Azilsartan dicyclohexylamine as an angiotensin II antagonist, and pharmaceutical composition for treating or preventing cardiovascular disease containing the same as an active ingredient

Abstract

To provide an active ingredient for preventing and / or treating cardiovascular disease, demonstrating pharmacokinetic effects equivalent to or better than azilsartan medoxomil potassium salt.SOLUTION: The present invention relates to an azilsartan dicyclohexylamine compound, represented by formula 1, serving as an angiotensin II antagonist, and a pharmaceutical composition comprising the same as an active ingredient for preventing or treating cardiovascular disease. This invention features high solubility and stability, offering pharmaceutically excellent physical properties.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to azilsartan dicyclohexylamine as an angiotensin II antagonist, and a pharmaceutical composition for treating or preventing cardiovascular diseases, which contains the same as an active ingredient. [Background technology]

[0002] Antihypertensive drugs are divided into vasodilators and sympathetic nerve inhibitors, with ARB-type drugs, a type of vasodilator, tending to overwhelmingly occupy more than 70% of all antihypertensive drug prescriptions on the market. Among these drugs, azilsartan medoxomil has recently been attracting attention because it has a higher trough / peak ratio than drugs with the same mechanism and is advantageous in regulating blood pressure 24 hours a day.

[0003] Azilsartan medoxomil is a substance that has a modified chemical structure of candesartan, as shown below, and has the pharmacological property of binding strongly to the AT1 receptor and dissociating slowly.

[0004] [ka]

[0005] That is, it inhibits the binding of angiotensin II to the AT1 receptor, thereby suppressing vasoconstriction and aldosterone secretion, thereby lowering blood pressure.

[0006] Azilsartan medoxomil is a type of prodrug intended to solve the problems of azilsartan's very low solubility and bioavailability, and is known to act as azilsartan in the body after ingestion, with azilsartan being its pharmacologically active ingredient (see Non-Patent Document 1).

[0007] The commercially widely used salt form of azilsartan medoxomil is the potassium salt, and its angiotensin II receptor antagonist activity has been disclosed in U.S. Patent No. 7,157,584 (Patent Document 1) by Kuroita Takanobu et al. of Takeda Co., Ltd. (Japan). This is a human hypertension treatment agent, and is available in film-coated tablets of 20 mg, 40 mg, and 80 mg under the trade name "EDARBI Tablets." TM " is sold commercially.

[0008] Meanwhile, azilsartan dicyclohexylamine is known as an intermediate compound for synthesizing azilsartan medoxomil in Korean Patent No. 10-2220011 (Patent Document 2). In Korean Patent No. 10-2220011, azilsartan dicyclohexylamine is synthesized as a key intermediate in a one-pot reaction, and ionic liquid and eutectic solvent are used as environmentally friendly solvents instead of organic solvents to increase reactivity so that the reaction can be carried out even at temperatures below 50°C, reducing the production of related substances, and producing azilsartan medoxomil with high purity, high yield, and competitiveness.

[0009] However, Korean Patent Publication No. 10-2220011 only discloses azilsartan dicyclohexylamine as a key intermediate compound required in the synthesis of azilsartan medoxomil, and the pharmacological and pharmacokinetic usefulness of azilsartan medoxomil is not known.

[0010] Additionally, the entire contents of Non-Patent Document 1 and Patent Documents 1 and 2 are hereby incorporated by reference into the specification of the present invention to the extent that they are not inconsistent with the contents of the present invention. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] U.S. Patent No. 7,157,584 [Patent Document 2] Korean Patent No. 10-2220011 [Non-patent literature]

[0012] [Non-Patent Document 1] “Azilsartan: Current Evidence and Perspectives in Management of Hypertension”, Hindawi International Journal of Hypertension Volume 2019, Article ID 1824621, 8pages. Summary of the Invention [Problem to be solved by the invention]

[0013] The solubility characteristics of an active ingredient are extremely important because if the active ingredient dissolves too slowly from a pharmaceutical formulation, the blood concentration of the active ingredient will not reach an effective level and will not be able to fully exert its desired effect.

[0014] In addition, if the active ingredient is easily decomposed or denatured over time, the pharmaceutical preparation will have problems in terms of efficacy and stability, so the storage stability of the active ingredient is also very important.

