JP2003073315A - Anti-inflammatory vegetable ingredients - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition manifesting an excellent effect by using a compound or a fraction having excellent anti-inflammatory effect obtained from vegetables which have been used in traditional medical treatment. SOLUTION: This composition manifesting excellent anti-inflammatory effect is obtained by formulating a new compound R-(-)-7-phenyl-hepta-4,6-diyn-2-ol which has anti-inflammatory effect, separated from vegetables belonging to Bidens genus or the vegetable belonging to Bidens genus including the compound, especially formulating Bidens pilosa or its extract.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a plant-derived useful ingredient having excellent anti-inflammatory properties and low cytotoxicity.

[0002]

2. Prior Art and Problems to be Solved by the Invention
In bone fractures, various internal organ diseases, etc., inflammation is often accompanied as a biological defense reaction regardless of the presence or absence of infection. Inflammation is accompanied by fever, swelling, and pain, and quenching inflammation has been an important medical tool in ancient times and in modern times. Although there are various steroid compounds such as cortisone and various non-steroidal anti-inflammatory drugs starting with aspirin as anti-inflammatory drugs, they all have fairly strong side effects, and the ideal anti-inflammatory drug is still in the human hands. The reality is that it is not included.

[0003] The present invention, from the plants that have been widely used as a folk medicine in the treatment of ancient various inflammatory diseases, a plant which is extremely excellent in high safety anti-inflammatory effects Biden
Since the components considered to be major anti-inflammatory agents of spirosa can be newly separated, it is intended to provide an oral anti-inflammatory agent having a mild action, which contains the present compound.

[0004]

The compound of the present invention is a novel compound not found in the literature, which was discovered from Bidens pilosa, a plant of the genus Sengangusa, belonging to the Asteraceae family. Biden
s Asteraceae Bidens plant, which is represented by pilosa, as described in detail in Japanese Patent Application No. 2000-105559,
Since there are many varieties because they cross with each other over a wide variety of species, botany is also confusing, and scientific names, Japanese names, Chinese names are also difficult to identify because they correspond to each other, but in the present invention The plants of the genus Sengangusa used include those listed below.

Bidens pilosa L. (Kosendangsa, Koshironosendangsa, Kama Toyokusa) Bidens pilosa L. var. minor
(Blume) Sherff
Bidens pilosa L. var. biset
osa Ohtani et Suzuki ( Ayuyukisen Dangusa) Bidens pilosa L. f. decumbe
ns Scherff Bidens pilosa L. var. radia
ta Scherff (May contain Tachiawa Yukisen Dangusa, Hiawayu Yukisen Dangusa) Bidens pilosa L. var. radia
ta Schultz Bipontinus (Shironosen Dangusa, Scutellaria baicalensis) Bidens biternata Lour. Mer
roll et Scherff Bidens bipinnata L. (Kobano Sengakusa, Sengakusa) Bidens cernua
L. (Willow Taukogi) Bidens frontosa L. (Bidens frondosa, Say Takata Acanthopanax) Bidens parviflora Willd (e buckwheat Roh Bidens) Bidens radiata Thuill. va
r. pinnatifida (Turcz.) Kit
amura (Ezonotaucogi) Bidens tripartita L. (Taukogi)

[0006] This plant is mainly referred to as Hamofusa in China / Taiwan, but it has many synonyms. It is also known as Dojisou, Oni Needle grass, Mitsui Oni grass, Trifoliat needle grass, Stab needle grass, Born needle grass, White flower There are names such as 蝦 箝 草, 腦 草, 绖 脤, Akasai, Kingokubanban, Fukaso, Minamifusa, 蝦 Kosashi, and Kazuko, and which scientific name each corresponds to. Not clear.

The flower has a shape peculiar to the Asteraceae, and several tongue-shaped flowers such as white or yellow rounded petals, and a large number of yellow-brown tubular flowers gather in the center. Some lack the tongue-shaped flower. The stem is square and has knots colored light purple. The leaves, which are divided into three or five feathers, have a handle, and are often opposite to each other with jagged edges.

In Japan, it is found south of the warm regions of Honshu, in Taiwan,
Distributed in China and other tropical regions of the world, the plant height is 25 cm ~
It is about 1 m long and usually winters if it is an annual plant, but if it is blessed with mild climate conditions, the flowers bloom one after another all year round. There are needles with barbs on the top of black-brown seeds that are carried along with the clothes of animals and humans, and the number of needles is often not constant due to mating.
In China, it is called the Onirushusa genus.

Plants of the genus Spendanga , especially bidens
Since ancient times, pilosa has been widely used in the tropical and temperate regions of Africa, Latin America, Asia, etc. for the treatment of diabetes, inflammatory diseases, digestive diseases, infectious diseases, rheumatism, etc. . For example, in Taiwan, it is widely used for acute and chronic appendicitis, nephritis, gastroenteritis, diarrhea, influenza, pharyngitis, toothache, hepatitis, and duodenitis, and is said to have a protective effect on the liver. In Africa, wound healing and severe emesis
It has been used for stomachache, constipation, intestinal parasite, dysentery, diarrhea, abdominal pain, etc. Leaf juice is said to be used for burns, conjunctivitis, otitis, and even hemostatic agents. It is said that ground soup and root dishes are effective against malaria, and the Zulu tribe chews the shoots and uses them as rheumatic drugs. In China, it is used for enteritis, bacillary dysentery, and pharyngitis, and the plant is crushed or decocted to be used for wound healing and chronic ulcers. On the islands of Central America, juice is used as an eye drop, on ulcers in Venezuela and Brazil, and in the Andes of Bolivia to lower blood pressure. It is also used to promote diuresis, biliary secretion, and antipyretic rubella and pyorax.

The inventors of the present invention have obtained the TPA for the extract of this plant.
(12-O-tetradecanoylphorbo
1-13-acetate) -induced mouse ear edema inhibition test was performed, and an inhibitory effect comparable to that of indomethacin used as a control was observed. Therefore, isolation and purification of an anti-inflammatory agent of this plant was attempted, and its action was investigated. It was possible to obtain the compounds which are considered to be representative. The process will be described below.

[0011]

[Experiment 1] Mouse ear edema inhibition test 7 kg of dried above ground parts of Bidens pilosa were extracted with 80 L of ethyl acetate, and the extract was concentrated and dried to obtain 14
9 g of extract (A) was obtained. The residue is methanol 20
It was extracted with L, and the extract was concentrated and dried to obtain 238 g of extract (B). Indomethacin, a non-steroidal anti-inflammatory drug, was used as a positive control.

Six 6-week-old male ddY mice of 1 group were used, and each sample was placed on the inside and outside of the right ear of the mouse by 0.5.
A total of 1 mg was applied per mg. Thirty minutes after that, 1 μg of TPA was applied to both surfaces of the auricle in the same manner as the sample, and 5 hours after the edema due to TPA reached its maximum, the ear thickness was measured and the inhibition rate was calculated by comparison with the control group.

Control group Indomethacin group Extract (A) group Extract (B) group Inhibition rate (%) 0.0 79.4 53.3 79.1

There is also an epidemiological investigation report that colon cancer is rarely generated in normal users of aspirin, which is a nonsteroidal anti-inflammatory drug. As mentioned above, Bidens pilos
Since a has a strong anti-inflammatory effect, abnormal colon crypts in the mouse large intestine (a lesion of the large intestine caused by administration of a carcinogen etc.
When the inhibitory effect against F) was tested, the extract of this plant showed an inhibitory effect equivalent to or higher than that of piroxicam used as a positive control group.

[0015]

[Experiment 2] Inhibition test on abnormal colonic crypts induced by azoxymethane Using 6 6-week-old male ddY mice in 1 group, after preliminarily breeding for 1 week, 10 mg of azoxymethane (AOM) per kg of body weight was subcutaneously injected into the right lower limb. Was administered once a week for 2 weeks. Daily human dose of Bidens pilosa 3 times daily
The extract A and B corresponding to 5 times as much as g were dissolved in drinking water for one day and drunk from the day before the first administration of AOM. Piroxicam was used as a positive control in humans at a daily dose of 0.6
It was given by dissolving in drinking water in the calculation of g. After 4 weeks from the first administration of AOM, the large intestine was removed, and after extension and fixation with formalin, abnormal colonic foci stained with methylene blue were measured under a microscope.

Control group Piroxicam group Extract (A) group Extract (B) group Inhibition rate (%) 100 60.3 52.4 61.7

Next, nitric oxide (NO) plays an important role as a mediator of infection, inflammation, and immune reaction in the living body, in addition to information transmission in the circulatory system and nervous system, and is involved in the control of apoptosis and carcinogenesis. In recent years, it has become clear that it has various functions. In particular, it is said that NO synthase is induced in an inflammatory reaction and NO is excessively produced, and this becomes reactive nitrogen oxides by the action of active oxygen and metal ions, and exacerbates or suppresses inflammation depending on conditions. . Bidens pilosa
Has been reported to have a cyclooxygenase inhibitory action, and it is considered that by inhibiting cyclooxygenase, it inhibits the synthesis of prostaglandin and exerts an anti-inflammatory action. Further, NO has an action of activating cyclooxygenase, and suppressing NO production results in suppression of prostaglandin synthesis.
Therefore, substances that suppress NO production are expected to have anti-inflammatory effects.

Many polyacetylene compounds and flavonoid compounds have been reported as components found in Bidens pilosa . It is known that a plant of the Asteraceae family has a polyacetylene compound at every site, and it is also known that certain polyacetylene compounds and flavonoid compounds have anti-inflammatory properties. Bidens pilosa is despite widely used as a folk medicine in many inflammatory diseases, also, B
Despite the large number of isolated compounds from idens pilosa , no potent compound has been proved as an anti-inflammatory component. Therefore, the inventor measured the inhibitory activity of NO production as an index of anti-inflammatory activity,
I thought about searching for active ingredients. As a measuring method, a macrophage-like cell line (RAW264) was stimulated with LPS in the presence of a specimen sample, and the amount of NO ₂ in the culture supernatant was measured using a Griess reagent. The survival rate of macrophages was measured by the MTT method.

As a result, the ethyl acetate extract (A) was found to have a stronger NO production inhibitory activity than the methanol extract (B), and depending on the concentration, the cytotoxicity was alleviated but the N content was still strong.
It exhibited O production inhibitory activity.

[0020]

[Experiment 3] Measurement of NO production inhibitory activity The RAW264 cell line was 5% fetal bovine serum (FBS), 50 U / mL penicillin, and 50 μg / m streptomycin.
RPMI-1640 containing 20 mM of L, L-glutamine
The cells were cultured at 37 ° C in the presence of 5% carbon dioxide gas. RAW264 cells with a cell number of 1 × 10 ⁶ / mL were dispensed into a 96-well plate by 100 μL each, and after culturing for 4 hours, 100 μL of a medium containing a sample and LPS (0.4%) dissolved in distilled water.
mg / mL) 10 μL was added. After culturing for 24 hours, 100 μL of the culture supernatant was collected, and Griess reagent (sulfanilamide 1%, naphthylethylenediamine 0.
1%, 3% phosphoric acid solution) was added and left at room temperature for 10 minutes, then 5
Absorbance was measured at 40 nm (control 700 nm), and NO ₂ amount was measured by a calibration curve obtained by Na nitrite.

The number of viable cells of macrophages (measurement of survival rate) is 3- (4,5-dimethylthiozo).
l-2-yl) -2,5-diphenyl-tetr
It was measured by a colorimetric method using azolumbromide (MTT). That is, 100 μL for NO measurement
Of the supernatant of MTT (5 mg / mL inP
After adding 10 µL of BS (-) and incubating at 37 ° C for 30 minutes, the medium was removed, 100 µL of DMSO was added, and the mixture was allowed to stand at room temperature for 10 minutes, and then the absorbance at 540 nm (control 700 nm) was measured to determine the number of viable cells. I asked.

Μg / mL NO production ratio Cell viability vs. 100 100 Extract A 100 8.2 51.4 50 26.1 94.0 25 59.5 97.0 Extract B 100 66.6 98. 9 50 77.9 94.9 25 92.4 89.1

[0023]

[Experiment 4] Separation of active ingredient 116 g of extract A was added to activated carbon 7 to remove chlorophyll.
It was adsorbed on 5 g and eluted with acetone / ethyl acetate / THF sequentially, and the acetone / ethyl acetate fraction was further n-
Change the concentration of hexane / vinegar ethyl mixture [10/1] →→→ [1
/ 2], and then gradient elution was performed while sequentially changing to ethyl acetate alone, ethyl acetate / methanol [1/1], and methanol alone.

While monitoring the NO production inhibitory activity, the fraction having a relatively high activity was further fractionally eluted with methanol on an LH20 column, and the fraction having a strong activity was further eluted with n -hexane / vinegar on a silica gel column. Change the concentration of the ethylene mixture [2
0/1] →→→ sequentially changes to [1/2], then ethyl acetate alone, ethyl acetate / methanol [2/1] →→→ [1 /
2], gradient elution was performed while sequentially changing to methanol alone. The more active fraction was analyzed by normal phase HPLC (se
nshu PAK Silica-4251-N10φ
X 250 mm) and fractionated with n -hexane / ethyl acetate [7/3] at a flow rate of 5 mL / min, and UV2 at 10.7 minutes
101 mg of compound X was obtained as a peak at 54 nm.

Compound X was a colorless oily substance and turned yellow by light. From EI-MS, molecular weight 184, HR-M
From S, m / z = 184.0889, which was in agreement with the theoretical value, and the molecular formula was estimated to be C ₁₃ H ₁₂ O.

[0026] In ¹ H-NMR ^1.31ppm (3H,
d, J = 6.35), 2.19 ppm (brs), 2.
52 ppm (1H, dd, J = 17.09, 6.1
0), 2.57 ppm (1H, dd, J = 17.09,
5.62), 4.03 ppm (1H, ddd-lik
e, J = 5.62, 6.10, 6.35), 7.28-
A signal of 7.49 ppm (5H, m) was observed.

1.31 ppm is a methyl group, 2.19 pp
It is considered that m is an alcoholic hydroxyl group and 7.28-7.49 ppm is a signal derived from monosubstituted benzene. Also 2.
52 and 2.57 ppm are two non-equivalent protons having a methine group next to each other, and they affect each other by geminal.
Furthermore, it is presumed that the neighboring protons affect each other.

4.03 ppm is 1.31 ppm from J value
With a signal that seems to be the methyl group of 2.52 ppm, 2.
It is thought to be adjacent to two non-equivalent protons of 57 ppm. Furthermore, 121.8 ppm from ¹³ C-NMR
Quaternary carbon, 128.4, 129.0, 132.5pp
The three signals of the tertiary carbon of m are monosubstituted benzenes.
22.5, 30.1 and 66.4 ppm are 1st grade,
It is a signal of secondary and tertiary carbon. Also, 67.4-8
There were four quaternary carbon signals at 0.7 ppm, and it was considered that these carbons were connected by triple bonds. ¹ H
− ¹ HCOSY, ¹ H− ¹³ CCOSY, INADEQU
When 2D-NMR spectra such as ATE and HMBC were examined, it was presumed that a methylene group and a benzene ring were connected to the quaternary carbon, a methine group was next to the methyl group, and a methylene group was next to the methyl group. Was done. This was also proved by decoupling.

In the MS spectrum, the molecular weight is 184,
The base peak was 140. In general, the C—C bond next to the oxygen atom is easily broken, so it is considered that the secondary alcohol in the structure of compound X is broken and the 140 fragment appears as a base peak. Fragments below the base peak matched the literature values.

[ ¹ H-NMR Data of Compound X] ppm H-1 1.31 (3H, d, J = 6.35) H-2 4.03 (1H, ddd-like, J = 5.62, 6.10, 6.35) H-3 2.52 (1H, dd, J = 17.09, 6.10) 2.57 (1H, dd, J = 17.09, 5.62) H-2 '~6' 7.28-7.49 (5H, m ) C 2 -OH 2.19 (brs) spectra in ppm from measurement data TMS in CDCl ₃ 400 MHz

[ ¹³ C-NMR Data of Compound X] ppm spectrum measured in CDCl ₃ at 100 MHz 1 22.5 q data expressed in ppm from TMS 2 66.4 d 3 30.1 t 4 80.7 s 5 74.0 s 6 67.4 s 7 75.4 s 1 '121.8 s 2' 132.5 d 3 '128.4 d 4' 129.0 d 5 '128.4 d 6' 132.5 d

Next, in order to determine the coordination of the secondary hydroxyl group of compound X, the absolute configuration was determined using the new Mosher method.

First, 125 μL of pyridine and R-(−)-α-methoxy-α-t were added to compound X (6.8 mg).
rifluoromethyl-phenylacet
icacid chloride [R-(-) MTP
A] 37 μL was added, and the mixture was stirred at room temperature for 24 hours.
After completion of the reaction, the solvent was distilled off, and n -hexane: ethyl acetate =
As a result of purification using HPLC with 2: 1 as an elution solvent, 6.8 mg of (−)-MTPA ester was obtained.
Similarly, compound X (6.8 mg) was added to pyridine 125 μm.
L, S-(+)-α-methoxy-α-trifl
uoromethyl-phenylacetic a
cid chloride [S-(+) MTPA] 37
Add μL and perform the same operation to get the corresponding (+)-MT
A PA ester was obtained.

Next, these (+) and (-) MTPAs
For each ester, protons were assigned by ¹ H-NMR, and the Δδ {= δ (−) − δ (+)} value was obtained.

[ ¹ H-NMR spectrum data and Δδ value] (−) MTPA ester (+) MTPA ester Δδ value H-1 1.471 1.386 0.085 H-3 2.699 2.703-0. 004 2.648 2.651 -0.003

MTPA is on the upper side, carbinol proton (proton at the base of MTPA ester oxygen) is on the lower side, and the proton group with Δδ> 0 is on the right side, Δδ> 0.
When the proton group with δ <0 was placed on the left side, the configuration at the carbon at position 2 was found to be R.

From this result, it is clear that the compound has the R configuration, and the structure of the compound X has a value of [α] _D ²³ of −3.
Since it is 4.7 ° (c = 0.28, EtOH), R-(−)-7-phenylhepta-4,
It was determined to be 6-diyn-2-ol (X).

[Compound X]

The compound X is Ming-Huey C
hang et al. in Bidens pilosa L .; va
r. A compound isolated from minor (Blume) Sherff and named pilosolA (J. Chi
n. Chem. Soc. 47, is a structure in which very close and 1131,2000), pilosolA the [alpha] value of _D ²⁶ is exactly the reverse, + 6 ° (c = 0.1, Me
OH) and the absolute configuration of the asymmetric carbon has not been determined. From these facts, compound X is pilos
It is considered to be a compound different from olA.

[NO Production Inhibitory Activity of Compound X] μg / mL NO Production Ratio Cell viability vs. 100 100 Compound X 100 0.0 0.5 0.5 〃 〃 50 4.5 72.7 〃 〃 25 40 0.0 91.9 〃 〃 12.5 47.7 99.8

The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto.

[0042]

[Example 1] Preparation of healthy tea The above-ground portion of bidens pilosa cultivated cleanly was harvested, washed and cut, sterilized by steaming for 30 minutes, hot air dried, finely chopped, and mixed with roasted barley in equal amounts, The flavor was adjusted by adding about 4% ginger powder. Approximately 3 g of each was packaged in a tea bag to give healthy tea. This product is suitable as a healthy tea for daily drinking, which is fragrant, has no habit, and does not get tired when 1 tea bag is added with 1 to 1.2 L of water and boiled for about 5 minutes. Examples suggesting the effect of this health tea are as in Examples 2 to 4.

[0043]

[Example 2] In the four cases listed here, although a baby was diagnosed with atopic dermatitis by the medical examination, the mother avoided the drug and did not use the ointment. This is an example of administration as shown at a temperature of about body temperature. In all cases, the frequency of defecation increased during this period, and the condition of the stools also improved.

[Example 1] Infant atopic dermatitis Name Age: O. A. 3 months Female onset site: around face / ear / neck, root of limbs and joint administration method: 30-40 mL before lactation, 50 before and after bathing
~ 60mL Daily dose: About 10 times in total, about 400mL Over time: Face / ear in 1 month, cervical symptoms disappeared in 2 months, 3
~ 4 months almost completely cured

[Example 2] Infant atopic dermatitis Name Age: K. A. 4 months Female onset site: Ear, neck, cheek, arm joint administration method: Before sleeping / before breastfeeding 30-60 mL each time Daily dose: About 10 times in total, about 500 mL After: About 2 weeks cheeks first , The symptoms of other parts almost disappeared in about 5 weeks

[Example 3] Infant atopic dermatitis Name: Age T. B. 1 year and a half woman Onset site: hand, arm, face, calf Administration method: As needed Daily dose: 10 times or more in total, 1 to 1.2 L Over time: The rash disappeared from the face in about one and a half months, and others 1 to
It disappeared two months later, but in the latter half of the year, it has not recurred at all.

[Example 4] Infant atopic dermatitis Name Age: 0. C. 2-year-old and half-male Onset site: ear, neck, arm, and knee back administration method: As needed Daily dose: 10 times or more in total, 1.5 to 1.8 L Over time: From about 2 months, rash and itching gradually disappeared He was completely cured in three months, but in the latter half of the year, he had no recurrence.

[0048]

Third Embodiment H. Mr. (male, 53 years old) has urticaria that develops after sweating, taking a bath, and after exercise, and its causal relationship with food has been denied, and he has been troubled for many years instead of suppressing the symptoms by taking antihistamines. In order to improve his constitution, he took a quick walk for 30-40 minutes every morning, and had him drink 10 or more cups of the health tea of Example 1 every day. As a result, urticaria almost disappeared after about 6 months.

[0049]

Example 4 K. K. He (male, 29 years old) had systemic dermatitis and was diagnosed with psoriasis by his doctor. He went to the hospital for about a year and was treated with topical steroids, but did not improve. Therefore, when the healthy tea of Example 1 was taken at a temperature slightly higher than the body temperature and ingested more than 10 cups every day, the eye bear disappeared after about 2 weeks, and the itch gradually disappeared from about 4 to 5 months later. ,
Six months later, the symptoms disappeared systemically.

[0050]

Example 5 Bidens pilosa dried product 50k
750 L of hot water was added to g and static extraction was performed at about 90 ° C. After solid-liquid separation, the residue was further extracted with 500 L of water, and the extracts were combined and concentrated under reduced pressure to about 30 L at about 40 ° C. and then spray-dried. 12.1 kg of dried extract was obtained.

[0051]

Example 6 0.2 kg of Avicel was added to 1 kg of the dried extract obtained in Example 5 to give 300 mg tablets. When a man (45 years old) diagnosed with alcoholic hepatitis was administered 4 tablets daily, he recovered completely after 3 months. Before administration of GOT GPT γGTP 80 64 73 After administration 38 33 20

[0052]

Example 7 Bidens pilosa dried product 72k
Add 10 times amount of 50% ethanol to g and add 8 at about 50 ℃.
After extraction by heating for an hour, the mixture was left overnight and filtered, and the filtrate was concentrated under reduced pressure and freeze-dried to obtain 13 kg of dried extract.

[0053]

[Example 8] 1 kg of the dried extract obtained in Example 7 was added to 60 L.
Was dissolved in purified water, and 10 g of activated carbon was added and stirred to prepare a medicated cream containing 10% of the decolorized and filtered solution. Sodium lauryl sulfate 30 inside the upper arms of 10 volunteers
% Water solution was applied and bandaged for 5 hours, all were red and inflamed. Immediately after applying this cream to the inflamed area and applying the same before going to bed and at waking up, 8 of 10 people completely disappeared in the morning of the following morning and 2 of the 10 people in the morning of the next morning.

[0054]

Example 9 500 g of the dried extract obtained in Example 7 was dissolved in 100 L of physiological saline to prepare an gargle. Five volunteers, who had swollen tonsils and redness in their throat, were given this mouthwash 5 times a day, and all of them reported that they became lighter and easier the next day.

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Claims (3)

[Claims] 1. R-(-)-7-phenylhepta
-4,6-diyn-2-ol. 2. An extract derived from a plant of the genus Sengangusa containing the compound of claim 1. 3. A composition containing the plant of the genus Spendanga itself containing the compound of claim 1 or the extract of claim 2.