Potassium salt of benzimidazole compound and preparation method therefor, composition and application thereof

Abstract

The preparation method for the compound, composition and application thereof in preparing an angiotensin II receptor antagonist or application in preparing medicine for preventing and/or treating hypertension, chronic heart failure and diabetic nephropathy. After entering a human body, when releasing azilsartan, the compound releases hydroxyligustrazine or NO at the same time, thus generating a synergistic effect with azilsartan. The compound therefore has stronger and longer blood pressure lowering effect, more obvious and longer lasting heart rate lowering effect and high safety, and achieves ideal protective effect for heart and kidney functions. ##STR00001##

Claims

1. Compound of formula I: ##STR00023##

2. A method for preparing the compound according to claim 1, comprising: reacting a compound of formula II with a potassium salt reagent in a solvent to form the compound of formula I, ##STR00024##

3. The preparation method according to claim 2, wherein the solvent is selected from water, ether solvents, ketone solvents, alcohol solvents, ester solvents, aromatic hydrocarbon solvents, alkane solvents, nitrile solvents, and a mixture thereof.

4. The preparation method according to claim 2, wherein the potassium salt reagent is one or more organic acid potassium salts, one or more inorganic acid potassium salts, or a mixture thereof; wherein the organic acid potassium salt is selected from potassium biphthalate, potassium acetate, potassium formate, potassium di-tert-butyl phosphate, dipotassium glycyrrhizinate, potassium 2-ethylhexanoate, potassium ethylxanthogenate, potassium sorbate, potassium phthalimide, potassium maleimide, potassium oxalate, potassium olefinate, potassium citrate, potassium malate, potassium gluconate, potassium lactate, potassium tartrate, potassium salicylate, potassium fumarate, potassium stearate, and potassium laurate, and wherein the inorganic acid potassium salt is selected from potassium nitrate, potassium sulfate, potassium sulfite, potassium bromate, potassium hydrogencarbonate, potassium thiocyanate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and potassium hydrogen phthalate.

5. The preparation method according to claim 4, further comprising adding the compound of formula II into the solvent to form a first solution; adding the potassium salt into the first solution to form a reaction mixture; and maintaining a temperature of the reaction mixture between room temperature and a reflux temperature of the solvent.

6. The preparation method according to claim 5, further comprising: cooling the temperature of the reaction mixture to between about 10 C. to about 10 C.; obtaining the compound of formula I after filtration and drying.

7. The preparation method according to claim 5, further comprising adding an anti-solvent to the reaction mixture; filtering and drying a solid to obtain the compound of formula I; wherein the anti-solvent is selected from methyl tetrahydrofuran, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, isopropyl ether, ethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, nitroethane, n-hexane, cyclohexane, pentane, n-heptane, benzene, toluene, xylene, and a mixture thereof.

8. A pharmaceutical composition, comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.

9. A method for treating hypertension, comprising administering an effective amount of the compound according to claim 1.

10. The preparation method of claim 2, wherein the solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, acetone, butyl ketone, methyl ethyl ketone, 4-methyl-2-pentanone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, t-butyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, nitroethane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, malononitrile, benzene, toluene, xylene, n-hexane, cyclohexane, pentane, n-heptane, and a mixture thereof.

11. The preparation method of claim 2, wherein a ratio between a volume of solvent to per gram of the compound of formula II is 5 to 100 ml.

12. The preparation method of claim 4, wherein a molar ratio between the compound of formula II to K of the potassium salt reagent is about 1:0.3-3.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is an H-NMR spectrum of QR01019K in Example 1.

(2) FIG. 2 is an X-ray powder diffraction spectrum of QR01019K in Example 1.

DETAILED DESCRIPTION OF THE INVENTION

(3) The potassium salt of the compound according to the present disclosure and preparation method and use thereof will be described in detail below in connection with exemplary embodiments. Those skilled in the art can refer to the contents herein to appropriately replace or modify the process parameters or conditions. It is to be understood that all such alternatives and modifications are intended to be included within the scope of the present application. The products and methods of the present disclosure have been described in terms of preferred embodiments, and those skilled in the art can make modifications and/or alterations and combinations of the products and/or methods described herein to implement and apply the technical solutions of the present disclosure without departing from the content, spirit and scope of the present disclosure.

Example 1

(4) QR01019 (1.0 g) was dissolved in dichloromethane (5 ml), stirred at room temperature to form a solution, and potassium phthalimide (0.27 g) was added to the solution. The reaction was incubated for 4 hours, cooled to 50 C., filtered, and the solvent was evaporated to dryness to give a solid of amorphous QR01019K.

