Ligustilide derivatives for treating central nervous system disorders. RU patent 2462462.

FIELD: medicine.

SUBSTANCE: invention refers to a dietary and pharmaceutical composition containing ligustilide to be applied in a method of treating or preventing depression, generalised anxiety disorders, dysphoria, obsessive-compulsive behaviour, and affective disorders, as well as to a non-therapeutic application of the dietary composition containing ligustilide.

EFFECT: higher efficacy of the applied derivatives.

6 cl, 17 ex, 6 tbl

The present invention relates to organic compounds of General formula I, as defined below, for use in the treatment of disorders associated with impaired neuropterida, as well as to dietary and pharmaceutical compositions containing such compounds, and their use.

It is well known that impaired neuropterida, such as low levels of neuropterida associated with mental illness, such as depression and generalized anxiety disorder (GAD), and increased susceptibility to stress.

Compounds that increase the levels of neurotransmitters in the brain and thus improve neuropterida, therefore, demonstrate antidepressant properties, as well as favorable impacts on a wide range of other mental disorders ("Neurotransmitters, drugs and brain function" R.A.Webster (ed.), John Wiley & Sons, New York, 2001, p.187-211, 289-452, 477-498). Important neurotransmitters are serotonin, dopamine, noradrenaline (norepinephrine), acetylcholine, glutamate, GABA and neuropeptides. Increase neuropterida is achieved by increasing the concentration of neurotransmitter in the synaptic cleft, which enables enlarged or elongated nanoperiodic by inhibiting reuptake into the presynaptic nerve endings, or by preventing the catabolism of the neurotransmitter inhibition of degradation enzymes, such as monoamine oxidase a and B.

Tricyclic antidepressant compounds (TCA), such as imipramine, amitriptyline, and clomipramine, for example, inhibit the reuptake of serotonin and norepinephrine. They rightly considered as the most effective available antidepressants, but have a number of obstacles as they interact with a number of receptors in the brain, for example with cholinergic receptors. Most significantly, what TCA taken in too large doses are unsafe, often demonstrating acute cardiotoxicity.

Another class of antidepressants are the so-called SSRI (selective serotonin reuptake inhibitors SSRIs), including fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine, which block the serotonin Transporter (SERT) - dependent high-affinity sodium chloride Transporter neurotransmitter, which completes the serotonergic nanoperiodic capture of a serotonin. It is proved that they are effective in the treatment of depression and anxiety and are generally better tolerated than TCA. The use of drugs usually begins with a low dosage, and the dosage can be increased to a therapeutic level. The usual side effect is nausea. Other possible side effects include loss of appetite, dry mouth, sweating, infection, constipation, yawning, tremors, somnolence, and sexual dysfunction.

In addition, compounds that prevent the catabolism of neurotransmitters more clearly through inhibition of monoaminooxidase (MAO) a and b, show antidepressant effects. MAO catalyzes the oxidation of neurotransmitters, containing amino groups, such as serotonin, norepinephrine and dopamine.

In addition, modulators of neuropterida exert pleiotropic actions on mental and cognitive functions. These features are clearly different from the effects described for food/plant components with antioxidant function, which exhibit a neuroprotective effect by reducing oxidative stress.

In addition, patients often suffer from generalized anxiety disorder (GAD) as a co-depression illness or by itself. GAD is a very common anxiety and chronic illness in the primary case (~10% of patients) (Wittchen et al. 2005. European Neuropsychopharm. 15: 357-376). Patients are first brought before a physician with multiple physical symptoms. GAD differs chronic and anxiety anxiety and stress (>6 months), which causes a disability and are uncontrollable, accompanied by a characteristic syndrome sverhsostoyatelnosti (including restlessness, muscle tension and problems associated with sleep). If untreated GAD takes chronic, fljuktuirujushchee over and tends to become more severe with age. GAD patients suffer from subsyndromal depression and constitute the highest rate of direct and indirect economic costs to health from all anxiety and depressive disorders. Despite the high percentage of GAD few of the victims are diagnosed, treated or given a referral to a psychiatrist, because you need easy ways to diagnose, contributing to the recognition and monitoring of patients. Regardless of the specific diagnosis, the doctors need effective treatments related to symptoms of GAD. An SSRI such as paroxetine are effective in the treatment of GAD [Stocchi et al. 2003 J Clin Psych, 63(3):250-258]. Moreover, systematic reviews, and placebo-controlled RCT (randomized clinical trials) show that some SSRI (ESCITALOPRAM, paroxetine and sertraline), SNRI (selective serotonin reuptake inhibitors norepinephrine) venlafaxine, some benzodiazepines (alprazolam and diazepam), tricyclic imipramine and partial 5-HT1A agonist buspirone, are all effective for emergency treatment. In General, the treatment is often negligible, and the symptoms appear again when the period of treatment ceases. Therefore, continuous long-term treatment or prevention of disease compounds, which have lesser side effects than SSRI, and can be used for extended periods of time, is preferable to medication.

There is a need for compounds for the treatment or prevention of mental diseases and/or disorders, which do not show negative side effects known as antidepressants. Many patients are interested in alternative methods of treatment, which could minimize side effects associated with high dosage of drugs, and to provide additional clinical benefits. Severe depression is a prolonged and recurrent disease, which is usually poorly diagnosed. In addition, many patients suffer from moderate depression or depression of moderate severity. Thus, there is increasing interest in the development of compounds as well as pharmaceutical and/or dietary compositions that can be used for treatment of mental diseases/disorders or to prevent the development of mental diseases/disorders such as depression and dysthymia in people with increased risk, and to stabilize the mood.

It is known that unstable mood is associated with disturbed, i.e. reduced, neuropterida and that it also leads to increased susceptibility to stress.

Thus, the mood is influenced by the biosynthesis of neurotransmitters, the processing of neurotransmitters, the accumulation of neurotransmitters, release of neurotransmitters reuptake of neurotransmitters and receptor binding of neurotransmitters, especially when the neurotransmitter is serotonin. Unstable mood may occur in animals, including humans, as depression, stress, unhappiness/discontent, irritability and dysphoria and/or disorder of behavior, emotions and thinking process.

Thus, there is a need for compounds for harmonization and normalization of mood and achieve emotional balance in order to sustain daily life stresses and to maintain physical and psychological health.

In addition, the compounds of this invention have application in veterinary medicine, including: preventing stress in farm animals in the mass production of livestock products and/or during transport to the processing (slaughter); the prevention of the deterioration of meat quality of farm animals during transport to the processing; to prevent pulling out feathers and cannibalism in poultry; and to reduce stress in domestic animals.

According to the present invention, this need is satisfied by using known compounds of General formula I,

R 1 is hydrogen or hydroxy;

provided that R 2 is a butyl or butyryl, if R 1 is hydroxy, and R 2 represents a butyl, if R 1 is hydrogen; or

R 1 and R 2 , taken together, represent a 1-propylidene or 1-butylidene, optionally substituted hydroxy, stands, or 3-(α,β-dimethylaminoethoxy);

the dotted line indicates an optional bond;

X is optionally substituted C4 aliphatic residue selected from the group consisting of X1, x2, X3, X4 and X5;

X is x2, X3 or X5 if the dotted line in formula (I) is absent; and

X is X1, X4 or X5 if the dotted line indicates the relationship in the formula (I);

R 3 and R 4 are, independently of one another, hydrogen or hydroxy; and

R 5 represents a hydroxy or butyryl.

