WO2018064945A1 - 药物组合物 - Google Patents

药物组合物 Download PDF

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WO2018064945A1
WO2018064945A1 PCT/CN2017/103651 CN2017103651W WO2018064945A1 WO 2018064945 A1 WO2018064945 A1 WO 2018064945A1 CN 2017103651 W CN2017103651 W CN 2017103651W WO 2018064945 A1 WO2018064945 A1 WO 2018064945A1
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compound
formula
pharmaceutically acceptable
salt
group
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PCT/CN2017/103651
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English (en)
French (fr)
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王朝东
陈永凯
胡柳
曾弦
康代武
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武汉朗来科技发展有限公司
武汉启瑞药业有限公司
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Priority to US16/340,035 priority Critical patent/US11096928B2/en
Priority to CN201780062294.2A priority patent/CN109803657B/zh
Priority to EP17857826.6A priority patent/EP3524250A4/en
Publication of WO2018064945A1 publication Critical patent/WO2018064945A1/zh

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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
    • A61K31/33—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
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the field of medicine, and in particular to a pharmaceutical composition comprising a neutral endopeptidase (NEP) inhibitor and an azilsartan ester derivative.
  • NEP neutral endopeptidase
  • Cardiovascular disease also known as circulatory disease, refers to a series of diseases involving the circulatory system.
  • the circulatory system mainly includes the heart and blood vessels (arteries, veins, and microvessels).
  • cardiovascular disease is the number one cause of death worldwide, with more deaths from cardiovascular disease each year than any other cause of death.
  • Common cardiovascular diseases include: hypertension, heart failure, coronary heart disease, heart disease, atherosclerosis, angina pectoris, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmia, housing Tremor, cardiac fibrosis, atrial flutter, harmful vascular remodeling, myocardial infarction and its sequelae.
  • Cardiovascular diseases generally have similar causes, processes, and treatments. Most cardiovascular diseases can be prevented by addressing risk factors such as tobacco use, unhealthy diet, obesity, high blood pressure, diabetes, and elevated blood lipids.
  • the World Health Organization believes that a combination of drugs, such as cholesterol-lowering statins and blood pressure lowering drugs, as well as aspirin, can significantly reduce the risk of cardiovascular recurrence or death.
  • any combination of cardiovascular disease drugs with different mechanisms of action does not necessarily have a beneficial effect. Therefore, the development of a pharmaceutical composition that can exert a combined therapeutic effect may provide a more effective control effect on cardiovascular diseases.
  • Neutral endopeptidase is a zinc metalloproteinase on the surface of endothelial cells. Inhibition of NEP can increase atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). ), the levels of C-type natriuretic peptide (CNP), bradykinin and adrenomedullin, so NEP inhibitors can play a role in diuresis, vasodilation, improvement of endothelial function, and inhibition of vascular smooth muscle cell proliferation under pathological conditions, thereby Improve vascular hemodynamics, prevent atherosclerosis, and delay the progression of heart failure.
  • NEP atrial natriuretic peptide
  • BNP brain natriuretic peptide
  • CNP C-type natriuretic peptide
  • bradykinin bradykinin
  • adrenomedullin adrenomedullin
  • Angiotensin II (Ang II) is an important regulator of the regulation of humoral homeostasis in the body, involving blood pressure, electrolyte balance, etc.
  • a large number of literatures have confirmed that Ang II is in hypertension, arterial disease, cardiac hypertrophy, heart failure and diabetes.
  • the pathogenesis of kidney disease plays a major role. Because the abnormal increase of Ang II level is directly related to the occurrence and development of hypertension, cardiac hypertrophy, heart failure, etc., blocking the binding of Ang II to its specific receptor can protect the heart and blood vessels, and the blood vessels are tight.
  • Angiotensin Receptor Blockers ARB have been proven in many randomized clinical trials to reduce the risk of cardiovascular mortality and morbidity. ARB drugs have been widely used in hypertension abroad.
  • biphenyl tetrazolium including losartan (losartan), valsartan (valsartan), irbesartan (irbesartan), candesartan cilexetil and azsarartan medoxomil
  • non-biphenyltetrazolium including eprosartan and telmisartan
  • Chinese patent application CN1615134A discloses a pharmaceutical composition comprising valsartan or a pharmaceutically acceptable salt thereof and a NEP inhibitor or a pharmaceutically acceptable salt thereof;
  • Chinese patent application CN105693543A discloses a Sacobitril (AHU) containing NEP inhibitor. 377, CAS No. 149709-62-6) salts and pharmaceutically acceptable adjuvants and AT1 receptor antagonists such as losartan, eprosartan, valsartan, irbesartan, etc.
  • Chinese patent application CN105837464A discloses a NEP inhibitor containing sacuron and sodium medicinal excipients and other active ingredients such as losartan, eprosartan, valsartan, irbesartan, etc. or pharmaceutically acceptable thereof A pharmaceutical composition of a salt.
  • the above compound is a sultan drug coupled with ligustrazine or a NO donor, and is a prodrug of angiotensin II receptor antagonist azilsartan (TAK-536), which releases hydroxyprosin in vivo or NO, thus effective synergy with azilsartan, enhance antihypertensive effect, has a certain heart rate reduction effect, reduce adverse reactions, and has an ideal protective effect on patients' heart and kidney.
  • TAK-536 angiotensin II receptor antagonist azilsartan
  • the pressure effect has a more obvious and lasting effect of lowering heart rate, and has high safety, and has an ideal protective effect on the heart and kidney function of the patient, and can be used for preventing and/or treating hypertension, chronic heart failure, diabetic nephropathy and the like.
  • the present invention has found that a neutral endopeptidase inhibitor or a pharmaceutically acceptable salt or ester thereof and an angiotensin II receptor antagonist of the formula (I) or a pharmaceutically acceptable salt or ester thereof are used in combination
  • Unexpected synergistic effect has been achieved, which significantly enhances the efficacy of any single prescription. Not only is the blood pressure lower and more stable, but the heart rate reduction effect is more obvious and lasting. At the same time, it has a more obvious effect on improving heart function. Chronic heart failure has a good effect, can be used in lower dose or lower frequency applications, and can reduce the incidence of side effects of a single drug.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) at least one neutral endopeptidase inhibitor or a pharmaceutically acceptable salt or ester thereof, (b) at least one of the following a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier:
  • Each a is the same or different and is independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 1 represents a substituted or unsubstituted following groups: C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl group, (CH 2 ) n O(CH 2 ) m , Aryl or heteroaryl, wherein In a, b, c represents a number of carbon atoms in the alkyl chain, independently selected from 4, 5 or 6, wherein (CH 2) n O (CH 2) m of n, m Independently selected from 1, 2, 3, 4, 5 or 6;
  • R 2 represents hydrogen, halogen, nitro, cyano, or a substituted or unsubstituted group: C 1 -C 8 alkoxy, C 1 -C 8 alkyl, C 1 -C 8 alkylsulfonylamino , arylsulfonylamino, heteroarylsulfonylamino, aminosulfonyl, amino;
  • R 3 represents a group which is absent or substituted or unsubstituted: C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkoxy, C 2 -C 8 alkyne Base, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, Aryl, heteroaryl, wherein Wherein b and c represent the number of carbon atoms of the alkyl chain, independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 4 represents a cyano group, or a substituted or unsubstituted group of an aryl group, an arylsulfonyl group, a heteroaryl group, a C 1 -C 8 alkoxy group, a C 1 -C 8 nitrate group, a C 1 -C group. 8 alkyl, C 1 -C 8 nitrate;
  • R 5 represents a cyano group, or a substituted or unsubstituted group: aryl, heteroaryl, C 1 -C 8 alkoxy, C 1 -C 8 nitrate, C 1 -C 8 alkyl, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, (CH 2) n O (CH 2) m, wherein R 3, R 4, a, m, n independently of one another each as defined above;
  • R 6 and R 7 independently represent hydrogen, unsubstituted or substituted C 1 -C 8 alkoxy or C 1 -C 8 alkyl;
  • R 8 and R 9 independently represent hydrogen, unsubstituted or substituted C 1 -C 8 alkoxy, C 1 -C 8 nitrate or C 1 -C 8 alkyl.
  • a pharmaceutical pack comprising separate containers comprising (a) at least one neutral endopeptidase inhibitor or a pharmaceutically acceptable thereof in a container A pharmaceutical composition of a salt or ester and a pharmaceutically acceptable carrier comprising, in a second container, (b) at least one compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier Pharmaceutical composition.
  • the present invention provides the use of the above pharmaceutical composition or pharmaceutical pack for the preparation of a medicament for preventing and/or treating cardiovascular diseases.
  • the present invention provides the use of the above pharmaceutical composition or pharmaceutical pack for the prevention and/or treatment of a cardiovascular disease.
  • the present invention provides a NEP inhibitor or a pharmaceutically acceptable salt or ester thereof for use in combination with a compound of the formula (I) or a pharmaceutically acceptable salt or ester thereof for prevention and prevention / or use in drugs for the treatment of cardiovascular disease.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt or ester thereof for use in combination with a NEP inhibitor or a pharmaceutically acceptable salt or ester thereof for prevention and / or use in drugs for the treatment of cardiovascular disease.
  • the present invention provides a method for preventing and/or treating cardiovascular diseases, which comprises administering to a patient in need thereof at least one neutral endopeptidase inhibitor or a pharmaceutically acceptable salt thereof Or an ester, and at least one compound of the formula (I) or a pharmaceutically acceptable salt or ester thereof.
  • a neutral endopeptidase inhibitor or a pharmaceutically acceptable salt thereof Or an ester
  • at least one compound of the formula (I) or a pharmaceutically acceptable salt or ester thereof may be used.
  • the patients in need thereof are administered in the form of a single preparation or a preparation independent of each other, and may be administered simultaneously, sequentially, or at appropriate intervals as needed.
  • one or more includes one or more than one, including, but not limited to, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • halogen means fluoro, chloro, bromo and iodo.
  • the substituent may be unsubstituted or optionally further substituted by one or more substituents which may be the same or different selected from the above.
  • Alkyl as used singly or as a suffix or prefix in the present invention is intended to include both branched and straight-chain saturated fats having from 1 to 20 carbon atoms (or the specific number if a specific number of carbon atoms are provided) A hydrocarbon group.
  • C 1 -C 8 alkyl means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • an alkyl group When an alkyl group is substituted by a substituent, it includes an alkyl group substituted with one or more halogens, for example, an alkyl group substituted with 1, 2, 3, 4, 5, 6 halogens, such as a trifluoromethyl group.
  • alkenyl as used herein, alone or as a suffix or prefix, is intended to include a chain comprising alkenyl or olefins having from 2 to 20 carbon atoms, if specified, the specific number of carbon atoms. And a linear aliphatic hydrocarbon group.
  • C 2-6 alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3 Methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • alkynyl used alone or as a suffix or prefix in the present invention is intended to include alkynyl or alkyne containing from 2 to 20 carbon atoms (or the specific number if a specific number of carbon atoms is provided) Branched and linear aliphatic hydrocarbon groups.
  • alkynyl eg, 1-propynyl, 2-propynyl
  • 3-butynyl pentynyl, hexynyl, and 1-methylpent-2-ynyl.
