AMINOPYRIDINE COMPOUND

Abstract

An aminopyridine compound that may be used as an aldehyde trapping agent, and specifically disclosed is a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

##STR00001##

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, ##STR00031## wherein, L is selected from —O— and —(CR.sub.4R.sub.5).sub.n—; R.sub.1 is selected from —C.sub.1-6 alkyl- and —C.sub.3-5 cycloalkyl-, and the —C.sub.1-6 alkyl- and —C.sub.3-5cycloalkyl-are optionally substituted by 1, 2 or 3 R.sub.a; ring A is selected from phenyl, pyridyl and 5-membered heteroaryl, and the phenyl, pyridyl and 5-membered heteroaryl are optionally substituted by 1, 2 or 3 R.sub.3; and when ring A is selected from phenyl and pyridyl, then R.sub.2 is selected from —C.sub.5-6 alkyl-and —C.sub.3-5 cycloalkyl-, and the —C.sub.5-6 alkyl- and —C.sub.3-5 cycloalkyl-are optionally substituted by 1, 2 or 3 R.sub.b; when ring A is selected from 5-membered heteroaryl, then R.sub.2 is selected from —C.sub.1-6 alkyl-and —C.sub.3-5 cycloalkyl-, and the —C.sub.1-6 alkyl- and —C.sub.3-5 cycloalkyl-are optionally substituted by 1, 2 or 3 R.sub.c; R.sub.3 is selected from H, F, Cl, Br, I and CH.sub.3; R.sub.4 and R.sub.5 are each independently selected from H and CH.sub.3; n is selected from 0, 1 and 2; R.sub.a, R.sub.b and R.sub.c are each independently selected from F, Cl, Br and I; the “5-membered heteroaryl” comprises 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from —O—, —NH—, —S— and N, respectively.

2. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.1 is selected from CH.sub.2, C(CH.sub.3).sub.2, C(CH.sub.2CH.sub.3).sub.2, cyclopropyl and cyclobutyl, and the CH.sub.2, C(CH.sub.3).sub.2, C(CH.sub.2CH.sub.3).sub.2, cyclopropyl and cyclobutyl are optionally substituted by 1, 2 or 3 R.sub.a.

3. The compound or the pharmaceutically acceptable salt thereof according to claim 2, wherein R.sub.1 is selected from C(CH.sub.3).sub.2, C(CH.sub.2CH.sub.3).sub.2, cyclopropyl and cyclobutyl.

4. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein when ring A is selected from phenyl and pyridyl, then R.sub.2 is selected from C(CH.sub.2CH.sub.3).sub.2, cyclopropyl and cyclobutyl.

5. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein when ring A is selected from 5-membered heteroaryl, then R.sub.2 is selected from C(CH.sub.3).sub.2, C(CH.sub.2CH.sub.3).sub.2, cyclopropyl and cyclobutyl.

6. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein L is selected from a single bond, —O—, CH.sub.2 and —CH.sub.2CH.sub.2—.

7. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is selected from phenyl, pyridyl, pyrrolyl, furyl, thienyl, oxazolyl and thiazolyl, and the phenyl, pyridyl, pyrrolyl, furyl, thienyl, oxazolyl and thiazolyl are optionally substituted by 1, 2 or 3 R.sub.3.

8. The compound or the pharmaceutically acceptable salt thereof according to claim 7, wherein ring A is selected from ##STR00032##

9. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit ##STR00033## is selected from ##STR00034##

10. The compound or the pharmaceutically acceptable salt thereof according to claim 9, wherein the structural unit ##STR00035## is selected from ##STR00036## ##STR00037## ##STR00038##

11. The compound or the pharmaceutically acceptable salt thereof according to claim 1, selected from, ##STR00039## wherein, T.sub.1, T.sub.3 and T.sub.4 are each independently selected from N and CR.sub.3; T.sub.2, T.sub.5 and T.sub.6 are selected from CR.sub.3; T.sub.7 is selected from N and CR.sub.3; T.sub.8 is selected from O and S; R.sub.3 is selected from H, F, Cl, Br, I and CH.sub.3; R.sub.1, R.sub.2 and L are as defined in claim 1.

12. A compound represented by the following formula or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the following compounds: ##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045##

13. A method for treating diseases related to an aldehyde trapping agent in a subject in need thereof, comprising: administering an effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 1 to the subject.

14. The method according to claim 13, wherein, the diseases related to the aldehyde trapping agent is xerophthalmia.

15. A method for treating diseases related to an aldehyde trapping agent in a subject in need thereof, comprising: administering an effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 12 to the subject.

16. The method according to claim 15, wherein, the diseases related to the aldehyde trapping agent is xerophthalmia.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0072] FIG. 1 is the test result of in vitro aldehyde-trapping ability of the compound of the present disclosure.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0073] The present disclosure is described in detail by the embodiments below, but it does not mean that there are any adverse restrictions on the present disclosure. The present disclosure has been described in detail herein, and its specific embodiments have also been disclosed, for one skilled in the art, it is obvious to make various modifications and improvements to the embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

Embodiment 1

[0074] ##STR00028##

[0075] Synthetic Route:

##STR00029##

Step 1: Preparation of Compound 1-3

[0076] Compound 1-1 (1 g, 3.98 mmol, 1 eq) and compound 1-2 (1.44 g, 4.38 mmol, 1.1 eq) were dissolved in toluene (20 mL), and tetrakistriphenylphosphine (460 mg, 398.08 μmol, 0.1 eq) was added to the reaction solution. The reactor was replaced three times with nitrogen, and the mixture was heated to 130° C. and stirred for 2 hours. The mixture was cooled to room temperature, filtered, and the filter cake was rinsed with 5 mL of toluene. The filter cake was collected and dried to obtain compound 1-3 without further purification.

