KR20180124400A - Sacubitril conjugate, preparation method thereof, and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a sacbityl conjugate, a method for producing the same, and a pharmaceutical composition containing the same.
The saccharide complex according to the present invention exhibits excellent thermal stability and water stability, and can be mass-produced in a uniform quality. Therefore, it is preferably included as an active ingredient of a pharmaceutical composition for the treatment or prevention of cardiovascular diseases.

Description

TECHNICAL FIELD The present invention relates to a saccharide complex, a saccharide complex, a saccharide complex, a saccharide complex, a saccharide complex, a saccharide complex, a saccharide complex,

The present invention relates to a sacbityl conjugate, a method for producing the same, and a pharmaceutical composition containing the same.

According to statistics from the World Health Organization (WHO), the global mortality rate of cardiovascular diseases in the world is over 30% in 2011, and it is the number one disease in the world. In particular, the rate of growth in Asia such as Japan and Korea is high. This is presumably due to an increase in risk factors for coronary artery disease due to changes in transition to an aging society and eating habits.

Background Art Cardiovascular disease is a disease characterized by abnormalities of the heart and blood vessels, including certain endocrine disorders including vascular endothelial dysfunction, including atherosclerosis, hypertension, dyslipidemia, coronary artery disease (heart attack), stroke, dementia, Arrhythmia, heart failure, congestive heart disease, myocardial disease, and the like.

Among these cardiovascular diseases, heart failure refers to a heart condition that can not supply enough blood to the body. It initially appears to be a form of decreased exercise capacity. However, when symptoms progress, the blood supply capacity of the heart is rapidly decreased, It can not supply enough blood and causes a fatal condition such as a heart attack. Heart failure is one of the most popular health problems, with a high mortality rate that goes beyond the mortality rate of infectious diseases and the number is increasing.

Ent Restorative ^{TM (TM} Entresto, Novartis, Inc.) is a preparation to a commercially developed for the treatment of chronic heart failure including congestive heart failure, and a complex, in particular comprising a pharmacologically active ingredient of two different mechanisms of action is as shown. Specifically, the complex is an angiotensin II receptor blocker having vasoconstrictive action and sodium retention action. Valsartan, which functions to lower blood pressure through vasodilation, and saccharide, which functions to reduce the burden due to cardiac dysfunction, (Sacubitril) component.

Saku bit reel is the IUPAC name 4 - {[(2 S, 4 R) - l- (4- biphenyl-yl) -5-ethoxy-4-methyl-5-oxo-2 fentanyl to] amino} -4 -oxo-butanoic acid (4 - {[(2 S , 4 R) -l- (4-biphenylyl) -5-ethoxy-4-methyl-5-oxo-2-pentanyl] amino} -4-oxobutanoic acid) as , And neprilysin (NEP) enzymes to enhance the protective neurohormonal system of the heart, thus being usefully used as a cardiovascular therapeutic agent.

A method for preparing sacbitur is disclosed in U.S. Patent No. 5,217,996, which is generally prepared in the form of a saccharide monosodium salt. In the case of saccharide monosodium salt, there is not much reported in the literature, but it is very weak to moisture and heat and thus it is not suitable for use as a raw material for pharmaceuticals.

Generally, in order to be useful for pharmaceutical use, physicochemical properties such as solubility, stability, non-hygroscopicity and processability should be excellent. Highly stable drugs have the advantage that they do not deteriorate even after storage for a long time. Drugs with high solubility can be rapidly absorbed in stomach and intestines when taken orally, have.

Accordingly, a variety of techniques have been proposed to satisfy the above-mentioned properties.

For example, U.S. Patent No. 8,946,481 discloses a reaction scheme for preparing a saccharide hemicalcium salt.

International Patent Publication No. 2017-003483 discloses a saccharide hemicalcium salt in crystalline form, amorphous form, solvate form and hydrate form, International Patent Publication No. 2017-009784 discloses a crystalline saccharitol sodium salt and a method for preparing the same. However, the improvement of the physical properties of the compound is not mentioned.

These patents disclose a salt type saccharide, but they are poor in terms of physical properties, so that it is difficult to process and store into a formulation, and sufficient pharmacological effects can not be obtained, and commercial production is difficult. Therefore, there is still a need for research on sacchibilites which not only can provide physiologically required physicochemical properties, but also can be mass-produced through a simple and reproducible process.

U.S. Patent No. 5,217,996 (June 6, 1993), Biaryl substituted 4-amino-butyric acid amides U.S. Patent No. 8,946,481 (Oct. 26, 2012), Process for preparing biaryl substituted 4-amino butyric acid or derivatives thereof and their use in the production of NEP inhibitors International Patent Publication No. 2017-003483 (2015.07.02), Sacubitril calcium salts International Patent Publication No. 2017-009784 (2016.07.13), Solid state forms of trisodium salt of valsartan / sacubitril complex and sacubitril

In order to solve the above-mentioned conventional problems, the inventors of the present invention have conducted various studies on sacchabityl compounds having improved stability over conventional sacchbutyral compounds based on the above-mentioned previous research results, A saccharide complex having a saccharide compound bonded to a saccharide and a saccharide compound having a saccharide structure, and a saccharide complex having saccharides and saccharides, wherein the saccharide complex has improved stability against moisture and heat.

