WO2020101450A1 - Derivative compounds of azilsartan, intermediates thereof, preparation method therefor, and pharmaceutical composition comprising same - Google Patents

Abstract

The present invention provides a novel azilsartan derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The novel azilsartan derivative compound of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof exhibits an excellent medicinal effect in the treatment or prevention of hypertension in addition to having excellent pharmacological properties such as solubility, stability, specific absorptivity, etc. Therefore, the novel azilsartan derivative compound, the optical isomer thereof, or the pharmaceutically acceptable salt thereof can be formulated together with a pharmaceutically acceptable carrier or a therapeutic agent for hypertension and as such, can be advantageously used as an active ingredient of a pharmaceutical composition for protecting the heart and vessels.

Description

Azilsartan derivative compounds, intermediates thereof, methods of preparation thereof, and compositions comprising the same

The present invention relates to a novel azartartan derivative compound or a pharmaceutically acceptable salt thereof, an intermediate thereof, a method for preparing the same, and a composition comprising the same as an angiotensin II antagonist useful in the treatment of hypertensive disease.

Hypertension refers to a chronic disease in which blood pressure is higher than the normal range. Hypertension causes the heart to do more to circulate blood through the blood vessels. Blood pressure is summarized by two measurements of the systolic highest blood pressure and diastolic lowest blood pressure at the pulse, normal blood pressure at rest is 100-140 mmHg at contraction, 60-90 mmHg at relaxation, and blood pressure is continuously above 140/90 mmHg. Say you have high blood pressure.

Hypertension is divided into essential hypertension and secondary hypertension. About 90 to 95% are classified as 'essential hypertension' with no clear underlying medical cause, and the remaining 5 to 10% (secondary hypertension) are associated with other health conditions affecting the kidneys, arteries, heart or endocrine system. Is caused.

Hypertension is a major risk factor for stroke, myocardial infarction (heart attack), heart failure, vascular aneurysms (eg aortic aneurysms), lower extremity aneurysms, and may also cause chronic renal failure. Even moderately high arterial blood pressure can be associated with shortened life expectancy, and diet and lifestyle changes can improve blood pressure control to reduce risk, and in those cases where this is not effective or insufficient, medication is often need.

Among the drugs under development as a therapeutic agent for hypertension, Azilsartan is an angiotensin II receptor antagonist, which blocks the vasoconstriction activity of angiotensin II by selectively blocking the binding of angiotensin II and vascular smooth muscle AT1 receptor. Among them, the potassium compound of Azilsartan Medoxomil has the chemical name (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl-2-ethoxy-1 {[2 '-(5- oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7carboxylate monopotassium salt MW = 606.62) and its structural formula is as follows.

Potassium nitrite medoxomil is a pro-drug that hydrolyzes upon absorption, is a selective AT1 sub-type angiotensin II receptor antagonist, and the Azilsartan medoxomil potassium is Takeda His angiotensin II receptor antagonist activity is disclosed in Japanese Patent Application 2004-048928 and Korean Patent Application 10-2006-7016710 by Takanobu Kuroita (Japan). It is a commercially available therapeutic agent for hypertension in humans. It is commercially available under the trade name Lee Dal-bi as a film coated tablet of 20mg, 40mg, and 80mg.

Pharmaceutical products must be effective, safe and stable. The effectiveness, safety and stability of the pharmaceutical product are not only closely related to the effectiveness and stability of the active ingredient itself, but also the properties of the pharmaceutical preparation, such as the stability of the active ingredient in the pharmaceutical preparation, and the active ingredient from the pharmaceutical preparation, etc. It is affected by the dissolution properties, and these are extremely important. Even if the pharmaceutical preparation is effective and safe immediately after preparation, when the active ingredient is easily decomposed or denatured over time, the pharmaceutical preparation has problems in effectiveness and stability. On the other hand, with regard to the dissolution characteristics of the active ingredient from the pharmaceutical preparation, 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 cannot sufficiently exhibit the expected effect. . On the other hand, if the dissolution of the active ingredient from the pharmaceutical preparation is too fast, the blood concentration of the active ingredient may increase rapidly in vivo and the risk of side effects may increase.

Therefore, there is a need to develop a drug as a therapeutic agent for hypertension, which has pharmacologically superior properties such as solubility, stability, and non-absorption, and has an effect equal to or greater than that of azilsartan medoxomil potassium salt.

[Advanced technical literature]

[Patent Document]

Japanese patent application 2004-048928

Korean Patent Application 10-2006-7016710

U.S. Patent No. 5,616,599

Korean Patent Publication No. 2007-0020411

It is an object of the present invention to provide novel azilsartan derivative compounds, optical isomers and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a novel method for preparing azartartan derivative compounds, optical isomers and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for preparing an intermediate for preparing a novel nitrite derivative compound, an optical isomer and a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a composition effective for the prevention and treatment of hypertension, which includes a novel nitrite derivative compound, an optical isomer and a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention provides a novel nitrite derivative compound and a method for producing the same. In addition, the present invention provides an intermediate production method for preparing the novel azilsartan derivative compound of the present invention. In addition, the present invention provides a method for preparing a pharmaceutically acceptable salt using the novel azilsartan derivative compound of the present invention. Hereinafter, this will be described in detail.

In this specification, in defining compounds such as Formula 1, Formula 1-1, Formula 1-2, Formula 1A, Formula 1A1, Formula 1B, Formula 1B1, Formula 2 to 7, Formula 6-1, Formula 7-1, etc. Concepts defined as follows are used. The following definitions also apply to terms used individually or as part of a larger group throughout this specification, unless specifically indicated otherwise.

The term "alkyl" when used alone or in combination with "heteroalkyl" refers to a straight, branched or cyclic hydrocarbon radical, respectively, each carbon atom having one or more cyano, hydroxy, alkoxy, oxo, Halogen, carbonyl, sulfonyl, cyanyl, and the like.

The term "alkoxy" refers to -O-alkyl, where alkyl is as defined above.

The term "heteroalkyl" means an alkyl containing one or more hetero atoms selected from N, O, S.

The term "aryl" means an aromatic group including phenyl, naphthyl, and the like, and may be optionally substituted with one or more alkyl, alkoxy, halogen, hydroxy, carbonyl, sulfonyl, cyanyl, and the like.

The term “heteroaryl” includes one or more, such as 1 to 4, or, in some embodiments, 1 to 3 heteroatoms selected from N, O, and S, the remaining ring atoms being carbons from 5 to 7 -Aromatic aromatic, monocyclic ring; The other ring atom is carbon and at least one ring is aromatic and at least one is selected from N, O, and S, including one or more, for example 1 to 4, or in some embodiments 1 to 3 heteroatoms Heteroatoms are 8- to 12-membered bicyclic rings present in aromatic rings; And one or more, for example 1 to 4, or in some embodiments 1 to 3 heteroatoms selected from N, O, and S, the remaining ring atoms are carbon and at least one ring is aromatic and at least one Heteroatoms refer to 11- to 14-membered tricyclic rings present in aromatic rings. Examples of the heteroaryl group include pyridyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, Tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolyl, indolyl, indolinyl, pyrrolyl, thiophenyl, pyridinyl, triazolyl, quinolinyl, pyrazolyl, pyrrolopyridinyl , Pyrazolopyridinyl, benzooxazolyl, benzothiazolyl, indazolyl and 5,6,7,8-tetrahydroisoquinoline.

In addition, m of R ₂ means the number of substituents that can be substituted, that is, it means the number of R ₂ , and when m is 0, it means that all hydrogen atoms are substituted, and when R ₂ is 2 or more, each other It can be the same or different.

In addition, R ₃ may be the same or different from each other, and when R ₃ are all hydrogen atoms, it means that -NH ₂ is substituted.

In addition, n means the number of alkylene (-CH _2- ), and when n is 0, it means that the atom is bonded.

In addition, the terms and abbreviations used in this specification have their original meanings unless defined otherwise.

Novel nitrite derivative compound, optical isomer thereof or pharmaceutically acceptable salt thereof and method for preparing the same

The present invention provides a novel azilsartan derivative compound represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Chemical Formula 1,

R ₁ and R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

A is H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, N (R ₃ ) ₂ ,

,

or

ego,

R ₃ is H or a C _1-6 alkyl group,

R _a to R _c are each independently an aryl group or a heteroaryl group,

R _d to R _f and R _g are each independently a C _1-6 alkyl group or a C _1-6 alkoxy group,

m is any integer from 0 to 4,

n is an integer of 0-6.

The novel azilsartan derivative compound according to the formula (I) of the present invention, its optical isomer or its pharmaceutically acceptable salt can be obtained with high purity, its hygroscopicity is remarkably low, its heat stability is excellent, and its electrostatic property is low. It has excellent physical and chemical properties such as low cost. Therefore, the novel azilsartan derivative compound according to the formula (I) of the present invention, its optical isomer, or a pharmaceutically acceptable salt thereof is easy to formulate, has excellent stability, and is pre-arranged during the storage / distribution period after preparation with the preparation process or preparation with the preparation It does not require strict storage conditions, so mass production is easy and economical. In addition, the novel azilsartan derivative compound according to the formula (I) of the present invention, its optical isomer or its pharmaceutically acceptable salt has excellent plasma stability, and exhibits excellent bioavailability when taken orally, thereby exhibiting excellent therapeutic effect. .

In the embodiments of the present invention, the novel nitrousartan derivative may be a novel ester compound of nitrousartan.

In the present invention, preferably, R ₁ is a C _1-6 alkyl group, R ₂ is a C _1-6 alkoxy group, A is hydrogen, m is 1, n can be 0, more preferably R ₁ may be a t-butyl group, and R ₂ may be a methoxy group.

Further, in the present invention, preferably, R ₁ is a C _1-6 alkyl group, R ₂ is a C _1-6 alkoxy group, A is a C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 Hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, N (R ₃ ) ₂ ,

,

or

, R _a to R _c are each independently an aryl group, R _d to R _f are each independently C _1-6 alkyl, R _g is a C _1-6 alkoxy group, m is 1, n is 0 Can be

Preferably A is

And R _a to R _c may each independently be an aryl group. More preferably, it may be any one selected from trityl, t-butyl dimethylsilyl (TBDMS) and t-butyl dicarbonyl (BOC), and is limited to this. It is not.

The structure of the most preferred compound of formula 1 of the present invention according to the above may be a compound represented by the following formula 1-1 or formula 1-2.

[Formula 1-1]

[Formula 1-2]

The novel nitrite derivative compounds according to [Chemical Formula 1-1] and [Chemical Formula 1-2] of the present invention, optical isomers thereof, or pharmaceutically acceptable salts thereof can be obtained with high purity, and the hygroscopicity is remarkably low. It has excellent thermal stability, low electrostaticity and low cost, and has excellent physical and chemical properties. Therefore, the novel nitrite derivative compounds according to [Chemical Formula 1-1] and [Chemical Formula 1-2] of the present invention, their optical isomers or their pharmaceutically acceptable salts are easy to formulate, have excellent stability, and prepare the formulation. It is easy and economical for mass production because it does not require separate strict storage conditions during the storage / distribution period after manufacture as a process or preparation. In addition, the novel nitrite derivative compounds according to [Chemical Formula 1-1] and [Chemical Formula 1-2] of the present invention, optical isomers thereof or pharmaceutically acceptable salts thereof have excellent plasma stability, and are excellent when taken orally. It can show excellent bioavailability and show excellent therapeutic effect.

In the present invention, the acceptable salt of the present invention may be a sodium salt represented by the following formula 1A or a potassium salt represented by the following formula 1B.

