WO2018014660A1 - Use of aromatic farnesyl compounds - Google Patents

Abstract

The invention provides a use of aromatic farnesyl compounds and pharmaceutical salts thereof in the preparation of slimming medicaments, slimming foods, slimming drinks and slimming health products.

Description

Use of aromatic farnesyl compounds Technical field

The invention relates to the application field of compounds in preparing slimming drugs, in particular to the application of aromatic farnesyl compounds in weight loss.

Background technique

Obesity is mainly caused by increased energy intake or reduced consumption and genetic mutations, which cause the energy balance in the body to be broken. Excessive energy is stored in fat cells by triglycerides, and the fat cells become larger. At present, obesity has become a chronic disease worldwide. The incidence of obesity has been rising in the past 10 years. Obesity is not only a serious disease, but also causes metabolic synthesis such as atherosclerosis, hyperglycemia, hyperlipemia and hypertension. Signs, and obesity tends to be multi-aged and younger. Dieting and exercise are the safest and most effective way to treat obesity. However, for obese patients, dieting and exercise alone can not have obvious effects, so weight-loss drugs and functional foods are receiving more and more attention.

Summary of the invention

The invention provides the application of a class of aromatic farnesyl compounds and medicinal salts thereof in diet foods, weight loss health products, diet drinks, slimming drugs, non-toxic side effects and remarkable therapeutic effects.

The medicament of the present invention is an injection solution, a tablet, a powder, a granule, a pill, a capsule, an oral liquid, an ointment, a cream or a spray; and is administered orally, intragastrically, by injection, sprayed, physically or chemically. The method of administration is administered or is administered by mixing or wrapping other substances.

The medicament of the present invention also includes a pharmaceutically acceptable salt of the compound.

The food or health care product according to the present invention is an oral liquid, a tea drink, a lozenge, a capsule, a drink or an effervescent tablet.

The application of the present invention includes daily health care, prevention of diabetes, or an auxiliary effect during/after treatment of diabetes.

The structural formula of the aromatic farnesyl compound of the present invention is a compound represented by the following formula (I):

among them,

R1-R5 is selected from the group consisting of hydrogen, a C1-C5 alkyl group, a nitro group, a fluorine group, a chlorine group, a bromine group, an ester group, a hydroxyl group, an amide group, and an alkoxy group;

R6 is selected from the group consisting of hydrogen and alkoxy;

R7 is selected from the group consisting of hydroxyl, aldehyde, ester, and carboxyl;

X is selected from the group consisting of oxygen, hydrogen, carbonyl, and hydroxyl;

The 1' configuration is selected from the group consisting of R or S;

The 2'-3' position is selected from a carbon-carbon single bond or a carbon-carbon double bond;

The 14' position is selected from an ester group and a carboxyl group;

n is selected from 1-3.

The above aromatic farnesyl compound is selected from any one of the following S1 to S38:

The aromatic farnesyl compound and the pharmaceutically acceptable salt thereof provided by the invention The hydroquinone farnesyl compound and the pharmaceutically acceptable salt thereof provided by the invention can prepare a medicament for treating and/or preventing obesity, or can prepare a slimming function The drug or functional health supplement; the experiment proves that the hydroquinone farnesyl compound provided by the invention can effectively inhibit obesity, control body weight, and has a significant effect in lowering blood sugar.

detailed description

The invention is described in detail below with reference to the embodiments, but the following examples should not be construed as limiting the scope of the invention.

The experimental methods used in the following examples are conventional methods unless otherwise specified.

The materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

The Ganoderma lucidum fruit entity was purchased from Beijing Tongrentang Pharmacy.

Example 1

Preparation of compounds represented by S13 and S28, S31-S38

(1) Preparation of extract of Ganoderma lucidum

The Ganoderma lucidum fruiting body was cut and weighed 5 kg. The extract was refluxed 3 times with 15 L of 95% ethanol-water (volume percent) solution for 1 hour each time. The extracts were combined and concentrated to dryness under reduced pressure to yield 170 g.

The extract was further dissolved in 600 ml of distilled water, extracted three times with an equal volume of n-hexane, and the organic phase was discarded. The aqueous phase was extracted three more times with an equal volume of ethyl acetate. aqueous phase was discarded and ethyl acetate extracts were combined. Ethyl acetate was evaporated to dryness with a rotary evaporator (RE-52AA, purchased from Shanghai Yarong Biochemical Instrument Factory) to obtain 54 g of extract, which was designated as LZ-E.

(2) Preparation of the compound

The LZ-E prepared in the step (1) was separated by silica gel column chromatography to obtain a n-hexane:ethyl acetate system (n-hexane:ethyl acetate volume ratio: 9:1, 4:1, 7:3, 1:1) Gradient elution was performed, and each gradient was washed with 3 retention volumes of 500 ml each. According to the thin layer chromatography performance analysis, the fraction LZ-F1 was obtained in a system of n-hexane:ethyl acetate (volume ratio: 9:1); the fraction LZ was obtained in n-hexane:ethyl acetate (volume ratio: 4:1). -E2 - LZ-E3; fractions LZ-E4, LZ-E5 were obtained in n-hexane:ethyl acetate (volume ratio: 7:3); obtained in n-hexane:ethyl acetate (volume ratio: 1:1) Fraction LZ-E6; a total of 6 fractions were obtained, and the fractions were freeze-dried.

The content of the active substance in LZ-E4 was found to be high by thin layer chromatography analysis, and thus the fraction was further separated by an ODS reversed-phase silica gel column. Elution was carried out in 10%, 20%, 30%, 40%, 50%, 70%, 90% aqueous methanol solution, and each elution system was washed with 3 retention volumes, each retention volume being 500ml. According to the thin layer chromatography behavior, the 254nm UV lamp was used to judge the different fractions, and the fraction LZ-E4-1 was obtained in the methanol aqueous solution with 10% by volume; in the methanol aqueous solution system with 20% by volume Fractions LZ-E4-2 to LZ-E4-4; fractions LZ-E4-5 to LZ-E4-10 are obtained in a methanol aqueous solution system having a volume percentage of 30%; methanol in a volume percentage of 40% The fraction LZ-E 4-11-LZ-E 4-14 is obtained in the aqueous solution system; the fraction LZ-E4-15-LZ-E4-18 is obtained in a methanol aqueous solution system having a volume percentage of 50%; A fraction of 70% in a 90% aqueous methanol system obtained fractions LZ-E4-19 to LZ-E4-23; a total of 23 subfractions were obtained, and the fractions were freeze-dried.

The LZ-E4-12 fraction was found to have a higher content of active substances by thin layer chromatography, and thus the LZ-E4-12 fraction was further subjected to HPLC separation. Acid water in a volume percentage of 56% acetonitrile (the acid water here is 0.01% trifluoroethylene by volume) The aqueous solution of the acid was prepared as an eluent by HPLC. The flow rate was 2 ml/min, and the peaks of 18.9, 21.2, 24.5, 26.2, 30.2, 35.8 min were collected to obtain the formulas S31, S32, S33, S34, S35, S36. The compound shown.

The LZ-E4-14 fraction was further separated by HPLC analysis, and the LZ-E4-14 fraction was further subjected to HPLC separation. Prepare HPLC by using 52% acetonitrile in water (the acid water is 0.01% aqueous solution of trifluoroacetic acid) as the eluent. The flow rate is 2ml/min and the concentration is 21.1min. The chromatographic peak gave LZ-E4-14-1; the LZ-E4-14-1 was subjected to HPLC chiral separation of 45% acetonitrile at a flow rate of 2 ml/min, and the peaks of 31.1 min and 32.5 min were collected to obtain the formula S13. , the compound shown in S28.

