KR100860539B1 - Composition for preventing or treating an ischemic disease containing aminothiophene derivatives - Google Patents

Abstract

An aminothiophene derivative is provided to decrease ischemic apoptosis, thereby being used as a composition for preventing and treating ischemic diseases mediated by the ischemic apoptosis or for protecting organs. A composition for preventing or treating ischemic diseases comprises an aminothiophene derivative represented by a formula(1) or (2), or a pharmaceutically acceptable salt thereof as an effective ingredient, wherein the ischemic disease is cerebral ischemia, cardiac ischemia, diabetic cardiovascular diseases, cardiac failure, cardiac hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, cerebral wound, Alzheimer's disease, Parkinson's disease, hypoxia in newborn, glaucoma and diabetic neuropathy. In the formulae, R^1 is H, CO2R^2, CH2OR^2, CONR^2R^3, or a group(1); each R^2 and R^3 is independently H, or C1-6 linear or branched alkyl, or halogen or hydroxy substituted alkyl; B is H, phenyl, or C1-3 alkyl or halogen substituted phenyl; n is an integer from 0 to 2; Y is S, O, SO or SO2; Z is H, halogen, NO2, NH2, C1-3 linear or branched alkyl or OR^4; R^4 is H or C1-3 linear or branched alkyl; and A is CH, N or N-O. Further, the ischemic diseases are selected from cerebral ischemic damage, Ischemic Heart Failure, cardiac failure, retinal ischemia or Alzheimer's disease.

Description

COMPOSITION FOR PREVENTING OR TREATING AN ISCHEMIC DISEASE CONTAINING AMINOTHIOPHENE DERIVATIVES}

1 is a result of measuring the degree of apoptosis of the aminothiophene derivative of the present invention inhibits ischemic cell death induced by hypoxia,

2 and 3 are results showing that the aminothiophene derivatives of Examples 1 and 2 inhibit cerebral infarction induced by cerebral ischemia, respectively.

The present invention relates to a pharmaceutical composition for preventing or treating ischemic disease containing an aminothiophene derivative as an active ingredient.

Ischemia refers to a reduced state of blood supply to body organs, tissues or sites caused by contraction or blockage of blood vessels. After ischemia, even if reperfusion of blood occurs, nerve cells are damaged, resulting in various sequelae. Such ischemia is often associated with coronary artery disease, cardiovascular disease, angina pectoris, headache or other vascular symptoms. Such ischemia ultimately leads to irreversible damage, ie necrosis of cells and tissues.

Ischemic diseases such as myocardial infarction, arrhythmia, and insufficiency caused by cellular damage and deterioration during ischemia / reperfusion have high prevalence, mortality, and difficulty in cure. See Wang, QD et al., Cardiovasc. Res. 55: 25-37, 2002). In addition, ischemia / reperfusion injury is involved in various physiological mechanisms such as metabolism, immune response and changes in ionic constant, oxygen free radicals, etc. See Harse, DJ et al., Mol. Cell. Biochem. 186: 177-184, 1998). To date, there have been active researches on the development of therapeutic agents and surgical procedures with new action points, but the techniques for protecting cardiomyocytes from ischemia / reperfusion have not been commercialized. Therefore, there is a need for development of a prophylactic or therapeutic agent for ischemic heart disease or a cardioprotective agent that can slow the progression of cardiomyocyte damage due to ischemia and alleviate reperfusion injury.

It is also increasingly clear that when ischemia is eliminated by the return of blood flow, the production of reactive oxygen species (ROS) is accelerated, which leads to a much more pronounced decrease in glutathione leading to the development of more serious diseases. have. Similar diseases are observed upon stopping or returning blood flow in the implantation of various organs such as the heart, liver, lungs, pancreas and blood vessels. The disease is also a problem when cutting and removing organs. Free radicals and reactive free radicals that are believed to cause disease are detected in both the cytoplasmic cells and organelles that make up tissue, especially mitochondria producing ATP, which contributes to the cell's primary energy source. In mitochondria, it has been observed that the respiratory chain is the main source of these reactive molecules and causes their concentration to rise significantly during ischemia and reperfusion.

In ischemic diseases, apoptosis or cell necrosis is caused by ischemia. Especially, apoptosis after reperfusion is a major cause of tissue damage. And ischemic colitis and ischemic acute renal failure.

In the case of ischemic disease, cerebral ischemia, depletion of energy supply causes depletion of energy source, and ischemic cell death is activated by excessive activation of cell membrane receptors. Glutamic acid accumulates outside the cell and calcium accumulates inside the cell. And various biochemical changes such as damaging lipids, proteins and nucleic acids, resulting in damage to brain tissue (Liu, PK, J. Biomed. Sci. 10: 4-13, 2003; Lipton, P., Physiol. Rev. 79: 1431-1568, 1999; and Renolleau, S. et al., Stroke 29: 1454-1460, 1998).

In the case of ischemic heart disease, myocardial infarction, arrhythmia and heart failure, it is reported that lipid membrane activation causes cell membrane damage, pH change and calcium migration, resulting in ischemic cell death (Ferrari, R. Rev. Port). Cardiol. 5: 7-20, 2000; Webster, KA et al., J. Clin.Invest . 104: 239-252, 1999; Katz, AM et al., J. Mol. Cell.Cardiol. 2:11 . -20, 1985; and Vandeplassche, G. et al. Basic Res. Cardiol. 85: 384-391, 1990), in the case of retinal ischemia, associated with ischemic cell death associated with glutamate-mediated retinal cell death Is known (see Napper, GA et al., Vis. Neurosci. 16: 149-158, 1999). It has also been reported that ischemic cell death occurs due to insufficient blood flow to the large intestine, and ischemic colitis, an ischemic disease caused by arterial occlusion and fluid abnormalities due to cell necrosis (Saegesser, F. et al. , Pathobiol.Annu . 9: 303-337, 1979).

Minocycline, a tetracycline family of antibiotics known to inhibit ischemic cell death, is known to have cerebral infarction (see Yrjanheikki, J. et al., Proc. Natl. Acad. Sci. USA 96: 13496-13500, 1999), myocardial infarction ( See Scarabelli, TM 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), and is also known to be effective in the treatment of ischemic diseases.

In addition, injury or death of neurons caused by ischemia is known to be a major cause of several neurological diseases, including stroke, brain trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma and diabetic neurosis [GJ Zoppo et al. , Drugs 54 , 9 (1997); I. Sziraki et al. , Neurosci. 85 , 1101 (1998).

Therefore, the present inventors are trying to develop a compound that exhibits a pharmacological effect against the ischemic disease, while specific aminocyphene derivatives inhibit ischemic cell death, thereby ischemic cell death mediated by ischemic cell death, cerebral ischemia, diabetes Prevention and treatment or long-term protection of ischemic diseases such as cardiovascular disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, brain trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma and diabetic neurosis The present invention has been completed by revealing that it can be used zero.

Accordingly, it is an object of the present invention to provide a composition for the prevention or treatment of ischemic diseases containing a specific aminothiophene derivative as an active ingredient.

Another object of the present invention is to provide a composition for long-term protection containing the aminothiophene derivative as an active ingredient.

In accordance with the above object, the present invention provides a composition for the prevention or treatment of ischemic diseases containing an aminothiophene derivative of the following formula (1) or (2), or a pharmaceutically acceptable salt thereof as an active ingredient.

Where

이며, 이때 R²와 R³는 서로R ¹ is H, —CO ₂ R ² , —CH ₂ OR ² , —CONR ² R ³ , or

Where R ² and R ³ are

Independently H, or C ₁ to C ₆ straight or branched alkyl, or alkyl substituted with halogen or hydroxy;

B is H, phenyl, or phenyl substituted with C ₁ -C ₃ alkyl or halogen;

n is an integer from 0 to 2;

Y is S, O, SO or SO ₂ ;

Z is H, halogen, NO ₂ , NH ₂ , C ₁ -C ₃ straight or branched alkyl, or OR ⁴ , wherein R ⁴ is H, or C ₁ -C ₃ straight or branched alkyl;

A is CH, N, or N-O.

In addition, according to the other object, the present invention provides a composition for long-term protection containing the aminothiophene derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Hereinafter, the present invention will be described in more detail.

Preferred among the aminothiophene derivatives of the present invention, in Formula 1,

이며, 이때 R²와 R³는 서로 독립적으로 H 또는 메틸이고;R ¹ is H, —CO ₂ R ² , —CH ₂ OR ² , —CONR ² R ³ , or

Wherein R ² and R ³ are independently of each other H or methyl;

B is H, phenyl, or phenyl substituted with C ₁ -C ₃ alkyl or halogen;

n is 0 or 1;

Y is S, O, SO or SO ₂ ;

Z is H, halogen, NO ₂ , NH ₂ , C ₁ -C ₃ straight or branched alkyl, or OR ⁴ , wherein R ⁴ is H, or C ₁ -C ₃ straight or branched alkyl;

A is a compound that is CH, N, or N-O.

