KR20190031725A - Fimasartan prodrug - Google Patents

Abstract

The present invention relates to a fimasartan prodrug, which has an excellent effect of preventing or treating hypertension, and to a preparing method thereof, and a pharmaceutical composition including the fimasartan prodrug as an active ingredient. The fimasartan prodrug is represented by chemical formula 1. In chemical formula 1, R_1 and R_2 are each independently hydrogen or a linear or branched C_1-C_6 alkyl group, R_3 is AA or BB, and Y_1 and Y_2 are each independently a linear or branched C_1-C_6 alkyl group or a C_3-C_6 cycloalkyl group.

Description

{FIMASARTAN PRODRUG}

TECHNICAL FIELD The present invention relates to a phimassalant prodrug and a method for producing the same, and more particularly, to a phimassaltan prodrug having excellent intestinal permeability, a method for producing the same, and a pharmaceutical composition containing the same as an effective ingredient.

Hypertension is a chronic disease in which blood pressure is above normal range. Blood pressure is summarized as two measures of systolic systolic blood pressure and diastolic diastolic blood pressure. The normal blood pressure at rest is 60 to 90 mmHg when relaxed to 100 to 140 mmHg when contracted, and the blood pressure is constantly 140/90 mmHg or more Hypertension is said to be. Hypertension is classified into essential hypertension and secondary hypertension. About 90 to 95% of hypertension is classified as 'essential hypertension' without definite underlying medical cause. The remaining 5-10% (secondary hypertension) is due to other health conditions affecting the kidneys, arteries, heart, or endocrine system. Hypertension is a major risk factor for stroke, myocardial infarction (heart attack), heart failure, aneurysms of the blood vessels (eg, aortic aneurysms), and ischemic aneurysms. Although arterial blood pressure is only slightly higher, it may be associated with reduced life expectancy.

Currently, one of the most prescribed medications for hypertensive patients is the calcium channel blocker, which lowers blood pressure by blocking the role of calcium in the heart and blood vessels. In addition, a variety of hypertensive agents have been developed, including beta-blockers that slow heart beats, alpha-blockers that are commonly used in patients with hypertension with hypertrophy of the prostate, and diuretics that control blood pressure by removing body water and salts These antihypertensive agents have been reported to cause various side effects such as constipation, dizziness, headache, ankle swelling, asthma, depression, erectile dysfunction and insomnia.

In this situation, antihypertensive drugs using prodrugs are emerging as a new alternative to complement the limited functions of existing drugs and to reduce various side effects.

Fimarsartan has reported that (2-n-butyl-5-dimethylamino thiocarbonyl methyl-6-methyl-3- [ 3H) -one}, and has a structure represented by the following formula (1a).

[Formula 1a]

In general, Pimassartan is an antihypertensive agent of the ARB (Angiotensin II Receptor Blocker) family, which blocks the angiotensin II receptor type 1 (AT ₁ receptor) through oral administration and inhibits angiotensin II hypertension It is known that the hypotensive effect of hypotensive hypertensive patients with hypertrophic hypertension is very good.

Pimacaltan exhibits excellent pharmacological activity, but has low solubility and has been prepared and used in the form of a salt or with various excipients for its improvement.

Therefore, it is necessary to study the prodrug of Pimassartan which has various advantages such as increase of bioavailability when the physicochemical properties such as solubility is excellent.

Korean Patent Publication No. 10-2014-0047483

It is an object of the present invention to provide a prodrug of Pimassartan or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a process for the preparation of a prodrug of Pimacartan or a pharmaceutically acceptable salt thereof.

It is still another object of the present invention to provide a pharmaceutical composition comprising a prodrug of Pimacartan or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention provides a prodrug of Pimacartan or a pharmaceutically acceptable salt thereof.

The present invention also provides a process for the preparation of a prodrug of Pimacartan or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical composition comprising a prodrug of Pimacartan or a pharmaceutically acceptable salt thereof as an active ingredient.

Pima Saltan Pro Drug  Or a pharmaceutically acceptable salt thereof.

The present invention provides a pharmacartan prodrug of the formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In formula (1)

R ₁ and R ₂ are each independently hydrogen or a linear or branched C ₁ -C ₆ alkyl group;

또는

이며;R ₃ is

or

;

Y ₁ and Y ₂ are each independently a linear or branched C ₁ -C ₆ alkyl group or a C ₃ -C ₆ cycloalkyl group;

Y ₃ , Y ₄ and Y ₅ are each independently hydrogen or a linear or branched C ₁ -C ₆ alkyl group;

Y ₆ is an alkali metal.

In the present invention, the term " prodrug " means a drug whose chemical and physiological properties have been controlled by chemically changing a certain drug. Although the drug itself does not exhibit physiological activity, it is administered chemically or enzymatically It is said to exert its effect by turning into the original drug.

In the present invention, the term " alkyl group " may refer to a linear or branched monovalent alkyl or monovalent hydrocarbon. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, isobutyl, -Butyl, and the like.

