KR20240039252A - Azilsartan dicyclohexylamine as an angiotensin ⅱ antagonist, and pharmaceutical composition comprising the same as an active ingredient for preventing or treating cardiovascular disease - Google Patents

Abstract

The present invention relates to azilsartan dicyclohexylamine as an angiotensin II antagonist and a pharmaceutical composition for treating or preventing cardiovascular disease using it as an active ingredient. More specifically, azilsartan represented by the following formula (1) as an angiotensin II antagonist: It is a dicyclohexylamine compound and a pharmaceutical composition for treating or preventing cardiovascular disease containing it as an active ingredient. The present invention not only has high solubility and stability and has excellent pharmaceutical physical properties, but also exhibits pharmacokinetic effects equal to or greater than azilsartan medoxomil potassium salt, so that it can be used for the prevention and/or treatment of cardiovascular diseases. It can be usefully used as an active ingredient.
[Formula 1]

Description

Azilsartan dicyclohexylamine as an angiotensin II antagonist and a pharmaceutical composition for the treatment or prevention of cardiovascular disease containing it as an active ingredient DISEASE}

The present invention relates to azilsartan dicyclohexylamine as an angiotensin II antagonist and a pharmaceutical composition for treating or preventing cardiovascular disease using it as an active ingredient.

Hypertension treatments are divided into vasodilators and sympathetic nervous system inhibitors, and ARB series treatments, a type of vasodilator, dominate the market, accounting for more than 70% of all prescriptions for hypertension treatments. Among these, azilsartan medoc. Somil has recently been attracting attention for its advantage in controlling blood pressure for 24 hours, as it has the lowest/maximum effect ratio compared to drugs with the same mechanism.

Azilsartan medoxomil is a substance that has changed the chemical structure of candesartan as shown below, and has the pharmacological property of strongly binding to AT1 receptors and slowly dissociating.

In other words, it causes blood vessel constriction by inhibiting the binding between angiotensin II and AT1 receptors and lowers blood pressure by inhibiting the secretion of aldosterone.

Azilsartan medoxomil is a type of prodrug to solve the problems of very low solubility and bioavailability of azilsartan. It is known that after taking it, it acts as azilsartan in the body, and the pharmacologically active ingredient is azilsartan. There is (see non-patent document 1).

The commercially widely used salt form of azilsartan medoxomil is the potassium salt, and its angiotensin II receptor antagonist activity is disclosed in U.S. Patent Registration US 7157584 B2 (Patent Document 1) by Takanobu Kuroita et al. of Takeda (Japan). It is done. This is a treatment for high blood pressure in humans and is sold under the brand name Idalbee™ in 20mg, 40mg, and 80mg film-coated tablets.

Meanwhile, azilsartan dicyclohexylamine is known as an intermediate compound for synthesizing azilsartan medoxomil in Korean Patent Registration KR 10-2220011 B1 (Patent Document 2). In Korea Patent Registration KR 10-2220011 B1, azilsartan dicyclohexylamine is synthesized as a key intermediate for one-pot reaction, and the reaction is possible even under 50℃ by using ionic liquid and eutectic solvent as an eco-friendly solvent instead of organic solvent. It reduces the production of related substances by increasing reactivity and produces high purity, high yield, and competitive azilsartan medoxomil.

However, what is disclosed in the Korean patent registration KR 10-2220011 B1 is only azilsartan dicyclohexylamine as a key intermediate compound required in the process of synthesizing azilsartan medoxomil, and nothing is known about its pharmacological and pharmacokinetic usefulness. .

In addition, the entire contents of Non-Patent Document 1 and Patent Documents 1 to 2 are cited and incorporated as the content of the specification of the present invention to the extent that they do not conflict with the content of the present invention.

US 7157584 B2 (2007.01.02.) KR 10-2220011 B1 (2021.02.19.)

“Azilsartan: Current Evidence and Perspectives in Management of Hypertension”, Hindawi International Journal of Hypertension Volume 2019, Article ID 1824621, 8 pages.

If the dissolution of the active ingredient from the pharmaceutical preparation is too slow, the blood concentration of the active ingredient cannot reach an effective level and the expected effect cannot be sufficiently shown, so the dissolution characteristics of the active ingredient are extremely important.

In addition, if the active ingredient is easily decomposed or denatured over time, problems may arise in the effectiveness and stability of the pharmaceutical preparation, so storage stability of the active ingredient is also very important.

