CN108113988A - A kind of ROMK inhibitor combines the purposes in treatment and/or preventing hypertension or the drug of heart failure is prepared with ARB - Google Patents

A kind of ROMK inhibitor combines the purposes in treatment and/or preventing hypertension or the drug of heart failure is prepared with ARB Download PDF

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Publication number
CN108113988A
CN108113988A CN201711220751.4A CN201711220751A CN108113988A CN 108113988 A CN108113988 A CN 108113988A CN 201711220751 A CN201711220751 A CN 201711220751A CN 108113988 A CN108113988 A CN 108113988A
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purposes
azilsartan
romk
romk inhibitor
angiotensin
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桂雨舟
曹国庆
杨昌永
张连山
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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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
    • A61K31/435—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Combine the purposes in treatment and/or preventing hypertension or the drug of heart failure is prepared with ARB the present invention relates to a kind of ROMK inhibitor.

Description

A kind of ROMK inhibitor is combined with ARB is preparing treatment and/or preventing hypertension or the heart Purposes in the drug of force failure
Technical field
Combine the present invention relates to a kind of ROMK inhibitor with angiotensin II receptor antagonist (ARB) and preparing treatment And/or the purposes in preventing hypertension or the drug of heart failure.
Background technology
Kidney priopticon secretion potassium channel (renal outer medullary potassium channel, ROMK) is also referred to as Internally-oriented rectification type potassium-channel 1.1 (inward-rectifying potassium channels 1.1, Kirl.1), suppression The function of ROMK processed can effectively inhibit Na in the case where not causing hypokalemia+-K+-2Cl-The salt of transport protein is inhaled again Function is received, the effect of promoting the excretion of urine, play diuretic antihypertensive.
Patent application WO2016091042A1 (publication date 2016.06.16) discloses a kind of ROMK inhibitor compounds, knot Shown in structure such as following formula (I)
Azilsartan is a kind of Angiotensin II for being used to treat vascular hypertension of Japanese Takeda Pharmaceutical Company Limited's exploitation Receptor antagonist (ARB) drug, Azilsartan are a kind of pro-drugs, and A Qisha is hydrolyzed to rapidly during gastrointestinal tract absorbs Smooth acid, and play drug effect.Azilsartan (Azilsartan) is put down in vivo by selective exclusion Angiotensin II with blood vessel Sliding flesh ATI receptors with reference to and the vasoconstriction of Angiotensin II is blocked to act on, so as to reduce blood pressure.But as directly performance Because its molecular structure contains carboxyl, the poor drug that influences of body absorption plays curative effect, is unfavorable for being prepared into the Azilsartan of drug effect Pharmaceutical dosage form, in order to improve bioavilability and solubility, patent application WO2012097697A1 (publication date 2012.07.26) A kind of Azilsartan organic amine salt compound is disclosed, shown in structure such as following formula (I)
Hypertension is most common cardiovascular and cerebrovascular disease.There are nearly 2.63 hundred million high blood in the statistical result showed of 2010, China Press patient, it is contemplated that the year two thousand twenty, this number will be increased to 4.19 hundred million, increase by 59%.The base common as cardiovascular and cerebrovascular disease Plinth disease, influence of the hypertension to China human mortality health is huge, and serious threat people's health.Therefore, controlled by drug Hypertension is treated to have very important significance.
The hypertension therapeutic guideline in newest Europe, the U.S. and Australia is short of money diuretics and angiotensin-ii receptor Anti-agent (ARB) is all used as hypertension first-line treatment drug.When single therapy still cannot be reduced to normal arterial pressure scope, it is necessary to It is combined with other kinds of drug, further controls blood pressure.In Primary Care, addition diuretics is most-often used connection Decompression scheme is closed, diuretics can be used in combination with the antihypertensive drugs including ARB.
However traditional diuretics has the risk of security when being combined with ARB.Thiazide diuretic and loop diuretic can Cause hypokalemia, prolonged application person needs periodic monitoring blood potassium, and mends potassium in right amount.Thiazide diuretic is because that can cause blood uric acid liter Height merges gout person's disabling；It is used with caution for hyperuricemia and renal insufficiency person.Potassium-sparing diuretic can cause hyperkalemia Disease should not have the depressor such as angiotensin converting enzyme inhibitor (ACEI) or angiotensins for protecting potassium effect with other II receptor antagonists (ARB) are combined.Therefore, the higher diuretics of security clinically has good application prospect.