[0015] Therefore, the present invention aims to provide a novel azilsartan salt compound that not only has pharmacologic superior physical properties such as solubility and stability, but also has pharmacokinetic effects equivalent to or greater than those of azilsartan medoxomil potassium salt. [Means for solving the problem]

[0016] The present invention has been devised to solve the above-mentioned problems of the conventional technology, The present invention provides an azilsartan dicyclohexylamine compound represented by the following chemical formula 2, which is an angiotensin II antagonist:

[0017] [ka]

[0018] The present invention also provides a pharmaceutical composition for treating or preventing cardiovascular diseases, comprising azilsartan dicyclohexylamine represented by Chemical Formula 2 as an active ingredient. Effect of the Invention

[0019] The present invention not only has excellent pharmacologic physical properties due to its high solubility and stability, but also exhibits pharmacokinetic effects equivalent to or greater than those of azilsartan medoxomil potassium salt, and can therefore be usefully used as an active ingredient in the prevention and / or treatment of cardiovascular diseases. [Brief description of the drawings]

[0020] [Figure 1] 1 is a graph showing the results of a pharmacokinetic test of the present invention in rats. [Diagram 2] 1 is a graph showing the results of storage stability testing of the present invention (X-axis is time in weeks, Y-axis is related substances in %). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The present invention will be described in detail below.

[0022] One aspect of the present invention is The angiotensin II antagonist is an azilsartan dicyclohexylamine compound represented by the following chemical formula 3:

[0023] [ka]

[0024] As disclosed in Patent Document 2 (Korean Patent Registration No. 10-2220011), azilsartan dicyclohexylamine is known as a key intermediate compound for synthesizing azilsartan medoxomil, but its pharmacological and pharmacokinetic properties as an angiotensin II antagonist are unknown. Therefore, the present inventors have found that azilsartan dicyclohexylamine is not only useful as an intermediate compound, but also has higher stability and superior pharmacological effects than azilsartan, and have completed the present invention. The stability and pharmacological properties of azilsartan dicyclohexylamine will be understood through the examples described below.

[0025] In addition, as disclosed in Patent Document 2 (Korean Patent Publication No. 10-2220011), a method for synthesizing and preparing azilsartan dicyclohexylamine is known, and the specific details thereof can be understood by referring to the known details, and the description thereof will be omitted.

[0026] Another aspect of the present invention is a pharmaceutical composition for treating or preventing cardiovascular disease, comprising azilsartan dicyclohexylamine represented by the above formula 2 as an active ingredient.

[0027] The composition of the present invention may be prepared by further comprising one or more pharma- ceutically acceptable carriers in addition to the active ingredient for administration.

[0028] The pharma- ceutically acceptable carrier may be saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more of these components, and other conventional additives such as antioxidants, buffers, bacteriostatic agents, etc. may be added as necessary.

[0029] In addition, a diluent, dispersant, surfactant, binder, or lubricant may be added to formulate the compound into an injectable dosage form such as an aqueous solution, suspension, or emulsion, a pill, capsule, granule, or tablet.

[0030] The composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the desired method, and the dosage range varies depending on the patient's weight, sex, age, health condition, diet, administration time, administration method, excretion rate, and the degree of disease. Liquid dosage forms for oral administration can include pharmacologic acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can include adjuvants, such as wetting agents, emulsions, and suspensions, as well as sweeteners, flavorings, and the like.

[0031] The daily dose of the active ingredient of the azilsartan dicyclohexylamine of the present invention to be administered can be a single dose or an effective amount divided into several smaller doses administered over the course of a day. In general, the total daily dose for therapeutic or prophylactic purposes may be preferably 0.5-500 mg, more preferably about 1 mg-100 mg, even more preferably 10 mg-80 mg, and even more preferably 20 mg-80 mg, and can be administered once or in several doses per day.

[0032] The compositions of the present invention may also be used alone or in combination with other drugs for hormone therapy, other hypertension drug formulation therapy, diabetes (e.g., drug-A glyflozins such as DPP-IV, SGLT2, etc.) and hyperlipidemia (e.g., statins such as atorvastatin, rosuvastatin, pitavastatin, etc.), and biological response modifiers.

