WO2017157248A1 - 三乙酰基-3-羟基苯基腺苷在制备治疗动脉粥样硬化药物中的应用 - Google Patents

三乙酰基-3-羟基苯基腺苷在制备治疗动脉粥样硬化药物中的应用 Download PDF

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WO2017157248A1
WO2017157248A1 PCT/CN2017/076304 CN2017076304W WO2017157248A1 WO 2017157248 A1 WO2017157248 A1 WO 2017157248A1 CN 2017076304 W CN2017076304 W CN 2017076304W WO 2017157248 A1 WO2017157248 A1 WO 2017157248A1
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atherosclerosis
treatment
inflammatory
triacetyl
pharmaceutical composition
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PCT/CN2017/076304
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English (en)
French (fr)
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朱海波
王晶
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江苏天士力帝益药业有限公司
中国医学科学院药物研究所
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Priority to KR1020187029500A priority Critical patent/KR20180120766A/ko
Priority to CA3017400A priority patent/CA3017400A1/en
Priority to JP2018548733A priority patent/JP7390106B2/ja
Priority to EP17765790.5A priority patent/EP3431091A4/en
Priority to AU2017233089A priority patent/AU2017233089B2/en
Priority to KR1020227043112A priority patent/KR20230004891A/ko
Priority to US16/084,743 priority patent/US20190070208A1/en
Priority to RU2018134663A priority patent/RU2795163C2/ru
Publication of WO2017157248A1 publication Critical patent/WO2017157248A1/zh
Priority to ZA2018/06811A priority patent/ZA201806811B/en

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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  • the present invention relates to the use of triacetyl-3-hydroxyphenyladenosine and a pharmaceutical composition containing the same for the preparation of a medicament for preventing or/and treating hyperlipemia associated with mononucleosis, and for the preparation of prophylaxis or And the application in the treatment of atherosclerosis drugs belongs to the field of medical technology.
  • cardiovascular disease has become the number one killer of human health and life due to changes in eating habits and living standards.
  • Atherosclerosis is one of the main pathological basis of cardiovascular and cerebrovascular diseases. In the process of atherosclerosis, it is accompanied by an intensified immune response and inflammatory response. Lymphocytes and lipids accumulate in the aortic intima. Lipid-rich macrophages—foam cells, secreting inflammatory mediators MCP-1, IL-6 and other inflammatory factors induce monocyte migration into the vascular endothelium, stimulate smooth muscle cell migration and proliferation, and participate in plaque formation, development, and rupture And thrombosis.
  • Monocytes are continuously produced in the bone marrow as an intermediate cell, circulate in the blood and migrate into tissues, and then further differentiate into macrophages, dendritic cells, and the like.
  • high-fat diet-fed apoE -/- mice increased the number of monocytes in circulating blood by a factor of 4, while the inflammatory phenotype of Ly6C hi monocytes increased by 14-fold, resulting in a significant increase.
  • inflammatory mononuclear cells derived from bone marrow are precursors of inflammatory macrophages, which are the main components of atherosclerotic plaques, and a large number of studies have shown that in atherosclerosis.
  • monocytes/macrophages are activated. Macrophages continuously phagocytose ox-LDL and develop into foam cells, and the formation of foam cells is an important marker of early atherosclerosis. Thereby activating the inflammatory signaling pathway and aggravating the progression of the inflammatory response. Therefore, inflammatory monocytes play an important role in the occurrence and development of porridge.
  • Triacetyl-3-hydroxyphenyladenosine (Patent No. ZL200980101131.6, Bulletin No. CN101874036B, Announcement Day 2012.01.25) is a new screening of cordycepin derivatives with significant lipid-lowering activity in the Institute of Materia Medica, Chinese Academy of Medical Sciences. It is a pre-clinical research stage characterized by structural type compounds with small toxic and side effects and good pharmacokinetics. There are no reports of the use of this compound in the treatment of atherosclerotic inflammatory mononucleosis.
  • the technical problem to be solved by the present invention is to provide a triacetyl-3-hydroxyphenyl adenosine represented by the formula (I) for use in the preparation of a medicament for preventing or/and treating a mononucleosis associated with hyperlipidemia, And in the preparation of a medicament for preventing or/and treating atherosclerosis.
