JP4842996B2 - Anti-depressant / anti-stress composition - Google Patents

Description

  The present invention relates to a composition having an antidepressant / anti-stress action, which contains an N-acyl derivative of tryptamine.

  In modern society, modern people are forced to live under the stress of stress in the face of complex and diverse human relationships and dizzying social changes. For this reason, depression, which is said to be caused by stress or the like, has become a major social problem as one of the modern diseases. Drugs such as tranquilizers, antidepressants, and anxiolytics are used for the treatment of neurosis, depression, schizophrenia, etc., and their effects have been recognized.

  Examples of antidepressants include imipramine and desipramine, which have a reuptake inhibitory action on noradrenaline (NA) and serotonin (5-HT), and tranylcypromine, which has a monoamine oxidase inhibitory action, and are used for the treatment. . In both cases, an antidepressant effect is expressed by increasing the concentration of monoamines at nerve endings and synaptic clefts.

  Tryptamine is a compound having an indole skeleton similarly to 5-HT. In addition, melatonin, which is known to have an effect on nerve function and endocrine function, is a similar substance having an indole skeleton, and therefore various physiological activities have been reported through the action of various tryptamine derivatives on 5-HT receptors and melatonin receptors. Has been.

  To date, blood pressure lowering action (Patent Document 1), melatonin antagonism (Patent Document 2), cognitive impairment prevention effect (Patent Document 3), migraine, vascular headache prevention effect (Patent Document 4, Patent Document 5), A patent application has been filed for a spontaneous movement suppression effect (Patent Document 6) and various other central nervous system disease prevention effects (Patent Document 7 and Patent Document 8).

  Among N-acyl derivatives of tryptamine, N-acetyltryptamine (ethanoic acid [2- (1H-indol-3-yl) ethyl] amide) has been reported to act on melatonin receptors (Non-patent Document 9). However, there are no reports on antidepressant and anti-stress effects. Other N-acyl derivatives of tryptamine have not been clarified about their physiological activities.

JP-A-60-105678 JP-A-4-173777 JP-T 6-501713 JP-A-7-179344 Japanese National Patent Publication No. 10-501212 JP-A-10-77229 JP-A-61-69774 JP-A-7-309867 Br J Pharmacol 111,295-301 (1994), FEBS Letters 412, 79-85 (1997)

  An object of the present invention is to provide a highly safe antidepressant / antistress composition that acts on the central nervous system of humans and animals.

  In order to solve the above-mentioned problems, the present inventors have found that the N-acyl derivative of tryptamine represented by the general formula (1) is obtained by a psychopharmacological study in which a mouse forced swimming test is applied. It has been found that 29 compounds represented by saturated or unsaturated hydrocarbons, or physiologically acceptable salts, hydrates or solvates thereof have antidepressant and anti-stress effects, and have completed the present invention. .

In the general formula (1), R represents CH ₃ (N-acetyltryptamine: ethanoic acid [2- (1H-indol-3-yl) ethyl] amide), C ₁₇ H ₃₃ (N-oleyltryptamine: 9-octadecenoic acid [2- (1H-indol-3-yl) ethyl] amide), C ₂₁ H ₄₃ (N-behenoyltryptamine: doeicosanoic acid [2- (1H-indol-3-yl) ethyl] amide) ), N-acyl derivatives of tryptamine which is C ₂₃ H ₄₇ (N-lignocelloyltryptamine: tetraeicosanoic acid [2- (1H-indol-3-yl) ethyl] amide) are highly effective and suitable. .

