Compounds useful for treatment or prevention of muscular dystrophy and derivatives for treatment, amelioration or prevention of muscular dystrophy in medicinal use thereof

Abstract

The present invention relates to a novel compound and a medicinal use of the novel compound. In particular, the present invention relates to a novel compound useful for the treatment and/or prevention of muscular dystrophy, including Duchenne muscular atrophy, and a medicinal use of the novel compound.

Claims

1. A compound represented by Chemical formula 1 ##STR00006## wherein L is selected from the group consisting of straight or branched alkyl having 1 to 3 carbon atoms and benzyl.

2. The compound according to claim 1, wherein the compound is 1-(3-hydroxy-3-methylbutanoyloxy)ethyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate; (3-hydroxy-3-methylbutanoyloxy)methyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate; 2-(3-hydroxy-3-methylbutanoyloxy)ethyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate; or 4-(3-hydroxy-3-methylbutanoyloxy)benzyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate.

3. A pharmaceutical composition, comprising the compound of claim 1 as an active ingredient.

4. The pharmaceutical composition according to claim 3, wherein the compound is 1-(3-hydroxy-3-methylbutanoyloxy)ethyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate; (3-hydroxy-3-methylbutanoyloxy)methyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate; 2-(3-hydroxy-3-methylbutanoyloxy)ethyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate; or 4-(3-hydroxy-3-methylbutanoyloxy)benzyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate.

5. A method for treating muscular dystrophy, comprising: administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1.

6. The method according to claim 5, wherein the muscular dystrophy is progressive muscular dystrophy.

7. The method according to claim 5, wherein the muscular dystrophy is Duchenne muscular atrophy.

8. The method according to claim 5, wherein the compound is 1-(3-hydroxy-3-methylbutanoyloxy)ethyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate; (3-hydroxy-3-methylbutanoyloxy)methyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate; 2-(3-hydroxy-3-methylbutanoyloxy)ethyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate; or 4-(3-hydroxy-3-methylbutanoyloxy)benzyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the concentration-time trend of ataluren in the blood after a single oral administration of the compound of Example 3. In FIG. 1, Δ denotes the administration group of Example 3 compound, and .box-tangle-solidup. denotes the administration group of ataluren, standard substance.

DETAILED DESCRIPTION

(2) Hereinafter, examples and the like will be described in detail to help the understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art to which the present invention pertains.

(3) 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.

Example 1

1-(3-hydroxy-3-methylbutanoyloxy)ethyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate

(4) ##STR00002##

(5) 200 mg of ataluren, 127 mg of 1-chloroethyl 3-hydroxy-3-methylbutanoate and 688 mg of cesium carbonate were suspended in 10 ml of acetonitrile. It was stirred under reflux overnight and then concentrated. After dilution with 10 ml of water, the mixture was extracted three times with 10 ml of dichloromethane, dried over anhydrous magnesium sulfate, concentrated again, and purified by silica gel chromatography (5% methanol, dichloromethane) to obtain 210 mg of the compound as a white solid.

(6) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.25 (6H, s), 1.72 (3H, d), 2.40 (2H, s), 5.55 (1H, q), 7.25-7.32 (2H, m), 7.61-7.65 (2H, m), 8.10-8.25 (2H, m), 8.22 (1H, d), 8.80 (1H, s)

Example 2

(3-hydroxy-3-methylbutanoyloxy)methyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate

(7) ##STR00003##

(8) 200 mg of ataluren, 117 mg of chloromethyl 3-hydroxy-3-methylbutanoate and 688 mg of cesium carbonate were suspended in 10 ml of acetonitrile. It was stirred under reflux overnight and then concentrated. After dilution with 10 ml of water, the mixture was extracted three times with 10 ml of dichloromethane, dried over anhydrous magnesium sulfate, concentrated again, and purified by silica gel chromatography (5% methanol, dichloromethane) to obtain 190 mg of the compound as a white solid.

(9) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.23 (6H, s), 2.33 (2H, s), 6.85 (2H, s), 7.15-7.32 (2H, m), 7.50-7.63 (2H, m), 8.06-8.15 (2H, m), 8.18 (1H, d), 8.76 (1H, s)

Example 3

2-(3-hydroxy-3-methylbutanoyloxy)ethyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate

(10) ##STR00004##

(11) 200 mg of ataluren and 227 mg of 2-hydroxyethyl 3-hydroxy-3-methylbutanoate were suspended in 7 ml of tetrahydrofuran. 201 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 86 mg of dimethylaminopyridine were added, stirred overnight, and then concentrated. After dilution with 10 ml of water, the mixture was extracted three times with 10 ml of dichloromethane, dried over anhydrous magnesium sulfate, concentrated again, and purified by silica gel chromatography (3% methanol, dichloromethane) to obtain 314 mg of the compound as an oil. A small amount of normal hexane was added thereto and left for 2 days to obtain 250 mg of the above compound as a white solid.