  • aryl as used herein means an aromatic ring structure composed of 5 to 20 carbon atoms.
  • an aromatic ring structure containing 5, 6, 7 and 8 carbon atoms may be a monocyclic aromatic group such as a phenyl group; a ring structure comprising 8, 9, 10, 11, 12, 13 or 14 carbon atoms It may be polycyclic such as naphthyl.
  • the aromatic ring may be substituted with one or more of the above substituents at one or more ring positions.
  • aryl also includes polycyclic ring systems having two or more rings wherein two or more carbons are shared by two adjacent rings (the ring is a "fused ring"), wherein at least One ring is aromatic and the other ring may be, for example, a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and/or heterocyclic group.
  • polycyclic rings include, but are not limited to, 2,3-dihydro-1,4-benzodioxadiene and 2,3-dihydro-1-benzofuran.
  • cycloalkyl as used herein is intended to include saturated cyclic groups having the indicated number of carbon atoms. These terms may include fused or bridged polycyclic systems.
  • the cycloalkyl group has 3 to 40 carbon atoms in its ring structure. In one embodiment, the cycloalkyl has 3, 4, 5 or 6 carbon atoms in its ring structure.
  • C 3-6 cycloalkyl means a group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • heteroaryl refers to a heteroaromatic heterocycle having at least one ring heteroatom such as sulfur, oxygen or nitrogen.
  • miscellaneous Aryl groups include single ring systems and polycyclic systems (eg, having 2, 3 or 4 fused rings).
  • heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, fluorene , pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, 1,2,4 -thiadiazolyl, isothiazolyl, benzothienyl, fluorenyl, oxazolyl, benzimidazolyl, benzoxazolyl, azabenzoxazolyl, imidazothiazolyl, benzo[1] 4] dioxolyl, benzo[1,3]dioxolyl and the
  • a heteroaryl has from 3 to 40 carbon atoms and in other embodiments from 3 to 20 carbon atoms. In some embodiments, a heteroaryl group contains 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, a heteroaryl has 1 to 4, 1 to 3 or 1 to 2 heteroatoms. In some embodiments, a heteroaryl has 1 heteroatom.
  • heterocyclyl refers to a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring containing from 3 to 20 atoms, wherein 1, 2, 3, 4 or 5 Ring atoms are selected from nitrogen, sulfur or oxygen, and unless otherwise indicated, may be attached via carbon or nitrogen, wherein the -CH 2 - group is optionally replaced by -C(O)-; and unless otherwise stated to the contrary
  • the ring nitrogen atom or the ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or a ring nitrogen atom, optionally quaternized; wherein -NH in the ring is optionally acetyl, formyl, methyl Or a methylsulfonyl group; and the ring is optionally substituted with one or more halogens.
  • heterocyclic group when the total number of S atoms and O atoms in the heterocyclic group exceeds 1, these hetero atoms are not adjacent to each other.
  • the heterocyclic group is bicyclic or tricyclic, at least one ring may be optionally a heteroaromatic or aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclic group is a monocyclic ring, it must not be aromatic. Examples of heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl.
  • the compounds of the invention may also contain one or more asymmetric centers.
  • Asymmetric carbon atoms may exist in the (R) or (S) configuration, with only one asymmetric center, resulting in a racemic mixture containing multiple asymmetric centers, resulting in a mixture of diastereomers.
  • the substituent may exist in a cis or trans isomer form.
  • the compounds of formula (I) also include all possible stereoisomers thereof, which are single stereoisomers or stereoisomers (for example R-isomers or S-isomers, or E-isomers) The form of any mixture of any ratio of the bulk or Z-isomer).
  • Single stereoisomers (e.g., single enantiomers or single diastereomers) of a compound of the invention can be achieved by any suitable prior art method (e.g., chromatography, particularly, for example, chiral chromatography). Separation.
  • the compounds may also exist in tautomeric forms.
  • the compounds of the invention include all possible tautomers of the compounds of formula (I) which are in the form of a single tautomer or any mixture of said tautomers in any ratio.
  • NEP inhibitors of the invention and the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both acidic centers (eg carboxyl groups) Also containing a basic center (e.g., an amino group), it can also form an internal salt.
  • acid addition salts include, but are not limited to, hydrochloride, hydrofluoride, hydrobromide, hydroiodide, sulfate, pyrosulfate, phosphate, nitrate, methanesulfonate , ethanesulfonate, 2-hydroxyethanesulfonate, besylate, tosylate, sulfamate, 2-naphthalenesulfonate, formate, acetoacetate, pyruvic acid, silicate , cinnamate, benzoate, acetate, glycolate, trifluoroacetate, trimethylacetate, propionate, butyrate, hexanoate, heptanoate, ten Monoacid salt, stearate, ascorbate, camphorate, camphor sulfonate, citrate, fumarate, malate, maleate, hydroxymaleate, oxalate, water Salicylate, succinate, glu
  • NEP inhibitor of the present invention and the compound of formula (I) may also exist in various pharmaceutically acceptable ester forms including, but not limited to, methyl ester, ethyl ester, propyl ester, and different Propyl ester, butyl ester, isobutyl ester, tert-butyl ester and the like.
  • the NEP inhibitor and the pharmaceutically acceptable salt of the compound of formula (I) are independently selected from the group consisting of Na, K or NH 4 salts; NEP inhibitors or pharmaceutically active compounds of formula (I)
  • the above acceptable esters are independently selected from the group consisting of methyl, ethyl or propyl esters.
  • the NEP inhibitor may be a shakusto, a stereoisomer thereof or a mixture thereof in any ratio.
  • the compound of formula (I) has the structure shown below:
  • the pharmaceutically acceptable salt of the compound of the formula (I) is a K salt; further preferably, the K salt of the compound of the formula (I) has the structure represented by the following formula (II):
  • the K salt of the compound of formula (I) has the structure shown below:
  • (a) is at least one of the following compounds or a pharmaceutically acceptable salt or ester thereof:
  • (a) is at least one of the following compounds:
  • (a) is AHU 377, AHU 377 ethyl ester, AHU 377Na, AHU 377K, N-(3-carboxy-1-oxopropyl)-(4S)-p-phenylphenyl.
  • (b) is the following compound 1K:
  • the compound 1K may be amorphous, any one of the crystal forms I, II, III, IV, or a mixture of any of a plurality of ratios; further preferably, the compound 1K may be the crystal form I, crystal form of the compound 1K. A mixture of II or any ratio of the two.
  • the mass ratio of (a) to (b) is (0.5-10): 1, for example, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1. 4:1, 3:1, 2:1, 1:1, 0.5:1; preferably (0.5-5):1, more preferably (0.5-3):1, for example: 3:1, 2.5:1 , 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.45:1, 1.4:1, 1.35:1, 1.3:1, 1.25:1, 1.2:1, 1.15 : 1, 1.1: 1, 1.05: 1, 1:1, 0.95: 1, 0.9: 1, 0.85: 1, 0.8: 1, 0.75: 1, 0.7: 1, 0.65: 1, 0.6: 1, 0.55: 1 , 0.5:1.
  • cardiovascular diseases include, but are not limited to, hypertension, heart failure, coronary heart disease, rheumatic heart disease, congenital heart disease, left ventricular dysfunction, endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy , diabetic cardiomyopathy, supraventricular and ventricular arrhythmia, atrial fibrillation, cardiac fibrosis, atrial flutter, harmful vascular remodeling, myocardial infarction And its sequelae, atherosclerosis, angina pectoris, primary and secondary pulmonary hypertension, renal vascular hypertension.
  • the pharmaceutical compositions or pharmaceutical packs of the invention can be prepared by methods well known in the art.
  • the pharmaceutical composition of the present invention or the pharmaceutical composition in the pharmaceutical pack may be formulated into various dosage forms suitable for oral, inhalation, rectal, topical, parenteral, etc., including, but not limited to, powders suitable for oral administration, Tablets (including various coated tablets, sustained release or controlled release tablets), troches, capsules (including soft and hard capsules), granules, pills, dispersible powders, aqueous or oily suspensions, Aqueous or oily solutions, emulsions, elixirs, syrups, etc., powders or liquid aerosols suitable for inhalation, suppository for rectal, etc.
  • the present invention may also be administered as separate pharmaceutical compositions in different dosage forms or in different dosage intervals by combining separate drugs in the form of a pharmaceutical pack.
  • Pharmaceutically acceptable carriers include, but are not limited to, fillers (or diluents), binders, disintegrants, lubricants, wetting agents, auxiliary lipids, glidants, sweeteners, flavoring agents, solvents, dissolution aids Agents, suspending agents, isotonic agents, buffers, preservatives, antioxidants, colorants, foaming agents, and the like. Those skilled in the art can select the above pharmaceutically acceptable carrier according to actual needs.
  • fillers which may be used include, but are not limited to, lactose, sucrose, microcrystalline cellulose, starch, mannitol, mannitol-starch, etc.
  • binders which may be used include, but are not limited to, microcrystalline cellulose, Povidone, tragacanth, glucose solution, gum arabic, gelatin solution, sucrose, starch paste, etc.
  • disintegrators which can be used include, but are not limited to, croscarmellose sodium, low-substituted hydroxypropyl cellulose , crospovidone, sodium starch glycolate, alginic acid, dry starch, bentonite, methyl cellulose, agar, carboxymethyl cellulose, etc.
  • lubricants that can be used include, but are not limited to, talc, magnesium or calcium Stearate, cedar, etc.
  • humectants which may be used include, but are not limited to, propylene glycol monostearate,
  • the dosage of the active ingredient of the pharmaceutical composition or pharmaceutical pack of the present invention, and its appropriate unit dosage in a pharmaceutical composition or pharmaceutical pack, can be determined by methods well known in the art.
  • the dose to be administered may be orally administered in an amount of from 1 to 200 mg, preferably from 5 to 150 mg, more preferably from 5 to 100 mg per day, based on the amount of the compound represented by the formula (I).
  • the pharmaceutical composition or the pharmaceutical pack of the present invention may further contain other active ingredients such as a diuretic, a calcium ion antagonist and the like.
  • An advantage and a beneficial effect of the technical solution of the present invention in comparison with the prior art is that the combination of the NEP inhibitor of the present invention and the angiotensin II receptor antagonist represented by the formula (I) can be unexpectedly obtained.
  • the synergistic effect is more stable or long-lasting in terms of lowering blood pressure and/or lowering the heart rate, and also has a good effect of improving cardiac function.
  • the technical solution of the present invention has a good curative effect in treating acute and chronic heart failure, and can be applied at a lower dose or a lower frequency to achieve a corresponding effect, and can reduce the incidence of side effects of a single drug.
  • Figure 1 is a 1 H-NMR spectrum of Compound 1K
  • Figure 2 is an X-ray powder diffraction pattern of the amorphous form of Compound 1K;
  • Figure 3 is an X-ray powder diffraction pattern of Form I
  • Figure 4 is an X-ray powder diffraction pattern of Form II
  • Figure 5 is an X-ray powder diffraction pattern of Form III
  • Figure 6 is an X-ray powder diffraction pattern of Form IV.
  • Form II 100 mg was added, and 2.5 ml of isopropyl acetate was added to obtain a suspension, which was stirred in a water bath at 80 ° C for 8 hours, filtered, and dried.
