Oxadiaryl heptane dimer compound in rhizoma kaempferiae, pharmaceutical composition of oxadiaryl heptane dimer compound and preparation method and application of oxadiaryl heptane dimer compound

Abstract

The invention discloses an oxadiaryl heptane dimer compound in rhizoma kaempferiae as well as a pharmaceutical composition, a preparation method and application thereof, and relates to the technical field of medicines. The oxadiaryl heptane dimer compound is extracted from rhizoma kaempferiae for the first time, and the structure of the compound is a novel compound reported for the first time; the oxadiaryl heptane dimer compound separated from rhizoma kaempferiae has obvious activity of promoting GLP-1 secretion, and is an effective active substance for preparing a GLP-1 secretion promoter; meanwhile, the oxadiaryl heptane dimer compound extracted from the rhizoma kaempferiae has the effects of reducing blood sugar and losing weight.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to an oxadiarylheptane dimer compound in kaempferia galanga, a pharmaceutical composition thereof, a preparation method thereof and an application thereof. Background Art

[0002] Type 2 diabetes mellitus (T2DM) is a complex metabolic disease, the main feature of which is insulin resistance or insufficient insulin secretion leading to increased blood sugar levels in the body. Long-term abnormal increase in blood sugar levels often leads to serious complications, such as retinopathy, nephropathy, hypertension, central nervous system lesions, diabetic foot, etc.

[0003] At present, in addition to insulin, there are a variety of oral hypoglycemic drugs on the market, including biguanides, α-glucosidase inhibitors, insulin secretagogues, insulin sensitizers, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP4) inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, etc. However, due to the various side effects of existing oral hypoglycemic drugs (such as acute hypoglycemia, weight gain, gastrointestinal discomfort and liver toxicity, etc.), their application is limited. Therefore, anti-diabetic drugs with high efficiency and low risk of hypoglycemia are currently a hot topic of research.

[0004] Glucagon-like peptide 1 (GLP-1) is an incretin hormone secreted by enteroendocrine epithelial L cells, which can stimulate insulin secretion and reduce glucagon secretion in a glucose-dependent manner. Currently, there are two glucose-lowering drugs on the market that act on GLP-1: GLP-1 receptor agonists and DPP-4 inhibitors. Most GLP-1 receptor agonists are peptide analogs, which have disadvantages such as high cost, injection, and gastrointestinal and pancreatic side effects. In addition, existing DPP4 inhibitors are all synthetic compounds, which have problems such as low selectivity and poor safety. Different from the above-mentioned GLP-1 receptor agonists and DPP-4 inhibitors, GLP-1 secretagogues do not depend on endogenous GLP-1 concentrations and are suitable for oral administration. They have the advantages of higher efficiency and less risk of hypoglycemia, and are a new direction for the current research and development of GLP-1 drugs.

[0005] Traditional Chinese medicine, which has been used in China for thousands of years, is an important source for exploring new anti-diabetic drugs. Kaempferia galanga is an important herbal medicine. Related studies have shown that Kaempferia galanga has a wide range of pharmacological effects, including antioxidant, anti-inflammatory, analgesic, anthelmintic, anti-cancer, anti-thrombotic, anti-tuberculosis, anti-angiogenesis, sedative, etc. Kaempferia galanga has a variety of chemical components, including volatile oils, terpenes, diarylheptanoids, flavonoids, cyclic peptides and other chemical components.

[0006] In this regard, the inventors believe that how to extract and prepare effective active substances for GLP-1 secretagogues from Kaempferia galanga in order to obtain anti-diabetic drugs with higher efficiency and lower risk of hypoglycemia is a technical problem that technicians in this field urgently need to solve.

[0007] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention and should not be regarded as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art. Summary of the invention

[0008] In view of the above technical problems, the embodiments of the present invention provide an oxadiarylheptane dimer compound from Kaempferia galanga, a pharmaceutical composition thereof, a preparation method thereof and an application thereof, so as to solve the problems raised in the above background technology.

[0009] An oxadiarylheptane dimer compound, the structural formula of which is one of Formulas 1-21, the specific structure of which is described in Example 1 and the attached Figure 1 ; At the same time; this oxadiarylheptane dimer compound was named: Kaemgalangin.

[0010] A use of the above-mentioned oxadiarylheptane dimer compound in the preparation of a GLP-1 secretagogue drug.

[0011] A use of the above-mentioned oxadiarylheptane dimer compound in the preparation of blood sugar lowering drugs or weight loss drugs.

[0012] An application of the above-mentioned oxadiarylheptane dimer compound in the preparation of health food; the health food has the function of lowering blood sugar or losing weight.

