JPH05306252A - New macrocarpal and its production - Google Patents

Abstract

PURPOSE:To obtain macrocarpals as new physiologically active substances isolated from an extracted solution of a plant of the genus Eucalyptus with a solvent. CONSTITUTION:Macrocarpals A to F of formula I (R is residue of molecular formula C15H25O), having the following melting points and specific rotatory power [alpha]<20>D, A: 190-200 deg.C; -94.7 (C=0.28 ethanol). B: 196-198 deg.C: -14.0 (C=0.10, methanol). C: 91-94 deg.C; -36.9 (C=1, methanol). D: 132-134 deg.C; -20.2 (C=0.10 methanol). E: 190-192 deg.C; +33.5 (C=0.04, methanol), F: 123-125 deg.C; +70.0 (C=0.10, methanol). Macrocarpal A is shown by formula II, has inhibitory activity against aldose reductase and antimicrobial activity. Macrocarpal B is a steric isomer of macrocarpal A and macrocarpal D is shown by formula III. A plant of the genus Eucalyptus is extracted with a solvent (preferably hydrous acetone) and each of macrocarpals is separated and collected from the prepared extract by a well-known separation method.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel macrocarpals and a method for producing the same.

[0002]

2. Description of the Related Art Eucalyptus plants are tall trees native to Australia and New Zealand and are cultivated in various parts of Japan. The essential oil (eucalyptus oil) obtained from the leaves has a refreshing sensation and is used as a medicinal agent for nasal catarrhals and bronchial catarrhs, as well as for poultices, toothpaste, and insect prevention. In addition, this plant is characterized by an extremely fast growth rate and is suitable for substance production. However, the macrocarpal of the present invention is a novel substance, and it is not yet known that this substance exists in Eucalyptus plants, and naturally its manufacturing method is not known.

[0003]

[Means for Solving the Problems] The present inventors isolated a physiologically active substance more effective than an eucalyptus extract, determined its partial chemical structure, named it macrocarpars, and completed the present invention. I arrived. That is, the present invention has novel macrocarpars having the following characteristics and pharmaceutically acceptable salts thereof, having the following structural formula:

[0004]

[Chemical 2] [In the formula, R represents a residue represented by a molecular formula C ₁₅ H ₂₅ O. 〕And

It has one physicochemical property selected from the following groups a to f: melting point 198 to 200 ° C. specific optical rotation

[0006]

[Equation 7]

Ultraviolet absorption spectrum (in ethanol) 27
5 (32000), 393 (13000) ¹ H-NMR spectrum δ (ppm) 10.07 (2H, s) -CHO 3.47 (1H, dd, J = 4.2,12.7) 2.29 (1H, td, J = 3.7,12.7) 2.01 (1H, m) 1.92 ~ 1.31 (6H, m) 1.31 ~ 1.14 (2H, m) 1.10 (6H, s) ≡C-CH ₃ 1.09 (3H, s) ≡ C-CH ₃ 0.85-1.07 (3H, m) 0.80 (3H, d, J = 2.4) = CH-CH ₃ 0.78 (3H, d) , J = 2.7) = CH-CH ₃ 0.69 (3H, s) ≡C-CH ₃ 0.45 to 0.65 (2H, m) three-membered ring

¹³ C-NMR spectrum M δ (ppm) d 193.94-CHO d 193.78-CHO s 171.74 benzene ring s 171.12 benzene ring s 169.71 benzene ring s 112.36 benzene ring s 107.02 benzene ring s 106.96 benzene ring s 77.21 -OC-d 59.04 s 51.07 d 50.88 t 45.91 d 42.82 t 41.51 t 37.48 d 31 .46 q 30.12 d 28.98 d 27.93 t 25.99 q 25.74 q 22.57 t 22.17 q 20.95 s 20.95 three-membered ring q 19.10.10 q 18.24 * M: Multiplicity (s = C, d = CH, t = CH ₂ , q = CH ₃ , DEPT method. The same applies hereinafter)

B: melting point 196-198 ° C. specific rotation

[0010]

[Equation 8]

Ultraviolet absorption spectrum (in ethanol) 27
6 (45000), 392 (7300) ¹ H-NMR spectrum δ (ppm) 10.01 (1H, s) -CHO 100.00 (1H, s) -CHO 3.25 (1H) 2.32 (1H, td, J = 3.4,13.0) 1.96 (1H, td, J = 6.6,9.7) 1.80-1.46 (5H, m) 1.46-1.08 (4H, m) 1.13 ( 6H, s) ≡C-CH ₃ 1.01 (3H, s) ≡C-CH ₃ 0.99 (3H, s) = CH-CH ₃ 0.91 (2H, m) 0.76 (3H, d , J = 6.3) = CH-CH ₃ 0.70 (3H, d, J = 6.3) ≡C-CH ₃ 0.62 to 0.43 (2H, m) 3-membered ring

¹³ C-NMR spectrum M δ (ppm) d 193.94-CHO d 193.78-CHO s 171.74 benzene ring s 171.12 benzene ring s 169.71 benzene ring s 112.36 benzene ring s 107.02 benzene ring s 106.96 benzene ring s 77.21 -OC-d 59.04 s 51.07 d 50.88 t 45.91 d 42.82 t 41.51 t 37.48 d 31 .46 q 30.12 d 28.98 d 27.93 t 25.99 q 25.74 q 22.57 t 22.17 q 20.95 s 20.95 three-membered ring q 19.10.10 q 18.24

C: melting point 91 to 94 ° C. specific rotation

[0014]

[Equation 9]

Ultraviolet absorption spectrum (in ethanol) 27
6 (26000), 390 (4000) ¹ H-NMR spectrum δ (ppm) 10.03 (2H, s) -CHO 5.48 (1H, slike) C = C-H 3.01 (1H, m) 2 .30 to 1.85 (5H, m) 1.80 to 1.45 (5H, m) 1.35 to 0.90 (5H, m) 1.15 (3H, s) ≡C-CH ₃ 1. 08 (3H, s) ≡C-CH ₃ 1.04 (3H, s) ≡C-CH ₃ 0.80 (3H, d) = CH-CH ₃ 0.75 (3H, d) = CH-CH ₃ 0.68 (3H, d) = CH -CH 3

¹³ C-NMR spectrum M δ (ppm) d 193.2-CHO d 192.9-CHO s 171.5 benzene ring s 171.2 benzene ring s 169.4 benzene ring s 156.6 = C d 124.7 = C s 110.0 benzene ring s 106.5 benzene ring s 106.2 benzene ring s 74.4 -O-C≡ d 54.4 s 53.2 d 43.0 t 38.7 d 38 .1 t 37.7 d 37.7 t 35.7 t 29.7 d 28.0 t 27.7 q 27.6 q 26.7 q 25.0 q 24.6 q 22.0 q 18.0

D: melting point 132-134 ° C. specific rotation

[0018]

[Equation 10]

Ultraviolet absorption spectrum (in ethanol) 27
7 (26000), 350 (2300) ¹ H-NMR spectrum δ (ppm) 10.07 (2H, s) -CHO 5.64 (1H, s) C = C-H 3.54 (1H, dd, J = 4.3,12.9) 2.93 (1H, m) 2.34 (1H, td, J = 4.3,12.1) 2.27 to 1.95 (4H, m) 1.82 (1H, br.d) 1 0.75 to 1.15 (7H, m) 1.16 (3H, s) ≡C-CH ₃ 1.10 (3H, s) ≡C-CH ₃ 0.92 (3H, d, J = 7.0) = CH-CH ₃ 0.89 (3H, s) ≡ C-CH ₃ 0.80 (3H, d, J = 6.2) = CH-CH ₃ 0.77 (3H, d, J = 6.2) = CH-CH ₃

¹³ C-NMR spectrum M δ (ppm) d 193.8-CHO d 193.8-CHO s 172.2 benzene ring s 172.1 benzene ring s 171.0 benzene ring s 154.2 = C d 123.3 = C s 110.4 benzene ring s 107.4 benzene ring s 107.3 benzene ring s 75.3 -O-C≡ s 74.2 d 53.1 d 47.8 d 42.2 t 37 .2 t 37.2 t 36.8 d 36.1 t 30.8 d 28.9 t 28.7 q 28.3 q 28.3 q 27.5 q 25.7 q 22.9 q 19.4

E: melting point 190 to 192 ° C. specific optical rotation

[0022]

[Equation 11]

Ultraviolet absorption spectrum (in ethanol) 27
7 (27000), 350 (5900) ¹ H-NMR spectrum δ (ppm) 10.08 (2H, s) -CHO 5.44 (1H, dlike) C = C-H 3.50 (1H, m) 2 .50 to 2.20 (2H, m) 2.05 (1H, brs) 1.90 to 1.12 (11H, m) 1.17 (6H, s) ≡C-CH ₃ 1.10 (3H, s) ≡C-CH ₃ 1.05 (3H, d, J = 7.9) ≡C-CH ₃ 0.83 (3H, d, J = 7.0) ＝ CH-CH ₃ 0.79 (3H, d, J) = 7.2) = CH-CH ₃

¹³ C-NMR spectrum M δ (ppm) d 193.86-CHO d 193.68-CHO s 172.23 benzene ring s 170.86 benzene ring s 168.84 benzene ring s 153.35 = C d 123.42 = C s 111.53 Benzene ring s 107.44 Benzene ring s 107.34 Benzene ring s 75.00-O-C≡d 53.30 d 48.009 t 45.71 d 41.81 s 41 .72 t 38.79 t 36.12 d 34.09 d 29.04 q 28.25 q 28.00 q 25.35 q 24.72 t 24.01 q 23.77 q 22.83 t 22.08

F: melting point 123 to 125 ° C. specific rotation

[0026]

[Equation 12]

Ultraviolet absorption spectrum (in ethanol) 27
7 (13000), 373 (4600) ¹ H-NMR spectrum δ (ppm) 10.07 (2H, s) -CHO 5.41 (1H, d, J = 3.6) C = C-H 3.3 (1H ) 2.43 (1H, m) 2.15 to 1.90 (3H, m) 1.85 to 1.20 (10H, m) 1.15 (3H, d, J = 8.4) = CH-CH ₃ 1.14 (3H, s) ≡C-CH ₃ 1.06 (3H, s) ≡C-CH ₃ 1.04 (3H, s) ≡C-CH ₃ 0.92 (3H, d, J = 5.8 ) = CH-CH ₃ 0.79 (3H, d, J = 6.0) = CH-CH ₃

¹³ C-NMR spectrum M δ (ppm) d 193.58-CHO d 193.51 -CHO s 173.24 Benzene ring s 170.50 Benzene ring s 170.26 Benzene ring s 153.22 = C d 123.64 = C s 114.72 benzene ring s 108.34 benzene ring s 107.68 benzene ring s 75.10 -O-C≡ d 53.98 d 47.48 d 41.84 s 41.56 t 41 .12 t 37.53 t 35.98 d 32.19 d 28.55 q 28.23 q 28.13 q 25.83 q 23.87 q 23.41 q 23.24 t 22.47 t 21.74 And a method for producing the same.

As a result of comparing the partial chemical structural formulas, physicochemical properties and biological properties described later of the above-described macrocarpals of the present invention with those of existing compounds, there is no known compound, It can be seen that pearls are novel bioactive substances. The method for producing macrocarpals according to the present invention is characterized by collecting from a Eucalyptus plant containing macrocarpals.

Any Eucalyptus plant can be used in the present invention as long as it contains Macrocarpals. The macrocarpals are obtained by extracting from Eucalyptus plants and collecting from the extract. The extraction material can be any part of the Eucalyptus plant, but especially leaves. The reason is that the leaves have a higher content of macrocarpals than other parts and are easy to handle. Further, these may be fresh materials or dried products, and may be subjected to treatment such as grinding. In the examples, an example was described in which macrocalpars were extracted from the leaves of Eucalyptus macrocarpa.

As the extraction method used in the present invention, any known method used for extracting plant components can be adopted. For example, eucalyptus leaves may be soaked in a solvent at 10 to 30 ° C. for about 5 hours to 1 week, or about 30 to
You may extract for about 1 to 12 hours, heating at about 60 degreeC.

The solvent used for extraction is, for example, n
Hydrocarbons such as hexane and cyclohexane, ethers such as ethyl ether and isopropyl ether, ketones such as acetone and methyl ethyl ketone, and halogenated carbons such as dichloromethane and chloroform. Macrocalpearls can be efficiently extracted by using these solvents. Especially, water-containing acetone is preferable.

The extract thus obtained may be concentrated under reduced pressure by a conventional method to give a thick extract. This extract may be subjected to solvent fractionation by a conventional method. In order to separate and collect each of the macrocarpars from these extracts, known separation methods such as column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC) and the like can be used. As a packing material for chromatography, silica gel, alumina, cellulose, dextran, polyamide resin, chemically bonded silica gel (octadecylsilane, n-octylsilane, etc.) and the like can be used. As the solvent used for chromatography, a single solvent may be used, or a plurality of solvents may be mixed and used. The type of organic solvent varies depending on the type of chromatography used, but in the case of silica gel chromatography, for example, n-hexane, benzene, ethyl ether, chloroform, methanol, acetic acid and the like can be mentioned. Above all, a mixed solvent of chloroform-methanol and chloroform-acetic acid is preferable. Sephad
In the case of gel filtration chromatography such as ex LH-20 (trade name), methanol or the like is preferable as the solvent. In the case of chemically bonded silica gel, acetonitrile, methanol, etc. are desirable. After increasing the purity in this way, each of the macrocarpars can be crystallized from the concentrated liquid.

One of the thus obtained macrocarpars, which has the above-mentioned physicochemical properties of a (hereinafter referred to as macrocarpal A), has the following physicochemical properties. ..

1) Elemental analysis value: Consists of carbon, hydrogen and oxygen, and does not contain nitrogen, phosphorus, sulfur and halogen. Examples of elemental analysis values of this substance are as follows. C 70.76%, H 8.58% 2) Melting point: 198-200 ° C 3) Molecular weight: 472 That is, in the negative FAB mass analysis, a pseudo molecular ion peak at m / z 471 (M-1) is observed. 4) Specific rotation:

[0036]

[Equation 13]

5) Ultraviolet absorption spectrum: As shown in FIG. 6) Infrared absorption spectrum: As shown in FIG. 7) Hydrogen nuclear magnetic resonance spectrum: as shown in FIG. 8) Solubility in solvent: Soluble in ethyl ether, chloroform, dichloromethane, ethyl acetate, ethanol, methanol, but insoluble in water. 9) Distinction between basic, acidic and neutral: It is an acidic substance. 10) Color of substance: colorless 11) Rf value: Rf value when silica gel thin layer chromatography (manufactured by Merck & Co., TLC aluminum plate thickness 0.2 mm, Kieselgel 60F ₂₅₄ ) is carried out by a conventional method. is there. The detection was carried out by coloring with sulfuric acid. 1) Chloroform: methanol (3: 1) Rf = 0.242 2) Chloroform: acetic acid (20: 1) Rf = 0.28 12) Color reaction: ferric chloride reaction, 2,4-dinitrophenylhydrazine reaction , Ninhydrin reaction, Rydon-Smith reaction, Dragendorff reaction negative. 13) Shape of substance: tabular crystal 14) Crystallographic property: monoclinic system, P2 ₁

From the above physicochemical properties, C ₂₉ H ₄₂ O ₅ is most suitable as the molecular formula of the physiologically active substance Macrocarpal A. As a result of an X-ray crystallographic analysis of the physiologically active substance Macrocalpearl A, the chemical structure of this substance was determined as shown in the following structural formula.

[0039]

[Chemical 3]

Table 1 shows more detailed physicochemical properties of the above-mentioned compounds having physicochemical properties b to f (hereinafter referred to as macrocarpars B to F, respectively).

[0041]

[Table 1]

From the above physicochemical properties, it is presumed that Macrocarpearl B is a stereoisomer of Macrocarpearl A and Macrocarpearl D has the following chemical structure.

[0043]

[Chemical 4]

Specific examples of the salts of macrocarpals of the present invention include inorganic salts with hydrochloric acid, sulfuric acid, phosphoric acid and the like as acid addition salts or acetic acid, lactic acid, propionic acid, maleic acid, oleic acid, palmitic acid, Citric acid, succinic acid,
Organic acid salts with tartaric acid, fumaric acid, glutamic acid, pantothenic acid, lauryl sulfonic acid and the like can be mentioned.

[Action] The biological properties of Macrocarpal A are as follows. Macrocarpal A has aldose reductase inhibitory activity and antibacterial activity. 1) Aldose reductase inhibitory activity The aldose reductase inhibitory activity value of Macrocal Pearl A is shown below. Preparation of Enzyme Solution The aldose reductase enzyme preparation was prepared from the porcine lens by the method of S. Hayman et al. (Journal of Bio
logical Chemistry, 240, 877-882, 1965). That is, the porcine lens cryopreserved (-80 ° C) was homogenized with distilled water and centrifuged at 10,000 g for 15 minutes. The supernatant was used as a 40% ammonium sulfate solution, and the supernatant obtained by centrifugation at 10,000 g for 10 minutes was added with 0.05 M Na
The dialyzed solution dialyzed overnight in a Cl solution was used as an enzyme preparation.

Activity measurement method The activity of aldose reductase was measured by the method of Hyman et al. (Supra). That is, final concentration 0.4 M lithium sulfate, 0.1 mM NADPH (reduced nicotina
800 μl of 40 mM phosphate buffer solution (pH 6.2) prepared so as to contain mide adenine dinucleotide phosphate) and 3 mM dl-glyceraldehyde as a substrate.
To the above, 100 μl of the above enzyme solution and 100 μl of a drug solution prepared by dissolving compounds of various concentrations in 1% DMSO were added, and the change in absorbance at 340 nm at 25 ° C. for 2 minutes was measured by a spectrophotometer (Hitachi: U- 3200). Further, the amount of change in absorbance when 1% DMSO was added instead of the drug solution was set to 100%, and the result is shown in Table 2 as a 50% inhibitory concentration (IC ₅₀ ).

[0047]

[Table 2]

Thus, it was found that Macrocarpal A has an aldose reductase inhibitory activity,
For example, it is valuable as a drug for therapeutic treatment of diabetic complications such as cataract, neuropathy, retinopathy, and renal disorder, particularly cataract and neuropathy.

2) Antibacterial Activity Next, the antibacterial activity of macrocarpals will be described.
The minimum inhibitory concentration (MIC) by the agar dilution method is 3rd
As shown in the table.

[0050]

[Table 3]

By selectively acting on Gram-positive bacteria, macrocarpars can be used for treating and preventing diseases caused by these bacteria. In addition, since this substance is extracted from Eucalyptus plants, it can be used as a preservative for foods.

When the macrocarpars of the present invention or a pharmaceutically acceptable salt thereof is used as an aldose reductase inhibitor, it is mixed with an appropriate pharmacologically acceptable carrier, excipient or diluent and powdered. , Granules, tablets, capsules,
It can be administered orally or parenterally in the form of an injection or the like, and when used as a therapeutic agent for cataract, it can be used as an eye drop or an eye ointment.

The dose varies depending on the kind of compound, administration route, symptoms, age of the patient, body weight, etc., but when administered orally to an adult diabetic patient, the daily dose is about 500 to 10,000 mg, This amount is preferably divided into 1 to 3 times a day. When used as an eye drop, it is desirable to administer a single dose to a few drops 3 to 5 times a day as an eye drop or a suspension containing the active ingredient in an amount of about 0.05 to 10%. In the case of an ophthalmic ointment, the active ingredient is mixed in a commonly used ophthalmic ointment base in an amount of about 0.05 to 10% to prepare a formulation, which is administered 1 to 4 times daily depending on the symptom.

[0054]

EXAMPLE Next, an example of the physiologically active substance macrocarpal A will be shown, but this example is merely an example and does not limit the present invention. That is, it goes without saying that many modification or modification means not exemplified here can be used. Example 1 Eucalyptus macrocarp
The fresh leaf (2880 g) of a) was freeze-dried to obtain 1110 g of dried leaf. This was extracted three times with 80% acetone water (11 liters). After concentrating the second and third extracts under reduced pressure,
The solvent was fractionated with ethyl acetate. That is, p
After adjusting to H3, the mixture was extracted with ethyl acetate (2 liters) three times. The ethyl acetate layer was washed with a 5% aqueous sodium hydrogen carbonate solution having a pH of 9 and further with sodium hydroxide to give a pH of 12
It was washed with a 5% aqueous sodium hydrogen carbonate solution adjusted to.
The ethyl acetate layer (neutral fraction) was dehydrated with anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 30 g of a crude paste. This was washed with hexane and loaded on a silica gel (Merck, 250 g) column (4.6φ × 33 cm) equilibrated with chloroform / methanol (10: 1) in three portions.
Chloroform / methanol (10: 1) 2,500 ml and then chloroform / methanol (5: 1) 2,500 ml were flown, and then the active fraction was eluted with chloroform / methanol (2: 1) 810 ml. Collect three active fractions obtained,
After concentration under reduced pressure, the residue was suction-dried with a vacuum pump to obtain 2.23 g of a crude active substance containing all of Macrocarpal AF.

This active fraction was subjected to Se equilibration with methanol.
phadex LH-20 (trade name, made by Pharmacia, 75g: 2.6
φ × 52 cm) column was loaded. Develop with methanol 3
00 drops were collected. The active fraction (fraction No. 17-38) obtained here was concentrated under reduced pressure and then suction-dried with a vacuum pump to obtain 353 mg of a crudely purified product. Next, this was loaded onto a silica gel (Merck, 30 g: 2φ × 21 cm) column that had been previously filled with chloroform / acetic acid (200: 1), developed with 400 ml of chloroform / acetic acid (200: 1), and the eluent Was collected in 300 drops. The active fraction (fraction No. 13-29) obtained here was concentrated under reduced pressure, and the precipitated crystals were collected and recrystallized from methanol to obtain 47 mg of colorless plate crystals of macrocarpal A.

Fraction N of the above active fractions
Crystals of macrocarpal BF were obtained in the same manner for those having different o.

[0057]

INDUSTRIAL APPLICABILITY The novel physiologically active substance macrocarpars of the present invention, particularly macrocarpal A, exhibits aldose reductase inhibitory activity and antibacterial activity as described above, and thus is useful as an aldose reductase inhibitor and an antibacterial agent. is there.

[Brief description of drawings]

FIG. 1 is an ultraviolet absorption spectrum of a physiologically active substance, Macrocarpar A, measured in ethanol.

FIG. 2 is an infrared absorption spectrum of the physiologically active substance macrocarpal A measured in potassium bromide.

FIG. 3 is a hydrogen nuclear magnetic resonance spectrum of the physiologically active substance Macrocarpar A measured in deuterated chloroform.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display part A61K 31/11 AED 8413-4C 35/78 ADZ C 7180-4C (72) Inventor Yoshiko Hori Saitama Prefecture 8-37 Hanakage-cho, Sakado City (72) Inventor Hiroshi Aida 2-16-5 Negishi, Urawa City, Saitama Prefecture (72) Inventor Yoshifumi Arai 10 Okameka, Yaizu City, Shizuoka Prefecture Sapporo Lobby Co., Ltd. 72) Inventor Yoshiyuki Nakamura, 10 Okameka, Yaizu City, Shizuoka Prefecture, Sapporo Pharma Co., Ltd. (72) Inventor, Nobuhiro Watanabe 10 Okameka, Yaizu City, Shizuoka Prefecture, Sapporo Pharma Co., Ltd.

Claims (3)

[Claims] 1. A novel macrocarpal compound having the following characteristics and a pharmaceutically acceptable salt thereof. It has the following structural formula: ## STR1 ## wherein R represents a residue represented by the molecular formula C ₁₅ H ₂₅ O. ] And has one physicochemical property selected from the following groups a to a: Melting point 198 to 200 ° C. Specific optical rotation ## EQU1 ## Ultraviolet absorption spectrum (in ethanol) 275 (32)
000), 393 (13000) ¹ H-NMR spectrum δ (ppm) 10.07 (2H, s) -CHO 3.47 (1H, dd, J = 4.2,12.7) 2.29 (1H, td, J = 3.7,12.7) 2.01 (1H, m) 1.92 to 1.31 (6H, m) 1.31 to 1.14 (2H, m) 1.10 (6H, s) ≡C-CH ₃ 1 0.09 (3H, s) ≡ C-CH ₃ 0.85-1.07 (3H, m) 0.80 (3H, d, J = 2.4) = CH-CH ₃ 0.78 (3H, d, J = 2.7) = CH-CH ₃ 0.69 (3H, s) ≡C-CH ₃ 0.45 to 0.65 (2H, m) Three-membered ring ¹³ C-NMR spectrum M δ (ppm) d 193.94 -CHO d 193.78 -CHO s 171.74 Benzene ring s 171.12 Benzene ring s 169.71 Benzene ring s 112.36 Benzene ring s 107.02 Benzene ring s 106.96 Benzene ring s 77.21 -O -C≡d 59.04 s 51.07 d 50.88 t 45.91 d 42.82 t 41.51 t 37.48 d 31.46 q 30.12 d 28.98 d 27.93 t 25. 99 q 25.74 q 22.57 t 22.17 q 20.95 s 20.95 three-membered ring q 19.10.10 q 18.24 * M: multiplicity (s = C, d = CH, t = CH ₂ , q = CH ₃ , DEPT method) b: Melting point 196-198 ° C Specific optical rotation [Equation 2] UV absorption spectrum (in ethanol) 276 (45)
000), 392 (7300) ¹ H-NMR spectrum δ (ppm) 10.01 (1H, s) -CHO 100.00 (1H, s) -CHO 3.25 (1H) 2.32 (1H, td, J = 3.4,13.0) 1.96 (1H, td, J = 6.6,9.7) 1.80-1.46 (5H, m) 1.46-1.08 (4H, m) 1.13 (6H, s) ≡C-CH ₃ 1.01 (3H, s) ≡C-CH ₃ 0.99 (3H, s) = CH-CH ₃ 0.91 (2H, m) 0.76 (3H, d, J = 6.3) = CH-CH ₃ 0.70 (3H, d, J = 6.3) ≡C-CH ₃ 0.62 to 0.43 (2H, m) Three-membered ring ¹³ C-NMR spectrum M δ (ppm) d 193.94-CHO d 193.78-CHO s 171.74 benzene ring s 171.12 benzene ring s 169.71 benzene ring s 112.36 benzene ring s 107.02 benzene ring s 106.96 benzene ring s 777 .21 -O-C≡ d 59.04 s 51.07 d 50.88 t 45.91 d 42.82 t 41.51 t 37.48 d 31.46 q 30.12 d 28.98 d 27. 93 t 25.99 q 25.74 q 22.57 t 22.17 q 20.95 s 20.95 three-membered ring q 19.10.10 q 18.24 c: Point 91 to 94 ° C. Specific rotation [Number 3] UV absorption spectrum (in ethanol) 276 (26
000), 390 (4000) ¹ H-NMR spectrum δ (ppm) 10.03 (2H, s) -CHO 5.48 (1H, slike) C = C-H 3.01 (1H, m) 2.30 ~ 1.85 (5H, m) 1.80 ~ 1.45 (5H, m) 1.35 ~ 0.90 (5H, m) 1.15 (3H, s) ≡C-CH ₃ 1.08 ( 3H, s) ≡C-CH ₃ 1.04 (3H, s) ≡C-CH ₃ 0.80 (3H, d) = CH-CH ₃ 0.75 (3H, d) = CH-CH ₃ 0. 68 (3H, d) = CH—CH ₃ ¹³ C-NMR spectrum M δ (ppm) d 193.2-CHO d 192.9-CHO s 171.5 benzene ring s 171.2 benzene ring s 169.4 benzene Ring s 156.6 = C d 124.7 = C s 110.0 Benzene ring s 106.5 Benzene ring s 106.2 Benzene ring s 74.4 -O-C≡ d 54.4 s 53.2 d 43 .0 t 38.7 d 38.1 t 37.7 d 37.7 t 35.7 t 29.7 d 28.0 t 27.7 q 27.6 q 26.7 q 25.0 q 24.6 q 22.0 q 18.0 d: Melting point 132-134 ° C Specific optical rotation [Equation 4] UV absorption spectrum (in ethanol) 277 (26
000), 350 (2300) ¹ H-NMR spectrum δ (ppm) 10.07 (2H, s) -CHO 5.64 (1H, s) C═C−H 3.54 (1H, dd, J = 4.3 , 12.9) 2.93 (1H, m) 2.34 (1H, td, J = 4.3,12.1) 2.27 to 1.95 (4H, m) 1.82 (1H, br.d) 1.75 ~ 1.15 (7H, m) 1.16 (3H, s) ≡C-CH ₃ 1.10 (3H, s) ≡C-CH ₃ 0.92 (3H, d, J = 7.0) = CH- CH ₃ 0.89 (3H, s) ≡ C-CH ₃ 0.80 (3H, d, J = 6.2) = CH-CH ₃ 0.77 (3H, d, J = 6.2) = CH-CH ₃ ¹³ C-NMR spectrum M δ (ppm) d 193.8-CHO d 193.8-CHO s 172.2 benzene ring s 172.1 benzene ring s 171.0 benzene ring s 154.2 = C d 123.3 = Cs 110.4 benzene ring s 107.4 benzene ring s 107.3 benzene ring s 75.3 -O-C≡ s 74.2 d 53.1 d 47.8 d 42.2 t 37.2 t 37 .2 t 36.8 d 36.1 t 30.8 d 28.9 t 28.7 q 28.3 q 28.3 q 27.5 q 25.7 q 22.9 q 19.4 e: melting point 190 〜192 ℃ Specific rotation [Equation 5] UV Osamu spectrum (in ethanol) 277 (27
000), 350 (5900) ¹ H-NMR spectrum δ (ppm) 10.08 (2H, s) -CHO 5.44 (1H, dlike) C═C−H 3.50 (1H, m) 2.50 ~ 2.20 (2H, m) 2.05 (1H, brs) 1.90 ~ 1.12 (11H, m) 1.17 (6H, s) ≡ C-CH ₃ 1.10 (3H, s) ≡C-CH ₃ 1.05 (3H, d, J = 7.9) ≡C-CH ₃ 0.83 (3H, d, J = 7.0) ＝ CH-CH ₃ 0.79 (3H, d, J = 7.2) ) = CH-CH ₃ ¹³ C-NMR spectrum M δ (ppm) d 193.86-CHO d 193.68-CHO s 172.23 benzene ring s 170.86 benzene ring s 168.84 benzene ring s 153.35. = C d 123.42 = C s 111.53 Benzene ring s 107.44 Benzene ring s 107.34 Benzene ring s 75.00 -O-C≡d 53.30 d 48.009 t 45.71 d 41. 81 s 41.72 t 38.79 t 36.12 d 34.09 d 29.04 q 28.25 q 28.00 q 25.35 q 24.72 t 24.01 q 23.77 q 22.83 t 22.08 f: melting point 123 to 125 ° C. specific rotation [Equation 6] External absorption spectrum (in ethanol) 277 (13
000), 373 (4600) ¹ H-NMR spectrum δ (ppm) 10.07 (2H, s) -CHO 5.41 (1H, d, J = 3.6) C = C-H 3.3 (1H) 2 .43 (1H, m) 2.15 to 1.90 (3H, m) 1.85 to 1.20 (10H, m) 1.15 (3H, d, J = 8.4) = CH-CH ₃ 1. 14 (3H, s) ≡C-CH ₃ 1.06 (3H, s) ≡C-CH ₃ 1.04 (3H, s) ≡C-CH ₃ 0.92 (3H, d, J = 5.8) = _{CH-CH 3 0.79 (3H,} d, J = 6.0) = CH-CH 3 13 C-NMR spectrum M δ (ppm) d 193.58 -CHO d 193.51 -CHO s 173.24 benzene ring s 170.50 benzene ring s 170.26 benzene ring s 153.22 = Cd 123.64 = C s 114.72 benzene ring s 108.34 benzene ring s 107.68 benzene ring s 75.10 -O-C≡ d 53.98 d 47.48 d 41.84 s 41.56 t 41.12 t 37.53 t 35.98 d 32.19 d 28.55 q 28.23 q 28.13 q 25.83 q 23 .87 q 23.41 q 23.24 t 22.47 t 21.74 2. The Eucalyptus plant is extracted with a solvent, and the macrocarpals according to claim 1 are collected from the extract, and the macrocarpals according to claim 1 and pharmaceutically acceptable thereof. Of producing salt. 3. The method for producing macrocal pearls and a pharmaceutically acceptable salt thereof according to claim 2, wherein the Eucalyptus plant is Eucalyptus macrocarpa.