WO2009155753A1 - 肌醇衍生物或其盐在制备糖苷酶抑制剂药物或治疗糖尿病药物中的用途 - Google Patents

肌醇衍生物或其盐在制备糖苷酶抑制剂药物或治疗糖尿病药物中的用途 Download PDF

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WO2009155753A1
WO2009155753A1 PCT/CN2008/072123 CN2008072123W WO2009155753A1 WO 2009155753 A1 WO2009155753 A1 WO 2009155753A1 CN 2008072123 W CN2008072123 W CN 2008072123W WO 2009155753 A1 WO2009155753 A1 WO 2009155753A1
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inositol
medicaments
inhibition
inositol derivative
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PCT/CN2008/072123
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English (en)
French (fr)
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孙明杰
王霆
舒向荣
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广州威尔曼新药开发中心有限公司
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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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • 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

Definitions

  • the invention relates to the use of inositol and inositol derivatives, in particular to the use in the pharmaceutical field. Background technique
  • Diabetes is one of the most common chronic diseases. With the improvement of people's living standards, the aging of the population and the increase in the incidence of obesity, the incidence of diabetes is increasing year by year.
  • the disease is caused by genetic and environmental factors, causing absolute or relative lack of insulin secretion and decreased sensitivity of target tissue cells to insulin, causing a series of metabolic disorders such as protein, fat, water and electrolytes, of which hyperglycemia is the main marker. .
  • Type 1 diabetes ie, absolute insulin deficiency caused by destruction of islet cells, also known as insulin-dependent type - IDDM
  • type II diabetes due to insulin resistance and insufficient insulin secretion, also known as non-insulin dependence Type - NIDDM
  • the general treatment methods for diabetes are diet therapy, insulin therapy, oral hypoglycemic agents and traditional Chinese medicine therapy, among which oral hypoglycemic agents occupy a dominant position in the treatment of type I I.
  • Oral hypoglycemic agents are mainly sulfonylureas, biguanides and glycosidase inhibitors.
  • the side effect of the glycosidase inhibitor is small, and the mechanism of action is to competitively inhibit the glycosidase in the proximal epithelial cells of the small intestine brush border, delay the digestion and absorption of carbohydrates, and delay the disaccharide, oligosaccharide and polysaccharide. Absorption, delay to reduce the increase in postprandial blood glucose.
  • Glycosidases include amylase, maltase, and sucrase, and are responsible for the conversion of polysaccharides into monosaccharides in the body.
  • the study of its inhibitors began with the wild scorpionmycin of the 1960s, and new inhibitors were subsequently discovered, mostly alkaloids.
  • INOSITOL also known as cyclohexanol, molecular formula: C 6 H 12 0 6 , molecular weight: 180. 16, months
  • stereoisomers of alcohol which are cis-inos i to epi- inositols muco-inos i tol, allo-inositol, myo-inos i tol, neo-inos i tol, scyl lo-inos i tol , L-chrio-inositol and D_chrio_inositol.
  • Inositol is mainly used in the following areas:
  • inositol As food fortification additives, nutrients, health drinks, children's foods are added with inositol, inositol is a biological activity, is an indispensable ingredient in the organism. If higher animals lack inositol, they will grow stagnant, hair will fall off, and their physiological activities will be out of balance. The daily intake of inositol in humans is 1-2 grams.
  • cisplatin also known as sequoyitol
  • sequoyitol is more common, and its structure is as follows:
  • cetroxol The activity of cetroxol is manifested in two aspects: First, for rapidly dividing tumor cells, cetromethoxol freezes the mitotic spindle, thereby stopping tumor cells in G2 and M stages until death. The second is to inhibit the migration of tumor cells. Citamin alcohol is known to be widely used clinically as an antitumor drug.
  • the inventors have found through extensive experiments that the inositol derivative of the structure shown below has a glycosidase inhibitory effect, and the mother nucleus has a six-membered ring structure.
  • R may be _0_ or -NH - or _ ⁇ , may be a saturated chain alkyl group _C n H 2n _ (( n 26 ), R 2 is ⁇ , -CH 3 , - C00H, a cyclic alkyl group - C n H 2n - - ( n > 3 ), phenyl or fluorenylphenyl, etc. wherein ⁇ is preferably a d - 4 saturated chain alkyl group.
  • the inventors have also found that even if the molecular formula is the same, the spatial stereostructure is different, and the inhibition thereof The effect is also different.
  • the preferred stereostructure of the mother nucleus is 5-myo-, further preferably R is -supplement or -0-, most preferably Ri n is 0, and R 2 is -CH 3 .
  • the present invention provides the use of the above inositol derivative or a salt thereof for the preparation of a glycosidase inhibitor or a medicament for treating diabetes.
  • the above inositol derivative or a salt thereof can be used as a glycosidase inhibitor in vitro, and can also be used for the prevention and treatment of diabetes, and is particularly suitable for the treatment of type II diabetes, and the amount of administration varies depending on the active ingredient of the drug.
  • the effective amount of daily inhibitor content of 150-45 Omg is appropriate, the course of treatment according to the severity of the disease, usually 300mg; three times a day, each time 100mg.
  • the above inositol derivative or a salt thereof may also be combined with a sulfonylurea drug, a biguanide hypoglycemic agent, an ⁇ -glucosidase inhibitor, an insulin sensitizer, an insulin secretagogue, an insulin or a proprietary Chinese medicine, and the like.
  • Hypoglycemic drugs are used in combination in the treatment of diabetes.
  • the amount of the above glycosidase inhibitor and other therapeutic drugs for treating diabetes can be used according to the degree of different individual diseases, for example, the above-mentioned drugs and the glycosidase inhibitor of the present invention are used in combination of 1:10 - 1:15 by weight.
  • the above sulfonylurea drug may be selected from the group consisting of Glipizide, Gliquidone, Gl iclazide, Glimepiride, Glyburide (Glibenclamide) or Tolbutamide;
  • the above-mentioned biguanide hypoglycemic agent can be selected from Metformin;
  • ⁇ -glucosidase inhibitor can be selected from Acarbose or Voglibose ( Voglibose);
  • Incretin secretion agent can be selected from Repaglinide or Nateglinide Starlix 0
  • the glycosidase inhibitor drug or the diabetes therapeutic drug can be prepared into an orally administered preparation, an inhalation preparation, a suppository or an injection preparation.
  • the oral preparation is an active ingredient mixed with a conventional pharmaceutical adjuvant such as an excipient, a disintegrating agent, a binder, a lubricant, an antioxidant, a coating agent, a coloring agent, a fragrance, a surfactant, etc., using conventional
  • a conventional pharmaceutical adjuvant such as an excipient, a disintegrating agent, a binder, a lubricant, an antioxidant, a coating agent, a coloring agent, a fragrance, a surfactant, etc.
  • the preparation technique is prepared into an oral preparation such as granules, capsules, tablets, etc.
