KR20210101164A - Hybrid compounds and preparation method for the same - Google Patents

Abstract

Disclosed in the present invention is a hybrid compound formed by combining valsartan or a pharmaceutically acceptable salt thereof and sacubitril or a pharmaceutically acceptable salt thereof, which can be used as a main component of a pharmaceutical composition that reduces the risk of heart failure through a dual action of improving the protective neurohormonal system of the heart by inhibiting angiotensin receptor and neprilysin enzyme compared to an existing angiotensin receptor (ACE) inhibitor.

Description

Hybrid compound and its manufacturing method

Cross-Citation with Related Applications

The present invention claims the benefit of priority based on Korean Patent Application No. 10-2020-0014828 filed on February 7, 2020 and Korean Patent Application No. 10-2020-0028623 filed on March 6, 2020, , all contents disclosed in the literature of the corresponding Korean patent application are incorporated as a part of this specification.

technical field

The present invention relates to a novel hybrid compound formed by combining two or more compounds exhibiting pharmacological activity, and more particularly, to a compound to which valsartan and sacubitril are bound. More specifically, it relates to a compound in which valsartan and sacubitril are combined as a single hybrid compound for use as a main component of a pharmaceutical composition exhibiting the pharmacological activity of valsartan and sacubitril. Furthermore, the present invention relates to a method for preparing the hybrid compound.

An ingredient that is expected to exert the efficacy of a drug directly or indirectly is called an active ingredient, and a drug containing one active ingredient is called a single agent. On the other hand, a drug containing two or more active ingredients is referred to as a combination drug. Single drug and combination drug have different aspects in the design and approval process of drug formulation. In the case of combination drug, mutual pharmacological action, safety, stability, and blood profile of two or more active ingredients should be looked at in terms of each individual active ingredient. Therefore, a more detailed approach is required in the formulation design and approval process compared to a single drug.

An ingredient that is expected to exert the efficacy of a drug directly or indirectly is called an active ingredient, and a drug containing one active ingredient is called a single agent. On the other hand, a drug containing two or more active ingredients is referred to as a combination drug. Single drug and combination drug have different aspects in the design and approval process of drug formulation. In the case of combination drug, mutual pharmacological action, safety, stability, and blood profile of two or more active ingredients should be looked at in terms of each individual active ingredient. Therefore, a more detailed approach is required in the formulation design and approval process compared to a single drug.

Among pharmaceuticals, ACE inhibitors (angiotensin-converting enzyme inhibitors) have been commercialized as a treatment for heart failure, but a dual action drug that lowers the risk of heart failure by preventing harmful effects on the cardiovascular system and improving the protective neurohormonal system of the heart. there was no Although substances such as ACE inhibitors and endopeptidase may be useful in the control of hypertension, hypertension, a polygenic disease, is not adequately controlled by monotherapy.

In order to satisfy this, Korean Patent Registration No. 10-1549318 describes a composition comprising valsartan and sacubitril as active ingredients and a salt thereof and a pharmaceutically acceptable composition. Dual action compounds and combinations of angiotensin receptor and endopeptidase, in particular angiotensin receptor blocker and neutral endopeptidase extract, double acting molecules linked via a non-covalent bond, such as two having the same or different mode of action on one molecule Dual acting compounds or combinations of active agents are disclosed. Since hypertension is a multifactorial disease, it does not have different mechanisms, so there is a need for an effective combination therapy that does not have harmful side effects. Accordingly, Korean Patent Registration No. 10-1549318 discloses trisodium and 2.5 hydrate of valsartan and sacubitril. This known co-crystal salt is currently sold under the trade name Entresto of Novartis, and in this co-crystal, valsartan contains two acidic groups. It consists of a carboxylic acid and a tetrazole, i.e., a carboxylic acid and a Na cation, a tetrazole and a Na cation, and also a bifunctional chemical with sacubitril. This dual-acting compound, particularly a combination agent, is distinct from a combination obtained by simply physically mixing the two active agents.

Korean Patent No. 10-2149125 discloses a co-amorphous calcium salt different from that of Korean Patent No. 10-1549318. In the background of development in Korean Patent No. 10-2149125, it is reported that trisodium 2.5 hydrate disclosed in Korean Patent No. 10-1549318 has low stability and water solubility and very poor ease of formulation. Therefore, it is known that a co-amorphous calcium salt has been developed to overcome this problem. However, Korean Patent Registration No. 10-2149125 discloses that sacubitril-calcium salt and valstan free acid are combined to use only 0.5 equivalents of calcium, and thus the tetrazole group of valsartan and the amide group of sacubitril are in a stable bonding state. Since it is difficult to exist as a , there is a part different from the development contents disclosed in Korean Patent Registration No. 10-2149125.

In addition, interest in co-crystals has recently increased in the pharmaceutical field. Specifically, it is possible to develop a drug containing two or more active ingredients in the form of a co-crystal (drug-drug co-crystal) as a main ingredient. For example, a phase 2 clinical trial has been conducted on the co-crystal of tramadol and celecoxib, and the European Ministry of Food and Drug Safety (EMA) has published a new approval standard for the co-crystal. In addition to the interest in the drug-drug co-crystal, it is expected that interest will increase in the future for a compound in which a drug-functional component (nutraceuticals) is combined or a compound in a form in which a drug-inorganic salt is combined. Furthermore, interest in a single novel compound in the form obtained by co-precipitation of two or more compounds will also increase.

Korean Patent Registration No. 10-0984939 discloses a combination formulation comprising (i) the AT 1-antagonist valsartan or a pharmaceutically acceptable salt thereof, and (ii) an NEP inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. It relates to a pharmaceutical composition comprising a, specifically, a combination agent comprising valsartan and sacubitril as active ingredients, and for the treatment of hypertension, etc. for medicinal use is disclosed. The technical feature of this patent is that in treating hypertension by co-administration of valsartan and sacubitril, which have been known as antihypertensive drugs, it shows that valsartan or sacubitril has a synergistic therapeutic effect compared to when valsartan or sacubitril is administered alone. .

