KR101062908B1 - Pharmaceutical composition for the treatment of hypertension comprising olmesartan derivative - Google Patents

Abstract

The present invention relates to novel compounds useful for the treatment or prevention of hypertension, atherosclerosis and hemorrhagic heart failure and their use in medicine.

Olmesartan prodrugs, high blood pressure

Description

Anti-hypertensive pharmaceutical composition containing olmesartan derivative}

The present invention relates to novel compounds useful for the treatment or prevention of hypertension, atherosclerosis or hemorrhagic heart failure, pharmaceutical compositions comprising them and the pharmaceutical use of the new compounds.

Olmesartan is an angiotensin II receptor antagonist and is an imidazole family of drugs widely used in the treatment of hypertension. However, the bioavailability of olmesartan is extremely low, and in order to overcome such low bioavailability, prodrug-type olmesartan medoxomil has been developed and commercially available (Daewoong Pharmaceutical, Olmetec Tablet ™).

However, the bioavailability of olmesartan medoxomil is also very low as about 26%, and the development of a new olmesartan derivative having improved bioavailability is required.

Therefore, the technical problem to be achieved by the present invention is to provide a new olmesartan derivative with improved absorption, that is, bioavailability.

In order to achieve the above technical problem, the present invention provides an olmesartan derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical composition for the treatment or prevention of hypertension, hemorrhagic heart failure or atherosclerosis, comprising the olmesartan derivative or a pharmaceutically acceptable salt thereof.

The present invention is based on the surprising finding that the olmesartan derivative is superior in bioabsorption than many other olmesartan prodrugs.

"Pharmaceutically acceptable salts" of the present invention refer to salts that are made with no toxic or low acid or base. When the compounds of the present invention are relatively basic, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid and a suitable inert solvent. Pharmaceutically acceptable acid addition salts include propionic acid, isobutyl acid, oxalic acid, malic acid, malonic acid, benzoic acid, succinic acid, suberic, fumaric acid, manderic acid, phthalic acid, benzenesulfonic acid, p-torylsul Phonic acid, citric acid, tartaric acid, methanesulfonic acid, hydrochloric acid, bromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide, phosphorous acid Salts formed of, and the like, but are not limited thereto. It also includes, but is not limited to, salts of amino acids such as arginate and analogs of organic acids such as glucuronic or galactunoric acids.

Compounds of the present invention include hydrate or solvate forms and may exist in solvated as well as unsolvated forms. The compounds of the present invention may exist in crystalline or amorphous form, and all such physical forms are included within the scope of the present invention. In addition, the compound of the present invention may have a chiral carbon atom, which is an optical center, such that racemates, enantiomers, and the like may exist, and these are also included in the scope of the present invention.

The present invention also provides a pharmaceutical composition comprising an olmesartan derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or additive. Olmesartan derivatives or pharmaceutically acceptable salts thereof of the present invention may be administered alone or in admixture with any convenient carrier, excipient, and the like, and such dosage forms may be single or repeated dose formulations.

The pharmaceutical composition of the present invention may be a solid preparation or a liquid preparation. Solid preparations include, but are not limited to, powders, granules, tablets, capsules, suppositories, and the like. Solid form preparations may include, but are not limited to, excipients, flavors, binders, preservatives, disintegrants, lubricants, fillers and the like. Liquid formulations include, but are not limited to, solutions such as water, propylene glycol solutions, suspensions, emulsions, and the like, and may be prepared by adding suitable colorants, flavors, stabilizers, viscosity agents, and the like.

For example, the powder may be prepared by simply mixing the olmesartan derivative of the present invention with a suitable pharmaceutically acceptable excipient such as lactose, starch and microcrystalline cellulose. Granules are compounds of the present invention or pharmaceutically acceptable salts thereof; Pharmaceutically acceptable excipients; And a pharmaceutically acceptable binder such as polyvinylpyrrolidone and hydroxypropyl cellulose, and then prepared by using a wet granulation method using a solvent such as water, ethanol, isopropanol, or a dry granulation method using a compressive force. Can be. Tablets may also be prepared by mixing the granules with a suitable pharmaceutically acceptable glidant such as magnesium stearate and then tableting using a tableting machine.

The pharmaceutical composition of the present invention may be administered orally, by injection (eg, intramuscular injection, intraperitoneal injection, intravenous injection, infusion, subcutaneous injection, implant), inhalant, nasal administration, depending on the condition and condition of the individual to be treated. It may be administered as a vaginal agent, rectal agent, sublingual agent, transdermal agent, topical agent, and the like, but is not limited thereto. It may be formulated into a suitable dosage unit dosage form comprising a pharmaceutically acceptable carrier, excipient, vehicle that is commonly used and non-toxic depending on the route of administration. Depot formulations capable of continually releasing the drug for a period of time are also within the scope of the present invention.

