WO2019144484A1 - 一种斯诺普利单水合物晶型及其制备方法 - Google Patents

一种斯诺普利单水合物晶型及其制备方法 Download PDF

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WO2019144484A1
WO2019144484A1 PCT/CN2018/079619 CN2018079619W WO2019144484A1 WO 2019144484 A1 WO2019144484 A1 WO 2019144484A1 CN 2018079619 W CN2018079619 W CN 2018079619W WO 2019144484 A1 WO2019144484 A1 WO 2019144484A1
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sinopril
monohydrate
weight
monohydrate crystal
crystal according
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French (fr)
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贾力
周雨杨
陈帆
李飞杨
林敏�
李书慧
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福州大学
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Priority to US16/761,284 priority Critical patent/US20210188773A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the invention belongs to the field of medicine, relates to a novel sinopril monohydrate and a preparation method thereof; a pharmaceutical composition containing the new crystalline form of sinopril, and a sinopril monohydrate and the same
  • a pharmaceutical composition containing the new crystalline form of sinopril, and a sinopril monohydrate and the same
  • the use of the composition for the preparation of a medicament for treating pulmonary hypertension, hypertension, and congestive heart failure.
  • Captopril also known as Capoten (Cap) is the first orally effective angiotensin-converting enzyme inhibitor (ACEI) (Jia Li. Angiotensin-converting enzyme inhibitor Advances in Research. Advances in Physiological Sciences, 1985, 16:229-234).
  • ACEI angiotensin-converting enzyme inhibitor
  • Ondetti et al completed the chemical synthesis and preliminary pharmacological experiments of Cap.
  • ACEI has been widely used in the treatment of hypertension and heart failure in countries around the world. Since the 1990s, as Cap's patent has expired, China began to imitate the drug to meet the needs of 1-2.7 billion hypertensive patients, and China immediately became the world's largest Cap producer.
  • ACEI dimercapto conjugate
  • Cap-Cap dimercapto conjugate
  • CapNO is a novel mechanism targeting sGC (soluble guanylate cyclase).
  • the main pharmacological effects include: 1. The effect of captopril on the core of ACEI: continuous expansion of blood vessels, reducing pulmonary hypertension; 2. The role of NO: direct resistance to the formed vasoconstrictor; selective reduction of pulmonary vascular resistance, pulmonary artery pressure And mild relaxation of airway smooth muscle to reduce airway resistance, increase pulmonary circulation blood flow, improve lung ventilation / blood flow ratio; inhibit platelet aggregation; mildly inhibit gastrointestinal smooth muscle; expand in vitro and in vivo animal blood vessels, for each Hypertension models are effective; increasing tumor blood flow and oxygen consumption to enhance tumor radiotherapy; reducing intraocular pressure and increasing ocular fluid outflow are beneficial to the treatment of glaucoma.
  • Cap-NO compared to Cap are: 1) it can slightly inhibit gastrointestinal secretion and movement. Therefore, Cap-NO is suitable for patients with hypertension and gastric ulcer. Because most hypertensive patients take sympathetic inhibitors, symptoms of parasympathetic relative advantages, such as increased gastrointestinal secretion, ulcer disease, etc., Cap-NO can avoid and overcome this side effect. 2) Relaxing the airway smooth muscle, this effect has the therapeutic characteristics that Cap does not have in the treatment of occlusive emphysema and chronic heart failure caused by pulmonary blood stasis, that is, reducing respiratory resistance, increasing pulmonary circulation blood flow, and improving lung Ventilation / blood flow ratio. On the other hand, the user can avoid Cap's dry cough and wheezing.
  • Cap-NO Prevention of atherosclerosis. Cap itself does not see any effect of preventing atherosclerosis, but Cap-NO has this effect. 4) Lower blood cholesterol. 5) Unlike Cap, Cap-NO is a drug that is effective both in oral and injectable. 6) Our recent results indicate that Cap-NO can significantly inhibit the adhesion of tumor cells to vascular endothelial cells, suggesting that Cap-NO may have a role in preventing tumor metastasis.
  • Cap-NO nitrosyl hydrazide group
  • -SNO is a unique group in which the S-N single bond has the properties of a partial double bond and also has the property of ion pair.
  • the ion pair property is dominant, such as high temperature, metal ion, alkaline condition or strong acidity, the S—N single bond tends to break, and the compound accelerates decomposition.
  • the sinopril Only when the -SNO is in a specific chemical environment can the sinopril be stabilized and its decomposition slowed down. Therefore, it is particularly necessary to prepare a sinopril in a solid state, particularly a stable crystalline state.
  • the present invention differs from the prior art in that the present invention further optimizes the reaction conditions by 1) reducing the nucleophilic attack of the proton (H + ) on the S atom in the reaction environment, avoiding the hydrolysis of the S—N single bond; 2) adding a water molecule that further stabilizes the S—N single bond by hydrogen bonding and dipole-dipole interaction; 3) adding EDTA-2Na ⁇ 2H 2 O to the reaction system to complex a very small amount of Cu in the reaction solution Metal ions such as 2+ , Cu + , Fe 2+ , Fe 3+ prevent them from catalyzing the hydrolysis of S—N single bonds.