[0013] A pharmaceutical composition, wherein the active ingredient in the pharmaceutical composition comprises the above-mentioned oxadiarylheptane dimer compound or a pharmaceutically acceptable salt of the above-mentioned oxadiarylheptane dimer compound.

[0014] Preferably, it also includes at least one of a pharmaceutically acceptable carrier, excipient, adjuvant and vehicle.

[0015] A use of the pharmaceutical composition as described above in the preparation of a GLP-1 secretagogue drug.

[0016] A use of the above-mentioned pharmaceutical composition in the preparation of a blood sugar lowering drug or a weight loss drug or a health food with blood sugar lowering and weight loss functions.

[0017] A method for extracting oxadiarylheptane dimer compounds as described above, wherein the raw material for extracting the oxadiarylheptane dimer compounds is Kaempferia galanga.

[0018] Preferably, the method for extracting oxadiarylheptane dimer compounds comprises the following steps:

[0019] The rhizomes of Kaempferia galanga were crushed, and cold-extracted with 90% ethanol for three times, and the ethanol extracts were combined;

[0020] The combined ethanol extracts are decompressed to recover ethanol to obtain an extract, the extract is dispersed in water and then extracted with ethyl acetate, and concentrated to obtain an ethyl acetate extract portion;

[0021] The ethyl acetate extract was subjected to silica gel column chromatography, and gradient elution was performed using methanol-chloroform with volume ratios of 0:100, 5:95, 10:90, 20:80, 50:50 and 100:0 as eluents to obtain multiple primary fractions;

[0022] The multiple primary fractions were subjected to silica gel column chromatography using acetone-petroleum ether in a volume ratio of 10:90-50:50 as eluent to obtain multiple secondary fractions;

[0023] The multiple secondary fractions were chromatographed on a reverse phase silica gel column using methanol-water with a volume ratio of 50:50, 70:30, and 90:10 as eluent to obtain multiple tertiary fractions;

[0024] Multiple tertiary fractions were successively chromatographed on a silica gel column using petroleum ether-acetone and chloroform-methanol as eluents, and then chromatographed on a Sephadex LH-20 column using chloroform-methanol with a volume ratio of 1:1 as eluent, and finally purified by semi-preparative high performance liquid phase to obtain oxadiarylheptane dimer compounds.

[0025] An oxadiarylheptane dimer compound, a pharmaceutical composition thereof, a preparation method thereof, and an application thereof provided in an embodiment of the present invention have the following beneficial effects:

[0026] 1. The present invention extracts 21 oxadiarylheptane dimer compounds from the rhizomes of Kaempferia galanga for the first time, and the structures of these 21 diterpenoid compounds are new compounds reported for the first time;

[0027] 2. The oxadiarylheptane dimer compounds isolated from the rhizomes of Kaempferia galanga in the present invention have obvious activity in promoting GLP-1 secretion, indicating potential hypoglycemic and weight-loss effects;

[0028] 3. The preparation method of the present invention is simple and easy to operate, has a high yield, is environmentally friendly and safe, and has high feasibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is a schematic diagram of the structural formula of compound 1-21 of the present invention;

[0030] Figure 2 The promoting effect of compounds 1-21 of the present invention on the secretion of GLP-1 in NCl-H716 cells; cholic acid (CA) was used as a positive control, and the values ​​are expressed as mean ± standard deviation (n = 3). DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0032] In view of the above technical problems, the embodiments of the present invention provide an oxadiarylheptane dimer compound from Kaempferia galanga, a pharmaceutical composition thereof, a preparation method thereof and an application thereof, so as to solve the problems raised in the above background technology.

[0033] Embodiment 1:

[0034] Preparation of compound 1-21:

[0035] The dried rhizome of Kaempferia galanga was crushed and extracted with 90% ethanol for three times. The ethanol extracts were combined and the ethanol was recovered under reduced pressure to obtain an extract. The extract was dispersed in water and extracted with ethyl acetate. The ethyl acetate extract was concentrated to obtain the ethyl acetate extract. The ethyl acetate extract was then chromatographed on a silica gel column using methanol-chloroform (0:100, 5:95, 10:90, 20:80, 50:50 and 100:0, v / v) as the eluent for gradient elution to obtain 11 fractions from Fr.1 to Fr.11. Fr.5 was chromatographed on a silica gel column (acetone-petroleum ether, 10:90-50:50) to obtain 9 fractions from Fr.5-1 to Fr.5-9. Fr.5-7 was chromatographed on a Rp-C column to obtain 11 fractions from Fr.1 to Fr.11. 18 Column chromatography (methanol-water, 50:50, 70:30, 90:10, v / v) gave three fractions, Fr.5-7-1-Fr.5-7-3. Fr.5-7-2 was subjected to multiple silica gel column chromatography (petroleum ether-acetone; chloroform-methanol, etc.), Sephadex LH-20 column chromatography (chloroform-methanol = 1:1), and semi-preparative high performance liquid purification (acetonitrile-water, methanol-water) to give compound 1-21.