[Formula 1A]

[Formula 1B]

In Formulas 1A and 1B,

R ₁ and R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

R ₃ is H or a C _1-6 alkyl group,

m is any integer from 0 to 4,

n is an integer of 0-6.

The compound according to [Chemical Formula 1A] or [Chemical Formula 1B] of the present invention can be obtained with high purity, and has excellent physicochemical properties such as remarkably low hygroscopicity, excellent heat stability, low static electricity and low cost. . Therefore, the compound according to [Chemical Formula 1A] or [Chemical Formula 1B] of the present invention is easy to formulate, has excellent stability, and does not require a separate strict storage condition during the storage / distribution period after preparation as a formulation manufacturing process or as a formulation. It is easy to produce and economical. In addition, the compounds according to [Chemical Formula 1A] or [Chemical Formula 1B] of the present invention have excellent plasma stability, and exhibit excellent bioavailability when taken orally, thereby exhibiting excellent therapeutic effects.

In embodiments of the present invention, in the above formula [Compound 1], [Formula 1A], and [Formula 1B], R ₁ is a C _1-6 alkyl group, R ₂ is a C _1-6 alkoxy group, A Is hydrogen, trityl, t-butyl methylsilyl (TBDMS) or t-butyl dicarbonyl (BOC), m is 1, n is 0 have. Preferably, R ₁ is tert butyl; R2 is methoxy; X is -OH, Cl, Br or I; W is H or -Ph ₃ ; A is H or -Ph ₃ , n may be 0 and m may be 1.

In the present invention, acceptable salts include alkali salts, alkaline earth metal salts, and zinc (Zn). It can be strontium (Sr), basic amino acid salt (lysine, arginine, histidine), preferably sodium (Na), potassium (K), lithium (Li), calcium (Ca), magnesium (Mg), zinc (Zn) ), And more preferably sodium and potassium.

In the present invention, the structure of the most preferred compound of Formula 1A of the present invention may be a compound represented by Formula 1A1 below, and the most preferred structure of Formula 1B may be a compound represented by Formula 1B1 below.

[Formula 1A1]

[Formula 1B1]

The compound according to [Chemical Formula 1A1] or [Chemical Formula 1B1] of the present invention can be obtained with high purity, has excellent low hygroscopicity, excellent heat stability, low physical static electricity, low cost, and excellent physical and chemical properties. . Therefore, the compounds according to [Chemical Formula 1A1] or [Chemical Formula 1B1] of the present invention are easy to formulate, have excellent stability, and do not require separate stringent storage conditions during preparation / preparation during preparation / preparation of the preparation process or mass production. This is easy and economical. In addition to this, the compounds according to the compounds according to [Chemical Formula 1A1] or [Chemical Formula 1B1] of the present invention have excellent plasma stability, and exhibit excellent bioavailability when taken orally, thereby exhibiting excellent therapeutic effects.

In addition, the present invention provides a method for preparing a compound represented by Chemical Formula 1, which will be described in detail below.

The present invention provides a method for preparing a compound represented by Formula 1 by reacting a compound represented by Formula 6 and a compound represented by Formula 7 below.

[Formula 6]

In Chemical Formula 6,

R ₁ to R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

R ₃ is H or a C _1-6 alkyl group,

X is any of -OH, F, Cl, Br and I,

m is any integer from 0 to 4,

n is any one of 0 to 6,

[Formula 7]

In Chemical Formula 7,

W is H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, N (R ₃ ) ₂ ,

,

or

ego,

R ₃ is H or a C _1-6 alkyl group,

M is H, C _1-6 alkyl, Na or K,

R _a to R _c are each independently an aryl group or a heteroaryl group,

R _d to R _f and R _g are each independently a C _1-6 alkyl group or a C _1-6 alkoxy group,

[Formula 1]

In Chemical Formula 1,

R ₁ and R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

A is H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, N (R ₃ ) ₂ ,

,

or

ego,

R ₃ is H or a C _1-6 alkyl group,

R _a to R _c are each independently an aryl group or a heteroaryl group,

R _d to R _f and R _g are each independently a C _1-6 alkyl group or a C _1-6 alkoxy group,

m is any integer from 0 to 4,

n is an integer of 0-6.

When M is H or a C _1-6 alkyl group in -OM of Chemical Formula 7, a covalent bond may be formed with O (oxygen atom), and when M is Na or K, an ion bond with O (oxygen atom), that is, , -O ^- type anions and cations represented by Na ⁺ or K ⁺ can form ionic bonds.

M of Formula 7 may be preferably H, C _1-6 alkyl or Na, and is a compound represented by Compound 1-1 by condensation reaction with 4- (bromomethyl) -2-methoxyphenyl pivalate. Can be produced.

The reaction may include a coupling reaction performed in the presence of a base, and the base is potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, diisopropylamine, triethylamine, diethylamine, etc. Can be used, and the type of base is not limited thereto.

In addition, the formula 7 used in the method for preparing the compound of formula 1 of the present invention can be directly prepared according to methods known in the art, and in the method for preparing the compound of formula 1 of the present invention, the coupling reaction is It can be made by a method known in the art (US Patent No. 5,616,599, Korean Patent Publication No. 2007-0020411).

As a solvent for the condensation reaction, a polar solvent such as dimethylformamide (DMF), dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO), etc. may be used, and the temperature of the reaction is 20 to 110 ° C, preferably It can be carried out at 50 ~ 70 ℃.

When A in Formula 1 is H (hydrogen atom), the step of deprotecting the functional group W in Formula 7 may be further included. That is, when W is substituted with a functional group other than a hydrogen atom, in order to prepare a compound in which A in Formula 1 is a hydrogen atom, a reaction in which a substituent is removed in the presence of a base or an acid may be further performed.

[Scheme 1]

In the embodiments of the present invention, in the deprotection reaction, W is a trityl group, a t-butyl dimethylsilyl group (TBDMS) and a t-butyl dicarbonate group (tert-butyl dicarbonyl, BOC).

The deprotection reaction can be carried out under acidic conditions, wherein the acid is preferably acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc., and more preferably hydrochloric acid. As the reaction solvent, organic solvents such as methanol, ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, acetonitrile, ethyl acetate, and isopropyl ether and purified water can be used, and the reaction temperature is 0 ° C to 110 ° C. , Preferably 15 ℃ ~ 30 ℃, most preferably can be carried out in the range of 20 ℃ ~ 25 ℃.

In addition, the deprotection reaction may be performed under basic conditions, wherein the base may include an inorganic base consisting of NaHCO ₃ , Na ₂ CO ₃ , Mg (OH) ₂ , Cs ₂ CO ₃ , and Zn (OH) ₂ It is possible, and the type of inorganic base is not limited thereto.

The present invention provides a method for preparing a pharmaceutically acceptable salt of a compound represented by Formula 1 by reacting the compound represented by Formula 1 with at least one selected from Na + or K +. Specifically, the compound represented by the formula (1) is reacted with potassium 2-ethyl hexanoate or sodium 2-ethyl hexanoate (Sodium 2-ethyl hexanoate) and represented by the formula (1) Potassium or sodium salts of the compounds can be prepared.

In embodiments of the present invention, K + may be used in the form of potassium 2-ethyl hexanoate, and Na + is sodium 2-ethyl hexanoate. ).

In embodiments of the present invention, the step of forming the salt may be performed under at least one solvent selected from the group consisting of acetone, ethyl acetate, isopropyl ether, or mixtures thereof.

The present invention comprises the steps of preparing a compound represented by the following formula [1-1] by reacting the compound represented by the following formula [6-1] with a compound represented by the following formula [7-1] Provided is a method for preparing an azilsartan derivative compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 6-1]

[Formula 7-1]

[Formula 1-1]

In embodiments of the present invention, the method may further include the step of purifying the compound represented by Formula 1-1.

The purification step

Preparing a mixed solution by adding the compound represented by Chemical Formula 1-1 to a solvent;

It may include the step of obtaining a solid from the mixed solution.

In the embodiments of the present invention, the solvent used in the purification step may be ethanol, acetone, acetonitrile, water, or a mixture thereof, specifically, a mixture of acetonitrile and water.

In embodiments of the present invention, the sodium salt or potassium salt of the compound represented by Chemical Formula [1-1] may be prepared by reacting the compound represented by Chemical Formula 1-1 with Na + or K +. Specifically, the compound represented by Chemical Formula 1-1 is reacted with Potassium 2-ethyl hexanoate or Sodium 2-ethyl hexanoate to form [1]. The sodium salt or potassium salt of the compound represented by -1] can be prepared.

In embodiments of the present invention, the step of forming the salt may be performed under at least one solvent selected from the group consisting of acetone, ethyl acetate, isopropyl ether, or mixtures thereof.

In addition, in the present invention, a compound represented by Formula 6 may be prepared from a compound represented by Formula 5 below.

[Formula 5]

In Chemical Formula 5,

R ₁ to R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

R ₃ is H or a C _1-6 alkyl group,

m is any integer from 0 to 4,

n is an integer of 0-6.

[Formula 6]

In Chemical Formula 6,

R ₁ to R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

R ₃ is H or a C _1-6 alkyl group,

X is any of -OH, F, Cl, Br and I,

m is any integer from 0 to 4,

n is an integer of 0-6.

In embodiments of the present invention, the step of preparing a compound represented by Formula 6 from the compound represented by Formula 5 may be performed by halogenating a substitution reaction of the compound represented by Formula 5. The halogenation substitution reaction may be performed by a method known in the art, and a halogenation substitution reaction may be performed using a halogenating agent such as phosphorus tribromide (PBr ₃ ) or thionyl chloride (SOCl ₂ ), and more Phosphorous tribromide can be used as a preferred halogenating agent. The reaction solvent may be an organic halogen solvent such as dichloromethane or chloroform, and the type of the reaction solvent is not limited thereto.

In the present invention, the compound represented by Formula 5 may be prepared by reducing the compound represented by Formula 4 below.

[Formula 4]

In Chemical Formula 4,

R ₁ to R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

R ₃ is H or a C _1-6 alkyl group,

m is any integer from 0 to 4,

n is an integer of 0-6.

The reducing agent used in the reduction may be lithium borohydride (LiBH ₄ ), potassium borohydride (KBH ₄ ), sodium borohydride (LiBH ₄ ), lithium aluminum hydride (LiAlH ₄ ), and the like. , Preferably, lithium borohydride (LiBH ₄ ) and sodium borohydride (NaBH ₄ ) are useful, and more preferably sodium borohydride (NaBH ₄ ) can be used. Sodium borohydride has the advantages of low commercial cost, easy post-treatment, and eco-friendliness.

As the reaction solvent, a solvent such as tetrahydrofuran, dioxane, methanol, ethanol, or isopropanol may be used, and preferably tetrahydrofuran may be used.

Further, in the present invention, a compound represented by Chemical Formula 4 may be prepared by ester-reacting a compound represented by Chemical Formula 2 and a compound represented by Chemical Formula 3 in the presence of a base.

[Formula 2]

In Chemical Formula 2,

R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N (R ₃ ) ₂ ,

R ₃ is H or a C _1-6 alkyl group,

m is any integer from 0 to 4,

n is an integer of 0-6.

[Formula 3]

R ₁ is H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N (R ₃ ) ₂ ,

R ₃ is H or a C _1-6 alkyl group,

X is any one selected from the group consisting of F, Cl, Br and I.

In the method for preparing the compound of formula 4 of the present invention, the esterification reaction can be carried out according to methods known in the art. For example, pyridine, diisopropylethylamine, triethylamine, pyrrolidine, calcium carbonate, sodium carbonate, and caustic soda can be used as the base used in the presence of a base, preferably pyridine, di Isopropylamine, triethylamine, piperidine can be used and more preferably pyridine can be used. The reaction solvent may be an organic halogenated solvent such as dichloromethane, chloroform, and the like, but is not limited thereto.

In embodiments of the present invention, R1 in [Formula 1], [Formula 2], [Formula 3], [Formula 4], [Formula 5] [Formula 6] or [Formula 7] is tert butyl; R2 is methoxy; X is -OH, Cl, Br or I; W is H or -Ph ₃ ; M is methyl or H; A is H or -Ph ₃ , n may be 0 and m may be 1.

Composition comprising a novel azilsartan derivative compound of Formula 1, use thereof

The present invention provides a pharmaceutical compound composition for the treatment or prevention of hypertension, and the use thereof, using the nitrite derivative compound represented by Formula 1 of the present invention and a pharmaceutically acceptable salt thereof as an active ingredient.

The composition may include at least one selected from the sodium salt represented by the formula (1A) and the potassium salt represented by the formula (1B), and may preferably include the salts represented by the following compounds (1A and 1B). In addition, one or more active ingredients having the same or similar function as the present invention may be included.

[Formula 1A]

[Formula 1B]

In Formulas 1A and 1B,

R ₁ and R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

R ₃ is H or a C _1-6 alkyl group,

m is any integer from 0 to 4,

n is an integer of 0-6.

The composition may include a compound represented by the following Chemical Formula 1-1 or a pharmaceutically acceptable salt thereof, and specifically, from the group consisting of a compound represented by the following Chemical Formula 1-1, a sodium salt thereof and a potassium salt thereof It may include one or more selected.

[Formula 1-1]

On the other hand, it provides a pharmaceutical composition comprising an nitrite derivative compound represented by Formula 1 of the present invention, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. In addition, the present invention is a pharmaceutical composition for the prevention or treatment of hypertension, comprising the azilsartan derivative compound represented by Formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, the treatment of the disease For use of the azilsartan derivative compound represented by Formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the azilsartan derivative compound represented by Formula 1 above, an optical isomer thereof or a pharmaceutical thereof It provides a method for treating the disease, comprising administering to the subject an acceptable salt.

In addition, the present invention provides a use of the nitrite derivative compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of hypertension, and the prevention or treatment of hypertension It provides an azilsartan derivative compound represented by Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

In the pharmaceutical composition, treatment method and use, the nitrite derivative compound may be a compound represented by Formula 1-1 or a pharmaceutically acceptable salt thereof, specifically, a compound represented by Formula 1-1, It may be one or more selected from the group consisting of sodium salts and potassium salts thereof.

As used in the present invention, the term prophylaxis refers to all actions that suppress hypertension or delay the onset of disease by administration of the pharmaceutical composition according to the present invention.

As used in the present invention, the term treatment means any action in which symptoms of hypertension are improved or beneficially altered by administration of a pharmaceutical composition according to the present invention.

The composition of the present invention may be prepared by including at least one pharmaceutically acceptable carrier in addition to the above components for administration. Pharmaceutically acceptable carriers can be used by mixing one or more of these components: saline, sterile water, Ringer's solution buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and, if necessary, antioxidants, buffers Other conventional additives, such as, bacteriostatic agents, may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate into injectable formulations such as aqueous solution suspensions, emulsions, pills, capsules, granules, or tablets. Furthermore, it can be preferably formulated according to each disease or ingredient by using methods appropriate in the art or using methods described in Remington's Pharmaceutical Science (latest version), Mack Publishing Company, Easton PA.

The composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is the patient's weight, sex, age, health status, diet , The administration time, administration method, excretion rate, and the extent of the disease vary in scope. The daily dosage of the novel azilsartan ester derivative compound of Formula 1 or 2A, 2B of the present invention is about 1 mg to 100 mg, preferably 10 mg to 80 mg, more preferably 20 mg to 80 mg, divided once or several times a day It is more preferable to administer.

For the prevention and treatment of hypertension, the composition of the present invention alone or hormone therapy, treatment of other hypertensive drug preparations, diabetes (e.g. DPP-IV, SGLT2, etc., drug-A Glyflozines) and hyperlipidemia treatment (e.g. atorvastatin, Statins such as rochevastatin, phytavastatin) and biological response modifiers.

For the prevention and treatment of hypertension, the composition of the present invention alone or hormone therapy, treatment of other hypertensive drug preparations, diabetes (e.g., DPP-IV, SGLT2, etc. Drug-A Glyflozines) and hyperlipidemia treatment (e.g. atorvastatin Statins such as Rochevastatin and Pitavastatin) and a drug using a biological response modifier and a combination of 2 or 3 agents may be used.

The contents of the nitrite sartan derivatives of the present invention, optical isomers thereof or pharmaceutically acceptable salts thereof also apply to the pharmaceutical compositions as long as there is no contradiction.

The novel azilsartan derivative compound represented by Formula 1 of the present invention, its optical isomer, or a pharmaceutically acceptable salt thereof has excellent pharmaceutical properties such as solubility, stability, non-absorption, and the treatment or prevention of hypertension. It has the effect of showing excellent efficacy. Therefore, there is an effect that can be usefully used as an active ingredient of a pharmaceutical composition for protecting the heart and blood vessels by being formulated with a pharmaceutically acceptable carrier or a drug for treating hypertension.

1 is a result of the stability analysis in the plasma over time of the nitrite salt compound (AZM) of the nitrite salt of the nitrite compound or a salt thereof and Comparative Example 2 according to the present invention.

2 is a result of concentration in plasma over time after oral intake of a suspension of an azilsartan derivative compound or a salt thereof according to the present invention.

3 is a result of the maximum concentration in plasma and area under the curve (AUC) according to oral intake of a suspension of an nitrite derivative compound or a salt thereof according to the present invention.

4 is a result of concentration in plasma over time after oral intake of a solution of an azilsartan derivative compound or a salt thereof according to the present invention.

FIG. 5 shows the maximum concentration in plasma and area under the curve (AUC) according to oral intake of a solution of an azilsartan derivative compound or a salt thereof according to the present invention.

Hereinafter, preferred embodiments are provided to help understanding of the present invention. However, the following examples are only provided to more easily understand the present invention, and the present invention is not limited by the examples. When preparing the compound of the present invention, the reaction order can be appropriately changed. That is, any reaction step may be performed first or any substituent change may be inserted, and if necessary, any reagent other than the illustrated reagents may be used.

Various methods for synthesizing starting materials for synthesizing the compounds of the present invention are known, and when the starting materials are commercially available, they can be purchased and used from a supplier. Hereinafter, the structural analysis device used in the Examples was Bruton 400mhz for Proton NMR, Agilent HP1100 LC-MS for LC-MS, and reagents and solvents not specifically mentioned by the manufacturer were purchased from Aldrich.

First, in the following Examples, compounds used for synthesis were prepared as in the following Preparation Examples. The following examples can be appropriately modified and changed by those skilled in the art within the scope of the present invention.

<Production Example 1: Synthesis of 4-formyl-2-methoxyphenyl pivalate>

Preparation Example 1-1: Preparation of 4-formyl-2-methoxyphenyl pivalate-1

15.3 g of 4-hydroxy-3-methoxybenzaldehyde was dissolved in 610 ml of dichloromethane and then cooled to 0 ° C. 1.3 mL of pivaloyl chloride was added dropwise to the solution, followed by stirring under ice cooling for 10 minutes. Thereafter, 1.5 mL of pyridine or 4-dimethylaminopyridine (2.3 g) was added dropwise for 20 minutes, stirred under ice-cooling (0 ° C) for 1 hour, and the temperature was raised to room temperature and stirred for 24 hours. 610 mL of 1.0 M hydrochloric acid aqueous solution was added to the reaction solution, and after stirring for 20 minutes, the organic layer was separated. A mixture of 30.4 g sodium bicarbonate and 610 mL purified water was added to the organic layer, stirred for 20 minutes, and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 19.2 g (81%) of the labeled compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (s, 9H), 3.90 (s, 3H), 7.20-7.22 (d, 1H), 7.48-7.49 (d, 1H), 7.50 (s, 1H) , 9.97 (s, 1H)

IR (KBr) 1725, 1640, 1275, 1080, 770cm ^-1 ,

mp: 135-138 ℃,

MS (ESI) m / z (M + 1); 237.10 (100%), 238.11 (14.4% 0, 239.11 (1.8%),

Elemental Analysis: C, 66.09. H, 6.80; O, 27.09.

Preparation Example 1-2: Preparation of 4-Formyl-2-methoxyphenyl pivalate-2

After adding 1000 ml of dichloromethane to 100 g (0.66 mol, 1.0 eq) of 4-hydroxy-3-methoxy-benzaldehyde, the mixture was cooled to 0 to 5 ° C. 4.01 g (0.03 mol, 0.05 eq) of 4-dimethylaminopyridine was added and stirred while maintaining 5 ° C. or less. 83.21 g (0.69 mol, 1.05 eq) of pivaloyl chloride was added, and 76.48 g (0.76 mol, 1.15 eq) of triethylamine was kept at 10 ° C. or lower, added dropwise for 2 hours, and stirred for 1 hour. After confirming the completion of the reaction, 800 mL of cooling water was added to the reactor at 0-5 ° C. and the organic layer was separated. The separated organic layer was dried over 50 g of anhydrous magnesium sulfate, filtered and the solvent was concentrated under reduced pressure to obtain 155.29 g (100.00%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.40 (s, 9H), 3.90 (s, 3H), 7.20-7.22 (d, 1H), 7.48-7.49 (d, 1H), 7.50 (s, 1H) , 9.97 (s, 1H)

<Synthesis method of 4- (hydroxymethyl) -2-methoxyphenyl pivalate>

Preparation Example 2-1: Preparation of 4- (hydroxymethyl) -2-methoxyphenyl pivalate

24.5 g of the compound obtained in Preparation Example 1-1 was dissolved in 350 mL of ethanol, and then cooled to 0 ° C. 13.7 g of sodium borohydride was added and stirred at 0 ° C. for 4 hours to prepare a reaction solution. 150 ml of 5% acetic acid aqueous solution was added dropwise to the reaction solution at 0 ° C. for 30 minutes, the temperature was raised to room temperature, and 150 ml of ethyl acetate was added to separate the organic layer. The organic layer was washed with 200 mL of 10% sodium bicarbonate aqueous solution and water, and then the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ), filtered, and distilled under reduced pressure to obtain 18.5 g (75%) of the labeled solid compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (s, 9H), 2.56 (br s, 1H), 3.78 (s, 3H), 4.59 (s, 2H), 6.86-6.88 (dd, 1H), 6.94-6.96 (d, 2H)

IR (KBr) 3350, 3150, 1765, 1725, 1640, 1430, 1275, 1055, 745cm ^-1 ,

mp: 135-138 ℃, mp correction 37 ~ 40 ℃ (actual measurement)

MS (ESI) m / z (M + 1); 239.12 (100%), 240.12 (14.2%),

Elemental Analysis: C, 65.53. H, 7.61; O, 26.86.