Thus, in the compound of formula (I) above, X1 may be substituted by one or (if one of R 3 and R 4 is hydroxy) two hydroxy groups (where R 3 and R 4 are both hydroxy).

Compounds of General formula I, as described above, act as inhibitors of serotonin reuptake, thus extending the time when serotonin is available for neuropterida. This leads to the effect of balancing the mood and effect of the weaker stress.

The compounds used in the present invention are selected from the group of derivatives of phthalide, which are replaced by the lactones 2-hydroxymethylbenzene acid according to IUPAC rule C-473. This class of compounds is based on the 1(3H)-isobenzofuranone C 8 H 6 O 2 .

The preferred compounds used for the purpose the present invention, are selected from the group consisting of (E)-sentineled E; sentineled; sentineled; 3-butyl-4,5,6,7-tetrahydro-3,6,7-trihydroxy-1(3H)-isobenzofuranone; 3-butyl-1(3H)-isobenzofuranone; 3-butylphthalide; 3-butylidenephthalide; 3-proprietaria; coinsure (lovage-Ola); ligustilide; sentineled F; 3-hydroxy-sentineled A; angeloueconomics F; sentineled M; 3-hydroxy-8-oxo-sentineled And; ligustilide; 6,7-dihydro-(6S,7R)-dihydroxysuccinic, 3A,4-dihydro-3-(3-methylbutyrate)-1(3H)-isobenzofuranone; sedanolide and kneeled, and mixtures thereof. Preferred options for implementation are listed in Table 1.

The list of preferred compounds used according to the present invention

Structure

(E)-E sentineled

sentineled With

sentineled In

3-butyl-4,5,6,7-tetrahydro-3,6,7-trihydroxy-1(3H)-isobenzofuranone

3-butyl-1(3H)-isobenzofuranone

3-n-butylphthalide

3-butylidenephthalide

3-propylidene

counsel (lovage-ol)

ligustilide

sentineled F

3-hydroxy-sentineled And

angeloueconomics F

sentineled M

3-hydroxy-8-oxo-sentineled And

ligustilide

6,7-dihydro-(6S,7R)-dihydroxysuccinic

3A,4-dihydro-3-(3-methylbutyrate)-1(3H)-isobenzofuranone

sedanolide

The most preferred compounds are selected from the group consisting of ligustilide, 3-butylphthalide, 3-butylidenephthalide, 3-proprietaria, sedanolide, sentineled And sentineled In and sentineled With, as well as mixtures.

Thus, in one aspect the invention relates to a compound of General formula I with the definitions of X and R 1-R 5 , as given above, preferably to a compound selected from the group consisting of (E)-sentineled E; sentineled; sentineled; 3-butyl-4,5,6,7-tetrahydro-3,6,7-trihydroxy-1(3H)-isobenzofuranone; 3-butyl-1(3H)-isobenzofuranone; 3-butylphthalide; 3-butylidenephthalide; 3-proprietaria; coinsure (lovage-ol); ligustilide; sentineled F; 3-hydroxy-sentineled A; angeloueconomics F; sentineled M; 3-hydroxy-8-oxo-sentineled A; ligustilide; 6,7-dihydro-(6S,7R)-dihydroxysuccinic, 3A,4-dihydro-3-(3-methylethylidene)-1(3H)-isobenzofuranone; sedanolide; and kneeled, and their mixtures.

More preferably the compound is selected from the group consisting of ligustilide, 3-butylphthalide, 3-butylidenephthalide, 3-proprietaria, sedanolide, sentineled And sentineled In and sentineled With, as well as mixtures for use in the treatment of disorders associated with impaired or reduced neuropterida or for use in the manufacture of compositions suitable for the treatment of disorders associated with impaired neuropterida.

Animals are mainly human, pet or companion animal (preferably cats and dogs), farm animals (preferably poultry, cattle, goats, sheep, pigs and animals for fur farming, such as mink, foxes and hares, as well as animals used for aquaculture, such as fish, such as salmon and trout, as well as crustaceans such as shrimp.

In one preferred embodiment of the present invention the compounds of this invention are used to prevent stress in domestic animals and farm animals in the mass production of products of animal husbandry, during transport to the processing (slaughtering) and/or to prevent losses in the production of milk or eggs, and the deterioration of meat quality of these farm animals during transport to processing.

In another preferred embodiment of the present invention the compounds of this invention are used to prevent pulling out feathers and cannibalism in poultry and/or to prevent losses associated with this quality of meat and produce the eggs and all.

In the following a preferred embodiment of the present invention the compounds of this invention are used to maintain the circadian rhythm in humans, for alleviating and/or preventing symptoms associated with a disturbed circadian rhythm in humans. Thus, the mood will stabilize and achieve an emotional balance to cope with daily life stress and maintain physical and psychological health. In addition, facilitated and/or prevent symptoms associated with a disturbed circadian rhythm, such as reduced cognitive function and memory, and mental and physical fatigue, so that the overall quality of life improves, and the subjects of which such compounds are introduced, benefit from the conservation of vital energy. In addition, the disturbance of circadian rhythms caused by long-range flights (disorder biorhythms in connection with the flight across multiple time poles), and shift work, and the symptoms associated with it, alleviated and/or prevented.

Thus, unstable mood, which may manifest as stress, sadness, unhappiness/discontent and irritability, dysphoria and/or disorder of behavior, emotions and thinking process, prevents the introduction of compounds of General formula I, as defined above, to animals, including humans.

In another aspect the invention relates to the use of compounds of General formula I, as defined above, for treating disorders associated with impaired or reduced neuropterida, or for the manufacture of a composition for the treatment of disorders associated with impaired neuropterida, specifically for the production of antidepressant, tools, reducing obsessive-compulsive behaviour, relaxant, improves sleep means and/or a sedative for insomnia, as well as for use as a tool for balancing mood, as a means of improving mood/vitality, as a means to overcome stress, as a means of improving the condition and/or as a means of reducing stress, sadness, unhappiness/discontent, irritability and restlessness.

In another aspect the invention relates to compositions, particularly to dietary compositions containing at least one compound of General formula I, as defined above, as well as pharmaceutical compositions containing at least one compound of General formula I, as defined above, and common pharmaceutical carrier for use in the treatment of disorders associated with impaired neuropterida.

Further, the invention relates to a method of treating disorders associated with impaired neuropterida in animals, including humans, with the described method, including (a) preparation of a composition containing a compound of formula I, and (b) the introduction of effective doses of the indicated compositions to animals, including humans, in need thereof.

Then, the invention relates to a method of balancing mood and/or relieve stress in animals, including humans, with the described method, including the introduction of effective doses of the compounds of General formula I, as defined above, to animals, including humans, in need thereof.

Animals in the context of the present invention include humans and include mammals, fish and birds. Preferred "animals are people, Pets or animals, companion, farm animals, animals for fur farming and animals for aquaculture. More preferred "animals are people, Pets and farm animals.

Examples of Pets are dogs, cats, birds, aquarium fish, Guinea pigs (males) rabbits, rabbits and ferrets.

Examples of farm animals are fish (such as salmon and trout), animals for aquaculture (such as shrimp), pigs, horses, ruminants (cattle, goats, sheep) and poultry (such as geese, chickens, broiler chickens, hens, quail, ducks, turkeys).

Examples of animals for fur farming are mink, foxes and rabbits.

In a preferred embodiment of the present invention the compound of General formula I, as defined above, is used for preventing stress in farm animals, in the mass production of products of animal husbandry, during transport to the processing and/or to prevent deterioration of meat quality of these farm animals during transport to processing. These farm animals are mainly poultry (such as geese, broiler chickens, hens, quail, ducks, chickens, turkeys), cattle, sheep, goats and pigs.

In another preferred embodiment of the present invention the compound of General formula I, as defined above, to impose bedroom animals to reduce stress, tension and aggressiveness and compulsive behavior in stress conditions, such as separation, change or loss of the owner, the separation during the holidays and the content of the so-called "places for animals", the content in shelters and other conditions of dense keeping and breeding.

In another preferred embodiment of the present invention the compound of General formula I, as defined above, is administered to poultry (such as geese, broiler chickens, hens, quail, ducks, chickens, turkeys) to prevent pulling out feathers and cannibalism, which, for example, to losses in the form of meat quality and egg production.

In the following a preferred embodiment of the present invention the compound of General formula I, as defined above, is administered to a person to save the circadian rhythm in humans, for alleviating and/or preventing symptoms associated with a disturbed circadian rhythm in humans.

The term "compound of General formula I" includes any substance or extract from a plant containing such a connection is provided for General formula I, preferably in the amount of at least 50 wt.%, more preferably in an amount of from 70 to 90 wt.%, most preferably in the amount of at least 90 wt.% on the basis of the total mass of vegetable matter or extract. The terms "substance from a plant" and "herbal substance"used in the context of the present invention, means any part of the plant.

Compounds according to formula I, as defined above, and which are used according to the present invention, can be selected well-known in the art methods [see, for example, Beck J. et al. 1995-Natural Products 58(7):1047-1055] from various plants such as Angelica glauca, Angelica acutiloba, Angelica sinensis, Angelicae dahuricae, Apium graveolens, Ligusticum acutilobum, Ligusticum officinale, Ligusticum sinense, Ligusticum wallichii, Ligusticum chuanxiong, Cnidium officinale, Rhizoma chuanxiong, Pleurospermum hookeri, Trachyspermum roxburghianum, Meum athamanticum, Lomatium torreyi, Scutellaria baicalensis, Opopanax chironium, Cenolophium denudatum, Coriandrum sativuum and Silaum silaus. Therefore, any substance, extract, or resin of these plants or any other plant material or extract containing a separate connection is provided for General formula I, especially in the amount of at least 50 wt.%, preferably in an amount of from 70 to 90 wt.%, more preferably in the amount of at least 90 wt.% on the basis of the total mass of vegetable matter or extract, is also included in the expression "a compound of formula I".

The compounds used here can also be of synthetic origin. Thus, the compound of formula I" means both "natural" (highlighted) and synthetic (artificial) compound of formula I. In this case are included and CIS (Z)- and TRANS (E)-isomers.

3-n-butylphthalide, seniority a, b and C and sedanolide can be obtained by distillation and fractionation of the extract of the seeds of Apium graveolens or by supercritical fluid CO2 extraction, if necessary, with subsequent distillation. Supercritical fluid extraction/distillation is the preferred method for the extraction Ligusticum.

In a preferred embodiment of the present invention compounds of General formula I is used in the form of product distillation (distillate) ligusticum or in the form of a mixture with distillate ligusticum as one component, which contains the following five falicov:

3-n-butylphthalide,

3-n-butylidenephthalide,

sentineled And,

sedanolide and

Z-ligustilide. Preferably this distillate/mixture contains at least 40 wt.%, preferably at least 55%, more preferably at least 65%, most preferably at least 85 wt.% these 5 falicov together based on the total weight of distillate/mixture. In the distillate/mixture preferably the number of Z-ligustilide is:

the number within at least 30 to 60 wt.%,

more preferably at least 40 wt.%,

even more preferably, at least 50 wt.%;

preferably the number sentineled And is:

the number within at least 10-40 wt.%,

preferably, at least 10 wt.%,

more preferably at least 20 wt.%,

even more preferably, at least 30 wt.%;

preferably the number sedanolide is:

within approximately from 0.1 to 8 wt.%,

preferably, at least 0.5 wt.%,

more preferably, at least 1.0 wt.%,

even more preferably at least 3 wt.%; and

preferably the amount of 3-n-butylphthalide is

within about 0.1 to 5 wt.%,

preferably, at least 0.5 wt.%,

more preferably at least 2 wt.%,

even more preferably at least 3 wt.%,

all quantities based on the total weight of distillate/mixture.

Diet compositions according to the present invention, furthermore, may contain protective hydrocolloids, binders, film formers, kapsulirujushchej agents/substances, materials for wall cladding, matrix compounds, coatings, emulsifiers, surfactants, solubilizing agents (oils, fats, waxes, lecithins etc), adsorbents, carriers, fillers, co-compounds, dispersing agents, moisturizing agents, weighting materials, auxiliary substances (solvents), flowing agents, hiding the taste substances, gelling agents, gel forming agents, antioxidants and antibacterial agents.

The term "dietary composition" includes any type of food, such as (fortified) food products/food and drinks, including diet and dietary supplements.

In addition to the pharmaceutically acceptable carrier and at least one of the compounds of General formula I with the definitions of X, R 1-R 5 and the preferred definitions as given above, the pharmaceutical compositions according to the present invention, furthermore, may contain conventional pharmaceutical additives and adjuvant, excipients or diluents, including, but without limitation, water, gelatin of any origin, vegetable gums, ligninsulfonate, talc, sugars, starch, Arabic gum, vegetable oil, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers and the like. The carrier substance may be an organic or inorganic inert substance suitable for oral/parenteral/injectable use.

Diet and the pharmaceutical compositions according to the present invention may be in any galenical form that is suitable for introduction into the body of the animal, including the human body, especially in any form that is conventional for oral administration, e.g. in solid form such as (additives/supplements for) food or feed, food or feed pre-mix, fortified food or feed, tablets, pills, granules, dragées, capsules, and effervescent formulations such as powders and tablets, or in liquid form such as solutions, emulsions or suspensions, such as, beverages, pastes and oily suspension. The paste can be filled into capsules with hard or soft shell. Examples of other applicable forms are forms transdermal, parenteral or injectable administration. Dietary and pharmaceutical compositions can be in the form of controlled (delayed) release.

Examples of food are dairy products such as yoghurts.

Examples of enriched foods are piketirovany grain concentrates, bakery products such as cakes and buns.

Drinks include non-alcoholic and alcoholic drinks as well as liquid preparations for addition to drinking water and liquid food. Non-alcoholic drinks are, for example, soft drinks, sports drinks, fruit juices, lemonades, similar to water drinks (i.e. based drinks water with low content of calories), tea and milk-based drinks. Liquid food are, for example, soups and dairy products (for example, muesli drinks).

Compounds of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, can be used for the production of medicaments for the treatment of disorders associated with impaired or reduced neuropterida.

In the context of this invention "treatment" also includes joint treatment as well as prevention. "Warning" may be a warning the first event (primary prevention) or the prevention of recurrence (secondary prevention).

Thus, the present invention also relates to a method for preventing disorders associated with neuropterida in animals, including humans, to the specified method, including the introduction of effective doses of the compounds of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, to animals, including humans, in need thereof. In this sense, an effective dose of a compound of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, especially can be used to preserve mental health to preserve a balanced cognitive function, for to help reduce the risk of mood swings, to help maintain a positive mood and to maintain cognitive health, to normalize sleeping patterns (also called sleep architecture), reducing the time of sleep onset, generally to promote and maintain good quality of sleep, normalization of the circadian rhythm (rhythm) of the subject, which means the restoration of the biorhythm of the subject to its normal, healthy biorhythms.

In the context of this invention, the term "disorder" includes a disease.

Pharmaceutical and dietary compositions for treatment of disorders associated with impaired neuropterida include their use as antidepressants, tools, improving mood/vitality; means to overcome stress; tools that improve the state; funds, reduce anxiety, and means for reducing obsessive-compulsive behavior; ward, improves sleep assets and/or sedatives for insomnia; normalizing the circadian rhythm (the rhythm). They improve, reinforce and support the physiological neuropterida, especially in the Central nervous system, and, therefore, can alleviate mental dysfunction.

Antidepressants are medicines to treat mental, behavioral and emotional/affective, neurotic, neurodegeneration associated with food and stress disorders, such as unipolar depression, bipolar depression, acute depression, chronic depression, acute depression, dysthymia, postpartum depression, premenstrual dysphoria/syndrome (PMS), menopausal depressive symptoms, aggression, attention deficit disorder (ADS), social anxiety disorder, seasonal emotional disturbances, anxiety (disorders), such as generalized anxiety disorder (GAD), fibromyalgia syndrome, chronic fatigue, sleep disorders (insomnia), posttraumatic stress disorder, panic disorder type, obsessive-compulsive disorder, tired leg syndrome, nervousness, migraine/primary headaches and pain in General, vomiting, bulimia, anorexia nervosa, compulsive overeating, gastrointestinal disorders, burn syndrome, irritability and apathy.

Antidepressants can also be used for the production of compositions for primary or secondary prevention and/or treatment of neurocognitive disorders. In addition, they can be effective in the treatment of depressive symptoms or other symptoms associated with impaired neuropterida appearing as concomitant disease with such chronic diseases as cardiovascular disease, strokes, cancer, Alzheimer's disease, Parkinson's disease and others.

Compounds of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, as well as (this mixture of plant substances and herbal extracts (essentially) containing them (especially in the amount of at least 30 wt.%, preferably in quantities of at least 50 wt.%, more preferably in an amount of from 70 to 90 wt.%, most preferably in the amount of at least 90 wt.% on the basis of the total mass of vegetable matter or extract), and dietary/pharmaceutical compositions containing them are thus suitable for the treatment of animals, including humans.

In particular, animal companion (Pets and farm animals can be in the States in which we need to strengthen or improve neuropterida. This condition may occur, for example, after capture, or transport, or when the content when the animals develop similar disorders and animals discressionary, or aggressive, or demonstrate stereotyped behavior or anxiety, and obsessive-compulsive behavior.

Thus, compounds of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, can be mainly used as antidepressants for animals, including humans, preferably to human, animal companions (Pets and farm animals.

In the following embodiment, the present invention compounds of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, have found application as improving mood funds generally, as well as for the production of compositions for such applications (plant substances/extracts, dietary/pharmaceutical compositions). "Improving mood tool", or "activator emotional health, or improving the viability of the tool means that the mood of the subject, which was treated by this means, improved that self-esteem increased and/or that negative thoughts and/or negative voltage can be reduced/minimized. This also means that the emotions are balanced and/or that common, especially mental health and vitality improved or saved, and that the risk of mood swings reduced (or reduced) and that positive mood (or saved) saved.

Compounds of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, also can usually be used as a means of reducing anxiety, and/or reducing obsessive-compulsive behavior in animals, including humans, preferably for humans, Pets and farm animals.

A means of reducing anxiety, indicates that chronic stress and anxiety anxiety and stress ease and loosen up. Syndrome sverhsostoyatelnosti, including restlessness, muscle tension and sleep problems, decreases. Social and other phobias are eliminated. In General, the social environment is perceived less threatening. The subject is emotionally relaxed, feels better mood and enjoys the company and communicate with other people.

"Relaxant", or "improving sleep remedy", or "sedative for insomnia" means improved sleep onset (reducing the time of sleep onset, latency to sleep) and using the subject easier to fall into sleep, normalize sleep patterns or to maintain undisturbed sleep during the night. It also means to adjust the circadian rhythm associated with sleep disturbances due to desynchronize or shift work, and to prevent and relieve symptoms associated with insomnia, i.e. the deterioration of cognitive function and memory, mental and physical fatigue, meditation, and improve overall quality of life and vitality.

In addition, compounds of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, as well as compositions containing an effective dose, are suitable for treatment, prevention and relief of symptoms associated with stress; to treat, prevent and relieve symptoms associated with work overload, exhaustion and/or fatigue, to increase resistance or tolerance to stress and/or to support and facilitate relaxation in normal healthy individuals, i.e. such compositions have effect, as a means to overcome stress.

In addition, compounds of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, as well as compositions containing an effective dose, are suitable for treatment, prevention and relief of anxiety and obsessive-compulsive behavior in humans and animals.

The following variant of implementation of the present invention relates to the use of compounds of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, and to the use of compositions containing them (plant materials/extracts, dietary/pharmaceutical compositions), as a means of improving state", i.e. as a means to reduce irritability and fatigue, to reduce, or prevent, or alleviate physical and mental fatigue and to increase energy in more General terms, especially to boost the output of mental energy, in patients or normal healthy individuals. In addition, to improve cognitive abilities in General, and especially to maintain or improve attention and concentration, memory and ability to memorize, learning ability, language processing, the ability to solve the problem and intellectual activity; to improve short-term memory; to enhance mental alertness and acuity, ability to concentrate; to enhance mental focus; to reduce mental fatigue; to maintain cognitive health, to maintain a balanced cognitive function, to regulate hunger and satiety, as well as to regulate motility.

The present invention relates not only to compounds of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, and their compositions (i.e. a mixture(s) of the plant extracts (especially)containing them; dietary/pharmaceutical compositions containing them, for use as medicaments, especially for the treatment of disorders associated with impaired neuropterida, as well as to methods for treating themselves of such disorders as mentioned above.

For humans a suitable daily dosage of the compounds of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, for the purposes of the present invention may be in the range of from 0.001 mg per kg body weight to about 20 mg per kg of body weight per day. More preferred is a daily dosage of from about 0.01 to about 10 mg per kg of body weight, and especially preferred is a daily dosage of from about 0.05 to 5.0 mg per kg of body weight. The number of plant substances or plant extracts containing such a compound of General formula I, can be calculated accordingly.

In solid dosage units of drugs for human compound of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, and accordingly is in the amount of from about 0.1 mg to about 1000 mg, preferably from about 1 mg to about 500 mg per unit dosage.

In dietary compositions, especially in food and beverages for humans, the compound of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, respectively, is present in the amount of approximately from 0.0001 (1 mg/kg) to about 5 wt.% (50 g/kg), preferably from about 0,001% (10 mg/kg) to about 1 wt.% (10 g/kg), more preferably from about 0.01 (100 mg/kg) to about 0.5 wt.% (5 g/kg) based on the total weight of the food product or beverage.

Food and drinks in a preferred embodiment of the invention, the amount of compounds of General formula I with the definitions of X, R 1 and R 2 is from 10 to 30 mg per serving, ie, 120 mg / kg of food or drink.

For animals, excluding humans, a suitable daily dosage of the compounds of General formula I with the definitions of X, R 1 and R 2 and the preferences as given above, for the purposes of the present invention may be in the range from 0.001 mg per kg body weight to about 1000 mg per kg of body weight per day. More preferred is a daily dosage from about 0.1 mg to 500 mg per kg of body weight, and especially preferred is a daily dosage from about 1 mg to 100 mg per kg of body weight.

For animal companions (Pets) fit the same daily dosage for humans.

Further, the invention is illustrated by the following examples.

3-n-butylphthalide used in the experiments described below was obtained from Advanced Synthesis, PO Box 437920, San Ysidro, CA 92173. Seniority and kneeled were obtained from AnalytiCon Discovery GmbH Hermannswerder Haus 17, 14473 Potsdam, Germany, and ligustilide was synthesized by chemists DSM Nutritional Products Ltd., Kaiseraugst, Switzerland. The purity of all products was >95%.

Example 1

The inhibition of the absorption of serotonin and substitution labeled citalopram compounds of the formula I

Cell line SOME-293 stably expressing the Transporter serotonin reuptake person (hSERT), was obtained from R. Blakely, Vanderbilt University, USA. Cells were grown according to standard methods in the environment of the Needle, the modified Dulbecco purchased in Bioconcept, Allschwil, Switzerland) containing 10% fetal bovine serum, penicillin, streptomycin, L-glutamine and antibiotic G418, and perseval by trypsinization. One day before the test cells were sown in the above environment. Directly before the test environment was replaced with bicarbonate-buffered Krebs Ringers purchased from Sigma Chemicals Ltd., with the addition of 35 microns pargyline, 2.2 mm CaCl2 , 1 mm ascorbic acid and 5 mm N-2-hydroxyethylpiperazine-N'-2-econsultancy acid (buffer, called "Hepes"). The absorption of serotonin cells was determined by adding labeled (3H) serotonin (Amersham Biosciences GE Healthcare, Slough, UK) to a concentration of 20 nm and incubation for 30 minutes at room temperature. After removal of uninvolved tags careful washing (three times) with the above buffer is serotonin were determined using a liquid scintillation counter.

The effect of the compounds of formula I on the uptake of serotonin was identified by its inclusion in the analyzed sample in the range of concentrations between 0.03 and 100 μm for 10 minutes prior to and during the addition of (3H) serotonin/citalopram. The absorption of serotonin through the conveyor inhibited by ligustilide, 3-butylphthalide, mencionados And, mencionados With, mencionados In and knedlikam respectively dose-dependent manner, with the values of IC 50 , as shown in Table 2.

The inhibition of the absorption of serotonin in transfected cells SOME 293 compounds of the formula I

Substance

IC 50 absorption of serotonin, labeled with tritium

Ligustilide

20,4+/-5,8 μm (n=4)

3-n-butylphthalide

35,2+/-6,7 μm (n=3)

Sentineled And

32,5+/-9,1 μm (n=2)

Sentineled With

to 31.4+/-10,9 μm (n=2)

Sentineled In

75,0+/-11,0 μm (n=2)

40,5+/-15,0 μm (n=3)

Extract of celery

99,2+/-5,8 µg/ml (n=2)

Extract of wild celery

29,9+/-8,3 µg/ml (n=2)

Since the experiments were performed twice or more (n)shows the average +/- standard error of the mean (s.e.m.).

Example 2

Inhibition of monoamine oxidase compounds of the formula I

As substrates for the enzymes monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-b) were used organic amines p-tyramine or benzyl amine, respectively. The number obtained in this reaction H 2 O 2 was determined by reaction with vanillic acid, catalyzed by horseradish peroxidase (HRP).

Reactions were carried out in titration microplate made of polystyrene. The enzyme MAO (final concentration of 2 U/ml) was mixed or p-tyramine (Sigma, final concentration 0.5 mm) or benzylamine (Sigma, final concentration 0.5 mm), as needed, and pigmentosum solution (containing vanillic acid (Fluka), 4-aminoantipyrine (Fluka) and horseradish peroxidase (Sigma), a final concentration of 0.25 mm, 0.125 mm and 1 U/ml, respectively) in 0.2 M potassium phosphate buffer pH of 7.6. Reactions were monitored in titration microplate reader absorbance, for example Spectramax M5 (Molecular Devices Corporation). The optical density was measured at 495 nm every 15 seconds for 40 minutes and the initial reaction rate was calculated by linear regression using SOFTmaxPro (Molecular Devices Corporation).

Action ligustilide, 3-butylphthalide, sentineled With and kneeled on monoaminooxidase enzymes was determined by their inclusion in the analyzed sample in the concentration range between 0.03 and 100 μm for 10 minutes prior to and during incubation with the substrate. To determine the effect of compounds on the part of the reaction catalyzed by HRP, the enzyme MAO was replaced by H 2 O 2 (Molecular Probes, final concentration 0.2 mm). Tricyclic diterpenes and their derivatives according to formula I dose-dependent manner inhibited both responses containing MAO-a and MAO-b, while the control reaction was not affected. The measured IC50 values in the inhibition of the activity of monoaminooxidase ligustilide, 3-butylphthalide, mencionados With and knedlikam respectively shown in Table 3.

Inhibition of MAO-a and MAO-b compounds of the formula I

Substance

IC50 [μm] for inhibition of MAO-A.

IC50 [μm] for inhibition of MAO-b

Ligustilide

15,7+/-0,2 s.e.m. n=2

24,9+/was 3.7 s.e.m. n=2

3-n-butylphthalide

8,1+/-1,2 s.e.m. n=2

56,1+/-10,2 s.e.m. n=2

Sentineled With

2,72+/-0,16 s.e.m. n=2

2,14+/-0,24 s.e.m. n=2

>100 μm n=2

108,8+/ - 17, 7C s.e.m. n=2

Example 3

The effect of the compounds of formula I in the test of the primary observation test (Irvine) in mice

The method, which was first identified toxic dose, the valid range of doses and main effects tested (test) connections on the behavior and physiological function, has been the method described Irwin 1968 Psychopharmaco, 13:222-257.

Mice were administered the test substance (3-n-butylphthalide, ligustilide) and watched them while comparing with the control group, which was introduced media (text not made in "blind conditions"). 3 groups subjected to processing, compared with the same control at the same time. At the same time watching all the animals in the group subjected to processing.

Change behavior, physiological symptoms and symptoms of neurotoxicity, pupil diameter, and rectal temperature were recorded according to the mesh of the normalized observation, derived from observation of Irvine, above. The grid includes the following items: mortality*seizures*tremor*, Straub*, sedation, agitation, abnormal gait* ("skiing", walking on tiptoe), jumping*, impaired motor coordination*, cramps*, piloerection*, stereotypie* (hyrcania, chewing, head movements, jerking his head*scratching*breath*, aggression*, fear, reactivity to touch, muscle the tone, the loss of the installation of reflex, ptosis century, exophthalmia, loss of capture, akinesia, numbness, loss of traction (stretching), loss of corneal reflex, analgesia, defecation, salivation, lacrimation, pupil diameter (Unit=1/45 mm) and rectal temperature.

The observations were carried out after 15, 30, 60, 120 and 180 minutes after administration of the test substance and also after 24 hours. The symptoms marked (*)were observed continuously from 0 to 15 minutes after injection. Was taken 5 mice per group.

3-butylphthalide (purity of 98.5%) was dissolved in 3% DMSO, 3% tween 80 in physiological solution (0.9% wt./about. NaCl) and injected into mice intraperitoneally.

3-n-butylphthalide

At the dose of 100 mg/kg of body weight 3-n-butylphthalide showed a slight sedative effects (5/5 mice after 15 and 30 minutes and at 2/5 after 60 minutes) and low muscle tone (5/5 mice after 15 and 30 minutes and at 3/5 after 60 minutes).

At a dose of 200 mg/kg of body weight he showed moderate sedative effects (5/5 mice after 60 and 120 minutes), reduced fear and low muscle tone in 60 minutes.

At a dose of 300 mg/kg of body weight he showed marked sedation in 4/4 mice after 15 minutes and 30 minutes, moderate sedation in 4/4 mice after 60 minutes and 120 minutes and a slight solace in 4/4 mice after 180 minutes.

3-butylphthalide at a dose of 300 mg/kg also reduced fear and muscle tone through 120 minutes

In General, 3-butylphthalide showed dose-dependent sedation, reduction of fear and the effect of muscle relaxation.

Ligustilide (purity, 98.9 per cent) at a dose of 30 mg/kg caused a slight solace in 3 mice after 30 minutes.

At the dose of 100 mg/kg, it caused a minor solace in all 5 mice within 15 to 30 minutes and 3 mice after 60 minutes; it reduced muscle tone in 2 mice after 30 minutes.

In General, 3-butylphthalide and ligustilide showed dose-dependent sedation, reduction of fear and the effect of muscle relaxation.

Example 4

Swimming the Porsolt test using 3-n-butylphthalide and ligustilide

"Behavioral test of despair" or "Test the forced swimming the Porsolt" is an approved model of depression (see .Nagatsu 2004 NeuroToxicology, 25:11-20, and Porsolt et al. 1977, Arch. Int. Pharmacodyn., 229:327-336). He responds to the increase in neuropterida certain neurotransmitters, including serotonin, dopamine and norepinephrine.

A test that determines the antidepressant activity was performed as described by Porsolt et al. above. Mice were forced to swim in a situation from which they could not be saved, quickly became motionless. Antidepressants reduce the duration of immobility.

Mice are individually placed in a cylinder (height=24 cm, diameter=13 cm)containing 10 cm of water (22°C), from which they could not escape. Mice were placed in water for 6 minutes and measured the duration of immobility during the last 4 minutes.

Was investigated 10 mice for each of the four groups. The test was performed blindly, i.e. the person who conducted the experiment, did the mice injections and therefore did not know to which of the four groups is each mouse.

3-n-butylphthalide (purity of 98.5%) was estimated in each of the 3 doses of 10, 30 and 80 mg/kg of body weight, introduced intraperitoneally 30 minutes before the test, and compared with the control group. Input 3-n-butylphthalide was dissolved in physiological solution containing 3 wt.% DMSO and 3 wt.% Tween® 80 (the so-called "media"). The control group was intraperitoneally injected carrier consisting of a physiological solution containing 3 wt.% DMSO and 3 wt.% Tween® 80.

The results are shown in Table 4.

The decrease in the "time of stillness" in the application of 3-n-butylphthalide

The concentration of 3-n-butylphthalide [mg/kg mass of body]

The duration of immobility [seconds] ± Standard error of the mean

0 (control group)

157,4±13,2

132,4±9,3

USD 128.0±15,3

129,0±15,4

3-n-butylphthalide in the range between 10 and 80 mg/kg showed a tendency to decrease immobility time to approximately 18%.

The decrease in the "time of stillness" in the application ligustilide

Concentration ligustilide [mg/kg body weight]

The duration of immobility [seconds] ± Standard error of the mean

0 (control group)

158,7±10,1

128,9±15,1

164,2±15,5

147,1±12,1

Ligustilide at a dose of 10 mg/kg showed a tendency to decrease immobility time to approximately 18%, but not at higher doses.

Example 5

Test elevated plus maze when using 3-n-butylphthalide

The method, which detects anxiolytic activity was the method described Handley et al. 1984. (Naunyn-Schm Arch Pharm 387:1-5. Rodents avoid open spaces (open sleeves elevated cross maze). Anxiolytic drugs increase exploratory activity in the open arms.

The maze consists of 4 hoses of equal length and width (14×5 cm), mounted in the form of a plus sign (+). Two opposing sleeve is blocked by a wall with a height of 12 cm (closed sleeves). 2 other hoses have no walls (open arms). The maze is raised above the floor 56 see the Mouse is placed in the center of the labyrinth (in the centre plus) and leave to study for 5 minutes. Record number of entries in open and closed sleeves and time spent in open arms. The group explored 10 mice. The test was performed "blind".

3-n-butylphthalide was tested at doses of 10, 30 and 80 mg/kg of body weight.

The results are shown in Table 6.

Treatment (mg/kg) r.o. - 24 hour, 5 hours and 1 hour before the test

The open sleeve of the Number of inputs

Outdoor sleeve time (sec)

The mean number ± sem

% change

The mean number ± sem

% change

the 2.4±0.5

18,2±4.9

3-n-butylphthalide (10)

a 3.5±0.7

24,3±4.6

3-n-butylphthalide (30)

3,1±0.5

23,0±3.8

3-n-butylphthalide (80)

3,0±0.8

26,4±5.3

3-n-butylphthalide showed a tendency to moderate the increase in the number of entries and time spent in the open arm. It did not affect the inputs to the closed sleeve. Thus, 3-n butylphthalide has a moderate anxiolytic activity.

Example 6

The test of "burying balls" as test anxiety, or obsessive-compulsive behavior

Oil extract of celery seed, rich in phthalide was tested in the test burying balls. The crude oil extract from the seeds of celery odorous (Apium graveolens), obtained by supercritical fluid CO2 extraction from seeds was purchased from Guanzhou Honsea Sunshine Bio Science & Technology, Guangzhou, 510620, people's Republic of China. This extract (66,15 g) was distilled for about 2 hours at ~30 cm installation Cuellar at a temperature of 125°C, under a pressure of 0.02 mbar. The distillate contained 18,12% butylphthalide, 0,87% butylidenephthalide, 35,37% sentineled, 20,99% sedanolide, 2,23% C16 fatty acids 3.14% oleic acid based on the total mass of oil extract of celery seed.

It is reported that the behavior of "defensive burying" of mice is sensitive to a number of lungs (eg, diazepam) and strong (e.g., haloperidol) tranquilizers (Broekkamp et al., 1986 Eur J Pharmacol. 126:223-229), in addition to an SSRI (e.g., fluvoxamine, fluoxetine, citalopram), tricyclic antidepressants (e.g. imipramine, desipramine) and selective inhibitors of the uptake of norepinephrine (e.g. reboxetine), at doses that do not cause sedation. The model can reflect or behavior such as anxiety, or obsessive-compulsive behavior (see De Boer et al. 2003 Eur J Pharmacol 463:145-161).

Test "defensive burying" was performed in cells Type II (16×22 cm), which were covered with normal bedding material for rodents to a depth of 4 cm, and the litter was carefully aligned manually, to ensure a uniform surface. Surface litter was placed twelve glass balls, the configuration of 3×4, evenly spaced.

In the beginning of the test mice are individually placed in a test cell and left to study for 30 minutes At the end of the test, the mice were removed from the cells, and counted the number of balls that have been closed (i.e. at least 2/3 covered with litter).

Before testing, the following animals were prepared fresh cells and litter.

Oil extract of celery seed were compared after sub-chronic oral administration in doses of 50, 100, 200, 300 mg/kg fluoxetine at a dose of 10 mg/kg as a reference substance and corn oil as the carrier. Oil extract of celery seed, fluoxetine and media was administered orally through a feeding tube 24, -5, -1 hour before the test.

After each dose, the mice were returned to home cages until the next dose or the beginning of the test.

The effects of an oil extract of celery seed (Apium graveolens) and fluoxetine in the test "defensive burying" in mice

Treatment (mg/kg) r.o., -24, -5, -1 hour

Test "defensive burying"

% buried balls

Apium graveolens (50)

Apium graveolens (100)

Apium graveolens (200)

Apium graveolens (300)

Fluoxetine (10)

Oil extract of celery seed showed a tendency to decrease number of buried balls compared to the control with the introduction of media. The effect was approximately half of the effect of the selective inhibitor of serotonin reuptake fluoxetine.

Example 7

Inhibition of uptake of dopamine compounds of the formula I

The action of certain neurotransmitters, including dopamine, are governed by their rapid absorption and elimination of synaptic connections in the cytoplasmic membrane transport proteins. The dopamine Transporter in the Central dopaminergic neurons is responsible for return up to 90% of released neurotransmitter. The monoamine transporters represent high-affinity targets for a number of psychotropic drugs, such as cocaine, amphetamine and antidepressants. Blocking the transporters and as a result preventing neural absorption, these drugs increase the levels of extracellular concentrations of neurotransmitters in the Central and peripheral nervous system, contributing to their behavioral and spontaneous effects.

Cells CHO-Ki/hDAT expressing the human dopamine Transporter (hDAT), were sown before the study. Cells (2×10 5 /ml) were incubated with the compound of General formula I (3-n-butylphthalide) and/or the media in a modified Tris-HEPES buffer at a pH of 7.1 at 25°C for 20 minutes before adding 50 nm [ 3 H]dopamine for 10 minutes. Specific signal was determined in the presence of 10 μm nomifensine. Then the cells were solubilizers with 1% SDS lytic buffer. The decrease in absorption [ 3 H]dopamine to 50 percent or more (≥50%) relative to controls with the introduction of the media indicates significant inhibitory activity. Compounds were screened at 10; 1; 0,1; 0.01 and 0.001 μm. The same concentrations were simultaneously applied to a separate group of untreated cells and evaluated for possible cytotoxicity associated with the drug only if there was significant inhibition of absorption.

Connection

*Nomifensine

3-n-butylphthalide

22,0 μm

*Indicates used standard reference substance

Giros, 1992 Mol. Pharmacol. 42:383-390, 1992.

Pristupa, et al. 1994. Mol. Pharmacol. 45:125-135 mA.

Example 8

Inhibition of uptake of norepinephrine compounds of the formula I

The action of certain neurotransmitters, including norepinephrine, are governed by their rapid absorption and elimination of synaptic connections in the cytoplasmic membrane transport proteins. The norepinephrine Transporter in the Central adrenergic neurons is responsible for return up to 90% of released neurotransmitter. The monoamine transporters represent high-affinity targets for a number of psychotropic drugs, such as cocaine, amphetamine and antidepressants. Blocking the transporters and as a result preventing neural absorption, these drugs increase the levels of extracellular concentrations of neurotransmitters in the Central and peripheral nervous system, contributing to their behavioral and spontaneous effects.

Stably expressing recombinant human norepinephrine Transporter cells MDCK kidney dogs were seeded the day before the examination. Cells (2×10 5 /ml) pre-incubated with the compound of the formula I (3-n-butylphthalide) and/or the media in a modified buffer Tris-HEPES at pH of 7.1 at 25°C for 20 minutes, then added a 25 nm [ 3 H]norepinephrine for incubation for 10 minutes. Then the cells in the wells washed twice, solubilizers with 1% SDS lytic buffer and the lysate was shortchanged in order to determine the uptake of [ 3 H]norepinephrine. Specific signal was determined in the presence of 10 μm desipramine. The decrease in absorption [ 3 H]norepinephrine by up to 50 percent or more (≥50%) relative to control media indicates significant inhibitory activity. Compounds were screened at 10; 1; 0,1; 0.01 and 0.001 μm. The same concentrations were simultaneously applied to a separate group of untreated cells and evaluated for possible cytotoxicity associated with the drug only if there was significant inhibition of absorption.

Reference data:

Inhibitor

*Desipramin

3-n-butylphthalide

of 23.7 μm

*Indicates used standard reference substance

♦Experiment was performed twice

Galliet et al. 1995. J. Exp. Biol. 198:2197-2212.

