A pentacyclic triterpenoid compound, and a preparation method and application thereof

Abstract

The present application relates to a kind of pentacyclic triterpenoids and its preparation method and application.The pentacyclic triterpenoids provided by the present application belong to methylsuccinic acylitans type triterpenoid compounds and analogs, the compound shows good inhibitory activity to cyclooxygenase-2 (COX-2), can be used for preparing anti-inflammatory drug;The present application takes oleanolic acid or ursolic acid as matrix, under the action of condensing agent, with organic diacid monomethyl ester or organic diacid monomethyl ester acyl chloride is reacted, so as to introduce specific organic diacid monomethyl ester acyl in the 3-position hydroxyl of matrix, reaction condition is mild, synthesis speed is fast, yield is high, the present application provides a kind of efficient, fast method for methylsuccinic acylitans type triterpenoid compounds and analogs.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a pentacyclic triterpenoid compound and a preparation method and application thereof. BACKGROUND

[0002] Cynomorium songaricum is a kind of parasitic plant belonging to Cynomorium, which parasitizes on the root of Nitraria tangutorum Bobr. It is also known as not old medicine, ground hair ball, rusty stick, and lock strict son. Its rhizome can be used as medicine, which can tonify yin and protect yang, promote metabolism, enhance immune function, and delay aging. Its efficacy has been recorded in the early Qin Dynasty, and it was first used as medicine in the Han Dynasty, and was highly valued by famous doctors in past dynasties. The Compendium of Materia Medica records that it is sweet, warm, and non-toxic, and can tonify yin qi, benefit essence and blood, and benefit large intestine. The New Compendium of Materia Medica records that it can benefit essence and excite yang, moisten dryness and nourish muscle, and treat flaccidity and weakness. The Chinese Materia Medica records that it can tonify kidney, moisten intestine, and strengthen waist and knees, and is used to treat male impotence, female infertility, blood dryness, constipation, and flaccidity and weakness of waist and knees. Modern medical research shows that it is effective for aging symptoms from mild memory impairment to dementia, mainly by protecting hippocampal neurogenesis from A beta or superoxide anion-induced damage and changing brain-derived neurotrophic factors (BDNF) and serum corticosterone levels to improve cognitive memory factors. The active substances mainly include triterpenoids, steroids, lignans, and flavonoids, especially natural methyl malonyl oleanane-type triterpenoids, which have significant activity in antioxidant, antiviral, and treatment of neurological diseases. However, due to the low content, it is difficult to separate and extract, and a large amount of the compound can be obtained by chemical synthesis method to meet the subsequent biological activity research.

[0003] At present, there is no literature report on the synthesis and anti-inflammatory activity of natural methyl malonyl oleanane-type triterpenoids and analogs, therefore, it is of great significance to develop an economical and efficient synthesis method of natural methyl malonyl oleanane-type triterpenoids and analogs and to use it in the field of pharmaceutical and cosmetic industry for anti-inflammatory activity. SUMMARY

[0004] The present application aims at overcoming the shortcomings of the prior art and providing a pentacyclic triterpenoid compound and a preparation method and application thereof.

[0005] To achieve the above-mentioned object, the technical scheme adopted by the present application is as follows:

[0006] In a first aspect, the present application provides a pentacyclic triterpenoid compound, the structural formula of which is as follows:

[0007]

[0008] In the formula, -R1 is an organic diacid monomethyl ester acyl group, -R2 is -CH3 or -H, and -R3 is -CH3 or -H.

[0009] As a preferred embodiment of the present application, the organic diacid monomethyl ester acyl group includes any one of malonic acid monomethyl ester acyl group, succinic acid monomethyl ester acyl group, fumaric acid monomethyl ester acyl group, maleic acid monomethyl ester acyl group, glutaric acid monomethyl ester acyl group, adipic acid monomethyl ester acyl group, suberic acid monomethyl ester acyl group, azelaic acid monomethyl ester acyl group, sebacic acid monomethyl ester acyl group, dodecanedioic acid monomethyl ester acyl group.

[0010] In a second aspect, the present application provides a preparation method of the pentacyclic triterpenoid compound according to the first aspect, comprising the following steps:

[0011] S1, in the presence of an organic solvent, the crude reaction product is obtained by stirring and reacting the pentacyclic triterpenoid raw material and the organic diacid monomethyl ester acyl chloride under the action of an organic amine;

[0012] S2, the organic solvent in the crude reaction product obtained in step S1 is removed by vacuum evaporation to obtain a concentrate;

[0013] The pentacyclic triterpenoid raw material includes at least one of oleanolic acid and ursolic acid;

[0014] S2, the concentrate obtained in step S2 is subjected to silica gel column chromatography to obtain the pentacyclic triterpenoid compound.

[0015] As a preferred embodiment of the present application, the molar ratio of the organic diacid monomethyl ester acyl chloride to the pentacyclic triterpenoid raw material is (1-2):1.

[0016] As a preferred embodiment of the present application, the organic diacid monomethyl ester acyl chloride includes any one of malonic acid monomethyl ester acyl chloride, succinic acid monomethyl ester acyl chloride, fumaric acid monomethyl ester acyl chloride, maleic acid monomethyl ester acyl chloride, glutaric acid monomethyl ester acyl chloride, adipic acid monomethyl ester acyl chloride, suberic acid monomethyl ester acyl chloride, azelaic acid monomethyl ester acyl chloride, sebacic acid monomethyl ester acyl chloride, dodecanedioic acid monomethyl ester acyl chloride.

[0017] As a preferred embodiment of the present application, step S1 specifically comprises: dissolving the organic diacid monomethyl ester in the organic solvent at 0-5℃, then sequentially adding 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and 1-hydroxybenzotriazole, and stirring and reacting for 20-40min to obtain a reaction mixture containing the organic diacid monomethyl ester acyl chloride; adding the pentacyclic triterpenoid raw material and the organic amine to the reaction mixture containing the organic diacid monomethyl ester acyl chloride at 0-5℃, and continuing to stir and react for 3-8h to obtain the crude reaction product;

[0018] The organic diacid monomethyl ester includes any one of malonic acid monomethyl ester, succinic acid monomethyl ester, fumaric acid monomethyl ester, maleic acid monomethyl ester, glutaric acid monomethyl ester, adipic acid monomethyl ester, suberic acid monomethyl ester, azelaic acid monomethyl ester, sebacic acid monomethyl ester, dodecanedioic acid monomethyl ester.

