WO2019170135A1 - Medicine composition preparation method - Google Patents

Abstract

The present invention provides a medicine composition preparation method, comprising: (1) taking a first active component, a second active component, a first ingredient and a second ingredient; (2) mixing the first active component, the second active component and the first ingredient to disperse the first active component and the second active component in the first ingredient added therein to obtain a first mixture; (3) preparing the first mixture by adopting dry granulation to obtain a first particle; and (4) adding the second ingredient into the first particle by means of additional method, and mixing to obtain a second mixture.

Description

Method for preparing pharmaceutical composition

This application claims priority to the prior application of the patent application No. 201101196583.8, filed on March 9, 2018, to the Chinese National Intellectual Property Office, entitled "Preparation of Pharmaceutical Compositions". The entire contents of this prior application are incorporated herein by reference.

Technical field

The invention belongs to the field of medicine, and in particular relates to a preparation method of a pharmaceutical composition.

Background technique

Cardiovascular disease, also known as circulatory disease, refers to a series of diseases involving the circulatory system. The circulatory system mainly includes the heart and blood vessels (arteries, veins, and microvessels). According to statistics, cardiovascular disease is the number one cause of death worldwide, with more deaths from cardiovascular disease each year than any other cause of death. Common cardiovascular diseases include: hypertension, heart failure, coronary heart disease, heart disease, atherosclerosis, angina pectoris, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmia, housing Tremor, cardiac fibrosis, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae. Cardiovascular diseases generally have similar causes, processes, and treatments. Most cardiovascular diseases can be prevented by addressing risk factors such as tobacco use, unhealthy diet, obesity, high blood pressure, diabetes, and elevated blood lipids.

The World Health Organization believes that a combination of drugs, such as cholesterol-lowering statins and blood pressure lowering drugs, as well as aspirin, can significantly reduce the risk of cardiovascular recurrence or death. However, any combination of cardiovascular disease drugs with different mechanisms of action does not necessarily have a beneficial effect. Therefore, the development of a pharmaceutical composition that can exert a combined therapeutic effect may provide a more effective control effect on cardiovascular diseases.

Neutral endopeptidase (NEP, also known as neutral endopeptidase) is a zinc metalloproteinase on the surface of endothelial cells. Inhibition of NEP can increase atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). ), the levels of C-type natriuretic peptide (CNP), bradykinin and adrenomedullin, so NEP inhibitors can play a role in diuresis, vasodilation, improvement of endothelial function, and inhibition of vascular smooth muscle cell proliferation under pathological conditions, thereby Improve vascular hemodynamics, prevent atherosclerosis, and delay the progression of heart failure.

Angiotensin II (Ang II) is an important regulator of the regulation of humoral homeostasis in the body, involving blood pressure, electrolyte balance, etc. A large number of literatures have confirmed that Ang II is in hypertension, arterial disease, cardiac hypertrophy, heart failure and diabetes. The pathogenesis of kidney disease plays a major role. Because the abnormal increase of Ang II level is directly related to the occurrence and development of hypertension, cardiac hypertrophy, heart failure, etc., blocking the binding of Ang II to its specific receptor can protect the heart and blood vessels, and the blood vessels are tight. Angiotensin Receptor Blockers (ARB) have been proven in many randomized clinical trials to reduce the risk of cardiovascular mortality and morbidity. ARB drugs have been widely used in hypertension abroad. And other prevention and treatment of heart and kidney diseases, the current clinical use of ARB can be divided into two categories according to the structure: (1) biphenyl tetrazolium, including losartan (losartan), valsartan (valsartan), irbesartan (irbesartan), candesartan cilexetil and azsarartan medoxomil; (2) non-biphenyltetrazolium, including eprosartan and telmisartan ).

Chinese patent application CN1615134A discloses a pharmaceutical composition comprising valsartan or a pharmaceutically acceptable salt thereof and a NEP inhibitor or a pharmaceutically acceptable salt thereof; Chinese patent application CN105693543A discloses a Sacobitril (AHU 377) comprising a NEP inhibitor. , CAS No. 149709-62-6) salt and medicinal adjuvants and combinations of AT1 receptor antagonists such as losartan, eprosartan, valsartan, irbesartan, etc. or a pharmaceutically acceptable salt thereof Chinese patent application CN105837464A discloses a NEP inhibitor containing sacuron and sodium medicinal excipients and other active ingredients such as losartan, eprosartan, valsartan, irbesartan, etc. or a pharmaceutically acceptable salt thereof Pharmaceutical composition.

The Chinese Patent Application Publication No. CN103709154A discloses for the first time a compound of the formula (I):

The above compound is a sultan drug coupled with ligustrazine or a NO donor, and is a prodrug of angiotensin II receptor antagonist azilsartan (TAK-536), which releases hydroxyprosin in vivo or NO, thus effective synergy with azilsartan, enhance antihypertensive effect, has a certain heart rate reduction effect, reduce adverse reactions, and has an ideal protective effect on patients' heart and kidney. Applicants have found in further studies that the potassium salt of the compound of formula (I), ie the compound of the formula (II) below, has better solubility, higher bioavailability, and is more potent and longer-lasting. The pressure effect has a more obvious and lasting effect of lowering heart rate, and has high safety, and has an ideal protective effect on the heart and kidney function of the patient, and can be used for preventing and/or treating hypertension, chronic heart failure, diabetic nephropathy and the like.

However, Applicants have found in further formulation process studies that it is difficult to prepare a neutral endopeptidase and a compound of formula (I) for use in the preparation of a pharmaceutical composition using an existing process such as a fluidized bed process. A pharmaceutical composition product having good release properties.

Summary of the invention

In order to improve the above technical problems, the present invention provides a method for preparing a pharmaceutical composition, comprising:

(1) taking a first active component, a second active component, a first auxiliary component and a second auxiliary material;

(2) mixing the first active component, the second active component, and the first adjuvant to disperse the first active component and the second active component in an incorporation In an excipient to obtain a first mixture;

(3) preparing the first mixture by dry granulation to obtain a first granule;

(4) adding a second auxiliary material to the first particles by an external addition method, and mixing to obtain a second mixture;

And optionally, with or without the addition of a third adjuvant in steps (2) and/or (4);

among them,

The first active component is at least one selected from the group consisting of a neutral endopeptidase inhibitor and a precursor thereof, an active metabolite, a stereoisomer, a pharmaceutically acceptable salt, a prodrug, and a solvate;

The second active component is at least one selected from the group consisting of a compound represented by the following formula (I) or a precursor thereof, an active metabolite, a stereoisomer, a pharmaceutically acceptable salt, a prodrug and a solvate:

或者

Where R represents

or

Each a is the same or different and is independently selected from 0, 1, 2, 3, 4, 5 or 6;

(CH ₂) _nO(CH ₂) _m、

芳基或杂芳基，其中

中的C _b、C _c分别代表包含b或c个碳原子的烷基；b、c相同或不同，彼此独立地选自0、1、2、3、4、5或6，其中(CH ₂) _nO(CH ₂) _m中的n、m相同或不同，彼此独立地选自1、2、3、4、5或6； R ₁ represents a substituted or unsubstituted group: C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl,

(CH ₂ ) _n O(CH ₂ ) _m ,

Aryl or heteroaryl, wherein

Wherein C _b and C _c represent an alkyl group each containing b or c carbon atoms; b and c are the same or different and are independently selected from each other, 0, 1, ₂ , 3, 4, 5 or 6, wherein (CH _{2 n} , _m in _n O (CH ₂ ) _m is the same or different, independently selected from each other, 1, 2, 3, 4, 5 or 6;