  • the results of XRD and HPLC showed that the crystal form I content was about 95%.
  • the type II content is about 5%.
  • the control group was given 0.5% sodium carboxymethylcellulose (hereinafter referred to as CMC-Na); the compound 1 group and the compound 1K were dissolved in 0.5% CMC-Na, and the doses were all administered at an effective dose of 1 mg/kg of azilsartan.
  • the administration volume was 4 mL/kg, which was administered by intragastric administration.
  • the systolic blood pressure and heart rate of the animals before administration were used as reference values.
  • the systolic blood pressure and heart rate of SHR were compared before and after administration. Take the average three times. The results are shown in Tables 1 and 2 below.
  • 18-week-old male SHR rats purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • SHR rats purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • the implant is fixed to the abdominal wall, and the postoperative daily care is performed after suturing.
  • Animals with systolic blood pressure exceeding 160 mm Hg were selected into groups, with 6 animals in each group, a total of 9 groups.
  • a group of WKY rats (provided by Beijing Weitong Lihua Co., Ltd.) was set as a normal control.
  • the drug was administered once a day, and was administered by intragastric administration.
  • the administration volume was 4 mL/kg for 4 weeks.
  • the groups were administered as follows:
  • the blank control group was given 0.5% CMC-Na;
  • Compound 1K was administered compound 1K, dissolved in 0.5% CMC-Na, and the dose was administered at an effective dose of 1 mg/kg of azilsartan;
  • the valsartan group was given valsartan and dissolved in 0.5% CMC-Na at a dose of 30 mg/kg;
  • Potassium azilsartan mezate was administered to the group of potassium azilsartan citrate, dissolved in 0.5% CMC-Na, and the dose was administered at an effective dose of 1 mg/kg of azilsartan;
  • AHU 377K group was given AHU 377K, dissolved in 0.5% CMC-Na, the dose was 30mg/kg;
  • AHU377 ammonium salt group was given AHU377 ammonium salt, dissolved in 0.5% CMC-Na, the dosage was 30mg/kg;
  • LCZ696 group was given LCZ696, dissolved in 0.5% CMC-Na, the dose was 60mg/kg;
  • the valsartan + AHU 377K group was given valsartan and AHU 377K simultaneously, dissolved in 0.5% CMC-Na, valsartan dose 30mg/kg, AHU 377K dose 30mg/kg;
  • Azisartan potassium potassium + AHU 377K group was given both azilsartan potassium and AHU 377K, dissolved in 0.5% CMC-Na, and the dose of azilsartan potassium was 1 mg/kg effective dose of azilsartan. , AHU 377K dose of 30mg / kg;
  • the compound 1K+AHU 377K group was simultaneously administered with compound 1K and AHU 377K, and dissolved with 0.5% CMC-Na.
  • Compound 1K was administered at a dose of 1 mg/kg of azilstan and AHU 377K was administered at a dose of 30 mg/kg.
  • Compound 1K + AHU377 ammonium salt group was simultaneously administered compound 1K and AHU377 ammonium salt, dissolved in 0.5% CMC-Na, compound 1K dose was 1 mg / kg azilstan effective dose, AHU377 ammonium salt dose 30 mg / kg .
  • DSI remote pressure gauge was used to detect blood pressure and heart rate. On the 28th day of administration, SHR systolic blood pressure and heart rate were measured. The results are shown in Table 3 below.
  • the drug combination of the present invention has a significant antihypertensive effect compared to any single administration, and its effect on the regulation of heart rate is also markedly improved.
  • the buck curve was more stable, and the blood pressure and heart rate were lower. Longer-lasting, synergistic technical results. Therefore, lower dose or lower frequency applications can be used to achieve antihypertensive effects, and can also be used to reduce the incidence of side effects of a single drug.
  • Example 11 Therapeutic effect of pharmaceutical composition on acute heart failure caused by coronary artery ligation
  • the compound drug of the present invention can significantly reduce the mean arterial pressure of the acute heart failure animal, improve the ejection fraction, and have a good therapeutic effect on acute heart failure caused by myocardial ischemia, compared with the unilateral and other combinations. A synergistic effect.
  • Azilsartan mesylate derivative, NEP inhibitor, dioleoylphosphatidylcholine, cholesterol, sodium glycocholate and soybean sterol are dissolved in a mixed solvent of ethanol and n-hexane, and uniformly mixed in a rotary thin film evaporator.
  • the organic solvent was removed under reduced pressure to obtain a phospholipid membrane; a sodium citrate-sodium citrate buffer solution having a pH of 6.0 was added, shaken, and stirred for 30 minutes to complete the phospholipid membrane.
  • the hydration was emulsified by a tissue masher at a high speed for 10 minutes, and filtered through a 0.45 ⁇ m microporous membrane to prepare a liposome suspension, which was spray-dried to obtain a medicated liposome powder, which was then combined with nectar.
  • Alcohol, microcrystalline cellulose and croscarmellose sodium are mixed, uniformly mixed through 60 mesh sieve, hydroxypropyl cellulose is added, ethanol solution is prepared to prepare soft material, granulated by 20 mesh sieve, dried at 50 ° C, dried The granules and magnesium stearate were uniformly mixed, sieved through a 18 mesh sieve, compressed, and coated to prepare a liposome tablet.
