HK1106502B - Derivatives of 14.15-dihydro 20.21-dinoreburnamenin-14-ol, and applications thereof - Google Patents

Description

14, 15-dihydro-20, 21-dinoreburnamenin-14-ol derivative and application thereof

Technical Field

The present invention relates to novel 14, 15-dihydro 20, 21-dinoreburnamenin 14-ol derivatives and their use as human pharmaceuticals.

Background

Depression is one of the most common psychological problems. In france, the proportion of people suffering from depression is 14.9%, including one third of those who have not received medical treatment. One of every five women is affected by the disease. Since 1970, the incidence of announced depression has increased 6-fold. From 1992 to 1997, the proportion of people suffering from depression increased, particularly among young people between the ages of 20 and 29 (+ 65%). Therefore, it becomes especially important to find better treatments for depression, especially since traditional antidepressants are not effective in some patients.

Derivatives of 20, 21-dinoreburnamenine, including 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol, are known to have vasodilatory properties, particularly cerebral vasodilatory properties, and to have activity in modulating tyrosine hydroxylase in the blue spot (Bourde et al, neurochem. int, 23(6), 567-. They are used in the cerebral vascular channels and in all syndromes caused by changes in the cerebral circulation volume. Patent application FR2381048, published on 9/15/1978, describes these derivatives and their first known therapeutic use. This patent application is described in the appended certificate application FR2433528 published on 3/14 1980.

More specifically, patent application FR2381048 describes derivatives of 20, 21-dinoreburnamenine and processes for their preparation. The pharmacological properties of these compounds are also described: these compounds are useful cerebral oxygenators and vascular modulators, which particularly increase cerebral flux in the cerebral microcirculation. Patent application FR2433528 also describes a process for the preparation of a particular isomer derived from 20, 21-dinoreburnamenine, and the isomer obtained by this process.

Patent application WO 89/04830, published on 6.1.1989, describes new 20, 21-dinoreburnamenine alternative derivatives, processes for their preparation and their use as medicaments, in particular as antidepressants.

Depression is a pathological mental disorder accompanied by nervous mood changes and mental and motor activity retardation. It is morbid, more or less long-term, showing some grief and reduced energy tonicity. Bilateral depression is characterized by alternating stages: the first stage is marked by marked depression and dullness, and the second stage by euphoria and hyperactivity.

The main symptoms used to diagnose depression in humans are: depressed mood, a decrease in significant interest or enjoyment, eating problems, sleep problems, anxiety or dullness in mental activities, tiredness or loss of energy, lack of self-esteem, or excessive feelings of passing, diminished ability to think or concentrate, or erratic, pathological thoughts (60% of cases), thoughts of suicide (15% of cases).

Causes of depression include:

1/genetic factors

The most likely affected are those with depression in close relatives or who have suffered depression. The risk of these people suffering from depression is 15%, while the risk of people without depression in close relatives is only 2 to 3%.

2/Biochemical factors

Current studies of depression are directed to neurotransmitters. It was further noted that 5-hydroxytryptamine deficiency or imbalance resulted in insomnia and decreased appetite, and that reduction in norepinephrine had an effect on loss of energy and loss of enjoyment.

3/environmental factors

Children who have experienced a loss of relatives, such as parents, are likely to develop depression after they grow up. Familial relationships, interpersonal problems and family difficulties, occupational or other conflicts may also cause autism, alienation and lead to depression. Capital difficulties and other pressures also have a significant impact.

Seasonal factors cannot be ignored: in the months of lowest sun exposure, the incidence of depression is higher. Seasonal depression occurs only during the shortest period of sun exposure in a year, so it occurs in winter and disappears in spring. Symptoms include tiredness, depression, lack of vitality and loss of interest, problems of concentration and libido, sudden desire to eat sweet, increased sleep or increased weight in the winter. It is therefore sometimes referred to as winter depression. 2% of all adults in central europe are affected by seasonal depression, and women are affected 4 times more than men.

Depression is often accompanied by other psychological problems, or it is accompanied by another psychological problem. Acute panic attacks and obsessive-compulsive disorders are the most common problems.

Schizophrenia is a chronic psychosis characterized by schizophrenia or incoordination that disturbs the thought process (it becomes isolated and disorganized from the outside), changes behavior (it becomes strange and autistic) and causes affective disorders (paleness and paradoxical), which is associated with abstract and symbolic delirium that produces the effects of auditory and common sensory hallucinations and experiences a loss of ambiance from the sense of oneself.

Two psychiatric disorders, manic-depressive (bipolar depression) and schizophrenia, have the same genetic cause: the expression of various genes located in some brain cells and in the myelin sites, which transmit electrical signals, is reduced. Although these two diseases have different clinical courses, they have some similar symptoms and are usually treated with similar drugs.

The prior art describes two main forms of treatment for depression and schizophrenia: treatment by medication and psychotherapy. All types of depression are adapted by drug therapy including the use of antidepressants. Antidepressants act on neurotransmitter balance. Psychotherapy aids the patient, but cannot be the only treatment. Other forms of treatment such as behavioral or cognitive therapy (particularly for neurostimulative depression), vibrational therapy and shock therapy (as the ultimate means).

The progression of depression changes rapidly and depends on many parameters: etiology, patient personality, etc.

A depressed patient may last 6 months or longer, sometimes ending in an extreme suicide pattern, if not given any treatment. Up to 15% of patients with major depression suicidality. After treatment, approximately 60% of all cases recurred.

Depression can be judged by the DSM IV standard (Diagnostic and Statistical Manual of mental Disorders, 4th edition, American Psychiatric Association Publisher: Washington DC): DSM IV is the symptom and statistical benchmark for delirium, published by the american psychiatric association. Major depression, i.e. major and most common types of depression, according to DSM IV criteria, wherein only 10 to 25% of patients seek treatment, is characterized by one or several episodes of mood change or loss of interest for at least two weeks, with at least four additional symptoms of depression: these symptoms may be due to, for example, changes in appetite, weight, sleep or mental activity; reduced vitality, reduced self-esteem, or feelings of guilt, thinking, concentration, difficulty in making judgment, or recurrent thoughts of death, planning or attempting suicide.

Major depressive disorders include Treatment Resistant Depression (TRD), and major periodic episode depression (MRDD), which is associated with hypomanic episodes.

The common conventional antidepressants available on the market fall into the following main groups: tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOs) (MAOIs), selective 5-hydroxytryptamine recapture inhibition inhibitors (SSRIs), 5-hydroxytryptamine and norepinephrine recapture inhibition inhibitors (SNDRIs), norepinephrine and selective 5-hydroxytryptamine antidepressants (NASSAs), and 5-hydroxytryptamine receptor modulators.

Disclosure of Invention

There remains a need for compounds that can treat depression, major depression in patients who may not be effective in the treatment of traditional antidepressants as described above. This is the object of the invention described and claimed below.

It has been found that novel 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol derivatives are useful in treating patients with depression.

Accordingly, an object of the present invention is, in one aspect, a compound of formula (I)

Wherein R represents a group-AR ', wherein A represents a heteroatom and R' represents:

-C is selected from linear or branched C₁-C₆Alkyl radical, C₁-C₆Alkenyl radical, C₁-C₆Alkynyl, arylalkyl (e.g., benzyl, alkoxyarylalkyl, heteroarylalkyl, and heterocycloalkyl);

-formula-R₁-CO-O-R₂Esters of formula (I) wherein R₁Represents C selected from linear or branched C₁-C₆Alkyl radical, C₂-C₆Alkenyl or C₂-C₆Radical of alkynyl, and R₂Represents the following group

Hydrogen, straight or branched C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl or C₃-C₁₂Cycloalkyl, preferably C₃-C₆Or C₆-C₁₂A cycloalkyl group;

-formula (la)Amides of formula (I) wherein R₃Represents C selected from linear or branched C₁-C₆Alkyl radical, C₂-C₆Alkenylene or C₂-C₆A radical of alkynylene, and Y represents a radical selected from hydrogen, linear or branched C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, aryl, arylalkyl, heteroarylalkyl or heterocycloalkyl groups; and Z represents C selected from hydrogen, linear or branched₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, aryl, arylalkyl, heteroarylalkyl or heterocycloalkyl, Y and Z may together form a group which may be substituted by one or several C₁-C₆Alkyl, aryl, heteroaryl or halogen substituted C₃-C₆Cycloalkyl or C₂-C₆A heterocyclic group;

is at least one ofThe amine is substituted by C selected from straight chain or branched chain₁-C₆Alkyl radical, C₂-C₆Alkenyl or C₂-C₆(iii) aminoalkyl of alkynyl, wherein Y and Z are as defined above;

or a pharmaceutically acceptable salt thereof, including isomers, enantiomers, diastereomers and mixtures thereof.

Pharmaceutically acceptable addition salts include, for example, the addition salts of inorganic or organic acids, in particular the salts formed from hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid hydrate, aspartic acid, ascorbic acid, alkanoyl monosulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkanoyl disulfonic acids such as methanedisulfonic acid, α, β -ethanedioic acid and aryl monosulfonic acids such as benzenesulfonic acid and aryl disulfonic acids, which salts are mentioned only for illustrative purposes and are not intended to be limiting.

The term "alkyl" denotes a hydrocarbon, straight-chain or branched radical, preferably containing from 1 to 6 carbon atoms, such as, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, n-hexyl.

An "aryl" group is an aromatic mono-or bicyclic hydrocarbon group, typically containing 5 to 6 chains, 5 to 10 carbon atoms. Examples of aryl are phenyl and naphthyl. "heteroaryl" is an aromatic carbon-containing group containing at least one heteroatom, such as nitrogen, sulfur or oxygen, in the ring.

The term "heterocycle" refers to an aromatic mono-or bicyclic hydrocarbon group containing at least one heteroatom, such as nitrogen, sulfur or oxygen, in the ring. The ring may have at least one unsaturation. Examples of heterocyclyl radicals include, in particular, piperidine, piperazine, pyrrolidine, morpholine, piperazidine-like, piperidine-like, thiomorpholine, tetrahydropyridine, thiophene, furan, pyridine, pyrimidine, pyridazine, pyrazinyl.

"alkoxy" corresponds to an alkyl group as defined above bonded to the rest of the molecule via an ether bond.

"halogen" means a fluorine, iodine, bromine or chlorine atom. "heteroatom" refers to nitrogen, oxygen and sulfur atoms.

An "arylalkyl", "heteroarylalkyl" or "heterocycloalkyl" group is an aryl, heteroaryl or heterocyclyl group, as defined above, joined to the remainder of the molecule through an alkyl chain, respectively. Specific examples of arylalkyl groups are benzyl and phenethyl.

According to a preferred embodiment of the invention, R' represents the formula R₁-CO-O-R₂A group shown in the formula, wherein R₁Represents C₁-C₆Alkyl, preferably-CH₂-a group. Especially according to this embodiment, R₂Preferably represents a hydrogen atom which may be substituted by one or several C₁-C₆Alkyl substituted C₁-C₆Alkyl or C₃-C₆A heterocyclic group. According to another preferred embodiment of the invention, R' represents formulaAmides of formula (I) wherein R₃As defined above, and Y and Z together form C which may be substituted by one or several C₁-C₆Alkyl substituted C₃-C₆A heterocyclic group.

According to another aspect of the inventionIn a preferred embodiment, R' represents aminoalkyl, selected from the group consisting ofAt least one amine substituted C shown₁-C₆Alkyl, wherein Y and Z together form a group which may be substituted by one or several C₁-C₆Alkyl substituted C₂-C₆A heterocyclic group.

According to another preferred embodiment of the invention, R' represents heteroarylalkyl.

Particularly preferred compounds of the present invention are of the formula:

compounds (Ia), (Id), (Ie), (If) and (Ig) are preferred in the present invention, and compound (Ie) is particularly preferred.

The compound of formula (I) is characterised in that it has two enantiomeric forms, 3 α and 16 α, and each of these enantiomers is characterised, if applicable, by a pair of diastereomers of the carbon 14 form: a pair of ((3 α, 14 α) and (3 α, 14 β)) and a pair of ((14 α, 16 α) and (14 β, 16 α)).

Advantageously, in the compounds of formula (I), the hydrogen atoms in positions 3 and 16 are in trans and the group R in position 14 may be of alpha or beta type (the terms alpha and beta refer to substituents other than hydrogen according to the steroid derivative naming convention).

In the present invention, the 3 α form corresponds to the formula (I) wherein the carbon at the 3-position is in the S configuration and the carbon at the 16-position is in the R configuration. In the present invention, the 16 α form corresponds to formula (I) when the carbon at position 3 is in the R configuration and the carbon at position 16 is in the S configuration.

It is therefore a particular object of the present invention that the compound of formula (I) or one of its pharmaceutically acceptable salts is in the form of a racemic or optically active mixture.

The compound of formula (I) or one of its pharmaceutically acceptable salts is preferably selected from one of the following compounds having formula (I):

a) dextrorotatory and/or levorotatory (3 α) compounds; and

b) dextrorotatory and/or levorotatory (16 alpha) compounds,

and wherein the molar ratio of the mixture of the two levorotatory and dextrorotatory diastereomers present in compounds a) and b) may be the same or different.

According to a preferred embodiment of the invention, the compound of formula (I) or one of its pharmaceutically acceptable salts is selected from one of the following compounds having formula (I):

a) dextrorotatory and/or levorotatory forms of the compound (3 α, 14 α);

b) dextrorotatory and/or levorotatory forms of the compound (3 α, 14 β);

c) dextrorotatory and/or levorotatory forms of the compound (14 α, 16 α); and

d) dextrorotatory and/or levorotatory forms of the compound (14 β, 16 α).

In the present invention, the "trans epimer" refers to a epimer in which the hydrogen atoms at carbon 3 and carbon 16 are always in the trans positions, and the substituent R is in the trans position with respect to the hydrogen atom at carbon 16. In the present invention, the term "cis epimer" refers to a epimer in which the hydrogen atoms at carbon 3 and carbon 16 are always in the trans position, and the substituent R is in the cis position with respect to the hydrogen atom at carbon 16.

According to a preferred embodiment of the invention, the compound of formula (I) or one of its pharmaceutically acceptable salts represents the majority obtained during the synthesis, which may be the trans epimer or the cis epimer.

In a preferred embodiment of the invention, the compound is the epimer (Ie1) consisting of the pair of enantiomers (3 α, 14 β) and (16 α, 14 α) of the formula:

it can be seen that in this epimer (Ie1), the substituent at the carbon 14 position (in this case ethyl morpholine) is always in the trans position relative to the hydrogen at the carbon 16 position and the hydrogen at the carbon 3 and carbon 16 positions are always in the trans position.

More particularly, the preferred compound is the enantiomer (Ie1b) which was washed out of the column (second eluted compound) when the epimer (Ie1) ((3 α, 14 β) and (16 α, 14 α) pair) was subjected to HPLC (high performance liquid chromatography), wherein the column used had a stationary phase consisting of silica gel particles (particle size 5 μm) with cellulose tris (2, 5-xylenecarbamate) attached and the mobile phase used was acetonitrile.

We will now describe the use of a compound in which the group R in compound (I) represents a hydrogen atom to which is attached a double bond between carbon 14 and carbon 15, as a medicament, which compound satisfies the following formula (Ij):

the compound (Ij) is obtained in particular by dehydration of a compound of formula (I) in which the radical R represents a radical-AR' as defined above.

In particular, we will describe in the specification a compound (Ij1) comprising the following two enantiomers:

a second aspect of the invention is directed to a compound of formula (I) according to the invention for use as a medicament, and a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.

In particular, the invention relates to the use of a compound of formula (I) according to the invention or of a composition according to the invention for producing a pharmaceutical composition for the treatment and/or prophylaxis of depression.

In particular, the invention relates to the use of a compound or a composition according to the invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of Major Depressive Disorder (MDD) (cf. 14, 15, 16), wherein the group R of compound (I) can also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15 (formula (Ij) in particular (Ij 1)).

The compounds of the present invention are more effective antidepressants and have a more rapid effect than traditional antidepressants.

According to another particular aspect, the group R of compound (I) may also represent a compound or composition of the invention having a hydrogen atom bearing a double bond between carbon 14 and carbon 15 for the treatment or prevention of patients with depression who are partially or completely resistant to conventional antidepressant therapy (TRD patients), such as antidepressants belonging to the class consisting of tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective 5-hydroxytryptamine recapture inhibitors (SSRIs), 5-hydroxytryptamine and norepinephrine recapture inhibitors (SNDRIs), norepinephrine and selective 5-hydroxytryptamine antidepressants (NASSAs) or 5-hydroxytryptamine receptor modulators.

According to another particular aspect, the group R of compound (I) may also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15, for use in patients resistant to traditional antidepressant treatment as well as in patients with depression, in particular major depression, making them susceptible to such treatment.

According to another particular aspect, the group R of compound (I) may also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15, a compound or a composition of the invention for use in the treatment and/or prevention of bipolar major depressive disorder, in particular major periodic depressive disorder (MRDD), as defined by DSM IV.

According to another particular aspect, the group R of compound (I) may also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15, for the treatment and/or prevention of Depression of a severity of more than 26 points when evaluated on the HAMD (Hamilton Depression) scale or more than 35 points when evaluated on the madrs (montgomery and saberg depressing rating scale) scale.

According to another particular aspect, the compounds or compositions of the invention, in which the group R of compound (I) may also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15, are used for the treatment and/or prevention of schizophrenia.

Thus, the compounds of the invention in which the group R of compound (I) may also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15 are useful for the treatment and/or prevention of depression and/or schizophrenia, in particular for correcting the negative symptoms of depression in both directions (ref.17) and schizophrenia (ref.18).

Since testing of the compounds of the invention on Balb/c mice showed that these compounds are capable of: 1) largely restores the noradrenaline activated phenotype in the locus coeruleus; 2) restoring noradrenaline activated innervation in the prefrontal cortex; 3) restoring a hypothalamic secretin phenotype in a subterminal hypothalamic neuron; and 4) after being deprived of sleep, turning these syngeneic mice from incapacitating to increasing tachy-sleep; according to a new aspect, the invention also relates to the use of said compounds, in which the group R of compound (1) may also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15, for the preparation of a medicament or pharmaceutical composition for the prevention and/or treatment of wake-sleep cycle disorders. The wake-sleep cycle disorder is in particular selected from: narcolepsy, hypersomnia, and long-term sub-arousal (hypoarousal) states.

According to a new aspect, the object of the present invention is the use of a compound of formula (I) according to the invention, in which the group R of compound (I) may also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15, or of a composition according to the invention, for the preparation of a medicament for the treatment and/or prevention of symptomatic frontal disorders of the cognitive sector (mild cognitive impairment (ref 18)), such as pre-dementia and dementia or behavioural problems associated with alzheimer's disease or parkinson's disease (ref 12): hypoactivity, attention problems, moral problems (see reference 21, Attention Deficit Hyperactivity (ADHD)) are described. Thus, according to this new aspect, the invention is directed to such use, wherein the symptomatic frontal lobe problem of the cognitive component is selected from: pre-dementia and dementia disorders associated with alzheimer's disease or parkinson's disease (ref 12), or behavioral disorders selected from attention and prodder problems.

According to another particular aspect, the object of the present invention is the use of a compound of formula (I) according to the invention or of a composition according to the invention, in which the radical R of the compound (I) may also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15, for the preparation of a pharmaceutical composition for the treatment and/or prevention of memory problems, which are particularly associated with ageing or with Alzheimer's disease or Parkinson's disease.

More particularly, the object of the present invention is the use of a compound of formula (I) according to the invention or one of its pharmaceutically acceptable salts as a medicament which can be administered orally, intravenously, intraperitoneally or intramuscularly, or by any other means to obtain the antidepressant effect according to the invention, or to sensitize patients suffering from major depression who are resistant to conventional antidepressant treatment to such treatment, or to obtain the desired prevention or treatment in the above-mentioned uses.

The pharmaceutical active or pharmaceutical compositions of the present invention may be contained in any oral galenical dosage form commonly used including tablets, capsules and liquids such as, for example, cyenna and suspensions containing various coloring, flavoring and stabilizing masking agents.

To prepare the oral galenical dosage form of the invention, the active ingredient may be mixed with various conventional materials such as starch, calcium carbonate, lactose, sucrose and dicalcium phosphate to facilitate the encapsulation process. Magnesium stearate serves as an additive, if necessary, to provide a useful lubricating function.

The active ingredient of the pharmaceutical composition may be dissolved or suspended in a pharmaceutically acceptable sterile liquid such as sterile water, a sterile organic solvent, or a suspension of a mixture of the two liquids. Preferably, such a liquid is suitable for parenteral injection.

When the active substance is sufficiently soluble, it may be dissolved in a physiological salt solution such as a pharmaceutically acceptable sterile liquid; if not sufficiently soluble, it may be dissolved in an aqueous solution of a suitable organic solvent such as propylene glycol or polyethylene glycol. Aqueous propylene glycol solutions containing from 10 to 75% by weight of ethylene glycol are generally suitable. By way of further example, other compositions may be obtained by dispersing the active substance as a very fine concentrate in an aqueous solution of starch granular cellulose or sodium carboxymethyl, or in a suitable oil such as peanut oil.

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

Preferably, the pharmaceutical composition is in unit dosage form, such as a tablet or capsule. In this form, the composition is subdivided into unit doses containing appropriate quantities of the active: the unit dose may be a small package of the composition, for example a powder, a vial or a vial. The amount of active in a unit dose of a composition may be varied or adjusted to 2mg or less, or 50mg or more, depending on the particular need and activity of the active.

A suggested oral dose of the compound of formula (I) may be 20 to 60 mg/day, which may be administered in 2 or 3 portions, preferably at meal time. A dose of 20 mg/day is effective in most depression patients, but 40mg or even 60mg may be necessary.

One of ordinary skill in the art will appreciate that the method of administration of such compounds may vary significantly in accordance with the present invention. In addition to other oral administrations, sustained release compositions may be preferred. Other methods of administration may include, but are not limited to: intravenous injection, intramuscular and intraperitoneal injection, subcutaneous implantation, and buccal, sublingual, transdermal, rectal and intranasal administration.

According to a particular embodiment, the invention relates to the use of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that the daily dose for an adult human is between 20 and 60 mg.

The specialist will be able to determine the appropriate dose for each patient; the dosage may vary as a function of the age, weight and response to treatment of the particular patient. The dosage examples given above represent averages. However, it may also be administered in smaller or larger doses than this average.

A process for the preparation of a compound of formula (I): according to the invention, those compounds defined in formula (I) can be prepared by the following process, starting from 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol.

1) Preparation of 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol

Treating the optically active compound of formula (II) or (II') to produce a 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol compound.

(II) (II’)

Using a reducing agent; the resulting product is two diastereomeric pairs of 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol [ (3 α, 14 α), (3 α, 14 β) ] and [ (14 α, 16 α), (14 β, 16 α) ], or mixtures thereof, and if desired, the reaction product is treated with an inorganic or organic acid to form a salt.

The products of formulae (II) and (II') can be prepared as described in French patent application FR 2190113. Racemic mixtures of compounds of formula (II) can be isolated by cleavage.

A pair of diastereoisomers (. + -.) of 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol or a mixture of two diastereoisomers with a very variable ratio can be obtained by reducing one of the two enantiomers of formula (II). The experiments described in french patent application FR 2623503 show that in practice only one of the two diastereomers is obtained (see example B).

The compounds of the general formula (II) can be used in racemic form or in optically active form. It is evident that the reduced compound of 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol obtained from the product of general formula (II) has the corresponding stereochemical form.

The compounds of formula (II) can be used in the form of one of their addition salts with inorganic or organic acids. In this case, depending on the selected operating conditions, the product 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol can be obtained in salified or nonsalified form.

Racemic or optically active mixtures of 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol compounds can also be prepared as described in french patent application publication No. FR2381048 and french additional certificate application publication No. FR 2433528.

In a preferred case of an embodiment of the present invention, the above-described method is performed as follows.

The reducing agent used may be a hydride, in particular a mixed hydride, such as a mixture of lithium hydride and aluminum hydride, sodium aluminum diethylhydride, sodium borohydride, lithium borohydride, diisobutyl-aluminum hydride. The reduction is carried out using an organic solvent or solvent mixture, for example an ether, such as diethyl ether, tetrahydrofuran, or an aromatic hydrocarbon, such as toluene, benzene, xylene. The reduction reaction is carried out at a temperature of-20 ℃ to the reflux temperature of the reaction medium. Preferably at room temperature. If a metal hydride is used as the reducing agent, 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol is released from the intermediate complex formed from the hydride by current methods such as addition of an aqueous alkaline solution, e.g., sodium hydroxide.

Reducing the trans-3 alpha compound (II) to form (+) (3 alpha, 14 alpha) 14, 15-dihydro-20, 21-dinoreburnamenine-14-ol compound. Reduction of the trans 16 α compound (II') to yield (-) (14 β, 16 α)14, 15-dihydro 20, 21-dinoreburnamenine-14-ol compound.

Treatment of these compounds with an acid such as hydrochloric acid gives the most common (-) (3 α, 14 β)14, 15-dihydro-20, 21-dideoxyneurin-14-ol and (+) (14 α, 16 α)14, 15-dihydro-20, 21-dideoxyneurin-14-ol types, respectively (see scheme below and FIG. 2).

The schematic diagram shows the general method for the synthesis of optically isomeric 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol compounds from compounds of general formula (II) (Belgian patent publication BE 764166 describes the application for compounds of general formula (II)).

One of the diastereomers, or a mixture of diastereomers, may be isolated by conventional methods: chromatography, direct crystallization, differential dissolution methods such as differential dissolution in hot toluene.

2) Preparation of Compounds of formula (I)

The compounds of the invention can be prepared from 14, 15-dihydro-20, 21-dinoreburnamenin-14-ol by O-alkylation or N-alkylation in the presence of a strong base such as NaH, or from the above-synthesized compounds of the invention.

Drawings

FIG. 1: FIG. 1 shows the amount of TH (tyrosine hydroxylase) protein measured after direct transformation of frozen coronary brain sections on nitrocellulose filters, expressed in arbitrary units (UTA for arbitrary tyrosine hydroxylase units) at each anatomical interval (80 μm), control mice (white bars) and treatment mice (gray bars) treated with a compound of formula (If 1).

FIG. 2: the post-pre distribution of the number of TH-containing cells in LC was determined by immunohistochemistry from control balb/c mice (white bars) and treatment mice (gray bars) treated with the molecule of formula (Ie 1).

Fig. 3A and 3B: positive TH fiber distribution was obtained on prefrontal cortex samples from Balb/c mice assayed by immunohistochemistry in control mice (fig. 3A) and mice after serial treatment with the molecule of formula (Ie1) (fig. 3B). The positive TH fibers are subjected to picture strengthening treatment. A signal "molecular layer" is shown on these figures.

Detailed Description

In examples 1 to 9 given below:

the hydrogen atoms in positions-3 and 16 being trans (the bond may be (3. beta., 16. alpha.) or 3. alpha., 16. beta.)

At the 14 position, the terms α and β refer to substituents other than hydrogen.

Further, the compounds synthesized in examples 1 to 9 given below may be in the form of a mixture of two epimers (in other words, four diastereomers) or a single epimer, a cis epimer or a trans epimer (in other words, two enantiomers). These two epimers are defined as a function of the position (before or after) of the R group carried by the carbon atom at position 14 and as a function of its position relative to the hydrogen at position 16 of the carbon.

Each epimer has two enantiomers as a function of the position (before or after) of the hydrogen atoms in positions 3 and 6 (these hydrogen atoms are always trans).

In the examples 1 to 9 given below, the term "2 epimer" means that the compound (original or synthesized) is in the form of a mixture of two epimers (four diastereomers), and the term "1 epimer" means that the compound (original or synthesized) is in the form of a single epimer (two enantiomers), cis epimer or trans epimer.

Example 1: a compound of formula (Ia): method for preparing (+/-) (16 alpha) 14, 15-dihydro 14-ethoxycarbonylmethoxy-20, 21-dinoreburnamenine

50mg (0.19mmol) of compound (1) was dissolved in 4ml of anhydrous Dimethylformamide (DMF), and then 19mg of 60% NaH (1.2eq) was added. Once the evolution of gas had ceased, 25. mu.l (1.2eq) of ethyl bromoacetate were added and stirred at room temperature overnight. The reaction medium is then concentrated and washed with dichloromethane (CH)₂Cl₂) The residue was dissolved. The organic phase was washed with water. Over magnesium sulfate (MgSO)₄) Dry, filter and evaporate until dry. In the presence of oxygenOn a silica column (eluent is CH)₂Cl₂MeOH in 99: 1, then CH₂Cl₂MeOH 98: 2 mix). To obtain a compound of formula (Ia) in the form of 2 epimers: 28mg of this white powder (Ia1) and 3mg of a yellow, viscous solid (Ia 2). Yield: 46% (42% Ia1 and 4% Ia 2). Melting point of 105-108 deg.C

RMN 1H CDCl₃(300MHz)δ(ppm)：1.25(m，2H，-CH₂)；1.27(t，3H，-CH₂CH₃)；1.79(m，2H，-CH₂)；2.33(m，4H，2-CH₂)；2.72(m，3H，-CH₂，-CH)；3.12(m，3H，-CH₂，-CH)；4.11(m，AB system，2H，-COCH₂，J＝15.9Hz)；4.22(q，2H，-CH₂CH₃)；5.77(m，1H，CHOH)；7.15(m，aromatic 2H，H)；7.45(dd，1H，aromatic H，J＝7.22Hz，J＝1.55Hz)；7.68(dd，1H，aromatic H，J＝7.03Hz，J＝1.69Hz)。

Example 2: a compound of formula (Ib 1): method for preparing (+/-) (3 beta, 16 alpha) 14, 15-dihydro 14-carboxyl methoxyl 20, 21 dinoreburnamenine sodium

182mg (0.51mmol) of the compound (Ia) were dissolved in 8ml of Tetrahydrofuran (THF)/H₂O is in a mixture of 3: 1. 485. mu.l (0.95eq) of 1N soda solution were added. Stir at room temperature overnight. Concentrating THF with CH₂Cl₂And water. By CH₂Cl₂The aqueous phase was washed three times. The aqueous phase was concentrated and the resulting solid was dried. 160mg of the desired compound are obtained as a yellow solid. Yield: 90% and a melting point of 200 ℃.

RMN 1H MeOD(300MHz)δ(ppm)：1.31(m，1H，-CH)；1.59(m，1H，-CH)；1.87(m，4H，2-CH₂)；2.41(m，2H，-CH₂)；2.71(m，2H，-CH₂)；2.93(m，3H，-CH₂，-CH)；3.13(m，1H，-CH)；3.92(m，AB system，2H，-COCH₂，J＝15Hz)；5.70(m，1H，CHOH)；7.07(m，aromatic 2H，H)；7.39(d，1H，aromatic H，J＝7.1Hz)；7.70(d，1H，aromatic H，J＝7.9Hz)。

Example 3: formula (Ic 1): method for preparing (+/-) (3 beta, 16 alpha) 14, 15-dihydro 14- [2- (N-methyl-piperazine-1-yl) -2-oxo-ethoxy ]20, 21-dinoreburnamenine

(Ib 1): most of the epimers isolated after the synthesis of compound (Ib).

80mg (0.23mmol) of compound (Ib1) are dissolved in 5ml DMF. Mu.l (1.2aq) of N-methylpiperazine, 53mg (1.2eq) of 1- (3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDCI.HCl) and 37mg (1.2eq) of 1-hydroxybenzotriazole hydrate (HOBt.H.H.₂O). After stirring at room temperature for 48 hours, the reaction mixture was concentrated. By CH₂Cl₂Dissolving the residue with NaHCO₃The saturated solution washes the organic phase. Over MgSO₄Dried, filtered and concentrated. The resulting yellow oil was purified on a silica column (eluent CH)₂Cl₂MeOH in 95: 5, then CH₂Cl₂MeOH in 90: 10 mix). 50mg of a viscous yellow powder (Ic1) were obtained. Yield: 53 percent, and the melting point is 44-48 DEG C

RMN 1H CDCl₃(300MHz)δ(ppm)：1.26(m，1H，-CH)；1.60(m，1H，-CH)；1.82(m，4H，2-CH₂)；2.34(m，6H，3-CH₂)；2.42(m，3H，-CH₂，-CH)；2.75(m，3H，-CH₂，-CH)；3.04(m，3H，-CH₂，-CH)；3.42(m，2H，-CH₂)；3.60(m，2H，-CH₂)；4.19(m，AB system，2H，-COCH₂，J＝13.5Hz)；5.78(m，1H，CHOH)；7.12(m，aromatic 2H，H)；7.44(d，1H，H aromatic)；7.55(d，1H，Haromatic)。

Example 4: compound (Id): synthesis of (+/-) (3 beta, 16 alpha) 14, 15-dihydro-14-benzyloxy-20, 21-dinoreburnamenine

The same procedure as used for the synthesis of compound (Ia) (example 1) was used, with benzyl bromide instead of ethyl bromoacetate. Yield 52% (Id) (two epimers were not separated). Melting point 112-115 deg.C.

RMN 1H(300MHz，CDCl₃)δ(ppm)1.15-1.35(m，2H)；1.78-2.02(m，4H)；2.18-2.40(m，2H)；2.54-2.89(m，3H)；2.94-3.21(m，3H)；4.48-4.73(m，2H)；5.74(m，1H)；7.13(m，2H)；7.18-7.38(m，5H)；7.45(m，1H)；7.54(m，1H)。

Example 5: compound (Ig): synthesis of (+ -) - (3 beta, 16 alpha) 14, 15-dihydro-14- (3-methyl- [1, 2, 4] oxadiazol-5-ylmethoxy) 20, 21-dinoreburnamenine

The initial methyl ester was synthesized in the same manner as in the synthesis of compound (Ia) except that ethyl bromoacetate was replaced with methyl bromoacetate.

209mg (2.82mmol) of oxime acetamide and 113mg (2.82mmol) of 60% NaH are dissolved in 10ml of anhydrous divinyl dioxide. A molecular sieve spatula was added and the reaction mixture was heated to 65 ℃ for 1 hour. At this temperature, 320mg (0.94mmol) of methyl ester dissolved in 10ml of anhydrous divinyl dioxide were added and the reaction mixture was heated to 75 ℃ overnight. The reaction mixture was concentrated with NaHCO₃The unsaturated solution dissolves the residue, triturates and filters. The resulting yellow solid was purified on a silica column (eluent CH2Cl 2/Me)OH mixed 99: 1). The two epimers were separated. 79mg of the major epimer (Ig1) were obtained as a white powder. Yield: the majority of the epimer was 23% and a small portion of the epimer was not separated. Melting point: 124-125 ℃.

RMN 1H(300MHz，CDCl₃)δ(ppm)：1.21-1-38(m，1H)；1.60-1.73(m，1H)；1.75-2.03(m，4H)；2.29-2.55(m，5H)；2.65-2.96(m，3H)；2.98-3.23(m，3H)；4.68(d，1H，J＝14.1Hz)；4.80(d，1H，J＝14.1Hz)；5.83(m，1H)；7.16(m，2H)；7.46(m，1H)；7.59(m，1H)。

Example 6: compound (Ih): synthesis of (+ -) - (3 beta, 16 alpha) 14, 15-dihydro-14- (2-hydroxy-ethoxy) 20, 21-dinoreburnamenine

300mg (1.12mmol) of compound (1) was put into 10ml of anhydrous DMF for suspension, and 54mg (1.2eq) of 60% NaH was added. 492mg (5.0eq) of ethylene carbonate were added and the reaction mixture was heated to 110 ℃ for 1 hour and then to 80 ℃ for 4 hours.

Concentrating the reaction mixture with CH₂Cl₂The residue was dissolved. The organic phase was washed twice with water and once with a saturated solution of NaHCO 3. Over MgSO₄Dried, filtered and concentrated. The brown oil obtained is purified on a silica column (eluent CH)₂Cl₂MeOH in 99: 1, then CH₂Cl₂MeOH 98: 2, then CH₂Cl₂MeOH 96: 4 mix).

The compound obtained is of the 2 epimer form: 111mg (Ih1) of a beige solid and 100mg of a beige solid (Ih 2). Yield 61% (32% of (Ih1) and 29% of the other epimer).

RMN 1H(400MHz，CDCl₃)δ(ppm)：1.22-1.38(m，1H)；1.78-2.18(m，6H)；2.21-2.41(m，2H)；2.61(m，1H)；2.71-2.85(m，2H)；2.97-3.20(m，3H)；3.56-3.82(m，4H)；5.61(m，1H)；7.14(m，2H)；7.44(m，1H)；7.52(m，1H)。

Melting point: 129-132 deg.C

Example 7: synthesis of Compound (Ie)

Trans epimer

a) Synthesis of 4- (2-chloroethane) -morpholine

5.0g (26.9mmol) of the hydrochloride of 4- (2-chloroethylmorpholine) were dissolved in 16mL of distilled water. Potassium carbonate (K) was added in 15g portions₂CO₃). The aqueous solution was extracted five times with ethyl acetate (AcOEt). Over MgSO₄Dry, filter and concentrate the organic phase.

3-3794-2 (chloroethylmorpholine) was obtained as a clear yellow oil.

Yield: 84 percent.

b) Compound (Ie): synthesis of (±) (3 β, 14 β, 16 α)14, 15-dihydro 14- (2-morpholin-4-yl-ethoxy) 20, 21-dinoreburnamenine and (±) (3 β, 14 α, 16 α)14, 15-dihydro 14- (2-morpholin-4-yl-ethoxy) 20, 21-dinoreburnamenine

500mg (1.86mmol) of compound (1) was put into 20mL of anhydrous DMF and suspended. 90mg (1.2eq) of 60% NaH was added and the mixture was stirred at room temperature for 45 minutes. 558mg (2.0eq) of 4- (2-chloroethane) morpholine dissolved in 10mL of anhydrous DMF was added followed by 140mg (0.5eq) of sodium iodide. After stirring for 8 hours at 45 ℃ 90mg (1.2eq) of 60% NaH, 558mg (2.0eq) of 4- (2-chloroethane) morpholine and 280mg (1.0eq) of sodium iodide in 2ml of anhydrous DMF were added at the same temperature. Heating is continued for 18 hours, then90mg (1.2eq) of 60% NaH, 558mg (2.0eq) of 4- (2-chloroethyl) morpholine and 280mg (1.0eq) of sodium iodide in 2ml of anhydrous DMF were added. Stirring was continued for 24 hours at 45 ℃. Concentrating the reaction mixture with CH₂Cl₂The residue was dissolved. The organic phase was washed three times with water. Over MgSO₄Dried, filtered and concentrated. The obtained residue was used in Et₂O dissolved, insoluble material filtered and the filtrate concentrated. The brown oil obtained is purified on a silica column (eluent CH)₂Cl₂/MeOH/NH₂OH mixed at 99: 0.5).

Two epimers were obtained: 340mg of a viscous yellow solid (Iel) and 29mg (Ie2) of a yellow solid. Yield: 52% (48% of (Iel) and 4% of (Ie 2)).

(Iel)：

RMN 1H(300MHz，CDCl₃)δ(ppm)0.86(m，1H)；1.18-1.40(m，1H)；1.78-1.92(m，4H)；2.21-2.41(m，2H)；2.48-2.92(m，9H)；2.98-3.15(m，3H)；3.59(m，1H)；3.70-3.92(m，5H)；5.62(m，1H)；7.08-7.21(m，2H)；7.44(m，1H)；7.63(m，1H).

Melting point: 116 deg.C-118 deg.C

(Ie2)：

RMN 1H(300MHz，CDCl₃)δ(ppm)1.12-1-32(m，1H)；1.79-2.82(m，16H)；2.95-3.21(m，3H)；3.43-3.80(m，6H)；5.69(bs，1H)；7.11(m，2H)；7.34-7.52(m，2H).

Melting point: 91-93 deg.C

c) The two enantiomers (Iela) and (Ielb) were separated by HPLC for the preparation of chiralcel

Each enantiomer of the compound (Iel) is obtained by usingOD-H was prepared by chromatography under the following conditions:

preparative liquid chromatography:

column: 250x20mmOD-H5pm

Mobile phase: acetonitrile

Flow rate: 20ml/min

And (3) detection: UV 300nm

Temperature: 25 deg.C

Analytical liquid chromatography:

column: 250x46mmOD-H 5pm

Mobile phase: acetonitrile

Flow rate: 10ml/min

And (3) detection: UV 230nm

Temperature: 25 deg.C

And (4) conclusion:

the following two enantiomers (Iela) and (Ielb) were obtained from 582mg of the starting product (Table 1).

Table 1: characterization of the two enantiomers separated by preparative chiralel HPLC

Example 8: compound (If 1): synthesis of (+ -) - (3 β, 16 α)14, 15-dihydro 14- ((2-morpholin-4-yl-ethylcarbamoyl) -methoxy) 20, 21-dinoreburnamenine

The same synthesis as for compound (Ic) was used, substituting 4- (2-aminoethylmorpholine) for N-methylpiperazine. 56mg of a yellow powder (If1) are obtained. Yield: 56%, melting point: 181-184 ℃.

RMN 1H(400MHz，CDCl₃)δ(ppm)1.18-1.35(m，1H)；1.50-1.71(m，1H)；1.75-1.93(m，4H)；2-32-2.83(m，11H)；2.91-3.17(m，3H)；3.38(m，2H)；3.55-3.72(m，4H)；3.99(d，1H，J＝14.57Hz)；4.12(d，1H，J＝14.57Hz)；5.69(m，1H)；7.13(m，3H)；7.35-7.52(m，2H)。

Example 9: compound (Ii): synthesis of (+ -) - (3 beta, 16 alpha) 14, 15-dihydro-14- (2-morpholin-4-yl-ethylamino) 20, 21-dinoreburnamenine

200mg (0.75mmol) of compound (1) was dissolved in 4mL4- (2-aminoethyl) morpholine, and the reaction mixture was heated to 110 ℃ for 4 days. The mixture was cooled to room temperature and the residue was dissolved in CH2Cl 2. The organic phase was washed 10 times with water. Over MgSO₄Dried, filtered and concentrated. The resulting brown oil was dissolved in ether, filtered and the filtrate was concentrated. The brown solid obtained is purified on a silica column (eluent CH)₂Cl₂MeOH 98: 2, then CH₂Cl₂MeOH 96: 4 mix). 44mg of a viscous yellow oil containing the two epimers were obtained. Yield: 15 percent.

RMN 1H(300MHz，CDCl₃)δ(ppm)1.18-1-38(m，3H)；1.78-2.81(m，17H)；2.93-3.21(m，3H)；3.40-3.57(m，1H)；3.61-3.78(m，3H)；5.18-5.40(m，1H)；7.03-7.21(m，2H)；7.31-7.64(m，2H)。

Example 10: pharmacological protocols

The molecules were chosen as a function of their ability to:

1) active expression of protein in the blue spots (LC) of Balb/c mice;

2) they display the capacity of a large population of cells in which the Tyrosine Hydroxylase (TH) phenotype is restored by treatment.

The content of TH protein was determined after direct transfer of coronal sections of frozen brains onto nitrocellulose filters. Thus, the exact sampling of the protein distribution is once every 80 μm (thereby defining each anatomical interval), which is revealed by quantitative immunochemistry. Quantification was performed using a series of brain homogenates containing increasing amounts of TH protein.

With the same anatomical sampling, the number of immune positive cells of TH is determined starting from a coronal brain section fixed by immunohistochemistry.

These analyses were performed with vehicle-treated animals and mice treated with a single intraperitoneal injection of the test molecule (20 mg/kg in 100. mu.l). Three days after injection, the animals died.

Typical results are shown in figure 1. It clearly shows that the increase in induction of the TH gene occurs at a specific level in the nucleus. The amount of TH protein was determined 3 days after single injection to the treated group and control group mice. The amount of TH protein per anatomical interval along the bottom-up axis is determined. Each represents mean ± standard error of control (black bars) and treatment (cross-hatched bars). In this figure, an asterisk "^*"means significant (p) results<0.05); star sign "^***"means that the results are very significant (p)<0.0005). Total increase in TH content found in LC was 13 + -3% (using ANOVA II test, p<0001)。

Biological activity

All molecules of the general formula (examples) were synthesized and screened in vitro, taking into account the ability to induce increased Tyrosine Hydroxylase (TH) expression in the blue spot (LC) of mice of the innate Balb/c variety. This genetic pattern was previously demonstrated to demonstrate the ability of molecules administered by external means to allow the appearance of "latent" noradrenaline cells (ref.1 and 2). Table 2 below contains examples of the results of such screening.

Molecule	Amount of TH measured in LC
		A compound of formula (1)	120±4**
Compounds of formula (Ia1)	151±5**
		A compound of formula (Id)	129±5**
A compound of formula (Ie1)	138±4****
		A compound of formula (If1)	113±4**
A compound of formula (Ig1)	118±3**
		Formula (II)(Ij1) Compound	123±2**

TABLE 2

For each example in this specification, 100 μ l of vehicle or a single dose of 20mg/kg product was injected into control and treatment animals by intraperitoneal (i.p.) method. Animals died three days after injection, their brains were removed, frozen and cut into 20 μm frontal sections. In the LC-containing region, samples were taken every 80 μm and the sections were transferred directly onto nitrocellulose filters (ref.3). TH is determined by immunochemistry. Results represent mean ± standard error obtained for each treatment group over the entire structure. They were used in corresponding control groups^**p<0.02；^***p<0.002；^****p<The percentage of the average found in 0.0002 represents.

Complementary results were obtained in the examples described using the compound of formula (Ie1), which, when administered acutely or continuously, showed a significant increase in the norepinephrine cell population in the locus coeruleus as shown in the following graph:

the results in figure 2 show the posterior-anterior distribution of the number of TH-containing cells in LC as determined by immunohistochemistry in Balb/c control mice and in mice treated by formula (Ie 1).

Each represents the mean ± standard error obtained per 80 μm anatomical interval in each experimental group.^***Represents p<0.0001, determined by ANOVA II (therapeutic factor). It should be noted that there is a very significant increase in the number of TH expressing cells. The mean values obtained for the control and treatment groups were equal to 996. + -. 1 and 1250. + -. 58, respectively, throughout the structure. (a dose of 20mg/kg was administered, with continuous treatment i.p. on days 0, 3, 6, 9 and 12, and animals died on day 16).

This phenomenon can be stabilized by appropriate continuous therapy (e.g., 20mg/kg, i.p. injections every 3 days for 15 days, see fig. 2). Under these conditions, the increase in the number of positive supermarkeyth cells present in the LC remained 24 days after cessation of treatment.

A very significant increase in noradrenergic fiber density of the prefrontal cortex (figure 3) can be seen in animals treated with compound (Ie1) while cells reappear in LC.

FIG. 3 results show the distribution of positive TH fibers on the prefrontal cortex samples of Balb/c mice. Left side: in control mice, the typical orientation of noradrenergic fibers (parallel to the surface of the cortex) as confirmed by immunocytochemical reactions associated with the presence of TH protein was noted to be present in the molecular layer of the prefrontal cortex. And on the right: the figure shows the increase in positive density of TH fibers, which was determined to occur in the same brain area after continuous treatment (5 i.p. injections of molecule (Iel); once every three days, 20mg/kg each). Animals died three days after the last injection. The dotted line marks the molecular layer boundary of the prefrontal cortex.

It is also shown that:

oral molecules (Iel) effective

This activity is a dose dependent on the intraperitoneal (i.p.) and oral (p.o.) methods. Half the effective amount (DE50) was 0.5 and 1.5mg/kg, respectively. Thus, the molecule in the preferred embodiment is 30 times more efficient than its direct synthetic precursor of formula (1) (see 4, 5 and 6).

The two enantiomeric pairs are separated during the synthesis of the molecule (Ie). The enantiomeric pair of formula (Ie1) was separated into two pure products (Ie1a and Ie1 b). Compound (Ie1b) is twice as active as form (Ie1a) and is therefore the preferred form.

The inventors have also demonstrated that the group R of compound (I) can also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15, and in particular that compound (Ie1) has another innovative activity: activation of hypothalamic secretin (hypocretin) expression in lateral hypothalamic cell populations, under normal physiological conditions these peptides are only slightly expressed in balbc/c, or not expressed at all. This property is the same as its direct synthetic precursor, the compound of formula (1). Table 3 below illustrates such results for two chemical entities:

watch III

Here, the distribution of cells expressing a hypothalamic secretin in the lateral hypothalamus was investigated with posterior-anterior sampling at intervals of 80 μm thick in succession. Cells are recognized by immunocytochemistry using specific antibodies. The two molecules studied were administered in a single dose of 20mg/kg, i.p. method. Animals died three days after injection. Thus, approximately one hundred supernumary cell populations are identified in the posterior third of the brain core.

The molecule in the preferred example (Ie1b) was also tested for behavioral activity, a heel suspension test (TST), at a dose of 1mg/kg, i.p., as demonstrated by antidepressants in the Balb/c variant (ref 7). The experiment given as an example was performed three days after a single dose injection, the effect being comparable to imipramine (30mg/kg, i.p. 30 min before the experiment) (see table 4 below).

	n	Dosage to be administered	Average fixed time(s)	Standard deviation of	P (Standard test)
						Excipients	8	0	180
Compound (elb)	7	1mg/kg i.p.	130	15.8	0.009
						Imipramine	5	30mg/kg i.p.	70	15.5	0.0001

TABLE 4

The fixed time measured at the 6 minute period was significantly reduced three days after a single dose injection of compound (Ielb), racemic (Ie1) active isomer. The results are the average of n animals.

Receptor curves made "in vitro" at a concentration of 10 micromolar compound (Ie1) on 74 receptors and channels showed that it neither interacts with voltage dependent Na, K and Ca and SK + Ca channels nor with the catecholamine transport system, which was suspected of having a moderate binding affinity for the M1 and 5HT5A receptors.

Biodistribution studies of the molecule (Ie1) after 45 minutes of i.p. and oral administration at high doses (20 and 60mg/kg, respectively) showed that:

-after i.p. administration of compound (Ie), in the presence of compound (1), (synthetic precursor) is undetectable.

Compound (Ie1) accounted for 89% of brain concentration and compound 1 accounted for only 11% after p.o. administration at the same time.

For compound (Ie1), the brain concentration/liver concentration ratio was consistent in both dosing methods (0.41 and 0.49, respectively).

These results demonstrate that the compounds of the invention, in which the group R of compound (I) may also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15, and in particular the preferred compounds (Ie1) and more preferably (Ielb), are responsible in particular for the effects observed above, and that their biodistribution in the brain is favourable.

In summary, the compounds of the invention, in which the group R of compound (I) may also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15, and in particular the preferred compound (Ie1) and more preferably (Ielb), are capable of inducing plasticity phenomena into the brain, which allow the recovery of the quiescent noradrenaline cell population of the locus coeruleus complex in the brains of Balb/c mice. This phenotypic awakening is associated with an increased norepinephrine innervation of the prefrontal cortex of genetically pure mutant mice that have a low density of proneural innervation. Preferred compounds are identified. It is activated by oral administration. It is thirty times more active than its direct chemical precursor with similar properties. The compounds of the invention, in which the group R of compound (I) may also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15, are also capable of long-term activation of specific neuronal populations expressing a hypothalamic secretin in the lateral hypothalamus.

The potential efficacy of this family on central norepinephrine mediators (particularly the forehead), and on hypothalamic secretin neurons associated with sleep-wake cycles and animal depression patterns, is known (ref 8, 9). Emotions (ref 10, 11) and cognitive phenomena (ref 12) are managed in view of the special controls exerted on humans by noradrenaline neurons. In view of the lack of functional frontal lobe and prefrontal lobe in several psychiatric and neurological disorders, as well as direct evidence of the previously observed loss of functional frontal lobe and prefrontal lobe in major depressive disorders (ref 10, 11, 12) and major degenerative syndromes such as alzheimer's disease and parkinson's disease (ref 12, 13). Due to the resistance to current therapy in many patients, the group R of compound (I) may also represent a hydrogen atom bearing a double bond between carbon 14 and carbon 15, and particularly preferably the compound (Ie1) and more preferably (Ielb) of the present invention are useful for the prevention or treatment of depressive syndromes, in particular major depressive disorder, resistant depressive disorders such as those defined in DSM4 (ref 14, 15, 16), and for the correction of the negative symptoms of bipolar depression (ref 17) and schizophrenia (ref 18). Such molecules are also useful in the treatment of symptomatic frontal disorders of the cognitive segment (mild cognitive impairment (ref 9)); pre-dementia and dementia disorders associated with alzheimer's disease or parkinson's disease (ref 20), or behavioral disorders including hypoactive, attention problems, prodder problems (attention deficit-hyperactivity (ADHD) type (ref 21)), and sleep problems, in particular hypoactive or manifested as hypersomnia (narcolepsy).

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Claims (10)

1. A compound of the formula (I)

Wherein R represents a group-AR ', wherein A represents an oxygen atom and R' represents:

-quilt formulaSubstituted by the indicated aminesIs selected from straight or branched C₂-C₆An alkyl group, wherein Y and Z together form a heterocyclic group selected from piperazine, morpholine, thiomorpholinyl;

or a pharmaceutically acceptable salt thereof, including isomers, enantiomers, diastereomers and mixtures thereof.

2. The compound of claim 1, having the formula:

3. a compound according to any one of claims 1-2, wherein the hydrogen atoms in positions 3 and 16 are in trans position and the group R in position 14 may be in alpha or beta form.

4. A compound according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a racemic or optically active mixture.

5. The compound of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from one of the following compounds of formula (I):

a) dextrorotatory and/or levorotatory (3 α) compounds; and

b) dextrorotatory and/or levorotatory (16 alpha) compounds,

and wherein the molar ratio of the mixture of the two levorotatory and dextrorotatory diastereomers present in compounds a) and b) may be the same or different.

6. The compound of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from one of the following compounds of formula (I):

a) a compound of the (3 α, 14 α) type;

b) (3 α, 14 β) type compounds;

c) a compound of the (14 α, 16 α) type; and

d) (14. beta., 16. alpha.) type compound.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient.

8. Use of a compound according to any one of claims 1 to 6, or a composition according to claim 7, for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of depression.

9. Use of a compound according to any one of claims 1 to 6, or a composition according to claim 7, for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of major depressive disorders.

10. The use of claim 9, wherein the major depression is resistant depression.