Republic of Korea Patent No. 10-1549318 Republic of Korea Patent Registration No. 10-2149125 Republic of Korea Patent Registration No. 10-0984939

The problem to be solved in this case patent is a single hybrid compound formed by combining two or more known or unknown drugs, or a single hybrid compound formed by combining a drug and a functional ingredient, or a drug and an inorganic salt. to provide a single hybrid compound. Specifically, the known valsartan and trisodium and 2.5 hydrate crystals of valsartan and sacubitril overcome the ease of preparation due to the low stability and water solubility, and parts that are difficult to form supramolecular sieves of sacubitril calcium salt and valsartan free acid are removed. To provide a hybrid compound formed by combining valsartan or a pharmaceutically acceptable salt thereof with high yield and high purity, and sacubitril or a pharmaceutically acceptable salt thereof. Such compounds have the characteristics of a combination drug in terms of pharmacological activity, but show a pattern similar to that of a single drug in terms of formulation design.

The present invention achieves the above problems by providing two or more drugs as a hybrid compound in which one molecule of valsartan or a pharmaceutically acceptable salt thereof and sacubitril or a pharmaceutically acceptable salt thereof are combined using various binding means. can do. Physicochemical bonding means such as co-precipitation, co-crystal, ionic bonding, non-ionic bonding, covalent bonding, non-covalent bonding and hydrogen bonding may be employed as such means.

The hybrid compound presented in the present invention is used as a main component of a drug. Hybrid compounds are two or more components (active moieties) that exert pharmacological action in the form of a single compound. provides convenience. Furthermore, compared with pharmaceuticals containing each component individually, bioavailability can be increased even in the phase of pharmacological activity, thereby enhancing the therapeutic effect.

1 to 4 are diagrams showing the binding confirmation test results of the valsartan sacubitril magnesium salt hybrid compound using high performance liquid chromatography (HPLC) according to Experimental Example 2.
5 is a view showing the results of the binding confirmation test of the valsartan sacubitril magnesium salt hybrid compound using solubility according to Experimental Example 3.
6 to 9 are diagrams showing the binding confirmation test results of the valsartan sacubitril magnesium salt hybrid compound using a differential scanning calorimeter (DSC) according to Experimental Example 4.
10 is a view showing the results of the binding confirmation test of valsartan magnesium chloride and sacubitril magnesium chloride using liquid chromatography mass spectrometry (LC/MS).

The inventors of the present invention provide two pharmacologically active substances as an effective ingredient for heart failure, two compounds having a dual action, namely, valsartan having two acid groups in the carboxylic acid and tetrazole groups, and sacubitril having one acid group in the carboxyl group. During research and development to develop a formulation of Because it is difficult, it was confirmed that it is difficult to use it pharmaceutically.

Accordingly, the inventors of the present invention generally manufacture each component in a mixing step to increase productivity and patient convenience, but recently two substances have been developed and commercialized as dual-acting compounds or combinations, complexes, prodrugs, etc. Taking this into consideration, various metals or metal compounds are added to the free acid of valsartan and sacubitril or to valsartan chloride and sacubitril chloride to prepare each metal salt, and the two prepared drugs are non-covalently bonded. It was confirmed that it was possible to synthesize a hybrid compound with good solubility and a pharmaceutically acceptable salt linked by a linking moiety with high purity and high yield by becoming a single molecular sieve.

The hybrid compound of valsartan/sacubitril of the present invention is a novel compound that has not been reported so far.

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

hybrid compound

The inclusion of a plurality of ingredients exhibiting pharmacological activity in a single dosage form is often seen in a typical drug development process. In treating a specific disease, it is often more effective to act on multiple targets rather than one target, and furthermore, administering a combination drug rather than administering two or more single agents is advantageous in pharmacoeconomics and helps to reduce side effects. This is because the convenience of taking is improved. However, in the development of the combination drug, the stability problem that occurs between drugs, the difference in solubility of each drug, and the incompatibility between the drugs become the main issues, and therefore, a means to solve this is urgent.

The present invention provides a hybrid compound formed by combining two or more drugs as a means to replace the inclusion of two or more drugs (or a component that exhibits or assists pharmacological action, such as a functional ingredient, hereinafter the same) in one formulation aim to do

Specifically, the present invention provides a hybrid compound formed by combining valsartan or a pharmaceutically acceptable salt thereof and sacubitril or a pharmaceutically acceptable salt thereof.

In the present invention, the term "hybrid compound" refers to a single compound formed by combining two or more drugs or active substances regardless of any binding form, and the physical and chemical properties are distinguished from each drug or active substance to be bound. , and excludes simple physical mixtures. For example, co-precipitation of two or more drugs or active substances, co-crystals, co-amorphous compounds, ionic compounds, non-ionic compounds, covalent compounds, non-covalent compounds and hydrogen-bonded compounds are included. Certain salts, ester compounds, and prodrugs of hybrid compounds will also meet the definition of hybrid compounds as defined herein.

The hybrid compound according to the present invention has increased solubility in water, improved stability, and unique melting properties measured by differential scanning calorimetry (DSC), compared to previously known sodium conjugates, and can be used in manufacturing, storage and It is advantageous in the formulation design stage to provide convenience of the formulation.

In addition, the hybrid compound has an excellent effect in relation to the increase in pharmacological effect and/or alleviation of side effects. In addition, in terms of pharmaceuticals, it has various advantages in the manufacturing process because it is possible to design equivalent to a single drug when developing a formulation. For example, effects such as an increase in solubility of individual drugs constituting the hybrid compound, an increase in bioavailability, and an increase in stability based on intramolecular binding force can be expected.

On the other hand, with respect to a specific drug, there is no established theoretical system as to whether this drug can form a hybrid compound with any other drug. In addition, there is no established theory about whether a specific drug should be used as a free base or in the form of a salt, in the form of a specific crystal or hydrate in order to generate a hybrid compound, and it must be confirmed experimentally. . That is, even if a hybrid compound is not formed between a specific drug in free form and another specific drug in free form, a hybrid compound can be generated when a specific salt of the drug is used. It corresponds to the realm of new technological ideas derived through

In the hybrid compound of the present invention, the active ingredient is valsartan or a pharmaceutically acceptable salt thereof, and sacubitril or a pharmaceutically acceptable salt thereof. It means to include the main ingredient as a substance or a group of substances (including herbal medicines for which pharmacologically active ingredients, etc. are not identified) that are expected to directly or indirectly express the efficacy of the compound.

Specifically, in the present invention, valsartan or a pharmaceutically acceptable salt thereof and sacubitril or a pharmaceutically acceptable salt thereof have overall neutrality, and a weight ratio thereof is 1:1 to 4, preferably It has a weight ratio of 1:1 to 3, most preferably 1:1.

