WO2016086790A1 - Pharmaceutical composition of nep inhibitor and use thereof - Google Patents

Abstract

Disclosed are a pharmaceutical composition comprising a neutral endopeptidase (NEP) inhibitor and a use thereof in the preparation of a drug for treating and preventing diseases associated with NEP. The composition comprises: (i) (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3,5,7-trioxa-12-azahexadecane-16-acid (compound 1) or a pharmaceutical salt thereof, and/or (ii) an angiotensin II antagonist or a pharmaceutical salt thereof, and/or (iii) an angiotensin-converting enzyme inhibitor, and (iv) a pharmaceutically acceptable carrier.

Description

NEP inhibitor drug combination and its application Technical field

The invention belongs to the field of biomedicine, and particularly relates to a NEP inhibitor drug combination and application thereof.

Background technique

Essential hypertension is a multi-gene disease that cannot be completely controlled by a single treatment. In 2000, about 3.33 million adults in the developed countries and about 65 million (one-third of adults) in the United States suffered from high blood pressure. Long-term and uncontrolled hypertensive vascular disease will eventually lead to pathological changes in target organs such as the heart and kidneys. Sustained high blood pressure can also lead to an increase in the incidence of stroke. Therefore, the nature of hypertensive vascular disease is multifactorial. Therefore, in some cases, drugs with different mechanisms of action can be used in combination with the control of hypertension and for cardiovascular complications caused by hypertension.

Shanghai Hansen Company Patent CN201410001940.2 discloses the following structure:

Its chemical name is (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo- 3,5,7-Trioxa-12-azahexadecane-16-acid (Compound 1) is a novel neutral endopeptidase inhibitor. Neutral endopeptidase (EC3.4.24.11; enkephalinase; ATP) is a zinc-containing metalloproteinase that cleaves peptide substrates at the amino terminus of various hydrophobic residues. Substrates of the enzyme include, but are not limited to, atrial natriuretic peptide (ANP, also known as ANF), brain natriuretic peptide (BNP), methionine enkephalin and leucine enkephalin, bradykinin, nerve Kinin A, endothelin-1 and substance P. ANP is a powerful vasodilator and natriuretic drug. Infusion of ANP into normal subjects resulted in a significant increase in urinary sodium excretion and reproducibility of diuresis, including an increase in sodium excretion fraction, urine flow rate, and glomerular filtration rate. However, ANP has a short circulating half-life and NEP in the renal cortical membrane is an important enzyme capable of degrading the peptide. (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3,5, 7-Trioxa-12-azahexadecane-16-acid is capable of lowering plasma levels of ANP and thus can cause natriuretic and diuretic effects.

Angiotensin II is a hormone that causes vasoconstriction, which in turn causes hypertension and heart strain. Angiotensin II is known to interact with receptors on the surface of target cells. Two receptor subtypes of angiotensin II have been identified, known as AT1 and AT2. Recently, substances capable of binding to the AT1 receptor have been identified. It is now known that angiotensin receptor blockers (ARBs, angiotensin II antagonists) are capable of causing blood loss by preventing angiotensin II from binding to its receptor on the vessel wall. Because of their ability to inhibit the AT1 receptor, such antagonists can be used to combat hypertension, or to treat congestive heart failure and other indications.

ACE inhibitors, also known as angiotensin-converting enzyme inhibitors, have two binding sites at the active site, one of which contains Zn2+, which is the necessary binding site for the ACE inhibitor effective group. Once bound, the activity of ACE disappears. There are three types of existing ACE inhibitors that bind to Zn2+: (1) contain sulfhydryl (SH), such as captopril; (2) contain carboxyl (COO-), such as enalapril, ramipril , perindopril, benazepril, etc.; (3) contains phosphonic acid groups (POO-), such as fosinopril. In general, carboxyl-containing ACE inhibitors bind to Zn2+ more strongly than the other two types, so the effect is also stronger. Many ACE inhibitors are prodrugs, such as enalapril, which contain COOC2H5, which must be converted to COOH in vivo to become enalapril (enalaprilat) in order to bind to Zn2+. Similarly, the POOR of fosinoprul must be converted to POOH with fosimoprilat to function. ACE inhibitors can prevent the formation of AngII, thereby eliminating the contraction of blood vessels by AngII, stimulating the release of aldosterone, increasing blood volume, increasing blood pressure and promoting hypertrophic effects of cardiovascular hypertrophy, and is beneficial to the prevention and treatment of hypertension, heart failure and cardiovascular remodeling. ACE inhibitors reduce the inactivation of bradykinin and thus preserve the action of bradykinin. It is known that bradykinin activates the kinin B2 receptor, which in turn activates phosphatase C (PLC), produces IP3, releases intracellular Ca2+, activates NO synthase, and produces NO. Increased intracellular Ca2+ also activates phosphatase A2 (PLA2) on the cell membrane, inducing PGI2. Both NO and PGI2 have diastolic blood vessels, lower blood pressure, anti-platelet aggregation and anti-cardiovascular hypertrophy and remodeling. It can alleviate myocardial ischemia-reperfusion injury and protect the heart muscle against free radical damage. It can increase the sensitivity of insulin to patients with diabetes and hypertension. It is mainly used in the treatment of hypertensive patients with heart failure or diabetes and kidney disease; treatment of congestive heart failure and myocardial infarction, and treatment of diabetic nephropathy and other nephropathy.

The dose is lowered by the combined use of drugs with different mechanisms of action. For example, the required dose is not only often smaller, but can also be applied at a lower frequency, or can be used to reduce the incidence of side effects.

Summary of the invention

In order to overcome the deficiencies of the prior art, the inventors have intensively studied to find Compound 1 or a pharmaceutically acceptable salt thereof and/or an angiotensin II antagonist such as valsartan or a pharmaceutically acceptable salt thereof and/or an ACE inhibitor drug. Combination co-administration can produce significant efficacy in a higher percentage of treated patients, regardless of etiology, with a higher response rate.

The object of the present invention is to provide (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13- Trioxo-3,5,7-trioxa-12-azahexadecane-16-acid (Compound 1), and/or vascular tight A pharmaceutical composition comprising a tensin II antagonist, and/or an ACE inhibitor, the pharmaceutical composition comprising:

(i) (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3 , 5,7-trioxa-12-azahexadecane-16-acid or a pharmaceutically acceptable salt thereof, and/or

(ii) an angiotensin II antagonist or a pharmaceutically acceptable salt thereof, and/or

(iii) an ACE inhibitor or a pharmaceutically acceptable salt thereof, and

(iv) a pharmaceutically acceptable carrier.

