JPS6038325A - Narcotic sedative agent - Google Patents

Abstract

PURPOSE:To obtain a narcotic sedative agent by using a specific steroid saponin or its salt originated from starfish. CONSTITUTION:The narcotic and sedative agent containing the steroid saponin of formula I (R<1> is group of formula II, -COCH3, etc.; R<2> is H or SO3H; R<3> is H, group of formula III, etc.) or its salt as an active component. The steroid saponin of formula I can be prepared by purifing the extract of e.g. Asterias amuransis, Acantaster planci, etc. It has been found newly that the compound has narcotic and sedative activity, and is useful as a narcotic sedative agent. The activity is dependent to the dose, and the agent is applied at a dose of 0.1- 3g/day for narcotic by oral administration, and 30mg-1.5g/day for sedative by oral administration.

Description

BACKGROUND OF THE INVENTION Technical Field The invention relates to novel uses of certain steroidal saponins. That is, it relates to a hypnotic and sedative agent containing steroid saponin as an active ingredient.

PRIOR ART Saponins have only seen progress in research over the last decade due to their difficulty in purification and isolation and the complexity of their structures.

Characteristics of saponins include foaming properties in aqueous solutions, red blood cell destruction activity (hemolytic activity), and fish toxicity, but general pharmacological effects include expectorant, antitussive, anti-inflammatory, central depressant, and health-boosting effects. In recent years, some purified saponins have been reported to have antiulcer, antiallergic, and antitumor effects.

Saponins are classified into steroid saponins and triterpenoid saponins depending on the chemical structure of their sapogenin moieties. Among these, steroid saponins are mainly obtained from plants, and only a few are obtained from animals, especially marine organisms. , 5tsroidea).

On the other hand, anxiety, tension, excitement, insomnia, and the like have become common problems in modern society, and various hypnotic and sedative drugs have been developed.

However, regarding the above-mentioned starfish-derived steroid saponins, not only are there no drugs containing these as active ingredients, but also no scientific data have been reported that confirms their hypnotic and sedative effects. Additionally, no pharmacological data exist for purified single saponins.

The present inventor has already discovered that some steroid saponins derived from starfish have a blood pressure lowering effect. (Japanese Patent Application No. 58-106375) Summary of the Invention The present invention is based on the discovery that starfish-derived steroidal saponins have hypnotic and sedative effects.

Therefore, the hypnotic and sedative agent according to the present invention is characterized in that it contains a steroid saponin represented by the following formula or a salt thereof as an active ingredient.

0 ■ [1] Structure Steroid P saponi to be used in the present invention: y + 'r,
It is a compound represented by the above formula [1] or a salt thereof.

Specific examples of these include the following.

Compound (+): aβ-sodiosulfonate oxy-6α
, ξ-dihydroxy-ru-oxo-5α-cholester
9Q])-cy-6a-yl o-β-logalactopyranosyl-(1→3)-〇-β-D-fucopyranosyl(
1→2)-〇-β-D-galactopyranosyl(1→4
)-0-[β-D-quinozeviranosyl(1→2)]-
〇-β-Dxylo21) ξ-dihydroxy -Z
(-oxo -5α-choleat -9(11)-
en-6α-ylo-β-D-galactopy
r\anoayl −(1→3) −〇 −β −D
-fucopyranosyl -(1-+2)
-〇-β-D -galactopyrnnosyl
-(1-+4) -0-Cβ-D -kutnoJr
anolIyl -(1→2) ]-]o-β-D-x
ylopyranosyl-(1→3)-〇-β-D
-quinovopyra-nosld6) Compound (2); 3β-sodiosulfonateoxy-6α
, 20ξ-dihydroxy-ru-oxo-5α-cholest-901)-en-6α-yl〇-β-D-fucopyranosyl-(1→2)-〇-β-D-galactopyranosyl-(1→4)- 04β-D-Kino, I? Pyranosyl (
1→2)]-]0-β-D-xylopyranosyl 1→3
)-〇-β-〇-quinozeviranoside compound (3L3β, 6α, 20ξ-trihydroxy-'
2: U-oxo-5α-cholest-9a1)-en-
6α-yl〇-β-D-7 cobylanosyl (1→2)-
〇-β-D-galactopyranosyl (1→4)-〇-[
β-D-quinodepyranosyl (1→2)]-]〇-β-
D-xylopyranosyl 1→3)-〇-β-D-quinodeviranoside compound (41:3β-hyProxy6α-0-(β-D
-Fucopyranosyl-(1→2)-β-D-galactopyranosyl-(1→4)-[β-D-Kino day? Pyranosyl (1→2)]-β-D-xylopyranosyl-(1→3)
-β-D-quinozeviranosyl)-5α-zoregnar 90
1)-ene(3-β-hydroxy-6-α-o-(β-D
-fucopyra-nosyl -(1→2)-β-
D-galactopyranosyl-(1→4
)-[β-D-qujnovopyranosyl
-(1-) 2 ) ) -β-D -xylopyr
anosyl-(1-p3)-β-D-quln
ovopyranosyl)-5α-pregn
-9(ll)-ene) Compound (5): 3β-radiosulfonateoxy-6α, addition ξ-dihydroxy-
baroxo-5α-cholester-9Q11-ene-6α-
yl O-β-D-7 cobylanosyl (1→3)-〇-β
-D-fucopyranosyl(1→2)-〇-β-D-galactopyranosyl(1→4)-0-(β-D-quinozeviranosyl(1→2)'J-0-β- D-xylopyranosyl-(1→3)-〇-β-D-quinodigiranoside,
and compound (6): 3β-sodiosulfonateoxy-ξ-methyl-6α, 2I)ξ-dihydroxy-yl-5α-cholester 9a1)-en-6α-yl〇-β-D-fucopyranosyl-(l →3) -0-β-D-
Fucopyranosyl-(1→2)-〇-β-D-galacto2
Lanosyl-(1→4)-0-[β-D-quino2pyranosyl(1→2)]-]0-β-D-xylopyranosyl-1→3)-〇-β-D-quinodepyranoside.

In addition, the salt of the compound of the above formula [1] means that R2 is 5O3H
In this case, it refers to a structure in which H is substituted with an arbitrary cation. Examples include alkali metals or alkaline earth metals such as NaSK, Ca, Mg, ammonium salts, and amine salts. Na is a compound +1),
(2L, (5) and (6) have been described above.

Method for obtaining steroid saponin Obtaining source The steroid saponin used in the present invention is obtained from, for example, the purple starfish (Asterlas amuransls Cc).
, f] versi-color 5ladsn)
can be obtained by extraction from the whole individual and isolation and purification of the extract (compounds (1) and (2)) ~
(Collection of abstracts from the 103rd annual meeting of the Pharmaceutical Society of Japan, p253 (19
83) and Chem, pharm, Bull, 2
611864 (1978)). Then, (3) can be fermented from these compounds by a known substitution reaction.

A synthetic method in which a sugar moiety is attached to the aglycon by known methods is also possible.

Furthermore, crown-of-thorns starfish (Acantaster planet)
Compound (5) was obtained by similar extraction, isolation and purification operations from L).
) and (6) can be obtained □.

Compound (4) was obtained by alkali treatment of the saponin mixture of crown-of-thorns starfish.
+1o1) can be isolated from the unrun rinse following the reaction (Tetrahedron I,
ett, 859 (1977) and Chem, ph.
arm, Bul 1, 26.1864 (1978
)).

In addition, when R2 is 803 Nm, it can be returned to -dust neutrality to give 5O3H (503H as it is), and easily reacted with the above-mentioned alkali metals, alkaline earth metals, ammonium, and amines. salts can be derived.

As an example of extraction, the method for extracting and isolating compounds (1) and (2) is as shown by Shimouchi.

The purple starfish is extracted by immersing it in water, and the extract is passed through a reversed-phase adsorbent. The adsorbent is first extracted with water to remove the oil part, and then extracted with a water-soluble organic solvent (e.g., lower alcohol such as methanol, ethanol, lower ketone such as acetone, acetonitrile, preferably methanol).
Alternatively, the oil portion extracted with a water-soluble organic solvent containing an appropriate amount of water is collected. If necessary, this fraction is dissolved in a small amount of water and poured into a large amount of water-soluble organic solvent (e.g., lower ketones such as acetone, lower alcohols such as methanol, ethanol, acetonitrile, preferably methanol) to precipitate. get. For this fraction,
Chromatography using a heavy phase adsorbent (preferably silica gel) [Developing solvent is a mixed solvent of chlorinated organic solvent (e.g. chloroform), alcohol (e.g. methanol) and water, or alcohol (e.g. -phthanol) and water] and a reverse phase support [e.g.
If necessary, the desired compound can be obtained by purification by chromatography using Licrosolep RP-8J (Merck & Co., Ltd.).

Confirmation of the physical and chemical properties and structure of the steroid saponins mentioned above can be confirmed by, for example, the potassium rhodizonate test, melting point measurement and optical rotation, as well as CD, IR, FABMS, CI.
This can be carried out by MS, 13CNMR, elemental analysis, and other Nosvector analysis (Patent Application No. 58-10).
6375 specification).

Structure-Activity Relationship As shown in the above formula 0, the present steroid saponin, basically, cholesta-9(II)-en-l, - is pregnathic.
901)-Ene skeleton aglycone, and a sugar moiety (0-β-D-
Fucopyranosyl (1→2)-〇-β-D-galactopyranosyl-(1→4)-〇-[β-D-quino-pyranosyl-(1→2)]-〇-β-D-xylopyra Noshiru 1
→3)-〇-β-D-quinozepyranoside), and in either case, it can be expected to be effective as a hypnotic sedative.

Hypnotic and Sedative Drug The hypnotic and sedative drug according to the present invention contains a steroid saponin represented by the above formula [1] as an active ingredient. The hypnotic and sedative agent may consist of either steroidal saponins alone or in mixture with each other, or may consist of auxiliary ingredients in a liquid or solid formulation, such as excipients, binders, diluents; It can be either.

The dosage form may be any administrable form such as powder, granules, tablets, capsules, troches, suppositories, injections, etc., and can be administered orally or parenterally.

The dosage may be adjusted depending on age, body weight, and symptoms, but as a hypnotic agent, 0.1 to 3 g of saponin is administered orally per day for adults, preferably 30 mg to 1 g at a time.
~Can be taken in several doses.

On the other hand, as a sedative, 30 mg per day for adults can be administered orally.
mg to 1.5 g, preferably 10 mg to 500 mg at a time
mg can be taken in one to several divided doses.

Hypnotic effect 1) Experimental method Using 9 male ddY mice, the test substance was added at 0.1
Inject intraperitoneally at a rate of ml/l□g, and add 40 mgAg of thiobental sodium to 0.1 m
It was administered into the tail vein at a rate of 1710 g, and the loss of righting reflex was used as an indicator for investigation. In addition, statistical processing of the results was performed using a seven-way test.

2) The experimental results diagram shows the effect of sodium thiobental on sleep time for compound f1. ), (2), and (31) show the effect of prolonging sleep time.

In the case of compound (1), thiopentane in the Mail water administration group
Luna? The average loss of righting reflex during administration of IJum was 5.
29 minutes versus 21) and 40 mg/k
In the g-administered group, the prolongation of the IIIj drowsiness effect was reduced in a dose-dependent manner with a significant difference of 12.91 minutes and 26.15 minutes.

Also, when added to compound (2), 5.10, 40 mg
/kg administration group: 11.64 minutes, 18.72 minutes, respectively.
Prolongation was observed at 25.86 minutes and 44.32 minutes, and furthermore, for compound (3), the duration was 13.75 minutes, 18.07 minutes, and 46 minutes in the 101 and 40 mg/kg administration groups, respectively.
．． A dose-dependent prolongation of sleep time was observed to 19 minutes.

Similarly, in compound (4), 10, Al, 50 m
A dose-dependent prolongation of sleep time was observed in the gAg administration group.

Sedative effect 1) Experimental method Compound (
]), (21, (31) are administered intravenously and the sedative effect is observed.

Regarding compound (4), the sedative effect is similarly observed after intraperitoneal administration or oral administration.

2) Experimental results In the case of compound (1), a tacostatic effect was observed with administration of 50 mg/kg, and with compound (2), administration of I (I mgAg) was observed.A similar effect was also observed with compound (3). The results were obtained.

On the other hand, with compound (4), when 25 to 50 mg AK was administered intraperitoneally, a decrease in locomotor activity and a ptosis effect were observed 5 to 10 minutes after administration. In addition, 100-20
Oral administration of 0 mgkg resulted in a decrease in locomotor activity and a muscle relaxant effect.

Lethal effect 1) Experimental method Thirty-three ddY male mice weighing 2f) to 30g were used, and the test substance was 0.9% N! IcI dissolved in water was administered intraperitoneally or into the tail vein at a ratio of 0.1 ml/1 (1, ?), and general symptoms were observed and the lethal effect was investigated.

2) Experimental Results Table 1 shows the lethal effects of compounds t1), f2) and (3) upon intravenous administration to mice. There were no cases of death when compound (1) having a hexasaccharide was administered at 50 mg/kg. However, at doses of 80 mg/kg or more, all patients developed respiratory distress and died within 1 hour after administration. On the other hand, for compound (2) with pentasaccharide, 10 mg/k
There were no cases of death with administration of 1,130 mg/kg or more (1 out of 3 cases died with administration of 25 mg/kg or more; all cases died with administration of 1130 mg/kg or more. Furthermore, compound (4) died at 300 mg/kg or more
All cases died after oral administration of more than 1 kg.

Table 1

[Brief explanation of the drawing]

The figure is a graph showing the sleep-enhancing effects of compounds (1), (2) and (3) on thiopentalina. ■ indicates the NaCl water administration group; d) indicates the number of experimental animals. Applicant's agent Kiyoshi Inomata

Claims (1)

[Claims] A hypnotic and sedative agent containing a steroid saponin or its salt represented by the following formula as an active ingredient. 1 H