阅读说明：本技术 氟乙基去甲美金刚胺用于预防和治疗焦虑的用途 (Use of fluoroethyl normemantine for the prevention and treatment of anxiety ) 是由 G·鲁宾斯坦 于 2018-12-17 设计创作，主要内容包括：本发明涉及氟乙基去甲美金刚胺或其盐之一,其单独或与化学抗抑郁治疗或认知和行为技术组合用于治疗焦虑,特别是创伤后应激状态。(The present invention relates to fluoroethyl normemantine or one of its salts for use in the treatment of anxiety, in particular post-traumatic stress states, alone or in combination with chemoantidepressant therapy or cognitive and behavioural techniques.)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof

For use in the treatment or prevention of anxiety in a patient.

2. A compound for use according to claim 1, characterized in that the pharmaceutically acceptable salt corresponds to formula (II)

Wherein, X^-Denotes a counter anion selected from the group consisting of chloride, bromide, iodide, acetate, methanesulfonate, benzenesulfonate, camphorsulfonate, tartrate, dibenzoate, ascorbate, fumarate, citrate, phosphate, salicylateOxalate, hydrobromide and tosylate.

3. A compound for use according to any one of claims 1 or 2, wherein anxiety is accompanied by depression.

4. Compound for use according to any one of claims 1 or 2, characterized in that the anxiety disorder observed is accompanied by insomnia.

5. Compound for use according to any one of claims 1 to 4, characterized in that anxiety disorders are selected from the group consisting of post-traumatic stress disorder (ESPT), specific phobias, social phobias, generalized anxiety disorder, panic disorder with or without agoraphobia, and obsessive compulsive disorder.

6. Compound for use according to any one of claims 1 to 5, characterized in that it is used in the treatment for preventing the appearance of anxiety disorders associated with post-traumatic stress.

7. Compound for use according to any one of claims 1 to 5, characterized in that anxiety disorders are associated with post-traumatic stress, in particular with established post-traumatic stress.

8. A compound for use according to any one of claims 1 to 7, wherein anxiety is accompanied by acute anxiety episodes and morbidity.

9. A combination, in particular for simultaneous, separate or sequential use, comprising the following components: a component (A) comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient

A component (B) comprising propranolol and at least one pharmaceutically acceptable excipient.

10. A combination product comprising the following components: a component (A) comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof

A component (C) comprising an antidepressant; wherein each of components (a) and (C) is formulated with at least one pharmaceutically acceptable excipient.

11. The product of claim 9, further comprising component (D) comprising ketamine formulated with a pharmaceutically acceptable excipient.

12. The product of claim 10, further comprising component (D) comprising ketamine formulated with a pharmaceutically acceptable excipient.

13. The product of claim 9, wherein components (a) and (B) are suitable for simultaneous, separate or sequential administration.

14. The product of claim 10, wherein components (a) and (C) are suitable for simultaneous, separate or sequential administration.

15. The product according to claim 11, wherein components (a), (B) and (D) are suitable for simultaneous, separate or sequential administration.

16. The product according to claim 12, wherein components (a), (C) and (D) are suitable for simultaneous, separate or sequential administration.

17. The product according to any one of claims 9 to 16 for use in the prevention or treatment of anxiety in a patient.

18. The product according to any one of claims 9 or 13 for use in the prevention or treatment of anxiety in patients who have suffered repeated abuse, particularly during childhood.

Technical Field

The present invention relates to the discovery of the use of pharmaceutical ingredients in the treatment of anxiety and depression related disorders.

Background

A number of molecules have been developed to treat anxiety and depression-related anxiety. However, these molecules have a number of disadvantages, in particular substantial side effects, causing a relative increase in lethargy, or even psychotic states leading to schizophrenia, or requiring a large treatment period (days or even weeks) to show therapeutic effect, with the risk of anxiogenic effects during the treatment.

Anxiety disorder

Anxiety in humans is a concern, insecurity, feeling of physical or mental illness, or anticipation of an uncertain danger. Anxiety is divided into two categories: state anxiety and idiosyncratic anxiety. State anxiety is a "normal" anxiety that is related to the specific condition in which the subject finds himself. Idiosyncratic anxiety is a "pathological" anxiety disorder that forms part of a subject. It is permanent, regardless of the particular situation.