In the present invention, the hybrid compound may be composed of amorphous valsartan and amorphous sacubitril hemicalcium salt, but is not limited thereto.

In the present invention, the term “amorphous” refers to a state in which compound molecules are aggregated without exhibiting a specific crystalline form, as is well known. It is meant to include mixtures in which no crystalline form is observed.

In the present invention, the term "valsartan" refers to N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)[biphenyl-4-yl]methyl]-L- Angiotensin receptor blocker (ARB, angiotensin II antagonist), which has the following structural formula and has the following structural formula, is a polypeptide that increases blood pressure by constricting blood vessels. It is used not only as an antihypertensive agent to relax blood vessels by blocking the action of angiotensin II, which causes blood clots, but also for the treatment of cardiovascular diseases such as heart failure, ischemic heart disease, stroke, kidney disease, and the like.

In the present invention, the term "sacubitril" means 4-{[(2S,4R)-1-(4-biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-fentanyl] Amino}-4-oxobutanoic acid (4-{[(2S,4R)-1-(4-biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid ) and has the following structural formula, sacubitril is usefully used as a therapeutic agent for the cardiovascular system by inhibiting the action of the neprilysin (NEP) enzyme to improve the protective neurohormonal system of the heart.

As described above, the prior literature discloses the advantages of co-administration of valsartan and sacubitril. In particular, Korean Patent No. 10-1549318 discloses a dual action compound in which valsartan and sacubitril are linked through a non-covalent bond. to start However, the compound actually disclosed in the above patent is only a supramolecular complex formed by the bonding of 6 valsartan, 6 sacubitril, and 18 sodium ions and 15 water molecules, which is different from the hybrid compound of the present invention. can

In the present invention, the term "pharmaceutically acceptable salt" refers to a salt in a form that can be used pharmaceutically among salts, which are substances in which cations and anions are bonded by electrostatic attraction, and are usually metal salts, organic salts, and organic salts. salts with bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. For example, as metal salts, alkali metal salts (lithium salt, sodium salt, potassium salt, etc.), alkaline earth metal salt (calcium salt, hemicalcium salt, magnesium salt, barium salt, etc.), alkali metal earth metal salt (sodium calcium salt, potassium salt, etc.) hemicalcium salt, etc.) aluminum salt and the like; Salts with organic bases include triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine , salts with ammonium and the like; Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like; Examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like; Examples of salts with basic amino acids include salts with arginine, lysine, ornithine; The salt with an acidic amino acid may be a salt with aspartic acid, glutamic acid, etc., preferably hemicalcium salt, calcium salt, tripotassium salt, triammonium salt, dipotassium hemicalcium salt, sodium calcium salt, magnesium salt, lithium It may be a salt, but is not limited thereto.

In the present invention, the hybrid compound may be composed of an amorphous valsartan calcium salt and an amorphous sacubitril, but is not limited thereto.

In the present invention, the hybrid compound may be composed of an amorphous valsartan calcium salt and an amorphous sacubitril hemicalcium salt, but is not limited thereto.

In the present invention, the hybrid compound may be composed of a crystalline valsartan calcium salt and an amorphous sacubitril hemicalcium salt, but is not limited thereto.

In the present invention, the hybrid compound may be composed of valsartan sacubitril calcium salt, but is not limited thereto.

In the present invention, the term "valsartan sacubitril calcium salt" means that one molecular sieve is formed by non-covalent bonding between valsartan and sacubitril by calcium.

In the present invention, the hybrid compound may be composed of valsartan sacubitril tripotassium salt, but is not limited thereto.

In the present invention, the term "valsartan sacubitril tripotassium salt" means that one molecular sieve is formed by non-covalent bonding between valsartan and sacubitril by tripotassium.

In the present invention, the hybrid compound may be composed of valsartan sacubitril triammonium salt, but is not limited thereto.

In the present invention, the term "valsartan sacubitril triammonium salt" means that one molecular sieve is formed by non-covalent bonding between valsartan and sacubitril by triammonium.

In the present invention, the hybrid compound may be composed of valsartan sacubitril dipotassium hemicalcium salt, but is not limited thereto.

In the present invention, the term "valsartan sacubitril dipotassium hemicalcium salt" means that one molecular sieve is formed by non-covalent bonding between valsartan and sacubitril by dipotassium hemicalcium.

In the present invention, the hybrid compound may be composed of amorphous valsartan sacubitril sodium calcium salt, but is not limited thereto.

In the present invention, the term "valsartan sacubitril sodium calcium salt" means that one molecular sieve is formed by non-covalent bonding between valsartan and sacubitril by sodium calcium.

In the present invention, the hybrid compound may be composed of valsartan sacubitril magnesium salt, but is not limited thereto.

In the present invention, the term "valsartan sacubitril magnesium salt" means that one molecular sieve is formed by non-covalent bonding between valsartan and sacubitril by magnesium.

Specifically, valsartan sacubitril magnesium salt means that valsartan, sacubitril, and magnesium are included in a ratio of 2:2:3, that is, 1:1:1.5 as shown in Formula 1 above.

[Formula 1]

In addition, one molecule of sacubitril can bind to racemic valsartan or each isomer. Specifically, as shown in Formula 2 below, two molecules of sacubitril and one molecule of magnesium, and two molecules of valsartan and one molecule of magnesium may be combined.

[Formula 2]

Preferably, as shown in Formula 1 above, two molecules of valsartan and two molecules of magnesium, and two molecules of sacubitril and one molecule of magnesium are combined to form a complex by hybridizing with the amide group of sacubitril while the tetrazole group of valsartan has a negative charge. (Complex). The complex provided by such a hybrid bond can be crystallized in a single solvent, and after the solvent is removed, the complex may exist in a solid state, crystalline, partially crystalline, or amorphous. This complex is distinguished from a combination obtained by simply physically mixing, which is already known in Korean Patent No. 10-1549318.

In the present invention, the valsartan sacubitril magnesium salt hybrid compound may exhibit an endothermic onset temperature of 232°C±2 and an endothermic temperature of 238°C±2 in temperature differential scanning calorimetry (DSC) analysis, but is not limited thereto.

In the present invention, the content of magnesium included in the valsartan sacubitril magnesium salt hybrid compound may be 3.7 to 4.1 wt%, more preferably 3.8 to 4.0 wt%, but is not limited thereto.

In the present invention, the moisture content in the valsartan sacubitril magnesium salt hybrid compound may be 4.3 to 5.7 wt%, more preferably 4.5 to 5.5 wt%, but is not limited thereto.

