Use of a compound in the manufacture of a medicament for the prevention or treatment of supraventricular arrhythmias

Abstract

The present application discloses the use of a compound of formula (I), in particular of formula (IB), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of supraventricular arrhythmias, in particular atrial fibrillation. The compounds have a good effect on supraventricular arrhythmias, preferably atrial arrhythmias, in particular atrial fibrillation, and can meet the needs of prevention and treatment.

Description

TECHNICAL FIELD

[0001] The present application relates to the use of a compound in the preparation of a medicament for preventing or treating supraventricular arrhythmia. The present application also relates to a pharmaceutical composition and the use thereof in the preparation of a medicament for preventing or treating supraventricular arrhythmia. BACKGROUND

[0002] The compound of formula (I) is a known compound in the prior art, and is known to have anti-tumor activity.

[0003]

[0004] However, the inventors of the present application surprisingly found that the compound of formula (I) has a very good effect on supraventricular arrhythmia, preferably atrial arrhythmia, in particular atrial fibrillation (abbreviated as "AF"), and can meet the needs of prevention and treatment, thus completing the present application. SUMMARY

[0005] One aspect of the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating supraventricular arrhythmia.

[0006] The compound of formula (I) has a chiral center, which usually exists in two specific configurations of formula (IA) or formula (IB). The inventors of the present application surprisingly found that although the two structures are very similar, the compound of formula (IB) has a much better effect on supraventricular arrhythmia than the compound of formula (IA). Therefore, in one embodiment, the compound of formula (I) described in the present application is a compound of formula (IB) (or a pharmaceutically acceptable salt thereof).

[0007]

[0008] In one embodiment, the supraventricular arrhythmia is atrial arrhythmia. In a preferred embodiment, the atrial arrhythmia is atrial fibrillation. DETAILED DESCRIPTION

[0009] The present application is further illustrated by the following specific examples. It should be appreciated that the examples are not intended to limit the scope of the present application. The raw materials, reagents, etc. used in the examples are all known to those skilled in the art and can be obtained by commercial or literature methods; the test or characterization methods used are also known to those skilled in the art.

[0010] Example 1: Preparation and separation of the compound of formula (I), the compound of formula (IA) and the compound of formula (IB)

[0011]

[0012] Step 1: Synthesis of intermediate M-1

[0013] To a solution of sophoridine (24.82 g, 0.10 mol) and potassium tert-butoxide (39.27 g, 0.35 mol) in THF (200 ml) was added tert-butyl nitrite (15.47 g, 0.15 mol) dropwise at 0 °C under nitrogen protection. The reaction was continued for 0.5-1.0 h until completion. TLC detection showed that the reaction was completed. 3N hydrochloric acid solution (700 ml, pH = 1-2) was added. The mixture was stirred at room temperature for 0.5-1.0 h. Filtration was performed and the filter cake was dried to obtain M-1 (30.00 g, yield 96%). LCMS [M+H] + 278.36 (C 15 H 23 N3O2: 277.36).

[0014] Step 2: Synthesis of the compound of formula (I)

[0015] To a solution of M-1 (25.10 g, 0.08 mol) and ammonium chloride (25.67 g, 0.48 mol) in water (125 ml) was added zinc powder (18.31 g, 0.28 mol) in batches at 20-30 °C under stirring. The reaction was continued for 3-5 h until completion. TLC detection showed that the reaction was completed. Filtration was performed at room temperature. Oxalic acid (14.41 g, 0.16 mol) was added to the filtrate, which was stirred for 0.5-1.0 h. 30% sodium hydroxide (75 ml, pH = 9-10) was added dropwise, and the mixture was stirred for 0.5-1.0 h. Filtration was performed, and dichloromethane (300 ml x 3) was added to the filtrate for extraction. Anhydrous sodium sulfate was added for drying. The filtrate was evaporated under reduced pressure to obtain the compound of formula (I) (20.00 g, yield 95%). LCMS [M+H] + 264.38 (C 15 H 25 N3O: 263.38).

[0016] Step 3: Separation of the compound of formula (IA) and the compound of formula (IB)

[0017] The obtained compound of formula (I) (20.00 g, 0.076 mol) was purified and separated by column chromatography on silica gel (300-400 mesh) with a mixture of dichloromethane and methanol (V 二氯甲烷 :V 甲醇 = 30:1-5:1) to obtain the compound of formula (IA) (8.00 g, yield 40%) and the compound of formula (IB) (8.00 g, yield 40%).

[0018] The compound of formula (IA): LCMS [M+H] + 264.38 (C 15 H25 N3O: 263.38). 1 HNMR (400 MHz, D20) δ 3.92-3.79 (m, 2H), 3.58-3.45 (m, 1H), 3.30-3.12 (m, 1H), 2.96-2.89 (m, 2H), 2.89-2.80 (m, 1H), 2.63-2.05 (m, 4H), 2.01-1.65 (m, 4H), 1.62-1.48 (m, 6H), 1.35-1.04 (m, 2H).

[0019] a compound of formula (IB): LCMS [M+H] + 264.38 (C 15 H 25 N3O: 263.38). 1 HNMR (400 MHz, D20) δ 3.92-3.79 (m, 2H), 3.58-3.45 (m, 1H), 3.30-3.12 (m, 1H), 2.96-2.89 (m, 2H), 2.89-2.80 (m, 1H), 2.63-2.05 (m, 4H), 2.01-1.65 (m, 4H), 1.62-1.48 (m, 6H), 1.35-1.04 (m, 2H).

[0020] In the following description, the compound of formula (IA) is sometimes referred to as “H208A”, and the compound of formula (IB) is sometimes referred to as “H208B”.

[0021] Step 4: Single crystal diffraction test of the compound of formula (IA) and the compound of formula (IB)

[0022] To determine the stereo-configuration of the compound of formula (IA) (H208A) and the compound of formula (IB) (H208B), single crystal diffraction tests were performed on both. H208A was made into a single crystal using the free base of the compound, while H208B was in the form of an oil and was difficult to make into a crystal, so it was made into a dihydrochloride salt using a conventional method, and then the test was completed using a single crystal of the dihydrochloride salt.

[0023] Instrument

[0024] Detector: Rigaku Oxford Diffraction XtaLAB Synergy four-cycle diffractometer, equipped with a HyPix-6000HE area detector.

[0025] Cooling system: Oxford Cryostream 800

[0026] Other parameters:

[0027] Cu: 50W, microfocus source with multilayer mirror (p-CMF)

[0028] Distance of crystal to CCD detector: d = 35 mm

[0029] Tube voltage: 50 kV

[0030] Tube current: 1 mA

[0031] Crystal culture

[0032] A 20 mg sample of H208A was dissolved in 0.6 mL dichloromethane / n-hexane (1 :5) at room temperature and the sample solution was placed in a 4 mL semi-sealed sample vial and slowly evaporated at 45 °C. Colorless prismatic crystals were obtained the next day.

[0033] A 20 mg sample of H208B dihydrochloride was dissolved in 1.1 mL ethanol / n-heptane (5:6) at room temperature and the sample solution was placed in a 4 mL semi-sealed sample vial and slowly evaporated at room temperature. Colorless block crystals were obtained the next day.

[0034] Data collection

[0035] For H208A, 62194 diffraction points were collected in the diffraction experiment, of which 11225 were independent diffraction points (Rint= 0.0682). The diffraction collection range was 2Q = 4.416 to 133.18°, and the diffraction index range was -6 < h < 6, -37 < k < 31, -23 < 1 < 23. Structure analysis used SHELXT (Sheldrick, G. M. 2015. Acta Cryst. A 71, 3-8), and structure refinement used SHELXL (against F 2 )(Sheldrick, G. M. 2015. Acta Cryst. C 71, 3-8). Of the 11225 independent diffraction points, 896 parameters participated in structure refinement. After refinement, S = 1.065, R1= 0.0361, wR2= 0.0914. The residual electron density values were 0.12 and

