Pentabenzyl compounds and their use in the treatment of diabetes

Abstract

The application belongs to the technical field of medicine, discloses compounds (I), (II) and (III) and pharmaceutically acceptable salts of the compounds, and application of a pharmaceutical composition of the compounds in preparation of a medicine for treating diabetes, and the compounds are expected to become a leading medicine for treating diseases related to diabetes.

Description

Technical Field

[0001] This invention relates to a pentabenzyl compound and its pharmaceutically acceptable salt, pharmaceutical compositions containing such compounds, and the application of such compounds in the treatment of diabetes, belonging to the field of pharmaceutical technology. Background Technology

[0002] Gastrodia elata, a traditional and precious Chinese medicine, is the dried tuber of the plant *Gastrodia elata* Blume, belonging to the genus *Gastrodia* in the family Orchidaceae. It has a long history of use. As a traditional and valuable Chinese medicine, Gastrodia elata is used to treat various neuralgia and related neurological disorders. It also has effects such as strengthening the body, enhancing memory, and promoting blood circulation. [1,2] It has wide applications in the pharmaceutical and food industries. Through long-term research by scholars both domestically and internationally on the chemical composition and pharmacological activities of Gastrodia elata and its processed products, more than 100 chemical components, mainly p-hydroxybenzyl alcohol derivatives or p-hydroxybenzyl-substituted derivatives, have been isolated and identified from Gastrodia elata. [3-7] Among them, p-hydroxybenzyl alcohol and gastrodin are considered characteristic active ingredients of Gastrodia elata. The Chinese Pharmacopoeia lists gastrodin as a quality control component of Gastrodia elata. [8] Meanwhile, pharmacological studies have also revealed that p-hydroxybenzyl alcohol derivatives and gastrodin possess various in vitro and in vivo pharmacological activities, and gastrodin also exhibits certain efficacy against cardiac hypertrophy and fibrosis, as well as tumor immune responses. [9-12] However, studies have also shown that gastrodin-removed gastrodin extract still retains its anti-hypoxia, sedative, hypnotic, and anti-inflammatory effects, while higher doses of gastrodin do not exhibit these effects. [3,34,35] Based on this, our research group has previously conducted a relatively systematic study on the chemical composition and pharmacological activity of Gastrodia elata water extract, and obtained trace component N with strong sedative and hypnotic effects. 6 -(4-Hydroxybenzyl)-adenosine (NHBA) [13,14] And pelicin, which can significantly improve learning and memory

[15] These findings prove that other novel and potent medicinal components do indeed exist in Gastrodia elata.

[0003] Diabetes mellitus is a group of metabolic diseases characterized by chronically elevated blood glucose levels. Commonly used oral hypoglycemic agents mainly include insulin secretagogues, metformin, alpha-glucosidase inhibitors, thiazolidinediones, and DPP-4 enzyme inhibitors. Among them, alpha-glucosidase inhibitors work by delaying the absorption of carbohydrates in the upper small intestine, thus lowering postprandial blood glucose and improving fasting blood glucose. Marketed alpha-glucosidase inhibitors mainly include acarbose and voglibose, which often have side effects such as gastrointestinal reactions. The clinical demand for new and effective hypoglycemic drugs remains enormous. Searching for effective hypoglycemic drugs from natural sources has been a research hotspot for scholars both domestically and internationally, and some progress has been made, such as the original Chinese hypoglycemic natural drug, Mulberry Twig Total Alkaloids Tablets.

[0004] References:

[0005] [1] Medical School of Jiangsu University. Dictionary of Traditional Chinese Medicine [M]. Shanghai: Shanghai Science and Technology Press, 1977: 315-317.

[0006] [2] Editorial Committee of Chinese Materia Medica, State Administration of Traditional Chinese Medicine. Chinese Materia Medica [M]. Shanghai: Shanghai Science and Technology Press, 1999: 716-722.

[0007] [3]Zhan HD; Zhou HY; Sui YPThe rhizome of Gastrodia elata Blume–anethnopharmacological review[J].J.Ethnopharmacol,2016,189:361-385.

[0008] [4]Wang ZW; Li Y.; Liu DH; et al.Chemical constituents from therhizomes of Gastrodia elata f.glauca and their potential neuroprotectiveeffects[J].Phytochem.Lett.2018;24:167-171.

