2-benzylbenzofuran and diaryl acetone compounds or pharmaceutically acceptable salts thereof and application of 2-benzylbenzofuran and diaryl acetone compounds or pharmaceutically acceptable salts thereof

Abstract

The invention relates to the field of medicines, and particularly provides 2-benzylbenzofuran and diaryl acetone compounds which are separated from a traditional Chinese medicine argillaceae and have a novel structure or pharmaceutically acceptable salts thereof, and application of the 2-benzylbenzofuran and diaryl acetone compounds or pharmaceutically acceptable salts thereof in myocardial protection. And a good myocardial protection effect is achieved.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to a class of novel 2-benzylbenzofuran and diarylacetone compounds separated from a traditional Chinese medicine, or pharmaceutically acceptable salts thereof, and applications thereof. Background Art

[0002] There are many causes of cardiovascular disease, including myocardial ischemia / reperfusion injury, hyperlipidemia, atherosclerosis, and the toxic side effects of tumor drugs. Due to the high incidence, low cure rate, and many complications of cardiovascular disease, it is extremely important to develop and research myocardial protective drugs with low toxicity, high efficiency, and different mechanisms of action.

[0003] Traditional Chinese medicine and Chinese herbal compound prescriptions have a lot of clinical experience in the treatment of cardiovascular diseases. They have the characteristics of good efficacy, strong activity and low toxicity and side effects. Natural compounds can be used as an important source of lead compounds in the research and development of drugs for the treatment of cardiovascular diseases, such as Guanxin Danshen Recipe, Vinegar Willow Flavonoid Tablets, Ginkgo Leaf Tablets, Ilex Podophyllum Injection and other Chinese herbal compound prescriptions and some compounds from Chinese herbal medicines, such as puerarin and breviscapine, all have good myocardial protective activity and are widely used in clinical practice. The project team has been committed to the discovery of the material basis of the efficacy of commonly used Chinese medicines and active lead compounds. Combining clinical applications, literature research and laboratory myocardial protective activity screening, it was found that the Chinese medicine Bai Tuling extract has good myocardial protective activity.

[0004] The Bai Tuling studied by this project team is the dried rhizome of Heterosmilaxyunnanensis Gagnep., a plant of the genus Smilax in the Liliaceae family. It is mainly distributed in Shaanxi, Gansu, Anhui, Sichuan, and Yunnan provinces and regions. It has the effects of clearing away heat and detoxifying, removing dampness, and promoting joints. It is the only ministerial drug in the anti-tumor Chinese medicine compound Kushen injection, and the highly polar water part is used as medicine. Chemical composition and pharmacological activity studies have shown that the water part of Bai Tuling contains chemical components such as phenolic acid glycosides, flavonoid glycosides, sterol glycosides, azoglycosides, and some monophenolic acids, amino acids, and polysaccharides, and has pharmacological activities such as diuresis, anti-inflammatory, promoting joints, antibacterial, detoxification, and analgesia. However, there are few studies on Bai Tuling at present, and the types and quantities of compounds are not comprehensive enough. The highly polar parts are mainly glycoside compounds, and the pharmacological activity research is also mainly based on crude extracts.

[0005] At present, there is no report on the isolation of the above-mentioned 2-benzylbenzofuranoside compounds from the traditional Chinese medicine Bai Tuling, nor is there any report on the preparation method of the above-mentioned monomer and the myocardial protective activity. Summary of the invention

[0006] In view of the above technical status, the technical problem to be solved by the present invention is to provide new 2-benzylbenzofuran compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and use thereof in the preparation of myocardial protective drugs.

[0007] The first aspect of the present invention provides a class of new compounds 1-15 (1-14: heteroyunoside A-N, 15: heteroyunoneoside A) derived from white earthworms and pharmaceutically acceptable salts of compounds 1-15, the structures of which are as follows:

[0008]

[0009] The second aspect of the present invention provides a method for preparing new 2-benzylbenzofuranoside and its precursor diarylacetone compound in white turmeric, which comprises the following steps: extracting the white turmeric medicinal material with 95%, 85%, and 75% ethanol and water by refluxing, extracting the concentrated extract with an organic solvent, precipitating with 85% alcohol, macroporous resin column chromatography, Sephadex LH-20 gel column chromatography and preparative HPLC to obtain the above-mentioned compounds 1 to 15, and analyzing and identifying the structures thereof by spectral means such as UV, IR, NMR, MS, and ECD, which are a class of 2-benzylbenzofuranoside and diarylacetone compounds with novel structures, and the above-mentioned substances have not been reported so far.

[0010] The third aspect of the present invention is to provide a pharmaceutical composition comprising an effective dose of one, two, or more than one of Compounds 1 to 15 or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

[0011] In the present invention, as one embodiment, the pharmaceutical composition of the present invention contains 0.1 to 95% by weight of the compound of the present invention. In a unit dosage form, the content of the compound of the present invention is generally 0.1 to 100 mg, and a preferred unit dosage form contains 4 to 50 mg.

[0012] In the present invention, as one of the embodiments, the dosage form of the pharmaceutical composition is selected from tablets, capsules, pills, granules, oral liquids or suspensions.

[0013] In the present invention, as one embodiment, the content of the compound of the present invention in a unit dosage form is generally 0.1 to 100 mg, and a preferred unit dosage form contains 4 to 50 mg.

[0014] The pharmaceutical composition of the compounds of this invention can be prepared according to methods well known in the art. When used for this purpose, if necessary, the compounds of this invention can be combined with one or more solid or liquid pharmaceutical excipients and / or adjuvants to prepare suitable application forms or dosage forms that can be used as human medicine or veterinary medicine.

[0015] The compound of the present invention or the pharmaceutical composition containing the same can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.

[0016] The administration route of the compound of the present invention or the pharmaceutical composition containing the compound can be injection, which includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection.

[0017] The dosage form for administration can be a liquid dosage form or a solid dosage form. For example, the liquid dosage form can be a true solution, a colloid, a microparticle dosage form, an emulsion dosage form, or a suspension dosage form. Other dosage forms include tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, and the like.

[0018] The compound of the present invention can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0019] For example, in order to formulate a unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of carriers include diluents and absorbents, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; wetting agents and binders, such as water, glycerol, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrants, such as dry starch, alginate, agar powder, brown seaweed starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors, such as sucrose, tristearin, cocoa butter, hydrogenated oil, etc.; absorption promoters, such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0020] For example, in order to make the dosing unit into a pill, various carriers known in the art can be widely used. Examples of carriers include diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinyl pyrrolidone, monostearate glyceride, kaolin, talc, etc.; binders, such as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.

[0021] For example, in order to prepare the dosing unit into a capsule, the active ingredient compound of the present invention is mixed with the above-mentioned various carriers, and the resulting mixture is placed in a hard gelatin capsule or a soft capsule. The active ingredient compound of the present invention can also be prepared into a microcapsule, suspended in an aqueous medium to form a suspension, or loaded into a hard capsule or prepared as an injection for use.

[0022] For example, the compound of the present invention is made into an injection preparation, such as a solution, a suspension solution, an emulsion, or a freeze-dried powder injection. This preparation may be aqueous or non-aqueous, and may contain one or more pharmacodynamically acceptable carriers, diluents, adhesives, lubricants, preservatives, surfactants, or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, fatty acid esters, and the like. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose, or glycerol may be added to the injection preparation. In addition, conventional cosolvents, buffers, pH regulators, and the like may also be added. These excipients are commonly used in the art.