Example 9

Preparation of soft gelatin capsules

Can be cooked soft gelatin capsule (500 mg)containing the following ingredients:

Ingredient

Quantity per capsule

Oil extract of celery seed

Lecithin

The soybean oil

A healthy person for the treatment of moderate chronic dysthymia can be assigned to two capsules a day for 3 months.

Example 10

Preparation of soft gelatin capsules

Can be cooked soft gelatin capsule (600 mg)containing the following ingredients:

Ingredient

Quantity per capsule

Oil extract of celery seed

Evening primrose oil (evening primrose biennial)

Vitamin B 6

For the treatment of premenstrual syndrome and premenstrual dysphoric disorder, you can apply one capsule per day, preferably in the second half of the menstrual cycle.

Example 11

Preparation of tablets

Can be cooked tablet 400 mg, contain the following ingredients:

Ingredient

Quantity per tablet

3-n-butylphthalide

Standardized extract of Passiflora

Green tea extract, for example TEAVIGO® from DSM Nutritional Products, Kaiseraugst, Switzerland

For General health, enhance and facilitate stress, you can apply one tablet twice a day for 3 months.

Example 12

Preparation of soluble, aromatic soft drink

Ingredient

Amount [g]

3-n-butylphthalide

Sucrose, fine powder

Ascorbic acid, fine powder

Citric acid, anhydrous powder

Lemon flavouring

Trinacria citrate, anhydrous powder

Tricalcium phosphate

β-Carotene 1% CWS from DNP AG, Kaiseraugst, Switzerland

The total number

All the ingredients are mixed and sieved through a sieve of 500 μm. The resulting powder was placed in a suitable container and mixed with a turbulent mixer for at least 20 minutes. To prepare the drink is taken 125 g of the obtained mixed powder and filled with one liter of water to get a drink.

Ready-to-drink soft drink contains approximately 30 mg of 3-n-butylphthalide per serving (250 ml).

As a reinforcing means and for General health, you can drink 2 servings per day (240 ml).

Example 13

Preparation of enriched, not subjected to heat treatment, the grain concentrate

Ingredient

Amount [g]

3-n-butylphthalide

Glucose syrup

Syrup invert sugar

Syrup of sorbitol

The kernel oil coconut

Fat baking

Lecithin

Utverjdenie palm oil

Dried and chopped Apple

Corn flakes

Rice chips

Wheat chips

Roasted hazelnuts

Skimmed milk powder

Orange flavor 74863-33

Citric acid

The total number

3-n-butylphthalide pre-mixed with dry skim milk and placed in a planetary mixer. Add corn flakes and rice crisps, and all gently stirred. Then add the dried and chopped apples. In the first vessel for cooking food mix sugar, water and salt in quantities above (solution 1). In the second vessel is mixed glucose, invert syrup and syrup sorbitol in amounts above (solution 2). The mixture of fat for baking, butter kernel, coconut, lecithin and emulsifying substance is a fatty phase. Solution 1 was heated to 110°C. Solution 2 is heated to 113°C and then cooled in a cold water bath. Then the solutions 1 and 2 are combined. The fat melt phase at 75°C in a water bath. The fatty phase is added to the combined mixture of solution 1 and 2. Orange flavoring and citric acid is added to the liquid sugar-fat mixtures. Liquid mass add to dry ingredients and mix well in a planetary mixer. The mass is placed on a cutting Board and roll to the desired thickness. The mass is then cooled to room temperature and cut into pieces. Not subjected to a heat treatment briquetted grain concentrate contains ~25 mg oregano extract per serving (30 g). For overall health and enhance you can eat 1-2 cereal "bars" in the day.

Example 14

Dry food for dogs that contains 3-n-butylphthalide or ligustilide to relieve stress and recovery dogs

Commercial main feed dog (for example, Mera Dog "Brocken", MERA-Tiernahrung GmbH, Marienstraβe 80-84, D-47625 Kevelaer-Wetten, Germany) is sprayed with a solution of 3-n-butylphthalide or ligustilide enough for introduction to a subject a daily dose of 50 mg of 3-n-butylphthalide or ligustilide per kg of body weight. Food composition is dried to a content of dry matter of about 90% by weight. For medium dogs weighing 10 kg, eat about 200 grams of dry food per day, food for dogs contains approximately 2500 mg of 3-n-butylphthalide or ligustilide per kg of food. For heavier dogs food mixture is prepared accordingly.

Example 15

Dry cat food that contains 3-n-butylphthalide or ligustilide

Commercial staple food for cats (e.g., Happy Cat "Adult", Tierfeinnahrung, Südliche Hauptstraße 38, D-86517 Wehringen, Germany) is mixed with a solution of 3-n-butylphthalide or ligustilide enough to introduce the subject with a daily dose of 100 mg 3-butylphthalide or ligustilide per kg of body weight. For the average cat weighing about 5 kg, consuming approximately 400 g of dry food per day, cat food contains 1250 mg/kg

Example 16

"Food" for dogs that contains 3-n-butylphthalide or ligustilide

Commercial "food" for dogs (for example, Mera Dog "Biscuit" for dogs, as provided Mera Tiernahrung GmbH, Marienstrasse 80-84, 47625 Kevelaer-Wetten, Germany) is sprayed with a solution of 3-n-butylphthalide or ligustilide sufficient for the introduction of "treats" 5-50 mg of 3-n-butylphthalide or ligustilide per gram "treats". Food composition is dried to a content of dry mass to 90% by weight.

Example 17

Commercial treats for cats containing 3-n-butylphthalide or ligustilide

Commercial treats for cats (for example, Whiskas Dentabits for cats, as provided by Whiskas, Masterfoods GmbH, Eitzer Str. 215, 27283 Verden/Aller, Germany) is sprayed with a solution of 3-n-butylphthalide or ligustilide sufficient for the introduction of "treats" 5-50 mg of 3-n-butylphthalide or ligustilide per gram "treats". Food composition is dried to a content of dry mass to 90% by weight.

1. Dietary or pharmaceutical composition comprising ligustilide, for use in the treatment or prevention of depression, generalized anxiety disorder, dysphoria, obsessive-compulsive behavior, and mood disorders.

2. The composition according to claim 1, which exists in the form of food in solid or liquid form, such as soups or milk products, in the form of fortified foods, such as piketirovany grain concentrates, bakery products such as cakes and buns, in the form of dietary supplements such as tablets, pills, granules, dragées, capsules, and effervescent formulations, in the form of non-alcoholic beverages such as soft drinks, sports drinks, fruit juices, lemonades, teas and milk-based drinks.

3. The composition according to claim 1 or 2, which is used in animals.

4. Non-therapeutic use of diet compositions containing ligustilide, as a means of improving mood/vitality; a means to overcome stress; a means of reducing anxiety; means for reducing tension, sadness, unhappiness, frustration, or irritability; or to normalize and maintain circadian rhythms, or to relieve or prevent symptoms associated with a disturbed circadian rhythms, which are caused by long-range flights (disorder biorhythms in connection with the flight through several time zones or shift work.