Accordingly, the present invention provides a novel azilsartan salt compound that not only has excellent pharmaceutical physical properties such as solubility and stability, but at the same time has pharmacokinetic effects equivalent to or better than azilsartan medoxoyl potassium salt. We would like to provide.

The present invention was devised to solve the problems of the prior art described above,

Provided is an azilsartan dicyclohexylamine compound represented by the following formula (1) as an angiotensin II antagonist:

[Formula 1]

In addition, the present invention provides a pharmaceutical composition for treating or preventing cardiovascular disease containing azilsartan dicyclohexylamine represented by Formula 1 as an active ingredient.

The present invention not only has excellent pharmaceutical physical properties due to its high solubility and stability, but also exhibits pharmacokinetic effects equal to or greater than azilsartan medoxomil potassium salt, making it effective in preventing and/or treating cardiovascular diseases. It can be usefully used as an ingredient.

Figure 1 is a graph showing the results of a rat pharmacokinetic test of the present invention.
Figure 2 is a graph showing the results of the storage stability test of the present invention (the

Hereinafter, the present invention will be described in detail.

One aspect of the present invention is,

Azilsartan dicyclohexylamine compound represented by the following formula (1) as an angiotensin II antagonist:

[Formula 1]

As disclosed in Patent Document 2 (KR 10-2220011 B1), azilsartan dicyclohexylamine is known as a key intermediate compound for synthesizing azilsartan medoxomil, but its pharmacology and pharmacokinetics as an angiotensin II antagonist are unknown. Nothing is known about it. Accordingly, the present inventors discovered that azilsartan dicyclohexylamine is not only useful as an intermediate compound, but also has higher stability and superior pharmacological effects than azilsartan, and completed the present invention. The stability and pharmacological properties of azilsartan dicyclohexylamine will be understood through examples to be described later.

In addition, as disclosed in Patent Document 2 (KR 10-2220011 B1), the synthesis and production method of azilsartan dicyclohexylamine is known, and specific details thereof can be understood by referring to the known contents. The explanation is omitted.

In addition, another aspect of the present invention is a pharmaceutical composition for treating or preventing cardiovascular disease containing azilsartan dicyclohexylamine represented by Formula 1 above as an active ingredient.

For administration, the composition of the present invention may be prepared by including one or more pharmaceutically acceptable carriers in addition to the above active ingredients.

Pharmaceutically acceptable carriers may be saline solution, sterilized water, Ringer's buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and a mixture of one or more of these ingredients. Antioxidants and buffers may be added as needed. , bacteriostatic agents, etc., other common additives can be added.

Additionally, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate injectable formulations such as aqueous suspensions and emulsions, pills, capsules, granules, or tablets.

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 depends on the patient's weight, gender, age, health condition, and diet. , the range varies depending on the administration time, administration method, excretion rate, and disease severity. Liquid dosage forms for oral administration can include pharmacologically acceptable emulsions, solutions, suspensions, syrups and elixirs, including inert diluents commonly used in the industry such as water. Such compositions may contain adjuvants such as wetting agents, emulsions and suspending agents, as well as sweeteners, flavors and the like.

Azilsartan dicyclohexylamine of the present invention The daily dosage of the active ingredient to be administered may be a single dose or the effective amount may be divided into several smaller doses administered over the course of the day. Typically, the total daily dose for therapeutic or prophylactic purposes may preferably be 0.5 to 500 mg, preferably about 1 mg to 100 mg, more preferably 10 mg to 80 mg, even more preferably 20 mg to 80 mg, , can be administered once a day or in divided doses.

In addition, the composition of the present invention can be used alone or for hormonal treatment, treatment with other antihypertensive drugs, diabetes (e.g. DPP-IV, SGLT2, etc. Drug-A Glyflozines) and hyperlipidemia treatment (e.g. atorvastatin, rosuvastatin, pitta). It can be used as a combination of two or three drugs with drugs using statins (vastatin, etc.) and biological response regulators.

In particular, compounds used to treat cardiovascular diseases include ACE inhibitors, HMGCoA reduction inhibitors, beta-adrenergic blockers, calcium channel blockers, diuretics, antithrombotic agents such as aspirin, nitrated ACE inhibitors, nitrated HMGCoA reduction inhibitors, nitro It may also be administered in combination with one or more drugs selected from the group consisting of nitrated beta-adrenergic blockers, nitrated aspirin and nitrated diuretics:

The above cardiovascular diseases include, but are not limited to, heart failure, myocardial infarction, ischemic stroke, arteriosclerosis, ocular and pulmonary hypertension, hypertension, diabetic nephropathy, peripheral vascular disease, left ventricular dysfunction and hypertrophy, liver fibrosis, and portal hypertension. You can.