  Further, N-palmitoyl tryptamine (hexadecanoic acid [2- (1H-indol-3-yl) ethyl] amide), N-stearoyl tryptamine (octadecanoic acid [octadecanoic acid [octadecanoic acid [octadecanoic acid [octadecanoic acid]]] 2- (1H-indol-3-yl) ethyl] amide), N-eicosanoyl tryptamine (eicosanoic acid [2- (1H-indol-3-yl) ethyl] amide), N-behenoyltryptamine (doeicosanoic) acid [2- (1H-indol-3-yl) ethyl] amide), N-lignocelloyl tryptamine (tetraeicosanoic acid [2- (1H-indol-3-yl) ethyl] amide), N-hexaeicosanoyl Tryptamine (hexaeicosanoic acid [2- (1H-indol-3-yl) ethyl] amide), N-25 (Z) -propacontanoyltryptamine (25 (Z) -docosaenoic acid [2- (1H-indol-3- yl) ethyl] amide) is contained as a lipid component of cacao (Theobroma cacao), Annona reticulata, and Annona cherimola. (Z Levensm Unters Forsch A, 208, 39-46 (1999), Phytochemistry, 34, 1633-1635 (1993), J Chin Chem Soc, 46, 77-86 (1999)), cacao, Fat-soluble fractions obtained from Gyushinri, Cherimoya, or N-acyl derivatives of tryptamine obtained from these plants are also suitable as active ingredients of the antidepressant / antistress composition of the present invention.

  Furthermore, the composition having an antidepressant and antistress action of the present invention is a composition comprising the N-acyl derivative of tryptamine as an active ingredient.

  The N-acyl derivative of tryptamine, which is an active ingredient of the present invention found by the present applicant, has an antidepressant and antistress action and is highly safe. Further, the N-acyl derivative of tryptamine of the present invention can be easily synthesized, and natural products such as cacao (Theobroma cacao), gyushinri (Annoma reticulata), cherimoya (Annona cherimola) and the like, It can also be obtained by extraction from lipid components.

  Therefore, the N-acyl derivative of tryptamine of the present invention can be used as a medicine alone or mixed with other medicines or any pharmaceutical carriers, diluents, coating agents, etc., in any dosage form. Moreover, the food / beverage products which have an antidepressant effect and an anti-stress action can also be provided by mix | blending the N-acyl derivative of tryptamine with various food / beverage products.

  As a method for evaluating antidepressant and anti-stress effects, the present inventors used a mouse forced swimming test developed by Porsolt in 1977 as a screening method for psychotropic drugs shown in Test Example 1, and used tryptamine derivatives. As a result of studying the antidepressant and anti-stress effects of the compound, it is an N-acyl derivative of tryptamine represented by the general formula (1), and R is a saturated or unsaturated hydrocarbon having 1 to 29 carbon atoms. It has been found that the compounds, or physiologically acceptable salts, hydrates or solvates thereof, have a strong antidepressant and antistress action.

  The antidepressant and anti-stress effects of N-acyl derivatives of tryptamine have been clarified for the first time by the present invention.

In the general formula (1), R is CH ₃ (N-acetyltryptamine: ethanoic acid [2- (1H-indol-3-yl) ethyl] amide), C ₁₇ H ₃₃ (N-oleyltryptamine: 9 -octadecenoic acid [2- (1H-indol -3-yl) ethyl] amide), C 21 H 43 (N- behenoyl tryptamine: doeicosanoic acid [2- (1H- indol-3-yl) ethyl] amide) Any N-acyl derivative of tryptamine which is C ₂₃ H ₄₇ (N-lignocelloyltryptamine: tetraeicosanoic acid [2- (1H-indol-3-yl) ethyl] amide) is preferred because of its high effect.

  Further, N-palmitoyl tryptamine (hexadecanoic acid [2- (1H-indol-3-yl) ethyl] amide), N-stearoyl tryptamine (octadecanoic acid [octadecanoic acid [octadecanoic acid [octadecanoic acid [octadecanoic acid]]] 2- (1H-indol-3-yl) ethyl] amide), N-eicosanoyl tryptamine (eicosanoic acid [2- (1H-indol-3-yl) ethyl] amide), N-behenoyltryptamine (doeicosanoic) acid [2- (1H-indol-3-yl) ethyl] amide), N-lignocelloyl tryptamine (tetraeicosanoic acid [2- (1H-indol-3-yl) ethyl] amide), N-hexaeicosanoyl Tryptamine (hexaeicosanoic acid [2- (1H-indol-3-yl) ethyl] amide), N-25 (Z) -propacontanoyltryptamine (25 (Z) -docosaenoic acid [2- (1H-indol-3- yl) ethyl] amide) is contained as a lipid component of cacao (Theobroma cacao), Annona reticulata, and Annona cherimola. (Z Levensm Unters Forsch A, 208, 39-46 (1999), Phytochemistry, 34, 1633-1635 (1993), J Chin Chem Soc, 46, 77-86 (1999)), cacao, Fat-soluble fractions obtained from Gyushinri and Cherimoya or N-acyl derivatives of tryptamine obtained from these plants can also be suitably used as the antidepressant / antistress composition of the present invention.

