HK1131741A - Eucalyptus extract, method of preparation and therapeutic uses thereof - Google Patents

Description

Eucalyptus extracts, method for preparing same and therapeutic uses thereof

The invention relates to the use of eucalyptus extracts for producing a medicament or food supplement for treating and/or preventing illnesses (affections) or pathological states (pathologies) caused by a disturbance of the reuptake of the following neuro mediators (neuro dissateurs): dopamine, 5-hydroxytryptamine and/or norepinephrine. Preferably, said extract is enriched in at least one compound of formula (I) or any one of its diastereoisomeric forms:

wherein R1 forms together with the carbon atom to which it is attached a group C ═ CH2, groupOrAnd R2 represents isobutyl, α -isobutyl or β -isobutyl.

The invention also relates to the use of at least one compound of formula (I) above for preparing a medicament or food supplement for the treatment and/or prevention of a condition or pathology resulting from a disorder of the reuptake of said neuro-mediators.

There are many species of eucalyptus (over 600 species) most of which are native to australia and tasmania, and a few of which are native to the eastern new guinea and malaysia. Eucalyptus belongs to the family myrtaceae, whose name comes from the characteristic shape of their flowers. This is because the word "Eucalyptus (Eucalyptus)" means "well-covered" and the dark refers to a cover (formed by fused petals) that is worn over the stamen of the flower. Eucalyptus is generally a beautiful and large tree that can reach 80 to 100 meters high in their country of origin, and 3 to 20 meters in milder climates. Their smooth bark falls off in pale to pale grey stripes. Generally, they are characterized by the binary nature of the leaves. In the case of Eucalyptus globulus Labill, the immature leaf is oval-oblong, pale grayish green, with blue edges, embracing and stemless, while the mature leaf is sickle-shaped, grayish green, drooping, with twisted petioles and in a straight orientation (two faces equal). Flower buds are formed from a quadrangular pyramid shaped calyx covered by a cap that rises during flowering to expose a number of stamens with long white filaments and yellow anthers. The fruit is a capsule with a diameter of 2 to 2.5cm comprising black or light brown seeds.

In phytotherapy, three species are mainly used in the european pharmacopoeia: eucalyptus globulus, Eucalyptus globulus (e.multibactea r.t.baker), and Eucalyptus globulus (eucalypus smithii r.t.baker). The leaves of the oldest branches (sickle-shaped and petioled), essential oils and eucalyptol obtained therefrom were used.

Eucalyptus leaves are conventionally used by oral and topical routes to treat respiratory disorders (bronchitis, throat inflammation, nasal congestion, cold, etc.) or by application to treat wounds, skin ulcers, etc.

Because of their antibacterial, mucolytic and expectorant activities, the essential oil of eucalyptus and eucalyptol (or 1, 8-cineole) are included in many formulations used to treat respiratory tract disorders. Essential oils are used as anthelmintics and in veterinary medicine.

Known pharmacological properties of eucalyptus essential oils to date are: antimicrobial, expectorant and antitussive properties (WICHTL M. and ANTON R., 1999-plants per behaviour-177-, 155(1): 61-65), antiviral properties (TAKASAKI et al, 1990-Structures of emugulbal-G1, -G2 and G3 from Eucalyptus grandis, and three new inhibitors of Epstein activity-chem.pharm.Bull.38 (5), 1444-1446), and anti-HIV properties (WICHTL M. and ANTON R., 1999-plants of rapeutiques-177-179).

Unexpectedly and surprisingly, the applicant has revealed the use of an extract of eucalyptus in the preparation of a medicament or food supplement for the treatment and/or prevention of pathologies or pathological conditions due to disorders of the reuptake of neuro-mediators.

The field of the invention is therefore eucalyptus extracts for which valuable pharmacological properties have been observed and for which new therapeutic uses have therefore been envisaged. The invention does not relate to such eucalyptus essential oils per se, for which a large number of reference books have been recorded.

Advantageously, said medicament or food supplement is used for the treatment and/or prevention of a pathological condition due to a disturbance of the reuptake of neuro-mediators, said pathological condition being selected from the group consisting of:

-a neurological disease, disorder or condition,

-a psychiatric disease, disorder or condition,

-memory, attention and vigilance (vigilance) disorders associated with neurological and psychiatric diseases, disorders or conditions,

-a functional body disorder,

-dependence on addictive substances.

Preferably, the treatment and/or prevention of said condition or pathology comprises inhibiting reuptake of neural mediators.

Within the scope of the present invention, "neuromediator" means: dopamine and/or 5-hydroxytryptamine and/or norepinephrine.

In the context of the present invention, "Eucalyptus (Eucalyptus)" means a species preferably belonging to the genera Eudesmia, Symphomytus and Umbilicaria (Corymbia) and more particularly the following species: eucalyptus globulus L., Eucalyptus globulus L.S.Johnson 1 Blaxenic (Eucalyptus macrocarpa Hook.), Eucalyptus globulus L.A.S.Johnson1 Blaxenic (Eucalyptus macrocarpa Hook.), Eucalyptus cinerea (Eucalyptus macrocarpa F.Muell. ex Benth.), Eucalyptus globulus (Eucalyptus globulus L.S.Johnson 1 K.D.Highll., Eucalyptus leptopoda Benth., Eucalyptus globulus (Eucalyptus occidentalis End1.), Eucalyptus globulus (Eucalyptus globulus Labill. T.Baker), Eucalyptus globulus (Eucalyptus globulus Labill. Baker) and Eucalyptus globulus (Eucalyptus globulus T.Baker).

These examples illustrate the invention, but do not limit its scope.

Advantageously, the eucalyptus extract is obtained from the leaves, flowers, fruits, stems or trunks of eucalyptus; and preferably from the leaves of eucalyptus.

Advantageously, the eucalyptus extract used according to the invention is characterized in that it comprises at least one compound of formula (I) or any one of its diastereoisomeric forms.

Said formula (I) includes in particular the 4 compounds of the macrocarpal family, namely:

-eucalyptal A, a fruit tree: (5- ((1R) -1- ((11S, 7R) -7-hydroxy-3, 3, 7, 11-tetramethyltricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) in which R1, together with the carbon atom to which it is attached, forms a radicalAnd R2 represents β -isobutyl.

Experimental formula (II): c₂₈H₄₀O₆

Molecular weight: 472g/mol

Advantageously, the mass fraction of macrocarpal a in the eucalyptus extract according to the invention is greater than or equal to 0.1% and strictly less than 3%.

-Eucalyptal macrocarpa B: (5- ((1S) -1- ((11S, 7R) -7-hydroxy-3, 3, 7, 11-tetramethyltricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) in which R1, together with the carbon atom to which it is attached, forms a radicalAnd R2 represents α -isobutyl.

Experimental formula (II): c₂₈H₄₀O₆

Molecular weight: 472g/mol

Advantageously, the mass fraction of macrocarpal B in the eucalyptus extract according to the invention is greater than or equal to 0.1% and strictly less than 3%.

-Eucalyptal macrocarpa C: (5- ((1R) -1- ((11S) -3, 3, 11-trimethyl-7-methylenetricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde), wherein R1 together with the carbon atom to which it is attached forms the group C ═ CH2, and R2 represents β -isobutyl.

Experimental formula (II): c₂₈H₃₈O₅

Molecular weight: 454g/mol

Advantageously, the mass fraction of macrocarpal C in the eucalyptus extract according to the invention is greater than or equal to 0.1% and strictly less than 3%.

-Eucalyptal E, a fruit tree: (5- (1- (3, 3, 11-trimethyl-7-methylenetricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) in which R1 together with the carbon atom to which it is attached forms the group C ═ CH2, and R2 represents isobutyl.

Experimental formula (II): c₂₈H₃₈O₅

Molecular weight: 454g/mol

Advantageously, the mass fraction of macrocarpal G in the eucalyptus extract according to the invention is greater than or equal to 0.1% and strictly less than 5%.

The eucalyptus extract is obtained by an extraction method carried out starting from conventional steps known to the person skilled in the art.

Leaves, flowers, fruits, stems or trunks of Eucalyptus (Eucalyptus sp.) or a mixture of these parts are ground and then extracted with an organic solvent which may be an alkane (pentane, hexane, heptane, octane, cyclohexane), ether oxide (exteoxide) (tetrahydrofuran, dioxane, diethyl ether), an ester (ethyl acetate, isopropyl acetate), an alcohol (methanol, ethanol, propanol, isopropanol, butanol, octanol), a ketone (methyl ethyl ketone, methyl isobutyl ketone), a halogenated hydrocarbon (chloroform, dichloromethane) or a mixture of water and a water-miscible organic solvent (e.g. a water-alcohol mixture).

The extraction is performed at a plant/solvent ratio of about 1/1 to about 1/20 and can be repeated 2 to 3 times. The temperature of the extraction solvent may be equal to or higher than ambient temperature and may reach the boiling temperature of the solvent used. The time for contacting the plant with the solvent is from about 30 minutes to about 72 hours.

Then, solid-liquid separation is performed, and the plant is separated from the solvent by filtration or centrifugation.

The resulting filtrate may be:

-or direct drying by complete evaporation of the extraction solvent, thus producing the final extract;

or more or less concentrated. In the case of mixed extraction solvents (e.g. water-alcohol mixtures), concentration is continued until the organic solvent present has evaporated off. In the case of organic solvents, a certain amount of water is added to the concentrate obtained. The liquid-liquid purification step is carried out by adding to the aqueous phase an immiscible solvent which may be an alkane (e.g. hexane), an ether oxide (e.g. diethyl ether), an ester (e.g. ethyl acetate), an alcohol (e.g. butanol), a ketone (e.g. methyl ethyl ketone) or a halogenated hydrocarbon (e.g. chloroform). Performing one, two or three liquid-liquid extractions. The combined organic phases may be dehydrated over sodium sulfate before the drying.

The solution obtained was concentrated in vacuo at a temperature ranging from ambient to boiling temperature.

Drying of the final extract is carried out by lyophilization or by more conventional methods known to those skilled in the art (nebulization, oven, etc.). Preferably, the drying temperature does not exceed about 60 ℃.

The extract may be stabilized by adding an antioxidant such as ascorbic acid or citric acid in an amount of about 0.05g to about 1g per 100g of dry extract.

A very noteworthy aspect of the present invention is that the pharmacological properties of eucalyptus extract, which inhibit the reuptake of neuro-mediators, are more advantageous, since said extract is enriched in at least one compound of formula (I) or in any one of its diastereoisomeric forms.

Thus, the eucalyptus extract is preferably enriched with at least one compound of formula (I).

Within the scope of the present invention, "eucalyptus extract enriched in macrocarpal a" means a eucalyptus extract in which the mass fraction of macrocarpal a is greater than or equal to 3% and strictly less than 90%, preferably greater than or equal to 3% and less than 50%, more preferably greater than or equal to 3% and less than 40%, and still more preferably greater than or equal to 3% and less than 20%.

Within the scope of the present invention, "eucalyptus extract enriched in macrocarpal B" means a eucalyptus extract in which the mass fraction of macrocarpal B is greater than or equal to 3% and strictly less than 90%, preferably greater than or equal to 3% and less than 50%, more preferably greater than or equal to 3% and less than 40%, and still more preferably greater than or equal to 3% and less than 20%.

Within the scope of the present invention, "eucalyptus extract enriched in macrocarpal C" means a eucalyptus extract in which the mass fraction of macrocarpal C is greater than or equal to 3% and strictly less than 90%, preferably greater than or equal to 3% and less than 50%, more preferably greater than or equal to 3% and less than 40%, and still more preferably greater than or equal to 3% and less than 20%.

Within the scope of the present invention, "eucalyptus extract enriched in macrocarpal G" means a eucalyptus extract in which the mass fraction of macrocarpal G is greater than or equal to 5% and strictly less than 90%, preferably greater than or equal to 5% and less than 50%, more preferably greater than or equal to 5% and less than 40%, and still more preferably greater than or equal to 5% and less than 20%.

Applicants have demonstrated the effect of eucalyptus extract on dopamine and/or norepinephrine and/or 5-hydroxytryptamine reuptake.

Due to their pharmacological properties of inhibiting the reuptake of these neuro-mediators, said extracts are particularly useful for the preparation of a medicament or food supplement for the treatment and/or prevention of a number of pathologies or pathological states resulting from dopamine and/or 5-hydroxytryptamine and/or norepinephrine deficiency.