[0009] [5]Wang ZW; Li Y.; Liu DH; et al.Four new phenolic constituents from the rhizomes of Gastrodia elata Blume[J].Nat.Prod.Res.2019,33:1140-1146.

[0010] [6]Chen SY; Geng CA; Ma YB; et al. Melatonin receptors agonisticactivities of phenols from Gastrodia elata[J].Nat.Prod.Bioprospect,2019,9:297-302.

[0011] [7]Chen SY; Geng CA; Ma YB; et al.Polybenzyls from Gastrodiaelata,their agonistic effects on melatonin receptors and structure-activityrelationships[J].Bioorg.Med.Chem.; 2019,27:3299-306.

[0012] [8] Acetyl gastrodin clinical validation collaborative group. Short-term observation of the efficacy of acetyl gastrodin in the treatment of neurasthenia and vascular headache [J]. Chinese Journal of Neuropsychiatry, 1986, 12: 269-270.

[0013] [9] Liu J.; Mori A. Antioxidant and pro-oxidant activities of p-hydroxybenzyl alcohol and vanillin: effects on free radicals, brainperoxidation and degradation of benzoate, deoxyribose, amino acids and DNA [J]. Neuropharm.; 1993, 32: 659-669.

[0014]

[10] Lee YS; Ha JH; Yong CS; et al. Inhibitory effects of constituents of Gastrodia elata BI. On glutamate-induced apoptosis in IMR-32Human neuroblastoma cells. [J]. Arch. Pharm. Res.; 1999, 22: 404-409.

[0015]

[11] Hsieh C.L.;Chang C.H.;Chiang S.Y.;et al.Anticonvulsive and freeradical scavenging activities of vanillyl alcohol in ferric chloride-inducedepileptic seizures in Sprague-Dawley rats[J].Life Sci.2000,67:1185-1195.

[0016]

[12] Yu S.J.;Kim J.R.;Lee C.K.;et al.Gastrodia elata Blume and anActive component,p-hydroxybenzyl alcohol reduce focal ischemic brain injurythrough antioxidant related gene expressions[J].Biol.Pharm.Bull.;2005,28:1016-1020.

[0017]

[13] Zhang Y.;Li M.;Kang R.X.;at al.NHBA isolated from Gastrodia elataexerts sedative and hypnotic effects in sodium pentobarbital-treated mice[J].Pharm.Biochem.Behav.2012,102:450–457.

[0018]

[14] He J.;Luo Z.;Huang L.;et al.Ambient mass spectrometry imagingmetabolomics method provides novel insights into the action mechanism of drugcandidates[J].Anal.Chem.2015,87:5372–5379.

[0019]

[15] Liu Z.;Wang W.;Feng N.;et al.Parishin C′s prevention A1-42-induced inhibition of long-term potentiation is related to NMDA receptors[J].Acta Pharm.Sin.B 2016,6:189–197. Summary of the Invention

[0020] The technical problem to be solved by the present invention is to provide a class of pentabenzyl compounds with therapeutic effects on diabetes, their pharmacodynamically acceptable salts, and pharmaceutical compositions thereof.

[0021] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0022] The first aspect of the present invention is to provide pentabenzyl compounds as shown in general formulas (I), (II) and (III) and their pharmaceutically acceptable salts.

[0023] Specifically, pentabenzyl compounds as shown in (I) and their pharmaceutically acceptable salts are provided:

[0024]

[0025] Among them, R1 and R2 have one and only one selected from And the other one is selected from H, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH3CHCH3, OCH2CH2CH2CH3, OCH2CH(CH3)2, OC(CH3)3, HCOO, CH3COO, CH3CH2COOO;

[0026] R3, R4, R5, R6, R8, and R9 are each independently selected from H, CH3, CH2CH3, CH2CH2CH3, CH3CHCH3, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, HCO, CH3CO, and CH3CH2CO;

[0027] R7, R 10Each independently selected from H, CH3, CH2CH3, CH2CH2CH3, CH3CHCH3, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, HCO, CH3CO, CH3CH2CO, OH , OCH3, OCH2CH3, OCH2CH2CH3, OCH3CHCH3, OCH2CH2CH2CH3, OCH2CH(CH3)2, OC(CH3)3, HCOO, CH3COO, CH3CH2COO.

[0028] Pentame compounds as shown in formula (II) and their pharmaceutically acceptable salts:

[0029]

[0030] Among them, R1 and R2 have one and only one selected from And the other one is selected from H, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH3CHCH3, OCH2CH2CH2CH3, OCH2CH(CH3)2, OC(CH3)3, HCOO, CH3COO, CH3CH2COOO;

[0031] R3, R4, R5, R6, R8, and R9 are each independently selected from H, CH3, CH2CH3, CH2CH2CH3, CH3CHCH3, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, HCO, CH3CO, and CH3CH2CO;

[0032] R7, R 10 Each independently selected from H, CH3, CH2CH3, CH2CH2CH3, CH3CHCH3, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, HCO, CH3CO, CH3CH2CO, OH , OCH3, OCH2CH3, OCH2CH2CH3, OCH3CHCH3, OCH2CH2CH2CH3, OCH2CH(CH3)2, OC(CH3)3, HCOO, CH3COO, CH3CH2COO.

[0033] Pentame compounds as shown in formula (III) and their pharmaceutically acceptable salts:

[0034]

[0035] R1, R2, R3, R4, and R5 are each independently selected from H, CH3, CH2CH3, CH2CH2CH3, CH3CHCH3, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, HCO, CH3CO, and CH3CH2CO;

[0036] R6, R7, R8, and R9 are each independently selected from H, CH3, CH2CH3, CH2CH2CH3, CH3CHCH3, CH2CH2CH2CH3, CH2CH(CH3)2, C(CH3)3, HCO, CH3CO, CH3CH2 CO, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH3CHCH3, OCH2CH2CH2CH3, OCH2CH(CH3)2, OC(CH3)3, HCOO, CH3COO, CH3CH2COO.

[0037] The compounds further preferred by the present invention are selected from the following group:

[0038]

[0039] The second aspect of the present invention is to provide a method for preparing the compound described in the first aspect.

[0040] Take p-hydroxybenzyl alcohol (CAS: 623-05-2), place it in a round-bottom flask, then add distilled water (weight ratio of p-hydroxybenzyl alcohol to p-hydroxybenzyl alcohol 30:1 to 50:1), heat under reflux for 30 to 50 hours, and then concentrate to obtain an extract. Separate by reversed-phase ODS column chromatography, using dry ODS mixing and wet packing of the column, and elute sequentially with 5% acetonitrile / water (A), 10%-20% acetonitrile / water (B), 25% acetonitrile / water (C), 30% acetonitrile / water (D), 50% acetonitrile / water (E), and 100% acetonitrile / water (F). Take 10 g of p-hydroxybenzyl alcohol (CAS: 623-05-2), place it in a round-bottom flask, then add 250 mL of distilled water, heat under reflux for 40 hours, and then concentrate to obtain an extract. Separation was performed using reversed-phase ODS column chromatography. The ODS was mixed with dry powder and then packed onto the column using a wet method. The sample was then eluted sequentially with 5% acetonitrile / water (1.0 L), 10%-20% acetonitrile / water (0.5 L), 25% acetonitrile / water (0.5 L), 30% acetonitrile / water (0.5 L), 50% acetonitrile / water (0.5 L), and 100% acetonitrile / water (0.3 L), and designated as the corresponding fraction AF.

[0041] Fraction D, eluted with 30% acetonitrile / water, was analyzed by TLC. Fractions with similar compositions were combined to obtain Da1, Da2, D-b1~D-b8, D-c1~D-c6, D-d1~D-d7, and D-e1~D-e15. D-b4 (71 mg) was separated into D-b4a~D-b4d by preparative thin-layer chromatography on silica gel (n-hexane-ethyl acetate-methanol, 6:2.5:1); among which, D-b4b was separated by reversed-phase semi-preparative HPLC (MG-II C). 18 Compound (II) was separated by chromatographic column (methanol-water 59:41, 2.0 mL / min). D-b5 (99 mg) was separated by silica gel preparative thin-layer chromatography (n-hexane-ethyl acetate-methanol, 6:2.5:1) to obtain D-b5a~D-b5d; among which, D-b5b was separated by reversed-phase semi-preparative HPLC (pentafluorophenyl column, acetonitrile-water 56:44, 2.0 mL / min), and then by reversed-phase semi-preparative HPLC (MG-II C). 18 Compounds (I) and (III) were separated by a chromatographic column with a mobile phase of methanol-water 7:3 and a flow rate of 2.0 mL / min.