It is disclosed in patent application WO2010129379, WO2013062900, WO2014099633, WO2013090271 ROMK inhibitor and the composition of some angiotensin II receptor antagonists, but it is unaware of whether it possesses synergistic effect.
ROMK inhibitor is new diuretics, and compound shown in formula (I) reduces K by inhibiting ROMK passages+Outflow, from And inhibit Na indirectly+-K+-2Cl-Cotransport the function of albumen, inhibits Na+And Cl-Reabsorption, play the effect of diuresis.Meanwhile Compound 1 inhibits K+Secretion, so as in the case where not significantly affecting serum potassium, inhibit Na+And Cl-Reabsorption, Achieve the effect that diuresis and decompression.
It needs to find suitable ROMK inhibitor and be used in combination with angiotensin II receptor antagonist, made with reaching collaboration With.
The content of the invention
The present invention, which provides a kind of angiotensin II receptor antagonist and combines with ROMK inhibitor, is preparing treatment and/or in advance Purposes in anti-hypertension or heart failure drugs, which is characterized in that the ROMK inhibitor is logical formula (I) compound represented Or its stereoisomer,
Wherein,
R1Selected from alkyl, halogen, halogenated alkyl, hydroxyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl, carboxyl or Alkoxy carbonyl group；
R2Selected from hydrogen atom, alkyl, halogen, cyano, carboxyl, alkoxy carbonyl group, hydroxyalkyl, halogenated alkyl, nitro, alcoxyl Base, cycloalkyl, heterocycle, aryl or heteroaryl；
R3Selected from following groups：
R4、R5It is respectively selected from hydrogen atom, alkyl, halogen, cyano, nitro, alkoxy, cycloalkyl, heterocycle, aryl or miscellaneous Aryl；
R6Selected from hydrogen atom, alkyl or halogen；
N is 0,1 or 2.
Preferably, the ROMK inhibitor structures are as shown in logical formula (II),
Wherein,
R1、R2、R4, n is as defined in formula (I).
It is furthermore preferred that the ROMK inhibitor structures are as shown in logical formula (III),
Wherein,
R1、R2、R4, n is as defined in formula (I).
It is further preferred that the ROMK inhibitor structures are as shown in formula (IV),
In a preferred scheme of the invention, further relate to the angiotensin II receptor antagonist selected from Losartan, Valsartan, Irbesartan, Olmesartan, olmesartan medoxomil, Telmisartan, candesartan Cilexetil, Eprosartan, methanesulfonic acid are according to general One or more of Luo Shatan, Azilsartan, Azilsartan or Azilsartan organic amine salt, optional, also comprise hydrogen Chlorothiazide.
It is furthermore preferred that the angiotensin II receptor antagonist is for Azilsartan or derivatives thereof, as Azilsartan, Azilsartan or Azilsartan organic amine salt, the structure of the Azilsartan organic amine salt can be such as general formula (I ') or general formula Shown in (II '),
Purposes of the present invention, wherein, the ratio of Azilsartan and organic amine in the Azilsartan organic amine salt For 2: 1, the organic amine is selected from ethanolamine or choline.The Azilsartan organic amine salt can exist with composite form.
It is further preferred that shown in the Azilsartan organic amine salt structure such as general formula (I ' -1) or general formula (II ' -1),
In the present invention, the dosage of the angiotensin II receptor antagonist can be 0.1-1000mg.
In the present invention, the ROMK inhibitor is 0.1-1000mg.
The invention further relates to a kind of angiotensin II receptor antagonists and ROMK inhibitor drug combination to prepare Purposes in prevention and/or treatment hypertension or heart failure drugs, wherein, angiotensin II receptor antagonist presses down with ROMK The ratio of preparation is 0.001~1000: 1, preferably 0.1~10: 1, more preferable 1: 1.