Preparation Example 2-2: Preparation of 4- (hydroxymethyl) -2-methoxyphenyl pivalate

Into 4-formyl-2-methoxyphenyl pivalate 155.29 g (0.66 mol, 1.0eq) prepared in Preparation Example 1-2, 900 mL of tetrahydrofuran was added and cooled to 0-5 ° C. Sodium borohydride 12.43 g (0.33 mol, 0.5 eq) was added and heated to room temperature, followed by stirring for 1 hour. After confirming the completion of the reaction by HPLC, after cooling to 0 ° C. or less, 900 ml of 20% cold brine was slowly added, 900 ml of ethyl acetate was added, and the organic layer was layer separated and concentrated under reduced pressure. The organic layer was dried over 100 g of anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure. 750 ml heptane was added to the concentrate, and then cooled to 15-20 ° C., stirred for 30 minutes, cooled to 0-5 ° C., stirred for 1 hour, and filtered to obtain a solid. The solid was dried under reduced pressure at room temperature for 13 hours to give 134.39 g (85.81%) of the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.38 (s, 9H), 2.56 (br s, 1H), 3.78 (s, 3H), 4.59 (s, 2H), 6.86-6.88 (dd, 1H), 6.94-6.96 (d, 2H)

Preparation Example 3: Preparation of 4- (bromomethyl) -2-methoxyphenyl pivalate (4- (bromomethyl) -2-methoxyphenyl pivalate)

24.5 g of the compound obtained in Preparation Example 2-1 was dissolved in 30 mL of dichloromethane, and then cooled to 0 ° C. A solution in which 2.1 g phosphorous tribromide was dissolved in 20 mL of dichloromethane was added dropwise over 20 minutes, and stirred at 0 ° C for 4 hours. Thereafter, 500 mL of purified water was added dropwise at 0 ° C for 30 minutes, heated to room temperature, stirred for 30 minutes, and then the organic layer was separated. 10% sodium bicarbonate aqueous solution was added to the organic layer, and after stirring for 20 minutes, the organic layer was separated. After washing the obtained organic layer with 300 mL of saturated aqueous sodium chloride solution, the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. After distillation under reduced pressure, 60 mL of isopropyl ether and 100 mL of n-hexane were added to the obtained residue, and the mixture was stirred at room temperature for 4 hours to obtain a solid. The resulting solid was filtered and dried at room temperature to obtain 21.5 g (69%) of the labeled compound.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.23 (s, 9H), 3.83 (s, 3H), 4.69 (s, 2H), 6.76 (d, 1H), 6.98 (s, 1H), 7.06 (d , 1H)

IR (KBr) 1775, 1725, 1680, 1480, 1275, 1020, 765cm ^-1 ,

mp: 189-192 ℃,

MS (ESI) m / z (M + 1) 301.04 (100%), 303.03 (97.3%), 3302.04 (14.4%), 304.04 (14.1%), 303.04 (1.5%), 305.04 (1.5%),

Elemental Analysis: C, 51.84. H, 5.69; Br, 26.53, O, 15.94.

< Methyl 2-ethoxy-1-((2 '-(N'-hydroxycarbaimidoyl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole Synthesis of -7-carboxylate or its optical isomer>

Preparation Example 4-1: methyl 2-ethoxy-1-((2 '-(N'-hydroxycarbaimidoyl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] Imidazole-7-carboxylate (methyl 2-ethoxy-1-((2 '-(N'-hydroxycarbamimidoyl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [ Preparation of d] imidazole-7-carboxylate)

15.5 g of triethylamine and 7.2 g of hydroxyamine hydrochloride were added to 250 mL of dimethylsulfoxide (DMSO), and after stirring at room temperature for 30 minutes, the insoluble suspension was filtered off and washed with 150 mL of tetrahydrofuran (THF). Did. The filtered solution was collected and concentrated under reduced pressure to remove THF. Methyl 1-((2'-cyano- [1,1'-biphenyl] -4-yl) methyl) -2-ethoxy-1H-benzo [d] in the obtained filtrate (DMSO solution containing hydroxyamine) ] Imidazole-7-carboxylate (methyl 1-((2'-cyano- [1,1'-biphenyl] -4-yl) methyl) -2-ethoxy-1H-benzo [d] imidazole-7-carboxylate ) 41.1 g was added and stirred at 75-80 ° C. for 15 hours to terminate the reaction, and the reaction solution was cooled to room temperature.

The methyl 1-((2'-cyano- [1,1'-biphenyl] -4-yl) methyl) -2-ethoxy-1H-benzimidazole-7-carboxylate used in this preparation is conventional. It was prepared and used according to literature (J. Med. Chem. Vol. 36, pp2182-2195, 1993).

The obtained reaction solution was separated into layers using 800 mL of water and 800 mL of ethyl acetate, and the water layer was extracted three times (500 mLx3 times) with 500 mL of ethyl acetate. The obtained ethyl acetate organic layer was collected, extracted with 250 mL of 1N hydrochloric acid solution, adjusted to pH 10 by adding 1N NaOH solution to the obtained aqueous layer, and extracted twice with 500 mL of ethyl acetate (500 mLx2 times). The organic layer was washed with water and brine, and then dried using magnesium sulfate (MgSO ₄ ). Thereafter, the solvent was concentrated under reduced pressure to obtain a crude compound, and ethyl acetate-methanol-hexane solvent was added to obtain 38.1 g (85%) of a compound as a solid label.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.42 (t, 3H), 3.72 (s, 3H), 4.62 (q, 2H), 5.51 (s, 2H), 5.55 (br s, 2H), 6.93 (d, 2H), 7.19 (t, 1H), 7.29 (d, 1H), 7.34-7.42 (m, 5H), 7.46 (d, 1H), 7.70 (d, 1H), 9.18 (br s, 1H)

IR (KBr) 3440, 3345, 1715, 1640, 1545, 1435, 1275, 1040, 760cm ^-1 ,

mp: 207-209 ° C.

Preparation Example 4-2: Methyl (Z) -2-ethoxy-1-((2 '-(N'-hydroxycarbamidoyl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [ d] Preparation of imidazole-7-carboxylate

76.00 g (1.10 mol) of hydroxylamine hydrochloride was added to 450 mL of dimethyl sulfoxide (DMSO), and then 101.06 g (1.20 mol) of sodium bicarbonate was added to increase the temperature to 50 ° C. 90 g of methyl 1-((2'-cyano- [1,1'-biphenyl] -4-yl) methyl) -2-ethoxy-1H-benzo [d] imidazole-7-carboxylate after heating up (0.22 mol) was added and stirred at reflux at 92 ° C. for 6 hours. After confirming the completion of the reaction, the mixture was cooled to 60 ° C, and 1800 mL of purified water was added for 1 hour. After cooling to 25 ° C., it was stirred for 30 minutes. The resulting solid was filtered and washed with 180 mL of purified water. After stirring at reflux with 450 mL of ethanol for 1 hour, the precipitated solid was filtered. Drying at 40 ° C. yielded 71.36 g (0.16 mol) of the title compound in 73.4% yield.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.42 (t, 3H), 3.72 (s, 3H), 4.62 (q, 2H), 5.51 (s, 2H), 5.55 (br s, 2H), 6.93 (d, 2H), 7.19 (t, 1H), 7.29 (d, 1H), 7.34-7.42 (m, 5H), 7.46 (d, 1H), 7.70 (d, 1H), 9.18 (br s, 1H)

<Methyl 2-ethoxy-1-((2 '-(5-oxo-2,5-dihydro1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]- 4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate synthesis method>

Preparation Example 5-1: methyl 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1 '-Biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (methyl 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro- Preparation of 1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate)

44.5 g of the compound obtained in Preparation Example 4-1 and 8.5 g of pyridine were added and dissolved in 300 mL of a dimethylformamide solution, and then 21.1 g of 2-ethyl hexyl chloroformate was added, stirred for 30 minutes under ice cooling, and then 300 mL of water and ethyl acetate It was extracted by adding 3 times (500 mLx3 times) to 500 mL. The obtained organic layer was washed with water and dried using magnesium sulfate, and then the solvent was concentrated under reduced pressure to obtain a residue, 800 mL of xylene was added, heated to reflux for 2 hours (reflux), and concentrated under reduced pressure to obtain a solid residue. Next, 200 mL (3: 1 (v: v)) of chloroform-ethyl acetate was added to the residue, and after standing at room temperature for 24 hours, filtered and the obtained solid was washed with methanol and dried to obtain 37.6 g of the title compound as a prism crystal form. (80%).

The manufacturing method used in this preparation was prepared according to the method of the known literature (J. Med. Chem. Vol 36, No. 26, pp5228-5235, 1996).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.39 (t, 3H), 3.68 (s, 3H), 4.60 (q, 2H), 5.53 (s, 2H), 7.00 (d, 2H), 7.19 (t, 1H), 7.24 (d, 2H), 7.46 (d, 2H), 7.52-7.56 (m, 1H), 7.63-7.71 (m, 3H), 12.4 (br s, 1H)

IR (KBr) 1780, 1720, 1550, 1470, 1285, 1040, 760cm ^-1 ,

mp: 196-197 ° C.

Preparation Example 5-2: Methyl 2-ethoxy-1-((2 '-(5-oxo-2,5-dihydro1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4 Preparation of -yl) methyl) -1H-benzo [d] imidazole-7-carboxylate

Methyl (Z) -2-ethoxy-1-((2 '-(N'-hydroxycarbamidoyl)-[1,1'-biphenyl] -4-yl prepared in Preparation Example 4-2 ) Methyl) -1H-benzo [d] -imidazole-7-carboxylate 80 g (0.18 mol) was dissolved in 720 mL of dimethylsulfoxide (DMSO) followed by 1,1'-carbonyldiimidazole (CDI) ) 35.02 g (0.22 mol) was added and stirred at 25 ° C. for 1 hour. Then, 2,3,4,6,7,8,9,10-octahydropyrimidido [1,2-a] azepine (DBU) 35.07 g (0.23 mol) was added and stirred at 25 ° C for 30 minutes. After confirming the completion of the reaction, the reaction solution was added dropwise to 3 L of purified water for 1 hour, and the pH was adjusted to 4-4.5 with a 5% aqueous hydrochloric acid solution and stirred for 1 hour. The resulting solid was filtered and washed with 320 mL of purified water. Recrystallized with 400 mL of acetone, and the precipitated solid was filtered. It was dried at 40 ° C. for 10 hours to obtain 72.65 g (0.15 mol) in a yield of 85.8% of the target compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.39 (t, 3H), 3.68 (s, 3H), 4.60 (q, 2H), 5.53 (s, 2H), 7.00 (d, 2H), 7.19 (t, 1H), 7.24 (d, 2H), 7.46 (d, 2H), 7.52-7.56 (m, 1H), 7.63-7.71 (m, 3H), 12.4 (br s, 1H)

Preparation Example 6: Methyl 2-ethoxy-1-((2 '-(5-oxo-4-trityl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[ 1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (methyl 2-ethoxy-1-((2 '-(5-oxo-4-trityl Preparation of -4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate)

47.1 g of the compound obtained in Preparation Example 5-1 was dissolved in 300 mL of dimethylformamide (DMF). Then, 15.5 g of triethylamine and 30.5 g of trityl chloride were added and reacted at 60-70 ° C. for 10 hours. After cooling the reaction solution to room temperature and adding 300 ml of water, 300 ml of ethyl acetate was added 3 times (300 mLx3 times) to extract and the resulting organic layer was extracted with 300 mL of ammonium chloride aqueous solution (NH ₄ Cl) 3 times (300 mLx3 times) and After each washing with water, dried over magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure to obtain a solid labeled compound.

The labeling compound was recrystallized from ethyl acetate-isopropyl ether (1: 3) to obtain 62.7 g (88%) of the compound as a solid label.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.40 (t, 3H), 3.68 (s, 3H), 4.61 (q, 2H), 5.54 (s, 2H), 6.68-6.90 (m, 20H) , 6.93-7.07 (3H), 7.25-7.45 (m, 3H)

IR (KBr) 1780, 1720, 1550, 1470, 1285, 1040, 760cm ^-1 ,

mp: 196-197 ℃,

MS (ESI) m / z (M + 1); 713.27 (100%), 714.27 (50.8%), 715.28 (11.9%), 716.28 (2.4%), 715.27 (1.8%).

Preparation Example 7: 2-ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H- Preparation of benzimidazole-7-carboxylic acid

After dissolving 13.99 g (0.35 mol) of sodium hydroxide in 280 mL of purified water, methyl 2-ethoxy-1-((2 '-(5-oxo-dihydro-1,2,4) prepared in Preparation Example 5-2 -Oxadiazole-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] -imidazole-7-carboxylate 28 g (0.06 mol) was added thereto. The mixture was stirred at 50 ° C for 2 hours. After confirming the completion of the reaction, the reaction solution was cooled to room temperature and washed with 140 mL of methylene chloride. After heating the reaction solution to 45 ° C, 160 mL of acetone, 26.5 g of acetic acid, and 98 mL of purified water were added to precipitate a solid. The reaction solution was cooled to room temperature and stirred for 1 hour. The resulting solid was filtered and washed with a mixed solvent of 9 mL of acetone and 18 mL of purified water. After washing, the solid was added to 56 mL of acetone, stirred at room temperature for 1 hour, and the precipitated solid was filtered. The solid was dried at 40 ° C. for 10 hours to obtain 25.7 g (0.055 mol) in 92.3% yield of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.38 (t, 3H), 4.58 (q, 2H), 5.68 (s, 2H), 7.06 (d, 2H), 7.18 (t, 1H), 7.24 (d, 2H), 7.47 (d, 1H), 7.52-7.57 (m, 2H), 7.65 (d, 2H), 7.67 (d, 1H), 12.44 (br s, 1H) 13.13 (br s, 1H)

Example 1: 3-methoxy-4- (pivaloyloxy) benzyl 2-ethoxy-1-((2 '-(5-oxo-4-trityl-4,5-dihydro-1,2 , 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (3-methoxy-4- ( pivaloyloxy) benzyl 2-ethoxy-1-((2 '-(5-oxo-4-trityl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] Preparation of -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate)

35.6 g of the compound prepared according to Preparation Example 6 was dissolved in 250 mL of N, N-dimethylacetamide (DMAC). After adding 7.7 g of triethylamine to the mixture and stirring for 2 hours under ice-cooling, 15.5 g of the compound (4- (bromomethyl) -2-methoxyphenyl pivalate) obtained in Preparation Example 3 was added, followed by stirring at room temperature for 2 hours. The reaction solution was prepared by stirring at 60 ° C for 4 hours. The reaction solution temperature was lowered to room temperature, and a mixed solution of 550 mL of ethyl acetate, 50.6 mL of ammonium chloride and 600 mL of purified water was added and stirred for 30 minutes. After separating the organic layer, 53.6 g of ammonium chloride and 600 mL of purified water were added and stirred for 30 minutes. The organic layers were collected, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 33.2 g (72%) of a compound as a solid label.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 (s, 2H), 6.63 (d, 1H), 7.11 (m, 2H), 7.29-7.33 (m, 19H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H ), 8.0 (s, 1H),

IR (KBr) 2240, 1745, 1715, 1650, 1275, 1050, 750cm ^-1 ,

mp: 215 ℃ (decom),

MS (ESI) m / z (M + 1) 919.36 (100.0%), 920.37 (62.5%), 922.37 (5.1%), 920.36 (1.5%),

Elemental Analysis: C, 74.49; H, 5.48; N, 6.10. O, 13.93.

Example 2: 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxa Diazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (3-methoxy-4- (pivaloyloxy) benzyl 2 -ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl)- Synthesis of 1H-benzo [d] imidazole-7-carboxylate)

10.3 g of the compound prepared according to Example 1 was dissolved in 120 mL of methanol, and a solution of 200 mL of methanol was added dropwise to 40 mL of 1.0 M hydrochloric acid aqueous solution while stirring under ice-cooling, followed by stirring for 2 hours under ice-cooling and 6 hours at room temperature. It was stirred. The concentrated solution obtained by evaporating the methanol solvent under reduced pressure was mixed with 100 mL of isopropyl ether, stirred and the obtained residue was filtered and dried under reduced pressure to obtain 5.46 g (72%) of a compound as a solid label.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 (s, 2H), 6.63 (d, 1H), 7.11 (d, 2H), 7.29-7.33 (m, 5H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H ), 11.47 (br s, 1H)

IR (KBr) 2210, 1785, 1745, 1610, 1225, 1050, 755cm ^-1 ,

MS (ESI) m / z (M + 1) 676.24 (100.0%), 677.24 (41.8%), 678.24 (10.8%), 677.23 (1.5%), 679.25 (1.1%).

<3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole- 3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] Synthesis of imidazole-7-carboxylate>

Example 3-1: 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4 -Oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate ((3-methoxy-4- (pivaloyloxy ) benzyl 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) Synthesis of methyl) -1H-benzo [d] imidazole-7-carboxylate))

2-ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H- To a solution containing 5.0 g of benzimidazole-7-carboxylic acid and 1.69 mL of triethylamine and 50 mL of THF, 1.81 mL of 2,4,6-trichlorobenzoyl chloride was added dropwise under ice-cooling to prepare a mixture. After the mixture was stirred at room temperature for 12 hours, insoluble materials were filtered off and the filtrate was concentrated. The residue was dissolved in 50 mL of methylene chloride, and 2.6 g of 4- (hydroxymethyl) -2-methoxyphenyl pivalate prepared according to Preparation Example 2-1 and 1.61 g of N, N-dimethylaminopyridine were added under ice cooling. To prepare a mixture. After stirring the prepared mixture for 4 hours at room temperature, the reaction mixture was diluted with 150 mL of chloroform, washed with water, saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate and concentrated. After adding diisopropyl ether to the residue, a solid compound was obtained therefrom. The obtained solid compound was dissolved in 18 mL of ethanol under reflux, 0.1 g of activated carbon was added to the solution, and the mixture was refluxed and stirred for 30 minutes. The insoluble material was removed by filtration, and the filtrate was cooled at room temperature. After 12 hours, the precipitated sieve was collected by filtration, and the solid was washed with ice-cold ethanol, and dried under reduced pressure at room temperature to obtain 3.0 g (50%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 (s, 2H), 6.63 (d, 1H), 7.11 (d, 2H), 7.29-7.33 (m, 5H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H ), 11.47 (br s, 1H)

IR (KBr) 2210, 1785, 1745, 1610, 1225, 1050, 755cm ^-1 ,

MS (ESI) m / z (M + 1) 676.24 (100.0%), 677.24 (41.8%), 678.24 (10.8%), 677.23 (1.5%), 679.25 (1.1%).

Example 3-2: 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4 -Oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate ((3-methoxy-4- (pivaloyloxy ) benzyl 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) Synthesis of methyl) -1H-benzo [d] imidazole-7-carboxylate))

2-ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H- Benzimidazole-7-carboxylic acid 50 g (0.11 mol, 1 eq), 4- (hydroxymethyl) -2-methoxyphenyl pivalate 28.59 g (0.12 mol, 1.1 eq) is N, N-dimethylacetamide ( DMAc) dissolved in 200 ml. Under ice-cooling, potassium carbonate 22.67 g (0.16 mol, 1.5 eq), p-toluenesulfonyl chloride 22.88 g (0.12 mol, 1.1 eq), DMAP (4-dimethylaminopyridine) 2.0 g (16.35 mmol, 0.15 eq) were added. After stirring at room temperature for 2-3 hours, the reaction solution was cooled, and 400 ml of ethyl acetate was added to separate the organic layer. After washing the obtained organic layer with 400 ml of 20% brine, the organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was concentrated under reduced pressure. 200 ml of acetonitrile was added to the residue, followed by heating to dissolve, stirred under ice-cooling for 2 hours, and then filtered to obtain a solid. The obtained solid was dried under reduced pressure at 35 ° C. to give 59.01 g (80%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 (s, 2H), 6.63 (d, 1H), 7.11 (d, 2H), 7.29-7.33 (m, 5H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H ), 11.47 (br s, 1H)

Example 3-3: 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4 -Oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate ((3-methoxy-4- (pivaloyloxy ) benzyl 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) Synthesis of methyl) -1H-benzo [d] imidazole-7-carboxylate))

2-ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H- Benzimidazole-7-carboxylic acid 50 g (0.109 mol, 1 eq), 4- (hydroxymethyl) -2-methoxyphenyl pivalate 28.59 g (0.120 mol, 1.1 eq), N, N-dimethylacetamide ( DMAcC). Under ice-cooling, potassium carbonate 22.67 g (0.164 mol, 1.5 eq), p-toluenesulfonyl chloride 22.88 g (0.120 mol, 1.1 eq), DMAP 2.0 g (16.35 mmol, 0.15 eq) were added. Stir at room temperature for 2-3 hours. After cooling the reaction solution, 400 ml of ethyl acetate was added. 400 ml of 20% brine was slowly added. After neutralization with 10% acetic acid solution, the organic layer was separated.

The organic layer was washed with 400 ml of 20% brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure. 200 ml of acetonitrile was added to the residue, followed by heating to dissolve. After stirring for 2 hours under ice cooling, the solid was filtered. The solid was dried under reduced pressure at 35 ° C. to give 59.01 g (80%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): substantially the same as Example 3-2.

Example 3-4: 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4 -Oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate ((3-methoxy-4- (pivaloyloxy ) benzyl 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) Synthesis of methyl) -1H-benzo [d] imidazole-7-carboxylate))

2-ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H- Benzimidazole-7-carboxylic acid 50 g (0.109 mol, 1 eq), 4- (hydroxymethyl) -2-methoxyphenyl pivalate 28.59 g (0.120 mol, 1.1 eq), N, N-dimethylacetamide ( DMAc) dissolved in 200 ml. Under ice-cooling, potassium carbonate 22.67 g (0.164 mol, 1.5 eq), p-toluenesulfonyl chloride 22.88 g (0.120 mol, 1.1 eq), DMAP 2.0 g (16.35 mmol, 0.15 eq) were added and stirred at room temperature for 2-3 hours Did. After cooling the reaction solution, 400 ml of ethyl acetate was added. 400 ml of 20% brine was slowly added. After neutralization with 10% acetic acid solution, the organic layer was separated. The organic layer was washed with 400 ml of 20% brine, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure. After adding 200 ml of acetonitrile to the residue and dissolving it by heating, the mixture was stirred for 2 hours under ice-cooling and the solid was filtered.

After 150 ml of acetone and 300 ml of purified water were added to the filtered solid, the mixture was stirred at 40 to 45 ° C for 3 hours. After stirring and filtering at room temperature for 1 hour, the obtained solid was washed with 75 ml of acetone / purified water = 1/2 and then 150 ml of purified water. The washed solid was dried under reduced pressure at 35 ° C. to give 57.32 g (77%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): substantially the same as Example 3-2.