Accordingly, an object of the present invention is to provide the above-mentioned sacbityl conjugate.

Another object of the present invention is to provide a method for producing the sacbituric compound.

It is still another object of the present invention to provide a pharmaceutical composition comprising the sacchvitlir conjugate as an active ingredient.

In order to accomplish the above object, the present invention provides a sacbityl conjugate of the following formula (1), wherein the saccharide is combined with saccharide monosodium salt:

[Chemical Formula 1]

(In the above formula (1), X and n are as described in the specification.)

In addition,

a) dissolving saccharide of the following formula (2) or a salt thereof in a solvent to prepare a solution;

b) adding a sodium-containing compound to the solution obtained in step a);

c) adding a saccharide to the solution obtained in step b); And

d) separating the solid form of the sacchabityl complex from the solution obtained in the step c).

(2)

[Chemical Formula 1]

(In the above formula (1), X and n are as described in the specification.)

The present invention also provides a pharmaceutical composition comprising the sacchvitlir conjugate as an active ingredient.

Although the sacchabityl conjugate according to the present invention has an amorphous structure, it can be stored at room temperature for a long period of time by having improved thermal stability and moisture stability compared to sacchvitil derivatives including saccharide monosodium salt in the past, It can be used as a pharmaceutical composition for treating or preventing hypertension or heart failure.

1 is a graph showing the X-ray powder diffraction analysis results of a sacbituric coupling agent according to Example 1. Fig.

Hereinafter, the present invention will be described in more detail.

The terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary terms and the inventor may appropriately define the concept of the term in order to best describe its invention It should be construed as meaning and concept consistent with the technical idea of the present invention.

The present invention provides a sacbituric conjugate of the following formula 1 wherein a saccharide monosodium salt and a saccharide are combined:

[Chemical Formula 1]

(In the formula 1,

X is a saccharide,

n is 0.5? n? 3.

The saccharide complex of formula (1) is formed by combining saccharide monosodium salt with saccharide. At this time, the sacbituric complex of the present invention maintains the form of neutral molecule without chemical modification of each molecule through interaction of two or more molecules, and differs from salt in which each molecule is ionized and mutually interacts with each other. In general, the crystalline form of a drug used as a raw material of a drug affects properties such as solubility, dissolution rate, extrusion rate, and melting point, and the physical properties of such a drug are very important for manufacturing pharmaceuticals and securing pharmacological effects. Generally, even if the same drug is crystalline, the purification process is stable and excellent in reproducibility. On the other hand, the amorphous form has a high solubility and thus has the advantage of being rapidly absorbed in the stomach and intestines. However, it has a disadvantage that its stability is lower than that of the crystalline form. The conventional saccharide monosodium salt used as a raw material for pharmaceuticals has both amorphous and crystalline forms, but neither of them has satisfactory properties in pharmaceuticals. Thus, the present invention formed a sacbityl conjugate exhibiting amorphousness and excellent stability. The sacbityl conjugate according to the present invention is in an amorphous form, but is stabilized by saccharides and exhibits more stable characteristics with respect to moisture and heat. As a result, the physiologically required physicochemical properties such as heat stability, non-hygroscopicity and processability as a formulation of the sacbituric conjugate are improved, which is suitable for the preparation of pharmaceutical formulations and exhibits improved pharmacological effects.

The sugars include monosaccharides such as glucose, galactose, fructose, rhamnose, xylose, arabinose and apiose; Disaccharides such as lactose, sucrose, maltose, rutinose, neohesperidose, sophorose, sambubiose, laminaribiose and the like; Triglycerides such as gentiotriose, glucosyl lutinose, glucosyl neohesperidos and the like; Polysaccharides such as dextran; Sugars in addition to those sugars; And sugar alcohols such as mannitol, sorbitol, arabitol, glycerol, xylitol, and the like.

Preferably, the sugar X in the above formula (1) may be at least one selected from the group consisting of glucose, fructose, lactose, mannitol and sorbitol, more preferably at least one selected from the group consisting of glucose, mannitol and sorbitol It can be more than a species.

In Formula 1, n may be 0.5 to 3, preferably 0.5 to 1.

The sacbituric complexes according to the present invention were confirmed by X-ray powder diffraction analysis and differential scanning calorimetry, and the results are shown in FIGS. 1 and 2, respectively.

1, a sacbituric complex according to an embodiment of the present invention is prepared by X-ray powder diffraction (XRPD) using a Cu-K? ₁ line (? = 1.54060?) It can be confirmed that it represents an amorphous structure.

The present invention provides a process for preparing a sacbityl complex of formula (1).

Specifically, the present invention provides a method for preparing a saccharide complex of formula (1), comprising the steps of: a) dissolving saccharide or its salt of formula (2) in a solvent to prepare a solution; b) adding a sodium-containing compound to the solution obtained in step a); c) adding a saccharide to the solution obtained in step b); And d) separating the solid form of the sacchabityl complex from the solution obtained in step c)

(2)

[Chemical Formula 1]

(In the formula 1,

X is a saccharide,

n is 0.5? n? 3.

Hereinafter, each step will be described in detail as follows.

First, in step (a), a solution of saccharide or its salt of formula (2) is dissolved in a solvent to prepare a solution.

The saccharide represented by the formula (2) may be saccharide or a pharmaceutically acceptable salt thereof.

Examples of the pharmaceutically acceptable saccharide salt include saccharide salts such as saccharide salt, saccharide sodium salt, saccharide hemin sodium salt, saccharide potassium salt, saccharide hemiccium salt, and saccharide hemimagnesium And a salt thereof. Preferably, it may be at least one selected from the group consisting of sacbitol potassium salt, sacbituric hemicalcium salt, saccharide sodium salt, and saccharide hemimagnesium salt.

The saccharide of the above formula (2) or a salt thereof may be commercially available or may be directly prepared by a conventional method.

The solvent used in the step a) is at least one selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, diethyl ether, butyl acetate, methanol, ethanol, 1-propanol, 2-propanol, , At least one selected from the group consisting of isopentanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, methylene chloride, dimethyl formamide, and dimethyl sulfoxide. Preferably, it may be at least one selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, dichloromethane, chloroform and diethyl ether, and more preferably ethyl acetate.

The solvent may be used in an amount of 1 to 50 times by volume, preferably 5 to 25 times by volume based on the volume of the saccharide.

The step a) may be carried out by dissolving saccharide by adding a solvent or by adding a solvent to a saccharide salt, and then adding an acid to dissolve the saccharide.

At this time, the pH of the acid is adjusted to the mixture of the saccharide salt and the solvent so that the saccharide free acid can be stably dissolved in the solvent phase. The acid may include at least one member selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, and bromic acid. Preferably, it may be at least one member selected from the group consisting of hydrochloric acid, phosphoric acid and acetic acid, more preferably hydrochloric acid.

The solution obtained from the step a) can be further subjected to a process of extraction and concentration if necessary.

Subsequently, in step b), the sodium-containing compound is added to the solution obtained in step a) described above.

In step b) of the present invention, the sodium-containing compound is added to the solution prepared in the above step a) to react with the saccharide to prepare a saccharide monosodium salt.

The sodium-containing compound used in step b) may be selected from the group consisting of sodium 2-ethylhexanoate, sodium chloride, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium acetate, sodium methoxide and sodium ethoxy), and the like. And preferably at least one selected from the group consisting of sodium 2-ethylhexane, sodium hydroxide, sodium carbonate and sodium methoxide.

The sodium-containing compound may be added in an amount of 0.5 to 5 equivalents, preferably 0.8 to 2.0 equivalents based on 1 equivalent of saccharide. If the amount of the sodium-containing compound is within the above range, a saccharide monosodium salt having one equivalent of sodium bonded to one equivalent of saccharide may be prepared.

In addition, if necessary in step b), the reaction can be carried out by further adding a solvent.

The solvent which can be used in step b) is not particularly limited as long as it is miscible with the solvent of step a) and does not inhibit the smooth progress of the reaction. For example, at least one selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, diethyl ether, methanol, ethanol, n-propanol, isopropanol, t-butanol and acetone.

The solution obtained through the step b) may further be subjected to extraction and concentration processes, if necessary.

Subsequently, in the step c), the saccharide is added to the solution obtained in the above step b).

In step c) of the present invention, a saccharide is added to the saccharide monosodium salt prepared by the reaction of the above step b) to prepare a sacbityl conjugate.

The saccharides used in step c) are as described above.

In the step c), the saccharide may be added in an amount of 0.5 to 5 equivalents, preferably 0.8 to 2 equivalents based on 1 equivalent of saccharide. When the amount of the saccharide is within the above range, a sacbituric conjugate in which a saccharide monosodium salt and a saccharide are stably bound can be produced.

Additionally, in step c), if necessary, a further solvent may be added to carry out the reaction, wherein the usable solvent is as described in step b) above.

The solution obtained through the step c) can be further subjected to extraction and concentration processes, if necessary.

Subsequently, step d) separates the solid form of the sacbityl complex from the solution obtained in step c) above.

In the step d) of the present invention, the desired compound in solid form can be isolated from the solution prepared in the above step c) by a conventional method.

For example, the separation may be performed by cooling the solution obtained in the step c) and then precipitating a solid succinyl bitartrate, or adding a precipitation solvent to the solution obtained in the step c) It is possible to precipitate a bit-reel combination.

Specifically, the cooling may be accomplished by cooling the solution prepared in the step c), precipitating the solid naturally and then separating the precipitated solid.

The cooling may be performed at a temperature of -20 to 20 ° C, preferably 0 to 20 ° C. In addition, the cooling can be performed for 1 to 3 hours.

On the other hand, in the separation, the precipitation solvent is added to the solution prepared in the step c), and the mixture is stirred to precipitate a solid, and the precipitated solid is separated to produce a sacbituric complex. At this time, cooling may be further performed as necessary after the precipitation solvent is added.

At this time, the separation can be carried out at a temperature of 0 to 60, preferably 5 to 30, and when cooling, can be carried out under the conditions described above.

The precipitation solvent may be at least one selected from the group consisting of pentane, hexane, heptane, cyclohexane, petroleum ether, and methyl t-butyl ether.

The precipitation solvent may be used in an amount of 5 to 50 times by volume, preferably 5 to 40 times by volume based on the volume of the saccharide.

The product obtained through the above steps a) to d) is subjected to a post-treatment such as washing, recovery, drying and purification according to a conventional method to obtain a high purity sacabityl complex.

The saccharide conjugate of the present invention can be useful for preventing, treating or ameliorating cardiovascular diseases, especially hypertension or heart failure.

Accordingly, the present invention provides a pharmaceutical composition for the prevention and treatment of hypertension or heart failure comprising the above-mentioned sacurtyl complex as an active ingredient.

The pharmaceutical composition of the present invention may further comprise, as an active ingredient, the sacchvitlir conjugate and appropriate carriers, excipients, diluents and the like conventionally used in the production of a pharmaceutical composition.

These carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose , Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

In addition, the pharmaceutical composition of the present invention may be formulated into any pharmaceutical preparation by appropriately adding various pharmaceutically acceptable additives. Such additives may be pharmacologically acceptable or pharmacologically acceptable, and any of them may be used without impairing the object of the present invention. The additive may be a disintegrant, an acidifier, a foaming agent, an artificial sweetener, a flavoring agent, a lubricant, a colorant, a stabilizer, a buffer, an antioxidant, a surfactant, and the like.

Examples of the disintegrators include corn starch, potato starch, calmelose calcium, sodium calomel, and low-substituted hydroxypropylcellulose. Examples of the acidulant include citric acid, tartaric acid, malic acid and the like. Examples of the foaming agent include sodium bicarbonate and the like. Examples of the artificial sweetener include sodium saccharin, potassium glutyltin, aspartame, stevia, and soymatin. Examples of the fragrance include lemon, lemon lime, orange, menthol and the like. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid esters, talc, and stearic acid. Examples of the coloring agent include yellow ferric oxide, red ferric oxide, edible yellow No. 4 and No. 5, edible red No. 3, No. 102, and edible blue No. 3. Examples of the buffer include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, Salts and the like. Examples of the antioxidant include ascorbic acid, sodium nitrite, sodium sulfite, sodium hydrogen sulfite, sodium edetate, erythorbic acid, tocopheryl acetate, tocopherol, butylhydroxyanisole, dibutylhydroxytoluene, have. Examples of the surfactant include sodium lauryl sulfate, polyoxyethylene sorbitan aliphatic ester (polysorbate 80), polyoxyethylene hardened castor oil, and the like.

These additives may be suitably used singly or in combination of two or more.

The pharmaceutical composition of the present invention is characterized by containing saccharide as an active ingredient in an amount of 0.1 to 99% by weight, preferably 0.1 to 95% by weight, more preferably 1 to 70% by weight, based on 100% by weight of the total pharmaceutical composition .

The pharmaceutical compositions according to the present invention may be administered to a patient in an effective amount via a variety of routes, for example, oral or parenteral routes. Preferably, the compositions of the present invention are prepared in an oral dosage form such as capsules, tablets, dispersions and suspensions. The capsule or tablet may be in enteric coated form, or may contain pellets of enteric coated sacbituric conjugate.

The dose of the sacbitil conjugate according to the present invention is usually appropriately selected depending on the pharmaceutical use (indications), but is not particularly limited as long as it is a therapeutically effective amount or a prophylactically effective amount. The typical daily dose of the sacbutyryl conjugate may be from 0.01 mg to 2000 mg / kg, preferably from 0.1 mg to 1000 mg / kg, more preferably from 1 mg to 500 mg / kg on an adult basis. The sacbutyryl conjugate may be administered in single or divided doses per day. However, the actual dosage of the active ingredient should be determined in light of various relevant factors, such as the route of administration, the age, sex and weight of the patient, and the severity of the disease, and accordingly, It does not.

The saccharide complex according to the present invention has improved stability against moisture and heat and is not susceptible to moisture and can be stored at room temperature for a long period of time. In addition, since it is possible to produce the product without the denaturation in the quality of the product in the commercial production, it is suitable for mass production and is efficient, and it is possible to stably provide the saccharide conjugate suitable for the raw material of the pharmaceutical, Prevention or treatment.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the present invention. Such variations and modifications are intended to be within the scope of the appended claims.

Example  And Comparative Example

The respective materials prepared in the following examples and comparative examples were analyzed in the following manner, and the results obtained were described in the respective examples and comparative examples.

(1) X-ray powder diffraction: D2 Phaser X-ray powder diffraction spectrometer (Bruker) was used to measure the Cu-K _{alpha 1} ray (wavelength? = 1.54050?) Respectively.

(2) Purity: High Performance Liquid Chromatography (HPLC) was used to measure the following conditions:

Column: Capcellpak C18 MGII (inner diameter 4.6 mm x length 250 mm, stationary phase particle size 5 um, SHISEIDO)

Detection wavelength: 267 nm

Flow rate: 1.0 ml / min

Mobile phase: acetonitrile: methanol: pH 3.0 buffer = 30: 25: 45 (%, v / v)

Column temperature: 25 캜.

Thereafter, the chemical purity was calculated from all the peak areas except for the solvent peak shown in the chromatogram obtained from the measurement and the peak area of the objective compound.

(3) Water content: Measured using a Karl Fisher titration method.

(4) Sodium content: Ion exchange chromatography (IC) was used to measure the following conditions:

Device: ICS-2100 (Thermo)

Column: Ionpac CS17 (inner diameter 4 mm x length 250 mm, stationary phase particle size 7 um, Thermo)

Flow rate: 1.0 ml / min

Mobile phase: Eluent Generator Cartridge MSA, Thermo

Column temperature: 30 占 폚.

(5) Nuclear Magnetic Resonance (NMR): Measured using a 400 MHz ¹ H-NMR apparatus (Jeol) in a dimethylsulfoxide (DMSO) solvent.

[Example 1] Preparation of sacbityl conjugate (glucose)

5.0 g (11.6 mmol) of saccharide hemicalcium salt and 50 ml of ethyl acetate were added to the reactor, followed by stirring at 25 and 24 ml of 2 N HCl were added. The reaction was stirred for 25 to 15 minutes to give a clear two-phase solution. The organic layer was separated and washed with 60 mL of water. The separated organic layer was concentrated as a colorless solution to prepare an ethyl acetate solution of saccharide free acid.

To the obtained saccharide free acid ethyl acetate solution, 50 ml of methanol was added. To the mixture was added 1.93 g (11.6 mmol) of 2-ethylhexane sodium, and the mixture was stirred for 2 hours while maintaining the internal temperature at 35.

Then, 2.3 g (11.6 mmol) of D - (+) - glucose monohydrate was added to the mixture, followed by stirring overnight at 35 ° C. The mixture was concentrated under reduced pressure, 100 ml of methyl t-butyl ether was added to the concentrate, and the mixture was stirred at room temperature overnight. The resulting solid was collected on a Buchner funnel, washed with 30 ml of methyl t-butyl ether and dried under nitrogen to give 4.02 g (yield: 66.2%) of the desired compound.

The analytical values of the objective compounds thus prepared are as follows:

Purity: 99.9%

Water content: 0.52%

Sodium content: 3.6%

^{1 H-NMR (DMSO-d} 6, 400 MHz): δ 8.28-8.30 (d, 1H), δ 7.21-7.62 (m, 9H), δ 4.87-4.88 (m, 1H), δ 4.22 (m, 1H ), 3.80-3.90 (m, 2H),? 3.95 (m, 1H),? 3.02-3.65 (m, 10H),? 2.98-2.99 (m, 3H),? 1.07 (m, 2H),? 2.05 (m, 2H),? 1.61

The results of XRD analysis of the objective compound thus prepared are shown in Fig.

As shown in Fig. 1, it can be confirmed that the target compound has an amorphous structure.

[Example 2] Preparation of sacbutyr complex (acetonitrile, methanol, heptane)

50 ml of acetonitrile and 5 ml of methanol were added to a solution of saccharide free acid ethyl acetate prepared in the same manner as in Example 1 above. To the reaction mixture was added 1.93 g of 2-ethylhexane sodium, and the mixture was stirred for 2 hours while maintaining the internal temperature at 35.

Then, 2.3 g of D - (+) - glucose monohydrate was added to the mixture, followed by stirring overnight at 35 ° C. The mixture was concentrated under reduced pressure, 100 ml of heptane was added to the concentrate, and the mixture was stirred at room temperature overnight. The resulting solid was collected on a Buchner funnel, washed with 30 ml of heptane, and dried under nitrogen to give the desired compound (3.54 g, yield: 58.3%).

The analytical values of the objective compounds thus prepared are as follows:

Moisture: 0.42%

Sodium content: 3.7%

^The results of ¹ H-NMR and XRD measurements were the same as in Example 1 above.

[Example 3] Preparation of sacbityl conjugate (acetone)

50 ml of acetone was added to a solution of saccharide free acid ethyl acetate prepared in the same manner as in Example 1 above. To the reaction mixture was added 1.93 g of 2-ethylhexane sodium, and the mixture was stirred for 2 hours while maintaining the internal temperature at 35.

Then, 2.3 g of D - (+) - glucose monohydrate was added to the mixture, followed by stirring overnight at 35 ° C. The mixture was concentrated under reduced pressure, 100 ml of methyl t-butyl ether was added to the concentrate, and the mixture was stirred at room temperature overnight. The resulting solid was collected on a Buchner funnel, washed with 30 ml of methyl t-butyl ether and dried under nitrogen to give 3.62 g (yield: 59.5%) of the desired compound.

The analytical values of the objective compounds thus prepared are as follows:

Water content: 0.63%

Sodium content: 3.7%

^The results of ¹ H-NMR and XRD measurements were the same as in Example 1 above.

[Example 4] Preparation of sacbityl conjugate (ethyl acetate)

Ethyl acetate (50 ml) was added to the solution of ethyl acetate of saccharide free acid prepared in the same manner as in Example 1 above. To the reaction mixture was added 1.93 g of 2-ethylhexane sodium, and the mixture was stirred for 2 hours while maintaining the internal temperature at 35.

Then, 2.3 g of D - (+) - glucose monohydrate was added to the mixture, followed by stirring overnight at 35 ° C. The mixture was concentrated under reduced pressure, 100 ml of methyl t-butyl ether was added to the concentrate, and the mixture was stirred at room temperature overnight. The resulting solid was collected on a Buchner funnel, washed with 30 ml of methyl t-butyl ether, and dried under nitrogen to give the desired compound (3.55 g, yield: 58.4%).

The analytical values of the objective compounds thus prepared are as follows:

Moisture: 0.48%

Sodium content: 3.6%

^The results of ¹ H-NMR and XRD measurements were the same as in Example 1 above.

[Example 5] Preparation of sacbutyr complex (ethanol)

50 ml of ethanol was added to a solution of saccharide free acid ethyl acetate prepared in the same manner as in Example 1 above. To the reaction mixture was added 1.93 g of 2-ethylhexane sodium, and the mixture was stirred for 2 hours while maintaining the internal temperature at 35.

Then, 2.3 g of D - (+) - glucose monohydrate was added to the mixture, followed by stirring overnight at 35 ° C. The mixture was concentrated under reduced pressure, 100 ml of methyl t-butyl ether was added to the concentrate, and the mixture was stirred at room temperature overnight. The resulting solid was collected on a Buchner funnel, washed with 30 ml of methyl t-butyl ether, and dried under nitrogen to give 3.79 g (yield: 62.3%) of the desired compound.

The analytical values of the objective compounds thus prepared are as follows:

Moisture: 0.58%

Sodium content: 3.7%

^The results of ¹ H-NMR and XRD measurements were the same as in Example 1 above.

[Example 6] Preparation of sacbutyr complex (isopropanol)

50 ml of isopropanol was added to a solution of saccharide free acid ethyl acetate prepared in the same manner as in Example 1 above. To the reaction mixture was added 1.93 g of 2-ethylhexane sodium, and the mixture was stirred for 2 hours while maintaining the internal temperature at 35.

Then, 2.3 g of D - (+) - glucose monohydrate was added to the mixture, followed by stirring overnight at 35 ° C. The mixture was concentrated under reduced pressure, 10 ml of isopropanol and 100 ml of methyl t-butyl ether were added to the concentrate, and the mixture was stirred at room temperature overnight. The resulting solid was collected on a Buchner funnel, washed with 30 ml of methyl t-butyl ether, and dried under nitrogen to give 3.42 g (yield: 56.3%) of the title compound.

The analytical values of the objective compounds thus prepared are as follows:

Moisture: 0.42%

Sodium content: 3.6%

^The results of ¹ H-NMR and XRD measurements were the same as in Example 1 above.

[Example 7] Preparation of sacbutyr complex (isopropanol, methanol, acetonitrile)

50 ml of isopropanol was added to a solution of saccharide free acid ethyl acetate prepared in the same manner as in Example 1 above. To the reaction mixture was added 1.93 g of 2-ethylhexane sodium, and the mixture was stirred for 2 hours while maintaining the internal temperature at 35.

Then, 2.3 g of D - (+) - glucose monohydrate was added to the mixture, followed by stirring overnight at 35 ° C. The mixture was concentrated under reduced pressure, and 10 ml of methanol, 50 ml of acetonitrile and 100 ml of methyl t-butyl ether were added to the concentrate, and the mixture was stirred at room temperature overnight. The resulting solid was collected on a Buchner funnel, washed with 30 ml of methyl t-butyl ether and dried under nitrogen to give 3.67 g (yield: 60.3%) of the title compound.

The analytical values of the objective compounds thus prepared are as follows:

Moisture: 0.58%

Sodium content: 3.6%

^The results of ¹ H-NMR and XRD measurements were the same as in Example 1 above.

[Example 8] Preparation of sacbityl conjugate (isopropanol)

50 ml of isopropanol was added to a solution of saccharide free acid ethyl acetate prepared in the same manner as in Example 1 above. To the reaction mixture was added 1.93 g of 2-ethylhexane sodium, and the mixture was stirred for 2 hours while maintaining the internal temperature at 35.

Then, 2.3 g of D - (+) - glucose monohydrate was added to the mixture, followed by stirring overnight at 35 ° C. The mixture was concentrated under reduced pressure, 10 ml of isopropanol and 150 ml of methyl t-butyl ether were added to the concentrate, and the mixture was stirred at room temperature overnight. The resulting solid was collected on a Buchner funnel, washed with 30 ml of methyl t-butyl ether and dried under nitrogen to give 4.03 g (yield 66.3%) of the desired compound.

The analytical values of the objective compounds thus prepared are as follows:

Water content: 0.56%

Sodium content: 3.7%

^The results of ¹ H-NMR and XRD measurements were the same as in Example 1 above.

[Example 9] Preparation of sacbityl conjugate (mannitol)

Ethyl acetate (50 ml) was added to the solution of ethyl acetate of saccharide free acid prepared in the same manner as in Example 1 above. To the reaction mixture was added 1.93 g of 2-ethylhexane sodium, and the mixture was stirred for 2 hours while maintaining the internal temperature at 35.

Subsequently, the mixture was concentrated under reduced pressure, 15 ml of methanol was added to the concentrate, and the mixture was stirred at room temperature for 2 hours. 2.1 g of mannitol was dissolved in 10 ml of water, added to the stirred mixture, and stirred at 25 ° C for 2 hours. The resulting solid was collected on a Buchner funnel, washed with 30 ml of methanol and dried under nitrogen to give 4.39 g (yield: 61.4%) of the desired compound.

The analytical values of the objective compounds thus prepared are as follows:

Purity: 99.44%

Sodium content: 4.0%

^{1 H-NMR (DMSO-d} 6, 400 MHz): δ 8.25-8.27 (d, 1H), δ 7.21-7.60 (m, 9H), δ 3.94-3.96 (m, 2H), δ 3.93 (m, 1H 2H),? 2.05 (m, 2H),? 1.72 (m, 2H),? 4.52 (m, 6H),? 3.35-3.55 , 1.09 (m, 3H), 8 1.02 (m, 3H)

[Example 10] Preparation of sacbityl conjugate (sorbitol)

50 ml of methanol was added to a solution of saccharide free acid ethyl acetate prepared in the same manner as in Example 1 above. To the reaction mixture was added 1.93 g of 2-ethylhexane sodium, and the mixture was stirred for 2 hours while maintaining the internal temperature at 35.

Then, 2.1 g of sorbitol was added to the mixture, followed by stirring at 40 DEG C for 2 hours. The mixture was concentrated under reduced pressure, 90 ml of methyl t-butyl ether was added to the concentrate, and the mixture was stirred at room temperature for 2 hours. The resulting solid was collected on a Buchner funnel, washed with 30 ml of methyl t-butyl ether, and dried under nitrogen to obtain 3.37 g (yield: 47.1%) of the desired compound.

[Example 11] Preparation of sacbityl conjugate (lactose)

90 ml of acetonitrile was added to a solution of saccharide free acid ethyl acetate prepared in the same manner as in Example 1 above. 1.93 g of 2-ethylhexane sodium was added to the reaction mixture, and the mixture was stirred for 12 hours while maintaining the internal temperature at 40.

Then, 4.2 g of lactose was added to the mixture, followed by cooling to 0 and stirring for 2 hours. The resulting solid was collected on a Buchner funnel, washed with 30 ml of acetonitrile and dried under nitrogen to give 5.37 g (yield: 59.6%) of the desired compound.

The analytical values of the objective compounds thus prepared are as follows:

Purity: 99.91%

^{1 H-NMR (DMSO-d} 6, 400 MHz): δ 8.42-8.44 (d, 1H), δ 7.23-7.54 (m, 9H), δ 3.22-5.19 (m, 24H), δ 2.95 (m, 1H ), delta 2.55-2.70 (m, 2H), delta 2.13 (m, 2H), delta 1.95-2.05 (m, 2H), delta 1.72 , 3H), [delta] 1.02 (m, 3H)

[Example 12] Preparation of a sacbityl conjugate (fructose)

90 ml of acetonitrile was added to a solution of saccharide free acid ethyl acetate prepared in the same manner as in Example 1 above. 1.93 g of 2-ethylhexane sodium was added to the reaction mixture, and the mixture was stirred for 12 hours while maintaining the internal temperature at 45.

Then 2.1 g of fructose was added to the mixture, followed by stirring at 45 캜 for 2 hours. The mixture was concentrated under reduced pressure, 10 ml of isopropanol and 100 ml of methyl t-butyl ether were added to the concentrate, and the mixture was stirred at room temperature for 2 hours. The resulting solid was collected on a Buchner funnel, washed with 30 ml of methyl t-butyl ether and dried under nitrogen to give 4.27 g (yield: 70.3%) of the title compound.

The analytical values of the objective compounds thus prepared are as follows:

Purity: 99.92%

Sodium content: 3.6%

^{1 H-NMR (DMSO-d} 6, 400 MHz): δ 8.33-8.35 (d, 1H), δ 7.21-7.62 (m, 9H), δ 3.05-3.97 (m, 15H), δ 2.55-2.70 (m (M, 2H),? 2.19 (m, 2H),? 1.95-2.05

[Comparative Example 1] Preparation of sacchbutyral monosodium

The reactor was charged with 5.0 g (12.1 mmol) of saccharide free acid and 35 ml of acetone and stirred. 3.2 ml (6.1 mmol) of 20% sodium carbonate aqueous solution was added to the reaction mixture, followed by stirring at 30 for 2 hours. The reaction mixture was concentrated in vacuo at 40, and the gas was removed at 40 for 1 hour.

Then 60 ml of isopropyl acetate was added to the reaction mixture and stirred at 30 overnight. The resulting solid was filtered, washed with isopropyl acetate, and dried in vacuo at 50 for 4 hours to give 4.25 g (yield: 80.95%) of the desired compound.

The analytical values of the objective compounds thus prepared are as follows:

Purity: 99.89%

Moisture: 0.62%

Sodium content: 5.76%

^{1 H-NMR (DMSO-d} 6, 400 MHz): δ 8.78-8.80 (d, 1H), δ 7.21-7.60 (m, 9H), δ 3.93-3.95 (m, 2H), δ 3.84-3.87 (m , 1.25 (m, 2H), 1.95-2.05 (m, 2H),? 1.72 (m, [delta] 1.07-1.11 (m, 3H), [delta] 1.00-1.02 (m, 3H)

Experimental Example  One. Thermal stability  evaluation

In order to comparatively evaluate the thermal stability of the saccharide conjugate of Example 1 and the saccharide monosodium salt of Comparative Example 1, the compound was placed in a light-tight sealed glass vessel and kept at relative humidity of 75% and 40 for 7 days, The impurity content was measured. The results obtained are shown in Tables 1 and 2 below.

Example 1 water
(%) Variation Impurity content (Max. Impurity)
(weight%) Initial (Initial) 99.90 - 0.04 3 days 99.90 - 0.04 7 days 99.90 - 0.04

Comparative Example 1 water
(%) Variation Impurity content (Max. Impurity)
(weight%) Initial (Initial) 99.84 - 0.10 3 days 99.83 0.01 0.11 7 days 99.81 0.03 0.13

As shown in Tables 1 and 2, the saccharide complex of the present invention exhibited excellent thermal stability as compared with the saccharide monosodium salt of the comparative example.

The analytical results of the compounds prepared in the above-mentioned Examples and Comparative Examples and the results of Experimental Example 1 show that the sacbituric conjugate according to the present invention has improved thermal stability and moisture stability compared to saccharide monosodium salt of the prior art Thus, processability and stability of the preparation are improved, so that it can be provided to a patient as a drug having a more stable and effective pharmacological effect.

Claims (16)

A sacurvitol conjugate of the formula (1) wherein the saccharide is combined with a saccharide:
[Chemical Formula 1]

The method according to claim 1,
The saccharide may be at least one selected from the group consisting of glucose, galactose, fructose, rhamnose, xylose, arabinose, apiose, lactose, sucrose, maltose, lutinose, neohesperidos, soporos, sambu bios, laminaribiose, A sacbutyryl conjugate comprising at least one member selected from the group consisting of glucose, glucose, glucose, glucose, glucosyl neothiepidose, dextran, mannitol, sorbitol, arabitol, glycerol and xylitol. a) dissolving saccharide of the following formula (2) or a salt thereof in a solvent to prepare a solution;
b) adding a sodium-containing compound to the solution obtained in step a);
c) adding a saccharide to the solution obtained in step b); And
d) separating the solid form of the sacchabityl complex from the solution obtained in the step c).
(2)

[Chemical Formula 1]

(In the formula 1,
X is a saccharide,
n is 0.5? n? 3. The method of claim 3,
Wherein the saccharide salt of step a) is selected from the group consisting of a saccharide salt, a saccharide salt, a saccharide hemin sodium salt, a saccharide salt, a saccharide hemicalcium salt and a saccharide hemimarcium salt. , Wherein the saccharide is at least one selected from the group consisting of a saccharide and a saccharide. The method of claim 3,
The solvent of step a) may be selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, diethyl ether, methanol, ethanol, 1-propanol, 2-propanol, Wherein the saccharide is at least one selected from the group consisting of methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, methylene chloride, dichloromethane, chloroform, dimethylformamide and dimethyl sulfoxide. The method of claim 3,
Wherein an acid is further added in the step a). The method according to claim 6,
Wherein the acid comprises at least one member selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, and bromic acid. The method of claim 3,
Wherein the sodium-containing compound in step b) is at least one selected from the group consisting of sodium 2-ethylhexane, sodium chloride, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium acetate, sodium methoxide and sodium ethoxide, A method for manufacturing a bit-reel combination. The method of claim 3,
The saccharide in step c) is selected from the group consisting of glucose, galactose, fructose, rhamnose, xylose, arabinose, apiose, lactose, sucrose, maltose, lutinose, neohesperidos, sophorose, sambucus bios, , At least one selected from the group consisting of glycyrrhizin, glycyrrhizin, glycyrrhizic acid, glycyrrhizic acid, glycyrrhizin, glycyrrhizin, glycyrrhizin, Way. The method of claim 3,
The saccharide of step c) is added in an amount of 0.5 to 5 equivalents based on 1 equivalent of saccharide. The method of claim 3,
The separation of step d) is carried out by cooling the solution obtained in step c) or by adding a precipitation solvent to the solution obtained in step c). 12. The method of claim 11,
Wherein the cooling is carried out at a temperature of from -20 to 20 占 폚. 12. The method of claim 11,
Wherein the precipitation solvent comprises at least one selected from the group consisting of pentane, hexane, heptane, cyclohexane, petroleum ether and methyl t-butyl ether. 12. The method of claim 11,
Wherein said separation is performed at 0 to 60. A pharmaceutical composition for preventing or treating cardiovascular diseases, which comprises the sacchvitlir conjugate according to any one of claims 1 and 2 as an active ingredient. 16. The method of claim 15,
Wherein the cardiovascular disease is hypertension or heart failure.

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