JP3007097B2 - Hypnotic composition - Google Patents

Description

The present invention relates to 6-isopropoxy-9-oxoxanthen-2-carboxylic acid (6-isopropoxyxanthone-2).
-Also called carboxylic acids) as active ingredients. The composition is a prostaglandin
It is a novel sleeping pill composition that acts by antagonizing E ₂ (hereinafter abbreviated as PGE ₂ ).

Problems to be Solved by the Invention Various compounds have been known as sleeping pills, and their action mechanisms are various.

However, known sleeping pills have some drawbacks,
There is a constant need for sleeping pills that work by new mechanisms.

Means for Solving the Problems The present inventors have previously found that PGE ₂ suppresses both slow wave sleep and paradoxical sleep and increases awake time (Refs. 1 and 2; The present invention is summarized at the end of the “Detailed description of the invention”). This effect of PGE _{2 on} sleep / wake was also demonstrated in a continuous infusion experiment into unrestricted rats showing a normal circadian rhythm (Reference 2).

Meanwhile, PGE ₂ has been known to have an increased temperature action (Reference 4-7), also is where widely accepted is that the sleep-wake is closely related to the body temperature.

Thus, the result of increased arousal by PGE ₂ The present inventors have found that, whether a result of the primary and specific effects of PGE _2, or brought secondarily by temperature rise due to PGE ₂ It was unknown whether there was.

The present inventors have been further studying to clarify the mechanism of action of the arousal action of PGE ₂ , and found that 6-isopropoxy-9-oxoxanthene-2-carboxylic acid was converted to PGE ₂
Antagonized the wakeful action of PGE ₂ without antagonizing the body's warming action and increased both slow-wave sleep and paradoxical sleep, thus elucidating the mechanism of action of PGE ₂ on wakefulness . The present invention has been achieved based on such knowledge.

That is, the present invention provides a hypnotic composition containing 6-isopropoxy-9-oxoxanthene-2-carboxylic acid as an active ingredient.

The 6-isopropoxy-9-oxoxanthene-2-carboxylic acid used in the present invention has the following structure: (Melting point = 264-267 ° C .; hereinafter abbreviated as compound I), which is considered to be useful for treating allergic symptoms (US Pat. No. 3,949,084; West German Patent Application Publication No. 2,2).
No. 34,251). Further, it has been reported that compound I antagonizes PGE ₂ in isolated smooth muscle specimens, and is classified as an antagonist of EP ₁ receptor, one of the subtypes of PGE ₂ receptor (Reference 3). Further, Compound I
Is also known to be a specific inhibitor of the prostaglandin D ₂ (hereinafter abbreviated as PGD ₂ ) receptor in human platelets, although the activity is weak (Reference 10). However, the hypnotic activity of Compound I has not been known at all.

Compound I is described, for example, in U.S. Pat.
It can be produced according to the method described in No. 4 or the method of Exchlein et al. (Reference 19).

The sleeping pill composition of the present invention together with the active ingredient compound I,
It contains a pharmaceutically acceptable carrier, diluent, and / or excipient. These carriers, diluents and excipients may be selected from those commonly used in the art, and the production of the present composition may be performed according to a conventional method in the art.

The sleeping pill composition of the present invention can be administered orally (gavage, enteral tract) or parenterally, for example, by suppository, injection (muscular, subcutaneous, intravenous) or continuous intravenous infusion.

The dose of Compound I is about 0.001 to about 5 mg / kg per day.
And preferably in the range of 0.01 to 0.1 mg / kg.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 Synthesis of Compound I Metallic sodium (2.3 g; 0.1 mol) was dissolved in isopropyl alcohol (100 ml), and 6-chloroxanthone-2-carboxylic acid (5.5 g; 0.02 mol) in DMF (about
40 ml) solution was added. The mixture is refluxed for 40-50 hours,
It was then evaporated to dryness. The residue was dissolved in water, decolorized with activated carbon and filtered.

The precipitate formed by acidifying the filtrate was collected, washed with water, and recrystallized from ethanol to give compound I (33% yield; mp 264-267 ° C).

