WO2011063764A1 - 阿齐沙坦有机胺盐及其制备方法和用途 - Google Patents

阿齐沙坦有机胺盐及其制备方法和用途 Download PDF

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WO2011063764A1
WO2011063764A1 PCT/CN2010/079222 CN2010079222W WO2011063764A1 WO 2011063764 A1 WO2011063764 A1 WO 2011063764A1 CN 2010079222 W CN2010079222 W CN 2010079222W WO 2011063764 A1 WO2011063764 A1 WO 2011063764A1
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Prior art keywords
organic amine
azilsartan
preparation
amine salt
salt according
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PCT/CN2010/079222
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English (en)
French (fr)
Inventor
吕爱锋
杨宝海
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江苏豪森医药集团有限公司
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Priority to CN2010800449716A priority Critical patent/CN102548988B/zh
Priority to BR112012012484A priority patent/BR112012012484A2/pt
Priority to US13/512,652 priority patent/US20120238606A1/en
Priority to MX2012005776A priority patent/MX2012005776A/es
Priority to JP2012540278A priority patent/JP2013512199A/ja
Priority to EP10832671.1A priority patent/EP2508522A4/en
Application filed by 江苏豪森医药集团有限公司 filed Critical 江苏豪森医药集团有限公司
Priority to CA2782224A priority patent/CA2782224A1/en
Priority to AU2010324249A priority patent/AU2010324249B2/en
Priority to RU2012124332/04A priority patent/RU2554947C2/ru
Publication of WO2011063764A1 publication Critical patent/WO2011063764A1/zh
Priority to ZA2012/02683A priority patent/ZA201202683B/en
Priority to HK12104992.6A priority patent/HK1164310A1/xx

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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
    • C07D413/02—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton

Definitions

  • the present invention relates to azilsartan organic amine salt and a process for the preparation thereof, and to a pharmaceutical composition comprising a therapeutically effective amount of the compound, and its use for the preparation of an antihypertensive drug. Background technique
  • Azilsartan is a selective angiotensin II type 1 receptor (ATI) antagonist that blocks the contractile vasoconstriction of angiotensin- ⁇ by selectively blocking the binding of angiotensin II to vascular smooth muscle ATI receptors. Thereby lowering blood pressure.
  • ATI angiotensin II type 1 receptor
  • Azilsartan has a carboxyl group in its molecular structure, which is poorly absorbed in the body and is not suitable for preparation into a pharmaceutical dosage form. In order to improve its bioavailability, it can be made into an active ester by chemical modification, ie, azisartan, but its bioavailability is not ideal. In addition, the modification makes the molecular structure of the drug complicated and increases the difficulty of synthesis. . Summary of the invention
  • the present invention has found that the salt formation of azilsartan and organic amine can improve its pharmacokinetic characteristics, improve its bioavailability, and is more suitable for conventional preparation processes.
  • B is an organic amine selected from the group consisting of methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethanolamine, piperazine, dibenzylethylenediamine, meglumine, amino Butanetriol, tetramethyl Quaternary ammonium or choline; preferably ethanolamine
  • Another object of the present invention is to provide a process for the preparation of the above compound which comprises separately adding azilsartan acid and an organic amine B to an alcoholic organic solvent, and forming a salt at room temperature or under heating.
  • the alcohol solvent described therein is selected from the group consisting of methanol, ethanol, propanol or isopropanol.
  • Another object of the present invention is to provide a pharmaceutical composition for treating hypertension comprising a therapeutically effective amount of azilsartan organic amine salt as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention provides the use of azilsartan organic amine salt and a pharmaceutical composition containing the same for the preparation of an antihypertensive drug.
  • the drug substance is in a form that is convenient to handle and handle. This is important not only from the viewpoint of obtaining a commercially viable preparation method, but also from the viewpoint of subsequently preparing a pharmaceutical preparation containing the active compound.
  • the chemical stability, solid state stability and "shelf life" of the active ingredients are also very important factors.
  • the drug substance and the composition comprising the same should preferably be capable of being effectively stored for a considerable period of time, while the physicochemical properties of the active ingredient (e.g., its chemical composition, density, hygroscopicity, and solubility) do not exhibit significant changes.
  • the effective amount of the active ingredient means an effective non-toxic dose, preferably in the range of 0.001 to 100 mg/kg of total body weight, more preferably 0.001 to 50 mg/kg.
  • oral or parenteral administration is preferred, including topical, rectal, transdermal, injection or continuous infusion.
  • the human oral administration dose preferably comprises from 0.05 to 3500 mg of the active ingredient, most preferably from 0.5 to 1000 mg of the active ingredient. It is preferred to use a lower dose oral administration form. Of course, high dose parenteral administration can also be administered when it is safe and convenient for the patient.
  • the above dosages relate to the preferred amount of active ingredient expressed as the free acid.
  • the optimal dose and interval of the individual dose of the active ingredient depends on the nature and extent of the treatment of the disease, the dosage form, the route and the site, the specific patient to be treated, and the best solution can be commonly used. Technical determination. It will also be apparent to those skilled in the art that the optimal course of treatment, i.e., the number of doses of the active ingredient administered per day for a given period of time, can be determined by those skilled in the art using commonly used procedures for determining the course of treatment.
  • the compounds of the present invention can be administered orally or parenterally, and can be formulated into tablets, pills, powders, and granules for various routes of administration.
  • the active ingredient is mixed with at least one inert diluent.
  • Oral formulations may also include, in addition to inert diluents, such as lubricants, glidants, and antioxidants, as is conventional practice. If capsules, tablets, and pills are prepared, a buffer is included in the formulation. Tablets and pills can also be formulated as sustained release formulations.
  • the parenteral administration preparation of the present invention includes a sterile aqueous solution, although a nonaqueous solution of the emulsion can also be used.
  • These dosage forms may also include adjuvants such as preservatives, wetting agents, penetrants, buffers, emulsifiers and dispersing agents.
  • the sterilization may be carried out by filtration using a bacteria retaining filter, adding a sterilizing agent to the composition, and sterilizing by irradiating the composition or heating the composition.
  • the salt of the present invention has a markedly increased solubility in a conventional solvent such as water, methanol and 0.1% hydrochloric acid, and is suitable for use in a conventional preparation.
  • the salt of the present invention has an improved stability property.
  • the salt of the present invention has a better bioavailability.
  • the salt of the present invention is prepared in high yield, high purity, fast, convenient and low cost, wherein the ethanolamine salt and the choline salt are advantageous in the process route.
  • Test Example 1 Inhibition of angiotensin II-induced pressor response by a compound of the present invention in rats
  • test compound After establishing an angiotensin II (All, 100 ng/kg, i.v.) induced pressor response, equimolar doses of test compound were administered. After 24 hours, sputum was administered, and the increase in blood pressure was measured based on the calculation of the inhibition rate with respect to the blood pressure value before administration. All compounds were suspended in 0.5% methylcellulose and orally administered in a volume of 2 mL/kg. The test results are expressed as mean SEM (Table 1).
  • Test Example 2 Inhibition of angiotensin II-induced pressor response by a compound of the present invention in dogs
  • male beagle dogs (weight 12.0-14.7 kg, KITAYAMA LABES, CO., LTD.) were used. They were anesthetized with sodium pentobarbital (50 mg/kg, i.p.) and inserted into the tracheal tube to control the airway. Shave the femoral region and the posterior neck and sterilize (polypyrrolidone iodine solution, MEIJI SEIKA KAISHA, LTD to fix the dog in the dorsal position, cut the right femoral region. Insert the catheter (5F, MILLER INDUSTRIES) and place Place the polyurethane tube in the femoral artery and in the femoral vein.
  • Penicillin G potassium (MEIJI SEIKA KAISHA, LTD., 40000 units) was administered once a day for 3 days from the next day. After 3 days of recovery, the dog was used for the test.
  • the dog was placed in a small metabolic cage.
  • the catheter tube inserted into the femoral artery was connected to a conduction unit (MILLER INDUSTRIES), passed through a DC amplifier (N4777, NEC San-ei Instruments) and a blood pressure monitoring amplifier (N4441, NEC San-ei Instruments) in the recorder (RECTI-HORIZ) Systemic blood pressure (mean blood pressure:) was recorded on 8K, NEC San-ei Instruments.
  • the polyurethane tube inserted into the femoral vein was fixed outside the cage and used to give All (PEPTIDE INSTITUTE, INC.).
  • test results are expressed as mean SEM (Table 2).
  • the compounds of the invention have significant long-lasting and potent pharmacological effects.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

本发明涉及阿齐沙坦有机胺盐及其制备方法和用途。具体而言，本发明涉及式（I）所示的阿齐沙坦有机胺盐、其制备方法，以及含有治疗有效量的该化合物的药物组合物，及其在制备抗高血压药物中的用途。

Description

阿齐沙坦有机胺盐及其制备方法和用途 技术领域
本发明涉及阿齐沙坦有机胺盐及其制备方法， 以及含有治疗有效 量的该化合物的药物组合物， 及其用于制备抗高血压药物中的用途。 背景技术
阿齐沙坦为选择性血管紧张素 II 1型受体 (ATI)拮抗剂， 通过选择 性阻断血管紧张素 II与血管平滑肌 ATI受体的结合而阻断血管紧张素 Π的收缩血管作用， 从而降低血压。
阿齐沙坦分子结构中具有羧基， 其体内吸收较差， 不利于被制备 成药用剂型。 为了提高其生物利用度， 可以通过化学修饰的方法将其 制成活性酯， 即阿齐沙坦酯， 但其生物利用度亦不理想， 另外修饰使 得该药物分子结构复杂化， 增加了合成难度。 发明内容
本发明通过研究发现， 将阿齐沙坦与有机胺成盐能够很好地改善 其药物动力学特征， 提高其生物利用度， 更适合于常规制剂工艺。
本发明的目的在于提供式 （I) 所示的阿齐沙坦有机胺盐， 具有下 列结构：
Figure imgf000002_0001
(I) 其中， B 为有机胺， 选自甲胺、 二甲胺、 三甲胺、 乙胺、 二乙胺、 三 乙胺、 乙醇胺、 哌嗪、 二苄基乙二胺、 葡甲胺、 氨基丁三醇、 四甲基 基季铵或胆碱； 优选为乙醇胺
Figure imgf000003_0001
本发明的另一目的在于提供制备上述化合物的方法， 该方法包括 在醇类有机溶剂中分别加入阿齐沙坦酸和有机胺 B, 室温或者加热下 使之成盐。 其中所述的醇类溶剂选自甲醇、 乙醇、 丙醇或异丙醇。
本发明的另一目的在于提供一种用于治疗高血压的药物组合物， 其中含有作为有效成分的治疗有效量的阿齐沙坦有机胺盐和药学上可 接受的载体。
进一步， 本发明提供阿齐沙坦有机胺盐以及含有它们的药物组合 物在制备抗高血压药物中的用途。
在药物组合物的配制过程中， 重要的是药物物质是一种可方便操 作和处理的形式。 不仅从获得商业上可行的制备方法的角度来说， 而 且从随后制备含该活性化合物的药物制剂的角度来说， 这都是很重要 的。
此外， 在制备药物组合物的过程中， 重要的是患者给药后， 提供 一种可靠的、 可再现的和恒定的药物血桨浓度曲线。
活性成分的化学稳定性、 固态稳定性和 "储存寿命"同样是非常重 要的因素。 该药物物质以及包含它的组合物应该优选能够有效地储存 相当一段时间，而活性成分的物理化学特性 (例如它的化学组成、密度、 吸湿性和溶解度)没有表现出显著的变化。
此外， 提供尽可能化学纯形式的药物同样是非常重要的。
本领域熟练技术人员可以理解， 典型地， 如果一种药物可以很容 易地以稳定形式获得， 那么可以提供如下优点： 易于处理、 易于制备 合适的药物制剂以及具有可靠的溶解特征。
活性成分有效量是指有效无毒剂量， 优选 0.001〜100 mg/kg总体 重的范围， 更优选 0.001〜50 mg/kg。 当治疗需要阿齐沙坦有机胺盐治 疗的患者时， 优选口服或非肠胃给药包括局部、 直肠、 经皮、 注射或 持续输液。人类口服给药剂量优选包括 0.05〜3500 mg活性成分，最优 选 0.5〜1000 mg活性成分。 使用较低剂量的口服给药形式为优选。 然 而， 在对患者安全方便时， 也可以施用高剂量非肠胃给药。 上述剂量 涉及优选的以游离酸表示的活性成分的量。
本领域技术人员应当肯定， 活性成分个体剂量的最佳给药数量及 间隔视治疗疾病的性质及程度， 给药剂型、 途径及部位， 治疗的具体 患者而定， 并且该最佳方案可通过常用技术确定。 本领域技术人员也 应当明白， 最佳疗程， 即既定时间内每天给予活性成分的剂量次数可 经本领域技术人员使用常用的确定疗程的试验确定。
本发明的化合物可口服或非肠胃给药， 可制成包括片剂、 丸剂、 粉剂及颗粒剂用于各种给药途径。 在这些固体制剂中， 活性成分至少 与一种惰性稀释剂相混合。 按照常规操作， 口服制剂也可包括除惰性 稀释剂以外的其他物质， 如润滑剂、 助流剂及抗氧化剂。 若制成胶囊、 片剂及丸剂， 制剂中包括缓冲剂。 片剂及丸剂还可制成持续释放剂型。
尽管也可采用乳剂的非水溶液， 本发明的非肠胃给药制剂包括无 菌水溶液。 这些剂型也可包括佐剂， 如防腐剂、 润湿剂、 渗透剂、 缓 冲剂、 乳化剂及分散剂。 其灭菌可采用细菌截留滤器 (bacteria retaining filter)过滤， 向组合物中加入灭菌剂， 照射组合物或加热组合物的方法 灭菌。
本发明的盐与阿齐沙坦及其酯相比， 主要优点如下：
(1) 本发明的盐在常规的溶剂， 如水中、 甲醇和 0.1%盐酸中的溶 解度明显增加， 适用于常规制剂。
(2) 本发明的盐具有改善的稳定性的特性。
(3) 本发明的盐具有更好的生物利用度。
(4) 本发明的盐以高收率、高纯度、快速、方便和低成本进行制备， 其中乙醇胺盐、 胆碱盐在工艺路线中有优势。 具体实施方式 实施例一
阿齐沙坦乙醇胺盐的制备
将阿齐沙坦酸（1.37 g)加入到甲醇（30 ml) 中， 室温下加入乙醇 胺 （0.183 g)， 升温至回流， 滤去不溶物， 滤液减压浓缩去溶剂， 剩余 物加丙酮 （20 ml) 搅拌 2h， 过滤， 烘干， 得白色固体 1.45克。
1H (DMSO-d6+D20) δ: 1.35 (t, 3H, CH3)， 2.83 (t, 2H, CH2)， 3.55 (t, 2H, CH2)， 4.52 (q, 2H, CH2)， 5.65 (s, 2H, CH2)， 7·03〜7·51 (m, 11H)。 实施例二
阿齐沙坦胆碱盐的制备
阿齐沙坦 ( 1.37g) 和 46%胆碱水溶液 (0.79g) 于乙醇 (20ml) 中 回流 2h， 室温搅一天， 减压蒸干， 加乙酸乙酯 （20ml)， 搅 2h， 过滤 得白色固体。
1H NMR(DMSO-d6+D20) δ: 1.35 (t, 3H, CH3)， 3.83 (t, 2H, CH2),
3.55 (t, 2H, CH2), 3.06 (s, 9H), 4.52 (q, 2H, CH2)， 5.65 (s, 2H, CH2)， 7.05—7.50 (m, 11H)。 试验例一 在大鼠体内本发明化合物对于血管紧张素 II诱发的增压应 答的抑制作用
用戊巴比妥 (50 mg/kg, i.p.)麻醉雄性 Sprague-Dawley大鼠 (9-11周 龄， CLEA Japan, Inc.),分离股动脉和静脉并用填充了含肝素的盐水 (200 U/mL)的聚乙烯管插管。 该导管经皮下插入后颈并固定。 恢复期后， 使 用该大鼠进行试验。 动脉导管与偶联了血压检测放大器的压力传感器 (2238, NEC San-eilnstruments)相连， 压力被记录于记录仪 (RECTI-HORIZ 8K, NEC San-eilnstruments)上。建立血管紧张素 II (All, 100 ng/kg, i.v.)诱发的增压应答后， 给予等摩尔剂量的测试化合物。 24 小时后给予 ΑΠ,测量血压的增加， 基于其计算相对于给药前血压值的 抑制率。 所有化合物均悬浮于 0.5%甲基纤维素中并以 2 mL/kg的体积 口服给药。 试验结果以均值士 SEM表示 (表 1)。
表 1
Figure imgf000005_0001
试验结论： 本发明化合物具有显著长效且强效的药理学作用。 试验例二 在狗体内本发明化合物对于血管紧张素 II诱发的增压应答 的抑制作用
对于本试验， 使用雄性比格犬 (；体重 12.0-14.7 kg, KITAYAMA LABES,CO.， LTD.)。 它们经戊巴比妥钠 (50 mg/kg, i.p.)麻醉， 插入气管 导管以控制气道。 剃光股区和后颈， 并进行消毒 (聚烯吡酮碘溶液， MEIJI SEIKA KAISHA, LTD 以背卧位固定狗， 切开右侧股区。 插 入镜导管 (5F, MILLER INDUSTRIES)且置于股动脉中并在股静脉中放 置聚氨酯管。 导管和管从皮下经过， 并固定在背部。 接着缝合切开的 区域并肌内注射青霉素 G钾 (MEIJI SEIKA KAISHA, LTD., 40000单位） 以预防感染。 从第二天开始， 每天给予青霉素 G钾 (40000单位:)一次， 持续 3天。 恢复 3天后， 使用狗进行试验。
在试验过程中， 将狗置于小代谢笼内。 为了测量， 插入股动脉的 镜导管与传导单元 (MILLER INDUSTRIES)相连， 通过 DC 放大器 (N4777, NEC San-ei Instruments)和血压监测放大器 (N4441, NEC San-ei Instruments)在记录仪 (RECTI-HORIZ 8K, NEC San-ei Instruments)上记 录全身血压 (平均血压:)。插入股静脉内的聚氨酯管固定于笼外并用于给 予 All (PEPTIDE INSTITUTE, INC.)。 该试验在禁食下进行， 在给予测 试化合物之前给予 3或 4次 ΑΠ (100 ng/kg, i.v.)以确定血管加压药应答 稳定。相应于等摩尔量化合物 A的测试化合物悬浮于 0.5%甲基纤维素 中并口服给予 2 mL/kg。 给药后， 在各测量时间点给予 ΑΠ并测量血压 的增加， 基于其计算相对于给药前血压值的抑制率。 试验结果以均值 士 SEM表示 (表 2)。
表 2
Figure imgf000006_0001
试验结论： 本发明化合物具有显著长效且强效的药理学作用。

Claims

Figure imgf000007_0001
2、 根据权利要求 1所述的阿齐沙坦有机胺盐， 其中 B选自甲胺、 二甲胺、 三甲胺、 乙胺、 二乙胺、 三乙胺、 乙醇胺、 哌嗪、 二苄基乙 二胺、 葡甲胺、 氨基丁三醇、 四甲基季铵、 四乙基季铵或胆碱。
3、 根据权利要求 1所述的阿齐沙坦有机胺盐， 其中 B为式 （Π) 的乙醇胺。
OH
(II)
4、 根据权利要求 1所述的阿齐沙坦有机胺盐， 其中 B为式 （III)
Figure imgf000007_0002
(III)
5、 一种制备如权利要求 1-4任一项所述的阿齐沙坦有机胺盐的方 法， 该方法包括在醇类有机溶剂中分别加入阿齐沙坦酸和有机胺 B, 室温或者加热下使之成盐。
6、 根据权利要求 5所述的方法， 其中所述的醇类有机溶剂选自甲 醇、 乙醇、 丙醇或异丙醇。
7、 一种用于治疗高血压的药物组合物， 该药物组合物含有作为有 效成分的治疗有效量的如权利要求 1-4 任一项所述的阿齐沙坦有机胺 盐和药学上可接受的载体。
8、 如权利要求 1-4任一项所述的阿齐沙坦有机胺盐， 或如权利要 所述的药物组合物在制备抗高血压药物中的应用。
PCT/CN2010/079222 2009-11-30 2010-11-29 阿齐沙坦有机胺盐及其制备方法和用途 WO2011063764A1 (zh)

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CN105503848A (zh) * 2014-10-13 2016-04-20 江苏豪森药业集团有限公司 阿齐沙坦有机胺盐复合物及其制备方法和用途
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KR102220011B1 (ko) * 2020-05-15 2021-02-25 대봉엘에스 주식회사 친환경 용매를 이용한 아질사탄의 제조방법 및 이에 관한 핵심 중간체 화합물

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WO2016058563A1 (en) 2014-10-15 2016-04-21 Zentiva, K.S. A process for preparing highly pure azilsartan

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