In the present invention, the hybrid compound may be composed of valsartan sacubitril lithium salt, but is not limited thereto.

In the present invention, the term "valsartan sacubitril lithium salt" means that one molecular sieve is formed by non-covalent bonding between valsartan and sacubitril by lithium.

In the present invention, the hybrid compound may consist of valsartan sacubitril free base, but is not limited thereto.

In the present invention, the term "valsartan sacubitril free base" refers to a non-salt form as valsartan sacubitril as distinct from any salt.

The hybrid compound according to the present invention shows excellent stability that can be used as a single main ingredient of a drug, and each hybrid compound is a different compound that shows a clear difference in melting point and XRD pattern from other hybrid compounds.

A pharmaceutical composition for preventing or treating hypertension or heart failure, comprising a valsartan-sacubitril hybrid compound as a main ingredient

The present invention provides a pharmaceutical composition for preventing or treating hypertension or heart failure, comprising a valsartan-sacubitril hybrid compound as a main component.

In the present invention, the term “hypertension” refers to a disease that occurs when an adult 18 years of age or older has a systolic blood pressure of 140 mmHg or more or a diastolic blood pressure of 90 mmHg or more.

In the present invention, the term "heart failure" refers to any condition characterized by impaired heart function due to systolic or diastolic dysfunction, particularly impaired ventricular function (ventricular dysfunction).

In the present invention, the term "prevention" refers to any action of inhibiting or delaying the progression of hypertension or renal failure by administration of the pharmaceutical composition of the present invention comprising the valsartan-sacubitril hybrid compound.

In the present invention, the term "treatment" refers to any action in which hypertension or renal failure disease is improved or beneficially changed by administration of the pharmaceutical composition of the present invention comprising the valsartan-sacubitril hybrid compound.

In the present invention, the term “pharmaceutical composition” refers to a mixture in which the active ingredient of the present invention is mixed with other chemical ingredients such as a diluent or carrier.

The pharmaceutical composition of the present invention may further include suitable carriers, excipients, diluents and the like commonly used in the preparation of pharmaceutical compositions.

Such carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose. , polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, various pharmaceutically acceptable additives may be appropriately added to the pharmaceutical composition of the present invention to be formulated into any pharmaceutical formulation. These additives are pharmaceutically acceptable and pharmacologically acceptable, and any additives may be used within a range that does not impair the purpose of the present invention. The additive may include a disintegrant, a lubricant, a colorant, a surfactant, a stabilizer, and the like, but is not particularly limited thereto.

Examples of the disintegrant include corn starch, potato starch, calmellose calcium, carmellose sodium, and low-substituted hydroxypropyl cellulose. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, talc, and stearic acid. Examples of the colorant include yellow iron trioxide, red iron trioxide, food yellow No. 4 and No. 5, food red No. 3 and No. 102, and food blue No. 3, and the like. Examples of the surfactant include sodium lauryl sulfate, polyoxyethylene sorbitan aliphatic ester (polysorbate 80), and polyoxyethylene hydrogenated castor oil. The above additives may be appropriately used alone or in combination of two or more.

The pharmaceutical composition of the present invention may contain the hybrid compound as a main component 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 pharmaceutical composition. . The pharmaceutical composition according to the present invention may be administered to a patient in an effective amount via various routes, for example, oral or parenteral routes. Preferably, the compositions of the present invention can be prepared in oral dosage forms such as capsules, tablets, dispersions and suspensions. The dosage of the hybrid compound of the present invention is usually appropriately selected depending on the pharmaceutical use (indication), but is not particularly limited as long as it is a therapeutically effective amount or a prophylactically effective amount.

The hybrid compound according to the present invention is suitable for mass production and efficient because it can be stored for a long time due to improved stability, and can be manufactured without alteration in product quality during commercial production.

Method for preparing hybrid compounds

The present invention provides a method for preparing a hybrid compound comprising valsartan or a pharmaceutically acceptable salt thereof and sacubitril or a pharmaceutically acceptable salt thereof, comprising:

(1) determining the form of valsartan capable of forming the hybrid compound and preparing the same;

(2) preparing the same by determining the form of sacubitril capable of forming the hybrid compound;

(3) dissolving the compound prepared in steps (1) and (2); and

(4) precipitating the solid compound from the solution of step (3)

It provides a manufacturing method comprising a.

In the present invention, the form of valsartan capable of forming the hybrid compound may be selected from amorphous valsartan, amorphous valsartan calcium salt, crystalline valsartan calcium salt, valsartan potassium salt, valsartan magnesium salt, and valsartan lithium salt. and is not limited thereto.

In the present invention, the form of sacubitril capable of forming the hybrid compound is amorphous sacubitril, sacubitril cyclohexylamine salt, sacubitril hemicalcium salt, sacubitril magnesium salt, and sacubitril. It may be selected from the group consisting of disodium hemicalcium salt and sacubitril triammonium salt, but is not limited thereto.

In the present invention, the method for preparing the valsartan sacubitril magnesium salt hybrid compound comprises:

(1) preparing valsartan sodium salt;

(2) preparing sacubitril sodium salt;

(3) dissolving valsartan sodium salt and sacubitril sodium salt prepared in steps (1) and (2); and

(4) precipitating the solid compound from the solution of step (3)

A valsartan sacubitril magnesium salt hybrid compound may be prepared, including, but not limited to.

Specifically, the method may further include, but is not limited to, ion-exchanging the valsartan sodium salt prepared in step (1) with a valsartan magnesium salt.

Thereafter, it may be reacted with the sacubitril sodium salt prepared in step (2) to prepare valsartan sacubitril magnesium salt.

When the reaction proceeds as described above, there is an advantage in that purity and yield can be increased compared to the case of using a free base.

Specifically, a magnesium metal ion and a magnesium compound may be used to prepare the valsartan magnesium salt and the sacubitril magnesium salt. Specifically, the magnesium compound may be any one selected from the group consisting of magnesium chloride, magnesium bromide, magnesium hydroxide and magnesium oxide. can be used, but is not limited thereto.

In this case, the amount of magnesium may be used in an amount of 1.5 to 2.0 equivalents, preferably 2.0 equivalents, but is not limited thereto.

As the solvent used for preparing the valsartan magnesium salt and sacubitril magnesium salt, alcohols such as methanol, ethanol, propanol, butanol, etc. and acetone capable of dissolving the sacubitril and valsartan conjugate may be used, and preferably methanol. may be, but is not limited thereto.