In the case of conditions or pathologies that can be treated and/or prevented by means of the eucalyptus extract according to the invention, the following may be mentioned as suitable by way of illustrative and non-limiting examples:

-neurological diseases, disorders or conditions:

for example, neurodegenerative diseases (alzheimer's disease, huntington's chorea, parkinson's disease, cerebrovascular accidents, cranial traumas), amyotrophic lateral sclerosis, senile dementia, frontotemporal dementia (d meetings from-temporales), vascular dementia (d meetings vascularires), migraine, neuropathic pain of central origin (douleur sneuropathies d' origin central);

-a psychiatric disease, disorder or condition:

for example, depression (intrinsic, refractory, reactive or iatrogenic), depressive state, schizophrenia, bipolar disorder, generalized anxiety, stress-related disorders (maladies li e au stress), panic attack, obsessive compulsive disorder, post-traumatic stress syndrome (depression de stress-transactions), attention deficit hyperactivity disorder (trombones de l' hyperactivie), eating disorders (in particular, bulimia, anorexia), phobias (in particular, agoraphobia), autism;

-memory, attention and vigilance disorders associated with neurological and psychiatric diseases, disorders or conditions;

-functional somatic disorders:

for example, chronic fatigue syndrome, fibromyalgia, irritable colon syndrome, gastroesophageal reflux, loss of libido, erectile dysfunction, urinary incontinence;

dependence on addictive substances:

the addictive substance is especially nicotine, alcohol, opium preparation, cannabinoids, and psychostimulant.

This is because the medicament or food supplement according to the invention is advantageously used for inducing withdrawal from nicotine, alcohol, opiates, cannabinoids, psychostimulants, and preventing relapse in abstinent persons.

The medicament or food supplement according to the invention is advantageously used as a replacement therapy for addictive substances and for the prevention and/or treatment of the withdrawal-related depressive syndrome.

One skilled in the art will be able to appreciate other pathological conditions for which treatment requires such inhibition.

Applicants present herein in a non-limiting manner a number of references which mention the link between said pathological conditions and their treatment by means of triple inhibitors of dopamine and/or 5-hydroxytryptamine and/or norepinephrine reuptake. Examples of each "class" have been given.

Dopamine, 5-hydroxytryptamine and norepinephrine play a common role in the development and survival of neurons (Lauder j.m., Trends Neurosci, 1993, 16; 233). Certain neurological pathological conditions such as Parkinson's disease (Hornykiewicz O., AdvCytopharmacol.1971, 1; 369) are caused by dopamine deficiency; monoamine oxidase inhibitors that increase dopamine, 5-hydroxytryptamine and norepinephrine levels are used for the treatment of parkinson's disease and other neurological disorders (Ebadi m., Curr Drug targets.2006, 7; 1513). Therefore, the eucalyptus extract according to the present invention is advantageously used for the treatment of these neurological diseases.

Depression is a common emotional pathology characterized by a strong feeling of sadness, pessimistic thoughts, self-depreciation, often accompanied by loss of vitality, enthusiasm, and libido. The inability to feel pleasure (also known as anhedonia) in a normally pleasant experience is also considered a common symptom of depression. Depression is currently treated with selective inhibitors of 5-hydroxytryptamine reuptake such as fluoxetine, citalopram or paroxetine, selective inhibitors of norepinephrine reuptake such as reboxetine, or mixed inhibitors of 5-hydroxytryptamine and norepinephrine reuptake such as milnacipran or venlafaxine. However, an important role in pleasure and motivation (motility) is attributed to dopaminergic neurons projecting into the brain region known as the nucleus accumbens (Koob G.F.Sem. neurosci.1992, 4, 139; Salamone J.D.Behav. brain Res.1994, 61, 117). Thus, the symptoms of depression can be advantageously treated by dopamine, 5-hydroxytryptamine and norepinephrine reuptake inhibitors such as eucalyptus extract according to the invention.

In animals (Di Chiara G and Imperato A., Proc Natl Acad Sci U SA.1988, 85; 5274) and humans (Brody et al, Am J Psychiatry, 2004, 161; 1211), absorption of addictive substances, including nicotine, increases extracellular dopamine levels in the ventral striatum. Smoking cessation may be accompanied by depressive syndrome (Wilhelm K et al, drug alcohol Rev, 2006, 25; 97). Thus, the eucalyptus extract according to the present invention can be advantageously used as a replacement therapy for addictive substances (e.g., nicotine), and for preventing or treating withdrawal-related depression syndrome.

Functional disorders, also known as somatotropic (somatotrope) disorders, are conditions that involve a major physiological function and are not due to organic damage but rather to the way organs (liver, heart, etc.) function. Functional somatic disorders may be the root cause of later-onset diseases. Among these disorders, fibromyalgia is a disorder combining diffuse or local pain, chronic fatigue, symptoms of depression, and memory and attention-concentration disorders (RooksDS, Curr OpinRheumatol.2007, 19; 111). Symptoms of fibromyalgia are treated by mixed inhibitors of norepinephrine/5-hydroxytryptamine reuptake (vitto o., humpschopharmacol.2004, 19Suppl 1: S27). Therefore, the addition of a component contributing to dopaminergic robustness (tonus papaminergique) as in the eucalyptus extract according to the invention is advantageous for the preparation of a medicament or food supplement for the treatment and/or prevention of functional body disorders.

Advantageously, the medicament is in oral or injectable form.

Advantageously, the oral form is selected from tablets, gelatin capsules (g6 lue), capsules (capsules), liquid preparations such as syrups, drinkable solutions or powders for drinkable suspensions.

Advantageously, the food (or nutritional or dietary) supplement is packaged in unit dosage form, i.e. presentation form(s), such as gelatin capsules, pastilles, tablets, pills and other similar forms, as well as powder sachets (sachets de poudre), liquid ampoules, vials equipped with dropper tubes and other similar forms of liquid or powder formulation to be taken in small measured units.

The results obtained from the eucalyptus extract according to the invention, enriched with at least one compound of formula (I) or any one of its diastereoisomeric forms, demonstrate that the benefits of the invention can be extended to any composition based on at least one compound of formula (I) or any one of its diastereoisomeric forms, whether they are obtained by chemical means, biochemical means, or from a plant extract.

The invention therefore also relates to the use of at least one compound of formula (I) or any one of its diastereoisomeric forms, for the preparation of a medicament or food supplement for the treatment and/or prevention of neurological disorders or pathologies resulting from a disorder of neuronal reuptake, psychiatric disorders or pathologies and related conditions, functional somatic syndromes, and dependence on addictive substances. Preferably, the treatment and/or prevention of said condition or pathology comprises inhibiting reuptake of neural mediators.

Due to their pharmacological properties of inhibiting the reuptake of these neuro-mediators, the compounds of formula (I) and their diastereoisomeric forms are particularly useful for the preparation of a medicament or food supplement for the treatment and/or prevention of a number of conditions or pathologies resulting from dopamine and/or 5-hydroxytryptamine and/or norepinephrine deficiency.