Depression (depression)

Depression is characterized by so-called depressive episodes in which the patient experiences a depression, a decline in energy, and a decrease in activity. During depression, there is also a change in ability to experience pleasure, a loss of interest, and a rapid decline in concentration. There is also significant fatigue (even after minimal activity), sleep disturbance, etc. Patients often experience reduced self-esteem, feelings of guilt and self-deterioration, which can be extreme to death willingness and create suicidal thoughts. Depending on the number and severity of symptoms, three severity levels of depression are defined: mild, moderate and severe.

A number of anxiety and depression related psychiatric disorders are listed in the disease classification proposed by the world health Organization (OMS) (CMI 10):

phobic anxiety disorders: f40

The subject exhibits anxiety symptoms triggered entirely or substantially by one or more specific and innocuous conditions. As a result, patients will try to avoid these situations or worrisome to tolerate them. This phobic anxiety is often associated with depression.

Mixed anxiety and depressive disorders: f41.2

In this case, the subject exhibited both anxiety and depression symptoms, with no apparent dominance, nor to the extent that a separate diagnosis was required.

Obsessive compulsive disorder (TOC): f42

This disease is characterized by recurrent compulsive thoughts or compulsions. Compulsive thoughts repeatedly and pointlessly invade the subject's consciousness, even if the subject tries to avoid them. Compulsive behavior is also a repetitive stereotypical activity in which the subject does not have direct pleasure, but does not perform the activity autonomously. Their purpose is to prevent the occurrence of objectively unlikely events that afflict the subject. The subject is generally aware that his or her behavior is paradoxical and repeatedly attempts to counter the behavior. This disease is almost always accompanied by anxiety and depression.

Post-traumatic stress disorder (ESPT): f43.1

Post-traumatic stress disorder occurs after a subject has suffered (directly or indirectly) a traumatic event (death, death threat, severe injury or sexual assault, etc.). By definition, this "traumatic" event is threatening and elicits a strong fear response, representing an extreme stress situation. It causes a specific set of symptoms and behaviors. For example: flashback (repetitive and invasive memory of events, nightmare, etc.), avoidance behavior (memory, thoughts, people, condition, etc. that avoid evoking a traumatic event), cognitive and emotional changes (propensity to self-blame, persistent negative emotions, etc.), and ultimately nervous system hyperactivity (excessive vigilance, difficulty falling asleep, etc.). People with this syndrome also often develop profound depression or suicidal ideation (Shalev, am. J. Psychiatry 155,5, page 630-637, month 5 1998). This post-traumatic stress disorder phenomenon is associated with severe distortion of the memory coding of the event. Memory is stored for long periods of time, but there is a bias in which some aspects of memory are absent, with memory enhancement disturbing other details of the subject.

Thus, there is a real need for new solutions to effectively address anxiety disorders (whether or not accompanied by depression).

Treatment of anxiety and depression combined disorders:

conventional treatments for anxiety (whether or not accompanied by depression) include behavioral therapy, lifestyle modification, and drug therapy. However, a large number of drugs used to treat these diseases are known to have unpleasant side effects, or to lead to addiction or dependence (Thesis a. dubois 2015 universal de Bordeaux). Most of the current therapeutic regimens for the treatment of anxiety-related diseases and some of their side effects can be found in the following reviews: guidelines for the pharmaceutical protocol of analog disorders, dependent-complex and posttherapeutic protocol in primary care, B.Bandelow, International journal of psychiatric in Clinical Practice, 2012; 16:77-84.

For example, among the first used substances, there are barbiturate derivatives, known as barbiturates, which were widely used in the 1950 s, but with a high risk of addiction or intolerance.

Other drugs for the treatment of anxiety and depression, in particular benzodiazepines, were later developedClass, which is represented by diazepam (b)

Etc.). These molecules initially appeared to be effective and relatively well tolerated, and have been and still are widely used, particularly in france and the united states. Dinitrogen benzeneThe class has the ability to bind to cellular receptors, which normally bind GABA (gamma-aminobutyric acid). This natural compound is the major inhibitor of the central nervous system. By binding to cell receptors, benzodiazepines

The class increases the affinity of these receptors for GABA, thereby increasing its potency by a factor of ten. However, it has been shown that there is significant drug dependence on these molecules as well as other undesirable effects (impaired cognitive function)Schizophrenia, lethargy, withdrawal syndrome, rebound phenomenon, etc.), and alternative solutions are sought. In addition, benzodiazepines have not been foundAre effective in treating TOC and other diseases associated with anxiety and depression.