Example 3-5: 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4 -Oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate ((3-methoxy-4- (pivaloyloxy ) benzyl 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) Synthesis of methyl) -1H-benzo [d] imidazole-7-carboxylate))

2-ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H- Benzimidazole-7-carboxylic acid 50 g (0.109 mol, 1 eq), 4- (hydroxymethyl) -2-methoxyphenyl pivalate 28.59 g (0.120 mol, 1.1 eq), N, N-dimethylacetamide ( DMAc) dissolved in 200 ml. Under ice-cooling, potassium carbonate 22.67 g (0.164 mol, 1.5 eq), p-toluenesulfonyl chloride 22.88 g (0.120 mol, 1.1 eq), DMAP 2.0 g (16.35 mmol, 0.15 eq) were added and stirred at room temperature for 2-3 hours Did. After cooling the reaction solution, 400 ml of ethyl acetate was added. 400 ml of 20% brine was slowly added, neutralized with a 10% acetic acid solution, and the organic layer was separated.

The organic layer was washed with 400 ml of 20% brine, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure. 200 ml of ethyl acetate was added to the residue, followed by heating to dissolve, followed by stirring under ice-cooling for 2 hours, and then filtering the solid. The filtered solid was dried under reduced pressure at 35 ° C. to give 47.94 g (65%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): substantially the same as Example 3-2.

Example 4: 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxa Diazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate ((3-methoxy-4- (pivaloyloxy) benzyl) 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) Synthesis of -1H-benzo [d] imidazole-7-carboxylate))

Sodium 2-ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H -10 g of benzimidazole-7-carboxylate was dissolved in 150 mL of N, N-dimethylacetamide (DMAC). 3.1 g of NaI was added under ice-cooling, and 6.3 g of the compound (4- (bromomethyl) -2-methoxyphenyl pivalate) obtained in Preparation Example 3 was added and stirred at 0-5 ° C. for 2 hours to prepare a reaction solution. . A mixed solution of 200 mL of ethyl acetate, 40.0 g of ammonium chloride and 200 mL of purified water was added and stirred for 30 minutes. After separating the organic layer, a mixture of 20.0 g of sodium chloride and 200 mL of purified water was added and stirred for 30 minutes. The organic layers were collected, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 12.5 g (88%) of the labeled compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 (s, 2H), 6.63 (d, 1H), 7.11 (d, 2H), 7.29-7.33 (m, 5H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H ), 11.47 (br s, 1H)

IR (KBr) 2210, 1785, 1745, 1610, 1225, 1050, 755cm ^-1 ,

MS (ESI) m / z (M + 1) 676.24 (100.0%), 677.24 (41.8%), 678.24 (10.8%), 677.23 (1.5%), 679.25 (1.1%).

<Preparation of sodium nitrite pivalate salt>

Example 5-1: Sodium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (a sodium nitrite pivalate sodium salt) Produce

3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -Yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] Dissolve 6.8 g of imidazole-7-carboxylate in 100 mL of acetone and add 1.5 mL of triethylamine It was stirred for 30 minutes under ice cooling. A solution of 1.75 g of sodium 2-ethylhexanoate in 25 mL of acetone was added dropwise for 20 minutes, stirred for 30 minutes, and stirred at 45-50 ° C for 10 hours to prepare a reaction solution. The reaction solution was concentrated under reduced pressure to obtain a residue, and purified by silica gel chromatography to obtain 4.56 g (65%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 ( s, 2H), 6.63 (d, 1H), 7.11 (m, 2H), 7.29-7.33 (m, 5H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H)

IR (KBr) 2240, 1745, 1715, 1650, 1275, 1050, 750cm ^-1 ,

mp: 215 ℃ (decom),

MS (ESI) m / z (M + 1), 699.24 (100.0%), 700.24 (41.8%), 701.24 (10.8%), 700.23 (1.5%), 702.25 (1.1%),

Chemical Formula: C ₃₈ H ₃₅ N ₄ NaO _8,

Elemental Analysis: C, 65.32; H, 5.05; N, 8.02. Na, 3.29; O, 18.32.

Example 5-2: Sodium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (a sodium nitrite pivalate sodium salt) Synthesis of

3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -Yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate After adding 500ml of acetone to 50g (73.887mmol), 40 ~ 45 ℃ It was dissolved by heating. After adding sodium 2-ethylhexanoate 13.51g (81.276mmol, 1.1eq) at 40 ~ 45 ℃, it was refluxed for 1-2 hours. After stirring at room temperature for 2-3 hours, the solid was filtered and dried under reduced pressure at 35 ° C. to give 33.55 g (65%) of the title compound.

1H-NMR (400 MHz, DMSO-d ₆ ) 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 (s , 2H), 6.63 (d, 1H), 7.11 (m, 2H), 7.29-7.33 (m, 5H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H)

<Preparation of nitrite sartan pivalate potassium salt>

Example 6-1: Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Produce

3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -Yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] Dissolve 6.8 g of imidazole-7-carboxylate in 150 mL of acetone and add 1.5 mL of triethylamine It was stirred for 30 minutes under ice cooling. A solution of 1.85 g of potassium 2-ethylhexanoate in 40 mL of acetone was added dropwise for 20 minutes, stirred for 30 minutes, and stirred at 45-50 ° C for 10 hours to prepare a reaction solution. The reaction solution was concentrated under reduced pressure to obtain a residue, and purified by silica gel chromatography to obtain 3.95 g (55%) of the title compound as a solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 ( s, 2H), 6.63 (d, 1H), 7.11 (m, 2H), 7.29-7.33 (m, 5H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H) ,

IR (KBr) 2240, 1745, 1715, 1650, 1275, 1050, 750cm ^-1 ,

mp: 215 ℃ (decom),

MS (ESI) m / z (M + 1), 699.24 (100.0%), 700.24 (41.8%), 701.24 (10.8%), 700.23 (1.5%), 702.25 (1.1%),

Chemical Formula: C ₃₈ H ₃₅ N ₄ NaO ₈ ,

Elemental Analysis: C, 65.32; H, 5.05; N, 8.02. Na, 3.29; O, 18.32.

Example 6-2: Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, Preparation of 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (potassium nitrite pivalate)

3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -Yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate After adding 350 ml of acetone to 35 g (51.721 mmol), 40 ~ 45 ℃ It was dissolved by heating. After adding potassium 2-ethylhexanoate 10.37g (56.893mmol, 1.1eq) at 40 ~ 45 ℃, it was refluxed for 1-2 hours. After stirring at room temperature for 2-3 hours, the solid was filtered off and dried under reduced pressure at 35 ° C. to give 26.39 g (71%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 ( s, 2H), 6.63 (d, 1H), 7.11 (m, 2H), 7.29-7.33 (m, 5H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H)

Example 6-3: Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Synthesis of

3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -Yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate After adding 500ml of acetone to 50g (73.887mmol), 40 ~ 45 ℃ It was dissolved by heating. After adding potassium 2-ethylhexanoate 14.82g (81.276mmol, 1.1eq) at 40 ~ 45 ℃, it was refluxed for 1-2 hours. Stir at room temperature for 2-3 hours. The solid was filtered off and dried under reduced pressure at 35 ° C. to give 37.50 g (71%) of the title compound.

1H-NMR (400 MHz, DMSO-d ₆ ): 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 ( s, 2H), 6.63 (d, 1H), 7.11 (m, 2H), 7.29-7.33 (m, 5H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H)

Example 6-4: Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Synthesis of

3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -Yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate 50 ml (73.887 mmol) was added with 500 ml of ethyl acetate, and then 50 to 55 It was dissolved by heating to ℃. Subsequently, 14.82 g (81.276 mmol, 1.1 eq) of potassium 2-ethylhexanoate was added at 50 to 55 ° C., refluxed for 1 to 2 hours, stirred at room temperature for 2 to 3 hours, the solid was filtered, and the pressure was reduced. Dried at 35 ° C. to give 33.80 g (64%) of the title compound.

1H-NMR (400 MHz, DMSO-d ₆ ) 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 (s , 2H), 6.63 (d, 1H), 7.11 (m, 2H), 7.29-7.33 (m, 5H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H)

Example 6-5: Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Synthesis of

3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -Yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate After adding 18 ml of ethyl acetate to 4.54 g (6.709 mmol), 50 ~ Dissolved by heating to 55 ° C. At 54 ° C., a solution of 1.11 g (6.709 mmol, 1.0 eq) of potassium 2-ethylhexanoate in 5 ml of ethyl acetate was added dropwise over 15 minutes. After refluxing for 1-2 hours, the mixture was stirred at room temperature for 2-3 hours. The solid was filtered off and dried under reduced pressure at 35 ° C. to give 3.06 g (64%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): substantially the same as Example 6-4.

Example 6-6: Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Synthesis of

3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -Yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate 50 ml (73.887 mmol) was added with 800 ml of isopropyl ether, and then 50- Dissolved by heating to 55 ° C. After adding potassium 2-ethylhexanoate 14.82g (81.276mmol, 1.1eq) at 50 ~ 55 ℃, it was refluxed for 1-2 hours. After stirring at room temperature for 2-3 hours, the solid was filtered and dried at 35 ° C. under reduced pressure to give 35.91 g (68%) of the title compound.

1H-NMR (400 MHz, DMSO-d ₆ ) 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 (s , 2H), 6.63 (d, 1H), 7.11 (m, 2H), 7.29-7.33 (m, 5H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H)

Example 6-7: Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Synthesis of

3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -Yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate 50 ml of isopropyl ether was added to 3 g (4.433 mmol) and then 50- Dissolved by heating to 55 ° C. A solution in which 0.81 g (4.433 mmol, 1.0 eq) of potassium 2-ethylhexanoate was dissolved in 5 ml of isopropyl ether was added dropwise at 55 ° C. for 5 minutes. After refluxing for 1-2 hours, the mixture was stirred at room temperature for 2-3 hours. The solid was filtered off and dried under reduced pressure at 35 ° C. to give 2.43 g (77%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): substantially the same as Example 6-6.

Example 6-8: Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Synthesis of

3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3 -Yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate 5.0g (7.389mmol) was added 30ml of tert-butanol and 50 ~ Dissolved by heating to 55 ° C. A solution in which 1.35 g (7.389 mmol, 1.0 eq) of potassium 2-ethylhexanoate was dissolved in 5 ml of tert-butanol was added dropwise at 58 ° C. for 10 minutes. After stirring at 60 ~ 70 ℃ for 2-3 hours, it was stirred at room temperature for 2-3 hours. The solid was filtered off and dried under reduced pressure at 35 ° C. to give 3.98 g (75%) of the title compound.

