JP2002284683A - Appetite suppressant - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new type of medicine having low toxicity and little adverse effect, and having appetite suppressing or appetite inhibiting effect. SOLUTION: The appetite suppressant includes pipecolic acid or a medically acceptable salt thereof as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a drug having an appetite-suppressing or appetite-reducing action, and more particularly to an appetite suppressant containing pipecolic acid or an acid addition salt thereof as an active ingredient.

[0002]

2. Description of the Related Art In recent years, obesity has tended to increase as food conditions have improved and living has improved, or due to mental stress. Obesity is a condition in which the amount of adipose tissue occupying the body is abnormally increased, and is a cause of adult illness. Gallstone disease, fatty liver, infertility, osteoarthritis, etc. are likely to be complicated.

[0003] Obesity is classified into two types: regulatory obesity due to abnormally high appetite and metabolic obesity in which there is an abnormality in metabolism irrespective of eating style and proliferation occurs in fat. The basis of obesity treatment is a combination of diet and exercise therapy, but this has limitations, and pharmacotherapy is expected to be particularly effective for severe obesity.

[0004] Amphetamine-based drugs (stimulants) are known to have the strongest action as drugs having an appetite suppressing or reducing appetite, but they belong to central stimulants, Care must be taken when using it because it also produces an excitatory effect. Similarly, fenfluramine, mazindol, phentermine, and the like are known as cafilon and sympathomimetics that have awakening effects and suppress appetite by central action, but none of them are sufficient in terms of effect and side effects. I can't say.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a new type of a drug having an appetite suppressing or reducing appetite with low toxicity and few side effects.

[0006]

Means for Solving the Problems The present inventors have made intensive studies to achieve the above object, and as a result, a racemic form of pipecolic acid represented by the following structural formula, which is an analog of lysine which is a kind of amino acid, The present inventors have found that the optically active substance and its acid addition salt have an excellent appetite suppressing or appetite-reducing action, and have completed the present invention.

[0007]

Embedded image

[0008] That is, the present invention is an appetite suppressant comprising pipecolic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION L-Pipecolic acid according to the present invention
Although the body exists widely in plants, both optically active and racemic forms are known in the art, for example [Fujii, M.
iyoshi, Bull. Chem. Soc. Japan
n 48, 1341 (1975)], [R. T. Shu
man et al. , J. et al. Org. Chem. 55 , 7
38 (1990)].

The active ingredient of the present invention, pipecolic acid, may be any of racemic, L-form and D-form, but L-form is particularly preferred.

The pharmaceutically acceptable salts of pipecolic acid include salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, acetic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid and the like. Examples include salts with organic acids, preferably hydrochloride, lactate, malate and tartrate.

With respect to the pharmacological action of pipecolic acid or an acid addition salt thereof, it is known that the release of GABA which is an inhibitory neurotransmitter is increased and the uptake is suppressed.
It has never been known to have an appetite-suppressing action or an appetite-reducing action, and was first found by the present inventors. It should be noted that, as apparent from the test examples described below, pipecolic acid has an appetite-suppressing effect similar to that of the L-form, and administration of pipecolic acid when compared with the precursor lysine. A significant difference in the amount is observed. The acute toxicity of L-isomer to rats is as low as 0% even at 200 mg / kg c.p. (intraperitoneal administration), indicating that it is a very safe compound.

When pipecolic acid or a salt thereof is used as an appetite suppressant, it is administered alone or diluted with a pharmaceutically acceptable solid or liquid carrier. The preferred preparation form and administration form are appropriately determined according to the age, sex, weight, degree of symptoms, treatment time, etc. of the patient.

Therapeutic doses are generally between 5 and 100 for parenteral administration.
mg / kg-day, 100-1000 mg / k by oral administration
g.day, and can be administered once to three times a day. For oral administration, it is used in the form of tablets, capsules, powders, granules, liquids, elixirs and the like, and for parenteral administration, it is used in the form of a sterile liquid.

As an example of a solid carrier, a gelatin type capsule is usually used. As an excipient, gelatin: sugars such as lactose, glucose, mannitol, xylitol and erythritol: starches such as corn, wheat, rice and corn starch: fatty acids such as stearic acid: fatty acids such as calcium stearate and magnesium stearate Salt: sodium carbonate: sodium hydrogen phosphate: talc:
Vegetable oil: alcohol such as stearyl alcohol: gum:
And polyalkylene glycol.

These capsules, tablets, granules and powders are
It generally contains 10 to 90% by weight, preferably 30 to 70% by weight, of a pipecolic acid compound as an active ingredient. As the liquid carrier, water, physiological saline, textrose or a similar saccharide solution, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are generally preferred.

When administered parenterally by intramuscular injection, intravenous injection, or subcutaneous injection, it is used as a sterile solution to which other solutes such as salt or glucose are added. Suitable solvents for injection include sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, glucose, liquid for intravenous injection,
Electrolyte solution (for intravenous injection) and the like. In the case of these injections, usually 1 to 50% by weight, preferably 1% by weight.
It may be desirable to include 〜25% by weight of the active ingredient.

In the case of a liquid preparation for oral administration, 10 to 90% by weight
Suspension or syrup containing the active ingredient is preferred.

Next, the present invention will be described specifically with reference to examples, but the present invention is not limited to these examples.

[0020]

EXAMPLES <Formulation Example 1> 54 g of erythritol and 45 g of corn starch were thoroughly mixed, and 1 g of this was added to 20 g of water.
Of L-pipecolic acid was added, granulated and dried, and then passed through a No. 32 sieve to obtain a powder containing 1%.

<Preparation Example 2> 51 g of glucose, 34 g of corn starch, 10 g of talc and 3 g of sodium hydrogen phosphate are sufficiently mixed, and then an aqueous solution obtained by dissolving 1 g of L-pipecolic acid in 20 g of water is added, followed by granulation and drying. It was sized. 1 g of a magnesium stearate lubricant was added to the mixture, mixed, and then made into a tablet of 100 mg per tablet by a conventional method.

[Appetite Suppression Test] Test animals and test feed in Experimental Examples 1 to 4: Cobb strain broiler male chicks, 2 days old, were separately raised. The number n of wings used in the experiment is shown in FIGS.

The feed fed was a commercial feed (Toyohashi Feed “H
i-Health Bait AX SAFETY (trade name) was used.

Method of administration of the solution: Administration of the chick to the ventricle
This was performed using an acrylic stereotaxic apparatus and a Hamilton microsyringe (Davis, JL, Mas).
Uoka, D .; T. , Gerbrandt, J .; F. ,
Cherkin, A .; 1979. Autoradio
graphic distribution of L-
prolinein chickens after int
raceebral injection. Phys
iol. Behav. 22, 693-695). Oral administration was performed by attaching a vinyl hose to the tip of a 1 ml syringe (manufactured by Terumo Corporation) and inserting the tip into the capsule through the pharynx.

Test Example 1: Effect of intraventricular administration of L-pipecolic acid on feed intake of chicks The chicks were fasted for 3 hours, during which time only water was given freely.
L-Pipecolic acid was dissolved in 0.85% saline containing 0.1% Evans blue at two levels of 0.5 mg and 1.0 mg, and administered to the chick ventricle.
And 120 minutes of food intake. As a control, 0.85% physiological saline containing 0.1% Evans blue was used, and 10 μl was administered per bird. At the end of the experiment, the chicks were sacrificed and individuals for which no pigment was found in the ventricle were excluded from the calculations.

As shown in FIG. 1, a significant suppression of feed intake was observed in the group administered with 1 mg of L-pipecolic acid 30 minutes after feeding the feed compared to the control group as shown in FIG.
This effect continued even after 60 minutes. At 120 minutes, the suppression began to be released, but the feed intake was still significantly lower than in the control group. However, in the 0.5 mg L-pipecolic acid administration group, no significant difference was observed at each time from the control group. L produced from L-lysine in the brain
-Pipecolic acid was found to have a function of suppressing feeding behavior.

Test Example 2: Effect of ventricular administration of D-pipecolic acid on feed intake of chicks It is known that L-pipecolic acid taken as a nutrient is also metabolized to D-pipecolic acid by microorganisms in the digestive tract. Therefore, the same experiment was performed except that D-pipecolic acid was administered instead of L-pipecolic acid in Test Example 1. That is, the chicks were fasted for 3 hours, during which time they were given only water. 0.5 mg of D-pipecolic acid in 0.85% saline containing 0.1% of Evans blue was added.
0 mg was dissolved at two levels and administered to the chick ventricle, after which the food intake for 30, 60 and 120 minutes was investigated.
Controls contain 0.1% Evans blue.
Using 85% physiological saline, 10 μl was administered per bird. At the end of the experiment, the chicks were sacrificed and individuals without pigment in the ventricle were excluded from the calculation. As shown in FIG. 2, it was found that the same effect as in the L type was also obtained in the D type.