[0033] In particular, the compounds used for treating cardiovascular diseases may be administered in combination with one or more drugs selected from the group consisting of ACE inhibitors, HMG-CoA reductase inhibitors, β-adrenergic blockers, calcium channel blockers, diuretics, antithrombotic agents such as aspirin, nitrated ACE inhibitors, nitrated HMG-CoA reductase inhibitors, nitrated β-adrenergic blockers, nitrated aspirin and nitrated diuretics.

[0034] The cardiovascular diseases can be exemplified without limitation by heart failure, myocardial infarction, ischemic stroke, arteriosclerosis, ocular and pulmonary hypertension, hypertension, diabetic nephropathy, peripheral vascular disease, left ventricular dysfunction and hypertrophy, liver fibrosis, portal hypertension, etc.

[0035] Hereinafter, the present invention will be described in more detail with reference to examples. However, it is clearly stated that the following examples are only for the purpose of detailed description of the invention and are not intended to limit the scope of rights thereby.

[0036] Examples 1. Evaluation of solubility The solubility of three main components, azilsartan free base, azilsartan medoxomil potassium, and azilsartan dicyclohexylamine, depending on pH was evaluated.

[0037] The results were as shown in Table 1 below.

[0038] [Table 1]

[0039] As a result of the test, the solubility of the three main components depending on pH was shown to be high in the order of AZ < AZD at pH 1.2 and pH 4.0 which are acidic conditions, AZMk < AZ < AZD at pH 6.8, and AZ < AZMk < AZD in water.

[0040] Among the three main components of azilsartan, it was shown that the solubility of azilsartan dicyclohexylamine salt was particularly high at a particularly high pH, while the influence of pH on solubility was different.

[0041] 2. Rat Pharmacokinetics (1) Pharmacokinetics-design * Animal: Rat (male, 8 weeks old) - Administration: Oral administration (fasting for 16 hours before administration) - Blood sampling method: Jugular vein blood sampling - Blood sampling points: 0.082, 0.25, 0.5, 1, 2, 4, 8, 24 hr

[0042] [Table 2]

[0043] (2) Results of Pharmacokinetics The results were as shown in Table 3 below.

[0044] [Table 3]

[0045] As can be confirmed from Table 3 above, Cmax and AUC were shown to be high in the order of AZ < AZMk < AZD, respectively, and thus the bioavailability was also shown to be high in this order. For reference, the relative bioavailability compared with AZ was about 1.3 for AZMK, about 1.7 for AZD, and it was confirmed that AZD had a bioavailability about 30% higher than that of AZMK.

[0046] Therefore, it is predicted that the bioavailability of azilsartan will depend on the solubility of the drug, rather than on the degree of biopermeability. Also, considering that azilsartan itself is an active ingredient that produces pharmacological effects, it can be confirmed that AZD, which has a high bioavailability of azilsartan, also has excellent pharmacological effects.

[0047] In addition, no particular toxicity or abnormal symptoms were observed in the preclinical studies.

[0048] 3. Stability testing A two-week storage stability test was conducted on azilsartan (AZ) and azilsartan dicyclohexylamine (AZD) at room temperature (RT) and 65°C (60% RH).

[0049] The results are shown in Figure 2. As can be seen from Figure 2, AZD not only showed higher stability than azilsartan at room temperature, but also showed relatively greater stability at high temperatures, confirming that it is an extremely stable substance.

[0050] 4. Excipient compatibility testing

[0051] [Table 4]

[0052] [Table 5]

[0053] [Table 6]

[0054] As a result of the compatibility test of the commonly used solubilizers, azilsartan free base showed suitable results when mixed with excipients other than polyvinylpyrrolidone, Eudragit® E PO, and Labrafil, and azilsartan dicyclohexylamine showed suitable results when mixed with excipients other than sodium lauryl sulfate and Labrafil. Therefore, it is believed that the results can be used as a reference for selecting excipients that can be preferentially selected when considering the design of dosage forms and the selection of excipients.

Claims

1. A pharmaceutical composition for treating or preventing cardiovascular disease, comprising azilsartan dicyclohexylamine represented by the following chemical formula 1 as an active ingredient. 【Chemistry 1】

2. The pharmaceutical composition for treating or preventing cardiovascular disease according to claim 1, wherein the treatment or prevention of cardiovascular disease is treatment or prevention of hypertension.

3. 2. The pharmaceutical composition for treating or preventing cardiovascular disease according to claim 1, which does not contain sodium lauryl sulfate and Labrafil.

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