  • the material was sieved for use; the azisartan ester derivative, NEP inhibitor, mannitol, croscarmellose sodium was poured into a three-dimensional mixer for 5 min, stirred at 3 rpm, cut at 30 rpm; then added with stearin The calcium acid is mixed evenly; the total mixed material is tableted in a rotary tableting machine to form a tablet.
  • the material was sieved for use; the azisartan ester derivative, NEP inhibitor, mannitol-starch, crospovidone were premixed for 5 min, stirred at 3 rpm, cut at 30 rpm; granulated in a dry granulator; The granules were placed in a three-dimensional mixer, and then magnesium stearate was added for total mixing; the total mixed materials were tableted in a rotary tableting machine.
  • the material was sieved for use; the azisartan ester derivative, the NEP inhibitor, the lactose, the croscarmellose sodium were premixed for 5 min, stirred at 3 rpm, and cut at 30 rpm; the povidone was dissolved in an appropriate amount of water (configured into 5% solution), adding aqueous binder solution, granulating, fluidized bed drying; placing the dried granules into a three-dimensional mixer, adding magnesium stearate for total mixing; total mixing materials in a rotary tableting machine Tableting.
  • the material was sieved for use; the azisartan ester derivative, NEP inhibitor, microcrystalline cellulose 101, crospovidone, talc powder were premixed for 5 min, stirred at 3 rpm, and cut at 30 rpm; in a dry granulator The granules were placed in a three-dimensional mixer, and microcrystalline cellulose 102 and magnesium stearate were added for total mixing; the total mixed materials were tableted in a rotary tableting machine.
  • the material was sieved for use; the azisartan ester derivative, NEP inhibitor, mannitol, croscarmellose sodium was poured into a three-dimensional mixer for 5 min, stirred at 3 rpm, cut at 30 rpm; then added with stearin The calcium acid is mixed evenly; the total mixed material is tableted in a rotary tableting machine to form a tablet.

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Abstract

涉及一种药物组合物，包含：(a)至少一种中性内肽酶抑制剂或其药学上可接受的盐或酯、(b)至少一种如式(I)所示化合物或其药学上可接受的盐或酯、以及可药用载体。联合给药比单独给药具有更佳的药用效果。

Description

药物组合物 技术领域
本发明涉及医药领域，具体涉及一种含有中性内肽酶(NEP)抑制剂和阿齐沙坦酯衍生物的药物组合物。
背景技术
心血管疾病，又称为循环系统疾病，是指一系列涉及循环系统的疾病。循环系统主要包括心脏、血管(动脉、静脉、微血管)。据统计，心血管疾病是全球的头号死因，每年死于心血管疾病的人数多于任何其它死因。常见的心血管疾病包括：高血压、心衰、冠心病、心脏病、动脉粥样硬化、心绞痛、左心室功能不全、肥厚性心肌病、糖尿病性心肌病、室上性和室性心律失常、房颤、心脏纤维化、心房扑动、有害的血管重塑、心肌梗塞及其后遗症等。心血管疾病一般有着相似的病因、病发过程及治疗方法，大多数心血管疾病都可以通过解决诸如烟草使用、不健康饮食、肥胖、高血压、糖尿病和血脂升高等危险因素而得到预防。
世界卫生组织认为通过药物组合，例如，降低胆固醇的他汀类药物和降血压药物以及阿斯匹林联合运用，能够大幅度减少心血管疾病复发或死亡的危险。然而，将不同作用机制的心血管疾病药物任意组合不一定会得到有利效果。因此，开发能发挥联合治疗作用的药物组合物可能对心血管疾病提供更加有效的防治效果。
中性肽内切酶(neutral endopeptidase，NEP，也称中性内肽酶)是一种内皮细胞表面的锌金属肽酶，抑制NEP可增高心房利钠肽(ANP)、脑利钠肽(BNP)、C型利钠肽(CNP)、缓激肽和肾上腺髓质素的水平，因此NEP抑制剂在病理状态下可发挥利尿、扩血管、改善内皮功能、抑制血管平滑肌细胞增生的作用，从而改善血管血流动力学状态、防止动脉粥样硬化形成，延缓心衰的病程进展。
血管紧张素II(Ang II)是机体内调节体液动态平衡的重要调控因子，涉及到血压、电解质平衡等，大量文献证实，Ang II在高血压病、动脉疾病、心脏肥大、心力衰竭及糖尿病、肾病等的发病机制上都起着主要的作用。由于Ang II水平的异常持续增高与高血压、心脏肥厚、心力衰竭等的发生发展直接有关，因此，阻断Ang II与其特异性的受体结合，能起到心脑血管的保护作用，血管紧张素II受体拮抗剂(Angiotensin Receptor Blockers,ARB)在降低心血管病死亡率和病残率的效益方面已经在诸多随机临床试验中得到了证实，ARB药物在国外已较广泛用于高血压病及其他心肾疾病的防治，目前临床使用的ARB依据结构可分为2类：(1)联苯四氮唑类，包括氯沙坦(losartan)、缬沙坦(valsartan)、厄贝沙坦(irbesartan)、坎地沙坦酯(candesartan cilexetil)及阿齐沙坦酯(Azilsartan medoxomil)；(2)非联苯四氮唑类，包括依普罗沙坦(eprosartan)及替米沙坦(telmisartan)。
中国专利申请CN1615134A公开了包含缬沙坦或其可药用盐和NEP抑制剂或其可药用盐的药物组合物；中国专利申请CN105693543A公开了包含NEP抑制剂沙库比曲(Sacubitril，AHU  377，CAS No.149709-62-6)的盐和药用辅料以及AT1受体拮抗剂例如氯沙坦、依普沙坦、缬沙坦、厄贝沙坦等或其可药用盐的药物组合物；中国专利申请CN105837464A公开了包含NEP抑制剂沙库比曲钠和药用辅料以及其他活性成分例如氯沙坦、依普沙坦、缬沙坦、厄贝沙坦等或其可药用盐的药物组合物。
公开号为CN103709154A的中国专利申请首次公开了结构如下式(I)所示的化合物：
Figure PCTCN2017103651-appb-000001
上述化合物是偶联了川芎嗪或NO供体的沙坦类药物，是血管紧张素II受体拮抗剂阿齐沙坦(TAK-536)的前药，该化合物在体内释放出羟基川芎嗪或NO，从而与阿齐沙坦发生有效的协同作用，增强抗高血压疗效，具有一定的降心率作用，减少不良反应，对患者心肾也具有较理想的保护作用。申请人在进一步的研究中发现式(I)化合物的钾盐，即结构如下式(II)所示的化合物，溶解性能更好，生物利用度更高，具有更强效和更长效的降压效果，同时具有更明显且持久的降心率效果，且安全性高，对患者心肾功能具有较理想的保护作用，能够用于预防和/或治疗高血压、慢性心衰、糖尿病肾病等。
Figure PCTCN2017103651-appb-000002
发明内容
本发明发现，中性内肽酶抑制剂或其药学上可接受的盐或酯和式(I)所示的血管紧张素II受体拮抗剂或其药学上可接受的盐或酯在联合使用时取得了意想不到的协同效果，显著增强了任一单方的药效，不仅降压更平稳和持久，降心率效果也更明显和持久，同时对改善心脏功能有更明显的作用，治疗急、慢性心衰具有较好的疗效，可以采用较低剂量或较低频率的应用来达到相应效果，并可以降低单一药物的副作用发生率。
根据本发明的一个方面，本发明提供了一种药物组合物，其包含(a)至少一种中性内肽酶抑制剂或其药学上可接受的盐或酯、(b)至少一种如下式(I)所示化合物或其药学上可接受的盐或酯、以及可药用载体：
Figure PCTCN2017103651-appb-000003
其中，R代表
Figure PCTCN2017103651-appb-000004
Figure PCTCN2017103651-appb-000005
或者
Figure PCTCN2017103651-appb-000006
每一个a相同或不同，独立地选自0、1、2、3、4、5或6；
R1代表取代或未取代的下列基团：C1-C8烷基、C2-C8烯基、C2-C8炔基、
Figure PCTCN2017103651-appb-000007
(CH2)nO(CH2)m、
Figure PCTCN2017103651-appb-000008
芳基或杂芳基，其中
Figure PCTCN2017103651-appb-000009
中的b、c代表烷基链的碳原子个数，独立地选自0、1、2、3、4、5或6，其中(CH2)nO(CH2)m中的n、m独立地选自1、2、3、4、5或6；
R2代表氢、卤素、硝基、氰基，或取代或未取代的下列基团：C1-C8烷氧基、C1-C8烷基、C1-C8烷基磺酰基氨基、芳基磺酰基氨基、杂芳基磺酰基氨基、氨基磺酰基、氨基；
R3代表不存在，或取代或未取代的下列基团：C1-C8烷基、C1-C8烷氧基、C2-C8烯烃氧基、C2-C8炔烃氧基、C1-C6烷氧基-C1-C6烷基、
Figure PCTCN2017103651-appb-000010
芳基、杂芳基，其中
Figure PCTCN2017103651-appb-000011
中的b、c代表烷基链的碳原子个数，独立地选自0、1、2、3、4、5或6；
R4代表氰基，或取代或未取代的下列基团：芳基、芳基磺酰基、杂芳基、C1-C8烷氧基、C1-C8硝酸酯基、C1-C8烷基、C1-C8硝酸酯；
R5代表氰基，或取代或未取代的下列基团：芳基、杂芳基、C1-C8烷氧基、C1-C8硝酸酯、C1-C8烷基、C1-C8烯基、C1-C8炔基、
Figure PCTCN2017103651-appb-000012
Figure PCTCN2017103651-appb-000013
(CH2)nO(CH2)m，其中R3、R4、a、m、n彼此独立地具有如上所述的定义；
R6和R7独立地代表氢，无取代或取代的C1-C8烷氧基或C1-C8烷基；
R8和R9独立地代表氢，无取代或取代的C1-C8烷氧基、C1-C8硝酸酯或C1-C8烷基。