The present invention is also characterized in that the treatment or prevention of hypertension, atherosclerosis and / or hemorrhagic heart failure of an olmesartan derivative or a pharmaceutically acceptable salt thereof, i.e., comprises an olmesartan derivative or a pharmaceutically acceptable salt thereof Provided are compositions for the treatment or prevention of hypertension, arteriosclerosis or hemorrhagic heart failure.

In use for the treatment of the above-mentioned diseases, in particular hypertension, the compounds of the present invention may be administered from about 0.2 mg to about 200 mg daily, with a daily dosage of about 2 mg to about 60 mg being preferred. However, the dosage may vary depending on the condition of the patient (age, sex, weight, etc.), the severity of the condition being treated, the compound used and the like. If desired, the total daily dose may be divided for convenience and divided several times throughout the day. The dosage is an amount effective for treating hypertension and for treating hemorrhagic heart failure, i.e., lowering blood pressure and reducing bleeding by adjusting the hemodynamics imposed on the heart.

The present invention is useful for the treatment or prevention of hypertension, atherosclerosis or hemorrhagic heart failure, and provides a pharmaceutical composition with improved bioabsorption.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

Example 1 Synthesis of Olmesartan Prodrug (Derivative) According to the Present Invention

The new olmesartan derivative was prepared in two steps as follows.

4- (2- Hydroxypropane -2-yl-2-propyl-1-((2 '-(1- Trityl -1H- Tetrazole -5-yl) biphenyl-4-yl) methyl ) -1H- Imidazole -5- Carboxylic acid  Manufacturing (Step 1)

In acetone (200 mL) 4- (1-hydroxy-1-methylethyl) -2-propyl-1H-imidazole-5-carboxyl ester 1 (20 g, 83.6 mmol), 5- (4 '-( Bromomethyl) biphenyl-2-yl) -1-trityl-1H-tetrazol 2 (51.3 g, 92.0 mmol), K ₂ CO ₃ (40 g) and PEG 200 (2.0 g) after dissolution It was refluxed for hours. The mixture was filtered, concentrated under reduced pressure and dissolved in isopropyl alcohol (280 mL) and stirred with potassium hydroxide (9.4 g, 167.2 mmol) at 50-60 ° C. for 4 hours. The mixture was concentrated under reduced pressure, dissolved in distilled water (200 mL) and washed with methylene chloride (50 mL). The water layer was adjusted to pH 4 with 2N hydrochloric acid. The resulting fine solid was filtered and washed with water to give compound 3 (45.1 g, 78.3%).

¹ H NMR (300 MHz, DMSO) δ 7.76 (d, J = 7.4 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.40-7.27 (m, 9H), 7.02 (d, J = 8.1 Hz, 2H), 6.87-6.85 (m, 8H), 5.58 (s, 2H), 2.41 (t, J = 6.6 Hz, 2H), 1.46 (m, 8H), 0.73 (t, J = 7.4 Hz, 3H)

One-( Benzoyloxy ) Ethyl-1-((2 '-(1H-) Tetrazole -5-yl) biphenyl-4-yl) methyl ) -4- (2- Hydropropane -2-yl) -2-propyl-1h- Imidazole -5- Carboxyl  Synthesis of Esters (Step 2)

4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl in dimethyl acetamide (70 mL) 4-yl) methyl) -1H-imidazole-5-carboxylic acid 3 (10 g, 14.52 mmol) and potassium carbonate powder (2.4 g, 17.4 mmol) were added and stirred at 60 ° C. for 30 minutes. 1-chloroethyl benzoester 4- 1 (4 g, 21.8 mmol) and potassium iodide (1.2 g, 7.3 mmol) were added to the mixture and stirred at 60 ° C. for 2 hours 30 minutes. Then dimethyl acetamide was removed from the mixture with water and the mixture was extracted with ethyl acetate. Magnesium sulfate was added to the organic layer, and the remaining water was removed by filtration. The mixture was concentrated under reduced pressure and separated by column chromatography (ethyl acetate: normal hexane = 1: 7) to obtain a white compound 5-1 (10.8 g, 88.9%).

