WO2017198205A1 - 化合物及其制备方法、组合物和应用 - Google Patents

化合物及其制备方法、组合物和应用 Download PDF

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WO2017198205A1
WO2017198205A1 PCT/CN2017/085012 CN2017085012W WO2017198205A1 WO 2017198205 A1 WO2017198205 A1 WO 2017198205A1 CN 2017085012 W CN2017085012 W CN 2017085012W WO 2017198205 A1 WO2017198205 A1 WO 2017198205A1
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potassium
group
solvent
compound
formula
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PCT/CN2017/085012
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English (en)
French (fr)
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雷四军
方祥
陈永凯
冯伟
王朝东
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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 EP17798768.2A priority Critical patent/EP3447054B1/en
Priority to US16/302,030 priority patent/US11008311B2/en
Publication of WO2017198205A1 publication Critical patent/WO2017198205A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to a potassium salt of a benzimidazole derivative and a preparation method, composition and application thereof.
  • Hypertension is the most common cardiovascular disease and a major risk factor for congestive heart failure, stroke, coronary heart disease, renal failure, and increased morbidity and mortality in aortic aneurysms.
  • Antihypertensive drugs play a key role in the treatment and prevention of hypertension. With the deepening of the understanding of the pathogenesis of hypertension, many antihypertensive drugs with better curative effects, such as diuretics, ⁇ -blockers, calcium channel antagonists, angiotensin converting enzyme inhibitors (ACEI, Angiotensin II, an AT1 receptor antagonist (ABR, sartan), has been continuously discovered and successfully applied in clinical practice.
  • ACEI angiotensin converting enzyme inhibitors
  • ABR AT1 receptor antagonist
  • statin of the AT1 receptor antagonist has stable blood pressure, good curative effect, long duration of action, and good patient tolerance, especially in preventing stroke, delaying diabetes and non-diabetic nephropathy. It has many advantages in improving left ventricular hypertrophy and protection against target organs, and does not affect bradykinin degradation and prostaglandin synthesis, thus causing dry cough and angioedema, and has become a global antihypertensive drug market. Mainstream varieties.
  • the anti-hypertensive drug of sartan has a blood pressure lowering efficiency of only about 50-60% and has a certain degree of adverse reactions. Therefore, the development of a small-dose long-acting antihypertensive drug with stronger antihypertensive effect, less adverse reactions and better protection of target organs has become a hot research direction.
  • the above compound is a sartan drug linked to ligustrazine or a NO donor, and is an angiotensin II receptor antagonist Azi A prodrug of sartan (TAK-536), which releases hydroxyprosin or NO in the body, thereby effectively synergistically acting with azilsartan to enhance antihypertensive effects, having a certain heart rate reduction effect, and reducing adverse effects.
  • TAK-536 angiotensin II receptor antagonist
  • the reaction also has a desirable protective effect on the heart and kidney of the patient.
  • the object of the present invention is to provide an antihypertensive drug with a more potent and longer-lasting antihypertensive effect, which has a more obvious and lasting effect of lowering heart rate, and has high safety, and is ideal for heart and kidney function of patients.
  • the protective effect can be used for preventing and/or treating hypertension, chronic heart failure, diabetic nephropathy and the like.
  • the invention provides a compound of formula I:
  • the R 2 represents hydrogen, halogen, trifluoromethyl, C 1 -C 8 alkoxy, C 1 -C 8 alkyl, nitro, sulfonamide, amino or nitrile;
  • R 4 represents aryl, substituted aryl, arylsulfonyl, heteroaryl, substituted heteroaryl, nitrile, trifluoromethyl, C 1 -C 8 alkoxy, C 1 -C 8 nitrate Or C 1 -C 8 alkyl;
  • R 5 represents phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, nitrile, trifluoromethyl, C 1 -C 8 alkoxy, C 1 -C 8 nitrate, C 1 -C 8- alkyl, C 1 -C 8 alkene, C 1 -C 8 alkyne, Or (CH 2 ) n O(CH 2 ) m , wherein R 3 , R 4 , a, m, n are as defined above;
  • the R 6 and R 7 represent hydrogen, C 1 -C 8 alkoxy or C 1 -C 8 alkyl
  • R 8 and R 9 represents hydrogen, C 1 -C 8 alkoxy, C 1 -C 8 nitrate or C 1 -C 8 alkyl;
  • R 11 substituted aryl, each substituent may be the same or different, wherein R 11 represents hydrogen or C 1 -C 6 alkyl;
  • the substituted heteroaryl group is optionally substituted by one or more C 1 -C 6 alkyl groups, C 1 -C 6 alkoxy groups, halogens, and the respective substituents may be the same or different.
  • the compounds of the invention have the structure shown below:
  • a process for the preparation of a compound of formula I comprising the step of contacting a compound of formula II with a potassium salt reagent.
  • the compound of the formula II can be produced by a method known in the art, for example, the method disclosed in CN103709154A, where CN103709154A is introduced in its entirety.
  • the preparation method includes the step of contacting QR01019 with a potassium salt reagent.
  • the structure of OR01019 is as follows:
  • the compound of the formula II is contacted with a potassium salt reagent in a solvent.
  • the solvent is selected from a mixture of one or more of a polar solvent and a non-polar solvent, or the solvent is selected from the group consisting of water, an ether solvent, a ketone solvent, an alcohol solvent, an ester solvent, an aromatic hydrocarbon solvent, a mixture of one or more of an alkane solvent and a nitrile solvent.
  • the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, ethylene glycol Ether, methyl tert-butyl ether, acetone, methyl ethyl ketone, 4-methyl-2-pentanone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, acetic acid Butyl ester, tert-butyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, nitroethane, N,N-dimethylformamide, dimethyl sulfoxide, ace
  • the compound of formula II need not be completely dissolved in the solvent, even in the absence of a solvent, the reaction may still occur after contact with the potassium salt reagent, so that any amount of solvent may be omitted or used.
  • the amount of solvent used per gram of the compound of formula II is at least about 0.1 ml, further preferably from about 2 to 300 ml, more preferably from about 5 to 100 ml, and most preferably from about 10 to 50 ml.
  • the potassium salt agent is selected from the group consisting of a mixture of one or more of an organic acid potassium salt and a mineral acid potassium salt.
  • the potassium salt of an organic acid is selected from the group consisting of potassium hydrogen phthalate, potassium acetate, potassium formate, potassium di-tert-butyl phosphate, dipotassium glycyrrhizinate, potassium 2-ethylhexanoate, potassium ethyl xanthate, sorbic acid.
  • the potassium olefinate is selected from potassium olefinate of C3 or higher, preferably potassium C02 of C3-C26, such as potassium acrylate, potassium crotonate, potassium octadeceenoate and the like.
  • the potassium salt reagent does not need to be dissolved beforehand, and of course, it may be dissolved in the above solvent in advance.
  • some potassium salt reagents are stored in a solvent because they are unstable or dangerous, and the potassium salt reagents stored in the solvent can be directly used at this time.
  • the molar ratio of K in the compound of Formula II to the potassium salt reagent is from about 1:0.3 to 3, more preferably from about 1:0.9 to about 2, and most preferably from about 1:0.95 to about 1.5.
  • the compound of formula II is first placed in a solvent and then the potassium salt reagent is added.
  • the temperature may be between room temperature and the reflux temperature of the solvent; further preferably, after the potassium salt reagent is added, the temperature may be between 0 ° C and reflux of the solvent. Between temperatures, it is more preferred that the temperature be between room temperature and the reflux temperature of the solvent.
  • room temperature means from about 18 ° C to about 30 ° C, preferably from about 20 ° C to about 24 ° C, more preferably about 22 ° C.
  • the product may be dissolved in the solution or may be directly precipitated from the solution.
  • the product is directly precipitated from the solution, after the reaction, it is filtered and dried to give a compound of the formula I.
  • it is cooled prior to filtration and has a cooling temperature of from about -50 ° C to about 30 ° C, more preferably from about -10 ° C to about 10 ° C, most preferably from about 0 ° C to about 5 ° C.
  • the solvent in the solution is removed to give a compound of formula I or an anti-solvent is added to the solution, filtered and dried to give a compound of formula I.
  • the method of removing the solvent is, for example, spin drying or the like. Preferably, it is cooled prior to filtration and has a cooling temperature of from about -50 ° C to about 30 ° C, preferably from about -10 ° C to about 10 ° C, most preferably from about 0 ° C to about 5 ° C.
  • the anti-solvent is selected from the group consisting of a reagent in which the solubility is inferior to the selected solvent, such as methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, and different Propyl ether, diethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, nitroethane, n-hexane, cyclohexane, pentane, n-heptane, benzene, toluene, xylene a mixture of one or more of them.
  • a reagent in which the solubility is inferior to the selected solvent such as methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-buty
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, optionally further comprising a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be formulated into powders for oral administration, tablets, (including various coated tablets, sustained release or controlled release tablets), troches, capsules (including soft capsules and hard capsules), Granules, pills, dispersible powders, aqueous or oily suspensions, aqueous or oily solutions, emulsions, elixirs, Syrup, etc.; powder or liquid aerosol suitable for inhalation; cream, ointment, gel, aqueous or oily solution suitable for topical application, aqueous or oily suspension, etc.; suitable for transgastric administration A sterile aqueous or oily injection or lyophilized powder injection, suppository or the like for intravenous, subcutaneous or intramuscular injection for parenteral administration.
  • Pharmaceutically acceptable carriers include, but are not limited to, excipients, lubricants, binders, disintegrants, water soluble polymers, inorganic salts, solvents, dissolution aids, suspending agents, isotonic agents, buffers, preservatives Agents, antioxidants, colorants, sweeteners, sour agents, foaming agents and flavoring agents, and the like.
  • the pharmaceutical composition of the present invention may further comprise other active ingredients, such as other active ingredients for preventing and/or treating hypertension, such as calcium ion antagonists (dihydropyridines, aralkylamines, phenylthiazide). Leather and triphenyl piperazine).
  • Suitable amounts of the compound of formula I and various pharmaceutically acceptable carriers and/or other active ingredients in the pharmaceutical compositions can be determined by those skilled in the art according to conventional methods.
  • the term "effective amount” or “therapeutically effective amount” refers to an amount of a compound of the invention sufficient to achieve the intended application, including but not limited to, the treatment of a disease as defined below.
  • the therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, etc. It is readily determined by one of ordinary skill in the art.
  • the particular dosage will vary depending on the particular compound selected, the dosage regimen upon which it is administered, whether it is administered in combination with other compounds, the timing of administration, the tissue to be administered, and the physical delivery system carried.
  • the invention provides the use of a compound of formula I according to the invention or a pharmaceutical composition according to the invention for the preparation of an angiotensin II receptor antagonist, or for the preparation for prophylaxis and/or Use in the treatment of hypertension, chronic heart failure, and diabetic nephropathy.
  • the invention also provides the use of a compound of formula I or a pharmaceutical composition of the invention as an angiotensin II receptor antagonist.
  • the invention further provides the use of a compound of formula I or a pharmaceutical composition according to the invention for the prevention and/or treatment of hypertension, chronic heart failure, diabetic nephropathy.
  • the applicant also studied the salt formation reaction of the compound of formula II with other basic metal reagents, including sodium, magnesium, calcium salts, etc., and selected a variety of different organic and inorganic alkali metal reagents. The reaction was carried out, but the stability of the obtained salt was not good, and the obtained product was not high in purity and could not be used as a medicine.
  • the compound of the present invention has a more potent and longer-lasting effect of lowering blood pressure and lowering heart rate than the compound of formula II;
  • the compound of the present invention has better solubility and higher bioavailability than the compound of formula II;
  • the compound of the present invention enters the human body to release valproxazine or NO while releasing azilsartan, thereby effectively synergistically acting with azilsartan;
  • the compound of the invention has high safety and has an ideal protective effect on heart and kidney function of patients.
  • C 1 -C 8 should be understood to describe 1, 2, 3, 4, 5, 6, 7, and 8 carbon atoms.
  • C 2 -C 8 should be understood to mean 2, 3, 4, 5, 6, 7, and 8 carbon atoms.
  • aryl as used herein means an aromatic ring structure composed of 6 to 20 carbon atoms.
  • an aromatic ring structure containing 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 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.
  • heteroaryl also referred to as “aromatic heterocycle” refers to having at least one ring heteroatom (eg 1, 2, 3, 4 or 5 heteroatoms selected from O, S or N) Heteroaromatic heterocyclic ring.
  • Heteroaryl groups include monocyclic 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.
  • a heteroaryl group contains 3 to 14, 4 to 14, 5 to 7, or 5 to 6 ring-forming atoms.
  • a heteroaryl has 1 to 4, 1 to 3 or 1 to 2 heteroatoms.
  • a heteroaryl has 1 heteroatom.
  • Example 2 is an X-ray powder diffraction pattern of QR01019K in Example 1.
  • QR01019 (1.0g) was dissolved in dichloromethane (5ml), stirred at room temperature to form a solution, potassium phthalimide (0.27g) was added to the solution, the reaction was kept for 4h, cooled to -50 ° C, filtered The solvent was spin-dried to obtain an amorphous QR01019K.
  • the compound QR01019 (1.0 g) was dissolved in refluxing ethanol (15 ml) to form a solution, the solution was cooled to 50 ° C, and potassium 2-ethylhexanoate (0.30 g) in ethanol (1 ml) was slowly added dropwise to the solution. The solution was slowly cooled to 0 ° C, and the mixture was further stirred for 5 hours, filtered, and dried under reduced pressure at 60 ° C. The obtained solid was an amorphous QR01019K.
  • QR01019 (1.0 g) was dissolved in dichloromethane (20 ml) under reflux to form a solution. The solution was cooled to room temperature. Potassium acetate (0.16 g) was added to the solution, the reaction was incubated for 2 h, filtered, and the solvent was evaporated to dryness. Amorphous QR01019K.
  • QR01019 (1.0g) was dissolved in 1,4-dioxane (30ml), heated to 50 ° C to form a solution, potassium phthalimide (0.27g) was added to the solution, and the reaction was kept for 30 minutes. It was cooled to -50 ° C, filtered, and the solvent was evaporated to dryness to give an amorphous solid.
  • the compound QR01019 (1.0 g) was dissolved in refluxing acetone (20 ml) to form a solution, the solution was cooled to 40 ° C, and potassium 2-ethylhexanoate (0.30 g) in acetone (1 ml) was slowly added dropwise to the solution. The solution was slowly cooled to 0 ° C, and the mixture was further stirred for 5 hours, filtered, and dried under reduced pressure at 60 ° C. The obtained solid was an amorphous QR01019K.
  • QR01019 (1.0g) was dissolved in dichloromethane (5ml), stirred at room temperature to form a solution, potassium maleimide (0.20g) was added to the solution, the reaction was kept for 4h, cooled to -50 ° C, filtered, solvent spinning The dried solid was an amorphous QR01019K.
  • QR01019 (1.0g) was dissolved in N,N-dimethylformamide (5ml), stirred at room temperature to form a solution, potassium nitrate (0.15g) was added to the solution, the temperature was raised to 30 ° C, the reaction was kept for 4 h, and cooled to room temperature. After filtration, 100 ml of n-hexane was added to the filtrate, and the resulting solid was an amorphous QR01019K.
  • QR01019 (1.0g) was dissolved in dimethyl sulfoxide (5ml), stirred at room temperature to form a solution, potassium thiocyanate (0.14g) was added to the solution, the temperature was raised to 40 ° C, the reaction was kept for 4 h, cooled to room temperature, and filtered. 100 ml of methyl tert-butyl ether was added to the filtrate, and the resulting solid was an amorphous QR01019K.
  • QR01019 (1.0g) was dissolved in tetrahydrofuran (5ml), stirred at room temperature to form a solution, dipotassium hydrogen phosphate (0.20g) was added to the solution, the reaction was incubated for 4h, cooled to -50 ° C, filtered, and the solvent was evaporated to dryness. Amorphous QR01019K.
  • QR01019 (1.0g) was dissolved in 1,4-dioxane (5ml), heated to 50 ° C to stir to form a solution, potassium dihydrogen phosphate (0.20g) was added to the solution, the reaction was kept for 4 hours, and cooled to room temperature. Filtration, solvent-dried solid obtained as amorphous QR01019K.
  • QR01019 (0.5g) was dissolved in toluene (2.5ml), heated to 80 ° C to form a solution, cooled to room temperature, 60% sodium hydride (0.029g) was added to the solution, the reaction was stirred for 4h, and n-hexane was added to the reaction solution. (25 ml), the solid was precipitated, filtered, and the obtained solid was obtained as a sodium salt of QR01019.
  • the control group was given 0.5% sodium carboxymethylcellulose (hereinafter referred to as CMC-Na); the OR01019 group and the QR01019K group were dissolved in 0.5% CMC-Na, and the doses were all administered at an effective dose of 1 mg/kg of azilsartan.
  • the drug 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, and the time was measured three times. take the average. The results are shown in Tables 1 and 2 below.
  • the QR01019K group has a more potent and long-lasting heart rate reduction effect than QR01019.
  • SD rats purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • 12 rats SPF grade, weighing 180-220 g, half male and half female. They were randomly divided into 2 groups, 6 in each group, and 3 in each group.
  • QR010109 and QR01019K were dissolved in 0.5% CMC-Na, and the drug concentration (in terms of azisartan) was 0.1 mg/mL.