[0023] In addition, if necessary, colorants, preservatives, perfumes, flavoring agents, sweeteners or other materials may be added to the pharmaceutical preparations.

[0024] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

[0025] The dosage of the pharmaceutical composition of the compound of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of administrations, and the purpose of treatment, so the therapeutic dose of the present invention can vary widely. Generally speaking, the dosage of the pharmaceutical ingredients of the present invention is well known to those skilled in the art. It can be appropriately adjusted according to the actual amount of the drug contained in the final preparation of the compound composition of the present invention to achieve the requirement of its therapeutically effective amount and complete the prevention or treatment purpose of the present invention.

[0026] The fourth aspect of the technical solution of the present invention is to provide the use of the compound or pharmaceutically acceptable salt thereof described in the first aspect and the pharmaceutical composition described in the third aspect in the preparation of cardiovascular disease drugs.

[0027] In the present invention, as one of the embodiments, the cardiovascular disease includes cor pulmonale, heart failure, myocardial ischemia, myocardial infarction or angina pectoris.

[0028] In the present invention, as one of the embodiments, the suitable daily dosage range of the compound of the present invention is: the dosage of the compound of the present invention is 0.001-100 mg / Kg body weight, preferably 0.1-60 mg / Kg body weight, more preferably 1-30 mg / Kg body weight, and most preferably 2-15 mg / Kg body weight.

[0029] In the present invention, as one embodiment, the daily dose of the compound of the present invention taken by adult patients is 10 to 500 mg, preferably 20 to 100 mg, which can be taken once or divided into 2 to 3 doses;

[0030] In the present invention, as one embodiment, the dosage for children is 5 to 30 mg per kg body weight, preferably 10 to 20 mg / kg body weight.

[0031] The above dosage can be administered in a single dosage form or divided into several, such as two, three or four dosage forms, which is limited by the clinical experience of the administering physician and the dosage regimen of the treatment. The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs.

[0032] The present invention also provides a method for preparing compounds 1 to 15, the method comprising:

[0033] The medicinal material of Heterosmilax yunnanensis Gagnep. was extracted by reflux with 95%, 85%, and 75% ethanol and water. After concentration, the extract was extracted with an organic solvent, precipitated with 85% alcohol, chromatographed with a macroporous resin column, chromatographed with a Sephadex LH-20 gel column, and separated and purified by preparative HPLC to obtain the above compounds 1 to 15.

[0034] The present invention uses a Langendorff perfusion system to separate primary rat cardiomyocytes for culture, uses an oxygen-deficient environment to prepare a cardiomyocyte hypoxia model, and after treatment with a positive drug NAC and a test compound, counts living cells by Alamar blue staining to evaluate cell damage.

[0035] The results showed that a large number of cardiomyocytes in the hypoxia treatment group underwent apoptosis and necrosis. After treatment with the positive drug NAC and the test compound, the survival rate of cells in some groups was significantly improved, and there was a significant difference compared with the cells in the hypoxia model group. In particular, the EC 50 The EC values ​​of compounds 2, 3, 4, 5, and 6 were 0.56 μM. 50 They are 1.26 μM, 9.02 μM, 2.20 μM, 2.13 μM and 9.10 μM respectively.

[0036] The present invention separates a class of novel 2-benzylbenzofuranoside compounds (1-14) and their precursor diarylacetone compounds (15) from white turmeric. In an in vitro myocardial protective activity evaluation, compounds 1-6 have significant myocardial protective activity on rat myocardial cells.

[0037] The 2-benzylbenzofuranoside compounds separated from the white radix turmeric have in vitro myocardial protection activity and have the efficacy of treating cardiovascular diseases. DETAILED DESCRIPTION

[0038] The following examples are used to further illustrate the present invention, but are not intended to limit the effective scope of the present invention in any way.

[0039] Example 1. Preparation of White Tuling Monomer Compounds 1 to 15

[0040] 100 kg of dried tubers of Bai Tuling were crushed and extracted three times with 95%, 85%, and 75% ethanol and water respectively, each time for 2 hours. The supernatant was collected after filtration, and the three extracts were combined. The solvent was recovered under reduced pressure to obtain a total ethanol-water extract of about 24.5 kg. The ethanol in the total extract was removed, and then the extract was extracted three times with an equal volume of ethyl acetate. After the ethyl acetate fraction was concentrated under reduced pressure, 520 g of extract was obtained. The remaining water fraction was precipitated with 85% alcohol to remove macromolecular sugars, proteins and other substances, and about 6142 g of extract was obtained after concentration. The extract was dissolved in 3L of water and separated by macroporous resin column chromatography twice (d = 14.5cm, h = 82cm, column volume 13.5L), and eluted with 0%, 5%, 15%, 30%, 50%, 70%, and 95% ethanol respectively, and seven sub-fractions were obtained, which were named BTL-A to BTL-G in sequence.

[0041] Dissolve the BTL-D part (about 110 g in total) in 250 mL of water, wet sample loading, and perform gel column chromatography (d = 11.7 cm, h = 67.0 cm), and sequentially elute with 0%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, and 95% ethanol, and concentrate to obtain 343 bottles of fractions from Fra.D-1 to Fra.D-343. Fra.D-76 to Fra.D-83 were combined and subjected to Sephadex LH-20 gel column chromatography (ethanol: water = 0% to 95% gradient elution), recorded as column A, to obtain 213 fractions from A.1 to A.213; A.128 to A.168 were detected by HPLC and mainly contained two chromatographic peaks with the same retention time and UV. A.128 to A.168 were analyzed by C 18 Reverse phase semi-preparative liquid chromatography column purification (MeCN / H2O / AcOH, 15:85:0.1, v / v / v) gave compounds 1 (90.0 mg) and 2 (33.9 mg);

[0042] Fra.D-91 to Fra.D-97 were combined and separated by Flash reverse phase ODS pressure column chromatography (methanol: water = 0% to 100% gradient elution), denoted as F1 column, to obtain 12 fractions from F1.1 to F1.12; F1.6 to F1.11 mainly contained one chromatographic peak after HPLC detection, and C 18 Reverse phase semi-preparative liquid chromatography column purification (MeCN / H2O / AcOH, 18:82:0.1, v / v) gave compound 3 (14.3 mg);

[0043] Fra.D-98 to Fra.D-103 were combined and separated by Flash reverse phase ODS pressure column chromatography (methanol: water = 0% to 100% gradient elution), recorded as F2 column, to obtain 9 fractions from F2.1 to F2.9; F2.5 was detected by HPLC to contain mainly one chromatographic peak, which was analyzed by C 18 Reverse phase semi-preparative liquid chromatography column purification (MeCN / H2O / AcOH, 18:82:0.1, v / v) gave compound 4 (21.0 mg);

[0044] The remaining fractions of Fra.D-76 to Fra.D-83 and Fra.D-84 to Fra.D-87 were combined and separated by polyamide column chromatography (ethanol: water = 0% to 95% gradient elution), recorded as JXA2 column, to obtain 40 fractions from JXA2.1 to JXA2.40; JXA2.5 to JXA2.9 mainly contained one chromatographic peak after HPLC detection, and C 18 Reverse phase semi-preparative liquid chromatography column purification (MeOH / H2O / AcOH, 32:68:0.1, v / v) gave compound 5 (37.0 mg);

[0045] For Fra.D-140~Fra.D-142, use C 18 Reverse phase semi-preparative liquid chromatography column purification (MeCN / H2O, 20:80, v / v) gave compound 6 (10.0 mg);

[0046] For Fra.D-190~Fra.D-196, use C 18 Reverse phase semi-preparative liquid chromatography column purification (MeOH / H2O, 40:60, 0.2% acetic acid, v / v) gave compound 7 (4.0 mg);

[0047] For Fra.D-127~Fra.D-135, use C 18 Reverse phase semi-preparative liquid chromatography column purification (MeOH / H2O, 40:60, 0.2% acetic acid, v / v) gave compound 8 (8.0 mg).

[0048] Fra.D-20 to Fra.D-21 were combined and separated by Flash reverse phase ODS pressure column chromatography (methanol: water = 0% to 100% gradient elution), recorded as F6 column, and 12 fractions F6.1 to F6.12 were obtained. F6.6 to F6.7 were combined and separated by Flash reverse phase ODS pressure column chromatography (methanol: water = 0% to 100% gradient elution), recorded as F7 column, and 8 fractions F7.1 to F7.8 were obtained. F7.4 contained the same UV absorption peak as compound 1 after HPLC detection, and was purified by C 18 Reverse phase semi-preparative liquid chromatography column purification (MeCN / H2O / AcOH, 15:85:0.1, v / v / v) gave compound 9 (45.0 mg);

[0049] Fra.D-46 to Fra.D-50 were combined and separated by Flash reverse phase ODS pressure column chromatography (methanol: water = 0% to 100% gradient elution), recorded as F10 column, and 9 fractions F10.1 to F10.9 were obtained. F10.4 to F10.9 were combined and separated by polyamide column chromatography again, recorded as JXA7 column, and 26 components JXA7.1 to JXA7.26 were obtained. Among them, JXA7.2 to JXA7.4 contained the same UV absorption peak as compound 1 by HPLC detection, and C 18 Reverse phase semi-preparative liquid chromatography column purification (MeCN / H2O / AcOH, 18:82, v / v) gave compounds 10 (8.0 mg), 11 (8.3 mg) and 12 (2.5 mg);

[0050] C at F10.2 18 The product was purified by reverse phase semi-preparative liquid chromatography column (MeOH / H2O / AcOH, 25:75, v / v) to give compound 15 (13.2 mg).

[0051] The BTL-C part (about 94 g in total) was dissolved in 250 mL of water, wet loaded, and separated by gel column chromatography (d = 9.0 cm, h = 72.0 cm), and eluted with 0%, 5%, 10%, 15%, 20%, 30%, 50%, and 95% ethanol in sequence, and concentrated to obtain 120 bottles of Fra.C-1 to Fra.C-120. Fra.C-28 to Fra.C-30 were combined and separated by polyamide column chromatography (ethanol: water = 0% to 95% gradient elution), recorded as JXAC1 column, and 22 fractions of JXAC1.1 to JXAC1.22 were obtained; JXAC1.2 mainly contained one chromatographic peak after HPLC detection, and was purified by C 18 Reverse phase semi-preparative liquid chromatography column purification (MeOH / H2O / AcOH, 25:75:0.1, v / v) gave compound 13 (6.0 mg);

[0052] Fra.C-31 to Fra.C-37 were combined and separated by Flash reverse phase ODS pressure column chromatography (methanol: water = 0% to 100% gradient elution), denoted as FC1 column, to obtain 10 fractions FC1.1 to FC1.10; FC1.8 was detected by HPLC to contain mainly one chromatographic peak, which was analyzed by C 18 The product was purified by reverse phase semi-preparative liquid chromatography column (MeOH / H2O, 35:65, v / v) to give compound 14 (2.9 mg).

[0053] The structures of compounds 1 to 14 were analyzed and identified by spectroscopic methods such as UV, IR, NMR, and MS. Compounds 1 to 14 are a class of novel 2-benzylbenzofuranoside compounds, and compound 15 is a diarylacetone compound, the biogenic precursor of compounds 1 to 14.

[0054] The spectral information and NMR signal attribution of the above new compounds are as follows:

[0055] Compound 1

[0056]

[0057] Heteryunoside A: light brown amorphous powder; specific rotation [α] 20D-81.0 (c 0.10, H2O); UV (H2O) λ max (logε)255(4.62),213sh(4.97),202(5.03)nm; IRν max 3385,2923,1626,1508,1490,1425,1363,1291,1241,1171,1077,1041,649cm -1 ; HRESIMS m / z 627.1914[M+H] + (calcd for C 28 H 35 O 16 ,627.1920).

[0058] 1 H NMR (500 MHz, CD3OD), δ H:3.96(2H,s,H-α),6.37(1H,s,H-3),6.76(1H,d,J=2.0Hz,H-5),6.89(1H,br s,H-7),6.44(1H,d,J=8.5Hz,H-5'),6.58(1H,d,J=8.0Hz,H-6'),3.82(3H,s,4'-OCH3),5.00(1H,d,J=7 .5Hz,H-1"),4.89(1H,overlap,H-1"'),3.44-3.55(6H,overlap,H-2",H-2"',H-3",H-3"',H-5",H-5"') ,3.38(1H,t,J=9.0Hz,H-4"),3.34(1H,t,J=9.0Hz,H-4"′),3.67(1H,dd,J=6.0,12.0Hz,H-6"a),3.70(1H ,dd,J=6.0,12.0Hz,H-6″′a), 3.88(1H,dd,J=2.5,12.0Hz,H-6″b), 3.93(1H,dd,J=2.5,12.0Hz,H-6″′b).

[0059] 13 C NMR (125 MHz, CD3OD), δ C :29.3(C-α),158.4(C-2),100.9(C-3),115.9(C-3a),151.4(C-4),100.0(C-5),156.9(C-6), 95.2(C-7),157.5(C-7a),118.6(C-1'),145.0(C-2'),135.1(C-3'),148.6(C-4'),103.9(C-5 '),121.0(C-6'),56.5(4'-OCH3),102.1(C-1"),74.9(C-2"),77.9(C-3",C-3″′),71.4(C-4" ), 78.1 (C-5", C-5"'), 62.7 (C-6"), 103.0 (C-1"'), 74.8 (C-2"'), 71.6 (C-4"'), 62.5 (C-6"').