  • an inhalation preparation, a suppository or an injection preparation can also be prepared by adding an auxiliary agent by a conventional method.
  • Figure 1 is a graph showing the inhibitory effect of different concentrations of acarbose on o-glucosidase.
  • Figure 2 is a graph showing the inhibitory effect of different concentrations of acarbose on oc-amylase.
  • Figure 3 is a graph showing the inhibitory effect of different concentrations of acarbose on glucoamylase.
  • Figure 4 is a graph showing the inhibitory effect of different concentrations of acarbose on glucoamylase.
  • Figure 5 is a graph showing the inhibition type of acarbose to oc-glucosidase.
  • Figure 6 is a graph showing the inhibition of oc-amylase by acarbose.
  • Figure 7 is a graph showing the inhibition of glucoamylase by acarbose.
  • Figure 8 is a graph showing the inhibitory effect of different concentrations of cetroxol on oc-glucosidase.
  • Fig. 9 is a graph showing the inhibitory effect of different concentrations of cetroxol on ⁇ -galactosidase.
  • Figure 10 is a graph showing the inhibition type of octetilol against oc-glucosidase.
  • Figure 11 is a graph showing the inhibition of ⁇ -galactosidase by cetroxol.
  • Figure 12 is a graph showing the inhibitory effect of inositol on oc-glucosidase at different concentrations.
  • Figure 13 is a graph showing the inhibition type of ⁇ -galactosidase by the inositol.
  • Figure 14 is a graph showing the inhibitory effect of different concentrations of pine alcohol on glucoamylase.
  • Figure 15 is a graph showing the inhibition of glucoamylase by pinitol.
  • Figure 16 is a structural diagram of nine inositol isomers. detailed description
  • Experimental Example 1 was used to analyze the inhibitory effect of inositol and its derivatives on glycosidase in different configurations, further indicating that the stereoconfiguration is different, and the inhibitory effect of glycosidase is also different. When the substituents are different, the inhibitory effect is different.
  • Experimental Example 2 verified the hypoglycemic effect of inositol derivatives;
  • Experimental Example 3 verified that inositol derivatives significantly reduced adrenaline-induced hyperglycemia;
  • Experimental Example 4 verified that inositol derivatives can reduce alloxan induction High blood sugar, elevated serum insulin, lower serum triglyceride and cholesterol levels.
  • Test method The substances to be tested described below refer to citrofloxacin, mesoinositol and pinitol.
  • the ⁇ -glucosidase (EC 3.2.1.20) inhibition assay the substrate was p-nitrophenyl-a-D-glucopyranoside Sigma N1377 (PNPG), and the activity was calculated from the release amount of PNP.
  • PNPG p-nitrophenyl-a-D-glucopyranoside Sigma N1377
  • control drug acarbose
  • substance to be tested were configured in a series concentration (acarbose was 15.2, 5.07, 1.69, 0.56, 0.19, 0.02 mg/mL, and the substances to be tested were 100, 10, 1, 0.1, 0. Olmg / mL concentration), take lOuL; ⁇ _glucosidase into lU / ml, take 10uL, respectively, into a 96-well plate containing 10uL PNGP (20mmol / L), 160uL pH7.0 buffer, The mixture was incubated at 37 ° C for 15 minutes, 10 uL, lmol / L Na 2 C0 3 was added to terminate the reaction, and 405 was allowed to measure the absorbance. Calculate IC 5 . value.
  • ⁇ -glucosidase (EC 3.2.1.21), the substrate is PNPG, and the activity is calculated as the amount of PNP released.
  • concentration of acarbose and the substance to be tested is configured (acarbose is 100, 10, 1, 0.1,
  • test substances are 100, 10, 1, 0.1, 0.01mg/mL concentration), take 10uL; ⁇ -glucosidase is formulated into 2.5U/ml, take lOuL, respectively, and add 10uL PNGP (25mmol/L),
  • Alpha-galactosidase (EC 3.2.1.22), substrate selected PNPG, and enzyme activity was calculated by measuring the amount of PNP produced.
  • the concentration of acarbose and the substance to be tested is configured (the acarbose and the substance to be tested are both 100, 10,
  • ⁇ -galactosidase (EC 3.2.1.23), and the substrate was selected from o-nitrophenyl- ⁇ -D-galactopyranoside (0NPG), and the enzyme activity was calculated by measuring the amount of 0NP produced.
  • the acarbose and the test substance are configured in a series concentration (all acarbose and the test substance are 100, 10, 1, 0.1, 0.01 mg/mL), and 10 uL; ⁇ -D-galactosidase is formulated. 20U/ml, 10uL, added to a 96-well plate containing lOuL 0NGP (50mmol / L), 160uL pH7.0 buffer, incubated at 37 ° C for 15 minutes, added lOuL, lmol / L Na 2 C0 3 termination Reaction, absorbance was measured at 405 nm. Calculate IC 5 . value.
  • the substrate is selected from soluble starch.
  • Glucose amylase (EC 3.2.1.3), the substrate is selected from starch solution.
  • sucrose (EC 3.2.1.26), substrate 5% sucrose solution.
  • Trehalase (EC 3.2.1.28), substrate 5% trehalose solution.
  • Group 1 The inhibition of glycosidase by acarbose
  • Acarbose has an inhibitory effect on o-glucosidase, o-amylase, glucoamylase and sucrase, its IC 5 .
  • the values were 0.132, 0.047, 0.001, and 0.185 mmol/L, respectively, which were competitive inhibitions, with Ki of 0.74, 1.64, and 0.001 mmol/L, respectively.
  • Ki 0.74, 1.64, and 0.001 mmol/L
  • Cetirizine has an inhibitory effect on oc-glucosidase and ⁇ -D-galactosidase, and its IC 5 .
  • the values were 0.962 mmol/L and 25.77 mmol/L, respectively, which were competitive inhibition.
  • the inhibition of ⁇ -amylase, glucoamylase and trehalase at 5 mg/ml was 14%, 30% and 15%, respectively.
  • the Ki for oc-glucosidase and ⁇ -galactosidase were 5.733 mmol/L and 11.51 mmol/L, respectively.
  • the experimental data is processed in Figure 8-11.
  • Neutitol has a certain inhibitory effect on oc-glucosidase, its IC 5 .
  • the value is 5.303 mM, which is competitive inhibition.
  • the inhibition of oc-galactosidase at 29 mg/ml was 29%.
  • the Ki for oc-glucosidase was: 18.620 mmol/L.
  • the experimental data is processed in Figure 12-13.
  • Antagonistic IC 5 of glucoamylase The value of 2. 1 ⁇ 2 mol/L, 5 mg/ml inhibited ⁇ -glucosidase and trehalase by 16% and 26%, respectively, for ⁇ -glucosidase, oc-galactosidase, ⁇ _ Galactosidase, oc-amylase, sucrase and trehalase have no inhibitory effects.
  • the type of inhibition of glucoamylase was non-competitive inhibition, and Ki was 9.2 ⁇ ol/L.