In the case of conditions or pathologies that can be treated and/or prevented by means of said compounds according to the invention, the following may be mentioned as appropriate by way of illustrative and non-limiting examples:

-neurological diseases, disorders or conditions:

for example, neurodegenerative diseases (alzheimer's disease, huntington's chorea, parkinson's disease, cerebrovascular accidents, cranial traumas), amyotrophic lateral sclerosis, senile dementia, frontotemporal dementia, vascular dementia, migraine, neuropathic pain of central origin;

-a psychiatric disease, disorder or condition:

for example, depression (endogenous, refractory, reactive or iatrogenic depression), depressive state, schizophrenia, bipolar disorder, generalized anxiety, stress-related disorders, panic attacks, obsessive compulsive disorder, post-traumatic stress syndrome, attention deficit hyperactivity disorder, eating disorders (especially, bulimia, anorexia), phobias (especially, agoraphobia), autism;

-memory, attention and vigilance disorders associated with neurological and psychiatric diseases, disorders or conditions;

-functional somatic disorders:

for example, chronic fatigue syndrome, fibromyalgia, irritable colon syndrome, gastroesophageal reflux, loss of libido, erectile dysfunction, urinary incontinence;

dependence on addictive substances:

the addictive substance is especially nicotine, alcohol, opium preparation, cannabinoids, and psychostimulant.

This is because the medicament or food supplement according to the invention is advantageously used for inducing withdrawal from nicotine, alcohol, opiates, cannabinoids, psychostimulants, and preventing relapse in abstinent persons.

The medicament or food supplement according to the invention is advantageously used as a replacement therapy for addictive substances and for the prevention and/or treatment of the withdrawal-related depressive syndrome.

One skilled in the art will be able to appreciate other pathological conditions for which treatment requires such inhibition.

Advantageously, the present invention relates to the use of macrocarpal a, macrocarpal B, macrocarpal C and/or macrocarpal G for the preparation of a medicament or food additive for the treatment and/or prevention of neurological or pathological conditions, psychiatric or pathological conditions and related disorders, functional somatic syndromes, and dependence on addictive substances due to disorders of dopamine and/or 5-hydroxytryptamine and/or norepinephrine reuptake.

Tests carried out using compounds of formula (I) and their diastereoisomeric forms show that these compounds play a role in the inhibition of dopamine and/or 5-hydroxytryptamine and/or norepinephrine reuptake.

Advantageously, the medicament is in oral or injectable form.

The compounds of formula (I) and diastereoisomeric forms thereof according to the invention may be obtained by purification of plant extracts or by chemical or biochemical synthesis as described in the following documents: total Synthesis of (-) -Macrocarpal C.StereoSelective coupling Reaction with a Novel HexaSubstisted Benzene Cr (CO)₃Complex as a Biomimetic Chiral Benzyl Cation Equivalent/Tanaka，Tetsuaki；Mikamiyama，Hidenori；Maeda，Kimiya；Iwata，Chuzo；In，Yasuko；Ishida，Toshimasa/Journal of Organic Chemistry(1998)，63(26)，9782-9793。

The compounds may be isolated from "eucalyptus extract" or from "an extract enriched in at least one macrocarpal of formula (I)". The techniques allowing their purification are chromatographic techniques which are conventional to the person skilled in the art. The extract has reverse phase (preferably Symet ry)5 μm (Waters)) as stationary phase and a preparative column with an acetonitrile/water/trifluoroacetic acid mixture (in a proportion of 95/5/0.1%) as mobile phase.

Such fraction has a purity of greater than or equal to 90% of the compound of formula (I).

Preferably, such fractions have a purity greater than or equal to 90% of macrocarpal a, macrocarpal B, macrocarpal C and/or macrocarpal G.

According to the present invention, it is reasonably envisaged that macrocarpal a and/or macrocarpal B and/or macrocarpal C and/or macrocarpal G are used for the preparation of a medicament or food supplement for the treatment and/or prevention of overweight or obesity.

The invention also relates to a concentrated eucalyptus extract, characterized in that it comprises at least one compound of formula (I) or any one of its diastereoisomeric forms:

wherein R1 forms together with the carbon atom to which it is attached a group C ═ CH2, groupOrAnd R2 represents isobutyl, alpha-isobutyl or beta-isobutyl,

and in that:

-the mass fraction of macrocarpal a is greater than or equal to 3% and strictly less than 90%, preferably greater than or equal to 3% and less than 50%, more preferably greater than or equal to 3% and less than 40%, and still more preferably greater than or equal to 3% and less than 20%;

-the mass fraction of macrocarpal B is greater than or equal to 3% and strictly less than 90%, preferably greater than or equal to 3% and less than 50%, more preferably greater than or equal to 3% and less than 40%, and still more preferably greater than or equal to 3% and less than 20%;

-the mass fraction of macrocarpal C is greater than or equal to 3% and strictly less than 90%, preferably greater than or equal to 3% and less than 50%, more preferably greater than or equal to 3% and less than 40%, and still more preferably greater than or equal to 3% and less than 20%; and

-parts by mass of macrocarpal G greater than or equal to 5% and strictly less than 90%, preferably greater than or equal to 5% and less than 50%, more preferably greater than or equal to 5% and less than 40%, and still more preferably greater than or equal to 5% and less than 20%.

Preferably, the present invention relates to the use of said concentrated eucalyptus extract as a medicament or food supplement.

Finally, the invention relates to a process for preparing such a concentrated eucalyptus extract.

The method for obtaining said extract comprises the following steps:

-grinding the leaves and/or flowers and/or fruits and/or stems and/or trunks of eucalyptus,

-extracting at least once with an organic solvent or with a mixture of water and a water-miscible organic solvent.

The extraction is performed at a plant/solvent ratio of about 1/1 to about 1/20 and can be repeated 2 to 3 times. The temperature of the extraction solvent may be equal to or higher than ambient temperature and may reach the boiling temperature of the solvent used. The time for contacting the plant with the solvent is from about 30 minutes to about 72 hours.

Preferably, the solvent is selected from alkanes (pentane, hexane, heptane, octane, cyclohexane), ether oxides (tetrahydrofuran, dioxane, diethyl ether), esters (ethyl acetate, isopropyl acetate), alcohols (methanol, ethanol, propanol, isopropanol, butanol, octanol), ketones (methyl ethyl ketone, methyl isobutyl ketone), halogenated hydrocarbons (chloroform, dichloromethane) or mixtures of water and water-miscible organic solvents (e.g. water-alcohol mixtures).

Preferably, the extraction solvent is dichloromethane or isopropyl acetate.

-drying the filtrate in the case of a water-miscible extraction solvent, and then dissolving in a water-immiscible solvent.

The filtrate was concentrated in the case of a water-immiscible solvent.

-solid-liquid separation by techniques known to the person skilled in the art.