[0019] The molar ratio of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to the organic diacid monomethyl ester is (1-1.2):1; the molar ratio of the 1-hydroxybenzotriazole to the organic diacid monomethyl ester is (1-1.2):1.

[0020] It can be understood that the temperature control in step S1 is at 0-5℃, which can avoid high temperature to make the reaction product unstable, even decomposed.

[0021] As a preferred embodiment of the present application, step S1 specifically comprises: dissolving the pentacyclic triterpenoid raw material in an organic solvent at 0-5℃, sequentially adding an organic amine and an organic diacid monomethyl ester acyl chloride, incubating and stirring for 20-40min, and then incubating and stirring for 1-5h after warming to 16-26℃, to obtain a reaction crude product.

[0022] As a preferred embodiment of the present application, the organic amine comprises at least one of triethylamine, diethylamine, trimethylamine, dimethylamine and tetramethylamine.

[0023] As a preferred embodiment of the present application, the volume ratio of the organic amine to the mass of the pentacyclic triterpenoid raw material is (2-5):10.

[0024] As a preferred embodiment of the present application, the organic solvent is at least one of N,N-dimethylformamide and dichloromethane.

[0025] As a preferred embodiment of the present application, the volume ratio of the organic solvent to the mass of the pentacyclic triterpenoid raw material is (8-10)mL:1g.

[0026] In a third aspect, the present application provides a use of the pentacyclic triterpenoid compound in the first aspect in preparation of an anti-inflammatory drug.

[0027] As a preferred embodiment of the present application, the dosage form of the anti-inflammatory drug comprises tablets, granules and capsules.

[0028] As a preferred embodiment of the present application, the anti-inflammatory drug comprises the pentacyclic triterpenoid compound and further comprises a pharmaceutically acceptable carrier.

[0029] Further, the pharmaceutically acceptable carrier comprises at least one of diluents, disintegrants, binders, lubricants and stabilizers.

[0030] In a fourth aspect, the present application provides a use of the pentacyclic triterpenoid compound in the first aspect in preparation of an anti-inflammatory cosmetic.

[0031] Compared with the prior art, the present application has the following beneficial effects:

[0032] (1) The five-ring triterpenoid compound provided by the application belongs to methyl malonyl oleanane type triterpenoid compounds and analogs, and the compound shows good inhibitory activity on cyclooxygenase-2 (COX-2) and can be used for preparing anti-inflammatory drugs;

[0033] (2) The application takes oleanolic acid or ursolic acid as a mother body, reacts with organic dimethyl ester or organic dimethyl ester acyl chloride under the action of a condensing agent, introduces specific organic dimethyl ester acyl groups into the 3-position hydroxyl group of the mother body, the reaction condition is mild, the synthesis speed is fast, and the yield is high, and the application provides a high-efficiency and fast method for methyl malonyl oleanane type triterpenoid compounds and analogs. DETAILED DESCRIPTION

[0034] In order to better illustrate the purpose, technical scheme and advantages of the application, the application will be further described below in combination with specific examples.

[0035] Unless otherwise specified, other materials, reagents and the like used in the following examples and application examples can be obtained from commercial channels.

[0036] Unless otherwise specified, the methods used in the following examples and application examples are conventional methods in the art.

[0037] Examples 1-20

[0038] The examples of the five-ring triterpenoid compound described in the application, and the preparation method of the five-ring triterpenoid compound, include the following steps:

[0039] S1, at 0°C, the reactant B is dissolved in 100 mL of dry and anhydrous N,N-dimethylformamide, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and 1-hydroxybenzotriazole are sequentially added at 0°C, and stirred at 0°C for 30 min, then 10 g of the reactant A and 3 mL of triethylamine are added, and stirred at 0°C for 8 h to obtain a reaction crude product;

[0040] The molar ratio of the reactant A to the reactant B is 1:1;

[0041] The molar ratio of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride to the reactant B is 1.1:1;

[0042] The molar ratio of 1-hydroxybenzotriazole to the reactant B is 1.1:1;

[0043] S2, after the reaction is completed through thin layer detection, the reaction crude product obtained in step S1 is subjected to vacuum evaporation to remove the organic solvent, 50 mL of ethyl acetate and 50 mL of deionized water are added for extraction, an organic phase is obtained, the organic phase is dried by anhydrous sodium sulfate, and then filtered and concentrated to obtain a concentrate; the reactant A and the reactant B are shown in Table 1.

[0044] S3, the concentrate obtained in step S2 is subjected to silica gel column chromatography to obtain the pentacyclic triterpenoid compound, and the yield thereof is shown in Table 1, the yield = (theoretical yield of the compound - actual yield of the compound) / the theoretical yield of the compound.

[0045] The pentacyclic triterpenoid compound obtained in the above examples 1-20 is subjected to nuclear magnetic resonance detection.

[0046] The structural characterization data of the compound obtained in example 1 are as follows:

[0047] 1 H NMR (400 MHz, CDC13) δ 5.21 (t, J = 3.6 Hz, 1H, H-12), 3.67 (s, 3H, H-4'), 4.48 (dd, J = 10.4, 5.9 Hz, 1H, H-3), 3.30 (s, 2H, H-2'), 2.75 (dd, J = 13.8, 4.6 Hz, 1H, H-18), 1.91 (td, J = 13.7, 3.9 Hz, 2H, H-16), 1.05, 0.87, 0.86, 0.84, 0.82, 0.76, 0.70 (each s, each 3H, CH3x7);

[0048] 13 CNMR (100 MHz, CDC13) δ 181.7 (C-28), 166.1 (C-3'), 165.1 (C-1'), 142.6 (C-13), 121.5 (C-12), 81.4 (C-3), 54.3, 51.4 (C-4'), 46.5, 45.6, 44.9, 40.6 (C-2'), 40.1, 38.3, 37.1, 36.8, 36.0, 32.8, 31.4, 26.6, 24.9, 22.6, 22.4, 17.1, 16.0, 15.5, 14.3;

[0049] MS (ESI) m / z: [M+H] + Theoretical value 557.38, [M+H] + Found 557.35.