Test Example 3 (Reference Example): Influence of intraventricular administration of L-lysine monohydrochloride on feed intake of chicks To confirm the effect on L-lysine, a precursor of L-pipecolic acid, An experiment was performed.

That is, chicks were fasted for 3 hours, during which time they were given water only. 0.1 L-lysine monohydrochloride
1m in 0.85% saline containing 0.1% Evans Blue
g, 2 mg and 4 mg were dissolved and administered to the chick ventricle, after which the food intake at 30, 60 and 120 minutes was investigated. As a control, 0.85% physiological saline containing 0.1% Evans blue was used, and 10 μl was administered per bird. At the end of the experiment, the chicks were sacrificed and individuals for which no pigment was found in the ventricle were excluded from the calculations.

As shown in FIG. 3, as shown in FIG. 3, administration of 1 mg at which L-lysine had an effect on L-lysine did not suppress food intake, but required a larger amount to achieve the effect. It turns out that it is necessary.

Test Example 4: Effect of oral administration of L-pipecolic acid and L-lysine on feed intake of chicks From the results of Test Examples 1 to 3, L-lysine is metabolized to L-pipecolic acid. In addition, it was revealed that the substance had an antifeeding effect in the brain. Therefore, the present experiment was performed to clarify whether or not this effect is exhibited even when taken orally. In this experiment, the administration of the feed was started 30 minutes after oral administration in consideration of the absorption of L-lysine and L-pipecolic acid.

That is, the chicks were fasted for 3 hours, and only water was freely given during that time. After that, the chicks were divided into 7 groups,
The group was orally administered 1 ml of physiological saline as a control. The other six groups were administered with L-pipecolic acid or L-lysine dissolved in 1 ml of physiological saline in 0.1, 0.2 and 0.4 mmol, respectively. Feeding was started 30 minutes after that, and the feed intake at 30, 60 and 120 minutes was investigated.

The results are shown in FIG.
No significant difference was detected between the sample intakes of the L-pipecolic acid and L-pipecolic acid at 120 minutes.
The value was significantly reduced in the 4 mmol group as compared with the other administration groups.
On the other hand, since no effect was observed with an equivalent amount of L-lysine, it was found that the effect of L-pipecolic acid on food intake was also effective by oral administration.

Test Example 5: L to mouse food intake
Effect of oral administration of-and D-pipecolic acid: 8-week-old mice were fasted for 17 hours, and L-pipecolic acid and D-pipecolic acid solution were orally administered, and allowed to freely ingest for 3 hours after 30 minutes. The pipecolic acid dosed was 0.
It was 200 μmol in 2 ml. Saline was administered to the control. The number of animals used was control (6), L
-Pipecolic acid (L-PA) (6 animals), D-Pipecolic acid (D-PA) (6 animals), unit of feed intake is g.

As shown in Table 1, the results were from 60 minutes after administration.
Remarkable suppression of intake in the L-PA administration group was observed over 120 minutes and 120 minutes to 180 minutes.

[0036]

[Table 1]

[0037]

As described above, since the appetite suppressant of the present invention has an excellent appetite suppressing or appetite-reducing action, it is useful as a therapeutic agent for obesity.

[Brief description of the drawings]

FIG. 1 is a drawing showing the effect of intraventricular L-pipecolic acid administration on feed intake of male broiler chicks.

FIG. 2 is a graph showing the effect of intraventricular D-pipecolic acid administration on feed intake of male broiler chicks.

FIG. 3 is a graph showing the effect of intraventricular L-lysine monohydrochloride administration on feed intake of male broiler chicks.

FIG. 4. L- to feed intake of male broiler chicks
Drawing which shows the effect of the oral administration of pipecolic acid and L-lysine.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C054 AA02 CC01 DD32 EE01 FF01 4C086 AA01 AA02 BC21 MA01 MA04 MA52 MA66 NA14 ZA70

Claims (2)

[Claims] An appetite suppressant comprising pipecolic acid or a pharmaceutically acceptable salt thereof as an active ingredient. 2. The appetite suppressant according to claim 1, wherein the pipecolic acid is in an L form.