(5) Melting point: 135-145 C.

(6) MS/HRMS m/z: 717 [M+H].sup.+; 677 [MK].sup..

(7) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 1.44 (t, 3H), 1.46 (t, 3H), 2.38 (s, 3H), 2.41 (s, 3H), 2.44 (s, 3H), 4.64 (q, 2H), 5.29 (d, 1H), 5.32 (d, 1H), 5.52 (d, 1H), 5.56 (d, 1H), 6.86 (q, 1H), 6.90 (d, 2H), 7.18 (m, 2H), 7.22 (d, 2H), 7.33 (m, 1H), 7.36 (m, 1H), 7.46 (d, 1H), 7.52 (dd, 1H), 7.75 (d, 1H).

(8) The H-NMR spectrum and the X-ray powder diffraction spectrum are shown in FIG. 1 and FIG. 2 respectively.

Example 2

(9) The compound QR01019 (1.0 g) was dissolved in ethanol (15 ml) under reflux to form a solution. The solution was cooled to 50 C., and potassium 2-ethylhexanoate (0.30 g) in ethanol (1 ml) was slowly added dropwise to the solution. The solution was slowly cooled to 0 C., and further incubated under stirring for 5 hours, filtered, and dried under reduced pressure at 60 C. The obtained solid was amorphous QR01019K.

(10) MS/HRMS m/z: 717 [M+H].sup.+; 677 [MK].sup..

Example 3

(11) QR01019 (1.0 g) was dissolved in dichloromethane (20 ml) under reflux to form a solution. The solution was cooled to room temperature, and potassium acetate (0.16 g) was added to the solution. The reaction was incubated for 2 hours, filtered, and the solvent was evaporated to dryness to give a solid of amorphous QR01019K.

(12) MS/HRMS m/z: 717 [M+H].sup.+; 677 [MK].sup..

Example 4

(13) QR01019 (1.0 g) was dissolved in 1,4-dioxane (30 ml), heated to 50 C. to form a solution, and potassium phthalimide (0.27 g) was added to the solution. The reaction was incubated for 30 mins, cooled to 50 C., filtered, and the solvent was evaporated to dryness to give a solid of amorphous QR01019K.

(14) MS/HRMS m/z: 717 [M+H].sup.+; 677 [MK].sup..

Example 5

(15) The compound QR01019 (1.0 g) was dissolved in acetone (20 ml) under reflux to form a solution. The solution was cooled to 40 C., and potassium 2-ethylhexanoate (0.30 g) in acetone (1 ml) was slowly added dropwise to the solution. The solution was slowly cooled to 0 C., and the mixture was further incubated under stirring for 5 hours, filtered, and dried under reduced pressure at 60 C. The obtained solid was amorphous QR01019K.

(16) MS/HRMS m/z: 717 [M+H].sup.+; 677 [MK].sup..

Example 6

(17) QR01019 (1.0 g) was dissolved in dichloromethane (5 ml), stirred at room temperature to form a solution, and potassium maleimide (0.20 g) was added to the solution. The reaction was incubated for 4 hours, cooled to 50 C., filtered, and the solvent was evaporated to dryness to give a solid of amorphous QR01019K.

(18) MS/HRMS m/z: 717 [M+H].sup.+; 677 [MK].sup..

Example 7

(19) QR01019 (1.0 g) was dissolved in N,N-dimethylformamide (5 ml), stirred at room temperature to form a solution, and potassium nitrate (0.15 g) was added to the solution. The temperature was raised to 30 C., and the reaction was incubated for 4 hours, cooled to room temperature, filtered. 100 ml of n-hexane was added to the filtrate, filtered and the obtained solid was amorphous QR01019K.

(20) MS/HRMS m/z: 717 [M+H].sup.+; 677 [MK].sup..

Example 8

(21) QR01019 (1.0 g) was dissolved in dimethyl sulfoxide (5 ml), stirred at room temperature to form a solution, and potassium thiocyanate (0.14 g) was added to the solution. The temperature was raised to 40 C., and the reaction was incubated for 4 hours, cooled to room temperature and filtered. 100 ml of methyl tert-butyl ether was added to the filtrate, filtered and the obtained solid was amorphous QR01019K.

(22) MS/HRMS m/z: 717 [M+H].sup.+; 677 [MK].sup..