Aminothiophene derivatives used in the present invention include not only pharmaceutically acceptable salts thereof, but also all solvates, hydrates and stereoisomers that may be prepared therefrom.

Pharmaceutically acceptable salts of the aminothiophene derivatives used in the present invention can be exemplified by acid addition salts formed with pharmaceutically acceptable free acids. The free acid may be an organic acid or an inorganic acid, and an organic acid may be citric acid, acetic acid, maleic acid, fumaric acid, glucoic acid, methanesulfonic acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, Galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid and the like can be used, and as the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, and the like can be used. have.

The acid addition salt used in the present invention is a conventional method, that is, dissolving the aminothiophene derivative of Formula 1 or Formula 2 in a water miscible organic solvent such as acetone, methanol, ethanol, acetonitrile and the like and adding an excess organic acid, It can be prepared by adding an aqueous acidic acid solution of an inorganic acid followed by precipitation or crystallization, evaporating the solvent or excess acid from the mixture and then drying or suction filtering the precipitated salt.

Examples of suitable aminothiophene derivatives for use in the present invention are as follows, and the respective structural formulas thereof are shown in Table 1 below:

1) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

2) 3- (2-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

3) 3- [2- (4-nitro-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

4) 3- [2- (4-amino-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

5) 3- [2- (4-methyl-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

6) 3- [2- (pyridin-2-ylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

7) 3- [2- (4-methoxy-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

8) 3- [2- (2-methoxy-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

9) 3- [2- (3-methoxy-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

10) 3- [2- (4-hydroxy-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

11) 3- [2- (pyridin-4-ylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

12) 3- [2- (1-oxy-pyridin-4-ylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

13) 3- [3- (4-bromo-phenylsulfanyl) -propionylamino] -thiophene-2-carboxylic acid methyl ester;

14) 3- (3-phenylsulfanyl-propionylamino) -thiophene-2-carboxylic acid methyl ester;

15) 3- [3- (pyridin-2-ylsulfanyl) -propionylamino] -thiophene-2-carboxylic acid methyl ester;

16) 3- [4- (4-bromo-phenylsulfanyl) -butylylamino] -thiophene-2-carboxylic acid methyl ester;

17) 3- [2- (4-bromo-phenylsulfanyl) -2-phenyl-acetylamino] -thiophene-2-carboxylic acid methyl ester;

18) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid;

19) 3- [2- (4-bromo-phenylsulfanyl) -2-phenyl-acetylamino] -thiophene-2-carboxylic acid;

20) N- (2-hydroxymethyl-thiophen-3-yl) -2-phenylsulfanyl-acetamide;

21) 2- (4-bromo-phenylsulfanyl) -N- (2-hydroxymethyl-thiophen-3-yl) -acetamide;

22) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid amide;

23) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid dimethylamide;

24) 2- (4-bromo-phenylsulfanyl) -N- [2- (4,5-dihydro-oxazol-2-yl) -thiophen-3-yl] -acetamide;

25) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid (2-hydroxy-ethyl) -amide;

26) 3- [2- (4-bromo-phenoxy) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

27) 3- [2- (4-nitro-phenoxy) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

28) 3- [2- (4-amino-phenoxy) -acetylamino] -thiophene-2-carboxylic acid methyl ester;

29) 2- (4-bromo-phenoxy) -N- (2-hydroxymethyl-thiophen-3-yl) -acetamide;

30) 2- (2-phenylsulfanyl-acetylamino) -thiophene-3-carboxylic acid methyl ester;

31) 2- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester;

32) 2- [2- (2-methoxy-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester;

33) 2- [2- (3-methoxy-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester;

34) 2- [2- (4-methyl-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester;

35) 2- [2- (4-methoxy-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester;

36) 2- [2- (pyridin-2-yl-sulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester;

37) 2- [2- (4-hydroxy-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester;

38) 2- [2- (pyridin-4-ylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester;

39) 2- [3- (4-bromo-phenylsulfanyl) -propionylamino] -thiophene-3-carboxylic acid methyl ester;

40) 2- (3-phenylsulfanyl-propionylamino] -thiophen-3-carboxylic acid methyl ester;

41) 2- [3- (pyridin-2-ylsulfanyl) -propionylamino] -thiophene-3-carboxylic acid methyl ester;

42) 2- [2- (4-bromo-phenylsulfanyl) -2-phenyl-acetylamino] -thiophene-3-carboxylic acid methyl ester; And

43) 2- [2- (4-bromo-phenylsulfanyl) -2-phenyl-acetylamino] -thiophene-3-carboxylic acid.

The aminothiophene derivative represented by Chemical Formula 1 used in the present invention is prepared by a process comprising reacting a compound of Chemical Formula 3 with a compound of Chemical Formula 5 in the presence of a suitable solvent and a base (nucleophilic substitution reaction). Can be:

Wherein, R ¹ , B, n, Z, Y and A are the same as defined in Formula 1,

L is a halide group, a mesylate group or a tosylate group as a leaving group.

At this time, the base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5,4,0] unde-7-cene (DBU), or NaOH, Inorganic bases such as Na ₂ CO ₃ , K ₂ CO ₃ , and Cs ₂ CO ₃ can be used in equivalent or excessive amounts.

As the reaction solvent of the reaction, ether solvents such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide, etc. may be used alone or in combination. , The reaction temperature is from 0 ° C. to the boiling point of the solvent used.

In addition, the aminothiophene derivative represented by Chemical Formula 2 used in the present invention may be reacted with a compound of Chemical Formula 5 (nucleophilic substitution reaction) in the presence of a suitable solvent and a base (nucleophilic substitution reaction). Can be prepared by:

[Formula 5]

Wherein, R ¹ , B, n, Z, Y and A are as defined in Formula 1, and L is a leaving group, a halide group, a mesylate group or a tosylate group.

In this case, the base and the reaction solvent used are the same as those used in the preparation of the aminothiophene derivative of Chemical Formula 1.

On the other hand, among the compounds of the formula (3) used in the reaction, in particular, the compound represented by the formula (3a) when R ¹ is an ester group, as shown in Scheme 1 below, 3-aminothiophene carboxylic acid alkyl ester of the formula (6) Derivatives can be prepared through the amide formation reaction as a starting material, the compound of formula (4) can be prepared in the same manner. At this time, the aminothiophene carboxylic acid alkyl ester derivative of the formula (6) can be used commercially available.

In the scheme, n, B are as defined in the formula (1), L is a leaving group, halide group, mesylate group or tosylate group, D is OH, Br or Cl.

In the amide formation reaction of Scheme 1, when D is a bromide group (Br) or a chloride group (Cl), it may be carried out in the presence of a base, and the base and reaction conditions used here are substituted when preparing the compound of Formula 1 The same as in the reaction, and when D is a hydroxy group, 1,3-dicyclohexylcarbodimide (DCC), 1,3-diisopropylcarbodimide (DIC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), 1,1-carbonyldiimidazole (CDI) can be carried out in the presence of a condensing agent, wherein the reaction solvent is dichloromethane or chloroform, tetrahydrofuran, DMF and the like Can be used. The reaction temperature is from room temperature to the boiling point of the solvent.

Meanwhile, when n is 1 in the 3-aminothiophene derivative of Chemical Formula 1, the compound of Chemical Formula 7 having a double bond as shown in Scheme 2 may be represented by an equivalent or excess of the compound of Chemical Formula 5 in the presence of an appropriate solvent and base 1 It can also be obtained by 4-addition reaction. In addition, the 2-aminothiophene derivative of the formula (2) can be prepared by the same method. At this time, the base and reaction conditions used are the same as those used in the preparation of the compound of Formula 1.

R ¹ , in the above scheme Y, Z, A and B are as defined in the formula (1).

The compound of Formula 7 is prepared by removing the leaving group L by reacting the compound of Formula 3 when n is 1 with an equivalent or excess of base in a conventional manner, or, alternatively, The compound represented by the formula (6) and acryloyl halide may be prepared by the amide formation reaction.

In addition, in the aminothiophene derivative of Formula 1, various other aminothiophene derivatives used in the present invention may be prepared from 3-aminothiophene derivatives (compounds of Formula 1a) in which R ¹ is an ester group, which is represented by the following scheme. 3 is shown.

In the scheme, R ² , Y, Z, A and B are as defined in the formula (1).

As shown in Scheme 3, the carboxylic acid derivative of Formula 1b may be prepared by hydrolyzing the ester group of the aminothiophene derivative of Formula 1a with a base. In this case, the solvent may be used alone or mixed with an alcohol solvent such as methanol or an ether solvent such as tetrahydrofuran, dioxane, etc., and sodium hydroxide and potassium hydroxide may be used as the base. The base amount can be used from 1 to 5 equivalents, and the reaction temperature is from 0 ° C. to the boiling point of the solvent.

In addition, the carboxylic acid derivative of the formula (1b) is 1,3-dicyclohexyl carbodimide (DCC), 1,3-diisopropylcarbodimide (DIC), 1- (3-dimethylaminopropyl) -3 Aminothiophene derivatives of Formula 1c by reacting with a condensing agent such as ethylcarbodiimide (EDC), 1,1-carbonyldiimidazole (CDI), and then reacting with 2-chloroethylamine hydrochloride under an excess of base. Can be converted to At this time, the reaction solvent may be used alone or mixed with an ether solvent such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, DMF, dimethyl sulfoxide and the like, and as a base pyridine, triethyl Organic bases such as amines, N, N-diisopropylethylamine, 1,8-diazabicyclo [5,4,0] unde-7-cene (DBU), or NaOH, Na ₂ CO ₃ , K ₂ CO ₃ , Inorganic bases such as Cs ₂ CO ₃ and the like can be used in equivalent or excessive amounts. The reaction temperature is from 0 ° C. to the boiling point.

In addition, the aminothiophene derivative of Chemical Formula 1c may be prepared by an oxazolidine heterocyclic formation reaction in the presence of a base. In this case, for example, DBU may be used as the base, and tetrahydrofuran, benzene, toluene, or the like may be used as the solvent. The reaction temperature is from room temperature to the boiling point of the solvent.

On the other hand, by reducing the ester group of the aminothiophene derivative of the general formula (1a) through a reduction reaction can be prepared an alcohol derivative of the general formula (1e). In the reduction reaction, the aminothiophene derivative of Formula 1a may be reacted with a sodium borohydride reducing agent in an alcohol solvent such as methanol, or by reacting with a lithium borohydride reducing agent in a tetrahydrofuran solvent to obtain an alcohol derivative. . At this time, the reducing agent may be used in equivalent or excessive amounts, the reaction temperature is from 0 ℃ to the boiling point of the solvent.

On the other hand, the composition containing an aminothiophene derivative or a pharmaceutically acceptable salt thereof according to the present invention shows a strong inhibitory activity against ischemic cell death. Thus, the composition of the present invention is an ischemic disease mediated by ischemic cell death, such as cerebral ischemia, cardiac ischemia, diabetic vascular heart disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, brain trauma, Alzheimer's disease It can be usefully used to prevent or treat diseases, Parkinson's disease, neonatal hypoxia, glaucoma, diabetic neurosis and the like. In addition, such ischemic cell death may be induced by hypoxic conditions.

In addition, the compositions of the present invention can be used for long-term protection by inhibiting ischemic cell death.

A pharmaceutical composition containing an aminothiophene derivative or a pharmaceutically acceptable salt thereof according to the present invention can be orally or parenterally administered at the time of administration, can be used in the form of a general pharmaceutical formulation, and when formulated, It may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like.

Solid preparations for oral administration may be prepared by mixing at least one excipient, for example starch, calcium carbonate, sucrose, lactose or gelatin, with one or more aminothiophene derivatives. . In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.

Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. can be used in addition to commonly used simple diluents such as water and liquid paraffin. have.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent or suspending solvent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. may be used, and the bases of the suppositories may include witepsol and macrogol ( Macrogol), Tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

In addition, the dosage of the pharmaceutical composition comprising the aminothiophene derivative of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and the adult weighs 70 kg. Based on the patient, the active ingredient may generally be administered at 0.1-1000 mg / day, preferably 1-500 mg / day, and may be dividedly administered once to several times a day at regular intervals.

Hereinafter, the present invention will be described in more detail with reference to Examples.

However, the following examples are illustrative of the present invention, and the content of the present invention is not limited by the examples.

In the present invention, the molecular structure of the compounds was confirmed by infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, photoluminescence measurement or elemental analysis of representative compounds and comparison of actual values.

Production Example 1 3- (2-bromo-acetylamino) -thiophene-2-carboxylic acid methyl ester

1.52 g (9.68 mmol) of 3-aminothiophen-2-carboxylic acid methyl ester compound was dissolved in 20 ml of tetrahydrofuran, 1.20 ml (13.55 mmol) of bromoacetylbromide and 2.00 ml (14.52 m) of triethylamine. Mol) was added dropwise, and the reaction mixture was stirred for one day under a nitrogen atmosphere. The solvent was removed by distillation under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 6: 1), to obtain 2.50 g (yield 93%) of the title compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.86 (s, 3H), 4.33 (s, 2H), 7.94 (m, 2H), 10.58 (s, 1H), Mass (m / e) M ⁺ 278 , 215, 157, 125

Preparation Example 2 3- (3-Bromo-propionylamino) -thiophene-2-carboxylic acid methyl ester

0.96 g (6.11 mmol) of 3-aminothiophen-2-carboxylic acid methyl ester compound was dissolved in 10 ml of tetrahydrofuran, and 1.87 g (12.22 mmol) of 3-bromopropionic acid and 1,3-di After adding 1.90 mL (12.22 mmol) of isopropylcarbodiimide dropwise, the reaction mixture was stirred for 24 hours under a nitrogen atmosphere. The solvent was removed by distillation under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 4: 1), to obtain 0.95 g (yield 53%) of the title compound.

¹ H NMR (300 MHz, CDCl 3); δ 3.01 (t, 2H), 3.68 (t, 2H), 3.90 (s, 3H), 7.48 (d, 1H),

8.12 (d, 1 H)

Mass (m / e) M ⁺ 293, 291

Preparation Example 3 3- (2-Bromo-butynylamino) -thiophene-2-carboxylic acid methyl ester

0.50 g (3.18 mmol) of 3-aminothiophen-2-carboxylic acid methyl ester compound was dissolved in 10 ml of tetrahydrofuran, 1.06 g (6.36 mmol) of 4-bromo butyric acid and 1,3-diiso After 0.98 mL (6.36 mmol) of propylcarbodiimide was added dropwise, the reaction mixture was stirred for 24 hours under a nitrogen atmosphere. The solvent was removed by distillation under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 6: 1), to obtain 0.44 g (yield 45%) of the title compound.

¹ H NMR (300 MHz, CDCl 3); δ 2.27 (m, 2H), 2.62 (t, 2H), 3.52 (t, 2H), 3.90 (s, 3H),

7.47 (d, 1 H), 8.11 (d, 1 H), 10.22 (brs, 1 H)

Mass (m / e) M ⁺ 306

Production Example 4 3-Acryloylamino-thiophene-2-carboxylic acid methyl ester

488 mg (1.64 mmol) of the compound obtained in Preparation Example 2 were dissolved in 5 ml of dichloromethane, 0.25 ml (1.80 mmol) of triethylamine was added dropwise, and the reaction mixture was stirred for 24 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and the organic solvent layer was dried over anhydrous sodium sulfate. The resultant was filtered, distilled under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 6: 1) to obtain 0.35 g (yield 100%) of the title compound.

¹ H NMR (300 MHz, CDC3) δ 3.91 (s, 3H), 5.82 (d, 1H), 6.27 (dd, 1H), 6.43 (d, 1H), 7.49 (d, 1H), 8.20 (d, 1H) , 10.38 (brs, 1 H)

Mass (m / e) M ⁺ 211

Production Example 5 3- (2-Bromo-2-phenyl-acetylamino) -thiophene-2-carboxylic acid methyl ester

0.11 g (0.71 mmol) of 3-aminothiophen-2-carboxylic acid methyl ester compound was dissolved in 3 ml of tetrahydrofuran, and 0.30 g (1.41 mmol) of bromo phenyl acetic acid and 1,3-diisopropylka After 0.22 mL (1.41 mmol) of bodyimide was added dropwise, the reaction mixture was stirred for 2 hours under a nitrogen atmosphere. The solvent was removed by distillation under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 4: 1), to obtain 0.23 g (95% yield) of the title compound.

¹ H NMR (300 MHz, CDC3); δ 3.89 (s, 3H), 5.54 (s, 1H), 7.25 to 7.46 (m, 4H), 7.54 to 7.57 (m, 2H), 8.08 (d, 1H)

Mass (m / e) M ⁺ 355, 274, 184, 90

Production Example 6 2- (2-Bromo-acetylamino) -thiophene-3-carboxylic acid methyl ester

0.10 g (0.64 mmol) of 2-aminothiophen-3-carboxylic acid methyl ester compound was dissolved in 4 ml of tetrahydrofuran, 0.083 ml (0.95 mmol) of bromoacetylbromide and 0.13 ml (0.95 m) of triethylamine. Mol) was added dropwise, and the reaction mixture was stirred for 2 hours under a nitrogen atmosphere. The solvent was removed by distillation under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 5: 1), to obtain 0.15 g (yield 89%) of the title compound.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 3.95 (s, 3H), 4.11 (s, 2H), 6.80 (d, 1H), 7.24 (d, 1H), 11.80 (brs, 1H), Mass (m / e) M ⁺ 277, 157, 125, 97

Preparation Example 7 2- (3-Bromo-propionylamino) -thiophene-3-carboxylic acid methyl ester

3.00 g (19.1 mmol) of 2-aminothiophen-3-carboxylic acid methyl ester compound were dissolved in 20 ml of tetrahydrofuran, 5.84 g (38.2 mmol) of 3-bromopropionic acid and 1,3-di 5.92 mL (38.2 mmol) of isopropylcarbodiimide was added dropwise, and the reaction mixture was stirred for 24 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 6: 1), to obtain 4.80 g (yield 86%) of the title compound.

¹ H NMR (300 MHz, CDCl 3); δ 3.07 (t, 2H), 3.70 (t, 2H), 3.90 (s, 3H), 6.76 (d, 1H),

7.20 (d, 1 H), 11.08 (brs, 1 H)

Mass (m / e) M ⁺ 293, 291

Preparation Example 8 2-Acryloylamino-thiophene-3-carboxylic acid methyl ester

500 mg (1.71 mmol) of the compound obtained in Preparation Example 7 was dissolved in 5 ml of dichloromethane, 0.36 ml (2.57 mmol) of triethylamine was added dropwise, and the reaction mixture was stirred for 2 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and the organic solvent layer was dried over anhydrous sodium sulfate. The resultant was filtered, distilled under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 6: 1) to obtain 0.33 g (yield 91%) of the title compound.

¹ H NMR (300 MHz, CDCl 3); δ 3.90 (s, 3H), 5.88 (dd, 1H), 6.31 (dd, 1H), 6.49 (dd, 1H),

6.77 (d, 1 H), 7.21 (d, 1 H), 11.15 (brs, 1 H)

Mass (m / e) M ⁺ 211

Production Example 9 2- (2-Bromo-2-phenyl-acetylamino) -thiophene-3-carboxylic acid methyl ester

0.35 g (2.23 mmol) of 2-aminothiophen-3-carboxylic acid methyl ester compound was dissolved in 15 ml of tetrahydrofuran, 0.96 g (4.46 mmol) of bromo phenyl acetic acid, and 1,3-diisopropylka. After 0.70 mL (4.46 mmol) of bodyimide was added dropwise, the reaction mixture was stirred under nitrogen atmosphere for one day. The solvent was removed by distillation under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 4: 1), to obtain 0.75 g (yield 95%) of the title compound.

Example 1 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester

1.0 g (3.60 mmol) of the compound obtained in Preparation Example 1 was dissolved in 15 ml of tetrahydrofuran, and 0.82 g (4.32 mmol) of 4-bromobenzenethiol and 0.65 ml (4.68 mmol) of triethylamine were added dropwise. The reaction mixture was stirred under nitrogen atmosphere for 1 hour. The solvent was removed by distillation under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 6: 1), to obtain 1.27 g (yield 91%) of the title compound.

¹ H NMR (300 MHz, CDCl 3); δ 3.77 (s, 2H), 3.90 (s, 3H), 7.28 (t, 2H), 7.40 (d, 2H), 7.45 (d, 1H), 8.09 (d, 1H), 11.16 (br, NH)

Mass (m / e) M ⁺ 386

Example 2 3- (2-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester

100 mg (0.36 mmol) of the compound obtained in Preparation Example 1 and 0.044 mL (0.44 mmol) of benzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give 61 mg (yield 55%) of the title compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.80 (s, 2H), 3.90 (s, 3H), 7.19-7.31 (m, 3H), 7.41-7.47 (m, 3H), 8.11 (d, 1H) , 11.25 (s, 1H)

Mass (m / e) M ⁺ 307 , 157, 123, 77

Example 3 3- [2- (4-nitro-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester

100 mg (0.36 mmol) of the compound obtained in Preparation Example 1 and 83 mg (0.43 mmol) of 4-nitrobenzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane). : Ethyl acetate = 10: 1) gave 95 mg (yield 75%) of the title compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.87 (s, 2H), 3.91 (s, 3H), 7.44-7.48 (m, 3H), 8.07-8.17 (m, 3H), 11.11 (s, 1H)

Mass (m / e) M ⁺ 352 , 157, 138, 125

Example 4 3- [2- (4-Amino-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester

0.19 g (0.55 mmol) of the compound obtained in Example 3 was dissolved in 10 ml of methanol, and 96 mg (0.28 mmol) of Raney-nickel was added at room temperature, followed by reaction at room temperature for 3 hours under hydrogen pressure. After the reaction was terminated, the mixture was filtered through celite, and the reaction solution was filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography (Hex: EtOAc = 2: 1) to obtain 0.15 g of the title compound (yield 88%). Got it.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 3.72 (s, 2H), 3.87 (s, 3H), 5.30 (s, 2H), 6.47 (d, 2H, J = 8.6 Hz), 7.14 (d, 2H , J = 8.6 μs), 7.90 (d, 1H, J = 5.4 μs), 7.95 (d, 1H, J = 5.4 μs), 10.90 (s, 1H)

Mass (m / e) M ⁺ 322 , 165, 124, 94, 65

Example 5 3- [2- (4-Methyl-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester

100 mg (0.36 mmol) of the compound obtained in Preparation Example 1 and 54 mg (0.43 mmol) of 4-methyl benzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane). : Ethyl acetate = 10: 1) gave 95 mg (yield 82%) of the title compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.24 (s, 3H), 3.99 (s, 3H), 4.10 (s, 2H), 7.14 (d, 2H, J = 8.1 Hz), 7.30 (d, 2H , J = 8.1 μs), 7.89 (d, 1H, J = 5.5 μs), 7.94 (d, 1H, J = 8.1 μs), 10.88 (s, 1H)

Mass (m / e) M ⁺ 321 , 157, 137, 66

Example 6 3- [2- (pyridin-2-ylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester

100 mg (0.36 mmol) of the compound obtained in Preparation Example 1 and 48 mg (0.44 mmol) of 2-mercetopyridine were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: Ethyl acetate = 4: 1) afforded 109 mg (98% yield) of the title compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.80 (s, 3H), 4.09 (s, 2H), 7.16 (q, 1H, J = 4.8 GHz), 7.43 (d, 1H, J = 8.1 GHz), 7.69 (t, 1H, J = 8.1 μs), 7.88 (d, 1H, J = 5.41 μs), 7.98 (d, 1H, J = 5.4 μs), 8.46 (d, 1H, J = 4.8 μs), 10.85 ( s, 1 H)

Mass (m / e) M ⁺ 308

Example 7 3- [2- (4-methoxy-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester

1.00 g (3.60 mmol) of the compound obtained in Preparation Example 1 and 0.53 ml (4.31 mmol) of 4-methoxybenzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n- Hexane: ethyl acetate = 4: 1) afforded 0.99 g (yield 81%) of the title compound.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.69 (s, 3H), 3.87 (s, 3H), 3.90 (s, 2H), 6.92 (d, 2H, J = 9.0 Hz), 7.41 (d, 2H , J = 9.0 μs), 7.90 (d, 1H, J = 6.0 μs), 7.94 (d, 1H, J = 6.0 μs), 10.89 (s, 1H)

Mass (m / e) M ⁺ 337 , 180, 152, 139

Example 8 3- [2- (2-methoxy-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester

0.50 g (1.80 mmol) of the compound obtained in Preparation Example 1 and 0.26 ml (2.16 mmol) of 2-methoxybenzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n- Hexane: ethyl acetate = 4: 1) afforded 0.40 g (67% yield) of the title compound.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 3.82 (s, 3H), 3.83 (s, 3H), 3.95 (s, 2H), 6.91 (t, 1H), 7.01 (d, 1H), 7.19-7.27 (m, 2H), 7.89 (d, 1H, J = 5.4 μs), 7.95 (d, 1H, J = 5.4 μs), 10.80 (brs, 1H)

Mass (m / e) M ⁺ 337, 85

Example 9 3- [2- (3-methoxy-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester

0.5 g (1.80 mmol) of the compound obtained in Preparation Example 1 were used and reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title. 0.41 g (yield 68%) of the compound was obtained.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 3.72 (s, 3H), 3.84 (s, 3H), 4.07 (s, 2H), 6.77 (d, 1H), 6.94-6.96 (m, 2H), 7.24 (t, 1H), 7.90 (d, 1H, J = 5.4 μs), 7.96 (d, 1H, J = 5.4 μs), 10.85 (brs, 1H)

Mass (m / e) M ⁺ 338 , 85

Example 10 3- [2- (4-hydroxy-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester

0.2 g (0.72 mmol) of the compound obtained in Preparation Example 1 were used and reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain the title. 0.18 g (yield 80%) of was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 3.83 (s, 2H), 3.87 (s, 3H), 6.72 (d, 2H), 7.29 (d, 2H), 7.89 (d, 1H), 7.94 (d, 1H), 9.70 (s, 1H), 10.87 (s, 1 H)

Mass (m / e) M ⁺ 324

Example 11 3- [2- (pyridin-4-ylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester

Using 0.2 g (0.72 mmol) of the compound obtained in Preparation Example 1, the reaction was carried out in the same manner as in Example 1, and then separated by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title. 0.18 g (yield 83%) of was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 3.82 (s, 3H), 4.25 (s, 2H), 7.33 (d, 2H), 7.92 (d, 2H), 8.39 (d, 2H), 10.69 (s, 1H)

Mass (m / e) M ⁺ 309

Example 12 3- [2- (1-oxy-pyridin-4-ylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester

120 mg (0.38 mmol) of the compound obtained in Example 11 were dissolved in 8 ml of dichloromethane, and 100 mg (0.582 mmol) of 3-chloroper benzoic acid were added, and the reaction mixture was stirred for 3 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography (methanol: ethyl acetate = 1:19) to give 84 mg (yield 100%) of the title compound.

¹ H NMR (300 MHz, DMSO-d ₆ ); δ 3.85 (s, 3H), 4.17 (d, 1H), 4.48 (d, 1H), 7.73 (m, 2H), 7.82 (m, 3H), 8.77 (d, 1H), 10.23 (br, 1H)

Mass (m / e) M ⁺ 324

Example 13 3- [3- (4-Bromo-phenylsulfanyl) -propionylamino] -thiophene-2-carboxylic acid methyl

63 mg (0.30 mmol) of the compound obtained in Preparation Example 4 were used, and the reaction was carried out in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain the title. 97 mg (yield 80%) of were obtained.

¹ H NMR (300 MHz, CDCl3): δ 2.70 (t, 2H), 3.25 (t, 2H), 3.90 (s, 3H), 7.24 (d, 2H), 7.42 (d, 2H), 7.46 (d, 1H ), 8.08 (d, 1H), 10.18 (br, NH)

Mass (m / e) M ⁺ 400

Example 14 3- (3-phenylsulfanyl-propionylamino) -thiophene-2-carboxylic acid methyl ester

95 mg (0.45 mmol) of the compound obtained in Preparation Example 4 were used and reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain the title. Compound 135 mg (yield 93%) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 2.72 (t, 2H), 3.27 (t, 2H), 3.89 (s, 3H), 7.18 (m, 3H), 7.39 (d, 2H), 7.46 (d, 1H ), 8.10 (d, 1 H), 10.18 (br, 1 H)

Mass (m / e) M ⁺ 321

Example 15 3- [3- (pyridin-2-ylsulfanyl) -propionylamino] -thiophene-2-carboxylic acid methyl ester

100 mg (0.47 mmol) of the compound obtained in Preparation Example 4 were used, and the reaction was carried out in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain the title. Compound 110 mg (72% yield) was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 2.88 (t, 2H), 3.52 (t, 2H), 3.88 (s, 3H), 6.96 (m, 1H), 7.16 (d, 1H), 7.44 (m, 2H ), 8.15 (d, 1H), 8.46 (d, 1H), 10.20 (br, NH)

Mass (m / e) M ⁺ 322

Example 16 3- [4- (4-Bromo-phenylsulfanyl) -butylylamino] -thiophene-2-carboxylic acid methyl ester

Using 100 mg (0.33 mmol) of the compound obtained in Preparation Example 3, the reaction was carried out in the same manner as in Example 1, and then separated by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain the title. 109 mg (yield 80%) of were obtained.

¹ H NMR (300 MHz, CDCl 3): δ 2.03 (m, 2H), 2.57 (t, 2H), 2.98 (t, 2H), 3.89 (s, 3H), 7.20 (dd, 2H), 7.37 (d, 2H ), 7.46 (d, 1H), 8.10 (d, 1H), 10.16 (br, NH)

Mass (m / e) M ⁺ 415, 413

Example 17 3- [2- (4-Bromo-phenylsulfanyl) -2-phenyl-acetylamino] -thiophene-2-carboxylic acid methyl ester

234 mg (0.66 mmol) of the compound obtained in Preparation Example 5 were used, and the reaction was carried out in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain the title. 230 mg (yield 74%) of compound were obtained.

¹ H NMR (300 MHz, CDCl 3): δ 3.90 (s, 3H), 5.02 (s, 1H), 7.29-7.56 (m, 10H), 8.06 (d, J = 5.5 Hz, 1H)

Mass (m / e) M ⁺ 462

Example 18 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid

0.50 g (1.30 mmol) of the compound obtained in Example 1 was dissolved in 6 mL of tetrahydrofuran, and 1.30 mL (2.60 mmol) of 2 N sodium hydroxide solution was added dropwise, and the reaction mixture was heated and stirred for 2 hours under a nitrogen atmosphere. . After acidification with 1 N hydrochloric acid solution, the mixture was extracted with ethyl acetate and brine, the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was dissolved in ethyl acetate and filtered to give 0.39 g (yield 80%) of the title compound.

¹ H NMR (CD3OD, 300 MHz): δ 3.69 (s, 2H), 7.12 (m, 4H), 7.26 (d, 1H), 7.49 (d, 1H)

Mass (m / e) M + 372

Example 19 3- [2- (4-Bromo-phenylsulfanyl) -2-phenyl-acetylamino] -thiophene-2-carboxylic acid

Using 1 g (2.16 mmol) of the compound obtained in Example 17, the reaction was carried out in the same manner as in Example 18, and then dissolved in dichloromethane and filtered to obtain 0.77 g (yield 80%) of the title compound.

¹ H NMR (300 MHz, CDCl 3): δ 5.03 (s, 1H), 7.23-7.59 (m, 10H), 8.04 (d, J = 5.4 Hz, 1H), 11.36 (brs, 1H)

Mass (m / e) M + 448

Example 20 N- (2-hydroxymethyl-thiophen-3-yl) -2-phenylsulfanyl-acetamide

After dissolving 0.31 g (1.01 mmol) of the compound obtained in Example 2 in 8 ml of tetrahydrofuran and adding 95 mg (2.52 mmol) of lithium aluminum hydride dropwise at 0 ° C., the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. Was stirred. After the reaction was completed, the reaction solution was acidified with 1N HCl, extracted with ethyl acetate and brine, and the organic solvent layer was dried over anhydrous sodium sulfate, and purified by column chromatography (hexane: ethyl acetate = 2: 1). 0.11 g (40% yield) of the title compound were obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.08 (s, 2H), 4.71 (d, 2H), 5.61 (t, 1H), 7.28 (d, 1H), 7.37-7.46 (m, .1H), 7.53-7.65 (m, 5H)

Mass (m / e) M ⁺ 279 , 170, 152, 128, 77

Example 21 2- (4-Bromo-phenylsulfanyl) -N- (2-hydroxymethyl-thiophen-3-yl) -acetamide

0.50 g (1.30 mmol) of the compound obtained in Example 1 were used and reacted in the same manner as in Example 20, followed by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title. 0.28 g (yield 54%) of the compound was obtained.

¹ H NMR (300 MHz, CDCl 3): δ 2.75 (br, OH), 3.78 (s, 2H), 4.56 (s, 2H), 7.19 (m, 4H), 7.44 (dd, 2H), 8.91 (br, NH )

Mass (m / e) M ⁺ 359, 357

Example 22 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid amide

Dissolve 300 mg (0.81 mmol) of the compound obtained in Example 18 in 7 ml of tetrahydrofuran, 262 mg (1.21 mmol) of di (2-pyridyl) carbonate and 10 mg (0.08 mmol) of 0.1 equivalent of dimethylaminopyridine. After the dropwise addition, the reaction mixture was stirred for 3 hours under a nitrogen atmosphere, and then 1 ml of excess ammonia water was added, and the reaction mixture was stirred for 24 hours under a nitrogen atmosphere. The solvent was removed by distillation under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 1: 1), to obtain 168 mg (yield 56%) of the title compound.

¹ H NMR (300 MHz, CDCl 3): δ 3.76 (s, 2H), 5.54 (br, 2H), 7.26 (m, 5H), 8.15 (d, 1H), 11.79 (br, NH)

Mass (m / e) M ⁺ 371

Example 23 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid dimethylamide

300 mg (0.81 mmol) of the compound obtained in Example 18 and 1 ml of dimethylamine were reacted in the same manner as in Example 22, followed by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1). Separation was carried out to give 162 mg (50% yield) of the title compound.

¹ H NMR (300 MHz, CDCl 3): δ 3.23 (s, 6H), 3.74 (s, 2H), 7.26 (m, 3H), 7.38 (d, 2H), 8.06 (d, 1H), 11.55 (br, NH )

Mass (m / e) M ⁺ 399

Example 24 2- (4-Bromo-phenylsulfanyl) -N- [2- (4,5-dihydro-oxazol-2-yl) -thiophen-3-yl] -acetamide

Step 1) Dissolve 160 mg (0.43 mmol) of the compound obtained in Example 18 in 4 ml of tetrahydrofuran, and 139 mg (0.65 mmol) of di (2-pyridyl) carbonate and 5 mg (0.043 equivalent) of dimethylaminopyridine. mmol) was added dropwise, the reaction mixture was stirred for 1 hour under a nitrogen atmosphere, and then 0.12 ml (0.86 mmol) of triethyl amine and 100 mg (0.86 mmol) of 2-chloroethylamine hydrochloride were added to the reaction mixture. Stir for 24 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 2: 1), to obtain 65 mg (yield 35%) of the intermediate amide compound.

¹ H NMR (300 MHz, CDCl 3): δ = 3.69 (m, 6H), 6.10 (br, 1H), 7.29 (m, 5H), 11.73 (br, NH)

Mass (m / e) M + 434

Step 2) 60 mg (0.14 mmol) of the intermediate amide compound obtained in Step 1 were dissolved in 2 ml of tetrahydrofuran and 0.031 ml (0.21 mmol) of DBU was added dropwise, and the reaction mixture was heated to reflux for 1 hour under a nitrogen atmosphere. . The solvent was removed by distillation under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 4: 1), to obtain 50 mg (90%) of the title compound.

¹ H NMR (300 MHz, CDCl 3): δ 3.77 (s, 2H), 4.06 (t, 2H), 4.39 (t, 2H), 7.26 (m, 2H), 7.36 (m, 3H), 8.11 (d, 1H), 11.59 (br, NH)

Mass (m / e) M + 398, 396

Example 25 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid (2-hydroxy-ethyl) -amide

230 mg (0.62 mmol) of the compound obtained in Example 18 and 1 ml of ethanol amine were reacted in the same manner as in Example 22, followed by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1). To obtain 103 mg (40% yield) of the title compound.

¹ H NMR (300 MHz, CDCl 3): δ 3.46 (m, 4H), 4.01 (s, 2H), 4.73 (t, OH), 7.34 (d, 2H), 7.49 (d, 2H), 7.69 (d, 1H), 8.21 (br, NH)

Mass (m / e) M + 415, 355

Example 26 3- [2- (4-Bromo-phenoxy) -acetylamino] -thiophene-2-carboxylic acid methyl ester

200 mg (0.72 mmol) of the compound obtained in Preparation Example 1 and 163 mg (0.94 mmol) of 4-bromophenol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: Ethyl acetate = 6: 1) afforded 224 mg (84%) of the title compound.

¹ H NMR (300 MHz, CDCl 3): δ 3.91 (s, 3H), 4.63 (s, 2H), 6.94 (d, 2H), 7.42 (d, 2H), 7.46 (dd, 1H), 8.15 (d, 1H), 11.22 (br, NH)

Mass (m / e) M + 370

Example 27 3- [2- (4-Nitro-phenoxy) -acetylamino] -thiophene-2-carboxylic acid methyl ester

200 mg (0.72 mmol) of the compound obtained in Preparation Example 1 and 131 mg (0.94 mmol) of 4-nitrophenol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl Acetate = 3: 1) afforded 174 mg (72% yield) of the title compound.

¹ H NMR (300 MHz, CDCl 3): δ 3.94 (s, 2H), 4.77 (s, 2H), 7.16 (d, 2H), 7.52 (d, 1H), 8.16 (d, 1H), 8.29 (d, 2H)

Mass (m / e) M + 370

Example 28 3- [2- (4-Amino-phenoxy) -acetylamino] -thiophene-2-carboxylic acid methyl ester

80 mg (0.24 mmol) of the compound obtained in Example 27 were reacted in the same manner as in Example 3, followed by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound. 45 mg (yield 6%) of compound were obtained.

¹ H NMR (300 MHz, CDCl 3): δ 3.52 (br, NH 2), 3.28 (s, 3H), 4.58 (s, 2H), 6.66 (d, 2H), 6.89 (d, 2H), 7.48 (d, 1H), 8.17 (d, 1H), 11.20 (br, NH)

Mass (m / e) M + 306

Example 29 2- (4-Bromo-phenoxy) -N- (2-hydroxymethyl-thiophen-3-yl) -acetamide

After reacting in the same manner as in Example 20 using 111 mg (0.30 mmol) of the compound obtained in Example 26, the residue was separated by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title thereof. 68 mg (66% yield) of compound were obtained.

¹ H NMR (300 MHz, CDCl 3): δ 3.01 (t, OH), 4.60 (s, 2H), 4.69 (d, 2H), 6.85 (dd, 2H), 7.20 (d, 1H), 7.35 (d, 1H), 7.43 (dd, 2H), 8.83 (br, NH)

Mass (m / e) M + 342

Example 30 2- (2-phenylsulfanyl-acetylamino) -thiophene-3-carboxylic acid methyl ester

100 mg (0.36 mmol) of the compound obtained in Preparation Example 6 and 0.066 mL (0.65 mmol) of benzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give 141 mg (yield 85%) of the title compound.

¹ H NMR (300 MHz, DMSO-d6) δ 3.66 (s, 3H), 3.99 (s, 2H), 6.85 (d, 1H), 6.99 (d, 1H), 7.05 (d, 1H), 7.15 (t, 2H_), 7.21 (d, 2H)

Mass (m / e) M + 307, 157, 123, 77

Example 31 2- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester

300 mg (1.08 mmol) of the compound obtained in Preparation Example 6 and 0.40 g (2.16 mmol) of 4-bromo benzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n- Hexane: ethyl acetate = 4: 1) afforded 610 mg (89% yield) of the title compound.

¹ H NMR (300 MHz, DMSO-d6) δ 3.84 (s, 3H), 4.20 (s, 2H), 7.04 (d, 1H, J = 6.0 Hz), 7.17 (d, 1H, J = 6.0 Hz), 7.35 (d, 2H, J = 8.7 Hz), 7.52 (d, 2H, J = 8.7 Hz), 11.51 (brs, 1H), Mass (m / e) M + 386, 169, 85

Example 32 2- [2- (2-Methoxy-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester

500 mg (1.80 mmol) of the compound obtained in Preparation Example 6 and 0.26 ml (2.16 mmol) of 2-methoxy benzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n- Hexane: ethyl acetate = 4: 1) to give 510 mg (yield 86%) of the title compound.

¹ H NMR (300 MHz, DMSO-d6) δ 3.79 (s, 3H), 3.81 (s, 3H), 4.02 (s, 2H), 6.89 (t, 1H), 6.97-7.01 (m, 2H), 7.13- 7.25 (m, 3H), 11.51 (brs, 1H)

Mass (m / e) M + 337

Example 33 2- [2- (3-methoxy-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester

500 mg (1.80 mmol) of the compound obtained in Preparation Example 6 and 0.26 ml (2.16 mmol) of 3-methoxy benzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n- Hexane: ethyl acetate = 4: 1) afforded 560 mg (93% yield) of the title compound.

¹ H NMR (300 MHz, DMSO-d6) δ 3.60 (s, 3H), 3.72 (s, 3H), 4.02 (s, 2H), 6.66 (d, 1H, J = 8.4 Hz), 6.83-6.85 (m, 2H), 6.91 (d, 1H, J = 8.4 μs), 7.05-7.15 (m, 3H), 11.46 (brs, 1H) Mass (m / e) M + 337

Example 34 2- [2- (4-Methyl-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester

500 mg (1.80 mmol) of the compound obtained in Preparation Example 6 and 0.26 ml (2.16 mmol) of 4-methyl benzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane). : Ethyl acetate = 4: 1) afforded 510 mg (yield 89%) of the title compound.

¹ H NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 3.70 (s, 3H), 3.95 (s, 2H), 6.88 (d, 1H, J = 5.7 Hz), 6.98-7.04 (m, 3H), 7.16 (d, 2H, J = 8.1 Hz), 11.45 (brs, 1H)

Mass (m / e) M + 321

Example 35 2- [2- (4-methoxy-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester

500 mg (1.80 mmol) of the compound obtained in Preparation Example 6 and 0.26 ml (2.16 mmol) of 4-methoxy benzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n- Hexane: ethyl acetate = 4: 1) afforded 590 mg (98% yield) of the title compound.

¹ H NMR (300 MHz, DMSO-d6) δ 3.71 (s, 3H), 3.86 (s, 3H), 4.01 (s, 2H), 6.90 (d, 1H, J = 8.7 Hz), 7.03 (d, 1H, J = 5.7 Hz), 7.18 (d, 1H, J = 5.7 Hz), 7.40 (d, 2H, J = 8.7 Hz), 11.61 (brs, 1H)

Mass (m / e) M + 337

Example 36 2- [2- (pyridin-2-yl-sulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester

300 mg (1.08 mmol) of the compound obtained in Preparation Example 6 and 0.14 g (1.29 mmol) of 2-merctopyridine were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: Ethyl acetate = 4: 1) afforded 270 mg (83% yield) of the title compound.

¹ H NMR (300 MHz, DMSO-d6) δ 3.81 (s, 3H), 4.18 (s, 2H), 7.02 (d, 1H), 7.15-7.18 (m, 2H), 7.46 (d, 1H), 7.70 ( t, 1H), 8.49-8.51 (m, 1H), 11.65 (brs, 1H)

Mass (m / e) M + 308

Example 37 2- [2- (4-hydroxy-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester

100 mg (0.34 mmol) of the compound obtained in Preparation Example 6 and 54 mg (0.43 mmol) of 4-mercetophenol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: Ethyl acetate = 2: 1) afforded 110 mg (90% yield) of the title compound.

¹ H NMR (300 MHz, DMSO-d6) δ 3.86 (s, 3H), 3.94 (s, 2H), 6.72 (d, 2H), 7.03 (d, 1H), 7.18 (d, 1H), 7.28 (d, 2H), 9.67 (s, 1H), 11.59 (s, 1H)

Mass (m / e) M + 323

Example 38 2- [2- (pyridin-4-ylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester

After 200 mg (0.72 mmol) of the compound obtained in Preparation Example 6 and 95 mg (0.89 mmol) of 4-mercetopyridine were reacted in the same manner as in Example 1, silica gel column chromatography (n-hexane: Ethyl acetate = 4: 1) afforded 210 mg (95% yield) of the title compound.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 3.83 (s, 3H), 4.37 (s, 2H), 7.06 (d, 1H), 7.18 (d, 1H), 7.34 (d, 2H), 8.40 (d , 2H), 11.44 (s, 1H)

Mass (m / e) M ⁺ 309

Example 39 2- [3- (4-Bromo-phenylsulfanyl) -propionylamino] -thiophene-3-carboxylic acid methyl ester

100 mg (0.47 mmol) of the compound obtained in Preparation Example 8 and 0.12 g (0.61 mmol) of 4-bromo benzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n- Hexane: ethyl acetate = 4: 1) afforded 170 mg (91%) of the title compound.

¹ H NMR (300 MHz, CDCl 3): δ 2.76 (t, 2H), 3.27 (t, 2H), 3.89 (s, 3H), 6.74 (d, 1H), 7.18 (d, 1H), 7.24 (d, 2H), 7.39 (d, 2H), 10.99 (br, NH)

Mass (m / e) M ⁺ 400

Example 40 2- (3-phenylsulfanyl-propionylamino] -thiophene-3-carboxylic acid methyl ester

100 mg (0.47 mmol) of the compound obtained in Preparation Example 8 and 0.063 mL (0.61 mmol) of benzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl Acetate = 6: 1) afforded 140 mg (94% yield) of the title compound.

¹ H NMR (300 MHz, CDCl 3): δ 2.77 (t, 2H), 3.28 (t, 2H), 3.88 (s, 3H), 6.73 (d, 1H), 7.18 (m, 4H), 7.39 (d, 2H), 10.98 (br, NH)

Mass (m / e) M + 321

Example 41 2- [3- (pyridin-2-ylsulfanyl) -propionylamino] -thiophene-3-carboxylic acid methyl ester

100 mg (0.47 mmol) of the compound obtained in Preparation Example 8 and 68 mg (0.61 mmol) of 2-mercetopyridine were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: Ethyl acetate = 6: 1) to give 121 mg (yield 80%) of the title compound.

¹ H NMR (300 MHz, CDCl 3): δ 2.95 (t, 2H), 3.53 (t, 2H), 3.87 (s, 3H), 6.73 (d, 1H), 6.97 (m, 1H), 7.16 (m, 2H), 7.44 (m, 1H), 8.46 (d, 1H), 11.02 (br, NH)

Mass (m / e) M + 322

Example 42 2- [2- (4-Bromo-phenylsulfanyl) -2-phenyl-acetylamino] -thiophene-3-carboxylic acid methyl ester

1.20 g (3.48 mmol) of the compound obtained in Preparation Example 9 were used and reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1) to obtain the title. 916 mg (57% yield) of the compound were obtained.

¹ H NMR (300 MHz, DMSO): δ = 3.84 (s, 3H), 5.95 (s, 1H), 7.08 (d, 1H), 7.17 (d, 1H), 7.34-7.42 (m, 5H), 7.51 -7.54 (m, 4H), 11.55 (br, NH)

Mass (m / e) M + 462

Example 43 2- [2- (4-Bromo-phenylsulfanyl) -2-phenyl-acetylamino] -thiophene-3-carboxylic acid

Using 160 mg (0.35 mmol) of the compound obtained in Example 42, the reaction was carried out in the same manner as in Example 19, and then separated by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title 121 mg (yield 77%) of compound were obtained.

¹ H NMR (300 MHz, DMSO): δ 3.85 (s, 1H), 7.10 (d, 1H), 7.23-7.52 (m, 10H)

Mass (m / e) M + 448

The aminothiophene derivatives prepared as in the above examples were subjected to the following experiments and evaluated for various pharmacological effects.

Experimental Example 1 Inhibitory Effect on Ischemic Cell Death

In order to measure the ischemic cell death inhibitory effect of aminothiophene derivatives at the cellular stage, the following experiment was performed.

Cardiomyocyte line H9c2 cells (ATCC, CRL-1446) were incubated in DMEM (Dulbecco's modified Eagle's medium) supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin (100 × solution). Diameter such that 35 ㎜ cell number 1 × 10 ⁴ in the dish, and the cells were incubated 48 hours at 37 ℃, CO ₂ incubator. Only DMSO (0.1%) was treated (control), or the solution of the derivatives (10 μM) of Examples 1 to 50 in DMSO was dispensed and washed once with PBS after 30 minutes, followed by chemical hypoxia. DMSO (106 mmol NaCl, 4.4 mmol KCl, 1 mmol mgCl ₂ , 38 mmol NaHCO ₃ , 2.5 mmol CaCl ₂ , 20 mmol 2-deoxy glucose, 1 mmol NaCN)]. Control) or a solution in which 10 μM of the derivative was dissolved in DMSO for 1 to 2 hours while measuring the degree of cell damage under a microscope, and washed twice with 1 ml of PBS at the time of titration, followed by 1 ml of 3.7 Cells were fixed by treatment with% formaldehyde. It was washed again with 1 ml of PBS and stained with DAPI, and then washed 3 times with 1 ml of PBS. Cell death was observed by fluorescence microscopy and the observed cell death was converted into percent. Meanwhile, in Comparative Examples, a compound represented by the following Chemical Formula 8 (KR-31378, Korea Research Institute of Chemical Technology), which is known to have an ability to inhibit ischemic cell death, as a comparative substance (Lee, MH et al ., Res. Commun.Mol.Pathol.Pharmacol . 110: 361-370, 2001; Hong , KW et a l, J. Pharmacol Exp Ther 301:.... 210-216, see 2002), the processing and the degree of cell death (%) in the same manner as in the above derivative It was measured, and the results are shown in Table 2 and FIG. In the results of Table 2 and FIG. 1 below, "control" represents a group treated with DMSO only, and "cell" represents a group not treated with DMSO.

As can be seen in Table 2 and Figure 1, the aminothiophene derivatives used in the present invention showed a strong inhibitory effect on ischemic cell death.

Experimental Example 2 Inhibitory Effect of Aminothiophene Derivatives on Cerebral Ischemia

In order to measure the brain ischemia inhibitory effect of the aminothiophene derivative in an animal model, the following experiment was performed.

200-250 g of adult male Sprague-Dawley rats were anesthetized with 75 mg / kg of ketamine and 5 mg / kg of rumpun. Nine animals each were assigned to the compound administration group. The midline of the neck was dissected to separate the external carotid artery (ECA) and the internal carotid artery (ICA) located outside the two cranial canals. Next, a middle cerebral artery (MCA) was ligated by pushing a 0.37 mm diameter nylon thread about 20-22 mm from the whole carotid artery (CCA) toward the internal carotid artery (ICA). An interruption of blood supply through vascular occlusion of the middle cerebral artery was maintained for 2 hours to induce stroke due to ischemia. The body temperature of the rats was kept constant at 37.8 ° C throughout the experiment. After 6 hours of ischemia, 30 mg / kg of the compound of Example 1 was intraperitoneally administered. After 28 days of stroke induction, images of the stroke model were obtained using a 3.0-T, 65-cm aperture superconductung MRI apparatus manufactured by the present inventors. Photographing was performed using a fast spin-echo (FSE) method. The imaging parameters were repetition time (TR) 4000 msec and echo time 96 msec, and 15 sections of 2 mm thickness were used. The field of view (FOV) was 60 mm and the resolution was 128 × 128. Three duplicates were taken, and the volume of the infarct was measured with Osiris (Osiris ver. 4.02). The results are shown in Table 3 and FIG. 2. In the results of Table 3 and FIG. 2, 'control' represents a group treated with DMSO only.

As can be seen in Table 3 and Figure 2, the aminothiophene derivative (Example 1) used in the present invention showed a strong inhibitory effect on cerebral ischemic cell death in the brain disorder model of transient cerebral ischemia in rats.

In addition, the experiment was performed under the same conditions as above except that the compound of Example 2 was used instead of the compound of Example 1 and 5 and 3 mice were assigned to the control group and the compound-administered group of Example 2, respectively. It is shown in Table 4 and FIG. In the results of Table 4 and FIG. 3, the 'control' represents a group treated with DMSO only.

As shown in Table 4 and Figure 3, the aminothiophene derivative (Example 2) used in the present invention showed an inhibitory effect on cerebral ischemic cell death in the brain disorder model of transient cerebral ischemia in rats.

A method for preparing a formulation containing an aminothiophene derivative according to the present invention as an active ingredient is illustrated below, but the present invention is not necessarily limited thereto.

Preparation Example 1 Tablet (Direct Pressurization)

After sifting 5.0 mg of the active aminoaminophene derivative, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were prepared by mixing with pressure and purification.

Preparation Example 2 Tablet (Wet Assembly)

5.0 mg of an aminothiophene derivative as an active ingredient was sieved, followed by mixing 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of Polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved, mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate, and prepared by pressurized purification.

Preparation Example 3 Powder and Capsule

After sifting 5.0 mg of the active aminoaminophene derivative, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.

<Example 4> Injection

Injectables were prepared by mixing 100 mg of the aminothiophene derivative, 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

Since the aminothiophene derivative used in the present invention can significantly reduce ischemic cell death, the composition containing it as an active ingredient is cerebral ischemia, cardiac ischemia, diabetic vascular heart disease mediated by ischemic cell death, heart failure, cardiomyopathy, retina It can be usefully used as a prophylactic or therapeutic agent for the prevention and treatment of ischemic diseases such as ischemia, ischemic colitis, ischemic acute renal failure, stroke, brain trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma and diabetic neuropathy.

Claims (6)

A composition for preventing or treating ischemic diseases containing an aminothiophene derivative represented by the following Chemical Formula 1 or 2, or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1]

[Formula 2]

Where R ¹ is H, —CO ₂ R ² , —CH ₂ OR ² , —CONR ² R ³ , or

Where R ² and R ³ are Independently H, or C ₁ to C ₆ straight or branched alkyl, or alkyl substituted with halogen or hydroxy; B is H, phenyl, or phenyl substituted with C ₁ -C ₃ alkyl or halogen; n is an integer from 0 to 2; Y is S, O, SO or SO ₂ ; Z is H, halogen, NO ₂ , NH ₂ , C ₁ -C ₃ straight or branched alkyl, or OR ⁴ , wherein R ⁴ is H, or C ₁ -C ₃ straight or branched alkyl; A is CH, N, or N-O. The method of claim 1, R ¹ is H, —CO ₂ R ² , —CH ₂ OR ² , —CONR ² R ³ , or

Wherein R ² and R ³ are independently of each other H or methyl; B is H, phenyl, or phenyl substituted with C ₁ -C ₃ alkyl or halogen; n is 0 or 1; Y is S, O, SO or SO ₂ ; Z is H, halogen, NO ₂ , NH ₂ , C ₁ -C ₃ straight or branched alkyl, or OR ⁴ , wherein R ⁴ is H, or C ₁ -C ₃ straight or branched alkyl; A is CH, N, or N-O, characterized in that the composition for the prevention or treatment of ischemic disease. The method of claim 1, A composition for preventing or treating ischemic disease, wherein the aminothiophene derivative is selected from the group consisting of the following compounds: 1) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 2) 3- (2-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 3) 3- [2- (4-nitro-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 4) 3- [2- (4-amino-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 5) 3- [2- (4-methyl-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 6) 3- [2- (pyridin-2-ylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 7) 3- [2- (4-methoxy-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 8) 3- [2- (2-methoxy-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 9) 3- [2- (3-methoxy-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 10) 3- [2- (4-hydroxy-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 11) 3- [2- (pyridin-4-ylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 12) 3- [2- (1-oxy-pyridin-4-ylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 13) 3- [3- (4-bromo-phenylsulfanyl) -propionylamino] -thiophene-2-carboxylic acid methyl ester; 14) 3- (3-phenylsulfanyl-propionylamino) -thiophene-2-carboxylic acid methyl ester; 15) 3- [3- (pyridin-2-ylsulfanyl) -propionylamino] -thiophene-2-carboxylic acid methyl ester; 16) 3- [4- (4-bromo-phenylsulfanyl) -butylylamino] -thiophene-2-carboxylic acid methyl ester; 17) 3- [2- (4-bromo-phenylsulfanyl) -2-phenyl-acetylamino] -thiophene-2-carboxylic acid methyl ester; 18) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid; 19) 3- [2- (4-bromo-phenylsulfanyl) -2-phenyl-acetylamino] -thiophene-2-carboxylic acid; 20) N- (2-hydroxymethyl-thiophen-3-yl) -2-phenylsulfanyl-acetamide; 21) 2- (4-bromo-phenylsulfanyl) -N- (2-hydroxymethyl-thiophen-3-yl) -acetamide; 22) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid amide; 23) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid dimethylamide; 24) 2- (4-bromo-phenylsulfanyl) -N- [2- (4,5-dihydro-oxazol-2-yl) -thiophen-3-yl] -acetamide; 25) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thiophene-2-carboxylic acid (2-hydroxy-ethyl) -amide; 26) 3- [2- (4-bromo-phenoxy) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 27) 3- [2- (4-nitro-phenoxy) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 28) 3- [2- (4-amino-phenoxy) -acetylamino] -thiophene-2-carboxylic acid methyl ester; 29) 2- (4-bromo-phenoxy) -N- (2-hydroxymethyl-thiophen-3-yl) -acetamide; 30) 2- (2-phenylsulfanyl-acetylamino) -thiophene-3-carboxylic acid methyl ester; 31) 2- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester; 32) 2- [2- (2-methoxy-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester; 33) 2- [2- (3-methoxy-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester; 34) 2- [2- (4-methyl-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester; 35) 2- [2- (4-methoxy-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester; 36) 2- [2- (pyridin-2-yl-sulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester; 37) 2- [2- (4-hydroxy-phenylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester; 38) 2- [2- (pyridin-4-ylsulfanyl) -acetylamino] -thiophene-3-carboxylic acid methyl ester; 39) 2- [3- (4-bromo-phenylsulfanyl) -propionylamino] -thiophene-3-carboxylic acid methyl ester; 40) 2- (3-phenylsulfanyl-propionylamino] -thiophen-3-carboxylic acid methyl ester; 41) 2- [3- (pyridin-2-ylsulfanyl) -propionylamino] -thiophene-3-carboxylic acid methyl ester; 42) 2- [2- (4-bromo-phenylsulfanyl) -2-phenyl-acetylamino] -thiophene-3-carboxylic acid methyl ester; And 43) 2- [2- (4-bromo-phenylsulfanyl) -2-phenyl-acetylamino] -thiophene-3-carboxylic acid. The method of claim 1, The ischemic diseases include cerebral ischemia, cardiac ischemia, diabetic vascular heart disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, brain trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma and diabetic neurosis The composition for the prevention or treatment of ischemic diseases, characterized in that selected from the group consisting of. delete delete

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