[0036] For H208B dihydrochloride, 40390 diffraction points were collected in the diffraction experiment, of which 3331 were independent diffraction points (Rint= 0.1071). The diffraction collection range was 2Q = 8.102 to 133.17°, and the diffraction index range was -11 < h < 11, -11 < k < 8, -51 < 1 < 51. Structure analysis used SHELXT (Sheldrick, G. M. 2015. Acta Cryst. A 71, 3-8), and structure refinement used SHELXL (against F2 Of the 3331 unique reflections, 215 parameters participated in the structure refinement. After refinement, S = 1.128, R1= 0.0727, wR2= 0.1722. The residual electron density values were 0.69 and

[0037] Results

[0038] For H208A, the results are found in Tables I to V; for H208B dihydrochloride, the results are found in Tables VI to XI. The results confirm that H208A and H208B have the configurations shown in Formula (IA) and Formula (IB), respectively, of the present specification.

[0039] Table I: Summary of X-ray crystal data for H208A single crystal

[0040]

[0041] Table II: Atomic coordinates (x10 4 ) and equivalent isotropic displacement parameters (A 2 x10 3 )

[0042]

[0043]

[0044]

[0045] Table III: Bond lengths for H208A single crystal

[0046]

[0047]

[0048]

[0049] Table IV: Bond angles (°) for H208A single crystal

[0050]

[0051]

[0052]

[0053] Table V: Torsion angles (°) for H208A single crystal

[0054]

[0055]

[0056]

[0057]

[0058] Table VI: Summary of X-ray crystal data for H208B dihydrochloride monohydrate

[0059]

[0060] Table VII: Atomic coordinates (x 10 4 ) and equivalent isotropic displacement parameters (A 2 x 10 3 )

[0061]

[0062] Table VIII: Bond lengths (A) for H208B dihydrochloride monohydrate

[0063]

[0064]

[0065] Table IX: Bond angles (°) for H208B dihydrochloride monohydrate

[0066]

[0067] Table X: Hydrogen bonds (A) for H208B dihydrochloride monohydrate

[0068]

[0069]

[0070] 1 1 + X, + Y, + Z; 2 -1 / 2 - X, -1 / 2 + Y, 3 / 4 - Z; 3 1 / 2 - X, -1 / 2 + Y, 3 / 4 - Z; 4 3 / 2 - Y, 1 / 2 + X, -1 / 4 + Z

[0071] Table XI: Torsion angles (°) for H208B dihydrochloride monohydrate

[0072]

[0073] Example 2: Effects on rat model of electrical stimulation-induced atrial fibrillation

[0074] 1. Materials

[0075] 1.1. Animals

[0076] SD rats, male, 60, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., license number: SCXK(Jing)2016-0011;

[0077] 1.2. Drugs

[0078] H208A (purity: more than 98%); H208B (purity: more than 98%).

[0079] 2. Methods

[0080] 2.1 Test grouping and administration

[0081] The animals were randomly divided into 6 groups, namely model control group, H208A 10 mg / kg, H208A 40 mg / kg, H208B 5 mg / kg, H208B 10 mg / kg, H208B 20 mg / kg; the administration method was single injection, and the model group was given the same amount of solvent (0.9% sodium chloride injection)

[0082] 2.2 Test method

[0083] After the rats were anesthetized, the neck skin was cut, the right jugular vein was separated, the distal end was ligated, the intracardiac electrode was inserted into the vein, and the intracardiac electrocardiogram was carefully observed. The most obvious channel of the intracardiac P wave was defined as the stimulation channel. After intravenous administration, the S1S1 program stimulation was stimulated with voltage 10V, frequency 20Hz, wave width 10ms, stimulation duration 5min, and the electrocardiogram of the rats was observed after stopping the stimulation. The changes of electrocardiogram of the drug intervention group and the model control group were evaluated, and the onset and termination time of atrial fibrillation of each group was recorded. The onset time and incidence of atrial fibrillation were calculated.