The LZ-E4-18 fraction was further separated by HPLC analysis, and the LZ-E4-18 fraction was further subjected to HPLC separation. Prepared by HPLC with a solution of 46% by volume of acetonitrile in water (the acid water in an aqueous solution of 0.01% trifluoroacetic acid) was used as an eluent at a flow rate of 2 ml/min and collected for 15.4 min. The chromatographic peak gave LZ-E4-18-1; the LZ-E4-18-1 was subjected to HPLC chiral separation of 40% acetonitrile at a flow rate of 2 ml/min, and the peaks of 25.1 min and 26.4 min were collected to obtain the formula S37. , the compound shown in S38.

The conditions of the above thin layer chromatography are as follows:

Thin layer board: Qingdao Ocean Thin Layer Board Company. Thin layer condition unfolding system: chloroform:methanol=20:1, 2 ml; temperature 25 °C

The above HPLC chromatographic conditions were as follows: The sample was prepared as a 10 mg/ml solution in a chromatographically pure methanol at a loading of 15 μL each time, and the column was a Kromasil 10×250 mm C18 semi-preparative column at a column temperature of 25 ° C and a wavelength of 210 nm. Detection.

Example 2

Synthesis of compounds represented by S1-S30

synthetic route

Compound A is a benzaldehyde derivative with different substituents. The specific structural formula is shown in the following table:

Table 1: Benzaldehyde derivatives represented by compounds

Compound B: Vinylmagnesium bromide (1M in THF, 16 ml, 16 mmol) was added dropwise to a solution (15 ml) of A (15.0 mmol) in EtOAc. It was diluted with aq. EtOAc (3 mL). After vacuum concentration, the extract was subjected to silica gel column chromatography (hexane/ethyl acetate, 10:1) to afford Compound B.

Compound 1'R-C: To a solution of Compound B (10 mmol) in anhydrous dichloromethane (30 ml) was added celite (3 g) and stirred for 5 min. Subsequently, PCC (pyridinium chlorochromate, 2.56 g) was added, and the mixture was stirred for 3 hours, and then concentrated in vacuo. EtOAc EtOAc EtOAc EtOAc A solution of (R)-methyl-CBS oxazol borane catalyst in toluene (1.0 mol/L, 1 mmol, 1 mL) and borane in dimethyl sulfide (10 mol/L, 1 mmol, 1 mL) at room temperature The reaction mixture was stirred at room temperature for 5 h, then aq. EtOAc (EtOAc) The crude product was obtained by flash chromatography on silica gel (hexane/ethyl acetate, 10:1) to afford compound 1

Compound 1'S-C: To a solution of Compound B (10 mmol) in dry methylene chloride (30 ml) was added celite (3 g) and stirred for 5 min. Subsequently, PCC (pyridinium chlorochromate, 2.56 g) was added, and the mixture was stirred for 3 hours, and then concentrated in vacuo. EtOAc EtOAc EtOAc EtOAc The solution was added to a toluene solution of (S)-methyl-CBS oxazole borane catalyst (1.0 mol/L, 1 mmol, 1 mL) and a solution of borane in dimethyl sulfide (10 mol/L, 1 mmol, 1 mL) at room temperature. The reaction mixture was stirred at room temperature for 5 h, then aq. EtOAc (EtOAc) The crude product was obtained by flash chromatography on silica gel (hexane/ethyl acetate, 10:1) to afford compound 1'S-C.

(E)-6,10-Dimethyl-2-methylene undec-5,9-dienol (E): To a solution of geraniol (4 g, 32.4 mmol) in carbon tetrachloride (50 ml) Triphenylphosphine (10.2 g, 38.9 mmol) was added. The system was stirred under heating and reflux for 1 hour, then cooled to 0 ° C, 20 ml of n-hexane solution was added, stirred for 5 min, filtered, and the filtrate was concentrated in vacuo to afford yel.

Add n-butyllithium (2.68) to tetramethylethylenediamine (TMEDA, 19.5 ml, 130 mmol) cooled to -78 °C. A solution of M in n-hexane (48.5 ml, 130 mmol) afforded white crystals. After stirring for 10 min, 2-methyl-propanol (6.82 ml, 81.0 mmol). The system was stirred at room temperature for 22 hours. When a dark orange gum appeared in the system, it was cooled to -78 ° C and 10 ml of a solution of geraniol chloride in diethyl ether was added. The system was stirred at room temperature for 1 hour. The temperature was lowered to 0.degree. C. and diluted with EtOAc EtOAc (EtOAc)EtOAc. After concentration in vacuo, the extract was purified by silica gel column chromatography (hexane/ethyl acetate, 10:1) to afford (E)-6,10-dimethyl-2-methylene eleven-5,9 -dienol (E) (4.81 mg, 90%).

(E)-6,10-Dimethyl-2-methylene eleven-5,9-adienal (F): to (E)-6,10-dimethyl-2-methylene Activated manganese dioxide (14.4 g, 162 mmol) was added to a solution of -5,9-dienol (B) (3.95 g, 90%) in n-hexane (10 mL). The system was stirred at room temperature for 6 hours, filtered and concentrated in vacuo. EtOAc EtOAcjjjjjjjj Methylenyl undec-5,9-dienal (F) (5.01 g, 75%).

(E)-6,10-Dimethyl-2-methylene eleven-5,9-dienoic acid (G): (F)-6,10-dimethyl-2 cooled to 0 °C -methylalkenyl eleven-5,9-dienal (C) (850 mg, 4.12 mmol), 2-methyl-2-butene (4.90 ml, 41.2 mmol) in tert-butanol (20 ml), water ( An aqueous solution (5 ml) of sodium dihydrogen phosphate (2.54 g, 20.9 mmol) and sodium hypochlorite (80%, 1.14 g, 12.4 mmol) were added to 10 ml of the mixed solution. The system was stirred at room temperature for 1 hour. It was diluted with brine (30 ml) and then extracted with dichloromethane (30 mL). After concentration in vacuo, the extract was purified by silica gel column chromatography (hexane/ethyl acetate, 10:1) to afford (E)-6,10-dimethyl-2-methylene eleven-5,9 -Dienoic acid (G) (760 mg, 83%).

Compound 1 'RH: Toluene solution of (E)-6,10-dimethyl-2-methylene eleven-5,9-dienoic acid (D) (35.1 mg, 158 μmol) cooled to 0 °C Diisopropylamine (110 μL, 631 μmol), 2,4,6-trichlorobenzoyl chloride (100 μL, 631 μmol), 4-(dimethylamino)pyridine (154 mg, 1.26 mmol) were added. Subsequently, 1'R-C (40.1 mg, 124 μmol) in toluene was added and diluted with 2 ml of toluene. The system was stirred at room temperature for 8 hours. Diluted with EtOAc (10 mL), EtOAc (EtOAc)EtOAc. After vacuum concentration, the extract was purified by silica gel column chromatography (hexane/ethyl acetate, 10:1) toield (1, R, 5E)-1'-[2",5"-di(methoxy) Methoxy)phenyl]prop-2-en-1-yl-6,10-dimethyl-2-methylene eleven-5,9-dienyl ester (E) (67.0 mg, 92%).