Specifically, in the step of precipitating the solid compound, a crystallization solvent may be used, and the crystallization solvent may be any one of a linear chain alkane solvent such as pentane, hexane, heptane, ether, or ethyl acetate, preferably For example, it may be ethyl acetate, but is not limited thereto.

Matters mentioned in the hybrid compound of the present invention and the preparation method of the hybrid compound are equally applied as long as they do not contradict each other.

Hereinafter, preferred examples are presented to help the understanding of the present invention, but the following examples are merely illustrative of the present invention, and various changes and modifications are possible within the scope and spirit of the present invention, and such changes and modifications Specific aspects also fall within the scope of the present invention.

preparation of materials

Materials used in the following Preparation Examples and Examples were prepared by purchasing from Sigma-Aldrich, Merck, and the like.

manufacturing example

<Production Example 1>

Valsartan Calcium Salt tetrahydrate

Preparation of valsartan calcium salt tetrahydrate

4.36 g of valsartan and 1.43 g of a 25-28 wt% aqueous ammonia solution were added to 49 mL of purified water, and the mixture was heated and stirred at 50°C. 7 mL of a 26 wt% aqueous calcium chloride solution was added dropwise to the reaction solution for 15 minutes, stirred at room temperature for 2 hours, filtered, and dried under air circulation at 44° C. for 16 hours to prepare 5.23 g (95% yield) of the title compound did.

Moisture 13.52%

DSC(°C)=157(s),166(w).

<Production Example 2>

Sacubitril Cyclohexylamine Salt

Preparation of sacubitril cyclohexylamine salt

Pour 100 mL of ethyl acetate into a 500 mL flask, and 10.8 g of SB.HCl ((2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride) After adding 4.25 g of succinic anhydride and maintaining the temperature at 15~25℃, dissolve 3.76 g of TEA (triethylamine) in 50 mL of ethyl acetate and add dropwise over 1 hour. When the dropwise addition is complete, the mixture is stirred at room temperature for 1 hour, separated by injecting 100 mL of purified water, and then washed with 100 mL of purified water and 20 mL of 10% aqueous sodium chloride solution.

After the separated solution was concentrated under reduced pressure, 100 mL of ethyl acetate was injected, and 3.54 g of cyclohexylamine was added dropwise, followed by stirring at room temperature for 2 hours.

After filtration and drying, 14.2 g (89.6% yield) of the title compound was prepared.

<Production Example 3>

Sacubitril hemicalcium salt

Preparation of sacubitril hemicalcium salt

1.00 g of the sacubitril cyclohexylamine salt obtained in Preparation Example 2 was added to a mixed solution of 10 mL of purified water and 0.5 mL of isopropyl alcohol, followed by heating and stirring. To the reaction solution, 180 mg of calcium chloride dihydrate was dissolved in 2 mL of purified water, cooled to room temperature, filtered, and dried under reduced pressure at 50° C. for 16 hours to prepare 0.67 g (64% yield) of the title compound.

Moisture 1.99%

XRD analysis result amorphous

<Example 1>

Preparation of sacubitril hemicalcium salt/hydrate

11.5 g of sacubitril hemicalcium salt obtained by the method of Preparation Example 3 was dissolved by heating in 12 mL of methanol, and 70 mL of purified water was added, stirred under reflux for 10 minutes, cooled to 35° C., and stirred for 1 hour more. The resulting solid was filtered, washed with an appropriate amount of purified water, and dried under air circulation at 45° C. for 19 hours to obtain 11.0 g of the title compound.

Moisture 4.99%

DSC(°C)=113(s), 137(w), 204(w).

<Experimental Example 1>

Sacubitril hemicalcium salt and hydrate stability test

1) Packaging method

product name long term, acceleration harsh Example 1 compound PE bag (double packaging) and paper box petridish (open)

2) Storage conditions

division Storage conditions Test period analysis cycle accelerated test 40℃±2℃RH 75±5% 2 weeks Early, 5, 13 days long-term preservation test 25℃±2℃RH 60±5% 2 weeks Early, 5, 13 days harsh test Room temperature, normal pressure (15~25℃) 2 weeks Early, 5, 13 days

3)Result

moisture(%)

division Early 5 days later 13 days later accelerated test 4.79 4.89 4.72 long-term preservation 5.00 4.68 harsh test 5.14 4.95

Purity (area %)

division Early 5 days later 13 days later accelerated test 100 100 100 long-term preservation 100 100 harsh test 100 100

DSC(℃)

division Early 5 days later 13 days later accelerated test 110(s), 136(w), 205(w) 110(s), 136(w), 205(w) 110(s), 137(w), 205(w) long-term preservation 110(s), 137(w), 205(w) 110(s), 136(w), 205(w) harsh test 110(s), 136(w), 205(w) 110(s), 136(w), 205(w)

As a result of a stability test under severe, long-term, and accelerated conditions for 2 weeks under the same conditions as above, it was confirmed that the crystals were stable in moisture, purity, and crystalline form, and Sacubitril Hemicalcium Salt hydrate is 1.25 hydrate.

<Example 2>

Preparation of amorphous valsartan and amorphous sacubitril hemicalcium salt hybrid compound

0.45 g of sacubitril hemicalcium salt.hydrate obtained in Example 1 and 0.44 g of valsartan calcium salt tetrahydrate obtained in Preparation Example 1 were placed in a mixed solution of 2 mL of dichloromethane and 2 mL of ethyl acetate, and heated and stirred until completely dissolved. The solvent was removed under reduced pressure and dried under air circulation at 45° C. for 3 days to obtain 760 mg (88% yield) of the title compound.

moisture 1.62%

Amorphous as a result of XRD analysis

Valsartan : Sacubitril = 1.01:1 (HPLC)

<Example 3>

Method for preparing amorphous valsartan calcium salt and amorphous sacubitril hybrid compound

2.44 g of sacubitril cyclohexylamine salt obtained in Preparation Example 2 was dissolved in 20 mL of ethyl acetate, 2 mL of 2N aqueous hydrochloric acid solution and 15 mL of distilled water were added, followed by vigorous stirring. After stopping the stirring, the organic layer was separated, 2.02 g of valsartan calcium salt tetrahydrate obtained in Preparation Example 1 was added, and 1/3 volume of the obtained solution was taken and concentrated using a rotary evaporator. 7 mL of isopropyl ether was added to the concentrated residue to crystallize, filtered, and dried under air circulation at 45° C. for 16 hours to obtain 0.80 g (90% yield) of the title compound.