In a preferred embodiment of the invention, the reaction is carried out by adding a base, preferably sodium carbonate (Na)₂CO₃) One or more liquid-liquid extractions are performed. The combined aqueous alkaline phases are acidified by addition of an acid, preferably hydrochloric acid (HCl), and extraction is then performed by one to several liquid-liquid extractions with a water-immiscible solvent. Advantageously, said acidification results in obtaining a pH approximately equal to 1.

The combined organic phases can be dehydrated over sodium sulfate and then concentrated in vacuo at a temperature from ambient to boiling temperature.

The concentrate is dried by conventional drying methods (atomization, oven, etc.) at a temperature preferably not exceeding 60 ℃, thereby producing an eucalyptus aldehyde G-rich extract. The extract may be stabilized by adding an antioxidant such as ascorbic acid or citric acid in an amount of 0.05g to 1g per 100g of dry extract.

In a particular embodiment of the invention, the eucalyptus extract or the so-called "eucalyptus extract" enriched in at least one compound of formula (I) or in any one of its diastereoisomeric forms is also obtained by an extraction process using a supercritical fluid as extraction solvent.

Leaves, flowers, fruits, stems or trunks of eucalyptus (species of the genus eucalyptus) or mixtures of these parts, with or without grinding, are then extracted with a supercritical fluid, which may be carbon dioxide.

Preferably, the use of supercritical CO is carried out under the following conditions₂The first extraction:

-the temperature of the fluid is from about 40 ℃ to about 80 ℃, and preferably from about 40 ℃ to about 60 ℃;

-at a pressure of from about 80 bar to about 250 bar, and preferably from about 100 bar to about 200 bar;

-the duration of extraction is from about 1 hour to about 6 hours;

the flow rate of the fluid is adjusted by the person skilled in the art depending on the quantity of material to be extracted and the size of the autoclave used. Preferably, the CO used in the process of the invention₂The flow rate of (A) is from 2 to 15 kg/hour, advantageously from 8 to 12 kg/hour;

■ for a plant amount of 200 to 1000 grams, preferably about 500 grams; and

■ for an autoclave having a capacity of 2 to 10 litres, a capacity of about 5 litres is preferred.

In this first extraction step, organic cosolvents of the following classes may be added: alcohols (including ethanol), ether oxides, esters, or mixtures of two or more of these solvents.

The thus extracted plant may then optionally be subjected to a second extraction. Preferably, the extraction fluid is supercritical CO with or without a CO-solvent₂. The operating conditions were as follows:

-the temperature of the fluid is from about 40 ℃ to about 80 ℃, and preferably from about 40 ℃ to about 60 ℃;

-at a pressure of from about 80 bar to about 250 bar, and preferably from about 100 bar to about 200 bar;

the flow rate of the fluid is between 2 and 15 kg/hour, advantageously between 8 and 12 kg/hour;

■ for a plant amount of 200 to 1000 grams, preferably about 500 grams; and

■ for an autoclave having a capacity of 2 to 10 litres, a capacity of about 5 litres is preferred.

Advantageously, the extraction is carried out at a plant/cosolvent mass ratio of about 1/0.1 to 1/5.

This second extraction step can be repeated if necessary. The duration of extraction is from about 1 hour to about 3 hours for each additional extraction step.

The extract obtained is then evaporated.

The skilled person will adjust the operating conditions of the supercritical fluid process to obtain a more or less concentrated eucalyptus extract.

Drying of the final extract is carried out by lyophilization or by more conventional methods known to those skilled in the art (nebulization, oven, etc.). Preferably, the drying temperature does not exceed about 60 ℃.

The extract may be stabilized by adding an antioxidant such as ascorbic acid or citric acid in an amount of about 0.05g to about 1g per 100g of dry extract.

The invention will be better understood by means of the following examples, which, however, do not limit the scope of the invention.

Example 1: preparation method of Eucalyptus globulus Labill extract

The leaves of eucalyptus globulus are ground and then extracted with 5 volumes of ethanol at ambient temperature. The contact time of the plants with the solvent was 48 hours.

The plants were separated from the solvent by filtration.

The filtrate obtained was dried in vacuo at a temperature of 60 ℃.

The extract thus obtained was used in the in vitro test shown in example 5.

The obtained extract contains about 0.65G of macrocarpal A/100G of dry extract, about 0.7G of macrocarpal B/100G of dry extract, about 0.4G of macrocarpal C/100G of dry extract, and about 1G of macrocarpal G/100G of dry extract.

Example 2: preparation method of Eucalyptus globulus Labill extract

Leaves of Eucalyptus globulus Labill were ground and then extracted three times with 5 volumes of 50% v/v ethanol under reflux. The contact time of the plants with the solvent is about 1 hour.

The plants were separated from the solvent by filtration.

The obtained filtrate was concentrated to 0.5 volume. Liquid-liquid purification was carried out by adding methylene chloride. Liquid-liquid extraction was performed 3 times. The organic phases were combined and dehydrated over sodium sulfate. The final extract was dried in vacuo at 60 ℃.

The obtained extract contains about 1.3G of macrocarpal A/100G of dry extract, about 1.4G of macrocarpal B/100G of dry extract, about 0.8G of macrocarpal C/100G of dry extract, and about 2G of macrocarpal G/100G of dry extract.

Example 3: preparation method of Eucalyptus globulus Labill extract

Leaves of Eucalyptus globulus Labill were ground and then extracted twice with 5 volumes of a 50% v/v ethanol/water mixture under reflux conditions (approximately 1 hour).

The plants were separated from the solvent by filtration.

The filtrate obtained was concentrated and then stabilized by adding 0.1g citric acid per 100g of dry extract.

The concentrate was frozen and then dried by lyophilization.

The obtained extract contains about 0.3G of macrocarpal A/100G of dry extract, about 0.35G of macrocarpal B/100G of dry extract, about 0.2G of macrocarpal C/100G of dry extract, and about 0.5G of macrocarpal G/100G of dry extract.

Example 4：

537g of eucalyptus leaves were ground and then placed in an autoclave. At 40 ℃ and 150 bar, with supercritical CO at a flow rate of 10 kg/h₂The extraction was carried out for 4 hours.

Subjecting the leaves thus extracted to the use of supercritical CO at 50 deg.C at 150 bar₂Second extraction of the/ethanol mixture. For every 1 weight parts of plants, 1 volume of ethanol was used. Extracted in this way for 2 hours and 15 minutes, then by passing only C0 under the same operating conditions₂To dry the leaves, for 30 minutes.

273.7g of the extract were recovered and dried by evaporation of the solvent. 27.9G of extract containing 6.85G of macrocarpal G per 100G of dry extract were thus obtained.

Example 5: evaluation of Eucalyptus globulus leaf extract for reuptake clip of 5-hydroxytryptamine, dopamine and norepinephrine

Uptake assays were performed in vitro on synapses of rats.

1) Evaluation of 5-hydroxytryptamine (or 5-HT) reuptake

The protocol used for this evaluation is that described in the following documents: perovic, S. and Muller W.E.G., 1995-Pharmacological profile of hypercumextract: effect on serotonin uptake by postsynapttic receptors, Arzneim-Forsch. drug Res., 45: 1145-1148.

The principle is as follows:

in a medium containing 118mM NaCl, 5mM KCl, 2.5mM MgSO₄、1.2mM NaH₂PO₄、25mM NaHCO₃11mM glucose, 10. mu.M EGTA and 50. mu.M ascorbic acid in buffer (pH 7.4) in the presence or absence (control) of Eucalyptus globulus Labill extract or imipramine (reference) prepared according to example 1, the mixture will be diluted with waterSynapses obtained from the rat brain with 0.1. mu. Ci³H]-5-hydroxytryptamine together at 37 ℃ for 15 minutes. Baseline activity was determined by the following method: the same mixture was incubated in the presence of 10 μ M imipramine at 37 ℃ for 15 minutes to block reuptake.

After incubation, the sample was rapidly filtered through a glass fiber filter (GB/B, Packard) in vacuo and rinsed twice with ice cold incubation buffer to remove free [ alpha ], [ solution ] and [ solution ], [ solution ] in a solution of the buffer³H]-5-hydroxytryptamine. The filters were dried and the retained radioactivity was measured by scintillation counter (Topcount, Packard) using scintillation cocktail (Microscint O, Packard).

The results are expressed as the percentage inhibition of [3H ] -5-hydroxytryptamine reuptake relative to the control (see Table 1).

2) Evaluation of dopamine (or DA) reuptake

The protocol used for this evaluation is that described in the following documents: janowsky A., Berger P., Vocci F., Labarca R., Skolnick P, and Paul S.M., 1996-Characterization of sodium-dependent [ 2 ]³H]GBR-12935 binding inbrain：a radioligand for selective labelling of the dopaminetransport complex，J.Neurochem.，46，1272-1276。

The principle is as follows:

synaptic mediators (synapses of rat striatum) were complexed with 0.1. mu. Ci in buffer (see 5-hydroxytryptamine reuptake) in the presence or absence (control) of Eucalyptus globulus Labill extract or GBR 12909 (reference) prepared according to example 1³H]-DA together at 37 ℃ for 15 minutes.

Baseline activity was determined by the following method: the same mixture was incubated in the presence of 10 μ M GBR 12909 at 37 ℃ for 15 minutes to block reuptake.

After incubation, the samples were rapidly filtered through a glass fiber filter (GB/B, Packard) in vacuo and cooled with ice cold temperatureThe incubation buffer is rinsed twice to remove free³H]-dopamine. The filter was dried and the retained radioactivity was measured by scintillation counter (Topcount, Packard) using scintillation fluid (Microscint 0, Packard).

The result is expressed as relative to the control³H]Percent inhibition of dopamine reuptake (see table 1).

3) Assessment of norepinephrine (or NE) reuptake

The protocol used for this evaluation is that described in the following documents: perovic, S. and Muller W.E.G., 1995-Pharmacological profile of hypercumextract: effect on serotonin uptake by postsynapttic receptors, Arzneim-Forsch. drug Res., 45: 1145-1148.

The principle is as follows:

synaptic mediators (synapses of rat hypothalamus) were contacted with 0.1. mu. Ci in buffer (see reuptake of 5-hydroxytryptamine) in the presence or absence (control) of Eucalyptus globulus Labill extract or protripiline (reference) prepared according to example 1³H]-NE were incubated together at 37 ℃ for 20 minutes.

Baseline activity was determined by the following method: the same mixture was incubated in the presence of 10 μ M protriptyline at 37 ℃ for 20 minutes to block reuptake.

After incubation, the sample was rapidly filtered through a glass fiber filter (GB/B, Packard) in vacuo and rinsed twice with ice cold incubation buffer to remove free [ alpha ], [ solution ] and [ solution ], [ solution ] in a solution of the buffer³H]-NE. The filter was dried and the retained radioactivity was measured by scintillation counter (Topcount, Packard) using scintillation fluid (Microscint O, Packard).

The result is expressed as relative to the control³H]Percent inhibition of norepinephrine reuptake (see table 1).

4) As a result:

results are expressed as percent inhibition of reuptake of the neural mediators evaluated (see table 1).

TABLE 1: evaluation of Eucalyptus globulus leaf extract for reuptake of 5-hydroxytryptamine, dopamine and norepinephrine

Testing	Concentration (μ g dry extract/ml solution)	% inhibition
			Reuptake of 5-hydroxytryptamine	110100	343103
Reuptake of dopamine	110100	491102
			Reuptake of norepinephrine	110100	-1411101

Significant inhibition of reuptake of 5-hydroxytryptamine and dopamine was observed at 10 μ g/ml, and significant inhibition of reuptake of these three neurotransmitters was observed at 100 μ g/ml.

Example 6: eucalyptus extracts rich in macrocarpal G evaluation of Eucalyptus extracts without macrocarpal G and of pure macrocarpal G

Leaves of Eucalyptus globulus Labill were ground and then extracted with 5 volumes of dichloromethane. Extraction was performed twice (1 hour) under reflux conditions.

Then filtered in vacuo. The combined filtrates were concentrated to 2 volumes.

By adding 1 volume of 0.1M sodium carbonate (Na)₂CO₃) To perform three liquid-liquid extractions.

The depleted dichloromethane phase was retained. After dehydration over sodium sulfate, concentration and drying in vacuo at 60 ℃, the residue obtained constitutes the "macrocarpal-poor extract" (less than 0.1% by mass of macrocarpal G).

The combined basic aqueous phases were acidified by adding 1M hydrochloric acid (HCl) until a pH approximately equal to 1 was obtained, then extracted by three liquid-liquid extractions using dichloromethane. The organic phase is dehydrated over sodium sulfate, then concentrated and dried in vacuo at maximum 60 ℃. The dry residue obtained constitutes the "eucalyptus macrocarpal G-rich extract". The extract contains 7% of macrocarpal G by mass.

The concentrated extract has reverse phase (symmetry)5 μm (Waters)) as stationary phase and a preparative column with an acetonitrile/water/trifluoroacetic acid mixture (in a proportion of 95/5/0.1%) as mobile phase.

The purity of the macrocarpal G of the obtained fraction was about 97%.