1'S-H: To a solution of (E)-6,10-dimethyl-2-methylene eleven-5,9-dienoic acid (D) (35.1 mg, 158 μmol) in toluene cooled to 0 °C Diisopropylamine (110 μL, 631 μmol), 2,4,6-trichlorobenzoyl chloride (100 μL, 631 μmol), 4-(dimethylamino)pyridine (154 mg, 1.26 mmol) were added. Then add 1'R-C (40.1 mg, 124 μmol of a toluene solution was diluted with 2 ml of toluene. The system was stirred at room temperature for 8 hours. Diluted with EtOAc (10 mL), EtOAc (EtOAc)EtOAc. After concentrating in vacuo, EtOAc (EtOAc:EtOAc)

Compound 1 'RI (S1-S15): 1'RH (15.1 mg, 32.9 μmol) at room temperature, Grubbs 1st generation catalyst (1.4 mg, 1.6 μmol) in degassed dichloromethane (2 ml) was stirred for 5 hours. Then, Grubbs 1st generation catalyst (1.4 mg, 1.6 μmol) was added again and stirred for 3 hours. After concentrating in vacuo, EtOAc (EtOAc:EtOAc)

1'S-I (S16-S30): 1'S-H (15.1 mg, 32.9 μmol), Grubbs 1st generation catalyst (1.4 mg, 1.6 μmol) in degassed dichloromethane (2 ml) was stirred at room temperature for 5 hours. Then, Grubbs 1st generation catalyst (1.4 mg, 1.6 μmol) was added again and stirred for 3 hours. After vacuum concentration, the extract was subjected to silica gel column chromatography (hexane/ethyl acetate, 10:1) to afford compound 1'S-I.

Example 3

Compound represented by S1-S38

The prepared compounds were subjected to nuclear magnetic resonance, infrared detection, and mass spectrometry to determine the structure of each compound.

The NMR instruments used were BrukerMercury-500 and BrukerMercury-600 MHz (Brook Spectrometer), the infrared chromatograph was Nicolet IS5FT-IR (American Nicholin Instruments Co., Ltd.), and the mass spectrometer was Bruker APEX III 7.0T. APEX II FT-ICR (Brook Spectrometer).

S1,[(R,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-phenylfuran-2(5H)-one], yellow Oily,

_{^{1 H NMR (CDCl 3, 500MHz}} ): δ H; 7.33 (t, 8.3,2H), 7.27 (t, 8.3,1H), 7.24 (s, 1H), 7.15 (d, 8.3,2H), 6.43 (s , 1H), 5.09 (t, 7.0, 1H), 5.06 (t, 7.0, 1H), 2.39 (t, 7.0, 2H), 2.33 (m, 2H), 2.02 (m, 2H), 1.96 (m, 2H) ), 1.66 (s, 3H), 1.58 (s, 6H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C : 174.0, 147.1, 141.5, 136.8, 133.2, 131.5, 128.9 (×2), 127.5 (× 2), 127.1, 124.1, 122.2, 82.1, 39.6, 26.8, 25.7, 25.4, 21.2, 17.8, 16.2positive HRTOFMS m/z [M+H] ⁺ 311.2009 (calculated C ₂₁ H ₂₆ O ₂ , 311.2006).

S2,[(R,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(2-naphthyl)-furan-2 (5H) -ketone], yellow oil,

_{^{1 H NMR (CDCl 3, 500MHz}} ): δ H; 8.08 (d, 8.4,1H), 7.91 (d, 8.0,1H), 7.86 (d, 8.0,1H), 7.60 (t, 7.6,1H), 7.56 (t, 7.6, 1H), 7.44 (t, 7.6, 1H), 7.39 (m, 1H), 7.36 (m, 1H), 6.66 (s, 1H), 5.13 (t, 7.0, 1H), 5.06 (t) , 7.0, 1H), 2.43 (t, 7.0, 2H), 2.33 (m, 2H), 2.02 (m, 2H), 1.97 (m, 2H), 1.66 (s, 3H), 1.58 (s, 6H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C 173.8, 147.4, 136.9.134.0, 133.8, 131.5, 131.3, 130.7, 129.6, 129.1, 126.9, 126.1125.4, 124.1, 123.5, 122.6, 122.5, 79.3, 39.6, 26.6, 25.7, 25.7, 25.5, 17.7, 16.2; positive HRTOFMS m/z [M+H] ⁺ 361.2162 (calc. C ₂₅ H ₂₈ O ₂ , 361.2162).

S3,[(R,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(2-methoxymethyl)phenyl]furan -2(5H)-ketone], yellow oil,

¹ H NMR (CDCl ₃ , 500 MHz): δ _H ; 7.27 (s, 1H), 7.21. (t, 7.7, 1H), 7.15 (d, 7.5, 1H), 6.93 (t, 7.5, 1H), 6.81 (d) , 7.5, 1H), 6.23 (s, 1H), 6.01 (s, 2H), 3.50 (s, 3H), 2.38 (t, 7.5, 2H), 2.29 (m, 2H), 2.03 (m, 2H), 1.96 (m, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 1.58 (s, 3H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C 174.1, 153.0, 147.1, 136.8, 133.1, 131.5,129.8,126.6,124.2,122.6,122.1,121.3,115.8,95.2,78.0,50.9,39.6,26.5,25.7,25.7,25.4,17.1,16.1positive HRTOFMS m/z[M+H] ⁺ 371.2221 (calculated value C ₂₃ H ₃₀ O ₄ , 371.2217).

S4,[(R,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(2-hydroxy)phenyl]furan-2 (5H )-ketone], yellow oil,

¹ H NMR (CDCl ₃ , 500 MHz): δ _H ; 7.27 (s, 1H), 7.21. (t, 7.7, 1H), 7.15 (d, 7.5, 1H), 6.93 (t, 7.5, 1H), 6.81 (d) , 7.5, 1H), 6.23 (s, 1H), 2.38 (t, 7.5, 2H), 2.29 (m, 2H), 2.03 (m, 2H), 1.96 (m, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 1.58 (s, 3H); δ _H ; ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C 174.1, 153.0, 147.1, 136.8, 133.1, 131.5, 129.8, 126.6, 124.2, 122.6, 122.1 , 121.3,115.8,78.0,39.6,26.5,25.7,25.7,25.4,17.1,16.1positive HRTOFMS m / z [m + H] + 327.1954 ( calcd for _{C 21 H 26 O 3, 327.1953} ).

S5, [(R,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(2-nitro)phenyl]furan-2 ( 5H)-ketone], yellow oil,

_{^{1 H NMR (CDCl 3, 500MHz}} ): δ H 8.17 (d, 8.3,1H), 7.68 (t, 7.6,1H), 7.54 (d, 7.9,1H), 7.53 (m, 1H), 7.33 (s, 1H), 6.53 (s, 1H), 5.06 (m, 2H), 2.38 (t, 7.6, 2H), 2.26 (m, 2H), 1, 99 (m, 2H), 1.95 (m, 2H), 1.66 (s, 3H), 1.58 (s, 6H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C 173.7, 148.1, 147.1, 137.0, 134.7, 133.6, 132.3, 131.5, 129.4, 128.1, 125.3, 124.1, 122.3 , 78.4, 39.6, 26.6, 25.7, 25.7, 25.4, 17.7, 16.1 positive HRTOFMS m/z [M+H] ⁺ 356.1855 (calc. C ₂₁ H ₂₅ NO ₄ , 356.1856).