  Cacao (Theobroma cacao) is a small Takagi tree of the Aogiri family, and its seeds are said to be cacao beans and are the main raw materials for chocolate and cocoa. Generally, N-acyl derivatives of tryptamine in cacao are contained in cacao husk (cacao shell), which is a part of cacao bean skin, and not contained in the endosperm (nib) part normally used for food. It is preferable to extract from cacao husk because it is considered. Annona reticulata is a plant belonging to the family Vanillaceae, and its N-acyl derivative of tryptamine is obtained from the seed, so that it can be extracted from the seed. Since the N-acyl derivative of tryptamine is obtained from the trunk, it is preferably extracted from the trunk.

  As a method for obtaining a fat-soluble fraction of cacao, gyushinri, cherimoya, for example, after pulverizing each raw material, fat-soluble components such as n-hexane, diethyl ether, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, and ethanol are extracted. It can be obtained by performing extraction at room temperature or warm reflux with a possible solvent or a mixture thereof, and concentrating the extract to dryness.

  Thus, the N-acyl derivative of tryptamine of the present invention was extracted from a natural product such as a plant produced by chemical synthesis, enzymatic reaction, microbial conversion, etc. using tryptamine and a fatty acid. A thing can also be used suitably.

  In addition, regarding the safety of the N-acyl derivative of tryptamine of the present invention, tryptamine and various fatty acids are widely present in nature, and the N-acyl derivative of tryptamine is edible as described above, such as cacao and gyushinri. Therefore, its safety is considered to be very high.

  Since the antidepressant / antistress composition of the present invention is characterized by comprising an N-acyl derivative of tryptamine as an active ingredient, it is a single or other pharmaceutical or optional pharmaceutical carrier, diluent, coating agent. Etc. and can be used in any dosage form. As the administration method, it can be used orally, parenterally, rectally or by any other administration route. For oral administration, powders, tablets, granules, fine granules, capsules, liquid preparations for oral administration, etc. can be exemplified. For parenteral administration, injections, inhalants, etc. For rectal administration, suppositories, rectal capsules and the like can be exemplified.

  The effective amount of the N-acyl derivative of tryptamine, which is the main component of the antidepressant / anti-stress composition of the present invention, varies depending on age, body weight, administration method, administration period, and necessary treatment, and is generally defined. However, for humans (adult 70 kg), the daily dose is preferably 5 mg to 5 g, more preferably 10 mg to 1 g.

  Next, since the N-acyl derivative of tryptamine of the present invention has high safety as described above, a composition having antidepressant and anti-stress effects is provided by blending it with various foods and drinks. Can do. For example, as a composition, sweets such as chewing gum, chocolate, snacks, biscuits, juices, soft drinks, fruit drinks, lactic acid drinks, milk, tea, coffee, cocoa drinks, ice cream, sorbets, frozen confectionery such as ice confectionery, Mention may be made of yogurt and other foods.

  Hereinafter, the present invention will be specifically described by way of examples of synthesis methods, examples of extraction and purification from natural products, test examples, pharmaceuticals and foods and drinks, but the present invention is not limited to these examples. Absent.

[Example 1]
Method for synthesizing N-acyl derivatives of tryptamine N-acyl derivatives of various tryptamines can be easily synthesized by condensing tryptamine and chlorides of various fatty acids. In addition, any N-acyl derivative of tryptamine can be synthesized by changing the type of fatty acid. As a specific example, N-lignocelloyltryptamine (tetraeicosanoic)
The synthesis method of acid [2- (1H-indol-3-yl) ethyl] amide) is shown below. Tryptamine hydrochloride (2 mmol), triethylamine (2 mmol), and lignoceric acid chloride (2 mmol) were reacted in 10 ml of chloroform at room temperature for 2 hours. The reaction solution was extracted by adding 10 ml of water and 10 ml of chloroform, and the chloroform layer was washed three times with a saturated saline solution, and water was further removed with anhydrous sodium sulfate. The chloroform layer was concentrated under reduced pressure, and the precipitate was recrystallized from acetone to obtain N-lignocelloyltryptamine (yield 75%). The melting point and ¹ H-NMR data of N-lignocelloyltryptamine are shown below.
Melting point: 120 ° C
¹ H-NMR (CDCl ₃ ): δ 8.05 (1H, brs), 7.61 (1H, d, J = 7.6Hz), 7.38 (1H, d, J = 7.6Hz), 7.21 (1H, t, J = 7.6 Hz), 7.13 (1H, t, J = 7.6Hz), 7.04 (1H, d, J = 1.8Hz), 5.47 (1H, brs), 3.62 (2H, m), 2.98 (2H, t, J = 6.4 Hz), 2.09 (2H, t, J = 7.6), 1.56 (2H, m), 1.26 (42H, brs), 0.88 (3H, t, J = 6.6Hz)

[Example 2]
Example of extraction and purification of N-acyl derivative of tryptamine from natural products 100 g of ground cocoa bean skin (cocoa husk) was subjected to Soxhlet extraction with diethyl ether for 2 hours. The extract was concentrated and dried, loaded onto a silica gel column, and triacylglycerides were removed with benzene / diethyl ether (6: 4 v / v). Next, elution was performed with 400 ml of diethyl ether, and the eluate was concentrated and purified by HPLC. Using an ODS silica gel column, elution was performed with acetonitrile / THF / water (90: 7: 3 v / v), and peaks detected were collected while monitoring with a fluorescence detector (excitation wavelength: 281 nm, measurement wavelength: 330 nm). Each fraction was concentrated and appropriately recrystallized to obtain an N-acyl derivative of tryptamine (N-lignocelloyltryptamine and N-behenoyltryptamine are obtained as main components from cacao husk). Details of these extraction and purification methods are described in Z Levensm Unters Forsch A, 208, 39-46 (1999).

[Test Example 1]
Evaluation of tranquilizing effect by mouse forced swimming test As a method for evaluating the antidepressant and antistress effects of the present invention, the mouse forced swimming test developed by Porsolt in 1977 was adopted as a screening method for psychotropic drugs. This is one of the most frequently used animal model experiments for depression. In this test, the mouse is forced to swim in a limited space to cause “immobility”. This immobility state is thought to reflect a kind of “despair state” in which stressed animals abandon their escape from water, and is associated with depression and stress in humans. In fact, antidepressants have been found to specifically reduce the duration of immobility in this situation, and this shortening has been found to have a significant correlation with clinical titer.

  Specific operations applied in this test are shown below. Mice were forced to swim in a plastic cylinder containing 25 ° C. water to a depth of 15 cm. After forced swimming for 5 minutes, it was dried in a dryer at 30 ° C. for 15 minutes and returned to the home cage. On the next day, the test substance was intraperitoneally administered to the mouse, one hour later, forced swimming was again applied for 5 minutes, and the duration of the immobility that appeared was measured using a stopwatch. The state in which the mouse floated on the water and was stationary was determined to be immobile. In the evaluation, the immobility duration of the control not administered with the test substance was set as 100, and the relative amobility duration for this was used as an index. A significant difference test was performed for this value, and a statistically significant difference was tested. That is, in this evaluation method, the smaller the value of the relative immobility state duration, the higher the antidepressant and anti-stress effects. In the experiment, male ddY mice were used, and 6 mice per group were used. All tests were conducted between 1 pm and 6 pm.