根据本发明的另一个方面，本发明提供了一种药物包，包含彼此独立的容器，其在一个容器中包含含有(a)至少一种中性内肽酶抑制剂或其药学上可接受的盐或酯以及可药用载体的药物组合物，在第二个容器中包含含有(b)至少一种式(I)所示化合物或其药学上可接受的盐或酯以及可药用载体的药物组合物。
根据本发明的另一个方面，本发明提供了上述药物组合物或药物包在制备用于预防和/或治疗心血管疾病的药物中的用途。
根据本发明的另一个方面，本发明提供了上述药物组合物或药物包用于预防和/或治疗心血管疾病的药物的用途。
根据本发明的另一个方面，本发明提供了NEP抑制剂或其药学上可接受的盐或酯在制备用于和式(I)所示化合物或其药学上可接受的盐或酯联合预防和/或治疗心血管疾病的药物中的用途。
根据本发明的另一个方面，本发明提供了式(I)所示化合物或其药学上可接受的盐或酯在制备用于和NEP抑制剂或其药学上可接受的盐或酯联合预防和/或治疗心血管疾病的药物中的用途。
根据本发明的另一个方面，本发明提供了一种预防和/或治疗心血管疾病的方法，该方法给予有需要的患者至少一种中性内肽酶抑制剂或其药学上可接受的盐或酯，以及至少一种式(I)所示化合物或其药学上可接受的盐或酯。本领域技术人员可以理解，上述至少一种中性内肽酶抑制剂或其药学上可接受的盐或酯以及至少一种式(I)所示化合物或其药学上可接受的盐或酯可以以单一制剂形式或者彼此独立的制剂形式给予有需要的患者，可以根据需要同时给予、顺序给予、或者间隔适当的时间给予。
术语解释和说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请记载和保护的范围。
本申请说明书和权利要求书记载的数值范围，当该数值范围被定义为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～10的整数”应当理解为记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数。当该数值范围被定义为“数”时，应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。 例如，“0～10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
本申请说明书使用的“一个或多个”包括一个或多于一个，例如包括但不限于1、2、3、4、5、6、7、8、9或10个。
本发明使用的“卤素”指氟、氯、溴和碘。
“取代”意指被任选一个或多个任意取代基取代。适宜的取代基包括但不限于卤素、氨基、氰基、硝基、羰基(氧代)、巯基(硫代)、羟基、醚基、羧基、烷基、烷氧基、烯基、炔基、烯氧基、炔氧基、芳基、杂芳基、环烷基、杂环基、取代的酰基、取代的磺酰基、取代的酯基、-CH＝CHCO2H、-CH＝CHCO2烷基。所述取代基可以无取代或任选被一个或多个相同或不同的选自上列的取代基进一步取代。
本发明单独使用或用作后缀或前缀的“烷基”意在包括具有1至20个碳原子(或若提供了碳原子的具体数目，则指该具体数目)的支链和直链饱和脂族烃基。例如，“C1-C8烷基”表示具有1、2、3、4、5、6、7或8个碳原子的直链和支链烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基和己基。当烷基被取代基取代时，其包括被一个或多个卤素取代的烷基，例如被1、2、3、4、5、6个卤素取代的烷基，例如三氟甲基。
本发明单独使用或用作后缀或前缀的“烯基”意在包括具有2至20个碳原子(若提供了碳原子的具体数目，则指该具体数目)的包含烯基或烯烃的支链和直链脂族烃基。例如，“C2-6烯基”表示具有2、3、4、5或6个碳原子的烯基。烯基的实例包括但不限于乙烯基、烯丙基、1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基丁-2-烯基、3-甲基丁-1-烯基、1-戊烯基、3-戊烯基和4-己烯基。
本发明单独使用或用作后缀或前缀的“炔基”意在包括具有2至20个碳原子(或若提供了碳原子的具体数目，则指该具体数目)的包含炔基或炔烃的支链和直链脂族烃基。例如乙炔基、丙炔基(例如l-丙炔基、2-丙炔基)、3-丁炔基、戊炔基、己炔基和1-甲基戊-2-炔基。
本发明使用的术语“芳基”指由5至20个碳原子构成的芳族环结构。例如：包含5、6、7和8个碳原子的芳族环结构可以是单环芳族基团例如苯基；包含8、9、10、11、12、13或14个碳原子的环结构可以是多环的例如萘基。芳环可在一个或多个环位置取代有上述那些取代基。术语“芳基”还包括具有两个或更多个环的多环环系，其中两个或更多个碳为两个相邻环所共有(所述环为“稠环”)，其中至少一个环是芳族的且其它环例如可以是环烷基、环烯基、环炔基、芳基和/或杂环基。多环的实例包括但不限于2,3-二氢-1,4-苯并二氧杂环己二烯和2,3-二氢-1-苯并呋喃。
本发明使用的术语“环烷基”意在包括具有指定数目碳原子的饱和环基。这些术语可包括稠合或桥接的多环系统。环烷基在其环结构中具有3至40个碳原子。在一个实施方案中，环烷基在其环结构中具有3、4、5或6个碳原子。例如，“C3-6环烷基”表示例如环丙基、环丁基、环戊基或环己基的基团。
本发明使用的“杂芳基”指具有至少一个环杂原子(例如硫、氧或氮)的杂芳族杂环。杂 芳基包括单环系统和多环系统(例如具有2、3或4个稠环)。杂芳基的实例包括但不限于吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、呋喃基、喹啉基、异喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、异噁唑基、吡唑基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、异噻唑基、苯并噻吩基、嘌呤基、咔唑基、苯并咪唑基、苯并噁唑基、氮杂苯并噁唑基、咪唑并噻唑基、苯并[1,4]二氧杂环己烯基、苯并[1,3]二氧杂环戊烯基等。在一些实施方案中，杂芳基具有3至40个碳原子且在其它实施方案中具有3至20个碳原子。在一些实施方案中，杂芳基包含3至14个、4至14个、3至7个或5至6个成环原子。在一些实施方案中，杂芳基具有1至4个、1至3个或1至2个杂原子。在一些实施方案中，杂芳基具有1个杂原子。
除非另有说明，本发明使用的术语“杂环基”指包含3至20个原子的饱和、不饱和或部分饱和的单环、二环或三环，其中1、2、3、4或5个环原子选自氮、硫或氧，除非另有说明，其可通过碳或氮连接，其中-CH2-基团任选被-C(O)-代替；及其中除非另有相反说明，环氮原子或环硫原子任选被氧化以形成N-氧化物或S-氧化物或环氮原子任选被季铵化；其中环中的-NH任选被乙酰基、甲酰基、甲基或甲磺酰基取代；及环任选被一个或多个卤素取代。应该理解的是，当杂环基中S原子和O原子的总数超过1时，这些杂原子不彼此相邻。若所述杂环基为二环或三环，则至少一个环可任选为杂芳族环或芳族环，条件是至少一个环是非杂芳族的。若所述杂环基为单环，则其一定不是芳族的。杂环基的实例包括但不限于哌啶基、N-乙酰基哌啶基、N-甲基哌啶基、N-甲酰基哌嗪基、N-甲磺酰基哌嗪基、高哌嗪基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、四氢异喹啉基、四氢喹啉基、二氢吲哚基、四氢吡喃基、二氢-2H-吡喃基、四氢呋喃基、四氢噻喃基、四氢噻喃-1-氧化物、四氢噻喃-1,1-二氧化物、1H-吡啶-2-酮和2,5-二氧代咪唑烷基。
根据不同取代基的位置和性质，本发明的化合物还可以包含一个或多个不对称中心。不对称碳原子可以(R)或(S)构型存在，仅有一个不对称中心时，产生外消旋混合物，含有多个不对称中心时，得到非对映异构体混合物。在某些情况下，由于围绕特定键的旋转受阻还可能存在不对称性，例如该中心键连接特定化合物的两个被取代的芳族环。并且，取代基还可以顺式或反式异构的形式存在。
式(I)化合物还包括其各自所有可能的立体异构体，其是单一立体异构体或所述立体异构体(例如R-异构体或S-异构体，或者E-异构体或Z-异构体)的任意比例的任意混合物的形式。可通过任意适合的现有技术方法(例如色谱法，特别是例如手性色谱法)实现本发明的化合物的单一立体异构体(例如单一对映异构体或单一非对映异构体)的分离。
另外，所述化合物还可以互变异构体的形式存在。本发明化合物包括式(I)化合物所有可能的互变异构体，其是单一互变异构体或所述互变异构体的任意比例的任意混合物的形式。
所有这些异构体及它们的混合物都包括在本发明中。
本领域技术人员可以理解，本发明的NEP抑制剂和式(I)所示化合物可以以各种药学上可接受的盐的形式存在。如果这些化合物具有碱性中心，则其可以形成酸加成盐；如果这些化合物具有酸性中心，则其可以形成碱加成盐；如果这些化合物既包含酸性中心(例如羧基) 又包含碱性中心(例如氨基)，则其还可以形成内盐。
在本发明中，酸加成盐包括但不限于：盐酸盐、氢氟酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、焦硫酸盐、磷酸盐、硝酸盐、甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、甲苯磺酸盐、氨基磺酸盐、2-萘磺酸盐、甲酸盐、乙酰乙酸、丙酮酸、月硅酸酯、肉桂酸酯、苯甲酸盐、醋酸盐、二羟乙酸盐、三氟乙酸盐、三甲基乙酸盐、丙酸盐、丁酸盐、己酸盐、庚酸盐、十一酸盐、硬脂酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、富马酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、草酸盐、水杨酸盐、琥珀酸盐、葡萄糖酸盐、奎尼酸盐、双羟萘酸盐、甘醇酸盐、酒石酸盐、乳酸盐、2-(4-羟基苯甲酰基)苯甲酸盐、环戊烷丙酸盐、二葡糖酸盐、3-羟基-2-萘甲酸盐、烟酸盐、扑酸盐、果胶酯酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、衣康酸盐、三氟甲磺酸盐、十二烷基硫酸盐、对甲苯磺酸盐、萘二磺酸盐、丙二酸盐、己二酸盐、藻酸盐、扁桃酸盐、葡庚酸盐、甘油磷酸盐、磺基水杨酸盐、半硫酸或硫氰酸盐、天冬氨酸盐等；碱加成盐例如碱金属盐、碱土金属盐和铵盐等，具体包括但不限于：钠盐、锂盐、钾盐、铵盐(包括与NH3和有机胺形成的盐)、铝盐、镁盐、钙盐、钡盐、铁盐、亚铁盐、锰盐、亚锰盐、锌盐、NH4盐、甲胺盐、三甲胺盐、二乙胺盐、三乙胺盐、丙胺盐、三丙胺盐、异丙胺盐、叔丁胺盐、N,N'-二苄基乙二胺盐、二环己胺盐、1,6-己二胺盐、苄胺盐、乙醇胺盐、N,N-二甲基乙醇胺盐、N,N-二乙基乙醇胺盐、三乙醇胺盐、氨丁三醇盐、赖氨酸盐、精氨酸盐、组氨酸盐、葡糖胺盐、N-甲基葡糖胺盐、二甲基葡糖胺盐、乙基葡糖胺盐、葡甲胺盐、甜菜碱盐、咖啡因盐、氯普鲁卡因盐、普鲁卡因盐、利多卡因盐、吡啶盐、甲基吡啶盐、哌啶盐、吗啉盐、哌嗪盐、嘌呤盐、可可碱盐、胆碱盐等。
本领域技术人员可以理解，本发明的NEP抑制剂和式(I)所示化合物也可以以各种药学上可接受的酯的形式存在，包括但不限于甲酯、乙酯、丙酯、异丙酯、丁酯、异丁酯、叔丁酯等。
在优选的实施方案中，NEP抑制剂和式(I)所示化合物的药学上可接受的盐独立地选自Na、K或NH4盐；NEP抑制剂或式(I)所示化合物的药学上可接受的酯独立地选自甲酯、乙酯或丙酯。
根据本发明示例性的实施方案，所述NEP抑制剂可以是沙库比曲、其立体异构体或它们任意比例的混合物。
在优选的实施方案中，式(I)所示化合物具有如下式所示结构：
Figure PCTCN2017103651-appb-000014
Figure PCTCN2017103651-appb-000015
在优选的实施方案中，式(I)所示化合物的药学上可接受的盐为K盐；进一步优选，式(I)所示化合物的K盐具有如下式(II)所示结构：
Figure PCTCN2017103651-appb-000016
其中，R如上定义。
在进一步优选的实施方案中，式(I)所示化合物的K盐具有如下式所示结构：
Figure PCTCN2017103651-appb-000017
Figure PCTCN2017103651-appb-000018
在优选的实施方案中，(a)为至少一种下列化合物或其药学上可接受的盐或酯：
(S)-(2-联苯-4-基)-1-(1H-四唑-5-基)乙基氨基)甲基膦酸、
(S)-5-(N-(2-(膦酰基甲基-氨基)-3-(4-联苯基)-丙酰基)-2-氨基乙基)四唑、
(±)N-(1-氧-2-巯甲基-3-苯丙酰基)甘氨酸、
N-((2S)-2-(4-联苯基甲基)-4-羧基-5-苯氧基戊酰基)甘氨酸、