  • the present invention provides the following technical solutions:
  • a first aspect of the present invention provides a triacetyl-3-hydroxyphenyl adenosine represented by the formula (I) in the preparation of a mononucleotide-promoting drug associated with the prevention or/and treatment of hyperlipidemia.
  • a second aspect of the present invention provides a triacetyl-3-hydroxyphenyl adenosine represented by the formula (I) for use in the preparation of a medicament for preventing or/and treating atherosclerosis,
  • the prevention or/and treatment of atherosclerosis refers to prevention or/and treatment of inflammatory mononucleosis accompanied by atherosclerosis.
  • the treatment of atherosclerosis by triacetyl-3-hydroxyphenyladenosine refers to a process of inhibiting the migration of inflammatory monocytes from the bone marrow into the circulating blood, and improving the atherosclerosis-induced circulating blood inflammatory mononucleus.
  • Significant increase in cells reducing the number of circulating monocytes, Ly6C hi inflammation, reducing the level of serum MCP-1 inflammatory chemokines, reducing inflammation, thereby reducing the formation of arterial plaque.
  • the present invention demonstrates the significant role of triacetyl-3-hydroxyphenyladenosine in the treatment of atherosclerotic mononucleosis using pharmacodynamic studies to enable triacetyl-3-hydroxyphenyladenosine in the treatment of arteries.
  • the clinical application of atherosclerosis mononuclear cells has scientific basis.
  • a third aspect of the present invention provides a pharmaceutical composition for use in the preparation of a medicament for preventing or/and treating a mononucleosis associated with hyperlipidemia, and a pharmaceutical composition for preventing or/and The application in the treatment of atherosclerosis drugs.
  • the prevention or/and treatment of atherosclerosis refers to prevention or/and treatment of inflammatory mononucleosis accompanied by atherosclerosis.
  • the pharmaceutical composition comprises the triacetyl-3-hydroxyphenyl adenosine of the first aspect and a pharmaceutically acceptable carrier or additional agent.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 95% by weight.
  • the compound of the present invention or the pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.
  • the dosage form can be in a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
  • a preferred pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a pill, and an injection
  • the compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • diluents may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agent may be water, ethanol, or different Propyl alcohol, etc.
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group
  • disintegrant can be dry starch, microcrystalline cellulose, low substituted
  • Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • the active ingredient of the present compound may be first mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • a variety of diluents, binders, wetting agents, disintegrants, glidants useful in the preparation of tablets of the compounds of the invention are also useful in the preparation of capsules of the compounds of the invention.
  • a suitable amount of a solubilizing agent, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added as a solvent with water, ethanol, isopropanol, propylene glycol or a mixture thereof.
  • the solubilizing agent or the glidant may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure adjusting agent It may be sodium chloride, mannitol, glucose, phosphate, acetate or the like. For preparing a lyophilized powder injection, mannitol, glucose or the like may also be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of the compound of the invention will range from 0.001 to 150 mg/kg body weight, preferably from 0.1 to 100 mg/kg body weight, more preferably from 1 to 60 mg/kg body weight, and most preferably from 2 to 30 mg/kg body weight.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • the invention provides a new therapeutic drug for the chronic diseases of atherosclerosis, which is complicated and has poor therapeutic effect, triacetyl-3-hydroxyphenyladenosine, which is used for treating atherosclerosis inflammation.
  • the curative effect is remarkable, the side effects are small, and the use is safe.
  • IMM-H007 reduces peripheral blood Ly6C hi monocytes
  • A Isolation of peripheral blood mononuclear cells from apoE-/- mice fed a high-fat diet, labeled with anti-CD11b, -CD90, -B220, -CD49b, -NK1.1, -Ly-6G antibodies Door analysis of CD11b hi CD90 lo B220 lo CD49b lo NK1.1 lo Ly-6G lo monocyte ratio, and (B) further analysis of Ly-6C hi monocytes and Ly-6C lo monocytes using Ly6C antibody labeling, cells The ratios were all expressed by mean ⁇ SEM.
