FR2946535A1 - COMPOSITION COMPRISING A MOLECULE PROMOTING NEURONE-GLY INTERACTION, IN PARTICULAR FOR PREVENTING THE FORMATION OF THE GLIAL SCAR AND INDUCING NEURAL REGENERATION. - Google Patents

Abstract

The invention relates to especially pharmaceutical compositions comprising at least one arylcyclohexylamine derivative, or at least one pharmaceutically acceptable salt thereof, as an active agent modulating the neuron-glia interaction, in particular for inducing neural regeneration, in particular particularly in the chronic treatment of spinal cord trauma or to limit or prevent glial scarring or other astrocytic reaction that may be an impediment to neuronal survival or axonal regrowth.

Description

The present invention relates to a novel use of an arylcyclohexylamine derivative, or at least a pharmaceutically acceptable salt thereof, as an active agent modulating the neuron-glia interaction, in particular to limit or prevent the scar. glial or other astrocytic reaction that may be an impediment to neuronal survival or axonal regrowth. The invention also relates to neural regeneration, as well as associated pharmaceutical compositions.

10 STATE OF THE ART

The amyclohexylamines derive essentially structurally from two well-known compounds, phencyclidine (PCP), that is to say (1-phenylcyclohexyl) -N piperidine of formula: and ((thienyl-2) -1 Cyclohexyl) -N piperidine (TCP) of formula: Phencyclidine (PCP), whose pharmacological activity was studied around 1958, was introduced as an analgesic and anesthetic under the name of Sernyl and then abandoned because of its side effects. psychodysleptic type. TCP belongs to the arylcyclohexylamine series such as PCP 's and can find uses in anesthesia as well. additive ~ u for tr lllrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr 1 on 2 Other studies on PCP have shown that this molecule can act as a noncompetitive antagonist of N-methyl-D-aspartate (NMDA), which is an interesting property for brain protection, especially against the associated damage to the presence of glutamate, because the toxicity of excitatory amino acids such as glutamate is at the root of the major brain damage encountered during ischemia, anoxia, hypoglycaemia or epilepsy. It is also believed that the toxicity of amino acids is implicated in certain neurodegenerative disorders, US Patent 5,179,109 describes in particular the use of arylcyclohexylamines, acting as antagonists of NMDA, in neuroprotection, and it is noted that acute treatment in neuroprotection, referring to pathologies such as cranial trauma, trauma of the spinal cord, stroke, ischemia or anoxia, consists of stopping the cascade of chemical events causing the death of neurons by excitotoxicity, in a short time (maximum 24 hours) after an injury. On the other hand, patent FR 2 818 147 describes the use of 1- [2-methyl-1- (2-thienyl) dicyclohexyl] piperidine, also called gacycline, in the treatment of pain. Thus, arylcyclohexylamines have been mainly used in acute cerebral protection or in the treatment of pain. Some studies (McKfnney et al., PNAS, 1999, 96, pages 11631-11636; / Vacher and McEwen, Hippocampus, 2006, 16, pages 267-270) have attempted to show the apparent link between activation of glutamate receptors (NMDA and non-NMDA) and 'induction of neuritic shoots as well as the establishment of appropriate synaptic connections during development, In fact, the NMDA receptor antagonists (here MK-801) have shown that they can induce axonal budding on cultures of CA3 and CA1 neurons in the hippocampus and that, unlike control cultures during synaptogenesis, these effects persisted beyond 15 days of culture. However, such acute treatment with MK-801, which is a nonspecific antagonist of the present invention, has been shown to be effective with the physical activity of the cell. PR / 0.

Moreover, neurotrophic factors have proved effective for the regrowth of axons (Deumens et al., Progress in Neurob / o / ogy, 2005, 77 pages 57-89), without however mentioning their functional recovery. Thus, it is important to find active agents, more particularly small chemical molecules, that can be used in pharmacological treatment, especially chronic, to modulate the neuron-glia interaction, in particular to limit or prevent any astrocytic reaction which could constitute an obstacle to neuronal survival or axonal regrowth, such as the formation of a glial scar, and thus promote the regeneration and recovery of nerve pathway functions damaged by an injury.

OBJECT OF THE INVENTION The main object of the present invention is to provide a new active agent for modulating the neuron-glia interaction, and in particular when it is involved in the pathophysiology of the disease, acute or chronic nervous system centrally leading to an absence of spontaneous regeneration.

It is also a principal object of the present invention to provide a novel active agent for modulating neuron-glia interaction, and in particular to limit or prevent the formation of a glial scar of damaged nerve tissue after traumatic injury. The main object of the present invention is also to provide a new active agent for inducing axonal regeneration of neurons. The main object of the present invention is also to provide a new active agent. in the chronic treatment of spinal cord injuries, to allow the regeneration of neural tissue. The present invention finally aims to provide pharmaceutical compositions containing such agents.

nrc-, CIRIPTInM r1F 11rM \ / FNI-T-inNI 35 uIe is an uterine and i (a) pienCeL, oh`11tUel.1t a public prOPIeTM in our societies. spinal cord, and more generally the central nervous system (CNS) induce structural and functional modifications of the neural networks leading to significant sensorimotor alterations, thus the interruption of the long myelinated pathways and the damage of the non-myelinated local circuits lead to deficits. specific neurological disorders One of the main therapeutic strategies considered after spinal cord injury is to promote axonal regeneration by modulating the glial environment to restore homeostasis, since the formation of a glial scar occurs rapidly after the trauma. It consists mainly of astrocytes that become hyperplastic and hypertrophic (called astrocytes). active) and also a heterogeneous set of cells including microglia, oligodendrocytes, fibroblasts and other inflammatory cells. These environmental changes lead to (i) the formation of a physical barrier, the prolongations of astrocytes then having a very strong adhesion between them, and (ii) the appearance of a biochemical barrier at the same time by the negative regulation ( 'down-regulatiort') of growth factors or the upregulation ('lipregulation') of growth-inhibiting molecules (Ridet et al, Trends Neurosc., 1997, 20, pp. 570-577, Fitch and Neurasci., 1999, 19, pp. 8182-8198). Thus, the formation of a dense glial scar is one of the main obstacles to neural repair.

The astrocyte is one of the essential components of central nervous system homeostasis of higher vertebrates characterized by a wide variety of roles, depending on age and physiological conditions. It contributes essentially to the ionic balance and to the supply of energy, in the form of glucose absorbed into the bloodstream by the penvular feet, transformed into glycogen and restored by the neuron in the form of lactic acid FOC HP1) v rj), (1) Fibrillary Acidic Protein (GFAP), the principal structural protein of the intermediate filaments of the cytoskeleton. astrocytes. The absence of GFAP is correlated, at first, with greater permissiveness of astrocytes to neuronal survival and neuritic growth, and second, with significant changes in the expression and organization of the extracellular matrix, and adhesion molecules known to be partly responsible for the permissive properties of these glial cells (Ferret et al, PNAS, July 22, 2003, 100 (15), pages 8999-9004). From a developmental point of view, Vimentin is the major protein of the cytoskeletal intermediate filaments, expressed by the radiatic fold and immature astrocytes of the embryonic CNS. This one is highly permissive. During astrocyte differentiation, it is progressively replaced by GFAP, which becomes the protein of the intermediate filaments of the mature astrocyte. To date, there is little data on the presence of NMDA receptors on astrocytes, and on their possible role in their interaction with neurons. Some astrocyte subtypes have NMDA receptors and in particular express NR2B subunits after ischemia injury. Lalo et al (1. Neurosci., 2006, 26, pages 2673-2683) report the presence of functional NMDA receptors on cortical astrocytes and demonstrate their involvement in the transmission of signals between astrocytes and neurons. These signals are affected by the noncompetitive antagonist MK8O1. In addition, Kommers et al. (Deve / opn7enta / Braira Res, 2002, 137, pages 159-148) demonstrate that phosphorylation of GFAP, is under the control of NMDA, and r17 ~~~, .This effect t ç -once. i'ÿ pc = ir Or = hc astroCytaif e: surVer lai ^ it during the course of nn'ne S and astrocytes, NMDA., very, ncécément, Kato and ai (ngess> OOé, 59, n ettent tecultures eurone a u_ .1, ut it o de ~ i-A It ciuit; pd1 IC l.1iuta111d1.0 is SUpplruée by NM Finally, the signaling in the opposite direction, between also under the control of receivers Read that However, besides these mechanistic studies, it has not been identified molecules inducing regeneration of axons, especially following an injury to the nervous system where the cellular environment is by definition mixed, that is to say including among others neurons and astrocytes. The subject of the present invention thus relates to the use of a composition comprising at least one arylcyclohexylamine or at least one ns a pharmaceutically acceptable acid addition salt of this arylcyclohexylamine, having the formula: R2 R, yX N__I3 (I)

R3 wherein - R1 is R4 wherein R4 and R4 'are the same or different groups and independently represent a hydrogen atom, a halogen atom, preferably a fluorine atom or an iodine atom, or a linear or branched alkyl radical containing between 1 and 6 carbon atoms, R.sup.1 represents a hydrogen atom, the OH or radical, a linear or branched alkyl, alkenyl or alkoxy radical containing between 1 and 6 carbon atoms, preferably, the radical CH, the radical CH CH or the radical OCH, R and R are identical or different groups and hydrogen in the form of a hydrogen atom, and .. y .. radmCe linear alkyl o; ramification comprising between LOrr "~ r ~ rhonos. ~ a ~ t ~ (it ~~ I t, ~ nfi vPr7t ~ iF I ruoirlO i, irn,! uiiii (di (aryl aryl or ur radical UH, or R3 and R3 'together with the nitrogen atom to which they are attached form a radical or in which R5 and R5' are identical or different groups and independently represent a hydrogen atom, a halogen atom or an OH radical; or the radical CH2R6, with R6 representing a hydrogen atom, a halogen atom, preferably a chlorine atom or a bromine atom, the OH radical or a linear or branched carboxylate radical containing between 1 and 6 carbon atoms preferably, the radical CH3COO, and n is equal to 0, 1 or 2, X, Y and Z are identical or different atoms chosen independently from a methylene group -CH2-, an oxygen atom or a sulfur atom, and the XY and YZ bonds are the same or different and independently selected from a single bond or a double bond, with the exception X-Y-Z comprising two double bonds, for inducing axonal regeneration of neurons, that is to say in particular the regrowth of neuron axons. A second object of the present invention relates to the use of a composition comprising at least one arylcyclohexylamine or at least one addition salt with a pharmaceutically acceptable acid of this arylcyclohexylamine, corresponding to the formula (I) above, for the chronic treatment of spinal cord injuries. The chronic treatments according to the invention relate to any Dathotoc] IE dlI SVStlme nVY "VPIIX entr ~ I imnligi ant an alt cati c I Interaction neurofl ('asti orvte or po (ive in the more severe estates n (li ~ IrP id f ..) A (C) nn "" cicatrix dictates and VIS4'11t OSr 7c] rtl I_I ~ IF' ~ f'y f ~ y ~ c ~ i ~ c ~ i m ~ i m ius pathologies such as traumatismes Iraniens, 10 15 20

spinal cord trauma, stroke, ischemia or anoxia. By chronic treatment is meant treatment spread over time, that is to say a treatment whose duration is greater than four days. This chronic treatment may be administered by a daily dose. This chronic treatment is administered by repeated doses, identical or different, of a pharmaceutical composition according to the present invention. Thus, the present invention relates to the administration spread over time, in succession or in combination with another treatment, of at least 2, 3, 4, or 5 times the pharmaceutical composition comprising a compound of formula (I), including all these variants. According to a variant of the present invention, the pharmaceutical composition can be administered as a single dose in the form of controlled release spread over a period generally greater than three days. Typically a first dose can be administered from the sixth hour after the traumatic event. It is also advantageous to administer a first dose between 24 and 48 hours after the traumatic event.

It is advantageous to administer an identical daily dose. The treatment period is advantageously greater than six days, and may for example be at least 15 days. The duration of treatment is adapted according to the pathology and the morphology of the patient. This chronic treatment is therefore distinct from acute treatment.

Acute treatment concerns a generally single administration of an effective dose, or at least for a reduced period, generally less than two days. Finally, a third object of the present invention relates to the use of a composition comprising at least an arylcyclohexylamine or at least one addition salt with a pharmaceutically acceptable acid of this arylcyclohexylamine, responding to a traumatic lesion of a traumatic lesion.

In particular according to the invention, said pathology is selected from the group consisting of head trauma, spinal cord trauma, stroke, ischemia or anoxia.

According to the invention, said composition is used more particularly to limit or prevent the formation of a glial scar on damaged nerve tissue. The various embodiments presented below relate to the three objects of the invention set out above.

According to a first embodiment, the composition according to the invention comprises at least one arylcyclohexylamine which corresponds to the formula:

Wherein R 2, R 3, R 3 ', R 4 and R 4' have the same meanings as above. According to one variant, said arylcyclohexylamine corresponds to the formula: in which R 2, previously. With regard to the first embodiment of the invention as well as all of its possible variants, the furan group may be grouped together by one of the carbon atoms located in the group. ## STR1 ## have the same meanings as cyclohexane by one of the beta atoms of the oxygen atom, as shown in the general formula (Tic) below: R 2 Wherein R 2, R 3, R 3 ', R 4 and R 4' have the same meanings as above According to a second embodiment, the composition according to the invention comprises at least one arylcyclohexylamine which corresponds to the formula: R Wherein R 2, R 3, R 3 ', R 4 and R 4' have the same meanings as above According to one variant, said arylcyclohexylamine corresponds to the formula: ## STR2 ## .'- 7 ("10n One [7 Oont the same requirements as e) FY1rDOSI 10n -" 10n InVentlOn R3) in which R1, R3, R3 ', R4 and R4' have the same meanings as above. According to a first variant, said arylcyclohexylamine corresponds to the formula: (Wb) in which R2, R4, R4 ', R5 and R5' have the same meanings as previously. According to a second variant, said arylcyclohexylamine corresponds to the formula: ## STR2 ## in which R, R 4, R 4 ', R 5 and R 5' have the same meaning as in accordance with a third variant, said arylcyclohexylamine corresponds to the formula: In a fourth preferred variant, said at least one arylcyclohexylamine is 1- [2-methyl-1- (2-thienyl) cyclohexyl] piperidine, also known as gacycline, in racemic form or in substantially pure form. one of its enantiomers or diastereoisomers, represented by the formula: (IVe) Finally, according to a fifth particularly preferred variant, said at least one arylcyclohexylamine is the racemic form of the compound 1- [a-2-methyl-1- ( 2-thienyl) cyclohexyl] piperidine or one of its enantiomers essentially pure, each of the enantiomers of this compound being represented by the following formulas (VI) and (VI`): This pair of enantiomers gacycline in which the piperidine and methyl group of cyclohexane are located in relation to each other is also called GK 11. Concerning the third embodiment of the invention as well as all of its variants the thiophene group can be connected to the cyclohexane group by one of the carbon atoms located in alpha of the sulfur atom, as shown in formulas (IVa) to (IVf) above, but can also be connected to the cyclohexane group by a 7 of the carbon atoms located in beta of the sulfur atom, such as: on the 1 nd general! ug; Wherein R2, R3, R3 ', R4 and R4' have the same meanings as above. According to all of the embodiments and all of their variants, the invention also includes all the possible isomers of the molecules referred to by the general formulas shown, which each have at least one center of symmetry. The arylcyclohexylamines of the invention may be prepared by conventional methods or as those described in French Patent No. 2,639,225 to Neureva. Finally, according to all of the previously mentioned embodiments, the composition according to the invention acts in particular at the place where the neuron-plaice interaction is involved in the pathophysiological mechanism of an acute or chronic disease of the nervous system. centrally leading to an absence of spontaneous regeneration. The pharmaceutical compositions of the invention contain an effective amount of at least one compound of formula (I) as defined above, as well as a pharmaceutically acceptable carrier. It is known to those skilled in the art various forms of excipients adapted to the mode of administration and some of which may promote the effectiveness of the active molecule, for example by promoting a release profile making this molecule active overall more effective for the intended treatment. The pharmaceutical compositions of the invention are thus administrable in various forms, more especially for example in injectable, sprayable or unmanageable form, for example intramuscularly, intravenously, subcutaneously, intradermally, orally, or in vivo. It is important to try, in particular, Tablets, gummies, powders, granules and oral agents, whether they are beneficial or not. The compounds may be in the form of powders, freeze-dried or not, to be diluted at the time of use in a vehicle. for injection, aqueous or oily or in the form of suspensions or aqueous or oily injectable solutions in which the active ingredient can be combined with conventional adjuvants.When a solid composition in the form of tablets is prepared, the active ingredients are added to the active ingredients. 'associat ion, micronized or not, a pharmaceutical vehicle which may be composed of diluents such as lactose, microcrystalline cellulose, starch and formulating adjuvants such as binders (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc ...), agents d flow such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate. Wetting agents, suspending agents, or surfactants may be added to the formulation. The tablets may be bare, sugar-coated (for example with sucrose) or coated with various polymers or other suitable materials. The tablets may have an instant, delayed or prolonged release. The preparations can be obtained by mixing the active ingredients with dry pharmaceutical vehicles (simple mixing or dry granulation, wet granulation, hot melting), liquid or semi-solid. A preparation in syrup or elixir form may contain the active ingredients together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable colorant. For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing dispersing agents and / or pharmacologically compatible solubilizing agents, for example propylene glycol or butylene glycol, are generally used. Thus, to prepare an injectable aqueous solution intravenously, an alcohol, such as ethanol or a hydrophilic surfactant, is prepared in an aqueous solution such as ethanol or a surfactant. tahle Dar flew away. mad I it slll lr) III f = r iras. Pi ll lcipes <a t ifs by 1) 11! icjiyt eride; e OR r. Jr; byte of giyceroi Four

the local administration can be used creams, ointments, gels, eye drops. For transdermal administration, patches may be used. For administration by inhalation, an aerosol containing a biologically compatible propellant gas is used; it is also possible to use a system containing the active ingredients alone or in combination with an excipient, in the form of a powder. The active ingredients can also be formulated in the form of microcapsules or miemspheres, optionally with one or more supports or additives. Among the sustained-release forms useful in the case of chronic treatments, the implants can be used. These can be prepared as an oily suspension or as a suspension of miemspheres in an isotonic medium. The present invention covers in particular the use of a compound according to the present invention, for the manufacture of a composition, in particular a pharmaceutical composition. The pharmaceutical compositions of the invention containing an effective amount of at least one compound of formula (I) as defined above, may also contain other pharmacologically active substances. The invention also covers a method of therapeutic treatment of an animal or a human being in need thereof, characterized in that it comprises administering thereto a therapeutically effective amount of a compound according to the invention of formula (1) above. In each active agent dosage unit according to the invention is present in an amount adapted to the daily doses envisaged. In general, each dosage unit is suitably adjusted according to the dosage and type of administration intended, for example tablets, capsules and the like, sachets, ampoules, syrups and the like, drops, so that such a dosage unit contains from 0.01 to 1000 mg of active agent according to the invention, preferably from 0.5 to 500 mg often the unit Insane (Ht admnist-ro ine to four times are xer7 ~ plt's of average situations, can In addition, in the usual practice, the appropriate dosage for each patient is determined by the physician according to the mode of administration, the age, the patient's age, the age of the patient, the age of the patient, the age of the patient, and the age of the patient. In the examples which follow, any characteristic which would appear novel in relation to any state of the art is an integral part of the present invention and protection is sought in its function and function. néralité. In the examples, all percentages are by weight (unless otherwise indicated), the temperature is in degrees Celsius, pressure is atmospheric pressure unless otherwise specified. The chemicals used are commercial unless otherwise indicated.

DESCRIPTION OF THE FIGURES FIG. 1 is given with reference to Examples 1 and 2, and presents the results of GFAP / Map2 double labeling on control (high) and treated (low) embryonic cultures. Figure 2 is given with reference to Examples 1 and 2, and shows the results of Map2 labeling on a control (left) and treated (right) culture.

EXAMPLES, EXAMPLE 1

A) Preparation of cultures Mixed neuron-astrocyte cultures obtained from an 18-day rat fetal brain cortex (termed E18) were cultured for 15 days on glass coverslips contained in 12-well multiwell plates. well. 1 ~ ~ nll ~ 1 innc th ienvi) cyclohexyl) pipendine; Lions 1 ~ 's 2-niethv ~ rnntena the o wc_ "~ 1 1 thenvl)) r V ~ ll if 11: nri nc, ti) l1COi They are obtained by serial dilutions from a stock solution at a concentration of 1 × 10 -2 m / L. The culture medium in which the solutions are prepared is composed of MEM (FIG. minimum essential medium) supplemented with glucose (6g / l) and horse serum 10% No antibiotics are added to the culture medium to avoid possible interactions c) Treatment of cultures - Control: the crop is subject to a scratch by means of a tapered plastic tip traversing the diameter of the glass slide from top to bottom, then immediately afterwards, the culture medium is replaced by freshly prepared culture medium and whose composition is described in b) - Cultures treated: these cultures are also subjected to a scratch and, immé Afterwards, the culture medium is replaced by freshly prepared culture medium containing 1-Vi 9-2-methyl-1- (2-thienyl) cyclohexyl] piperidine at a concentration of 20 or 50 pmol. This treatment is continued for 4 weeks with weekly change of the culture medium containing the molecule. The cultures are then fixed and processed for the immunocytochemical detection of GFAP on the one hand, and of Map2, on the other hand, proteins specific for the astrocytic and axonal cytoskeleton respectively. For this, the culture medium is replaced by fixative (paraformaldehyde 4%) for 45 min and then after rinsing with phosphate buffer the cultures are treated with immunocytochemistry. The two markers are revealed by means of a suitable secondary antibody coupled to a fluorochrome (red for GFAP and green for Map2). After mounting slides on slide, cultures are observed from a fluorescence microscope. D) Results In the control cultures (Figure high) a scratched zone (arrows) is clipC nrnInnn e, nrAn ai, i. In the treated cultures (Figure 1, bottom), the GFAP astrocytes have invaded the scratched zone, which is crossed by numerous axons (arrows and spines). Figure 2). There is also accumulation of many neuronal cell bodies (Figure 2, arrowheads) on the edge of the scratched region. This shows that the compounds of the invention induce axonal regeneration of neurons, especially in the case of spinal cord injuries or a pathology involving the formation of a glial scar. EXAMPLE 2

a) Preparation of cultures Mixed neuron-astrocyte cultures obtained from 18-day-old rat fetal brain cortex were cultured for 15 days on glass coverslips contained in 12-well multiwell plates.

b) Preparation of solutions containing 1- [cis-2-methyl-1- (2-thienyl) cyclohexyl] piperidine The solutions of 1- [α-2-methyl-1- (2-thienyl) cyclohexyl] piperidine with concentrations of 20 pmol / l and 50 pmol / l are prepared as described in Example 1.

C) Treatment of cultures - Control: the culture is subjected to a scratch, then the culture medium is replaced 24 hours later by freshly prepared culture medium and whose composition is described in Example 1 (b). Treated cultures: these cultures are also subjected to a scratch and the culture medium is replaced 24 hours later by freshly prepared culture medium containing eis-2-methyl-1- (2-hr) -Physin-1H-1H-1H-1H-1H- continued during serial / OC, Weekly Weekend (III) (English), analyzed for the immunocytochemical detection of GFAP on the one hand, and of Map2 as described in Example 1.

d) Results The result is qualitatively similar to that obtained after immediate treatment.

EXAMPLE 3

A) Preparation of cultures Postnatal astrocyte cultures are obtained from neonatal rat cortex (2, 7 or 10 days). In this case, the culture medium used is DMEM / F12 supplemented with glucose (6 g / l) and fetal calf serum (10%). The preparation of the solutions is as described in Example 1 except for the changed culture medium.

b) Treatment of cultures Two types of protocols are used i- On the one hand, certain cultures are subjected to a treatment for 15 days by a solution of 1- [cis-2-methyl-1- (2-thienyl) cyclohexyl) ] piperidine as described in Example 1.

On the other hand, some cultures are scratched and treated 24h later with a solution of 1- [α 2-methyl-1- (2-thienyl) cyclohexyl] pipiperidine as described in Example 1. The treatment is renewed once a week for 15 days.

c) Results In non-scratched and treated astrocyte cultures, no effect of treatment was found on cell morphology. They are comparable to untreated control astrocytes.

(i) with labeled astrocyte cultures at a point where: ## EQU1 ##, ## STR1 ## in which: ## STR1 ## The treatment with 1- [α -2-methyl-1- (2-thienyl) cyclohexyl] is also indicated in non-truncated cultures (controls d). Piperidine has no direct effect on a primary culture of cortex astrocytes, which therefore shows, in comparison with the other examples, a restoration of the neurone-fold interaction induced by the compounds of the invention.

EXAMPLE 4 a) Preparation of the cultures The post-natal astrocyte cultures are prepared as described in Example 3. In this case, these cultures are scratched and seeded with embryonic neurons (E18) prepared as described in Example 1 B) Treatment of cultures These cultures are subjected to a treatment for 15 days after the scratching by a solution of 1- [α -2-methyl-1- (2-thienyl) cyclohexyl] piperidine as described in Example 1. C) Results The markings show that, irrespective of the culture, the neurons have difficulty adhering to the astrocyte mat and form clusters interconnected by axonal prolongations. The effect of the treatment results only in an increase in both the number and the size of these neuronal clusters. No obvious difference in the ability to cross the scratched area is observed between control and treated cultures,

d) Conclusion Treatment with [cis-2-methyl-1- (2-thienyl) cyclohexylipiperidine has no direct effect on co-culture of post-natal astrocytes / pneumonucleotides. However, there may be some embryonic neuron neurons that are secreted in the general interest.

Considering that the scratch-type lesion represents a good in vitro phenocopy of a traumatic lesion in vivo, we can conclude that a chronic treatment of a mixed culture neuronsastrocytes subjected to a scratch, by an aryicyclohexylamine derivative of formula (I), and in particular 1- [cis 2-methyl-1- (2-thienyl) cyclohexyl] piperidine, has a modulatory effect of the glial scar and allows axonal regrowth through the scratched area. The positive effect is obtained only when the neurons and astrocytes have been cultured from the start, which is a phenocopy of the normal development of the nervous system of a mammal. The astrocyte-neuron complex seems to be the target of the arylcyclohexylamine used in treatment, since no effect is obtained on the astrocyte cultures. Finally, chronic treatment, which aims to repair the damage caused by an injury, by allowing pro-regenerative mechanisms to take over the degenerative mechanisms, seems to modulate the environment of the injured neurons long enough for the new neural connections. can be stable and functional in vivo. Homeostasis in the neuron-astrocyte medium is restored sufficiently to allow regeneration of the axons. The inventor has thus demonstrated by the present invention that a chronic treatment, that is to say. up to 28 days after injury, with derivatives of the arylcyclohexylamine family, particularly noncompetitive NMDA receptor antagonists, target the neuron-astrocyte interaction, neuronal arousal L, axonal regeneration At the location of the lesion represented by the scratch, the increased permissibility of the reactive astrocytes would allow the axons to regenerate and establish new stable and functional connections, and this would not be necessary. Thus, the present invention is not intrinsic, unlike other nonselective NMDA receptor antagonists, such as MK-801.

Claims (4)

REVENDICATIONS1. A composition comprising at least one arylcyclohexylamine or at least one pharmaceutically acceptable acid addition salt thereof, having the formula: (I) wherein R 1 is R 4 in which R 4 and R 4 are identical groups or different and independently representing a hydrogen atom, a halogen atom, preferably a fluorine atom or an iodine atom, or a linear or branched alkyl radical having between 1 and 6 carbon atoms, R2 represents a hydrogen atom, the OH radical or a linear or branched alkyl, alkenyl or alkoxy radical containing between 1 and 6 carbon atoms, preferably the radical CH, the radical CHCH, or the radical OCHi, Ri R 'are groups different identical represent independently a hydrogen atom, a linear or branched alkyl radical having between 1 and carbon atoms, said radical being optionally substituted by at least one aryl radical or an OH radical, or PP in which R5 and R5 'are identical or different groups, wherein R5 and R5' are identical or different groups and independently represent a hydrogen atom, a halogen atom, an OH radical or the radical CH2R6, with Rs representing a hydrogen atom, a halogen atom, preferably a chlorine atom or a bromine atom, the OH radical or a linear or branched carboxylate radical containing between 1 and 6 carbon atoms, preferably the radical CH3COO, and n is equal to 0, 1 or 2, - X, Y and Z are identical or different atoms chosen independently from a methylene group -CH 2 -, an oxygen atom or a sulfur atom, and the XY and YZ bonds are the same or different and independently selected from a single bond or a double bond, with the exception of XYZ comprising two double bonds, to induce axonal regeneration of neurons. 20 2. A composition comprising at least one arylcyclohexylamine or at least one aracocyclohexylamine ph acid addition salt, having the formula: wherein identical or different and independently representing a hydrogen atom, a halogen atom, preferably a fluorine atom or an iodine atom, or a linear or branched alkyl radical having between 1 and 6 carbon atoms, R2 represents a hydrogen atom, the OH radical or a linear or branched alkyl, alkenyl or alkoxy radical containing between 1 and 6 carbon atoms, preferably the radical CH3, the radical CH2CH3 or the radical OCH3, R3 and R3 'are identical groups or different and independently represent a hydrogen atom, a linear or branched alkyl radical having between 1 and 6 carbon atoms, said radical being optionally substituted by at least an aryl radical or an OH radical, or R3 and R3 'form, with the nitrogen atom to which they are bonded, a radical (CH) n R55 or 1 1 in which R5 and R5' are identical groups or in which Rf , and R; ' are identical or different groups and independently represent a hydrogen atom, a halogen atom, an OH radical or the radical CH: R6, with R6 representing a hydrogen atony, a halogen atom, preferably an atom of chlorine or a bromine atom, the OH radical or a carboxylic acid radical, wherein the radicals of gold, the radicl (II) (1 (3X, Y and Z) are identical or different atoms chosen independently from a methylene group -CH 2 -, an oxygen atom or a sulfur atom, and the XY and YZ bonds are identical or different and independently selected from a single bond or a double bond, to the exception of XYZ comprising two double bonds, for the chronic treatment of spinal cord injuries. 3. A composition comprising at least one arylcyclohexylamine or at least one pharmaceutically acceptable acid addition salt thereof, having the formula: wherein - R1 is R2 Y (I) R4 wherein R4 and R11 'are identical or different groups independently representing a hydrogen atom, a halogen atom, preferably a fluorine atom or an iodine atony, or a linear or branched alkyl radical having between 1 and 6 carbon atoms, R represents a hydrogen atom, the OH radical or an alkyl, alkenyl or linear or branched alkoxy radical; wherein the radical radical (-H 1 adical CH 1 CH or OCH 5C radical) is independently linear or linear alkyl radical, or branched radical comprising between 1 and 6 carbon atoms, said radical being optionally substituted by at least one aryl radical or an OH radical, or R3 and R3 'form, with the nitrogen atom to which they are bonded, a radical CHI} n E _en In which R5 and R5 'are identical or different groups and independently represent a hydrogen atom, a halogen atom, an OH radical or the radical CH2R6, with R6 representing a hydrogen atom, a halogen atom; , preferably a chlorine atom or a bromine atom, the OH radical or a linear or branched carboxylate radical containing between 1 and 6 carbon atoms, preferably the radical CH3COO, and n is equal to 0, 1 or 2, X Y and Z are identical or different atoms independently selected from a methylene group -CF1-, an oxygen atom or a sulfur atom, and the XY and YZ bonds are the same or different and independently selected from a single bond or a double bond, with the exception of XYZ comprising two double bonds , to prevent or treat a pathology involving traumatic injury to the central nervous system inducing the formation of a Glial scar 4. Composition according to claim 3, characterized in that said pathology is selected from the group consisting of a cranial trauma, a traumatism of the spinal cord, an accident 1 / ~~ (~ II ~ ir rPrPHt I inrrh mie ni ni wherein said at least one arylcyclohexylamine or said at least one of said at least one salt of said at least one of said at least one arylcyclohexylamine, said at least one of said at least one addition to a pharmaceutically acceptable acid of this arylcyclohexylamine limits or prevents the formation of a glial scar on damaged nerve tissue 6. Composition according to one of claims 1 to 5, characterized in that said at least one arylcyclohexylamine or said at least one pharmaceutically acceptable acid addition salt of said arylcyclohexylamine acts at the place where the neuron-glia interaction is involved in the physiopathological mechanism of an acute or chronic disease of the central nervous system leading to an absence of regeneration 7. Composition according to one of claims 1 to 6, characterized in that said at least one arylcyclohexylamine corresponds to the formula: R5 ', R5 in which R2, R4, R4', R5 and R5 'have the same meanings as before. Composition according to one of Claims 1 to 6, characterized in that the said at least one arylcyclohexylamine corresponds to the formula ## STR1 ## wherein Composition according to Claim 8, characterized in that the said at least one arylcyclohexylamine corresponds to the formula (IVd) in which R2 has the same meaning as before 10. Composition according to Claim 8 or 9, characterized in that [at least one arylcyclohexylamine is 1- [2-methyl-1- (2-thienyl) cyclohexyl] piperidine, in racemic form or substantially pure form of one of its enantiomers or diastereoisomers, represented by the formula (IVe) according to one of claims 8 to 10, characterized in that said at least one arylcyclohexylamine is the racemic form of the compound 1- [cis-2-methyl-1- (2-thienyl) cyclohexyl] piperidine or one of its essentially pure enantiomers, each of the enantiomers res of this compound being represented by the following formulas (VI) and (VI '):