The invention further relates to a kind of angiotensin II receptor antagonists and ROMK inhibitor drug combination to prepare Purposes in prevention and/or treatment hypertension or heart failure drugs, wherein, angiotensin II receptor antagonist gives medicament Measure as 1-500mg, preferred dosage includes following point value or any numerical value between them, as 2mg, 2.5mg, 3mg, 5mg、6mg、7mg、8mg、10mg、12.5mg、15mg、20mg、25mg、30mg、35mg、40mg、50mg、100mg、150mg、 200mg, 250mg or 400mg, the dosage of ROMK inhibitor is 0.5-400mg, and preferred dosage includes following point Value or any numerical value between them, as 1mg, 2mg, 2.5mg, 3mg, 5mg, 6mg, 7mg, 8mg, 10mg, 12.5mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 50mg, 100mg, 150mg, 200mg, 250mg or 400mg.
Combine the invention further relates to a kind of angiotensin II receptor antagonist with ROMK inhibitor and preparing prevention And/or the purposes in treatment hypertension or heart failure drugs, wherein, administration time pushes away for angiotensin II receptor antagonist It recommends once a day, ROMK inhibitor is recommended once a day.
The angiotensin II receptor antagonist of the present invention has with ROMK inhibitor drug combination cooperates with drug action.
A kind of pharmaceutical composition for further relating to angiotensin II receptor antagonist and ROMK inhibitor of the present invention, comprising The pharmaceutical preparation of one or more pharmaceutical carriers optionally, excipient and/or diluent.Medicine can be made in described pharmaceutical composition Acceptable any dosage form on.For example, angiotensin II receptor antagonist and the pharmaceutical preparation of ROMK inhibitor can match somebody with somebody Tablet, capsule, pill, granule, solution, suspension, syrup, injection are made as (including parenteral solution, Injectable sterile Powder and concentrated solution for injection), suppository, inhalant or spray.
In addition, the described pharmaceutical composition of the present invention can also be with any suitable administering mode, such as take orally, stomach Outside, the modes such as rectum, transpulmonary or local administration are applied to the patient or subject for needing this treatment.When for being administered orally When, described pharmaceutical composition can be made into oral formulations, such as oral solid formulation, such as tablet, capsule, pill, granule； Or, oral liquid, such as oral solution, oral suspensions, syrup.When oral formulations are made, the drug system Agent can also include suitable filler, adhesive, disintegrant, lubricant etc..When for parenteral administration, the pharmaceutical composition Object can be made into injection, including parenteral solution, injection sterile powder and concentrated solution for injection.When injection is made, the medicine The conventional method in existing pharmaceutical field can be used to be produced in compositions.When preparing injection, the pharmaceutical composition Additives can be added without in object, suitable additives can be also added according to the property of drug.It is described when for rectally Pharmaceutical preparation can be made into suppository etc..During for transpulmonary administration, described pharmaceutical composition can be made into inhalant or spray etc..
The angiotensin II receptor antagonist of the present invention can be administered alone with ROMK inhibitor combinations or with one Kind or a variety of second therapeutic agents are used in combination.Therefore, in certain preferred aspects, the pharmaceutical composition also contains One or more second therapeutic agents.In certain preferred aspects, the second therapeutic agent is selected from：Diuretics, Ca2+ overloading Medicine, beta receptor blocking agent, angiotensin converting enzyme inhibitor (ACEI) or 1 adrenergic antagonists, the diuretics are selected from Hydrochioro, the calcium antagonist are selected from nifedipine, felodipine, Amlodipine or lacidipine, the beta receptor blocking agent Selected from Propranolol, bisoprolol or labetalol, the angiotensin converting enzyme inhibitor (ACEI) be selected from captopril, Fosinopril, enalapril or Ramipril, the 1 adrenergic antagonists are selected from Metoprolol, Labetalol, Te La Azoles piperazine, can Lean, the pyridine of piperazine second or reserpine.
Each ingredient (for example, angiotensin II receptor antagonist and ROMK inhibitor and second therapeutic agent) to be combined can It is administered simultaneously or sequentially separates medication successively.It for example, can be by angiotensin II receptor antagonist of the present invention and ROMK Prior to, concurrently with, or after inhibitor combination, using second therapeutic agent.In addition, each ingredient to be combined can also be with same preparation Form or the administering drug combinations in the form of separated different preparations.