[0036] It should be noted that the fraction Fr.5 obtained by gradient elution is subjected to silica gel column chromatography to obtain Fr.5-1-Fr.5-9, and then fraction Fr.5-7 is selected from Fr.5-1-Fr.5-9 for column chromatography to obtain Fr.5-7-1-Fr.5-7-3, and then fraction Fr.5-7-2 is selected from Fr.5-7-1-Fr.5-7-3 for purification and elution to obtain the target substance. This is the reverse process of the entire experimental method. After research, we found that the target molecule obtained from fraction Fr.5-7-2 has the target activity. Therefore, the compound in fraction Fr.5-7-2 was taken as the final target substance, the screening and extraction method was traced back, and the separation and acquisition method of the target substance was directly given.

[0037] Structural data of compound 1-21:

[0038] Optical rotation was measured by a Jasco model 1020 polarimeter (Horiba, Tokyo, Japan). Infrared spectra (IR) were measured by a Bio-Rad FTS-135 infrared spectrometer (Hercules, California, USA) using the KBr pellet method. Ultraviolet spectra were measured by a UV-2401PC ultraviolet spectrometer (Shimadzu, Kyoto, Japan). ECD spectra were measured by Applied Photophysics circular dichroism spectrometer (Agilent, Santa Clara, United States); nuclear magnetic resonance spectra (1D and 2D NMR) were measured by Avance III-600 superconducting nuclear magnetic resonance spectrometer (Bruker, Bremerhaven, Germany), using deuterated chloroform or deuterated acetone as solvent; high-resolution mass spectrometry (HRMS) was measured by LCMS-IT-TOF mass spectrometer (Shimadzu, Kyoto, Japan); thin layer chromatography silica gel and column chromatography silica gel (200-300 mesh) were purchased from Qingdao Meigao and Qingdao Ocean Chemical Group Co., Ltd., and Sephadex LH-20 was purchased from Amersham Bioscience (Sweden). CHP20P MCI gel was purchased from Mitsubishi Chemical Corporation (Tokyo, Japan).

[0039]

[0040] KaemgalanginA1(1)

[0041] Molecular formula: C 39 H 42 O 11

[0042] Molecular weight: 686

[0043] Appearance: Colorless colloid

[0044] HRESIMS m / z 685.2646[MH] - (calcd.for C 39 H 41 O 11 ,m / z 685.2654);

[0045] UV(MeOH)λ max (logε):195(4.13),286(2.88)nm;

[0046] IR(KBr)ν max :3416,2923,1613,1516,1448,1382,1295,1269,1225,1155,1126,1032,826cm -1 ;

[0047] ECD(MeOH)λ max (Δε)195(+7.94),200(-21.24),217(+6.16),225(+3.05),240(+10.00),273(+4.55),293(+5.53),317(+2.28)nm;

[0048] (c 0.09, MeOH);

[0049] 1 HNMR and 13 CNMR (DEPT) data are shown in Table 1.

[0050]

[0051] Kaemgalangin A2(2)

[0052] Molecular formula: C 39 H 42 O 11

[0053] Molecular weight: 686

[0054] Appearance: White colloid

[0055] HRESIMS m / z 687.2795[M+H] + (calcd.for C 39 H 43 O 11,m / z 687.2800);

[0056] UV(MeOH)λ max (logε):195(4.16),286(2.92)nm;

[0057] IR(KBr)ν max :3431,2924,1614,1516,1499,1449,1383,1297,1274,1234,1156,1126,1035,827cm -1 ;

[0058] ECD(MeOH)λ max (Δε)195(+3.25),199(-22.53),208(+42.90),227(+3.46),295(+7.56)nm;

[0059] (c 0.10, MeOH);

[0060] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Table 1.

[0061]

[0062] Kaemgalangin A3(3)

[0063] Molecular formula: C 39 H 42 O 11

[0064] Molecular weight: 686

[0065] Appearance: White colloid

[0066] HRESIMS m / z 687.2809[M+H] + (calcd.for C 39 H 43 O 11 ,m / z 687.2800);

[0067] UV(MeOH)λ max (logε):195(4.14),222(3.40),282(2.83)nm;

[0068] IR(KBr)ν max:3427,2922,1614,1515,1455,1382,1274,1226,1157,1128,1044,827cm -1 ;

[0069] ECD(MeOH)λ max (Δε)195(+36.91),206(-47.20),218(+5.09),224(+2.55),238(+12.81),262(+5.42)nm;

[0070] (c 0.09, MeOH);

[0071] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Table 1.