As a further preferred embodiment, the angiotensin II antagonist is selected from the group consisting of losartan, irbesartan, olmesartan, telmisartan, valsartan, azilsartan, candesartan, and epro Sartan, losartan, saprisartan, elizaartan, tamsaltan, elsartan or a pharmaceutically acceptable salt thereof; preferably from valsartan, candesartan, telmisartan, losartan , azilsartan or a pharmaceutically acceptable salt thereof or a combination thereof.

As a further preferred embodiment, the ACE inhibitor is selected from the group consisting of enalapril, cilazapril, quinapril, ramipril, benazepril, perindopril, spironolide, fosump , captopril, benazepril or a pharmaceutically acceptable salt thereof or a combination thereof; preferably from enalapril, ramipril, fosinopril, benazepril or a pharmaceutically acceptable salt thereof or combination.

As a still further preferred aspect, the pharmaceutical composition further comprises (v) a diuretic.

As a still further preferred embodiment, the diuretic is selected from the group consisting of furosemide, ethenic acid, bumetanide, torsemide, hydrochlorothiazide, chlorthalidone, benzfluorothiazide, cyclopentazine, and poly Thiazide, metoprazine, indapamide or a pharmaceutically acceptable salt thereof, or a combination thereof.

As a still further preferred embodiment, the (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13 The pharmaceutically acceptable salt of trioxo-3,5,7-trioxa-12-azahexadecane-16-acid is selected from the group consisting of calcium, sodium or ammonium salts thereof.

As a still further preferred embodiment, the (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13 -Trioxo-3,5,7-trioxa-12-azahexadecane-16-acid is a crystalline free acid, the powder X-ray diffraction pattern of which is located at 6.4 ± 0.2 °, 15.9 ± 0.2 °, a peak at a diffraction angle (2θ) of 20.8 ± 0.2° and 19.0 ± 0.2°; preferably, the powder X-ray diffraction pattern thereof is further included at 20.4 ± 0.2°, 19.2 ± 0.2°, 26.0 ± 0.2°, 18.0 ± 0.2°, and 7.9. a peak at a diffraction angle (2θ) of ±0.2°; more preferably, the powder X-ray diffraction pattern further includes at 25.70±0.2°, 7.5±0.2°, 24.7±0.2°, 20.2±0.2°, 10.2±0.2° and A peak at a diffraction angle (2θ) of 16.5 ± 0.2°.

As a still further preferred embodiment, the (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13 - a pharmaceutically acceptable salt of trioxo-3,5,7-trioxa-12-azahexadecane-16-acid is a calcium salt polymorph, the powder X-ray diffraction pattern of which is located at 20.8 ± 0.2 °, 11.3 ± 0.2 °, 3.9 ± 0.2 ° and 19.2 ± 0.2 ° diffraction angle (2θ) peak; preferably its powder X-ray diffraction pattern also includes 11.7 ± 0.2 °, 14.8 ± 0.2 °, 20.3 ± 0.2 °, 5.6 ±0.2°, 19.9±0.2°; more preferably, the powder X-ray diffraction pattern further includes at 13.5±0.2°, 5.9±0.2°, 12.7±0.2°, 24.8±0.2°, 14.6±0.2°, and 31.6±0.2 The peak at the diffraction angle (2θ) of °.

As a still further preferred embodiment, the pharmaceutically acceptable carrier is selected from the group consisting of a diluent or a filler, a disintegrant, a binder, a glidant, a lubricant, a colorant, or a combination thereof.

As a still further preferred embodiment, the diluent or filler is selected from the group consisting of powdered sugar, compressible sugar, glucose, sucrose, lactose, dextrin, mannitol, microcrystalline cellulose, sorbitol, starch or combinations thereof, diluent Or the filler is used in an amount of 4% to 60%, preferably 20% to 40% by weight of the composition; the disintegrant is selected from the group consisting of starch, clay, cellulose, alginate, gum, crosslinked polymer, soybean polysaccharide , guar gum or a combination thereof, the disintegrant is used in an amount of 0% to 65%, preferably 1% to 40% by weight of the composition; the binder is selected from the group consisting of starch, cellulose and derivatives thereof, sucrose, glucose , corn syrup, gelatin, povidone or a combination thereof, the binder is used in an amount of from 1% to 60%, preferably from 5% to 40%, more preferably from 10% to 30% by weight of the composition; the glidant or The lubricant is selected from the group consisting of colloidal silica, magnesium trisilicate, starch, talc, calcium orthophosphate, magnesium stearate, aluminum stearate, calcium stearate, calcium carbonate, magnesium oxide, polyethylene glycol, Powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, hard The sodium acyl fumarate or a combination thereof, the amount of the flow aid is from 0% to 10%, preferably from 0.1% to 2% by weight of the composition; the lubricant is used in an amount of from 0% to 5% by weight of the composition, preferably 0.5. % to 5%.

As a still further preferred embodiment, the cross-linked polymer is selected from the group consisting of cross-linked polyvinylpyrrolidone (cross-linked povidone), croscarmellose sodium, croscarmellose calcium or a combination thereof; The cellulose and its derivatives are selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose or a combination thereof, preferably hydroxypropyl cellulose, more preferably low substituted hydroxypropyl Cellulose.

As a still further preferred aspect, the pharmaceutical composition comprises:

(i) (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3 , 5,7-trioxa-12-azahexadecane-16-acid or a pharmaceutically acceptable salt thereof, and

(iv) a pharmaceutically acceptable carrier.

Wherein, (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13–

The trioxo-3,5,7-trioxa-12-azahexadecane-16-acid or a pharmaceutically acceptable salt thereof is in a pharmaceutically effective amount, preferably from 10 to 80% by weight of the pharmaceutical composition, More preferably, it is 30-70%, and the balance is a pharmaceutically acceptable carrier.

As a still further preferred aspect, the pharmaceutical composition comprises:

(i) (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3 , 5,7-trioxa-12-azahexadecane-16-acid or a pharmaceutically acceptable salt thereof, and

(ii) an angiotensin II antagonist or a pharmaceutically acceptable salt thereof, and/or

(iii) an ACE inhibitor or a pharmaceutically acceptable salt thereof, and

(iv) a pharmaceutically acceptable carrier.

Wherein (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3, The weight ratio of 5,7-trioxa-12-azahexadecane-16-acid or a pharmaceutically acceptable salt thereof to an angiotensin II antagonist or a pharmaceutically acceptable salt thereof is from 100:1 to 1:100; Preferably the weight ratio is from 10:1 to 1:10;

(9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3,5, a weight ratio of 7-trioxa-12-azahexadecane-16-acid or a pharmaceutically acceptable salt thereof to an ACE inhibitor or a pharmaceutically acceptable salt thereof of from 100:1 to 1:100; preferably a weight ratio of 10 :1~1:10.