  • the experimental data is processed in Figure 14 - 15. The above data sets are organized into the following table:
  • the inhibitory activity was determined, and the experimental data of the obtained series of derivatives were as follows:
  • Drugs and reagents cetromethoxine, wm0624, hypoglycemic, 50% glucose injection, glucose determination kit, the above reagents are commercially available.
  • mice were randomly divided into 9 groups, 7 of which were orally administered with m. lmg/l Og body weight, wm0624, cetromethoxol 25, 50, 100 mg/kg and hypoglycemic 75 mg/kg, normal.
  • the group and the model group (control group) were given an equal volume of distilled water for 7 consecutive days.
  • 5 ⁇ ie, all the rats were given a dose of cisplatin and water, and then fasted for 2.
  • 5h that is, all the rats were fasted for 1. 5h, then fasted for 2.
  • 5h that is, all The mice were fasted for 10 h.
  • mice were intraperitoneally injected with 2g/kg of glucose, and the normal group was injected with the same volume of normal saline. After 30, 60, 90, 120 minutes after injection, the mice were bled with blood from the venous plexus, and the serum was separated and oxidized by glucose. Enzymatic determination of blood sugar.
  • RESULTS As shown in Table 3, compared with the normal group, the blood glucose of the model group was significantly increased at 30, 60, 90, and 120 minutes after intraperitoneal injection of glucose. Compared with the model group, wm0624 and citrofloxacin in the low-dose and middle-dose groups significantly reduced glucose-induced hyperglycemia 30, 60, 90, and 120 minutes after intraperitoneal injection of glucose; wm0624 and citrofloxacin high-dose group And the hypoglycemic group significantly reduced glucose-induced hyperglycemia at 30, 60, 90, and 120 minutes after intraperitoneal injection of glucose; the effect of hit 0624 and cetroxol was dose-dependent, touching 0624 with cetromethorone 100 mg/ The hypoglycemic effect of kg is equivalent to that of hypoglycemic 75 mg/kg.
  • Model group 1 12 238. 1 ⁇ 56. 205. 7 ⁇ 23. 162. 9 ⁇ 11. 140. 9 ⁇ 11.
  • mice were randomly divided into 6 groups, 4 of which were orally administered with octreotol 25, 50, 100 mg/kg and glibenclamide 10 mg/kg, respectively.
  • the model group was given an equal volume of distilled water for 7 consecutive days. After the last administration, fasting hypoglycemic was given for 1 hour, and then fasted for 5 hours. After the other groups were fasted for 3 hours, the doses of cisplatin and water were given respectively, and then fasted for 3 hours. After fasting for 6 hours, except for the normal group, the same volume of normal saline was injected, and the other groups were injected with epinephrine 0.2 mg/kg intraperitoneally. 30 minutes after the injection, the mice were decapitated and the serum was separated and determined by glucose oxidase method. blood sugar. At the same time, the liver was taken and the liver glycogen was measured by the anthrone method.
  • results As shown in Table 4, the blood glucose of the model group was significantly higher than that of the normal group. Compared with the model group, the cisplatin group and the glibenclamide group significantly reduced adrenaline-induced hyperglycemia. Simultaneously, The liver glycogen of the model group was significantly reduced. Compared with the model group, the low-dose hepatic glycogen content was significantly increased in the low-dose and high-dose groups of cetroxol, and the low dose of hepatic glycogen was significantly increased in the middle dose group and the glibenclamide group. Table 4 Effect of cetriol and glibenclamide on blood glucose elevation in adrenaline-induced mice
  • the model group was compared with the normal group # # ⁇ 0. 01 ; citreol and glibenclamide were compared with the model group, * ⁇ 0.05, ** ⁇ 0. 01
  • Experimental Example IV citrate Effect of alloxan diabetes model rats
  • mice 9 rats were randomly selected as the normal group, and the remaining 74 rats were fasted for 14-16 hours, intraperitoneal injection of pentobarbital sodium 30mg/kg, anesthesia followed by intravenous injection of alloxan 48mg/kg, injection four After 96 hours of oxypyrimidine, blood was taken from the venous plexus of the eyelid to predict blood sugar, and the removal did not cause diabetes (hyperglycemia), that is, the blood glucose level was less than 200 mg/dl after fasting for 10 hours.
  • diabetes hyperglycemia
  • the blood glucose level it was divided into 5 groups, 11 in each group, 4 of which were orally administered with citrate alcohol 25, 50, 100 mg/kg and Jiangtangling 75 mg/kg according to lml/100 g body weight.
  • the normal group and the model group were given the same volume.
  • the distilled water was measured for 18 days, and the fasting blood glucose was measured on the 6th and 12th day after the administration, that is, the Jiangtangling group was fasted for 8 hours, and then fasted for 2 hours.
  • the other groups were given the dose of cetroxol after fasting for 7 hours. And an equal volume of water.
  • blood was collected from the posterior venous plexus, serum was separated, and blood glucose was measured by the glucose oxidase method.
  • the two pathology researchers read the film separately, according to the degree of each lesion, recorded as "-”, “+”, “++”, “+++”, respectively, converted to "0,,,,,,1” , "2", "3" points, calculate the average integral value of each group.
  • the fasting blood glucose of the model group was significantly higher than that of the normal group.
  • the low-dose group of cetroxol had a tendency to reduce the induction of hyperglycemia by alloxan on the 12th day after administration, and significantly reduced the hyperglycemia induced by alloxan on the 18th day.
  • the cisplatin middle dose group, the high dose group and the Jiangtangling group significantly reduced alloxan-induced hyperglycemia on the 6th +1 day after administration, and the hypoglycemic effect of cetroxol was dose-dependent.
  • wm0612 weigh 50g of wm0612, 230g of microcrystalline fiber, 20g of talc powder; place microcrystalline fiber and talc in the grinder, then add it to 0612, grind and mix for 20-30 minutes, until the hook Then, it is filled in No. 1 capsule, and the random sampling is controlled at about 300 mg per pellet.
  • 20 tablets were randomly selected, and the average loading error of each of the loadings relative to 20 capsules was not more than 20%, and the error of any one of the loadings exceeding 10% was not more than 20%.
  • wm0621 weigh 50g of wm0621, 180g of microcrystalline fiber, 47g of starch, 3g of polyvinylpyrrolidone, 20g of talc; half of the microcrystalline fiber, starch and talc are placed in the grinder, then wm0621 is added. Grind and mix for 30 minutes until well mixed. Then add the other half of the milled microcrystalline fiber and the polyvinylpyrrolidone dissolved in a small amount of water, mix thoroughly, and then open it into the oven (60 ° C) until it is dry and form a pellet. The resulting particulate material was tableted so that each tablet weighed about 300 mg. 20 of them were randomly selected, and the weight of each piece was determined to be no more than 7.5% relative to the average piece weight of 20 pieces.

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Description

肌醇衍生物或其盐在制备糖苷酶抑制剂药物或治疗糖尿病药物中的用途
本申请要求于 2008 年 6 月 25 日提交中国专利局、 申请号为 200810126340.3、 发明名称为 "肌醇衍生物或其盐在制药中的用途" 的中国专 利申请的优先权， 其全部内容通过引用结合在本申请中。 技术领域
本发明涉及肌醇及肌醇衍生物的用途， 尤其涉及在制药领域中的用途。 背景技术
糖尿病是最常见的慢性病之一。 随着人们生活水平的提高，人口老龄化以 及肥胖发生率的增加，糖尿病的发病率呈逐年上升趋势。 此病是由于遗传和环 境因素相互作用，引起胰岛素绝对或相对分泌不足以及靶组织细胞对胰岛素敏 感性降低， 引起蛋白质、 脂肪、 水和电解质等一系列代谢紊乱综合征， 其中高 血糖为主要标志。
糖尿病患者中 I型糖尿病（即胰岛细胞破坏而导致的胰岛素绝对缺乏， 也 称胰岛素依赖型—— IDDM ) 占 10%, I I型糖尿病 (由于胰岛素抵抗并胰岛素分 泌不足所致， 亦称非胰岛素依赖型—— NIDDM ) 占 90%。
目前糖尿病的一般治疗方法为饮食疗法、胰岛素疗法、 口服降糖药和中医 药疗法等， 其中在 I I型的治疗中口服降糖药占有主要地位。 口服降糖药主要 有磺脲类、 双胍类和糖苷酶抑制剂等。 其中以糖苷酶抑制剂副作用为小， 其作 用机理是竟争性地抑制小肠刷状缘的近腔上皮细胞内的糖苷酶，延緩碳水化合 物的消化吸收， 延迟双糖、 低聚糖和多糖的吸收， 延迟减轻餐后血糖的升高。 糖苷酶包括淀粉酶、 麦芽糖酶和蔗糖酶等，在体内承担将多糖转化为单糖的功 能。 其抑制剂的研究始于 60年代的野尻霉素， 其后不断发现新的抑制剂， 大 多为生物碱类。
月几醇 （ INOSITOL ), 又名环己六醇， 分子式： C6H1206,分子量： 180. 16, 月几 醇立体异构体有 9种,分另 ll为 cis-inos i to epi- inositols muco-inos i tol、 allo-inositol 、 myo-inos i tol 、 neo-inos i tol 、 scyl lo-inos i tol 、 L-chrio-inositol和 D_chrio_inositol。 肌醇主要用于以下方面：
1、 医药工业上： 目前多用于治疗肝硬化症、 脂肪肝、 肝炎、 血管硬化、 胆固醇过高等症， 可以制成烟酸肌醇脂，脉通等药物， 也是制造复合维生素的 原料。
2、 营养保健品和化妆品方面： 作为食品强化添加剂、 营养剂， 保健饮料、 儿童食品都加有肌醇， 肌醇是一种生物活素， 是生物体中不可缺少的成分。 高 等动物若缺少肌醇， 会出现生长停滞， 毛发脱落， 体内生理活动失去平衡。 人 体每天肌醇的摄入量为 1-2克。
肌醇衍生物中以西曲依醇（又名红杉醇， sequoyitol )比较多见， 其结构 下：
Figure imgf000004_0001
西曲依醇的活性表现在两个方面： 一是对迅速分裂的肿瘤细胞， 西曲依醇 冻结有丝分裂纺锤体， 从而使肿瘤细胞停在 G2期和 M期， 直至死亡。 二是抑 制肿瘤细胞的迁移。 西曲依醇已知作为抗肿瘤药物在临床上广泛应用。
发明内容
本发明的目的在于提供肌醇衍生物或其盐的新用途， 即在制药中的新用 途。 发明人经过大量的实验， 发现下图结构的肌醇衍生物具有糖苷酶抑制作 用， 其母核为六元环结构。
Figure imgf000005_0001
其中， R可以是 _0_或- NH -或 _ \ , 可以是饱和链式烷基 _CnH2n_ ( ( n 26 ), R2是 Η、 - CH3、 - C00H、 环形烷基- CnH2n - - ( n > 3 ), 苯基或曱苯基等。 其中 ^优选 d - 4饱和链式烷基。 发明人研究还发现即使分子式相同，但空间立体结构不同， 其抑制效果也 不尽相同。 其中优选的母核立体结构为 5-myo-, 进一步优选 R为-應-或 -0-, 最优选 Ri n为 0, R2为 -CH3。 最优选的立体结构为：
Figure imgf000005_0002
鉴于上述发现， 本发明提供了上述肌醇衍生物或其盐在制备糖苷酶抑制 剂类药物或治疗糖尿病药物中的应用。
上述肌醇衍生物或其盐在体外可用作糖苷酶抑制剂使用，也可用于糖尿病 的预防和治疗， 尤其适用于 I I型糖尿病的治疗， 给药量因药物活性组分的不 同有所不同， 对成人来说， 釆用各制剂的常规使用方法， 有效量以每天抑制剂 含量 150-45 Omg比较合适， 疗程根据病情轻重酌情考虑， 一般为 300mg; 每天 三次， 每次 100mg。
上述上述肌醇衍生物或其盐还可和磺酰脲类药物、 双胍类降糖药、 α -葡 萄糖苷酶抑制剂、 胰岛素增敏剂、 促胰岛素分泌剂、 胰岛素类或中成药等其它 降糖药物联合应用于糖尿病的治疗。上述糖苷酶抑制剂和其它治疗糖尿病药物 的使用量可根据不同个体病情程度酌量使用，如上述药物与本发明糖苷酶抑制 剂按重量配比为 1: 10 - 1: 15联合应用。
其中， 上述磺酰脲类药物可选自格列吡嗪 （ Glipizide )、 格列喹酮 (Gliquidone), 格列齐特（ Gl iclazide )、 格列美脲（ Gl imepir ide )、 格列本 脲（Glibenclamide)或曱苯横丁脲 (Tolbutamide ); 上述双胍类降糖药可选 用二曱双胍（Metformin); α _葡萄糖苷酶抑制剂可选用阿卡波糖（Acarbose) 或伏格列波糖 (Voglibose); 促胰岛素分泌剂可选用瑞格列奈（Repaglinide) 或那格列奈 (胺） (NateglinideStarlix )0
所述糖苷酶抑制剂类药物或治疗糖尿病药物可制备成经口给药的制剂、 吸入制剂、栓剂或注射制剂。口服制剂是活性组分与常规的药用辅剂如赋形剂、 崩解剂、 粘合剂、 润滑剂、 抗氧化剂、 包衣剂、 着色剂、 芳香剂、 表面活性剂 等混合， 使用常规的制剂技术将其制备成颗粒剂、 胶嚢、 片剂等口服制剂； 同 样， 吸入制剂、 栓剂或注射制剂也可加入辅剂釆用常规的方法制得。
为了更好的理解本发明的本质，下面将在具体实施例中详细说明上述肌醇 衍生物对糖苷酶的抑制效果及动物试验中的降糖效果，以说明其在制药领域中 的新用途。 附图说明
图 1为不同浓度阿卡波糖对 o-葡萄糖苷酶的抑制效果图。
图 2为不同浓度阿卡波糖对 oc-淀粉酶的抑制效果图。
图 3为不同浓度阿卡波糖对葡萄糖淀粉酶的抑制效果图。
图 4为不同浓度阿卡波糖对葡萄糖淀粉酶的抑制效果图。
图 5为阿卡波糖对 oc-葡萄糖苷酶的抑制类型图。
图 6为阿卡波糖对 oc-淀粉酶的抑制类型图。
图 7为阿卡波糖对葡萄糖淀粉酶的抑制类型图。
图 8为不同浓度西曲依醇对 oc-葡萄糖苷酶的抑制效果图。
图 9为不同浓度西曲依醇对 β -半乳糖苷酶的抑制效果图。 图 10为西曲依醇对 oc-葡萄糖苷酶的抑制类型图。
图 11为西曲依醇对 β_半乳糖苷酶的抑制类型图。
图 12为不同浓度中肌醇对 oc-葡萄糖苷酶的抑制效果图。
图 13为中肌醇对 β_半乳糖苷酶的抑制类型图。
图 14为不同浓度松醇对葡萄糖淀粉酶的抑制效果图。
图 15为松醇对葡萄糖淀粉酶的抑制类型图。
图 16为 9种肌醇异构体的结构图。 具体实施方式
以下实验例可以详细地说明本发明。实验例一用于分析不同构型的肌醇及 其衍生物对糖苷酶的抑制效果， 进一步说明了立体构型不同， 其糖苷酶的抑制 效果也不同， 取代基不同时， 其抑制效果也不同； 实验例二验证了肌醇衍生物 的降糖作用；实验例三验证了肌醇衍生物能够显著的降低肾上腺素诱发的高血 糖； 实验例四验证了肌醇衍生物能够降低四氧嘧啶诱发的高血糖，升高血清胰 岛素， 降低血清甘油三脂及胆固醇含量。
实验例一、 几种不同构型化合物对糖苷酶抑制效果的比较
(一）试验方法： 下文中所述待测物质分别指西曲依醇、 中肌醇和松醇。
1、 oc-葡萄糖苷酶抑制实验
α-葡萄糖苷酶（EC 3.2.1.20)抑制实验， 底物为对硝基苯基 - a -D-吡喃 葡萄糖苷 Sigma N1377 (PNPG), 以 PNP的释放量计算活性。
将对照药 （阿卡波糖）和待测定物质配置系列浓度（阿卡波糖为 15.2, 5.07, 1.69, 0.56, 0.19, 0.02mg/mL,待测物质均为 100, 10, 1, 0.1, 0. Olmg/mL 浓度），取 lOuL; α_葡萄糖苷酶配成 lU/ml,取 10uL,分别加入到含有 10uL PNGP ( 20mmol/L), 160uL pH7.0緩冲液的 96孔板中， 37°C保温 15分钟，加入 10uL, lmol/L Na2C03终止反应， 405讓处测定吸光度。 计算 IC5。值。
配制 20, 10, 5, 2.5, 1.25mmol/L浓度的 PNPG, 100, 50mg/mL的待测物 质， 80, 40mg/mL阿卡波糖， 按上述方法， 测定 405讓处吸光度。 然后根据所 得数据处理后得出抑制类型。 2、 葡萄糖苷酶抑制实验
β -葡萄糖苷酶（EC 3.2.1.21 ), 底物为 PNPG, 以 PNP的释放量计算活性。 将阿卡波糖和待测物质配置系列浓度（阿卡波糖为 100, 10, 1, 0.1,
0. Olmg/mL, 待测物质均为 100, 10, 1, 0.1, 0.01mg/mL浓度）， 取 10uL; β -葡萄糖苷酶配成 2.5U/ml, 取 lOuL, 分别加入到含有 10uL PNGP ( 25mmol/L ),
160uL pH5.0緩冲液的 96孔板中， 60°C保温 15分钟，加入 10uL, lmol/L Na2C03 终止反应， 405讓处测定吸光度。 计算 IC5。值。
3、 a-半乳糖苷酶抑制实验
α-半乳糖苷酶（EC 3.2.1.22 ), 底物选用 PNPG, 通过测定生成的 PNP含 量计算酶活性。
将阿卡波糖和待测物质配置系列浓度（阿卡波糖和待测物质均为 100, 10,
1, 0.1, 0.01mg/mL浓度）， 取 10uL; α -半乳糖苷酶配成 5U/ml , 取 10uL, 分 别加入到含有 lOuL PNPG ( 50mmol/L), 160uL pH6.0緩冲液的 96孔板中， 37 °C保温 15分钟， 加入 lOuL, lmol/L Na2C03终止反应， 405讓处测定吸光度。 计算 IC5。值。
4、 半乳糖苷酶抑制实验
β -半乳糖苷酶（ EC 3.2.1.23 ), 底物选用邻硝基苯- β -D-吡喃半乳糖苷 ( 0NPG ), 通过测定生成的 0NP含量计算酶活性。
将阿卡波糖和待测物质配置系列浓度（阿卡波糖和待测物质均为 100, 10, 1, 0.1, 0.01 mg/mL 浓度）， 取 10uL; β - D半乳糖苷酶配成 20U/ml, 取 10uL, 分别加入到含有 lOuL 0NGP ( 50mmol/L ), 160uL pH7.0緩冲液的 96孔板中， 37°C保温 15分钟， 加入 lOuL, lmol/L Na2C03终止反应， 405nm处测定吸光度。 计算 IC5。值。
配制 50, 40, 30, 20, 10mmol/L浓度的 0NPG, 100, 50mg/mL的待测物质， 按上述方法， 测定 405nm时吸光度， 用以计算抑制类型。
5、 ex-淀粉酶抑制实验
o-淀粉酶（EC 3.2.1.1 ), 底物选用可溶性淀粉。
取 lOuL 2% 淀粉溶液， 70 uL緩冲液 （pH 6.8) , 10uL lOU/mL酶液， 加 lOuL抑制剂 （阿卡波糖为 10, 5, 1, 0.1, 0. Olmg/mL, 待测物质均为 100, 10, 1, 0.1, 0. Olmg/mL浓度）混匀， 置于 37 °C水浴 lOmin, 加 100uL 3, 5- 二硝基水杨酸中止反应， 然后沸水浴 5 min , 于 540 讓波长测吸光值。 计算
IC5。值。
配制 20, 15, 10, 5, 2.5g/L浓度的淀粉， 10, 5mg/mL阿卡波糖， 按上 述方法， 加入 3, 5-二硝基水杨酸试剂 （DNS试剂）， 测定 540nm时吸光度， 用 以计算抑制类型。
6、 葡萄糖淀粉酶抑制实验
葡萄糖淀粉酶（EC 3.2.1.3), 底物选用淀粉溶液。
取 lOuL 2% 淀粉溶液， 70 uL緩冲液 ( H 6.8) , 10uL 10U/mL酶液， 加 lOuL抑制剂 (阿卡波糖为 0.1, 0.025, 0.00625, 0.00156, 0.000391mg/mL, 待测物质均为 100, 10, 1, 0.1, 0.01mg/mL浓度）混匀,置于 37 °C水浴 lOmin, 加 lOOuL 3 , 5 -二硝基水杨酸中止反应， 然后沸水浴 5 min , 于 540 讓波长 测吸光值。 计算 IC5。值。
配制 20, 15, 10, 5, 2.5g/L浓度的淀粉， 100, 50mg/mL的待测物质，
0.01, 0.0025mg/mL阿卡波糖， 按上述方法， 加入 DNS试剂， 测定 540讓处吸 光度， 用以计算抑制类型。
7、 蔗糖酶抑制实验
蔗糖酶（EC 3.2.1.26 ), 底物选用 5% 蔗糖溶液。
