WO2017141968A1 - Pharmaceutical composition having anxiolytic action, and processed food product - Google Patents

Abstract

A pharmaceutical composition and a processed food product having a component with an anxiolytic action are provided: an anxiolytic pharmaceutical composition and processed food product which contain the 1,2,3,4-tetrahydrocyclopenta[b]indole shown in expression (1), and further, an anxiolytic pharmaceutical composition and processed food product which have the 7-methoxy-1,2,3,4-tetrahydrocyclopenta[b]indole shown in expression (2) as the main component.

Description

Pharmaceutical composition and processed food having anxiolytic action

The present invention relates to a pharmaceutical composition and a processed food having an anxiolytic action that alleviates the effects of stress on humans and animals that have received stress.

When humans and animals are stressed, they not only affect their behavior, but may also affect their physical functions. When this happens, an anxiolytic agent may be taken. For example, benzodiazepine anxiolytics alleviate mental anxiety and tension by slowing down brain activity by strengthening the action of GABA (Gamma Amino Butyric Acid), an inhibitory transmitter in the central nervous system. To do. Benzodiazepine drugs such as diazepam are known as anxiolytic agents.

Many types of anti-anxiety agents have been proposed other than benzodiazepines. In particular, as an indole system, Patent Document 1 discloses a tricyclic indole-2-carboxylic acid derivative represented by the formula (10) or a pharmaceutically acceptable salt thereof as an anxiolytic agent.

... (10)

Patent Document 2 also relates to an antagonist of serotonin 5-HT ₆ receptor that controls the homeostasis of calcium ions in cells, and substituted 2,3,4,5-tetrahydro- of the general formula (11). The form of 1h-pyrido [4,3-b] indole is disclosed. This compound is said to be usable as an anxiolytic agent.

(11)

JP 07-188166 A Special table 2010-523556

Benzodiazepine anxiolytic drugs have been reported from pharmacokinetically long to short ones in the body. In consideration of continuing to take for a certain period, those with a short half-life are often preferred. Therefore, there is a demand for substances having an anxiolytic action with a short half-life.

The present invention has been conceived in view of the above problems, and provides a pharmaceutical composition and a processed food having an anti-anxiety component that improves the stress state.

More specifically, the pharmaceutical composition according to the present invention is characterized by containing 1,2,3,4-tetrahydrocyclopenta [b] indole represented by the formula (1).

... (1)

The pharmaceutical composition further comprises 7-methoxy-1,2,3,4-tetrahydrocyclopenta [b] indole of the formula (2).

... (2)

Moreover, it is a processed food containing at least either the formula (1) or the formula (2).

1,2,3,4-Tetrahydrocyclopenta [b] indole and 7-methoxy-1,2,3,4-tetrahydrocyclopenta [b] indole can relieve stress and have a half-life. Within a few hours.

Therefore, these substances can be used as suitable anxiolytic agents. In addition, processed foods containing these substances have anxiolytic effects and are effective in relieving stress. In addition, since these substances are hardly soluble, they can be taken orally, so that it is easy to take them into the body.

It is a schematic diagram which shows the method of giving SART stress. It is a graph which shows the anxiolytic effect when 1,2,3,4-tetrahydrocyclopenta [b] indole is administered every day for 7 days. 2 is a graph showing an anxiolytic effect when 1,2,3,4-tetrahydrocyclopenta [b] indole is orally administered once. 6 is a graph showing the anxiolytic effect when 7-methoxy-1,2,3,4-tetrahydrocyclopenta [b] indole is administered daily for 7 days. Represents the pharmacokinetics of 1,2,3,4-tetrahydrocyclopenta [b] indole and 7-methoxy-1,2,3,4-tetrahydrocyclopenta [b] indole (change in serum volume after administration) It is a graph.

Hereinafter, the anxiolytic drug composition and the processed food having anxiolytic action according to the present invention will be described with reference to drawings and examples. The following description exemplifies an embodiment and an example of the present invention, and the present invention is not limited to the following description. The following description can be modified without departing from the spirit of the present invention.