R ₂ represents hydrogen, halogen, nitro, cyano, or a substituted or unsubstituted group: C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkylsulfonylamino , arylsulfonylamino, heteroarylsulfonylamino, aminosulfonyl, amino;

芳基、杂芳基，其中

中的b、c代表烷基链的碳原子个数，独立地选自0、1、2、3、4、5或6； R ₃ represents a group which is absent or substituted or unsubstituted: C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₂ -C ₈ alkoxy, C ₂ -C ₈ alkyne Base, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl,

Aryl, heteroaryl, wherein

Wherein b and c represent the number of carbon atoms of the alkyl chain, independently selected from 0, 1, 2, 3, 4, 5 or 6;

R ₄ represents a cyano group, or a substituted or unsubstituted group of an aryl group, an arylsulfonyl group, a heteroaryl group, a C ₁ -C ₈ alkoxy group, a C ₁ -C ₈ nitrate ester (-C ₁ -C) _8- alkyl-ONO ₂ ), C ₁ -C ₈ alkyl;

(CH ₂) _nO(CH ₂) _mCH ₃，其中R ₃、R ₄、a、m、n彼此独立地具有如上所述的定义； R ₅ represents a cyano group, or a substituted or unsubstituted group: aryl, heteroaryl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ nitrate, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ alkynyl,

(CH ₂ ) _n O(CH ₂ ) _m CH ₃ , wherein R ₃ , R ₄ , a, m, n independently of each other have the definitions as described above;

R ₆ and R ₇ independently represent hydrogen, unsubstituted or substituted C ₁ -C ₈ alkoxy or C ₁ -C ₈ alkyl;

R ₈ and R ₉ independently represent hydrogen, unsubstituted or substituted C ₁ -C ₈ alkoxy, C ₁ -C ₈ nitrate or C ₁ -C ₈ alkyl;

The first auxiliary material is selected from at least one of a filler, a disintegrant, and a lubricant;

The second auxiliary material is selected from at least one of a disintegrant and a lubricant;

The third adjuvant is selected from at least one of, but not limited to, an auxiliary lipid, a glidant, a sweetener, a flavoring agent, a preservative, an antioxidant, a colorant, and a foaming agent.

According to an exemplary embodiment of the present invention, the neutral endopeptidase inhibitor or the pharmaceutically acceptable salt of the compound of the formula (I) is the same or different and is independently selected from Na, K or an ammonium salt (eg, The addition salt of NH ₃ ); the neutral endopeptidase inhibitor or the pharmaceutically acceptable prodrug of the compound of formula (I) is the same or different and is independently selected from the group consisting of, but not limited to, methyl ester and ethyl ester. , propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester;

According to an embodiment of the invention, the first active component is selected from at least one of the following compounds, pharmaceutically acceptable salts, prodrugs or solvates thereof:

(S)-(2-biphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethylamino)methylphosphonic acid,

(S)-5-(N-(2-(phosphonomethyl-amino)-3-(4-biphenyl)-propionyl)-2-aminoethyl)tetrazole,

(±) N-(1-oxo-2-indolyl-3-phenylpropionyl)glycine,

N-((2S)-2-(4-biphenylmethyl)-4-carboxy-5-phenoxypentanoyl)glycine,

N-(α-rhamnopyranosylphosphonamide)-L-leucine-L-tryptophan,

N-[N-[(L)-1-carboxy-2-phenylethyl]-L-phenylalanyl]-(R)-alanine,

N-[N-[((1S)-carboxy-2-phenyl)ethyl]-(S)-phenylalanyl]-β-alanine,

N-(S)-[3-mercapto-2-(2-methylphenyl)propanoyl]-(S)-2-methoxy-(R)-alanine,

3-[1,1'-biphenyl]-4-yl-N-[diphenoxyphosphinyl)-methyl]-L-alanyl-β-alanine,

N-(1-(N-hydroxycarbamoyl-methyl)-1-cyclopentanecarbonyl)-L-phenylalanine,

N-[2-mercaptomethyl-3-phenyl-propionyl]-3-aminobenzoic acid,

4-[[2-(indolylmethyl)-1-oxo-3-phenylpropyl]amino]benzoic acid,

N-[2-acetylthiomethyl-3-phenyl-propionyl]-3-aminobenzoic acid,

N-[2-mercaptomethyl-3-(2-methylphenyl)-propionyl]-methionine,

N-(3-phenyl-2-(fluorenylmethyl)-propionyl)-(S)-4-(methylindenyl)-methionine,

N-[1-(2-carboxy-4-phenylbutyl)-cyclopentanecarbonyl]-(S)-isoserine,

N-[2(S)-nonylmethyl-3-(2-methylphenyl)propanoyl]-(S)-isoserine,

N-(1-(3-(N-tert-Butoxycarbonyl-(S)-prolylamino)-2(S)-tert-butoxy-carbonylpropyl)cyclopentanecarbonyl)-O-benzyl -(S)-serine,

3(S)-[2-(acetylthiomethyl)-3-phenyl-propionyl]amino-ε-caprolactam,

N-[1-(acetylthiomethyl)-cyclopentylcarbonyl]-(S)-methionine,

N-[2-acetylthiomethyl-3-(2-methyl-phenyl)propanoyl]-methionine,

N-[2(S)-nonylmethyl-3-(2-methylphenyl)-propionyl]methionine,

N-[2-(indolylmethyl)-1-oxo-3-phenylpropyl]-β-alanine,

7-[[2-(indolylmethyl)-1-oxo-3-phenylpropyl]amino]-heptanoic acid,

N-[N-[1(S)-carboxy-3-phenylpropyl]-(S)-phenylalanyl]-(S)-isoserine,

N-[1-[[1(S)-carbonyl-3-phenylpropyl]amino]-cyclopentylcarbonyl]-(S)-isoserine,

N-[1-[[1(S)-benzyloxycarbonyl-3-phenylpropyl]amino]-cyclopentylcarbonyl]-(S)-isoserine,

N-[N-[(L)-[1-[(2,2-Dimethyl-1,3-dioxolan-4-yl)-methoxy]carbonyl]-2-phenylethyl ]-L-phenylalanyl]-(R)-alanine,

N-(2-carboxy-4-thienyl)-3-indolyl-2-benzylpropanamide,

2-(2-mercaptomethyl-3-phenylpropionylamino)thiazole-4-ylcarboxylic acid,

(L)-(1-((2,2-Dimethyl-1,3-dioxolan-4-yl)-methoxy)carbonyl)-2-phenylethyl)-L-phenylpropanoid Aminoacyl-β-alanine,

Cis-4-[[[1-[2-carboxy-3-(2-methoxyethoxy)propyl]-cyclopentyl]carbonyl]amino]-cyclohexanecarboxylic acid,

3-(1-[6-endo-hydroxymethylbicyclo[2,2,1]heptane-2-exo-carbamoyl]cyclopentyl)-2-(2-methoxyethyl)propane acid,

3-[1-(cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-r-1-carbamoyl)cyclopentyl]-2S-(2-methoxyethoxy-methyl)propionic acid ,

(S)-cis-4-[1-[2-(5-indanyloxy-carbonyl)-3-(2-methoxyethoxy)propyl]-1-cyclopentanoylamino] 1-cyclohexanecarboxylic acid,

1,1'-[dithiobis-[2(S)-(2-methylbenzyl)-1-oxo-3,1-propylene]]-bis-(S)-isoserine,

1,1'-[Dithiobis-[2(S)-(2-methylbenzyl)-1-oxo-3,1-propylene]]-bis-(S)-methylthioamide acid,

4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) Amino)-4-oxobutyric acid,

N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutyric acid.