Moisture 2.30%

Amorphous as a result of XRD analysis

<Example 4>

Preparation of amorphous valsartan calcium salt and amorphous sacubitril hemicalcium salt hybrid compound

Sacubitril hemicalcium salt.0.91 g obtained in Example 1 and 1.10 g of valsartan calcium salt tetrahydrate obtained in Preparation Example 1 were placed in 5 mL of methyl alcohol and heated until completely dissolved. The completely dissolved hot solution was filtered, the resulting solution was removed by removing the solvent using a vacuum rotary evaporator, and the resulting residue was added to 10 mL of isopropyl acetate, evaporated under reduced pressure twice, 8 mL isopropyl acetate was added, and refluxed for 2 hours. After stirring, the mixture was further stirred at room temperature for 5 hours. The reaction mixture was filtered and dried under air circulation at 45° C. for 15 hours to obtain 1.85 g (97% yield) of the title compound.

Moisture 4.58%

Amorphous as a result of XRD analysis

Valsartan : Sacubitril = 0.96 : 1 (HPLC)

<Example 5>

Preparation of crystalline valsartan calcium salt and amorphous sacubitril hemicalcium salt hybrid compound

0.44 g of valsartan was added to 6 mL of purified water, 0.16 g of 28% aqueous ammonia was added to dissolve it at room temperature, 0.51 g of sacubitril cyclohexylamine salt was added, and the mixture was heated to 50° C. and stirred. To the reaction solution, 0.62 g of calcium chloride dihydrate was dissolved in 2 mL of purified water and added dropwise over 15 minutes, stirred for 1 hour, and further stirred in a 30-35° C. water bath for 2 hours, and the resulting solid was filtered. After washing twice with 1 mL purified water, it was dried under air circulation at 45° C. for 16 hours to obtain 0.89 g (90% yield) of the title compound.

Moisture 8.47%

DSC(°C)=157(s), 168(w).

Valsartan : Sacubitril = 0.98 : 1 (HPLC)

<Example 6>

Preparation of valsartan potassium salt 3.5 hydrate

Add 4.36 g of valsartan to the flask, pour 10 mL of acetone, dissolve 1.38 g of potassium hydroxide in 1 mL of purified water, mix with 10 mL of acetone, and add dropwise over 15 minutes. Upon completion of the dropwise addition, the mixture was stirred at 40° C. for 30 minutes, then stirred at room temperature for 15 hours or more to form crystals, filtered and dried under air circulation at 45° C. for 15 hours or more to prepare 5.02 g (87.1% yield) of the title compound. .

Moisture 11.2%, 11.3%

As a result of XRD analysis, it is a crystalline form

Diffraction angle (2θ value): 4.68, 8.85, 9.26, 11.24, 12.64, 13.86, 14.87, 15.40, 16.45, 17.83, 18.3, 19.00, 21.35, 23.18, 24.01, 25.52, 26.65, 26.99

DSC(℃) : 131.4℃

<Example 7>

Preparation of sacubitril potassium salt

Add 3.06 g of sacubitril to the flask, add 30 mL of ethyl acetate and 12 mL of purified water, and add 3.6 mL of 2N hydrochloric acid solution dropwise. The organic layer is separated, washed with 6 mL of purified water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. When the concentration under reduced pressure is completed, 10 mL of tetrahydrofuran is injected, and 384 mg of potassium carbonate is dissolved in 5 mL of purified water and injected, stirred at 60° C. for 1 hour, and concentrated under reduced pressure. After injecting 20 mL of acetone, it was concentrated under reduced pressure and dried under reduced pressure to prepare 2.18 g (80.6%) of the title compound.

<Example 8>

Preparation of valsartan sacubitril tripotassium salt hybrid compound

Into the flask, 513 mg of valsartan potassium salt 3.5 hydrate, 450 mg of sacubitril potassium salt, 3 mL of ethyl acetate, and heating to 65°C to dissolve. After the temperature is gradually cooled to room temperature, 1 mL of heptane is added dropwise, stirred in a gel state for at least 15 hours, then 3 mL of heptane is added and stirred at room temperature for at least 15 hours. The reaction mixture was filtered and dried under air circulation at 45° C. for 15 hours to obtain 902 g (93.5% yield) of the title compound.

Amorphous as a result of XRD analysis

<Example 9>

Preparation of valsartan sacubitril tripotassium salt hybrid compound

Into the flask, 513 mg of valsartan potassium salt 3.5 hydrate, 450 mg of sacubitril potassium salt, 3 mL of ethyl acetate, and heating to 65°C to dissolve. Concentrate under reduced pressure, inject 5 mL of isopropyl aethate, cool the temperature to 10° C. or less to form a solid, add 5 mL of heptane dropwise, and stir for 15 hours or more. The reaction mixture was filtered and dried under air circulation at 45° C. for 15 hours to obtain 875 mg (90.7% yield) of the title compound.

Amorphous as a result of XRD analysis

<Example 10>

Preparation of valsartan sacubitril triammonium salt hybrid compound

Into the flask, 800 mg of valsartan and 811 mg of sacubitril are added, 10 mL of ethyl acetate is injected, and 1.6 mL of 7N methanolic ammonia solution is added dropwise. After stirring at room temperature for 2 hours, it was concentrated under reduced pressure.

After concentration, 5 mL of ethyl acetate and 5 mL of heptane are injected, and the mixture is stirred for more than 5 hours. The reaction mixture was filtered and dried under air circulation at 45° C. for 15 hours to obtain 765 mg (85.2% yield) of the title compound.

<Example 11>

Preparation of valsartan sacubitril dipotassium hemicalcium salt hybrid compound

Put 579 mg of valsartan dipotassium salt, 457 mg of sacubitril hemicalcium salt, 5 mL of isopropyl acetate, and heat to 60~65℃ to dissolve it. After injecting 5 mL of heptane, the mixture was stirred at room temperature for at least 15 hours to produce a solid, filtered and dried under air circulation at 45° C. for at least 15 hours to prepare 823 mg (90.3% yield) of the title compound.