  • C whole blood CD11b monocytes
  • D whole peripheral blood Ly6C hi monocytes
  • Figure 3 is a comparison of serum MCP-1 and IL-6 levels in apoE-/- mice in the experimental example of the present invention.
  • Figure 4 is a comparison of the number of inflammatory mononuclear cells in the arterial plaque of each group of apoE-/- mice in the experimental example of the present invention.
  • Fig. 5 is a comparison of the staining of oil red O in the aortic root and aorta of each group of apoE-/- mice in the experimental example of the present invention.
  • the animals were raised in the Animal Experimental Center of the Institute of Materia Medica, Chinese Academy of Medical Sciences.
  • the breeding conditions were SPF, temperature 21 ⁇ 2°C, relative humidity 50 ⁇ 5%, photoperiod 12/12, and 5 per cage.
  • the normal group was given normal basal diet, and the high-fat diet group was given high-fat diet (79.8% basal diet, 20% lard, 0.2% cholesterol), and the animals were free to eat and drink.
  • the feed was commissioned by Beijing Huakang Biotechnology Co., Ltd.
  • IMM-H007 can significantly reduce the number of monocytes in circulating blood of Syrian golden hamsters compared with the model group.
  • OCT frozen slice embedding agent American cherry; sodium pentobarbital, sigma company; PEG6000, sigma company; glycine, sigma company; paraformaldehyde, oil red O, sigma company; HE staining solution, Taiwan Besso company.
  • Multi-purpose low-temperature high-speed centrifuge Eppendorff, Germany; frozen slicer, Lycra, Germany; water-proof constant temperature water bath; En Vision multi-function microplate reader, PerkinElmer, USA; small animal anesthesia machine, American Matrx product.
  • apoE-/- mice C57BL background, 5-7 weeks old, weighing 18-22 g, male, SPF grade; purchased from Beijing Experimental Animal Research Institute.
  • Circulating blood cells 50 ul of blood was taken from the heart puncture, placed in 450 ul heparin anticoagulant, 1 ml of red blood cell lysate was added, lysed for 10 min, centrifuged at 1800 r for 3 min, the supernatant was aspirated, and the cells were suspended in 100 ul PBS for use. The mice were sacrificed by blood in the iliac vein, and the serum was separated and stored at -80 °C.
  • CD90-PE 3ul, B220-PE3ul, CD49b-PE3ul, NK1.1-PE3ul, Ly-6G-PE3ul, CD11b-percp 6ul, Ly-6C–FITC 3ul set single positive tube and blank control tube, incubate for 30 min
  • the cells were washed 3 times with PBS, and the cells were re-selected with 400 ul of PBS, filtered, and flow-through.
  • the monocytes were identified as: CD11b hi CD90 lo B220 lo CD49b lo NK1.1 lo Ly-6G lo cells.
  • Ly6C is highly expressed as inflammatory monocyte LY6C hi monocytes, and Ly6C is lowly expressed as a resident phenotype monocyte Ly6Clo monocyte.
  • mice After the mice were finished with spleen and bone marrow, the hearts were slowly perfused with normal saline, and the hearts of the mice were isolated and stored in 4% paraformaldehyde.
  • the adipose tissue was separated, washed with PBS, and mixed with enzyme (type XI collagenase 125 U/ml, hyaluronidase 60 U/ml, deoxyribose synthase 60 U/ml, type I collagenase 450 U/ml, dissolved in 2.5 In mlPBS, the blood vessels were cut with scissors, incubated at 37 ° C for 1 h, filtered through a 0.22 um filter, centrifuged at 1600 rpm / 3 min, the supernatant was discarded, and 100 ul of PBS was added to suspend the antibody:
  • Mouse serum inflammatory factors were analyzed using the BD flow mouse inflammatory factor assay kit (Cat. No. 552364).
  • the slicer freezer temperature was set to -19 °C and the sample head was set to -21 °C before heart tissue sectioning.
  • the heart in 4% paraformaldehyde is embedded in OCT, the liquid nitrogen is rapidly frozen, and the tissue is placed on the microtome sample stage for temperature equilibration. After the tissue block was repaired, it was serially sliced, and the slice thickness was 8 ⁇ m, which was attached to a clean poly-lysine coated glass slide.
