Method for treating conditions mediated by ppar using macelignan   

TECHNICAL FIELD

The present invention relates to a method for treating conditions mediated by PPAR, which comprises administering an effective amount of macelignan or a pharmaceutically acceptable salt thereof to a subject.

BACKGROUND ART

PPAR (peroxisome proliferator activated receptor) refers to an intranuclear receptor whose ligand is a peroxisome proliferator, a compound capable of increasing the number of peroxisome. Also, it is known that PPAR has three isoforms of PPARα, PPARδ and PPARγ (J. Steroid Biochem. Molec. Biol., 51, 157, 1994; Gene Expression, 4, 281, 1995;Biochem. Biophys. Res. Commun., 224, 431, 1996).

PPAR mainly controls expression of genes participating in fat metabolism or genes participating in differentiation of adipocytes (J. Invest. Dermatol. 111, 1116-1121, 1998; J. Med. Chem., 43, 527-550, 2000). Among the above PPAR isoforms, PPARα is expressed mainly in the liver, the retina and the adipose tissue, and participates in oxidation of fatty acids, neutralization of toxic materials, or inflammatory reactions. PPARγ is expressed mainly in the adipocytes, the immune cells, the adrenal gland, the spleen and the small intestine, and is known to function as a central mediator in the differentiation of adipocytes. PPARδ is not expressed in a tissue-specific manner but expressed broadly, and the function of PPARδ is not clearly understood (Endocrinology., 137, 354, 1996).

Because PPAR has an important role in fat metabolism, many studies have been conducted to develop a medicine for treating metabolic diseases in which PPAR is involved. It is known that when PPARα is activated, expression of enzymes increasing fatty acid decomposition and decreasing fatty acid synthesis in the liver increases, thereby decreasing synthesis of triglycerides and production and secretion of VLDL (very low density lipoprotein). It is also known that activation of PPARα result in activation of LPL (lipoprotein lipase), and reduced production of apoC-III which is inducing generation of VLDL (Curr. Pharm Des., 3: 1-14, 1997). Additionally, it is known that fibrate, known as a ligand of PPARα, reduces triglycerides by 20-50%, and reduces LDL while increasing HDL (Atherosclerosis, 171: 1-13, 2003). Therefore, ligands of PPARα are useful for treating obesity, dyslipidemia and cardiovascular diseases caused by accumulation of triglycerides (Curr. Opin. Lipidol., 10: 245-257, 1999).

In addition, activation of PPARγ causes maximization of sugar receptability of adipocytes, stimulates differentiation of adipocytes and reduces insulin resistance (Tren. Pharmacol. Sci., 25:331-336, 2004). Therefore, ligands of PPARγ can act as medicine for treating non-insulin-dependent diabetes mellitus (Type 2 diabetes mellitus) caused by insulin resistance. Currently, TZD pharmaceuticals such as pioglitazone and rosiglitazone, which are typical ligands of PPARγ, are used as medicines for treating non-insulin-dependent diabetes mellitus.

As mentioned above, since PPAR is a target in the treatment of metabolic diseases including diabetes, diabetic complications, or the like, many attempts have been made to date to develop PPAR ligands for activating PPAR. U.S. Pat. No. 6,939,875 discloses a composition useful for treating PPAR-mediated diseases. It is also disclosed that the composition of U.S. Pat. No. 6,939,875 is effective for treating non-insulin-dependent diabetes mellitus, obesity, eating disorders, appetite suppressing, leptin level modulation, and metabolic syndrome. Additionally, U.S. Pat. No. 6,967,212 discloses a composition comprising a substituted azole acid derivative acting as a PPAR agonist. It is also disclosed that the composition of U.S. Pat. No. 6,967,212 is effective for treating insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidernia, obesity, syndrome X, dysmetabolic syndrome, inflammation, diabetic complications, impaired glucose homeostasis, impaired glucose tolerance, hypertriglyceridemia or atherosclerosis. Further, other substances effective for treating various PPAR-mediated diseases are disclosed (U.S. Pat. Nos. 6,930,120, 7,041,691 and 7,037,914).

However, PPAR ligands that have been known to date cause side effects such as liver toxicity, hypoglycemic conditions and obesity. Hence, it is required to develop a ligand capable of activating PPAR from a natural source that causes low side effects such as toxicity. Nevertheless, there have been few studies to develop a ligand capable of activating PPAR from a natural source.

Meanwhile, Myristica fragrans is a perennial plant cultivated in the tropics. Fruits of Myristica fragrans, known as mace or nutmeg, have been used as spice for a long time. Macelignan is a typical lignan-based compound, which is found in Myristica fragrans (Phytochemistry, 59: 169-17, 2002). It is reported that macelignan has the functions of enhanced activity of caspase-3 inducing apoptosis (Biol. Pharm. Bull., 27: 1305-1307, 2004), an antibacterial effect against oral microorganisms (Korean Laid-Open Patent No. 10-2005-0035954), inhibited peroxidation of cerebral cell lipids and inhibited production of active oxygen (Biochem. Biophys. Res. Commu., 331: 1264-1269), or the like. However, any studies of the interrelation between macelignan and PPAR have not yet been reported.

DISCLOSURE OF THE INVENTION

Therefore, the inventors of the present invention have conducted intensive studies to search for a substance effective. for treating PPAR-mediated diseases, such as diabetes mellitus, diabetic complications, obesity or hyperlipidemia, from various natural sources. Finally, we have found that macelignan isolated from Myristica fragrans is effective for activating PPAR, and thus for treating PPAR-mediated diseases. The present invention is based on this finding.

Therefore, it is an object of the present invention to provide a method for treating PPAR-mediated diseases, which comprises administering an effective amount of macelignan or a pharmaceutically acceptable salt thereof to a subject.

In order to accomplish the above object, the present invention provides a method for treating PPAR-mediated diseases, which comprises administering an effective amount of macelignan or a pharmaceutically acceptable salt thereof to a subject.

Hereinafter, the present invention will be explained in more detail.

According to the present invention, the method for treating PPAR-mediated diseases comprises administering an effective amount of macelignan represented by the following Formula (I) or a pharmaceutically acceptable salt thereof to a subject.

Macelignan used in the method according to the present invention is commercially available or may be isolated and purified from a natural source. Otherwise, macelignan may be prepared by a chemical synthetic process known to those skilled in the art.

Preferably, macelignan used in the method according to the present invention may be isolated and purified from a natural source. More preferably, macelignan may be isolated and purified from Myristica fragrans, and most preferably from nutmeg or aril of Myristica fragrans. Additionally, macelignan may be isolated and purified from other myristicaceae plants, such as Myristica argentea Warb (Nat. Prod. Lett., 16: 1-7, 2002), Machilus thunbergii (Bio. Pharm. Bull., 27: 1305-1307, 2004), or Leucas aspera (Chem. Pharm. Bull., 51: 595-598, 2003).

Preferably, macelignan used in the present invention may be isolated and purified from nutmeg via a separation process using solvent extraction and chromatography which are known in the art.

For example, extraction of macelignan from nutmeg may be carried out by using any one solvent selected from the group consisting of water, organic solvents including C1˜C6 alcohols, such as ethanol, methanol, propanol, isopropanol and butanol, acetone, ether, chloroform, ethyl acetate, methylene chloride, hexane, cyclohexane, petroleum ether, diethyl ether, and benzene, or a mixed solvent thereof. Preferably, such extraction may be performed by using water or a C1˜C6 alcohol. Most preferably, macelignan used in the present invention may be extracted by using methanol as a solvent.

For extraction, methanol may be added to nutmeg powder in an amount of 1˜20 times (on the weight basis) of the amount of nutmeg powder, but not limited thereto. Preferably, methanol may be added to nutmeg powder in an amount of 2˜5 times (on the weight basis) of the amount of nutmeg powder in order to increase extraction efficiency.

Extraction of nutmeg is performed preferably at room temperature under ambient pressure. Although extraction time depends on extraction temperature, extraction is performed generally for 6˜96 hours, and preferably for 36˜72 hours. Additionally, extraction using a shaker may further increase extraction efficiency.

Nutmeg is used in the extraction, after it is collected and washed, and optionally dried. As a drying process, a sun drying process, a shade drying process, a hot air drying process or a natural drying process may be used. Additionally, in order to increase extraction efficiency, nutmeg or a dried product thereof may be pulverized in a mill.

Isolation of macelignan from the extract can be performed by using a separation process based on chromatography generally known to those skilled in the art. For example, the extract is loaded to a silica gel column chromatography to obtain different fractions having different levels of polarity, and then a specific fraction is further subjected to reverse phase column chromatography and high performance liquid chromatography (HPLC) to isolate macelignan.

According to a preferred embodiment, extraction of macelignan used in the present invention is performed by pulverizing dried nutmeg into a size of 20˜40 mesh, and adding methanol thereto in an amount of three times of the amount of nutmeg powder to carry out extraction for 48 hours at room temperature. The extract obtained as described above is centrifuged, the precipitate is removed, and the supernatant is collected to obtain nutmeg extract containing macelignan. Then, the nutmeg extract is fractionated into an ethyl acetate layer, a butanol layer and a water layer, and the ethyl acetate layer is subjected to a silica gel column and eluted with hexane and ethyl acetate (10:1 (v/v)) to obtain a desired fraction. The fraction is further subjected to a silica gel column and eluted with hexane and ethyl acetate (20:1 (v/v)) to obtain a desired fraction, which, in turn, is subjected to a RP-18 column and eluted with 80% methanol to obtain isolated macelignan.

Macelignan used in the method of the present invention acts as a ligand to PPAR, thereby activating PPAR. This has been demonstrated by the inventors of the present invention for the first time.

According to an embodiment of the present invention, it has been found that macelignan used in the present invention is bound to PPAR, particularly PPARα and PPARγ, thereby activating PPAR, through a known method for detecting a ligand capable of being bound to PPAR to activate genes having the PPAR response element (PPRE).

When PPAR is activated, it is bound to a DNA sequence referred to as PPRE (PPAR response element) to control the expression of target genes. Mainly, expression of target genes of PPAR involved in fat metabolism increases. Therefore, according to another embodiment of the present invention, macelignan has been investigated as to whether it increases expression of CD36, CPT-1, PDK 4, ACO, LPL and PEPCK, known as target genes of PPAR. As a result, it was shown that treatment with macelignan significantly increases expression of the target genes of PPAR.

Meanwhile, it is known that as PPAR is activated, sugar receptability of adipocytes is maximized and the differentiation of adipocytes is stimulated (Trends in Pharmacological Sciences, 25: 331-336, 2004). Therefore, according to still another embodiment of the present invention, macelignan has been investigated as to whether it activates PPAR to stimulate the differentiation of adipocytes. As a result, it was shown that macelignan used in the present invention can stimulate differentiation of 3T3-L1, pre-adipocytes (see FIG. 10).

According to still another embodiment of the present invention, it was shown that macelignan has the effect of treating or preventing obesity, hyperlipidemia and cardiovascular diseases caused by obesity by reducing body weight significantly in an obesity/diabetes mouse model. Additionally, according to yet another embodiment of the present invention, it was demonstrated that macelignan has the effect of treating or preventing non-insulin-dependent diabetes mellitus by reducing blood sugar significantly in an obesity/diabetes mouse model.

In brief, it can be seen that macelignan is a ligand of PPARα that increases fat decomposition and of PPARγ that increases insulin sensitivity, has the use for inhibiting obesity and metabolic diseases including hyperlipidemia and cardiovascular disease by significantly reducing body weight and triglycerides in blood in an obesity/diabetes model, and shows the use for inhibiting non-insulin-dependent diabetes mellitus by reducing blood sugar in the same model.

Therefore, macelignan is useful for a method for treating PPAR-mediated diseases.

As used herein, “PPAR-mediated diseases” refer to diseases or conditions of which are prevented, treated, reduced and alleviated by the activation of PPAR. Preferably, PPAR-mediated diseases include: NIDDM (non-insulin-dependent diabetes mellitus), hyperinsulinemia, obesity, hyperglycemia, hyperlipidemia, syndrome X, hypercholesterolemia, hyperlipoproteinemia, atherosclerosis, hypertension, insulin resistance, dysmetablic syndrome, diabetic complications, impaired glucose homeostasis, impaired glucose tolerance, hypertriglyceridemia, osteoporosis (J. Biol. Chem. 275: 14388-14393, 2000), glomerulonephritis (Kidney Int., 14-30, 2001), or diabetic nephropathia (Kidney Int., 60: 14-30, 2001).

The method for treating PPAR-mediated diseases according to the present invention comprises administering an effective amount of a composition having macelignan or a pharmaceutically acceptable salt thereof to a subject. Herein, the term “effective amount” means such an amount that a response higher than the response of the negative control can be obtained, and preferably an amount sufficient to treat or prevent PPAR-mediated diseases. The effective amount of composition having macelignan or a pharmaceutically acceptable salt according to the present invention is 0.1˜200 mg/day/kg (body weight), preferably 1˜30 mg/day/kg (body weight), but is not limited thereto. However, the effective amount is determined considering various factors, including disease and disease severity, age, body weight, health, sex, diet and excretion of a patient, administration route, administration period, frequency of treatment, and combination of other drugs. In addition, the term “subject” refers to a mammal in need of treatment or prevention of PPAR-mediated diseases, preferably, a human.

According to the present invention, macelignan may be used in the form of a salt, preferably a pharmaceutically acceptable salt. Preferably, the salt includes an acid addition salt formed with a pharmaceutically acceptable free acid. Such free acids include organic acids and inorganic acids. Particular examples of the organic acids include, but are not limited to: citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluene sulfonic acid, glutamic acid and aspartic acid. Additionally, particular examples of the inorganic acids include, but are not limited to: hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.

Hereinabove, the term “pharmaceutically acceptable” refers to substances that are physiologically acceptable have no inhibitory effect of active ingredients, and cause no allergic reactions or similar reactions, such as gastrointestinal disorders or fainting, when administered to a human or an animal.

Meanwhile, according to the present invention, macelignan or a pharmaceutically acceptable salt thereof may be formulated with a carrier suitable for the particular administration route. Such carriers include all kinds of solvents, dispersing agent, oil-in-water or water-in-oil emulsion, aqueous compositions, liposomes, microbeads and microsomes. Administration routes of the pharmaceutical composition according to the present invention include, but are not limited to, oral or parenteral routes. Particular examples of parenteral administration routes include transdermal, nasal, intraperitoneal, intramuscular, subcutaneous or intravenous routes.

When macelignan or a pharmaceutically acceptable salt thereof according to the present invention is orally administered, it may be formulated into the form of powder, granules, tablets, pills, sugar-coated tablets, capsules, liquid, gel, syrup, suspension, wafer, or the like, together with a suitable carrier for oral administration by using a process known to those skilled in the art. Particular examples of suitable carriers include: saccharides, such as lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol; starch, such as corn starch, wheat starch, rice starch and potato starch; cellulose, such as methyl cellulose, sodium carboxymethyl cellulose and hydroxyprpylmethyl cellulose; and fillers, such as gelatin, polyvinyl pyrrolidone, or the like. If necessary, it is possible to further add a disintegrating agent, such as a crosslinking agent, polyvinyl pyrrolidone, agar, alginic acid or sodium alginate. In addition, the pharmaceutical composition according to the present invention may further comprise an anti-agglomerating agent, a lubricant, a wetting agent, a fragrance agent and a preservative.

Meanwhile, when macelignan or a pharmaceutically acceptable salt thereof is administered via a parenteral route, it may be formulated into the form of a composition for injection, transdermal administration or nasal inhalation, together with a carrier suitable for parenteral administration by using a process generally known to those skilled in the art. In the case of a composition for injection, it is necessary to sterilize the composition and to protect the composition from being contaminated with microorganisms such as bacteria and fungi. Particular examples of the carriers suitable for injection administration include, but are not limited to: water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), a mixture thereof and/or a solvent or dispersion medium containing vegetable oil. More preferably, suitable carriers include Hanks\' balanced salt solution, Ringer\'s solution, PBS (phosphate buffered saline) containing triethanol amine or sterilized water for injection, isotonic solution such as 10% ethanol, 40% propylene glycol or 5% dextrose, or the like. To protect the injection formulation from being contaminated with microorganisms, the formulation may further comprise various antibacterial agent and antifungal agent, such as paraben, chlorobutanol, phenol, sorbic acid, thimerosal, or the like. In most cases, an injection formulation may further comprise an isotonic agent such as sugar or sodium chloride.

Compositions for transdermal administration may be formulated into the form of ointment, cream, lotion, gel, solution for external use, pasta, liniment, aerosol, or the like. Herein, the term “transdermal administration” refers to local administration of a pharmaceutical composition on the skin, resulting in delivery of an effective amount of active component contained in the pharmaceutical composition into the skin. The above formulations are described in more detail in a textbook (Remington\'s Pharmaceutical Science, 15th Edition, 1975, Mack Publishing Company, Easton, Pa.), widely known in the field of pharmaceutical chemistry.

In the case of an inhalation formulation, the compound used in the method according to the present invention may be conveniently delivered in the form of an aerosol spray formulation from a pressurized pack or an atomizer by using a suitable propellant, such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of a pressurized aerosol, dosage unit may be determined by providing a valve capable of delivering a metered amount of drug. For example, a gelatin capsule or a cartridge used in an inhalator or insufflator may comprise a powder mixture containing the compound and a suitable powder base such as lactose or starch.

Other pharmaceutically acceptable carriers are described in more detail in [Remington\'s Pharmaceutical Science, 19th Edition, Mack Publishing Company. Easton, Pa, 1995].

Additionally, macelignan or a pharmaceutically acceptable salt thereof used in the method according to the present invention may further comprise at least one buffer (e.g. saline or PBS), carbohydrate (e.g. glucose, mannose, sucrose or dextran), antioxidant, bacteriostatic agent, chelating agent (e.g. EDTA or glutathione), adjuvant (e.g. aluminum hydroxide), suspending agent, thickening agent and/or preservative.

Meanwhile, macelignan or a pharmaceutically acceptable salt thereof may be formulated using known method in the art so as to provide rapid, durable or delayed release of the active component after the administration to a subject.

Further, according to the present invention, macelignan or a pharmaceutically acceptable salt thereof may be administered in combination with a known compound, such as TZD, having the effect of preventing or treating PPAR-mediated diseases.

After carrying out a toxicity test upon the oral administration of macelignan to rats, lethal dose 50% (LD50) in an oral toxicity test was shown to be 2,000 mg/kg or more.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of the present invention will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings in which:

FIG. 1 is a flow chart of a process for isolating macelignan from nutmeg of Myristica fragrans;

FIG. 2 is 13C-NMR spectrum of macelignan according to the present invention;

FIG. 3 is 1H-NMR spectrum of macelignan according to the present invention;

FIG. 4 is 1H-1H COSY spectrum of macelignan according to the present invention;

FIG. 5 is 1H-13C HMBC spectrum of macelignan according to the present invention;

FIG. 6 is EI-Mass spectrun of macelignan according to the present invention;

FIG. 7 is a graph illustrating the effect of macelignan according to the present invention upon the activation of PPARα (A) or PPARγ (B), in concentration;

FIG. 8 is a result showing the effect of macelignan according to the present invention upon the expression of target genes of PPARα;

A: CD36

B: CPT-1

C: PDK4

D: ACO;

FIG. 9 is a result showing the effect of macelignan according to the present invention upon the expression of target genes of PPARγ;

A: LPL

B: PEPCK

FIG. 10 is a result showing the effect of macelignan according to the present invention upon the differentiation of adipocytes 3T3-L1 of mouse fibroblasts;

FIG. 11 is a result showing the effect of macelignan according to the present invention upon the blood sugar in an obesity/diabetes mouse model;

FIG. 12 is a graph illustrating the effect of macelignan according to the present invention upon the glucose tolerance in an obesity/diabetes mouse model;

FIG. 13 is a graph illustrating the effect of macelignan according to the present invention upon the insulin concentration in blood in an obesity/diabetes mouse model;

FIG. 14 is a graph illustrating the effect of macelignan according to the present invention upon the adiponectin concentration in blood in an obesity/diabetes mouse model;

FIG. 15 is a graph illustrating the effect of macelignan according to the present invention upon the diet intake in an obesity/diabetes mouse model;

FIG. 16 is a graph illustrating the effect of macelignan according to the present invention upon the body weight in an obesity/diabetes mouse model;

FIG. 17 is a graph illustrating the effect of macelignan according to the present invention upon the amount of adipose tissue in an obesity/diabetes mouse model;

FIG. 18 is a graph illustrating the effect of macelignan according to the present invention upon the triglyceride concentration in muscle cell in an obesity/diabetes mouse model;

FIG. 19 is a graph illustrating the effect of macelignan according to the present invention upon the concentration of triglycerides in blood in an obesity/diabetes mouse model;

FIG. 20 is a graph illustrating the effect of macelignan according to the present invention upon the concentration of free fatty acids in blood in an obesity/diabetes mouse model;

FIG. 21 is a graph illustrating the effect of macelignan according to the present invention upon the total cholesterol concentration in blood in an obesity/diabetes mouse model;

FIG. 22 is a graph illustrating the effect of macelignan according to the present invention upon the HDL-cholesterol concentration in blood in an obesity/diabetes mouse model;

FIG. 23 is a graph illustrating the effect of macelignan according to the present invention upon the IL-6 concentration in blood in an obesity/diabetes mouse model;

FIG. 24 is a graph illustrating the effect of macelignan according to the present invention upon the TNF-α concentration in blood in an obesity/diabetes mouse model;

FIG. 25 is a graph illustrating the effect of macelignan according to the present invention upon the amount of triglycerides in the liver tissue in an obesity/diabetes mouse model;

FIG. 26 is a result showing the effect of macelignan according to the present invention upon the expression of target genes of PPARα in the liver tissue of an obesity/diabetes mouse model;

A: CD36

B: ACO

C: CPT-1; and

FIG. 27 is a result showing the effect of macelignan according to the present invention upon the expression of target genes of PPARγ in the liver tissue of an obesity/diabetes mouse model;

A: CD36

B: LPL

C: ACS

D: GyK.

Reference will now be made in detail to the preferred embodiments of the present invention. It is to be understood that the following examples are illustrative only and the present invention is not limited thereto.

<1-1> Isolation And Purification of Macelignan

To 100 g of dried and pulverized nutmeg, 400 ml of 75% methanol was added, and the mixture was left at room temperature for 2 days. The extracted solution was filtered and concentrated under vacuum to obtain methanol extract of nutmeg (7 g). Next, the extract was fractionated into an ethyl acetate layer, a butanol layer and a water layer, and each fraction was concentrated under vacuum to obtain an ethyl acetate fraction, a butanol fraction and a water fraction. The ethyl acetate fraction (4.2 g) was subjected to silica gel column chromatography (Merck Kieselgel 66; 70-230 mesh) using hexane and ethyl acetate (10:1 (v/v)) as an eluant to obtain fraction III (1 g). Additionally, fraction III was subjected to silica gel column chromatography (Merck Kieselgel 66; 70-230 mesh) using hexane and ethyl acetate (20:1 (v/v)) as an eluant to obtain fraction III-B (0.52 g). Then, fraction III-B was further subjected to Rp-18 column chromatography (Merck LiChroprep; 25-40 μm) using 80% methanol as an eluant to obtain a single substance, fraction III-B-2 (0.5 g). The above isolation process is shown in FIG. 1 in the form of a flow chart.

<1-2> Structural Analysis

To determine the structure of the single substance, fraction III-B-2, 1H-NMR spectrometry and 13C-NMR spectrometry were performed at 600 MHz and 150 MHz, respectively (solvent: DMSO). The results are shown in FIG. 2 and FIG. 3. To determine the 1H-1H interrelation and 1H-13C interrelation based on the results of 1H-NMR spectrometry and 13C-NMR spectrometry, 1H-1H COSY spectrometry and 1H-13C HMBC spectrometry were performed. The results are shown in FIG. 4 and FIG. 5. The following Table 1 shows the overall results of 1H-NMR, 13C-NMR, 1H-1H COSY and 1H-13C HMBC spectrometry.

TABLE 1 Position 13C-NMR 1H-NMR 1H-1H COSY 1H-13C HMBC 1 135.4 2 109.2 6.72 brs C-7, C-6, C-4, C-3 3 147.3 4 145.1 5 107.9 6.79 d(7.8) 6.61 C-6, C-4, C-3, C-1 6 121.7 6.61 dd(7.8) 6.79 C-7, C-5, C-4, C-2, C-1 7 38.2 2.23 dd(13.2, 9.3) 1.64, 2.66 C-8, C-6, C-2, C-1 2.66 dd(13.2, 4.8) 1.64, 2.23 C-9, C-8, C-6, C-2, C-1 8 38.7 1.64 brs 0.75, 2.23, 2.66 C-7 9 16.0 0.75 d(6.3) 1.64 C-8, C-7  1′ 132.4  2′ 112.9 6.66 brs C-7′, C-6′, C-4′, C-3′  3′ 147.1  4′ 144.4  5′ 115.2 6.66 d(7.9) 6.53 C-6′, C-4′, C-3′, C-1′  6′ 121.0 6.53 d(7.9, 1.1) 6.66 C-7′, C-5′, C-4′, C-2′, C-1′  7′ 38.0 2.17 dd(13.2, 9.3) 1.64, 2.66

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