Example 9

(23) QR01019 (1.0 g) was dissolved in tetrahydrofuran (5 ml), stirred at room temperature to form a solution, and dipotassium hydrogen phosphate (0.20 g) was added to the solution. The reaction was incubated for 4 hours, cooled to 50 C., filtered, and the solvent was evaporated to dryness to give a solid of amorphous QR01019K.

(24) MS/HRMS m/z: 717 [M+H].sup.+; 677 [MK].sup..

Example 10

(25) QR01019 (1.0 g) was dissolved in 1,4-dioxane (5 ml), heated to 50 C. under stirring to form a solution, and potassium dihydrogen phosphate (0.20 g) was added to the solution. The reaction was incubated for 4 hours, cooled to room temperature, filtered, and the solvent was evaporated to dryness to give a solid of amorphous QR01019K.

(26) MS/HRMS m/z: 717 [M+H].sup.+; 677 [MK].sup..

Example 11: Preparation of QR01019 Sodium Salt

(27) QR01019 (0.5 g) was dissolved in toluene (2.5 ml), heated to 80 C. to form a solution, cooled to room temperature, and 60% sodium hydride (0.029 g) was added to the solution. The reaction was stirred for 4 hours, and n-hexane (25 ml) was added to the reaction mixture to precipitate a solid, which was filtered and dried to give a solid of QR01019 sodium salt.

(28) MS: 701 [M+H].sup.+; 677 [MNa].sup..

(29) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 1.40 (d, 3H), 1.41 (t, 3H), 2.35 (s, 3H), 2.39 (s, 3H), 2.40 (s, 3H), 4.61 (q, 2H), 5.27 (q, 2H), 5.49 (q, 2H), 6.80 (q, 1H), 6.83 (d, 2H), 7.15 (m, 4H), 7.32 (td, 2H), 7.43 (m, 2H), 7.72 (dd, 1H).

Example 12: Antihypertensive Efficacy Test of QR01019K in Spontaneously Hypertensive Rats

(30) 12-week-old spontaneously hypertensive rats (hereinafter referred to as SHR, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.) were anesthetized with 2.5% sodium pentobarbital for intraperitoneal injection. The blood pressure sensing catheter of a blood pressure implant was inserted into the abdominal aorta, the implant was fixed to the abdominal wall, and the postoperative daily care was performed after suturing. Animals with systolic blood pressure exceeding 160 mmHg were selected into a total of 3 groups with 8 animals in each group. The control group was given 0.5% CMC-Na (sodium carboxymethylcellulose); in the OR01019 group and the QR01019K group, the compounds were dissolved in 0.5% CMC-Na, and the doses were all administered at an effective dose of 1 mg/kg of azilsartan with an administration volume of 4 mL/kg by intragastric administration. The systolic blood pressure and heart rate of the animals before the administration were used as reference values, and the changes of systolic blood pressure and heart rate of SHR at each time point before and after administration were compared, in which the systolic blood pressure and heart rate of SHR were measured three times at each time point and then averaged. The results are shown in Tables 1 and 2 below.

(31) TABLE-US-00001 TABLE 1 Changes in systolic blood pressure at each time point before and after the oral administration of QR01019 and QR01019K (mean value (mmHg) standard error) 1 hour 3 hours 5 hours Before after after after adminis- adminis- adminis- adminis- Groups tration tration tration tration Control group 0.0 0.0 5.4 7.1 3.5 4.6 4.5 4.0 QR01019 group 0.0 0.0 4.9 4.8 22.0 3.6* 30.5 3.5* QR01019K group 0.0 0.0 7.0 3.4 34.3 1.9* 46.5 2.5* 7 hours 10 hours 24 hours after after after adminis- adminis- adminis- Groups tration tration tration Control group 4.1 3.2 2.9 2.3 2.7 6.4 QR01019 group 38.8 2.3* 33.0 1.7* 10.2 2.1 QR01019K group 49.4 4.1* 45.3 3.3* 25.9 3.4* *P < 0.01 (relative to the control group).

(32) It can be seen from the results in Table 1 that 3 hours after the administration, as compared with the control group, all administration groups showed significantly decreased systolic blood pressures. Furthermore, all administration groups achieved drug efficacy peak times of 5 to 7 hours after the administration, and the QR01019K group had a more potent and longer-lasting antihypertensive effect than QR01019.

(33) TABLE-US-00002 TABLE 2 Change in heart rate at each time point before and after the oral administration of QR01019 and QR01019K (mean value (times/minute) standard error) 1 hour 3 hours 5 hours Before after after after adminis- adminis- adminis- aadminis- Groups tration tration tration tration Control group 0.0 0.0 0.14 2.9 6.4 2.8 0.3 2.7 QR01019 group 0.0 0.0 3.4 2.6 2.33 2.6* 6.5 2.8* QR01019K group 0.0 0.0 3.6 2.4 5.0 2.5* 10.1 3.0* 7 hours 10 hours 24 hours after after after adminis- adminis- adminis- Groups tration tration tration Control group 0.1 2.9 2.5 2.5 4.3 2.8 QR01019 group 6.2 3.0* 12.3 2.8* 6.7 2.6* QR01019K group 17.5 3.0* 25.4 2.4* 28.6 8* *P < 0.05 (relative to one-way variance comparison of the control group).

(34) As can be seen from Table 2, the QR01019K group had a more potent and longer-lasting effect of reducing heart rate than QR01019.

(35) The efficacy test of the following compounds (potassium salts) was also performed according to the above method, showing that as similar to QR01019K, these compounds had more potent and longer-lasting effects of lowering blood pressure and heart rate effects than their corresponding unsalted compounds.

(36) ##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022##

Example 13: Pharmacokinetic Study

(37) 12 SD rats, SPF grade, weighing 180-220 g (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.) were taken with half male and half female. They were randomly divided into 2 groups with 6 in each group, 3 males and 3 females. QR010109 and QR01019K were dissolved in 0.5% CMC-Na with a drug concentration of 0.1 mg/mL based on azilsartan, and administered intragastrically in an administration volume of 10 ml/kg and a dose of 1.0 mg/kg based on azilsartan. Blood was collected from the jugular vein at different time points after administration (before administration and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours after administration, respectively), blood samples were collected, and the concentrations of plasma azisartan were measured. The various pharmacokinetic parameters are shown in Table 3 below.

(38) TABLE-US-00003 TABLE 3 Main pharmacokinetic parameters of single intravenous administration of each compound in rats C.sub.max T.sub.max AUC.sub.0-24 T.sub.1/2 Compounds (ng/mL) (hr) (ng/mL*hr) (hr) QR01019 1254 390 0.58 0.20 6386 1220 6.16 1.01 QR01019K 3735 803 0.5 0.0 18573 2919 7.51 1.60 C.sub.max: Blood drug peak concentration, T.sub.max: Blood pressure peak time, AUC.sub.last: Area under the time curve, T.sub.1/2: Half life

(39) As can be seen from the results in Table 3, the bioavailability of QR01019 is about of that of QR01019K.

Example 14: Stability Test of the Compounds

(40) The applicants investigated the stability of the compounds by taking 200 mg of each of QR01019K and QR01019 sodium salt compounds which were subjected to the following test:

(41) an inner self-sealing PVC bag containing the test compound was vacuumed and an aluminum foil as an interlayer was used to wrap the inner PVC bag and then was vacuumed. Further, another aluminum foil, as an outer layer wrapping the interlayer together with a desiccant, was vacuumed and then charged with nitrogen gas; examination conditions: 25 C., 60% humidity. The index of inspection was the total impurity content. Samples were taken at different time points, and at each time point three samples were taken and tested to give an average value. The sampling time points were day 0, day 15, and day 30. The compound prepared in Example 11 could not be improved in purity to meet the drug purity standard. The test results are shown in Table 4 below.

(42) TABLE-US-00004 TABLE 4 Stability test (% total impurity content) Sampled time (day) Investigated compound 0 15 30 QR01019K 1.52 5.95 13.28 QR01019 sodium salt 20.76 29.47 43.25

Example 15: Determination of Equilibrium Solubility of QR01019 Potassium Salt

(43) 20 mg of each of QR01019 and QR01019K was weighed respectively, put into 10 mL of a dissolution medium, and shaken at 372 C., 250 r/min for 24 h, and the equilibrium solubility was measured. The results are shown in Table 5 below.

(44) TABLE-US-00005 TABLE 5 equilibrium solubility for 24 h (g/ml) QR01019, based QR01019K, based Dissolving medium on azilsartan on azilsartan pH 1.0 (hydrochloric 2.01 18.70 acid solution) pH 4.5 (acetate buffer) 0.06 2.30 pH 6.8 (phosphate buffer) 1.60 25.90 pH 7.8 (phosphate buffer) 13.60 400.50 Pure water 0.74 542.00

(45) It can be seen from Table 5 that the addition concentrations of QR01019K in both acidic and neutral media are much higher than QR01019.