In the present invention, so-called " drug combination or combination " is a kind of administering mode, including two kinds of drugs priorities or simultaneously Administration various situations, it is so-called herein refer to " simultaneously " same dosage period give angiotensin II receptor antagonist with ROMK inhibitor, such as two kinds of drugs are given in 2 days or in 1 day.So-called " successively or in succession " is administered, then is included in difference The situation of angiotensin II receptor antagonist and ROMK inhibitor is given in dosage period respectively.These administering modes, belong to In administering drug combinations of the present invention.
The present invention also provides a kind of method for treating hypertension, including giving foregoing angiotensins to cancer patient II receptor antagonists and ROMK inhibitor.
" effective quantity " of the present invention, which includes, to be enough to improve or prevent to cure the symptom of word illness or the amount of illness.Effective quantity Still mean that the amount for being enough to allow or promoting diagnosis.It can be according to following factor for the effective quantity of particular patient or veterinary science subject And change：As illness to be treated, the general health of patient, the method and approach of administration and dosage and side effect are serious Property.Effective quantity can be the maximum dose or dosage regimen for avoiding notable side effect or toxic action.
Detailed description of the invention
In the description and claims of this application, unless otherwise stated, science used herein and skill Art noun has the normally understood meaning of those skilled in the art institute.However, it for a better understanding of the present invention, is provided below The definition and explanation of part relational language.In addition, as the definition and explanation of term provided herein and people in the art When the normally understood meaning of member institute is inconsistent, with the definition of term provided herein and it is construed to accurate.
" halogen or halogen atom " of the present invention refers to fluorine atom, chlorine atom, bromine atoms, iodine atom etc..
" cyano " of the present invention refers to the groups such as-CN.
" hydroxyl " of the present invention refers to the groups such as-OH.
" carboxyl " of the present invention refers to the groups such as-COOH.
" carbonyl " of the present invention refers to the groups such as-CO-.
" nitro " of the present invention refers to-NO2Wait groups.
" alkyl " of the present invention refers to the alkyl containing 1-20 carbon atom of linear chain or branch chain, including such as " C1-6Alkane Base ", " C1-4Alkyl " etc., specific example includes but not limited to：It is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, secondary Butyl, tertiary butyl, n-pentyl, isopentyl, 2- methyl butyls, neopentyl, 1- ethyl propyls, n-hexyl, isohesyl, 3- methylpents Base, 2- methyl amyls, 1- methyl amyls, 3,3- dimethylbutyls, 2,2- dimethylbutyls, 1,1- dimethylbutyls, 1,2- bis- Methyl butyl, 1,3- dimethylbutyls, 2,3- dimethylbutyls, 2- ethyl-butyls, 1,2- dimethyl propyls etc..
" cycloalkyl " of the present invention refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, including 3 To 14 carbon atoms, 3 to 12 carbon atoms are preferably included, more preferable cycloalkyl ring includes 3 to 8 carbon atoms, most preferably cycloalkanes Basic ring includes 5 to 6 carbon atoms, most preferably cyclopropyl.The non-limiting example of monocyclic cycloalkyl includes cyclopropyl, ring fourth Base, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc., preferably Cyclopropyl, cyclohexenyl group.Polycyclic naphthene base includes the cycloalkyl of loop coil, condensed ring and bridged ring.
" heterocycle " of the present invention refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, including 3 To 14 annular atoms, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but The loop section of-O-O- ,-O-S- or-S-S- are not included, remaining annular atom is carbon.Preferably include 3 to 12 annular atoms, wherein 1-4 A is hetero atom, and more preferable heterocyclic ring includes 3 to 8 annular atoms, and more preferable heterocyclic ring includes 5 to 6 annular atoms.It is monocyclic The non-limiting example of heterocycle include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base, Pyranose, tetrahydrofuran base etc..Multiring heterocyclic includes the heterocycle of loop coil, condensed ring and bridged ring.
" hydroxyalkyl " of the present invention refer to by HO- alkyl-in a manner of the group that connects, wherein alkyl is as defined above institute It states.Non-limiting example includes hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisobutyl etc..
" alkoxy " of the present invention refers to the group connected in a manner of-O- (alkyl) or-O- (unsubstituted cycloalkyl), Wherein alkyl, cycloalkyl are as defined above.Non-limiting example include methoxyl group, ethyoxyl, propoxyl group, butoxy, Ring propoxyl group etc..