(12) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.28 (6H, s), 2.56 (2H, s), 4.50 (2H, t), 4.59 (2H, t), 7.28-7.35 (2H, m), 7.60-7.65 (2H, m), 8.18-8.25 (2H, m), 8.39 (1H, d), 8.83 (1H, s)

Example 4

4-(3-hydroxy-3-methylbutanoyloxy)benzyl 3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoate

(13) ##STR00005##

(14) 150 mg of ataluren and 178 mg of 4-(hydroxymethyl)phenyl 3-hydroxy-3-methylbutanoate were suspended in 6 ml of tetrahydrofuran. 151 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 65 mg of dimethylaminopyridine were added, stirred overnight, and then concentrated. After dilution with 10 ml of water, the mixture was extracted three times with 10 ml of dichloromethane, dried over anhydrous magnesium sulfate, concentrated again, and purified by silica gel chromatography (3% methanol, dichloromethane) to obtain 242 mg of the compound as a white solid.

(15) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.38 (6H, s), 2.76 (2H, s), 5.40 (2H, s), 7.11 (2H, d), 7.25-7.35 (2H, m), 7.50 (2H, d), 7.60-7.63 (2H, m), 8.23-8.27 (2H, m), 8.38 (1H, d), 8.85 (1H, s)

Example 5

Pharmacokinetic Evaluation

(16) A pharmacokinetic study of Example 3 compound was performed as follows. That is, after a single oral administration of a test substance to SD (Sprague-Dawley) rats, the efficacy of the compound of the present invention was verified by tracking the kinetics of ataluren released into the blood by metabolic process and comparing it with a standard substance. Specifically, after preparing the test substance (Example 3 compound and ataluren standard, respectively), a single oral administration at a dose of 0.141 mol/kg to rats was performed, and blood was collected at a predetermined time, and then plasma was separated. Analysis of the drug was performed using HPLC (XBridge column C.sub.18, Waters, Mobile phase 0.1% formic acid:acetonitrile (35:65, %/%)) and MS/MS (ESI positive, MRM). A calibration solution of 5, 50, 100, 500, 1000 and 5000 ng/ml was prepared by mixing the rat blank plasma and each standard solution in a ratio of 9:1, and the calibration was performed therewith. In addition, QC sample was prepared as 100, 750 and 2500 ng/ml concentration by mixing rat blank plasma and standard solution for QC in a ratio of 9:1. As for the pretreatment method, 100 μl of the plasma sample was transferred to a centrifuge tube, 10 μl of the internal standard solution and 300 μl of methanol were added and mixed for about 30 seconds. The tube was centrifuged at 3000×g (4° C.) for about 5 minutes, and the supernatant was transferred to an LC vial and then injected into the instrument. And the concentration of the active ingredient, that is, ataluren in rat plasma was quantified by applying a previously verified assay. 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). Pharmacokinetic parameter results were expressed as mean (Mean) and standard deviation (SD), and were statistically processed using the SPSS program (Statistical Package for the Social Sciences, 10.0K, USA).

(17) As a result of the test, after oral administration of Example 3 compound (0.141 mmol/kg, n=3), the mean AUC.sub.t of ataluren in plasma was 327171 hr*ng/ml, the mean AUC.sub.i was 335533 hr*ng/ml, and the mean C.sub.max was 26560 ng/ml. The average T.sub.max of ataluren was 2.00 hr, and the average t.sub.1/2 was 3.93 hr, and the bioavailability was 123.1% compared to that of orally administered standard substance. The trend of ataluren blood concentration over time after oral administration of Example 3 compound is shown in FIG. 1.

Assessment of Ataluren Blood Concentration After Administration

(18) TABLE-US-00001 TABLE 1 Compound administered AUC.sub.t AUCi Cmax Tmax t.sub.1/2 Dose (n = 3) hr * ng/ml hr * ng/ml ng/ml hr hr Example 3 327,171 335,533 26,560 2.00 3.93 0.141 mmol/kg ataluren 265,692 266,618 28,049 8.00 2.08 0.141 mmol/kg

(19) As shown in Table 1, not only the bioavailability of the compound according to the present invention was greatly improved compared to ataluren, but also the onset time of the drug was able to be accelerated, and in particular, it was confirmed that the duration of the drug effect could be extended through the increased half-life.