取 ΙΟιιμ 1 5% 蔗糖溶液， 70 μ 1緩冲液 (ρΗ6.8) , 10 μ 1 5U/mL酶液， 加 ΙΟμ Ι 抑制剂 (阿卡波糖为 100, 10, 1, 0.1, 0. Olmg/ml, 待测物质均为 100, 10, 1, 0.1, 0. Olmg/ml 浓度） 混匀， 置于 37 °C水浴 lOmin , 加 100 μ 1 3 , 5-二硝基水杨酸中止反应， 然后沸水浴 5 min , 于 540 nm波长测吸 光值。 计算 IC5。值。
配制 25, 20, 15, 10, 5g/L浓度的蔗糖溶液， 10, 5mg/ml的待测物质和 阿卡波糖， 按上述方法， 加入 DNS试剂， 测定 540讓处吸光度， 用以计算抑制 类型。
8、 海藻糖酶抑制实验 海藻糖酶（EC 3.2.1.28 ), 底物选用 5% 海藻糖溶液。
取 25uL 5% 海藻糖溶液， 25uL緩冲液 ( H 6.0) , 25 μ 1 lU/mL酶液， 加 25 μ 1 抑制剂（阿卡波糖为 100, 10, 1, 0.1, 0. Olmg/mL, 待测物质均为 100, 10, 1, 0.1, 0. Olmg/mL浓度）混匀， 置于 37 °C水浴 30min, 加 100 μ 13 , 5- 二硝基水杨酸中止反应， 然后沸水浴 5 min , 于 540 讓波长测吸光值。 计算 IC5。值。
(二） 实验结果：
第一组： 阿卡波糖对糖苷酶的抑制结果
阿卡波糖对 o-葡萄糖苷酶、 o-淀粉酶、 葡萄糖淀粉酶和蔗糖酶有抑制作 用， 其 IC5。值分别为 0.132、 0.047、 0.001和 0.185mmol/L, 均为竟争性抑制， Ki 分别为 0.74、 1.64、 0.001 mmol/L。 对 β _半乳糖苷酶、 α_半乳糖苷酶、 β-葡萄糖苷酶和海藻糖酶几乎没有抑制效果。 实验数据处理得图 1 -7。
第二组： 西曲依醇对糖苷酶的抑制结果
西曲依醇对 oc-葡萄糖苷酶和 β -D-半乳糖苷酶有抑制作用， 其 IC5。值分别 为 0.962 mmol/L和 25.77mmol/L, 均为竟争性抑制。 5mg/ml时对 α -淀粉酶， 葡萄糖淀粉酶和海藻糖酶抑制分别为 14%, 30%和 15%。 对 oc-葡萄糖苷酶和 β_ 半乳糖苷酶的 Ki分别为： 5.733 mmol/L和 11.51 mmol/L。 而对 β -葡萄糖苷 酶， α-半乳糖苷酶和蔗糖酶没有抑制效果。 实验数据处理得图 8- 11。
第三组： 中肌醇（myo- inositol )对糖苷酶的抑制结果
中肌醇对 oc-葡萄糖苷酶有一定抑制作用，其 IC5。值为 5.303mM, 为竟争性 抑制。 5mg/ml时对 oc-半乳糖苷酶抑制为 29%。 对 β_葡萄糖苷酶， β -半乳糖 苷酶， oc-淀粉酶， 葡萄糖淀粉酶， 蔗糖酶和海藻糖酶没有抑制作用。 对 oc-葡 萄糖苷酶的 Ki为： 18.620 mmol/L。 实验数据处理得图 12- 13。
第四组： 松醇对糖苷酶的抑制结果
松醇对葡萄糖淀粉酶的 IC5。值为 2. ½mol/L, 5mg/ml时对 α -葡萄糖苷酶 和海藻糖酶的抑制分别为 16%和 26%, 对 β-葡萄糖苷酶， oc-半乳糖苷酶， β_ 半乳糖苷酶， oc-淀粉酶， 蔗糖酶和海藻糖酶没有抑制作用。 对葡萄糖淀粉酶 抑制类型为非竟争性抑制， Ki为 9.2匪 ol/L。 实验数据处理得图 14 - 15 将以上几组数据整理得如下表格：
不同物质对各种糖苷酶的抑制数据
Figure imgf000011_0001
由上表可以看出： 对于糖苷酶的抑制效果， 西曲依醇的效果优于中肌醇, 中肌醇的效果又优于松醇。
9 种肌醇立体异构体的结构见附图 16。 其中西曲依醇为中肌醇 ( myo-inositol ) 的衍生物、 而松醇则为 D_chrio_inositol的衍生物。 虽然西 曲依醇和松醇的结构相似， 但由于立体构型不同， 其糖苷酶抑制效果也不同， 我们进一步对这九种异构体进行抑酶活性比较， 结果发现， 相同取代基条件下， 其中 5位取代的 myo-结构是活性最好的。 选定母核为中肌醇（5- myo- )的结构作为优选结构，将 R由 -0-替换为 -ΝΗ-, 对其支链进行衍生 （支链衍生物釆用本公司的编号） 并测定抑酶活性， 所得一 系列衍生物的实验数据如下：
不同衍生物对糖苷酶的抑制作用 （IC5。： 单位 mg/mL)
Figure imgf000012_0001
由上表看出， 当取代基不同时， 其抑制效果也不同， 其中以 -（R1-R2) 为 -CH3时其对糖苷酶的抑制效果相对较好， 因此又用 R为 -0-, -(RH12)为- CH 时即西曲依醇进行了小鼠在体实验。 实验如下： 实验例二、 优化结构后的肌醇衍生物对小鼠降糖作用
实验材料： 昆明种小鼠， 体重 19-25g , 雄性。
药物及试剂： 西曲依醇、 wm0624、 降糖灵、 50%葡萄糖注射液、 葡萄糖测 定试剂盒， 以上试剂可从市场途径购得。
实验方法： 取小鼠 107 只， 随机分为 9组， 其中 7组分别按 0. lmg/ l Og 体重经口给予 wm0624、 西曲依醇 25、 50、 100mg/kg和降糖灵 75mg/kg , 正常 组及模型组（对照组）给予等体积的蒸馏水， 连续 7天。 末次给药前降糖灵组 禁食 8. 5h,给药再禁食 1. 5h, 其余各组禁食 7. 5h后分别给予西曲依醇各剂量 和水， 再禁食 2. 5h, 即所有小鼠禁食 10h。 除正常组外， 其余各组腹腔注射葡 萄糖 2g/kg , 正常组注射等体积的生理盐水， 注射后 30、 60、 90、 120分钟， 小鼠眼眶后静脉丛取血， 分离血清， 以葡萄糖氧化酶法测定血糖。
统计处理： 实验数据以 ±SD表示， 并用 t检验统计表示组间差异。
结果： 如表 3所示， 与正常组相比， 模型组小鼠腹腔注射葡萄糖后 30、 60、 90、 120分钟， 血糖极显著升高。 与模型组相比， wm0624与西曲依醇小剂 量组和中剂量组在腹腔注射葡萄糖后 30、 60、 90、 120分钟， 显著降低葡萄糖 诱发的高血糖； wm0624 与西曲依醇大剂量组和降糖灵组在腹腔注射葡萄糖后 30、 60、 90、 120分钟， 极显著降低葡萄糖诱发的高血糖； 碰 0624与西曲依醇 的作用基本呈剂量依赖性， 碰 0624与西曲依醇 100mg/kg的降糖作用与降糖灵 75mg/kg相当。
表 3 西曲依醇、 碰 0624和降糖灵对正常小鼠糖耐量的影响
组别 剂量 给药 动物 血糖 ( mg/dl )
mg/kg 途径 数 30min 60min 90min 120min 正常组 一 11 107. 2±18. 104. 5±10. 104. 1±13. 104. 4±12.