S6, [(R,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(p-methyl)phenyl]furan-2 ( 5H)-ketone], yellow oil,

_{^{1 H NMR (CDCl 3, 500MHz}} ): δ H; 7.18 (d, 7.9,2H), 7.13 (d, 7.9,2H), 7.08 (s, 1H), 5.83 (s, 1H), 5.12 (t, 7.5 , 1H), 5.07 (t, 7.5, 1H), 2.40 (m, 2H), 2.35 (s, 3H), 2.31 (m, 2H), 2.04 (m, 2H), 1.98 (m, 2H), 1.67 ( s, 3H), 1.59 (s, 3H), 1.58 (s, 3H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C : 174.0, 147.9, 139.1, 136.8, 133.5, 132.1, 131.5, 129.5 (×2 ), 126.6 (×2), 124.1, 122.6, 82.2, 39.6, 26.6, 25.7, 25.7, 25.4, 21.2, 17.7, 16.2positive HRTOFMS m/z [M+H] ⁺ 325.2166 (calculated value C ₂₂ H ₂₈ O ₂ , 325.2162).

S7, [(R,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(p-ethyl)phenyl]furan-2 ( 5H)-ketone], yellow oil,

_{^{1 H NMR (CDCl 3, 500MHz}} ): δ H; 7.20 (d, 7.9,2H), 7.13 (d, 7.9,2H), 7.06 (s, 1H), 5.84 (s, 1H), 5.12 (t, 7.5 , 1H), 5.07 (t, 7.5, 1H), 2.65 (q, 7.6, 2H), 2.41 (m, 2H), 2.32 (m, 2H), 2.05 (m, 2H), 1.98 (m, 2H), 1.67 (s, 3H), 1.59 (s, 3H), 1.58 (s, 3H), 1.23 (t, 7.6, 3H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C : 174.0, 147.9, 145.4, 136.8 , 133.5, 132.4, 131.5, 128.4 (×2), 126.6 (×2), 124.1, 122.6, 82.3, 39.6, 28.6, 26.6, 25.7, 25.7, 25.4, 17.7, 16.2, 15.5; positive HRTOFMS m/z [M +H] ⁺ 339.2322 (calculated C ₂₃ H ₃₀ O ₂ , 339.2319).

S8,[(R,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(p-isopropyl)phenyl]furan-2 (5H)-ketone], yellow oil,

¹ H NMR (CDCl ₃ , 500 MHz): δ _H ; ¹³ C NMR (CDCl ₃ , 125 MHz): 7.26 (d, 7.9, 2H), 7.19 (d, 7.9, 2H), 7.10 (s, 1H), 5.87 ( s, 1H), 5.15 (m, 2H), 5.08 (m, 2H), 2.94 (m, 1H), 2.41 (m, 2H), 2.33 (m, 2H), 2.06 (m, 2H), 2.00 (m) , 2H), 1.69 (s, 3H), 1.62 (s, 6H), 1.28 (s, 3H), 1.26 (s, 3H); δ _C : 174.0, 150.1, 147.9, 136.8, 133.5, 132.5, 131.5, 127.0 (×2), 126.7, 126.6, 124.2, 122.6, 82.2, 39.6, 33.9, 26.625.7, 25.7, 25.4, 23.9 (×2), 17.7, 16.2; positive HRTOFMS m/z [M+H] ⁺ 353.2475 ( Calculated C ₂₄ H ₃₂ O ₂ , 353.2475).

S9,[(R,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(p-tert-butyl)phenyl]furan-2 (5H)-ketone], yellow oil,

_{^{1 H NMR (CDCl 3, 500MHz}} ): δ H; 7.40 (d, 7.6,2H), 7.18 (d, 7.6,2H), 7.07 (s, 1H), 5.85 (s, 1H), 5.11 (t, 7.5 , 1H), 5.07 (t, 7.5, 1H), 2.40 (m, 2H), 2.31 (m, 2H), 2.05 (m, 2H), 1.98 (m, 2H), 1.67 (s, 3H), 1.59 ( s, 6H), 1.31 (s, 9H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C : 174.0, 152.3, 147.9, 136.8, 133.5, 132.1, 131.5, 126.4 (×2), 125.9 (×2) , 124.1, 122.6, 82.2, 39.6, 34.7, 31.2 (×3), 26.6, 25.7, 25.7, 25.4, 17.7, 16.2positive HRTOFMS m/z [M+H] ⁺ 367.2632 (calculated C ₂₅ H ₃₄ O ₂ , 367.2632).

S10, [(R,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(p-methoxy)phenyl]furan-2 (5H)-ketone], yellow oil,

_{^{1 H NMR (CDCl 3, 500MHz}} ): δ H; 7.17 (d, 7.6,2H), 7.05 (d, 7.6,2H), 6.89 (s, 1H), 5.82 (s, 1H), 5.12 (t, 7.5 , 1H), 5.07 (t, 7.5, 1H), 3.81 (s, 3H), 2.40 (m, 2H), 2.32 (m, 2H), 2.04 (m, 2H), 1.99 (m, 2H), 1.67 ( s, 3H), 1.59 (s, 6H); ¹³ C NMR (CDCl ₃ , 125 MHz) δ _C : 174.0, 160.3, 147.8, 136.8, 133.7, 131.5, 128.2 (×2), 127.0, 124.1, 122.6, 114.3 ( × 2), 82.1,55.4,39.7,26.6,25.7,25.7,25.4,17.7,16.2positive HRTOFMS m / z [m + H] + 341.2115 ( calcd for _{C 22 H 28 O 3, 341.2111} ).

S11, [(R,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(p-nitro)phenyl]furan-2 ( 5H)-ketone], yellow oil,

_{^{1 H NMR (CDCl 3, 500MHz}} ): δ H; 8.07 (d, 7.6,2H), 7.48 (d, 7.6,2H), 7.29 (s, 1H), 5.82 (s, 1H), 5.01 (t, 7.5 , 1H), 4.97 (t, 7.5, 1H), 2.32 (m, 2H), 2.19 (m, 2H), 1.92 (m, 2H), 1.82 (m, 2H), 1.67 (s, 3H), 1.57 ( s, 3H), 1.45 (s, 3H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C : 174.0, 147.9, 145.9, 141.8, 137.7, 137.2, 131.2, 127.2 (×2), 123.8, 123.6 (× 2), 121.4, 89.5, 39.6, 26.6, 25.7, 25.7, 25.5, 17.7, 16.1, positive HRTOFMS m/z [M+H] ⁺ 356.1852 (calc. C ₂₁ H ₂₅ NO ₄ , 356.1856).

S12, [(R,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(2,5-dimethoxy)phenyl] Furan-2(5H)-one], yellow oil,

_{^{1 H NMR (CDCl 3, 500MHz}} ): δ H; 7.19 (s, 1H), 6.82 (m, 2H), 6.76 (s, 1H), 6.19 (s, 1H), 5.10 (t, 7.6,1H), 5.06 (t, 7.6, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 2.35 (m, 2H), 2.26 (m, 2H), 2.03 (m, 2H), 1.97 (m, 2H) , 1.67 (s, 3H), 1.59 (s, 3H), 1.58 (s, 3H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C 176.7, 151.1, 148.8, 137.7, 132.9, 132.1, 123.9, 123.4, 125.3, 123.4, 117.1, 117.1, 113.1, 79.8, 55.8, 56.1, 40.7, 27.6, 26.8, 26.1, 25.8, 17.7, 16.2positive HRTOFMS m/z [M+H] ⁺ 371.2218 (calculated C ₂₃ H ₃₀ O ₄ , 371.2217).