Hereinafter, the present invention will be described in more detail through examples. However, it should be made clear that the following examples are only for detailed description of the invention and are not intended to limit the scope of rights.

Example

1. Solubility evaluation

Solubility evaluation was conducted according to pH of the three main components: azilsartan free base, azilsartan medoxomil potassium, and azilsartan dicyclohexylamine.

The results were as shown in Table 1 below.

No. menstruum Azilsartan unsalted
(AZ) Azilsartan medoxomil potassium salt
(AZMk) Azilsartan
Dicyclohexylamine salt
(AZD) One pH 1.2 4.7 ㎍/㎖ - 14.1 ㎍/㎖ 2 pH 4.0 1.1 ㎍/㎖ - 3.1 ㎍/㎖ 3 pH 6.8 963.0 ㎍/㎖ 39.1 ㎍/㎖ 2604.9 ㎍/㎖ 4 water 37.3 ㎍/㎖ 766.2 ㎍/㎖ 896.5 ㎍/㎖

As a result of the test, the solubility of the three main components according to pH was high in the order of AZ < AZD under acidic conditions of pH 1.2 and pH 4.0, and at pH 6.8, AZMk < AZ < AZD, and in water, AZ < AZMk < AZD. showed.

While the three main components of azilsartan have different effects on solubility of pH, the solubility of azilsartan dicyclohexylamine salt was found to be particularly high at high pH.

2. let Pharmacokinetic test (Rat Pharmacokinetics )

(1) Test method (Pharmacokinetics-design)

* Animal: Rat (male, 8 weeks old)

-Dosage: Oral administration (fast for 16 hours before administration)

-Blood collection method: Jugular vein blood collection

-Blood collection points: 0.082, 0.25, 0.5, 1, 2, 4, 8, 24 hr

(2) Pharmacokinetics results

The results were as shown in Table 3 below.

As can be seen in Table 3, Cmax and AUC were high in the order AZ < AZMk < AZD, respectively, and bioavailability was also high in the same order. For reference, the relative bioavailability compared to AZ is about 1.3 for AZMK and about 1.7 for AZD, and it was confirmed that AZD has approximately 30% higher bioavailability than AZMK.

Accordingly, the bioavailability of azilsartan is expected to vary depending on the drug exposure depending on the solubility rather than the biopermeability factor, and considering that azilsartan itself is an active ingredient that exhibits pharmacological effects, the bioavailability of azilsartan It can be seen that this high AZD also has excellent pharmacological effects.

In addition, no particular toxicity or abnormal signs were observed in the preclinical test.

3. Stability test

Storage stability tests were conducted on azilsartan (AZ) and azilsartan dicyclohexylamine (AZD) for two weeks at room temperature (RT) and 65°C (60%RH).

The results were the same as in Figure 2, and as can be seen in Figure 2, azilsartan dicyclohexylamine (AZD) not only shows higher stability than azilsartan at room temperature, but also shows relatively greater stability at high temperatures. As a result, it was confirmed that it was a very stable material.

4. Excipient compatibility test

(1) Test method

(2) Sample

(3) Test results

As a result of testing the compatibility of commonly used solubilizers, azilsartan free base shows suitable results when mixed with excipients excluding polyvinylpyrrolidone, Eudragit®E PO, and Labrafil, and azilsartan dicyclohexylamine Since it shows suitable results when mixed with excipients except sodium lauryl sulfate and Labrafil, it can be used as data to select excipients that can be selected first when considering formulation design and excipient selection.

Claims (4)

Azilsartan dicyclohexylamine compound represented by the following formula (1) as an angiotensin II antagonist:
[Formula 1]
A pharmaceutical composition for the treatment or prevention of cardiovascular disease comprising azilsartan dicyclohexylamine represented by formula 1 of claim 1 as an active ingredient. The pharmaceutical composition for treating or preventing cardiovascular disease according to claim 2, wherein the treatment or prevention of cardiovascular disease is treatment or prevention of high blood pressure. The pharmaceutical composition for treating or preventing cardiovascular disease according to claim 2, characterized in that it does not contain sodium lauryl sulfate and Labrafil.