WO2019242764A1 - 糖苷类化合物在制备防治糖尿病并发症的药物中的应用 - Google Patents

糖苷类化合物在制备防治糖尿病并发症的药物中的应用 Download PDF

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WO2019242764A1
WO2019242764A1 PCT/CN2019/092383 CN2019092383W WO2019242764A1 WO 2019242764 A1 WO2019242764 A1 WO 2019242764A1 CN 2019092383 W CN2019092383 W CN 2019092383W WO 2019242764 A1 WO2019242764 A1 WO 2019242764A1
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compound
preparation
test
diabetes
group
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PCT/CN2019/092383
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English (en)
French (fr)
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杨成
苏丹
钟治晖
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成都中创蜀洋生物科技有限公司
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Priority to US17/255,222 priority Critical patent/US20210346414A1/en
Priority to EP19822580.7A priority patent/EP3811948A4/en
Publication of WO2019242764A1 publication Critical patent/WO2019242764A1/zh

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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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention relates to the field of medicine, in particular to the application of a glycoside compound in the preparation of a medicament for preventing and treating diabetes complications.
  • Diabetes Meltus, DM
  • diabetes is a common endocrine and metabolic disease with protein and fat metabolism disorders as the main clinical manifestations due to the relative or absolute lack of insulin secretion in the body resulting in excessive blood sugar.
  • IDF International Diabetes Federation
  • the symptomatic treatment of diabetes is to control blood glucose indicators, but patients need to take medication for life, and with the development of the disease, complications such as hypertension, coronary heart disease, hyperlipidemia, retinopathy, diabetic nephropathy, and diseased feet will occur. According to World Health Organization statistics, more than 50% of diabetes deaths are caused by cardiovascular and cerebrovascular diseases, and 10% are caused by renal disease. Clinical data show that about 10 years after the onset of diabetes, 30% to 40% of patients will have at least one complication, and once the complication occurs, it is difficult to reverse drug treatment, so diabetes complications should be prevented as soon as possible.
  • Diabetic microangiopathy is more specific, and its main features are thickening of the basement membrane and the deposition of clear-like substances.
  • Microcirculation in patients with diabetes is abnormal to varying degrees, and abnormalities of basement membrane and microcirculation affect each other, which promotes the aggravation and development of microvascular disease.
  • Microangiopathy is mainly manifested in the retina, kidney, myocardium, nerve tissue and toes.
  • diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy are the main places to reflect diabetic microangiopathy.
  • Diabetic retinopathy is one of the most common microvascular complications of diabetes, and it is the main cause of vision loss in the elderly. The longer the duration of diabetes, the worse the glycemic control, and the higher the risk of retinopathy and impaired vision.
  • the retinal blood vessel wall begins to break, it means the occurrence of retinopathy.
  • the abnormal blood vessel wall oozes or oozes into the eyeball, it can cause vision loss or deformation.
  • the prevalence of retinopathy in diabetic patients is higher, while the incidence of proliferative lesions is 3.3% to 7.4%. Its pathogenesis is not fully understood, but inflammation, oxidative stress, and microvascular changes play an important role in the deterioration of retinal function.
  • Diabetic nephropathy is one of the most serious complications of diabetes. Diabetic nephropathy is the main microvascular complication of diabetes. It mainly refers to diabetic glomerulosclerosis, a glomerular lesion with mainly vascular damage. Early asymptomatic, blood pressure can be normal or high. Its incidence increases with the duration of diabetes. In the early stage of diabetes, the kidney volume increases, and the glomerular filtration rate increases, showing a high filtration state. Later, interstitial proteinuria or microalbuminuria gradually appears, and continuous proteinuria, edema, hypertension, and small kidneys appear as the course of the disease increases. Reduced ball filtration rate, followed by renal insufficiency and uremia, is one of the main causes of death in diabetes.
  • diabetic retinopathy and nephropathy and other microvascular diseases are not yet clear. Generally, they are caused by a variety of risk factors. They are irreversible. Blood glucose is effectively controlled, but complications cannot be controlled accordingly.
  • the technical problem to be solved by the present invention is that the existing methods for treating diabetic microangiopathy are mainly prevented by controlling indexes such as blood glucose, blood lipid, blood pressure and the like before the occurrence of the lesion, and by physical means such as laser, condensation or vitreous cutting after the occurrence of the lesion.
  • the present invention provides the application of a glycoside compound that solves the above problems in the preparation of a medicament for the prevention and treatment of diabetic complications, and is particularly beneficial for the treatment of diabetic microangiopathy.
  • the present invention is achieved through the following technical solutions:
  • the present invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof in the preparation of a medicament for the prevention and treatment of complications of diabetes:
  • formula (I) represents the following two isomer structures:
  • R 1 to R 7 are each independently selected from H, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, or C 2 to C 6 alkynyl.