  • the drug was administered by intragastric administration. 10 ml/kg, administered at a dose of 1.0 mg/kg (based on azisartan).
  • the index of investigation is the total impurity content.
  • the samples are sampled at different time points. Each batch is sampled and tested three times. The average value is taken. The sampling time is 0, 15, and 30 days.
  • the compound prepared in Example 11 cannot be improved due to the purity. To the standard of medicine.
  • the test results are shown in Table 4 below.
  • Dissolving medium QR01019/based on azisartan QR01019K/based on azisartan pH 1.0 (hydrochloric acid solution) 2.01 18.70 pH 4.5 (acetate buffer) 0.06 2.30 pH 6.8 (phosphate buffer) 1.60 25.90 pH 7.8 (phosphate buffer) 13.60 400.50 Pure water 0.74 542.00

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Abstract

其制备方法、组合物以及其在制备血管紧张素II受体拮抗剂中的应用，或者在制备用于预防和/或治疗高血压、慢性心衰、糖尿病肾病的药物中的应用。所述化合物进入人体内后在释放出阿齐沙坦的同时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，具有更强效和更长效的降血压功效和更明显且持久的降心率作用，且安全性高，对患者心肾功能有较理想的保护作用。

Description

化合物及其制备方法、组合物和应用 技术领域
本发明涉及药物化学领域，具体涉及一种苯并咪唑衍生物的钾盐及其制备方法、组合物和应用。
背景技术
高血压(Hypertension)是最常见的心血管疾病，也是导致充血性心力衰竭、脑卒中、冠心病、肾功能衰竭、主动脉瘤的发病率和病死率升高的主要危险因素。抗高血压药物在高血压的治疗与防治中起着关键作用。随着对高血压发病机制认识的不断深入，许多具有较佳疗效的抗高血压药物，比如利尿剂、β-受体阻滞剂、钙通道拮抗剂、血管紧张素转化酶抑制剂(ACEI，普利类)、血管紧张素II AT1受体拮抗剂(ABR，沙坦类)，不断被发现并成功应用于临床。经过多年的临床实践，确证AT1受体拮抗剂沙坦类药物由于其降血压平稳、疗效佳、作用时间长、患者耐受性好，尤其在预防卒中、延缓糖尿病和非糖尿病肾病的肾功能不全、改善左心室肥厚、对靶器官的保护作用等方面具有较多优势，且不影响缓激肽降解和前列腺素合成，从而不引起干咳和血管神经性水肿，现已成为全球抗高血压药物市场的主流品种。但是沙坦类抗高血压药物的降血压有效率仅约为50-60％，且具有一定程度的不良反应。因此，开发降压效果更强、不良反应更少，并对靶器官有较佳保护作用的小剂量长效降压药已成为一个热门的研究方向。
公开号为CN103709154A的中国专利申请首次公开了结构如下式II所示的化合物：
Figure PCTCN2017085012-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。
发明内容
本发明的目的在于提供具有更强效和更长效降压效果的抗高血压药物，该药物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。
根据本发明的一个方面，本发明提供一种如式I所示的化合物：
Figure PCTCN2017085012-appb-000002
其中，R代表
Figure PCTCN2017085012-appb-000003
Figure PCTCN2017085012-appb-000004
a＝0、1、2、3、4、5或6；
所述R1代表C2-C8烷基、C2-C8烯烃基、C2-C8炔烃基、
Figure PCTCN2017085012-appb-000005
(CH2)nO(CH2)m、
Figure PCTCN2017085012-appb-000006
苯基、取代苯基、杂芳基或取代杂芳基，其中的
Figure PCTCN2017085012-appb-000007
中的b、c＝0、1、2、3、4、5或6，其中的(CH2)nO(CH2)m中的n、m＝1、2、3、4、5或6；
所述R2代表氢、卤素、三氟甲基、C1-C8烷氧基、C1-C8烷基、硝基、磺酰胺基、氨基或腈基；
所述R3代表C1-C8烷基、C1-C8烷氧基、C2-C8烯烃氧基、C2-C8炔烃氧基、(C1-C6)O(C1-C6)、
Figure PCTCN2017085012-appb-000008
芳基、取代芳基、杂芳基或取代杂芳基，其中的
Figure PCTCN2017085012-appb-000009
中的b、 c＝0、1、2、3、4、5或6；
所述R4代表芳基、取代芳基、芳基磺酰基、杂芳基、取代杂芳基、腈基、三氟甲基、C1-C8烷氧基、C1-C8硝酸酯或者C1-C8烷基；
所述R5代表苯基、取代苯基、杂芳基、取代杂芳基、腈基、三氟甲基、C1-C8烷氧基、C1-C8硝酸酯、C1-C8烷基、C1-C8烯烃基、C1-C8炔烃基、
Figure PCTCN2017085012-appb-000010
Figure PCTCN2017085012-appb-000011
或(CH2)nO(CH2)m，其中R3、R4、a、m、n如上所定义；
所述R6和R7代表氢、C1-C8烷氧基或C1-C8烷基；
所述R8和R9代表氢、C1-C8烷氧基、C1-C8硝酸酯或C1-C8烷基；
所述的取代芳基是指一个或多个选自羟基、C1-C6烷基、C1-C6烷氧基、卤素、硝基、氨基、腈基、三氟甲基、-CH＝CHCO2R11取代的芳基，各取代基可相同或不同，其中的R11代表氢或C1-C6烷基；
所述的取代杂芳基为任选被一个或多个C1-C6烷基、C1-C6烷氧基、卤素取代，各取代基可相同或不同。
在优选的实施方案中，本发明的化合物具有如下式所示结构：
Figure PCTCN2017085012-appb-000013
根据本发明的另一个方面，本发明还提供了式I化合物的制备方法，包括如下步骤：将如式II所示的化合物与钾盐试剂接触反应。其中，式II所示的化合物可以通过本领域已知的方法，例如CN103709154A中公开的方法制备得到，在此将CN103709154A全文引入。
Figure PCTCN2017085012-appb-000014
其中，R的定义同上。以QR01019K为例，其制备方法包括将QR01019与钾盐试剂接触反应的步骤。其中，OR01019的结构如下式所示：
Figure PCTCN2017085012-appb-000015
在本发明中，优选地，将如式II所示的化合物与钾盐试剂在溶剂中接触反应。
本领域技术人员可以理解，各种溶剂均可用于本发明中。
优选地，溶剂选自极性溶剂、非极性溶剂中的一种或多种的混合物，或者溶剂选自水、醚类溶剂、酮类溶剂、醇类溶剂、酯类溶剂、芳烃类溶剂、烷烃类溶剂、腈类溶剂中的一种或多种的混合物。更优选，溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、甲基四氢呋喃、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、甲基叔丁基醚、丙酮、丁甲乙酮、4-甲基-2-戊酮、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸正丁酯、乙酸异丁酯、乙酸仲丁酯、乙酸叔丁酯、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、硝基乙烷、N,N-二甲基甲酰胺、二甲亚砜、乙腈、丙二腈、苯、甲苯、二甲苯、正己烷、环己烷、戊烷、正庚烷中的一种或多种的混合物。
本领域技术人员可以理解，式II化合物无需完全溶解在溶剂中，甚至是在不使用溶剂的情况下，其与钾盐试剂接触后反应仍然可以发生，因此可以不使用或者使用任意量的溶剂。在优选的实施方案中，每克式II化合物所用溶剂的量至少为约0.1ml，进一步优选约2-300ml，更优选约5-100ml，最优选约10-50ml。
在本发明中，钾盐试剂选自有机酸钾盐、无机酸钾盐中的一种或多种的混合物。优选，有机酸钾盐选自邻苯二甲酸氢钾，乙酸钾，甲酸钾，磷酸二叔丁酯钾，甘草酸二钾、2-乙基己酸钾、乙基黄原酸钾、山梨酸钾、邻苯二甲酰亚胺钾、马来酰亚胺钾、草酸钾、烯酸钾、 柠檬酸钾、苹果酸钾、葡萄酸钾、乳酸钾、酒石酸钾、水杨酸钾、富马酸钾、硬脂酸钾、月桂酸钾中的一种或多种的混合物；无机酸钾盐选自硝酸钾，硫酸钾，亚硫酸钾，溴酸钾，碳酸氢钾，硫氰酸钾，磷酸氢二钾，磷酸二氢钾，邻苯二甲酸氢钾中的一种或多种的混合物。烯酸钾选自C3以上的烯烃酸钾，优选C3-C26的烯烃酸钾，例如丙烯酸钾、丁烯酸钾、十八碳烯酸钾等等。
本领域技术人员可以理解，钾盐试剂无需事先溶解，当然也可以事先溶解在上述溶剂中。另外，有些钾盐试剂因不稳定或者比较危险而被保存在溶剂中，此时可以直接使用这些被保存在溶剂中的钾盐试剂。在优选的实施方案中，式II化合物和钾盐试剂中K的摩尔比为约1:0.3-3，更优选约1:0.9-2，最优选约1:0.95-1.5。
在优选的实施方案中，先将式II化合物置于溶剂中，然后再加入钾盐试剂。优选，在将式II化合物置于溶剂中后，温度可处于在室温至所述溶剂的回流温度之间；进一步优选，在加入钾盐试剂后，温度可处于在0℃至所述溶剂的回流温度之间，更优选温度在室温至所述溶剂的回流温度之间。术语“室温”指约18℃至约30℃，优选约20℃至约24℃，更优选约22℃。
本领域技术人员可以理解，在本发明中，因产物在不同溶剂中的溶解度不同，以及反应后反应体系的温度不同，产物可能会溶解在溶液中，也可能会从溶液中直接析出。
在优选的实施方案中，对于产物从溶液中直接析出的情况，在反应后，过滤，干燥得到式I化合物。优选，在过滤前冷却，冷却温度为约-50℃至约30℃，更优选约-10℃至约10℃，最优选约0℃至约5℃。
在优选的实施方案中，对于产物溶解在溶液中的情况，在反应后，过滤去除杂质，去除溶液中的溶剂得到式I化合物或者在溶液中加入反溶剂，过滤，干燥得到式I化合物。去除溶剂的方式例如旋干等。优选，在过滤前冷却，冷却温度为约-50℃至约30℃，优选约-10℃至约10℃，最优选约0℃至约5℃。优选，反溶剂选自化合物在其中溶解性比所选溶剂差的试剂，例如甲基四氢呋喃、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、甲基叔丁基醚、异丙醚、乙醚、二氯甲烷，1,2-二氯乙烷、氯仿、四氯化碳、硝基乙烷、正己烷、环己烷、戊烷、正庚烷、苯、甲苯、二甲苯中的一种或多种的混合物。
根据本发明的另一个方面，本发明还提供了一种药物组合物，含有治疗有效量的式I所示化合物，还可根据需要含有药学上可接受的载体。本发明的药物组合物可以制成用于口服的散剂、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、 糖浆剂等等；适于吸入使用的粉末或液体气雾剂；适于局部使用的霜剂、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、栓剂等等。药学上可接受的载体包括但不限于赋形剂、润滑剂、粘合剂、崩解剂、水溶性聚合物、无机盐、溶剂、溶解助剂、悬浮剂、等渗剂、缓冲液、防腐剂、抗氧剂、着色剂、甜味剂、酸味剂、起泡剂和调味剂等等。
本发明的药物组合物中还可以进一步含有其他活性成分，例如其他用于预防和/或治疗高血压的活性成分，如钙离子拮抗剂(二氢吡啶类、芳烷基胺类、苯硫氮革类和三苯哌嗪类)。
