JPS632928A - Analgesic - Google Patents

Abstract

PURPOSE:To obtain a drug containing 20-hydroxyecdyson as an active component, free from side effect and useful as an analgesic. CONSTITUTION:The objective agent contains 20-hydroxyecdyson of formula as an active component. The compound of formula is a metamorphosis hormone of insect inducing ecdysis and metamorphosis of insects and crustaceans during the growth and is practically used for the induction of ecdysis of crustacean for bait in fishing industry. It has been found that the compound has remarkable effect to safely mitigate various kinds of pain including neuralgia without causing side effect. The compound of formula can be produced by extracting Pfaffia iresinoides Spreng belonging to Amaranthaceae family with water, water-soluble organic solvent (e.g. methanol)or their mixture. It is administered as an analgesic at a rate of 10-50mg/day. LD50 of the compound is 6.4g/kg by peritoneal infusion of mouse.

Description

[Detailed Description of the Invention] 3. A detailed description of the present invention relates to an analgesic drug. Furthermore, the present invention relates to a method for producing 20-hydroquine echnosone, which is used as the active ingredient of this analgesic.

20-Hydroquine ecdysone is a compound represented by the structural formula.

This compound is an insect metamorphosis hormone that induces molting and metamorphosis during the growth process of insects and crustaceans.
It has been put into practical use to induce molting in crustaceans.

Furthermore, this compound has been recognized to be effective in promoting metabolism in hepatocytes, hyperglycemia, antilipidemia, etc. in mammals.

The inventors discovered that the insect metamorphosis hormone 20-human [J.
Achylanthes fauriei Lev,
et van, ), and it has been successfully isolated (Pharmacological Journal 8)-, 325 (+967)
).

In addition, this compound was completely synthesized by Kametani et al.
etters) I'2-1. -, 4855 (
1980) ).

However, when 20-hydroquine ecdysone is obtained from Inocosterone, the yield is extremely low at about 0.02%, and furthermore, it is obtained as a mixture with inocosterone, making separation and purification of the two extremely difficult. In addition, even in the case of total synthesis, a mixture of stereoisomers is obtained, making it difficult to separate the desired product.

Inventors (j:, 20-Hydroxyecdysone exhibits an extremely excellent analgesic effect on pain such as neuralgia in humans-
In addition to newly discovering that 4
Iresinoides (Prarriairesinoides)
It was discovered that this 20-hydroquine ecdysone is contained in a high content in 20-hydroquine ecdysone and can be isolated easily and in high yield, leading to the present invention.

By the way, Brazilian ginseng is a herbal medicine made from a plant of the Amaranthaceae family that grows naturally in South America, and has been used as a folk medicine by the Indians since ancient times for nourishment, tonicity, strength, and the treatment of diabetes. However, the raw material is not just one type of plant, and herbal medicines that are plants of the genus Baffia and have the same J or Una morphology are called by these names.

The inventors have discovered that Pfaffia paniculata (Pfaffia paniculata), which is one of the raw material plants for Brazilian ginseng,
6 kinds of puffuoside A, which is a new skeletal nortriterpenoid with antitumor activity, puffic acid and its saponin glycoside, from the root of P. aniculata Kuntze.
-F was isolated and reported [Tetrahedron Letters, 1057 (1983), Phytochemistry J
? 3, 139°+703 (1983)].

The inventors have now discovered that 20-hydroxyecdysone ('',
Among the raw material plants for Brazilian ginseng, we found that it exists in particularly high amounts in Paffia irezinoides. That is, according to the research conducted by the inventors, 20-hydroxyecdysone is contained in the roots, stems, leaves, and soil of Paffia iresinoides in the following amounts.

Paffia irreginoides root 0.62 (wt%) stem
0.17 Leaf 0.92 Ground 1 part 029 20-Hydroxyecdysone is isolated from Paphia irenonoides by extraction with water or a water-soluble 6-organic solvent or a water-organic solvent.

Water-soluble organic solvents include methanol, ethanol,
Acetone and the like can be used, and methanol is particularly preferred from the viewpoint of economy and yield. As extraction solvent it is also possible to use mixtures of organic solvents and water.

The extraction operation is carried out according to a conventional method by adding the above-mentioned extraction solvent to shredded or crushed roots or aerial parts of Paffia irreginoides, and then cooling or heating the mixture.

An extract is obtained by distilling off the extraction solvent from the extract thus obtained.

Isolation of 20-hydroxyecdysone from such an extract is carried out according to a conventional method as described below.

First, the extract is dissolved in water and extracted with a higher alcohol that is difficult to mix with water, such as butyl alcohol or amyl alcohol. The solvent is distilled off from the extract to dryness. The obtained residue is recrystallized from methanol-ethyl acetate. Alternatively, purification may be performed by chromatography using alumina, silica gel, Sephadex, resin, or the like.

” Duplicate operations give 20-hydroquinoecdysone with +np 240-242°C.

According to the research conducted by the inventors, isolated 20-hydrogine ecnoson was administered to 20 patients suffering from neuralgia etc.
When administered and observed, it was effective in 11 cases (55%), with slight r
A total of 95% of the 8 patients (40%) who responded to T showed improvement in their symptoms, indicating a very good effect.

20-Human (Using J Kinoecdysone as analgesic-4
The actual effective dose is 10 mg to 50 mg/day, and 1.1) 6o is administered intraperitoneally to 6.4 g/Kg of a mouse and intraperitoneally to a mouse of 10 g/Kg or more [-1].

For administration, powders, tablets, or
It is administered orally as a capsule or the like. Alternatively, it can also be administered transdermally as a poultice.

Next, the present invention will be described in detail by illustrating some embodiments. However, the present invention is not limited thereto.

Example I Preparation of 20-Hydroquine Ecdysone 409 g of shredded Paffia irreginoides root were
% methanol aqueous solution 1 ρ each at a time of cold extraction 3 times
The extraction solvent was distilled off from the obtained extract under reduced pressure, and then 1 g of water was added to the residue to dissolve it, and the solution was diluted with l-butanol for 30 minutes.
Extracted twice (2.5 ρ in total). The extract was concentrated under reduced pressure;
693 g of residue was obtained. This residue was dissolved in silica gel 30
Column chromatography was performed using 0 g of ethyl acetate, and both fractions eluted with edyl acetate-methanol (95:5) were collected.
The solvent was distilled off to dryness, and the residue was then recrystallized from ethyl acetate-methanol. This results in mp
1.25 g of colorless columnar crystals of 20-hydroxyecdysone having a temperature of 242°C were obtained (yield: 031%).

In identifying the product, various methods were used, including mixing with a standard, thin layer chromatography, infrared absorption (IR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy.

Mixing effect: None Thin layer chromatography developing solution - Ethyl acetate/ethanol - Rf-0,60
Chloroform/methanol/water: Rr=0.55 (65
/35/l O) IR spectrum m8,1cm': 3400,
1650'IINMR spectrum (CellJ)
: 1.07S, 1.20S.

1.37S, 1.57S Example 2 Analgesic effect on neuralgia etc. First, tablets each containing 5 mg of 20-hydroxyecdysone were prepared according to the following procedure.

20-hydrogine ecdysone IO, Og, or 20-
100g of dry extract powder of Paffia irreginoides containing 10% hydroxyecdysone, 338g of lactose (248g when dry extract powder is used), 2 crystalline cellulose
48g.

2g cornstarch and 2g magnesium stearate
Add and mix well, make slurp with a tablet machine, coarsely crush and select with an oranator, and granulate 1. This granule 60
Compress 0g into tablets in a conventional manner and make 2000 plain tablets, each containing 5m
Take 2 tablets containing g at a time, 3 times a day, between each meal.
The drug was orally administered for 1 day, and the progress was observed, and 11 patients (52%) showed a continued response (obvious improvement in subjective symptoms).
), slightly effective (slight improvement in subjective symptoms) 8
(40%), total improvement of symptoms was observed in 95%, and 1 was ineffective.
(5%). There were no chief complaints regarding side effects during the entire administration period.

Data regarding the clinical cases described above are shown in the following table.

20-Human 0xycinoxine administration example 10 ma 3 times a day between meals -11= Note that there is no change in the analgesic effect when administering in other dosage forms, such as granules, powders, and capsules. However, by changing the dosage form, the duration of the effect can be changed.

For example, capsules can be prepared as follows.

20-Hydroxyecdysone]0. OOg, or 20-
Add 390 g of lactose (300 g when dry extract powder is used) to 100 g of dry extract powder of Paffia irenoides containing 10% hydroquine ecdysone, mix well, and manufacture 2000 capsules using a capsule filling machine. 1 capsule contains 5 mg of 20-hydroxyecdysone.

As described above, by using 20-hydroxyecdysone as an active ingredient, it is possible to prepare analgesics that have remarkable effects on various types of pain including neuralgia safely and without side effects. -On the other hand, this 20-hydroxyecdysone can be easily and inexpensively isolated from Paffia iresinoides. Therefore, the present invention has a beneficial development in the pharmaceutical industry (and one other person).

Claims (1)

[Claims] 1. An analgesic containing 20-hydroxyecdysone as an active ingredient. 2. In what is stated in claim 1, 20-
Hydroxyecdysone is present as an isolated product or in Pfaffia irezinoides, which belongs to the Amaranthaceae family.
iresinoides Spreng. ), an analgesic that exists as a processed product. 3. The analgesic according to claim 2, wherein the treated product is a dried extract of Paffia irreginoides. 4. An analgesic according to any one of claims 1 to 3, which is in the form of a powder, granule, tablet, capsule, or poultice. 5 Paffia irreginoides, which belongs to the Amaranthaceae family, was treated with water,
A method for producing 20-hydroxyecdysone, which is characterized by carrying out an extraction treatment using a water-soluble organic solvent or a mixture thereof as a solvent.