Compound having effect of improving insulin resistance or its pharmaceutically acceptable salt and preparation method and application thereof

Abstract

The invention discloses a compound having an effect of improving insulin resistance or a pharmaceutical salt thereof, and a preparation method and application thereof, and relates to the technical field of chemical drugs; the invention discloses a plurality of compounds having an effect of improving insulin resistance obtained by extraction and separation from red ganoderma lucidum, and the compounds have the effects of activating Akt or phosphorylation of insulin receptor substrate 1, promoting glucose uptake in a dose-dependent manner, lowering blood sugar and reducing fat, indicating the value of the compounds in preparing drugs for preventing or treating diseases related to insulin resistance.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical medicines, and in particular to a compound having the effect of improving insulin resistance or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof. Background Art

[0002] Insulin resistance is a type of metabolic syndrome and is closely related to many diseases, such as diabetes, polycystic ovary syndrome, Alzheimer's disease, non-alcoholic fatty liver disease, hypertension, atherosclerosis and obesity. At present, there are 11 drugs approved for insulin resistance in the world, 7 drugs in phase III clinical trials, 7 drugs in phase II clinical trials, 7 drugs in phase I clinical trials, and 13 drugs that have been terminated. In addition, the indications of these drugs are mostly for metabolic diseases caused by insulin resistance, such as diabetes, the cause of which is insulin resistance. These drugs are mainly aimed at controlling blood sugar and delaying the occurrence of diabetic complications, so they cannot completely cure diabetes. In addition, these drugs are mostly chemical drugs and organic heterocyclic drugs. Many side effects have been found in the clinical use process, such as gastrointestinal discomfort such as nausea and vomiting, acute kidney injury and vitamin B deficiency. Based on the above understanding, it is necessary and urgent to find safe drugs that can directly improve insulin resistance. Summary of the invention

[0003] In order to overcome the existing technical defects, the purpose of the present invention is to provide a compound or a pharmaceutical salt thereof having the effect of improving insulin resistance, and a preparation method and application thereof. The present invention discloses a plurality of compounds having the effect of improving insulin resistance obtained by extraction and separation from red ganoderma lucidum, and the compounds have the effects of activating Akt phosphorylation or insulin receptor substrate 1 phosphorylation, promoting glucose uptake in a dose-dependent manner, lowering blood sugar and reducing fat.

[0004] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0005] In a first aspect, a compound or a pharmaceutically acceptable salt thereof having the effect of improving insulin resistance is provided, wherein the compound is used to activate Akt phosphorylation and promote glucose uptake; the compound has a structure shown in Formula I:

[0006]

[0007] In a second aspect, a compound or a pharmaceutically acceptable salt thereof having the effect of improving insulin resistance is provided, wherein the compound is used to activate phosphorylation of insulin receptor substrate 1 and reduce blood sugar and fat weight; the compound has a structure shown in Formula II:

[0008]

[0009] In the present invention, the pharmaceutically acceptable salts of the above compounds may be sodium salts, potassium salts, ammonium salts, amino acid salts, lactates, hydrochlorides, phosphates, acetates, malates, citrates or aspartates, etc. The present invention does not specifically limit the pharmaceutical salts.

[0010] In a third aspect, a method for preparing the compound having the effect of improving insulin resistance as described in the first aspect is provided, wherein the method comprises the following steps:

[0011] (1) Ganoderma lucidum is crushed, extracted with an organic solvent, and concentrated under reduced pressure to obtain an extract, which is suspended in warm water and extracted with ethyl acetate to obtain an ethyl acetate extract;

[0012] (2) The ethyl acetate extract was separated by MCI gel CHP 20P column chromatography, and gradient eluted with methanol-water solution with volume ratios of 40:60, 45:55, 50:50, 55:45, 65:35, 75:25, 85:15, 90:10, 95:5, and 100:0, respectively. The eluate was detected by TLC, and the same fractions were combined to obtain 17 fractions from Fr.1 to Fr.17;

[0013] (3) Fr.4 was separated by Sephadex LH-20 column chromatography with methanol as the eluent. After the sample was eluted, TLC was used for detection. The same fractions were combined to obtain two fractions, Fr.4.1 and Fr.4.2;

[0014] (4) Fr.4.2 was separated by RP-18 column chromatography and eluted with a methanol-water solution gradient with a volume ratio of 20:80, 23:77, 28:72, 33:67, 38:62, 43:57, 48:42, and 53:47, respectively. After the sample was eluted, it was detected by TLC, and the same fractions were combined to obtain a total of 5 fractions, Fr.4.2.1-Fr.4.2.5;

[0015] (5) Fr.4.2.4 was separated by Sephadex LH-20 column chromatography, eluted with a methanol-water solution with a volume ratio of 70:30, and then purified by silica gel column chromatography, and gradient eluted with a dichloromethane-methanol solution with a volume ratio of 15:1, 8:1, and 3:1, respectively. After the sample was eluted, it was detected by TLC, and the same fractions were combined to obtain a total of 8 fractions from Fr.4.2.4.1 to Fr.4.2.4.8;

[0016] (6) Fr.4.2.4.3 was subjected to solid phase extraction and gradient eluted with dichloromethane-methanol solution with a volume ratio of 10:1, 5:1, and 3:1, respectively. After the sample was eluted, it was detected by TLC, and the same fractions were combined to obtain a total of 4 fractions, Fr.4.2.4.3.1-Fr.4.2.4.3.4;

[0017] (7) Fr.4.2.4.3.2 was separated by Sephadex LH-20 column chromatography using methanol as eluent, and then purified by semi-preparative HPLC to obtain the compound, which was then chirally resolved to obtain the target compound of formula I.

[0018] Furthermore, in step (1), the organic solvent is an ethanol solution, and the volume ratio of the ethanol solution to Ganoderma lucidum is 6:1; the number of reflux extractions is 1 to 3 times, and the number of extractions is 3 to 5 times.

[0019] Preferably, the ethanol solution is 80% ethanol solution; the number of reflux extractions is 2 times, and the number of extractions is 4 times.

[0020] Preferably, in step (2), the amount of methanol-water with a volume ratio of 40:60, 45:55, 50:50, 55:45, 65:35, 75:25, 85:15, 90:10, 95:5, and 100:0 is 181 L, 136 L, 59 L, 136 L, 136 L, 136 L, 136 L, 136 L, 96 L, and 136 L, respectively.

[0021] Preferably, in step (4), the amount of methanol-water used in a volume ratio of 20:80, 23:77, 28:72, 33:67, 38:62, 43:57, 48:42, 53:47 is 15-20 L.

[0022] Further, in step (7), the conditions of the semi-preparative HPLC are: the mobile phase is an acetonitrile-water solution with a volume ratio of 20:80 at 0-25 min, and the mobile phase is an acetonitrile-water solution with a volume ratio of 25:75 at 25.1-60 min, with a flow rate of 3 mL / min; the water in the mobile phase contains 0.05% TFA;

[0023] The elution solvent for the chiral separation is n-hexane-ethanol with a volume ratio of 88:12, and the ethanol in the elution solvent contains 0.05% TFA.

[0024] In a fourth aspect, a method for preparing the compound having the effect of improving insulin resistance as described in the second aspect is provided, the preparation method comprising the following steps:

[0025] (1) Ganoderma lucidum is crushed, extracted with an organic solvent, and concentrated under reduced pressure to obtain an extract, which is suspended in warm water and extracted with ethyl acetate to obtain an ethyl acetate extract;

[0026] (2) the ethyl acetate extract was separated by Sephadex LH-20 column chromatography using methanol as the eluent, and the elution was detected by TLC. The same fractions were combined to obtain three fractions, namely Fr.A-Fr.C;

[0027] (3) Fr.B was chromatographed on an MCI gel CHP 20P column using a gradient elution of methanol-water solution with a volume ratio of 40:60, 45:55, 50:50, 55:45, 65:35, 75:25, 85:15, 90:10, 95:5, and 100:0, followed by TLC detection. The same fractions were combined to obtain 12 fractions, including Fr.BA-Fr.BL;

[0028] (4) Fr.BB was chromatographed on a Sephadex LH-20 column using methanol as the eluent. After elution, TLC was used for detection. The same fractions were combined to obtain three fractions, Fr.BB1-Fr.BB3;

[0029] (5) Fr.BB2 was chromatographed on an MCI gel CHP 20P column using a gradient elution with a methanol-water solution having a volume ratio of 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 65:35, 75:25, 85:15, 90:10, 95:5, and 100:0, followed by TLC detection. The same fractions were combined to obtain a total of 7 fractions, namely Fr.BB21-Fr.BB27;

[0030] (6) Fr.BB22 was chromatographed on a YMC-GEL ODS-A-HG column, and gradient eluted with a methanol-water solution with a volume ratio of 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 65:35, 75:25, 85:15, 90:10, 95:5, and 100:0, and detected by TLC after elution. The same fractions were combined to obtain a total of 8 fractions, Fr.BB221-Fr.BB228;

[0031] (7) Fr.BB226 was purified by the first semi-preparative HPLC to obtain the target compound described in Formula II.

[0032] Furthermore, in step (1), the organic solvent is an ethanol solution, and the volume ratio of the ethanol solution to Ganoderma lucidum is 10:1; the extraction flow rate is 230 mL / min, and the number of extractions is 3 to 5 times.

[0033] Preferably, the ethanol solution is a 95% ethanol solution; the number of extractions is 4, and the extractions are equal volume extractions.

[0034] Furthermore, in step (7), the first half of the preparative HPLC conditions are: the mobile phase is an acetonitrile-water solution with a volume ratio of 31:69, and the water contains 0.05% TFA; the flow rate is 3 mL / min.

[0035] The preparation method of the compound represented by formula III is similar to the preparation method of the compound represented by formula II, except that when the target compound represented by formula II is prepared in step (7), one component obtained at the same time is further purified by a second semi-preparative HPLC to obtain the target compound represented by formula III.

[0036] Preferably, in the method for preparing the compound of formula III, the second semi-preparative HPLC conditions are: the mobile phase is an acetonitrile-water solution with a volume ratio of 23:77, and the water contains 0.05% TFA; the flow rate is 3 mL / min.

[0037] Preferably, in the preparation method of the present invention, the red ganoderma is produced in Baoshan, Yunnan, and the temperature of the warm water is between 25°C and 40°C; the volume of the eluent and the gradient eluent can be adaptively adjusted according to the specific weight of the sample and experimental requirements.

[0038] In a fifth aspect, a pharmaceutical composition is provided, comprising the compound having an effect of improving insulin resistance or a pharmaceutically acceptable salt thereof according to the first aspect and / or the second aspect and / or the compound having an effect of improving insulin resistance having a structure shown in formula III or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or adjuvant;

[0039]

[0040] The pharmaceutical composition described in the present invention uses at least one of the compounds described in the first aspect and the second aspect or their pharmaceutically acceptable salts as the main active ingredient, and does not exclude changes in the preparation system and administration method, derivatives after simple chemical modification and adjustment of the above-mentioned multiple compounds, and the combined use of multiple compounds (i.e., using one or more of the above-mentioned three compounds).

[0041] In the present invention, the compounds provided by the present invention can be formulated as active ingredients in a non-toxic, inert and pharmaceutically acceptable carrier medium; the formulated drugs can be administered by conventional routes, including but not limited to oral, intramuscular, intraperitoneal, intravenous, subcutaneous, intradermal, or topical administration.

[0042] When the dosage form of the pharmaceutical composition of the present invention is a drug for oral administration, it contains a safe and effective amount of the above-mentioned compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and / or adjuvant. The drug for oral administration can be prepared into common dosage forms such as tablets, pills, powders, granules, capsules, emulsions, syrups, ointments, suppositories, etc.; in the present invention, no specific limitation is made to the carriers and / or adjuvants.

[0043] The pharmaceutical composition of the present invention can also be prepared into an injection, which can be prepared by mixing with water for injection, physiological saline or glucose water under a sterile environment. The injection can be prepared by conventional methods.

[0044] In the sixth aspect, provided is the use of the compound having an effect of improving insulin resistance as described in the first aspect or the second aspect or its pharmaceutical salt, the compound having an effect of improving insulin resistance with a structure shown in formula III or its pharmaceutical salt, and the pharmaceutical composition as described in the fifth aspect in the preparation of a drug for activating Akt phosphorylation and / or treating diseases related to insulin resistance.

[0045] Specifically, the above-mentioned related diseases such as insulin resistance are prone to metabolic syndrome and type II diabetes.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] The present invention discloses new compounds (Formula I and Formula II) extracted and separated from Ganoderma lucidum with the effect of improving insulin resistance, wherein the compound shown in Formula I can activate Akt phosphorylation and promote glucose uptake in a dose-dependent manner, and the compounds shown in Formula II and Formula III can activate insulin receptor substrate 1 phosphorylation and reduce blood sugar and fat weight, indicating the value of the various compounds provided by the present invention in preparing drugs for preventing or treating diseases related to insulin resistance.

[0048] Additional aspects and advantages of the present invention will be given in part in the following description, which will become obvious from the following description, or may be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 This is a schematic diagram of the test results of the cell viability experiment of the compound (+)-Spiroganodermaine G in the present invention;

[0050] Figure 2 This is a schematic diagram of the test results of the AKT phosphorylation experiment of the compound (+)-Spiroganodermaine G in the present invention;

[0051] Figure 3 This is a schematic diagram of the test results of the glucose uptake experiment of the compound (+)-Spiroganodermaine G of the present invention;

[0052] Figure 4 It is a schematic diagram of the test results of glucose uptake experiment and dosage of the compound (+)-Spiroganodermaine G in the present invention;

[0053] Figure 5Schematic diagram of the test results of the cell viability experiment of the compounds (+)-Spiroapplanatumine K and (+)-Spirolingzhine D in the present invention;

[0054] Figure 6 This is a schematic diagram of the test results of the compounds (+)-Spiroapplanatumine K and (+)-Spirolingzhine D in the present invention improving the expression of p-IRS1;

[0055] Figure 7 The figure is a picture of the weight changes of mice in different experimental groups in the insulin resistance mouse model of the present invention;

[0056] Figure 8 It is a schematic diagram of the weight change trend of mice in different experimental groups in the insulin resistance mouse model of the present invention;

[0057] Fig. 9 It is a schematic diagram of the change trend of food intake of mice in different experimental groups in the insulin resistance mouse model of the present invention;

[0058] Fig.10 This is a schematic diagram of blood sugar changes in mice in different experimental groups after glucose injection in the insulin resistance mouse model of the present invention;

[0059] Fig.11 The pictures are of the changes in the weight of liver, epididymis, subcutaneous tissue and brown fat of mice in different experimental groups in the insulin resistance mouse model of the present invention;

[0060] Fig.12 It is a schematic diagram of the weight change trend of the liver, epididymis, subcutaneous and brown fat of mice in different experimental groups in the insulin resistance mouse model of the present invention. DETAILED DESCRIPTION

[0061] In order to more fully understand the technical content of the present invention, the present invention will be further introduced and illustrated in conjunction with the accompanying drawings and specific embodiments below; it is obvious that the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments; based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making creative work are within the scope of protection of the present invention.

[0062] For those skilled in the art, the features, benefits and advantages of the present invention will become apparent by reading the contents disclosed in this specification.

[0063] Unless otherwise indicated, all percentages, parts and ratios are calculated based on the total weight of the composition of the present invention. The term "weight content" may be represented herein by the symbol "%".

[0064] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0065] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs or other chemical components that improve insulin resistance.

[0066] The term "compound (+)-Spiroganodermaine G" is a compound of formula I, "compound (+)-Spiroapplanatumine K" is a compound of formula II, and "compound (+)-Spirolingzhine D" is a compound of formula III.

[0067] Example 1

[0068] This example provides the extraction and separation method and structural identification of the above compounds.

[0069] 1. A method for extracting and isolating the compound (+)-Spiroganodermaine G, comprising the following steps:

[0070] 1.1. Take 500 kg of Ganoderma lucidum produced in Baoshan, Yunnan, crush it, extract it twice with 6 times the volume of 80% ethanol, and concentrate it under reduced pressure to obtain 24.6 kg of extract, suspend it in warm water, and extract it 4 times with an equal volume of ethyl acetate to obtain 11.5 kg of ethyl acetate extract;

[0071] 1.2. The ethyl acetate extract (11.5 kg) was separated by MCI gel CHP 20P column chromatography, and gradient eluted with methanol / water (40:60, 181 L, 45:55, 136 L, 50:50, 59 L, 55:45, 136 L, 65:35, 136 L, 75:25, 136 L, 85:15, 136 L, 90:10, 136 L, 95:5, 96 L, 100:0, 136 L), and the eluate was collected and detected by TLC. The same fractions were combined to obtain 17 fractions from Fr.1 to Fr.17;

[0072] 1.3, Fr.4 (78.7 g) was separated by Sephadex LH-20 column chromatography with methanol as eluent, and the sample was detected by TLC after elution, and the same fractions were combined to obtain two fractions, Fr.4.1 and Fr.4.2;

[0073] 1.4, Fr.4.2 (72.4 g) was separated by RP-18 column chromatography, and gradient eluted with methanol-water solution with volume ratios of 20:80, 23:77, 28:72, 33:67, 38:62, 43:57, 48:42, 53:47, and detected by TLC after the sample was eluted. The same fractions were combined to obtain 5 fractions from Fr.4.2.1 to Fr.4.2.5;

[0074] 1.5, Fr.4.2.4 (10.5 g) was separated by Sephadex LH-20 column chromatography, eluted with a methanol-water solution with a volume ratio of 70:30, and then purified by silica gel column chromatography, and gradient eluted with a dichloromethane-methanol solution with a volume ratio of 15:1, 8:1, and 3:1, respectively. After the sample was eluted, it was detected by TLC, and the same fractions were combined to obtain 8 fractions from Fr.4.2.4.1 to Fr.4.2.4.8;

[0075] 1.6, Fr.4.2.4.3 (1.3 g) was subjected to solid phase extraction (SPE), and gradient eluted with dichloromethane-methanol solution with volume ratios of 10:1, 5:1, and 3:1, respectively. After the sample was eluted, it was detected by TLC, and the same fractions were combined to obtain a total of 4 fractions, namely Fr.4.2.4.3.1-Fr.4.2.4.3.4;

[0076] 1.7, Fr.4.2.4.3.2 (550.4 mg) was separated by Sephadex LH-20 column chromatography with methanol as eluent, and then purified by semi-preparative HPLC [acetonitrile / water, water containing 0.05% TFA, 20:80 (0-25 min), 25:75 (25.1-60 min), flow rate 3 mL / min] to obtain the compound, and the compound was chiral resolved (eluting solvent was n-hexane-ethanol with a volume ratio of 88:12; ethanol contained 0.05% TFA) to obtain the target compound (+)-Spiroganodermaine G (1.7 mg, t R =8.8min).

[0077] It is worth noting that the compound purified by semi-preparative HPLC is a pair of enantiomers, and therefore, chiral resolution is required to obtain the target compound (+)-Spiroganodermaine G.

[0078] 2. Extraction and separation of compound (+)-Spiroapplanatumine K and compound (+)-Spirolingzhine D

[0079] 2.1. Ganoderma lucidum 50 kg produced in Yunnan was crushed and extracted with 10 times the volume fraction of 95% ethanol by percolation at an extraction flow rate of 230 ml / min. The ethanol was recovered under reduced pressure to obtain 2.7 kg of extract. The extract was suspended in warm water and extracted with ethyl acetate in equal volume for 4 times to obtain 2.4 kg of ethyl acetate extract.

[0080] 2.2. The ethyl acetate extract was separated by Sephadex LH-20 column chromatography with methanol as the eluent. After elution, TLC was used for detection. The same fractions were combined to obtain three fractions, namely Fr.A-Fr.C.

[0081] (3) Fr.B (813.7 g) was chromatographed on an MCI gel CHP 20P column using a gradient elution with a methanol-water solution having a volume ratio of 40:60, 45:55, 50:50, 55:45, 65:35, 75:25, 85:15, 90:10, 95:5, and 100:0, followed by TLC detection. The same fractions were combined to obtain 12 fractions, including Fr.BA-Fr.BL.

[0082] (4) Fr.BB (20.4 g) was chromatographed on a Sephadex LH-20 column using methanol as the eluent. After elution, TLC was used for detection. The same fractions were combined to obtain three fractions, namely Fr.BB1-Fr.BB3.

[0083] (5) Fr.BB2 (14.8 g) was purified by MCI gel CHP 20P column chromatography and eluted with a methanol-water solution with a volume ratio of 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 65:35, 75:25, 85:15, 90:10, 95:5, and 100:0, respectively. After elution, TLC was used for detection. The same fractions were combined to obtain 7 fractions, namely Fr.BB21-Fr.BB27;

[0084] (6) Fr.BB22 (5.3 g) was chromatographed on a YMC-GEL ODS-A-HG column and eluted with a methanol-water solution in a volume ratio of 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 65:35, 75:25, 85:15, 90:10, 95:5, and 100:0, respectively. After elution, TLC was used for detection. The same fractions were combined to obtain 8 fractions, namely Fr.BB221-Fr.BB228;

[0085] (7) Fr.BB226 (1.5 g) was purified by semi-preparative HPLC (mobile phase: acetonitrile-water solution with a volume ratio of 31:69, water containing 0.05% TFA, flow rate 3 mL / min) to obtain the target compound (+)-Spiroapplanatumine K (11.8 mg, t R =11.0min);

[0086] (8) One component obtained at the same time was purified by semi-preparative HPLC (the mobile phase was acetonitrile-water solution with a volume ratio of 23:77, water containing 0.05% TFA, flow rate 3 mL / min) to obtain the target compound (+)-Spirolingzhine D (39.3 mg, t R =15.2min).

[0087] The compounds (+)-Spiroganodermaine G, (+)-Spiroapplanatumine K and (+)-Spirolingzhine D prepared above were identified, and the identification results are as follows.

[0088] The structural formulas of the compounds (+)-Spiroganodermaine G, (+)-Spiroapplanatumine K and (+)-Spirolingzhine D are as follows:

[0089]

[0090] Compound (+)-Spiroganodermaine G(1), yellow colloid, [α] D 25 +34.3(c 0.02,MeOH); CD(MeOH)Δε 232 +6.50,Δε 256 –0.34,Δε 319 +0.51,Δε 360 –1.01; UV(MeOH)λ max (logε)370(3.58),254(3.86),220(4.15)nm; HRESIMS m / z 319.1178[MH] - (calcd for C 17 H 19 O 6 ,319.1187); 1 H and 13 C NMR data are shown in Table 1.

[0091] Compound (+)-Spiroapplanatumine K(2), yellow colloid, [α] D 25 +160.0(c 0.01,MeOH); CD(MeOH)Δε 237 +3.91,Δε 320 –2.33,Δε 365 +3.92; UV(MeOH)λ max (logε)373(3.57),255(3.82),225(3.91)nm; HRESIMS m / z 319.1171[M+H] + (calcd for C 17 H 19 O 6 ,319.1176); 1 Hand 13 C NMR data are shown in Table 1.

[0092] Compound (+)-Spirolingzhine D(3), yellow colloid, [α] D 25 +148.0 (c 0.03, MeOH), (+)-Spirolingzhine D is a known compound, which was published by the applicant in Phytochemistry in 2015. After careful comparison of HPLC retention time, NMR, optical rotation and circular dichroism spectra, it was confirmed to be the same compound.

[0093] Table 1: Compounds (+)-Spiroganodermaine G (1) and (+)-Spiroapplanatumine K (2) 1 H and 13 C NMR data

[0094]

[0095]

[0096] Embodiment 2:

[0097] This embodiment provides an injection, and the preparation method of the injection is as follows:

[0098] The compound (+)-Spiroganodermaine G prepared in Example 1 is added with an injection solvent according to a conventional method, finely filtered, and sterilized by filling to prepare an injection solution.

[0099] Alternatively, the compound (+)-Spiroapplanatumine K prepared in Example 1 can be added with an injection solvent according to a conventional method, finely filtered, and sterilized by filling to prepare an injection solution.

[0100] Alternatively, the compound (+)-Spirolingzhine D prepared in Example 1 can be added with an injection solvent according to a conventional method, finely filtered, and sterilized by filling to prepare an injection solution.

[0101] Alternatively, two or three compounds (+)-Spiroganodermaine G, (+)-Spiroapplanatumine K and (+)-Spirolingzhine D prepared in Example 1 are mixed in any proportion, and an injection solution is prepared by adding an injection solvent according to a conventional method, fine filtering, and filling and sterilization.

[0102] Embodiment 3:

[0103] This embodiment provides a pharmaceutical tablet, and the preparation method of the pharmaceutical tablet is as follows:

[0104] The compound (+)-Spiroganodermaine G prepared in Example 1 can be prepared into tablets by conventional methods with various pharmaceutical excipients.

[0105] Specifically, the compound (+)-Spiroganodermaine G is used as a pharmaceutical active ingredient, and one or more commonly used excipients are used as auxiliary ingredients for preparing pharmaceutical tablets, and tablet samples containing 1-100 mg of the pharmaceutical ingredient per tablet are prepared according to a certain ratio.

[0106] Alternatively, the compound (+)-Spiroapplanatumine K prepared in Example 1 can be prepared into tablets by conventional methods with various pharmaceutical excipients.

[0107] Specifically, the compound (+)-Spiroapplanatumine K is used as a pharmaceutical active ingredient, and one or more commonly used excipients are used as auxiliary ingredients for preparing pharmaceutical tablets, and tablet samples containing 1-100 mg of the pharmaceutical ingredient per tablet are prepared according to a certain ratio.

[0108] Alternatively, the compound (+)-Spirolingzhine D prepared in Example 1 can be prepared into tablets by conventional methods with various pharmaceutical excipients.

[0109] Specifically, the compound (+)-Spirolingzhine D is used as a pharmaceutical active ingredient, and one or more commonly used excipients are used as auxiliary ingredients for preparing pharmaceutical tablets, and tablet samples containing 1-100 mg of the pharmaceutical ingredient per tablet are prepared according to a certain ratio.

[0110] Alternatively, two or three compounds (+)-Spiroganodermaine G, (+)-Spiroapplanatumine K and (+)-Spirolingzhine D prepared in Example 1 can be mixed in any proportion and prepared into tablets by adding various pharmaceutical excipients according to conventional methods.

[0111] Specifically, 2 or 3 compounds (+)-Spiroganodermaine G, (+)-Spiroapplanatumine K, and (+)-Spirolingzhine D are mixed in any proportion and used as active pharmaceutical ingredients, and one or more commonly used excipients are used as auxiliary ingredients for preparing combined pharmaceutical tablets, and tablet samples containing 1-100 mg of the pharmaceutical ingredient per tablet are prepared in a certain proportion.

[0112] Embodiment 4:

[0113] This embodiment provides a drug capsule, and the preparation method of the drug capsule is as follows:

[0114] The compound (+)-Spiroganodermaine G prepared in Example 1 was mixed with various pharmaceutical excipients according to conventional methods to prepare capsules.

[0115] Specifically, the compound (+)-Spiroganodermaine G is used as a pharmaceutical active ingredient, and one or more commonly used excipients are used as auxiliary ingredients for preparing pharmaceutical capsules, and a capsule preparation containing 1-100 mg of the compound ingredient in each capsule is prepared according to a certain ratio.

[0116] Alternatively, the compound (+)-Spiroapplanatumine K prepared in Example 1 can be prepared into capsules by conventional methods with various pharmaceutical excipients.

[0117] Specifically, the compound (+)-Spiroapplanatumine K is used as a pharmaceutical active ingredient, and one or more commonly used excipients are used as auxiliary ingredients for preparing pharmaceutical capsules, and a capsule preparation containing 1-100 mg of the compound ingredient in each capsule is prepared according to a certain ratio.

[0118] Alternatively, the compound (+)-Spirolingzhine D prepared in Example 1 can be prepared into capsules by conventional methods with various pharmaceutical excipients.

[0119] Specifically, the compound (+)-Spirolingzhine D is used as the active ingredient of the drug, and one or more commonly used excipients are used as auxiliary ingredients for preparing drug capsules, and a capsule preparation containing 1-100 mg of the compound ingredient in each capsule is prepared according to a certain ratio.

[0120] Alternatively, two or three compounds (+)-Spiroganodermaine G, (+)-Spiroapplanatumine K and (+)-Spirolingzhine D prepared in Example 1 are mixed in any proportion and prepared into capsules by conventional methods with various pharmaceutical excipients.

[0121] Specifically, 2 or 3 compounds (+)-Spiroganodermaine G, (+)-Spiroapplanatumine K, and (+)-Spirolingzhine D are mixed in any proportion and used as active pharmaceutical ingredients, and one or more commonly used excipients are used as auxiliary ingredients for preparing combined pharmaceutical capsules, and the mixture is prepared in a certain proportion so that each capsule contains 1-100 mg of the compound ingredients.

[0122] Embodiment 5:

[0123] This embodiment provides a solid beverage, and the preparation method of the solid beverage is as follows:

[0124] Take 1 part of the compound (+)-Spiroganodermaine G prepared by the method of Example 1 and 10 parts of non-dairy creamer, mix them well, and prepare a solid beverage according to a conventional method;

[0125] Alternatively, 1 part of the compound (+)-Spiroapplanatumine K prepared by the method of Example 1 and 10 parts of non-dairy creamer are mixed and prepared into a solid beverage according to a conventional method;

[0126] Alternatively, 1 part of the compound (+)-Spirolingzhine D prepared by the method of Example 1 and 10 parts of non-dairy creamer are mixed and prepared into a solid beverage according to a conventional method;

[0127] Alternatively, 1 part of 2 or 3 compounds (+)-Spiroganodermaine G, (+)-Spiroapplanatumine K, and (+)-Spirolingzhine D prepared by the method of Example 1 are taken in any proportion, and 10 parts of non-dairy creamer are mixed, and a solid beverage is prepared according to a conventional method.

[0128] Embodiment 6:

[0129] In this example, Cell Count Kit-8, ECL kit and Glucose Colorimetric / Fluorometric Assay Kit were used to detect the activities of AKT phosphorylation, IRS1 phosphorylation and glucose uptake of the above compounds.

[0130] Related experimental tests of compound (+)-Spiroganodermaine G:

[0131] Cell viability assay: The cell viability assay was performed using a conventional Cell Count Kit-8 assay. The specific steps are as follows:

[0132] 1. C2C12 cells (5×10 5 cells / mL) were seeded into 96-well plates with fresh DMEM, and after overnight cell culture, the cells were treated with methanol or DMSO for 24 h;

[0133] 2. Then add Cell Count Kit-8 to each well and incubate at 37°C for 1 hour;

[0134] 3. Measure the absorbance of each well at 450 nm using an enzyme reader.

[0135] The test results of the cell viability experiment of compound (+)-Spiroganodermaine G are as follows Figure 1 shown.

[0136] AKT phosphorylation assay:

[0137] 1. Take the following compounds and dissolve them in DMSO to form 20 mM storage solution; compound (+)-7 is the compound (+)-Spiroganodermaine G provided by the present invention;

[0138]

[0139] 2. Grow C2C12 cells in DMEM containing 10% FBS (fetal bovine serum) until contact inhibition occurs. Replace the cell culture medium with fresh DMEM containing 2% horse serum, 100 U / mL penicillin and 100 μg / mL streptomycin, and incubate at 37°C for 4 days.

[0140] 3. Add 100 nM insulin to the induction medium for 24 h while the cells are differentiating to simulate insulin resistance. After 24 h of compound treatment, extract total protein from the cell line and use quantitative protein samples;

[0141] 4. Equal amounts of protein extracts were separated by 8% SDS-PAGE and transferred to PVDF membranes. The membranes were blocked with 5% bovine serum albumin and then incubated with designated antibodies overnight at 4°C, followed by incubation with horseradish peroxidase (HRP)-conjugated secondary antibodies at room temperature;

[0142] 5. Visualize and measure the bands using the ECL kit. Perform density measurement analysis on the immunoblotting results using ImageJ software.

[0143] The test results of the AKT phosphorylation experiment of compound (+)-Spiroganodermaine G are as follows Figure 2 shown.

[0144] Glucose uptake experiment:

[0145] 1. Incubate the differentiated C2C12 cells in DMEM (low glucose) for 6 h;

[0146] 2. Add the above compounds to high-glucose DMEM. After 30 minutes of compound treatment, add insulin (100 nmol / L) and continue culturing for 4 hours;

[0147] 3. Use a glucose colorimetric / fluorescence assay kit to determine the glucose content in the culture supernatant.

[0148] The test results of the glucose uptake experiment of compound (+)-Spiroganodermaine G are as follows Figure 3 shown.

[0149] Related experimental tests of compounds (+)-Spiroapplanatumine K and (+)-Spirolingzhine D:

[0150] Cell viability assay

[0151] For the cell viability test, see the cell viability test of compound (+)-Spiroganodermaine G; the test results of the cell viability test of compounds (+)-Spiroapplanatumine K and (+)-Spirolingzhine D are as follows: Figure 5 shown.

[0152] Figure 5 Among them, 30A is compound (+)-Spirolingzhine D, and 30B is (+)-Spiroapplanatumine K.

[0153] Among them, after C2C12 cells were treated with 20 μM compound for 24 h, the expression of p-IRS1 was detected by Western blot. The test results are as follows Figure 6 shown.

[0154] Insulin resistance mouse model:

[0155] 1. C57BL6 / J male mice (30), 6 weeks old, were randomly divided into a normal chow diet (ND) control group (10 mice) and a high fat diet (HFD) model group (20 mice) according to body weight after 3 days of adaptive feeding. They were fed with ND (10 kcal% Fat) and HFD (60 kcal% Fat) for 14-16 weeks, respectively. During this period, the growth status of the mice was closely monitored, and the food intake and weight of the mice were recorded regularly. In addition, the living conditions of the two groups of mice were the same.

[0156] 2. After feeding on a high-fat diet for 3 months, the mice were given the compound (+)-Spirolingzhine D (32.4 mg / kg) + (+)-Spiroapplanatumine K (7.6 mg / kg) for 17 days and the weight and food intake of the mice were closely monitored and recorded. Figure 7 , Figure 8 and Fig. 9 shown.

[0157] 3. After the administration, the glucose tolerance test (GTT) was performed. After fasting for 12 hours, the mice were intraperitoneally injected with glucose (20% solution, 2 g / kg). The blood glucose of the mice was measured with a blood glucose meter at 0, 15, 30, 60 and 120 minutes after the injection of glucose. The test results are as follows: Fig.10 shown.

[0158] After the administration, the liver, epididymis, subcutaneous tissue and brown fat weights of the mice were measured. Fig.11 and 12 shown.

[0159] Test result analysis:

[0160] like Figure 1 and Figure 5 As shown, by CCK-8 method, compared with the blank control group, the cell viability of the compound (+)-Spiroganodermaine G, (+)-Spiroapplanatumine K, and (+)-Spirolingzhine D groups did not change significantly, indicating that the compounds provided by the present invention have high safety.

[0161] like Figure 2As shown, the compound (+)-Spiroganodermaine G was able to significantly activate AKT phosphorylation at a concentration of 40 μM.

[0162] like Figure 3 and Figure 4 As shown, C2C12 cells were treated with 40 μM compound (+)-Spiroganodermaine G for 24 h, and glucose uptake was measured, with metformin (Met) as a positive control. It was found that compound (+)-Spiroganodermaine G improved glucose uptake in cells stimulated by insulin and attenuated the disruption of the insulin signaling pathway in myotubes. #P<0.05 and ###P<0.001 (compared with the control group without insulin stimulation); *P<0.05 and **P<0.01 (compared with the model group stimulated only by insulin).

[0163] like Figure 6 As shown: Figure 6 30A is (+)-Spirolingzhine D. Figure 6 30B in the figure is (+)-Spiroapplanatumine K. After C2C12 cells were treated with 20 μM of the compound for 24 h, the expression of p-IRS1 was detected by Western blot. Figure 6 It was found that the compound (+)-Spirolingzhine D improved insulin stimulation and attenuated the disruption of the insulin signaling pathway in myotubes ( Figure 6 The compound (+)-Spiroapplanatumine K improved the disruption of the insulin signaling pathway in insulin-stimulated myotubes ( Figure 6 Figure C in the figure).

[0164] like Figure 7-8 As shown: Figure 7-8 In the above formula: 1(32.4mg / kg)+2(7.6mg / kg) is (+)-Spirolingzhine D(32.4mg / kg)+(+)-Spiroapplanatumine K(7.6mg / kg). Figure 7 It was found that after 16 weeks of high-fat diet, the body weight of ND did not change significantly, while the body weight of the HFD group and the HFD + compound (+)-Spirolingzhine D (32.4 mg / kg) + (+)-Spiroapplanatumine K (7.6 mg / kg) group increased (P<0.05). Figure 8It was found that after 17 days of treatment, the weight gain rate of mice in the group injected intraperitoneally with the compound (+)-Spirolingzhine D (32.4 mg / kg) + (+)-Spiroapplanatumine K (7.6 mg / kg) was significantly lower than that in the model group (P<0.05).

[0165] like Fig. 9 As shown: Fig. 9 In the figure: 1(32.4mg / kg)+2(7.6mg / kg) is (+)-Spirolingzhine D(32.4mg / kg)+(+)-Spiroapplanatumine K(7.6mg / kg). Effects of compound (+)-Spirolingzhine D(32.4mg / kg)+(+)-Spiroapplanatumine K(7.6mg / kg) on ​​food intake of mice induced by high-fat diet. Close attention was paid to the food intake of the intraperitoneal injection of the compound (+)-Spirolingzhine D (32.4 mg / kg) + (+)-Spiroapplanatumine K (7.6 mg / kg) on ​​day 17. The results confirmed that the food intake of the HFD group was reduced compared with the ND group. As the administration time increased, the food intake of the HFD + compound (+)-Spirolingzhine D (32.4 mg / kg) + (+)-Spiroapplanatumine K (7.6 mg / kg) mice was significantly lower than that of the HFD group, and the difference was significant (P<0.05). This result indicates that the compound may affect appetite and energy metabolism by affecting the hypothalamus.

[0166] like Fig.10 As shown: Fig.10In the middle: 1 (32.4 mg / kg) + 2 (7.6 mg / kg) is (+)-Spirolingzhine D (32.4 mg / kg) + (+)-Spiroapplanatumine K (7.6 mg / kg). After intraperitoneal injection of glucose, the islet sensitivity of mice in the ND group did not change significantly (P>0.05). Compared with the ND group, the GTT in the HFD group and the HFD+compound (+)-Spirolingzhine D (32.4 mg / kg) + (+)-Spiroapplanatumine K (7.6 mg / kg) group was significantly increased from 15 minutes later, and the GTT reached the highest value at 30 minutes. However, the blood glucose trend of the HFD+compound (+)-Spirolingzhine D (32.4 mg / kg) + (+)-Spiroapplanatumine K (7.6 mg / kg) mice at different times decreased more significantly, confirming that the compound (+)-Spirolingzhine D (32.4 mg / kg) + (+)-Spiroapplanatumine K (7.6 mg / kg) has better tolerance to glucose.

[0167] like Fig.11 and 12 As shown: Fig.11 and 12 In: 1(32.4mg / kg)+2(7.6mg / kg) is (+)-Spirolingzhine D(32.4mg / kg)+(+)-Spiroapplanatumine K(7.6mg / kg). Compared with the ND group, the weight of liver, epididymis, subcutaneous and brown adipose tissue in the HFD group increased significantly (P<0.05). After administration, the weight of epididymis, subcutaneous and brown adipose tissue in the HND+compound (+)-Spirolingzhine D(32.4mg / kg)+(+)-Spiroapplanatumine K(7.6mg / kg) group was significantly reduced (P<0.05), confirming that HND+compound (+)-Spirolingzhine D(32.4mg / kg)+(+)-Spiroapplanatumine K(7.6mg / kg) can reduce fat weight. This result indicates that the compound acts through the insulin resistance signaling pathway, combined with the above-mentioned effect on the hypothalamus, suggesting that this type of compound is not the only mechanism of action.

[0168] In summary, the compound (+)-Spiroganodermaine G provided by the present invention can significantly activate AKT phosphorylation at a concentration of 40 μM, and the regulation of glucose uptake is dose-dependent; the compounds (+)-Spiroapplanatumine K and (+)-Spirolingzhine D can both significantly activate IRS1 phosphorylation at 20 μM; the blood glucose and body weight of mice fed with the compound (+)-Spirolingzhine D (32.4 mg / kg) + (+)-Spiroapplanatumine K (7.6 mg / kg) are significantly lower than those of the control group, and the weight of the epididymis, subcutaneous and brown fat is significantly reduced, indicating that the compounds (+)-Spiroganodermaine G, (+)-Spiroapplanatumine K and (+)-Spirolingzhine D have a certain effect of improving the activity of insulin resistance.

[0169] When the compounds provided by the present invention are specifically applied to therapeutic drugs, the therapeutic drugs use one or more of the above-mentioned compounds or their pharmaceutically acceptable salts as the main active ingredients, and do not exclude changes in the formulation system and administration method, derivatives of the above-mentioned compounds after simple chemical modification and adjustment, and the combined use of multiple active substances.

[0170] The technical solutions provided by the embodiments of the present invention are introduced in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the embodiments of the present invention. The description of the above embodiments is only applicable to help understand the principles of the embodiments of the present invention. At the same time, for those skilled in the art, according to the embodiments of the present invention, there will be changes in the specific implementation methods and application scopes. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof having an effect of improving insulin resistance, It is characterized in that The compound is used to activate Akt phosphorylation and promote glucose uptake; the compound has a structure shown in Formula I:

2. A method for preparing the compound having the effect of improving insulin resistance as claimed in claim 1, It is characterized in that The following steps are involved: (1) Ganoderma lucidum is crushed, extracted with an ethanol solution by refluxing, and concentrated under reduced pressure to obtain an extract, which is suspended in warm water and extracted with ethyl acetate to obtain an ethyl acetate extract, wherein the temperature of the warm water is between 25° C. and 40° C.; (2) The ethyl acetate extract was separated by MCI gel CHP 20P column chromatography, and gradient eluted with methanol-water solution with volume ratios of 40:60, 45:55, 50:50, 55:45, 65:35, 75:25, 85:15, 90:10, 95:5, and 100:0, respectively. The eluate was detected by TLC, and the same fractions were combined to obtain 17 fractions from Fr.1 to Fr.17; (3) Fr.4 was separated by Sephadex LH-20 column chromatography with methanol as the eluent. After the sample was eluted, TLC was used for detection. The same fractions were combined to obtain two fractions, Fr.4.1 and Fr.4.2; (4) Fr.4.2 was separated by RP-18 column chromatography and eluted with a methanol-water solution gradient with a volume ratio of 20:80, 23:77, 28:72, 33:67, 38:62, 43:57, 48:42, and 53:47, respectively. After the sample was eluted, it was detected by TLC, and the same fractions were combined to obtain a total of 5 fractions, Fr.4.2.1-Fr.4.2.5; (5) Fr.4.2.4 was separated by Sephadex LH-20 column chromatography, eluted with a methanol-water solution with a volume ratio of 70:30, and then purified by silica gel column chromatography, and gradient eluted with a dichloromethane-methanol solution with a volume ratio of 15:1, 8:1, and 3:1, respectively. After the sample was eluted, it was detected by TLC, and the same fractions were combined to obtain a total of 8 fractions from Fr.4.2.4.1 to Fr.4.2.4.8; (6) Fr.4.2.4.3 was subjected to solid phase extraction and gradient eluted with dichloromethane-methanol solution with a volume ratio of 10:1, 5:1, and 3:1, respectively. After the sample was eluted, it was detected by TLC, and the same fractions were combined to obtain a total of 4 fractions, Fr.4.2.4.3.1-Fr.4.2.4.3.4; (7) Fr.4.2.4.3.2 was separated by Sephadex LH-20 column chromatography using methanol as eluent, and then purified by semi-preparative HPLC to obtain the compound, which was then chirally resolved to obtain the compound of formula I.

3. The preparation method according to claim 2, It is characterized in that In step (1), the volume ratio of the ethanol solution to the red ganoderma is 6:1; the number of reflux extractions is 1 to 3 times, and the number of extractions is 3 to 5 times.

4. The preparation method according to claim 2, It is characterized in that In step (7), the conditions of the semi-preparative HPLC are: the mobile phase is an acetonitrile-water solution with a volume ratio of 20:80 at 0-25 min, and the mobile phase is an acetonitrile-water solution with a volume ratio of 25:75 at 25.1-60 min, with a flow rate of 3 mL / min; the water in the mobile phase contains 0.05% TFA; The elution solvent for the chiral separation is n-hexane-ethanol with a volume ratio of 88:12, and the ethanol in the elution solvent contains 0.05% TFA.

5. A method for preparing a compound having the effect of improving insulin resistance, It is characterized in that The following steps are involved: (1) Ganoderma lucidum is crushed, extracted by diafiltration with an ethanol solution, and concentrated under reduced pressure to obtain an extract, which is suspended in warm water and extracted with ethyl acetate to obtain an ethyl acetate extract, wherein the temperature of the warm water is between 25° C. and 40° C.; (2) the ethyl acetate extract was separated by Sephadex LH-20 column chromatography using methanol as the eluent, and the elution was detected by TLC. The same fractions were combined to obtain three fractions, namely Fr.A-Fr.C; (3) Fr.B was chromatographed on an MCI gel CHP 20P column using a gradient elution of methanol-water solution with a volume ratio of 40:60, 45:55, 50:50, 55:45, 65:35, 75:25, 85:15, 90:10, 95:5, and 100:0, followed by TLC detection. The same fractions were combined to obtain 12 fractions, including Fr.BA-Fr.BL; (4) Fr.BB was chromatographed on a Sephadex LH-20 column using methanol as the eluent. After elution, TLC was used for detection. The same fractions were combined to obtain three fractions, Fr.BB1-Fr.BB3; (5) Fr.BB2 was chromatographed on an MCI gel CHP 20P column using a gradient elution with a methanol-water solution having a volume ratio of 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 65:35, 75:25, 85:15, 90:10, 95:5, and 100:0, followed by TLC detection. The same fractions were combined to obtain a total of 7 fractions, namely Fr.BB21-Fr.BB27; (6) Fr.BB22 was chromatographed on a YMC-GEL ODS-A-HG column, and gradient eluted with a methanol-water solution with a volume ratio of 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 65:35, 75:25, 85:15, 90:10, 95:5, and 100:0, and detected by TLC after elution. The same fractions were combined to obtain a total of 8 fractions, Fr.BB221-Fr.BB228; (7) Fr.BB226 was purified by the first semi-preparative HPLC to obtain an intermediate component and a compound of formula II; (8) The intermediate component was further purified by second semi-preparative HPLC to obtain the compound of formula III; The compound of formula II is used to activate insulin receptor substrate 1 phosphorylation and reduce blood sugar and fat weight; the compound of formula II has the structure shown below: The formula III has the structure shown below:

6. The preparation method according to claim 5, It is characterized in that In step (1), the volume ratio of the ethanol solution to Ganoderma lucidum is 10:1; the extraction flow rate is 230 mL / min, and the number of extractions is 3 to 5 times.

7. The preparation method according to claim 5, It is characterized in that In step (7), the first half of the preparative HPLC conditions are: the mobile phase is an acetonitrile-water solution with a volume ratio of 31:69, and the water contains 0.05% TFA; the flow rate is 3 mL / min; The second half preparative HPLC conditions in step (8) are as follows: the mobile phase is an acetonitrile-water solution with a volume ratio of 23:77, and the water contains 0.05% TFA; the flow rate is 3 mL / min.

8. Pharmaceutical compositions, It is characterized in that The pharmaceutical composition comprises the compound having an effect of improving insulin resistance as claimed in claim 1 or a pharmaceutically acceptable salt thereof, and / or a compound or a pharmaceutically acceptable salt thereof prepared by the method for preparing the compound having an effect of improving insulin resistance as claimed in claim 5, and a pharmaceutically acceptable carrier.

9. Use of the compound having an effect of improving insulin resistance as claimed in claim 1 or its pharmaceutically acceptable salt, the compound or its pharmaceutically acceptable salt prepared by the method for preparing the compound having an effect of improving insulin resistance as claimed in claim 5, and the pharmaceutical composition as claimed in claim 8 in the preparation of drugs for treating insulin resistance.

Images