[0042] A third aspect of the present invention is to provide a pharmaceutical composition comprising compounds of formulas (I), (II), and (III) and their pharmaceutically acceptable salts. The pharmaceutical composition contains a therapeutically effective amount of the pentabenzyl derivatives of the present invention and their pharmaceutically acceptable salts, and optionally contains a pharmaceutically acceptable carrier.

[0043] Typically, the pharmaceutical compositions of this invention contain 0.1-95% by weight of the compounds of this invention.

[0044] Pharmaceutical compositions of the compounds of the present invention can be prepared according to methods known in the art. For this purpose, if desired, the compounds of the present invention can be combined with one or more solid or liquid pharmaceutical excipients and / or adjuvants to formulate suitable administration or dosage forms for use as human or veterinary medicine.

[0045] The compounds of the present invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum, with oral administration being preferred.

[0046] The compounds of this invention or pharmaceutical compositions containing them can be administered by injection. Injection includes intravenous injection, intramuscular injection, subcutaneous injection, and intradermal injection.

[0047] Dosage forms can be liquid or solid. Liquid dosage forms include true solutions, colloids, microparticles, emulsions, and suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and lyophilized powder injections.

[0048] The extracts or compounds of this invention can be formulated into ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations, and various microparticle delivery systems.

[0049] To formulate unit-dosage dosage forms into tablets, a wide variety of carriers known in the art can be used. Examples of carriers include diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and aluminum silicate; humectants and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, methylcellulose, and ethylcellulose; disintegration inhibitors such as sucrose, tristearate, cocoa butter, and hydrogenated oil; absorption promoters such as quaternary ammonium salts and sodium dodecyl sulfate; and lubricants such as talc, silica, corn starch, stearates, boric acid, liquid paraffin, and polyethylene glycol. Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0050] For example, various carriers known in the art can be widely used to formulate the drug delivery unit into pills. Examples of carriers include diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, gelucire, kaolin, talc, etc.; binders such as gum arabic, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste, or flour paste, etc.; and disintegrants such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.

[0051] For example, to formulate the drug delivery unit into a capsule, the active ingredient, the extract or compound of the present invention, is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or a soft capsule. Alternatively, the active ingredient, the compound of the present invention, can be formulated as a microcapsule, suspended in an aqueous medium to form a suspension, or filled into a hard capsule or formulated as an injectable preparation for use.

[0052] For example, the extracts or compounds of this invention can be formulated into injectable preparations, such as solutions, suspension solutions, emulsions, and lyophilized powders for injection. These preparations can be aqueous or non-aqueous and may contain one or more pharmacodynamically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants, or dispersants. Diluents may be selected from water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. Furthermore, to prepare isotonic injections, appropriate amounts of sodium chloride, glucose, or glycerol can be added to the injectable formulation. In addition, conventional solubilizers, buffers, pH adjusters, etc., may also be added. These excipients are commonly used in the art.

[0053] In addition, colorants, preservatives, flavorings, tasters, sweeteners or other materials may be added to pharmaceutical preparations if necessary.

[0054] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0055] The dosage of the compounds and pharmaceutical compositions of this invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality, and individual response of the patient or animal, the route of administration, frequency of administration, and therapeutic purpose. Therefore, the therapeutic dosage of this invention can vary widely. Generally speaking, the dosage of the pharmaceutical components used in this invention is well known to those skilled in the art. The actual amount of drug contained in the final formulation of the compound composition according to this invention can be appropriately adjusted to achieve the required therapeutic dose and fulfill the preventive or therapeutic purpose of this invention. The appropriate daily dosage range for the compounds of this invention is 0.001-150 mg / kg body weight, preferably 0.01-100 mg / kg body weight, more preferably 0.01-60 mg / kg body weight, and most preferably 0.1-10 mg / kg body weight. The above dosages can be administered in a single dose or divided into several doses, such as two, three, or four doses. This is limited by the clinical experience of the dispensing physician and the administration regimen, including the use of other treatment methods.

[0056] The total dose required for each treatment can be divided into multiple administrations or administered as a single dose. The compounds and compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs, with dosage adjustments.

[0057] The fourth aspect of the present invention is to provide the use of compounds of formulas (I), (II) and (III) and their pharmaceutically acceptable salts in the preparation of medicaments for the prevention and / or treatment of diabetes, and in the preparation of medicaments for the prevention and / or treatment of prediabetes.

[0058] This invention demonstrates that compounds (I), (II), and (III) possess PTP1B enzyme and α-glucosidase inhibitory activities. Except for compound 6, compounds (I), (II), and (III), or pharmaceutically acceptable salts, have not been publicly reported.

[0059] Beneficial technical effects

[0060] In their research on the active components of the traditional Chinese medicine Gastrodia elata, the inventors of this invention evaluated the activity of these compounds through PTP1B inhibition and α-glucosidase inhibition experiments. The results showed that compounds (I), (II), and (III) possess certain PTP1B and α-glucosidase inhibitory effects. These are valuable new lead compounds for the development of drugs for the prevention and treatment of diabetes. Attached image description:

[0061] Figure 1 Compound separation process Detailed Implementation

[0062] The following experimental examples further illustrate the present invention, but do not limit the invention in any way.

[0063] Example 1: The isolation and purification process of compounds 1-6 is as follows:

[0064] Take 10 g of p-hydroxybenzyl alcohol (CAS: 623-05-2), place it in a round-bottom flask, add 250 mL of distilled water, heat under reflux for 40 hours, and then concentrate to form an extract. Separate by reversed-phase ODS column chromatography. After dry mixing with ODS and wet packing, the sample is loaded onto the column and eluted sequentially with 5% acetonitrile / water (1.0 L), 10%-20% acetonitrile / water (0.5 L), 25% acetonitrile / water (0.5 L), 30% acetonitrile / water (0.5 L), 50% acetonitrile / water (0.5 L), and 100% acetonitrile / water (0.3 L), and designated as the corresponding fraction AF.

[0065] Fraction D, eluted with 30% acetonitrile / water, was analyzed by TLC. Fractions with similar compositions were combined to obtain Da1, Da2, D-b1~D-b8, D-c1~D-c6, D-d1~D-d7, and D-e1~D-e15. D-b4 (71 mg) was separated into D-b4a~D-b4d by preparative thin-layer chromatography on silica gel (n-hexane-ethyl acetate-methanol, 6:2.5:1); among which, D-b4b (27 mg) was separated by reversed-phase semi-preparative HPLC (MG-II C). 18 Compound 5 (8.0 mg, t) was separated by a chromatographic column (methanol-water 59:41, 2.0 mL / min). R=97.0 min). D-b5 (99 mg) was separated into D-b5a to D-b5d by silica gel preparative thin-layer chromatography (n-hexane-ethyl acetate-methanol, 6:2.5:1); among which, D-b5b (50 mg) was separated by reversed-phase semi-preparative HPLC (pentafluorophenyl column, acetonitrile-water 56:44, 2.0 mL / min), and then by reversed-phase semi-preparative HPLC (MG-II C). 18 The chromatographic column, with methanol-water 7:3 as the mobile phase and a flow rate of 2.0 mL / min, separated D-b5b1, D-b5b2, D-b5b3 and compound 4 (5.0 mg, t) R =30.0 min). D-b5b2 was separated by semi-preparative normal-phase HPLC (Silica column, n-hexane-ethanol 85:15, 2.0 mL / min) to obtain compound 1 (14.0 mg, t). R =36.8min) and 6 (10.0mg, t R =33.5min), compound 3 (10.0 mg, t) was isolated from D-b5b3 using the same method. R =30.4min) and 2 (15.0mg, t R =40.9min).

[0066] Compound 1: A brown gelatinous substance, readily soluble in acetone and methanol, sparingly soluble in water; UV(MeOH)λ max (logε)205(4.58),226(4.26),282(3.69); IRν max 3360,3019,2918,2848,1890,1697,1611,1510,1439,1365,1248,1173,1103,1042,912,879,820,777cm -1 ;(+)-HRESIMS m / z 541.1982[M+Na] + (calcd.for C 34 H 30 O5Na, 541.1986).

[0067] Compound 2: A brown gelatinous substance, readily soluble in acetone and methanol, sparingly soluble in water; UV(MeOH)λ max (logε)205(4.57),225(4.33),282(3.68); IRν max 3382,3020,2923,2851,1674,1648,1612,1512,1474,1442,1367,1229,1173,1104,1044,1015,943,913,879,828,778cm-1 ;(+)-HRESIMS m / z 541.1986[M+Na] + (calcd.for C 34 H 30 O5Na, 541.1986).

[0068] Compound 3: A brown gelatinous substance, readily soluble in acetone and methanol, sparingly soluble in water; UV(MeOH)λ max (logε)205(4.58),225(4.28),282(3.49); IRν max 3382,3018,2923,2851,2700,1889,1696,1651,1611,1510,1439,1357,1247,1174,1107,1016,912,824,779cm -1 ;(+)-HRESIMS m / z541.1979[M+Na] + (calcd.for C 34 H 30 O5Na, 541.1986).

[0069] Compound 4: A brown gelatinous substance, readily soluble in acetone and methanol, sparingly soluble in water; UV(MeOH)λ max (logε)205(4.54),225(4.31),281(3.65); IRν max 3383,3018,2921,2850,1700,1647,1612,1512,1474,1443,1368,1236,1173,1134,1104,1044,911,878,823,782cm -1 ;(+)-HRESIMS m / z541.1979[M+Na] + (calcd.for C 34 H 30 O5Na, 541.1986).

[0070] Compound 5: Pale yellow gelatinous substance (MeOH); UV(MeOH)λ max (logε)204(4.92),228(4.54),284(4.00); IRν max 3328,3019,2917,2842,2706,2607,1889,1672,1611,1509,1439,1366,1234,1173,1110,1015,914,818,774,725cm -1;(+)-HRESIMS:m / z541.1986[M+Na] + (calcd.for C 34 H 30 O5Na, 541.1986).

[0071] Compound 6: A brown gelatinous substance, readily soluble in acetone and methanol, sparingly soluble in water; UV(MeOH)λ max (logε)204(4.47),225(4.23),281(3.59); IRν max 3330,3020,2925,2854,1675,1612,1597,1512,1476,1442,1361,1204,1145,1102,1052,1016,911,822,773cm -1 ;(+)-HRESIMS m / z541.1978[M+Na] + (calcd.for C 34 H 30 O5Na, 541.1986).

[0072] Example 1: α-glucosidase inhibitory activity of compounds 1-6

[0073] Experimental methods:

[0074] Using p-nitrophenyl-α-D-glucopyranoside (pNPG) as a substrate, p-nitrophenol (pNP) is generated under the catalysis of α-glucosidase. This product exhibits an absorption peak at 405 nm. The activity of α-glucosidase is expressed as the amount of pNP generated within a certain time. After pre-incubating the test sample with α-glucosidase, the substrate is added, and the effect of the test sample on pNP generation is detected; the half-maximal inhibitory concentration (IC50) of the test sample is then calculated. 50 .

[0075] Experimental results:

[0076] At a final concentration of 10 μM, compounds 1-6 significantly inhibited α-glucosidase activity; and their half-maximal inhibitory concentration (IC50) was further determined and calculated. 50 The specific results are shown in Table 1.

[0077] Table 1. Inhibitory activities of compounds 1-6 against α-glucosidase

[0078]

[0079] Example 2: PTP1B enzyme inhibitory activity of compounds 1-6

[0080] Experimental method: The sample, buffer (50 mmol / L citrate, pH 6.0, 0.1 mol / L NaCl, 1 mmol / L EDTA and 1 mmol / L DTT), PTP1B (0.05-0.1 μg), 2 mmol / L pNPP (p-nitro-phenyl phosphate) and H2O were added to a 96-well plate. After reacting at 30℃ for 30 min, the reaction was terminated with 0.5 mol / L NaOH, and the absorbance change was detected at 410 nm using a microplate reader.

[0081] Evaluation metrics: OD value is read at 410nm, sample pNP concentration is obtained, and inhibition rate is calculated.

[0082] Inhibition rate (%) = [C 待测 -C 空白 ] / [C 模型 -C 空白 ]×100%

[0083] Experimental results: At a concentration of 10 μM, compound 6 was found to significantly inhibit the activity of PTP1B enzyme, with an inhibition rate of 84.6%; further, the half-maximal inhibitory concentration (IC50) was determined to be 4.74 × 10⁻⁶. -6 .

Claims

1. The pentabenzyl compounds and their pharmaceutically acceptable salts as shown below, characterized in that, The compounds are selected from the following group: 。 2. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the compound of claim 1, its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

3. The use of the compound of claim 1 and its pharmaceutically acceptable salt or the pharmaceutical composition of claim 2 in the preparation of a medicament for the treatment and prevention of diabetes.

4. The use of the compound of claim 1 and its pharmaceutically acceptable salt or the pharmaceutical composition of claim 2 in the preparation of a medicament for the treatment and prevention of prediabetes.

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