  • this patent obtains a new crystalline form of sinopril monohydrate at a higher pH.
  • the above conditions change so that sinopril can be stored in a more stable form for a long time at a higher temperature.
  • the sinopril monohydrate loses the stabilizing effect of the crystallization water, and can gradually decompose and release NO, and exerts the drug effect.
  • the present inventors unexpectedly discovered a new crystalline form of sinopril monohydrate which can be stably stored in a 4 ° C environment for 12 months.
  • Another object of the present invention is to provide a method for preparing a crystal of sinopril monohydrate which is simple in operation, reproducible, and easy to scale up.
  • Another object of the present invention is to provide a pharmaceutical composition for treating pulmonary hypertension, hypertension, and congestive heart failure.
  • a further object of the present invention is to provide the use of the above-described snoopy monohydrate crystals and compositions for the preparation of a medicament for the treatment of pulmonary hypertension, hypertension, and congestive heart failure.
  • the preparation method is specifically:
  • step b Add 60 to 90 parts by weight of hydrochloric acid to the solution obtained in step a, adjust the pH to 4.0;
  • step c Draw the red mixture obtained in step b, and dry to obtain a crystal of sinopril monohydrate.
  • the reaction described in the step a is carried out at 10 ° C or lower.
  • step a The EDTA-2Na ⁇ 2H 2 O described in step a should be added before the reaction.
  • the reaction solvent described in the step a is 15 ⁇ 5 wt% of saline solution.
  • the concentration of hydrochloric acid described in step b is from 12% by weight to 24% by weight, preferably from 18% by weight to 24% by weight.
  • the pH of the solution described in step b should be adjusted to 4.0 after adding hydrochloric acid.
  • step c The drying method described in step c, the temperature is below 40 °C.
  • the purpose of adding EDTA-2Na ⁇ 2H 2 O is to complex the metal ions such as Cu 2+ , Cu + , Fe 2+ and Fe 3+ present in the reaction system to prevent these metal ions from catalyzing S- N single bond hydrolysis.
  • the rotation speed should not be lower than 600 rpm, otherwise it is easy to agglomerate when it is precipitated.
  • the pharmaceutical composition for treating pulmonary hypertension, hypertension, and congestive heart failure of the present invention comprises a therapeutically effective amount of the above-mentioned sinopril monohydrate crystal as an active ingredient, and one or more pharmaceutically acceptable substances Carrier.
  • the snoopril monohydrate crystals and compositions of the present invention can be used in the manufacture of a medicament for the treatment of pulmonary hypertension, hypertension, and congestive heart failure.
  • the pharmaceutically acceptable carrier described above refers to a conventional pharmaceutical carrier in the pharmaceutical field, for example, a diluent, an excipient such as water, starch, pregelatinized starch, sucrose, etc.; a binder such as a cellulose derivative, lactose, gelatin , polyvinylpyrrolidone, etc.; wetting agent such as glycerin; disintegrating agents such as agar, calcium carbonate, sodium hydrogencarbonate, etc.; absorption enhancers such as quaternary ammonium salts; surfactants such as cetyl alcohol, etc.; adsorption carriers such as kaolin Etc.; lubricants such as talc, magnesium stearate, polyethylene glycol, and the like; in addition, other excipients such as flavoring agents and the like may be added to the composition.
  • a diluent an excipient such as water, starch, pregelatinized starch, sucrose, etc.
  • a binder such as
  • the snoopril monohydrate crystals of the present invention can be administered to a patient in need of such treatment by oral, nasal inhalation, rectal or parenteral administration in the form of a composition.
  • a composition When used orally, it can be prepared into conventional solid preparations such as tablets, coated tablets, powders, granules, capsules, etc.; for rectal or parenteral administration, it can be used as a suppository or ointment.
  • Agents, suspending agents, and the like are tablets, coated tablets, granules, capsules and the like, and more preferred forms are coated tablets and capsules.
  • compositions of the present invention can be prepared according to conventional methods of manufacture in the pharmaceutical arts.
  • the active ingredient is mixed with one or more carriers which are then prepared in the preparations which are required.
  • the pharmaceutical composition of the present invention preferably contains an active ingredient in a mass ratio of 0.1% to 50%, and most preferably contains an active ingredient in a mass ratio of 0.5% to 30%.
  • the sinopril monohydrate crystal of the invention is the most stable form of sinopril currently available, can be stored at a relatively high temperature for a long time, and the stable solid form of sinopril is very good in medicine. It is conveniently prepared into various administration forms.
  • the preparation method of the snoopy monohydrate crystal is simple in operation, good in reproducibility, and easy to be industrially scaled up.
  • the crystal was characterized by TG-DSC synchronous thermal analysis, PXRD, UV-vis, FTIR, Raman, etc., which proved that the crystal was first discovered.
  • the sinopril monohydrate crystal was used to treat hypertensive rats and pulmonary hypertension rats, which proved to have good curative effect.