  • the compound is a compound represented by formula (III) or an enantiomer or diastereomer thereof, or a racemic mixture thereof, or an isotope thereof:
  • the compound is a compound represented by formula (IV) or an enantiomer or diastereomer thereof, or a racemic mixture thereof, or an isotope thereof:
  • the complication is a complication caused by type 1 diabetes or type 2 diabetes.
  • the complication is microvascular disease.
  • microvascular lesions are renal lesions and retinopathy.
  • the medicament is administered via sublingual, inhalation, oral or injection.
  • injection includes intradermal injection, subcutaneous injection, intramuscular injection and intravenous injection.
  • the invention also provides a pharmaceutical composition for preventing and treating diabetes complications, which is prepared by using the aforementioned compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, and adding a pharmaceutically acceptable excipient. Made of preparations.
  • the present invention also provides the use of the aforementioned compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof in the preparation of a food, a health product, or a food additive for preventing and treating diabetic complications.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, excipient, and / or formed salt is usually chemically or physically compatible with other ingredients constituting a pharmaceutical dosage form, and It is physiologically compatible with the receptor.
  • salt is an acidic and / or basic salt formed by a compound or a stereoisomer thereof with an inorganic and / or organic acid and a base, and also includes a zwitterionic salt (internal salt), and also includes a quaternary salt.
  • Ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by appropriately mixing a compound, or a stereoisomer thereof, with a certain amount of an acid or a base (for example, an equivalent amount).
  • salts may be precipitated in solution and collected by filtration, or recovered after evaporation of the solvent, or prepared by freeze-drying after reaction in an aqueous medium.
  • the salt described in the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluorate, phosphate, acetate, propionate, succinate Acid salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • an “isotope body” refers to any form of a compound in which at least one atom of a natural isotopic abundance is replaced with an isotopically enriched form different from the natural abundance.
  • Isotope bodies can be based on hydrogen substitution with deuterium and / or tritium.
  • 12C of natural abundance can be replaced by 13C or 14C
  • 16O of natural abundance can be replaced by 17O or 18O, or any combination thereof.
  • Isotope enrichment can be achieved to any degree, including 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80 %, 90%, 95%, 99%, and 100% enrichment, including any of these values and their fractions.
  • the purpose of the present invention is to provide an application of a glycoside compound in the preparation of a medicine for treating diabetic retinopathy:
  • the compound has a significant blood glucose lowering effect and has a good therapeutic effect on diabetes
  • the compound has a certain tendency to lower the levels of UREA and CREA, reduce the degree of mesangial or mesangial cell proliferation, and has a certain protective effect on the kidney; at the same time, the compound can significantly reduce the degree of degeneration of the retinal ganglion cell layer, indicating that the compound has Reduce the degeneration of retinal ganglion cell layer in animals. Therefore, the compound has a certain degree of protection for the kidneys and retinas of diabetic animals, and has good economic and social value.
  • the dosage of the compound for the treatment of diabetic lesions is related to the dosage. The more the dosage of the compound, the better the effect.
  • FIG. 1 is the hypoglycemic result of representative animals of each group of the present invention.
  • FIG. 2 is a retina pathological staining picture of representative animals of each group of the present invention
  • Figure 3 shows the score of the retinal ganglion cell layer of each group of the present invention; among them, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001 vs. negative control group;
  • Figure 4 is a kidney pathological staining diagram of representative animals in each group
  • Figure 5 shows the glomerular pathological scores of the kidneys of each group of animals.
  • the compound can be obtained from the compound reported in the literature "Isolation and identification of chemical constituents of Coptis chinensis aqueous extract" (Li Xuegai et al., Journal of Shenyang Pharmaceutical University, March 2012, Vol. 29, Issue 3, pp. 193-198) 15 ⁇ ⁇ ⁇ Obtained.
  • Identification after preparation indicate the test number, test substance name and concentration, preparation volume, storage conditions, validity period, responsible person and preparation date, etc .;
  • Identification after preparation indicate the test number, test substance name and concentration, preparation volume, storage conditions, validity period, responsible person and preparation date, etc .;
  • Identification after preparation indicate the test number, test substance name and concentration, preparation volume, storage conditions, validity period, responsible person and preparation date, etc.
  • Glucose injection 50% product of Hubei Kelun Pharmaceutical Co., Ltd., specification: 20mL / pack, batch number: B160915B).
  • mice Species: db / db, db / m mice;
  • Age about 9 weeks of age
  • Weight The average value of db / m mice is 26.7 ⁇ 34.0g, and the individual value of body weight is within the range of mean ⁇ 20% (the weight of the animal at the beginning of the test). Within the range of ⁇ 20% (the weight of the animal at the beginning of the test);
  • the main inspection results during the adaptation period are consistent with the quality indicators required at the time of order; the general state of the animals is normal; the weight of the animals reaches the weight range required by the test; the abnormal animals that fail the test are not included in the test.
