WO2016086790A1 - Composition pharmaceutique d'inhibiteur de la nep et utilisation associée - Google Patents

Composition pharmaceutique d'inhibiteur de la nep et utilisation associée Download PDF

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WO2016086790A1
WO2016086790A1 PCT/CN2015/095626 CN2015095626W WO2016086790A1 WO 2016086790 A1 WO2016086790 A1 WO 2016086790A1 CN 2015095626 W CN2015095626 W CN 2015095626W WO 2016086790 A1 WO2016086790 A1 WO 2016086790A1
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pharmaceutical composition
pharmaceutically acceptable
acceptable salt
compound
group
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PCT/CN2015/095626
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English (en)
Chinese (zh)
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王培全
张磊
李成海
包如迪
徐耀昌
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上海翰森生物医药科技有限公司
江苏豪森药业集团有限公司
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Priority to CN201580049644.2A priority Critical patent/CN107072977B/zh
Publication of WO2016086790A1 publication Critical patent/WO2016086790A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame

Definitions

  • the invention belongs to the field of biomedicine, and particularly relates to a NEP inhibitor drug combination and application thereof.
  • 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.
  • Compound 1 is a novel neutral endopeptidase inhibitor.
  • Neutral endopeptidase EC3.4.24.11; enkephalinase; ATP
  • ATP 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.
  • 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.
  • ARBs angiotensin receptor blockers
  • ACE inhibitors also known as angiotensin-converting enzyme inhibitors
  • Zn2+ which is the necessary binding site for the ACE inhibitor effective group. Once bound, the activity of ACE disappears.
  • 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.
  • SH sulfhydryl
  • COO- carboxyl
  • POO- phosphonic acid groups
  • 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+.
  • 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.
  • PLC phosphatase C
  • 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.
  • 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.
  • 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:
  • an angiotensin II antagonist or a pharmaceutically acceptable salt thereof (ii) an angiotensin II antagonist or a pharmaceutically acceptable salt thereof, and/or
  • 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.
  • 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.
  • the pharmaceutical composition further comprises (v) a diuretic.
  • 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.
  • 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.
  • 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 (2 ⁇ ) 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.
  • 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 (2 ⁇ ) of 16.5 ⁇ 0.2°.
  • 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 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.
  • 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 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.
  • the pharmaceutical composition comprises:
  • 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.
  • the pharmaceutical composition comprises:
  • an angiotensin II antagonist or a pharmaceutically acceptable salt thereof (ii) an angiotensin II antagonist or a pharmaceutically acceptable salt thereof, and/or
  • 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;
  • composition of the pharmaceutical composition is as follows:
  • composition of the pharmaceutical composition is as follows:
  • composition of the pharmaceutical composition is as follows:
  • composition of the pharmaceutical composition is as follows:
  • composition of the pharmaceutical composition is as follows:
  • composition of the pharmaceutical composition is as follows:
  • composition of the pharmaceutical composition is as follows:
  • 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.
  • 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.
  • 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.
  • 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.
  • composition(%) Compound 1 calcium salt 25 62.2%
  • Cross-linked povidone 2 5.0% talcum powder 0.4 1.0%
  • 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 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.
  • composition(%) 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.
  • Example 2 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:
  • 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, 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.
  • Example 3 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:
  • composition(%) 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.
  • Example 4 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:
  • 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.
  • Example 5 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:
  • 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.
  • Example 6 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:
  • 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.
  • 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.
  • the coating may be carried out using an Opadry coating polymer to obtain a coated tablet.
  • Example 7 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:
  • Example 5 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.
  • composition(%) 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.
  • 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.
  • the coating may be carried out using an Opadry coating polymer to obtain a coated tablet.
  • Example 8 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:
  • 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.
  • Example 9 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:
  • Example 8 and Example 9 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.
  • 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.
  • Example 10 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:
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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).
  • test compound 1 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:
  • 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.
  • 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).
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • test compound 1 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • the test results show that the combination of compound 1 and sartan has significant improvement on venous congestion of heart failure zebrafish.
  • 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.
  • 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:
  • 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.
  • 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:
  • Compound 1 and Ply-like drug composition have significant improvement on cardiac expansion of heart failure zebrafish
  • 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:
  • Compound 1 and Ply-like pharmaceutical composition have significant improvement on venous stasis in heart failure zebrafish
  • 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.
  • 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:
  • 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%
  • 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. .
  • Compound 1 and Ply-like drug composition have significant improvement on blood flow velocity in zebrafish with heart failure
  • 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.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un inhibiteur de l'endopeptidase neutre (NEP), et l'utilisation de cette composition dans la préparation d'un médicament destiné au traitement et à la prévention de maladies associées à la NEP. La composition comprend : (i) le (9R,11S)-11-([1,1'-biphényl]-4-ylméthyl)-2,6,9-triméthyl-4,8,13-trioxo-3,5,7-trioxa-12-azahexadécane-16-acide (composé 1) ou un sel pharmaceutique de celui-ci, et/ou (ii) un antagoniste de l'angiotensine II ou un sel pharmaceutique de celui-ci, et/ou (iii) un inhibiteur de l'enzyme de conversion de l'angiotensine, et (iv) un support pharmaceutiquement acceptable.
PCT/CN2015/095626 2014-12-03 2015-11-26 Composition pharmaceutique d'inhibiteur de la nep et utilisation associée WO2016086790A1 (fr)

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CN101119718A (zh) * 2005-02-18 2008-02-06 索尔瓦药物有限公司 包含nep-抑制剂，内源性内皮素产生***抑制剂和利尿剂的药物组合物

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CN104230865B (zh) * 2013-06-13 2018-01-09 上海翰森生物医药科技有限公司 联芳基取代的4‑氨基丁酸衍生物及其制备方法和用途

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Publication number Priority date Publication date Assignee Title
CN101119718A (zh) * 2005-02-18 2008-02-06 索尔瓦药物有限公司 包含nep-抑制剂，内源性内皮素产生***抑制剂和利尿剂的药物组合物

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