As a still further preferred embodiment, the composition of the pharmaceutical composition is as follows:

As a still further preferred embodiment, the composition of the pharmaceutical composition is as follows:

As a still further preferred embodiment, the composition of the pharmaceutical composition is as follows:

As a still further preferred embodiment, the composition of the pharmaceutical composition is as follows:

As a still further preferred embodiment, the composition of the pharmaceutical composition is as follows:

As a still further preferred embodiment, the composition of the pharmaceutical composition is as follows:

As a still further preferred embodiment, the composition of the pharmaceutical composition is as follows:

As a still further preferred embodiment, the pharmaceutical composition may be prepared in the form of a pharmaceutical preparation such as a tablet, a capsule, a granule, a coated tablet, or a solid dispersion.

Another object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of hypertension, acute or chronic heart failure, congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy , supraventricular or ventricular arrhythmia, petition fibrillation, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina pectoris, renal insufficiency, diabetes, secondary aldosteronism , primary or secondary pulmonary hypertension, renal failure, renal vascular hypertension, diabetic retinopathy, migraine, peripheral vascular disease, Raynaud's disease, hyperplasia of the cavity, cognitive dysfunction, glaucoma or stroke medication Applications.

As a still further preferred embodiment, the hypertension is selected from the group consisting of malignant hypertension, essential hypertension, renal vascular hypertension, diabetic hypertension, isolated systolic hypertension or other secondary hypertension; Renal failure includes diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary nephropathy, and renal vascular hypertension.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, or other components such as physiological/pharmaceutical Accepted carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

As is well known to those skilled in the art, the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; additionally, the preferred mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I), or a pharmaceutically acceptable salt The type can be verified according to traditional treatment options.

DRAWINGS

Figure 1 shows the dissolution profile of HAS-000129 calcium salt capsule (the ordinate is the release and the abscissa is the time (minutes)).

Figure 2 is a graph showing blood pressure changes in hypertensive rats treated with oral administration for one week.

Figure 3 is a graph showing heart rate changes in rats treated with oral administration for one week.

detailed description

The present invention is further described in detail with reference to the accompanying drawings, but by no way of limitation,

Example 1

Component	Composition per unit (mg)	composition(%)
Compound 1 calcium salt	25	62.2%
Microcrystalline cellulose	7	17.4%
Low substituted hydroxypropyl cellulose	5	12.4%
Cross-linked povidone	2	5.0%
talcum powder	0.4	1.0%
Colloidal silica	0.2	0.5%
Magnesium stearate	0.6	1.5%
total	40.2	100%

Magnesium stearate, colloidal silica and microcrystalline cellulose were first sieved through a 30 mesh screen. The above mixture, the active ingredient Compound 1 calcium salt polymorph, crosslinked polyvinylpyrrolidone and povidone were then mixed in a hopper mixer for about 120 revolutions. The mixture was pressed with a roller press using a pressure of 30 kN. After pressing, the mixture was milled using a grinder and sieved through a 18 mesh screen to give the final internal phase or granules. The granules are filled in capsules to form capsules.

The dissolution test of the obtained capsule was completed on the dissolution apparatus of ERWEKA DT827LH. The specific dissolution method and conditions were as follows: Take this product, according to the Chinese Pharmacopoeia (2010 edition, part 2) dissolution measurement method (Appendix XC second method), pH 6.8 phosphate buffer 900ml is the dissolution medium, the rotation speed is 50 rpm, according to the law. 10 ml samples were taken at 10 min, 20 min, 30 min, 45 min, and 60 min, respectively, and the drug concentration was determined by HPLC to calculate the release percentage. The dissolution profile of the Compound 1 calcium salt capsule is shown in FIG.

Example 2

Component	Composition per unit (mg)	composition(%)
Compound 1 calcium salt	123	35.1
Valsartan	98	28
Microcrystalline cellulose	61	17.41
Low substituted hydroxypropyl cellulose	43.5	12.44
Cross-linked povidone	17.5	4.98
Colloidal silica	1.75	0.5
Magnesium stearate	5.25	1.5
total weight	350	100

The active ingredient Compound 1 calcium salt and valsartan were first sieved through a 40 mesh sieve. Microcrystalline cellulose and crospovidone were added to the active ingredient, and the mixture was sieved through a 20 mesh sieve. The mixture was then mixed and rotated about 100 revolutions in a hopper mixer. The low-substituted hydroxypropylcellulose and colloidal silica were then added to the hopper mixer, which was then rotated 100 revolutions and finally magnesium stearate was added. The powdered mixture is then compressed into tablets.

The tablets prepared in Example 2 were each placed under different conditions to examine the stability of the preparation. The results are shown in the table:

Example 3

Component	Composition per unit (mg)	composition(%)
Compound 1	125	11.3
Valsartan	125	11.3
Microcrystalline cellulose	32	14.5
Povidone	70	31.8
Cross-linked povidone	21.6	9.8
Colloidal silica	3.2	1.4

Magnesium stearate	3.2	1.4
total weight	420	100.0

Magnesium stearate, colloidal silica and microcrystalline cellulose were first sieved through a 30 mesh screen. The above mixture, active ingredient compound 1 and valsartan, crospovidone and povidone were then mixed in a hopper mixer for about 120 revolutions. The mixture was pressed with a roller press using a pressure of 30 kN. After pressing, the mixture was milled using a grinder and sieved through a 18 mesh screen to give the final internal phase or granules. The granules are filled in capsules to form capsules.

The capsules prepared in Example 3 were placed under different conditions to examine the stability of the preparation. The results are shown in the table:

Example 4

Component	Composition per unit (mg)	composition(%)
Compound 1 calcium salt	80	25
Acisartanamine salt	80	25
Microcrystalline cellulose	128	40
Povidone	5.6	1.75
Cross-linked povidone	20	6.25
Colloidal silica	1.6	0.5
Magnesium stearate	4.8	1.5
total weight	320	100

The active ingredient Compound 1 calcium salt and acesartan were first sieved through a 40 mesh sieve. Microcrystalline cellulose and crospovidone were added to the active ingredient, and the mixture was sieved through a 20 mesh sieve. The mixture was then mixed and rotated about 100 revolutions in a hopper mixer. The povidone and colloidal silica were then added to the hopper mixer and rotated 100 revolutions. Finally add magnesium stearate. The powdered mixture is then compressed into tablets.

The tablets prepared in Example 4 were placed under different conditions to examine the stability of the preparation. The results are shown in the table:

It can be seen from the experimental data of the stability of the preparations of Example 2, Example 3 and Example 4 that the preparation of the present invention can maintain good stability under a certain temperature and humidity condition, although the angiotensin II antagonist valsartan in the preparation, The dissolution rate of azelsartan was slightly slower than that of compound 1, but it also reached more than 90% in about 30 minutes, which was consistent with the dissolution effect of compound 1, which was in line with clinical application standards.