[0084] 2.3 Statistical analysis

[0085] The obtained data results were represented by , normal distribution test was performed by SPSS statistical software, and single factor variance analysis was used for normal distribution, and non-parametric test was used for non-normal distribution.

[0086] 3. Results

[0087] 3.1 Incidence:

[0088] During the test, all animals developed atrial fibrillation after electrical stimulation, with an incidence of 100%, indicating that the modeling was successful.

[0089] 3.2 Onset time:

[0090] Comparing with model group, no significant effect was observed in H208A groups (P>0.05), while the onset time of AF was significantly shortened in H208B groups, and the effect of H208B 10mg / kg and H208B 20mg / kg groups was statistically significant (P<0.05, P<0.01), as shown in Table XII.

[0091] Table XII Comparison of the effects of H208A and H208B on the rat intra-cardiac electrical stimulation-induced AF model

[0092]

[0093]

[0094] Note: Compared with the model group, *P<0.05, **P<0.01

[0095] 4. Conclusion

[0096] H208B injection can significantly improve the onset of intra-cardiac electrical stimulation-induced AF in rats and shorten the duration of AF; its effect is significantly better than that of H208A.

[0097] Example 3: Effects on the rat acetylcholine calcium chloride-induced AF model

[0098] 1. Materials

[0099] 1.1. Animals

[0100] SD rats, male, 70, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., license number: SCXK (Jing) 2016-0011;

[0101] 1.2. Drugs

[0102] H208A (purity: more than 98%); H208B (purity: more than 98%). Acetylcholine (ACh) and calcium chloride (CaCl2) are commercially available.

[0103] 2. Methods

[0104] 2.1 Test grouping and administration

[0105] The animals were randomly divided into 7 groups, namely the model control group, H208A-low, medium and high (10, 20, 40mg / kg) and H208B-low, medium and high (5, 10, 20mg / kg); the administration method was single injection, and the model group was given the same amount of solvent (0.9% sodium chloride injection)

[0106] 2.2 Test method

[0107] After the quarantine of animals, the model was reproduced by injecting the modeling drug (a mixed solution of 60 μg / ml ACh and 10 mg / ml CaCl2, 1 ml / kg) through the tail vein, once a day for 7 days. The drug was administered 5 min before modeling on the 7th day, and the injection of acetylcholine calcium chloride was performed after the administration. The start and end time of the typical atrial fibrillation waveform of each group was recorded, and the onset time of atrial fibrillation, the incidence of ventricular fibrillation, mortality and heart rate were calculated.

[0108] 2.3 Statistical analysis

[0109] The results of the obtained data are represented by SPSS statistical software was used for normal distribution test. Single factor analysis of variance was used for normal distribution, and non-parametric test was used for non-normal distribution.

[0110] 3 Results

[0111] 3.1 Incidence:

[0112] During the experiment, all animals developed atrial fibrillation after 7 days of acetylcholine calcium chloride administration, with an incidence of 100%, indicating that the modeling was successful.

[0113] 3.2 Onset time:

[0114] Compared with the model control group, no obvious effect was observed in the H208A-low, medium and high dose groups (P>0.05), and the onset time of atrial fibrillation was significantly shortened in the H208B-low, medium and high dose groups, among which the H208B-medium and high dose groups had statistical significance (P<0.05, P<0.01), as shown in Table XIII.

[0115] Table XIII Comparison of the effects of H208A and H208B on the acetylcholine calcium chloride model in rats

[0116]

[0117] Note: Compared with the model group, *P<0.05, **P<0.01.

[0118] 4 Conclusion

[0119] H208B injection can significantly improve the onset of atrial fibrillation induced by acetylcholine calcium chloride in rats and shorten the duration of atrial fibrillation, and its effect is significantly better than that of H208A.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of atrial fibrillation:

2. The use according to claim 1, wherein the compound of formula (I) is a compound of formula (IB):

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