¹ H NMR (300 MHz, DMSO) δ 7.90 (d, J = 7.4 Hz, 2H), 7.87-7.76 (d, J = 7.4 Hz, 2H), 7.70-7.65 (m, 6H), 7.41-7.28 (m , 9H), 7.01-6.92 (m, 8H), 6.88 (d, J = 7.9 Hz, 1H), 5.36 (s, 2H), 5.15 (s, 1H), 2.44 (t, J = 7.8 Hz, 2H) , 1.49 (q, J = 7.6 Hz, 2H), 1.46-1.44 (m, 9H), 0.74 (t, J = 7.8 Hz, 3H)

To 58 mL of a mixed solution of acetone and water (acetone: water = 3.5: 1) 1- (benzoyloxy) ethyl-4- (2-hydroxypropan-2-yl) -2-propyl-1-((2'- (1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxyester (10 g, 11.9 mmol) with hydrochloric acid (3.03 mL, 35.8 mmol ) Was added and stirred at room temperature for 4 hours. 174 mL of water was added dropwise to the contents and stirred for 30 minutes. Then, filtered to remove tritanol (tritanol), and concentrated under reduced pressure to remove acetone. The remaining water layer was adjusted to pH 5 with sodium bicarbonate and extracted with ethyl acetate. Magnesium sulfate was added to the clear ethyl acetate extract, dried and concentrated under reduced pressure. The mixture was separated by column chromatography (acetate: normal hexane = 1: 2) to give a white compound 1- (benzoyloxy) ethyl-1-((2 '-(1H-tetrazol-5-yl) biphenyl- 4-yl) methyl) -4- (2-hydropropan-2-yl) -2-propyl-1h-imidazole-5-carboxyl ester 6-1 (6.8 g, 91.9%) was obtained.

¹ H NMR (300 MHz, DMSO) δ 7.89 (d, J = 7.9 Hz, 2H), 7.66-7.54 (m, 4H), 7.49 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 7.5 Hz, 1H), 7.10 (q, J = 7.6 Hz, 1H), 7.01 (d, J = 7.9 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 5.42 (d, J = 4.5 Hz, 2H), 5.17 (s, 1H), 2.59 (t, J = 7.5 Hz, 2H), 1.58 (q, J = 7.4 Hz, 2H), 1.48-1.46 (m, 9H), 0.87 (t, J = 7.4 Hz, 3H)

Example 2 Synthesis of Comparative Examples

Comparative Example 1-9 was synthesized in a similar manner to the synthesis method for olmesartan derivatives according to the present invention.

For example, Comparative Examples 2 and 4 were prepared by the following method.

Preparation of Comparative Example 2 (2,4 -dioxo- 1,2,3,4 -tetrahydropyrimidin- 5 - yl) methyl 1-((2 '-(1H- tetrazol -5-yl) biphenyl-4-yl) methyl) -4- (2-hydro-oxy-propan-2-yl) -1H- imidazol-2-propyl-5-synthesis of carboxylic ester

4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl in dimethyl acetamide (50 mL) 4-yl) methyl) -1H-imidazol-5-carboxylic acid 3 (10 g, 14.52 mmol), 5- (chloromethyl) pyrimidine-2,4 (1H, 3H) -dione 7 (3.5 g , 21.8 mmol) and diisopropyl ethylamine (2.4 g, 29.04 mmol) were added and stirred at 60 ° C. for 8 hours. The dimethyl acetamide was then removed from the mixture with water and the mixture was extracted with ethyl acetate. Magnesium sulfate was added to the organic layer, and the remaining water was removed by filtration. The mixture was concentrated under reduced pressure and separated by column chromatography (ethyl acetate: normal hexane = 1: 4) to obtain a white compound 8 (9.6 g, 81.3%).

¹ H NMR (300 MHz, DMSO) δ 11.05 (d, J = 13.0 Hz, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.69-7.63 (m, 3H), 7.51-7.32 (m, 9H ), 7.01 (d, J = 8.1 Hz, 2H), 6.89 (m, 8H), 5.43 (d, J = 6.5 Hz, 3H), 4.85 (s, 2H), 2.59 (t, J = 7.5 Hz, 2H ), 1.57 (q, J = 7.5 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H)

To 60 mL of a mixed solution of acetone and water (acetone: water = 3.5: 1) (2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) methyl 4- (2-hydrooxo Propan-2-yl) -2-propyl-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazol-5- Carboxylic ester (10 g, 12.3 mmol) and hydrochloric acid (3.13 mL, 36.9 mmol) were added, followed by stirring at room temperature for 4 hours. 180 mL of water was added dropwise to the contents, stirred for 30 minutes, and then filtered to remove tritanol. Thereafter, the mixture was concentrated under reduced pressure to remove acetone. The remaining water layer was adjusted to pH 5 with sodium bicarbonate and extracted with ethyl acetate. Magnesium sulfate was added to the clear ethyl acetate extract, dried and concentrated under reduced pressure. The mixture was separated by column chromatography (acetate: normal hexane = 1: 2) to give a white compound (2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) tetrazole- 5-yl) biphenyl-4-yl) methyl) -4- (2-hydroxypropan-2-yl) -2-propyl-1H-imidazole-5-carboxyester 9 (6.4 g, 91.4%) Got.