[0072]

[0073] Kaemgalangin A4(4)

[0074] Molecular formula: C 39 H 42 O 11 ,

[0075] Molecular weight: 686

[0076] Appearance: White colloid

[0077] HRESIMS m / z 687.2793[M+H] + (calcd.for C 39 H 43 O 11 ,m / z 687.2800);

[0078] UV(MeOH)λ max (logε):195(4.17),221(3.44),280(2.86)nm;

[0079] IR(KBr)ν max :3432,2925,1615,1515,1454,1367,1276,1226,1161,1129,1039,826cm -1 ;

[0080] ECD(MeOH)λ max(Δε)195(+53.45),205(-49.35),217(-3.10),227(-9.64),244(+7.22)nm;

[0081] (c 0.09, MeOH);

[0082] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Table 1.

[0083]

[0084] Kaemgalangin B1(5)

[0085] Molecular formula: C 42 H 48 O 13

[0086] Molecular weight: 760

[0087] Appearance: White colloid

[0088] HRESIMS m / z 761.3160[M+H] + (calcd.for C 42 H 49 O 13 ,m / z 761.3168);

[0089] UV(MeOH)λ max (logε):200(3.99),230(3.35),273(3.17)nm;

[0090] IR(KBr)ν max :3433,2924,1604,1515,1453,1383,1271,1156,1127,1033,815cm -1 ;

[0091] ECD(MeOH)λ max (Δε)198(-13.06),211(+11.80),232(+4.08),239(+4.34),284(+2.63),311(-0.46)nm;

[0092] (c 0.09, MeOH);

[0093] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Table 2.

[0094]

[0095] Kaemgalangin B2(6)

[0096] Molecular formula: C 42 H 48 O 13 ,

[0097] Molecular weight: 760

[0098] Appearance: White colloid

[0099] HRESIMS m / z 761.3168[M+H] + (calcd.for C 42 H 49 O 13 ,m / z 761.3168);

[0100] UV(MeOH)λ max (logε):200(4.11),273(3.32)nm;

[0101] IR(KBr)ν max :3421,2922,1604,1515,1453,1383,1271,1156,1126,1033,815cm -1 ;

[0102] ECD(MeOH)λ max (Δε)196(-14.23),210(+9.50),229(+1.92),235(+2.26),267(-2.10),284(-0.56),304(-2.97),332(-0.03)nm;

[0103] (c 0.06, MeOH);

[0104] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Table 2.

[0105]

[0106] Kaemgalangin B3(7)

[0107] Molecular formula: C 40 H 44 O 11 ,

[0108] Molecular weight: 700

[0109] Appearance: White colloid

[0110] HRESIMS m / z 699.2812[MH] - (calcd.for C 40 H 43 O 11 ,m / z 699.2811);

[0111] UV(MeOH)λ max (logε):195(4.10),221(3.55),271(3.30)nm;

[0112] IR(KBr)ν max :3399,2938,1613,1514,1451,1383,1268,1134,1034,823cm -1 ;

[0113] ECD(MeOH)λ max (Δε)197(-17.94),212(+11.00),232(+4.39),239(+5.05),254(+3.79),270(+4.97),313(-0.81)nm;

[0114] (c 0.09, MeOH);

[0115] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Table 2.

[0116]

[0117] Kaemgalangin B4(8)

[0118] Molecular formula: C 42 H 48 O 13 ,

[0119] Molecular weight: 760

[0120] Appearance: White colloid

[0121] HRESIMS m / z 759.3019[MH] - (calcd.for C 42 H 47 O 13 ,m / z 759.3022);

[0122] UV(MeOH)λ max (logε):200(4.12),271(3.30)nm;

[0123] IR(KBr)ν max :3433,2924,1605,1515,1453,1382,1272,1156,1127,1033,813cm -1 ;

[0124] ECD(MeOH)λ max (Δε)195(+15.75),202(-0.31),213(+8.06),234(-0.61),276(+4.06)nm;

[0125] (c 0.08, MeOH);

[0126] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Tables 3 and 4.