  • Aortic full-length oil red O staining cut the full length of the aorta, oil red O staining for 4h, isopropyl alcohol rinse, fixed with a stereo microscope, camera photo.
  • IMM-H007 significantly reduced the number of monocytes in circulating blood of apoE-/- mice (Fig. 2C, Table 2) and the number of inflammatory monocytes compared to the model group (Fig. 2D, Table 3). .
  • IMM-H007 could significantly quantify the number of inflammatory Ly6Chi monocytes in arterial plaques (Fig. 4).

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Abstract

式(I)所示的腺苷衍生物在制备预防或/和治疗高脂血症所伴随的单核细胞增多药物中的应用，及在制备预防或/和治疗动脉粥样硬化药物中的应用，其中预防或/和治疗动脉粥样硬化是指预防或/和治疗动脉粥样硬化所伴随的炎症单核细胞增多。

Description

三乙酰基-3-羟基苯基腺苷在制备治疗动脉粥样硬化药物中的应用 技术领域
本发明涉及三乙酰基-3-羟基苯基腺苷及含有其的药物组合物在制备预防或/和治疗高脂血症所伴随的单核细胞增多药物中的应用，及在制备预防或/和治疗动脉粥样硬化药物中的应用，属于医药技术领域。
背景技术
无论是西方发达国家还是中国，由于饮食习惯和生活水平的变化，心血管疾病已成为人类健康与生命的头号杀手。
动脉粥样硬化是心脑血管疾病的主要病理基础之一，在动脉粥样硬化形成过程中，始终伴随着加剧的的免疫应答和炎症反应，淋巴细胞和脂质堆积在主动脉内膜。富含脂质的巨噬细胞—泡沫细胞，分泌炎症介质MCP-1，IL-6等炎症因子诱导单核细胞迁移入血管内皮，刺激平滑肌细胞迁移和增殖并参与斑块的形成、发展、破裂和血栓形成。
单核细胞作为一种中间细胞持续的在骨髓中产生，在血液中循环并迁移入组织，然后进一步分化为巨噬细胞、树突细胞等。高脂膳食喂养的apoE-/-小鼠与chow饮食相比，其循环血中的单核细胞数目增长4倍，而炎症表型Ly6Chi单核细胞有14倍之多的增长，从而显著增加动脉粥样斑块中巨噬细胞数量。在动脉粥样硬化小鼠的研究中发现，由骨髓衍生的炎症单核细胞是炎症巨噬细胞的前体，是构成动脉斑块的主要成分，并且大量的研究结果显示在动脉粥样硬化中单核/巨噬细胞均被活化。巨噬细胞不断的吞噬ox-LDL进而发展为泡沫细胞，而泡沫细胞的形成是早期动脉粥样硬化的重要标志。从而激活炎症信号通路，加剧炎症反应进程。因而炎症单核细胞在动粥的的发生和发展过程中扮演着重要的角色。
三乙酰基-3-羟基苯基腺苷(专利号ZL200980101131.6，公告号CN101874036B，公告日2012.01.25)是中国医学科学院药物研究所在虫草素衍生物中筛选出具有显著调血脂活性的新结构类型化合物，并且毒副作用小、药代动力学良好等特征，目前处于临床前研究阶段。目前尚无该化合物在治疗动脉粥样硬化炎症单核细胞增多中应用的报道。
发明内容
本发明解决的技术问题是提供如式(Ⅰ)所示的三乙酰基-3-羟基苯基腺苷在制备预防或/和治疗高脂血症所伴随的单核细胞增多药物中的应用，及在制备预防或/和治疗动脉粥样硬化药物中的应用。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供了如式(Ⅰ)所示的三乙酰基-3-羟基苯基腺苷在制备预防或/和治疗高脂血症所伴随的单核细胞增多药物中的应用，
Figure PCTCN2017076304-appb-000001
本发明技术方案的第二方面是提供了如式(Ⅰ)所示的三乙酰基-3-羟基苯基腺苷在制备预防或/和治疗动脉粥样硬化药物中的应用，
Figure PCTCN2017076304-appb-000002
进一步的，所述的预防或/和治疗动脉粥样硬化是指预防或/和治疗动脉粥样硬化所伴随的炎症单核细胞增多。