Example 5

Component	Composition per unit (mg)	composition(%)
Compound 1 calcium salt	125	48.1
Enalapril maleate	5	1.9
Microcrystalline cellulose	32	12.3
Povidone	70	26.9
Cross-linked povidone	21.6	8.3
Colloidal silica	3.2	1.2
Magnesium stearate	3.2	1.2
total weight	260	100.0

Magnesium stearate, colloidal silica and microcrystalline cellulose were first sieved through a 30 mesh screen. The above mixture, the active ingredient Compound 1 calcium salt and enalapril maleate, crospovidone and povidone were then mixed in a hopper mixer for about 120 revolutions. The mixture was pressed with a roller press using a pressure of 30 kN. After pressing, the mixture was milled using a grinder and sieved through a 18 mesh screen to give the final internal phase or granules. The granules are filled in an aluminum plastic bag to prepare granules.

The granules prepared in Example 5 were placed under different conditions to investigate the stability of the preparation. The results are shown in the table:

Example 6

Component	Composition per unit (mg)	composition(%)
Compound 1 calcium salt	120	42.1
Fosinopril sodium	5	1.8
Microcrystalline cellulose	32	11.2
Low substituted hydroxypropyl cellulose	32	11.2
Cross-linked povidone	89.6	31.4
Colloidal silica	3.2	1.1
Magnesium stearate	3.2	1.1
total weight	285	100

The active ingredient Compound 1 calcium salt and fosinopril sodium were first sieved through a 40 mesh sieve. Microcrystalline cellulose and crospovidone were added to the active ingredient, and the mixture was sieved through a 20 mesh sieve. The mixture was then mixed and rotated about 100 revolutions in a hopper mixer. The low-substituted hydroxypropylcellulose and colloidal silica were then added to the hopper mixer and rotated 100 revolutions. Finally add magnesium stearate. The powdered mixture is then compressed into tablets.

The granules prepared in Example 6 were placed under different conditions to investigate the stability of the preparation. The results are shown in the table:

Example 7

Component	Composition per unit (mg)	composition(%)
Compound 1	80	25.0
Perindopril	5	1.5
Microcrystalline cellulose	203	63.4
Low substituted hydroxypropyl cellulose	5.6	1.75
Cross-linked povidone	20	6.25
talcum powder	3.2	1.0
Magnesium stearate	3.2	1.0
total weight	320	100.0

Magnesium stearate, talc, and microcrystalline cellulose were first sieved through a 30 mesh screen. The above mixture, the active ingredient compound 1 and perindopril, crospovidone and low-substituted hydroxypropylcellulose were then mixed in a hopper mixer for about 120 revolutions. The mixture was pressed with a roller press using a pressure of 250 kN. After pressing, the mixture was milled using a grinder and sieved through a 18 mesh screen to give the final internal phase or granules. The granules were mixed with crospovidone and talc sifted through a 30 mesh sieve in a hopper mixer for about 50 revolutions. Then, the obtained mixture was mixed with magnesium stearate sieved through a 30 mesh sieve in a hopper mixer for about 50 revolutions. The resulting final mixture is then compressed into tablets using a tablet press. Alternatively, the coating may be carried out using an Opadry coating polymer to obtain a coated tablet.

The coated tablets prepared in Example 7 were placed under different conditions to examine the stability of the preparation. The results are shown in the table:

It can be seen from the experimental data of the stability of the preparations of Example 5, Example 6 and Example 7 that the preparation of the present invention can maintain good stability under a certain temperature and humidity condition, although the ACE inhibitor enalapril and Fu in the preparation are good. The dissolution rate of sipril and perindopril was slightly slower than that of compound 1, but the dissolution rate was more than 90% in about 30 minutes, which was consistent with the dissolution effect of compound 1, and also met the clinical application criteria.

Example 8

Component

Composition per unit (mg)

composition(%)

Compound 1	80	10.0
Valsartan	80	10.0
Perindopril	4	5.0
PEG4000	100	12.5
PEG6000	300	37.5
Microcrystalline cellulose	46	5.75
Povidone	80	10
Cross-linked povidone	100	12.5
Colloidal silica	4.0	0.5
Magnesium stearate	6.0	0.75
total weight	800	100.0

The PEG4000 and PEG6000 were uniformly mixed and heated to 65 ° C. After the two were completely melted, the compound 1, valsartan and perindopril were sequentially added, and the drug was completely dissolved by stirring. The mixture is cooled to room temperature and micronized to obtain a solid dispersion of the drug.

Magnesium stearate, colloidal silica and microcrystalline cellulose were sieved through a 30 mesh screen. The above mixture, the solid dispersion of the drug, crospovidone and povidone were then mixed in a hopper mixer for about 120 revolutions. The mixture was pressed with a roller press using a pressure of 30 kN. After pressing, the mixture was milled using a grinder and sieved through a 18 mesh screen to give the final internal phase or granules. The granules were mixed with crospovidone and colloidal silica sieved through a 30 mesh sieve in a hopper mixer for about 50 revolutions. Then, the obtained mixture was mixed with magnesium stearate sieved through a 30 mesh sieve in a hopper mixer for about 50 revolutions. The resulting final mixture is then compressed into tablets using a tablet press. Alternatively, the coating may be carried out using an Opadry coating polymer to obtain a coated tablet.

The coated tablets prepared in Example 8 were placed under different conditions to examine the stability of the preparation. The results are shown in the table:

Example 9

Component	Composition per unit (mg)	composition(%)
Compound 1	80	25
Valsartan	72	22.5
Hydrochlorothiazide	25	7.8
Microcrystalline cellulose	111	34.7
Povidone	5.6	1.75
Cross-linked povidone	20	6.25
Colloidal silica	1.6	0.5
Magnesium stearate	4.8	1.5
total weight	320	100

The active ingredient Compound 1, Valsartan and Hydrochlorothiazide were first sieved through a 40 mesh sieve. Microcrystalline cellulose and crospovidone were added to the active ingredient, and the mixture was sieved through a 20 mesh sieve. The mixture was then mixed and rotated about 100 revolutions in a hopper mixer. The povidone and colloidal silica were then added to the hopper mixer and rotated 100 revolutions. Finally add magnesium stearate. The powdered mixture is then compressed into tablets.

The tablets prepared in Example 9 were each placed under different conditions to examine the stability of the preparation. The results are shown in the table:

It can be seen from the experimental data of the stability of the preparations of Example 8 and Example 9 that the preparation of the present invention can maintain good stability under a certain temperature and humidity condition, although the preparation of angiotensin II antagonist and ACE inhibitor has just begun. The dissolution rate is a little slower than that of the compound 1, but the dissolution rate is more than 90% in about 30 minutes, which is consistent with the dissolution effect of the compound 1, and also meets the clinical application standard.

Example 10

Component	Composition per unit (mg)	composition(%)
Compound 1 calcium salt	80	20.0
Olmesartan	80	20.0
Hydrochlorothiazide	25	6.2
Microcrystalline cellulose	119	29.8
Povidone	40	10.0
Cross-linked povidone	40	10.0
Colloidal silica	4	1.0
Magnesium stearate	12	3.0
total weight	400	100

The active ingredient Compound 1 calcium salt, olmesartan and hydrochlorothiazide were first sieved through a 30 mesh sieve. Microcrystalline cellulose and crospovidone were added to the therapeutic agent and the mixture was sieved through a 20 mesh sieve. The mixture was then mixed and rotated about 100 revolutions in a hopper mixer. The povidone and colloidal silica were then added to the hopper mixer and rotated 100 revolutions. Finally add magnesium stearate. The powdered mixture is then compressed into tablets. Alternatively, the coating may be carried out using an Opadry coating polymer to obtain a coated tablet.

The coated tablets prepared in Example 10 were placed under different conditions to examine the stability of the preparation. The results are shown in the table:

It can be seen from the experimental data of the stability of the preparation of the example 10 that the preparation of the invention can maintain good stability under a certain temperature and humidity condition, although the diuretic hydrochlorothiazide in the preparation can be more than 90% dissolved in about 30 minutes, and can The dissolution effect of compound 1 and olmesartan tends to be consistent, which is also in line with clinical application standards.

Example 11

(Efficacy of Compound 1 and Valsartan Composition in Rat Model of Renal Hypertension)

In order to evaluate the antihypertensive effect of Compound 1 and its combination with valsartan on hypertension, the inventors performed the following experiment in a hypertensive model rat induced by renal artery stenosis. The experimental method is briefly described as follows:

1. Modeling: 64 male Sprague Dawley (SD) rats weighing 180-200 g (provided by Vital River Laboratories, Beijing, China) for unilateral renal artery constriction surgery. Establish a model of renal hypertension.

2. Animal selection: The rat tail artery pressure was tested for 5 weeks after the operation, and the animal's blood pressure was observed. The animals with stable systolic blood pressure increased more than 160 mmHg (mmHg) were selected for pharmacodynamic test. The number of animals selected was 8.

3. Test group: The experiment was divided into 8 groups, namely sham operation group, hypertension model group, valsartan group, compound group 1, LCZ696 group, compound 1 and valsartan molar ratio (0.5:1) group, compound 1 The molar ratio of valsartan (1:1), compound 1 and valsartan molar ratio (2:1).

4. Animal administration: Animals were started from 9:00-10:00 A.M per day (control animals were given the same volume of vehicle (0.5% sodium carboxymethylcellulose (CMC-Na)), test group and treatment plan. as follows:

5. Experimental observation: After the administration, the physiological changes after the administration of the animals are closely observed, mainly for clinical characterization, and if abnormal phenomena are recorded and analyzed in time; respectively, 6-8 hr after administration (15:30-17:30 P. Rat tail artery blood pressure and heart rate were measured at M) and 24 hr (09:30-11:30 next day) and the experiment lasted for one week.

6. Analytical method: After the end of the experiment, Mean±SEM was calculated using Graphpad Prism software. The difference significance test was performed using t-test, one way ANOVA test or two way ANOVA test (P<0.05 was considered significant between the two groups). difference).

7. Analysis of the results:

1) Compound 1 and valsartan alone can reduce arterial blood pressure in rats for one week.

a) As shown in the results of Figure 2, blood pressure (including systolic blood pressure, diastolic blood pressure, and mean arterial pressure) in the sham-operated group remained within the normal range during one week of testing.

b) The arterial pressure of the model group is stable in the state of hypertension (systolic pressure between 180-190 mmHg), demonstrating surgery More successful, renal artery stenosis surgery resulted in stable hypertensive symptoms in rats.

c) Relative to the model group, in the treatment group of valsartan, LCZ696 and test compound 1, the blood pressure of the animals showed a slow fluctuation in the course of one week of administration; the specific performance was 6-8 after each administration. The hourly antihypertensive effect was the most obvious, and it rose slightly after 24 hours (Fig. 2). Consistent with the literature reports, the antihypertensive time of valsartan and LCZ696 was faster, and the antihypertensive effect after the first administration was significantly faster than that. Test drug compound 1.

In summary, the test drug compound 1 alone has a certain antihypertensive effect, and the antihypertensive effect of continuous administration can achieve the same antihypertensive effect as valsartan and LCZ696 (Fig. 2).

2) Different combinations of compound 1 and valsartan showed significant antihypertensive effect

The test compound 1 and valsartan were dosed at a molar ratio of 0.5:1, 1:1 and 2:1, and the animals were orally administered for one week. The test results showed:

a) Test compound 1 and valsartan have the same antihypertensive effect as the control drug LCZ696 in the first half of the administration according to the molar ratio of 0.5:1 and 1:1; the administration from the 5th to the 7th day The results show that the antihypertensive effect is better than LCZ696.

b) The compatibility of the test compound 1 with valsartan in a molar ratio of 2:1 was slightly lower than LCZ696 in the first half of the administration (Fig. 2). The antihypertensive effect of the last two days of administration can basically achieve the same effect as LCZ696.

c) Comparison of the antihypertensive effects of three different compatible doses showed that the antihypertensive effect of the combined administration was better than that of the single administration group.

d) In addition, the test results also showed that the therapeutic effects of different proportions of compatibility were different. The test compound 1 and valsartan had a better antihypertensive effect than the 2:1 ratio according to the molar ratio of 0.5:1 and 1:1. The compatibility dose, especially the 0.5:1 compatibility dose, is better than the 1:1 and 2:1 antihypertensive effects (Figure 2).

3) Compound 1 reduces and stably controls heart rate in hypertensive rats

a) The test results showed that the heart rate observation of the animals in the sham operation group for one week showed that the average heart rate fluctuated between 330 beats/min to 360 beats/min. In the hypertensive model group, the average heart rate before administration was 370 beats/min to 380 beats/min (Fig. 3).

b) Compared with the hypertensive model group animals, the heart rate of valsartan treatment animals showed a slight slowdown during one week of continuous administration, especially the last two days of treatment. The heart rate of the test compound 1 treated animals showed a significant slowdown 24 hours after the first administration (380 beats/min slowed to 360 beats/min). The heart rate of the animals administered after one week was stable between 340 beats/min to 360 beats/min, similar to the heart rate of the sham-operated animals and LCZ696 treated animals.

c) In addition, the test results also showed that the heart rate of the rats in the combination group was lower and the control was better than that of the single drug group (Fig. 3).

4) Different combinations of Compound 1 and valsartan showed better effects in reducing heart rate in hypertensive rats

The test compound 1 and valsartan were orally administered to the animals for one week at a molar ratio of 0.5:1, 1:1, 2:1, and the test results showed:

a) Three different compatibility doses were consistent with the control drug LCZ696 in the first few days; however, the dose from the 5th to the 7th day showed that the three compatibility doses were better than LCZ696 for heart rate mitigation (Figure 3).

b) Comparison of heart rate adjustment results for three different companion doses showed that the compound dose of test compound 1 and valsartan was better than the compatibility dose of 0.5:1 and 1:1 in a molar ratio of 2:1 (Fig. 3).

8. Test results:

1) Test compound 1 alone has a certain significant antihypertensive effect. At the same time, test compound 1 had a significant slowing of heart rate in hypertensive animals, and the heart rate of hypertensive animals decreased to the heart rate of sham-operated animals one week after administration.

2) Test compound 1 and valsartan have significant antihypertensive effects. The antihypertensive effects of different ratios are not the same, and they are better than the effects of compound 1 alone. At the same time, it was found that the antihypertensive effect of the test compound 1 and valsartan in a molar ratio of 0.5:1 and 1:1 was significantly better than that of the 2:1 compatible preparation.

3) The compatibility of test compound 1 with valsartan has a significant slowing of heart rate in hypertensive animals. The compatibility of the test compound 1 and valsartan in a molar ratio of 2:1 is superior to the effect of the 0.5:1 and 1:1 compatibility preparations.

Example 12

(Efficacy observation of compound 1 and sartan composition in zebrafish heart failure model)

In order to evaluate the therapeutic effect of Compound 1 and its angiotensin (II) antagonist (sartan drug) composition on heart failure, the inventors selected verapamil-induced zebrafish heart failure model to evaluate the efficacy of the compound. The selected sartans include valsartan, candesartan, telmisartan and losartan. The experimental method is briefly described as follows:

1. Establish the model: select the appropriate number of AB zebrafish juveniles and place them in a 6-well plate (Nest Biotech) for feeding and adaptation. In the experiment, pre-treatment with screening drugs for 4h, add 200μM verapamil and continue treatment for 30min. Zebrafish heart failure model.

2. Compatibility ratio: All the sartan drugs compatible with compound 1 were combined with compound 1 in a ratio of 1:1 molar ratio, and the normal control group and the model control group were set.

3. Test procedure: The zebrafish juveniles were treated with drugs in groups. After the drug treatment, 10 zebrafish were randomly selected from each group and photographed under a dissecting microscope (magnification: 56 times) (SMZ645, Nikon), and the zebra was measured and calculated. The heart area of the fish and the area of blood stasis.

4. Analysis of results: After the end of the experiment, the improvement rate of zebrafish heart expansion and the improvement rate of venous blood stasis were calculated according to the following formula.

1) Therapeutic effect of pericardial edema caused by heart failure:

2) Improvement of venous congestion caused by heart failure:

In addition, 10 zebrafish were randomly selected, and the zebrafish blood flow video (Zebralab 3.3 (PB2084C), ViewPoint Life Sciences, France) was recorded under the heartbeat blood flow analysis system, and the zebrafish cardiac output and blood flow were calculated according to the following formula. speed.

3) Influence on cardiac output:

4) Effects on blood flow velocity:

Statistical analysis was performed using analysis of variance and Dunnett's T-test (p < 0.05 indicating significant differences).

5. Experimental results:

1) Compound 1 and its combination with sartan have significant improvement in cardiac expansion of heart failure zebrafish

After verapamil induction, the zebrafish heart increased significantly, and the positive compound digoxin pretreatment group significantly reduced the expansion of the heart area. Similar to digoxin, Compound 1 and its composition with different ratios of sartans in a molar ratio of 1:1 also significantly reduced the expansion of cardiac area. The heart area of zebrafish in different groups was calculated by the above formula. The list of heart enlargement improvement rates is as follows (p<0.001 for all experimental groups):

The test results demonstrate that Compound 1 and its combination with sartan have a significant improvement in heart enlargement of heart failure zebrafish. Among them, the compound 1 and candesartan or telmisartan pharmaceutical composition has a better effect on the heart enlargement of heart failure zebrafish than the pharmaceutical composition of LCZ696, AHU377 + valsartan, and basically reaches the positive compound digoxin. Effect; Compound 1 and Compound 1 and valsartan pharmaceutical composition for heart failure The improvement of zebrafish heart enlargement is much higher than that of LCZ696, AHU377+ valsartan pharmaceutical composition or the positive compound digoxin.

2) Compound 1 and its combination with sartan have significant improvement in venous congestion of heart failure zebrafish

After verapamil induction, zebrafish blood increased significantly, and the positive compound digoxin pretreatment significantly reduced the area of blood stasis; similar to digoxin, compound 1 and its combination with sartan in a molar ratio of 1:1 After treatment, it was found to have a significant improvement in venous congestion in heart failure zebrafish. The improvement rate of venous congestion calculated by the above formula is as follows:

Group number	Component type	Improvement rate of venous congestion
1	LCZ696	58%
2	Compound 1	58%
3	AHU377+ valsartan	53%
4	Compound 1 + valsartan	74%
5	Compound 1 + candesartan	65%
6	Compound 1 + telmisartan	72%
7	Digoxin (positive compound)	68%

The test results show that the combination of compound 1 and sartan has significant improvement on venous congestion of heart failure zebrafish. Among them, the improvement effect of compound 1 on venous congestion of heart failure zebrafish basically reached the effect of LCZ696, AHU377+ valsartan pharmaceutical composition, slightly lower than the effect of the positive compound digoxin; but compound 1 and valsartan, kan The pharmaceutical composition of dexlandam and telmisartan has a better effect on the venous congestion of heart failure zebrafish than the LCZ696, AHU377+ valsartan pharmaceutical composition, and can achieve or exceed the effect of the positive compound digoxin.

3) Compound 1 and its combination with sartan have significant improvement in cardiac output of heart failure zebrafish

The test set the cardiac output of the normal control group to be 100%, and verapamil induced a significant decrease in cardiac output of the zebrafish. After digoxin treatment, cardiac output increased significantly, and cardiac output increased by approximately 60%. Similar to digoxin, Compound 1 and its pharmaceutical compositions with different sartans in a molar ratio of 1:1 have the same therapeutic effect. The list of cardiac output increase rates calculated by the above formula is as follows:

Group number	Component type	Cardiac output increase rate
1	LCZ696	73%
2	Compound 1	94%
3	AHU377+ valsartan	83%
4	Compound 1 + valsartan	71%
5	Compound 1 + candesartan	59%
6	Compound 1 + telmisartan	54%
7	Digoxin (positive compound)	60%

The results of the test showed that Compound 1 and its combination with valsartan had significant improvement on cardiac output of heart failure zebrafish, especially compound 1 was effective in cardiac output of heart failure zebrafish; Compound 1 The effect of the pharmaceutical composition with candesartan and telmisartan on the cardiac output of heart failure zebrafish can basically achieve the effect of the positive compound digoxin.