  • Example 1 is a powder X-ray diffraction (PXRD) pattern of the spinopril monohydrate crystal of Example 1;
  • Example 2 is a thermogravimetric-differential scanning calorimetry (TG-DSC) synchronous thermal analysis diagram of the spinopril monohydrate crystal of Example 1.
  • TG-DSC thermogravimetric-differential scanning calorimetry
  • FTIR Fourier transform infrared spectroscopy
  • UV-vis ultraviolet-visible
  • Figure 6 is a graph showing the stability of the spinopril monohydrate crystal of Example 1;
  • Figure 7 is a photomicrograph of the spinopril monohydrate crystal of Example 1.
  • captopril and 3.5 g of sodium nitrite were dissolved in 35 mL of 15 wt% saline which had been cooled to 0 ° C, and 20 mg of EDTA-2Na ⁇ 2H 2 O was added, and the mixture was stirred at 700 rpm for 1 h in an ice bath, then 24 wt% was added dropwise.
  • the hydrochloric acid was adjusted to pH 4.0 to precipitate a large amount of red sinopril monohydrate crystals, suction filtered, air-dried at room temperature (25 ° C), or lyophilized for 8 hours, and stored in a refrigerator at 4 ° C or -20 ° C.
  • Example 1 The powder X-ray diffraction (PXRD) pattern of sinopril monohydrate crystal is shown in Figure 1.
  • the PXRD characteristics are as follows:
  • the temperature was raised from 25 ° C to 150 ° C, the heating rate was 2.0 K / min, and the N 2 atmosphere was obtained.
  • the results are shown in FIG. 2 .
  • the DSC has an endothermic peak when the temperature reaches 41.9 °C.
  • the crystal of sinopril monohydrate begins to lose crystal water rapidly, and the rate of weight loss accelerates.
  • the weight loss of the crystal of sinopril monohydrate stops, and there is a small endothermic peak, which is Snowp.
  • the monohydrate crystal completely loses crystal water, undergoes a phase change, and changes from a solid phase to an oily state.
  • the measured weight loss value was 7.1%, the theoretical weight loss value was 6.8%, and the theoretical weight loss value was 11.4%, which was determined to be monohydrate.
  • UV-vis spectrophotometric test of the sample of snoopril monohydrate of Example 1 Preparation of a methanol solution of 2 mg/mL of sinopril monohydrate crystals, scanning at 800-200 nm, measured at There are absorption peaks at 333 nm and 551 nm, which are consistent with the UV absorption characteristics of sinopril. After amplification, the absorption peak at 551 nm can be seen, as shown in Fig. 5.
  • the spinopril monohydrate crystal of Example 1 was divided into two portions and placed in a Petri dish to form a thin layer of ⁇ 5 mm at 4 ° C ⁇ 2 ° C, relative humidity 60% ⁇ 10%, 25 ° C ⁇ 2 Placed at °C, relative humidity 60% ⁇ 10% for 3 months (90 days).
  • the snoopril monohydrate crystal of Example 1 was observed under an optical microscope at a magnification of 10 ⁇ 10, and it was found to be a rhombohedral crystal, as shown in FIG.
  • the preparation method comprises the following steps: uniformly mixing the crystals of the sinopril monohydrate with each auxiliary material, sieving, and directly compressing the powder into 100 pieces, each piece weighing 200 mg, containing 54.5 mg of sinopril monohydrate crystal. .
  • the preparation method comprises the following steps: uniformly mixing the crystals of the sinopril monohydrate with each auxiliary material, sieving, and then charging the mixture into 100 gelatin capsules each weighing 200 mg, containing 50 mg of sinopril monohydrate crystals.
  • SHR spontaneous hypertension model
  • SS/Jr salt-sensitive hypertension model
  • SHR spontaneous hypertension model
  • SS/Jr salt-sensitive hypertension model
  • Rats in the 50 mg/kg dose group were given 5 mL of aqueous solution containing freshly prepared sinopril monohydrate (10 mg/mL) (SHR hypertensive rats) each morning, or with freshly prepared sinopril monohydrate. 0.9% NaCl solution (SS/Jr hypertensive rats).
  • Rats in the 500 mg/kg dose group were administered orally. Rats were administered continuously for 3 months. Check your weight once a week.
  • Pulmonary hypertension (PAH) rats with successful intraperitoneal injection of monocrotaline were divided into 4 groups: saline control group, 50 mg/kg captopril group, 10 mg/kg sinopril group, 50 mg/ The knopril group, 7 rats in each group, was intragastrically administered daily, and 5 groups of healthy rats (9 rats) were routinely bred for 30 days. RESULTS: None of the rats in the healthy group died. The number of PAH rats in the saline control group was reduced from 9 to 1, 50 mg/kg captopril group and 10 mg/kg sinopril group PAH rats. Only 3 were reduced, and the number of PAH rats in the 50 mg/kg sinopril group was reduced from 7 to 5.