" alkoxy carbonyl group " of the present invention refers to the group connected in a manner of alkoxy -C O-, the wherein definition of alkoxy such as It is upper described.Non-limiting example includes methoxycarbonyl group, carbethoxyl group, propylene carbonyl oxygen, tertbutyloxycarbonyl etc..
" aryl " of the present invention refer to the pi-electron system with conjugation 6 to 14 yuan of full carbon are monocyclic or fused polycycle ( It is exactly the ring of shared adjacent carbon atoms pair) group is preferably 6 to 8 yuan of aryl, more preferable phenyl and naphthalene, most preferably phenyl. The aryl rings can be condensed on heteroaryl, heterocycle or cycloalkyl ring, wherein being with the ring that precursor structure links together Aryl rings, non-limiting example include：
" heteroaryl " of the present invention refer to the pi-electron system with conjugation 5 to 15 yuan of full carbon are monocyclic or fused polycycle Group, further include 1 to 4 it is heteroatomic, wherein hetero atom is selected from one or more oxygen, sulphur or nitrogen.Preferably 5 to 8 yuan Heteroaryl, more preferably 5 yuan to 6 yuan of heteroaryl, even more preferably furyl, thienyl, pyridyl group, pyrrole radicals, N- alkane Base pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can be condensed in aryl, heterocycle or ring On alkyl ring, wherein the ring to link together with precursor structure is heteroaryl ring, non-limiting example includes：
" substituted " refers to one or more of group hydrogen atom, preferably at most 5, more preferably 1~3 hydrogen atom Substituted independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technology personnel can determine and (pass through experiment or theoretical) may or impossible to take in the case where not paying excessive make great efforts Generation.For example, amino or hydroxyl with free hydrogen may be unstable when being combined with the carbon atom with unsaturated (such as olefinic) key Fixed.
Advantageous effect of the invention
Compared with prior art, technical scheme has the following advantages：
(1) angiotensin II receptor antagonist of the present invention can effectively solve ROMK inhibition with ROMK inhibitor drug combination The tolerance of agent delays pathogen drug resistance problems, improves the effect of drug.
(2) research has shown that, angiotensin II receptor antagonist of the present invention can inhibit with ROMK inhibitor drug combinations Increased heart rate caused by ROMK inhibitor medicaments, and reduce periphery oedema incidence.
Specific embodiment
Exemplary tests scheme of the composition of the present invention presented below in hypertension medical usage, to show the present invention The favorable activity or advantageous effects of composition.It is understood that following testing programs are only to present invention Example, without limiting the scope of the present invention.Those skilled in the art, can be to the present invention's under the introduction of this specification Technical solution carries out appropriate modification or change, without departing from the spirit and scope of the present invention.
The influence of embodiment 1, the present composition to spontaneous hypertensive rat blood pressure and heart rate
Test sample：Azilsartan ethanolamine salt (can be according to patent application (shown in formula (I ' -1) or formula (II ' -1)) It is prepared by method in WO2012097697A1), ROMK inhibitor compounds A (can be according in patent application WO2016091042A1 Method prepare).
Shown in structure such as formula (I ' -1) or formula (II ' -1),
Comparison medicine：Hydrochioro (HCTZ) is commercially available.
Experimental animal：Spongtangeous hypertension model rat (Spontaneously Hypertensive Rats, SHR, north Capital experimental animal Technology Co., Ltd. of dimension tonneau China provides), male 10, female 10.Animal is to week old during facility：11 weeks. Experimental animal production licence number：SCXK (capital) 2012-0001, the term of validity：On 01 19th, 2017.Beijing's experimental animal matter Measure the quality certification：NO.11400700123914.All these rats be all by INNOVIVE provide without special pathogenic original It is bred in (special pathogen free, SPF) the barrier environment of laboratory animals.The raising of experimental animal, operating procedure is all It is to nurse according to experimental animal and carried out using the laboratory standard that the committee (IACUC) ratifies.Experimental animal use is permitted It can the number of card：SYXK (Shanghai) 2015-0019.
The material sources such as reagent：
Numb essence drug (yellow Jackets) is purchased from Toronto Research Chemicals；
Sodium carboxymethylcellulose (CMC-Na).
Test solution is prepared：
Required sodium carboxymethylcellulose is accurately weighed, double distilled water is added to be configured to 0.5% concentration, magnetic agitation mixing To clarification.2~8 DEG C of preservations.
