CN118063289A - Pentagene compounds and application thereof in treating diabetes - Google Patents

Pentagene compounds and application thereof in treating diabetes Download PDF

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CN118063289A
CN118063289A CN202211463046.8A CN202211463046A CN118063289A CN 118063289 A CN118063289 A CN 118063289A CN 202211463046 A CN202211463046 A CN 202211463046A CN 118063289 A CN118063289 A CN 118063289A
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pharmaceutically acceptable
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郭庆兰
石建功
叶菲
田金英
雷小强
李江
李雪晨
张敏
陈冬婷
丁祉萍
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Institute of Materia Medica of CAMS
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Abstract

The invention belongs to the technical field of medicines, and discloses compounds (I), (II) and (III) and pharmaceutically acceptable salts thereof, and application of a pharmaceutical composition thereof in preparing a medicament for treating diabetes, which are expected to become therapeutic drug lead of diseases related to diabetes.

Description

Pentagene compounds and application thereof in treating diabetes
Technical Field
The invention relates to a pentameric benzyl compound and pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compound, and application of the compound in the aspect of treating diabetes, and belongs to the technical field of medicines.
Background
The traditional rare traditional Chinese medicine gastrodia elata is the dry tuber of gastrodia elata (Gastrodia elata Blume) belonging to the genus gastrodia (Gastrodia R.Br.) of the orchidaceae, and has long application history. Rhizoma Gastrodiae is used as a traditional rare traditional Chinese medicine for treating various neuralgia and nervous disorders, and has effects [1,2] of strengthening body constitution, improving memory and promoting blood circulation, and has wide application in medicine and food industries. Through long-term researches on chemical components and pharmacological activities of gastrodia elata and processed products thereof by domestic and foreign scholars, over 100 chemical components [3-7] mainly comprising p-hydroxybenzyl alcohol derivatives or p-hydroxybenzyl substituted derivatives are separated and identified from gastrodia elata, wherein the p-hydroxybenzyl alcohol and the gastrodin are considered as characteristic active ingredients of the gastrodia elata. Gastrodin is used as quality control component [8] of rhizoma Gastrodiae in Chinese pharmacopoeia. Meanwhile, pharmacological researches also find that the p-hydroxybenzyl alcohol derivative and the gastrodin have various in-vivo and in-vitro pharmacological activities, and the gastrodin also has a certain drug effect [9-12] on cardiac hypertrophy and fibrosis and tumor immune response. However, studies have also shown that the gastrodia elata extract after removal of gastrodin still retains anti-hypoxia, sedative, hypnotic and anti-inflammatory effects, whereas higher doses of gastrodin do not have the above effects [3,34,35]. Based on the above, the present subject group has carried out relatively systematic studies on the chemical components and pharmacological activities of the aqueous extract of gastrodia elata, and has obtained trace components N 6 - (4-hydroxybenzyl) -adenosine (NHBA) [13,14] with strong sedative hypnotic effect, paricine [15] with remarkable improving learning and memory effect, etc., which proves that other novel strong medicinal components do exist in gastrodia elata.
Diabetes is a group of metabolic diseases characterized by chronic increases in blood glucose levels. The commonly used oral hypoglycemic drugs mainly comprise insulin secretagogues, metformin, alpha-glucosidase (alpha-glucosidase) inhibitors, thiazolidinediones, DPP-4 enzyme inhibitors and the like; wherein, the action mechanism of the alpha-glycosidase inhibitor is to delay the absorption of carbohydrate at the upper part of the small intestine, thereby reducing postprandial blood sugar and improving fasting blood sugar. The alpha-glycosidase inhibitors on the market mainly comprise acarbose and voglibose, and usually have side effects such as gastrointestinal reactions. The clinical requirements of the novel effective hypoglycemic drugs are still huge, the effective drugs with hypoglycemic effect are searched from the natural drugs, which is always a hotspot of the study of students at home and abroad, and certain achievements, such as the natural mulberry twig total alkaloids tablet of the natural hypoglycemic drugs originally created in China, are obtained.
Reference is made to:
[1] chinese medicine dictionary [ M ]. Shanghai: shanghai science and technology Press 1977:315-317.
[2] Chinese herbal administration "China Ben Cao Committee". Chinese Ben Cao [ M ]. Shanghai: shanghai science and technology publishers 1999:716-722.
