Edaravone prodrug compound and pharmaceutical use thereof in treatment or alleviation of neurodegenerative or motor neuron disease

Abstract

The present invention provides a novel prodrug of an edaravone compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising same as an active ingredient, and a use thereof in treatment or alleviation of neurodegenerative and/or motor neuron disease.

Claims

1. A compound represented by the following Chemical formula 1 or a pharmaceutically acceptable salt thereof: ##STR00025## In Chemical Formula 1, R.sub.1 and R.sub.2 are each independently hydrogen or (C.sub.1-C.sub.3)alkyl, R.sub.3 is any one selected from the group consisting of (C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.7)cycloalkyl, phenyl, —CH.sub.2NH.sub.2, —CH(CH.sub.3)NH.sub.2, —CH(CH.sub.2OH)NH.sub.2, —CH(CH(CH.sub.3)OH)NH.sub.2, —CH(CH.sub.2SH)NH.sub.2, —CH(CH(CH.sub.3).sub.2)NH.sub.2, —CH(C(CH.sub.3).sub.3)NH.sub.2, —CH(CH.sub.2CH(CH.sub.3).sub.2)NH.sub.2, —CH(CH(CH.sub.3)CH.sub.2CH.sub.3)NH.sub.2, —CH(CH.sub.2CH.sub.2SCH.sub.3)NH.sub.2, pyrrolidin-2-yl, —CH(CH.sub.2Ph)NH.sub.2, —CH(CH.sub.2PhOH-p)NH.sub.2, —CH(1H-indole-3-yl-CH.sub.2)NH.sub.2, —CH(CH.sub.2CO.sub.2H)NH.sub.2, —CH(CH.sub.2CH.sub.2CO.sub.2H)NH.sub.2, —CH(CH.sub.2CONH.sub.2)NH.sub.2, —CH(CH.sub.2CH.sub.2CONH.sub.2)NH.sub.2, —CH(1H-imidazol-4-yl-CH.sub.2)NH.sub.2, —CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2, and —CH.sub.2CH.sub.2CH.sub.2NHC(NH)NH.sub.2.

2. The compound or a pharmaceutically acceptable salt thereof according claim 1, wherein the compound is 3-methyl-1-phenyl-1H-pyrazol-5-yl 4-acetylpiperazine-1-carboxylate; (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-acetyl-2-methylpiperazine-1-carboxylate; (R)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-acetyl-2-methylpiperazine-1-carboxylate; 3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(cyclohexanecarbonyl)piperazine-1-carboxylate; 3-methyl-1-phenyl-1H-pyrazol-5-yl 4-benzoylpiperazine-1-carboxylate; 3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-aminoacetyl)piperazine-1-carboxylate; (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-aminopropanoyl)piperazine-1-carboxylate; (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-amino-3-hydroxypropanoyl)piperazine-1-carboxylate; (R)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-amino-3-mercaptopropanoyl)piperazine-1-carboxylate; (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-amino-3-methylbutanoyl)piperazine-1-carboxylate; (R)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-((S)-2-amino-3-methylbutanoyl)-2-methylpiperazine-1-carboxylate; (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-((S)-2-amino-3-methylbutanoyl)-2-methylpiperazine-1-carboxylate; (R)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-((S)-2-amino-3-methylbutanoyl)-2-ethylpiperazine-1-carboxylate; (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-((S)-2-amino-3-methylbutanoyl)-3-methylpiperazine-1-carboxylate; (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-amino-3,3-dimethylbutanoyl)piperazine-1-carboxylate; (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-amino-4-(methylthio)butanoyl)piperazine-1-carboxylate; (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-amino-3-phenylpropanoyl)piperazine-1-carboxylate; (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2,4-diamino-4-oxobutanoyl)piperazine-1-carboxylate; or (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2,6-diaminohexanoyl)piperazine-1-carboxylate.

3. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. A method for treating or alleviating Alzheimer's disease, Parkinson's disease, or Lou Gehrig's disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

5. A pharmaceutical composition comprising the compound of claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. A method for treating or alleviating Alzheimer's disease, Parkinson's disease, or Lou Gehrig's disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising the compound of claim 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 is a graph of the blood concentration of edaravone over time that appears after intravenous administration of a comparative compound, edaravone, and a single oral administration of a compound of Example 10, one embodiment according to the present invention. In FIG. 1, .box-tangle-solidup. is the result of the edaravone intravenous administration group, and Δ is the result of the oral administration group of the Example 10 compound.

(2) FIG. 2 is a graph of the blood concentration of edaravone over time that appears after intravenous administration of edaravone, a comparative compound, and a single oral administration of a compound of Example 15, another embodiment according to the present invention. In FIG. 2, .box-tangle-solidup. is the result of the edaravone intravenous administration group, and Δ is the result of the oral administration group of the Example 15 compound.

MODE FOR INVENTION

(3) The present invention will be described in more detail based on the following examples, but this is not intended to limit the scope of the present invention. In addition, those of ordinary skill in the art will be able to add various modifications and variations to the present invention within the scope not detrimental to the spirit of the present invention.

(4) First, examples of the compound of Chemical Formula 1 according to the present invention are described below. Representative examples along with specific preparation steps are described below, and compounds having different substituents may be prepared through similar steps. Those of ordinary skill in the art will be able to easily prepare compounds of Chemical Formula 1 with different substituents with reference to the following representative examples.

Reference Example 1: 3-methyl-1-phenyl-1H-pyrazol-5-yl 4-methylpiperazine-1-carboxylate Hydrochloride

(5) ##STR00003##

(6) 1.0 g of 1-methylpiperazine was dissolved in 10 ml of dichloromethane, and 1.2 ml of pyridine (1.5 eq.) was added. The reaction solution was cooled to 0° C. or less under an argon gas environment, and then 3.5 g (1.2 eq.) of triphosgene diluted in 15 ml of dichloromethane was slowly added thereto and stirred. After stirring at room temperature for 2 hours, it was washed with 25 ml of saturated brine, and the organic layer was separated. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain a yellow oily substance. After completely dissolving by adding 10 ml of acetonitrile, 1.74 g (1.0 eq.) of edaravone and 9.76 g (3 eq.) of cesium carbonate were added thereto. After stirring at room temperature for 4 hours, the reaction solution was filtered using Celite, and the filtrate was recovered and concentrated under reduced pressure. The residue was dissolved with 25 ml of ethyl acetate, washed with 25 ml of saturated brine, and the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 1.0 ml of concentrated hydrochloric acid solution and 10 ml of ethyl acetate were added to the concentrated residue, followed by concentration under reduced pressure. 10 ml of ethyl acetate was added thereto, and after concentration under reduced pressure, this process was repeated three times to crystallize to obtain 0.61 g of the title compound. (Yield 18.1%)

(7) .sup.1H NMR (400 MHz, DMSO-d6) δ 2.05 (s, 3H), 2.70 (s, 3H), 2.77-3.30 (m, 8H), 5.95 (s, 1H), 7.15-7.42 (m, 5H)

