JPH0128732B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel diterpenoids. The diterpenoid of the present invention is represented by the following general formula []. [In the formula, R represents a hydrogen atom or an acetyl group] The diterpenoid of the present invention represented by the above general formula [] has an anticancer effect and is useful as a pharmaceutical. It has been known that Oridonin, a diterpenoid with anticancer activity, exists in Isodon japonicus and Rabdosia rubesens, which are plants of the Labiatae family. The present inventors have isolated two novel diterpenoids represented by the above general formula [] that have excellent anticancer effects from Rabdosia exisa, a plant of the Lamiaceae family that is different from these plants. They succeeded in separating the particles and completed the present invention. The cabbage cabbage used in the production of the compound of the present invention is a perennial plant distributed in Yunnan, Liaoning, Sichuan, Hubei, etc. in China, and the stem is square and grows straight up, about 50 cm.
It reaches ~1m in length, and the leaf blades have opposite stalks, and the length is approx.
It is a plant with leaves that are 3.5 to 5.5 cm x 5 to 7 cm in size, ovate to oval with a pointed tip. A decoction of the petiole has long been known to have anti-inflammatory properties, and has been taken internally to treat stomatitis and sore throat, and used externally to treat joint pain in the limbs and neck. However, its components have not yet been elucidated, and it is also not known that there are components in the plant that have anticancer effects. The compound of the present invention is obtained by previously extracting the above-mentioned cauliflower with ether according to a conventional method, and is isolated from this ether extract as follows. That is, the above extract is concentrated to dryness, dissolved in methanol, treated with activated carbon, concentrated to dryness, and then dissolved in acetone. This acetone solution was passed through a neutral alumina column and eluted with benzene and ether to obtain a compound of the above general formula [] in which R is an acetyl group (hereinafter, this benzene eluate is named "exisanin B") and R is a hydrogen atom (hereinafter this ether eluate is named "exisanin A")
get. The details of the above production method and the physical properties of the compound of the present invention obtained thereby will be clarified in the Examples below. When the compound of the present invention thus obtained is used as a medicine, it can be formulated into a formulation depending on the route of administration, together with a conventional pharmaceutical carrier. For example, for oral administration, tablets, capsules, granules, powders,
For parenteral administration, it is prepared in the form of liquid preparations, main injections, suppositories, etc. Carriers that can be used in preparing solid dosage forms for oral administration include conventional excipients,
A binder, a lubricant, a coloring agent, a disintegrant, etc. can be used. Excipients include lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methyl cellulose, carboxymethyl cellulose, glycerin, sodium alginate, gum arabic, etc. Binders include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, Gum arabic, citric acid, sucrose, etc. can be used, lubricants include magnesium stearate, talc, etc., and colorants and disintegrants that are commonly known can be used. Furthermore, the tablets may be coated by a well-known method. or,
Liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc., and are prepared by conventional methods. When preparing a main injection, add a PH adjusting agent, a buffering agent, a stabilizer, an isotonic agent, a local anesthetic, etc. to the compound of the present invention, and use a conventional method to prepare the main injection for subcutaneous, intramuscular, or intravenous use. can be manufactured. As bases for producing suppositories, oily bases such as cacao butter, polyethylene glycol, lanolin, fatty acid trigcerides, and Witepsol (registered trademark: Dynamite Nobel) can be used. The dosage of the preparation (anticancer drug) prepared in this way varies depending on the patient's symptoms, weight, age, etc.
Although it cannot be absolutely limited, the amount of the compound of the present invention is usually in the range of about 50 to 1000 mg per day for adults, and this is preferably administered in 1 to 4 divided doses per day. Next, the manufacturing method, physical properties, and pharmacological action of Exaicin A and Exaicin B, which are the compounds of the present invention, will be explained in more detail with reference to Examples. Example 1 After pulverizing 9 kg of dried leaves of fragrant chana, ether 20
A deep green ether extract was obtained. This ether extract was concentrated to dryness to obtain 430 g of crude extract, which was dissolved by adding 5 methanol, followed by excessive decolorization by adding 400 g of activated carbon to recover a yellow methanol solution. This methanol solution was concentrated to obtain 93 g of extracted extract. 200ml of this extract 9.3g
of acetone, applied to a 200g column of neutral alumina, and eluted with benzene (elution rate 3ml/
After the first 1,400 ml was flowed away, 1,200 ml of the benzene eluate was fractionally concentrated to obtain 2.6 g of exisanine B, a white powder with a melting point of 240 to 243°C. [α] ²⁰ _D = -13.9 (C = 1.00, pyridine) Elemental analysis value (as C ₂₂ H ₃₂ O ₆ ) Theoretical value (%): C67.32, H8.22 Actual value (%): C67.75, H8.24 ν max (KBr): 3400, 1740, 1726, 1713,
1646, 1250, 1104, 1023, 990, 975, 895 cm ^-1 λ max (C ₂ H ₅ OH): 230 nm (ε = 7901) Example 2 The column of Example 1 was further eluted with ether (elution rate 3 ml/min ) and 800 ml of the ether eluate was fractionated and concentrated to obtain 1.6 g of exisanin A as a white powder having a melting point of 262-264°C. [α] ²⁰ _D = -27.7゜ (C = 1.01, pyridine) Elemental analysis value (as C ₂₀ H ₃₀ O ₅ ) Theoretical value (%) C68.54 H8.63 Actual value (%) C68.20 H8.71 ν max (KBr): 3430~3380, 1713, 1645,
1260, 1099, 1080, 1021, 1000, 968, 938 cm ^-1 λ max (C ₂ H ₅ OH): 234 nm (ε = 5557) <Pharmacological test> Exisanin A and exisanin obtained in Example 1 and Example 2 The antitumor effect of B was tested using mouse transplantable tumors ^p388 and Sarcoma 180. p ³⁸⁸ cells were added at 1 x ¹⁰⁶ cells/mouse to BDF ₁ male mice (25-29 g), and Sarcoma 180 cells were added at 5 cells/mouse to BDF 1 male mice (25-29 g).
×10 ⁶ mice/ICR/JCL male mice (27~
(30 g) were each intraperitoneally implanted. The specimen (exisanin A or exisanin B) was dissolved or suspended in physiological saline and administered intraperitoneally to 6 mice per group at a volume ratio of 1.0 ml/100 g body weight once a day for 7 consecutive days starting the day after tumor implantation. . The dosage was 2.5, 5, 10, or 20 mg/Kg/day for each of Exisanin A and Exisanin B, the average survival days at each dosage were determined, and these were calculated using only physiological saline that does not contain the compound of the present invention. Compared with the average survival days in the administered untreated control group, the rate of increase in survival (%) was calculated according to the formula below. Increase in survival rate (%) = average survival days of sample administration group - average survival days of untreated control group / average survival days of untreated control group x 100 The results are shown in Table 1 below. 【table】

Claims (1)

[Claims] 1. General formula [In the formula, R represents a hydrogen atom or an acetyl group] A novel diterpenoid represented by the following.