In the present invention, the "cycloalkyl group" may refer to a monovalent hydrocarbon of a ring chain. Examples of the cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. It is not limited thereto.

In the present invention, the " alkali metal " may be lithium, sodium, or potassium.

According to another embodiment of the present invention,

Wherein R ₁ and R ₂ are each independently hydrogen or a linear or branched C ₁ -C ₄ alkyl group;

또는

이며;R ₃ is

or

;

Y ₁ and Y ₂ are each independently a linear or branched C ₁ -C ₄ alkyl group or a C ₆ cycloalkyl group;

Y ₃ , Y ₄ and Y ₅ are each independently hydrogen or a linear or branched C ₁ -C ₄ alkyl group;

Y ₆ is potassium.

Further, according to another embodiment of the present invention,

In Formula 1, R ₁ and R ₂ are each independently hydrogen, a methyl group or an isopropyl group;

또는

이며;R ₃ is

or

;

Y ₁ and Y ₂ are each independently methyl, ethyl, isopropyl, tert-butyl or cyclohexyl,

Y ₃ , Y ₄ and Y ₅ are each independently hydrogen or a tert-butyl group;

Y ₆ is potassium.

In one embodiment of the present invention, at least one of R < ₁ > and R < ₂ > is hydrogen. That is, R ₁ and R ₂ may be hydrogen, at least one of R ₁ and R ₂ may be hydrogen, and the other may be a linear or branched C ₁ -C ₆ alkyl group.

In the present invention, the pharmacologically acceptable salts of the prodrugs of Pimassartan are not particularly limited as those commonly used in the art such as acid addition salts formed by an acceptable free acid. As the pharmaceutically acceptable free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid and the like can be used. As the organic acids, there can be used tartaric acid, methanesulfonic acid, p- toluenesulfonic acid, Citric acid, lactic acid, glycolic acid, maleic acid, maleic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, glucuronic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. Can be used. At this time, the pharmaceutically acceptable salt is preferably hydrochloride, but is not limited thereto.

In addition, bases can be used to make pharmaceutically acceptable metal salts. Here, the pharmaceutically acceptable metal salt may be an alkali metal salt such as lithium, sodium, or potassium, and the pharmaceutically acceptable metal salt is preferably, but not limited to, potassium salt.

The compounds of formula I according to the present invention also include possible solvates and hydrates which may be prepared from pharmaceutically acceptable salts and all possible optical isomers, stereoisomers and mixtures thereof are also included within the scope of the present invention do. At this time, the solvate, hydrate and stereoisomer of the compound represented by Formula 1 may be prepared by using methods commonly known in the art.

In the present invention, the compound of Formula 1 may be prepared in a crystalline form or in an amorphous form, and may be optionally hydrated or solvated when the compound of Formula 1 is prepared in crystalline form.

In addition, the prodrugs of the present invention or the pharmaceutically acceptable salts thereof may be selected from the group consisting of the following compounds.

The pharmacartan prodrug of the present invention or a pharmaceutically acceptable salt thereof is remarkably excellent in solubility as compared with the trihydrate of the poorly soluble drug Pimersartan potassium salt. In addition, the palmasaltan prodrug of the present invention or a pharmaceutically acceptable salt thereof has an excellent intestinal permeability.

Accordingly, the Pimassaltan prodrug according to the present invention or its pharmaceutically acceptable salt can be expected to have an excellent effect of preventing or treating hypertension, and having excellent compliance with medication.

Pima Saltan Prodrug  Manufacturing method

The present invention provides a process for preparing a prodrug of Pimassa tans or a pharmaceutically acceptable salt thereof represented by the above formula (1).

Preferably, the prodrugs of the palmasalans of the present invention or pharmaceutically acceptable salts thereof can be prepared by the following Production Method 1 or 2, but are not limited thereto. In particular, those skilled in the art will appreciate that the prodrugs of the present invention may be prepared by various methods using well known techniques well known in the art.

Further, it can be produced by changing or modifying reagents, solvents and reaction sequence used in Production Method 1 or 2 of the present invention. Detailed procedures for the preparation of the prodrugs of the present invention of phimacartan or its pharmaceutically acceptable salts are described in detail in each of these examples.

Production Method 1

According to an embodiment of the present invention, the process for the preparation of the < RTI ID = 0.0 > pharmacartan < / RTI > prodrug of the present invention, or a pharmaceutically acceptable salt thereof,

(S1) dissolving a Pimassartan of Formula (I) in a solvent;

(S2) To the solution obtained in (S1), triethylamine; Formalin or isobutylaldehyde; 4-dimethylaminopyridine; And acetic anhydride or pivaloyl chloride to prepare a reaction mixture; And

(S3) A solvent is added to the reaction mixture obtained in (S2), followed by concentration under reduced pressure

.

[Formula 1a]

In the present invention, the (S1) a solvent phase may be daily for an organic, for example, nitriles (nitrile) a linear or branched C ₁ to alcohol of C _5, C ₂ to C _5, C ₂ to esters of C ₁₀ sulfoxide, C ₃ to C ₁₀ a, may be a ketone, or a mixture thereof in the C ₃ to C _10. But it may preferably be tetrahydrofuran, ethyl acetate, dimethylformamide, n-hexane, isopropanol, acetonitrile, ethanol or a mixture thereof, more preferably tetrahydrofuran, ethyl acetate or a mixture thereof, But is not limited thereto. Further, when the solvent is a solvent which is miscible with water, the solvent may further comprise water.

In the present invention, the reaction mixture of step (S2) may further include stirring at room temperature for one day.

In the present invention, the (S3) solvent of step may be daily for an organic, for example, halogenated hydrocarbons, C ₁ to C ₅ hydrocarbon-based solvent, C ₃ to C ₁₀ ester, C ₁ to C ₅ of the system Solvent or a mixture thereof. But is not limited to, ethyl acetate, toluene, dichloromethane, chloroform or a mixture thereof. In addition, in step (S3), it may be preferable to use a solvent having a low miscibility with water.

In the present invention, the step (S3) may further comprise the step of washing the organic layer with a brine after adding a solvent.

In the present invention, the step (S3) may further include a column chromatography step after concentration under reduced pressure.

Production Method 2

According to another embodiment of the present invention, a method for the preparation of the palmasaltan prodrug of the present invention, or a pharmaceutically acceptable salt thereof,

(S1) a step of dissolving the base addition salt of Pimersartan of Formula 1a or a hydrate thereof in a solvent;

(S2) Potassium iodide is added to the lysate obtained in (S1) above; And adding 1-chloroethyl cyclohexyl carbonate or di-tert-butyl chloromethyl phosphate to the reaction mixture to prepare a reaction mixture; And

(S3) A solvent is added to the reaction mixture obtained in (S2), followed by concentration under reduced pressure

.

In the present invention, the base addition salt of the castor oil of Formula 1a may be a pharmaceutically acceptable base addition salt, for example, a sodium salt; Potassium salt; Calcium salt; Amine salts such as ammonia, alkylamines, N-methyl-D-glucamine, osginine, lysine, and the like.

In one embodiment of the present invention, the base addition salt of the castor oil of Formula 1a may be a potassium salt, and more specifically, a monohydrate of the potassium salt of the castor oil of Formula 1a.

In the present invention, the (S1) a solvent phase may be daily for an organic, for example, nitriles (nitrile) a linear or branched C ₁ to alcohol of C _5, C ₂ to C _5, C ₂ to esters of C ₁₀ sulfoxide, C ₃ to C ₁₀ a, may be a ketone, or a mixture thereof in the C ₃ to C _10. But is not limited to, dimethylformamide, tetrahydrofuran, ethyl acetate, n-hexane, isopropanol, acetonitrile, ethanol or a mixture thereof, more preferably dimethylformamide. Further, when the solvent is a solvent which is miscible with water, the solvent may further comprise water. In the present invention, the reaction mixture of step (S2) may further include stirring at room temperature for one day.

In the present invention, the (S3) solvent of step may be daily for an organic, for example, halogenated hydrocarbons, C ₁ to C ₅ hydrocarbon-based solvent, C ₃ to C ₁₀ ester, C ₁ to C ₅ of the system Solvent or a mixture thereof. But is not limited to, ethyl acetate, toluene, dichloromethane, chloroform or a mixture thereof. In addition, in step (S3), it may be preferable to use a solvent having a low miscibility with water.

In the present invention, the step (S3) may further comprise the step of washing the organic layer with a brine after adding a solvent.

In the present invention, the step (S3) may further include a column chromatography step after concentration under reduced pressure.

In addition, the palmasaltan prodrug of the present invention or a pharmaceutically acceptable salt thereof can be prepared by a variety of methods by those skilled in the art using known techniques well known in the art.

Preferably, the pharmaceutically acceptable salt of the Pima saccharide prodrug of the present invention can be prepared using the Pima saccharide prodrug of the present invention prepared by Preparation Method 1 or 2 above.

Pima Saltan Pro Drug  PHARMACEUTICAL COMPOSITION CONTAINING AS ACTIVE INGREDIENT, USE OF THE SAME,

The present invention provides a pharmaceutical composition comprising as an active ingredient a prodrug of Pimersartan of Formula 1 or a pharmaceutically acceptable salt thereof.

In the present invention, the composition may be used as a pharmaceutical composition for the treatment of stroke, stroke, stroke, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, Or a pharmaceutical composition for treating or preventing renal failure.

The pharmaceutical composition of the present invention comprising the prodrug of the present invention or a pharmaceutically acceptable salt thereof can exhibit a therapeutic or preventive effect by being converted into a castor oil in the body, Can be used for the treatment or prophylaxis of stroke, cerebral infarction, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, heart failure, inflammation or renal failure.

In the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable additive.

Such pharmacologically acceptable is physiologically acceptable and is generally administered to humans, usually without the occurrence of an allergic reaction such as a gastrointestinal disorder, dizziness, or the like, or a similar reaction, For use, see Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA.

The additive may be a carrier, an excipient, an extender, an antioxidant, a buffer, a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a suspending agent, a surfactant and an antiseptic agent. For example, the additive may be selected from the group consisting of lactose, dextrose, calcium silicate, corn starch, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Wherein the aqueous solution is selected from the group consisting of methylcellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, stearic acid, magnesium stearate, calcium stearate, gellan tin, mineral oil, Alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, or mixtures thereof. However, the additives that may be included in the composition according to the present invention are not limited to the above listed materials, and they are merely illustrative.

The pharmaceutical composition of the present invention may be formulated according to a conventional method, and may be prepared into an oral preparation or a parenteral administration preparation, and preferably it may be an oral administration preparation.

In the present invention, the pharmaceutical preparations for oral administration may be solid preparations such as tablets, pills, powders, granules and capsules, or liquid preparations such as suspensions, solutions, emulsions and syrups, More preferably, it may be a tablet.

When the pharmaceutical composition of the present invention is formulated into an oral solid preparation, examples of the additives to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate , Gelatin, talc, and the like.

When the pharmaceutical composition is formulated into a liquid preparation for oral administration, various additives such as water, a simple diluent such as liquid paraffin, a wetting agent, a sweetener, a fragrance, a preservative, an antiseptic, a colorant, have.

When the pharmaceutical composition of the present invention is prepared in the form of an injection, the additive may include water, saline solution, glucose aqueous solution, pseudosugar solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, Rides, and the like.

In the present invention, the content of the additive contained in the pharmaceutical composition is not particularly limited and may be appropriately controlled within the range of contents used for usual formulation.

The preferred dosage of the prodrug of the present invention of the palmasaltan or a pharmaceutically acceptable salt thereof depends on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art .

In the present invention, the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically), and the dose may be appropriately determined depending on the body weight, age, sex, The range may vary depending on the condition, diet, time of administration, method of administration, duration or interval of administration, excretion rate, sickness specificity, nature of the preparation, severity of the disease and the like.

The pharmaceutical composition of the present invention may further comprise a pharmacologically active substance other than the prodrug of phimacaltan of the present invention or a pharmaceutically acceptable salt thereof. The pharmacologically active substance may have similar or the same pharmacological activity as the prodrug of phimecartan or a pharmacologically acceptable salt thereof, or may have other pharmacological activity.

The other pharmacologically active substances contained in the pharmaceutical composition may be selected from the group consisting of therapeutic agents for hyperlipidemia such as amlodipine, lercardipine, nicardipine, simvastatin, atorvastatin, pravastatin and rosuvastatin, metformin, hydrochlorothiazide, cytarglyptin, Or a pharmaceutically acceptable salt thereof, or a mixture of these, for the treatment of diabetes such as lipid, lignin, linagliptin, saxagliptin, teneligliptin, anagliptin, meloglyptin, twotogliptin, gemigliptin, More preferably amlodipine, rosuvastatin, atorvastatin, hydrochlorothiazide, cyctigliptin, bilagogliptin, linagliptin, pharmaceutically acceptable salts thereof, or a mixture thereof.

The pharmaceutical composition of the present invention can be used alone, for improving, alleviating, treating or preventing diseases, or in combination with methods using surgery, hormone therapy, drug therapy and biological response modifiers.

The present invention also provides a method for preventing or treating stroke, stroke, stroke, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, heart failure, inflammation or renal failure There is provided the use of a prodrug of said palmatartan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. Pimassalant prodrugs or pharmaceutically acceptable salts thereof for the preparation of medicaments may be mixed with pharmaceutically acceptable adjuvants, diluents, carriers and the like, and may be formulated with a combination preparation together with other active agents to have a synergistic effect have.

The present invention also relates to a method for the treatment of diabetes mellitus, comprising administering to a mammal, including a human, an effective amount of a prodrug of Pimassartan or a pharmaceutically acceptable salt thereof for the treatment of stroke, stroke, stroke, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt- , Hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, heart failure, inflammation or renal failure. The prophylactic or therapeutic method of the present invention not only treats the disease itself before the onset of the symptoms, but also inhibits or avoids the symptoms thereof, by administering the above-mentioned Pimassaran progag or a pharmaceutically acceptable salt thereof. In the management of disease, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition, and the route by which the active ingredient is to be administered. The frequency of dose and dose will vary with the age, weight and response of the individual patient. Appropriate dosing regimens can be readily selected by those of ordinary skill in the art which will of course consider these factors. In addition, the prophylactic or therapeutic method of the present invention may further comprise administration of a therapeutically effective amount of an additional active agent which is useful in the treatment of the disease, together with the said palmasaltan prodrug, or a pharmaceutically acceptable salt thereof, Additional active agents may exhibit synergistic or additive effects with the < RTI ID = 0.0 > Pimasartan < / RTI > prodrug or a pharmaceutically acceptable salt thereof.

The matters mentioned in the pharmaceutical composition, use treatment method of the present invention are applied as long as they are not mutually contradictory.

The prodrugs of the palmasalans of the present invention or their pharmaceutically acceptable salts exhibit excellent solubility and intestinal permeability. Therefore, the prodrug of the present invention of Pimasartan or its pharmaceutically acceptable salt can be expected to have an excellent effect of preventing or treating hypertension, and exhibiting excellent compliance with medication.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited thereto.

Example

< Example  1> Preparation of a compound of the formula 1-1 ((5- (4 '- ((2-butyl-5- (2- (dimethylamino) -2-thioxoethyl) -4-methyl-6-oxopyrimidin- yl) methyl) - [1,1'-biphenyl] -2-yl) -2H-tetrazol-2-yl) methyl acetate )

[Chemical Formula 1-1]

To the solution was added triethylamine (0.42 mL, 3 mmol), 35% formalin (0.31 mL, 4 mmol), 4-dimethylaminopyridine (12 mg, 0.1 mmol) and acetic anhydride (0.28 mL, 3 mmol), and the mixture was stirred overnight at room temperature to prepare a reaction mixture. The resulting reaction mixture was concentrated under reduced pressure, dissolved by adding ethyl acetate, and then the organic layer was washed with brine. The crude product was purified by column chromatography (ethyl acetate: n-hexane = 3: 1) to obtain the title compound (0.63 g, 55%, foam solid ).

_{^{1 H NMR (DMSO d6):}} δ 0.85 (t, 3H), 1.31 (m, 2H), 1.58 (m, 2H), 2.11 (s, 3H), 2.20 (s, 3H), 2.65 (m, 2H) 2H), 6.52 (s, 2H), 7.11-7.82 (m, 8H), 3.45 (s, 3H)

< Example  2 > Preparation of Compound (1-2) ((5- (4 '- ((2-butyl- 5- (2- (dimethylamino) -2-thioxoethyl) -4-methyl-6-oxopyrimidin- yl) methyl) - [1,1'-biphenyl] -2-yl) -2H-tetrazol-2-yl) methyl acetate hydrochloride )

[Chemical Formula 1-2]

(0.58 g, 0.87 mmol) was dissolved in acetone (5 mL), and then concentrated hydrochloric acid (0.08 mL, 0.92 mmol) was added thereto and concentrated under reduced pressure to give the title compound (0.52 g, 98% ).

_{^{1 H-NMR (DMSO d6)}} δ 0.82 (t, 3H), 1.32 (m, 2H), 1.50 (m, 2H), 2.12 (s, 3H), 2.33 (s, 3H), 2.91 (m, 2H) 2H), 6.51 (s, 2H), 7.11-7.82 (m, 8H), 3.45 (s, 3H)

< Example  3> Preparation of Compound (1-3) ((5- (4 '- ((2-butyl-5- (2- dimethylamino) -2-thioxoethyl) -4-methyl-6-oxopyrimidin- yl) methyl) - [1,1'-biphenyl] -2-yl) -2H-tetrazol-2-yl) methyl pivalate )

[Chemical Formula 1-3]

To the solution was added triethylamine (0.42 mL, 3 mmol), 35% formalin (0.31 mL, 4 mmol), 4-dimethylaminopyridine (12 mg, 0.1 mmol) and pivaloyl chloride (0.37 mL, 3 mmol) were added and the reaction mixture was stirred at room temperature overnight. The resulting reaction mixture was concentrated under reduced pressure, dissolved by adding ethyl acetate, and then the organic layer was washed with brine. The crude product was purified by column chromatography (ethyl acetate: n-hexane = 3: 1) to give the title compound (0.44 g, 36%, foamy solid ).

_{^{1 H-NMR (DMSO d6)}} δ 0.86 (t, 3H), 1.14 (s, 9H), 1.32 (m, 2H), 1.58 (m, 2H), 2.20 (s, 3H), 2.64 (m, 2H) 2H), 6.57 (s, 2H), 7.10-7.77 (m, 8H), 3.45 (s, 3H)

< Example  4> Preparation of Compound (1-5) (1- (5- (4'- (2-butyl-5- (2- (dimethylamino) -2-thioxoethyl) -4-methyl-6-oxopyrimidin- yl) methyl) - [1,1'-biphenyl] -2-yl) -2H-tetrazol-2-yl) -2-methylpropyl acetate)

[Chemical Formula 1-5]

(0.42 mL, 3 mmol), isobutylaldehyde (0.36 mL, 4 mmol), 4-dimethylaminopyridine (12 mg, 0.1 mmol) were dissolved in tetrahydrofuran (10 mL) ) And acetic anhydride (0.28 mL, 3 mmol) were added, and the mixture was stirred overnight at room temperature to prepare a reaction mixture. The resulting reaction mixture was concentrated under reduced pressure, dissolved by adding ethyl acetate, and then the organic layer was washed with brine. The washed organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate: n-hexane = 3: 1) to give the title compound (1.16 g, 94% ).

