FR2865649A1 - Use of 14,15-dihydro-20,21-dinor-14-eburnameninol to prepare a pharmaceutical composition for treating or preventing major depression - Google Patents

Abstract

14,15-Dihydro-20,21-dinor-14-eburnameninol (I) is used to prepare a pharmaceutical composition for treating or preventing major depression. 14,15-Dihydro-20,21-dinor-14-eburnameninol of formula (I), where the hydrogens at positions 3 and 16 are trans and the hydroxy group is in alpha or beta conformation, is used to prepare a pharmaceutical composition for treating or preventing major depression. An independent claim is also included for the use of (I) to prepare a pharmaceutical composition for treating patients with depression resistant to conventional antidepressants in order to make such patients sensitive to conventional antidepressant treatment. [Image] ACTIVITY : Antidepressant. No biological data given. MECHANISM OF ACTION : None given.

Description

The subject of the invention is a novel therapeutic application of 14,15

  dihydro 20,21-dinoreburnamenin-14-ol for the treatment of major depressions in humans, particularly for the treatment of patients resistant to conventional antidepressant treatments.

  Depression is one of the most common psychological disorders. In France, the depressive rate is 14.9% of which almost a third is not medically supported. One in five women would be affected.

  The prevalence of reported depression has increased six-fold since 1970. Between 1992 and 1997, the rate of depressive illness increased particularly among young people aged 20 to 29 (+ 65%), who were affected at the same time by 20% increase in unemployment.

  The risk of developing major depression over the course of life varies, according to the studies, from 10 to 25% for women and from 5 to 12% for men.

  Major depression is one of the categories of depression listed in the DSM IV (American Classification of Mental Disorders), and is characterized by the symptoms it presents. Notably, major depression, formerly called melancholic depression, is to be distinguished from other clinical groups such as reaction depressive states, depression due to exhaustion, depression related to the terrain (depression of the child, the pregnant woman, elderly person) or seasonal depression.

  It is therefore particularly essential to find treatments that are better adapted to this type of depression, especially since some patients do not respond to conventional antidepressants.

  The derivatives of 20,21-dinoreburnamenine, including 14,15-dihydro-20,21dinoreburnamenin-14-ol, are already known for their vasodilator properties, especially cerebral and for their activity in the regulation of tyrosine hydroxylase in the locus coeruleus (Bourde et al., Neurochem Int., 23 (6), 567-574, 1993). They are used in cerebral vasculopathies and all syndromes caused by impaired cerebral circulation.

  These derivatives and their first known therapeutic application have been described in the patent application FR 2,381,048, published on September 15, 1978. This patent application was the subject of an application for a certificate of addition FR 2 433 528 published on March 14, 1980.

  More particularly, application FR 2 381 048 describes the derivatives of 20,21-dinoreburnamenine and their process of preparation. The pharmacological properties of these compounds are also described: these compounds are high-value oxygenators and vasoregulators, which in particular lead to an increase in cerebral microcirculation.

  On the other hand, application FR 2 433 528 describes the process for preparing a particular isomer derived from 20,21-dinoreburnamenine, and the isomer obtained by this process.

  The application WO 89/04830, published June 1989, describes new substituted derivatives of 20,21-dinoreburnamenine, their method of preparation and their use as a medicine, especially as an antidepressant.

  Depression is a pathological psychic state associating a painful modification of the mood and a slowing down of the intellectual and motor activity. It is a morbid condition, more or less durable, characterized by sadness and a decrease in the energy tone.

  The main symptoms for diagnosing depression in a person are: - depressed mood, - marked decrease in interest or pleasure, - eating disorders, - sleep disorders, - restlessness or psychomotor retardation, - tiredness or loss of energy, - self-evaluation or feeling of excessive guilt, decreased ability to think or concentrate or indecision, morbid thoughts (in 60% of cases), - suicidal thoughts (in 15% of cases).

  The causative factors of depression include: 1 / The hereditary factor People whose close relatives are suffering from or have suffered from depression are more likely to have it. They have a 15% risk of developing depression whereas people whose close relatives are not depressed have only 2-3% risk of developing one.