1 4 7 1
模型组 一 12 238. 1±56. 205. 7±23. 162. 9±11. 140. 9±11.
8# # 8# # 6* * 25 口服 12 173.9±34.2 176.1±12. 140.4±13. 133.8±15. 西曲依 4* * 7 * * 2
醇 50 口服 12 178.6 144.9±12. 143.9±12.
±35· 1* 3** 6
100 口服 12 170.4±15.8 162.1±19. 138.4±9.3 127.4±12.
7 * * 6* *
25 口服 12 183.4±16.4 186.3±14. 156.4±17. 143.2±16. wm0624 6* * 4* * 1
+1
50 口服 12 182.1±15.7 188.5 151.9±14. 153.8±13.
±32· 7* 2** 9
100 口服 12 180.0±14.8 182.4±20. 142.4±10. 137.8±10.
0* * 1 * * 8 * * 降糖灵 75 口服 12 180.0±30.4 156.1±16. 142.4±16. 126.0±20.
0* * 3** 0* *
模型组与正常组比较 ##ρ<0.01; 西曲依醇、 wm0624、 降糖灵与模型组比 较， *p<0.05, **p<0.01 实验例三、 西曲依醇对肾上腺素诱发小鼠血糖升高的影响
实验方法： 取小鼠 71只， 随机分为 6组， 其中 4组分别按 0. lmg/10g体 重经口给予西曲依醇 25、 50、 100mg/kg和优降糖 10mg/kg, 正常组及模型组 给予等体积的蒸馏水， 连续 7天。 末次给药前禁食 lh后给予优降糖， 然后再 禁食 5h, 其余各组禁食 3h后分别给予西曲依醇各剂量和水， 然后再禁食 3h。 即禁食 6h后， 除正常组注射等体积的生理盐水外， 其余各组腹腔注射肾上腺 素 0.2mg/kg, 注射后 30分钟， 小鼠断头取血， 分离血清， 以葡萄糖氧化酶法 测定血糖。 同时取肝脏， 以蒽酮法测定肝糖原。
结果： 如表 4所示， 与正常组相比， 模型组小鼠血糖极显著升高。 与模型 组相比，西曲依醇各剂量组和优降糖组显著降低肾上腺素诱发的高血糖。同时， 模型组小鼠肝糖原极显著降低。 与模型组相比， 西曲依醇小剂量组和大剂量组 极显著升高低下的肝糖原含量，西曲依醇中剂量组和优降糖组显著升高低下的 肝糖原含量。 表 4 西曲依醇和优降糖对肾上腺素诱发小鼠血糖升高的影响
Figure imgf000015_0001
模型组与正常组比较 # # ρ<0. 01 ; 西曲依醇、 优降糖与模型组比较， *ρ<0. 05 , **ρ<0. 01 实验例四、 西曲依醇对四氧嘧啶糖尿病模型大鼠的影响
实验方法： 随机取出大鼠 9只为正常组， 其余 74只大鼠禁食 14-16h后， 腹腔注射戊巴比妥钠 30mg/kg , 麻醉后股静脉注射四氧嘧啶 48mg/kg , 注射四 氧嘧啶后 96h眼眶后静脉丛取血， 预测血糖， 去除未造成糖尿病 （高血糖）， 即禁食 10h血糖低于 200mg/dl者。 根据血糖值分为 5组， 每组 11只， 其中 4 组分别按 lml/ 100g 体重经口给予西曲依醇 25、 50、 100mg/kg 和降糖灵 75mg/kg , 正常组及模型组给予等体积的蒸馏水， 连续 18天， 分别于给药后第 6、 12天测空腹血糖， 即降糖灵组禁食 8h后给药， 再禁食 2h; 其余各组禁食 7h后给予西曲依醇各剂量和等体积的水。 然后， 眼眶后静脉丛釆血， 分离血 清， 以葡萄糖氧化酶法测定血糖， 结果见表 7。 第 18天时， 降糖灵组禁食 8h 后给药， 再禁食 2h; 其余各组禁食 7h后给予待测物质各剂量和等体积的水。 即所有小鼠禁食 10h后， 股动脉取血， 再颈推脱臼处死大鼠， 肝组织匀浆， 测 肝组织中丙二醛的含量和超氧化物歧化酶活力； 并测定血清中血糖，胰岛素水 平、 胆固醇含量、 甘油三酯含量、 丙二醛含量、 超氧化物歧化酶活力； 胰腺浸 泡在 10%福尔马林中， 石蜡包埋切片， HE染色。 由两名病理专业研究人员分别 阅片， 根据每种病变程度， 记为" - "、" +"、" ++"、" +++" , 分别换算成" 0，，、，， 1 "、" 2"、" 3" 分， 计算每组的平均积分值。
结果： 如表 5所示， 与正常组相比， 模型组大鼠空腹血糖极显著升高。 与 模型组相比， 西曲依醇的小剂量组在给药后第 12天时有降低四氧嘧啶的诱发 高血糖的趋势， 在第 18天时极显著降低ο ο 四氧嘧啶诱发的高血糖。 西曲依醇中 剂量组、大剂量组和降糖灵组在给药后第 6 +1天起极显著降低四氧嘧啶诱发的高 血糖， 西曲依醇的降糖作用基本呈剂量依赖性。
如表 6所示， 与正常组相比， 模型组大鼠血清胰岛素水平显著降低。 与模 型组相比， 西曲依醇的小剂量组、 中剂量组和降糖灵组有升高四氧嘧啶糖尿病 小鼠血清胰岛素的趋势，西曲依醇大剂量组明显升高四氧嘧啶糖尿病小鼠血清 胰岛素。
如表 7所示， 与正常组相比，模型组大鼠血清甘油三酯和胆固醇含量极显 著升高。 与模型组相比， 西曲依醇各剂量组显著降低血清甘油三酯和胆固醇含 量， 而降糖灵组对血清胆固醇和甘油三酯含量无明显影响。 表 5 西曲依醇和对四氧嘧啶糖尿病大鼠血糖的影响
组别 1 剂 给 动 空腹血糖 ( mg/d l )
！
里 药 物 给药前 1 给药后
