JP5376786B2 - Nerve cell activation composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composition having excellent nerve cell activation action. <P>SOLUTION: The composition for nerve cell activation comprises a compound represented by the formula (1) as an active ingredient. The composition for nerve cell activation comprises a compound represented by the formula (1) and at least one selected from the group consisting of a compound represented by the formula (2) and a compound represented by the formula (3). <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention relates to a nerve cell activation composition containing a compound represented by the formula (1).

A nerve is composed of nerve cells, and is divided into a central nervous system that exists in the midline of the body for information integration, and a peripheral nervous system that exists as a separate fiber existing outside the center. This is a convenient distinction depending on the location, and there is no significant difference in their functional structure. When a failure occurs in these tissues, various symptoms occur due to impaired information transmission. For example, it begins with memory impairment such as dementia and Alzheimer's disease, facial paralysis, gastroasthenia, impotence, extraocular muscle paralysis, difficulty in urinating, bowel movement abnormalities, numbness in limbs, pain, dizziness, ulceration, etc. Is a serious symptom. Since nerves have weak regenerative power, regenerative medicine such as transplantation is mainly used for such symptoms. On the other hand, in recent years, there is a demand for a therapeutic or preventive drug such as a simpler oral preparation.
Japanese Clinical Vol. 64, 8, 1553-1559 (2006.8.1)

  The main object of the present invention is to provide a composition having an excellent nerve cell activation effect.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a compound represented by the following formula (1) (hereinafter sometimes referred to as compound 1) has a nerve cell activation effect. . Compound 1 is known to have strong cytotoxicity. The present inventors have found for the first time that Compound 1 specifically has a cell activation action on nerve cells, even though nerve cells have the same structure as normal cells. It has been done. Furthermore, the compound 1 is composed of a compound represented by the following formula (2) (hereinafter sometimes referred to as compound 2) and a compound represented by the following formula (3) (hereinafter sometimes referred to as compound 3). It discovered that the nerve cell activation effect increased by mix | blending at least 1 sort (s) selected from a group. The present invention has been completed as a result of further studies based on these findings.

That is, the present invention provides the following neuronal cell activation composition.
Item 1. The nerve cell activation composition characterized by containing the compound represented by following formula (1) as an active ingredient.

Item 2. Item 2. The composition according to Item 1, further comprising at least one selected from the group consisting of a compound represented by the following general formula (2) and a compound represented by the general formula (3): ;

[In General Formula (2), R represents —CN, —OH (H ₂ O), —CH ₃ or a group:

Show]

[In general formula (3), two

Are the same or different and represent a single bond or a double bond]
Item 3. Item 3. The composition according to Item 2, comprising at least one compound represented by the formula (2) in a total amount of 0.000005 to 1 part by weight with respect to 1 part by weight of the compound represented by the formula (1).
Item 4. Item 2 or 3 comprising at least one compound represented by the general formula (3) in a total amount of 0.0000034 to 0.09 parts by weight with respect to 1 part by weight of the compound represented by the formula (1). A composition according to any one of the above.
Item 5.
A method for activating nerve cells, comprising adding a compound represented by the following formula (1).

  According to the composition of the present invention, an excellent nerve cell activation action by Compound 1 is exhibited, and the function and activity of nerve cells are enhanced. Further, the combined use of Compound 1 and at least one selected from the group consisting of Compound 2 and Compound 3 can further enhance the nerve cell activation action.

  Such a composition of the present invention is considered to be particularly effective for the prevention or treatment of neurological diseases that conventionally had to rely on regenerative medicine.

  The nerve cell activation composition of this invention contains the following compound 1 as an active ingredient. In the present invention, the nerve cell activation action refers to an action that increases the function and activity of nerve cells and increases their vitality. Hereinafter, each component will be described.

(1) Compound 1
Compound 1 is a compound represented by the following formula (1) that is known to act as an antipyretic analgesic, and is commercially available from Daito Corporation.

  In the composition of the present invention, Compound 1 is usually administered in an amount of about 50 to 2400 mg, preferably about 100 to 1600 mg, more preferably about 150 to 800 mg per day for an adult (15 years or older, body weight of about 60 kg). Blend in.

  By using at least one selected from the group consisting of the compound 2 represented by the following general formula (2) and the compound 3 represented by the following general formula (3) in combination with the compound 1, the nerve of compound 1 The activation effect is further enhanced.

(2) Compound 2
Compound 2 is a compound represented by the following general formula (2), and is commercially available from DSM Nutrition Japan Co., Ltd.

[In General Formula (2), R represents —CN, —OH (H ₂ O), —CH ₃ or a group:

Show]
In the present invention, R of the compound 2 is preferably —CN.
Although the said compound 2 can also be used individually by 1 type, you may use it in combination of 2 or more type.

  The compounding quantity of the compound 2 in the composition of this invention can be suitably set based on the compounding quantity of the compound 1 so that there may exist the effect of this invention. When the compounding amount of Compound 1 is 1 part by weight, the compounding ratio of Compound 2 is generally about 0.000005 to 1 part by weight, preferably about 0.00002 to 0.16 part by weight, more preferably about 0.0. About 00008 to 0.075 parts by weight. With such a blending ratio, the nerve activation action of the composition of the present invention is remarkably exhibited. Especially the compounding quantity of the compound 2 is in the range of the said compounding ratio, Comprising: As an adult (15 years old or more, weight about 60 kg) daily amount, about 0.0125-2400 mg, Preferably it is about 0.025-1200 mg, and more It is desirable to blend so that the dose is preferably about 0.05 to 600 mg.

(3) Compound 3
Compound 3 is a compound represented by the following general formula (3), and is commercially available from DSM Nutrition Japan Co., Ltd.

In the general formula (3), two

Are the same or different and each represents a single bond or a double bond, preferably a double bond. Although the said compound 3 may be used individually by 1 type, you may use it in combination of 2 or more type.

  The compounding amount of the compound 3 in the composition of the present invention can be appropriately set based on the compounding amount of the compound 1 so that the effect of the present invention is exhibited. When the compounding amount of the compound 1 is 1 part by weight, the total amount And usually about 0.0000034 to 0.09 parts by weight, preferably about 0.00024 to 0.014 parts by weight, more preferably about 0.00096 to 0.00625 parts by weight. By containing Compound 1 and Compound 3 at such a ratio, the nerve cell activation action of Compound 1 is enhanced.

  Particularly, the compounding amount of compound 3 is within the range of the compounding ratio, and the compounding amount is about 0.25 to 40 mg, preferably 0.5 to 20 mg as a daily dose for an adult (over 15 years old, body weight about 60 kg). It is desirable that the amount is about 1 to 10 mg.

  As one of the preferred embodiments in which the effect of the present invention is remarkably exhibited, Compound 1 is contained in an adult (over 15 years old, body weight of about 60 kg) as a daily dose of about 150 to 800 mg; At least one compound 2 is in the range of about 0.00008 to 0.075 parts by weight and contains about 0.05 to 600 mg; at least one of compound 3 is about 0.00096 to 0.00625 parts by weight The composition which is in the range and contains about 1 to 10 mg is exemplified.

(4) Dosage form The composition of the present invention can be prepared into various pharmaceutical dosage forms, whether orally or parenterally, according to a conventionally known method. For example, liquid preparations (including syrups) Oral preparations in the form of solid preparations such as liquid preparations (including suspensions), tablets, pills, powders, granules, capsules (including soft capsules); liquid preparations such as liquids, drops, injections, and eye drops And parenteral preparations in the form of solid preparations such as tablets, pills and capsules (including soft capsules). The composition of the present invention is preferably in the form of a film-coated tablet, sugar-coated tablet, sweetener-coated tablet, capsule, sublingual tablet, intravenous injection, edible film and the like.

  When the composition of the present invention is a liquid preparation, it can be stored frozen, or it may be stored after removing moisture by lyophilization or the like. Freeze-dried preparations, dry syrups and the like are used by dissolving again by adding distilled water for injection, sterilized water or the like at the time of use.

  For example, when the composition of the present invention is prepared as an injection, drip, etc., as a diluent, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan Fatty acid esters and the like can be used. In this case, a sufficient amount of sodium chloride, glucose or glycerin for adjusting a solution that is isotonic with the body fluid may be contained in the composition of the present invention. Moreover, you may add the solubilizing agent, buffering agent, soothing agent, etc. which are generally used in this field | area.

  When the composition of the present invention is prepared as a solid agent, for example, in the case of a tablet, a carrier conventionally known in this field can be widely used as a carrier. Examples of such carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, silicic acid; water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin Binders such as solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, crystalline cellulose, hydroxypropylcellulose, hypromellose, sodium alginate; dry starch, agar powder, laminaran powder, sodium bicarbonate, polyoxyethylene sorbitan fatty acid Disintegrants such as esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, crospovidone, povidone, low substituted hydroxypropylcellulose; stearin, cocoa butter, Disintegration inhibitors such as additive oils; Absorption accelerators such as quaternary ammonium salts and sodium lauryl sulfate; Moisturizers such as glycerin; Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; Purified talc and stearin Lubricants such as acid salts, boric acid powder and polyethylene glycol can be used. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets. Moreover, the composition containing the said active ingredient can be filled into the conventionally well-known capsule which uses gelatin, a pullulan, starch, gum arabic, hydroxypropyl methylcellulose (HPMC), etc. as a raw material, and can be set as a capsule.

  Moreover, when preparing in the form of a pill, a conventionally well-known thing can be widely used as a support | carrier in this field | area. Examples include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, ethanol, and disintegrants such as laminaran and agar. Can be used.

  In addition to the above, for example, surfactants, absorption promoters, adsorbents, fillers, preservatives, stabilizers, emulsifiers, solubilizers, salts that regulate osmotic pressure, dosage units of the preparations obtained It can be appropriately selected and used according to the form.

  Moreover, you may contain other active ingredients, such as an amino acid, vitamins, and inorganic salts. Examples of other active ingredients include valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, lysine, glycine, alanine, asparagine, glutamine, serine, cysteine, cystine, tyrosine, proline, hydroxyproline, aspartic acid, glutamic acid , Amino acids such as hydroxylysine, arginine, ornithine, histidine; vitamins such as vitamin A1, vitamin A2, carotene, lycopene (provitamin A), vitamin B6, vitamin B1, vitamin B2, ascorbic acid, nicotinamide, biotin; Examples thereof include alkali metal salts such as sodium chloride and potassium chloride, and inorganic salts such as citrate, acetate and phosphate.

  The dose of the composition of the present invention is not particularly limited as long as the effect of the present invention is exhibited, and can be appropriately set depending on the dosage form, patient age, sex, degree of medical condition, etc. The dosage is about 0.83 to 40 mg / kg, preferably about 1.67 to 26.77 mg / kg, more preferably 2.5 to 13.33 mg / kg per day for adults (15 years old and over, body weight about 60 kg). It is about kg.

  The composition of the present invention thus obtained can exert an excellent nerve cell activation action, so that the function and activity of nerve cells are increased and the vitality thereof is increased, urination difficulty, bowel movement abnormalities, numbness of limbs, pain It is useful for the prevention or treatment of diseases that cause damage to the transmission pathways of the nervous system such as dizziness and ulcers (or diseases caused by disorders of the nervous system transmission pathway).

(5) Method for Activating Neurons The present invention also provides a method for activating neurons characterized by adding Compound 1 above. Moreover, at least 1 sort (s) selected from the group which consists of the said compound 2 and the compound 3 can also be added in combination. Specific types, compounding amounts, and the like of Compound 1, Compound 2, and Compound 3 in the method of the present invention are as described in the above (1) to (3).

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Formulation Examples, but the present invention is not limited thereto.
<Test example>
(1) Cryopreserved P19 EC cells cells (mouse embryonic tumor cell line provided by RIKEN) were cultured in a DMEM liquid medium containing 15% of inactivated fetal bovine serum (hereinafter referred to as FBS).
(2) The cells were cultured at 1 × 10 ⁵ cells / ml / well in a DMEM liquid medium (without FBS) containing retinoic acid (1 μM) at 37 ° C. and a CO ₂ concentration of 5% for 1 day.

(Use a 6-well plate and culture at 2 mL per well)
(3) The supernatant was removed and cultured in a liquid medium containing a test substance having a concentration shown in Tables 1 to 3 below (concentration in the liquid medium).
(4) After 12 hours, the number of floating cells (dead cells) was measured, and the nerve cell activation rate was calculated from the following formula. In this test example, the floating cell is a neuronal cell that cannot be obtained with sufficient function and activity and has died. The results are shown in Tables 1-3.

Nerve cell activation rate = (A / B) × 100 (%)
A: At the time of administration of each test substance: (initial cell number-floating cell number) / initial cell number B: When the test substance is not administered (corresponding to Comparative Example 1): (initial cell number-floating cell number) / initial cell number

Cell differentiation is a process that takes place after the growth of cells, and the structure changes so that cells perform their own functions in organs and tissues. Since cell differentiation deviates from the normal cell cycle, fragile cells that have not achieved sufficient function and activity are killed. In this test system, the activity and action that led to the survival of cells (neural cells) that would normally die if compounds 1 to 3 were not added were evaluated by the cell viability. Therefore, it was considered that an increase in the survival rate by measuring the survival rate indicated that the cells were activated and supplemented with an activity sufficient to survive, and this rate was set as a nerve cell activation rate.

  As shown in Example 1, it was shown that Compound 1 has a nerve cell activation effect. As shown in Comparative Example 2, when acetaminophen, which is also known as an antipyretic analgesic, was used, about half of the cells became floating cells (dead cells). Further, as apparent from Comparative Examples 3 to 9, when acetaminophen, compound 2 and compound 3 were blended, no nerve cell activation effect was shown.

  Furthermore, it was shown that the nerve cell activation effect of Compound 1 is further enhanced by adding Compound 2 and Compound 3 (Examples 2 to 14). In particular, as shown in Examples 2, 3 and 10, it was confirmed that the nerve cell activation rate was enhanced by 20% or more compared to the control (Comparative Example 1).

  The formulation example of this invention is shown below.

  When the effectiveness test which makes the patient who complains of numbness of limbs take the prescription examples 1-5, the effectiveness and usefulness of each prescription example were confirmed.

処方例１８及び１９に使用された化合物２※２は、Ｒ＝−ＣＨ_３の化合物である。

Compound 2 * 2 used in Formulation Examples 18 and 19 is a compound with R = —CH ₃ .

Claims (1)

A compound represented by the following formula (1) 1, in neural cell activating composition containing the compound 3 represented as an active ingredient a compound represented by the following general formula (2) 2 and the following general formula (3) There,
The ratio (molar ratio) of Compound 1 and Compound 2 is Compound 1: Compound 2 = 1: 0.0012 to 1: 0.0108, and the ratio (Molar ratio) of Compound 1 and Compound 3 is Compound 1: Compound 3. = 1: 0.0000017 to 1: nerve cell activating composition, which is a 0.009 (provided that the compound 3 and the ratio of compound 1 (molar ratio) compound 3: compound 1 = 4.8: It is 1000-2.4: 1000, and the ratio (molar ratio) of compound 3 and compound 2 is compound 3: compound 2 = 2.4: 2.4-4.8: 10.8. Except composition) .

[In general formula (2), R represents -CN]

[In general formula (3), two

Indicates a double bond]