[0050] The structural characterization data of the compound obtained in example 2 are as follows:

[0051] 1H NMR (400 MHz, CDC13) δ 5.23 (t, J = 3.7 Hz, 1H, H-12), 3.66 (s, 3H, H-5'), 4.48 (dd, J = 10.1, 5.7 Hz, 1H, H-3), 2.77 (dd, J = 13.7, 4.6 Hz, 1H, H-18), 2.73 (m, 2H, H-3'), 2.63 (m, 2H, H-2'), 1.93 (td, J = 13.9, 3.7 Hz, 2H, H-16), 1.03, 0.89, 0.85, 0.83, 0.82, 0.76, 0.69 (each s, each 3H, CH3x7);

[0052] 13 CNMR (100 MHz, CDC13) δ 181.6 (C-28), 166.3 (C-4'), 165.2 (C-l'), 142.3 (C-13), 121.2 (C-12), 81.5 (C-3), 54.5, 51.3 (C-5'), 46.5, 45.6, 44.8, 40.1, 39.7, 38.3, 37.1, 36.8, 36.0, 32.8, 31.4, 29.3 (C-2'), 26.6 (C-3'), 24.7, 22.7, 22.3, 17.3, 16.1, 15.5, 14.1;

[0053] MS (ESI) m / z: [M+H] + Theoretical value 571.39, [M+H] + Found 571.41.

[0054] The structural characterization data of the compound obtained in Example 3 are as follows:

[0055] 1 H NMR (400 MHz, CDC13) δ 6.33 (d, J = 12.4 Hz, 2H, H-2', H-3'), 5.25 (t, J = 3.7 Hz, 1H, H-12), 3.69 (s, 3H, H-5'), 4.43 (dd, J = 9.9, 5.5 Hz, 1H, H-3), 2.79 (dd, J = 13.5, 4.7 Hz, 1H, H-18), 1.91 (td, J = 13.7, 3.6 Hz, 2H, H-16), 1.03, 0.89, 0.88, 0.85, 0.82, 0.77, 0.69 (each s, each 3H, CH3x7);

[0056] 13CNMR (100 MHz, CDC13) δ 181.3 (C-28), 167.3 (C-4'), 166.2 (C-1'), 142.5 (C-13), 133.9 (C-3'), 130.7 (C-2'), 121.3 (C-12), 81.3 (C-3), 54.6, 51.1 (C-5'), 46.5, 45.6, 44.8, 40.3, 39.6, 38.3, 37.5, 36.8, 36.0, 32.9, 31.4, 24.3, 22.8, 22.3, 17.5, 16.3, 15.5, 14.3;

[0057] MS (ESI) m / z: [M+H] + Theoretical value 569.38, [M+H] + Found 569.40.

[0058] The structural characterization data of the compound obtained in Example 4 are as follows:

[0059] 1 HNMR (400 MHz, CDC13) δ 6.47 (d, J = 3.9 Hz, 2H, H-2', H-3'), 5.24 (t, J = 3.6 Hz, 1H, H-12), 3.73 (s, 3H, H-5'), 4.45 (dd, J = 10.3, 5.7 Hz, 1H, H-3), 2.77 (dd, J = 13.7, 4.6 Hz, 1H, H-18), 1.90 (td, J = 13.7, 3.6 Hz, 2H, H-16), 1.01, 0.88, 0.87, 0.83, 0.82, 0.77, 0.71 (each s, each 3H, CH3x7);

[0060] 13 CNMR (100 MHz, CDC13) δ 181.1 (C-28), 167.3 (C-4'), 166.4 (C-1'), 142.5 (C-13), 133.6 (C-3'), 130.8 (C-2'), 121.7 (C-12), 81.7 (C-3), 54.6, 51.9 (C-5'), 46.8, 45.6, 44.3, 40.3, 39.7, 38.3, 37.6, 36.8, 36.1, 32.9, 31.1, 24.3, 22.7, 22.5, 17.5, 16.5, 15.5, 14.0;

[0061] MS (ESI) m / z: [M+H] + Theoretical value 569.38, [M+H] + Found 569.40.

[0062] Structural characterization data for the compound obtained in Example 5 are:

[0063] 1 H NMR (400 MHz, CDC13) δ 5.24 (t, J = 3.7 Hz, 1H, H-12), 3.69 (s, 3H, H-6'), 4.45 (dd, J = 10.7, 5.4 Hz, 1H, H-3), 2.79 (dd, J = 13.3, 4.7 Hz, 1H, H-18), 2.36 (m, 2H, H-4'), 2.34 (m, 2H, H-2'), 2.29 (m, 2H, H-3'), 1.96 (td, J = 13.3, 3.9 Hz, 2H, H-16), 1.01, 0.89, 0.85, 0.83, 0.81, 0.76, 0.68 (each s, each 3H, CH3x7);

[0064] 13 CNMR (100 MHz, CDC13) δ 181.6 (C-28), 167.3 (C-5'), 167.0 (C-1'), 142.3 (C-13), 121.2 (C-12), 81.5 (C-3), 54.6, 51.7 (C-6'), 46.5, 45.6, 45.0, 40.1, 39.7, 38.4, 37.1, 36.6, 36.1, 33.3 (C-4'), 32.8, 31.4, 29.7 (C-2'), 24.7, 22.7, 22.3, 20.3 (C-3'), 17.3, 16.5, 15.3, 14.1;

[0065] MS (ESI) m / z: [M+H] + Calcd 585.41, [M+H] + Found 585.46.

[0066] Structural characterization data for the compound obtained in Example 6 are:

[0067] 1H NMR (400 MHz, CDC13) δ 5.23 (t, J = 3.7 Hz, 1H, H-12), 3.63 (s, 3H, H-7'), 4.46 (dd, J = 10.4, 5.5 Hz, 1H, H-3), 2.71 (dd, J = 13.7, 4.7 Hz, 1H, H-18), 2.37 (m, 2H, H-2'), 2.33 (m, 2H, H-5'), 1.96 (td, J = 13.3, 3.9 Hz, 2H, H-16), 1.68 (m, 4H, H-3', H-4'), 1.02, 0.90, 0.83, 0.82, 0.80, 0.79, 0.69 (each s, each 3H, CH3x7);

[0068] 13 CNMR (100 MHz, CDC13) δ 181.3 (C-28), 171.3 (C-6'), 170.1 (C-1'), 142.1 (C-13), 121.3 (C-12), 81.5 (C-3), 54.9, 51.9 (C-7'), 46.9, 45.6, 45.2, 41.3, 39.9, 38.5, 37.3, 36.6, 36.2, 33.9 (C-2'), 33.3 (C-5'), 32.8, 31.4, 24.7, 24.3 (C-3'), 24.1 (C-4'), 22.8, 22.3, 17.3, 16.5, 15.1, 14.3;

[0069] MS (ESI) m / z: [M+H] + Calcd 599.43, [M+H] + Found 599.41.

[0070] The structural characterization data of the compound obtained in Example 7 are as follows:

[0071] 1 H NMR (400 MHz, CDC13) δ 5.24 (t, J = 3.8 Hz, 1H, H-12), 3.63 (s, 3H, H-9'), 4.41 (dd, J = 10.5, 5.4 Hz, 1H, H-3), 2.73 (dd, J = 13.7, 4.3 Hz, 1H, H-18), 2.36 (m, 2H, H-2'), 2.32 (m, 2H, H-7'), 1.96 (td, J = 13.3, 3.9 Hz, 2H, H-16), 1.66 (m, 4H, H-3', H-6'), 1.63 (m, 4H, H-4', H-5'), 1.03, 0.93, 0.82, 0.81, 0.80, 0.77, 0.70 (each s, each 3H, CH3x7);

[0072] 13 CNMR (100 MHz, CDC13) δ 181.3 (C-28), 172.9 (C-8'), 172.2 (C-1'), 142.3 (C-13), 121.2 (C-12), 81.5 (C-3), 54.7, 51.9 (C-9'), 46.8, 45.6, 45.1, 41.6, 39.7, 38.3, 37.5, 36.7, 36.1, 34.2 (C-2'), 33.6 (C-7'), 32.8, 31.4, 28.7 (C-4'), 28.5 (C-5'), 25.1 (C-3'), 25.0 (C-6'), 24.7, 22.8, 22.1, 17.3, 16.5, 15.5, 14.3;

[0073] MS (ESI) m / z: [M+H] + Calculated 627.46, [M+H] + Found 627.49.

[0074] The structural characterization data of the compound obtained in Example 8 are as follows:

[0075] 1 HNMR (400 MHz, CDC13) δ 5.21 (t, J = 3.6 Hz, 1H, H-12), 3.61 (s, 3H, H-10'), 4.43 (dd, J = 10.3, 5.4 Hz, 1H, H-3), 2.76 (dd, J = 13.3, 4.1 Hz, 1H, H-18), 2.35 (m, 2H, H-2'), 2.32 (m, 2H, H-8'), 1.96 (td, J = 13.3, 3.9 Hz, 2H, H-16), 1.66 (m, 4H, H-3', H-7'), 1.33 (m, 4H, H-4', H-6'), 1.26 (m, 2H, H-5'), 1.02, 0.95, 0.84, 0.81, 0.79, 0.76, 0.69 (each s, each 3H, CH3x7);

[0076] 13CNMR (100 MHz, CDC13) δ 181.5 (C-28), 173.0 (C-9'), 172.8 (C-1'), 142.3 (C-13), 121.1 (C-12), 81.5 (C-3), 54.9, 51.9 (C-10'), 46.8, 45.7, 45.1, 41.6, 39.6, 38.3, 37.5, 36.7, 36.3, 34.2 (C-2'), 33.6 (C-8'), 32.7, 31.4, 29.3 (C-4'), 29.1 (C-5'), 29.0 (C-6'), 25.1 (C-3'), 25.0 (C-7'), 24.7, 22.8, 22.1, 17.1, 16.5, 15.3, 14.1;

[0077] MS (ESI) m / z: [M+H] + Calcd 641.47, [M+H] + Found 641.43.

[0078] The structural characterization data of the compound obtained in Example 9 are as follows:

[0079] 1 HNMR (400 MHz, CDC13) δ 5.21 (t, J = 3.7 Hz, 1H, H-12), 3.62 (s, 3H, H-11'), 4.42 (dd, J = 10.3, 5.4 Hz, 1H, H-3), 2.77 (dd, J = 13.5, 4.3 Hz, 1H, H-18), 2.35 (m, 2H, H-2'), 2.31 (m, 2H, H-9'), 1.97 (td, J = 13.3, 3.9 Hz, 2H, H-16), 1.69 (m, 4H, H-3', H-8'), 1.37 (m, 4H, H-4', H-7'), 1.28 (m, 4H, H-5', H-6'), 1.03, 0.93, 0.87, 0.81, 0.79, 0.77, 0.68 (each s, each 3H, CH3x7);

[0080] 13CNMR (100 MHz, CDC13) δ 181.5 (C-28), 173.2 (C-10'), 173.0 (C-1'), 142.5 (C-13), 121.1 (C-12), 81.5 (C-3), 54.8, 51.9 (C-11'), 46.9, 45.7, 45.3, 41.6, 39.7, 38.3, 37.3, 36.7, 36.1, 34.5 (C-2'), 33.7 (C-9'), 32.7, 31.4, 29.4 (C-4'), 29.3 (C-5'), 29.1 (C-6'), 29.0 (C-7'), 25.1 (C-3'), 25.0 (C-8'), 24.6, 22.9, 22.1, 17.3, 16.5, 15.3, 14.0;

[0081] MS (ESI) m / z: [M+H] + Theoretical value 655.49, [M+H] + Found 655.51.

[0082] The structural characterization data of the compound obtained in Example 10 are as follows:

[0083] 1 HNMR (400 MHz, CDC13) δ 5.19 (t, J = 3.6 Hz, 1H, H-12), 3.61 (s, 3H, H-13'), 4.41 (dd, J = 10.4, 5.5 Hz, 1H, H-3), 2.79 (dd, J = 13.5, 4.3 Hz, 1H, H-18), 2.35 (m, 2H, H-2'), 2.32 (m, 2H, H-11'), 1.96 (td, J = 13.6, 3.9 Hz, 2H, H-16), 1.67 (m, 4H, H-3', H-10'), 1.34 (m, 4H, H-4', H-9'), 1.31 (m, 4H, H-6', H-7'), 1.28 (m, 4H, H-5', H-8'), 1.01, 0.95, 0.87, 0.83, 0.79, 0.76, 0.69 (each s, each 3H, CH3x7);

[0084] 13CNMR (100 MHz, CDC13) δ 180.9 (C-28), 173.1 (C-12'), 173.0 (C-1'), 142.1 (C-13), 121.4 (C-12), 81.3 (C-3), 54.9, 51.9 (C-13'), 46.8, 45.7, 45.5, 41.6, 39.9, 38.3, 37.5, 36.7, 36.1, 34.3 (C-2'), 33.7 (C-11'), 32.7, 31.4, 29.7 (C-6'), 29.4 (C-7'), 29.2 (C-5'), 29.0 (C-8'), 29.0 (C-4'), 28.7 (C-9'), 25.3 (C-3'), 25.0 (C-10'), 24.6, 22.9, 22.5, 17.3, 16.1, 15.3, 14.3;

[0085] MS (ESI) m / z: [M+H] + Calcd 683.52, [M+H] + Found 683.51.

[0086] The structural characterization data of the compound obtained in Example 11 are as follows:

[0087] 1 HNMR (400 MHz, CDC13) δ 5.21 (t, J = 3.6 Hz, 1H, H-12), 3.67 (s, 3H, H-4'), 4.48 (dd, J = 10.4, 5.9 Hz, 1H, H-3), 3.30 (s, 2H, H-2'), 2.75 (dd, J = 13.8, 4.6 Hz, 1H, H-18), 1.91 (td, J = 13.7, 3.9 Hz, 2H, H-16), 0.95 (d, J = 6.4 Hz, 3H, CH3), 0.86 (d, J = 6.4 Hz, 3H, CH3), 1.05, 0.84, 0.82, 0.76, 0.70 (each s, each 3H, CH3x5);

[0088] 13 CNMR (100 MHz, CDC13) δ 181.7 (C-28), 166.1 (C-3'), 165.1 (C-1'), 142.6 (C-13), 121.5 (C-12), 81.4 (C-3), 54.3, 51.4 (C-4'), 46.5, 45.6, 44.9, 40.6 (C-2'), 40.1, 38.3, 37.1, 36.8, 36.0, 32.8, 31.4, 26.6, 24.9, 22.6, 22.4, 17.1, 16.0, 15.5, 14.3;

[0089] MS (ESI) m / z: [M+H] + Calcd 557.38, [M+H] + Found 557.35.

[0090] The structural characterization data of the compound obtained in Example 12 are as follows:

[0091] 1 HNMR (400 MHz, CDC13) δ 5.21 (t, J = 3.6 Hz, 1H, H-12), 3.69 (s, 3H, H-5'), 4.48 (dd, J = 10.1, 5.5 Hz, 1H, H-3), 2.77 (dd, J = 13.7, 4.7 Hz, 1H, H-18), 2.75 (m, 2H, H-3'), 2.63 (m, 2H, H-2'), 1.95 (td, J = 13.9, 3.7 Hz, 2H, H-16), 0.96 (d, J = 6.4 Hz, 3H, CH3), 0.86 (d, J = 6.4 Hz, 3H, CH3), 1.03, 0.89, 0.82, 0.73, 0.70 (each s, each 3H, CH3x5);

[0092] 13 CNMR (100 MHz, CDC13) δ 181.3 (C-28), 166.3 (C-4'), 165.0 (C-1'), 142.3 (C-13), 121.4 (C-12), 81.5 (C-3), 54.5, 51.5 (C-5'), 46.5, 45.6, 44.6, 40.1, 39.8, 38.3, 37.1, 36.9, 36.0, 32.8, 31.5, 29.3 (C-2'), 26.7 (C-3'), 24.7, 22.6, 22.3, 17.3, 16.3, 15.5, 14.0;

[0093] MS (ESI) m / z: [M+H] + Calcd 571.39, [M+H] + Found 571.33.

[0094] The structural characterization data of the compound obtained in Example 13 are as follows:

[0095] 1HNMR (400 MHz, CDC13) δ 6.35 (d, J = 12.4 Hz, 2H, H-2', H-3'), 5.22 (t, J = 3.6 Hz, 1H, H-12), 3.67 (s, 3H, H-5'), 4.43 (dd, J = 9.9, 5.5 Hz, 1H, H-3), 2.79 (dd, J = 13.5, 4.7 Hz, 1H, H-18), 1.96 (td, J = 13.6, 3.6 Hz, 2H, H-16), 0.95 (d, J = 6.4 Hz, 3H, CH3), 0.87 (d, J = 6.4 Hz, 3H, CH3), 1.03, 0.87, 0.81, 0.76, 0.69 (each s, each 3H, CH3x5);

[0096] 13 CNMR (100 MHz, CDC13) δ 181.1 (C-28), 167.7 (C-4'), 166.6 (C-l'), 142.5 (C-13), 133.9 (C-3'), 130.7 (C-2'), 121.3 (C-12), 81.6 (C-3), 54.6, 51.4 (C-5'), 46.5, 45.7, 44.8, 40.3, 39.6, 38.6, 37.5, 36.8, 36.4, 32.9, 31.5, 24.3, 22.8, 22.4, 17.5, 16.3, 15.6, 14.3;

[0097] MS (ESI) m / z: [M+H] + Theoretical value 569.38, [M+H] + Found 569.41.

[0098] The structural characterization data of the compound obtained in Example 14 are as follows:

[0099] 1 HNMR (400 MHz, CDC13) δ 6.35 (d, J = 12.4 Hz, 2H, H-2', H-3'), 5.22 (t, J = 3.6 Hz, 1H, H-12), 3.67 (s, 3H, H-5'), 4.43 (dd, J = 9.9, 5.5 Hz, 1H, H-3), 2.79 (dd, J = 13.5, 4.7 Hz, 1H, H-18), 1.96 (td, J = 13.6, 3.6 Hz, 2H, H-16), 0.95 (d, J = 6.4 Hz, 3H, CH3), 0.87 (d, J = 6.4 Hz, 3H, CH3), 1.03, 0.87, 0.81, 0.76, 0.69 (each s, each 3H, CH3x5);

[0100] 13 CNMR (100 MHz, CDC13) δ 181.3 (C-28), 167.6 (C-4'), 166.7 (C-1'), 142.5 (C-13), 133.9 (C-3'), 130.7 (C-2'), 121.7 (C-12), 81.7 (C-3), 54.6, 51.6 (C-5'), 46.8, 45.7, 44.3, 40.3, 39.7, 38.3, 37.6, 36.8, 36.1, 32.9, 31.3, 24.3, 22.7, 22.5, 17.5, 16.5, 15.5, 14.1;

[0101] MS (ESI) m / z: [M+H] + Calcd 569.38, [M+H] + Found 569.41.

[0102] The structural characterization data of the compound obtained in Example 15 are as follows:

[0103] 1 HNMR (400 MHz, CDC13) δ 5.21 (t, J = 3.7 Hz, 1H, H-12), 3.67 (s, 3H, H-6'), 4.45 (dd, J = 10.7, 5.4 Hz, 1H, H-3), 2.79 (dd, J = 13.3, 4.7 Hz, 1H, H-18), 2.39 (m, 2H, H-4'), 2.35 (m, 2H, H-2'), 2.29 (m, 2H, H-3'), 1.96 (td, J = 13.3, 3.9 Hz, 2H, H-16), 0.97 (d, J = 6.4 Hz, 3H, CH3), 0.85 (d, J = 6.4 Hz, 3H, CH3), 1.05, 0.88, 0.80, 0.75, 0.71 (each s, each 3H, CH3x5);

[0104] 13 CNMR (100 MHz, CDC13) δ 181.3 (C-28), 168.0 (C-5'), 167.3 (C-1'), 142.3 (C-13), 121.2 (C-12), 81.5 (C-3), 54.6, 51.6 (C-6'), 46.5, 45.7, 45.0, 40.1, 39.7, 38.3, 37.1, 36.6, 36.1, 33.5 (C-4'), 32.8, 31.4, 29.7 (C-2'), 24.6, 22.7, 22.3, 20.1 (C-3'), 17.3, 16.5, 15.3, 14.1;

[0105] MS (ESI) m / z: [M+H] + Calcd 585.41, [M+H] + Found 585.38.

[0106] The structural characterization data of the compound obtained in Example 16 are as follows:

[0107] 1 HNMR (400 MHz, CDC13) δ 5.23 (t, J = 3.6 Hz, 1H, H-12), 3.63 (s, 3H, H-7'), 4.44 (dd, J = 10.4, 5.5 Hz, 1H, H-3), 2.76 (dd, J = 13.7, 4.5 Hz, 1H, H-18), 2.37 (m, 2H, H-2'), 2.32 (m, 2H, H-5'), 1.97 (td, J = 13.5, 3.9 Hz, 2H, H-16), 1.67 (m, 4H, H-3', H-4'), 0.95 (d, J = 6.6 Hz, 3H, CH3), 0.89 (d, J = 6.5 Hz, 3H, CH3), 1.02, 0.87, 0.82, 0.79, 0.75 (each s, each 3H, CH3x5);

[0108] 13 CNMR (100 MHz, CDC13) δ 181.3 (C-28), 171.3 (C-6'), 170.1 (C-1'), 142.1 (C-13), 121.3 (C-12), 81.6 (C-3), 54.9, 51.8 (C-7'), 46.9, 45.6, 45.2, 41.3, 39.9, 38.5, 37.3, 36.6, 36.2, 33.9 (C-2'), 33.3 (C-5'), 32.8, 31.4, 24.7, 24.2 (C-3'), 24.1 (C-4'), 22.7, 22.3, 17.3, 16.5, 15.1, 14.3;

[0109] MS (ESI) m / z: [M+H] + Calcd 599.43, [M+H] + Found 599.45.

[0110] The structural characterization data of the compound obtained in Example 17 are as follows:

[0111] 1H NMR (400 MHz, CDC13) δ 5.23 (t, J = 3.6 Hz, 1H, H-12), 3.63 (H3s, 3H, H-9'), 4.40 (dd, J = 10.5, 5.4 Hz, 1H, H-3), 2.71 (dd, J = 13.4, 4.3 Hz, 1H, H-18), 2.39 (m, 2H, H-2'), 2.32 (m, 2H, H-7'), 1.94 (td, J = 13.3, 3.9 Hz, 2H, H-16), 1.68 (m, 4H, H-3', H-6'), 1.64 (m, 4H, H-4', H-5'), 0.93 (d, J = 6.4 Hz, 3H, CH3), 0.87 (d, J = 6.5 Hz, 3H, CH3), 0.94, 0.91, 0.88, 0.79, 0.76 (each s, each 3H, CH3x5);

[0112] 13 CNMR (100 MHz, CDC13) δ 181.2 (C-28), 172.8 (C-8'), 172.3 (C-l'), 142.3 (C-13), 121.1 (C-12), 81.1 (C-3), 54.9, 51.9 (C-9'), 46.7, 45.6, 45.1, 41.6, 39.7, 38.3, 37.5, 36.7, 36.2, 34.2 (C-2'), 33.7 (C-7'), 32.8, 31.4, 28.7 (C-4'), 28.5 (C-5'), 25.0 (C-3'), 24.7 (C-6'), 24.5, 22.8, 22.1, 17.3, 16.5, 15.5, 14.1;

[0113] MS (ESI) m / z: [M+H] + Calculated 627.46, [M+H] + Found 627.43.

[0114] The structural characterization data of the compound obtained in Example 18 are as follows:

[0115] 1HNMR (400 MHz, CDC13) δ 5.24 (t, J = 3.6 Hz, IH, H-12), 3.63 (s, 3H, H-10'), 4.43 (dd, J = 10.3, 5.4 Hz, IH, H-3), 2.77 (dd, J = 13.3, 4.3 Hz, IH, H-18), 2.38 (m, 2H, H-2'), 2.30 (m, 2H, H-8'), 1.97 (td, J = 13.3, 4.1 Hz, 2H, H-16), 1.68 (m, 4H, H-3', H-7'), 1.33 (m, 4H, H-4', H-6'), 1.27 (m, 2H, H-5'), 0.96 (d, J = 6.4 Hz, 3H, CH3), 0.85 (d, J = 6.4 Hz, 3H, CH3), 1.02, 0.88, 0.86, 0.79, 0.76 (each s, each 3H, CH3x5);

[0116] 13 CNMR (100 MHz, CDC13) δ 181.4 (C-28), 173.1 (C-9'), 172.8 (C-l'), 142.3 (C-13), 121.1 (C-12), 81.7 (C-3), 54.6, 51.9 (C-10'), 46.9, 45.7, 45.4, 41.6, 39.8, 38.3, 37.6, 36.7, 36.1, 34.0 (C-2'), 33.7 (C-8'), 32.7, 31.4, 29.3 (C-4'), 29.1 (C-5'), 28.8 (C-6'), 25.1 (C-3'), 24.9 (C-7'), 24.7, 22.8, 22.2, 17.3, 16.5, 15.2, 14.3;

[0117] MS (ESI) m / z: [M+H] + Calcd 641.47, [M+H] + Found 641.49.

[0118] The structural characterization data of the compound obtained in Example 19 are:

[0119] 1HNMR (400 MHz, CDC13) δ 5.20 (t, J = 3.6 Hz, IH, H-12), 3.62 (s, 3H, H-11'), 4.41 (dd, J = 10.3, 5.5 Hz, IH, H-3), 2.78 (dd, J = 13.7, 4.4 Hz, IH, H-18), 2.33 (m, 2H, H-2'), 2.30 (m, 2H, H-9'), 1.97 (td, J = 13.3, 3.9 Hz, 2H, H-16), 1.67 (m, 4H, H-3', H-8'), 1.33 (m, 4H, H-4', H-7'), 1.28 (m, 4H, H-5', H-6'), 0.97 (d, J = 6.5 Hz, 3H, CH3), 0.87 (d, J = 6.5 Hz, 3H, CH3), 1.05, 0.87, 0.82, 0.77, 0.71 (each s, each 3H, CH3x5);

[0120] 13 CNMR (100 MHz, CDC13) δ 181.3 (C-28), 173.0 (C-10'), 172.7 (C-l'), 142.5 (C-13), 121.3 (C-12), 81.5 (C-3), 54.9, 51.9 (C-11'), 46.8, 45.7, 45.4, 41.6, 39.8, 38.3, 37.6, 36.7, 36.0, 34.6 (C-2'), 33.7 (C-9'), 32.7, 31.5, 29.5 (C-4'), 29.1 (C-5'), 29.0 (C-6'), 28.8 (C-7'), 25.1 (C-3'), 24.9 (C-8'), 24.7, 22.9, 22.3, 17.3, 16.1, 15.3, 14.1;

[0121] MS (ESI) m / z: [M+H] + Calculated 655.49, [M+H] + Found 655.50.

[0122] The structural characterization data for the compound obtained in Example 20 are:

[0123] 1HNMR (400 MHz, CDC13) δ 5.21 (t, J = 3.7 Hz, 1H, H-12), 3.62 (s, 3H, H-13'), 4.44 (dd, J = 10.1, 5.3 Hz, 1H, H-3), 2.81 (dd, J = 13.7, 4.3 Hz, 1H, H-18), 2.35 (m, 2H, H-2'), 2.31 (m, 2H, H-11'), 1.99 (td, J = 13.6, 3.8 Hz, 2H, H-16), 1.66 (m, 4H, H-3', H-10'), 1.34 (m, 4H, H-4', H-9'), 1.32 (m, 4H, H-6', H-7'), 1.29 (m, 4H, H-5', H-8'), 0.97 (d, J = 6.6 Hz, 3H, CH3), 0.83 (d, J = 6.4 Hz, 3H, CH3), 1.06, 0.86, 0.82, 0.78, 0.73 (each s, each 3H, CH3x5);

[0124] 13 CNMR (100 MHz, CDC13) δ 181.3 (C-28), 173.2 (C-12'), 173.0 (C-l'), 142.3 (C-13), 121.4 (C-12), 81.6 (C-3), 54.9, 51.7 (C-13'), 46.8, 45.9, 45.5, 41.7, 39.9, 38.5, 37.5, 36.9, 36.1, 34.5 (C-2'), 33.6 (C-11'), 32.7, 31.5, 29.6 (C-6'), 29.4 (C-7'), 29.1 (C-5'), 29.0 (C-8'), 28.9 (C-4'), 28.7 (C-9'), 25.5 (C-3'), 25.1 (C-10'), 24.6, 22.6, 22.5, 17.4, 16.1, 15.3, 14.1;

[0125] MS (ESI) m / z: [M+H] + Calcd 683.52, [M+H] + Found 683.54.

[0126] From the above results, it can be seen that the five-ring triterpenoid compounds shown below are successfully prepared in Examples 1-20:

[0127] wherein -R1, -R2and -R3are shown in Table 1.

[0128] Table 1

[0129]

[0130]

[0131] Example 1

[0132] To verify the efficacy of the five-ring triterpenoid compounds described in the present application, the compounds obtained in Examples 1-20 were used as test samples, and indomethacin and resveratrol were used as control samples, and the following tests were performed:

[0133] (1) The samples were dissolved in ethyl acetate and diluted to a concentration of 1 μM with reaction buffer; the volume ratio of ethyl acetate to reaction buffer solution was 2:1;

[0134] (2) A reaction mixture was prepared, which comprised 950 mL of reaction buffer, 10 mL of COX-2, and 10 mL of hematin;

[0135] (3) Test group: 1 mL of the sample obtained in step (1) and 1.15 mL of the reaction mixture obtained in step (2) were added to a 100% initial activity tube, which was incubated in a 37°C water bath for 15 minutes; 20 μL of reaction buffer was added to the 100% initial activity tube;

[0136] Control group: inactive COX-2 (10 mL) and reaction buffer (20 mL) were added to a background tube;

[0137] Each group was stimulated by adding arachidonic acid (10 mL) and continued to be incubated for 2 minutes, and the reaction was terminated by adding 50 mL of 1M hydrochloric acid solution and 100 mL of saturated stannous chloride solution, respectively;

[0138] (4) An ELISA method (COX-2 inhibitor screening kit: 96 analyses, Cayman Company) was used to quantify the prostaglandin, and the reaction contents were diluted 10 times with reaction buffer and transferred to a 96-well microplate coated with mouse anti-rabbit IgG, followed by adding 1 mL of prostaglandin screening AchE tracer and 1 mL of prostaglandin screening antiserum; the plate was covered with plastic film, incubated in the orbit (Kunming mouse) at room temperature for 18 hours; the wells were washed 6 times with a washing buffer containing 0.05% polysorbate-20, and the plate was removed from the reaction; then Ellman reagent (200 mL) was added to each well, and incubation was continued at room temperature for 60-90 minutes; the plate was recorded until the absorbance of the control wells produced an OD value between 0.3 and 0.8 at 415 nm; the inhibition rate was calculated according to the following formula: inhibition rate = (control group OD value-test group OD value) / control group OD value*100%; the IC 50 value was calculated by regression analysis (probit analysis, SPSS 16.0). The test results are shown in Table 2.