1H-NMR (400 MHz, DMSO-d ₆ ) 1.23 (s, 9H), 1.32 (t, 3H), 3.83 (s, 3H), 4.29 (q, 2H), 5.26 (s, 2H), 5.46 (s , 2H), 6.63 (d, 1H), 7.11 (m, 2H), 7.29-7.33 (m, 5H), 7.48 (t, 1H), 7.58 (t, 1H), 7.74-7.89 (m, 4H)

<Preparation of existing nitrite medoxomil compound and its potassium salt>

Comparative Example 1: (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl-2-ethoxy-1-{[2 '-(5-oxo-4,5-dihydro- Preparation of 1,2,4-oxadiazol-3-yl) biphenyl-4-yl] -methyl} -1H-benzimidazole-7-carboxylate (azylsartan medoxomil compound)

2-ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H- Benzimidazole-7-carboxylic acid (83.5 g), triethylamine (28.2 mL) and THF (835 mL) were added dropwise with 2,4,6-trichlorobenzoyl chloride (30.2 mL) under ice-cooling. did. After the mixture was stirred at room temperature for 12 hours, insoluble materials were removed by filtration, and the filtrate was concentrated. The residue was dissolved in methylene chloride (835 mL), and 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (28.7 g) and N, N-dimethylaminopyridine (26.9 g) were ice-cooled. The mixture was prepared by addition underneath. The resulting mixture was stirred at room temperature for 4 hours, then diluted with chloroform (2500 mL), washed with water, saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate and concentrated. After obtaining the residue as a solid form using diisopropyl ether, a solution was prepared by dissolving the solid under reflux in ethanol (300 mL). Activated carbon (1.7 g) was added to the solution, stirred at reflux for 30 minutes, and then the insoluble material was removed by filtration. The filtered filtrate was cooled to room temperature for 12 hours to obtain precipitated crystals through filtration, washed with ice-cold ethanol, and dried at room temperature under reduced pressure to obtain the title compound (50.0 g, 50%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) 1.40 (t, 3H), 2.16 (s, 3H), 4.60 (q, 2H), 5.11 (s, 2H), 5.55 (s, 2H), 700 ( d, 2H), 7.20-7.23 (m, 3H), 7.46-751 (m, 1H), 7.53 (dd, 1H), 7.54 (dd, 1H) 7.56-7.68 (m, 2H), 7.73 (d, 1H) ), 12.374 (br s, 1H)

Comparative Example 2: (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl-2-ethoxy-1-{[2 '-(5-oxo-4,5-dihydro- Preparation of 1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylate potassium salt (azitartan medoxomil potassium salt)

(5-methyl-2-oxo-1,3-dioxol-4-yl) methyl-2-ethoxy-1-{[2 '-(5-oxo-4,5-dihydro-1,2, 50 g (87.946 mmol) of 4-oxadiazole-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylate was dissolved in 500 ml of acetone at a temperature of 50 ° C. Thereafter, 17.64 g (96.741 mmol, 1.1 eq) of potassium 2-ethylhexanoate was added at 20 to 25 ° C., followed by stirring for 1 to 2 hours, and stirring under ice cooling for 2 to 3 hours. Then, the precipitated crystals were filtered and dried under reduced pressure at 25 ° C. to give 34.68 g (65%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 1.42 (t, 3H), 2.16 (s, 3H), 4.61 (q, 2H), 5.11 (s, 2H), 5.52 (s, 2H), 6.87 ( d, 2H), 7.19-7.22 (m, 3H), 7.25 (d, 1H), 7.33-7.39 (m, 2H), 7.50 (d, 2H), 7.73 (d, 1H)

<Experiment 1> Purity evaluation

Example 3-1, Example 3-2, Example 3-4, and Example 3-2 of the azilsartan pivalate free base prepared according to the preparation method of Example 3-2 and Example 3-2 Purity of sodium nitrate salt, potassium nitrite of nitrite prepared according to Example 6-3, Example 6-4 and Example 6-6 was measured using HPLC, and the results are shown in Table 1 below. .

Free base	Example 3-1	Example 3-2	Example 3-4	Example 3-5
water	99.78%	99.82%	99.87%	99.80%
salt	Example 6-2	Example 6-4	Example 6-6	Example 5-2
water	99.92%	99.87%	99.85%	99.79%

As can be seen from the table, Examples 3-1, Example 3-2, Example 3-4 and Example 3-2, Example 5-2, and the nitrite free radical prepared by the preparation method of Example 3-5 It was confirmed that the purity of the nitrite salt of the nitrite salt prepared in Example 6-3, Example 6-4, and Example 6-5 was 99.5% or more. It is very difficult to introduce a separate purification process due to its poorly soluble nature, and the nitrite free radical of the present invention and the free nitrite salt of the nitrite can be secured with high purity, which is very suitable for pharmaceutical use, only by manufacturing. Yes, it was confirmed.

<Experimental Example 2> Characterization evaluation

Low hygroscopicity is a very important factor for the processing and storage of actual medicines among the properties required for compounds to be used as pharmaceutical raw materials. In order to measure the hygroscopicity of the compounds according to the present invention, an azilsartan pivalate free base prepared in Examples 3-2, 3-4 and 3-5 was prepared and Example 6-3, carried out After vacuum drying (P ₂ O ₅ , 1 day or more) of the nitrite potassium salt of nitrite prepared in Example 6-4 and Example 6-6 and Comparative Example 2, the initial moisture value was measured by the Karl Fischer method. , Moisture measurement device (model name: Hydrosorb 1000, manufacturer: Quantachrome Instruments) using a 25 ℃ and relative humidity 15, 35, 55, 75, 95% of the moisture was automatically measured moisture, the results are shown in Table 2 below It was described. However, the initial moisture value was set to be a moisture value in a state that is continuously dried and no longer reduced.

	Initial moisture value		Relative humidity 15%	Relative humidity 35%	Relative humidity 55%	Relative humidity 75%	Relative humidity 95%
Example 3-2	0.18%	0.17%	0.17%	0.16%	0.19%	0.20%
Example 3-4	0.12%	0.13%	0.14%	0.13%	0.14%	0.15%
Example 3-5	0.14%	0.13%	0.14%	0.15%	0.16%	0.17%
Example 6-3	0.14%	0.13%	0.14%	0.15%	0.15%	0.16%
Example 6-4	0.16%	0.17%	0.17%	0.16%	0.19%	0.20%
Example 6-6	0.12%	0.13%	0.14%	0.13%	0.15%	0.16%
Comparative Example 2	0.28%	0.59%	2.64%	4.25%	8.35%	12.15%

(Unit: Jungrang%)

Referring to the above table, nitrite pyrvalate free base prepared according to Example 3-2, Example 3-4 and Example 3-5 and Example 6-3, Example 6-4 and Example 6 The nitrite potassium pivalate potassium salt prepared according to -6 showed a very low hygroscopicity of about 0.2% at the relative humidity of the entire range where the experiment was conducted, and it was found that it can be stably stored even when the raw material is exposed to moisture in the air.

Accordingly, it was confirmed that the nitrite-sartan pivalate free base of the present invention and the potassium nitrite-pithalate potassium salt have excellent non-hygroscopic (non-hygroscopic) properties that are not humidified even when exposed to air at normal relative humidity.

On the other hand, it was confirmed that the compound prepared according to Comparative Example 2 has a very poor property as a raw material for pharmaceutical use by drawing moisture in the air exponentially as the relative humidity increases, and Comparative Example 2 is too large for formulation. It is expected that it is difficult to formulate or require separate strict conditions for formulation.

Therefore, compared to the nitrite potassium salt of azilsartan medoxomil prepared according to Comparative Example 2, the azilsartan pivalate free base and potassium salt of the present invention have excellent non-humidity characteristics, and are excellent in formulating as a raw material for formulation. It can be seen that formulation is easy and economical.

<Experimental Example 3> Stability test

Good stability in the solid state is an important factor for tablets and capsules, so nitrite prepared by the preparation method of Examples 3-1, 3-3, 3-4 and 3-5 to evaluate stability Sartan pivalate free base and the compounds prepared in Example 5-2, Example 6-3, Example 6-4, Example 6-6 and Comparative Example 2 in harsh conditions at 100 ° C (confidential) It was stored for 1 week, and the relative stability to heat was measured by HPLC, and the results are shown in Table 3 below.

division	Initial value	One week later
Example 3-1	99.78%	99.69%
Example 3-2	99.82%	99.77%
Example 3-4	99.87%	99.85%
Example 3-5	99.80%	99.76%
Example 6-3	99.92%	99.89%
Example 6-4	99.87%	99.86%
Example 6-6	99.85%	99.83%
Example 5-2	99.79%	99.75%
Comparative Example 2	98.20%	96.80%

Referring to the above table, nitrite pyrvalate free base prepared according to Example 3-2, Example 3-4 and Example 3-5 and Example 5-2, Example 6-3, Example 6 The compounds prepared in -4 and Examples 6-6 showed excellent stability to heat, and Comparative Example 2 was found to have relatively poor stability to heat.

Thus, the nitrite sarvalidate free base, sodium salt, and potassium salt prepared according to the present invention have significantly better stability than conventional nitrite medoxomil potassium salts.

<Experimental Example 4> Electrostatic test

Compounds that generate a lot of static electricity can cause problems such as equipment and sticking during processing by quantitative measurement and pharmaceutical formulation, so static electricity is an important factor in formulation. Example 3-1, Example 3-2, Example 3-4 and Example 3-2, Example 6-2, Example 6-3, and Example 3-2, Example 6-2 of the free base prepared by the preparation method of Example 3-5 To confirm the electrostatic properties of the compounds according to Example 6-4, Example 6-6 and Comparative Example 2, Example 3-1, Example 3-2, Example 3-4, Example 3-5, and Example Example 5-2, Example 6-2, Example 6-3, Example 6-4 and the Faraday cage device for measuring the static electricity by shielding the external static electric field of the sample of Comparative Example 2 (model name: 325 Faraday Cage with SmartStirTM, manufacturer: AMETEK PAR) was tested for the electrostatic properties of each compound and the results are shown in Table 4.

	Electrostatic (nc / g)
Example 3-1	15 nc / g
Example 3-2	8 nc / g
Example 3-4	6 nc / g
Example 3-5	10 nc / g
Example 6-2	7 nc / g
Example 6-3	10 nc / g
Example 6-4	11 nc / g
Example 5-2	14 nc / g
Comparative Example 2	25 nc / g

Referring to the above table, Example 3-1, Example 3-2, Example 3-4 and Example 3-2 and Example 5-2 of the nitrite free base prepared by the preparation method of Example 3-5, Example It was confirmed that the samples prepared in Example 6-3, Example 6-4 and Example 6-6 had lower electrostatic properties than the samples of Comparative Example 2.

Accordingly, the nitrite free radicals, sodium nitrite pivalate sodium salt and potassium salt prepared according to the present invention have low static electricity compared to the comparative example 2, which is a conventional nitrite medoxomil potassium salt. It can be seen that the workability is remarkably low.

<Experimental Example 5> Cost (volume per unit weight) test

When a compound is used as a raw material for a drug and processed into a tablet, the cost of the solid (volume per unit weight) may affect process convenience and the size of the formulation, and when the cost is large, the processability is very poor. As it can, cost effectiveness is an important factor in formulation. Example 3-1, Example 3-2, Example 3-4 and Example 3-2, Example 6-2, Example 6-3, and Example 3-2, Example 6-2 of the free base prepared by the preparation method of Example 3-5 Example 3-1, Example 3-2, Example 3-4, Example 3-5, Example 5 to confirm the cost of the samples of Example 6-4, Example 6-6 and Comparative Example 2 -2, Example 6-3, Example 6-4, Example 6-6, and the samples prepared in Comparative Example 2 were placed in a measuring cylinder and repeated 20 times or more at a height of 10 cm vertically to compress sufficiently. To drop naturally. The cost was measured before and after tapping, and the results are shown in Table 5.

	Before tapping	After tapping
Example 3-1	3.88mL / g	2.65 mL / g
Example 3-2	3.76 mL / g	2.71 mL / g
Example 3-4	3.62 mL / g	2.65 mL / g
Example 3-5	3.79mL / g	2.70 mL / g
Example 6-3	3.22mL / g	2.31mL / g
Example 6-4	3.86 mL / g	2.77 mL / g
Example 6-6	3.73 mL / g	2.67 mL / g
Example 5-2	3.89mL / g	2.68 mL / g

Referring to the above table, it was confirmed that the compounds of Example 5-2, Example 6-3, Example 6-4, and Example 6-6 had a cost reduction effect. In general, since the pharmaceutical raw material in powder form has a high cost, it is designed as a formulation (tablet or capsule) that can be administered to the human body after compression molding at all times, so if the cost is large, the processability of the formulation is very poor.

Accordingly, it was found that the nitrite satan pivalate or the salt thereof of the present invention has excellent physicochemical properties of pharmaceutical processability.

<Experiment 6> Evaluation of inhibitory activity against AT1 (IC50)

The following experiment was performed for the experiment for verifying the inhibitory activity of AT ₁ of the nitrite derivative compound prepared according to Example 6-3 of the present invention.

After adding 45 μl assay buffer (50 mM Tris-HCl, 5 mMMgCl ₂ , 1 mM EDTA, and 0.005% CHAPS, pH 7.4) to a 96-well plate with 10 μg of AT ₁ attached, and standing at room temperature for 90 minutes, 5 μl ¹²⁵ I-Sar ¹ -Ile ⁸ -AII (final concentration is 0.6 nM) is added and stirred for 5 hours to react. Simultaneously, the prepared MFC-1101 is added to a 45 µl assay buffer in a concentration gradient and left at room temperature for 90 minutes. Immediately thereafter, unlinked MFC-1101 was removed using 200 µl assay buffer per well, and 5 µl ¹²⁵ I-Sar ¹ -Ile ⁸ -AII was added and stirred for 5 hours to react. After that, washing was performed twice using 200 µl assay buffer per well, and the inhibition of AT ₁ activity was measured using a 96-well plate analyzer capable of measuring ¹²⁵ I, and the results are shown in Table 6 below.

compound	IC50 (n Μ )
Example 6-3	2.9 (2.6-3.2)
Azilsartan	2.6 (1.7-4.1)

Referring to the above table, the nitrite derivative compound prepared according to Example 6-3 has an IC50 value of 2.9 nM, which is a measure of inhibition of AT ₁ activity, and exhibits efficacy similar to that of Azilsartan (IC50 2.6 nM). see.

Therefore, it can be seen that the nitrite derivative compound prepared according to Example 6-3 of the present invention can exhibit excellent pharmacological effects.

<Experimental Example 7> Pharmacokinetic evaluation of the nitrite potassium pivalate potassium salt of the present invention

Bioequivalence was assessed through pharmacokinetic testing of the nitrite potassium salt of the present invention.

(1) Analysis of stability in plasma

After the intravenous administration of the potassium nitrite of the present invention, the concentration of the potassium salt of the nitrite derivative compound of the present invention in the plasma of the rat separated from the blood of the rat collected for each time was measured, and the result is FIG. 1. Same as

(2) Suspension and solution After oral intake, plasma concentration, plasma maximum concentration and AUC analysis over time

Suspension and solution in 0.5% carboxymethylcellulose (CMC) solution of nitrite-sarbita pivalate free base (MFC) according to Example 3-4 of the present invention, and potassium nitrite (MFCk) nitrite according to Example 6-3 All were prepared, and the concentration of the nitrite of the present invention was measured in plasma separated from the blood of rats collected for each time after administration under the conditions shown in Table 7 below, and the results are shown in FIGS. 2 to 5.

gender	Number of animals	Route of administration	Dose (mg / kg)	Dosage amount (mL / kg)
M	3	oral-	One	5

2 to 5 show the results of blood concentrations of nitrite in the oral ingestion of the nitrous acid pivalate free base (MFC) of the present invention and the potassium salt of azilsartan pivalate (MFCk).

2 and 3 are when a suspension containing azilsartan pivalate free base (MFC) and azilsartan pivalate potassium salt (MFCk) is administered, and FIGS. 4 and 5 are azilsartan pivalate free bases (MFC) shows the results of blood concentrations of nitrite of nitrite when administered with a solution containing potassium nitrite salt (MFCk).

As shown in Figures 2 to 5, the nitrite pivalate free base (MFC) and the nitrite pivalate potassium salt (MFCk) according to the present invention exhibit a sufficient effect in the blood even when taken orally. It can be seen that it has an excellent therapeutic effect.

Since the specific parts of the present invention have been described in detail above, it is obvious that for those skilled in the art, this specific technology is only a preferred embodiment, and the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (21)

1. An azilsartan derivative compound represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

   [Formula 1]

   

   In Chemical Formula 1,

   R ₁ and R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

   A is H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, N (R ₃ ) ₂ ,

   

   ,

   

   or

   

   ego,

   R ₃ is H or a C _1-6 alkyl group,

   R _a to R _c are each independently an aryl group or a heteroaryl group,

   R _d to R _f and R _g are each independently a C _1-6 alkyl group or a C _1-6 alkoxy group,

   m is any integer from 0 to 4,

   n is an integer of 0-6.
2. According to claim 1,

   The pharmaceutically acceptable salt is

   Is represented by the following formula 1A or 1B,

   Azilsartan derivative compounds, optical isomers thereof or pharmaceutically acceptable salts thereof:

    [Formula 1A]

   

   [Formula 1B]

   

   In Formulas 1A and 1B,

   R ₁ and R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

   R ₃ is H or a C _1-6 alkyl group,

   m is any integer from 0 to 4,

   n is an integer of 0-6.
3. The method according to claim 1 or 2,

   R ₁ is a C _1-6 alkyl group,

   R ₂ is a C _1-6 alkoxy group,

   A is hydrogen, trityl, t-butyl dimethylsilyl (TBDMS) or t-butyl dicarbonate (tert-butyl dicarbonyl, BOC),

   m is 1, n is 0,

   Azilsartan derivative compounds, optical isomers thereof or pharmaceutically acceptable salts thereof.
4. According to claim 3,

   R ₁ is a t-butyl group and R ₂ is a methoxy group,

   Azilsartan derivative compounds, optical isomers thereof or pharmaceutically acceptable salts thereof.
5. The method according to claim 1 or 2,

   R ₁ is a C _1-6 alkyl group,

   R ₂ is a C _1-6 alkoxy group,

   A is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 hydroxyalkyl group, a C _1-6 cyanoalkyl group, a C _1-6 haloalkyl group, N (R ₃ ) ₂ ,

   

   ,

   

   or

   

   ego,

   R _a to R _c are each independently phenyl,

   R _d to R _f and R _g are each independently a C _1-6 alkyl group or a C _1-6 alkoxy group,

   m is 1,

   n is 0,

   Azilsartan derivative compounds, optical isomers thereof or pharmaceutically acceptable salts thereof.
6. The method of claim 5,

   A is

   

   And R _a to R _c are each independently an aryl group,

   Azilsartan derivative compounds, optical isomers thereof or pharmaceutically acceptable salts thereof.
7. The method of claim 5,

   A is a trityl group (trityl), t-butyl dimethyl silyl group (tert-butyl methylsilyl, TBDMS) and t-butyl dicarbonate group (tert-butyl dicarbonyl, BOC) is any one selected from the nitrite-sartan derivative compound, its Optical isomers or pharmaceutically acceptable salts thereof.
8. According to claim 1, wherein the compound represented by Formula 1 is that represented by the following Formula 1-1, nitrite compound derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

   [Formula 1-1]

   
9. The nitrite salt compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 8, wherein the pharmaceutically acceptable salt is a potassium salt or a sodium salt.
10. According to claim 1, wherein the compound represented by Formula 1 is that represented by the following Formula 1-2, an nitrite derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

    [Formula 1-2]

    

    In Chemical Formula 1-2, Ph is a phenyl group.
11. Comprising the steps of reacting the compound represented by the following formula (6) and the compound represented by the following formula (7) to prepare a nitrite compound represented by the formula (1)

    A method for preparing an azilsartan derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

    [Formula 6]

    

    In Chemical Formula 6,

    R ₁ to R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

    R ₃ is H or a C _1-6 alkyl group,

    X is any of -OH, F, Cl, Br and I,

    m is any integer from 0 to 4,

    n is any one of 0 to 6,

    [Formula 7]

    

    In Chemical Formula 7,

    W is H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, N (R ₃ ) ₂ ,

    

    ,

    

    or

    

    ego,

    R ₃ is H or a C _1-6 alkyl group,

    M is H, C _1-6 alkyl, Na or K,

    R _a to R _c are each independently an aryl group or a heteroaryl group,

    R _d to R _f and R _g are each independently a C _1-6 alkyl group or a C _1-6 alkoxy group,

    [Formula 1]

    

    In Chemical Formula 1,

    R ₁ and R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

    A is H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, N (R ₃ ) ₂ ,

    

    ,

    

    or

    

    ego,

    R ₃ is H or a C _1-6 alkyl group,

    R _a to R _c are each independently an aryl group or a heteroaryl group,

    R _d to R _f and R _g are each independently a C _1-6 alkyl group or a C _1-6 alkoxy group,

    m is any integer from 0 to 4,

    n is an integer of 0-6.
12. The method of claim 11,

    When A in Formula 1 is H,

    Further comprising the step of deprotecting the functional group W of Formula 7,

    In the above, W is any one selected from trityl, t-butyl methylsilyl (TBDMS) and t-butyl dicarbonyl (BOC).

    A method for preparing an azilsartan derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
13. The method of claim 11,

    R ₁ is tert butyl,

    R ₂ is methoxy, X is -OH, Cl, Br or I,

    W is H or -Ph ₃

    M is methyl or H,

    A is H or -Ph ₃ ,

    n is 0 and m is 1,

    A method for preparing an azilsartan derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
14. The method of claim 11,

    The reaction comprises a condensation reaction performed in the presence of a base containing at least one selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, diisopropylamine, triethylamine and diethylamine, A method for preparing an azilsartan derivative compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
15. A nitrite compound comprising reacting a compound represented by the following formula [6-1] with a compound represented by the following formula [7-1] to prepare a compound represented by the following formula [1-1] Methods for preparing derivative compounds, optical isomers thereof or pharmaceutically acceptable salts thereof:

    [Formula 6-1]

    

    [Formula 7-1]

    

    [Formula 1-1]

    
16. The method of claim 15, further comprising the step of reacting the compound represented by the formula (1-1) with Na + or K +, to prepare a nitrite compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof Way.
17. The method of claim 16, wherein the step of reacting the compound represented by Formula 1-1 with Na + or K + comprises reacting the compound represented by Formula 1-1 with potassium 2-ethyl hexanoate or It is to react with sodium 2-ethyl hexanoate (Sodium 2-ethyl hexanoate),

    A method for preparing an azilsartan derivative compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
18. 18. The nitrite derivative compound, an optical isomer thereof, or a pharmaceutically acceptable compound thereof according to claim 16 or 17, wherein the reaction is performed under at least one solvent selected from the group consisting of acetone, ethyl acetate and isopropyl ether. Methods for preparing possible salts.
19. A pharmaceutical composition for treating or preventing hypertension, comprising the nitrite compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
20. The method of claim 19,

    The composition is a pharmaceutical composition comprising at least one selected from the sodium salt represented by the formula (1A) and the potassium salt represented by the formula (1B):

    [Formula 1A]

    

    [Formula 1B]

    

    In Formulas 1A and 1B,

    R ₁ and R ₂ are each independently H, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _1-6 cyanoalkyl group, C _1-6 haloalkyl group, or N ( R ₃ ) ₂ ,

    R ₃ is H or a C _1-6 alkyl group,

    m is any integer from 0 to 4,

    n is an integer of 0-6.
21. The method of claim 19,

    The composition is a pharmaceutical composition comprising at least one member selected from the group consisting of a compound represented by Formula 1-1, a sodium salt thereof and a potassium salt thereof:

    [Formula 1-1]

    

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