  2 / The biochemical factor Current research on depression concerns neurotransmitters. It was noted that a deficiency or imbalance of serotonin resulted in a loss of sleep and a decrease in appetite. But also that a decrease in noradrenaline affects the loss of energy, the lack of pleasure.

  3 / Environmental factors Children who have experienced the loss of a loved one such as their parents are more likely to develop depressions later in life. Difficulties in relationships, communication problems, and family, work, and other conflicts can also contribute to loneliness, alienation, and depression. Financial difficulties and other tensions can also have a significant impact.

  Seasonal factors should not be neglected: the rate of depression is higher in the months with the lowest sunshine.

  The prior art has two main types of treatments for depression.

  Drug treatment with antidepressants, indicated in all forms of depression. They act on the balance of neurotransmitters.

  Antidepressants are effective in 75% of people with severe depression.

  Psychotherapies: they help the sick but can not act as the only treatment.

  There are other forms of treatment such as behavioral and cognitive therapies (especially neurotic depressions), seismotherapy or electroshock (used as a last resort).

  The evolution of depression is very variable and depends on many parameters: etiology, personality of the subject, ....

  Apart from any treatment, it usually happens that the depression lasts 6 months or more, with in some cases, as extreme termination, suicide. Up to 15% of people with severe major depressive disorder commit suicide.

  Depression can be diagnosed by the DSM IV criteria (Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association Publisher, 4th Edition, Washington DC); DSM IV is a diagnostic and statistical benchmark for mental disorders developed by the American Psychiatry Association.

  According to the DSM IV criteria, major depression (also called MDD Major Depressive Disorders) is particularly distinguished dysthymic disorders (minor depression) characterized by chronic depression but less severe than major depression and the episode can last at least two years, episode that can lead to major depression in more than one third of cases.

  According to the DSM IV criteria, major depression, the severe and most common form of depression, for which only 10 to 25% of patients seek treatment, is characterized by one or more episodes of mood or mood change. at least two weeks of loss of interest with at least four additional symptoms of depression; these last symptoms may be, for example, a change in appetite, weight, sleep, or psychomotor activity; a decrease in energy, a feeling of worthlessness or guilt, a difficulty in thinking, concentrating, making decisions, or recurrent thoughts of death, or ideation, plans, suicide attempts.

  To be able to characterize a major depressive episode, a symptom must be either newly present or have worsened compared to the person's condition during a previous episode. Symptoms should persist for most of the day, almost daily, for at least two consecutive weeks. This episode must be accompanied by clinically significant distress or deterioration of social and occupational functioning. In some people with milder episodes, the operation may appear normal but requires a particularly strong effort.

  By definition, a major depressive episode is not due to the direct physiological effects of drug abuse (for example, in the context of withdrawal / withdrawal from alcohol or cocaine intoxication) or side effects. during medications or treatments (eg steroids), or exposure to a toxin. Similarly, the episode is not due to the direct physiological effects of a medical condition in general (eg, hyperthyroidism).

  Major depression includes depression resistant to conventional antidepressant treatment (TRD for Treatment Resistant Depression). It appears that 30 to 46% of depressed patients show a partial response or no response to antidepressants (Fava et al., Psychiatric Clin North Am., 19, 2, 179-200, 1996).

  Current and currently marketed classical antidepressants belong to the following major classes: - tricyclic antidepressants (TCA), - monoamine oxidase inhibitors (MAO) (MAOIs), - selective serotonin reuptake inhibitors (SSRIs), - inhibitors of reuptake of norepinephrine and serotonin (SNDRIs), - selective antidepressants of serotonin and norepinephrine (NASSAs), - modulators of the serotonin receptor.

  Treatment-resistant depressions (TRDs) represent a more debilitating and chronic form of MDD (Kornstein et al., J. Clin Psychiatry, 62, Suppl.116, 18-25, 2001). According to the model proposed by Thase et al. (Thase et al., J. Clin Psychiatry, 58, Suppl 13, 23-29, 1997), the stages of the TRD can be evaluated as follows: - Stage I: Failure to at least one adequate test of a antidepressant of a major class; - Stage II: Stage I failure plus failure to adequately test an antidepressant of a different class from that used in stage I; - Stage III: Stage II failure plus failure to adequately test a tricyclic antidepressant; - Stage IV: Stage III failure plus failure to adequately test an MAO inhibitor; and Stage V: Failure Stage IV Plus Failure to Bilateral Electroconvulsive Therapy (ECT) Therapy.