The protocol used subsequently was the same as that used in example 5 for the evaluation of 5-hydroxytryptamine reuptake. The results obtained are compiled in table 2 below.

TABLE 2: comparison of Activities of "Eucalyptal G-enriched extract", "Eucalyptal G-free extract" and "Eucalyptal G-enriched fraction on 5-Hydroxytryptamine reuptake

Testing	Concentration (μ g extract/ml solution)	% inhibition
			Extract rich in macrocarpal G	15	101
Eucalyptal G-poor extract	15	37
			Eucalyptal E, a fruit tree	0.3	103.8

It was observed that the higher the level of macrocarpal G, the greater the percentage inhibition of 5-hydroxytryptamine reuptake.

Example 7: determining 50% Inhibitory Concentrations (IC) of macrocarpal A, macrocarpal B, macrocarpal C and macrocarpal G for reuptake of said neuromedia compared to hyperforin₅₀)

The protocol used was that of example 5. These protocols were repeated for different concentrations of macrocarpal A, B, C and G and hyperforin.

The obtained inhibition curves enable the following ICs to be obtained₅₀The value:

TABLE 3: determination of 50% Inhibition Concentration (IC) of macrocarpal A, macrocarpal B, macrocarpal C, macrocarpal G and hyperforin against 5-hydroxytryptamine, norepinephrine and dopamine reuptake₅₀)

These results enable the demonstration that these 4 compounds are carriers of neuromediator reuptake inhibitory activity. In addition, the activity levels of these 4 compounds were observed to be on the same scale.

Claims (26)

1. Use of eucalyptus extract for the preparation of a medicament or food supplement for the treatment and/or prevention of neurological or pathological conditions, psychiatric or pathological conditions and related disorders due to disorders of dopamine and/or 5-hydroxytryptamine and/or norepinephrine reuptake, functional somatic syndromes, and dependence on addictive substances.

2. Use according to claim 1, characterized in that the treatment and/or prevention of said neurological disorders or pathologies, psychiatric disorders or pathologies and related disorders, functional somatic syndromes, and dependence on addictive substances comprises the inhibition of the reuptake of dopamine and/or 5-hydroxytryptamine and/or norepinephrine.

3. Use according to claim 1, characterized in that the eucalyptus extract comprises at least one compound of formula (I) or any one of its diastereoisomeric forms:

wherein R1 forms together with the carbon atom to which it is attached a group C ═ CH2, groupOrAnd R2 represents isobutyl, α -isobutyl or β -isobutyl.

4. Use according to claim 3, characterized in that the compound of formula (I) is macrocarpal A (5- ((1R) -1- ((11S, 7R) -7-hydroxy-3, 3, 7, 11-tetramethyltricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) in which R1 forms, together with the carbon atom to which it is attached, the radicalAnd R2 represents β -isobutyl; and the mass part of the compound in the eucalyptus extract is more than or equal to 0.1% and strictly less than 3%.

5. Use according to claim 3, characterized in that the compound of formula (I) is macrocarpal B (5- ((1S) -1- ((11S, 7R) -7-hydroxy-3, 3, 7, 11-tetramethyltricyclo (6.3.0.0(2, 4)) undec-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) in which R1 forms, together with the carbon atom to which it is attached, the radicalAnd R2 represents α -isobutyl; and the mass part of the compound in the eucalyptus extract is more than or equal to 0.1% and strictly less than 3%.

6. Use according to claim 3, characterized in that the compound of formula (I) is macrocarpal C (5- ((1R) -1- ((11S) -3, 3, 11-trimethyl-7-methylenetricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde), wherein R1 forms, together with the carbon atom to which it is attached, the group C ═ CH2, and R2 represents β -isobutyl; and the mass part of the compound in the eucalyptus extract is more than or equal to 0.1% and strictly less than 3%.

7. Use according to claim 3, characterized in that the compound of formula (I) is macrocarpal G (5- (1- (3, 3, 11-trimethyl-7-methylenetricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) in which R1 forms, together with the carbon atom to which it is attached, the group C ═ CH2, and R2 represents isobutyl; and the mass part of the compound in the eucalyptus extract is more than or equal to 0.1% and strictly less than 5%.

8. Use according to claim 1, characterized in that the eucalyptus extract is enriched with at least one compound of formula (I) as defined in claim 3.

9. Use according to claim 8, characterized in that the eucalyptus extract is enriched with macrocarpal A, the macrocarpal A enriched extract comprising greater than or equal to 3% and strictly less than 90% in parts by mass of macrocarpal A.

10. Use according to claim 8, characterized in that the eucalyptus extract is enriched with macrocarpal B, the macrocarpal B enriched extract comprising greater than or equal to 3% and strictly less than 90% by mass of macrocarpal B.

11. Use according to claim 8, characterized in that the eucalyptus extract is enriched with macrocarpal C, the macrocarpal C enriched extract comprising greater than or equal to 3% and strictly less than 90% in parts by mass of macrocarpal C.

12. Use according to claim 8, characterized in that the eucalyptus extract is enriched with macrocarpal G, the macrocarpal G enriched extract comprising greater than or equal to 5% and strictly less than 90% by mass of macrocarpal G.

13. Use according to claim 1, characterized in that said extract is derived from eucalyptus trees selected from the group consisting of the species belonging to the genera Eudesmia, Symphomyrtus and parachuting, and the following species: eucalyptus globulus, Eucalyptus kartzvehiana l.a.s.johnson1 Blaxell, Eucalyptus robusta, Eucalyptus cinerea (cinerea), Eucalyptus dorrigoensis (Blakely) l.a.s.johnson 1k.d.hill, Eucalyptus leptopoda benth, Eucalyptus west, Eucalyptus viridis, Eucalyptus mulberculiformis, and Eucalyptus glumae.

14. Use according to claim 1, characterized in that the eucalyptus extract is selected from the group consisting of extracts of leaves, flowers, fruits, stems and trunks of eucalyptus.

15. The use according to claim 1, characterized in that said neurological pathological condition or disorder, psychiatric pathological condition or disorder or related disorder, functional somatic syndrome, or dependence on an addictive substance is selected from the group consisting of:

-neurological diseases such as neurodegenerative diseases (alzheimer's disease, huntington's chorea, parkinson's disease, cerebrovascular accidents, cranial traumas), amyotrophic lateral sclerosis, senile dementia, frontotemporal dementia, vascular dementia, migraine, neuropathic pain of central origin;

psychiatric disorders, such as depression (endogenous, refractory, reactive or iatrogenic depression), depressive state, schizophrenia, bipolar disorder, generalized anxiety, stress-related disorders, panic attacks, obsessive compulsive disorder, post-traumatic stress syndrome, attention deficit hyperactivity disorder, eating disorders (especially, bulimia, anorexia), phobias (especially, agoraphobia), autism;

-memory, attention and vigilance disorders associated with neurological pathologies or psychiatric disorders;

-functional somatic syndromes, such as chronic fatigue syndrome, fibromyalgia, irritable colon syndrome, gastroesophageal reflux, loss of libido, erectile dysfunction, urinary incontinence;

-dependence on addictive substances, in particular nicotine, alcohol, opiates, cannabinoids, psychostimulants.

16. Use according to claim 1, characterized in that the medicament is in oral or injectable form.

17. At least one compound of formula (I) or any one of its diastereoisomeric forms:

wherein R1 forms together with the carbon atom to which it is attached a group C ═ CH2, groupOrAnd R2 represents isobutyl, α -isobutyl or β -isobutyl;

use in the manufacture of a medicament or food supplement for the treatment and/or prevention of neurological or pathological conditions, psychiatric or pathological conditions and related disorders resulting from disorders of dopamine and/or 5-hydroxytryptamine and/or norepinephrine reuptake, functional somatic syndromes, and dependence on addictive substances.

18. Use according to claim 17, characterized in that the treatment and/or prevention of said neurological disorders or pathologies, psychiatric disorders or pathologies and related disorders, functional somatic syndromes, and dependence on addictive substances comprises the inhibition of the reuptake of dopamine and/or 5-hydroxytryptamine and/or norepinephrine.

19. Use according to claim 17, characterized in that the compound of formula (I) is:

-macrocarpal a (5- ((1R) -1- ((11S, 7R) -7-hydroxy-3, 3, 7, 11-tetramethyltricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) in which R1 forms, together with the carbon atom to which it is attached, a radicalAnd R2 represents β -isobutyl;

-macrocarpal B (5- ((1S) -1- ((11S, 7R) -7-hydroxy-3, 3, 7, 11-tetramethyltricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) in which R1 forms, together with the carbon atom to which it is attached, a radicalAnd R2 represents α -isobutyl;

-macrocarpal C (5- ((1R) -1- ((11S) -3, 3, 11-trimethyl-7-methylenetricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) wherein R1 together with the carbon atom to which it is attached forms the group C ═ CH2, and R2 represents β -isobutyl; or

-macrocarpal G (5- (1- (3, 3, 11-trimethyl-7-methylenetricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) wherein R1 together with the carbon atom to which it is attached forms the group C ═ CH2, and R2 represents isobutyl.

20. Use according to claim 17, characterized in that macrocarpal a, macrocarpal B, macrocarpal C or macrocarpal G are obtained by chemical synthesis, by biochemical synthesis or from plant extracts.

21. The use according to claim 17, characterized in that said neurological pathological condition or disorder, psychiatric pathological condition or disorder or related disorder, functional somatic syndrome, or dependence on an addictive substance is selected from the group consisting of:

-neurological diseases such as neurodegenerative diseases (alzheimer's disease, huntington's chorea, parkinson's disease, cerebrovascular accidents, cranial traumas), amyotrophic lateral sclerosis, senile dementia, frontotemporal dementia, vascular dementia, migraine, neuropathic pain of central origin;

psychiatric disorders, such as depression (endogenous, refractory, reactive or iatrogenic depression), depressive state, schizophrenia, bipolar disorder, generalized anxiety, stress-related disorders, panic attacks, obsessive compulsive disorder, post-traumatic stress syndrome, attention deficit hyperactivity disorder, eating disorders (especially, bulimia, anorexia), phobias (especially, agoraphobia), autism;

-memory, attention and vigilance disorders associated with neurological pathologies or psychiatric disorders;

-functional somatic syndromes, such as chronic fatigue syndrome, fibromyalgia, irritable colon syndrome, gastroesophageal reflux, loss of libido, erectile dysfunction, urinary incontinence;

-dependence on addictive substances, in particular nicotine, alcohol, opiates, cannabinoids, psychostimulants.

22. Use according to claim 17, characterized in that the medicament is in oral or injectable form.

23. Eucalyptus extract, characterized in that it comprises at least one compound of formula (I) or any one of its diastereoisomeric forms:

wherein R1 forms together with the carbon atom to which it is attached a group C ═ CH2, groupOrAnd R2 represents isobutyl, alpha-isobutyl or beta-isobutyl,

and is

-macrocarpal a, i.e. (5- ((1R) -1- ((11S, 7R) -7-hydroxy-3, 3, 7, 11-tetramethyltricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) in which R1 forms together with the carbon atom to which it is attached a radical, is greater than or equal to 3% and strictly less than 90% by massAnd R2 represents a beta-isobutyl group,

-macrocarpal B, i.e. (5- ((1S) -1- ((11S, 7R) -7-hydroxy-3, 3, 7, 11-tetramethyltricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) in which R1 forms together with the carbon atom to which it is attached a radical, in a mass fraction greater than or equal to 3% and strictly less than 90%, said macrocarpal B being a compound of formula (i)And R2 represents an alpha-isobutyl group,

-the mass fraction of macrocarpal C, i.e. (5- ((1R) -1- ((11S) -3, 3, 11-trimethyl-7-methylenetricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) is greater than or equal to 3% and strictly less than 90%, wherein R1 forms, together with the carbon atom to which it is attached, the group C ═ CH2, and R2 represents β -isobutyl, and

-the mass fraction of macrocarpal G, i.e. (5- (1- (3, 3, 11-trimethyl-7-methylenetricyclo (6.3.0.0(2, 4)) undecan-11-yl) -3-methylbutyl) -2, 4, 6-trihydroxybenzene-1, 3-dicarbaldehyde) is greater than or equal to 5% and strictly less than 90%, wherein R1 forms, together with the carbon atom to which it is attached, the group C ═ CH2, and R2 represents isobutyl.

24. Process for preparing the extract according to claim 23, characterized in that it comprises the following steps:

-grinding the leaves and/or flowers and/or fruits and/or stems and/or trunks of eucalyptus,

-extracting at least once with a supercritical fluid, with or without a cosolvent, recovering the extract, and optionally drying said extract, or

Extracting at least once with an organic solvent or a mixture of water and a water-miscible organic solvent, performing solid-liquid separation, and concentrating the filtrate.

25. The process according to claim 24, characterized in that the organic solvent is dichloromethane or isopropyl acetate.

26. The process according to claim 24, characterized in that said concentration step corresponds to at least one liquid-liquid extraction by addition of a base, acidification and then at least one liquid-liquid extraction with a solvent immiscible with water.