  • the average volume of pleural effusion in the 50 mg/kg captopril group was 3.3 mL, and the average volume of pleural effusion in the 10 mg/kg sinopril group and 50 mg/kg sinopril group was observed. 1.2 mL and 0.5 mL, respectively; mean right ventricular mass index (RVMI), blank control group, 50 mg/kg captopril group, 10 mg/kg sinopril group, 50 mg/kg sinopril group were 71.3%, 53.8%, 59.2%, 37.8%.
  • RVMI right ventricular mass index
  • the above results indicate that sinopril monohydrate can significantly improve the survival rate of PAH rats, reduce pulmonary artery pressure (P ⁇ 0.05), reduce pleural effusion (P ⁇ 0.05), and reduce right heart burden (P ⁇ 0.05). Pulmonary hypertension rats have a significant therapeutic effect.

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Abstract

本发明首次报道了一种新型的斯诺普利单水合物晶型，其制备方法，以及这种晶型在制备用于治疗肺动脉高压、高血压、充血性心力衰竭的药物组合物中的应用。其制备方法包括：将卡托普利、亚硝酸钠和EDTA-2Na·2H 2O溶于15±5wt％的食盐水中反应后，调节溶液pH从而使斯诺普利单水合物晶体析出。斯诺普利单水合物晶体可以稳定保存于4℃环境中，达12个月之久。

Description

一种斯诺普利单水合物晶型及其制备方法 技术领域
本发明属于医药领域，涉及一种新型的斯诺普利单水合物及其制备方法；以该斯诺普利新晶型为活性成分的药物组合物，以及斯诺普利单水合物及其组合物在制备治疗肺动脉高压、高血压、充血性心力衰竭的药物中的应用。
背景技术
卡托普利，又名开博通(Capoten,Cap)，是第一个口服有效的血管紧张素转化酶抑制剂(angiotensin-converting enzyme inhibitor,ACEI)(贾力.血管紧张素转化酶抑制剂的研究进展.生理科学进展,1985,16:229-234)。1977年，Ondetti等人完成了Cap的化学合成和初步药理实验工作。随后二十年，ACEI在世界各国被广泛用于治疗高血压和心力衰竭。九十年代以来，由于Cap的专利已到期，我国开始大量仿制该药以满足1-2.7亿高血压患者的需要，中国随即一跃成为世界最大Cap生产国。然而新型ACEI，如Enalapril和Lisinopril等正在逐步取代Cap。因此，我们认为利用和改造现有的Cap生产工艺，生产出药效高、副作用少的Cap衍生新药，具有创新引领和拓展我国Cap生产的重大经济和科学意义。
ACEI，尤其是Cap，在美国等发达国家的使用为我们提供了大量宝贵的资料。口服Cap后，部分药物以原形经尿排泄，其余大部分主要代谢为二巯基共轭物(Cap-Cap)，其本身也有降压作用。现已知道急性肾衰是大量服用ACEI后常见的不良反应。约有1.2％的患者可出现蛋白尿，其中1/4的患者可能发展为肾病综合症。约有10％的患者在服用Cap的早期可出现味觉改变、药疹、药热、瘙痒和嗜酸细胞增多症。长期使用Cap后，5-20％的患者可出现干咳，有时伴有喘息。极少数患者出现骨髓抑制现象。这些不良反应在无还原性巯基的ACEI(如Enalapril,Lisinopril等)中很少发生。那么，是否可以替换掉Cap中的还原性巯基，将其改造成带有NO的新药，同时利用NO扩张肾动脉，舒张支气管等作用克服Cap的不良反应？
斯诺普利(巯亚硝基卡托普利，S-nitrosocaptopril，CapNO)正是在这种思路的引导下产生的，其最早文献报道和化合物专利出现在1988～1989年，它是以Cap为化学母核，将Cap的巯基(-SH)改造为亚硝酰巯基(-SNO)后形成的一种在 生物体内既可释放NO，又具有ACEI性质的双重功能化合物。根据RSNO类化合物的生化反应式，分解产物是RSSR(如Cap-Cap、Cap-SR)和NO，NO的氧化终产物是NO 2和NO 3。
CapNO是一种以sGC(soluble guanylate cyclase，可溶性鸟苷酸环化酶)为靶点的全新机制的药物。其主要药理作用包括：1.卡托普利母核的ACEI作用：持续扩张血管、降低肺动脉高压；2.NO的作用：直接对抗已生成的缩血管物质；选择性降低肺血管阻力、肺动脉压和轻度松驰呼吸道平滑肌从而降低呼吸道阻力、增加肺循环血流、改善肺的通气/血流比；抑制血小板的聚集；轻度抑制胃肠平滑肌；扩张离体和在体动物的血管，对各种高血压模型都有效；增加肿瘤的血流量与耗氧量从而增强肿瘤的放射治疗；降低眼内压和增加眼液流出而有利于青光眼的治疗。
与Cap相比，Cap-NO的主要优势在于：1)它可轻度抑制胃肠的分泌和运动。所以，Cap-NO适用于高血压兼胃溃疡患者。因为，多数高血压患者服用交感神经抑制剂后，常出现副交感神经相对优势的症状，如胃肠分泌增加，溃疡病加重等，Cap-NO可避免和克服这一副作用。2)松驰呼吸道平滑肌，这一作用在治疗堵塞性肺气肿，肺瘀血造成的慢性心功能不全时具有Cap本身所不具有的治疗特性，即降低呼吸道阻力，增加肺循环血流，改善肺的通气/血流比。另一方面，服用者可避免Cap的干咳和喘息现象。3)预防动脉粥样硬化。Cap本身并未见任何防止动脉粥样硬化的作用，但Cap-NO却有这种作用。4)降低血胆固醇。5)与Cap不同，Cap-NO是一种口服和注射都有效的药物。6)我们最近的研究结果表明，Cap-NO可显著抑制肿瘤细胞粘附于血管内皮细胞，提示Cap-NO可能具有预防肿瘤转移的作用。
而Cap-NO的最大的缺陷在于，其中的亚硝酰巯基(-SNO)很不稳定，其分解自由能仅为30kcal/mol左右，很容易发生均裂，释放出NO。这是Cap-NO发挥药效的必要步骤，同时也是其不稳定的原因——由此造成Cap-NO在体外极易分解，难以工业化生产。如不能解决这一技术瓶颈问题，即使Cap-NO的药效再优越，也很难上市。
我们从化学结构上对亚硝酰巯基进行了深入的研究，发现-SNO是一种独特的基团，其中的S—N单键具有部分双键的性质，同时也具有离子对的性质， 当离子对性质占优时，如高温、存在金属离子、碱性条件或强酸性条件下，S—N单键倾向于断裂，化合物加速分解。只有让-SNO处于特定的化学环境中，才能稳定斯诺普利，减慢其分解。因此，制备固体状态的斯诺普利显得尤为必要，特别是稳定的结晶状态。
在此之前，我们独家成功地合成了固态Cap-NO的结晶外，全球其它实验室均采用液体形式的Cap-NO进行研究，因为固态的Cap-NO很难得到。固态Cap-NO结晶的合成为Cap-NO的市场化、成药化打下了基础。此专利(斯诺普利结晶的制备和质量检测，专利号CN1072208)采用的技术方案是，让等摩尔量的Cap和NaNO 2在水溶液中完全反应后，调节反应混合物的pH≤2.5，充分搅拌下，斯诺普利以有机酸的形式结晶析出，然后抽滤、干燥。
本发明与现存技术的不同在于，本发明进一步优化了反应条件，通过1)降低反应环境中质子(H +)对S原子的亲核进攻，避免了S—N单键的水解；2)加入一个水分子，使其通过氢键和偶极-偶极作用，进一步稳定S—N单键；3)在反应体系中加入EDTA-2Na·2H 2O，以络合反应液中极微量的Cu 2+、Cu +、Fe 2+、Fe 3+等金属离子，防止它们催化S—N单键的水解。本专利通过优化以上反应条件，在更高的pH下得到了斯诺普利单水合物新晶型，上述条件的改变使斯诺普利可以以更稳定的形式长期保存于较高温度下。进入体内后，斯诺普利单水合物失去结晶水的稳定化作用，又可以逐渐分解释放出NO，发挥药效。
技术问题
针对斯诺普利的最大缺陷——稳定性差，本发明的目的在于提供一种稳定形式的斯诺普利。本发明人在研究中意外地发现了斯诺普利单水合物新晶型，可以稳定保存于4℃环境中，达12个月之久。
技术解决方案
斯诺普利单水合物(S-Nitrosocaptopril monohydrate)，化学名为1-((2S)-2-甲基-3-亚硝基巯基-1-氧代丙基)-L-脯氨酸单水合物，化学结构式如下所示：
Figure PCTCN2018079619-appb-000001
本发明的另一个目的在于提供一种制备斯诺普利单水合物晶体的方法，该方法操作简便，重现性好，易于放大生产。
本发明的另一个目的在于提供一种治疗肺动脉高压、高血压、充血性心力衰竭的药物组合物。
本发明进一步的目的在于提供上述斯诺普利单水合物晶体和组合物在制备治疗肺动脉高压、高血压、充血性心力衰竭的药物方面的用途。
本发明的目的是通过如下技术方案实现的：
将卡托普利、亚硝酸钠和EDTA-2Na·2H 2O溶于食盐水中反应后，调节溶液pH从而使斯诺普利单水合物晶体析出。
优选地，所述制备方法具体为：
a.将卡托普利200～300重量份、亚硝酸钠70～100重量份和EDTA-2Na·2H 2O0.4～1.5重量份溶于已冷却至0℃的食盐水700～1000重量份中，使溶液混合均匀后，反应15～120分钟；
b.向步骤a所得溶液中滴加60～90重量份盐酸，调节pH至4.0；
c.抽滤步骤b所得红色混合物，进行干燥，得到斯诺普利单水合物晶体。
步骤a所述的反应在10℃以下进行。
步骤a所述的EDTA-2Na·2H 2O应在反应前加入。
步骤a所述的反应溶剂为15±5wt％的食盐水。
步骤b所述的盐酸浓度为12wt％～24wt％，优选为18wt％～24wt％。
步骤b所述的溶液加盐酸后pH应调至4.0。
步骤c所述的干燥方法，温度在40℃以下。
上述制备过程中，为使卡托普利完全反应，亚硝酸钠稍过量是必要的。
上述制备过程中，加入EDTA-2Na·2H 2O的目的在于络合反应体系中存在的极微量Cu 2+、Cu +、Fe 2+、Fe 3+等金属离子，防止这些金属离子催化S—N单键水解。
上述制备过程中，用15±5wt％食盐水做溶剂，由于同离子效应，斯诺普利单水合物晶体得以在更高的pH条件下析出，可减少强酸性环境中质子(H +)对S原子的亲核进攻，进而使S—N单键水解。
上述制备过程中，转速不宜低于600rpm，否则析出时容易结块。
本发明的用于制备治疗肺动脉高压、高血压、充血性心力衰竭的药物组合物含有治疗有效量的上述斯诺普利单水合物晶体为活性成分，以及含有一种或多种药学上可接受的载体。
本发明斯诺普利单水合物晶体和组合物可以用于制备治疗肺动脉高压、高血压、充血性心力衰竭的药物。
上文所述药学上可接受的载体是指药学领域常规的药物载体，例如：稀释剂、赋形剂如水、淀粉、预胶化淀粉、蔗糖等；黏合剂如纤维素衍生物、乳糖、明胶、聚乙烯吡咯烷酮等；润湿剂如甘油等；崩解剂如琼脂、碳酸钙、碳酸氢钠等；吸收促进剂如季铵盐等；表面活性剂如十六烷醇等；吸附载体如高岭土等；润滑剂如滑石粉、硬脂酸镁、聚乙二醇等；另外还可以在组合物中加入其它辅料如矫味剂等。
本发明斯诺普利单水合物晶体可以组合物的形式通过口服、鼻吸入、直肠或肠外给药的方式施用于需要这种治疗的患者。用于口服时，可将其制成常规的固体制剂如片剂、包衣片剂、粉剂、颗粒剂、胶囊剂等；用于直肠或肠外给药时，可将其制成栓剂、软膏剂、悬浮剂等。优选的形式是片剂、包衣片剂、颗粒剂、胶囊剂等，更优选的形式是包衣片剂和胶囊剂。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如使活性成分与一种或多种载体混合，然后将其制备成所需剂型。
本发明的药物组合物优选含有质量比为0.1％～50％的活性成分，最优选含有质量比为0.5％～30％的活性成分。
有益效果
本发明斯诺普利单水合物晶体是目前能得到的最稳定的斯诺普利存在形式，可以长期保存于较高温度下，而且稳定的固体形式的斯诺普利成药性非常好，可以很方便地制备成各种给药形式。该斯诺普利单水合物晶体的制备方法操作简便，重现性好，易于工业放大生产。通过TG-DSC同步热分析、PXRD、UV-vis、FTIR、Raman等对该晶体进行表征，证明该晶体是首次发现。将该斯诺普利单水合物晶体用于治疗高血压大鼠及肺动脉高压大鼠，证明其具有良好的疗效。
附图说明
图1为实施例1斯诺普利单水合物晶体的粉末X射线衍射(PXRD)图；
图2为实施例1斯诺普利单水合物晶体的热重-差示扫描量热法(TG-DSC)同步热分析图；
图3为实施例1斯诺普利单水合物晶体的傅里叶变换红外光谱(FTIR)图；
图4为实施例1斯诺普利单水合物晶体的拉曼光谱(Raman)图；
图5为实施例1斯诺普利单水合物晶体的紫外-可见(UV-vis)光谱及局部放大图；
图6为实施例1斯诺普利单水合物晶体的稳定性实验图；
图7为实施例1斯诺普利单水合物晶体的显微照片。
本发明的最佳实施方式
下面结合实施例对本发明作进一步的阐述，以使本专业的技术人员更全面地理解本发明，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求书所限定的保护范围为准。
实施例1
将10g卡托普利和3.5g亚硝酸钠溶于35mL已冷却至0℃的15wt％食盐水中，并加入20mgEDTA-2Na·2H 2O，冰浴条件下转速700rpm搅拌1h，随即逐滴加入24wt％的盐酸调节pH至4.0，使红色斯诺普利单水合物晶体大量析出，抽滤，室温(25℃)下晾干，或冻干8h，保存于4℃或-20℃冰箱中。
本发明的实施方式
实施例2
将10g卡托普利和4.0g亚硝酸钠溶于40mL已冷却至0℃的15wt％食盐水中，冰浴条件下转速1000rpm搅拌15min，随即逐滴加入18wt％的盐酸调节pH至4.0，使红色斯诺普利单水合物晶体大量析出，抽滤，在不超过40℃的烘箱中干燥1～8h，或室温(25℃)下在真空干燥箱中干燥10min～2h，保存于4℃或-20℃冰箱中。
实施例3
