 g of the title compound(yield: 98%).

¹H NMR(300MHz, CDCl₃): δ 3.90(s, 3H), 3.95(s, 3H), 3.97(s, 3H), 4.03(s, 2H), 7.49(s, IH), 8.43(s, IH), 11.77(br, NH); MS(IIiZe₅ M⁺)I SSl.

Preparative Example 7: Synthesis of methyl 2-(2-bromo-acetylaminoV3A5-trimethoxy- benzoate

The same procedure as described in the Preparative Example 1 was repeated except that 0.2 g (0.83 mmol) of methyl 2-amino-3,4,5-trimethoxy-benzoate was used as a starting material and n-hexane:ethyl acetate=2:l was used as an eluent, respectively, to obtain 0.26 g of the title compound(yield: 88%).

¹B. NMR (300 MHz, CDCl₃): δ 3.89-3.94 (m, 12H), 4.03 (s, 2H), 7.22 (s, IH), 8.81 (bis, IH);

MS(m/e, M⁺): 361, 226, 194, 166.

Preparative Example 8: Synthesis of methyl 2-(3-bromo-propionylaminoVbenzoate

The same procedure as described in the Preparative Example 4 was repeated except that 0.31g (2.05mmol) of methyl 2-amino-benzoate and 0.42 ml (4.10 mmol) of 3- bromopropionic acid were used as a starting material, and n-hexane:ethyl acetate=5:l was used as an eluent, respectively, to obtain 390 mg of the title compound(yield: 67%).

¹H NMR(300MHz, DMSO-d₆): δ 3.04 (t, 2H), 3.72 (t, 2H), 3.94 (s, 3H), 7.1 l(t, IH), 7.56 (t, IH), 8.04 (d, IH), 8.72 (d, IH), 11.21 (brs, IH);

MS(m/e, M⁺): 285, 151, 144, 11.

Preparative Example 9: Synthesis of methyl 2-(3-bromo-ρropionylamino)-4-chloro- benzoate

The same procedure as described in the Preparative Example 8 was repeated except that 0.30 g (1.62 mmol) of methyl 2-amino-4-chloro-benzoate was used as a starting material and n-hexane:ethyl acetate=7:l was used as an eluent, respectively, to obtain 0.50 g of the title compound(yield: 98%).

¹H NMR (300 MHz, CDCl₃): δ 3.04 (t, J = 6.8 Hz, 2H), 3.71 (t, J = 6.8 Hz, 2H), 7.08 (dd, J= 8.4, 2.1 Hz, IH), 7.97 (d, J= 8.4 Hz, IH), 8.84 (d, J= 2.1 Hz, IH), 11.25 (brs, IH);

MS(m/e, M⁺): 321, 185, 153, 107. Preparative Example 10: Synthesis of methyl 2-(3-bromo-propionylaminoV5-chloro- benzoate

The same procedure as described in the Preparative Example 8 was repeated except that 0.30 g (1.62 mmol) of methyl 2-amino-5-chloro-benzoate compound was used as a starting material and n-hexane:ethyl acetate=10:l was used as an eluent, respectively, to obtain 0.51 g of the title compound(yield: 99%).

¹H NMR (300 MHz, CDCl₃): δ 3.03 (t, J = 6.8 Hz, 2H), 3.71 (t, J= 6.8 Hz, 2H), 3.95 (s, 3H)₃ 7.50 (dd, J= 9.0, 2.4 Hz, IH), 8.00 (d, J= 2.4 Hz, IH), 8.70 (d, J= 9.0 Hz, IH), 11.10 (bra, IH);

MS(m/e, M⁺): 321, 185, 153, 107. _,

Preparative Example 11: Synthesis of methyl 3,5-dibromo-2-(3-bromo-propionylaminoV benzoate

The same procedure as described in the Preparative Example 8 was repeated except that 0.31 g (1.00 mmol) of methyl 2-amino-3,5-dibromo-benzoate was used as a starting material and n-hexane: ethyl acetate=3:l was used as an eluent, respectively, to obtain 0.31 g of the title compound(yield: 69%).

Preparative Example 12: Synthesis of methyl 2-(3-bromo-propionylaminoV4,5- dimethoxy -benzoate

The same procedure as described in the Preparative Example 8 was repeated except that 0.30 g (1.42 mmol) of methyl 2-amino-4,5-dimethoxy-benzoate was used as a starting material and n-hexane: ethyl acetate=4:l was used as an eluent, respectively, to obtain 0.48 g of the title compound (yield: 98%).

¹H NMR (300 MHz, CDCl₃): 3.04 (t, J = 6.8 Hz, 2H), 3.71 (t, J = 6.8 Hz, 2H), 3.89-4.01 (m, 9H), 7.46 (s, IH), 8.47 (s, IH), 11.31 (bra, IH); MS(m/e, M⁺): 345, 211, 164, 109.

Preparative Example 13: Synthesis of methyl 2-(3-bromo-propionylaminoV3A5- trimethoxy-benzoate

The same procedure as described in the Preparative Example 8 was repeated except that 0.30 g (1.24 mmol) of methyl 2-amino-3,4,5-trimethoxy-benzoate was used as a starting material and n-hexane:ethyl acetate=2:l was used as an eluent, respectively, to obtain 0.45 g of the title compound (yield: 98%). 1H NMR (300 MHz, CDCl₃): δ 2.99 (t, J = 6.6 Hz, 2H), 3.70 (t, J = 6.6 Hz, 2H),

3.80-3.94 (m, 12H), 7.21 (s, IH), 8.20 (brs, IH); MS(m/e, M⁺): 375, 241, 194, 166.

Preparative Example 14: Synthesis of methyl 2-(2-bromo-2-phenyl-acetylamino)-5- chloro-benzoate

The same procedure as described in the Preparative Example 4 was repeated except that 0.35 g (1.89 mmol) of methyl 2-amino-4-chloro-benzoate and 0.81 g (3.78 mtnol) of bromo phenyl acetic acid were used as a starting material and n-hexane: ethyl acetate=4:l was used as an eluent, respectively, to obtain 541 mg of the title compound (yield: 75 %).

And then, even without NMR data, the following procedure was conducted.

Preparative Example 15: Synthesis of methyl 3,5-dibromo-2-(2-bromo-2-phenyl- acetylaminoVbenzoate

The same procedure as described in the Preparative Example 4 was repeated except that 0.54 g (1.75 mmol) of methyl 2-amino-3,5-dibromo-benzoate and 0.81 g(3.78 mmol) of bromo phenyl acetic acid were used as a starting material and n-hexane: ethyl acetate=10:l was used as an eluent, respectively, to obtain 0.43 g of the title compound(yield: 49 %).

¹H NMR (300 MHz, CDCl₃): δ 3.73 (s, 3H), 5.56 (s, IH), 7.34-7.41 (m, 4H), 7.58- 7.60 (m, 2H), 7.87 (dd, 1), 9.01 (brs, IH).

Preparative Example 16: Synthesis of methyl 2-acryloylamino-benzoate

390 mg (1.36 mmol) of the compound obtained in Preparative Example 8 was dissolved in 5 ml of tetrahydrofuran, to which 0.28 ml (2.04 mmol) of triethylamine was added dropwise. The resulting mixture was stirred for 5 hours under a nitrogen atmosphere, the solvent was removed under a reduced pressure, and the residue was shaken with a mixture of ethyl acetate and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, to obtain a crude product, which was purified by column chromatography (hexane:ethyl acetate=4:l) to obtain 0.20 g of the title compound (yield: 75%).

1H NMR(300MHz, DMSOd₆): δ 3.93(s, 3H), 5.79(d, IH), 6.38(d, IH), 6.43(d, IH), 7.10(t, IH), 7.56(t, IH), 8.04(d, IH), 8.81(d, IH), 11.33(s, IH); MS(m/e, M⁺): 206.

Preparative Example 17: Synthesis of methyl 2-acryloylamino-4-chloro-benzoate

The same procedure as described in the Preparative Example 16 was repeated except that 0.40 g (1.25 mmol) of the compound obtained in Preparative Example 9 was used as a starting material and n-hexane:ethyl acetate=7:l was used as an eluent, respectively, to obtain 0.26 g of the title compound (yield: 87 %).

Preparative Example 18: Synthesis of methyl 2-acryloylamino-5-chloro-benzoate

The same procedure as described in the Preparative Example 16 was repeated except that 0.30 g (0.93 mmol) of the compound obtained in Preparative Example 10 was used as a starting material and n-hexane:ethyl acetate=8:l was used as an eluent, respectively, to obtain 0.20 g of the title compound (yield: 91 %).

Preparative Example 19: Synthesis of methyl 2-acryloylamino-3,5-dibromo-benzoate

The same procedure as described in the Preparative Example 16 was repeated except that 0.44 g (1.00 mmol) of the compound obtained in Preparative Example 11 was used as a starting material and n-hexane: ethyl acetate=3:l was used as an eluent, respectively, to obtain 0.34 g of the title compound(yield: 95 %).

Preparative Example 20: Synthesis of methyl 2-acryloylamino-4,5-dimethoxy-benzoate

The same procedure as described in the Preparative Example 16 was repeated except that 0.48 g (1.35 mmol) of the compound obtained in Preparative Example 12 was used as a starting material and n-hexane: ethyl acetate=4:l was used as an eluent, respectively, to obtain 0.37 g of the title compound(yield: 99 %).

Preparative Example 21: Synthesis of methyl 2-acryloylamino-3,4,5-trimethoxy - benzoate

The same procedure as described in the Preparative Example 16 was repeated except that 0.27 g (0.72 mmol) of the compound obtained in Preparative Example 13 was used as a starting material and n-hexane:ethyl acetate=2:l was used as an eluent, respectively, to obtain 0.20 g of the title compound(yield: 95 %).

Example 1 : Synthesis of methyl 2-[^"2-(4-bromo-phenylsulfanylVacetylaminol-benzoate

0.10 g (0.37 mmol) of compound obtained in Preparative Example 1 was dissolved in 4 ml of tetrahydrofuran, to which, 77 mg (0.41 mmol) of 4-bromo-benzenethiol and 0.067 ml (0.48 mmol) of triethylamine ware added dropwise. The resulting mixture was stirred for 1 hour under a nitrogen atmosphere, the solvent was removed under a reduced pressure, and the residue was shaken with a mixture of ethyl acetate and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure, to obtain a crude product, which was purified by column chromatography (hexane: ethyl acetate=6:l) to obtain 0.1 g of the title compound (yield: 70%).

¹H NMR(300MHz, CDCl₃): δ 3.79(s, 2H), 3.92 (s, 3H), 7.11 (t. IH), 7.28(m, IH), 7.38(dd, IH), 7.52(t, IH)₅ 8.01(dd, IH), 8.66(d, IH), 11.78 (br, NH); MS(m/e, M⁺): 380.

Example 2: Synthesis of methyl 2-(2-phenylsulfanyl-acetylaminoVbenzoate

The same procedure as described in the Example 1 was repeated except that 0.1 g (0.37 mmol) of the compound obtained in Preparative Example 1 and 0.046 ml (0.44 mmol) of benzenethiol were used as a starting material and n-hexane:ethyl acetate=6:l was used as an eluent, respectively, to obtain 86 mg of the title compound(yield: 78 %).

¹H NMR(300MHz, CDCl₃): δ 3.82(s, 2H), 3.92 (s, 3H), 7.08 (t, IH), 7.19(m, 3H), 7.41(d, 2H), 7.51(t, IH), 7.56(dd, IH), 8.67(d, IH), 11.82 (br, NH); MS(m/e, M⁺): 301.

Example 3: Synthesis of methyl 2-[2-(pyridin-2-ylsulfanylVacetylamino]-benzoate

The same procedure as described in the Example 1 was repeated except that 0.15 g (0.55 mmol) of the compound obtained in Preparative Example 1 and 0.10 g (0.91 mmol) of 2-mercapto-pyridine were used and n-hexane: ethyl acetate=2:l was used as an eluent, respectively, to obtain 0.16 g of the title compound(yield: 99 %).

¹H NMR (300M Hz, DMSOd₆): δ 3.81(s, 3H), 4.09(s, 2H), 7.12-7.18(m, 2H), 7.42(d, IH), 7.60(t, IH), 7.68(t, IH), 7.90(d, IH), 8.39-8.44(m, 2H), 11.23(brs, IH); MS(m/e, M^"1): 303.

Example 4: Synthesis of methyl 2-[2-(4-bromo-phenylsulfanylVacetylammo1-5-chloro- benzoate

The same procedure as described in the Example 1 was repeated except that 0.31 g

(1.00 mmol) of the compound obtained in Preparative Example 3 was used and n- hexane: ethyl acetate^ :1 was used as an eluent, respectively, to obtain 363 mg of the title compound(yield: 88 %).

¹H NMR(300MHz, CDCl₃): δ 3.78-3.93 (m, 5H), 7.27 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.48 (dd, J = 9.0, 2.7 Hz, IH), 7.99 (d, J = 2.7 Hz, IH), 8.67 (d, J = 9.0 Hz, IH), 11.72 (brs, IH);

MS (m/e, M⁺): 415, 185, 122, 63.

Example 5: Synthesis of methyl 2-[^"2-r4-bromo-phenylsulfanyl)-acetylamino1-4-chloro- benzoate The same procedure as described in the Example 1 was repeated except that 0.20 g (0.65 mmol) of the compound obtained in Preparative Example 2 was used and n- hexane: ethyl acetate=10:l was used as an eluent, respectively, to obtain 0.20 g of the title compound (yield: 75 %). 1H NMR(300MHz, CDCl₃): δ 3.78(s, 2H), 3.92(s, 3H), 7.07(dd, IH), 7.29(m, 3H),

7.39(dd, IH), 7.94(d, IH), 8.78(d, IH), 11.83(br, NH);

MS(m/e, M⁺): 415.

Example 6: Synthesis of 2-(4-bromo-phenylsulfanyl)-N-(3,4-dimethyl-phenyl^')- acetamide

The same procedure as described in the Example 1 was repeated except that 0.12 g (0.49 mmol) of the compound obtained in Preparative Example 4 was used and n- hexane:ethyl acetate=4:l was used as an eluent, respectively, to obtain 0.16 g of the title compound(yield: 94 %). 1H NMR(300M , DMSOd₆): 2.16(s, 3H)₃ 2.18(s, 3H), 3.84(s, 2H), 7.04(d, IH),

7.26(m, IH), 7.32-7.36(m, 4H), 7.51(d, 2H), 10.03(s, IH); MS(m/e, M⁺): 352.

Example 7: Synthesis of N-(3,4-dimethyl-phenyl^')-2-phenylsulfanyl-acetamide

The same procedure as described in the Example 2 was repeated except that 0.12 g (0.49 mmol) of the compound obtained in Preparative Example 4 was used and n- hexane: ethyl acetate=4:l was used as an eluent, respectively, to obtain 0.12 g of the title compound(yield: 92 %). 1H NMR(300M Hz, DMSOd₆): δ 2.16(s, 3H), 2.18(s, 3H), 3.83(s, 2H), 7.04(d, IH),

7.17-7.42(m, 7H), 10.02(s, IH);

MS(m/e, M⁺): 272.

Example 8: Synthesis of methyl 3,5-dibromo-2-[2-f4-bromo-phenylsulfanyr)- acetylaminoj-benzoate

The same procedure as described in the Example 1 was repeated except that 0.25 g (0.57 mmol) of the compound obtained in Preparative Example 5 was used and n- hexane: ethyl acetate=5:l was used as an eluent, respectively, to obtain 0.13 g of the title compound(yield: 41 %). 1H NMR(300MHz, CDCl₃): δ 3.77 (s, 2H), 3.83 (s, 3H), 7.23-7.28 (m, 2H), 7.41-

7.45 (m, 2H), 7.91 (dd, J = 15.0, 2.2 Hz, 2H), 9.25 (brs, IH); MS(m/e, M⁺): 538.

Example 9: Synthesis of methyl 2-|^"2-(4-bromo-phenylsulfanylVacetylaminol-4,5- dimethoxy-benzoate The same procedure as described in the Example 1 was repeated except that 0.30 g (0.90 mmol) of the compound obtained in Preparative Example 6 was used and n- hexane:ethyl acetate=4:l was used as an eluent, respectively, to obtain 0.33 g of the title compound(yield: 83 %). 1H NMR(300MHz, CDCl₃): 3.78(s, 2H), 3.89(s, 3H)₅ 3.91(s, 3H), 3.95(s, 3H),

7.28(m, 2H), 7.39(m, 3H), 8.44(s, IH), 11.84(br, NH); MS(m/e, M⁺): 440.

Example 10: Synthesis of methyl 4,5-dimethoxy-2-r2-phenylsulfanyl-acetylaminol- benzoate

The same procedure as described in the Example 2 was repeated except that 0.30 g (0.90 mmol) of the compound obtained in Preparative Example 6 and 0.12 ml (1.17 mmol) of benzenethiol were used and n-hexane:ethyl acetate=6:l was used as an eluent, respectively, to obtain 0.28 g of the title compound(yield: 85 %).

¹H NMR(300MHz, CDCl₃): δ 3.64(s, 2H), 3.88(s, 3H), 3.91(s, 3H), 3.95(s, 3H), 7.17(m, 3H), 7.41(m, 3H), 8.46(s, IH), 11.86(br, NH);

MS(m/e, M⁺): 440.

Example 11: Synthesis of methyl 2-|^"2-r4-bromo-phenylsulfanvD-acetylamino]-3,4,5- trimethoxy-benzoate

The same procedure as described in the Example 1 was repeated except that 0.25 g (0.70 mmol) of the compound obtained in Preparative Example 7 was used and n- hexane:ethyl acetate=2:l was used as an eluent, respectively, to obtain 0.31 g of the title compound(yield: 95 %).

¹H NMR(300MHz, CDCl₃): 3.72-3.79 (m, 8H), 3.87-3.91 (m, 6H), 7.17 (s, IH), 7.25-7.43 (m, 4H), 9.07 (brs, IH);

MS(m/e, M⁺): 471, 241, 226, 122.

Example 12: Synthesis of methyl 2-[3-(4-bromo-phenylsulfanylVpropionylamino]- benzoate

The same procedure as described in the Example 1 was repeated except that 86 mg (0.42 mmol) of the compound obtained in Preparative Example 16 was used as a starting material and n-hexane: ethyl acetate=4:l was used as an eluent, respectively, to obtain 0.16 g of the title compound(yield: 96 %).

¹H NMR (300MHz, DMSOd₆): 2.71(t, 2H, J=6.9Hz), 3.27(t, 2H, J=6.9Hz), 3.84(s, 3H), 7.20(t, IH, J=7.5Hz), 7.32(d, 2H, J=8.4Hz), 7.50(d, 2H, J=8.4Hz), 7.60(t, IH, J=7.2Hz), 7.89(d, IH, J=7.2Hz), 8.17(d, IH, J=8.4Hz), 10.54(s, IH); MS(m/e, M⁺): 396. Example 13: Synthesis of methyl 2-(3-phenylsulfanyl-propionylamino)-benzoate

The same procedure as described in the Example 2 was repeated except that 0.10 g (0.49 mmol) of the compound obtained in Preparative Example 16 and 0.07 ml (0.63 mmol) of benzenethiol were used and n-hexane: ethyl acetate=2:l was used as an eluent, respectively, to obtain 0.13 g of the title compound(yield: 86 %).

¹H NMR(300MHz, DMSOd₆): 2.71(t, 2H, J=6.9Hz), 3.26(t, 2H, J=6.9Hz), 3.84(s, 3H), 7.17-7.24(m, 2H), 7.31-7.39(m, 4H), 7.60(t, IH), 7.89(d, IH, J=7.8Hz), 8.19(d, IH₃ J=8.4Hz), 10.56(s, IH); MS(HiZe₅ M⁺)^Io.

Example 14: Synthesis of methyl 2-r3-(4-methoxy-phenylsulfanyl)-propionylamino]- benzoate

The same procedure as described in the Example 1 was repeated except that 0.20 g

(0.98 mmol) of the compound obtained in Preparative Example 16 and 0.14 ml (1.18 mmol) of 4-methoxy benzenethiol were used and n-hexane: ethyl acetate=4:l was used as an eluent, respectively, to obtain 0.15 g of the title compound(yield: 45 %).

¹H NMR(300MHz, DMSO-d₆): δ 2.63(t, 2H), 3.13(t, 2H), 3.74(s, 3H), 3.85(s, 3H), 6.92(d, 2H, J=8.7 Hz), 7.19(t, IH, J=7.4 Hz), 7.38(d, 2H, J=8.7 Hz), 7.60(t, IH, J= 7.4 Hz), 7.89(d, IH, J=8.1 Hz), 8.18(d, IH, J= 8.1 Hz), 10.55(s, IH); MS(m/e, M⁺): 345.

Example 15: Synthesis of methyl 2-r3-(^"pyridin-2-ylsulfanylVpropionylaminol-benzoate

The same procedure as described in the Example 3 was repeated except that 0.44 g

(2.15 mmol) of the compound obtained in Preparative Example 16 and 0.31 g (2.80 mmol) of 2-mercaptopyridine were used and n-hexane: ethyl acetate=5:l was used as an eluent, respectively, to obtain 0.57 g of the title compound(yield: 83 %). 1H NMR(300M Hz, DMSOd₆): δ 2.82(t, 3H, J=6.9 Hz), 3.42(t, 3H, J=6.9 Hz), 3.83(s,

IH), 7.13-7.20(m, 2H), 7.30(d, IH), 7.61-7.65(m, 2H), 7.89(d, IH), 8.20(d, IH), 8.47(d,

IH), 10.56(s, IH);

MS(HiZe₅ M⁺)^H.

Example 16: Synthesis of methyl 5-chloro-2-[^"3-(pyridin-2-ylsulfanylVpropionylamino1- benzoate

The same procedure as described in the Example 15 was repeated except that 0.20 g (0.84 mmol) of the compound obtained in Preparative Example 18 was used and n- hexane:ethyl acetate=8:l was used as an eluent, respectively, to obtain 0.16 g of the title comρound(yield: 56 %).

¹H NMR(300MHz, CDCl₃): δ 2.81 (t, J = 7.2 Hz, 2H), 3.41 (t, J = 7.2 Hz, 2H), 3.83 (s, 3H), 7.12 (m, IH), 7.29 (d, J = 8.4 Hz, IH), 7.61-7.68 (m, 2H), 7.82 (d, J = 2.7 Hz, IH), 8.17 (d, J = 8.4 Hz, IH), 8.45 (dd, J = 4.8, 0.6 Hz, IH), 10.49 (bra, IH); MS(m/e, M⁺): 350, 166, 111, 78.

Example 17: Synthesis of methyl 4-chloro-2-[3-φyridm-2-ylsulfanylVpropionylamino1- benzoate

The same procedure as described in the Example 15 was repeated except that 0.20 g (0.84 mmol) of the compound obtained in Preparative Example 17 was used and n- hexane:ethyl acetate=7:l was used as an eluent, respectively, to obtain 0.27 g of the title compound(yield: 91 %).

¹H NMR(300MHz, CDCl₃): δ 2.92 (t, J = 7.2 Hz, 2H), 3.54 (t, J = 7.2 Hz, 2H), 3.90 (s, 3H), 6.96-7.06 (m, 2H), 7.17 (d, J = 7.8 Hz, IH), 7.44-7.49 (m, IH), 7.93 ((d, J = 8.7 Hz, IH), 8.45 (dd, J = 4.2, 0.9 Hz, IH), 8.85 (d, J = 2.1 Hz, IH), 11.14 (brs, IH); MS(m/e, M⁺): 350, 208, 138, 78.

Example 18: Synthesis of methyl 3,5-dibromo-2-[3-fpyridin-2-ylsulfanyl)- propionylaminoi-benzoate

The same procedure as described in the Example 15 was repeated except that 0.18 g

(0.50 mmol) of the compound obtained in Preparative Example 19 was used and n- hexane: ethyl acetate=3:l was used as an eluent, respectively, to obtain 0.11 g of the title compound(yield: 47 %).

¹H NMR(300MHz, CDCl₃): δ 2.88 (t, J = 7.2 Hz, 2H), 3.53 (t, J = 7.2 Hz, 2H), 3.88 (s, 3H), 6.99-7.03 (m, IH), 7.21 (d, J = 8.0 Hz, IH), 7.50 (t, J = 8.0 Hz, IH), 7.92 (dd, J = 11.0, 2.2 Hz, 2H), 8.46 (d, J = 4.5 Hz, IH), 8.63 (brs, IH); MS(m/e, M⁺): 473.9, 249.9, 110.4, 54.9.

Example 19: Synthesis of methyl 4,5-dimethoxy-2-[3-(pyridin-2-ylsulfanylV propionylamino] -benzoate

The same procedure as described in the Example 15 was repeated except that 0.18 g (0.68 mmol) of the compound obtained in Preparative Example 20 was used and n- hexane:ethyl acetate=3:l was used as an eluent, respectively, to obtain 0.40 g of the title compound (yield: 72 %).

¹H NMR(300MHz, CDCl₃): 2.95 (t, J = 7.2 Hz, 2H), 3.55 (t, J = 7.2 Hz, 2H), 3.88-3.97 (m, 9H), 6.95-6.70 (m, IH), 7.16 (d, J = 7.2 Hz, IH), 7.43-7.48 (m, 2H), 8.44- 8.50 (m, 2H), 11.19 (brs, IH);

MS(m/e, M⁺): 376, 265, 166, 112.

Example 20: Synthesis of methyl 3,4,5-trimethoxy-2-[3-(pyridin-2-ylsulfanylV propionylamino^"|-benzoate

The same procedure as described in the Example 15 was repeated except that 0.21 g (0.70 mmol) of the compound obtained in Preparative Example 21 was used and n- hexane:ethyl acetate=2:l was used as an eluent, respectively, to obtain 0.22 g of the title compound(yield: 75 %).

¹H NMR(300MHz, CDCl₃): 7.24-7.31(m, 4H), 7.81-7.88(m, 2H), 8.44(d, J = 3.3 Hz, 2H);

MS(m/e, M⁺): 406, 295, 166, 112.

Example 21: Synthesis of 2-[2-f4-bromo-phenylsulfanylVacetylamino] -benzoic acid

650 mg (1.70 mmol) of compound obtained in Example 1 was dissolved in 10 ml of tetrahydrofuran, to which 2.6 ml (5.2 mmol, 3.0 eq) of 2N sodium hydroxide solution was added dropwise. The resulting mixture was stirred for 3 hours under a nitrogen atmosphere, acidified with 1 N of hydrochloric acid solution, and the residue was shaken with a mixture of ethyl acetate and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure to obtain a crude product, which was purified by column chromatography (methanol:methylene chloride=l : 10) to obtain 0.54g of the title compound (yield: 87%).

¹H NMR(300MHz, CDCl₃): 3.73(s, 2H), 6.95(t, IH), 7.21(m, 2H), 7.27(m, 3H), 7.96(m, 3H), 7.96(d, IH), 8.35(d, IH);

MS(m/e, M⁺): 366.

Example 22: Synthesis of 2-r3-(pyridm-2-ylsulfmyl)-propionylamino^"l-benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.20 g (0.63 mmol) of the compound obtained in Example 15 was used and methanol:methylene chloride=l:10 was used as an eluent, respectively, to obtain 0.18 g of the title compound(yield: 94 %).

¹H NMR(300MHz, CDCl₃): 2.96(t, 2H), 3.57(t, 2H), 7.15(t, 2H), 7.34(d, IH), 7.51(t, IH), 7.65(t, IH), 8.15(d, IH), 8.48(d, IH), 8.57(d, IH).

Example 23: Synthesis of 2-r2-(^"4-bromo-phenylsulfanyl)-acetylaminol-4-chloro-benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.15

(0.36 mmol) of the compound obtained in Example 5 was used and the crude product was recrystallized from ethyl acetate, to obtain 0.09 g of the title compound (yield: 61 %). 1H NMR(300MHz, CDCl₃): 4.08(s, 2H), 7.33(dd, IH), 7.52(d, 2H), 7.63(d, 2H),

8.22(d, IH), 8.86(d, IH);

Example 24: Synthesis of 2-[2-(4-bromo-phenylsulfanyl)-acetylaininol-4,5-dimethoxy- benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.31 g (0.69 mmol) of the compound obtained in Example 9 was used and methanokmethylene chloride=l:10 was used as an eluent, respectively, to obtain 0.29 g of the title compound (yield: 87 %). 1H NMR(300MHz₃ CDCl₃): 3.74(s,2H), 3.84(s, 3H), 3.94(s, 3H), 7.23(m, 5H)₃

7.50(s, IH), 8.41(br, NH), 11.77(s, CO2H)

Example 25: Synthesis of 4,5-dimethoxy-2-(2-phenylsulfanyl-acetylamino)-benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.25 g

(0.69 mmol) of the compound obtained in Example 10 was used and methanol methylene chloride=l:10 was used as an eluent, respectively, to obtain 0.21 g of the title compound (yield: 86 %).

¹H NMR(300MHz, CDCl₃): 3.80(s,2H), 3.87(s, 3H), 3.96(s, 3H), 7.24(m, 4H),7.37(d, 2H), 7.50(s, IH), 8.56(br, NH), 11.80(s, CO2H)

Example 26: Synthesis of 2-[2-r4-bromo-phenylsulfanyl)-acetylamino]-5-chloro-benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.20 g

(0.48 mmol) of the compound obtained in Example 4 was used and methanol :methylene chloride=l:20 was used as an eluent, respectively, to obtain 0.19 g of the title compound(yield: 96 %).

¹H NMR(300MHz, CDCl₃): 3.77 (s, 2H), 7.28 (d, J = 8.7 Hz₅ 2H), 7.38-7.46 (m, 3H), 8.03 (d, J = 2.7 Hz, IH), 8.63 (d, J = 9.0 Hz, IH); MS(m/e, M⁺) 398.9, 227.9, 201.1, 120.8, 63.0.

Example 27: Synthesis of 3,5-dibromo-2-[2-(4-bromo-phenylsulfanylVacetylamino^~|- benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.10 g

(0.19 mmol) of the compound obtained in Example 8 was used and methanol:methylene chloride=l:20 was used as an eluent, respectively, to obtain 0.04 g of the title compound(yield: 37 %). 1H NMR(300 MHz, DMSOd₆): 3.86(s, 2H), 6.87-6.90(m, 2H), ?.49-7.52(m, 2H),

7.88-7.99(m, 2H), 10.48(brs, IH). Example 28: Synthesis of S-chloro^-rS-fpyridin^-ylsulfanviypropionylaminoi-benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.27 g

(0.77 mmol) of the compound obtained in Example 16 was used and methanol:methylene

was used as an eluent, respectively, to obtain 0.20 g of the title compound(yield: 76 %).

¹H NMR(300 MHz, DMSO-d₆): 2.81 (t, J = 6.9 Hz, 2H), 3.40 (t, J = 6.9 Hz, 2H), 7.10 (dd, J = 6.6, 5.1 Hz, IH), 7.27 (d, J = 8.1 Hz, IH), 7.59-7.66 (m, 2H), 7.88 (d, J = 2.6 Hz, IH), 8.43-8.46 (m, 2H), 11.08 (brs, IH);

MS(m/e, M⁺): 337.4, 185.1, 126.0, 72.0, 59.0

Example 29: Synthesis of 4-chloro-2-r3-rpyridin-2-ylsulfanyl)-propionylamino]-benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.30 g (0. 86 mmol) of the compound obtained in Example 17 was used and methanohmethylene chloride=l :20 was used as an eluent, respectively, to obtain 0.17 g of the title compound(yield: 56 %).

¹H NMR(300 MHz, DMSOd₆): 2.82 (t, J = 6.9 Hz, 2H), 3.41 (t, J = 6.9 Hz, 2H), 7.08-7.30 (m, 3H), 7.59-7.98 (m, IH), 7.95 (d, J = 8.7 Hz, IH), 8.43 (dd, J - 5.1, 0.9 Hz, IH), 8.57 (d, J = 0.9 Hz, IH), 11.47 (brs, IH);

MS(m/e, M⁺): 337, 185, 126, 72, 59.

Example 30: Synthesis of 4,5-dimethoxy-2-r3-(pyridin-2-ylsulfanyiypropionylamino^'l- benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.10 g (0. 26 mmol) of the compound obtained in Example 19 was used and methanol methylene chloride=l:20 was used as an eluent, respectively, to obtain 0.04 g of the title compound(yield: 37 %).

¹H NMR(300MHz, CDCl₃): δ 2.91 (t, J = 7.5 Hz, 2H), 3.55 (t, J = 7.5 Hz₅ 2H), 3.89 (s, 3H), 3.92 (s, 3H), 7.03 (dd, J = 6.0, 5.1 Hz, IH), 7.22-7.27 (m, IH)₅ 7.47-7.54 (m, 2H), 8.31 (s, IH), 8.50 (d, J = 4.5 Hz₅ IH)₅ 11.22 (brs, IH)₅ MS(m/e, M⁺): 362.1, 251.0, 181.9, 137.4, 78.0.

Example 31: Synthesis of 3,5-dibromo-2-[3-(pyridm-2-ylsulfanyl)-propionylammo^~l- benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.25 g (0.53 mmol) of the compound obtained in Example 18 was used as a starting material and methanol:methylene chloride=l:10 was used as an eluent, respectively, to obtain 0.08 g of the title comρound(yield: 33 %).

¹H NMR(300 MHz, DMSO-d₆): 2.72 (t, J = 6.9 Hz, 2H), 3.41 (t, J = 6.9 Hz, 2H), (dd, J - 7.2, 5.1 Hz, IH), 7.29 (d, J = 7.8 Hz, IH), 7.64 (t, J = 7.8 Hz, IH), 7.81 (d, J = 2.4 Hz, IH), 7.90 (d, J = 2.4 Hz, IH), 8.46 (d, J = 4.8 Hz, IH), 11.45 (brs, IH).

Example 32: Synthesis of 3A5-trimemoxy-2-r3-(pyridin-2-ylsulfanylVpropionylamino^~|- benzoic acid

The same procedure as described in the Example 21 was repeated except that 1.21 g

(2.98 mmol) of the compound obtained in Example 20 was used and methanol:methylene chloride=l :20 was used as an eluent, respectively, to obtain 0.42 g of the title compound(yield: 36 %). 1H NMR(300MHz, CDC13): 2.88(d, J = 7.5 Hz, 2H), 3.54(d, J = 7.5 Hz, 2H),

3.80-3.94(m, 9H), 7.02(t, J = 7.5 Hz, IH), 7.20-7.23(m, 2H), 7.50(td, J = 7.5, 1.8 Hz,

IH), 8.54(d, J = 4.5 Hz, IH), 8.63(brs, IH);

MS(m/e, M⁺): 341, 281, 227, 111, 67.

Example 33: Synthesis of 2-r2-(4-bromo-phenylsulfanylVacetylaniino]-3A5- trimethoxy-benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.20 g (0.43 mmol) of the compound obtained in Example 11 was used and methanol methylene chloride=l :20 was used as an eluent, respectively, to obtain 0.09 g of the title compound(yield: 44 %).

¹H NMR(300 MHz, DMSO-d₆): 3.66(s, 3H), 3.80-3.84(m, 8H), 7.16(s, IH), 7.34(d, J = 8.6 Hz, 2H), 7.50(d, J = 8.6 Hz, 2H), 9.71(brs, IH);

MS(m/e, M⁺): 455.5, 227.1, 126.1, 97.1, 59.0.

Example 34: Synthesis of N-(2-hydroxymethyl-phenylV3-(pyridin-2-ylsulfanyl)- propionylamide

0.40 g (1.27 mmol) of compound obtained in Example 15 was dissolved in 5 ml of tetrahydrofuran. Next, 0.12 g(3.16 mmol) of lithium aluminum hydride was added dropwise to the resulting mixture at 0 ^°C , and, then, the resulting mixture was stirred for

20 minutes under a nitrogen atmosphere. After the completion of the reaction, the resulting mixture was acidified with 1 N of HCl solution, and was shaken with a mixture of ethyl acetate and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under a reduced pressure to obtain a crude product, which was purified by column chromatography (hexane: ethyl acetate =1:1) to obtain 0.17g of the title compound(yield: 48%).

¹H NMR (300 MHz, CDCl₃): 2.50 (brs, IH), 2.85 (t, J= 7.2 Hz₃ 2H), 3.54 (t, J= 7.2 Hz, 2H), 4.70 (d, J= 4.8 Hz, 2H), 6.99-7.13 (m, 2H), 7.21-7.24 (m, 2H), 7.33 (t, J= 6.9 Hz, IH), 7.50 (t, J= 7.2 Hz, IH), 7.97 (d, J= 8.1 Hz, IH), 8.44 (d, J= 4.5 Hz, IH), 8.72 (brs, IH).

Example 35: Synthesis of phenyl 2-[2-(4-bromo-phenylsulfanviyacetylammo]-5-chloro- benzoate

70 mg (0.18 mmol) of compound obtained in Example 26 was dissolved in 2 ml of tetrahydrofuran. Next, 0.04 ml(0.27 mol, 1.5 eq) of diisopropylcarbodiimide was added dropwise to the resulting mixture, and, then, the resulting mixture was stirred for 30 mins. And then, after 25 mg (0.27 mol, 1.5 eq) of phenol was added dropwise to the resulting mixture, the resulting mixture was stirred for a day under a nitrogen atmosphere. The solvent was removed under a reduced pressure, and the residue was shaken with a mixture of ethyl acetate and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure to obtain a crude product, which was purified by column chromatography (hexane:ethyl acetate=10:l), to obtain 60 mg of the title compound (yield: 50 %). 1H NMR(300MHz, CDCl₃): 3.75 (s, 2H), 7.13-7.58 (m, 10H), 8.23 (d, J = 2.7 Hz,

IH), 8.71 (d, J = 9.0 Hz, IH), 11.52 (brs, IH), MS(m/e, M⁺): 476, 383, 365, 200, 121.

Example 36: Synthesis of methyl 2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]- 5-chloro-benzoate

The same procedure as described in the Example 1 was repeated except that 0.14 g (2.98 mmol) of the compound obtained in Preparative Example 14 was used as a starting material and n-hexane: ethyl acetate =9:1 was used as an eluent, respectively, to obtain 0.50 g of the title compound (yield: 34 %).

¹H NMR(300MHz, DMSO): 3.82(s, 3H), 5.61(s, IH), 7.34-7.42(m, 4H), 7.51- 7.56(m, 4H), 7.96(d, 2H), 8.36(s, IH), 11.41(br, NH)

Example 37: Synthesis of methyl 3.5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-2-phenyl- acetylaminoj-benzoate

The same procedure as described in the Example 1 was repeated except that 0.19 g (0.38 mmol) of the compound obtained in Preparative Example 15 was used and n- hexane:ethyl acetate =10:1 was used as an eluent, respectively, to obtain 0.11 g of the title compound (yield: 47 %).

¹H NMR(300MHz, CDCl₃): 3.60 (s, 3H), 5.03 (s, IH), 7.24-7.28 (m, 2H), 7.34- 7.41 (m, 5H), 7.49-7.52 (m, 2H), 7.86 (dd, J = 12.0, 2.4 Hz, 2H), 9.23 (brs, IH).

Example 38: Synthesis of 2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino^~|-5- chloro-benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.10 g (0.20 mmol) of the compound obtained in Example 36 was used and n-hexane:ethyl acetate =2:1 was used as an eluent, respectively, to obtain 0.05 g of the title compound(yield: 52 %). 1H NMR(300MHz, DMSO): 5.71(s, IH), 7.31(d, IH), 7.34-7.63(m, 9H), 8.07(d,

IH), 8.60(s, IH), 12.3 l(br, NH)

Example 39: Synthesis of 3,5-dibromo-2-[^"2-(4-bromo-phenylsulfanylV2-phenyl- acetylamino] -benzoic acid

The same procedure as described in the Example 21 was repeated except that 0.08 g

(0.13 mmol) of the compound obtained in Example 37 was used and n-hexane: ethyl acetate =2:1 was used as an eluent, respectively, to obtain 0.05 g of the title compound(yield: 52 %). 1H NMR(300MHz, CDCl₃): 5.27(s, IH), 7.30-7.42(m, 7H), 7.53(d, J = 6.8 Hz,

2H), 7.78(d, J = 2.1 Hz₃ IH), 7.94(d, J = 2.1 Hz, IH).

Example 40: Synthesis of N-[2-(4,5-dihydro-oxazol-2-yl>phenyl]-3-(pyridin-2- ylsulfanyp-propionamide

400 mg (1.32 mmol) of compound obtained in Example 22 was dissolved in 2 ml of tetrahydrofuran. Next, 428 mg(1.98 mmol) of di-(2-pyridyl) carbonate and 16 mg (0.13 mmol) of 0.1N dimethylaminopyridine were added dropwise to the resulting mixture, and, then, the resulting mixture was stirred for 1 hour under a nitrogen atmosphere . hi addition, after 0.55 ml(3.96 mmol) of triethyl amine and 459 mg(3.96 mmol) of 2-chloro ethyl amine hydrochloride salt were added to the resulting mixture, the resulting mixture was stirred for 24 hours under a nitrogen atmosphere. The solvent was removed under a reduced pressure, and the residue was shaken with a mixture of ethyl acetate and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure to obtain a crude product, which was purified by column chromatography (hexane: ethyl acetate =2:1) to obtain 221 mg of phenyl amide compound (yield: 46 %).

¹H NMR(300MHz, CDCl₃): δ 2.85(t, 2H), 3.52(t, 2H), 3.70(m, 4H)₅ 6.63(br, NH), 6.97(dd, IH), 7.10(t, IH), 7.12(d, IH)₅ 7.44(m₅ 3H),8.44(d, Ih), 8.62(d, IH); MS(m/e, M⁺): 363(M±1). 164 nig (0.45 mmol) of the phenylamide compound thus obtained was dissolved in 2 ml of tetrahydrofuran, to which 0.10 ml (0.68 mmol) of DBU was added dropwise. The resulting mixture was refluxed under a nitrogen atmosphere for 3 hours, the solvent was removed under a reduced pressure, and the residue was shaken with a mixture of ethyl acetate and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under a reduced pressure, to obtain a crude product, which was purified by column chromatography (hexane: ethyl acetate =2:1), to obtain 112 mg of the title compound (yield: 76 %).

¹H NMR(300MHz, CDCl₃): 2.89(t, 2H), 3.54(t, 2H), 4.05(t, 2H), 4.33(t, 2H), 6.98(d, IH), 7.07(t, IH), 7.20(d, IH), 7.46(m, 2H), 7.83(d, IH), 8.43(dd, IH), 8.74(d, IH), 12.27(br, NH);

MS(m/e, M⁺): 327.

Example 41: Synthesis of 2-(4-bromo-phenylsulfanviyN-[5-chloro-2-(4.3-dihydro- oxazol-2-yl)-phenyl]-acetamide

The same procedure as described in the Example 40 was repeated except that 0.24 g (0.60 mmol) of the compound obtained in Example 23 was used and n-hexane:ethyl acetate =4:1 was used as an eluent, respectively, to obtain 0.13 g of the title compound(yield: 51 %). 1H NMR(300MHz, CDCl₃): 3.76(s, 2H), 4.01(t, 2H), 4.34(t, 2H), 7.06(dd, IH),

2.25(m, 2H), 7.38(d, 2H), 7.75(d, IH), 8.80(s, IH), 12.76(br, NH); MS(m/e, M⁺): 426.

Example 42: Synthesis of 2-(4-bromo-phenylsulfanyl)-N-r2-(4,5-dihvdro-oxazol-2-yl)- 4, 5 -dimethoxy-phenyl] -acetamide

The same procedure as described in the Example 40 was repeated except that 0.18 g (0.42 mmol) of the compound obtained in Example 24 was used and n-hexane: ethyl acetate =2:1 was used as an eluent, respectively, to obtain 0.07 g of the title compound(yield: 38 %).

¹H NMR(300MHz, CDCl₃): 3.76(s, 2H)₅ 3.88(s, 3H), 3.95(s, 3H), 3.99(t, 2H), 4.3 l(t, 2H), 7.29(d, 3H)₅ 7.34(d, 2H)₅ 8.48(s, IH)₅ 12.66(s, IH);

MS(m/e, M⁺): 451.

Example 43: Synthesis of 2-(^'4-bromo-phenylsulfanyl^')-N-[4-chloro-2-(^'4.5-dihvdro- oxazol-2-ylVphenyll-acetamide

The same procedure as described in the Example 40 was repeated except that 0.15 g (0.38 mmol) of the compound obtained in Example 26 was used and n-hexane: ethyl acetate =5:1 was used as an eluent, respectively, to obtain 0.04 g of the title compound (yield: 27 %). ¹H NMR(300MHz, CDCl₃): 3.75(s, 2H)₅ 4.04 (t, J = 9.3 Hz₅ 2H), 4.35 (t, J - 9.3 Hz, 2H)₅ 7.23-7.41 (s, 5H), 7.80 (d, J = 2.4 Hz, IH), 8.68 (d, J = 9.0 Hz, IH), 12.62 (brs, IH);

MS(m/e, M⁺): 426, 223, 180, 124.

Example 44: Synthesis of N-[^"2-(4,5-dihydro-oxazol-2-yl)-4,5-dimethoxy-phenyll-2- phenylsulfanyl-acetamide

The same procedure as described in the Example 40 was repeated except that 0.25 g (0.59 mmol) of the compound obtained in Example 25 was used and n-hexane: ethyl acetate =2:1 was used as an eluent, respectively, to obtain 0.13 g of the title compound(yield: 60 %).

¹H NMR(300MHz, CDCl₃): 3.80(s, 2H), 3.87(s, 3H), 8.94(s, 3H), 4.05(t, 2H), 4.32(t, 2H), 7.20(s, IH), 7.29(d, 3H), 7.41(d, 2H), 8.50(s, IH)₅ 12.78(br₅ NH); MS(m/e, M⁺): 372.

Example 45: Synthesis of N-|^"4-chloro-2-(4,5-dihvdro-oxazol-2-yl)-phenyl]-3-(pyridin-2- ylsulfanyp-propionamide

The same procedure as described in the Example 40 was repeated except that 0.10 g

(0.17 mmol) of the compound obtained in Example 28 was used and n-hexane:ethyl acetate =3:1 was used as an eluent, respectively, to obtain 0.02 g of the title compound(yield: 19 %).

¹H NMR(300MHz, CDCl₃): 2.90 (t, J = 7.2 Hz, 2H)₅ 3.55 (t, J = 7.2 Hz₅ 2H)₅ 4.08 (t, J = 9.3 Hz, 2H)₅ 4.37 (t, J = 9.3 Hz, 2H), 6.98 (d, J = 5.1 Hz, IH), 7.17 (d, J = 8.1 Hz, IH)₅ 7.38-7.62 (m, 2H), 7.81 (d, J = 2.4 Hz, IH), 8.42 (d, J = 3.3 Hz, IH)₅ 8.73 (d, J = 9.0 Hz₅ IH)₅ 12.18 (brs, IH);

MS(m/e, M⁺): 361, 250, 166, 77.

Example 46: Synthesis of N-r5-chloro-2-(4,5-dmvdro-oxazol-2-ylVphenyl1-3-(pyridin-2- ylsulfanvD-propionamide

The same procedure as described in the Example 40 was repeated except that 0.14 g (0.40 mmol) of the compound obtained in Example 29 was used and n-hexane: ethyl acetate =4:1 was used as an eluent, respectively, to obtain 0.02 g of the title compound(yield: 13 %).

¹H NMR(300MHz, CDCl₃): δ 2.91(t, J = 7.2 Hz, 2H), 3.56(t, J = 7.2 Hz₅ 2H), 4.07(t, J = 9.3 Hz₅ 2H), 4.36(t, J = 9.3 Hz, 2H)₅ 6.95-7.06(m, 2H)₅ 7.18(d, J = 8.1 Hz₅ IH), 7.44- 7.50(m, IH), 7.75(d, J = 8.1 Hz, IH), 8.43(d, J = 4.8 Hz, IH), 8.86(d, J = 1.8 Hz, IH)₅ 12.32(brs, IH).

MS(m/e, M⁺): 36I₅ 251, 166, 112. Example 47: Synthesis of N-[2-(4,5-dmvdro-oxazol-2-ylV4,5-dimethoxy-phenyl^'l-3- φyridin-2-ylsulfanyl)-propionamide

The same procedure as described in the Example 40 was repeated except that

0.16 g (0.44 mmol) of the compound obtained in Example 30 was used and n- hexane:ethyl acetate =3:1 was used as an eluent, respectively, to obtain 0.02 g of the title compound(yield: 12 %).

¹H NMR(300MHz, CDCl₃): 2.91 (t, J = 7.2 Hz, 2H), 3.56 (t, J = 7.2 Hz, 2H), 3.88 (s, 3H), 3.96 (s, 3H), 4.06 (t, J = 9.3 Hz, 2H), 4.34 (t, J = 9.6 Hz, 2H), 6.95-7.00 (m, IH), 7.18 (d, J = 8.1 Hz, IH), 7.26 (s, IH), 7.30 (s, IH), 7.44-7.50 (m, IH), 8.44 (d, J = 4.2 Hz₃ IH), 8.54 (s, IH), 12.25 (brs, IH).

Example 48: Synthesis of 3-(4-bromo-phenylsulfanylVN-f6-(4,5-dihvdro-oxazol-2-yl^')- 2,3 ,4-trimethoxy-phenyl] -propionamide

The same procedure as described in the Example 40 was repeated except that 0.20 g (0.44 mmol) of the compound obtained in Example 32 was used and n- hexane:ethyl acetate =1:2 was used as an eluent, respectively, to obtain 0.02 g of the title compound(yield: 7.2 %).

¹H NMR(300MHz, CDCl₃): 3.76-3.92(m, 13H), 4.25(t, J = 9.6 Hz, 2H), 7.12(s, IH), 7.25(d, J = 8.7 Hz, 2H), 7.40(d, J = 8.7 Hz, 2H), 9.91(brs, IH);

MS(m/e, M⁺) 482, 279, 252, 236.

Example 49: Synthesis of 2-f2-(4-bromo-phenylsulfanyl)-acetylamino]-N-(2-chloro- ethyl)-4,5-dimethoxy-benzamide

250 mg (0.59 mmol) of compound obtained in Example 24 was dissolved in 6 ml of tetrahydrofuran. Next, 192 mg(0.89 mmol) of di-(2-pyridyl) carbonate and 7 mg(0.06 mmol) of 0.1N dimethyl amino pyridine were added dropwise to the resulting mixture, and, then, the resulting mixture was stirred for 3 hours under a nitrogen atmosphere . In addition, after 0.25 ml (1.77 mmol) of triethyl amine and 205 mg (1.77 mmol) of 2- chloro ethyl amine hydrochloride salt were added to the resulting mixture, the resulting mixture was stirred for 24 hours under a nitrogen atmosphere. The solvent was removed under a reduced pressure, and the residue was shaken with a mixture of ethyl acetate and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under a reduced pressure to obtain a crude product, which was purified by column chromatography (hexane: ethyl acetate=l:l) to obtain 115 mg of the title compound (yield: 40 %). 1H NMR(300MHz, CDCl₃): 3.74(m, 6H), 3.89(s, 3H), 3.93(s, 3H), 6.38(br, NH),

6.90(s, IH), 7.27(d, 2H), 7.38(d, 2H), 8.30(s, IH), l l,80(br, NH); MS(m/e, M⁺): 487.

Example 50: Synthesis of N-C2-chloro-ethylV4,5-dimethoxy-2-(2-phenylsulfaiiyl- acetylaminoVbenzamide

250 mg (0.72 mmol) of compound obtained in Example 26 was dissolved in 6 ml of tetrahydrofuran. Next, after 233 mg(1.08 mmol) of di-(2-pyridyl) carbonate and 9 mg(0.07 mmol) of 0.1N dimethyl amino pyridine were added dropwise to the resulting mixture, and, then, the resulting mixture was stirred for 1 hours under a nitrogen atmosphere . In addition, after 0.30 ml (2.16 mmol) of triethyl amine and 251 mg (2.16 mmol) of 2-chloro ethyl amine hydrochloride salt were added to the resulting mixture, the resulting mixture was stirred for 24 hours under a nitrogen atmosphere. The solvent was removed under a reduced pressure, and the residue was shaken with a mixture of ethyl acetate and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and distilled under a reduced pressure to obtain a crude product, which was purified by column chromatography (hexane: ethyl acetate =1:1) to obtain 135 mg of the title compound(yield: 46 %).

¹H NMR(300MHz, CDCl₃) 3.61-3.68(m, 6H), 3.88(s 3H), 3.93(s 3H), 6.37br, NH), 6.90(s IH), 7.26(d, 3H), 7.40(d, 2H), 8.30(s, IH), 11.80(br, NH) 7.97 (d, J= 8.1 Hz, IH), 8.44 (d, J= 4.5 Hz, IH), 8.72 (brs, IH); MS(m/e, M⁺): 408.

The N-phenylamide derivatives according to the present invention were assayed for pharmacological effects through the following experiments.

Experimental Example 1 : Inhibitory Effect on Ischemic Cell Death

The N-phenylamide derivatives of the present invention were assayed for inhibitory effect of ischemic cell death in cells according to the following procedure. Cardiomyocyte cell line H9c2 cells were cultured in DMEM (Dulbecco's modified

Eagle's medium) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin (lOOxsolution). l*10⁴ cells thus obtained were inoculated into 35 mm dishes and incubated at 37 ^°C for 48 hours in a CO₂ incubator. The cells for control examples were then treated with 0.1% DMSO only and the cells for experimental examples treated with a solutions made by dissolving the derivatives of Examples 1 to 50 (10 μM) in DMSO, respectively. After 30 minutes, the cells were washed with PBS once.

While the cells are continuously treated with the DMSO solution for control examples or with 10/xM of the derivative solutions for experimental exmples, together with chemical hypoxia solution (106 mmol NaCl, 4.4 mmol KCl, 1 mmol MgCl₂, 38 mmol NaHCO₃, 2.5 mmol CaCl₂, 20 mmol 2-deoxy glucose, 1 mmol NaCN) for 1 to 2 hours, the cell damage was observed by microscope. When some damages were observed, the cells were washed with 1 ml of PBS twice, and fixed with 1 ml of 3.7% formaldehyde. The cells thus obtained were washed with 1 ml of PBS again, stained with DAPI, and then washed with 1 ml of PBS in three times. The cell deaths of the cells were observed by a fluorescence microscope, and degrees of the observed cell death were converted to percentages (%).

Meanwhile, in the comparative example, the same procedure as described in the

Experimental Example 1 was repeated except that a compound of Formula VI, which is known to have inhibitory effects on ischemic cell death, was used [Lee, M. H. et ah, Res. Commun. MoI. Pathol. Pharmacol. 110: 361-370, 2001; Hong, K. W. et al, J.

Pharmacol. Exp. Ther. 301:210-216, 2002].

The results were summarized in Table 2 below and Figure 1. In the Table 2 and Figure 1, "control" means a group treated with DMSO and "cell" means a group which is not treated with DMSO.

The Inhibitory Effect of N-phenylamide Derivatives.

- continued-

As shown in Table 2 and Figure 1, the N-phenylamide derivatives of the present invention showed an inhibitory effect on ischemic cell death.

Experimental Example 2: Effect of N-phenylamide derivative on a brain-disordered rat induced by a temporary brain ischemia

The N-phenylamide derivatives of the present invention were assayed for inhibitory effects of brain ischemia in the rat as follows:

For the experiment, an adult male Sprague-Dawley rat (200 to 25Og) was anesthetized using 75 mg/kg of ketamine and 5 mg/kg of rumpun and the rats were divided into three groups, including a control group (N=4), a comparative group (N=4), and an experimental group (N=4). Then, in order to induce a stroke caused by ischemia, the neck of the rat was incised along the midline thereof, and then, an external carotid artery(ECA), and an intermal carotid artery(ICA) located outside of the cranial cavity were isolated. Next, after a nylon ligature having a diameter of 0.37 mm was pushed from a commolon carotid artery(CCA) into about 20 to 22 mm in direction of ICA, the middle cerebral artery(MCA) was ligated to occlude its blood supply for 2 hours. During the experiment, the body temperature of the rat was constantly maintained at 37.8 ^"C .

For the experimental example, at όhous after occlusion, 30 mg/kg of compound of Example 15 was intraperitoneally administered. At 24 days after stroke induction, the image of the rat model suffering from stroke was obtained by using a superconducting MRI with a 65cm bore, operated on 3.0 T, wherein the fast spin echo(FSE), which is a kind of technique of high speed measurement technique, is used. The imaging parameters were as follows: the repetition image (TR)₃ 4000 msec; the echo time, 96 msec; field of view (FOV), 60 mm; and the resolution, 128 X 128. Further, 15 slices with width of 2 mm was scanned and the scan was repeated 3 times per a slice. Next, brain infarct volumes(%) were calculated by using Osiris ver 4.02 based on the image thus obtained. For the comparative example, the same procedure as described in the

Experimental Example 2 was repeated except that a compound of Formula 6 was used. Further, in the control example, the rat was treated with DMSO. The results were summarized in Table 3 below and Figure 2.

As shown in Table 3 and Figure 2, the N-phenylamide derivative of the subject invention showed a remarkable inhibitory effect on ischemic cell death of the brain- disordered rat induced by a temporary brain ischemia.

Formulations comprising the compounds of the present invention as effective ingredients are illustrated in the following formulation examples, but are not construed to limit the scope of the present invention.

Formulation Example 1 : Tablet (Direct Compression)

After being sieved, 5.0 mg of a compound of the present invention was mixed with 14.1 mg of lactose, 0.8 mg of crospovidone USUF and 0.1 mg of magnesium stearate and compressed into tablets.

Formulation Example 2: Tablet (Wetting Formulation)

After being sieved, 5.0 mg of a compound of the present invention was mixed with 16.0 mg of lactose and 4.0 mg of starch. To the resulting mixture, solution of 0.3 mg of polysolvate 80 in purified water was added, followed by granulation. Next, the resulting granules were dried, sieved, mixed with 2.7 mg of colloidal silicon dioxide and

2.0 mg of magnesium stearate, and compressed into tablets.

Formulation Example 3: Powder and Capsule 5.0 mg of a compound of the present invention was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filled in a hard gelatine capsule No. 5, using a suitable apparatus.

Formulation Example 4: Injection solution

An injection was prepared by mixing 100 mg of a compound of the present invention, 180 mg of mannitol, 26 mg of Na₂HPO₄- 12H₂O and 2974 mg of distilled water.

Industrial Applicability

As described hereinbefore, the N-phenylamide derivatives of the present invention can reduce an ischemic cell death significantly. Consequently, the pharmaceutical compositions comprising them as an effective ingredient can be effectively used for preventing or treating ischemic diseases mediated by a ischemic cell death, such as brain ischemia, heart ischemia, diabetic cardiovascular disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, head trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma or diabetic neuropathy, and for protecting organs.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof: <Formula I>

wherein:

R¹ is H, -CO₂R⁵, -CH₂OR⁵, -CONR⁵R⁶ or ^cT , R⁵ and R⁶ being each independently H, or C₁-C₆ alkyl which optionally have one or more halogen substituents;

B is H, or phenyl having one or more optional C_1-3 alkyl or halogen substituents substituents;

Y is S, O, SO₅ Or SO₂;

Z is H, halogen, hydroxyl, or C₁-C₃ alkoxyl; and

A is CH or N, n is O, 1 or 2; with the proviso that when n is O, B is phenyl having one or more optional C₁-C₃ alkyl or halogen substituents, and when n is 1 , A is N

2. The compound of claim 1, wherein

R¹ is -CO₂R⁵, -CH₂OR⁵, or "^o , R⁵ and R⁶ being each independently H or methyl;

B is H, or phenyl having one or more optional C₁-C₃ alkyl or halogen substituents; n is O or 1;

Y is S;

Z is H or halogen;

A is CH or N; with the proviso that when n is O, B is phenyl having one or more optional C₁-C₃ alkyl or halogen substituents, and when n is 1, A is N.

3. The compound of claim 1, which is selected from the group consisting of: Methyl 2-[3-(pyridin-2-ylsulfanyl)-ρropionylamino]-benzoate; Methyl 5-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

Methyl 4-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

Methyl 3_J5-dibromo-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

Methyl 4,5-dimethoxy-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

Methyl 3,4,5-trimethoxy-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

5-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

4-chloro-2- [3 -(pyridin-2-ylsulfanyl)-propionylamino] -benzoic acid;

4,5-dimethoxy-2-[3-(ρyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

3 ,5 -dibromo-2- [3 -(pyridin-2-ylsulfanyl)-propionylamino] -benzoic acid;

3,4,5-trimethoxy-2-[3-(pyridm-2-ylsulfanyl)-propionylamino]-benzoic acid;

N-(2-hydroxymethyl-phenyl)-3-(pyridin-2-ylsulfanyl)-propionylamide;

Methyl 2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-5-chloro-benzoate;

Methyl 3₅5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-benzoate;

2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-5-chloro-benzoic acid;

3,5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-benzoic acid;

N-[2-(4,5-dihydro-oxazol-2-yl)-phenyl]-3-(pyridin-2-ylsulfanyl)-propionamide;

N-[4-chloro-2-(4,5-dihydro-oxazol-2-yl)-phenyl]-3-(pyridin-2-ylsulfanyl)-propionamide;

N-[2-(4,5-dihydro-oxazol-2-yl)-4,5-dimethoxy-phenyl]-3-(pyridin-2-ylsulfanyl)- propionamide.

4. A process for preparing the compound of Formula I comprising subjecting a compound of Formula II to a nucleophilic substitution reaction with a compound of Formula III in the presence of an organic solvent and a base:

wherein:

R¹, R², R³, R⁴, B, n, Z₅ Y and A are the same as defined in claim 1, and

L is a leaving group selected from the group consisting of halogen, methanesulfonyloxy and toluenesulfonyloxy.

5. The process according to claim 4, wherein: the base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8- diazabicyclo[5,4,0]-unde-7-cene(DBU), NaOH, Na₂CO₃, K₂CO₃, and Cs₂CO₃.

6. The process according to claim 4, wherein: the organic solvent is selected from the group consisting of tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, dimethylformamide(DMF), dimethylsulfoxide, and a mixture thereof.

7. A composition for preventing or treating ischemic diseases, comprising the compound of Formula I' or the pharmaceutically acceptable salt thereof:

wherein:

R¹ is H, -CO₂R⁵, -CH₂OR⁵, -CONR⁵R⁶ or ^V ^', R⁵ and R⁶ being each independently H or C₁-C₆ alkyl having one or more optional halogen substituents;

B is H, or phenyl having one or more optional C₁-C₃ alkyl or halogen substituents; n is O, 1 or 2;

Y is S, O, SO, or SO₂;

Z is H₅ halogen, hydroxyl, or C₁-C₃ alkoxyl; and A is CH or N.

8. The composition according to claim 7, wherein

R¹ is H, -CO₂R⁵, -CH₂OR⁵, -CONR⁵R⁶ or Α>', R⁵ and R⁶ being each independently H or methyl;

Y is S, O, SO, Or SO₂;

Z is H, halogen, hydroxyl, or C₁-C₃ alkoxyl; and

A is CH or N.

9. The composition according to claim 7, wherein the compound of formula F is selected from the group consisting of

Methyl 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-benzoate;

Methyl 2-(2-phenylsulfanyl-acetylamino)-benzoate;

Methyl 2-[2-(pyridin-2-ylsulfanyl)-acetylamino]-benzoate;

Methyl 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-5-chloro-benzoate;

Methyl 2- [2-(4-bromo-phenylsulfanyl)-acetylamino] -4-chloro-benzoate;

2-(4-bromo-phenylsulfanyl)-N-(3,4-dimethyl-phenyl)-acetamide;

N-(3,4-dimethyl-phenyl)-2-phenylsulfanyl-acetamide;

Methyl 3, 5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-benzoate;

Methyl 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-4,5-dimethoxy-benzoate;

Methyl 4,5-dimethoxy-2-[2-phenylsulfanyl-acetylamino]-benzoate;

Methyl 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-3,4,5-trimethoxy-benzoate;

Methyl 2-[3-(4-bromo-phenylsulfanyl)-propionylamino]-benzoate;

Methyl 2-(3-phenylsulfanyl-propionylamino)-benzoate;

Methyl 2-[3-(4-methoxy-phenylsulfanyl)-propionylamino]-benzoate;

Methyl 2-[3-(pyridin-2-ylsulfanyl)-ρropionylamino]-benzoate;

Methyl 5-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

Methyl 4-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

Methyl 3,5-dibromo-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

Methyl 4,5-dimethoxy-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

Methyl 3,4,5-trimethoxy-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoate;

2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-benzoic acid;

2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-4-chloro-benzoic acid;

2-[2-(4-bromo-ρhenylsulfanyl)-acetylamino]-4,5-dimethoxy-benzoic acid;

4,5-dimethoxy-2-(2-phenylsulfanyl-acetylamino)-benzoic acid; 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-5-chloro-benzoic acid;

3,5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-benzoic acid;

5-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylaniino]-benzoic acid;

4-chloro-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

4,5-dimethoxy-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

3,5-dibromo-2-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzoic acid;

3 ,4, 5-trimethoxy-2- [3 -(pyridin-2-ylsulfanyl)-propionylamino] -benzoic acid;

2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-3,4,5-trimethoxy-benzoic acid;

N-(2- hydroxymethyl-phenyl)-3-(pyridin-2-ylsulfanyl)-propionylamide;

Phenyl 2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-5-chloro-benzoate;

Methyl 2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-5-chloro-benzoate;

Methyl 3,5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-benzoate;

2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-5-chloro-benzoic acid;

3,5-dibromo-2-[2-(4-bromo-phenylsulfanyl)-2-phenyl-acetylamino]-benzoic acid;

N-[2-(4,5-dihydro-oxazol-2-yl)-phenyl]-3-(pyridin-2-ylsulfanyl)-propionamide;

2-(4-bromo-phenylsulfanyl)-N-[5-chloro-2-(4,5-dihydro-oxazol-2-yl)-phenyl]- acetamide;

2-(4-bromo-phenylsulfanyl)-N-[2-(4,5-dihydro-oxazol-2-yl)-4,5-diniethoxy-phenyl]- acetamide;

2-(4-bromo-phenylsulfanyl)-N-[4-chloro-2-(4,5-dihydro-oxazol-2-yl) phenyl]-acetamide;

N-[2-(4,5-dihydro-oxazol-2-yl)-4,5-dimethoxy-phenyl]-2-phenylsulfanyl-acetamide;

N-[5-chloro-2-(4,5-dihydro-oxazol-2-yl)-phenyl]-3-(pyridin-2-ylsulfanyl)-propionamide;

N-[2-(4,5-dihydro-oxazol-2-yl)-4,5-dimethoxy-phenyl]-3-(pyridin-2-ylsulfanyl)- propionamide;

3-(4-bromo-phenylsulfanyl)-N-[6-(4,5-dihydro-oxazol-2-yl)-2,3,4-trimethoxy-phenyl]- propionamide;

2-[2-(4-bromo-phenylsulfanyl)-acetylamino]-N-(2-chloro-ethyl)-4,5-dimethoxy- benzamide; and

N-(2-chloro-ethyl)-4,5-dimethoxy-2-(2-phenylsulfanyl-acetylamino)-benzamide.

10. The composition according to claim 7, wherein the ischemic disease is selected from the group consisting of brain ischemia, heart ischemia, diabetic cardiovascular disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, head trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma and diabetic neuropathy, which are mediated by ischemic cell death.

11. The composition according to claim 10, wherein the ischemic cell death is induced by hypoxemia.

12. A composition for protecting organs, comprising the compound of claim 7 or the pharmaceutically acceptable salt thereof.