mg/ 途 数 1 6天 1 12天 18天 kg 径 1
正常 1 9 86. 1±11. 4 83. 4±12. 3 1 93 5±12. 0 组 1
模型 9 425. 0±111. 0# # 1 420. 9±78. 2" 1 425. 8±128. 2" 1 411 1±69. 9* 组 1 25 9 426.2±108. Τ* 418.8±83.7 386.3±95.4 216.7±60.8 服
西曲 50 10 428.4±107.4# # 225.1±119.0** 188.0±79.4 依醇 服
10 9 429.2±105.2" 300.9土 207.6±138.0** 170.8±72.7 0 服 103.4**
降糖 75 口服 10 438.2±129.1** 192.5土 264.4±136.4** 104.2±22.7 人 82.5**
： +1
表 6 西曲依醇对四氧嘧啶糖尿病大鼠血清胰岛素的影响 组别 剂量 给药 动物 胰岛素
( mg/kg ) 途径 数 (μΐυ/ml )
正常组 9 15.25±5.73
模型组 9 7.86±2.18**
西曲依醇 25 口服 9 8.87±2.21
50 口服 10 9.31±4.52
100 口服 9 11.22±3.67*
降糖灵 75 口服 10 12.18±8.75 模型组与正常组比较 # # p<0.01; 西曲依醇、 降糖灵与模型组比较, *p<0.05。 表 7 西曲依醇和降糖灵对四氧嘧啶糖尿病大鼠血脂的影响 组别 剂量 给药 动物 胆固醇 甘油三酯
( mg/kg ) 途径 数 (mg/dl ) (mg/dl ) 正常组 9 59.8±12.6 56.5±13.1 模型组 9 82.7±16.4" 75.7±10.5" 西曲依醇 25 口服 9 68. 0±10. 2* 47. 2±17. 9**
50 口服 10 60. 5±10. 8** 60. 0±19. 6*
100 口服 9 59. 8±9. 8** 62. 5±12. 0* 降糖灵 75 口服 10 72. 0±12. 3 86. 7±15. 3 模型组与正常组比较 # # p< 0. 01 ; 西曲依醇、降糖灵与模型组比较， *p< 0. 05 , * *ρ< 0. 01。
通过以上实验例可以得出， 此类肌醇衍生物具有糖苷酶抑制效果， 可以作 为降糖药物的组分， 其中西曲依醇的抑制作用强， 可作为此类药物中的优选化 合物。 制剂实施例 1 将此类糖苷酶抑制剂制成胶嚢剂
以 wm0612为例，称取 wm0612物质 50g , 230g的微晶纤维， 20g的滑石粉； 将微晶纤维和滑石粉置于研磨器中， 再加入碰0612 , 研磨混合 20-30分钟， 直至混勾， 然后灌装于 1号胶嚢中， 随机抽样每粒装量控制在约 300mg。 其中 随机抽取 20粒， 测定其每个装量相对于 20粒的平均装量误差大于 1 0%的不得 超过两粒， 超过 1 0%的任一粒装量误差不得大于 20%。
制剂实施例 2 将此类糖苷酶抑制剂制成片剂
以 wm0621为例， 称取 wm0621物质 50g , 180g的微晶纤维， 47g淀粉， 3g 聚乙烯吡咯烷酮， 20g滑石粉； 将一半的微晶纤维、 淀粉和滑石粉置于研磨器 中， 再加入 wm0621 , 研磨混合 30分钟， 直至混合均匀。 再加入另一半经研磨 处理过的微晶纤维和加少量水溶解了的聚乙烯吡咯烷酮， 充分混合均勾后， 平 铺开放入烘箱中 （60摄氏度）， 直至干燥后结成颗粒状。 将所得颗粒状物质， 进行压片， 使得每片重约为 300mg。 随机抽取其中 20片， 测定其每片的重量 相对于 20片的平均片重的误差不得超过 7. 5%。
以上实施例只是用于进一步说明本发明， 而不是用来限制本发明的保护范 围。 凡是在本发明保护范围内所做出的具体实施方式及应用范围上的些许变动， 也属于本发明的保护范围。

Claims

权 利 要 求
1、 肌醇衍生物或其盐在制备糖苷酶抑制剂类药物或治疗糖尿病药物中的 用途， 所述肌醇衍生物具有如下结构：
Figure imgf000019_0001
其中， R是- 0-或-應-或 \, ^是饱和链式烷基-(^211- ({) 11 26 ), R2是 H、 _CH3、 _C00H、 环形烷基、 苯基或曱苯基。
2、 根据权利要求 1所述的用途， 其中所述肌醇衍生物的 ^是 饱和链 式烷基。
3、 根据权利要求 1所述的用途， 其中所述肌醇衍生物的母核立体结构为 5_myo -的结构。
4、 根据权利要求 3所述的用途， 其中所述 R是 -0-或 -NH -。
5、 根据权利要求 4所述的用途， 其中所述 ^中！！为 0, R2为 -CH3。
6、 根据权利要求 1 - 5 任一项所述的用途， 其中所述治疗糖尿病药物还 含有磺酰脲类药物、 双胍类降糖药、 α_葡萄糖苷酶抑制剂、 胰岛素增敏剂、 促胰岛素分泌剂、 胰岛素类或中成药类降糖药物中的至少一种。
7、 根据权利要求 1所述的用途， 其中所述糖苷酶抑制剂类药物或治疗糖 尿病药物可制备成经口给药的制剂、 吸入制剂、 栓剂或注射制剂。
PCT/CN2008/072123 2008-06-25 2008-08-25 肌醇衍生物或其盐在制备糖苷酶抑制剂药物或治疗糖尿病药物中的用途 WO2009155753A1 (zh)

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