实施例1斯诺普利单水合物晶体的粉末X射线衍射(PXRD)图谱如图1所示，PXRD特征如下表：
2θ 晶面间距D值 相对强度
9.529 9.2741 33.1
14.309 6.1846 49.2
16.133 5.4892 17.5
16.659 5.3173 93.2
17.499 5.0638 100
17.828 4.9712 66.6
18.603 4.7657 57.3
19.233 4.6111 80.5
19.955 4.4457 22.5
21.491 4.1313 47.4
22.936 3.8742 44.3
23.184 3.8334 30.2
24.998 3.5592 19.4
26.638 3.3437 67.1
26.915 3.3099 73.3
28.910 3.0858 38
33.099 2.7042 39
33.479 2.6744 17.6
33.703 2.6571 16.5
37.576 2.3916 29.7
实施例4
对实施例1斯诺普利单水合物晶体进行热重-差示扫描量热法(TG-DSC)同步热分析：
从25℃升温至150℃，升温速率2.0K/min，N 2气氛，结果如图2所示。温度达到41.9℃时DSC有一个吸热倒峰。此时斯诺普利单水合物晶体开始迅速失去结晶水，失重速率加快；至104.0℃时，斯诺普利单水合物晶体失重停止，有一个小的吸热倒峰，此时斯诺普利单水合物晶体完全失去结晶水，发生相变，从固相变为油状。测得失重值为7.1％，理论失重值为6.8％，理论上分解失重值为11.4％，确定为单水合物。
实施例5
对实施例1斯诺普利单水合物晶体进行傅里叶变换红外光谱(FTIR)及拉曼光谱(Raman)测试，分别如图3、图4所示，结果如下：
FTIR：1334cm -1、1507cm -1(N＝O)，1102cm -1(S—N)，2975cm -1(νO—H)，1625cm -1(δH 2O)；
Raman光谱中2988cm -1，2930cm -1，2882cm -1处的强峰也显示O—H的存在。
实施例6
对实施例1斯诺普利单水合物晶体进行紫外-可见(UV-vis)分光光度法测试： 配制2mg/mL斯诺普利单水合物结晶的甲醇溶液，800～200nm扫描，测得在333nm和551nm处有吸收峰，符合斯诺普利的紫外吸收特征，放大后可见551nm处吸收峰，如图5所示。
实施例7
斯诺普利单水合物晶体稳定性实验：
将实施例1斯诺普利单水合物晶体分为两份，置于培养皿中，摊成≤5mm的薄层，在4℃±2℃、相对湿度60％±10％，25℃±2℃、相对湿度60％±10％两种条件下放置3个月(90天)。试验期间，前60天，每隔5天；第60～90天，每隔10天分别取样一次，观察药物性状，然后配制成浓度约为2mg/mL的甲醇溶液，并以HPLC法测定含量，流动相为H 3PO 4水溶液(pH＝2.0)：甲醇＝50:50，流速1mL/min，检测波长215nm(卡托普利)、333nm(斯诺普利)，柱温40℃。
结果如图6所示，在4℃±2℃、相对湿度60％±10％条件下，90天后含量仅减少4.2％左右，在25℃±2℃、相对湿度60％±10％条件下，90天后含量减少22.4％左右。说明本发明斯诺普利单水合物晶体在4℃±2℃、相对湿度60％±10％条件下非常稳定。
实施例8
斯诺普利单水合物晶体显微照片：
将实施例1斯诺普利单水合物晶体置于放大倍数10×10的光学显微镜下观察，可见其为菱形片状晶体，如图7所示。
实施例9
20g片剂处方：
Figure PCTCN2018079619-appb-000002
制备方法：将斯诺普利单水合物晶体与各辅料混合均匀后，过筛，采用粉末直接压片的方法制成100片，每片重200mg，含斯诺普利单水合物晶体54.5mg。
实施例10
20g胶囊剂处方：
Figure PCTCN2018079619-appb-000003
制备方法：将斯诺普利单水合物晶体与各辅料混合均匀后，过筛，然后将混合物装入100个明胶胶囊，每个胶囊重200mg，含斯诺普利单水合物晶体50mg。
实施例11
实施例1斯诺普利单水合物晶体对高血压模型大鼠的作用：
高血压大鼠SHR(自发性高血压模型)和SS/Jr(盐敏感型高血压模型)被随机分成3个斯诺普利单水合物剂量组：0、50和500mg/kg，每组由10雌10雄两种性别的大鼠组成。50mg/kg剂量组的大鼠，每天早晨自己饮用5mL含新配制斯诺普利单水合物(10mg/mL)的水溶液(SHR高血压大鼠)、或含新配制斯诺普利单水合物的0.9％NaCl溶液(SS/Jr高血压大鼠)。500mg/kg剂量组的大鼠则施行灌胃给药。大鼠连续给药3个月。每周检查一次体重。SHR大鼠(n＝7)连续饮用50mg/kg的斯诺普利单水合物后8周，体重、心率和收缩/舒张压分别是355±6g、356±75次/min、126±10/111±23mmHg。同期对比，对照组(n＝7)的体重、心率和收缩/舒张压分别是350±4g、397±48次/min、172±8/165±3mmHg。结果表明，斯诺普利具有显著的降压作用(P<0.01)。SS/Jr大鼠(n＝8)连续饮用50mg/kg的Cap-NO后9周，体重、心率和收缩/舒张压分别是349±8g、400±45次/min、123±20/109±28mmHg。同期对比，对照组(n＝8)的体重、心率和收缩/舒张压分别是379±9g、418±52次/min、177±28/159±24mmHg。结果表明，在SS/Jr大鼠，斯诺普利具有显著的降压作用(P<0.05)。对比试验还表明，服用斯诺普利后，SHR和SS/Jr大鼠的血压可降到正常Wistar大鼠的血压范围内(123±11/101±12mmHg,n＝7)。
实施例12
实施例1斯诺普利单水合物晶体对肺动脉高压模型大鼠的作用：
将野百合碱腹腔注射造模成功的肺动脉高压(PAH)大鼠分为4组，分别为生理盐水空白对照组、50mg/kg卡托普利组、10mg/kg斯诺普利组、50mg/kg斯诺普利组，每组7只，每天施行灌胃给药，和健康大鼠(9只)共5组一起常规饲养30天。结果健康组大鼠无一死亡，生理盐水灌胃的空白对照组PAH大鼠由9 只减少到1只，50mg/kg卡托普利组和10mg/kg斯诺普利组PAH大鼠由7只减少到3只，50mg/kg斯诺普利组PAH大鼠由7只减少到5只。解剖死亡大鼠发现，50mg/kg卡托普利组大鼠胸腔积液平均体积为3.3mL，而10mg/kg斯诺普利组和50mg/kg斯诺普利组大鼠胸腔积液平均体积分别为1.2mL和0.5mL；平均右心室质量指数(RVMI)方面，空白对照组、50mg/kg卡托普利组、10mg/kg斯诺普利组、50mg/kg斯诺普利组分别为71.3％、53.8％、59.2％、37.8％。以上结果表明斯诺普利单水合物可以显著提高PAH大鼠的存活率，降低肺动脉压力(P<0.05)，减少胸腔积液(P<0.05)，减轻右心负担(P<0.05)，对肺动脉高压大鼠具有显著的治疗作用。

Claims (10)

  1. 一种斯诺普利单水合物晶体，其特征在于，所述斯诺普利单水合物的化学名为1-((2S)-2-甲基-3-亚硝基巯基-1-氧代丙基)-L-脯氨酸单水合物，化学结构式如下所示：
    Figure PCTCN2018079619-appb-100001
  2. 如权利要求1所述的斯诺普利单水合物晶体，其特征在于，所述的斯诺普利单水合物晶体显示出的X射线衍射图案包含在9.529±0.2、14.309±0.2、16.133±0.2、16.659±0.2、17.499±0.2、17.828±0.2、18.603±0.2、19.233±0.2、19.955±0.2、21.491±0.2、22.936±0.2、23.184±0.2、24.998±0.2、26.638±0.2、26.915±0.2、28.910±0.2、33.099±0.2、33.479±0.2、33.703±0.2和37.576±0.2的2θ角度上出现峰。
  3. 一种制备如权利要求1或2所述的斯诺普利单水合物晶体的方法，其特征在于，所述方法包括如下顺序的步骤：
    a.将卡托普利200～300重量份、亚硝酸钠70～100重量份和EDTA-2Na·2H 2O0.4～1.5重量份溶于已冷却至0℃的食盐水700～1000重量份中，使溶液混合均匀后，反应15～120分钟；
    b.向步骤a所得溶液中滴加60～90重量份盐酸，调节pH至4.0；
    c.抽滤步骤b所得红色混合物，进行干燥，得到斯诺普利单水合物晶体。
  4. 如权利要求3所述的斯诺普利单水合物晶体的制备方法，其特征在于，步骤a所述的反应在10℃以下进行。
  5. 如权利要求3所述的斯诺普利单水合物晶体的制备方法，其特征在于，步骤a所述的EDTA-2Na·2H 2O应在反应前加入。
  6. 如权利要求3所述的斯诺普利单水合物晶体的制备方法，其特征在于，步骤a所述的食盐水的浓度为15±5wt％。
  7. 如权利要求3所述的斯诺普利单水合物晶体的制备方法，其特征在于，步骤b所述的盐酸浓度为18wt％～24wt％。
  8. 如权利要求3所述的斯诺普利单水合物晶体的制备方法，其特征在于，步骤c所述的干燥方法，温度在40℃以下。
  9. 如权利要求1或2所述的一种斯诺普利单水合物晶体的应用，其特征在于，所述的斯诺普利单水合物晶体在制备治疗肺动脉高压、高血压、充血性心力衰竭的药物组合物中的应用。
  10. 根据权利要求9所述的斯诺普利单水合物晶体的应用，其特征在于，所述的药物组合物包括斯诺普利单水合物晶体和药学上可接受的载体。
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