Amorphous as a result of XRD analysis

DSC(℃) : 233.2℃

<Example 12>

Preparation of valsartan sacubitril dipotassium hemicalcium salt hybrid compound

Put 579 mg of valsartan dipotassium salt, 457 mg of sacubitril hemicalcium salt, 4 mL of acetone, and heat to 30~40℃ to dissolve it. After stirring at room temperature for 15 hours or more, a solid was produced, filtered, and dried under air circulation at 45° C. for 15 hours or more to prepare 720 mg (73.1% yield) of the title compound.

Amorphous as a result of XRD analysis

DSC(℃) : 119.6℃, 231.8℃

<Example 13>

Preparation of amorphous valsartan sacubitril sodium and calcium salt hybrid compound

Add 653 mg of valsartan to 5 mL of acetone, dissolve 120 mg of sodium hydroxide in 1 mL of water, and wash with 2 mL of acetone. 817 mg of valsartan calcium tetrahydrate was added and suspended, and 1.42 g of sacubitril hemicalcium salt 1.25 hydrate was added, washed with 1 mL of methanol to dissolve, concentrated under reduced pressure, and then concentrated under reduced pressure by adding 8 mL of acetonitrile, followed by repeating acetonitrile. Add 8 mL of nitrile, dissolve by heating, precipitate at 50°C, stir at room temperature for 5 hours, filter, wash twice with 1.5 mL of acetonitrile, wash twice with 1.5 mL of diisopropyl ether, air at 44°C for 18 hours Cycle drying to obtain 2.67 g (95.9% yield) of the title compound.

Moisture: 2.20%

XRD: Amorphous

<Example 14>

Preparation of valsartan sacubitril magnesium salt hybrid compound

In a 250 mL three-necked flask, 60 mL of methanol and 10 g of valsartan were added, dissolved at room temperature, and 2.02 g of sodium hydroxide was added to prepare sodium valsartan chloride. To the reaction solution, 4.37 g of magnesium chloride was dissolved in 10 mL of distilled water and stirred under reflux for 1 hour, and 10.14 g of sacubitril sodium salt was added to the reaction solution, followed by reflux and stirring for 1 hour. After the reaction solution was concentrated using a vacuum rotary evaporator, 100 mL of acetone was added to the residue obtained, stirred at 30-35° C. for 1 hour, cooled to room temperature, and filtered to remove inorganic substances. After removing the solvent from the filtrate obtained in the above process using a vacuum rotary evaporator, 100 mL of ethyl acetate was added, stirred under reflux for 1 hour, cooled to 10° C., and filtered. The target product was obtained by vacuum drying at 60° C. for 12 hours with a purity of 99.9%, a yield of 96%, and a ratio of 36.7:63.7 HPLC (19.4 g).

<Example 15>

Preparation of valsartan sacubitril magnesium salt hybrid compound

In a 250 mL three-neck flask, 180 mL of methanol and 30 g of valsartan were added, dissolved at room temperature, and 6.06 g of sodium hydroxide was added to prepare sodium valsartan chloride. To the reaction solution, 13.11 g of magnesium chloride was dissolved in 30 mL of distilled water and stirred under reflux for 1 hour, and 30.42 g of sacubitril sodium salt was added to the reaction solution, followed by reflux stirring for 1 hour. After the reaction solution was concentrated using a reduced pressure rotary evaporator, 150 mL of acetone was added to the obtained residue, followed by azeotropic concentration using a reduced pressure rotary evaporator. 300 ml of acetone was added to the obtained residue, stirred at 30-35° C. for 1 hour, and then cooled to room temperature to remove inorganic substances through a filtration process. To the filtrate obtained in the above process, the solvent was removed using a vacuum rotary evaporator, 300 ml of ethyl acetate was added, the mixture was stirred under reflux for 1 hour, and the mixture was cooled to 5° C. and filtered. It was vacuum dried at 60° C. for 12 hours to obtain a target product having a purity of 99.9%, a yield of 98%, and a ratio of HPLC 37.0:63.0 (59.4 g).

<Example 16>

Preparation of valsartan sacubitril magnesium salt hybrid compound

To a 250 mL three-neck flask, 50 mL of methanol and 10 g of valsartan were added, dissolved at room temperature, and 1.93 g of sodium hydroxide was added to prepare sodium valsartan chloride. To the reaction solution, 2.84 g of magnesium chloride was dissolved in 10 mL of distilled water and added thereto, followed by stirring under reflux for 1 hour to prepare valsartan magnesium salt. In a separate 250ml three-neck flask, 50ml of methanol and 10.15g of sacubitril sodium were added, dissolved at room temperature, and 1.56g of magnesium chloride was dissolved in 7ml of distilled water, stirred under reflux for 1 hour, and added to the prepared valsartan magnesium salt reaction solution. was added and refluxed for 2 hours. The reaction solution was concentrated using a reduced pressure rotary evaporator, and 50 mL of acetone was added to the obtained residue, followed by azeotropic concentration using a reduced pressure rotary evaporator. 100 ml of acetone was added to the obtained residue, stirred at 30-35° C. for 1 hour, and then cooled to room temperature to remove inorganic substances through a filtration process. To the filtrate obtained in the above process, the solvent was removed using a vacuum rotary evaporator, 100 mL of ethyl acetate was added, the mixture was stirred under reflux for 1 hour, and the mixture was cooled to 5°C and filtered. It was vacuum dried at 60° C. for 12 hours to obtain a target product having a purity of 99.9%, a yield of 98%, and a ratio of HPLC 36.1:63.9 (19.8 g).

<Experimental Example 2>

Binding confirmation test of valsartan sacubitril magnesium salt hybrid compound using high performance liquid chromatography (HPLC)

The valsartan sacubitril magnesium salt crystals obtained in Examples 14 to 16 in a single solvent were analyzed by HPLC to confirm that the ratio of valsartan to sacubitril was 1:1. A standard of valsartan free acid and sacubitril sodium salt was dissolved at a molecular weight ratio of 1:1 and detected at a wavelength of 254 nm. As a result, a peak area value of about 37:63 to 36:64 was obtained, and the results were carried out under the same HPLC conditions. As a result of checking the ratio of the target product obtained in Examples 14 to 16, it was confirmed that a bond was formed in a 1:1 ratio as shown in FIGS. 1 to 4 (see FIGS. 1 to 4 ).

<Experimental Example 3>

Binding confirmation test of valsartan sacubitril magnesium salt hybrid compound using solubility

Hybrid bonding was confirmed by a solubility test in ethyl acetate, a crystallization solvent used in preparing the valsartan sacubitril magnesium salt hybrid compound according to Example 14. As a result of preparing valsartan magnesium chloride and sacubitril magnesium chloride, respectively, and performing a solubility test in ethyl acetate, it was confirmed that sacubitril magnesium chloride was well dissolved in ethyl acetate. As a result of the solubility, sacubitril magnesium chloride and valsartan magnesium chloride became a new bonding state, and the two compounds in ethyl acetate were crystallized into one molecular sieve rather than fractionally crystallized, resulting in a hybrid compound with a new solubility in a 1:1 ratio. was confirmed (see FIG. 5).

<Experimental Example 4>

Binding confirmation test of valsartan sacubitril magnesium salt hybrid compound using differential scanning calorimetry (DSC)

Melting values of each of the prepared valsartan magnesium chloride and sacubitril magnesium chloride were measured using a differential scanning calorimeter, and the physical mixture of the two materials and the valsartan sacubitril magnesium salt hybrid compound prepared by <Example 14> By comparing the calorific value of , a hybrid compound having a new calorific value was identified (see FIGS. 6 to 9 ).

<Experimental Example 5>

Binding Confirmation Test of Valsartan Magnesium Chloride and Sacubitril Magnesium Chloride Using Liquid Chromatography Mass Spectrometry (LC/MS)

The mass when the co-crystal was formed was confirmed using liquid chromatography mass spectrometry. The exact mass value of 1759.77 was also confirmed from the actual liquid chromatography mass spectrometry value to confirm the hybrid bonding of valsartan magnesium chloride and sacubitril magnesium chloride according to <Example 14> (see FIG. 10 ).

<Comparative Example 1>

Combination review of sacubitril magnesium chloride and valsartan free acid

When the tetrazole end group of valsartan does not have a negative charge, it was confirmed whether it was bound to sacubitril magnesium chloride as follows.

Add 60 mL of methanol and 10 g of valsartan to a 250 mL three-neck flask, dissolve at room temperature, dissolve 2.2 g of magnesium chloride in 10 mL of distilled water to the reaction solution, add it, stir under reflux for 1 hour, and add Sacubitril to the same reaction solution After adding 10.14 g of sodium salt, the mixture was stirred under reflux for 1 hour. After the reaction solution was concentrated using a vacuum rotary evaporator, 100 mL of acetone was added to the residue obtained, stirred at 30-35° C. for 1 hour, cooled to room temperature, and filtered to remove inorganic substances. After removing the solvent from the filtrate obtained in the above process using a reduced pressure rotary evaporator, 100 mL of ethyl acetate was added, stirred under reflux for 1 hour, and cooled to 10° C., but crystals were not formed and the target product could not be obtained.

<Comparative Example 2>

Joint amorphous production of sacubitril calcium/valsartan according to the embodiment of Korean Patent Registration No. 10-2149125

After adding 10 g of sacubitril calcium and 300 mL of methanol, it was dissolved by stirring at room temperature for 20 minutes. Thereafter, 1.2 equivalents of valsartan was added and dissolved while stirring for 30 minutes. Then, all methanol was evaporated using a concentrator until crystals were precipitated. And according to Korean Patent Registration No. 10-2149125, 50 mL of ethyl acetate was added to proceed with crystallization, but all were dissolved and no crystals were obtained.

The hybrid compound according to the present invention can be used as a main component of a pharmaceutical composition for the treatment and prevention of chronic heart failure.

Claims (20)

A hybrid compound formed by combining valsartan or a pharmaceutically acceptable salt thereof and sacubitril or a pharmaceutically acceptable salt thereof. The hybrid compound according to claim 1, comprising amorphous valsartan and amorphous sacubitril hemicalcium salt. The hybrid compound according to claim 1, comprising an amorphous valsartan calcium salt and an amorphous sacubitril. The hybrid compound according to claim 1, comprising an amorphous valsartan calcium salt and an amorphous sacubitril hemicalcium salt. The hybrid compound according to claim 1, comprising crystalline valsartan calcium salt and amorphous sacubitril hemicalcium salt. The hybrid compound according to claim 1, comprising valsartan sacubitril calcium salt. The hybrid compound according to claim 1, comprising valsartan sacubitril tripotassium salt. The hybrid compound according to claim 1, comprising valsartan sacubitril triammonium salt. The hybrid compound according to claim 1, comprising valsartan sacubitril dipotassium hemicalcium salt. The hybrid compound according to claim 1, comprising amorphous valsartan sacubitril sodium calcium salt. The hybrid compound according to claim 1, comprising valsartan sacubitril magnesium salt. The hybrid compound according to claim 1, comprising valsartan sacubitril lithium salt. The hybrid compound according to claim 1, comprising valsartan sacubitril free base. The hybrid compound according to claim 11, wherein the valsartan sacubitril magnesium salt hybrid compound is represented by the following formula (1):
[Formula 1]

The hybrid compound according to claim 11, wherein the valsartan sacubitril magnesium salt hybrid compound exhibits an endothermic onset temperature of 232°C±2 and an endothermic temperature of 238°C±2 in temperature differential scanning calorimetry (DSC) analysis. The hybrid compound according to claim 11, wherein the magnesium content is 3.7 to 4.1 wt%. The hybrid compound according to claim 11, wherein the moisture content is 4.3 to 5.7 wt%. A method for preparing a hybrid compound comprising the combination of valsartan or a pharmaceutically acceptable salt thereof according to claim 1 and sacubitril or a pharmaceutically acceptable salt thereof, comprising:
(1) determining the form of valsartan capable of forming the hybrid compound and preparing the same;
(2) preparing the same by determining the form of sacubitril capable of forming the hybrid compound;
(3) dissolving the compound prepared in steps (1) and (2); and
(4) precipitating the solid compound from the solution of step (3)
A manufacturing method comprising a. 19. The method of claim 18, wherein the form of valsartan capable of forming the hybrid compound is selected from amorphous valsartan, amorphous valsartan calcium salt, crystalline valsartan calcium salt, valsartan potassium salt, valsartan magnesium salt and valsartan lithium salt. Characterized by the manufacturing method. The method according to claim 18, wherein the form of sacubitril capable of forming the hybrid compound is amorphous sacubitril, sacubitril cyclohexylamine salt, sacubitril hemicalcium salt, sacubitril magnesium salt, and sacubit. A production method, characterized in that it is selected from the group consisting of reel disodium hemicalcium salt and sacubitril triammonium salt.

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