[0127]

[0128] Kaemgalangin B5(9)

[0129] Molecular formula: C 40 H 44 O 11 ,

[0130] Molecular weight: 700

[0131] Appearance: White colloid

[0132] HRESIMS m / z 699.2810[MH] - (calcd.for C 40 H 43 O 11 ,m / z 699.2811);

[0133] UV(MeOH)λ max (logε):195(4.12),223(3.61),268(3.34)nm;

[0134] IR(KBr)ν max :3434,2934,1613,1515,1453,1376,1268,1242,1162,1129,1084,1033,815cm -1 ;

[0135] ECD(MeOH)λ max (Δε)195(+5.71),200(-4.76),216(+3.19),232(-1.68),273(+3.86),291(+1.19),309(+1.84),329(+0.76)nm;

[0136] (c 0.12, MeOH);

[0137] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Tables 3 and 4.

[0138]

[0139] Kaemgalangin B6(10)

[0140] Molecular formula: C 42 H 48 O 14 ,

[0141] Molecular weight: 776

[0142] Appearance: White colloid

[0143] HRESIMS m / z 799.2941[M+Na] + (calcd.for C 42 H 48 O 14 Na, m / z 799.2936);

[0144] UV(MeOH)λ max (logε):200(4.08),229(3.49),277(3.20)nm;

[0145] IR(KBr)ν max :3433,2924,1631,1598,1515,1454,1428,1383,1271,1218,1158,1128,1033,814cm -1 ;

[0146] ECD(MeOH)λ max (Δε)195(+11.89),201(-9.35),211(+6.40),230(-3.77)nm,245(+2.98),274(+3.35),290(+2.91)nm;

[0147] (c 0.08, MeOH);

[0148] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Tables 3 and 4.

[0149]

[0150] Kaemgalangin B7(11)

[0151] Molecular formula: C 42 H 48 O 13 ,

[0152] Molecular weight: 760

[0153] Appearance: White colloid

[0154] HRESIMS m / z 761.3164[M+H] + (calcd.for C 42 H 49 O 13 ,m / z 761.3168);

[0155] UV(MeOH)λ max (logε)200(4.15),269(3.34)nm;

[0156] IRν max 3434,2935,1608,1515,1454,1369,1271,1237,1156,1126,1033,813cm -1 ;

[0157] ECD(MeOH)λ max (Δε)196(+24.43),210(+2.30),218(+3.76),235(-2.90),246(-0.65),260(-1.91),277(-0.15),287(-1.24),318(+1.09)nm;

[0158] (c 0.10, MeOH);

[0159] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Tables 3 and 4.

[0160]

[0161] Kaemgalangin B8(12)

[0162] Molecular formula: C 40 H 44 O 11 ,

[0163] Molecular weight: 700

[0164] Appearance: White colloid

[0165] HRESIMS m / z 699.2809[MH] - (calcd.for C 40 H 43 O 11 ,m / z 699.2811);

[0166] UV(MeOH)λ max (logε)195(4.10),222(3.56),268(3.30)nm;

[0167] IRν max 3432,2929,1613,1515,1452,1379,1267,1239,1130,1031,815cm -1 ;

[0168] ECD(MeOH)λ max (Δε)196(+18.39),202(-2.39),206(-0.39),209(-0.74),218(+1.68),233( -3.20),246(-0.70),260(-1.66),276(+0.30),289(-0.49),317(+1.02)nm;

[0169] (c 0.12, MeOH);

[0170] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Tables 3 and 4.

[0171]

[0172] Kaemgalangin B9(13)

[0173] Molecular formula: C 41 H 50 O 13 ,

[0174] Molecular weight: 750

[0175] Appearance: White colloid

[0176] HRESIMS m / z 749.3174[MH] - (calcd.for C 41 H 49 O 13 ,m / z 749.3179);

[0177] UV(MeOH)λ max (logε)195(4.16),224(3.50),278(2.89)nm;

[0178] IRν max 3433,2939,1613,1594,1516,1459,1241,1123,1033,818cm -1 ;

[0179] ECD(MeOH)λ max (Δε)195(+13.60),201(-14.19),213(+3.45),232(-3.89),250(+1.20)nm;

[0180] (c 0.12, MeOH);

[0181] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Tables 3 and 5.

[0182]

[0183] Kaemgalangin B 10 (14)

[0184] Molecular formula: C 40 H 48 O 12 ,

[0185] Molecular weight: 720

[0186] Appearance: White colloid

[0187] HRESIMS m / z 743.3032[M+Na] + (calcd.for C 40 H 48 O 12 Na, m / z 743.3038);

[0188] UV(MeOH)λ max (logε)195(3.26),224(2.56),278(2.04)nm;

[0189] IRν max 3434,2925,1613,1515,1453,1383,1266,1230,1129,1032,819cm -1 ;

[0190] ECD(MeOH)λ max (Δε)195(+1.39),202(-2.28),215(-0.01),229(-0.86),246(+0.24)nm;

[0191] (c 0.08, MeOH);

[0192] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Tables 3 and 5.

[0193]

[0194] Kaemgalangin B 11 (15)

[0195] Molecular formula: C 39 H 48 O 11 ,

[0196] Molecular weight: 690

[0197] Appearance: White colloid

[0198] HRESIMS m / z 691.3114[M+H] + (calcd.for C 39 H 47 O 11 ,m / z 691.3113);

[0199] UV(MeOH)λ max (logε)195(4.11),223(3.39),277(2.91)nm;

[0200] IRν max 3430,2924,1613,1515,1451,1382,1274,1239,1126,1073,1036,825cm -1 ;

[0201] ECD(MeOH)λ max (Δε)195(+10.89),201(-15.54),213(+5.36),229(-2.31),240(+4.42),277(+1.83),289(+2.95),309(+1.28)nm;

[0202] (c 0.09, MeOH);

[0203] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Tables 3 and 5.

[0204]

[0205] Kaemgalangin B 12 (16)

[0206] Molecular formula: C 39 H 46 O 11 ,

[0207] Molecular weight: 690

[0208] Appearance: White colloid

[0209] HRESIMS m / z 691.3115[M+H] + (calcd.for C 39 H 47 O 11 ,m / z 691.3113);

[0210] UV(MeOH)λ max (logε)195(4.27),224(3.53),281(3.04)nm;

[0211] IRν max 3433,2928,1613,1515,1450,1374,1274,1238,1123,1036,824cm -1 ;

[0212] ECD(MeOH)λ max (Δε)195(+10.55),203(-28.56),216(-0.36),228(-9.14),240(+5.13),280(+0.85)nm;

[0213] (c 0.09, MeOH);

[0214] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Tables 3 and 5.

[0215]

[0216] Kaemgalangin B 13 (17)

[0217] Molecular formula: C 41 H 48 O 13 ,

[0218] Molecular weight: 748

[0219] Appearance: White colloid

[0220] HRESIMS m / z 771.2985[M+Na] + (calcd.for C 41 H 48 O 13 Na, m / z 771.2987);

[0221] UV(MeOH)λ max (logε)195(4.13),225(3.49),277(2.91)nm;

[0222] IRν max 3433,2925,1613,1595,1515,1459,1425,1380,1338,1270,1234,1125,1034,822cm -1 ;

[0223] ECD(MeOH)λ max (Δε)195(+11.41),202(-18.14),217(-1.44),232(-8.94),250(+0.89)nm;

[0224] (c 0.13, MeOH);

[0225] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Tables 3 and 5.

[0226]

[0227] Kaemgalangin C1(18)

[0228] Molecular formula: C 39 H 46 O 11 ,

[0229] Molecular weight: 690

[0230] Appearance: White colloid

[0231] HRESIMS m / z 691.3111[M+H] + (calcd.for C 39 H 47 O 11 ,m / z 691.3113);

[0232] UV(MeOH)λ max (logε)195(3.97),223(3.32),281(2.87)nm;

[0233] IRν max 3430,2923,1612,1514,1451,1384,1273,824cm -1 ;

[0234] ECD(MeOH)λ max (Δε)195(+2.26),203(+12.41),210(-0.59),233(+5.86),276(+1.04),289(+1.89),300(+0.87)nm;

[0235] (c 0.09, MeOH);

[0236] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Table 6.

[0237]

[0238] Kaemgalangin C2(19)

[0239] Molecular formula: C 39 H 46 O 11 ,

[0240] Molecular weight: 690

[0241] Appearance: White colloid

[0242] HRESIMS m / z 691.3111[M+H] +(calcd.for C 39 H 47 O 11 ,m / z 691.3113);

[0243] UV(MeOH)λ max (logε)195(4.09),225(3.44),281(2.98)nm;

[0244] IRν max 3425,2924,1612,1597,1514,1438,1383,1273,1237,822cm -1 ;

[0245] ECD(MeOH)λ max (Δε)199(+14.28),210(-8.83),231(+4.77),242(+1.12)nm; (c 0.08, MeOH);

[0246] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Table 6.

[0247]

[0248] Kaemgalangin C3(20)

[0249] Molecular formula: C 39 H 46 O 11 ,

[0250] Molecular weight: 690

[0251] Appearance: White colloid

[0252] HRESIMS m / z 691.3107[M+H] + (calcd.for C 39 H 47 O 11 ,m / z 691.3113);

[0253] UV(MeOH)λ max (logε)195(4.12),225(3.47),281(3.03)nm;

[0254] IRν max 3424,2924,1613,1513,1451,1383,1274,1036,827cm-1 ;

[0255] ECD(MeOH)λ max (Δε)195(+22.10),203(+1.17),209(+17.42),235(-6.86),248(+3.00)nm;

[0256] (c 0.09, MeOH);

[0257] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Table 6.