ROMK inhibitor compounds A：Weigh Compound (1.11mg) adds in 0.5% CMC-Na solution (22.20mL), Be vortexed scattered, the ultrasound about 80min that becomes smaller to the compound bulk in CMC-Na solution, until without significantly greater granular compound In the presence of being placed in stir about 15min on magnetic stirring apparatus, to liquid in homodisperse suspension, the concentration of gained suspension is 0.05mg/mL, 2~8 DEG C are kept in dark place, and room temperature, mixing are preheated to before administration；
Identical preparation method compound concentration is the suspension of 0.15mg/mL, and 2~8 DEG C are kept in dark place；
Identical preparation method compound concentration is the suspension of 0.50mg/mL, and 2~8 DEG C are kept in dark place.
Azilsartan ethanolamine salt：It is 0.15mg/ according to preparation method compound concentration identical ROMK inhibitor compounds A The suspension of mL, 2~8 DEG C are kept in dark place.
Hydrochioro (HCTZ)：It is 12.5mg/mL according to preparation method compound concentration identical ROMK inhibitor compounds A Suspension, 2~8 DEG C are kept in dark place；
According to the suspension that preparation method compound concentration identical ROMK inhibitor compounds A is 25mg/mL, 2~8 DEG C are kept away Light preserves.
The heeling-in of blood pressure implanted device：
Rat adapts to environment, and (week old is 12 weeks after adaptation) performs the operation after a week, with 2% Nembutal sodium solution (60mg/kg, ip.) is anaesthetized；Implanted device heeling-in operation is carried out in experiment within the -10th day and the -9th day：Rat abdomen does notch Operation separates abdominal aorta, and the blood pressure sensing probe conduit of implanted device is inserted into abdominal aorta, with biogum hemostasis seals, so Implanted device is fixed on stomach wall afterwards, and sutures muscle and skin, sterilize and subcutaneous administration Lepetan analgesia (0.5mg/kg, s.c.).Single cage is raised after animal regains consciousness, and Cefradine (10mg/kg, an ip.) prevention is injected intraperitoneally in postoperative three days daily Infection.
Grouping：
Blood pressure when continuous monitoring 2 was small in postoperative 7th day, reached using 2 hourly average systolic pressures~160mmHg moves as standard screening Object, qualified animal enter experiment, and underproof animal is removed.The animal of experiment will be selected by 2 hourly average systolic pressures point Group, every group of valid data are at least 8 animals, every time the 4th day detection animal blood pressure after administration, and recovery is horizontal to before being administered will It is administered again, carries out efficacy testing.Dosage regimen and arrangement of time are as shown in table 2.Every group of at least 4 homogeneity are not moved object, only The requirement and the requirement of pharmacodynamics guideline that number coincidence statistics is examined.Basic blood pressure and the heart when continuous monitoring 24 is small after grouping Rate.By to animal basic blood pressure measure and count after, each group it is actual enter group size of animal as shown in table 1 (one in Vehicle groups Jenny was popped one's head in failure from the 13rd day cause blood pressure, abnormal signal, therefore was rejected to prevent from interfering data).
Table 1, specific experiment scheme and grouping
Remarks：HCTZ groups are reduced with drug combination group size of animal, are not recovered the reason is that 2 SHR rats are postoperative, are rejected；
Ip is intraperitoneal injection；Po is oral.
The collection of data：
Animal is in testing the -10th day and the -9th day heeling-in implanted device (totally 18 animals), because receiver quantity limits, administration And the measure of blood pressure is divided to two groups of progress.Qualified animal, which is selected, in the -3rd day monitoring 2h blood pressure enters experiment (on experimental program is shown in Table).0th day continuous monitoring blood pressure and heart rate for 24 hours.After 1st day at 10 points in the morning gave solvent or positive drug and monitored administration for the first time Blood pressure for 24 hours.At 10 points in 2nd day morning and the 3rd day at 10 points in the morning give solvent or positive drug, and the morning 10 on day 3 for the first time respectively Point starts continuous monitoring 48h blood pressures and heart rate to the 5th day at 10 points in the morning terminates.Again through eluting for 24 hours, 10 points of difference of the 7th day morning Give compound A low dose groups (0.1mg/kg) and Hydrochioro (25mg/kg).Previous group administration and record period are repeated, according to Secondary record compound A middle dose groups (0.3mg/kg) and Hydrochioro (50mg/kg), compound A high doses group (1.0mg/kg) With drug combination group Azilsartan ethanolamine salt (0.3mg/kg)+compound A (0.3mg/kg).Until whole compounds administrations and Record end.