  In the following, an ether extract is used as a test substance as a fat-soluble fraction of N-acetyltryptamine, N-oleyltryptamine, N-behenoyltryptamine, N-lignocelloyltryptamine and cacao husk which are the products of the present invention, and anti-positive as a positive control. Table 1 shows the results of a test conducted using imipramine, which is a depressant.

  As a result, N-acetyltryptamine, N-oleyltryptamine, N-behenoyltryptamine, and N-lignocelloyltryptamine all showed an immobility time shortening effect as compared with the control group. In particular, N-acetyltryptamine and N-lignocelloyltryptamine were found to have an immobility time shortening effect similar to that of imipramine, which is an antidepressant.

Example 3
<Powder>
Lactose 60 parts Potato starch 30 parts N-Lignocelloyltryptamine 10 parts

Example 4
<tablet>
D-mannitol 40 parts Lactose 35 parts Crystalline cellulose 10 parts N-acetyltryptamine 10 parts Hydroxypropyl cellulose 5 parts

Example 5
<chocolate>
Powdered sugar 41.8 parts Cocoa bitter 20 parts Whole milk powder 20 parts Cocoa butter 17 parts N-oleyltryptamine 1 part Fragrance 0.2 parts

Example 6
<candy>
Granulated sugar 50 parts Minamata 33 parts Citric acid 2 parts N-Lignocelloyltryptamine 0.5 parts Fragrance 0.2 parts Water 14.3 parts

Example 7
<Chewing gum>
Powdered sugar 54 parts Gum base 20 parts Minamata 14.5 parts Glucose 10 parts Fragrance 1 part N-Behenoyltryptamine 0.5 parts

Claims (5)

N-acyl derivative of tryptamine represented by the general formula (1) obtained by synthesis with tryptamine and a fatty acid, wherein R is a saturated or unsaturated hydrocarbon having 1 to 29 carbon atoms, or physiologically An antidepressant / antistress composition comprising 0.5% by weight or more of an N-acyl derivative of tryptamine containing an acceptable salt, hydrate or solvate.

N-acyl derivative of tryptamine represented by general formula (1) obtained by extracting cacao husk of cacao (Theobroma cacao) with an organic solvent selected from n-hexane, diethyl ether, dichloromethane, chloroform, and tetrahydrofuran at room temperature or by heating under reflux. And an N-acyl derivative of tryptamine containing R or a saturated or unsaturated hydrocarbon having 1 to 29 carbon atoms, or a physiologically acceptable salt, hydrate or solvate thereof. .Anti -depressant / anti-stress composition characterized by containing 5% by weight or more .

N-acyl derivative of tryptamine represented by general formula (1) obtained from Annona reticulata, wherein R is a saturated or unsaturated hydrocarbon having 1 to 29 carbon atoms, or a physiologically acceptable compound thereof An antidepressant / antistress composition comprising 0.5% by weight or more of an N-acyl derivative of tryptamine containing a salt, hydrate or solvate obtained.

N-acyl derivative of tryptamine represented by the general formula (1) obtained from Annona cherimola, wherein R is a saturated or unsaturated hydrocarbon having 1 to 29 carbon atoms, or a physiologically acceptable compound thereof An antidepressant / antistress composition comprising 0.5% by weight or more of an N-acyl derivative of tryptamine containing a salt, hydrate or solvate obtained.

R is CH ₃ (N-acetyltryptamine: ethanoic acid [2- (1H-indol-3-yl) ethyl] amide), C ₁₇ H ₃₃ (N-oleyltryptamine: 9-octadecenoic acid [2- (1H- indol-3-yl) ethyl] amide), C 21 H 43 (N- behenoyl tryptamine: doeicosanoic acid [2- (1H- indol-3-yl) ethyl] amide), C 23 H 47 (N- ligno The antidepressant according to any one of claims 1 to 4, which is an N-acyl derivative of tryptamine which is seroeyltryptamine: tetraeicosanoic acid [2- (1H-indol-3-yl) ethyl] amide). -Anti-stress composition.