Synthesis Example 1

(8) ##STR00004##

(9) After dissolving the benzyl piperazine-1-carboxylate derivative in 10-fold volume of dichloromethane, 1.2 equivalents of triethylamine and 1.1 equivalents of the activated ester compound were added. The mixture was stirred for 2 hours at room temperature under an argon gas environment, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran, 5% amount of palladium adsorbed on 10 wt % pure carbon was added thereto, followed by stirring at room temperature under hydrogen gas at atmospheric pressure. After the reaction was completed, the reaction solution was filtered, and the filtrate was recovered and concentrated under reduced pressure. It was purified by column chromatography using silica gel (eluent: a mixture of dichloromethane and methanol) to obtain an acylated piperazine intermediate. A 10-fold volume of dichloromethane was added thereto, dissolved, and 1.5 equivalents of pyridine were added. The reaction solution was cooled to 0° C. or less under an argon gas environment, and then 1.2 equivalents of triphosgene diluted in 15-fold volume of dichloromethane were slowly added dropwise and stirred. After stirring for 2 hours while maintaining 0-5° C., the mixture was washed with saturated brine and the organic layer was separated. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain a yellow oily substance. After 10-fold volume of acetonitrile was added and completely dissolved, 1.0 equivalent of edaravone and 3.0 equivalent of cesium carbonate were added thereto. After stirring at room temperature to confirm the completion of the reaction, the reaction solution was filtered using Celite, and the filtrate was recovered and concentrated under reduced pressure. The residue was dissolved with 10-fold volume of ethyl acetate, washed with saturated brine, and the organic layer was separated, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated residue was purified by column chromatography using silica gel (eluent: a mixture of ethyl acetate and normal hexane) to obtain the target compound.

Synthesis Example 2

(10) ##STR00005##

(11) After dissolving the benzyl piperazine-1-carboxylate derivative in 5-fold volume of dichloromethane and 5-fold volume of N-methyl-2-pyrrolidone (NMP), 1.0 equivalent of amino acid in which the amine group was protected with t-butoxycarbonyl (Boc), 1.1 equivalent of diisopropylcarbodiimide (DIPC), and 1.2 equivalent of triethylamine were added. The mixture was stirred for 2 hours at room temperature under an argon gas environment, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran, 5% amount of palladium adsorbed on 10 wt % pure carbon was added thereto, followed by stirring at room temperature under hydrogen gas at normal pressure. After the reaction was completed, the reaction solution was filtered, and the filtrate was recovered and concentrated under reduced pressure. It was purified by column chromatography using silica gel (eluent: a mixture of dichloromethane and methanol) to obtain an acylated piperazine intermediate. A 10-fold volume of dichloromethane was added thereto, dissolved, and 1.5 equivalents of pyridine were added. The reaction solution was cooled to 0° C. or less under an argon gas environment, and then 1.2 equivalents of triphosgene diluted in 15-fold volume of dichloromethane were slowly added dropwise and stirred. After stirring at room temperature for 2 hours, it was washed with saturated brine and the organic layer was separated. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain a yellow oily substance. After 10-fold volume of acetonitrile was added thereto and completely dissolved, 1.0 equivalent of edaravone and 3.0 equivalent of cesium carbonate were added thereto. After stirring at room temperature to confirm the completion of the reaction, the reaction solution was filtered using Celite, and the filtrate was recovered and concentrated under reduced pressure. The residue was dissolved with 10-fold volume of ethyl acetate, washed with saturated brine, and the organic layer was separated, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated residue was purified by column chromatography using silica gel (eluent: a mixture of ethyl acetate and normal hexane). To the obtained intermediate, 5 equivalents of a 1,4-dioxane solution in which 4N-hydrochloric acid was dissolved was added to completely dissolve, and the mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. After 10-fold volume of ethyl acetate was added thereto, it was concentrated under reduced pressure. (This was repeated 3 times) Finally, 10-fold volume of ethyl acetate was added, and the obtained suspension was filtered to obtain the target compound in a solid state.

Example 1: 3-Methyl-1-phenyl-1H-pyrazol-5-yl 4-acetylpiperazine-1-carboxylate

(12) ##STR00006##

(13) Using 1.0 g of benzyl piperazine-1-carboxylate and 0.36 ml of acetyl chloride, 0.64 g (42.9%) of the title compound as a pale yellow solid was obtained according to the method of Synthesis Example 1. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 2: (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-acetyl-2-methylpiperazine-1-carboxylate

(14) ##STR00007##

(15) Using 1.0 g of (S)-benzyl 2-methylpiperazine-1-carboxylate and 0.34 ml of acetyl chloride, 0.60 g (41.1%) of the title compound as a pale yellow solid was obtained according to the method of Synthesis Example 1. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 3: (R)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-acetyl-2-methylpiperazine-1-carboxylate