[0060] Compound 2

[0061]

[0062] heteryunoside B: light brown amorphous powder; specific rotation [α] 20D-32.0 (c 0.10, MeOH); UV (H2O) λ max(logε)255(4.32),215sh(4.69),201(4.79)nm;IRν max 3373,2923,1614,1502,1457,1362,1294,1255,1167,1077,1043,925,800,634cm -1 ;HRESIMS m / z 649.1729[M+Na] + (calcd for C 28 H 34 O 16 Na,649.1739)。

[0063] 1 H NMR(500MHz,CD3OD),δ H :4.20(2H,dd,J=16.0,28.5Hz,H-α),6.32(1H,s,H-3),6.41(1H,d,J=1.5Hz,H-5),6.73(1H,br s,H-7),6.75(1H,d,J=8.5Hz,H-5'),6.66(1H,d,J=8.5Hz,H-6'),3.83(3H,s,4'-OCH3),4.83(1H,d,J=7.5Hz,H-1"),4.67(1H,d,J=8.0Hz,H-1″′),3.52(1H,t,J=8.0Hz,H-2″′),3.17(1H,m,H-3″′),3.42-3.48(4H,overlap,H-3",H-4″′,H-5",H-5″′),3.36-3.41(2H,overlap,H-2",H-4"),3.71(1H,overlap,H-6”a),3.91(1H,dd,J=2.5,12.0Hz,H-6"b),3.66(1H,dd,J=4.5,12.0Hz,H-6”'a),3.73(1H,overlap,H-6″′b)。

[0064] 13 C NMR(125MHz,CD3OD),δ C:29.5(C-α),157.6(C-2),100.9(C-3),114.3(C-3a),151.4(C-4),99.8(C-5),157.3(C-6),92 .5(C-7),157.9(C-7a),125.6(C-1'),145.3(C-2'),140.5(C-3'),148.9(C-4'),109.9(C-5'), 120.8(C-6'),56.8(4'-OCH3),103.1(C-1"),74.9(C-2"),78.1(C-3"),71.4(C-4"),78.0(C-5" ,C-3″′),62.5(C-6″),107.4(C-1″′),75.5(C-2″′),70.8(C-4″′),78.4(C-5″′),62.0(C-6″′).

[0065] Compound 3

[0066]

[0067] heteryunoside C: light brown amorphous powder; specific rotation [α] 20D-20.8 (c 0.10, H2O); UV (H2O) λ max (logε)254(4.11),201(4.60)nm; IRν max 3366,2921,1629,1507,1447,1363,1294,1251,1165,1078,1026,925,894,669cm -1 ; HRESIMS m / z 627.1912[M+H] + (calcd for C 28 H 35 O 16 ,627.1920).

[0068] 1 H NMR (500 MHz, DMSO-d6), δ H:3.89(2H,s,H-α),6.33(1H,br s,H-3),6.39(1H,d,J=2.0Hz,H-5),6.50(1H,d,J=2.0Hz,H-7),6.48(1H,d,J=8.5Hz,H-5'),6 .84(1H,d,J=8.5Hz,H-6'),3.72(3H,s,4'-OCH3),4.82(1H,d,J=7.5Hz,H-1"),4.48(1H,d,J=7 .5Hz,H-1″′),3.29(1H,t,J=7.5Hz,H-2″′),3.16-3.25(7H,overlap,H-2",H-3",H-3″′,H-4" ,H-4″′,H-5″,H-5″′),3.50(2H,overlap,H-6″a,H-6″′a),3.65(2H,overlap,H-6″b,H-6″’b).

[0069] 13 C NMR (125 MHz, DMSO-d6), δ C :27.9(C-α),154.6(C-2),100.3(C-3),111.2(C-3a),150.4(C-4),98.2(C-5),155.4(C-6),91 .7(C-7),156.0(C-7a),117.4(C-1'),148.7(C-2'),134.5(C-3'),151.7(C-4'),103.8(C-5'), 125.4(C-6'),56.2(4'-OCH3),101.0(C-1"),73.3(C-2"),76.4(C-3"),69.5(C-4",C-4″′),77. 1(C-5″), 60.5(C-6″), 105.9(C-1″′), 74.0(C-2″′), 76.1(C-3″′), 77.2(C-5″′), 60.7(C-6″′).

[0070] Compound 4

[0071]

[0072] heteryunoside D: light brown amorphous powder; specific rotation [α] 20D-44.8 (c 0.10, H2O); UV (H2O) λ max (logε)255(4.47),214sh(4.88),201(4.94)nm; IRν max3374,2922,1615,1507,1461,1362,1285,1234,1167,1095,1074,1044,1019,626cm -1 ;HRESIMS m / z 627.1912[M+H] + (calcd for C 28 H 35 O 16 ,627.1925)。

[0073] 1 H NMR(500MHz,CD3OD),δ H :3.96(2H,s,H-α),6.32(1H,br s,H-3),6.41(1H,d,J=1.5Hz,H-5),6.73(1H,br s,H-7),6.51(1H,d,J=9.0Hz,H-5'),6.89(1H,d,J=9.0Hz,H-6'),3.82(3H,s,4'-OCH3),4.84(1H,d,J=7.5Hz,H-1"),4.66(1H,d,J=8.0Hz,H-1″′),3.51(1H,t,J=8.0Hz,H-2″′),3.41-3.44(4H,overlap,H-2",H-3",H-3″′,H-5"),3.39(1H,m,H-4"),3.46(1H,t,J=9.0Hz,H-4″′),3.28(1H,m,H-5″′),3.71(1H,dd,J=5.5,12.0Hz,H-6"a),3.91(1H,dd,J=2.0,12.0Hz,H-6”b),3.73(1H,dd,J=4.5,12.0Hz,H-6″′a),3.80(1H,dd,J=2.0,12.0Hz,H-6”'b)。

[0074] 13 C NMR(125MHz,CD3OD),δ C:29.2(C-α),156.9(C-2),100.8(C-3),114.4(C-3a),151.4(C-4),99.7(C-5),157.3(C-6),92.5 (C-7),157.9(C-7a),119.3(C-1'),150.0(C-2'),135.3(C-3'),152.9(C-4'),104.4(C-5'),127 .0(C-6'),56.6(4'-OCH3),103.1(C-1"),74.9(C-2"),78.0(C-3"),71.4(C-4"),78.1(C-5"),62 .5 (C-6"), 107.1 (C-1"'), 75.3 (C-2"'), 77.6 (C-3"'), 70.7 (C-4"'), 78.3 (C-5"'), 62.0 (C-6"').

[0075] Compound 5

[0076]

[0077] heteryunoside E: light brown amorphous powder; specific rotation [α] 20D-60.8 (c 0.10, H2O); UV (H2O) λ max (logε)279sh(4.07),255(4.55),201(5.01)nm; IRν max 3372,2922,1628,1613,1499,1457,1434,1293,1255,1166,1128,1078,1040,627cm -1 ; HRESIMS m / z 649.1737[M+Na] + (calcd for C 28 H 34 O 16 Na,649.1739).

[0078] 1 H NMR (500 MHz, DMSO-d6), δ H:4.27(1H,d,J=17.0Hz,H-αa),3.99(1H,d,J=17.0Hz,H-αb),6.28(1H,br s,H-3),6.38(1H,d,J=2.0Hz,H-5),6.49(1H,br s,H-7),6.74(1H,d,J=9.0Hz,H-5'),6.56(1H,d,J=8.5Hz,H-6'),3.73(3H,s,4'- OCH3),4.83(1H,d,J=7.5Hz,H-1"),4.47(1H,d,J=7.5Hz,H-1″′),3.31(1H,t,J=7 .5Hz,H-2″′),3.17-3.26(6H,overlap,H-2″,H-3″,H-3″′,H-4”,H-4″′,H-5”),3. 12(1H,m,H-5″′), 3.48(2H,m,H-6″a,H-6″′a), 3.65(2H,overlap,H-6″b,H-6″’b).

[0079] 13 C NMR (125 MHz, DMSO-d6), δ C :28.1(C-α),155.3(C-2),100.4(C-3),111.1(C-3a),150.4(C-4),98.0(C-5),155.4(C-6),91 .7(C-7),156.0(C-7a),123.8(C-1'),144.2(C-2'),139.5(C-3'),147.5(C-4'),109.1(C-5'), 118.8(C-6'),55.9(4'-OCH3),100.9(C-1"),73.3(C-2"),76.5(C-3"),77.1(C-5"),60.5(C-6" ), 106.3(C-1″′), 73.9(C-2″′), 76.2(C-3″′), 69.5(C-4″,C-4″′), 77.4(C-5″′), 60.7(C-6″′).

[0080] Compound 6

[0081]

[0082] heteryunoside F: brown amorphous powder; specific rotation [α] 20D-26.2 (c 0.10, H2O); UV (H2O) λ max (logε)255(4.43),203(4.86)nm; IRν max3373,2926,1628,1506,1446,1340,1296,1242,1163,1078,1044,1023,926cm -1 ;HRESIMS m / z 627.1914[M+H] + (calcd for C 28 H 35 O 16 ,627.1920)。

[0083] 1 H NMR(500MHz,DMSO-d6),δ H :3.88(2H,s,H-α),6.33(1H,br s,H-3),6.29(1H,d,J=2.0Hz,H-5),6.68(1H,br s,H-7),6.41(1H,d,J=9.0Hz,H-5'),6.53(1H,d,J=8.5Hz,H-6'),3.74(3H,s,4'-OCH3),4.89(1H,d,J=7.0Hz,H-1"),4.48(1H,d,J=7.5Hz,H-1″′),2.99(1H,t,J=7.5Hz,H-2″′),3.15-3.22(4H,overlap,H-4",H-4″′,H-5",H-5″′),3.45-3.49(3H,overlap,H-2",H-3",H-3″′),3.47(2H,overlap,H-6"a,H-6″′a),3.71(2H,overlap,H-6”b,H-6”'b)。

[0084] 13 C NMR(125MHz,DMSO-d6),δ C:28.2(C-α),155.5(C-2),100.0(C-3),112.3(C-3a),150.0(C-4),98.7(C-5),155.5(C-6),90.7 (C-7),155.8(C-7a),117.4(C-1'),144.1(C-2'),133.8(C-3'),147.3(C-4'),102.8(C-5'),119 .5(C-6'),55.8(4'-OCH3),99.7(C-1"),82.6(C-2"),76.0(C-3"),69.5(C-4"),76.8(C-5"),60. 6(C-6″), 104.5(C-1″′), 74.9(C-2″′), 76.3(C-3″′), 69.4(C-4″′), 76.9(C-5″′), 60.5(C-6″′).

[0085] Compound 7

[0086]

[0087] heteryunoside G: brown amorphous powder; specific rotation [α] 20D-39.0 (c 0.10, H2O); UV (H2O) λ max (logε)256(4.47),216sh(4.87),203(4.93)nm; IRν max 3366,2921,1624,1507,1447,1339,1163,1077,1044,669cm -1 ; HRESIMS m / z 597.1822[M+H] + (calcd for C 27 H 33 O 15 ,597.1814).

[0088] 1 H NMR (500 MHz, CD3OD), δ H:3.95(2H,s,H-α),6.28(1H,br s,H-3),6.37(1H,d,J=2.0Hz,H-5),6.71(1H,br s,H-7),6.44(1H,d,J=8.5Hz,H-5'),6.57(1H,d,J=8.5Hz,H-6'),3.82(3H,s,4'-OCH3),4.97(1H,d,J=7.5Hz, H-1"),4.62(1H,d,J=7.5Hz,H-1″′),3.25(1H,t,J=7.5Hz,H-2″′),3.36(1H,t,J=9.0Hz,H-3″′),3.63-3.64(2 H,overlap,H-2",H-3"),3.43-3.48(3H,overlap,H-4",H-4″′,H-5"),3.71(1H,dd,J=5.5,12.0Hz,H-6”a),3. 91(1H,dd,J=1.5,12.0Hz,H-6"b), 3.25(1H,dd,J=2.0,12.0Hz,H-5"'a), 3.84(1H,dd,J=5.5,12.0Hz,H-5"'b).

[0089] 13 C NMR (125 MHz, CD3OD), δ C :29.2(C-α),157.1(C-2),100.6(C-3),114.5(C-3a),151.2(C-4),99.8(C-5),157.5(C-6),9 2.5(C-7,157.8(C-7a),118.8(C-1'),144.9(C-2'),135.1(C-3'),148.5(C-4'),103.8(C-5' ),120.9(C-6'),56.5(4'-OCH3),101.9(C-1"),83.8(C-2"),77.0(C-3"),71.0(C-4"),77.9( C-5"), 62.4 (C-6"), 106.3 (C-1"'), 75.8 (C-2"'), 77.4 (C-3"'), 71.1 (C-4"'), 67.2 (C-5"').

[0090] Compound 8

[0091]

[0092] heteryunoside H: brown amorphous powder; specific rotation [α] 20D-29.4 (c 0.10, H2O); UV (H2O) λ max(logε)252(4.36),204(4.86)nm;IRν max 3393,2930,1624,1500,1446,1346,1298,1245,1162,1077,1044,612cm -1 ;HRESIMS m / z 649.1735[M+Na] + (calcd for C 28 H 34 O 16 Na,649.1750)。

[0093] 1 H NMR(500MHz,DMSO-d6),δ H :3.87(2H,s,H-α),6.26(1H,br s,H-3),6.49(1H,brs,H-5),6.49(1H,br s,H-7),6.42(1H,d,J=8.5Hz,H-5'),6.53(1H,d,J=8.5Hz,H-6'),3.74(3H,s,4'-OCH3),4.81(1H,d,J=7.0Hz,H-1"),4.23(1H,d,J=7.5Hz,H-1″′),2.99(1H,t,J=7.5Hz,H-2″′),3.04(1H,t,J=9.5Hz,H-4″′),3.23-3.25(4H,overlap,H-2",H-3",H-3″′,H-4"),3.50(1H,m,H-5"),3.02(1H,overlap,H-5″′),3.98(1H,dd,J=2.0,12.0Hz,H-6"a),3.63(1H,overlap,H-6”b),3.42(1H,dd,J=5.5,12.0Hz,H-6″′a),3.63(1H,overlap,H-6”'b)。

[0094] 13 C NMR(125MHz,DMSO-d6),δ C:28.1(C-α),155.3(C-2),99.9(C-3),111.2(C-3a),150.2(C-4),98.0(C-5),155.3(C-6),91.8( C-7),155.9(C-7a),117.3(C-1'),144.1(C-2'),133.9(C-3'),147.3(C-4'),102.8(C-5'),119. 5(C-6'),55.8(4'-OCH3),100.8(C-1"),73.2(C-2"),76.5(C-3"),69.4(C-4"),76.0(C-5"),68. 0(C-6″), 103.3(C-1″′), 73.7(C-2″′), 76.3(C-3″′), 70.1(C-4″′), 76.9(C-5″′), 61.0(C-6″′).

[0095] Compound 9

[0096]

[0097] heteryunoside I: light yellow amorphous powder; specific rotation [α] 20D-58.1 (c 0.12, MeOH); UV (MeOH) λ max (logε)278sh(3.77),256(4.28),206(4.73)nm; IRν max 3379,2924,1623,1508,1463,1425,1363,1316,1274,1236,1168,1077,1043,895,642cm -1 ; HRESIMS m / z 787.2310[MH] + (calcd for C 34 H 43 O 21 ,787.2302).

[0098] 1 H NMR (500 MHz, DMSO-d6), δ H: 3.94 (2H, s, H-α), 6.38 (1H, br s, H-3), 6.61 (1H, d, J = 2.0 Hz, H-5), 6.84 (1H, br s, H-7), 6.50 (1H, d, J = 9.0 Hz, H-5'), 6.87 (1H, d, J = 8.5 Hz, H-6'), 3.72 (3H, s, 4'-OCH3), 4.91 (1H, d, J = 7.5 Hz, H-1"), 4.84 (1H, d, J = 7.5 Hz, H-1″′), 4.50 (1H, d, J = 8.0 Hz, H-1""), 3.30 (1H, t, J = 8.0 Hz, H-2""), 3.11 - 3.26 (9H, overlap, H-2", H-2″′, H-3", H-3”', H-3"", H-4", H-4″′, H-4″′', H-5""), 3.36 - 3.39 (2H, overlap, H-5", H-5″′), 3.45 (3H, m, H-6"a, H-6″′a, H-6""a), 3.68 (3H, overlap, H-6”b, H-6”'b, H-6""b).

[0099] 13 13C NMR (125 MHz, DMSO-d6), δ C : 27.9 (C-α), 155.9 (C-2), 100.2 (C-3), 113.3 (C-3a), 150.0 (C-4), 98.5 (C-5), 155.4 (C-6), 92.9 (C-7), 155.4 (C-7a), 117.2 (C-1'), 148.6 (C-2'), 134.4 (C-3'), 151.8 (C-4'), 103.9 (C-5'), 125.5 (C-6'), 56.2 (4'-OCH3), 100.5 (C-1"), 73.3 (C-2"), 76.4 (C-3"), 69.7 (C-4"), 77.0 (C-5"), 60.8 (C-6"), 100.7 (C-1″′), 73.2 (C-2″′), 76.6 (C-3″′), 69.8 (C-4″′), 77.1 (C-5″′), 60.7 (C-6″′), 105.8 (C-1""), 74.0 (C-2""), 76.0 (C-3""), 69.5 (C-4""), 77.2 (C-5""), 60.7 (C-6"").

[0100] Compound 10

[0101]

[0102] heteryunside J:free solvent and solvent [α]20D-68.1(c 0.11,MeOH):UV(MeOH)λ max (log) 287sh(3.69),256(4.49),209(4.85)nm:IRν max 3390,2927,1628,1510,1490,1425,1359,1293,1241,1164,1078,1046,894,669cm -1 HRESIMS m / z 781.2155[M+Na] + (calcd for C). 33 H 42 O 20 And,781.2162).

[0103] 1 H NMR(500MHz,CD3OD),δ H :3.96(2H,s,H-α),6.37(1H,br s,H-3),6.74(1H,d,J1.5Hz,H-5),6.86(1H,br s,H-7),6.44(1H,d,J9.0Hz,H-5'),6.58(1H,d,J8.5Hz,H-6'),3.82(3 H,s,4'-OCH3), 4.99(1H,d,J8.0Hz,H-1"),5.04(1H,d,J7.5Hz,H-1′′), 4.63(1H,d,J7.5Hz,H-1"”),3.46(1H,m,H-2"),3.64(1H,m,H-2′′),3 (1H,overlap,H-2′′′'),3.65(1H,t,J6.0Hz,H-3′′′),3.35-3.41(3H,over lap,H-4",H-4′′′,H-3""),3.48-3.54(4H,overlap,H-3",H-5",H-5′′′,H-4 ""),3.67(1H,dd,J3.0,12.0Hz,H-6"a),3.88(1H,dd,J2.5,12.0Hz,H-6 "b),3.70(1H,dd,J2.5,12.0Hz,H-6′′a),3.92(1H,dd,J2.0,12.0Hz,H- 6′′b), 3.26(1H,overlap,H-5""a),3.84(1H,dd,JS5.5,12.0Hz,H-5""b).

[0104] 13C NMR (125 MHz, CD3OD), δ C :29.3(C-α),158.4(C-2),101.0(C-3),116.0(C-3a),151.4(C-4),100.1(C-5),156.8(C-6),95.4(C-7),157.4(C- 7a),118.5(C-1'),145.0(C-2'),135.1(C-3'),148.6(C-4'),103.9(C-5'),121.0(C-6'),56.5(4'-OCH3),102.2(C -1"),74.8(C-2"),77.9(C-3"),71.4(C-4"),78.2(C-5"),62.6(C-6"),101.7(C-1″′),83.7(C-2″′),77.8(C-3″′), 71.2(C-4″′),77.9(C-5″′),62.6(C-6″′),106.2(C-1""),75.7(C-2""),77.4(C-3""),71.1(C-4""),67.2(C-5"").

[0105] Compound 11

[0106]

[0107] heteryunoside K: white amorphous powder; specific rotation [α] 20D-69.7 (c 0.11, MeOH); UV (MeOH) λ max (logε)279sh(3.66),256(4.29),206(4.67)nm; IRν max 3392,2924,1627,1498,1467,1427,1365,1294,1173,1080,1040,688cm -1 ; HRESIMS m / z 663.1893[M+Na] + (calcdfor C 29 H 36 O 16 Na,663.1896).

[0108] 1 H NMR (500 MHz, CD3OD), δ H: 3.97 (2H, s, H-α), 6.41 (1H, br s, H-3), 6.77 (1H, d, J = 1.5 Hz, H-5), 6.89 (1H, br s, H-7), 6.68 (1H, d, J = 8.5 Hz, H-5'), 6.68 (1H, d, J = 9.0 Hz, H-6'), 3.77 (3H, s, 2'-OCH3), 3.84 (3H, s, 4'-OCH3), 5.00 (1H, d, J = 7.5 Hz, H-1"), 4.90 (1H, overlap, H-1″′), 3.46 - 3.47 (4H, overlap, H-2", H-2″′, H-3", H-3″′), 3.38 (1H, m, H-4"), 3.53 (1H, m, H-5"), 3.35 (1H, m, H-4″′), 3.50 (1H, m, H-5″′), 3.67 (1H, dd, J = 5.0, 12.0 Hz, H-6”a), 3.88 (1H, dd, J = 2.5, 12.0 Hz, H-6"b), 3.70 (1H, dd, J = 6.0, 12.0 Hz, H-6”'a), 3.92 (1H, dd, J = 2.5, 12.0 Hz, H-6″′b).

[0109] 13 13C NMR (125 MHz, CD3OD), δ C : 29.4 (C-α), 158.3 (C-2), 101.1 (C-3), 115.8 (C-3a), 151.5 (C-4), 100.1 (C-5), 157.1 (C-6), 95.2 (C-7), 157.5 (C-7a), 124.5 (C-1'), 147.4 (C-2'), 140.7 (C-3'), 149.3 (C-4'), 108.2 (C-5'), 120.9 (C-6'), 60.9 (2'-OCH3), 56.7 (4'-OCH3), 102.1 (C-1"), 74.9 (C-2"), 77.9 (C-3", C-3″′), 71.4 (C-4"), 78.1 (C-5", C-5″′), 62.7 (C-6"), 102.9 (C-1″′), 74.8 (C-2″′), 71.6 (C-4″′), 62.5 (C-6″′).