After the test, with the method for excessive sucking carbon dioxide by animal euthanasia, dissection animal recycles implanted device. The implanted device clear water of recycling is cleaned, 2.5% glutaraldehyde solution disinfection 8-10h is soaked in, uses the normal saline flushing 3 of sterilizing Time, it is spare.
Table 2, dosage regimen and arrangement of time
Remarks：The elution phase means previous drug administration, after elution, enters back into the administration of next dosage, animal Or the same identical a batch.
Data analysis：
DSI remote sensing pressure measuring units every five seconds for example records a data automatically, is calculated using software using hour as timing node, Calculation interval average value is as initial data.Blood pressure and heart rate initial data are calculated with Ponemah Software 5.0 to be analyzed, 0hr, 4hr, 10hr, 14h before first administration are provided, for 24 hours 4hr, 8hr, 12hr, 16hr, 20hr after r and continuous 3 administrations, Blood pressure and the heart rate average value ± standard error of r for 24 hours, 30hr, 36hr, 48hr.
All data are entered into Excel document, and are represented in a manner of mean+/-standard error, and conspicuousness is poor It is different to be compared using two analysis of variance (two-way ANOVA).* 0.001 tables of P ＜ 0.05, * * P ＜ 0.01, * * * P ＜ Show that administration group has significant difference compared with solvent control group.#P ＜ 0.05, ##P ＜ 0.01, ###P ＜ 0.001 represent joint Administration group has significant difference compared with group is applied alone.
Experimental result：
Experiment conclusion：
Administering drug combinations group (Azilsartan ethanolamine salt (0.3mg/kg)+ROMK inhibitor compounds A is understood by experimental result (0.3mg/kg)) after first administration 10h and three times be administered after 4h to 36h Each point in time, with Azilsartan ethanolamine Salt (0.3mg/kg) is applied alone group to compare, and is respectively provided with significant difference；
The results show that compared with control group HCTZ, each dosage groups of ROMK inhibitor compounds A exist mean arterial pressure changing value Single-dose and three times be administered after, mean arterial pressure changing value significantly reduces；
Typical time period point mean arterial pressure change rate has also obtained similar as a result, each dosage of ROMK inhibitor compounds A After group is administered in single-dose and three times, mean arterial pressure change rate significantly reduces.The knot of the mean arterial pressure of typical time period point Fruit shows that for ROMK inhibitor compounds A after single-dose (0.1mg/kg) and each dosage are administered three times, mean arterial pressure is notable It reduces；Administering drug combinations the group 4h after first administration, 10h and for 24 hours to three times be administered after 48h Each point in time, with A Qisha Smooth ethanolamine salt (0.3mg/kg) is applied alone group to compare, and is respectively provided with significant difference；
The front and rear mean arterial pressure for 24 hours of administration the results show that after continuous administration three times in 48h, with control group compared with, ROMK The 0.1 of inhibitor compound A, the equal conspicuousness of 0.3 and 1.0mg/kg mean arterial pressures reduces, in each typical time period point to dynamic Object average heart rate does not generate conspicuousness influence；
ROMK inhibitor compounds A has apparent antihypertensive effect, and each dosage group is to heart rate without significantly affecting；ROMK presses down The effective dose of inhibitor compound A antihypertensive effects is 0.1mg/kg, and maximum reducing dosage is 0.3mg/kg.
In conclusion the Azilsartan ethanolamine salt of the present invention has significant association with ROMK inhibitor compounds A combinations Same-action is significantly better than the antihypertensive effect of hypertension one-component Azilsartan ethanolamine salt or compound A and is better than The effect of control group HCTZ, therefore, the decompression of Azilsartan ethanolamine salt of the present invention and ROMK inhibitor compound A drug combinations Significant effect.

Claims (12)

1. a kind of angiotensin II receptor antagonist is combined with ROMK inhibitor is preparing treatment and/or preventing hypertension or the heart Purposes in force failure drug, which is characterized in that the ROMK inhibitor is logical formula (I) compound represented or its alloisomerism Body,
Wherein,
R1Selected from alkyl, halogen, halogenated alkyl, hydroxyl, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl, carboxyl or alcoxyl Carbonyl；
R2Selected from hydrogen atom, alkyl, halogen, cyano, carboxyl, alkoxy carbonyl group, hydroxyalkyl, halogenated alkyl, nitro, alkoxy, cycloalkanes Base, heterocycle, aryl or heteroaryl；
R3Selected from following groups：
R4、R5It is respectively selected from hydrogen atom, alkyl, halogen, cyano, nitro, alkoxy, cycloalkyl, heterocycle, aryl or heteroaryl；
R6Selected from hydrogen atom, alkyl or halogen；
N is 0,1 or 2.
2. purposes as described in claim 1, which is characterized in that the ROMK inhibitor structures as shown in logical formula (II),
Wherein,
R1、R2、R4, n it is as defined in claim 1.
3. purposes as claimed in claim 2, which is characterized in that the ROMK inhibitor structures as shown in logical formula (III),
Wherein,
R1、R2、R4, n it is as defined in claim 1.
4. purposes as claimed in claim 3, which is characterized in that the ROMK inhibitor structures be as shown in formula (IV),
5. such as the purposes any one of claim 1-4, which is characterized in that the angiotensin II receptor antagonist choosing From selected from Losartan, Valsartan, Irbesartan, Olmesartan, olmesartan medoxomil, Telmisartan, candesartan Cilexetil, Yi Puluosha One or more of smooth, eprosartan mesylate, Azilsartan, Azilsartan or Azilsartan organic amine salt.
6. purposes as claimed in claim 5, which is characterized in that the structure such as general formula (I ˊ) of the Azilsartan organic amine salt or Shown in general formula (II ˊ),
7. purposes as claimed in claim 6, which is characterized in that Azilsartan in the Azilsartan organic amine salt with it is organic The ratio of amine is 2:1, the organic amine is selected from ethanolamine or choline.
8. purposes as claimed in claim 7, which is characterized in that the Azilsartan organic amine salt exists with composite form.
9. purposes as claimed in claim 8, which is characterized in that the Azilsartan organic amine salt structure such as formula (I ˊ -1) or formula Shown in (II ˊ -1),
10. according to the purposes any one of claim 1-9, which is characterized in that the angiotensin-ii receptor antagonism Agent has synergistic effect with ROMK inhibitor.
11. according to the purposes any one of claim 1-9, it is characterised in that also combine with Hydrochioro.
12. the drug containing the angiotensin II receptor antagonist any one of claim 1-9 Yu ROMK inhibitor Composition, also comprising one or more pharmaceutically useful excipient, diluent or carrier.
CN201711220751.4A 2016-11-29 2017-11-28 A kind of ROMK inhibitor combines the purposes in treatment and/or preventing hypertension or the drug of heart failure is prepared with ARB Pending CN108113988A (en)

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Cited By (1)

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WO2020173476A1 (en) * 2019-02-28 2020-09-03 江苏恒瑞医药股份有限公司 Pharmaceutical composition containing renal outer medullary k channel inhibitor and preparation method therefor

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Publication number Priority date Publication date Assignee Title
CN102603723A (en) * 2011-01-20 2012-07-25 江苏豪森医药集团有限公司 Azilsartan organic amine salts, and preparation method and application thereof
CN105980379A (en) * 2014-12-08 2016-09-28 江苏恒瑞医药股份有限公司 Pyridinecarboxamide derivatives, preparation method therefor and pharmaceutical uses thereof

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Publication number Priority date Publication date Assignee Title
CN102603723A (en) * 2011-01-20 2012-07-25 江苏豪森医药集团有限公司 Azilsartan organic amine salts, and preparation method and application thereof
CN105980379A (en) * 2014-12-08 2016-09-28 江苏恒瑞医药股份有限公司 Pyridinecarboxamide derivatives, preparation method therefor and pharmaceutical uses thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020173476A1 (en) * 2019-02-28 2020-09-03 江苏恒瑞医药股份有限公司 Pharmaceutical composition containing renal outer medullary k channel inhibitor and preparation method therefor

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