S13, [(R,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(2,5-hydroxy)phenyl]furan-2 (5H)-ketone], yellow oil,

_{^{1 H NMR (CDCl 3, 500MHz}} ): δ H; 7.18 (s, 1H), 6.83 (m, 2H), 6.76 (s, 1H), 6.19 (s, 1H), 5.10 (t, 7.6,1H), 5.06(t, 7.6, 1H), 2.35 (m, 2H), 2.26 (m, 2H), 2.03 (m, 2H), 1.97 (m, 2H), 1.67 (s, 3H), 1.59 (s, 3H) , 1.58 (s, 3H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C 176.7, 151.3, 148.5, 137.6, 132.8, 132.1, 123.9, 123.4, 125.3, 123.4, 117.1, 117.1, 113.1, 79.8, 40.7, 27.6, 26.8, 26.1, 25.8, 17.7, 16.2 positive HRTOFMS m/z [M+H] ⁺ 343.1834 (calc. C ₂₁ H ₂₆ O ₄ , 343.1831).

S14, [(R,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(2,6-fluoro)phenyl]furan-2 (5H)-ketone], yellow oil,

_{^{1 H NMR (CDCl 3, 500MHz}} ): δ H; 7.33 (m, 1H), 7.07 (s, 1H), 6.90 (m, 2H), 6.22 (s, 1H), 5.513 (t, 7.6,1H), 5.07(t, 7.6, 1H), 2.41 (m, 2H), 2.32 (m, 2H), 2.04 (m, 2H), 1.99 (m, 2H), 1.66 (s, 3H), 1.61 (s, 3H) , 1.59 (s, 3H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C : 174.0, 158.7, 155.2, 148.6, 135.7, 135.1, 132.6, 132.0, 124.5, 123.5, 117.3, 116.0, 115.8, 79.8, 39.7 , 26.6, 25.7, 25.7, 25.4, 17.7, 16.2; positive HRTOFMS m/z [M+H] ⁺ 347.1817 (calc. C ₂₁ H ₂₄ F ₂ O ₄ , 347.1817).

S15, [(R,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(3,4,5-fluoro)phenyl] Furan-2(5H)-one], yellow oil,

¹ H NMR (CDCl ₃ , 500 MHz): δ _H ; 7.27 (m, 1H), 7.02 (s, 1H), 6.91 (m, 1H), 5.77 (s, 1H), 5.08 (m, 2H), 2.41 ( m, 2H), 2.30 (m, 2H), 2.02 (m, 2H), 1.99 (m, 2H), 1.65 (s, 3H), 1.59 (s, 6H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C : 172.9, 146.4 (×2), 137.2, 134.6, 131.8, 131.6, 124.0 (×2), 122.3 (×2), 110.9, 110.7, 80.2, 39.6, 26.6, 25.7, 25.6, 25.4, 17.7, 16.2 ;positive HRTOFMS m/z [M+H] ⁺ 365.1725 (calc. C ₂₁ H ₂₃ F ₃ O ₄ , 365.1723).

S16, [(S,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-phenylfuran-2(5H)-one], yellow Oily,

NMR data identical compound S1, positive HRTOFMS m / z [M + H] + 311.2008 ( calcd for _{C 21 H 26 O 2, 311.2006} ).

S17,[(S,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(2-naphthyl)-furan-2 (5H) -ketone], yellow oil,

NMR data of the compound S2 identical; positive HRTOFMS m / z [M + H] + 361.2161 ( calcd for _{C 25 H 28 O 2, 361.2162} ).

S18, [(S,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(2-methoxymethyl)phenyl]furan -2(5H)-ketone], yellow oil,

NMR data of the compound S3 same, positive HRTOFMS m / z [M + H] + 371.2215 ( calcd for _{C 23 H 30 O 4, 371.2217} ).

S19, [(S,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(2-hydroxy)phenyl]furan-2 (5H )-ketone], yellow oil,

NMR data S4 same compound, positive HRTOFMS m / z [M + H] + 327.1951 ( calcd for _{C 21 H 26 O 3, 327.1953} ).

S20, [(S,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(2-nitro)phenyl]furan-2 ( 5H)-ketone], yellow oil,

NMR data of the compound S5 same; positive HRTOFMS m / z [M + H] + 356.1852 ( calcd for _{C 21 H 25 NO 4, 356.1856} ).

S21, [(S,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(p-methyl)phenyl]furan-2 ( 5H)-ketone], yellow oil,

NMR data of the compound S6 same; positive HRTOFMS m / z [M + H] + 325.2160 ( calcd for _{C 22 H 28 O 2, 325.2162} ).

S22, [(S,E)-3-(4,8-dimethyl-n-decane-3,7-dien-1-yl)-5-(p-ethyl)phenyl]furan-2 ( 5H)-ketone], yellow oil,

NMR data of the same compound S7; positive HRTOFMS m / z [ M + H] + 339.2322 ( calcd for _{C 23 H 30 O 2, 339.2319} ).

S23, [(S,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(p-isopropyl)phenyl]furan-2 (5H)-ketone], yellow oil,

NMR data S8 same compound; positive HRTOFMS m / z [M + H] + 353.2475 ( calcd for _{C 24 H 32 O 2, 353.2475} ).

S24, [(S,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(p-tert-butyl)phenyl]furan-2 (5H)-ketone], yellow oil,

NMR data of compound S9 same; positive HRTOFMS m / z [M + H] + 367.2632 ( calcd for _{C 25 H 34 O 2, 367.2632} ).

S25, [(S,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(p-methoxy)phenyl]furan-2 (5H)-ketone], yellow oil,

NMR data S10 same compound; positive HRTOFMS m / z [M + H] + 341.2115 ( calcd for _{C 22 H 28 O 3, 341.2111} ).

S26, [(S,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(p-nitro)phenyl]furan-2 ( 5H)-ketone], yellow oil,

NMR data S11 same compound; positive HRTOFMS m / z [M + H] + 356.1858 ( calcd for _{C 21 H 25 NO 4, 356.1856} ).

S27, [(S,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(2,5-dimethoxy)phenyl] Furan-2(5H)-one], yellow oil,

NMR data S12 same compound; positive HRTOFMS m / z [M + H] + 371.2215 ( calcd for _{C 23 H 30 O 4, 371.2217} ).

S28, [(S,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(2,5-hydroxy)phenyl]furan-2 (5H)-ketone], yellow oil,

NMR data of the same compound S13; positive HRTOFMS m / z [ M + H] + 343.1830 ( calcd for _{C 21 H 26 O 4, 343.1831} ).

S29,[(S,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(2,6-fluoro)phenyl]furan-2 (5H)-ketone], yellow oil,

NMR data S14 same compound; positive HRTOFMS m / z [M + H] + 347.1817 ( calcd for _{C 21 H 24 F 2 O 4} , 347.1817).

S30, [(S,E)-3-(4,8-Dimethyl-n-decane-3,7-dien-1-yl)-5-(3,4,5-fluoro)phenyl] Furan-2(5H)-one], yellow oil,

NMR data S15 same compound; positive HRTOFMS m / z [M + H] + 365.1723 ( calcd for _{C 21 H 23 F 3 O 4} , 365.1723).

S31, [(2Z,5E)-2-(2-(2,5-dimethylphenyl))ethylidene-6,10-dimethyl-n-tetradecane-5,9-geranic acid], Yellow oil,

¹ H NMR (MeOD, 500 MHz): δ _H ; 7.38 (s, 1H), 6.93 (d, 2.8, 1H), 6.75 (d, 8.6, 1H), 6.71 (dd, 8.6, 2.8), 5.11 (t, 7.1,1H), 5.06 (t, 6.8, 1H), 3.52 (s, 3H), 2.32 (m, 2H), 2.27 (m, 2H), 2.00 (m, 2H), 1.92 (m, 2H), 1.68 (s, 3H), 1.61 (s, 6H); ¹³ C NMR (MeOD, 125 MHz): δ _C : 171.6, 151.1, 148.7, 146.9, 137.1, 135.8, 131.6, 125.0, 123.8, 123.6, 118.3, 118.0, 114.1 , 107.6, 56.9, 43.0, 27.2, 26.1, 25.8, 25.7, 17.7, 16.1: positive HRTOFMS m/z [M+H] ⁺ 373.2011 (calc. C ₂₂ H ₂₈ O ₅ 373.2010).