Later, another class of anxiolytic and antidepressant molecules was developed, which is based on the action of another neurotransmitter: serotonin (5-hydroxytryptamine or 5-HT). It is a neurotransmitter that is released when a transmitting neuron and a receiving neuron exchange information. Selective serotonin reuptake inhibitors or ISRSs including fluoxetineAnd vortioxetine

Some information between the firing neuron and the receiving neuron is lost because the neurotransmitter is recaptured by the firing neuron and does not reach the receiving neuron. ISRS works by preventing the emitting neuron from recapturing serotonin, increasing the likelihood that serotonin is recognized by the receiving neuron, thereby increasing stimulation of that neuron. To exploit this property, a number of ISRS molecules have been developed (see for example patent EP0216555a 2). The results against anxiety and depression are very promising, but side effects (especially behavioral disinhibition, etc.) are also observed. In addition, evidence has been provided that ISRS is effective in reducing the severity of ESPT symptoms, particularly for paroxetine and sertraline (P carier, Annales mcico-serologiques 166, 2008, 747-. However, side effects (delusions, serotonin syndrome, etc.) and a certain number of intolerances or ineffectiveness are again present, demonstrating the need to combine ISRS with other antidepressants (mood stabilisers, etc.).

Glutamate is another neurotransmitter and is also an intensive subject for the development of new drugs. Glutamate is currently believed to activate multiple types of receptors (m.teigell-Webb, EPHP paper): glutamate acts on three ionotropic receptors, characterized and named by their most selective agonists: N-methyl-D-aspartate (NMDA), alginate (KA), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. Studies on NMDA receptors have progressed more rapidly as studies have shown that NMDA receptors are involved in important aspects of brain function. NMDA receptors exert multiple physiological effects: neuronal differentiation, formation of synaptic connections during development, synaptic plasticity in adults. In particular, it has been shown that in adults, NMDA receptors are involved in learning and short-term memory; in certain areas of the hippocampus, which contribute to enhancement of synaptic efficiency (or long-term potentiation), the areas serve as media for information storage. Finally, the involvement of the NMDA receptor in the increase in anxiety Behavior following exposure to stress (R.E. Adamerk et al, Physiology & Behavior, Vol.65, No. 4/5, pp.723-737, 1999) makes it a major target for the development of ESPT therapy. It should be noted that the novelty of glutamate receptors lies in the dual dependence on agonist (and co-agonist) binding and membrane potential, unlike other ligand-activated receptor channels. At the glutamate site, the competitive agonist and antagonist bind. Uncompetitive NMDA receptor antagonists are molecules that are capable of binding to a regulatory site other than glutamate. For example, NMDA receptor inhibiting peptides have been developed for the treatment of anxiety (patent EP 2175873).

In addition, a so-called "channel blocker" is a drug that binds within the channel associated with the NMDA receptor when the NMDA receptor is in an "open" position (depolarizing cells and binding glutamate). The best known "channel blockers" include ketamine, memantine, and the like. The latter molecule has shown neuroprotective effects. For example, it has been used for the treatment of alzheimer's disease, but it has also been tested for the treatment of behavioural disorders in children (autism), as described for example in patent US2010081723a 1.

It is also noted that non-competitive antagonists that bind to the phencyclidine (PCP) site of the NMDA receptor (e.g., ketamine, dezocyclopine, memantine) have been tested for anxiety associated with post-traumatic stress (Arthur l. womble, AANAJournal 2013 april, volume 81, phase 2). For ketamine and dezocine, side effects (hallucinations, flashback, delusions, etc.) largely mask the positive results of these studies. It should be noted that ketamine strongly inhibits sensory filtration.

However, the development of ketamine was still carried out by several groups which demonstrated that this molecule had interesting preventive effects when injected in a single injection 1 week before fear conditioning in rodents (c.denny et al, Neuropsychopharmacology (2017), 1-13), causing a significant reduction in tetany during stationary phase. However, for this model, effects were only observed at high doses (30mg/kg), and were not reproducible if treatment was accompanied (or immediately preceded) by conditioning or protective treatment was performed prematurely (1 month earlier).

US 2014/057988 a1 also proposes the use of ketamine as an NMDA receptor antagonist for inhibiting, ameliorating or treating the development of mild anxiety, which is defined in the literature as a feeling of discomfort or anxiety. The document discusses and cites the use of memantine in the treatment of dementia, but memantine has no anxiolytic effect and has schizophreniform adverse side effects.

WO 2014/191424 describes the use of memantine derivatives, in particular 2-fluoroethyl normemantine, in the treatment of neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.

Memantine has also been used to treat anxiety disorders (whether or not accompanied by depression), such as ESPT and obsessive compulsive disorder (g.sai, review article CNS Drugs 2012; 26(8): 663-690). Generally, the effect of memantine is positive when used in combination with other molecules (potentiation therapy). When used as monotherapy, its efficacy is much weaker and controversial. For example, for the treatment of TOC, memantine has been combined with ISRS (such as fluoxetine or citalopram) or with other tricyclic antidepressants (such as clomipramine). Generally, memantine is well tolerated as an adjunct therapy at low daily doses (less than about 15 mg/day). However, when too high a dose is administered, side effects such as dysphoria, lethargy, nausea have been observed. The results used in animal models of ESPT are not convincing, but in some cases studies of human ESPT, the use of memantine as an additional treatment appears to improve the symptoms in these patients. In any event, memantine alone does not reduce or treat anxiety, whether mild or severe, whether or not accompanied by depression. Other uses in combination with other molecules include the use of memantine in combination with an inhibitor of synaptic vesicle glycoprotein SV2A (U.S. patent 2016030391a1) and a memantine/melatonin combination (patent EP 2905021 a 1).

Furthermore, while memantine appears to have few side effects and is well tolerated, it appears to have undesirable over-sedation (somnolence, fatigue, apathy, etc.) and also causes an increase in dizziness at high doses (NR Swerdlow, neuropsychopharma, 2009, 34, 1854-. Furthermore, memantine is known to have no anxiolytic effect (especially at high doses) and can cause schizophrenic side effects.

Finally, it appears that different antagonists do not act in a single manner at the NMDA receptor, and thus even if structurally similar, the advantages and disadvantages of one antagonist are not necessarily the same as those of another.

For secondary treatment of ESPT, the last class of molecules has been proposed: catecholamine drugs (F. Ducrocq, L' Enc phase, 2005; 31: 212-26). They have been used in pharmaceutical interventions aimed at directly inhibiting noradrenergic hyperreactivity and have been studied by open and double-blind trials on small numbers of patients. These drugs include clonidine, guanfacine, prazosin and propranolol. Of these molecules, propranolol is the subject of the most proven work to date. Thus, such non-selective beta-adrenergic blockers were theoretically described as early as 1994, and were able to reduce the emotional memory consolidation phenomenon that occurs immediately after a traumatic event (Cahill L., Nature 1994; 371: 702-4). Early on, Famularo et al tested molecules in childhood disease by studies based on a 3-stage B-a-B (off-on-off) design, involving 4 weeks of treatment and 2 weeks of withdrawal before and after. In this study, 8 of 11 children enrolled in the group had significantly improved ESPT symptoms (repetitive and autonomic nervous system hyperactivity) during the treatment period, but this improvement disappeared during drug withdrawal (Famularo R, Am J Dis Child 1990; 142: 1244-7). This last factor greatly limits the importance of propranolol beyond its use as an adjunct to ESPT cognitive therapy.

Prescription-related situations also indicate a lack of effective regimens for treating ESPT. A recent study (TonixPhamaceuticals Holding Corp. (TNXP) FORM 8-K | Current report, 2016. 12.8. month. 8. United STATES SECURITIES AND EXCHANGE COMMISON, Washington, 20549, according to Securies EXCHANGE Act, Chapter 13 or 15(d) 1934) showed that, in the United STATES, although FDA approved only the ISRS class for the treatment of ESTD, the first class of prescribed drugs was benzodiazepineClass, 55% of patients, in contrast to ISRS 53% of patients.

Facing the need for an effective regimen for the treatment of ESPT, the applicant therefore envisages the use of a molecule for the treatment of anxiety (whether or not accompanied by depression) which is structurally derived from memantine but which, by introducing fluorine atoms, generates a very different dipole moment. With particular regard to ESPT, applicants have surprisingly found that this molecule can both exert a protective effect (i.e., by administration concomitant with a traumatic event) and be useful for subsequent treatment or even delayed treatment. Applicants further determined that this molecule did not exhibit many of the undesirable side effects of prior art or proposed treatments under investigation.

Disclosure of Invention

Accordingly, a first object of the present invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof

For use in the treatment or prevention of anxiety in a patient.

The compound (I) for use according to the invention is characterized by the absence of schizophrenia inducing effect.

The term "no schizophrenia inducing effect" means that compound (I) does not induce schizophrenia or associated symptoms such as schizophrenic delusions, paranoid delusions, hallucinations, attention deficit disorder, withdrawal, disorganization or confusion at doses used to treat or prevent anxiety disorders.

In a second embodiment, the invention relates to a compound for use according to the first embodiment, characterized in that the pharmaceutically acceptable salt corresponds to formula (II)

Wherein, X^-Denotes a counter anion selected from chloride, bromide, iodide, acetate, methanesulfonate, benzenesulfonate, camphorsulfonate, tartrate, dibenzoate, ascorbate, fumarate, citrate, phosphate, salicylate, oxalate, hydrobromide and tosylate.

A third object of the present invention is to provide a compound for use according to any one of embodiments 1 or 2, characterized in that anxiety disorders are accompanied by depression.

The compounds are characterized by their absence of schizophrenia inducing effect.

It is an object of a fourth embodiment of the present invention to provide a compound for use according to any one of embodiments 1 or 2, characterized in that the observed anxiety disorder is accompanied by insomnia.

In a fifth embodiment, the invention further relates to a compound for use according to any one of embodiments 1 to 4, characterized in that the anxiety disorder is selected from the group consisting of post traumatic stress disorder (ESPT), specific phobias, social phobias, generalized anxiety disorder, panic disorder with or without agoraphobia, and obsessive compulsive disorder.

Said compounds are characterized by the absence of schizophrenia inducing effects.

In a sixth embodiment, the present invention further relates to a compound for use according to any one of embodiments 1 to 5, characterized in that it is for use in the treatment of preventing the appearance of anxiety disorders related to post-traumatic stress.

Said compounds are characterized by the absence of schizophrenia inducing effects.

Treatment of anxiety disorders associated with post-traumatic stress disorder in particular includes treatment of any combination of at least one of the DSM 5 criteria for PTSD, selected from: flashback, avoidance, negative cognition and mood, and hyperresponsiveness.

Flashback is particularly a related nightmare. Negative cognition and mood refer to a depressive state.

According to an embodiment of the invention, compound (I) or (II) may be administered in a dose of 1mg to 1000mg, such as 5 to 250mg, such as 5 to 100mg and preferably 5 to 30mg, of compound (I) or (II). The dose in question may be administered, for example, 1 to 4 times per day, for example 1 time per day, for example twice per day, in particular 3 times per day or even 4 times per day.

According to a particular embodiment, the compound (I) for use according to the invention is characterized in that it has no schizophrenia inducing effect. In a seventh embodiment, the present invention relates to a compound for use according to embodiment 6, characterized in that the treatment comprises the administration of the compound concomitantly with the traumatic event causing post-traumatic stress.

An eighth embodiment of the invention further relates to a compound for use according to embodiment 6, characterized in that the treatment comprises administration of the compound for 4 to 18 weeks after a traumatic event causing post-traumatic stress.

The compound may be administered for 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 weeks.

A ninth embodiment resides in providing a compound for use according to any one of embodiments 1 to 5, characterized in that anxiety is associated with post-traumatic stress, in particular with established post-traumatic stress.

Said compounds are characterized by the absence of schizophrenia inducing effects.