[0077] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.18 (d, J=2.0 Hz, 1H), 7.74 (s, 2H), 7.57 (d, J=2.0 Hz, 1H), 6.84 (s, 2H), 4.30 (dq, J=2.5, 7.0 Hz, 4H), 1.32 (dt, J=4.8, 7.2 Hz, 6H).

Step 2: Preparation of Compound 1-4

[0078] Compound 1-3 (500 mg, 1.49 mmol, 1 eq) and triethylamine (472.55 mg, 4.67 mmol, 0.65 mL, 3.14 eq) were dissolved in tetrahydrofuran (10 mL), cooled to 0° C., and benzyl chloroformate (600.00 mg, 3.52 mmol, 500.00 μL, 2.37 eq) was added dropwise thereto. After the addition was completed, the reaction was stirred at 0 to 25° C. for 12 hours. After the reaction was completed, the mixture was added with water (20 mL) to quench the reaction, extracted with ethyl acetate (30 mL*3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated.

[0079] The residue was purified by column chromatography (petroleum ether:ethyl acetate=2:1) to obtain compound 1-4.

[0080] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.32 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.53−7.37 (m, 5H), 6.89 (s, 2H), 5.32 (s, 2H), 4.44−4.27 (m, 4H), 1.34 (dt, J=5.5, 7.0 Hz, 6H).

Step 3: Preparation of Compound 1-5

[0081] Compound 1-4 (300 mg, 637.62 μmol, 1 eq) was dissolved in tetrahydrofuran (20 mL), cooled to 0° C., and methylmagnesium bromide (3 M, 6.38 mL, 30 eq) was added dropwise thereto. After the addition was completed, the reaction was stirred at 0° C. for 2 hours. After the reaction was completed, the mixture was added with water (20 mL) to quench, extracted with ethyl acetate (30 mL*3), and the organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=2:1) to obtain compound 1-5.

[0082] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.30-9.17 (m, 1H), 8.26 (s, 1H), 7.43-7.28 (m, 7H), 5.26-5.12 (m, 2H), 1.72 (s, 6H), 1.69 (s, 6H).

Step 4: Preparation of Compound 1

[0083] Compound 1-5 (50 mg, 112.99 μmol, 1 eq) and Pd/C (100 mg, 10% content) were added to methanol (10 mL), and the reaction was stirred at 25° C. for 3 hours under the protection of hydrogen sphere (15 psi). After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 1.

[0084] .sup.1H NMR (400 MHz, MeOD) δ 8.09 (d, J=2.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 1.63 (s, 12H).

Experimental Embodiment 1: Experiment of Aldehyde-Trapping Ability in Vitro

1. Experimental Objective and Process

[0085] Objective: xerophthalmia is caused by inflammations inside the eye, and these inflammations would produce some aldehydes in vivo. If these aldehydes are not eliminated in time, the symptoms of inflammations would be accelerated and worsen the xerophthalmia. In this experiment, by simulating the in vivo environment, a relatively preferred compound was selected according to the complexing ability of the drug and the aldehyde in vivo.

[0086] Process: sulfobutyl-B-cyclodextrin (310 mg) was dissolved in phosphate buffer (1.25 mL) to prepare a solution.

[0087] Nonanal (5.0 mg, 32 μmol, 1.0 eq) and glyceryl trioleate (300 mg) were added into a reaction flask at room temperature. After the above prepared solution was added thereto, linoleic acid (300 mg) was then added thereto, and finally a dimethyl sulfoxide (0.15 mL) solution containing the compound of the present disclosure (32 μmol, 1.0 eq) was added thereto. The reaction solution was reacted at 20 to 23° C.

[0088] After stirring and reacting for 10 minutes, 100 minutes, 200 minutes, and 300 minutes, respectively, the reaction solution was allowed to stand for 2 minutes, layered and then sampled for high performance liquid detection.

[0089] Sampling method: 25 μL of the upper emulsion layer and 50 μL of the lower aqueous phase were sampled with a pipette, and diluted with 1 mL of methanol.

2. Experimental Results

[0090] Nonanal has weak ultraviolet absorption at a wavelength of 254 nm, and has little influence on the content of complexation product as a whole. Therefore, the percentage content of the complexed compound at 254 nm in high performance liquid phase was compared to observe the ability of the compound to trap and complex aldehyde. See FIG. 1 and Table 3:

##STR00030##

[0091] The HPLC analysis method is shown in Table 1 below, which is XBRIGE 2.5 m, 3.0*100 mm 5-95CD_XBEH_12 min_0.8.lcm

TABLE-US-00001 TABLE 1 Chromatographic column XBridge BEH C18 3.0*100 mm, 2.5 μm Detection wavelength 220, 254 nm Column temperature 40° C. Flow rate 0.8 mL/min Injection volume 1 μL Mobile phase A: 0.02% aqueous ammonia solution B: acetonitrile Gradient elution Time (minutes) A % B % 0.01 95 5 6.00 15 85 9.00 5 95 12.00 5 95

[0092] The specific TIPLC data of the percentage content of the complex product of the compound of the present disclosure are as shown in Table 2 below:

TABLE-US-00002 TABLE 2 Time (minutes) Compound 10 100 200 300 1 1.095 4.751 8.764 12.496

TABLE-US-00003 TABLE 3 Statistics of test results of aldehyde-trapping ability of the compound Regression Area under the curve AUC Compound Linear equation Slope coefficient R.sup.2 (min. conversion rate) Compound 1 y = 0.0394x + 0.0394 R.sup.2 = 0.9996 1874 0.7705

[0093] Conclusion: The compound of the present disclosure has remarkable ability and speed to complex aldehyde.