_{^{1 H-NMR (DMSO d6)}} δ 0.57 (d, 3H), 0.87 (t, 3H), 0.96 (d, 3H), 1.34 (m, 2H), 1.61 (m, 2H), 2.10 (s, 3H) 2H), 2.20 (s, 3H), 2.25 (m, 2H), 2.64 (s, 6.82 (d, 1 H), 7.08-7.84 (m, 8 H)

< Example  5> Preparation of a compound of the formula 1-7 (1- (5- (4 '- ((2-butyl-5- (2- (dimethylamino) -2-thioxoethyl) -4-methyl-6-oxopyrimidin- yl) methyl) - [1,1'-biphenyl] -2-yl) -2H-tetrazol-2-yl) -2-methylpropyl pivalate )

[Chemical Formula 1-7 Compound]

(0.42 mL, 3 mmol), isobutylaldehyde (0.37 mL, 4 mmol), and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were dissolved in tetrahydrofuran (10 mL) ), Pivaloyl chloride (0.37 mL, 3 mmol) was added, and the reaction mixture was stirred overnight at room temperature to prepare a reaction mixture. The resulting reaction mixture was concentrated under reduced pressure, dissolved by adding ethyl acetate, and then the organic layer was washed with brine. The crude organic layer was purified by column chromatography (ethyl acetate: n-hexane = 3: 1) to obtain the title compound (0.73 g, 55%, foam solid ).

_{^{1 H-NMR (DMSO d6)}} δ 0.64 (d, 3H), 0.87 (t, 3H), 0.94 (d, 3H), 1.13 (s, 9H), 1.33 (m, 2H), 1.59 (m, 2H) 2H), 2.32 (s, 3H), 2.32 (s, 3H), 2.31 6.82 (d, 1 H), 7.09 - 7.80 (m, 8 H)

< Example  6> Preparation of a compound of the formula 1-9 (1- (5- (4 '- ((2-butyl-5- (2- (dimethylamino) -2-thioxoethyl) -4-methyl-6-oxopyrimidin- yl) methyl) - [1,1'-biphenyl] -2-yl) -2H-tetrazol-2-yl) ethyl cyclohexyl carbonate )

[Chemical Formula 1-9 compound]

Potassium iodide (30 mg, 0.18 mmol) and 1-chloroethylcyclohexyl carbonate (0.40 mL, 2.2 mmol) were added to the solution of dimethylformamide (8 mL) in pyrimelamine potassium salt monohydrate (1 g, 1.8 mmol) , And the mixture was stirred overnight at room temperature to prepare a reaction mixture. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with brine. The washed organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate: n-hexane = 3: 1) to give the title compound (0.71 g, 59% ).

_{^{1 H-NMR (DMSO d6)}} δ 0.84-1.70 (m, 20H), 2.20 (s, 3H), 2.52-2.70 (m, 2H), 3.48 (s, 3H), 3.50 (s, 3H), 3.81 ( (s, 2H), 4.30-4.65 (m, 1H), 5.30 (s, 2H), 6.20

< Example  Preparation of a compound of the formula 1-11 (1- (5- (4 '- ((2-butyl-5- (2- dimethylamino) -2-thioxoethyl) -4-methyl-6-oxopyrimidin- yl) methyl) - [1,1'-biphenyl] -2-yl) -2H-tetrazol-2-yl) ethyl isopropyl carbonate )

[Chemical Formula 1-11 Compound]

Potassium iodide (30 mg, 0.18 mmol) and 1-chloroethyl isopropyl carbonate (0.34 ml, 2.2 mmol) were added to dimethylsemal potassium salt monohydrate (1 g, 1.8 mmol) , And the mixture was stirred overnight at room temperature to prepare a reaction mixture. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with brine. The washed organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate: n-hexane = 3: 1) to give the title compound (0.76 g, 67% ).

_{^{1 H-NMR (DMSO d6)}} δ 0.86 (t, 3H), 1.08-1.28 (d, 6H), 1.31 (m, 2H), 1.59 (m, 2H), 1.71 (d, 3H), 2.20 (s, 3H), 3.81 (s, 2H), 4.59-4.81 (m, IH), 5.30 (s, 2H), 6.18 (m, 1 H), 7.06-7.88 (m, 8 H)

< Example  Preparation of a compound represented by the formula 1-13 (1- (5- (4 '- ((2-butyl-5- (2- dimethylamino) -2-thioxoethyl) -4-methyl-6-oxopyrimidin- yl) methyl) - [1,1'-biphenyl] -2-yl) -2H-tetrazol-2-yl) ethyl ethyl carbonate )

[Chemical Formula 1-13]

Potassium iodide (30 mg, 0.18 mmol) and 1-chloroethyl ethyl carbonate (0.29 mL, 2.2 mmol) were added to dimethylformamide (8 mL) by dissolving it in a solution of potassium salt potassium salt monohydrate (1 g, 1.8 mmol) The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with brine. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with brine. The washed organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate: n-hexane = 3: 1) to give the title compound (0.74 g, 66% ).

_{^{1 H-NMR (DMSO d6)}} δ 0.86 (t, 3H), 1.09-1.25 (t, 3H), 1.31 (m, 2H), 1.59 (m, 2H), 1.71 (d, 3H), 2.20 (s, 3H), 3.81 (s, 2H), 3.99-4.20 (m, 2H), 5.30 (s, 2H), 6.12 (m, 1 H), 7.06-7.70 (m, 8 H)

< Example  9> Preparation of Compound (1-15) ( di - tert - butyl  ((5- (4 '- ((2-butyl-5- (2- (dimethylamino) -2-thioxoethyl) -4-methyl-6- oxopyrimidin- 1 (6H) -yl) -biphenyl] -2-yl) -2H-tetrazol-2-yl) methyl)

[Compound (1-15)

Potassium iodide (30 mg, 0.18 mmol) and di-tert-butyl chloromethyl phosphate (0.57 g, 2.2 mmol) were added to dimethylformamide (8 mL) by dissolving in a solution of potassium palmate potassium salt monohydrate (1 g, 1.8 mmol) And the mixture was stirred at room temperature overnight to prepare a reaction mixture. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with brine. The washed organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (chloroform: methanol = 99: 1) to give the title compound (0.33 g, 25% Respectively.

_{^{1 H-NMR (CDCl 3)}} δ 0.90 (t, 3H), 1.33-1.45 (s, 18H), 1.36 (m, 2H), 1.63 (m, 2H), 2.35 (s, 3H), 2.62 (m, 2H), 3.50 (s, 3H), 3.53 (s, 3H), 3.87 (s, 2H), 5.28 (s, 2H), 5.36-6.19 (d, 2H), 7.07-7.54

< Example  Preparation of a compound represented by the formula 1-16 ((5- (4 '- ((2-butyl-5- (2- dimethylamino) -2-thioxoethyl) -4-methyl-6-oxopyrimidin- yl) methyl) - [1,1'-biphenyl] -2-yl) -2H-tetrazol-2-yl) methyl dihydrogen phosphate )

[Chemical Formula 1-16]

Dissolve dichloromethane (40 mL) in Pimersartan-methyl di-tert-butyl phosphate (0.5 g, 0.7 mmol) and cool to 10 ° C or lower. Trifluoroacetic acid (6 mL, 78.3 mmol) was added and stirred at 10 ° C or lower for 2 hours and then concentrated under reduced pressure. Ethyl acetate (5 mL) and n-hexane (3 mL) were added and the resulting solid was filtered to give the title compound (0.25 g, 59%).

_{^{1 H-NMR (DMSO d6)}} δ 0.85 (t, 3H), 1.31 (m, 2H), 1.55 (m, 2H), 2.22 (s, 3H), 2.69 (m, 2H), 3.45 (s, 3H) , 3.49 (s, 3H), 3.83 (s, 2H), 5.33 (s, 2H), 5.79-6.26 (d, 2H), 7.11-7.80

< Example  11> Preparation of Compound (1-17) ( potassium  (5 - (4 '- ((2-butyl-5- (2- (dimethylamino) -2-thioxoethyl) -4-methyl-6- oxopyrimidin- 1 (6H) -biphenyl] -2-yl) -2H-tetrazol-2-yl) methyl hydrogenphosphate )

[Chemical Formula 1-17]

Dissolve dichloromethane (10 mL) and methanol (5 mL) in a solution of Pimersartan-methylphosphoric acid (0.2 g, 0.33 mmol) and then add 0.1 N potassium hydroxide ethanol solution (3.27 mL, 0.33 mmol). And the mixture was stirred at room temperature for 1 hour to prepare a reaction mixture. The resulting reaction mixture was concentrated under reduced pressure to give the title compound (0.13 g, 63%, solid).

_{^{1 H-NMR (DMSO d6)}} δ 0.79 (t, 3H), 1.25 (m, 2H), 1.51 (m, 2H), 2.16 (s, 3H), 2.59 (m, 2H), 3.41 (s, 3H) , 3.45 (s, 3H), 3.78 (s, 2H), 5.26 (s, 2H), 5.65-6.05 (d, 2H), 7.02-7.72

Comparative Example

< Comparative Example  1> Pima Saltan  Base

[Formula 1a]

The Pimasartan base of Formula 1a was prepared in the same manner as described in Example 4 of Korean Patent Laid-Open Publication No. 10-2004-0032639.

< Comparative Example  2> Pima Saltan Potassium salt Trihydrate cargo

[Chemical Formula 1b]

The Pimersartan potassium salt trihydrate of Formula 1b was prepared by the same method as described in Example 5 of Korean Patent Laid-Open No. 10-2004-0032639.

Experimental Example

< Experimental Example  1> parallel Artificial membrane  Permeability analysis PAMPA ) Was used to measure the permeability of the compound of the present invention

The following experiments were performed using Parallel Artificial Membrane Permeability Assay (PAMPA) to determine the permeability of the compounds of the present invention.

Solubility measurement

Before proceeding with the PAMPA experiment of the present invention, solubility experiments were performed at the following three concentrations for the purpose of measuring the solubility of each compound. 1 ml of buffer was placed in a glass test tube, and the compound of Example was added in three concentrations as shown below, mixed well, and the degree of precipitation was visually observed for 5 minutes. The results are shown in Table 1 below.

[Table 1]

As shown in Table 1, the experiment was carried out at 12.5 [mu] M, in which all compounds did not precipitate.

Experimental conditions

PAMPA (Parallel Artificial Membrane Permeability Assay) was measured using a double sink (Pion, GI PAMPA) and cultured in a 96-well plate for 4 hours. A 10 mM stock solution of the compound was prepared in DMSO. Reference compounds were prepared with Verapamil, Antipyrine and Ranitidine at a pH of 7 and 50 μM, respectively. Test compounds were prepared at pH 7 to 12.5 μM. The measurement was carried out with a UV detector, but in the case of the compound of Example 5, all the test samples were lowered when measured with a UV detector, and the measurement was difficult, and the permeability was calculated by reanalyzing with LC / MS / MA.

Results analysis method

Permeability (P _e , cm / sec) was analyzed by the method shown in Table 2 below.

[Table 2]

Experimental Method

Dissociate 1.5 ml of donor buffer in a deep well plate and add 7.5 μL of 10 mM compound stock to prepare a mixture (10 mM stock → final 50 μM, buffer pH 7.4). The prepared mixture was dispensed into a 3-well plate (500 μL) in a deep well plate. For blank measurement, a 96-well donor buffer was dispensed into a UV plate at a rate of 150 μL per well, and the UV value was measured. For reference compound determination, the mixture in the deep well plate was dispensed on a UV plate at 150 μL per well, and the UV value was measured. 200 [mu] L of the prepared mixture was dispensed into 3 wells per compound on a donor plate of a PAMPA sandwich. The acceptor plate was turned over and the membrane was soaked in 5 μL of GIT-0 lipid solution. The acceptor plate was dispensed into each well with 200 μL of acceptor sink buffer. The acceptor plate and the donor plate were combined and incubated at 25 ° C for 4 hours. After incubation for 4 hours, the acceptor plate and the donor plate were separated, and 150 μL of each well was transferred to a UV plate. The UV value was measured using PION PAMPA EXPLORER (Version 3.8) software. PAMPA permeability was analyzed using a PAMPA explore program. The results are shown in Table 3 below.

PAMPA  Experiment result

[Table 3]

As shown in Table 3, the compounds of the present invention were found to have excellent intestinal permeability as compared to the trihydrate of the pimecartan potassium salt, and in particular, intramuscular permeability of the compound of Example 1 was lower than that of the parmesalan potassium salt trihydrate 7 times higher.

Therefore, the compound according to the present invention can reduce the intake of existing Pimalsartan preparations which have the effect of preventing or treating hypertension, while increasing the prevention or treatment effect of hypertension, thereby enhancing the patient's compliance with medicines and also having advantages .

Claims (8)

A prodrug of a palmatartan represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In formula (1)
R ₁ and R ₂ are each independently hydrogen or a linear or branched C ₁ -C ₆ alkyl group;
R ₃ is

or

;
Y ₁ and Y ₂ are each independently a linear or branched C ₁ -C ₆ alkyl group or a C ₃ -C ₆ cycloalkyl group;
Y ₃ , Y ₄ and Y ₅ are each independently hydrogen or a linear or branched C ₁ -C ₆ alkyl group;
Y ₆ is an alkali metal. The method according to claim 1,
R ₁ and R ₂ are each independently hydrogen or a linear or branched C ₁ -C ₄ alkyl group;
R ₃ is

or

;
Y ₁ and Y ₂ are each independently a linear or branched C ₁ -C ₄ alkyl group or a C ₆ cycloalkyl group;
Y ₃ , Y ₄ and Y ₅ are each independently hydrogen or a linear or branched C ₁ -C ₄ alkyl group;
Y &lt; ₆ &gt; is a prodrug of Pimercartan, or a pharmaceutically acceptable salt thereof. The method according to claim 1,
R ₁ and R ₂ are each independently hydrogen, a methyl group or an isopropyl group;
R ₃ is

or

;
Y ₁ and Y ₂ are each independently methyl, ethyl, isopropyl, tert-butyl or cyclohexyl,
Y ₃ , Y ₄ and Y ₅ are each independently hydrogen or a tert-butyl group;
Y &lt; ₆ &gt; is a prodrug of Pimercartan, or a pharmaceutically acceptable salt thereof. The method according to claim 1,
At least one of R &lt; ₁ &gt; and R &lt; ₂ &gt; is hydrogen, or a pharmaceutically acceptable salt thereof. The method according to claim 1,
Wherein the pharmacologically acceptable salt of the prodrug of the palmatartan is a hydrochloride or potassium salt, or a pharmaceutically acceptable salt thereof. The method according to claim 1,
Wherein the prodrug of Pimassartan or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:

A pharmaceutical composition comprising as an active ingredient a Pimacaltan prodrug according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is selected from the group consisting of stroke, stroke, stroke, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof, for the prophylaxis or treatment of at least one disease selected from the group consisting of: