JPH1077229A - Inhibitor against spontaneous movement - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare an inhibitor against spontaneous movement capable of effectively inhibiting human and animal spontaneous movement and useful for preventing the wondering around caused by senile dementia, etc., by using a specific 5-methoxytryptamine derivative as an active ingredient. SOLUTION: This inhibitor against spontaneous movement includes 5- methoxytryptamine derivative having a docosahexaenoyl group of the formula as an active ingredient. For example, the 5-methoxytryptamine derivative of the formula is obtained by reacting 5-methoxytryptamine with corresponding docosahexaenoic chloride in a solvent in the presence of triethylamine, etc. The compound of the formula is commonly administered in a daily dose of 1g by dividing into one or several doses. The inhibitor against spontaneous movement can be administered as an orally administering agent such as powder, granule, tablet and syrup, or a parenterally administering agent such as injection, an agent for intrarectal administration and skin preparation for external use.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a locomotor activity inhibitor comprising a 5-methoxytryptamine derivative having a docosahexaenoyl group as an active ingredient.

[0002]

2. Description of the Related Art In recent years, as the elderly population has increased, care for the elderly has become a major social problem. Family members are the most common caregivers, but the family is generally exhausted because the care period is long, generally on a yearly basis. In particular, wandering at night due to senile dementia not only poses a high risk of accident to the person, but also hinders the sleep of the family and increases their physical and mental fatigue. Since wandering in dementia is considered to be a symptom manifested by an increase in anxiety of the patient, it is desired to administer a drug for soothing the mental state of the patient. However, drugs such as tranquilizers currently used in clinical practice have strong side effects, and it is not desirable to administer them to elderly people whose metabolic function is systemically reduced. That is, it is desired to supply a drug having a mild side effect and a mild action.

[0003] In general, exercise performed by humans and animals spontaneously without being forced by others is called spontaneous exercise. It is known that the spontaneous movement increases when anxiety is felt such as being placed in a new environment. The above-mentioned wandering at night is also considered as a kind of spontaneous exercise.

[0004] N-acetyl-5-methoxytryptamine is called melatonin and is a hormone synthesized in the pineal gland. Its secretion shows a circadian rhythm and is considered to be a hormone that controls the diurnal rhythm, and a sleep-inducing effect has been reported in humans (Proc. Natl. Acad. Sci., 91,
1824, 1994). On the other hand, it has been reported that docosahexaenoic acid (DHA), which is an n-3 series polyunsaturated fatty acid, has effects such as improvement of memory, learning ability, immunosuppression, etc., as well as reduction of aggressiveness (J . Clin. Inv., 97,1129,
1996). In addition, it is known that both melatonin and DHA are components existing in a living body and have few side effects even when administered in large amounts.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a locomotor activity inhibitor which can suppress the locomotor activity of humans and animals.

[0006]

Means for Solving the Problems The present inventors have proposed a 5-methoxytryptamine derivative represented by the following formula (I):
The present invention has been completed based on a new finding that it exhibits an excellent locomotor activity-suppressing action.

That is, the present invention provides a compound of the formula (I)

[0008]

Embedded image

The present invention provides a locomotor activity inhibitor comprising a 5-methoxytryptamine derivative represented by the formula (1) as an active ingredient.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The 5-methoxytryptamine derivative having a docosahexaenoyl group represented by the above formula (I) of the present invention can be obtained, for example, by adding 5-methoxytryptamine and the corresponding docosahexaenoic acid chloride to a solvent such as triethylamine Can be produced by reacting in the presence of

The dosage of the 5-methoxytryptamine derivative of the present invention varies depending on age, sex, body weight, symptoms, or administration form, but is generally about 1 g per day, and may be divided into one or several doses. Can be taken.

The 5-methoxytryptamine derivative according to the present invention can be administered orally or parenterally for treatment.

[0013] Oral preparations may be solid preparations such as powders, granules, capsules and tablets or liquid preparations such as syrups and elixirs. In addition, parenteral preparations include injections, rectum preparations, skin external preparations, and inhalants. These preparations are prepared in a conventional manner by adding a pharmaceutically acceptable production auxiliary to the active ingredient. Furthermore, it is also possible to prepare a sustained-release preparation by a known technique.

To prepare a solid preparation for oral administration, the active ingredient is mixed with excipients such as lactose, starch, crystalline cellulose, calcium lactose, magnesium aluminate metasilicate, silicic anhydride and the like to form a powder. Alternatively, if necessary, a binder such as sucrose, hydroxypropylcellulose, polyvinylpyrrolidone and the like, and a disintegrant such as carboxymethylcellulose and calcium carboxymethylcellulose are added and granulated by wet or dry granulation. To produce tablets, these powders and granules may be compressed as they are or by adding a lubricant such as magnesium stearate or talc. These granules or tablets are coated with an enteric base such as hydroxypropylmethylcellulose phthalate, methacrylic acid, methyl methacrylate copolymer and the like, and enteric-coated preparations, or coated with ethylcellulose, carnauba wax, hydrogenated oil, etc. You can also. To produce capsules, powders or granules can be filled in hard capsules, or the active ingredient can be dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film to give soft capsules. .

To prepare a liquid preparation for oral administration, the active ingredient and a sweetening agent such as sucrose, sorbitol, and glycerin are dissolved in water, and a clear syrup is further added. Alternatively, gum arabic, tragacanth, polysorbate 80, sodium carboxymethylcellulose and the like may be added to form an emulsion or suspension. These liquid preparations may optionally contain a flavoring agent,
You may add a coloring agent, a preservative, etc.

In preparing an injection, the active ingredient may be converted into hydrochloric acid, sodium hydroxide, lactose, sodium lactate,
Dissolve in distilled water for injection together with a pH adjuster such as sodium monohydrogen phosphate and sodium dihydrogen phosphate, and an isotonic agent such as sodium chloride and glucose, and aseptically filter and fill into ampoules, or mannitol, dextrin , Cyclodextrin, gelatin and the like may be added and freeze-dried under vacuum to give a dissolvable injection before use. In addition, lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil and the like may be added to the active ingredient and emulsified in water to prepare an emulsion for injection.

To prepare a rectal preparation, the active ingredient and a suppository base such as cocoa butter and fatty acid tri-, di- and monoglycerides and polyethylene glycol are moistened, melted, poured into a mold and cooled. The active ingredient may be dissolved in polyethylene glycol, soybean oil or the like, and then coated with a gelatin film.

To prepare an external preparation for skin, the active ingredient is added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol and the like, and if necessary, moistened and kneaded to obtain an ointment, or rosin, alkyl acrylate After kneading with an adhesive such as a polymer, it is spread on a nonwoven fabric such as polyethylene to form a tape. To make an inhalant,
The active ingredient is dissolved or dispersed in a propellant such as Freon gas and filled into a pressure-resistant container to form an aerosol.

The medicament of the present invention having the above constitution can be produced by a known production method, for example, the method described in the Japanese Pharmacopoeia 10th Edition General Rules for Preparations or a method with appropriate improvements.

[0020]

The present invention will be described in more detail with reference to Synthesis Examples and Test Examples.

Synthesis Example 1 Synthesis of 5-methoxytryptamine derivative Oxalyl chloride (0.08 mL, 0.1 mL) was added to a solution of docosahexaenoic acid (0.099 g, 0.3 mmol) in tetrahydrofuran (2 mL).
After stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure to prepare docosahexaenoic acid chloride. Then, 5-methoxytryptamine (0.057 g, 0.3 mmol),
To a solution of triethylamine (0.06 mL, 0.4 mmol) in dichloromethane (2.0 mL) was added the above prepared solution of docosahexaenoic acid chloride in dichloromethane (1.0 mL) at 0 ° C, and the mixture was further stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (treated with a 5% hexane solution of triethylamine) (hexane / ethyl acetate = 1/1) to give the desired 5-methoxytryptamine derivative (I) having a docosahexaenoyl group (0.090 g). , 0.18 mmol, 60%)
I got

¹ H NMR (CDCl ₃ , 400 MHz) δ 0.97 (3H,
t, J = 7.5 Hz), 2.07 (2H, m), 2.16 (2H, t, J = 7.2
Hz), 2.38 (2H, m), 2.77-2.88 (10H, m), 2.93 (2H, m
t, J = 6.7 Hz), 3.59 (2H, ddd, 6.7, 6.7, 5.9 Hz),
3.85 (3H, s), 5.28-5.43 (12H, m), 5.56 (1H, br
t, 5.9 Hz, CO-NH), 6.86 (1H, dd, J = 2.4, 8.8 Hz),
6.99 (1H, d, J = 2.4 Hz), 7.02 (1H, d, J = 2.4 H
z), 7.250 (1H, d , J = 8.8 Hz), 8.10 (1H, br, NH). 13 C NMR (CDCl 3) δ 14.23, 20.52, 23.38, 25.32, 25.
51, 25.54, 25.60, 36.52, 39,55, 55.91, 100.50, 11
1.96, 112.42, 112.68, 122.76, 126.98, 127.72,127.8
4, 128.05, 128.10, 128.22, 128.24, 128.28, 128.56,
129.22, 131.53, 132.03, 154.08, 172.28.IR (neat) 3408, 3298, 3013, 2962, 2934, 1651, 158
3, 1527, 1485, 1440, 1392, 1356, 1267, 1217, 1172,
1072, 1035, 923, 829, 796, 711, 430 cm ^-1 . Mass (m / z) 500 (M ⁺ ).

Test Method for Spontaneous Momentum The test substance was prepared in advance by Cremophor EL (Sigma Chemic).
al Co.) and the final cremophor EL immediately before the test.
It was diluted in physiological saline to a concentration of 10%. Four-week-old Crj: CD-1 (ICR) male mice were quarantined and bred for 5 days, and those considered healthy from the observation of body weight and general condition were used for the experiment. Animal temperature 24 ± 2 ℃, humidity 55 ± 10
%, Ventilation rate 13 times / hour, lighting 12 hours (7 am to 7 pm
Time). The sample was a high-pressure steam-sterilized solid feed (MF, manufactured by Oriental Yeast Co., Ltd.), and the drinking water was freely ingested well water (residual chlorine concentration of about 2 ppm) to which sodium hypochlorite was added, using a water bottle. The test consisted of three trials of three mice per group, and a test substance solution (10 ml / kg) was administered from the tail vein at a rate of 2 ml / min. After administration, transfer to a cage with a magnetic field line sensor, and increase spontaneous
Every minute, it was measured with a spontaneous locomotion sensor of an experimental animal (NA-AS01, manufactured by Neuroscience Corporation).

The obtained test results are expressed as a mean value ± standard error. A variance analysis was performed for the control group, test substance group and control substance group of each test group, and when the difference between the groups was significant, Dunnett's multiple A test (Dunnet's multiple test) was performed. The significance level in the test was set to 5% or less.

Test Example 1 As a test substance, 100 mg / kg of the 5-methoxytryptamine derivative (DHA-MT) of the present invention was used, and the locomotor activity was measured according to the test method described above. Table 1 shows the results. The administration of this substance confirmed a significant decrease in locomotor activity.

Comparative Test Example 1 Ethyl docosahexaenoate (DHA-Et) was used as a test substance.
Locomotor activity was measured using 60 mg / kg according to the test method described above. Table 1 shows the results.

Comparative Test Example 2 Spontaneous locomotor activity was measured using melatonin (40 mg / kg) as a test substance according to the test method described above. Table 1 shows the results.

Comparative Test Example 3 As a test substance, a mixture of melatonin 40 mg / kg and ethyl docosahexaenoate 60 mg / kg was used, and the locomotor activity was measured according to the test method. Table 1 shows the results.

[0029]

[Table 1] Table 1. Spontaneous momentum ─────────────────────────────────── Spontaneous momentum Substance name Dose ───────時間 Time period after administration (min) (mg / kg) 0-10 10-20 20-30 30-40 40-50 50-60 ───不 No test substance included-383 334 332 313 253 131 (control) ± 34 ± 37 ± 35 ± 51 ± 34 ± 90 ----------------------------------------- ----------------------------- DHA-MT 100 267 79 75 52 68 109 ± 46 ± 16 ± 19 ± 15 ± 42 ± 62 ------------------------------------------------- --------------------- DHA-Et 60 367 355 326 347 257 246 ± 4 ± 47 ± 40 ± 13 ± 83 ± 27 Melatonin 40 319 325 329 318 276 218 ± 24 ± 57 ± 13 ± 19 ± 35 ± 13 DHA-Et 60 349 380 303 256 287 217 + Melatonin 40 ± 17 ± 31 ± 24 ± 34 ± 53 ± 35 35 ────────── ────────────

[0030]

Industrial Applicability The locomotor inhibitor of the present invention effectively suppresses locomotor activity of humans and animals. Therefore, wandering in senile dementia and the like can be suppressed.

Claims (1)

[Claims] [Claim 1] The following formula: A locomotor inhibitor comprising, as an active ingredient, a 5-methoxytryptamine derivative represented by the formula: