Compounds for promoting myocardial regeneration, methods for preparing same, pharmaceutical compositions and uses thereof

Abstract

To provide a novel compound that can improve regeneration and repair of myocardial cells, and thereby provide a non-invasive, therapeutic method for myocardial infarction.SOLUTION: The present invention discloses a novel 3-aryl-2-propen-1-one series derivative and a synthesis processes thereof. Besides, the present invention also discloses use of a pharmaceutical composition and a series derivative thereof for promoting myocardial regeneration.SELECTED DRAWING: Figure 2

Description

[Technology Field]

[0001] The present invention relates to a novel compound, a method for preparing the same, and its use; more specifically, to a novel 3-aryl-2-propen-1-one derivative, a method for preparing the same, a pharmaceutical composition containing the same, and the use of these for promoting myocardial regeneration. [Background technology]

[0002] Myocardial infarction is a common acute heart disease in clinical practice, caused by a sudden interruption of blood circulation in a portion of the heart muscle. Consequently, the cardiomyocytes are damaged by oxygen deprivation. Generally, once a myocardial infarction occurs, the damaged and dead cardiomyocytes cannot regenerate. Only fibrous scars are formed, covering and repairing the area containing the damaged and dead cardiomyocytes. While fibrous scars help maintain the integrity of the heart, hard fibrous scars cannot contract, further hindering cardiac reconstruction and causing dysfunction. These can lead to heart diseases such as heart failure, arrhythmias, and cardiac shock.

[0003] Currently, treatment for myocardial infarction includes interventional therapies and drug administration. For example, interventional therapies include balloon angioplasty, stenting, and coronary artery bypass surgery, while drug administration includes thrombolytic agents, calcium channel blockers, nitrates, angiotensin-converting enzyme inhibitors, beta-antagonists, and narcotic analgesics.

[0004] However, the above treatment methods developed in clinical practice and basic medical research have not been able to improve the regeneration of myocardial tissue and may cause side effects. Currently, there is no effective treatment other than waiting for the damaged myocardial tissue to self-repair.

[0005] Therefore, in both clinical practice and basic medical research, it is urgent to develop related technologies to promote myocardial regeneration and to provide effective pharmaceuticals for treating myocardial infarction. [Overview of the Initiative]

[0006] According to the above drawbacks, an object of the present invention is to provide a novel compound that improves the regeneration and repair of cardiomyocytes, and thereby provides a non-invasive method for treating myocardial infarction.

[0007] To achieve the above object, the present invention provides a novel compound represented by the following formula (I).

[0008]

Chemical 1

[0009] In the above formula (I), X1 is a hydrogen atom or an unsubstituted alkyl group having 1 to 6 carbon atoms.

[0010] In the above formula (I), X2 is an oxygen atom ( * -O- * ), an amino group ( * -NH- * or * -NX4- * ).

[0011] In the above formula (I), X3 is a hydrogen atom ( * -H), a hydroxy group ( * -OH) or * -X2-(CO)-(Y) p -Z group.

[0012] In the above formula (I), Y is an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 12 carbon atoms, an arylenealkylene group having 7 to 18 carbon atoms or an arylene group having 6 to 18 carbon atoms.

[0013] In the above formula (I), Z is * -COOH, * -COOCH3, * -OCOCH3, * -NHCOOC(CH3)3, * -F, * -Cl, * -Br or * -I.

[0014] In the above formula (I), p is 0 or 1

[0015] Preferably, in formula (I) above, Z is * -COOH, * -COOCH3, * -OCOCH3, * -NHCOOC(CH3)3 or * It is -Cl.

[0016] In this specification, the phrase "alkyl group having 1 to 6 carbon atoms" means a linear or branched alkyl group, and the entire functional group represented by X1 has a total of 1 to 6 carbon atoms. * This indicates the binding site.

[0017] Preferably, X1 may be a methyl group, an ethyl group, a propyl group, or an isopropyl group, but is not limited to these.

[0018] Preferably, in formula (I) above, X2 is * -NX4- * And X4 is * -X2-(CO)-(Y) p -Z group. More preferably, X4 is represented by the following formula (i). [Case 2]

[0019] In this specification, the term "alkylene group having 1 to 6 carbon atoms" means a linear or branched alkylene group, and the entire functional group represented by Y has a total of 1 to 6 carbon atoms. Similarly, in this specification, the term "alkenylene group having 2 to 12 carbon atoms" means a linear or branched alkenylene group, and the entire functional group represented by Y has a total of 2 to 12 carbon atoms. In this specification, the term "arylenealkylene group having 7 to 18 carbon atoms" means a group containing an arylene group bonded to an alkylene group, and the entire functional group represented by Y has a total of 7 to 18 carbon atoms. In other words, the total number of carbon atoms in the arylene and alkylene groups is 7 to 18. In this specification, the term "arylene group having 6 to 18 carbon atoms" means a single aromatic ring or a polyaromatic ring formed by multiple aromatic rings bonded or fused together, and the entire functional group represented by Y has a total of 6 to 18 carbon atoms.

[0020] Preferably, in the above formula (I), the alkylene group having 1 to 6 carbon atoms represented by Y is a methylene group ( * -CH2- * ), ethylene group ( * -CH2CH2- * ), ethylidene group ( * -CH(CH3)- * ), propylene group ( * -CH2CH2CH2- * ), isopropylidene group ( * -C(CH3)2- * ) or butylene group ( * -CH2CH2CH2CH2- * ) may also be, but is not limited to these. The C2-C12 alkenylene group represented by Y above is a vinylene group ( * -CH=CH- * ), propenylene group ( * -CH2CH=CH- * or * -CH=CHCH2- * ) or butylene group ( * -CH2CH2-CH=CH- * , *-CH2CH=CHCH2- * or * -CH=CHCH2CH2- * ) may also be, but is not limited to these. The arylenealkylene group having 7 to 18 carbon atoms represented by Y above is a cresylene group ( * -CH2C6H4- * ), triylene group ( * -C6H3(CH3)- * ) or phenylenedi methylene group ( * -CH2C6H4CH2- * ) may also be, but is not limited to these. The arylene group having 6 to 18 carbon atoms represented by Y above is a phenylene group ( * -C6H4- * ), biphenylene group ( * -C6H4-C6H4- * ) or naphthylene group ( * -C 10 H6- * ) may be, but is not limited to, these.

[0021] More specifically, in formula (I) above, the phenylene group may be an orthophenylene group, a metaphenylene group, or a paraphenylene group.

[0022] Preferably, the phenylene group is an orthophenylene group.

[0023] More specifically, in formula (I) above, the cresylene group may be an ortho-cresylene group, a meta-cresylene group, or a para-cresylene group.

[0024] Preferably, the above-mentioned cresylene group is a meta-cresylene group.

[0025] According to the present invention, the novel compound may be any of the following compounds 1 to 15, but is not limited to these.

[0026] [C3] [C4]

[0027] Another object of the present invention is to provide a method for preparing a novel compound, comprising the step of reacting reactant A with reactant B at a temperature of 0°C to 25°C. Reactant A is a coumaric acid derivative, a caffeic acid derivative, or a cinnamic acid derivative, and reactant B is an acid compound, an anhydride compound, an acyl chloride compound, or an ester compound.

[0028] Preferably, the reaction between substance A and reactant B is carried out under alkaline conditions (in the range of pH 9 to pH 12) at a temperature of 0°C to 25°C.

[0029] Preferably, reactant A is paracoumaric acid, caffeic acid, methyl caffeate, or 4-aminocinnamic acid.

[0030] Preferably, reactant B is acetylsalicylic acid, 3-chlorophenylacetic acid, tert-butoxycarbonyl-γ-n-aminobutyric acid, glutaric acid anhydride, adipic acid anhydride, methyl adipoyl chloride, or monomethyl fumarate.

[0031] Another object of the present invention is to provide the use of 3-aryl-2-propen-1-one derivatives to promote myocardial regeneration.

[0032] To achieve the above objective, the present invention provides a method for preparing a pharmaceutical composition containing a compound represented by the following formula (II) for promoting myocardial regeneration.

[0033] [C5]

[0034] R1 is a hydroxyl group, an unsubstituted alkyl group having 1 to 6 carbon atoms, an unsubstituted alkoxy group having 1 to 6 carbon atoms, a substituted alkanoic acid group having 1 to 6 carbon atoms, a substituted cycloalkanoic acid group having 7 to 12 carbon atoms, a substituted or unsubstituted arylamine group having 6 to 18 carbon atoms, a substituted or unsubstituted phenol group having 6 to 18 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyridyl group, or an unsubstituted thiazolyl group.

[0035] R2 is a hydrogen atom, a hydroxyl group, an unsubstituted alkyl group having 1 to 6 carbon atoms, or an amino group. * -NH2), acetoxy group ( * -OCOCH3), * -O-CH2-CH=CH2 or * -X2(CO)-(Y) p It is a -Z group.

[0036] R3 is a hydrogen atom, a hydroxyl group, an unsubstituted alkyl group having 1 to 6 carbon atoms, an unsubstituted alkoxy group having 1 to 6 carbon atoms, or * -O-CO-(Y) p -It is either a Z group, or R2 and R3 are bonded to form a group represented by the following formula (ii).

[0037] [C6]

[0038] R4 consists of a hydrogen atom, an unsubstituted alkoxy group with 1 to 6 carbon atoms, * -O-CH2-CH=CH2 or the group represented by formula (iii) below.

[0039] [C7]

[0040] A is a benzene ring, a thiophene ring, or a pyridine ring.

[0041] X2 is an oxygen atom ( * -O- * ) or amino group ( * -NH- * or * -NX4- * )

[0042] Y is an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 12 carbon atoms, an arylenealkylene group having 7 to 18 carbon atoms, or an arylene group having 6 to 18 carbon atoms.

[0043] Z is a pyridyl group ( * -C5H4N), an acetyl group ( * -COCH3), * -COOH, * -COOCH3, * -OCOCH3, * -NHCOOC(CH3)3, * -F, * -Cl, * -Br or * -I.

[0044] p is 0 or 1.

[0045] Briefly, the above 3-aryl-2-propen-1-one derivatives contain not only the above novel compounds 1 to 15 but also other commercially available cinnamic acid derivatives.

[0046] Preferably, in the above formula (II), Z is * -COCH3, * -COOH, * -COOCH3, * -OCOCH3, * -NHCOOC(CH3)3 or * -Cl.

[0047] Preferably, in the above formula (II), X2 is * -O- * , * -NH- * or * -NX4- * and X4 is * -X2-(CO)-(Y) p -Z group.

[0048] More preferably, X4 is represented by the following formula (i).

[0049] [C8]

[0050] Preferably, in the above formula (II), R3 is * -CH3, * -O-CH2-CH=CH2, * -NH2 or * -O-CO-(Y) p It is a -Z group.

[0051] Preferably, in formula (II) above, R2 is * -X2(CO)-(Y) p If it is a -Z group, then R1 is a hydroxyl group.

[0052] Preferably, in the above formula (II), Y is an alkenylene group, then Z is * -COOCH3

[0053] Preferably, in formula (II) above, X2, Y, p and Z are the same as the groups in formula (I) above. Furthermore, in formula (II) above, Z is a pyridyl group ( * -C5H4N) or acetyl group ( * It is also (COCH3).

[0054] Preferably, in the above formula (II), R1 is * -OH, * -OCH3, * -OCH2C6H4OH, * -OCH(COOH)CH(OH)COOH, * -O-CH(COOH)CH2(C6H3)(OH2), * -O(C6H7)(OH)3(COOH), * -NHC6H4OH, * -C4H3S(CH3), * -C6H4OH, * -(N)-C4H4N, * -C5H4N or * It is -C3SN(NH2)(CH3).

[0055] Preferably, the 3-aryl-2-propen-1-one derivative is useful for promoting the regeneration and repair of damaged cardiomyocytes and may be, but is not limited to, one of compounds 1 to 15 and the following compounds 16 to 46.

[0056] [C9] [C10] [C11]

[0057] Furthermore, the present invention also provides a pharmaceutical composition for promoting myocardial regeneration. The pharmaceutical composition contains the above-mentioned 3-aryl-2-propen-1-one derivatives (e.g., compounds 1 to 46) and a pharmaceutically acceptable carrier.

[0058] In summary, the present invention provides novel 3-aryl-2-propen-1-one derivatives and methods for synthesizing the same. These novel compounds are useful for promoting the regeneration and repair of damaged cardiomyocytes. Furthermore, the present invention also provides the use of these 3-aryl-2-propen-1-one derivatives to promote cardiomyocyte regeneration. [Brief explanation of the drawing]

[0059] [Figure 1] Figure 1 shows the α-MHC expression levels of cardiomyocytes treated with compounds 1 to 46. The bar graph shows the α-MHC expression level, and the line graph shows the cell viability. [Figure 2] Figure 2 shows the percentage of cryoinjury in the hearts of zebrafish given compositions containing compounds 1 to 46, respectively. [Modes for carrying out the invention]

[0060] The following embodiments are proposed to illustrate the use of the compounds and pharmaceutical compositions of the present invention for myocardial regeneration. Those skilled in the art will readily understand the advantages and effects of the present invention from the following examples. The descriptions proposed herein are merely preferred embodiments for illustrative purposes and are not intended to limit the scope of the invention. Various modifications and variations may be made without departing from the spirit and scope of the invention in order to carry out or apply this disclosure.

[0061] Example 1: Synthesis of Compounds 1 to 15 The novel compounds described in the present invention are prepared by reacting reactant A with reactant B under alkaline conditions at a temperature of 0°C to 25°C. Reactant A is a coumaric acid derivative, a caffeic acid derivative, or a cinnamic acid derivative, and reactant B is an acid compound, an anhydride compound, an acyl chloride compound, or an ester compound.

[0062] compound 1 Paracoumaric acid (1 g, 6.0 mmol) was dissolved in 8 ml of 10% (w / w) sodium hydroxide solution and cooled to 5°C to 10°C. Then, glutaric acid anhydride (0.97 g, 8.4 mmol) dissolved in 5 ml of tetrahydrofuran was slowly added to the reaction mixture. After stirring for 30 minutes, 40 ml of water and 40 ml of ethyl acetate were added to the reaction mixture to adjust the pH to 5.2. The organic layer was separated, concentrated and dried, and then 50 ml of water was added to adjust the pH to 9.33, and then to 5.0 using 1N hydrochloric acid to precipitate. After stirring for 1 hour, the precipitate was filtered and dried to obtain 0.5335 g of a light beige powder with 100% HPLC purity.

[0063] The structure of compound 1 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 1 is as follows. 1 H-NMR (500MHz, DMSO-d6): δ12.255(s, 2H), 7.723(d, 2H), 7.577(d, 1H), 7.166(d, 2H), 6.494(d, 1H), 2.618(t, 2H), 2.330(t, 2H), 1.841(tt, 2H). Mass spectrometry: [M+H] + ;C 14 H 15O6;279.0859.

[0064] compound 2 Caffeic acid (0.3 g, 1.6 mmol) was added to 6 ml of acetonitrile and mixed uniformly. Then triethylamine (0.46 ml, 3.3 mmol) was added and the mixture was stirred for 5 minutes. The reaction mixture was cooled to 5°C to 10°C using an ice bath, and then glutaric acid anhydride (0.17 g, 1.5 mmol) dissolved in 2 ml of tetrahydrofuran was slowly added. After 2 hours of reaction, the reaction mixture was dried and separated by adding 30 ml of ethyl acetate and 30 ml of 10% (w / w) ammonium chloride. The aqueous layer was back-extracted with 30 ml of ethyl acetate, and the mixed organic layer was dried to obtain 0.2685 g of a white solid. The above white solid was crystallized using isopropyl acetate and acetone to obtain 0.1339 g of a white powder with 100% PLC purity.

[0065] The structure of compound 2 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 2 is as follows. 1 H-NMR (500MHz, CD3OD): δ7.576 (d, 1H), 7.347-6.913 (m, 3H), 6.392-6.287 (d+d, 1H), 2.705-2.669(m, 2H), 2.483-2.447(m, 2H), 2.152-1.986(m, 2H). Mass spectrometry: [M+H] + ;C 14 H 15 O7;295.0812.

[0066] compound 3 Caffeic acid (0.25 g, 1.4 mmol) was added to 5 ml of tetrahydrofuran, followed by the addition of triethylamine (0.76 ml, 5.4 mmol). After mixing for several minutes, the reaction mixture was concentrated and dried, and 7 ml of tetrahydrofuran was added to the residue and stirred until dissolved. After cooling to 5°C to 10°C in an ice bath, glutaric acid anhydride (0.4 g, 3.4 mmol) dissolved in 3 ml of tetrahydrofuran was slowly added. After stirring for 1 hour, the reaction mixture was dried and separated by adding 30 ml of ethyl acetate and 30 ml of water. The organic layer was further washed with 30 ml of brine and then dried with anhydrous sodium sulfate. The solvent was evaporated, and the residue was crystallized using isopropyl acetate and acetone to obtain 0.1629 g of a white powder with 100% HPLC purity.

[0067] The structure of compound 3 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 3 is as follows. 1 H-NMR (500MHz, CD3OD); δ7.645(d, 1H), 7.537-7.513(m, 2H), 7.278(d, 1H), 6 .482(d, 1H), 2.703-2.663(m, 4H), 2.463-2.425(m, 4H), 2.009-1.969(m, 4H). Mass spectrometry: [M+NH4] + 426.1402.

[0068] compound 4 Paracoumaric acid (1 g, 6.0 mmol) was dissolved in 10 ml of acetonitrile, and then triethylamine (2.5 ml, 17.9 mmol) was added. After cooling to 0°C to 10°C, a solution of glutaric acid anhydride (0.93 g, 7.3 mmol) dissolved in 5 ml of dichloromethane was slowly added. After the addition, the reaction mixture was concentrated and dried to obtain a brown oil. 30 ml of water was added, and the aqueous layer was washed three times with 30 ml of dichloromethane each time, and twice with 30 ml of ethyl acetate each time. Finally, the pH of the aqueous layer was adjusted to 4.8 to precipitate the desired compound. After filtration, 0.2542 g of a white solid with HPLC purity of 99.2% was obtained.

[0069] The structure of compound 4 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 4 is as follows. 1 H-NMR (500MHz, DMSO-d6): δ7.717(d, 2H), 7.569(d, 1H), 7.150(d, 2H), 6.488(d, 1H), 2.583(t, 2H), 2.250(t, 2H), 1.656-1.558(m, 4H). Mass spectrometry: [M+H] + ;C 15 H 17 O6;293.1013.

[0070] compound 5 Under nitrogen, paracoumaric acid (0.333 g, 2.0 mmol) was dissolved in 10 ml of tetrahydrofuran anhydride, and then methyl adipoyl chloride (0.36 g, 2.0 mmol) was added using a syringe. The reaction mixture was cooled in an ice bath, and then ethylenediamine (0.3 g, 3.0 mmol) was slowly added. After stirring at room temperature for 2-3 hours, the solvent was removed using a rotary dryer. Dichloromethane and water were added and liquid extraction was performed. The organic layer was dried, and the crude product was purified by column chromatography using 50% methanol as an eluent to obtain 17 mg of HPLC-purified product.

[0071] The structure of compound 5 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 5 is as follows. 1 H-NMR (500MHz, CD3OD): δ7.675-7.629(m, 3H), 7.150(d, 2H), 6.463(d, 1H), 3.667(s, 3H), 2.620(t, 2H), 2.401(t, 2H), 1.751-1.736(m, 4H). Mass spectrometry: [M+H] + ;C 16 H 19 O6;307.1181;[M+Na] + ;329.1000.

[0072] compound 6 Under nitrogen, caffeic acid (0.369 g, 2.0 mmol) was dissolved in 10 ml of tetrahydrofuran anhydride, and then methyl adipoyl chloride (0.5146 g, 3.0 mmol) was added using a syringe. The solution was cooled in an ice bath, and then ethylenediamine (0.5129 g, 5.0 mmol) was slowly added. After stirring at room temperature for 2 to 3 hours, the solvent was removed using a rotary dryer. Dichloromethane and water were added, and liquid extraction was performed. The organic layer was then dried. 13.8 mg of the product with 100% HPLC purity was obtained by reverse-phase column chromatography using a 50% to 60% methanol aqueous solution as the eluent.

[0073] The structure of compound 6 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 6 is as follows. 1 H-NMR (500MHz, CD3OD): δ7.635(d, 1H), 7.523(dd, 1H), 7.498(d, 1H), 7.264(d, 1H); 6.48 1(d, 1H), 3.670(s, 6H), 2.638-2.599(m, 4H), 2.418-2.384(m, 4H), 1.747-1.723(m, 8H). Mass spectrometry: [M+NH4] + 482.2059.

[0074] compound 7 Paracoumaric acid (1 g, 6.0 mmol) was dissolved in 10 ml of 10% (w / w) sodium hydroxide solution. After cooling to 5°C to 10°C, a solution of acetylsalicylic acid anhydride (2.45 g, 7.2 mmol) dissolved in 3 ml of tetrahydrofuran was slowly added. After stirring for 30 minutes, the reaction mixture was evaporated, and 30 ml of water and 40 ml of ethyl acetate were added. The organic layer was washed again with 20 ml of water adjusted to pH 4 to 5. The organic layer was further washed three times with 5% ammonium chloride solution, then with 40 ml of water, and the pH was adjusted to 6.0 with sodium bicarbonate. After separation, the organic layer was dried over anhydrous sodium sulfate. The solution was then concentrated and dried to obtain 1.9 g of a white solid. 30 ml of dichloromethane was added to obtain a solid, which was washed twice with water, and the pH was adjusted to 7.37. The organic layer was then dried over anhydrous sodium sulfate, concentrated and dried to obtain 49.6 mg of a white solid with HPLC purity of 89.9%.

[0075] The structure of compound 7 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 7 is as follows. 1 H-NMR (500MHz, CD3OD): δ8.200(dd, 1H), 7.741-7.682(m, 4H), 7.459(t, 1H), 7.259-7.241(m, 3H), 6.500(d, 1H), 2.264(s, 3H). Mass spectrometry: [M+H] + ;C 18 H 15 O6;327.0860;[M+Na] + ;349.0677.

[0076] compound 8 Acetylsalicylic acid (1.8 g, 10.0 mmol), 20 ml of toluene, and 3 drops of dimethylformamide were added to a 250 ml single-neck flask. After stirring at 40°C for 3 minutes, thionyl chloride (1.8 ml, 24.8 mmol) was added to the reaction mixture, and the mixture was then heated at 60°C for 2 hours. After cooling to 25°C, all excess thionyl chloride and solvent were removed using a rotary dryer. 20 ml of toluene was added to the reaction mixture, and the solvent was removed again to obtain a pale yellow liquid. Then, caffeic acid (1.81 g, 10.0 mmol), 20 ml of tetrahydrofuran, and triethylamine (1.5 ml, 10.0 mmol) were added to the liquid, and the mixture was stirred at room temperature for 3 hours. Then, 20 ml of saturated ammonium chloride solution was added. After separation, the organic layer was evaporated to obtain 4.82 g of an off-white solid. The solid was dissolved in 40 ml of ethyl acetate and washed with 40 ml of water. The organic layer was dried, filtered, and evaporated to obtain 3.74 g of an orange liquid. The desired product was collected by column chromatography (silica gel: 63.4 g; column diameter: 4.5 cm; column length: 13.5 cm; and eluent: dichloromethane:methanol = 1:0 to 50:1), and 56 mg of the desired compound with HPLC purity of 94.6% was obtained by repeat column chromatography.

[0077] The structure of compound 8 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 8 is as follows. 1 H-NMR (500MHz, CD3OD): δ8.242-8.207(m, 1H), 7.708(t, 1H), 7.602(d, 1H) , 7.451(t, 1H), 7.407-6.968(m, 4H), 6.425-6.312(d+d, 1H), 2.266(s, 3H). Mass spectrometry: [M+H] + ;C 18 H 15 O7;343.0822;[M+NH4] + ;360.1091.

[0078] compound 9 A mixture of paracoumaric acid (0.304 g, 2.0 mmol), triethylamine (2.9 ml, 28.0 mmol), and acetonitrile (4.0 ml) was added to pre-prepared crude 3-chlorophenylacetyl chloride (0.8 g, 1.4 mmol), and the mixture was cooled in an ice bath. After addition, the ice bath was removed, and the solution was stirred at room temperature for 1 hour. Water and 1,2-dichloroethane were added to the reaction mixture and extracted, adjusting the pH to approximately 6.0. After stirring for 0.5 hours, the solvents in the separated layers and organic layers were evaporated, leaving a residue (2.8 g). The residue was purified using silica gel column chromatography (eluent: ethyl acetate:dichloromethane = 1:1.5) to obtain 26 mg of a white solid with HPLC purity of 87.8%.

[0079] The structure of compound 9 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 9 is as follows. 1 H-NMR (500MHz, CD3OD): δ7.661(d, 1H), 7.635(d, 2H), 7.423(s, 1H), 7.342(d, 1H), 7.324-7.312(m, 2H), 7.146(d, 2H), 6.457(d, 1H), 3.939(s, 2H). Mass spectrometry: [M+H] + ;C 17 H 14 ClO4;317.0580.

[0080] compound 10 3-chlorophenylacetic acid (1.71 g, 10.0 mmol), 20 ml of toluene, and 2 drops of dimethylformamide were added to a 250 ml single-neck flask. After stirring at 24 °C for 5 minutes, thionyl chloride (1.5 ml, 20.7 mmol) was added, and the mixture was heated at 65 °C for 1 hour. After cooling to 25 °C, excess thionyl chloride and solvent were removed using a rotary dryer. Next, 25 ml of tetrahydrofuran was added to the reaction mixture, and the solvent was removed again to obtain 2.18 g of a pale yellow liquid. Next, caffeic acid (1.81 g, 10.0 mmol), 20 ml of tetrahydrofuran, and triethylamine (1.4 ml, 10 mmol) were added to the liquid, and the reaction mixture was stirred at room temperature for 4 hours. Next, 20 ml of saturated ammonium chloride solution was added, and the organic layer was separated. The solvent in the organic layer was removed using a rotary dryer to obtain 5.13 g of an off-white solid. The above solid was purified using column chromatography (silica gel: 67.4 g; column diameter: 4 cm; column length: 14 cm; and eluent: ethyl acetate:heptane = 1:3 to 1:1), and the desired product with HPLC purity of 97.6% was collected.

[0081] The structure of compound 10 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 10 is as follows. 1 H-NMR (500MHz, CD3OD): δ7.613(d, 1H), 7.511-7.478(m, 2H), 7.356-7.281(m, 6H), 7.250-7.214(m, 3H), 6.455(d, 1H), 3.726(s, 2H), 3.696(s, 2H). Mass spectrometry: [M+H] + ;C 25 H 19 Cl2O6; 485.0569.

[0082] compound 11 0.43 g, 2.5 mmol of 3-chlorophenylacetic acid, 10 ml of toluene, and 2 drops of dimethylformamide were added to a 100 ml single-neck flask. After stirring at 24°C for 10 minutes, 0.5 ml, 6.9 mmol of thionyl chloride was added, and the mixture was heated at 65°C for 1 hour. After cooling the reaction mixture to 25°C, excess thionyl chloride and solvent were removed using a rotary dryer. Next, 10 ml of toluene was added to the reaction mixture, and the solvent was removed again to obtain a pale yellow liquid. Next, 0.49 g, 2.5 mmol of methyl caffeate, 10 ml of tetrahydrofuran, and 0.4 ml, 2.9 mmol of triethylamine were added to the liquid, and the reaction mixture was stirred at room temperature for 3 hours. Next, 20 ml of saturated ammonium chloride solution was added to separate the organic layer. The organic layer was then washed with 20 ml of saturated sodium bicarbonate solution and 20 ml of water. The organic layer was dried, filtered, and evaporated to obtain an orange liquid. Using column chromatography (silica gel: 51.6 g; column diameter: 4.5 cm; column length: 10 cm; and eluent: ethyl acetate:heptane = 1:5), 27.3 mg of the product with HPLC purity of 98.6% was obtained.

[0083] The structure of compound 11 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 11 is as follows. 1 H-NMR (500MHz, CD3OD): δ7.618(d, 1H), 7.503-7.476(m, 2H), 7.344-7.266(m, 6H) ), 7.242-7.205(m, 3H), 6.490(d, 1H), 3.767(s, 3H), 3.713(s, 2H), 3.686(s, 2H). Mass spectrometry: [M+H] + ;C 26 H 21 Cl2O6; 499.0719.

[0084] compound 12 1.59 g, 7.8 mmol of tert-butoxycarbonyl-γ-n-aminobutyric acid was added to a 250 ml single-neck flask under nitrogen. 8 ml of tetrahydrofuran and 2.2 ml, 15.8 mmol of triethylamine were then added, and the reaction mixture was stirred at -20°C for 5 minutes. A mixture of 0.96 ml, 7.8 mmol of trimethylacetyl chloride and 5 ml of tetrahydrofuran was then added to the reaction mixture for 10 minutes, and the mixture was stirred at 0°C for 2 hours. A mixture of 0.7 g, 3.9 mmol of caffeic acid and 8 ml of tetrahydrofuran was then added to the reaction mixture for 2 minutes, and the mixture was stirred at room temperature for 45 hours. 30 ml of saturated ammonium chloride solution was then added. The organic layer was separated and evaporated. 30 ml of ethyl acetate was added to the residue, and the mixture was washed with 30 ml of water. The solvent in the organic layer was then removed, yielding 2.13 g of a white solid. After purification by column chromatography (silica gel: 65 g; column diameter: 4 cm; column length: 15 cm; and eluent: dichloromethane:methanol = 50:1 to 20:1), 17.8 mg of product with HPLC purity of 97.4% was obtained.

[0085] The structure of compound 12 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 12 is as follows. 1 H-NMR (500MHz, CD3OD): δ7.644(d, 1H), 7.535-7.507(m, 2H), 7.293(d, 1H), 6.845(d, 1H), 3.173-3.134(m, 4H), 2.637-2.596(m, 4H), 1.885-1.846(m, 4H), 1.440(s, 18H). Mass spectrometry: [M+H] + ;C 27 H 39 N2O 10 ;551.2591;[M+Na] + ;573.2414.

[0086] compound 13 4-aminocinnamic acid (0.201 g, 1.0 mmol) and 2 ml of tetrahydrofuran were mixed at room temperature, then glutaric acid anhydride (0.169 g, 2.0 mmol) was added, and the mixture was stirred for 1.5 hours. The precipitate was then filtered and washed with water to obtain 0.336 g of a white solid with HPLC purity of 98.2%.

[0087] The structure of compound 13 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 13 is as follows. 1 H-NMR (500MHz, CD3OD): δ7.643-7.611 (m, 3H), 7.551 (d, 2H), 6.401 (d, 1H), 2.454 (t, 2H), 2.393 (t, 2H), 1.978 (tt, 2H). Mass spectrometry: [M+H] + ;C 14 H 16 NO5;278.1067.

[0088] compound 14 0.72 g, 5.5 mmol of monomethyl fumarate, 10 ml of toluene, and 2 drops of dimethylformamide were added to a 100 ml single-neck flask. After stirring at 17°C for 3 minutes, 0.9 ml of thionyl chloride (11.0 mmol) was added, and the mixture was heated at 60°C for 3 hours. After cooling the reaction mixture to 30°C, all excess thionyl chloride and solvent were removed using a rotary dryer. Next, 0.82 g, 5.0 mmol of 4-aminocinnamic acid, 10 ml of tetrahydrofuran, and 1.4 ml, 10.0 mmol of triethylamine were added to the residue, and the mixture was stirred at 0°C for 30 minutes, then at room temperature for 19 hours. Subsequently, 20 ml of saturated ammonium chloride solution and 5 ml of water were added to the reaction mixture, and the organic layer was separated. The aqueous layer was back-extracted twice with 20 ml of dichloromethane. The mixed organic layers were dried, filtered, and evaporated to obtain a yellow solid. Column chromatography (silica gel: 52.9 g; column diameter: 4 cm; column length: 11 cm; and eluent: ethyl acetate:heptane = 1:3 to 1:0) yielded 22.5 mg of the desired product with a purity of 94.0%.

[0089] The structure of compound 14 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 14 is as follows. 1 H-NMR (500MHz, DMSO-d6): δ12.283(br s, 1H), 10.709(s, 1H), 7.707(d, 2H), 7.663(d, 2H), 7.523(d, 1H), 7.211(d, 1H), 6.726(d, 1H), 6.430(d, 1H), 3.746(s, 3H). Mass spectrometry: [M+H] + ;C 14 H 14 NO5;276.0866.

[0090] compound 15 Acetylsalicylic acid (1.0 g, 5.5 mmol), 20 ml of toluene, and 3 drops of dimethylformamide were added to a 100 ml single-neck flask. After stirring at 20°C for 3 minutes, thionyl chloride (0.9 ml, 11.0 mmol) was added, and the mixture was heated at 60°C for 1.5 hours. After cooling to 35°C, all excess thionyl chloride and solvent were removed using a rotary dryer. Then, 10 ml of tetrahydrofuran was added to the residue, and the mixture was evaporated again to obtain 1 g of a pale yellow liquid. Next, 4-aminocinnamic acid (0.81 g, 5.0 mmol), 10 ml of tetrahydrofuran, and 1.4 ml of triethylamine (10.0 mmol) were added, and the mixture was stirred first at 0°C for 1 hour, and then at room temperature for 22 hours. Then, 25 ml of saturated ammonium chloride solution and 5 ml of water were added to the reaction mixture, and the organic layer was separated. The solvent was removed using a rotary dryer to obtain 0.91 g of a yellow solid. After purification by column chromatography (silica gel: 64.7 g; column diameter: 4 cm; column length: 12.5 cm; and eluent: ethyl acetate:heptane = 1:5 to 1:1), 10.7 mg of the product was obtained with HPLC 92.7%.

[0091] The structure of compound 15 is shown in Table 1 below. The nuclear magnetic resonance spectrum of compound 15 is as follows. 1H-NMR (500MHz, DMSO-d6): δ10.523(s, 1H), 7.948(dd, 1H), 7.765(td, 1H), 7.700(d, 2H), 7.666-7.627(m, 3H), 7. 564(td, 1H), 7.508(d, 1H), 7.378(t, 1H), 7.321(t, 1H), 7.236(d, 2H), 6.369(d, 1H), 2.230(s, 3H), 2.154(s, 3H). Mass spectrometry: [M+H] + ;C 27 H 22 NO8;488.1348;[M+Na] + ;510.1171.

[0092] [Table 1]

[0093] Example 2: Use of compounds 1 to 46 to improve myocardial regeneration The compound represented by the following formula (II) can promote the regeneration and repair of damaged cardiomyocytes.

[0094] [C12]

[0095] In the above formula (II), R1 is a hydroxyl group, an unsubstituted alkyl group having 1 to 6 carbon atoms, an unsubstituted alkoxy group having 1 to 6 carbon atoms, a substituted alkanoic acid group having 1 to 6 carbon atoms, a substituted cycloalkanoic acid group having 7 to 12 carbon atoms, a substituted or unsubstituted arylamine group having 6 to 18 carbon atoms, a substituted or unsubstituted phenol group having 6 to 18 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyridyl group, or an unsubstituted thiazolyl group.

[0096] R2 is a hydrogen atom, a hydroxyl group, an unsubstituted alkyl group having 1 to 6 carbon atoms, or an amino group. * -NH2), acetoxy group ( * -OCOCH3), * -O-CH2-CH=CH2 or * -X2(CO)-(Y) p It is a -Z group.

[0097] R3 is a hydrogen atom, a hydroxyl group, an unsubstituted alkyl group having 1 to 6 carbon atoms, an unsubstituted alkoxy group having 1 to 6 carbon atoms, or * -O-CO-(Y) p -It is either a Z group, or R2 and R3 are bonded to form a group represented by the following formula (ii).

[0098] [C13]

[0099] R4 consists of a hydrogen atom, an unsubstituted alkoxy group with 1 to 6 carbon atoms, * -O-CH2-CH=CH2 or the group represented by formula (iii) below.

[0100] [C14]

[0101] A is a benzene ring, a thiophene ring, or a pyridine ring.

[0102] X2 is an oxygen atom ( * -O- * ) or amino group ( * -NH- * or * -NX4- * )

[0103] Y is an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 12 carbon atoms, an arylenealkylene group having 7 to 18 carbon atoms, or an arylene group having 6 to 18 carbon atoms.

[0104] Z is * -C5H4N, * -COCH3, * -COOH, * -COOCH3, * -OCOCH3, * -NHCOOC(CH3)3, * -F, * -Cl, * -Br or * -I is

[0105] p is either 0 or 1.

[0106] In addition to compounds 1 to 15 mentioned above, the compound represented by formula (II) also contains compounds 16 to 46. The structures of compounds 1 to 46 are shown in Tables 2 to 4.

[0107] [Table 2] [Table 3] [Table 4]

[0108] As active ingredients, compounds 1 to 46 are each mixed with a pharmaceutically acceptable carrier to form a pharmaceutical composition for promoting myocardial regeneration, a health food for preventing myocardial infarction, and a health food for maintaining the prognosis of myocardial infarction.

[0109] As represented by formula (II) above, the compound used for myocardial regeneration may be a salt or an ester. For example, one of the compounds represented by formula (II) above reacts with alkali metals or alkaline earth metals to form a sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, carbonate, nitrate, bicarbonate, hydrochloride, sulfate, or silicate. Alternatively, one of the compounds represented by formula (II) reacts with alcohols to form esters such as methyl ester, ethyl ester, propyl ester, butyl ester, amyl ester, methyl acetate, ethyl acetate, butyl formate, butyl acetate, butyl valerate, butyl propionate, methyl butyrate, or ethyl butanoate.

[0110] The above-mentioned "pharmaceutically acceptable carrier" or "acceptable carrier" contains pharmaceutically or food-grade acceptable excipients or additives such as starch, corn starch, gelatin, gum arabic, food coloring, spices, flavorings, and preservatives. The routes of administration include oral administration, cutaneous administration, intraperitoneal administration, intravenous administration, nasal administration, and ocular administration. The preferred route of administration is oral administration.

[0111] The dosage of the above-mentioned pharmaceutical composition shall be determined by a healthcare professional in accordance with common sense in the field, depending on the patient's age, weight, health condition, type of disease, disease progression, and location of the lesion. The above-mentioned pharmaceutical composition may be administered alone or in combination with other drugs. The administration process should be carried out by a healthcare professional in accordance with routine pharmacy practices.

[0112] The amount of active ingredients in the above-mentioned health food may be adjusted according to a specific group. Preferably, the above amount is suitable for a daily intake. The packaging may also display recommended usage, standards and conditions for a specific group (e.g., pregnant women or patients with kidney disease) or other precautions when taking it with other foods or drugs, thereby ensuring the safety of purchasers who take it without instructions from a doctor, pharmacist, or other relevant party.

[0113] Test Example 1: Activity Evaluation of Compounds 1 to 46 for Myocardial Regeneration Myosin is a functionally and structurally important component of the cardiomyocyte and is composed of myosin heavy chains. Among these, α-cardiac myosin heavy chain (α-MHC) is encoded by the MYH6 gene, which is specifically expressed in cardiomyocytes during the early stages of cardiac development. The MYH6 gene is mainly expressed in the atria and plays a crucial role in the contractile action of cardiomyocytes. Furthermore, this gene serves as a clue to recognizing the heart in transcriptional regulation involved in the induction and maintenance of cardiomyocyte lineages. α-MHC is an important protein in the early stages of cardiac development, and the expression level of α-MHC in the H9C2 cell line (cardiomyoblasts) is an appropriate indicator for evaluating the effect of studies that promote stem cell differentiation and maintain the prognosis of myocardial infarction.

[0114] 1.1: Cell culture of the H9C2 cell line The H9C2 cell line is a rat-derived cardiomyocyte, purchased from the Food Industry Development Research Institute (Taiwan). The culture medium is 90% (v / v) Dulbecco modified Eagle medium containing 4 mM L-glutamine (Gibco®, Cat. 12800017) and 10% (v / v) fetal bovine serum (Gibco®, Cat. 10437028), adjusted to contain 4.5 g / L glucose and 1.5 g / L sodium bicarbonate (Sigma, Cat. S5761). Cells were cultured at 37°C in 5% (v / v) CO2 under an atmospheric environment.

[0115] 1.2: MTT test for cell viability testing To find a suitable compound concentration that does not cause cytotoxicity, cells were cultured at a 90% culture density and placed in 24-well plates at a concentration of 1.5 × 10⁶ 4 Cells were seeded at the specified cell / well concentration. After 24 hours, compounds 1 to 46 and DMSO (Sigma, Cat. D4540) were added at concentrations of 0.2 to 30 μg / ml and treated for 48 hours (each group was treated three times). After washing with PBS buffer (phosphate-buffered saline), 0.5 mg / ml MTT (thiazolyl blue tetrazolium bromide; Sigma, Cat. M2128) was added, and the 24-well plates were incubated at 37°C for 4 hours. Subsequently, blue-violet crystals were observed under a microscope. The supernatant was then removed, and 200 μL of DMSO was added to dissolve the crystals. Each sample was mixed again using a pipette, and the absorbance at 570 nm was measured (the value is the average of three measurements). The value for the DMSO group was 100%, meaning that the cell viability was 100%. In the following tests, the concentration of the compounds was selected so that the cell viability was within the range of 80% to 120%, and it was confirmed that the growth of cardiomyocytes was not affected, as shown in Figure 1 below.

[0116] 1.3: Cell destruction and harvesting H9C2 cells were cultured at approximately 90% culture density and placed in 24-well plates in a 1.5 × 10⁶ container. 4Cells were seeded at the specified cell / well concentration. After 24 hours, compounds 1 to 46 and DMSO were added for 48 hours (each group was treated three times). The concentrations of compounds 1 to 46 are listed in Table 5 below. After washing with PBS buffer, 0.05% (w / v) 200 μL / well of trypsin was added for 5 minutes. The cell culture medium was then added to stop the trypsin reaction. The cell suspension was centrifuged at 4°C and 1000 rpm for 3 minutes, and the cells were washed three times with PBS buffer. The cells were then resuspended in PBS and frozen at -80°C. The cells were gently mixed to thaw. The freeze-thaw cycle was repeated three times to disrupt the cells. Finally, the solution was centrifuged at 4°C and 3000 rpm for 15 minutes, the supernatant was collected, and then stored at -20°C.

[0117] [Table 5]

[0118] 1.4: Determination of α-MHC expression levels α-MHC expression levels were determined using a rat myosin heavy chain 6, cardiac alpha (MYH6) ELISA kit (MyBioSource, Cat.MBS753946) and an ELISA reader. The absorbance values ​​at 450 nm read by the ELISA reader were then recorded (the values ​​are the average of three readings). The DMSO group's value was set to 100%, and the relative expression levels of the α-MHC groups treated with compounds 1 to 46 were calculated.

[0119] As shown in Figure 1, after treating H9C2 cells with compounds 1 to 46, the cells nevertheless grew normally (cell viability in the range of 80% to 120%), and α-MHC expression levels increased in all treatment groups compared to the DMSO-treated group. In other words, compounds 1 to 46 actually promote α-MHC expression levels in H9C2 cells. This indicates that compounds 1 to 46 can promote and repair myocardial regeneration.

[0120] Test Example 2: Evaluation of the effects of compounds 1 to 46 on myocardial regeneration in zebrafish. Frostbite-induced cardiac damage (up to 30%) in zebrafish repairs itself within 21 days. Therefore, adult zebrafish are a suitable animal model for studying cardiac injury. After cardiac injury in zebrafish, the regeneration process involves three stages: the first is the proliferation of cardiomyocytes, the second is the regeneration of pericardial cells, and the final is the regeneration of vascular endothelial cells.

[0121] To evaluate the effects of compounds for myocardial regeneration and repair, transformed zebrafish (Tg-fli1-eGFP) were anesthetized and cardiac frostbite was performed. Therefore, the vascular endothelial cells of transformed zebrafish can express green fluorescent protein. After frostbite damage was inflicted on the zebrafish heart, the damaged cells could not express green fluorescent protein, allowing for the evaluation of the damaged area of ​​the heart.

[0122] 2.1: Performing cardiac injury in adult zebrafish Cardiac cryogenic injury was performed in zebrafish using a 6 mm long and 0.8 mm wide cryoprobe. To perform cardiac injury, anesthetized adult zebrafish were placed ventrally upward in a sponge slit. The skin and muscle between the two pectoral fins were incised, and then the underlying silvery subcutaneous tissue was gently opened with forceps to access the heart. The cryoprobe was then gently inserted into the chest to make contact with the heart for cryogenic injury.

[0123] To evaluate the regeneration and repair of zebrafish hearts, cardiac aspiration was performed. During cardiac aspiration, the branchial arches in the thoracic region were incised to access the ventricles and visualize the arterial ball and ventricles. The arterial ball was then removed using arterial forceps, and the heart was excised to complete the cardiac aspiration.

[0124] In the present invention, all experimental steps relating to cryogenic injury or cardiac collection are the same as those described above.

[0125] 2.2: Evaluation of the effects of compounds 1 to 46 on myocardial regeneration in zebrafish After inducing cryogenic injury in transformed zebrafish, they were given a 12.5 μg / g test dose daily for 7 days. On day 8, the zebrafish were sacrificed, the area of ​​cardiac injury was calculated, and cardiac collection was performed to further evaluate the effect of promoting myocardial regeneration and repair in the zebrafish.

[0126] Since the vascular endothelial cells of transformed zebrafish can express green fluorescent protein, the fluorescent regions can indicate undamaged areas. In other words, areas without fluorescence are damaged areas, and by calculating the proportion of these areas relative to the heart, the percentage of cryogenically damaged areas can be obtained.

[0127] The group given a test sample containing only the solvent is shown as the solvent group. To confirm the percentage of damage area in the solvent group, zebrafish with cardiac injuries were given a test sample containing only the solvent for 7 days. The percentage of the low-temperature damage area was 27%. Next, zebrafish with cardiac injuries were given test samples containing compounds 1 to 46 for 7 days, and the percentage of the low-temperature damage area for each group was calculated and is shown in Figure 2. As shown in Figure 2, the percentage of the low-temperature damage area in all groups given test samples containing compounds 1 to 46 for 7 days was clearly reduced compared to the result with the solvent group. In other words, compounds 1 to 46 can actually promote myocardial regeneration and repair in zebrafish.

[0128] While various features and advantages of this disclosure, as well as details of its structure and characteristics, have been described above, these descriptions are illustrative only. Details, in particular the shape, dimensions, and arrangement of each part, are modifiable within the scope of the principles of this disclosure as expressed by the broad general meaning of the attached claims.

Claims

1. A pharmaceutical composition for promoting myocardial regeneration, comprising a compound represented by the following formula (II): [Case 1] (In formula (II), R1 is a hydroxy group, an unsubstituted alkyl group having 1 to 6 carbon atoms, an unsubstituted alkoxy group having 1 to 6 carbon atoms, a substituted alkanoic acid group having 1 to 6 carbon atoms, a substituted cycloalkanoic acid group having 7 to 12 carbon atoms, a substituted or unsubstituted arylamine group having 6 to 18 carbon atoms, a substituted or unsubstituted phenol group having 6 to 18 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyridyl group, or an unsubstituted thiazolyl group. R2 is a hydrogen atom, a hydroxy group, an unsubstituted alkyl group having 1 to 6 carbon atoms, an amino group, an acetoxy group, * -O-CH2-CH=CH2 or * -X2(CO)-(Y) p It is a -Z group. R3 is a hydrogen atom, a hydroxy group, an unsubstituted alkyl group having 1 to 6 carbon atoms, an unsubstituted alkoxy group having 1 to 6 carbon atoms, or * -O-CO-(Y) p It is a -Z group, or R2 and R3 combine to form a group represented by formula (ii) below. [Case 2] R4 is a hydrogen atom, an unsubstituted alkoxy group having 1 to 6 carbon atoms, * -O-CH2-CH=CH2 or a group represented by the following formula (iii): [C3] A is a benzene ring, a thiophene ring, or a pyridine ring. X2 is * -O- * , * -NH- * or * -NX4- * and X4 is represented by the following formula (i). [C4] Z is * -C5H4N, * -COCH3, * -COOH, * -COOCH3, * -OCOCH3, * -NHCOOC(CH3)3, * -F, * -Cl, * -Br or * -I, Y is an unsubstituted alkylene group having 1 to 6 carbon atoms, an unsubstituted alkenylene group having 2 to 12 carbon atoms, an unsubstituted arylene alkylene group having 7 to 18 carbon atoms, or an unsubstituted arylene group having 6 to 18 carbon atoms. p is 0 or 1.

2. Z, * -C5H4N, * -COCH3, * -COOH, * -COOCH3, * -OCOCH3, * -NHCOOC(CH3)3 or * 2. The pharmaceutical composition for promoting myocardial regeneration according to claim 1, wherein the compound is -Cl.

3. R2, * -CH3, * -O-CH2-CH=CH2, * -NH2 or * -O-CO-(Y) p 3. The pharmaceutical composition for promoting myocardial regeneration according to claim 1 or 2, wherein the -Z group is a -Z group.

4. R2, * -X2(CO)-(Y) p 3. The pharmaceutical composition for promoting myocardial regeneration according to claim 1 or 2, wherein when R1 is a -Z group, R1 is a hydroxy group.

5. When Y is an alkenylene group, Z is * 5. The pharmaceutical composition for promoting myocardial regeneration according to claim 1, wherein the compound is -COOCH3.

6. 2. The pharmaceutical composition for promoting myocardial regeneration according to claim 1, wherein the compound represented by formula (II) is selected from the group consisting of formulae 1 to 46 below. [C5] [C6] [C7] [C8]

7. 7. The pharmaceutical composition for promoting myocardial regeneration according to any one of claims 1 to 6, further comprising a pharmaceutically acceptable carrier.

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