  The Massachusetts General Hospital (MGH Boston) has determined a method for classifying the TRD process from: - Item 1: no response for each trial to a commercial antidepressant generating an overall resistance score (1 point per test) (at least 6 weeks of an adequate dose of antidepressant); - Item 2: optimization of the dosage, optimization of the duration and increase / combination of each test (based on the MGH or the antidepressant treatment response questionnaire) (0.5 point per test and by optimization / strategy); and - Item 3: ECT increases the total by 3 points.

  It can be noted that TRD is a relatively common event in clinical practice, with over 50 to 60% of patients failing to achieve adequate responses after antidepressant treatment.

  Among these major depression, we can also mention major recurrent depressive disorders (also called MRDD for Major Recurrent Depressive Disorders), disorders that are associated with hypomanic episodes.

  The severity of these depressive disorders, from mild to severe, can be assessed using conventional and validated numerical scales, such as the Hamilton Depression Scale (HAMD) or the Montgomery and Asberg Depression Rating (MADRS) scale. Scale) which are the most used. According to these scales, a depression will be considered severe if its symptoms result in a score greater than 26 for the HAMD scale or 35 for the MADRS scale.

  Thus, it remains to be able to have compounds capable of treating disorders of major depression in a patient or treating patients with TRD depression, especially major, who are resistant to treatment with conventional antidepressants as mentioned above.

  This is precisely the subject of the invention described and claimed hereinafter.

  It has surprisingly been found that the use of 14,15dihydro-20,21-dinoreburnamenyl-4-ol, here called BC19 when in the form of a racemic mixture, made it possible to treat patients suffering from major depression and / or or TRD.

  On the other hand, it has also been surprisingly demonstrated that the use of 14,15-dihydro-20,21-dinoreburnamenyl-4-ol makes it possible to render susceptible to conventional antidepressant treatments the patients with major depression who were resistant to these treatments.

  The subject of the invention is therefore the use of a compound of formula (I)

NOT

  OH 16 (I) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the treatment or prevention of major depression (MDD).

  In another aspect, the subject of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition intended for the treatment or prevention of patients Depressed patients who are partially or totally resistant to conventional antidepressant medications (patients with DRE), such as antidepressants in the tricyclic antidepressant (TCA) class, monoamine oxidase inhibitors (MAOIs), selective serotonin, (SSRIs) norepinephrine and serotonin reuptake inhibitors (SNDRIs), selective serotonin and norepinephrine (NASSAs) antidepressants, or serotonin receptor modulators.

  In a preferred aspect, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment or prevention of patients suffering from major depression and resistant partially or totally to conventional antidepressant treatments (patients with MDD and TRD).

  In a particular aspect, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention, characterized in that the major depression is a bipolar type depression according to the invention. nomenclature of DSM IV, including major recurrent depressive disorder (MRDD).

  In a particular aspect, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention, characterized in that the severity of depression when evaluated by the Hamilton Depression Scale (HAMD) has a score greater than 26 or the MADRS (Montgomery and Asberg Depression Rating Scale) has a score greater than 35.

  In yet another aspect, the subject of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition intended to make sensitive to conventional antidepressant treatments patients with major depression resistant to these treatments.

  By pharmaceutically acceptable addition salts, mention may be made here of, for example, the addition salts with inorganic or organic acids, in particular the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, formic and benzoic acids. , maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkylsulphonic acids such as acid methanedisulfonic acid, 3-ethanedisulfonic acid, and arylmonosulfonic acids, such as benzenesulphonic acid and aryldisulphonic acids, these salts being mentioned for illustrative purposes only but without being a limitation.

  The compound of formula (I) is characterized by two enantiomeric forms 3a and 16a, and is characterized for each of these enantiomers by a pair of diastereoisomers according to the configuration of carbon 14: the pair (3a, 14a) 14, 15-dihydro 21-dinoreburnamenyl-4-ol and (3α, 14α) 14,15-dihydro-20,21-dinoreburnamino-14-ol; and the (14a, 16a) 14,15dihydro-20,21-dinoreburnamenyl-4-ol and (-) (14 (3, 16a) 14,15-dihydro-20,21-dinoreburnamenin-4-ol pair.

  The rotatory powers were measured, which allowed to determine the signs (+) and (-) attributed to each isomer.

  The different compounds are described in Figure 1 of the article published by Bourde et al. (Neurochem Int., 1993, 23, 567-574).

  The subject of the invention is therefore, according to a particular aspect, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a racemic or optically active mixture.

  The subject of the invention is furthermore the use according to the present invention, characterized in that the compound of formula (I) or one of its pharmaceutically acceptable salts is chosen from the following compounds of formula (I): a) (3a) () 14,15-dihydro-20,21-dinoreburnameninol; and (b) (16a) () 14,15-dihydro-20,21-dinoreburnamenin-14-ol, and wherein the mixture of the two (+) and (-) diastereoisomers present in these compounds a) and b) is in proportion equimolar or not.

  The subject of the invention is also the use according to the present invention, characterized in that the compound of formula (I) or a pharmaceutically acceptable salt thereof is chosen from the following compounds of formula (I): a) ( 3a, 14a) 14,15-dihydro-20,21-dinoreburnamenin-14-ol; b) (3a, 14 (3) 14,15-dihydro-20,21-dinoreburnamenin-14-ol; c) (14a, 16a) 14,15-dihydro-20,21-dinoreburnamenin-14-ol; and d) (14 (3, 16a) 14,15-dihydro-20,21-dinoreburnamenin-14-ol.

  More particularly, the invention therefore relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention, for the preparation of an orally administrable pharmaceutical composition. , intravenously, intraperitoneally, intramuscularly or by any other route to obtain an antidepressant effect according to the present invention, or render sensitive to major antidepressant treatments patients with major depression who were resistant to these treatments.

  The active substances of the pharmaceutical compositions according to the invention may be in any of the usual oral dosage forms comprising tablets, capsules and liquid preparations such as elixirs and suspensions containing various masking substances of color, taste and taste. stabilization.

  To achieve the oral dosage forms according to the invention, the active substance can be mixed with various conventional materials such as starch, calcium carbonate, lactose, sucrose and dicalcium phosphate to facilitate the encapsulation process. Magnesium stearate, as an additive, provides a useful lubricant function if necessary.

  The active substances of the pharmaceutical compositions according to the invention may be dissolved or suspended in a sterile pharmaceutically acceptable liquid, such as sterile water, a sterile organic solvent or a mixture of these two liquids. Preferably, such a liquid is suitable for parenteral injection.

  When the active substance is sufficiently soluble it can be dissolved in a normal saline solution such as a pharmaceutically acceptable sterile liquid; if it is insufficiently soluble, it can be dissolved in aqueous solutions of a suitable organic solvent, for example propylene glycol or polyethylene glycol. Aqueous propylene glycol containing from 10 to 75% by weight of the glycol is generally suitable. In other examples, other compositions can be obtained by dispersing the active substance in very fine concentrate in the aqueous carboxymethyl solution of starch or sodium cellulose, or in a suitable oil, for example peanut oil.

  Liquid pharmaceutical compositions such as sterile solutions or suspensions may be used for intramuscular, intraperitoneal or subcutaneous injection.

  Preferably the pharmaceutical composition is in the form of unit doses, for example as tablets or capsules. In such form, the composition is subdivided into unit doses containing appropriate amounts of the active substance; the unit doses may be packaged compositions, for example powders, vials or ampoules. The amount of the active substance in a unit dose of composition can be varied or adjusted by 2 mg or less of mg or more, depending on the particular need and the activity of the active substance.

  The recommended oral dose of 14,15-dihydro-20,21-dinoreburnamenyl-4-ol for humans may be 20 to 60 mg / day and this dose may be administered in two or three separate doses, preferably at a meal . Most resistant melancholic patients respond at the dose of 20 mg / day, but 40 mg or even 60 mg may be needed.

  Those skilled in the art also know that the routes of administration of the compounds of this invention may change significantly. In addition to other oral administrations, sustained release compositions may be promoted. Other routes of administration may include, but are not limited to, intravenous, intramuscular and intraperitoneal injections, subcutaneous implants, as well as oral, sublingual, transdermal, topical, rectal and intranasal administrations.

  According to a particular embodiment, the subject of the invention is the use of a compound of formula (I) or of its pharmaceutically acceptable salts according to the invention, characterized in that the daily dose is 20 to 60 mg in adults.

  The specialist can determine the appropriate dosage for each patient; this dosage may vary depending on the age, weight and response to treatment of a given patient. The above dosage examples are representative of the average. However, it is possible to administer more or less significant doses relative to this average.

  Process for the preparation of the compounds of formula (I): according to the invention, the compounds as defined by formula (I) may be prepared by the following processes from the treatment of optically active compounds of formula (II) form 3a form 16a by a reducing agent; the two pairs of diastereoisomers [(3a, 14a), (3a, 1413)] and [(14a, 16a), (14 (3, 16a)] of formula (I), or their mixture, are obtained and treated if desired, the product of the reaction with a mineral or organic acid to form the salt.

  The products of formula (II) and (II ') can be prepared for example as indicated in the French patent application published under the number FR 2 190 113.

  The racemic mixture of the compounds of formula (II) can be separated by resolution.

  By reduction of one of the two enantiomers of formula (II), one can obtain a pair of diastereoisomers () of formula (I) or mixtures in very variable proportions of the two diastereoisomers. The experiment described in the French patent application published under the number FR 2623503 shows that one obtains practically only one of the two diastereoisomers (see example B).

  The compounds of formula (II) used can be in racemic or optically active form.

  The reduction compound (s) of formula (I) obtained from the product of formula (II) are, of course, in the corresponding stereochemical form.

  The compounds of formula (II) can be used in the form of one of their addition salts with mineral or organic acids. If this is the case, the products of formula (I) may be obtained in salt form or not, depending on the operating conditions chosen.

  The racemic or optically active mixtures of the compounds of general formula (I) may also be prepared as indicated in the French patent application published under the number FR 2 381 048 and in the application for a French certificate of addition published under the number FR 2. 433,528.

  Under preferred conditions of implementation of the invention, the method described above is carried out in the following manner.

  The reducing agent used may be a hydride, especially a mixed hydride, such as, for example, lithium aluminum mixed hydride, sodium aluminum diethylhydride, sodium hydroboride, sodium hydroboride and the like. lithium, diisobutyl aluminum hydride.

  The reduction reaction is carried out in an organic solvent or a mixture of solvents such as for example an ether such as ethyl ether, tetrahydrofuran, or an aromatic hydrocarbon such as toluene, benzene, xylene.

  The reduction reaction can be carried out at a temperature ranging from 20 ° C. to the reflux temperature of the reaction medium. It is advantageously carried out at room temperature.

  In the case of the use as reducing agent of a metal hydride, the compound of formula (I) is released from the complex formed intermediately with the hydride, according to current practice, by addition of an aqueous alkaline solution such as by for example, a solution of sodium hydroxide.

  The reduction of the trans (3a) compound can lead to the compound (+) (3a, 14a) 14,15-dihydro-20,21-dinoreburnamenin 14-o1 The reduction of the compound (II ') trans 16a can lead to the compound (- ) (14P, 16a) 14,15-dihydro-20,21-dinoreburnamenin-14-ol.

  These compounds can be treated with an acid, for example hydrochloric acid, to obtain the (-) (3a, 14 (3) 14, 15-dihydro-20,21-dinoreburnamenin 14-ol and (+) ( 14a, 16a) 14,15-dihydro-20,21-dinoreburnamenin 14-ol (see diagram below and FIG. 2).

  Diagram showing the general route of synthesis of the optically active isomers of the compounds of formula (I) from the compounds of formula (II) (compounds of formula (II) described in Belgian patent document published under No. BE 764166)

H

H

NOT

  (IA) (the A) Ho 14 reduction reduction

H

H

acid acid

NOT

  (IAm) É N (Al) The isolation of one or other of the disatereoisomers of their mixture can be achieved by usual methods: chromatography, direct crystallization, differential solubilization such as for example the differential solubilization in hot toluene. The legends of the figures and examples that follow are intended for

  illustrate the invention without in any way limiting its scope.

LEGENDS OF FIGURES

  Figure 1: Representation of the four forms present in the racemic mixture BC19 in acid solution As indicated, these four forms correspond to two pairs of diastereoisomers which have either the configuration 16a or the configuration 3a. There is no spontaneous transformation possible from configuration 3a (left) to configuration 16a (right).

  Figure 2: Representation of the reaction to obtain the diastereoisomer (3a, 143) from (3a, 14a) and the diastereoisomer (14a, 14a) from (14 (3, 14a) under the action of an acid.

EXAMPLES

  EXAMPLE 1 Processes for Preparing the Compounds According to the Invention Example A: Processes for Preparing Racemic Mixtures such as BC19 or Optically Active Compounds of the Invention The racemic or optically active mixtures of the compounds of general formula (I) can in particular be prepared as indicated in the French patent application published under the number FR 2 381 048 and in the application for a certificate of French addition published under the number FR 2 433 528.

  Example B: Processes for the Preparation of the Diastereoisomers of the Invention The diastereoisomers (3a, 14a), (3a, 14 (3), (14a, 16a) and (140, 16a) of formula (I) according to the invention can be obtained as described in the French patent application published under the number FR 2623503. Such methods are briefly described below.

  Example B1: (14 f3, 16a) 14,15-dihydro-20,21-dinoreburn-14-ol (I ') 10.8 g of (16a) (+) 20,21-dinoreburnamenin-14 (15H) are dissolved In 110 ml of anhydrous toluene, 18.9 ml of 25% diethyl aluminum-sodium dihydride in toluene are added in ten minutes under an inert atmosphere and stirred for one hour at room temperature. It is hydrolyzed by addition of 20 ml of 5N sodium hydroxide and heated at 90 ° C. for two hours. The toluene is distilled off and simultaneously 100 ml of water are introduced. The mixture is brought to ambient temperature, the product obtained is filtered off with suction, washed with water and dried under reduced pressure and 10.7 g of expected product is recovered which recrystallizes from methanol and melts at 254 ° C. [alpha] D = -36 ° C. = 0.6% DMF).

  Circular Dichroism (dioxane): Max. 225 nm As = - 8 Max. 237 nm As = + 9.5 Max. 280 nm As = -2 NMR spectrum 1H (pyridine) 250 MHZ 8 (ppm): 5.78 (H borne by C14). Possible structure with equatorial OH, axial OH not detected.

  C 17 H 20 N 2 O M = 268.36 g / mol F = 254 ° C Example B2: (3a, 14a) 14,15-dihydro-21-dinoreburnamenin-1-ol (I The procedure is as in Example 1 starting from 15 g of (3a) (-) (20,21-dinoreburnamenin-14 (15H) -one and gives 15 g of the expected product containing very little product having axial OH, after recrystallization from methanol, the product melting at 254 C.

  [alpha] D = + 32.5 1 c = 1% DMF) Circular Dichroism (dioxane): Max. 227nmAe = + 10 Max. 238 nm A s = - 10 Max. 288nmAs = + 2 NMR spectrum 1H (pyridine) 250 MHZ 6 (ppm): 5.79 (H borne by C14). Possible structure with equatorial OH, axial OH not detected.

  C 17 H 20 N 2 O M = 268.36 g / mol F = 254 C Example B3: (14a, 16a) 14,15dihydro 20,21-dinoreburnamenin-14-ol (IAA) 2.75 g of the product obtained are suspended in Example 1 in 55 ml of 2N hydrochloric acid and heated for 1 hour 30 minutes at 50 ° C. 55 ml of ice water are added to the solution obtained and the mixture is brought to an alkaline pH by addition of 10 ml of aqueous ammonia. Be and stir for 15 minutes at room temperature. The precipitate is filtered off with suction, washed with water and dried at 50 ° C. under reduced pressure to give 2.75 g of product (axial and equatorial OH mixture). This is chromatographed under pressure on silica, eluted with a mixture of ethyl acetate methanol-ammonia (97-3-0.3). 1.70 g of product (axial OH) are obtained. Mp = 234 C.

  [alpha] D = + 150 2 c = 1% DMF).

  Circular Dichroism (dioxane): Max .: 230 nm A g = + 19 Max. 1.75 1 H NMR (pyridine): 250 MHz (ppm): 6.26 (H from C14). Possible structure with axial OH, equatorial OH not detected.