N-(α-鼠李吡喃糖基膦酰胺)-L-亮氨酸-L-色氨酸、
N-[N-[(L)-1-羧基-2-苯基乙基]-L-苯丙氨酰基]-(R)-丙氨酸、
N-[N-[((1S)-羧基-2-苯基)乙基]-(S)-苯丙氨酰基]-β-丙氨酸、
N-(S)-[3-巯基-2-(2-甲基苯基)丙酰基]-(S)-2-甲氧基-(R)-丙氨酸、
3-[1,1'-联苯]-4-基-N-[二苯氧基氧膦基)-甲基]-L-丙氨酰基-β-丙氨酸、
N-(1-(N-羟基氨基甲酰基-甲基)-1-环戊烷羰基)-L-苯丙氨酸、
N-[2-巯基甲基-3-苯基-丙酰基]-3-氨基苯甲酸、
4-[[2-(巯基甲基)-1-氧代-3-苯基丙基]氨基]苯甲酸、
N-[2-乙酰硫基甲基-3-苯基-丙酰基]-3-氨基苯甲酸、
N-[2-巯基甲基-3-(2-甲基苯基)-丙酰基]-甲硫氨酸、
N-(3-苯基-2-(巯基甲基)-丙酰基)-(S)-4-(甲基巯基)-甲硫氨酸、
N-[1-(2-羧基-4-苯基丁基)-环戊烷羰基]-(S)-异丝氨酸、
N-[2(S)-巯基甲基-3-(2-甲基苯基)丙酰基]-(S)-异丝氨酸、
N-(1-(3-(N-叔丁氧羰基-(S)-脯氨酰氨基)-2(S)-叔丁氧基-羰基丙基)环戊烷羰基)-O-苄基-(S)-丝氨酸、
3(S)-[2-(乙酰硫基甲基)-3-苯基-丙酰基]氨基-ε-己内酰胺、
N-[1-(乙酰硫基甲基)-环戊羰基]-(S)-甲硫氨酸、
N-[2-乙酰硫基甲基-3-(2-甲基-苯基)丙酰基]-甲硫氨酸、
N-[2(S)-巯基甲基-3-(2-甲基苯基)-丙酰基]蛋氨酸、
N-[2-(巯基甲基)-1-氧代-3-苯基丙基]-β-丙氨酸、
7-[[2-(巯基甲基)-1-氧代-3-苯基丙基]氨基]-庚酸、
N-[N-[1(S)-羧基-3-苯基丙基]-(S)-苯丙氨酰基]-(S)-异丝氨酸、
N-[1-[[1(S)-羰基-3-苯基丙基]氨基]-环戊基羰基]-(S)-异丝氨酸、
N-[1-[[1(S)-苄氧基羰基-3-苯基丙基]氨基]-环戊基羰基]-(S)-异丝氨酸、
N-[N-[(L)-[1-[(2,2-二甲基-1,3-二氧戊环-4-基)-甲氧基]羰基]-2-苯基乙基]-L-苯丙氨酰基]-(R)-丙氨酸、
N-(2-羧基-4-噻吩基)-3-巯基-2-苄基丙酰胺、
2-(2-巯基甲基-3-苯基丙酰氨基)噻唑-4-基甲酸、
(L)-(1-((2,2-二甲基-1,3-二氧戊环-4-基)-甲氧基)羰基)-2-苯基乙基)-L-苯丙氨酰基)-β-丙氨酸、
顺-4-[[[1-[2-羧基-3-(2-甲氧基乙氧基)丙基]-环戊基]羰基]氨基]-环己烷甲酸、
3-(1-[6-内-羟基甲基二环[2,2,1]庚烷-2-外-氨基甲酰基]环戊基)-2-(2-甲氧基乙基)丙酸、
3-[1-(顺-4-羧基羰基-顺-3-丁基环己基-r-1-氨基甲酰基)环戊基]-2S-(2-甲氧基乙氧基-甲基)丙酸、
(S)-顺-4-[1-[2-(5-茚满基氧基-羰基)-3-(2-甲氧基乙氧基)丙基]-1-环戊烷酰氨基]-1-环己烷甲酸、
1,1'-[二硫代双-[2(S)-(2-甲基苄基)-1-氧代-3,1-亚丙基]]-双-(S)-异丝氨酸、
1,1'-[二硫代双-[2(S)-(2-甲基苄基)-1-氧代-3,1-亚丙基]]-双-(S)-甲硫氨酸、
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸、
N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸。
在进一步优选的实施方案中，(a)为至少一种下列化合物：
N-[1-(乙酰硫基甲基)-环戊羰基]-(S)-甲硫氨酸乙酯、
N-[2-乙酰硫基甲基-3-(2-甲基-苯基)丙酰基]-甲硫氨酸乙酯、
N-(1-(3-(N-叔丁氧羰基-(S)-脯氨酰氨基)-2(S)-叔丁氧基-羰基丙基)环戊烷羰基)-O-苄基-(S)-丝氨酸甲酯、
3(S)-[2-(乙酰硫基甲基)-3-苯基-丙酰基]氨基-ε-己内酰胺、
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸 (AHU 377或沙库必曲)、
N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸、
N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钠、
N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钾、
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸乙酯(AHU 377乙酯或沙库必曲乙酯)、
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸钠(AHU 377Na或沙库必曲钠)、
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸钾(AHU 377K或沙库必曲钾)、
4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸铵(AHU 377铵盐或沙库必曲铵盐)。
在优选的实施方案中，(a)为AHU 377、AHU 377乙酯、AHU 377Na、AHU 377K、N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸、N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钠、N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钾或4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸铵；
在优选的实施方案中，(b)为如下化合物1K：
Figure PCTCN2017103651-appb-000019
进一步优选，化合物1K可以为无定型、晶型I、II、III、IV中的任一种、或者多种的任意比例的混合物；进一步优选，化合物1K可以为化合物1K的晶型I、晶型II或二者的任意比例的混合物。
在本发明中，(a)与(b)的质量比为(0.5-10):1，例如：10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、1:1、0.5:1；优选为(0.5-5):1，更优选为(0.5-3):1，例如：3:1、2.5:1、2:1、1.9:1、1.8:1、1.7:1、1.6:1、1.5:1、1.45:1、1.4:1、1.35:1、1.3:1、1.25:1、1.2:1、1.15:1、1.1:1、1.05:1、1:1、0.95:1、0.9:1、0.85:1、0.8:1、0.75:1、0.7:1、0.65:1、0.6:1、0.55:1、0.5:1。
在本发明中，心血管疾病包括但不限于：高血压、心衰、冠心病、风湿性心脏病、先天性心脏病、左心室功能不全、内皮功能障碍、舒张期功能障碍、肥厚性心肌病、糖尿病性心肌病、室上性和室性心律失常、房颤、心脏纤维化、心房扑动、有害的血管重塑、心肌梗塞 及其后遗症、动脉粥样硬化、心绞痛、原发性和继发性肺性高血压、肾血管性高血压等。
可以用本领域公知的方法来制备本发明的药物组合物或药物包。本发明的药物组合物或者药物包中的药物组合物可以制成适于口服、吸入、直肠、局部、胃肠外等给药途径的各种剂型，包括但不限于：适于口服的散剂、片剂(包括各种包衣片剂、缓释或控释片剂)、锭剂、胶囊剂(包括软胶囊和硬胶囊)、颗粒剂、丸剂、可分散粉末、水性或油性混悬剂、水性或油性溶液剂、乳剂、酏剂、糖浆剂等，适于吸入的粉末或液体气雾剂等，适于直肠的栓剂等，适于局部的霜剂、软膏剂、凝胶、水性或油性溶液剂、水性或油性混悬剂等，适于经胃肠外给药的静脉内、皮下或肌内注射用无菌水性或油性的注射剂或冻干粉针剂等。本发明还可以通过将独立的药物组合于药物包形式，以不同的剂量形式将独立的组分进行给药或以不同的给药间隔进行给药。
可药用载体包括但不限于填充剂(或稀释剂)、粘合剂、崩解剂、润滑剂、湿润剂、辅助脂质、助流剂、甜味剂、矫味剂、溶剂、溶解助剂、悬浮剂、等渗剂、缓冲液、防腐剂、抗氧剂、着色剂、起泡剂等。本领域技术人员可以根据实际需要选择上述可药用载体。例如：可以使用的填充剂(稀释剂)包括但不限于乳糖、蔗糖、微晶纤维素、淀粉、甘露醇、甘露醇-淀粉等；可以使用的粘合剂包括但不限于微晶纤维素、聚维酮、黄蓍胶、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖、淀粉糊等；可以使用的崩解剂包括但不限于交联羧甲基纤维素钠、低取代羟丙基纤维素、交联聚维酮、淀粉羟乙酸钠、藻酸、干淀粉、膨润土、甲基纤维素、琼脂、羧甲基纤维素等；可以使用的润滑剂包括但不限于滑石粉、镁或钙的硬脂酸盐、石松子等；可以使用的湿润剂包括但不限于丙二醇一硬脂酸酯、脱水山梨醇一油酸酯、二甘醇一月桂酸酯和聚氧乙烯月桂基醚等；可以使用的辅助脂质包括但不限于磷脂酰乙醇胺、磷脂酰胆碱、胆固醇等；可以使用的助流剂包括但不限于胶体二氧化硅等；可以使用的甜味剂包括但不限于蔗糖、乳糖、甘露醇、人工甜味剂(例如环磺酸钠和糖精)等；可以使用的矫味剂包括但不限于薄荷和水杨酸甲酯等。
可以用本领域公知的方法确定本发明的药物组合物或者药物包中活性成分的给药剂量、及其在药物组合物或者药物包中的合适的单位剂量。例如，给药剂量按式(I)所示化合物的含量计可以是每天1-200mg，优选5-150mg，更优选5-100mg口服给药。
本发明的药物组合物或药物包中还可以进一步含有其他活性成分，例如利尿剂、钙离子拮抗剂等。
与现有技术相比，本发明技术方案的优点和有益效果在于，将本发明的NEP抑制剂和式(I)所示的血管紧张素II受体拮抗剂联合使用，可以取得预料不到的协同效果，在降血压和/或降心率等方面的效果更为平稳或持久，同时还可具有良好的改善心脏功能的作用。为此，本发明的技术方案在治疗急、慢性心衰具有较好的疗效，可以采用较低剂量或较低频率的应用来达到相应效果，以及可以降低单一药物的副作用发生率。
附图说明
图1为化合物1K的1H-NMR图谱；
图2为化合物1K无定型形式的X-射线粉末衍射图谱；
图3为晶型I的X-射线粉末衍射图；
图4为晶型II的X-射线粉末衍射图；
图5为晶型III的X-射线粉末衍射图；
图6为晶型IV的X-射线粉末衍射图。
具体实施方式
下文将结合具体实施例，进一步阐述本发明。应当理解，这些实施例旨在示例性地说明本发明，而并非限制本发明的保护范围。此外，应当理解，在阅读了本发明公开的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些改动和修改后的技术方案同样属于本发明保护的范围。
实施例1.化合物1K的制备
Figure PCTCN2017103651-appb-000020
将化合物1(1.0g)溶于二氯甲烷(5ml)中，室温搅拌形成溶液，往溶液中加入邻苯二甲酰亚胺钾(0.27g)，保温反应4h，冷却至-50℃，过滤，溶剂旋干所得固体为化合物1K(无定型)。
熔点：135-145℃。
MS/HRMS m/z：717[M+H]+；677[M-K]-。
1H-NMR(400MHz,DMSO-d6)δ：1.44(t，3H)，1.46(t，3H)，2.38(s，3H)，2.41(s，3H)，2.44(s，3H)，4.64(q，2H)，5.29(d，1H)，5.32(d，1H)，5.52(d，1H)，5.56(d，1H)，6.86(q，1H)，6.90(d，2H)，7.18(m，2H)，7.22(d，2H)，7.33(m，1H)，7.36(m，1H)，7.46(d，1H)，7.52(dd，1H)，7.75(d，1H)。
1H-NMR图谱和X射线粉末衍射图谱分别见图1和图2。
实施例2.化合物1K晶型I的制备
取15mg化合物1K，加入0.2ml乙醇/异丙醚(体积比为1:5)混合溶液，得悬浊液，室温搅拌1天，过滤，干燥，得到晶型I。XRD检测图谱见附图3；DSC：184℃。
实施例3.化合物1K晶型II的制备
取1.1g化合物1K，加入10ml乙酸乙酯，得澄清溶液，室温搅拌3小时，过滤，干燥，得到产品0.88g，所得晶型II的XRD检测图谱见附图4；DSC：145.4℃。
实施例4.化合物1K晶型III的制备
取100mg化合物1K，加入1.0ml四氢呋喃，得悬浊液，室温搅拌1天，过滤，干燥，所得晶型III的XRD检测图谱见附图5；DSC：187.3℃。