  • Feeding density ⁇ 5 / cage
  • Feeding method free intake (except when the test has special requirements);
  • Detection of nutritional ingredients conventional nutritional composition indicators: crude protein, crude fat, crude fiber, crude ash, moisture, calcium and phosphorus; amino acid indicators: threonine, cystine + methionine, valine, isoleucine, leucine Amino acid, tyrosine + phenylalanine, histidine, lysine, arginine, tryptophan, refer to the National Standard of the People's Republic of China GB14924.3-2010;
  • Species drinking water for experimental animals (reverse osmosis water);
  • Water supply method Drinking water bottle, free intake.
  • db / db mouse model blood glucose greater than 7.8mmol / L was included in the type 2 diabetes model group (the minimum blood glucose in the db / db model group was 7.8mmol / L, which was significantly higher than the db / m control group average of 5.6).
  • Test group design db / m group, db / db mice are divided into the following six groups: blank control group (without glucose), negative control group (model group), positive control group (350mg / kg metformin), low H2 Dose group (40mg / kg), H2 medium dose group (80mg / kg), H2 high dose group (160mg / kg);
  • Grouping method According to the fasting blood glucose measured before the first administration, the patients were randomly divided into groups. The specific grouping information is shown in Table 1 below.
  • Dosing frequency once a day for 12 consecutive weeks; db / m group, blank control group and negative control group: given distilled water; positive control group: given the positive drug metformin; other administration groups: given different doses of Test drug H2; The day of administration is defined as the first day of the test.
  • Tests for homogeneity of variance are performed first.
  • P ⁇ 0.05 repeated measures analysis of variance
  • ANOVA repeated measures analysis of variance
  • P ⁇ 0.05 the differences in groups are statistically significant
  • ANOVA single factor analysis of variance
  • K-W method the Kruskal-Wallis H rank sum test
  • the variance is uneven (P ⁇ 0.05)
  • the Kruskal-Wallis H rank sum test (KW method) is used for statistical analysis.
  • Collection frequency blood glucose was measured once every 2 weeks after grouping, and then after glucose was measured, the sampling site: tail vein, sampling volume: about 1 drop, blood glucose detection: real-time detection by blood glucose meter.
  • the blood glucose of each group of animals is shown in Table 3 and Figure 1.
  • the blood glucose of the blank control group and the negative control group showed an upward trend.
  • the positive drug metformin group has a significantly lower blood glucose value from the negative control group since the 15th day of administration (P ⁇ 0.001), indicating that the positive drug can significantly reduce blood glucose in db / db mice; low-dose test drugs H2 has no obvious hypoglycemic effect.
  • the blood glucose level of the middle-dose group was significantly lower than that of the negative control group (P ⁇ 0.01) from 15 days after administration, and the blood glucose level of 72 days after administration was significantly lower than that of the negative control group (P ⁇ 0.001).
  • mice in the high-dose group of the test drug H2 began to be significantly lower than that of the negative control group at 43 days after administration, which was (20.84 ⁇ 0.66) vs (13.87 ⁇ 1.76) mmol / L (P ⁇ 0.01).
  • the above-mentioned change was more obvious, which was (23.46 ⁇ 1.87) vs (13.07 ⁇ 1.71) mmol / L (P ⁇ 0.001).
  • the blood glucose of mice in the db / m group did not change significantly during the whole experiment and was significantly lower than that of other groups. This shows that the positive drug is equivalent to the hypoglycemic effect of the test drug high-dose group, and even better than that of the high-dose group.
  • retinal ganglion cell layer of each group of animals experienced different degrees of degeneration.
  • pathological grading principles refer to the standard (Fermented, Milk, Has-Anti-diabetic, Effects: Anti-diabetic, Effective of Fermented, Milk, Containing, Conjugated Linoleic, Acid, Type, Type II, Diabetes, Melitus, Korean. .36, No. 2 (2016).) It is divided into 0 to 4 grades. The larger the value, the more severe the disease.
  • the grading scores of retinal ganglion cell layer degeneration in each group of animals are shown in Table 4 and Figures 2-3.
  • N indicates normal tissue morphology
  • E indicates a change in tissue morphology
  • - indicates no such lesion.
  • the morphology of the retinal ganglion cell layer in the db / m group (one animal had abnormal retinal ganglion cell layers, which may be caused by specimen preparation) and the test drug H2 high dose group, and the remaining db / db
  • the omental ganglion cell layer of each group of animals has different degrees of degeneration; compared with the negative control group, the use of metformin positive drugs has almost no improvement in the symptoms of retinopathy, and the H2 provided by the present invention has a good effect of improving retinopathy, and With the increase of the dose of H2, the effect increased significantly.
  • the high dose of the test drug H2 significantly reduced the degree of degeneration of the retinal ganglion cell layer (P ⁇ 0.05), indicating that the test drug H2 can treat the degeneration of the retinal ganglion cell layer in animals. efficacy. After 12 weeks of continuous administration, no significant abnormal reaction was observed in each group of db / db mice. There was no statistically significant difference in body recombination, and no significant abnormality was found in gross anatomy, indicating that the test drug had no significant toxic and side effects on the animals. .
  • urea nitrogen (UREA) in the db / m group was significantly lower than that in the db / db group (P ⁇ 0.05).