[0258]

[0259] Kaemgalangin C4(21)

[0260] Molecular formula: C 39 H 46 O 11 ,

[0261] Molecular weight: 690

[0262] Appearance: White colloid

[0263] HRESIMS m / z 691.3110[M+H] + (calcd.for C 39 H 47 O 11 ,m / z 691.3113);

[0264] UV(MeOH)λ max (logε)195(4.01),225(3.36),281(2.91)nm;

[0265] IRν max 3426,2923,1613,1514,1439,1383,1275,1237,1037,824cm -1 ;

[0266] ECD(MeOH)λ max (Δε)195(+11.54),201(+4.59),209(+20.39),235(-3.69),250(+2.41)nm;

[0267] (c 0.09, MeOH);

[0268] 1 H-NMR and 13 C-NMR (DEPT) data are shown in Table 6.

[0269] Table 1. Compounds 1-4 1 H-NMR and 13 C NMR data

[0270]

[0271]

[0272] Table 2. Compounds 5-7 1 H-NMR and 13 C NMR data

[0273]

[0274]

[0275] Table 3. Compounds 8-17 13 C NMR data

[0276]

[0277] Table 4. Compounds 8-12 1 H NMR data

[0278]

[0279] Table 5. Compounds 13-17 1 H NMR data

[0280]

[0281]

[0282] Table 6. Compounds 18-21 1 H NMR data

[0283]

[0284]

[0285] Embodiment 2:

[0286] The compounds have GLP-1 secretion promoting activity.

[0287] 1 Materials and Methods

[0288] 1.1 Materials

[0289] NCl-H716 cells were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai); bovine serum was purchased from Shanghai Longtian Biotechnology Co., Ltd. (Shanghai); and human GLP-1 ELISA kit was purchased from SAB (Maryland, USA).

[0290] 1.2 Instruments

[0291] Flex Station 3 desktop multifunctional microplate reader (Bio-RAD 680, USA); FlexA-200 full-wavelength microplate analyzer was purchased from Hangzhou Aosheng Instrument Co., Ltd.; analytical balance ME104E was purchased from Mettler-Toledo Instrument (Shanghai) Co., Ltd.; electric constant temperature incubator (DHP-9082) was purchased from Shanghai Yiheng Technology Co., Ltd.

[0292] 1.3 Experimental process

[0293] GLP-1 secretion experiment: NCl-H716 cells were cultured in RPMI-1640 medium containing 10% FBS and 1% PS at 37°C in an incubator with 5% CO2 saturated humidity; when the cells grew to 80%-90%, the diluted cell suspension was inoculated into a 24-well plate (5×10 5 Each well was starved for 1 hour after adding KRBH working solution III; each well was starved for 2 hours after adding KRBH working solution IV containing the compound, the supernatant was collected, and then the GLP-1 content in the supernatant was detected using a human GLP-1 ELISA kit.

[0294] 2. Results:

[0295] Compound 1-21 was evaluated for its ability to promote GLP-1 secretion in NCI-H716 cells at a concentration of 50 μM. Compared with the control group, compound 1-21 significantly increased GLP-1 secretion ( Figure 2 and Table 7). In particular, the secretion promotion rates of compounds 1, 2, and 16 on GLP-1 were 146.6±31.1%, 159.0±16.6%, and 142.9±2.7%;

[0296] The secretion promoting rates of compounds 3, 15, 19, and 21 on GLP-1 were 84.4-107.7%. The remaining compounds also had significant GLP-1 secretion promoting activity. This indicates that the oxadiarylheptane dimer compounds in the traditional Chinese medicine Kaempferia galanga are effective active substances for preparing GLP-1 secretion promoters, and also have potential effects of lowering blood sugar, lowering blood lipids, and reducing weight.

[0297] Table 7. Effects of compounds on promoting GLP-1 secretion in NCI-H716 cells a

[0298]

[0299]

[0300] a The secretion promotion rate was expressed as the percentage increase of GLP-1 content compared with the control group; b Cholic acid (CA) was used as a positive control.

[0301] 3. Conclusion:

[0302] The present invention separates 21 new oxadiarylheptane dimer compounds from Kaempferia galanga, and at a concentration of 50 μM, the 21 new oxadiarylheptane dimer compounds separated have significant GLP-1 secretion promoting activity. The present invention shows that the oxadiarylheptane dimer compounds in Kaempferia galanga have the effects of lowering blood sugar, lowering blood lipids and reducing weight.

[0303] It should be noted that GLP-1 is a biological molecule related to insulin regulation and blood sugar control: GLP-1 is an insulin secretagogue before insulin secretion, which can promote insulin secretion, increase insulin sensitivity, inhibit glucagon secretion, and act on the central nervous system to reduce appetite and increase satiety.

[0304] Embodiment 3:

[0305] Preparation Example:

[0306] 1. Take any one of compounds 1-21 or any combination thereof, dissolve it with a small amount of DMSO, add injection water as usual, filter it, and sterilize it by filling to prepare an injection solution.

[0307] 2. Take any one of compounds 1-21 or any combination thereof, dissolve it with a small amount of DMSO, dissolve it in sterile water for injection, stir to dissolve, filter with a sterile suction funnel, filter aseptically, dispense into ampoules, freeze-dry at low temperature, and aseptically seal to obtain powder injection.

[0308] 3. Take any one of compounds 1-21 or any combination thereof, add excipients at a weight ratio of 9:1 to the excipients to prepare powders.

[0309] 4. Take any one of compounds 1-21 or any combination thereof, add excipients at a weight ratio of 5:1 to the excipients, and granulate and tablet.

[0310] 5. Take any one of compounds 1-21 or any combination thereof and prepare an oral liquid according to a conventional oral liquid preparation method.

[0311] 6. Take any one of compounds 1-21 or any combination thereof, add excipients at a weight ratio of 5:1 to the excipients, and prepare capsules.

[0312] 7. Take any one of compounds 1-21 or any combination thereof, add excipients at a weight ratio of 3:1 to the excipients, and prepare capsules.

[0313] 8. Take any one of compounds 1-21 or any combination thereof, add excipients at a weight ratio of 5:1 to the excipients to prepare granules.

[0314] The embodiments described above are only descriptions of the preferred implementation modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the protection scope determined by the claims of the present invention.

Claims

1. An oxadiarylheptane dimer compound, characterized in that: The structural formula is one of formula 1-21:

2. Use of the oxadiarylheptane dimer compound as claimed in claim 1 in the preparation of a GLP-1 secretagogue drug.

3. Use of the oxadiarylheptane dimer compound according to claim 1 in the preparation of hypoglycemic drugs or weight-loss drugs.

4. A use of the oxadiarylheptane dimer compound according to claim 1 in preparing health food; characterized in that: The health food has the function of lowering blood sugar or losing weight.

5. A pharmaceutical composition, characterized in that The active ingredient in the pharmaceutical composition includes the oxadiarylheptane dimer compound as described in claim 1 or a pharmaceutically acceptable salt of the oxadiarylheptane dimer compound.

6. The pharmaceutical composition according to claim 5, characterized in that It also includes at least one of a pharmaceutically acceptable carrier, excipient, adjuvant and vehicle.

7. Use of the pharmaceutical composition according to claim 5 or 6 in the preparation of a GLP-1 secretagogue drug.

8. Use of the pharmaceutical composition according to claim 5 or 6 in the preparation of a hypoglycemic drug or a weight-loss drug or a health food having the function of hypoglycemic and weight-loss.

9. A method for extracting oxadiarylheptane dimer compounds as claimed in claim 1, characterized in that: The raw material for extracting the oxadiarylheptane dimer compound is Kaempferia galanga.

10. The method for extracting oxadiarylheptane dimer compounds according to claim 1, characterized in that: The following steps are involved: The rhizomes of Kaempferia galanga were crushed, and cold-extracted with 90% ethanol for three times, and the ethanol extracts were combined; The combined ethanol extracts are decompressed to recover ethanol to obtain an extract, the extract is dispersed in water and then extracted with ethyl acetate, and concentrated to obtain an ethyl acetate extract portion; The ethyl acetate extract was subjected to silica gel column chromatography, and gradient elution was performed using methanol-chloroform with volume ratios of 0:100, 5:95, 10:90, 20:80, 50:50 and 100:0 as eluents to obtain multiple primary fractions; The multiple primary fractions were subjected to silica gel column chromatography using acetone-petroleum ether in a volume ratio of 10:90-50:50 as eluent to obtain multiple secondary fractions; The multiple secondary fractions were chromatographed on a reverse phase silica gel column using methanol-water with a volume ratio of 50:50, 70:30, and 90:10 as eluent to obtain multiple tertiary fractions; Multiple tertiary fractions were successively chromatographed on a silica gel column using petroleum ether-acetone and chloroform-methanol as eluents, and then chromatographed on a Sephadex LH-20 column using chloroform-methanol with a volume ratio of 1:1 as eluent, and finally purified by semi-preparative high performance liquid phase to obtain oxadiarylheptane dimer compounds.

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