[3]Zhan H.D.;Zhou H.Y.;Sui Y.P.The rhizome of Gastrodia elata Blume–anethnopharmacological review[J].J.Ethnopharmacol,2016,189:361-385.
[4]Wang Z.W.;Li Y.;Liu D.H.;et al.Chemical constituents from the rhizomes of Gastrodia elata f.glauca and their potential neuroprotective effects[J].Phytochem.Lett.2018;24:167-171.
[5]Wang Z.W.;Li Y.;Liu D.H.;et al.Four new phenolic constituents from the rhizomes of Gastrodia elata Blume[J].Nat.Prod.Res.2019,33:1140-1146.
[6]Chen S.Y.;Geng C.A.;Ma Y.B.;et al.Melatonin receptors agonistic activities of phenols from Gastrodia elata[J].Nat.Prod.Bioprospect,2019,9:297-302.
[7]Chen S.Y.;Geng C.A.;Ma Y.B.;et al.Polybenzyls from Gastrodia elata,their agonistic effects on melatonin receptors and structure-activity relationships[J].Bioorg.Med.Chem.;2019,27:3299-306.
[8] The clinical verification of the cooperative group of the acetylgastrodine, the recent curative effect observation of the acetylgastrodine for treating neurasthenia and vascular headache [ J ]. J.J. Chinese journal of neuropsychiatric diseases, 1986,12:269-270.
[9]Liu J.;Mori A.Antioxidant and pro-oxidant activities of p-hydroxybenzyl alcohol and vanillin:effects on free radicals,brain peroxidation and degradation of benzoate,deoxyribose,amino acids and DNA[J].Neuropharm.;1993,32:659-669.
[10]Lee Y.S.;Ha J.H.;Yong C.S.;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.
[11]Hsieh C.L.;Chang C.H.;Chiang S.Y.;et al.Anticonvulsive and free radical scavenging activities of vanillyl alcohol in ferric chloride-induced epileptic seizures in Sprague-Dawley rats[J].Life Sci.2000,67:1185-1195.
[12]Yu S.J.;Kim J.R.;Lee C.K.;et al.Gastrodia elata Blume and an Active component,p-hydroxybenzyl alcohol reduce focal ischemic brain injury through antioxidant related gene expressions[J].Biol.Pharm.Bull.;2005,28:1016-1020.
[13]Zhang Y.;Li M.;Kang R.X.;at al.NHBA isolated from Gastrodia elata exerts sedative and hypnotic effects in sodium pentobarbital-treated mice[J].Pharm.Biochem.Behav.2012,102:450–457.
[14]He J.;Luo Z.;Huang L.;et al.Ambient mass spectrometry imaging metabolomics method provides novel insights into the action mechanism of drug candidates[J].Anal.Chem.2015,87:5372–5379.
[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.
Disclosure of Invention
The invention aims to solve the technical problem of providing a pentameric benzyl compound with the function of treating diabetes mellitus and pharmaceutically acceptable salts thereof, and a pharmaceutical composition thereof.
In order to solve the technical problems of the invention, the invention provides the following technical scheme:
according to a first aspect of the technical scheme, the invention provides pentameric benzyl compounds shown in general formulas (I), (II) and (III) and pharmaceutically acceptable salts thereof.
Specifically, provided are pentameric benzyl compounds as shown in (I) and pharmaceutically acceptable salts thereof:
Wherein, R 1 and R 2 are one and only one is selected from And the other is selected from H、OH、OCH3、OCH2CH3、OCH2CH2CH3、OCH3CHCH3、OCH2CH2CH2CH3、OCH2CH(CH3)2、OC(CH3)3、HCOO、CH3COO、CH3CH2COOO;
R 3、R4、R5、R6、R8、R9 are each independently selected from H、CH3、CH2CH3、CH2CH2CH3、CH3CHCH3、CH2CH2CH2CH3、CH2CH(CH3)2、C(CH3)3、HCO、CH3CO、CH3CH2CO;
R 7、R10 are 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.
Pentameric benzyl compounds shown as a formula (II) and pharmaceutically acceptable salts thereof:
Wherein, R 1 and R 2 are one and only one is selected from And the other is selected from H、OH、OCH3、OCH2CH3、OCH2CH2CH3、OCH3CHCH3、OCH2CH2CH2CH3、OCH2CH(CH3)2、OC(CH3)3、HCOO、CH3COO、CH3CH2COOO;
R 3、R4、R5、R6、R8、R9 are each independently selected from H、CH3、CH2CH3、CH2CH2CH3、CH3CHCH3、CH2CH2CH2CH3、CH2CH(CH3)2、C(CH3)3、HCO、CH3CO、CH3CH2CO;
R 7、R10 are 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.
Pentameric benzyl compounds shown in formula (III) and pharmaceutically acceptable salts thereof:
R 1、R2、R3、R4、R5 are each independently selected from H、CH3、CH2CH3、CH2CH2CH3、CH3CHCH3、CH2CH2CH2CH3、CH2CH(CH3)2、C(CH3)3、HCO、CH3CO、CH3CH2CO;
R 6、R7、R8、R9 are 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.
Further preferred compounds of the invention are selected from the group consisting of:
according to a second aspect of the present invention, there is provided a process for the preparation of the compound of the first aspect.
Placing p-hydroxybenzyl alcohol (CAS: 623-05-2) into a round bottom flask, adding distilled water (the weight ratio of the distilled water to the p-hydroxybenzyl alcohol is 30:1-50:1), heating and refluxing for 30-50 hours, and concentrating into an extract. Separating with reversed phase ODS column chromatography, mixing ODS dry method, loading sample after wet method column loading, eluting 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) sequentially. 10 g of p-hydroxybenzyl alcohol (CAS: 623-05-2) was taken in a round-bottomed flask, then added to 250 ml of distilled water, heated under reflux for 40 hours, and then concentrated to an extract. The column was separated by reverse phase ODS column chromatography, and the ODS was dry-mixed and loaded after wet-packed, and eluted sequentially with 5% acetonitrile/water (1.0L), 10% -20% acetonitrile/water (0.5L), 25% acetonitrile/water (0.5L), 30% acetonitrile/water (0.5L), 50% acetonitrile/water (0.5L), 100% acetonitrile/water (0.3L), designated as the corresponding components A to F.
And eluting the component D of the part by 30% acetonitrile/water, detecting by TLC, and combining the components with similar components to obtain Da1, da2, D-b 1-D-b 8, D-c 1-D-c 6, D-D1-D-D7 and D-e 1-D-e 15.D-b4 (71 mg) was separated by silica gel preparative thin layer chromatography (n-hexane-ethyl acetate-methanol, 6:2.5:1) to give D-b4 a-D-b 4D; wherein D-b4b was isolated by reverse phase semi-preparative HPLC (MG-II C 18 column, methanol-water 59:41,2.0 mL/min) to give compound (II). D-b5 (99 mg) was separated by silica gel preparative thin layer chromatography (n-hexane-ethyl acetate-methanol, 6:2.5:1) to give D-b5 a-D-b 5D; wherein D-b5b was separated by reverse phase semi-preparative HPLC (pentafluorophenyl column, acetonitrile-water 56:44,2.0 mL/min), followed by reverse phase semi-preparative HPLC (MG-II C 18 column, methanol-water 7:3 as mobile phase, 2.0 mL/min) to give compounds (I) and (III).
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II) and (III) and pharmaceutically acceptable salts thereof. The pharmaceutical composition contains a therapeutically effective amount of the pentameric benzyl derivatives and pharmaceutically acceptable salts thereof, and optionally contains a medicinal carrier.
Typically, the pharmaceutical compositions of the present invention contain 0.1 to 95% by weight of the compound of the present invention.
Pharmaceutical compositions of the compounds of the present invention may be prepared according to methods well known in the art. For this purpose, the compounds of the invention may, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or auxiliaries, in suitable administration forms or dosage forms which can be used as human or veterinary medicine.
The compound of the present invention or a pharmaceutical composition containing it may be administered in unit dosage form by the enteral or parenteral route, such as oral, intramuscular, subcutaneous, nasal, oral mucosal, dermal, peritoneal or rectal, etc., preferably oral.
The route of administration of the compounds of the invention or pharmaceutical compositions containing them may be by injection. Injections include intravenous, intramuscular, subcutaneous, intradermal, and the like.
The administration dosage form may be liquid dosage form or solid dosage form. For example, the liquid dosage form may be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.
The extract or the compound of the invention can be prepared into common preparations, sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
For the purpose of shaping the unit dosage form into a tablet, various carriers known in the art can be widely used. Examples of carriers are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; humectants and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, dextrose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like; disintegrants such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose, ethylcellulose, and the like; disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oils and the like; absorption promoters such as quaternary ammonium salts, sodium lauryl sulfate, and the like; lubricants such as talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets.
For example, in order to make the administration unit into a pill, various carriers well known in the art can be widely used. Examples of carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, gelucire, kaolin, talc, etc.; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, and the like; disintegrants such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.
For example, in order to make the administration unit into a capsule, the extract or the compound of the present invention as an active ingredient is mixed with the above-mentioned various carriers, and the thus-obtained mixture is placed in a hard gelatin capsule or a soft capsule. The active ingredient of the compound can be prepared into microcapsules, and the microcapsules can be suspended in an aqueous medium to form a suspension, or can be filled into hard capsules or prepared into injection for application.
For example, the extracts or compounds of the invention may be formulated as injectable preparations, such as solutions, suspension solutions, emulsions, freeze-dried powder for injection, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxy isostearyl alcohol, polyoxyethylene sorbitol fatty acid esters, and the like. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and further, a conventional cosolvent, a buffer, a pH adjuster, and the like may be added. These adjuvants are commonly used in the art.
In addition, colorants, preservatives, flavors, flavoring agents, sweeteners, or other materials may also be added to the pharmaceutical formulation, if desired.
For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
The dosage of the compounds, pharmaceutical compositions of the present invention to be administered depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, character and individual response of the patient or animal, the route of administration, the number of times of administration, the purpose of treatment, and thus the therapeutic dosage of the present invention may vary widely. Generally, the dosages of pharmaceutical ingredients used in the present invention are well known to those skilled in the art. The amount of the actual drug contained in the final formulation of the compound composition of the present invention may be appropriately adjusted to achieve the therapeutically effective amount thereof, thereby achieving the preventive or therapeutic object of the present invention. The extract or compound of the present invention is used in an amount of 0.001 to 150mg/kg body weight, preferably 0.01 to 100mg/kg body weight, more preferably 0.01 to 60mg/kg body weight, most preferably 0.1 to 10mg/kg body weight, per day of the suitable dosage range of the compound of the present invention. The above-mentioned dosages may be administered in a single dosage form or divided into several, e.g., two, three or four dosage forms, which are limited to the clinical experience of the administering physician and include dosage regimens employing other therapeutic means.
The total dose required for each treatment may be divided into multiple or single doses. The compounds, compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents and adjusted in dosage.
The fourth aspect of the technical scheme of the invention provides application of the compounds shown in the formulas (I), (II) and (III) and pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating diabetes and application in preparing medicines for preventing and/or treating pre-diabetes.
The present invention shows that the compounds of compounds (I), (II) and (III) have PTP1B enzyme and alpha-glucosidase inhibitory activity. Except for compound 6, compounds (I), (ii) and (III) or pharmaceutically acceptable salts are not disclosed.
Beneficial technical effects
In the research process of active ingredients of traditional Chinese medicine gastrodia elata, the inventor carries out activity evaluation on the compounds through PTP1B inhibition and alpha-glucosidase inhibition experiments, and results show that the compounds (I), (II) and (III) have certain PTP1B inhibition and alpha-glucosidase inhibition effects. Belongs to a new lead compound with value in the development process of medicines for preventing and treating diabetes.
Description of the drawings:
Fig. 1: compound isolation procedure
Detailed Description
The following experimental examples can further illustrate the invention but do not limit it in any way.
The isolation and purification procedure for example 1, compounds 1-6 was as follows:
10g of p-hydroxybenzyl alcohol (CAS: 623-05-2) was taken in a round-bottomed flask, then added to 250 ml of distilled water, heated under reflux for 40 hours, and then concentrated to an extract. The column was separated by reverse phase ODS column chromatography, and the ODS was dry-mixed and loaded after wet-packed, and eluted sequentially with 5% acetonitrile/water (1.0L), 10% -20% acetonitrile/water (0.5L), 25% acetonitrile/water (0.5L), 30% acetonitrile/water (0.5L), 50% acetonitrile/water (0.5L), 100% acetonitrile/water (0.3L), designated as the corresponding components A to F.
And eluting the component D of the part by 30% acetonitrile/water, detecting by TLC, and combining the components with similar components to obtain Da1, da2, D-b 1-D-b 8, D-c 1-D-c 6, D-D1-D-D7 and D-e 1-D-e 15.D-b4 (71 mg) was separated by silica gel preparative thin layer chromatography (n-hexane-ethyl acetate-methanol, 6:2.5:1) to give D-b4 a-D-b 4D; wherein D-b4b (27 MG) was isolated by reverse phase semi-preparative HPLC (MG-II C 18 column, methanol-water 59:41,2.0 mL/min) to give compound 5 (8.0 MG, t R =97.0 min). D-b5 (99 mg) was separated by silica gel preparative thin layer chromatography (n-hexane-ethyl acetate-methanol, 6:2.5:1) to give D-b5 a-D-b 5D; wherein D-b5b (50 MG) was separated by reverse phase semi-preparative HPLC (pentafluorophenyl chromatography, acetonitrile-water 56:44,2.0 mL/min) followed by reverse phase semi-preparative HPLC (MG-II C 18 chromatography, methanol-water 7:3 as mobile phase, 2.0 mL/min) to afford D-b5b1, D-b5b2, D-b5b3 and compound 4 (5.0 MG, t R =30.0 min). The D-b5b2 was separated by semi-preparative normal phase HPLC (Silica column, n-hexane-ethanol 85:15,2.0 mL/min) to give compounds 1 (14.0 mg, t R =36.8 min) and 6 (10.0 mg, t R =33.5 min), and compounds 3 (10.0 mg, t R =30.4 min) and 2 (15.0 mg, t R =40.9 min) were separated from the D-b5b3 by the same method.
Compound 1 is brown jelly, is easy to dissolve in acetone and methanol, and is difficult to dissolve in water ;UV(MeOH)λmax(logε)205(4.58),226(4.26),282(3.69);IRνmax 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 C34H30O5Na,541.1986).
Compound 2 is brown jelly, is easy to dissolve in acetone and methanol, and is difficult to dissolve in water ;UV(MeOH)λmax(logε)205(4.57),225(4.33),282(3.68);IRνmax 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 C34H30O5Na,541.1986).
Compound 3 is brown jelly, is easy to dissolve in acetone and methanol, and is difficult to dissolve in water ;UV(MeOH)λmax(logε)205(4.58),225(4.28),282(3.49);IRνmax 3382,3018,2923,2851,2700,1889,1696,1651,1611,1510,1439,1357,1247,1174,1107,1016,912,824,779cm-1;(+)-HRESIMS m/z 541.1979[M+Na]+(calcd.for C34H30O5Na,541.1986).
Compound 4 is brown jelly, is easy to dissolve in acetone and methanol, and is difficult to dissolve in water ;UV(MeOH)λmax(logε)205(4.54),225(4.31),281(3.65);IRνmax 3383,3018,2921,2850,1700,1647,1612,1512,1474,1443,1368,1236,1173,1134,1104,1044,911,878,823,782cm-1;(+)-HRESIMS m/z 541.1979[M+Na]+(calcd.for C34H30O5Na,541.1986).
Compound 5 pale yellow gum (MeOH);UV(MeOH)λmax(logε)204(4.92),228(4.54),284(4.00);IRνmax 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 C34H30O5Na,541.1986).
Compound 6 is brown jelly, is easy to dissolve in acetone and methanol, and is difficult to dissolve in water ;UV(MeOH)λmax(logε)204(4.47),225(4.23),281(3.59);IRνmax 3330,3020,2925,2854,1675,1612,1597,1512,1476,1442,1361,1204,1145,1102,1052,1016,911,822,773cm-1;(+)-HRESIMS m/z 541.1978[M+Na]+(calcd.for C34H30O5Na,541.1986).
Experimental example 1. Alpha. -glucosidase inhibitory Activity examples of Compounds 1 to 6
The experimental method comprises the following steps:
p-nitrophenyl-alpha-D-glucopyranoside (pNPG) is used as a substrate, and p-nitrophenol (p-nitrophenol, pNP) is generated under the catalysis of alpha-glucosidase, and the product has an absorption peak at 405 nm. The production of pNP over a period of time indicates the activity of the alpha-glucosidase. Pre-incubating a sample to be tested with alpha-glucosidase, adding a substrate, and detecting the influence of the sample to be tested on the generation of pNP; and the median inhibitory concentration IC 50 of the test sample was calculated.