¹ H NMR (300 MHz, DMSO) δ 11.07 (d, J = 13.1 Hz, 2H), 7.69-7.63 (m, 2H), 7.56 (t, J = 7.5 Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.2 Hz, 2H), 5.43 (d, J = 6.5 Hz, 3H), 4.85 (s, 2H), 2.59 (t, J = 7.5 Hz, 2H), 1.57 ( q, J = 7.5 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H)

Preparation of Comparative Example 4 1-((2 '-(1H -tetrazol -5-yl) biphenyl-4-yl) methyl ) -4- (2 -hydrooxypropan- 2-yl) -N- (6-arsenide to hexyl) -1H- imidazol-2-propyl-5-synthesis of carboxylic amide

4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl in dimethylformamide (50 mL) -4-yl) methyl) -1H-imidazol-5-carboxylic acid 3 (10 g, 14.52 mmol), 6-nitrohexane-1-amine 10 (2.8 g, 18.9 mmol), hydroxybenzotriazole (2.6 g, 18.9 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodimide (4.2 g, 21.78 mmol) and triethylamine (3.04 mL, 21.78 mmol) were added at 60 ° C. for 6 hours. Stirred. Thereafter, dimethylformamide was removed from the mixture using water, and the mixture was extracted with ethyl acetate. Magnesium sulfate was added to the organic layer, and the remaining water was removed by filtration. The mixture was concentrated under reduced pressure and separated by column chromatography (ethyl acetate: normal hexane = 1: 3) to obtain a white compound 11 (9.3 g, 78.8%).

¹ H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.63-7.50 (m, 2H), 7.43-7.31 (m, 10H), 7.01 (d , J = 5.6 Hz, 2H), 6.87 (d, J = 6.8 Hz, 8H), 6.19 (s, 1H), 5.55 (s, 2H), 4.49 (t, J = 6.9 Hz, 2H), 3.18 (q , J = 7.7 Hz, 2H), 2.36 (t, J = 7.7 Hz, 2H), 1.83 (m, 2H), 1.52 (s, 6H), 1.51-1.43 (m, 4H), 1.29-1.27 (m, 4H), 0.75 (t, J = 7.2 Hz, 3H)

Tritanol was removed in the same manner as in Comparative Example 2 to obtain white compound 12 (6.1 g, 88.4%).

¹ H NMR (300 MHz, DMSO) δ 9.61 (t, J = 5.1 Hz, 1H), 7.69-7.49 (m, 4H), 7.03 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 6.15 (s, 1H), 5.6 (s, 2H), 4.52 (t, J = 7.0 Hz, 2H), 3.19 (q, J = 7.4 Hz, 2H), 1.90-1.83 (m, 2H ), 1.50-1.46 (m, 10H), 1.32 (s, 4H), 0.85 (t, J = 7.3 Hz, 3H)

Experimental Example 1 Plasma Hydrolysis of Prodrug

Synthesized compounds were actually absorbed by the body and hydrolyzed to the active metabolite olmesartan.

A commercially available comparative olmesartan medoxomill, an olmesartan derivative according to the present invention and each of the comparative examples were dissolved in a well-soluble organic solvent (methanol or acetonitrile) at a concentration of 1 mg / ml. 50 microliters of the solution in which the test compound was dissolved in 1.2 ml of plasma preheated to 37.5 ° C. was shaken for 30 minutes while maintaining 37.5 ° C. After the reaction, 5 ml of acetonitrile was added to terminate the reaction, and the supernatant was analyzed by HPLC by centrifugation for 5 minutes.

The analysis conditions are as follows. The HPLC system was used by Agilent, the column was ODS C18 (4.6 × 25 mm), the flow rate was 1.0 ml / min, the injection volume was 20 microliters, and the measurement wavelength was 250 nm. The mobile phase was as follows.

0-10 minutes Buffer A: Buffer B = 75: 25

10 to 35 minutes Buffer A: Buffer B = 0: 100

35-45 minutes Buffer A: Buffer B = 0: 100

45-50 minutes Buffer A: Buffer B = 75: 25

(As a basic buffer, 4.08 g of potassium dihydrogen phosphate was dissolved in 2000 mL of water, and a solution adjusted to pH 3.5 with 0.015 mol / L aqueous solution of phosphate was used. For buffer A, 1600 mL of basic buffer and 400 mL of acetonitrile were mixed. One solution, buffer B was a mixture of 420 mL of basic buffer and 1580 mL of acetonitrile.)

The results are shown in Table 1 below.

Before the reaction
Drug area After the reaction
Drug area After the reaction
Active Metabolites (Olmessatans) Olmesartan Medocsomil 2646118 N.D. 2134659 Comparative Example 1 3572269 3223514 N.D. Comparative Example 2 3237542 3118936 N.D. Comparative Example 3 2791679 2797040 N.D. Comparative Example 4 2054331 2068094 N.D. Comparative Example 5 2383693 2356513 N.D. Comparative Example 6 2630884 2599218 N.D. Comparative Example 7 2608925 2116877 N.D. Olmesatan derivative of the present invention 3065282 2629320 178561 Comparative Example 9 - - 1474680 Comparative Example 8 2328102 2269815 -

(N.D .: not detected.)

In Comparative Example 1-8, there was a slight change in the peak area of the derivative, which is the original drug after reacting with plasma, but the isolated olmesartan, which is an active metabolite, was hardly detected. Therefore, Comparative Example 1-8 was expected to be difficult to use as a prodrug of olmesartan.

In the case of olmesartan medoxomil and Comparative Example 9, a large amount of olmesartan was formed after reacting with plasma. In Comparative Example 9, the prodrug itself was not analyzed, but the production of olmesartan, an activator produced after reacting with plasma, was confirmed.

For olme Satan prodrugs according to the invention it did react with a large amount of blood plasma olme Satan not generated, and the limit in the evaluation method using plasma in vitro experiments in Given the differences in in vivo experiments, its availability could not be ignored.

Experimental Example 2 Evaluation of Absorption Using Rat

Since it is very difficult to determine the actual bioabsorption rate using only plasma hydrolysis evaluation, rats were used to evaluate the uptake of prodrugs and the production of olmesartan in the blood.

A suspension was prepared to be 20 mg / 5 ml / Kg, and the suspension was administered to rats (n = 4) to compare the pharmacokinetics with olmesartan medoxomil, a commercial drug. Specifically, the test substance is prepared and administered so as to suspend olmesartan medoxomil in pH 6.8 phosphate buffer to 20mg / 5ml / Kg, and the same mole (mole) in proportion to the molecular weight of the olmesartan derivative according to the comparative example and the present invention. Suspensions were prepared and administered to mice. Blood was collected once every hour after dosing to analyze olmesartan concentrations in the blood. Analysis was performed by LC / MS / MS.

The results are shown in Tables 2 and 3 and FIG. 1.

Time (hr) Olmesartan
Medox Mill Comparative Example 1 Comparative Example 2 Olmesatan derivative of the present invention Comparative Example 9 0 3.0 1.7 2.0 1.6 1.3 0.5 124.3 6.5 4.9 1242.1 24.4 One 131.0 14.7 1.8 985.7 28.6 2 114.6 2.9 1.8 591.3 20.4 3 87.2 2.8 1.6 321.5 11.9 4 52.1 8.0 2.9 217.3 7.4 6 38.0 1.1 2.0 125.6 6.2 8 30.1 1.9 2.4 97.2 4.9 10 33.3 0.9 5.7 72.2 3.0

(Unit: ng / ml)

Olmesartan
Medox Mill Comparative Example 1 Comparative Example 2 Olmesatan derivative of the present invention Comparative Example 9 AUC (last) 501.9 32.8 21.7 3013.8 100.4 Cmax (ng / ml) 153.6 17.9 8.0 1374.7 32.6 Tmax (hours) 1.0 0.8 3.8 0.9 0.8

In the case of Comparative Examples 1 and 2 in vitro Similar to plasma utilization experiments, little olmesartan was detected in rat blood. In the case of the olmesatan prodrug, the derivative according to the present invention, the AUC was nearly 6 times higher than that of the control mesametan medoxomill. In Comparative Example 9, in vitro Plasma utilization experiments produced a large amount of olmesartan, but rat uptake experiments showed very low bioabsorption rates.

1 is a result of measuring the concentration of olmesartan, an olmesartan, an olmesartan derivative according to the present invention, and some olmesartan derivatives used as comparative examples in rats after oral administration to mice in the blood.

Claims (2)

Olmesartan derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof. <Formula 1>

A pharmaceutical composition for treating or preventing hypertension, hemorrhagic heart failure or atherosclerosis, comprising the olmesartan derivative of claim 1 or a pharmaceutically acceptable salt thereof.

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