其中，所述的三乙酰基-3-羟基苯基腺苷治疗动脉粥样硬化是指能够抑制炎症单核细胞从骨髓前移入循环血的过程，改善动脉粥样硬化诱导的循环血炎症单核细胞的显著增多，降低循环血Ly6Chi炎症单核细胞数量，降低血清MCP-1炎症趋化因子的水平，减轻炎症反应，从而发挥降低动脉斑块的形成的作用。
本发明采用药效学研究方法证实了三乙酰基-3-羟基苯基腺苷在治疗动脉粥样硬化单核细胞增多的显著作用，使三乙酰基-3-羟基苯基腺苷在治疗动脉粥样硬化单核细胞增多方面的临床应用具备科学依据。
本发明技术方案的第三方面是提供了一种药物组合物在制备预防或/和治疗高脂血症所伴随的单核细胞增多药物中的应用，以及该药物组合物在制备预防或/和治疗动脉粥样硬化药物中的应用。其中，所述的预防或/和治疗动脉粥样硬化是指预防或/和治疗动脉粥样硬化所伴随的炎症单核细胞增多。所述的药物组合物包含第一方面所述的三乙酰基-3-羟基苯基腺苷以及药学上可接受的载体或附加剂。
该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔黏膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以使液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。优选的药物组合物的剂型选自片剂、胶囊、丸剂、注射剂。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂、可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基 纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物先与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各种稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物做溶剂加入适量本领域常用的增溶剂、助溶剂、PH调剂剂、渗透压调节剂。增溶剂或助流剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；PH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可以加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或者药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/kg体重，优选为0.1-100mg/kg体重，更优选为1-60mg/kg体重，最优选为2-30mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其它治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
有益的技术效果
本发明为动脉粥样硬化这一病机复杂、治疗效果欠佳的慢性疾病提供了一种新的治疗药物—三乙酰基-3-羟基苯基腺苷，其在治疗动脉粥样硬化炎症单核细胞增多方面，疗效显著，毒副作用小，使用安全。
附图说明
为了使本发明的内容更容易被清楚的理解，下面根据本发明的具体实施例并结合附图，对本发明作进一步详细的说明，其中，
图1为本发明所述实验例中金黄地鼠循环血单核细胞数量比较；
图2为本发明所述实验例中apoE-/-小鼠循环血单核细胞，炎症单核细胞及居住表型单核细胞流式分析结果比较；IMM-H007降低外周血Ly6Chi单核细胞.(A)分离高脂膳食喂养的apoE-/-小鼠外周血单核细胞，用抗-CD11b,-CD90,-B220,-CD49b,-NK1.1,–Ly-6G抗体进行标记，划门分析CD11bhiCD90loB220loCD49blo NK1.1loLy-6Glo单核细胞比例，并且(B)进一步采用Ly6C抗体标记分析Ly-6Chi单核细胞和Ly-6Clo单核细胞，细胞比例均采用mean±SEM.表示(C)全血CD11b单核细胞(D)全外周血Ly6Chi单核细胞；
图3为本发明所述实验例中apoE-/-小鼠血清MCP-1及IL-6水平比较；
图4为本发明所述实验例中各组apoE-/-小鼠动脉斑块炎症单核细胞数量比较；