S32, [(2Z,5E)-2-(2-(2,5-dihydroxyphenyl)-2-oxoethylidene)-6,10-dimethyl-n-tetradecane-5,9- Geranic acid], yellow oil,

¹ H NMR (MeOD, 500 MHz): δ _H ; 7.70 (s, 1H), 7.13 (d, 2.7, 1H), 7.04 (dd, 8.8, 2.7), 6.82 (d, 8.8, 1H), 5.06 (t, 7.1,1H), 4.99 (t, 6.9, 1H), 2.65 (m, 2H), 2.20 (m, 2H), 1.94 (m, 2H), 1.75 (m, 2H), 1.62 (s, 3H), 1.58 (s, 3H), 1.54 (s, 3H); ¹³ C NMR (CDCl ₃ , 125 MHz): δ _C : 198.7, 170.1, 157.2, 150.7, 145.9, 137.6, 132.9, 126.6, 125.4, 124.0, 121.3, 119.9, 115.9, 40.6, 29.2, 28.5, 27.6, 25.9, 16.2, 15.8: positive HRTOFMS m/z [M+H] ⁺ 359.1853 (calc. C ₂₁ H ₂₆ O ₅ , 359.1853).

S33, [(2Z, 5E, 9E)-2-(2-(2,5-dimethylphenyl)-2-oxoethylidene)-11-hydroxy-6,10-dimethyl-n-decene Tetralin-5,9-geranic acid], yellow oil,

¹ H NMR (MeOD, 500 MHz): δ _H ; 6.64 (d, 8.5, _1H ), 6.61 (d, 2.8, 1H), 6.52 (dd, 8.5, 2.8), 5.78 (t, 7.1, 1H), 5.39 ( t, 7.1, 1H), 5.14 (t, 7.3, 1H), 3.94 (s, 2H), 3.69 (d, 7.7, 2H) 2.33 (m, 2H), 2.19 (m, 2H), 2.10 (m, 2H) ), 2.00 (m, 2H), 1.66 (s, 3H), 1.61 (s, 3H); ¹³ C NMR (MeOD, 125 MHz): δ _C : 172.3, 151.2, 149.3, 140.5, 136.7, 135.8, 133.3, 128.0 , 126.8, 124.6, 117.8, 116.9, 114.8, 69.0, 40.6, 35.9, 31.5, 28.5, 27.3, 16.2, 13.7: positive HRTOFMS m/z [M+H] ⁺ 361.2010 (calculated value C ₂₁ H ₂₈ O ₅ , 361.2010 ).

S34, [(2Z,5E)-2-(2-(2,5-dimethylphenyl))ethylidene-6,10-dimethyl-n-tetradecane-5,9-folate], Yellow oil,

¹ H NMR (MeOD, 500 MHz): δ _H ; 6.64 (d, 8.5, _1H ), 6.61 (d, 2.8, 1H), 6.52 (dd, 8.5, 2.8), 5.98 (t, 7.1, 1H), 5.13 ( t, 7.3, 1H), 5.10 (t, 7.3, 1H), 3.69 (d, 7.7, 2H), 2.33 (m, 2H), 2.19 (m, 2H), 2.05 (m, 2H), 2.00 (m, 2H), 1.68 (s, 3H), 1.62 (s, 3H), 1.61 (s, 3H); ¹³ C NMR (MeOD, 125 MHz): δ _C : 172.3, 151.2, 149.3, 140.5, 136.7, 133.3, 128.0, 125.5, 124.4, 117.8, 116.9, 114.8, 40.435.9, 31.5, 28.5, 27.7, 25.9, 17.8, 16.2: positive HRTOFMS m/z [M+H] ⁺ 345.2063 (calculated C ₂₁ H ₂₈ O ₄ , 345.2060) .

S35, [(2Z,5E,9E)-2-(2-(2,5-dimethylphenyl)-2-oxoethylidene)-11-aldehyde-6,10-dimethyl-form Tetradecan-5,9-geranic acid], yellow oil,

¹ H NMR (MeOD, 500 MHz): δ _H ; 6.64 (d, 8.5, _1H ), 6.61 (d, 2.8, 1H), 6.52 (dd, 8.5, 2.8), 5.78 (t, 7.1, 1H), 5.39 ( t, 7.1, 1H), 5.14 (t, 7.3, 1H), 3.69 (d, 7.7, 2H) 2.33 (m, 2H), 2.19 (m, 2H), 2.10 (m, 2H), 2.00 (m, 2H) ), 1.66 (s, 3H), 1.61 (s, 3H); ¹³ C NMR (MeOD, 125 MHz): δ _C : 194.0, 172.3, 151.2, 149.3, 140.5, 136.7, 135.8, 133.3, 128.0, 126.8, 124.6, 117.8, 116.9, 114.8, 40.6, 35.9, 31.5, 28.5, 27.3, 16.2, 13.7: positive HRTOFMS m/z [M+H] ⁺ 359.1854 (calc. C ₂₁ H ₂₆ O ₅ , 359.1854).

S36, [(E)-2-(2-(2,5-dihydroxyphenyl)-2-oxoethyl)-6,10-dimethyl-n-tetradecane-5,9-folate] Yellow oil,

¹ H NMR (MeOD, 500 MHz): δ _H ; 7.38 (d, 2.9, 1H), 7.08 (dd, 8.9, 2.9, 1H), 6.79 (d, 8.9, 1H), 5.18 (t, 7.1, 1H), 5.10 (t, 7.1, 1H), 3.50 (dd, 17.9, 9.2, 1H), 3.16 (dd, 17.9, 4.4, 1H), 3.03 (m, 2H), 2.14 (m, 2H), 2.05 (m, 2H) ), 1.99 (m, 2H), 1.87 (m, 2H), 1.64 (s, 3H), 1.61 (s, 3H), 1.58 (s, 3H); ¹³ C NMR (MeOD, 125 MHz): δ _C : 205.0 , 176.4, 156.3, 150.2, 136.2, 131.6, 125.6, 125.0, 124.3, 120.0, 119.3, 115.4, 40.3, 40.1, 32.6, 27.3, 26.1, 25.7, 17.7, 16.1; positive HRTOFMS m/z [M+H] ⁺ 361.2013 (calculated value C ₂₁ H ₂₈ O ₅ , 361.2010).

S37, (R)-[5-(2,5-dihydroxyphenyl)-3-(4-methyl-n-pentane-3-en-1-yl)furan-2(5H)-one], none Color oil,

¹ H NMR (MeOD, 500 MHz): δ _H ; 7.35 (d, 1.4, 1H), 6.76 (d, 8.6, 1H), 6.65 (dd, 8.6, 2.9, 1H), 6.53 (d, 2.9, 1H), 6.20 (d, 1.4, 1H), 5.12 (t, 7.1, 2H), 2.30 (m, 2H), 2.28 (m, 2H), 1.64 (s, 3H), 1.57 (s, 3H); ¹³ C NMR ( MeOD, 125MHz): δ _C : 174.6, 151.3, 149.5, 148.2, 133.1, 132.7, 123.9, 123.6, 117.0, 116.8, 113.2, 78.3, 26.6, 25.9, 25.7, 17.7; positive HRTOFMS m/z [M+H] ⁺ 275.1281 (calculated C ₁₆ H ₁₈ O ₄ , 275.1281).