As the substance having an anxiolytic action according to the present invention, 1,2,3,4-tetrahydrocyclopenta [b] indole (hereinafter referred to as “TCI”) is used. This substance is a known substance and has CAS number 2047-91-8.

... (1)

In addition, 7-methoxy-1,2,3,4-tetrahydrocyclopenta [b] indole (hereinafter referred to as “7-MeO-TCI”) of the formula (2) in which a methoxy group is attached to this substance is used. This substance is a known substance and has CAS number 89169-57-3.

... (2)

In particular, 7-MeO-TCI has no odor peculiar to indole-based substances and is almost odorless, so it can be easily used for humans. Moreover, even if it uses for processed food, it can ingest without resistance.

Pharmaceutical compositions based on these substances are in the form of drugs such as capsules, granules, solutions, emulsions, suspensions, powders, tablets, liquids, soaking agents, decoction, troches, flow extracts. Preparations, tinctures, eye drops, nasal drops, ointments, creams, lotions, injections, suppositories and the like.

These preparations are pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, solubilizers, suspension agents, coating agents, diluents, etc. It is formulated with known auxiliaries that can usually be used in the technical field. The pharmaceutical composition of the present invention may contain other pharmacologically active ingredients in addition to the effective ingredients of the present invention.

Solid preparations are, for example, powders, granules, tablets, capsules, sugar-coated tablets and the like. The active ingredient of the present invention as an active ingredient and a diluent (eg lactose, dextrose, sucrose, cellulose, corn starch, potato starch) Etc.), lubricants (eg silica, talc, stearic acid, magnesium stearate, calcium stearate, polyethylene glycol etc.), binders (eg starch, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone etc.), discrete An agent (for example, starch, alginic acid, alginate, etc.), a saturant, a colorant, a sweetener, a wetting agent (for example, lecithin, polysorbate, lauryl sulfate, etc.) can be contained. These can be formulated by known methods such as mixing, granulating, tableting, sugar coating and the like.

Liquid preparations can be in the form of syrups, solutions, emulsions and suspensions, for example. The suspension and emulsion can contain, for example, natural rubber, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, polyvinyl alcohol and the like as a carrier.

The processed food according to the present invention contains the above-mentioned substances, particularly 7-MeO-TCI as a main component. Processed food forms include candy, gum, jelly, gummy candy (confections containing gelatin), biscuits, cookies, rice crackers, bread, noodles, fish and livestock products, tea, soft drinks, coffee drinks, milk drinks , Whey beverages, lactic acid bacteria beverages, carbonated beverages, yogurt, ice cream, pudding, etc., as well as soft processed foods, dry extracts, capsules, granules, powders, tablets, liquids, soaking agents, decoction, Extracts such as lozenges, flow extracts, tinctures, and alcoholic beverages may also be included. Moreover, you may use as an extract of electronic cigarette. Hereinafter, description will be made based on examples.

As an example, an experiment using a mouse was performed. As a mouse, a ddY male mouse (purchased from Nippon SLC Co., Ltd.) having a body weight of about 20-25 g (4 weeks old) was used. Normal breeding of mice was performed at a room temperature of 24 ± 1 ° C. under a light / dark cycle every 12 hours (from 7 am to 7 pm, lighting), and 8 mice / gauge were used. Feed (MF (trade name), oriental yeast) and water were ingested freely.

Some mice were subjected to Specific Alternation of Rhythm in temperature (SART) to be in a chronic stress state. Specifically, a mouse breeding cage is prepared in both a breeding room at room temperature of 24 ° C. (hereinafter “room temperature breeding room”) and an animal breeding chamber having a temperature of 4 ° C. (hereinafter referred to as “cold breeding room”). Between 9:00 and 16:00, mice were moved between the cages every hour, and stress was applied by exposure to changes in environmental temperature for 7 days from 16:00 to 9:00 in the next morning in a 4 ° C chamber. added. The room temperature room and the room temperature room were switched according to the SART stress loading method until 11:00 in the morning of the experiment.

Fig. 1 shows a schematic diagram of the SART stress loading method. Room A is a room-temperature breeding room and Room B is a cold room. The mouse is moved between both chambers for each cage. The line in the figure represents the movement of the rearing cage. In addition, the number written at the turning point of the line is the time. Mice that are switched between room temperature room (Room A) and cold room room (Room B) every hour from 9:00 to 16:00 every day are left in the cold room (Room B) from 16:00 to 9:00 the next morning. Is done. Chronic stress is created by exposure to such temperature changes for 7 days. A mouse subjected to SART stress is called a “SART stress mouse”. In addition, the mouse | mouth which did not give stress (it is also called a "non-stress mouse | mouth") performed the movement between gauges on the schedule similar to SART stress in order to remove the element of the stress accompanying a movement. Of course, this movement was designed not to cause stress due to temperature.

TCI and 7-MeO-TCI were each suspended orally in 0.5% sodium carboxymethylcellulose (CMC · Na). When examining the acute effect of the drug, it was administered only once (single administration) 60 minutes before the start of the test. When examining the effect of chronic administration, it was administered once a day for 7 days (daily oral administration). In SART-stressed mice, these drugs were orally administered every day from the start of stress loading, and non-stressed mice were also administered with the same schedule. In the case of chronic administration, the test was conducted 24 hours after the final administration in order to exclude the effects of acute effects.

¡Elevated cross maze was used for the degree of stress. Elevated plus maze test was conducted in Hata (“Anxiety-Like Behavior in Elevated Plus-Maze Tested in Repeated Cold-Stressed Mice”, Taeko Hata et al., Jpn. According to the same procedure.

The elevated cross maze device has a structure in which two gray plastic plates with a width of 5 cm and a length of 65 cm intersect at a position 40 cm above the floor. The platform, which is the central intersection of the device, is 5 cm square, and has two open arms (OA) and two closed arms (CA) protruding from each side. Each arm is 30 cm long. The CA is provided with 15 cm high walls on three sides.

Therefore, when the mouse is on the OA, it is exposed to the environment of a thin high place, and when it is on the CA, it is in an environment where the three sides are partitioned by a wall. For the measurement in the elevated plus maze test, the mouse was placed on the platform so that the head was facing OA, the behavior was observed for 5 minutes, and the residence time in OA and CA was measured.

And the ratio (%) of the open arm (OA) staying time was calculated by the following formula (1).

... (1)

Here, “OA stay time (seconds)” indicates the total time in seconds that the mouse was on an open arm without a wall. The “total test time (seconds)” is 5 minutes (300 seconds) here.

Mice are likely to feel anxiety on OA and feel secure on CA. On the other hand, the curiosity of mice has a desire to explore the environment in which they are placed. Therefore, although there is anxiety, the time for searching on the OA can be used as a measure of how much anxiety is felt as a percentage of the total time on the OA. Number (1) calculates the percentage of time spent in OA during the total test time.

FIG. 2 shows improvement in anxiety when TCI is orally administered every day. The horizontal axis represents the dose of TCI (mg / kg / day), indicating that administration was performed according to the body weight of the mouse. The administration was given for 7 days. The vertical axis represents the ratio (%) of the OA stay time. In the graph, the white bar is for a non-stressed mouse (denoted as “Non-stress”), and the black bar is for a SART stressed mouse (denoted as “SART stress”).

Referring to FIG. 2, the dose is zero when no TCI is given. Non-stressed mice were on approximately 17% OA, while SART-stressed mice were on OA for less than 10%. This is thought to be due to the feeling of anxiety as a result of applying constant stress, and a long period of time on CA where it can be relieved.

However, as the TCI was administered at 10 (mg / kg / day) and 20 (mg / kg / day), the ratio of the OA residence time of the SART stressed mice became the same as that of the non-stressed mice. Therefore, it can be concluded that the stress state was relieved in the SART stressed mice by the administration of TCI.

FIG. 3 shows the results of measuring the ratio (%) of OA stay time when one TCI was orally administered to non-stressed mice and SART stressed mice. The horizontal axis represents the dose of TCI (mg / kg), which indicates that an amount corresponding to body weight was administered. The vertical axis represents the ratio (%) of the OA stay time. The white bar and the black bar are the same as those in FIG. As the dose increased, the ratio (%) of OA residence time in SART stress mice increased.

And, when TCI in an amount of 40 (mg / kg) was administered, it became very close to the state of non-stressed mice. The amount of 40 (mg / kg) corresponds to twice the amount that was effective after administration for 7 days in FIG.

As described above, it was found that TCI exerts an anxiolytic effect by administering a certain amount even if it is a single dose.

FIG. 4 is a graph showing the results when 7-MeO-TCI was administered daily for 7 days. The horizontal axis represents the dose of 7-MeO-TCI (mg / kg / day), and the vertical axis represents the ratio (%) of the OA residence time. The white bars and black bars are the same as those in FIGS.

When 7-MeO-TCI was not administered, the ratio (%) of OA residence time was significantly different between non-stressed mice and SART-stressed mice, and SART-stressed mice were mostly covered with CA. I was on top.

However, when 7-MeO-TCI was administered 20 (mg / kg / day), the ratio of OA staying time (%) was the same as that of non-stressed mice. In other words, it was possible to conclude that 7-MeO-TCI alleviated mouse anxiety.

FIG. 5 (a) and FIG. 5 (b) are the results of measuring the pharmacokinetics using high performance liquid chromatography (High Performance Liquid Chromatography). 5A shows the case of TCI, and FIG. 5B shows the case of 7-MeO-TCI. In both FIG. 5 (a) and FIG. 5 (b), the horizontal axis represents time (minutes), and the vertical axis represents serum concentration (ng / ml).

For mouse serum, 40 mg / kg body weight of TCI or 7-MeO-TCI was orally administered once and collected after 30 minutes, 60 minutes, 90 minutes, 120 minutes, and 240 minutes by centrifugation. did. Measurement at each time was performed with n = 3 (number of samples = 3). In addition, blood was collected by right atrial puncture after the lapse of a predetermined time after administration of each substance.

Referring to FIG. 5 (a), TCI had a serum concentration peaked within 30 minutes after administration, and the half-life was approximately 60 minutes. In addition, referring to FIG. 5 (b), 7-MeO-TCI also had a serum concentration peak at about 30 minutes after administration, and the half-life could be estimated to be about 60 minutes. In addition, comparing FIGS. 5A and 5B, the serum concentration of 7-MeO-TCI is very small compared to TCI. Since the dose is the same, 7-MeO-TCI can be said to absorb less than TCI.

On the other hand, from the results shown in FIG. 4, 7-MeO-TCI exhibits an anxiolytic effect similar to that of TCI in daily administration. Therefore, it can be said that 7-MeO-TCI exhibits an anxiolytic action even if the amount of absorption is small.

As described above, TCI and 7-MeO-TCI can be absorbed into the body by ingestion and exert an anxiolytic effect. In addition, its half-life is as short as about 1 hour.

TCI and 7-MeO-TCI, which are anti-anxiety substances according to the present invention, have the effect of relieving stress and feeling anxious. Therefore, pharmaceutical compositions and processed foods containing these substances have an effect of relieving stress.

Claims (4)

1. (1) An anxiolytic pharmaceutical composition comprising, as a main component, 1,2,3,4-tetrahydrocyclopenta [b] indole represented by the formula:
   

   

   ... (1)
2. (2) An anxiolytic pharmaceutical composition comprising, as a main component, 7-methoxy-1,2,3,4-tetrahydrocyclopenta [b] indole represented by the formula:
   

   

   ... (2)
3. (1) A processed food having an anxiolytic action comprising 1,2,3,4-tetrahydrocyclopenta [b] indole represented by the formula:
   

   

   ... (1)
4. (2) A processed food having an anxiolytic action comprising 7-methoxy-1,2,3,4-tetrahydrocyclopenta [b] indole represented by the formula:
   

   

   ... (2)
   
   

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