图5为本发明所述实验例中各组apoE-/-小鼠主动脉根部及主动脉全长油红O染色情况比较。
具体实施方式
下面的实施例用来进一步说明本发明，但这并不意味着对本发明的任何限制。
实验例1：三乙酰基-3-羟基苯基腺苷(IMM-H007)在治疗高脂血症伴随的单核细胞增多中的应用
一、实验材料
1.试剂
雅培CD3700全血细胞分析试剂，包括稀释液，溶血剂，鞘液，洗涤液，酶清洁液；EDTA-2K抗凝剂
2.仪器
全血细胞分析仪(美国，雅培)。
3.实验动物
6-8周龄叙利亚金黄地鼠(LVG hamster，源引进于Charles River Laboratories)20只，体重90-120g，雄性，SPF级，购自北京维通利华实验动物技术有限公司。
二、实验方法
1.动物分组及饲养
动物适应性喂养7天后按体重随机分为正常对照组(n＝13)、高脂饲料组(n＝13)、IMMH007低剂量组(50mg/kg，n＝13)、IMMH007中剂量组(100mg/kg，n＝13)、IMMH007高剂量组(200mg/kg，n＝13)，每天灌胃给药2次。动物饲养于中国医学科学院药物研究所动物实验中心二部，饲养条件为SPF级，温度21±2℃，相对湿度50±5％，光照周期为12/12，5只每笼。正常组给予正常基础饲料，高脂饲料组给予高脂饲料(79.8％基础饲料，20％猪油，0.2％胆固醇)，动物自由摄食、饮水。饲料委托北京华阜康生物科技有限公司生产。
2.观察指标及测定方法
2.1循环血单核细胞测定
动物禁食12小时，眼角取血，每只200ul左右，溶于30ulEDTA-2K抗凝剂(20g/L，生理盐水配制)中，轻轻混匀，避免凝血，全血细胞分析仪分析全血细胞。
三.实验结果
IMM-H007对高脂饮食喂养的叙利亚金黄地鼠循环血单核细胞的影响。
由图1及表1可见，与模型组相比，IMM-H007可以显著降低叙利亚金黄地鼠循环血中单核细胞数量。
表1 IMM-H007对叙利亚金黄地鼠循环血单核细胞的影响
Figure PCTCN2017076304-appb-000003
实验例2.三乙酰基-3-羟基苯基腺苷(IMM-H007)在治疗动脉粥样硬化小鼠模型循环血单核细胞增多中的应用
一、实验材料
1试剂
OCT冰冻切片包埋剂，美国樱花；戊巴比妥钠，sigma公司；PEG6000，sigma公司；甘氨酸，sigma公司；多聚甲醛，油红O，sigma公司；HE染色液，台湾贝索公司。
2.仪器
多用途低温高速离心机，德国Eppendorff；冰冻切片机，德国莱卡；隔水式恒温水浴；En Vision多功能酶标仪，美国PerkinElmer股份有限公司；小动物麻醉机，美国Matrx产品。
3.实验动物
apoE-/-小鼠(C57BL背景)，5-7周龄，体重18-22g，雄性，SPF级；购自北京实验动物研究所。
二、实验方法
1.动物分组及饲养
动物适应性喂养7天后按体重随机分为高脂饲料组(n＝7)、IMMH007低剂量组(50mg/kg，n＝7)、IMMH007中剂量组(100mg/kg，n＝7)、IMMH007高剂量组(200mg/kg，n＝9)，每天灌胃给药1次。动物饲养于中国医学科学院药物研究所 动物实验中心二部，饲养条件为SPF级，温度21±2℃，相对湿度50±5％，光照周期为12/12，5只每笼。所有组别给予高脂饲料(70％基础饲料加20％猪油和0.2％胆固醇)，动物自由摄食、饮水。饲料委托北京华阜康生物科技有限公司生产。实验中每1周记录体重一次。
2.观察指标及测定方法
2.1循环血单核细胞测定
动物禁食12小时，提取以下细胞：
循环血细胞：心脏穿刺取血50ul，置于450ul肝素抗凝剂中，加入红细胞裂解液1ml，裂解10min，1800r离心3min，吸弃上清，100ulPBS混悬细胞，备用。小鼠内眦静脉取血致死，分离血清，-80℃保存。
向上述的血细胞加入抗体：
CD90-PE 3ul，B220-PE3ul，CD49b-PE3ul，NK1.1-PE3ul，Ly-6G–PE3ul，CD11b-percp 6ul，Ly-6C–FITC 3ul，设置单阳管和空白对照管，冰砂孵育30min，PBS洗涤3次，用400ul PBS重选细胞，过滤，流式检测。单核细胞鉴定为：CD11bhiCD90loB220loCD49bloNK1.1loLy-6Glo细胞。进一步根据Ly6C的表达情况，Ly6C高表达为炎症单核细胞LY6Chi单核细胞，Ly6C低表达为居住表型单核细胞Ly6Clo单核细胞。