  • UREA urea nitrogen
  • the dose of the test drug H2 significantly reduced the UREA level (P ⁇ 0.001).
  • the UREA change rate shows that compared with the negative control group, the test drug H2 has a tendency to reduce UREA, and the dose trend of the test drug H2 is more obvious.
  • CREA serum creatinine
  • the kidney index in the db / m group was significantly higher than that in the db / db group (P ⁇ 0.001), and there was no significant difference between the db / db groups.
  • kidneys were dissected and the histopathological results showed that the standard reference standards for classification (Fermented, Milk, Has, Anti-diabetic, Effects: Anti-diabetic, Effect of Fermented, Milk, Containing, Conjugated Linoleic Acid, Onion Type, Diabetes, Melitus, Food, Korean). ., Vol. 36, No. 2 (2016).).
  • the kidney grading scores of each group of animals are shown in Table 6 and Figure 4. Kidney histopathological staining is shown in Figure 5.
  • N indicates normal tissue morphology
  • E indicates a change in tissue morphology
  • - indicates no such lesion.
  • glycoside compounds are added to any food, food additive, or made into a health product through a reasonable formula and a preparation method, and are used for preventing and treating diabetic complications belonging to the protection scope of the present application.

Abstract

糖苷类化合物在制备防治糖尿病并发症的药物中的应用。所述化合物有一定的降低UREA和CREA水平，减轻肾小球系膜或系膜细胞增生程度的趋势，有一定保护肾脏作用。所述化合物可显著减轻视网膜神经节细胞层变性程度，有减轻动物视网膜神经节细胞层变性作用。所述化合物对糖尿病动物的肾脏和视网膜具有一定程度的保护作用。

Description

糖苷类化合物在制备防治糖尿病并发症的药物中的应用 技术领域
本发明涉及医药领域，具体涉及一种糖苷类化合物在制备防治糖尿病并发症的药物中的应用。
背景技术
随着社会的发展，糖尿病(Diabetes Mellitus,DM)患病率明显增加，已成为影响人类健康的重要疾病之一。糖尿病是因机体胰岛素分泌相对或绝对不足导致血糖过高，而引起的以蛋白质和脂肪代谢紊乱为主要临床表现的一种常见的内分泌代谢性疾病。根据国际糖尿病联盟(IDF)发布的第八版全球糖尿病地图显示，2017年全球有4.25亿糖尿病患者，预计2045年，将会有近7亿糖尿病患者。糖尿病对症治疗方式为控制血糖指标，但患者需要终生服药，而且随着病情的发展会产生高血压、冠心病、高血脂、视网膜病变、糖尿病肾病及病足等并发症。据世界卫生组织统计，50％以上糖尿病死亡者是由心脑血管所致，10％是肾病变所致。临床数据显示，糖尿病发病后10年左右，将有30％～40％的患者至少会发生一种并发症，且并发症一旦发生，药物治疗很难逆转，因此应尽早预防糖尿病并发症。
糖尿病微血管病变是比较特异的，其主要特征是基底膜增厚并有透明样物质沉积。糖尿病患者的微循环有不同程度的异常，基底膜病变异常与微循环异常相互影响，促使微血管病变的加重和发展。微血管病变主要表现在视网膜、肾、心肌、神经组织及足趾。临床上常以糖尿病性视网膜病变、糖尿病性肾病和糖尿病性神经系统病变为反映糖尿病性微血管病变的主要场所。
糖尿病视网膜病变(DR)是糖尿病最常见的微血管并发症之一，其是导致老年人视力丧失的主要原因。糖尿病病程越长，血糖控制越差，视网膜病变及视力受损的风险就越高。当视网膜血管壁开始被破坏，即意味着视网膜病变的发生。当异常的血管壁渗血或渗液到眼球中，可以导致视力丧失或变形。视网膜病变在糖尿病患者中的患病率为较高，而增生性病变发生率3.3％～7.4％。其发病机制尚不完全清楚，但炎症、氧化应激和微血管改变在视网膜功能恶化中起着重要作用。现有的治疗糖尿病视网膜病变的方法主要通过在发生病变前期控制血糖、血脂、血压等指标进行预防，及发生病变后通过激光、冷凝或玻璃体切割等物理手段治疗。对于后期的药物治疗，目前只有基因泰克公司研发的雷珠单抗(Lucentis,Ranibizumab注射液)，用于治疗伴或不伴黄斑水肿(DME)视网膜病变的治疗药物上市，但其价格昂贵。因此，继续开发新型视网膜病变治疗药物是我们目前需要解决的问 题。
糖尿病肾脏病变是糖尿病最严重的并发症之一，糖尿病肾病为糖尿病主要的微血管并发症，主要指糖尿病性肾小球硬化症，一种以血管损害为主的肾小球病变。早期多无症状，血压可正常或偏高。其发生率随着糖尿病的病程延长而增高。糖尿病早期肾体积增大，肾小球滤过率增加，呈高滤过状态，以后逐渐出现间隙蛋白尿或微量白蛋白尿，随着病程的延长出现持续蛋白尿、水肿、高血压、肾小球滤过率降低，进而肾功能不全、尿毒症，是糖尿病主要的死亡原因之一。
糖尿病视网膜病变及肾脏病变等微血管病变的病因和发病机制目前尚不十分明确，一般是由多种危险因素作用所致，是不可逆，血糖得到有效控制，但并发症无法得到相应的控制。
发明内容
本发明所要解决的技术问题是：现有的治疗糖尿病微血管病变的方法主要通过在发生病变前期控制血糖、血脂、血压等指标进行预防，及发生病变后通过激光、冷凝或玻璃体切割等物理手段治疗，针对糖尿病微血管病变的治疗药物稀缺，本发明提供了解决上述问题的糖苷类化合物在制备防治糖尿病并发症的药物中的应用，尤其是利于治疗糖尿病微血管病变。本发明通过下述技术方案实现：
本发明提供了式(I)所示化合物、或其药学上可接受的盐、或其溶剂合物在制备防治糖尿病并发症的药物中的用途：
Figure PCTCN2019092383-appb-000001
其中，式(I)表示如下两个同分异构体结构：
Figure PCTCN2019092383-appb-000002
其中，R 1～R 7分别独立地选自H、C 1～C 6烷基、C 2～C 6链烯基或C 2～C 6炔基。
进一步地，所述化合物为式(II)所示的化合物：
Figure PCTCN2019092383-appb-000003
进一步地，所述化合物为式(III)所示的化合物或其对映或非对映异构体、或其外消旋体混合物、或其同位素体：
Figure PCTCN2019092383-appb-000004
进一步地，所述化合物为式(IV)所示的化合物或其对映或非对映异构体、或其外消旋体混合物、或其同位素体：
Figure PCTCN2019092383-appb-000005
进一步地，所述并发症是由1型糖尿病或2型糖尿病引起的并发症。
进一步地，所述并发症为微血管病变。
进一步地，所述微血管病变为肾脏病变和视网膜病变。
进一步地，所述药物的给药途径为：舌下含化、吸入、口服或注射。其中，注射包括皮内注射、皮下注射、肌肉注射和静脉注射。
本发明还提供了一种防治糖尿病并发症的药物组合物，它是以前述的化合物、或其药学上可接受的盐、或其溶剂合物为活性成分，加上药学上可接受的辅料制备而成的制剂。
本发明还提供了前述的化合物、或其药学上可接受的盐、或其溶剂合物在制备防治糖尿病并发症的食品、保健品或食品添加剂中的应用。
本发明中，“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
本发明中，“盐”是将化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明中，“同位素体”是指其中天然同位素丰度的至少一个原子被不同于天然丰度的同位素富集形式置换的化合物的任何形式。同位素体可以氢置换为氘和/或氚为基础。同样地，天然丰度的12C可被13C或14C置换，天然丰度的16O被17O或18O置换等或任何组合。可实现同位素富集到任何程度，包括1％、5％、10％、15％、20％、25％、30％、 35％、40％、45％、50％、60％、70％、80％、90％、95％、99％和100％富集，包括其中的任何值及其分数。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
本发明具有如下的优点和有益效果：
本发明的目的是提供一种糖苷类化合物在制备治疗糖尿病视网膜病变的药物中的应用：
所述化合物降血糖效果显著，对糖尿病有良好的治疗效果；
所述化合物有一定的降低UREA和CREA水平，减轻肾小球系膜或系膜细胞增生程度的趋势，有一定保护肾脏作用；同时，化合物可显著减轻视网膜神经节细胞层变性程度，说明化合物有减轻动物视网膜神经节细胞层变性作用。因此化合物对糖尿病动物的肾脏和视网膜具有一定程度的保护作用，具有良好的经济和社会价值。且对于治疗糖尿病病变的化合物用药与用量有关，化合物用量越多效果越好。
附图说明
此处所说明的附图用来提供对本发明实施例的进一步理解，构成本申请的一部分，并不构成对本发明实施例的限定。在附图中：
图1为本发明各组代表动物降血糖结果；
图2为本发明各组代表动物视网膜病理染色图片；