4) Compound 1 and its combination with sartan have significant effects on blood flow velocity in heart failure zebrafish sartan

The experiment found that after the induction of verapamil, the blood flow velocity of zebrafish was significantly reduced, and the blood flow of the positive compound digoxin pretreatment was significantly accelerated. After treatment with Compound 1 and its sartan drug in a 1:1 molar ratio, it was found that the blood flow of zebrafish was significantly accelerated. The list of bleeding flow increase rates calculated by the above formula is as follows:

Group number	Component type	Blood flow increase rate
1	LCZ696	46%
2	Compound 1	54%
3	AHU377+ valsartan	44%
4	Compound 1 + valsartan	41%
5	Compound 1 + candesartan	33%
6	Compound 1 + telmisartan	39%
7	Digoxin (positive compound)	28%

The test results show that Compound 1 and its combination with valsartan have significant improvement in blood flow velocity of heart failure zebrafish; Compound 1 and valsartan, candesartan, telmisartan pharmaceutical composition The improvement of blood flow velocity of heart failure zebrafish is also higher than that of the positive compound digoxin.

Example 13

(Evaluation of the efficacy of Compound 1 and Ply-like drug composition in zebrafish heart failure model)

In order to evaluate the therapeutic effect of Compound 1 and its angiotensin-converting enzyme (ACE) antagonist (Puli) combination on heart failure, the inventors selected the efficacy of verapamil-induced zebrafish heart failure model on compounds. Conduct an evaluation. The selected sartan drugs include: benazepril, ramipril, fosinopril, enalapril and the like. The experimental method is as in Example 12, and the experimental results are as follows:

1) Compound 1 and Ply-like drug composition have significant improvement on cardiac expansion of heart failure zebrafish

After verapamil induction, the zebrafish heart increased significantly, and the positive compound digoxin pretreatment treatment group significantly reduced the expansion of the heart area. Similar to digoxin, the ratio of compound 1 to the prion was 1: 1 The pharmaceutical composition has a significant improvement effect on heart enlargement of heart failure zebrafish. The list of heart enlargement improvement rates calculated by the above formula is as follows:

Group number	Component type	Improvement rate of heart enlargement
1	LCZ696	66%
2	Compound 1 + benazepril	46%
3	Compound 1 + fosinopril	56%
4	Compound 1 + Ramipril	69%
5	Compound 1 + enalapril	61%
6	Digoxin (positive compound)	89%

2) Compound 1 and Ply-like pharmaceutical composition have significant improvement on venous stasis in heart failure zebrafish

After verapamil induction, zebrafish blood increased significantly, and the positive compound digoxin pretreatment significantly reduced the area of blood stasis. After drug treatment, it was found that sartan drugs significantly improved the venous congestion of heart failure zebrafish. Similar to digoxin, Compound 1 and different Ply drugs have a significant improvement in venous congestion of heart failure zebrafish according to a molar ratio of 1:1. The list of improvement rates for venous congestion is calculated by the above formula. as follows:

Group number	Component type	Improvement rate of venous congestion
1	LCZ696	57%
2	Compound 1 + benazepril	66%
3	Compound 1 + fosinopril	87%
4	Compound 1 + Ramipril	82%
5	Compound 1 + enalapril	81%
6	Digoxin (positive compound)	62%

The test results show that Compound 1 and Ply-like pharmaceutical composition have significant improvement effects on venous congestion of heart failure zebrafish, especially the pharmaceutical composition of Compound 1 and fosinopril, ramipril and enalapril. The improvement of venous congestion in heart failure zebrafish has been greatly improved compared to LCZ696 and the positive compound digoxin.

3) Combination of Compound 1 and Plygi has a significant improvement in cardiac output of heart failure zebrafish

The test set the cardiac output of the normal control group to be 100%, and verapamil induced a significant decrease in cardiac output of the zebrafish. After digoxin treatment, cardiac output increased significantly. Similar to digoxin, Compound 1 and the different sartans have the same therapeutic effect in a pharmaceutical composition with a molar ratio of 1:1. The list of cardiac output increase rates calculated by the above formula is as follows:

Group number	Component type	Heart rate increase rate
1	LCZ696	72%
2	Compound 1 + benazepril	70%
3	Compound 1 + fosinopril	53%
4	Compound 1 + Ramipril	87%
5	Compound 1 + enalapril	63%
6	Digoxin (positive compound)	58%

The test results show that Compound 1 and Ply-like drug composition have significant improvement on heart output of heart failure zebrafish, especially compound 1 and ramipril drug composition have significant effect on cardiac output of heart failure zebrafish. .

4) Compound 1 and Ply-like drug composition have significant improvement on blood flow velocity in zebrafish with heart failure

The experiment found that after the induction of verapamil, the blood flow velocity of zebrafish was significantly reduced, and the blood flow of the positive compound digoxin pretreatment was significantly accelerated. After treatment with Compound 1 and Ply-like drugs in a molar ratio of 1:1, the blood flow of zebrafish was significantly accelerated. The list of bleeding flow increase rates calculated by the above formula is as follows:

Group number	Component type	Blood flow increase rate
1	LCZ696	66%
2	Compound 1 + benazepril	70%

3	Compound 1 + fosinopril	55%
4	Compound 1 + Ramipril	76%
5	Compound 1 + enalapril	50%
6	Digoxin (positive compound)	46%

The test results show that Compound 1 and Ply-like drug composition have significant improvement on blood flow velocity of heart failure zebrafish; especially compound 1 and benazepril, ramipril pharmaceutical composition against heart failure zebrafish The effect of improving blood flow velocity is remarkable.

It should be noted that the above embodiments are only for explaining the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand Modifications or equivalent substitutions, in particular the pharmaceutical compositions of Examples 12, 13, the compounds 1 of the invention and the corresponding angiotensin (II) antagonists (sartans) and/or angiotensin converting enzymes ( ACE) antagonists (Pulis) are studied in a molar ratio of 1:1. According to the technical problem solved by the present invention, different compatibility ratios of the pharmaceutical compositions (for example, 1:10, 1:5, 1: 2, 1:1.1, 1.11, 1, 2:1, 5:1, 10:1 and other different ratios of the pharmaceutical composition) the effect produced should also meet the object of the present invention, the technical solution will not deviate from the present invention The spirit and scope of the technical solutions are intended to be included within the scope of the appended claims.

Claims (20)

1. A pharmaceutical composition comprising:

   (i) (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3 , 5,7-trioxa-12-azahexadecane-16-acid or a pharmaceutically acceptable salt thereof, and/or

   (ii) an angiotensin II antagonist or a pharmaceutically acceptable salt thereof, and/or

   (iii) an ACE inhibitor or a pharmaceutically acceptable salt thereof, and

   (iv) a pharmaceutically acceptable carrier.
2. The pharmaceutical composition according to claim 1, wherein said angiotensin II antagonist is selected from the group consisting of losartan, irbesartan, olmesartan, telmisartan, valsartan, and azusa. Tantan, candesartan, eprosartan, losartan, saprisartan, ilartartan, tamsaltan, elsartan or a pharmaceutically acceptable salt thereof; preferably from valsartan, candesartan And telmisartan, losartan, azilsartan or a pharmaceutically acceptable salt thereof or a combination thereof.
3. The pharmaceutical composition according to claim 1, wherein said ACE inhibitor is selected from the group consisting of enalapril, cilazapril, quinapril, ramipril, benazepril, and perindopril. , sulpiride, fosinopril, captopril, benazepril or a pharmaceutically acceptable salt thereof, or a combination thereof, preferably from enalapril, ramipril, fosinopril, benaze Or a pharmaceutically acceptable salt thereof or a combination thereof.
4. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition further comprises (v) a diuretic; said diuretic is selected from the group consisting of furosemide, ethenic acid, bumetanide, and a carrier Lasemide, hydrochlorothiazide, chlorthalidone, benzfluorothiazide, cyclopentathiazide, poritizine, metoprazine, indapamide or a pharmaceutically acceptable salt thereof, or a combination thereof.
5. The pharmaceutical composition according to claim 1, wherein said (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-tri The pharmaceutically acceptable salt of methyl-4,8,13-trioxo-3,5,7-trioxa-12-azahexadecane-16-acid is selected from the group consisting of calcium, sodium or ammonium salts thereof.
6. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable carrier is selected from the group consisting of a diluent or a filler, a disintegrant, a binder, a glidant, a lubricant, a colorant, or a combination thereof.
7. The pharmaceutical composition according to claim 6, wherein the diluent or filler is selected from the group consisting of powdered sugar, compressible sugar, glucose, sucrose, lactose, dextrin, mannitol, microcrystalline cellulose, sorbitol , starch or a combination thereof, diluent or filler is used in an amount of 4% to 60%, preferably 20% to 40% by weight of the composition; the disintegrant is selected from the group consisting of starch, clay, cellulose, alginate, gum , cross-linked polymers, soy a sugar, guar gum or a combination thereof, the disintegrant is used in an amount of from 0% to 65%, preferably from 1% to 40% by weight of the composition; the binder is selected from the group consisting of starch, cellulose and derivatives thereof, sucrose, Glucose, corn syrup, gelatin, povidone or a combination thereof, the binder is used in an amount of from 1% to 60%, preferably from 5% to 40%, more preferably from 10% to 30% by weight of the composition; the glidant Or the lubricant is selected from the group consisting of colloidal silica, magnesium trisilicate, starch, talc, calcium orthophosphate, magnesium stearate, aluminum stearate, calcium stearate, calcium carbonate, magnesium oxide, polyethylene glycol. , powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, sodium stearyl fumarate or a combination thereof, the amount of the flow aid is 0 of the weight of the composition From 0.01% to 10%, preferably from 0.1% to 2%; the lubricant is used in an amount of from 0% to 5%, preferably from 0.5% to 5% by weight of the composition.
8. The pharmaceutical composition according to claim 7, wherein the crosslinked polymer is selected from the group consisting of crosslinked polyvinylpyrrolidone, croscarmellose sodium, croscarmellose calcium or a combination thereof; The cellulose and its derivatives are selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose or a combination thereof, preferably hydroxypropyl cellulose, more preferably low substituted hydroxy group. Propyl cellulose.
9. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition comprises:

   (i) (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3 , 5,7-trioxa-12-azahexadecane-16-acid or a pharmaceutically acceptable salt thereof, and

   (iv) a pharmaceutically acceptable carrier;

   Wherein (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3, The content of 5,7-trioxa-12-azahexadecane-16-acid or a pharmaceutically acceptable salt thereof is a pharmaceutically effective amount, preferably 10 to 80% by weight, more preferably 30 to 70 by weight of the pharmaceutical composition. %, the rest are pharmaceutically acceptable carriers.
10. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition comprises:

    (i) (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3 , 5,7-trioxa-12-azahexadecane-16-acid or a pharmaceutically acceptable salt thereof, and

    (ii) an angiotensin II antagonist or a pharmaceutically acceptable salt thereof, and/or

    (iii) an ACE inhibitor or a pharmaceutically acceptable salt thereof, and

    (iv) a pharmaceutically acceptable carrier;

    Wherein (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3, The weight ratio of 5,7-trioxa-12-azahexadecane-16-acid or a pharmaceutically acceptable salt thereof to an angiotensin II antagonist or a pharmaceutically acceptable salt thereof is from 100:1 to 1:100; Preferably the weight ratio is from 10:1 to 1:10;

    (9R,11S)-11-([1,1'-biphenyl]-4-ylmethyl)-2,6,9-trimethyl-4,8,13-trioxo-3,5, a weight ratio of 7-trioxa-12-azahexadecane-16-acid or a pharmaceutically acceptable salt thereof to an ACE inhibitor or a pharmaceutically acceptable salt thereof of from 100:1 to 1:100; preferably a weight ratio of 50 :1~1:50.
11. The pharmaceutical composition according to claim 10, wherein the composition of the pharmaceutical composition is as follows:

    
12. The pharmaceutical composition according to claim 11, wherein the composition of the pharmaceutical composition is as follows:

    
13. The pharmaceutical composition according to claim 10, wherein the composition of the pharmaceutical composition is as follows:

    
14. The pharmaceutical composition according to claim 13, wherein the composition of the pharmaceutical composition is as follows:

    
15. The pharmaceutical composition according to claim 10, wherein the composition of the pharmaceutical composition is as follows:

    
16. The pharmaceutical composition according to claim 11, wherein the composition of the pharmaceutical composition is as follows:

    
17. The pharmaceutical composition according to claim 13, wherein the composition of the pharmaceutical composition is as follows:

    
18. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a granule, a coated tablet or a solid dispersion.
19. The pharmaceutical composition according to claim 1 for use in the treatment or prevention of hypertension, acute or chronic heart failure, congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular or Ventricular arrhythmia, petition fibrillation, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina pectoris, renal insufficiency, diabetes, secondary aldosteronism, primary or Application in secondary pulmonary hypertension, renal failure, renal vascular hypertension, diabetic retinopathy, migraine, peripheral vascular disease, Raynaud's disease, hyperplasia of the cavity, cognitive dysfunction, glaucoma or stroke medication.
20. The use according to claim 19, wherein said hypertension is selected from the group consisting of malignant hypertension, essential hypertension, renal vascular hypertension, diabetic hypertension, isolated systolic hypertension or other secondary Hypertension; renal failure includes diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary nephropathy, renal vascular hypertension disease.

Images