An oxad diarylheptane dimer compound in kaempferia, a pharmaceutical composition thereof, and a preparation method and application thereof

Abstract

The application discloses an oxadibarylheptane dimer compound in kaempferia galanga, a pharmaceutical composition of the compound, and a preparation method and application of the compound, and relates to the technical field of medicines. The oxadibarylheptane dimer compound is extracted from kaempferia galanga for the first time, and the structure of the compound is a newly reported compound. The oxadibarylheptane dimer compound separated from kaempferia galanga has obvious GLP-1 secretion promoting activity, and is an effective active substance for preparing a GLP-1 secretion promoter. Meanwhile, the oxadibarylheptane dimer compound extracted from kaempferia galanga has blood sugar reducing and weight loss effects.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical technology, and in particular to a kaempferia galanga oxadiaryl heptane dimer compound, a pharmaceutical composition thereof, a preparation method and application thereof. BACKGROUND

[0002] Type 2 diabetes mellitus (T2DM) is a complex metabolic disease, and its main feature is that insulin resistance or insufficient insulin secretion leads to an increase in blood glucose levels in the body; long-term abnormal increase in blood glucose levels often leads to serious complications, such as retinopathy, nephropathy, hypertension, central nervous system disease, diabetic foot, etc.

[0003] At present, in addition to insulin, there are also various oral hypoglycemic drugs on the market, including biguanides, alpha-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 various side effects (such as acute hypoglycemia, weight gain, gastrointestinal discomfort, and liver toxicity, etc.) of existing oral hypoglycemic drugs, their application is limited. Therefore, antidiabetic drugs with high efficiency and low risk of hypoglycemia are currently a hot research topic.

[0004] Glucagon-like peptide 1 (GLP-1) is an intestinal incretin hormone secreted by the intestinal endocrine L cell, which can stimulate insulin secretion in a glucose-dependent manner and reduce glucagon secretion. There are two types of GLP-1-reducing 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 the disadvantages of high cost, injection administration, gastrointestinal and pancreatic side effects, etc., and existing DPP4 inhibitors are all artificial synthetic compounds, which have the problems of low selectivity and poor safety. Unlike the above-mentioned GLP-1 receptor agonists and DPP-4 inhibitors, GLP-1 secretagogues are independent of endogenous GLP-1 concentration, and are suitable for oral administration, with the advantages of higher efficiency and lower risk of hypoglycemia, which is a new direction for the research and development of GLP-1 drugs.

[0005] Traditional Chinese medicine has been used in China for thousands of years, and is an important source for exploring new antidiabetic drugs. Kaempferia galanga is an important herb, and relevant studies have shown that it has a wide range of pharmacological effects, such as antioxidant, anti-inflammatory analgesic, anthelmintic, anticancer, antithrombotic, antitubercular, antiangiogenic, sedative, etc.; and kaempferia galanga has diverse chemical components, including volatile oil, terpenes, diarylheptanes, flavonoids, cyclic peptides, etc.

[0006] To this end, the inventors believe that how to extract the active substance of GLP-1 secretagogue from Kaempferia galanga L. to obtain an anti-diabetic drug with higher efficiency and lower risk of hypoglycemia is a technical problem that needs to be solved by those skilled in the art.

[0007] The information disclosed in this section is only intended to increase the understanding of the overall background of the present application and should not be considered as admitting or implying in any form that the information constitutes prior art known to those skilled in the art. SUMMARY

[0008] To solve the above technical problems, the present application provides a Kaempferia galanga L. oxadiarylheptane dimer compound, a pharmaceutical composition thereof, a preparation method and application thereof.

[0009] An oxadiarylheptane dimer compound, the structural formula of which is one of formulae 1-21, and the specific structure of formula 1-21 is shown in the description of Example 1 and the accompanying drawings. Figure 1 Meanwhile, the oxadiarylheptane dimer compound is named Kaemgalangin.

[0010] An application of the oxadiarylheptane dimer compound as described above in the preparation of a GLP-1 secretagogue drug.

[0011] An application of the oxadiarylheptane dimer compound as described above in the preparation of a hypoglycemic drug or a weight loss drug.

[0012] An application of the oxadiarylheptane dimer compound as described above in the preparation of a health food; the health food has the functions of reducing blood sugar or losing weight.

[0013] A pharmaceutical composition, the active ingredient in the pharmaceutical composition comprising the oxadiarylheptane dimer compound as described above or a pharmaceutically acceptable salt of the oxadiarylheptane dimer compound.

[0014] Preferably, at least one of a pharmaceutically acceptable carrier, excipient, adjuvant and vehicle is further included.

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

[0016] An application of the pharmaceutical composition as described above in the preparation of a hypoglycemic drug or a weight loss drug or a health food with the functions of reducing blood sugar and losing weight.

[0017] An extraction method of the oxadiarylheptane dimer compound as described above, the raw material of the oxadiarylheptane dimer compound being Kaempferia galanga L.

[0018] Preferably, the extraction method of the oxa-bisarylheptane dimer compound comprises the following steps:

[0019] The rhizomes of Kaempferia galanga are crushed, and 90% ethanol is used for cold extraction for 3 times, and the ethanol extracts are combined;

[0020] The combined ethanol extract is concentrated under reduced pressure to obtain an extract, which is dispersed in water and extracted with ethyl acetate to obtain an ethyl acetate extraction part;

[0021] The ethyl acetate extraction part is subjected to silica gel column chromatography, and gradient elution is carried out with methanol-chloroform with volume ratios of 0:100, 5:95, 10:90, 20:80, 50:50 and 100:0 in sequence to obtain multiple primary fractions;

[0022] The multiple primary fractions are subjected to silica gel column chromatography with acetone-petroleum ether with volume ratios of 10:90-50:50 as eluent respectively to obtain multiple secondary fractions;

[0023] The multiple secondary fractions are subjected to reversed-phase silica gel column chromatography with methanol-water with volume ratios of 50:50, 70:30 and 90:10 as eluent respectively to obtain multiple tertiary fractions;

[0024] The multiple tertiary fractions are subjected to silica gel column chromatography with petroleum ether-acetone and chloroform-methanol as eluent in sequence, then subjected to Sephadex LH-20 column chromatography with chloroform-methanol with a volume ratio of 1:1 as eluent, and finally subjected to semi-preparative high performance liquid purification to obtain the oxa-bisarylheptane dimer compound.

[0025] The oxa-bisarylheptane dimer compound, the pharmaceutical composition thereof, the preparation method and the application thereof provided by the embodiment of the present application have the following beneficial effects:

[0026] 1. The 21 oxa-bisarylheptane dimer compounds are extracted from the rhizomes of Kaempferia galanga for the first time, and the structures of the 21 diterpenoid compounds are new compounds reported for the first time;

[0027] 2. The oxa-bisarylheptane dimer compound separated from the rhizomes of Kaempferia galanga has obvious GLP-1 secretion promoting activity, indicating that it has potential hypoglycemic and weight loss effects;

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

[0029] Figure 1 The structural formula of the compound 1-21 of the present application is shown in the schematic diagram;

[0030] Figure 2 Promotion of GLP-1 secretion in NCI-H716 cells by compounds 1-21 of the present application; 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 application will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, any other embodiments obtained by a person skilled in the art without creative work fall within the protection scope of the present application.

[0032] To solve the above-mentioned problems in the background art, the embodiments of the present application provide a kaempferia galanga oxydibarylheptane dimer compound, a pharmaceutical composition thereof, and a preparation method and application thereof.

[0033] Embodiment 1:

[0034] Preparation of compound 1-21:

[0035] The dried root stem of kaempferia galanga was crushed, and then extracted three times by cold extraction with 90% ethanol. The ethanol extracts were combined, and ethanol was recovered under reduced pressure to obtain an extract. The extract was dispersed in water, and then extracted with ethyl acetate. The ethyl acetate extraction part was concentrated to obtain the ethyl acetate extraction part, and then the ethyl acetate extraction part was subjected to silica gel column chromatography, and eluted with methanol-chloroform (0:100, 5:95, 10:90, 20:80, 50:50 and 100:0, v / v) as an eluent gradient to obtain 11 fractions of Fr.1-Fr.11; Fr.5 was subjected to silica gel column chromatography (acetone-petroleum ether, 10:90-50:50) to obtain 9 fractions of Fr.5-1-Fr.5-9; Fr.5-7 was subjected to Rp-C 18 column chromatography (methanol-water, 50:50, 70:30, 90:10, v / v) to obtain 3 fractions of 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), Sephadex LH-20 column chromatography (chloroform-methanol = 1:1), and semi-preparative high performance liquid purification (acetonitrile-water, methanol-water) to obtain compound 1-21.

[0036] It should be noted that the flow Fr.5-7-2 obtained by purifying and eluting the flow Fr.5-7-2 from Fr.5-7-1-Fr.5-7-3 is the reverse process of the whole experimental method, and we found that the target molecule obtained from the flow Fr.5-7-2 has the target activity, so the compound in the flow Fr.5-7-2 is the final target substance, and the extraction method is traced back to give the separation and acquisition method of the target substance.

[0037] Structural data of compound 1-21:

[0038] Optical rotation was determined by a Jasco model 1020 polarimeter (Horiba, Tokyo, Japan); infrared spectra (IR) were determined by a Bio-Rad FTS-135 infrared spectrometer (Hercules, California, USA) using KBr pellets; ultraviolet spectra were determined by a UV-2401PC ultraviolet spectrometer (Shimadzu, Kyoto, Japan). ECD spectra were determined by an Applied Photophysics circular dichroism spectrometer (Agilent, Santa Clara, United States); nuclear magnetic resonance spectra (1D and 2D NMR) were determined by an Avance III-600 superconducting nuclear magnetic resonance spectrometer (Bruker, Bremerhaven, Germany) using deuterated chloroform or deuterated acetone as the solvent; high resolution mass spectra (HRMS) were determined by an 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 Haizhuan Chemical Group Co., Ltd., and Sephadex LH-20 (Sephadex LH-20) was purchased from Amersham Bioscience (Sweden). CHP20P MCI gel was purchased from Mitsubishi Chemical Corporation (Tokyo, Japan).

[0039]

[0040] Kaemgalangin A1 (1)

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

[0042] Mol. Wt.: 686

[0043] Appearance: colorless gum

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

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

[0046] IR (KBr) v max : 3416, 2923, 1613, 1516, 1448, 1382, 1295, 1269, 1225, 1155, 1126, 1032, 826 cm -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 listed in Table 1.

[0050]

[0051] Kaemgalangin A2 (2)

[0052] Mol. Formula: C 39 H 42 O 11

[0053] Mol. Wt.: 686

[0054] Appearance: white gum

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

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

[0057] IR (KBr) v max : 3431, 2924, 1614, 1516, 1499, 1449, 1383, 1297, 1274, 1234, 1156, 1126, 1035, 827 cm -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 listed in Table 1.

[0061]

[0062] Kaemgalangin A3 (3)

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

[0064] Molecular Weight: 686

[0065] Property: white gum

[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 (log ε): 195 (4.14), 222 (3.40), 282 (2.83) nm;

[0068] IR (KBr) v max3427, 2922, 1614, 1515, 1455, 1382, 1274, 1226, 1157, 1128, 1044, 827 cm -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 listed in Table 1.

[0072]

[0073] Kaemgalangin A4 (4)

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

[0075] Molecular Weight: 686

[0076] Property: white gum

[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 (log ε): 195 (4.17), 221 (3.44), 280 (2.86) nm;

[0079] IR (KBr) v max : 3432, 2925, 1615, 1515, 1454, 1367, 1276, 1226, 1161, 1129, 1039, 826 cm -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 listed in Table 1.

[0083]

[0084] Kaemgalangin B1 (5)

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

[0086] Molecular Weight: 760

[0087] Property: white gum

[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 (log ε): 200 (3.99), 230 (3.35), 273 (3.17) nm;

[0090] IR (KBr) v max : 3433, 2924, 1604, 1515, 1453, 1383, 1271, 1156, 1127, 1033, 815 cm -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 listed in Table 2.

[0094]

[0095] Kaemgalangin B2(6)

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

[0097] Molecular Weight: 760

[0098] Property: white gum

[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 (log ε): 200 (4.11), 273 (3.32) nm;

[0101] IR (KBr) v max : 3421, 2922, 1604, 1515, 1453, 1383, 1271, 1156, 1126, 1033, 815 cm -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] Mol. Wt: 700

[0109] Appearance: white gum

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

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

[0112] IR (KBr) v max : 3399, 2938, 1613, 1514, 1451, 1383, 1268, 1134, 1034, 823 cm -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 listed in Table 2.

[0116]

[0117] Kaemgalangin B4 (8)

[0118] Mol. Formula: C 42 H 48 O 13 ,

[0119] Mol. Wt: 760

[0120] Appearance: white gum

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

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

[0123] IR (KBr) v max : 3433, 2924, 1605, 1515, 1453, 1382, 1272, 1156, 1127, 1033, 813 cm -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 listed in Tables 3 and 4.

[0127]

[0128] Kaemgalangin B5 (9)

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

[0130] Molecular Weight: 700

[0131] Property: white gum

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

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

[0134] IR (KBr) v max : 3434, 2934, 1613, 1515, 1453, 1376, 1268, 1242, 1162, 1129, 1084, 1033, 815 cm -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 listed in Tables 3 and 4.

[0138]

[0139] Kaemgalangin B6 (10)

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

[0141] Molecular Weight: 776

[0142] Property: white gum

[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 (log ε): 200 (4.08), 229 (3.49), 277 (3.20) nm;

[0145] IR (KBr) v max : 3433, 2924, 1631, 1598, 1515, 1454, 1428, 1383, 1271, 1218, 1158, 1128, 1033, 814 cm -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 listed in Tables 3 and 4.

[0149]

[0150] Kaemgalangin B7 (11)

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

[0152] Molecular Weight: 760

[0153] Property: white gum

[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 (log ε) 200 (4.15), 269 (3.34) nm;

[0156] IR v max 3434, 2935, 1608, 1515, 1454, 1369, 1271, 1237, 1156, 1126, 1033, 813 cm -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 listed in Tables 3 and 4.

[0160]

[0161] Kaemgalangin B8 (12)

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

[0163] Molecular Weight: 700

[0164] Property: White gum

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

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

[0167] IR v max 3432, 2929, 1613, 1515, 1452, 1379, 1267, 1239, 1130, 1031, 815 cm -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 listed 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 gum

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

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

[0178] IR v max 3433, 2939, 1613, 1594, 1516, 1459, 1241, 1123, 1033, 818 cm -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 listed 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 gum

[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 (log ε) 195 (3.26), 224 (2.56), 278 (2.04) nm;

[0189] IR v max 3434, 2925, 1613, 1515, 1453, 1383, 1266, 1230, 1129, 1032, 819 cm -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 listed 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] Property: white gum

[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 (log ε) 195 (4.11), 223 (3.39), 277 (2.91) nm;

[0200] IR v max 3430, 2924, 1613, 1515, 1451, 1382, 1274, 1239, 1126, 1073, 1036, 825 cm -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 listed 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] Property: white gum

[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 (log ε) 195 (4.27), 224 (3.53), 281 (3.04) nm;

[0211] IR v max 3433, 2928, 1613, 1515, 1450, 1374, 1274, 1238, 1123, 1036, 824 cm -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 listed 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] Property: white gum

[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 (log ε) 195 (4.13), 225 (3.49), 277 (2.91) nm;

[0222] IR v max 3433, 2925, 1613, 1595, 1515, 1459, 1425, 1380, 1338, 1270, 1234, 1125, 1034, 822 cm -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 listed in Tables 3 and 5.

[0226]

[0227] Kaemgalangin C1(18)

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

[0229] Molecular Weight: 690

[0230] Property: white gum

[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 (log ε) 195 (3.97), 223 (3.32), 281 (2.87) nm;

[0233] IR v max 3430, 2923, 1612, 1514, 1451, 1384, 1273, 824 cm -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] Property: white gum

[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 (log ε) 195 (4.09), 225 (3.44), 281 (2.98) nm;

[0244] IR v 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 listed in Table 6.

[0247]

[0248] Kaemgalangin C3 (20)

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

[0250] Molecular Weight: 690

[0251] Property: white gum

[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 (log ε) 195 (4.12), 225 (3.47), 281 (3.03) nm;

[0254] IR v 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 listed in Table 6.

[0258]

[0259] Kaemgalangin C4 (21)

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

[0261] Molecular Weight: 690

[0262] Property: white gum

[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 (log ε) 195 (4.01), 225 (3.36), 281 (2.91) nm;

[0265] IR v max 3426, 2923, 1613, 1514, 1439, 1383, 1275, 1237, 1037, 824 cm -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. Compound 1-4 1 H-NMR and 13 C NMR data

[0270]

[0271]

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

[0273]

[0274]

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

[0276]

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

[0278]

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

[0280]

[0281]

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

[0283]

[0284]

[0285] Example 2:

[0286] Compound GLP-1 secretion promoting activity.

[0287] 1 Materials and Methods

[0288] 1.1 Materials

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

[0290] 1.2 Instruments

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

[0292] 1.3 Experimental process

[0293] GLP-1 secretion experiment: NCI-H716 cells were cultured with RPMI-1640 medium containing 10% FBS and 1% PS at 37°C and 5% CO2 saturated humidity in an incubator; when the cells grew to 80%-90%, the diluted cell suspension was inoculated in a 24-well plate (5×10 5 cells per well), differentiated for two days; KRBH working solution III was added to each well for 1h; KRBH working solution IV containing the compound was added to each well for 2h, the supernatant was collected, and then the GLP-1 content in the supernatant was detected by human GLP-1 ELISA kit.

[0294] 2. Results:

[0295] Compounds 1-21 were evaluated for promoting GLP-1 secretion in NCI-H716 cells at a concentration of 50 μM. Compared with the control group, compounds 1-21 significantly increased GLP-1 secretion Figure 2 and Table 7). In particular, the GLP-1 secretion rates of compounds 1, 2, 16 were 146.6±31.1%, 159.0±16.6% and 142.9±2.7%, respectively;

[0296] The GLP-1 secretion rates of compounds 3, 15, 19 and 21 were 84.4-107.7%. The remaining compounds also had obvious GLP-1 secretion promoting activity. It is shown that the oxygen hetero diaryl heptane dimer compounds in the traditional Chinese medicine Kaempferia rotunda are effective active substances for preparing GLP-1 secretion promoters, and also have potential effects of reducing blood sugar, reducing lipids and losing weight, etc.

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

[0298]

[0299]

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

[0301] 3. Conclusion:

[0302] The 21 new oxa-diarylheptane dimer compounds are isolated from Kaempferia galanga Linn, and the 21 new oxa-diarylheptane dimer compounds have significant GLP-1 secretion activity at a concentration of 50 μM. The oxa-diarylheptane dimer compounds in Kaempferia galanga Linn have the effects of reducing blood sugar, reducing fat and losing weight.

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

[0304] Example 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 water for injection according to the conventional method, filter, fill, sterilize and prepare an injection.

[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 filter funnel, and then sterilely filter, divide into ampoules, freeze-dry at low temperature, and then sterilely seal to obtain a powder injection.

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

[0309] 4. Take any one of compounds 1-21 or any combination thereof, and add excipients according to the weight ratio of 5:1 to prepare granules for tabletting.

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

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

[0312] 7. Take any one of compounds 1-21 or any combination thereof, and add excipient in a ratio of 3:1 by weight of compound to excipient to make a capsule.

[0313] 8. Take any one of compounds 1-21 or any combination thereof, and add excipient in a ratio of 5:1 by weight of compound to excipient to make a granule.

[0314] The above described embodiments are only to illustrate the preferred embodiments of the present application, and are not intended to limit the scope of the present application. Any modification and improvement of the technical solutions of the present application made by those skilled in the art without departing from the design spirit of the present application shall fall within the protection scope of the present application.

Claims

1. An oxadiaromatic heptane dimeric compound characterized by, a structure according to one of formulas 1-21:

2. Use of the oxadibarylheptane dimeric compound of claim 1 in the preparation of a GLP-1 secretagogue medicament.

3. Use of the oxadibarylheptane dimeric compound of claim 1 in the preparation of a hypoglycemic medicament or a weight loss medicament.

4. Use of the oxad diarylheptane dimeric compound according to claim 1 in the preparation of a health food; characterized in that, The health food has the functions of reducing blood sugar or losing weight.

5. A pharmaceutical composition, characterized by, The active ingredient in the pharmaceutical composition includes the oxadibarylheptane dimeric compound of claim 1 or a pharmaceutically acceptable salt of the oxadibarylheptane dimeric compound.

6. The pharmaceutical composition of claim 5, wherein, At least one of a pharmaceutically acceptable carrier, excipient, adjuvant and vehicle is further included.

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

8. Use of the pharmaceutical composition of claim 5 or 6 in the preparation of a hypoglycemic medicament or a weight loss medicament or a health food having the functions of reducing blood sugar or losing weight.

9. The method of claim 1, wherein the method is a method of extracting an oxadiaromatic heptane dimer compound. The method comprises the following steps: The rootstock of Kaempferia galanga L. is crushed and extracted with 90% ethanol for 3 times, and the ethanol extracts are combined; The ethanol extracts are combined and concentrated under reduced pressure to obtain an extract, which is dispersed in water and extracted with ethyl acetate to obtain an ethyl acetate extract part; The ethyl acetate extract part is subjected to silica gel column chromatography, and gradient elution is performed with methanol-chloroform as eluent in the following order: 0:100, 5:95, 10:90, 20:80, 50:50 and 100:0, to obtain multiple primary fractions; The multiple primary fractions are subjected to silica gel column chromatography with acetone-petroleum ether as eluent in the following order: 10:90-50:50, to obtain multiple secondary fractions; The multiple secondary fractions are subjected to reverse phase silica gel column chromatography with methanol-water as eluent in the following order: 50:50, 70:30, 90:10, to obtain multiple tertiary fractions; The multiple tertiary fractions are subjected to silica gel column chromatography with petroleum ether-acetone and chloroform-methanol as eluent in the following order, and then subjected to Sephadex LH-20 column chromatography with chloroform-methanol as eluent in the order of 1:1, and finally subjected to semi-preparative high performance liquid chromatography, to obtain the oxadibarylheptane dimeric compound.

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