图3为本发明各组动物视网膜节细胞层评分；其中，*P<0.05，**P<0.01，***P<0.001vs.阴性对照组；
图4为各组代表动物肾脏病理染色图；
图5为各组动物肾脏肾小球病理评分情况。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明白，下面结合实施例和附图，对本发明作进一步的详细说明，本发明的示意性实施方式及其说明仅用于解释本发明，并不作为对本发明的限定。
实施例1、糖苷类化合物的药理活性
测定了H2(即(IV)式化合物)对自发Ⅱ型糖尿病db/db小鼠治疗作用的研究试验，具体试验和结果如下：
Figure PCTCN2019092383-appb-000006
该化合物可以通过文献《黄连水提液化学成分的分离与鉴定》(李雪改等，沈阳药科大学学报，2012年3月第29卷第3期，第193-198页)中报道的化合物15的制备方法得到。
1、试验遵循的法规：
《药品注册管理办法》(国家食品药品监督管理局局令第28号，2007年10月01日)；
《药物非临床研究质量管理规范》(国家食品药品监督管理局局令第2号，2003年09月01日)。
2、试验材料
2.1供试品
名称或代号：H2；
来源：成都中创蜀洋生物科技有限公司实验室；
性状：固体；
保存条件：≤-15℃，密闭干燥保存；
配制方法：蒸馏水配制；
配制后标识：注明试验编号、试验物质名称及浓度、配制体积、保存条件、有效期、责任人及配制日期等；
配制后暂存条件：2～8℃密闭保存；
配制后有效期：5天；
2.2对照品
名称或代号：二甲双胍；
来源：中美上海施贵宝制药有限公司；
性状：固体；
规格及浓度：0.5g/片；
批号：AAN0329；
保存条件：2℃～8℃，密闭干燥保存；
有效期：2018.11；
配制方法：蒸馏水配制；
配制后标识：注明试验编号、试验物质名称及浓度、配制体积、保存条件、有效期、责任人及配制日期等；
配制后暂存条件：2～8℃密闭保存；
配制后有效期：5天。
2.3溶剂对照品
名称或代号：蒸馏水；
配置后性状：无色澄明液体；
保存条件：2～8℃密闭保存；
配制后标识：注明试验编号、试验物质名称及浓度、配制体积、保存条件、有效期、责任人及配制日期等。
2.4其他主要试剂
葡萄糖注射液50％(湖北科伦药业有限公司产品，规格：20mL/支装，批号：B160915B)。
卓越金锐血糖试纸(Roche Diognostics GmbH公司产品，规格：100片试纸/盒、批号：475761)。
2.5主要仪器、器械
罗氏卓越精采型血糖仪(Roche Diognostics GmbH公司产品)。
3、试验系统
3.1试验动物
种属：db/db、db/m小鼠；
等级：SPF级；
使用动物数量和性别：db/db 72只(雄性)，db/m12只(雄性)；
年龄：约9周龄；
体重：db/m小鼠平均值26.7～34.0g，体重个体值在均数±20％范围内(试验开始时动物体重)，db/db小鼠平均值40.7～55.6g，体重个体值在均数±20％范围内(试验开始时动物体重)；
来源：常州卡文斯实验动物有限公司，生产许可证号：SCXK(苏)2016-0010。
3.2饲养管理
(1)环境适应
适应期主要检查结果：与订购时要求的质量指标一致；动物一般状态正常；动物体重达到试验要求的体重范围；不合格的异常动物未纳入本试验。
(2)饲养地点
华西海圻医药科技有限公司SPF区(第3栋)(实验动物使用许可证号：SYXK(川)2009-123)。
(3)饲养条件
饲养密度：≤5只/笼；
笼具空间位移频度：<1次/周。
(4)饲养环境条件
饲养环境条件标准：中华人民共和国国标GB14925-2010。
(5)饲料
种类：大小鼠维持饲料；
制造单位：上海斯莱克实验动物有限责任公司提供；
给料方法：自由摄取(试验有特殊要求时除外)；
营养成分检测：常规营养成分指标：粗蛋白、粗脂肪、粗纤维、粗灰分、水分、钙和磷；氨基酸指标：苏氨酸、胱氨酸+蛋氨酸、缬氨酸、异亮氨酸、亮氨酸、酪氨酸+苯丙氨酸、组氨酸、赖氨酸、精氨酸、色氨酸，参照中华人民共和国国家标准GB14924.3-2010；
饲料污染物含量的确认：化学污染物指标：砷、铅、镉、汞、六六六、滴滴涕、黄曲霉毒素B1、菌落总数、大肠菌群、霉菌和酵母菌数、致病菌(沙门氏菌)，参照中华人民共和国国家标准GB14924.2-2001。
(6)饮水
种类：实验动物饮用水(反渗透水)；
供水方法：饮水瓶盛装，自由摄取。
4、试验方法
4.1模型建立
db/db小鼠模型：血糖大于7.8mmol/L纳入2型糖尿病模型组(db/db模型组血糖最小值7.8mmol/L，显著高于db/m对照组平均值5.6)。
4.2动物分组
试验组别设计：db/m组，db/db小鼠分为以下六组：空白对照组(不给予葡萄糖)，阴 性对照组(模型组)，阳性对照组(350mg/kg二甲双胍)，H2低剂量组(40mg/kg)，H2中剂量组(80mg/kg)，H2高剂量组(160mg/kg)；
动物数量：每组12只；
性别：雄性；
分组方法：根据首次给药前所测得的空腹血糖进行随机分组，具体分组信息见下表1。
表1 动物分组情况表
Figure PCTCN2019092383-appb-000007
Figure PCTCN2019092383-appb-000008
Figure PCTCN2019092383-appb-000009
Figure PCTCN2019092383-appb-000010
4.3给药剂量
具体剂量设计见表2。
表2 给药设计表
Figure PCTCN2019092383-appb-000011
给药频率：每日一次，连续给药12周；db/m组、空白对照组及阴性对照组：给予蒸馏水；阳性对照组：给予阳性药二甲双胍；其他各给药组：分别给予不同剂量的受试药H2；给药当天定义为试验第1天。
5、统计分析与结果判定
所获数据采用EXCEL和IBM SPSS Statistics22进行数据分析。
先进行方差齐性检验，当方差齐时(P≥0.05)，采用重复测量方差分析(Repeated measures ANOVA)对血糖及体重的组别差异进行统计学检验，组别差异有统计学意义时(P<0.05)，采用单因素方差分析(ANOVA)中的LSD法对各时间点的组间差异进行比较；重复测量方差分析显示组间差异无统计学意义时(P≥0.05)，则统计分析结束。当方差不齐时(P<0.05)，采用Kruskal-Wallis H秩和检验(K-W法)进行统计分析。当Kruskal-Wallis H秩和检验显示差异有统计学意义时(P<0.05)，则采用Mann-Whitney U检验(M-W法)对各时间点组间差异进行比较；当Kruskal-Wallis H秩和检验显示差异无统计学意义时(P≥0.05)，统计分析结束。
其他指标均数的组别差异，当方差齐时(P≥0.05)，采用单因素方差分析(ONE-WAY ANOVA)对组别差异进行统计学检验，组别差异有统计学意义时(P<0.05)，采用LSD法对组间差异进行比较；单因素方差分析显示组间差异无统计学意义时(P≥0.05)，则统计分析结束。当方差不齐时(P<0.05)，采用Kruskal-Wallis H秩和检验(K-W法)进行统计分析，当 Kruskal-Wallis H秩和检验显示差异有统计学意义时(P<0.05)，则采用Mann-Whitney U检验(M-W法)对组间差异进行比较；当Kruskal-Wallis H秩和检验显示差异无统计学意义时(P≥0.05)，统计分析结束。
6、试验结果
6.1降血糖效果检测
采集频率：分组后每2周测定血糖1次，接着测定给葡萄糖后，采样部位：尾静脉，采样量：约1滴，血糖检测：血糖仪实时检测。
动物各组血糖如表3和图1所示。给药期间，空白对照组、阴性对照组小鼠血糖呈上升趋势。与阴性对照组相比，阳性药二甲双胍组从给药15天开始血糖值极显著低于阴性对照组(P＜0.001)，说明阳性药物能显著降低db/db小鼠血糖；低剂量受试药H2无明显降糖效果，中剂量组血糖值从给药15天开始极显著低于阴性对照组(P＜0.01)、给药72天时血糖极显著低于阴性对照组(P＜0.001)，受试药H2高剂量组小鼠血糖给药43天开始血糖值极显著低于阴性对照组，为(20.84±0.66)vs(13.87±1.76)mmol/L(P＜0.01)，而给药第57天上述改变更为明显，为(23.46±1.87)vs(13.07±1.71)mmol/L(P＜0.001)。db/m组小鼠的血糖在整个试验过程中无明显改变且显著低于其他各组。说明阳性药与受试药高剂量组的降血糖效果相当，甚至优于受药高剂量组的降血糖效果。
表3 各组血糖测定值(MEAN±SEM，单位mmol/L)
Figure PCTCN2019092383-appb-000012
备注：*P<0.05，**P<0.01，***P<0.001vs.阴性对照组。
6.2防治视网膜病变效果
在该试验周期内，与正常对照组动物相比，除受试药H2高剂量组外，其余各组动物的视网膜节细胞层均发生不同程度变性。根据视网膜节层细胞变性严重程度，病理分级原则标准参照文献(Fermented Milk has Anti-diabetic Effects:Anti-diabetic Effect of Fermented Milk Containing ConjugatedLinoleic Acid on Type II Diabetes Mellitus，Korean J.Food Sci.An.,Vol.36,No.2(2016).)分为0～4级，数值越大说明病变程度越重。各组动物视网膜节细胞层变性分级评分详见表4以及图2～3所示。
表4 动物眼球病理染色结果
Figure PCTCN2019092383-appb-000013
Figure PCTCN2019092383-appb-000014
Figure PCTCN2019092383-appb-000015
注：“N”代表组织形态结构正常；“E”代表组织形态结构有改变；“-”代表无该病变。
在该试验周期内，db/m组(有1只动物视网膜节细胞层异常，可能是标本制片导致)和受试药H2高剂量组动物网膜神经节细胞层形态正常，其余db/db各组动物网膜神经节细胞层均有不同程度的变性；与阴性对照组相比，采用二甲双胍阳性药几乎没有改善视网膜病变症状，而本发明提供的H2具有良好的改善视网膜病变的作用，且随着H2给药剂量的提高，效果显著增加，最终受试药H2高剂量显著减轻了视网膜神经节细胞层变性程度(P<0.05)，说明受试药H2有治疗动物视网膜节细胞层变性的功效。在连续给药12周后，db/db小鼠各组均未见明显异常反应，体重组间差异无统计学意义，大体解剖未见明显异常，说明受试药对动物无明显毒副性作用。
6.3防治肾功能的影响
(1)给药前后血尿素氮(UREA)、血肌酐(CREA)变化及肾脏指数
给药前后血肌酐(CREA)变化及肾脏指数变化如表5所示。
给药前db/m组尿素氮(UREA)显著低于db/db组(P<0.05)，与阴性对照组相比，阳性药组和受试药H2各剂量组UREA无统计学差异；给药12周后，与阴性对照组相比，受试药H2中剂量能极显著降UREA水平(P<0.001)其余各组均无显著差异。UREA变化率显示，与阴性对照组相比，受试药H2有降低UREA的趋势，且受试药H2中剂量趋势更明显。
给药前各组血肌酐(CREA)无明显差异(P≥0.05)。给药12周后，与阴性对照组相比，阳性药有降低CREA的趋势，但无统计学差异；受试药H2有降低CREA的趋势，且受试药H2中剂量能显著降CREA水平(P<0.05)。CREA变化率显示，与阴性对照组相比，正常对照组CREA变化率显著降低(P<0.05)；阳性药和受试药H2有降低CREA的趋势，且受试药H2效果更为显著，且受试药H2低剂量显著性降低了CREA变化率。
db/m组肾脏指数极显著的高于db/db组(P<0.001)，db/db各组之间无显著差异。
表5 给药前后血肌酐(CREA)变化及肾脏指数(MEAN±SEM)
Figure PCTCN2019092383-appb-000016
备注：*P<0.05，**P<0.01，***P<0.001vs.阴性对照组。
(2)治疗后肾脏病理的变化
试验结束后解剖取肾脏，肾脏组织病理结果显示，分级原则标准参照文献(Fermented Milk has Anti-diabetic Effects:Anti-diabetic Effect of Fermented Milk Containing ConjugatedLinoleic Acid on Type II Diabetes Mellitus，Korean J.Food Sci.An.,Vol.36,No.2(2016).)。各组动物肾脏分级评分详见表6和图4所示。肾脏组织病理染色见图5所示。
在该试验周期内，与db/m相比，db/db各组动物肾脏肾小球系膜或系膜细胞均有增生(P<0.001)，阳性药和受试药H2高剂量有减轻肾小球系膜或系膜细胞增生程度的作用趋势，但与阴性对照组相比，不具有统计学差异。
表6 各组动物肾脏分级评分结果
Figure PCTCN2019092383-appb-000017
Figure PCTCN2019092383-appb-000018
Figure PCTCN2019092383-appb-000019
注：“N”代表组织形态结构正常；“E”代表组织形态结构有改变；“-”代表无该病变。
实施例2、
将上述糖苷类化合物经合理配方及制备方法加入任意食品、食品添加剂或制成保健品，用于防治糖尿病并发症均属于本申请保护范围。
以上所述的具体实施方式，对本发明的目的、技术方案和有益效果进行了进一步详细说明，所应理解的是，以上所述仅为本发明的具体实施方式而已，并不用于限定本发明的保护范围，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 式(I)所示化合物、或其药学上可接受的盐、或其溶剂合物在制备防治糖尿病并发症的药物中的用途：
    Figure PCTCN2019092383-appb-100001
    其中，R 1～R 7分别独立地选自H、C 1～C 6烷基、C 2～C 6链烯基或C 2～C 6炔基。
  2. 根据权利要求1所述的用途，其特征在于：所述化合物为式(II)所示的化合物：
    Figure PCTCN2019092383-appb-100002
  3. 根据权利要求1所述的用途，其特征在于：所述化合物为式(III)所示的化合物或其对映或非对映异构体、或其外消旋体混合物、或其同位素体：
    Figure PCTCN2019092383-appb-100003
  4. 根据权利要求3所述的用途，其特征在于：所述化合物为式(IV)所示的化合物或其对映或非对映异构体、或其外消旋体混合物、或其同位素体：
    Figure PCTCN2019092383-appb-100004
  5. 根据权利要求1所述的用途，其特征在于：所述并发症是由1型糖尿病或2型糖尿病引起的并发症。
  6. 根据权利要求5所述的用途，其特征在于：所述并发症为微血管病变。
  7. 根据权利要求6所述的用途，其特征在于：所述微血管病变为肾脏病变和视网膜病变。
  8. 根据权利要求1所述的用途，其特征在于：所述药物的给药途径为：舌下含化、吸入、口服或注射。
  9. 一种防治糖尿病并发症的药物组合物，其特征在于：它是以权利要求1～4任一项所述的化合物、或其药学上可接受的盐、或其溶剂合物为活性成分，加上药学上可接受的辅料制备而成的制剂。
  10. 权利要求1～4任一项所述的化合物、或其药学上可接受的盐、或其溶剂合物在制备防治糖尿病并发症的食品、保健品或食品添加剂中的应用。
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