Experimental results:
At a final concentration of 10 mu M, compounds 1-6 have an obvious inhibition effect on alpha-glucosidase activity; and further determine and calculate the median inhibitory concentration IC 50. The specific results are shown in Table 1.
TABLE 1 inhibitory Activity of Compounds 1-6 on alpha-glucosidase
Experimental example 2 PTP1B enzyme inhibitory Activity examples of Compounds 1-6
The experimental method comprises the following steps: samples, buffer (50 mmol/L citate, pH 6.0,0.1mol/L NaCl,1mmol/L EDTA and 1mmol/L DTT), PTP1B (0.05-0.1. Mu.g), 2mmol/L pNPP (p-nitro-phenyl phosphate) and H 2 O were added to a 96-well plate, reacted at a constant temperature of 30℃for 30 minutes, and the reaction was terminated with 0.5mol/LNaOH and absorbance change was detected at 410nm using a microplate reader.
Evaluation index: OD value is read at 410nm, the concentration of the sample pNP is obtained, and the inhibition rate is calculated.
Inhibition (%) = [ C To be measured -C Blank space ]/[C Model -C Blank space ] ×100%
Experimental results: at the concentration of 10 mu M, the compound 6 has obvious inhibition effect on the PTP1B enzyme activity, and the inhibition rates are all 84.6%; and a half inhibition concentration of 4.74×10 -6 was measured in a further step.

Claims (8)

1. A pentameric benzyl compound represented by formula (I) and pharmaceutically acceptable salts thereof:
Wherein, R 1 and R 2 are one and only one is selected from And the other is selected from H、OH、OCH3、OCH2CH3、OCH2CH2CH3、OCH3CHCH3、OCH2CH2CH2CH3、OCH2CH(CH3)2、OC(CH3)3、HCOO、CH3COO、CH3CH2COOO;
R 3、R4、R5、R6、R8、R9 are each independently selected from H、CH3、CH2CH3、CH2CH2CH3、CH3CHCH3、CH2CH2CH2CH3、CH2CH(CH3)2、C(CH3)3、HCO、CH3CO、CH3CH2CO;
R 7、R10 are 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.
2. A pentameric benzyl compound represented by formula (ii) and pharmaceutically acceptable salts thereof:
Wherein, R 1 and R 2 are one and only one is selected from And the other is selected from H、OH、OCH3、OCH2CH3、OCH2CH2CH3、OCH3CHCH3、OCH2CH2CH2CH3、OCH2CH(CH3)2、OC(CH3)3、HCOO、CH3COO、CH3CH2COOO;
R 3、R4、R5、R6、R8、R9 are each independently selected from H、CH3、CH2CH3、CH2CH2CH3、CH3CHCH3、CH2CH2CH2CH3、CH2CH(CH3)2、C(CH3)3、HCO、CH3CO、CH3CH2CO;
R 7、R10 are 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.
3. A pentameric benzyl compound represented by formula (III) and pharmaceutically acceptable salts thereof:
R 1、R2、R3、R4、R5 are each independently selected from H、CH3、CH2CH3、CH2CH2CH3、CH3CHCH3、CH2CH2CH2CH3、CH2CH(CH3)2、C(CH3)3、HCO、CH3CO、CH3CH2CO;
R 6、R7、R8、R9 are 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.
4. A compound according to any one of claims 1 to 3, and pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts are selected from salts of compounds of general formula (I), (ii) and (III) with organic or inorganic acids.
5. A compound according to any one of claims 1 to 3, selected from the group consisting of:
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
7. Use of a compound according to any one of claims 1 to 5 and pharmaceutically acceptable salts thereof or a pharmaceutical composition according to claim 6 for the preparation of a medicament for the treatment and prophylaxis of diabetes.
8. Use of a compound according to any one of claims 1 to 5, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 6, for the preparation of a medicament for the treatment and prophylaxis of pre-diabetes.
CN202211463046.8A 2022-11-22 2022-11-22 Pentagene compounds and application thereof in treating diabetes Pending CN118063289A (en)

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