  C 17 H 20 N 2 O M = 268.36 g / mol F = 234 C Example B4: (3a, 14 (3) 14,15-dihydro-20,21-dinoreburnamenin-14-ol (I ') The procedure is as in the example 3 starting from 13.3 g of product obtained in Example 2 and obtaining 7.7 g of product (axial OH) F = 234 C [alpha] D = -152.5 2.5 c = 1% DMF ) Circular Dichroism (dioxane): Max. : 228 nm A s = - 20 Max. : 290nmAs = + 1.5 NMR spectrum H (pyridine) 250 MHZ S (ppm): 6.23 (H from C, 4). Possible structure with axial OH, equatorial OH not detected.

  C 17 H 20 N 2 O M = 268.36 g / mol F = 234 ° C Example 2: Pharmaceutical forms: a) tablets: tablets having the following formula: 14,15-dihydro-20,21-dinoreburnamenyl-4-ol (BC19) were prepared : 30 mg Excipient qs for one tablet (details of excipient: lactose, wheat starch, treated starch, rice starch, magnesium stearate, talc) b) capsules: tablets having the following formula: 14,15-dihydro were prepared , 21-dinoreburnamenin-4-ol (BC19): 30 mg Excipients: sucrose (115 mg / gel), starch, stearic acid, lactose, talc, shellac, povidone, methacrylic polymers.

  Example 3: Pharmacological study; determination of the acute toxicity of BC19 or 14,15-dihydro-20,21-dinoreburnamenyl-4-ol Acute toxicity is determined on batches of 10 male and female mice, weighing 2022 g, fasting since the previous evening. .

  The product is administered intravenously, in solution in physiological saline, added a few drops of hydrochloric acid (the products to be tested are then in hydrochloric solution).

  Mortality is recorded daily for one week. Lethal doses (LD 50) were determined by the method of Lichfield J.T. and Wilcoxon F. (J. Pharm Exp Therap.96, 99 (1949)). The results obtained showed no toxicity of the compound BC19 at effective doses.

Claims (10)

  1. Use of a general compound of formula (I) NOT   OH 16 (I) for which the hydrogen atom in the 3-position and the hydrogen atom in the 16-position are trans, the hydroxyl radical in the 14-position may be in the form of a or (3, or l a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for treating and / or preventing depressions. major.   2. Use according to claim 1, characterized in that the patients with major depression that one seeks to treat or prevent are partially or totally resistant to treatment with conventional antidepressants.   3. Use according to claim 1 or 2, characterized in that the depression is a bipolar type depression according to the nomenclature of DSM IV.   4. Use according to claim 3, characterized in that the bipolar-type depression is a major recurrent depressive disorder (MRDD).   5. Use of a compound as described in claim 1, for the preparation of a pharmaceutical composition intended to render susceptible to conventional antidepressant treatments in patients with major depression resistant to these conventional antidepressant treatments.   6. Use according to one of claims 1 to 5, characterized in that the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a racemic or optically active mixture.   7. Use according to one of claims 1 to 6, characterized in that the compound of formula (I) or a pharmaceutically acceptable salt thereof is chosen from the following compounds of formula (I): a) (3a) ) () 14,15-dihydro-20,21-dinoreburnamenin 14-01; and b) (16a) () 14,15dihydro 20,21-dinoreburnamenin 14-ol, and wherein the mixture of the two (+) and (-) diastereoisomers present in these compounds a) and b) is in equimolar proportion or no.   8. Use according to one of claims 1 to 6, characterized in that the compound of formula (I) or a pharmaceutically acceptable salt thereof is chosen from the following compounds of formula (I): a) (3a, 14a) 14,15-dihydro-20,21-dinoreburnamenin-14-ol; b) (3a, 14 (3) 14,15dihydro-20,21-dinoreburnamenin-14-ol; c) (14a, 16a) 14,15-dihydro-20,2-difluorobutamenin-14-ol; and d) (14 (3, 16a) 14,15-dihydro-20,21dinoreburnamenin 14-ol.   9. Use according to one of claims 1 to 8, wherein the pharmaceutical composition is administered orally, intravenously, intraperitoneally or intramuscularly.   10. Use according to one of claims 1 to 8, wherein is administered 20 to 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt per day in the patient to be treated.