小鼠取完脾脏及骨髓后，用生理盐水缓慢灌流心脏，分离小鼠心脏，保存于4％多聚甲醛中。
2.2主动脉全长动脉斑块中Ly6Chi单核细胞含量分析
动物禁食12小时后，眼角取血致死后，于体式显微镜下剪开小鼠的胸，腹腔，生理盐水灌流心脏及血管，在保持血管湿润的状态下，剥离主动脉全长，取出其表面的脂肪组织，分离后，用PBS洗涤，加入混合酶(Ⅺ型胶原酶125U/ml，透明质酸酶60U/ml，脱氧核糖合酶60U/ml，Ⅰ型胶原酶450U/ml，溶于2.5mlPBS中)，用剪刀将血管剪碎，于37℃孵育消化1h，0.22um滤膜过滤，1600rpm/3min离心，弃上清，加入100ulPBS混悬，加入抗体：
CD90-PE3ul，B220-PE3ul，CD49b-PE3ul，NK1.1-PE3ul，Ly-6G–PE3ul，CD11b-percp 6ul，Ly-6C–FITC 3ul，F4/80-APC 10ul，CD11C-APC 4ul，I-Ab-APC 4ul，设置单阳管和空白对照管，冰砂孵育30min，PBS洗涤3次，用400ul PBS重选细胞，过滤，流式检测。
2.3血清炎症因子分析
小鼠血清炎症因子采用BD流式小鼠炎症因子检测试剂盒分析(货号：552364)。
2.4主动脉根部及主动脉全长斑块面积分析
2.4.1冰冻切片的制备
心脏组织切片前将切片机冷冻箱温度设为-19℃，样品头设为-21℃。存于4％多聚甲醛的心脏包埋于OCT中，液氮快速冷冻，再将组织放入切片机样品台上进行温度平衡。组织块修快后连续切片，切片厚度为8um，贴于干净的多聚赖氨酸包被载玻片上。
2.4.2油红O染色
2.4.2.1冰冻切片油红O染色：用异丙醇配制5‰的油红O储备液，然后以水以3:2的比例混匀，用双层滤纸过滤，加入染缸中，将选好的片子放入吊篮中，置于染缸中染色2h，用60％的异丙醇分色数秒，自来水轻柔冲洗，苏木素复染3-5min，自来水冲洗2min返蓝，甘油明胶封片，镜下观察拍照。
2.4.2.2主动脉全长油红O染色：剪开主动脉全长，油红O染色4h，异丙醇漂洗，与体式显微镜下固定，相机拍照。
3.数据分析
数据以平均值±标准误来表示，所有数据采用Graphpad Prism5.0软件进行ONEWAY-ANOVA统计分析；对图像进行对比分析。
三实验结果
3.1 IMM-H007对动脉粥样硬化小鼠循环血单核细胞的影响
由图2可见，与模型组相比，IMM-H007可以显著降低apoE-/-小鼠循环血中单核细胞数量(图2C，表2)和炎症单核细胞数量(图2D，表3)。
表2 IMM-H007对apoE -/-小鼠循环血单核细胞的影响
Figure PCTCN2017076304-appb-000004
表3 IMM-H007对apoE-/-小鼠循环血炎症单核细胞的影响
Figure PCTCN2017076304-appb-000005
3.2IMM-H007对动脉粥样硬化小鼠血清炎症因子水平的影响
进一步观察IMM-H007对小鼠血清炎症因子的影响，结果发现，IMM-H007可以显著降低血清中MCP-1的水平(图3A)和IL-6的水平(图3B)。
3.3IMM-H007对动脉粥样硬化小鼠动脉斑块炎症单核细胞数量的影响
进一步观察IMM-H007对小鼠动脉斑块中炎症单核细胞数量的影响，结果发现，IMM-H007可以显著动脉斑块中炎症Ly6Chi单核细胞的数量(图4)。
3.4IMM-H007对动脉粥样硬化小鼠动脉斑块形成的影响
通过对apoE-/-小鼠主动脉根部及主动脉全长的油红O染色，结果发现，IMM-H007可以显著降低apoE-/-小鼠主动脉全长及主动脉根部的动脉斑块面积(图5)。

Claims (9)

  1. 如式(Ⅰ)所示的三乙酰基-3-羟基苯基腺苷在制备预防或/和治疗高脂血症所伴随的单核细胞增多药物中的应用，
    Figure PCTCN2017076304-appb-100001
  2. 如式(Ⅰ)所示的三乙酰基-3-羟基苯基腺苷在制备预防或/和治疗动脉粥样硬化药物中的应用，
    Figure PCTCN2017076304-appb-100002
  3. 根据权利要求2的应用，其特征在于，所述的预防或/和治疗动脉粥样硬化是指预防或/和治疗动脉粥样硬化所伴随的炎症单核细胞增多。
  4. 根据权利要求2的应用，其特征在于，所述的预防或/和治疗动脉粥样硬化是指能够改善动脉粥样硬化诱导的炎症单核细胞的显著增多，降低循环血Ly6Chi炎症单核细胞数量，降低血清MCP-1炎症趋化因子的水平，减轻炎症反应，减少动脉斑块的形成。
  5. 一种药物组合物在制备预防或/和治疗高脂血症所伴随的单核细胞增多药物中的应用，其特征在于，所述的药物组合物包含如式(Ⅰ)所示的三乙酰基-3-羟基苯基腺苷及药学上可接受的载体或赋形剂，
    Figure PCTCN2017076304-appb-100003
  6. 一种药物组合物在制备预防或/和治疗动脉粥样硬化药物中的应用，其特征在于，所述的药物组合物包含如式(Ⅰ)所示的三乙酰基-3-羟基苯基腺苷及药学上可接受的载体或赋形剂，
    Figure PCTCN2017076304-appb-100004
  7. 根据权利要求6的应用，其特征在于，所述的预防或/和治疗动脉粥样硬化是指预防或/和治疗动脉粥样硬化所伴随的炎症单核细胞增多。
  8. 根据权利要求5-7任一项的应用，其特征在于，所述的药物组合物为片剂、胶囊、丸剂或注射剂。
  9. 根据权利要求5-7任一项的应用，其特征在于，所述的药物组合物为缓释制剂、控释制剂或各种微粒给药系统。
PCT/CN2017/076304 2016-03-14 2017-03-10 三乙酰基-3-羟基苯基腺苷在制备治疗动脉粥样硬化药物中的应用 WO2017157248A1 (zh)

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CA3017400A CA3017400A1 (en) 2016-03-14 2017-03-10 Use of triacetyl-3-hydroxyphenyladenosine for treatment of hyperlipidemia
JP2018548733A JP7390106B2 (ja) 2016-03-14 2017-03-10 アテローム性動脈硬化症の治療用医薬の調製におけるトリアセチル－３－ヒドロキシフェニルアデノシンの応用
EP17765790.5A EP3431091A4 (en) 2016-03-14 2017-03-10 USE OF TRIACETYL-3-HYDROXYPHENYLADENOSINE IN THE PREPARATION OF PHARMACEUTICAL PRODUCTS FOR THE TREATMENT OF ATHEROSCLEROSIS
AU2017233089A AU2017233089B2 (en) 2016-03-14 2017-03-10 Use of triacetyl-3-hydroxyphenyladenosine in preparing pharmaceuticals for treatment of atherosclerosis
KR1020227043112A KR20230004891A (ko) 2016-03-14 2017-03-10 죽상동맥경화증의 치료용 약제의 제조에 있어서의 트리아세틸-3-하이드록시페닐아데노신의 용도
US16/084,743 US20190070208A1 (en) 2016-03-14 2017-03-10 Use of triacetyl-3-hydroxyphenyladenosine in preparing pharmaceuticals for treatment of atherosclerosis
RU2018134663A RU2795163C2 (ru) 2016-03-14 2017-03-10 Триацетил-3-гидроксифениладенозин для получения фармацевтических препаратов для уменьшения количества циркулирующих в крови моноцитов
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CN107334775A (zh) 2017-11-10
CA3017400A1 (en) 2017-09-21
AU2017233089A1 (en) 2018-10-04

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