According to an embodiment of the invention, the first active component is selected from at least one of the following compounds:

N-[1-(acetylthiomethyl)-cyclopentylcarbonyl]-(S)-methionine ethyl ester,

N-[2-acetylthiomethyl-3-(2-methyl-phenyl)propanoyl]-methionine ethyl ester,

N-(1-(3-(N-tert-Butoxycarbonyl-(S)-prolylamino)-2(S)-tert-butoxy-carbonylpropyl)cyclopentanecarbonyl)-O-benzyl -(S)-serine methyl ester,

3(S)-[2-(acetylthiomethyl)-3-phenyl-propionyl]amino-ε-caprolactam,

4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) Amino)-4-oxobutyric acid (AHU 377 or Shakubis),

N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutyric acid,

N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutyrate,

N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutyrate,

4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) Ethylamino-4-oxobutyric acid ethyl ester (AHU 377 ethyl ester or sarbuterol ethyl ester),

4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) Sodium amino)-4-oxobutyrate (AHU 377Na or sulphur sodium),

4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) Potassium amino)-4-oxobutanoate (AHU 377K or Shakubit potassium),

4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) Amido)-4-oxobutyric acid ammonium (AHU 377 ammonium salt or sarbuteramine ammonium salt).

For example, the first active component is selected from the group consisting of AHU 377, AHU 377 ethyl ester, AHU 377Na, AHU 377 ammonium salt, AHU 377K, N-(3-carboxy-1-oxopropyl)-(4S)-pair -Phenylphenylmethyl)-4-amino-2R-methylbutyric acid, N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4 -Amino-2R-methylbutyrate, N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutyric acid Potassium or 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2- Amido)amino-4-oxobutanoic acid ammonium.

According to an embodiment of the present invention, the second active component is a K salt selected from the compound of the formula (I), for example, a compound represented by the following formula (II):

Where R has the definitions described above;

As an example, the K salt of the compound of formula (I) is selected from the structures shown in the formula:

According to an embodiment of the present invention, the filler in the first adjuvant is selected from the group consisting of starch, lactose, lactose monohydrate, cellulose lactose, pregelatinized starch, sucrose, mannitol, sorbitol, calcium phosphate, dextrin, micro At least one of crystalline cellulose, calcium hydrogen phosphate, mannitol-starch composite; for example, the filler is selected from at least one of microcrystalline cellulose and mannitol.

According to an embodiment of the present invention, the disintegrant in the first adjuvant is selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, methylcellulose, low-substituted hydroxypropyl At least one of a base cellulose, crospovidone, and chitosan; for example, the disintegrant is selected from at least one of croscarmellose sodium and crospovidone.

According to an embodiment of the present invention, the lubricant in the first auxiliary material is selected from the group consisting of magnesium stearate, colloidal silica, talc, sodium lauryl sulfate, calcium stearate, and polyethylene glycol 4000. At least one of polyethylene glycol 6000, sodium stearyl fumarate, glyceryl monostearate, hydrogenated vegetable oil; for example, the lubricant is selected from at least magnesium stearate and colloidal silica One.

According to an embodiment of the present invention, the disintegrant in the second adjuvant is selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, methylcellulose, low-substituted hydroxypropyl At least one of a base cellulose, crospovidone, and chitosan; for example, the disintegrant is selected from at least one of croscarmellose sodium and crospovidone.

According to an embodiment of the present invention, the lubricant in the second auxiliary material is selected from the group consisting of magnesium stearate, colloidal silica, talc, sodium lauryl sulfate, calcium stearate, and polyethylene glycol 4000. At least one of polyethylene glycol 6000, sodium stearyl fumarate, glyceryl monostearate, hydrogenated vegetable oil; for example, the lubricant is selected from at least magnesium stearate and colloidal silica One.

Unless otherwise stated, the above-described suitable excipients of known specifications can be used in the pharmaceutical compositions of the present invention. For example, suitable excipients can include various commercially available specifications such as granules or micronized excipients. Suitable examples include, for example, microcrystalline cellulose having a particle diameter of 10 to 200 μm, and/or colloidal silica having a surface area of about 200 m ² /g as long as it can be applied to the production method of the present invention.

It should be understood that in addition to the solid excipients, the excipients suitable for use in the pharmaceutical formulations of the invention may also be in liquid or colloidal form.

According to an embodiment of the present invention, in the step (1), the first active component is formulated in an amount of 5 to 70 parts by weight, preferably 5 to 40 parts by weight.

According to an embodiment of the invention, the second active ingredient is formulated in an amount of from 5 to 70 parts, for example from 5 to 40 parts.

According to an embodiment of the present invention, the filler is prescribed in the first excipient in an amount of 5 to 90 parts, for example, 30 to 70 parts.

According to an embodiment of the present invention, the amount of the disintegrant in the first excipient is from 1 to 29 parts, for example from 1.5 to 26 parts, such as from 6 to 15 parts.

According to an embodiment of the invention, the lubricant is formulated in the first excipient in an amount of from 0.025 to 7.5 parts, for example from 0.05 to 5 parts, such as from 0.25 to 2.5 parts.

According to an embodiment of the present invention, the formulation amount of the disintegrant in the second adjuvant is from 0.3 to 17.5 parts, for example, from 0.5 to 8 parts, such as from 2 to 5 parts.

According to an embodiment of the invention, the lubricant is formulated in the second excipient in an amount of from 0.025 to 7.5 parts, for example from 0.05 to 5 parts, such as from 0.25 to 2.5 parts.

According to an embodiment of the present invention, in the step (2), the first active component, the second active component, the filler of the first adjuvant, the disintegrant, and the lubricant may be mixed, and then the first auxiliary material is added. Lubricating oil is mixed;

According to an embodiment of the invention, the mixing time of the step (2) is 2-15 minutes, for example 5-10 minutes.

According to an embodiment of the present invention, the dry granulation of the step (3) is carried out under the following conditions: a roll width of 25 mm, a roll diameter of 200 mm, a roll gap of 2 mm, and a feed rotation speed of 7-70 rpm, preferably 7 rpm, 34 rpm, 50 rpm, 70 rpm. The pinch speed is 3-12 rpm, preferably 3 rpm, 8 rpm, 12 rpm, and the sizing speed is 200-700 rpm, preferably 200 rpm, 550 rpm, 600 rpm, 700 rpm.

According to an embodiment of the invention, the mixing time of the step (4) is from 1 to 12 minutes, preferably from 3 to 5 minutes.

Preferably, the second mixture obtained in step (4) comprises a first granule and a second auxiliary attached to the surface of the first granule.

According to an embodiment of the invention, the attachment can be achieved by adsorption or adhesion, such as physical adsorption.

According to an embodiment of the present invention, the method further comprises the step (5) of preparing the second mixture into a preparation, for example, tableting or filling the second mixture;

According to an embodiment of the present invention, the step of drying in the step (5) may be followed by a drying step, and the drying may be drying under reduced pressure; preferably, the drying temperature is 5 to 60 ° C, for example, 10 to 50 ° C, as 10 ° C, 20 ° C, 25 ° C, 40 ° C, 50 ° C; preferably, the drying time is 0.5-18 hours, for example 1-16 hours.

The present invention also provides a pharmaceutical composition prepared by the above production method.