Example 1 Action of Compound I A. Experimental method Male Sprague-Dawley rats (280-380 g)
The patient was operated on under pentobarbital anesthesia (50 mg / kg body weight). A stainless cannula (0.35 mm outside diameter) for continuous infusion into the third ventricle was stereotactically inserted 9 mm from the 3.4 mm outer brain surface of bregma at an angle of 20 ° to the mid-sagittal plane. Electrodes for electroencephalography (EEG) recording were placed on the frontal parietal surface of the cerebrum, and indifferent electrodes were attached to the frontal skull. Some rats have a thermistor probe implanted into their thalamus region. Cannula,
The electrodes and thermistor probe were fixed to the skull with dental cement. Electrodes for electromyography (EMG) recording were attached to the muscle at the top. Details of these experimental methods have already been reported (References 2, 8, and 9).

After surgery, each rat was allowed to recover in an individual cage for one week.
A continuous infusion of saline into the third ventricle of each rat was then started and continued until the end of the experiment, except during the period of infusion of the test solution. The test solution was prepared by dissolving the test substance in physiological saline. The injection of the physiological saline or the test solution was performed at a rate of 10 µ per hour (10 µ / hr). Injections and recordings of EEG, EMG, and brain temperature were performed via slip rings to ensure that the rat's incense was not restricted. Rats were acclimated to continuous infusion and other experimental conditions for about 5 days before the start of the experiment.

One experiment consists of a three-day record of the baseline, experimental, and recovery dates. The experiment was performed at a temperature of 25 ± 1 ° C and a relative humidity of 60 ±
Performed in a sound-insulated, electromagnetically shielded laboratory adjusted to 6%. Lighting period is from 8:00 to 20:00,
The dark period was set from 20:00 to 8:00.

Injection of the test solution is performed for 6 hours from 23:00 to 5:00 (night administration) or 12:00 to 18:00 (day administration) on the experimental day. Either infusion was performed: 1) night administration of Compound I (2.1, 6.3, or 21 pmol / min); 2) night administration of PEG ₂ (10 pmol / min); 3) compound I (21 pmol / min). ) And PGE ₂ (10 pmol / min) concurrently at night; and 4) Compound I (21 pmol / min) during the day.

Compound I had limited solubility in physiological saline, and could not be administered at higher doses.

EEG and EMG records were determined to be slow-wave sleep, paradox sleep, or arousal based on the criteria (Reference 8) given by Honda, and the amounts of each were tested. The brain temperature was measured at 3-minute intervals using a thermistor probe (manufactured by Takara Industries). The numerical values recorded during each 30 minutes were averaged to obtain the brain temperature for that time period. The experimental and recovery day records were compared to that of the baseline day and statistical tests were performed using paired t-tests.

PGE ₂ and Compound I used in the experiments were obtained from Ono Pharmaceutical Co., Ltd. (Osaka) and Glaxo Group, respectively.
Research Limited (Glaxo Group Research Ltd., He
rtfordshire, UK).

B. Results The results of the above injections 1) to 4) are shown in FIGS. 1 to 3, Tables 1 and 2.

FIG. 1 shows quantitative changes in slow wave sleep (SWS), paradox sleep (PS), and arousal when Compound I was administered to unrestrained rats at rates of 2.1, 6.3, and 21 pmol / min ( (In minutes). ○ indicates the average amount of sleep or wakefulness on the reference day, and ● indicates the average amount of wakefulness on the experiment day (standard error is shown together). ** is P <0.01 and *** is P <0.001 by paired t-test.

FIG. 2 is a graph showing hourly SWS and PS amounts during a 24-hour period from dark to light, when Compound I was administered to unrestrained rats at a rate of 21 pmol / min at night. ○
Represents the average amount of sleep on the reference day, and ● represents the average amount of sleep on the experimental day (n = 9; standard error is also shown). * Is P <0.05 and ** is P <0.01 by paired t-test.

FIG. 3 shows compound I (21 pmol / min) alone, compound I
(21 pmol / min) and PGE ₂ (10 pmol / min), or
PGE ₂ (10 pmol / min) alone administered to unrestrained rats at night for 24 hours from dark to light or 12
It is a graph which shows the amount of awakening per hour (upper part) and the brain temperature every 30 minutes (lower part) with respect to time.は indicates the average arousal level (A, n = 9; B, n = 6; C, n = 5; standard error is shown together) and brain temperature (A ′, n) = 5; B ',
n = 3; C ', n = 3; the standard errors are 0.42, 0.48, and 0.81 ° C. or less for A', B ', and C', respectively; By a paired t-test,
* Indicates P <0.05 and ** indicates P <0.01.

Table 1 shows that when Compound I, PGE ₂ , or both were administered to unrestrained rats at night, the SW that appeared during that period
FIG. 10 shows the total amount of S, PS, and arousal, the duration of each episode, and the frequency of appearance, in comparison with the values in saline-injected rats at the same time on the base day. Each value in the table is shown as an average value ± standard error.

Table 2 shows the total amount of SWS, PS, and arousal that appeared during the day when Compound I was administered to unrestrained rats during the period, the duration and frequency of each episode, and the same time period on the reference day. 3 shows the values in comparison with the values in rats injected with physiological saline. Each value in the table is shown as an average value ± standard error.

1) Nighttime administration of Compound I When nighttime administration of Compound I alone (23:00 to 5:00), the amount of SWS and PS increases at any infusion rate of 2.1, 6.3, and 21 pmol / min. However, the arousal amount decreased (FIG. 1). When Compound I was infused at a rate of 21 pmol / min, SWS and PS were 122
% And 161%, while alertness is 82% of the baseline value
% (Table 1). Also, at this injection rate, PS
Increased from immediately after the start of the infusion of Compound I, and remained higher than the value on the reference day until one hour after the end of the infusion. Similarly, SW
S also showed an increase during compound I injection. After 12 o'clock in the light period after the injection of Compound I, SWS and PS tended to decrease, which can be interpreted as a recoil phenomenon (FIG. 2).
The bias from baseline recordings in hourly quantitative changes in SWS, PS, and alertness disappeared on the recovery day.

Looking at the respective episodes of SWS, PS, and arousal, there was no statistically significant change in episode duration or frequency of appearance other than significantly longer PS episode duration (first table). Compound I resulted in increased SWS and PS due to the synergistic effects of both prolonged duration and increased frequency of each episode. The reduction in wake-up time was primarily due to a reduction in episode duration.

With regard to brain temperature, Compound I infusion did not result in any change compared to the baseline day recording (FIG. 3A ').
However, a slight increase in brain temperature was observed after 12:30 in the light period after the injection of Compound I. This increase in brain temperature is due to SWS and PS
Decreased (Fig. 2) and increased arousal (Fig. 3).

2) When the night administered nightly dose of PGE ₂ PGE ₂ alone, SWS and PS decreased respectively 82% and 39% of the reference date, wake time 118%
Increased. A decrease in SWS is due to a decrease in episode duration, a decrease in PS is due to both a decrease in duration of the episode and a decrease in its frequency, and an increase in arousal is due to an increase in the frequency of the episode (Hereinafter, Table 1).

In addition, the brain temperature increased sharply when PGE ₂ was injected, but this phenomenon appeared with a decrease in SWS and PS and an increase in arousal (Table 1, FIGS. 3C and C ′).

3) When the compound I and the co-night administration of Compound I and PGE ₂ of PGE ₂ was nighttime administered simultaneously, SWS that appeared during the injection time, respectively of the total amount of PS, and wakefulness was substantially the same as that of the reference date (Table 1). Also,
Quantitative changes in hourly arousal is not Nanito different from those of the reference date, wake effects caused by the injection of PGE ₂ has been canceled (Figure 3 B).

On the other hand, the brain temperature indicate a rise in similar to the case by a single injection of PGE _2, were not at all inhibited (Fig. 3 B ').

4) Daytime administration of Compound I When Compound I alone is administered during the daytime (12: 00-18: 00), SW
S increased and alertness decreased. PS also tended to increase, but the change was not statistically significant. The increase in SWS was due to an increase in the duration of the episode, and the decrease in arousal was due to a synergistic effect of both a decrease in the duration of the episode and a decrease in its frequency. The increase in PS seems to have been caused by an apparent increase in the frequency of PS episodes (see
table).

C. Discussion In this study, continuous infusion of Compound I, PGE ₂ , and a mixture of both, and saline was performed at a very slow rate of 10 μ / hr (10 μ / hr),
The rats were not strained. In addition, slip
The use of rings prevented the behavior of the rats. Under such experimental conditions, as described in the previous detailed report (Reference 2), rats behaved normally and showed a clear circadian rhythm on the reference date.

The present inventors have previously shown that PGE ₂ reduces both SWS and PS (References 1 and 2). Moreover, whereas PGE ₂ has been known to have a temperature rise acts (Reference 4-7). It is widely accepted that sleep and wake are closely related to brain or body temperature, but there are reports to date that often the sleep or wake response is dissociated from the body temperature response. Has been observed (References 15 to 17). In the experiment of injecting PGE ₂ into the brain performed by the present inventors before, no increase in body temperature was caused by the minimum effective dose of PGE ₂ which exerts an effect of suppressing sleep and increasing arousal (Reference 1).

However, whether only by these findings, increased arousal by PGE ₂ is the result brought secondarily by temperature rise due to either or PGE _2, the primary and specific effects of PGE ₂ Cannot answer the question clearly. Therefore, in this study, to investigate further the detail PGE ₂ acts with a compound I as a PGE ₂ antagonist, in which was described above experiment.

In this experiment, PGE ₂ (10 pmol / min) was administered at night, resulting in a decrease in sleep (SWS and PS) and an increase in arousal. The results were similar to the effects obtained in the medium administration day previous PGE ₂ (Reference 2). Also, PG
E ₂ is increased the body temperature in the above doses, but this result was already good agreement with the results of other groups have been published.

In the present study, continuous infusion of Compound I (21 pmol / min) alone reduced arousal and increased sleep without affecting body temperature.

Also, infusion of Compound I with PGE ₂ inhibited the decrease in sleep caused by PGE ₂ but did not inhibit the rise in body temperature. That is, the compound I (21p mol / min) is the awakening effect of PGE ₂ (10p mol / min) was antagonized, PGE ₂ (10p mol /
Min) did not antagonize the effect of increasing body temperature.

These findings strongly suggest that PGE ₂ enhances alertness through a mechanism that is completely different from that associated with elevated body temperature.

As also noted above, Compound I has been reported to antagonize PGE ₂ in isolated smooth muscle specimens are classified as antagonists of EP ₁ receptor which is one of subtypes of PGE ₂ receptors ( Reference 3). In the human platelets, activity has been shown to be weak, a specific inhibitor of PGD ₂ receptor (Reference 10). PGE ₂ and PGD ₂ have the opposite effect on sleep and wakefulness, that is, PGE ₂ increases arousal (References 1, 2, and 11), while PGD ₂ has an effect of promoting sleep (References 11 to 14). Have. Thus, Compound I third results of this study obtained by ventricular infusion alone, the endogenous PGE ₂ which functions in the direction of promoting wakefulness in the brain compound I is described as antagonized. This description is an increase in arousal caused by PGE ₂ is supported by the fact that no longer seen as administering a compound I and PGE ₂ at the same time.

When Compound I was administered alone, both SWS and PS increased, and no specificity was observed for either SWS or PS. The increase in SWS and PS by night administration of Compound I was due to a synergistic increase in the length of each episode and an increase in the frequency of occurrence, while a decrease in arousal was caused by a decrease in the length of the episode . That is, the rats to which Compound I was administered seemed to sleep a lot for a long time and could not keep awake for a long time.

Furthermore, in this experiment, when Compound I was administered during the day, sleep and sleep were almost the same as when Compound I was administered at night.
There was an effect on arousal (although there was no statistically significant difference in PS increase). Therefore, it is not clear whether the sleep / wake mechanism administered by PGE ₂ involves a circadian rhythm, but it may function all day.

The change in sleep / wake caused by Compound I was accompanied by a recoil phenomenon. In our previous work, PGE ₂
A recoil phenomenon was observed after sleep suppression or arousal enhancement due to (Reference 2). There is a view that natural sleep / wake is partially controlled by some regulatory mechanism that maintains homeostasis (Reference 18). From this point of view, it can be said that the changes in sleep / wake caused by PGE ₂ or its antagonist are similar to natural sleep / wake.

The results obtained in this study support the speculation that PGE ₂ endogenously present in the brain plays a fundamental role in the physiological regulatory mechanisms of sleep and wakefulness. is intended to support that the hypnotic which act by antagonizing the action of the PGE _2.

Example 2 Oral Administration of Compound I Wistar male rats (230 to 270 g) were subjected to the same operation as in Example 1 and chronically implanted EEG and EMG recording electrodes. After a 5-7 day recovery period, the following experiment was performed. The lighting was set to be in the light period from 6:00 to 18:00 and in the dark period from 18:00 to 6:00.

The experiment consists of a reference date and an experiment date. Solvent on base date,
On the experimental day, each compound was orally administered to each rat between 17:20 and 17:40 immediately before the dark period using a gastric probe. As a solvent, a 5% aqueous solution of gum arabic was used, Compound I was suspended in the same solvent, and 3 mg / kg body weight was administered. The dose was 0.3 ml. EEG and EMG recordings were performed from 18:00 after administration of the solvent or Compound I.

The amount of appearance of sleep including both slow wave sleep and paradox sleep increased for 9 hours from the start of recording by administration of Compound I [243.5 ± 19.1 minutes (experimental day) vs. 202.4 ± 4.0 minutes (reference day) ) (N = 6), p <0.05], indicating that Compound I has a sleep-inducing effect not only when administered centrally but also when administered peripherally.

Example 3 Preparation Example A tablet was prepared using the following ingredients: Amount (mg / tablet) Compound I 2 Microcrystalline cellulose 46.5 Starch 50 Magnesium stearate 0.5 Talc 1 Total 100.0 The respective ingredients were mixed and compressed. Each gave 100.0 mg of tablets.

References 1.Matsumura, H., Goh, Y., Ueno, R., Sakai, T. & Hayaishi,
O. (1988) Brain Res. 444, 265-272.

2.Matsumura, H., Honda, K., Goh, Y., Ueno, R., Sakai, T., In
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6. Frstermann, U., Heldt, R. & Hertting, G. (1983) Ps
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7.Eguchi, N., Hayashi, H., Urade, Y., Ito, S. & Hayaishi,
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8.Honda, K., Komoda, Y., & Nishida, S., Nagasaki, H., Hig
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[Brief description of the drawings]

FIG. 1 shows slow wave sleep (SW) when Compound I was administered to unrestrained rats at 2.1, 6.3, and 21 pmol / min at night.
FIG. 6 is a graph showing quantitative changes in S), paradoxical sleep (PS), and arousal. FIG. 2 is a graph showing hourly SWS and PS amounts during a 24-hour period from dark to light, when Compound I was administered to unrestrained rats at a rate of 21 pmol / min at night. FIG. 3 shows that Compound I (21 pmol / min) alone and Compound I (2
Both 1p mol / min) and PGE ₂ (10p mol / min) or PGE,
₂ Hourly arousal and brain temperature every 30 hours for 24 hours from dark to light or 12 hours in dark, when (10 pmol / min) alone was administered to unrestrained rats at night FIG.

Continuation of the front page (56) References JP-A-48-103577 (JP, A) JP-B-48-717 (JP, B1) Brain Res. , 444 (1988) p. 265-272 Brain Res. , 481 (1989) p. 242-249 Br. J. Pharmacol. , Proc. Suppl. , 85 (1985) p. 273 Proc. Matl. Acad. Sc i. U. S. A. , 86 [14] (1989) p. 5666-5669 (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 31/00-31/80 C07D 311/00-311/96 CA (STN)

Claims (1)

(57) [Claims] 1. A hypnotic composition comprising 6-isopropoxy-9-oxoxanthene-2-carboxylic acid as an active ingredient.