In a tenth embodiment, the invention relates to a compound for use according to embodiment 9, characterized in that a patient suffering from anxiety disorder receives an antidepressant treatment selected from the group consisting of behavioral therapy and pharmacological antidepressant treatment.

Pharmacological antidepressant therapy refers to the administration of at least one chemical molecule known for the treatment of depression. These include serotonin reuptake inhibitors such as fluoxetine (fluoxetine), vortioxetine (voroxetine), sertraline, paroxetine, citalopram, escitalopram, duloxetine, milnacipran, venlafaxine, indapane, zimelidine, dapoxetine.

In an eleventh embodiment, the present invention relates to a compound for use according to embodiment 10, characterized in that the patient is receiving propranolol-based therapy.

According to a twelfth embodiment, the present invention relates to a compound for use according to any one of embodiments 1 to 11, characterized in that anxiety disorders are accompanied by episodes and episodes of acute anxiety.

In a thirteenth embodiment, the present invention further relates to a combination, in particular for simultaneous, separate or sequential use, comprising the following components: a component (A) comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient

A component (B) comprising propranolol and at least one pharmaceutically acceptable excipient.

A particular embodiment of the product according to the invention is characterized in that it is devoid of schizophrenia inducing effect.

A fourteenth embodiment of the present invention is to provide a combination product comprising the following components: a component (A) comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof

Component (C) comprising an antidepressant, in particular one of the serotonin reuptake inhibitors described in embodiment 10; wherein each of components (a) and (C) is formulated with at least one pharmaceutically acceptable excipient.

A particular embodiment of the product according to the invention is characterized in that it is devoid of schizophrenia inducing effect.

In a fifteenth embodiment, the invention further relates to a product according to embodiment 13, further comprising component (D) comprising ketamine formulated with a pharmaceutically acceptable excipient.

In a sixteenth embodiment, the invention further relates to a product according to embodiment 14, further comprising component (D) comprising ketamine formulated with a pharmaceutically acceptable excipient.

In a seventeenth embodiment, the present invention further relates to a product according to embodiment 13, wherein components (a) and (B) are suitable for simultaneous, separate or sequential application.

In an eighteenth embodiment, the present invention relates to a product according to embodiment 14, wherein components (a) and (C) are suitable for simultaneous, separate or sequential administration.

In a nineteenth embodiment, the present invention relates to a product according to embodiment 15, wherein components (a), (B), and (D) are suitable for simultaneous, separate, or sequential administration.

According to a twentieth embodiment, the present invention relates to a product according to embodiment 16, wherein components (a), (C) and (D) are suitable for simultaneous, separate or sequential administration.

In a twenty-first embodiment, the present invention relates to a product according to any one of embodiments 13 to 20 for use in the prevention or treatment of anxiety in a patient.

According to a twenty-second embodiment, the invention relates to a product for use according to embodiment 21, characterized in that the patient is receiving cognitive behavioral therapy.

According to a twenty-third embodiment, the invention further relates to a product for use according to embodiment 22, characterized in that the treatment of anxiety disorders follows cognitive behavioral therapy.

In a twenty-fourth embodiment, the present invention relates to the use of a product according to any of embodiments 13 or 17 for the prevention or treatment of anxiety in patients suffering from excessive repeated abuse, in particular during childhood.

According to a twenty-fifth embodiment, the invention provides a product for use according to embodiment 24, characterized in that the patient is receiving cognitive behavioral therapy.

According to a twenty-sixth embodiment, the invention further relates to a product for use according to embodiment 25, characterized in that components (a) and (B) are used separately, simultaneously and after cognitive behavioral therapy.

In fact, the applicant has recently discovered a polarized derivative of memantine, 2-fluoroethylnormemantine (femm) (see formula I), which has improved affinity for NMDA receptors (patent WO2014191424a 1).

The molecule (I) may be in equilibrium with a protonated form of formula (II) wherein X^-Denotes a counter anion derived from a biological medium or selected from chloride, bromide, iodide, acetate, methanesulfonate, benzenesulfonate, camphorsulfonate, tartrate, dibenzoate, ascorbate, fumarate, citrate, phosphate, salicylate, oxalate, hydrobromide, tosylate. Thus, the product of formula (II) is a pharmaceutically acceptable salt of the product of formula (I).

For example, it is noted that one particularly preferred pharmaceutically acceptable salt of fluoroethyl normemantine, whose counter anion is chloride, i.e., FENM-HCl.

Research tests carried out during the development of femm as a biomarker show that this molecule effectively binds to the PCP (phencyclidine) site of the NMDA receptor when the channel of the NMDA receptor is in the "open" state, thus preventing in particular excessive Ca²⁺And (4) flowing into the cells. Interestingly, this enhanced affinity is not due to strong binding to NMDA receptors, but to the high specificity of the molecule for the brain regions where the receptors are located, and to its prolonged residence time in these regions. In fact, the existing correlation between femm and monoclonal antibodies demonstrating biomarker efficiency disappeared when ketamine was injected. These preliminary tests also showed rapid passage of the blood/brain barrier.

Surprisingly, the applicant has demonstrated that compound (I) (or a salt thereof, in particular FENM-HCl) can be used for the treatment of anxiety (whether or not accompanied by depression). With particular regard to ESPT, the applicant has surprisingly found that compound (I) or a pharmaceutically acceptable salt thereof can act both in a protective manner (that is to say, by being administered simultaneously at the traumatic event) and during subsequent treatment or even delayed treatment. Applicants further determined that this molecule did not exhibit many of the undesirable side effects of prior art or proposed treatments under investigation.

The applicant has also demonstrated anxiolytic activity (light and dark box test and light gradient) of the product (I) described herein. In contrast, memantine has been shown to have no anxiolytic activity under the same conditions.

Product (I) described herein has a very significant anxiolytic activity and its affinity (in Ki) for the NMDA receptor is of the same order of magnitude as memantine.

In the light and dark box test (which is based on the natural aversion of rodents to light), the increase in time spent in illuminated compartments is considered to reflect a lower anxiety level; this was found in rodents treated with product (I) according to the invention. Memantine was not found to have any effect, so it could be concluded and confirmed that it had no anxiolytic effect.

Furthermore, the inventors have also demonstrated by sensory filtration tests that, unlike memantine, product (I) does not induce any schizophrenia inducing effect.

This is a key feature of product (I), namely the treatment of anxiety (whether or not accompanied by depression) without inducing schizophrenia inducing effects.

In the context of the present invention, the expression "administration concomitantly with a traumatic event" refers to the administration of compound (I) within a time window of 48 hours before to 72 hours after the traumatic event. The "administration concomitant to a traumatic event" may also be from 48 hours before the traumatic event to 48 hours after the traumatic event, or from 48 hours before the traumatic event to 24 hours after the traumatic event, or from 24 hours before the traumatic event to 48 hours after the traumatic event, or from 24 hours before the traumatic event to 72 hours after the traumatic event. In all cases, concomitant administration may extend for 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 weeks to achieve more effective protection.

It is therefore a first object of the present invention to provide a method of treating patients suffering from anxiety disorders, whether or not accompanied by depression, by specifically administering a compound of formula (I) or a pharmaceutically acceptable salt of formula (II). In particular, the method does not induce schizophrenia induction.

The invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt of formula (II) for producing a medicament for treating anxiety disorders (whether or not associated with depression).

As described in the examples below, the anxiolytic and possibly antidepressant activity of the compounds of formula (I) can be assessed using a suitable animal paradigm.

Thus, with the help of the experimental example of a light and dark box, the applicant found that the compound of formula (I) or (II) according to the invention has significant anxiolytic properties, which occur at the first injection of a dose of 10mg/kg, in contrast to memantine which causes an increase in the time spent in the dark compartment. By way of comparison, molecules such as fluoxetine had such anxiolytic activity 7 days after treatment at a dose of 5 mg/kg.

Open field experiments conducted in the presence of optical gradients validated this finding. Under these conditions, the compounds according to the invention significantly limit the avoidance of rodents on the brightest areas of the field during the irradiation period, or even eliminate it completely, in particular at a dose of 10 mg/kg.

Similarly, through forced swimming experiments, the applicant found that the compounds according to the invention cause a significant reduction in the immobility time of rats (compared to rats treated with memantine or ketamine), which reflects the antidepressant behaviour of these molecules and compounds.

The applicant has also demonstrated the surprising advantage of the compounds according to the invention in the treatment of anxiety disorders (whether or not accompanied by depression) by using them in a fear conditioning test with a resolution phase and a stabilization phase. This paradigm, which is generally used to test the effectiveness of ESPT treatment, shows that the compounds according to the invention, in particular at doses of 10mg/kg and 20mg/kg, are able to protect patients from the persistence of the disease during the stationary phase in a surprising manner and will be more apparent when the compounds are administered concomitantly with the conditioning phase. In the same test, no effect was observed with propranolol. The effect observed with femm was equal to or greater than that observed with c.denny with ketamine injected in greater amounts one week prior to conditioning. Still surprisingly, the applicant noticed that similar beneficial effects in intensity, more particularly for the same dose, can be observed when the compound according to the invention is administered before the stabilization phase, i.e. during the combined ESPT syndrome. In the same test, no effect was observed with propranolol.

Finally, the compounds according to the invention are also effective in eliminating persistent diseases, in particular when the compounds are administered during the remission phase, more particularly when the compounds are administered at a dose of 20 mg/kg. In this test, propranolol reduced tetany during the remission phase, but this beneficial effect disappeared during the stationary phase.

It should also be noted that when memantine is administered during the withdrawal phase, a significant rebound effect will be observed during the stationary phase. In addition to demonstrating a different mechanism of action of memantine with femm, this effect is consistent with the clinically observed ineffectiveness of memantine in ESPT treatment.

Furthermore, the applicant observed that, when the beneficial effects of the compounds according to the invention were found, no inhibition of the pro-rush action was recorded, whereas memantine produced an inhibitory effect. The absence of schizophrenia inducing effects is very advantageous for the development of new therapeutic approaches to anxiety (whether or not accompanied by depression), since for most molecules proposed elsewhere (including benzodiazepines in general)

Class, particularly diazepam and ketamine), this schizophrenia inducing effect was observed.

The compounds according to the invention can be administered in various ways to obtain an anxiolytic or antidepressant effect. The compounds according to the invention can be administered to the patient to be treated either orally or parenterally (subcutaneously or intravenously, etc.) alone or in the form of pharmaceutical preparations.

The amount of compound administered may vary and may be any amount that causes an anxiolytic and/or antidepressant effect. The amount of compound administered may vary within a wide range, depending on the patient and the method of administration, from 0.01mg/kg to 20mg/kg, preferably from 0.05mg/kg to 15mg/kg of patient body weight per dose.

A unit dose of a compound according to the invention may comprise, for example, from 5mg to 1000mg, preferably from 5 to 30mg, and may be administered, for example, from 1 to 4 times per day.

The present invention relates to the use of pharmaceutical products formulated from compounds according to the invention in combination with a medicament or cognitive behavioral therapy for the treatment of anxiety disorders, whether or not accompanied by depression.

For the purposes of the present invention, "cognitive behavioral therapy" or TCC refers to cognitive behavioral psychotherapy, which comprises a group of treatments for psychiatric disorders (in particular addiction, psychosis, depression and anxiety), which treatments share a method of therapy based on scientific psychological knowledge. It follows a relatively standardized scheme. Which generally assesses the progress of the patient during treatment. It is accepted as a evidence-based medical approach. TCC is peculiar in that it addresses the patient's difficulties "here and there" by practical exercise centered on observable symptoms of menstruation and by intervention by therapists aimed at intervening in conscious or unconscious psychological processes (also known as cognitive processes), which are considered to be the source of mood and patient illness. Standardization of TCC practice helps to recognize its effectiveness through its reproducibility, which is one of the requirements of scientific methods. They are particularly useful in anxiety disorders (especially phobias) and addiction.

In particular, the applicant proposes the combined prophylactic administration of ketamine and a medicament containing a compound according to the invention after traumatic exposure to treat ESPT. Similarly, applicants propose the combined administration of propranolol in combination with cognitive therapy during the initial treatment period of ESPT and treatment with a pharmaceutical product containing a compound according to the invention during the drug withdrawal period to treat anxiety in patients suffering from abuse, particularly during childhood.

Detailed Description