The invention also provides a pharmaceutical formulation precursor comprising a mixture of the first particles and a second adjuvant attached to the surface of the first particles.

The present invention also provides a pharmaceutical preparation comprising the above-mentioned pharmaceutical preparation precursor formed by a formulation. Preferably, the formulation of the formulation may be, for example, a tableting or filling capsule step. Preferably, the drying step can also be carried out after tableting.

The invention also provides the use of the pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of cardiovascular diseases.

According to the present invention, the cardiovascular disease is selected from the group consisting of: hypertension, heart failure, chronic heart failure, coronary heart disease, rheumatic heart disease, congenital heart disease, left ventricular dysfunction, endothelial dysfunction, diastolic dysfunction, hypertrophy Cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmia, atrial fibrillation, cardiac fibrosis, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina pectoris, primary And secondary pulmonary hypertension, renal vascular hypertension.

The invention also provides a method of preventing and/or treating a cardiovascular disease comprising administering the pharmaceutical composition or pharmaceutical formulation precursor to an individual in need thereof.

Term explanation and explanation

Unless otherwise stated, the definitions of groups and terms recited in the specification and claims of the present application include their definitions, exemplary definitions, preferred definitions, definitions in the tables, and definitions of specific compounds in the examples. Etc., can be combined and combined with each other arbitrarily. Such combinations and combinations of group definitions and compound structures are intended to be within the scope of the present disclosure.

When the numerical range is defined as "integer", it should be understood that the two endpoints of the range and each integer within the range are recited. For example, "an integer of 0 to 10" should be understood to mean each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. When the numerical range is defined as a "number", it is to be understood that the two endpoints of the range, each integer in the range, and each fraction in the range are recited. For example, "a number of 0 to 10" should be understood to mean not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 but also at least one of each integer. And the sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.

As used herein, "one or more" includes one or more than one, including, but not limited to, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

As used herein, "halogen" means fluoro, chloro, bromo and iodo.

"Substituted" means substituted with one or more optional substituents. Suitable substituents include, but are not limited to, halogen, amino, cyano, nitro, carbonyl (oxo), decyl (thio), hydroxy, ether, carboxy, alkyl, alkoxy, alkenyl, alkynyl, Alkenyloxy, alkynyloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted acyl, substituted sulfonyl, substituted ester, -CH=CHCO ₂ H, -CH=CHCO ₂ alkane base. The substituent may be unsubstituted or optionally further substituted by one or more substituents which may be the same or different selected from the above.

"Alkyl" as used singly or as a suffix or prefix in the present invention is intended to include both branched and straight-chain saturated fats having from 1 to 20 carbon atoms (or the specific number if a specific number of carbon atoms are provided) A hydrocarbon group. For example, "C ₁ -C ₈ alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. When an alkyl group is substituted by a substituent, it includes an alkyl group substituted with one or more halogens, for example, an alkyl group substituted with 1, 2, 3, 4, 5, 6 halogens, such as a trifluoromethyl group.

"Alkenyl" as used herein, alone or as a suffix or prefix, is intended to include a chain comprising alkenyl or olefins having from 2 to 20 carbon atoms, if specified, the specific number of carbon atoms. And a linear aliphatic hydrocarbon group. For example, "C _2-6 alkenyl" means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3 Methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.

The "alkynyl" used alone or as a suffix or prefix in the present invention is intended to include alkynyl or alkyne containing from 2 to 20 carbon atoms (or the specific number if a specific number of carbon atoms is provided) Branched and linear aliphatic hydrocarbon groups. For example, ethynyl, propynyl (eg, 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl.

The term "aryl" as used herein means an aromatic ring structure composed of 5 to 20 carbon atoms. For example, an aromatic ring structure containing 5, 6, 7 and 8 carbon atoms may be a monocyclic aromatic group such as a phenyl group; a ring structure comprising 8, 9, 10, 11, 12, 13 or 14 carbon atoms It may be polycyclic such as naphthyl. The aromatic ring may be substituted with one or more of the ring positions described above. The term "aryl" also includes polycyclic ring systems having two or more rings wherein two or more carbons are shared by two adjacent rings (the ring is a "fused ring"), wherein at least One ring is aromatic and the other ring may be, for example, a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and/or heterocyclic group. Examples of polycyclic rings include, but are not limited to, 2,3-dihydro-1,4-benzodioxadiene and 2,3-dihydro-1-benzofuran.

The term "cycloalkyl" as used herein is intended to include saturated cyclic groups having the indicated number of carbon atoms. These terms may include fused or bridged polycyclic systems. The cycloalkyl group has 3 to 40 carbon atoms in its ring structure. In one embodiment, the cycloalkyl has 3, 4, 5 or 6 carbon atoms in its ring structure. For example, "C _3-6 cycloalkyl" means a group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

As used herein, "heteroaryl" refers to a heteroaromatic heterocycle having at least one ring heteroatom such as sulfur, oxygen or nitrogen. Heteroaryl groups include monocyclic systems and polycyclic systems (eg, having 2, 3 or 4 fused rings). Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, fluorene , pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, 1,2,4 -thiadiazolyl, isothiazolyl, benzothienyl, fluorenyl, oxazolyl, benzimidazolyl, benzoxazolyl, azabenzoxazolyl, imidazothiazolyl, benzo[1] 4] dioxolyl, benzo[1,3]dioxolyl and the like. In some embodiments, a heteroaryl has from 3 to 40 carbon atoms and in other embodiments from 3 to 20 carbon atoms. In some embodiments, a heteroaryl group contains 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, a heteroaryl has 1 to 4, 1 to 3 or 1 to 2 heteroatoms. In some embodiments, a heteroaryl has 1 heteroatom.

The term "heterocyclyl" as used herein, unless otherwise indicated, refers to a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring containing from 3 to 20 atoms, wherein 1, 2, 3, 4 or 5 Ring atoms are selected from nitrogen, sulfur or oxygen, and unless otherwise indicated, may be attached via carbon or nitrogen, wherein the -CH ₂ - group is optionally replaced by -C(O)-; and unless otherwise stated to the contrary The ring nitrogen atom or the ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or a ring nitrogen atom, optionally quaternized; wherein -NH in the ring is optionally acetyl, formyl, methyl Or a methylsulfonyl group; and the ring is optionally substituted with one or more halogens. It should be understood that when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these hetero atoms are not adjacent to each other. If the heterocyclic group is bicyclic or tricyclic, at least one ring may be optionally a heteroaromatic or aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is a monocyclic ring, it must not be aromatic. Examples of heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl. , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, indanyl, tetrahydropyranyl, dihydrogen -2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 - dioxoimidazolidinyl.

Depending on the location and nature of the different substituents, the compounds of the invention may also contain one or more asymmetric centers. Asymmetric carbon atoms may exist in the (R) or (S) configuration, with only one asymmetric center, resulting in a racemic mixture containing multiple asymmetric centers, resulting in a mixture of diastereomers. In some cases, there may also be asymmetry due to the hindrance of rotation around a particular bond, such as the two substituted aromatic rings that link the particular compound to the central bond. Also, the substituent may exist in a cis or trans isomer form.

The compounds of formula (I) also include all possible stereoisomers thereof, which are single stereoisomers or stereoisomers (for example R-isomers or S-isomers, or E-isomers) The form of any mixture of any ratio of the bulk or Z-isomer). Single stereoisomers (e.g., single enantiomers or single diastereomers) of a compound of the invention can be achieved by any suitable prior art method (e.g., chromatography, particularly, for example, chiral chromatography). Separation.

Additionally, the compounds may also exist in tautomeric forms. The compounds of the invention include all possible tautomers of the compounds of formula (I) which are in the form of a single tautomer or any mixture of said tautomers in any ratio.

All such isomers and mixtures thereof are included in the present invention.

Those skilled in the art will appreciate that the NEP inhibitors of the invention and the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (such as a carboxyl group) and a basic center ( For example, an amino group, it can also form an internal salt.

In the present invention, acid addition salts include, but are not limited to, hydrochloride, hydrofluoride, hydrobromide, hydroiodide, sulfate, pyrosulfate, phosphate, nitrate, methanesulfonate , ethanesulfonate, 2-hydroxyethanesulfonate, besylate, tosylate, sulfamate, 2-naphthalenesulfonate, formate, acetoacetate, pyruvic acid, silicate , cinnamate, benzoate, acetate, glycolate, trifluoroacetate, trimethylacetate, propionate, butyrate, hexanoate, heptanoate, ten Monoacid salt, stearate, ascorbate, camphorate, camphor sulfonate, citrate, fumarate, malate, maleate, hydroxymaleate, oxalate, water Salicylate, succinate, gluconate, quinate, pamoate, glycolate, tartrate, lactate, 2-(4-hydroxybenzoyl)benzoate, Cyclopentane propionate, digluconate, 3-hydroxy-2-naphthoate, nicotinate, pamoate, pectate ester, 3-phenylpropionate, picrate, Pivalate, itaconate, trifluoromethyl Acid salt, lauryl sulfate, p-toluenesulfonate, naphthalene disulfonate, malonate, adipate, alginate, mandelate, glucoheptanoate, glycerol phosphate, sulfonate a base salicylate, a hemisulfuric acid or a thiocyanate, an aspartic acid salt or the like; a base addition salt such as an alkali metal salt, an alkaline earth metal salt, an ammonium salt, etc., specifically including but not limited to: a sodium salt, a lithium salt, Potassium salts, aluminum salts, magnesium salts, calcium salts, barium salts, iron salts, ferrous salts, manganese salts, manganese salts, zinc salts, ammonium salts (including salts with NH ₃ and organic amines (NH ₄ salts) , methylammonium salt, trimethylammonium salt, diethylammonium salt, triethylammonium salt, propylammonium salt, tripropylammonium salt, isopropylammonium salt, tert-butylammonium salt, N,N'-dibenzylethylenediammonium salt , dicyclohexylammonium salt, 1,6-hexanediammonium salt, benzylammonium salt, ethanolammonium salt, N,N-dimethylethanolammonium salt, N,N-diethylethanolammonium salt, triethanolammonium salt , tromethamine salt, lysine salt, arginine salt, histidine salt, glucosamine salt, N-methyl glucosamine salt, dimethyl glucosamine salt, ethyl glucosamine salt , meglumine, betaine, caffeine, chloroprocaine, procaine , lidocaine salt, pyridinium salt, methylpyridine salt, piperidine salt, morpholine salt, piperazine salt, sulfonium salt, theobromine salt, choline salt) and the like.

The beneficial effects of the invention are:

1. The preparation process, formulation and precursor thereof according to the present invention are particularly suitable for preparing a compound represented by the formula (I) or a precursor thereof, an active metabolite, a stereoisomer, or a pharmaceutically acceptable substance having good dissolution or release properties. The acceptable pharmaceutical compositions of the salts, prodrugs and solvates surprisingly improve the problem that it is difficult to obtain a pharmaceutical composition having a satisfactory performance in a conventional process, and the dissolution property of the preparation is remarkably improved, and the drug can be effectively promoted. freed.

2. The invention effectively improves the material flowability problem in the process, for example, by improving the fluidity of the material, thereby ensuring that the difference in tablet weight of the tableting process product is small, and the difference in the weight of the final product can be controlled within ±5%. Etc.

3. By using the process of the present invention and the formulation and its precursor, the preparation process can be carried out at room temperature, avoiding the high temperature drying step leading to decomposition of the active ingredient.

4. The preparation process of the invention has the advantages of simple preparation process and easy industrialization and large production.

Detailed ways

The invention will be further described in detail below with reference to specific embodiments. It is understood that the following examples are merely illustrative of the invention and are not to be construed as limiting the scope of the invention. The technology that is implemented based on the above-described contents of the present invention is encompassed within the scope of the present invention.

The starting materials and reagents used in the following examples are commercially available or can be prepared by known methods unless otherwise stated.

Example 1 Preparation of the first active component

Add Shakubiqu to acetone solvent, stir at room temperature, cool to 0-10 °C, add a little excess of concentrated ammonia water, add dropwise, continue stirring for 4h, filter, wash with acetone, vacuum dry, get AHU377 ammonium salt, purity More than 99.5%, MS: m/z = 412.3 (M+H) ⁺ .

The preparation of AHU 377K is similar to this process, replacing concentrated ammonia with potassium hydroxide.

Example 2 Preparation of Second Active Component: Preparation of Compound 1K

Compound 1 (1.0 g) was dissolved in dichloromethane (5 ml), stirred at room temperature to form a solution, potassium phthalimide (0.27 g) was added to the solution, the reaction was kept for 4 h, cooled to -50 ° C, filtered The solvent was dried to give the compound 1K (amorphous).

Melting point: 135-145 ° C.

MS / HRMS m / z: 717 [M + H] ⁺ ; 677 [MK] ^- .

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.44 (t, 3H), 1.46 (t, 3H), 2.38 (s, 3H), 2.41 (s, 3H), 2.44 (s, 3H), 4.64 (q, 2H), 5.29 (d, 1H), 5.32 (d, 1H), 5.52 (d, 1H), 5.56 (d, 1H), 6.86 (q, 1H), 6.90 (d, 2H), 7.18 ( m, 2H), 7.22 (d, 2H), 7.33 (m, 1H), 7.36 (m, 1H), 7.46 (d, 1H), 7.52 (dd, 1H), 7.75 (d, 1H).

It was found that the composition consisting of only the products of Examples 1 and 2 (100 mg: 50 mg) (excluding the formulation excipient) had a hygroscopic weight gain of 28.31% at a relative humidity of 92.5% and a temperature of 25 ° C for 5 days.

Example 3

Weigh the prescribed amount of compound 1K, AHU 377 ammonium salt, mannitol in the first auxiliary material, microcrystalline cellulose, colloidal silica, crospovidone, and mix it into a mixer with a 40 mesh sieve, and mix for 6 minutes. An additional portion of the first auxiliary magnesium stearate was added and mixed for 3 minutes.

The granules were prepared by a dry granulator. The granulation conditions were: a roll width of 25 mm, a roll diameter of 200 mm, a roll gap of 2 mm, a feed speed of 34 rpm, a pinch speed of 3 rpm, and a granule speed of 550 rpm.

Weighing the colloidal silica in the second auxiliary material of the prescription amount, after passing through the 40 mesh sieve, mixing with the cross-linked povidone, magnesium stearate (addition part) and the above-mentioned particles in the second auxiliary material, and putting it into the mixer to mix 3 In minutes, the total mixed particles physically adsorbed to each other are obtained. The total mixed granules were compressed, the hardness was 80-120 N, and the difference in tablet weight was within ±5%. The product was obtained by drying under reduced pressure at 25 ° C for 5 hours.

Example 4

Weighed the prescribed amount of compound 1K, AHU 377 ammonium salt, microcrystalline cellulose in the first auxiliary material, colloidal silica, crospovidone, mixed into a mixer with a 40 mesh sieve, mixed for 6 minutes, and then added Add a portion of the first excipient magnesium stearate and mix for 2 minutes.

The granules were prepared by a dry granulator. The granulation conditions were: roll width 25 mm, roll diameter 200 mm, roll gap 2 mm; feed speed 70 rpm, pressure wheel speed 3 rpm, granule rotation speed 700 rpm, screen aperture 18 mesh.

Weighing the colloidal silica in the second auxiliary material of the prescription amount, after passing through the 40 mesh sieve, mixing with the cross-linked povidone, magnesium stearate (addition part) and the above-mentioned particles in the second auxiliary material, and putting it into the mixer to mix 3 In minutes, the total mixed particles physically adsorbed to each other are obtained. The total mixed granules were compressed, the hardness was 80-120 N, and the difference in tablet weight was within ±5%. The product was obtained by drying under reduced pressure at 20 ° C for 8 hours.

Example 5

Weighed the prescribed amount of compound 1K, AHU 377 potassium salt, mannitol in the first auxiliary material, microcrystalline cellulose, colloidal silica, crospovidone, mixed into a mixer through a 40 mesh sieve, and mixed for 5 minutes. An additional portion of the first adjuvant magnesium stearate was added and mixed for 2 minutes.

The granules were prepared by a dry granulator. The granulation conditions were: a roll width of 25 mm, a roll diameter of 200 mm, a roll gap of 2 mm, a feed speed of 7 rpm, a pinch speed of 12 rpm, and a sizing speed of 200 rpm.

Weigh the colloidal silica in the second auxiliary material of the prescription amount, and after mixing through the 40 mesh sieve, mix with the cross-linked povidone, magnesium stearate (addition part) and the above particles in the second auxiliary material, and mix it into the mixer. In minutes, the total mixed particles physically adsorbed to each other are obtained. The total mixed granules were compressed, the hardness was 80-120 N, and the difference in tablet weight was within ±5%. The product was obtained by drying under reduced pressure at 40 ° C for 3 hours.

Example 6

Weighed the prescribed amount of compound 1K, AHU 377 ammonium salt, microcrystalline cellulose in the first auxiliary material, colloidal silica, crospovidone, mixed into a mixer with a 40 mesh sieve, mixed for 6 minutes, and then added Add a portion of the first excipient magnesium stearate and mix for 3 minutes.

The granules were prepared by a dry granulator. The granulation conditions were: a roll width of 25 mm, a roll diameter of 200 mm, a roll gap of 2 mm, a feed speed of 50 rpm, a pinch speed of 8 rpm, and a sizing speed of 600 rpm.

Weighing the colloidal silica in the second auxiliary material of the prescription amount, after passing through the 40 mesh sieve, mixing with the cross-linked povidone, magnesium stearate (addition part) and the above-mentioned particles in the second auxiliary material, and putting it into the mixer to mix 3 In minutes, the total mixed particles physically adsorbed to each other are obtained. The total mixed granules were compressed, the hardness was 80-120 N, and the difference in tablet weight was within ±5%. The product was obtained by drying under reduced pressure at 10 ° C for 16 hours.

Example 7

Weighed the prescribed amount of compound 1K, AHU 377 ammonium salt, mannitol in the first auxiliary material, microcrystalline cellulose, colloidal silica, crospovidone, mixed into a mixer through a 40 mesh sieve, and mixed for 5 minutes. An additional portion of the first auxiliary magnesium stearate was added and mixed for 3 minutes.

The granules were prepared by a dry granulator. The granulation conditions were: a roll width of 25 mm, a roll diameter of 200 mm, a roll gap of 2 mm, a feed speed of 34 rpm, a pinch speed of 12 rpm, and a sizing speed of 200 rpm.

Weigh the colloidal silica in the second auxiliary material of the prescription amount, and after mixing through the 40 mesh sieve, mix with the cross-linked povidone, magnesium stearate (addition part) and the above particles in the second auxiliary material, and mix it into the mixer. In minutes, the total mixed particles physically adsorbed to each other are obtained. The total mixed granules were compressed, the hardness was 80-120 N, and the difference in tablet weight was within ±5%. The product was obtained by drying under reduced pressure at 50 ° C for 1 hour.

Comparative Example 1

Prepare 8% HPC (hydroxypropyl cellulose) solution for use, weigh the prescribed amount of compound 1K, AHU 377 ammonium salt, microcrystalline cellulose in the first auxiliary material, crospovidone into the fluidized bed, spray preparation Good binder granulation, after the preparation is completed, it is dried in a fluidized bed to a moisture content of ≤1.0%. The colloidal silica in the prescribed amount of the second auxiliary material was weighed through a 40 mesh sieve, mixed with the crosslinked povidone, magnesium stearate and the first particles in the second auxiliary material, and mixed in a mixer for 3 minutes. The total mixed granules were compressed, the hardness was 80-120 N, and the difference in tablet weight was within ±5%. Drying is the finished product.

Comparative Example 2

Weighed the prescribed amount of compound 1K, AHU 377 ammonium salt, microcrystalline cellulose in the first auxiliary material, mannitol, crospovidone, colloidal silica, and mixed in a mixer for 7 minutes, then added the second auxiliary material. Magnesium stearate was mixed for 3 minutes and compressed using a rotary tableting machine. Since the particle size of AHU 377 ammonium salt and compound 1K is small, about 10 μm, the fluidity is very poor, and a large amount of a flow aid and a filler cannot solve the problem of the fluidity of the sample during the tableting process. As a result, the sample weight difference fluctuates greatly during the tableting process (the difference in tablet weight is more than 5%), and the qualified product cannot be obtained.

Comparative Example 3

Prepare 8% HPC ethanol solution for use, weigh the prescribed amount of compound 1K, AHU 377 ammonium salt, mannitol in the first excipient, microcrystalline cellulose, crospovidone into the wet granulator, premix for 8 minutes. Thereafter, the prepared binder solution is granulated by spraying, and after the preparation is completed, the granules are sieved by a swing granulator 20 mesh, and then dried to a moisture content of ≤1%. Weighing the prescription amount of the second auxiliary material, the colloidal silica is mixed with the 40 mesh sieve, and then mixed with the cross-linked povidone, magnesium stearate (addition portion) and the first particles in the second auxiliary material, and put into the mixer. Mix for 3 minutes. The total mixed granules were compressed, the hardness was 100-140 N, and the difference in tablet weight was within ±5%. Drying is the finished product.

Example 8

The dissolution rates of the drugs in Examples 3-7 were compared in Comparative Examples 1 and 3.

Instrument: RC-12AD intelligent dissolution tester (Tianjin Tianda Tianfa Technology Co., Ltd.).

Method: Paddle method, sample 5ml, discard 2ml of the initial filtrate, take the filtrate in the liquid phase vial, the filter membrane is 0.45μm pore size polyethersulfone material.

Medium: 900 ml of 0.1 M HCl medium containing 0.5% Tween 80.

Speed: 50 rpm.

Temperature: 37 ° C.

The resulting product dissolution data is shown in the following table:

The results show that the preparation process of the present invention can produce a product having an unexpected dissolution effect and is suitable for industrial production.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and scope of the present invention are intended to be included within the scope of the present invention.

Claims (10)

A method for preparing a pharmaceutical composition, comprising: (1) taking a first active component, a second active component, a first auxiliary component and a second auxiliary material; (2) mixing the first active component, the second active component, and the first adjuvant to disperse the first active component and the second active component in an incorporation In an excipient to obtain a first mixture; (3) preparing the first mixture by dry granulation to obtain a first granule; (4) adding a second auxiliary material to the first particles by an external addition method, and mixing to obtain a second mixture; And optionally, with or without the addition of a third adjuvant in steps (2) and/or (4); among them, The first active component is at least one selected from the group consisting of a neutral endopeptidase inhibitor and a precursor thereof, an active metabolite, a stereoisomer, a pharmaceutically acceptable salt, a prodrug, and a solvate; The second active component is at least one selected from the group consisting of a compound represented by the following formula (I) or a precursor thereof, an active metabolite, a stereoisomer, a pharmaceutically acceptable salt, a prodrug and a solvate:

Where R represents

or

Each a is the same or different and is independently selected from 0, 1, 2, 3, 4, 5 or 6; R ₁ represents a substituted or unsubstituted group: C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl,

(CH ₂ ) _n O(CH ₂ ) _m ,

Aryl or heteroaryl, wherein

Wherein C _b and C _c represent an alkyl group each containing b or c carbon atoms; b and c are the same or different and are independently selected from each other, 0, 1, ₂ , 3, 4, 5 or 6, wherein (CH _{2 n} , _m in _n O (CH ₂ ) _m is the same or different, independently selected from each other, 1, 2, 3, 4, 5 or 6; R ₂ represents hydrogen, halogen, nitro, cyano, or a substituted or unsubstituted group: C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkylsulfonylamino , arylsulfonylamino, heteroarylsulfonylamino, aminosulfonyl, amino; R ₃ represents a group which is absent or substituted or unsubstituted: C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₂ -C ₈ alkoxy, C ₂ -C ₈ alkyne Base, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl,

Aryl, heteroaryl, wherein

Wherein b and c represent the number of carbon atoms of the alkyl chain, independently selected from 0, 1, 2, 3, 4, 5 or 6; R ₄ represents a cyano group, or a substituted or unsubstituted group of an aryl group, an arylsulfonyl group, a heteroaryl group, a C ₁ -C ₈ alkoxy group, a C ₁ -C ₈ nitrate ester (-C ₁ -C) _8- alkyl-ONO ₂ ), C ₁ -C ₈ alkyl; R ₅ represents a cyano group, or a substituted or unsubstituted group: aryl, heteroaryl, C ₁ -C ₈ alkoxy, C ₁ -C ₈ nitrate, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkenyl, C ₁ -C ₈ alkynyl,

(CH ₂ ) _n O(CH ₂ ) _m CH ₃ , wherein R ₃ , R ₄ , a, m, n independently of each other have the definitions as described above; R ₆ and R ₇ independently represent hydrogen, unsubstituted or substituted C ₁ -C ₈ alkoxy or C ₁ -C ₈ alkyl; R ₈ and R ₉ independently represent hydrogen, unsubstituted or substituted C ₁ -C ₈ alkoxy, C ₁ -C ₈ nitrate or C ₁ -C ₈ alkyl; The first auxiliary material is selected from at least one of a filler, a disintegrant, and a lubricant; The second auxiliary material is selected from at least one of a disintegrant and a lubricant; The third adjuvant is selected from at least one of, but not limited to, an auxiliary lipid, a glidant, a sweetener, a flavoring agent, a preservative, an antioxidant, a colorant, and a foaming agent. The preparation method according to claim 1, wherein the neutral endopeptidase inhibitor or the pharmaceutically acceptable salt of the compound of the formula (I) is the same or different and is independently selected from Na and K independently of each other. Or an ammonium salt (such as an addition salt with NH ₃ ); a neutral endopeptidase inhibitor or a pharmaceutically acceptable prodrug of a compound of formula (I), which is the same or different, independently selected from one another including but not limited to Methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester; Preferably, the first active component is selected from at least one of the following compounds, pharmaceutically acceptable salts, prodrugs or solvates thereof: (S)-(2-biphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethylamino)methylphosphonic acid, (S)-5-(N-(2-(phosphonomethyl-amino)-3-(4-biphenyl)-propionyl)-2-aminoethyl)tetrazole, (±) N-(1-oxo-2-indolyl-3-phenylpropionyl)glycine, N-((2S)-2-(4-biphenylmethyl)-4-carboxy-5-phenoxypentanoyl)glycine, N-(α-rhamnopyranosylphosphonamide)-L-leucine-L-tryptophan, N-[N-[(L)-1-carboxy-2-phenylethyl]-L-phenylalanyl]-(R)-alanine, N-[N-[((1S)-carboxy-2-phenyl)ethyl]-(S)-phenylalanyl]-β-alanine, N-(S)-[3-mercapto-2-(2-methylphenyl)propanoyl]-(S)-2-methoxy-(R)-alanine, 3-[1,1'-biphenyl]-4-yl-N-[diphenoxyphosphinyl)-methyl]-L-alanyl-β-alanine, N-(1-(N-hydroxycarbamoyl-methyl)-1-cyclopentanecarbonyl)-L-phenylalanine, N-[2-mercaptomethyl-3-phenyl-propionyl]-3-aminobenzoic acid, 4-[[2-(indolylmethyl)-1-oxo-3-phenylpropyl]amino]benzoic acid, N-[2-acetylthiomethyl-3-phenyl-propionyl]-3-aminobenzoic acid, N-[2-mercaptomethyl-3-(2-methylphenyl)-propionyl]-methionine, N-(3-phenyl-2-(fluorenylmethyl)-propionyl)-(S)-4-(methylindenyl)-methionine, N-[1-(2-carboxy-4-phenylbutyl)-cyclopentanecarbonyl]-(S)-isoserine, N-[2(S)-nonylmethyl-3-(2-methylphenyl)propanoyl]-(S)-isoserine, N-(1-(3-(N-tert-Butoxycarbonyl-(S)-prolylamino)-2(S)-tert-butoxy-carbonylpropyl)cyclopentanecarbonyl)-O-benzyl -(S)-serine, 3(S)-[2-(acetylthiomethyl)-3-phenyl-propionyl]amino-ε-caprolactam, N-[1-(acetylthiomethyl)-cyclopentylcarbonyl]-(S)-methionine, N-[2-acetylthiomethyl-3-(2-methyl-phenyl)propanoyl]-methionine, N-[2(S)-nonylmethyl-3-(2-methylphenyl)-propionyl]methionine, N-[2-(indolylmethyl)-1-oxo-3-phenylpropyl]-β-alanine, 7-[[2-(indolylmethyl)-1-oxo-3-phenylpropyl]amino]-heptanoic acid, N-[N-[1(S)-carboxy-3-phenylpropyl]-(S)-phenylalanyl]-(S)-isoserine, N-[1-[[1(S)-carbonyl-3-phenylpropyl]amino]-cyclopentylcarbonyl]-(S)-isoserine, N-[1-[[1(S)-benzyloxycarbonyl-3-phenylpropyl]amino]-cyclopentylcarbonyl]-(S)-isoserine, N-[N-[(L)-[1-[(2,2-Dimethyl-1,3-dioxolan-4-yl)-methoxy]carbonyl]-2-phenylethyl ]-L-phenylalanyl]-(R)-alanine, N-(2-carboxy-4-thienyl)-3-indolyl-2-benzylpropanamide, 2-(2-mercaptomethyl-3-phenylpropionylamino)thiazole-4-ylcarboxylic acid, (L)-(1-((2,2-Dimethyl-1,3-dioxolan-4-yl)-methoxy)carbonyl)-2-phenylethyl)-L-phenylpropanoid Aminoacyl-β-alanine, Cis-4-[[[1-[2-carboxy-3-(2-methoxyethoxy)propyl]-cyclopentyl]carbonyl]amino]-cyclohexanecarboxylic acid, 3-(1-[6-endo-hydroxymethylbicyclo[2,2,1]heptane-2-exo-carbamoyl]cyclopentyl)-2-(2-methoxyethyl)propane acid, 3-[1-(cis-4-carboxycarbonyl-cis-3-butylcyclohexyl-r-1-carbamoyl)cyclopentyl]-2S-(2-methoxyethoxy-methyl)propionic acid , (S)-cis-4-[1-[2-(5-indanyloxy-carbonyl)-3-(2-methoxyethoxy)propyl]-1-cyclopentanoylamino] 1-cyclohexanecarboxylic acid, 1,1'-[dithiobis-[2(S)-(2-methylbenzyl)-1-oxo-3,1-propylene]]-bis-(S)-isoserine, 1,1'-[Dithiobis-[2(S)-(2-methylbenzyl)-1-oxo-3,1-propylene]]-bis-(S)-methylthioamide acid, 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) Amino)-4-oxobutyric acid, N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutyric acid; Preferably, the first active component is selected from at least one of the following compounds: N-[1-(acetylthiomethyl)-cyclopentylcarbonyl]-(S)-methionine ethyl ester, N-[2-acetylthiomethyl-3-(2-methyl-phenyl)propanoyl]-methionine ethyl ester, N-(1-(3-(N-tert-Butoxycarbonyl-(S)-prolylamino)-2(S)-tert-butoxy-carbonylpropyl)cyclopentanecarbonyl)-O-benzyl -(S)-serine methyl ester, 3(S)-[2-(acetylthiomethyl)-3-phenyl-propionyl]amino-ε-caprolactam, 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) Amino)-4-oxobutyric acid (AHU 377 or Shakubis), N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutyric acid, N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutyrate, N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutyrate, 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) Ethylamino-4-oxobutyric acid ethyl ester (AHU 377 ethyl ester or sarbuterol ethyl ester), 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) Sodium amino)-4-oxobutyrate (AHU 377Na or sulphur sodium), 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) Potassium amino)-4-oxobutanoate (AHU 377K or Shakubit potassium), 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl) Amido)-4-oxobutyric acid ammonium (AHU 377 ammonium salt or sarbuteramine ammonium salt); For example, the first active component is selected from the group consisting of AHU 377, AHU 377 ethyl ester, AHU 377Na, AHU 377 ammonium salt, AHU 377K, N-(3-carboxy-1-oxopropyl)-(4S)-pair -Phenylphenylmethyl)-4-amino-2R-methylbutyric acid, N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4 -Amino-2R-methylbutyrate, N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenylmethyl)-4-amino-2R-methylbutyric acid Potassium or 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2- Amido)amino-4-oxobutanoic acid; Preferably, the second active component is a K salt selected from the compound of the formula (I), for example, a compound represented by the following formula (II):