实施例5.化合物1K晶型IV的制备
将50mg化合物1K溶于1.0ml正丁醇中，得澄清溶液，搅拌下加入5.0ml正庚烷，析出固体，过滤，所得晶型IV的XRD检测图谱见附图6；DSC熔点：144.7℃。
实施例6.化合物1K晶型I和晶型II的混合物的制备
取100mg晶型II，加入2.5ml乙酸异丙酯，得悬浊液，于80℃水浴中搅拌8小时，过滤，干燥，经XRD和HPLC检测结果可知，晶型I含量约为95％，晶型II含量约为5％。
实施例7.化合物1K在自发性高血压大鼠上的抗高血压药效试验
取12周龄的自发性高血压大鼠(以下简称SHR，购自北京维通利华实验动物技术有限公司)，以2.5％的戊巴比妥钠进行腹腔注射麻醉，将血压植入子的血压感应导管插入腹主动脉，植入子固定于腹壁，缝合后进行术后日常看护。选取收缩压超过160mm Hg的动物进入分组，每组8只动物，共3组。对照组给予0.5％的羧甲基纤维素钠(以下简称CMC-Na)；化合物1组和化合物1K采用0.5％CMC-Na溶解，给药剂量均以1mg/kg阿齐沙坦有效剂量计，给药体积为4mL/kg，均灌胃给药，以给药前动物的收缩压和心率为基准值，比较给药前、后各时间点SHR的收缩压和心率变化，每个时间点测三次取平均值。结果见下表1和表2。
表1.化合物1、化合物1K口服给药前、后各时间点收缩压变化(平均值(mmHg)±标准误差)
Figure PCTCN2017103651-appb-000021
Figure PCTCN2017103651-appb-000022
*P<0.01(相对于对照组)。
从表1结果可以看出，给药3小时后各给药组与对照组比较收缩压均显著下降，在给药 5-7小时药效达峰，化合物1K组具有比化合物1更强效和长效的降压效果。
表2.化合物1、化合物1K口服给药前、后各时间点心率变化(平均值(次/分钟)±标准误差)
Figure PCTCN2017103651-appb-000023
Figure PCTCN2017103651-appb-000024
*P<0.05(相对于对照组单因素方差比较)。
从表2结果可以看出，化合物1K组具有比化合物1更强效和长效的降心率效果。
实施例8.4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸铵(AHU 377铵盐或沙库必曲铵盐)的制备
Figure PCTCN2017103651-appb-000025
将沙库比曲加入丙酮溶剂中，室温搅拌，冷却至0-10℃，滴加稍过量的浓氨水，滴加完毕，继续搅拌4h，过滤，丙酮洗涤，真空干燥，得目标化合物，纯度大于99.5％，MS：m/z＝412.3(M+H)+。
实施例9.药物组合物在自发性高血压大鼠上的抗高血压药效试验
取18周龄雄性SHR大鼠(购自北京维通利华实验动物技术有限公司)，以2.5％的戊巴比妥钠进行腹腔注射麻醉，将血压植入子的血压感应导管插入腹主动脉，植入子固定于腹壁，缝合后进行术后日常看护。选取收缩压超过160mm Hg的动物进入分组，每组6只动物，共9组。另设一组WKY大鼠(北京维通利华有限公司提供)作为正常对照。每天给药一次，均灌胃给药，给药体积为4mL/kg，共给药4周，各组给药如下：
正常对照组不给予任何药物；
空白对照组给予0.5％的CMC-Na；
化合物1K组给予化合物1K，采用0.5％CMC-Na溶解，给药剂量以1mg/kg阿齐沙坦有效剂量计；
缬沙坦组给予缬沙坦，采用0.5％CMC-Na溶解，给药剂量30mg/kg；
阿齐沙坦酯钾组给予阿齐沙坦酯钾，采用0.5％CMC-Na溶解，给药剂量以1mg/kg阿齐沙坦有效剂量计；
AHU 377K组给予AHU 377K，采用0.5％CMC-Na溶解，给药剂量30mg/kg；
AHU377铵盐组给予AHU377铵盐，采用0.5％CMC-Na溶解，给药剂量30mg/kg；
LCZ696组给予LCZ696，采用0.5％CMC-Na溶解，给药剂量60mg/kg；
缬沙坦+AHU 377K组同时给予缬沙坦和AHU 377K，采用0.5％CMC-Na溶解，缬沙坦给药剂量30mg/kg，AHU 377K给药剂量30mg/kg；
阿齐沙坦酯钾+AHU 377K组同时给予阿齐沙坦酯钾和AHU 377K，采用0.5％CMC-Na溶解，阿齐沙坦酯钾给药剂量以1mg/kg阿齐沙坦有效剂量计，AHU 377K给药剂量30mg/kg；
化合物1K+AHU 377K组同时给予化合物1K和AHU 377K，采用0.5％CMC-Na溶解，化合物1K给药剂量以1mg/kg阿齐沙坦有效剂量计，AHU 377K给药剂量30mg/kg。
化合物1K+AHU377铵盐组同时给予化合物1K和AHU377铵盐，采用0.5％CMC-Na溶解，化合物1K给药剂量以1mg/kg阿齐沙坦有效剂量计，AHU377铵盐给药剂量30mg/kg。
DSI遥控测压仪检测血压、心率，给药第28天，分别测定SHR收缩压及心率变化。结果见下表3。
表3.自发性高血压大鼠的降压和降心率作用
组别 收缩压变化(mmHg) 心率变化(次/分钟)
正常对照组 3.2±2.0 8.2±3.3
空白对照组 8.3±5.4 10.1±2.9
化合物1K组 -50.4±4.7 -29.3±4.1
缬沙坦组 -30.6±3.5 -10.6±3.2
阿齐沙坦酯钾组 -33.5±3.2 -11.1±3.7
AHU 377K组 -15.6±2.5 -8.1±2.8
AHU377铵盐组 -18.5±2.5 3±2.1
LCZ696组 -52.4±5.8 -23.2±4.3
缬沙坦+AHU 377K组 -36.5±4.2 -16.2±3.1
阿齐沙坦酯钾+AHU 377K组 -42.0±3.4 -14.4±4.1
化合物1K+AHU 377K组 -65.7±4.9 -45.2±5.3
化合物1K+AHU377铵盐组 -60.3±5.9 -30±1.5
从表3结果可以看出，本发明的药物组合后较任一单方给药有显著的降压作用，并且其对心率的调节也有明显改善作用。在实验过程中还发现，其降压曲线更平稳，降压和降心率 更长效，取得了协同的技术效果。因此可以采用较低剂量或较低频率的应用来达到降压效果，也可以用来降低单一药物的副作用发生率。
实施例10.药物组合物在慢性心衰大鼠上的治疗效果研究
取5周龄雄性DSS大鼠(购自北京维通利华实验动物技术有限公司)，随机分组，每组10只，低盐饲养1组为正常对照组，高盐饲养9组。低盐饲养给予0.3％氯化钠，高盐饲养给予8％氯化钠以诱导高血压-心肌肥厚-心衰模型。自6周龄时开始连续饲养5周后，在11周龄时开始给药，各组给药剂量与实施例8相同，给药连续7周。18周龄时处死动物进行血压、心房钠尿肽(ANP)的考察。结果见下表4。
表4.慢性心衰大鼠的治疗效果
Figure PCTCN2017103651-appb-000026
从表4结果可以看出，发明复方药物较单方及其他组合能显著提高ANP的分泌，改善大鼠心脏功能，血压水平更接近正常水平，以上数据表明，该组合物治疗慢性心衰时具有更好的疗效，取得了协同效果。
实施例11.药物组合物在冠状动脉结扎引起的急性心衰动物上的治疗效果研究
取雄性SD大鼠(购自北京维通利华实验动物技术有限公司)，施行冠状动脉结扎术(Coronary artery ligation,CAL)制作心力衰竭模型。术后1周，通过心脏彩超检查大鼠的心肌梗死面积，梗死面积介于30％～50％的为造模成功。正常对照组除未进行动脉结扎外，其他操作同上。将造模成功的大鼠随机分为9组，每组10只，各组给药剂量与实施例9相同。连续给药4周后心脏彩超检测心脏功能，考察平均动脉压(MAP)及左心室射血分数(EF)的变化。结果见下表5。
表5.心衰大鼠平均动脉压及左心室射血分数
组别 MAP(mmHg) EF(％)
正常对照组 135.8±11.6 76.9±9.5
空白对照组 197.4±10.2 30.5±2.4
化合物1K组 145.5±8.9 48.6±5.3
缬沙坦组 154.4±11.2 35.3±2.1
阿齐沙坦酯钾组 150.4±10.8 45.1±5.2
AHU 377K组 170.6±14 37.4±3.9
AHU377铵盐组 172±14 32±5.7
LCZ696组 142.3±10.8 58.2±4.3
缬沙坦+AHU 377K组 156.5±10.5 49.5±4.5
阿齐沙坦酯钾+AHU 377K 149.3±9.8 48.3±6.7
化合物1K+AHU 377K组 134.3±10.6 66.1±5.8
化合物1K+AHU377铵盐组 146.3±8.5 62.6±4.7
从表5结果可以看出，本发明复方药物较单方及其他组合能明显降低急性心衰动物的平均动脉压，提高射血分数，对心肌缺血引起的急性心衰有良好的治疗效果，取得了协同效果。
实施例12
将阿齐沙坦酯衍生物、NEP抑制剂、乳糖和微晶纤维素预混5min，搅拌3rpm，切割30rpm；将聚维酮溶于适量水中(按0.36g聚维酮溶于2g水折算)，开启搅拌切割，同时加入粘合剂水溶液，软材过30目筛制粒，湿颗粒60℃干燥至水分1％-2％，24目筛整粒，干颗粒称重，将交联羧甲基纤维素钠和硬脂酸镁加入干颗粒中，混合均匀，压片，制成片剂。
Figure PCTCN2017103651-appb-000027
实施例13
将阿齐沙坦酯衍生物、NEP抑制剂、二油酰磷脂酰胆碱、胆固醇、甘氨胆酸钠和大豆甾醇溶于乙醇和正己烷的混合溶剂中，混合均匀，于旋转薄膜蒸发器上减压除去有机溶剂，得到磷脂膜；加入pH为6.0的枸橼酸-枸橼酸钠缓冲溶液，振摇，搅拌30分钟，使磷脂膜完全 水化，用组织捣碎机高速匀质乳化10分钟，0.45μm微孔滤膜过滤，制得脂质体混悬液，喷雾干燥，制得含药的脂质体粉末，再将其与甘露醇、微晶纤维素和交联羧甲基纤维素钠混合，过60目筛混合均匀，加入羟丙基纤维素，乙醇溶液制备软材，过20目筛制粒，50℃干燥，将干颗粒和硬脂酸镁混合均匀，过18目筛整粒，压片，包衣，制得脂质体片剂。
Figure PCTCN2017103651-appb-000028
实施例14
将物料过筛备用；将阿齐沙坦酯衍生物、NEP抑制剂、甘露醇、交联羧甲基纤维素钠倒入三维混合机中预混5min，搅拌3rpm，切割30rpm；再加入硬脂酸钙，混合均匀；总混物料于旋转压片机中压片制成片剂。
Figure PCTCN2017103651-appb-000029
实施例15
将物料过筛备用；将阿齐沙坦酯衍生物、NEP抑制剂、甘露醇-淀粉、交联聚维酮预混5min，搅拌3rpm，切割30rpm；在干法制粒机中制粒；将制得颗粒放入三维混合机，再加入硬脂酸镁进行总混；总混物料于旋转压片机中压片。
Figure PCTCN2017103651-appb-000030
Figure PCTCN2017103651-appb-000031
实施例16
将物料过筛备用；将阿齐沙坦酯衍生物、NEP抑制剂、乳糖、交联羧甲基纤维素钠预混5min，搅拌3rpm，切割30rpm；将聚维酮溶于适量水中(配置成5％的溶液)，加入粘合剂水溶液，制粒，流化床干燥；将干燥后的颗粒放入三维混合机，再加入硬脂酸镁进行总混；总混物料于旋转压片机中压片。
Figure PCTCN2017103651-appb-000032
实施例17
将物料过筛备用；将阿齐沙坦酯衍生物、NEP抑制剂、微晶纤维素101、交联聚维酮、滑石粉预混5min，搅拌3rpm，切割30rpm；在干法制粒机中制粒；将制得颗粒放入三维混合机，再加入微晶纤维素102、硬脂酸镁进行总混；总混物料于旋转压片机中压片。
Figure PCTCN2017103651-appb-000033
实施例18
将物料过筛备用；将阿齐沙坦酯衍生物、NEP抑制剂、甘露醇、交联羧甲基纤维素钠倒入三维混合机中预混5min，搅拌3rpm，切割30rpm；再加入硬脂酸钙，混合均匀；总混物料于旋转压片机中压片制成片剂。
Figure PCTCN2017103651-appb-000034
Figure PCTCN2017103651-appb-000035
以上对本发明的示例性实施方案进行了说明。但是，本发明不拘囿于此。凡在本发明的精神和原则范围内进行的任何修改、等同替换、改进等，均应属于本发明的保护范围。

Claims (10)

  1. 一种药物组合物，其特征在于，包含(a)至少一种中性内肽酶抑制剂或其药学上可接受的盐或酯、(b)至少一种如下式(I)所示化合物或其药学上可接受的盐或酯、以及可药用载体：
    Figure PCTCN2017103651-appb-100001
    其中，R代表
    Figure PCTCN2017103651-appb-100002
    Figure PCTCN2017103651-appb-100003