(16) ##STR00008##

(17) Using 1.0 g of (R)-benzyl 2-methylpiperazine-1-carboxylate and 0.34 ml of acetyl chloride, 0.72 g (49.3%) of the title compound as a pale yellow solid was obtained according to the method of Synthesis Example 1. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 4: 3-Methyl-1-phenyl-1H-pyrazol-5-yl 4-(cyclohexanecarbonyl)piperazine-1-carboxylate

(18) ##STR00009##

(19) Using 1.0 g of benzyl piperazine-1-carboxylate and 0.67 ml of cyclohexanecarbonyl chloride, 0.41 g (22.8%) of the title compound as a pale yellow solid was obtained according to the method of Synthesis Example 1. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 5: 3-Methyl-1-phenyl-1H-pyrazol-5-yl 4-benzoylpiperazine-1-carboxylate

(20) ##STR00010##

(21) Using 1.0 g of benzyl piperazine-1-carboxylate and 0.58 ml of benzoyl chloride, 0.84 g (47.4%) of the title compound as an off-white solid was obtained according to the method of Synthesis Example 1. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 6: 3-Methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-aminoacetyl)piperazine-1-carboxylate Hydrochloride

(22) ##STR00011##

(23) Using 1.0 g of benzyl piperazine-1-carboxylate and 0.80 g of N-Boc-glycine, 0.42 g (24.4%) of the title compound as an off-white solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 7: (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-aminopropanoyl)piperazine-1-carboxylate Hydrochloride

(24) ##STR00012##

(25) Using 1.0 g of benzyl piperazine-1-carboxylate and 0.86 g of N-Boc-alanine, 0.38 g (21.3%) of the title compound as an off-white solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 8: (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-amino-3-hydroxypropanoyl)piperazine-1-carboxylate Hydrochloride

(26) ##STR00013##

(27) Using 1.0 g of benzyl piperazine-1-carboxylate and 1.45 g of N-Boc-O-TBS-serine, 0.29 g (15.6%) of the title compound as an off-white solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 9: (R)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-amino-3-mercaptopropanoyl)piperazine-1-carboxylate Hydrochloride

(28) ##STR00014##

(29) Using 1.0 g of benzyl piperazine-1-carboxylate and 1.71 g of N-Boc-S-triisopropylsilyl-cysteine, 0.18 g (9.3%) of the title compound as a pale yellow solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 10: (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-amino-3-methylbutanoyl)piperazine-1-carboxylate Hydrochloride

(30) ##STR00015##

(31) Using 1.0 g of benzyl piperazine-1-carboxylate and 0.99 g of N-Boc-valine, 0.39 g (20.4%) of the title compound as an off-white solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 11: (R)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-((S)-2-amino-3-methylbutanoyl)-2-methylpiperazine-1-carboxylate Hydrochloride

(32) ##STR00016##

(33) Using 1.0 g of (R)-benzyl 2-methylpiperazine-1-carboxylate and 0.93 g of N-Boc-valine, 0.35 g (18.8%) of the title compound as an off-white solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 12: (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-((S)-2-amino-3-methylbutanoyl)-2-methylpiperazine-1-carboxylate Hydrochloride

(34) ##STR00017##

(35) Using 1.0 g of (S)-benzyl 2-methylpiperazine-1-carboxylate and 0.93 g of N-Boc-valine, 0.30 g (16.1%) of the title compound as an off-white solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 13: (R)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-((S)-2-amino-3-methylbutanoyl)-2-ethylpiperazin-1-carboxylate Hydrochloride

(36) ##STR00018##

(37) Using 1.0 g of (R)-benzyl 2-ethylpiperazine-1-carboxylate and 0.87 g of N-Boc-valine, 0.15 g (8.3%) of the title compound as an off-white solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 14: (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-((S)-2-amino-3-methylbutanoyl)-3-methylpiperazin-1-carboxylate Hydrochloride