Where R has the definitions described above; Preferably, the K salt of the compound of formula (I) is selected from the structures shown in the formula:

The preparation method according to claim 1 or 2, wherein the filler in the first adjuvant is selected from the group consisting of starch, lactose, lactose monohydrate, cellulose lactose, pregelatinized starch, sucrose, mannitol, and sorbus. At least one of an alcohol, a calcium phosphate, a dextrin, a microcrystalline cellulose, a calcium hydrogen phosphate, a mannitol-starch composite; for example, the filler is selected from at least one of microcrystalline cellulose and mannitol; The disintegrant in the first adjuvant is selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, methylcellulose, low-substituted hydroxypropylcellulose, cross-linked polycondensation At least one of ketene and chitosan; for example, the disintegrant is selected from at least one of croscarmellose sodium and crospovidone; The lubricant in the first auxiliary material is selected from the group consisting of magnesium stearate, colloidal silica, talc, sodium lauryl sulfate, calcium stearate, polyethylene glycol 4000, polyethylene glycol 6000, ten At least one of sodium octafumarate, glyceryl monostearate, hydrogenated vegetable oil; for example, the lubricant is selected from at least one of magnesium stearate and colloidal silica; The disintegrant in the second auxiliary material is selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, methylcellulose, low-substituted hydroxypropylcellulose, cross-linked polycondensation At least one of ketene and chitosan; for example, the disintegrant is selected from at least one of croscarmellose sodium and crospovidone; The lubricant in the second auxiliary material is selected from the group consisting of magnesium stearate, colloidal silica, talc, sodium lauryl sulfate, calcium stearate, polyethylene glycol 4000, polyethylene glycol 6000, ten At least one of sodium octa-fumarate, glyceryl monostearate, hydrogenated vegetable oil; for example, the lubricant is selected from at least one of magnesium stearate and colloidal silica. The preparation method according to any one of claims 1 to 3, wherein, in the step (1), the first active component is formulated in an amount of 5 to 70 parts by weight, preferably 5 parts by weight. -40 servings; The second active component is formulated in an amount of 5 to 70 parts, for example, 5 to 40 parts; The prescription amount of the filler in the first auxiliary material is 5 to 90 parts, for example, 30 to 70 parts; The formulation amount of the disintegrant in the first auxiliary material is 1-29 parts, for example, 1.5-26 parts, such as 6-15 parts; The prescription amount of the lubricant in the first auxiliary material is 0.025-7.5 parts, for example, 0.05-5 parts, such as 0.25-2.5 parts; The formulation amount of the disintegrant in the second auxiliary material is 0.3-17.5 parts, for example, 0.5-8 parts, such as 2-5 parts; The lubricant is formulated in the second excipient in an amount of from 0.025 to 7.5 parts, for example from 0.05 to 5 parts, such as from 0.25 to 2.5 parts. The preparation method according to any one of claims 1 to 4, wherein in the step (2), the first active component, the second active component, the filler of the first adjuvant, and a disintegrator may be used. Mixing with a lubricant, and then adding a lubricant of the first auxiliary material for mixing; Preferably, the second mixture obtained in the step (4) comprises a first particle and a second auxiliary material attached to the surface of the first particle; Preferably, the attachment is achieved by adsorption or adhesion, such as physical adsorption. The preparation method according to any one of claims 1 to 5, further comprising the step (5) of preparing the second mixture into a preparation, for example, tableting or filling the second mixture; Preferably, the step of drying in the step (5) may be followed by a drying step, and the drying may be drying under reduced pressure; preferably, the drying temperature is 5 to 60 ° C, for example, 10 to 50 ° C, such as 10 ° C, 20 ° C, 25 ° C, 40 ° C, 50 ° C; preferably, the drying time is 0.5-18 hours, for example 1-16 hours. A pharmaceutical composition prepared by the preparation method according to any one of claims 1 to 6. A pharmaceutical formulation precursor comprising a first particle and a second adjuvant attached to a surface of the first particle; Wherein the first particles and the second auxiliary materials have the definitions as defined in any one of claims 1-6. A pharmaceutical preparation in which the pharmaceutical preparation precursor of claim 8 is formulated. Use of the pharmaceutical composition of claim 7 for the manufacture of a medicament for the prevention and/or treatment of cardiovascular diseases; The cardiovascular disease is selected from the group consisting of: hypertension, heart failure, chronic heart failure, coronary heart disease, rheumatic heart disease, congenital heart disease, left ventricular dysfunction, endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, Diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, cardiac fibrosis, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina pectoris, primary and secondary Pulmonary hypertension, renal vascular hypertension.