[0110] Compound 12

[0111]

[0112] heteryunoside L:free solvent with inorganic solvent [α]20D-17.9(c 0.10,MeOH):UV(MeOH)λ max (log) 279sh(3.56),256(4.08),217sh(4.43),204(4.53)nm:IRν max 3378,2921,1615,1505,1457,1363,1298,1256,1165,1077,1044,925,894,669cm -1 HRESIMS m / z759.2335[M+H] + (calcd for C). 33 H 43 O 20 ,759.2342).

[0113] 1 H NMR(500MHz,CD3OD),δ H :4.20(2H,dd,J17.0,28.5Hz,H-α),6.32(1H,br s,H-3),6.38(1H,d,J1.5Hz,H-5),6.71(1H,br s,H-7),6.75(1H,d,J9.0Hz,H-5'),6.66(1H,d,J9.0Hz,H-6'),3.83(3H ,s,4'-OCH3),4.97(1H,d,J7.5Hz,H-1"),4.61(1H,d,J7.5Hz,H-1′′),4 67(1H,d,J8.0Hz,H-1""),3.63(1H,m,H-2"),3.26(1H,dd,J3.0,7.5Hz, H-2′′),3.52(1H,t,J6.0Hz,H-2""),3.64(1H,overlap,H-3"),3.37(1H,t ,JS9.0Hz,H-3′′),3.18(1H,m,H-3""),3.39-3.50(6H,overlap,H-4",H-5 ",H-4′′",H-4"",H-5""),3.70(1H,dd,J64.5,12.0Hz,H-6"a),3.91(1H,dd, JH1.5,12.0Hz,H-6"b),3.16(1H,m,H-5′′′a),3.84(1H,dd,JS5.5,12.0Hz,H -5′′b),3.67(1H,overlap,H-6""a),3.72(1H,dd,J2.5,12.0Hz,H-6""b).

[0114] 13 C NMR (125 MHz, CD3OD), δ C :29.5(C-α),157.6(C-2),101.0(C-3),114.3(C-3a),151.3(C-4),99.8(C-5),157.2(C-6),92.5(C-7),157.8(C-7 a),125.6(C-1'),145.3(C-2'),140.5(C-3'),148.9(C-4'),109.9(C-5'),120.8(C-6'),56.7(4'-OCH3),101.9(C- 1"),83.8(C-2"),77.8(C-3"),71.0(C-4"),77.9(C-5"),62.4(C-6"),106.3(C-1″′),75.8(C-2″′),77.4(C-3″′), 71.1(C-4″′),67.2(C-5″′),107.4(C-1""),75.5(C-2""),78.4(C-3""),70.8(C-4""),78.0(C-5""),62.0(C-6"").

[0115] Compound 13

[0116]

[0117] heteryunoside M: white amorphous powder; specific rotation [α] 20D-48.5 (c 0.04, MeOH); UV (MeOH) λ max (logε)257(4.23),205(4.69)nm; IRν max 3386,2927,1629,1599,1508,1459,1422,1309,1289,1243,1225,1126,1079,1062,1041,1024,925,900.0,817,767cm -1 ; HRESIMS m / z 643.1863[M+H] + (calcd for C 28 H 35 O 17 ,643.1869).

[0118] 1 H NMR (500 MHz, DMSO-d6), δ H:3.88(2H,br s,H-α),6.26(1H,s,H-3),6.48(1H,s,H-5),6.41(1H,d,J=8.5Hz,H-5'),6.55(1H,d,J=8.5Hz,H-6'),3.74(3H,s,4'-OCH 3),4.75(1H,d,J=7.5Hz,H-1"),4.81(1H,d,J=7.5Hz,H-1″′),3.19(1H,t,J=7.5Hz,H-2"),3.29(1H,t,J=7.5Hz,H-2″′), 3.14-3.15(3H,overlap,H-3",H-3″′,H-4″′),3.23-3.25(3H,overlap,H-4",H-5",H-5″′),3.47(1H,dd,J=5.0,12.0Hz, H-6″a), 3.59(1H,dd,J=2.5,12.0Hz,H-6″b), 3.49(1H,dd,J=5.0,12.0Hz,H-6″′a), 3.66(1H,dd,J=2.5,12.0Hz,H-6″′b).

[0119] 13 C NMR (125 MHz, DMSO-d6), δ C :28.2(C-α),156.0(C-2),100.3(C-3),112.9(C-3a),146.9(C-4),99.5(C-5),145.6(C-6),125. 3(C-7),146.0(C-7a),117.2(C-1'),144.1(C-2'),133.9(C-3'),147.4(C-4'),102.9(C-5'),119 .5(C-6'),55.8(4'-OCH3),101.4(C-1"),73.3(C-2"),76.4(C-3"),69.4(C-4"),77.1(C-5"),60 .5 (C-6"), 104.8 (C-1"'), 73.8 (C-2"'), 76.3 (C-3"'), 69.6 (C-4"'), 77.2 (C-5"'), 60.6 (C-6"').

[0120] Compound 14

[0121]

[0122] heteryunoside N: light brown amorphous powder; specific rotation [α] 20D-23.0 (c 0.10, MeOH); UV (MeOH) λ max(logε) 256 (3.91), 206 (4.55) nm; IR ν max 3380, 2924, 1613, 1506, 1458, 1378, 1257, 1156, 1081, 815 cm -1 ; HRESIMS m / z 487.1210 [M+Na] + (calcd for C 22 H 24 O 11 Na, 487.1211).

[0123] 1 H NMR (500 MHz, CD3OD), δ H : 4.10 (1H, d, J = 15.5 Hz, H-αa), 4.03 (1H, d, J = 15.5 Hz, H-αb), 6.06 (1H, br s, H-3), 6.78 (1H, d, J = 8.5 Hz, H-4), 6.81 (1H, d, J = 8.5 Hz, H-5), 6.26 (1H, d, J = 2.0 Hz, H-3'), 6.09 (1H, d, J = 2.0 Hz, H-5'), 3.85 (3H, s, 6-OCH3), 4.84 (1H, d, J = 7.5 Hz, H-1"), 3.40 - 3.46 (2H, overlap, H-2", H-5"), 3.37 - 3.39 (2H, overlap, H-3", H-4"), 3.69 (1H, m, H-6"a), 3.89 (1H, m, H-6”b).

[0124] 13 C NMR (125 MHz, CD3OD), δ C : 23.1 (C-α), 160.3 (C-2), 102.8 (C-3), 126.4 (C-3a), 110.6 (C-4), 110.3 (C-5), 145.5 (C-6), 132.9 (C-7), 145.0 (C-7a), 58.0 (6-OCH3), 106.4 (C-1'), 158.7 (C-2'), 95.9 (C-3'), 158.5 (C-4'), 98.0 (C-5'), 158.0 (C-6'), 102.7 (C-1"), 74.9 (C-2"), 78.1 (C-3"), 71.2 (C-4"), 78.2 (C-5"), 62.5 (C-6").

[0125] Compound 15

[0126]

[0127] heteryunoneoside A:synthetic solvent with a solvent [α]20D-37.0(c 0.10,MeOH):UV(MeOH)λ max (log)275(3.32),231sh(4.16),207(4.74)nm:IRν max 3394,2923,1698,1625,1511,1470,1402,1346,1295,1245,1078,1034,929,669cm -1 HRESIMS m / z 505.1320[M+Na] + (calcd for C). 22 H 26 O 12 And,505.1317).

[0128] 1 H NMR(500MHz,CD3OD),δ H :3.70(1H,overlap,H-1a),3.68(1H,d,J12.0Hz,H-1b),3.70(1H,overlap,H-3a),3.76(1H,d,J18 .0Hz,H-3b),6.20(1H,d,J2.0Hz,H-6),6.04(1H,d,J2.5Hz,H-8),6.42(1H,d,J8.5Hz,H-5'),6.5 0(1H,d,J8.5Hz,H-6'),3.81(3H,s,4'-OCH3),4.79(1H,d,J7.5Hz,H-1"),3.37-3.44(4H,overlap ,H-2",H-3",H-4",H-5"),3.69(1H,dd,J5.0,12.0Hz,H-6"a),3.88(1H,dd,J1.5,13.0Hz,H-6"b).

[0129] 13 C NMR(125MHz,CD3OD),δ C:44.1(C-1),212.5(C-2),38.1(C-3),104.6(C-4),158.7(C-5),95.8(C-6 ),158.6(C-7),97.9(C-8),158.1(C-9),116.8(C-1'),145.1(C-2'),135. 1(C-3'),148.8(C-4'),104.0(C-5'),121.9(C-6'),56.5(4'-OCH3),102. 7(C-1"),74.8(C-2"),78.0(C-3"),71.2(C-4"),78.1(C-5"),62.5(C-6").

[0130] Test Example 1: In vitro myocardial protective activity test of the monomeric compound of Psoralea corylifolia

[0131] Experimental samples and positive drugs: monomer compounds 1 to 15 isolated from white radix scutellariae, positive drug N-acetylcysteine ​​(NAC), prepared with DMSO, with an initial concentration of 1.0×10 -2 mol·L -1 , dilute and administer as needed.

[0132] Groups: (1) Blank group (Ctrl): normal culture group; (2) Model group (Mo): hypoxia treatment group; (3) Positive drug group (NAC): hypoxia + N-acetylcysteine ​​treatment group; (4) Sample group: hypoxia + corresponding test compound treatment group.

[0133] Cell isolation and culture: Male rats (6 weeks old) were anesthetized by intraperitoneal injection of 10000U / kg heparin and intraperitoneal injection of sodium pentobarbital at a dose of 50mg / kg. The heart was quickly opened and the heart was immediately placed in ice-cold PBS. The connective tissue was cleaned and the aorta was stripped. The heart was suspended in a Langendorff perfusion apparatus and fixed. The temperature of the heart and the perfusion fluid was kept at 37°C. Krebs-Henseleit buffer KHB (containing NaCl: 118mM, KCl: 4.8mM, HEPES: 25mM, K2PO4: 1.25mM, MgSO4: 1.25mM, glucose: 11mM, taurine: 5mM, pH 7.4) was retrogradely perfused through the aorta for 5 minutes, and then the digestion solution (containing 0.7mg / mL type II collagenase, 0.2mg / mL hyaluronidase, 0.1% BSA and 25μM Ca) was replaced. 2+ ) continued perfusion for 10 minutes, supplemented with Ca 2+ When the heart softens, cut the heart and place it in KHB. Cut the atrial and basal tissues and cut the ventricular tissue into about 1 mm 3The fragments were gently blown with a pipette until single cells and cell clusters fell off, and filtered through a 240μm nylon mesh. The filtrate was centrifuged at 500 rpm and placed in KHB. The centrifugation was repeated once and the supernatant was removed. The precipitated cells were suspended in DMEM medium (containing 2mg / mL BSA, 2mM L-carnitine, 5mM creatine, 5mM taurine, 100μg / mL penicillin and 100μg / mL streptomycin). After the cells were counted, they were plated on a Laminin-coated culture dish and cultured in a 37℃, 5% CO2 incubator. The cells were allowed to adhere for 2 hours before subsequent treatment.

[0134] Preparation of cell hypoxia model and drug treatment: After pretreatment with the test compound or antioxidant positive agent N-acetylcysteine ​​(NAC) at a final concentration of 10 μM for 2 hours, the cells were placed in a hypoxic cell culture incubator for 24 hours. After adding Alamar Blue reagent for 6 hours, the number of remaining cells was measured on a fluorescence microplate reader (excitation wavelength 530 nm, emission wavelength 590 nm), and the difference in cell survival rate between the test group and the model group was statistically analyzed. After pretreatment with the test compound at a final concentration of 0.08-250 μM for 2 hours, the cells were placed in a hypoxic cell culture incubator for 24 hours. After adding Alamar Blue reagent for 6 hours, the number of remaining cells was measured on a fluorescence microplate reader, and the EC values ​​of the active compounds under test were statistically analyzed based on the difference in cell survival rates at different concentrations. 50 value.

[0135] The results are shown in Table 1: A large number of apoptosis and necrosis occurred in the myocardial cells in the hypoxia treatment group. After treatment with the positive drug NAC and the test compounds 1, 2, 3, 4, 5, and 6, the cell survival rate was significantly improved, and there was a significant difference compared with the cells in the hypoxia model group. Among them, the test compounds 1, 2, 3, 4, 5, and 6 were able to increase the myocardial cell survival rate in a dose-dependent manner. EC 50 They are 0.56 μM, 1.26 μM, 9.02 μM, 2.20 μM, 2.13 μM and 9.10 μM respectively.

[0136] The experimental results show that some of the tested compounds 1 to 6 of the 2-benzylbenzofuran class of the white earthworm of the present invention can improve the energy production disorder of myocardial cells, exert a myocardial protective effect, and can be used to prepare myocardial protective drugs.

[0137] Table 1. Statistics of relative survival rate of cardiomyocytes in hypoxic environment

[0138]

Claims

1. A novel 2-benzylbenzofuran or diarylacetone compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound has the following structure:

2. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises one, two, or more than two compounds according to claim 1 or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

3. The pharmaceutical composition according to claim 2, characterized in that The pharmaceutical composition contains 0.1 to 95% by weight of one, two, or more than two compounds according to claim 1 or pharmaceutically acceptable salts thereof.

4. The pharmaceutical composition according to claim 2, characterized in that The dosage form of the pharmaceutical composition is selected from tablets, capsules, pills, granules, oral liquids or suspensions.

5. The pharmaceutical composition according to claim 4, characterized in that The dosage unit of the dosage form contains the compound or a pharmaceutically acceptable salt thereof in an amount of 0.1 to 100 mg, preferably 4 to 50 mg.

6. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of claims 2 to 5 in the preparation of a drug for treating cardiovascular diseases.

7. The use according to claim 6, characterized in that: The cardiovascular disease includes cor pulmonale, heart failure, myocardial ischemia, myocardial infarction or angina pectoris.

8. The method for preparing the compound of claim 1, characterized in that The preparation method is as follows: extracting Heterosmilax yunnanensis Gagnep. medicinal material with 95%, 85%, 75% ethanol and water by reflux, extracting the concentrated extract by organic solvent extraction, 85% alcohol precipitation, macroporous resin column chromatography, Sephadex LH-20 gel column chromatography and preparative HPLC separation and purification to obtain the above compounds 1 to 15.

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