S38, (S)-[5-(2,5-dihydroxyphenyl)-3-(4-methyl-n-pentane-3-en-1-yl)furan-2(5H)-one], none Color oil,

NMR data S37 same compound positive HRTOFMS m / z [M + H] + 275.1284 ( calcd for _{C 16 H 18 O 4, 275.1281} ).

Example 4

Effect of compounds represented by S1-S38 on lipolysis

Test sample solution: Accurately weigh 38 compounds shown in S1-S38 prepared in Example 3, and prepare 2 mM in DMSO for activity test (final concentration 20 μM, dissolved in a small amount of DMSO after preparation, diluted with distilled water until The corresponding concentration, control the final volume fraction of DMSO <0.1%; isoproterenol 10μM as a positive control, dissolved in a small amount of DMSO after preparation, diluted with distilled water to the corresponding concentration, control the final volume fraction of DMSO <0.1%.

Isolation and culture of primary mature adipocytes from SD rats: Male Sprague-Dawley rats were sacrificed by dislocation, and the adipose tissue of the epididymis was taken and washed three times with PBS solution containing double antibody, then cut into small pieces of about 1 mm3, and added with type I. Collagenase in PBS (1 mg/ml type I collagenase, 120 mmol/L NaCl, 4.8 mmol/L KCl, 2.5 mmol/L CaCl ₂ , 1.2 mmol/L KH ₂ PO ₄ , 1.2 mmol/L MgSO ₄ , 15 mmol/L NaHCO ₃ , 25 mmol/L Hepes, 200 nmol/L adenosine, 1% BSA, pH 7.4), water bath 37 ° C, 100 rpm 40 min. The cells were collected by centrifugation at 1000 rpm for 10 min at 1000 um nylon membrane, and the cells were washed with phenol red-free DMEM culture medium, repeated 3 times, and incubated for 2 hours at 37 ° C in a 5% carbon dioxide incubator.

Establishment of an obese cell model: The mature adipocytes were incubated for 24 hours at 300 rpm for 3 min, and 100 ul of cells per cell were added to a 5 ml capped centrifuge tube, and then the experimental group was added with DMEM containing OA at a concentration of 0.5 mmol/L OA. The culture medium and the control group were added to normal DMEM medium, incubated for 24 hours, and centrifuged at 500 rpm for 3 minutes to collect the cells, which were obese cells.

Obese cells were centrifuged at 500 rpm for 24 min after OA treatment for 3 min, washed three times to remove residual OA, and then cells were dispensed into 1.5 ml EP tubes according to 20 ul cell volume/500 ul DMEM (control DMEM contained the same concentration of DMSO, The experimental group DMEM contains different test samples). In this experiment, isoproterenol was used as a positive drug. After 24 hours, the cell culture solution was collected, centrifuged at 200 rpm for 30 seconds, the cell culture solution was collected, and the glycerol-degrading enzyme was fired by heating at 70 ° C for 10 minutes, and then the amount of glycerin released from the culture solution was measured using a glycerol assay kit at 490 nm.

The results are shown in Table 2. S5/S8/S9/S13/S20/S24/S28 significantly stimulated lipolysis of fat cells, and can be used as a candidate compound for weight loss drugs for further screening.

Table 2 Lipid decomposition of primary obese fat cells by compounds represented by S1-S38

	Glycerol mol/L PCV		Glycerol mol/L PCV
Model control	8.2	Isoproterenol	12.66**
S1	9.6	S20	11.82*
S2	8.9	S21	8.9
S3	9.2	S22	8.5
S4	9.3	S23	9.1
S5	10.65*	S24	12.34**
S6	9.9	S25	8.8
S7	9.1	S26	9.1
S8	11.72*	S27	9.0
S9	11.33*	S28	11.09*
S10	8.9	S29	8.9
S11	9.2	S30	9.3
S12	8.4	S31	9.2
S13	12.01**	S32	8.9
S14	9.0	S33	9.2
S15	9.1	S34	8.7
S16	8.7	S35	8.9
S17	8.6	S36	9.3
S18	9.2	S37	9.1
S19	9.1	S38	9.4

Example 5

Effects of seven compounds represented by S5, S8, S9, S13, S20, S24 and S28 on body weight and food intake of obese mice induced by high fat diet

Materials: The sample solution to be tested was 7 compounds of S5, S8, S9, S13, S20, S24, and S28 described in Example 3. Each sample was accurately weighed and formulated into a 10 mg/ml solution with 0.5% CMC-Na for activity testing. ICR mice (8 weeks old, male, D12492 high fat feeding for 5 weeks) were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., temperature 20-24 degrees Celsius, constant humidity 50-60%, light 12 hours (8:00) -20:00), soundproofing, free feeding, drinking water, and experimenting after one week in the environment.

METHODS: A total of 200 male healthy ICR mice, 22-24 g, were used for one week after adaptive feeding. Random selection Take 10 as a control group and give normal feed. The remaining 190 were given D12492 high fat feed. After 4 weeks of feeding, screening was performed according to body weight (15% increase in body weight compared with the control group), and 106 were finally screened. They were randomly divided into 9 groups (7 drug-administered groups + model group + positive drug rosiglitazone group), and each drug-administered group was intragastrically administered at 3 mg/kg.

(1) Determine the body weight of each group weekly and record the food intake;

(2) After 5 weeks of administration, the mice were anesthetized and sacrificed 4 hours after fasting, weighing, calculating Lee index to measure liver and kidney weight, and calculating organ/body weight ratio;

Lee index = [weight (g) / body length (cm)] ^ (1/3)

(3) Taking blood, using Beijing Fuan Technology Co., Ltd. mouse GLP-1 ELISA kit (batch number 201606), mouse GIP ELISA kit (batch number 201606), mouse CCK8 kit (batch number 201606), mouse MTL The kit (batch number 201606) and the mouse Ghrelin kit (batch number 201606) measure intestinal hormone related indicators (GLP1: glucagon-like peptide 1, GIP: glucose-dependent insulin-releasing polypeptide, CCK8: cholecystokinin, MTL: Motilin, Ghrelin: ghrelin). Measurement method reference

(4) Aseptic operation Take part of the cecal feces and store at -80 °C to determine intestinal probiotics.

According to the "Technical Specifications for Health Food Inspection and Evaluation" (2003), the fecal sample homogenate was diluted in a 10-fold gradient and inoculated on the corresponding medium, and the Bifidobacterium, Lactobacillus and Enterococcus faecalis count.

RESULTS: Compared with the control group, the body weight of the model group increased significantly, and there was no significant change in the rosiglitazone group. S5/S9/S13 showed significant difference with the model group after the third week. In the 5-week food intake statistics, 7 The food intake of the mice in the drug-administered group was inhibited. In the determination of the Lee index, the Lee index of the five drug-administered groups S5/S9/S13/S24/S28 was significantly lower than that of the model group, and S5/S9/S13 The kidney index of the three groups was significantly higher than that of the model group.

Table 3 Effects of seven compounds indicated by S5, S8, S9, S13, S20, S24 and S28 on body weight and food intake in mice

Table 4 Effects of seven compounds represented by S5, S8, S9, S13, S20, S24 and S28 on intestinal hormone and intestinal flora in mice

Example 6

Effects of seven compounds represented by S5, S8, S9, S13, S20, S24 and S28 on body weight and food intake of ob/ob obese model mice

Materials: The sample solution to be tested was 7 compounds of S5, S8, S9, S13, S20, S24, and S28 described in Example 3. Each sample was accurately weighed and formulated into a 10 mg/ml solution with 0.5% CMC-Na for activity testing. Ob/ob mice (8 weeks old, Male, mouse common breeding feed) purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., temperature 20-24 degrees Celsius, constant humidity 50-60%, light 12 hours (8:00-20:00), soundproof, Freely ingestion, drinking water, and experimenting after one week of adaptation to the environment. The blood glucose meter is a product of Roche, Germany.

METHODS: Male C57 mice were used for 8 weeks, weighing 20-22 g, and 10 as normal control group (1). Male ob/ob mice were 8 weeks old and weighed 30-32 g. Fasting blood glucose was measured according to blood glucose and body weight. Group: (2) model control group, (3) compound S5 administered 3 mg/kg, (4) compound S8 administered 3 mg/kg (5) compound S9 administered 3 mg/kg, (6) compound S13 administered 3 mg/kg Kg, (7) Compound S13 was administered at 3 mg/kg, (8) Compound S24 was administered at 3 mg/kg (9) Compound S28 was administered at 3 mg/kg, 10 rats in each group, and administration was continued for 5 weeks. The model control group was given an equal amount of 0.5% CMC-Na.

(1) Determine the body weight of each group weekly and record the food intake;

(2) After 5 weeks of administration, the mice were anesthetized and sacrificed 4 hours after fasting, weighing, calculating Lee index to measure liver and kidney weight, and calculating organ/body weight ratio;

Lee index = [weight (g) / body length (cm)] ^ (1/3)

(3) Taking blood, using Beijing Fuan Technology Co., Ltd. mouse GLP-1 ELISA kit (batch number 201606), mouse GIP ELISA kit (batch number 201606), mouse CCK8 kit (batch number 201606), mouse Ghrelin The kit (batch number 201606) measures gut hormone-related indicators (GLP1: glucagon-like peptide 1, GIP: glucose-dependent insulin-releasing polypeptide, CCK8: cholecystokinin, Ghrelin: ghrelin). Measurement method reference

(4) Aseptic operation Take part of the cecal feces and store at -80 °C to determine intestinal probiotics.

According to the "Technical Specifications for Health Food Inspection and Evaluation" (2003), the fecal sample homogenate was diluted in a 10-fold gradient and inoculated on the corresponding medium, and the Bifidobacterium, Lactobacillus and Enterococcus faecalis count.

RESULTS: Compared with the control group, the body weight of the model group increased significantly, and S5/S8/S9/S13/S20/S24/S28 showed significant difference with the model group after the second week. In the 5-week food intake statistics, 7 The food intake of the mice in the drug-administered group was inhibited. In the determination of the Lee index, the Lee index of the five drug-administered groups S5/S9/S13/S24/S28 was significantly lower than that of the model group, and S5/S9/S13/S24 The kidney index of these 4 groups was significantly higher than that of the model group.

Table 5 Effects of seven compounds indicated by S5, S8, S9, S13, S20, S24 and S28 on body weight and food intake in mice

Example 7

Effects of seven compounds represented by S5, S8, S9, S13, S20, S24 and S28 on gastric emptying and small bowel propulsion in mice

Materials: The sample solution to be tested was seven compounds represented by S5, S8, S9, S13, S20, S24, and S28 described in Example 3. Each sample was accurately weighed and formulated into a 10 mg/ml solution with 0.5% CMC-Na for activity testing. ICR mice (8 weeks old, male, D12492 high fat feeding for 5 weeks) were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., temperature 20-24 degrees Celsius, constant humidity 50-60%, light 12 hours (8:00) -20:00), soundproofing, free feeding, drinking water, and experimenting after one week in the environment.

METHODS: A total of 200 male healthy ICR mice, 22-24 g, were used for one week after adaptive feeding. Ten randomly selected ones were used as control groups to give ordinary feed. The remaining 190 were given D12492 high fat feed. After 4 weeks of feeding, screening was performed according to body weight (15% increase in body weight compared with the control group), and 95 screens were finally screened. They were randomly divided into 9 groups (7 drug-administered groups + model group + positive drug rosiglitazone group), and each drug-administered group was intragastrically administered at 3 mg/kg. Fasting for 12 h before the last administration, and 2 h after the administration, each mouse was intraperitoneally injected with 0.25 ml of 0.04% phenol red solution (containing 10% gelatin). After 20 minutes, the animals were sacrificed, and the stomach and small intestine were taken out. The small intestine was placed on a white paper, and the stomach was placed in 30 ml of 0.5 mol per liter of sodium hydroxide solution. The stomach was cut along the stomach and the stomach contents were thoroughly washed. Centrifuge 5 ml at 3000 rpm for 10 minutes. The upper layer solution was subjected to colorimetric measurement at a wavelength of 560 nm using a UV-1750 Shimadzu UV-Vis spectrophotometer, and the absorbance was measured. Calculate the gastric phenol red emptying rate.

Emptying rate = (1 - mouse stomach phenol red A) / phenol red A base value * 100%

The gastric emptying rate was evaluated by gastric index of gastric phenol red emptying rate. Intestinal propulsion, the small intestine propulsion rate was evaluated by multiplying the percentage of phenol red in the small intestine and the percentage of the small intestine by 100% as the intestinal propulsion rate.

As shown in Table 7, compared with the blank control, these seven compounds all have a certain effect on inhibiting gastric emptying, especially the compounds S5/S8/S9/S13, which inhibit the gastric phenol red emptying rate and the small intestine. The rate of advancement is very significant.

Table 6 Effects of seven compounds represented by S5, S8, S9, S13, S20, S24 and S28 on gastric emptying and small bowel propulsion in mice

Grouping	Gastric phenol red emptying rate	Small intestine propulsion rate
Control group	0.63	0.65
Model group	0.72#	0.74#
Rosiglitazone	0.70	0.74
S5	0.56*	0.65*
S8	0.60*	0.63*
S9	0.54**	0.64*
S13	0.52**	0.61*
S20	0.59*	0.71
S24	0.62*	0.66
S28	0.68	0.75

Claims (9)

1. The use of an aromatic farnesyl compound in the preparation of a slimming drug, a diet food, a slimming drink, and a weight loss health care product.
2. The use according to claim 1, wherein the aromatic farnesyl compound has the formula: (I):

   

   among them,

   R1-R5 is selected from the group consisting of hydrogen, a C1-C5 alkyl group, a nitro group, a fluorine group, a chlorine group, a bromine group, an ester group, a hydroxyl group, an amide group, and an alkoxy group;

   R6 is selected from the group consisting of hydrogen and alkoxy;

   R7 is selected from the group consisting of hydroxyl, aldehyde, ester, and carboxyl;

   X is selected from the group consisting of oxygen, hydrogen, carbonyl, and hydroxyl;

   The 1' configuration is selected from the group consisting of R or S;

   The 2'-3' position is selected from a carbon-carbon single bond or a carbon-carbon double bond;

   The 14' position is selected from an ester group and a carboxyl group;

   n is selected from 1-3.
3. The use according to claim 1, wherein the aromatic farnesyl compound has the formula:

   
4. The use according to claim 1, wherein the aromatic farnesyl compound has the formula:

   
5. The use according to claim 1, wherein the aromatic farnesyl compound has the formula:

   
6. The use according to claim 1, wherein the aromatic farnesyl compound has the formula:

   
7. The use according to claim 1, wherein the aromatic farnesyl compound has the formula:

   
8. The use according to claim 1, wherein the aromatic farnesyl compound has the formula:

   
9. The use according to claim 1, wherein the structural formula of the aromatic farnesyl compound is: