JP2692742B2 - New lignans - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention relates to novel lignans having a protease inhibitory activity.

[Prior Art and Challenges] In recent years, in the field of pancreatitis treatment, the advent of proteolytic enzyme inhibitors has led to dramatic progress such as improvement of symptoms of acute pancreatitis or prevention of acute pancreatitis.

However, at present, the severe form of acute pancreatitis is determined to be alive or dead within a few days, and it has been desired to develop a more proteolytic enzyme inhibitor.

[Means for Solving the Problems] As a result of intensive studies to solve the above problems, the present inventors have found novel lignans having excellent proteolytic enzyme inhibitory activity, and completed the present invention. It was

 That is, the present invention is as follows.

Formula I below (However, A represents an acetyl group or a hydrogen atom.) A lignan (hereinafter referred to as a compound of formula I).

Formula II below (However, B represents a methyl group or a hydrogen atom.) A lignan (hereinafter referred to as a compound of formula II).

Formula III below (Hereinafter, referred to as a compound of formula III).

Hereinafter, the compounds of formula I to formula III are collectively referred to as the compound of formula.

The compound of the formula can be obtained, for example, as follows.

Asahi [Cannabis sativa L. dry seeds] is heated from 0 ° C to a temperature not higher than the boiling point of the solvent used, using one or more mixed solvents selected from water, methanol, ethanol, acetone, ethyl acetate and methyl ethyl ketone. Or an ultrasonic extraction at room temperature from 0 ° C. to obtain an extract.

This extract was suspended in water, distributed extraction was performed using a low-polarity solvent, and the remaining water-soluble part from which low-polarity impurities were removed was
Partition extraction is performed using one or more mixed solvents selected from ethyl acetate, n-butanol, and methyl ethyl ketone to obtain an extract. The extract is subjected to column chromatography or high performance liquid chromatography once or several times as it is or after drying, and the eluate is fractionated to obtain a fraction. At this time, as an elution solvent, water, methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, benzene, ether, petroleum ether, n-hexane or the like can be used alone or as a mixed solvent. The compound of formula can be obtained by recrystallizing or pulverizing the thus obtained fraction. Further, if necessary, acetylation may be appropriately performed, or an acid may be added and the mixture may be heated and further methylated.

Examples of the low polar solvent include benzene, chloroform, ether, n-hexane and cyclohexane.

Examples of adsorbents for column chromatography or high performance liquid chromatography include silica gel, ODS-silica gel, porous polymer gel and the like.

When recrystallizing or powdering, water, methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, benzene, chloroform, ether, petroleum ether, n-
A single solvent or a mixed solvent of more than hexane or cyclohexane is used.

For the acetylation, a general acetylating agent can be used, and for example, acetylation with acetic anhydride in pyridine is preferable.

Examples of the acid include hydrobromic acid, and the heating temperature is suitably 80 to 130 ° C.

For the methylation, a general methylating agent can be used, and for example, methyl iodide or dimethylsulfate is suitable.

Next, it will be described with reference to Examples that the compound of the formula has excellent proteolytic enzyme inhibitory activity and is useful as a therapeutic agent for pancreatitis.

Experimental example Each enzyme solution [plasmin (human plasma, Boehringer), thrombin (human plasma, Boehringer), trypsin (bovine pancreas, Boehringer)] was given to a tester.
100μ, Tris-HCl buffer (pH8.3) 50μ (final concentration 3
3.3mM), water (20mM calcium chloride solution for trypsin) 25μ, solution containing the compound obtained in the Examples below 25μ
Incubate for 5 minutes at 37 ° C, then add 50 μm of TAME (p-toluenesulfonyl-L-arginine methyl ester) (final concentration 15 mM) and react at 37 ° C for 30 minutes to react with 3.5N sodium hydroxide and 3.5N hydroxyl. Equivalent mixture of amine 500μ
To stop the reaction and leave it at room temperature for 25 minutes,
The activity was measured by the hestrin method. That is, 250% of 6% trichloroacetic acid and 2.0 ml of 0.2 M ferric chloride solution were added to develop color, the absorbance at 525 nm was measured, and the inhibition rate was determined by the following formula.

A control group was prepared in the same manner except that 25 μm of water was added instead of the compound obtained in the example.

A: Absorbance of substrate only B: Absorbance of control group C: Absorbance of sample The results are shown in the following table.

From the above results, the proteolytic enzyme inhibitory activities of the following compounds are remarkable and are useful as excellent therapeutic agents for pancreatitis.

Next, when an acute toxicity test of the compound of the formula was carried out using male ICR mice, no death occurred and no weight loss was observed after oral administration of 1 g / kg.

Thus, the compound of the formula has extremely low toxicity and high safety.

Next, the dose and formulation of the compound of the present invention will be explained.

The compounds of the formula can be administered to animals and humans as such or together with conventional pharmaceutical carriers. The administration form is not particularly limited and may be appropriately selected and used as needed. Examples thereof include oral preparations such as tablets, capsules, granules, fine granules and powders, and parenteral preparations such as injections and suppositories. Can be

In order to exert the intended effect as an oral agent, it depends on the patient's age, body weight and degree of disease, but usually 50 mg to 5 g as the weight of the compound of formula is to be taken in divided doses several times a day in adults. Seems appropriate. Oral preparations include, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose,
It is manufactured according to a conventional method using corn starch, inorganic salts and the like.

In this type of preparation, in addition to the above-mentioned excipients, a binder,
Disintegrant, surfactant, lubricant, fluidity enhancer, flavoring agent,
Coloring agents, fragrances and the like can be used. Specific examples are as follows.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methyl cellulose,
Sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, low-substituted hydroxypropylcellulose.

[Surfactant] Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80.

[Lubricant] Talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The following compounds can also be administered as suspensions, emulsions, syrups, and elixirs, and these various dosage forms may contain flavoring agents and coloring agents.

In order to exert a desired effect as a parenteral agent, it depends on the age, body weight, and degree of disease of the patient, but usually, in adults, the weight of the compound of the formula is 0.1 mg to 1 g per day by intravenous infusion or infusion. Intravenous injection, subcutaneous injection, and intramuscular injection seem appropriate.

This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. be able to. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation can be frozen after filling into a vial or the like, water can be removed by a usual freeze-drying technique, and a liquid preparation can be prepared from the freeze-dried product immediately before use. Further, if necessary, an isotonic agent, a stabilizer, a preservative, a soothing agent, and the like may be appropriately added.

Examples of other parenteral preparations include liquid preparations for external use, ointments such as ointments, suppositories for rectal administration, and the like, and are produced according to a conventional method.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1 10 kg of Asahi kernel was heated under reflux with water-ethanol (1: 1) 8 for 3 hours and extracted three times. The obtained extracts were combined and the solvent was distilled off under reduced pressure to obtain 3.44 kg of a dried extract. This dried extract was suspended in water 20 and partitioned and extracted with chloroform 20 three times.

The aqueous layer was partitioned and extracted with n-butanol 20 four times to obtain an n-butanol extract, and the solvent was distilled off under reduced pressure to obtain 239.1 g of a dried extract. The dried extract was suspended in water 3, subjected to a porous polymer gel (Diaion HP-20, manufactured by Mitsubishi Kasei) column chromatography, and eluted successively with 40 water and 50 methanol.

The solvent in the methanol eluate was distilled off under reduced pressure to obtain 171.7 g of dried extract. This extract was added to silica gel (Kieselgel
Column chromatography (10 cmφ × 46 cm) using 60, 70-230 mesh, manufactured by Merck Ltd., and fractions eluted with a mixed solvent of chloroform-methanol (1: 1) were collected by high performance liquid chromatography [YMC R-354
(ODS), 50mmφ × 50cm, made by Yamamura Chemical Co., Ltd.
The fraction eluted with a mixed solvent of methanol (1: 1) was powdered with methanol to obtain 740 mg of a white powdery substance.
The physicochemical properties of this white powdery substance are as follows, and from these data, 6,7-dihydroxy-4-
(3,4-dihydroxyphenyl) -N ^1, N ² - bis - [2-
(4-Hydroxyphenyl) ethyl] -2,3-naphthalene dicarboxamide {6,7-Dihydroxy-4- (3,4-dih
ydroxyphenyl) -N ¹ , N ² -bis- [2- (4-hydroxyphe
nyl) ethyl] -2,3-naphthalene dicarboxamide} structure.

FD-MS m / z: 595 (M + H) ⁺ Proton-Nuclear Magnetic Resonance Spectrum (δ ppm in DMSO-d ₆ ): 2.29 (2H, t, J = 7Hz), 2.72 (2H, t, J = 7Hz), 3.06 (2H, brt, J = 7Hz), 3.40 (2H, brt, J = 7Hz), 6.58 (1H, dd, J = 2,8Hz), 6.65 (2H, d, J = 8Hz), 6.69 (2H, d, J = 8Hz), 6.72 (1H) , d, J = 2Hz), 6.80 (1H, d, J = 8Hz), 6.86 (1H, s), 6.87 (2H, d, J = 8Hz), 7.03 (2H, d, J = 8Hz), 7.17 ( 1H, s), 7.29 (1H, br), 7.68 (1H, br), 7.73 (1H, br s) ¹³ C-nuclear magnetic resonance spectrum (δ ppm in DMSO-d ₆ ): 33.4 (t), 33.9 ( t), 40.4 (t), 40.7 (t), 108.7 (d), 109.8 (d), 114.6 (d), 114.8 (d) x 4,117.7 (d), 121.1 (d), 124.4 (d), 127.4 ( s), 128.3 (s), 128.6 (s), 128.6 (d) x 2,128. (d) x 2, 128.9 (s), 129.3 (s), 129.4 (s), 130.6 (s), 134.8 (s) , 144.1 (s) × 2, 147.1 (s), 147.5 (s), 155.1 (s), 155.2 (s), 167.5 (s), 168.3 (s) Example 2 Example 1 The resulting compound 920mg was dissolved in dry pyridine 10 ml, after stirring for 12 hours at room temperature was added acetic anhydride 5 ml,
The reaction solution was allowed to stand in ice water and partitioned and extracted with 100 ml of ethyl acetate. After drying the ethyl acetate layer over sodium sulfate, the solvent was distilled off under reduced pressure and ethyl acetate-chloroform (1: 1) was added.
The crystals were recrystallized from to give 1.18 g of colorless needles.

The physicochemical properties of this colorless needle-like substance are as shown below, and from these data, 6,7-diacetoxy-4-
(3,4-diacetoxy phenyl) -N ^1, N ² - bis - [2-
(4-acetoxyphenyl) ethyl] -2,3-naphthalene dicarboxamide {6,7-Diacetoxy-4- (3,4-dia
cetoxyphenyl) -N ¹ , N ² -bis- [2- (4-acetoxyphe
nyl) ethyl] -2,3-naphthalene dicarboxamide} structure.

Melting point: 204-207 ° C FD-MS m / z: 847 (M + H) ⁺ Proton-Nuclear Magnetic Resonance Spectrum (δ ppm in CDCl ₃ ): 2.24 (3H, s), 2.26 (3H, s), 2.27 (3H, s), 2.29 (3H.s), 2.31 (3H, s), 2.33 (3H, s), 2.42 (2H.dt, J = 7,14Hz), 2.90 (2H, t, J = 8Hz), 3.26 (2H, ddt, J = 7,7,14Hz), 3.62 (2H, dd , J = 7,7Hz), 6.20 (1H, br s), 6.94 (2H, d, J = 8Hz), 7.00 (2H, d, J = 8Hz), 7.10 (2H, d, J = 8Hz), 7.12 (1H, dd, J = 2,8Hz), 7.14 (1H, d, J = 2Hz), 7.18 (1H, br), 7.25 (3H, d, J = 8Hz), 7.34 (1H, s), 7.64 ( 1H, s), 7.86 (1H, s) ¹³ C-nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 20.6 (q) × 2,20.7 (q) × 2,21.1 (q) × 2, 34.1 (t ), 34.9 (t), 41.2 (t), 41.4 (t), 120.2 (d), 121.5 (d) × 2, 121.7 (d) × 2, 122.0 (d), 123.6 (d), 125.5 (d), 128.4 (D), 128.5 (d), 129.8 (d) x 2, 129.8 (d) x 2, 130.8 (s), 130.9 (s), 132.1 (s), 133.2 (s), 135.1 (s), 135.4 (s) , 136.5 (s) × 2,142.0 (s), 142.3 (s), 142.4 (s), 143.0 (s), 149.1 (s), 149.3 (s), 167.7 (s), 168.0 (s), 168.1 (s), 168.3 (s), 168.8 (s), 169.5 (s), 169.6 (s) Example 3 192 mg of the compound obtained in Example 1 was dissolved in 2 ml of dry pyridine, 3 ml of 48% hydrobromic acid was added, and the mixture was sealed in a glass sealed tube and kept for 90 days for 2 days. Heated to ° C. After cooling, the reaction solution was allowed to stand in water and partitioned and extracted with 200 ml of ethyl acetate. The ethyl acetate layer was dried over calcium chloride, the solvent was evaporated under reduced pressure, and the residue was triturated with n-hexane-ether (1: 1) to obtain 114 mg of a yellow powder substance.

The physicochemical properties of this yellow powder substance are as shown below. From these data, 6,7-dihydroxy-4-
(3,4-Dihydroxyphenyl) -N- [2- (4-hydroxyphenyl) ethyl] -2,3-naphthalenecarboximide {6,7-Dihydroxy-4- (3,4-dihydroxyph
enyl) -N- [2- (4-hydroxyphenyl) ethyl] -2,
3-naphthalene dicarboximide} structure was determined.

FD-MS m / z: 480 (M + Na) ⁺ Proton-Nuclear Magnetic Resonance Spectrum (δ ppm in CD ₃ OD): 2.79 (2H, t, J = 8Hz), 3.68 (2H, dd, J = 8,8Hz), 6.63 (1H, dd, J = 2,8Hz) ), 6.66 (2H, d, J = 9Hz), 6.80 (1H, d, J = 2Hz), 6.92 (1H, d, J = 8Hz), 6.99 (2H, d, J = 9Hz), 7.15 (1H, d, J = 0.5Hz), 7.28 (1H, s), 7.88 (1H, s) ¹³ C-nuclear magnetic resonance spectrum (δ ppm in CD ₃ OD): 34.5 (t), 40.4 (t), 112.2 (d ), 113.4 (d), 116.1 (d), 116.3 (d) × 2, 118.3 (d), 122.2 (s), 122.6 (d), 122.9 (d), 126.5 (s), 128.1 (s), 130.5 (s ), 130.8 (d) × 2.132.8 (s), 132.9 (s), 139.8 (s), 145.9 (s), 146.4 (s), 150.3 (s), 150.4 (s), 156.9 (s), 169.2 (S), 170.0 (s) Example 4 42 mg of the compound obtained in Example 3 was dissolved in 2 ml of acetone,
2 mg of potassium carbonate and 1 ml of methyl iodide were added, and the mixture was heated under reflux for 12 hours. After cooling, leave the reaction mixture in water and wash with ethyl acetate.
Partitioned and extracted with 0 ml. The ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the mixture was subjected to medium-pressure silica gel column chromatography (CIG column, 22 mmφ × 300 mm, Kusano Scientific Co., Ltd.), and n-hexane-ethyl acetate (1 : 1)
The fraction eluted with the mixed solvent of was recrystallized from ethyl acetate to obtain 20 mg of a colorless needle-shaped substance.

The physicochemical properties of this colorless needle-like substance are as shown below, and from these data, 6,7-dimethoxy-4- (3,4
-Dimethoxyphenyl) -N- [2- (4-methoxyphenyl) ethyl] -2,3-naphthalenedicarboxyimide {6,7-Dimethoxy-4- (3,4-dimethoxyphenyl)-
N- [2- (4-methoxyphenyl) ethyl] -2,3-napht
halene dicarboximide} structure.

Melting point: 199 to 200 ° C EI-MS m / z: 527 (M ⁺ ) Proton-Nuclear Magnetic Resonance Spectrum (δ ppm in CDCl ₃ ): 2.90 (2H, d, J = 8Hz), 3.77 (3H, s), 3.80 (3H, s), 3.83 (2H, d, J = 8Hz), 3.88 (3H, s), 4.00 (3H, s), 4.07 (3H, s), 6.81 (2H, d, J = 9Hz), 6.91 (1H, d, J = 2Hz), 6.98 (1H, dd, J) = 2,8Hz), 7.06 (1H, d, J = 8Hz), 7.15 (1H, s), 7.17 (2H, d, J = 9Hz), 7.32 (1H, s), 8.17 (1H, s) ¹³ C -Nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 33.8 (t), 39.6 (t), 55.2 (q), 55.9 (q) x 2, 56.0 (q), 56.2 (q), 107.2 (d), 108.5 (d), 110.9 (d), 113.2 (d), 113.9 (d) × 2, 122.1 (d), 122.4 (d), 122.7 (d), 126.8 (s), 127.2 (s), 129.9 (d ) × 2, 130.4 (s), 131.7 (s), 131.8 (s), 138.2 (s), 148.7 (s), 149.1 (s), 151.5 (s) × 2, 158.3 (s), 167.6 (s), 168.1 (S) Example 5 350 mg of the compound obtained in Example 1 was dissolved in 0.8 ml of dry pyridine, and 3 ml of 48% hydrobromic acid was added, Sealed in Las steel sealed tube was heated for 3 days at 120 ° C.. After cooling, the reaction solution was left in cold water and partitioned and extracted with 200 ml of ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to dryness.

Dissolve 270 mg of the reaction product in 5 ml of acetone and add 2 m of potassium carbonate.
g and 2 ml of methyl iodide were added, and the mixture was heated under reflux for 12 hours. After cooling, the reaction solution was left in water and partitioned and extracted with 100 ml of ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the mixture was subjected to medium-pressure silica gel column chromatography (CIG column, 22 mmφ × 300 mm, Kusano Scientific Co., Ltd.), and n-hexane-ethyl acetate (1 The fraction eluted with the mixed solvent of 1: 1) was recrystallized from acetone to obtain 14 mg of a colorless columnar substance.

The physicochemical properties of this colorless columnar substance are as shown below, and from these data, methyl-6,7-dimethoxy-
4- (3,4-dimethoxyphenyl) -2-naphthoate {Methyl-6,7-dimethoxy-4- (3,4-dimethoxyphen
yl) -2-naphthoate} structure.

Melting point: 180.6 ° C EI-MS m / z: 382 (M ⁺ ) Proton-Nuclear Magnetic Resonance Spectrum (δ ppm in CDCl ₃ ): 3.85 (3H, s), 3.91 (3H, s), 3.96 (3H, s), 3.98 (3H, s), 4.03 (3H, s), 7.01 (1H, d, J = 8Hz), 7.04 (1H, d, J = 2Hz), 7.07 (1H, dd, J = 2.8Hz), 7.27 (1H, s), 7.28 (1H, br s), 7.89 ( 1H, d, J = 2Hz), 8.44 (1H, br d, J = 2Hz) ¹³ C-nuclear magnetic resonance spectrum (δ ppm in CDCl ₃ ): 52.1 (q), 55.9 (q), 56.0 (q) × 2,56.1 (q), 104.8 (d), 107.8 (d), 111.3 (d), 113.2 (d), 122.1 (d), 124.9 (d), 125.4 (s), 128.6 (d), 129.0 (s ), 130.3 (s), 133.2 (s), 138.9 (s), 148.6 (s), 148.9 (s), 149.9 (s), 151.4 (s), 167.5 (s) Example 6 Corn starch 44 g Crystalline cellulose 40 g calcium carboxymethylcellulose 5 g light compounds anhydride obtained in silicic acid 0.5g magnesium stearate 0.5g example 1 10 g total 100 g uniform ~ according to the recipe of the Mixture to give tablets of one tablet 200mg and compression molded at a tableting machine. Each tablet contains 20 mg of the compound obtained in Example 1, and 10 to 25 tablets per day for an adult are divided into several doses.

Example 7 Crystalline cellulose 84.5 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Compound obtained in Example 10 10 g Total 100 g According to the above formulation, a part of and was uniformly mixed, compression molded, and then ground. Then, the remaining amount of and was added and mixed, and the mixture was compression-molded with a tableting machine to obtain 200 mg tablets.

One tablet contains 20 mg of the compound obtained in Example 2, and 10 to 25 tablets daily for an adult are taken in several doses.

Example 8 Crystalline cellulose 49.5 g 10% hydroxypropylcellulose ethanol solution 35
g Carboxymethyl cellulose calcium 5 g Magnesium stearate 0.5 g Compound obtained in Example 10 10 g Total 100 g According to the above prescription, and were uniformly mixed,
The mixture was wetted by a conventional method, granulated by an extrusion granulator, dried and crushed, mixed with each other, and compression-molded with a tableting machine to obtain a tablet of 200 mg per tablet.

20 mg of the compound obtained in Example 3 is contained in one tablet, and 10 to 25 tablets for adults are to be taken in several divided doses per day.

Example 9 Cornstarch 34.5 g Magnesium stearate 50 g Carboxymethylcellulose calcium 5 g Light anhydrous silicic acid 0.5 g Compound obtained in Example 10 10 g Total 100 g According to the above formulation, the After compression molding, it was crushed by a crusher and sieved to obtain granules.

1 g of this granule contains 100 mg of the compound obtained in Example 4, and 2 to 5 g of an adult is taken in several divided doses per day.

Example 10 55 g crystalline cellulose 10% hydroxypropylcellulose ethanol solution 35
g Compound obtained in Example 5 10 g Total 100 g were mixed uniformly according to the above recipe, and the mixture was kneaded. After granulation by an extrusion granulator, the granules were dried and sieved to obtain granules.

1 g of this granule contains 100 mg of the compound obtained in Example 5, and 2 to 5 g of an adult is taken in several divided doses per day.

Example 11 Corn starch 89.5 g Light anhydrous silicic acid 0.5 g Compound obtained in Example 10 10 g Total 100 g According to the above-mentioned formulation, 1 to 3 were uniformly mixed, and 200 mg was filled in a No. 2 capsule.

20 mg of the compound obtained in Example 1 is contained in one capsule of this capsule, and 10 to 25 capsules for an adult are taken in several divided doses per day.

Example 12 Soybean oil 5 g Distilled water for injection 89.5 g Soybean phospholipid 2.5 g Glycerin 2 g Compound obtained in Example 1 1 g Total amount 100 g Dissolved in and according to the above formulation, and added to it. Emulsified to obtain an injection.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location C07C 235/84 9547-4H C07C 235/84 C07D 209/66 C07D 209/66

Claims (3)

(57) [Claims] (1) The following formula I (Wherein A represents an acetyl group or a hydrogen atom). 2. The following formula II (However, B shows a methyl group or a hydrogen atom.) Lignans represented by these. 3. The following formula III The lignan represented by.