    或者
    Figure PCTCN2017103651-appb-100004
    每一个a相同或不同，独立地选自0、1、2、3、4、5或6；
    R1代表取代或未取代的下列基团：C1-C8烷基、C2-C8烯基、C2-C8炔基、
    Figure PCTCN2017103651-appb-100005
    (CH2)nO(CH2)m、
    Figure PCTCN2017103651-appb-100006
    芳基或杂芳基，其中
    Figure PCTCN2017103651-appb-100007
    中的b、c代表烷基链的碳原子个数，独立地选自0、1、2、3、4、5或6，其中(CH2)nO(CH2)m中的n、m独立地选自1、2、3、4、5或6；
    R2代表氢、卤素、硝基、氰基，或取代或未取代的下列基团：C1-C8烷氧基、C1-C8烷基、C1-C8烷基磺酰基氨基、芳基磺酰基氨基、杂芳基磺酰基氨基、氨基磺酰基、氨基；
    R3代表不存在，或取代或未取代的下列基团：C1-C8烷基、C1-C8烷氧基、C2-C8烯烃氧基、C2-C8炔烃氧基、C1-C6烷氧基-C1-C6烷基、
    Figure PCTCN2017103651-appb-100008
    芳基、杂芳基，其中
    Figure PCTCN2017103651-appb-100009
    中的b、c代表烷基链的碳原子个数，独立地选自0、1、2、3、4、5或6；
    R4代表氰基，或取代或未取代的下列基团：芳基、芳基磺酰基、杂芳基、C1-C8烷氧基、C1-C8硝酸酯基、C1-C8烷基、C1-C8硝酸酯；
    R5代表氰基，或取代或未取代的下列基团：芳基、杂芳基、C1-C8烷氧基、C1-C8硝酸酯、C1-C8烷基、C1-C8烯基、C1-C8炔基、
    Figure PCTCN2017103651-appb-100010
    Figure PCTCN2017103651-appb-100011
    (CH2)nO(CH2)m，其中R3、R4、a、m、n彼此独立地具有如上所述的定义；
    R6和R7独立地代表氢，无取代或取代的C1-C8烷氧基或C1-C8烷基；
    R8和R9独立地代表氢，无取代或取代的C1-C8烷氧基、C1-C8硝酸酯或C1-C8烷基；
    优选，中性内肽酶抑制剂或式(I)所示化合物的药学上可接受的盐独立地选自Na、K或NH4盐；中性内肽酶抑制剂或式(I)所示化合物的药学上可接受的酯独立地选自甲酯、乙酯或丙酯；
    优选，式(I)所示化合物具有如下式所示结构：
    Figure PCTCN2017103651-appb-100012
    Figure PCTCN2017103651-appb-100013
  2. 一种药物包，包含彼此独立的容器，其特征在于，在一个容器中包含含有(a)至少一种中性内肽酶抑制剂或其药学上可接受的盐或酯以及可药用载体的药物组合物，在第二个容器中包含含有(b)至少一种式(I)所示化合物或其药学上可接受的盐或酯以及可药用载体的药物组合物：
    其中式(I)所示化合物具有权利要求1中的定义。
  3. 根据权利要求1所述的药物组合物或权利要求2所述的药物包，其特征在于，式(I)所示化合物的药学上可接受的盐为K盐；
    进一步优选，式(I)所示化合物的K盐具有如下式(II)所示结构：
    Figure PCTCN2017103651-appb-100014
    其中，R具有权利要求1中的定义；
    进一步优选，式(I)所示化合物的K盐具有如下式所示结构：
    Figure PCTCN2017103651-appb-100015
    Figure PCTCN2017103651-appb-100016
    进一步优选，式(I)所示化合物的K盐为化合物1K的无定型、晶型I、II、III、IV中的任一种、或者多种的任意比例的混合物；
    Figure PCTCN2017103651-appb-100017
    进一步优选，式(I)所示化合物的K盐为化合物1K的晶型I、晶型II或二者的任意比例的混合物。
  4. 根据权利要求1所述的药物组合物或权利要求2所述的药物包，其特征在于，(a)为至少一种下列化合物或其药学上可接受的盐或酯：
    (S)-(2-联苯-4-基)-1-(1H-四唑-5-基)乙基氨基)甲基膦酸、
    (S)-5-(N-(2-(膦酰基甲基氨基)-3-(4-联苯基)-丙酰基)-2-氨基乙基)四唑、
    (±)N-(1-氧-2-巯甲基-3-苯丙酰基)甘氨酸、
    N-((2S)-2-(4-联苯基甲基)-4-羧基-5-苯氧基戊酰基)甘氨酸、
    N-(α-鼠李吡喃糖基膦酰胺)-L-亮氨酸-L-色氨酸、
    N-[N-[(L)-1-羧基-2-苯基乙基]-L-苯丙氨酰基]-(R)-丙氨酸、
    N-[N-[((1S)-羧基-2-苯基)乙基]-(S)-苯丙氨酰基]-β-丙氨酸、
    N-(S)-[3-巯基-2-(2-甲基苯基)丙酰基]-(S)-2-甲氧基-(R)-丙氨酸、
    3-[1,1'-联苯]-4-基-N-[二苯氧基氧膦基)甲基]-L-丙氨酰基-β-丙氨酸、
    N-(1-(N-羟基氨基甲酰基甲基)-1-环戊烷羰基)-L-苯丙氨酸、
    N-[2-巯基甲基-3-苯基-丙酰基]-3-氨基苯甲酸、
    4-[[2-(巯基甲基)-1-氧代-3-苯基丙基]氨基]苯甲酸、
    N-[2-乙酰硫基甲基-3-苯基-丙酰基]-3-氨基苯甲酸、
    N-[2-巯基甲基-3-(2-甲基苯基)丙酰基]-甲硫氨酸、
    N-(3-苯基-2-(巯基甲基)-丙酰基)-(S)-4-(甲基巯基)-甲硫氨酸、
    N-[1-(2-羧基-4-苯基丁基)-环戊烷羰基]-(S)-异丝氨酸、
    N-[2(S)-巯基甲基-3-(2-甲基苯基)-丙酰基]-(S)-异丝氨酸、
    N-(1-(3-(N-叔丁氧羰基-(S)-脯氨酰氨基)-2(S)-叔丁氧基-羰基丙基)环戊烷羰基)-O-苄基-(S)-丝氨酸、
    3(S)-[2-(乙酰硫基甲基)-3-苯基-丙酰基]氨基-ε-己内酰胺、
    N-[1-(乙酰硫基甲基)-环戊羰基]-(S)-甲硫氨酸、
    N-[2-乙酰硫基甲基-3-(2-甲基-苯基)丙酰基]-甲硫氨酸、
    N-[2(S)-巯基甲基-3-(2-甲基苯基)-丙酰基]蛋氨酸、
    N-[2-(巯基甲基)-1-氧代-3-苯基丙基]-β-丙氨酸、
    7-[[2-(巯基甲基)-1-氧代-3-苯基丙基]氨基]-庚酸、
    N-[N-[1(S)-羧基-3-苯基丙基]-(S)-苯丙氨酰基]-(S)-异丝氨酸、
    N-[1-[[1(S)-羰基-3-苯基丙基]氨基]-环戊基羰基]-(S)-异丝氨酸、
    N-[1-[[1(S)-苄氧基羰基-3-苯基丙基]氨基]-环戊基羰基]-(S)-异丝氨酸、
    N-[N-[(L)-[1-[(2,2-二甲基-1,3-二氧戊环-4-基)-甲氧基]羰基]-2-苯基乙基]-L-苯丙氨酰基]-(R)-丙氨酸、
    N-(2-羧基-4-噻吩基)-3-巯基-2-苄基丙酰胺、
    2-(2-巯基甲基-3-苯基丙酰氨基)噻唑-4-基甲酸、
    (L)-(1-((2,2-二甲基-1,3-二氧戊环-4-基)-甲氧基)羰基)-2-苯基乙基)-L-苯丙氨酰基)-β-丙氨酸、
    顺-4-[[[1-[2-羧基-3-(2-甲氧基乙氧基)丙基]-环戊基]羰基]氨基]-环己烷甲酸、
    3-(1-[6-内-羟基甲基二环[2,2,1]庚烷-2-外-氨基甲酰基]环戊基)-2-(2-甲氧基乙基)丙酸、
    3-[1-(顺-4-羧基羰基-顺-3-丁基环己基-r-1-氨基甲酰基)环戊基]-2S-(2-甲氧基乙氧基甲基)丙酸、
    (S)-顺-4-[1-[2-(5-茚满基氧基羰基)-3-(2-甲氧基乙氧基)丙基]-1-环戊烷酰氨基]-1-环己烷甲酸、
    1,1'-[二硫代双-[2(S)-(2-甲基苄基)-1-氧代-3,1-亚丙基]]-双-(S)-异丝氨酸、
    1,1'-[二硫代双-[2(S)-(2-甲基苄基)-1-氧代-3,1-亚丙基]]-双-(S)-甲硫氨酸、
    4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸、
    N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸；
    优选，(a)为至少一种下列化合物：
    N-[1-(乙酰硫基甲基)-环戊羰基]-(S)-甲硫氨酸乙酯、
    N-[2-乙酰硫基甲基-3-(2-甲基-苯基)丙酰基]-甲硫氨酸乙酯、
    N-(1-(3-(N-叔丁氧羰基-(S)-脯氨酰氨基)-2(S)-叔丁氧基-羰基丙基)环戊烷羰基)-O-苄基-(S)-丝氨酸甲酯、
    3(S)-[2-(乙酰硫基甲基)-3-苯基-丙酰基]氨基-ε-己内酰胺、
    4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸、
    N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸、
    N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钠、
    N-(3-羧基-1-氧代丙基)-(4S)-对-苯基苯基甲基)-4-氨基-2R-甲基丁酸钾、
    4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸乙酯、
    4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸钠、
    4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸钾、
    4-(((2S,4R)-1-([1,1'-联苯]-4-基)-5-乙氧基-4-甲基-5-氧代戊烷-2-基)氨基)-4-氧代丁酸铵。
  5. 根据权利要求1-4中任一项所述的药物组合物或药物包，其特征在于，(a)与(b)的质量比为(0.5-10):1，优选为(0.5-5):1，更优选为(0.5-3):1。
  6. 根据权利要求1-5中任一项所述的药物组合物或药物包在制备用于预防和/或治疗心血管疾病的药物中的用途。
  7. 中性内肽酶抑制剂或其药学上可接受的盐或酯在制备用于和式(I)所示化合物或其药学上可接受的盐或酯联合预防和/或治疗心血管疾病的药物中的用途，其中式(I)所示化合物具有权利要求1中的定义；
    优选，中性内肽酶抑制剂或式(I)所示化合物的药学上可接受的盐独立地选自Na、K或NH4盐；中性内肽酶抑制剂或式(I)所示化合物的药学上可接受的酯独立地选自甲酯、乙酯或丙酯；
    进一步优选，式(I)所示化合物的药学上可接受的盐为K盐；
    进一步优选，式(I)所示化合物的K盐具有权利要求3中的定义；
    优选，(a)具有权利要求4中的定义。
  8. 式(I)所示化合物或其药学上可接受的盐或酯在制备用于和中性内肽酶抑制剂或其药学上可接受的盐或酯联合预防和/或治疗心血管疾病的药物中的用途，其中式(I)所示化合物具有权利要求1中的定义；
    优选，中性内肽酶抑制剂或式(I)所示化合物的药学上可接受的盐独立地选自Na、K或NH4盐；中性内肽酶抑制剂或式(I)所示化合物的药学上可接受的酯独立地选自甲酯、乙酯或丙酯；
    进一步优选，式(I)所示化合物的药学上可接受的盐为K盐；
    进一步优选，式(I)所示化合物的K盐具有权利要求3中的定义；
    优选，(a)具有权利要求4中的定义。
  9. 根据权利要求7或8所述的用途，其特征在于，(a)与(b)的质量比为(0.5-10):1，优选为(0.5-5):1，更优选为(0.5-3):1。
  10. 根据权利要求6-8中任一项所述的用途，其特征在于，心血管疾病选自：高血压、心衰、冠心病、风湿性心脏病、先天性心脏病、左心室功能不全、内皮功能障碍、舒张期功能障碍、肥厚性心肌病、糖尿病性心肌病、室上性和室性心律失常、房颤、心脏纤维化、心房扑动、有害的血管重塑、心肌梗塞及其后遗症、动脉粥样硬化、心绞痛、原发性和继发性肺性高血压、肾血管性高血压。
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