(38) ##STR00019##

(39) Using 1.0 g of (S)-benzyl 3-methylpiperazine-1-carboxylate and 0.93 g of N-Boc-valine, 0.36 g (19.3%) of the title compound as an off-white solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 15: (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-amino-3,3-dimethylbutanoyl)piperazine-1-carboxylate Hydrochloride

(40) ##STR00020##

(41) Using 1.0 g of benzyl piperazine-1-carboxylate and 1.05 g of N-Boc-t-leucine, 0.38 g (19.2%) of the title compound as an off-white solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 16: (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-amino-4-(methylthio)butanoyl)piperazine-1-carboxylate Hydrochloride

(42) ##STR00021##

(43) Using 1.0 g of benzyl piperazine-1-carboxylate and 1.13 g of N-Boc-methionine, 0.28 g (13.6%) of the title compound as an off-white solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 17: (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2-amino-3-phenylpropanoyl)piperazine-1-carboxylate Hydrochloride

(44) ##STR00022##

(45) Using 1.0 g of benzyl piperazine-1-carboxylate and 1.20 g of N-Boc-phenylalanine, 0.35 g (16.4%) of the title compound as an off-white solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 18: (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2,4-diamino-4-oxobutanoyl)piperazine-1-carboxylate Hydrochloride

(46) ##STR00023##

(47) Using 1.0 g of benzyl piperazine-1-carboxylate and 1.05 g of N-Boc-asparagine, 0.15 g (7.6%) of the title compound as a brown solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

Example 19: (S)-3-methyl-1-phenyl-1H-pyrazol-5-yl 4-(2,6-diaminohexanoyl)piperazine-1-carboxylate Dihydrochloride

(48) ##STR00024##

(49) Using 1.0 g of benzyl piperazine-1-carboxylate and 1.57 g of N,N′-di-Boc-lysine, 0.20 g (9.0%) of the title compound as a brown solid was obtained according to the method of Synthesis Example 2. The results of nuclear magnetic resonance analysis and mass spectrometry are shown in Table 2 below.

(50) The results of nuclear magnetic resonance analysis and mass spectrometry of the above examples are shown in Table 2 below.

(51) TABLE-US-00002 TABLE 2 Compound Nuclear Magnetic Resonance Analysis Mass Analysis Example 1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 2.18 (3H, s), 2.32 (3H, s), 3.35- [M + 1].sup.+, 329.0 3.65 (8H, m), 6.10 (1H, s), 7.45-7.66 (5H, m) Example 2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.30 (3H, d), 2.17 (3H, s), 2.30 (3H, [M + 1].sup.+, 343.0 s), 3.28-3.55 (6H, m), 4.32 (1H, q), 6.07 (1H, s), 7.40-7.58 (5H, m) Example 3 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.30 (3H, d), 2.17 (3H, s), 2.30 (3H, [M + 1].sup.+, 343.0 s), 3.28-3.55 (6H, m), 4.32 (1H, q), 6.07 (1H, s), 7.40-7.58 (5H, m) Example 4 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.32-1.60 (10H, m), 2.20 (3H, s), [M + 1].sup.+, 397.1 2.32-2.35 (1H, m), 3.38-3.95 (8H, m), 6.09 (1H, s), 7.32-7.50 (5H, m) Example 5 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 2.18 (3H, s), 3.35-3.65 (8H, m), [M + 1].sup.+, 391.0 6.10 (1H, s), 7.40-7.69 (10H, m) Example 6 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 2.20 (3H, s), 3.30-3.60 (8H, m), [M + 1].sup.+, 344.0 3.80-3.82 (2H, m), 6.08 (1H, s), 7.31-7.46 (5H, m), 8.35 (3H, br s) Example 7 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.16 (3H, d), 2.17 (3H, s), 3.30- [M + 1].sup.+, 358.0 3.60 (8H, m), 3.74 (1H, q), 6.05 (1H, s), 7.35-7.49 (5H, m), 8.25 (3H, br s) Example 8 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 2.16 (3H, s), 3.32-3.58 (8H, m), [M + 1].sup.+, 374.0 3.65-3.68 (1H, m), 3.82-4.02 (2H, m), 6.07 (1H, s), 7.28-7.50 (5H, m), 8.22 (3H, br s) Example 9 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 2.15 (3H, s), 2.94-3.19 (2H, m), [M + 1].sup.+, 390.1 3.30-3.59 (8H, m), 3.78-3.88 (1H, t), 6.07 (1H, s), 7.29-7.50 (5H, m), 8.21 (3H, br s) Example 10 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.94 (6H, d), 1.95-2.05 (1H, m), [M + 1].sup.+, 386.1 2.17 (3H, s), 3.30-3.65 (8H, m), 4.22 (1H, d), 6.07 (1H, s), 7.30- 7.49 (5H, m), 8.14 (3H, br s) Example 11 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.91 (6H, d), 1.33 (3H, d), 1.96- [M + 1].sup.+, 400.1 2.01 (1H, m), 2.18 (3H, s), 3.30-3.61 (6H, m), 4.20 (1H, d), 4.35- 4.38 (1H, m), 6.06 (1H, s), 7.28-7.52 (5H, m), 8.56 (3H, br s) Example 12 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.92 (6H, d), 1.35 (3H, d), 1.96- [M + 1].sup.+, 400.1 2.00 (1H, m), 2.15 (3H, s), 3.28-3.60 (6H, m), 4.21 (1H, d), 4.36- 4.38 (1H, m), 6.07 (1H, s), 7.28-7.52 (5H, m), 8.44 (3H, br s) Example 13 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.90 (6H, d), 0.95 (3H, t), 1.64- [M + 1].sup.+, 414.1 1.68 (2H, m), 1.98-2.00 (1H, m), 2.16 (3H, s), 3.28-3.60 (6H m), 4.19 (1H, d), 4.40-4.43 (1H, m), 6.07 (1H, s), 7.30-7.52 (5H, m), 8.21 (3H, br s) Example 14 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.90 (6H, d), 1.31 (3H, d), 1.97- [M + 1].sup.+, 400.1 2.01 (1H, m), 2.18 (3H, s), 3.32-3.60 (6H, m), 4.22 (1H, d), 4.38- 4.45 (1H, m), 6.07 (1H, s), 7.31-7.58 (5H, m), 8.46 (3H, br s) Example 15 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.95 (9H, s), 2.18 (3H, s), 3.30- [M + 1].sup.+, 400.1 3.60 (8H, m), 4.20 (1H, s), 6.08 (1H, s), 7.31-7.51 (5H, m), 8.14 (3H, br s) Example 16 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 2.04-2.08 (2H, m), 2.15 (3H, s), [M + 1].sup.+, 418.1 2.20 (3H, s), 2.57 (2H, t), 3.28-3.66 (9H, m), 6.06 (1H, s), 7.29- 7.52 (5H, m), 8.80 (3H, br s) Example 17 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 2.17 (3H, s), 3.15-3.68 (10H, m), [M + 1].sup.+, 434.1 3.97-4.02 (1H, m), 6.10 (1H, s), 7.31-7.62 (10H, m), 8.36 (3H, br s) Example 18 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 2.15 (3H, s), 2.56-2.65 (2H, m), [M + 1].sup.+, 401.1 3.33-3.55 (8H, m), 3.89-3.92 (1H, m), 6.10 (1H, s), 6.66 (2H, br s), 7.31-7.55 (5H, m), 8.47 (3H, br s) Example 19 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.22-1.25 (2H, m), 1.58-1.62 [M + 1].sup.+, 415.1 (2H, m), 1.79-1.84 (2H, m), 2.15 (3H, s), 2.78-2.82 (2H, m), 3.30- 3.62 (9H, m), 5.67 (3H, br s), 6.07 (1H, s), 7.31-7.50 (5H, m), 8.81 (3H, br s)

Experimental Example 1: Pharmacokinetic Evaluation

(52) The pharmacokinetic test of the compounds of Examples and Reference Example was carried out as follows. That is, after a single oral administration of the test compound to SD (Sprague-Dawley) rats, the efficacy of the compound of the present invention was verified by tracking the kinetics of the edaravone released into the blood by metabolic processes and comparing it with a standard substance. Specifically, edaravone, a standard substance, was administered intravenously and orally, respectively, and the test compounds were administered orally. Then, the concentration of edaravone in blood was evaluated. The standard substance and the test compounds were each prepared in the same manner and then administered to rats at a dose of 0.1 mmol/kg, and blood was collected at a predetermined time and plasma was separated. Analysis of the drug was performed using HPLC (XBridge column Cis, Waters, mobile phase 0.1% formic acid:acetonitrile (30:70, %/%)) and MS/MS (ESI positive, MRM). Each commercial standard solution was mixed in a ratio of 9:1 with rat plasma to prepare and calibrate at concentrations of 5, 50, 100, 500, 1000 and 5000 ng/ml. In addition, the QC sample was prepared by mixing the rat plasma and the standard solution for QC at a ratio of 9:1, and at concentrations of 100, 750 and 2,500 ng/ml. In the pretreatment method, 100 μl of plasma sample was transferred to a tube for centrifugation, 10 μl of an internal standard solution and 300 μl of methanol were added, followed by mixing for about 30 seconds. The tube was centrifuged at 3,000×g (4° C.) for about 5 minutes, the supernatant was taken and transferred to an LC vial, and then injected into the instrument. In addition, the concentration of an active ingredient, that is, edaravone, in rat plasma was quantified by applying a previously validated analysis method. For pharmacokinetic parameters, WinNonlin 5.2 (Pharsight, USA) program was used, and AUC.sub.0-t, AUC.sub.0-∞, C.sub.max, T.sub.max, and t.sub.1/2 were calculated by noncompartment modeling (best fit). The pharmacokinetic parameter results were expressed as mean and standard deviation (SD), and statistically processed using the SPSS program (Statistical Package for the Social Sciences, 10.0K, USA).

(53) After the test, each bioavailability after oral administration of standard substance and test compounds is summarized in Table 3 below.

(54) TABLE-US-00003 TABLE 3 Test Compound Bioavailability (F, %) Standard substance 4.9 (edaravone) Example 1 23.0 Example 2 20.5 Example 3 19.2 Example 4 29.6 Example 5 32.3 Example 6 54.9 Example 7 56.5 Example 8 49.1 Example 9 48.8 Example 10 88.2 Example 11 59.8 Example 12 57.2 Example 13 46.9 Example 14 64.5 Example 15 60.7 Example 16 41.1 Example 17 56.6 Example 18 57.0 Example 19 71.2 Reference Example 1 12.0

(55) For the representative Example 10 compound, the average AUC.sub.t is 9,835 hr*ng/ml, the average AUC.sub.i is 9,856 hr*ng/ml, the average C.sub.max is 1,803 ng/ml, the average T.sub.max is 1.00 hour, the average t.sub.1/2 is 2.51 hours, and the bioavailability was 88.2%. On the other hand, for Example 15 compound, the average AUC.sub.t was 6,772 hr*ng/ml, the average AUC.sub.i was 6,795 hr*ng/ml, the average C.sub.max was 1,696 ng/ml, the average T.sub.max was 0.42 hours, and the average t.sub.1/2 was 2.69 hours, and the bioavailability was 60.7%. After oral administration of Example 10 compound and Example 15 compound, the blood concentration of edaravone over time is as shown in FIGS. 1 and 2, respectively.

(56) As shown in the results of Table 3, in particular, the oral bioavailability of the compounds of Example 10, Example 19, Example 14, and Example 15 was excellent.