本领域技术人员根据常规方法能够确定药物组合物中式I化合物以及各种药学上可接受的载体和/或其他活性成分的合适的量。术语“有效量”或者“治疗有效量”是指足以实现预期应用(包括但不限于如下定义的疾病治疗)的本发明所述化合物的量。治疗有效量可以因以下因素而改变：预期应用(体外或者体内)，或者所治疗的受试者和疾病病症如受试者的重量和年龄、疾病病症的严重性和给药方式等，其可以由本领域普通技术人员容易地确定。具体剂量将取决于以下因素而改变：所选择的特定化合物、所依据的给药方案、是否与其它化合物联合给药、给药的时间安排、所给药的组织和所承载的物理递送系统。
根据本发明的另一个方面，本发明提供了本发明所述式I化合物或本发明所述药物组合物在制备血管紧张素II受体拮抗剂中的用途，或者在制备用于预防和/或治疗高血压、慢性心衰、糖尿病肾病的药物中的用途。
根据本发明的另一个方面，本发明还提供所述式I化合物或本发明所述药物组合物作为血管紧张素II受体拮抗剂的用途。
根据本发明的另一个方面，本发明还提供所述式I化合物或本发明所述药物组合物用于预防和/或治疗高血压、慢性心衰、糖尿病肾病的用途。
本申请人还对式II化合物与其他碱性金属试剂成盐反应进行了研究，包括钠、镁、钙盐等均进行了试验，分别选择了多种不同的有机和无机的碱金属试剂与之进行反应，但是所得到的盐稳定性均不佳，所得产品纯度均不高，无法成药。
本发明的有益效果包括但不限于：
1、本发明的化合物与式II化合物相比，具有更强效和更长效的降血压和降心率效果；
2、本发明的化合物与式II化合物相比，溶解性能更好，生物利用度更高；
3、本发明的化合物进入人体在释放出阿齐沙坦的同时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；
4、本发明的化合物安全性高，对患者心肾功能具有较理想的保护作用。
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、列表中记载的定义、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或应被理解为“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，C1-C8应当理解为记载了1、2、3、4、5、6、7和8个碳原子数。C2-C8应当理解为记载了2、3、4、5、6、7和8个碳原子数。
本发明使用的术语“芳基”指由6至20个碳原子构成的芳族环结构。例如：包含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。
本发明使用的“杂芳基”，又称为“芳杂环”，是指具有至少一个环杂原子(例如1、2、3、4或5个选自O、S或N的杂原子)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、5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。
附图说明
图1是实施例1中QR01019K的H-NMR图谱；
图2是实施例1中QR01019K的X射线粉末衍射图谱。
具体实施方式
下面将结合示例性的具体实施例，对本发明化合物钾盐及其制备方法和应用进行详细的说明。本领域技术人员可以借鉴本文内容，适当对工艺参数或条件进行替换或改动。应当理解，所有类似的替换和改动都应被涵盖在本申请的保护范围内。本发明的产品和方法已经通过较佳实施例进行了描述，本领域技术人员在不背离本发明内容、精神和范围的情况下，可以对本文所述的产品和/或方法进行改动或适当变更与组合，从而实现和应用本发明的技术方案。
实施例1：
将QR01019(1.0g)溶于的二氯甲烷(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无定型的QR01019K。
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)。
H-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：
将化合物QR01019(1.0g)溶于回流的乙醇(15ml)中，形成溶液，将溶液冷却至50℃，往溶液中慢慢滴加2-乙基己酸钾(0.30g)的乙醇(1ml)溶液，慢慢降温至0℃，继续保温搅拌5h，过滤，60℃减压烘干，所得固体为无定型的QR01019K。
MS/HRMS m/z：717[M+H]+；677[M-K]-。
实施例3：
将QR01019(1.0g)溶于回流的二氯甲烷(20ml)中，形成溶液，将溶液冷却至室温，往溶液中加入乙酸钾(0.16g)，保温反应2h，过滤，溶剂旋干所得固体为无定型的QR01019K。
MS/HRMS m/z：717[M+H]+；677[M-K]-。
实施例4：
将QR01019(1.0g)溶于的1,4-二氧六环(30ml)中，加热至50℃形成溶液，往溶液中加入邻苯二甲酰亚胺钾(0.27g)，保温反应30min，冷却至-50℃，过滤，溶剂旋干所得固体为无定型的QR01019K。
MS/HRMS m/z：717[M+H]+；677[M-K]-。
实施例5：
将化合物QR01019(1.0g)溶于回流的丙酮(20ml)中，形成溶液，将溶液冷却至40℃，往溶液中慢慢滴加2-乙基己酸钾(0.30g)的丙酮(1ml)溶液，慢慢降温至0℃，继续保温搅拌5h，过滤，60℃减压烘干，所得固体为无定型的QR01019K。
MS/HRMS m/z：717[M+H]+；677[M-K]-。
实施例6：
将QR01019(1.0g)溶于二氯甲烷(5ml)中，室温搅拌形成溶液，往溶液中加入马来酰亚胺钾(0.20g)，保温反应4h，冷却至-50℃，过滤，溶剂旋干所得固体为无定型的QR01019K。
MS/HRMS m/z：717[M+H]+；677[M-K]-。
实施例7：
将QR01019(1.0g)溶于N,N-二甲基甲酰胺(5ml)中，室温搅拌形成溶液，往溶液中加入硝酸钾(0.15g)，升温至30℃，保温反应4h，冷却至室温，过滤，滤液中加入100ml正己烷，过滤，所得固体为无定型的QR01019K。
MS/HRMS m/z：717[M+H]+；677[M-K]-。
实施例8：
将QR01019(1.0g)溶于二甲亚砜(5ml)中，室温搅拌形成溶液，往溶液中加入硫氰酸钾(0.14g)，升温至40℃，保温反应4h，冷却至室温，过滤，滤液中加入100ml甲基叔丁基醚，过滤，所得固体为无定型的QR01019K。
MS/HRMS m/z：717[M+H]+；677[M-K]-。
实施例9：
将QR01019(1.0g)溶于四氢呋喃(5ml)中，室温搅拌形成溶液，往溶液中加入磷酸氢二钾(0.20g)，保温反应4h，冷却至-50℃，过滤，溶剂旋干所得固体为无定型的QR01019K。
MS/HRMS m/z：717[M+H]+；677[M-K]-。
实施例10：
将QR01019(1.0g)溶于1,4-二氧六环(5ml)中，加热至50℃搅拌形成溶液，往溶液中加入磷酸二氢钾(0.20g)，保温反应4h，冷却至室温，过滤，溶剂旋干所得固体为无定型的QR01019K。
MS/HRMS m/z：717[M+H]+；677[M-K]-。
实施例11：QR01019钠盐的制备
将QR01019(0.5g)溶于甲苯(2.5ml)中，加热至80℃形成溶液，冷却至室温，往溶液中加入60％氢化钠(0.029g)，搅拌反应4h，往反应液中加入正己烷(25ml)，析出固体，过滤，烘干所得固体为QR01019钠盐。
MS：701[M+H]+；677[M-Na]-。
1H-NMR(400MHz,DMSO-d6)δ：1.40(d，3H)，1.41(t，3H)，2.35(s，3H)，2.39(s，3H)，2.40(s，3H)，4.61(q，2H)，5.27(q，2H)，5.49(q，2H)，6.80(q，1H)，6.83(d，2H)，7.15(m，4H)，7.32(td，2H)，7.43(m，2H)，7.72(dd，1H)。
实施例12：QR01019K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(下称CMC-Na)；OR01019组和QR01019K组采用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.QR01019、QR01019K口服给药前、后各时间点收缩压变化(平均值(mmHg)±标准误差)
Figure PCTCN2017085012-appb-000016
*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，QR01019K组具有比QR01019更强效和长效的降压效果。
表2.QR01019、QR01019K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 PCTCN2017085012-appb-000017
*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，QR01019K组具有比QR01019更强效和长效的降心率效果。
还按照上述相同方法测试了如下化合物(钾盐)的药效试验，发现这些化合物与QR01019K类似，均具有比其相应的未成盐化合物更强效和更长效的降血压和降心律效果。
Figure PCTCN2017085012-appb-000018
Figure PCTCN2017085012-appb-000019
Figure PCTCN2017085012-appb-000020
Figure PCTCN2017085012-appb-000021
实施例13：药代动力学研究
取SD大鼠(购自北京维通利华实验动物技术有限公司)12只，SPF级，体重为180-220g，雌雄各半。随机分成2组，每组6只，雌雄各三只。以0.5％的CMC-Na溶解QR010109和QR01019K，药物浓度(以阿齐沙坦计)为0.1mg/mL，灌胃给药，给药体积为 10ml/kg，给药剂量为1.0mg/kg(以阿齐沙坦计)。于给药后不同时间点(分别为给药前以及给药后0.25、0.5、1、2、3、4、6、8、10和24h)颈静脉采血，收集血样，检测血浆阿齐沙坦的浓度，各项药代动力学参数见下表3。
表3.各化合物大鼠单次静脉给药主要药代动力学参数
Figure PCTCN2017085012-appb-000022
Cmax：血药达峰浓度，Tmax:血压达峰时间，AUClast：时间曲线下面积，T1/2:半衰期从表3结果可以看出，QR01019的生物利用度约为QR01019K的1/3。
实施例14：化合物的稳定性试验
申请人对化合物稳定性进行了考察，取QR01019K和QR01019钠盐化合物各200mg，采用如下方式进行考察：内层PVC材质自封袋抽真空,中层铝箔抽真空,外层铝箔干燥剂抽真空充氮气；考察条件：25℃，60％湿度。考察指标为总杂质含量，于不同时间点取样检测，每批次取样检测三次，取平均值，取样时间为：0、15、30天，实施例11制备得到的化合物由于纯度无法提高，达不到入药标准。试验结果见下表4。
表4.稳定性试验(总杂质含量％)
Figure PCTCN2017085012-appb-000023
实施例15：QR01019钾盐的平衡溶解度测定
分别称取QR01019和QR01019K各20mg，投入10mL溶解介质中，在37±2℃，250r/min的速度下震荡24h，测定平衡溶解度，结果见下表5。
表5.24h平衡溶解度(μg/ml)
溶解介质 QR01019/以阿齐沙坦计 QR01019K/以阿齐沙坦计
pH 1.0(盐酸溶液) 2.01 18.70
pH 4.5(醋酸盐缓冲液) 0.06 2.30
pH 6.8(磷酸盐缓冲液) 1.60 25.90
pH 7.8(磷酸盐缓冲液) 13.60 400.50
纯水 0.74 542.00
从表5结果可以看出，QR01019K在酸性和中性介质中的加和浓度都远高于QR01019。

Claims (10)

  1. 一种式I所示的化合物：
    Figure PCTCN2017085012-appb-100001
    其特征在于，式I中R代表
    Figure PCTCN2017085012-appb-100002
    Figure PCTCN2017085012-appb-100003
    Figure PCTCN2017085012-appb-100004
    a＝0、1、2、3、4、5或6；
    所述R1代表C2-C8烷基、C2-C8烯烃基、C2-C8炔烃基、
    Figure PCTCN2017085012-appb-100005
    (CH2)nO(CH2)m、
    Figure PCTCN2017085012-appb-100006
    芳基、取代芳基、杂芳基或取代杂芳基，其中的
    Figure PCTCN2017085012-appb-100007
    中的b、c＝0、1、2、3、4、5或6，其中的(CH2)nO(CH2)m中的n、m＝1、2、3、4、5或6；
    所述R2代表氢、卤素、三氟甲基、C1-C8烷氧基、C1-C8烷基、硝基、磺酰胺基、氨基或腈基；
    所述R3代表C1-C8烷基、C1-C8烷氧基、C2-C8烯烃氧基、C2-C8炔烃氧基、(C1-C6)O(C1-C6)、
    Figure PCTCN2017085012-appb-100008
    苯基、取代苯基、杂芳基或取代杂芳基，其中的
    Figure PCTCN2017085012-appb-100009
    中的b、c＝0、1、2、3、4、5或6；
    所述R4代表芳基、取代芳基、苯磺酰基、杂芳基、取代杂芳基、腈基、三氟甲基、C1-C8烷氧基、C1-C8硝酸酯或者C1-C8烷基；
    所述R5代表芳基、取代芳基、杂芳基、取代杂芳基、腈基、三氟甲基、C1-C8烷氧基、 C1-C8硝酸酯、C1-C8烷基、C1-C8烯烃基、C1-C8炔烃基、
    Figure PCTCN2017085012-appb-100010
    Figure PCTCN2017085012-appb-100011
    或(CH2)nO(CH2)m，其中R3、R4、a、m、n如上所定义；
    所述R6和R7代表氢、C1-C8烷氧基或C1-C8烷基；
    所述R8和R9代表氢、C1-C8烷氧基、C1-C8硝酸酯或C1-C8烷基；
    所述的取代芳基是指一个或多个选自羟基、C1-C6烷基、C1-C6烷氧基、卤素、硝基、氨基、腈基、三氟甲基、-CH＝CHCO2R11取代的芳基，各取代基可相同或不同，其中的R11代表氢或C1-C6烷基；
    所述的取代杂芳基为任选被一个或多个C1-C6烷基、C1-C6烷氧基、卤素取代的杂芳基，各取代基可相同或不同。
  2. 如权利要求1所述的化合物，其特征在于，具有如下式所示结构：
    Figure PCTCN2017085012-appb-100012
    Figure PCTCN2017085012-appb-100013
  3. 如权利要求1或2所述的化合物的制备方法，其特征在于，包括如下步骤：
    将如式II所示的化合物与钾盐试剂接触反应；优选，将如式II所示的化合物与钾盐试剂在溶剂中接触反应
    Figure PCTCN2017085012-appb-100014
  4. 如权利要求3所述的制备方法，其特征在于，所述溶剂选自极性溶剂、非极性溶剂中的一种或多种的混合物，或者所述溶剂选自水、醚类溶剂、酮类溶剂、醇类溶剂、酯类溶剂、芳烃类溶剂、烷烃类溶剂、腈类溶剂中的一种或多种的混合物；
    优选地，所述溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、甲基四氢呋喃、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、甲基叔丁基醚、丙酮、丁甲乙酮、4-甲基-2-戊酮、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸正丁酯、乙酸异丁酯、乙酸仲丁酯、乙酸叔丁酯、二氯甲烷、1,2-二氯乙烷、氯仿、四氯化碳、硝基乙烷、N,N-二甲基甲酰胺、二甲亚砜、乙腈、丙二腈、苯、甲苯、二甲苯、正己烷、环己烷、戊烷、正庚烷中的一种或多种的混合物；
    优选地，每克式II化合物所用溶剂的量至少为约0.1ml，进一步优选约2-300ml，更优选约5-100ml，最优选约10-50ml。
  5. 如权利要求3或4所述的制备方法，其特征在于：所述钾盐试剂选自有机酸钾盐、无机酸钾盐中的一种或多种的混合物；
    优选地，所述有机酸钾盐选自邻苯二甲酸氢钾，乙酸钾，甲酸钾，磷酸二叔丁酯钾，甘草酸二钾、2-乙基己酸钾、乙基黄原酸钾、山梨酸钾、邻苯二甲酰亚胺钾、马来酰亚胺钾、草酸钾、烯酸钾、柠檬酸钾、苹果酸钾、葡萄酸钾、乳酸钾、酒石酸钾、水杨酸钾、富马酸钾、硬脂酸钾、月桂酸钾中的一种或多种的混合物；所述无机酸钾盐选自硝酸钾，硫酸钾，亚硫酸钾，溴酸钾，碳酸氢钾，硫氰酸钾，磷酸氢二钾，磷酸二氢钾，邻苯二甲酸氢钾中的一种或多种的混合物；
    优选地，式II化合物和钾盐试剂中K的摩尔比为约1:0.3-3，更优选约1:0.9-2，最优选约1:0.95-1.5。
  6. 如权利要求3-5中任一项所述的制备方法，其特征在于，先将式II化合物置于溶剂中，然后再加入钾盐试剂；
    优选地，在将式II化合物置于溶剂中后，温度在室温至所述溶剂的回流温度之间；
    优选地，在加入钾盐试剂后，温度在0℃至所述溶剂的回流温度之间，更优选温度在室 温至所述溶剂的回流温度之间。
  7. 如权利要求3-6中任一项所述的制备方法，其特征在于，在反应后，过滤，干燥得到式I化合物；优选地，在过滤前冷却，冷却温度为约-50℃至约30℃，优选约-10℃至约10℃，最优选约0℃至约5℃。
  8. 如权利要求3-6中任一项所述的制备方法，其特征在于，在反应后，过滤去除杂质，去除溶液中的溶剂得到式I化合物或者在溶液中加入反溶剂，过滤，干燥得到式I化合物；
    优选地，在过滤前冷却，冷却温度为约-50℃至约30℃，优选约-10℃至约10℃，最优选约0℃至约5℃；
    优选地，反溶剂选自甲基四氢呋喃、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、甲基叔丁基醚、异丙醚、乙醚、二氯甲烷，1,2-二氯乙烷、氯仿、四氯化碳、硝基乙烷、正己烷、环己烷、戊烷、正庚烷、苯、甲苯、二甲苯中的一种或多种的混合物。
  9. 一种药物组合物，含有治疗有效量的如权利要求1或2所述的化合物以及药学上可接受的载体。
  10. 如权利要求1或2所述的化合物或如权利要求9所述的药物组合物在制备血管紧张素II受体拮抗剂中的应用，或者在制备用于预防和/或治疗高血压、慢性心衰、糖尿病肾病的药物中的应用。
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