[0139] Table 2

[0140]

[0141]

[0142] As can be seen from Table 2, the pentacyclic triterpenoid compounds prepared in Examples 1-20 of the present application exhibit good inhibitory activity on cyclooxygenase COX-2, and the effect is obviously better than that of indomethacin and resveratrol, which indicates that the pentacyclic triterpenoid compounds prepared in the present application are suitable for preparing anti-inflammatory drugs or anti-inflammatory cosmetics.

[0143] Examples 21-40

[0144] The examples of the pentacyclic triterpenoid compounds, the preparation method of the pentacyclic triterpenoid compounds, include the following steps:

[0145] S1, 10 g of the reactant A is dissolved in 80 mL of anhydrous dichloromethane at 0℃, 3 mL of triethylamine and the reactant B are sequentially added, the molar ratio of the reactant B to the reactant A is 1:1, and the reaction is stirred at 0℃ for 30 min; then the temperature is increased to room temperature (25℃), and the reaction is incubated at room temperature for 5 h; after the reaction is completed by thin layer detection, the organic solvent is removed by evaporation under reduced pressure, 50 mL of ethyl acetate and 50 mL of deionized water are added for extraction, and the organic phase is obtained; the organic phase is dried over anhydrous sodium sulfate, and then filtered and concentrated to obtain a concentrate; the reactant A and the reactant B are as shown in Table 3.

[0146] S2, the concentrate obtained in step S1 is subjected to silica gel column chromatography to obtain the pentacyclic triterpenoid compound, and the yield is as shown in Table 3, the yield = (theoretical yield of the compound - actual yield of the compound) / the theoretical yield of the compound.

[0147] The pentacyclic triterpenoid compounds obtained in the above Examples 21-40 are subjected to nuclear magnetic resonance detection.

[0148] It can be known from the detection of carbon spectrum and hydrogen spectrum that the pentacyclic triterpenoid compounds as shown below are successfully prepared in Examples 21-40:

[0149] Among them, -R1, -R2 and -R3 are as shown in Table 3.

[0150] Table 3

[0151]

[0152]

[0153] Effect Example 2

[0154] To verify the efficacy of the pentacyclic triterpenoids obtained in Examples 21-40, the procedure of Effect Example 1 was followed. The results of the testing showed that the pentacyclic triterpenoids obtained in Examples 21-40 had an inhibition rate of COX-2 of no less than 90%, and an IC50 of no more than 45 μM. 50 no more than 45 μM.

[0155] Finally, it should be noted that the above examples are merely used to illustrate the technical solutions of the present application and not to limit the scope of protection of the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced by equivalents without departing from the spirit and scope of the present application.

Claims

1. A pentacyclic triterpenoid compound, characterized in that, A structure formula is as follows: ， Wherein, R1 is organic diacid monomethyl ester acyl, R2 is -CH3 or -H, and R3 is -CH3 or -H; The organic diacid monomethyl ester acyl is selected from any one of succinic acid monomethyl ester acyl, maleic acid monomethyl ester acyl, adipic acid monomethyl ester acyl, suberic acid monomethyl ester acyl, azelaic acid monomethyl ester acyl, sebacic acid monomethyl ester acyl, dodecanedioic acid monomethyl ester acyl.

2. A method for preparing the pentacyclic triterpenoid compound as described in claim 1, characterized in that, Comprising the following steps: S1, in the presence of an organic solvent, by stirring reaction of a pentacyclic triterpenoid raw material and organic diacid monomethyl ester or organic diacid monomethyl ester acyl chloride under the action of an organic amine, to obtain a reaction crude product; The organic diacid monomethyl ester acyl chloride is selected from any one of succinic acid monomethyl ester acyl chloride, maleic acid monomethyl ester acyl chloride, adipic acid monomethyl ester acyl chloride, suberic acid monomethyl ester acyl chloride, azelaic acid monomethyl ester acyl chloride, sebacic acid monomethyl ester acyl chloride, dodecanedioic acid monomethyl ester acyl chloride; The organic diacid monomethyl ester is selected from any one of succinic acid monomethyl ester, maleic acid monomethyl ester, adipic acid monomethyl ester, suberic acid monomethyl ester, azelaic acid monomethyl ester, sebacic acid monomethyl ester, dodecanedioic acid monomethyl ester; S2, the reaction crude product obtained in step S1 is evaporated to remove the organic solvent under reduced pressure to obtain a concentrate; The pentacyclic triterpenoid raw material is selected from at least one of oleanolic acid and ursolic acid; S3, the concentrate obtained in step S2 is subjected to silica gel column chromatography to obtain the pentacyclic triterpenoid compound.

3. The method for preparing the pentacyclic triterpenoid compound as described in claim 2, characterized in that, The molar ratio of the organic diacid monomethyl ester acyl chloride to the pentacyclic triterpenoid raw material is (1-2):

1.

4. The method for preparing the pentacyclic triterpenoid compound as described in claim 2, characterized in that, Step S1 specifically comprises: dissolving the organic diacid monomethyl ester in the organic solvent at 0-5℃, then sequentially adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, and stirring and reacting for 20-40 min, adding the pentacyclic triterpenoid raw material and the organic amine to the above reaction mixture at 0-5℃, and continuing to stir and react for 3-8 h to obtain the reaction crude product.

5. The method for preparing the pentacyclic triterpenoid compound as described in claim 2, characterized in that, Step S1 specifically comprises: dissolving the pentacyclic triterpenoid raw material in the organic solvent at 0-5℃, sequentially adding the organic amine and the organic diacid monomethyl ester acyl chloride, stirring and reacting for 20-40 min, and then stirring and reacting for 1-5 h after being warmed to 16-26℃ to obtain the reaction crude product.

6. Use of the pentacyclic triterpenoid compound of claim 1 in the preparation of an anti-inflammatory drug.

7. Use according to claim 6, wherein The dosage form of the anti-inflammatory drug is selected from tablets, granules, and capsules.

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